Preparation of piperazine derivatives as 5-HT7 receptor antagonists

Article abstract of DOI:10.1016/j.bmc.2008.04.023

Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT₇ receptor antagonists. Most of the compounds showed the IC₅₀ values of 12-580 nM. Four methyl branched analogues were also obtained, but the activity for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a good activity on 5-HT₇ receptors and a good selectivity on 5-HT_1a, 5-HT_2a, 5-HT_2c, and 5-HT₆ receptors.

Full text of DOI:10.1016/j.bmc.2008.04.023

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 5405–5412
Preparation of piperazine derivatives as 5-HT7 receptor antagonists
Juhee Yoon,a Eun A Yoo,a Ji-Yeon Kim,a Ae Nim Pae,b Hyewhon Rhim,b
Woo-Kyu Park,c Jae Yang Kongc and Hea-Young Park Chooa,*
aSchool of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea
bBiochemicals Research Center, Korea Institute of Science & Technology, PO Box 131, Cheongryang,
Seoul 130-650, Republic of Korea
cPharmaceutical Screening Research Team, Korea Research Institute of Chemical Technology, Daejeon 305-343, Republic of Korea
Received 27 February 2008; revised 8 April 2008; accepted 10 April 2008
Available online 15 April 2008
Abstract—Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-
[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT7 receptor antagonists.
Most of the compounds showed the IC50 values of 12–580 nM. Four methyl branched analogues were also obtained, but the activity
for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a
good activity on 5-HT7 receptors and a good selectivity on 5-HT1a, 5-HT2a, 5-HT2c, and 5-HT6 receptors.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
depression, and possibly psychosis.4,5 Therefore agents
active at 5-HT7 receptor might be effective in the treat-
ment of sleep disorders, depression, schizophrenia, cor-
onary heart disease, migraine, and cognitive disorders.2
Serotonin is a neurotransmitter which has many impor-
tant implications in the control of numerous behavioral
and physiological processes both in peripheral and cen-
tral nervous system. The serotonergic system is known
to modulate mood, emotion, sleep, and appetite. It also
participates in memory formation. In the periphery,
serotonin induces both contraction and relaxation of
coronary artery in various species.1–3
Recently, some selective 5-HT7 receptor antagonists
such as SB-258719 and DR 4004 were discovered from
the high-throughput screening of compound li-
braries.6–9 The sulfonamide derivative SB-258719
showed a modest affinity but high selectivity, whereas
the teterahydrobenzindole derivative DR4004 showed
a high affinity but a moderate selectivity. Structurally re-
lated SB-269970 showed the highest affinity and the best
selectivity known to date to 5-HT7 receptor.10,11
Out of the fourteen subtypes, which have been reported
to date, the 5-HT7 subtype is the most recently discov-
ered one. The 5-HT7 receptors belong to GPCRs, and
high level of the receptors have been observed in the
thalamus, hypothalamus, brainstem, and hippocampus
in the brain, and blood vessels in the periphery.2
Since SB-269970 showed high activity and selectivity on
5-HT7 receptor, we designed and synthesized a number
of piperazine derivatives based on the structure of SB-
269970 and evaluated them as 5-HT7 receptor antago-
nists. (Fig. 1).
Even though the role of 5-HT7 receptors in both CNS
and periphery has not been fully clarified, biochemical
and neuroanatomical studies have suggested that the
5-HT7 receptors must have a role in smooth muscle
relaxation, vasorelaxation, control of circadian rhythms,
2. Results
2.1. Chemistry
Keywords: 5-HT7 receptor antagonists; Piperazine; Sulfonamide; 5-
HT2c receptor antagonists.
The reported pharmacophoric hypothesis generated by
catalyst suggested the minimal structural requirements
for 5-HT7 antagonism consisted of an aromatic ring, a
*
Corresponding author. Fax: +82
hypark@edwha.ac.kr
2
3277 2821; e-mail:
0968-0896/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.04.023

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J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
N
N
N
S
O
O
O
DR-4004
N
H
SB-258719
Ar1
H
N
N
H
N
N
HO
S
Ar2
N
O
S
O
O O
3a-x
SB-269970
Figure 1. 5-HT7 receptor antagonists.
basic nitrogen atom, a H-bonding acceptor group and a
˚
2.2. Biological evaluation
hydrophobic region at 4.9–5.9 A apart from the basic
center.12 Therefore, we designed sulfonamide derivatives
3a–x to possess the arylsulfonamide and piperazine moi-
eties as well as a three carbon spacer through the struc-
tural analysis of the reported 5-HT7 antagonists based
on the pharmacophoric hypothesis.
The synthesized compounds were evaluated in vitro
against the human recombinant 5-HT7 serotonin recep-
tor from stable CHO cell line. [3H]LSD binding assay
results are shown in Tables 1 and 2. Several compounds
showed good activity with IC50 values less than 150 nM.
The 5-HT7 antagonists of synthesized compounds
showed different activities depending on the substitution
on piperazine or sulfonyl group. Most active compound
(3o) showed the IC50 value of 12 nM, which has m-tri-
fluoromethylphenyl substitution on piperazine as well
as naphthyl substitution on sulfonyl group. Seven active
compounds were further evaluated for their selectivity
over 5-HT1a, 5-HT2a, 5-HT2c, and 5-HT6 receptors (Ta-
ble 3).
