Synthesis and pharmacological evaluation of novel 1′-[2- (difluoromethoxy)benzyl]-2′H,5′H-spiro[8-azabicyclo[3.2.1]octane-3, 4′-imidazolidine]-2′,5′-diones and their derivatives

Article abstract of DOI:10.1002/ardp.201300289

A series of novel 1′-[2-(difluoromethoxy)benzyl]-2′H,5′H- spiro[8-azabicyclo[3.2.1]octane-3,4′-imidazolidine]-2′, 5′-dione substituted hydantoins (5-32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data. The novel molecules were screened for anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScPTZ)-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9, 10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared to phenytoin.

Full text of DOI:10.1002/ardp.201300289

370
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Full Paper
Synthesis and Pharmacological Evaluation of Novel 10-[2-
(Difluoromethoxy)benzyl]-20H,50H-spiro[8-azabicyclo[3.2.1]-
octane-3,40-imidazolidine]-20,50-diones and Their Derivatives
Malavalli Madaiah1, Maralekere K. Prashanth1, Hosakere D. Revanasiddappa1, and Bantal Veeresh2
1
Department of Chemistry, University of Mysore, Manasagangotri, Mysore, Karnataka, India
Department of Pharmacology, G Pullareddy College of Pharmacy, Mehdipatnam, Hyderabad, Andhra Pradesh,
2
India
A series of novel 10-[2-(difluoromethoxy)benzyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-imidazoli-
dine]-20,50-dione substituted hydantoins (5–32) were synthesized using an appropriate synthetic route
and characterized by elemental analysis and spectral data. The novel molecules were screened for
anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol
(ScPTZ)-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9,
10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with
lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared
to phenytoin.
Keywords: Anticonvulsant / Isocyanate / Maximal electroshock / ScPTZ / Spirohydantoins
Received: August 6, 2013; Revised: September 29, 2013; Accepted: October 1, 2013
DOI 10.1002/ardp.201300289
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
Introduction
have been approved to treat epilepsy. Although these drugs
have been shown to be effective in epileptic syndromes in a
number of patients, their efficacy does not appear to be
superior to that of the established antiepileptic drugs.
Therefore, the ideal antiepileptic should prevent different
types of seizures without producing side effects that affect
adversely patients’ quality of life. Taking into consideration
the above continued search for safer, more effective, and
possibly antiepileptogenic drugs is urgently necessary. The
incomplete information on the pathogenesis of human
epilepsy and the complex mechanism of action of majority
of antiepileptic drugs makes it difficult to use rational
methodologies of discovery. Conceptually, there are two
different methods of obtaining new anticonvulsants, namely
knowledge-based approaches and screening approaches [6, 7].
Knowledge-based approaches rely on the use of different
pharmacophores that were established through the analysis
of structural characteristics of clinically effective anticonvul-
sant active compounds. Serendipitous approaches involve a
comprehensive screening process that utilizes rodent models.
Conventionally, most screening programs employ mice and
rats to assess efficacy against either electrically or chemically
induced seizures [8, 9].
Epilepsy is a common neurologic affliction characterized by
excessive temporary neuronal discharge that affects about 1%
of the world’s population [1] and it is affecting a large section
of people, both male and female, throughout the world [2]. It
is characterized by recurrent seizures of cerebral origin,
presenting with episodes of sensory, motor, or autonomic
phenomenon with or without loss of consciousness [3]. The
known potential causes of epilepsy include brain tumors,
infections, traumatic head injuries, developmental malfor-
mations, cerebrovascular diseases, febrile seizures, and status
epilepticus [4]. Even though significant advances have been
made in epilepsy research, convulsions in 25% of epileptics
are inadequately controlled by standard drug therapy [5].
In recent times several new drugs, for example, levetir-
acetam, felbamate, lamotrigine, gabapentin, and topiramate,
Correspondence: Hosakere D. Revanasiddappa, Department of Chem-
istry, University of Mysore, Manasagangotri, Mysore 570 006, Karnataka,
India.
E-mail: hdrevanasiddappa@yahoo.com
Fax: þ91 821 2419363
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Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Pharmacological Evaluation of Novel Imidazolidinediones
371
Figure 1. Structure of different cyclic imides (a) 5-cyclic, (b) 6-cyclic, (c) 7-cyclic, and (d) 8-cyclic imides.
The structure–activity relationship (SAR) studies of clinical-
ly available antiepileptic drugs and other anticonvulsant
active compounds showed that most of these compounds
included 5- or 6-member cyclic imides moiety in their
molecules (Fig. 1). Hydantoins, a class of cyclic imides, have
been demonstrated to possess good anticonvulsant proper-
ty [10–12]. Depending on the nature of substitution on the
hydantoin ring, a wide range of other pharmacological
properties, e.g., antihypertensive [13], herbicidal [14], antitu-
mor [15], anti-HIV [16], antibacterial [17], and antiviral [18]
activities, have also been identified.
A pharmacophore model has been put forward as a result of
conformational investigations of the clinically established
anticonvulsant drugs such as carbamazepine, phenytoin,
and mephenytoin [19, 20]. The suggested pharmacophore
model for derivatives should have at least one aryl ring (R),
one electron donor atom (D), and a second donor atom in
close proximity to the NH group forming hydrogen bond
acceptor (HBA)/donor (HBD) units. The title compounds (5–32)
possessed all the required pharmacophoric elements (Fig. 2)
as the phenyl ring attached to the nitrogen moiety can be
referred to as the aryl ring (R – lipophilic aryl ring), the
nitrogen of the hydantoin ring can act as a HBD, and
the amide keto group of the hydantoin ring can act as a HBA.
The proposed hydantoins seems to resemble phenytoin.
With this as background and in continuation of our research
program on design and synthesis of new anticonvulsant
agents [21–23], the present work highlights the importance of
the synthesis of prototypes of diazaspirohydantoins and
efficacy of their anticonvulsant activity.
ethanolic media using sodium cyanide and ammonium
carbonate at heating temperature. The introduction of the
substituent aryl groups at N position of hydantoin ring was
achieved via selective N-alkylation reaction by reacting aryl
halide in presence of potassium carbonate and acetonitrile
solvent [26, 27]. Target key intermediate 4 was accomplished
by deprotection of tert-butyl carboxylate group from com-
pound 3 with dioxane in HCl and followed by basification
with sodium carbonate solution [28]. The aim of step 5 was to
introduce respective sulfonylchloride/isocynates at the N-
position of azaspiro bicyclic moiety [29, 30] to lead to the
desired compounds (5–32) for SAR study. This was furnished
by normal condensation reaction with good yield. The proton
spectral data agree with respect to the number of protons and
their chemical shifts with the proposed structures. The proton
spectral data of the compound 4 shows resonance at
d 8.69 ppm (s, 1H, NH). In all the synthesized compounds
(5–32), the above resonance disappeared, which confirmed the
condensation between the amino group and carbonyl group.
The formation of the hydantoin ring was confirmed by 1H
NMR, IR, and mass spectra. The chemical structures, physical
data, and yield of all the synthesized compounds are given in
Table 1.
Pharmacology
Some of the new derivatives obtained by the above-mentioned
procedure were undertaken for the initial anticonvulsant
studies by the anticonvulsant drug development (ADD)
program protocol [31, 32]. The profile of anticonvulsant
activity was established after i.p. injections into mice and
evaluated in the maximal electroshock (MES), subcutaneous
pentylenetetrazol (scPTZ), and neurotoxicity screens, using
doses of 30, 100, and 300 mg/kg at two different time intervals.
These data are presented in Table 2.
Results and discussion
Chemistry
The synthetic pathway utilized in the preparation of 10-[2-
(difluoromethoxy)benzyl]-20H,50H-spiro[8-azabicyclo[3.2.1]oc-
tane-3,40-imidazolidine]-20,50-dione derivatives is outlined as
shown in Scheme 1. The synthesis begins with protection of 8-
azabicyclo[3.2.1]octan-3-one hydrochloride 1 with di-tert-butyl
dicarbonate using dry dichloromethane as a solvent. Under
Bucherer–Bergs condition, azaspiro bicyclic hydantoin 3 was
made [24, 25]. The reaction was carried out in aqueous
It is well documented that one of the important core
fragments of anticonvulsants is defined by nitrogen heterocy-
clic system, usually lactam or imide, with attached phenyl or
alkyl groups [33, 34]. This common template is found in the
structures of first-generation anticonvulsants such as meph-
enytoin or phenytoin [7, 35–37]. At the present time, there are
two in vivo models that are routinely used by most AED
discovery programs. They include the MES and scPTZ model.
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M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Figure 2. Anticonvulsant agents showing essential pharmacophoric elements present in their structure hydrogen bond donor (HBD) unit;
lipophilic aryl ring (Ar), electron donor (D).
The MES and scPTZ seizure models represent the two animal
seizure models most widely used in the search for new
AEDs [38, 39]. All of the titled compounds were evaluated
initially in the MES and scPTZ, seizure models. The acute
neurological toxicity (NT) was determined in the rotarod test.
