1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2004.09.003

Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT₆ receptor ligands, among which N,N-dimethyl-N-{2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl}amine 8t and N-methyl-N-{2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl}amine 8u showed high affinity for 5-HT₆ receptors with K_i = 3.7 and 5.7 nM, respectively. Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT₆ receptor ligands, among which N,N-dimethyl-N-{2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl}amine 8t and N-methyl-N-{2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl}amine 8u showed high affinity for 5-HT₆ receptors with K_i = 3.7 and 5.7 nM, respectively.

Full text of DOI:10.1016/j.bmcl.2004.09.003

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5499–5502
1-(2-Aminoethyl)-3-(arylsulfonyl)-1H-indoles as novel 5-HT6
receptor ligands
Ronald Bernotas,a,* Steven Lenicek,b Schuyler Antane,b Guo Ming Zhang,c
Deborah Smith,c Joseph Coupet,c Boyd Harrisonb and Lee E. Schechterc
aChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
bChemical and Screening Sciences, Wyeth Research, CN8000, Princeton, NJ 08543-8000, USA
cNeuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
Received 27 July 2004; revised 1 September 2004; accepted 3 September 2004
Available online 30 September 2004
Abstract—Novel 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles were prepared. Binding assays indicated they are 5-HT6 receptor lig-
ands, among which N,N-dimethyl-N-{2-[3-(1-naphthylsulfonyl)-1H-indol-1-yl]ethyl}amine 8t and N-methyl-N-{2-[3-(1-naph-
thylsulfonyl)-1H-indol-1-yl]ethyl}amine 8u showed high affinity for 5-HT6 receptors with Ki = 3.7 and 5.7nM, respectively.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
5-HT6 antagonist.3 These compounds incorporate a
common feature of many 5-HT6 selective ligands: an
arylsulfonyl group( Fig. 1).
Considerable attention has been focused on the 5-HT6
receptor because of its CNS localization and the thera-
peutic implications of its proposed role in learning and
memory.1 Intense interest in 5-HT6 receptors has led
to the discovery of several classes of high affinity lig-
ands. Initial reports from Roche identified sulfonamides
including Ro 04-6790 (1) as selective 5-HT6 antago-
nists.2 In 1998, scientists at SmithKline described a ser-
ies of arylsulfonamide-substituted arylpiperazines from
which SB-271046 (2) was identified as a potent, selective
One approach to developing novel serotonergic ligands
is to reverse the relative roles of the 1- and 3-positions
on the indole ring. Among the first examples of this
NH2
NH2
CH3
HO
Cl
N
N
H
F
H
N
3
5
4
6
NMe2
NMe2
S
S
N
NHMe
MeO
N
N
N
H
NH
S
MeHN
N
NH
Me
O
O
S
O
O
NH2
S
Cl
NR1R2
NR1R2
1
2
N
Figure 1. Early 5-HT6 ligands.
R3
X
N
SO2Ar
SO2Ar
Keywords: Serotonin 5-HT6 indoles GPCR.
*
7
8
Corresponding author. Tel.: +1 484 865 2168; fax: +1 484 865
9399; e-mail: bernotr@wyeth.com
Figure 2. Examples of ꢀflippedꢁ serotonergic ligands.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.09.003

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R. Bernotas et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5499–5502
approach is 5-HT2C agonist 4, described by Roche.4a In
this ligand, the location of the aminoethyl side chain is
ꢀflippedꢁ from the 3-position of the indole ring as in sero-
tonin (3) to the indole nitrogen. A similar approach was
used by NPS to developnovel 5-HT 1D ligands including
6 based on 5.4b We have adopted a similar approach to
targets 8.8 Secondary amines could be prepared from
tertiary amines by refluxing 8 (R1, R2 5 H) with
1-chloroethylchloroformate (ACE–Cl) as described by
Olofson et al.9 Alternatively, the basic side chain was
introduced by reacting 11 with 1,2-dichloroethane and
a base under phase-transfer conditions to give 12. Heat-
ing 12 with an amine (R1R2NH) provided compounds 8.
