Design and synthesis of novel diphenyl oxalamide and diphenyl acetamide derivatives as anticonvulsants

Article abstract of DOI:10.1002/ardp.201100108

A series of novel N¹-substituted-N²,N ²-diphenyl oxalamides 3a-l were synthesized in good yield by stirring diphenylcarbamoyl formyl chloride (2) and various substituted aliphatic, alicyclic, aromatic, heterocyclic amines

Full text of DOI:10.1002/ardp.201100108

Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
57
Full Paper
Design and Synthesis of Novel Diphenyl Oxalamide and
Diphenyl Acetamide Derivatives as Anticonvulsants
Anna Pratima G. Nikalje, Mangesh Ghodke, and Amol Girbane
Department of Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Aurangabad (M.S.), India
A series of novel N1-substituted-N2,N2-diphenyl oxalamides 3a–l were synthesized in good yield by
stirring diphenylcarbamoyl formyl chloride (2) and various substituted aliphatic, alicyclic, aromatic,
heterocyclic amines in DMF and K2CO3. Also 2-substituted amino-N,N-diphenylacetamides 5a–m were
designed by pharmacophore generation and synthesized by stirring 2-chloro-N,N-diphenylacetamide
(4) and various substituted amines in acetone using triethyl amine as a catalyst. All the synthesized
compounds were screened for anticonvulsant activity in Swiss albino mice by MES and ScPTZ induced
seizure tests. Neurotoxicity screening and behavioral testing was also carried out. Some of the
synthesized test compounds were found to be more potent than the standard drug.
Keywords: Anticonvulsant / Chloroacetyl chloride / Diphenyl amine / MES / ScPTZ
Received: March 26, 2011; Revised: May 19, 2011; Accepted: June 10, 2011
DOI 10.1002/ardp.201100108
Introduction
research aimed at achieving successful delivery of GABA into
the CNS has resulted in the discovery of various GABA analogs
with improved pharmacological activities [7].
Epilepsy is a collective term given to a group of syndromes
that involves spontaneous, intermittent, abnormal electrical
activity in the brain, which manifests as seizures [1].
Antidepressants and anticonvulsants are amongst the most
widely utilized drugs for the treatment of CNS disorders [2].
Presence of g-amino butyric acid (GABA) in brain tissue
together with its biosynthetic enzyme glutamate decarbox-
ylase (GAD) was described simultaneously in three independ-
ent publications in 1950 [3]. One of the first indications that
GABA could play an important role in brain function came
from studies with the convulsant hydrazides which inhibit
its synthesis [4]. Further elegant electrophysiological studies
soon confirmed that GABA was indeed an important inhibi-
tory neurotransmitter [5]. The peripheral administration of
GABA cannot be usefully performed since this neurotrans-
mitter is able to cross the blood brain barrier (BBB) only when
extremely high doses are applied, which produces severe
adverse side effects [6]. Hence, over the past few decades,
One of the approaches to analog-based drug discovery is
the concept of bioisosteric replacement, which continues to
play an important role in bio-organic and medicinal chem-
istry in the design of novel pharmacological tools as well as
new therapeutic agents with optimal pharmacological pro-
file and improved pharmacokinetic properties [8, 9]. In the
present work we have synthesized two series of potent anti-
convulsant agents which were selected for pharmacophoric
studies: N1-substituted-N2,N2-diphenyl oxalamides 3a–l and
2-substituted amino-N,N-diphenyl acetamides 5a–m as
GABA modulating agents. The presence of hydrophobic unit,
distal ring system and hydrogen bonding domain was
essential for anticonvulsant activity as depicted by the
models. The basic structure of synthesized compounds has
all the proposed pharmacophoric elements necessary for the
anticonvulsant activity such as: A) hydrophobic diphenyl
–
ring as aryl ring system, B) –NH–C O acting as HBD: hydro-
–
gen bond acceptor/donor moiety and C) distal hydrophobic
domain at terminal position for controlling the pharmaco-
kinetic properties of the compounds (Fig. 1). The anticonvul-
sant properties depend on the kind and location of the
substituent at the distal phenyl ring. Compounds containing
N–H group are necessary for hydrogen bonding which may be
responsible for the bioactivity.
