Synthesis and characterization of some heteroaromatic derivatives of 3-but-2-enoyl-chromen-2-one and their potential as anti-inflammatory agents

Article abstract of DOI:10.1002/jhet.1772

A novel series of chromen-2-ones containing pyrazole, isoxazole, oxazine, and thiazine substitutions have been synthesized by reacting 3-[3-(4-chloro-phenyl)-acryloyl]-chromen-2-one and 3-[3-(3-methoxy-phenyl)- acryloyl]-chromen-2-one with various cyclizing agents such as hydrazine, phenylhydrazine, urea, and thiourea. The structures of all the synthesized compounds were confirmed by the use of IR, ¹H-NMR, mass spectroscopy, and elemental analysis data. All the newly synthesized compounds were evaluated for their anti-inflammatory activity at a dose of 100 mg/kg body weight in carrageenan-induced rat paw edema model. The entire series of the compounds exhibited moderate to good anti-inflammatory activity, with the percentage inhibition of edema formation ranging from 39.99 to 63.15 against the reference drug ibuprofen (100 mg/kg) that showed 78.96% inhibition at the third hour. Compounds 3a, 3c, and 3d showed good inhibitory activity, whereas compounds 3b, 3e, 3f, and 3j showed moderate inhibitory activity at the third hour.

Full text of DOI:10.1002/jhet.1772

Month 2013
Synthesis and Characterization of Some Heteroaromatic Derivatives of
3
-But-2-enoyl-chromen-2-one and Their Potential as Anti-inflammatory
Agents
a
b
c
Priyanka Dixit, Avinash C. Tripathi, and Shailendra K. Saraf *
a
Babu Banarasi Das Northern India Institute of Technology, Lucknow 227105, Uttar Pradesh, India
b
c
Faculty of Pharmacy, Babu Banarasi Das Northern India Institute of Technology, Lucknow 227105, Uttar Pradesh, India
Faculty of Pharmacy, Babu Banarasi Das Northern India Institute of Technology, Faizabad Road, Lucknow 227105, Uttar
Pradesh, India
*
E-mail: dirpharmniec@gmail.com
Received April 29, 2012
DOI 10.1002/jhet.1772
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of chromen-2-ones containing pyrazole, isoxazole, oxazine, and thiazine substitutions have
been synthesized by reacting 3-[3-(4-chloro-phenyl)-acryloyl]-chromen-2-one and 3-[3-(3-methoxy-
phenyl)-acryloyl]-chromen-2-one with various cyclizing agents such as hydrazine, phenylhydrazine, urea,
1
and thiourea. The structures of all the synthesized compounds were confirmed by the use of IR, H-NMR, mass
spectroscopy, and elemental analysis data. All the newly synthesized compounds were evaluated for their anti-
inflammatory activity at a dose of 100 mg/kg body weight in carrageenan-induced rat paw edema model. The
entire series of the compounds exhibited moderate to good anti-inflammatory activity, with the percentage
inhibition of edema formation ranging from 39.99 to 63.15 against the reference drug ibuprofen (100 mg/kg)
that showed 78.96% inhibition at the third hour. Compounds 3a, 3c, and 3d showed good inhibitory activity,
whereas compounds 3b, 3e, 3f, and 3j showed moderate inhibitory activity at the third hour.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
(Coumarins) have been reported to possess anti-inflammatory,
anticancer, antimicrobial activities, and antioxidant proper-
ties [8–14]. Coumarin and its hydroxy-derivative can
reduce tissue edema and inflammation by inhibiting pros-
taglandin biosynthesis, which involves fatty acid hydro-
peroxy intermediates. Natural products such as esculetin,
fraxetin, daphnetin, and other related coumarin derivatives
are recognized as inhibitors not only of the lipoxygenase
and cycloxygenase enzymic systems, but also of the
neutrophil-dependent superoxide anion generation [15].
