Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter

Article abstract of DOI:10.1016/S0968-0896(03)00428-0

The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, which were modified at the connective between the diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure-activity relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [³H]GBR12935 in rat striatal membranes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC₅₀ values of nanomolar range. The SAR suggested that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenylamino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity.

Full text of DOI:10.1016/S0968-0896(03)00428-0

Bioorganic & Medicinal Chemistry 11 (2003) 3953–3963
Novel Diphenylalkyl Piperazine Derivatives with High Affinities
for the Dopamine Transporter
Makoto Kimura,a,* Tomoko Masuda,a Koji Yamada,a Masaki Mitani,a Nobuo Kubota,a
Nobuyuki Kawakatsu,a Kenichi Kishii,a Masato Inazu,b Yuji Kiuchi,c Katsuji Oguchid
and Takayuki Namikia,*
aPOLA Chemical Industries, Inc., Pharmaceutical R&D Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama,
Kanagawa 244-0812, Japan
bDepartment of Pharmacology, and Intractable Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku,
Shinjuku-ku, Tokyo 160-8402, Japan
cDepartment of Pathophysiology, School of Pharmaceutical Sciences, Showa University, 1-5-8Hatanodai, Shinagawa-ku,
Tokyo 142-8555, Japan
dDepartment of Pharmacology, School of Medicine, Showa University, 1-5-8Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Received 16 April 2003; accepted 16 June 2003
Abstract—The novel diphenyl piperazine derivatives containing the phenyl substituted aminopropanol moiety, including 1-[4,4-
bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, which were modified at the connective between the
diphenyl and piperazine moieties, have been found to be potent dopamine uptake inhibitors. To study the further structure–activity
relationship (SAR) of these compounds, a new series was synthesized, with modifications at the 2-hydroxy-3-phenylaminopropyl
moiety of 1. The series was evaluated for dopamine transporter (DAT) binding affinity with [3H]GBR12935 in rat striatal mem-
branes. Most of the compounds showed moderate to high DAT binding affinities and some were approximately equivalent in
activity to compound 1 or GBR12909 as a dopamine uptake inhibitor, with IC50 values of nanomolar range. The SAR suggested
that on exhibiting a potent interaction with the DAT, there is probably a steric limitation around the benzene ring of the phenyl-
amino moiety of 1, allowing only small-sized substituents with the exception of basic moieties at the 4-position. In addition, the
SAR at the 3-amino-2-propanol moiety of 1 suggested that either the nitrogen atom with an electron donating substituent or the
unsubstituted nitrogen atom and also the hydroxy group are desirable for elicitation of a potent DAT binding affinity.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
interest and effort have been focused on the SARs of
DA uptake inhibitors, which have led mainly two types
of them, tropane and diphenyl piperazine derivatives
represented respectively by Win 35,4285 and
GBR129096 (Fig. 1). They have included potent and
selective DA uptake inhibitors and some have been in
preclinical development or clinical trials. They have
shown great promise as treatments of CNS disorders
such as Parkinson’s disease,7 depression,3 or cocaine
addiction,8 and have also helped to characterize biolo-
gical and pharmacological profiles of the DAT.
Dopamine (DA) is a neurotransmitter involved in many
biological processes in the central nervous system (CNS)
and the dopaminergic neurotransmission is terminated
by a uptake mechanism through the DAT located in the
dopaminergic nerves terminals.1 Dopaminergic neuro-
transmission has been reported to be closely associated
with CNS disorders such as Parkinson’s disease,2
depression,3 and cocaine abuse,4 therefore much effort
has been focused on the research of the DAT, which has
been one of the most attractive targets for the treatment
of these CNS disorders. In the last two decades, great
In our previous study,9 we found that the novel diphe-
nyl piperazine derivatives containing the phenyl sub-
stituted aminopropanol moiety, including 1-[4,4-bis(4-
fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)pro-
pyl]piperazine 1 (Fig. 1), which were modified at the
*Corresponding authors: Tel.: +81-45-826-7264; fax: +81-45-826-
7249. E-mail: m-kimura@pola.co.jp (M. Kimura); t-namiki@pola.co.jp
(T. Namiki).
0968-0896/03/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00428-0

3954
M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
Figure 1.
connective between the diphenyl and piperazine moi-
eties, exhibited moderate to high DAT binding affinities
in rat striatal membranes. Furthermore, from an in vivo
pharmacological study, compound 1 was also found to
produce significant and dose-dependent increases of rat
striatal extracellular DA levels, which were much
greater than those by GBR12909. These findings sug-
gested that these diphenyl piperazine derivatives are
potent DA uptake inhibitors in the CNS and can serve
as new structural molecules as DA uptake inhibitors
different from GBR12909 analogues with the diphe-
nylmethoxyalkyl and phenylalkyl moieties at the 1-
and 4-position of the piperazine or piperizine ring
and their bioisosteric moieties.10À16 Therefore, we
attempted to study further their SARs as DA uptake
inhibitors. In this paper, we describe the syntheses of
a new series of diphenylalkyl piperazine derivatives,
which were modified at the 2-hydroxy-3-(phenylami-
no)propyl moiety in compound 1, and their DAT
binding affinities using [3H]GBR12935 in rat striatal
membranes.
hydrin derivatives 3a–k in the presence of potassium
carbonate and potassium iodide in ethanol, afforded the
desirable diphenylalkyl piperazine derivatives 4a–k
(Scheme 1). Reduction of the 4-nitro derivative 4e with
tin(II) chloride gave the amine derivative 5 (Scheme 2).
Deprotection of the benzyl group in the 4-benzyloxy
derivative 4i using palladium catalyst in methanol con-
taining formic acid gave the 4-hydroxy derivative 6
(Scheme 2). The N-acetyl 9a and N-mesyl 9b derivatives,
4-pyridyl derivative 10a, 3,5-di-tert-butyl-4-hydroxy
derivative 10b, and 2-acetoxy 12 and 2-methoxy 13
propanol derivatives were synthesized as shown in
Schemes 3 and 4. Alkylation of N-substituted anilines
7a–e with epibromohydrin using sodium hydride (NaH)
in N,N-dimethylformamide (DMF), followed by the
treatment of the resultant epoxides 8a–e with 1-[4,4-
bis(4-fluorophenyl)butyl]piperazine in ethanol, afforded
the desirable diphenylalkyl piperazine derivatives 9a–e
(Scheme 3). Deprotection of the tert-butoxycarbonyl
(Boc) groups in 9c and 9d with hydrogen chloride in
ethyl acetate gave the 4-pyridyl derivative 10a and the
3,5-di-tert-butyl-4-hydroxy derivative 10b, respectively
(Scheme 3). Acetylation of 9e with acetic anhydride in
pyridine, followed by deprotection of the Boc group in
the resultant compound 11 with hydrogen chloride in
ethyl acetate, afforded an acetate 12 (Scheme 4).
Alkylation of 1 with iodomethane in the presence of
NaH in DMF gave a methoxide 13 as a sole product
(Scheme 4).
Chemistry
The diphenylalkyl piperazine derivatives 4a–h, 5, and 6
containing various substituents on the benzene ring of
the phenylamino moiety, N-methyl derivative 4j, and
benzylamino derivative 4k were synthesized as shown in
Schemes 1and 2 . Treatment of epichlorohydrin with the
corresponding aniline derivatives 2a–j and benzylamine
2k in ethanol, followed by alkylation of 1-[4,4-bis(4-
fluorophenyl)butyl]piperazine with the resultant chloro-
All of the final compounds synthesized as described
above were used for the pharmacological evaluations in
the forms of their corresponding salts listed in Table 1.
Scheme 1. Reagents and conditions: (a) epichlorohydrin, EtOH, reflux, 42–72%; (b) 1-[4,4-bis(4-fluorophenyl)butyl]piperazine, K2CO3, KI, EtOH,
reflux, 31–78%.

M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
3955
Results andDiscussion
[3H]GBR12935 binding studies
Diphenylalkyl piperazine derivatives synthesized as
described above were evaluated for their competitive
binding assays using [3H]GBR12935 to label the DAT in
rat striatal membranes.17 The results are shown in Table 1.
At first, diphenylalkyl piperazine derivatives 4a–h, 5, 6,
and 10b having the mono-, di-, and tri-substituents with
various physico-chemical properties at the meta- and/or
para-position of the benzene ring in the phenylamino
moiety were evaluated, including 4-pyridyl 10a and
benzyl 4k derivatives. The 4-fluoro 4a, 4-methoxy 4b, 4-
methyl 4c, and 4-chloro 4d derivatives showed potent
binding affinities for the DAT with IC50 values of low
nanomolar range, which were similar to 1 or GBR12909,
a known potent DA uptake inhibitor. These findings
suggest that the electronic and hydrophobic properties of
the substitutent at the 4-position have no great influence
on these affinities. This possibility is supported by the
Scheme 2. Reagents and conditions: (a) SnCl2, EtOH, heat, 81%;
(b) 10% Pd-black, HCOOH, MeOH, room temperature, 95%.
