Synthesis and pharmacological study of 1-acetyl/propyl-3-aryl-5-(5-chloro- 3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazoline

Article abstract of DOI:10.1016/j.ejmech.2010.07.032

A series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H- pyrazol-4-yl)-2-pyrazolines were synthesized in one step by condensing suitably substituted propenones, hydrazine and acetic/propionic acid. The newly synthesized pyrazolines were characterized by analytical and spectral data. The new compounds were screened for analgesic and anti-inflammatory activity and most of them showed good activity comparable with that of standard drugs Pentazocin and Diclofinac sodium respectively.

Full text of DOI:10.1016/j.ejmech.2010.07.032

European Journal of Medicinal Chemistry 45 (2010) 4640e4644
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological study of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-
methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazoline
,
b
b
K.S. Girisha a, Balakrishna Kalluraya a , Vijaya Narayana , Padmashree
*
a Department of Studies in Chemistry, Mangalore University, Mangalagangotri 574 199, Karnataka, India
b NGSM Institute of Pharmaceutical Sciences, Deralakatte, Mangalore 574 199, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazolines were
synthesized in one step by condensing suitably substituted propenones, hydrazine and acetic/propionic
acid. The newly synthesized pyrazolines were characterized by analytical and spectral data. The new
compounds were screened for analgesic and anti-inflammatory activity and most of them showed good
activity comparable with that of standard drugs Pentazocin and Diclofinac sodium respectively.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Received 18 January 2010
Received in revised form
14 July 2010
Accepted 19 July 2010
Available online 24 July 2010
Keywords:
Pyrazoles
Pyrazolines
Propenones
Anti-inflammatory activity
Analgesic activity
1. Introduction
2. Results and discussion
Pyrazoles are novel class of heterocyclic compounds possessing
wide variety of application in the agrochemical and pharmaceu-
tical industries [1]. Derivatives of pyrazoles are found to show
good antibacterial [2], anti-inflammatory [3], analgesic [4], anti-
cancer, radioprotective [5], anti-convulsant [6] and anti-depres-
sant activity [7]. Pyrazolines are well known and important
nitrogen containing five membered heterocyclic compounds.
Several pyrazoline derivatives have been found to possess
considerable biological activities which stimulated research
activities in this field [8e12]. After the pioneer work of Fischer and
2.1. Chemistry
The synthesis of hitherto unreported title compounds was
prepared as outlined in Scheme 1. 1-Phenyl-5-chloro-3-methyl-1H-
pyrazole-4-carboxaldehyde
literature method [14]. The 3-(5-chloro-3-methyl-1-phenyl-1H-
pyrazol-4-yl)-1-(aryl)-2-propen-1-one was prepared by the
1 was prepared according to the
2
reaction of aldehyde 1 with appropriately substituted acetophe-
nones in ethanol medium employing alcoholic potassium hydroxide
as the catalyst at 0e5 ꢀC (Table 1). When these propenones 2 were
treated with hydrazine hydrate in acetic acid/propionic acid under
reflux gave 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-
1H-pyrazol-4-yl)-2-pyrazolines 3. The structures of the newly
synthesized compounds have been established on the basis of
spectral and analytical data.
In the IR spectra of compounds 3aem the carbonyl absorption
bands were observed in the region of 1710e1725 cmꢁ1. The CeH
stretching band was seen around 2925e3025 cmꢁ1 whereas the
eC]N stretching was observed around 1587e1610 cmꢁ1. In the 1H
NMR spectra of these compounds the chiral CH proton appeared as
doublet of a doublet, while the pro-chiral methylene protons
appeared as two distinct doublet of a doublet there by indicating
the magnetic non-equivalency of the two protons.
Knovenagal in the late nineteenth century [13], the reaction of a,b-
unsaturated aldehyde and ketones with hydrazines became one of
the most popular method for the preparation of 2-pyrazolines. In
view of these observations and in continuation of our search for
biologically active pyrazole derivatives [14e16], we herein report
the synthesis and pharmacological activity of a series of 1-acetyl/
propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-
pyrazolines 3.
* Corresponding author. Tel.: þ91 9448824075; fax: þ91 0824-2287367.
E-mail address: bkalluraya@gmail.com (B. Kalluraya).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.032

K.S. Girisha et al. / European Journal of Medicinal Chemistry 45 (2010) 4640e4644
4641
O
2.2. Pharmacological activities
H3C
CH3
H3C
CHO
Cl
R1
O
The newly synthesized compounds were evaluated for their
anti-inflammatory activity using albino rats [17]. The results are
summarized in Table 2. Anti-inflammatory results showed that
compounds 3b, 3d, 3e, 3i, 3k and 3m showed significant activity
comparable with that of the standard drug. The activity was
significant at the beginning but as the elapse of time the activity
was not very significant.
