Synthesis and anti-inflammatory evaluation of some pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1007/s00044-010-9312-7

Novel series of pyrazolo[3,4-b]pyridines with basic skeleton different from the known COX inhibitors were synthesized from 5-amino-1-[4-(aminosulfonyl) phenyl]-3-phenyl-1H-pyrazole, which in turn was prepared by the condensation of (4-sulfamoylphenyl)hydrazine with α-cyanoacetophenone. All the newly synthesized compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema assay. Some of the most potent compounds were evaluated in different COX and LOX assays. Some of the new compounds were found to possess moderate anti-inflammatory activity.

Full text of DOI:10.1007/s00044-010-9312-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:239–244
DOI 10.1007/s00044-010-9312-7
ORIGINAL RESEARCH
Synthesis and anti-inflammatory evaluation of some
pyrazolo[3,4-b]pyridines
•
Pawan K. Sharma Karan Singh Surender Kumar
•
•
•
Pawan Kumar S. N. Dhawan Sukhbir Lal
•
•
•
Holger Ulbrich Gerd Dannhardt
Received: 22 September 2009 / Accepted: 13 January 2010 / Published online: 5 February 2010
Ó Springer Science+Business Media, LLC 2010
Abstract Novel series of pyrazolo[3,4-b]pyridines with
basic skeleton different from the knownCOX inhibitors were
synthesized from 5-amino-1-[4-(aminosulfonyl)phenyl]-3-
phenyl-1H-pyrazole, which in turn was prepared by the
condensation of (4-sulfamoylphenyl)hydrazine with a-cy-
anoacetophenone. All the newly synthesized compounds
were tested for their in vivo anti-inflammatory activity by
carrageenan-induced rat paw edema assay. Some of the most
potent compounds were evaluated in different COX and
LOX assays. Some of the new compounds were found to
possess moderate anti-inflammatory activity.
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as
aspirin, indomethacin, or ibuprofen are widely used in the
treatment of acute or chronic inflammation and offer symp-
tomatic pain relief (Reitz and Isakson, 1995; Lombardino,
1985). Conventional NSAIDs exert nonselective inhibition
(Dannhardt and Kiefer, 2001) of cyclooxygenase (COX)
enzymes, which catalyzes the rate-limiting step in the for-
mation of prostanoids from arachidonic acid (Smith and
Langenbach, 2001; Dennis, 2000; Marnett et al., 1999;
Jakobsson et al., 1999; Tanioka et al., 2000). Two isoforms
of the COX enzyme (known as COX-1 and COX-2) have
been identified (Xie et al., 1991; Kujubu et al., 1991). COX-1
is constitutively present in platelets and all tissues and pro-
duces prostaglandins (PGs) which exert cytoprotective effect
in the gastrointestinal tract and control renal function in the
kidneys (Ormrod et al., 2002). Differently, COX-2 is acti-
vated by pro-inflammatory stimuli and facilitates the release
of prostaglandins involved in inflammatory process (Kana-
pure and Letts, 2004). The development of multibillion
dollar drugs, celecoxib (Penning et al., 1997), and rofecoxib
(Prasit et al., 1999) (Chart 1) enthused the medicinal
chemists all over the world to search for new structurally
different anti-inflammatory drugs. A perusal of literature
reveals that the synthesis of fused pyrazole derivatives
containing the well-established pharmacophore, (4-amin-
osulfonyl)phenyl group, for evaluation as anti-inflammatory
drug is still in its infancy. The limited studies performed
indicate that fusion of pyrazole ring to other heterocycles
such as in compounds 1 (Bertenshaw et al., 1996; Seibert
et al., 1994) and 2 (Baruah et al., 2004) (Chart 1) is well
tolerated in terms of both in vitro and in vivo activities.