Pyrazole derivatives such as phenylbutazone, oxyphenbuta-
zone, and celecoxib exhibit anti-inflammatory, antipyretic,
and analgesic properties [16]. 3,4-Diarylisoxazole scaffold
is one of the frequently found pharmacophore in a wide
variety of NSAIDs (such as Valdecoxib), protein kinase
Inflammation is a complex phenomenon involving
humoral and cellular reactions through a number of inflam-
matory mediators [1]. The classical nonsteroidal anti-
inflammatory drugs (NSAIDs) are important therapeutic
agents widely used in the treatment of pain and inflammation
[
2,3]. The existence of the enzyme cyclooxygenase (COX)
in its two distinct isoforms, and thus nonselective action
of classical NSAIDs, results in certain mechanism-based
side effects including dyspepsia, gastrointestinal ulcerations,
bleeding, and nephrotoxicity [4,5]. Therefore, development
of novel compounds having anti-inflammatory and analgesic
activities with an improved safety profile is still a necessity.
Thus, the discovery of novel anti-inflammatory agents
has been attracting a lot of interest [6,7]. Chromen-2-ones
©
2013 HeteroCorporation

P. Dixit, A. C. Tripathi, and S. K. Saraf
Vol 000
inhibitors, and antihypertensive agents. The phenysulpho-
namide group located at the para-position is known to in-
teract effectively with the COX-II side pocket through
slow tight-binding kinetics [5]. 1,3-Oxazine ring with a
wide range of substituents, such as 1,3-oxazinanes, are
being explored as anti-inflammatory agents and agents
for treating ulcers, allergies, asthma, arthritis, and diabe-
tes. 1,3-Oxazine ring system also occur in some natural
antibiotics [17]. In view of these observations, it was
considered appropriate to synthesize some new chemical
entities, incorporating the two active pharmacophores in
a single molecular framework and to evaluate their anti-
inflammatory activity [18].
thiourea resulted in the synthesis of pyrazole, isoxazole,
oxazine, and thiazine substituted chromen-2-ones in the
third step of the reaction [18–20]. A total of 10 compounds
(3a–j) were synthesized as analogs of chromen-2-one. The
synthesis of the new compounds was carried out as
outlined in Scheme 1.
All the newly synthesized compounds were evaluated
for their anti-inflammatory activity, at a dose of 100 mg/kg
body weight (b.w.), using carrageenan-induced rat paw
edema model by Winter et al. [21]. This model reliably
predicts the anti-inflammatory efficacy of the NSAIDs,
and during the second phase, it detects the compounds
that act as anti-inflammatory agents as a result of inhibi-
tion of prostaglandin amplification [22]. The entire series
of investigated compounds exhibited moderate to good
anti-inflammatory activity, with the percentage inhibition
of edema formation ranging from 39.99 to 63.15, against
the reference drug ibuprofen (100mg/kg) that showed a
78.96% inhibition at third hour (Figure 1). Compounds
3c and 3d were found to be the most active compounds
in the series and showed good inhibitory activity, whereas
compounds 3a, 3b, 3e, 3f, and 3j showed moderate
inhibitory activity. The anti-inflammatory activity of these
compounds was comparable with that of the standard drug
ibuprofen, although not equal (Tables 1 and 2). The syn-
thesized derivatives of chromen-2-one may be free from
the gastrointestinal side effects, as they do not possess
any free carboxylic group.
RESULTS AND DISCUSSION
In the first step, 3-acetylcoumarin (1a) was synthesized
by Knoevenagel reaction by reacting salicylaldehyde
with ethylacetoacetate in the presence of catalytic quantity
of piperidine at room temperature [6]. Acryloyl-chromen-
2
-ones (2a–b) were synthesized by the reaction of 3-
acetylcoumarin with aromatic aldehydes (4-chloro and
-methoxybenzaldehyde), in the second step of the reac-
3
tion, which is an example of Claisen–Schmidt condensa-
tion reaction. Refluxing of acryloyl-chromen-2-ones such
as 3-[3-(4-chloro-phenyl)-acryloyl]-chromen-2-one (2a)
and 3-[3-(3-methoxy-phenyl)-acryloyl]-chromen-2-one
(
2b), with hydrazine hydrate, phenylhydrazine, urea, and
Scheme 1. Synthesis of chromen-2-one derivatives.