Correspondence: Anna Pratima G. Nikalje, Department of
Pharmaceutical Chemistry, Y.B. Chavan College of Pharmacy, Dr.Rafiq
Zakaria Campus, Rauza Bagh, P.B. No. 33, Aurangabad (M.S.) 431001
India.
E-mail: ana@k.st
Fax: þ91 240 2381129
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58
A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
O
O
Ar
O
Ar
H2
C
N
N
H
C
N
N
H
C
B
B
A
A
A = Aryl ring system
B = Hydrophobic domain
C = Distal aryl ring
_
_
5(a l)
3(a m)
Figure 1. Proposed elements for the anticonvulsant activity in basic structure of compounds 3a–l and 5a–m.
Chemistry
N1-substituted-N2,N2-diphenyl oxalamides 3a–l. The reaction
of diphenyl amine and chloroacetyl chloride gave 2-chloro-
N,N-diphenylacetamide (4) which on reaction with appropri-
ate substituted amines in acetone gave 2-substituted amino-
N,N-diphenylacetamides 5a–m. The physical characterization
of synthesized compounds 3a–l and 5a–m is summarized in
Table 1.
The protocol for the synthesis of target compounds 3a–l and
5a–m is shown in Scheme 1. Reaction of diphenyl amine and
oxalyl chloride in DMF gave diphenylcarbamoyl formyl
chloride (2) which on reaction with various substituted
aromatic, aliphatic, alicyclic and heterocyclic amines gave
O
O
O
N
H
Cl
CH2
Cl
Cl
Cl
DMF
DMF
(1)
N
N
Cl
O
O
O
Cl
(4)
(2)
K2CO3
DMF
R1-NH2 / Heteroaryl amine
TEA
R-NH2
Acetone
N
N
H
N
O
R1
O
O
R
N
H
5(a−m)
3(a−l)
R/R1 = Aromatic, Alicyclic,Aliphatic/Heterocylic amine
Scheme 1. Synthesis of N1-substituted-N2,N2-diphenyl oxalamides and 2-substituted amino-N,N-diphenylacetamides.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
Novel Oxalamides and Acetamides as Anticonvulsants
59
Table 1. (continued )
Table 1. Physical constants of the synthesized compounds 3a–l
and 5a–m.
Code
R/R1
% Yield
Mp 8C
Rf value
Code
R/R1
% Yield
Mp 8C
Rf value
5c
88
126
0.62
H
C
3
H
O
3a
73.26
212
0.42
H
O
N
5d
80
135
0.68
3b
3c
70
81
220
235
0.46
0.62
H
3C
5e
5f
85
81
140
170
0.70
0.59
Cl
H
O
N
N
3d
83
245
0.68
N
N
N
5g
75
210
0.44
O
O
O
3e
3f
90
84
212
240
0.70
0.51
5h
5i
78
79
180
195
0.51
0.73
H
NO2
N
N
5j
90
91
133
142
0.65
0.68
3g
3h
85
91
230
260
0.44
0.59
N
H3C
Cl
S
H3C
H2C
H
N
5k
5l
N
N
H2N
H
3C
3i
3j
93
96
210
215
0.73
0.65
H
3C
90
93
128
130
0.66
0.74
H
3C
C
5m
N
H2
H3C
CH3
ꢀ
Melting points were uncorrected.
ꢀꢀ Solvent system chosen for Rf value determination was benzene/
ethanol (8:2).
3k
3l
92
88
242
218
0.68
0.74
H
O
H2
C
H
3C
Pharmacology
O
5a
5b
86
84
145
165
0.42
Anticonvulsant screening
H
O
All the study protocols related to anticonvulsant activity
testing were approved by the Institutional Animal Ethics
Committee and the ethical clearance was obtained from
the Committee for the Purpose of Control and Supervision
of Experiments on Animals (CPCSEA/IAEC/Pharm. Chem.
05/2009-10/11). Swiss albino mice, of either sex weighing
18 to 25 g were procured from Yash Pharm Pune
H
C
3
0.46
continued
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A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
(860/b104/CPCSEA). Animals were housed in polypropylene
cages and under standard conditions of temperature
(25 ꢁ 28C), 12 h/12 h light/dark cycles and were fed with
standard pellet diet (Chakan Oil Mills, Sangli) and water
was given ad libitum. All the solutions of standard drugs
and PTZ were prepared in 0.9% sodium chloride solution.
