New 1-arylindoles based serotonin 5-HT7 antagonists. Synthesis and binding evaluation studies

Article abstract of DOI:10.1016/j.ejmech.2014.01.055

Based on 5-HT_1A and 5-HT₇ ligand MR25003 scaffold, a new series of 1-aryl indole analogues were prepared and evaluated against 5-HT₇ receptors. Modulations of aryl moieties provided a large number of new indolic derivative

Full text of DOI:10.1016/j.ejmech.2014.01.055

European Journal of Medicinal Chemistry 75 (2014) 159e168
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
New 1-arylindoles based serotonin 5-HT7 antagonists. Synthesis
and binding evaluation studies
,
a,
*
Charlène Sagnes a, Guy Fournet a, Grzegorz Satala b, Andrzej J. Bojarski b , Benoît Joseph
*
a Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR CNRS 5246, Université de Lyon, Université Claude Bernard e Lyon 1,
Bâtiment Curien, 43 Bd du 11 Novembre 1918, F-69622 Villeurbanne, France
b Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on 5-HT1A and 5-HT7 ligand MR25003 scaffold, a new series of 1-aryl indole analogues were
prepared and evaluated against 5-HT7 receptors. Modulations of aryl moieties provided a large number
of new indolic derivatives. Most of compounds tested have displayed 5-HT7 affinity in the nanomolar
range. Among them, 1-(naphthyl)indole derivative 3p (Ki (5-HT7) ¼ 4.5 nM) showed also a good selec-
tivity over 5-HT1A, 5-HT2A and 5-HT6 receptors. This compound was pharmacology characterized as an
antagonist.
Received 19 December 2013
Received in revised form
20 January 2014
Accepted 24 January 2014
Available online 28 January 2014
Ó 2014 Elsevier Masson SAS. All rights reserved.
Keywords:
Serotonin
5-HT7
5-HT1A
Antagonist
Indole
1. Introduction
ligands may be an important and indispensable research tool for
precise determination of functional and physiopathological role of
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter
that mediates its effects on the central and peripheral nervous
system via interaction with receptors. At least seven serotonin re-
ceptor families have been identified on the basis of their sequence
homology, pharmacology, and signal transduction [1]. The human
5-HT7 receptor subtype is the most recent 5-HT receptor and was
first identified by Bard in 1993 [2]. The seven-transmembrane
domain G-protein-coupled receptor 5-HT7 was found to be posi-
tively coupled to an adenylate cyclase second messenger system. Its
widespread distribution in CNS (thalamus, hypothalamus, limbic
and cortical regions) is correlated with important functional roles
in thermoregulation, circadian rhythm, endocrine regulation,
sleeping, schizophrenia, depression and memory [3]. The 5-HT7
receptor subtype was also found in the periphery (spleen, kidney,
heart, coronary artery, smooth muscle and gastrointestinal tract).
Currently, numerous nanomolar agonists and antagonists of 5-HT7
receptors have been reported [4]. A remarkable structural diversity
of 5-HT7 ligands is observed indicating the continued interest in the
development of 5-HT7 ligands with suitable drug-like properties
for pre-clinical validation. Moreover, new selective 5-HT7 receptor
5-HT7 receptor subtype.
The N-phenylpyrrole moiety emerged as a 5-HT7 pharmaco-
phore from a virtual screening performed on a chemolibrary and
realized by Rault et al., in 2005 [5]. Pharmacomodulation studies
led to the preparation of MR25003 as a potent 5-HT1A/5-HT7 ligand
(Ki 5-HT1A ¼ 41 nM, Ki 5-HT7 ¼ 21 nM).
In continuation of our research work on the design of 5-HT7
ligands [6,7] and based on 5-HT7 pharmacophore model for 5-HTR
antagonism (one basic centre, two hydrophobic groups, a one
hydrogen bond acceptor) [8], we have developed a new series of 5-
HT7 1-arylindole ligands. In this project, we have modulated the
nature of the central heterocycles of MR25003 by substituting the
pyrrole ring by an indole to evaluate the impact in the 5-HT7
binding affinity and the 5-HT7/5-HT1A selectivity (Fig. 1). The
structural modifications comprised also modulation of aryl sub-
stituent at the N1 position of indole and piperazine.
2. Results and discussion
2.1. Chemistry
* Corresponding authors.
E-mail addresses: bojarski@if-pan.krakow.pol (A.J. Bojarski), benoit.joseph@
univ-lyon1.fr (B. Joseph).
Target compounds of general structure I were obtained in two
steps from commercially available indole-3-carbaldehyde
1
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.055

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C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
Table 1
Copper-mediated arylation yield.
N
R
Y
N
N
Entry
Ar
2 e Yield (%)
MeO
1a
Ph
o-MePh
m-MePh
p-MePh
o-EtPh
p-(4-Ph)Ph
o-iPrPh
o,m-diMePh
naphth-1-yl
naphth-2-yl
o-F3CPh
o-MeOPh
o-NCPh
pyridin-3-yl
pyridin-2-yl
2a ꢁ 89
2b ꢁ 23
2c ꢁ 75
2d ꢁ 67
2e ꢁ 25
2f ꢁ 72
2g ꢁ 21
2h ꢁ 20
2i ꢁ 23
2j ꢁ 92
2k ꢁ 8
2a
N
Y = N or C
Me
3a
N
Ar
4a
5a
indole analogues I
6b
MR25003
Fig. 1. Structure of MR25003 and the proposed indole analogues.
7a
8a
9a
10b
11a
12a
13a
14a
15c
2l ꢁ 68
2m ꢁ 25
2n ꢁ 70
2o ꢁ 86
(Scheme 1). N-Arylation of 1 was mediated by copper(I) oxide in the
presence of aryl halide in basic medium. After optimization, we
found that the use of 0.3 equivalents of copper(I) oxide, 2 equiva-
lents of aryl bromide or aryl iodide and 2 equivalents of potassium
carbonate in dimethylformamide at reflux led to the total con-
sumption of 1 and gave 1-arylindole-3-carbaldehydes 2aen in
moderate-to-good yields (Table 1).
a
Aryl iodide.
b
c
Aryl bromide.
SNAr
.
The use of ortho-substitued aryl halide decreases dramatically
the reaction yield (entry 2, 5, 7, 8, 9,11 and 13). In the case of 1-iodo-
2,5-dimethylbenzene, the formation of the coupling compound
was not observed. The preparation of 2o was also problematic.
Copper mediated N-arylation of 1 with 2-iodopyridine led to the
1,2-bis(pyridin-2-yl)indole-3-carbaldehyde in 41% yield [9]. An
alternative method was carried out to get the desired compound
2o. This compound was obtained from the sodium salt of 1 through
a nucleophilic substitution reaction with 2-fluoropyridine to give
2o in 84% yield [9].
The affinities (Ki) for the most potent 1-arylindole derivatives 3
for the 5-HT7 receptor were determined to be between 4.5 and
20 nM. For compounds 4a and 4b, about a 2-fold decrease in 5-HT7
affinity was observed (Ki ¼ 33e92 nM) was observed when
compared to their arylpiperazine analogues 3a and 3d, respectively.
Compound with a phenyl group at the N1 position of indole shows
nanomolar 5-HT7 affinities (3a, Ki ¼ 54 nM). To improve the affinity,
the introduction of ortho-substituent such as an alkyl group (Me,
iPr) on phenyl ring is primordial. In these cases, high 5-HT7R affinity
was measured (3d, Ki ¼ 18 nM; 3k, Ki ¼ 15 nM, 3m, Ki ¼ 18 nM).
The shift of the same substituent from ortho-position to meta- or
para-position led to decrease in 5-HT7 affinity (3g, Ki ¼ 65 nM; 3h,
Ki ¼ 94 nM). A bulky substituent such as biphenyl or naphth-2-yl at
Compounds 2aeo were submitted to a reductive amination with
N-substituted piperazines or 4-phenyl-1,2,3,6-tetrahydropyridine
and sodium cyanoborohydride (1 equivalent) to provide final
compounds 3 and 4 in fair yields (46e92%).
2.2. Biological studies
Table 2
Receptor binding results for N-arylindoles 3 and 4.
All prepared compounds 3 and 4 were tested as fumarate salts
(except 3j, 3n and 3v: free bases) in competition binding experi-
ments for native serotonin 5-HT1A (rat hippocampus) and cloned
human 5-HT7 (stably expressed in HEK-293 cells) receptors, ac-
cording to previously published procedures [10]. Binding results of
3 and 4 are reported in Table 2.
Ki ꢂ SEM (nM)a
3,4b
Ar
R
5-HT1A
5-HT7
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Ph
Ph
Ph
o-MePh
o-MePh
o-MePh
m-MePh
p-MePh
o-EtPh
p-(4-Ph)Ph
o-iPrPh
Ph
216 ꢂ 8
10 ꢂ 1
54 ꢂ 3
o-MeOPh
o-HOPh
Ph
o-MeOPh
Me
Ph
Ph
Ph
Ph
Ph
o-MeOPh
Ph
o-MeOPh
Ph
o-MeOPh
o-HOPh
Ph
Ph
Ph
Ph
Ph
10.8 ꢂ 0.3
27 ꢂ 1
17 ꢂ 1
95 ꢂ 3
18 ꢂ 2
15 ꢂ 1
8.7 ꢂ 0.4
3907 ꢂ 430
65 ꢂ 8
2912 ꢂ 180
90 ꢂ 11
332 ꢂ 21
134 ꢂ 9
49,000
R
N
94 ꢂ 7
N
CHO
CHO
48 ꢂ 6
a or b
1920 ꢂ 120
15 ꢂ 2
c
118 ꢂ 9
N
N
N
Ar
3a-y
o-iPrPh
58 ꢂ 5
17 ꢂ 2
H
Ar
2a-o
o,m-diMePh
o,m-diMePh
naphth-1-yl
naphth-1-yl
naphth-1-yl
naphth-2-yl
o-F3CPh
o-MeOPh
o-NCPh
pyridin-2-yl
pyridin-2-yl
pyridin-3-yl
Ph
324 ꢂ 40
17 ꢂ 2
18 ꢂ 3
1
6.9 ꢂ 1.1
34 ꢂ 4
545 ꢂ 38
70 ꢂ 12
57 ꢂ 6
c
4.5 ꢂ 1
20 ꢂ 3
Ph
N
1950 ꢂ 130
81 ꢂ 11
86 ꢂ 3
4440 ꢂ 470
20 ꢂ 3
3s
3t
70 ꢂ 3
3u
3v
3w
3x
4a
4b
36 ꢂ 2
41 ꢂ 4
N
Ar
4a-b
95 ꢂ 13
55 ꢂ 8
189 ꢂ 16
62 ꢂ 4
o-MeOPh
Ph
Ph
190 ꢂ 18
89 ꢂ 4
60 ꢂ 8
92 ꢂ 6
Scheme 1. Synthesis of compounds 2, 3 and 4. Reagents and conditions: (a) ArX
(2 equiv), Cu2O (0.3 equiv), K2CO3 (2 equiv), DMF, rflx, 3 days (2aen); (b) NaH
(1.5 equiv), 2-fluoropyridine (1.7 equiv), DMF, 100 ꢀC, 16 h (2o); (c) N-substituted
piperazine or 4-phenyl-1,2,3,6-tetrahydropyridine (2 equiv), NaBH3CN (1 equiv), AcOH
(1 equiv), MeOH, 70 ꢀC, 18 h (3e4).
o-MePh
Ph
178 ꢂ 3
33 ꢂ 4
a
Inhibition constants (Ki) were determined from three separate experiments, run
in triplicate.
b
Compounds tested as fumarate salts except for 3j, 3n and 3v (free bases).

