Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT1A receptors

Article abstract of DOI:10.1021/jm0111200

It has been proposed that 5-HT_1A receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT_1A receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]-thiophene derivatives to arylpiperazines, typical 5-HT_1A receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT_1A receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT_1A receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K_i < 50 nM) and the 5-HT_1A receptors (K_i < 20 nM) were further explored for their ability to stimulate [³⁵S]GTPγS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [³⁵]GTPγS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT_1A receptors, respectively. Compound 8g exhibited agonist activity (EC₅₀ = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,1 antagonized the R(+)-8-OH-DPAT-stimulated GTPγS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.

Full text of DOI:10.1021/jm0111200

4128
J . Med. Chem. 2002, 45, 4128-4139
Syn th esis a n d Molecu la r Mod elin g of New
1-Ar yl-3-[4-a r ylp ip er a zin -1-yl]-1-p r op a n e Der iva tives w ith High Affin ity a t th e
Ser oton in Tr a n sp or ter a n d a t 5-HT1A Recep tor s
Lara Oru´s,† Silvia Pe´rez-Silanes,† Ana-M. Oficialdegui,† J avier Mart´ınez-Esparza,† J uan-C Del Castillo,‡
Marisa Mourelle,‡ Thierry Langer,§ Salvatore Guccione,| Giuseppina Donzella,|, Eva M. Krovat,§
Konstantin Poptodorov,§ Berta Lasheras,# Santiago Ballaz,# Isabel Herv´ıas,# Rosa Tordera,#
J oaqu´ın Del R´ıo,# and Antonio Monge*,†
Department of Medicinal Chemistry, Centro de Investigacio´n en Farmacobiologı´a Aplicada (CIFA), Universidad de Navarra,
C/ Irunlarrea s/ n, 31080, Pamplona, Spain, Vita Invest S.A. Av. Barcelona 69 08970 Sant J oan Desp´ı, Barcelona, Spain,
Institute of Pharmacy, University of Innsbruck, Austria, Dipartimento di Scienze Farmaceutiche, Universita` di Catania,
Catania, Italy, and Department of Pharmacology, Centro de Investigacio´n en Farmacobiologı´a Aplicada (CIFA),
Universidad de Navarra, C/ Irunlarrea s/ n, 31080, Pamplona, Spain
Received December 6, 2001
It has been proposed that 5-HT1A receptor antagonists augment the antidepressant efficacy of
selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepres-
sants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized,
and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor affinity. The design was based
in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]-
thiophene derivatives to arylpiperazines, typical 5-HT1A receptor ligands. In binding studies,
several compounds showed affinity at the 5-HT transporter and at 5-HT1A receptors. Molecular
modeling studies predicted the pharmacophore elements required for high affinity binding and
the features that enable to discriminate between agonist, partial agonist, or antagonist action
at 5-HT1A receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior
to the binding step along with enthalpy and enthropy compensations might be responsible to
explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems
to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other
bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full
agonist, which interacts closely by long-range forces or directly. The compounds showing the
higher affinity at both the 5-HT transporter (Ki < 50 nM) and the 5-HT1A receptors (Ki < 20
nM) were further explored for their ability to stimulate [35S]GTPγS binding or to antagonize
8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [35]GTPγS binding to rat hip-
pocampal membranes, an index of agonist/antagonist action at 5-HT1A receptors, respectively.
Compound 8g exhibited agonist activity (EC50 ) 30 nM) in this assay, whereas compounds 7g
and 8h ,i behaved as weak partial agonists and 7h -j and 8j,l antagonized the R(+)-8-OH-
DPAT-stimulated GTPγS binding. Functional characterization was performed by measuring
the antagonism to 8-OH-DPAT-induced hypothermia in mice.
In tr od u ction
drenoreceptor antagonist, accelerates and in some cases
enhances the onset of antidepressant effects when given
in combination with SSRIs. The effect of pindolol has
been related to an antagonist effect on somatodendritic
5-HT1A autoreceptors, although the partial agonist
properties of pindolol at 5-HT1A and â-adrenoceptors
suggest that other mechanisms of action are still
posible.3
In previous studies,4-6 we have reported the synthesis
of a series of 1-aryl-3-[4-arylpiperazin-1-yl]propane,
which showed moderate to high affinity at 5-HT trans-
porter and 5-HT1A receptors (general structure A, Chart
1). The benzo[b]thiophene derivatives 15 and 26 (Chart
1) showed the higher affinity. As a continuation of our
research program, we have analyzed a new set of
derivatives (general structure B, Chart 2) with the aim
of obtaining efficacious 5-HT transporter blockers with
high antagonist potency at 5-HT1A autoreceptors. We
considered two series of benzo[b]thiophen derivatives
The selective 5-HT reuptake inhibitors (SSRIs) are
effective in major depression. However, there are two
serious problems in the pharmacological treatment of
depression, the 2-6 week delay in the onset of thera-
peutic benefit after antidepressant administration and
the lack of a consistent response to treatment in
aproximately 30% of patients.1 SSRIs are thought to
have a delayed onset partly because of the need to
overcome the inhibitory influence of 5-HT1A somatoden-
dritic autoreceptors, which inhibit the firing rate of
serotonergic neurons.2 Pindolol, a 5-HT1A/1B and â-a-
* To whom correspondence should be addressed. Tel: 3448 425600
ext. 6343. Fax: 3448 425652. E-mail: amonge@unav.es.
† Department of Medicinal Chemistry, Universidad de Navarra.
‡ Vita Invest S.A. Av. Barcelona 69 08970 Sant J oan Desp´ı.
§ University of Innsbruck.
| Universita` di Catania.
The molecular modeling study is part of the G. Donzella’s gradu-
ation thesis.
#
Department of Pharmacology, Universidad de Navarra.
10.1021/jm0111200 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/07/2002

1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4129
Ch a r t 1. Structures of the Investigated Compounds
Sch em e 1a
Ch a r t 2. General Structure of the Presented
Compounds
a
Reagents: (ii) THF, K2CO3, room temperature. (iii) Methanol,
BH4Na, 0 °C. R ) H, F. Ar1: (a) 1-Naphthyl, (b) 2-quinolyl, (c)
3-quinolyl, (d) 4-quinolyl, (e) 5-quinolyl, (f) 6-quinolyl, (g) 8-quinolyl,
(h) 8-quinaldinyl, (i) 4-indolyl, (j) 2,3-dihydro-1,4-benzodioxin-5-
yl, (k) 1,3-benzodioxol-4-yl, (l) 3,4-dihydro-2H-1,5-benzo[b]dioxepin-
6-yl, and (m) 5-benzo[b]thiophenyl.
Sch em e 2
(series I and II) (Chart 2) in which we explored the
influence of different benzocondensed arylpiperazines.
described for its analogue 3,4-dihydro-2H-6-nitro-1,5-
benzo[b]dioxepinpiperazine in ref 30 (see Experimental
Section).
Ch em istr y
The general strategy for the synthesis of the target
compounds is summarized in Scheme 1. An aliphatic
nucleophilic substitution in tetrahydrofurane (THF) and
K2CO3 affords the corresponding 1-(3-benzo[b]thiophen-
yl)-3-[4-arylpiperazin-1-yl]propanone derivatives 5a -
j,l,m and 6a ,g-l. The reduction of these ketones with
sodium borohydride in methanol at 0 °C gave the
corresponding alcohol derivatives 7a -j,l,m and 8a ,g-
l. 1-(3-Benzo[b]thiophenyl)-3-chloropropan-1-one deriva-
tives (3 and 4) were synthesized by a Friedel-Craft
acylation of the corresponding benzo[b]thiophene pre-
cursors (Scheme 2). Benzo[b]thiophene is commercially
available while 5-fluorobenzo[b]thiophene was prepared
as described.7
For the synthesis of the piperazines 11a -m , two
synthetic strategies were followed via amino precursors
11a ,c,e-m (Scheme 3) or via chloro precursors 11b,d
(Scheme 4). In the first synthetic route, in the cases in
which the amino precursor was not commercially avail-
able, the nitro precursor was reduced with hydrazine
monohydrate and Ni-Raney in methanol. The biblio-
graphic references for the synthesis of the nitro precur-
sors are depicted in Scheme 3. The preparation of the
4-nitro-1,3-benzodioxolpiperazine was carried out from
3-nitrocatechol with dibromomethane by the method
The second strategy started with the chloro precur-
sors, which react with the piperazine in an aromatic
nucleophilic substitution (Scheme 4). This route was
chosen for 2-quinolylpiperazine8 (quipazine) 11b and
4-quinolylpiperazine9 11d . All compounds were char-
acterized by physical constants, elemental analysis, IR,
1
and H NMR.
Molecu la r Mod elin g. To determine the pharma-
cophore elements required to discriminate functional
effect at 5-HT1A receptors and 5-HT transporter inhibi-
tion, a molecular modeling study using the CATA-
LYST10 software package was undertaken. The auto-
matic identification of pharmacophoric pattern based on
atomistic comparison has been extensively described
(e.g., Disco, Compair, Family).11 Another promising
approach for defining alignment rules focuses on the
consideration of chemical features rather than explicit
atoms.12,13 Within the program CATALYST, feature-
based alignments are produced in a three step proce-
dure: (i) for each molecule, a conformational model is
generated using a quasi random sampling approach
with sequential poling,14 which has been shown to
produce a good coverage of the conformational space;15-16
(ii) each conformer is examined for the presence of

4130 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Oru´s et al.
Sch em e 3a
a
Reagents: (iv) Methanol, NH2-NH2‚H2O, Ni-Raney. (v) K2CO3, C6H5Cl, 4. (vi) C6H5Cl, 4. (vii) Diisopropylethylamine, C6H5Cl, 4.
(viii) p-TosOH, C6H5Cl, 4.
Sch em e 4a
a
Reagents: (ix) 4 (b). (x) Toluene, 4 (d ).
chemical features; and (iii) a set of chemical features
common to the input molecules that correlates best with
biological activity is determined. Global minimum en-
ergy conformation is not always the bioactive conforma-
tion, above all in the case of ionizable or charged
structures where hydrophobic interactions are not
structural determinants by strong intramolecular pack-
ings.
