Antidepressant activity of carbamates and urea derivatives

Article abstract of DOI:10.1007/s00044-011-9797-8

Thirteen (13) compounds of N-phenyl-O-alkyl carbamates (1 and 3), N,N-diethyl-N′-alkyl/aryl/phenylpiperazinoureas (4-6, 8-12), N-phenyl-N′-phenylpiperazino/imidazoureas (2, 7), and N-ethyl-(N′- phenylpiperazino) thioureas 13 were synthesized and tested for their antidepressant-like activity in mice. It was found that compound N-phenyl-O-heptyl carbamate 1 and N-phenyl-N′-phenylpiperazinourea 2 showed 32.5 and 27.7% antidepressant activity in the forced swim test in mice, respectively. Considering other carbamates it was found that a decrease in alkyl chain length caused a marked decline in the antidepressant activity. Compounds 1-4 show even higher activities in the forced swim test than the standard phenelzine. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9797-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2709–2715
DOI 10.1007/s00044-011-9797-8
ORIGINAL RESEARCH
Antidepressant activity of carbamates and urea derivatives
•
Shahnaz Perveen Nasreen Fatima
•
•
Muhammad Aitmaud Khan Ahsana Dar
•
•
Khalid M. Khan Nighat Afza Wolfgang Voelter
•
Received: 26 March 2011 / Accepted: 10 September 2011 / Published online: 29 September 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Thirteen (13) compounds of N-phenyl-O-alkyl
carbamates (1 and 3), N,N-diethyl-N0-alkyl/aryl/phenylpi-
perazinoureas (4–6, 8–12), N-phenyl-N0-phenylpiperazino/
imidazoureas (2, 7), and N-ethyl-(N0-phenylpiperazino)
thioureas 13 were synthesized and tested for their antide-
pressant-like activity in mice. It was found that compound
N-phenyl-O-heptyl carbamate 1 and N-phenyl-N0-phenyl-
piperazinourea 2 showed 32.5 and 27.7% antidepressant
activity in the forced swim test in mice, respectively.
Considering other carbamates it was found that a decrease
in alkyl chain length caused a marked decline in the anti-
depressant activity. Compounds 1–4 show even higher
activities in the forced swim test than the standard
phenelzine.
Introduction
In recent years, psychiatrics focused their research on the
discovery of more efficient drugs for depressive disorders
having also fewer side effects. Depression is a chronic
illness just like diabetes or asthma. There are many factors
which can trigger depression, such as being out of job, very
serious illness, i.e., cancer, HIV etc., divorce, flunking out
of school, loss in business. Sometimes there is no apparent
factor that triggers a depression. There are many pre-
scription drugs that can cause depression; fortunately,
depression is a highly treatable condition. However, to
alleviate the depressant, antidepressants are normally taken
as a medication.
MAOIs (monoamine oxidase inhibitors), tricyclic, and
tetracyclic compounds are commonly used as antidepres-
sants. These medications are very popular among the
psychiatrists and in general practitioners. Unsatisfactory
efficiency and unfavorable side effects alert the scientist to
search for better therapeutic antidepressant drugs. Antide-
pressants are often used for the treatment of anxiety,
bipolar, and eating disorders or chronic pain. Antidepres-
sant drugs change the mood of patients from poignant to
happiness and are therefore often referred to as ‘‘mood
brighteners’’.
Keywords Antidepressant ꢀ Carbamates ꢀ
Urea derivatives ꢀ Forced swim test ꢀ Thiourea
S. Perveen (&) ꢀ N. Afza
PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr.
Salimuzzaman Siddiqui, Karachi 75280, Pakistan
e-mail: dr_shahnaz_perveen@yahoo.com
N. Fatima
Department of Chemistry, University of Karachi, Karachi 75270,
Pakistan
Dibenzocycloheptenes and related classes of tricyclic
compounds are well known for their antidepressant activity
(Stach, 1969; Bloom and Tretter, 1969; Siegismund and
Friedrich, 1970; Burg and Delobelle, 1970; Traber and
Horstmann, 1990; Epling et al., 1988; Hoffsommer et al.,
1962). Sertraline, escitalopram, fluxetine, and venlafaxine
are commonly prescribed antidepressants in the US since
2005 (Czygan, 2003). Newly developed antidepressants,
(serotonin syndrome) possess harmful effects resulting
from the overstimulation of serotonin receptors. Selective
M. A. Khan ꢀ A. Dar ꢀ K. M. Khan
H. E. J. Research Institute of Chemistry, International Center for
Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
W. Voelter
¨
¨
¨
¨
Interfakultares Institut fur Biochemie Der Universitat Tubingen,
Hoppe-Seyler-Straße 4, D-72076 Tu¨bingen, Germany
e-mail: wolfgang.voelter@uni-tuebingen.de
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Med Chem Res (2012) 21:2709–2715
Serotonin Reuptake Inhibitor (SSRI) medication is now
very common in use, but unexpected discontinuation may
result in both, somatic and psychological withdrawal
symptoms. Therefore, novel antidepressant medications
lacking these drawbacks are needed.
