4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel 5-HT6 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2005.01.005

The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl) indoles which exhibit high affinity towards the 5-HT₆ receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl) indole 5g showed superior affinity (K_i = 1 nM) towards the 5-HT ₆ receptor as well as excellent selectivity (>2000-fold) against the closely related subtype 5-HT₇ receptor.

Full text of DOI:10.1016/j.bmcl.2005.01.005

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1393–1396
4-(2-Aminoethoxy)-N-(phenylsulfonyl)indoles as novel
5-HT6 receptor ligands
Ping Zhou,* Yinfa Yan, Ronald Bernotas, Boyd L. Harrison, Donna Huryn,
Albert J. Robichaud, Guo Ming Zhang, Deborah L. Smith and Lee E. Schechter
Chemical and Screening Science and Neuroscience Discovery Research, Wyeth Research, CN 8000, Princeton, NJ 08543-8000, USA
Received 16 September 2004; revised 4 January 2005; accepted 6 January 2005
Abstract—The preparation of a novel class of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles which exhibit high affinity towards the
5-HT6 receptor is reported here. Among these compounds, 4-(2-methylaminoethoxy)-N-(phenylsulfonyl)indole 5g showed superior
affinity (Ki = 1 nM) towards the 5-HT6 receptor as well as excellent selectivity (>2000-fold) against the closely related subtype 5-HT7
receptor.
Ó 2005 Elsevier Ltd. All rights reserved.
The potential role of 5-HT6 receptor ligands in the treat-
ment of various central nervous system disorders such as
learning and memory impairments has stimulated a
surge of interest in this area.1 In 1998, Bromidge and
co-workers reported SB-271046 (1), a potent and selec-
tive 5-HT6 antagonist which later entered into clinical
trials.2–4 SB-271046 is a benzothiophene-sulfonamide,
which incorporates an o-methoxy-piperazinyl-benzene
moiety 2.
NR1R2
O
H
N
H
N
N
N
OMe
N
N
H
H
4
3
2
H
N
NR1R2
O
H
N
N
MeO
N
MeO
NH
S
Me
N
O
O
S
NH
Me
S
Ph
O
5
S
Cl
O
O
1
O
S
Cl
1
Scheme 1. Design of 4-(2-aminoethoxy)-N-phenylsulfonylindoles as 5-
HT6 ligands.
SB-271046
methoxy-piperazinyl-benzene moiety 2.5,6 Additional
work showed that the 4-(2-aminoethoxy)indole piece 4
(Scheme 1) was equally valuable as an aromatic head-
piece for ligand design in this area.5,6 Hence we envi-
During the course of our previous studies in the design
and synthesis of novel 5-HT1A inhibitors, we found 4-
piperazinylindole 3 was a good replacement for the o-
sioned
sulfonamides 5 would be an interesting class of target
molecules for 5-HT6 receptor. By this analogy, the
that
4-(2-aminoethoxy)indole
N-phenyl-
*
Corresponding author. Tel.: +1 732 274 4661; fax: +1 732 274
4505; e-mail: zhoup@wyeth.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.005