This three-dimensional (3D) array of chemical fea-
tures (called a hypothesis) provides a relative alignment
for each input molecule. In CATALYST, the chemical
features considered can be H bond acceptors and donors,
aliphatic and aromatic hydrophobes, positive and nega-
tive charges, positive and negative ionizable groups, and
aromatic planes.17 Multiple hypotheses are produced
and ranked according to how well they explain the
biological activity of the input molecule set. In a
hypothesis, each pharmacophoric function is character-
ized by points defined by the location constraint (x,y,z
coordinates in Cartesian space) surrounded by a toler-
ance sphere.
In a first step, a model describing the common feature
pharmacophore of all 19 5HT transport inhibitors was
generated using the HipHop algorithm within CATA-
LYST. The highest ranking resulting model (Hypo-1.01-
1, Figure 1) was obtained when the maximum miss of
one function was allowed to consist of six features (one
hydrophobic and three hydrophobic aromatic functions,
one positive ionizable, and one H bond acceptor func-
tion). All compounds of the training set except one of

1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4131
F igu r e 1. Mapping of the most potent 5HT transporter inhibitor (7f, Ki ) 2.2 nM, fit value ) 6.0) fitted onto common feature
pharmacophore model Hypo-1.01-1 obtained for inhibitors of the 5HT transporter. Pharmacophore features are color-coded (cyan,
hydrophobic; blue, hydrophobic aromatic; red, positive ionizable; green, H bond acceptor).
Ta ble 1. Compounds of Series I: Structure and Affinity for
Ta ble 2. Compounds of Series II: Structure and Affinity for
5-HT1A Receptors and for 5-HT Transporter
5-HT1A Receptors and for 5-HT Transporter
Ki (nM)
Ki (nM)
5-HT1A
receptor
5-HT
transporter
5-HT1A
receptor
5-HT
transporter
compd
Ar1
1-naphthyl
2-quinolyl
3-quinolyl
4-quinolyl
5-quinolyl
6-quinolyl
8-quinolyl
compd
Ar1
1-naphthyl
8-quinolyl
8-quinaldinyl
7a
7b
7c
7d
7e
7f
7g
7h
7i
66.7
377
995
301
36.8
546
6.3
10.2
5.5
5.7
81.7
6.4
4.2
19.4
32.5
2.2
24
9.9
4.1
50
8a
8g
8h
8i
62
2.7
2.5
5.9
6
7.5
9.4
7.3
16
4-indolyl
8j
2,3-dihydro-1,4-
benzodioxin-5-yl
1,3-benzodioxol-4-yl
3,4-dihydro-2H-1,5-
benzo[b]dioxepin-6-yl
8k
8l
9.4
3
58
21.2
8-quinaldinyl
4-indolyl
7j
2,3-dihydro-1,4-benzo-
dioxin-5-yl
7l
3,4-dihydro-2H-1,5-
benzo[b]dioxepin-6-yl
5-benzo[b]thiophenyl
1.9
77
fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)pi-
perazin-1-yl]1-propanol) (Chart 1, Figure 2) (compounds
previously synthesized in our department with the same
aim), 7g, and 8h ,i. As all compounds exhibit affinity
values in the low nanomolar range, no feature misses
were allowed. The best model obtained for receptor
antagonists (Hypo-3.01, represented in Figure 3 with
compound 7i) consists of six features (two hydrophobic
functions, one positive ionizable, one H bond donor, one
lipophilic H bond acceptor, and one aromatic ring with
direction constraint). In contrast to the models described
before for 5-HT transporter inhibition, the “right” part
of the pharmacophore consists of an aromatic system
containing a directed H bond acceptor function. When
using this model for in silico filtering of compounds
described in this study, only receptor antagonists are
found exhibiting fit values for the model in a range of
3.0-6.0. The fit values are calculated for comparing a
compound and a hypothesis. The quality of the mapping
is indicated by the fit value. A higher fit value repre-
sents a better fit. The computed fit value depends on
two parameters: how close the features in the molecule
are to the centers of the corresponding location con-
straints in the hypothesis and the weights assigned to
the hypothesis features (in our case, a value of one per
feature, giving a total fit of 6.0 for a compound perfectly
fitting to all features of the model).
7m
913
3.2
the less active molecules (8k , Ki ) 58 nM) are able to
map all functions of this model. If all of the active
compounds retrieved from a 3D structural database
using the CATALYST pharmacophore hypothesis should
map all of the features of a model, our best model for
5-HT transporters was able to retrieve more than 94%
(18 out of 19) of the active compounds in Tables 1 and
2.
When no miss of features was allowed during model
generation, a slightly modified model was obtained
containing one hydrophobic feature less than the previ-
ously calculated hypothesis (Hypo-4.01, Figure 2). More-
over, in this model, which is able to retrieve all
compounds of the training set, the hydroxy groups of
the compounds are represented as H bond donors.
In a second step, the generation of pharmacophore
models permitting the discrimination between 5HT1A
receptor antagonistic and partial agonistic activity was
envisaged. Therefore, we calculated common feature
models starting both from the four potent antagonists
8j and 7h -j and from the five partial agonists 22225
(1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piper-
azin-1-yl]1-propanol) (Chart 1, Figure 1), 84226 (1-(5-

4132 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Oru´s et al.
F igu r e 2. Common feature pharmacophore model Hypo-4.01-1 obtained for inhibitors of the 5HT transporter. Pharmacophore
features are color-coded (blue, hydrophobic aromatic; red, positive ionizable; green, H bond acceptor).
F igu r e 3. Mapping of compound 7i on the best common feature pharmacophore model obtained for receptor antagonists (Hypo-
3.01). Pharmacophore features are color-coded (cyan, hydrophobic; red, positive ionizable; magenta, H bond donor; brown, aromatic
ring; green, H bond acceptor).
F igu r e 4. Compound 8h mapped on common feature pharmacophore model obtained for partial agonists (Hypo-p.Ago-4.10-2).
Pharmacophore features are color-coded (blue, hydrophobic aromatic; red, positive ionizable; brown, aromatic ring; green, H bond
acceptor).
On the other hand, when using the partial agonists
for model generation, a hypothesis containing five
features was obtained (Hypo-p.Ago-4.10-2, represented
in Figure 4 with compound 8h ). This hypothesis is also
different from those calculated from the 5-HT trans-
porter inhibitors.
In contrast to the model for antagonists, the “left” part
of the partial agonist pharmacophore (Figure 4) consists
now of a directed aromatic ring function and the right
part contains both a hydrophobic function (mapping the
fluoro-substituted aromatic ring) and another H bond
acceptor. Moreover, the hydroxyl group in these com-
pounds is recognized as acting as a H bond acceptor too.
When using this hypothesis as a 3D query for database
search of the compounds under investigation, partial
agonists are retrieved with fit values in a range of 3.6-
5.0, which is somehow less selective than the model for
antagonists.

1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4133
Ta ble 3. Effect of Selected Compounds on [35S]GTPγS Binding
Biologica l Resu lts a n d Discu ssion
in Isolated Rat Hippocampal Membranesa
All of the synthesized compounds (19 piperazine
derivatives) were evaluated for their affinity at 5-HT1A
receptors and the 5-HT transporter. Structure and
binding data of the compounds are shown in Tables 1
and 2. The inhibition constant (Ki) was obtained from
the IC50 by the Cheng-Prusoff equation.21
basal fmol GTPγS maximal fmol GTPγS increase
compds
bound/mg protein
bound/mg protein
(%)
R(+)-8-OH-
13.50 ( 0.8
25.9 ( 1.6
91.85**
DPAT
7g
7h
7i
11.87 ( 1.12
11.20 ( 1.21
13.36 ( 3.32
15.57 ( 4.31
13.87 ( 1.31
14.43 ( 0.90
10.08 ( 0.81
11.87 ( 1.70
14.41 ( 1.43
15.55 ( 1.71
12.48 ( 1.54
16.87 ( 3.12
16.10 ( 1.91
23.87 ( 2.21
18.43 ( 1.10
13.66 ( 2.90
14.00 ( 0.32
17.70 ( 1.62
31.00*
11.42
26.3
The inspection of binding data with compounds from
series I and II (benzothiophene and 5-fluorobenzo[b]-
thiophene derivatives) permitted the assessment of the
following structure-activity relationships (SARs):
All of the compounds showed affinity for both recep-
tors. The best results were obtained with nine of them
(7g-j and 8g-j,l). The presence of fluoro at the benzo-
[b]thiophene (series I or II) did not appear to influence
decisively in the affinity of the synthesized compounds,
suggesting that the aromatic system in terms of elec-
tronic structure and π clouds is not directly involved in
the recognition and binding process for these chemo-
types at the 5-HT1A receptor whether electronic factors
play a substantial role in the trasporter recognition and
binding process. Conformational changes due to a
different folding of the molecule as a consequence of the
fluorine withdrawn effects may account for the reduced
selectivity at the receptor. Nevertheless, the presence
of a heteroatom and its position appear to be critical
for the affinity at 5-HT1A receptors, with the compounds
derived from 8-quinolyl showing the best results. Het-
eroatoms may lead to additional cooperative noncova-
lent interactions finally increasing the “ligand valency”18
in terms of contacting points in the recognition and
binding process, i.e., extending the pharmacophore
capability. The methyl group of the quinaldine ring does
not significantly affect the affinities suggesting that no
strict steric constrains are in the binding process, which
might be mainly governed by electronic more than steric
factors. Modification of the distance between the het-
eroatoms in the piperazines j-l affects the affinity to
the 5-HT transporter. Changing the heteroatoms ar-
rangement may lead to their improper location, there-
fore repulsive interactions, or their exclusion from
advantageous binding interactions.
7j
3.4
8g
8h
8i
71.38**
27.7*
35.5*
17.94
22.83
8j
8l
Compounds tested at concentrations from 10-10 to 10-5. Values
represent the mean ( SEM from three separate experiments.
