Exploring 6-(substituted sulfonyl)imidazopyridines as a potential scaffold for the design of 5-HT6 ligands

Article abstract of DOI:10.1007/s00706-012-0893-3

Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease. We have focused on the 5-HT₆ receptor in order to identify potent ligands. Herein we report the design of a novel series of 6-sulfonylimidazole derivatives substituted with an alkylamino chain at the 2- or 3-position, their synthesis, and their ability to interact with 5-HT ₆ receptors as evaluated in radioligand binding assays.

Full text of DOI:10.1007/s00706-012-0893-3

Monatsh Chem (2013) 144:429–435
DOI 10.1007/s00706-012-0893-3
ORIGINAL PAPER
Exploring 6-(substituted sulfonyl)imidazopyridines as a potential
scaffold for the design of 5-HT6 ligands
•
Valeria Moas Heloire Christophe Furman
•
•
Patricia Melnyk Pascal Carato
Received: 22 March 2012 / Accepted: 29 November 2012 / Published online: 16 January 2013
Ó Springer-Verlag Wien 2013
Abstract Cognitive dysfunction is a characteristic of
various forms of dementia such as Alzheimer’s disease. We
have focused on the 5-HT6 receptor in order to identify
potent ligands. Herein we report the design of a novel
series of 6-sulfonylimidazole derivatives substituted with
an alkylamino chain at the 2- or 3-position, their synthesis,
and their ability to interact with 5-HT6 receptors as eval-
uated in radioligand binding assays.
the potential application for 5-HT6 receptor antagonists in
the treatment of cognitive impairments associated with
Alzheimer’s disease (AD) and schizophrenia. Thus,
research efforts led to the discovery of 5-HT6 ligands
which have already entered clinical trials for anxiety and
cognitive impairment associated with these diseases and
displayed encouraging results [4]. A great number of
agonist and antagonist 5-HT6 ligands (Fig. 1) have been
reported, and many of them are built around an indole
scaffold, such as MS-245 [5, 6], E-6837 [7] and WAY-466
[8].
Keywords Bioorganic chemistry ꢀ Heterocycles ꢀ
Receptors ꢀ Tin compounds
The purpose of our present study was to identify novel,
potent 5-HT6 antagonists for potential use in the treatment
of AD. In the course of our extensive studies on the
chemistry and pharmacological reactivities, the indole
moiety was replaced by its isostere imidazopyridine, pos-
sessing a bridgehead nitrogen atom. Imidazopyridine
derivates 12–15 were designed (Fig. 1). As described for
5-HT6 ligands, they were characterized by the presence of
some important structural requirements, such as an ami-
noethyl side chain in position 2 or 3 of the imidazopyridine
and an arylsulfonyl moiety on the other side of the scaffold
at the 6-position [4]. The affinity of the synthesized com-
pounds for the human recombinant 5-HT6 receptor was
evaluated.
Introduction
Serotonin 5-HT6 receptors have attracted considerable
interest owing to their high affinity toward a wide range of
psychiatric drugs and their specific distribution in the brain
regions associated with learning and memory such as
the cerebral cortex, hippocampus and striatum [1, 2]. The
5-HT6 receptor was first cloned in 1993 and is one of the
most recently discovered 5-HT receptor subtypes. It is
positively coupled to adenylate cyclase and appears to
regulate glutaminergic, cholinergic and dopaminergic
neuronal activity, together with learning-associated neu-
ronal remodelling [3]. This modulatory activity suggests
Results and discussion
V. M. Heloire ꢀ C. Furman ꢀ P. Melnyk ꢀ P. Carato (&)
Univ Lille Nord de France, 59000 Lille, France
e-mail: pascal.carato@univ-lille2.fr
In order to build the imidazopyridine central core, various
conditions have been reported [9]. The reaction was
attempted in one step by refluxing commercially available
2-amino-5-bromopyridine (1) in ethanol or butanol with
the corresponding 1-bromoacetone 2 or 2-bromoaldehyde
3. Under these conditions, 2-amino-5-bromopyridine was
V. M. Heloire ꢀ P. Melnyk ꢀ P. Carato
UDSL, EA 4481, UFR Pharmacie, 59000 Lille, France
C. Furman
UDSL, EA 4483, UFR Pharmacie, 59000 Lille, France
123