1394
P. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1393–1396
NR1R2
O
Cl
Cl
O
c
N
OH
S
Ph
O
5
O
a
(Method A)
O
b
(Method B)
N
H
f
N
N
H
6
O
S
Ph
NH2
7
N3
O
O
d
8
O
e
N
N
O
O
S
Ph
O
O
S
Ph
9
10
Scheme 2. Synthesis of 4-(2-aminoethoxy)-N-(phenylsulfonyl)indoles. Reagents and conditions: (a) HOCH2CH2Cl/PPh3/DEAD/THF, 82%; (b)
NaH/THF/PhSO2Cl, 86%; (c) R1R2NH, heat, 57–92%; (d) NaN3/DMF, 96%; (e) PPh3/H2O, 80%; (f) aldehyde or ketone, NaBH(OAc)3, 31–98%.
4-(2-aminoethoxy)indole moiety can be viewed as a
replacement for the o-methoxy-piperazinyl-benzene unit
of SB-271046 (1) (Scheme 1). Herein, we describe the
synthesis of this novel class of compounds 5 and their
affinity towards the 5-HT6 receptor.7
oxy)indole 7 in 82% yield.8 Reaction of 7 with sodium
hydride and subsequent treatment with phenylsulfonyl
chloride gave N-phenylsulfonylindole 8 in excellent
yield.9 Treatment of the chloride 8 with an excess of
the appropriate amines in DMF at 80 °C overnight
(Method A) gave 57–92% yields of the target compounds
5a–j after chromatography and HCl salt formation.
Alternatively, compounds 5k–n could be prepared via
reductive alkylation of the primary amine 10 with alde-
hydes or ketones in the presence of NaBH(OAc)3 (Meth-
od B).10 The requisite primary amine 10 was readily
obtained in two steps from the corresponding chloride
The synthesis of 4-(2-aminoethoxy)indole N-phenylsulf-
onamides 5 was carried out as shown in Scheme 2, and
summarized in Table 1. Thus, treatment of commercially
available 4-hydroxyindole 6 with 2-chloroethanol in the
presence of triphenylphosphine and DEAD in THF at
ambient temperature for 2 h afforded 4-(2-chloroeth-
Table 1. Synthesis of 4-, 5- and 6-(2-aminoethoxy)-N-(phenylsulfonyl)indoles 5, 10, 13 and 16
4
5
O
N
6
1R2RN
O
S
Ph
O
Compound R1
R2
Point attached Method Overall yield (%) Mpa (°C)
5a
5b
5c
5d
5e
5f
–CH2CH2OCH2CH2–
–CH2(CH2)2CH2–
–CH2(CH2)3CH2–
–CH2(CH2)4CH2–
4-
4-
4-
4-
4-
4-
4-
4-
4-
4-
A
A
A
A
A
A
A
A
A
A
B
59
65
62
58
60
36
60
63
61
64
49
17
19
34
54
11
33
140–142
90–92
131–133
195–197
238–240
200–202
202–204
188–190
196–198
214–216
229–230
189–190
194–196
140–142
198–200
171–173
183–185
–CH2CH2N(Me)CH2CH2–
–CH2CH2N(Me)CH2CH2CH2–
5g
5h
5i
H
Me
Et
H
H
i-Pr
PhCH2
5j
H
5k
5l
H
O(CH2CH2)2CH– 4-
3-MeOC6H3CH2– 4-
3-MeOC6H3CH2– 4-
H
3-MeOC6H3CH2–
B
5m
5n
10
13
16
B
Me
H
Me
H
4-
4-
5-
6-
B
—
—
—
H
H
H
H
a Melting points were taken on mono HCl salts except compounds 5e,f, which were prepared as di HCl salts.

P. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1393–1396
1395
8 via the intermediate azide 9. While the reductive alkyl-
ation of 10 with a ketone led to mono-alkylated product
(Table 1, 5k), reactions of 10 with an aldehyde afforded
mixtures of mono- and dialkylated products with the lat-
ter predominating (Table 1, 5l–n).
indoles. Disubstituted compounds showed diminished
activities compared with its corresponding monosubsti-
tuted analogues (compare Table 2, 5m vs 5l and 5n vs
5g). For monosubstituted 5, again the smaller the size
of the substituent group, the higher the 5-HT6 affinity.
For example, N-isopropylaminoethoxy indole 5i has a
Ki = 19 nM whereas its N-ethyl and methyl analogue
5h and 5g displaces Ki value of 6 and 1 nM, respectively.
Based on these observations, examination of intermedi-
ate 10, which has the smallest R1 and R2 (both are
hydrogen substituents), in the 5-HT6 assay showed it
to have high superior affinity (Ki = 2 nM). Conse-
quently, compound 13 and 16, which are the regioisom-
ers of 10, were also synthesized from commercially
available 5-hydroxyindole and 6-methoxyindole, respec-
tively, as shown in Scheme 3. Both analogues 13 and 16
showed, however, reduced affinities for the 5-HT6 recep-
tor compared to 10, underscoring the importance of the
4-substitution pattern for these derivatives. Further
The synthesized compounds 5a–n were evaluated in
radioligand binding assays to measure their 5-HT6 and
5-HT7 affinities and the results are summarized in Table
2. For cyclic disubstituted aminoethoxy compounds 5a–
f, it appears that the 5-HT6 affinity decreases as the ring
size increases. For example, piperidinylethoxy indole 5c
has a Ki value of 7 nM whereas its homopiperidinyl ana-
logue 5d shows 3-fold reduced affinity. This trend is
more apparent for the N-methyl piperazinyl 5e and N-
methylhomopiperazinyl compounds 5f, where introduc-
tion of an additional methylene unit resulted in more
than 6-fold decrease in activity. Similar observation
was also made for the acyclic substituted aminoethoxy
Table 2. Biological activities of 4-, 5- and 6-(2-aminoethoxy)-N-(phenylsulfonyl)indoles 5a–n, 10, 13 and 16
Compound
5-HT6 Ki (nM)
5-HT7 Ki (nM)
Ki ratio 5-HT7/5-HT6
cAMP 5-HT6
IC50 (nM)
Imax (%)
5a
5b
5c
5d
5e
5f
28 3.1
7800 560
6100 372
279
763
257
91
ND
ND
100
8
7
0.5
0
400 73
198 27
ND
0
1800
5
90 10
ND
ND
22
18 0.5
1
2000 152
5500 83
2700 25
2200 154
3700 21
7700 374
1700 14
1000 755
1300 276
ND
306
23
ND
ND
120
1
ND
5g
5h
5i
1
6
0.1
0.1
2200
617
405
34
308 63
334 32
ND
100
100
ND
ND
91
0
0
19 0.5
50 0.5
5j
ND
5k
5l
6 0
12 0.5
1000
108
ND
753
1350
260
70
223 19
ND
ND
1
ND
ND
83
5m
5n
10
13
16
156
4
4
2
1
3000 269
2700 720
2600 223
1600 140
345 103
222 64
ND
1
2
0.4
1
92
10
ND
ND
23 0.5
ND
ND = not determined.
NH2
Cl
HO
c, d
a, b
O
O
N
H
N
N
O
S
Ph
O
S
Ph
11
O
O
13
12
e, f, g
h, i
Cl
N
H2N
O
N
O
O
O
S
Ph
N
H
O
S
Ph
MeO
O
15
14
16
Scheme 3. Synthesis of 5- and 6-(2-aminoethoxy)-N-(phenylsulfonyl)indoles. Reagents and conditions: (a) HOCH2CH2Cl/PPh3/DEAD/THF, 24%;
(b) NaH/THF/PhSO2Cl, 68%; (c) NaN3/DMF, 99%; (d) PPh3/H2O, 67%; (e) NaH/THF/PhSO2Cl, 86%; (f) BBr3/CH2Cl2, 54%; (g) HOCH2CH2Cl/
PPh3/DEAD/THF, 89%; (h) NaN3/DMF, 91%; (i) PPh3/H2O, 87%.