Significant increase, *p < 0.05; **p < 0.01 (one way ANOVA
followed by Student-Newman-Keuls test).
a
bonds upon ligand binding followed by rigid body
movements of TMH4 and -6 relative to each other and
to the other TMHs, switching on the conversion to an
active receptor structure.19-20
The piperazine ring of the ligands whether proto-
nated19,20 may interact with the aspartic acid in TMH3
or that highly conserved closer to intracellular end of
the TMHs intracellular end. A negative area outside the
Asp116, which is a key residue in the ligand binding,
might be a guide region for the interaction.18-20 Con-
sidering the ambiguous character of the piperazine ring,
an uncharged form of it may exist allowing for a
different binding mode or representing a silent state of
the ligand before binding.19-21
Compounds with no agonistic activity in this system
were then tested in antagonism studies (Table 4). The
selective 5-HT1A receptor antagonist WAY 100635 did
not alter GTPγS binding by itself but fully prevented
the 8-OH-DPAT-induced effect, a result in keeping with
previous studies. All other compounds in Table 4
exhibited antagonist activity at 5-HT1A receptors, as
inferred from the inhibition of R(+)-8-OH-DPAT-
stimulated [35S]GTPγS binding. The compounds 8j and
7h -j exhibited antagonist activity with minimal or not
detectable agonist effect.
In vivo, pharmacological evaluation of the antagonist
activity at 5-HT1A receptors was assessed by measuring
mouse rectal temperature (Table 5). All of the com-
pounds antagonizing (+)-8-OH-DPAT-stimulated GTPγS
binding were assayed. The 5-HT1A receptor agonist
8-OH-DPAT, 0.5 mg/kg s.c., produced a marked decrease
in rectal temperature, an effect probably mediated
through activation of somatodendritic 5-HT1A receptors.
This study also showed that the compounds 7g,i,j and
8i,j at 10 mg/kg i.p. significantly antagonized the
hypothermic response to 8-OH-DPAT at different times
after administration. Consequently, in vitro and in vivo
studies for 5-HT1A receptor function rather appear to
reflect an antagonist profile of compounds 7h -j and 8j,l
at this 5-HT receptor subtype. According to current
theories (see Introduction), 5-HT uptake blockers with
an additional antagonist activity at somatodendritic
5-HT1A receptors may be efficacious antidepressants
with quicker onsets of action.
The compounds that exhibited high affinity at 5-HT1A
receptors (Ki < 20 nM) and the 5-HT transporter (Ki <
50 nM) were selected to determine the agonist or
antagonist action at 5-HT1A receptors by means of [35S]
GTPγS binding assays in hippocampal membranes.
For agonist activity, the effects of nine compounds
were compared with the selective 5-HT1A receptor
agonist R(+)-8-hydroxy-2-di-n-propylamino-tetralin (8-
OH-DPAT) for stimulation of [35S] GTPγS binding
(Table 3). Compound 8g produced a significant stimula-
tion (% increase ) 71.38%) in a concentration-dependent
manner (EC50 ) 31 nM), whereas the compounds 7g and
8h ,i only partially stimulated GTPγS binding by 31,
27.7, and 33.5%, respectively. The data suggest that 8g
is a 5-HT1A receptor full agonist while 7g and 8h ,i only
show a partial agonist action.
Hydrogen-bonding capability seems to be important
to break the hydrogen-bonding network, i.e., interhelical
hydrogen bonds (presumably at amino acids in TMH1,
-2, -3, and -7 with their constrain relative to each other)
or to attenuate them as recently reported at Asn54-
(TMH1)-Asp82(TMH2) or alternatively to form other
Con clu sion s
In this study, we synthesized two series of benzo[b]-
thiophene (I and II) derivatives with different arylpip-

4134 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Oru´s et al.
Ta ble 4. Inhibition of (+)-8-OH-DPAT-Stimulated [35S]GTPγS Binding in Hippocampal Membranesa
basal fmol GTPYγS
bound/mg protein
maximal fmol GTPγS
bound/mg protein
inhibition
(%)
compd
IC50 (nM)
control (R(+)-8-OH-DPAT)
12.98 ( 0.9
16.34 ( 1.00
16.37 ( 2.33
12.28 ( 3.64
12.84 ( 1.09
18.53 ( 0.80
19.29 ( 3.38
11.22 ( 1.60
19.07 ( 2.16
18.69 ( 1.08
23.83 ( 1.41**
15.89 ( 0.98
19.69 ( 3.06
12.47 ( 3.03
13.92 ( 1.34
19.09 ( 0.43
21.38 ( 2.45
10.06 ( 1.23
18.90 ( 6.2
WAY 100635
104
69
98
90
90
5.7 ( 2.2
18.03 ( 1.5
31.47 ( 14
31.19 ( 16
56.21 ( 10
3.80 ( 1.8
16.12 ( 45
31.16 ( 6.4
360 ( 82
7g
7h
7i
7j
8h
8i
8j
8l
80
110
101
84
20.42 ( 2.40
a
Values represent the mean ( SEM from three separate experiments. *P < 0.05 vs basal. R(+)-8-OH-DPAT used at a single 1 µM
-12
concentration. All other compounds tested at concentrations from 10
concentration.
to 10-5 M in the presence of the above indicated 8-OH-DPAT
Ta ble 5. Time-Dependent Effects of WAY 100635 and Selected Compounds on 8-OH-DPAT-Induced Hypothermia in Micea
change in body temp (°C)
dose
compds
(mg/kg)
15 min
30 min
60 min
control (R(+)-8-OH-DPAT)
-3.05 ( 0.12
-0.71 ( 0.21**
-2.38 ( 0.34
-0.80 + 0.30**
-2.10 ( 0.27
-2.19 ( 0.45
-2.08 ( 0.24*
-1.03 ( 0.32**
-2.90 ( 0.27
-1.38 ( 0.37**
-2.85 ( 0.14
-2.50 ( 0.36
-3.28 ( 0.46
-0.95 ( 0.17**
-1.49 ( 0.19*
-1.33 ( 0.40**
-2.85 ( 0.15
-0.95 ( 0.15**
-1.86 ( 0.37
-0.52 ( 0.24**
-2.46 ( 0.41
-2.31 ( 0.22
-1.59 ( 0.25
0.84 ( 0.22**
-2.47 ( 0.26
-1.03 ( 0.28**
2.45 ( 0.40
-2.07 ( 0.13
0.35 ( 0.09**
-1.09 ( 0.10
-0.20 ( 0.19**
-1.76 ( 0.26
-1.62 ( 0.09
-1.13 ( 0.22
-0.80 ( 0.22**
-1.94 ( 0.35
-0.50 ( 0.09**
1.92 ( 0.22
WAY 100635
1
1
10
1
10
1
10
1
10
1
10
1
10
1
10
7g
7h
7i
7j
8h
8i
8j
1.71 ( 0.44
1.48 ( 0.25
-3.61 ( 0.34
-0.89 ( 0.19**
-1.04 ( 0.16*
-0.72 ( 0.16**
-2,72 ( 0.84
-0.95 ( 0.16**
-1.04 ( 0.13*
-0.84 ( 0.10**
a
8-OH-DPAT was given always at a single dose of 0.5 mg/kg, s.c. All other drugs were given 30 min before 8-OH-DPAT. Values (means
+ SEM) correspond to changes in rectal temperature measured immediately before first drug injection and at different times after 8-OH-
DPAT. *p < 0.05; **p < 0.01 vs 8-OH-DPAT group (one way ANOVA followed by Student-Newman-Keuls test).
erazines in order to obtain new compounds with affinity
at both the 5-HT1A receptor and the 5-HT transporter.
All of the compounds showed high affinity for both sites.
From GTPγS binding assays, it could be concluded that
8g exhibited agonist activity, whereas compounds 7g
and 8h ,i behaved as weak partial agonists and 7h -j
and 8j,l antagonized the 8-OH-DPAT-stimulated GTPγS
binding. Body temperature studies in mice revealed also
an antagonist activity at this 5-HT receptor subtype.
Using ligand-based modeling techniques, we established
chemical features based on pharmacophore models.
Elements required for high affinity binding and the
features that enable one to discriminate between opti-
mal 5-HT1A receptor agonist, partial agonist, or antago-
nist activity were determined. Our models particularly
emphasize the role of the hydrogen-bonding capability
of the ligands in affecting the receptor operating as well
as the inhibition of the 5-HT transporter. By calculating
the fit values of compounds to the different models
obtained, it is possible to predict in silico the biological
effect of molecules to the targets under investigation.
High affinity ligands are assumed to adopt energeti-
cally favorable conformations in the receptor orienting
their molecular features toward the target in a more
optimal way than the low affinity compounds. Binding
of full agonists seems to induce larger conformational
changes into helices 3 and 6 than into the other
transmembrane helices. Receptor activation induces
rigid body movements of these transmembrane helices
relative to other transmembrane helices. Partial ago-
nists and antagonists are unable to do this as the full
agonist, which interacts closely by long-range forces or
directly at amino acids in transmembrane helix 4 for
inducing the above rigid body movements of transmem-
brane helices 3 and 6 relative to each other. Agonist
binding (largest changes into transmembrane helices 2,
4, and 5) has stronger effects on the helical packing and
overall structure of the receptor than binding of the
antagonist. The binding of agonist might constrain the
movements of the third intracellular loop more than did
the partial agonist and the antagonist.19,20 Solvent
interactions in desolvation prior to the binding step
along with enthalpy/entropy compensations might be
responsible to explain agonist/partial agonist and an-
tagonist character.21-23 Conversion into a proper struc-
ture for G-protein interactions has also been reported
by conformational-structural changes at TMHs I2 and
I3.20
Exp er im en ta l Section
Ch em istr y. Melting points were determined using a Met-
tler FP82+FP80 apparatus and are uncorrected. Elemental
analyses were obtained from vacuum-dried samples (over
phosphorus pentoxide at 3-4 mmHg, 24 h, at ca. 80-100 °C)
with a Leco CHN-900 instrument and are within (0.4% of the
calculated values except where otherwise stated. Infrared
spectra were recorded on a Perkin-Elmer 681 apparatus, using
potassium bromide tablets for solids products and sodium
chloride plates for oil products; the frequencies are expressed

1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4135
in cm-1. 1H NMR spectra were recorded on a Brucker AC-200E
(200 MHz) instrument, with tetramethylsilane (TMS) as the
internal reference, at a concentration of ca. 0.1 g/mL and with
dimethyl sulfoxide-d6 (DMSO-d6) or chloroform (CDCl3) as
solvents; chemical shifts are expressed in parts per million
(ppm) relative to internal TMS in δ units, and the coupling
constants (J ) values are in hertz (Hz). The mass spectra were
recorded on a Hewlett-Packard 5988-A instrument at 70 eV.
