Novel (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides with high affinity and selectivity for the 5-HT(6) receptor.

Article abstract of DOI:10.1016/S0960-894X(01)00558-3

The discovery of (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides and their binding affinities for a selection of 5-HT and dopamine subreceptors is described. Many compounds show high affinity (pK(i)>8) for the 5-HT(6) receptor and >100-fold selectivity against a range of other receptors. Structure-activity relationships of these compounds are discussed.

Full text of DOI:10.1016/S0960-894X(01)00558-3

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2843–2846
Novel (4-Piperazin-1-ylquinolin-6-yl) Arylsulfonamides with High
Affinity and Selectivity for the 5-HT6 Receptor
Steven M. Bromidge,a Kerry Griffith,a Tom D. Heightman,a Andrew Jennings,a
b
Frank D. King,a Stephen F. Moss,a,*Helen Newman, Graham Riley,b
Carol Routledge,b Halina T. Serafinowskaa and David R. Thomasb
aDiscovery Chemistry Europe, GlaxoSmithKline, Discovery Research, New Frontiers Science Park, ThirdAvenue, Harlow,
Essex CM19 5AW, UK
bDepartment of Neurosciences Research, GlaxoSmithKline, Discovery Research, New Frontiers Science Park, ThirdAvenue, Harlow,
Essex CM19 5AW, UK
Received 10 May 2001; revised 20 July 2001; accepted 3 August 2001
Abstract—The discovery of (4-piperazin-1-ylquinolin-6-yl) arylsulfonamides and their binding affinites for a selection of 5-HT and
dopamine subreceptors is described. Many compounds show high afffinity (pKi>8) for the 5-HT6 receptor and >100-fold selec-
tivity against a range of other receptors. Structure–activity relationships of these compounds are discussed. # 2001 Elsevier Science
Ltd. All rights reserved.
The possible role of the 5-HT6 receptor in learning and
memory disorders has encouraged significant recent
interest.1 We have recently reported the discovery of a
5-HT6 receptor antagonist, 1 (SB-271046).2 This com-
pound demonstrates high and selective affinity for the 5-
HT6 receptor (pKi 8.9), is moderately brain penetrant
and has excellent oral bioavailability. In separate beha-
vioural3 and neurochemical4 studies, compound 1 pro-
duced indications of improvement in cognitive function.
from the methoxy group. We reasoned that the corre-
sponding basic piperazine nitrogen in a 4-piper-
azinylquinoline system, as in 2 (SB-331711), would
place it in the same region of space and might thereby
represent a biologically active replacement for the
methoxyphenyl piperazine unit. Interestingly, naphthyl
analogues of piperazinylquinolines of similar structure
to 2 have been reported with high binding affinity for
the 5-HT1 subreceptor.5 This Letter reports our key
findings regarding the synthesis of piperazine derived
quinoline arylsulfonamides, such as 2, and their corre-
sponding 5-HT6 affinities and selectivities against a
range of relevant 5-HT and dopamine receptors.
Chemistry
Novel 4-piperazinyl quinoline arylsulfonamides (2, 6a–
s) (Table 1) were prepared as shown in Scheme 1. Thus,
displacement reactions on 4-chloro-6-nitroquinoline6 3
with excess functionalised or non-functionalised piper-
azines in refluxing toluene gave good yields of the 4-
piperazine derivatives 4. The intermediate NH-piper-
azines 4 were protected as N-Boc derivatives then cata-
lytically reduced to the amines 5. Subsequently, these
amines were coupled with aromatic sulfonyl chlorides to
give sulfonamides, which were deprotected by treatment
with acidified THF at reflux to afford the target com-
pounds 2, 6a–s. The 2,6-dimethylpiperazine analogue 6t
The aim of this investigation was to further explore the
scope of activity of related sulfonamide structures.
Molecular modelling and single X-ray diffraction stud-
ies on 1 indicated that the preferred conformation of the
piperazine ring is as indicated above with the unsub-
stituted nitrogen atom in a ‘northerly’ direction, away
*Corresponding author. Tel.: +44-1279-627722; fax: +44-1279-
622790; e-mail: steve_moss-1@sbphrd.com
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00558-3