1396
P. Zhou et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1393–1396
3. Bromidge, S. M.; Brown, A. M.; Clarke, S. E.; Dodgson,
K.; Gager, T.; Grassam, H. L.; Jeffrey, P. M.; Joiner, G.
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5. (a) Mewshaw, R. E.; Zhou, P.; Zhou, D.; Meagher, K. L.;
Asselin, M.; Evrard, D. A.; Gilbert, A. M. US 6313126,
November 6, 2001; (b) Mewshaw, R. E.; Zhou, D.; Zhou,
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6. Mewshaw, R. E.; Meagher, K. L.; Zhou, P.; Zhou, D.;
Shi, X.; Scerni, R.; Smith, D.; Schechter, L. E.; Andree, T.
H. Bioorg. Med. Chem. Lett. 2002, 12, 307.
7. For recent reports on related 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,
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8. For reports on O-alkylations of hydroxyindoles under
Mitsunobo conditions, see: Mewshaw, R. E.; Kavanagh,
J.; Stack, G.; Marquis, K. L.; Shi, X.; Kagan, M. Z.;
Webb, M. B.; Katz, A. H.; Park, A.; Kang, Y. H.; Abou-
Gharbia, M.; Scerni, R.; Wasik, T.; Cortes-Burgos, L.;
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Cockett, M. I.; Ochalski, R.; Coupet, J.; Andree, T. H. J.
Med. Chem. 1997, 40, 4235.
optimization led to the secondary amine 5g which was
more potent than the parent amine 10.
The synthesized compounds 5a–n, 10, 13 and 16 were
also evaluated in radioligand binding assay to measure
5-HT7 affinity except compound 5m and the values were
used for the determination of binding selectivity of 5-
HT6 over 5-HT7 receptor. As shown in Table 2, the
selectivity, calculated as Ki ratio of 5-HT7/5-HT6, rang-
ing from 20- to >2000-fold was seen for these com-
pounds, with 5g being the most selective (>2000-fold).
For those compounds which demonstrated 5-HT6 affin-
ity less than 10 nM, additional cellular profiling (cAMP
accumulation) was conducted to determine intrinsic
activity at the 5-HT6 receptor. The results indicated that
compounds, 5b, 5g and 5h, were able to fully block the
effect of 5-HT with Imax of 100%. These derivatives
showed moderate antagonist potencies (IC50 range:
308–344 nM), and future work will be focused on opti-
mization of their intrinsic activities.
In summary, a novel class of 4-(2-aminoethoxy)-N-
(phenylsulfonyl)indoles were designed and synthesized.
Radioligand binding assays indicate they are potent 5-
HT6 receptor ligands. Among these compounds, 4-(2-
methylaminoethoxy)-N-(phenylsulfonyl)indole 5g show-
ed high affinity towards the 5-HT6 receptor with a
Ki = 1 nM and excellent selectivity (>2000-fold) over
the 5-HT7 receptor. Furthermore, it was shown that 5g
was a full antagonist at the 5-HT6 receptor with moder-
ate intrinsic potency.
References and notes
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Commun. 1993, 23, 2717.
10. For references on reductive amination of primary amines
using NaBH(OAc)3, see: Abdel-Magid, A. F.; Carson, K.
G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem. 1996, 61, 3849.
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