immobility inhibition, the highest % inhibition in immo-
bility time in mice as compared to the reference drug
phenelzine.
N-Phenyl-N0-phenylpiperazinourea 2, N-phenyl-O-ethyl
carbamate 3, and N,N-diethyl-N0-(p-carboxyphenyl)urea 4
showed also considerable antidepressant activity, 27.7,
21.6, and 16.7%, respectively. Comparison of the antide-
pressant activities of compounds 1 and 3 (Table 1) indi-
cates that the activity of the compounds increases with
prolongation of the non-polar side chain (Perveen et al.,
2010). For the N,N-diethyl-N0-(p-carboxyphenyl)urea 4 an
antidepressant activity of 16.7% was determined, while its
o-analog 6 shows only 3.5% antidepressant activity. The
increase of the antidepressant activity from the meta to the
ortho to the para analog (9–6–4) (Perveen et al., 2011)
seems to be caused by the decrease of the steric hindrance
of the carboxyl group and the positive charge imposed on
C-2 and C-6 position by the carboxyl group in meta posi-
tion 9 (Table 1). N,N-diethyl-N0-substituted ureas seem to
be less potent antidepressants than N0-monoalkyl/aryl
derivatives as is demonstrated by the comparison of the
activities of compound 8 (15.5%) with that of 2 (27.7%).
No activity was found for the thiourea compound N-ethyl-
N0-phenylpiperazino thiourea 13 which has an ethyl group
instead of a phenyl or diethyl group at the nitrogen of urea
bridge. In N,N-diethyl-N0-(p-chlorophenyl)urea 5 a chloro
group is attached at para position of the phenyl ring which
is not a strong electron-withdrawing group as compared to
the carboxyl group in compound 4 (Perveen et al., 2011).
This makes compound 5 less antidepressant (7.04%);
substitution of the para position in compounds 5 and 4 by
hydrogen further reduces electronic effects in the aromatic
ring, which causes a further reduction of the antidepressant
activity. A very enhanced depressant activity was found for
the compound N-phenyl-N0-imidazourea 7 (60.8%), two
structural properties may cause this strong biological
effect, first, the proton, attached to the nitrogen of the urea
bridge which causes less steric hindrance compared to an
alkyl or aryl group, and second the imidazole moiety the
nitrogens of which may form hydrogen bridges with
receptors.
A series of urea compounds are natural products with
important biological activities (Fournier et al., 1991).
Besides, they are used as dyes for cellulose fiber, antioxi-
dants in gasoline, corrosion inhibitors, agricultural pesti-
cides, herbicides, and antitumors (Fournier et al., 1991;
Bigi et al., 2000; Takahiro et al., 1987). Several unsym-
metrical ureas are known for their efficient pharmaceutical
and herbicidal effects (Groszek, 2002; Yonova and
Stoilkova, 2005). Potent antiglycation and antidepressant
activities were reported for a series of symmetrical and
unsymmetrical disubstituted ureas (Khan et al., 2009;
Perveen et al., 2011).
Symmetrical and urea derivatives are used as drug
precursors, such as HIV protease inhibitor, CCK-b recep-
tor, endothelin antagonist, and have cytokinin activity,
HDL-elevating, antiviral, antifungal, analgesic, and insect
control properties (Lam et al., 1994; Castro et al., 1996;
von Geldern et al., 1996; Bruce and Zwar, 1966; Struga
et al., 2007; Daniel et al., 2005; Miesel, 1981; Richardson
and Whittle, 1984). Aryl urea derivatives are considered to
have therapeutic agents for inflammatory and/or immuno-
modulatory diseases by the inhibition of p38 kinase
(Ranges et al., 2002). Tetrasubstituted urea derivatives are
considered as cholinergic (Butler et al., 1988). In the
present study, the antidepressant effect of carbamates and a
series of 1,3-disubstituted and trisubstituted urea deriva-
tives are reported.