KOH
EtOH
N
Cl
N
N
+
N
0-5 °C
R1
2
1
The analgesic activity for the compounds was determined by tail
immersion method [18]. The results are summarized in Table 3.
Compounds 3b, 3d, 3f, 3g, 3j, 3l and 3m showed activity compa-
rable with that of the standard after 30 min of treatment. However
at a longer duration of time the activity of the drugs are not so
significant except 3g which contain an electron withdrawing nitro
group at the para-position.
NH2NH2, R2CO2H
Δ
R2
N
O
N
N
R1
H3C
3. Conclusion
Cl
N
A series of acetyl/propyl pyrazolines carrying a pyrazole moiety
have been synthesized in good yield and screened for their anti-
inflammatory and analgesic activity. The results indicated that
compounds bearing electron withdrawing nitro group in the aryl
moiety showed the highest analgesic activity.
3
Scheme 1. Synthesis of pyrazolines.
4. Experimental section
Table 1
Characterization data of 3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-
(substituted aryl)-2-propen-1-one 2.
4.1. General
Compd. R1
Yield M.P.
(%)
CHN analysis
Found (Calc)
C
Melting points were determined in open capillary tubes and
are uncorrected. The purity of the compounds were confirmed by
thin layer chromatography using silica gel plates in petroleum
ether:ethyl acetate(9.2:0.8) system as mobile phase. 1H NMR and
13C NMR spectra were recorded on Bruker Avance-II 400 MHz
NMR spectrometer using CDCl3/DMSO-d6 as solvent. TMS was
employed as internal standard. Chemical shift values are
(ꢀC)
H
N
2a
2b
2c
H
84
61e64
69e70
70.66 (70.70) 4.74 (4.68) 8.61 (8.68)
71.36 (71.32) 5.12 (5.09) 8.29 (8.32)
4-CH3 78
4-
81
113e115 68.11 (68.09) 4.80 (4.86) 7.96 (7.94)
OCH3
expressed in
d scale down field from TMS. The IR spectra were
2d
2e
2f
3-NO2 97
176e180 65.10 (65.05) 3.80 (3.84) 11.41 (11.43)
156e162 63.84 (63.88) 3.92 (3.95) 7.86 (7.84)
149e152 56.85 (56.81) 3.53 (3.51) 5.93 (6.97)
172e176 65.08 (65.05) 3.82 (3.84) 11.46 (11.43)
4-Cl
4-Br
86
98
obtained in KBr disc on a Shimadzu-8400 FTIR spectrophotometer.
The mass spectra were recorded on a Waters Micromass Q-Tof
Micro LC mass spectrometer. CHN analysis was carried on a Ele-
mentar Vario-El-III model analyzer.
2g
4-NO2 98
Solvent for recrystallization: EtOH.
Table 2
Anti-inflammatory activity data of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazolene 3.
Compd.
Change in paw volume (in mL) after (ꢂSEa)
30 min
60 min
90 min
120 min
150 min
3a
e
e
e
e
e
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
0.0667 ꢂ 0.033**
0.0 ꢂ 0.0**
0.1 ꢂ 0.0577**
0.0667 ꢂ 0.033**
0.1 ꢂ 0.0**
0.033 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.1667 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.367 ꢂ 0.033ns
0.300 ꢂ 0.0577ns
0.1667 ꢂ 0.033**
0.1 ꢂ 0.0**
0.0667 ꢂ 0.033**
0.1 ꢂ 0.0**
0.0 ꢂ 0.0**
0.0667 ꢂ 0.033**
0.033 ꢂ 0.033**
0.1 ꢂ 0.0**
0.0667 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.033 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.333 ꢂ 0.033ns
0.133 ꢂ 0.033**
0.1667 ꢂ 0.033**
0.033 ꢂ 0.033**
0.133 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.333 ꢂ 0.033
0.033 ꢂ 0.033**
0.033 ꢂ 0.0333**
0.033 ꢂ 0.033**
0.06 ꢂ 0.033**
0.433 ꢂ 0.033ns
0.133 ꢂ 0.033**
0.133 ꢂ 0.033**
0.033 ꢂ 0.033**
0.2 ꢂ 0.0**
0.133 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.3 ꢂ 0.0ns
0.1 ꢂ 0.0**
0.1667 ꢂ 0.033**
0.3667 ꢂ 0.033ns
0.300 ꢂ 0.0577ns
0.200 ꢂ 0.0577**
0.1 ꢂ 0.0**
0.2667 ꢂ 0.033ns
0.0667 ꢂ 0.033**
0.1667 ꢂ 0.033**
0.033 ꢂ 0.033**
0.1667 ꢂ 0.033**
0.0667 ꢂ 0.033**
0.333 ꢂ 0.033
0.033 ꢂ 0.033**
0.2667 ꢂ 0.033ns
0.0 ꢂ 0.0**
0.2667 ꢂ 0.033ns
0.033 ꢂ 0.033**
0.3667 ꢂ 0.033
0.033 ꢂ 0.033**
0.033 ꢂ 0.033**
0.3667 ꢂ 0.033
0.033 ꢂ 0.033**
Control
Standard (diclofinac sodium)
0.367 ꢂ 0.033
0.033 ꢂ 0.033**
0.033 ꢂ 0.033**
For all other comparisons P > 0.05.