O
CHO
O
C
O
C
Piperidine
stir, rt,
CH3
OH
H C
3
O
CH3
O
O
20 min
1a
Piperidine, Glac. CH COOH,
3
reflux, 4h
O
Thiourea,
reflux
5 hrs
NH2
Hydrazine
hydrate,
R1 or R2 Reflux, 9 hrs
R
1
or R
2
S
N NH
O
N
O
O
1
2a or 2b
O O
R
2
O
Hydrazine
hydrate,
Urea,
reflux
14 hrs
3j
3
a or 3b
Phenyl-
hydrazine,
Reflux,
Hydroxyl-
amine
Reflux, 5 hrs
hydrochloride,
Reflux, 9hrs
R1 or R2
N
10 hrs
N
O
R1 or R2
NH
2
N
O
N
O
R2
N
H
O
O
N
O
3
c or 3d
3f or 3g
O O
R1 or R2
O
O
3h or 3i
3e
Where R1
=
=
R2
,
OCH3
Cl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Characterization of 3-But-2-enoyl-chromen-2-ones
Figure 1. Percent edema inhibition at third hour after treatment with chromen-2-one analogs.
Table 1
Mean paw volume measured after treatment with chromen-2-one analogs (3a–j).
Mean paw volume ꢁ SEM
Dose
Compounds
(mg/kg b.w.)
1 h
3 h
5 h
7 h
Control
Ibuprofen
0.5% CMC
100
0.486 ꢁ 0.009
0.380 ꢁ 0.009
0.344 ꢁ 0.005
0.420 ꢁ 0.008
0.368 ꢁ 0.007
0.382 ꢁ 0.004
0.348 ꢁ 0.004
0.354 ꢁ 0.10
0.448 ꢁ 0.009
0.428 ꢁ 0.008
0.338 ꢁ 0.014
0.444 ꢁ 0.017
0.522 ꢁ 0.012
0.282 ꢁ 0.009
0.290 ꢁ 0.005
0.369 ꢁ 0.012
0.302 ꢁ 0.006
0.298 ꢁ 0.005
0.300 ꢁ 0.005
0.302 ꢁ 0.008
0.386 ꢁ 0.010
0.370 ꢁ 0.008
0.288 ꢁ 0.015
0.384 ꢁ 0.017
0.522 ꢁ 0.015
0.254 ꢁ 0.009
0.254 ꢁ 0.005
0.342 ꢁ 0.009
0.266 ꢁ 0.007
0.264 ꢁ 0.008
0.276 ꢁ 0.005
0.278 ꢁ 0.009
0.360 ꢁ 0.010
0.342 ꢁ 0.010
0.270 ꢁ 0.017
0.354 ꢁ 0.019
0.558 ꢁ 0.012
0.240 ꢁ 0.009
0.242 ꢁ 0.007
0.334 ꢁ 0.007
0.244 ꢁ 0.008
0.252 ꢁ 0.008
0.268 ꢁ 0.006
0.258 ꢁ 0.010
0.344 ꢁ 0.008
0.344 ꢁ 0.008
0.202 ꢁ 0.018
0.336 ꢁ 0.017
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
100
100
100
100
100
100
100
100
100
100
j
Values are expressed as mean ꢁ SEM, n = 5, P < 0.01 compared with vehicle treated group using one-way analysis of variance followed by Dunnett’s test.
b.w., body weight; CMC, carboxymethyl cellulose.
Table 2
Percent edema inhibition after treatment with chromen-2-one analogs (3a–j).
Anti-inflammatory activity (% edema inhibition)
Dose
Compounds
(mg/kg b.w.)
1 h
3 h
5 h
7 h
Control
0.5% CMC
Ibuprofen
100
100
100
100
100
100
100
100
100
100
100
ꢀ45.45
ꢀ18.75
ꢀ40.53
ꢀ56.25
ꢀ36.36
ꢀ38.70
ꢀ28.14
ꢀ29.28
ꢀ39.48
ꢀ80.01
ꢀ21.93
78.96
44.10
42.87
63.15
56.76
42.87
42.87
39.99
41.85
31.59
43.89
32.13
41.37
5.55
12.00
12.00
3.03
11.52
22.23
11.10
21.42
16.68
8.82
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
39.99
30.00
20.01
20.01
23.07
24.33
17.64
23.67
9.39
8.55
j
Values are expressed as mean ꢁ SEM, n = 5, P < 0.01 compared with vehicle treated group using one-way analysis of variance followed by Dunnett’s test.
b.w., body weight; CMC, carboxymethyl cellulose.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Dixit, A. C. Tripathi, and S. K. Saraf
Vol 000
CONCLUSIONS
State: Solid; Color: Light yellow; Yield: 85.10%; Melting
Range: 70–72 C; IR (KBr, cm ): 1739.67 (Cyclic C═O stretch-
ing), 1677.95 (C═O stretching), 1614.31 (C═C stretching); MS
ꢂ
ꢀ1
From the results, it has been concluded that
m/z (M+ 1): 189.03.