C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
161
the N1 position of indole dramatically reduced the affinity for the 5-
NMe2
NMe2
HT7 receptor (3j, Ki ¼ 1920 nM; 3r, Ki ¼ 4440 nM). Interestingly, the
replacement of phenyl ring by a naphth-1-yl group retained the
affinity (3o, Ki ¼ 34 nM). Substitution of the phenyl by a pyridinyl
moiety led to weaker 5-HT7 ligands (3v, Ki ¼ 189 nM; 3x,
Ki ¼ 60 nM) and even for 2-pyridyl group, 5-HT1A affinity was
better than 5-HT7.
a
N
Ar
5a-d
N
H
As regards the N-substituent of the piperazine, the presence of a
phenyl or a substituted phenyl substituent was crucial to retain the
5-HT7 affinity (3d, Ki ¼ 18 nM; 3e, Ki ¼ 8.7 nM). This observation
was confirmed by the poor binding result obtained for 3f
(Ki ¼ 3907 nM). The presence of ortho-methoxyphenylpiperazine
(o-MPP) instead of phenyl or 2-hydroxyphenyl group led to the
most potent 5-HT7 ligands (3b, Ki ¼ 10.8 nM; 3e, Ki ¼ 8.7 nM; 3n,
Ki ¼ 6.9 nM; 3p, Ki ¼ 4.5 nM).
Scheme 2. Synthesis of compounds 5. Reagents and conditions: (a) ArX (1.3 equiv),
Cu2O (0.3 equiv), K2CO3 (1.5 equiv), DMF, MW, 120 min 240 ꢀC.
3. Conclusion
In conclusion, we analysed the impact of the substitution of the
pyrrole ring of MR25003 by indole nucleus on 5-HT7/5-HT1A
binding affinities. 1-Arylindoles 3 were prepared in two steps and
showed nanomolar 5-HT7 receptor affinity. Among the compounds
tested, the 1-naphthyl derivative 3p was found to be a high affinity
5-HT7R antagonist with acceptable selectivity profile versus 5-HT
receptors.
Finally, we examined the 5-HT7/5-HT1A receptor selectivity
for the 1-arylindole series. The 5-HT7 selectivity was improved
when the phenyl group was not substituted (e.g. 3a, 3d, 3m, 3o).
o-MPP is a well-known 5-HT1A privileged structure, this data
was confirmed by the binding results. Compound 3b shows
no selectivity and 3e, 3l, 3n a low 2e3 fold 5-HT7 receptors
selectivity over 5-HT1A receptors. An exception was observed for
the compound 3p where the selectivity over 5-HT1A receptors
was retained (15 fold) compared to 3o (16 fold). Compounds 3n
and 3p were selected as lead compounds, exhibiting low nano-
molar 5-HT7 affinity and moderate 5-HT7 selectivity (especially
3p).
Both compounds 3n and 3p displayed a good selectivity over 5-
HT2A and 5-HT6 receptors (Table 3). The 5-HT7 agonist and antag-
onist effects of ligands 3n and 3p were assessed by determining the
adenylate cyclase activity [11]. The biological studies were per-
formed by CEREP (Celle Levescaut, France). Compounds 3n and 3p
did not display agonist activity but showed an antagonist activity
(data not reported).
The feasibility of imaging the 5-HT7 receptors in the brain by
positron emission tomography (PET) studies represents an
interesting field to provide significant advances in the under-
standing of the neurobiology and eventual dysfunctions of
the 5-HT7 receptor [12]. Considering the low nanomolar affinity
of 3p for the 5-HT7 receptors and in spite of a moderate 5-HT7/5-
HT1A receptor selectivity, the compound 3q can be considered
as a first potential 11C radiolabelling precursor of 1-arylindole
series.
4. Experimental section
4.1. Chemistry
General methods: Commercial reagents (Fluka, Aldrich) were
used without purification. Solvents were distillated prior to use.
Melting points were determined using a Büchi capillary instrument
and are uncorrected. IR spectra were recorded on a PerkineElmer
681 infrared spectrophotometer. 1H and 13C NMR spectra were
recorded on a Bruker Avance 300 MHz spectrometer. Chemical
shifts are reported in ppm (d) relative to tetramethylsilane as an
internal standard. The following abbreviations were used to
designate the multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, m ¼ multiplet, br ¼ broad. Mass spectra were recorded
with a PerkineElmer SCIEX API spectrometer. Elemental analyses
were performed on a Thermoquest Flash 1112 series EA analyser.
Elemental analyses were found to be within ꢂ0.4 of the theoretical
values. Purity of tested compounds was >95%. Thin Layer Chro-
matography (TLC) analyses were conducted on aluminium sheets
silica gel Merck 60F254. The spots were visualized using an ultra-
violet light. Flash chromatography was carried out on silica gel 60
(40e63 mm, Merck) using the indicated solvents. The light petro-
leum ether refers to the fraction boiling at 40e60 ꢀC.
1-Aryltryptamines 5 were also prepared to evaluate their 5-HT7
and 5-HT1A binding affinities (Scheme 2). Following the same N-
arylation reaction to get 2, compounds 5 were prepared from
commercially available N,N-dimethyltryptamine in good yields
(85e92%). The 5-HT7 binding results were disappointing compared
to those of corresponding 3 (Table 4).
4.1.1. General procedure for preparation of compounds 2ae2n
A suspension of indole-3-carbaldehyde 1 (0.411 g, 2.8 mmol),
Cu2O (0.3 equiv), K2CO3 (2.0 equiv) and aryl halide (2.0 equiv) in
anhydrous DMF (5.6 mL) was refluxed for 72 h. After cooling to RT,
the reaction mixture was filtrated over a celite pad eluting with
EtOAc. Solvents were removed and the residue dissolved in EtOAc
(20 mL) washed successively by 2.5% aqueous NH4OH, 1 M HCl and
saturated aqueous NaCl. The organic phase was dried over Na2SO4,
Thus,
a N,N-dimethylaminoethyl chain turned out to be
favourable for 5-HT1A and selectivity over 5-HT7 receptors. Com-
pounds 5 were nanomolar 5-HT1A receptor ligands and the deriv-
ative 5a showed the highest 5-HT1A selectivity versus 5-HT7
receptors (19 fold).
Table 4
Receptor binding results for 1-aryltryptamines 5.
Ki ꢂ SEM (nM)a
Table 3
5b
Ar
5-HT1A
5-HT7
5-HT2A and 5-HT6 receptor binding affinities for 3n and 3p.
Inhibition (%)a
5a
5b
5c
5d
Ph
o-MePh
o,m-diMePh
naphth-1-yl
62 ꢂ 8
59 ꢂ 4
1200 ꢂ 109
283 ꢂ 21
317 ꢂ 28
649 ꢂ 47
3b
5-HT2A at 1
m
M
5-HT2A at 10 nM
5-HT6 at 1
m
M
5-HT6 at 10 nM
76 ꢂ 10
144 ꢂ 16
3n
3p
0
10
0
6
86
50
0
3
a
Inhibition constants (Ki) were determined from three separate experiments, run
a
Experiments performed by CEREP.
3n: free base; 3p: fumarate salt.
in triplicate.
b
b
Compounds tested as fumarate salts.

162
C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
filtered and concentrated. The residue was purified by flash column
chromatography on silica gel (PE/EtOAc 9:1 to 7:3) to furnish the
desired compound.
H
Ar), 8.39e8.42 (m, 1H, HAr), 10.14 (s, 1H, CHO); 13C NMR (75 MHz,
CDCl3): 111.3 (CH), 119.9 (Cq), 122.4 (CH), 123.6 (CH), 124.8 (CH),
d
125.2 (2 ꢃ CH),125.7 (Cq),127.3 (2 ꢃ CH),128.1 (CH),128.7 (2 ꢃ CH),
129.2 (2 ꢃ CH), 137.3 (Cq), 137.6 (Cq), 138.2 (CH), 139.8 (Cq), 141.3
(Cq), 185.1 (CHO); IR (KBr, cmꢁ1): 3027, 2943, 2821, 1597, 1489,
1456, 1251, 1003, 761, 744; MS (ESI): m/z 298 [MþH]þ.
4.1.1.1. 1-Phenyl-1H-indole-3-carbaldehyde (2a) (CAS: 32542-59-9).
Starting aryl halide ¼ iodobenzene. Yield: 89% (557 mg); mp 70e
72 ꢀC; 1H NMR (300 MHz, CDCl3):
d 7.31e7.40 (m, 2H, HAr), 7.46e
7.62 (m, 6H, HAr), 7.93 (s, 1H, HAr), 8.39 (dd, 1H, J ¼ 2.3, 6.1 Hz, HAr),
4.1.1.7. 1-[2-(1-Methylethyl)phenyl]-1H-indole-3-carbaldehyde (2g).
Starting aryl halide ¼ 1-iodo-2-(1-methylethyl)benzene. Yield:
21% (155 mg); mp 99e101 ꢀC (EtOAc/PE); 1H NMR (300 MHz,
10.12 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d
111.2 (CH), 119.8
(Cq), 122.3 (CH), 123.6 (CH), 124.7 (CH), 124.9 (2 ꢃ CH), 125.6 (Cq),
128.4 (CH), 130.1 (2 ꢃ CH), 137.6 (Cq), 138.2 (Cq), 138.3 (CH), 185.0
(CHO); IR (KBr, cmꢁ1): 3100, 3040, 1655, 735, 690; MS (ESI): m/z
222 [MþH]þ.
CDCl3):
d
1.11 (d, 3H, J ¼ 6.8 Hz, CH3), 1.18 (d, 3H, J ¼ 6.8 Hz, CH3),
2.59e2.64 (m, 1H, CH), 7.04 (d, 1H, J ¼ 7.9 Hz, HAr), 7.28e7.42 (m,
4H, HAr), 7.57 (m, 2H, HAr), 7.79 (s, 1H, HAr), 8.41 (d, 1H, J ¼ 7.5 Hz,
H
Ar), 10.13 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d 23.5 (CH3), 24.6
4.1.1.2. 1-(2-Methylphenyl)-1H-indole-3-carbaldehyde (2b) (CAS:
(CH3), 27.9 (CH), 111.1 (CH), 119.2 (Cq), 122.0 (CH), 123.2 (CH), 124.5
(CH), 124.6 (Cq), 127.0 (CH), 127.1 (CH), 128.2 (CH), 130.1 (Cq), 135.1
(Cq), 139.3 (CH), 139.4 (CH), 146.5 (Cq), 185.0 (CHO); IR (KBr, cmꢁ1):
3056, 2720, 1654, 1575, 1460, 1456, 792, 748; MS (ESI): m/z 264
[MþH]þ.
196496-26-1). Starting aryl halide
¼
1-iodo-2-methylbenzene.
2.08 (s, 3H,
Yield: 23% (153 mg); oil; 1H NMR (300 MHz, CDCl3):
d
CH3), 7.03 (d, 1H, J ¼ 7.9 Hz, HAr), 7.29e7.38 (m, 4H, HAr), 7.40e7.47
(m, 2H, HAr), 7.78 (s, 1H, HAr), 8.38 (dd, 1H, J ¼ 1.1, 6.0 Hz, HAr), 10.11
(s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d 17.6 (CH3), 111.2 (CH),
119.4 (Cq), 122.2 (CH), 123.3 (CH), 124.6 (CH), 124.9 (Cq), 127.3 (CH),
127.9 (CH), 129.6 (CH), 131.6 (CH), 135.6 (Cq), 136.7 (Cq), 138.5 (Cq),
138.9 (CH), 185.1 (CHO); IR (KBr, cmꢁ1): 3100, 3040, 1660, 745; MS
(ESI): m/z 236 [MþH]þ.
4.1.1.8. 1-(2,3-Dimethylphenyl)-1H-indole-3-carbaldehyde (2h).
Starting aryl halide ¼ 1-iodo-2,3-dimethylbenzene. Yield: 20%
(140 mg); mp 90e91 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
d
1.93 (s, 3H, CH3), 2.40 (s, 3H, CH3), 7.02 (d, 1H, J ¼ 7.9 Hz, HAr), 7.17
(d, 1H, J ¼ 7.5 Hz, HAr), 7.24e7.38 (m, 4H, HAr), 7.76 (s, 1H, HAr), 8.38
4.1.1.3. 1-(3-Methylphenyl)-1H-indole-3-carbaldehyde (2c).