Thin-layer chromatography (TLC) was run on Merck silica
gel 60 F-254 plates with the indicated solvents and revealed
with iodine, and the plates were scanned under ultraviolet
light at 254 and 366 nm. Column chromatography was carried
out with Merck silica gel 60 (70-230 mesh ASTM).
2H, H3 + H6); 8.28 (dd, 2H, H4 + H5); 8.84 (c, 1H, H2). Anal.
(C13H15N3) C, H, N.
1-(8-Qu in a ld in yl)p ip er a zin e (h ). Yield 30%. IR (KBr):
3414 cm-1 1 NMR (DMSO-d6) δ (free base): 2.85 (s, 3H, CH3),
.
3.54 (d, 4H, N4(CH2)2); 3.69 (t, 4H, N1(CH2)2); 7.19-7.41 (m,
4H, H3 + H4 + H5 + H6); 7.94 (d, 1H, H7, J ) 8.47). Anal.
(C14H17N3) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of th e P ip er a zin es
(c,f,k ,m ). A suspension of the corresponding amino precursor
10c,f,k ,m (0.12 mmol) and bis(chloroethyl)amine hydrochloride
(0.12 mmol) in chlorobenzene (250 mL) was stirred under
reflux for 24 h. Once the reaction mixture was cooled, the
solvent was removed under reduced pressure. The residue was
treated with 2 N NaOH (75 mL) and extracted with AcOEt (3
× 75 mL). The extracts were dried (Na2SO4), and after it was
evaporated, the residue was purified by flash chromatography
(SP: silica gel), eluting with dichloromethane/MeOH (90:10)
(V:V). In some cases, the hydrochloride salt of the product was
formed by adding some drops of concentrated hydrochloric acid
to a solution of the piperazine free base in acetone.
Syn th esis of 4-Nitr o-(1,3-ben zod ioxolyl) (9k ). A mixture
of 6.2 mmol of nitrocathecol, 18.6 mmol of K2CO3, 9.3 mmol of
1,2-dibromomethane, and 0.62 mmol of tetrabutylammonium
bromide in toluene (30 mL) was refluxed for 24 h under N2
atmosphere. Once the reaction mixture was cooled, the solvent
was removed under reduced pressure. The obtained product
was purified by flash chromatography (SP: silica gel), eluting
with toluene; yield 40%; mp 118 °C. IR (KBr): 1546, 1358 cm-1
.
1-(3-Qu in olyl)p ip er a zin e (c). Yield 17%. IR (KBr): 3485
1
cm-1
.
NMR (DMSO-d6) δ (free base): 3.57 (d, 4H, N4(CH2)2);
1 NMR (DMSO-d6) δ (free base): 6.16 (s, 2H, O-CH2-O); 6.87
(t, 1H, H6); 7.01 (d, 1H, H7); 7.55 (d, 1H, H5). Anal. (C7H5NO4)
C, H, N.
3.83 (t, 4H, N1(CH2)2); 7.31 (d, 1H, H4, J ) 1.9 Hz); 7.37-7.53
(m, 2H, H6 + H8); 7.65 (dd, 1H, H5, J ) 6 Hz; J ) 2 Hz); 7.86
(d, 1H, H7); 8.74 (s, 1H, H2). Anal. (C13H15N3) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of th e Am in e
P r ecu r sor s 10i,k ,m . Ni-Raney and hydrazine monohydrate
(1 mol) were added to a well-stirred solution of the correspond-
ing nitro derivative 9i,k ,m (1 mol) in methanol at 0 °C. The
stirring was continued for 2-3 h. The reaction mixture was
filtered over Celite, and the solvent was removed under
reduced pressure. The obtained product was purified by flash
chromatography (SP: silica gel), eluting with dichloromethane.
1-(6-Qu in olyl)p ip er a zin e (f). Yield 63%. IR (KBr): 3423
1
cm-1
.
NMR (DMSO-d6) δ (free base): 3.23 (d, 4H, N4(CH2)2);
3.80 (t, 4H, N1(CH2)2); 7.24-7.54 (m, 2H, H2 + H7); 7.80-8.04
(m, 3H, H3 + H4 + H5); 8.38 (s, 1H, H8). Anal. (C13H15N3) C,
H, N.
1-(1,3-Ben zod ioxol-4-yl)p ip er a zin e Hyd r och lor id e (k ).
1
Yield 25%; mp 225-228 °C. IR (KBr): 3373 cm-1
.
NMR
(DMSO-d6) δ: 3.28 (d, 8H, piperazine), 6.00 (s, 2H, O-CH2-
O), 6.58 (t, 1H, H5 + H7), 6.83 (t, 1H, H6), 9.14 (bs, 1H, HCl).
Anal. (C11H17N2O2‚HCl) C, H, N.
4-Am in oin d ole (10i). Yield 67%; mp 106-108 °C. IR
1
(KBr): 3368 cm-1
.
NMR (DMSO-d6) δ (free base): 5.09 (s,
2H, NH2); 6.48 (s, 1H, H6); 6.60 (d, 2H, H5 + H7, J ) 8.04);
6.76 (t, 1H, H3); 7,06 (t, 1H, H2); 10.71 (s, 1H, NH). Anal.
(C8H8N2) C, H, N.
1-(5-Ben zo[b]th iop h en yl)p ip er a zin e (m ). Yield 36%. IR
1
(KBr): 3455 cm-1
.
NMR (DMSO-d6) δ (free base): 2.85 (s,
3H, CH3); 3.54 (d, 4H, N4(CH2)2); 3.69 (t, 4H, N1(CH2)2); 7.17
(dd, 1H, H6); 7.32-7.41 (m, 3H, H2 + H4 + H6); 7.70 (d, 1H,
H3, J ) 5.4 Hz); 7.86 (d, 1H, H7). Anal. (C12H14N2S) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of th e 1-(3-Ben zo-
[b]th iop h en yl)-3-[4-(a r yl)p ip er a zin -1-yl]p r op a n on e De-
r iva tives 5a -m a n d 6a ,g-l. A suspension of 1-(benzo[b]-
thiophenyl)-3-chloropropanone (3) or 3-chloro-1-(5-fluoro-
benzo[b]thiophenyl)propanone (4) (depending on series I or II),
the corresponding arylpiperazine (a -m ), and K2CO3 in THF
was stirred during 72 h at room temperature. After the solvent
was evaporated, the obtained residue was purified by flash
chromatography (SP: silica gel), eluting with hexane/AcoEt
(50:50) (V:V). In some cases, the hydrochloride salt of the
product was formed by adding some drops of concentrated
hydrochloric acid to a solution of the compound in acetone.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(n a p h th -1-yl)p ip er a zin -
1-yl]p r op a n -1-on e Hyd r och lor id e (5a ). Yield 25%; mp 223-
4-Am in o-(1,3-ben zod ioxolyl) (10k ). Yield 90%; mp 136-
138 °C. IR (KBr): 3348 cm-1 1 NMR (DMSO-d6) δ (free base):
.
3.42 (b.s., 2H, NH2); 5.83 (d, 2H, O-CH2-O); 6.26 (t, 1H, H5
+ H7); 6.60 (t, 1H, H6). Anal. (C7H7NO2) C, H, N.
5-Am in oben zo[b]th iop h en e (10m ). Yield 66%; mp 270-
1
272 °C. IR (KBr): 3412 cm-1
.
NMR (CDCl3) δ (free base):
6.70 (dd, 1H, H6); 7.02 (d, 1H, H4); 7.07 (d, 1H, H3); 7.30 (d,
1H, H2); 7.56 (d, 1H, H7). Anal. (C8H7NS) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of th e P ip er a zin es
(a ,e,g,h ). A suspension of the corresponding amino precursor
10a ,e,g,h (0.12 mmol), bis(chloroethyl)amine hydrochloride
(0.12 mmol), and K2CO3 (0.12 mmol) in chlorobenzene (250
mL) was stirred under reflux for 24 h. Once the reaction
mixture was cooled, the solvent was removed under reduced
pressure. The residue was treated with 2 N NaOH (75 mL)
and extracted with AcOEt (3 × 75 mL). The extracts were dried
(Na2SO4), and after it was evaporated, the residue was purified
by flash chromatography (SP: silica gel), eluting with dichlo-
romethane/MeOH (90:10) (V:V). In some cases, the hydrochlo-
ride salt of the product was formed by adding some drops of
concentrated hydrochloric acid to a solution of the piperazine
free base in acetone.
226 °C. IR (KBr): 1668 cm-1 1 NMR (DMSO-d6) δ: 3.33-3.86
.
(b.s., 12H, CH2); 7.18 (d, 1H, H2, J ) 7.2); 7.41-7.54 (m, 4H,
H3′ + H5′ + H5 + H6); 7.67 (d, 1H, H4, J ) 8.00); 7.90-7.94 (m,
1H, H7′); 8.11 (d, 1H, H4); 8.23 (d, 2H, H6′ + H8, J ) 7.2); 8.64
(d, 1H, H7, J ) 7.5); 9.19 (s, 1H, H2), 9.42 (bs, 1H, HCl). Anal.
(C25H24N2OS‚HCl‚0.5H2O) C, H, N.