The synthetic procedures used in the preparation of 3a–
x are illustrated in Scheme 1.
Substituted aryl piperazine was reacted with 1-bromo-3-
chloro-propane and triethylamine to give 1-(3-chloro-
propyl)-4-(substituted phenyl)-piperazines 2. Then
nucleophilic displacement of chlorine of 2 by the nitro-
gen of p-methoxybenzene sulfonamide or 2-naphthyl-
sulfonamide afforded the desired compounds 3a–x,
respectively. Twenty-four compounds which have differ-
ent substituents such as –H, –CF3, –OCH3, –F, and –Cl2
were prepared and the structure of the synthesized com-
pounds is given in Table 1.
3. Discussion
The fact that the 5-HT7 receptor may be of value as a
novel therapeutic target has spurred extensive studies
on 5-HT7 antagonists and recently many reports were
made as a result.13–15 Also it was reported that the 5-
HT7 receptor antagonists showed an antidepressant-like
effect on sleep disorders and depression. The affinity of
some antipsychotic drugs for the 5-HT7 receptor led to
the speculation that this 5-HT7 receptor may mediate
the therapeutic actions of these compounds.16–18
The sulfonamide derivatives which have a methyl group
at the C-3 position of the three carbon spacer, as SB-
258719 showed high selectivity, were synthesized using
1,3-butanediol as a spacer unit (Scheme 2). Mono tosy-
lation of 1,3-butanediol to 1-tosyl-3-hydroxy-butane fol-
lowed by reaction with substituted aryl piperazine gave
2-hydroxyl-4-(4-substituted aryl piperazinyl)butanes
4a–d. Further tosylation of hydroxyl group of 4a–d
and substitution of tosyl group with 4-methoxybenzene
sulfonamide or 2-naphthylsulfonamide was achieved to
result in the desired compounds 6a–d.
A few arylamides linked with a spacer to phenyl-pipera-
zine were reported as active structure for 5-HT7
antagonists.18
O
Ar1
N
H N S Ar
2
2
H
N
Cl
Triethylamine
Br
O
NaH
Ar2
N
N Ar1
HN
Ar1
N
Cl
N
S
O O
2
3
1
Scheme 1. Synthesis of the target compounds 3a–x.

J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
5407
Table 1. IC50 values of the sulfonamide derivatives 3a–x against 5-HT7
receptor
Table 2. IC50 values of the sulfonamide derivatives 6a–d against 5-HT7
receptor
O
Ar1
Ar1
H3C
N
N
H
H
N
N
Ar2
N
N
S
S
O O
O O
CH3
3
6
Compound
Ar1
Ar2
IC50 (nM)
Compound
Ar1
IC50 (nM)
3a
3b
3c
3d
3e
3f
3-CF3C6H4
4-CF3C6H4
2-OCH3C6H4
3-OCH3C6H4
4-OCH3C6H4
2-FC6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
4-OCH3C6H4
89
384
6a
6b
6c
6d
3-CF3C6H4
2-OCH3C6H4
4-FC6H4
107
580
373
377
37
339
9314
289
C6H5
3g
3h
3i
4-FC6H4
47
103
3,4-Cl2C6H3
C6H5CH2
C6H5
Table 3. IC50 values of the selected sulfonamide derivatives against 5-
HT receptors
949
3j
>10,000
>10,000
>10,000
Compound
Binding affinity, IC50 (nM)
3k
3l
4-NO2C6H4
4-COCH3C6H4
O
5-HT1a
receptor
5-HT2a
receptor
5-HT2c
receptor
5-HT6
receptor
3m
3n
4-OCH3C6H4
4-OCH3C6H4
>10,000
>10,000
3a
3c
3g
3o
3q
3v
6a
44
272
39
352
5168
74
57
9665
4886
91
2839
>10,000
>10,000
1956
O
O
O
29
95
85
4.6
215
39
241
215
2634
768
19
1824
1349
6925
3o
3p
3q
3r
3-CF3C6H4
4-CF3C6H4
2-OCH3C6H4
3-OCH3C6H4
4-OCH3C6H4
2-FC6H4
C10H7
C10H7
C10H7
C10H7
C10H7
C10H7
C10H7
C10H7
C10H7
C10H7
12
567
20
223
3241
140
53
methoxy compounds (3c and 3q) showed 200–300 times
higher activity than p-methoxy congeners (3e and 3s),
respectively. Similarly m-CF3 substituted compounds
showed higher activity than p-CF3 congeners (3a > 3b
and 3o > 3p). However, in the case of fluorine, the above
postulated trend failed, and p-F substituted compounds
(3g and 3u) showed higher activity than o-F substituted
congeners (3f and 3t).
3s
3t
3u
3v
3w
3x
4-FC6H4
3,4-Cl2C6H3
C6H5CH2
C6H5
124
476
681
The 5-HT7 antagonists of synthesized compounds
showed a different activity depending on the substitution
on piperazine. The introduction of carbonyl group (3l,
3m, and 3n) resulted in the complete loss of activity.
Compounds which have –CF3, –OCH3, or –F substi-
tuted phenyl group on piperazine showed a high activity
with IC50 values ranging in 12–375 nM. The position of
substituents on phenyl also affected the activity as
shown in 3c–e and 3q–s. For these methoxyphenyl
substituted analogues, the order was o->m->p- and o-
Only two substitutions on the sulfonyl group were com-
pared, though the study on the effect of substitution on
sulfonyl group was not conclusive. General 2-naphthyl
substituted compounds showed a little higher activity
than 4-methoxyphenyl substituted compounds.
