Synthesis and anti-inflammatory activity of 1-acetyl-5-substitute daryl-3-(β-aminonaphthyl)-2-pyrazolines and β-(substitute daminoethyl) amidonaphthalenes

Article abstract of DOI:10.1016/S0223-5234(00)01179-X

The title compounds were prepared by reaction of β-acetylamino-naphthalene with different aromatic aldehydes followed by cyclisation with hydrazine hydrate and with different primary or secondary amines (Mannich's reaction), respectively. The structures of new compounds were confirmed by ¹H-NMR and IR spectral data. Anti-inflammatory and ulcerogenic activities in vivo were evaluated and compared with the standard drugs, phenylbutazone and indomethacin. Some compounds of the series exhibited promising anti-inflammatory activity with a lower ulcerogenic liability than the standard drugs.

Full text of DOI:10.1016/S0223-5234(00)01179-X

Eur. J. Med. Chem. 36 (2001) 81–92
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© 2000 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(00)01179-X/SCO
Short communication
Synthesis and anti-inflammatory activity of 1-acetyl-5-substitute
daryl-3-(b-aminonaphthyl)-2-pyrazolines and b-(substituted aminoethyl)
amidonaphthalenesꢀ
Ekta Bansal†, V.K. Srivastava, Ashok Kumar*
Medicinal Chemistry Division, Department of Pharmacology, L.L.R.M. Medical College, Meerut 250004, U.P., India
Received 20 January 2000; revised 6 July 2000; accepted 11 July 2000
Abstract – The title compounds were prepared by reaction of b-acetylamino-naphthalene with different aromatic aldehydes followed
by cyclisation with hydrazine hydrate and with different primary or secondary amines (Mannich’s reaction), respectively. The
1
structures of new compounds were confirmed by H-NMR and IR spectral data. Anti-inflammatory and ulcerogenic activities in
vivo were evaluated and compared with the standard drugs, phenylbutazone and indomethacin. Some compounds of the series
´
exhibited promising anti-inflammatory activity with a lower ulcerogenic liability than the standard drugs. © 2001 Editions
scientifiques et me´dicales Elsevier SAS
´
Zusammenfassung – dkflsdhgkfdjz © 2000 Editions scientifiques et me´dicales Elsevier SAS
chalcones / pyrazolines / substituted amidonaphthalene / anti-inflammatory activity / ulcerogenic activity / acute toxicity
1. Introduction
2. Chemistry
Naphthalene, an aromatic nucleus has gained
prominence after the discovery of naproxen [1] and
nabumetone [2] which are currently useful drugs for
the treatment of various inflammatory disorders. Het-
erocyclic/aliphatic functionalised systematic variation
at b-position of naphthalene nucleus remarkably in-
crease the anti-inflammatory activity [3–5]. Pyrazoli-
nes are also well known for their pronounced
anti-inflammatory activity [6–10]. In view of these
observations, it was thought worthwhile to synthesise
some new b-substituted naphthylpyrazolines and b-
substituted amidonaphthalenes to evaluate them for
their anti-inflammatory activity.
The synthetic routes of compounds are outlined in
figure 1. Compound (1), i.e. b-acetylaminonaph-
thalene was prepared by reacting b-aminonaphthalene
with acetylchloride in benzene. Compound (1) on
refluxing with various aromatic aldehydes for 10 h in
the presence of 2 % NaOH yielded b-aminonaphthyl
substituted chalcones (2a–2e) which on cyclisation
with 90 % hydrazine hydrate in the presence of few
drops of glacial acetic acid afforded 1-acetyl-5-substi-
tuted aryl-3-(b-aminonaphthyl)-2-pyrazolines (3a–3e)
[11]. On the other side, compound 1 underwent Man-
nich’s reaction (i.e. reaction of compound 1 with
various primary or secondary amines in the presence
of formaldehyde) to yield b-(substituted aminoethyl)
amidonaphthalenes (2a%–2t%).
ꢀ A part of this paper has been presented at the XXXI
Annual Conference of India Pharmacology Society held at
Central Drug Research Institute (CDRI), Lucknow, U.P. from
18 to 20 December, 1998.