1-(1-Naph th yl)piper azin e Hydr och lor ide (a). Yield 35%;
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-2-yl)p ip er a zin -
1-yl]p r op a n -1-on e (5b). Yield 38%; mp 92-96 °C. IR (KBr):
1
mp 235-237 °C. IR (KBr): 3375 cm-1
.
NMR (DMSO-d6) δ
(free base): 2.14 (s, 4H, N4(CH2)2); 3.07 (s, 4H, N1(CH2)2); 7.19
(d, 1H, H2 J ) 7.2); 7.28-7.50 (m, 4H, H3 + H4 + H6 + H7);
7.94 (dd, 1H, H8 J 56 ) 7.2 J 57 ) 3.6); 8.18 (dd, 1H, H5 J 78 ) 7.2
J 68 ) 3.7). Anal. (C14H16N2‚HCl) C, H, N.
1664 cm-1 1 NMR (CDCl3) δ (free base): 2.66 (t, 4H, N4(CH2)2);
.
2.94 (t, 2H, COCH2CH2); 3.25 (t, 2H, COCH2); 3.76 (t, 4H, N1-
(CH2)2); 6.96 (d, 1H, H3, J ) 7.9); 7.21-7.25 (m, 1H, H6′); 7.41-
7.56 (m, 4H, H5 + H6 + H5′ + H7′); 7.68 (d, 1H, H4′); 7.85-7.90
(m, 2H, H7 + H8′); 8.33 (s, 1H, H2); 8.74 (d, 1H, H4). Anal.
(C24H23N3OS) C, H, N.
1-(5-Qu in olyl)p ip er a zin e (e). Yield 23%. IR (KBr): 3368
1
cm-1
.
NMR (DMSO-d6) δ (free base): 2.96 (s, 8H, N(CH2)4);
7.15 (c, 1H, H4); 7.33 (c, 1H, H7); 7.44-7.54 (m, 1H, H3); 7.61-
7.73 (m, 1H, H2); 8.53 (dd, 1H, H6); 8.77-8.93 (m, 1H, H8).
Anal. (C13H15N3) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-3-yl)p ip er a zin -
1-yl]p r op a n -1-on e (5c). Yield 38%; mp 112-114 °C. IR
1
(KBr): 1665 cm-1
.
NMR (CDCl3) δ (free base): 2.75 (t, 4H,
1-(8-Qu in olyl)p ip er a zin e (g). Yield 17%. IR (KBr): 3296
N4(CH2)2); 2.96 (t, 2H, COCH2); 3.21-3.36 (m, 6H, N1(CH2)3);
7.31 (d, 1H, H4, J ) 1.9 Hz); 7.37-7.53 (m, 4H, H5 + H6 + H6′
+ H8′); 7.65 (dd, 1H, H5, J ) 6 Hz; J ) 2 Hz); 7.86 (d, 1H, H7′);
1
cm-1
.
NMR (DMSO-d6) δ (free base): 3.03 (d, 4H, N4(CH2)2);
3.31 (t, 4H, N1(CH2)2); 7.09-7.15 (m, 1H, H7); 7.45-7.51 (m,

4136 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Oru´s et al.
7.97 (d, 1H, H7, J ) 8 Hz); 8.32 (s, 1H, H2); 8.74 (s, 1H, H2′);
8.78 (d, 1H, H4). Anal. (C24H23N3OS) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-4-yl)p ip er a zin -
1-(5-F lu or oben zo[b]th iop h en -3-yl)-3-[4-(n a p h th -1-yl)-
p ip er a zin -1-yl]p r op a n -1-on e Hyd r och lor id e (6a ). Yield
1
28%; mp 236-238 °C. IR (KBr): 1667 cm-1
.
NMR (DMSO-
d6) δ (free base): 3.24-3.44 (b.s., 12H, CH2); 7.17 (d, 1H, H2′,
1-yl]p r op a n -1-on e (5d ). Yield 43%; mp 134-136 °C. IR
1
(KBr): 1615 cm-1
.
NMR (CDCl3) δ (free base): 2.81-2.85
J ) 7.2); 7.33-7.54 (m, 3H, H3′ + H5′ + H6); 7.64 (d, 1H, H4′,
(m, 4H, N4(CH2)2); 3.02 (t, 2H, CO-CH2); 3.24-3.32 (m, 6H,
N1(CH2)3); 6.84 (d, 1H, H3, J ) 4.9 Hz); 7.43-7.51 (m, 3H, H5
+ H6 + H6′); 7.65 (t, 1H, H7′);7.85 (t, 1H, H7); 7.99-8.06 (m,
2H, H5′ + H8′); 8.35 (s, 1H, H2); 8.71-8.79 (m, 2H, H2′ + H4).
Anal. (C24H23N3OS) C, H, N.
J ) 8.00); 7.89 (t, 1H, H7′); 8.16 (t, 1H, H4); 8.29 (d, 2H, H6′
+
H8′, J ) 7.2); 8.32 (dd, 1H, H7, J ) 7.5); 9.19 (s, 1H, H2). Anal.
(C25H23FN2OS‚HCl‚0.5H2O) C, H, N.
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(q u in ol-8-yl)-
p ip er a zin -1-yl]p r op a n -1-on e Hyd r och lor id e (6g). Yield
38%; mp 215-217 °C. IR (KBr): 1673 cm-1. 1H NMR (DMSO-
d6) δ (free base): 3.38 (b.s., 12H, CH2); 7.19 (d, 1H, H3′, J )
7.02); 7.36-7.60 (m, 4H, H5′ + H6′ + H7′ + H6); 8.18 (c, 2H, H4
+ H7); 8.33 (d, 1H, H4′, J ) 8.27); 8.88 (d, 1H, H2′, J ) 2.95);
9.22 (s, 1H, H2). Anal. (C24H22FN3OS‚HCl) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-5-yl)p ip er a zin -
1-yl]p r op a n -1-on e Dih yd r och lor id e (5e). Yield 28%; mp
1
212-214 °C. IR (KBr): 1689 cm-1
.
NMR (DMSO-d6) δ: 3.26
(s, 4H, N1(CH2)2); 3.38 (b.s., 6H, COCH2 + N4(CH2)2); 3.77 (d,
2H, COCH2CH2); 7.29 (t, 1H, H3′); 7.49-7.59 (m, 2H, H4′
+
H6′); 7.61-7.81 (m, 2H, H2′ + H7′); 8.13 (d, 1H, H4, J 45 ) 7.94);
8.64 (c, 2H, H5 + H6); 8.93 (d, 1H, H8′); 9.13 (d, 2H, H7 + H2);
10.88 (b.s., 1H, HCl). Anal. (C24H23N3OS‚2HCl) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-6-yl)p ip er a zin -
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(q u in a ld in -8-
yl)piper azin -1-yl]pr opan -1-on e Dih ydr och lor ide (6h ). Yield
1
23%; mp 230-232 °C. IR (KBr): 1662 cm-1
.
NMR (DMSO-
d6) δ: 2.63 (s, 3H, CH3); 2.72 (d, 4H, N1(CH2)2); 2.82 (d, 2H,
COCH2CH2); 3.29 (t, 6H, N4(CH2)2+COCH2); 7.36-7.88 (m, 5H,
1-yl]p r op a n -1-on e (5f). Yield 32%; mp 208-210 °C. IR
1
(KBr): 1672 cm-1
.
NMR (DMSO-d6) δ (free base): 2.78 (bs,
quinaldine); 8.16-8.28 (m, 1H, H6); 8.32 (dd, 1H, H7, J F7
)
4H, N4(CH2)2); 2.98 (t, 2H, COCH2CH2); 3.22-3.40 (m, 6H,
COCH2 + N1(CH2)2); 7.24-7.56 (m, 4H, H5 + H6 + H2′ + H7′);
7.82-8.04 (m, 3H, H3′ + H4′ + H5′); 8.28 (d, 1H, H4); 8.38 (s,
1H, H8′); 8.70-8.80 (m, 2H, H7 + H2). Anal. (C24H23N3OS) C,
H, N.
5.84); 8.71 (d, 1H, H4, J F4 ) 7.94); 9.27 (s, 1H, H2); 11.56 (b.s.,
1H, HCl). Anal. (C25H24FN3OS‚2HCl‚H2O) C, H, N.
1-(5-F lu or oben zo[b]th iop h en -3-yl)-3-[4-(in d ol-4-yl)p ip -
er a zin -1-yl]p r op a n -1-on e (6i). Yield 27%; mp 76-78 °C. IR
(KBr): 3397; 1661 cm-1 1 NMR (DMSO-d6) δ (free base): 2.69
.
(b.s., 4H, N1(CH2)2); 2.83 (t, 2H, COCH2CH2); 3.10 (b.s., 4H,
N4(CH2)2); 3.31 (t, 2H, COCH2CH2); 6.41 (t, 2H, H3′ + H5′); 6.97
(q, 2H, H6′ + H7′); 7.33 (c, 1H, H2′); 7.80 (d, 1H, H6, J 67 ) 8.00);
8.12 (c, 1H, H7), 8.30 (d, 1H, H4, J F4 ) 10.7); 9.13 (s, 1H, H2);
10.98 (s, 1H, NH). Anal. (C23H22FN3OS‚0.5H2O) C, H, N.
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(2,3-d ih yd r o-
1,4-ben zod ioxin -5-yl)p ip er a zin -1-yl]p r op a n -1-on e Hyd r o-
ch lor id e (6j). Yield 23%; mp 191-193 °C. IR (KBr): 1668
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-8-yl)p ip er a zin -
1-yl]p r op a n -1-on e Dih yd r och lor id e (5g). Yield 39%; mp
1
150-152 °C. IR (KBr): 1658 cm-1
.
