Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfonamides as selective 5-HT2A receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2009.12.067

A novel series of 5-HT_2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)b

Full text of DOI:10.1016/j.bmc.2009.12.067

Bioorganic & Medicinal Chemistry 18 (2010) 1665–1675
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of (phenylpiperazinyl-propyl)arylsulfon-
amides as selective 5-HT2A receptor antagonists
Euna Yoo a, Juhee Yoon a, Ae Nim Pae b, Hyewhon Rhim b, Woo-Kyu Park c, Jae Yang Kong c,
Hea-Young Park Choo a,
*
a College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
b Biochemicals Research Center, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea
c Pharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 5-HT2A ligands that contain a (phenylpiperazinyl-propyl)arylsulfonamides skeleton
was synthesized. Thirty-seven N-(cycloalkylmethyl)-4-methoxy-N-(3-(4-arylpiperazin-1-yl)propyl)-
arylsulfonamide and N-(4-(4-arylpiperazin-1-yl)butan-2-yl)-arylsulfonamide compounds were obtai-
ned. The binding of these compounds to the 5-HT2A, 5-HT2C, and 5-HT7 receptors was evaluated. Most
of the compounds showed IC50 values of less than 100 nM and exhibited high selectivity for the
5-HT2A receptor. Among the synthesized compounds, 16a and 16d showed good affinity at 5-HT2A
(IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–100 times) and 5-HT7 (1500–3000
times).
Received 12 October 2009
Revised 22 December 2009
Accepted 30 December 2009
Available online 4 January 2010
Keywords:
5-HT2A receptor antagonists
Piperazine
Ó 2010 Elsevier Ltd. All rights reserved.
Sulfonamide
1. Introduction
structurally diverse antagonists of this receptor have been pub-
lished (Fig. 1).5
Serotonin (5-hydroxytryptamine, 5-HT) has been recognized as
an effector in various types of smooth muscle, as an agent that en-
hances platelet aggregation and a neurotransmitter in the central
nervous system (CNS). As a major modulatory transmitter in the
brain, 5-HT is involved in the control of numerous behavioral
and physiological processes. Perceptive operational studies have
revealed that 5-HT elicits these responses through at least 14 sub-
types of 5-HT receptors.1–3
Today, there is evidence that 5-HT2 receptors might be involved
in schizophrenia, depression, anxiety, appetite control, and cardio-
vascular function. The three 5-HT2 receptor family subtypes, 5-
HT2A, 5-HT2B, and 5-HT2C, are G-protein coupled receptors (GPCRs)
that couple to the Gq and G11 proteins eliciting their second mes-
senger effects through increases in the activity of phospholipase
C (diacylglycerol pathway) and/or phospholipase A (arachidonic
acid pathway). These subtypes share an overall amino acid homol-
ogy of approximately 50%. 5-HT2A receptors are broadly distributed
in the prefrontal, parietal, and somatosensory cortex, claustrum
and platelets. The 5-HT2A receptor has been implicated as a thera-
peutic target for schizophrenia and depression.4 5-HT2 receptors
were first identified in 1979 and since the early 1980s, numerous,
Classification of 5-HT2A ligands is difficult because they ap-
pear to belong to so many different chemical classes. The 2-
aryltryptamine 1, for example, is a new antagonist member of
the indolealkylamine class. Eplivanserin (2), a phenylalkylamine
is a highly selective 5-HT2A antagonist that has been shown to
improve sleep maintenance, by reducing wake after sleep onset,
decreasing the number of awakenings, increasing the total sleep
time, and improving the quality of sleep. MDL-100907 (3)
which is one of the more highly studied selective 5-HT2A antag-
onists is an arylpiperidine,6,7 and fananserin (4) is a newer aryl-
piperazine antagonist.8 Piperazine amides and sulfonamides,
such as EMD-281014 (5)9 and 6, show high affinity as 5-HT2A
antagonists.10–12
Several pharmacophore models for 5-HT2A receptors have
been proposed based on the structure–activity relationships of
known antagonists. Typically, the essential geometric character-
istics are described by the distances between two aromatic
rings (4.6–7.3 Å) and the distances between each aromatic ring
and the basic amine nitrogen (5.2–8.4 Å and 5.7–8.5 Å). The re-
ported pharmacophoric hypothesis suggested the minimal
structural requirements for 5-HT2A antagonism consisted of
two aryl rings and a basic nitrogen.13 Based on our previous
work,14 we designed arylsulfonamide derivatives 11–24 and 28
to possess the arylpiperazine moieties as well as a three carbon
spacer.
* Corresponding author. Fax: +82 2 3277 2821.
E-mail address: hypark@ewha.ac.kr (H.-Y. Park Choo).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.12.067

1666
E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
N
F
O
N
N
HO
N
H
2
, Eplivanserin
1
F
OCH3O
O
O
N
S
N
N
N
H3CO
4, Fananserin
3, MDL-100907
F
O
O
H
S
N
N
O
N
N
F
F
N
F
NC
F
F
6
5
, EMD-281014
Figure 1. 5-HT2A antagonists.
uents such as 1-naphtyl, 2-naphtyl, 8-quinolinyl, 4-OCH3 phenyl, 4-
CF3 phenyl, 4-F phenyl, and 4-NO2 phenyl group were prepared and
the structures of the synthesized compounds are given in Tables 1
and 2.
2. Results
2.1. Chemistry
The sulfonamide derivatives which have a methyl group at the
C-3 position of the three carbon spacer were synthesized using 1,3-
butanediol as a space unit (Scheme 2). Mono-tosylation of 1,3-
butanediol to 1-tosyl-3-hydroxy-butane followed by reaction with
substituted arylpiperazine gave 4-(4-(R-phenyl)piperazin-1-yl)bu-
tan-2-ol 26a–d. Further tosylation of the hydroxyl group of 26a–d
and substitution of the tosyl group with 2-naphthylsulfonamide
was achieved to yield the desired compounds 28a–d (Table 3).
The synthetic procedures used to prepare arylsulfonamides 11–
24 are illustrated in Scheme 1.
Substituted arylpiperazine was reacted with N-(3-bromopro-
pyl)phthalimide and triethylamine to give 2-(3-(4-(R1-phenyl)pip-
erazin-1-yl)propyl)isoindoline-1,3-dione 7a–d. Hydrazine mono-
hydrate was used to cleave N-alkylated phthalimide and 3-(4-(R1-
phenyl)piperazin-1-yl)propan-1-amine was produced. Then cyclo-
hexyl/cyclopropylcarboxaldehyde were used to introduce a cyclo-
alkyl group on the nitrogen of sulfonamide. Reductive amination
took place between 3-(4-(R1-phenyl)piperazin-1-yl)propan-1-
amine 8a–d and two kinds of aldehyde in the presence of sodium tri-
acetoxyborohydrideasareducingagent. Lastly, N-(R2-methyl)-3-(4-
(R1-phenyl)piperazin-1-yl)propan-1-amine 9a–d and 10a–d were
converted to the desired sulfonamide derivatives 11–24 by nucleo-
philic displacement. Thirty-three compounds with different substit-
2.2. Biological evaluation
All the synthesized compounds were evaluated in vitro against
the human recombinant 5-HT2A serotonin receptor in stable CHO
cell line. [3H]Ketanserin binding assay results are shown in Tables
1–3. Most compounds showed good binding affinity to the 5-HT2A
O
R1
R1
N
Br
O
N
N
HN
N
O
R1
N
N
H2N
N
a
b
8
O
7
R1
O
S
R1
O
c
R2
Ar
Cl
N
R2
O
R2
H
N
Ar
N
N
S
HN
N
O
d
O
11-17; R2= cyclohexyl
18-24; R2= cyclopropyl
9; R2= cyclohexyl
10; R2= cyclopropyl
Scheme 1. Reagents and conditions: (a) TEA, CH3CN, reflux, overnight; (b) NH2NH2ÁH2O, EtOH, reflux, 5 h; (c) Na(OCOCH3)3BH, CH2Cl2, rt, overnight; (d) NaH, DMF, 100 °C,
overnight.

E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
1667
Table 1
3. Discussion
Structure and IC50 values of the cyclohexylmethyl derivatives 11–17
R1
It is well known that arylpiperazine-containing compounds can
bind to at least three populations of neurotransmitter receptors
(serotonergic, dopaminergic, and adrenergic). Therefore, the devel-
opment of compounds that have good affinity and selectivity for
the 5-HT2A receptor as therapeutic agents and chemical tools is
important. The structural diversity of 5-HT2A ligands presents a
challenge in terms of defining a pharmacophore model. However,
as mentioned above, the pharmacophore models that have been
proposed agree that two aryl rings and a basic nitrogen are re-
quired for binding at the receptor.15 Therefore, on the basis of these
pharmacophore models, we synthesized and evaluated (phenyl-
piperazinyl-propyl)arylsulfonamides. In order to obtain com-
pounds that have good affinity and selectivity for 5-HT2A
receptor antagonism, we modified three parts of structure that
are the cycloalkyl group, the phenylpiperazine group, and the aryl-
sulfonamide group.
First of all, we explored the influence of different substituents at
the first position, cyclohexylmethyl and cyclopropylmethyl group
on the nitrogen of sulfonamide for 5-HT2A receptor affinity. As a re-
sult, cyclohexylmethyl derivatives 11–17 showed increased affin-
ity on the 5-HT2A receptor with IC50 values ranging from 0.5 to
59.9 nM. Compared to our previous work, the introduction of
cyclohexylmethyl group on the nitrogen of sulfonamide enhanced
the 5-HT2A receptor affinity. Compound 15d (IC50 = 3.4 nM) exhib-
ited better affinity than the previously reported compound
4-methoxy-N-{3-[4-(p-fluorophenyl)-piperazin-1-yl]-propyl}-ben-
zene sulfonamide on the 5-HT2A receptor (IC50 = 74 nM).14 Also,
when compared with cyclopropylmethyl derivatives, cyclohexylm-
ethyl derivatives proved to have increased affinity against 5-HT2A
receptor with higher selectivity over 5-HT7 receptor. Cyclopro-
pylmethyl derivatives showed higher affinity than cyclohexylm-
ethyl derivatives against 5-HT7 receptor. Therefore, we could say
that cyclohexylmethyl derivatives are more selective for the
5-HT2A receptor. In the case of compound 16d, this compound
showed 3000 times higher affinity against 5-HT2A over 5-HT7
receptor. Among the synthesized compounds, 16a and 16d exhib-
ited high 5-HT2A receptor affinity (IC50 = 0.7 nM and 0.5 nM,
respectively) and good selectivity over 5-HT2C (IC50 = 65 nM and
24 nM, respectively) and 5-HT7 (IC50 = 1236 nM and 1508 nM,
respectively).
In subsequent experiments, we performed modification of the
phenylpiperazine group by introduction of different substituted
phenylpiperazines such as 2-OCH3 phenylpiperazine (b), 3-CF3
phenylpiperazine (c), and 4-F phenylpiperazine (d) to determine
the optimal substituent on the piperazine. Compounds that had
1-phenylpiperazine (a) without any substituent demonstrated
modest affinity. The introduction of 4-F phenyl group on the piper-
azine improved binding affinity to the 5-HT2A receptor, with the
exception of 23d (23a >23d) as shown in compounds 15d
(IC50 = 3.4 nM), 16d (IC50 = 0.5 nM), 17d (IC50 = 5.1 nM), 22d
(IC50 = 72.5 nM), 24d (IC50 = 3.4 nM), and 28d (IC50 = 8.3 nM). The
results led us to conclude that, among the phenylpiperazine deriv-
atives, the compounds with a 4-F substituent were superior to oth-
ers (R1 = 2-OCH3 and 3-CF3) in terms of 5-HT2A receptor affinity
and selectivity over 5-HT2C and 5-HT7 receptor. In contrast, some
2-OCH3 phenylpiperazine compounds showed good affinity
against 5-HT7 receptor (17b, 22b, and 24b). Concerning the substi-
tution on the piperazine, our results are in accordance with the
structure of other 5-HT2A active agents as shown in Figure 1.