430
V. M. Heloire et al.
Fig. 1 Structures of some
5-HT6 ligands and target
compounds 12–15
N
MeO
N
I
Cl
H
N
N
N
H
H
N
O
O
S
S
S
O
O
O
O
N
H
N
H
MS-245 Ki = 2.3 nM
E-6837 Ki = 0.7 nM
WAY-466 Ki = 1.0 nM
R
2-position
3-position
O
O
S
N
12
15
R
N
N
13
14
12-15
not totally consumed, the purification of reaction media
was difficult and the desired compounds 4 and 5 were
obtained in low yields of 35 and 39 %, respectively. Fur-
thermore, the formation of side products was observed
(Scheme 1). During the synthesis of compound 4,
by-product 4a was isolated in 13 % yield, owing to a
competing N-alkylation reaction of substituted imidazo-
pyridine. To overcome this limitation, we turned our
attention to the well-known two-step synthesis of imi-
dazopyridine involving the formation and isolation of
pyridinium salts. The first step was carried out in ethyl
acetate (preferred to the commonly used 1,2-dichloroeth-
ane), with 2-amino-5-bromopyridine and the corresponding
1-bromoacetone or 2-bromoaldehyde compounds 2 or 3.
After stirring for 1 day at room temperature, the starting
material 1 was totally reacted and the bromide intermedi-
ates were filtered, washed with ethyl acetate and then
refluxed for the second step in ethanol. This methodology
avoided the formation of N-alkylated by-products and
afforded imidazopyridine compounds 4 and 5 in good
yields of 75 and 72 %, respectively (Scheme 1). Depro-
tection of the phthalimide group was classically performed
with hydrazine hydrate in ethanol to give the corresponding
ethylamino compounds 6 and 7 [10]. Treatment with ethyl
acetate and purification by chromatography on silica gel
furnished compounds 6 and 7 in excellent yields of 90 and
93 %, respectively. It is worth emphasising that no water
was used in the treatment to eliminate the amine and form
phthalhydrazide; indeed we observed that the compounds
were partially soluble in water and could not be totally
extracted with an organic phase. Under such conditions the
yield dropped to 50 and 60 %, respectively.
A reductive amination in dichloromethane with acetal-
dehyde and NaBH(OAc)3 as the reducing reagent (3 eq)
afforded compounds 8 and 9 (Scheme 2). In the series
substituted at the 2-position with ethylamino chain (6), the
reaction gave the desired compound 8 in low yield (30 %)
and a by-product 8a (16 %). When the amount of
O
Scheme 1
N
Br
O
O
O
2
Br
Br
a. Ethanol or butanol
reflux, 24h
Br
NH2
N
NH2-NH2. H2O
N
N
N
O
N
N
Ethanol 95°
reflux, 4h
NH2 or b. i) ethyl acetate, rt, 24h
ii) ethanol 95°, reflux, 24h
6 : 2 position (90%)
7 : 3 position (93%)
1
4 : 2 position 35% a and 75% b
5 : 3 position 39% a and 72% b
O
CHO
Br
N
Br
O
N
O
3
N
N
-
Br
+
O
O
4a 13% a
O
N
O
123

Exploring 6-(substituted sulfonyl)imidazopyridines as a potential scaffold
431
Scheme 2
N
Br
Br
Br
N
N
N
CHO
+
N
N
N
H3C
N
Br
NH2
N
8a (6%)
N
8 (60%)
N
NaBH(OAc)3
N
CH2Cl2
rt, 24h
6 : 2 position
7 : 3 position
Br
N
+
N
+
-
9a (9%)
CH3CO2
O
9 (72%)
Scheme 3
O
O
Bu3Sn
RSO2Cl
PdCl2(PPh3)2
Bu3Sn-SnBu3
Pd(PPh3)4
S
Br
N
N
N
N
R
N
N
N
N
N
Toluene
110°C, 18 h
Toluene
reflux, 24h
12 - 14
10 : 2 position (22%)
11 : 3 position (31%)
8 : 2 position
9 : 3 position
3 position
-
2 position
12 (47%)
R
13 (62%)
14 (41%)
NaBH(OAc)3 was increased to 5 eq, the yield of compound
8 increased to 60 % and that of side product 8a decreased
(6 %). The formation of side product 8a could be explained
according to a Pictet–Spengler reaction. Thus, an ethyl
group was introduced at the nitrogen atom by reductive
amination and a Pictet–Spengler reaction between the
intermediate derivative and acetaldehyde occurred at the
3-position of the imidazopyridine. The higher reactivity of
the position 3 of imidazopyridine has already been reported
[11, 12]. In the second series, with the 3-position substi-
tuted by ethylamino chain (7), reductive amination in
dichloromethane with acetaldehyde and NaBH(OAc)3
(5 eq) afforded the corresponding derivative 9 in 72 %
yield and a by-product 9a (5 %). In these conditions, the
2-position could not react, and this position is slightly
reactive [13]. The formation of side product 9a could be
explained by an additional nucleophilic substitution at the
1-position of the imidazopyridine with an acetyl group
which could come from the reducing agent NaBH(OAc)3.