Results and discussions
Two carbamates 1 and 3 were synthesized by the reaction of
heptanol and ethanol with phenyl isocyanate (Scheme 1),
and the urea derivatives 4–6 and 8–12 by the reaction
of p-carboxyaniline, p-chloroaniline, o-carboxyaniline,
1-phenylpiperazine, m-carboxyaniline, aniline, N,N-dim-
ethylethylene diamine, and 2,6-dimethylaniline, respec-
tively, with N,N-diethylcarbamyl chloride (Scheme 2).
Compounds 2 and 7 were prepared by the reaction of phenyl
isocyanate with 1-phenylpiperazine and imidazole, respec-
tively (Scheme 3). N-Ethyl-N0-phenylpiperazino thiourea
13 was prepared by treating 1-phenylpiperazine with ethyl
thiocyanate (Scheme 4).
Experimental
General
Ethanol and heptyl alcohol were dried by using magnesium
turning. 1-phenylpiperazine, imidazole, o-,m-,p-amino-
benzoic acid, p-chloroaniline, aniline, N,N-dimethylethyl-
ene diamine, phenyl isocyanate, ethyl thiocyanate, and
diethylcarbamyl chloride were of reagent grade (Merck,
Darmstadt) and used directly without purification. IR
The compounds 1–13 were tested for antidepressant
activity in mice using the forced swim test protocol
(Porsolt et al., 1978; Dar and Khatoon, 1997). The com-
pound N-phenyl-O-heptyl carbamate 1 showed 32.5% of
123

Med Chem Res (2012) 21:2709–2715
2711
Scheme 1 Synthetic route for
the preparation of carbamates
NH
C O
C
OR
N
r.t.
OH
R
+
R = heptyl/ethyl
Phenyl isocyanate
N-Phenyl-O-heptyl/ethyl carbamate
1, 3
Scheme 2 Synthetic route for
the preparation of 4–6, 8–12
O
O
r.t.
NH2
+
R
NH
R
Cl C N
C
N
R= alkyl/aryl/
Diethylcarbamyl N,N-Diethyl-N'-alkyl/aryl/phenylpiperazinoureas
1-phenylpiperazine chloride
4-6, 8-12
Scheme 3 Synthetic route for
the preparation of compounds 2
and 7
O
C
N
N
H
N
N-Phenyl-N'-phenylpiperazinourea
N
C
O
2
O
Phenyl isocynate
N
C
N
H
N
N-Phenyl-N'-imidazourea
7
Scheme 4 Synthetic route for
the preparation of compound 13
S
C
H
N
N
H
N
C2H5
N
N
1,4-Dioxane
0°C, 1-1.5hr
N
C
C2H5
S
+
Ethyl thiocyanate
1-Phenylpiperazine
N-Ethyl-N'-phenylpiperazino thiourea
13
spectroscopic analysis was carried out using a FT IR
spectrophotometer (Avatar 320) equipped with a Smart
Specul ATR Thermospectra Tech 035-603 for liquids, and
a Thermo Spectra-Tech 035-703 for solids. The values are
reported in cm-1. The 1H NMR spectroscopy was per-
formed on a Bruker AC 400 (400 MHz) spectrometer and
the values are reported in d (ppm). TMS was taken as
internal standard. EI MS spectra were recorded on a
Finnigan-MAT-311A apparatus and the values are reported
in m/z.
reaction, the mixture was poured into ice-cold water with
continuous stirring. The solid obtained was filtered, dried,
and afforded pure N-phenyl-O-heptyl carbamate 1 in
quantitative yields (Scheme 1). While in the case of etha-
nol, two products were formed after purification by column
chromatography afforded, N-phenyl-O-ethyl carbamate 3
and symmetrical 1,3-disubstituted ureas (Scheme 1).
