An efficient synthesis of pharmacologically active derivatives of 1,3,4-oxadiazoles

Article abstract of DOI:10.1002/jhet.5570430214

A simple and environmental friendly microwave irradiation method is devised for the synthesis of derivatives of 1,3,4-oxadiazoles viz., 6a-e and 7h-q in 75-90% yield. Structures of the newly synthesised compounds were confirmed by physical, analytical and

Full text of DOI:10.1002/jhet.5570430214

Mar-Apr 2006
An Efficient Synthesis of Pharmacologically Active Derivatives of
1,3,4-Oxadiazoles
345
Ravindra R. Kamble* and Belagur S. Sudha
Department of Chemistry and Food Science, Yuvaraja's College, University of Mysore, Mysore- 570 005, India.
e-mail: ravichem1234@rediffmail.com
Received June 16, 2005
A simple and environmental friendly microwave irradiation method is devised for the synthesis of deriva-
tives of 1,3,4-oxadiazoles viz., 6a-e and 7h-q in 75-90% yield. Structures of the newly synthesised com-
1
13
pounds were confirmed by physical, analytical and spectral (ir, H and C nmr and ms) data and screened
for antiinflammatory, anticonvulsant, antidiuretic and antihaemostatic activities. Some of the compounds
have shown potent activities.
J. Heterocyclic Chem., 43, 345 (2006).
Under the framework of “green chemistry” we have
activity. Compounds with 2-fluoro phenyl group at 3-posi-
tion and chlorine and bromine at 7-position have shown
excellent diuretic activity [12]. An isoxazole analog of (-)
nicotine is a potent antagonist at the α-4/β-2 sub type of
necronal nicotinic acetylcholine receptor that exists in
mammalian brain [13-14]. Barbachyn et al have identified
phenyl isoxazolines [15] as novel and viable antibacterial
agents. Hence, the present work involves the incorporation
of oxadiazole, the 1,3-dipolar cycloaddition product of
sydnone with isoxazole to explore their structure activity
relationship (SAR).
The importance of thiadiazepines and their derivatives
as potent antimicrobial agents is well established [16].
Some of the thiadiazepines find use as intermediates in the
preparation of substituted caprolactams useful for the
treatment of HIV diseases [17]. Triazole derivatives such
as estazolame, triazolame and alprazolame are success-
fully used as tranquillisers, hypnotics and depressants
respectively in clinical practices. 1,2,4-Triazole nucleus
has been incorporated into a wide variety of therapeuti-
developed an environmentally benign synthesis of isoxa-
zoles and 1,3,4-thiadiazepines integrated with oxadiazoles.
The combination of solvents, acids and long reaction time
period make synthetic methods environmentally haz-
ardous. The microwaves enhance the rate of chemical
reactions and hence they have gained popularity over the
usual homogenous and heterogenous reactions [1-2].
Microwave assisted syntheses provide an opportunity to
work with open vessels, thus avoiding the risk of high-
pressure development and with a possibility of carrying
out the reaction on a large scale in addition to the associ-
ated selectivity and ease of manipulation [3].
The chemistry of heterocycles has been an interesting
branch of organic chemistry as it offers a challenging task
in the development of new synthetic strategies. Sydnone
provides an interesting chemistry and its derivatives pos-
sess diverse chemotherapeutic properties. Hence, it is a
serendipitous heterocycle which has gained importance
due to its transformation into various heterocycles by 1,3-
dipolar cycloaddition reaction [4]. This concept has been
adopted to synthesise a number of heterocyclic compounds
by one-pot process from 3-arylsydnones [5-8].
cally interesting compounds including H /H histamine
1
2
receptor molecules, cholinesterase active agents, antianxi-
ety agents and sedatives [18]. Hence, we have also inte-
grated the oxadiazole with 1,3,4-thiadiazepine fused with
1,2,4-triazole to study their pharmacological significance.
In the light of these observations and as a part of our pro-
gramme towards non-traditional approach to the experi-
mental set up of organic reactions, the concept of
“microwave induced organic reaction enhancement”
Derivatives of isoxazoles were tested for ability to
inhibit the protein kinase C (PKC) dependent signal trans-
mission [9]. The mechanism for metabolic isoxazole ring
opening during the antiinflammatory activity and anti HIV
activity has also been studied [10-11]. A series of isoxa-
zole derivatives were prepared and tested for diuretic

346
R. R. Kamble and B. S. Sudha
Vol. 43
Scheme 1
4-Bromo-3-[p-(3'-phenyl-acryl-1'-oyl)] phenylsydnone (3a).
(MORE) has been utilized for rapid and efficient synthesis
of the title compounds, which have found to be pharmaco-
logically active (Table 1-4). The reproducibility of synthe-
ses through microwave irradiations was also assessed.
4-Bromo-3-(p-acetylphenyl)sydnone (1) was obtained
by literature method [4]. The reaction of 1 with aromatic
aldehyde 2a-e in presence of sodium hydroxide afforded
the expected 4-bromo-3-[p-(3'-phenyl acryl-1'-oyl)]
phenylsydnone (3a-e) [19] which on microwave irradia-
tion in acetic anhydride underwent 1,3-dipolar cycloaddi-
tion to 5-methyl-3-[p-(3'-aryl-acryl-1'-oyl)phenyl]-3H-2-
A solution of 2.82 g (0.01 mole) of 4-bromo-3-(p-acetyl-
phenyl)sydnone (1) and benzaldehyde (2a) of 1.06 g (0.01 mole)
dissolved in 20 ml of dry ethanol was taken in a borosil beaker
(100 ml), a catalytic quantity of sodium hydroxide (1-2 pellets)
was added and the reaction mixture was subjected to microwave
irradiation inside a microwave oven for 8 minutes (at 210 watts)
and then cooled in an ice bath. The product that formed was col-
lected by filtration, washed with 1:1 ethanol/water (5 ml) fol-
lowed by water till the washings were neutralised. The residue
was recrystallised from absolute ethanol to give bright yellow
crystals of 3a in yield 2.63 g (73%); mp: 212-213˚; ir: sydnone
-1
1
4
CO 1729 and enone CO 1653 cm ; H nmr: δ 7.95-7.74 (m, 9H,
oxo-∆ -1,3,4-oxadiazole (4a-e) [4]. The intermolecular
phenyl protons), 8.16 (d, 1H, C -H, J = 12 Hz), 8.24 (d, 1H, C -
3'
2'
cyclocondensation of 4a-e with hydroxylamine hydrochlo-
13
H, J = 12 Hz); C nmr: 96.40 (C ), 119.0 (C ), 121.5-135.0
4
2'
2
ride afforded 5-methyl-3-[p-(5'-aryl-4',5'-dihydro-∆ -isox-
(ArC), 141.2 (C ), 164.0 (C ), 169.5 (C ); ms: m/z 372 (M+2),
3'
1'
5
4
azol-3'-yl)phenyl]-3H-2-oxo-∆ -1,3,4-oxadiazole (6a). 5-
+
+
370 (M ), 342 (M+2-NO), 340 (M -NO), 314 (M+2-NO-CO),
312 (M -NO-CO), 270 (M+2-PhC H O), 268 (M -PhC H O,
Methyl-3-[p–(8'-aryl-3'-substituted-7',8'-dihydro-s-[1,2,4]-
triazolo[3,4-b]-1,3,4-thiadiazepine-6'-yl)-phenyl]-3H-2-
+
+
2
2
2 2
Base peak), 240 (M+2-PhC H O-NO), 238 (M+2-PhC H O-
2
2
2 2
4
NO), 103 (PhC H ).
oxo-∆ -1,3,4-oxadiazole (7h-q) was formed on intermole-
2
2
Anal. Calcd. for C H BrN O : C, 55.01; H, 2.99; N, 7.55.
cular cyclocondensation of 4a-e with 4-amino-3-mer-
capto-1,2,4-triazole [20] 5f-g (Scheme 1).
