Synthesis and anticonvulsant activity of some novel 3-aryl amino/amino-4-aryl-5-imino-Δ2-1,2,4-thiadiazoline

Article abstract of DOI:10.1016/j.ejmech.2007.05.008

A series of 3-aryl amino/amino-4-aryl-5-imino-Δ²-1,2,4-thiadiazoline have been synthesized using an appropriate synthetic route and characterized by elemental analyses and spectral data. The anticonvulsant activity of all the synthesized compounds was evaluated against maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (ScPTZ) induced seizure models in mice. The neurotoxicity was assessed using the rotorod method. All the test compounds were administered at doses of 30, 100, and 300 mg/kg body weight and the anticonvulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. Some of the compounds were evaluated for the Phenobarbitone induced hypnosis potentiation test. Among the compounds tested, all except 2h showed protection from MES seizures, whereas only 3b was found to be active in the ScPTZ test.

Full text of DOI:10.1016/j.ejmech.2007.05.008

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 749e754
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and anticonvulsant activity of some novel 3-aryl
amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazoline
a
b
Arun Gupta a, Pradeep Mishra a, Sushil K. Kashaw a, , Varsha Jatav , J.P. Stables
*
a Pharmaceutical Chemistry Division, Department of Pharmaceutical Sciences, Dr. H.S.Gour University, Sagar, MP 470003, India
b Preclinical Pharmacology Section, Epilepsy Branch, National Institutes of Health, Bethesda 20892-9020, USA
Received 27 November 2006; received in revised form 4 May 2007; accepted 24 May 2007
Available online 3 June 2007
Abstract
A series of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazoline have been synthesized using an appropriate synthetic route and
characterized by elemental analyses and spectral data. The anticonvulsant activity of all the synthesized compounds was evaluated against maximal
electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (ScPTZ) induced seizure models in mice. The neurotoxicity was
assessed using the rotorod method. All the test compounds were administered at doses of 30, 100, and 300 mg/kg body weight and the anticon-
vulsant activity was noted at 0.5 and 4 h time intervals after the drug administration. Some of the compounds were evaluated for the Phenobar-
bitone induced hypnosis potentiation test. Among the compounds tested, all except 2h showed protection from MES seizures, whereas only 3b
was found to be active in the ScPTZ test.
Published by Elsevier Ltd.
Keywords: Thiadiazoline; Anticonvulsant; Neurotoxicity
1. Introduction
gingival hyperplasia, hirsutism and megaloblastic anemia
[4,5]. The past decade has witnessed a continuous interest in
the development of anticonvulsant drugs.
In continuation of our earlier work [6,7], the present paper
report on the synthesis, anticonvulsant and neurotoxicity eval-
uation of some new 3-aryl amino/amino-4-aryl-5-imino-D2-
1,2,4-thiadiazoline.
Epilepsy is a central nervous system (CNS) malfunction
that leads either to generalized hyperactivity involving essen-
tially all parts of the brain or hyperactivity of only a portion of
the brain [1e3]. It has been estimated that adequate control of
seizures could not be obtained in up to 20% of the patients
with epilepsy using first generation of antiepileptic drugs
(phenobarbital, phenytoin, carbamazepine, sodium valproate
and diazepam). A group of new drugs including felbamate, ga-
bapentin, lamotrigine, oxacarbazepine, topiramate, milace-
mide, vigabatrin and zonisamide is entering into clinical
practice. The convulsions of approximately 25% of epileptics
are adequately controlled by current clinically available drugs.
Current drug therapy is accompanied by numerous side effects
including drowsiness, ataxia, gastrointestinal disturbances,
2. Chemistry
The synthesis of 3-aryl amino/amino-4-aryl-5-imino-D2-
1,2,4-thiadiazoline was accomplished as showed in Fig. 1.
