Synthesis and pharmacological evaluation of indole-based sigma receptor ligands

Article abstract of DOI:10.1016/j.ejmech.2011.08.031

A series of novel indole-based analogs were prepared and their affinities for sigma receptors were determined using in vitro radioligand binding assays. The results of this study identified several compounds with nanomolar sigma-2 affinity and significant

Full text of DOI:10.1016/j.ejmech.2011.08.031

European Journal of Medicinal Chemistry 46 (2011) 5154e5161
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological evaluation of indole-based sigma receptor ligands
Christophe Mésangeaua, Emanuele Amataa, Walid Alsharifa, Michael J. Semineriob, Matthew J. Robsonb,
,
Rae R. Matsumotob, Jacques H. Poupaertc, Christopher R. McCurdya
*
a Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA
b Department of Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26506, USA
c Université Catholique de Louvain, 74 Avenue Emmanuel Mounier, B-1200 Brussels, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel indole-based analogs were prepared and their affinities for sigma receptors were
determined using in vitro radioligand binding assays. The results of this study identified several
compounds with nanomolar sigma-2 affinity and significant selectivity over sigma-1 receptors. In
particular, 2-(4-(3-(4-fluorophenyl)indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9f)
Received 11 July 2011
Received in revised form
23 August 2011
Accepted 23 August 2011
Available online 29 August 2011
was found to display high affinity at sigma-2 receptors with good selectivity (
s
-1/
s
-2 ¼ 395). The
pharmacological binding profile for this compound was established with other relevant non-sigma sites.
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
Sigma-2 receptors
Indole
1. Introduction
also could lead to the development of new therapeutics, particu-
larly in oncology.
Sigma receptors are classified into two subtypes denoted sigma-
1 and sigma-2 [1]. The sigma-1 receptor has been purified and
cloned in several species and is well characterized at the functional
and structural level [2,3]. It is expressed in the central nervous
system and is also widely distributed in peripheral organs and
tissues such as heart and spleen [4]. The sigma-2 receptor suffers
from a lower degree of knowledge, in part because this protein has
not yet been cloned. These receptors are associated with functions
and disorders such as inflammation [5], depression [6,7], anxiety
[8], Alzheimer’s disease [9], epilepsy and drug abuse [10e12].
Cancer diagnosis and treatment is also an area of great interest in
current sigma receptor research. Indeed sigma receptor over-
expression in malignant tissues suggest that tumors may be visu-
alized by SPECT or PET imaging using radiolabeled sigma ligands
[13e16]. The sigma-2 subtype is upregulated in proliferative cells
where the density of sigma-2 receptors was found to be 10-fold
higher than in quiescent cells [17]. Additional studies have shown
that sigma ligands, especially sigma-2 agonists, can inhibit prolif-
eration and induce apoptosis in tumor cells which give sigma
ligands possible application as agents for the treatment of cancer
[18,19]. Therefore, the finding of selective sigma-2 receptor ligands
may aid in the isolation and characterization of this receptor, but
Several classes of structurally diverse compounds have been
shown to possess a high affinity for sigma receptors (for a review
see Narayanan et al. [20]). While several selective, high-affinity
sigma-1 ligands are available [21e25], potent sigma-2 receptor
selective ligands are less common. Siramesine (Lu28-179,
s
-1 ¼ 17 nM,
s
-2 ¼ 0.12 nM) and 5-bromo-N-(4-(6,7-dimethoxy-
3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide
(
s
-1 ¼ 12,900 nM,
s
-2 ¼ 8.2 nM) are two of the most highly
selective sigma-2 ligands identified to date [26,27].
In our previous work we reported the synthesis and biological
evaluation of a series of benzoazoles with high, mixed affinity for
sigma-1 and sigma-2 receptors [28]. Among the compounds
described in this early study, 3-(4-(4-cyclohexylpiperazin-1-yl)
butyl)benzo[d]thiazol-2(3H)-one (1) exhibited a subnanomolar
sigma-2 affinity and a modest preference for sigma-2 versus sigma-
1 with a selectivity ratio of 11 (Fig. 1). The goal of the present study
was to prepare novel sigma ligands with selectivity for sigma-2 and
we decided to use this compound as our lead structure.
2. Results and discussion
2.1. Chemistry
The strategy we chose involved the replacement of the benzo-
thiazole heterocycle of 1 by the more stable and versatile indole
ring (Fig. 1). Several parts of the new molecule 4a were then
* Corresponding author. Tel.: þ1 662 915 5882; fax: þ1 662 915 5638.
E-mail address: cmccurdy@olemiss.edu (C.R. McCurdy).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.08.031

C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
5155
Scheme 1. Synthesis of indole derivatives 4ae4f. Reagents and conditions: (a) 1,4-
dibromobutane, KOH, TBAI, DMF, 0 ꢀC / rt, 2 h; (b) Cyclic amine, K2CO3, DMF,
60 ꢀC, 2 h.
Fig. 1. Structures of 1 and its indole analog 4a.
indole (5) with the appropriate boronic acid under Suzuki conditions
[29]. Indoles 6ae6c underwent an easy and clean deprotection with
magnesium and ammonium chloride in methanol to give the cor-
responding derivatives 7ae7c. N-alkylation of the heterocycles with
1,4-dibromobutane gave the bromo intermediates 8ae8c which
were then reacted with A-, B- and C-ring to give 3-substituted-
indole derivatives 9ae9i.
modified to develop new indole-based sigma receptor ligands.
These modifications were made at three different positions: an
acetyl group was introduced at the 5 position of the indole ring, the
1-cyclohexylpiperazine (A-ring, Fig. 2) was replaced by other cyclic
amines (B- and C-ring) and finally different aryl groups (D-, E- and
F-rings) were introduced at the 3 position of the heterocycle.
The introduction of an acetyl group on the 5 position of the
indole was motivated by previous work in our laboratory in the
benzoazole series (data not shown) which hinted at this group
giving better sigma-2 selectivity. Similarly, we decided to replace
the piperazine group of 4a by two cyclic amines that were
described in the literature as potentially sigma-2 preferring and
gave good results selectivity-wise in the benzoazole series: 1-(4-
fluorophenyl)piperazine (B-ring) and 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (C-ring) [27]. Furthermore, the decision to
introduce an aryl group in the C-3 indole position was inspired by
the work of Perregaard who successfully converted a 3-(amino-
butyl)indole with mixed affinity for sigma receptors to the sigma-2
selective ligand siramesine by adding a 4-fluorophenyl ring in the
NH position of the indole [26]. The aryl groups we chose were the
unsubstituted phenyl group (D-ring), the metabolically more stable
4-fluorophenyl ring (E-ring), and the H-bond acceptor and phenyl-
bioisostere furan ring (F-ring).
2.2. Pharmacology
All final compounds were tested for in vitro affinity at sigma-1
and sigma-2 receptors using well-established assay conditions
[30e34]. The sigma-1 receptors were labeled with 5 nM [3H](þ)-
pentazocine and the sigma-2 receptors were labeled with 3 nM
[3H]di-o-tolylguanidine (DTG) in the presence of 300 nM
(þ)-pentazocine to block sigma-1 receptors. Non-specific binding
was determined in the presence of 10
mM haloperidol. Ten
concentrations of each sigma compound (0.1e1000 nM) were used
in the assays. The chemical structures, sigma binding affinities and
selectivity ratios of the new compounds are summarized in Table 1.