N-Phenyl-O-heptyl carbamate 1 Recrystallized from
cyclohexane (Yield 95%). mp 205–207 °C. 1H NMR
(CDCl3) d; 8.40 (1H, br.s, NH), 7.42–7.25 (4H, m, H2,3,5,6),
7.08 (1H, m, H4), 3.84 (2H, t, J = 6.8 Hz, CH2), 1.72–1.64
(2H, m, CH2), 1.30–1.21 (8H, m, 4CH2), 0.84 (3H, t,
J = 9.0 Hz, CH3)—EI MS: m/z (rel. abund. %), 235 (M?,
21), 220 (13), 206 (36), 136 (55), 119 (87), 77 (45)—Anal.:
Calcd for C14H21NO2: C, 71.46; H, 9.00; N, 5.95%. Found:
C, 71.49; H, 8.89; N, 5. 97%.
General procedure for the preparation
of carbamates (1 and 3)
0.1 mol (11.9 g) of phenyl isocyanate was treated with
0.7 mol heptanol at room temperature and the progress of
reaction was monitored by TLC. The TLC showed that
a single product was formed. After completion of the
N-Phenyl-O-ethyl carbamate 3 Recrystallized from
cyclohexane (Yield 40%). mp 58–60 °C. 1H NMR (CDCl3)
123

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Med Chem Res (2012) 21:2709–2715
Table 1 % Inhibition immobilities compared to standard phenelzine of synthesized N-phenyl-O-alkyl carbamates, N,N-diethyl-N’-alkyl/aryl/
phenylpiperazinoureas, N-phenyl-N’-phenylpiperazino/imidazoureas and N-ethyl-N’-phenylpiperazino thiourea (1–13)
Sr. #.
1
Compound
Structure
Yield %
95
% Inhibition immobility
N-Phenyl-O-heptyl carbamate
32.5%;
H
N
OC H
7
15
C
O
2
3
4
5
6
N-Phenyl-N-phenylpiperazinourea
93
40
86
85
78
27.7%;
21.6%;
16.74%;
7.04%;
3.52%;
O
C
H
N
N
N
N-Phenyl-O-ethyl carbamate
H
N
OC H
2
5
C
O
N,N-Diethyl-N0-(p-carboxyphenyl)urea
N,N-Diethyl-N0-(p-chlorophenyl)urea
N,N-Diethyl-N0-(o-carboxyphenyl)urea
O
C
NH
N
CO H
2
O
NH
C
N
Cl
O
C
NH
N
CO H
2
O
C
7
8
N-Phenyl-N0-imidazourea
87
91
60.8%:
15.5%:
H
N
N
N
N,N-Diethyl-N0-phenylpiperazinourea
O
C
N
N
N
9
N,N-Diethyl-N0-(m-carboxyphenyl)urea
88
6.87%:
O
CO H
2
NH
C
N
123

Med Chem Res (2012) 21:2709–2715
2713
Table 1 continued
Sr. #.
10
Compound
Structure
Yield %
96
% Inhibition immobility
N,N-Diethyl-N0-phenylurea
6.6%:
O
C
NH
N
11
12
N,N-Diethyl-N0-ethylene(N00, N00-dimethyl)urea
N,N-Diethyl-N0-(2,6-dimethylphenyl)urea
80
90
1.76%:
O
C
CH
3
NH
N
N
H C
3
CH
O
C
Nil
3
NH
N
CH
3
13
N-Ethyl-N0-phenylpiperazino thiourea
84
Nil
S
C H
2
5
N
C
N
H
N
14
Phenelzine
15.9%;
NH
NH
2
; % Inhibition immobility
: % Increase immobility
0
0
d; 8.36 (1H, br.s, NH), 7.40–7.27 (4H, m, H2,3,5,6), 7.05
(1H, m, H4), 4.12 (2H, q, J = 9.0 Hz, CH2), 1.25 (3H, t,
J = 9.0 Hz, CH3)—EI MS: m/z (rel. abund. %); 165 (M?,
87), 150 (49), 136 (27), 119 (100), 77 (34)—Anal.: Calcd
for C9H11NO2: C, 65.44; H, 6.71; N, 8.48%. Found: C,
65.51; H, 6.67; N, 8.44%.