NMR (DMSO-d6) δ: 3.38
(b.s., 12H, CH2); 7.24 (t, 1H, H3′); 7.41-7.63 (m, 4H, H4′ + H5′
+ H6′ + H7′); 8.35-8.55 (m, 2H, H5 + H6); 8.68 (d, 1H, H4, J 45
) 7.15); 8.70 (d, 1H, H7, J 67 ) 8.7); 8.71 (dd, 1H, H2′); 9.15
(s, 1H, H2); 9.35 (s, 1H, HCl). Anal. (C24H23N3OS‚2HCl) C, H,
N.
cm-1 1H NMR (DMSO-d6) δ: 3.05 (t, 4H, N1(CH2)2); 3.23 (t,
.
1-(Ben zo[b]t h iop h en -3-yl)-3-[4-(q u in a ld in -8-yl)p ip er -
2H, COCH2CH2); 3.60 (t, 4H, N4(CH2)2) 3.72 (t, 2H, COCH2);
4.24 (b.s., 4H, O(CH2)2); 6.55 (d, 2H, H6′ + H8′); 6.76 (t, 1H,
H7′); 7.40 (dd, 1H, H6, J 67 ) 8.94, J 46 ) 2.5); 8.18 (c, 1H, H7);
8.30 (dd, 1H, H4, J F4 ) 10.7); 9.20 (s, 1H, H2); 10.83 (bs, 1H,
HCl). Anal. (C23H23FN2O3S‚HCl) C, H, N.
a zin -1-yl]p r op a n -1-on e Dih yd r och lor id e (5h ). Yield 45%;
1
mp 199-200 °C. IR (KBr): 1663 cm-1
.
NMR (DMSO-d6) δ:
2.86 (s, 3H, CH3); 3.28-3.96 (m, 12H, CH2); 7.41-7.73 (m, 6H,
H3′ + H5′ + H5 + H6 + H6′ + H7′); 8.11 (c, 1H, H4′); 8.50 (d, 1H,
H4, J 45 ) 8.04); 8.61 (t, 1H, H7); 9.15 (s, 1H, H2); 11.39 (bs,
1H, HCl). Anal. (C25H25N3OS‚2HCl) C, H, N.
1-(5-Flu or oben zo[b]th ioph en -3-yl)-3-[4-(1,3-ben zodioxol-
4-yl)p ip er a zin -1-yl]p r op a n -1-on e (6k ). Yield 28%; mp 84-
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(in d ol-4-yl)p ip er a zin -1-
1
86 °C. IR (KBr): 1667 cm-1
.
NMR (DMSO-d6) δ (free base):
yl]p r op a n -1-on e (5i). Yield 20%; mp 83-85 °C. IR (KBr):
2.68 (t, 4H, N1(CH2)2); 2.92 (t, 2H, COCH2CH2); 3.19 (t, 6H,
1
3397; 1661 cm-1
.
NMR (DMSO-d6) δ (free base): 2.69 (bs,
COCH2 + N4(CH2)2); 5.91 (s, 2H, O-CH2-O), 6.46 (c, 2H, H5′
4H, N4(CH2)2); 2.83 (t, 2H, COCH2CH2); 3.10 (bs, 4H, N1-
(CH2)2); 3.31 (t, 2H, COCH2CH2); 6.41 (t, 2H, H3′ + H5′); 6.91-
7.04 (m, 2H, H5 + H6); 7.24 (t, 1H, H2′); 7.43-7.56 (m, 2H, H6′
+ H7′); 8.10 (dd, 1H, H4, J 45 ) 8.3, J 46 ) 1.7); 8.65 (d, 1H, H7,
J 76 ) 8.1); 9.06 (s, 1H, H2); 11.03 (s, 1H, NH). Anal. (C23H23N3-
OS) C, H, N.
+ H7′), 6.75 (t, 1H, H6′), 7.20 (dd, 1H, H6, J 67 ) 8.44, J 46
2.5); 7.77 (c, 1H, H7); 8.37 (s, 1H, H2); 8.46 (dd, 1H, H4 J F4
10.76). Anal. (C22H23FN2O3S) C, H, N.
)
)
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(3,4-d ih yd r o-
2H -1,5-b en zo[b]d ioxep in -6-yl)p ip er a zin -1-yl]p r op a n -1-
on e (6l). Yield 30%; mp 195-196 °C. IR (KBr): 1670 cm-1
.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(2,3-d ih yd r o-1,4-ben zo-
d ioxin -5-yl)p ip er a zin -1-yl]p r op a n -1-on e Dih yd r och lo-
1H NMR (CDCl3) δ (free base): 2.20 (q, 2H, CH2); 2.73 (t, 4H,
N1(CH2)2); 2.95 (t, 2H, COCH2CH2); 3.09 (t, 4H, N4(CH2)2); 3.25
1
r id e (5j). Yield 23%; mp 183-185 °C. IR (KBr): 1664 cm-1
.
NMR (DMSO-d6) δ: 3.11 (t, 6H, N1(CH2)3); 3.55 (t, 4H, N4-
(CH2)2) 3.76 (d, 2H, COCH2); 4.28 (d, 4H, O(CH2)2); 6.53 (d,
2H, H6′ + H8′); 6.76 (t, 1H, H7′); 7.43-7.57 (m, 2H, H5 + H6);
(t, 2H, COCH2); 4.25 (q, 4H, O-(CH2)2-O); 6.63 (t, 2H, H9′
+
H7′); 6.84 (t, 1H, H8′); 7.20 (dd, 1H, H6, J 67 ) 8.44, J 46 ) 2.5);
7.79 (c, 1H, H7); 8.41 (s, 1H, H2); 8.48 (dd, 1H, H4, J F4 ) 10.76).
Anal. (C24H21FN2O3S) C, H, N.
8.10 (dd, 1H, H4, J 45 ) 8.3, J 46 ) 1.4); 8.61 (dd, 1H, H7, J 67
)
8.90, J 57 ) 1.5); 9.13 (s, 1H, H2); 11.38 (bs, 1H, HCl). Anal.
Gen er a l P r oced u r e for P r ep a r a tion of th e 1-(3-Ben zo-
[b]t h iop h en yl)-3-[4-(a r yl)p ip er a zin -1-yl]-p r op a n ol De-
r iva tives 7a -m a n d 8a ,g-l. An excess of sodium borohydride
was added to a well-stirred suspension of the corresponding
1-(3-benzo[b]thiophenyl)-3-[4-(aryl)piperazin-1-yl]propanone
5a -m and 6a ,g-l (3 mmol) in methanol, over a period of 15
min at 0 °C. The reaction mixture was stirred over a period of
1 h and after the solvent was evaporated. The obtained product
was washed with plenty of water and extracted with ethyl
acetate (3 × 20 mL) and dried with anhydrous Na2SO4. The
solvent was removed under reduced pressure, and in the cases
in which the hydrochloride was formed, this was carried out
by dissolving the free base in AcoEt and by adding an
equimolar quantity of HCl(c).
(C23H24N2O3S‚2HCl‚H2O) C, H, N.
1-(Ben zo[b]th ioph en -3-yl)-3-[4-(3,4-dih ydr o-2H-1,5-ben -
zo[b]d ioxep in -6-yl)p ip er a zin -1-yl]p r op a n -1-on e (5l). Yield
1
28%; mp 195-197 °C. IR (KBr): 1664 cm-1
.
NMR (DMSO-
d6) δ (free base): 2.10 (t, 6H, N1(CH2)3); 2.98 (t, 4H, N4(CH2)2);
3.08 (d, 2H, COCH2); 4.20-4.34 (m, 6H, benzodioxepine); 6.58-
6.70 (m, 2H, H7′ + H9′); 6.82 (t, 1H, H8′); 7.38-7.56 (m, 2H, H5
+ H6); 7.84 (d, 1H, H4); 8.37 (s, 1H, H2); 8.79 (d, 1H, H7). Anal.
(C24H26N2O3S) C, H, N.
1-(Ben zo[b]t h iop h en -3-yl)-3-[4-(b en zo[b]t h iop h en -5-
yl)p ip er a zin -1-yl]p r op a n -1-on e (5m ). Yield 54%; mp 140-
1
142 °C. IR (KBr): 1668 cm-1
.
NMR (CDCl3) δ (free base):
2.78 (b.s., 6H, N1(CH2)3); 3.00 (t, 2H, COCH2) 3.26 (b.s., 4H,
N4(CH2)2); 7.07 (d, 1H, H4′); 7.21-7.30 (m, 4H, H2′ + H3′ + H6′
+ H7′); 7.68-7.75 (m, 2H, H5 + H6); 7.70 (d, 1H, H4); 8.35 (s,
1H, H2); 8.77 (d, 1H, H7). Anal. (C23H23N2O3S2) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(n a p h th -1-yl)p ip er a zin -
1-yl]p r op a n -1-ol Dih yd r och lor id e (7a ). Yield 48%; mp 95-
97 °C. IR (KBr): 3414 cm-1 1 NMR (CDCl3) δ (free base): 2.10
.

1-Aryl-3-[4-arylpiperazin-1-yl]-1-propane Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19 4137
(c, 2H, CHOHCH2); 2.71-2.87 (t, 6H, N1(CH2)3); 3.17 (bs, 4H,
N4(CH2)2); 5.35 (t, 1H, CHOH); 6.94-7.18 (m, 2H, H6 + H5);
7.18-7.56 (m, 7H, naphthyle); 7.76-7.86 (m, 2H, H4 + H7);
8.15 (s, 1H, H2). Anal. (C25H26N2OS‚2HCl) C, H, N.
1H, H7′); 7.33 (t, 2H, H5 + H6); 7.41 (s, 1H, H2); 7.78 (d, 1H,
H4 + H7, J ) 7.60). Anal. (C23H26N2O3S‚2HCl) C, H, N.
1-(Ben zo[b]th ioph en -3-yl)-3-[4-(3,4-dih ydr o-2H-1,5-ben -
zo[b]d ioxep in -6-yl)p ip er a zin -1-yl]p r op a n -1-ol (7l). Yield
1
59%; mp 184-186 °C. IR (KBr): 3365 cm-1
.