3. Pharmacological results and discussion
All new compounds were tested in vivo in order to
evaluate their pharmacological activity.
* Correspondence and reprints.
† Part of Ph.D. Thesis.

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E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2000) 81–92
Hence it may be concluded that substitution with
The anti-inflammatory effects of all the compounds
phenyl moiety having methoxy group either at ortho
or para position enhances the activity. Of the two (o
and p), o-isomer is more active. Figure 2 shows the
anti-inflammatory activity of compound 3d and
phenylbutazone at three different doses (25, 50 and
100 mg kg−1 per oral). Further, compound 3d exhib-
ited less ulcerogenic potentiality as compared with
phenylbutazone (UD50 of 3d=132.9 mg kg−1 i.p. and
UD50 of phenylbutazone=66.6 mg kg−1 i.p.). Ulcero-
genic potentiality of the compounds (oral administra-
tion) is given in the table III.
On the other side of series (route 2), almost all the
compounds showed potent anti-inflammatory activ-
ity. However, some compounds have shown more
potent activity than phenylbutazone (but less than
indomethacin) such as, compound 2d%, in which
phenyl ring, having an electronegative atom, i.e. ‘Cl’
at m-position, is present as substituent; compound
2n%, in which phenyl moiety is having an acidic group
and an electronegative atom, i.e. ‘Br’ at p-position;
compound 2o%, in which an acidic group is attached to
the phenyl moiety and two Br atoms at ortho and
of this series have been reported in tables I and II.
The characteristic feature of route (1) of this series
is the presence of substituted alkyl chain at amino
group of b-aminonaphthalene and their conversion
into five-membered ring structure. All the compounds
(2a–2e and 3a–3e) exhibited more or less anti-inflam-
matory activity. It was observed that compound hav-
ing furyl group (compound 2b) as substituent showed
the least activity (17.97 %) while compound substi-
tuted with phenyl ring having methoxy group at ei-
ther ortho or para positions exhibited the maximum
percent inhibition of oedema. However, ortho com-
pound (2d) showed more activity (39.32 %) than the
corresponding para compound (2c) (33.70 %). Com-
pounds having phenyl group as substituent (2a)
showed 24.72 % activity and the compound substi-
tuted with phenyl group having dimethylamino group
at p-position exhibited 29.21 % inhibition. Cyclisation
of chalcones into pyrazolines in general, enhanced the
activity. Compounds 3c and 3d exhibited more potent
activity than that of phenylbutazone but less activity
than indomethacin, the reference drugs.
Figure 1.

Bansal et al. / European Journal of Medicinal Chemistry 36 (2001) 81–92
83
Table I. Characterisation data and anti-inflammatory activity of compounds (2a–2e and 3a–3e).
Compound R%
number
m.p. Yield Recrystallisation Molecular
Molecular Anti-inflammatory ALD50 (mg kg−1
(°C) (%)
solvent
formula
weight a
activity b
p.o.; maximum
dose tested)
(% inhibition)
1
–
122 90
138 70
ethanol–water
DMF
C12H11NO
C19H15NO
185
273
–
–
2a
24.72
\800
2b
2c
126 65
134 60
acetone
C17H13NO2 263
17.97
\800
methanol–water C20H17NO2 303
33.70 c
\1600
2d
144 65
methanol
C20H17NO2 303
39.32 c
\1600
2e
3a
152 70
126 50
acetic
acid–water
C21H20N2O 316
29.21 c
35.71
\1000
\1600
ethanol
C21H19N3O 329
3b
3c
118 40
112 45
acetone
C19H17N3O2 319
23.21
\800
–pet.ether
acetone–benzene C22H21N3O2 359
42.85 c
\1600
3d
3e
136 40
142 35
ethanol
DMF
C22H21N3O2 359
C23H24N4O 372
46.43
51.78 c
67.85
\1600
\1600
37.50 c
a C, H, N were found within 90.4 %.
b All compounds were tested at a dose of 50 mg kg−1 p.o. except 3d which was tested at 25, 50 and 100 mg kg−1 p.o.
c PB0.001.