(d, 1H, J ¼ 7.5 Hz, HAr), 10.10 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
Starting aryl halide
¼
1-iodo-3-methylbenzene. Yield: 75%
2.46 (s, 3H,
d 14.1 (CH3), 20.3 (CH3), 111.2 (CH),119.0 (Cq),121.9 (CH), 123.0 (CH),
(153 mg); mp 109e110 ꢀC; 1H NMR (300 MHz, CDCl3):
d
124.3 (CH), 124.6 (Cq), 125.2 (CH), 126.4 (CH), 130.7 (CH), 134.0 (Cq),
136.5 (Cq), 138.5 (Cq), 138.9 (Cq), 139.2 (CH), 184.8 (CHO); IR (KBr,
cmꢁ1): 3111, 2918, 2813, 1664, 1609, 1578, 1476, 1456, 1381, 1084,
758; MS (ESI): m/z 250 [MþH]þ.
CH3), 7.24e7.37 (m, 5H, HAr), 7.41e7.48 (m, 2H, HAr), 7.81 (s, 1H,
H
Ar), 8.40 (d, 1H, J ¼ 7.1 Hz, HAr), 10.05 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3):
d 21.3 (CH3), 111.1 (CH), 119.4 (Cq), 121.6 (CH),
122.1 (CH),123.2 (CH), 124.4 (CH),125.2 (CH), 125.4 (Cq),128.9 (CH),
129.6 (CH), 137.3 (Cq), 137.8 (Cq), 138.3 (Cq), 140.0 (CH), 184.8
(CHO); IR (KBr, cmꢁ1): 3047, 2810, 1716, 1668, 1607, 1497, 1461, 1177,
1081; MS (ESI): m/z 236 [MþH]þ.
4.1.1.9. 1-(Naphth-1-yl)-1H-indole-3-carbaldehyde (2i).
Starting aryl halide ¼ 1-iodonaphthalene. Yield: 23% (175 mg);
mp 110e112 ꢀC (CH2Cl2); 1H NMR (300 MHz, CDCl3):
d 7.01 (d, 1H,
J ¼ 8.3 Hz, HAr), 7.22e7.27 (m, 1H, HAr), 7.35e7.40 (m, 2H, HAr), 7.46
(t, 1H, J ¼ 7.7 Hz, HAr), 7.56e7.66 (m, 3H, HAr), 7.95 (s, 1H, HAr), 8.01
(d, 1H, J ¼ 8.8 Hz, HAr), 8.06 (d, 1H, J ¼ 8.6 Hz, HAr), 8.44 (d, 1H,
4.1.1.4. 1-(4-Methylphenyl)-1H-indole-3-carbaldehyde (2d).
Starting aryl halide
¼
1-iodo-4-methylbenzene. Yield: 67%
2.47 (s, 3H, CH3), 7.29e
(415 mg); oil; 1H NMR (300 MHz, CDCl3):
d
J ¼ 7.7 Hz, HAr), 10.15 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d 111.5
7.42 (m, 6H, HAr), 7.46 (dd, 1H, J ¼ 1.9, 6.8 Hz, HAr), 7.89 (s, 1H, HAr),
(CH), 119.7 (Cq), 122.2 (CH), 122.6 (CH), 123.4 (CH), 124.6 (CH), 124.9
(Cq), 125.3 (CH), 125.5 (CH), 127.2 (CH), 127.7 (CH), 128.6 (CH), 129.9
(CH), 130.0 (Cq), 134.3 (Cq), 134.5 (Cq), 139.4 (Cq), 139.9 (CH), 185.1
(CHO); IR (KBr, cmꢁ1): 3115, 3051, 2836, 1649, 1530, 1181, 771, 748;
MS (ESI): m/z 272 [MþH]þ.
8.38 (dd, 1H, J ¼ 1.9, 6.8 Hz, HAr), 10.07 (s, 1H, CHO); 13C NMR
(75 MHz, CDCl3):
d 21.2 (CH3), 111.1 (CH), 119.4 (Cq), 122.2 (CH),
123.3 (CH), 124.5 (CH), 124.7 (2 ꢃ CH), 125.5 (Cq), 130.5 (2 ꢃ CH),
135.5 (Cq), 137.6 (Cq), 138.4 (CH þ Cq), 184.9 (CHO); IR (KBr, cmꢁ1):
3045, 2919, 2733, 1675, 1386, 1080, 814, 754; MS (ESI): m/z 236
[MþH]þ.
4.1.1.10. 1-(Naphth-2-yl)-1H-indole-3-carbaldehyde (2j).
Starting aryl halide ¼ 2-bromonaphthalene. Yield: 92% (699 mg);
4.1.1.5. 1-(2-Ethylphenyl)-1H-indole-3-carbaldehyde (2e).
mp 121e122 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
d 7.31e7.41
Starting aryl halide
¼
1-iodo-2-ethylbenzene. Yield: 25%
(m, 2H, HAr), 7.53 (d, 1H, J ¼ 7.7 Hz, HAr), 7.57e7.62 (m, 3H, HAr),
(175 mg); oil; 1H NMR (300 MHz, CDCl3):
d
1.03 (t, 3H, J ¼ 7.5 Hz,
7.88e7.97 (m, 4H, HAr), 8.02 (d, 1H, J ¼ 8.7 Hz, HAr), 8.44 (d, 1H,
CH3), 2.39 (q, 2H, J ¼ 7.5 Hz, CH2), 7.04 (d, 1H, J ¼ 7.9 Hz, HAr), 7.22e
7.39 (m, 4H, HAr), 7.50e7.54 (m, 2H, HAr), 7.81 (s, 1 H, HAr), 8.47 (d,
1H, J ¼ 7.5 Hz, HAr), 10.07 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
J ¼ 8.1 Hz, HAr), 10.11 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d 111.2
(CH), 119.8 (Cq), 122.3 (CH), 122.8 (CH), 123.1 (CH), 123.6 (CH), 124.7
(CH), 125.6 (Cq), 127.0 (CH), 127.5 (CH), 127.9 (CH), 128.0 (CH), 130.1
(CH), 132.6 (Cq), 133.5 (Cq), 135.5 (Cq), 137.6 (Cq), 138.5 (CH), 185.0
(CHO); IR (KBr, cmꢁ1): 3092, 3054, 2815, 1656, 1530, 1474, 1454,
1296, 1134, 733; MS (ESI): m/z 272 [MþH]þ.
d
14.4 (CH3), 23.5 (CH2), 110.6 (CH), 118.7 (Cq), 121.5 (CH), 122.6
(CH), 124.0 (CH), 124.1 (Cq), 126.7 (CH), 127.5 (CH), 129.3 (CH), 129.4
(CH), 135.4 (Cq), 138.3 (Cq), 139.1 (CH), 140.9 (Cq), 184.4 (CHO), IR
(neat, cmꢁ1): 3055, 2972, 2722, 1682, 1379, 1077, 746; MS (ESI): m/z
250 [MþH]þ.
4.1.1.11. 1-[2-(Trifluoromethyl)phenyl]-1H-indole-3-carbaldehyde
(2k). Starting aryl halide ¼ 1-iodo-2-(trifluoromethyl)benzene.
Yield: 8% (65 mg); mp 93e95 ꢀC (EtOAc/PE); 1H NMR (300 MHz,
4.1.1.6. 1-(Biphenyl-4-yl)-1H-indole-3-carbaldehyde (2f).
Starting aryl halide
(599 mg); mp 152e153 ꢀC (EtOH); 1H NMR (300 MHz, CDCl3):
7.36e7.40 (m, 2H, HAr), 7.42e7.44 (m, 1H, HAr), 7.49 (d, 2H,
¼
1-bromo-4-phenylbenzene. Yield: 72%
CDCl3):
d
6.99 (d, 1H, J ¼ 8.1 Hz, HAr), 7.29e7.39 (m, 2H, HAr), 7.50 (d,
1H, J ¼ 7.3 Hz, HAr), 7.69e7.78 (m, 2H, HAr), 7.80 (s,1H, HAr), 7.93 (dd,
d
1H, J ¼ 1.5, 7.5 Hz, HAr), 8.37 (d, 1H, J ¼ 7.5 Hz, HAr), 10.11 (s, 1H,
J ¼ 7.7 Hz, HAr), 7.53e7.57 (m, 1H, HAr), 7.60 (d, 2H, J ¼ 8.5 Hz, HAr),
CHO); 13C NMR (75 MHz, CDCl3):
d 111.3 (CH),120.2 (Cq),122.5 (CH),
7.66 (d, 2H, J ¼ 7.1 Hz, HAr), 7.80 (d, 2H, J ¼ 8.5 Hz, HAr), 7.96 (s, 1H,
123.2 (Cq, JCeF ¼ 271.7 Hz), 123.8 (CH), 124.9 (Cq), 125.1 (CH), 128.2

C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
163
(CH, JCeF ¼ 4.9 Hz), 128.8 (Cq, JCeF ¼ 31.1 Hz), 130.4 (CH), 131.1 (CH),
133.8 (CH), 135.9 (Cq, JCeF ¼ 2.3 Hz), 140.1 (Cq), 140.3 (CH), 185.6
(CHO); IR (KBr, cmꢁ1): 3045, 2734, 1662, 1605, 1578, 1504, 1464,
1312, 1057, 776, 754; MS (ESI): m/z 290 [MþH]þ.
product was purified by flash chromatography on silica gel using
system solvent indicated below.
4.1.2.1. 1-Phenyl-3-[(4-phenylpiperazinyl)methyl]-1H-indole (3a).
System solvent: CH2Cl2/MeOH 97:3; yield: 61% (112 mg); oil; 1H
4.1.1.12. 1-(2-Methoxyphenyl)-1H-indole-3-carbaldehyde (2l).
NMR (300 MHz, CDCl3):
d 2.78 (br s, 4H, CH2N), 3.27 (br s, 4H,
Starting aryl halide
¼
1-iodo-2-methoxybenzene. Yield: 68%
3.63 (s, 3H, OCH3), 7.10e
CH2N), 3.90 (s, 2H, CH2Ar), 6.85 (t, 1H, J ¼ 7.5 Hz, HAr), 6.92 (d, 2H,
J ¼ 7.9 Hz, HAr), 7.18e7.28 (m, 4H, HAr), 7.33e7.40 (m, 2H, HAr), 7.52
(d, 4H, J ¼ 4.4 Hz, HAr), 7.57 (d, 1H, J ¼ 8.7 Hz, HAr), 7.81 (d, 1H,
(478 mg); oil; 1H NMR (300 MHz, CDCl3):
d
7.15 (m, 2H, HAr), 7.20 (d, 1H, J ¼ 7.5 Hz, HAr), 7.29e7.37 (m, 2H, HAr),
7.41e7.51 (m, 2H, HAr), 7.87 (s, 1H, HAr), 8.38 (d, 1H, J ¼ 7.1 Hz, HAr),
J ¼ 7.4 Hz, HAr); 13C NMR (75 MHz, CDCl3):
d 49.3 (2 CH2), 53.2
10.07 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d 55.3 (CH3), 111.1
(2 ꢃ CH2), 53.7 (CH2), 110.6 (CH), 113.6 (Cq), 116.1 (2 ꢃ CH), 119.6
(CH), 120.1 (CH), 120.3 (CH), 122.6 (CH), 124.3 (2 ꢃ CH), 126.4 (CH),
127.5 (CH), 129.2 (2 ꢃ CH), 129.4 (Cq), 129.7 (2 ꢃ CH), 136.2 (Cq),
139.8 (Cq), 151.5 (Cq); IR (neat, cmꢁ1): 3080, 3040, 3020, 1595, 740,
690; MS (ESI): m/z 368 [MþH]þ; Anal. calcd for C25H25N3 C4H4O4: C
72.03, H 6.04, N 8.70, found: C 72.14, H 6.10, N 8.91; mp (fumarate);
174e176 ꢀC dec. (EtOH).
