Synthesis and biological screening of novel indolalkyl arenes targeting the serotonine Transporter

Article abstract of DOI:10.1002/ardp.201300321

A series of functionalized indolylalkylarenes 3-16(a and b) were synthesized and their affinities for the serotonin transporter were investigated in vitro. Compounds 3-12(a and b) were obtained by nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series of azaheterocycles. Compounds 14-16(a and b) were prepared in a two-step sequence by reaction of 3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b showed good binding affinities (K_i = 33.0, 48.0, and 17 nM, respectively). The other synthesized compounds showed moderate or no affinity in the binding studies. The affinities for the serotonin transporter of a new series of functionalized indolylalkylarenes 3-16(a and b) were investigated in vitro. With K_i values of 33.0, 48.0, and 17 nM, compounds 3b, 4b, and 5b, respectively, showed good binding affinities. The other synthesized compounds showed moderate or no affinity in the binding studies.

Full text of DOI:10.1002/ardp.201300321

174
Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Full Paper
Synthesis and Biological Screening of Novel Indolalkyl Arenes
Targeting the Serotonine Transporter
Claudia Ojeda-Gómez1, Hernán Pessoa-Mahana1, Patricio Iturriaga-Vásquez2,
Carlos David Pessoa-Mahana3, Gonzalo Recabarren-Gajardo3, and Claudio Méndez-Rojas1
1
Faculty of Chemical and Pharmaceutical Sciences, Department of Organic and Physical Chemistry, University
of Chile, Santiago, Chile
Millennium Institute for Cell Dynamics and Biotechnology, Santiago, Chile
Faculty of Chemistry, Pharmacy Department, Pontificia Universidad Católica de Chile, Santiago, Chile
2
3
A series of functionalized indolylalkylarenes 3–16(a and b) were synthesized and their affinities for
the serotonin transporter were investigated in vitro. Compounds 3–12(a and b) were obtained by
nucleophilic substitution of 3-(1H-indol-3-yl)propyl-4-methylbenzenesulfonates 2(a and b) with a series
of azaheterocycles. Compounds 14–16(a and b) were prepared in a two-step sequence by reaction of
3-(1H-indol-3-yl)-2-methylpropanal with substituted 1,2-phenylenediamines. Compounds 3b, 4b, and 5b
showed good binding affinities (Ki ¼ 33.0, 48.0, and 17 nM, respectively). The other synthesized
compounds showed moderate or no affinity in the binding studies.
Keywords: Benzimidazole / Indole / Serotonine transporter
Received: August 26, 2013; Revised: September 30, 2013; Accepted: October 1, 2013
DOI 10.1002/ardp.201300321
Introduction
fact that up to a third of patients do not respond to treatment,
including a delayed onset of action of about 4–6 weeks,
supports new research in this field [8–10].
Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter
that plays an important role in a variety of physiological
functions, either in the central nervous system or in the
peripheral tissues. It is synthesized mainly at the central level
in the raphe nucleus and substantia nigra. At the peripheral level,
it is found in the enterochromaffin cells of the gastrointesti-
nal tract [1–5]. The serotonin transporter (SERT) is a specific
monoaminergic carrier protein, which regulates the seroto-
nin level at the intersynaptic cleft. Alterations of SERT
densities in the brain are related to several neurodegenerative
and psychiatric disorders such as Parkinson’s disease and
depression [6, 7]. For these reasons, the SERT protein has
become recognized as an interesting molecular target in
antidepressant therapy. Selective serotonin reuptake inhib-
itors (SSRIs) are considered the second generation of
antidepressants and represent the most widely prescribed
drugs in the world. However, antidepressants in general,
including SSRIs, suffer from a variety of drawbacks, and the
The indole framework has been extensively studied and
recognized as an SSRI [6, 11–17]; examples of promising
structures together with their binding affinities are given in
Fig. 1.
Recently, the FDA approved the use of vilazodone (VIII, Fig. 2),
an indole derivative, as a new antidepressant drug acting as
dual ligand, SERT inhibitor (IC50 ¼ 0.5 nM; Ki ¼ 0.1 nM), and
partial agonist at the 5HT1A receptor (IC50 ¼ 0.2 nM) [18–21].