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E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2001) 81–92
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E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2001) 81–92
87
Figure 2. The bar diagram showing mean % anti-inflammatory activity of compound 3d and Phenylbutazone at three graded doses.
Figure 3. The bar diagram showing mean % anti-inflammatory activity of compounds 2d%, 2o% and Phenylbutazone at three graded
doses.
para position of phenyl ring are present; compound
2q% in which two NO2 groups at ortho and para
position are attached to the phenyl ring. These com-
pounds (2d%, 2n%, 2o%, 2q%) exhibited (57.57, 40.38,
59.61 and 42.30 %, respectively) inhibition of oedema
in rat paw.
electronegative atom at ortho or para position
or having some acidic group in the ring or ꢀNO2
group, then it shows promising anti-inflammatory
activity.
Figure 3 shows the anti-inflammatory activity of
compounds 2d%, 2o% and the reference drug phenylbu-
tazone at three graded doses (25, 50 and 100 mg kg−1
per oral).
Therefore, it may be concluded that when the com-
pound is substituted with a phenyl moiety having an

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E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2000) 81–92
Table III. Ulcerogenic liability of compounds 3d, 2d%, 2n%, 2o%,
2p%, 2r%, phenylbutazone and indomethacin.
4. Experimental protocols
4.1. Chemistry
Serial
number
Compound
Dose
Ulcerogenic
(mg kg−1 p.o) liability
The melting points are uncorrected. Carbon and hy-
drogen analysis were performed on CHN analyses,
Carlo Erba 1108, Heracus, at the Central Drug Re-
search Institute (Lucknow). Analysis (C, H, N) were
within 0.4 % of the theoretical values. The IR spectra
were recorded on Backman-Acculab-10 spectrophoto-
meter (wmax in cm−1). The 1H-NMR spectra were
recorded in CDCl3 on Brucker 400-FT instrument, Mass
spectra were determined on JEOL-JMS-D-300 spec-
trometer. Silica gel-G plates were used for TLC, the
eluent was a mixture of methanol–benzene in 2:8
proportion.
incidence
(%)
1
Indomethacin
1.8
3.6
5.4
60
80
100
30
25
2
3
4
5
6
7
8
Phenylbutazone
50
100
25
50
60
20
3d
50
100
25
30
50
20
2d%
2n%
2o%
2p%
2r%
50
100
25
20
50
50
4.1.1. i-Acetylaminonaphthalene (1)
To a solution of b-aminonaphthalene (0.01 mol) in
dry benzene (50 mL), acetylchloride (0.01 mol) was
added drop by drop at 0–5 °C. The reaction mixture
was stirred for 1 h and kept overnight. The reaction
mixture was distilled off and then poured onto ice. The
solid thus obtained was recrystallised from ethanol–wa-
ter. Physical, analytical and spectroscopic data are given
in tables I and IV, respectively.
50
100
25
70
90
30
50
100
25
40
60
60
50
100
25
60
90
40
4.1.2. i-Aminonaphthyl-substituted chalcones (2a–2e)
A solution of b-acetylamino naphthalene (0.01 mol)
in absolute ethanol (50 mL) is refluxed with various
aromatic aldehydes in the presence of 2 % NaOH for 10
h, concentrated, cooled and poured onto ice. The solids
thus obtained were recrystallised from appropriate sol-
vents. Physical, analytical and spectroscopic data of
compounds (2a–2e) are given in tables I and III,
respectively.
50
100
60
80
Considering ulcerogenic liabilities of potent com-
pounds, compound 2d% was found to possess less
ulcerogenic potentiality as compared with phenylbu-
tazone whereas compound 2o% possessed nearly the
same ulcerogenic liability as phenylbutazone (UD50 of
2d%=182.5 mg kg−1 i.p., UD50 of 2o%=69.18 mg kg−1
i.p. and UD50 of phenylbutazone=66.6 mg kg−1 i.p.).