In addition, the affinity of 9f for monoamine transporters and
several serotonin and dopamine receptors was determined. A
binding profile of the compound was also prepared by NovaScreen/
Caliper Life Sciences (Hanover, MD). The results of these experi-
ments are summarized in Tables 2 and 3.
The preparation of compounds 4ae4f is outlined in Scheme 1.
Treatment of indole (2a) or 5-acetyl-indole (2b) with 1,4-
dibromobutane in the presence of potassium hydroxide in DMF
gave the bromo derivatives 3ae3b. These were then coupled with
1-cyclohexylpiperazine (A-ring, Fig. 2), 1-(4-fluorophenyl)pipera-
zine (B-ring) or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (C-
ring) in the presence of potassium carbonate in DMF to afford target
compounds 4ae4f.
As shown in Table 1, the lead compound 1 had a high affinity for
sigma-1 and sigma-2 receptors (4.17 and 0.39 nM, respectively) and
The synthesis of final compounds 9ae9i is described in Scheme 2.
Intermediates 6ae6c were prepared with excellent yields by
reaction of commercially available 3-bromo-1-(phenylsulfonyl)
Scheme 2. Synthesis of 3-substituted-indole derivatives. Reagents and conditions: (a)
Arylboronic acid, K2CO3, Pd(Pɸ3)4, benzene/EtOH, reflux, 16 h; (b) Mg, NH4Cl, MeOH/
THF, rt, 2 h; (c) 1,4-dibromobutane, KOH, TBAI, DMF, 0 ꢀC / rt, 2 h; (d) Cyclic amine,
K2CO3, DMF, 60 ꢀC, 2 h.
Fig. 2. R2- and R3-rings.

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C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
Table 1
Sigma receptor binding affinities and selectivity ratios of 1, 4ae4f, 9ae9i and haloperidol.a
Compd
R1
R2
R3
s
-1 (Ki, nM)
s-2 (Ki, nM)
s-1/s-2
1
4a
4b
4c
4d
4e
4f
9a
9b
9c
9d
9e
9f
9g
9h
9i
e
e
e
4.17 ꢁ 0.62
3.28 ꢁ 0.32
0.39 ꢁ 0.06
1.90 ꢁ 0.16
13.32 ꢁ 0.61
3.66 ꢁ 0.83
2.31 ꢁ 0.02
3.30 ꢁ 0.30
1.42 ꢁ 0.10
12.30 ꢁ 2.34
9.96 ꢁ 1.19
46.29 ꢁ 7.18
22.55 ꢁ 1.10
83.33 ꢁ 3.90
7.45 ꢁ 0.71
10.07 ꢁ 2.01
157.0 ꢁ 1.6
12.02 ꢁ 1.15
80.60 ꢁ 14.10
10.7
1.7
5.4
38.4
2.3
0.6
10.2
7.5
22.3
15.4
4.0
14.4
395.8
3.4
H
H
H
A-ring
B-ring
C-ring
A-ring
B-ring
C-ring
A-ring
B-ring
C-ring
A-ring
B-ring
C-ring
A-ring
B-ring
C-ring
H
H
H
H
H
H
D-ring
D-ring
D-ring
E-ring
E-ring
E-ring
F-ring
F-ring
F-ring
71.50 ꢁ 1.53
140.7 ꢁ 5.7
CH3CO
CH3CO
CH3CO
5.33 ꢁ 2.12
2.13 ꢁ 0.31
14.55 ꢁ 1.42
92.43 ꢁ 1.90
222.33 ꢁ 22.41
713.5 ꢁ 163.5
90.87 ꢁ 12.30
1202 ꢁ 73.89
2948.4 ꢁ 374.4
34.50 ꢁ 4.84
279.0 ꢁ 40.5
613.66 ꢁ 38.29
3.35 ꢁ 0.80
H
H
H
H
H
H
H
H
H
1.8
51.1
0.042
Haloperidol
a
Affinities (Ki in nM) were determined in rat brain homogenates. Sigma-1 receptors were labeled with [3H](þ)-pentazocine. Sigma-2 receptors were labeled with [3H]DTG
in the presence of (þ)-pentazocine to block sigma-1 receptors. Nonspecific binding was determined in the presence of haloperidol. The values in this table represent the
mean ꢁ SEM from replicate assays.
a small selectivity for sigma-2 versus sigma-1 receptors (
s
-1/
s
-
sigma-2 receptor (Ki ¼ 3.66 nM). Introduction of an acetyl group in
the C-5 position of the indole provided compounds (4de4f) with
high affinities for both sigma receptors, but no meaningful selec-
tivity. Compounds 9ae9i were subsequently prepared to examine
the influence of various aryl cycles attached in position 3 of the
indole and, as depicted in Table 1, these pharmacomodulations gave
mixed results. Generally most of the compounds displayed
decreased affinities for both sigma receptors and a small selectivity.
However 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines 9f and 9i
proved to be potent and selective sigma-2 selective ligands. In
particular, compound 9f with a 4-fluorophenyl ring in the C-3
position of its core ring presented a high affinity for the sigma-2
receptor (7.45 nM) and a weak affinity of 2948 nM for the sigma-
2 ¼ 10.7). The replacement of the benzothiazolone core by an indole
core resulted in no change in affinity for sigma-1 receptors and
a slight decrease in affinity for sigma-2. As a result, 4a does not
exhibit a preference for sigma-2 receptors, but this decrease in
selectivity is not significant, while the change of the central
template gives us access to a whole new class of potent sigma
ligands. The next step was the replacement of the piperazine
moiety with two different putative sigma-2 preferring elements
(B- and C-ring). The 1-(4-fluorophenyl)piperazine compound 4b
showed only a slight selectivity (s-1/s-2 ratio of 5) while the 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline derivative 4c exhibited
an interesting selectivity of 38 along with a high affinity for the
Table 2
Nonsigma protein binding affinities of compound 9f.a
Radioligand
Nonspecific binding
Ki (nM)
Monoamine transporters
Dopamineb
40e80 pM [125I]RTI-55
40e80 pM [125I]RTI-55
40e80 pM [125I]RTI-55
5
5
5
m
m
m
M mazindol
M imipramine
M mazindol
5000 ꢁ 1000
295 ꢁ 82
Serotoninb
Norepinephrineb
Other Receptors
1350 ꢁ 110
Dopamine D1
0.18 nM [3H]SCH-23390
0.2e0.5 nM [3H]YM-09151-2
0.2e0.5 nM [3H]YM-09151-2
0.5 nM [3H]8eOHeDPAT
0.1 nM [125I]DOI
1
1
1
1
m
m
m
m
M SCH-23390
>10000
c
d
Dopamine D2
M chlorpromazine
M chlorpromazine
M dihydroerotamine
870 ꢁ 260
d
Dopamine D3
544 ꢁ 90
e
e
Serotonin 5-HT1A
Serotonin 5-HT2A
1510 ꢁ 410
1270 ꢁ 310
10 mM 5-HT
a
Affinities (Ki in nM) were determined using standard assays conditions. The values in this table represent the mean ꢁ SEM from replicate assays. Values of >10000 nM
signify that there was less than 30% displacement of the radioligand at that concentration.
b
HEK293 cells expressing hBAT, hSERT or hNERT.
LhD1 cells.