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S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2843–2846
Table 1. Receptor binding affinites of 4-piperazinyl quinolines
Compd
Ar
pKi 5-HT6 Sel. versus 9 receptor subtypesa
6a
7.6
8.8
9.2
9.3
NDb
100
6b
6c
6d
1260
320
Scheme 1. Reagents and conditions: (i) Piperazine (4 equiv), toluene,
reflux, 24 h (73–98%); (ii) (BOC)2O, K2CO3, THF–H2O (1:1), rt, 3
days (92–96%); (iii) H2, 5% Pd/C, EtOH, rt, 24 h (11–99%); (iv) (a)
ArSO2Cl, CH2Cl2, pyridine (2 equiv), rt, 24 h; (b) c.HCl–THF (1:4.6
v/v), reflux, 1.5 h (9–85% over two steps).
6e
6f
6g
6h
2
8.9
9.0
8.5
8.4
8.7
8.9
8.8
8.2
9.0
8.7
8.7
8.1
500
160
80
(Table 2) was prepared by an analogous procedure
except that Boc protection was not required for the
coupling step due to steric hindrance. N-Substituted
derivatives 6u and 6v were prepared similarly to 6t. The
2- and 3-methyl quinolines 9a and 9b (Table 3) were pre-
pared similarly, starting from 4-chloro-2-methyl-6-nitro-
quinoline,7 and 4-chloro-3-methyl-6-nitroquinoline,8
respectively.
200
320
1000
160
25
The 3-piperazinyl analogue 8 was prepared starting
from 3-bromo-6-nitroquinoline9 (Scheme 2). A Buch-
wald10 type palladium(0) catalysed cross-coupling reac-
tion afforded the 3-piperazinyl nitroquinoline which was
reduced to give the amino quinoline 7 in an overall yield
of 56%. The coupling reaction to afford 8 was achieved
in 32% yield.
6i
6j
Results and Discussion
6k
6l
Variation of left-hand side aryl
Parallel synthesis rapidly afforded a large number of
compounds with a generally favourable range of 5-HT6
affinities and selectivities, and a selection is shown in
Table 1. Several compounds (e.g., 6c, 6d and 6f) have
nanomolar affinity for the 5-HT6 receptor and >100-
fold selectivity over a range of nine relevant receptor
subtypes. Detailed selectivity profiles of selected com-
pounds against 10 5-HT and dopamine subreceptors are
shown in Table 4. Large 4-substituents (e.g., 6b–d) were
favoured over 3,5-dichlorosubstitution (6a). Consistent
with this finding was that bicyclic aromatics also afforded
generally excellent affinity and selectivity.
250
130
200
40
6m
6n
6o
aSelectivity was determined against the nine receptor subtypes detailed
in Table 4. Selectivity ratio is defined as the antilogarithm of the
smallest difference between the pKi value at the 5-HT6 receptor and
the range of comparator receptors.
Chloronaphthyl derivatives 6f and 6g showed excellent
affinities but variable selectivities, the 2-linked isomer 6f
being superior.
bND, not determined; generally if the binding affinity at the 5-HT6
receptor has a value of pKi <8.0, the selectivities at other receptors
has not been determined.
The benzothiophene derivative 2 showed a better bind-
ing profile than the corresponding benzofuran analogue

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2843–2846
2845
6h. Generally, substituted benzothiophenes gave
Variation of piperazine and quinoline substitution
encouraging results and were investigated in some
detail. The 5-HT6 receptor affinity was relatively insen-
sitive to the size of the 3-alkyl substitutent (2, 6i, 6j)
whereas the substituent size had a significant effect on
selectivity, the ethyl derivative 6i being optimal. 5,7-
Dichloro substitution (6k) led to poor selectivity.
Based on the encouraging activity of the benzothio-
phene derivatives, a limited study was undertaken to
explore modifications to the piperazine and quinoline
rings in combination with the favoured 3-methyl-5-
chlorobenzothiophene left hand side. Substitution in the
piperazine ring has a marked effect on 5-HT6 receptor
affinity (Table 2). A methyl substituent at the 3-position
was tolerated with both enantiomers, 6p and 6q, show-
ing almost identical profiles to compound 2. However,
The benzothiophene-3-sulfonamides, 6l and 6n, dis-
played excellent binding profiles. 5-, 7- and 5,7-dichloro-
substitution (6l–n) was clearly favoured over 4,6-
disubstitution as seen by the modest affinity and poor
selectivity of 6o.
i
increasing further the size of this substituent to Pr (6r)
led to a 10-fold drop in 5-HT6 affinity. The 2,5-dimethyl
(6s) and 3,5-dimethyl (6t) derivatives also had reduced
affinity. N-Alkylation, however, was tolerated as exem-
plified by 6u and 6v, which had similar profiles to
compound 2.
Table 2. Receptor binding affinites of substituted piperazine analo-
gues
The poor binding affinity of the 3-piperazine derivative
8 (Table 2), which was 80-fold lower than the corre-
sponding 4-piperazine analogue 6u, highlights the impor-
tance of the position of attachment of the piperazine ring
in the quinoline nucleus.
Compd
Ra
pKi
5-HT6
Sel. versus 9
receptor subtypesb
6p
8.9
8.7
7.7
7.5
8.3
9.0
8.7
7.1
320
320
NDc
ND
160
250
130
ND
The 2- and 3-methylquinoline derivatives, 9a and 9b,
showed no overall advantage compared to the des-methyl
analogue 2 (Table 3).
6q
6r
6s
6t
6u
6v
8
Functional activity
When evaluated in a model of human cloned 5-HT6
receptor function,11 compounds 2, 6g, 6l, 6p–r, 6u–v and
9a–b were all found to reverse the 5-HT-stimulated
adenylyl cyclase activity, which is consistent with
antagonist profiles. However, when tested in the absence
of 5-HT, the compounds produced some stimulation of
basal adenylyl cyclase activity, consistent with partial
agonism in this system. The functional profile of action
of these compounds is under further investigation and
will be the subject of a future publication.
Summary
A number of compounds have been identified (e.g., 2,
6c–e, 6i, 6p, 6q) which show excellent 5-HT6 binding
aCompounds 6p–6v are 4-substituted, 8 is 3-substituted.
b,cAs defined in Table 1.
Table 3. Binding affinities of methyl derivatives 9a and 9b
Compd
Postn
Subtst.
pKi
5-HT6
Sel. versus 9
receptor subtypesa
9a
9b
2—
3—
8.9
8.6
250
100
Scheme 2. Reagents and conditions; (i) Pd(0) bis(dibenzylideneace-
tone) (7 mol%), BINAP (16 mol%), Cs2CO3, N-methylpiperazine,
reflux, 18 h (56%); (ii) Fe, NH4Cl, EtOH–H2O, reflux, 6 h (96%); (iii)
ArSO2Cl, CH2Cl2, pyridine (2 equiv), rt, 24h (32%).
aAs defined in Table 1.