Appreciation of these findings coupled with our ongoing
efforts toward the development of novel anti-inflammatory
Keywords COX ꢀ 5-LOX ꢀ Anti-inflammatory drug ꢀ
Pyrazolopyridine ꢀ Fused pyrazole derivatives
P. K. Sharma (&) ꢀ K. Singh ꢀ S. Kumar ꢀ P. Kumar ꢀ
S. N. Dhawan
Department of Chemistry, Kurukshetra University, Kurukshetra
136119, India
e-mail: talk2pawan@gmail.com
S. Lal
Institute of Pharmaceutical Sciences, Kurukshetra University,
Kurukshetra 136119, India
H. Ulbrich ꢀ G. Dannhardt
Institute of Pharmacy, Johannes Gutenberg-University of Mainz,
Staudingerweg 5, 55099 Mainz, Germany
Present Address:
K. Singh
GVK Biosciences Private Limited, Hyderabad 500016, India
123

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Med Chem Res (2011) 20:239–244
H2NO2S
H2NO2S
H2NO2S
Chart 1 Motivation for the
synthesis of pyrazolopyridines 3
H2NO2S
H2NO2S
N
N
N
N
O
N
X
N
CF3
N
N
O
O
CH3
CF3
N
Y
N
H
R1
R2
H3C
2
1 X = S, O, CH2
Y = S, CH2
Celecoxib
Rofecoxib
3
Scheme 1 General synthetic
pathways for the preparation of
pyrazolo[3,4-b]pyridines
H2NO2S
O
CN
NHNH2
N
N
EtOH
Reflux
+
H2N
H2NO2S
4
6
5
ethyl acetoacetate or
diethyl malonate or
ethyl cyanoacetate,
gl. AcOH, reflux
O
O
R1
gl. AcOH,
reflux
R2
H2NO2S
H2NO2S
3'
2'
1
5'
2
N
6'
N
N
N
3
N
N
4
R1
6
5
R2
HO
R1
3e-g
3a-d
agents (Sharma and Sawhney, 1997; Sawhney and Sharma,
1993; Sawhney et al., 1991, 1992, 1993), we thought it of
interest to synthesize some fused pyrazolo[3,4-b]pyridines
(3) (Chart 1) containing the well-established pharmaco-
phore, (4-aminosulfony)phenyl, with a view to examine the
effect of fusing the pyrazole ring to a pyridine ring. In this
article, we report the synthesis and anti-inflammatory (AI)
evaluation of a new series of pyrazolo[3,4-b]pyridines (3).
Selected compounds showing good AI activity were also
tested in different COX and LOX assays.
procedures (Vincenzo and Salvators, 1972; Singh et al.,
1979). The reaction of 5-aminopyrazoles with unsymmet-
rical 1,3-diketones has been a subject matter of intense
investigation in the past. However, it has been unambigu-
ously established that the reaction of 5-aminopyrazoles
with (i) fluorinated b-diketones is initiated exclusively by
the attack of the amino group on the carbonyl carbon
adjoining the CF3 group (Singh et al., 2004) and (ii)
b-ketoesters is initiated exclusively by the attack of the
amino group on the ester carbonyl carbon (Tabak et al.,
1964). Thus, simple coupling of 6 with various 1,3-dike-
tones, ethyl acetoacetate, diethyl malonate, or ethyl cya-
noacetate in refluxing acetic acid afforded the desired
pyrazolo[3,4-b]pyridines (3a–g) in moderate yields. The
structures of all the new pyrazolopyridines 3a–g were
Chemistry
Synthesis of various 4-(3-phenyl-1H-pyrazolo[3,4-b]pyri-
din-1-yl)benzenesulfonamides (3) is summarized in
Scheme 1. The starting compound 3-oxo-3-phenylpropa-
nenitrile (5) was readily prepared by the reaction of
2-bromo-1-phenyl-1-ethanone with potassium cyanide in
aqueous ethanol at 50°C following literature procedure
(Gakhar et al., 1971). 4-Hydrazinobenzenesulfonamide (4)
was prepared via diazotization of sulfanilamide followed
by reduction of the corresponding diazonium salt with
stannous chloride (Soliman, 1979). Reaction of 4 with
5 in refluxing ethanol gave 4-(5-amino-3-phenyl-1H-
pyrazol-1-yl)benzenesulfonamide (6) following literature
1
confirmed by their spectral data (IR, H NMR, and MS)
and elemental analysis.