CHOp-D2 or CHOp-D3 cells.
HEK-h5-HT1A or HEK-h5-HT2A cells.
c
d
e

C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
5157
Table 3
chromatography (TLC). Column chromatography was performed on
silica gel 60 (Sorbent Technologies). Melting points were deter-
mined on an Electrothermal 9100 apparatus and are uncorrected.
1H and 13C NMR spectra were obtained on a Bruker 500 MHz,
400 MHz, or Bruker 400 MHz Ultra Shield. The high resolution mass
spectra (HRMS) were recorded on a Waters Micromass Q-Tof
Micromass spectrometer with a lock spray source. The mass spectra
(MS) were recorded on a WATERS ACQUITY Ultra Performance LC
with ZQ detector in ESI or APCI mode. Elemental analysis (C, H, N)
were recorded on an elemental analyzer, PerkineElmer CHN/SO
Series II Analyzer. Chemical names were generated using Chem-
Draw Ultra (CambridgeSoft, version 10.0). Except where otherwise
noted, 1H and 13C NMR data for final compounds are given for
materials in their salt form.
Summary of binding profile of 9f in 64 radioligand/enzyme assays at 10ꢂ5 M and
10ꢂ7 M.a
Assay name
50% Inhibition
(10ꢂ7 M)
50% Inhibition
(10ꢂ5 M)
Adrenergic,
Adrenergic,
Adrenergic,
Cannabinoid, CB1
Cannabinoid, CB2
Dopamine D4.2
Glycine, Strychnine
Histamine, H1
Histamine, H2
a1
a2
b1
No
No
No
No
No
No
Yes
No
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Muscarinic, M1
Muscarinic, M2
Muscarinic, central
Opioid,
m
4.1.1. General procedure for the synthesis of 1-(4-bromobutyl)indole
and derivatives (3a, 3b and 8ae8c)
Calcium channel, type L (BZT)
Sodium, Site 2
Neurokinin, NK2 (NKA)
The method adopted for the synthesis of 1-(4-bromobutyl)
indole (3a) is described. Potassium hydroxide (3.83 g, 68.3 mmol)
and tetrabutylammonium iodide (0.2 g, 0.54 mmol) were added,
under mechanical stirring, to a solution of indole (2a) (2 g,
17.1 mmol) in anhydrous DMF (25 mL). The reaction mixture was
stirred at room temperature for 45 min and cooled to 0 ꢀC. 1,4-
Dibromobutane was then added and the mixture was stirred for
15 min at 0 ꢀC and for 1 h at room temperature. The mixture was
poured into 70 mL of water, extracted with methylene chloride
(3 ꢃ 50 mL), and the combined organic layers were washed with
brine and dried. The solvent was removed in vacuo, and the residue
was chromatographed on a silica gel column using a gradient of
hexanes/ethyl acetate (10:0 to 9:1) as the eluent to give 2.92 g (68%)
of 1-(4-bromobutyl)indole as a pale yellow oil. 1H NMR (400 MHz,
a
Details of each assay condition can be accessed through Caliper’s web site at
www.caliperls.com.
1 receptor, giving this indole one of the best sigma-1/sigma-2
selectivity ratios (
s
-1/s
-2 ¼ 395) described so far. Because many
ligands for sigma receptors also bind to non-sigma sites, we
decided to submit 9f to an extensive selectivity profile character-
ization. As can be seen from Table 2, compound 9f had essentially
no affinity for dopamine and norepinephrine transporters and
a low affinity for serotonin transporters. It also showed no
measurable affinity for the D1 receptor and very low affinities for
dopaminergic receptors D2 and D3 and serotoninergic receptors 5-
HT1A and 5-HT2A. The compound was then tested by NovaScreen in
64 radioligand/enzyme assays (neurotransmitter related, steroids,
ion channels, second messengers, prostaglandins, growth factors/
hormones, brain/gut peptides, enzymes) at two concentrations of
10ꢂ5 M and 10ꢂ7 M. The summary of this “profiling” is presented in
Table 3. A radioligand displacement of more than 50% was observed
in 16 assays at the concentration of 10ꢂ5 M and in only the glycine,
strychnine-sensitive assay at the concentration of 10ꢂ7 M. This
compound seems to be a reasonably clean sigma-2 selective ligand
and therefore could be of great interest as a lead for further
development or as a pharmacological tool.
CDCl3):
d
7.72 (d, J ¼ 7.8 Hz, 1H), 7.39 (d, J ¼ 8.2 Hz, 1H), 7.29 (t,
J ¼ 7.2 Hz, 1H), 7.19 (t, J ¼ 7.7 Hz, 1H), 7.12 (d, J ¼ 3.0 Hz, 1H), 6.58 (d,
J ¼ 2.9 Hz, 1H), 4.15 (t, J ¼ 6.8 Hz, 2H), 3.38 (t, J ¼ 6.5 Hz, 2H), 2.02
(quint, J ¼ 7.3 Hz, 2H), 1.86 (quint, J ¼ 7.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3):
d 127.75, 127.69, 121.63, 121.15, 119.47, 109.39,
101.43, 101.37, 45.54, 33.20, 30.06, 28.91. MS (ESI) m/z 252 [M þ H]þ
for 79Br, 254 [M þ H]þ for 81Br.
4.1.2. 1-[1-(4-Bromobutyl)indol-5-yl]-ethanone (3b)
This compound was prepared from 5-acetylindole (2b) as
described for 3a. 67% yield, white solid. mp 67e68 ꢀC 1H NMR
(400 MHz, CDCl3)
d
8.31 (s, 1H), 7.90 (d, J ¼ 8.7, 1H), 7.35 (d, J ¼ 8.7,
3. Conclusion
1H), 7.16 (d, J ¼ 3.0, 1H), 6.63 (d, J ¼ 3.1, 1H), 4.18 (t, J ¼ 5.3, 2H), 3.38
(t, J ¼ 6.4, 2H), 2.67 (s, 3H), 2.05e2.00 (m, 2H), 1.87e1.80 (m, 3H).
13C NMR (100 MHz, CDCl3)
d 198.21, 138.44, 129.59, 129.20, 128.06,
We synthesized a series of 4-(indol-1-yl)butan-1-amines and
evaluated their binding affinity for sigma receptors. Several high-
affinity sigma-2 receptor ligands with significant selectivity for
sigma-2 versus sigma-1 were identified. The best result was
obtained with the ligand bearing a 4-fluorophenyl ring in the C-3
123.39, 121.89, 109.13, 103.41, 45.72, 32.79, 29.84, 28.83, 26.61. MS
(ESI) m/z 316 [M þ Na]þ for 79Br, 318 [M þ Na]þ for 81Br.
4.1.3. General procedure for the synthesis of 1-(4-(4-
position of its indole core and
a
6,7-dimethoxy-1,2,3,4-
cyclohexylpiperazin-1-yl)butyl)indole and other final products
(4ae4f, 9ae9i)
tetrahydroisoquinoline as the distal cyclic amine. This compound,
which displayed a high affinity for the sigma-2 receptor (7.45 nM)
and a weak affinity for the sigma-1 receptor (2948 nM), was also
submitted to an extensive selectivity profile characterization and
only exhibited moderate affinity for the glycine, strychnine-
sensitive assay at the 10ꢂ7 M concentration.