All the tested compounds showed protection against MES test
indicative of their ability to inhibit the seizure spread.
Compounds 15 and 17 showed protection against the MES
model at 30 mg/kg while some compounds that showed
protection against the MES model at 100 mg/kg include 5, 6, 8,
9, 10, 11, 16, 18, 23, 24, and 27, which showed activity at 0.5
and 4.0 h indicating that drug is potent having a rapid onset
of action and long duration of action, while 7, 12, 13, 14, 20,
21, 22, 25, 26, 28, 31, and 32 showed activity at 0.5 h only
showing rapid onset and short duration of action. Some of the
compounds, i.e., 19 and 30, showed activity only at 0.5 h, at
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Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Pharmacological Evaluation of Novel Imidazolidinediones
373
Scheme 1. General method for the synthesis of compounds 5–32. Reagents and conditions: (a) Boc anhydride, triethylamine,
dichloromethane, rt, 16 h; (b) ammonium carbonate, sodium cyanide, ethanol/water, rt, 24 h, 50°C, 24 h; (c) anhydrous potassium carbonate,
1-(bromomethyl)-2-(difluoromethoxy)benzene, acetonitrile, reflux, 6 h; (d) dioxane in HCl, rt, 4 h; (e) sodium carbonate solution, rt, 1 h;
and (f) R ¼ sulfonyl chloride/isocyanate, triethylamine, dichloromethane, rt, 16 h.
high dose level of 300 mg/kg indicating that they have rapid
onset and shorter duration of action with low potency.
All test compounds except 19 were found to be active in the
scPTZ test, a test used to identify compounds that elevate
seizure threshold. Compounds 12, 15, and 22 showed activity
at a dose of 30 mg/kg while 5, 6, 8, 9, 10, 11, 13, 14, 16, 17, 18,
20, 21, 23, 24, 25, 26, 27, 29, 30, and 31 showed activity at
dose of 100 mg/kg comparable to sodium valproate. All the
potent compounds are found to be short acting, except 5, 6,
9, 10, 11, 16, and 18 that were found to be active at 4 h at the
dose of 100 mg/kg, which indicated their long duration of
action.
activity in MES test rather than the scPTZ screen, while 50% of
the compounds had equal activity on both models.
In neurotoxicity screen, compounds 6, 9, 10, 18, 23, and 27
did not show neurotoxicity in the maximum administered
dose (300 mg/kg) and the remaining compounds were found
to be less neurotoxic as compared to phenytoin.
Some selected compounds were evaluated for their CNS
behavioral activity in mice using actophotometer and CNS
depressant study using Porsolt’s forced swim pool test. The
results are presented in Tables 3 and 4, respectively. In the
behavioral study using actophotometer, the compound 23
showed no behavioral despair effect when compared to
phenytoin as represented in Table 3. Compounds 17 and 27
did show decreased locomotor activity in the 30-min interval
but did not show any significant behavior despair effect in 1-h
time period. All others were found to decrease behavioral
Thus, in general, these compounds are short-acting
anticonvulsants. Secondly, the protection was afforded by
100% and 90% of the compounds in the MES and scPTZ screen,
respectively. In addition, 40% of compounds had greater
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M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Table 1. Chemical structures, weights, yields, and melting points
of the compounds 5–32.
Table 2.
Anticonvulsant and neurotoxicity screening of
compounds.a)
Weight Yield m.p.
MES
screen
PTZ
screen
Neurotoxicity
screen
Compound
R
(mg)
(%)
(°C)
5
6
7
8
3,4-(H3C)2C6H3SO2
2-H3CC6H4SO2
3-BrC6H4SO2
2-FC6H4SO2
2,5-(H3C)2C6H3SO2
4-H3CC6H4SO2
102
98
107
96
102
95
92
97
103
94
102
97
93
69
68
66
66
69
66
61
65
71
64
70
66
63
68
65
70
76
70
74
71
70
76
74
72
73
75
75
74
216
202
209
237
205
208
201
203
222
228
235
218
221
210
245
235
239
236
232
240
238
242
237
246
237
248
252
244
Compound
0.5 h 4 h 0.5 h 4 h
0.5 h
4 h
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
100
100
100
100
100
100
100
100
100
100
30
100
100
300
100
100
100
100
300
300
300
100
100
100
100
300
300
300
300
100
100
300
300
100
300
300
300
300
300
30
100
100
300
100
100
100
100
30
100
100
30
100
100
100
–
100
100
300
300
100
100
100
100
300
300
100
100
300
100
–
100
–
–
–
100
100
–
300
300
–
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3-ClC6H4SO2
–
–
4-F,2-H3CC6H3SO2
4-H3COC6H4SO2
4-H3CC6H4CH2SO2
3- FC6H4SO2
3,5-(H3C)2C6H3SO2
4-H5C2C6H4SO2
3-H3CC6H4SO2
2-NCC6H4SO2
4-H3CSC6H4NHCO
3-FC6H4NHCO
100
100
100
100
–
300
300
300
300
100
–
100
30
–
98
95
100
–
–
100
300
100
100
100
100
100
100
100
100
100
100
300
100
100
30
–
103
105
98
106
102
99
111
108
102
73
104
107
112
300
100
100
100
–
300
300
300
300
–
100
100
30
300
300
100
100
300
300
300
100
300
–
4-FC6H4NHCO
2-ClC6H4NHCO
3-ClC6H4NHCO
3-CNC6H4NHCO
4-(H3C)2HCC6H4NHCO
2-(H3C)2HCC6H4NHCO
3-H5C2C6H4NHCO
C6H5NHCO
3-H3CC6H4NHCO
3,5-(H3C)2C6H4NHCO
2-Cl,3,5-(H3C)2C6H3NHCO
100
100
100
100
100
300
100
100
100
300
ꢀ
300
300
300
–
300
300
300
–
300
100
100
100
100
100
–
300
300
300
300
300
100
–
300
300
300
ꢀ
Phenytoin
Sodium valporate
ꢀ
ꢀ
300
–
activity of the animals. Among the compounds, the aryl
derivative exhibited activity. Similarly, results were
Evaluation of compounds in the mouse intraperitoneal MES,
scPTZ, and NT screens.
6
obtained in Porsolt’s swim pool test with compound 23 in
which an increase in the slight immobility time by the
compounds indicated the CNS depressant effect. Rest of the
tested compounds showed no significant variation from
control.
a)
Doses of 30, 100, and 300 mg/kg of the compounds were
administered and the protection and neurotoxicity measured
after 0.5 and 4 h. The figures indicate the minimal dose required
to cause protection or neurotoxicity in 50% or more of the
animals. The dash (–) indicates the absence of anticonvulsant
activity or neurotoxicity. ꢀ denotes not tested.
In past years, the discovery and development of anticon-
vulsant drugs have been the noticeable research fields. The
search for new compounds combining strong anticonvulsant
activity is in progress. Many sulfonamide and carboxamide
derivatives have been discovered as potent anticonvulsant
drugs and the SAR studies have been reported [40]. In the
present study, the anticonvulsant activity of 28 newly
synthesized spiroazahydantoins derivatives of sulfonamide
and carboxamide were tested. For several decades, antiepilep-
tic drug research has focused on identifying new potential
drugs based on their anticonvulsant activity against single
acute seizures induced by various stimulators. All established
antiepileptic drugs have anticonvulsant activity. Thus, this
test may, in some way, distinguish the potential utility of
compounds against different seizure types.
We synthesized a series of 28 new N-substituted spiroaza-
hydantoins derivatives having different groups at phenyl
ring. However, to know which series of compounds had
better activity, we synthesized two series of compounds like
sulfonamide and carboxamide; the results demonstrated that
the anticonvulsant activity was in the order: sulfonamide >
carboxamide. This is evident from the fact that five
compounds in sulfonamide series and two compounds in
carboxamide series were more active compared to phenytoin.
Certain selected structures for active anticonvulsants has
been shown to possess a hydrophobic unit (R), an electron
donor group (D), and hydrogen bond donor unit (HBD). In the
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Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Pharmacological Evaluation of Novel Imidazolidinediones
375
Table 3. Behavioral study on some selected compounds using
actophometer.
at different positions on the phenyl ring bearing compounds
11, 23, and 24 and more electronegative (lipophilic) fluorine
groups at different positions on the phenyl ring bearing
compounds 8, 12, 15, 21, and 22 showed moderate activity. The
compounds 6, 9, 10, 18, 30, and 31 bearing electron donating
(hydrophobic) methyl group at different positions on the
phenyl ring showed good anticonvulsant activity. The
electron-donating ethyl, isopropyl, and methoxy groups at
different positions on the phenyl ring bearing compounds 13,
17, 26, 27, and 28 showed moderate anticonvulsant activity.
The influence of cyano groups at different positions on the
phenyl ring bearing compounds 19 and 25 practically reduces
the anticonvulsant activity.