Aryl thiourea (1) was prepared by reacting aromatic/hetero ar-
omatic amines with ammonium thiocyanate in the presence of
concentrated hydrochloric acid. Aryl thiourea (1) and thiourea
were oxidatively cyclised to yield 3-aryl amino-4-aryl-5-im-
ino-D2-1,2,4-thiadiazoline whereas two moles of aryl thiourea
were oxidatively cyclised into 3-amino-4earyl-5-imino-D2-
1,2,4-thiadiazoline.
* Corresponding author. Tel.: þ917582240757; fax: þ917582244094.
E-mail address: sushilkashaw@gmail.com (S.K. Kashaw).
0223-5234/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.ejmech.2007.05.008

750
A. Gupta et al. / European Journal of Medicinal Chemistry 43 (2008) 749e754
S
compounds showed preferably only MES seizures’ protec-
tion. Out of seventeen compounds only four (2d, 3ae3c)
showed prolonged activity. Three compounds 2b, 3a and 3b
exhibited potent anticonvulsant activity at 30 mg/kg at 0.5 h
(Table 1).
Heat
Ar-NH2
+
NH4SCN
Ar-NH-C-NH2
(1)
Ar
S
S
N
H2O2
H2N
NH
In the neurotoxicity test, compounds 2i and 2j did not
show toxicity at the highest administered dose (300 mg/kg),
whereas all remaining compounds showed toxicity at
100 mg/kg or 300 mg/kg doses. Compounds 2b and 3d ex-
hibited prolonged neurotoxicity. Some selected compounds
(Table 5) were evaluated for sedative-hypnotic effect using
Phenobarbitone induced hypnosis potentiation test. Com-
pounds 2c, 2d and 3b showed significant ( p < 0.05) percent-
age increase in sleeping time of the animals. These results
indicate that synthesized compounds exhibited potent anti-
convulsant activity without significantly inducing sleep (ex-
cept 2c, 2d and 3b).
NH2-C-NH2
Ar-NH-C-NH2
+
N
S
(2)
H2O2
Ar
N
Ar
N
H
NH
N
S
(3)
Fig. 1. Scheme for the synthesis of title compounds.
In conclusion the present results have revealed that a num-
ber of 3-aryl amino/amino-4-aryl-5-imino-D2-1,2,4-thiadiazo-
lines exhibit a range of activities in anticonvulsant screen
and some of the compounds showed significant increase in
sleeping time. Compounds 2b, 3a and 3b exhibited potent an-
ticonvulsant activity in MES screen at 30 mg/kg. Prepared
compounds are more selective for MES screen than ScPTZ
test.
3. Pharmacology
All the compounds were injected intraperitoneally into the
mice and evaluated in the initial anticonvulsant screening
with at least three dose levels (30, 100 and 300 mg/kg), fol-
lowing the anticonvulsant drug development (ADD) program
protocol [8,9]. The profile of anticonvulsant activity was es-
tablished by MES pattern test and ScPTZ seizure threshold
test. Minimal motor impairment was measured by the rotorod
(neurotoxicity, NT) test. Sedative-hypnotic activity was
established by Phenobarbitone induced hypnosis potentiation
test.
Table 1
Anticonvulsant activity and minimal motor impairment of compounds 2ae2j
and 3ae3g
Intraperitoneal injection in micea
4. Results and discussion
Code
MES
0.5 h
ScPTZ
0.5 h
Neurotoxicity screenb
Discovery and development of new chemical entity for
treatment of epilepsy rely heavily on the use of predictable
animal models. Presently, there are three in vivo models that
are routinely used by most AED discovery programs. These
include the maximal electroshock seizures, the ScPTZ and
kindling models. Of these the MES and ScPTZ models repre-
sent the two animal seizures models most widely used in the
search for new AEDs.