Given our interest in the search of novel indole derivatives
with antidepressant properties [22], we decided to synthesize
a new series of indolalkylarenes in order to obtain better
affinities in SERT binding. The strategy followed was to
connect the indole framework with different heterocyclic
moieties using two to three carbon linkers as spacer.
The series were built based mainly on the idea of combining
the well-known SERT affinity of the 3-indolyl(alkyl) moiety,
with different azaheterocyclic skeletons bearing electron-
acceptor functional groups or directly connected to
p-deficient rings, a decision which allowed us to assess their
impact on binding of the serotonine transporter.
Correspondence: Dr. Claudia Ojeda-Gómez and Dr. Hernán Pessoa-
Mahana, Faculty of Chemical and Pharmaceutical Sciences, Department
of Organic and Physical Chemistry, University of Chile, Casilla 233,
Santiago, Chile.
Compounds 3–5(a and b) were chosen based on their
structural analogy to the well-known long chain arylpiperazine
E-mail: claudia.ojeda.g@gmail.com, hpessoa@ciq.uchile.cl
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Novel Indolalkyl Arenes as Antidepressants
175
Figure 1. Bioactive indole analogs.
family, with different methylenic spacers connecting the
piperazine ring and the phenyl-haloarene ring. As has been
described, arylpiperazine compounds have been shown to
possess high affinities in both SERT and 5-HT1A receptor binding
studies [23, 24]. On the other hand, derivatives 6–7(a and b) were
mainly considered due to their 5-HT1A and SERT/DAT activity,
described for these kinds of compounds [25–27]. As far as we
know, there are no reports for compounds 8(a and b) in relation
ring [31]. Furthermore, the benzimidazole ring has been
successfully incorporated in a variety of structures displaying
high bioactivity on serotonine 5-HT1A/5-HT3 receptors [32, 33].
In summary, the aim of this work was to assess the impact
of incorporating new bioactive p-deficient heterocyclic
moieties on the well-known SERT effect of 5-fluoroindole
derivatives.
to antidepressant effects. However, the benzoxazinone ring, Results and discussion
which is structurally related to compound 8, has been described
as a multitarget agent in the central nervous system [28]. The
phenylpyrazole scaffold 9–11(a and b) has been reported to
exhibit pharmacological activity as promiscuous ligand in D2,
5-HT1A, 5-HT1B, and 5-HT1D receptors [29, 30].
Chemistry
The novel compounds were synthesized according to
Scheme 1. Compounds 1(a and b) were prepared as previously
reported [22]. These compounds 1(a and b) were reacted with
p-toluenesulfonyl chloride in CH2Cl2 to give tosyl derivatives 2
(a and b) in 65–82% yield. Subsequent reaction of 2(a and b) in
basic medium with substituted commercial heterocyclic
amines (piperazine, piperidine, pyrazole, phthalimide, benz-
oxazolinone, and benzimidazole) led to the expected
substitution products 3–12(a and b) as shown in Scheme 1.
As an extension of this work, six indole ethylbenzimidazole
derivatives, compounds 14–16(a and b), connected at C-1,
were also prepared as biligands. As mentioned above,
numerous compounds containing the benzimidazole ring
have been described as having central activity at the level of
5-HT2A and D2 receptors. The planned synthetic strategy to
get 3-indolylpropanal considered first the preparation of
Finally,
a short series of indole ethylbenzimidazole
derivatives, 14–16(a and b), were synthesized and their SERT
affinities evaluated. These compounds, to the best of our
knowledge, have not been described in SERT studies, only
compounds structurally related, such as the benzothiazole
Figure 2. Vilazodone structure.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Scheme 1. Synthesis of compounds 1(a and b) to (12a and b). Reagents and conditions: (i) N,N-DMA, H2SO4 4%, 3,4-dihydro-2-pyran,
reflux; (ii) TsCl, CH2Cl2, DMAP, N(Et)3, room temperature; and (iii) K2CO3, DMF, reflux conditions.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Novel Indolalkyl Arenes as Antidepressants
177
Scheme 2. Synthesis of compounds 13(a and b) to 16(a and b). Reagents and conditions: (i) iodine, CH2Cl2, room temperature; and
(ii) EtOH, reflux.