= 07.2 Hz, H3 ,5 ), 6.97
0
dd, J3 ,2
0
(2H, d, J2 ,3
0
0
= 8.0, J3 ,4
0
= 50,60
= 50,40
0
= 8.0 Hz, H2 ,6 ), 6.82 (1H, t,
0
= 60,50
40
4 ,(3 ,5 ) = 7.2 Hz, H ), 3.61 (4H, t, J1 ,2 = 4.8 Hz,
0
0
0
00 00
J
00 00
2CH2), 3.15 (4H, t, J2 ,1 = 4.8 Hz, 2CH2)—EI MS: m/z
(rel. abund. %); 281 (M?, 8), 204 (56), 189 (16), 161 (43),
119 (100), 77 (98)—Anal.: Calcd for C17H19N3O: C, 72.57;
H, 6.81; N, 14.94%. Found: C, 72.53; H, 6.87; N, 14.89%.
N-Phenyl-N0-imidazourea 7 Recrystallized from hexane
Preparation of N-phenyl-N0-phenylpiperazinourea 2 and
N-phenyl-N0-imidazourea 7
1
(Yield 87%). H NMR (DMSO-d6) d; 10.12 (1H, s, NH),
7.98 (1H, dd, J2,4 = 2.1, J2,5 = 1.5 Hz, H2), 7.84 (1H, dd,
5
J5,4 = 4.1, J5,2 = 1.5 Hz, H ), 7.63–7.58 (2H, m, H /H ),
2
6
0 0
For the preparation of 2 and 7, to a mixture of (0.7 mol)
1-phenylpiperazine/imidazole in 20–25 mL of 1, 4-dioxane
was added at 0 °C dropwise neat 10.85 mL (11.9 g,
0.1 mol) phenyl isocyanate. The reaction mixture was then
allowed to stir at room temperature for 1–1.5 h. After
completion of the reaction (TLC analysis), the mixture
was poured into ice-cold water yielding fine crystals of
N-phenyl-N0-phenylpiperazinourea 2 and N-phenyl-N0-
imidazourea 7 (Scheme 3).
3
5
4
0
0
0
7.35–7.30 (2H, m, H /H ), 6.86–6.77 (1H, m, H ), 6.61
(1H, dd, J4,5 = 4.1, J4,2 = 2.1 Hz, H4);—EI MS: m/z (rel.
abund. %); 187 (M?, 8), 120 (10), 110 (46), 77 (100)—
Anal.: Calcd for C10H9N3O: C, 64.16; H, 4.85; N, 22.45%.
Found: C, 64.14; H, 4.86; N, 22.47%.
General procedure for the preparation of N,N-diethyl-N0-
alkyl/aryl/phenylpiperazinoureas 4–6 and 8–12
N-Phenyl-N0-phenylpiperazinourea
2
Recrystallized
from hexane (Yield 93%). mp 280 °C 1H NMR (CDCl3) d;
8.15 (2H, d, J = 9.0 Hz, H2,6), 8.00 (1H, br.s, NH), 7.32
(2H, dd, J = 9.0, 2.5 Hz, H3,5), 7.03 (1H, m, H4), 7.67 (2H,
To a solution of (0.7 mol) aryl/alkylamine/phenylpiper-
azine, N, N-diethylcarbamyl chloride was added dropwise
(Scheme 2) at room temperature with continuous stirring.
123

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Med Chem Res (2012) 21:2709–2715
Progress of reaction was monitored via TLC (Mukund
et al., 2004). After completion of reaction the reaction
mixture was purified with hexane, then evaporated in vacuo
and the resultant solid residue was crystallized from an
appropriate solvent to afford the pure derivatives 4–6 and
8–12, respectively.
H4), 5.81 (1H, br.s., NH), 3.32 (2H, q, J = 7.0 Hz, CH2),
3.16 (2H, q, J = 7.1 Hz, CH2), 1.15 (3H, t, J = 7.0 Hz,
CH3), 1.1 (3H, t, J = 7.1 Hz, CH3)—IR mmax cm-1 (KBr):
3294, 2950, 2931, 1643, 1599, 1500, 1442, 1316, 1236—EI
MS: m/z (rel. abund. %); 192 (M?, 19), 177 (33), 163 (39),
134 (55), 100 (82), 92 (78), 77 (100)—Anal.: Calcd for
C11H16N2O: C, 68.72; H, 8.39; N, 14.57%. Found: C,
68.66; H, 8.32; N, 14.52%.