The anticonvulsant and neurotoxicity test results for the
titled compounds are reported in, along with the data of clin-
ically used drugs. All the 3-aryl amino/amino-4-aryl-5-imino-
D2-1,2,4-thiadiazolines except 2h were active in the MES
screen, indicating their ability to prevent seizure spread. At
a dose of 100 mg/kg, compounds that showed protection
were 2c, 2d, 3a and 3g at 0.5 h. Compound 3b was found
to be active in the ScPTZ test, a test used to identify com-
pound that elevate seizures’ threshold. Only 2h exhibited
no activity at maximum administered dose. Compounds 2d,
3ae3c showed rapid onset of action and prolonged duration,
on the other hand remaining compounds acted very fast but
with short duration of activity. It should be noted that only
few standard anticonvulsants exhibited broad spectrum of ac-
tivity by showing activity in both models. Our synthesized
4 h
4 h
0.5 h
4 h
2a
2b
300
30
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
100
300
100
100
100
100
100
100
00
e
e
e
300
e
2c
2d
100
100
300
300
300
e
300
300
30
e
e
300
e
e
e
e
e
2e
2f
2g
e
e
e
e
e
e
2h
2i
e
e
e
e
e
e
2j
3a
e
e
e
e
300
300
300
e
e
300
e
300
300
300
100
100
100
100
100
100
e
e
3b
3c
30
100
300
300
300
100
30
e
3d
3e
e
300
e
e
e
e
e
e
3f
3g
e
e
e
Phenytoin
Carbamazepine
100
e
e
100
100
300
30
a
Doses of 30, 100 and 300 mg/kg were administered. The figures in the ta-
ble indicate the minimum dose whereby bioactivity was demonstrated in half
or more of the mice. The animals were examined 0.5 and 4 h after injections
were made. The dash (e) indicates an absence of activity at maximum dose
administered (300 mg/kg).
b
Neurotoxicity at 100 mg/kg (0.25 h and 1 h).

A. Gupta et al. / European Journal of Medicinal Chemistry 43 (2008) 749e754
751
5. Experimental protocol
dilute ammonia. The precipitate thus obtained was collected
and recrystallised from ethanol (95%). Physico-chemical data
of the compounds (2ae2j) are presented in Table 2.
5.1. Chemistry
5.1.3. Synthesis of (aryl)-[4-(aryl)-5-imino-4,5-dihydro-3H-
[1,2,4] thiadiazol-3-yl]-amine (3ae3g)
Melting points were determined in open capillary tubes in
a Thomas Hoover melting point apparatus and are uncor-
rected. The purity of the compounds was confirmed by thin
layer chromatography using silica gel glass plates and solvent
system of benzeneeethanol (9:1). The spots were developed in
iodine chamber and visualized under ultra violet lamp. Infra-
red (IR) and 13C nuclear magnetic resonance (13C NMR) spec-
tra were recorded for the compounds in test in Shimadzu FTIR
8000 (KBr) and 13C Advance Bruker 300 MHz spec-
trophotometers, respectively. Chemical shifts are reported in
parts per million (ppm) using tetramethylsilane (TMS) as an
internal standard. Elemental analysis (C, H, N) was under-
taken with Perkin Elemer-2400 instrument and the measured
values agreed within ꢀ0.4% with the calculated. Mass spectra
were obtained on Joel SX 102/M-6000 mass spectrometer
applying FAB method.
Compounds 1 were oxidatively cyclised into 3-aryl amino-
4-aryl-5-imino-D2-1,2,4-thiadiazoline. The product was recrystallised
from hot ethanol. Physico-chemical and spectroscopic data of
the compounds (3ae3g) are presented in Tables 3 and 4,
respectively.
5.2. Pharmacological evaluation
The anticonvulsant evaluation was carried out using re-
ported procedures. Male albino mice (CF-1 strain, 18e25 g)
and male albino rats (SpragueeDawley, 100e150 g) were
used as experimental animals. The compounds were sus-
pended in 0.5% methyl celluloseewater mixture or in polyeth-
ylene glycol (PEG).