Post-treatment
(locomotor activity score)b)
Activity score
control
(24 h prior)
Compounda)
0.5 h after
1 h after
6
10
17
23
420 ꢂ 15.56
217 ꢂ 24.43
339 ꢂ 28.72
386 ꢂ 19.61
247 ꢂ 17.58
298 ꢂ 32.23NS
47 ꢂ 8.31
55 ꢂ 7.49
52 ꢂ 6.72
39 ꢂ 9.16
219 ꢂ 34.72
370 ꢂ 27.56
104 ꢂ 11.27
59 ꢂ 4.92
310 ꢂ 23.14
379 ꢂ 19.47
212 ꢂ 13.12
63 ꢂ 6.37
27
Phenytoinc)
a)
The compounds were tested at a dose level of 100 mg/kg (i.p.).
Each score represents the mean ꢂ SEM of six mice, significantly
different from control at p < 0.05, and NS denotes the non-
significant value (Student’s t-test).
b)
Conclusion
c)
The compounds were tested at a dose level of 30 mg/kg (i.p.).
Considering the results of all the synthesized compounds, the
following may be concluded. All of the compounds substituted
with phenyl group at different positions of hydantoin
ring showed better anticonvulsant activity. The results
demonstrated that the anticonvulsant activity was in the
order: sulfonamide > carboxamide compared to phenytoin.
Compounds 6, 9, 10, 18, 30, and 31 emerged as a prototype,
being effective in i.p. MES screens, and also exhibited activity
against scPTZ model of seizure. Some titled compounds
exhibited lesser CNS depression and neurotoxicity compared
to phenytoin/carbamazepine, as evident from the CNS studies.
The electron-donating (hydrophobic) methyl groups at differ-
ent positions ortho, meta, and para on the phenyl ring bearing
compounds display maximum potent anticonvulsant activity.
They may act as lead molecules for future investigations.
present study, a series of the active compounds possess all
the requirements essential for anticonvulsant activity as
proposed by Dimmock et al. [31, 32]. Thus, our new proposal
for a pharmacophore model includes not only three factors
but also an additional hydrophobic binding site for
bioactivity. From the results of this study, the following SARs
could be derived. The substitution patterns at different
position of sulfonamide and carboxamide were compared
further to increase structure–anticonvulsant activity relation-
ship; we introduced different substituents at different
positions of aryl ring like simple phenyl ring, electron-
donating methyl group, moderate electronegative atom
chlorine, more electronegative fluorine group, and electron-
withdrawing cyano groups. The results demonstrated that the
simple phenyl ring bearing compound 29 was moderately Experimental
active. Similarly, the moderate electronegative chlorine atom
Materials
Melting points were determined in one end open capillary tubes
Table 4. CNS study on selected compounds in forced swim pool
test.
on a Büchi 530 melting point apparatus and are uncorrected. The
1H NMR spectra were recorded on Bruker Avance ꢁ400 MHz NMR
instrument using TMS as an internal standard and DMSO-d6 as a
solvent. Chemical shifts are given in parts per million (d-scale), and
coupling constants are given in Hertz. Mass spectra were recorded
on Perkin-Elmer LC–MS PE Sciex API/65 spectrophotometer. IR
spectra were recorded using KBr on 8400S Shimadzu Fourier
Transform spectrophotometer (nmax in cmꢁ1). Silica gel column
chromatography was performed using Merck 7734 silica gel (60–
120 mesh), and Merck-made TLC plates. Elemental analysis (C, H,
and N) was undertaken with Perkin-Elmer model 240C analyzer.
Immobility timeb) (s)
Control
(24 h prior)
Post-treatmentc)
(60 min after)
Compounda)
PEG
6
10
23
160.00 ꢂ 13.37
148.17 ꢂ 7.85
139.53 ꢂ 12.63
137.33 ꢂ 10.81
142.50 ꢂ 9.35
143.33 ꢂ 8.42
173.50 ꢂ 11.53NS
145.83 ꢂ 9.65
147.33 ꢂ 4.55
151.50 ꢂ 6.71
148.17 ꢂ 13.70NS
169.00 ꢂ 11.63
27
Carbamazepined)
Synthesis of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-
carboxylate (1)
A mixture of 8-azabicyclo[3.2.1]octan-3-one hydrochloride (4 g,
24.74 mmol), triethylamine (3.75 g, 37.12 mmol), and di-tert-butyl
dicarbonate (5.94 g, 27.22 mmol) in dry dichloromethane (40 mL)
was stirred at room temperature for 16 h. After completion of the
reaction (TLC), the reaction mixture was poured into water and
a)
Compounds were tested at a dose of 100 mg/kg (i.p.).
Control animals were administered PEG (i.p.).
Each value represents the mean ꢂ SEM of six mice significantly
different from the control at p < 0.05 (NS, not-significant).
Tested at 30 mg/kg (i.p.).
b)
c)
d)
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M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
extracted with dichloromethane (3 ꢀ 40 mL), dried over anhy-
drous Na2SO4 and concentrated in vacuo to give the crude product,
which was recrystallized from hexane to get the pure product.
White color solid: (5 g, 90%); 1H NMR (300 MHz, DMSO-d6): d 4.49
(s, 2H), 2.67 (s, 2H), 2.34 (d, J ¼ 15.72 Hz, 2H), 2.09 (d, J ¼ 4.70 Hz,
2H), 1.63 (d, J ¼ 12.37 Hz, 2H), 1.51 (s, 9H), MS: m/z 225.3 (Mþ),
226.3 (Mþ1).
dione (100 mg 0.28 mmol), triethylamine (43.20 mg, 0.43 mmol),
and sulfonyl chloride (0.31 mmol) in dichloromethane (4 mL) was
stirred at room temperature for 16 h. After completion of the
reaction (TLC), it was quenched with sodium carbonate solution,
extracted with dichloromethane (3 ꢀ 4 mL), dried over Na2SO4,
and concentrated in vacuo to give the crude product, which was
purified by column chromatography on silica employing
dichloromethane/methanol (9:1) as an eluent to obtain pure
product.
Synthesis of tert-butyl 20,50-dioxo-8H-spiro[8-azabicyclo-
[3.2.1]octane-3,40-imidazolidine]-8-carboxylate (2)
A mixture of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxyl-
ate (5 g, 22.2 mmol) and ammonium carbonate (4.69 g,
48.82 mmol) was taken in ethanol (25 mL) and water (25 mL). A
solution of sodium cyanide (2.28 g, 46.60 mmol) in water (10 mL)
was added dropwise to the reaction mixture and it was stirred at
room temperature for 24 h, to 50°C for 24 h, and cooled to room
temperature. After completion of the reaction (TLC), solid was
filtered, washed with water (100 mL), and dried in vacuo to get
hydantoin. White color solid: (5.1 g, 78%); 1H NMR (400 MHz,
DMSO-d6): d 10.79 (s, 1H), 8.38 (s, 1H), 4.07 (s, 2H), 2.14 (s, 2H), 1.96
(t, J ¼ 26.32 Hz, 4H), 1.57 (s, 2H), 1.41 (s, 9H); MS: m/z 295.3 (Mþ),
296.3 (Mþ1).
10-[2-(Difluoromethoxy)benzyl]-8-[(3,4-dimethylphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (5)
White color solid: (102 mg, 69%); m.p. ¼ 216°C; 1H NMR (400 MHz,
DMSO-d6): d 8.69 (s, 1H), 7.63 (s, 1H), 7.56 (d, J ¼ 7.88 Hz, 1H), 7.35
(t, J ¼ 7.88 Hz, 2H), 7.20 (q, J ¼ 7.60 Hz, 2H), 7.06 (t, J ¼ 18.04 Hz,
1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.25 (s, 2H), 2.29 (s, 6H), 2.19
(q, J ¼ 3.24 Hz, 2H), 1.82 (t, J ¼ 7.60 Hz, 2H), 1.16–1.18 (m, 4H); MS:
m/z 519.6 (Mþ), 520.6 (Mþ1); IR (KBr) 1650, 1340 cmꢁ1; Anal. calcd.
for C25H27F2N3O5S: C, 57.79; H, 5.24; N, 8.09%; Found: C, 57.77; H,
5.21; N, 8.06%.