•
•
Although considering all the newly synthesized com-
pounds of the series together, the presence of chlorine
and methoxy groups in the aromatic ring at the
fifth-position of the pyrazoline nucleus gave rise to
an increase in the anti-inflammatory activity.
General procedure for the synthesis of acryloyl-chromen-2-
ones (2a–b).
3-Acetylcoumarin (0.01 M, 1.88 g) and 4-
chlorobenzaldehyde (0.012 M, 1.69 g) or 3-methoxyben-
zaldehyde (0.012M, 1.63mL) were dissolved in 10mL of n-
butanol with heating, and glacial acetic acid (0.3mL) and
piperidine (0.3 mL) were added. The reaction mixture was
refluxed for 7–8 h, and then the solvent was removed under
vacuum. The residue was triturated with 10 mL of ethanol until a
precipitate was formed. The precipitate was filtered off,
recrystallized from acetone, and re-precipitated with ethanol. The
progress of the reaction was monitored by TLC using chloroform
and n-hexane (2:9) as the solvent system.
The bulkier substituents while increasing lipophilicity
gave better anti-inflammatory activity.
•
The results obtained expound that the compounds sub-
stituted with pyrazoline nucleus 3a, 3b, 3c, and 3d
exhibited the maximum per cent inhibition of edema.
This also confirmed that the compound 3c and 3d,
substituted with N-phenyl pyrazoline at third position of
chromen-2-one, gave rise to increased anti-inflammatory
activity.
Compound 3e substituted with 3-methoxy-phenyl and
isoxazole showed more activity than the compound 3g
substituted with 3-methoxy-phenyl and pyrazole.
The synthesized derivatives of chromen-2-one may be
free from the gastrointestinal side effects, as they do not
possess any free carboxylic group.
3-[3-(4-Chloro-phenyl)-acryloyl]-chromen-2-one (2a). State:
Solid; Color: Dark yellow; Yield: 65.55%; Melting Range: 110–
ꢂ
ꢀ1
112 C; IR (KBr, cm ): 1718.46 (Cyclic C═O stretching),
608.52 (C═O stretching), 1560.30 (C═C stretching); MS m/z
M + 1): 311.06.
-[3-(3-Methoxy-phenyl)-acryloyl]-chromen-2-one (2b). State:
Solid; Color: Dark yellow; Yield: 60.35%; Melting Range: 92–
1
(
•
•
3
ꢂ
ꢀ1
9
4 C; IR (KBr, cm ): 1722.31 (Cyclic C═O stretching),
604.66 (C═O stretching), 1487.01(C═C stretching); MS m/z
M + 1): 307.12.
General procedure for the synthesis of chromen-2-one
analogs of pyrazoline (3a–d). To a solution of 2a (0.01 M,
.10 g)/2b (0.01 M, 3.06 g) with hydrazine hydrate (0.01 M,
.49 mL) or phenylhydrazine (0.01 M, 0.99 mL) in 20mL of
1
(
•
The synthesized derivatives of chromen-2-one may act
as selective COX-2 inhibitors, as carrageenan-induced
rat paw edema model predicts the anti-inflammatory
activity of the NSAIDs during the second phase by
detecting the result of inhibition of prostaglandins.
3
0
ethanol, alcoholic NaOH (0.025 M, 5 mL) was added, and the
reaction mixture was refluxed for 8–10 h. The excess solvent was
removed, and the reaction mixture was poured onto crushed ice.
The precipitated solid was filtered, dried, and recrystallised from
acetone. The progress of the reaction was monitored by TLC,
using methanol and chloroform as the solvent system.
EXPERIMENTAL
The chemicals and reagents were procured from S. D. Fine
3-[5-(4-Chloro-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]-chromen-
Chemicals, Mumbai, India and were used as such. Melting points
were determined by open capillary method and are uncorrected.
