Transformations of naproxen into pyrazolecarboxamides: Search for potent anti-inflammatory, analgesic and ulcerogenic agents

Article abstract of DOI:10.1007/s00044-013-0650-0

Many derivatives of naproxen containing a variety of pyrazolecarboxamides were synthesized through the reaction of naproxenoyl hydrazide with formylpyrazole, acetylacetone, enaminone, Mannich base, and arylhydrazonomalononitrile derivatives. Also, many derivatives of naproxen were synthesized through the reaction of naprexenoyl chloride with amine derivatives containing pyrazole moiety. The synthesized compounds were screened for anti-inflammatory, analgesic, and ulcerogenic activities. Screening of anti-inflammatory revealed that compound 5 having a 1,3-diphenyl-pyrazol-4-yl moiety had the most promising activity. Compounds 8, 9, and 12, possessing 3,5-dimethyl-pyrazol-1-yl, 3-phenyl-pyrazol-1-yl, and 3,5-diamino-4-(4- methoxyphenylazo)-pyrazol-1-yl groups, respectively, showed moderate activity. Moreover, compounds 8 and 12 showed higher analgesic activity than the reference drug. In ulcerogenic effect, compound 22 which has methoxphenyl pyrazoline moiety devoid of ulcerogenic effect.

Full text of DOI:10.1007/s00044-013-0650-0

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0650-0
ORIGINAL RESEARCH
Transformations of naproxen into pyrazolecarboxamides: search
for potent anti-inflammatory, analgesic and ulcerogenic agents
•
Abdullah G. El-Sehemi Samir Bondock
•
Yousry A. Ammar
Received: 29 January 2013 / Accepted: 25 May 2013
Ó Springer Science+Business Media New York 2013
Abstract Many derivatives of naproxen containing a
variety of pyrazolecarboxamides were synthesized through
the reaction of naproxenoyl hydrazide with formylpyraz-
ole, acetylacetone, enaminone, Mannich base, and arylhy-
drazonomalononitrile derivatives. Also, many derivatives
of naproxen were synthesized through the reaction of
naprexenoyl chloride with amine derivatives containing
pyrazole moiety. The synthesized compounds were
screened for anti-inflammatory, analgesic, and ulcerogenic
activities. Screening of anti-inflammatory revealed that
compound 5 having a 1,3-diphenyl-pyrazol-4-yl moiety
had the most promising activity. Compounds 8, 9, and 12,
possessing 3,5-dimethyl-pyrazol-1-yl, 3-phenyl-pyrazol-1-
yl, and 3,5-diamino-4-(4-methoxyphenylazo)-pyrazol-1-yl
groups, respectively, showed moderate activity. Moreover,
compounds 8 and 12 showed higher analgesic activity than
the reference drug. In ulcerogenic effect, compound 22
which has methoxphenyl pyrazoline moiety devoid of
ulcerogenic effect.
Introduction
Currently available non-steroidal anti-inflammatory drugs
(NSAIDs) like ibuprofen, naproxen, diclofenac, indometh-
acin, and flurbiprofen exhibit gastric toxicity. Long-term use
of these drugs has been associated with gastrointestinal (GI)
ulceration, bleeding, and nephrotoxicity (Kimmey, 1992).
The GI damage from NSAIDs is generally attributed to two
factors, local irritation by the carboxylic acid moiety,
common to most NSAIDs (topical effect) and decreased
tissue prostaglandin production, which undermines the
physiological role of cytoprotective prostaglandins in
maintaining the GI health and homeostasis (Smith et al.,
1998; Hawkey et al., 2000). The pharmacological activity of
NSAIDs is related to the suppression of prostaglandin bio-
synthesis from arachidonic acid by inhibiting cyclooxy-
genases (COXs) (Smith et al., 1998; Warner et al., 1999).
Chronic use of NSAIDs, including ibuprofen, may elicit
appreciable GI toxicity (Lanza, 1998). Naproxen was one of
the leading NSAIDs used for relieving arthritic pain, but its
long-term use invites GI complications ranging from stom-
ach irritation to life threatening GI ulceration and bleeding
(Cash and Klippel, 1994; Davies and Wallace, 1997; Wal-
lace, 1997). These clinical shortcomings comprise a major
challenge confronting medicinal chemists to develop safer
agents that spare COX-1 and subsequently its gastric cyto-
protective role. It was discovered that COXs exist in two
isoforms, COX-1 and COX-2, which are regulated differ-
ently (Marnett and Kalgutkar, 1999; Marnett and Kalgutkar,
1998). COX-1 provides cytoprotection in the gastrointesti-
nal tract whereas inducible COX-2 mediates inflammation
(Almansa et al., 2003). Therefore, synthetic approaches
based upon NSAIDs chemical modification have been
undertaken with the aim of improving the NSAID safety
profile (Farag et al., 2013). Pyrazole derivatives have been
Keywords Naproxen Á Pyrazoles Á Hydrazides Á
Chalcones Á Anti-inflammatory activity
A. G. El-Sehemi Á S. Bondock Á Y. A. Ammar
Chemistry Department, Faculty of Science, King Khalid
University, 9004 Abha, Saudi Arabia
S. Bondock
Chemistry Department, Faculty of Science, Mansoura
University, Mansoura 35516, Egypt
Y. A. Ammar (&)
Chemistry Department, Faculty of Science, Al-Azahr University,
Nasr City, Cairo, Egypt
e-mail: yossry@yahoo.com
123

Med Chem Res
reported to possess significant anti-inflammatory activity
(Sukuroglu et al., 2005; Machado et al., 2007; Mathew et al.,
2011; Youssef et al., 2010; Froravanti et al., 2010). Previous
studies described that the derivatization of the carboxylate
function of representative NSAIDs, resulted in an increased
anti-inflammatory activity with reduced ulcerogenic effect
(Kalgutkar et al., 2000; Duflos et al., 2001).
Results and discussion
Chemistry
The synthesis of the target compounds is depicted in
Schemes 1–3. The starting material 2-(6-methoxy-2-naph-
thyl)propanoic acid hydrazide (3) was prepared in two
consequence steps by esterification of racemic naproxen,
2-(6-methoxy-2-naphthyl)propanoic acid (1), with boiling
ethanol containing a catalytic amount of concentrated
H2SO4 followed by treatment of the resulting ester 2 with
hydrazine hydrate in refluxing absolute ethanol (Amir
et al., 2007). The hydrazide derivatives have proved to be a
good synthons for construction of many biological active
heterocyclic compounds. In fact, some evidences suggest
that the hydrazone moiety possess a pharmacophoric
character for the inhibition of COX (Reitz et al., 1994).
Thus, condensation of the hydrazide 3 with each of
4-formylantipyrine and 1,3-diphenyl-4-formylpyrazole
(Kira et al., 1969) in refluxing ethanol afforded the
respective hydrazone derivatives 4 and 5. The structures of
the latter products were confirmed by spectroscopic studies
and elemental analysis. The IR spectrum of compound 4,
In an attempt to discover new and useful agents for
treating inflammatory diseases, we have replaced the car-
boxylic acid group of naproxen with additional heterocy-
cles, which have been found to possess an interesting
profile of anti-inflammatory activity with significant
reduction of their ulcerogenic effect. Structure modifica-
tions suggested in the present investigation focused mainly
on studying the effect of linking various polysubstituted
pyrazoles. The substitution pattern of the target compounds
includes various functionalities that would act as hydrogen-
bond forming centers, such as the carbonyl, amide, amino,
cyano, hydroxy, and carbethoxy groups. In addition, vari-
ation in the nature and size of other substituents was also
attempted, as it would offer variable electronic, lipophilic,
and steric environment that would influence the targeted
biological activity.
Scheme 1 Synthetic pathways
to compounds 2–7
Me
CO2H
MeO
Me
1
OHC
Me
E OH/H SO
t
N Me
Me
2
4
H
N
N
O
Me
N
Me
Ph
N
N
Ph
O
CO2Et
EtOH/
MeO
MeO
O
4
MeO
Ph
2
OHC
Me
Ph
N2H4.H2O
Me
N
H
N
N
N
N
N
Ph
H
N
Ph
O
NH2
EtOH/
O
5
MeO
Cl
O
3
Me
Cl
HO
Me
N
H
N
Ph
N
N
N
HO
pyridine/
N
Ph
O
MeO
Me
6
-HCl
O
Me
H
N
Ph
N
N
N
O
MeO
Me
7
123