The structure of compound 9a was confirmed by full
spectral data (1H, 13C, COSY, HMBC, HSQC).
bromo atom or tributyltin group at the 6-position. The coupling
reaction with 5-tri-n-butyltin derivatives 10 and 11 in dry
toluene under inert atmosphere with dichloro(diphenylphos-
phine)palladium and the desired chlorosulfonyl reagent
afforded the corresponding products 12–14 [15]. In the series
substituted at the 3-position, starting from compound 11, the
final product 15 with a phenylsulfonyl group at the 6-position
could never be obtained, and we could only isolate imidazo-
pyridine product without the tributyltin group.
The affinity of the synthesized compounds for the
human 5-HT6 receptor was determined using [3H]-lysergic
acid diethylamide (LSD) as the radioligand (Table 1).
Indeed, compounds 12 and 13, with a diethylaminoethyl
chain at the 2-position, inhibited 5 and 14 % of specific
binding at 1 lM (relative to control), respectively. Deriv-
ative 14 presented higher activity with 38 % inhibition.
The presence of the diethylamino chain at the 3-position
of the imidazopyridine (10) seemed to be favourable,
Table 1 5-HT6 receptor binding assays of synthesized compounds
(12–14)
Starting from derivatives 8 and 9, the Stille reaction affor-
ded intermediates 10 and 11. Working in dry toluene under
inert atmosphere with tetrakis(triphenylphosphine)palladium
and hexabutylditin provided the best results but, unfortunately,
only low yields of 22 and 31 %, respectively, were obtained
(Scheme 3) [14]. Indeed, we observed degradation of the
reactionmediaandformationofreducedby-productswithouta
Compound
Inhibition of control specific binding/%a
12
13
14
a
5
14
38
Competition binding assay at 1 lM giving the displacement (%) of
compounds (radioligand, [3H]-LSD; n = 3)
123

432
V. M. Heloire et al.
1.8 Hz), 8.29 (s, 1H, H3), 9.35 (d, 1H, H5, J = 1.8 Hz) ppm;
13C NMR (DMSO-d6): d = 23.0, 33.0, 36.0, 38.0, 54.0, 112.0,
113.5, 114.0, 123.7, 124.0, 130.3, 132.4, 132.6, 135.3, 135.6,
137.0, 137.3, 139.6, 170.0, 201.0 ppm; MS (APCI?): m/z =
585.2, 587.3 ([M ? H]?).
compared with compounds 12 and 13 with a diethylamino
chain at the 2-position. Nevertheless, these new compounds
exhibited much lower affinities than many known ligands
which have nanomolar activities.
General procedure for the synthesis of compounds
4 and 5
Conclusion
Novel imidazopyridine compounds were designed accord-
ing to a 5-HT6 pharmacophore model, synthesized and
evaluated. These derivatives (12–14) have an aminoethyl
side chain in position 2 or 3 of the imidazopyridine and
an aryl sulfonyl moiety on the other side of the scaffold at
the 6-position. Unfortunately, this novel series presented
only low affinities for the 5-HT6 receptor. Other work in
our laboratory will involve the variation of the position
of the arylsulfonyl moiety on the imidazopyridine,
together with the reversion of the sulfonyl function.
Taking into account the results of this study, the synthe-
sis of compounds substituted with an aminoethyl side
chain in position 3 of the imidazopyridine will be
favoured.