Progress of the reactions was monitored by TLC on precoated
silica gel G plates, using iodine vapors and UV chamber as
visualizing agents. IR spectra were recorded on Shimadzu 8400S
and Perkin Elmer RX1 FTIR spectrophotometers, and values are
expressed in cm . H-NMR spectra were recorded on Bruker
DRX-300 (at 300 MHz) spectrometer, and chemical shifts are
reported in parts per million (d value), taking TMS (d 0 ppm for
2-one (3a). State: Solid; Color: Dark yellow; Yield: 82.20%;
ꢂ
ꢀ1
Melting Range: 172–174 C; IR (KBr, cm ): 1598.88 (C═N
stretching), 1490.87 (C═C stretching), 1234.36 (C—O); H-NMR
1
(
3
CDCl , d ppm): 1.257–1.283 (d, 2H of pyrazoline), 2.076–2.173
(
t, 1H of pyrazoline), 7.141–7.115 (d, 1H, Ar—H), 7.261–7.232 (d,
ꢀ
1
1
1H of chromen-2-one), 7.321–7.352 (t, 1H of chromen-2-one), 8.722
s, 1H, 4-H of chromen-2-one); MS m/z (M + 1): 325.10; Anal. Calcd
for C18 13ClN : C, 68.24; H, 5.03; N, 8.24. Found: C, 68.47; H,
5.05; N, 8.46.
-[5-(3-Methoxy-phenyl)-4,5-dihydro-1H-pyrazol-3-yl]-chromen-
-one (3b). State: Solid; Color: Dark yellow; Yield: 82.81%;
(
H
2 2
O
1
H-NMR) as an internal standard. Mass spectra were recorded on
3
a JEOL-AccuTOF JMS-T100LC mass spectrometer instrument
using ESI technique. Elemental analysis was performed on an
Elemental Vario EL III analyzer.
2
ꢂ
ꢀ1
Melting Range: 188–190 C; IR (KBr, cm ): 1598.88 (C═N
stretching), 1487.01 (C═C stretching), 1261.36 (C—O); H-NMR
1
General procedure for the synthesis of 3-acetylcoumarin
(
CDCl
pyrazoline), 7.341–7.360 (d, 1H of chromen-2-one), 7.125–7.148 (d,
H, Ar—H), 6.933–6.940 (d, 1H of chromen-2-one), 6.851–6.879
d, 1H, Ar—H), 8.013 (s, 1H, 4-H of chromen-2-one); MS m/z
M+ 1): 321.14; Anal. Calcd for C19 : C, 75.54; H, 5.08;
N, 7.07. Found: C, 75.56; H, 5.29; N, 7.08.
-[5-(4-Chloro-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-
-yl]-chromen-2-one (3c). State: Solid; Color: Reddish brown;
3 3
, d ppm): 2.171 (s, 3H, —OCH ), 2.341–2.386 (d, 2H of
(
(
1a).
Salicyladehyde (0.2M, 20.94 mL), ethylacetoacetate
0.2 M, 25.32mL), and a few drops (2 mL) of piperidine were
1
(
(
mixed at room temperature. A small magnetic stirrer bead was
introduced, and the contents were stirred vigorously until a
viscous solution was formed (usually in 30min). The flask was
removed from the stirrer and the yellowish solid filtered off. The
filter cake (precipitate) was washed with distilled water. The
product was recrystallized from absolute ethanol to obtain a
yellow crystalline solid. The progress of the reaction was
monitored by TLC, using chloroform and n-hexane (1:9) as the
solvent system [6].
16 2 3
H N O
3
3
ꢂ
ꢀ1
Yield: 64.30%; Melting Range: 170–172 C; IR (KBr, cm ):
1598.88 (C═N stretching), 1487.01 (C═C stretching),
1257.50 (C—O), 756.04 (C—Cl); H-NMR (CDCl
1
3
, d ppm):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis and Characterization of 3-But-2-enoyl-chromen-2-ones
1
2
.043–2.057 (t, 1H of pyrazoline), 2.743–2.829 (d, 2H of
1488.94 (C═C stretching), 1245.93 (C—O stretching); H-
NMR (CDCl , d ppm): 2.078–2.174 (t, 3H, OCH ), 7.138–
7.164 (d, 1H, Ar—H), 7.263 (s, 1H of pyrazoline), 7.702–7.728
d, 1H of chromen-2-one), 7.797–7.891 (d, 1H of chromen-2-
one), 8.611 (s, 1H, 4-H of chromen-2-one); MS m/z (M + 1):
pyrazoline), 7.375–7.400 (d, 1H of chromen-2-one), 7.283–7.301
3
3
(
(
d, 1H, Ar—H), 7.740–7.794 (t, 1H of chromen-2-one), 7.939
s, 1H, 4-H of chromen-2-one); MS m/z (M+ 1): 401.15; Anal.