3-indolylpropanol 1(a and b) followed by oxidation. However,
the oxidative step was not successful under a variety of
experimental conditions, causing both degradation and
generation of multiple products. We therefore decided to
carry out the proposed synthesis using Michael addition [34]
by reaction between commercially available 1H-indoles and
methacrolein in the presence of iodine as a catalyst [35]. The
reaction produced 3-(1H-indol-3-yl)-2-methylpropanal 13a
and 3-(5-fluoro-1H-indol-3-yl)-2-methylpropanal 13b (Scheme 2).
These adducts were purified and further reacted with commer-
cial substituted o-phenylendiamines, to give the corresponding
3-indolyethylbenzimidazoles 14–16(a and b) [36, 37].
The SERT binding affinities of 3-indolylpropylpiperazine
series 3(a and b)–5(a and b) are shown in Table 1. The
affinities for SERT were strongly dependent on the aromatic
frameworks linked to the piperazine ring, along with
the substitution pattern on the indole moiety. The
binding affinities for compounds 3a–5a (R ¼ H) showed that
by increasing the methylenic chain (n ¼ 0–2) between
the aromatic and the piperazine ring, higher binding
affinities are obtained (Ki ¼ 28,570, 8710, and 65 nM for 3a,
4a, and 5a, respectively). Compounds 3b–5b (R ¼ F) showed
higher affinities (Ki ¼ 33.0, 48.0, and 17.7 nM, respectively),
compared to the unfluorinated derivatives 3a–5a (R ¼ H),
supporting the observation that SERT affinity at the
indole family is favored by electron-withdrawing groups
attached to the C-5 position, as has been described. We
think that the influence of the spacer between the
piperazine ring and the aryl group may be a second
contributing factor to the final effect. The results are
summarized in Table 1.
Pharmacology
The affinities of compounds 3(a and b) to 16(a and b) for the
human SERT (Ki) expressed in HEK-293 cells (PerkinElmer)
were assessed by displacement of [3H]paroxetine binding.
Inhibition constants (Ki) were calculated from the Cheng–
Prushoff equation [38].
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Table 1. Binding affinity of indole derivatives toward SERT.
substituents resulted detrimental for SERT affinity. The
importance of the C-5 fluorinated indolyl portion on SERT
affinity was confirmed. Considering the obtained results,
strong p-donor molecular frameworks linked to the indolyl-
propyl moiety may probably increase the Ki affinities for SERT.
Binding data, HEK-293
Compound
Ki (nM)
Compound
Ki (nM)
[3H]Paroxetine
3a R ¼ H
3b R ¼ F
4a R ¼ H
4b R ¼ F
5a R ¼ H
5b R ¼ F
6a R ¼ H
6b R ¼ F
7a R ¼ H
7b R ¼ F
8a R ¼ H
8b R ¼ F
9a R ¼ H
9b R ¼ F
1.1a)
28570
33.0
8710
48.0
65.0
17.7
14690
557
NE
1969
NE
NE
90285
1723
10a R ¼ H
10b R ¼ F
11a R ¼ H
11b R ¼ F
12a R ¼ H
12b R ¼ F
14a R ¼ H
14b R ¼ F
15a R ¼ H
15b R ¼ F
16a R ¼ H
16b R ¼ F
NE
14540
NE
NE
NE
10057
NE
1829
NE
NE
NE
Experimental
Melting points were determined on a hot-stage apparatus and are
uncorrected. The IR spectra were recorded in KBr discs on an FT-IR
Bruker IFS 55 spectrophotometer, and wave numbers are
reported in cmꢀ1. The 1H and 13C NMR spectra were run on a
Bruker DRX-300 spectrometer (300 and 75 MHz, respectively) in
CDCl3 or DMSO-d6. Chemical shifts were recorded in ppm (d)
relative to TMS as an internal standard; J values are given in Hz.