Med Chem Res
Me
Me
156.9, 156.9, and 172.8 ppm due to C=N, OCH2 of furan
ring, and amidic carbonyl carbon, respectively.
O
O
N
Me
Me
Me
N
Next, we focussed our attention to use the hydrazide 3 as
versatile precursor for construction of pyrazole scaffold via
its reaction with acetylacetone, enaminones, Mannich base,
and arylhydrazonomalononitrile. Thus, refluxing of hydra-
zide 3 with acetylacetone in glacial acetic acid afforded 3,5-
dimethylpyrazole derivative 8 in good yield. The structure of
the latter product was assigned by IR spectrum which lacked
absorption bands due to the carbohydrazide moiety CON-
O
MeO
EtOH/AcOH
(8)
Ph
Me
O
N
Ph
N
N
O
AcOH
MeO
(9)
S
N
1
Me
HNH2. Its H-NMR spectrum exhibited four characteristic
S
N
N
singlets at d 2.16, 2.46, 3.86, and 6.16 ppm assigned for two
CH3, OCH3, and pyrazole-H4, respectively. The carbonyl
carbon atom showed a signal at 174.0 ppm in 13C NMR
spectrum.
O
3
O
AcOH
MeO
(10)
O
Reaction of the hydrazide 3 with enaminones, namely,
3-dimethylamino-1-phenyl-propenone and 3-dimethyla-
mino-1-thiophen-2-ylpropenone (Al-Omran et al., 1997) in
boiling glacial acetic afforded, in each case, only one
isolable product that was identified as pyrazole derivatives
9 and 10 based on their microanalysis and spectral data.
The formation of regioisomeric pyrazole products 9 and 10
is in the line with reported results published earlier by
Stanovic and Svete (2004) who stated that selectivity of
reaction of enaminone with hydrazines is acid catalyzed
and controlled by reaction conditions: under mild condi-
tions (20–80 °C), the dimethylamine substitution products
are formed, whereas up on heating at (90–120 °C) further
cyclization takes place to give pyrazoles. Pyrazole deriv-
atives 9 and 10 based on their microanalysis and spectral
data. The structure of 9, as representative example, was
Me
Ph
N
HCl
N
Ph
N
O
MeO
EtOH/AcOH
(11)
Ar
N
N
H2N
Me
CN
CN
Ar NH
EtOH/
N
N
NH2
N
O
MeO
Ar = 4-MeO-C6H4-
(12)
Scheme 2 Synthetic pathways to compounds 8–12
for example, revealed absorption bands at 3352, 1670, and
1656 cm-1 corresponding to an NH and two amidic car-
1
bonyl groups. Its H-NMR spectrum revealed, besides the
1
expected naproxen signals, four new singlets at d 2.56,
3.22, 8.01, and 10.99 ppm attributed to CH3, –NCH3,
–N=CH, and –NH protons, respectively. The 13C NMR
spectrum revealed 26 carbon types, the most important
signals being displayed at 156.7, 171.9, and 176.7 ppm
characteristic for the azomethine carbon and two amidic
carbonyl carbons.
substantiated by the H-NMR spectrum which displayed
new pair of doublets at d 7.12 and 7.77 ppm with coupling
constant (J = 7.5 Hz) corresponding to pyrazole protons at
positions 4 and 5, respectively. The formation of com-
pounds 9 and 10 may be rationalized via initial addition of
the amino group in hydrazide 3 to the enaminone double
bond, followed by elimination of dimethylamine molecule
as depicted in Scheme 2.
In addition, cyclocondensation of the hydrazide 3 with
2-chloro-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (Jensen, 1959) in refluxing pyridine gave the non-
isolable hydrazone 6 which in situ underwent cyclization
through elimination of HCl molecule to give N-[1-(3-
methyl-1-phenyl-1H-furo[2,3-c]pyrazol-4-ylidene)-2-(6-
methoxynaphthalen-2-yl)propionylhydrazide (7). The IR
spectrum of compound 7 showed absorption bands at 3214
and 1659 cm-1 due to an NH and amidic carbonyl group.
Its 1H-NMR spectrum exhibited four characteristic singlets
at d 2.20, 3.86, 5.94, and 9.29 ppm which were assigned to
CH3, OCH3, OCH2 of furan ring, and NH protons,
respectively. Moreover, its 13C NMR spectrum showed 26
carbon types, the most important signals appeared at d
Moreover, the reaction of hydrazide 3 with Mannich base,
namely, 3-dimethylamino-1-phenylpropan-1-one hydrochlo-
ride (Blicke and Burckhalter, 1942) in warming ethanol
containing a catalytic amount of acetic acid gave only a sole
product that was identified as 2-(6-methoxynaphthalen-2-yl)-
1-(5-phenyl-2,3-dihydropyrazol-1-yl)propan-1-one (11). The
structure of product 11 was deduced from its elemental
1
analysis and spectral data. The H-NMR spectrum showed
two triplets at d 1.94 and 4.80 ppm due to H-3 and H-4 of
pyrazoline ring. Its 13C NMR spectrum showed the presence
of 22 carbon types. Furthermore, 1-[3,5-diamino-4-(4-meth-
oxyphenylazo)-pyrazol-1-yl]-2-(6-methoxynaphthalen-2-yl)
propan-1-one (12) was obtained through the reaction of the
123

Med Chem Res
Scheme 3 Synthesis of
pyrazolecarboxamides 14–23
Me
Me
H
N
Me
N
N
O
MeO
O
Ph
14
H2N
Me
N
Me
pyridine
dioxane
N
NH2
N
O
Me
Ar
H
N
Ph
Me
N
N
N
NH
N
H
O
Cl
H2N
Pyridine /dioxane
MeO
N
SOCl2
NH2
1
15
O
N
Toluene
MeO
Ar
NH2
Me
Ar = 4-MeO-C6H4-
13
S
N
NH
e
n
a
NH2
Py
r
i
d
Me
x
i
n
Me
H
o
e
i
/
d
d
i
o
/
N
x
a
e
n
e
n
i
O
S
d
COCH3
i
r
MeO
y
P
Me
Me
16
N
NH
Me
H
Me
N
H
N
ArCHO
KOH / EtOH
O
MeO
COCH3
O
O
MeO
17
18-20
Me
Ar
H
N
18, Ar=Ph
N2H4.H2O / EtOH
19,Ar=4-MeO-C6H4-
O
20,Ar=3-methylthienyl
N
MeO
NH
21-23
21, Ar=Ph
22,Ar=4-MeO-C6H4-
23,Ar=3-methylthienyl
Ar
hydrazide 3 with 2-[(4-methoxyphenyl)hydrazono] malono-
nitrile in ethanol under reflux condition.
3.34, and 10.00 ppm attributed to CH3, NCH3, and amidic
NH proton, respectively.
Structure modifications of the carboxylic group in
naproxen was also extended to attain pyrazolecarboxa-
mides through another synthetic route. Thus, interaction of
the naproxenoyl chloride (13) (Al-Sehemi et al. 2006),
obtained by refluxing of 1 with thionyl chloride in toluene,
with each of 4-aminoantipyrine, 4-arylazo-3,5-dimethyl-
pyrazole (Tsai and Wang, 2005), and 2-(3,5-dimethyl-1H-
pyrazol-4-ylthio)aniline (Steiner et al., 1993) in refluxing
dioxane containing a catalytic amount of pyridine fur-
nished the respective pyrazolecarboxamides 14–16 as
outlined in Scheme 3.
In a similar manner, reaction of 13 with p-aminoaceto-
phenone under the same experimental condition afforded
N-(4-acetylphenyl)-2-(6-methoxynaphthalen-2-yl)propana-
mide (17). The presence of acetyl group in 17 makes it ver-
satile precursor for the synthesis of pyrazoline derivatives.
Thus, the Claisen–Schmidt condensation of 17 with aromatic
aldehydes, namely, benzaldehyde, p-anisaldehyde, and
3-methylthiophene-2-carboxaldehyde in ethanolic potas-
sium hydroxide furnished the chalcone derivatives 18–20.
The structure of the latter products were confirmed by IR
spectra which showed the characteristic band for conjugated
1
The structure of compounds 14–16 were elucidated
based on their microanalyses and spectral data. The IR
spectrum of compound 14, for example, showed strong
absorption bands at 3218, 1678, and 1660 cm-1 due to an
NH, amidic C=O, and pyrazole C=O groups, respectively.
C=O at 1639–1654 cm-1 and their H-NMR spectra dis-
played a pair of doublets at d 7.58–7.68 and 7.79–7.89 ppm,
with coupling constant value (J = 14.8–15.6 Hz), due to the
trans-olefinic protons. Cyclocondensation of chalcones
18–20 with hydrazine hydrate in boiling ethanol furnished
the respective pyrazolines 21–23. The structures of the latter
1
Its H-NMR spectrum revealed three singlets at d 1.91,
123