Considering oral administration of the compounds
and the reference drugs, compounds 3d (the most
active pyrazoline), 2d% and 2o% are found to be safer
than phenyl butazone and indomethacin with respect
to ulcerogenic liability while the acidic compounds
(2n%, 2p% and 2r%) showed more percent incidence than
phenylbutazone but less percent incidence (or equipo-
tency) than indomethacin. Ulcerogenic potentiality
(p.o.) is given in table IV.
4.1.3. 1-Acetyl-5-substituted aryl-3-(i-aminonaphthyl)-
2-pyrazolines (3a–3e)
To a solution of compound (2a–2e) (0.02 mol) in
ethanol, 99 % hydrazine hydrate (0.04 mol) and few
drops of glacial acetic acid were added. The reaction
mixtures were refluxed for 8–10 h, distilled in vacuum
and cooled. The separated solids were filtered, washed
with ether and recrystallised from appropriate solvents.
Physical, analytical and spectroscopic data of com-
pounds (3a–3e) are given in tables I and IV, respectively.
4.1.4. i-(Substituted aminoethyl) amidonaphthalenes
(2a%–2t%)
To a solution of b-acetylaminonaphthalene (0.01 mol)

E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2001) 81–92
Table IV. Spectral data of compounds (2a–2e), (3a–3e) and (2a%–2t%).
89
Compound [M]+ m/z
1H-NMR (CDCI3) l (ppm)
IR (KBr) (cm−1
)
2a
2b
2c
273
263
303
5.80 (ss, 1H, NꢀH), 6.75 (d, 1H, ꢀCOꢀCHꢁ)
1720 (CꢁO), 1620 (CHꢁCH), 3410 (NH), 1580
8.25–7.60 (m, 12H, ArꢀH), 8.60 (d, 1H,ꢁCHꢀAr) (C···C of aromatic ring)
5.85 (ss, 1H, NH), 6.70 (d, 1H, ꢀCOꢀCHꢁ)
8.65(d, 1H, ꢁCHꢀAr), 8.30–7.75 (m, 10H, ArꢀH) (C···C of aromatic ring), 1070 (CꢀOꢀC)
1750 (CꢁO), 1630 (CHꢁCH), 3400 (NH), 1580
5.75 (ss, 1H, NH), 6.80 (d, 1H, ꢀCOꢀCHꢁ) 8.65 1710 (CꢁO), 1640 (CHꢁCH), 3420 (NH), 1550
(d, 1H, ꢁCHꢀAr), 8.20–7.65 (m, 11H, ArꢀH),
3.70N (s, 3H, ArꢀCOCH3)
(C···C of aromatic ring)
2d
2e
3a
303
316
329
3.80 (s, 3H, ArꢀOCH3), 8.20–7.60 (m, 11H,
ArꢀH) 5.85 (ss, 1H, NꢀH), 8.70 (d, 1H,
ꢁCHꢀAr), 6.65 (d, 1H, ꢀCOꢀCHꢁ)
1730 (CꢁO), 1640 (CHꢁCH), 3410 (NH), 1560
(C···C of aromatic ring)
5.80 (ss, 1H, NH), 6.60 (d, 1H, ꢀCOꢀCHꢁ), 8.70 1730 (CꢁO), 1620 (CHꢁCH), 3420 (NH), 1550
(d, 1H, ꢁCHꢀAr), 8.25–7.60 (m, 11H, ArꢀH),
1.5 [s, 6H, ꢀN(CH3)2]
(C···C of aromatic ring)
2.60 (s, 3H, COꢀCH3), 7.65 (d, 2H, pyrazoline
CH2), 8.25–7.80 (m, 12H, ArꢀH), 8.40 (t, 1H,
ꢀCHꢀAr), 9.3 (s, 1H, NH exchangeable with
D2O)
3400 (NꢀH), 1530 (NꢀN), 1580 (CꢁN), 1510
(CꢀN), 1560 (C···C of aromatic ring), 1710
(CꢁO)
3b
3c
3d
3e
319
359
359
372
2.65 (s, 3H, COꢀCH3), 7.60 (d, 2H, pyrazoline
CH2), 8.35–7.95 (m, 10H, ArꢀH), 8.45 (t, 1H,
ꢀCHꢀAr), 9.25 (s, 1H, NH exchangeable with
D2O)
3420 (NꢀH), 1520 (NꢀN), 1560 (CꢁN), 1530
(CꢀN), 1510 (C···C of aromatic ring), 1740
(CꢁO), 1060 (CꢀOꢀC)