Scheme 3. Reagents and conditions: (a) NaH, epibromohydrin, DMF, room temperature, 34–100%; (b) 1-[4,4-bis(4-fluorophenyl)butyl]piperazine,
EtOH, room temperature, 18–74%; (c) HCl/AcOEt, room temperature, 50%.
Scheme 4. Reagents and conditions: (a) Ac2O, pyridine, room temperature, 89%; (b) HCl/AcOEt, room temperature, 91%; (c) NaH, CH3I, DMF,
room temperature, 29%.

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M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
Table 1. DAT binding affinities of diphenylalkyl piperazine derivatives
location due to the introduction of the methylene group
between the benzene ring and the nitrogen atom. Thus,
the results of the modifications of the benzene ring in the
phenylamino moiety of compound 1 including the benzyl
derivative described above suggest that on showing a
potent interaction with the binding site at the DAT, there
is probably a steric limitation around the benzene ring
and only small-sized substitutents with the exception of
basic moieties at the 4-position are allowed.
Compd
R1
R2 R3 n X
Salta IC50 (nM)b
Next, diphenylalkyl piperazine derivatives 4j, 9a, 9b, 12,
and 13, which were modified at the 3-amino-2-propanol
moiety of compound 1, were evaluated. The N-methyl
derivative 4j exhibited a potent binding affinity com-
parable to 1, while N-acetyl 9a and N-mesyl 9b deriva-
tives decreased the binding affinities compared with 1,
showing IC50 values of 38 and 10 nM, respectively. Thus,
the results of the modifications on the nitrogen atom of 1
indicate that an electron donating substituent such as a
methyl group or the unsubstituted nitrogen atom is more
favorable for a potent binding affinity for the DAT com-
pared with an electron withdrawing substituent such as an
acetyl or a mesyl group. Since a hydroxy group has been
known to be often important for molecular recognition
through the hydrophilic or hydrogen-bonded interaction,
the modification of the hydroxy group of 1 was attempted.
Replacement of the hydroxy group by the acetoxy group
12 and the methoxy group 13 induced slight reductions of
binding affinity. These findings suggest that the 2-propa-
nol moiety of 1 may exhibit a potent DAT binding affinity
through the hydrophilic or hydrogen-bonded interaction,
or there may be a steric limitation in the interaction of this
moiety with the binding site at the DAT.
4a
4b
4c
4d
4e
4f
4g
4h
4j
4k
5
6
9a
4-F
4-OMe
4-Me
4-Cl
H
H
H
H
H
H
H
H
Me
H
H
H
Ac
Ms
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0 CH
0 CH
0 CH
0 CH
0 CH
0 CH
0 CH
0 CH
0 CH
1CH
0 CH
0 CH
0 CH
0 CH
0 N
0 CH
A
A
A
B
C
B
C
B
D
A
B
B
C
D
B
4.00Æ0.23
3.00Æ0.16
4.00Æ0.41
3.00Æ0.32
8.00Æ0.50
109.00Æ19.00
12.00Æ0.72
43.00Æ5.00
3.00Æ0.21
81.00 Æ4.00
37.00Æ9.00
10.00Æ3.00
38.00Æ4.00
10.00Æ0.78
34.00Æ2.00
87.00Æ7.00
14.00Æ1.00
17.00Æ4.00
2.00Æ0.29
2.00Æ0.35
4-NO2
4-N(CH3)2
3,4-diCl
3,4,5-triOMe
H
H
4-NH2
4-OH
H
H
9b
10a
10b
12
13
1
GBR12909
H
3,5-di-tert-Bu-4-OH
B
H
H
H
Ac 0 CH
Me 0 CH
H 0 CH
D
A
A
C
aA, trihydrochloride; B, trimaleate; C, dihydrochloride; D, dimaleate.
bThe DAT was labeled with [3H]GBR12935. IC50 values represent the
concentrations inhibiting 50% of specific bindings and were calculated
by non-linear regression fitting. Each value indicates
Æstandard error from three experiments conducted in duplicates.
a mean
finding that the 4-nitro derivative 4e with an electron
withdrawing group and the 4-hydroxy derivative 6 with
an electron donating group both kept potent binding
affinities, although the activities were slightly less potent
than those of 4a–d. On the other hand, the 4-amino
derivative 5 and 4-pyridyl derivative 10a apparently
decreased the binding affinities as compared with other
4-substituted derivatives described above. The results
suggest that the basic property at the 4-position decrea-
ses the interaction with the binding site at the DAT,
probably due to the ionization of the group through its
strong basicity. The 4-dimethylamino derivative 4f
showed dramatically reduced binding affinity with IC50
value of 109 nM, which might be due to either excessive
bulkiness or basicity or their combination. Concerning
the 3,4-di- and 3,4,5-tri-substituted derivatives, 3,4-di-
chloro 4g, 3,4,5-tri-methoxy 4h, and 3,5-di-tert-butyl-4-
hydroxy 10b derivatives, they all caused decrease of
binding affinity as compared with the corresponding 4-
mono-substituted derivatives (4g vs 4d), (4h vs 4b), and
(10b vs 6), implying that there is probably an adverse
steric effect including the bulkiness at the meta-position
in interacting with the binding site at the DAT. The
benzyl derivative 4k also induced a slight decrease of
binding affinity compared with 1, which might indicate
the involvement of less favorable interaction of this
compound with the DAT. Namely, it is suggested that
the appropriate location of the benzene ring of 1 for the
binding site at the DAT sterically shifted to less favorable
In conclusion, we have synthesized a new series of
diphenylalkyl piperazine derivatives modified at the 2-
hydroxy-3-(phenylamino)propyl moiety of compound 1
and evaluated them for DAT binding affinities with
[3H]GBR12935. Most of the compounds showed mod-
erate to high DAT binding affinities and some were
approximately equivalent in activity to 1 or GBR12909.
The SAR through the modifications of the benzene ring
in the phenylamino moiety of 1 suggested that on exhi-
biting a potent interaction with the DAT, there is a
probably steric limitation around the benzene ring,
allowing only small-sized substituents except for basic
moieties at the 4-position. In addition, the SAR at the 3-
amino-2-propanol moiety of 1 suggested that the nitrogen
atom having an electron donating substituent or the
unsubstituted nitrogen atom is more preferable for a
potent DAT binding affinity compared with that having
an electron withdrawing substituent, and that the hydroxy
group also favors potent DAT binding affinity. Combined
with the previous results of the modifications in the
diphenylalkyl moiety of 1, we have selected compound 1
as a representative for further biological and pharmaco-
logical evaluations and now continue these studies.
Experimental
All melting points were determined using a Buchi
micromelting point apparatus without correction. IR

M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
3957
spectra were measured with a Nicolet FT-IR 205 spec-
1
N-(3-Chloro-2-hydroxypropyl)-4-(dimethylamino)aniline
trometer. H NMR spectra were recorded on a JEOL
(3f). A dark brown oil. Yield 42%. IR (KBr) cmÀ1
3420, 1604, 1507. 1H NMR (CDCl3) d 2.81(6H, s),
3.19–3.42 (2H, m), 3.52–3.64 (2H, m), 3.87–4.03 (1H,
:
GSX spectrometer (270 MHz). Chemical shifts were
reported in ppm (d) values, based on tetramethylsilane
as an internal standard. The following abbreviations
were used: s=singlet, d=doublet, t=triplet, q=quar-
tet, m=multiplet, dd=double doublet, dt=double tri-
plet, brs=broad singlet. MS spectra were recorded
using a JEOL SX-102 mass spectrometer. Elemental
analyses were performed by Yanaco CHN CORDER
MT-5 (C, H, N) and Flask Combustion (Cl). Column
chromatography were performed on silica gel (BW-200,
Fuji Silisia Chemical, Ltd., 100–200 mesh).
m), 6.61–6.83 (4H, m). FAB-MS m/z 229 [M+H]+.
N-(3-Chloro-2-hydroxypropyl)-3,4-dichloroaniline (3g).
A colorless oil. Yield 64%. IR (KBr) cmÀ1: 3409, 1599,
1496, 1240, 1134, 1090, 846, 806, 751. 1H NMR
(CDCl3) d 3.18 (1H, dd, J=7.6, 13.5 Hz), 3.33 (1H, dd,
J=4.1, 13.5 Hz), 3.62–3.74 (2H, m), 3.97–4.13 (1H, m),
6.48 (1H, dd, J=2.4, 8.4 Hz), 6.71(1H, d, J=3.0 Hz),
7.19 (1H, d, J=8.4 Hz). FAB-MS m/z 254 [M+H]+.
N-(3-Chloro-2-hydroxypropyl)-3,4,5-trimethoxyaniline
(3h). A colorless oil. Yield 63%. IR (KBr) cmÀ1: 3398,
1
N-(3-Chloro-2-hydroxypropyl)-4-fluoroaniline (3a).