17 11
2 3
Found: C, 55.05; H, 2.95; N, 7.52.
Compound 3b: Yield 3.46 g (90%); mp: 153-154˚; ir: sydnone
-1
1
CO 1730 and enone CO 1659 cm ; H nmr: δ 2.38 (s, 3H,
EXPERIMENTAL
ArCH ), 7.06 (d, 2H, N -phenyl protons, J = 5.8 Hz), 7.23 (d, 2H,
3
3
N - phenyl protons, J = 5.8 Hz), 7.43 (d, 2H, C - phenyl protons,
3
3'
Nicolet Impact – 410 FT –IR spectrophotometer was used to
record ir spectra in KBr discs. Bruker – 300 MHz FT-NMR spec-
J = 8.4 Hz), 7.62 (d, 2H, C - phenyl protons, J = 8.4 Hz), 7.91 (d,
3'
13
1H, C -H, J = 10 Hz), 8.14 (d, 1H, C -H, J = 10 Hz); C nmr:
3'
2'
1
13
trometer was used to record H and C nmr spectra at 300 MHz.
Mass spectra were recorded on a EI-70 eV spectrometer.
Elemental analyses results are within 0.4% of the calculated
value. Microwave irradiations were carried out in a BPL 2300 ET
domestic microwave oven.
25.0 (ArCH ), 106.0 (C ), 122.3 (C ), 126.1-136.9 (ArC), 140.0
3
4
2'
+
(C ), 165.8 (C ), 168.4 (C ); MS: m/z 386 (M+2), 384 (M ), 356
(M+2-NO), 354 (M -NO), 328 (M+2-NO-CO), 326 (M -NO-
CO), 270 (M+2-PhC H O), 268 (M -PhC H O, Base peak), 247,
3'
1'
5
+
+
+
2
2
2 2
221, 145, 117, 105, 104.

Mar-Apr 2006
An Efficient Synthesis of Pharmacologically Active Derivatives
347
Anal. Calcd. for C
Found: C, 56.10; H, 3.45; N, 7.25.
Compound 3c: Yield 3.4 g (85%); mp: 215-216˚; ir: sydnone
H
BrN O : C, 56.12; H, 3.40; N, 7.27.
tons, J = 5.9 Hz), 8.44 (d, 2H, C -phenyl protons, J = 5.9 Hz),
18 13
2
3
3'
13
8.63 (d, 1H, C -H, J = 11 Hz), 8.75 (d, 1H, C -H, J = 11 Hz);
C
3'
2'
nmr: 16.7 (CH ), 21.1 (ArCH ), 122.2 (C ), 123.6-145.1 (ArC),
3
3
2'
-1
1
146.8 (C ), 151.6 (C ), 158.1 (C ), 179.4 (C ); ms: m/z 320
CO 1722 and enone CO 1664 cm ; H nmr: δ 3.44 (s, 3H,
3'
5
2
1'
+
+
+
(M ), 204 (M -CH C H C H, Base peak), 160 (M -
OCH ), 7.24 (d, 2H, N -ArH, J = 5.8 Hz), 7.55 (d, 2H, N -ArH, J
3
6
4
2
3
3
3
+
CH C H C H-CO ), 145 (CH C H C H O ), 117
= 5.8 Hz), 7.68 (d, 2H, C -ArH, J = 8.4 Hz), 7.99 (d, 2H, C -
3
6
4
2
2
3
6
4
3
2
3'
3'
+
+
+
(CH C H C H O -CO), 104 (CH C H CH ), 43 (CH CO ).
ArH, J = 8.4 Hz), 8.23 (d, 1H, C -H, J = 10 Hz), 8.35 (d, 1H, C -
3
6
4
3
2
3
6
4
3
3'
2'
13
Anal. Calcd. for C
H N O : C, 71.24; H, 5.03; N, 8.74.
H, J = 10 Hz); C nmr: δ 52.1 (OCH ), 109 (C ), 119.4 (C ),
19 16 2 3
3
4
2'
Found: C, 71.29; H, 5.04; N, 8.72.
124-138.5 (ArC), 143 (C ), 166.0(C ), 167 (C ); ms: m/z
3'
1'
5
+
+
Compound 4c: Yield 3.09 g (92%); mp: 201-202˚; ir: C -CO
402(M+2), 400 (M ), 372 (M+2-NO), 370 (M -NO), 344 (M+2-
5
-1
1
+
1771, CO 1680 cm ; H nmr: δ 1.9 (s, 3H, C -CH ), 3.70 (s, 3H,
OCH ), 6.95 (d, 2H, C - phenyl protons, J = 6.2 Hz), 7.15 (d, 2H,
NO-CO), 342 (M -NO-CO), 270 (M+2-OCH C H C H O), 268
5
3
3
6 4 2 2
+
(M -OCH C H C H O, Base peak), 133 (OCH C H -C H ).
3
3'
3
6
4
2
2
3
6
4
2 2
C - phenyl protons, J = 6.2 Hz), 7.28 (d, 2H, N - phenyl protons,
Anal. Calcd. for C
H N BrO : C, 54.00; H, 3.25; N, 7.00.
3'
3
18 13 2 4
J = 6.7 Hz), 7.57 (d, 2H, N -phenyl protons, J = 6.7 Hz), 8.71 (d,
Found: C 53.96; H, 3.20; N, 6.98.
Compound 3d: Yield 3.55 g (88%); mp: 232-233˚; ir: sydnone
3
13
1H, C -H, J = 14 Hz), 8.84 (d, 1H, C -H, J = 14 Hz); C nmr:
3'
2'
-1
1
15.34 (CH ), 54 (OCH ), 123.1 (C ), 125.4-144.0 (ArC), 147.6
CO 1715 and enone CO 1668 cm ; H nmr: δ 7.11 (d, 2H, N -
3
3
2'
3
+
(C ), 155.0 (C ), 160.7 (C ), 181.3 (C ); ms: m/z 336 (M ), 204
(M -CH OC H C H, Base peak), 160 (M -CH OC H C H-
CO ), 133 (CH OC H C H O ), 43 (CH CO ).
phenyl protons, J = 5.8 Hz), 7.35 (d, 2H, N - phenyl protons, J =
3'
5
2
1'
3
+
+
5.8 Hz), 7.42 (d, 2H, C - phenyl protons, J = 8.4 Hz), 7.50 (d,
3
6
4
2
3
6 4 2
3'
+
+
2H, C - phenyl protons, J = 8.4 Hz), 7.63 (d, 1H, C -H, J = 10
2
3
6
4
3
2
3
3'
3'
13
Anal. Calcd. for C
H
N O : C, 67.85; H, 4.79; N, 8.33.
Hz), 7.95 (d, 1H, C -H, J = 10 Hz); C nmr: 100.5 (C ), 118.4
19 16
2 4
2'
4
Found: C, 67.88; H, 4.75; N, 8.36.
(C ), 119.0-133.0 (ArC), 141.6 (C ), 160.9 (C ), 172.0 (C ); ms:
2'
3'
1'
5
+
+
Compound 4d: Yield 3.03 g (89%); mp: 196-197˚; ir: C -CO
m/z 406 (M+2), 404 (M ), 376 (M+2-NO), 374 (M -NO), 348
(M+2-NO-CO), 346 (M -NO-CO), 270 (M+2-ClC H C H O),
268 (M -ClC H C H O, Base peak), 241, 165, 137, 124.
