Synthesis of pyrazole-based 1,5-diaryl compounds as potent anti-inflammatory agents

Article abstract of DOI:10.1007/s00044-011-9774-2

Series of 1,5-diaryl pyrazole ester derivatives have been synthesized and found to contain potent inhibitory activity against cyclooxygenase-2 (COX-2) enzyme. The article describes synthesis of the target pyrazole analogs and biological assay using Carrag

Full text of DOI:10.1007/s00044-011-9774-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2465–2475
DOI 10.1007/s00044-011-9774-2
ORIGINAL RESEARCH
Synthesis of pyrazole-based 1,5-diaryl compounds as potent
anti-inflammatory agents
•
Priyanka Shrivastava Praveen Singh
•
Ashish Kumar Tewari
Received: 21 January 2011 / Accepted: 28 July 2011 / Published online: 13 August 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Series of 1,5-diaryl pyrazole ester derivatives
have been synthesized and found to contain potent inhibi-
tory activity against cyclooxygenase-2 (COX-2) enzyme.
The article describes synthesis of the target pyrazole ana-
logs and biological assay using Carrageenan induced rat
paw for investigation.
cytokines, growth factors, hormones, and tumor promoters.
This activity required new protein synthesis and was
inhibitable by corticosteroids, giving rise to the concept
that there might be ‘‘consecutive COX activity,’’ further
referred to as COX-1, and an ‘‘inducible’’ one, further
referred to as COX-2. These two COX isoforms are
encoded by different genes, and COX-1 was hypothesized
to be ‘‘house keeping gene,’’ while COX-2 (Dannhardt and
Kiefer, 2001; Almansa et al., 2003) was thought to be
involved in inflammation, mitogenesis, and/or specialized
signal transduction.
Keywords 1,3-diarylpyrazole ester Á COX-2 Á
Carrageenan induced rat paw edema
Introduction
Most NSAIDs act as non-selective inhibitors of cyclo-
oxygenase (COX), by inhibiting the metabolism of ara-
chidonic acid (Insel, 1996) Majority of NSAIDs act non
selectively to COX (Dannhardt and Laufer, 2000; Carter,
2000; Talley, 1999; Hla and Neilson, 1992). COX-1 and
COX-2, are widely used to treat the signs and symptoms of
inflammation, particularly arthritic pain. Anti-inflamma-
tory and analgesic properties of anti pyrene and other
pyrazole (Tewari and Mishra, 2001) derivatives have found
their clinical application as NSAIDs. Among the highly
marketed COX-2 selective NSAID that comprise of the
pyrazole nucleus, celecoxib represents a potent anti-
inflammatory and analgesic compound. It is considered as a
typical model of the diaryl heterocycle template that is
known to selectively inhibit the COX-2 enzyme. Some
other examples of pyrazole derivatives as NSAIDs are
felcobutazone, mefobutazone, morazone, famprofazone,
and ramifenazone (Reynold, 1993; Amir and Kumar, 2005;
Gursoy et al., 2000; Kumar et al., 2003).
Various diaryl and triaryl pyrazole and imidazole ring
systems have continuously been used for the treatment of
pain and inflammation associated with various musculo-
skeletal disorders, attracted our interest due to their potent
biological activities (Tewari and Mishra, 2001; Tewari
et al., 2009, 2010a). The mechanism of NSAIDs (non
steroidal anti-inflammatory drugs) in reducing inflamma-
tory reactions involves the inhibition of COX enzymes,
COX are cyclooxygenase enzymes and catalyses second
step of prostaglandin synthesis. The biological studies
demonstrated increasing in COX activity in a variety of
cells after exposure to endotoxin, pro-inflammatory
The role of aromatic interactions becomes prominent
in drug receptor interactions (Meyer et al., 2003). The
importance of trimethylene bridge as synthetic spacer for
the detection of intramolecular interactions has been well
documented (Leonard, 1979). These points revealed us to
P. Shrivastava Á P. Singh Á A. K. Tewari (&)
Department of Chemistry, Faculty of Science,
Banaras Hindu University, Varanasi 221 005, India
e-mail: tashish2002@yahoo.com
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Med Chem Res (2012) 21:2465–2475
synthesize some pyrazole derivatives using trimethylene
spaces; 1,5-diaryl systems.
obtained by crystallization with 2% ethyl acetate in hexane.
Similarly, 5b with phthalimide afforded the synthesis of 6b.
The base catalyzed nucleophilic substitution of 5a and 5b
separately with 1 eq. of benzimidazole and DMF at r.t. gave
the synthesis of 7a and 7b, respectively (Scheme 2).
NH2
S
O
The base catalyzed nucleophilic substitution of 5a and
5b separately with 1 eq. of pyridone and DMF at r.t.
afforded the synthesis of 8a-I, 8a-II, 8b-I, and 8b-II,
respectively (Scheme 3). In the reaction, two products
were resulted (N-substituted and O-substituted). Both the
products were separated through column chromatography
and characterized by NMR spectroscopy. The compound
O
N
N
CF3
1
8a-I and 8a-II is confirmed by H-NMR and 13C-NMR
H3C
1
spectra. In H-NMR spectra of 8a-I, two triplet peaks of
Celecoxib
methylene group were observed at d 4.05–4.09 and d
4.28–4.32 due to the presence of N–CH2 and O–CH2,
respectively, while in 8a-II, only one triplet peak of
methylene groups was observed at d 4.36–4.39 due to the
same environment (i.e., presence of two O–CH2 groups). In
13C-NMR spectra of 8a-I, N–CH2 group arises at d 42.4
whereas in 8a-II, O–CH2 was observed at d 63.0 ppm.
