Identification of a novel series of 3-piperidinyl-5-sulfonylindazoles as potent 5-HT6 ligands

Article abstract of DOI:10.1016/j.bmcl.2009.04.108

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT

Full text of DOI:10.1016/j.bmcl.2009.04.108

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3214–3216
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Identification of a novel series of 3-piperidinyl-5-sulfonylindazoles 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 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:
Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer’s disease (AD)
and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive
enhancement, we have been focused on the 5-HT6 receptor—one of the emerging therapeutic targets
in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole
derivatives as potent 5-HT6 antagonists. The synthesis and SAR of this class of compounds are reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 March 2009
Revised 20 April 2009
Accepted 22 April 2009
Available online 3 May 2009
Keywords:
5-HT
Serotonin
5-Hydroxytryptamine
5-HT6
5-Hydroxytryptamine-6
Alzheimer’s disease
Schizophrenia
Cognition
Cognitive impairment
Cognitive dysfunction
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 the high affinity of therapeutically
important atypical antipsychotics and tricyclic antidepressants at
this receptor have stimulated significant interest in its pathophys-
iological function and potential therapeutic utility. Thus, the 5-HT6
receptor has been implicated in a range of diseases including anx-
iety, depression, schizophrenia, epilepsy, obesity, abnormal feeding
behavior, and most notably cognitive dysfunctions.1,3 Research ef-
forts in this area have led to the discovery of a number of potent
and selective 5-HT6 agonists and antagonists, for example, 1–5
(Chart 1).4–8 Currently a number of compounds are believed to
be active in phase I and II clinical trials for cognitive impairment
in AD and schizophrenia.4,7,8
As part of our continued efforts in identifying novel 5-HT6 li-
gands as potential treatments for CNS diseases,9,10 we explored
other heterocyclic templates as replacement of the indole core
while retaining the ArSO2 and basic amine pharmacophores in an
effort to expand our compound diversity and identify scaffolds
with unique and perhaps improved druglike properties. Herein,
Cl
H2N
H
N
H
N
X
NH
S
H
N
O
O
N
O
N
S
S
O
O
HN
3
1 X = N, Ro 04-6790, Ki = 55 nM
2 X = CH, Ro 63-0563, Ki = 12 nM
SB-271046
Ki = 1.3 nM
R
N
H
N
N
O
N
O
O
N
S
Ar
N
S
O
N
N
H
O
S
4
O
O
MS-245
Ki = 2.3 nM
5
6
SB-742457
Ki < 10 nM
Chart 1. Structures of 5-HT6 ligands.
we report identification of a novel series of 3-piperidinyl-5-sulf-
onylindazole derivatives 6 (Chart 1) as potent 5-HT6 ligands.
* Corresponding author. Tel.: +1 732 274 4415.
E-mail address: liuk1@wyeth.com (K.G. Liu).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.108