Microanalyses were made on a Fisons EA 1108 analyzer. High-
resolution mass spectra were recorded on a Thermo Finnigan
MAT 95XP mass spectrometer. Silica gel Merck 60 (70–230 mesh),
and aluminum sheets coated with silica gel 60 F254 were used
for column and TLC chromatography, respectively.
NE
a)
According to Thomas et al. [39].
Typical procedure for 3-[3-(4-{4-(trifluoromethyl)-
phenyl}-1-piperazinyl)propyl]-5-substituted-1H-indol
derivatives
3-[3-(4-{4-(Trifluoromethyl)phenyl}-1-piperazinyl)propyl]-
1H-indol derivative (3a) as a model
In general, compounds 6–16(a and b) showed lower
affinities for serotonine binding transporter experiments,
varying from inactive to poorly active, and they were shown as
NE (no effect). The piperidinyl derivatives 6(a and b), together
with 7(a and b) phthalimide derivatives, showed lower
affinities than 3 and 5(a and b), except for derivative 7a,
which did not display any effect. The same can be seen for the
benzoxazolinones 8(a and b), pyrazoles 9–11(a and b), and the
benzimidazoles 14–16(a and b) derivatives, which were not
able to displace the tritiated paroxetine, except compounds
9b and 14b in the SERT binding site.
The low affinities found for these compounds may be
attributed to the characteristic p-deficient effect exhibited by
both the pyrazole and imidazole rings, along with the electron-
withdrawing effect of the substituents such as chlorine,
fluorine, trifluoromethane, and nitro groups at these systems;
on the contrary, electron-donor groups may probably have a
more favorable effect on SERT binding in these molecules.
However, compounds 9(a and b), bearing a 4-fluorophenyl
group on the pyrazole ring, showed moderate affinities for
SERT, which may be ascribed in this case to the electronic
resonance effect on the aromatic ring. Compound 9b showed
a Ki ¼ 1723 nM, compared with 9a, Ki ¼ 90,285 nM. Further-
more, compounds 6 (piperidine derivatives) and 7 (phthal-
imide derivatives) showed the same tendency to increase the
affinities for SERT when a fluorine atom is attached to the C-5
indolyl group.
A mixture of 3-(3-indolyl)propyl-4-methylbenzenesulfonate (2a)
(0.2000 g, 0.61 mmol) in dry acetonitrile (30 mL), anhydrous
potassium carbonate (0.0840 g, 0.61 mmol), and 1-[4-(trifluoro-
methyl)phenyl]piperazine (0.1400 g, 0.61 mmol) was stirred for
6 h under reflux. After this time, water was added (30 mL) and
extracted with AcOEt (3 ꢁ 30 mL). The combined organic layers
were washed and dried over anhydrous Na2SO4. The organic
portion was filtered and the solvent evaporated to yield a crude,
that was purified by column chromatography (AcOEt), to afford
pure (3a) (0.1740 g, 74%); m.p.: 149–150°C. IR cmꢀ1: 3413 (N–H),
–
3062 (C–H arom.), 2939–2789 (C–H aliph.), 1614 (C C arom.).
–
1H NMR (CDCl3): 1.84 (q, 2H, H-20, J ¼ 7.2), 2.37 (t, 2H, H-30,
J ¼ 7.5 Hz), 2.49 (m, 4H, H-40 and H-60), 2.71 (t, 2H, H-10, J ¼ 7.5 Hz),
3.24 (m, 4H, H-50 and H-70), 6.9–7.1 (m, 5H, H-2, H-5, H-7, H-200 and
H-600), 7.33 (d, 1H, H-4, J ¼ 8.1), 7.49 (m, 3H, H-6, H-300 and H-500),
10.75 (s, 1H, NH). 13C NMR (CDCl3): 22.8 (CH2, C-10), 27.5 (CH2, C-20),
47.4 (CH2, C-50 and C-70), 52.9 (CH2, C-40 and C-60), 57.9 (CH2, C-30),
111.7, 114.4, 114.7, 117.9, 118.3, 118.4, 118.6, 121.1, 122.5, 123.6,
126.4, 126.5, 127.2, 127.6, 136.7 (C–N, C-3), 153.6 (C–N, C-100).