Similarly, N and O isomers in 8b-I and 8b-II was observed
Chemistry
All compounds were synthesized by a general experimental
procedure involving substitution reactions at room temper-
ature. 3-Methyl-1-phenyl-pyrazol-5-one 1 had been syn-
thesized from the reaction of ethyl acetoacetate and phenyl
hydrazine. The reaction of 1 with carbon disulfide followed
by methylation gave 4-(bis-methylsulfanyl-methylene)-
5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one (2a) and by
ethylation gave 4-(bis-ethylsulfanyl-methylene)-5-methyl-
2-phenyl-2, 4-dihydro-pyrazol-3-one (2b) (Tewari et al.,
2009). 2a and 2b are the key intermediate in the synthesis of
4-substituted pyrazoles. The base catalyzed alcoholysis of
2a and 2b followed by acidification gave pyrazole-ester 3a
and 3b, respectively, in very good yield. The mass spectrum
and elemental analysis are in accordance with the assigned
1
by H-NMR and 13C-NMR spectroscopy.
Biological activity
Materials and methods
Animals
All experiments have been conducted on adult Wistar
strain albino rats of either sex, weighing between 150 and
200 g. The animals were obtained from the Central Animal
House of the Institute of Medical Sciences, B.H.U. They
were kept in colony cages under identical housing condi-
tions at an ambient temperature of 25 2°C and 45–55%
relative humidity with a 12 h light–dark cycle in the
departmental animal room and fed on standard diet. Ani-
mals were acclimatized for a week before use.
1
structure. The H-NMR spectrum of 3a had a singlet at d
2.41 for methyl protons and a singlet at d 3.92 for methoxy
protons and a broad singlet at d 9.99 for hydroxyl proton.
The mass spectrum of 3a had the base peak at MS (m/z) M?
1
233. Similarly, the H-NMR and mass spectra of 3b were
found in accordance to the assigned structures. Treatment of
3a with excess of 1,3-dibromopropane (5 eq.) (Avasthi
et al., 1995) in mild basic conditions (anhydrous K2CO3)
using N,N-dimethylmethanamide (DMF) as solvent affor-
ded the synthesis of 5a with quantitative yield and purified
by column chromatography. Similarly, 5b was obtained by
treatment of 3b with excess of 1,3-dibromopropane in basic
medium. All products were obtained in quantitative yield
with high purity via 100–200 mesh SiO2, column chroma-
tography with ethyl acetate in chloroform as eluent mixture.
Reaction of 3a and 3b with 1,3-dibromopropane (0.5 eq) in
presence of K2CO3 and DMF afforded synthesis of 4a and
4b, respectively (Scheme 1).
Experimental model of inflammation
Carrageenan induced paw edema (Wintar et al., 1962) was
used throughout the investigation.
Standard drugs and solutions
(a) Powder of the pure Carrageenan was used and fresh
suspension was prepared in distilled water to make 1%
Carrageenan solution; (b) Fresh drug solutions were made
by adding 10 mg of drug in 500 mg carboxymethyl cel-
lulose (CMC) and 50 ml distilled water.
The base catalyzed nucleophilic substitution of 5a with
1 eq. of phthalimide in DMF as solvent at room temperature
gave 6a (Tewari et al., 2010b). The pure product was
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Med Chem Res (2012) 21:2465–2475
2467
Scheme 1
SR
SR
O
O
NHNH2
N
(a)
N
O
+
O
N
N
O
(1)
(2)
(a) = CS2 / Anhydr. K2CO3 / C6H6 / DMF
(b) = ROH / NaOC2H5 / H+/ H+2O
(c) = Br(CH2)3Br / K2CO3 / DMF
2. a; R=CH3
b; R=C2H5
(b)
O
O
O
R
R
R
O
O
O
N
N
(c)
N
N
O
O
OH
N
N
(4)
(3)
4. a; R=CH3
b; R=C2H5
3. a; R=CH3
b; R=C2H5
(c)
O
R
O
N
O
Br
N
(5)
5. a; R=CH3
b; R=C2H5
Experimental inflammation
solution in distilled water. A volume of 0.1 ml of Carra-
geenan solution was injected through a 26 gauge needle
into the plantar surface of the left hind paw below the
plantar aponeurosis. The volume of paw was measured
before and at different intervals for 3 h after injection of
It was produced by the following method:
(a) Carrageenan induced paw edema in rats: 1% Car-
rageenan suspension was prepared as a homogeneous
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O
O
R
R
O
O
O
N
N
O
Br
O
N
O
N
N
(a)
O
(6)
(5)
6. a; R=CH3
b; R=C2H5
5. a; R=CH3
b; R=C2H5
HN
(a)K2CO3 / DMF /
(b)
O
N
K CO / DMF / HN
(b)
2
3
O
R
O
N
N
N
O
N
(7)
7. a; R=CH3
b; R=C2H5
Scheme 2
Results and observations
carrageenan. The difference in paw volume before and
after administration of the phlogistic agent was taken as the
measure of pedal edema. The drugs whose effects have
been studied on this particular model were administered as
per schedule; (b) Measurement of paw volume: The vol-
ume of hind paw of the rats up to the ankle joint was
measured plathysmographically by the mercury displace-
ment method. The ankle joint of the rats was marked with a
skin marking pencil and the paw was dipped in the mer-
cury, so that the mark on the paw coincides with a prefixed
line kept constant on the syringe. The level of the mercury
was every time brought to the level of this line by adjusting
the height of the displaced mercury. The difference in the
paw volume before and after injection of the phlogistic
agents was taken as a measure of pedal edema. The change
in paw volume was expressed in ‘‘ml’’ of mercury
displaced.