A
1612, 1511, 1235, 805, 775. H NMR (CDCl3) d 3.21
mixture of 4-fluoroaniline (2.00 g, 18.0 mmol) and epi-
chlorohydrin (0.83 g, 8.97 mmol) in EtOH (25 mL) was
heated under reflux for 5 h. The mixture was cooled to
room temperature and concentrated in vacuo. The resi-
due was purified by silica gel column chromatography
(CHCl3/CH3OH=99:1as an eluent) to give 3a (0.82 g,
45%) as a colorless oil. IR (KBr) cmÀ1: 3398, 1508,
(1H, dd, J=6.8, 13.5 Hz), 3.37 (1H, dd, J=3.8, 13.5
Hz), 3.72–3.82 (2H, m), 3.76 (3H, s), 3.84 (6H, s), 3.98–
4.12 (1H, m), 5.91 (2H, s). FAB-MS m/z 276 [M+H]+.
4-Benzyloxy-N-(3-chloro-2-hydroxypropyl)aniline (3i). A
colorless oil. Yield 62%. IR (KBr) cmÀ1: 3411, 1603,
1
1254. H NMR (CDCl3) d 3.24 (1H, dd, J=7.0, 13.2
1
1220. H NMR (CDCl3) d 2.82 (1H, brs), 3.18 (1H, dd,
Hz), 3.39 (1H, dd, J=4.9, 13.2 Hz), 3.58–3.82 (2H, m),
4.01–4.14 (1H, m), 5.07 (2H, s), 6.71 (2H, t, J=7.8 Hz),
6.76–6.91(2H, m), 7.32–7.54 (5H, m). HRFAB-MS
calcd for C16H19ClNO2 [M+H]+: 292.1104. Found:
292.1098.
J=7.0, 13.5 Hz), 3.34 (1H, dd, J=4.6, 13.5 Hz), 3.61–
3.74 (2H, m), 3.97–4.12 (1H, m), 6.61–6.73 (2H, m),
6.92–7.04 (2H, m). FAB-MS m/z 204 [M+H]+.
Using this procedure, the following compounds 3b–k
were synthesized.
N-(3-Chloro-2-hydroxypropyl)-N-methylaniline (3j). A
yellow oil. Yield 59%. IR (KBr) cmÀ1: 3413, 1602, 1507,
751. H NMR (CDCl3) d 2.45 (1H, d, J=4.9 Hz), 2.99
(3H, s), 3.45 (2H, d, J=4.9 Hz), 3.60 (1H, dd, J=5.4,
11.4 Hz), 3.70 (1H, dd, J=4.1, 11.4 Hz), 4.08–4.23 (1H,
m), 6.69–6.93 (3H, m), 7.21–7.33 (2H, m). FAB-MS m/z
200 [M+H]+.
1
N-(3-Chloro-2-hydroxypropyl)-4-methoxyaniline (3b). A
colorless oil. Yield 52%. IR (KBr) cmÀ1: 3394, 1513,
1
1237, 1097, 824, 753. H NMR (CDCl3) d 3.07 (1H,
brs), 3.15 (1H, dd, J=7.3, 12.7 Hz), 3.31 (1H, dd,
J=4.0, 12.7 Hz), 3.61–3.70 (2H, m), 3.71(3H, s), 3.74–
3.79 (1H, m), 6.59–6.72 (2H, m), 6.76–6.92 (2H, m).
HRFAB-MS calcd for C10H15ClNO2 [M+H]+:
216.0791. Found: 216.0789.
N-(3-Chloro-2-hydroxypropyl)benzylamine (3k). A pale
yellow oil. Yield 46%. IR (KBr) cmÀ1: 3392, 1603, 1507.
1H NMR (CDCl3) d 2.66 (1H, dd, J=7.8, 11.9 Hz), 2.78
(1H, dd, J=4.1, 10.5 Hz), 3.52 (2H, d, J=5.9 Hz), 3.78
(2H, s), 3.89–4.04 (1H, m), 7.18–7.42 (5H, m). FAB-MS
m/z 200 [M+H]+.
N-(3-Chloro-2-hydroxypropyl)-4-methylaniline (3c).
A
pale yellow oil. Yield 72%. IR (KBr) cmÀ1: 3402, 1615,
1
1519, 1241, 1089, 914, 821, 742. H NMR (CDCl3) d
2.28 (3H, s), 3.10 (1H, brs), 3.18 (1H, dd, J=7.3, 13.5
Hz), 3.33 (1H, dd, J=4.1, 13.5 Hz), 3.62–3.69 (2H, m),
3.98–4.13 (1H, m), 6.58 (2H, dd, J=2.7, 11.7 Hz), 7.00
(2H, d, J=8.4 Hz). FAB-MS m/z 200 [M+H]+.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-fluorophenyl)
amino]-2-hydroxypropyl]piperazine (4a). A mixture of
3a (0.82 g, 4.03 mmol), 1-[4,4-bis(4-fluorophenyl)butyl]
piperazine (1.33 g, 4.03 mmol), potassium carbonate
(0.67 g, 4.85 mmol), and potassium iodide (0.07 g,
0.422 mmol) in EtOH (25 mL) was heated under
reflux for 5 h. After removal of insoluble materials by
filtration, the filtrate was concentrated in vacuo. The
residue was purified by silica gel column chromato-
graphy (CHCl3/CH3OH=99:1as an eluent) to give 4a
4-Chloro-N-(3-chloro-2-hydroxypropyl)aniline (3d).
A
colorless oil. Yield 72%. IR (KBr) cmÀ1: 3390, 1597,
1
1498, 1241, 1084, 828, 744, 667. H NMR (CDCl3) d
3.19 (1H, dd, J=7.3, 13.2 Hz), 3.35 (1H, dd, J=4.3,
13.2 Hz), 3.62–3.72 (2H, m), 3.96–4.13 (1H, m), 6.57–
6.71 (2H, m), 7.11–7.24 (2H, m). FAB-MS m/z 220
[M+H]+.
(1.55 g, 78%) as a pale yellow oil. IR (KBr) cmÀ1
:
3387, 1603, 1508, 1222. 1H NMR (CDCl3) d 1.41–
1.52 (2H, m), 1.92–2.03 (2H, m), 2.31-2.48 (10H, m),
2.63–2.69 (2H, m), 2.98 (1H, dd, J=5.9, 11.9 Hz),
3.19 (1H, dd, J=4.1, 11.9 Hz), 3.86 (1H, t, J=8.1
Hz), 3.87–4.02 (1H, m), 6.51–6.64 (2H, m), 6.77–7.03
(6H, m), 7.07–7.23 (4H, m). FAB-MS m/z 498
[M+H]+.
N-(3-Chloro-2-hydroxypropyl)-4-nitroaniline (3e). A yel-
low oil. Yield 45%. IR (KBr) cmÀ1: 3340, 1603, 1507.
1H NMR (CDCl3) d 2.57 (1H, d, J=5.7 Hz), 3.41–3.47
(1H, m), 3.53–3.60 (1H, m), 3.62–3.74 (2H, m), 4.11–
4.24 (1H, m), 4.77–4.92 (1H, m), 6.58–6.72 (2H, m),
+
7.93–8.14 (2H, m). FAB-MS m/z 231[M+H]
.

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M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
Using this procedure, the following compounds 4b–k
were synthesized.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(3,4,5-
trimethoxyphenyl)amino]propyl]piperazine (4h). A pale
yellow oil. Yield 48%. IR (KBr) cmÀ1: 3390, 1607, 1509,
1
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-meth-
oxyphenyl)amino]propyl]piperazine (4b). A pale yellow
oil. Yield 44%. IR (KBr) cmÀ1: 3440, 1604, 1512, 1235.
1H NMR (CDCl3) d 1.38–1.52 (2H, m), 1.87–2.13 (2H,
m), 2.32–2.57 (10H, m), 2.63–2.72 (2H, m), 2.98 (1H,
dd, J=6.5, 12.4 Hz), 3.20 (1H, dd, J=3.5, 12.4 Hz),
3.74 (3H, s), 3.82–4.04 (2H, m), 6.60 (2H, dd, J=2.2,
6.5 Hz), 6.77 (2H, dd, J=1.9, 6.5 Hz), 6.87–7.02 (4H,
m), 7.08–7.23 (4H, m). FAB-MS m/z 510 [M+H]+.
1221. H NMR (CDCl3) d 1.37–1.51 (2H, m), 1.98–2.13
(2H, m), 2.27–2.63 (10H, m), 2.64–2.73 (2H, m), 3.01
(1H, dd, J=6.5, 11.9 Hz), 3.23 (1H, dd, J=3.8, 11.9
Hz), 3.76 (3H, s), 3.82 (6H, s), 3.87 (1H, t, J=8.1Hz),
3.91–4.02 (1H, m), 5.91 (2H, s), 6.98 (3H, t, J=6.5 Hz),
7.07–7.21(3H, m), 7.36 (2H, s). FAB-MS m/z 570
[M+H]+.
1-[3-[(4-Benzyloxyphenyl)amino]-2-hydroxypropyl]-4-
[4,4-bis(4-fluorophenyl)butyl]piperazine (4i). A pale pur-
ple oil. Yield 47%. IR (KBr) cmÀ1: 3420, 1602, 1507,
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-meth-
ylphenyl)amino]propyl]piperazine (4c). A pale yellow oil.