5
-1
1
+
1768 and CO 1666 cm ; H nmr: δ 2.08 (s, 3H, C -CH ), 7.05
(d, 2H, N -phenyl protons, J = 7.2 Hz), 7.21 (d, 2H, N - phenyl
5
3
6
4 2 2
+
3
3
6
4 2 2
protons, J = 6.4 Hz), 7.54 (d, 2H, C - phenyl protons, J = 7.2 Hz),
Anal. Calcd. for C
H ClBrN O : C, 50.43; H, 2.47; N, 6.94.
3'
17 10 2 3
7.67 (d, 1H, C - phenyl protons, J = 6.4 Hz), 8.24 (d, 1H, C -H,
Found: C, 50.41; H, 2.45; N, 6.92.
Compound 3e: Yield 4.05 g (90%); mp: 153-154˚; ir: sydnone
3'
3'
13
J = 15 Hz), 8.35 (d, 1H, C -H, J = 15 Hz); C nmr: 15.0 (CH ),
2'
3
-1
1
120.1 (C ), 125.7-144.0 (ArC), 145.2 (C ), 155.0 (C ), 159.3
CO 1734 and enone CO 1650 cm ; H nmr: δ 7.10 (d, 2H, C -
2'
3'
5
3'
+
+
(C ), 188.7 (C ); ms: m/z 340 (M ), 204 (M -ClC H C H Base
peak), 160 (M -ClC H C H-CO ), 165 (ClC H C H O ), 137
phenyl protons, J = 5.0 Hz), 7.22 (d, 2H, C - phenyl protons, J =
2
1'
6 4 2
3'
+
+
5.0 Hz), 7.59 (d, 2H, N - phenyl protons, J = 6.9 Hz), 7.80 (d, 2H,
6
4
2
2
6 4 3 2
3
+
+
(ClC H C H O -CO), 131, 124, 43 (CH CO ).
N - phenyl protons, J = 6.9 Hz), 7.92 (d, 1H, C -H, J = 13 Hz),
6
4
3
2
3
3
3'
13
Anal. Calcd. for C
H N ClO : C, 63.44; H, 3.85; N, 8.22.
8.00 (d, 1H, C -H, J = 13 Hz); C nmr: 101.5 (C ), 116.8 (C ),
18 16 2 3
2'
4
2'
Found: C, 63.42; H, 3.84; N, 8.24.
Compound 4e: Yield 3.30 g (86%); mp: 182-183˚; ir: C -CO
120.1-133.9 (ArC), 140.6 (C ), 160.3 (C ), 169.0 (C ); ms: m/z
3'
1'
5
+
453 (M+4), 451 (M+2), 449 (M ), 423 (M+4-NO), 421 (M+2-
NO), 419 (M -NO), 395 (M+4-NO-CO), 393 (M+2-NO-CO),
391 (M -NO-CO), 270 (M+2-BrC H C H O), 268 (M -
5
-1
1
+
1784 and CO 1647 cm ; H nmr: 2.14 (s, 3H, C -CH ), 7.07 (d,
5
3
+
+
2H, N -phenyl protons, J = 7.2 Hz), 7.27 (d, 2H, N - phenyl pro-
3
3
6
4
2
2
tons, J = 6.4 Hz), 8.01 (d, 2H, C - phenyl protons, J = 7.2 Hz),
BrC H C H O, Base peak), 181.
3'
6
4 2 2
8.33 (d, 1H, C - phenyl protons, J = 6.4 Hz), 8.51 (d, 1H, C -H,
Anal. Calcd. for C
H
Br N O : C, 45.37; H, 2.24; N, 6.22.
3'
3'
17 10
2 2 3
13
J = 12 Hz), 8.60 (d, 1H, C -H, J = 12 Hz); C nmr: 14.9 (CH ),
Found: C, 45.36; H, 2.20; N, 6.19.
2'
3
119.4 (C ), 120.8-140.0 (ArC), 144.0 (C ), 155.01 (C ), 161.7
2'
3'
5
4
5-Methyl-3-[p-(3'-phenyl-acryl-1'-oyl)-phenyl]-3H- 2-oxo- ∆ -
1,3,4-oxadiazole (4a).
+
(C ), 181.6 (C ); ms: m/z 386 (M+2), 384 (M ), 211
2
1'
+
+
+
(BrC H C H O ), 209 (BrC H C H O ), 204 (M -
6
4
3
2
6
4
3
2
+
BrC H C H, Base peak), 183 (BrC H C H O -CO), 181
(BrC H C H O -CO), 170, 168, 160, 131 (50), 43 (CH CO ).
A mixture of 3a of 3.70 g (0.01 mole) and pure acetic anhy-
dride (3 ml) was taken in a borosil beaker (100 ml) and was
zapped inside microwave oven for duration of 8 minutes (at 280
watts). The reaction mixture was cooled, treated with water, fil-
tered and dried. Bright yellow crystals of 4a were obtained on
recrystallisation from methanol-dioxane mixture. Yield 2.90 g
6
4
2
6
4
3
2
+
+
6
4
3
2
3
Anal. Calcd. for C
H
N BrO : C, 56.12; H, 3.40; N, 7.27.
19 16
2
4
Found: C, 56.10; H, 3.38; N, 7.24.
2
5-Methyl-3-[p-(5'-phenyl-4',5'-dihydro-∆ -isoxazol-3'-yl)-
4
phenyl]-3H-2-oxo-∆ -1,3,4-oxadiazole (6a).
-1
1
(95%); mp: 137-138˚; ir: C -CO 1772 and CO 1652 cm ;
H
5
A mixture of chalcone 4a of 3.06 g (0.01 mole), hydroxy-
lamine hydrochloride (0.01 mole), DMF (20 ml) was taken in a
100 ml conical flask capped with a glass funnel and irradiated in
a microwave oven for 9 minutes (at 250 watts). The reaction mix-
ture was cooled and poured into cold water. The solid 6a sepa-
rated was filtered, washed with water and recrystallised from
nmr: δ 2.33 (s, 3H, C -CH ), 7.93-8.22 (m, 9H, phenyl protons),
5
3
13
8.67 (d, 1H, C -H, J = 13 Hz), 8.71 (d, 1H, C -H, J = 13 Hz);
C
3'
2'
nmr: 15.4 (CH ), 120.9 (C ), 123.3-142.8 (ArC), 150.1 (C ),
3
2'
5
144.2 (C ), 150.1 (C ), 155.0 (C ), 187.0 (C ); ms: m/z 306
3'
5
2
1'
+
+
+
(M ), 204 (M -PhC H, Base peak), 160 (M -PhC H-CO ), 131
(PhC H O ), 103 (PhC H O -CO), 90 (PhCH ), 43 (CH CO ).
2
2
2
+
+
+
+
3
2
3
2
3
ethanol to yield 2.89 g (90%); mp: 151-152˚; ir: C -CO 1769 and
Anal. Calcd. for C
Found: C, 70.56; H, 4.63; N, 9.17.
H
N O : C, 70.58; H, 4.61; N, 9.15.