When seven substituents (1-naphtyl, 2-naphtyl, 8-quinolinyl, 4-
OCH3 phenyl, 4-CF3 phenyl, 4-F phenyl, and 4-NO2 phenyl) on the
sulfonyl group were compared by keeping the phenylpiperazine
unsubstituted (R1 = H) and by keeping the cycloalkyl group on
N
Ar
N
N
S
O
O
11-17
Compound
R1
Ar
Binding affinity, IC50 (nM)
5-HT2A
5-HT2C
5-HT7
11
12
13
14
H
H
H
H
H
1-Naphtyl
2.6
7.1
13.2
4.2
50.7
156.2
293.6
45.7
79
195
456
110
87
4-CF3 Phenyl
4-F Phenyl
4-NO2 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
2-Naphtyl
15a
15b
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
17e
9.4
567
172
678
980
1236
500
888
1508
419
24
2-OCH3
3-CF3
4-F
16.3
19.5
3.4
200
33
40
65
70
66
H
0.7
2-OCH3
3-CF3
4-F
2-Naphtyl
2-Naphtyl
2-Naphtyl
11.6
13.1
0.5
34.6
59.9
29.1
5.1
24
H
8-Quinolinyl
8-Quinolinyl
8-Quinolinyl
8-Quinolinyl
8-Quinolinyl
842.7
117.9
38.8
135.8
66.5
2-OCH3
3-CF3
4-F
160
442
2296
3,4-Cl2
7.7
Table 2
Structure and IC50 values of the cyclopropylmethyl derivatives 18–24
R1
N
Ar
N
N
S
O
O
18-24
Compound
R1
Ar
Binding affinity, IC50 (nM)
5-HT2A
5-HT2C
5-HT7
18
19
20
21
H
H
H
H
H
1-Naphtyl
171
70.8
142
180
136
2210
726
72.5
35.9
85.8
221
51
1459
565
1981
1943
691
1976
1034
723
152
334
147
500
121
316
124
93
117
188
342
49.6
749
12.3
6.3
4-CF3 Phenyl
4-F Phenyl
4-NO2 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
4-OCH3 Phenyl
2-Naphtyl
22a
22b
22c
22d
23a
23b
23c
23d
24a
24b
24c
24d
2-OCH3
3-CF3
4-F
H
479
549
304
343
2-OCH3
3-CF3
4-F
2-Naphtyl
2-Naphtyl
2-Naphtyl
H
8-Quinolinyl
8-Quinolinyl
8-Quinolinyl
8-Quinolinyl
292
561
75
2159
8312
694
2-OCH3
3-CF3
4-F
8.3
4755
35.3
receptor with IC50 values less than 100 nM. The synthesized 5-HT2A
antagonists showed different affinities to the 5-HT2A receptor
depending on the substitution on the nitrogen of sulfonamide,
the piperazine, or the sulfonyl group. The most active compound
(16d) had an IC50 value of 0.5 nM, which has 4-F phenyl substitu-
tion on the piperazine and 2-naphtyl substitution on the sulfonyl
group of the cyclohexylmethyl containing compound. The synthe-
sized compounds were further evaluated for their selectivity on the
5-HT2A over the 5-HT2C and 5-HT7 receptor (Tables 1–3).

1668
E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
R
R
HN
N
N
HO
N
HO
OTs
HO
OH
a
25
b
26
O
R
R
Ar
S
NH2
O
N
N
H
Ar
O
N
N
c
TsO
N
S
d
O
27
28
Scheme 2. Reagents and conditions: (a) p-TsCl, pyridine, À20 °C, 30 min?À25 °C, 1 h; (b) CH3CN, reflux, 16 h; (c) p-TsCl, pyridine, rt, 16 h; (d) NaH, DMF, 100 °C, overnight.
values in the nanomolar range. Among the synthesized com-
pounds, 16a and 16d showed good affinity against 5-HT2A
(IC50 = 0.7 nM and 0.5 nM) and good selectivity over 5-HT2C (50–
100 times) and 5-HT7 (1500–3000 times).
Table 3
Structure and IC50 values of the sulfonamide derivatives 28a–d
R
5. Experimental
N
H
Ar
N
N
5.1. Materials and methods
S
O
O
All melting points of the synthesized compounds were taken
in Pyrex capillaries using electrothermal digital melting point
apparatus (Buchi) and were not corrected. 1H NMR and 13C
NMR spectra were recorded on Varian FT-NMR 400 (or 300)
and Bruker Advance 400 spectrometer. Mass spectral data were
obtained on a Jeol JMS 700 high resolution mass spectrometer
at the Korea Basic Science Institute (Daegu). Most of the reagents
were purchased from Aldrich Chemical Company and Merck
Company.
28
Compound
R
Ar
Binding affinity, IC50 (nM)
5-HT2A
5-HT2C
5-HT7
28a
28b
28c
28d
H
2-Naphtyl
2-Naphtyl
2-Naphtyl
2-Naphtyl
12.7
664
180
6.2
200
539
942
90
657
316
363
526
2-Methoxy
3-Trifluoromethyl
4-Fluoro
the nitrogen of sulfonamide fixed (R2 = cyclohexyl or cyclopropyl),
the 2-naphthylsulfonamides generally exhibited increased affinity
(16a; IC50 = 0.7 nM and 23a; IC50 = 35.9 nM) than other derivatives.
A study was conducted regarding the impact of the methyl
group at the C-3 position of the three carbon spacer between the
5.2. Procedures for the preparation of N-(R2-methyl)-4-
methoxy-N-(3-(4-(R1-phenyl) piperazin-1-yl)propyl)-Ar-
sulfonamides
arylpiperazine and the arylsulfonamide group on 5-HT2A, 5-HT2c
,
5.2.1. General procedure for the preparation of 2-(3-(4-(R1-
phenyl)piperazin-1-yl)propyl)isoindoline-1,3-dione (7a–d)
To a solution of N-(3-bromopropyl)phthalimide (1.86 mmol,
1 equiv) in dry acetonitrile (30 mL) were added R1-phenylpiper-
azine (1.86 mmol, 1 equiv) and triethylamine (3.72 mmol, 2 equiv)
and the mixture was refluxed for 16 h. After cooling to room tem-
perature, the mixture was quenched with water and extracted
with methylene chloride (3 Â 20 mL). The organic layer was
washed with brine, dried over Na2SO4, and the solvent was re-
moved in vacuo.
and 5-HT7 receptor affinity. Four naphthalene-2-sulfonamide
derivatives that had a methyl group at the C-3 position of the three
carbon spacer (28a–d) were synthesized and showed good affinity
to the 5-HT2A receptor (Table 3). Among them, 28d which have 4-F
phenylpiperazine group exhibited the best 5-HT2A receptor binding
affinity. These compounds also presented good selectivity. Against
the 5-HT2A receptor, 28a showed 16 and 50 times higher affinity
than against the 5-HT2c and the 5-HT7 receptor, respectively
(IC50 = 12.7 nM, 200 nM, and 657 nM, respectively), and 28d
showed 15 and 85 times higher affinity than against the 5-HT2c
and 5-HT7 receptor, respectively (IC50 = 6.2 nM, 90 nM, and
526 nM, respectively).
5.2.1.1. 2-(3-(4-Phenylpiperazin-1-yl)propyl)isoindoline-1,3-di-
one (7a). Light brown solid (83%), mp 126–127 °C: 1H NMR
(CDCl3, 400 MHz) d 7.84 (dd, J = 2.8 Hz, 2H), 7.69 (dd, J = 3.2 Hz,
2H), 7.23 (t, J = 8.4 Hz, 3H), 6.84 (dd, J = 7.6 Hz, 2H), 3.80 (t,
J = 6.8 Hz, 2H), 3.05 (t, J = 4.8 Hz, 4H), 2.55 (t, J = 4.8 Hz, 4H), 2.84
(t, J = 6.8 Hz, 2H), 1.95–1.88 (m, 2H).
4. Conclusion
Thirty-seven arylsulfonamides linked with a spacer to phenyl-
piperazine were synthesized and evaluated as 5-HT2A antagonists.
The synthesized compounds showed different affinity depending
on the substitution on the nitrogen of sulfonamide, the piperazine,
and the sulfonyl group. Compounds with a cyclohexylmethyl
group on the nitrogen of sulfonamide showed better affinity and
selectivity against 5-HT2A receptor than compounds with a cyclo-
propylmethyl group. And compounds with 4-F phenylpiperazine
and naphthalene-2-sulfonamide exhibited good affinity with IC50
5.2.1.2. 2-(3-(4-(2-(Methoxyphenyl)piperazin-1-yl)propyl)isoin-
doline-1,3-dione (7b). White solid (90%), mp 98 °C: 1H NMR
(CDCl3, 400 MHz) d 7.84 (dd, J = 3.2 Hz, 2H), 7.70 (dd, J = 3.2 Hz,
2H), 6.97 (t, J = 6.8 Hz, 1H), 6.89 (t, J = 6.8 Hz, 1H), 6.83 (t,
J = 6.8 Hz, 2H), 3.84 (s, 3H), 3.80 (t, J = 6.8 Hz, 2H), 2.92 (s, 4H),
2.58 (s, 4H), 2.49 (t, J = 6.8 Hz, 2H), 1.93–1.89 (m, 2H).

E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
1669
5.2.1.3. 2-(3-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)pro-
pyl)isoindoline-1,3-dione (7c). Yellow oil (85%): 1H NMR (CDCl3,
400 MHz) d 7.84 (dd, J = 2.8 Hz, 2H), 7.69 (dd, J = 3.2 Hz, 2H), 7.31
(t, J = 8.0 Hz, 1H), 7.06–7.02 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 3.80
(t, J = 6.8 Hz, 2H), 3.06 (t, J = 5.2 Hz, 4H), 2.54 (t, J = 5.2 Hz, 4H),
2.48 (t, J = 6.8 Hz, 2H), 1.92–1.89 (m, 2H).
1.73–1.64 (m, 4H), 1.31–1.20 (m, 2H), 1.14 (t, J = 12.0 Hz, 1H),
0.99 (q, J = 11.6 Hz, 2H).
5.2.3.2. N-(Cyclohexylmethyl)-3-(4-(2-methoxyphenyl)pipera-
zin-1-yl)propan-1-amine (9b). White solid (44%), mp 144–
146 °C: 1H NMR (CDCl3, 400 MHz) d 10.19 (br s, 1H), 7.05–7.00
(m, 1H), 6.93–6.90 (m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H),
3.13 (t, J = 5.2 Hz, 6H), 2.87 (s, 4H), 2.73 (dd, J = 10.0 Hz, 4H),
2.15–2.13 (m, 2H), 1.19 (d, J = 8.8 Hz, 3H), 1.76–1.67 (m, 4H),
1.31–1.24 (m, 2H), 1.03–0.99 (m, 2H).
5.2.1.4. 2-(3-(4-(4-Fluorophenyl)piperazin-1-yl)propyl)isoindo-
line-1,3-dione (7d). Pale yellow solid (80%), mp 93–94 °C: 1H
NMR (CDCl3, 400 MHz) d 7.84 (dd, J = 2.8 Hz, 2H), 7.69 (dd,
J = 3.2 Hz, 2H), 6.93 (t, J = 8.0 Hz, 2H), 6.80 (dd, J = 4.4 Hz, 2H),
3.80 (t, J = 6.8 Hz, 2H), 2.96 (s, 4H), 2.55 (s, 4H), 2.49 (t, J = 6.8 Hz,
2H), 1.93–1.90 (m, 2H).
5.2.3.3. N-(Cyclohexylmethyl)-3-(4-(3-(trifluoromethyl)phenyl)pip-
erazin-1-yl)propan-1-amine (9c). White solid (31%), mp 146–147 °C:
1H NMR (CDCl3, 400 MHz) d 10.16 (br s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.12
(d, J = 4.0 Hz, 2H), 7.06 (d, J = 4.0 Hz, 1H), 3.26 (t, J = 4.8 Hz, 4H), 3.14 (t,
J = 4.2 Hz, 2H), 2.83 (s, 4H), 2.75 (d, J = 4.2 Hz, 2H), 2.72 (t, J = 5.6 Hz,
2H), 2.21–2.15 (m, 2H), 1.88–1.83 (m, 3H), 1.73–1.64 (m, 3H), 1.30–
1.20 (m, 2H), 1.17–1.11 (m, 1H), 1.03–0.97 (m, 2H).