The method adopted for the synthesis of 1-(4-(4-cyclohexyl-
piperazin-1-yl)butyl)indole dioxalate (4a) is described. K2CO3
(0.2 g, 1.43 mmol) and 1-cyclohexylpiperazine (0.081 g, 0.47 mmol)
were added, under mechanical stirring, to a solution of 3a (0.12 g,
0.47 mmol) in anhydrous DMF (4 mL). The reaction mixture was
heated at 60 ꢀC for 2 h. After cooling, the mixture was poured into
20 mL of water, extracted with ethyl acetate (3 ꢃ 30 mL), and the
combined organic layers were washed with saturated aqueous NaCl
and dried. The solvent was removed in vacuo, and the residue was
chromatographed on a silica gel column using methylene chloride/
methanol (97:3) as the eluent. 1-(4-(4-Cyclohexylpiperazin-1-yl)
butyl)indole was isolated as a dioxalate salt (white solid, 0.073 g,
4. Experimental protocols
4.1. Chemistry
Reagents and starting materials were obtained from commercial
suppliers and were used without purification. Precoated silica gel
GF Uniplates from Analtech were used for thin-layer
30%). mp 230e233 ꢀC 1H NMR (400 MHz, DMSO-d6, 60 ꢀC):
d 7.55

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C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
(br s, 4H), 7.53 (d, J ¼ 7.9 Hz, 1H), 7.45 (d, J ¼ 8.2 Hz, 1H), 7.33 (d,
J ¼ 3.0 Hz, 1H), 7.12 (t, J ¼ 7.4 Hz, 1H), 7.00 (t, J ¼ 7.4 Hz, 1H), 6.42 (d,
J ¼ 2.8 Hz, 1H), 4.18 (t, J ¼ 6.9 Hz, 2H), 3.00 (s, 4H), 2.83e2.77 (m,
5H), 2.57 (t, J ¼ 7.3 Hz, 2H), 1.95e1.93 (m, 2H), 1.83e1.78 (m, 4H),
1.61e1.58 (m, 1H), 1.52e1.47 (m, 2H), 1.35e1.19 (m, 4H), 1.13e1.07
(s, 4H), 2.26 (t, J ¼ 7.1 Hz, 2H), 1.87e1.64 (m, 2H), 1.39 (d, J ¼ 7.0 Hz,
2H). 13C NMR (free amine, 100 MHz, DMSO-d6)
197.82, 156.39
d
(J ¼ 234.0 Hz), 148.37, 138.57, 130.92, 129.29, 128.01, 123.30, 121.38,
117.41 (d, J ¼ 7.6 Hz), 115.64 (d, J ¼ 21.8 Hz), 110.22, 102.98, 57.46,
53.05, 49.40, 46.03, 40.42, 40.21, 40.00, 39.59, 28.13, 27.02, 23.84.
Anal. calcd for C28H32FN3O9$5/4H2O: C, 56.42; H, 5.79; N, 7.10.
Found: C, 56.41; H, 5.83; N, 7.05. HRMS (TOF ESþ) calcd for
C24H29N3OF [M þ H]þ 394.2295, found 394.2290.
(m, 1H). 13C NMR (100 MHz, DMSO-d6, 60 ꢀC):
d 162.58, 135.49,
128.16, 127.95, 120.64, 120.14, 118.54, 109.42, 100.22, 63.20, 55.54,
49.78, 46.85, 44.91, 27.00, 26.65, 24.2, 24.38, 22.23. Anal. calcd for
C26H37N3O8: C, 60.10; H, 7.18; N, 8.09. Found: C, 60.58; H, 6.80; N,
8.09. HRMS (TOF ESþ) calcd for C22H34N3 [M þ H]þ 340.2753, found
340.2759.
4.1.8. 1-{1-[4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-
butyl]indol-5-yl}-ethanone oxalate (4f)
This compound was prepared from 3b and 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline as described for 4a. 41% yield, white
4.1.4. 1-(4-(4-(4-Fluorophenyl)piperazin-1-yl)butyl)indole
oxalate (4b)
solid. mp 170e171 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
d 8.29
This compound was prepared from 3a and 1-(4-fluorophenyl)
piperazine as described for 4a. 25% yield, white solid. mp
(s, 1H), 7.86 (d, J ¼ 8.7 Hz, 1H), 7.35 (d, J ¼ 8.7 Hz, 1H), 7.17 (s, 1H),
6.59 (d, J ¼ 10.8 Hz, 2H), 6.48 (s, 1H), 4.19e4.15 (m, 3H), 3.82e3.81
(m, 6H), 3.48 (s, 2H), 2.79e2.76 (m, 2H), 2.64 (s, 3H), 2.50e2.47 (m,
2H), 1.94e1.90 (m, 2H), 1.61e1.59 (m, 3H), 1.28e1.25 (m, 2H). 13C
160e162 ꢀC 1H NMR (400 MHz, DMSO-d6):
d
7.54 (d, J ¼ 7.8 Hz, 1H),
7.48 (d, J ¼ 8.1 Hz, 1H), 7.13e6.98 (m, 6H), 6.42 (s, 1H), 4.21e4.18 (m,
2H), 3.27e2.95 (m, 10H), 1.78e1.63 (m, 4H). 13C NMR (100 MHz,
NMR (free amine, 100 MHz, CDCl3)
d 198.20, 162.50, 147.42, 138.47,
DMSO-d6):
d
164.38, 156.47 (J ¼ 236.0 Hz), 146.73, 135.58, 128.59,
129.40, 128.00, 126.00, 123.28, 121.66, 111.37, 109.47, 109.26, 103.07,
57.26, 55.90, 55.44, 50.79, 46.40, 36.42, 31.37, 28.09, 26.56, 24.28.
Anal. calcd for C27H32N2O7$H2O: C, 63.02; H, 6.66; N, 5.44. Found: C,
63.26; H, 6.15; N, 5.46. HRMS (TOF ESþ) calcd for C25H31N2O3
[M þ H]þ 407.2335, found 407.2343.
128.15, 118.91, 117.67 (J ¼ 7.1 Hz), 115.43 (J ¼ 22.0 Hz), 109.75,
100.54, 55.29, 50.97, 46.67, 44.94, 27.09, 21.16. Anal. calcd for
C24H28FN3O4$¼H2O: C, 64.63; H, 6.44; N, 9.42. Found: C, 64.60; H,
6.05; N, 9.32. HRMS (TOF ESþ) calcd for C22H27N3F [M þ H]þ
352.2189, found 352.2206.