5
18 14
2 3
-1
1
C=N 1600 cm ; H nmr; δ 2.03 (s, 3H, C -CH ). 3.50 (dd, 1H,
5
3
C -H , J = 15.8 Hz, J = 11.0 Hz), 3.90 (dd, 1H, C -H , J
Compound 4b: Yield 2.75 g (86%); mp: 182-183˚; ir: C -CO
4'
B
BA
BX
4'
A
AB
5
-1 1
= 15.8 Hz, J = 4.50 Hz), 4.90-5.0 (dd, 1H, C -H , J = 4.49
1781 and CO 1658 cm ; H nmr: δ 2.09 (s, 3H, C -CH ), 2.32 (s,
AX
5'
X
XA
13
5
3
Hz, J = 11.0 Hz), 7.19-7.74 (m, 9H, phenyl protons); C nmr:
3H, ArCH ), 7.71 (d, 2H, N -phenyl protons, J = 7.0 Hz), 7.82 (d,
XB
3
3
δ 15.2 (C -CH ), 30.3 (C ), 69.8 (C ), 120.5-140.9 (ArC), 155
2H, N -phenyl protons, J = 7.0 Hz), 8.25 (d, 2H, C -phenyl pro-
5
3
4'
5'
3
3'

348
R. R. Kamble and B. S. Sudha
Vol. 43
+
+
5-Methyl-3-[p–(8'-phenyl-3'-substituted-7',8'-dihydro-s-[1,2,4]-
triazolo[3,4-b]-1,3,4-thiadiazepine-6'-yl)- phenyl]-3H-2-oxo-∆ -
1,3,4-oxadiazole (7h).
(C ), 156.4 (C ), 164.6 (C ); ms: m/z 321 (M ), 264 (M -
5
2
3'
+
+
4
CH NCO), 236 (M -CH NCO-CO), 146 (M -PhC H N O ,
3
3
3 3 2 2
+
Base peak), 119 (M -PhC H N O -HCN).
3
3 2 2
Anal. Calcd. for C
Found: C, 67.30; H, 4.69; N, 13.07.
Compound 6b: Yield 2.88 g (86%); mp: 170-171º; ir: C -CO
H N O : C, 67.28; H, 4.71; N, 13.08.
18 15 3 3
A solution of chalcone 3a of 3.06 g (0.01 mole) in DMF (20
ml) was taken in borosil beaker (100 ml). A few drops of piperi-
dine and 4-amino-3-mercapto-1,2,4-triazole 5f of 1.16 g (0.001
mole) were added. The mixture was zapped inside a microwave
oven for 10 minutes (at 280 watts) and then cooled in an ice bath.
The product formed was filtered, washed with ethanol (5 ml) and
crystallised from methane-dioxane (1:1) to get bright yellow nee-
5
-1
1
1773 and C=N 1605 cm ; H nmr: δ 2.00 (s, 3H, C -CH ), 2.24
5
3
(s, 3H, ArCH ), 3.20 (dd, 1H, C -H , J = 17.1 Hz, J = 11.84
3
4'
B
BA
BX
Hz), 4.15 (dd, 1H, C -H , J = 17.1 Hz, J = 4.70 Hz), 5.5-
4'
A
AB
AX
5.6 (dd, 1H, C -H , J = 4.68 Hz, J = 11.84Hz), 6.99 (d, 2H,
5'
X
AX
XB
C -phenyl protons, J = 6.5 Hz), 7.07 (d, 2H, C -phenyl protons,
5'
5'
dles, 2.47 g of 7h in 86% yield; mp: 165-166º; ir: C -CO 1775
5
J = 6.5 Hz), 7.41 (d, 2H, N -phenyl protons, J = 6.9 Hz), 7.50 (d,
3
-1
1
and C=N 1595 cm ; H nmr: δ 2.33 (s, 3H, C -CH ), 3.42 (dd,
1H, C -H , J = 17.60 Hz, J = 11.0 Hz), 4.05 (dd, 1H, C -
5
3
13
2H, N -phenyl protons, J = 6.9 Hz); C nmr: δ 17.6 (C -CH ),
3
5
3
7'
B
BA
BX
7'
20.9 (ArCH ), 29.2 (C ), 70.0 (C ), 118-142 (ArC), 150 (C ),
3
4'
5'
5
H , J = 17.60 Hz, J = 4.5 Hz), 5.0-5.5 (dd, 1H, C -H , J
A
AB
AX
8'
X
XA
+
+
157 (C ), 160.1 (C ); ms: m/z 335 (M ), 278 (M -CH NCO),
2
3'
3
= 4.50 Hz, J = 11.0 Hz), 7.32-7.50 (m, 9H, phenyl protons),
XB
+
+
250 (M -CH NCO-CO), 160 (M -PhC H N O , Base peak),
3
3 3 2 2
13
8.0 (s, 1H, C -H); C nmr: δ 15.4 (C -CH ), 40.1(C ), 40.5
3'
5
3
7'
+
133 (M -PhC H N O -HCN).
3
3 2 2
(C ), 120.0-139.9 (ArC), 148.0 (C ), 149 (C ), 153 (C ), 155
8'
10'
3'
5
Anal. Calcd. for C
Found: C, 68.02; H, 5.09; N, 12.54.
Compound 6c: Yield 3.19 g (91%); mp: 185-186º; ir: C -CO
H N O : C, 68.05; H, 5.11; N, 12.53.
19 17 3 3
+
+
+
(C ), 164.6 (C ); ms: m/z 404 (M ), 389 (M -CH ), 345 (M -
2
6'
3
+
+
CH -CO ), 304 (M -CH -CO -CH-N ), 229 (M -PhC H N O ,
3
2
3
2
2
3 3 2 2
5
Base peak), 202, 170.
-1
1
1765 and C=N 1598 cm ; H nmr: δ 2.10 (s, 3H, C -CH ), 3.73
5
3
Anal. Calcd. For C
H N O S: C, 59.39; H, 3.99; N, 20.78.
20 16 6 2
(s, 3H, ArOCH ), 3.30 (dd, 1H, C -H , J = 17.50 Hz, J =
3
4'
B
BA
BX
Found: C, 59.37; H, 3.97; N, 20.75.
Compound 7i: Yield 3.80 g (91%); mp: 171-172º; ir: C -CO
10.80 Hz), 4.00 (dd, 1H, C -H , J = 17.50 Hz, J = 7.02 Hz),
4'
A
AB
AX
5
5.2-5.4 (dd, 1H, C -H , J = 7.0 Hz, J = 10.75 Hz), 6.70 (d,
5'
X
XA
XB
-1
1
1769 and C=N 1599 cm ; H nmr: δ 2.05 (s, 3H, C -CH ), 2.30
5
3
2H, C -phenyl protons, J = 5.8 Hz), 7.08 (d, 2H, C -phenyl pro-
5'
5'
(s, 3H, ArCH ), 3.47 (dd, 1H, C -H , J = 16.50 Hz, J =
3
7'
B
BA
BX
tons, J = 5.8 Hz), 7.24 (d, 2H, N -phenyl protons, J = 6.0 Hz),
3
12.0 Hz), 4.51 (dd, 1H, C -H , J = 16.50 Hz, J = 4.49 Hz),
13
7'
A
AB
AX
7.33 (d, 2H, N -phenyl protons, J = 6.0 Hz); C nmr: δ 16.0 (C -
3
5
5.65-5.84 (dd, 1H, C -H , J = 4.49 Hz, J = 12.0 Hz), 6.90
8'
X
XA
XB
CH ), 30.6 (C ), 56.0 (OCH ), 68.5 (C ), 121.2-138.6 (ArC),
3
4'
3
5'
(d, 2H, C -phenyl protons, J = 8.0 Hz), 7.10 (d, 2H, C -phenyl
+
+
8'
8'
154 (C ), 158 (C ), 164.0 (C ); ms: m/z 351 (M ), 294 (M -
5
2
3'
protons, J = 8.0 Hz), 7.35 (d, 2H, N -phenyl protons, J = 6.4 Hz),
+
+
3
CH NCO), 266 (M -CH NCO-CO), 176 (M -PhC H N O ,
Base peak), 149 (M -PhC H N O -HCN).