5.2.2. General procedure for the preparation of 3-(4-(R1-phenyl)-
piperazin-1-yl)propan-1-amine (8a–d)
A solution of 2-(3-(4-(R1-phenyl)piperazin-1-yl)propyl)isoindo-
line-1,3-dione 7 (2 mmol, 1 equiv) and hydrazine monohydrate
(6 mmol, 3 equiv) in EtOH (20 mL) was refluxed for 5 h. After cool-
ing to room temperature, the mixture was alkalinized with 5%
NaOH (pH 8), the organic solvents were evaporated under vacuum,
and water was extracted with methylene chloride (3 Â 20 mL). The
organic layer was dried, Na2SO4 was filtered off, and the solvent
was evaporated to dryness.
5.2.3.4. N-(Cyclohexylmethyl)-3-(4-(4-fluorophenyl)piperazin-
1-yl)propan-1-amine (9d). White solid (29%), mp 186–187 °C: 1H
NMR (CDCl3, 400 MHz) d 10.28 (br s, 1H), 6.97 (t, J = 8.8 Hz, 2H),
6.87 (dd, J = 4.8 Hz, 2H), 3.15–3.13 (m, 6H), 2.83 (s, 4H), 2.75–
2.71 (m, 4H), 2.19–2.15 (m, 2H), 1.88–1.84 (m, 3H), 1.73–1.65
(m, 4H), 1.30–1.17 (m, 2H), 0.90 (q, J = 10.4 Hz, 2H).
5.2.2.1. 3-(4-Phenylpiperazin-1-yl)propan-1-amine (8a). Pale
yellow solid (42%), mp 75 °C: 1H NMR (CDCl3, 400 MHz) d 7.26 (t,
J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1H), 3.21
(t, J = 5.2 Hz, 4H), 2.79 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 5.2 Hz, 4H),
2.47 (t, J = 7.2 Hz, 2H), 1.72–1.65 (m, 2H), 1.35 (br s, 2H).
5.2.3.5. N-(Cyclopropylmethyl)-3-(4-phenylpiperazin-1-yl)pro-
pan-1-amine (10a). Yellow oil (59%): 1H NMR (CDCl3, 400 MHz) d
7.29–7.24 (m, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.90–6.84 (m, 1H), 3.24
(t, J = 4.8 Hz, 2H), 3.09 (s, 2H), 3.20 (t, J = 4.8 Hz, 2H), 2.79 (s, 2H),
2.73 (d, J = 8.0 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 4.8 Hz,
2H), 2.46 (t, J = 6.8 Hz, 2H), 0.89–0.85 (m, 1H), 0.66 (q, J = 8.0 Hz,
2H), 0.32 (q, J = 4.8 Hz, 2H).
5.2.2.2. 3-(4-(2-Methoxyphenyl)piperazin-1-yl)propan-1-amine
(8b). Yellow oil (94%): 1H NMR (CDCl3, 400 MHz) d 7.02–6.96 (m,
1H), 6.94–6.90 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.10 (s,
4H), 2.80 (t, J = 6.8 Hz, 2H), 2.67 (s, 4H), 2.49 (t, J = 7.2 Hz, 2H),
1.75–1.67 (m, 4H).
5.2.3.6. N-(Cyclopropylmethyl)-3-(4-(2-methoxyphenyl)pipera-
zin-1-yl)propan-1-amine (10b). Yellow oil (25%): 1H NMR
(CDCl3, 400 MHz) d 7.08–7.03 (m, 1H), 6.93 (d, J = 4.0 Hz, 2H),
6.88 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.34 (s, 4H), 3.20 (t,
J = 6.0 Hz, 4H), 3.14 (s, 4H), 2.85 (d, J = 7.6 Hz, 2H), 2.43 (t,
J = 5.6 Hz, 2H), 1.37–1.34 (m, 1H), 0.73 (q, J = 4.8 Hz, 2H), 0.46 (q,
J = 5.2 Hz, 2H).
5.2.2.3. 3-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)propan-
1-amine (8c). Yellow oil (59%): 1H NMR (CDCl3, 400 MHz) d 7.34 (t,
J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.08–7.04 (m, 2H), 3.25 (t, J = 5.2 Hz, 4H),
2.82 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 5.2 Hz, 4H), 2.49 (t, J = 7.2 Hz, 2H),
1.76–1.67 (m, 4H).
5.2.3.7. N-(Cyclopropylmethyl)-3-(4-(3-(trifluoromethyl)phenyl)-
piperazin-1-yl)propan-1-amine (10c). Yellow oil (86%): 1H NMR
(CDCl3, 400 MHz) d 7.16 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 4.0 Hz, 2H),
6.85 (d, J = 4.0 Hz, 1H), 3.26 (t, J = 7.4 Hz, 2H), 3.21 (t, J = 5.2 Hz, 4H),
3.02 (d, J = 6.8 Hz, 2H), 2.54 (t, J = 5.0 Hz, 4H), 2.43 (t, J = 7.2 Hz, 2H),
1.83–1.81 (m, 2H), 0.90–0.86 (m, 1H), 0.52 (q, J = 6.0 Hz, 2H), 0.18 (q,
J = 5.2 Hz, 2H).
5.2.2.4. 3-(4-(4-Fluorophenyl)piperazin-1-yl)propan-1-amine
(8d). Yellow oil (73%): 1H NMR (CDCl3, 400 MHz) d 6.96 (t,
J = 8.4 Hz, 2H), 6.90–6.85 (m, 2H), 3.12 (t, J = 4.8 Hz, 4H), 2.81 (t,
J = 6.4 Hz, 2H), 2.62 (t, J = 4.8 Hz, 4H), 2.48 (t, J = 7.2 Hz, 2H),
1.76–1.68 (m, 4H).
5.2.3. General procedure for the preparation of N-(R2-methyl)-3-
(4-(R1-phenyl)piperazin-1-yl)propan-1-amine (9a–d and 10a–d)
5.2.3.8. N-(Cyclopropylmethyl)-3-(4-(4-fluorophenyl)piperazin-
1-yl)propan-1-amine (10d). Yellow oil (71%): 1H (CDCl3,
400 MHz) d 6.99–6.95 (m, 2H), 6.89–6.86 (m, 2H), 3.16 (t,
J = 4.8 Hz, 4H), 2.79 (s, 4H), 2.74–2.68 (m, 4H), 2.62 (t, J = 4.8 Hz,
2H), 2.09–2.07 (m, 2H), 0.88 (s, 1H), 0.66 (q, J = 7.2 Hz, 2H), 0.32
(q, J = 5.2 Hz, 2H).
3-(4-(R1-phenylpiperazin-1-yl)propan-1-amine
8
(10 mmol,
1 equiv) and R2-carboxaldehyde (10 mmol, 1 equiv) were mixed
in methylene chloride (15 mL) and then treated with sodium tri-
acetoxyborohydride 3.0 g (14 mmol, 1.4 equiv). The mixture was
stirred at rt under a N2 atmosphere for 16 h. The reaction mixture
was quenched by adding aqueous satd NaHCO3, and the mixture
was extracted with methylene chloride (CH2Cl2). The CH2Cl2 ex-
tract was dried (MgSO4), and the solvent was evaporated.
5.2.4. General procedure for the preparation of N-(R2-methyl)-4-
methoxy-N-(3-(4-(R1-phenyl)piperazin-1-yl)propyl)-Ar-sulfon-
amide (11–24)
For the further conversion to sulfonamides, sodium hydride
(1 mmol, 2 equiv) was added to a suspension of N-(R2-methyl)-3-
(4-(R1-phenyl)piperazin-1-yl)propan-1-amine 9 and 10 (0.5 mmol,
1 equiv) in DMF (5 mL). After stirring at 60 °C for 30 min under
nitrogen, Ar-sulfonylchloride (0.75 mmol, 1.5 equiv) in DMF
(5 mL) was added. The reaction mixture was stirred at 100 °C for
5.2.3.1. N-(Cyclohexylmethyl)-3-(4-phenylpiperazin-1-yl)propan-1-
amine (9a). White solid (22%), mp 171–173 °C: 1H NMR (CDCl3,
400 MHz)
d 10.28 (br s, 1H), 7.30–7.26 (m, 3H), 6.90 (dd,
J = 7.2 Hz, 2H), 3.22 (s, 4H), 3.14 (t, J = 7.6 Hz, 2H), 2.83 (s, 4H),
2.75–2.70 (m, 4H), 2.19–2.14 (m, 2H), 1.85 (d, J = 8.0 Hz, 2H),

1670
E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
16 h. After cooling to rt, the mixture was quenched with satd NaH-
CO3 and extracted with ethyl acetate. The organic layer was
washed with water, dried over Na2SO4, and the solvent was re-
moved in vacuo. The crude product was purified by column chro-
matography to give ethyl acetate.
120.86, 116.82, 114.44, 56.40, 55.82, 55.61, 52.49, 47.62, 36.77,
31.10, 29.90, 26.60, 25.94, 24.62. HR-FABMS Calcd for C27H40N3O3S
(M++H): 486.2790, Found: 486.2795.
5.2.4.6. N-(Cyclohexylmethyl)-4-methoxy-N-(3-(4-(2-methoxy-
phenyl)piperazin-1-yl)propyl)benzenesulfonamide (15b). Brown
5.2.4.1. N-(Cyclohexylmethyl)-N-(3-(4-phenylpiperazin-1-yl)pro-
pyl)naphthalene-1-sulfonamide (11). Transparent oil, 13.9 mg
(14%): 1H NMR (CDCl3, 400 MHz) d 8.62 (d, J = 8.8 Hz, 1H), 8.23 (d,
J = 8.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.65
(t, J = 17.2 Hz, 1H), 7.58 (t, J = 16.0 Hz, 1H), 7.53 (t, J = 15.9 Hz, 1H),
7.28–7.24 (m, 2H), 6.90 (d, J = 10.0 Hz, 2H), 6.85 (t, J = 14.8 Hz,
1H), 3.30 (t, J = 15.2 Hz, 2H), 3.17 (d, J = 7.6 Hz, 2H), 3.10 (t,
J = 10.0 Hz, 4H), 2.36 (t, J = 10.0 Hz, 4H), 2.13 (t, J = 14.4 Hz, 2H),
1.66–1.59 (m, 7H), 1.16–1.06 (m, 4H), 0.83–0.78 (m, 2H). 13C NMR
(CDCl3, 100 MHz) d 151.46, 135.44, 134.58, 134.19, 130.17, 129.32,
129.06, 128.16, 126.97, 125.37, 124.29, 119.91, 116.21, 55.63,
53.36, 53.24, 49.26, 45.42, 36.01, 30.92, 29.92, 26.55, 25.97, 25.24.
HR-FABMS Calcd for C30H40N3O2S (M++H): 506.2841, Found:
506.2846.
oil, 158 mg (88%): 1H NMR (CDCl3, 400 MHz)
d 7.73 (dd,
J = 7.2 Hz, 2H), 7.01–6.92 (m, 4H), 6.90 (d, J = 7.2 Hz, 1H), 6.86 (d,
J = 8.4 Hz, 1H), 3.86 (s, 6H), 3.28 (s, 4H), 3.14 (t, J = 6.8 Hz, 2H),
2.88 (d, J = 4.0 Hz, 2H), 1.73–1.70 (m, 4H), 1.67 (m, 3H), 1.28–
1.16 (m, 8H), 0.88–0.84 (m, 4H). 13C NMR (CDCl3, 100 MHz) d
162.97, 152.27, 140.21, 130.83, 129.56, 123.78, 121.25, 118.80,
114.40, 111.41, 56.19, 55.90, 55.60, 52.95. HR-FABMS Calcd for
C28H42N3O4S (M++H): 516.2896, Found: 516.2894.