(CH), 112.2 (CH), 118.7 (Cq), 120.6 (CH), 121.5 (CH), 122.7 (CH), 123.9
(CH), 124.5 (Cq), 125.7 (Cq), 127.4 (CH), 129.8 (CH), 137.9 (Cq), 140.2
(CH), 153.8 (Cq), 184.7 (CHO); IR (neat, cmꢁ1): 3053, 1657, 1597, 741;
MS (ESI): m/z 252 [MþH]þ.
4.1.1.13. 2-(3-Formyl-1H-indol-1-yl)benzonitrile (2m) (CAS: 260553-
34-2). Starting aryl halide
(175 mg); mp 110e111 ꢀC (EtOH/Et2O); 1H NMR (300 MHz, CDCl3):
7.28e7.31 (m, 1H, HAr), 7.35e7.46 (m, 2H, HAr), 7.66 (td, 2H, J ¼ 1.3,
7.7 Hz, HAr), 7.85 (td, 1H, J ¼ 1.5, 8.3 Hz, HAr), 7.94 (d, 1H, J ¼ 7.7 Hz,
Ar), 8.00 (s, 1H, HAr), 8.40 (dd, 1H, J ¼ 1.8, 5.8 Hz, HAr), 10.16 (s, 1H,
CHO); 13C NMR (75 MHz, CDCl3):
110.1 (Cq), 110.7 (CH), 115.6 (Cq),
¼
2-iodobenzonitrile. Yield: 25%
d
4.1.2.2. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-phenyl-1H-
indole (3b). System solvent: CH2Cl2/MeOH 98:2; yield: 73%
H
(145 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.70 (br s, 4H, CH2N),
d
3.03 (br s, 4H, CH2N), 3.76 (s, 3H, OCH3), 3.79 (s, 2H, CH2Ar), 6.74e
6.92 (m, 4H, HAr), 7.08e7.16 (m, 3H, HAr), 7.24e7.28 (m, 1H, HAr),
7.42 (d, 4H, J ¼ 4.2 Hz, HAr), 7.47 (d, 1H, J ¼ 7.9 Hz, HAr), 7.74 (d, 1H,
120.3 (Cq), 122.3 (CH), 123.8 (CH), 124.9 (CH), 125.0 (Cq), 127.7 (CH),
129.2 (CH), 134.3 (CH), 134.5 (CH), 137.5 (Cq), 138.5 (CH), 139.8 (CH),
185.1 (CHO); IR (KBr, cmꢁ1): 3021, 2928, 1672, 1185, 1139, 723, 704;
MS (ESI): m/z 247 [MþH]þ.
J ¼ 7.2 Hz, HAr); 13C NMR (75 MHz, CDCl3):
d
50.8 (2 ꢃ CH2), 53.4
(2 ꢃ CH2), 53.5 (CH2), 55.4 (CH3), 110.5 (CH), 111.1 (CH), 113.6 (Cq),
118.3 (CH), 120.0 (CH), 120.2 (CH), 121.0 (CH), 122.5 (CH), 122.8 (CH),
124.2 (2 ꢃ CH), 126.3 (CH), 127.5 (CH), 129.6 (Cq), 129.6 (2 ꢃ CH),
136.2 (Cq), 139.8 (Cq), 141.5 (Cq), 152.3 (Cq); IR (neat, cmꢁ1): 3080,
3040, 3020, 1595, 745, 695; MS (ESI): m/z 398 [MþH]þ; Anal. calcd
for C26H27N3O C4H4O4: C 70.16, H 6.08, N 8.18, found: C 70.30, H
6.18, N 8.45; mp (fumarate): 187e188 ꢀC dec. (EtOH/Et2O).
4.1.1.14. 1-(Pyridin-3-yl)-1H-indole-3-carbaldehyde (2n) (CAS:
95504-82-8). Starting aryl halide ¼ 3-iodopyridine. Yield: 70%
(440 mg); mp 138e140 ꢀC (MeOH); 1H NMR (300 MHz, CDCl3):
d
7.39e7.48 (m, 3H, HAr), 7.65 (br s,1H, HAr), 7.94 (s,1H, HAr), 8.00 (d,
1H, J ¼ 8.3 Hz, HAr), 8.41 (d, 1H, J ¼ 8.3 Hz, HAr), 8.78 (br s, 1H, HAr),
8.92 (br s, 1H, HAr), 10.16 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
d
110.6 (CH), 120.4 (Cq), 122.5 (CH), 122.9 (CH), 124.4 (CH), 125.1
4.1.2.3. 2-{4-[(1-Phenyl-1H-indol-3-yl)methyl]piperazinyl}phenol
(CH), 125.5 (Cq), 132.3 (CH), 137.3 (Cq), 137.7 (CH), 146.0 (CH), 149.3
(CH), 149.8 (Cq), 185.0 (CHO); IR (KBr, cmꢁ1): 3073, 2738, 1673,
1654, 1616, 1587, 1485, 1463, 1083, 788, 739; MS (ESI): m/z 223
[MþH]þ.
(3c). System solvent: CH2Cl2/MeOH 99:1 to 98:2; yield: 72%
(139 mg); foam; 1H NMR (300 MHz, CDCl3):
d 2.60e2.85 (m, 4H,
CH2N), 2.92 (br s, 4H, CH2N), 3.87 (s, 2H, CH2Ar), 6.85 (dt,1H, J ¼ 1.5,
7.5 Hz, HAr), 6.94 (dt, 1H, J ¼ 1.3, 7.8 Hz, HAr), 7.07 (dt, 1H, J ¼ 1.3,
7.8 Hz, HAr), 7.16e7.27 (m, 2H, HAr), 7.32e7.39 (m, 2H, HAr), 7.51e
7.60 (m, 6H, HAr), 7.83e7.85 (m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
4.1.1.15. 1-(Pyridin-2-yl)-1H-indole-3-carbaldehyde (2o) (CAS:
890095-85-9). The compound was prepared from sodium salt of
indole-3-carbaldehyde and 2-fluoropyridine as described in refer-
ence [9]. Yield: 86% (541 mg); mp: 114e115 ꢀC (MeOH); 1H NMR
d
52.6 (2 ꢃ CH2), 53.5 (CH2Ar), 53.8 (2 ꢃ CH2), 110.6 (CH), 113.3 (Cq),
114.1 (CH), 119.97 (CH), 120.03 (CH), 120.3 (CH), 121.5 (CH), 122.6
(CH), 124.2 (2 ꢃ CH), 126.34 (CH), 126.36 (CH), 127.5 (CH), 129.4
(Cq), 129.7 (2 ꢃ CH), 136.1 (Cq), 139.2 (Cq), 139.7 (Cq), 151.6 (Cq); IR
(neat, cmꢁ1): 3320, 3050, 1664, 1596, 740, 696; Anal. calcd for
(300 MHz, CDCl3):
Ar), 7.95 (td, 1H, J ¼ 1.1, 7.7 Hz, HAr), 8.02e8.05 (m, 1H, HAr), 8.38 (s,
1H, HAr), 8.40 (dd, 1H, J ¼ 1.3, 5.3 Hz, HAr), 8.64 (dd, 1H, J ¼ 1.3,
4.7 Hz, HAr), 10.16 (s, 1H, CHO); 13C NMR (75 MHz, CDCl3):
112.8
d
7.33e7.45 (m, 3H, HAr), 7.64 (d, 1H, J ¼ 8.3 Hz,
H
C
25H25N3O 1/2C4H4O4: C 73.45, H 6.16, N 9.52, found: C 73.38, H
d
6.09, N 9.48; mp (fumarate): 161e163 ꢀC (EtOH/Et2O).
(CH), 115.7 (CH), 120.5 (Cq), 122.2 (CH), 122.3 (CH), 123.8 (CH), 125.1
(CH), 126.3 (Cq), 136.2 (Cq), 137.0 (CH), 139.0 (CH), 149.4 (CH), 150.9
(Cq), 185.4 (CHO); IR (KBr, cmꢁ1): 3101, 3050, 2821, 1649, 1224,
1083, 739; MS (ESI): m/z 223 [MþH]þ.
4.1.2.4. 3-[(4-Phenylpiperazinyl)methyl]-1-(2-methylphenyl)-1H-
indole (3d). System solvent: CH2Cl2/MeOH 95:5; yield: 78%
(149 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.09 (s, 3H, CH3), 2.75 (t,
4.1.2. General procedure for preparation of compounds 3 and 4
The derivative 2 (0.5 mmol) was added to a solution of the
amine (1.0 mmol, 2.0 equiv) and acetic acid (1.0 equiv) in MeOH
(2.0 mL). The sodium cyanoborohydride (1.0 equiv) was then added
at room temperature in one portion and reaction mixture was
refluxed overnight. After cooling to room temperature, 12 N HCl
was added carefully under fume hood until pH 2. Stirring was
continued for 15 min and 50% aqueous NaOH was added to obtain
pH 10e12. Methanol was then eliminated under vacuum and the
residue diluted in water and extracted with dichloromethane (3ꢃ).
Resulting organic layers were washed with saturated NaCl solution
and dried over Na2SO4. After removal of the solvent, the crude
4H, J ¼ 4.5 Hz, CH2N), 3.24 (t, 4H, J ¼ 4.9 Hz, CH2N), 3.88 (s, 2H,
CH2Ar), 6.85 (t, 1H, J ¼ 7.4 Hz, HAr), 6.93 (d, 2H, J ¼ 8.3 Hz, HAr),
7.02e7.05 (m, 1H, HAr), 7.17e7.19 (m, 3H, HAr), 7.23e7.28 (m, 2H,
H
Ar), 7.32e7.34 (m, 2H, HAr), 7.35e7.39 (m, 2H, HAr), 7.81e7.84 (m,
1H, HAr); 13C NMR (75 MHz, CDCl3):
d
17.9 (CH3), 49.3 (2 ꢃ CH2),
53.2 (2 ꢃ CH2), 53.7 (CH2), 110.7 (CH), 112.4 (Cq), 116.1 (2 ꢃ CH),
119.6 (CH), 119.7 (CH), 119 (CH), 122.3 (CH), 126.9 (2 ꢃ CH), 128.2
(CH), 128.3 (CH), 128.4 (Cq), 129.2 (2 ꢃ CH), 131.3 (CH), 135.8 (Cq),
137.5 (Cq), 138.2 (Cq), 151.5 (Cq); IR (neat, cmꢁ1): 3080, 3040, 3020,
1595, 740, 690; MS (ESI): m/z 382 [MþH]þ; Anal. calcd for C26H27N3
C4H4O4: C 72.71, H 6.28, N 8.44, found: C 72.71, H 6.32, N 8.60; mp
(fumarate): 185 ꢀC dec. (EtOH/Et2O).

