3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT6 receptor modulators

Article abstract of DOI:10.1016/j.bmcl.2010.01.073

Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT₆ receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT₆ binding affinity with K_i values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC₅₀ = 60 nM, E_max = 70%) and antagonists (6y: IC₅₀ = 17 nM, I_max = 86%) were identified in a 5-HT₆ adenylyl cyclase assay.

Full text of DOI:10.1016/j.bmcl.2010.01.073

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1657–1660
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT6 receptor modulators
b
c
c
c
b
Ronald C. Bernotas a, , Schuyler Antane , Rajesh Shenoy , Van-Duc Le , Ping Chen , Boyd L. Harrison ,
*
Albert J. Robichaud b, Guo Ming Zhang d, Deborah Smith d, Lee E. Schechter d
a Chemical Sciences, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA 19426, USA
b Chemical Sciences, Wyeth Pharmaceuticals, CN 8000, Princeton, NJ 08543, USA
c Neuroscience, Wyeth Pharmaceuticals, CN 8000, Princeton, NJ 08543, USA
d Albany Molecular Research, PO Box 15098, Albany, NY 12212, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT6 receptor ligands,
based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds
had good 5-HT6 binding affinity with Ki values <10 nM. Depending on substitution, both agonists (e.g., 6o:
EC50 = 60 nM, Emax = 70%) and antagonists (6y: IC50 = 17 nM, Imax = 86%) were identified in a 5-HT6 aden-
ylyl cyclase assay.
Received 16 December 2009
Revised 7 January 2010
Accepted 11 January 2010
Available online 21 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Serotonin
Agonist
Antagonist
5-HT6
Cyclase
Indole
Sulfone
Modulation of the human serotonergic system has long been
investigated for the treatment of mood disorders including anxiety
and depression. Recently, the human 5-HT6 receptor has been
targeted because of its CNS localization and the therapeutic impli-
cations of its proposed role in learning and memory.1 Scientists at
Roche identified sulfonamides including Ro 04-6790 (1) as selec-
tive 5-HT6 antagonists2 while researchers at SmithKline prepared
arylsulfonamide-substituted arylpiperazines including SB-271046
(2) as selective antagonists (Fig. 1).3 These compounds incorporate
a common feature of many 5-HT6 selective ligands: an arylsulfonyl
group.
H
N
N
NHMe
MeO
N
O O
S
O
S
O
S
N
MeHN
N
N
H
H
Me
NH2
Cl
1
2
Figure 1. Early 5-HT6 antagonists.
More recent efforts at identifying novel 5-HT6 ligands have
highlighted so-called ‘flipped’ indoles in which the regiochemical
relationship of the basic side chain and the arylsulfonyl group
are reversed from earlier indole-containing ligands. Typical of this
approach are 1-aminoalkyl-3-arylsulfonyl-1H-indoles 4,4 which
are based on earlier 1-arylsulfonyl-tryptamines 35 (Fig. 2). Deriva-
tives of type 4 had affinity for 5-HT6 receptors, which was gener-
ally similar to that of the substituted tryptamines, though they
were often only moderately potent agonists in a 5-HT6 in vitro
functional assay.
NR1R2
NR1R2
N
N
SO2Ar
SO2Ar
3
4
Figure 2. An example of a ‘flipped’ serotonergic ligand.
The affinity of these flipped ligands 4 for 5-HT6 receptors
prompted us to examine analogs in which the aminoalkyl side
chain is constrained as an azacycle such as pyrrolidine and
* Corresponding author.
E-mail address: bernotr@wyeth.com (R.C. Bernotas).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.01.073

1658
R. C. Bernotas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1657–1660
NR1R2
Me
N
MeO2C
NH2
15
O
N
a
X
CH(OCH3)2
( )m
NR
( )n
14
SO2Ar
Me
N
Me
N
4
N
X
( )m
NR
( )n
NH
MeO2C
MeO2C
N
b
SO2Ar
6
CH(OCH3)2
16
X
17
N
SO2Ar
Scheme 2. Reagents and conditions (from Coe10): (a) Na2SO4, AcOH, then
NaBH(OAc)3 and (b) 1 M HCl, MeOH, heat.