N,N-Diethyl-N0-(p-carboxyphenyl)urea 4 Recrystallized
1
from hexane (Yield 86%). H NMR (CDCl3) d; 9.52 (2H,
br.s, NH/OH), 7.63 (2H, d, J = 9.0 Hz, H3,5), 6.74 (2H, d,
J = 9.0 Hz, H2,6), 3.03 (4H, q, J = 7.1 Hz, 2CH2), 0.98
(6H, t, J = 7.1 Hz, 2CH3)—EI MS: m/z (rel. abund. %);
236 (M?, 23), 121 (35), 207 (12), 192 (16), 136 (18)—
Anal.: Calcd for C12H16N2O3: C, 61.00; H, 6.83; N,
11.86%. Found: C, 61.15; H, 6.72; N, 11.79%.
N,N-Diethyl-N0-ethylene-(N00,N00-dimethyl)urea 11 Re-
crystallized from hexane (Yield 80%). 1H NMR (CDCl3) d;
5.48 (br.s., 1H, NH), 3.70 (6H, br.s, 2CH3), 3.41 (2H, t,
J = 5.2 Hz, CH2), 3.19 (4H, q, J = 7.2 Hz, 2CH2), 3.10
(2H, t, J = 5.2 Hz, 2CH2), 0.88 (6H, t, J = 7.2 Hz,
2CH3)—EI MS: m/z (rel. abund. %), 187 (M?, 40), 159
(12), 128 (95)—Anal.: Calcd for C9H21N3O: C, 57.72; H,
11.30; N, 22.44%. Found: C, 57.62; H, 11.50; N, 22.35%.
N,N-Diethyl-N0-(2, 6-dimethylphenyl)urea 12 Recrys-
N,N-Diethyl N01-(4-chlorophenyl)urea 5 Recrystallized
1
from hexane (Yield 85%). H NMR (CDCl3) d; 7.45 (2H,
d, J = 8.8 Hz, H3,5), 7.26 (2H d, J = 8.8 Hz, H2,6), 4.82
(1H, br.s, NH), 3.04 (4H, q, J = 7.3 Hz, 2CH2), 1.31 (6H,
t, J = 7.3 Hz, 2CH3)—EI MS: m/z (rel. abund. %); 228
(M?2, 2), 226 (M?, 7), 211 (4), 197 (20), 154 (10)—Anal.:
Calcd for C11H15N2OCl: C, 58.28; H, 6.67; N, 12.36%.
Found: C, 58.301; H, 6.71; N, 12.44%.
1
tallized from hexane (Yield 90%). mp 357 °C. H NMR
(CDCl3) d; 8.30 (1H, br.s, NH), 7.03 (3H, m, Ar–H), 3.29
(6H, s, 2CH3), 2.49 (4H, br.s, 2CH2), 2.22 (6H, br.s,
2CH3)—EI MS: m/z (rel. abund. %); 220 (M?, 37), 205
(28), 191 (47),), 148 (33), 147 (100), 116 (85)—Anal.:
Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72%.
Found: C, 70.82; H, 9.19; N, 12.75%.
N,N-Diethyl-N0-(o-carboxyphenyl)urea 6 Recrystallized
1
from hexane (Yield 78%). H NMR (CDCl3) d; 9.86 (2H,
br.s, NH/OH), 8.05 (1H, dd, J = 7.7, 1.7 Hz, H3), 7.79
(1H, dd, J = 7.7, 1.5 Hz, H6), 7.33 (1H, t, J = 7.7 Hz, H4),
7.24 (1H, t, J = 7.7 Hz, H5), 3.01 (4H, q, J = 7.0 Hz,
2CH2), 0.99 (6H, t, J = 7.0 Hz, 2CH3)—EI MS: m/z (rel.
abund. %); 236 (M?, 25), 121 (30), 207 (10), 192 (18), 136
(15)—Anal.: Calcd for C12H16N2O3: C, 61.00; H, 6.83; N,
11.86%. Found: C, 61.21; H, 6.89; N, 11.67%.
N,N-Diethyl-N0-phenylpiperazinourea 8 Recrystallized
from hexane (Yield 91%). mp 251 °C. 1H NMR (CDCl3) d;
7.21 (1H, t, J4,(3,5) = 7.2 Hz, H4), 7.10 (2H, d, J2,3 = 6,5
= 7.2 Hz, H2,6), 6.93 (2H, t, J3,(4,2) = 5,(4,6) = 7.2 Hz,
H3,5), 3.47 (8H, br.s, 4CH2), 2.32 (4H, br.s, 2CH2), 1.53
(6H, br.s, 2CH3)—EI MS: m/z (rel. abund. %); 261 (M?,
16), 246 (35), 232 (21), 189 (29), 184 (35)—Anal.: Calcd
for C15H23N3O: C, 68.93; H, 8.87; N, 16.08%. Found: C,
68.97; H, 8.94; N, 16.11%.