164
C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
4.1.2.5. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-(2-
(CH3), 24.2 (CH2), 49.1 (2 ꢃ CH2), 53.0 (2 ꢃ CH2), 53.6 (CH2), 110.5
(CH), 112.1 (Cq), 116.0 (2 ꢃ CH), 119.5 (CH), 119.6 (CH), 119.7 (CH),
122.2 (CH), 126.7 (CH), 128.2 (Cq), 128.4 (CH), 128.5 (2 ꢃ CH), 129.0
(2 ꢃ CH), 129.5 (CH), 137.5 (Cq), 137.8 (Cq), 141.8 (Cq), 151.4 (Cq); IR
(neat, cmꢁ1): 3056, 2819, 1600, 1496, 1462, 1378, 742, 693; MS (ESI)
m/z 396 [MþH]þ; Anal. calcd for C27H29N3 C4H4O4 1/2H2O: C 71.52,
H 6.58, N 8.07, found: C 71.44, H 6.36, N 7.97. mp (fumarate): 169e
171 ꢀC (EtOH/Et2O).
methylphenyl)-1H-indole (3e). System solvent: CH2Cl2/MeOH 97:3;
yield 83% (170 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.08 (s, 3H,
CH3), 2.80 (br s, 4H, CH2N), 3.13 (br s, 4H, CH2N), 3.86 (s, 3H, OCH3),
3.89 (s, 2H, CH2Ar), 6.84e7.04 (m, 5H, HAr), 7.16e7.19 (m, 3H, HAr),
7.32e7.33 (m, 2H, HAr), 7.36e7.38 (m, 2H, HAr), 7.82e7.85 (m, 1H,
H
Ar); 13C NMR (75 MHz, CDCl3):
d
17.9 (CH3), 50.9 (2 ꢃ CH2), 53.4
(2 ꢃ CH2), 53.6 (CH2), 55.4 (OCH3), 110.6 (CH), 111.2 (CH), 112.5 (Cq),
118.3 (CH), 119.7 (CH), 119.8 (CH), 121.0 (CH), 122.2 (CH), 122.9 (CH),
126.8 (CH), 128.2 (2 ꢃ CH), 128.3 (CH), 128.5 (Cq), 131.2 (CH), 135.8
(Cq), 137.4 (Cq), 138.3 (Cq), 141.6 (Cq), 152.4 (Cq); IR (neat, cmꢁ1):
3040, 3020, 2805, 1590, 740; MS (ESI): m/z 412 [MþH]þ; Anal. calcd
for C27H29N3O C4H4O4: C 70.57, H 6.30, N 7.96, found: C 70.76, H
6.35, N 8.05; mp (fumarate): 180e181 ꢀC (EtOH/Et2O).
4.1.2.10. 1-(Biphenyl-4-yl)-3-[(4-phenylpiperazinyl)methyl]-1H-
indole (3j). The near white solid product was isolated from reaction
mixture by filtration; yield: 70% (155 mg); mp 131e132 ꢀC (EtOAc/
PE); 1H NMR (300 MHz, CDCl3):
d 2.76 (br s, 4H, CH2N), 3.24 (br s,
4H, CH2N), 3.88 (s, 2H, CH2Ar), 6.85 (t, 1H, J ¼ 7.2 Hz, HAr), 6.93 (d,
2H, J ¼ 7.9 Hz, HAr), 7.19e7.29 (m, 4H, HAr), 7.38e7.41 (m, 2H, HAr),
7.49 (t, 2H, J ¼ 7.2 Hz, HAr), 7.58e7.67 (m, 5H, HAr), 7.74 (d, 2H,
J ¼ 8.5 Hz, HAr), 7.84 (d, 1H, J ¼ 7.0 Hz, HAr); 13C NMR (75 MHz,
4.1.2.6. 1-(2-Methylphenyl)-3-[(4-methylpiperazinyl)methyl]-1H-
indole (3f). System solvent: EtOAc/EtOH 2:8 þ 1% Et3N; yield 73%
(116 mg); oil; 1H NMR (300 MHz, CDCl3):
d
2.06 (s, 3H, CH3), 2.32 (s,
CDCl3):
d
49.3 (2 ꢃ CH2), 53.3 (2 ꢃ CH2), 53.7 (CH2), 110.7 (CH), 113.8
3H, CH3), 2.44e2.66 (m, 8H, CH2N), 3.83 (s, 2H, CH2Ar), 6.99e7.02
(m, 1H, HAr), 7.14e7.19 (m, 3H, HAr), 7.29e7.31 (m, 2H, HAr), 7.35e
7.37 (m, 2H, HAr), 7.77e7.80 (m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
(Cq), 116.1 (2 ꢃ CH), 119.6 (CH), 120.2 (CH), 120.4 (CH), 122.7 (CH),
124.4 (2 ꢃ CH),127.1 (2 ꢃ CH),127.4 (CH),127.6 (CH), 128.3 (2 ꢃ CH),
129.0 (2 ꢃ CH), 129.2 (2 ꢃ CH), 129.5 (Cq), 136.3 (Cq), 139.0 (Cq),
139.3 (Cq), 140.3 (Cq), 151.5 (Cq); IR (KBr, cmꢁ1): 3027, 1596, 1522,
1489, 1456, 1231, 760, 743; MS (ESI): m/z 444 [MþH]þ. Anal. calcd
for C31H29N3: C 83.94, H 6.59, N 9.47, found: C 83.32, H 6.76, N 9.41.
d
17.6 (CH3), 45.9 (CH3), 52.8 (2 ꢃ CH2), 53.3 (CH2), 55.1 (2 ꢃ CH2),
110.3 (CH), 112.3 (Cq), 119.4 (CH), 119.6 (CH), 121.9 (CH), 126.6 (CH),
127.8 (2 ꢃ CH), 127.9 (CH), 128.1 (Cq), 130.9 (CH), 135.4 (Cq), 137.1
(Cq), 137.9 (Cq); IR (neat, cmꢁ1): 3043, 2934, 2796, 1497, 1459, 1262,
1163, 1009, 735; MS (ESI): m/z 320 [MþH]þ; Anal. calcd for
4.1.2.11. 1-[2-(1-Methylethyl)phenyl]-3-[(4-phenylpiperazinyl)
C
21H25N3 C4H4O4: C 68.95, H 6.71, N 9.65, found: C 70.01, H 6.59, N
methyl]-1H-indole (3k). System solvent: EtOAc/PE 1:9 to 3:7; yield:
9.47; mp (fumarate): 199e200 ꢀC (EtOH/Et2O).
50% (102 mg); oil; 1H NMR (300 MHz, CDCl3):
d 1.18 (d, 3H,
J ¼ 6.8 Hz, CH3), 1.22 (d, 3H, J ¼ 6.8 Hz, CH3), 2.73e2.83 (m, 5H,
CH2N þ CH), 3.32 (br s, 4H, CH2N), 3.97 (s, 2H, CH2Ar), 6.92 (t, 1H,
J ¼ 7.2 Hz, HAr), 7.01 (d, 2H, J ¼ 7.9 Hz, HAr), 7.09e7.12 (m, 1H, HAr),
7.24e7.35 (m, 7H, HAr), 7.50e7.59 (m, 2H, HAr), 7.91e7.93 (m, 1H,
4.1.2.7. 1-(3-Methylphenyl)-3-[(4-phenylpiperazinyl)methyl]-1H-
indole (3g). System solvent: EtOAc/PE 5:95 to 10:90; yield: 67%
(128 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.64 (s, 3H, CH3), 2.94
(br s, 4H, CH2N), 3.43 (br s, 4H, CH2N), 4.05 (s, 2H, CH2Ar), 7.12e7.15
(m, 3H, HAr), 7.36e7.56 (m, 9H, HAr), 7.85 (d, 1H, J ¼ 7.0 Hz, HAr), 8.14
H d 23.6 (CH3), 24.7 (CH3), 27.8 (CH),
Ar); 13C NMR (75 MHz, CDCl3):
49.2 (2 ꢃ CH2), 53.0 (2 ꢃ CH2), 53.6 (CH2), 110.5 (CH), 112.0 (Cq),
116.1 (2 ꢃ CH), 119.6 (CH), 119.7 (2 ꢃ CH), 122.3 (CH), 126.6 (CH),
126.8 (CH), 128.2 (Cq), 128.7 (CH), 128.9 (CH), 129.0 (CH), 129.1
(2 ꢃ CH), 136.8 (Cq), 138.4 (Cq), 146.9 (Cq), 151.5 (Cq); IR (neat,
~
n
3057, 2963, 2818, 1600, 1496, 1461, 1380, 1006, 742; MS
(d, 1H, J ¼ 6.4 Hz, HAr); 13C NMR (75 MHz, CDCl3):
d 21.3 (CH3), 48.9
(2 ꢃ CH2), 53.0 (2 ꢃ CH2), 53.5 (CH2), 110.5 (CH), 113.3 (Cq), 115.8
(2 ꢃ CH), 119.3 (CH), 119.9 (CH), 120.0 (CH), 120.9 (CH), 122.4 (CH),
124.6 (CH), 126.9 (CH), 127.2 (CH), 128.9 (2 ꢃ CH þ Cq), 129.3 (CH),
136.0 (Cq), 139.4 (Cq), 139.5 (Cq), 151.3 (Cq); IR (neat, cmꢁ1): 3054,
2825, 1600, 1496, 1460, 1006; MS (ESI): m/z 382 [MþH]þ; Anal.
calcd for C26H27N3 C4H4O4: C 72.41, H 6.28, N 8.44, found: C 72.19, H
6.20, N 8.27; mp (fumarate): 192 ꢀC dec. (EtOH/Et2O).
cmꢁ1):
(ESI): m/z 410 [MþH]þ; Anal. calcd for C28H31N3 C4H4O4 1/3H2O: C
72.29, H 6.76, N 7.90, found: C 72.19, H 6.69, N 8.01; mp (fumarate):
160e161 ꢀC (EtOH/Et2O).
4.1.2.12. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-[2-(1-
4.1.2.8. 1-(4-Methylphenyl)-3-[(4-phenylpiperazinyl)methyl]-1H-
methylethyl)phenyl]-1H-indole (3l). System solvent: EtOAc/PE 4:6
indole (3h). System solvent: EtOAc/PE 2:8; yield: 83% (158 mg);
to 9:1; yield: 60% (132 mg); foam; 1H NMR (300 MHz, CDCl3):
d 1.08
mp: 80e81 ꢀC; 1H NMR (300 MHz, CDCl3):
d
2.47 (s, 3H, CH3), 2.74
(d, 3H, J ¼ 6.8 Hz, CH3), 1.13 (d, 3H, J ¼ 6.8 Hz, CH3), 2.17 (m, 1H, CH),
2.79 (br s, 4H, CH2N), 3.12 (br s, 4H, CH2N), 3.85 (s, 3H, OCH3), 3.89
(s, 2H, CH2Ar), 6.84e7.01 (m, 5H, HAr), 7.15e7.18 (m, 3H, HAr), 7.24e
(br s, 4H, CH2N), 3.23 (br s, 4H, CH2N), 3.84 (s, 2H, CH2Ar), 6.84 (t,
1H, J ¼ 7.1 Hz, HAr), 6.92 (d, 2H, J ¼ 8.3 Hz, HAr), 7.16e7.38 (m, 9H,
H
Ar), 7.53 (d, 1H, J ¼ 7.9 Hz, HAr), 7.82 (d, 1H, J ¼ 7.1 Hz, HAr); 13C
7.33 (m, 2H, HAr), 7.42e7.50 (m, 2H, HAr), 7.81e7.84 (m, 2H, HAr); 13
C
NMR (75 MHz, CDCl3):
d
20.9 (CH3), 48.9 (2 ꢃ CH2), 52.9 (2 ꢃ CH2),
NMR (75 MHz, CDCl3): d 23.6 (CH3), 24.7 (CH3), 27.9 (CH), 50.9
53.4 (CH2), 110.4 (CH), 113.0 (Cq), 115.8 (2 ꢃ CH), 119.3 (CH), 119.8
(CH), 119.9 (CH), 122.3 (CH), 123.9 (2 ꢃ CH), 127.3 (CH), 128.9
(2 ꢃ CH),129.1 (Cq),130.0 (2 ꢃ CH),135.8 (Cq),136.1 (Cq),137.0 (Cq),
151.2 (Cq); IR (KBr, cmꢁ1): 3036, 2810, 1601, 1502, 1457, 1055; MS
(ESI): m/z 382 [MþH]þ; Anal. calcd for C26H27N3 C4H4O4 1/4H2O: C
71.76, H 6.32, N 8.37, found: C 71.74, H 6.12, N 8.19; mp (fumarate):
192 ꢀC dec. (EtOH/Et2O).