5
Figure 3. Design of 1-(azacyclyl)-3-arylsulfonyl-1H-indoles 5 as constrained 5-HT6
ligands.
an azacycle by reductive amination of a ketone (e.g., 15) with ani-
line 14 to give 16 followed by cyclization under acidic conditions
(Scheme 2).10 Coe’s reductive amination conditions applied to 10
and keto-azacycles 11 gave 12 in high yield.
piperidine, that is, 6 (Fig. 3). These compounds may be viewed as
‘flipped’ analogs of 1-arylsulfonyl-3-(azacyclyl)-1H-indoles
5
described by Cole et al.6 We report here the synthesis of a series
of indoles 6 and the biological activity of these compounds at the
5-HT6 receptor.
Cyclization of 12 was initially problematic. Attempts to form
the indole by reaction with orthoformates did not give the desired
enol ethers needed for ring formation. However, prolonged heating
of 12 with dimethylformamide dimethylacetal and para-toluene-
sulfonic acid gave enamines 13, often accompanied by small
amounts (ꢀ20%) of desired cyclization product 6. The enamines
were conveniently converted to 6 by further treatment with etha-
nolic acid, typically from the crude mixture of 6 and 13. Secondary
amines could then be easily prepared by dealkylation of the ter-
tiary amines 6 using 1-chloroethyl chloroformate in high yields
(6, R = H).11 With these in hand, diversity was achievable by reac-
tion with alkylhalides. By appropriate choice of starting nitroben-
zene 7, chloromethylarylsulfone 8, keto-azacycle 11 and
alkylating agent, we were able to vary X, Ar, R, and azacycles found
in compounds 6.
Initial attempts to synthesize 6 centered on the alkylation of
3-arylsulfonylindoles with halopiperidines and halopyrrolidines,
and by Mitsunobu reactions of 3-arylsulfonylindoles with hydrox-
ypiperidines and hydroxypyrrolidines. Unfortunately, these meth-
ods generally provided low yields or no product at all. Suspecting
there may be steric problems too difficult to overcome, especially
in light of potential competing elimination, another preparative
route was sought.
An alternative approach used a reductive amination to intro-
duce the key azacycles. The requisite arylsulfonylmethylene-
substituted anilines 10 were obtained by a vicarious nucleophilic
substitution (VNS) approach starting with nitrobenzenes
7
(Scheme 1).7 Thus, treatment of nitrobenzenes 7 and chlorometh-
ylsulfones 8 with KOtBu in THF at low temperatures (conditions
that favor ortho-substitution) provided 9.8 Noncommercial com-
pounds 8 were readily prepared by a one-pot method from the
corresponding arylsulfonyl chlorides.9 Nitro reduction, generally
using tin in hydrochloric acid, gave desired anilines 10. Coe et al.
developed an approach to 1-azacyclyl-1H-indoles 17 incorporating
All target compounds were tested for human-cloned 5-HT6
receptor affinity in a standard radioligand binding assay12 (Table
1). Early results led to some obvious conclusions about the SAR
of this class of compounds. Compounds 6a and 6b had relatively
weak affinity, attributed to the 4-piperidinyl isomer.
Higher 5-HT6 affinity was observed for both the 3-piperidinyl
(6c–6m) and 3-pyrrolidinyl analogs (6n–6dd). However, the
m
NR
m
NR
n
n
11
O
c
NO2
a
NO2
b
NH2
N
d
H
X
X
X
X
SO2Ar
SO2Ar
SO2Ar
7
9
10
12
m
NR
m
NR
m
NR
m
NH
n
n
n
n
N
e
N
g
N
f
N
H
X
X
X
X
NMe2
SO2Ar
SO2Ar
SO2Ar
6 (R not H)
SO2Ar
6 (R = H)
13
6
Scheme 1. (a) 8 (1.0 equiv), THF, À0 °C, then 1 M KOtBu/THF (1.1 equiv), À30 °C, 1 h, AcOH quench (X = H, Ar = Ph, 81%); (b) Sn (4.4 equiv), concd HCl, MeOH, 45–50 °C, 4–6 h
(X = H, Ar = Ph, 89%); (c) 11 (2.0 equiv), Na2SO4 (10 equiv), AcOH, 15–45 min, then NaBH(OAc)3 (3.0 equiv), 2–5 h; (d) Me2NCH(OMe)2 (as solvent), para-toluenesulfonic acid
hydrate (0.02–0.05 equiv), reflux, 2–5 d; (e) 2 M aqueous HCl, EtOH, 20 °C, 1–4 h; (f) CH3CH(Cl)C(O)Cl (2–3 equiv), DCE, reflux, 2–5 h, concentrate, then MeOH or EtOH, reflux,
2–24 h; and (g) RBr or RI (1.1 equiv), K2CO3 (1–2 equiv), DMF, 50–80 °C.