1
1221. H NMR (CDCl3) d 1.37–1.51 (2H, m), 1.89–2.04
1
Yield 72%. IR (KBr) cmÀ1: 3420, 1604, 1506, 1221. H
(2H, m), 2.27–2.52 (10H, m), 2.54–2.64 (2H, m), 2.95
(1H, dd, J=7.0, 12.4 Hz), 3.16 (1H, d, J=3.2, 12.4 Hz),
3.83 (1H, t, J=7.8 Hz), 3.88–4.03 (1H, m), 4.98 (2H, s),
6.51(2H, d, J=8.9 Hz), 6.63 (6H, d, J=8.9 Hz), 6.92
(4H, dt, J=2.2, 7.8 Hz), 7.08–7.23 (5H, m). FAB-MS
m/z 586 [M+H]+.
NMR (CDCl3) d 1.37–1.51 (2H, m), 1.96–2.12 (2H, m),
2.23 (3H, s), 2.28–2.54 (10H, m), 2.61–2.74 (2H, m),
3.01(1H, dd, J=6.2, 12.2 Hz), 3.22 (1H, dd, J=3.2,
12.2 Hz), 3.83 (1H, t, J=7.8 Hz), 3.92–4.03 (1H, m),
6.65 (2H, d, J=8.4 Hz), 6.91–7.04 (5H, m), 7.12–7.23
(3H, m), 7.36 (2H, s). FAB-MS m/z 494 [M+H]+.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methyl-
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-chlorophenyl)
amino]-2-hydroxypropyl]piperazine (4d). A colorless oil.
N-phenylamino)propyl]piperazine (4j). A yellow oil.
Yield 54%. IR (KBr) cmÀ1: 3425, 1601, 1507, 1223. H
NMR (CDCl3) d 1.38–1.52 (2H, m), 1.88–2.03 (2H, m),
2.32–2.54 (10H, m), 2.59–2.72 (2H, m), 2.98 (3H, s),
3.22 (2H, d, J=8.4 Hz), 3.85 (1H, t, J=7.8 Hz), 3.89–
4.02 (1H, m), 6.68–6.82 (5H, dt, J=1.9, 6.2 Hz), 7.16–
7.32 (8H, m). FAB-MS m/z 494 [M+H]+.
1
1
Yield 72%. IR (KBr) cmÀ1: 3440, 1603, 1506, 1220. H
NMR (CDCl3) d 1.38–1.52 (2H, m), 1.97–2.11 (2H, m),
2.21–2.54 (10H, m), 2.62–2.74 (2H, m), 2.99 (1H, dd,
J=5.9, 12.4 Hz), 3.21 (1H, dd, J=3.5, 12.4 Hz), 3.86
(1H, t, J=7.3 Hz), 3.88–4.02 (1H, m), 6.54 (2H, dd,
J=1.9, 7.0 Hz), 6.95 (4H, dt, J=1.9, 7.0 Hz), 7.08–7.22
(4H, m), 7.36 (2H, s). FAB-MS m/z 514 [M+H]+.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenyl-
methylamino)propyl]piperazine (4k). A yellow oil. Yield
62%. IR (KBr) cmÀ1: 3448, 1604, 1508, 1223. 1H NMR
(CDCl3) d 1.37–1.52 (2H, m), 1.88–2.03 (2H, m), 2.31–
2.84 (14H, m), 3.78–3.93 (2H, m), 3.83 (2H, s), 6.95 (4H,
t, J=6.5 Hz), 7.18–7.28 (4H, m), 7.33–7.44 (5H, m).
FAB-MS m/z 494 [M+H]+.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-nitro-
phenyl)amino]propyl]piperazine (4e). A yellow oil. Yield
69%. IR (KBr) cmÀ1: 3420, 1605, 1508, 1229. 1H NMR
(CDCl3) d 1.38–1.51 (2H, m), 1.89–2.02 (2H, m), 2.31–
2.58 (10H, m), 2.64–2.72 (2H, m), 3.11 (1H, dd, J=5.9,
11.3 Hz), 3.29–3.41(1H, m), 3.89 (1H, t, J=7.8 Hz),
3.89–4.03 (1H, m), 6.54 (2H, d, J=6.8 Hz), 6.95 (4H, dt,
J=2.4, 6.8 Hz), 7.07–7.21(4H, m), 8.08 (2H, dd, J=1.9,
7.3 Hz). HRFAB-MS calcd for C29H35F2N4O3
[M+H]+: 525.2677. Found: 525.2674.
1-[3-[(4-Aminophenyl)amino]-2-hydroxypropyl]-4-[4,4-bis
(4-fluorophenyl)butyl]piperazine (5). A mixture of 4e
(0.30 g, 0.572 mmol) and tin (II) chloride (0.48 g, 2.53
mmol) in EtOH (1mL) was heated in an oil bath of
90 ꢀC for 6 h under a nitrogen atmosphere. The mixture
was cooled to room temperature, poured into aqueous
saturated NaHCO3 (30 mL), and extracted with two 40
mL portions of AcOEt. The extracts were combined,
dried over Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromato-
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-dimethylamino-
phenyl)amino]-2-hydroxypropyl]piperazine (4f). A dark
brown oil. Yield 31%. IR (KBr) cmÀ1: 3407, 1602, 1507,
1
1223. H NMR (CDCl3) d 1.32–1.47 (2H, m), 1.92–2.04
(2H, m), 2.21–3.83 (14H, m), 2.85 (6H, s), 3.85 (1H, t,
J=7.4 Hz), 3.92–4.03 (1H, m), 6.61 (2H, d, J=7.4 Hz),
6.72 (2H, d, J=7.4 Hz), 7.01( 4H, t, J=7.4 Hz), 7.11–
7.23 (4H, m). FAB-MS m/z 523 [M+H]+.
graphy (CHCl3/CH3OH=99:1as an eluent) to give
5
(0.23 g, 81%) as a yellow oil. IR (KBr) cmÀ1: 3433,
1508, 1230. 1H NMR (CDCl3) d 1.37–1.51 (2H, m),
1.96–2.12 (2H, m), 2.28–2.58 (10H, m), 2.63–2.72 (2H,
m), 2.95 (1H, dd, J=5.4, 11.9 Hz), 3.18 (1H, dd, J=3.2,
11.8 Hz), 3.86 (1H, t, J=7.8 Hz), 3.88–4.03 (1H, m),
6.48–6.72 (3H, m), 6.87–7.03 (5H, m), 7.08–7.21(4H,
m). HRFAB-MS calcd for C29H37F2N4O [M+H]+:
495.2935. Found: 495.2943.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(3,4-dichlorophenyl)
amino]-2-hydroxypropyl]piperazine (4g). A colorless oil.
1
Yield 54%. IR (KBr) cmÀ1: 3388, 1601, 1507, 1223. H
NMR (CDCl3) d 1.37–1.52 (2H, m), 1.96–2.13 (2H, m),
2.31–2.58 (10H, m), 2.64–2.71 (2H, m), 2.96 (1H, dd,
J=5.9, 11.8 Hz), 3.20 (1H, d, J=11.8 Hz), 3.86 (1H, t,
J=8.1 Hz), 3.88–4.01 (1H, m), 6.44 (1H, dd, J=2.4, 8.9
Hz), 6.67 (1H, d, J=8.1Hz), 6.98 (4H, dt, J=2.2, 8.9
Hz), 7.08–7.22 (5H, m). HRFAB-MS calcd for
C29H34Cl2F2N3O [M+H]+: 548.2047. Found: 548.2052.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-hydoxyphenyl)a-
mino]-2-hydroxypropyl]piperazine (6). A solution of 4i
(2.98 g, 5.09 mmol) in MeOH (16 mL) was added to a
suspension of 10% Pd-black (0.82 g) in MeOH (20 mL)

M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
3959
containing formic acid (1.1 mL) and the mixture was
stirred for 3 h at room temperature under a nitrogen
atmosphere. After removal of insoluble materials by fil-
tration, the filtrate was poured into a mixture of ben-
zene (40 mL) and H2O (40 mL). The organic layer was
separated and the aqueous layer was extracted with two
40 mL portions of benzene. The organic layer and the
extracts were combined, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by silica gel
column chromatography (CHCl3/CH3OH=99:1as an
eluent) to give 6 (2.39 g, 95%) as a pale purple oil. IR
(1H, dd, J=5.4, 14.9 Hz), 3.86 (1H, dd, J=4.1, 14.9 Hz),
7.18–7.54 (5H, m). FAB-MS m/z 250 [M+H]+.
