Synthesis and SAR of (piperazin-1-yl-phenyl)-arylsulfonamides: A novel series of atypical antipsychotic agents

Article abstract of DOI:10.1016/j.bmcl.2010.06.150

(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for both 5-HT_2C and 5-HT₆ receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-piperazin-1-yl)- phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT_2C (IC₅₀ = 4 nM) and 5-HT₆ receptors (IC₅₀ = 3 nM) with good selectivity over other serotonin (5-HT_1A, 5-HT _2A, and 5-HT₇) and dopamine (D₂-D₄) receptor subtypes. In 5-HT_2C and 5-HT₆ receptor functional assays, this compound showed considerable antagonistic activity for both receptors.

Full text of DOI:10.1016/j.bmcl.2010.06.150

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5221–5224
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR of (piperazin-1-yl-phenyl)-arylsulfonamides: A novel series
of atypical antipsychotic agents
a
b
a
a
Chul Min Park a, , So Young Kim , Woo Kyu Park , Jung Hwan Choi , Churl Min Seong
*
a Medicinal Chemistry Research Center, Bio-Organic Division, Korea Research Institute of Chemical Technology, Sinseongno 19, Yuseong-gu, Daejeon 305-600, South Korea
b Pharmacology Research Center, Bio-Organic Division, Korea Research Institute of Chemical Technology, Sinseongno 19, Yuseong-gu, Daejeon 305-600, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
(Piperazin-1-yl-phenyl)-arylsulfonamides were synthesized and identified to show high affinities for
both 5-HT2C and 5-HT6 receptors. Among them, naphthalene-2-sulfonic acid isopropyl-[3-(4-methyl-pip-
erazin-1-yl)-phenyl]-amide (6b) exhibits the highest affinity towards both 5-HT2C (IC50 = 4 nM) and 5-
HT6 receptors (IC50 = 3 nM) with good selectivity over other serotonin (5-HT1A, 5-HT2A, and 5-HT7) and
dopamine (D2–D4) receptor subtypes. In 5-HT2C and 5-HT6 receptor functional assays, this compound
showed considerable antagonistic activity for both receptors.
Received 12 May 2010
Revised 15 June 2010
Accepted 30 June 2010
Available online 23 July 2010
Keywords:
Serotonin
Ó 2010 Elsevier Ltd. All rights reserved.
5-HT2C receptor
5-HT6 receptor
Antagonist
Arylsulfonamide
Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neu-
rotransmitter synthesized in serotonergic neurons in the central
nervous system (CNS) and plays an important role in the modula-
tion of anger, aggression, body temperature, mood, sleep, human
sexuality, appetite, and metabolism, as well as stimulating vomit-
ing.1,2 There are at least 15 different serotonin receptors that have
been cloned and divided into seven subclasses (5-HT1–7).3,4
The 5-HT2 subfamily consists of three G-protein coupled recep-
tors (GPCRs) which are coupled to Gq-protein and mediate excit-
atory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C
subtypes.5–7 The non-selective 5-HT agonist, m-chlorophenyl piper-
azine (mCPP), is known to induce symptoms of compulsive disorder,
depression, and anxiety in several animal models.8,9 As this mCPP-
induced anxiety seems to be mediated via 5-HT2C receptor, it has
been hypothesized that 5-HT2C receptor antagonists might be po-
tential drugs for the treatment of anxiety and other psychiatric
disorders.10,11
This study implies that 5-HT6 receptors modulate cholinergic neuro-
transmission and hence 5-HT6 receptor antagonists may be useful
for the treatment of memory dysfunction.
Thus, 5-HT2C/5-HT6 receptor antagonism would be important for
synergistically modulating schizophrenia, depression, and anxiety
which are induced from Alzheimer’s disease. Herein, we describe
the identification of (piperazin-1-yl-phenyl)-arylsulfonamides
antagonizing both 5-HT2C and 5-HT6 receptors.
In our research program to discover selective 5-HT2C/5-HT6
receptor antagonists, we began our investigation by high through-
put screening with in-house compounds. We found that compound
1 exhibited moderate affinity for 5-HT2C (IC50 = 0.47 lM) and 5-HT6
receptor (IC50 = 1.18 lM) as shown in Figure 1. Because arylsulfon-
amides were already found as good inhibitors of 5-HT6 receptor,17,18
the major focus in our optimization was to enhance binding affinity
towards 5-HT2C receptor.
The 5-HT6 receptor, one of the most recently identified serotonin
receptors, consists of 440 amino acids with seven transmembrane
domains and is positively coupled to the adenylate cyclase second-
ary messenger system.12,13 Initial in vivo experiments showed that
administration of antisense oligonucleotides (AOs), directed at
5-HT6 receptor mRNA, elicited a behavioral syndrome in rats con-
sisting of yawning, stretching, and chewing, which could be dose
dependently blocked by the muscarinic antagonist atropine.14–16
I
Me
µ
5-HT2C IC50 = 0.47
5-HT6 IC50 = 1.18
M
N
S
O
Me
µ
M
O
1
* Corresponding author.
E-mail address: parkcm@krict.re.kr (C.M. Park).
Figure 1. Hit compound acquired from HTS.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.150

