Substituted urea/thiourea derived from fluoxetine as potent appetite suppressants

Article abstract of DOI:10.1007/s00044-007-9041-8

A series of urea and thiourea analogues of fluoxetine (5-17) were synthesized and evaluated for their anorexigenic and antidepressant activities. The related conformationally restrained analogues (20-23) were also prepared for structure-activity relationship (SAR) studies. Many of these derivatives (5, 6, 8, 10, 12, 13, 16, and 23) exhibited significant anorexigenic activity and interestingly were devoid of antidepressant activity, thus emerging as a promising tool for further research work.

Full text of DOI:10.1007/s00044-007-9041-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2008) 17:103–113
DOI 10.1007/s00044-007-9041-8
ORIGINAL RESEARCH
Substituted urea/thiourea derived from fluoxetine as
potent appetite suppressants
Kalpana Bhandari Æ Nagarapu Srinivas Æ
Lata Sharma Æ Shipra Srivastava Æ Amar Nath Æ
Chandishwar Nath
Received: 18 October 2007 / Accepted: 31 October 2007 / Published online: 12 January 2008
¨
ꢀ Birkhauser Boston 2008
Abstract A series of urea and thiourea analogues of fluoxetine (5–17) were
synthesized and evaluated for their anorexigenic and antidepressant activities. The
related conformationally restrained analogues (20–23) were also prepared for
structure–activity relationship (SAR) studies. Many of these derivatives (5, 6, 8, 10,
12, 13, 16, and 23) exhibited significant anorexigenic activity and interestingly were
devoid of antidepressant activity, thus emerging as a promising tool for further
research work.
Keywords Fluoxetine Á Appetite suppressants Á Antidepressants Á
SSRIs Á Urea thiourea derivatives
Introduction
For several decades, pharmacologists have demonstrated the importance of central
serotonergic neurotransmission (Garattini et al., 1992; Kennett 1998) in the
suppression of feeding behavior. Serotonin (5-hydroxytryptamine, 5-HT), a
neurotransmitter, acts in the central nervous system to modulate the feeding
behavior in an inhibitory manner (Blundell 1984) and possibly plays a role in the
mediation of satiety (Shor-Posner et al., 1986). Serotonergic drugs act either by
releasing serotonin (Garattini et al., 1992) or inhibiting the reuptake of serotonin
C.D.R.I. communication No 7022
K. Bhandari (&) Á N. Srinivas Á L. Sharma Á S. Srivastava
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226001,
India
e-mail: bhandarikalpana@rediffmail.com
A. Nath Á C. Nath
Pharmacology Division, Central Drug Research Institute, Lucknow 226001, India

104
Med Chem Res (2008) 17:103–113
(SSRIs) (Kennett, 1998) into the synaptic cleft. In both cases the concentration of
serotonin increases at presynaptic terminals to increase the sensation of satiety.
Hence 5-HT-releasing agents and selective 5-HT uptake inhibitors have been
suggested as antiobesity agents. Various SSRIs (Goldstein et al., 1994; Wadden
et al., 1995; Fernstrom et al., 1988) have been tested as antiobesity medications.
Fluoxetine, arguably the most anorexigenic (Benfield et al., 1986) of the SSRIs, has
undergone considerable evaluation to determine its efficacy for weight loss. In
addition to its SSRI activity, fluoxetine also has a direct agonist action at the 5-HT2C
receptor (Stahl, 1998) and it is well known that the direct activation of some 5-HT2C
receptors reduces food consumption (Curzon et al., 1998).
Recently we reported that the replacement of hydrogen in the NHCH3 group in
fluoxetine and its substitution by various substructure (Bhandari et al., 2005)
resulted in a modest reduction in the antidepressant effect (the main activity) with
the retention of the anorexigenic effect (the side activity). These results prompted us
to take fluoxetine as an active pharmacophore for further diversification. Consid-
ering the anorexigenic activity of substituted urea/thiourea derivatives (Jackson
1976; Bhandari et al., 2004), we incorporated this moiety onto fluoxetine and thus
aimed to synthesize 1 as our target molecule. For structure–activity relationship
(SAR) studies we also prepared the related 1-aryloxy-2-aminomethyltetrahydro-
naphthalene urea/thiourea derivatives (2) as conformationally rigid analogues of
fluoxetine (Fig. 1).
Chemistry
The synthesis route adopted for the preparation of the urea/thiourea derivatives of
fluoxetine (5–17) and conformationally rigid analogues of fluoxetine (20–23) is
depicted in Schemes 1 and 2.