4.1.9. General procedure for the synthesis of 3-aryl-1-
4.1.5. 2-(4-(Indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline oxalate (4c)
(phenylsulfonyl)indoles 6ae6c
The method adopted for the synthesis of 3-phenyl-1-(phenyl-
sulfonyl)indole (6a) is described. To a solution of phenylboronic
acid (0.49 g, 4.1 mmol) in benzene (21 mL) and ethanol (10 mL)
were added potassium carbonate (0.680 g, 4.4 mmol) and 3-bromo-
1-(phenylsulfonyl)indole (5) (1.2 g, 3.4 mmol). The reaction mixture
was stirred at room temperature and deoxygenated by passing
through it a steam of argon for 15 min. Palladium triphenylphos-
phine tetrakis (0.039 mg, 0.034 mmol) was added and the solution
was refluxed for 16 h. After cooling, the mixture was poured into
25 mL of water, extracted with ethyl acetate (3 ꢃ 30 mL), washed
with saturated aqueous NaCl and dried. The solvent was removed in
vacuo, and the residue was chromatographed on a silica gel column
using hexane/ethyl acetate (9:1) to give 0.955 g (84%) of 3-phenyl-
1-(phenylsulfonyl)indole as a white solid. mp 144e146 ꢀC 1H NMR
This compound was prepared from 3a and 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline as described for 4a. 51% yield, white
solid. mp 186e187 ꢀC 1H NMR (400 MHz, DMSO-d6):
d 11.57 (br s,
2H), 7.55 (d, J ¼ 7.8 Hz, 1H), 7.49 (d, J ¼ 8.2 Hz, 1H), 7.38 (d,
J ¼ 3.0 Hz, 1H), 7.13 (t, J ¼ 7.3 Hz, 1H), 7.02 (t, J ¼ 7.4 Hz, 1H), 6.76 (s,
1H), 6.73 (s, 1H), 6.43 (d, J ¼ 2.8 Hz, 1H), 4.20 (t, J ¼ 6.6 Hz, 2H), 4.13
(s, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.31e3.29 (m, 2H), 3.10e3.06 (m,
2H), 2.93e2.91 (m, 2H), 1.83e1.71 (m, 4H). 13C NMR (100 MHz,
DMSO-d6):
d 164.62, 148.16, 147.57, 135.57, 128.60, 128.15, 123.55,
120.99, 120.66, 120.44, 118.91, 111.49, 109.77, 109.76, 100.53, 55.55,
55.48, 54.48, 51.61, 48.83, 44.93, 27.03, 24.65, 21.21. HRMS (TOF
ESþ) calcd for C23H29N2O2 [M þ H]þ 365.2229, found 365.2242.
4.1.6. 1-{1-[4-(4-Cyclohexyl-piperazin-1-yl)-butyl]indol-5-yl}-
ethanone dioxalate (4d)
(400 MHz, CDCl3)
7.81 (d, J ¼ 7.9 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J ¼ 7.4 Hz, 2H), 7.57e7.27
(m, 8H). 13C NMR (100 MHz, DMSO-d6)
137.07, 135.34, 134.00,
d
8.10 (d, J ¼ 8.2 Hz, 1H), 7.95 (d, J ¼ 7.3 Hz, 2H),
This compound was prepared from 3b and 1-cyclohexyl-
piperazine as described for 4a. 31% yield, white solid. mp
d
130.37, 129.52, 127.30, 126.59, 126.08, 124.79, 120.13, 113.85, 99.44.
224e227 ꢀC 1H NMR (free amine, 400 MHz, CDCl3):
d
8.16 (d,
MS (APCI) m/z 334.9 [M þ H]þ.
J ¼ 7.3 Hz, 1H), 7.74 (t, J ¼ 8.1 Hz, 1H), 7.23 (t, J ¼ 8.5 Hz, 1H),
7.06e7.03 (m, 1H), 6.48e6.45 (m, 1H), 4.04e3.99 (m, 2H), 2.63 (s,
4H), 2.53e2.51 (m, 3H), 2.45 (s, 4H), 2.45 (s, 1H), 2.26e2.21 (m, 2H),
1.85 (s, 2H), 1.73e1.70 (m, 4H), 1.52 (d, J ¼ 10.0 Hz, 1H), 1.37e1.35
(m, 2H), 1.14e1.13 (m, 4H), 1.03e0.99 (s, 1H). 13C NMR (100 MHz,
4.1.10. 3-(4-Fluorophenyl)-1-(phenylsulfonyl)indole (6b)
This compound was prepared from 3-bromo-1-(phenylsulfonyl)
indole (5) and 4-fluorophenylboronic acid as described for 6a. 91%
yield, white solid. 1H NMR (400 MHz, CDCl3):
d
8.07 (d, J ¼ 8.3 Hz,
free amine, CDCl3)
d
198.09, 138.33, 129.46, 129.27, 127.94, 123.23,
1H), 7.92 (d, J ¼ 7.5 Hz, 2H), 7.70 (d, J ¼ 7.9 Hz, 1H), 7.65 (s, 1H),
7.55e7.50 (m, 3H), 7.43 (t, J ¼ 7.9 Hz, 2H), 7.36 (t, J ¼ 7.4 Hz, 1H), 7.28
(t, J ¼ 7.4 Hz, 1H), 7.14 (t, J ¼ 8.6 Hz, 2H), 13C NMR (100 MHz, CDCl3):
121.53, 109.25, 103.00, 64.08, 57.19, 51.83, 48.37, 46.29, 27.96, 27.79,
26.56, 25.69, 25.43, 23.74. Anal. calcd for C28H39N3O9: C, 59.88; H,
7.00; N, 7.48. Found: C, 59.54; H, 6.83; N, 7.60. HRMS (TOF ESþ)
calcd for C24H36N3O [M þ H]þ 382.2858, found 382.2875.
d
162.56 (d, J ¼ 245.5 Hz), 138.38, 135.67, 134.11, 129.73 (d,
J ¼ 7.9 Hz), 129.54, 129.45, 129.20 (d, J ¼ 3.3 Hz), 127.03, 125.29,
123.92, 123.40, 122.99, 120.43, 116.09 (d, J ¼ 21.4 Hz), 114.07. MS (EI)
m/z 374 [M þ Na]þ.
4.1.7. 1-(1-{4-[4-(4-Fluorophenyl)-piperazin-1-yl]-butyl}indol-5-
yl)-ethanone dioxalate (4e)
This compound was prepared from 3b and 1-(4-fluorophenyl)
piperazine as described for 4a. 37% yield, white solid. mp
4.1.11. 3-(Furan-3-yl)-1-(phenylsulfonyl)-1H-indole (6c)
This compound was prepared from 3-bromo-1-(phenylsulfonyl)
indole (5) and furan-3-boronic acid as described for 6a. 97% yield,
140e142 ꢀC 1H NMR (free amine, 400 MHz, DMSO-d6)
d 8.28 (s, 1H),
7.76 (d, J ¼ 8.7 Hz,1H), 7.56 (d, J ¼ 8.7 Hz,1H), 7.49 (d, J ¼ 3.0 Hz,1H),
7.00 (t, J ¼ 8.9 Hz, 2H), 6.87 (dd, J ¼ 8.3, 5.4 Hz, 2H), 6.61 (d,
J ¼ 2.5 Hz, 1H), 4.21 (t, J ¼ 6.9 Hz, 2H), 2.98 (s, 4H), 2.58 (s, 3H), 2.39
yellow solid. mp 88e91 ꢀC 1H NMR (400 MHz, CDCl3)
d 8.08 (d,
J ¼ 8.3 Hz, 1H), 8.03e7.88 (m, 2H), 7.83 (s, 1H), 7.78e7.63 (m, 2H),
7.56e7.49 (m, 2H), 7.47e7.35 (m, 3H), 7.33e7.27 (m, 1H), 6.71

C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
5159
(s, 1H). 13C NMR (100 MHz, CDCl3)
d
143.45, 139.07, 138.10, 135.46,
(t, J ¼ 6.5 Hz, 2H), 2.06e2.00 (m, 2H), 1.91e1.78 (m, 3H). 13C NMR
133.90, 129.32, 129.14, 126.79, 125.13, 123.70, 122.44, 120.48, 117.67,
(100 MHz, CDCl3) d 142.96, 137.49, 136.62, 126.30, 124.88, 122.11,
115.41, 113.85, 109.66. MS (APCI) m/z 323.9 [M]þ.