P < 0.05; **P < 0.01; ***P < 0.001.
a
ꢂStandard error.

4642
K.S. Girisha et al. / European Journal of Medicinal Chemistry 45 (2010) 4640e4644
Table 3
Analgesic activity data of 1-acetyl/propyl-3-aryl-5-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-pyrazolene 3.
Compd.
Before treatment
After 30 min of treatment
After 60 min of treatment
After 90 min of treatment
3a
e
e
e
e
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
2.300 ꢂ 0.1155
1.867 ꢂ 0.03333
3.000 ꢂ 0.05773
2.200 ꢂ 0.1000
2.533 ꢂ 0.03333
2.533 ꢂ 0.03333
1.33 ꢂ 0.08819
1.767 ꢂ 0.08819
2.300 ꢂ 0.05774
2.000 ꢂ 0.05774
2.133 ꢂ 0.08819
1.833 ꢂ 0.03333
2.367 ꢂ 0.06667
3.300 ꢂ 0.1155**
2.900 ꢂ 0.05774***
3.700 ꢂ 0.05774**
2.500 ꢂ 0.05773*
3.967 ꢂ 0.03333**
3.467 ꢂ 0.08819**
2.333 ꢂ 0.03333**
2.900 ꢂ 0.05774**
4.667 ꢂ 0.08819**
2.767 ꢂ 0.1202**
3.800 ꢂ 0.1155***
3.100 ꢂ 0.05774**
2.900 ꢂ 0.05774*
4.567 ꢂ 0.08819***
3.700 ꢂ 0.05774***
4.733 ꢂ 0.08819***
3.067 ꢂ 0.08819*
4.733 ꢂ 0.2186**
4.767 ꢂ 0.1453**
2.700 ꢂ 0.1155
5.467 ꢂ 0.08819***
4.333 ꢂ 0.1764**
4.833 ꢂ 0.1202**
4.200 ꢂ 0.1528**
4.833 ꢂ 0.5239*
5.267 ꢂ 0.2028**
3.633 ꢂ 0.08819***
4.600 ꢂ 0.05773**
4.400 ꢂ 0.05773***
4.333 ꢂ 0.2186**
4.500 ꢂ 0.1732**
3.933 ꢂ 0.2333**
6.400 ꢂ 0.05773***
3.733 ꢂ 0.1202**
4.633 ꢂ 0.08819***
3.067 ꢂ 0.08819**
4.167 ꢂ 0.08819**
3.533 ꢂ 0.08819***
5.600 ꢂ 0.05773***
Standard (pentazocin)
For all other comparisons P > 0.05.
P < 0.05; **P < 0.01; ***P < 0.001.
4.2. Synthesis of 3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-
1-(aryl)-2-propen-1-one 2
N: 13.65 (13.70). 1H NMR: 400 MHz, CDCl3:
d
, 2.3 (s, 3H, CH3),
, 3.22e3.28 (dd, J ¼ 5.4 Hz
, 3.68e3.76 (dd, J ¼ 12.6 Hz & 17.8 Hz,
, 5.57e5.62 (dd, J ¼ 5.4 Hz & 12.6 Hz, 1H, eCHe),
d, 2.37
(s, 3H, eCOeCH3),
& 17.8 Hz, 1H, H of eCH2e),
1H, H of eCH2e),
d, 3.88 (s, 3H, OCH3), d
d
1-Phenyl-5-chloro-3-methyl-1H-pyrazole-4-carboxaldehyde
1
d
(2.2 g, 0.01 mol) was dissolved in 25 mL of ethanol. To this solution
suitably substituted acetophenones (0.1 mol) were added and the
reaction mixture was cooled to 0 ꢀC by means of ice-salt mixture. To
the cold reaction mixture ethanolic potassium hydroxide (0.4 mol)
was added slowly by maintaining the temperature at 0e5 ꢀC. Stir-
red the reaction mixture at this temperature for further 2 h. Filtered
the solid precipitated and washed with cold ethanol and dried.