Med Chem Res
products were established by IR spectra which showed dis-
appearance of C=O band of chalcones. A strong band
appeared at 1589–1608 cm-1 assigned to C=N of pyrazoline
ring. Compounds 21–23 showed an additional sharp band in
the region 3325–3395 cm-1 due to the NH stretching. Their
1H-NMR spectra revealed, in each case, the signals of CH2
protons of the pyrazoline ring in the region 3.32–3.39 and
3.60–3.75 ppm as a pair of doublets. The CH proton
appeared as double of doublets at 4.80–5.08 ppm. The 13C
NMR spectrum of compound 21, as a representative exam-
ple, displayed, besides the expected signals, three charac-
teristic signals at d 38.9, 63.5, and 161.8 ppm due to the
carbons of CH2, CH, and C=N of pyrazoline ring,
respectively.
as a reference standard. Results were expressed as
mean SE. Difference between vehicle control and
treatment groups was tested using one way ANOVA fol-
lowed by the least significant difference (LSD). Methods of
statistical analysis were done according to Armitage
(1971). According to Table 1, administration of many of
tested compounds 60 min prior to carrageenan injection at
dose of 10 mg/kg wt caused significant inhibition of paw
edema response.
The mean values of the inhibition of paw edema
response obtained for these compounds suggest that,
compounds 4, 5, 8, 9, 14, 21, 22, and 23 have good anti-
inflammatory activity and compound 5 was the most potent
derivative. Using the general structure provided in Fig. 1,
certain aspects of the structure activity relationships for
these compounds can be more clearly highlighted.
Biological evaluation
Compounds 4, 5, and 7, X was NH–N side chain ending
with substituted pyrazole (4; antipyrine, 5; 1,3-diphenyl-
pyrazol-4-yl, 7; furopyrazol-4-yl): the presence of 1,3-
diphenyl-pyrazol-4-yl moiety (5) resulted in the highest
anti-inflammatory activity among all the compounds
investigated in this study. The presence of 1,3-diphenyl-
pyrazol-4-yl moiety showed activity near to the references
drug. Replacement 1,3-diphenyl-pyrazol-4-yl moiety by
Anti-inflammatory activity possessed by NSAIDs is cred-
ited to the presence of carboxylic acid moiety which is
crucial for binding to COX-1 and COX-2. But this inhi-
bition is associated with GI and renal toxicities which
limits the use of NSAIDs. Thus, the biological evaluation is
done with the aim of retention in activity and reduction in
GI toxicity (Piazza et al., 2009).
Anti-inflammatory activity
Me
X
The anti-inflammatory activity of 12 of the newly synthe-
sized compounds: 4, 5, 7, 8, 9, 12, 14, 15, 19, 21, 22, and
23 were evaluated by applying carrageenan-induced paw
edema bioassay in rats (Winter et al., 1962) using naproxen
O
MeO
Fig. 1 General formula of the synthesized compounds
Table 1 Anti-inflammatory activity, analgesic activity, and ulcerogenic effect of the tested compounds assessed in comparison to naproxen as
reference
Compound Edema volume (mL)
nos.
Reaction time (sec)
Basal 1 h
Ulcer index
No. of
ulcer
rats/5
1 h
2 h
3 h
4 h
2 h
No. of
ulcer
Severity
Control
57.2 6.8 94.3 8.5 100.2 3.3 92.2 3.3 12.1 0.63 12.2 0.83 12.3 1.18 8.3 0.86 19.5 2.2
49.8 2.5 88.6 6.1 83.6 3.7 73.5 2.3 9.7 1.11 17.2 1.52 17.1 1.25 –
56.1 9.9 65.2 7.5 55.8 10.6 54.6 7.2 12.6 1.13 21.1 2.47 18.4 0.69 0.4 0.4 0.4 0.40
72.3 4.9 88.1 9.5 88.6 6.5 90.8 5.4 11.9 0.82 13.6 0.75 11.6 0.85 –
60.5 7.1 74.2 5.4 80.2 6.0 77.9 5.5 10.8 1.03 19.7 1.59 21.5 1.54 0.4 0.4 0.6 0.6
5
–
1
–
1
4
–
5
7
–
8
9
57.8 7.2 65.3 8.8 66.5 6.9 68.7 6.3 13.1 0.85 24.2 1.65 17.9 2.64 7.0 1.64 10.5 2.86 5
12
14
15
19
21
22
23
65.2 7.2 82.2 6.9 83.9 2.3 79.3 7.3 12.8 0.95 15.1 1.02 20.6 1.19 –
–
–
2
–
–
–
85.4 3.1 74.5 7.5 88.1 7.2 89.8 2.1 9.4 0.94 17.2 1.66 18.1 1.23 2.7 1.66 3.2 1.96
52.1 3.8 79.1 6.9 82.6 8.0 91.5 5.8 10.2 1.03 14.5 0.93 18.5 1.47 –
60.5 6.8 93.7 5.2 94.7 02 78.1 5.5 9.6 0.49 17.1 1.89 9.33 0.89 –
44.3 5.1 59.7 4.7 67.9 3.3 81.8 3.2 9.6 0.68 17.6 1.33 17.3 1.11 –
–
–
–
49.4 7.1 71.9 6.7 76.5 4.8 82.4 5.2 11.1 0.91 19.2 1.46 19.3 1.00 0.0 0.0 0.00 0.00 0
61.1 6.6 66.7 5.9 68.6 7.0 72.4 7.4 15.1 1.34 24.8 1.38 19.3 0.61 1.7 1.36 2.0 1.76
2
5
Naproxen 49.9 5.3 42.8 5.1 45.8 4.6 46.8 5.8 13.2 0.78 17.7 0.32 18.3 0.28 5.9 1.77 9.9 3.23
123

Med Chem Res
antipyrine moiety do not improve the anti-inflammatory
activity; compound 4 showed moderate activity. Further
introduction of furopyrazol-4-yl, as in 7 had a detrimental
effect on anti-inflammatory activity, compound 7 showed
weak anti-inflammatory activity. Compounds 8, 9, and 12,
the X was substituted pyrazole moiety; (8; 3,5-dimethyl-
pyrazol-1-yl, 9; 3-phenyl-pyrazol-1-yl, 12; 3,5-diamino-4-
(4-methoxyphenylazo)-pyrazol-1-yl): also, the presence of
phenyl-pyrazol-4-yl moiety (9) resulted in the highest anti-
inflammatory activity among this group. While, when
methyl moiety (8) or arylazo moiety and amino group (12)
were attached the pyrazole system caused lower potency.
Compounds 14 and 15, X was NH-pyrazole derivatives. In
general, treatment of 13 with aminopyrazole derivatives
proved to be detrimental to anti-inflammatory activity.
Compound 19 with chalcone moiety resulted in the lowest
anti-inflammatory activity among all the compounds
investigated in this study. Transformation of chalcone 19 to
dihydropyrazole 21–23 recorded better anti-inflammatory
activity with superior of compound 23 due to the presence
of thienyl moiety in position 3.
base line of the same group 1 and 2 h post administration.
Thus, it can be concluded that, compounds 4, 5, 8, 9, 12,
14, 15, 19, 21, 22, and 23 have significant analgesic
activity and compound 23 is the most potent one. Intro-
duction of dimethylpyrazole and diaminopyrazole moiety
to naproxen via carboxamide linkage in compounds 8 and
12 increased the analgesic activity more than naproxen.
Compounds 5, 14, 15, 22, and 23 which have diph-
enylpyrazole, antipyrine, aminopyrazole, and pyrazoline
moieties showed equipotent analgesic effect compared the
reference drug naproxen.
Ulcerogenic effect
The ulcerogenic effect of the most active anti-inflammatory
and analgesic derivatives: 5, 8, 9, 14, 22, and 23 was
evaluated (Woolfe and MacDonald, 1944). According to
Table 1, it has been found that compounds 5, 8, 14, and 23
have very little ulcerogenic effect with better safety margin
in comparison to naproxen. Interestingly, compound 22
exhibited no ulcerogenic effect in all of the experimental
animals. On the other hand, compound 9 resulted in ulcer
lesions in many of the experimental rats. Therefore, the
potential medicinal value of these compounds as anti-
inflammatory and analgesic agents that they have better
safety margin than naproxen on gastric mucosa. In ulcero-
genic effect compound 22 which has methoxphenyl pyr-
azoline moiety devoid of ulcerogenic effect.
As brief, compounds 5, 8, 9, and 23 caused significant
decrease in paw oedeama after 2, 3, and 4 h after drug
administration, while 21 and 22 gave their response after
2 h of administration and continued to the third hour.
Compound 14 showed the effect only after 2 h but com-
pound 4 significantly decreased the paw edema after 4 h
post administration. On the other hand, compounds 7, 12,
15, and 19 were inactive toward carrageenan-induced
edema in comparison to the standard reference naproxen
which markedly and significantly inhibited the paw edema
after 2, 3, and 4 h of carrageenan injection.
Conclusion
The present work aims to couple naproxen with a series of
functionalized pyrazoles through a carboxamide linkage to
achieve the synergistic effect and reducing the gastrointes-
tinal toxicity associated with naproxen. It is found to be the
appropriate method for increasing therapeutic effectiveness
of naproxen with safer pyrazole promoieties. The studies
showed that most of the synthesized pyrazolecarboxamides
can be successfully applied in attaining the goal of mini-
mized gastrointestinal toxicity with retention of desired anti-
inflammatory activity. Coupling of naproxen with pyrazoles
through a carboxamide linkage gives an opportunity in
medicinal chemistry to improve the clinical and therapeutic
effectiveness of a drug that is suffering from some undesir-
able properties hindering its clinical usefulness.
Analgesic activity
The analgesic activity of the above mentioned 12 deriva-
tives was also evaluated by applying hot-plate test (Woolfe
and MacDonald, 1944) using naproxen as a standard ref-
erence. Results were expressed as mean SE. Difference
between vehicle control and treatment groups was tested
using one-way ANOVA followed by the LSD. Methods of
statistical analysis were done according to Armitage
(1971). The results reported in Table 1 revealed that,
compounds 5, 8, 9, 22, and 23 showed significant analgesic
activity higher than that obtained by naproxen 1 and 2 h
post administration. While compounds 4, 14, and 21
exhibited equipotent analgesic effect or slightly less than
that of naproxen after 1 and 2 h of their administration.
Compounds 15 and 12 exhibited significant analgesic
activity higher than or slightly equipotent to naproxen only
after 2 h of administration. Compound 19 exhibited the
analgesic effect after 1 h of administration only. Com-
pound 7 have no analgesic activity in comparison to the
Experimental
Melting points were determined on a digital Gallen-Kamp
MFB-595 instrument and are uncorrected. IR spectra (KBr)
were measured on a Shimadzu 440 spectrometer. 1H-NMR
123