(
Calcd for C H ClN O : C, 68.19; H, 4.27; N, 6.19. Found: C,
24
17
2 2
3
8
18.12; Anal. Calcd for C H N O : C, 71.99; H, 4.13; N,
6
8.28; H, 4.38; N, 6.31.
-[5-(3-Methoxy-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-
19 14 2 3
.16. Found: C, 71.93; H, 4.28; N, 8.52.
3
General procedure for the synthesis of chromen-2-one
3
-yl]-chromen-2-one (3d).
State: Solid; Color: Reddish
ꢂ
analogs of oxazine (3h–i).
To a solution of 2a (0.01 M,
brown; Yield: 75.31%; Melting Range: 177–179 C; IR (KBr,
cm ): 1598.88 (C═N stretching), 1485.09 (C═C stretching),
ꢀ
1
3.10g) and urea (0.03mol, 1.3 g)/2b (0.01 mol, 3.06g) in 20mL
ethanol, 5 mL alcoholic KOH (0.02 M, 1.12 g) was added. The
reaction mixture was refluxed for 12–14 h and then poured in
1
1257.50 (C—O), 756.04 (C—Cl); H-NMR (CDCl
3
, d ppm):
1.297–1.317 (d, 2H of pyrazoline), 3.740–3.769 (t, 1H of
5
0mL of 10% cold HCl solution. The precipitated solid was
pyrazoline), 3.930 (s, 3H, —OCH ), 6.133–6.165 (d, 1H, Ar—H),
3
filtered, washed with water until free from acid, and recrystallised
from acetone. The progress of the reaction was monitored by
TLC, using ethyl acetate and hexane (2:8) as the solvent system.
-[2-Amino-4-(4-chloro-phenyl)-6H-[1,3]oxazin-6-yl]-chromen-
-one (3h). State: Solid; Color: Light yellow; Yield: 68.64%;
6.754–6.820 (t, 1H, Ar—H), 7.170–7.224 (t, 1H of chromen-2-
one), 7.355–7.378 (d, 1H of chromen-2-one), 8.014 (s,1H, 4-H of
chromen-2-one); MS m/z (M ): 396.16; Anal. Calcd for
C H N O : C, 68.24; H, 5.03; N, 8.24. Found: C, 68.47; H,
+
3
25 20 2 3
2
5.05; N, 8.42.
ꢀ1
ꢂ
Melting Range: 168–170 C; IR (KBr, cm ): 1598.88 (C═N
stretching), 11488.94 (C═C stretching), 1245.93 (C—O
General procedure for the synthesis of chromen-2-one
analogs of isoxazole (3e).
0.01 M, 0.82 g) dissolved in a minimum amount of hot acetic
acid was added to a solution of hydroxylamine hydrochloride
0.01 M, 0.695 g) in ethanol (15 mL). This solution was added to a
Anhydrous sodium acetate
3
stretching); H-NMR (CDCl , d ppm): 2.078–2.174 (t, 3H,
(
OCH ), 7.138–7.164 (d, 1H, Ar—H), 7.263 (s, 1H of pyrazoline),
3
7
.702–7.728 (d, 1H of chromen-2-one), 7.797–7.891 (d, 1H of
chromen-2-one), 8.611 (s, 1H, 4-H of chromen-2-one); MS m/z
M+ 1): 318.12; Anal. Calcd for C19 13ClN : C, 62.69; H,
.71; N, 6.14. Found: C, 62.89; H, 3.74; N, 6.15.