R. C. Bernotas et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1657–1660
1659
Table 1
5-HT6 binding and adenylyl cyclase activity for indoles 6a
m
NR
n
N
X
SO2Ar
6
Compd
Azacycle
Ar
X
R
5-HT6
Ki (nM)
5-HT6 cAMP accumulation assay
EC50 or IC50 (nM) Emax or Imax (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
4-Piperidinyl
4-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Piperidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
3-Pyrrolidinyl
Ph
Ph
Ph
Ph
Ph
3-FPh
3-FPh
3-FPh
3-FPh
3-FPh
1-Naphthyl
1-Naphthyl
8-Quinolinyl
Ph
Ph
3-FPh
3-FPh
3-FPh
H
H
H
H
H
H
CH2Ph
H
CH2Ph
H
Et
H
H
Me
Et
H
H
Me
H
CH2Ph
H
H
Me
H
H
Me
H
H
H
49 ( 6)
91 ( 4)
nt
nt
nt
nt
nt
nt
122 ( 16)
13 ( 1)
7.3 ( 0.9)
6.0 ( 0.6)
10.7 ( 0.3)
68 ( 3)
16 ( 1)
4.0 ( 0.3)
21 ( 1)
7.1 ( 0.5)
5.6 ( 0.3)
113 ( 2)
5.0 ( 0.3)
4.7 ( 0.1)
3.5 ( 0.7)
18 ( 1)
9.6 ( 1.4)
5.0 ( 0.5)
18 ( 2)
82 ( 3)
31 ( 4)
56 ( 21)
73 ( 12)
nt
203 ( 73)
18 ( 3) (ant)
nt
107 ( 7) (ant)
592 ( 5)
nt
60 ( 7)
68 ( 5)
398 ( 47)
nt
38 ( 4)
94 ( 2) (ant)
nt
nt
nt
125 ( 10)
17 ( 2) (ant)
80 ( 11) (ant)
107 ( 10) (ant)
60 ( 12) (ant)
82 ( 13) (ant)
76 ( 24) (ant)
99 ( 0.4)
52 ( 2)
78 ( 5)
75 ( 1)
nt
50 ( 0.4)
85 ( 0) (ant)
nt
87 ( 1) (ant)
71 ( 0.3)
nt
70 ( 0.3)
38 ( 0.4)
49 ( 0.7)
nt
5-OMe
5-OMe
5-OMe
5-F
H
H
H
H
H
H
H
4-F
5-F
5-F
6-F
5-Cl
6-Cl
H
6s
6t
3-FPh
3-FPh
3-FPh
3-FPh
50 ( 0.4)
70 ( 1) (ant)
nt
nt
nt
6u
6v
6w
6x
6y
6z
6aa
6bb
6cc
6dd
15 ( 1)
72 ( 5)
3-FPh
3-ClPh
3-ClPh
3-ClPh
1-Naphthyl
1-Naphthyl
8-Quinolinyl
8-Quinolinyl
H
Me
H
H
Me
H
3.2 ( 0.9)
1.3 ( 0.1)
4.6 ( 0.4)
23.3 ( 0.3)
6.0 ( 0.6)
1.5 ( 0.1)
2.8 ( 0.2)
48 ( 1)
86 ( 0) (ant)
H
6-OMe
H
H
H
H
100 ( 0) (ant)
100 ( 0) (ant)
98 ( 10) (ant)
64 ( 0) (ant)
97 ( 2) (ant)
Me
nt = not tested.
a
ant after the data in the cyclase assay indicates the tested compound was an antagonist and IC50 values and Imax values are given.
relatively narrow range of binding Ki values made some SAR trends
difficult to discern. Large substituents on the azacycle nitrogen (i.e.,
benzyl) reduced affinity while smaller groups (H, Me, Et) were well
tolerated. Similarly, larger groups (X) on the indole ring reduced
affinity, for example, 6w.