K. G. Liu et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3214–3216
3215
Table 2
CH3
N
CH3
N
O
Cyclase functional activity of selected compoundsa
I
a
b
c
Compound
IC50 (nM)
Imax (%)
N
F
CH3
6c
6g
6j
754
108
251
102
95
7
8
9
Cl
I
MgCl
d
100
100
100
CH3
N
CH3
N
6k
a
Antagonism of 5-HT stimulated cAMP formation in HeLa cells stably transfected
with human 5-HT6 receptors.12 IC50 and Imax values were determined in triplicate.
S
e
Ar
N
N
N
N
H
of 11 with 1 equiv of HCl. This is presumably due to obviating
the oxidation of the piperidine nitrogen by protonation and
preventing many of these side products from complicating the
reaction mixture. Absence of the acid in this procedure led to
the expected over-oxidized complex mixtures. Demethylation
H
11
CH3
N
10
H
N
O
S
O
O
O
f
S
Ar
Ar
of
6 (R = Me) with 1-chloroethyl chloroformate afforded the
N
N
N
N
H
unsubstituted piperidines 6 (R = H) which can then be further
substituted with other alkyl groups to expand the SAR
investigation.
H
6 (R = Me)
6 (R = H)
Scheme 1. Reagents and conditions: (a) Mg turnings, THF; (b) 2-fluoro-5-iodo-
benzoyl chloride, 53% (2-step); (c) NH2NH2, DMSO, 81%; (d) ArSH, CuI, K2CO3,
ethylene glycol, iPrOH, 60–95%; (e) (i) HCl, MeOH; (ii) Oxone, MeOH/H2O, 90–100%;
(f) (i) ACECl, 1,2-dichloroethane; (ii) MeOH, H2O, KOH, 30–80%.
The 3-piperidinyl-5-sulfonylindazole final compounds were
evaluated for their binding affinity to human 5-HT6 receptor in
a standard competition binding assay12 and the results are sum-
marized in Table 1. For N-Me derivatives 6 (R = H), a range of
arylsulfonyl groups were explored in order to establish the SAR
for this chemical series. The unsubstituted benzenesulfonyl
derivative 6a has a potency of 55 nM. Meta- and para-substitu-
tion (6b–i) of the PhSO2À moiety with a variety of groups
including neutral, electron-withdrawing, and electron-donating
groups did not appear to significantly affect the potency. None-
theless, para-substitution with the bulkier i-Pr group did provide
compound 6g with slightly improved potency. This trend of SAR
was further observed with more dramatically improved potency
of compounds with the much larger 1-naphthalenesulfonyl (6j)
and 2-naphthalenesulfonyl (6k) groups (Ki = 3.8 and 9.6 nM,
respectively). It was also observed that in general demethylated
piperidine analogs 6 (R = H) have comparable or slightly less
affinity as compared to their N-Me counterparts 6 (data not
shown).
The general synthesis of 3-piperidinyl-5-sulfonylindazole
derivatives 6 is depicted in Scheme 1. Grignard reagent 8, which
was prepared from commercially available chloride 7 under
standard conditions, was reacted with 2-fluoro-5-iodo-benzoyl
chloride at low temperatures (À78 °C to 0 °C) to provide 2-flu-
oro-benzophenone intermediate 9. Subsequent reaction with
NH2NH2 in DMSO afforded 5-iodo-indazole 10, a key common
intermediate, for efficient synthesis of final target compounds.
A variety of thiols were then utilized for coupling with 10, using
a procedure reported by Buchwald,11 to provide sulfides 11. Our
initial attempts to oxidize sulfides 11 to their corresponding
sulfones 6 with a number of oxidants such as mCPBA and
H2O2 under a variety of reaction conditions were not very fruit-
ful. The resultant complex reaction mixtures, over-oxidized prod-
ucts and low yields of desired products necessitated
broadening of our search. Fortunately, we found that oxidation
with Oxone went smoothly and efficiently after pretreatment
a
Selected compounds were further evaluated for their func-
tional activity in a 5-HT6 receptor cyclase assay.12 All of the
3-piperidinyl-5-sulfonylindazole derivatives evaluated showed
full antagonism as determined by blockage of 5-HT induced
cyclic AMP (cAMP) formation. The data is summarized in
Table 2.
In summary, we have identified a novel series of 3-piperidinyl-
5-sulfonylindazole derivatives as potent 5-HT6 ligands. Synthesis
and SAR of this class of compounds has been reported. The com-
pounds were shown to be full antagonists in a cyclic AMP func-
tional assay. Further profiling of this class of compounds will be
detailed in subsequent reports.
Table 1
5-HT6 binding affinity of 3-piperidinyl-5-sulfonylindazolesa
CH3
N
O
S
O
Ar
N
N
H
6 (R = H)
Acknowledgments
Compound
Ar
Ki (nM)
We thank James Mattes, Yanxuan Cai, Donald Herold, Sergio
Anis, and Alvin Bach for their discovery analytical chemistry
support.
6a
6b
6c
6d
6e
6f
6g
6h
6i
Ph
3-F-Ph
3-Cl-Ph
3-Me-Ph
4-F-Ph
4-CF3-Ph
4-iPr-Ph
4-CF3O-Ph
4-MeO-Ph
1-Naph
55
93
19
50
66
46
14
48
123
3.8
9.6
References and notes
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2-Naph
a
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