5222
C. M. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5221–5224
Me
Me
N
N
Hal
N
N
d
a or b
R1
NO2
N
H
R2
X
3 X = NO2
4 X = NH2
2
5
c
e, f, g, h
i
Me
Me
N
N
Me
N
N
N
j
N
R1
R
N
S
NH
S
O
O
O
N
Y
R2
O
8
7
6
Y = COR, SO2R, CONHR, R
O
N
Me
Me
O
N
O
N
k
l
Me
Me
N
N
S
O
N
NH2
N
N
H
O
9
10
11
Scheme 1. Reagents and conditions: (a) N-methylpiperazine (neat), 80 °C; (b) N-methylpiperazine, Pd2dba3, 1,10-bis(diphenylphosphino)ferrocene, NaO-t-Bu, 1,4-dioxane,
60 °C, 2 h; (c) Sn(II)Cl2ꢀH2O, EtOH/concd HCl, 60 °C, 1 h; (d) R1COR2, NaBH(OAc)3, AcOH, 1,2-dichloroethane, rt, 8 h; (e) RCOCl, Et3N, CH2Cl2, rt; (f) RSO2Cl, Et3N, CH2Cl2, rt; (g)
RNCO, pyridine, CH2Cl2, rt; (h) R–X, NaH, tetrabutylammonium iodide, DMF, rt; (i) 2-naphthalenesulfonyl chloride, pyridine, rt; (j) R–X, K2CO3, DMF, rt; (k) acetone,
NaBH(OAc)3, AcOH, 1,2-dichloroethane, AcOH, 50 °C, 8 h; (l) 2-naphthalenesulfonyl chloride, Et3N, CH2Cl2, rt, 3 h.
The general synthetic approaches to (piperazin-1-yl-phenyl)-
arylsulfonamides are presented in Scheme 1. The (N-methy-pipera-
zin-1-yl)-nitrobenzene 3 were synthesized from the halosubstitut-
ed nitrobenzene 2 by reacting with excess N-methylpiperazine
(neat) at 80 °C or by Buchwald type palladium(0) catalyzed cross-
coupling reaction.19 Nitrobenzenes 3 were reduced with SnCl2 in
EtOH and concentrated HCl to afford aromatic amines 4, which were
reductive alkylated with ketones using acetic acid and NaBH(OAc)3
in 1,2-dichloroethane at room temperature to furnish N-alkyl-
amines 5.20 Basic nitrogen of aromatic amines 5 were functionalized
using acid chlorides, sulfonyl chlorides, isocyanates, or alkyl halides
to afford trisubstitutedamines 6. Coupling of 2-naphthalenesulfonyl
chloride with aromatic amines 4 were conductedin pyridine at room
temperature to give arylsulfonamides 7, which were alkylated with
R–X (X = Br or I) in DMF at room temperature in the presence of
K2CO3 as a base to afford N-alkyl arylsulfonamides 8. The known
bipyridylamine 921 was reductive alkylated with acetone using ace-
tic acid and NaBH(OAc)3 in 1,2-dichloroethane at 50 °C to afford
N-isopropylamine 10, which was coupled with 2-naphthalenesulfo-
nyl chloride to furnish arylsulfonamide 11.
Earlier studies showed that the introduction of the pyridyl
ether21 or the terminal basic pharmacophore22 is important for
increasing binding affinities for 5-HT2C receptor. The functionaliza-