1-[3-(N-Acetyl-N-phenylamino)-2-hydroxypropyl]-4-[4,4-
bis(4-fluorophenyl)butyl]piperazine (9a). A mixture of 8a
(2.78 g, 14.5 mmol) and 1-[4,4-bis(4-fluorophenyl)-
butyl]piperazine (4.81 g, 14.6 mol) in EtOH (120 mL)
was stirred for 18 h at room temperature. After removal
of EtOH, the residue was purified by silica gel column
chromatography (CHCl3/CH3OH=99:1as an eluent)
to give 9a (1.33 g, 18%) as a pale yellow oil. IR (KBr)
cmÀ1: 3420, 1654, 1597, 1508, 1222. 1H NMR (CDCl3) d
1.36–1.51 (2H, m), 1.86 (3H, s), 1.86–2.03 (2H, m),
2.27–2.47 (10H, m), 2.52–2.61 (2H, m), 3.67 (1H, dd,
J=7.8, 13.8 Hz), 3.81–4.03 (3H, m), 6.94 (4H, t, J=8.4
Hz), 7.08–7.16 (4H, m), 7.22–7.31 (2H, m), 7.32–7.43
(3H, m). FAB-MS m/z 522 [M+H]+.
1
(KBr) cmÀ1: 3440, 1617, 1508, 1222. H NMR (CDCl3)
d 1.37–1.52 (2H, m), 1.88–2.03 (2H, m), 2.26–2.48 (10H,
m), 2.53–2.62 (2H, m), 2.95 (1H, dd, J=7.0, 12.4 Hz),
3.16 (1H, dd, J=3.2, 12.4 Hz), 3.83 (1H, t, J=7.8 Hz),
3.86–4.03 (1H, m), 6.51 (2H, d, J=8.9 Hz), 6.63 (2H, d,
J=8.9 Hz), 6.92 (4H, dt, J=2.2, 7.8 Hz), 7.07–7.24 (4H,
m). FAB-MS m/z 496 [M+H]+.
Using this procedure, the following compounds 9b–e
were synthesized.
N-Acetyl-N-(2,3-epoxypropyl)aniline (8a). NaH (60% in
mineral oil, 0.59 g, 14.8 mmol) was added to a solution
of acetanilide 7a (2.00 g, 14.8 mmol) in DMF (30 mL)
under ice bath cooling and the mixture was stirred for
15 min. To the mixture was added dropwise a solution
of epibromohydrin (2.03 g, 14.8 mmol) in DMF (5 mL)
over a period of 20 min with stirring under ice bath
cooling and the mixture was stirred for 4 h at room
temperature. The mixture was poured into a mixture of
benzene (50 mL) and H2O (50 mL) and the organic layer
was separated, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column
chromatography (CHCl3/CH3OH=99:1as an eluent) to
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-me-
thanesulfonyl-N-phenylamino)propyl]piperazine (9b). A
pale yellow oil. Yield 29%. IR (KBr) cmÀ1: 3442, 1602,
1
1508, 1340, 1222. H NMR (CDCl3) d 1.56–1.72 (2H,
m), 2.09–2.22 (2H, m), 3.11 (3H, s), 3.21–3.84 (14H, m),
4.07–4.22 (1H, m), 4.10 (1H, t, J=7.8 Hz), 7.07–7.23
(4H, m), 7.39–7.64 (9H, m). HRFAB-MS calcd for
C30H38F2N3O3S [M+H]+: 558.2602. Found: 558.2596.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[N-tert-butoxycarbo-
nyl-N-(4-pyridyl)amino]-2-hydroxypropyl]piperazine (9c).
A yellow oil. Yield 18%. IR (KBr) cmÀ1: 3423, 1706,
give 8a (2.78 g, 98%) as a pale yellow oil. IR (KBr) cmÀ1
:
1
1631, 1602, 1501, 1263. 1H NMR (CDCl3) d 1.85 (3H, s),
2.44 (1H, dd, J=2.4, 4.3 Hz), 2.76 (1H, dd, J=4.3, 4.9
Hz), 3.19–3.32 (1H, m), 3.60 (1H, dd, J=6.2, 14.0 Hz),
4.01(1H, dt, J=6.2, 14.0 Hz), 7.18–7.33 (2H, m), 7.42–
7.54 (3H, m). FAB-MS m/z 192 [M+H]+.
1593, 1508, 1223. H NMR (CDCl3) d 1.27–1.43 (2H,
m), 1.53 (9H, s), 1.92–2.13 (2H, m), 2.17–2.48 (10H, m),
2.53–2.63 (2H, m), 3.54 (1H, dd, J=7.6, 14.9 Hz), 3.82–
4.03 (3H, m), 6.95 (4H, dt, J=1.9, 8.9 Hz), 7.07–7.22
(4H, m), 7.26–7.43 (2H, m), 8.51(2H, dd, J=1.9, 4.9
+
Hz). FAB-MS m/z 581[M+H]
.
Using this procedure, the following compounds 8b–e
were synthesized.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[N-tert-butoxycarbo-
nyl-N-(3,5-di-tert-butyl-4-hydroxyphenyl)amino]-2-hydro-
xypropyl]piperazine (9d). A pale yellow oil. Yield 28%.
IR (KBr) cmÀ1: 3440, 1689, 1603, 1508, 1224. 1H NMR
(CDCl3) d 1.38–1.47 (2H, m), 1.41 (18H, s), 1.43 (9H, s),
1.93–2.01 (2H, m), 2.16–2.37 (10H, m), 2.51–2.62 (2H,
m), 3.53 (1H, dd, J=6.5, 13.2 Hz), 3.73 (1H, dd, J=9.1,
13.2 Hz), 3.78–4.02 (3H, m), 5.13 (1H, s), 6.87–7.03 (4H,
m), 7.12–7.23 (4H, m), 7.36 (2H, s). FAB-MS m/z 708
[M+H]+.
N-(2,3-Epoxypropyl)-N-methansulfonylaniline (8b).
A
pale yellow oil. Yield 34%. IR (KBr) cmÀ1: 1597, 1494,
1332. 1H NMR (CDCl3) d 2.52 (1H, q, J=2.4 Hz), 2.75
(1H, q, J=4.6 Hz), 3.02 (3H, s), 3.12–3.28 (1H, m), 3.37
(1H, dd, J=2.4, 4.6 Hz), 3.84 (1H, dd, J=6.8, 13.7 Hz),
7.28–7.53 (5H, m). FAB-MS m/z 228 [M+H]+.
4-[N-tert-Butoxycarbonyl-N-(2,3-epoxypropyl)amino]pyri-
dine (8c). This compound was used for the next reac-
tion without purification by silica gel column
chromatography.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-(N-tert-butoxycar-
bonyl-N-phenylamino)-2-hydroxypropyl]piperazine (9e).
A colorless oil. Yield 74%. IR (KBr) cmÀ1: 3433, 1697,
1508, 1223. 1H NMR (CDCl3) d 1.38–1.52 (2H, m), 1.42
(9H, s), 1.97–2.11 (2H, m), 2.29–2.53 (12H, m), 3.75
(1H, dd, J=8.4, 14.9 Hz), 3.85 (1H, t, J=8.1Hz), 3.97
(1H, dd, J=3.0, 14.9 Hz), 5.26–5.41 (1H, m), 6.96 (4H,
dt, J=3.0, 8.4 Hz), 7.13–7.22 (5H, m), 7.24–7.34 (4H,
m). FAB-MS m/z 580 [M+H]+.
N-tert-Butoxycarbonyl-3,5-di-tert-butyl-N-(2,3-epoxypro-
pyl)-4-hydroxyaniline (8d). This compound was used for
the next reaction without purification by silica gel col-
umn chromatography.
N-tert-Butoxycarbonyl-N-(2,3-epoxypropyl)aniline (8e).
A colorless oil. Yield 100%. IR (KBr) cmÀ1: 1699, 1598,
1497, 1379. 1H NMR (CDCl3) d 1.52 (9H, s), 2.50 (1H, q,
J=2.4 Hz), 2.79(1H, t, J=4.3Hz),3.18–3.32 (1H, m), 3.62
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-pyri-
dyl)amino]propyl]piperazine (10a). A solution of 4.0 N

3960
M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
HCl in AcOEt (3.0 mL) was added dropwise over a
period of 5 min to a solution of 9c (1.00 g, 1.72 mmol)
in AcOEt (36 mL) with stirring under ice bath cooling
and the mixture was stirred at room temperature for 48
h. After removal of the solvent, the residue was solidi-
fied with Et2O and filtered. The solids were dissolved in
a mixture of benzene (10 mL) and saturated aqueous
NaHCO3 (10 mL). The organic layer was separated,
dried over Na2SO4, and concentrated in vacuo to give
10a (0.41g, 50%) as a yellow oil, which was used for the
next reaction without further purification. IR (KBr)
cmÀ1: 3423, 1607, 1508, 1221. 1H NMR (CDCl3) d 1.38–
1.51 (2H, m), 1.93–2.12 (2H, m), 2.27–2.49 (10H, m),
2.54–2.63 (2H, m), 3.07 (1H, dd, J=5.7, 12.7 Hz), 3.21–
3.33 (1H, m), 3.86 (1H, t, J=7.8 Hz), 3.89–4.02 (1H, m),
4.61–4.73 (1H, m), 6.44 (1H, dd, J=1.4, 5.1 Hz), 6.94
(4H, dt, J=2.4, 4.9 Hz), 7.06–7.22 (5H, m), 8.18 (2H,
dd, J=1.4, 4.9 Hz). HRFAB-MS calcd for
C28H35F2N4O [M+H]+: 481.2779. Found: 481.2783.