Pharmacological results and discussion
The compounds synthesized were tested in vivo to evaluate
their anti-inflammatory activity by the classic carrageenan-
induced rat paw edema model at 20 mg kg-1 by oral route
(Table 1). Only two compounds, 3g and 3e showed
appreciable anti-inflammatory activity of 70% inhibition
123

Med Chem Res (2011) 20:239–244
241
Table 1 Anti-inflammatory activity and in vitro inhibitory potencies of compounds 3 and 6
H2NO2S
H2NO2S
N
N
N
N
N
R1
H2N
R2
6
3
Compounds
R1
R2
Inhibition paw edema (%)
% Inhibition
% Inhibition
% Inhibition
of COX-1 (10 lM)a of COX-2 (10 lM)b of 5-LOX (10 lM)c
0.5 h
2.0 h
3a
3b
3c
CF3
CF3
CF3
CF3
Ph
28
78
51
55
40
54
0
0
0
NT
0
NT
0
NT
0
S
3d
CH3 CH3
51
75
35
60
30
70
44
95
NT
NT
NT
0
3e
OH
OH
OH
–
NH2
OH
CH3
–
44
0
3f
25
NT
NT
NT
0
3 g
30
0
0
6
48
NT
NT
NT
16%
Diclofenac sodium
–
–
100
0.003 (IC50 (lM))
42% (0.01 lM)
a,c
Dannhardt and Lehr (1992)
b
Patrignani et al. (1996)
NT not tested
and 60% inhibition, respectively. Four compounds (3a, 3c,
3e, and 3g) showing good level of AI activity were further
evaluated for their inhibitory potency against COX-1/2 and
5-lipoxygenase (5-LOX) in an intact cell assay as described
earlier (Dannhardt et al., 1998). None of the compounds
showed any significant inhibition of COX-1, COX-2, or
5-LOX. However, compound 3e was found to be a
weak inhibitor of COX-1 (44% inhibition) at 10-lmol
concentration.
recorded on a Buck Scientific IR M500 instrument. 1H
NMR spectra were recorded on a Bruker 300-MHz
instrument. High-resolution mass spectra were measured in
EI mode on a Kratos MS-50 spectrometer. All the newly
synthesized compounds (3a–g, 6) were subjected to
microanalysis and gave satisfactory analytical results
(within 0.4% of the calculated values).
4-Hydrazinobenzenesulfonamide (4) (Soliman, 1979)
and 3-oxo-3-phenylpropanenitrile (5) (Gakhar et al., 1971)
were synthesized according to known literature methods.
In conclusion, novel pyrazolo[3,4-b]pyridines were
synthesized and screened for in vivo anti-inflammatory
activity. Even though few compounds have shown good in
vivo activity, this was not translated into in vitro activity.
Investigations to explain these phenomena are ongoing.
4-(5-Amino-3-phenyl-1H-pyrazol-1-yl)
benzenesulfonamide (6)
a-Cyanoacetophenone (5, 1.45 g, 0.01 mol) was dissolved
in 40-ml ethanol and 4-hydrazinobenzenesulfonamide (4,
1.87 g, 0.01 mol) was added. The reaction mixture was
refluxed for 2 h. The contents were cooled and the crys-
talline solid which separated out was filtered, washed with
cold ethanol, and crystallized from aqueous ethanol to give
6 (1.75 g, 56%). m.p. 136–138°C. IR cm-1 3378, 3279
NH2 str., 1326, 1162 SO2 str.; 1H NMR (DMSO-d6/CDCl3)
Experimental section
Chemical synthesis
Melting points were determined in open capillaries in
electrical apparatus and are uncorrected. IR spectra were
123

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Med Chem Res (2011) 20:239–244
d 5.99 (s, 1H, C4–H), 6.93 (bs, 2H, C5–NH2), 7.30–7.41 (m,
53%, m.p. 220–221°C. IR cm-1 3366, 3260 NH2 str., 1336,
1158 SO2 str.; H NMR (DMSO-d6/CDCl3) d 2.40 (s, 3H,
C4–CH3), 2.69 (s, 3H, C6–CH3), 6.74 (bs, 2H, SO2NH2),
1
00
3H, C3 –H, C4 –H, C5 –H), 7.80 (d, 2H, C2 –H, C6 –H,
00
00
00
00
0
J = 6.9 Hz), 7.88 (d, 2H, C2 –H, C6 –H, J = 8.6 Hz), 8.03
0
?
(d, 2H, C3 –H, C5 –H, J = 8.6 Hz); MS: M , m/z 314.
0
0
6.94 (s, 1H, C5–H), 7.49–7.67 (m, 5H, Ph–H), 8.04 (d, 2H,
0
0
0
0
C2 –H, C6 –H, J = 8.8 Hz), 8.66 (d, 2H, C3 –H, C5 –H,
J = 8.8 Hz); MS: M?, m/z 378.