3
3
3 3 2 2
7.44 (d, 2H, N -phenyl protons, J = 6.4 Hz), 8.3 (s, 1H, C -H);
+
3
3'
3
3 2 2
13
C nmr: δ 15.9 (C -CH ), 21.4 (ArCH ), 39.4 (C ), 40.4 (C ),
116.0-139.4 (ArC), 144.0 (C ), 145 (C ), 150 (C ), 154 (C ),
5
3
3
7'
8'
Anal. Calcd. for C
Found: C, 64.93; H, 4.91; N, 11.93.
Compound 6d: Yield 2.80 g (79%); mp: 177-178º; ir: C -CO
H N O : C, 64.95; H, 4.88; N, 11.96.
19 17 3 4
10'
3'
5
2
+
+
+
168.1 (C ); ms: m/z 418 (M ), 403 (M -CH ), 359 (M -CH -
6'
3
3
5
+
+
CO ), 318 (M -CH -CO -CH-N ), 243 (M -PhC H N O , Base
-1
1
2
3
2
2
3 3 2 2
1779 and C=N 1610 cm ; H nmr: 1.94 (s, 3H, C -CH ), 3.40
5
3
peak), 216, 184.
(dd, 1H, C -H , J = 16.50 Hz, J = 10.0 Hz), 3.98 (dd, 1H,
4'
B
AB
BX
Anal. Calcd. For C
H N O S: C, 60.27; H, 4.34; N, 20.08.
21 18 6 2
C -H , J = 16.50 Hz, J = 6.99 Hz), 5.5-5.6 (dd, 1H, C -H ,
4'
A
AB
AX
5'
X
Found: C, 60.25; H, 4.32; N, 20.10.
J
= 7.0 Hz, J = 10.0 Hz), 7.13 (d, 2H, C -phenyl protons, J
XA
XB 5'
Compound 7j: Yield 3.69 g (85); mp: 210-212º; ir: C -CO
= 7.8 Hz), 7.20 (d, 2H, C -phenyl protons, J = 7.8 Hz), 7.25 (d,
5
5'
-1
1
1784 and C=N 1610 cm ; H nmr: δ 2.25 (s, 3H, C -CH ), 3.40
(s, 3H, OCH ), 3.54 (dd, 1H, C -H , J = 17.0 Hz, J = 8.08
2H, N -phenyl protons, J = 5.6 Hz), 7.31 (d, 2H, N -phenyl pro-
5
3
3
3
13
tons, J = 5.6 Hz); C nmr: δ 20.0 (C -CH ), 29.0 (C ), 67.6
(C ), 116-137.4 (ArC), 152 (C ), 154 (C ), 163.5 (C ); ms: m/z
355 (M ), 298 (M -CH NCO), 270 (M -CH NCO-CO), 180
(M -PhC H N O , Base peak), 153 (M -PhC H N O -HCN).
3
7'
B
BA
BX
5
3
4'
Hz), 4.14 (dd, 1H, C -H , J = 17.0 Hz, J = 7.02 Hz), 5.2-
7'
A
AB
AX
5'
5
2
3'
+
+
+
5.7 (dd, 1H, C -H , J = 7.02 Hz, J = 8.0 Hz), 7.10 (d, 2H,
8'
X
XA
XB
3
3
+
+
C -phenyl protons, J = 8.0 Hz), 7.18 (d, 2H, C -phenyl protons,
8'
8'
3
3
2
2
3 3 2 2
J = 8.0 Hz), 7.45 (d, 2H, N -phenyl protons, J = 5.5 Hz), 7.60 (d,
Anal. Calcd. for C
H ClN O : C, 60.77; H, 3.97; N, 11.81.
3
18 14 3 3
13
2H, N -phenyl protons, J = 5.5 Hz), 8.5 (s, 1H, C -H); C nmr:
Found: C, 60.81; H, 3.92; N, 11.85.
Compound 6e: Yield 2.80 g (79%); mp. 203-204º; ir: C -CO
3
3'
δ 16.1 (C -CH ), 40.8 (C ), 41.5 (C ), 51.0 (OCH ), 117.0-
5
3
7'
8'
3
5
-1
1
136.0 (ArC), 142.0 (C ), 143.0 (C ), 152.0 (C ), 155.0 (C ),
1785 and 1603 (C=N) cm ; H nmr (CDCl ): δ 2.01 (s, 3H, C -
10'
3'
5
2
3
5
+
+
+
165.0 (C ); ms: m/z 434 (M ), 419 (M -CH ), 375 (M -CH -
CH ), 3.50 (dd, 1H, C -H , J = 15.45 Hz, J = 11.80 Hz), 3.80
6'
3
3
3
4'
B
BA
BX
+
+
CO ), 334 (M -CH -CO -CH-N ), 259 (M -PhC H N O , Base
(dd, 1H, C -H , J = 15.45 Hz, J = 5.69 Hz), 4.8-5.1 (dd, 1H,
2
3
2
2
3 3 2 2
4'
A
AB
AX
peak), 232, 200.
C -H , J = 5.70 Hz, J = 11.75 Hz), 7.08 (d, 2H, C -phenyl
5'
X
XA
XB
5'
Anal. Calcd. For C
H
N O S: C, 58.05; H, 4.18; N, 19.34.
protons, J = 6.1 Hz), 7.36 (d, 2H, C -phenyl protons, J = 6.1 Hz),
21 18
6 3
5'
Found: C, 58.09; H, 4.20; N, 19.35.
7.61 (d, 2H, N -phenyl protons, J = 6.0 Hz), 7.69 (d, 2H, N -
3
3
13
Compound 7k: Yield 3.85 g (88); mp: 154-155º; ir: C -CO
phenyl protons, J = 6.0 Hz); C nmr: δ 17.5 (C -CH ), 29.9 (C ),
5
5
3
4'
-1
1
1770 and C=N 1605 cm ; H nmr: δ 2.10 (s, 3H, C -CH ), 3.40
68.4 (C ), 120.1-143.4 (ArC), 156 (C ), 159 (C ), 166.7 (C ); ms:
5
3
5'
5
2
3'
+
+
(dd, 1H, C -H , J = 16.5 Hz, J = 7.85 Hz), 3.94 (dd, 1H,
m/z 401 (M+2), 399 (M ), 344 (M+2-CH NCO), 342 (M -
CH NCO), 316 (M+2-CH NCO-CO), 314 (M -CH NCO-CO),
7'
B
BA
BX
3
+
C -H , J = 16.5 Hz, J = 10.0 Hz), 4.0-4.65 (dd, 1H, C -H ,
7'
A
AB
AX
8'
X
3
3
3
+
J
= 10.0 Hz, J = 7.85 Hz), 7.0 (d, 2H, C -phenyl protons, J
226 (M+2-PhC H N O ), 224 (M -PhC H N O , Base peak),
XA
XB 8'
3
3
2
2
3 3 2 2
+
+
= 6.9 Hz), 7.25 (d, 2H, C -phenyl protons, J = 6.9 Hz), 7.41 (d,
199 (M -PhC H N O -HCN), 197 (M -PhC H N O -HCN).
8'
3
3
2
2
3 3 2 2
2H, N -phenyl protons, J = 6.4 Hz), 7.65 (d, 2H, N -phenyl pro-
Anal. Calcd. for C
Found: C, 54.00; H, 3.56; N, 10.48.
