A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands

Article abstract of DOI:10.1016/j.bmcl.2008.06.030

A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.

Full text of DOI:10.1016/j.bmcl.2008.06.030

Bioorganic & Medicinal Chemistry Letters 18 (2008) 3929–3931
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6
ligands
a
b
b
b
b
Kevin G. Liu a, , Jennifer R. Lo , Thomas A. Comery , Guo Ming Zhang , Jean Y. Zhang , Dianne M. Kowal ,
*
Deborah L. Smith b, Li Di a, Edward H. Kerns a, Lee E. Schechter b, Albert J. Robichaud a
a Chemical & Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA
b Discovery Neurosciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A regiospecific synthesis of a series of 1-sulfonyl azepinoindoles as potent 5-HT6 ligands is reported.
Received 27 May 2008
Revised 4 June 2008
Accepted 9 June 2008
Available online 13 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Azepinoindole
Indolenine
5-HT6
Indole
Fischer indole synthesis
The 5-HT6 receptor was first cloned in 1993 and is one of the
most recently discovered 5-HT receptor subtypes.1,2 Its brain selec-
tive location, together with high affinity of therapeutically impor-
tant atypical antipsychotics and tricyclic antidepressants at this
receptor has stimulated significant interest in its pathophysiologi-
cal function and potential therapeutic utility as CNS therapeutics.
The 5-HT6 receptor has been implicated in a range of diseases
including anxiety, depression, schizophrenia, epilepsy, obesity,
abnormal feeding behavior, and cognitive dysfunctions. Research
efforts in this area have led to the discovery of a number of potent
and selective 5-HT6 agonists and antagonists.3,4
As part of our continued efforts in identifying novel 5-HT6 li-
gands as potential treatments for CNS diseases, we continued our
earlier strategy5,6 of elaborating the simplified substituted trypt-
amine scaffold 1 (Fig. 1). Tryptamine derivatives 1 bearing a sulfo-
nyl group at indole N1 position have been reported to be potent 5-
HT6 ligands by Glennon,7 Russell,8 and Cole.5 We were interested in
rigidifying the molecule by tethering the amino side chain to the 2-
position of the indole core with the hope that the novel con-
strained 1-sulfonyl azepinoindole derivatives 2 may provide better
selectivity against other 5-HT subtypes than their acyclic
counterparts.7
This intermediate would allow for the facile derivatization at the
3- and 6-positions of the azepinoindole core. Traditional synthesis
of azepinoindoles (Fig. 2) involves Fischer indole synthesis from
arylhydrazines such as 4 and hexahydroazepin-4-one 5.9 This
non-regioselective synthesis provides a mixture of the desired
R
R
N
R
N
rigidifying molecule
N
N
S
O
S
O
O
Ar
O
Ar
2
1
Figure 1. Design of novel 5-HT6 ligands from substituted tryptamine template.
PG
N
PG
2
N
3
N
PG
1
O
4
5
NH2
+
5
N
H
For an efficient synthesis of 2, the azepinoindole intermediate 3
(Fig. 2) with a protecting group on the basic amine was required.
N 6
H
N
H
4
3
6
undesired regioisomer
* Corresponding author. Tel.: +1 732 274 4415.
E-mail address: liuk1@wyeth.com (K.G. Liu).
Figure 2. Traditional synthesis of azepinoindoles.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.06.030