nitrogen, as seen by comparing 6s to 6t and 6x to 6y. In both
analogous pairs, methylation of the pyrrolidine converted agonists
in the cyclase assay into antagonists. Overall, notable antagonists
include 6j, a potent antagonist (IC50 = 18 nM) which largely
blocked the effects of 5-HT6 in the adenylyl cyclase assay
(Imax = 85%), and 6y, which had an essentially identical antagonist
profile.13
Furthermore, larger arylsulfonyl groups such as naphthyl and
quinolinyl ring systems were acceptable and, in the case of the
quinolinyl analogs 6cc and 6dd, even among the highest affinity li-
gands. Other high affinity compounds included 6q, 6x, and 6y, with
Ki values <4 nM. Those compounds with excellent 5-HT6 affinity
(generally Ki < 20 nM) were tested in an adenylyl cyclase assay to
determine whether the ligands were able to modulate 5-HT6 func-
tion, based on the intracellular concentration of cAMP.12 Some of
the compounds tested demonstrated agonist activity, especially
the 3-piperidinyl analogs, while the 3-pyrrolidinyl analogs were
more often antagonists. Effects on functional activity from substit-
uents on the indole and the arylsulfonyl rings were often subtle,
though in general larger arylsulfonyl groups such as naphthyl
and quinolylsulfonyl resulted in antagonists (6l, 6aa–6dd). How-
ever, quinoline 6m was an agonist though rather weakly so. Even
chlorophenylsulfonyl-containing compounds (6y, 6z) were more
likely to be antagonists compared to the smaller phenylsulfonyl
(6d–6e, 6o) and fluorophenylsulfonyl analogs (6f–g, 6i, 6p–q, 6s).
Some exceptions to this general trend can be explained by the
increased steric requirements from alkylation of the pyrrolidine
A
series of 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles was
designed and synthesized as 5-HT6 ligands using azacycles as
constrained replacements for an aminoethyl moiety. Binding as-
says demonstrated compounds 6 are high affinity 5-HT6 receptor
ligands, many with Ki values less than 10 nM. In general, the
3-piperidinyl analogs were more likely to be agonists while the
3-pyrrolidinyl analogs were more often antagonists in a 5-HT6
adenylyl cyclase functional assay.
References and notes
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Chuang, T. T. Prog. Med. Chem. 2009, 48, 163.
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D.; Routledge, C.; Serafinowska, H.; Smith, D. R. Bioorg. Med. Chem. Lett. 2001,
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12. Binding assays were performed using cloned human 5-HT6 receptors stably
transfected into HeLa cells using [3H]-LSD as the radioligand. For the adenylyl
cyclase assay, HeLa cells transfected with the human 5-HT6 receptor were
used. The % efficacy is relative to serotonin. For detailed assay conditions, see:
Cole, D. C.; Stock, J. R.; Lennox, W. J.; Bernotas, R. C.; Ellingboe, J. W.; Boikess, S.;
Coupet, J.; Smith, D. L.; Leung, L.; Zhang, G. M.; Feng, X. D.; Kelly, M. F.; Galante,
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Schechter, L. J. Med. Chem. 2007, 50, 5535.
5. For N-sulfonylindoles as 5-HT6 ligands, see: Russell, M. G. N.; Baker, R. J.;
Barden, L.; Beer, M. S.; Bristow, L.; Broughton, H. B.; Knowles, M.; McAllister, G.;
Patel, S.; Castro, J. L. J. Med. Chem. 2001, 44, 3881; Tsai, Y.; Dukat, M.; Slassi, A.;
MacLean, N.; Demchyshyn, L.; Savage, J. E.; Roth, B. L.; Hufesein, S.; Lee, M.;
Glennon, R. A. Bioorg. Med. Chem. Lett. 2000, 10, 2295; Lee, M.; Rangisetty, J. B.;
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7. All new compounds provided satisfactory 1H NMR (300 or 400 MHz) and MS
data. Compounds (6a–6dd) were isolated as hydrochlorides and generally
provided satisfactory CHN analysis, though often as partial hydrates. For
additional details, including synthetic procedures and analytical data, see:
Bernotas, R. C.; Lenicek, S. E. US patent 6,995,176, 2006.
13. While compounds 6c–6dd were tested as their racemates, a related 7-
azaindole series of 5-HT6 modulators showed comparable binding and
functional activity for the separated enantiomers. Elokdah, H.; Li, D.;
McFarlane, G.; Bernotas, R. C.; Robichaud, A. J.; Magolda, R. L.; Zhang, G.-M.;
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