120.13, 119.85, 119.62, 109.79, 109.59, 107.87, 45.47, 33.03, 29.96,
28.84. MS (APCI) m/z 327 [M]þ for 79Br, 329 [M]þ for 81Br.
4.1.12. General procedure for the synthesis of 3-arylindoles 7ae7c
The method adopted for the synthesis of 3-phenylindole (7a) is
described. Mg (2.12 g, 875 mmol) and ammonium chloride (0.04 g,
0.8 mmol) were added to a stirred solution of 6a (0.85 g, 2.5 mmol)
in methanol (80 mL) and THF (20 mL). The exothermic mixture was
stirred for 2 h at room temperature and was concentrated under
reduced pressure. A saturated solution of ammonium chloride
(30 mL) was then added and the mixture was extracted with ethyl
acetate (3 ꢃ 100 mL). The organic layer was washed with water and
brine, dried and evaporated. The residue was chromatographed on
a silica gel column using hexane/ethyl acetate (8:2) to give 0.28 g
(60%) of 3-phenyl-1H-indole as a white solid. 1H NMR (400 MHz,
4.1.18. 1-[4-(4-Cyclohexyl-piperazin-1-yl)-butyl]-3-phenylindole
dioxalate (9a)
This compound was prepared from 8a and 1-cyclo-
hexylpiperazine as described for 4a. 21% yield, white solid. mp
242e244 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
d 7.96 (d,
J ¼ 8.0 Hz,1H), 7.67 (d, J ¼ 7.3 Hz, 2H), 7.45 (t, J ¼ 7.7 Hz, 2H), 7.39 (d,
J ¼ 8.2 Hz, 1H), 7.32e7.23 (m, 3H), 7.19 (t, J ¼ 7.4 Hz, 1H), 4.18 (t,
J ¼ 7.0 Hz, 2H), 2.70 (s, 4H), 2.55 (s, 4H), 2.47e2.30 (m, 2H),
2.03e1.86 (m, 4H), 1.81 (s, 2H), 1.75e1.63 (m, 1H), 1.60e1.55 (m,
2H), 1.37e1.17 (m, 5H), 1.12 (s, 1H). 13C NMR (free amine, 100 MHz,
CDCl3)
d 136.74, 135.66, 128.76, 127.29, 126.26, 125.71, 125.51,
CDCl3)
d
8.14 (d, J ¼ 7.4 Hz, 1H), 7.96 (s, 1H), 7.83 (d, J ¼ 7.1 Hz, 2H),
121.86, 120.04, 119.86, 116.74, 109.73, 63.99, 57.62, 52.52, 48.60,
46.26, 28.35, 28.01, 25.97, 25.66, 24.13. HRMS (TOF ESþ) calcd for
C28H38N3 [M þ H]þ 416.3066, found 416.3081.
7.61 (t, J ¼ 7.7 Hz, 2H), 7.55e7.34 (m, 3H), 7.31 (d, J ¼ 2.5 Hz, 1H). 13C
NMR (100 MHz, CDCl3)
d 136.77, 135.74, 129.02, 127.62, 126.19,
125.80, 122.55, 122.12, 120.51, 119.94, 118.20, 111.69. MS (APCI) m/z
193.1 [M]þ.
4.1.19. 1-{4-[4-(4-Fluorophenyl)-piperazin-1-yl]-butyl}-3-
phenylindole oxalate (9b)
4.1.13. 3-(4-Fluorophenyl)indole (7b)
This compound was prepared from 8a and 1-(4-fluorophenyl)
piperazine as described for 4a. 28% yield, white solid. mp
This compound was prepared from 6b as described for 7a. 80%
yield, white solid. mp 105e107 ꢀC 1H NMR (400 MHz, DMSO-d6):
195e197 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
d 8.00 (d,
d
11.40 (s, 1H), 7.85 (d, J ¼ 7.6 Hz, 1H), 7.73e7.67 (m, 3H), 7.51 (d,
J ¼ 7.9 Hz, 1H), 7.71 (d, J ¼ 7.5 Hz, 2H), 7.55e7.38 (m, 3H), 7.31 (d,
J ¼ 5.6 Hz, 3H), 7.23 (d, J ¼ 7.4 Hz,1H), 6.98 (t, J ¼ 8.5 Hz, 2H), 6.88 (s,
2H), 4.21 (t, J ¼ 6.9 Hz, 2H), 3.12 (s, 4H), 2.58 (s, 4H), 2.52e2.36 (m,
2H), 1.97 (m, 2H), 1.62 (m, 2H). 13C NMR (free amine, 100 MHz,
J ¼ 8.0 Hz, 1H), 7.25 (t, J ¼ 8.8 Hz, 2H), 7.19 (t, J ¼ 7.2 Hz, 2H), 7.12 (t,
J ¼ 7.2 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
d 161.47, 159.07,
136.78, 132.21, 128.09, 128.01, 124.84, 123.22, 121.37, 119.54, 118.70,
115.47, 115.26, 114.67, 111.88. MS (ESI) m/z 210 [M ꢂ H]þ.
CDCl3) d 158.39, 156.02, 147.94, 136.82, 135.71, 128.78, 127.33,
126.33, 125.62 (d, J ¼ 23.6 Hz), 121.99, 120.00 (d, J ¼ 17.7 Hz), 117.83
(d, J ¼ 7.6 Hz), 115.50 (d, J ¼ 22.0 Hz), 109.73, 77.40, 77.08, 76.76,
57.82, 53.16, 50.03, 46.29, 28.07, 24.18. Anal. calcd for
C30H32FN3O4$1/3 H2O: C, 68.82; H, 6.29; N, 8.03. Found: C, 68.95; H,
6.03; N, 8.01. HRMS (TOF ESþ) calcd for C28H31N3F [M þ H]þ
428.2502, found 428.2516.
4.1.14. 3-(Furan-3-yl)indole (7c)
This compound was prepared from 6c as described for 7a. 89%
yield, yellow solid. 1H NMR (400 MHz, CDCl3)
d
8.06 (s, 1H),
7.98e7.81 (m, 2H), 7.60 (s, 1H), 7.40 (d, J ¼ 7.7 Hz, 1H), 7.37e7.21 (m,
2H), 6.78 (s, 1H). 13C NMR (100 MHz, CDCl3)
143.06, 137.74, 136.57,
d
125.74, 122.55, 121.57, 120.30, 119.88, 119.72, 111.52, 109.92, 109.06.
MS (APCI) m/z 184.0 [M]þ.