Med Chem Res
and 13C spectra were recorded in DMSO-d6 on a Brucker
(500 MHz) spectrometer using TMS as an internal stan-
dard; chemical shifts are reported as dppm units. Mass
spectra were performed on a Shimadzu GSMS-QP 1000 Ex
mass spectrometer at 70 eV. The elemental analyses were
carried out at the Microanalytical Center, Cairo University,
Cairo, Egypt.
156.8, 156.9, 169.3, 174.6; Anal. Calcd for C30H26N4O2
(474.55): C, 75.93; H, 5.52; N, 11.81. Found: C, 75.85; H,
5.64; N, 11.76 %.
Synthesis of N-[1-(3-methyl-1-phenyl-1H-furo[2,3-
c]pyrazol-4-ylidene)-2-(6-methoxynaphthalen-2-
yl)propionyl hydrazide (7)
General procedure for the condensation
A mixture of the hydrazide 3 (2.44 g, 0.01 mol) and
2-chloro-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)
ethanone (2.5 g, 0.01 mol) in pyridine (30 mL) was
refluxed for 6 h, and then allowed to cool and poured into
ice cold water (100 mL) containing few drops of dilute
HCl. The precipitated solid was filtered off, dried, and
recrystallized from ethanol to give compound 7.
of the hydrazide 3 with heterocyclic aldehydes
To a solution of the hydrazide 3 (2.44 g, 0.01 mol) in
ethanol (30 mL), each of 1,3-dimethyl-1H-pyrazole-4-car-
boxaldehyde (2.48 g, 0.01 mol) and 1,5-dimethyl-3-oxo-2-
phenyl-2,3-dihydro-1H-pyrazol-4-carboxaldehyde (2.16 g,
0.01 mol) was added and the reaction mixture was refluxed
for 3 h. The solid obtained upon cooling was collected by
filtration, dried, and recrystallized from the ethanol.
Pale yellow powder, Yield (70 %), mp 287–288 °C; IR
(KBr) mmax/cm-1 : 3214 (NH), 3053 (CH–Ar), 2961–2934
(CH-sp3), 1659 (C=O), 1607 (C=N); 1H-NMR (DMSO-d6):
dppm = 1.35 (d, J = 6.5 Hz, 3H, CH3), 2.20 (s, 3H, CH3),
3.86 (s, 3H, OCH3), 4.0 (q, J = 6.5 Hz, 1H, CH), 5.94 (s,
2H, CH2), 7.13–7.78 (m, 11H, Ar–H), 9.29 (s, 1H, NH).
13C-NMR (DMSO-d6): dppm = 13.9, 18.4 (2CH3), 44.3
(CH), 55.1 (OCH3), 60.1 (OCH2 of furan ring), 105.6,
117.2, 118.5, 118.6, 125.2, 125.3, 125.5, 126.1, 126.4,
126.4, 126.9, 126.9, 128.1, 128.2, 128.3, 128.9, 129.1,
133.1, 133.2, 137.0, 156.8, 156.9, 172.8. Anal. Calcd for
C26H24N4O3 (440.49): C, 70.89; H, 5.49; N, 12.72. Found:
C, 70.74; H, 5.35; N, 12.81 %.
N-[(1E)-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-yl)methylene]-2-(6-methoxy)-2-naphthyl)-
propionylhydrazide (4)
Colorless powder, Yield (74 %), mp 213–215 °C; IR (KBr)
mmax/cm-1: 3352 (NH), 2969, 2935 (CH-sp3), 1670, 1656
(2C=O), 1604 (C=N); 1H-NMR (DMSO-d6): dppm = 1.43(d,
J = 6.5 Hz, 3H, CH3), 2.56 (s, 3H, CH3), 3.22 (s, 3H,
N–CH3), 3.62 (q, J = 6.5 Mz, 1H, CH), 3.86 (s, 3H, OCH3),
7.12–7.81 (m, 11H, Ar–H), 8.01 (s, 1H, N=CH), 10.99 (bs,
1H, NH); 13C-NMR (DMSO-d6): dppm = 12.12 (CH3),
18.74 (CH3), 40.1(CH), 45.9 (N–CH3), 55.1 (OCH3), 105.6
(C-5), 118.3 (C-7), 124.1 (C-4), 125.5 (C-8a), 126.31, 127.5,
128.4, 129.3, 130.3, 132.9, 133.9, 135.6, 136.5, 137.4, 137.7,
139.0, 141.9, 145.3, 156.7, 171.9, 176.7. MS (EI, 70 eV): m/z
(%) = 442 (M?, 10.2), 285 (44.9), 256 (60.5), 229 (67.5),
228 (35.4), 214 (100), 187 (63.5), 91 (50.6), 77 (55.3). Anal.
Calcd for C26H26N4O3 (442.51): C, 70.57; H, 5.92; N, 12.66.
Found: C, 70.43; H, 5.84; N, 12.71 %.
Synthesis of 1-(3,5-dimethyl-pyrazol-1-yl)-2-(6-
methoxynaphthalen-2-yl)propan-1-one (8)
To a solution of hydrazide 3 (2.44 g, 0.01 mol) in ethanol
(30 mL), acetyl acetone (1.3 g, 0.01 mol) and glacial
acetic acid (0.5 mL) were added. The reaction mixture was
heated under reflux for 8 h, then allowed to cool to room
temperature. The solid product thus formed was filtered
off, dried, and recrystallized from ethanol to give com-
pound 8. Colorless powder, Yield (65 %), mp 210–211 °C,
IR (KBr) mmax/cm-1: 3045 (CH–Ar), 2976–2948 (CH-
sp3), 1669 (C=O), 1599 (C=N); 1H-NMR (DMSO-d6):
dppm = 1.44 (d, J = 6.5 Hz, 3H, CH3), 2.16, 2.46 (2s, 6H,
2CH3-pyrazole), 3.85 (q, 1H, CH), 3.86 (s, 3H, OCH3),
6.16 (s, 1H, pyrazole-C4), 7.13–7.81 (m, 6H, Ar–H); 13C-
NMR (DMSO-d6): dppm = 13.4, 13.9, 18.4 (3CH3), 44.3
(CH), 55.1 (OCH3), 105.6, 111.5, 118.6, 125.5, 126.3,
126.8, 129.0, 133.1, 135.6, 136.2, 143.5, 151.3, 157.0,
174.0. MS (EI, 70 eV): m/z (%) = 308 (M?, 17.2), 214
(86.5), 213 (100), 185 (32.8), 157 (21.8), 128 (37.5), 96
(55.9). Anal. Calcd for C19H20N2O2 (308.37): C, 74.00; H,
6.54; N, 9.08. Found: C, 74.12; H, 6.68; N, 9.15 %.
N-[(1E)-(1,3-diphenyl-1H-pyrazol-4-yl)methylene]-2-(6-
methoxy-2-naphthyl)propionyl hydrazide (5)
Colorless powder, Yield (65 %), mp 195–196 °C; IR (KBr)
mmax/cm-1
:
3191(NH), 3052 (CH–Ar), 2969–2934
(CH-sp3), 1655 (C=O), 1602 (C=N); 1H-NMR (DMSO-d6):
dppm = 1.48 (d, J = 6.5 Hz, 3H, CH3), 3.84 (s, 3H, OCH3),
4.1 (q, J = 6.5 Hz, 1H, CH), 7.24–8.77 (m, 16H, Ar–H),
8.29 (s, 1H, Pyrazol-H5), 8.95(s, 1H, CH=N), 11.12 (bs, 1H,
NH); 13C-NMR (DMSO-d6): dppm = 18.2 (CH3), 43.9 (CH),
55.9 (OCH3), 105.6, 116.6, 116.9, 118.6, 118.7, 125.3,
125.7, 126.2, 126.9, 127.6, 128.3, 128.6, 128.9, 129.5, 131.9,
132.3, 133.2, 135.5, 136.4, 136.9, 138.9, 139.5, 151.7, 151.1,
123