1.88–2.03 (2H, m), 2.03 (3H, s), 2.27–2.63 (12H, m),
3.35 (2H, m), 3.86 (1H, t, J=8.1Hz), 4.34–4.43 (1H,
brs), 5.16 (1H, t, J=7.6 Hz), 6.63(2H, d, J=7.6 Hz),
6.70 (1H, t, J=7.6 Hz), 6.88–7.04 (5H, m), 7.21–7.24
(5H, m). HRFAB-MS calcd for C31H38F2N3O2
[M+H]+: 522.2932. Found: 522.2940.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-methoxy-3-(phenyl-
amino)propyl]piperazine (13). NaH (60% in mineral oil,
1.74 g, 43.5 mmol) was added to a solution of 1 (17.4 g,
36.3 mmol) in DMF (40 mL) and the mixture was stir-
red for 1h at room temperature. A solution of iodo-
methane (5.68 g, 40.0 mmol) in DMF (10 mL) was
added dropwise over a period of 30 min and the mixture
was stirred for 5 h at room temperature. The mixture
was poured into ice water (100 mL) and extracted with
two portions of AcOEt (80 mL). The extracts were
combined, washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica
gel column chromatography (CHCl3/CH3OH=99:1as
an eluent) to give 13 (5.12 g, 29%) as a pale yellow oil.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(3,5-di-tert-butyl-4-
hydroxyphenyl)amino]-2-hydroxypropyl]piperazine (10b).
This compound was prepared according to the proce-
dure described for 10a and used for the next reaction
without further purification.
1
IR(KBr) cmÀ1: 1603, 1508, 1227. H NMR (CDCl3) d
1.37–1.52 (2H, m), 1.87–2.03 (2H, m), 2.32–2.74 (12H,
m), 3.17 (1H, dd, J=5.1, 12.4 Hz), 3.27 (1H, dd, J=5.1,
12.4 Hz), 3.41 (3H, s), 3.49–3.61 (1H, m), 3.86 (1H, t,
J=7.8 Hz), 4.41–4.53 (1H, m), 6.52–6.72 (3H, m), 6.88–
7.03 (4H, m), 7.07–7.22 (6H, m). HRFAB-MS calcd for
C30H38F2N3O [M+H]+: 494.2983. Found: 494.2976.
1-[2-Acetoxy-3-(N-tert-butoxycarbonyl-N-phenylamino)-
propyl]-4-[4,4-bis(4-fluorophenyl)butyl]piperazine (11). A
mixture of 9e (6.60 g, 11.4 mmol) and acetic anhydride
(3.49 g, 34.2 mmol) in pyridine (85 mL) was stirred for
60 h at room temperature. After removal of the solvent,
the residue was dissolved in a mixture of benzene (50
mL) and H2O (50 mL), the organic layer was separated,
and the aqueous layer was extracted with two portions
of benzene. The organic layer and the extracts were
combined, washed with H2O and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (CHCl3/
CH3OH=97:3 as an eluent) to give 11 (6.28 g, 89%) as
a pale yellow oil. IR (KBr) cmÀ1: 1740, 1699, 1508,
1223, 1158. 1H NMR (CDCl3) d 1.37–1.51 (2H, m), 1.52
(9H, s), 1.86 (3H, s), 1.87–2.03 (2H, m), 2.26–2.54 (12H,
m), 3.75 (1H, dd, J=7.8, 14.6 Hz), 3.85 (1H, t, J=7.6
Hz), 4.00 (1H, dd, J=3.0, 14.6 Hz), 5.21–5.33 (1H, m),
6.95 (4H, dt, J=2.2, 6.5 Hz), 7.08–7.22 (6H, m), 7.29–
7.43 (3H, m). FAB-MS m/z 622 [M+H]+.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-fluorophenyl)amino]-
.
2-hydroxypropyl]piperazine trihydrochloride (4a 3HCl). A
solution of 7.0 N HCl in EtOH (2.5 mL) was added
dropwise to a solution of 4a (1.55 g, 3.11 mmol) in
EtOH (10 mL) under ice bath cooling and the mixture
was stirred for 1h at room temperature. The resultant
precipitates were collected by filtration and recrys-
.
tallized from EtOH to give 4a 3HCl (1.58 g, 84%) as
white crystals. Mp 208–211 ꢀC. IR (KBr) cmÀ1: 3377,
1510, 1236, 1226. 1H NMR (DMSO-d6) d 1.47–1.62
(2H, m), 1.97–2.13 (2H, m), 3.15–3.83 (14H, m), 4.03
(1H, t, J=8.1Hz), 4.23–4.32 (1H, m), 6.97–7.24 (8H,
m),
7.28–7.43
.
(4H,
m).
Anal.
calcd
for
C29H34F3N3O 3HCl: C, 57.39; H, 6.14; N, 6.92; Cl,
17.52. Found: C, 57.29; H, 6.12; N, 6.79; Cl, 17.31.
Using this procedure, the following diphenylalkyl
piperazine derivatives (4b, 4c, 4k, and 13) were con-
verted to their trihydrochlorides.
1-[2-Acetoxy-3-(phenylamino)propyl]-4-[4,4-bis(4-fluoro-
phenyl)butyl]piperazine (12). A solution of 4.0 N HCl in
AcOEt (18 mL) was added dropwise to a solution of 11
(7.40 g, 11.9 mol) in AcOEt (36 mL) over a period of 5
min with stirring under ice bath cooling, and then the
mixture was stirred for 7 h at room temperature. The
mixture was poured into a mixture of AcOEt (50 mL)
and saturated aqueous NaHCO3 (50 mL), the organic
layer was separated, and the aqueous layer was extrac-
ted with two portions of AcOEt. The organic layer and
the extracts were combined, washed with brine, dried
over Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(CHCl3/CH3OH=99:1as an eluent) to give 12 (5.66 g,
91%) as a pale yellow oil. IR (KBr) cmÀ1: 1736, 1603,
1508, 1236. 1H NMR (CDCl3) d 1.37–1.51 (2H, m),
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-methoxy-
.
phenyl)amino]propyl]-piperazine trihydrochloride (4b 3HCl)
.
White crystals. Yield 75%. Mp 207–210 ꢀC. IR (KBr)
cmÀ1: 3442, 1606, 1511, 1256, 1226. H NMR (DMSO-
1
d6) d 1.47–1.62 (2H, m), 1.97–2.13 (2H, m), 3.07–3.83
(14H, m), 3.76 (3H, s), 4.02 (1H, t, J=7.3 Hz), 4.32–
4.43 (1H, m), 7.00 (2H, d, J=8.6 Hz), 7.02–7.14 (4H,
m),
7.26–7.43
.
(6H,
.
m).
Anal.
calcd
for
C30H37F2N3O2 3HCl 2H2O: C, 55.01; H, 6.77; N, 6.41;
Cl, 16.24. Found: C, 55.28; H, 6.59; N, 6.43; Cl, 16.27.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-methyl-
.
phenyl)amino]propyl]piperazine trihydrochloride (4c 3HCl)
.
White crystals. Yield 96%. Mp 210–213ꢀC. IR (KBr)

M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
3961
1
cmÀ1: 3420, 1603, 1508, 1227. H NMR (DMSO-d6) d
(4h 3C4H4O4). White crystals. Yield 49%. Mp 163–
164 ꢀC. IR (KBr) cmÀ1: 3442, 1604, 1509, 1217. 1H
NMR (DMSO-d6) d 1.38–1.52 (2H, m), 1.92–2.03 (2H,
m), 2.61–3.12 (14H, m), 3.55 (3H, s), 3.76 (6H, s), 3.94–
4.02 (1H, m), 4.00 (1H, t, J=7.8 Hz), 5.97 (2H, s), 6.15
(6H, s), 7.12 (4H, t, J=8.4 Hz), 7.33 (4H, dd, J=5.9,
.
1.48–1.63 (2H, m), 1.95–2.13 (2H, m), 2.27 (3H, s), 3.18–
3.92 (14H, m), 4.00 (1H, t, J=7.8 Hz), 4.32–4.41(1H, m),
7.07–7.24 (8H, m), 7.32–7.44 (4H, m). Anal. calcd for
C30H37F2N3O 3HCl: C, 59.75; H, 6.69; N, 6.97; Cl, 17.64.
Found: C, 59.57; H, 6.70; N, 6.88; Cl, 17.57.
.
.
8.4 Hz). Anal. calcd for C32H41F2N3O4 3C4H4O4: C,
57.57; H, 5.82; N, 4.58. Found: C, 57.88; H, 5.71; N,
4.50.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylme-
.
thylamino)propyl]piperazine trihydrochloride (4k 3HCl)
.
White crystals. Yield 72%. Mp 235–238 ꢀC. IR (KBr)
cmÀ1: 3498, 1508, 1222. H NMR (DMSO-d6) d 1.57–
1-[3-[(4-Aminophenyl)amino]-2-hydroxypropyl]-4-[4,4-bis
(4-fluorophenyl)butyl]piperazine trimaleate (5 3C4H4O4).
1
.