(2 ꢃ CH2), 53.4 (2 ꢃ CH2), 53.6 (CH2), 55.4 (CH3), 110.6 (CH), 111.2
(CH), 112.2 (Cq), 118.4 (CH), 119.6 (CH), 119.7 (CH), 121.1 (CH), 122.2
(CH),122.9 (CH),126.6 (CH), 126.8 (CH), 128.4 (Cq),128.8 (CH),128.9
(CH), 129.0 (Cq), 136.9 (Cq), 138.4 (Cq), 141.6 (Cq), 147.1 (Cq), 152.4
(Cq); IR (KBr, cmꢁ1): 3043, 2956, 1495, 1459, 1237, 1027, 738; MS
(ESI): m/z 440 [MþH]þ; HRMS-ESI: m/z [MþH]þ calcd for
C29H34N3O: 440.27019, found: 440.27021.
4.1.2.9. 1-(2-Ethylphenyl)-3-[(4-phenylpiperazinyl)methyl]-1H-
4.1.2.13. 1-(2,3-Dimethylphenyl)-3-[(4-phenylpiperazinyl)methyl]-
1H-indole (3m). System solvent: EtOAc/PE 2:8 to 3:7; yield: 80%
(159 mg); mp 151e152 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
indole (3i). System solvent: EtOAc/PE 5:95 to 10:90; yield: 58%
(114 mg); oil; 1H NMR (300 MHz, CDCl3):
CH3), 2.57 (m, 2H, CH2), 2.89 (br s, 4H, CH2N), 3.38 (br s, 4H, CH2N),
d
1.18 (t, 3H, J ¼ 7.5 Hz,
d 1.94 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.75 (br s, 4H, CH2N), 3.24 (br s,
4.02 (s, 2H, CH2Ar), 6.98 (t,1H, J ¼ 7.5 Hz, HAr), 7.07 (d, 2H, J ¼ 8.1 Hz,
4H, CH2N), 3.87 (s, 2H, CH2Ar), 6.82 (t, 1H, J ¼ 7.2 Hz, HAr), 6.93 (d,
H
Ar), 7.17e7.20 (m, 1H, HAr), 7.31e7.44 (m, 7H, HAr), 7.53e7.55 (m,
2H, J ¼ 8.5 Hz, HAr), 6.99e7.03 (m, 1H, HAr), 7.15e7.29 (m, 8H, HAr),
2H, HAr), 7.95e8.05 (m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
d
14.9
7.82e7.85 (m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
d 14.5 (CH3), 20.5

C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
165
(CH3), 49.3 (2 ꢃ CH2), 53.1 (2 ꢃ CH2), 53.7 (CH2), 110.7 (CH), 112.2
(Cq), 116.0 (2 ꢃ CH), 119.5 (CH), 119.6 (CH), 119.8 (CH), 122.2 (CH),
125.8 (CH), 126.1 (CH), 128.3 (Cq), 128.5 (CH), 129.1 (2 ꢃ CH), 129.7
(CH),134.5 (Cq),137.7 (Cq),138.2 (Cq),138.5 (Cq),151.5 (Cq); IR (KBr,
cmꢁ1): 2931, 2812, 1601, 1578, 1480, 1387, 1080, 739; SM (ESI): m/z
396 [MþH]þ; Anal. calcd for C27H29N3 C4H4O4: C 72.78, H 6.50, N
8.21, found: C 72.45, H 6.64, N 8.16; mp (fumarate): >200 ꢀC (EtOH/
Et2O).
53.7 (2 ꢃ CH2), 53.8 (CH2), 111.0 (CH), 112.6 (Cq), 114.1 (CH), 119.9
(CH), 120.1 (2 ꢃ CH), 121.6 (CH), 122.4 (CH), 123.4 (CH), 125.2 (CH),
125.6 (CH), 126.4 (CH), 126.7 (CH), 127.0 (CH), 128.4 (CH), 128.5
(CH), 128.6 (Cq), 129.4 (CH), 130.5 (Cq), 134.5 (Cq), 135.9 (Cq), 138.5
(Cq), 139.2 (Cq), 151.6 (Cq); IR (KBr, cmꢁ1): 3049, 2936, 1595, 1491,
1453, 1247, 1003, 741; HRMS-ESI: m/z [MþH]þ calcd for C29H28N3O:
434.22324, found: 434.22329.
4.1.2.18. 1-(Naphth-2-yl)-3-[(4-phenylpiperazinyl)methyl]-1H-indole
4.1.2.14. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-(2,3-
dimethylphenyl)-1H-indole (3n). System solvent: EtOAc/PE 4:6;
yield: 60% (128 mg); mp 135e136 ꢀC (EtOAc/PE); 1H NMR
(3r). System solvent: EtOAc/PE 3:7 to 1:1; yield: 78% (162 mg); mp
128e129 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
d 2.62 (br s, 4H,
CH2N), 3.14 (br s, 4H, CH2N), 3.79 (s, 2H, CH2Ar), 6.75 (t, 1H,
J ¼ 7.2 Hz, CH2), 6.91 (d, 2H, J ¼ 8.1 Hz, HAr), 7.15e7.27 (m, 4H, HAr),
7.54e7.62 (m, 2H, HAr), 7.67 (d, 1H, J ¼ 8.1 Hz, HAr), 7.72 (s, 1H, HAr),
7.79 (dd, 1H, J ¼ 2.1, 8.8 Hz, HAr), 7.83 (d, 1H, J ¼ 8.1 Hz, HAr), 8.01e
8.05 (m, 2H, HAr), 8.11e8.14 (m, 2H, HAr); 13C NMR (75 MHz, CDCl3):
(300 MHz, CDCl3):
d 1.94 (s, 3H, CH3), 2.39 (s, 3H, CH3), 2.82 (br s,
4H, CH2N), 3.14 (br s, 4H, CH2N), 3.86 (s, 3H, OCH3), 3.91 (s, 2H,
CH2Ar), 6.84e7.04 (m, 5H, HAr), 7.16e7.28 (m, 6H, HAr), 7.82e7.85
(m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
d 14.5 (CH3), 20.5 (CH3),
50.8 (2 ꢃ CH2), 53.3 (2 ꢃ CH2), 53.6 (CH2), 55.4 (CH3), 110.7 (CH),
111.1 (CH), 112.1 (Cq), 118.3 (CH), 119.6 (CH), 119.7 (CH), 121.0 (CH),
122.1 (CH), 122.8 (CH), 125.8 (CH), 126.1 (CH), 128.4 (Cq),128.6 (CH),
129.6 (CH), 134.5 (Cq), 137.6 (Cq), 138.2 (Cq), 138.5 (Cq), 141.5 (Cq),
152.3 (Cq); IR (KBr, cmꢁ1): 3048, 2997, 1501, 1478, 1448, 1238, 1004,
733; MS (ESI): m/z 426 [MþH]þ; Anal. calcd for C28H31N3O: C 79.02,
H 7.34, N 9.87, found: C 78.88, H 7.33, N 10.00.
d
49.3 (2 ꢃ CH2), 53.2 (2 ꢃ CH2), 53.6 (CH2), 110.7 (CH), 113.8 (Cq),
116.1 (2 ꢃ CH), 119.6 (CH), 120.2 (CH), 120.4 (CH), 121.7 (CH), 122.7
(CH), 123.2 (CH), 126.1 (CH), 127.0 (CH), 127.6 (CH), 127.8 (CH), 127.9
(CH), 129.2 (2 ꢃ CH), 129.5 (Cq), 129.7 (CH), 131.8 (Cq), 133.9 (Cq),
136.4 (Cq), 137.2 (Cq), 151.5 (Cq); IR (KBr, cmꢁ1): 3058, 2935, 1595,
1507, 1469, 1452, 1236, 1132, 1002, 744; MS (ESI): m/z 418 [MþH]þ;
Anal. calcd for C29H27N3: C 83.42, H 6.52, N 10.06, found: C 83.60, H
6.49, N 9.56; mp (fumarate): 128e129 ꢀC (EtOH/Et2O).
4.1.2.15. 1-(Naphth-1-yl)-3-[(4-phenylpiperazinyl)methyl]-1H-indole
(3o). System solvent: EtOAc/PE 1:9; yield: 46% after recristalliza-
tion from MeOH (96 mg); mp 140e141 ꢀC (MeOH); 1H NMR
4.1.2.19. 3-[(4-Phenylpiperazinyl)methyl]-1-[2-(trifluoromethyl)
phenyl]-1H-indole (3s). System solvent: EtOAc/PE 2:8; yield: 49%
(93 mg); mp 101e103 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3): d 2.94 (br s, 4H, CH2N), 3.42 (br s, 4H, CH2N), 4.08
(s, 2H, CH2Ar), 7.02 (t,1H, J ¼ 7.5 Hz, HAr), 7.10 (d, 2H, J ¼ 7.5 Hz, HAr),
7.20 (d, 1H, J ¼ 7.9 Hz, HAr), 7.31 (dd, 1H, J ¼ 7.4 Hz, HAr), 7.35e7.37
(m, 1H, HAr), 7.43 (dd, 2H, J ¼ 7.5 Hz, HAr), 7.50 (s, 1H, HAr), 7.55e7.58
(m, 1H, HAr), 7.64e7.77 (m, 4H, HAr), 8.09e8.11 (m, 3H, HAr); 13C
d 2.78 (br s, 4H, CH2N), 3.36 (br s, 4H, CH2N), 3.92 (s, 2H, CH2Ar),
6.89 (t,1H, J ¼ 7.3 Hz, HAr), 6.98 (d, 2H, J ¼ 8.1 Hz, HAr), 7.03e7.09 (m,
1H, HAr), 7.22e7.28 (m, 3H, HAr), 7.31 (dd, 2H, J ¼ 7.7 Hz, HAr), 7.50
(d, 1H, J ¼ 7.7 Hz, HAr), 7.62 (t, 1H, J ¼ 7.4 Hz, HAr), 7.71 (t, 1H,
J ¼ 7.4 Hz, HAr), 7.87e7.92 (m, 2H, HAr); 13C NMR (75 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
49.2 (2 ꢃ CH2), 53.1 (2 ꢃ CH2), 53.6 (CH2),
110.9 (CH), 112.8 (Cq), 116.0 (2 ꢃ CH), 119.5 (CH), 119.9 (CH), 120.0
(CH),122.4 (CH),123.4 (CH),125.1 (CH),125.5 (CH),126.6 (CH),126.9
(CH), 128.3 (CH), 128.4 (CH), 128.5 (Cq), 129.1 (2 ꢃ CH), 129.2 (CH),
130.4 (Cq), 134.5 (Cq), 135.9 (Cq), 138.4 (Cq), 151.4 (Cq); IR (KBr,
cmꢁ1): 3054, 2904, 2799, 1598, 1575, 1499, 1450, 1407, 1001, 738,
690; Anal. calcd for C29H27N3 C4H4O4.1/4H2O: C 73.66, H 5.90, N
7.81, found: C 73.81, H 5.68, N 7.64; mp (fumarate): 202e203 ꢀC dec.
(EtOH/Et2O).
d
49.2 (2 ꢃ CH2), 52.9 (2 ꢃ CH2), 53.4 (CH2), 110.4 (CH), 112.7 (Cq),
116.1 (2 ꢃ CH), 119.6 (CH), 119.8 (CH), 120.2 (CH), 122.6 (CH), 125.0
(Cq, JCeF ¼ 271.0 Hz), 127.5 (CH, JCeF ¼ 5.0 Hz), 128.4 (Cq), 128.6 (Cq,
JCeF ¼ 30.5 Hz), 128.7 (CH), 129.1 (2 ꢃ CH), 129.3 (CH), 131.0 (CH),
132.9 (CH), 137.5 (Cq), 138.9 (Cq), 151.4 (Cq); IR (KBr, cmꢁ1): 3039,
2928, 2821,1601,1503,1465,1451,1316,1055,1004, 748; HRMS (CI):
m/z [MþH]þ calcd for C26H25F3N3: 436.2001, found: 436.2003; mp
(fumarate): 165e167 ꢀC (EtOH/Et2O).