5.2.4.7. N-(Cyclohexylmethyl)-4-methoxy-N-(3-(4-(3-(trifluoro-
methyl)phenyl)piperazin-1-yl)propyl)benzenesulfonamide
(15c). Brown oil, 157 mg (58%): 1H NMR (CDCl3, 400 MHz) d 7.74
(dd, J = 9.2 Hz, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.11 (s, 1H), 7.06 (m, 2H),
6.97 (d, J = 4.4 Hz, 2H), 3.86 (s, 3H), 3.22 (t, J = 4.2 Hz, 4H), 3.13 (t,
J = 7.6 Hz, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.56 (t, J = 4.8 Hz, 4H), 2.24
(t, J = 6.8 Hz, 2H), 1.80–1.72 (m, 6H), 1.68–1.55 (m, 5H), 1.226–
1.16 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 162.83, 151.54,
131.70, 129.75, 129.48, 123.36, 118.84, 115.98, 114.29, 112.30,
112.26, 55.79, 55.74, 55.50, 53.15, 48.84, 47.44, 36.79, 31.10,
26.66, 26.40, 26.06. HR-FABMS Calcd for C28H39F3N3O3S (M++H):
554.2664, Found: 554.2668.
5.2.4.2. N-(Cyclohexylmethyl)-N-[3-(4-phenyl-piperazine)-pro-
pyl]-4-trifluoromethylbenzenesulfonamide (12). Yellow oil,
32.6 mg (11%): 1H NMR (CDCl3, 400 MHz) d 7.93 (d, J = 8.0 Hz,
2H), 7.77 (d, J = 8.4 Hz, 2H), 7.29–7.24 (m, 2H), 6.92 (d,
J = 10.0 Hz, 2H), 6.86 (t, J = 15.6 Hz, 1H), 3.20–3.16 (m, 6H), 2.98
(d, J = 9.2 Hz, 2H), 2.54 (t, J = 10.0 Hz, 4H), 2.34 (t, J = 12.8 Hz, 2H),
1.80–1.70 (m, 7H), 1.23–1.16 (m, 4H), 0.90–0.86 (m, 2H). 13C
NMR (CDCl3, 100 MHz) d 151.41, 129.30, 127.82, 127.05, 126.35,
125.90, 119.96, 116.21, 55.62, 55.37, 53.34, 49.27, 47.37, 36.61,
31.02, 29.90, 26.56, 26.51, 26.31. HR-FABMS Calcd for
C27H37F3N3O2S (M++H): 524.2559, Found: 524.2556.
5.2.4.8. N-(Cyclohexylmethyl)-N-(3-(4-(4-fluorophenyl)pipera-
zin-1-yl)propyl)-4-methoxybenzenesulfonamide (15d). Brown
solid, 62 mg (31%), mp 81–82 °C: 1H NMR (CDCl3, 400 MHz) d
7.74 (dd, J = 6.8 Hz, 2H), 6.98–6.94 (m, 4H), 6.89–6.85 (m, 2H),
3.86 (s, 3H), 3.14–3.09 (m, 4H), 2.96–2.88 (m, 4H), 2.55 (t,
J = 4.8 Hz, 4H), 2.36 (t, J = 7.2 Hz, 2H), 1.80–1.72 (m, 4H), 1.28–
1.22 (m, 5H), 0.89–0.84 (m, 4H). 13C NMR (CDCl3, 100 MHz) d
162.82, 156.18, 148.16, 131.74, 129.48, 117.97, 117.90, 115.82,
115.60, 114.28, 55.79, 55.43, 53.39, 50.37, 47.44, 36.76, 31.09,
26.66, 26.40, 26.06. HR-FABMS Calcd for C27H39FN3O3S (M++H):
504.2696, Found: 504.2694.
5.2.4.3. N-(Cyclohexylmethyl)-N-[3-(4-phenyl-piperazine)-pro-
pyl]-4-fluorobenzenesulfonamide (13). White solid, 35.2 mg
(14%), mp 88–90 °C: 1H NMR (CDCl3, 400 MHz) d 7.83–7.80 (m,
2H), 7.26 (t, J = 16.0 Hz, 2H), 7.18 (t, J = 17.2 Hz, 2H), 6.93 (d,
J = 10.0 Hz, 2H), 6.86 (t, J = 14.4 Hz, 1H), 3.19 (t, J = 10.0 Hz, 4H),
3.14 (d, J = 8.0 Hz, 2H), 2.95 (d, J = 7.6 Hz, 2H), 2.55 (t, J = 10.0 Hz,
4H), 2.35 (t, J = 14.4 Hz, 2H), 1.78–1.68 (m, 7H), 1.28–1.23 (m,
4H), 0.90–0.85 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 166.34,
151.46, 136.21, 136.18, 130.03, 129.94, 129.32, 119.93, 116.46,
116.21, 55.53, 53.39, 49.33, 47.34, 36.65, 31.03, 26.60, 26.34,
26.01. HR-FABMS Calcd for C26H37FN3O2S (M++H): 474.2591,
Found: 474.2586.
5.2.4.9. N-(Cyclohexylmethyl)-N-(3-(4-phenylpiperazin-1-yl)pro-
pyl)naphthalene-2-sulfonamide (16a). White solid, 70 mg (37%),
mp 124–126 °C: 1H NMR (CDCl3, 400 MHz) d 8.38 (s, 1H), 7.96 (t,
J = 8.8 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 8.4 Hz, 1H),
7.65–7.60 (m, 2H), 7.28–7.24 (m, 2H), 6.91–6.87 (m, 3H), 3.46 (t,
J = 7.2 Hz, 4H), 3.24 (d, J = 6.8 Hz, 2H), 3.00 (s, 4H), 2.94 (d,
J = 7.2 Hz, 2H), 2.17 (s, 2H), 1.70–1.55 (m, 8H), 1.19–1.14 (m, 3H),
0.88–0.86 (m, 2H). 13C NMR (CDCl3, 100 MHz) d 150.06, 135.99,
134.96, 132.42, 129.64, 129.48, 128.96, 128.81, 128.07, 127.80,
122.85, 121.05, 116.94, 56.51, 55.50, 52.24, 47.61, 47.15, 36.76,
31.06, 26.564, 25.89, 24.14. HR-FABMS Calcd for C30H40N3O2S
(M++H): 506.2841, Found: 506.2846.
5.2.4.4. N-(Cyclohexylmethyl)-N-[3-(4-phenylpiperazine)-pro-
pyl]-4-nitrobenzenesulfonamide (14). Yellow solid, 59.6 mg
(23%), mp 82–87 °C: 1H NMR (CDCl3, 400 MHz)
d 8.35 (d,
J = 13.6 Hz, 2H), 7.99 (d, J = 13.6 Hz, 2H), 7.29–7.25 (m, 2H), 6.93
(d, J = 8.8 Hz, 2H), 6.86 (t, J = 14.8 Hz, 1H), 3.23–3.17 (m, 6H),
3.00 (d, J = 7.2 Hz, 2H), 2.56 (t, J = 10.0 Hz, 4H), 2.36 (t,
J = 14.0 Hz, 2H), 1.80–1.69 (m, 7H), 1.27–1.16 (m, 4H), 0.92–0.80
(m, 2H). 13C NMR (CDCl3, 100 MHz) d 151.38, 150.03, 145.97,
129.32, 128.49, 124.46, 119.98, 116.20, 55.55, 55.36, 53.38, 49.31,
47.37, 36.57, 30.96, 26.51, 26.37, 25.94. HR-FABMS Calcd for
C26H37N4O4S (M++H): 501.2536, Found: 501.2537.
5.2.4.10. N-(Cyclohexylmethyl)-N-(3-(4-(2-methoxyphenyl)pip-
erazin-1-yl)propyl)naphthalene-2-sulfonamide (16b). Pale yel-
low solid, 23 mg (15%), mp 128–129 °C: 1H NMR (CDCl3,
400 MHz) d 8.39 (s, 1H), 8.01–7.95 (m, 2H), 7.91 (d, J = 8.0 Hz,
1H), 7.77 (dd, J = 8.4 Hz, 1H), 7.67–7.59 (m, 2H), 7.06–7.00 (m,
1H), 6.91–6.81 (m, 3H), 3.87 (s, 3H), 3.49–3.31 (m, 6H), 2.27 (t,
J = 6.8 Hz, 2H), 3.13–3.06 (m, 4H), 2.96 (d, J = 8.0 Hz, 2H), 1.71–
1.44 (m, 8H), 1.17–1.15 (m, 3H), 0.90–0.86 (m, 2H). 13C NMR
5.2.4.5. N-(Cyclohexylmethyl)-4-methoxy-N-(3-(4-phenylpipera-
zin-1-yl)propyl)benzenesulfonamide (15a). Light brown solid,
45 mg (30%), mp 86–88 °C: 1H NMR (CDCl3, 400 MHz) d 7.72 (d,
J = 6.8 Hz, 2H), 7.26 (t, J = 8.0 Hz, 2H), 6.98 (d, J = 6.8 Hz, 2H),
6.91–6.87 (m, 3H), 3.86 (s, 3H), 3.46 (s, 4H), 3.14 (t, J = 6.8 Hz,
2H), 2.91–2.88 (m, 4H), 2.72 (d, J = 7.6 Hz, 2H), 2.12 (s, 2H), 1.70
(d, J = 7.6 Hz, 2H), 1.28–1.15 (m, 8H), 0.88–0.84 (m, 3H).. 13C
NMR (CDCl3, 100 MHz) d 163.02, 150.37, 130.73, 129.59, 129.45,
(CDCl3, 100 MHz)
d 152.25, 135.85, 135.01, 132.43, 129.69,
129.53, 129.01, 128.86, 128.09, 127.83, 124.29, 123.50, 122.79,
121.38, 119.05, 111.49, 56.53, 55.68, 52.88, 47.96, 47.48, 36.80,

E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
1671
31.08, 26.55, 25.89. HR-FABMS Calcd for C31H42N3O3S (M++H):
536.2947, Found: 536.2950.
1.71–1.62 (m, 8H), 1.15–1.05 (m, 3H), 0.95–0.80 (m, 2H). 13C
NMR (CDCl3, 75 MHz) d 151.05, 144.02, 138.32, 136.34, 131.21,
129.14, 125.31, 121.80, 118.51, 115.56, 111.86, 55.29, 52.72,
48.40, 46.74, 36.43, 30.68, 26.36, 25.82. HR-FABMS Calcd for
C30H38F3N4O2S (M++H): 575.2668, Found: 575.2665.
5.2.4.11. N-(Cyclohexylmethyl)-N-(3-(4-(3-(trifluoromethyl)phe-
nyl)piperazin-1-yl)propyl)naphthalene-2-sulfonamide (16c). Pale
yellow solid, 50 mg (24%), mp 74–75 °C: 1H NMR (CDCl3, 400 MHz)
d 8.39 (s, 1H), 7.98–7.94 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (dd,
J = 8.8 Hz, 1H), 7.66–7.59 (m, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.08–7.07
(m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 3.21 (t, J = 7.6 Hz, 2H), 3.15 (t,
J = 5.2 Hz, 4H), 3.05 (d, J = 7.6 Hz, 2H), 2.48 (t, J = 5.2 Hz, 4H), 2.34
(t, J = 7.2 Hz, 2H), 1.77–1.59 (m, 8H), 1.22–1.17 (m, 3H), 0.93–
5.2.4.16. N-(Cyclohexylmethyl)-N-[3-(4-(4-fluorophenyl)-piper-
azin-1-yl)-propyl]quinoline-8-sulfonamide (17d). Yellow oil,
112 mg (56%): 1H NMR (CDCl3, 400 MHz) d 9.06 (s, 1H), 8.50 (d,
J = 8.8 Hz, 1H), 8.22 (d, J = 10.0 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H),
7.61 (t, J = 15.6 Hz, 1H), 7.52–7.49 (m, 1H), 6.95 (t, J = 17.6 Hz,
2H), 6.87–6.83 (m, 2H), 3.46 (t, J = 14.8 Hz, 2H), 3.30 (d,
J = 7.6 Hz, 2H), 3.05 (t, J = 9.6 Hz, 4H), 2.43 (t, J = 10.0 Hz, 4H),
2.23 (t, J = 14.8 Hz, 2H), 1.71–1.64 (m, 8H), 1.16–1.08 (m, 3H),
0.94–0.80 (m, 2H). 13C NMR (CDCl3, 75 MHz) d 155.44, 150.89,
147.85, 144.06, 138.37, 136.30, 132.87, 128.82, 125.33, 121.78,
117.61, 115.39, 55.30, 53.00, 49.97, 46.72, 36.41, 30.68, 29.62,
26.38, 25.88, 25.08. HR-FABMS Calcd for C29H38FN4O2S (M++H):
525.2700, Found: 525.2703.