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S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2843–2846
Table 4. Receptor binding profiles of selected compounds
Receptora
Affinity (pKi)
2
6c
6.1
5.8
5.9
6d
6.2
6.5
6.8
6f
6.8
6.2
6.7
6i
6l
6.6
6.3
6.4
6p
6.0
5.6
6.4
<5.6
<5.2
6u
6.1
6.3
6.6
6.0
9a
6.1
5.9
6.5
5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2B
5-HT2C
5-HT6
6.0
5.7
6.2
<5.4
5.5
5.6
<5.9
<5.4
5.9
8.9Æ0.03
(n=3)
<5.3
<6
<5.6
<5.3
<5.6
8.7Æ0.07
(n=3)
<5.1
<5
<5.5
<5.3
<5.7
9.2Æ0.08
(n=3)
<5
6.3
6
<5.7
5.9
5.9
9.0Æ0.03
(n=3)
5.8
<5.7
<5.1
5.6
8.9Æ0.02
(n=6)
<5.3
<5.2
<6
<5.1
NDb
9.3Æ0.03
(n=3)
<5
<5.3
<5.6
9.0Æ0.09
(n=9)
5.6
<5
<5.4
<5.3
9.0Æ0.03
(n=3)
5.7
<5.1
<5.4
8.9Æ0.04
(n=3)
<5.3
<5.5
<5.7
5-HT7
Dopaminergic D2
Dopaminergic D3
<5
<5.3
<5.3
<5.5
<5.3
5.6
<5.4
<5.8
<5.8
<5
aReceptors and radioligands used in the binding assays: 5-HT1A (human cloned receptors [HCR] in HEK 293 cells, [3H]-8-OH-DPAT); 5-HT1B
(HCR in CHO cells, [3H]-5-HT); 5-HT1D (HCR in CHO cells, [3H]-5-HT); 5-HT2A (HCR in HEK 293 cells, [3H]ketanserin); 5-HT2B (HCR in HEK
293 cells, [3H]-5-HT); 5-HT2C (HCR in HEK 293 cells, [3H]mesulergine); 5-HT6 (HCR in HeLa cells, [3H]LSD); 5-HT7 (HCR in HEK 293 cells,
[3H]-5-CT); D2 (HCR in CHO cells, [125I]iodosulpride); D3 (HCR in CHO cells, [125I]iodosulpride).
bND, not determined.
G. W.; Bromidge, S. M.; Moss, S. F.; Newman, H.; Riley, G.;
Gager, T.; Brown, A. M.; Lightowler, S.; Middlemiss, D. N.
Br. J. Pharmacol. 1999, 127, 21P.
3. Rogers, D. C.; Robinson, T. L.; Quilter, C. A.; Hunter,
A. J.; Routledge, C.; Hagan, J. J. Br. J. Pharmacol. 1999, 127,
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tors. Selectivities of 2-substituted benzothiophene deri-
vatives are dependent on the size of the 3-substituent.
The preferred point of attachment of the piperazine ring
to the quinoline is at the 4-position. Those compounds
tested in a functional model were shown to reverse 5-
HT-stimulated adenyl cyclase activity. These com-
pounds are under further investigation for potential
utility in the treatment of CNS disorders.
4. Dawson, L. A.; Nguyen, H. Q.; Li, P. Br. J. Pharmacol.
2000, 130, 23.
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