3930
K. G. Liu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3929–3931
O
Cbz
Cbz
N
N
R2
R1
N
R1
ArSO2Cl
R2
HBr/HOAc
H
NaH, DMF
R1
7
R
R2
NH2
N
H
N
R
R
N
H
S
Ar
N
O
H
12
13
O
4
8
9
R
N
NH
Figure 3. Synthesis of 2,3-substituted indoles via rearrangement of 3,3-disubsti-
R'COR'', NaBH(OAc)3
tuted indolenines.10
N
N
S
Ar
S
Ar
O
O
product 3 and its regioisomer 6, the desired product generally
being isolated in poor yields.
O
O
2 (R H)
2 (R = H)
≠
Recently, we reported the synthesis of 2,3-substituted indoles 9
from 3,3-disubstituted indolenines 8 via acid-catalyzed rearrange-
ment (Fig. 3).10 Indolenines 8 could be conveniently synthesized
Figure 5. Synthesis of azepinoindoles as 5-HT6 ligands.
from arylhydrazines 4 and a-branched aldehydes 7 via Fischer in-
Table 1
dole-type synthesis.11,10 As part of our efforts in applying this
methodology to synthesis of biologically interesting compounds
for CNS diseases, we developed a novel and directed synthesis of
azepinoindoles, which is reported here.
5-HT6 binding affinity of 1-sulfonyl azepinoindole derivatives
2
3
N
4
R
1
5
Our approach to the construction of the azepinoindole core is
depicted in Figure 4. The synthesis involves heating equimolar
amounts of the common phenylhydrazine 4 and the commercially
available N-Cbz protected aldehyde 10 in HOAc. The Cbz protecting
group was chosen in preference to an acid labile Boc protecting
group due to the commonly utilized acidic conditions of the Fischer
indole reaction. In practice, the reaction components are heated for
2 h at 70 °C, whereupon complete formation of the indolenine
derivative is verified by LCMS. The reaction temperature is then in-
creased to 110 °C for an extended time (10–16 h), to effect rear-
rangement to the tricyclic azepinoindole 12 which is isolated in
50–70% yields after chromatographic purification.12 Additional
work is being conducted to explore the scope and limitations of
this methodology, the results of which will be reported in due
course.
After intermediate 12 was successfully prepared, the remaining
elaboration of the core 12 to the desired 5-HT6 ligands 2 was
straightforward, and depicted in Figure 5. Simple basic treatment
of the indole and commercially available arylsulfinyl chlorides in
DMF afforded the 1-substituted derivates 13 in good yields (60–
70%). Removal of the Cbz protecting group affords the secondary
amines 2a–n without incident. Further elaboration to the
substituted tertiary amines 2o–v can be easily performed under a
variety of reductive amination or alkylation conditions.
N 6
S
O
O
Ar
2
Compound
Ar
R
Kia (nM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
3-F-Ph
4-F-Ph
2-Cl-Ph
3-Cl-Ph
4-Cl-Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
n-Pr
i-Pr
Bn
PhCH2CH2
c-Pentyl
c-Hexyl
Et
193
33
23
19
41
18
68
29
89
46
24
19
33
12
19
50
124
85
3-Me-Ph
4-Me-Ph
3-CF3-Ph
4-CF3-Ph
5-Cl-Naph
2-MeO-Ph
4-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
3-MeO-Ph
Ph
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
319
504
324
253
12
2u
2v
1
These azepinoindole derivatives 2 were then evaluated for their
5-HT6 affinity over several serotonin subtype receptors. The results
are summarized in Table 1. For the range of 3-unsubstituted aze-
pinoindole derivatives (2a–n, R = H) synthesized, the optimal sul-
fonyl group identified was 3-methoxylbenzenesulfonyl group. A
number of 3-N-alkyl-6-(3-methoxybenzenesulfonyl) analogs (2o–
a
Displacement of [3H]-LSD binding to cloned h5-HT6 receptors stably expressed
in HeLa cells.6 Ki values were determined in triplicate.
reasons for this are not apparent, but one may hypothesize that
the azepinoindole derivatives with rigidified structures bind to
the 5-HT6 receptor in a constrained conformational mode, project-
ing this alkyl group unfavorably into the peptide backbone of the
receptor. Alternatively, the change in the pKa of the basic amine,
the required 5-HT binding appendage, upon alkylation, is not toler-
ated by the key aspartic or glutamic acid residue, ubiquitous in the
5-HT G-protein coupled receptors. Unfortunately, this class of com-
pounds did not show improved selectivity as initially expected
against other closely related 5-HT subtypes examined (e.g., 5-
HT2C Ki = 14 nM for 2l).
Selected compounds were evaluated for their 5-HT6 functional
activity by measuring their ability to produce cyclic AMP (cAMP)
through modulation of 5-HT6 receptor function in a cyclase assay.
In all cases, these azepinoindoles derivatives were shown to be
antagonists with modest functional affinity for the target receptor
(e.g., IC50 = 162 nM for 2l).
v, R
6¼ H) were prepared in order to further explore the SAR for this
chemical series. Although small alkyl substitution (R = Me, Et) af-
fords little loss of potency, larger alkyl groups abrogate affinity
quite effectively. This trend is not very consistent with the SAR ob-
served previously with other classes of 5-HT6 ligands13 in which
the substitution on the basic amine is oftentimes tolerated. The
Cbz
Cbz
N
N
Cbz
N
OHC
NH2
10
HOAc
N
H
N
H
N
4
11
12
Figure 4. Regiospecific synthesis of azepinoindoles.