The test compounds were administered in the form of
suspension made up of 5% Tween 80 in 0.9% sodium chloride
solutions. All of the test compounds were administered intra-
peritoneally in a volume of 0.01 mL/g for mice at doses of 30,
100 and 300 mg/kg. Anticonvulsant activity was assessed
after 30 min and 4 h of drug administration.
rent of 50 mA for 0.2 s via ear clip electrode as per the
reported procedure and the effect was assessed at 0.5 h after
administration of test compounds by recording the tonic
extension of the hind limbs at different doses. The reduction
in time or absence of hind limb tonic extension of seizure is
defined as protection.
Subcutaneous pentylenetetrazole (ScPTZ) seizure
threshold
Pentylenetetrazole dissolved in 0.9% sodium chloride
solution was administered in the posterior midline of the
mice and the onset and severity of convulsion was noted for
the control group. The test group was administered with the
selected compounds 0.5 h prior to the administration of
PTZ. Comparison of anticonvulsant activity by PTZ induced
seizure method (compared with standard) for compounds
3a–l is shown in graphical format in Fig. 2 and Fig. 3 displays
Maximum Electroshock (MES) test
The test compounds were administered intraperitoneally (ip)
at a dose of 30, 100 and 300 mg/kg. Maximum electroshock
seizure were elicited using electro convulsometer with cur-
Figure 2. Comparison of anticonvulsant activity by PTZ induced seizure method (compared with standard) for compounds 3a–l.
Figure 3. Comparison of anticonvulsant activity by PTZ induced seizure method (compared with standard) for compounds 5a–m.
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Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
Novel Oxalamides and Acetamides as Anticonvulsants
61
comparison of anticonvulsant activity by PTZ induced seizure
method (compared with standard) for compounds 5a–m in
graphical form.
group. In 5a the acidic proton of –OH group was found at d
10.7 ppm as a singlet. In compound 5c the peak for phenolic
–OH proton appeared at d 5.4 ppm.
The new derivatives obtained from the reaction sequence
were injected intraperitoneally into mice and evaluated in
the maximal electroshock (MES), subcutaneous pentylenete-
trazole (ScPTZ), locomotor activity and neurotoxicity screens,
using doses of 30, 100, and 300 mg/kg, and observation
carried out at two different time intervals (0.5 and 4 h).
These data are presented in Table 2.
Neurotoxicity screening
The neurotoxicity of all the test compounds was evaluated
using rotarod test. Minimal motor impairment [10–12] was
measured in mice by the rotarod test. The mice were trained
to balance on the accelerating rotarod (3.2 cm diameter) that
rotated at 10 revolutions/min. Neurotoxicity 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.
Compounds that showed protection against MES model at
30 mg/kg include 3g, 5a, 5g, 5k and 5m. Most of the com-
pounds exhibited activity only at 0.5 h, indicating that they
have rapid onset and shorter duration of action. Out of these
only 3e and 3i derivative showed protection against MES
model at 100 mg/kg.
Behavioral testing
The title compounds 3a–l and 5a–m were screened for their
behavioral effect using actophotometer (INCO, MEDICRAFT,
Model No. 600-40, Serial No. PA-018) [13] with the ip admin-
istration of drug (100 mg/kg) at 30 min and 1 h after drug
administration. The control group animals were adminis-
tered Tween 80. The behavior of animals inside the photocell
was recorded as a digital score. Increased scores suggest good
behavioral activity. The activity of the compounds was at
maximum at 1 h, therefore, the activity values at 1 h were
used to calculate percentage decrease in locomotor activity.
Compounds 3d, 3f, 3h, 5a, 5c, 5e, 5g, 5h, 5j and 5k were
found to be active in the ScPTZ test, a test used to identify
compounds that elevate seizure threshold. Compounds 3d,
5a and 5c showed activity at a dose of 30 mg/kg. Compounds
3f, 5e, 5g, 5j and 5k were active at a dose of 100 mg/kg.
Compounds 3h and 5h showed activity at a dose of
300 mg/kg comparable with diazepam, the standard drug.