Anal. calcd. for C22H24F3N3: C, 68.20; H, 6.24; N, 10.85; Found: C,
68.36; H, 6.40; N, 10.78.
3-[3-(4-{4-(Trifluoromethyl)phenyl}-1-piperazinyl)propyl]-5-
fluoro-1H-indole (3b)
Prepared from 3-(5-fluoro-3-indolyl)propyl-4-methylbenzenesulfo-
nate (2b) (0.200 g, 0.58 mmol), anhydrous potassium carbonate
(0.080 g, 0.58 mmol), and 1-[4-(trifluoromethyl)phenyl]piperazine
(0.132 g, 0.58 mmol). The crude was purified by column
chromatography (AcOEt), 73% yield, m.p.: 122–123°C. IR cmꢀ1
:
Conclusion
3431 (N–H), 3058 (C–H arom.), 2938–2792 (C–H aliph.), 1614
1
(C C). H NMR (CDCl3): 1.92 (q, 2H, H-20, J ¼ 7.5 Hz), 2.47 (t, 2H,
–
–
H-30, J ¼ 7.5 Hz), 2.60 (m, 4H, H-40 and H-60), 2.76 (t, 2H, H-10,
J ¼ 7.5 Hz), 3.97 (m, 4H, H-50 and H-70), 6.8–6.9 (m, 3H, H-2, H-200
In summary, the indole framework connected either to p-
deficient ring arenes or arenes bearing electron-withdrawing
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179
and H-600), 7.02 (s, 1H, H-7), 7.2 (m, 2H, H-4, H-5), 7.47 (d, 2H, H-300
and H-500, J ¼ 8.7), 8.01 (s, 1H, NH). 13C NMR (CDCl3): 21.9 (CH2,
C-10), 26.3 (CH2, C-20), 47.0 (CH2, C-50 and C-70), 52.1 (CH2, C-40 and
C-60), 57.2 (CH2, C-30), 102.8, 103.1, 109.2, 109.6, 110.7, 110.8,
113.5, 115.5, 115.6, 119.3, 119.7, 122.1, 125.4, 125.5, 125.7, 127.0,
127.1, 131.9 (C–N, C-3), 152.4 (C–N, C-100), 155.2 and 158.3 (C–F,
C-6). Anal. calcd. for C22H23F4N3: C, 65.17; H, 5.32; N, 10.36;
Found: C, 64.98; H, 5.40; N, 10.38.
(CH2, C-200), 52.9 (CH2, C-40 and C-60), 53.0 (CH2, C-50 and C-70), 58.2
(CH2, C-100), 60.3 (CH2, C-30), 110.9, 115.8, 118.7, 121.1, 121.5, 125.9,
127.3 (CH, C-600), 128.2 (CH, C-400 and C-800), 128.5 (CH, C-500 and
C-700), 136.1 (C–N, C-3) and 140.0 (C–C, C-300). Anal. calcd. for
C23H29N3: C, 79.50; H, 8.41; N, 12.09; Found: C, 79.22; H, 8.39;
N, 12.20.
5-Fluoro-3-[3-(4-phenylethyl-1-piperazinyl)propyl]-1H-
indole (5b)
3-[3-(4-{2-Fluorobenzyl}-1-piperazinyl)propyl]-1H-indole
Prepared from 3-(5-fluoro-3-indolyl)propyl-4-methylbenzenesulfo-
nate (2b) (0.200 g, 0.58 mmol), anhydrous potassium carbonate
(0.080 g, 0.58 mmol), and 1-phenylethylpiperazine (0.110 g,
0.58 mmol). The crude was purified by column chromatography
(AcOEt–hexane–MeOH 2.0:0.5:0.3), 76% yield, m.p.: 121–122°C.
IR cmꢀ1: 3423 (N–H), 3057 (C–H arom.), 2998–2780 (C–H aliph.),
(4a)
Prepared from 3-(3-indolyl)propyl-4-methylbenzenesulfonate (2a)
(0.200 g, 0.61 mmol), anhydrous potassium carbonate (0.084 g,
0.61 mmol), and 1-(2-fluorobenzyl)piperazine (0.106 g, 0.61 mmol).