Synthesis of tert-butyl 10-[2-(difluoromethoxy)benzyl]-
10-[2-(Difluoromethoxy)benzyl]-8-[(2-methylphenyl)-
20,50-dioxo-8H-spiro[8-azabicycle[3.2.1]octane-3,40-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-8-carboxylate (3)
imidazolidine]-20,50-dione (6)
A mixture of tert-butyl 20,50-dioxo-8H-spiro[8-azabicyclo[3.2.1]-
octane-3,40-imidazolidine]-8-carboxylate (5.1 g, 17.26 mmol),
anhydrous potassium carbonate (3.57 g, 25.90 mmol), and 1-
(bromomethyl)-2-(difluoromethoxy)benzene (4.50 g, 18.99 mmol)
in acetonitrile (50 mL) was refluxed for 6 h. After completion of
the reaction (TLC) the reaction mixture was cooled to room
temperature and filtered. Filtrate was concentrated in vacuo
to give the crude product, which was purified by column
chromatography over silica gel (60–120 mesh) using chloroform:
methanol (9:1) as an eluent to get pure product. White color solid:
(6.2 g, 81%); 1H NMR (400 MHz, DMSO-d6): d 8.80 (s, 1H), 7.33–7.34
(m, 1H), 7.19–7.19 (m, 2H), 7.07 (t, J ¼ 7.56 Hz, 1H), 6.44 (s, 1H), 4.56
(s, 2H), 4.10 (s, 2H), 2.20 (s, 2H), 1.94–1.98 (m, 4H), 1.67
(d, J ¼ 8.24 Hz, 2H), 1.41 (s, 9H); MS: m/z 451.2 (Mþ), 452.2 (Mþ1).
White color solid: (98 mg, 68%); m.p. ¼ 202°C; 1H NMR (400 MHz,
DMSO-d6):
d
8.80 (s, 1H), 7.92 (d, J ¼ 7.92 Hz, 1H), 7.57
(d, J ¼ 7.44 Hz, 1H), 7.40–7.41 (m, 2H), 7.33 (d, J ¼ 7.76 Hz, 1H),
7.19 (t, J ¼ 7.76 Hz, 2H), 7.05 (t, J ¼ 7.04 Hz, 1H), 6.47 (s, 1H),
4.55 (s, 2H), 4.17 (s, 2H), 2.62 (s, 3H), 2.05–2.07 (m, 4H),
1.81 (d, J ¼ 6.20 Hz, 4H); MS: m/z 505.5 (Mþ), 506.5 (Mþ1);
IR (KBr) 1652, 1344 cmꢁ1
; Anal. calcd. for C24H25F2N3O5S:
C, 57.02; H, 4.98; N, 8.31%; Found: C, 57.06; H, 4.99; N,
8.35%.
10-[2-(Difluoromethoxy)benzyl]-8-[(3-bromophenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (7)
White color solid: (107 mg, 66%); m.p. ¼ 209°C; 1H NMR (400 MHz,
DMSO-d6): d 8.73 (s, 1H), 8.03 (s, 1H), 7.88–7.93 (m, 1H), 7.54–7.58
(m, 2H), 7.33–7.40 (m, 1H), 7.18–7.22 (m, 2H), 7.03–7.08 (m, 1H),
6.47 (s, 1H), 4.55 (s, 2H), 4.34 (s, 2H), 2.19 (q, J ¼ 3.04 Hz, 2H), 1.87
(q, J ¼ 6.28 Hz, 4H), 1.29 (t, J ¼ 4.52 Hz, 2H); MS: m/z 570.4 (Mþ),
Synthesis of 10-[2-(difluoromethoxy)benzyl]-20H,50H-spiro-
[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-20,50-dione (4)
tert-Butyl-10-[2-(difluoromethoxy)benzyl]-20,50-dioxo-8H-spiro[8-
azabicyclo[3.2.1]octane-3,40-imidazolidine]-8-carboxylate (6.2 g,
13.73 mmol) was taken in dioxane (30 mL), cooled to 0°C. To the
above reaction mixture dioxane in HCl (60 mL) was added and
allowed to stir at room temperature for 4 h. After completion of
the reaction (TLC), dioxane was removed under vacuum and the
reaction mixture was neutralized with sodium carbonate
solution, extracted with dichloromethane (3 ꢀ 60 mL), dried over
Na2SO4 and concentrated in vacuo to get pure product. White
color solid: (3.9 g, 81%); 1H NMR (400 MHz, DMSO-d6): d 8.83 (s, 1H),
8.69 (s, 1H), 7.35–7.35 (m, 1H), 7.06–7.12 (m, 3H), 6.45 (s, 1H), 4.58
(s, 2H), 3.95 (s, 2H), 2.34 (d, J ¼ 2.64 Hz, 2H), 2.18 (d, J ¼ 6.36 Hz, 2H),
1.87–1.91 (m, 4H); MS: m/z 351.4 (Mþ), 352.4 (Mþ1).
571.4 (Mþ1); IR (KBr) 1656, 1341 cmꢁ1
; Anal. calcd. for
C23H22BrF2N3O5S: C, 48.43; H, 3.89; N, 7.37%; Found: C, 48.41;
H, 3.85; N, 7.36%.
10-[2-(Difluoromethoxy)benzyl]-8-[(2-fluorophenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (8)
White color solid: (96 mg, 66%); m.p. ¼ 237°C; 1H NMR (400 MHz,
DMSO-d6): d 8.77 (s, 1H), 7.86 (t, J ¼ 7.48 Hz, 1H), 7.73–7.75 (m, 1H),
7.33–7.50 (m, 3H), 7.19–7.20 (m, 2H), 7.32 (t, J ¼ 16.88 Hz, 1H),
6.47 (s, 1H), 4.56 (s, 2H), 4.32 (s, 2H), 2.20 (d, J ¼ 14.16 Hz, 1H),
2.00 (d, J ¼ 8.36 Hz, 1H), 1.86 (d, J ¼ 14.04 Hz, 2H), 1.52
(t, J ¼ 4.40 Hz, 2H), 1.13–1.15 (m, 2H), MS: m/z 509.5 (Mþ),
General procedure for the synthesis of azabicyclospiro-
510.5 (Mþ1); IR (KBr) 1653, 1340 cmꢁ1
; Anal. calcd. for
C23H22F3N3O5S: C, 54.22; H, 4.35; N, 8.25%; Found: C, 54.20; H,
4.32; N, 8.23%.
sulfonamides (5–19)
A mixture of 8-(3,4-dimethylbenzoyl)-10-[2-(difluoromethoxy)ben-
zyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-20,50-
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Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Pharmacological Evaluation of Novel Imidazolidinediones
377
10-[2-(Difluoromethoxy)benzyl]-8-[(2,5-dimethylphenyl)-
7.19–7.21 (m, 3H), 7.07 (s, 1H), 6.46 (s, 1H), 4.59 (s, 2H), 4.56 (s, 2H),
4.26 (s, 2H), 2.70 (q, J ¼ 7.64 Hz, 2H), 2.21 (t, J ¼ 7.92 Hz, 2H), 1.86
(t, J ¼ 7.56 Hz, 4H), 1.17 (t, J ¼ 8.28 Hz, 3H); MS: m/z 519.6 (Mþ),
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (9)
520.6 (Mþ1); IR (KBr) 1653, 1341 cmꢁ1
; Anal. calcd. for
White color solid: (102 mg, 69%); m.p. ¼ 205°C; 1H NMR (400 MHz,
DMSO-d6): d 8.81 (s, 1H), 7.73 (s, 1H), 7.32–7.34 (m, 3H), 7.19
(q, J ¼ 7.64 Hz, 2H), 6.98–6.98 (m, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.16
(s, 2H), 2.56 (s, 3H), 2.44 (s, 3H), 2.02–2.14 (m, 4H), 1.81–1.91
C25H27F2N3O5S: C, 57.79; H, 5.24; N, 8.09%; Found: C, 57.74;
H, 5.21; N, 8.02%.
10-[2-(Difluoromethoxy)benzyl]-8-[(3-fluorophenyl)-
(m, 4H); MS: m/z 519.7 (Mþ), 520.7 (Mþ1); IR (KBr) 1652, 1344 cmꢁ1
;
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
Anal. calcd. for C25H27F2N3O5S: C, 57.79; H, 5.24; N, 8.09%; Found:
C, 57.75; H, 5.21; N, 8.07%.
imidazolidine]-20,50-dione (15)
White color solid: (102 mg, 70%); m.p. ¼ 235°C; 1H NMR (400 MHz,
DMSO-d6): d 8.73 (s, 1H), 7.57–7.74 (m, 3H), 7.33–7.37 (m, 2H), 7.07–
7.22 (m, 3H), 6.46 (s, 1H), 4.55 (s, 2H), 4.34 (s, 2H), 2.19
(q, J ¼ 3.28 Hz, 2H), 1.87 (q, J ¼ 6.32 Hz, 4H), 1.30–1.31 (m, 2H); MS:
m/z 509.5 (Mþ), 510.5 (Mþ1); IR (KBr) 1653, 1342 cmꢁ1; Anal. calcd.
for C23H22F3N3O5S: C, 54.22; H, 4.35; N, 8.25%; Found: C, 54.20; H,
4.32; N, 8.23%.