In all experiments, Carrageenan was administered into the
left hind paw and the paw volume was measured before
and at intervals of 30, 90, and 180 min, after Carrageenan
injection, as shown in Tables 1 and 2. However, when the
rats were reused, Carrageenan injection was given into the
right hind paw.
Discussion and conclusion
Carrageenan which is a sulfated polysaccharide, extracted
from sea weed has been extensively used to induce
inflammation in a number of animal species. The Carra-
geenan induced rat hind paw edema is now routinely used
for the assay of anti-inflammatory agents (Wintar et al.,
1962). The reproducibility and the fact that the edema
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Med Chem Res (2012) 21:2465–2475
2469
O
O
R
R
O
O
N
(a)
N
O
N
O
Y
Br
N
(a) = Y-H / K2CO3 / DMF /
(8)
(5)
8. a; R=CH3
b; R=C2H5
5. a; R=CH3
b; R=C2H5
N
O
(II);
Y. (I);
N
O
CN
CN
Scheme 3
Table 1 Percentage edema
growth relative to control at
different time intervals
(Mean SEM)
Group
0 min
30 min
90 min
180 min
Control
Nimusilide
4a
0.99 0.067
1.18 0.064
1.15 0.044
1.17 0.064*
0.98 0.033*
0.84 0.056
0.78 0.050
0.89 0.038
0.91 0.086
1.27 0.043**
1.29 0.041
1.36 0.070
1.25 0.024
1.49 0.025
1.39 0.063
1.21 0.072
1.21 0.021
1.42 0.046
1.22 0.093
1.01 0.052*
0.99 0.0.043*
1.04 0.045
0.99 0.028*
1.15 0.022
1.34 0.029
6a
1.25 0.061
6b
1.11 0.052**
0.94 0.044***
1.05 0.028
1.18 0.034**
1.03 0.057**
1.16 0.012*
0.92 0.025***
1.18 0.050
8a-I
8b-I
Results are (Mean SEM) of 6
rats in each group. *p \ 0.05;
**p \ 0.01; ***p \ 0.001
8a-II
8b-II
0.81 0.028***
1.22 0.034
depends entirely on a local inflammatory reaction devoid of
antigenic properties, has made Carrageenan most widely
employed phlogistic agent in experimental pharmacology
(Di Rosa et al., 1971). A good correlation has been shown
to exist between the antiphlogistic and anti-inflammatory
effects of several drugs (Lombardino et al., 1975).
characterized by increased tissue water and plasma protein
exudation with neutrophil extravasations and metabolism
of the arachidonic acid by both cyclooxygenase and
lipooxygenase enzyme pathway. There are biphasic effects
in Carrageenan induced edema. The first phase begins
immediately after injection and diminishes in 1 h. The
second phase begins at 1 h and remains through 3 h. It is
suggested by Kulkarni et al. (1986) that the early hyper-
emia of Carrageenan induced edema results from the
release of histamine and serotonin. On the other hand,
delayed phase of Carrageenan induced edema results
mainly from the potentiating effect of PGs on mediator
release, especially of bradykinin. Hydrocortisone and
some anti-inflammatory drugs strongly inhibit the second
phase of Carrageenan induced edema. However, some
anti-inflammatory drugs are effective against both phases
The mediator involved in Carrageenan induced
inflammation has been extensively investigated and his-
tamine, serotonin, kinins, and PGs have been implicated
(Garcia-Leme, 1978). It has been proposed that histamine
and serotonin are responsible for the initial stages of the
edema, whereas kinins and PGs are responsible for later
stages of the inflammation (Di Rosa et al., 1971; Hols-
apple et al., 1980). In the present study, sub cutaneous
injection of 0.1 ml of 1% Carrageenan into the rat paw
produces plasma extravasations and inflammation
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Table 2 Paw edema at
different time intervals (ml/rat)
(Mean SEM)
Group
0 (min)
30 (min)
90 (min)
180 (min)
Control
100
100
100
100
100
100
100
100
100
0
130.1 6.54
(30.1)
138.7 4.47
(38.7)
122.3 5.17
(22.3)
Nimusilide
4a
0
0
0
0
0
0
0
0
110.8 2.58
(10.8)
107.90 3.14
(7.9)
102.54 2.52
(2.54)
115.1 2.88
(15.1)
124.4 3.37*
(24.4)
117.9 4.25
(17.9)
6a
105.9 2.59**
(5.9)
104.8 3.98***
(4.8)
98.3 2.54**
(1.7)
6b
138.9 3.56
(38.9)
144.7 6.54
(44.7)
139.3 7.58
(39.3)
8a-I
117.6 10.02
(17.6)
129.7 3.83*
(29.7)
118.5 8.34
(18.5)
8b-I
8a-II
8b-II
122.4 5.60
(22.4)
128.5 4.86
(28.5)
120.4 5.86
(20.4)
N = 6 = number of rats in each
group. Results in parentheses
indicate percentage change from
respective control group.