Preparation of N-ethyl-N0-phenylpiperazino thiourea 13
For the preparation of 13 (Scheme 4), to a mixture of 1-
phenylpiperazine (0.7 mol) in 20–25 mL of 1,4-dioxane
was added at 0 °C dropwise neat 8.60 mL (8.7 g, 0.1 mol)
ethyl thiocyanate. The reaction mixture was then allowed
to stir at room temperature for 1–1.5 h. After completion of
the reaction (TLC analysis), the mixture was poured into
ice-cold water yielding fine crystals of N-ethyl-N0-phenyl-
piperazino thiourea 13.
Recrystallized from hexane (Yield 84%). 1H NMR
0
0
0
= 8.1, J3 ,4
= 60,500
0
= 50,60
= 50,40
(CDCl3) d;0 7.66 (2H, dd, J3 ,2
=
0
0
0
7.0 Hz, H3 ,5 ), 6.97 (2H, d, J2 ,3
6.81 (1H, t, J4 ,(3 ,5 ) = 7.0 Hz, H4 ), 3.60 (4H, t,
= 8.1 Hz, H2 ,6 ),
0
0
0
0
0
00 00
J1 ,2 = 4.9 Hz, 2CH2), 3.42 (2H, q, J = 7.0 Hz, CH2),
00 00
3.17 (4H, t, J2 ,1 = 4.9 Hz, 2CH2), 0.99 (3H, t,
J = 7.0 Hz, CH3)—EI MS: m/z (rel. abund. %); 249 (M?,
19), 234 (34), 220 (26), 205 (74), 162 (100)—Anal.: Calcd
for C13H19N3S: C, 62.61; H, 7.68; N, 16.85%. Found: C,
62.66; H, 7.62; N, 16.81%.
N,N-Diethyl-N0-(m-carboxyphenyl)urea 9 Recrystallized
1
from hexane (Yield 88%). H NMR (CDCl3) d; 8.02 (1H,
td, J = 7.7, 1.2 Hz, H4), 7.95 (1H, m, H2), 7.61 (1H, t,
J = 7.7 Hz, H5), 7.53 (1H, td, J = 7.7, 1.2 Hz, H6), 3.03
(4H, q, J = 7.3 Hz, 2CH2), 1.29 (6H, t, J = 7.3 Hz,
2CH3)—EI MS: m/z (rel. abund. %), 236 (M?, 86), 207
(15), 192 (95), 152 (82)—Anal.: Calcd for C12H16N2O3: C,
61.00; H, 6.83; N, 11.86%. Found: C, 61.11; H, 6.74; N,
11.75%.
Anti-depressant test (forced swim test in mice) FST
Mice (20–30 g) of either sex were taken to perform the pre-
test session by placing them in a FST tank (glass tank;
height = 25 cm, diameter = 15 cm), filled with water of
25 °C up to the height of 15 cm for 15 min. Movement of
animals were noted carefully. Injured or ill animals, e.g.,
those showing symptoms of nose bleeding are discarded.
Animals received phenelzine as standard antidepressant
N,N-Diethyl-N0-phenylurea 10 Recrystallized from
1
hexane (Yield 96%). mp 80–82 °C. H NMR (CDCl3) d;
7.48 (2H, dd, J = 8.0, 1.2 Hz, H2,6), 7.26 (2H, ddd,
J = 8.0, 7.6, 1.0 Hz, H3,5), 6.97 (1H, dd, J = 7.6, 1.2 Hz,
123

Med Chem Res (2012) 21:2709–2715
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À
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Conclusion
Comparing the antidepressant activities of N-phenyl-O-
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prolongation of the non-polar side chain. Second, the
antidepressant activity of urea derivatives increases with
the presences of a strong electron-withdrawing group at
para position of phenyl ring. Compound N-phenyl-N0-
imidazourea 7 has reverse activity, it increase the depres-
sion to the animal.
Acknowledgments Dr. Shahnaz Perveen and Dr. Khalid M. Khan
are thankful for the financial support of Deutscher Akademischer
Austauschdienst (DAAD) Bonn, Germany and the National Core
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