10-[2-(Difluoromethoxy)benzyl]-8-[(4-methylphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (10)
White color solid: (95 mg, 66%); m.p. ¼ 208°C; 1H NMR (400 MHz,
DMSO-d6):
d
8.81 (s, 1H), 7.92 (d, J ¼ 7.92 Hz, 1H), 7.57
(d, J ¼ 7.44 Hz, 1H), 7.40–7.41 (m, 2H), 7.33 (d, J ¼ 7.76 Hz, 1H),
7.19 (t, J ¼ 7.76 Hz, 2H), 7.05 (t, J ¼ 6.04 Hz, 1H), 6.47 (s, 1H), 4.56 (s,
2H), 4.16 (s, 2H), 2.62 (s, 3H), 2.04–2.07 (m, 4H), 1.81 (d, J ¼ 7.20 Hz,
10-[2-(Difluoromethoxy)benzyl]-8-[(3,5-dimethylphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
4H); MS: m/z 505.5 (Mþ), 506.5 (Mþ1); IR (KBr) 1651, 1343 cmꢁ1
;
imidazolidine]-20,50-dione (16)
Anal. calcd. for C24H25F2N3O5S: C, 57.02; H, 4.98; N, 8.31%; Found:
C, 57.03; H, 4.91; N, 8.28%.
White color solid: (97 mg, 66%); m.p. ¼ 218°C; 1H NMR (400 MHz,
DMSO-d6): d 8.71 (s, 1H), 7.47 (s, 2H), 7.32–7.33 (m, 2H), 7.18–7.22
(m, 2H), 7.06 (s, 1H), 6.41 (s, 1H), 4.55 (s, 2H), 4.27 (s, 2H), 2.34
(s, 6H), 2.20 (q, J ¼ 2.92 Hz, 2H), 1.81–1.83 (m, 4H), 1.26 (t,
J ¼ 4.52 Hz, 2H); MS: m/z 519.7 (Mþ), 520.7 (Mþ1); IR (KBr) 1650,
1340 cmꢁ1; Anal. calcd. for C25H27F2N3O5S: C, 57.79; H, 5.24; N,
8.09%; Found: C, 57.76; H, 5.20; N, 8.06%.
10-[2-(Difluoromethoxy)benzyl]-8-[(3-chlorophenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (11)
White color solid: (92 mg, 61%); m.p. ¼ 201°C; 1H NMR (400 MHz,
DMSO-d6): d 8.73 (s, 1H), 7.91 (s, 1H), 7.78–7.86 (m, 3H), 7.61–7.65
(m, 2H), 7.33–7.40 (m, 1H), 7.03–7.22 (m, 1H), 6.47 (s, 1H), 4.56
(s, 2H), 4.35 (s, 2H), 2.19 (q, J ¼ 3.04 Hz, 2H), 1.83–1.86 (m, 4H),
1.23–1.28 (m, 2H); MS: m/z 525.96 (Mþ), 527 (Mþ2); IR (KBr) 1655,
1342 cmꢁ1; Anal. calcd. for C23H22ClF2N3O5S: C, 52.52; H, 4.22; N,
7.99%; Found: C, 52.51; H, 4.24; N, 7.95%.
10-[2-(Difluoromethoxy)benzyl]-8-[(4-ethylphenyl)sulfonyl]-
20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (17)
White color solid: (93 mg, 63%); m.p. ¼ 221°C; 1H NMR (400 MHz,
DMSO-d6): d 8.70 (s, 1H), 7.77 (d, J ¼ 8.24 Hz, 2H), 7.33–7.35 (m, 2H),
7.19–7.21 (m, 3H), 7.07 (s, 1H), 6.46 (s, 1H), 4.56 (s, 2H), 4.26 (s, 2H),
2.70 (q, J ¼ 7.64 Hz, 2H), 2.21 (t, J ¼ 10.92 Hz, 2H), 1.86
(t, J ¼ 7.56 Hz, 4H), 1.25 (t, J ¼ 8.28 Hz, 3H), 1.15 (q, J ¼ 16.76 Hz,
10-[2-(Difluoromethoxy)benzyl]-8-[(4-fluoro-2-methylphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (12)
2H); MS: m/z 519.6 (Mþ), 520.6 (Mþ1); IR (KBr) 1653, 1341 cmꢁ1
;
White color solid: (97 mg, 65%); m.p. ¼ 203°C; 1H NMR (400 MHz,
DMSO-d6): d 8.81 (s, 1H), 7.96 (q, J ¼ 5.80 Hz, 1H), 7.32–7.35 (m, 2H),
7.17–7.27 (m, 3H), 7.03–7.07 (m, 1H), 6.44 (s, 1H), 4.54 (s, 2H), 4.16
(s, 2H), 2.61 (s, 3H), 2.05–2.07 (m, 4H), 1.79–1.83 (m, 4H); MS: m/z
523.6 (Mþ), 524.6 (Mþ1); IR (KBr) 1653, 1341 cmꢁ1; Anal. calcd. for
C24H24F3N3O5S: C, 55.06; H, 4.62; N, 8.03%; Found: C, 55.02; H,
4.60; N, 8.01%.
Anal. calcd. for C25H27F2N3O5S: C, 57.79; H, 5.24; N, 8.09%; Found:
C, 57.75; H, 5.21; N, 8.02%.
10-[2-(Difluoromethoxy)benzyl]-8-[(3-methylphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (18)
White color solid: (98 mg, 68%); m.p. ¼ 210°C; 1H NMR (400 MHz,
DMSO-d6): d 8.70 (s, 1H), 7.67 (t, J ¼ 7.24 Hz, 2H), 7.49 (t, J ¼ 7.44 Hz,
2H), 7.35 (s, 1H), 7.18–7.19 (m, 2H), 7.09 (d, J ¼ 7.28 Hz, 1H), 6.45 (s,
1H), 4.56 (s, 2H), 4.29 (s, 2H), 2.39 (s, 3H), 2.21 (q, J ¼ 4.64 Hz, 2H),
1.84 (t, J ¼ 2.12 Hz, 4H), 1.22–1.24 (m, 2H); MS: m/z 505.5 (Mþ),
10-[2-(Difluoromethoxy)benzyl]-8-[(4-methoxyphenyl)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (13)
White color solid: (103 mg, 71%); m.p. ¼ 222°C; 1H NMR (400 MHz,
DMSO-d6): d 8.70 (s, 1H), 7.76–7.77 (m, 2H), 7.33–7.33 (m, 1H),
7.18–7.20 (m, 3H), 7.03–7.18 (m, 2H), 6.45 (s, 1H), 4.55 (s, 2H), 4.24
(s, 2H), 3.74 (s, 3H), 2.19 (q, J ¼ 3.20 Hz, 2H), 1.83 (q, J ¼ 5.16 Hz,
4H), 1.24–1.27 (m, 2H); MS: m/z 521.5 (Mþ), 522.5 (Mþ1); IR (KBr)
1650, 1343 cmꢁ1; Anal. calcd. for C24H25F2N3O6S: C, 55.27; H, 4.83;
N, 8.06%; Found: C, 55.25; H, 4.81; N, 8.03%.
506.5 (Mþ1); IR (KBr) 1652, 1343 cmꢁ1
; Anal. calcd. for
C24H25F2N3O5S: C, 57.02; H, 4.98; N, 8.31%; Found: C, 57.01; H,
4.94; N, 8.28%.
10-[2-(Difluoromethoxy)benzyl]-8-[(2-cyanobenzene)-
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (19)
10-[2-(Difluoromethoxy)benzyl]-8-[(4-methylbenzyl)-
White color solid: (95 mg, 65%); m.p. ¼ 245°C; 1H NMR (400 MHz,
DMSO-d6): d 8.78 (s, 1H), 8.12–8.12 (m, 3H), 7.88–7.90 (m, 2H), 7.08–
7.18 (m, 3H), 6.45 (s, 1H), 4.55 (s, 2H), 4.35 (s, 2H), 2.22
(d, J ¼ 2.84 Hz, 2H), 2.05 (d, J ¼ 8.48 Hz, 2H), 1.86 (d, J ¼ 6.24 Hz,
2H), 1.76 (d, J ¼ 2.92 Hz, 2H); MS: m/z 516.5 (Mþ), 517.5 (Mþ1); IR
sulfonyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-20,50-dione (14)
White color solid: (94 mg, 64%); m.p. ¼ 228°C; 1H NMR (400 MHz,
DMSO-d6): d 8.70 (s, 1H), 7.77 (d, J ¼ 8.24 Hz, 2H), 7.33–7.35 (m, 2H),
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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378
M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
(KBr) 1653, 1341 cmꢁ1; Anal. calcd. for C24H22F2N4O5S: C, 55.81; H,
4.29; N, 10.85%; Found: C, 55.78; H, 4.27; N, 10.82%.
Anal. calcd. for C24H23ClF2N4O4: C, 57.09; H, 4.59; N, 11.10%;
Found: C, 57.06; H, 4.54; N, 11.08%.