Primary amines were initially obtained by Gabriel syn-
thesis, displacing the chlorine in 12 with potassium pht-
halimide to give 13, which was in turn treated with
hydrazine to give 8 (R1, R2 = H). Alternatively, the
phase-transfer conditions of Alvarez-Builla and co-
workers allowed direct, one-stepintroduction of the
primary aminoethyl group onto 11 using 2-aminochlo-
roethane and base.10
developnovel 5-HT ligands. Glennon and others have
6
identified 1-arylsulfonyl-tryptamines 7 as 5-HT6 ligands
(Fig. 2).5 These reports led us to synthesize a series of 1-
(2-aminoethyl)-3-arylsulfonyl-1H-indoles 8 in which the
positions of the arylsulfonyl group and basic side chain
are exchanged (or ꢀflippedꢁ) relative to each other and to
investigate their 5-HT6 affinity.
2. Chemistry
A second route to 3-arylsulfonyl-1H-indoles 11 followed
the vicarious nucleophilic substitution (VNS) approach
developed by Wojciechowski and Makosza.11 Nitroben-
zenes 14 were reacted with ArSO2CH2Cl12 in the
presence of base under conditions, which favored
ortho-substitution to provide 15 (Scheme 2).13 Nitro
reduction provided aniline 16. Heating 16 with excess
ortho-ester and catalytic p-TsOH hydrate in 1,2-dichlo-
roethane followed by concentration in vacuo gave crude
iminoether 17, which was dissolved in THF and treated
with a slight excess of 1.0M KOtBu/THF to afford 11.
This one-pot approach avoided an aqueous workup of
17 and generally provided good yields of indoles 11.14
Direct alkylation of 3-arylsulfonyl-1H-indoles should
provide compound 8. The requisite 3-RSO2-1H-indoles
for this approach were prepared by two routes. The first
introduced a 3-arylthio substituent on indole 9 by reac-
tion with a thiol (ArSH) in the presence of iodine and
potassium iodide as described by Beveridge and Harris6
to give substituted indoles 10 (Scheme 1). Oxidation
with OxoneTM in acetone/aqueous sodium bicarbonate7
or with mCPBA afforded 3-arylsulfonyl-1H-indoles 11
in good yield. In the presence of base, direct alkylation
with aminoethylchlorides or bromides, that is,
R1R2N(CH2)nHal, generally as HCl salts, provided
NR1R2
NHR1
H
H
H
b
c
a
d
N
N
N
N
N
R3
SO2Ar
X
R3
R3
X
X
X
X
SAr
SO2Ar
SO2Ar
8 (R2 = H)
11
9
10
8
f
e
h
Cl
NPhth
g
N
N
X
X
SO2Ar
SO2Ar
12
13
Scheme 1. Synthesis of 1-(2-aminoethyl)-3-(arylsulfonyl)-1H-indoles 8. Reagents and conditions: (a) ArSH/I2ÆKI/EtOH/H2O; (b) OxoneTM/aq
NaHCO3/acetone, or mCPBA/CH2Cl2; (c) R1R2N(CH2)2Hal/NaH/DMF, or H2NCH2CH2Cl; (d) CH3CH(Cl)C(O)Cl/ClCH2CH2Cl/reflux, then
EtOH/reflux; (e) ClCH2CH2Cl/aq NaOH/1,2-DCE/PTC; (f) R1R2NH, heat; (g) PhthK/DMF; (h) H2NNH2/EtOH/reflux.
H
NO2
b
c
N
OR
d
NH2
NO2
a
N
R3
X
X
X
X
X
R3
SO2Ar
SO2Ar
SO2Ar
SO2Ar
15
17
11
16
14
Scheme 2. Vicarious nucleophilic substitution route to 3-(arylsulfonyl)-1H-indoles 11. Reagents and conditions: (a) ArSO2CH2Cl/THF/KOtBu/À65
to À20°C/1h, then AcOH quench; (b) Sn (4.4equiv)/4M aq HCl/MeOH/45°C/4–6h; (c) HC(OEt)3 or CH3C(OCH3)3 (5equiv)/p-TsOHÆH2O
(0.1equiv)/ClCH2CH2Cl/reflux; (d) 1.0M KOtBu/THF (1.3–1.5equiv)/THF/rt/5–30min.