2.70 (s, 3H, COꢀCH3), 7.75 (d, 2H, pyrazoline
CH2), 8.15–7.60 (m, 11H, ArꢀH), 8.30 (t, 1H,
ꢀCHꢀAr), 9.25 (s, 1H, NH exchangeable with
D2O), 3.70 (s, 3H, ArꢀOCH3)
3400 (NꢀH), 1500 (NꢀN), 1580 (CꢁN), 1510
(CꢀN), 1560 (C···C of aromatic ring), 1720
(CꢁO)
8.20–7.50 (m, 11H, ArꢀH) 7.70 (d, 2H,
pyrazoline CH2), 8.30 (t, 1H, ꢀCꢀAr), 2.75 (s,
3H, COꢀCH3), 3.80 (s, 3H, OCH3), 9.3 (s, 1H,
NH exchangeable with D2O)
1520 (NꢀN), 1590 (CꢁN), 1500 (CꢀN), 1750
(CꢁO), 1560 (C···C of aromatic ring), 3400
(NH)
2.60 (s, 3H, COꢀCH3), 7.70 (d, 2H, pyrazoline
CH2), 8.20–7.60 (m, 11H, ArꢀH), 8.35 (t, 1H,
ꢀCHꢀAr), 9.20 (s, 1H, NH exchangeable with
D2O), 1.45 [s, 6H, ꢀN(CH3)2]
3430 (NꢀH), 1520 (NꢀN), 1560 (CꢁN), 1500
(CꢀN), 1570 (C···C of aromatic ring), 1740
(CꢁO)
2a%
2b%
2c%
290
320
320
5.80 (s, 2H, ꢀCOꢀNHꢀ) 5.65 (hump, 1HꢀNH2), 3400 (NꢀH), 3060 (aromatic CꢀH), 2970, 2860
5.2–4.00 (m, 4H, CH2ꢀCH2), 8.30–7.50 (m, 12H, (aliphatic CꢀH), 1510 (C···C of aromatic ring),
ArꢀH)
1680 (CꢁO) 1220 (CꢀN)
5.80 (s, 2H, ꢀCOꢀNHꢀ), 5.65 (hump, 1HꢀNH2), 3410 (NꢀH), 3080 (aromatic CꢀH), 2960, 2850
5.2–4.00 (m, 4H, CH2ꢀCH2), 8.35–7.65 (m, 11H, (aliphatic CꢀH), 1500 (C···C of aromatic ring),
ArꢀH), 3.85 (s, 3H, ArꢀOCH3)
1670 (CꢁO) 1240 (CꢀN)
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.10 (m, 4H, CH2ꢀCH2),
8.25–7.50 (m, 11H, ArꢀH), 3.80 (s, 3H,
ArꢀOCH3)
3400 (NꢀH), 3020 (aromatic CꢀH), 2950, 2890
(aliphatic CꢀH), 1580 (C···C of aromatic ring),
1680 (CꢁO) 1210 (CꢀN)
2d%
2e%
324
324
5.85 (s, 1H, ꢀCOꢀNH), 5.60 (hump, 1H,
ꢀNHꢀCH2), 5.20–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.60 (m, 11H, ArꢀH)
3420 (NꢀH), 3040 (aromatic CꢀH), 2960, 2880
(aliphatic CꢀH), 1540 (C···C of aromatic ring),
1660 (CꢁO) 1230 (CꢀN), 680 (CꢀCl)
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.60 (m, 11H, ArꢀH)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic ring),
1670 (CꢁO) 1210 (CꢀN), 680 (CꢀCl)
(continued)

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E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2000) 81–92
Table IV. (Continued)
Compound [M]+ m/z
1H-NMR (CDCI3) l (ppm)
IR (KBr) (cm−1
)
2f%
332
5.85 (s, 1H, ꢀCOꢀNH), 5.75 (hump, 1H,
ꢀNHꢀCH2), 5.40–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.70 (m, 12H, ArꢀH), 2.50 (d, 2H,
ꢀCH2), 1.30 (d, 3H, ꢀCH3), 1.8 (m, 1H, ꢀCH)
3400 (NꢀH), 3060 (aromatic CꢀH), 2970, 2860
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN)
2g%
372
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.20–7.55 (m, 11H, ArꢀH), 1.38 (s, 3H, ꢀCH3)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN), 1640 (CꢁN),
1750 (CꢁO of quinazolinone ring), 1310
(NCN)
2h%
2i%
451
478