4.1.2.16. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-(naphth-1-
4.1.2.20. 1-(2-Methoxyphenyl)-3-[(4-phenylpiperazinyl)methyl]-1H-
yl)-1H-indole (3p). System solvent: EtOAc/PE 2:8 to 1:1; yield: 70%
indole (3t). System solvent: CH2Cl2/MeOH 99:1 to 98:2; yield: 73%
(157 mg); foam; 1H NMR (300 MHz, CDCl3):
d
2.87 (br s, 4H, CH2N),
(145 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.74 (br s, 4H, CH2N),
3.18 (br s, 4H, CH2N), 3.88 (s, 3H, OCH3), 3.97 (s, 2H, CH2Ar), 6.87e
7.06 (m, 5H, HAr), 7.14e7.26 (m, 2H, HAr), 7.37 (s, 1H, HAr), 7.41e7.46
(m, 1H, HAr), 7.52e7.63 (m, 4H, HAr), 7.93 (d, 1H, J ¼ 7.5 Hz, HAr),
3.24 (br s, 4H, CH2N), 3.79 (s, OCH3), 3.85 (s, 2H, CH2Ar), 6.84 (d, 1H,
J ¼ 7.3 Hz, HAr), 6.91e6.94 (m, 2H, HAr), 7.05e7.28 (m, 8H, HAr),
7.35e7.41 (m, 2H, HAr), 7.79e7.82 (m, 1H, HAr); 13C NMR (75 MHz,
7.94e8.00 (m, 2H, HAr); 13C NMR (75 MHz, CDCl3):
d
50.9 (2 ꢃ CH2),
CDCl3):
d
49.2 (2 ꢃ CH2), 53.1 (2 ꢃ CH2), 53.7 (CH2Ar), 55.7 (OCH3),
53.4 (2 ꢃ CH2), 53.7 (CH2), 55.4 (CH3), 110.9 (CH), 111.2 (CH), 113.0
(Cq), 118.3 (CH), 119.9 (2 ꢃ CH), 121.0 (CH), 122.3 (CH), 122.8 (CH),
123.6 (CH), 125.2 (CH), 125.6 (CH), 126.7 (CH), 126.9 (CH), 128.3
(CH), 128.4 (CH), 128.7 (Cq), 129.4 (CH), 130.5 (Cq), 134.5 (Cq), 136.1
(Cq), 138.4 (Cq), 141.6 (Cq), 152.4 (Cq); IR (KBr, cmꢁ1): 3045, 2935,
2811, 1594, 1499, 1452, 1238, 1005, 742; MS (ESI): m/z 448 [MþH]þ;
Anal. calcd for C30H29N3O C4H4O4: C 72.45, H 5.90, N 7.46, found: C
72.68, H 6.11, N 7.51.
111.0 (CH), 112.3 (Cq), 112.5 (CH), 116.0 (2 ꢃ CH), 119.5 (CH), 119.69
(CH), 119.73 (CH), 120.9 (CH), 122.1 (CH), 128.0 (CH), 128.1 (Cq),
128.5 (CH), 128.6 (Cq), 128.9 (CH), 129.1 (2 ꢃ CH), 137.2 (Cq), 151.5
(Cq), 154.3 (Cq); IR (neat, cmꢁ1): 3060, 1666, 1597, 745, 691; MS
(ESI): m/z 398 [MþH]þ; Anal. calcd for C26H27N3O C4H4O4: C 70.16,
H 6.08, N 8.18, found: C 70.26, H 6.00, N 8.18; mp (fumarate): 179 ꢀC
dec. (EtOH/Et2O).
4.1.2.21. 2-{[3-(4-Phenylpiperazinyl)methyl]indol-1-yl}benzonitrile
4.1.2.17. 2-{4-[(Naphthyl-1H-indol-3-yl)methyl]piperazinyl}phenol
(3u). System solvent: CH2Cl2/MeOH 99:1; yield: 71% (139 mg); 1H
(3q). System solvent: EtOAc/PE 3:7 to 1:1; yield: 60% (130 mg);
NMR (300 MHz, CDCl3): d 2.74 (br s, 4H, CH2N), 3.22 (br s, 4H,
foam; 1H NMR (300 MHz, CDCl3):
d
2.85 (br s, 4H, CH2N), 3.01 (br s,
CH2N), 3.84 (s, 2H, CH2Ar), 6.83 (t,1H, J ¼ 7.3 Hz, HAr), 6.92e6.94 (m,
4H, CH2N), 3.99 (s, 2H, CH2Ar), 6.92 (t, 1H, J ¼ 7.7 Hz, HAr), 7.03 (d,
1H, J ¼ 7.9 Hz, HAr), 7.09e7.16 (m, 2H, HAr), 7.20e7.32 (m, 3H, HAr),
7.42 (s, 1H, HAr), 7.45e7.50 (m, 1H, HAr), 7.55e7.67 (m, 4H, HAr),
2H, HAr), 7.20e7.29 (m, 4H, HAr), 7.33e7.36 (m, 1H, HAr), 7.40 (s, 1H,
H
Ar), 7.49 (dt,1H, J ¼ 1.1, 7.5 Hz, HAr), 7.63e7.65 (m,1H, HAr), 7.75 (dt,
1H, J ¼ 1.5, 7.5 Hz, HAr), 7.85 (d, 1H, J ¼ 7.9 Hz, HAr), 7.86 (d, 1H,
7.97e8.04 (m, 3H, HAr); 13C NMR (75 MHz, CDCl3):
d
52.7 (2 ꢃ CH2),
J ¼ 7.3 Hz, HAr); 13C NMR (75 MHz, CDCl3):
d
49.2 (2 ꢃ CH2), 53.2

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C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
(2 ꢃ CH2), 53.5 (CH2Ar), 109.6 (Cq), 110.3 (CH), 115.0 (Cq), 116.0
(2 ꢃ CH), 116.6 (Cq),119.5 (CH), 120.4 (CH), 121.0 (CH), 123.1 (CH),
127.2 (CH), 127.3 (CH), 127.5 (CH), 129.1 (2 ꢃ CH), 129.3 (Cq), 133.9
(CH), 134.6 (CH), 136.7 (Cq), 141.9 (Cq), 151.4 (Cq); IR (neat, cmꢁ1):
3060, 2227, 1666, 1596, 747, 694; MS (ESI): m/z 393 [MþH]þ; Anal.
calcd for C26H24N4 C4H4O4: C 70.85, H 5.55, N 11.02, found: C 70.68,
H 5.52, N 10.79; mp (fumarate): 173e175 ꢀC dec. (EtOH/Et2O).
(CH), 124.6 (2 ꢃ CH), 125.4 (2 ꢃ CH), 127.8 (CH), 127.4 (CH), 127.9
(CH), 128.8 (2 ꢃ CH), 130.0 (Cq), 130.1 (2 ꢃ CH), 135.4 (Cq), 136.5
(Cq), 140.2 (Cq), 141.5 (Cq); IR (neat, cmꢁ1): 3046, 1636, 1594, 1498,
742, 694; MS (ESI): m/z 365 [MþH]þ; Anal. calcd for C26H24N2
C4H4O4: C 74.98, H 5.87, N 5.83, found: C 75.30, H 5.84, N 5.96; mp
(fumarate): 165e167 ꢀC dec. (EtOH).
4.1.2.26. 3-[(3,6-Dihydro-4-phenyl-1(2H)-pyridinyl)methyl]-1-(2-
4.1.2.22. 3-[(4-Phenylpiperazinyl)methyl]-1-(pyridin-2-yl)-1H-indole
methylphenyl)-1H-indole (4b). System solvent: CH2Cl2/MeOH 98:2;
(3v). System solvent EtOAc/PE 1:1 to 7:3; yield: 92% (170 mg); mp
yield: 50% (95 mg); foam; 1H NMR (300 MHz, CDCl3):
d 2.09 (s, 3H,
113e114 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
d
2.74 (br s, 4H,
CH3), 2.60 (s, 2H, CH2N), 2.85 (t, 2H, J ¼ 5.8 Hz, CH2N), 3.31 (br s, 2H,
CH2N), 3.95 (s, 2H, CH2Ar), 6.09 (s,1H, ]CH), 7.01e7.06 (m,1H, HAr),
7.15e7.41 (m, 12H, HAr), 7.80e7.84 (m, 1H, HAr); 13C NMR (75 MHz,
CH2N), 3.23 (br s, 4H, CH2N), 3.84 (s, 2H, CH2Ar), 6.84 (t, 1H,
J ¼ 7.2 Hz, HAr), 6.92 (d, 2H, J ¼ 8.1 Hz, HAr), 7.16 (dd, 1H, J ¼ 5.1,
7.0 Hz, HAr), 7.24e7.35 (m, 4H, HAr), 7.51 (d, 1H, J ¼ 8.3 Hz, HAr), 7.74
(s, 1H, HAr), 7.79e7.84 (m, 2H, HAr), 8.21 (d, 1H, J ¼ 8.3 Hz, HAr), 8.57
CDCl3):
d 17.8 (CH3), 28.2 (CH2), 50.0 (CH2), 52.9 (CH2), 53.2 (CH2),
110.6 (CH), 112.4 (Cq), 119.6 (CH), 119.7 (CH), 122.2 (2 ꢃ CH), 124.9
(2 ꢃ CH), 126.8 (CH), 126.9 (CH), 128.1 (CH), 128.2 (CH), 128.3 (CH),
128.4 (2 ꢃ CH), 128.5 (Cq), 131.2 (CH), 134.9 (Cq), 135.7 (Cq), 137.3
(Cq), 138.2 (Cq), 141.0 (Cq); IR (neat, cmꢁ1): 3052, 1660, 1598, 1498,
742, 694; MS (ESI): m/z 379 [MþH]þ; Anal. calcd for C27H26N2
C4H4O4: C 75.28, H 6.11, N 5.66, found: C 75.37, H 6.12, N 5.79; mp
(fumarate): 155e157 ꢀC dec. (EtOH).
(d, 1H, J ¼ 3.8 Hz, HAr); 13C NMR (75 MHz, CDCl3):
49.3 (2 ꢃ CH2),
d
53.2 (2 ꢃ CH2), 53.7 (CH2), 113.1 (CH), 114.4 (CH), 115.5 (Cq), 116.1
(2 ꢃ CH), 119.6 (CH), 119.9 (CH), 120.1 (CH), 121.2 (CH), 123.4 (CH),
125.3 (CH), 129.1 (2 ꢃ CH), 130.5 (Cq), 135.6 (Cq), 138.4 (CH), 149.0
(CH), 151.5 (Cq), 152.5 (Cq); IR (KBr, cmꢁ1): 3058, 2951, 1595, 1484,
1450, 1220, 1128, 1002, 744; MS (ESI): m/z 369 [MþH]þ; Anal. calcd
for C24H24N4: C 78.23, H 6.56, N 15.21, found: C 77.80, H 6.34, N
15.59.
4.1.3. General procedure for preparation of 5
N-arylations were performed under microwave heating using a
Biotage Initiator at 2.45 GHz in a seal processed vial (0.5e2.0 mL).
The specified reaction temperature was fixed by continuous power
delivery adjustment. N,N-dimethyltryptamine (0.55 mmol), aryl
iodide (1.3 equiv), Cu2O (0.3 equiv) and K2CO3 (1.5 equiv) in
anhydrous DMF (1.2 mL) were heated 120 min at 240 ꢀC under
argon. After cooling to room temperature, the reaction mixture was
filtrated on Celite eluting with EtOAc. Filtrate was then concen-
trated under vacuum and chromatographied on silica gel using the
system solvent CH2Cl2/MeOH 95:5 þ εNH4OH.