0.90 (m, 2H). 13C NMR (CDCl3, 100 MHz)
d 151.52, 137.01,
134.87, 132.41, 129.73, 129.45, 129.37, 128.83, 128.66, 128.08,
127.71, 122.85, 118.83, 116.00, 112.27, 112.23, 55.63, 55.29,
53.06, 48.77, 47.19, 36.75, 31.07, 26.63, 26.22, 26.05. HR-FABMS
Calcd for C31H39F3N3O2S (M++H): 574.2715, Found: 574.2717.
5.2.4.12. N-(Cyclohexylmethyl)-N-(3-(4-(4-fluorophenyl)pipera-
zin-1-yl)propyl)naphthalene-2-sulfonamide (16d). White solid,
140 mg (45%), mp 116–117 °C: 1H NMR (CDCl3, 400 MHz) d 8.38
(s, 1H), 7.97 (t, J = 8.8 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (dd,
J = 8.4 Hz, 1H), 7.66–7.59 (m, 2H), 7.00–6.93 (m, 2H), 6.87–6.83
(m, 2H), 3.24–3.18 (m, 6H), 3.00 (d, J = 3.2 Hz, 2H), 2.86–2.46 (m,
6H), 1.74–1.57 (m, 8H), 1.20–1.15 (m, 3H), 0.94–0.86 (m, 2H). 13C
NMR (CDCl3, 100 MHz) d 156.42, 147.57, 136.55, 134.88, 132.38,
129.51, 129.40, 128.87, 128.68, 128.06, 127.72, 122.81, 118.40,
118.33, 115.89, 115.67, 55.76, 55.61, 52.93, 49.44, 47.36, 36.73,
31.04, 26.58, 25.96, 25.42. HR-FABMS Calcd for C30H39FN3O2S
(M++H): 524.2747, Found: 524.2742.
5.2.4.17. N-(Cyclohexylmethyl)-N-[3-(4-(3,4-dichlorophenyl)-pi-
perazin-1-yl)-propyl]quinoline-8-sulfonamide (17e). Brown so-
lid, 132 mg (47%), mp 111–115 °C: 1H NMR (CDCl3, 400 MHz) d
9.06 (s, 1H), 8.50 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 10.0 Hz, 1H), 8.01
(d, J = 9.6 Hz, 1H), 7.61 (t, J = 15.6 Hz, 1H), 7.52–7.49 (m, 1H),
7.26 (t, J = 8.8 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J = 12.0 Hz, 1H), 3.47
(t, J = 15.2 Hz, 2H), 3.29 (d, J = 7.6 Hz, 2H), 3.10 (t, J = 10.0 Hz, 4H),
2.41 (t, J = 10.4 Hz, 4H), 2.25 (t, J = 14.4 Hz, 2H), 1.70–1.65 (m,
8H), 1.14–1.08 (m, 3H), 0.92–0.82 (m, 2H). 13C NMR (CDCl3,
100 MHz)
d 151.16, 150.83, 144.36, 138.70, 136.56, 133.15,
5.2.4.13. N-(Cyclohexylmethyl)-N-(3-(4-phenylpiperazin-1-yl)pro-
pyl)quinoline-8-sulfonamide (17a). Brown oil, 53.7 mg (10%): 1H
NMR (CDCl3, 400 MHz) d 9.06 (s, 1H), 8.51 (d, J = 9.2 Hz, 1H), 8.22
(d, J = 10.0 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.61 (t, J = 15.6 Hz,
1H), 7.52–7.49 (m, 1H), 7.26 (t, J = 16.0 Hz, 2H), 6.90 (d,
J = 9.6 Hz, 2H), 6.85 (t, J = 14.8 Hz, 1H), 3.45 (t, J = 15.2 Hz, 2H),
3.32 (d, J = 7.6 Hz, 2H), 3.12 (t, J = 10.0 Hz, 4H), 2.42 (t,
J = 10.0 Hz, 4H), 2.22 (t, J = 14.8 Hz, 2H), 1.69–1.63 (m, 8H), 1.13
(s, 3H), 0.89–0.72 (m, 2H). 13C NMR (CDCl3, 75 MHz) d 150.40,
143.45, 137.70, 135.75, 132.32, 128.44, 128.25, 124.77, 121.23,
119.10, 115.37, 54.74, 52.32, 48.18, 46.15, 35.82, 30.09, 25.78,
25.15. HR-FABMS Calcd for C29H39N4O2S (M++H): 507.2794, Found:
507.2798.
130.60, 129.12, 125.64, 122.06, 117.29, 115.40, 55.59, 52.93,
48.77, 47.10, 36.75, 30.98, 26.65, 26.23, 26.08. HR-FABMS Calcd
for C29H37Cl2N4O2S (M++H): 575.2014, Found: 575.2009.
5.2.4.18. N-(Cyclopropylmethyl)-N-(3-(4-phenylpiperazin-1-yl)-
propyl)naphthalene-1-sulfonamide (18). Yellow oil, 133 mg
(27%): 1H NMR (CDCl3, 400 MHz) d 8.628 (d, J = 8.0 Hz, 1H), 8.22
(dd, J = 7.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H),
7.65 (t, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz,
1H), 7.25 (t, J = 8.0 Hz, 2H), 6.90 (d, J = 4.8 Hz, 2H), 6.85 (t,
J = 7.2 Hz, 1H), 3.45 (t, J = 7.4 Hz, 2H), 3.26 (d, J = 6.8 Hz, 2H), 3.10
(t, J = 5.0 Hz, 4H), 2.39 (t, J = 5.0 Hz, 4H), 2.18 (t, J = 6.8 Hz, 2H),
1.70–1.77 (m, 2H), 0.93–0.89 (m, 1H), 0.49 (q, J = 5.6 Hz, 2H),
0.16 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 150.59,
134.53, 133.55, 129.04, 128.44, 128.13, 127.31, 126.15, 124.46,
123.42, 119.01, 115.32, 54.76, 52.39, 50.65, 48.34, 44.26, 24.66,
9.11, 3.41. HR-FABMS Calcd for C27H34N3O2S (M++H): 464.2372,
Found: 464.2375.
5.2.4.14. N-(Cyclohexylmethyl)-N-[3-(4-(2-methoxyphenyl)-pip-
erazin-1-yl)-propyl]quinoline-8-sulfonamide (17b). Yellow oil,
62 mg (22%): 1H NMR (CDCl3, 400 MHz) d 9.07 (s, 1H), 8.50 (d,
J = 8.8 Hz, 1H), 8.21 (d, J = 10.0 Hz, 1H), 8.00 (d, J = 9.6 Hz, 1H),
7.60 (t, J = 15.6 Hz, 1H), 7.52–7.48 (m, 1H), 7.01–6.97 (m, 1H),
6.91 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 7.6 Hz, 1H), 3.85 (s, 3H), 3.45
(t, J = 16.0 Hz, 2H), 3.32 (d, J = 7.6 Hz, 2H), 3.11–3.01 (m, 4H),
2.46–2.41 (m, 4H), 2.22 (t, J = 15.2 Hz, 2H), 1.94 (d, J = 14.4 Hz,
2H), 1.70–1.62 (m, 6H), 1.37–1.27 (m, 3H), 0.94–0.87 (m, 2H). 13C
NMR (CDCl3, 75 MHz) d 164.28, 152.15, 150.89, 144.09, 141.20,
138.36, 132.85, 129.97, 125.35, 122.33, 121.75, 121.45, 118.60,
111.06, 55.44, 53.34, 50.49, 46.58, 36.36, 31.83, 30.68, 27.01,
26.61, 26.12. HR-FABMS Calcd for C30H41N4O3S (M++H):
537.2899, Found: 537.2897.
5.2.4.19. N-(Cyclopropylmethyl)-N-(3-(4-phenylpiperazin-1-yl)-
propyl)-4-(trifluoromethyl)benzenesulfonamide (19). Yellow
oil, 116 mg (31%): 1H NMR (CDCl3, 400 MHz) d 7.95 (d, J = 8.4 Hz,
2H), 7.77 (d, J = 8.4 Hz, 2H), 7.26 (t, J = 9.2 Hz, 2H), 6.93 (d,
J = 8.4 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 3.34 (t, J = 7.6 Hz, 2H), 3.19
(t, J = 5.0 Hz, 4H), 3.12 (d, J = 6.8 Hz, 2H), 2.59 (t, J = 5.0 Hz, 4H),
2.41 (t, J = 7.2 Hz, 2H), 1.89–1.84 (m, 2H), 0.94–0.86 (m, 1H), 0.53
(q, J = 5.6 Hz, 2H), 0.21 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3,
75 MHz)
d 150.57, 133.56, 130.23, 128.46, 128.14, 126.86,
125.45, 120.82, 119.08, 115.34, 54.77, 52.42, 48.42, 45.51, 25.61,
9.21, 3.50. HR-FABMS Calcd for C24H31F3N3O2S (M++H): 482.2089,
Found: 482.2090.
5.2.4.15. N-(Cyclohexylmethyl)-N-[3-(4-(3-trifluoromethylphe-
nyl)-piperazin-1-yl)-propyl]quinoline-8-sulfonamide (17c). Yel-
low oil, 105 mg (34%): 1H NMR (CDCl3, 400 MHz) d 9.06 (s, 1H),
8.50 (d, J = 8.8 Hz, 1H), 8.22 (d, J = 10.4 Hz, 1H), 8.01 (d, J = 9.6 Hz,
1H), 7.61 (t, J = 15.2 Hz, 1H), 7.52–7.49 (m, 1H), 7.08–6.70 (m,
4H), 3.47 (t, J = 15.2 Hz, 2H), 3.30 (d, J = 7.2 Hz, 2H), 3.17 (t,
J = 9.6 Hz, 4H), 2.43 (t, J = 10.0 Hz, 4H), 2.25 (t, J = 14.8 Hz, 2H),
5.2.4.20. N-(Cyclopropylmethyl)-4-fluoro-N-(3-(4-phenylpipera-
zin-1-yl)propyl)benzenesulfonamide (20). Yellow oil, 119 mg
(47%): 1H NMR (CDCl3, 400 MHz) d 7.85–7.81 (m, 2H), 7.26 (t,
J = 8.8 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 6.93 (d, J = 7.6 Hz, 2H), 6.86

1672
E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
(t, J = 7.2 Hz, 1H), 3.31 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 5.2 Hz, 4H), 3.08
(d, J = 6.8 Hz, 2H), 2.58 (t, J = 5.0 Hz, 4H), 2.41 (t, J = 7.2 Hz, 2H),
1.89–1.83 (m, 2H), 0.88–0.86 (m, 1H), 0.52 (q, J = 5.6 Hz, 2H),
0.19 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 165.87,
150.60, 135.77, 129.08, 128.37, 122.48, 115.68, 115.36, 54.85,
52.38, 48.43, 45.41, 25.59, 9.18, 3.47. HR-FABMS Calcd for
C23H31FN3O2S (M++H): 432.2121, Found: 432.2124.
2H). 13C NMR (CDCl3, 100 MHz) d 162.66, 158.29, 155.92, 148.06,
131.95, 129.19, 117.75, 117.70, 115.61, 115.39, 114.19, 55.63,
53.24, 52.93, 50.12, 46.11, 26.34, 9.96, 4.17. HR-FABMS Calcd for
C24H33FN3O3S (M++H): 462.2227, Found: 462.2223.