Med Chem Res
254–255 °C; IR (KBr) mmax/cm-1
:
3035 (CH–Ar),
General procedure for the reaction of the hydrazide 3
with enaminones
2974–2946 (CH-sp3), 1663 (C=O), 1611 (C=N); H-NMR
(DMSO-d6): dppm = 1.44 (d, J = 6.5 Hz, 3H, CH3), 1.94
(s, 2H, CH2-pyrazoline), 3.83 (q, J = 6.5 Hz, 1H, CH),
3.86 (s, 3H, OCH3), 4.8 (s, 2H, CH2-pyrazoline), 7.12–7.79
(m, 11H, Ar–H), 8.9 (s, 1H, NH). 13C-NMR (DMSO-d6):
dppm = 18.0 (CH3), 35.8, 42.7 (CH), 55.0 (OCH3), 60.2,
105.6, 118.5, 125.5, 126.1, 126.6, 127.5, 127.9, 128.1,
128.3, 128.5, 128.6, 128.6, 129.1, 132.9, 136.5, 137.3,
156.8, 172.3; Anal. Calcd for C23H22N2O2 (358.43): C,
77.07; H, 6.19; N, 7.82. Found: C, 77.11; H, 6.24; N,
7.72 %.
1
To a solution of the enaminone derivatives (0.001 mol) in
glacial acetic acid (10 mL), the hydrazide 3 (0.244 g,
0.001 mol) was added, and the reaction mixture was heated
under reflux for 8 h. The reaction mixture was allowed to
cool and then treated with ice cold water (30 mL) and the
formed product was collected by filtration, dried, and re-
crystallized from ethanol.
2-(6-Methoxynaphthalen-2-yl)-1-(5-phenyl-pyrazol-1-
yl)propan-1-one (9)
Synthesis of 1-[3,5-diamino-4-(4-methoxyphenylazo)-
pyrazol-1-yl]-2-(6-methoxynaphthalen-2-yl) propan-
1-one (12)
Colorless powder, Yield (76 %), mp 187–188 °C; IR (KBr)
mmax/cm-1: 3065 (CH–Ar), 2978–2942 (CH-sp3), 1667
(C=O), 1597 (C=N); H-NMR (DMSO-d6): dppm = 1.43
1
(d, J = 6.5 Hz, 3H, CH3), 3.77 (q, J = 6.5 Hz, 1H, CH),
3.86 (s, 3H, OCH3), 7.12–7.77 (2d, J = 7.5 Hz, 2H, H4,
H5-pyrazole),7.14–7.76 (m, 11H, Ar–H); 13C-NMR
(DMSO-d6): dppm = 18.1, (CH3), 42.7 (CH), 55.0 (OCH3),
105.5, 118.3, 125.0, 125.3, 125.9, 126.4, 126.5, 126.6,
127.3, 127.8, 128.2, 128.6, 128.9, 129.9, 133.1, 136.5,
136.5, 156.9, 172.1, 172.3; Anal. Calcd for C23H20N2O2
(356.42): C, 77.61; H, 5.66; N, 7.86. Found: C, 77.62; H,
6.58; N, 7.75 %.
To a solution of the hydrazide 3 (0.244 g, 0.001 mol) in
ethanol (20 mL), 2-[(4-methoxyphenyl)hydrazono]malon-
onitrile was added. The reaction mixture was refluxed for
6 h. After cooling to room temperature, the formed product
was filtered off and recrystallized from ethanol. Greenish
powder, Yield (78 %), mp 243–245 °C; IR (KBr) mmax/cm-1
:
3342, 3245 (NH2), 3064 (CH–Ar), 2979–2921 (CH-sp3),
1685 (C=O), 1609 (C=N); 1H-NMR (DMSO-d6):
dppm = 1.43 (d, J = 6.5 Hz, 3H, CH3), 3.75, 3.80 (2s, 6H,
2OCH3), 3.86 (q, J = 6.5 Hz, 1H, CH), 6.31, 8.22 (2s, 4H,
2NH2), 6.98–7.81 (m, 10H, Ar–H); 13C-NMR (DMSO-d6):
dppm = 18.2, (CH3), 42.2 (CH), 55.0, 55.2 (2OCH3), 105.5,
114.4, 118.4, 118.6, 122.5, 125.3, 125.7, 126.3, 126.7, 128.2,
128.6, 128.9, 129.1, 132.9, 133.1, 136.7, 156.9, 157.1, 157.2,
172.3; Anal. Calcd for C24H24N6O3 (444.49): C, 64.85; H,
5.44; N, 18.91. Found: C, 64.73; H, 5.30; N, 18.86 %.
2-(6-Methoxynaphthalen-2-yl)-1-(5-thiophen-2-ylpyrazol-
1-yl)propan-1-one (10)
Pale yellow powder, Yield (73 %), mp 218–219 °C; IR (KBr)
mmax/cm-1: 3063 (CH–Ar), 2973–2935 (CH-sp3), 1674
(C=O), 1612 (C=N); 1H-NMR (DMSO-d6): dppm = 1.42 (d,
J = 6.5 Hz, 3H, CH3), 3.85 (s, 3H, OCH3), 4.0 (q,
J = 6.5 Hz, 1H, CH), 7.12–8.99 (m, 11H, Ar–H); 13C-NMR
(DMSO-d6): dppm = 18.2, (CH3), 42.9 (CH), 55.0 (OCH3),
105.6, 118.3, 124.1, 125.5, 126.5, 127.2, 128.5, 129.0, 130.4,
133.9, 136.5, 137.71, 139.0, 141.9, 145.3, 156.7, 156.9, 172.2.
MS (EI, 70 eV): m/z (%) = 362 (M?, 22.8), 280 (65.2), 279
(60.2), 214 (100), 213 (85.9), 150 (32.8), 128 (26.2), 84(55.1),
77 (72.2). Anal. Calcd for C21H18N2O2S (362.44): C, 69.59;
H, 5.01; N, 7.73. Found: C, 69.68; H, 5.28; N, 7.69 %.
General procedure for the condensation of naproxenoyl
chloride with aminopyrazoles
A mixture of naproxenoyl chloride (0.248 g, 0.001 mol) and
the requisite aminopyrazoles, namely, 4-amino-1,5-dimethyl-
2-phenyl-1,2-dihydropyrazol-3-one (0.2 g, 0.001 mol), 3,5-
diamino-4-(4-methoxyphenylazo)-1H-pyrazole
(0.232 g,
0.001 mol), or 2-(3,5-dimethyl-1H-pyrazol-4-ylsulfanyl)-
phenylamine (0.219 g, 0.001 mol) in dioxane (20 mL) was
treated with pyridine (0.5 mL). The reaction mixture was
refluxed for 3 h, then allowed to cool. The solid product was
collected by filtration and recrystallized from ethanol to give
compounds 14–16.
Synthesis of 2-(6-methoxynaphthalen-2-yl)-1-(5-phenyl-
2,3-dihydropyrazol-1-yl)propan-1-one (11)
A mixture of the hydrazide 3 (0.244 g, 0.001 mol) and
3-dimethylamino-1-phenylpropan-1-one hydrochloride
(0.213 g, 0.001 mol) in ethanol 20 mL containing 5 mL of
acetic acid was refluxed for 8 h. The reaction mixture was
cooled, treated with ice cooled water (30 mL) and the
formed product was filtered off, dried, and recrystallized
from ethanol. Colorless powder, Yield (76 %), mp
N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-
4-yl)-2-(6-methoxynaphthalen-2-yl)propionamide (14)
Colorless powder, Yield (65 %), mp 184–186 °C; IR
(KBr) mmax/cm-1: 3218 (NH), 3039 (CH–Ar), 2979,
123