All the four compounds with methyl branch on three
carbon spacer showed a good activity as shown in Table
2. But it showed very limited effect on the introduction
Ar1
N
HN
N Ar1 H3C
N
N
H3C
OTs
H3C
OH
TsCl
TsCl
OH
OH
OH
4
Ar1
O
Ar1
N
N
H
H2N S Ar2
O
Ar2
N
H3C
N
S
O O
NaH
CH3
OTs
5
6
Scheme 2. Synthesis of the target compounds 6a–d.

5408
J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
of methyl group, and only one compound (6d) was more
active than its straight chain congener (3j and 3x).
ture was stirred at rt for 16 h. The reaction mixture
was made basic to pH 9 with saturated NaHCO3 solu-
tion, and extracted with ethyl acetate. The organic phase
was dried over Na2SO4 and evaporated in vacuo. The
crude product was purified by column chromatography
to give 1-(3-chloro-propyl)-4-Ar1-piperazine (dichloro-
methane/methanol = 20:1).
Since SB-258719 showed a modest affinity but high
selectivity, the methyl branch on the three carbon spacer
could be useful for the selectivity over different 5-HT
receptors.
Seven compounds with high 5-HT7 activity were further
evaluated for their selectivity on 5-HT1a, 5-HT2a, 5-
HT2c, and 5-HT6 receptors. Most of the evaluated com-
pounds showed good selectivity over 5-HT6 receptors,
but poor selectivity over 5-HT1a receptors. Among the
synthesized compounds, 3c showed good activity over
5-HT7 (IC50 = 37 nM) and good selectivity over 5-
HT1a (IC50 = 272 nM), 5-HT2a (5168 nM), 5-HT2c
(9665 nM), and 5-HT6 (>10,000 nM). Compound 3o
showed a poor selectivity but good activity for the most
of receptors with IC50 values of 12, 29, 95, and 91 nM
for 5-HT7, 5-HT1a, 5-HT2a, and 5-HT2c receptors,
respectively. The methyl branched compound 6a showed
moderate selectivity for 5-HT2a, 5-HT2c, and 5-HT6
receptors.
For the further conversion to sulfonamides, NaH
(0.5 mmol, 1 equiv) was added to a suspension of aryl-
benzenesulfonamide (0.5 mmol, 1 equiv) in DMF
(15 mL). After stirring at 60 °C for 30 min under nitro-
gen, 1-(3-chloro-propyl)-4-Ar1-piperazine (0.5 mmol,
1 equiv) in DMF (10 mL) was added. The reaction mix-
ture was stirred at 80 °C for 16 h. After cooling, the mix-
ture was extracted with ethyl acetate. The organic layer
was washed with water, dried over Na2SO4, and the sol-
vent was removed in vacuo. The crude product was puri-
fied by column chromatography to give Ar2-N-[3-(4-
Ar1-piperazin-1-yl)-propyl]-sulfonamide (ethyl acetate/
n-hexane/methanol = 10:1:1).
5.2.1. 4-Methoxy-N-{3-[4-(m-trifluoromethylphenyl)-pip-
erazin-1-yl]-propyl}-benzenesulfonamide (3a). Pale yellow
1
solid, 11 mg (5%), mp 93–95 °C: H NMR (400 MHz,
4. Conclusion
CDCl3) d 7.79 (m, 2H), 7.35 (m, 1H), 7.07 (m, 3H),
6.97 (m, 2H), 3.87 (s, 3H), 3.25 (s, 4H), 3.08 (t,
J = 11.6 Hz, 2H), 2.59 (s, 4H), 2.49 (t, J = 12.0 Hz,
2H), 1.70 (m, 2H). HR-FABMS Calcd for
C21H27F3N3O3S1 (M++H): 458.1725, Found: 458.1726.
Twenty-eight arylamides linked with a spacer to phenyl-
piperazine were synthesized and evaluated as 5-HT7
antagonists. The synthesized compounds showed differ-
ent activity depending on the substitution on piperazine.
Compounds which have –CF3, –OCH3, or –F substi-
tuted phenyl group on piperazine showed good activity
with IC50 values 12–375 nM. Among the synthesized
compounds, 3c showed good activity on 5-HT7
(IC50 = 37 nM) and good selectivity on 5-HT1a
5.2.2. 4-Methoxy-N-{3-[4-(p-trifluoromethylphenyl)-pip-
erazin-1-yl]-propyl}-benzenesulfonamide (3b). Yellow so-
1
lid, 7 mg (3%), mp 105–106 °C: H NMR (400 MHz,
CDCl3) d 7.79 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.97
(m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.29 (s,
4H), 3.08 (t, J = 11.6 Hz, 2H), 2.57 (s, 4H), 2.48 (t,
J = 11.6 Hz, 2H), 1.70 (m, 2H). HR-FABMS Calcd for
C21H27F3N3O3S1 (M++H): 458.1725, Found: 458.1722.
(IC50 = 272 nM),
5-HT2a
(9665 nM), and 5-HT6(>10,000 nM).