5.2.4.26. N-(Cyclopropylmethyl)-N-(3-(4-phenylpiperazin-1-yl)-
propyl)naphthalene-2-sulfonamide (23a). Yellow oil, 165 mg
(38%): 1H NMR (CDCl3, 400 MHz) d 8.395 (s, 1H), 7.97–7.93 (m,
2H), 7.90 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 8.8 Hz, 1H), 7.65–7.58
(m, 2H), 7.26 (t, J = 7.2 Hz, 2H), 6.91 (d, J = 7.6 Hz, 2H), 6.85 (t,
J = 7.2 Hz, 1H), 3.38 (t, J = 7.6 Hz, 2H), 3.16–3.13 (m, 6H), 2.53 (t,
J = 5.0 Hz, 4H), 2.40 (t, J = 8.8 Hz, 2H), 1.89–1.81 (m, 2H), 0.94–
0.87 (m, 1H), 0.51 (q, J = 5.6 Hz, 2H), 0.20 (q, J = 5.2 Hz, 2H). 13C
NMR (CDCl3, 100 MHz) d 151.29, 137.21, 134.65, 132.22, 129.11,
128.47, 127.71, 122.57, 119.66, 115.99, 55.56, 53.19, 49.07, 46.07,
26.26, 10.01, 4.17. HR-FABMS Calcd for C27H34N3O2S (M++H):
464.2372, Found: 464.2375.
5.2.4.21. N-(Cyclopropylmethyl)-4-nitro-N-(3-(4-phenylpipera-
zin-1-yl)propyl)benzenesulfonamide (21). Brown oil, 103 mg
(41%): 1H NMR (CDCl3, 400 MHz) d 8.40 (d, J = 6.8 Hz, 1H), 8.35
(d, J = 6.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 7.2 Hz, 1H),
6.93 (d, J = 8.4 Hz, 2H), 6.86 (t, J = 6.0 Hz, 1H), 3.37 (t, J = 7.4 Hz,
2H), 3.19 (t, J = 5.2 Hz, 4H), 3.14 (d, J = 6.8 Hz, 2H), 2.58 (t,
J = 5.0 Hz, 4H), 2.42 (t, J = 7.0 Hz, 2H), 1.89–1.85 (m, 2H), 0.88–
0.84 (m, 1H), 0.54 (q, J = 5.6 Hz, 2H), 0.21 (q, J = 5.2 Hz, 2H). 13C
NMR (CDCl3, 100 MHz) d 151.40, 150.01, 146.51, 129.29, 128.37,
124.49, 119.92, 116.17, 55.53, 53.41, 53.14, 49.30, 46.43, 26.49,
10.01, 4.39. HR-FABMS Calcd for C23H31N4O4S (M++H): 459.2066,
Found: 459.2071.
5.2.4.27. N-(Cyclopropylmethyl)-N-(3-(4-(2-methoxyphenyl)pip-
erazin-1-yl)propyl)naphthalene-2-sulfonamide (23b). Brown so-
lid, 134 mg (29%), mp 90–91 °C: 1H NMR (CDCl3, 400 MHz) d 8.40
(s, 1H), 7.98–7.93 (m, 2H), 7.90 (d, J = 7.0 Hz, 1H), 7.79 (dd,
J = 8.8 Hz, 1H), 7.65–7.60 (m, 2H), 7.02–6.99 (m, 1H), 6.91 (d,
J = 4.6 Hz, 2H), 6.86 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.38 (t,
J = 7.6 Hz, 2H), 3.15 (d, J = 6.8 Hz, 2H), 3.05 (s, 4H), 2.58 (s, 4H),
2.41 (t, J = 7.2 Hz, 2H), 1.88–1.83 (m, 2H), 0.91 (m, 1H), 0.51 (q,
J = 5.6 Hz, 2H), 0.20 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz)
d 152.47, 141.46, 137.43, 134.85, 132.43, 129.49, 129.39, 128.78,
128.53, 128.07, 127.66, 123.12, 122.78, 121.18, 118.39, 111.40,
55.85, 55.56, 53.59, 53.00, 50.74, 46.26, 26.34, 10.17, 4.33. HR-FAB-
MS Calcd for C28H36N3O3S (M++H): 494.2477, Found: 494.2476.
5.2.4.22. N-(Cyclopropylmethyl)-4-methoxy-N-(3-(4-phenylpi-
perazin-1-yl)propyl)benzenesulfonamide (22a). Yellow oil,
119 mg (43%): 1H NMR (CDCl3, 400 MHz) d 7.75 (d, J = 6.8 Hz,
2H), 7.26 (t, J = 8.0 Hz, 2H), 6.97–6.92 (m, 4H), 6.85 (t, J = 7.2 Hz,
1H), 3.86 (s, 3H), 3.29 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 1.0 Hz, 4H),
3.05 (d, J = 6.8 Hz, 2H), 2.58 (t, J = 5.0 Hz, 4H), 2.41 (t, J = 7.2 Hz,
2H), 1.88–1.81 (m, 2H), 0.90–0.86 (m, 1H), 0.51 (q, J = 5.6 Hz,
2H), 0.18 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 161.93,
150.62, 131.24, 128.50, 128.44, 119.01, 115.32, 113.45, 54.92,
52.54, 52.20, 48.42, 45.36, 25.59, 9.23, 3.44. HR-FABMS Calcd for
C24H34N3O3S (M++H): 444.2321, Found: 444.2318.
5.2.4.28. N-(Cyclopropylmethyl)-N-(3-(4-(3-(trifluoromethyl)-
phenyl)piperazin-1-yl)propyl)naphthalene-2-sulfonamide
(23c). Brown oil, 302 mg (53%): 1H NMR (CDCl3, 400 MHz) d 8.40
(s, 1H), 7.97–7.94 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.79 (dd,
J = 8.8 Hz, 1H), 7.66–7.59 (m, 2H), 7.33 (t, J = 8.0 Hz, 1H), 7.08–
7.06 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 3.38 (t, J = 7.4 Hz, 2H), 3.19–
3.15 (m, 6H), 2.53 (t, J = 5.0 Hz, 4H), 2.41 (t, J = 7.4 Hz, 2H), 1.89–
1.83 (m, 2H), 0.93–0.89 (m, 1H), 0.45 (q, J = 5.6 Hz, 2H), 0.20 (q,
5.2.4.23. N-(Cyclopropylmethyl)-4-methoxy-N-(3-(4-(2-methoxy-
phenyl)piperazin-1-yl)propyl)benzenesulfonamide
(22b). Pale
yellow solid, 138 mg (88%), mp 92–93 °C: 1H NMR (CDCl3,
400 MHz) d 7.75 (d, J = 7.0 Hz, 2H), 7.02–6.91 (m, 5H), 6.86 (d,
J = 8.0 Hz, 1H), 3.86 (s, 6H), 3.29 (t, J = 7.4 Hz, 2H), 3.08 (s, 4H),
3.06 (d, J = 6.8 Hz, 2H), 2.62 (s, 4H), 2.42 (t, J = 7.2 Hz, 2H), 1.87–
1.80 (m, 2H), 0.91–0.86 (m, 1H), 0.51 (q, J = 5.6 Hz, 2H), 0.19 (q,
J = 5.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz) d 162.74, 152.44,
141.50, 132.19, 129.33, 123.05, 121.14, 118.31, 114.27, 111.38,
55.88, 55.73, 55.53, 53.60, 52.93, 50.81, 46.21, 26.37, 10.06, 4.26.
HR-FABMS Calcd for C25H36N3O4S (M++H): 474.2427, Found:
474.2430.
J = 5.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz)
d 150.68, 136.53,
133.95, 131.51, 130.57, 128.66, 127.79, 127.03, 125.57, 121.87,
117.93, 114.88, 111.20, 54.68, 52.19, 47.78, 45.31, 25.52, 9.34,
3.46. HR-FABMS Calcd for C28H33F3N3O2S (M++H): 532.2246,
Found: 532.2247.
5.2.4.24. N-(Cyclopropylmethyl)-4-methoxy-N-(3-(4-(3-(trifluo-
romethyl)phenyl)piperazin-1-yl)propyl)benzenesulfonamide
(22c). Brown oil, 314 mg (48%): 1H NMR (CDCl3, 400 MHz) d 7.75
(d, J = 6.8 Hz, 2H), 7.34 (t, J = 8.0 Hz, 1H), 7.10–7.04 (m, 3H), 6.96 (d,
J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.29 (t, J = 7.4 Hz, 2H), 3.23 (t, J = 5.2 Hz,
4H), 3.05 (d, J = 6.8 Hz, 2H), 2.58 (t, J = 5.0 Hz, 4H), 2.43 (t,
J = 7.2 Hz, 2H), 1.83–1.81 (m, 2H), 0.90–0.86 (m, 1H), 0.52 (q,
J = 6.0 Hz, 2H), 0.18 (q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 100 MHz)
d 162.76, 151.50, 132.01, 131.62, 131.31, 129.67, 129.28, 118.75,
115.83, 115.79, 114.26, 112.13, 112.09, 55.69, 55.63, 53.10, 53.05,
48.71, 46.17, 26.41, 10.03, 4.24. HR-FABMS Calcd for
C25H33F3N3O3S (M++H): 512.2195, Found: 512.2193.
5.2.4.29. N-(Cyclopropylmethyl)-N-(3-(4-(4-fluorophenyl)pip-
erazin-1-yl)propyl)naphthalene-2-sulfonamide (23d). Brown
oil, 211 mg (40%): 1H NMR (CDCl3, 400 MHz) d 8.39 (s, 1H), 7.97–
7.93 (m, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.79 (dd, J = 8.8 Hz, 1H),
7.66–7.59 (m, 2H), 6.96 (t, J = 7.2 Hz, 2H), 6.87–6.84 (m, 2H), 3.38
(t, J = 7.6 Hz, 2H), 3.15 (d, J = 6.8 Hz, 2H), 3.07 (t, J = 4.8 Hz, 4H),
2.54 (t, J = 4.8 Hz, 4H), 2.41 (t, J = 7.4 Hz, 2H), 1.87–1.83 (m, 2H),
0.90–0.88 (m, 1H), 0.51 (q, J =5.2 Hz, 2H), 0.20 (q, J = 5.2 Hz, 2H).
13C NMR (CDCl3, 75 MHz) d 157.99, 147.29, 136.51, 133.96,
131.52, 128.57, 127.78, 127.03, 121.87, 117.00, 114.79, 54.79,
52.32, 49.35, 45.37, 25.55, 9.32, 3.48. HR-FABMS Calcd for
C27H33FN3O2S (M++H): 482.2278, Found: 482.2280.
5.2.4.25.
N-(Cyclopropylmethyl)-N-(3-(4-(4-fluorophenyl)pip-
5.2.4.30. N-(Cyclopropylmethyl)-N-(3-(4-phenylpiperazin-1-yl)-
propyl)quinoline-8-sulfonamide (24a). Yellow oil, 106 mg
(30%): 1H NMR (CDCl3, 400 MHz) d 9.05 (dd, J = 4.4 Hz, 1H),
8.50 (dd, J = 7.2 Hz, 1H), 8.22 (dd, J = 8.4 Hz, 1H), 8.00 (dd,
J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.50 (dd, J = 8.4 Hz, 1H),
7.26 (t, J=6.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.85 (t, J = 7.2 Hz,
1H), 3.62 (t, J = 7.6 Hz, 2H), 3.38 (d, J = 6.8 Hz, 2H), 3.15
erazin-1-yl)propyl)-4-methoxybenzenesulfonamide (22d). Yel-
low oil, 121 mg (31%): 1H NMR (CDCl3, 400 MHz) d 7.75 (d,
J = 9.6 Hz, 2H), 6.98–6.93 (m, 4H), 6.90–6.85 (m, 2H), 3.86 (s, 3H),
3.29 (t, J = 7 4 Hz, 2H), 3.11 (t, J = 5.0 Hz, 4H), 3.05 (d, J = 6.8 Hz,
2H), 2.58 (t, J = 5.0 Hz, 4H), 2.42 (t, J = 7.2 Hz, 2H), 1.88–1.80 (m,
2H), 0.90–0.85 (m, 1H), 0.51 (q, J = 6.0 Hz, 2H), 0.18 (q, J = 5.2 Hz,

E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
1673
(t, J = 5.0 Hz, 4H), 2.50 (t, J = 5.0 Hz, 4H), 2.34 (t, J = 7.4 Hz, 2H),
1.83–1.80 (m, 2H), 0.86 (m, 1H), 0.40 (q, J = 5.2 Hz, 2H), 0.14
(q, J = 5.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d 150.60, 150.29,
143.47, 137.94, 135.72, 132.21, 130.60, 128.35, 127.14, 123.54,
119.22, 117.35, 56.60, 52.50, 47.66, 43.71, 25.58, 9.62, 3.35.