5.1.1. Synthesis of aryl thiourea (1)
5.2.1. Anticonvulsant screening
Aryl amine (0.1 mol) was taken in 250 mL of beaker contain-
ing 100 mL distilled water. HCl (10 mL) was added and contents
were warmed to dissolve the amine. Ammonium thiocynate
(7.6 g, 0.1 mol) was added to the amine solution and the mixture
was heated. The mixture was poured on crushed ice, the precipi-
tate thus obtained was filtered off by suction and recrystallised
fromethanol. Spectralanalysis, melting pointandelementalanal-
ysis confirm the formation of the corresponding thiourea.
In the preliminary screening, each compound was adminis-
tered by i.p. injection at three dose levels (30, 100 and 300 mg/kg)
and the anticonvulsant activity was assessed after 30 min and
4 h intervals of administration. The anticonvulsant efficacy
was evaluated by the maximal electroshock induced seizures
(MES) and subcutaneous pentylenetetrazole (ScPTZ). The
data are presented in Table 1.
5.1.2. Synthesis of 4-(4-chloro-phenyl)-5-imino-4,5-
5.2.2. Neurotoxicity screen
dihydro-[1,2,4] thiadiazole-3-ylamine (2ae2j)
Minimal motor impairment was measured in mice by the ro-
torod test. The mice were trained to stay on an accelerating ro-
torod that rotates at 10 revolutions/min. The rod diameter was
3.2 cm. Trained animals were given i.p. injection of the test
compounds in doses of 30, 100 and 300 mg/kg. Neurotoxicity
was indicated by the inability of the animal to maintain equilib-
rium on the rod for at least 1 min in each of the three trials.
Corresponding aryl thiourea (1ae1g, 0.5 mol) was taken in
a conical flask equipped with separating funnel and condenser
and was dissolved in a warm 10 mL of HCl. Hydrogen peroxide
(60e70 mL) was added dropwise fromthe separatingfunnelwith
continuous stirring. The mixture was kept aside for 2 h. The oxi-
dized mixture was then diluted with water and neutralized with
Table 2
Physical constants of the synthesized compounds 2ae2j
Ar
N
H2N
NH
N
S
Code
M.p. (ꢁC)
Yield (%)
Mol. formula
Mol. wt.
Element (found (%)/calculated (%))a
2a
2b
2c
2d
2e
2f
2g
2h
2i
63
248
108
98
69
65
73
74
68
74
65
65
67
75
C12H10N4S
C9H10N4SO
C10H12N4SO
C8H7N4SF
C8H7N4SCl
C8H7N4SBr
C7H7N5S
242.30
222.27
236.30
210.23
226.5
N (23.07/23.11), S (13.27/13.20)
N (25.23/25.19), S (14.54/14.41)
N (23.73/23.69), S (13.55/13.54)
N (26.65/26.71), S (15.38/15.22)
N (24.93/24.72), S (14.07/14.12)
N (20.63/20.65), S (11.74/11.83)
N (36.17/36.22), S (16.80/16.56)
N (36.73/36.22), S (16.08/16.56)
N (36.65/36.22), S (16.87/16.56)
N (44.00/43.80), S (16.53/16.47)
160
107
84
271.14
193.23
193.23
193.23
194.22
89
C7H7N5S
C7H7N5S
C6H6N6S
210
103
2j
a
Elemental analyses for N and S were within 0.4% of the theoretical values.

752
A. Gupta et al. / European Journal of Medicinal Chemistry 43 (2008) 749e754
Table 3
Physical constants of the synthesized compounds (aryl)-[4-(aryl)-5-imino-4,5-dihydro-3H-[1,2,4]thiadiazol-3-yl]-amine
Ar
N
NH
NH
Ar
N
S
Code
Ar
M.p. (ꢁC)
162
Yield (%)
81
Mol. formula
Mol. wt.