4-[3-Phenyl-4,6-bis(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridin-1-yl]benzenesulfonamide (3a)
4-(4-Amino-6-hydroxy-3-phenyl-1H-pyrazolo[3,4-
b]pyridin-1-yl)benzenesulfonamide (3e)
A solution of 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)ben-
zenesulfonamide (6, 3.14 g, 0.01 mol) and 1,1,1,5,5,5-
hexafluoro-2,4-pentanedione (1.41 ml, 0.01 mol) in glacial
acetic acid (20 ml) was refluxed for 6 h. Excess of solvents
was removed and the contents were cooled. The solid which
separated out was filtered, washed with cold ethanol, and
crystallized from ethanol to give 3a. Yield 55%, m.p.
195–196°C. IR cm-1 3355, 3272 NH2 str., 1325, 1142 SO2
str.; 1H NMR (DMSO-d6/CDCl3) d 4.87 (bs, 2H, SO2NH2),
7.52–7.60 (m, 5H, Ph–H), 7.92 (s, 1H, C5–H), 8.14 (d, 2H,
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)
benzenesulfonamide (6) and ethyl cyanoacetate. Yield 58%,
m.p. 231–232°C. IR cm-1 3367, 3306, 3242 OH and NH2 str.,
1
1706 C=O str., 1346, 1161 SO2 str.; H NMR (DMSO-d6/
CDCl3) d 6.84 (bs, 5H, C5–H, SO2NH2, NH2), 7.32–7.43 (m,
0
0
3H, Ph–H), 7.77 (d, 2H, C2 –H, C6 –H, J = 8.0 Hz), 7.84 (d,
0
0
2H, Ph–H, J = 7.8 Hz), 8.04 (d, 2H, C3 –H, C5 –H,
J = 8.0 Hz), 9.78 (s, 1H, OH); MS: M?, m/z 381.
0
0
0
0
C2 –H, C6 –H, J = 8.8 Hz), 8.63 (d, 2H, C3 –H, C5 –H,
J = 8.8 Hz); MS: M?, m/z 486.0574 (C20H12F6N4O2S
requires: 486.0585).
4-(4,6-Dihydroxy-3-phenyl- 1H-pyrazolo[3,4-b]pyridin-1-
yl)benzenesulfonamide (3f)
4-[3,4-Diphenyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-
b]pyridin-1-yl]benzenesulfonamide (3b)
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-
yl)benzenesulfonamide (6) and diethyl malonate. Yield
41%, m.p. 224–225°C. IR cm-1 3363, 3305, 3241 OH and
1
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-
yl)benzenesulfonamide (6) and 4,4,4-trifluoro-1-phenylbu-
tane-1,3-dione. Yield 53%, m.p. 200–201°C. IR cm-1
3335, 3240 NH2 str., 1361, 1161 SO2 str.; 1H NMR
(DMSO-d6/CDCl3) d 4.94 (bs, 2H, SO2NH2), 7.49–7.62
NH2 str., 1706 C=O str., 1345, 1161 SO2 str.; H NMR
(DMSO-d6/CDCl3) d 6.80 (bs, 2H, SO2NH2), 6.87 (s, 1H,
C5–H), 7.32–7.43 (m, 3H, Ph–H), 7.59 (bs, 1H, C4–OH),
0
7.78 (d, 2H, C2 –H, C6 –H, J = 8.5 Hz), 7.85 (d, 2H, Ph–H,
0
0
0
J = 7.9 Hz), 8.05 (d, 2H, C3 –H, C5 –H, J = 8.5 Hz), 9.72
(s, 1H, C6–OH); MS: M?, m/z 382.0744 (C18H14N4O4S
requires: 382.0735).
0
(m, 8H, Ph–H), 8.01 (s, 1H, C5–H), 8.13 (d, 2H, C2 –H,
0
C6 –H, J = 8.8 Hz), 8.16–8.19 (m, 2H, Ph–H), 8.72 (d, 2H,
?
C3 –H, C5 –H, J = 8.8 Hz); MS: M , m/z 494.
0
0
4-(6-Hydroxy-4-methyl-3-phenyl-1H-pyrazolo[3,4-
b]pyridin-1-yl)benzenesulfonamide (3g)
4-[3-Phenyl-4-(2-thienyl)-6-(trifluoromethyl)-1H-
pyrazolo[3,4-b]pyridin-1-yl]benzenesulfonamide (3c)
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)ben-
zenesulfonamide (6) and ethyl acetoacetate. Yield 42%, m.p.