tion of phenyl moiety of the aniline unit of compound 1, with the
introduction of piperazine group or pyridyl ether motif, was
screened (Table 1). In particular, compound 6b containing an
N-methyl-piperazin-1-yl group at meta-position of the phenyl moi-
ety gave high binding affinity for 5-HT2C receptor (IC50 = 4 nM). In
contrast, the binding affinities of compounds 6a and 6c containing
N-methyl-piperazin-1-yl groups at ortho- or para-position of the
phenyl group were detrimental. Introduction of pyridin-3-yloxy
group on the 6-position of 3-pyridyl group (11) was not effective,
either. Gratifyingly, compounds 6a–c and 11 showed higher binding
affinities of 5-HT6 receptor than 5-HT2C receptor as we expected.
Having established that 3-substitution of the N-methyl-pipera-
zin-1-yl group was optimal, a series of analogues were prepared
investigating modifications of 2-naphthylsulfonyl moiety (Table
2). Although incorporation of a phenyl group (6e) instead of 2-naph-
thyl retained affinity for 5-HT2C receptor, substitutions in the region
of para-position of this phenyl group (6k, 6l, and 6n) reduced bind-
ing affinities and 1-naphthylsulfonyl derivative 6j also showed
reduction in affinity. 1-Naphthylcarbonyl substituted analogue 6h
showed the similar efficacy to its corresponding sulfonyl analogue
6j and carbonyl analogues 6f, 6m, and 6o were less efficacious than
their corresponding sulfonyl analogues 6e, 6b, and 6l. Substitution
of the sulfonyl linker with methylene or amido (6g or 6i) was detri-
mental. The effect of nitrogen substitution of arylsulfonamide 6b
was also carried out (Table 2). Substitution with 1-propyl and cyclo-
propylmethyl (8b and 8d) had similar binding affinities for 5-HT2C
receptor, while replacement with methyl, ethyl, cyclopentylmethyl,
benzyl, and 3-pyridylmethyl (8a, 8c, 8e, 8f, and 8g) gave weaker
binding affinities. N-Unsubstituted derivative 5h showed signifi-
cantly lower binding affinity (IC50 = 5147 nM). Replacement of
2-propyl with 3-pentyl and 2-butyl (6p and 6q) led to the reductions
in binding affinities. Within this series, arylsulfonamides with
2-propyl substituents 6b showed most potent compounds. As we
expected, most of arylsulfonamides also showed good binding
affinities for 5-HT6 receptor.
Compounds 6b, 6e, 6j, 8a–d, 8f, and 5h were examined further for
binding affinity toward several serotonergic and dopaminergic