(5168 nM),
5-HT2c
5. Experimental
5.2.3. 4-Methoxy-N-{3-[4-(o-methoxyphenyl)-piperazin-
1-yl]-propyl}-benzenesulfonamide (3c). Yellow oil,
83 mg (43%): H NMR (400 MHz, CDCl3) d 7.73 (d,
1
5.1. Materials and methods
J = 9.2 Hz, 2H), 6.91 (m, 5H), 3.79 (s, 3H), 3.20 (s,
3H), 3.04 (m, 6H), 2.56 (m, 4H), 2.42 (t, J = 6.4 Hz,
2H), 1.61 (m, 2H). HR-FABMS Calcd for C21H30N3O4S
(M++H): 420.1957, Found: 420.1953.
All the melting points of the synthesized compounds
were taken in Pyrex capillaries using electrothermal dig-
ital melting point apparatus (Buchi) and were not cor-
¨
1
rected. H NMR spectra were recorded on a 400 MHz
Varian FT-NMR using tetramethylsilane as an internal
standard. Mass spectra data were obtained on a Jeol
JMS 700 high resolution mass spectrometer at the Kor-
ea Basic Science Institute (Daegu). Most of the reagents
were purchased from Aldrich Chemical Company and
Merck Company.
5.2.4. 4-Methoxy-N-{3-[4-(m-methoxyphenyl)-piperazin-
1-yl]-propyl}-benzenesulfonamide (3d). Pale yellow solid,
61 mg (26%), mp 97–99 °C: 1H NMR (400 MHz,
CDCl3) d 7.80 (m, 2H), 7.17 (t, J = 16.4 Hz, 1H), 6.97
(m, 2H), 6.52 (d, J = 10.8 Hz, 1H), 6.46 (s, 1H), 6.44
(d, J = 10.8 Hz, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.20 (s,
4H), 3.08 (t, J = 11.6 Hz, 2H), 2.56 (s, 4H), 2.47 (t,
J = 11.6 Hz, 2H), 1.68 (m, 2H). HR-FABMS Calcd for
C21H30N3O4S (M++H): 420.1957, Found: 420.1959.
5.2. General procedure for the preparation of 4-methoxy-
N-{3-[4-(substituted phenyl)-piperazin-1-yl]-propyl}-ben-
zenesulfonamides (3a–x)
5.2.5. 4-Methoxy-N-{3-[4-(p-methoxyphenyl)-piperazin-
1-yl]-propyl}-benzenesulfonamide (3e). Pale yellow solid,
35 mg (17%), mp 116–119 °C: 1H NMR (400 MHz,
CDCl3) d 7.78 (m, 2H), 6.96 (m, 2H), 6.91 (m, 2H),
6.84 (m, 2H), 3.86 (s, 3H), 3.78 (s, 3H), 3.09 (m, 6H),
To a suspension of 1-(4-substituted aryl) piperazine
(0.5 mmol, 1 equiv) and triethylamine (0.75 mmol,
1.5 equiv) in dichloromethane was added 1-bromo-3-
chloro-propane (1.0 mmol, 2 equiv). The reaction mix-

J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
5409
2.58 (s, 4H), 2.47 (t, J = 11.6 Hz, 2H), 1.67 (m, 2H). HR-
FABMS Calcd for C21H30N3O4S (M++H): 420.1957,
Found: 420.1956.
3.87 (s, 3H), 3.37–3.40 (m, 4H), 3.07–3.10 (m, 2H),
2.56–2.64 (m, 4H), 2.52–2.54 (m, 2H), 2.51 (s, 3H),
1.70–1.74 (m, 2H). HR-FABMS Calcd for
C22H30N3O4S (M++H): 432.1957, Found: 432.1953.
5.2.6. 4-Methoxy-N-{3-[4-(o-fluorophenyl)-piperazin-1-
yl]-propyl}-benzenesulfonamide (3f). Yellow oil, 58 mg
(16%): H NMR (400 MHz, CDCl3) d 7.79 (m, 2H),
7.05 (m, 2H), 6.96 (m, 4H), 3.87 (s, 3H), 3.12 (s, 4H),
3.08 (t, J = 11.6 Hz, 2H), 2.60 (s, 4H), 2.48 (t,
J = 11.6 Hz, 2H), 1.67 (m, 2H). HR-FABMS Calcd for
C20H27FN3O3S (M++H): 408.1757, Found: 408.1752.
5.2.13. Benzyl-4-(4-methoxyphenyl sulfonylaminopropyl)-
piperazine-1-carboxylate (3m). Red brown oil, 37.7 mg
1
(19%): 1H NMR (400 MHz, CDCl3)
d 7.78 (d,
J = 8.8 Hz, 2H), 7.32–7.38 (m, 5H), 6.97 (d,
J = 8.8 Hz, 2H), 5.13 (s, 2H), 3.87 (s, 3H), 3.50–3.52
(m, 4H), 3.05–3.08 (m, 2H), 2.36–2.48 (m, 6H), 1.60–
1.70 (m, 2H). HR-FABMS Calcd for C22H30N3O5S
(M++H): 448.1906, Found: 448.1910.
5.2.7. 4-Methoxy-N-{3-[4-(p-fluorophenyl)-piperazin-1-
yl]-propyl}-benzenesulfonamide (3g). Pale yellow solid,
45 mg (22%), mp > 300 °C: 1H NMR (400 MHz,
CDCl3) d 7.72 (d, J = 7.2 Hz, 2H), 6.87–6.92 (m, 4H),
6.79–6.83 (m, 2H), 3.79 (s, 3H), 3.08–3.10 (m, 4H),
2.99–3.03 (m, 2H), 2.52–2.58 (m, 4H), 2.42–2.48 (m,
2H), 1.62–1.68 (m, 2H). HR-FABMS Calcd for
C20H27FN3O3S (M++H): 408.1757, Found: 408.1759.