Synthesized compounds exhibited neurotoxicity (NT) at a
dose of 100 and 300 mg/kg. Compounds 3c, 3d, 3f, 5a, 5c, 5f,
5g and 5h have shown NT. The NT of the compounds as
indicated by their inability to grasp the rotating rod for
sufficient time may be due to the increased blood brain
barrier penetration and accumulation at neuroprotein sites.
The compound 3a (R ¼ p-tolyl), 3c (R ¼ o-hydroxy), 3f (R ¼ o-
nitrophenyl), 3h (R ¼ thiosemicarbazide), 3i (R ¼ methyl),
and 5c (R1 ¼ p-hydroxyphenyl), 5d (R1 ¼ o-hydroxyphenyl),
5h (R1 ¼ piperidine), 5i (R1 ¼ pyrrolidine) and 5l
(R1 ¼ methyl) have shown better CNS depressant activity.
The compound 3d (R ¼ pyrimidine), 3e (R ¼ p-carboxyphenyl),
3i (R ¼ methyl), 3j (R ¼ N,N-dimethyl), 3l (R ¼ ethyl) in MES
and 3d (R ¼ pyrimidine), 3f (R ¼ o-nitrophenyl), 3h
(R ¼ thiosemicarbazide) and 5a (R1 ¼ p-carboxyphenyl), 5g
(R1 ¼ morpholine), 5j (R1 ¼ methylpiperazine), 5k (R1 ¼
ethylpiperazine), 5m (R1 ¼ ethyl) in MES and 5a (R1 ¼ p-car-
Result and discussion
In the present work a total of twenty-five derivatives of N1-
substituted-N2,N2-diphenyl oxalamides 3a–l and 2-substituted
amino-N,N-diphenyl acetamides 5a–m were synthesized by
conventional synthetic protocols using mild reaction con-
ditions. IR, 1H-NMR, and elemental analysis confirmed the
ring structures of products. The 1H-NMR spectrum of the
derivatives 3a and 3b shows the peak for aromatic protons
as a multiplate at d 7–8.2 ppm and –NH proton of secondary
amine as a singlet at d 8.3–8.5 ppm due to presence of the
double carbonyl group showing the downfield shift which
confirmed attachment of the oxalyl chloride moiety. In 3a
the protons of –CH3 of tolyl group were found at d 2.2 ppm as
singlet. The formation of 3e was confirmed by its IR and
1H NMR data. The IR spectrum shows bands at (KBr) 3465,
3360, 3115, 1735, and 1674, 1475 cmꢂ1 indicating the pres-
boxyphenyl),
5c
(R1 ¼ p-hydroxyphenyl),
5e
(R1 ¼
p-chlorophenyl), 5g (R1 ¼ morpholine), 5h (R1 ¼ pyrimidine),
5k (R1 ¼ ethylpiperazine) in PTZ have shown excellent anti-
convulsant activity as compared with results of standard drug
–
ence of O–H stretching, N–H stretching, C–H aromatic, C O
–
stretching, and C C stretching, respectively. In its 1H-NMR
–
–
ꢀ
spectrum, it displayed multiplet at d 7.5–8.2 ppm for aro-
matic protons, singlet at d 8.5ppm for -NH and singlet at d
10.8 ppm for –OH of carboxyl group. The derivatives 5a and
5c showed the peak for aromatic protons as a multiplet at d
6.6–8.2 ppm and –NH proton of secondary amine as a singlet
at d 4.3–4.6 ppm due to presence of the carbonyl group
showing the downfield shift, presence of –CH2 of aliphatic
alkyl group at d 3.8 ppm due to the presence of the carbonyl
(ꢀꢀP < 0.01, P < 0.05).
From correlation of activity with the structure of synthes-
ized derivatives, it has been observed that, in two series of
synthesized compounds polar, bulky and electron withdraw-
ing groups like nitro (3f) and carboxyl (3e and 5a) attached to
the phenyl ring increase the CNS activity. Also R1 ¼ methyl
substituted piperazine (5j) and ethyl substituted piperazine
(5k) proved to be more potent than the other derivatives.
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62
A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
Table 2. Anticonvulsant screening of the synthesized compounds 3a–l and 5a–m.