368.96
Element (found (%)/calculated (%))a
N (15.06/15.17), S (8.64/8.6)
3a
C22H16N4S
10-Naphthyl
3b
3c
143
141
73
85
C
18H20N4SO2
356.42
304.32
N (15.61/15.71), S (8.87/8.97)
H5C2O
40-Ethoxyphenyl
C14H10N4SF2
N (16.46/18.40), S (10.51/10.51)
F
40-Fluorophenyl
3d
293
43
C
12H10N6S
270.32
N (31.16/31.07), S (11.89/11.83)
N
20-Pyridyl
3e
313
309
64
70
C12H10N6S
270.2
N (31.84/31.07), S (11.39/11.83)
N
30-Pyridyl
3f
C12H10N6S
270.32
N (31.18/31.07), S (11.81/11.83)
N
40-Pyridyl
N
3g
210
90
C10H8N8S
272.29
N (41.24/41.13), S (11.77/11.75)
N
20-Pyrimidyl
a
Elemental analyses for N and S were within 0.4% of the theoretical values.
5.2.3. Phenobarbitone induced hypnosis potentiation test
The drug solution in polyethylene glycol (PEG 100) was
administered at a dose of 100 mg/kg to a group of six animals.
The animals were grouped into six each. Thirty minutes after
drug administration, animals were injected Phenobarbitone so-
dium. The animals fell asleep on their back. Sleeping time of
each rat was taken as the interval between the loss and return
of the righting reflex as indicated by inability and ability, re-
spectively, of the rat to right itself in three successive trials
when placed on its back. The time taken by animals to awake
was noted. The results are reported in Table 5. A control was
also performed after pre-treatment with test substance vehicle.

A. Gupta et al. / European Journal of Medicinal Chemistry 43 (2008) 749e754
753
Table 4
IR and 13C NMR spectroscopic data of the titled compounds
Ar
N
4
3
H2N
5
NH
2
1
N
S
Code
Ar
IR
13C NMR; 1H NMR
3
5
2
6
163 (C-3, C-5), 139.4 (C-10), 117.7 (C-2, C-6), 129.7
(C-30, C-50), 124.3 (C-40); 6.4e7.02 (m, 4H, Ar-H),
2 (s, 2H, NH2)
4
1
Cl
3415 (NH), 1578 (C]N), 1299
(CN), 725 (CS), 1618 (C]C)
2a
6'
7'
5'
8'
10'
163 (C-3, C-5), 141.2 (C-10), 109.4 (C-2), 126.6 (C-30, C-60),
119 (C-40), 128.6 (C-50), 125 (C-70), 121 (C-80), 134.3
(C-90, C-900), 124.7 (C-100); 6.55e7.61 (m, 7H, naphthalene),
2 (s, 2H, NH2)
9'
3411 (NH), 1568 (C]N), 1285
(CN), 636 (CS), 1616 (C]C)
4'
2b
1'
2'
3'
a
b
F
O
4'
163 (C-3, C-5), 132.9 (C-10), 116.9 (C-20, C-60), 115.2
(C-30, C-50), 147.5 (C-40), 64.7 (Ca), 14.8 (Cb); 1.33
(m, 3H, CH3), 3.98 (m, 2H, CH2), 6.4e7.02 (m, 4H, Ar-H),
2 (s, 2H, NH2)
5'
3'
3402 (NH), 1589 (C]N), 1295
(CN), 723 (CS), 1624 (C]C)