General procedure for the synthesis of
azabicyclospirocarboxamides 20–32
10-[2-(Difluoromethoxy)benzyl]-N-(3-chlorophenyl)-20,50-
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
A mixture of 8-(3,4-dimethylbenzoyl)-10-[2-(difluoromethoxy)ben-
zyl]-20H,50H-spiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-20,50-
dione (100 mg 0.28mmol), triethylamine (43.20 mg, 0.43 mmol),
and isocyanate (0.31 mmol) in dichloromethane (4 mL) was stirred
at room temperature for 16 h. The above general procedure was
followed to get the pure compounds. Structure verification data
for novel compounds (5–32) are documented in Supporting
Information File.
8-carboxamide (24)
White color solid: (102 mg, 71%); m.p. ¼ 240°C; 1H NMR (400 MHz,
DMSO-d6): d 8.71 (s, 1H), 7.71 (s, 1H), 7.70 (d, J ¼ 2.00 Hz, 1H), 7.40–
7.41 (m, 1H), 7.32–7.33 (m, 2H), 7.18–7.27 (m, 2H), 7.07
(t, J ¼ 8.40 Hz, 1H), 6.96–6.96 (m, 1H), 6.46 (s, 1H), 4.56 (s, 2H),
4.46 (s, 2H), 2.24 (q, J ¼ 3.24 Hz, 2H), 2.07 (t, J ¼ 5.96 Hz, 2H), 1.95
(t, J ¼ 4.44 Hz, 2H), 1.70 (d, J ¼ 7.88 Hz, 2H); MS: m/z 504.9 (Mþ), 506
(Mþ2); IR (KBr) 3363, 1628 cmꢁ1; Anal. calcd. for C24H23ClF2N4O4:
C, 57.09; H, 4.59; N, 11.10%; Found: C, 57.08; H, 4.56; N, 11.09%.
10-[2-(Difluoromethoxy)benzyl]-N-[4-(methylsulfanyl)-
phenyl]-20,50-dioxospiro[8-azabicyclo[3.2.1]octane-3,40-
10-[2-(Difluoromethoxy)benzyl]-N-(3-cyanobenzene)-
imidazolidine]-8-carboxamide (20)
20,50-dioxospiro[8-azabicyclo[3.2.1]octane-3,40-
White color solid: (103 mg, 70%); m.p. ¼ 235°C; 1H NMR (400 MHz,
DMSO-d6): d 8.82 (s, 1H), 8.55 (s, 1H), 7.47 (d, J ¼ 8.72 Hz, 2H), 7.34
(t, J ¼ 1.32 Hz, 1H), 7.17–7.19 (m, 4H), 7.08 (t, J ¼ 7.84 Hz, 1H), 6.45
(s, 1H), 4.57 (s, 2H), 4.46 (s, 2H), 2.47 (d, J ¼ 6.16 Hz, 2H), 2.42 (s, 3H),
2.26 (q, J ¼ 2.88 Hz, 2H), 1.96 (d, J ¼ 5.00 Hz, 2H), 1.69
(d, J ¼ 6.80 Hz, 2H); MS: m/z 516.6 (Mþ), 517.6 (Mþ1); IR (KBr)
3359, 1656 cmꢁ1; Anal. calcd. for C25H26F2N4O4S: C, 58.13; H, 5.07;
N, 10.85%; Found: C, 58.12; H, 5.05; N, 10.82%.
imidazolidine]-8-carboxamide (25)
White color solid: (99 mg, 70%); m.p. ¼ 238°C; 1H NMR (400 MHz,
DMSO-d6): d 8.59 (s, 1H), 7.51 (s, 1H), 7.47–7.50 (m, 2H), 7.32–7.37
(m, 1H), 7.18–7.22 (m, 2H), 7.18 (s, 3H), 6.45 (s, 1H), 4.56 (s, 2H),
4.44 (s, 2H), 2.25 (q, J ¼ 4.00 Hz, 2H), 2.06 (t, J ¼ 6.36 Hz, 2H), 1.94
(t, J ¼ 4.28 Hz, 2H), 1.68 (d, J ¼ 7.88 Hz, 2H); MS: m/z 495.5 (Mþ),
496.5 (Mþ1); IR (KBr) 3360, 1624 cmꢁ1
; Anal. calcd. for
C25H23F2N5O4: C, 60.60; H, 4.68; N, 14.13%; Found: C, 60.57; H,
4.62; N, 14.09%.
10-[2-(Difluoromethoxy)benzyl]-N-(3-fluorophenyl)-20,50-
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
10-[2-(Difluoromethoxy)benzyl]-N-[4-(propan-2-yl)phenyl]-
8-carboxamide (21)
20,50-dioxospiro[8-azabicyclo[3.2.1]octane-3,40-
White color solid: (105 mg, 76%); m.p. ¼ 239°C; 1H NMR (400 MHz,
DMSO-d6): d 8.83 (s, 1H), 8.74 (s, 1H), 7.34–7.52 (m, 3H), 7.19–7.29
(m, 4H), 7.04–7.11 (m, 1H), 6.45 (s, 1H), 4.57 (s, 2H), 4.48 (s, 2H),
2.26 (q, J ¼ 3.08 Hz, 2H), 2.08 (t, J ¼ 5.96 Hz, 2H), 1.96 (t, J ¼ 4.32 Hz,
2H), 1.71 (d, J ¼ 7.88 Hz, 2H); MS: m/z 488.5 (Mþ), 489.5 (Mþ1); IR
(KBr) 3358, 1622 cmꢁ1; Anal. calcd. for C24H23F3N4O4: C, 59.01; H,
4.75; N, 11.47%; Found: C, 59.04; H, 4.71; N, 11.45%.
imidazolidine]-8-carboxamide (26)
White color solid: (111 mg, 76%); m.p. ¼ 242°C; 1H NMR (400 MHz,
DMSO-d6): d 8.80 (s, 1H), 8.44 (s, 1H), 7.32–7.33 (m, 3H), 7.17–7.18
(m, 2H), 7.03–7.07 (m, 3H), 6.37 (s, 1H), 4.56 (s, 2H), 4.43 (s, 2H),
2.79 (t, J ¼ 6.88 Hz, 1H), 2.39 (d, J ¼ 2.68 Hz, 2H), 2.05 (t, J ¼ 6.16 Hz,
2H), 1.94 (d, J ¼ 5.00 Hz, 2H), 1.67 (d, J ¼ 13.84 Hz, 2H), 1.16
(d, J ¼ 6.84 Hz, 6H); MS: m/z 512.5 (Mþ), 513.5 (Mþ1); IR (KBr) 3356,
1631 cmꢁ1; Anal. calcd. for C27H30F2N4O4: C, 63.27; H, 5.90; N,
10.93%; Found: C, 63.25; H, 5.87; N, 10.91%.
10-[2-(Difluoromethoxy)benzyl]-N-(4-fluorophenyl)-20,50-
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
10-[2-(Difluoromethoxy)benzyl]-N-[2-(propan-2-yl)phenyl]-
8-carboxamide (22)
20,50-dioxospiro[8-azabicyclo[3.2.1]octane-3,40-
White color solid: (98 mg, 70%); m.p. ¼ 236°C; 1H NMR (400 MHz,
DMSO-d6): d 8.56 (s, 1H), 7.51 (s, 1H), 7.47–7.50 (m, 2H), 7.32–7.37
(m, 1H), 7.18–7.22 (m, 2H), 7.18 (s, 3H), 6.45 (s, 1H), 4.56 (s, 2H),
4.44 (s, 2H), 2.25 (q, J ¼ 4.00 Hz, 2H), 2.06 (t, J ¼ 6.36 Hz, 2H), 1.94
(t, J ¼ 4.28 Hz, 2H), 1.68 (d, J ¼ 13.88 Hz, 2H); MS: m/z 488.5 (Mþ),
imidazolidine]-8-carboxamide (27)
White color solid: (108 mg, 74%); m.p. ¼ 237°C; 1H NMR (400 MHz,
DMSO-d6): d 8.78 (s, 1H), 8.12 (s, 1H), 7.34–7.34 (m, 1H), 7.26–7.28
(m, 1H), 7.19–7.20 (m, 2H), 7.16–7.17 (m, 2H), 7.04–7.11 (m, 2H),
6.45 (s, 1H), 4.58 (s, 2H), 4.37 (s, 2H), 3.20–3.21 (m, 1H), 2.08
(t, J ¼ 5.56 Hz, 2H), 1.97–1.98 (m, 4H), 1.65 (d, J ¼ 7.88 Hz, 2H), 1.13
(d, J ¼ 6.84 Hz, 6H); MS: m/z 512.5 (Mþ), 513.5 (Mþ1); IR (KBr) 3359,
1626 cmꢁ1; Anal. calcd. for C27H30F2N4O4: C, 63.27; H, 5.90; N,
10.93%; Found: C, 63.22; H, 5.86; N, 10.90%.
489.5 (Mþ1); IR (KBr) 3361, 1629 cmꢁ1
; Anal. calcd. for
C24H23F3N4O4: C, 59.01; H, 4.75; N, 11.47%; Found: C, 58.98; H,
4.73; N, 11.44%.