4.1.20. 6,7-Dimethoxy-2-(4-(3-phenylindol-1-yl)butyl)-1,2,3,4-
tetrahydroisoquinoline oxalate (9c)
4.1.15. 1-(4-Bromobutyl)-3-phenylindole (8a)
This compound was prepared from 8a and 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline as described for 4a. 30% yield, white
solid. mp 189e190 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
This compound was prepared from 3-phenylindole (7a) as
described for 3a. 77% yield, colorless oil. 1H NMR (400 MHz, CDCl3)
d
8.05e8.03 (m, 1H), 7.74 (d, J ¼ 7.0 Hz, 2H), 7.52 (t, J ¼ 7.7 Hz, 2H),
d
7.98e7.96 (m, 2H), 7.68 (d, J ¼ 7.2 Hz, 2H), 7.53e7.36 (m, 3H), 7.31
7.43 (d, J ¼ 8.2 Hz, 1H), 7.40e7.22 (m, 4H), 4.32e4.11 (m, 2H),
(s, 1H), 7.29e7.24 (m, 2H), 7.19 (t, J ¼ 7.3 Hz, 1H), 6.59 (s, 1H), 6.49 (s,
1H), 4.22e4.19 (m, 2H), 3.83 (m, 6H), 3.51 (s, 2H), 2.81e2.79 (m,
2H), 2.70e2.68 (m, 2H), 2.53e2.50 (m, 2H), 1.97e1.95 (m, 2H),
3.48e3.33 (m, 2H), 2.18e2.00 (m, 2H), 1.95e1.88 (m, 2H). 13C NMR
(100 MHz, CDCl3)
d 136.80, 135.62, 128.85, 127.40, 126.38, 125.88,
125.39, 122.11, 120.18, 120.08, 117.09, 109.68, 45.57, 33.05, 30.0,
1.66e1.64 (m, 2H). 13C NMR (free amine, 100 MHz, CDCl3)
d 162.56,
28.85. MS (APCI) m/z 327 [M]þ for 79Br, 329 [M]þ for 81Br.
147.59, 147.28, 136.83, 136.83, 135.73, 135.73, 128.74, 127.28, 126.32
(d, J ¼ 6.9 Hz), 126.09, 125.67, 125.56, 121.86, 119.93 (d, J ¼ 14.3 Hz),
116.71, 111.46, 109.68 (d, J ¼ 19.9 Hz), 57.51, 55.93, 55.57, 50.94,
46.27, 36.42, 28.48, 28.10, 24.49. Anal. calcd for C31H34N2O6$½H2O:
C, 69.00; H, 6.54; N, 5.19. Found: C, 68.60; H, 6.11; N, 5.12. HRMS
(TOF ESþ) calcd for C29H33N2O2 [M þ H]þ 441.2542, found 441.2521.
4.1.16. 1-(4-Bromobutyl)-3-(4-fluorophenyl)indole (8b)
This compound was prepared from 7b as described for 3a. 83%
yield, colorless oil. 1H NMR (400 MHz, CDCl3):
d
7.86 (d, J ¼ 7.9 Hz,
1H), 7.60e7.56 (m, 2H), 7.37 (d, J ¼ 8.2 Hz, 1H), 7.26 (t, J ¼ 7.7 Hz,
1H), 7.20e7.16 (m, 2H), 7.12 (t, J ¼ 8.7 Hz, 2H), 4.18 (t, J ¼ 6.8 Hz, 2H),
3.38 (t, J ¼ 6.5 Hz, 2H), 2.08e2.01 (m, 2H), 1.92e1.85 (m, 2H). 13C
4.1.21. 1-(4-(4-Cyclohexylpiperazin-1-yl)butyl)-3-(4-fluorophenyl)
indole dioxalate (9d)
NMR (100 MHz, CDCl3):
d
161.60 (d, J ¼ 243.0 Hz), 136.87, 131.75 (d,
J ¼ 3.3 Hz), 128.99 (d, J ¼ 7.6 Hz), 126.50, 125.28, 122.35, 120.27,
120.03, 116.41, 115.79 (d, J ¼ 21.1 Hz), 109.82, 45.77, 33.08, 30.19,
29.03. MS (ESI) m/z 346 [M þ H]þ for 79Br, 348 [M þ H]þ for 81Br.
This compound was prepared from 8b and 1-cyclo-
hexylpiperazine as described for 4a. 28% yield, white solid. mp
248e249 ꢀC 1H NMR (400 MHz, DMSO-d6):
d 10.98 (br s, 4H), 7.81
(d, J ¼ 7.6 Hz, 1H), 7.70e7.65 (m, 3H), 7.53 (d, J ¼ 7.8 Hz, 1H),
7.26e7.09 (m, 4H), 4.20 (s, 2H), 2.98e2.47 (m, 11H), 1.88e1.75 (m,
6H), 1.56e1.47 (m, 3H), 1.23e1.04 (m, 5H). 13C NMR (125 MHz,
4.1.17. 1-(4-Bromobutyl)-3-furan-3-ylindole (8c)
This compound was prepared from 7c as described for 3a. 75%
yield, yellow oil. 1H NMR (400 MHz, CDCl3)
d
7.89e7.76 (m, 2H), 7.54
DMSO-d6):
d
164.73, 163.36, (d, J ¼ 241.0 Hz), 136.53, 131.91, 128.18
(t, J ¼ 1.6 Hz, 1H), 7.37 (d, J ¼ 8.1 Hz, 1H), 7.34e7.26 (m, 1H),
(d, J ¼ 7.6 Hz), 126.72, 125.28, 121.61, 119.86, 119.18, 115.64 (d,
7.25e7.15 (m, 2H), 6.80e6.64 (m, 1H), 4.15e4.09 (m, 2H), 3.45
J ¼ 20.8 Hz), 114.01, 110.44, 63.11, 56.27, 51.13, 47.54, 45.33, 27.33,

5160
C. Mésangeau et al. / European Journal of Medicinal Chemistry 46 (2011) 5154e5161
26.32, 25.30, 24.89, 22.86. Anal. calcd for C32H40FN3O8: C, 62.63; H,
6.57; N, 6.85. Found: C, 62.48; H, 6.25; N, 6.76. HRMS (TOF ESþ)
calcd for C28H37N3F [M þ H]þ 434.2972, found 434.2987.
J ¼ 2.2 Hz), 142.94, 137.45, 136.64, 126.29, 125.06, 121.96, 119.92 (d,
J ¼ 36.5 Hz), 117.78 (d, J ¼ 7.6 Hz), 115.62, 115.40, 109.81, 109.70,
107.62, 57.90, 53.22, 50.11, 46.26, 28.14, 24.28. Anal. calcd for
C30H32FN3O9$½H2O: C, 59.40; H, 5.48; N, 6.93. Found: C, 59.47; H,
5.15; N, 6.92. HRMS (TOF ESþ) calcd for C26H29N3OF [M þ H]þ
418.2295, found 418.2298.