R. Bernotas et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5499–5502
5501
H
H
tution of the phenyl portion of the indole ring, that is,
8b–d, though 5-F substitution (8e) had no effect on affin-
ity. Secondary amine 8f had somewhat weaker affinity
for the 5-HT6 receptor compared to the nonflipped ana-
log 7b but had slightly improved affinity relative to the
primary amine (8a). The tertiary amine (8g) was similar
to the primary. Consistent with the trends for the pri-
mary amines, substitution of the indole phenyl ring in
the tertiary amines did not improve and was often dele-
terious to receptor affinity. While sterically more
demanding basic side chains such as 8o lost affinity for
the receptor, 2-methyl substitution of the indole was tol-
erated (8p). Substitution of the arylsulfonyl ring (8q–s)
was generally tolerated regardless of position. The most
significant improvement in affinity occurred when 1-
naphthylsulfonyl was substituted for phenylsulfonyl on
the 3-position of the indole ring. Tertiary amine 8t had
excellent affinity for 5-HT6 receptors (Ki = 3.7nM) while
the corresponding secondary amine 8u was nearly as
good. In contrast, increasing the distance between the
phenyl ring and the sulfonyl group with a methylene
(21) resulted in a 50-fold loss in receptor affinity.
a
b
N
N
80%
98%
SH
SCH2Ph
18
19
NMe2
H
c
N
N
86%
SO2CH2Ph
SO2CH2Ph
21
20
Scheme 3. Reagents and conditions: (a) NaH/PhCH2Br/DMF; (b)
OxoneTM/aq NaHCO3/acetone; (c) Me2NCH2CH2Cl/NaH/DMF.
A one-carbon homolog with an additional methylene
between the phenyl ring and the sulfonyl group was also
prepared (Scheme 3). 3-Thio-1H-indole (18)15 was alkyl-
ated with benzylbromide to provide 19, which was oxi-
dized to 20. Alkylation provided compound 21.
3. Results and discussion
Those compounds with excellent 5-HT6 affinity (gener-
ally, Ki < 20nM) were tested in a cyclase assay to deter-
mine whether the ligands were able to modulate 5-HT6
function in vitro.17 A few compounds possessed weak,
partial agonist activity. Others at least partially blocked
the effect of serotonin on cyclic AMP levels. Of note was
8t, essentially a full antagonist (Imax = 97%) with good
potency (IC50 = 47nM).
Final compounds were tested for 5-HT6 affinity in a
standard radioligand binding assay16 using human-
cloned 5-HT6 receptors stably transfected in HeLa cells
(Table 1). Comparison of 3-(aminoethyl)-1-phenylsulfo-
nyl-1H-indole 7a to 1-(aminoethyl)-3-phenylsulfonyl-
1H-indole 8a showed ꢀflippingꢁ the relative locations of
the basic side chain and phenylsulfonyl resulted in only
a modest decrease in affinity for the 5-HT6 receptor.
Generally some loss in affinity accompanied most substi-
In summary, novel 1-(2-aminoethyl)-3-(arylsulfonyl)-
1H-indoles were prepared. These compounds invert
Table 1. Biological activities of 1-(aminoethyl)-3-(RSO2)-1H-indole monohydrochlorides (8, 21)16,17
Compound
Ar
R1
R2
R3
X
5-HT6 Ki (nM)
cAMP assay for 5-HT6
IC50 (nM)
Imax (%)
7a
7b
8a
8b
8c
8d
8e
8f
Ph
Ph
H
H
––
––
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
––
––
––
10.3
5.0 ( 0.5)
25 ( 2)
Me
H
H
Ph
Ph
H
––
Weak partial agonist
H
H
6-MeO
6-Cl
5-MeO
5-F
––
78% (1lM)
141 ( 14)
86% (1lM)
27 ( 3)
Ph
Ph
H
H
H
H
Ph
Ph
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
15.5 ( 0.5)
20 ( 0.2)
23 ( 1)
8g
8h
8ia
8ja
8k
8l
8ma
8n
8o
8p
8q
8r
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
––
Weak partial agonist
6-MeO
6-F
6-Cl
6-CN
4-F
5-F
7-MeO
5-MeO
––
Ph
Ph
46 ( 7)
42 ( 4)
Ph
Ph
42% (1lM)
98 ( 6)
44 ( 7)
Ph
Ph
25 ( 5)
23 ( 2.5)
80.5 ( 0.35)
Ph
Ph
–(CH2)5–
55% (1lM)
18 ( 1)
57 ( 3)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
4-MePh
3-FPh
2-CF3OPh
1-Naphthyl
1-Naphthyl
CH2Ph
––
––
13 ( 0.6)
16 ( 2)
Weak partial agonist
8s
––
––
792 ( 16)
47 ( 9)
359 ( 109)
100 ( 0)
97 ( 2)
97 ( 2)
8t
3.7 ( 0.4)
5.7 ( 0.1)
1011 ( 102)
8u
21
––
––
Me
a Isolated and tested as the free amines.