2c
2'
6'
1'
6'
5'
163 (C-3, C-5), 116.3 (C-30, C-50), 136.9 (C-10), 117.9
(C-20, C-6), 152.9 (C-40); 6.4e7.02 (m, 4H, Ar-H),
2 (s, 2H, NH2)
1'
4'
3398 (NH), 1590 (C]N), 1208
(CN), 709 (CS), 1617 (C]C), 1153 (CF)
2d
2e
2f
2'
3'
6'
N1'
2'
163 (C-3, C-5), 147.7 (C-20), 109.9 (C-30), 138.3 (C-40),
113.3 (C-50), 148.2 (C-60); 6.60e8.11 (m, 4H, pyridine ring),
2 (s, 2H, NH2)
5'
6'
3410 (NH), 1576 (C]N), 1282
(CN), 780 (CS), 1615 (C]C)
3'
2'
4'
N 1'
3'
4'
163 (C-3, C-5), 137.6 (C-20), 145.1 (C-30), 122.8 (C-40),
124.7 (C-50), 138.9 (C-60); 7.26e8.53 (m, 4H, pyridine ring),
2 (s, 2H, NH2)
3406 (NH), 1583 (C]N), 1322
(CN), 732 (CS), 1680 (C]C)
5'
2'
4'
3'
1'
N
3366 (NH), 1581 (C]N), 1240
(CN), 747 (CS), 1636 (C]C)
163 (C-3, C-5), 150.3 (C-20, C-60), 109.1 (C-30, C-50), 155.3
(C-40); 6.64e8.44 (m, 4H, pyridine ring), 2 (s, 2H, NH2)
2g
2h
2i
5'
6'
6'
1'
2'
N
5'
3403 (NH), 1558 (C]N), 1339
(CN), 731 (CS), 1621 (C]C)
163 (C-3, C-5), 169.3 (C-20), 157.9 (C-40, C-60), 110.3
(C-50); 6.58e8.38 (m, 3H, pyridine ring), 2 (s, 2H, NH2)
N3'
4'
5'
6'
Br
O
4'
163 (C-3, C-5), 140.3 (C-10), 118.5 (C-20, C-60), 132.5
(C-30, C-50); 6.4e7.02 (m, 4H, Ar-H),
2 (s, 2H, NH2), 113.1 (C-40)
1'
3407 (NH), 1576 (C]N), 1281
(CN), 701 (CS), 1618 (C]C)
2'
3'
a
5'
6'
3410 (NH), 1556 (C]N), 1282
(CN), 60 (CS), 1616 (C]C),
1217 (CeO)
163 (C-3, C-5), 133.6 (C-10), 117.3 (C-20, C-60), 115.1
(C-30, C-50), 150.7 (C-40), 55.9(Ca); 6.4e7.02
(m, 4H, Ar-H), 3.73 (m, 3H, CH3)
1'
4'
2j
2'
3'
(continued on next page)

754
A. Gupta et al. / European Journal of Medicinal Chemistry 43 (2008) 749e754
Table 4 (continued)
Ar
N
4
3
Ar'
N
H
5
NH
2
1
N
S
Code
Ar0
Ar
IR
13C NMR
6"
3'
2'
7"
1'
10'
8'
5"
9"
4'
5'
8"
163 (C-3, C-5), 140.8 (C-10), 141.2 (C-100), 109.4 (C-20, C-200),
126 (C-30, C-40, C-300, C-400), 119 (C-40, C-400), 128.6 (C-50, C-500),
125 (C-70, C-700), 121 (C-80, C-800), 134.3 (C-90, C-900), 124.7
(C-100, C-1000)
10"
9'
3453 (NH), 1571 (C]N), 1261
(CN), 704 (CS), 1606 (C]C)
3a
4"
1"
6'
7'
3"
5"
2"
5' 6'
6"
a
163 (C-3, C-5), 136 (C-10), 132.9 (C-100), 116.9 (C-20,
C-60, C-200, C-600), 115.2 (C-30, C-50, C-300, C-500),
147.5 (C-40, C-400)
4'
1'
O 4"
3419 (NH), 1576 (C]N), 1290
(CN), 720 (CS), 1667 (C]C),
1242(CeO)
a"
O
1"
3"
b
3b
3' 2'
b"
5' 6'
6"
N1"
3417 (NH), 1575 (C]N), 1297
(CN), 728 (CS), 1648 (C]C),