Code
MES
ScPTZ
Neurotoxicity
screen
Mean change in locomotor
activity mg/kg
% Inhibition
in score
0.5h
4h
0.5h
4h
0.5h
4h
30
100
300
30
100
300
3a
3b
3c
3d
3e
3f
3g
3h
3i
–
–
–
–
100
–
30
–
100
–
–
–
30
–
–
–
–
–
30
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
30
–
100
–
300
–
–
–
–
30
–
30
–
100
–
100
300
–
100
100
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
21 ꢁ 1.167
17 ꢁ 0.067
9.8 ꢁ 0.757
18.8 ꢁ 0.317
12 ꢁ 0.150
75.1 ꢁ 0.924
18.4 ꢁ 2.154
76.3 ꢁ 1.906
16.4 ꢁ 0.288
14 ꢁ 0.222
10 ꢁ 1.753
20.6 ꢁ 0.658
32.6 ꢁ 2.005
22.8 ꢁ 0.972
74.2 ꢁ 1.541
73.5 ꢁ 0.008
16 ꢁ 0.591
28 ꢁ 0.973
20.2 ꢁ 1.180
78.2 ꢁ 1.210
79 ꢁ 1.438
17 ꢁ 0.431
23 ꢁ 1.860
22.6 ꢁ 1.856
22.8 ꢁ 1.979
–
75.9 ꢁ 0.930
33.3 ꢁ 0.061
77.2 ꢁ 1.092
34.8 ꢁ 0.079
23.8 ꢁ 1.605
74.3 ꢁ 0.350
29.8 ꢁ 1.602
75.8 ꢁ 0.445
37.8 ꢁ 1.137
30.2 ꢁ 0.354
15.4 ꢁ 0.365
36.8 ꢁ 1.884
42.4 ꢁ 2.759
24.8 ꢁ 2.134
73.6 ꢁ 0.486
74.4 ꢁ 3.072
33.4 ꢁ 0.537
55.87 ꢁ 1.728
49.4 ꢁ 1.030
74 ꢁ 0.213
77.1 ꢁ 0.254
13 ꢁ 1.520
10.6 ꢁ 0.707
18 ꢁ 1.873
18.2 ꢁ 0.554
76.3 ꢁ 0.615
21 ꢁ 1.890
76.9 ꢁ 0.922
74.2 ꢁ 2.367
24.4 ꢁ 0.039
8.2 ꢁ 0.253
26.4 ꢁ 1.060
21.8 ꢁ 1.394
11.2 ꢁ 0.595
75.1 ꢁ 1.432
77.3 ꢁ 0.016
20 ꢁ 0.364
24.2 ꢁ 0.686
30 ꢁ 1.984
14.6 ꢁ 0.351
76.5 ꢁ 0.297
20.2 ꢁ 0.177
21 ꢁ 0.065
75.5 ꢁ 1.758
19.8 ꢁ 1.688
–
20.07
16.89
1.42
39.81
33.43
20.84
36.09
24.68
55.82
30.72
55.41
34.48
32.33
17.03
38.17
51.08
25.94
27.42
31.28
32.23
52.05
53.57
30.07
34.09
54.30
56.80
35.44
38.88
–
17
13.37
11.72
19.56
19.65
25.78
22.01
31.44
22.5
23.78
9.11
24.13
26.32
10.40
6.7
100
300
–
300
–
–
–
–
–
–
100
–
300
–
–
100
300
300
–
–
–
18.35
11.85
24.78
19.82
26.78
17.74
16.01
11.21
22.58
35.35
20.21
12.56
13.58
18.18
32.94
27.44
14.10
13.33
23.94
26.49
21.77
25.61
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3j
3k
3l
5a
5b
5c
5d
5e
5f
5g
5h
5i
9.36
18.57
27.25
36.67
18.38
10.05
24.57
25.60
22.97
21.24
–
72.3 ꢁ 0.654
45.4 ꢁ 0.774
48.4 ꢁ 1.259
31.2 ꢁ 1.040
39.2 ꢁ 1.570
–
5j
5k
5l
–
30
–
–
–
–
–
5m
30
–
–
–
Phenytoin 20
Diazepam
–
79.8 ꢁ 0.463
64.66
a Doses of 30, 100 and 300 mg/kg were administered, the figures in the table indicate the minimum dose whererby bioactivity was
demonstrated in half or more of the mice. The animals were examined 0.5 and 0.4 h after ip injection was made. The dash (–) indicates
an absence of activity at maximum dose administered (300 mg/kg).