The crude was purified by column chromatography (AcOEt–
hexane–MeOH 2.0:0.5:0.3), 56% yield, oil. IR cmꢀ1: 3409 (N–H),
1
0
–
1626 (C C). H NMR (CDCl ): 1.93 (q, 2H, H-2 , J ¼ 7.5 Hz), 2.46–2.7
–
3
3055 (C–H arom.), 2945–2779 (C–H aliph.), 1618 (C C). 1H NMR
–
–
(m, 16H, H-10, H-30, H-40, H-50, H-60, H-70 and H-100, H-200), 6.9–7.0
(m, 2H, H-4 and H-7), 7.22–7.34 (m, 7H, H-2, H-5, and H-phenylpip.),
8.74 (s, 1H, NH). 13C NMR (CDCl3): 22.0 (CH2, C-10), 26.3 (CH2, C-20),
32.6 (CH2, C-200), 52.2 (CH2, C-40 and C-60), 52.3 (CH2, C-50 and C-70),
57.4 (CH2, C-100), 59.6 (CH2, C-30), 102.7, 103.0, 109.0, 109.3, 110.7,
110.8, 115.3, 122.3, 125.2, 126.9, and 127.1 (CH, C-600), 127.5 (CH,
C-400 and C-800), 127.8 (CH, C-500 and C-700), 132.0 (C–N, C-3) and 139.3
(C–C, C-300). Anal. calcd. for C23H28FN3: C, 75.58; H, 7.72; N, 11.50;
Found: C, 75.61; H, 7.73; N, 11.53.
(CDCl3): 1.90 (q, 2H, H-20, J ¼ 7.6 Hz), 2.44–2.54 (m, 10H, H-30, H-40,
H-50, H-60 and H-70), 2.73 (t, 2H, H-10, J ¼ 7.5 Hz), 3.58 (s, 2H, H-80),
6.89 (s, 1H, H-2), 6.9–7.3 (m, 7H, H-5, H-6, H-7 and H-fluorobenzyl),
7.56 (d, 1H, H-4, J ¼ 7.8), 8.49 (s, 1H, NH). 13C NMR (CDCl3): 22.9
(CH2, C-10), 26.8 (CH2, C-20), 52.2 (CH2, C-40 and C-60), 52.8 (CH2, C-50
and C-70), 55.1 (CH2, C-80), 58.1 (CH2, C-30), 111.0, 115.1, 115.4,
115.8, 118.8, 118.9, 121.2, 121.7, 123.7, 123.8, 124.1, 124.3, 127.5,
128.8, 128.9, 131.6, 131.7 (C–N, C-3), 159.7 and 163.0 (C–F, C-600).
Anal. calcd. for C22H26FN3: C, 75.18; H, 7.46; N, 11.96; Found: C,
75.02; H, 7.54; N, 12.03.
3-[3-(3-(Trifluoromethyl)-1-piperidinyl)propyl]-1H-indole
(6a)
3-[3-(4-{2-Fluorobenzyl}-1-piperazinyl)propyl]-5-fluoro-1H-
Prepared from 3-(3-indolyl)propyl-4-methylbenzenesulfonate (2a)
(0.200g, 0.61mmol), anhydrous potassium carbonate (0.084g,
0.61 mmol), and 3-(trifluoromethyl)piperidine (0.093 g, 0.61 mmol).