H BrN O : C, 54.02; H, 3.53; N, 10.50.
3
3
18 14 3 3
13
tons, J = 6.4 Hz), 8.1 (s, 1H, C -H); C nmr: δ 17.4 (C -CH ),
3'
5
3

Mar-Apr 2006
An Efficient Synthesis of Pharmacologically Active Derivatives
349
40.6 (C ), 42.0 (C ), 117.0-141.0 (ArC), 145.0 (C ), 149.0
50.1 (OCH ), 123.2-139.5 (ArC), 145.0 (C ), 146.0 (C ), 151.0
3 10' 3'
7'
8'
10'
+
+
+
(C ), 153.0 (C ), 158.0 (C ), 169.4 (C ); ms: m/z 438 (M ), 423
(C ), 154.0 (C ), 159.9 (C ); ms: m/z 448 (M ), 433 (M -CH ),
3'
5
2
6'
5 2 6' 3
+
+
+
+
+
+
(M -CH ), 379 (M -CH -CO ), 338 (M -CH -CO -CH-N ),
263 (M -PhC H N O , Base peak), 236, 204.
389 (M -CH -CO ), 348 (M -CH -CO -CH-N ), 273 (M -
3 2 3 2 2
3
3
2
3
2
2
+
PhC H N O , Base peak), 246, 214.
3
3 2 2
3
3 2 2
Anal. Calcd. For C
H N O S: C, 58.92; H, 4.49; N, 18.74.
Anal. Calcd. For C
H N ClO S: C, 54.73; H, 3.44; N, 19.15.
22 20 6 3
20 15 6 2
Found: C, 54.76; H, 3.47; N, 19.18.
Found: C, 58.94; H, 4.52; N, 18.73.
Compound 7p: Yield 3.616 g (80%); mp: 146-147º; ir: C -CO
Compound 7l: Yield 4.50 g (93%); mp: 200-201º; ir: C -CO
5
5
-1
1
-1
1
1770 and C=N 1610 cm ; H nmr: δ 1.92 (s, 3H, C -CH ), 2.01
1765 and C=N 1590 cm ; H nmr: δ 2.15 (s, 3H, C -CH ),
3'
3
5
3
3.70 (dd, 1H, C -H , J = 15.0 Hz, J = 6.0 Hz), 3.94 (dd,
(s, 3H, C -CH ), 3.85 (dd, 1H, C -H , J = 13.0 Hz, J = 7.87
5 3 7' B BA BX
7'
B
BA
BX
Hz), 4.00 (dd, 1H, C -H , J = 17.60 Hz, J = 5.6 Hz), 5.11-
1H, C -H , J = 15.0 Hz, J = 9.4 Hz), 4.8-5.6 (dd, 1H, C -
7'
A
AB
AX
7'
A
AB
AX
8'
5.46 (dd, 1H, C -H , J = 5.6 Hz, J = 7.87 Hz), 6.95 (d, 2H,
H , J = 5.4 Hz, J = 6.0 Hz), 7.28 (d, 2H, C -phenyl pro-
8'
X
XA
XB
X
XA
XB
8'
tons, J = 7.0 Hz), 7.61 (d, 2H, C -phenyl protons, J = 7.0 Hz),
C -phenyl protons, J = 6.9 Hz), 7.10 (d, 2H, C -phenyl protons,
8
'
8
'
8'
J = 6.9 Hz), 7.48 (d, 2H, N -phenyl protons, J = 8.0 Hz), 7.59 (d,
7.80 (d, 2H, N -phenyl protons, J = 6.5 Hz), 8.01 (d, 2H, N -
3
3
3
13
13
2H, N -phenyl protons, J = 8.0 Hz); C nmr: δ 15.0 (C -CH ),
phenyl protons, J = 6.5 Hz), 8.4 (s, 1H, C -H); C nmr: δ
3
3'
3
3'
16.1 (C -CH ), 40.0 (C ), 40.9 (C ), 116-135.2 (ArC), 146.0
19.01 (C -CH ), 39.5 (C ), 40.2 (C ), 121.0-141.0 (ArC),
5
3
7'
8'
5
3
7'
8'
(C ), 148.9 (C ), 155.0 (C ), 157.0 (C ), 162.3 (C ); ms: m/z
146.0 (C ), 148.0 (C ), 156.0 (C ), 159.0 (C ), 164.0 (C );
10'
3'
5
2
6'
10'
3'
5
2
6'
+
+
+
+
+
+
452 (M ), 437 (M -CH ), 393 (M -CH -CO ), 352 (M -CH -
ms: m/z 484 (M+2), 482 (M ), 469 (M+2-CH ), 467 (M -
3
3
2
3
3
+
+
CO -CH-N ), 277 (M -PhC H N O , Base peak), 250, 218.
CH ), 309 (M+2-PhC H N O ), 307 (M -PhC H N O , Base
3
3
3
2
2
3
3
2
2
2
2
3 3 2 2
peak). 282, 280.
Anal. Calcd. For C H N ClO S: C, 55.69; H, 3.78; N, 18.56.
21 17 6 2
Anal. Calcd. For C
17.39. Found: C, 49.72; H, 3.15; N, 17.35.
Compound 7m: Yield 3.38 g (81%); mp: 163-164º; ir: C -CO
H
N BrO S: C, 49.70; H, 3.13; N,
Found: C, 55.72; H, 3.76; N, 18.59.
7q: Yield 4.32 g (87%); mp: 150-151º; ir: C -CO
20 15
6
2
Compound
1780 and C=N 1615 cm ; H nmr: δ 2.00 (s, 3H, C -CH ), 2.30 (s,
5
-1 1
5
3'
3
-1
1
1773 and C=N 1600 cm ; H nmr: δ 1.95 (s, 3H, C -CH ),
3H, C -CH ), 4.04 (dd, 1H, C -H , J = 17.67 Hz, J = 10.49
3'
3
5
3
7'
B
BA
BX
2.41 (s, 3H, C -CH ), 3.56 (dd, 1H, C -H , J = 14.0 Hz, J
Hz), 4.25 (dd, 1H, C -H , J = 17.67 Hz, J = 4.99 Hz), 5.15-
5
3
7'
B
BA
BX
7'
A
AB
AX
= 11.0 Hz), 3.98 (dd, 1H, C -H , J = 14.0 Hz, J = 5.1 Hz),
5.75 (dd, 1H, C -H , J = 4.99 Hz, J = 10.49 Hz), 7.14 (d, 2H,
7'
A
AB
AX
8' X XA XB
5.94-6.12 (dd, 1H, C -H , J = 5.1 Hz, J = 11.0 Hz), 7.35
C -phenyl protons, J = 5.5 Hz), 7.21 (d, 2H, C -phenyl protons, J =
8'
8'
X
XA
XB
8'
5.5 Hz), 7.50 (d, 2H, N
-phenyl protons, J = 6.0 Hz), 7.59 (d, 2H,
(d, 2H, C -phenyl protons, J = 9.0 Hz), 7.52 (d, 2H, C -phenyl
8'
8'
3
13
N
-phenyl protons, J = 6.0 Hz); C nmr: δ 15.6 (C -CH ), 17.5
protons, J = 7.0 Hz), 7.89 (d, 2H, N -phenyl protons, J = 8.0
3
3
3'
3
13
Hz), 7.95 (d, 2H, N -phenyl protons, J = 8.0 Hz); C nmr: δ
14.7 (C -CH ), 15.4 (C -CH ), 40.0 (C ), 40.5 (C ), 114-
(C -CH ), 39.0 (C ), 40.5 (C ), 118-139.0 (ArC), 145.0 (C ),
3
5
3
7'
8'
10'
147.0 (C ), 156.0 (C ), 158.0 (C ), 169.6 (C ); ms: m/z 498 (M+2),
3'
3
5
3
7'
8'
3' 5 2 6'
+
+
496 (M
), 483 (M+2-CH ), 481 (M -CH ), 439 (M+2-CH -CO ),
3 3 3 2
136.1 (ArC), 140.0 (C ), 141.0 (C ), 150.0 (C ), 153.0 (C ),
10'
3'
5
2
+
+
+
+
437 (M
-CH -CO ), 323 (M+2-PhC H N O , Base peak), 321
165.7 (C ); ms: m/z 418 (M ), 403 (M -CH ), 359 (M -CH -
CO ), 318 (M -CH -CO -CH-N ), 243 (M -PhC H N O ,
6'
3
3
3 2 3 3 2 2
+
+
+
(M
-PhC H N O , Base peak), 296, 294, 264, 262.