10-[2-(Difluoromethoxy)benzyl]-N-(2-chlorophenyl)-20,50-
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
10-[2-(Difluoromethoxy)benzyl]-N-(3-ethylphenyl)-20,50-
8-carboxamide (23)
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
White color solid: (106 mg, 74%); m.p. ¼ 232°C; 1H NMR (400 MHz,
DMSO-d6): d 8.29 (s, 1H), 7.50 (s, 1H), 7.41–7.49 (m, 2H), 7.30–7.35
(m, 1H), 7.26–7.27 (m, 2H), 7.14–7.23 (m, 2H), 7.04–7.09 (m, 1H),
6.46 (s, 1H), 4.56 (s, 2H), 4.40 (s, 2H), 2.36 (q, J ¼ 3.04 Hz, 2H), 2.08
(d, J ¼ 7.76 Hz, 2H), 1.98 (d, J ¼ 4.12 Hz, 2H), 1.68 (d, J ¼ 7.44 Hz,
8-carboxamide (28)
White color solid: (102 mg, 72%); m.p. ¼ 246°C; 1H NMR (400 MHz,
DMSO-d6): d 8.78 (s, 1H), 8.44 (s, 1H), 7.31–7.33 (m, 1H), 7.16–7.17
(m, 1H), 7.14 (d, J ¼ 7.68 Hz, 2H), 7.01–7.08 (m, 2H), 6.76
(d, J ¼ 6.96 Hz, 2H), 6.46 (s, 1H), 4.54 (s, 2H), 4.44 (s, 2H), 2.52
2H); MS: m/z 504.9 (Mþ), 506 (Mþ2); IR (KBr) 3359, 1621 cmꢁ1
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;
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Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
Pharmacological Evaluation of Novel Imidazolidinediones
379
(q, J ¼ 7.96 Hz, 2H), 2.25 (d, J ¼ 6.20 Hz, 2H), 2.01 (d, J ¼ 7.20 Hz,
4H), 1.66 (d, J ¼ 6.00 Hz, 2H), 1.24 (d, J ¼ 7.52 Hz, 3H); MS: m/z 498.5
(Mþ), 499.5 (Mþ1); IR (KBr) 3356, 1629 cmꢁ1; Anal. calcd. for
C26H28F2N4O4: C, 62.64; H, 5.66; N, 11.24%; Found: C, 62.61; H,
5.63; N, 11.20%.
housed at an ambient temperature of 25 ꢂ 2°C, in groups as
required per metabolic cages and allowed free access to chow
pellets and water. The light/dark cycle of 12 h:12 h was
maintained. All the synthesized test compounds were suspended
in 30% polyethylene glycol (PEG 200).
10-[2-(Difluoromethoxy)benzyl]-N-phenyl-20,50-dioxospiro-
Anticonvulsant screening
[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-8-
Anticonvulsant evaluations were undertaken using the reported
procedures [41, 42]. Initially all the test compounds were
administered i.p. in a volume of 0.01 mL/g body weight of mice
at doses of 30, 100, and 300 mg/kg to one to six animals.
Anticonvulsant activity was assessed after 30 min and 4 h of
administration. Activity was established using the MES and scPTZ
tests.
carboxamide (29)
White color solid: (98 mg, 73%); m.p. ¼ 237°C; 1H NMR (400 MHz,
DMSO-d6): d 8.78 (s, 1H), 8.50 (s, 1H), 7.38–7.41 (m, 1H), 7.25–7.27
(m, 1H), 7.22 (s, 5H), 7.16–7.17 (m, 1H), 6.89–6.90 (m, 1H), 6.45
(s, 1H), 4.54 (s, 2H), 4.44 (s, 2H), 2.33 (t, J ¼ 4.28 Hz, 2H), 2.05
(d, J ¼ 7.72 Hz, 2H), 1.96 (d, J ¼ 5.52 Hz, 1H), 1.94 (d, J ¼ 8.76 Hz,
1H), 1.66 (d, J ¼ 7.12 Hz, 2H); MS: m/z 470.5 (Mþ), 471.5 (Mþ1); IR
(KBr) 3355, 1624 cmꢁ1; Anal. calcd. for C24H24F2N4O4: C, 61.27; H,
5.14; N, 11.91%; Found: C, 61.27; H, 5.14; N, 11.91%.
Neurotoxicity screen
Minimal motor impairment was measured in mice by the
rotarod test [43]. Animals were divided in groups of four
animals and trained to stay on the accelerating rotarod that
rotates at 10 revolutions per minute. The rod diameter was
3.2 cm. Trained animals (able to stay on the rotarod for at least
two consecutive periods of 90 s) were given an i.p. injection of
the test compounds in doses of 30, 100, and 300 mg/kg.
Neurological deficit was indicated by the inability of the animal
to maintain equilibrium on the rod for at least 1 min in each of
the three trials. The dose at which animal fell off the rod was
determined.
10-[2-(Difluoromethoxy)benzyl]-N-(3-methylphenyl)-20,50-
dioxospiro[8-azabicyclo[3.2.1]octane-3,40-imidazolidine]-
8-carboxamide (30)
White color solid: (104 mg, 75%); m.p. ¼ 248°C; 1H NMR (400 MHz,
DMSO-d6): d 8.79 (s, 1H), 8.44 (s, 1H), 7.28–7.30 (m, 2H), 7.18–7.19
(m, 2H), 7.08–7.12 (m, 3H), 6.74–6.76 (m, 1H), 6.46 (s, 1H), 4.56
(s, 2H), 4.45 (s, 2H), 2.28 (t, J ¼ 2.60 Hz, 2H), 2.24 (s, 3H), 2.06
(t, J ¼ 5.92 Hz, 2H), 1.94 (t, J ¼ 4.64 Hz, 2H), 1.68 (d, J ¼ 13.80 Hz,
2H); MS: m/z 484.5 (Mþ), 485.5 (Mþ1); IR (KBr) 3361, 1628 cmꢁ1
;
Anal. calcd. for C25H26F2N4O4: C, 61.98; H, 5.41; N, 11.56%; Found:
C, 61.93; H, 5.38; N, 11.52%.
Behavioral test
Some of the title compounds (30 mg/kg) were screened for their
behavioral effects using an actophotometer [44] at 30 min and
1 h after injection in each group of six animals. Animals were
acclimatized to the dark environment 24 h before the test.
The control administered was 30% PEG only. The behavior of
the animal inside the photocell was recorded as digital score.
Increased score represented good behavioral activity.
10-[2-(Difluoromethoxy)benzyl]-N-(3,5-dimethylphenyl)-
20,50-dioxospiro[8-azabicyclo[3.2.1]octane-3,40-
imidazolidine]-8-carboxamide (31)
White color solid: (107 mg, 75%); m.p. ¼ 252°C; 1H NMR (400 MHz,
DMSO-d6): d 8.81 (s, 1H), 8.38 (s, 1H), 7.34–7.34 (m, 2H), 7.19–7.20
(m, 2H), 7.04–7.07 (m, 2H), 6.59–6.60 (m, 1H), 6.45 (s, 1H), 4.57
(s, 2H), 4.44 (s, 2H), 2.27 (t, J ¼ 8.16 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H),
2.07 (d, J ¼ 7.84 Hz, 2H), 1.95 (d, J ¼ 5.52 Hz, 2H), 1.68
(d, J ¼ 7.76 Hz, 2H); MS: m/z 498.5 (Mþ), 499.5 (Mþ1); IR (KBr)
3359, 1632 cmꢁ1; Anal. calcd. for C26H28F2N4O4: C, 62.64; H, 5.66;
N, 11.24%; Found: C, 62.60; H, 5.63; N, 11.19%.
CNS depressant study
The forced swim pool method was reported earlier by Porsolt
et al. [45]. Mice (six animals in each group) were placed in a
chamber (diameter 45 cm, height 20 cm) containing water up to
the height of 15 cm at 25 ꢂ 2°C. Two swim sessions were
conducted, an initial 15-min pre-test followed by a 5-min test
session 24 h later. The animals were administered an i.p. injection
(30 mg/ kg) of the test compound 30 min before the test session.
The period of immobility (passive floating without struggling,
making only those movements that were necessary to keep its
head above the surface) during the 5-min test period was
measured. This immobility reflected state of depression. Carba-
mazepine was used as a reference for comparison at a dose of
30 mg/kg (i.p., in PEG). The control animals were administered
30% PEG.