*p \ 0.05; **p \ 0.01;
116.8 10.02
(16.8)
128.7 3.83*
(28.7)
124.9 8.34
(24.9)
121.4 4.53
(21.4)
124.6 3.98**
(24.6)
116.8 4.75
(16.8)
***p \ 0.001
compared with that of control group (where it was 38.7% at
90 min).
30 min
90 min
180 min
50
40
30
20
10
0
Other drugs i.e., 4a, 8a-I, 8b-I, and 8a-II have shown
moderate to intermediate effects on inhibitory properties at
90 min, but 6b has shown no effect as anti-inflammatory
agent (Fig. 1).
Therefore, the results indicated that 6a is potent inhib-
itor of inflammation, and the anti-inflammatory effect of 6a
on inflammagen induced edema may depend on inhibition
of the formation of several inflammation mediators. The
structures of 6a (drug with maximum anti-inflammatory
activity) and 6b (drug with no anti-inflammatory activity)
were almost same except that in 6a ester moiety contained
methyl group and in 6b ester moiety contained ethyl group
which being bulkier than methyl group may affect the
activity of the particular drug. In conclusion, detailed
studies are needed to clarify the mechanism(s) of anti-
inflammatory effects of new pyrazole derivatives.
Control Nimusilide 4a
6a
6b
8a-I
8b-I
8a-II
8b-II
Drugs
Fig. 1 Effect of different drugs on carrageenan induced rat paw
edema
(Kulkarni et al., 1986; Vinegar et al., 1969). According to
Insel (1996), steroids and NSAIDs exert their effect by
inhibition of inflammation mediator formation.
Experimental
The results of present study shown that compound 6a
had shown to possess maximum inhibitory effect when
compared with control group. It was observed that maxi-
mum percentage of paw edema growth in control group at
90 min was 38.7% which was found to decrease up to 4.8%
in the group of rats treated with 6a. It shows very good
anti-inflammatory property than Nimusilide (where it was
7.90% at 90 min). 8b-II have also been found to possess
good anti-inflammatory property as the percentage paw
edema growth was shown to be only 24.0% when
All reactions were monitored by thin layer chromatography
over silica gel G TLC plates. The melting points were
recorded on electrically heated instrument and are uncor-
rected. NMR spectra were recorded on JEOL AL300
FTNMR spectrometer using TMS as internal reference and
chemical shift values are expressed in d, ppm units. Mass
spectra of the compounds were taken with JEOL SX 102/Da-
600 mass spectrometer. Analysis was performed on Exeter
Analytical Inc. ‘‘Model CE-440 CHN Analyzer’’ instrument.
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2471
Preparation of 3-methyl-1-phenyl-pyrazol-5-one (1)
bath for 1 h. In another 500-ml round-bottom flask, fitted with
guard tube (1) (30.0 g, 0.172 mol) was taken and 20 ml DMF
was added. It was stirred for 15 min. Then, carbon disulfide
(10.40 ml, 0.172 mol) was added slowly with stirring. It was
also stirred for 1 h in an ice bath. Then, the content of first
round bottom flask was added to second round bottom flask
with stirring and the reaction mixture was stirred for 6 h. With
the use of a dropping funnel, ethyl iodide (27.67 ml,
0.345 mol) was added very slowly along with 10 ml dry
benzene in ice cold condition. After complete addition, the
reaction was stirred for 6 h. The completion of reaction was
checked by TLC. Reaction was worked up. Solvents were
removed under pressure through rotary evaporator and the
reaction mixture was extracted with CHCl3/H2O (200/
200 9 2 ml). The CHCl3 layer was dried with anhydrous
Na2SO4 and filtered. Chloroform was removed and the
product was purified via SiO2-column chromatography. Elu-
ent used was 20% ethyl acetate in hexane.
In a 250-ml round-bottom flask, ethyl acetoacetate (48 ml,
0.385 mol) was taken and phenyl hydrazine (41.54 ml,
0.385 mol) was added slowly with stirring. The reaction
mixture was refluxed on a heating mantle for 2 h. The
completion of reaction was checked via TLC. The reaction
mixture was cooled and diethyl ether was slowly added
with stirring. After 10 min, light yellow colored precipitate
appeared which was filtered and washed with ether. Pure
white colored 3-methyl-1-phenyl-pyrazol-5-one (1) was
then recrystallized with hot aqueous ethanol.
Mp = 127°C. Yield = 60.20 g (90%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.20 (s, 3H, CH3), d
3.44 (s, 2H, CH2), d 7.18–7.87 (m, 5H, Ar–H).
Preparation of 4-(bis-methylsulfanyl-methylene)-
5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one (2a)
Mp = 40–44°C. Yield = 38.85 g (74%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.52 (s, 3H, CH3), d
1.31–1.44 (double-t, 6H, SCH2CH3 9 2) (J = 7.5, 7.2, 8.1,
7.5, 7.5 Hz), d 3.18-3.34 (double-q, 4H, CH2CH3 9 2)
(J = 7.5, 7.5, 7.2, 7.5, 7.2, 7.2 Hz), d 7.12–7.99 (m, 5H, Ar–H).
In a 500-ml round-bottom flask, fitted with guard tube,
anhydrous K2CO3 (59.48 g, 0.431 mol) was taken, and
20 ml DMF and 40 ml dry benzene were added and stirred
in an ice bath for 1 h. In another 500-ml round-bottom
flask, fitted with guard tube (1) (30.0 g, 0.172 mol) was
taken and 20 ml DMF was added. It was stirred for 15 min.