2
3
2
2
3
3
2
2
3 3 2 2
Anal. Calcd. For C
16.90. Found: C, 50.73; H, 3.44; N, 16.88.
H N BrO S: C, 50.71; H, 3.45; N,
Base peak), 216, 184.
Anal. Calcd. For C
21 17 6 2
H
N O S: C, 60.27; H, 4.34; N, 20.08.
6 2
21 18
Found: C, 60.25; H, 4.37; N, 20.11.
Compound 7n: Yield 3.63 g (84%); mp: 145-146º; ir: C -
Antiinflammatory Activity.
5
-1
1
Antiinflammatory activity was analysed using the carrageenan-
induced paw edema test in rats [21]. Male swiss rats (150-200 g)
were divided into control, standard and test groups, each consist-
ing of six rats. A group of rats was treated with Tween-80 (1%)
suspension i.p. (control). Another group was treated with 100
mg/kg of the suspension of the test compounds. After 30 minutes
the animals were injected with 0.1 ml of carrageenan (1% w/v) in
the sub plantar region of left hind paw of the rats. The volume of
the paw was measured using the mercury displacement technique
with the help of a plethysmometer both in control as well as in
standard animals including the test animals 2 hour and 4 hour after
injection. The initial volume of the paw was measured within 30
seconds of the injection. The percent inhibition of the inflamma-
tion after 2 hour and 4 hour was calculated using the % inhibition
= (1-v /v )×100, where v and v are the mean relative changes in
CO 1758 and C=N 1614 cm ; H nmr: δ 2.0 (s, 3H, C -CH ),
3'
3
2.29 (s, 3H, C -CH ), 2.51 (s, 3H, ArCH ), 3.34 (dd, 1H, C -
5
3
3
7'
H , J = 11.5 Hz, J = 10.1 Hz), 3.53 (dd, 1H, C -H , J
B
BA
BX
7'
A
AB
= 11.5 Hz, J
= 4.49 Hz), 4.88-5.13 (dd, 1H, C -H , J
=
AX
8'
X
XA
4.49 Hz, J = 10.1 Hz), 6.65 (d, 2H, C -phenyl protons, J =
XB
8'
6.9 Hz), 7.10 (d, 2H, C -phenyl protons, J = 6.9 Hz), 7.34 (d,
8'
2H, N -phenyl protons, J = 5.5 Hz), 7.44 (d, 2H, N -phenyl
3
3
13
protons, J = 5.5 Hz); C nmr: δ 14.5 (C -CH ), 15.9 (C -
CH ), 21.0 (ArCH ), 36.1 (C ), 38.0 (C ), 117.1-141.5 (ArC),
3'
3
5
3
3
7'
8'
143.4 (C ), 145.9 (C ), 152.0 (C ), 155.0 (C ), 164.2 (C );
10'
3'
5
2
6'
+
+
+
ms: m/z 432 (M ), 417 (M -CH ), 373 (M -CH -CO ), 332
3
3
2
+
+
(M -CH -CO -CH-N ), 257 (M -PhC H N O , Base peak),
3
2
2
3 3 2 2
230, 198.
Anal. Calcd. For C
H N O S: C, 61.09; H, 4.66; N, 19.43.
22 20 6 2
Found: C, 61.10; H, 4.62; N, 19.40.
Compound 7o: Yield 4.21 g (94%); mp: 221-222º; ir: C -CO
t
c
t
c
the volume of paw edema in the test and control respectively. The
results are summarised in Table 1.
5
-1
1
1769 and C=N 1606 cm ; H nmr: δ 2.15 (s, 3H, C -CH ), 2.31
3'
3
(s, 3H, C -CH ), 3.73 (s, 3H, OCH ), 3.85 (dd, 1H, C -H , J =
5
3
3
7'
B
BA
Anticonvulsant activity
17.64 Hz, J = 7.87 Hz), 4.00 (dd, 1H, C -H , J = 17.60 Hz,
BX
7'
A
AB
J
= 5.6 Hz), 5.11-5.46 (dd, 1H, C -H , J = 5.6 Hz, J
=
The anticonvulsant activity of title compounds was based on
maximal electroshock induced convulsions in rats [22]. Male
swiss rats were procured from Virus Diagnostic Laboratory,
Dharwad and maintained at Department of studies in Botany,
Karnatak University Dharwad, were fed with standard diet, water
AX
8'
X
XA
XB
7.87 Hz), 6.95 (d, 2H, C -phenyl protons, J = 6.0 Hz), 7.10 (d,
2H, C -phenyl protons, J = 6.0 Hz), 7.68 (d, 2H, N -phenyl pro-
tons, J = 6.9 Hz), 7.89 (d, 2H, N -phenyl protons, J = 6.9 Hz);
13
8'
8'
3
3
C nmr: δ 16.9 (C -CH ), 18.0 (C -CH ), 40.6 (C ), 41.2 (C ),
3'
3
5
3
7'
8'

350
R. R. Kamble and B. S. Sudha
Vol. 43
Table 1
Table 2
Results of Antiinflammatory Activity
Results of Anticonvulsant Activity
a
Compound
Dose Edema volume (ml) different)
% Inhibition
Compound Dose Time (sec) in various phases of convulsion Recovery/
mg/kg Flexion Extensor Clonus Stupor Death
mg/kg
interval (mean S.E.M
2hrs 4hrs
2hrs
4hrs
6a
6b
6c
6d
6e
7h
7i
7j
7k
7l
7m
7n
7o
7p
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
2.4
2.0
1.4
1.5
2.0
2.2
2.5
1.6
1.8
2.6
1.0
3.3
3.1
1.6
2.5
4.1
3.4
2.9
2.4
3.4
4.5
4.3
3.0
2.8
4.7
1.5
5.0
4.5
4.0
3.9
1.1
1.2
1.23
1.20
1.70
1.4
1.9
1.3
1.6
1.5
09
2.5
2.4
2.25
2.20
89
80
85
88
95
88
79
92
87
94
99
88
85
90
95
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
Recovery
6a
6b
6c
6d
6e
7h
7i
7j
7k
7l
7m
7n
7o
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0.32 0.02 0.28 0.02
0.31 0.15 0.29 0.18
0.29 0.01 0.16 0.02
0.30 0.01 0.21 0.02
0.35 0.02 0.24 0.01
0.32 0.02 0.17 0.01
0.35 0.02 0.14 0.01
0.30 0.02 0.10 0.01
0.34 0.02 0.11 0.01.