2-Amino-5-bromopyridine (6.9 g, 39.7 mmol) and 9.8 g
2-bromo-4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyr-
aldehyde or 2-(4-bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-
dione (33.1 mmol) were added to 100 cm3 ethyl acetate. The
mixture was stirred for 1 day at room temperature. The
precipitate was filtered and washed with 200 cm3 ethyl
acetate. The product was solubilised in 150 cm3 95 % eth-
anol and refluxed for 24 h. After cooling to room
temperature, the solvent was evaporated under reduced pres-
sure. The residue obtained was dissolved in 100 cm3 of an
aqueous solution of 5 % potassium carbonate and extracted
with dichloromethane (2 9 100 cm3). The organic phase was
dried over MgSO4, filtered and evaporated under reduced
pressure. The products were recrystallised in acetonitrile.
2-[2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethyl]-1H-
isoindole-1,3(2H)-dione (4, C17H12BrN3O2)
Experimental
Yield 75 %; m.p.: 195–196 °C; Rf = 0.3 (dichlorometh-
ane/methanol 94:6, v/v); H NMR (DMSO-d6): d = 3.00
1
TLC and column chromatography were carried out on
silica gel 60 F254 plates and on glass column silica gel 60
(40–63 mesh). All of the reagents and solvents were AR
grade. Melting points were determined on a Bu¨chi 510
(t, 2H, CH2, J = 7.6 Hz), 3.95 (t, 2H, NCH2, J = 7.6 Hz),
7.25 (dd, 1H, H7, J = 9.6 Hz, 2.0 Hz), 7.40 (dd, 1H, H8,
J = 9.6 Hz, 0.8 Hz), 7.75 (s, 1H, H3), 7.85 (m, 4H, HAr),
8.80 (dd, 1H, H5, J = 2.0 Hz, 0.8 Hz) ppm; 13C NMR
(DMSO-d6): d = 24.6, 36.9, 110.7, 113.5, 113.6, 123.6,
129.4, 132.0, 134.9, 135.9, 140.0, 138.6, 168.2 ppm; MS
(APCI?): m/z = 370.2, 372.3 ([M ? H]?).
1
capillary apparatus. H and 13C NMR spectra were recor-
ded on a Bruker AVANCE 300 spectrometer and chemical
shifts are expressed in ppm using tetramethylsilane as
internal standard. Mass spectra were recorded on a Ther-
mofinnigan Surveyor MSQ single quadrupole mass
spectrometer operating in electrospray, positive single ion
mode to monitor m/z.
2-[2-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethyl]-1H-
isoindole-1,3(2H)-dione (5, C17H12BrN3O2)
Yield 72 %; m.p.: 172–173 °C; Rf = 0.4 (dichlorometh-
1
6-Bromo-2-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-
ethyl]-1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-2-
oxobutyl]imidazo[1,2-a]pyridinium bromide
ane/methanol 94:6, v/v); H NMR (DMSO-d6): d = 3.35
(t, 2H, CH2, J = 6.4 Hz), 3.95 (t, 2H, NCH2, J = 6.4 Hz),
7.80 (m, 4H, HAr), 7.98 (d, 1H, H8, J = 9.5 Hz), 8.07 (s,
1H, H2), 8.13 (dd, 1H, H7, J = 9.5 Hz, 1.8 Hz), 9.40 (d,
1H, H4, J = 1.8 Hz) ppm; 13C NMR (DMSO-d6):
d = 22.7, 34.8, 111.4, 114.1, 122.1, 123.6, 125.0, 127.7,
131.9, 135.0, 136.0, 138.9, 168.0 ppm; MS (APCI?):
m/z = 369.9, 371.9 ([M ? H]?).