5.2.14. 4-Methoxy-N-{3-[4-(furan-2-yl-methanoyl)-pip-
erazin-1-yl]-propyl}-benzenesulfonamide (3n). Brown oil,
1
27.7 mg (13%): H NMR (400 MHz, CDCl3) d 7.87 (d,
J = 6.8 Hz, 2H), 7.80 (d, J = 6.8 Hz, 2H), 7.48 (dd,
J = 2.0 and 0.8 Hz, 1H), 6.97 (dd, J = 2.0 and 0.8 Hz,
1H), 6.48 (dd, J = 4.0 and 2.0 Hz, 1H), 3.87 (s, 3H),
3.07–3.10 (m, 2H), 2.46–2.51 (m, 8H), 1.65–1.75 (m,
2H), 0.85–0.88 (m, 2H). HR-FABMS Calcd for
C19H26N3O5S (M++H): 408.1593, Found: 408.1591.
5.2.8. 4-Methoxy-N-{3-[4-(3,4-dichlorophenyl)-piperazin-
1-yl]-propyl}-benzenesulfonamide (3h). Yellow oil,
1
43.9 mg (10.6%): H NMR (400 MHz, CDCl3) d 7.74
(d, J = 9.2 Hz, 1H), 7.25–7.28 (m, 2H), 6.94–6.98 (m,
2H), 6.72 (d, J = 12.0 Hz, 1H), 3.86 (s, 3H), 3.13–3.20
(m, 6H), 2.54 (t, J = 10.0 Hz, 4H), 2.39 (t, J = 14.4 Hz,
2H), 1.76–1.80 (m, 2H) HR-FABMS Calcd for
C20H26Cl2N3O3S (M++H): 458.1072, Found: 458.1074.
5.2.15. Naphthalene-2-sulfonic acid {3-[4-(3-trifluoro-
methylphenyl)-piperazin-1-yl]-propyl}-amide (3o). Pale
yellow solid, 105 mg (20%), mp 86–88 °C: 1H NMR
(400 MHz, DMSO d6) d 8.44 (s, 1H), 8.14 (m, 2H),
8.04 (m, 1H), 7.90 (d, J = 10.4 Hz, 1H), 7.84 (d,
J = 10.8 Hz, 1H), 7.68 (m, 3H), 7.46 (s, 1H), 7.05 (m,
1H), 3.05 (s, 4H), 2.84 (m, 2H), 2.32 (m, 4H), 2.25 (t,
J = 13.6 Hz, 2H), 1.55 (m, 2H). HR-FABMS Calcd for
C24H26F3N3O2S (M++H): 478.1776, Found: 478.1773.
5.2.9. 4-Methoxy-N-[3-(4-benzyl-piperazin-1-yl)-propyl]-
benzenesulfonamide (3i). Yellow oil, 16.4 mg (4.5%): H
1
NMR (400 MHz, CDCl3) d 7.78 (d, J = 9.2 Hz, 2H),
7.32 (d, J = 4.4 Hz, 4H), 6.96 (d, J = 9.2 Hz, 2H), 3.87
(s, 3H), 3.52 (s, 2H), 3.04 (t, J = 11.2 Hz, 2H), 2.42–
2.56 (m, 4H), 2.40 (t, J = 11.6 Hz, 4H), 1.59–1.62 (m,
2H) HR-FABMS Calcd for C21H30N3O3S (M++H):
404.2008, Found: 404.2007.
5.2.16. Naphthalene-2-sulfonic acid {3-[4-(4-trifluoro-
methylphenyl)-piperazin-1-yl]-propyl}-amide (3p). White
solid, 205 mg (66%), mp 136–139 °C: 1H NMR
(400 MHz, CDCl3) d 8.42 (s, 1H), 7.96 (m, 2H), 7.91
(d, J = 7.6 Hz, 1H), 7.82 (d, J = 10.4 Hz, 1H), 7.63 (m,
2H), 7.48 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H),
3.28 (s, 4H), 3.14 (t, J = 11.6 Hz, 2H), 2.55 (s, 4H),
2.46 (t, J = 11.6 Hz, 2H), 1.70 (m, 2H). HR-FABMS
Calcd for C24H27F3N3O2S (M++H): 478.1776, Found:
478.1777.
5.2.10.
4-Methoxy-N-[3-(4-phenyl-piperazin-1-yl)-pro-
pyl]-benzenesulfonamide (3j). Pale yellow solid, 92 mg
(48%), mp > 300 °C: 1H NMR (400 MHz, CDCl3) d
7.72 (d, J = 9.2 Hz, 2H), 7.18–7.22 (m, 2H), 6.85–9.92
(m, 4H), 6.81 (tt, J = 7.2 and 0.8 Hz, 1H), 3.79 (s, 3H)
3.14–3.17 (m, 4H), 3.00–3.03 (m, 2H), 2.50–2.56 (m,
4H), 2.42–2.45 (m, 2H), 1.62–1.65 (m, 2H). HR-FABMS
Calcd for C20H27N3O3S (M++H): 390.1851, Found:
390.1846.