Then, carbon disulfide (10.40 ml, 0.172 mol) was added
slowly with stirring. It was also stirred for 1 h in an ice
bath. Then, the content of first round bottom flask was
added to second round bottom flask with stirring and the
reaction mixture was stirred for 6 h. With the use of a
dropping funnel, methyl iodide (21.46 ml, 0.345 mol) was
added very slowly along with 10 ml dry benzene. The
addition of methyl iodide was accompanied with the use of
ice bath. After complete addition, the reaction was stirred
for 6 h. The completion of reaction was checked by TLC.
Reaction was worked up. Solvents were removed under
pressure through rotary evaporator and the reaction mixture
was extracted with CHCl3/H2O (200/200 9 2 ml). The
CHCl3 layer was dried with anhydrous Na2SO4 and fil-
tered. Chloroform was removed and the product was
purified via SiO2-column chromatography. Eluent used was
20% ethyl acetate in hexane.
Preparation of 5-hydroxy-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic acid methyl ester (3a)
In a 100-ml round-bottom flask, anhydrous NaOC2H5
(0.47 g, 0.007 mol) was dissolved in 10 ml dry methanol
and stirred for 15 min, and then compound (2a) (1 g,
0.004 mol) was added and refluxed over an oil bath fitted
with water condenser and guard tube at 80°C for 2 h. The
completion of reaction was confirmed by TLC. The reac-
tion mixture was worked up. Concentrated HCl (excess till
the orange color of reaction mixture turned to light yellow
color and the medium becomes acidic) was added slowly
drop wise to the reaction mixture, and then excess of water
was added with constant shaking. Light orange-yellow
precipitate appeared which was filtered and washed with
water over buchner-funnel.
Mp = 138–145°C. Yield = 0.8 g (96%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.41 (s, 3H, CH3), d
3.92 (s, 3H, OCH3), d 7.26–7.79 (m, 5H, Ar–H), d 9.99
(broad s, 1H, O–H). MS (m/z): 233(M?). Element analysis:
% C (calc.) 62.06 (found) 62.53; % N (calc.) 12.06 (found)
12.67; % H (calc.) 5.17 (found) 5.42.
Mp = 46–52°C. Yield = 40.54 g (85%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.52 (s, 3H, CH3), d
2.69 (s, 3H, SCH3), d 2.76 (s, 3H, SCH3), d 7.12–7.99
(m, 5H, Ar–H).
Preparation of 4-(bis-ethylsulfanyl-methylene)-
Preparation of 5-hydroxy-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic acid ethyl ester (3b)
5-methyl-2-phenyl-2, 4-dihydro-pyrazol-3-one (2b)
In a 500-ml round-bottom flask, fitted with guard tube,
anhydrous K2CO3 (59.48 g, 0.431 mol) was taken, and 20 ml
DMF and 40 ml dry benzene were added and stirred in an ice
The process was exactly same as used for synthesis of
compound (3a) but the solvent used was dry ethanol for
compound (3b).
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Med Chem Res (2012) 21:2465–2475
Mp = 95–100°C. Yield = 0.74 g (84%). 1H NMR
(t, 6H, CH3 9 2), d 4.15–4.19 (t, 4H, OCH2 9 2) (J = 6.0,
6.3 Hz), d 4.25–4.32 (q, 4H, OCH2CH3 9 2) (J = 7.2, 6.9,
7.2 Hz), d 7.26–7.51 (m, 10H, Ar–H). 13C NMR (300 MHz,
25°C, Si(CH3)4, CDCl3): d 14.2, 15.2, 29.9, 59.7, 72.3, 99.2,
123.1, 127.3, 128.7, 137.2, 150.7, 154.8, 162.7.
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 1.38–1.42 (t, 3H,
CH2CH3) (J = 5.7, 6.9 Hz), d 2.41 (s, 3H, CH3), d
4.35–4.42 (q, 2H, CH2CH3) (J = 6.9, 5.7, 7.2 Hz), d
7.27–7.79 (m, 5H, Ar–H), d 10.08 (broad s, 1H, O–H). MS
(m/z): 247(M?). Element analysis: % C (calc.) 63.41
(found) 63.90; % N (calc.) 12.06 (found) 12.50; % H (calc.)
5.69 (found) 5.57.
Preparation of 5-(3-bromo-propoxy)-3-methyl-
1-phenyl-1H-pyrazole-4-carboxylic acid methyl
ester (5a)
Preparation of 1,3-di(5-butoxy-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic acid methyl ester)-propane (4a)
Anhydrous K2CO3 (1.78 g, 0.013 mol) and compound (3a)
(3 g, 0.013 mol) were added in 20 ml DMF in a 100-ml
round-bottom flask, fitted with guard tube, and stirred for
30 min. 1,3-dibromopropane (1.31 ml, 0.064 mol) was
added and stirred at room temperature for 30 h. The
completion of reaction was checked by TLC and the
reaction mixture was worked up. Pure (5a) was obtained by
column loaded with SiO2 in CHCl3. Eluent used was pure
chloroform. Fluorescent green colored oily liquid.
Yield = 3.32 g (72%). 1H NMR (300 MHz, 25°C,
Si(CH3)4, CDCl3): d 2.14–2.22 (p, 2H, CH2) (J = 6.0, 6.0,
6.0, 6.0 Hz), d 2.47 (s, 3H, CH3), d 3.37–3.41 (t, 2H, CH2)
(J = 6.3, 6.3 Hz), d 3.87 (s, 3H, OCH3), d 4.29–4.34
(t, 2H, CH2) (J = 5.7, 5.7 Hz), d 7.26–7.62 (m, 5H, Ar–H).