d
, 6.99 (d, 2H, J ¼ 8.8 Hz, p-anisyl) &
d
: 7.73 (d, 2H each, J ¼ 8.8 Hz, p-
anisyl),
12.31 (CH3 of pyrazole),
pyrazoline),
d
, 7.37e7.55 (m, 5H, AreH). 13C NMR: 400 MHz, DMSO:
, 21.38 (acyl eCH3),
, 50.36 (eCHe of pyrazoline), d, 54.92 (OCH3), d
d,
d
d, 39.77 (eCH2e of
d
,
113e160.84 (12 signals, aromatic carbons, pyrazole carbon and C-3
of pyrazolin),
d
, 167.75 (eCOe). Mass: m/z, 409/411 (Mþ þ 1)/
(Mþ þ 3) (M.F. C22H21ClN4O2).
Compound 3d: R1 ¼3-NO2, R2 ¼ eCH3. M.P. 68e71 ꢀC, Yield:
71.35%. CHN Analysis: Found (Calc): C: 59.38 (59.51), H: 4.34 (4.28),
4.3. Synthesis of 1-acetyl/propyl-5-(5-chloro-3-methyl-1-phenyl-
1H-pyrazol-4-yl)-3-(aryl)-2-pyrazolene 3
N: 16.59 (16.52). IR (KBr): nC]O 1660 cmꢁ1
,
nC]N 1598 cmꢁ1
, 2.09 (s, 3H, CH3), , 2.45 (s,
, 3.35e3.42 (dd, J ¼ 5.2 Hz & 17.5 Hz, 1H, H of
, 3.78e3.85 (dd, J ¼ 12.4 Hz & 17.5 Hz, 1H, H of eCH2e),
, nCeH
2996 cmꢁ1. 1H NMR: 400 MHz, CDCl3:
3H, COeCH3),
eCH2e),
5.67e5.76 (dd, J ¼ 5.2 Hz & 12.4 Hz, 1H, eCHe),
d
d
3-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-(aryl)-2-
propen-1-one 2 (0.1 mol) was dissolved in 15 mL of acetic/pro-
pionic acid. To this reaction mixture hydrazine hydrate (0.1 mol)
was added. The reaction mixture was refluxed to boiling for about
12 h and allowed to cool to room temperature. The cooled reaction
mixture was added to 150 g of crushed ice with vigorous stirring.
The solution was neutralized with saturated sodium bicarbonate
solution and left for 6 h at room temperature. The solid separated
was filtered, washed with water and dried. Further purification was
done by recrystalization from ethanol.
d
d
d,
d, 7.41e8.6 (m, 9H,
AreH). Mass: m/z, 424/426 (Mþ þ 1)/(Mþ þ 3) (M.F. C21H18ClN5O3).
Compound 3e: R1 ¼4-Cl, R2 ¼ eCH3. M.P. 117e120 ꢀC, Yield:
70.24%. CHN Analysis: Found (Calc): C: 61.13 (61.03), H: 4.26 (4.39),
N: 13.63 (13.56) IR (KBr): nCO 1672 cmꢁ1
,
d
nC]N 1600 cmꢁ1
, 2.24 (s, 3H, eCH3),
, 3.23e3.30 (dd, J ¼ 5.52 Hz & 17.88 Hz, 1H,
, 3.75e3.83 (dd, J ¼ 12.5 Hz & 17.88 Hz, 1H, H of
, 5.53e5.58 (dd, J ¼ 5.52 Hz & 12.5 Hz, 1H, eCHe),
7.37e7.85 (m, 9H, AreH). 13C NMR: 400 MHz, DMSO:
, 12.82
(eCH3 of pyrazole), , 21.85 (acyl eCH3), , 39.78 (eCH2e of pyr-
azoline), , 51.20 (eCHe of pyrazoline), , 117.38e152.71 (12
, nCeH
2972 cmꢁ1
2.34 (s, 3H, COeCH3),
H of eCH2e),
eCH2e),
.