Bulkier compounds are more lipophilic and can cross the
blood brain barrier to exert their effect at CNS. In compound
3e the presence of polar bulkier group (p-COOH) increases the
activity.
in locomotor activity when compared to diazepam. Here the
activity is attributed to the presence of favorable structural
requirement such as aryl binding site with hydrophobic
group, hydrogen bonding domain –NHCO– group, electron
donor group and another hydrophobic aryl ring in these
oxalamide 3a–l and acetamide derivatives 5a–m. It can be
concluded that these elements acts as an important pharma-
cophore for showing anticonvulsant activity. Further acute
oral toxicity studies on these compounds are underway.
Conclusion
This communication illustrates synthesis of novel diphenyl
oxalamide and diphenylacetamide derivatives. A total of 25
derivatives was synthesized and their structures were con-
firmed by spectral and elemental analysis. Further their Experimental protocol
anticonvulsant activity was evaluated by MES, ScPTZ model.
Also they were screened for neurotoxicity. It can be con-
cluded from the results that compounds 3f, 3e and 5a were
found to exhibit significant anticonvulsant activity. All the
compounds were also screened for behavior study and CNS
depressant activity. In the behavioral study using actopho-
tometer scoring technique, the entire series of synthesized
compounds have shown decrease in locomotor activity where
1.42% was the lowest and 55.82% was the maximal decrease
Synthesis
All the recorded melting points were determined in open
capillary tubes and are uncorrected.
IR spectra were recorded on JASCO FT-IR 5300 spectropho-
tometer using KBr powder. 1H-NMR spectra were recorded on
Bruker advance II 400 1H-NMR spectrophotometer at
300 MHz frequency in CDCl3 using TMS as internal standard
and chemical shifts (d) are given in ppm relative to TMS. Mass
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Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
Novel Oxalamides and Acetamides as Anticonvulsants
63
spectra of some compounds were scanned on TOF MSþ 484
spectrophotometer. The spectral data was in accordance with
assumed structures. All the reactions were monitored by TLC
using precoated TLC plates and visualized by iodine vapor
[silica gel GF254 (E. Merck), benzene/ethanol (8:2)]. The
absence of TLC spots for starting materials and appearance
of new TLC spots at different Rf values ensured the com-
pletion of reaction. The IUPAC names of the synthesized
compounds were assigned and verified by Cambridge soft-
ware ChemDraw Ultra 8.0. Elemental analyses were recorded
on FLASH EA112 series at Shimadzu Analytical Centre and
found within ꢁ 0.4% of theoretical values.
7.6–7.8 (m, 4H, Ar–H), 8.0–8.1 (s, 1H, N–H). MS m/z 331. Anal.
calcd. for C21H18N2O2 (333): C, 76.36; H, 5.45; N, 8.48. Found:
C, 76.31; H, 5.41; N, 8.43.
N1-(2-Hydroxyphenyl)-N2,N2-diphenyloxalamide (3c)
IR (KBr) 3 475, 3 343, 3 150, 1 720, 1 650, 1 463. 1H-NMR
(CDCl3, 300 MHz, d ppm) 5.1–5.2 (s, 1H, OH), 6.7 (d, 1H,
Ar–H), 6.8–6.9 (d, 2H, Ar–H), 7.1–7.2 (t, 2H, Ar–H), 7.4–7.5
(d, 1H, Ar–H), 7.5–7.6 (m, 4H, Ar–H), 8.1–8.2 (s, 1H, N–H).
MS m/z 331. Anal. calcd. for C20H16N2O3 (332): C, 72.28; H,
4.81; N, 8.43. Found: C, 72.33; H, 4.82 N, 8.47.