Med Chem Res
2932 (CH-sp3), 1678 (C=O), 1660 (pyrazole C=O),
1601 (C=N); 1H-NMR (DMSO-d6): dppm = 1.56 (d,
J = 6.5 Hz, 3H, CH3), 1.91, 3.34 (2s, 6H, 2CH3-pyra-
zole), 3.84 (s, 3H, OCH3), 3.90 (q, 1H, CH), 7.25–8.89
(m, 11H, Ar–H), 10.0 (s, 1H, NH).13C-NMR (DMSO-
d6): dppm = 18.5, 21.0 (2 CH3), 40.1 (NCH3), 45.97
(CH), 55.1 (OCH3), 105.6, 118.5, 124.1, 125.4, 125.5,
126.3, 127.5, 128.5, 129.3, 130.2, 132.9, 133.9, 135.6,
137.7, 139.0, 141.9, 145.7, 156.9, 171.9, 182.1. MS (EI,
70 eV): m/z (%) = 415 (M?, 9.8), 258 (35.4), 230
(38.6), 203 (100), 202 (82.9), 188 (51.7), 157 (66.1), 77
(69.1). Anal. Calcd for C25H25N3O3 (415.48): C, 72.27;
H, 6.06; N, 10.11. Found: C, 72.30; H, 6.19; N,
10.28 %.
(30 mL) containing 0.5 mL of pyridine was refluxed for
3 h, then allowed to cool. The solid product that obtained
was collected by filtration, dried, and recrystallized from
ethanol to give compound 17. Pale yellow powder, Yield
(70 %), mp 168–170 °C, IR(KBr) mmax/cm-1: 3332 (NH),
2928 (CH-sp3), 1672 (C=O). 1H-NMR (DMSO-d6):
dppm = 1.52 (d, J = 6.5 Hz, 3H, CH3), 2.51 (s, 3H,
COCH3), 3.86 (s, 3H, OCH3), 4.00 (q, J = 6.5 Hz, 1H,
CH), 7.14–7.92 (m, 10H, Ar–H), 10.47 (s, 1H, NH). 13C-
NMR (DMSO-d6): dppm = 18.3 (CH3), 26.3 (CH3), 44.5
(CH), 55.1 (OCH3), 105.6, 118.3, 119.0, 125.4, 126.1,
126.3, 126.8, 128.3, 129.1, 129.3, 131.5, 133.2, 132.1,
136.5, 143.5, 157.9, 172.8, 196.3 (2C=O). Anal. Calcd for
C22H21NO3 (347.41): C, 76.06; H, 6.09; N, 4.03. Found: C,
76.10; H, 6.19; N, 4.18 %.
N-[5-amino-4-(4-methoxyphenylazo)-1H-pyrazol-3-yl]-2-
(6-methoxynaphthalen-2-yl)-propionamide (15)
General procedure for the synthesis of chalcones 18–20
Brown powder, Yield (63 %), mp 157–158 °C, IR (KBr)
mmax/cm-1: 3324, 3278, 3215 (NH2,NH), 3073 (CH–Ar),
A mixture of N-(4-acetylphenyl)-2-(6-methoxynaphthalen-
2-yl)propanamide (17) (0.694 g, 0.002 mol), appropriate
aromatic aldehyde (0.002 mol), and 10 % aqueous potas-
sium hydroxide (10 mL) in ethanol (25 mL) was stirred at
room temperature for about 3 h. The resulting solid was
filtered off, rinsed with water, dried, and crystallized from
ethanol.
1
2985–2919 (CH-sp3), 1678 (C=O), 1600 (C=N); H-NMR
(DMSO-d6): dppm = 1.53 (d, J = 6.5 Hz, 3H, CH3), 3.78,
3.80 (2s, 6H, 2OCH3), 3.86 (q, 1H, CH), 6.81, 8.06, 10.25
(3s, 4H, NH2 ? 2NH), 7.13–7.88 (m, 10H, Ar–H). 13C-
NMR (DMSO-d6): dppm = 18.51 (CH3), 42.5 (CH), 55.1,
55.9 (2OCH3), 105.6, 113.9, 118.6, 122.6, 125.7, 126.4,
126.6, 126.8, 126.9, 128.3, 128.4, 129.1, 133.3, 133.3,
134.7, 136.5, 146.4, 157.2, 159.8, 174.6. Anal. Calcd for
C24H24N6O3 (444.49): C, 64.85; H, 5.44; N, 18.91. Found:
C, 64.79; H, 5.39; N, 18.88 %.
2-(6-Methoxynaphthalen-2-yl)-N-[4-(3-phenylacryloyl)-
phenyl]propionamide (18)
Yellow crystals, yield (74 %), mp 217–218 °C, IR (KBr)
mmax/cm-1: 3245 (NH), 2984, 2845 (CH-sp3), 1678 (C=O),
1654 (C=O, chalcone); 1H-NMR (DMSO-d6): dppm = 1.52
(d, J = 6.5 Hz, 3H, CH3), 3.86 (s, 3H, OCH3), 4.03 (q,
J = 6.5 Hz, 1H, CH), 7.15–8.17 (m, 15H, Ar–H), 7.58 (d,
J = 14.8 Hz, 1H, CH=), 7.79 (d, J = 14.8 Hz, 1H, CH=),
10.03 (s, 1H, NH). 13C-NMR (DMSO-d6): dppm = 18.6
(CH3), 46.0 (CH), 55.1 (OCH3), 105.6, 118.5, 121.9, 125.5,
126.2, 126.8, 128.2, 128.3, 128.7, 128.7, 128.8, 128.9, 129.1,
129.4, 130.4, 132.2, 133.2, 134.2, 134.5, 134.7, 136.6, 143.3,
143.7, 157.1, 172.9, 186.5 (2C=O); Anal. Calcd for
C29H25NO3 (435.51): C, 79.98; H, 5.79; N, 3.22. Found: C,
79.90; H, 5.74; N, 3.29 %.
N-[2-(3,5-dimethyl-1H-pyrazol-4-ylsulfanyl)-phenyl]-2-(6-
methoxynaphthalen-2-yl)-propionamide (16)
Reddish brown powder, Yield (66 %), mp 205–207 °C, IR
(KBr) mmax/cm-1: 3258, 3223 (2NH), 3062 (CH–Ar),
1
2975–2924 (CH-sp3), 1665 (C=O), 1610 (C=N); H-NMR
(DMSO-d6): dppm = 1.45 (d, J = 6.5 Hz, 3H, CH3), 2.09,
2.59 (2s, 6H, 2CH3-pyrazole), 3.85 (q, 1H, CH), 3.86 (s, 3H,
OCH3), 7.13–7.87 (m, 11H, Ar–H ? NH), 9.65 (s, 1H, NH).
13C-NMR (DMSO-d6): dppm = 12.3, 13.2, 18.5 (3CH3),
44.6 (CH), 55.1 (OCH3), 105.6, 118.5, 118.7, 125.5, 125.6,
126.3, 126.6, 126.8, 127.0, 128.1, 128.4, 129.1, 129.2, 130.7,
133.2, 136.3, 145.6, 157.0, 157.1, 174.5. Anal. Calcd for
C25H25N3O2S (431.55): C, 69.58; H, 5.84; N, 9.74. Found: C,
69.62; H, 5.76; N, 9.65 %.
2-(6-Methoxynaphthalen-2-yl)-N-{4-[3-(4-methoxyphenyl)-
acryloyl)]-phenyl}-propionamide (19)
Yellow crystals, Yield (77 %), mp 229–231 °C, IR(KBr)
mmax/cm-1: 3244 (NH), 2975, 2839 (CH-sp3), 1659
(C=O), 1639 (C=O, chalcone); 1H-NMR (DMSO-d6):
dppm = 1.52 (d, J = 6.5 Hz, 3H, CH3), 3.82, 3.86 (2s, 6H,
2OCH3), 3.87 (q, 1H, CH), 7.29–8.14 (m, 14H, Ar–H),
7.61 (d, J = 15.2 Hz, 1H, CH=), 7.91 (d, J = 15.2 Hz, 1H,
CH =), 10.53 (s, 1H, NH). 13C-NMR (DMSO-d6):
Synthesis of N-(4-acetylphenyl)-2-(6-methoxynaphthalen-
2-yl)propanamide (17)
A mixture of naproxenoyl chloride (2.48 g, 0.01 mol) and
p-aminoacetophenone (1.35 g, 0.01 mol) in dioxane
123