10-[2-(Difluoromethoxy)benzyl]-N-(2-chloro-4,6-
dimethylphenyl)-20,50-dioxospiro[8-azabicyclo[3.2.1]-
octane-3,40-imidazolidine]-8-carboxamide (32)
White color solid: (112 mg, 74%); m.p. ¼ 244°C; 1H NMR (400 MHz,
DMSO-d6): d 8.78 (s, 1H), 8.34 (s, 1H), 7.34–7.34 (m, 2H), 7.19–7.20
(m, 2H), 7.04–7.07 (m, 1H), 6.59–6.60 (m, 1H), 6.45 (s, 1H), 4.57 (s,
2H), 4.44 (s, 2H), 2.27 (t, J ¼ 8.16 Hz, 2H), 2.22 (s, 3H), 2.16 (s, 3H),
2.07 (d, J ¼ 7.84 Hz, 2H), 1.95 (d, J ¼ 5.52 Hz, 2H), 1.68 (d,
J ¼ 7.76 Hz, 2H); MS: m/z 532.5 (Mþ), 534.5 (Mþ1); IR (KBr) 3361,
1629 cmꢁ1; Anal. calcd. for C27H27F2N5O4: C, 61.94; H, 5.20; N,
13.38%; Found: C, 61.89; H, 5.18; N, 13.34%.
The authors are grateful to G Pullareddy College of Pharmacy,
Mehdipatnam, Hyderabad, India for providing facilities to carry out
the anticonvulsant activity. One of the authors, M.M., is thankful to the
University of Mysore, Mysore for providing necessary facilities.
Pharmacology
Male albino mice (20–25 g) were used as experimental animals.
The Institutional Animal Ethics Committee (IAEC) reviewed and
approved all the animal procedures adopted. The animals were
The authors have declared no conflict of interest.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

380
M. Madaiah et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 370–380
References
[25] T. S. Yokum, M. G. Bursavich, S. A. Piha-Paul, D. A. Hall,
M. L. McLaughlin, Tetrahedron Lett. 1997, 38, 4013–4016.
[1] N. Pessah, M. Bialer, B. Wlodarczyk, H. H. Finnell, B. Yagen, J.
Med. Chem. 2009, 52, 2233–2242.
[26] Z. Congxiang, G. B. Brown, W. J. Brouillette, J. Med. Chem.
2004, 47, 6519–6528.
[2] E. Perucca, Br. J. Clin. Pharmacol. 1996, 42, 531–543.
[3] W. Loscher, D. Schmidt, Epilepsy Res. 2006, 69, 183–272.
[4] W. C. Loscher, Trends Pharmacol. Sci. 2002, 23, 113–118.
[5] N. Upton, Trends Pharmacol. Sci. 1994, 15, 456–463.
[6] R. Morphy, Z. Rankovic, J. Med. Chem. 2005, 48, 6523–6543.
[27] C. Pedregal, G. G. T. Modesta Espada, J. Elguero, E. J. V. Robert
Faure, J. Heterocyclic Chem. 1984, 21, 477–480.
[28] S. Anna, Z. Andrzej, Tetrahedron Lett. 2003, 44, 9323–9325.
[29] K. Susumu, H. Nobuhiro, T. Tatsuo, U. Kiyohisa, K. Hisato,
A. Hitoshi, H. Kohji, J. Med. Chem. 1990, 33, 229–239.
[30] P. Guillaume, S. B. William, B. C. Andre, J. Am. Chem. Soc. 2010,
132, 12817–12819.
[7] B. Hanna, O. Jolanta, C. Anna, K. Krzysztof, P. Maciej, Bioorg.
Med. Chem. 2011, 19, 6149–6156.
[31] J. R. Dimmock, G. B. Baker, Epilepsia 1994, 35, 648–655.
[8] H. S. White, Epilepsia 2003, 44, 2–8.
[32] J. R. Dimmock, S. C. Vashishtha, J. P. Stables, Pharmazie 2000,
55, 490–494.
[9] M. A. Rogawski, Epilepsy Res. 2006, 68, 22–28.
[10] H. H. Merritt, T. J. Putnam, Arch. Neurol. Psychiatry 1938, 39,
1003–1015.
[33] M. G. Wong, J. A. Defina, P. R. Andrews, J. Med. Chem. 1986, 29,
562–572.
[11] T. M. Hassell, M. C. Johnson, K. H. Dudley, Phenytoin Induced
Teratology and Gingival Pathology, Raven Press, New York 1980.
[34] L. Bruno-Blanch, J. Galvez, R. Garcia-Domenach, Bioorg. Med.
Chem. Lett. 2003, 13, 2749–2754.
[12] H. Xianran, Q. Guanpeng, Y. Jin, X. Yuling, W. Zhongyuan,
[35] K. Krzysztof, R. Sabina, O. Jolanta, Bioorg. Med. Chem. Lett.
2011, 21, 5800–5803.
Q. Guofu, H. Xianming, Eur. J. Med. Chem. 2010, 45, 3818–3830.
[13] J. J. Edmunds, S. Klutchko, J. M. Hamby, A. M. Bunker, C. J.
C. Connolly, R. T. Winters, I. I. I. Quin, I. Stircar, J. C. Hodges,
R. L. Panek, J. A. Keiser, A. M. Doherty, J. Med. Chem. 1995, 38,
3759–3771.
[36] Z. Y. Sun, C. H. Kwon, J. N. D. Wurpel, J. Med. Chem. 1994, 37,
2841–2845.
[37] W. J. Brouillette, V. P. Jestkov, M. L. Brown, M. S. Akhtar,
T. M. DeLorey, G. B. Brown, J. Med. Chem. 1994, 37, 3289–3293.
[14] S. Hanessian, J. Y. Sanceau, P. Chemla, Tetrahedron 1995, 51,
6669–6678.
[38] H. S. White, J. H. Woodhead, M. R. Franklin, E. A. Swinyard,
H. H. Wolf, General principles: experimental selection,
quantification and evaluation of antiepileptic drugs, in
Antiepileptic Drugs, 4th ed. (Eds.: R. H. Levy, R. H. Mattson,
B. S. Meldrum) Raven Press, New York 1995, pp. 99–110.
[15] K. I. Ahmed, Carbohydr. Res. 1998, 306, 567–573.
[16] R. N. Comber, R. C. Reynolds, J. D. Friedrich, R. A.
Manguikian, R. W. Buckheit, J. J. W. Truss, W. M. Shannon,
J. A. Secrist, J. Med. Chem. 1992, 35, 3567–3572.
[39] H. S. White, J. H. Woodhead, K. S. Wilcox, J. P. Stables,
H. J. Kupferberg, H. H. Wolf, Discovery and preclinical
development of antiepileptic drugs, in Antiepileptic Drugs
(Eds.: R. H. Levy, R. H. Mattson, B. S. Meldrum, E. Perucca)
Lippincott, Philadelphia, PA 2002, pp. 36–48.
[17] C. H. Oh, H. J. Kim, S. Y. Hong, Y. H. Lee, J. K. Cho, J. H. Cho,
Arch. Pharm. 1995, 328, 385–387.
[18] D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates,
M. MacCoss, S. G. Mills, L. Malkowitz, S. L. Gould, J. A.
DeMartino, M. S. Springer, D. Hazuda, M. Miller, J. Kessler,
R. Danzeisen, G. Carella, K. Holmes, J. Lineberger, W. A.
Schleif, E. A. Emini, Bioorg. Med. Chem. Lett. 2001, 11, 3099–
3102.
[40] N. Siddiqui, S. N. Pandeya, S. A. Khan, J. Stables, A. Rana,
M. Alam, M. F. Arshad, M. A. Bhat, Bioorg. Med. Chem. Lett. 2007,
17, 55–259.
[41] R. L. Krall, J. K. Penry, B. G. White, H. J. Kupferbeng,
[19] S. N. Pandeya, I. Ponnilavarasan, A. Pandey, R. Lakhan,
E. A. Swinyard, Epilepsia 1978, 19, 409–428.
J. P. Stables, Pharmazie 1999, 54, 923–925.
[42] R. J. Porter, J. J. Cereghino, G. D. Gladding, B. J. Hessie,
H. J. Kupferberg, B. Scoville, B. White, Cleve. Clin. Q 1984, 51,
293–305.
[20] M. G. Wong, J. A. Dejina, P. R. Andrews, J. Med. Chem. 1986, 29,
562–572.
[21] M. Madaiah, M. K. Prashanth, H. D. Revanasiddappa,
[43] P. Yogeshwari, D. Sriram, V. Saraswat, J. V. Ragavendran,
M. M. Kumar, R. Murugesan, R. Thirumurugan, J. P. Stables,
Eur. J. Pharm. Sci. 2003, 20, 341–346.
B. Veeresh, Arch. Pharm. Chem. Life Sci. 2013, 346, 200–209.
[22] M. Madaiah, M. K. Prashanth, H. D. Revanasiddappa,
B. Veeresh, Med. Chem. Res. 2013, 22, 2633–2644.
[44] J. R. Boisser, P. Simmon, Arch. Int. Pharmacodyn. Ther. 1965, 158,
212–220.
[23] M. K. Prashanth, M. Madaiah, H. D. Revanasiddappa,
B. Veeresh, Spectrochim. Acta A 2013, 110, 324–332.
[45] R. D. Porsolt, G. Anton, N. Blanet, M. Jalfre, Eur. J. Pharmacol.
1978, 47, 379–391.
[24] L. B. Milton, B. B. George, J. B. Wayne, J. Med. Chem. 1997, 40,
602–607.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com