Identification of a series of benzoxazoles as potent 5-HT6 ligands

Article abstract of DOI:10.1016/j.bmcl.2008.12.107

As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT₆ receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT₆ ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.

Full text of DOI:10.1016/j.bmcl.2008.12.107

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1115–1117
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of a series of benzoxazoles 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:
As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alz-
heimer’s disease (AD), we have been focused on the 5-HT6 receptor in order to identify potent and selec-
tive ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a
novel series of benzoxazole derivatives as potent 5-HT6 ligands. The synthesis and detailed SAR of this
class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic
AMP functional assay.
Received 18 November 2008
Revised 20 December 2008
Accepted 30 December 2008
Available online 3 January 2009
Keywords:
5-HT6
Ó 2009 Elsevier Ltd. All rights reserved.
5-Hydroxytryptamine-6
Alzheimer’s disease
AD
Cognition
Cognitive dysfunction is a characteristic of various forms of
dementia such as Alzheimer’s disease (AD) and a core feature of
schizophrenia.1–4 Numerous therapeutic targets have been pursued
in order to develop agents for cognitive enhancement in these CNS
diseases.5 As one of these emerging therapeutic targets, the 5-HT6
receptor was first cloned in 19936,7 and is one of the most recently
discovered 5-HT receptor subtypes. It is a member of the G-protein
superfamily, and is positively coupled to adenylate cyclase. It is
localized almost exclusively in the brain, including areas important
for learning and memory, such as the cerebral cortex and hippo-
campus. This brain-selective localization together with the noted
high affinity of therapeutically important atypical antipsychotics
and tricyclic antidepressants for this receptor have stimulated sig-
nificant interest in its pathophysiological function and potential
therapeutic utilities in CNS diseases.8 Numerous in vivo studies
have shown that blockade of 5-HT6 receptor function improves cog-
nition in a number of rodent behavioral models. In addition, in vivo
microdialysis studies have shown that 5-HT6 receptor antagonism
enhances neurotransmission at cholinergic and glutamatergic neu-
rons, as well as in other pathways. Therefore, it can be proffered
that antagonism of the 5-HT6 receptor can potentially provide an
effective treatment for cognitive impairment in AD and schizophre-
nia and has been the subject of intense research.9
prised of an indole or other heterocyclic core with a basic amine
and an arylsulfonyl moiety (e.g., 114–16 in Fig. 1). It was rather
apparent to us that the basic amine and arylsulfonyl moieties are
the necessary receptor pharmacophores and the indole core serves
merely as a template to hold these pharmacophores in the neces-
sary orientation that effectively interact with the 5-HT6 receptor
active site residues. As part of our continued efforts in identifying
novel 5-HT6 ligands as potential treatments for CNS diseases,17 we
explored other heterocyclic templates as replacement of the indole
core in an effort to expand our compound diversity and identify
scaffolds with unique and perhaps improved drug like properties.
Herein, we report identification of a novel series of benzoxazoles
3 (Fig. 1) as potent 5-HT6 ligands.
The general synthesis of 4–7—substituted arylsulfonylbenzox-
azole 3 is depicted in Scheme 1. Diazotization of aniline 4 (vide in-
fra) followed by reaction with KI provided iodide 5. The
R2
N
O
S
R
N
Ar
R1
O
Ar
O
S
R'
N
O
Template
2
1
O
S
In the last decade, a great number of 5-HT6 ligands of both ago-
O
nists and antagonists have been reported,10–13 and many are com-
4
Ar
N
O
5
N
N R
6
7
3
* Corresponding author. Tel.: +1 732 274 4415.
E-mail address: liuk1@wyeth.com (K.G. Liu).
Figure 1. Design of novel 5-HT6 ligands.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.12.107