0.23 0.02 0.10 0.02
0.29 0.01 0.13 0.01
0.20 0.01 0.15 0.01
0.22 0.02 0.14 0.01
0.28 0.02 0.20 0.02
0.23 0.02 0.18 0.02
0.27 0.02 0.11 0.02
15.80 17.60
18.40 14.70
23.70 52.90
21.10 38.24
07.90 29.00
15.80 50.00
08.00 59.00
21.00 70.00
10.80 67.70
40.00 70.00
24.00 62.00
47.40 55.90
42.11 58.84
26.40 41.18
40.00 47.06
28.90 67.70
7p
7q
7q
Control
(Saline)
Standard
Standard
(Ibuprofen)
Control
(Tween-80)
-
4.0
1.5
11.0
2.0
3.0
1.5
120 Recovery
100 Recovery
-
0.38 0.02 0.34 0.02
-
-
(Phenyntoin) 25
a
No. of animals in each group is 06.
Values are mean S.E.M., No.of animals in each group is 06.
bleeding time was measured and the results are shown in Table 4.
Results and Discussion.
and libitum. All protocols of animal experiments have been
approved by the Institutional Animal Ethics Committee (IAEC).
Six groups of three rats were selected and to the first group saline
(control) injected i.p. and placed corneal electrodes on the cornea
then applied the prescribed current. The different stages of con-
vulsions were noted and used as control. To the second group 25
mg/kg of phenyntoin sodium (standard) was injected i.p. and
after 30 minutes subjected to electroconvulsions. The same pro-
cedure was repeated for remaining four groups using test com-
pounds 6a-e and 7h-q. Various stages of convulsions were
recorded at different intervals. The mean value for each group
was calculated and compared with control. The results are sum-
marised in Table 2.
The microwave procedure for the present work owes its impor-
tance due to the fact that the title compounds were synthesized in
excellent yields with shorter reaction periods.
Structures of all the newly synthesised compounds were con-
firmed by spectral analyses. In ir spectra, compounds 3a-e have
shown two strong absorption bands in the range 1715-1734 and
-1
1650-1668 cm due to sydnone carbonyl and α,β-unsaturated
carbonyl functions. The compounds 4a-e have shown lactone car-
bonyl and α,β-unsaturated carbonyl stretching frequencies in the
-1
range 1768-1784 and 1647-1680 cm respectively. The absence
of α,β-unsaturated carbonyl stretching in the final products 6d-e
and 7h-q indicated their formation. These final compounds have
Diuretic Activity.
-1
shown bands around 1758-1785 and 1595-1615 cm due to the
presence of lactone carbonyl function and C=N moiety.
The H nmr spectra of the compounds 4a-e, 6a-e and 7h-q
Diuretic activity evaluation (Table 3) is based on the effects of
drugs on water and electrolytes excretion in rats [23]. The ani-
mals were marked, weighed and divided into six groups. To the
first group, a water load of 25 ml/kg (control) p.o. was adminis-
tered orally. To the second group frusemide (standard) was given
i.p. along with a water load of 25 ml/kg. To the remaining four
groups, suspension of test compounds (100 mg/kg) was adminis-
tered i.p. along water. The animals were observed for diuresis and
the volume of urine collected was measured periodically. Results
were expressed as the mean of six samples and were compared to
that of standard.
1
have shown a common peak in the range of δ 1.90-2.41 ppm due
to a C -methyl protons on oxadiazole ring. The compounds 3a-e
5
and 4a-e have exhibited two doublets for vinylic protons between
δ 7.63-8.84 with J values in the range 10-15 Hz. The coupling
constant values suggest that these molecules exist in E-form.
A singlet was obtained in the range of δ 1.92-2.15 ppm due to
C -methyl protons in 7m-q where as, C unsubstituted 7h-l have
3'
3'
shown a singlet for one proton in the range of δ 8.0-8.5 ppm.
Other peaks due to aromatic protons appeared in the expected
13
range. C nmr of all these compounds showed number of sig-
Antihaemostatic Activity.
nals, which are in consistent with the number of carbons in the
respective molecules.
Tail bleeding time in conscious mice [24] was used to deter-
mine antihaemostatic activity of title compounds. Mice of either
sex weighing 20-25 g were divided into seven groups comprising
of ten mice in each group. Test compounds were administered in
2 % gum acacia. Control group received 0.4 ml of 2 % gum aca-
cia. 30 minutes after administration of the test compounds tail
In the electron impact studies, all the compounds showed
molecular ion peaks at their respective m/z. The bromo deriva-
+
tives 3a-d have shown molecular ion peaks M and M+2 in the
abundance ratio 1:1 where as the compound 3e has shown low
+
abundant molecular ion peaks M , M+2 and M+4 due to the

Mar-Apr 2006
An Efficient Synthesis of Pharmacologically Active Derivatives
351
Table 3
Results of Diuretic Activity
standard drug used (67.7%) The compounds which have shown
promising activity are 7m (62%) and 7i (59%) both with tolyl
substituent and 7o (58.84%) with p-anisyl substituent respec-
tively. The other compounds especially the isoxazole derivatives
6a-e have shown weak antiinflammatory activity.
a
Compound.
Dose
Total amount of urine collected (ml)
mg/kg
15'
30'
60'
120'
240'
Amongst the compounds subjected to anticonvulsant activity
(Table 2), the compounds 6e, 7j, 7l, 7m, 7p and 7q were found to
possess very good activity compared to that of standard phenyn-
toin. The other compounds have shown weak to moderate activ-
ity compared to the standard drug used. The diuretic activity
(Table 3) results indicated that the thiadiazepine derivatives with
6a
6b
6c
6d
6e
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3.5
4.0
4.4
4.8
3.7
3.0
3.5
3.7
3.0
4.0
5.1
4.0
4.5
4.9
4.8
5.4
4.0
3.4
3.9
4.3
3.8
3.5
2.9
3.3
3.8
3.5
4.5
4.5
3.9
4.4
4.3
4.6
C -methyl substituent viz., 7m-q have produced good diuresis
3'
compared to the standard drug frusemide.
Incase of antihaemostasis analyses (Table 4) of final com-
pounds, none of them have shown activity more than or equal to
standard drug indomethacin. Only the thiadiazepine derivatives
with p-bromophenyl substituent 7q (478.5), p-chlorophenyl sub-
stituent 7p (423.5) have shown considerable antihaemostatic
activity. Interestingly, here also the isoxazole 6a-e derivatives
have not exhibited antihaemostasis.
Standard
(Frusemide)
Control
(Water)
25 ml/kg
0
0
0
3.4
3.2
REFERENCES AND NOTES
a
No. of animals in each group is 06.
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Table 4
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Results of Antihaemostatic Activity
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Dose
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Average bleeding
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S. E.M)
-1
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6a
6b
6c
6d
6e
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0.4 ml
10
165.0 40.4
142.5 19.6
170.3 30.5
185.4 20.3
122.7 14.2
389.5 24.6
359.8 14.3
366.4 20.3
398.1 15.6
334.7 20.8
421.3 17.5
405.3 18.3
400.0 16.3
423.5 25.8
478.5 35.7
89.20 12.80
491.10 49.50
2% Gum acacia (control)
Indomethacin (standard)
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shown base peak due to loss of 5-methyl-3-phenyl- 3H-2-oxo-
4
∆ -1,3,4-oxadiazole free radical.
The antiinflammatory activity (Table 1) revealed that that
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phenyl groups on thiadiazepine ring have shown activity more
than the standard ibuprofen. The compound 7k with p-chloro
phenyl substituent has shown antiinflammatory activity equal to
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352
R. R. Kamble and B. S. Sudha
Vol. 43
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