N1-Diphenyl-N2,N2-(pyrimidin-2-yl) oxalamide (3d)
IR (KBr) 3 345, 3 155, 1 722, 1 645, 1 460. 1H-NMR (CDCl3,
300 MHz, d ppm): 6.6 (t, 1H, Ar–H), 6.8–6.9 (t, 2H, Ar–H), 7.2–
7.3 (m, 4H, Ar–H), 7.5–7.6 (m, 4H, Ar–H), 8.2–8.3 (s, 1H, N–H),
8.4–8.5 (d, 2H, Ar–H). MS m/z 318. Anal. calcd. for C18H14N4O2
(318): C, 67.92; H, 4.40; N, 17.61. Found: C, 67.95; H, 4.51; N,
17.64.
Synthesis of (diphenyl carbamoyl) formyl chloride (2)
Diphenyl amine (1.86 g, 0.0011 M) and oxalyl chloride
(3.76 mL, 0.004 M) were dissolved in DMF (15 mL) and stirred
on magnetic stirrer for 30 min maintaining the temperature
below 0–58C. The reaction mixture was stirred further for 4 h
at room temperature. The precipitate obtained was washed
with water and filtered [14]. The crude product was recrystal-
lized from ethanol. M.p. 145–1488C, IR (KBr) 3115, 1730, 1665,
1465, 700 cmꢂ1, 1H-NMR (CDCl3, 300 MHz, d ppm) 7.5–7.6 (m,
6H, Ar–H), 7.8–7.9 (m, 4H, Ar–H).
4-(2-(Diphenylamino)-2-oxoacetamido) benzoic acid (3e)
IR (KBr) 3 465, 3 360, 3 115, 1 735, 1 674, 1 475. 1H-NMR
(CDCl3, 300 MHz, d ppm) 7.0–7.1 (t, 1H, Ar–H), 7.2–7.3
(m, 4H, Ar–H), 7.6–7.7 (m, 4H, Ar–H), 7.8–7.9 (d, 2H, Ar–H),
8.1–8.2 (s, 1H, N–H), 8.2–8.3 (d, 2H, Ar–H), 10.9 (s, 1H, OH
acidic). MS m/z 361 (Mþ1). Anal. calcd. for C21H16N2O4 (360):
C, 70.00; H, 4.44; N, 7.77. Found: C, 69.95; H, 4.45 N, 7.80.
Synthesis of N1-substituted-N2,N2-diphenyl oxalamide
(3a–3l)
Diphenylcarbamoyl formyl chloride (2) (0.001 M) and various
substituted aliphatic, alicyclic, aromatic and heterocyclic
amines (0.002 M) were stirred in DMF (15 mL) and K2CO3
(0.001 M) on magnetic stirrer for 2–3 h. The completion of
reaction was monitored by TLC. The reaction mixture was
poured into crushed ice or cold water. The solid obtained was
filtered and washed with sodium bicarbonate solution fol-
lowed by water. The crude product was recrystallized from
ethanol. The characterization data of the synthesized com-
pounds which have shown promising activity is presented
below.
Synthesis of 2-chloro-N,N-diphenylacetamide (4)
2-Chloro-N,N-diphenylacetamide (4) was prepared by reflux-
ing the diphenyl amine (1.69 g, 0.0011 M) and chloroacetyl
chloride (1.56 mL, 0.0014 M) in presence of 3 mL of DMF for
3 h in RBF. The temperature was maintained for 80–908C.
After completion of reaction, the mixture was poured into
crushed ice. The product obtained was filtered and washed
with cold water for several times. This crude product was
recrystallized with ethanol to get pale white colored com-
pound. M.p. 113–1188C, IR (KBr) 3145, 2965, 1722, 1675, 1485,
700 cmꢂ1, 1H-NMR (CDCl3, 300 MHz, d ppm) 4.1 (s, 2H, CH2),
7.2–7.6 (m, 6H, Ar–H), 7.8–7.9 (m, 4H, Ar–H).
N1,N1-Diphenyl-N2,N2-o-tolyloxamide (3a)
IR (KBr) 3 350, 3 115, 2 965, 1 730, 1 675, 1 473. 1H-NMR
(CDCl3, 300 MHz, d ppm) 2.3–2.4 (s, 3H, CH3), 6.8–6.9
(t, 1H, Ar–H), 7.1–7.2 (m, 4H, Ar–H), 7.3–7.4 (m, 4H, Ar–H),
7.5 (d, 1H, Ar–H), 7.6–7.8 (m, 4H, Ar–H), 8.1–8.2 (s, 1H, N–H).