1116
K. G. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1115–1117
4
7
I
N
H2N
I
N
N
O
a
N
O
b
NCbz
N
N
5
Cl
N
NCbz
a
N
NCbz
N
NCbz
O
14
O
6
O
13
5b
5
4
O
S
Scheme 3. Reagents and conditions: (a) benzyl 1-piperazinecarboxylate, K2CO3,
O
Ar
S
Ar
DMF, 77%; (b) ICl, HOAc, 65%.
N
O
N
O
c
b
N
NCbz
N
NCbz
Table 1
5-HT6 binding affinity of benzoxazole derivativesa
6
7
O
O
O
S
4
O
Ar
N
4
Ar
S
5
5
d, e
N
O
N
N R
6
N
N R
O
6
7
3
7
3
Compound
Position
Ar
R
Ki (nM)
Scheme 1. Reagents and conditions: (a) i—NaNO2, HCl, MeOH; ii—KI, 50–60%; (b)
ArSH, CuI, (CH2OH)2, i-PrOH, 60–90%; (c) mCPBA, CHCl3, 90–100%; (d) HBr in HOAc,
70–95%; (e) R0CHO, NaBH(OAc)3, 40–95%.
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
4
4
4
4
4
4
4
4
4
5
6
7
4
4
4
4
4
4
4
4
4
Ph
H
H
H
H
H
H
H
H
H
H
H
H
41
54
64
31
22
22
33
25
13
3.1
52
196
7.1
9.7
12
36
13
88
176
127
72
79
3-F-Ph
4-F-Ph
3-Cl-Ph
arylsulfonyl group was then introduced to the molecule by first
coupling of 5 with a thiol, using a procedure reported by Buch-
wald,18 followed by oxidation with mCPBA. The Cbz protecting
group of 7 was then removed by treatment with HBr in HOAc to
furnish the benzoxazole core ligands 3 (R = H), which were further
alkylated on the piperazine nitrogen via reductive amination under
standard conditions.
Synthesis of aniline intermediates 4 is depicted in Scheme 2. For
4–6 substituted analogs, the commercially available nitro substi-
tuted 2-aminophenols 8 were employed as starting materials.
Reaction of these aminophenols with CS2 in the presence of KOH
provided benzoxazol-2-thiones 9. Subsequent nucleophilic substi-
tution with Cbz-protected piperazine followed by reduction with
SnCl2 provided 4a–c. For 7-substituted analogs, commercially
available 10 was employed as the starting material and a similar
synthetic sequence was followed to provide 4d.
Alternatively, the iodo intermediate 5b, for synthesis of the 5-
sulfonylbenzoxazoles 3, can be more efficiently synthesized from
commercially available 2-chlorobenzoxazole 13. Aromatic nucleo-
philic substitution with Cbz-protected piperazine followed by di-
rect iodination at the 5-position affords the desired intermediate
(Scheme 3).
The final products, 3, were evaluated for their binding affinity to
human 5-HT6 receptor16 and the results are summarized in Table 1.
For the range of 4-arylsulfonyl N-unsubstituted benzoxazole deriv-
atives (3a–j, R = H) synthesized, the optimal sulfonyl group identi-
fied was the 1-naphthalenesulfonyl group (3j). Analogs with this 1-
naphthalenesulfonyl group at the alternate positions (3k–m) were
prepared in order to identify the optimal position for this moiety.
While the 7-(1-naphthalenesulfonyl) derivative 3m (Ki = 7.1 nM)
was comparable in potency to its 4-substituted counterpart 3j,
alternates were significantly less potent (6-substitution in particu-
lar) with a 15- to 60-fold reduction in affinity. This underscores our
4-iPr-Ph
3-CF3-Ph
4-CF3-Ph
3-MeO-Ph
2,5-diCl-Ph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
1-Naph
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
H
Me
Et
n-Pr
i-Pr
n-Bu
i-Bu
Ph(CH2)3
c-Bu
c-Pen
3u
3v
a
Displacement of [3H]-LSD binding to cloned human 5-HT6 receptors stably
expressed in HeLa cells.16 Ki values were determined in triplicate.
hypothesis that the relative positions of the key basic amine and
the arylsulfonyl pharmacophores for effective interaction with
the 5-HT6 receptor site are paramount. The ‘symmetry’ of affinity
between the 4- and 7-positions (Ki = 3.1 and 7.1 nM, respectively)
and between the 5- and 6-positions (Ki = 52 and 196 nM, respec-
tively) further supports this and is the basis of the design of this
class of compounds as 5-HT6 ligands. One should not ignore the
need for the proper heterocyclic core and its ability to positively
interact with the receptor site. However, our experience with these
and other 5-HT6 specific ligands supports the notion that the core
heterocycle serves as a template to hold the pharmacophores in
the required positions for effective interaction with the receptor
in order to achieve optimal affinity.
With that in mind, and maintaining the 1-naphthalenesulfonyl
group in the optimal 4-position, a number of N-substituted benz-
oxazole derivatives (3n–v, Table 1) were then prepared in order
to further explore the SAR of this series. While small alkyl substi-
tutions (R = Me, Et, i-Pr) are tolerated, larger alkyl groups signifi-
cantly reduce the potency. This tread is consistent with the SAR
of the azepinoindole 5-HT6 ligands we recently reported.13 The rea-
son for this, although unclear, is possibly that the conformational
rigidity of both the benzoxazoles and azepinoindoles and the
change of pKa of the basic amine upon alkylation contribute to this
SAR.
O2N
4
4
H
N
O2N
5
H2N
NH2
OH
N
O
a
5
b
N
NCbz
NCbz
S
6
6
O
4a 4-NH2
4b 5-NH2
4c 6-NH2
8
9a 4-NO2
9b 5-NO2
9c 6-NO2
H
N
NH2
NO2
N
d
c
N
S
e
O
O
OH
7
OH
NH2
4d
NH2
12
NH2
11
NO2
10
Selected compounds were further evaluated for their functional
activity in a 5-HT6 receptor cyclase assay.16 All of the benzoxazole
derivatives 3 evaluated showed full antagonism as determined by
blockage of 5-HT induced cyclic AMP (cAMP) formation. The data is
summarized in Table 2.
Scheme 2. Reagents and conditions: (a) CS2, KOH, 35–79%; (b) i—benzyl 1-
piperazinecarboxylate, xylenes, reflux; ii—SnCl2, HCl, EtOH, 24–50%; (c) H2, Pd/C,
89%; (d) CS2, KOH; (e) benzyl 1-piperazinecarboxylate, xylenes, reflux.

K. G. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1115–1117
1117
Table 2
Cyclase functional activity of selected benzoxazole derivativesa
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In summary, we have identified a novel series of benzoxazole
derivatives as potent 5-HT6 ligands. Synthesis and detailed SAR
of this class of compounds have been reported. The compounds
were shown to be full antagonists in a cyclic AMP functional assay.
Further profiling of this class of compounds will be detailed in sub-
sequent reports.
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Acknowledgments
17. Liu, K. G.; Lo, J. R.; Comery, T. A.; Zhang, G. M.; Zhang, J. Y.; Kowal, D. M.; Smith,
D. L.; Di, L.; Kerns, E. H.; Schechter, L. E.; Robichaud, A. J. Bioorg. Med. Chem. Lett.
2008, 18, 3929.
We thank James Mattes, Yanxuan Cai, Donald Herold, Sergio
Anis, and Alvin Bach for their discovery analytical chemistry
support.
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