5.85 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.25–4.00 (m, 4H, CH2ꢀCH2),
8.20–7.50 (m, 11H, ArꢀH), 1.38 (s, 3H, ꢀCH3)
3430 (NꢀH), 3060 (aromatic CꢀH), 2960, 2870
(aliphatic CꢀH), 1530 (C···C of aromatic
ring), 1670 (CꢁO) 1220 (CꢀN), 1640 (CꢁN),
1750 (CꢁO of quinazolinone ring), 1330
(NCN)
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.35–7.20 (m, 16H, ArꢀH)
3410 (NꢀH), 3040 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN), 1070
(CꢀOꢀC), 1140 (CꢀS)
2j%
494
468
5.80 (s, 1H, ꢀCOꢀNH), 5.65 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.20 (m, 16H, ArꢀH)
3420 (NꢀH), 3020 (aromatic CꢀH), 2970, 2850
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN), 1130 (CꢀS)
2k%
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.25–7.20 (m, 15H, ArꢀH), 4.0 (d, 2H, ꢀCH2),
4.8 (t, 1H, COCH2NH)
3400 (NꢀH), 3040 (aromatic CꢀH), 2970, 2850
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1680 (CꢁO) 1210 (CꢀN), 1120 (NꢀH)
2l%
386
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.25–7.60 (m, 12H, ArꢀH), 5.50 (ss, 1H,
indolic proton exchangeable with D2O), 4.0 (d,
2H, ꢀCH2), 4.8 (t, 1H, NH)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN), 3150 (CꢀS)
2m%
2n%
266
413
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.90 (m, 7H, ArꢀH), 5.0 (s, 1H, NHOH)
3420 (NꢀH), 3060 (aromatic CꢀH), 2970, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1220 (CꢀN), 3300 (OꢀH)
5.70 (s, 1H, ꢀCOꢀNH), 5.50 (hump, 1H,
ꢀNHꢀCH2), 5.25–4.00 (m, 4H, CH2ꢀCH2),
8.20–7.55 (m, 10H, ArꢀH), 11.60 (s, 1H,
COOH)
3420 (NꢀH), 3020 (aromatic CꢀH), 2980, 2850
(aliphatic CꢀH), 1560 (C···C of aromatic
ring), 1660 (CꢁO) 1230 (CꢀN), 3380 (OꢀH),
1720 (CꢁO of carboxylic group)
2o%
492
5.70 (s, 1H, ꢀCOꢀNH), 5.50 (hump, 1H,
ꢀNHꢀCH2), 5.25–4.00 (m, 4H, CH2ꢀCH2),
8.40–7.95 (m, 9H, ArꢀH), 11.80 (s, 1H,
COOH)
3420 (NꢀH), 3020 (aromatic CꢀH), 2980, 2850
(aliphatic CꢀH), 1560 (C···C of aromatic
ring), 1660 (CꢁO) 1230 (CꢀN), 3380 (OꢀH),
1720 (CꢁO of carboxylic group)
2p%
2q%
305
395
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.00 (m, 4H, CH2ꢀCH2),
8.30–7.55 (m, 12H, ArꢀH)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN)
5.85 (s, 1H, ꢀCOꢀNH), 5.60 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.15 (m, 4H, CH2ꢀCH2),
8.35–7.70 (m, 10H, ArꢀH), 5.70 (hump 1H,
NHꢀAr exchangeable with D2O)
3410 (NꢀH), 3040 (aromatic CꢀH), 2960, 2880
(aliphatic CꢀH), 1550 (C···C of aromatic
ring), 1670 (CꢁO) 1210 (CꢀN), 1380 (NO2)
2r%
334
5.70 (s, 1H, ꢀCOꢀNH), 5.50 (hump, 1H,
ꢀNHꢀCH2), 5.25–4.00 (m, 4H, CH2ꢀCH2),
8.40–7.80 (m, 11H, ArꢀH), 11.80 (s, 1H,
COOH)
3420 (NꢀH), 3020 (aromatic CꢀH), 2980, 2850
(aliphatic CꢀH), 1560 (C···C of aromatic
ring), 1660 (CꢁO) 1230 (CꢀN), 3370 (OꢀH),