5.2.17. Naphthalene-2-sulfonic acid {3-[4-(2-methoxy-
phenyl)-piperazin-1-yl]-propyl}-amide (3q). Yellow solid,
27 mg (5%), mp 100–102 °C: 1H NMR (400 MHz,
CDCl3) d 8.49 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.16
(d, J = 9.2 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.81 (d,
J = 8.0 Hz, 1H), 7.70 (m, 2H), 6.88 (m, 4H), 3.75 (s,
3H), 3.23 (t, J = 14.8 Hz, 2H), 2.88 (s, 4H), 2.40 (s,
4H), 2.29 (t, J = 13.6 Hz, 2H), 1.66 (m, 2H). HR-FAB-
MS Calcd for C24H30N3O3S (M++H): 440.2008, Found:
440.2004.
5.2.11. 4-Methoxy-N-{3-[4-(p-nitrophenyl)-piperazin-1-
yl]-propyl}-benzenesulfonamide (3k). Brown oil, 57.8 mg
(26%): 1H NMR (400 MHz, CDCl3)
d 8.34 (d,
J = 9.2 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 6.97 (d,
J = 8.8 Hz, 2H), 6.83 (d, J = 9.2 Hz, 2H), 3.86 (s, 3H),
3.44–3.50 (m, 4H), 3.09 (t, J = 6.0 Hz, 2H), 2.54–2.68
(m, 6H), 1.72–1.80 (m, 2H). HR-FABMS Calcd for
C20H27N4O5S (M++H): 435.1702, Found: 435.1706.
5.2.18. Naphthalene-2-sulfonic acid {3-[4-(3-methoxy-
phenyl)-piperazin-1-yl]-propyl}-amide (3r). Brown oil,
11 mg (5%): 1H NMR (400 MHz, CDCl3) d 8.47 (s,
1H), 8.20 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H),
8.06 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 10.4 Hz, 1H),
7.70 (m, 2H), 7.09 (t, J = 16.4 Hz, 1H), 6.40 (m, 3H),
3.71 (s, 3H), 3.20 (m, 2H), 3.04 (s, 4H), 2.37 (s, 4H),
5.2.12. 4-Methoxy-N-{3-[4-(4-acetophenyl)-piperazin-1-
yl]-propyl}-benzenesulfonamide (3l). Pale yellow solid,
31.2 mg (29%), mp > 300 °C: 1H NMR (400 MHz,
CDCl3) d 7.87 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 9.2 Hz,
2H), 6.98 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H),

5410
J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
2.27 (t, J = 14.0 Hz, 2H), 1.65 (m, 2H). HR-FABMS
Calcd for C24H30N3O3S (M++H): 440.2008, Found:
440.2005.
5.3. General procedure for the preparation of 4-methoxy-
N-{3-[4-(m-trifluoromethylphenyl)-piperazin-1-yl]-1-
methyl-propyl}-benzenesulfonamide (6a–d)
5.2.19. Naphthalene-2-sulfonic acid {3-[4-(4-methoxy-
phenyl)-piperazin-1-yl]-propyl}-amide (3s). Pale brown
solid, 26 mg (8%), mp 150–153 °C: 1H NMR
(400 MHz, CDCl3) d 8.43 (s, 1H), 8.14 (t, J = 18.8 Hz,
2H), 8.05 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 10.8 Hz,
1H), 7.69 (m, 2H), 6.80 (s, 4H), 3.67 (s, 3H), 3.31 (m,
2H), 2.83 (m, 4H), 2.25 (m, 4H), 2.23 (t, J = 13.6 Hz,
2H), 1.54 (m, 3H). HR-FABMS Calcd for C24H30N3O3S
(M++H): 440.2008, Found: 440.2009.
Tosyl chloride (14.1 g, 74 mmol) in 30 mL of pyridine
was added dropwise to the solution of 1,3-butanediol
(6.2 g, 68 mmol) in 20 mL pyridine at À20 °C. The mix-
ture was stirred at À25 °C for 1 h. Water was added, and
the mixture was stirred for 20 min. The reaction mixture
was extracted with chloroform, and the organic layer
was washed with saturated NaHCO3 solution and brine,
dried over Na2SO4 and the solvent was removed in va-
cuo. After column chromatography on silica gel (n-hex-
ane/ethyl acetate = 3:2), 1-tosyl-3-hydroxy-butane was
obtained in ca. 40% yield.
5.2.20. Naphthalene-2-sulfonic acid {3-[4-(2-fluoro-
phenyl)-piperazin-1-yl]-propyl}-amide (3t). Dark brown
1
oil, 130 mg (31%): H NMR (400 MHz, CDCl3) d 8.40
2-Hydroxy-4-tosyl-butane (0.5 mmol, 1 equiv) and 4-
Ar1-piperazine (0.75 mmol, 1.5 equiv) were refluxed in
acetonitrile (25 mL) for 16 h under nitrogen. On cooling
to rt, the solvent was removed in vacuo, the residue was
extracted with dichloromethane. The organic layer was
washed with water, dried over Na2SO4 and the solvent
was removed in vacuo. The crude oil was purified by col-
umn chromatography (methylene chloride/metha-
nol = 9:1). Tosyl chloride (0.75 mmol, 1.5 equiv) in
10 mL of pyridine was added to a pyridine solution of
(s, 1H), 7.95–7.98 (m, 2H), 7.91 (d, J = 8.0 Hz, 1H),
7.79 (d, J = 10.4 Hz, 1H), 7.61–7.66 (m, 2H), 6.90–7.07
(m, 4H), 3.29 (t, J = 15.2 Hz, 2H), 3.06 (s, 4H), 2.55
(s, 4H), 2.39 (t, J = 14.0 Hz, 2H), 1.67–1.82 (m, 2H).