In a 100-ml round-bottom flask, fitted with guard tube,
compound (3a) (5 g, 0.021 mol) was dissolved in 20 ml
DMF, and anhydrous K2CO3 (2.97 g, 0.021 mol) was
added and stirred at room temperature for 30 min. 1,3-
dibromopropane (1.09 ml, 0.011 mol) was added and stir-
red at room temperature for 24 h. The completion of
reaction was checked by TLC and the reaction mixture was
worked up as above. Pure (4a) was obtained with 10%
ethyl acetate in CHCl3. Pure X-ray quality crystals were
obtained with 2% ethyl acetate in hexane.
Mp = 58–60°C. Yield = 0.56 g (11%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 1.94–2.02 (p, 2H,
CH2) (J = 6.3, 6.0, 6.0, 5.7 Hz), d 2.456 (s, 6H, CH3 9 2),
d 3.81 (s, 6H, OCH3 9 2); d 4.15–4.19 (t, 4H, OCH2 9 2)
(J = 6.0, 6.0 Hz), d 7.26–7.52 (m, 10H, Ar–H). 13C NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 15.3, 30.09, 51.1,
72.5, 99.2, 123.3, 127.5, 137.3, 150.9, 155.1, 163.3. MS
(m/z): 505(M?). Element analysis: % C (calc.) 64.28
(found) 64.32; % N (calc.) 11.11 (found) 11.18; % H (calc.)
5.55 (found) 5.62.
Preparation of 5-(3-bromo-propoxy)-3-methyl-1-
phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (5b)
In a 100-ml round-bottom flask, fitted with guard tube,
compound (3b) (3 g, 0.012 mol) and K2CO3 (1.68 g,
0.012 mol) were stirred in 20 ml DMF for 20 min and 1,
3-dibromopropane (1.23 ml, 0.060 mol) was added. It was
stirred for 30 h at room temperature and the completion of
reaction was confirmed by TLC. The reaction mixture was
worked up and the product (5b) was purified via column
chromatography loaded with silica in chloroform.
Preparation of 1,3-di(5-butoxy-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic acid ethyl ester)-propane (4b)
In a 100-ml round-bottom flask, fitted with guard tube,
compound (3b) (0.46 g, 0.002 mol) was dissolved in 10 ml
DMF and anhydrous K2CO3 (0.26 g, 0.002 mol) was
added. It was stirred at room temperature for 1 h and (5b)
(0.7 g, 0.002 mol) was added. The reaction mixture was
stirred at room temperature for 24 h. Completion of reac-
tion was confirmed via TLC. Reaction mixture was worked
up. DMF removed under pressure by rotary evaporator and
crude product obtained through extraction with CHCl3/
H2O (20/20 9 2 ml). Organic layer was dried (Na2SO4),
filtered, removed, and pure (4b) was obtained by column
chromatography loaded with SiO2 in chloroform. Eluent
used was 15% ethyl acetate in CHCl3. The product
obtained was thick yellow oily compound.
Mp = 45–47°C. Yield = 3.15 g (70%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 1.37–1.41 (t, 3H,
OCH2CH3) (J = 6.9, 7.5 Hz), d 2.16–2.22 (p, 2H, CH2)
(J = 6.0, 6.3, 6.0 Hz), d 2.47 (s, 6H, CH3 9 2), d
3.35–3.39 (t, 2H, CH2) (J = 6.3, 6.6 Hz), d 4.30–4.37
(m, 4H, CH2, OCH2CH3), d 7.26–7.62 (m, 5H, Ar–H).
Preparation of 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-
2-yl)-propoxy]-3-methyl-1-phenyl-1H-pyrazole-
4-carboxylic acid methyl ester (6a)
Phthalimide (0.20 g, 0.001 mol) and anhydrous K2CO3
(0.19 g, 0.001 mol) were stirred in 15 ml DMF for 10 min
and (5a) (0.5 g, 0.001 mol) was added. The reaction was
stirred at r. t. for 24 h and the completion of reaction was
checked by TLC. After completion of reaction, solvent was
removed via rota vapor and the product was extracted with
Yield = 0.5 g (49%). 1H NMR (300 MHz, 25°C,
Si(CH3)4, CDCl3): d 1.32–1.37 (t, 3H, CH2CH3) (J = 6.9,
7.2 Hz), d 1.96–2.00 (t, 2H, CH2) (J = 6.0, 6.3 Hz), d 2.46
123

Med Chem Res (2012) 21:2465–2475
2473
CHCl3/H2O (20/20 9 2 ml). The CHCl3 layer was dried
(Na2SO4), filtered, evaporated, and pure (6a) was obtained
from 3% ethyl acetate in hexane mixture.
and pure (7a) was obtained as oily liquid through column
loaded with silica in chloroform. Eluent used was 5% ethyl
acetate in chloroform.