K. G. Liu et al. / Bioorg. Med. Chem. Lett. 18 (2008) 3929–3931
3. Glennon, R. A. J. Med. Chem. 2003, 46, 2795.
3931
In summary, we have reported a novel facile synthesis of 3-aryl-
sulfonyl azepinoindoles that possess good affinity for the 5-HT6
receptor. These analogs are prepared in 2–3 steps, depending on
the elaboration of the basic amine moiety, in a regiospecific man-
ner and moderate yields. Noted examples are antagonists at the
target receptor, with minimal selectivity versus closely related
serotonin subtype receptors.
4. Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Merce, R.; Codony, X.; Buschmann, H. Drug.
Discov. Today 2006, 11, 283.
5. Cole, D. C.; Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.; Bernotas, R. C.; Tawa, G.
J.; Mazandarani, H.; Smith, D. L.; Zhang, G.; Coupet, J.; Schechter, L. E. J. Med.
Chem. 2005, 48, 353.
6. Cole, D. C.; Ellingboe, J. W.; Lennox, W. J.; Mazandarani, H.; Smith, D. L.; Stock, J.
R.; Zhang, G.; Zhou, P.; Schechter, L. E. Bio. Med. Chem. Lett. 2005, 15, 379.
7. Tsai, Y.; Dukat, M.; Slassi, A.; MacLean, N.; Demchyshyn, L.; Savage, J. E.; Roth,
B. L.; Hufesein, S.; Lee, M.; Glennon, R. A. Bio. Med. Chem. Lett. 2000, 10, 2295.
8. 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,
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Acknowledgments
9. Hester, J. B., Jr.; Tang, A. H.; Keasling, H. H.; Veldkamp, W. J. Med. Chem. 1968,
11, 101.
10. Liu, K. G.; Robichaud, A. J.; Lo, J. R.; Mattes, J. F.; Cai, Y. Org. Lett. 2006, 8, 5769.
11. Liu, K. G.; Robichaud, A. J. Tetrahedron Lett. 2006, 48, 461.
We thank James Mattes, Yanxuan Cai, Bill Marathias, and Alvin
Bach for their discovery analytic chemistry support.
12. Procedure.
A mixture of phenylhydrazine 4 (1.50 g, 13.9 mmol) in AcOH
References and notes
(93 mL) was stirred at 70 °C for 1 h. Additional HOAc (184 mL) was added and
the mixture was heated at reflux overnight, concentrated, and purified by
chromatography with 10–100% EtOAc/Hex to provide 12 (2.5 g, 56%).
13. Liu, K. G. et al., Unpublished results.
1. Woolley, M. L.; Marsden, C. A.; Fone, K. C. F. Current Drug Targets: CNS & Neurol.
Disord. 2004, 3, 59.
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