1.73 (2H, m), 2.09–2.23 (2H, m), 2.85–3.84 (14H, m),
4.10 (1H, t, J=7.8 Hz), 4.26 (2H, s), 4.31–4.43 (1H, m),
7.20 (4H, t, J=8.9 Hz), 7.37–7.61(7H, m), 7.64–7.72
(2H, m). Anal. calcd for C30H37F2N3O 3HCl: C, 59.75;
H, 6.69; N, 6.97; Cl, 17.64. Found: C, 59.59; H, 6.74; N,
6.90; Cl, 17.69.
A dark brown powder. Yield 72%. Mp 153–155 ꢀC. IR
(KBr) cmÀ1: 3451, 1617, 1508, 1231. 1H NMR (DMSO-
d6) d 1.37–1.52 (2H, m), 1.97–2.13 (2H, m), 2.51–3.64
(14H, m), 3.92–4.03 (1H, m), 4.03 (1H, t, J=7.6 Hz),
6.15 (6H, s), 6.69 (2H, d, J=7.8 Hz), 7.03 (2H, d, J=8.4
Hz), 7.16 (4H, t, J=8.4 Hz), 7.32–7.43 (4H, m). Anal.
.
.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-methoxy-3-(phenyl-
.
calcd for C29H36F2N4O 3C4H4O4: C, 58.43; H, 5.74; N,
6.65. Found: C, 58.71; H, 5.71; N, 6.83.
amino)propyl]piperazine trihydrochloride (13 3HCl).
White crystals. Yield 70%. Mp 181–184 ꢀC. IR (KBr)
1
cmÀ1: 1602, 1507, 1159, 1222. H NMR (DMSO-d6) d
1 - [4,4 - Bis(4 - fluorophenyl)butyl] - 4 - [3 - [(4 - hydoxyphenyl)
.
1.58–1.73 (2H, m), 2.06–2.22 (2H, m), 3.17–3.84 (14H,
m), 3.50 (3H, s), 3.97–4.12 (1H, m), 4.10 (1H, t, J=8.1
Hz), 6.57 (1H, t, J=7.3 Hz), 6.74 (2H, d, J=7.3 Hz),
7.08–7.23 (6H, m), 7.41–7.54 (4H,m). Anal. calcd for
C30H37F2N3O 3HCl: C, 59.75; H,6.69; N, 6.97; Cl,
17.64. Found: C, 59.97; H, 6.69; N, 6.97; Cl, 17.82.
amino]-2-hydroxypropyl]piperazine trimaleate (6 3C4H4O4).
Pale yellow crystals. Yield 69%. Mp 160–162 ꢀC. IR
1
(KBr) cmÀ1: 3401, 3223, 1617, 1508, 1222. H NMR
(DMSO-d6) d 1.38–1.51 (2H, m), 1.93–2.11 (2H, m),
2.57–3.04 (13H, m), 3.05 (1H, dd, J=4.9, 12.4 Hz),
3.81–3.93 (1H, m), 4.00 (1H, t, J=8.1Hz), 6.17 (6H, s),
6.60 (4H, s), 7.12 (4H, t, J=8.9 Hz), 7.27–7.43 (4H, m).
Anal. calcd for C29H35F2N3O2 3C4H4O4; C, 58.36; H,
5.61; N, 4.98. Found: C, 58.15; H, 5.58; N, 5.12.
.
.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-chlorophenyl)amino]-
2-hydroxypropyl]piperazine trimaleate (4d 3C4H4O4)
.
.
A
solution of maleic acid (2.50 g, 21.5 mmol) in Et2O (125
mL) was added dropwise to a solution of 4d (3.60 g,
7.00 mmol) in Et2O (65 mL) under ice bath cooling, and
the mixture was stirred for 1h at room temperature.
The resultant precipitates were collected by filtration
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-pyri-
dyl)amino]propyl]piperazine trimaleate (10a 3C4H4O4).
.
A dark brown powder. Yield 70%. Mp 169–170 ꢀC. IR
(KBr) cmÀ1: 3449, 1578, 1509, 1224. 1H NMR (DMSO-
d6) d 1.48–1.57 (2H, m), 2.11–2.23 (2H, m), 2.82–3.24
(12H, m), 3.34 (1H, dd, J=6.2, 13.2 Hz), 3.47 (1H, dd,
J=5.9, 13.2 Hz), 3.92–4.03 (1H, m), 4.09 (1H, t, J=7.8
Hz), 6.19 (6H, s), 7.00 (2H, d, J=7.3 Hz), 7.19 (4H, t,
J=8.9 Hz), 7.38-7.52 (4H, m), 8.11–8.32 (1H, m), 8.62
.
and recrystallized from EtOH to give 4 3C4H4O4 (4.16 g,
69%) as white crystals. Mp 170–173 ꢀC. IR (KBr) cmÀ1
:
3438, 1602, 1578, 1508, 1223. 1H NMR (DMSO-d6) d
1.37–1.52 (2H, m), 1.98–2.13 (2H, m), 2.61–3.34 (14H, m),
3.87–4.03 (1H, m), 4.06 (1H, t, J=8.1Hz), 6.23 (6H, s),
6.65 (2H, dd, J=1.9, 6.8 Hz), 7.06–7.23 (6H, m), 7.37–
.
(1H, t, J=5.9 Hz). Anal. calcd for C28H34F2N4O 3
C4H4O4: C, 57.97; H, 5.59; N, 6.76. Found: C, 57.94; H,
5.57; N, 6.75.
.
7.53 (4H, m). Anal. calcd for C29H34ClF2N3O 3C4H4O4:
C, 57.11; H, 5.38; N, 4.87; Cl, 4.11. Found: C, 57.28; H,
5.34; N, 4.83; Cl, 4.09.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(3,5-di-tert-butyl-4-
tri-
maleate (10b 3C4H4O4). White crystals. Yield 27%. Mp
Using this procedure, the following diphenylalkyl
piperazine derivatives (4f, 4h, 5, 6, 10a, and 10b) were
converted to their trimaleates.
hydroxyphenyl)amino]-2-hydroxypropyl]piperazine
.
ꢀ
1
179–180 C. IR (KBr) cmÀ1: 3448, 1619, 1509, 1223. H
NMR (DMSO-d6) d 1.38–1.51 (2H, m), 1.40 (18H, s),
1.92–2.03 (2H, m), 2.57–3.82 (14H, m), 3.83–3.95 (1H,
m), 4.00 (1H, t, J=8.4 Hz), 6.17 (6H, s), 6.52 (2H, s),
7.12 (4H, t, J=8.9 Hz), 7.32–7.43 (4H, m). Anal. calcd
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(4-dimethylaminophenyl)
.
amino]-2-hydroxypropyl]piperazine trimaleate (4f 3C4H4O4)
.
A brown powder. Yield 70%. Mp 170–173 ꢀC. IR
(KBr) cmÀ1: 3427, 1608, 1503, 1224. 1H NMR (DMSO-
d6) d 1.37–1.52 (2H, m), 1.92–2.03 (2H, m), 2.50 (6H, s),
2.52–3.54 (14H, m), 3.92–4.01 (1H, m), 3.99 (1H, t,
J=7.3 Hz), 6.14 (6H, s), 6.72–6.81 (2H, m), 6.98–7.11
(2H, m), 7.12 (4H, t, J=8.4 Hz), 7.27–7.43 (4H, m).
.
for C37H51F2N3O2 3C4H4O4: C, 61.56; H, 6.64; N, 4.40.
Found: C, 61.72; H, 6.43; N, 4.28.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(4-nitrophe-
.
nyl)amino]propyl]piperazine dihydrochloride (4e 2HCl). A
.
Anal. calcd for C31H40F2N4O 3C4H4O4: C, 59.30; H,
6.02; N, 6.43. Found: C, 59.02; H, 6.01; N, 6.39.
solution of 7.0 N HCl in EtOH (1.2 mL) was added
dropwise to a solution of 4e (0.52 g, 0.991mmol) in
EtOH (10 mL) under ice bath cooling and the mixture
was stirred for 1h at room temperature. The resultant
precipitates were collected by filtration and recrystallized
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-[(3,4,5-
trimethoxyphenyl)amino]propyl]piperazine
trimaleate

3962
M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
.
from EtOH to give 4e 2HCl (0.44 g, 70%) as yellow
1223. 1H NMR (DMSO-d6) d 1.38–1.54 (2H, m),
2.02–2.14 (2H, m), 2.42–3.15 (12H, m), 2.99 (3H, s),
3.61–3.72 (3H, m), 3.99 (1H, t, J=7.8 Hz), 6.14 (4H,
s), 7.09 (4H, t, J=7.8 Hz), 7.32–7.46 (5H, m), 7.48–
7.54 (4H, m). Anal. calcd for C30H37F2N3O3S 2C4H4O4:
C, 57.79; H, 5.74; N, 5.32. Found: C, 57.62; H, 5.80; N,
5.24.
crystals. Mp 145–148 ꢀC. IR (KBr) cmÀ1: 3387, 1605,
1508, 1229. H NMR (DMSO-d6) d 1.57–1.72 (2H, m),
2.13–2.24 (2H, m), 3.16–3.92 (14H, m), 4.10 (1H, t,
J=7.8 Hz), 4.32–4.44 (1H, m), 6.82 (2H, d, J=9.5 Hz),
7.20 (4H, t, J=9.5 Hz), 7.42–7.53 (4H, m), 8.07 (2H, d,
J=9.5 Hz). Anal. calcd for C29H34F2N4O3 2HCl 2H2O:
C, 54.98; H, 6.36; N, 8.84; Cl, 11.19. Found: C, 55.21;
H, 6.24; N, 8.89; Cl, 11.20.