Mp = 74°C. Yield = 0.22 g (37%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.02–2.11 (p, 2H,
CH2) (J = 6.6, 6.9, 6.9, 6.6 Hz), d 2.46 (s, 3H, CH3), d
3.70–3.75 (t, 2H, NCH2) (J = 6.9, 7.5 Hz), d 3.82 (s, 3H,
OCH3), d 4.23–4.27 (t, 2H, OCH2) (J = 6.6, 6.3 Hz), d
7.26–7.84 (m, 9H, Ar–H). 13C NMR (300 MHz, 25°C,
Si(CH3)4, CDCl3): d 15.3, 28.9, 34.8, 51.0, 73.7, 99.3,
123.2, 127.5, 129.0, 132.0, 133.0, 137.5, 151.0, 155.1,
163.4, 168.1. MS (m/z): 420(M?). Element analysis: % C
(calc.) 65.87 (found) 66.26; % N (calc.) 10.02 (found)
10.15; % H (calc.) 5.01 (found) 5.14.
Yield = 0.70 g (43%). 1H NMR (300 MHz, 25°C,
Si(CH3)4, CDCl3): d 2.19–2.21 (p, 2H, CH2) (J = 4.8 Hz), d
2.47 (s, 3H, CH3), d 3.85 (s, 3H, OCH3), d 4.16–4.71 (double-
t, 4H, OCH2, NCH2) (J = 6.3, 6.9, 4.5, 5.4, 5.4, 7.2 Hz), d
7.52 (s, 1H, CH), d 7.27–8.03 (m, 9H, Ar–H). 13C NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 14.6, 29.0, 40.5, 50.3,
71.7, 98.7, 108.9, 119.3, 121.6, 122.2, 122.8, 127.1, 128.4,
132.7, 136.6, 142.4, 142.8, 150.0, 154.2, 162.4.
Preparation of 5-(3-benzimidazol-1-yl-propoxy)-3-
methyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl
ester (7b)
Preparation of 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-
2-yl)-propoxy]-3-methyl-1-phenyl-1H-pyrazole-
4-carboxylic acid ethyl ester (6b)
In a 100-ml round-bottom flask, fitted with guard tube,
benzimidazole (0.16 g, 0.001 mol) and anhydrous K2CO3
(0.19 g, 0.001 mol) were dissolved and stirred for 30 min
followed by addition of (5b) (0.5 g, 0.001 mol). The
reaction was stirred at r. t. for 48 h. Completion of reaction
was confirmed via TLC and the reaction was worked up.
DMF was removed using rotary evaporator and the product
was extracted with CHCl3/H2O (20/20 9 2 ml). The
CHCl3 layer was dried (Na2SO4), filtered, evaporated, and
pure (7b) was obtained as oily liquid.
Yield = 0.02 g (36%). 1H NMR (300 MHz, 25°C,
Si(CH3)4, CDCl3): d 1.34–1.39 (t, 3H, OCH2CH3)
(J = 6.9, 6.9 Hz), d 2.18–2.22 (t, 2H, CH2) (J = 5.7,
5.4 Hz), d 2.47 (s, 3H, CH3), d 4.08–4.36 (m, 6H,
CH3 9 3), d 7.26–7.78 (m, 9H, Ar–H). 13C NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 14.2, 15.3, 29.5,
41.2, 59.8, 72.1, 99.5, 109.3, 120.1, 122.0, 122.7, 127.8,
129.0, 133.2, 137.2, 142.9, 150.7, 154.7, 162.7.
Phthalimide (0.20 g, 0.001 mol) and anhydrous K2CO3
(0.19 g, 0.001 mol) were stirred in 15 ml DMF for 20 min
and (5b) (0.5 g, 0.001 mol) was added. The reaction was
stirred at r. t. for 24 h and the completion reaction was
checked by TLC. After completion of reaction, solvent was
removed via rota vapor and the product was extracted with
CHCl3/H2O (30/30 9 2 ml). The CHCl3 layer was dried
(Na2SO4), filtered, evaporated, and pure (6b) was obtained
from 3% ethyl acetate in hexane mixture.
Mp = 78–80°C. Yield = 0.30 g (51%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 1.33–1.38 (t, 3H,
CH2CH3) (J = 6.9, 7.2 Hz), d 2.04–2.08 (t, 2H, CH2)
(J = 6.9, 6.9 Hz), d 2.46 (s, 3H, CH3), d 3.69–3.74 (t, 2H,
NCH2) (J = 7.2, 7.2 Hz), d 4.25–4.32 (q, 4H, OCH2,
OCH2CH3) (J = 7.5, 6.9, 6.6 Hz), d 7.26–7.84 (m, 9H,
Ar–H). 13C NMR (300 MHz, 25°C, Si(CH3)4, CDCl3): d
14.3, 15.3, 28.8, 34.7, 59.8, 73.4, 99.5, 123.3, 127.4, 129.0,
132.0, 133.8, 137.4, 150.9, 155.0, 162.9, 168.0. MS (m/z):
434(M?). Element analysis: % C (calc.) 66.51 (found)
67.34; % N (calc.) 9.69 (found) 9.76; % H (calc.) 5.31
(found) 5.40.