1720 (CꢁO of carboxylic group)
(continued)

E. Bansal et al. / European Journal of Medicinal Chemistry 36 (2001) 81–92
91
Table IV. (Continued)
Compound [M]+ m/z
1H-NMR (CDCI3) l (ppm)
IR (KBr) (cm−1
)
2s%
569
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.10 (m, 4H, CH2ꢀCH2),
7.70–6.40 (m, 10H, ArꢀH), 9.55 (ss, 2H,
2×NHCO), 4.00 (t, 2H, 2×ꢀCH), 3.20 (dd,
4H, 2×ꢀCH2)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1210 (CꢀN), 1270 (NꢀN), 3330 (NꢀH),
1730, 1715, 1680 (CꢁO), 1660–1640 (ꢀNꢁC)
2t%
549
5.80 (s, 1H, ꢀCOꢀNH), 5.70 (hump, 1H,
ꢀNHꢀCH2), 5.30–4.10 (m, 4H, CH2ꢀCH2),
7.70–6.95 (m, 6H, ArꢀH), 9.55 (ss, 2H,
2×NHCO), 4.00 (t, 2H, 2×ꢀCH), 3.20 (dd,
4H, 2×ꢀCH2)
3410 (NꢀH), 3050 (aromatic CꢀH), 2950, 2870
(aliphatic CꢀH), 1520 (C···C of aromatic
ring), 1210 (CꢀN), 1270 (NꢀN), 3330 (NꢀH),
1730, 1715, 1680 (CꢁO), 1660–1640 (ꢀNꢁC)
(containing active methylene group) in ethanol (50–70
mL), formaldehyde (0.02 mol) and amine (0.02 mol)
(primary or secondary) were added dropwise and the
reaction mixtures were refluxed for 1 h, distilled and
poured onto ice. The separated solids were filtered,
washed with petroleum ether and recrystallised from
appropriate solvents. Physical, analytical and spectro-
scopic data are given in tables II and IV, respectively.
intraperitoneally) indomethacin and phenylbutazone
(control) were given. The animals were sacrificed 8 h
after drug treatment. The stomach, duodenum and je-
junum were removed and examined with a hand lens for
any evidence of (a) shedding of epithelium; (b) petechial
and frank haemorrhages and (c) erosion or discrete
ulceration with or without the presence of haemorrhage.
The detection of any one of these conditions was consid-
ered to be an evidence for ulcerogenic activity.
4.2. Pharmacology
4.2.3. Acute toxicity
4.2.1. Anti-inflammatory activity
The potent compounds were investigated for their
acute toxicity (ALD50) in Albino mice by following the
method of Smith [15].
Rats of either sex weighing 60–100 g were divided
into groups of ten animals each. A solution of car-
rageenin (1.0 % in 0.9 % saline) 0.05 mL was injected
under the planter aponeurosis of the right paw of the rat
by the method of Winter et al. [12].
References
Vt−V
Vt
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Anti-inflammatory activity (%)=
c 100
[2] Paul A.I., Goodman and Gilman’s The Pharmacological Basis
of Therapeutics, ninth ed., 1996, p. 621.
where Vt and Vc are the volumes of oedema in the
drug-treated and the control groups. Phenylbutazone
and indomethacin were used as the reference drugs for
comparison.
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.