HR-FABMS Calcd for C23H27FN3O2S (M++H):
428.1808, Found: 428.1805.
5.2.21. Naphthalene-2-sulfonic acid {3-[4-(4-fluoro-
phenyl)-piperazin-1-yl]-propyl}-amide (3u). Pale yellow
solid, 28 mg (7.2%), mp 143–145 °C: 1H NMR
(400 MHz, CDCl3) d 8.42 (s, 1H), 7.96 (d, J = 11.2 Hz,
2H), 7.91 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 10.4 Hz,
1H), 7.61–7.65 (m, 2H), 6.98 (t, J = 17.6 Hz, 2H),
6.86–6.89 (m, 2H), 3.13 (t, J = 10.4 Hz, 6H), 2.56 (t,
J = 10.0 Hz, 4H), 2.46 (t, J = 11.6 Hz, 2H), 1.65–1.71
(m, 2H). HR-FABMS Calcd for C23H27FN3O2S
(M++H): 428.1808, Found: 428.1805.
2-hydroxy-4-(4-Ar1-piperazine)-butane
(0.5 mmol,
1 equiv) at rt. The mixture was stirred at rt for 16 h.
To the reaction mixture, water (2 mL) was added and
stirred for 20 min. The reaction mixture was extracted
with chloroform. The organic layer was washed with
saturated NaHCO3 solution and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (n-hex-
ane/ethyl acetate = 3:2) to give 2-tosyl-4-(4-Ar1-pipera-
zine)-butane.
5.2.22. Naphthalene-2-sulfonic acid {3-[4-(3,4-dichloro-
phenyl)-piperazin-1-yl]-propyl}-amide (3v). Pale yellow
solid, 113 mg (23%), mp 146–148 °C: 1H NMR
(400 MHz, DMSO d6) d 8.44 (s, 1H), 8.15 (m, 2H),
8.04 (t, J = 13.2 Hz, 1H), 7.85 (m, 1H), 7.69 (m, 2H),
7.37 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 6.85 (d,
J = 12 Hz, 1H), 3.00 (m, 4H), 2.84 (m, 2H), 2.30 (s,
4H), 2.23 (t, J = 13.6 Hz, 2H), 1.53 (m, 2H). HR-FAB-
MS Calcd for C23H26Cl2N3O2S (M++H): 478.1123,
Found: 478.1119.
For the further conversion to sulfonamides, NaH
(0.5 mmol, 1 equiv) was added to a solution of 4-meth-
oxy-benzenesulfonamide (0.5 mmol, 1 equiv) in DMF
(15 mL), and the reaction mixture was stirred at 60 °C
for 30 min. under nitrogen. 2-Tosyl-4-(4-Ar1-pipera-
zine)-butane (0.5 mmol, 1 equiv) in DMF (10 mL) was
added slowly to the reaction mixture. The mixture was
stirred at 60° Covernight under nitrogen. After cooling,
the mixture was extracted with ethyl acetate. The organ-
ic layer was washed with brine, dried over Na2SO4, and
the solvent was removed in vacuo. The crude product
was purified by column chromatography (ethyl ace-
tate/n-hexane/methanol = 10:1:1).
5.2.23. Naphthalene-2-sulfonic acid [3-(4-benzyl-pipera-
zin-1-yl)-propyl]-amide (3w). Yellow solid, 40 mg (31%),
1
mp 110–113 °C: H NMR (400 MHz, DMSO d6) d 8.37
(s, 1H), 8.10 (m, 2H), 7.99 (d, J = 8.8 Hz, 1H), 7.75 (d,
J = 10.4 Hz, 1H), 7.63 (m, 2H), 7.26 (m, 2H), 7.18 (d,
J = 6.8 Hz, 1H), 3.30 (s, 2H), 2.75 (m, 2H), 2.27 (m,
2H), 2.12 (m, 8H), 1.42 (m, 2H). HR-FABMS Calcd
for C24H30N3O2S (M++H): 424.2059, Found: 424.2061.
5.3.1. 4-Methoxy-N-{3-[4-(m-trifluoromethylphenyl)-pip-
erazin-1-yl]-1-methyl-propyl}-benzenesulfonamide (6a).
Pale yellow oil, 90 mg (40%): 1H NMR (400 MHz,
CDCl3) d 7.74 (m, 2H), 7.32 (t, J = 13.2 Hz, 1H), 7.06
(m, 3H), 6.96 (m, 2H), 3.84 (s, 3H), 3.25 (m, 6H), 2.63
(m, 4H), 1.69 (m, 2H), 1.00 (s, 2H). HR-FABMS Calcd
for C22H29F3N3O3S (M++H): 472.1882, Found:
472.1883.