(4a, C29H22Br2N4O5)
2-Amino-5-bromopyridine (2.3 g, 13.2 mmol) and 3.3 g 2-(4-
bromo-3-oxobutyl)-1H-isoindole-1,3(2H)-dione (11.0 mmol)
were added to 100 cm3 ethanol or butanol. The mixture was
refluxed for 24 h. The solution was evaporated under reduced
pressure. The resulting crude product was purified by
chromatography on silica gel (40–63 mesh), eluting with
dichloromethane/methanol (95:5, v/v). Yield 13 %; m.p.:
176–177 °C; Rf = 0.2 (dichloromethane/methanol 90:10,
General procedure for the synthesis of compounds
6 and 7
1
v/v); H NMR (DMSO-d6): d = 3.15 (m, 4H, CH2), 3.87
2-[2-(6-Bromoimidazo[1,2-a]pyridin-2-yl or -3-yl)ethyl]-
1H-isoindole-1,3(2H)-dione (1.41 g, 3.81 mmol) and 0.95 g
hydrazine monohydrate (19 mmol) were added to 50 cm3
(m, 4H, NCH2), 5.70 (s, 2H, COCH2), 7.80 (m, 8H, HAr), 8.18
(d, 1H, H8, J = 9.7 Hz), 8.26 (dd, 1H, H7, J = 9.7 Hz,
123

Exploring 6-(substituted sulfonyl)imidazopyridines as a potential scaffold
433
7.13 (dd, 1H, H7, J = 9.6 Hz, 1.8 Hz), 7.36 (d, 1H, H8,
J = 9.6 Hz), 7.39 (s, 1H, H3), 8.16 (dd, 1H, H5, J = 1.8 Hz,
0.7 Hz) ppm; 13C NMR (CDCl3): d = 11.4, 26.1, 46.8, 52.3,
106.4, 109.8, 117.4, 125.4, 127.4, 143.3, 146.7 ppm; MS
(APCI?): m/z = 296.0, 298.0 ([M ? H]?).
95 % ethanol. The solution was refluxed for 4 h. After
cooling to room temperature, the reaction mixture was
evaporated under reduced pressure. The precipitate obtained
was triturated with ethyl acetate (2 9 100 cm3) and filtered.
The filtrate was evaporated under reduced pressure and the
oily residue was washed with ethyl ether (3 9 50 cm3). The
resulting crude product was purified by chromatography on
silica gel (40–63 mesh), eluting with dichloromethane/
methanol (95:5, v/v). The products were solubilized in dry
ethyl acetate and treated with 20 cm3 gaseous hydrochloric
acid in diethyl ether. The obtained precipitate was filtered
and washed with ethyl acetate (2 9 20 cm3) to afford the
desired compounds.
8-Bromo-2-ethyl-1,2,3,4-tetrahydro-1-methyldipyrido
[1,2-a:40,30-d]imidazole (8a, C13H16BrN3)
Yield 6 %; Rf = 0.6 (dichloromethane/methanol 90:10,
v/v); 1H NMR (CDCl3): d = 1.11 (t, 3H, CH3,
J = 7.1 Hz), 1.32 (d, 3H, CH3, J = 6.7 Hz), 2.62 (m,
3H, CH2), 2.96 (m, 2H, CH2), 3.09 (m, 1H, CH2), 4.05 (q,
1H, CH, J = 6.7 Hz), 7.10 (dd, 1H, H7, J = 9.5 Hz,
1.8 Hz), 7.37 (d, 1H, H8, J = 9.5 Hz), 7.86 (d, 1H, H5,
J = 1.1 Hz) ppm; 13C NMR (CDCl3): d = 13.3, 15.4,
22.8, 43.2, 46.9, 49.7, 106.3, 117.1, 122.6, 123.1, 126.4,
104.7, 142.9 ppm; MS (APCI?): m/z = 294.2, 296.2
([M ? H]?).
2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethanamine
dihydrochloride (6, C9H12BrCl2N3)
Yield 90 %; m.p.: 192–193 °C; Rf = 0.2 (dichlorometh-
1
ane/methanol 85:15, v/v); H NMR (DMSO-d6): d = 3.14
(m, 2H, CH2), 3.43 (t, 2H, NCH2, J = 6.7 Hz), 7.97 (d, 1H,
H8, J = 9.5 Hz), 8.07 (dd, 1H, H7, J = 9.5 Hz, 1.6 Hz),
8.17 (s, 1H, H2), 8.35 (brs, 3H, NH?, NH2), 9.38 (s, 1H,
H5) ppm; 13C NMR (DMSO-d6): d = 23.7, 37.9, 110.1,
113.8, 113.9, 129.1, 135.0, 135.3, 139.3 ppm; MS
(APCI?): m/z = 240.0, 242.0 ([M ? H]?).