NMR (CDCl3) δ
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-2-yl)p ip er a zin -
(free base): 2.02 (t, 2H, CH2CHOH); 2.50-2.68 (m, 6H, N1-
(CH2)3); 3.19 (bs, 4H, N4(CH2)2); 5.08 (t, 1H, CHOH), 4.22-
4.32 (m, 6H, benzodioxepine); 6.58-6.70 (m, 2H, H7′ + H9′);
6.82 (t, 1H, H8′); 7.38-7.56 (m, 2H, H5 + H6); 7.84 (d, 1H, H4);
8.37 (s, 1H, H2); 8.79 (d, 1H, H7). Anal. (C24H29N2O3S) C, H,
N.
1-yl]p r op a n -1-ol (7b). Yield 53%; mp 192-196 °C. IR (KBr):
1
3410 cm-1
.
NMR (CDCl3) δ (free base): 2.12 (t, 2H, CH2-
CHOH); 2.64-2.76 (m, 6H, N1(CH2)3); 3.82 (t, 4H, N4(CH2)2);
5.37 (t, 1H, CHOH), 6.98 (d, 1H, H3′, J ) 7.8 Hz); 7.24-7.92
(m, 10H, aromatic). Anal. (C24H25N3OS) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-3-yl)p ip er a zin -
1-(Ben zo[b]t h iop h en -3-yl)-3-[4-(b en zo[b]t h iop h en -5-
1-yl]p r op a n -1-ol (7c). Yield 27%; mp 98-100 °C. IR (KBr):
1
3392 cm-1
.
NMR (CDCl3) δ (free base): 2.13 (t, 2H, CH2-
yl)p ip er a zin -1-yl]p r op a n -1-ol (7m ). Yield 36%; mp 181-
1
183 °C. IR (KBr): 3412 cm-1
.
NMR (CDCl3) δ: 2.23-2.32
CHOH); 2.67-2.91 (m, 6H, N1(CH2)3); 3.36 (t, 4H, N4(CH2)2);
5.34 (t, 1H, CHOH), 7.29-7.52 (m, 5H, H2 + H5 + H6 + H6′
(m, 2H, CH2CHOH); 3.18-3.35 (m, 6H, N1(CH2)3); 3.60-83 (bs,
4H, N4(CH2)2); 5.08 (dd, 1H, CHOH), 7.17 (dd, 1H, H4′); 7.32-
7.41 (m, 4H, H5 + H6 + H2′ + H6′); 7.65 (s, 1H, H2); 7.70 (d,
1H, H3′, J ) 5.4 Hz); 7.86 (d, 1H, H7′); 7.97-8.01 (m, 2H, H4 +
H7); 10.99 (bs, 1H, HCl). Anal. (C23H25N2O3S2) C, H, N.
1-(5-F lu or oben zo[b]th iop h en -3-yl)-3-[4-(n a p h th -1-yl)-
+
H8′); 7.68 (d, 1H, H5′, J ) 6 Hz); 7.77-7.86 (m, 2H, H4 + H4′);
7.98 (d, 1H, H7, J ) 8 Hz); 8.78 (d, 1H, H2′). Anal. (C24H25N3-
OS) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-4-yl)p ip er a zin -
1-yl]p r op a n -1-ol Hyd r och lor id e (7d ). Yield 62%; mp 174-
p ip er a zin -1-yl]p r op a n -1-ol Dih yd r och lor id e (8a ). Yield
1
176 °C. IR (KBr): 3277 cm-1. H NMR (DMSO-d6) δ: 2.02 (t,
1
36%; mp 197-198 °C. IR (KBr): 3410 cm-1
.
NMR (DMSO-
2H, CH2CHOH); 2.50-2.60 (m, 6H, N1(CH2)3); 3.19 (bs, 4H,
N4(CH2)2); 5.08 (t, 1H, CHOH), 6.55 (s, 1H, OH); 6.98 (d, 1H,
H3′, J ) 4.7 Hz); 7.35-7.44 (m, 2H, H6 + H5); 7.50-7.57 (m,
d6) δ (free base): 2.31 (t, 2H; CH2CHOH); 3.33 (q, 6H,
N1(CH2)3); 3.65 (d, 4H, N4(CH2)2); 5.07 (t, 1H, CHOH); 7.16
(d, 1H, H2, J ) 7.2); 7.27 (t, 2H, H6 + H7); 7.28-7.55 (m, 4H,
H3′ + H4′ + H5′ + H6′); 7.66 (d, 1H, H8, J ) 8.16); 7.81-8.00
(m, 2H, H7′); 8.03-8.10 (m, 2H, H2 + H4). Anal. (C25H25FN2-
OS‚2HCl) C, H, N.
2H, H6′ + H2); 7.69 (t, 1H, H7′); 7.93-8.03 (m, 4H, H4 + H7
+
H8′ + H5′); 8.62 (d, 1H, H2′, J ) 4.6 Hz); 10.07 (bs, 1H, HCl).
Anal. (C24H25N3OS‚HCl) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-5-yl)p ip er a zin -
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(q u in ol-8-yl)-
p ip er a zin -1-yl]p r op a n -1-ol Hyd r och lor id e (8g). Yield 15%;
1-yl]p r op a n -1-ol (7e). Yield 48%; mp 127-129 °C. IR (KBr):
1
3368 cm-1
.
NMR (DMSO-d6) δ (free base): 2.00 (d, 2H, CH2-
mp 89-91 °C. IR (KBr): 3102 cm-1 1 NMR (DMSO-d6) δ (free
.
CHOH); 2.60 (t, 6H, N1(CH2)3); 3.02 (s, 4H, N4(CH2)2); 5.08 (t,
1H, CHOH), 5.62 (b.s., 1H, OH); 7.15 (d, 1H, H4′); 7.21-7.43
(m, 3H, H5 + H6 + H7′); 7.46-7.88 (m, 3H, H2′ + H3′ + H6′);
7.89-7.98 (m, 2H, H7 + H4); 8.44 (d, 1H, H8′, J ) 8.39); 8.87
(s, 1H, H2). Anal. (C24H25N3OS) C, H, N.
base): 2.52 (t, 2H, CH2CHOH); 3.37 (b.s., 12H, CH2-s); 5.03
(t, 1H, CHOH), 5.66 (bs, 1H, OH); 7.09 (t, 2H, H6 + H7); 7.19
(t, 1H, H3′); 7.23-7.28 (m, 3H, H5′ + H6′ + H7′); 7.68 (s, 1H,
H2); 7.97 (c, 1H, H4′); 8.26 (d, 1H, H4, J ) 7.40); 8.82 (d, 1H,
H2′). Anal. (C24H24FN3OS‚H2O‚HCl) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-6-yl)p ip er a zin -
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(q u in a ld in -8-
1-yl]p r op a n -1-ol (7f). Yield 77%; mp 156-158 °C. IR (KBr):
yl)p ip er a zin -1-yl]p r op a n -1-ol Dih yd r och lor id e (8h ). Yield
1
3335 cm-1
.
NMR (CDCl3) δ (free base): 2.02 (t, 2H, CH2-
1
48%; mp 148-150 °C. IR (KBr): 3375 cm-1
.
NMR (CDCl3) δ
CHOH); 2.50-2.68 (m, 6H, N1(CH2)3); 3.19 (b.s., 4H, N4(CH2)2);
5.08 (t, 1H, CHOH), 6.62 (bs, 1H, OH); 7.01 (d, 1H, H7′); 7.24-
7.54 (m, 4H, H5 + H6 + H2′ + H7′); 7.80-8.04 (m, 3H, H3′ + H4′
+ H5′); 8.28 (d, 1H, H4); 8.38 (s, 1H, H8′); 8.70-8.80 (m, 2H,
H7 + H2). Anal. (C24H25N3OS) C, H, N.
(free base): 2.11 (t, 2H, CHOHCH2); 2.75 (s, 3H, CH3); 2.82
(b.s., 6H, N1(CH2)3); 2.91 (t, 4H, N4(CH2)2); 5.31 (t, 1H, CHOH);
7.10 (c, 2H, H6′ + H7′); 7.27 (c, 2H, H5′ + H3′); 7.39 (d, 1H, H4,
J ) 2.33); 7.52 (s, 1H, H2); 7.55 (d, 1H, H6, J 46 ) 2.2); 7.78 (c,
1H, H4); 7.99 (d, 1H, H7). Anal. (C25H26FN3OS‚2HCl) C, H, N.
1-(5-F lu or oben zo[b]th iop h en -3-yl)-3-[4-(in d ol-4-yl)p ip -
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(qu in ol-8-yl)p ip er a zin -
1-yl]p r op a n -1-ol Dih yd r och lor id e (7g). Yield 19%; mp
er a zin -1-yl]p r op a n -1-ol Hyd r och lor id e (8i). Yield 26%; mp
1
169-171 °C. IR (KBr): 3314 cm-1
.
NMR (DMSO-d6) δ (free
1
171-173 °C. IR (KBr): 3414 cm-1
.
NMR (DMSO-d6) δ (free
base): 2.13 (t, 2H, CH2CHOH); 3.39 (bs, 12H, CH2); 5.11 (t,
1H, CHOH), 7.40 (q, 2H, H3′ + H4′); 7.58 (d, 1H, H5′, J ) 7.34);
base): 1.99 (d, 2H, CHOHCH2); 2.55 (d, 6H, N1(CH2)3); 2.55
(bs, 4H, N4(CH2)2); 5.02 (s, 1H, CHOH); 5.64 (bs, 1H, OH); 6.41
(t, 2H, H3′ + H5′); 6.98 (t, 3H, H2′ + H6′ + H7′); 7.29 (s, 1H, H2);
7.69 (d, 1H, H4, J F7 ) 4.92); 7.76 (d, 1H, H6, J 46 ) 2.48); 8.01
(t, 1H, H7). Anal. (C23H24FN3OS‚HCl‚H2O) C, H, N.
7.72 (t, 2H, H6′ + H7′); 7.86 (t, 2H, H5 + H6); 8.04 (q, 2H, H7
+
H4); 9.08 (d, 1H, H2′); 9.33 (s, 1H, H2); 11.19 (b.s., 1H, OH).
Anal. (C24H25N3OS‚2HCl) C, H, N.