HR-FABMS Calcd for C26H33N4O2S (M++H): 465.2324, Found:
465.2328.
5.3.1.1. 2-Hydroxy-4-tosyl-butane (25). Yellow oil (51%): 1H
NMR (CDCl3, 400 MHz) 7.80 (d, J = 7.6 Hz, 2H), 7.35 (d,
J = 8.8 Hz, 2H), 4.27–4.09 (m, 2H), 3.96–3.94 (m, 1H), 2.45 (s, 3H),
1.84–1.67 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H).
d
5.3.2. General procedure for the preparation of 4-(4-(R-
phenyl)piperazin-1-yl)butan-2-ol (26a–d)
1-Tosyl-3-hydroxybutane 25 (0.5 mmol, 1 equiv) and R-phenyl-
piperazine (0.75 mmol, 1.5 equiv) were refluxed in acetonitrile
(25 mL) for 16 h under nitrogen. After cooling to rt, the solvent
was removed in vacuo, the residue was dissolved in CH2Cl2 and
washed with satd NaHCO3 solution and brine. The organic layer
was dried over Na2SO4 and the solvent was removed in vacuo.
The crude oil was purified by column chromatography (ethyl ace-
tate/methanol = 1:1).
5.2.4.31. N-(Cyclopropylmethyl)-N-(3-(4-(2-methoxyphenyl)-
piperazin-1-yl)propyl)quinoline-8-sulfonamide (24b). Brown
oil, 117 mg (27%): 1H NMR (CDCl3, 400 MHz)
d 9.05 (dd,
J = 4.4 Hz, 1H), 8.50 (dd, J = 7.6 Hz, 1H), 8.21 (dd, J = 8.4 Hz, 1H),
8.00 (dd, J = 8.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.50 (q, J = 4.0 Hz,
1H), 7.01–6.97 (m, 1H), 6.93–6.90 (m, 2H), 6.85 (d, J = 8.0 Hz,
1H), 3.86 (s, 3H), 3.60 (t, J = 7.6 Hz, 2H), 3.39 (d, J = 7.2 Hz, 2H),
3.04 (s, 4H), 2.53 (s, 4H), 2.33 (t, J = 7.6 Hz, 2H), 1.82–1.78 (m,
2H), 0.87 (m, 1H), 0.41 (q, J = 5.2 Hz, 2H), 0.15 (q, J = 5.2 Hz, 2H).
13C NMR (CDCl3, 100 MHz) d 152.26, 150.93, 144.08, 141.28,
138.54, 136.41, 132.85, 128.91, 125.38, 122.87, 121.88, 120.94,
118.11, 111.18, 55.77, 55.35, 53.34, 50.57, 46.50, 26.19, 10.31,
4.01. HR-FABMS Calcd for C27H35N4O3S (M++H): 495.2430, Found:
495.2433.
5.3.2.1. 4-(4-(1-Phenylpiperazin-1-yl)butan-2-ol
(26a). Pale
yellow solid (96%), mp 107 °C: 1H NMR (CDCl3, 400 MHz) d 7.30–
7.24 (m, 3H), 6.91 (d, J = 7.0 Hz, 1H), 6.86 (t, J = 7.2 Hz, 1H), 4.02–
3.97 (m, 1H), 3.22–3.19 (m, 4H), 2.85–2.62 (m, 4H), 2.61–2.54
(m, 2H), 1.71–1.52 (m, 2H), 1.19 (d, J = 6.0 Hz, 3H).
5.3.2.2. 4-(4-(2-Methoxyphenyl)piperazin-1-yl)butan-2-ol
(26b). Yellow oil (88%): 1H NMR (CDCl3, 400 MHz) d 7.03–6.99 (m,
1H), 6.92–6.90 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 4.03–3.99 (m, 1H),
3.86 (s, 3H), 3.13 (s, 4H), 2.92 (s, 2H), 2.73 (s, 4H), 1.26 (t, J = 7.2 Hz,
2H), 1.20 (d, J = 6.4 Hz, 3H).
5.2.4.32. N-(Cyclopropylmethyl)-N-(3-(4-(3-(trifluoromethyl)ph-
enyl)piperazin-1-yl)propyl)quinoline-8-sulfonamide (24c). Dark
brown oil, 473 mg (32%): 1H NMR (CDCl3, 400 MHz) d 9.05 (dd,
J = 4.0 Hz, 1H), 8.50 (dd, J = 7.2 Hz, 1H), 8.22 (dd, J = 8.4 Hz, 1H), 8.01
(dd, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.43 (q, J = 4.0 Hz, 1H),
7.34 (t, J = 8.0 Hz, 2H), 7.09–7.03 (m, 2H), 3.63 (t, J = 7.6 Hz, 2H),
3.37 (d, J = 6.8 Hz, 2H), 3.19 (t, J = 5.2 Hz, 4H), 2.50 (t, J = 5.2 Hz,
4H), 2.35 (t, J = 7.6 Hz, 2H), 1.86–1.79 (m, 2H), 0.88–0.82 (m, 1H),
0.40 (q, J = 4.8 Hz, 2H), 0.13 (q, J = 4.8 Hz, 2H). 13C NMR (CDCl3,
5.3.2.3. 4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)butan-
2-ol (26c). Yellow oil (73%): 1H NMR (CDCl3, 400 MHz) d 7.34 (t,
J = 8.0 Hz, 1H), 7.10–7.03 (m, 3H), 4.02–3.97 (m, 1H), 3.28–3.21
(m, 4H), 2.85–2.60 (m, 4H), 2.59–2.53 (m, 2H), 1.74–1.52 (m,
2H), 1.19 (d, J = 6.0 Hz, 3H).
100 MHz)
d 151.33, 150.93, 144.05, 138.49, 136.44, 132.87,
131.22, 129.54, 128.92, 125.72, 125.36, 123.01, 120.31, 118.57,
115.54, 111.85, 55.59, 52.86, 48.46, 46.51, 26.27, 10.28, 4.00. HR-
FABMS Calcd for C27H32F3N4O2S (M++H): 533.2198, Found:
533.2195.
5.3.2.4. 4-(4-(4-Fluorophenyl)piperazin-1-yl)butan-2-ol (26d). Pale
yellow solid (41%), mp 94–96 °C: 1H NMR (CDCl3, 400 MHz) d 6.99–
6.93 (m, 2H), 6.88–6.84 (m, 2H), 4.02–3.97 (m, 1H), 3.15–3.12 (m,
4H), 2.87–2.62 (m, 4H), 2.61–2.56 (m, 2H), 1.74–1.52 (m, 2H), 1.19
(d, J = 6.0 Hz, 3H).
5.2.4.33.
N-(Cyclopropylmethyl)-N-(3-(4-(4-fluorophenyl)pip-
erazin-1-yl)propyl)quinoline-8-sulfonamide (24d). Brown oil,
443 mg (41%): 1H NMR (CDCl3, 400 MHz) d 9.05 (dd, J = 4.0 Hz,
1H), 8.50 (dd, J = 7.2 Hz, 1H), 8.22 (dd, J = 8.4 Hz, 1H), 8.00 (dd,
J = 8.0 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.50 (q, J = 4.0 Hz, 1H), 6.97
(m, 2H), 6.87–6.84 (m, 2H), 3.62 (t, J = 7.6 Hz, 2H), 3.38 (d,
J = 8.0 Hz, 2H), 3.07 (t, J = 5.2 Hz, 4H), 2.50 (t, J = 5.2 Hz, 4H), 2.34
(t, J = 7.6 Hz, 2H), 1.85–1.80 (m, 2H), 0.87–0.83 (m, 1H), 0.39 (q,
J = 4.8 Hz, 2H), 0.13 (q, J = 4.8 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d
157.83, 154.70, 150.24, 147.27, 147.25, 143.33, 137.76, 135.77,
132.35, 128.22, 124.65, 121.23, 116.93, 114.69, 54.90, 52.48,
52.37, 49.22, 45.79, 25.54, 9.61, 3.32. HR-FABMS Calcd for
C26H32FN4O2S (M++H): 483.2230, Found: 483.2227.
5.3.3. General procedure for the preparation of 4-(4-(R-phenyl)-
piperazin-1-yl)butan-2-yl-4-methyl benzenesulfonate (27a–d)
p-Toluenesulfonyl chloride (0.75 mmol, 1.5 equiv) in 10 mL of
pyridine was added to a pyridine solution of 4-(4-(R-phenyl)pip-
erazin-1-yl)butan-2-ol 26 (0.5 mmol, 1 equiv) at rt. The mixture
was stirred at rt for 16 h. The reaction mixture was quenched with
water and extracted with chloroform. The organic layer was
washed with saturated NaHCO3 solution and brine, dried over
Na2SO4 and the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel with ethyl acetate
to give 4-(4-(R-phenyl)piperazin-1-yl)butan-2-yl-4-methylben-
zenesulfonate.
5.3. Procedures for the preparation of N-(4-(4-(R1-
phenyl)piperazin-1-yl)butan-2-yl)-Ar-sulfonamides
5.3.3.1. 4-(4-1-Phenylpiperazin-1-yl)butan-2-yl 4-methylben-
zenesulfonate (27a). Yellow oil (31%): 1H NMR (CDCl3,
400 MHz) d 7.81 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.26 (t,
J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H),
4.77–4.72 (m, 1H), 3.13 (t, J = 4.8 Hz, 4H), 2.51–2.42 (m, 7H),
2.35–2.28 (m, 2H), 1.89–1.70 (m, 2H), 1.30 (d, J = 6.0 Hz, 3H).
5.3.1. General procedure for the preparation of 2-hydroxy-4-
tosyl-butane (25)
p-Toluenesulfonyl chloride (72 mmol, 1.1 equiv) in 30 mL of
pyridine was added dropwise to the solution of 1,3-butanediol
(0.68 mmol, 1 equiv) in 2 mL pyridine at À20 °C. The mixture
was stirred at À25 °C for 1 h. Pyridine was removed. The reaction
mixture was extracted with chloroform and water. The organic
layer was washed with satd NaHCO3 solution and brine, dried over
Na2SO4 and the solvent was removed in vacuo. The crude oil was
purified by column chromatography with ethyl acetate.
5.3.3.2. 4-(4-(2-Methoxyphenyl)piperazin-1-yl)butan-2-yl
4-
methylbenzenesulfonate (27b). Yellow oil (52%): 1H NMR
(CDCl3, 400 MHz) d 7.81 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),
7.15 (d, J = 8.0 Hz, 1H), 7.02–6.98 (m, 1H), 6.94–6.90 (m, 2H),
4.76–4.70 (m, 1H), 3.86 (s, 3H), 3.14–3.09 (m, 2H), 3.06–3.02 (m,

1674
E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
4H), 2.54–2.49 (m, 4H), 2.44 (s, 3H), 1.59 (d, J = 6.4 Hz, 2H), 1.32 (d,
J = 6.4 Hz, 3H).
(m, 1H), 1.49–1.43 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
100 MHz) d 151.31, 137.06, 134.90, 132.37, 129.81, 129.61, 129.34,
128.87, 128.50, 128.10, 127.76, 122.53, 119.07, 116.41, 116.37,
112.67, 112.63, 60.19, 49.08, 47.98, 43.14, 30.96, 13.41. HR-FABMS
Calcd for C25H29F3N3O2S (M++H): 492.1933, Found: 492.1929.
5.3.3.3. 4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)butan-
2-yl-4-methylbenzenesulfonate (27c). Yellow oil (34%): 1H NMR
(CDCl3, 400 MHz) d 7.81 (d, J = 6.4 Hz, 2H), 7.36–7.32 (m, 3H), 7.80–
7.03 (m, 3H), 4.76 (q, J = 6.4 Hz, 1H), 3.17 (t, J = 5.2 Hz, 4H), 2.51–
2.45 (m, 7H), 2.34 (q, J = 7.2 Hz, 2H), 1.30 (d, J = 6.4 Hz, 3H), 1.26
(t, J = 7.2 Hz, 2H).