1H NMR: 400 MHz, DMSO-d6:
d,
d
d
The spectral and analytical data of the compounds synthesized
according to this procedure are given below.
d
d,
d
Compound 3a: R1 ¼ H, R2 ¼ eCH3, M.P. 55e57 ꢀC, Yield: 78.71%.
d
d
CHN Analysis: Found (Calc): C: 66.82 (66.58), H: 5.13 (5.05), N:
d
d
14.38 (14.79). 1H NMR: 400 MHz, CDCl3:
d
, 2.18 (s, 3H, eCH3),
, 3.02e3.08 (dd, J ¼ 5.3 Hz & 17.6 Hz, 1H, H of
, 3.61e3.70 (dd, J ¼ 12.2 Hz & 17.6 Hz, 1H, H of eCH2e),
d
, 2.27
signals, aromatic carbons, pyrazole carbons and C-3 of pyrazoline),
(s, 3H, COeCH3),
eCH2e),
d
d
, 168.89 (eCOe). Mass: m/z, 413/415/417 (Mþ þ 1)/(Mþ þ 3)/
d
d
,
(Mþ þ 5) (M.F. C21H18Cl2N4O).
5.47e5.55 (dd, J ¼ 5.3 Hz & 12.2 Hz, 1H, H of eCHe),
d
, 6.99e7.55
Compound 3f: R1 ¼4-Br, R2 ¼ eCH3. M.P. 110e115 ꢀC, Yield:
89.5%. CHN Analysis: Found (Calc): C: 55.21 (55.1), H: 4.05 (3.96), N:
(m, 10H, AreH). Mass: m/z, 379/381 (Mþ þ 1)/(Mþ þ 3) (M.F.
C21H19ClN4O).
7.62 (7.75). 1H NMR: 400 MHz, CDCl3:
d
, 2.21 (s, 3H, eCH3),
, 3.20e3.26 (dd, J ¼ 5.6 Hz & 18.0 Hz, 1H, H of
, 3.73e3.8 (dd, J ¼ 12.6 Hz & 18.0 Hz, 1H, H of eCH2e),
, 7.45e7.56 (m,
, 7.59e7.61 (d, J ¼ 8.0 Hz, 2H, ortho protons of p-bro-
d, 2.55 (s,
Compound 3b: R1 ¼4-CH3, R2 ¼ eCH3, M.P. 79e83 ꢀC, Yield:
3H, eCOeCH3),
eCH2e),
d
80.01%. CHN Analysis: Found (Calc): C: 67.19 (67.26), H: 5.46 (5.39),
d
d,
N: 14.33 (14.26). IR (KBr): nC]O 1662 cmꢁ1
,
nC]N 1596 cmꢁ1
, 2.1 (s, 3H, eCH3), , 2.24 (s,
, 2.41 (s, 3H, eCOeCH3), , 3.12e3.18 (dd,
J ¼ 5.6 Hz & 17.7 Hz,1H, H of eCH2e), , 3.68e3.77 (dd, J ¼ 12.5 Hz &
17.7 Hz, 1H, H of eCH2e),
, 5.51e5.60 (dd, J ¼ 5.6 Hz & 12.5 Hz, 1H,
H of eCHe),
,
nCeH
5.41e5.45 (dd, J ¼ 5.6 Hz & 12.6 Hz,1H, H of eCHe),
d
3010 cmꢁ1. 1H NMR: 400 MHz, CDCl3:
3H, eCH3 of p-tolyl),
d
d
5H, AreH), d
d
d
mophenyl),
d
, 7.69e7.71 (d, J ¼ 8.0 Hz, 2H, meta protons of p-bro-
d
mophenyl). Mass: m/z, 457/459/461 (Mþ þ 1)/(Mþ þ 3)/(Mþ þ 5)
(M.F. C21H18BrClN4O).
d
d
, 7.12 (d, 2H, p-tolyl),
d
, 7.41 (d, 2H, p-tolyl),
d
,
Compound 3g: R1 ¼4-NO2, R2 ¼ eCH3. M.P. 81e84 ꢀC, Yield:
7.31e7.61 (m, 5H, AreH). Mass: m/z, 393/395 (Mþ þ 1)/(Mþ þ 3)
(M.F. C22H21ClN4O).