Fluoxetine (3) was prepared starting from acetophenone in four steps as reported
earlier (Bhandari et al., 2005), was treated with different isocyanates (4a, 4b) and
isothiocyanates (4c–m) to furnish the final urea and thioureas (5–17) (Scheme 1).
The isothiocyanates (4c-m) used in Scheme 1 were synthesized from the
corresponding primary amines using dicyclohexylcarbodiimide (DCC) and carbon
disulphide (Ankersen et al., 1998). The tetrahydronaphthalene urea/thiourea
derivatives (20–23) as conformationally rigid analogues of fluoxetine were
synthesized by the condensation of 19 (Bhandari et al., 2006) with different
isocyanates (4a, 4b) and isothiocyanates (4c, 4i) (Scheme 2).
F3C
R
R
O
O
X
O
X
N
NHMe
NR1R2
N
NR1R2
Me
Me
2
1
Fluoxetine
Fig. 1 Structures of fluoxetine and structures 1 and 2

Med Chem Res (2008) 17:103–113
105
F3C
F3C
R1
C
N
X
O
O
X
4a-m
NHMe
a
N
NHR1
Me
5-17
3
X=O, S
b
R1
C
R1
NH2
N
S
4c-m
Scheme 1 Reagents and conditions: (a) CH3CN; (b) DCC, CS2, dry THF –10ꢁC
F3C
F3C
O
O
O
d
a-c
Bn
H
N
N
Me
Me
F3C
e
19
18
4a,b,c,i
X
O
C
R1
N
X=O, S
X
N
NHR1
Me
20-23
Scheme 2 Reagents and conditions: (a) Bz.MeNH.HCl, (CH2O)n, n-propanol; (b) NaBH4/MeOH; (c)
NaH, p-fluorobenzotrifluoride, DMAC; (d) ClCOOCH3, KOH, NH2NH2H2O; (e) CH3CN
Results and discussion
All the synthesized compounds (5–17, 20–23) were screened for their effect on
gross behavior, appetite suppressant, and antidepressant activities by standard
methods (Bhandari et al., 2005). The results are summarized in Table 1 and
compared with that of fluoxetine.
The compounds tested had no significant effect on the gross behavior whereas
fluoxetine showed signs of stimulation. In the antidepressant test, all the compounds
(5, 7–12, 14–17, and 20–23) except 6 and 13 were found to be inactive. The
standard fluoxetine exhibited 100% reversal of reserpine-induced ptosis, sedation,
and crouching. Compounds 5, 6, 8, 10, 12, 13, 16, and 23 were found to have
significant anorexigenic activity (P B 0.05) with a significant decrease in milk
intake (36.73% to 62.45%) in comparison to the control group (Table 1). None of
the compounds exhibited better anorexigenic activity than fluoxetine. The most
anorexigenic (62.45%) compound (13) also displayed a significant antidepressant
activity. Compounds 12 and 23 emerged as the most active compounds with 59.18%
and 62.24% anorexigenic activity, respectively. We have previously reported that
compound 19 (Bhandari et al., 2006), the rigid analogue of fluoxetine, showed

106
Med Chem Res (2008) 17:103–113
Table 1 Pharmacological data of urea/thiourea analogs of fluoxetine (5–17, 20–23) at 75 lmol/kg i. p
Compound
X
R1
Anorexigenic Antidepressant Sedation
a
activity
Decrease in
activity
ptosis (%
incidence)
and
Milk intake
(mean SEM) milk intake
crouching
(median
score)
from control
(%)
Control
0.46 0.01
0
100
0•
0
4
0•
4
2•
4
0
4
4
4
4
4
0
2•
4
4
4
4
0
4
4
4
4
Reserpine
Fluoxetine
0.1 0.06
0.20 0.07
0.28 0.10
0.37 0.07
0.49 0.01
0.28 0.06
0.37 0.07
0.31 0.04
0.43 0.03
0.20 0.02
0.49 0.01
0.18 0.03
78.49*
55.48*
38.49*
19.57
5
O
S
Cyclohexyl
2-phenethyl
benzyl
80
6
40•
100
0
7
S
Control
8
S
O
S
S
S
p-tolyl
42.86*
23.67
80
9
2-phenethyl
Cyclohexyl
Phenyl
100
100
100
100
0
60•
100
100
100
100
0
10
36.73*
11.02
11
12
Benzoyl
59.18*
Control
13
S
S
S
S
S
4-Methylcyclohexyl
62.45*
13.06
22.04
50.20*
0.82
14
3,4,5-trimethoxyphenyl 0.42 0.04
15
Tert-butyl
0.38 0.06
0.24 0.06
0.48 0.01
0.49 0.01
0.48 0.01
0.32 0.07
0.48 0.01
0.18 0.10
16
4-methoxy-phenyl
isopropyl
17
Control
20
S
2-phenethyl
2.04
33.88
2.04
100
100
100
80
21
O
O
S
cyclohexyl
22
2-phenethyl
23
4-Methylcyclohexyl
62.24*
*Significant anorexigenic activity (P B 0.05); •significant antidepressant activity; athe antidepressant
activity of the fluoxetine and the compounds 5–17 and 20–23 was evaluated after 3 h of reserpine
treatment; control: saline-treated mice
significant appetite suppression (66.9%) along with stimulant and antidepressant
action. Conversion of its amino function into thiourea/urea resulted in the complete
loss of the antidepressant activity and reduction in the anorexigenic activity (20–
23). However in compound 23 the anorexigenic activity was retained (62.24%) and
was comparable to that of 19. The anorexigenic activity of the rigid analogue 23
may be attributed to the 4-methyl cyclohexyl function as its open chain counterpart
(13) demonstrated the best anorexigenic activity profile (62.45%) among the
synthesized compounds. These results indicate that substitution of H in NHMe of
fluoxetine by urea/thiourea moieties resulted in th ecomplete loss of the
antidepressant effect in most of the compounds whereas the anorexigenic activity
was retained partially or significantly.

Med Chem Res (2008) 17:103–113
107
Conclusion
Seventeen urea and thiourea analogs of fluoxetine were synthesized as potential
appetite suppressants, of which eight (5, 6, 8, 10, 12, 13, 16, and 23) showed
significant anorexigenic activity. All of these eight compounds (except 6 and 13, in
which the antidepressant activity was reduced to half) were devoid of undesired
antidepressant effect. Compounds 23 and 12 displayed 62.24% and 59.18%
anorexigenic activity, respectively, and were found to be the most active compounds
of the series. These identified urea and thiourea derivatives will be very useful for
further optimization work.
Experimental section
Chemistry
Melting points were determined in open capillaries in an electrically heated block and
are uncorrected. Infrared (IR) spectra of all the compounds were recorded on a
1
Perkin–Elmer AC–1 spectrophotometer. H nuclear magnetic resonance (NMR)
spectra were recorded on a Brucker WM 200 MHz spectrometer in deuterated
solvent (CDCl3) with tetramethylsilane (TMS) as an internal reference. Fast atom
bombardment (FAB) mass spectra were recorded on a Jeol SX 102/DA-6000 mass
spectrometer/data system using argon/xenon (6 kV, 10 mA) as the FAB gas. The
electrospray mass spectra were recorded on a Micromass Quattro II triple quadrupole
mass spectrometer. Microanalyses were determined on a Carlo Erba EA-1108
element analyzer within 0.4% of the theoretical value. Thin-layer chromatography
was performed on 7.5 9 3.0 cm precoated silica gel plastic plates (Aldrich). For
column chromatography, basic alumina from Acme Synthetic Chemicals and silica
gel of 60–120 mesh from Qualigen Fine Chemicals were used. Differently substituted
isocyanates (4a, 4b) were purchased from Aldrich. N-Methyl-3-phenyl-3-(4-
trifluoromethylphenoxy) propanamine(fluoxetine) (3) (Bhandari et al., 2005) and
methyl-[1-(4-trifluoromethylphenoxy)-1,2,3,4-tetrahydro naphthalen-2-yl-methyl]-
amine(19) (Bhandari et al., 2006), were prepared by known procedures.
Substituted isothiocyanates (4c–m)
A mixture of dicyclohexylcarbodiimide (DCC) (3 mmol) and carbondisulfide
(30 mmol) in tetrahydrofuran (THF) (4 mL) was cooled to –10ꢁC in an ice-salt bath
and treated dropwise with a solution of the appropriate amine (3 mmol) in THF
(2 mL). The reaction mixture was allowed to attain room temperature and was
stirred for 3 h. The reaction was monitored by TLC. Removal of the solvent under
reduced pressure afforded a white solid, which was triturated with diethylether
(2 mL) and the dicyclohexylthiourea was removed by filtration. The filtrate was
evaporated to afford the desired isothiocyanates (4c–m) in excellent yield as an oil
which was used as such for further reaction.

108
Med Chem Res (2008) 17:103–113
General procedure for the preparation of 3-substituted-1-methyl-1-[3-phenyl-3-
(4-trifluoromethyl-phenoxy)-propyl]-urea/thiourea (5–17) and 1-methyl-3-
substituted-1-[1-(trifluoromethyl-phenoxy)-1,2,3,4-tetrahydronaphthalen-2-
ylmethyl)urea/thiourea (20–23)
A mixture of compounds 3 or 19 (1 mmol) and differently substituted isocyanates
(4a, 4b)/isothiocyanates (4c–m) (1.2 mmol) in acetonitrile (5 mL) was stirred at
room temperature for 6–7 h. The reaction was then discontinued and the solvent
was distilled off to give the crude product, which was purified by either
crystallization or column chromatography using 20–30% ethylacetate:hexane as
an eluant to afford the desired ureas/thioureas (5–17 and 20–23), respectively.
3-Cyclohexyl-1-methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-urea
(5)
Compound 3 with cyclohexyl isocyanate (4a); yield 83%; m.p. 78–80ꢁC; MS (FAB)
m/z: 435 ((M + 1)+, 40%); 1H NMR: d 0.70–1.81 (m, 10H, cyclohexyl CH2), 2.06–
2.08 (m, 2H, NCH2-CH2), 2.78 (s, 3H, NMe), 3.35–3.50 (m, 3H, NCH2, N-CH),
5.11–5.17 (m, 1H, O-CH), 6.80–6.84 (d, 2H, J = 8.54Hz, ArH ortho to O), 7.19–
7.24 (m, 5H, ArH), 7.33–7.38 (d, 2H, J = 8.52Hz, ArH ortho to CF3); IR (KBr):
3361, 2930, 2854, 1621, 1333, 1109 cm-1. Analysis C24H29F3N2O2 (C, H, N):
calculated C 66.35, H 6.68, N 6.45, found C 66.62, H 6.50, N 6.34.
1-Methyl-3-phenethyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
thiourea (6)
Compound 3 with 2-phenylethyl isothiocyanate (4c); yield 77%; oil; MS (FAB) m/
z: 473 ((M + 1)+, 75%); 1H NMR: d 2.04–2.22 (m, 2H, NCH2-CH2), 2.81–2.89 (m,
2H, Ar-CH2), 3.03 (s, 3H, NMe), 3.74–3.95 (m, 4H, Me-NCH2, Ar-CH2-CH2-NH),
5.18–5.24 (m, 1H, O-CH), 6.82–6.87 (d, 2H, J = 8.66Hz, ArH ortho to O), 7.14–
7.33 (m, 10H, ArH), 7.40–7.45 (d, 2H, J = 8.7 Hz, ArH ortho to CF3); IR (neat):
3418, 2930, 2364, 1613, 1529, 1114 cm-1. Analysis C26H27F3N2OS (C, H, N):
calculated C 66.10, H 5.72, N 5.93, found C 66.45, H 5.46, N 5.74.
3-Benzyl-1-methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-thiourea
(7)
Compound 3 with benzyl isohtiocyanate (4d); yield 57%; oil; MS (ESI) m/z: 459
1
((M + 1)+, 50%); H NMR: d 2.15–2.21 (m, 2H, NCH2-CH2), 3.10 (s, 3H, NMe),
3.83–3.96 (m, 2H, NCH2-CH2), 4.53–4.62 (m, 1H, Ar-CH2), 4.76–4.86 (m, 1H, Ar-
CH2), 5.15–5.21 (m, 1H, O-CH), 6.68–6.73 (d, 2H, J = 8.34Hz, ArH ortho to O),
7.19–7.33 (m, 14H, ArH); IR (neat): 3419, 2925, 2362, 1613, 1532, 1067 cm-1
.
Analysis C25H25F3N2OS.1/4H2O (C, H, N): calculated C 64.86, H 5.51, N 6.05,
found C 64.55, H 5.33, N 5.66.

Med Chem Res (2008) 17:103–113
109
1-Methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-3-p-tolyl-thiourea
(8)
Compound 3 with p-tolyl isothiocyanate (4e); yield 33%; oil; MS (ESI) m/z: 459
1
((M + 1)+, 7%), 460 ((M + 2)+, 40%); H NMR: d 2.31–2.35 (m, 5H, Ar-CH3,
NCH2-CH2), 3.27 (s, 3H, NMe), 3.96–4.13 (m, 2H, NCH2-CH2), 5.29–5.35 (m, 1H,
O-CH), 6.86–6.99 (m, 4H, ArH), 7.07–7.11 (d, 2H, J = 8.06Hz, ArH), 7.34 (m, 5H,
ArH), 7.39–7.44 (d, 2H, J = 8.67 Hz, ArH ortho to CF3); IR (neat): 3377, 2365,
1614, 1521, 1116 cm-1. Analysis C25H25F3N2OS (C, H, N): calculated C 65.50, H
5.46, N 6.11, found C 65.59, H 5.60, N 5.94.
1-Methyl-3-phenethyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-urea
(9)
Compound 3 with 2-phenylethyl isocyanate (4b); yield 52%; oil; MS (FAB) m/z:
1
457 ((M + 1)+, 50%), 295 (100%); H NMR: d 2.07–2.12 (m, 2H, (Me)-NCH2-
CH2), 2.66–2.73 (m, 2H, Ar-CH2), 2.31 (s, 3H, NMe), 3.28–3.45 (m, 4H, (Me)-
NCH2, Ar-CH2-CH2), 5.14–5.20 (m, 1H, O-CH), 6.82–6.86 (d, 2H, J = 8.5Hz, ArH
ortho to O), 7.11–7.33 (m, 10H, ArH), 7.39–7.44 (d, 2H, J = 8.5Hz, ArH ortho to
CF3); IR (neat): 3372, 1629, 1526, 1248, 1114, 1067 cm-1. Analysis C26H27F3N2O2
(C, H, N): calculated C 68.42, H 5.92, N 6.14, found C 68.30, H 5.63, N 6.45.
3-Cyclohexyl-1-methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
thiourea (10)
Compound 3 with cyclohexyl isothiocyanate (4f); yield 67%; oil; MS (FAB) m/z:
451 ((M + 1)+, 60%); 1H NMR: d 1.01–1.93 (m, 10H, cyclohexyl CH2), 2.10–2.20
(m, 2H, NCH2-CH2), 3.05 (s, 3H, NMe), 3.90 (m, 2H, NCH2), 4.2 (m, 1H, N-CH),
5.17–5.23 (m, 1H, O-CH), 6.81–6.85 (d, 2H, J = 8.64Hz, ArH ortho to O), 7.19–
7.29 (m, 5H, ArH), 7.35–7.39 (d, 2H, J = 8.6Hz, ArH ortho to CF3); IR (neat):
2931, 2855, 1615, 1528, 1112, 1068 cm-1. Analysis C24H29F3N2OS.H2O (C, H, N):
calculated C 61.54, H 6.41, N 5.98, found C 61.85, H 6.40, N 5.84.
1-Methyl-3-phenyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-thiourea
(11)
Compound 3 with phenyl isothiocyanate (4g); yield 61%; m.p. 110–112ꢁC; MS
1
(FAB) m/z: 445 ((M + 1)+, 100%); H NMR: d 2.31–2.40 (m, 2H, NCH2-CH2),
3.28 (s, 3H, NMe), 3.97–4.12 (m, 2H, NCH2-CH2), 5.29–5.36 (m, 1H, O-CH), 6.87–
6.91 (d, 2H, J = 8.65Hz, ArH ortho to O), 7.08–7.36 (m, 10H, ArH), 7.40–7.44 (d,
2H, J = 8.54Hz, ArH ortho to CF3); IR (KBr): 3306, 2362, 1595, 1529, 1111 cm-1
.
Analysis C24H23F3N2OS.1/4H2O (C, H, N): calculated C 64.21, H 5.23, N 6.24,
found C 64.05, H 5.06, N 6.54.

110
Med Chem Res (2008) 17:103–113
3-Benzoyl-1-Methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
thiourea (12)
Compound 3 with benzoyl isothiocyanate (4h); yield 47%; oil; MS (FAB) m/z: 473
1
((M + 1)+, 15%); H NMR: d 2.29–2.37 (m, 2H, NCH2-CH2), 3.23 (s, 3H, NMe),
4.18–4.21 (m, 2H, NCH2-CH2), 5.46–5.49 (m, 1H, O-CH), 6.94–6.98 (d, 2H,
J = 8.48Hz, ArH ortho to O), 7.26–7.60 (m, 10H, ArH), 7.83–7.86 (d, 2H,
J = 7.4Hz, ArH); IR (neat): 2930, 2858, 1897, 1687, 1540, 1395, 1068 cm-1
.
Analysis C25H23F3N2O2S (C, H, N): calculated C 63.55, H 4.87, N 5.93, found: C
63.23, H 5.15, N 5.70.
1-Methyl-3-(4-methyl-cyclohexyl)-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-thiourea (13)
Compound 3 with 4-methylcyclohexyl isothiocyanate (4i); yield 64%; oil; MS (ESI)
1
m/z: 465 ((M + 1)+, 100%), 466 ((M + 2)+, 30%); H NMR: d 0.86–1.25 (m, 8H,
cyclohexyl protons, CH-CH3), 1.58–1.65 (m, 2H, cyclohexyl protons), 1.96–2.27
(m, 4H, cyclohexyl protons, O-CH-CH2), 3.12–3.14 (s, 3H, NMe), 3.90–4.3 (m, 3H,
N-CH2, N-CH), 5.26–5.29 (m, 1H, O-CH), 6.88 (d, 2H, J = 8.36Hz, ArH ortho to
O), 7.26–7.32 (m, 5H, ArH), 7.41–7.45 (d, 2H, J = 8.45Hz, ArH ortho to CF3); IR
(neat): 3754, 2929, 2856, 2115, 1615, 1524, 1163, 1116 cm-1. Analysis
C25H31F3N2OS (C, H, N): calculated C 64.66, H 6.68, N 6.03, found C 64.54, H
6.77, N 6.24.
1-Methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-3-(3,4,5-
trimethoxy-phenyl)-thiourea (14)
Compound 3 with 3,4,5-trimethoxy-phenyl isothiocyanate (4j); yield 51%; m.p.
1
122–125ꢁC; MS (FAB) m/z: 535 ((M + 1)+, 30%), 516 (100%); H NMR: d 2.34–
2.37 (m, 2H, NCH2-CH2), 3.30 (s, 3H, NMe), 3.77 (s, 6H, OCH3), 3.82 (s, 3H,
OCH3), 4.10 (m, 2H, N-CH2), 5.33 (m, 1H, O-CH), 6.46 (s, 2H, ArH containing
OMe grs), 6.89–6.93 (d, 2H, J = 8.38Hz, ArH ortho to O), 7.26–7.33 (m, 5H, ArH),
7.41–7.45 (d, 2H, J = 8.44Hz, ArH ortho to CF3); IR (KBr): 3755, 3431, 2930,
1600, 1539, 1122 cm-1. Analysis C27H29F3N2O4S.1/4H2O (C, H, N): calculated C
60.17, H 5.43, N 5.24, found C 60.06, H 5.77, N 4.96.
3-tert-Butyl-1-Methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
thiourea (15)
Compound 3 with tert-Butyl isothiocyanate (4k); yield 55%; oil; MS (FAB) m/z:
425 ((M + 1)+, 80%), 424 (M+, 40%); 1H NMR: d 1.49 (s, 9H, -C-(CH3)3), 2.28 (m,
2H, NCH2-CH2), 3.10 (s, 3H, NMe), 3.8–4.2 (m, 2H, NCH2), 5.2–5.4 (m, 1H, O-
CH), 6.87–6.92 (d, 2H, J = 8.62Hz, ArH ortho to O), 7.26–7.34 (m, 5H, ArH),

Med Chem Res (2008) 17:103–113
111
7.41–7.45 (d, 2H, J = 8.57 Hz, ArH ortho to CF3); IR (neat): 2963, 1615, 1529.
1358, 1116, 1068 cm-1. Analysis C22H27F3N2OS.H2O (C, H, N): calculated C
60.97, H 6.24, N 6.47, found C 61.17, H 6.29, N 6.20.
3-(4-Methoxyphenyl)-1-methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-thiourea (16)
Compound 3 with 4-methoxy-phenyl isothiocyanate (4l); yield 89%; oil; MS (ESI)
m/z: 475 ((M + 1)+, 60%); 1H NMR: d 2.21–2.31 (m, 2H, NCH2-CH2), 3.19 (s, 3H,
NMe), 3.70 (s, 3H, OCH3), 3.90–4.05 (m, 2H, N-CH2), 5.22–5.29 (m, 1H, O-CH),
6.71–6.94 (m, 6H, ArH), 7.18–7.36 (m, 7H, ArH); IR (neat): 3322, 2931, 2852,
1614, 1516, 1166 cm-1. Analysis C25H25F3N2O2S.H2O (C, H, N): calculated C
63.29, H 5.27, N 5.91, found C 62.90, H 5.38, N 5.53.
3-Isopropyl-1-methyl-1-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
thiourea (17)
Compound 3 with isopropyl isothiocyanate (4m); yield 76%; oil; MS (ESI) m/z: 433
((M + Na)+, 35%), 411 ((M + 1)+, 100%); 1H NMR: d 1.08–1.11 (d, 3H,
J = 6.49Hz, -CH-CH3), 1.17–1.20 (d, 3H, J = 6.50Hz, -CH-CH3), 2.24–2.31 (m,
2H, NCH2-CH2), 3.12 (s, 3H, NMe), 3.88–4.01 (m, 2H, NCH2), 4.53–4.60 (m, 1H,
CH-(Me)2), 5.24–5.30 (m, 1H, O-CH), 6.88–6.92 (d, 2H, J = 8.43Hz, ArH ortho to
O), 7.26–7.32 (m, 5H, ArH), 7.41–7.46 (d, 2H, J = 8.50Hz, ArH ortho to CF3); IR
(neat): 3401, 2362, 1741, 1525, 1218 cm-1. Analysis C21H25F3N2OS.1/2H2O (C, H,
N): calculated C 60.14, H 6.21, N 6.68, found C 60.42, H 6.20, N 6.75.
1-Methyl-3-phenethyl-1-[1-(trifluoromethyl-phenoxy)-1,2,3,4-
tetrahydronaphthalen-2-yl-methyl) thiourea (20)
Compound 19 with 2-phenylethyl isothiocyanate (4c); yield 58%; oil; MS (ESI) m/
1
z: 499 ((M + 1)+, 50%), 521 ((M + Na)+, 100%); H NMR: d 1.65–1.68 (m, 1H,
H-2), 2.04–2.06 (m, 1H, H-3), 2.58 (m, 1H, H-3), 2.87–2.92 (m, 4H, H-4, Ar-CH2),
3.02 (s, 3H, N-CH3), 3.70–4.17 (m, 4H, Ar-CH2-CH2, N-CH2,), 5.32–5.35 (d, 1H,
J = 5.94Hz, H-1), 7.00–7.05 (d, 2H, J = 8.6Hz, ArH ortho to O), 7.15–7.30 (m, 4H,
ArH), 7.51–7.56 (d, 2H, J = 8.6Hz, ArH ortho to CF3); IR (neat): 3425, 2932, 2363,
1613, 1527, 1327, 1117 cm-1. Analysis C28H29F3N2OS.1/2H2O (C, H, N):
calculated C 66.27, H 5.92, N 5.52, found C 66.43, H 4.63, N 5.27.
3-Cyclohexyl-1-methyl-1-[1-(4-trifluoromethyl-phenoxy)-1,2,3,4-tetrahydro-
naphthalen-2-yl-methyl) urea (21)
Compound 19 with cyclohexyl isocyanate (4a); yield 58%; m.p. 140–142ꢁC; MS
(ESI) m/z: 483 ((M + Na)+, 100%), 484 ((M + 1 + Na)+, 30%); 1H NMR: d 0.98–

112
Med Chem Res (2008) 17:103–113
1.37 (m, 5H, cyclohexyl CH2), 1.64–1.89 (m, 6H, cyclohexyl CH2, H-2), 2.10–2.15
(m, 1H, H-3), 2.47–2.50 (m, 1H, H-3), 2.87 (bs, 5H, N-CH3, H-4), 3.31–3.37 (m,
2H, N-CH2), 3.57 (m, 1H, cyclohexyl CH), 5.28–5.31 (d, 1H, J = 5.59Hz, H-1),
7.01–7.05 (d, 2H, J = 8.52Hz, ArH ortho to O), 7.19–7.26 (m, 4H, ArH), 7.52–7.57
(d, 2H, J = 8.46Hz, ArH ortho to CF3); IR (KBr): 3307, 2927, 2855, 1616, 1340,
1068 cm-1. Analysis C26H31F3N2O2 .1/2H2O (C, H, N): calculated C 66.52, H 6.82,
N 5.97, found C 66.17, H 6.55, N 5.81.
1-Methyl-3-phenethyl-1-[1-(trifluoromethyl-phenoxy)-1,2,3,4-tetrahydro-
naphthalen-2-ylmethyl) urea (22)
Compound 19 with 2-phenylethyl isocyanate (4b); yield 60%; oil; MS (ESI) m/z:
505 ((M + Na)+, 100%), 506 (M + Na + 1+, 36%); 1H NMR: d 1.57–1.64 (m, 1H,
H-2), 2.1 (m, 1H, H-3), 2.45 (m, 1H, H-3), 2.74–2.94 (m, 7H, H-4, N-CH3, Ar-CH2-
CH2-NH), 3.30–3.53 (m, 4H, MeN-CH2, Ar-CH2-CH2-NH), 5.23–5.26 (d, 1H,
J = 6.44Hz, H-1), 6.97–7.02 (d, 2H, J = 8.56Hz, ArH ortho to O), 7.19–7.34 (m,
9H, ArH), 7.51–7.55 (d, 2H, J = 8.24Hz, ArH ortho to CF3); IR (neat): 3021, 2402,
1216, 1116cm-1. Analysis C28H29F3N2O2 (C, H, N): calculated C 69.70, H 6.01, N
5.80, found C 69.59, H 6.14, N 5.72.
1-Methyl-3-(4-methyl-cyclohexyl)-1-[1-(4-trifluoromethyl-phenoxy)-1,2,3,4-
tetrahydro naphthlen-2-yl-methyl)thiourea (23)
Compound 19 with 4-methylcyclohexyl isothiocyanate (4i); yield 65%; oil; MS
(ESI) m/z: 491 ((M + 1)+, 50%); 1H NMR: d 0.87–1.38 (m, 8H, CH-CH3,
cyclohexyl protons), 1.58–1.78 (m, 3H, cyclohexyl protons, H-2), 2.13–2.17 (m, 3H,
H-3, cyclohexyl protons), 2.68 (m, 1H, H-3), 2.86–2.93 (m, 2H, H-4), 3.12 (s, 3H,
N-CH3), 3.8 (m, 1H, NH-CH), 4.1 (m, 2H, NCH2), 5.38–5.41 (d, 1H, J = 5.90Hz,
H-1), 7.05–7.09 (d, 2H, J = 8.6Hz, ArH ortho to O), 7.16–7.26 (m, 4H, ArH), 7.52–
7.57 (d, 2H, J = 8.48Hz, ArH ortho to CF3); IR (neat): 3425, 2930, 2818, 1596,
1351, 1115 cm-1. Analysis C27H33F3N2OS.1/4H2O (C, H, N): calculated C 67.43,
H 6.97, N 5.83, found C 67.77, H 6.75, N 5.62.
Pharmacology
The study was carried out in albino mice of either sex (weighing 16–20 g). Each
group consisted of five animals. All the compounds and the standard drug fluoxetine
were administered in a dose of 75 lmole/kg intraperitoneally (i.p.) as an aqueous
solution or a suspension in gum acacia. Gross behavioral effects, antidepressant, and
anorexigenic activities (Bhandari et al., 2005; Bhandari et al., 2006) were carried
out by standard tests and saline-treated control was observed concurrently (Table 1).
The antidepressant activity of the compounds was analyzed by the chi-square test
with Yate’s correction (one-sided P value) for ptosis and the Mann–Whitney U test

Med Chem Res (2008) 17:103–113
113
for sedation and crouching. For anorexigenic activity milk intake by the control and
the treated group was noted and the significance the of difference between them was
determined by the unpaired Student’s t-test (two-tailed p value) with the Welch
correction where required (Table 1).
Acknowledgements Financial assistance from Council of Scientific and Industrial Research, New Delhi
(SS and LS) and the University Grant Commission (NS) is gratefully acknowledged.
References
Ankersen M, Dorwald F, Stidsen C, Crider A (1998) Constrained somatostatin agonists and antagonists.
WO9818786
Benfield P, Heel RC, Lewis SP (1986) Fluoxetine-a review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic efficacy. Drugs 32:481–508
Bhandari K, Srivastava S, Shankar G (2004) Synthesis of tetrahydronaphthyl thioureas as potent appetite
suppressants. Bioorg Med Chem 12:4189–4196
Bhandari K, Srivastava S, Shankar G, Nath C (2005) Substituted propanolamines and alkylamines derived
from fluoxetine as potent appetite suppressants. Bioorg Med Chem 13:1739–1747
Bhandari K, Srivastava S, Shankar G, Nath C (2006) Synthesis and appetite suppressant activity of 1-
aryloxy-2-substituted aminomethyltetrahydronaphthalenes as conformationally rigid analogues of
fluoxetine. Bioorg Med Chem 14:2535–2544
Blundell JE (1984) Serotonin and appetite. Neuropharmacology 23:1537–51
Curzon G, Gibson EL, Oluyomi AO (1998) Appetite suppression by commonly used drugs depends on
5HT receptors but not on 5HT availability. Trends Pharmacol Sci 13:21–25
Fernstrom MH, Massoudi M, Kupfer DJ (1988) Fluvoxamine and weight loss. Biol Psychiatry 24:948–
949
Garattini S, Bizzi A, Codegoni AM, Mennini T (1992) Progress report on the anorexia induced by drugs
believed to mimic some of the effects of serotonin on the central nervous system. Am J Clin Nutr
55:160S–166S
Goldstein DJ, Rampey AH, Enas GG, Potvin JH, Fludzinski LA, Levine LR (1994) Fluoxetine: a
randomized clinical trial in the treatment of obesity. Int J Obes Relat Metab Disord 18:129–135
Jackson JL (1976) Thiurea derivatives. US pat 3,985,898
Kennett GA (1998) 5-HT drugs and eating disorders. Drugs 1:456–470
Shor-Posner G, Grinker JA, Marinescu C, Brown O, Leibowitz SF (1986) Hypothalamic serotonin in the
control of meal patterns and macronutrient selection. Brain Res Bull 17:663–671
Stahl SM (1998) Not so selective serotonin reuptake inhibitors. J Clin Psychiatry 59:343–344
Wadden TA, Bartlett SJ, Foster GD, Greenstein R, Wingate BJ, Stunkard AJ, Letizia KA (1995)
Sertraline and relapse prevention training following treatment by very low calorie diet. Obes Res
3:549–557