1-(Ben zo[b]t h iop h en -3-yl)-3-[4-(q u in a ld in -8-yl)p ip er -
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(2,3-d ih yd r o-
1,4-b en zod ioxin -5-yl)p ip er a zin -1-yl]p r op a n -1-ol Dih y-
a zin -1-yl]p r op a n -1-ol Dih yd r och lor id e (7h ). Yield 48%; mp
1
138-142 °C. IR (KBr): 3358 cm-1
.
NMR (DMSO-d6) δ (free
d r och lor id e (8j). Yield 40%; mp 147-150 °C. IR (KBr): 3360
1
cm-1
.
NMR (CDCl3) δ (free base): 2.05 (q, 2H, CHOHCH2);
base): 2.37 (t, 2H, CHOHCH2); 2.94 (s, 3H, CH3); 3.38 (bs, 6H,
N1(CH2)3); 3.76 (t, 4H, N4(CH2)2); 5.11 (t, 1H, CHOH); 7.37-
7.45 (m, 2H, H6′ + H7′); 7.54-7.85 (m, 5H, H6 + H5 + H5′ + H4′
+ H2); 7.97-8.07 (m, 2H, H4 + H7); 8.67 (d, 1H, H3, J ) 8.22);
12.21 (bs, 1H, OH). Anal. (C25H27N3OS‚2HCl) C, H, N.
2.64-2.88 (m, 6H, N1(CH2)3); 3.13 (bs, 4H, N4(CH2)2); 4.24 (d,
2H, 2He, J ) 5.6); 4.30 (d, 2H, Ha , J ) 13.6); 5.25 (t, 1H,
CHOH); 6.55 (c, 2H, H6′ + H8′); 6.77 (t, 1H, H7′); 6.98-7.13
(m, 2H, H6 + H4);7.44 (s, 1H, H2); 7.75 (c, 1H, H7). Anal.
(C23H25FN2O3S‚2HCl) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(in d ol-4-yl)p ip er a zin -1-
yl]p r op a n -1-ol Dih yd r och lor id e (7i). Yield 53%; mp >300
1-(5-Flu or oben zo[b]th ioph en -3-yl)-3-[4-(1,3-ben zodioxol-
°C. IR (KBr): 3396 cm-1 1 NMR (DMSO-d6) δ (free base): 2.00
.
4-yl)p ip er a zin -1-yl]p r op a n -1-ol (8k ). Yield 39%; mp 147-
(t, 2H, CHOHCH2); 2.55 (t, 6H, N1(CH2)3); 3.28 (bs, 4H, N4-
(CH2)2); 5.33 (t, 1H, CHOH); 5.62 (bs, 1H, OH); 6.42 (t, 2H,
H3′ + H5′); 6.99 (q, 2H, H6 + H5); 7.23-7.43 (m, 3H, H2′ + H6′
+ H7′); 7.57 (s, 1H, H2); 7.96 (q, 2H, H4 + H7); 11.03 (bs, 1H,
NH). Anal. (C23H25N3OS‚2HCl) C, H, N.
1
149 °C. IR (KBr): 3415 cm-1
.
NMR (CDCl3) δ (free base):
2.00-2.09 (m, 2H, CHOHCH2); 2.64-2.87 (m, 6H, N1(CH2)3);
3.24 (t, 4H, N4(CH2)2); 5.24 (t, 1H, CHOH); 5.92 (s, 2H,
O-CH2-O), 6.47 (c, 2H, H5′ + H7′), 6.77 (t, 1H, H6′), 7.09 (dd,
1H, H6, J 67 ) 8.44, J 46 ) 2.5); 7.44-7.50 (m, 2H, H2 + H7);
7.75 (c, 1H, H4). Anal. (C22H23FN2O3S) C, H, N.
1-(Ben zo[b]th iop h en -3-yl)-3-[4-(2,3-d ih yd r o-1,4-ben zo-
d ioxin -5-yl)p ip er a zin -1-yl]p r op a n -1-ol Dih yd r och lor id e
(7j). Yield 45%; mp 151-153 °C. IR (KBr): 3414 cm-1. 1H NMR
(DMSO-d6) δ (free base): 2.08 (b.s., 2H, CHOHCH2); 2.73 (bs,
6H, N1(CH2)3); 3.12 (bs, 4H, N4(CH2)2); 4.26 (d, 4H, O-CH2-
CH2-O); 5.33 (bs, 1H, CHOH); 6.54 (t, 2H, H6′ + H8′); 6.77 (t,
1-(5-F lu or ob en zo[b]t h iop h en -3-yl)-3-[4-(3,4-d ih yd r o-
2H -1,5-b en zo[b]d ioxep in -6-yl)p ip er a zin -1-yl]p r op a n -1-
1
ol (8l). Yield 52%; mp 125-127 °C. IR (KBr): 3414 cm-1
.
NMR (CDCl3) δ (free base): 2.03 (q, 2H, CH2); 2.17 (t, 2H,
CHOHCH2); 2.64-2.80 (m, 6H, N1(CH2)3); 3.09 (bs, 4H, N4-

4138 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 19
Oru´s et al.
(CH2)2); 4.23 (q, 4H, O-(CH2)2-O), 5.23 (t, 1H, CHOH); 6.55-
6.66 (m, 2H, H9′ + H7′); 6.81 (t, 1H, H8′); 7.06 (dd, 1H, H6, J 67
) 8.44, J 46 ) 2.5); 7.42-7.48 (m, 2H, H2 + H7); 7.73 (c, 1H,
H4). Anal. (C24H23FN2O3S) C, H, N.
fixed 8-OH-DPAT concentration (1 µM) by the assayed com-
pounds was calculated according to the formula: %I ) [(BDPAT
- BC) - (BT - BC)]/(BDPAT - BC) × 100, where BC is basal
binding in absence of 8-OH-DPAT, BDPAT is binding elicited
by 1 µM 8-OH-DPAT, and BT is binding elicited by 8-OH-DPAT
in the presence of increasing drug concentrations. Linear
regression analysis was used in order to estimate the IC50
values of the tested compounds.
8-OH-DP AT-In d u ced Hyp oth er m ia in Mice. The proce-
dures used for these studies were based on previously de-
scribed methods.27 Briefly, male Swiss mice (23-28 g) were
housed in groups of five and body temperature was measured
with a lubricated digital thermometer probe (pb0331, Panlab,
Barcelona) inserted to a depth of 2 cm into the rectum of the
mice. The temperature was recorded at 15, 30, and 60 min,
after injection of 8-OH-DPAT or the compound to be tested.
To study the antagonism to 8-OH-DPAT-induced hypothermia,
compounds or vehicle (control) were administered ip 30 min
before the injection of 8-OH-DPAT (0.5 mg/kg s.c.). The
hypothermic response to 8-OH-DPAT was measured as the
maximum decrease in body temperature recorded in this
period. The results were expressed as change in body temper-
ature (∆t) with respect to basal temperature, measured at the
beginning of the experiment. The obtained data were analyzed
by analysis of variance (ANOVA) followed by Student-
Newman-Keuls test.
Molecu la r Mod elin g. All calculations were performed
using the molecular Modeling package Catalyst 4.6 10 in-
stalled on Silicon Graphics O2 desktop workstations equipped
with a 200 MHz MIPS R5000 processor (128 or 256 MB RAM)
running the Irix 6.5 or 6.5+ operating system. The compounds
used in this study were built using the Catalyst 2D-3D
sketcher, and representative families of conformations were
generated for each molecule using the following parameters
for conformational analysis: maximum number of conformers,
255; generation type, best quality; energy range, 15.00 kcal/
mol beyond the calculated potential energy minimum. For
hypothesis generation, the default parameters were used.
Bin d in g to 5-HT Tr a n sp or ter . Binding studies to 5-HT
transporter were performed using rat frontal cortex homoge-
nates according to the procedure described by Marcusson.24
Briefly, rat cortical tissue was homogenized in Tris-HCl buffer
(50 mM, pH 7.4) and centrifuged at 4 °C for 10 min at 50 000g.
The supernatant was discharged, and the pellet was resus-
pended in Tris buffer and preincubated at 37 °C for 10 min.
The suspension was then washed twice by centrifugation and
resuspended in the same conditions as above. For displacement
assays, cortical membranes (4 mg tissue/mL) were incubated
with 0.1 nM [3H]paroxetine in Tris buffer, pH 7.4, containing
NaCl 120 mM and KCl 5 mM, for 60 min at 23 °C. The final
incubation volume was 2 mL, and nonspecific binding was
determined using 10 µM fluoxetine as the cold displacer. The
inhibition constants (Ki) were calculated using the equation
of Cheng and Prussof from the displacement curves analyzed
with the Receptor Fit Competition LUNDON program.
Ack n ow led gm en t. We are grateful to VITA-IN-
VEST S.A. for financial support. We also thank Sandra
Lizaso for skillful technical assistance. G.D. thanks Prof.
T. Langer for allowing a 3 month stage (grant by the
University of Catania) in his laboratory at the Univer-
sity of Innsbruck.
Bin d in g to 5-HT1A Recep tor s. Binding studies to 5-HT1A
receptors were performed using rat frontal cortex homogenates
according to the procedure described by Hoyer et al.25 Briefly,
rat cortical tissue was homogenized in Tris-HCl buffer 50 mM,
pH 7.7, and centrifuged at 4 °C for 15 min at 50 000g. The
supernatant was discharged, and the pellet was suspended in
Tris buffer and preincubated at 37 °C for 10 min. The
suspension was then centrifuged in the same conditions, and
the final pellet was resuspended in assay buffer (Tris-HCl 50
mM, pH 7.4, containing CaCl2 4 mM). For displacement assays,
cortical membranes (5 mg tissue/mL) were incubated with 2.5
nM [3H] 8-OH-DPAT in buffer assay for 15 min a 37 °C. The
final incubation volume was 0.4 mL, and nonspecific binding
was determined using 10 µM 8-OH-DPAT as the cold displacer.
The inhibition constants (Ki) were calculated as above.
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