68.4%. CHN Analysis: Found (Calc): C: 59.37 (59.51), H: 4.36 (4.28),
N: 16.55 (16.52). 1H NMR: 400 MHz, DMSO-d6:
d
, 2.26 (s, 3H,
, 3.31e3.37 (dd, J ¼ 5.72 Hz &
, 3.80e3.88 (dd, J ¼ 12.68 Hz &
Compound 3c: R1 ¼4-OCH3, R2 ¼ eCH3. M.P. 62e65 ꢀC, Yield:
87.7%. CHN Analysis: Found (Calc): C: 64.77 (64.62), H: 4.95 (5.18),
eCH3),
d, 2.40 (s, 3H, COeCH3), d
18.04 Hz, 1H, H of eCH2e),
d

K.S. Girisha et al. / European Journal of Medicinal Chemistry 45 (2010) 4640e4644
4643
18.04 Hz, 1H,
12.68 Hz, 1H, eCHe),
H
0f eCH2e),
d
,
5.61e5.65 (dd, J ¼ 5.72 Hz
, 7.97e7.99 (d,
, 8.21e8.24 (d,
&
(dd, J ¼ 5.56 Hz & 12.6 Hz, 1H, eCHe),
d
, 7.45e7.56 (m, 5H, AreH),
d
d
,
,
d, 7.49e7.84 (m, 5H, AreH),
d
7.59e7.61 (d, J ¼ 8.28 Hz, 2H, ortho protons of p-bromophenyl),
J ¼ 8.84 Hz, 2H, ortho protons of p-nitrophenyl),
d
7.69e7.71 (d, J ¼ 8.28 Hz, 2H, meta protons of p-bromophenyl). 13C
J ¼ 8.84 Hz, 2H, meta protons of p-nitrophenyl). 13C NMR:
NMR: 400 MHz, DMSO:
d
, 8.94 (propyl eCH3),
d
, 12.42 (pyrazole
eCH3), , 50.89
(pyrazoline eCHe), d, 117.85e153.29 (12 signals, aromatic carbons,
400 MHz, DMSO:
d
, 12.42 (pyrazole eCH3),
d, 21.59 (acyl eCH3),
d,
,
d, 26.81 (propyleCH2e), d, 38.8 (pyrazoline eCH2e), d
37.00 (pyrazoline eCH2e),
d
,
54.78 (pyrazoline eCHe),
d
117.59e152.58 (12 signals, aromatic carbons, pyrazoline carbons
pyrazole carbons and C-3 of pyrazoline), d,170.79 (eCOe). Mass: m/
and C-3 of pyrazoline),
d
, 167.82 (eCOe). Mass: m/z, 424/426
z, 471/473/475 (Mþ þ 1)/(Mþ þ 3)/(Mþ þ 5) (M.F. C22H20BrClN4O).
Compound 3m: R1 ¼4-NO2, R2 ¼ eCH2CH3. M.P. 72e75 ꢀC,
Yield: 62.86%. CHN Analysis: Found (Calc): C: 60.31 (60.34), H: 4.55
(Mþ þ 1)/(Mþ þ 3) (M.F. C21H18ClN5O3).
Compound 3h: R1 ¼ H, R2 ¼ eCH2CH3. M.P. 40e43 ꢀC, Yield:
87.1%. CHN Analysis: Found (Calc): C: 67.21 (67.26), H: 5.47 (5.39),
(4.60), N: 16.05 (15.99). 1H NMR: 400 MHz, CDCl3:
eCH2eCH3), d, 2.27 (s, 3H, eCH3), d
d
, 1.32 (t, 3H,
, 2.44e2.50 (q, 2H, eCH2eCH3),
, 3.33e3.38 (dd, J ¼ 5.8 Hz & 18.2 Hz, 1H, H of eCH2e), , 3.83e3.91
(dd, J ¼ 12.7 Hz & 5.8 Hz, 1H, H of eCH2e), , 5.62e5.67 (dd,
J ¼ 5.8 Hz & 12.7 Hz, 1H, H of eCHe), , 7.49e7.84 (m, 5H, AreH),
N: 14.3 (14.26). 1H NMR: 400 MHz, CDCl3:
d
,1.20 (t, 3H, eCH2eCH3),
, 2.29 (q, 2H, eCH2eCH3), , 3.04e3.10 (dd,
J ¼ 5.6 Hz & 17.7 Hz,1H, H of eCH2e), , 3.73e3.81 (dd, J ¼ 12.7 Hz &
17.7 Hz, 1H, H of eCH2e),
, 5.50e5.58 (dd, J ¼ 12.7 Hz & 5.6 Hz, 1H,
d, 2.21 (s, 3H, eCH3),
d
d
d
d
d
d
d
d
d
d
,
,
H of eCHe),
d
, 6.98e7.53 (m, 10H, AreH). Mass: m/z, 393/395
7.98e8.002 (d, J ¼ 8.8 Hz, 2H, ortho protons of p-nitrophenyl),
(Mþ þ 1)/(Mþ þ 3) (M.F. C22H21ClN4O).
8.23e8.25 (d, J ¼ 8.8 Hz, 2H, meta protons of p-nitrophenyl). Mass:
Compound 3i: R1 ¼4eCH3, R2 ¼ eCH2CH3. M.P. 65e69 ꢀC, Yield:
55.3%. CHN Analysis: Found (Calc): C: 67.85 (67.89), H: 5.77 (5.70),
m/z, 438/440 (Mþ þ 1)/(Mþ þ 3) (M.F. C22H20ClN5O3).