MS m/z 331 (Mþ1), 315, 241, 225, 169. Anal. calcd.
for C21H18N2O2 (330): C, 76.36; H, 5.45; N, 8.48; Found: C,
76.30; H, 5.43; N, 8.42.
2-(Substituted amino)-N,N-diphenylacetamide 5a–m
2-(Substituted amino)-N,N-diphenylacetamide 5a–m were pre-
pared by stirring 2-chloro-N,N-diphenylacetamide (4) (0.245 g,
0.001 M) and various substituted amines (0.001 M) in acetone
(15 mL) using triethyl amine (0.001 M) as a catalyst on mag-
netic stirrer for 8 h. The completion of reaction was moni-
tored by TLC. The product obtained was filtered, air dried and
recrystallized from ethanol. The characterization data of the
synthesized compounds which have shown promising
activity is presented below.
N1,N1-Diphenyl-N2-p-tolyloxamide (3b)
IR (KBr) 3 345, 3 155, 2 974, 1 724, 1 655, 1 453. 1H-NMR
(CDCl3, 300 MHz, d ppm) 2.3–2.4 (s, 3H, CH3), 7.1–7.2
(m, 4H, Ar–H), 7.3–7.4 (m, 4H, Ar–H), 7.5–7.6 (d, 2H, Ar–H),
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

64
A. P. G. Nikalje et al.
Arch. Pharm. Chem. Life Sci. 2012, 345, 57–64
4-((Diphenylcarbamoyl) methyl amino) benzoic acid (5a)
IR (KBr) 3 456, 3 345, 3 115, 2 965, 1 724, 1 680, 1 470.
1H-NMR (CDCl3, 300 MHz, d ppm) 3.8–3.9 (s, 3H, CH2), 4.0–
4.1 (s, 1H, N–H), 6.6–6.7 (d, 2H, Ar–H), 7.0–7.1 (t, 2H, Ar–H),
7.3–7.4 (m, 4H, Ar–H), 7.6–7.7 (m, 4H, Ar–H), 7.9–8.0 (d, 2H,
Ar–H), 11.1–11.2 (s, 1H, OH acidic). MS m/z 347 (Mþ1), 331,
302, 225, 169. Anal. calcd. for C21H18N2O3 (346): C, 72.83; H,
5.20; N, 8.09. Found: C, 72.88; H, 5.22; N, 8.13.
7.2–7.3 (m, 4H, Ar–H), 7.6–7.7 (m, 4H, Ar–H). MS m/z 337.
Anal. calcd. for C20H17ClN2O (337): C, 71.21; H, 5.04; N,
8.30. Found: C, 71.26; H, 5.09; N, 8. 35.
Authors are grateful to Mrs. Fatma Rafiq Zakaria, the Chairman, Maulana
Azad Education Trust and Dr. M. H. Dehghan, Principal, Y.B Chavan
College of Pharmacy, Aurangabad for encouragement and support.
The authors are thankful to Dr. Sayyed Ayyaz Ali, Assistant
Prof., Department of Pharmacology, for his guidance during the
pharmacological screening.
2-(o-Tolylamino)-N,N-diphenylacetamide (5b)
IR (KBr) 3 345, 3 120, 2 975, 1 720, 1 685, 1 483. 1H-NMR
(CDCl3, 300 MHz, d ppm) 2.3–2.4 (s, 3H, CH3), 3.8–3.9
(s, 2H, CH2), 4.0–4.1 (s, 1H, N–H), 6.3–6.4 (d, 1H, Ar–H), 6.4–
6.5 (t, 1H, Ar–H), 6.8–6.9 (t, 2H, Ar–H), 7.0–7.1 (t, 2H, Ar–H),
7.3–7.4 (m, 4H, Ar–H), 7.6–7.7 (m, 4H, Ar–H). MS m/z 316. Anal.
calcd. for C21H20N2O (316): C, 79.74; H, 6.37; N, 8.85. Found: C,
79.68; H, 6.40; N, 8.81.
The authors have declared no conflict of interest.
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4.1 (s, 1H, N–H), 6.3 (d, 1H, Ar–H), 6.4 (d, 1H, Ar–H), 6.5 (d, 1H,
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