2-(6-Bromo-1H-imidazo[1,2-a]pyridin-3-yl)-N,N-
diethylethanamine (9, C13H18BrN3)
Yield 72 %; Rf = 0.5 (dichloromethane/methanol 85:15,
v/v); 1H NMR (CDCl3): d = 1.00 (t, 6H, CH3,
J = 7.1 Hz), 2.60 (q, 4H, NCH2, J = 7.1 Hz), 2.76 (t,
2H, CH2, J = 6.6 Hz), 2.95 (t, 2H, NCH2, J = 6.9 Hz),
7.13 (dd, 1H, H7, J = 9.6 Hz, 1.8 Hz), 7.37 (s, 1H, H2),
7.43 (d, 1H, H8, J = 9.6 Hz), 8.18 (d, 1H, H5, J = 1.6 Hz)
ppm; 13C NMR (CDCl3): d = 11.6, 22.3, 46.8, 51.0, 106.7,
118.3, 123.6, 123.7, 126.7, 131.7, 143.7 ppm; MS
(APCI?): m/z = 296.0, 298.0 ([M ? H]?).
2-(6-Bromoimidazo[1,2-a]pyridin-3-yl)ethanamine
dihydrochloride (7, C9H12BrCl2N3)
Yield 93 %; m.p.: 95–96 °C; Rf = 0.2 (dichloromethane/
methanol 85:15, v/v); 1H NMR (DMSO-d6): d = 2.85 (t, 2H,
CH2, J = 6.7 Hz), 2.95 (t, 2H, CH2, J = 6.7 Hz), 7.25 (dd,
1H, H7, J = 9.5 Hz, 1.9 Hz), 7.40 (s, 1H, H2), 7.50 (d, 1H,
H8, J = 9.5 Hz), 8.70 (d, 1H, H5, J = 1.9 Hz) ppm; 13C
NMR (DMSO-d6): d = 21.2, 36.4, 111.1, 114.1,
122.9, 123.5, 127.8, 135.6, 139.2 ppm; MS (APCI?):
m/z = 240.0, 242.0 ([M ? H]?).
1-Acetyl-6-bromo-3-[2-(diethylamino)ethyl]imidazo[1,2-a]-
pyridinium acetate (9a, C17H24BrN3O3)
Yield 9 %; Rf = 0.6 (dichloromethane/methanol 85:15,
v/v); 1H NMR (CDCl3): d = 1.10 (t, 6H, CH3,
J = 7.1 Hz), 2.02 (s, 3H, CH3), 2.75 (q, 4H, NCH2,
J = 7.2 Hz), 2.92 (m, 2H, CH2), 3.10 (m, 2H, CH2), 7.21
(dd, 1H, H7, J = 9.5 Hz, 1.7 Hz), 7.42 (s, 1H, H2), 7.51 (d,
1H, H8, J = 9.5 Hz), 8.06 (d, 1H, H5, J = 1.0 Hz) ppm;
13C NMR (CDCl3): d = 10.3, 21.3, 22.5, 46.9, 50.3, 107.2,
118.3, 122.4, 123.8, 127.2, 131.5, 135.1, 143.8, 176.1 ppm.
General procedure for the preparation of products
8 and 9
In 15 cm3 dichloromethane 1.5 g 2-(6-bromoimidazo[1,2-a]-
pyridin-2-yl or -3-yl)ethanamine (6.2 mmol), 1.4 g acetal-
dehyde (31 mmol) and 6.6 g NaBH(OAc)3 (31 mmol) were
stirred at room temperature under inert atmosphere for 24 h.
The reaction mixture was quenched by adding 20 cm3 aque-
ous 1 M NaOH and the product was extracted with
dichloromethane. The product was purified by chromatogra-
phy on silica gel using dichloromethane/methanol (95:5, v/v)
to afford oily products.
General procedure for the preparation of products
10 and 11
In 30 cm3 dry toluene 1.0 g 2-(6-bromo-1H-imidazo[1,2-a]-
pyridin-2-yl or -3-yl)-N,N-diethylethanamine (3.6 mmol),
0.4 g tetrakis(triphenylphospine)palladium (0.36 mmol)
and 3.1 g hexa-n-butylditin (5.4 mmol) were stirred at
110 °C under inert atmosphere for 18 h. The solution was
evaporated under reduced pressure. The product was
purified by chromatography on silica gel using dichloro-
methane/methanol (97:3, v/v) to afford oily products.