Med Chem Res
dppm = 18.4 (CH3), 44.4 (CH), 55.1, 55.6 (2OCH3), 105.6,
114.3, 118.4, 118.6, 119.3, 125.1, 126.2, 126.8, 127.3,
128.3, 128.6, 129.1, 129.6, 130.6, 131.2, 131.7, 132.4,
133.2, 136.6, 143.3, 143.4, 157.0, 161.2, 164.1, 172.8,
187.3 (2C=O). MS (EI, 70 eV): m/z (%) = 465 (M?, 18.2),
358 (64.2), 332 (31.2), 304 (12.6), 280 (54.9), 253 (100),
237 (64.4), 213 (75.4), 107 (66.8), 77 (65.3). Anal. Calcd
for C30H27NO4 (465.54): C, 77.40; H, 5.85; N, 3.01.
Found: C, 77.55; H, 5.78; N, 3.17.
157.1, 157.1, 161.8, 172.5 (C=O). MS (EI, 70 eV): m/z
(%) = 449 (M?, 15.6), 418 (24.7), 372 (25.6), 304 (10.5),
292 (42.6), 264 (31.2), 236 (16.4), 213 (100), 145 (12.6), 77
(68.9). Anal. Calcd for C29H27N3O2 (449.54): C, 77.48; H,
6.05; N, 9.35. Found: C, 77.55; H, 6.16; N, 9.40 %.
2-(6-Methoxynaphthalen-2-yl)-N-{4-[5-(4-methoxyphenyl)-
4,5-dihydro-1H-pyrazol-3-yl]-pheny}-propionamide (22)
Colorless crystals, Yield (72 %), 254–256 °C, IR (KBr)
mmax/cm-1: 3337, 3215 (2NH), 2938, 2839 (CH-sp3), 1679
(C=O). 1H-NMR (DMSO-d6): dppm = 1.49 (d, J = 6.5 Hz,
3H, CH3), 3.32 (dd, J = 12.0, 5.4 Hz, 1H, pyrazoline HA-
4), 3.60 (dd, J = 7.8, 5 Hz, 1H, Pyrazoline HB-4), 3.72,
3.86 (2s, 6H, 2OCH3), 3.90 (q, 1H, CH), 4.8 (dd, J = 12.0,
5 Hz, 1H, pyrazoline H-5), 6.88–7.82 (m, 15H,
ArH ? NH), 10.26 (s, 1H, NH). 13C-NMR (DMSO-d6):
dppm = 18.6 (CH3), 40.5 (CH2 pyrazoline), 45.8 (CH),
54.9, 55.0 (2OCH3), 63.1 (CH pyrazoline), 105.6, 113.6,
113.9, 118.6, 118.9, 125.3, 125.8, 126.2, 126.4, 126.7,
127.6, 128.2, 128.3, 129.0, 133.1, 134.8, 136.8, 138.6,
139.0, 148.4, 156.9, 158.3, 172.3 (C=O). Anal. Calcd for
C30H29N3O3 (479.22): C, 75.13; H, 6.10; N, 8.76. Found:
C, 75.25; H, 6.18; N, 8.69 %.
2-(6-Methoxynaphthalen-2-yl)-N-{4-[3-(3-methylthiophen-
2-yl)-acryloyl)]phenyl}-propionamide (20)
Brown powder, Yield (72 %), mp 186–187 °C, IR(Br)
mmax/cm-1: 3312 (NH), 2965, 2829 (CH-sp3), 1686
(C=O), 1645 (C=O, chalcone); 1H-NMR (DMSO-d6):
dppm = 1.43 (d, J = 6.5 Hz, 3H, CH3), 2.36 (s, 3H, CH3),
3.86 (s, 3H, OCH3), 4.02 (q, 1H, CH), 7.32–8.07 (m, 12H,
Ar–H), 7.68 (d, J = 15.6 Hz, 1H, CH=), 7.89 (d,
J = 15.6 Hz, 1H, CH=), 10.5 (s, 1H, NH). 13C-NMR
(DMSO-d6): dppm = 12.9 (CH3), 18.5 (CH3), 46.0 (CH),
55.1 (OCH3), 105.6, 118.5, 118.6, 119.2, 125.4, 126.2,
126.8, 128.3, 128.6, 129.1, 129.7, 131.6, 132.0, 132.1,
133.2, 133.7, 134.2, 134.3, 136.5, 142.6, 143.5, 157.0,
172.9, 184.5 (2C=O). Anal. Calcd for C28H25NO3S
(455.57): C, 73.82; H, 5.53; N, 3.07. Found: C, 73. 79; H,
5.43; N, 3.18 %.
2-(6-Methoxynaphthalen-2-yl)-N-{4-[5-(3-methylthiophen-
2-yl)-4,5-dihydro-1H-pyrazol-3-yl]-pheny}-
propionamide (23)
General procedure for the synthesis of 5-aryl-4,5-
dihydro-1H-pyrazoles 21–23
Pale yellow powder, Yield (70 %), 237–238 °C, IR (KBr)
mmax/cm-1: 3310, 3270 (2NH), 2969, 2932 (CH-sp3), 1669
(C=O). 1H-NMR (DMSO-d6): dppm = 1.49 (d, J = 6.5 Hz,
3H, CH3), 2.18 (s, 3H, CH3), 3.35 (dd, J = 11.9, 4.8 Hz,
1H, pyrazoline HA-4), 3.75 (dd, J = 7.5, 4.8 Hz, 1H,
Pyrazoline HB-4), 3.86 (s, 3H, OCH3), 3.90 (q, 1H, CH),
5.08 (dd, J = 11.9, 4.8 Hz, 1H, pyrazoline H-5), 6.80–7.80
(m, 13H, Ar–H ? NH), 10.20 (s, 1H, NH). 13C-NMR
(DMSO-d6): dppm = 13.5 (CH3), 18.6 (CH3), 38.9 (CH2
pyrazoline), 45.9 (CH), 55.1 (OCH3), 59.3 (CH pyrazo-
line), 105.8, 118.4, 118.6, 119.0, 122.7, 125.3, 126.2,
126.7, 127.9, 128.3, 129.3, 130.1, 132.9, 133.8, 134.2,
136.8, 139.2, 139.8, 149.4, 157.1, 157.9 and 172.35 (C=O).
Anal. Calcd for C28H27N3O2S (469.60): C, 71.61; H, 5.80;
N, 8.95. Found: C, 71.53; H, 5.76; N, 8.87 %.
A solution of the appropriate chalcone 18–20 (0.01 mol)
and hydrazine hydrate (0.02 mol) in ethanol (30 mL) was
refluxed for 3 h. The reaction mixture was cooled and kept
at 0 °C overnight. The resulting solid was collected by
filtration and recrystallized from ethanol to give com-
pounds 21–23.
2-(6-Methoxynaphthalen-2-yl)-N-[4-(5-phenyl-4,5-
dihydro-1H-pyrazol-3-yl)-phenyl]propion-amide (21)
Colorless crystals, Yield (74 %), mp 265–266 °C, IR(KBr)
mmax/cm-1: 3325, 3215 (NH), 2975, 2856 (CH-sp3), 1674
(C=O), 1608 (C=N); 1H-NMR (DMSO-d6): dppm = 1.49 (d,
J = 6.65 Hz, 3H, CH3), 3.39 (dd, J = 11.6, 5.6 Hz, 1H,
pyrazoline HA-4), 3.65 (dd, J = 7.2, 5.6 Hz, 1H, pyrazoline
HB-4), 3.86 (s, 3H, OCH3), 4.00 (q, 1H, CH), 4.80 (dd,
J = 11.6, 5.6 Hz, 1H, pyrazoline H-5), 7.14–7.81 (m, 16H,
Ar–H ? NH), 10.27 (s, 1H, NH). 13C-NMR (DMSO-d6):
dppm = 18.5 (CH3), 38.9 (CH2 pyrazoline), 45.9 (CH), 55.1
(OCH3), 63.6 (pyrazole-C5), 105.6, 118.6, 119.0, 125.1,
125.4, 125.9, 126.3, 126.6, 126.8, 127.1, 127.3, 128.0, 128.3,
128.4, 128.9, 129.1, 133.2, 136.9, 138.2, 139.2, 143.0, 148.5,
Biological screening
Materials and methods
Animals-adult rats of both sexes weighing 150–200 g and
adult mice weighing 20–25 g were used in the experiments.
Animals were housed under standardized conditions for
123