C. M. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5221–5224
5223
Table 1
Table 2
Binding affinities for 5-HT2C and 5-HT6 receptors of phenyl moiety derivatives in
Binding affinities for 5-HT2C and 5-HT6 receptors of N-[3-(4-methyl-piperazin-l-yl)-
aniline unit of hit compound (IC50 values, unit: nM)a
phenyl]-arylsulfonamides (IC50 values, unit: nM)a
Me
Ar
Me
N
N
S
Me
O
N
O
R4
N
b
c
Compound
Ar
5-HT2C
5-HT6
Z
Me
R3
N
N
6a
4638
2191
R3
R4
5-HT2C
5-HT6
b
c
Compound
Z
6b
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
8a
8b
8c
8d
8e
6q
8f
SO2
SO2
CO
CH2
CO
2-Naphthyl
Ph
Ph
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
2-Propyl
3-Pentyl
Methyl
1-Propyl
Ethyl
Cyclopropylmethyl
Cyclopentylmethyl
2-Butyl
Benzyl
3-Pyridylmethyl
H
4
3
644
—
—
—
—
16
—
—
—
—
—
—
7
4
3
6
—
—
3
—
13
21
4164
>10000
97
>10000
100
106
243
420
462
7702
159
36
Me
Ph
N
1-Naphthyl
NHPh
1-Naphthyl
4-Me-Ph
4-Cl-Ph
2-Naphthyl
4-NO2-Ph
4-Cl-Ph
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
CO
6b
6c
4
3
N
SO2
SO2
SO2
CO
SO2
CO
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
Me
N
N
1715
27
7
16
6
11
168
32
34
O
N
11
1
>10000
467
422
N
I
8g
5h
5147
a
1180
All values are means of two or three separate competition experiments.
Displacement of [3H]-mesulergine binding to cloned human 5-HT2C receptors
b
expressed in CHO-Kl cell line.
c
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors expressed
a
All values are means of two or three separate competition experiments.
Displacement of [3H]-mesulergine binding to cloned human 5-HT2C receptors
b
in HEK293 cell line.
expressed in CHO-K1 cell line.
c
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors expressed
expressing the cloned human 5-HT2C receptors23,24 and 5-HT-
stimulated cAMP accumulation using HeLa cell line expressing the
cloned human 5-HT6 receptor.25 Compound 6b was able to block
in HEK293 cell line.
5-HT-stimulated bindingof [35S]GTP
cS in a dose-dependent manner
with IC50 value of 94 nM. It also blocked 5-HT-stimulated cAMP
binding (IC50 = 21 nM). These results showed that compound 6b
has antagonistic activities at both 5-HT2C and 5-HT6 receptors.
In summary, we report the synthesis and biological profiles of a
series of (piperazin-1-yl-phenyl)-arylsulfonamides. Most of com-
pounds, particularly 6b and 8b, have been identified to possess
the high binding affinity towards 5-HT2C and 5-HT6 receptors and
receptors (Table 3). All compounds except 5h and 6e showed higher
binding affinities for 5-HT2C and 5-HT6 receptor than other seroto-
nergic and dopaminergic receptor. In particular, the 5-HT2C/5-HT6
receptor selectivity of compounds 6b and 8b was greater than 25-
fold over 5-HT1A, 5-HT2A, 5-HT7, and dopamine (D2–D4) receptors.
The functional efficacies of compound 6b were evaluated by
measuring 5-HT-stimulated binding of [35S]GTP
cS using CHO cells
Table 3
Binding profiles over serotonin (5-HT1A–5-HT7) and dopamine (D2–D4) receptor subtypes (IC50 values, unit: nM)a
b
Compound
IC50 (nM)
5-HT2C
5-HT6
5-HT1A
5-HT2A
5-HT7
D2
D3
248
D4
6b
6e
6j
8a
8b
8c
8d
8f
4
21
100
36
7
16
6
32
5147
3
644
16
7
4
3
6
3
13
>1000
3399
298
95
3756
485
672
280
57
118
172
122
1423
389
218
88
NR
1006
2874
4425
3865
2059
3038
2044
1582
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>1000
2893
1195
2416
2508
1171
1426
943
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
50
1616
5h
2102
a
All values are means of two or three separate competitive experiments.
Receptors were all cloned human receptors expressed in CHO, HEK293 or SF9 cells, and [3H] radioligands were as follows: 8-OH-DPAT (5-HT1A), ketanserin (5-HT2A),
b
mesulergine (5-HT2C), LSD (5-HT6 and 5-HT7), and spiperone (D2–D4).

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C. M. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5221–5224
13. Gerard, C.; Martres, M. -P.; Lefevre, K.; Miquel, M. -C.; Verge, D.; Lanfumey, L.;
Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Res. 1997, 746, 207.
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with such compounds are now in progress.
Supplementary data
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.06.150.
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