Preparation of 5-[3-(3-cyano-4,6-dimethyl-2-oxo-
2H-pyridin-1-yl)-propoxy]-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic acid methyl ester (8a-I) and
5-[3-(3-cyano-4,6-dimethyl-pyridin-2-yloxy)-propoxy]-
3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid
methyl ester (8a-II)
Preparation of 5-(3-benzimidazol-1-yl-propoxy)-3-
methyl-1-phenyl-1H-pyrazole-4-carboxylic acid methyl
ester (7a)
In a 100-ml round-bottom flask, fitted with guard tube,
pyridone (0.42 g, 0.003 mol) and anhydrous K2CO3
(0.38 g, 0.003 mol) were dissolved in 20 ml DMF for
30 min and (5a) (1.0 g, 0.003 mol) was added slowly with
stirring. The reaction was stirred at r. t. for 48 h. The
completion of reaction was confirmed via TLC. Reaction
was worked up. Solvent was removed via rotary evaporator
and the product mixture was extracted with CHCl3/H2O
(60/60 9 2 ml). The CHCl3 layer was dried (Na2SO4),
filtered, and evaporated. The product mixture was crystal-
lized with 5% ethyl acetate in hexane and recrystallized
Benzimidazole (0.49 g, 0.004 mol) and anhydrous K2CO3
(0.57 g, 0.004 mol) were stirred in 20 ml DMF for 30 min
at r. t. and (5a) (1.48 g, 0.004 mol) was added slowly with
stirring. The reaction was stirred at room temperature for
30 h and the completion of reaction was confirmed via
TLC. DMF was removed via rotary evaporator and the
product was extracted with CHCl3/H2O (50/50 9 2 ml).
The CHCl3 layer was dried (Na2SO4), filtered, evaporated,
123

2474
Med Chem Res (2012) 21:2465–2475
with 2% ethyl acetate in hexane to obtain pure (8a-I) and
(8a-II).
3.6 Hz), d 5.97 (s, 1H, CH), d 7.26–7.69 (m, 5H, Ar–H).
13C NMR (300 MHz, 25°C, Si(CH3)4, CDCl3): d 14.3,
15.4, 20.6, 28.2, 42.4, 59.9, 73.4, 99.5, 101.3, 109.4, 115.3,
123.5, 127.8, 129.0, 137.3, 150.4, 150.8, 154.9, 157.9,
160.7, 162.8. MS (m/z): 434(M?). Element analysis: % C
(calc.) 66.51 (found) 66.02; % N (calc.) 9.69 (found) 9.03;
% H (calc.) 5.31 (found) 5.30.
(8b-II): Mp = 54–55°C. Yield = 0.10 g (17%). 1H
NMR (300 MHz, 25°C, Si(CH3)4, CDCl3): d 1.36–1.41
(t, 3H, OCH2CH3) (J = 6.9, 7.2 Hz), d 2.13–2.17 (m, 2H,
CH2) (J = 6.0, 6.6 Hz), d 2.42 (s, 6H, CH3 9 2), d 2.46 (s,
3H, CH3), d 4.32–4.41 (m, 6H, CH2 9 3, OCH2CH3,
OCH2 9 2), d 6.67 (s, 1H, CH), d 7.19–7.59 (m, 5H, Ar–
H). 13C NMR (300 MHz, 25°C, Si(CH3)4, CDCl3): d 14.4,
15.2, 19.9, 24.4, 29.0, 59.9, 62.9, 72.4, 93.8, 114.6, 117.4,
123.4, 127.2, 128.7, 137.4, 151.0, 154.1, 155.0, 160.4,
162.9, 163.5. MS (m/z): 434(M?). Element analysis: % C
(calc.) 66.51 (found) 66.33; % N (calc.) 9.69 (found) 9.51;
% H (calc.) 5.31 (found) 5.71.
(8a-I): Mp = 110–112°C. Yield = 0.20 g (17%). 1H
NMR (300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.04–2.11 (p,
2H, CH2) (J = 5.4, 5.7, 7.5 Hz, d 2.32–2.36 (d, 6H,
CH3 9 2) (J = 12.9 Hz), d 2.46 (s, 3H, CH3), d 3.85 (s,
3H, OCH3), d 4.05–4.09 (t, 2H, CH2) (J = 7.5, 7.8 Hz), d
4.28–4.32 (t, 2H, CH2) (J = 5.4, 5.4 Hz), d 5.98 (s, 1H,
CH), d 7.26–7.59 (m, 5H, Ar–H). 13C NMR (300 MHz,
25°C, Si(CH3)4, CDCl3): d 15.3, 20.6, 28.3, 42.4, 51.1,
73.5, 99.3, 101.4, 109.4, 115.3, 123.5, 127.8, 129.1, 137.3,
150.4, 150.8, 155.0, 157.9, 160.8, 163.3. MS (m/z):
421(M1). Element analysis: % C (calc.) 65.71 (found)
65.31; % N (calc.) 13.33 (found) 13.50; % H (calc.) 5.71
(found) 5.88.
(8a-II): Mp = 66–70°C. Yield = 0.06 g (5%). 1H NMR
(300 MHz, 25°C, Si(CH3)4, CDCl3): d 2.13–2.17 (p, 2H,
CH2), d 2.43 (s, 6H, CH3 9 2), d 2.46 (s, 3H, CH3), d 3.86
(s, 3H, OCH3), d 4.36–4.38 (q, 2H, OCH2) (J = 4.2 Hz), d
4.38–4.39 (t, 4H, OCH2 9 2) (J = 4.2 Hz), d 6.68 (s, 1H,
CH), d 7.21–7.60 (m, 5H, Ar–H). 13C NMR (300 MHz,
25°C, Si(CH3)4, CDCl3): d 15.2, 20.8, 24.5, 28.3, 29.1,
51.1, 63.0, 72.5, 93.9, 99.5, 109.4, 114.7, 123.6, 127.3,
128.8, 137.4, 151.0, 154.2, 160.5, 163.4, 163.6. MS (m/z):
421(M?). Element analysis: % C (calc.) 65.71 (found)
65.53; % N (calc.) 13.33 (found) 13.01; % H (calc.) 5.71
(found) 5.42.
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