4.1.22. 3-(4-Fluorophenyl)-1-(4-(4-(4-fluorophenyl)piperazin-1-yl)
butyl)indole oxalate (9e)
This compound was prepared from 8b and 1-(4-fluorophenyl)
piperazine as described for 4a. 54% yield, white solid. mp
4.1.26. 2-(4-(3-(Furan-3-yl)indol-1-yl)butyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline oxalate (9i)
214e216 ꢀC 1H NMR (500 MHz, DMSO-d6):
d 11.40 (br s, 2H), 7.84 (d,
J ¼ 7.9 Hz, 1H), 7.76 (s, 1H), 7.70e7.67 (m, 2H), 7.58 (d, J ¼ 8.2 Hz,
1H), 7.26 (t, J ¼ 8.6 Hz, 2H), 7.22 (t, J ¼ 7.6 Hz, 1H), 7.13 (t, J ¼ 7.5 Hz,
1H), 7.07 (t, J ¼ 8.7 Hz, 2H), 6.99e6.96 (m, 2H), 4.25 (t, J ¼ 6.7 Hz,
2H), 3.26 (br s, 4H), 3.10 (br s, 4H), 2.97 (br s, 2H), 1.85e1.83 (m, 2H),
This compound was prepared from 8c and 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline as described for 4a. 42% yield, white
solid. mp 156 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
d 7.90e7.78
(m, 2H), 7.52 (s, 1H), 7.40 (d, J ¼ 8.1 Hz, 1H), 7.30e7.24 (m, 2H), 7.21
(t, J ¼ 7.4 Hz, 1H), 6.72 (s, 1H), 6.61 (s, 1H), 6.51 (s, 1H), 4.18 (t,
J ¼ 6.9 Hz, 3H), 3.86e6.84 (m, 6H), 3.52 (s, 2H), 2.84e2.80 (m, 2H),
2.69 (t, J ¼ 5.7 Hz, 2H), 2.52 (t, J ¼ 7.2 Hz, 2H), 2.05e1.84 (m, 2H),
1.66 (br s, 2H). 13C NMR (125, MHz, DMSO-d6):
d 164.05, 160.38 (d,
J ¼ 240.4 Hz), 156.43 (d, J ¼ 235.1 Hz), 146.76, 136.44, 131.86 (d,
J ¼ 3.0 Hz), 128.18 (d, J ¼ 7.7 Hz), 126.70, 125.29, 121.63, 119.88,
119.16, 117.62 (d, J ¼ 7.7 Hz), 115.61 (d, J ¼ 21.0 Hz), 115.43 (d,
J ¼ 21.8 Hz), 114.08, 110.37, 55.31, 51.01, 46.72, 45.07, 27.04, 21.29.
Anal. calcd for C30H31F2N3O4: C, 67.28; H, 5.83; N, 7.85. Found: C,
67.08; H, 5.80; N, 7.73. HRMS (TOF ESþ) calcd for C28H30N3F2
[M þ H]þ 446.2408, found 446.2391.
1.72e1.60 (m, 2H). 13C NMR (free amine, 100 MHz, CDCl3)
d 147.56,
147.24, 142.89, 137.40, 136.68, 126.48, 126.27, 126.14, 125.10, 121.93,
120.05, 119.76, 119.70, 111.39, 109.80, 109.75, 109.51, 107.55, 57.65,
55.94, 55.91, 55.72, 51.06, 46.23, 28.64, 28.14, 24.58. HRMS (TOF
ESþ) calcd for C27H31N2O3 [M þ H]þ 431.2335, found 431.2356.
4.1.23. 2-(4-(3-(4-Fluorophenyl)indol-1-yl)butyl)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline oxalate (9f)
4.2. Pharmacology
This compound was prepared from 8b and 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline as described for 4a. 53% yield, white
In vitro competition binding assays were performed as follows.
Preparation of rat brain membrane and binding assays for the s1 and
s2 receptor were performed using methods published previously in
detail [30e34]. In brief, homogenates of whole rat brain excluding
solid. mp 182e184 ꢀC 1H NMR (500 MHz, DMSO-d6):
d 10.52 (br s,
2H), 7.84 (d, J ¼ 8.0 Hz, 1H), 7.75 (s, 1H), 7.70e7.67 (m, 2H), 7.58 (d,
J ¼ 8.2 Hz, 1H), 7.26 (t, J ¼ 8.8 Hz, 2H), 7.22 (t, J ¼ 7.6 Hz, 1H), 7.13 (t,
J ¼ 7.4 Hz, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 4.26 (t, J ¼ 6.8 Hz, 2H), 4.15
(br s, 2H), 3.72 (s, 3H), 3.70 (s, 3H), 3.32 (br s, 2H), 3.13e3.09 (m,
2H), 2.92 (br s, 2H), 1.90e1.85 (m, 2H), 1.75 (br s, 2H). 13C NMR
the cerebellum (400e500 mg) were taken in test tubes and incubated
with 5 nM [3H](þ)-pentazocine to label
s
-1 receptors, or 3 nM [3H]-
-2
DTG in the presence of 300 nM (þ)-pentazocine to label
s
receptors. Non-specific binding was determined in the presence of
(125 MHz, DMSO-d6):
d
164.34, 160.39 (d, J ¼ 240.4 Hz), 148.15,
10 mM haloperidol. Ten concentrations of each sigma compound
ranging from 0.1 to 1000 nM were incubated for 120 min at 25 ꢀC in
50 mM TriseHCl, pH 8.0 to measure their ability to displace the
radioligands from their binding sites. The total reaction volume was
147.55, 136.45, 131.85, 128.20 (d, J ¼ 7.7 Hz), 126.69, 125.32, 123.50,
121.64, 120.61, 119.90, 119.17, 115.61 (d, J ¼ 21.0 Hz), 114.11, 111.46,
110.40, 109.67, 55.53, 55.48, 54.51, 51.70, 48.90, 45.05, 26.92, 24.68,
21.29. HRMS (TOF ESþ) calcd for C29H32N2O2F [M þ H]þ 459.2448,
found 459.2456.
500 ml. The assay was terminated by the addition of 5 mL ice-cold
10 mM TriseHCl, pH 8.0, followed by two washes through glass
fiber filters presoaked in 1% polyethyleneimine for at least 45 min to
minimize non-specific binding. Both these assays were run in
duplicate. Counts were extracted from the filters using Ecoscint
(National Diagnostics, Manville, NJ) for at least 8 h prior to counting.
Ki values were calculated using the ChengePrusoff equation [35].
4.1.24. 1-[4-(4-Cyclohexyl-piperazin-1-yl)-butyl]-3-furan-3-
ylindole dioxalate (9g)
This compound was prepared from 8c and 1-cyclohexyl-
piperazine as described for 4a. 21% yield, white solid. mp
240e243 ꢀC 1H NMR (free amine, 400 MHz, CDCl3)
d 7.85e7.69 (m,
2H), 7.49 (s, 1H), 7.34 (d, J ¼ 8.1 Hz, 1H), 7.27e7.20 (m, 2H), 7.16 (t,
J ¼ 7.4 Hz, 1H), 6.69 (s, 1H), 4.11 (t, J ¼ 6.8 Hz, 2H), 2.72 (s, 4H), 2.54
(s, 4H), 2.45 (s, 1H), 2.40e2.27 (m, 2H), 1.94 (s, 2H), 1.87e1.81 (m,
4H), 1.61 (m, 2H), 1.55e1.48 (m, 2H), 1.28e1.22 (m, 3H), 1.15e1.08 (s,
Acknowledgments
This project was supported by grants from The National Institute
on Drug Abuse (DA023205, DA013978). The National Institute on
Drug Abuse arranged for the in vitro receptor and transporter
assays at Oregon Health and Science University (OHSU) and for the
Novascreen assays through contractual agreement with the
vendors.
1H). 13C NMR (free amine, 100 MHz, CDCl3)
d 142.90, 137.34, 136.57,
126.20, 125.09, 121.91, 120.03, 119.69, 119.67, 109.74, 109.69, 107.53,
64.17, 57.43, 52.06, 48.47, 46.14, 28.10, 27.92, 25.81, 25.54, 23.98.
Anal. calcd for C30H39N3O9$½H2O: C, 60.59; H, 6.79; N, 7.07. Found:
C, 60.20; H, 6.39; N, 7.01. HRMS (TOF ESþ) calcd for C26H36N3O
[M þ H]þ 406.2858, found 406.2874.
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