4.1.2.23. 3-{[4-(2-Methoxyphenyl)piperazinyl]methyl}-1-(pyridin-2-
yl)-1H-indole (3w). System solvent: EtOAc/PE 1:1; yield: 65%
(130 mg); mp 131e132 ꢀC (EtOAc/PE); 1H NMR (300 MHz, CDCl3):
d
2.93 (br s, 4H, CH2N), 3.19 (br s, 4H, CH2N), 3.83 (s, 3H, OCH3), 4.01
(s, 2H, CH2Ar), 6.82e7.02 (m, 4H, HAr), 7.13e7.17 (m, 1H, HAr), 7.22e
7.34 (m, 2H, HAr), 7.54 (d, 1H, J ¼ 8.3 Hz, HAr), 7.74e7.91 (m, 3H, HAr),
8.25 (d, 1H, J ¼ 8.1 Hz, HAr), 8.55 (d, 1H, J ¼ 3.6 Hz, HAr); 13C NMR
(75 MHz, CDCl3):
d
49.9 (2 ꢃ CH2), 52.8 (3 ꢃ CH2), 55.3 (CH3), 111.1
(CH), 112.9 (CH), 113.4 (CH), 114.5 (CH), 118.3 (CH), 119.5 (CH), 120.0
(CH), 120.9 (CH), 121.3 (CH), 123.4 (CH), 126.5 (CH), 130.3 (Cq), 135.4
(CH), 138.5 (CH), 140.9 (CH), 148.8 (Cq), 148.9 (Cq), 152.1 (Cq), 152.3
(Cq); IR (KBr, cmꢁ1): 3053, 2992, 1471, 1448, 1434, 1240, 1124, 747;
MS (ESI): m/z 399 [MþH]þ; Anal. calcd for C25H26N4O C4H4O4: C
67.69, H 5.88, N 10.89, found: C 67.89, H 6.10, N 10.90; mp (fuma-
rate): 140e141 ꢀC (EtOH/Et2O).
4.1.3.1. N,N-Dimethyl-1-phenyl-1H-indol-3-ethanamine (5a) (CAS:
109692-21-9). Yield: 90% (131 mg); oil; 1H NMR (300 MHz,
CDCl3):
d 2.40 (s, 6H, N(CH3)2), 2.71e2.77 (m, 2H, CH2), 3.01e3.07
(m, 2H, CH2), 7.13e7.23 (m, 3H, HAr), 7.30e7.37 (m, 1H, HAr), 7.49e
7.58 (m, 5H, HAr), 7.66 (d, 1H, J ¼ 7.4 Hz, HAr); 13C NMR (75 MHz,
CDCl3):
d
23.6 (CH2), 45.5 (2 ꢃ CH3), 60.2 (CH2), 110.5 (CH), 115.5
4.1.2.24. 3-[(4-Phenyl-1-piperazinyl)methyl]-1-(pyridin-3-yl)-1H-
(Cq), 119.1 (CH), 119.9 (CH), 122.4 (CH), 124.0 (2 ꢃ CH), 125.2 (CH),
126.0 (CH), 129.0 (Cq), 129.5 (2 ꢃ CH), 135.9 (Cq), 139.8 (Cq); IR
(neat, cmꢁ1): 3043, 1596, 1500, 737, 695; MS (ESI): m/z 265
[MþH]þ; Anal. calcd for C18H20N2 C4H4O4: C 69.46, H 6.39, N 7.36,
found: C 69.31, H 6.44, N 6.99; mp (fumarate): 120e122 ꢀC (EtOH/
Et2O).
indole (3x). System solvent: EtOAc/PE 6:4 þ 1% Et3N; yield: 70%
(129 mg); mp 85e86 ꢀC; 1H NMR (300 MHz, CDCl3):
d 2.78 (br s, 4H,
CH2N), 3.28 (br s, 4H, CH2N), 3.89 (s, 2H, CH2Ar), 6.90 (t, 1H,
J ¼ 7.2 Hz, HAr), 6.98 (d, 2H, J ¼ 8.3 Hz, HAr), 7.27e7.34 (m, 4H, HAr),
7.37 (s, 1H, HAr), 7.49 (dd, 1H, J ¼ 4.7, 8.1 Hz, HAr), 7.59 (d, 1H,
J ¼ 7.5 Hz, HAr), 7.88 (d, 1H, J ¼ 7.9 Hz, HAr), 7.93 (d, 1H, J ¼ 7.1 Hz,
H
Ar), 8.65 (d, 1H, J ¼ 3.8 Hz, HAr), 8.91 (d, 1H, J ¼ 2.3 Hz, HAr); 13C
4.1.3.2. N,N-Dimethyl-1-(2-methylphenyl)-1H-indol-3-ethanamine
NMR (75 MHz, CDCl3):
d
49.2 (2 ꢃ CH2), 53.2 (2 ꢃ CH2), 53.5 (CH2),
(5b). Yield: 92% (141 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.07 (s,
110.0 (CH), 114.8 (Cq), 116.0 (2 ꢃ CH), 119.6 (CH), 120.3 (CH), 120.7
(CH), 123.1 (CH), 124.1 (CH), 126.7 (CH), 129.1 (2 ꢃ CH), 129.5 (Cq),
131.1 (CH), 136.1 (Cq), 136.3 (Cq), 145.5 (CH), 147.4 (CH), 151.4 (Cq);
IR (KBr, cmꢁ1): 3036, 2941, 2824, 1599, 1557, 1488, 1457, 1002, 743;
MS (ESI): m/z 369 [MþH]þ; Anal. calcd for C24H24N4 C4H4O4: C
69.41, H 5.82, N 11.56, found: C 69.25, H 5.92, N 11.40; mp (fuma-
rate): 150e151 ꢀC (EtOH/Et2O).
3H, CH3), 2.40 (s, 6H, N(CH3)2), 2.73e2.76 (m, 2H, CH2), 3.02e3.07
(m, 2H, CH2), 7.00e7.03 (m, 2H, HAr), 7.14e7.19 (m, 2H, HAr), 7.27e
7.38 (m, 4H, HAr), 7.66e7.69 (m, 1H, HAr); 13C NMR (75 MHz, CDCl3):
d
17.8 (CH3), 23.8 (CH2), 45.6 (2 ꢃ CH3), 60.5 (CH2), 110.6 (CH), 114.4
(Cq), 119.0 (CH), 119.4 (CH), 122.1 (CH), 126.1 (CH), 126.8 (CH), 127.9
(Cq), 128.0 (CH), 128.1 (CH), 131.2 (CH), 135.8 (Cq), 137.3 (Cq), 138.4
(Cq); IR (neat, cmꢁ1): 3048, 2925, 1498, 1460, 738; MS (ESI): m/z
279 [MþH]þ; Anal. calcd for C19H22N2 C4H4O4: C 70.03, H 6.64, N
7.10, found: C 70.31, H 6.72, N 7.35; mp (fumarate): 110e111 ꢀC
(EtOH/Et2O).
4.1.2.25. 1-Phenyl-3-[(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)
methyl]-1H-indole (4a). System solvent: CH2Cl2/MeOH 98:2; yield:
66% (121 mg); foam; 1H NMR (300 MHz, CDCl3):
d 2.60 (s, 2H,
CH2N), 2.85 (t, 2H, J ¼ 5.7 Hz, CH2N), 3.31 (br s, 2H, CH2N), 3.93 (s,
4.1.3.3. N,N-Dimethyl-1-(2,3-dimethylphenyl)-1H-indol-3-
2H, CH2Ar), 6.10 (s, 1H, ]CH), 7.18e7.44 (m, 9H, HAr), 7.48e7.56 (m,
ethanamine (5c). Yield: 92% (148 mg); oil; 1H NMR (300 MHz,
4H, HAr), 7.59 (d, 1H, J ¼ 7.5 Hz, HAr), 7.83 (d, 1H, J ¼ 5.8 Hz, HAr); 13
C
CDCl3):
2.74e2.79 (m, 2H, CH2), 3.04e3.09 (m, 2H, CH2), 6.98e7.01 (m, 2H,
Ar), 7.12e7.24 (m, 5H, HAr), 7.65e7.69 (m, 1H, HAr); 13C NMR
d 1.92 (s, 3H, CH3), 2.37 (s, 3H, CH3), 2.42 (s, 6H, N(CH3)2),
NMR (75 MHz, CDCl3):
d 28.7 (CH2), 50.5 (CH2), 53.4 (CH2), 53.9
(CH2),111.1 (CH), 114.2 (Cq),120.4 (CH),120.7 (CH), 122.6 (CH),123.0
H

C. Sagnes et al. / European Journal of Medicinal Chemistry 75 (2014) 159e168
167
(75 MHz, CDCl3):
d
14.3 (CH3), 20.3 (CH3), 23.4 (CH2), 45.3 (2 ꢃ CH3),
For displacement studies the assay samples contained 1 nM
[3H]-8-OH-DPAT (170 Ci/mmol, PerkinElmer) for 5-HT1AR and
0.6 nM [3H]-5-CT (93.0 Ci/mmol, Hartmann Analytic GmbH) for 5-
60.5 (CH2), 110.6 (CH), 113.8 (Cq), 118.8 (CH), 119.2 (CH), 121.9 (CH),
125.6 (CH), 125.9 (CH), 126.3 (CH), 127.7 (Cq), 129.3 (CH), 134.3 (Cq),
137.4 (Cq), 138.2 (Cq), 138.3 (Cq); IR (neat, cmꢁ1): 3048, 2940, 1479,
1455, 737; MS (ESI): m/z 293 [MþH]þ; Anal. calcd for C20H24N2
C4H4O4: C 70.57, H 6.91, N 6.86, found: C 70.74, H 6.75, N 6.50; mp
(fumarate): 145e146 ꢀC (EtOH/Et2O).
HT7R. Both assays used 10
mM of 5-HT for non-specific binding
determination. Each compound was tested in triplicate at 7e8
concentrations (10ꢁ11e10ꢁ4 M). The inhibition constants (Ki) were
calculated from the ChengePrusoff equation [13]. Results were
expressed as means of at least three separate experiments.
4.1.3.4. N,N-Dimethyl-1-(naphth-1-yl)-1H-indol-3-ethanamine (5d).
Yield: 85% (147 mg); oil; 1H NMR (300 MHz, CDCl3):
d 2.50 (s, 6H,
Acknowledgements
N(CH3)2), 2.90 (br s, 2H, CH2), 3.16 (br s, 2H, CH2), 7.03 (d, 1H,
J ¼ 7.5 Hz, HAr), 7.11e7.22 (m, 3H, HAr), 7.41e7.60 (m, 5H, HAr), 7.73
(d, 1H, J ¼ 7.2 Hz, HAr), 7.94e7.98 (m, 2H, HAr); 13C NMR (75 MHz,
Financial support of the Regional Council of Rhône-Alpes and
the statutory funding from the Institute of Pharmacology, Polish
Academy of Sciences are acknowledged. C. S. thanks the Regional
Council of Rhône-Alpes for a Ph.D fellowship (Cluster de Chimie).
CDCl3):
d
23.9 (CH2), 45.6 (2 ꢃ CH3), 60.5 (CH2), 110.9 (CH), 114.9
(Cq), 119.1 (Cq), 119.7 (CH), 122.3 (CH), 123.6 (CH), 125.1 (CH), 125.6
(CH), 126.6 (CH), 126.9 (CH), 127.3 (CH), 128.2 (CH), 128.3 (2 ꢃ CH),
130.6 (Cq), 134.6 (Cq), 136.2 (Cq), 138.3 (Cq); IR (neat, cmꢁ1): 3043,
2931, 1469, 1454, 737; MS (ESI): m/z 315 [MþH]þ; Anal. calcd for
Appendix A. Supplementary data
C
22H22N2 C4H4O4: C 72.54, H 6.09, N 6.51, found: C 72.21, H 5.93, N
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.01.055.
6.28; mp (fumarate): 168e170 ꢀC (EtOH/Et2O).
4.2. Biological studies
References
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MicroBeta plate reader (Perkin Elmer), for 5-HT1AR and 5-HT7R,
respectively.

168
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