222–223°C. IR cm-1 3365, 3305, 3245 OH and NH2 str., 1706
C=O str., 1346, 1161 SO2 str.; 1H NMR (DMSO-d6/CDCl3) d
2.13 (s, 3H, C4-CH3), 6.84 (s, 1H, C5–H), 7.08 (bs, 2H,
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)
benzenesulfonamide (6) and 4,4,4-trifluoro-1-(thiophen-2-
yl)butane-1,3-dione. Yield 50%, m.p. 180–181°C. IR cm-1
3374, 3268 NH2 str., 1368, 1152 SO2 str.; 1H NMR
(DMSO-d6/CDCl3) d 6.80 (bs, 2H, SO2NH2), 7.23 (dd, 1H,
Th–4H, J = 5.0, 3.7 Hz), 7.48–7.61 (m, 6H, Ph–H, Th–
5H), 7.87 (d, 1H, Th–3H, J = 3.7 Hz), 7.91 (s, 1H, C5–H),
0
SO2NH2), 7.32–7.43(m, 3H, Ph–H), 7.78(d, 2H, C2 –H, C6 –H,
0
0
J = 8.5 Hz), 7.83 (d, 2H, Ph–H, J = 7.4 Hz), 8.03 (d, 2H, C3 –
?
H, C5 –H, J = 8.5 Hz), 9.92 (s, 1H, C6–OH); MS: M , m/z
380.0945 (C19H16N4O3S requires: 380.0943).
0
0
8.12 (d, 2H, C2 –H, C6 –H, J = 8.8 Hz), 8.63 (d, 2H, C3 –
0
0
?
H, C5 –H, J = 8.8 Hz); MS: M , m/z 500.0589 (C23
H15F3N4O2S2 requires: 500.0588).
0
Pharmacology
COX-1, COX-2, and 5-LOX assays
4-(4,6-Dimethyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-1-
yl)benzenesulfonamide (3d)
Selected compounds were tested in intact cell assays and
whole blood assays as described earlier (Dannhardt and
Lehr, 1992; Patrignani et al., 1996).
Synthesized from 4-(5-amino-3-phenyl-1H-pyrazol-1-yl)
benzenesulfonamide (6) and pentane-2,4-dione. Yield
123

Med Chem Res (2011) 20:239–244
243
Kanapure SP, Letts LG (2004) The eicosanoids. Wiley, London,
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Carrageenan-induced rat paw edema assay
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Male/female Wistrar rats (120–140 g) were fasted with
free access to water for 16 h prior to experiments. The rats
were dosed orally with a 1-ml suspension of test compound
in vehicle (0.5% carboxy methylcellulose). One group of
six rats was kept as a control and was administered vehicle
alone. Half an hour later edema was induced in rats by
intradermal injection of 0.1 ml of a 1% solution of carra-
geenan in 0.5% carboxy methylcellulose into the plantar
surface of the right hind paw (Winter et al., 1962). The paw
volume was measured before as well as 30 min and 2 h
after carrageenan injection using plethysmometer. The
mean increase in the paw volume in each group was cal-
culated according to the formula:
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(1999) Arachidonic acid oxygenation by COX-1 and COX-2
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58635, Celecoxib). J Med Chem 40:1347–1365
ꢀ
ꢁ
Vt
% Inhibition ¼ 1 ꢁ
ꢂ 100
Vc
where Vc is the mean edema volume in control group and
Vt is the mean edema volume in group treated with test
compounds.
Diclofenac sodium was used as standard drug for
comparison.
Prasit P, Wang Z, Brideau C, Chan CC, Charleson S, Cromlish W,
Ethier D, Evans JF, Ford-Hutchinson AW, Gauthier JY, Gordon
R, Guay J, Kargman S, Gresser M, Kennedy B, Leblanc Y, Leger
S, Mancini J, O’Neill GP, Ouellet M, Percival MD, Perrier H,
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active cyclooxygenase-2 inhibitor. Bioorg Med Chem Lett
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Acknowledgments We thank RSIC Panjab University, Chandigarh
for elemental analysis and some 1H NMR spectra. Thanks are also
due to the Mass Spectrometry Facility, University of California, San
Francisco, USA for running the mass spectra.
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