5.3.4.4. N-(4-(4-(4-Fluorophenyl)piperazin-1-yl)butan-2-yl)na-
phthalene-2-sulfonamide (28d). Yellow oil, 294 mg (59%): 1H
NMR (CDCl3, 400 MHz) d 8.41 (s, 1H), 7.97–7.93 (m, 2H), 7.90 (d,
J = 8.0 Hz, 1H), 7.81 (dd, J = 8.4 Hz, 1H), 7.66–7.58 (m, 2H), 6.97
(t, J = 9.2 Hz, 2H), 6.90–6.85 (m, 2H), 3.28–3.23 (m, 1H), 3.17–
3.088 (m, 4H), 2.99 (t, J = 11.2 Hz, 1H), 2.82–2.77 (m, 2H), 2.72–
2.67 (m, 1H), 2.55–2.50 (m, 2H), 1.80–1.70 (m, 1H), 1.46–1.40
(m, 1H), 0.93 (d, J = 6.4 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d
158.59, 156.22, 147.78, 136.98, 134.76, 132.24, 129.52, 129.22,
128.74, 128.34, 128.01, 127.63, 122.46, 118.15, 115.72, 115.50,
59.91, 50.41, 47.98, 43.00, 30.75, 13.35. HR-FABMS Calcd for
C24H29FN3O2S (M++H): 442.1965, Found: 442.1966.
5.3.3.4. 4-(4-(4-Fluorophenyl)piperazin-1-yl)butan-2-yl-4-meth-
ylbenzenesulfonate (27d). Yellow oil (22%): 1H NMR (CDCl3,
400 MHz) d 7.81 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.96 (t,
J = 8.4 Hz, 2H), 6.86 (dd, J = 4.8 Hz, 2H), 4.77–4.72 (m, 1H), 3.05 (t,
J = 4.8 Hz, 4H), 2.50–2.47 (m, 4H), 2.45 (s, 3H), 2.36–2.29 (m, 2H),
1.56–1.54 (m, 2H), 1.30 (d, J = 6.0 Hz, 3H).
5.3.4. General procedure for the preparation of N-(4-(4-(R-
phenyl)piperazin-1-yl)butan-2-yl)-Ar-sulfonamide (28a–d)
For the further conversion to sulfonamides, NaH (0.5 mmol,
1 equiv) was added to a solution of Ar-sulfonamide (0.5 mmol,
1 equiv) in DMF (15 mL), and the reaction mixture was stirred at
60 °C for 30 min under nitrogen. 4-(4-(R-Phenyl)piperazin-1-yl)-
butan-2-yl-4-methylbenzenesulfonate 27 (0.5 mmol, 1 equiv) in
DMF (10 mL) was added slowly to the reaction mixture. The mix-
ture was stirred at 100 °C overnight under nitrogen. After cooling
to rt, the mixture was quenched with satd NaHCO3 and extracted
with ethyl acetate. The organic layer was washed with brine, dried
over Na2SO4, and the solvent was removed in vacuo. The crude
product was purified by column chromatography with ethyl
acetate.
5.4. Radioligand binding assays16
5.4.1. [3H]Ketanserin binding to serotonin 5-HT2a receptor
For serotonin 5-HT2a binding, an aliquot of frozen membrane
from avCHO-K1 cell line expressing the human recombinant 5-
HT2a receptor and [3H]Ketanserin (1 nM) were used in the presence
of mianserin (0.5 AM) as nonspecific. The reaction mixture was
incubated for 15 min at 37 °C using 50 mM Tris–HCl (pH 7.4) buf-
fer, and harvested through Whatman GF/C glass fiber filter presoa-
ked in 0.05% Brij.
5.4.2. [3H]Mesulergine binding to serotonin 5-HT2c receptor
Frozen membranes from a stable CHO-K1 cell line expressing
the human recombinant 5-HT2c receptor were used. For the bind-
ing assay, [3H]Mesulergine (1 nM), receptor membrane and test
compounds were added into 50 mM Tris–HCl (pH 7.7) buffer con-
taining 0.1% ascorbic acid and 10 AM pargyline. Nonspecific bind-
ing was determined using 0.5 AM mianserin. The incubations were
performed for 30 min at 37 °C, and these were terminated by rapid
filtration through Whatman GF/C glass fiber filter presoaked in 1%
BSA.
5.3.4.1. N-(4-(4-Phenylpiperazin-1-yl)butan-2-yl)naphthalene-
2-sulfonamide (28a). White solid, 167 mg (47%), mp 88–90 °C:
1H NMR (CDCl3, 400 MHz) d 8.32 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H),
7.90 (d, J = 7.6 Hz, 1H), 7.81 (dd, J = 8.8 Hz, 1H), 7.66–7.58 (m,
2H), 7.27 (t, J = 7.6 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.88 (t,
J = 7.6 Hz, 1H), 3.29–3.17 (m, 5H), 2.99 (t, J = 10.8 Hz, 1H), 2.81–
2.76 (m, 2H), 2.71–2.65 (m, 1H), 2.55–2.49 (m, 2H), 1.80–1.70
(m, 1H), 1.46–1.40 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3,
100 MHz) d 151.23, 137.11, 134.82, 132.32, 129.53, 129.28, 128.76,
128.38, 128.05, 127.66, 122.52, 120.21, 116.50, 60.23, 49.63, 48.08,
43.30, 30.77, 13.39. HR-FABMS Calcd for C24H30N3O2S (M++H):
424.2059, Found: 424.2055.
5.4.3. [3H]LSD binding to serotonin 5-HT7 receptor
Membranes from stable CHO cell line expressing the human
recombinant 5-HT7 serotonin receptor (Perkin Elmer Life and
Analytical Sciences, Boston, USA) were used. For 5-HT7 receptor
binding assay, cell membrane, 3 nM [3H]LSD and appropriate con-
centrations of test compounds were added to 0.25 mL of 50 mM
Tris–HCl (pH 7.4) buffer containing 10 mM MgCl2 and 0.5 mM
EDTA. The mixture was incubated for 90 min at 27 °C, and the
reaction was terminated by rapid filtration through Whatman
GF/C glass fiber filter presoaked in 0.3% polyethylenimine. The fil-
ter was covered with Melti-Lex, sealed in a sample bag followed
by drying in the microwave oven, and counted by MicroBeta Plus
(Wallac, Finland). Nonspecific binding was determined in the
presence of 0.5 l M methiothepin. Competition binding studies
were carried out with 7–8 varied concentrations of the test com-
pounds run in duplicate tubes, and isotherms from three assays
were calculated by computerized nonlinear regression analysis
(GraphPad Prism Program, San Diego, USA) to yield inhibition val-
ues (IC50).
5.3.4.2. N-(4-(4-(2-Methoxyphenyl)piperazin-1-yl)butan-2-yl)-
naphthalene-2-sulfonamide (28b). White solid, 372 mg (49%),
mp 119–120 °C: 1H NMR (CDCl3, 400 MHz) d 8.43 (s, 1H), 7.95 (d,
J = 8.4 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.83 (dd, J = 8.8 Hz, 1H),
7.66–7.58 (m, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.99–6.92 (m, 2H), 6.87
(d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.30–3.25 (m, 1H), 3.13 (s, 4H),
3.03–2.95 (m, 1H), 2.87–2.81 (m, 2H), 2.68–2.64 (m, 1H), 2.59–
2.54 (m, 2H), 1.76–1.73 (m, 1H), 1.41–1.37 (m, 1H), 0.94 (d, 3H).
13C NMR (CDCl3, 100 MHz) d 152.39, 141.14, 137.22, 134.86,
132.40, 129.51, 129.36, 128.74, 128.46, 128.10, 127.66, 123.37,
122.63, 121.29, 118.77, 111.29, 60.74, 55.55, 51.17, 43.76, 30.44,
13.60. HR-FABMS Calcd for C25H32N3O3S (M++H): 454.2164, Found:
454.2160.
5.3.4.3. N-(4-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)bu-
tan-2-yl)naphthalene-2-sulfonamide (28c). Yellow oil, 153 mg
(40%): 1H NMR (CDCl3, 400 MHz) d 8.42 (s, 1H), 8.00–7.94 (m,
2H), 7.90 (d, J = 8.4 Hz, 1H), 7.81 (dd, J = 8.4 Hz, 1H), 7.66–7.58
(m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.11–7.10 (m, 2H), 7.05 (d,
J = 6.4 Hz, 1H), 3.28–3.19 (m, 5H), 3.01 (t, J = 11.2 Hz, 1H), 2.81–
2.76 (m, 2H), 2.74–2.69 (m, 1H), 2.55–2.50 (m, 2H), 1.78–1.73
Acknowledgment
This work was supported by a Korea Science Research Founda-
tion Grant (R01-2005-000-10046-0).

E. Yoo et al. / Bioorg. Med. Chem. 18 (2010) 1665–1675
1675
9. Bartoszyk, G. D.; van Amsterdam, C.; Böttcher, H.; Seyfried, C. A. Eur. J.
Pharmacol. 2003, 473, 229.
References and notes
10. Westkaemper, R. B.; Glennon, R. A. Curr. Top. Med. Chem. 2002, 2, 575.
11. Shireman, B. T.; Dvorak, C. A.; Rudolph, D. A.; Bonaventure, P.; Nepomuceno,
D.; Dvorak, L.; Miller, K. L.; Lovenberg, T. W.; Carruthers, N. I. Bioorg. Med. Chem.
Lett. 2008, 18, 2103.
12. Runyon, S. P.; Mosier, P. D.; Roth, B. L.; Glennon, R. A.; Westkaemper, R. B. J.
Med. Chem. 2008, 51, 6808.
13. Rowley, M.; Bristow, L. J.; Hutson, P. H. J. Med. Chem. 2001, 44, 477.
14. Yoon, J.; Yoo, E. A.; Kim, J.-Y.; Pae, A. N.; Rhim, H.; Park, W.-K.; Kong, J. Y.; Park
Choo, H.-Y. Bioorg. Med. Chem. 2008, 16, 5405.
1. Nichols, D. E.; Nichols, C. D. Chem. Rev. 2008, 108, 1614.
2. Mohammad-Zadeh, L. F.; Moses, L.; Gwaltney-Brant, S. M. J. Vet. Pharmacol.
Ther. 2008, 31, 187.
3. Schloss, P.; Williams, D. C. J. Psychopharmacol. 1998, 12, 115.
4. Awadallah, F. M. Sci. Pharm. 2008, 76, 415.
5. Ladduwahetty, T.; Boase, A. L.; Mitchinson, A.; Quin, C.; Patel, S.; Chapman, K.;
MacLeod, A. M. Bioorg. Med. Chem. Lett. 2006, 16, 3201.
6. Teegarden, B. R.; Shamma, H. A.; Xiong, Y. Curr. Top. Med. Chem. 2008, 8, 969.
7. Schmidt, C. J.; Kehne, J. H.; Carr, A. A. CNS Drug Rev. 1997, 3, 49.
8. Fletcher, S. R.; Burkamp, F.; Blurton, P.; Cheng, S. K. F.; Clarkson, R.; O’Connor,
D.; Spinks, D.; Tudge, M.; van Niel, M. B.; Patel, S.; Chapman, K.; Marwood, R.;
Shepheard, S.; Bentley, G.; Cook, G. P.; Bristow, L. J.; Castro, J. L.; Hutson, P. H.;
MacLeod, A. M. J. Med. Chem. 2002, 45, 492.
´
15. Bojarski, A. J.; Paluchowska, M. H.; Duszynska, B.; Kłodzinska, A.; Tatarczynska,
E.; Chojnacka-Wojcik, E. Bioorg. Med. Chem. 2005, 13, 2293.
16. Park, W.-K.; Jeong, D.; Cho, H.; Lee, S. J.; Cha, M. Y.; Pae, A. N.; Choi, K. I.; Koh, H.
Y.; Kong, J. Y. Pharmacol., Biochem. Behav. 2005, 82, 361.