1161 (CF)
163 (C-3, C-5), 00140 (C-10), 136.9 (C-100), 117.9
(C-20, C-60, C-2 , C-600), 116.3 (C-30, C-50, C-300, C-500),
152.9 (C-40, C-400)
2"
1'
5"
F
4'
3c
3d
3e
3"
2'
4"
3'
6'
4'
6'
N1'
N1'
3417 (NH), 1542 (C]N), 1324
(CN), 723 (CS), 1658 (C]C)
163 (C-3, C-5), 158.6 (C-10), 147.7 (C-20), 109.9 (C-30, C-300),
138.3 (C-40, C-400), 113.3 (C-50, C-500), 148.2 (C-60, C-600)
5'
6'
2'
3'
5'
2'
3'
2'
1'
N1"
2"
N
3"
6"
163 (C-3, C-5), 137.6 (C-20, C-200),134.4 (C-20), 145.1 (C-30),
145.1 (C-300), 122.8 (C-40, C-400), 124.7 (C-50, C-500), 138.9
(C-60, C-600)
3411 (NH), 1565 (C]N), 1289
(CN), 7 68 (CS), 1614 (C]C)
4"
5"
2"
5' 4'
2'
3"
3'
1'
N
1"
N
4"
3332 (NH), 1582 (C]N), 1240
(CeN), 747 (CS), 1636 (C]C)
163 (C-3, C-5), 150.3 (C-20, C-60, C-200, C-60), 109.1
(C-30, C-50, C-300, C-500), 1155.3 (C-40, C-400)
4'
3f
6'
6"
5'
5"
6'
6'
N1'
N1'
3427 (NH), 1568 (C]N), 2312
(CN), 722 (CS), 1643 (C]C)
163 (C-3, C-5), 158 (C-2), 169.3 (C-200), 157.9 (C-40, C-400),
110.3 (C-50, C-500), 157.9 (C-60, C-600)
3g
5
5
2'
2'
N
N
4' 3'
4' 3'
Acknowledgements
The authors deeply appreciate the assistance of the Antiep-
ileptic Drug Development program, Epilepsy Branch, Preclin-
ical Pharmacology Section, NIH, USA.
Table 5
Phenobarbitone induced hypnosis potentiation test for some selected
compounds
Code
Duration of sleep in
minutes ꢀ SEM
% Increase in sleep
References
2b
2c
86 ꢀ 5.85
116 ꢀ 4.33
95 ꢀ 4.76
92 ꢀ 5.31
123 ꢀ 5.54
83 ꢀ 4.38
88 ꢀ 5.48
79 ꢀ 4.87
8.8
46.8*
20.2
16.4
55.6*
5.1
[1] W. Loscher, Eur. J. Pharmacol. 342 (1998) 1e13.
[2] M.L. Scheuer, T.A. Pedley, N. Engl. J. Med. 323 (1990) 1468e1474.
[3] T.R. Browne, G.L. Holmes, N. Engl. J. Med. 344 (2001) 1145e1151.
[4] M.J. Brodie, Lancet 336 (1990) 350e354.
2d
3a
3b
3c
[5] M.J. Eadia, Drugs 27 (1984) 328e363.
[6] N. Aggarwal, P. Mishra, J. Pharm. Pharm. Sci. 7 (2004) 260e264.
[7] N. Aggarwal, P. Mishra, J. Zhejiang Univ. Sci. 6B (2005) 617e621.
[8] R.L. Krall, J.K. Penry, B.G. White, H.J. Kupferberg, E.A. Swinyard, Epi-
lepsia 19 (1978) 409e428.
3g
Phosphate buffer
solution (control)
11.4
e
*Significant at the level of p < 0.05 at dose of 100 mg/kg; number of animals
taken for the study n ¼ 6.
[9] R.J. Porter, B.J. Hessie, J.J. Cereghino, G.D. Gladding, H.J. Kupferberg,
B. Scoville, B.G. White, Fed. Proc. 44 (1985) 2645e2649.