-[2-Amino-4-(3-methoxy-phenyl)-6H-[1,3]oxazin-6-yl]-chromen-
-one (3i). State: Solid; Color: Light yellow; Yield: 86.78%;
Melting Range: 182–184 C; IR (KBr, cm ): 1693.38 (C═O
stretching), 1598.88 (C═C stretching), 1257.50 (C—O
stretching); H-NMR (CDCl , d ppm) 3.888 (s, 3H, OCH ),
(
solution of 2b (0.01 M, 3.06 g) in ethanol (20mL). The mixture
was refluxed on an oil bath for 9 h, concentrated, and then poured
onto crushed ice. The precipitated solid was filtered, dried, and
recrystallised from acetone. The progress of the reaction was
monitored by TLC, using methanol and chloroform (0.1:9.9) as
the solvent system.
(
H
2 3
O
3
3
2
ꢂ
ꢀ1
3
-[3-(3-Methoxy-phenyl)-isoxazole-5-yl]-chromen-2-one
1
3
3
(
3e). State: Solid; Color: Brown; Yield: 69.59%; Melting Range:
ꢂ
ꢀ1
2
.755 (s, 2H, NH ), 6.672–6.636 (d, 1H, Ar—H), 6.844–6.917
2
1
11–113 C; IR (KBr, cm ): 1631.67 (C═N stretching), 1512.09
1
(t, 1H of Ar—H), 7.243–7.255 (t, 1H of chromen-2-one), 7.493–
.511 (d, 1H of chromen-2-one). MS m/z (M + 1): 349.08; Anal.
Calcd for C20 : C, 68.96; H, 4.63; N, 7.04. Found: C,
9.04; H, 4.51; N, 7.17.
General procedure for the synthesis of chromen-2-one
analogs of thiazine (3j). A solution of 2b (0.01 M, 3.06 g) and
thiourea (0.03 mol, 2.3 g) in 20mL ethanol, 5 mL alcoholic KOH
0.02 M, 1.12g) was added. The reaction mixture was refluxed for
5h and then poured in 50mL of 10% cold HCl solution. The
precipitated solid was filtered, washed with water until free from
acid, and recrystallised from acetone. The progress of the reaction
was monitored by TLC, using ethyl acetate and hexane (1:9) as
the solvent system.
-[2-Amino-4-(3-methoxy-phenyl)-6H-[1,3]thiazin-6-yl]-
chromen-2-one (3j). State: Solid; Color: Dark yellow; Yield:
6.43%; Melting Range: 155–157 C; IR (KBr, cm ): 1600.81
C═N stretching), 1487.01 (C═C stretching), 1257.50 (C—O
(
(
C═C stretching), 1278.72 (C—O), 1382.87 (N—O); H-NMR
CDCl , d ppm): 2.074 (s, 3H, OCH ), 7.095–7.103 (d, 1H, Ar—
7
3
3
16 2 4
H N O
H), 7.195–7.204 (d, 1H of chromen-2-one), 7.261 (s, 1H, 4-H of
chromen-2-one), 7.465–7.509 (t, 1H of Ar—H), 7.799–7.825 (t,
6
1
H, 4-H of chromen-2-one); MS m/z (M + 1): 320.08; Anal. Calcd
for C19 : C, 61.47; H, 4.10; N, 4.39. Found: C, 61.46; H,
.21; N, 4.28.
General procedure for the synthesis of chromen-2-one
analogs of pyrazole (3f–g). A solution of 2a (0.01 M, 3.10 g)/
b (0.01 M, 3.06 g) and hydrazine hydrate (0.01 M, 0.49 mL)
H13NO
4
4
(
1
2
were dissolved in glacial acetic acid (25 mL). The reaction
mixture was refluxed on a water bath at a temperature of 70–90 C
for 4–5 h and then poured onto crushed ice. The precipitated solid
was filtered, dried, and recrystallised from acetone. The progress
of the reaction was monitored by TLC, using methanol and
chloroform as the solvent system.