1
.
.
.
1-[2-Acetoxy-3-(phenylamino)propyl]-4-[4,4-bis(4-fluoro-
.
phenyl)butyl]piperazine dimaleate (12 2C4H4O4). White
Using this procedure, the following diphenylalkyl
piperazine derivatives (4g and 9a) were converted to
their dihydrochlorides.
crystals. Yield 58%. Mp 159–160 ꢀC. IR (KBr) cmÀ1
:
1736, 1605, 1225. 1H NMR (DMSO-d6) d 1.62–1.74
(2H, m), 2.19 (3H, s), 2.82–3.64 (16H, m), 4.14 (1H, t,
J=8.1 Hz), 5.15 (1H, t, J=5.4 Hz), 6.31(4H, s), 6.67
(1H, t, J=7.3 Hz), 6.75 (4H, d, J=7.3 Hz), 7.22–7.44
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(3,4-dichlorophen-
yl)amino] - 2 - hydroxypropyl]piperazine dihydrochloride
.
(8H, m). Anal. calcd for C31H37F2N3O2 2C4H4O4: C,
62.14; H, 6.02; N, 5.57. Found: C, 62.02; H,6.02; N, 5.48.
ꢀ
.
(4g 2HCl). White crystals. Yield 53%. Mp 148–150 C.
1
IR (KBr) cmÀ1: 3452, 1604, 1509, 1217, 707. H NMR
(DMSO-d6) d 1.52–1.63 (2H, m), 2.11–2.23 (2H, m),
3.24–4.07 (14H, m), 4.10 (1H, t, J=7.8 Hz), 4.23–4.34
(1H, m), 6.71 (1H, dd, J=2.7, 8.9 Hz), 6.92 (1H, d,
J=2.4 Hz), 7.20 (4H, t, J=8.9 Hz), 7.34 (1H, d, J=8.9
Hz), 7.38–7.52 (4H, m). Anal. calcd for
[3H]GBR12935 binding studies
Binding assays for the DAT were determined according
to the published procedure.17 Briefly, the rat striatal
membranes were incubated with [3H]GBR12935 (1 nM
final concentration) and test compounds (final concen-
tration range: 10À11–10À5 M), which were diluted with
dimethyl sulfoxide solution (final dimethyl sulfoxide
concentration was less than 0.1%), for 60 min at 4 ꢀC in
50 mM Tris–citrate (pH 7.4) buffer containing 120 mM
NaCl and 4 mM MgCl2. [3H]GBR12935 (53 Ci/mmol)
was purchased from Du Pont-NEN (Boston, MA,
USA). The assay was terminated by filtration through
Whatman GB/F glass fiber filtermats, persoaked with
0.1% bovine serum albumin solution, with a Brandel
Cell Harvester (Gaithersberg, MD, USA). Filters were
assayed for radioactivity with Packard Tris-Carb Liquid
Scintillation Counter (Meriden, CT, USA) in 4 mL
Aquasol-2.
.
C29H33Cl2F2N3O 2HCl: C, 56.05; H, 5.68; N, 6.76; Cl,
22.82. Found: C, 56.32; H, 5.67; N, 6.54; Cl, 22.76.
1-[3-(N-Acetyl-N-phenylamino)-2-hydroxypropyl]-4-[4,4-
-
bis(4
fluorophenyl)butyl]piperazine dihydrochloride
ꢀ
.
(9a 2HCl). White crystals. Yield 66%. Mp 210–212 C.
IR (KBr) cmÀ1: 3420, 1652, 1595, 1225. 1H NMR
(DMSO-d6) d 1.58–1.73 (2H, m), 1.81 (3H, s), 2.21–2.35
(2H, m), 3.14–3.96 (14H, m), 4.01–4.13 (1H, m), 4.10
(1H, t, J=8.1Hz), 7.22–7.34 (4H, m), 7.36–7.54 (5H,
m),
7.55–7.64
.
(4H,
.
m).
Anal.
calcd
for
C31H37F2N3O2 2HCl 2H2O: C, 59.05; H, 6.87; N, 6.66;
Cl, 11.24. Found: C, 58.96; H, 6.82; N, 6.62; Cl, 11.32.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-methyl-N-
.
phenylamino)propyl]piperazine dimaleate (4j 2C4H4O4). A
solution of maleic acid (3.23 g, 27.8 mmol) in Et2O (60
mL) was added dropwise to a solution of 4j (3.45 g, 6.99
mmol) in Et2O (65 mL) under ice bath cooling, and the
mixture was stirred for 1h at room temperature. The
resultant precipitates were collected by filtration and
References andNotes
1. Kuhar, M. J. Life Sci. 1973, 13, 1623.
2. Bernheimer, H.; Birkmayer, W.; Hornykiewicz, O.; Jellin-
ger, K.; Seitelberger, F. J. Neurol. Sci. 1973, 20, 415.
3. Brown, A. S.; Gershon, S. J. Neural. Transm. Gen. Sect.
1993, 91, 75.
4. Ritz, M. C.; Lamb, R. J.; Goldberg, S. R.; Kuhar, M. J.
Science 1987, 237, 1219.
5. Milius, R. A.; Saha, J. K.; Madras, B. K.; Neumeyer, J. L.
J. Med. Chem. 1991, 34, 1728.
6. Van der Zee, P.; Koger, H. S.; Goojtes, J.; Hespe, W. Eur.
J. Med. Chem. 1980, 15, 363.
.
recrystallized from EtOH to give 4j 2C4H4O4 (5.02 g,
:
99%) as white crystals. Mp 180–182 ꢀC. IR (KBr) cmÀ1
1
3399, 1601, 1578, 1508, 1225. H NMR (DMSO-d6) d
1.38–1.53 (2H, m), 2.14–2.23 (2H, m), 2.71–3.23 (12H,
m), 3.00 (3H, s), 3.28 (1H, dd, J=7.3, 14.9 Hz), 3.45
(1H, dd, J=4.9, 14.9 Hz), 4.06 (2H, t, J=7.8 Hz), 6.21
(4H, s), 6.67 (1H, t, J=7.3 Hz), 6.77 (2H, m), 7.12–7.33
(6H, m), 7.38–7.53 (4H, m). Anal. calcd for
7. Nomoto, M. Jpn. J. Psychopharmacol. 1996, 16, 113.
8. Carroll, F. I.; Howell, L. L.; Kuhar, M. J. J. Med. Chem.
1999, 42, 2721.
.
C30H37F2N3O 2C4H4O4: C, 62.89; H, 6.25; N, 5.79.
Found: C, 62.77; H, 6.19; N, 5.69.
9. Kimura, M.; Masuda, T.; Yamada, K.; Mitani, M.;
Kubota, N.; Kawakatsu, N.; Kishii, K.; Inazu, M.; Kiuchi, Y.;
Oguchi, K.; Namiki, T. Bioorg. Med. Chem. 2003, 11, 1621.
10. Bogeso, K. P. J. Med. Chem. 1983, 26, 935.
11. Dutta, A. K.; Xu, C.; Reith, M. E. A. J. Med. Chem. 1996,
39, 749.
12. Matecka, D.; Rothman, R. B.; Radesca, L.; de Costa,
B. R.; Dersch, C. M.; Partilla, J. S.; Pert, A.; Glowa, J. R.;
Wojnicki, F. H. E.; Rice, K. C. J. Med. Chem. 1996, 39, 4704.
13. Matecka, D.; Lewis, D.; Rothman, R. B.; Dersch, C. M.;
Using this procedure, the following diphenylalkyl
piperazine derivatives (9b and 12) were converted to
their dimaleates.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(N-me-
thanesulfonyl - N - phenylamino)propyl]piperazine dimale-
.
ate (9b 2C4H4O4). White crystals. Yield 66%.
Mp.195–198 ꢀC. IR (KBr) cmÀ1: 3424, 1602, 1334,

M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 3953–3963
3963
Wojnicki, F. H. M.; Glowa, J. R.; DeVries, A. C.; Pert, A.;
Rice, K. C. J. Med. Chem. 1997, 40, 705.
14. Dutta, A. K.; Xu, C.; Reith, M. E. A. J. Med. Chem. 1998,
41, 3293.
15. Dutta, A. K.; Coffey, L. L.; Reith, M. E. A. J. Med.
Chem. 1998, 41, 699.
16. Husbands, S. M.; Izenwasser, S.; Kopajtic, T.; Bowen,
W. D.; Vilner, B. J.; Katz, J. L.; Newman, A. H. J. Med.
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