The crude was purified by column chromatography (hexane–
AcOEt 1.0:2.0), 80% yield, as a pale-yellow oil. IR cmꢀ1: 3416 (N–H),
indole (4b)
Prepared from 3-(5-fluoro-3-indolyl)propyl-4-methylbenzenesulfo-
nate (2b) (0.200 g, 0.58 mmol), anhydrous potassium carbonate
(0.800 g, 0.58 mmol), and 1-(2-fluorobenzyl)piperazine (0.112 g,
0.58 mmol). The crude was purified by column chromatography
(AcOEt–hexane–MeOH 2.0:0.5:0.3), 78% yield, m.p.: 112–113°C. IR
3056 (C–H arom.), 2946–2860 (C–H aliph.), 1619 (C C). 1H NMR
–
–
(CDCl3): 1.18–193 (m, 9H, H-20, H-200, H-300, H-400 and H-500), 2.31–2.34
(m, 1H, H-500), 2.41–2.46 (m, 2H, H-30), 2.76 (t, 2H, H-10), 2.88–3.08
(m, 2H, H-100), 6.92 (s, 1H, H-7), 7.15 (m, 2H, H-5 and H-6), 7.31 (d, 1H,
H-2, J ¼ 8.1), 7.59 (d, 1H, H-4), 8.03 (s, 1H, NH). 13C NMR (CDCl3): 22.9
(CH2, C-10), 23.4 (CH2, C-400), 24.2 (CH2, C-20), 27.3 (CH2, C-300), 40.5,
40.9, 41.2, 41.6 (CH, C-200), 52.3, 52.4 (CH2, C-100), 53.4 (CH2, C-500),
58.6 (CH2, C-30), 111.1 (CH, C-4), 116.3 (C–C, C-1), 118.9 (CH, C-7),
119.1 (CH, C-6), 121.2 (CH–C-5), 121.9 (CH, C-2), 127.5 (C–C, C-8),
125.2, 128.9, 132.6 (CF, CF3) and 136.3 (C–C, C-3). Anal. calcd. for
C17H21F3N2: C, 65.79; H, 6.82; N, 9.03; Found: C, 65.91; H, 6.72;
N, 8.99.
cmꢀ1: 3411 (N–H), 3054 (C–H arom.), 2945–2778 (C–H aliph.),
1
0
–
–
1625 (C C). H NMR (CDCl ): 1.91 (q, 2H, H-2 , J ¼ 7.5 Hz), 2.44–2.74
3
(m, 12H, H-10, H-30, H-40, H-50, H-60 and H-70), 3.64 (s, 2H, H-80), 6.8–
7.2 (m, 7H, H-2, H-5, H-7 and H-fluorobenzyl), 7.69 (td, 1H, H-4,
J ¼ 7.3, J ¼ 1.8), 8.67 (s, 1H, NH). 13C NMR (CDCl3): 22.0 (CH2, C-10),
26.1 (CH2, C-20), 51.6 (CH2, C-40 and C-60), 52.2 (CH2, C-50 and C-70),
54.3 (CH2, C-80), 57.3 (CH2, C-30), 102.7, 103.0, 109.0, 109.3, 110.7,
110.8, 114.3, 114.6, 115.2, 115.3, 122.3, 122.9, 123.0, 123.3, 123.5,
126.9, 127.0, 128.0, 128.1, 130.8, 130.9, 131.9 (C–N, C-3), 155.1 and
158.2 (C–F, C-6), 158.9 and 162.2 (C–F, C-600). Anal. calcd. for
C22H25F2N3: C, 71.52; H, 6.82; N, 11.37; Found: C, 71.49; H, 6.83; N,
11.37.
5-Fluoro-3-[3-(3-(trifluoromethyl)-1-piperidinyl)propyl]-1H-
indole (6b)
3-[3-(4-Phenylethyl-1-piperazinyl)propyl]-1H-indole (5a)
Prepared from 3-(3-indolyl)propyl-4-methylbenzenesulfonate (2a)
(0.200 g, 0.61 mmol), anhydrous potassium carbonate (0.084 g,
0.61 mmol), and 1-phenylethylpiperazine (0.116 g, 0.61 mmol).