N: 13.71 (13.77). IR (KBr): nC]O 1658 cmꢁ1
,
nC]N 1593 cmꢁ1
, 1.22 (t, 3H, eCH2eCH3),
, 2.45 (s, 3H, eCH3 of p-tolyl), , 2.83 (q, 2H,
, 3.21e3.37 (dd, J ¼ 17.8 Hz & 5.6 Hz, 1H, H of eCH2e),
, 3.68e3.76 (dd, J ¼ 17.8 Hz & 12.5 Hz, 1H, H of eCH2e),
5.57e5.61 (dd, J ¼ 12.5 Hz & 5.6 Hz, 1H, eCHe proton), , 7.67e7.69
(d, J ¼ 8 Hz, 2H, ortho protons of p-tolyl group), , 7.26e7.28 (d,
J ¼ 8 Hz, 2H, meta protons of p-tolyl group), , 7.36e7.55 (m, 5H,
AreH). 13C NMR: 400 MHz, DMSO:
, 8.96 (eCH3 of propyl), , 12.85
(eCH3 of pyrazole), , 21.54 (eCH3 of p-tolyl), , 27.49 (eCH2e of
propyl), , 39.78 (eCH2e of pyrazoline), , 51.05 (eCHe of pyrazo-
line), , 117.73e153.72 (12 signals, aromatic carbons, pyrazole
, nCeH
4.4. Pharmacological activity
2988 cmꢁ1. 1H NMR: 400 MHz, CDCl3:
2.29 (s, 3H, eCH3),
eCH2eCH3),
d
d,
d
d
4.4.1. Anti-inflammatory activity of the compound 3
d
The healthy albino rats weighing from 150 e 250 g were selected
and kept for 18 h fasting. The animals are weighed and devided into
control, standard and test groups and each group contained six rats.
The rats of the control, standard and test groups were orally treated
with suspension of 0.1 mL of 1% gum acacia (control), 10 mg/kg of
diclofinac sodium (standard) and 10 mg/kg of the test compounds
respectively.
After 30 min of the drug administration, animals are injected
with 0.1 mL of 1% carrageenan in normal saline was injected into the
sub-planter region of the right hind paw of the rats. Paw volumes
was measured immediately (0 h) and after 30 min, 60 min, 90 min,
120 min and 150 min respectively by using plethysmograph.
The experiments were carried out under normal laboratory
conditions. The animals were handled gently to avoid too much of
stress on them which could result in an increased adrenal output.
A mark was made at the lateral maleous of the left hind paw so
that the dipping was done to the same level while measuring the
paw volume.
d
d,
d
d
d
d
d
d
d
d
d
d
carbons and C-3 of pyrazoline), d, 172.35 (eCOe). Mass: m/z, 407/
409 (Mþ þ 1)/(Mþ þ 3) (M.F. C23H23ClN4O).
Compound 3j: R1 ¼4-OCH3, R2 ¼ eCH2CH3. M.P. 48e51 ꢀC, Yield:
77.46%. CHN Analysis: Found (Calc): C: 65.36 (65.32), H: 5.46 (5.48),
N: 13.21 (13.25). IR (KBr): nCO 1682 cmꢁ1
,
nC]N 1595 cmꢁ1
, 1.23 (t, 3H, eCH2eCH3),
, 2.82e2.88 (q, 2H, eCH2eCH3),
, 3.21e3.29 (dd, J ¼ 17.6 Hz & 7 5.5 Hz, 1H, H of eCH2e),
, nCeH
2982 cmꢁ1. 1H NMR: 400 MHz, CDCl3:
2.28 (s, 3H, eCH3),
eOCH3),
d
d
,
,
d
d
, 3.89 (s, 3H,
d
d
3.74e3.83 (dd, J ¼ 17.6 Hz & 12.6 Hz, 1H, H of eCH2e),
d, 5.59e3.67
(dd, J ¼ 12.6 Hz & 5.5 Hz, 1H, eCHe proton),
J ¼ 8.64 Hz, 2H, ortho protons of p-anisyl),
d, 6.96e6.98 (d,
The amount of oedema in the drug treated group was compared
in relation to the control group with corresponding time intervals.
The results were expressed as change in paw volume of oedema
over the untreated control group and were summarized in Table 2.
d
, 7.72e7.74 (d,
J ¼ 8.64 Hz, 2H, meta protons of p-anisyl),
d, 7.36e7.57 (m, 5H,
AreH). Mass: m/z, 423/425 (Mþ þ 1)/(Mþ þ 3) (M.F. C23H23ClN4O2).