5502
R. Bernotas et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5499–5502
6. Beveridge, S.; Harris, R. L. N. Aust. J. Chem. 1971, 24,
1229–1236.
7. Webb, K. S. Tetrahedron Lett. 1994, 35, 3457–3460.
the relative positions of the basic side chains and aryl-
sulfonyl groupin known 5-HT ligands and represent
6
one of the earliest applications of this approach to
5-HT6 receptors. Binding assays indicated these
compounds have high affinity for the target receptors,
especially 8t and 8u with Ki values of 3.7 and 5.7nM,
respectively. Compound 8t was essentially a full antago-
nist of moderate potency (IC50 = 47nM, Imax = 97%) in
a 5-HT6 functional (cyclase) assay.
1
8. All new compounds provided satisfactory H NMR (300
or 400MHz) and MS data. Tested compounds (8, 21) were
isolated as monohydrochlorides except as noted in the
table and generally provided satisfactory CHN analysis
though often as partial hydrates or solvates. Additional
experimental details including melting points can be found
in WO patent 2003101962.
9. Olofson, R. A.; Martz, J. T.; Senet, J. P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081–2082.
10. Cuadro, A. M.; Matia, M. P.; Garcia, J. L.; Vaquero, J. J.;
Alvarez-Builla, J. Synth. Commun. 1991, 21, 535–544.
11. Wojciechowski, K.; Makosza, M. Synthesis 1986, 651–
653; Wojciechowski, K.; Makosza, M. Tetrahedron Lett.
1984, 25, 4793–4796.
12. Antane, S. A.; Bernotas, R. C.; McDevitt, R.; Yan, Y.; Li,
Y. Synth. Commun. 2004, 34, 2443–2449.
13. Makosza, M.; Glinka, T.; Kinowski, A. Tetrahedron 1984,
40, 1863–1868.
References and notes
1. For reviews on serotonin 5-HT6 receptor ligands and their
biological functions, see: Russell, M. G. N.; Dias, R. Curr.
Top. Med. Chem. 2002, 2, 643–654; Glennon, R. A. J.
Med. Chem. 2003, 46, 2795–2812.
2. Sleight, A. J.; Boess, F. G.; Bos, M.; Levet-Trafit, B.;
Riemer, C.; Bourson, A. Br. J. Pharmacol. 1998, 124, 556–
562.
3. Bromidge, S. M.; Clarke, S. E.; Gager, T.; Griffith, K.;
Jeffrey, P.; Jennings, A. J.; Joiner, G. F.; King, F. D.;
Lovell, P. J.; Moss, S. F.; Newman, H.; Riley, G.; Rogers,
D.; Routledge, C.; Serafinowska, H.; Smith, D. R. Bioorg.
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therein.
4. (a) Bos, M.; Jenck, F.; Martin, J. R.; Moreau, J.-L.;
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1997, 40, 2762–2769; (b) Isaac, M.; Slassi, M.; Xin, T.;
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14. Compound 8s was prepared in low yield by direct
sulfonylation of 1-[2-(dimethylamino)ethyl]-1H-indole as
described in WO patent 2003101962.
15. Bourdais, J.; Lorre, A. Eur. J. Med. Chem. 1974, 9, 269–
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16. Binding assays were run using [3H]-LSD as the radiolig-
and. Compounds were all tested as the monohydrochlo-
ride salts except for 8i,8j, and 8m which were tested as the
free amines. For conditions see: Bernotas, R. C.; Lenicek,
S. E.; Antane, S. A.; Zhou, P.; Li, Y.; U.S. Patent
6,727,246.
17. Cyclase assay: HeLa cells transfected with the human 5-
HT6 receptor were washed with Krebs buffer and incu-
bated at 37°C in Krebs supplemented with 500lM IBMX
for 5min at 37°C. Cells were then stimulated with test
compound in the concentration range 0.1–10,000nM for
an additional 10min at 37°C. The assay was terminated
with the addition of 0.5M perchloric and intracellular
cAMP levels were determined by radioimmunoassay with
the cAMP Scintillation Proximity Assay System
(Amersham).