5.2.24. Naphthalene-2-sulfonic acid [3-(4-phenyl-pipera-
zin-1-yl)-propyl]-amide (3x). Yellow oil 13 mg (5%): H
1
NMR (400 MHz, CDCl3) d 8.36 (s, 1H), 7.97 (d,
J = 9.6 Hz, 2H), 7.80 (m, 2H), 7.58 (t, J = 15.2 Hz,
2H), 7.29 (t, J = 16.4 Hz, 1H), 7.25 (m, 2H), 6.88 (m,
2H), 3.51 (m, 2H), 3.21 (m, 4H), 2.87 (m, 4H), 2.72
(m, 2H), 0.86 (m, 2H). HR-FABMS Calcd for
C23H28N3O2S (M++H): 410.1902, Found: 410.1901.
5.3.2. 4-Methoxy-N-{3-[4-(o-methoxyphenyl)-piperazin-
1-yl]-1-methyl-propyl}-benzen sulfonamide (6b). Yellow
1
oil, 10 mg (6%): H NMR (400 MHz, CDCl3) d 7.76

J. Yoon et al. / Bioorg. Med. Chem. 16 (2008) 5405–5412
5411
(m, 2H), 6.97 (m, 2H), 6.91 (m, 2H), 6.82 (d, J = 9.2 Hz,
2H), 3.85 (s, 6H), 3.28 (m, 1H), 3.06 (m, 6H), 2.73 (m,
2H), 2.63 (m, 4H), 1.00 (s, 2H). HR-FABMS Calcd
for C22H32N3O4S (M++H): 434.2114, Found: 434.2111.
5.4.3. [3H]Ketanserin binding to serotonin 5-HT2a recep-
tor. For serotonin 5-HT2a binding, an aliquot of frozen
membrane from CHO-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 TrisÆHCl (pH 7.4) buf-
fer, and harvested through Whatman GF/C glass fiber
filter presoaked in 0.05% Brij.
5.3.3. 4-Methoxy-N-{3-[4-(p-fluorophenyl)-piperazin-1-
yl]-1-methyl-propyl}-benzenesulfonamide (6c). Brown
1
oil, 24 mg (6%): H NMR (400 MHz, CDCl3) d 7.74
(m, 2H), 6.93 (m, 4H), 6.86 (m, 3H), 3.84 (s, 3H), 3.26
(m, 1H), 3.09 (m, 4H), 2.60 (m, 4H), 1.76 (m, 1H),
1.59 (m, 1H), 1.00 (s, 2H). HR-FABMS Calcd for
C21H29FN3O3S (M++H): 422.1914, Found: 422.1902.
5.4.4. [3H]Mesulergine binding to serotonin 5-HT2c
receptor. Frozen membranes from stable CHO-K1 cell
line expressing the human recombinant 5-HT2c receptor
were used. For the binding assay, [3H]Mesulergine
(1 nM), receptor membrane and test compounds were
added into 50 mM TrisÆHCl (pH 7.7) buffer containing
0.1% ascorbic acid and 10 AM pargyline. Nonspecific
binding 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 What-
man GF/C glass fiber filter presoaked in 1% BSA.
5.3.4. 4-Methoxy-N-[3-(4-phenyl-piperazin-1-yl)-1-
methyl-propyl]-benzenesulfonamide (6d). Pale brown so-
1
lid, 30 mg (15%), mp 92–94 °C: H NMR (400 MHz,
CDCl3) d 7.77 (m, 2H), 7.27 (m, 2H), 6.96 (m, 4H),
6.88 (m, 1H), 3.85 (s, 3H), 3.20 (m, 4H), 2.96 (m, 2H),
2.76 (m, 4H), 2.53 (m, 2H), 1.74 (m, 1H), 1.44 (m,
1H), 0.95 (s, 2H). HR-FABMS Calcd for C21H30N3O3S
(M++H): 404.2008, Found: 404.2004.
5.4. Radioligand binding assays19
5.4.5. [3H]LSD binding to serotonin 5-HT6 and 5-HT7
receptor. For receptor binding assays, human 5-HT6 and
5-HT7 serotonin receptor expressed in HeLa cells were
used. Frozen membrane, 1.8 nM [3H]LSD and appropri-
ate concentrations of test compounds were added to
0.25 mL of assay buffer. Incubations were carried out
for 60 min at 37 °C, and these were terminated by rapid
filtration through Whatman GF/C glass fiber filter pres-
oaked in 0.3% polyethylenimine. Methiothepin and
50 mM TrisÆHCl (pH 7.4) containing 10 mM MgCl2 and
0.5 mM EDTA, were used as the nonspecific ligand or as-
say buffer, respectively.
5.4.1. [3H]LSD binding to serotonin 5-HT7 receptor.
Membranes from stable CHO cell line expressing the hu-
man recombinant 5-HT7 serotonin receptor (PerkinEl-
mer Life and Analytical Sciences, Boston, USA) were
used. For 5-HT7 receptor binding assay, cell membrane,
3 nM [3H]LSD and appropriate concentrations of test
compounds were added to 0.25 mL of 50 mM TrisÆHCl
(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 filter was covered with Melti-
Lex, sealed in a sample bag followed by drying in the
microwave oven, and counted by MicroBeta Plus (Wal-
lac, Finland). Nonspecific binding was determined in
the presence of 0.5 lM methiothepin. Competition bind-
ing studies were carried out with 7–8 varied concentra-
tions of the test compounds run in duplicate tubes, and
isotherms from three assays were calculated by computer-
ized nonlinear regression analysis (GraphPad Prism Pro-
gram, San Diego, USA) to yield inhibition values (IC50).
Acknowledgment
This work was supported by a Korea Science Research
Foundation Grant (R01-2005-000-10046-0).
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