Compound 3k: R1 ¼3-NO2, R2 ¼ eCH2CH3. M.P. 112e115 ꢀC,
Yield: 81.68%. CHN Analysis: Found (Calc): C: 60.28 (60.34), H: 4.67
4.4.2. Analgesic activity of compound 3
(4.60), N: 15.91 (15.99). 1H NMR: 400 MHz, DMSO-d6:
d
,1.10e1.19 (t,
, 2.78e2.83 (q, 2H,
, 3.32e3.38 (dd, J ¼ 5.7 Hz & 18.0 Hz, 1H, H of CH2),
, 3.84e3.92 (dd, J ¼ 12.58 Hz & 18.04 Hz, 1H, H of eCH2e),
5.59e5.64 (dd, J ¼ 5.7 Hz & 12.52 Hz, 1H, eCHe), , 7.38e7.52 (m,
5H, AreH), , 7.69e7.74 (t, 1H, 5H of m-nitrophenyl), , 8.15e8.17 (d,
1H, 6H of m-nitrophenyl), , 8.27e8.29 (d, 1H, 4H of m-nitro-
phenyl),
, 8.58 (s, 1H, 2H of m-nitrophenyl). 13C NMR: 400 MHz,
DMSO:
27.50 (eCH2e of propyl group),
51.63 (eCHe of pyrazoline),
The albino rats weighing about 150e200 g were made into
group of six animals and were held in position in a suitable
restrainer with the tail extending out. 3e4 cm area of the tail was
marked and immersed in the water bath thermostatically main-
tained at 55 ꢀC. The withdrawal time of the tail from hot water (in
seconds) was noted as reaction time, initially as tail flick latency
before the administration of any drug and then recorded at 30, 60
and 90 min after the administration of the test compounds and
pentazocin. The maximum cut off time for immersion was 30 s to
avoid the injury of the tissues of the tail. All the drugs are admin-
istered orally in 10 mg/kg body weight in 1% gum acacia. The
control animals received the vehicle only. The results of the anal-
gesic activity were summarized in Table 3.
3H, eCH2eCH3),
eCH2eCH3e),
d, 2.26 (s, 3H, eCH3), d
d
d
d,
d
d
d
d
d
d
, 8.87 (eCH3 of propyl group),
d
,12.79 (eCH3 of pyrazole),
d
d
,
,
d, 39.46 (eCH2e of pyrazoline),
d
, 117.31e151.3 (12 signals, aromatic
, 172.58 (eCOe).
carbons, pyrazole carbons and C-3 of pyrazoline),
d
Mass: m/z, 438/440 (Mþ þ 1)/(Mþ þ 3)(M.F. C22H20ClN5O3).
Compound 3l: R1 ¼4-Br, R2 ¼ eCH2CH3. M.P. 71e74 ꢀC, Yield:
77.68%. CHN Analysis: Found (Calc): C: 56.08 (56.01), H: 4.23 (4.27),
N: 11.85 (11.88). 1H NMR: 400 MHz, DMSO-d6:
d
, 1.07e1.16 (t, 3H,
, 2.71e2.77 (q, 2H, eCH2eCH3e)
, 3.22e3.28 (dd, J ¼ 5.56 Hz & 18.1 Hz, 1H, H of eCH2e),
3.76e3.83 (dd, J ¼ 12.6 Hz & 18.1 Hz, 1H, H of eCH2e), , 5.52e5.57
Acknowledgement
eCH2eCH3), d, 2.22 (s, 3H, eCH3), d
d
d
,
The authors are thankful to Head, SAIF, Punjab University for 1H
NMR, Mass and IR spectra and Department of Chemistry Mangalore
d

4644
K.S. Girisha et al. / European Journal of Medicinal Chemistry 45 (2010) 4640e4644
[8] Albert Levai, Arkivok IX (2005) 344e352.
University for CHN analysis. One of the author GKS is grateful to
UGC New Delhi for the junior research fellowship.
[9] Mohammad Shaharyar, Anees Ahamed Siddique, Mohamed Ashraf Ali,
Dharmarajan Sriram, Perumal Yogeeshwari, Bioorg. Med. Chem. Lett. 16
(2006) 3947e3949.
[10] I.G. Rathish, Kalim Javed, Shamin Ahmad, Sameena Bano, M.S. Alam, K.K. Pillai,
Surender Singh, Vivek Bagchi, Bioorg. Med. Chem. Lett. 19 (2009) 255e258.
[11] Bhaskar S. Bawane, Shankaraiah G. Konda, Gajanana G. Mandwad, Baseer
M. Shaikh, Eur. J. Med. Chem. 45 (2010) 171e178.
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