ꢂ
3
ꢂ
ꢀ1
4
(
3
-[5-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-chromen-2-one
1
stretching); H-NMR (CDCl , d ppm) 3.877 (s, 3H, OCH ), 2.091
s, 2H, NH ), 7.172–7.187 (d, 1H, Ar—H), 6.860–6.911 (t, 1H of
Ar—H), 7.471–7.537 (t, 1H of chromen-2-one), 7.758–7.677 (d,
H of chromen-2-one). MS m/z (M + 1): 365.12; Anal. Calcd for
S: C, 70.92; H, 4.43; N, 7.09. Found: C, 70.76; H,
3
3
(
3f). State: Solid; Color: Light yellow; Yield: 92.26%; Melting
(
ꢂ
ꢀ1
2
Range: 168–170 C; IR (KBr, cm ): 1712.67 (Cyclic C═O
stretching), 1600.81 (C═N stretching), 1487.01 (C═C stretching);
1
1
H-NMR (CDCl , d ppm): 7.262–7.306 (d, 1H, Ar—H), 7.362–
3
20 16 2 3
C H N O
7
(
.419 (t, 1H, Ar—H), 7.447–7.510 (d, 1H, Ar—H), 7.606–7.637
d, 1H, of chromen-2-one), 7.728–7.796 (t, 1H of chromen-2-
one), 8.611 (s, 1H, 4-H of chromen-2-one); MS m/z (M+ 1):
4
.28; N, 7.10.
Anti-inflammatory activity [23–25].
Male albino rats
weighing 100–225 g were used for the assessment of the anti-
inflammatory activity of the synthesized chromen-2-one
analogs. Animals were procured from the Animal House,
Faculty of Pharmacy, Northern India Engineering College,
Lucknow, Uttar Pradesh, India. The animals were housed in PP
cages with steel net, in temperature-controlled room under
3
7
23.17; Anal. Calcd for C18
.69. Found: C, 64.19; H, 3.38; N, 7.65.
-[5-(3-Methoxy-phenyl)-2H-pyrazole-3-yl]-chromen-2-one
3g). State: Solid; Color: Light yellow; Yield: 76.36%; Melting
2 2
H11ClN O : C, 64.09; H, 3.44; N,
3
(
ꢂ
ꢀ1
Range: 128–130 C; IR (KBr, cm ): 1598.88 (C═N stretching),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Dixit, A. C. Tripathi, and S. K. Saraf
Vol 000
ꢂ
standard living conditions of; 25 ꢁ 5 C and relative humidity of;
R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.; Bornemeier, D. A.; Dyer,
R. D. J Med Chem 1999, 42, 1161.
5
5ꢁ 5 with regular 12h light and 12h dark cycles and allowed
free access to standard laboratory food and water. All the animals
were treated humanely in accordance with the guidelines laid
down by the Institutional Animal Ethics Committee (IAEC). The
anti-inflammatory activity was approved by the IAEC with
protocol no. BBDGEI/IAEC/14/2011.
[3] Dannhardt, G.; Kiefer, W. Eur J Med Chem 2001, 36, 109.
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Mamledesai, S.; Thippeswamy, A. H.; Satyanarayana, D. Eur J Med
Chem 2009, 44, 1682.
Male albino rats weighing 100–225 g were divided into 12
groups of five animals each. The animals were starved overnight.
Group 1 (Control) received 1 mL of 0.5% carboxymethyl cellulose
[7] Tsai, W. J.; Shiao, Y. J.; Lin, S. J.; Chiou, W. F.; Lin, L. C.;
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(
CMC) suspension. Group 2 (standard), received Ibuprofen 100 mg/
kg. Group 3 to 12 were treated with the suspension of the test com-
pounds (3a–j), at a dose of 100mg/kg b.w. After 1 h of oral dosing,
sub-planter injection of 0.1 mL of 1% solution of carrageenan was
given into the left hind paw of each animal. The paw edema
volume was measured with a plethysmometer after 0, 1, 3, 5, and
[
10] Singh, P.; Kaur, M.; Holzer, W. Eur J Med Chem 2010, 45,
968.
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[
Bhirud, S. B.; Gill, C. H. Ind J Chem 2005, 44B, 422.
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7
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[17] Gilchrist, T. L. Heterocylic Chemistry II: Six-Membered Ring
Anti-inflammatory activity ð% edema inhibitionÞ ¼ Vt ꢀVc=
[
V ꢃ 100
t
2
[
t c
where V and V are the volumes of edema in the drug-treated and
the control groups.
[
All the values of the experimental results are expressed as
mean ꢁ SEM and analyzed by one-way analysis of variance
followed by Dunnett’s test for the possible significant (P < 0.01)
identification between various groups. Statistical analysis was
carried out using Graph pad prism 3.0 (Graph pad software, San
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Acknowledgment. We express our sincere gratitude to Central
Drugs Research Institute, Lucknow, India, for providing the
library facilities and sophisticated analytical instrument facilities.
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[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet