Synthesis of 4-arylpiperazine derivatives of moclobemide: Potential antidepressants with a dual mode of action

Article abstract of DOI:10.1081/SCC-200025581

We report here the synthesis of substituted 4-chloro-N-[3-oxo-3-(4-aryl-1- piperazinyl)-propyl] benzamides (5-9), as potential new antidepressants, incorporating in a single molecule structural moieties related to a dual pharmacological profile: MAO-A inh

Full text of DOI:10.1081/SCC-200025581

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Synthesis of 4‐Arylpiperazine
Derivatives of Moclobemide:
Potential Antidepressants
with a Dual Mode of Action
Hernán Pessoa‐Mahana a , Gonzalo Recabarren
Gajardo a , Ramiro Araya‐Maturana a , Johann
Kosche Cárcamo a & C. David Pessoa‐Mahana b
a Departamento de Química Orgánica y
Fisicoquímica, Facultad de Ciencias Químicas y
Farmacéuticas , Universidad de Chile , Casilla 233,
Santiago, 1, Chile
b Departamento de Farmacia , Pontificia
Universidad Católica de Chile , Santiago, Chile
Published online: 10 Jan 2011.
To cite this article: Hernán Pessoa‐Mahana , Gonzalo Recabarren Gajardo , Ramiro
Araya‐Maturana , Johann Kosche Cárcamo & C. David Pessoa‐Mahana (2004)
Synthesis of 4‐Arylpiperazine Derivatives of Moclobemide: Potential Antidepressants
with a Dual Mode of Action, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:14, 2513-2521, DOI:
10.1081/SCC-200025581
To link to this article: http://dx.doi.org/10.1081/SCC-200025581
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2513–2521, 2004
Synthesis of 4-Arylpiperazine Derivatives of
Moclobemide: Potential Antidepressants
with a Dual Mode of Action
1,
Hernan Pessoa-Mahana, Gonzalo Recabarren Gajardo,
1
*
´
Ramiro Araya-Maturana, Johann Kosche Carcamo,
1
1
´
and C. David Pessoa-Mahana2
1
´ ´ ´
Departamento de Quımica Organica y Fisicoquımica, Facultad de
´ ´
Ciencias Quımicas y Farmaceuticas, Universidad de Chile, Santiago, Chile
2
´
Departamento de Farmacia, Pontificia Universidad Catolica de Chile,
Santiago, Chile
ABSTRACT
We report here the synthesis of substituted 4-chloro-N-[3-oxo-3-(4-aryl-1-
piperazinyl)-propyl] benzamides (5–9), as potential new antidepressants,
incorporating in a single molecule structural moieties related to a dual
pharmacological profile: MAO-A inhibitor and 5-HT1A receptor affinity.
*
´ ´ ´
Correspondence: Hernan Pessoa-Mahana, Departamento de Quımica Organica
´ ´ ´
y Fisicoquımica, Facultad de Ciencias Quımicas y Farmaceuticas, Universidad de
Chile, Casilla 233, Santiago 1, Chile; E-mail: hpessoa@ciq.uchile.cl.
2513
DOI: 10.1080/SCC-200025581
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2514
Pessoa-Mahana et al.
INTRODUCTION
Depression is one of the most frequent psychiatric disorders, affecting up
to one third of all people at the same time. The causes of depression are multi-
factorial, although it is accepted that neurochemical disorders reflected by
alterations in the levels of some central neurotransmitters are ultimately
responsible for the appearance of the depressive symptoms.[1–3] The neuro-
transmitter serotonine (5-hydroxytryptamine, 5-HT) modulates the activity
of central nervous system and peripheral tissues by interaction with seven
classes of receptors (5-HT1–7), containing 15 distinct subpopulations of recep-
tors[4,5] where the 5-HT1A subtype is the best studied due to its involvement in
psychiatric disorders such as anxiety and depression.[6,7] A well-known class
of 5-HT1A receptor ligands are the “long chain” arylpiperazine derivatives.
Among these Buspirone a partial agonist at 5-HT1A receptors is an effective
antianxiety and was the first arylpiperazine approved for clinical use. On
the other hand Moclobemide, a reversible MAO-A inhibitor exerts its anti-
depressant therapeutic effect by preventing the degradation of neurotransmit-
ters and xenobiotic amines (oxidative deamination), modulating the level of
these biogenic amines.
Although, a variety of method for the synthesis of Moclobemide
and phenylpiperazine derivatives have been developed,[8–11] there is no
report dealing with the obtention of 4-arylpiperazine, connected with the
alkyl-p-chlorobenzamide framework of Moclobemide in a single chemical
entity.
In this article, we describe the synthesis of a series of molecular templates
of 4-chloro-N-[3-oxo-3-(4-aryl-1-piperazinyl)-propyl] benzamides, as poten-
tial antidepressants of dual action, based on coupling structural moieties
related to reversible MAO-A inhibitor Moclobemide and typical 5-HT1A
ligands (Fig. 1).
The synthesis of the title benzamides started by reaction of p-chlorobenzoyl
chloride with b-alanine hydrochloride, in the presence of anhydrous pyridine
under inert atmosphere to give the ester (2) (93.2%), which was further hydro-
lyzed in basic medium to provide the carboxylic acid (3) (91.5%) (Sch. 1). The
hydrolysis of the ester function of (2) had to be carried out with special care,

Synthesis of 4-Arylpiperazine Derivatives
2515
Figure 1.
Scheme 1. Reagents: (a) NH2(CH2)2-COOEt hydrochloride/anhydrous THF, dry
pyridine, N2 atmosphere; (b) KOH–EtOH (30 min); (c) SOCl2, 408C (3 hr); (d) substi-
tuted 4-phenylpiperazines/anhydrous THF, dry pyridine, N2 atmosphere.

2516
Pessoa-Mahana et al.
Table 1. The synthesis of 4-arylpiperazine deriva-
tives of Moclobemide (5–9) in excellent yields.
Compound
R
Yield (%)
5
6
7
8
9
Hydrogen
4-Nitro
95.0
96.2
94.7
93.6
98.3
2- Fluor
4-Fluor
2-Methoxy
in order to avoid competitive hydrolysis of the amide, which was detected as a
side reaction.
Reaction of the carboxylic acid (3) with thionyl chloride under smooth
conditions of heating gave the corresponding acid chloride (4), in near quan-
titative yield, which was rapidly identified by its IR spectrum (strong
carbonylic band at 1798 cm21), and reacted under inert atmosphere with
different 4-arylpiperazines to afford the expected 4-arylpiperazino benza-
mides (5–9) in high yields (Table 1).
In conclusion, we have described the synthesis of new 4-arylpiperazine
derivatives of Moclobemide (5–9) in excellent yields, through a four step
sequence, starting from commercially available reagents. The potential dual
pharmacological profile of the synthesized products could lead to a new
class of antidepressants. The corresponding biological assays of these
compounds are in progress.
EXPERIMENTAL
All reagents were obtained commercially and used without further
purification. Melting points were measured on a Kofler hot-stage apparatus
and are uncorrected. IR spectra were recorded with a FT Bruker spectro-
1
photometer for KBr. H-NMR and 13C-NMR spectra were obtained with a
Bruker DRX-300 spectrophotometer. The chemical shifts are expressed in
ppm (d scale) downfield from TMS, J values are given in Hertz for
solutions in CDCl3 unless otherwise indicated. Microanalysis was determined
on a Fisons EA 1108 analizer. Silica gel Merck 60 (70–230 mesh) and
DC-alufolien 60 F254 were normally used for column and TLC chromato-
graphy, respectively.
Ethyl 3-[(4-chlorobenzoyl) amino] propanoate (2). To a stirred solu-
tion of 3-amino-propanoate ethyl ester hydrochloride (b-alanine) (500 mg,

Synthesis of 4-Arylpiperazine Derivatives
2517
3.25 mmo1), in dry THF (50 mL) containing anhydrous pyridine (381.3 mg,
4.88 mmol) at 08C, was successively added 4-chloro benzoyl chloride
(569.7 mg, 3.25 mmol) under nitrogen atmosphere, the whole was then
stirred for 4 hr, upon this time the solution was poured into water (100 mL)
and extracted with ethyl acetate (3 ꢀ 50 mL). The combined organic layers
were dried (Na2SO4) and evaporated to dryness. The crude was purified by
silica gel column chromatography (CH2Cl2/AcOEt ¼ 1 : 1) to afford (2)
(775.8, 93.2%). M.p. 84–858C white crystals (ethanol). Anal. Calcd. for
C12H14ClNO3: C, 56.46; H, 5.53; N, 5.49. Found: C, 56.22; H, 5.47; N,
5.32%; IR nmax: 3338 (N-H), 1728 (COOEt), 1633 (CONH). 1H-NMR
(CDCl3) d: 1.28 (t, 3H, J ¼ 7.1, –CH2–CH3), 2.64 (t, 2H, J ¼ 5.9, –CH2–
COOEt), 3.72 (q, 2H, J ¼ 6.0, NH–CH2–CH2), 4.17 (q, 2H, J ¼ 7.1,
COOCH2CH3), 6.97 (br. t, 1H, CONH–), 7.4 (d, 2H, J ¼ 8.4, p-Cl–C6H4–,
3-H and 5-H), 7.71 (d, 2H, J ¼ 8.4, p-Cl–C6H4–, 2-H and -6-H). 13C-NMR
(CDCl3) d: 14.2, 33.8, 35.4, 60.9, 128.4 (2C), 128.8 (2C), 132.7, 137.7,
166.3, 172.9.
3-[(4-Chlorobenzoyl) amino] propionic acid (3). A solution of the ester
(2) (347 mg, 1.36 mmol) in 0.5 N KOH : EtOH (1 : 1 v/v), (50 mL) was stirred
at room temperature for 30 min. The mixture was concentrated in vacuo and
the aqueous residue was cooled at 108C and acidified with 0.1 N HCl to
pH 1, the resulting precipitate was filtered off to provide (3) (263 mg,
91.5%). Recrystallization from ethanol/petroleum ether (1 : 2) furnished
pure carboxylic acid (3) a white needles.
M.p. 168–1698C (ethanol/petroleum ether, 1 : 2). Anal. Calcd. for
C10H10Cl NO3: C, 52.86; H, 4.44; N, 6.17. Found: C, 52.75; H, 4.28; N,
6.11%; IR nmax: 3600–2870 (O-H), 3311 (N-H), 1702 (COOH), 1633
1
(NHC55O). H-NMR (DMSO-d6) d: 2.31 (t, 2H, J ¼ 7.0, –CH2–COOH),
3.24 (q, 2H, J ¼ 6.2, NH–CH2–CH2), 7.31 (d, 2H, J ¼ 8.6, p-Cl–C6H4–,
3-H and 5-H), 7.65 (d, 2H, J ¼ 8.6, p-Cl–C6H4-2-H and 6-H), 8.40 (br.t,
1H, ArCONH–), 12.2 (s, 1H, COOH). 13C-NMR (DMSO-d6) d: 34.1, 36.0,
128.8 (2C), 129.6 (2C), 133.6, 136.4, 165.63, 173.3.
3-[(4-Chlorobenzoyl) amino] propanoyl chloride (4). A solution of
carboxylic acid (3) (312 mg, 1.47 mmol) in thionyl chloride (40 mL) was
smoothly refluxed in an oil silicone bath, at 408C for 3 hr. The solvent
was then removed in vacuo, to afford (357.7 mg, 98.6%) of propanoyl chloride
(4) as a yellow pale oil, being immediately characterized by spectro-
scopic analysis and reacted. IR nmax: 1797 (–COCl), 1664 (HO–C55N–).
1H-NMR (CDCl3) d: 3.33 (t, 2H, J ¼ 6.2, CH2–CH2–COCl), 3.97
(t, 2H, J ¼ 6.2, C55N–CH2–CH2), 7.36 (d, 2H, J ¼ 8.6, p-Cl–C6H4,
3-H and 5-H), 7.90 (d, 2H, J ¼ 8.6, p-Cl–C6H4–, 2-H and 6-H).
13C-NMR (CDCl3) d: 46.9, 49.2, 128.6 (2C), 130.2 (2C), 133.5, 138.2,
143.8, 172.2.

2518
Pessoa-Mahana et al.
Preparation of 4-Chloro-N-[3-oxo-3-(4-aryl-1-piperazinyl)-
propyl]-benzamide Derivatives (5–9). Typical Procedure.
(5) As an Example
Propanoyl chloride (4) (292 mg, 1.19 mmol) in dry THF (10 mL) was
slowly added to a stirred solution at 08C of 4-phenyl-1-piperazine
(193 mg, 1.19 mmol), pyridine (94 mg, 1.19 mmol) and dry THF (50 mL)
in nitrogen atmosphere. The mixture was maintained with stirring for 6 hr
at room temperature and then poured into a water solution (100 mL). The
mixture was extracted with ethyl acetate (3 ꢀ 50 mL) and the organic
layers dried over MgSO4. Removal of the solvent afforded 4-chloro-N-[3-
oxo-3-(4-phenyl-l-piperazinyl)-propyl]-benzamide (5) (420 mg, 95%), as a
white powder which was purified by silica gel column chromatography
(CH2Cl2/AcOEt ¼ 1 : 1). m.p. 172–1738C (ethanol). Anal. Calcd for
C20H22ClN3O2: C, 64.60; H, 5.96; N, 11.30. Found: C, 64.52; H, 5.94;
N, 11.26%; IR vmax: 3295 (N-H), 1639 (C–O), 1632 (C55O), 1542 (N–
H). 1H-NMR (CDCl3) d: 2.67 (t, 2H, J ¼ 5.5, –CH2–CO–Pip.), 3.14–
3.18 (m, 4H, (2 ꢀ –CH2), Pip.), 3.60 (m, 2H, CONH–CH2–), 3.75–3.80
(m, 4H, (2 ꢀ –CH2), Pip.), 6.89–6.93 (m, 3H, C6H5), 7.25–7.31 (m, 3H,
C6H5 and –CONH–), 7.37 (d, 2H, J ¼ 8.6, p-Cl–C6H4–, 3-H and 5-H),
7.40 (d, 2H, J ¼ 8.6, p-Cl–C6H4 –2-H and 6-H). 13C-NMR d: 32.7,
35.6, 41.6, 45.3, 49.4, 49.6, 116.8 (2C), 121.0, 128.5 (2C), 128.8 (2C),
129.3 (2C), 132.8, 137.6, 150.8, 166.2, 170.3.
4-Chloro-N-[3-oxo-3-(4-(4-nitrophenyl)-1-piperazinyl)-propyl]-benza-
mide (6). Compound (6) (318 mg, 96.2%) yellow powder (column chromato-
graphed, AcOEt/CH2Cl2 ¼ 1 : 1). was prepared from (4) (195 mg, 0.793 mmol)
and 4-nitrophenyl piperazine (164 mg, 0.793 mmol); m.p. 165–1668C
(ethanol/petroleum ether ¼ 3 : 1). Anal. Calcd for C20H21Cl N4O4: C, 57.63;
H, 5.08; N, 13.44. Found: C, 57.36; H, 5.00; N, 13.24%; IR vmax: 3300
(N-H), 1642 (CONH), 1635 (COPip.). 1H-NMR (CDCl3) d: 2.70 (t, 2H,
J ¼ 5.5, 2CH2–CO–Pip.), 3.41–3.50 (m, 4H, (2 ꢀ CH2)-Pip.), 3.64–3.68
(m, 2H, p-CI–CONH–CH2–), 3.75–3.83 (m,4H, (2 ꢀ CH2)-Pip.), 6.82
(d, 2H, J ¼ 9.4, p-NO2–C6H4-20-H and 60-H), 7.21 (br t, 1H, ArCONH–),
7.39 (d, 2H, J ¼ 8.6, p-Cl–C6H4–3-H and 5-H), 7.73 (d, 2H, J ¼ 8.6, p-Cl-
C6H4–, 2-H and 6-H), 8.13 (d, 2H, J ¼ 9.4, p-NO2–C6H4–, 30-H and 50-H).
13C-NMR d: 32.8, 35.5, 40.9, 44.5, 46.7, 46.8, 113.0 (2C), 126.0 (2C), 128.5
(2C), 128.8 (2C), 132.7, 137.8, 139.1, 154.3, 166.3, 170.5.
4-Chloro-N-[3-oxo-3-(4-(2-fluorophenyl)-1-piperazinyl)-propyl]-benza-
mide (7). Compound (7) (795.3 mg, 94.7%) white powder (column
chromatographed, AcOEt/CH2Cl2 ¼ 1 : 1). was prepared from (4) (530mg,
2.15 mmol) and 2-fluorophenyl piperazine (388mg, 2.15mmol); m.p. 184–
1858C (ethanol–petroleum ether 1 : 1). Anal. Calcd for C20H21ClFN3O2: C,

Synthesis of 4-Arylpiperazine Derivatives
2519
61.68; H, 5.44; N, 10.80. Found: C, 61.46; H, 5.43; N, 10.82%; IR vmax
:
1
3308 (N–H), 1639 (C55O), 1635 (C55O), 1547 (N–H). H-NMR (DMSO-
d6) d: 2.65 (t, 2H, J ¼ 7.1, –CH2–CO–Pip.), 2.91–3.02 (m, 4H,
(2 ꢀ CH2)–Pip.), 3.46–3.54 (m, 2H, CONH–CH2–), 3.59–3.65 (m, 4H,
(2 ꢀ CH2)–Pip.), 6.93–7.15 (m, 4H, o-F–C6H4–), 7.53 (d, 2H, J ¼ 8.6,
p-Cl–C6H4-, 3-H and 5-H), 7.86 (d, 2H, J ¼ 8.6, p-Cl–C6H4–, 2-H and
6-H), 8.61 (br t, 1H, ArCONH–). 13C-NMR (DMSO-d6) d: 32.7, 36.5,
2
4
0
41.5, 45.5, 50.6, 50.9, 116.5 (d, JC-F ¼ 21Hz), 120 (d, JC–F ¼ 2.7 Hz),
3
0
2
123.3 (d, JC–F ¼ 7.9 Hz), 125.3 (d, JC–F ¼ 3.5 Hz), 128.9 (2C), 129.5
3
1
(2C), 133.6, 136.5, 140.0 (d, JC–F ¼ 8.3 Hz), 155.5 (d, JC–F ¼ 244 Hz),
165.6, 169.6.
4-Chloro-N-[3-oxo-3-(4-(4-fluorophenyl)-1-piperazinyl)-propyl]-ben-
zamide (8). Compound (8) (365 mg, 93.6%) white crystals was prepared from
(4) (246 mg, 1.0 mmol) and 4-fluorophenyl piperazine (180 mg, 1.0 mmol);
m.p. 148–1498C (ethanol/petroleum ether 2 : 1). Anal. Calcd for
C20H21ClFN3O2: C, 61.68; H, 5.44; N, 10.80. Found: C, 61.67; H, 5.35; N,
10.81%; IR vmax: 3292 (N–H), 1638 (C–O), 1632 (C55O), 1538 (N–H).
1H-NMR (CDCl3) d: 2.67 (t, 2H, J ¼ 5.5, –CH2–CO–Pip.), 3.04–3.10
(m, 4H, (2 ꢀ CH2)–Pip.), 3.57–3.61 (m, 2H, NH–CH2–), 3.74–3.80
(m, 4H, (2 ꢀ CH2)-Pip.), 6.84–7.01 (m, 4H o-F-C6H4–), 7.24 (br t, 1H,
ArCONH–), 7.38 (d, 2H, J ¼ 8.5, p-Cl–C6H4–, 3-H and 5-H), 7.72
(d, 2H, J ¼ 8.5, p-Cl–C6H4–, 2-H and 6-H). 13C-NMR (CDCl3) d: 32.7,
2
35.4, 41.5, 45.3, 50.4, 50.7, 115.8 (d, 2C, JC–F ¼ 22 Hz), 118.7
3
(d, 2C, JC–F ¼ 7.8 Hz), 128.5 (2C), 128.8 (2C), 132.7, 137.7, 147.5
(d, 4JC–F ¼ 2.3 Hz), 157.7 (d, 1JC–F ¼ 240 Hz), 166.2, 170.3.
4-Chloro-N-[3-oxo-3-(4-(2-methoxy phenyl)-1-piperazinyl)-propyl]
benzamide (9). Compound (9) (526 mg, 98.3%) was prepared from (4)
(328 mg, 1.33 mmol) and 2-methoxyphenyl piperazine (256 mg, 1.33 mmol);
m.p. 109–1108C white crystals (column chromatographed, AcOEt/
CH2Cl2 ¼ 2 : 1). Anal. Calcd for C21H24ClN3O3: C, 62.82; H, 6.03; N,
10.47. Found: C, 62.46; H, 6.15; N, 10.33%; IR vmax: 3308 (N-H), 1656
(C55O), 1621 (C55O), 1538 (N-H). 1H-NMR (CDCl3) d: 2.68 (t, 2H,
J ¼ 5.5, –CH2–CO–Pip.), 3.01–3.06 (m, 4H, (2 ꢀ CH2)–Pip.), 3.60–3.63
(m, 2H, NH-CH222), 3.72–3.81 (m, 4H, (2 ꢀ CH2)–Pip.), 3.87 (s, 3H,
o-OCH3-C6H4–), 6.83–7.06 (m, 4H o-OCH3-C6H4–), 7.38 (d, 3H, J ¼ 8.5,
p-Cl-C6H4 3-H, 5-H and p-Cl–C6H4CONH–), 7.74 (d, 2H, J ¼ 8.5,
p-Cl-C6H4, 2-H, 6-H). 13C-NMR (CDCl3) d: 32.7, 35.7, 41.9, 45.6, 50.5,
50.8, 55.4, 111.3, 118.4, 121.0, 123.7, 128.5 (2C), 128.7 (2C), 132.8, 137.6,
140.5, 152.2, 166.2, 170.3.

2520
Pessoa-Mahana et al.
ACKNOWLEDGMENTS
This work was supported by the Research Project CEPEDEQ- FACUL-
TAD of the Chemical and Pharmaceutical Sciences Faculty, University of
Chile, Santiago, Chile, and FONDECYT 1030916.
REFERENCES
1. Blier, P. The pharmacology of putative early-onset antidepressant strat-
egies. Eur. Neuropsychopharmacol. 2003, 13, 57–66.
2. Pessoa-Mahana, H.; Araya-Maturana, R.; Saitz, B.C.; Pessoa-Mahana, C.
David. A synthetic overview of new molecules with 5-HT1A binding affi-
nities. Minirev. Med. Chem. 2003, 3, 77–93.
3. Oficialdegui, A.M.; Martinez, J.; Perez, S.; Heras, B.; Irurzun, M.;
´
Palop, J.A.; Tordera, R.; Lasheras, B.; del Rıo, J.; Monge, A. Design,
synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-
arylpropane derivatives as potential antidepressants with a dual mode
of action. Serotonin reuptake inhibition and 5-HT1A receptor antagonism.
Il Farmaco 2000, 55, 345–353.
4. Glennon, R.A. Higher-end serotonin receptors: 5-HT5, 5-HT6, and 5-HT7.
J. Med. Chem. 2003, 46 (14), 2795–2812.
5. Mattson, R.J.; Catt, J.D.; Sloan, C.P.; Gao, Q.; Carter, R.B.; Gentile, A.;
Mahle, C.D.; Mattos, F.F.; McGvern, R.; VanderMaelen, C.P.;
Yocca, F.D. Development of a presynaptic 5-HT1A antagonist. Bioorg.
Med. Chem. Lett. 2003, 13, 285–288.
´
del Rıo, J.; Monge, A. New 3-[4-(aryl) piperazin-1-yl] -1-(benzo [b] thio-
´ ´
6. Orus, L.; Sainz, Y.; Perez, S.; Oficialdegui, A.M.; Martınez, J.; Lasheras, B.;
´
´
phen-2-yl)propane derivatives with dual action at 5-HT1A serotonin recep-
tors and serotonin transporter as a new class of antidepressants. Pharmazie
2002, 57 (6), 355–357.
7. Takeuchi, K.; Kohn, T.J.; Honigschmidt, N.A.; Rocco, P.V.;
Spinazze, P.G.; Koch, D.J.; Nelson, D.L.; Wainscott, D.B.; Ahmad, L.J.;
Shaw, J.; Threlkeld, P.G.; Wong, D.T. Advances toward new antidepress-
ants beyond SSRIs: 1-aryloxy-3-piperidinylpropan-2-ols with dual
5-HT1A receptor antagonism/SSRI activities. Part 1. Bioorg. Med.
Chem. Lett. 2003, 13, 1903–1905.
8. Ghambarpour, A.; Hadizadeh, H.; Piri, F.; Rashidi-Ranjbar, P. Synthesis,
conformational analysis and antidepressant activiiy of moclobemide new
analogues. Pharm. Acta Helv. 1997, 72, 119–122.

Synthesis of 4-Arylpiperazine Derivatives
2521
9. Pessoa-Mahana, H.; Astudillo, C.I.; Araya-Maturana, R. Synthesis of
N-(morpholinomethyl)benzamides as moclobemide analogues. Synth.
Commun. 2002, 32 (9), 1437–1445.
´
´
´
10. Lopez-Rodrıguez, M.L.; Ayala, D.; Benhamu, B.; Morcillo, M.J.; Viso, A.
Arylpiperazine derivatives acting at 5-HT1A receptors. Curr. Med. Chem.
2002, 9 (4), 443–469.
´
´
´
´
11. Lopez-Rodrıguez, M.L.; Morcillo, M.J.; Fernandez, E.; Benhamu, B.;
Tejada, I.; Ayala, D.; Viso, A.; Olivella, M.; Pardo, L.; Delgado, M.;
Manzanares, J.; Fuentes, J.A. Design and synthesis of S-(2)-2[[4-
(napht-l-yl)piperazin-1-yl]-methyl]-1,4-dioxoperhydropyrrolo[1,2-a]pyrazine
(CSP-2503) using computational stimulation. A 5-HT1A receptor agonist.
Bioorg. Med. Chem. Lett. 2003, 13, 1429–1432.
Received in the USA March 3, 2004