2-(6-Bromo-1H-imidazo[1,2-a]pyridin-2-yl)-N,N-
diethylethanamine (8, C13H18BrN3)
Yield 60 %; Rf = 0.4 (dichloromethane/methanol 90:10,
v/v); 1H NMR (CDCl3): d = 1.06 (t, 6H, CH3, J = 7.2 Hz),
2.65 (q, 4H, NCH2, J = 7.2 Hz), 2.95 (m, 4H, CH2, NCH2),
123

434
V. M. Heloire et al.
N,N-Diethyl-2-[6-(tributylstannyl)imidazo[1,2-a]-
pyridin-2-yl]ethanamine (10, C25H45N3Sn)
3.18 (q, 4H, NCH2, J = 7.3 Hz), 3.33 (m, 2H, CH2), 3.47
(m, 2H, NCH2), 6.75 (td, 1H, HAr, J = 1.1 Hz, 6.8 Hz),
7.16 (m, 1H, HAr), 7.50 (m, 4H, H5, HAr), 7.58 (m, 1H, H8),
7.87 (td, 1H, HAr, J = 1.4 Hz, 8.3 Hz), 8.04 (dt, 1H, HAr,
J = 1.1 Hz, 2.3 Hz, 6.8 Hz), 8.22 (dd, 1H, HAr,
J = 1.2 Hz, 7.2 Hz), 8.98 (d, 1H, H7, J = 9.1 Hz) ppm;
13C NMR (CDCl3): d = 8.5, 29.7, 47.0, 124.4, 125.7,
126.1, 126.5, 127.0, 128.3, 129.1, 131.3, 134.2, 140.6 ppm;
MS (APCI?): m/z = 428.9 ([M ? Na]?).
Yield 22 %; Rf = 0.4 (dichloromethane/methanol85:15, v/v);
1H NMR (CDCl3): d = 0.89 (t, 15H, CH3, J = 7.2 Hz), 1.09
(m, 6H, CH2, J = 7.3 Hz), 1.31 (m, 6H, CH2), 1.53 (m, 6H,
SnCH2), 3.02 (q, 4H, NCH2, J = 7.2 Hz), 3.28 (d, 4H, CH2,
NCH2, J = 2.4 Hz), 7.13 (d, 1H, H7, J = 8.9 Hz), 7.47 (m,
1H, H3, H8), 7.92 (s, 1H, H5) ppm; 13C NMR (CDCl3):
d = 9.8, 11.2, 13.9, 26.3, 27.7, 29.4, 46.6, 51.9, 106.9, 111.2,
118.3, 126.1, 128.7, 142.9, 147.3 ppm; MS (APCI?): m/z =
506.5 ([M ? H]?).
N,N-Diethyl-2-[6-(1-naphthalenylsulfonyl)imidazo[1,2-a]-
pyridin-3-yl]ethanamine (14, C23H25N3O2S)
N,N-Diethyl-2-[6-(tributylstannyl)imidazo[1,2-a]-
pyridin-3-yl]ethanamine (11, C25H45N3Sn)
Yield 41 %; Rf = 0.5 (dichloromethane/methanol90:10, v/v);
1H NMR (CDCl3): d = 1.17 (t, 6H, CH3, J = 7.2 Hz), 2.86(q,
4H, NCH2, J = 7.2 Hz), 3.02 (m, 2H, CH2), 3.20 (m, 2H,
NCH2), 6.75 (t, 1H, HAr, J = 6.8 Hz), 7.33 (t, 1H, 1 HAr,
J = 7.9 Hz), 7.43 (s, 1H, CH), 7.47 (m, 3H, HAr), 7.59 (d, 1H,
H8, J = 9.0 Hz), 7.83 (d, 1H, HAr, J = 7.5 Hz), 8.13 (d, 1H,
HAr, J = 6.9 Hz), 8.18 (d, 1H, 1 HAr, J = 7.2 Hz), 8.98 (d,
1H, H7, J = 9.2 Hz) ppm; 13C NMR (CDCl3): d = 10.5, 29.6,
46.8, 124.2, 125.4, 125.9, 126.7, 126.9, 128.2, 129.2, 130.9,
134.1, 141.6 ppm; MS (APCI?): m/z = 428.8 ([M ? Na]?).