Med Chem Res
light and temperature and received standard rat chow and
tap water and libitum. Animals were randomly assigned to
different experimental groups, each kept in a separate cage.
All animal procedures were performed after approval from
the Ethics committee of the National Research Center.
over the index finger and the presence or the absence of
gastric irritation is determined. The presence of a single or
multiple lesions (erosion, ulcer, or perforation) is consid-
ered to be positive (Amr and Abdulla, 2006). The number
of ulcers and the occurrence of hyperemia is noted
(determine ulcer index).
Drugs and chemicals
Acknowledgments The author is thankful to King Khalid Univer-
sity for the financial support of the Project No. (KKU-SCI-11-035).
Carrageenan Iambda Sigma–Aldrich chemical company
(USA), naproxen Khahira Pharmaceutical and Chemical
Company, Cairo, Egypt.
Conflict of interest The author has declared no conflict of interest.
Anti-inflammatory testing
References
The carrageenan rat paw edema model of inflammation
was used to evaluate the anti-inflammatory properties of
the tested compounds. Rats were randomly assigned to
treatment groups and sterile carrageenan lambda (100 ll of
a 1 % solution in saline) was injected sub-planter into right
hind paw of the rat. Carrageenan caused visible redness and
pronounced swelling that was well developed by 4 h and
persisted for more than 48 h. Right hind paw was measured
with a planimeter (Obukowics et al., 1998; Meng et al.,
1999) before, and at 1, 2, 3, and 4 h after carrageenan
injection. Due to water insolubility of the tested com-
pounds, they were dissolved in DMSO then injected i.p
(10 mg/kg b wt). The control animals were injected (i.p)
with appropriate volume of DMSO. The standard drug was
naproxen (10 mg/kg wt). Different compounds or naproxen
were given 1 h before carrageenan injection.
Almansa C, Alfon de Arriba J, Cavalcanti FL, Escamilla I (2003)
Synthesis and structure-activity relationship of a new series of
COX-2 selective inhibitors: 1,5-diarylimidazoles. J Med Chem
46:3463–3475
Al-Omran F, Al-Wadhi N, Abdel Khalil MM, Kaul K, Abu El-Khair
A, Elnagdi MH, (1997) 1-Substituted-3-dimethylaminoprop-2-
en-2-ones as building blocks in heterocyclic synthesis: routes to
6-aryl- and 6-heteroaryl-2H-pyran-2-ones and 6-and 4-arylpyri-
din-2(1H)-ones. J Chem Res (M): 601–615
Al-Sehemi AGM, El-Sharief AMSh, Ammar YA (2006) Propionic acids
in organic synthesis: novel synthesis of benzimidazole, 3,1-
benzoxazine, 3-aminoquinazoline and 3-aminothieno[2,3-d]pyrim-
idine derivatives containing 2-naphthyl propionyl moiety. Indian J
Chem 45B:450
Amir M, Kumar H, Javed SA (2007) Anti-inflammatory and gastro
sparing activity of some new indomethacin derivatives. Arch
Pharm Chem Life Sci 340:577–585
Amr AE, Abdulla MM (2006) Synthesis and anti-inflammatory
activities of new cyanopyrane derivatives fused with steroidal
nuclei. Arch Pharm Chem Life Sci 339:88–95
Analgesic testing
Armitage P (1971) Statistical methods in medical research, 1st edn.
Blackwell, Oxford, p 147
Blicke FF, Burckhalter JH (1942) The preparation of b-keto amines
by the Mannich reaction. J Am Chem Soc 64:451–454
Cash JM, Klippel JH (1994) Second-line drug therapy for rheumatoid
arthritis. N Engl J Med 330:1368–1375
Davies NM, Wallace JL (1997) Nonsteroidal anti-inflammatory drug-
induced gastrointestinal toxicity: new insights into an old
problem. J Gastroenterol 32(1):127–133
Duflos M, Nourrisson MR, Brelet J, Courant J, Le Baut G, Grimaud
N, Petit JY (2001) N-pyridinyl-indole-3-(alkyl) carboxamides
and derivatives as potential systemic and topical inflammation
inhibitors. Eur J Med Chem 36:545–553
The hot-plate test was performed on mice by using an elec-
tronically controlled hot-plate (ugo Basile, Italy) heated to
52 °C (0.1 C), for possible centrally mediated analgesic effect
of the drugs. Twelve groups of rats each were given vehicle
and/or the different compounds and the last group received
naproxen (20 mg/kg wt) 60 min prior to testing. Latency to
lick a hind paw or jumping (Winter et al., 1962) was recorded
sequentially before and at 1 and 2 h post treatment.
Farag AA, Khalifa EM, Sadik NA, Abbas SY, Al-Sehemi AG,
Ammar YA (2013) Synthesis, characterization and evaluation of
some novel 4(3H)-quinazolinone derivatives as anti-inflamma-
tory and analgesic agents. Med Chem Res 22:440–452
Froravanti R, Bolasco A, Manna F, Rossi F, Orallo F, Ortuso F,
Alcaro S, Cirilli R (2010) Synthesis and biological evaluation of
N-substituted-3,5-diphenyl-2-pyrazoline derivatives as cycloox-
ygenase (COX-2) inhibitors. Eur J Med Chem 45:6135–6138
Hawkey C, Laine L, Simon T, Beaulieu A, Maldonado-Cocco J,
Acevedo E, Shahane A, Quan H, Bolognese J, Mortensen E
(2000) Comparison of the effect of rofecoxib, ibuprofen and
placebo on the gastroduodenal mucosa of patients with osteo-
arthritis: a randomized, double blind, placebo-controlled trial.
Arthritis Rheum 43:370–377
Ulcerogenic effects
Groups of 5 male Wistar rats with a weight between 150
and 175 g are used. They are starved 48 h prior to drug
administration. The test compounds are administered orally
in 10 mL/kg as aqueous suspension. Doses are chosen
which are highly active in the activity (10 mg/kg) and
used. The animals are sacrificed after 7 h. Stomachs are
removed and placed on saline soaked filter paper until
inspection. A longitudinal incision along the greater cur-
vature is made with fine scissor. The stomach is inverted
123

Med Chem Res
Jensen BS (1959) The synthesis of 1-phenyl-3-methyl-4-acyl-
pyrazolones-5. Acta Chem Scand 13:1668–1675
Kalgutkar AS, Marnett AB, Crews BC, Remmel RP, Marnett LJ
(2000) Ester and amide derivatives of the nonsteroidal antiin-
flammatory drug, indomethacin, as selective cyclo-oxygenase-2
inhibitor. J Med Chem 43:2860–2870
Kimmey MB (1992) NSAIDS, ulcers, and prostaglandins. J Rheuma-
tol 19:68–73
Kira MA, Abdel-Rahman MO, Gadalla KZ (1969) The vilsmeier-
haack reaction–III cyclization of hydrazones to pyrazoles.
Tetrahedron Lett 2:109–110
Lanza FL (1998) A guideline for the treatment and prevention of
NSAID-induced ulcers. Am J Gastroenterol 93:2037–2046
MachadoP, Rosa FA, RossattoM, Sant’Anna GS, Sauzem PD, SilvaRMS,
Rubin MA, Ferreira J, Bonacorso HG, Zanatta N, Martinsa MAP
(2007) Synthesis and structure of novel 4,5-dihydro-1H-pyrazoles:
salicylic acid based analgesic agents. ARKIVOC xvi: 281–297
Marnett LJ, Kalgutkar AS (1998) Design of selective inhibitors of
cyclooxygenase-2 as nonulcerogenic anti-inflammatory agents.
Curr Opin Chem Biol 2(4):482–490
Marnett LJ, Kalgutkar AS (1999) Cyclooxygenase 2 inhibitors:
discovery, selectivity and the future. Trends Pharmacol Sci 20:
465–469
Mathew A, Sheej M, Kumar A, Radh K (2011) Design, synthesis and
biological evaluation of pyrazole analogues of natural piperine
hygeia. J D Med 3:48–56
Reitz DB, Li JJ, Norton MB, Reinhard EJ, Collins JT, Anderson GD,
Gregory SA, Koboldt CM, Perkins WE, Seibert K, Isakson PC
(1994) Selective cyclooxygenase inhibitors: novel 1,2-diarylcy-
clopentenes are potent and orally active COX-2 inhibitors. J Med
Chem 37:3878–3984
Smith CJ, Zhang Y, Koboldt CM, Muhammad J, Zwefel BS, Shaffer
A, Talley JJ, Masferrer JL, Serbert K, Isakson PC (1998)
Pharmacological analysis of cyclo-oxygenase-1 in in-flamma-
tion. Proc Natl Acad Sci USA 95:13313–13318
Stanovic B, Svete J (2004) Synthesis of heterocycles from alkyl
3-(dimethylamino)propenoates and related enaminones. Chem
Rev 104:2433–2480
Steiner B, Koos M, Matulova M, Proksa B (1993) Synthesis of
2-acetyl-3-methyl-4H-1,4-benzothiazine and its derivatives.
Monatsh Chem 124:425–430
Sukuroglu M, Ergun BC, Unlu S, Sahin MF, Kupeli E, Yesilada E,
Banoglu E (2005) Synthesis, analgesic and anti-inflammatory
activity of [6-(3,5-dimethyl-4-chloro pyrazole-1-yl)-3 (2H)-py-
ridazinon-2-yl]. Arch Pharm Res 28:509–517
Tsai PC, Wang IJ (2005) Synthesis and solvatochromic properties of
some disazo dyes derived from pyrazolo[1,5-a]pyrimidine
derivatives. Dyes Pigment 64:259–264
Wallace JL (1997) Nonsteroidal anti-inflammatory drugs and gastro-
enteropathy: the second hundred years. Gastroenterology 112:
1000–1016
Warner TD, Giuliano F, Vaynovie I, Bukasa A, Mitchell JA, Vave JR
(1999) Non-steroid drug selectivities for cyclo-oxygenase-1
rather than cyclo-oxygenase-2 are associated with human
gastro-intestinal toxicity: a full in vitro analysis. Proc Natl Acad
Sci USA 96:7563–7568
Meng L, Mohan R, Kwok BHB, Elofssof M, Sin N, Crews CM (1999)
Epoxomicin,
a potent and selective proteasome inhibitor,
exhibits in vivo anti-inflammatory activity. Proc Natl Acad Sci
USA 96:10403–10408
Obukowics MG, Walseh DJ, Salsgiver WJ, Martin-Berger CL, Chinn
KS, Duffin KL, Ras A, Needleman P (1998) Novel selective delta 6
or delta 5 fatty acid desaturase inhibitors as anti-inflammatory
agents in mice. J Pharmacol Exp Ther 287:157–166
Piazza GA, Keeton AB, Tinsley HN, Gary BD, Whitt JD, Mathew B,
Thaiparambil J, Coward L, Gorman G, Li Y, Sani B, Hobrath JV,
Maxuitenko YY (2009) A novel sulindac derivative that does not
inhibit cyclooxygenases but potently inhibits colon tumor cell
growth and induces apoptosis with antitumor activity. Cancer
Prev Res 2:572–580
Winter GA, Rislfy EA, Nuss GW (1962) Carrageenin-induced edema
in hind paw of the rat as an assay for anti-inflammatory drugs.
Proc Soc Exp Biol Med 111:544–547
Woolfe G, MacDonald AD (1944) Evaluation of analgesic action of
pethidine hydrochloride (Demerol). J Pharmacol Exp Ther
80:300–307
Youssef AM, White MS, Villanueva EB, El-Ashmawy IM, Klegeris
A (2010) Synthesis and biological evaluation of novel pyrazolyl-
2,4-thiazolidinediones as anti-inflammatory and neuroprotective
agents. Bioorg Med Chem 18:2019–2028
123