Yield 31 %; Rf = 0.4 (dichloromethane/methanol 85:15,
v/v); 1H NMR (CDCl3): d = 0.90 (t, 15H, CH3,
J = 7.2 Hz), 1.11 (q, 6H, CH2, J = 7.1 Hz), 1.35 (m,
6H, CH2), 1.55 (m, 6H, SnCH2), 2.65 (q, 4H, NCH2,
J = 7.1 Hz), 2.85 (t, 2H, CH2, J = 6.5 Hz), 3.05 (t, 2H,
NCH2, J = 7.0 Hz), 7.13 (d, 1H, H7, J = 8.8 Hz), 7.40 (s,
1H, H2), 7.57 (d, 1H, H8, J = 8.8 Hz), 7.88 (s, 1H, H5)
ppm; 13C NMR (CDCl3): d = 9.7, 11.5, 13.7, 24.5, 27.4,
29.2, 46.3, 52.4, 106.2, 119.9, 122.2, 124.2, 127.8, 134.5,
142.7 ppm; MS (APCI?): m/z = 506.5 ([M ? H]?).
Competition binding assay
General procedure for the preparation of products
12–14
Stock solutions of the compounds were prepared in DMSO
and further diluted with the binding buffer to the desired
concentration. Final DMSO concentrations in the assay
were less than 0.1 %. The competitive binding experiments
were performed as described earlier [16].
Briefly [3H]-LSD (2.5 nM) as radioligand for the human
serotonin 5-HT6 receptor was added to 15 lg of mem-
branes resuspended in 550 mm3 (final volume) binding
buffer (50 mM Tris–HCl pH 7.4, 10 mM MgCl2, 0.5 mM
EDTA). After 1 h at 37 °C, the incubation was stopped and
the solutions were rapidly filtered over Unifilter-96 GF/C
filter (pre-soaked in 0.5 % PEI) on a Filtermate Unifilter
96-Harveste (Perkin Elmer) and washed with 9 9 500 mm3
of ice-cold wash buffer.
Compound10or11(0.2 g, 0.39 mmol)in30 cm3 drytoluene
was placed under inert atmosphere and 0.03 g PdCl2(PPh3)2
(0.04 mmol) and the desired aryl chloride (0.59 mmol) were
added. The reaction was refluxed for 24 h. The solution was
evaporated under reduced pressure and the product was
purified by chromatography on silica gel using dichloro-
methane/methanol (85:15, v/v) to afford oily products.
N,N-Diethyl-2-[6-(phenylsulfonyl)imidazo[1,2-a]-
pyridin-2-yl]ethanamine (12, C19H23N3O2S)
Yield 47 %; Rf = 0.5 (dichloromethane/methanol 85:15,
v/v); 1H NMR (CDCl3): d = 1.34 (t, 6H, CH3,
J = 7.3 Hz), 3.17 (q, 4H, NCH2, J = 7.3 Hz), 3.31 (m,
2H, CH2), 3.45 (m, 2H, NCH2), 6.75 (td, 1H, HAr,
J = 1.0 Hz, 6.8 Hz), 7.14 (m, 1H, HAr), 7.27 (s, 1H,
HAr), 7.38 (m, 2H, H7, HAr), 7.46 (d, 1H, HAr, J = 9.1 Hz),
7.56 (s, 1H, H5), 7.88 (m, 1H, H8), 8.08 (d, 1H, HAr,
J = 6.8 Hz) ppm; 13C NMR (CDCl3): d = 8.8, 23.9, 46.9,
51.6, 110.8, 112.4, 116.8, 124.9, 125.0, 125.9, 126.3,
128.2, 129.9, 141.7, 145.0 ppm; MS (APCI?): m/z =
357.1 ([M ? H]?).
The radioactivity on the filters was measured using a
TopCount NXTTM microplate scintillation counter (Perkin
Elmer) using 40 mm3 of MicroScintTM 40 (Perkin Elmer)
after 30 min resting. The nonspecific binding was deter-
mined in the presence of 5 lM serotonin (Sigma).
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