The crude was purified by column chromatography (AcOEt–
Prepared from 3-(5-fluoro-3-indolyl)propyl-4-methylbenzenesulfo-
nate (2b) (0.210 g, 0.60 mmol), anhydrous potassium carbonate
(0.084 g, 0.60 mmol), and 3-(trifluoromethyl)piperidine (0.093 g,
0.60 mmol). The crude was purified by column chromatography
(hexane–AcOEt 1.0:2.0), 75% yield, as a pale-yellow oil. IR cmꢀ1
:
hexane–MeOH 2.0:0.5:0.3), 80% yield, m.p.: 126.5–17.5°C. IR cmꢀ1
:
3425 (N–H), 3057 (C–H arom.), 2947–2861 (C–H aliph.), 1628
1
0 00 00 00
–
(C C). H NMR (CDCl ): 1.19–1.94 (m, 9H, H-2 , H-2 , H-3 , H-4 and
–
3
3423 (N–H), 3055 (C–H arom.), 2946–2772 (C–H aliph.), 1617
1
(C C). H NMR (CDCl3): 1.91 (q, 2H, H-20, J ¼ 7.5 Hz), 2.43–2.61
H-500), 2.24–2.32 (m, 1H, H-500), 2.43 (t, 2H, H-30, J ¼ 7.5), 2.71 (t, 2H,
H-10, J ¼ 7.5), 2.88–3.07 (m, 2H, H-100), 6.92 (td, 1H, H-5, J ¼ 9,
J ¼ 2.4), 6.99 (s, 1H, H-7), 7.21–7.25 (m, 2H, H-2 and H-4), 8.03 (s, 1H,
NH). 13C NMR (CDCl3): 22.7 (CH2, C-10), 23.3 (CH2, C-400), 24.1 (CH2,
C-20), 27.2 (CH2, C-300), 40.8, 41.2 (CH, C-200), 52.4 (CH2, C-100), 53.4
–
–
(m, 12H, H-30, H-40, H-50, H-60, H-70 and H-200), 2.77 (m, 4H, H-10 and
100), 6.86 (s, 1H, H-2), 7.0–7.18 (m, 5H, H-5, H-6, H-7, H-400 and H-800),
7.25 (m, 3H, H-500, H-600 and H-700), 7.58 (d, 1H, H-4, J ¼ 7.5), 8.60
(s, 1H, NH). 13C NMR (CDCl3): 22.8 (CH2, C-10), 27.1 (CH2, C-20), 33.3
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180
C. Ojeda-Gómez et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
(CH2, C-500), 58.4 (CH2, C-30), 103.6, 103.9 (CH, C-5), 110.0, 110.4 (CH,
C-3), 111.5, 111.6 (CH, C-4), 116.4, 116.5 (C–C, C-1), 123.0 (CH–C-2),
125.1, 127.8, 128.8 (C–F, CF3), 128.0 (C–C, C-8), 132.8 (C–C, C-3),
156.1 and 159.2 (C–F, C-6). Anal. calcd. for C17H20F4N2: C, 62.18; H,
6.14; N, 8.53; Found: C, 61.97; H, 6.16; N, 8.60.
118.6 (CH, C-6), 119.3 (CH, C-400), 121.7 (CH, C-5), 122.0 (C–H, C-2),
122.3 (CH, C-500), 123.7 (CH, C-300), 127.2 (C–C, C-600), 131.1 (C–C,
00
–
C-8), 136.4 (C–C, C-3), 142.2 (C–C, C-1 ), 168.9 (C O). Anal. calcd.
–
for C18H16N2O2: C, 73.98; H, 5.52; N, 10.95; Found: C, 74.04;
H, 5.50; N, 10.88.
1-[3-(5-Fluoro-3-indolyl)propyl]benzo[c]-3-isoxazolone
(8b)
General method for the preparation of compounds 7a,b
and 8a,b
Prepared from 2-benzoxazolinone (0.078 g, 0.58 mmol), anhy-
drous potassium carbonate (0.080 g, 0.58 mmol), and 3-(5-fluoro-3-
indolyl)propyl-4-methylbenzenesulfonate derivative 2b (0.200 g,
0.58 mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 78% yield, m.p.: 112–113°C. IR cmꢀ1: 3305
–
2-[3-(3-Indolyl)propyl]isoindoline-1,3-dione (7a)
A mixture of phthalimide (0.090 g, 0.61 mmol) in dry DMF (5 mL)
and anhydrous potassium carbonate (0.085 g, 0.61 mmol) was
stirred under reflux for 1 h. Then the derivative 2a (0.200 g,
0.61 mmol) was added. The reaction mixture was stirred under
reflux overnight. The solvent was evaporated in vacuo to obtain a
crude, which was purified by column chromatography (hexane/
AcOEt 2:1) to yield pure 7a (0.110 g, 59%). m.p.: 121–122°C. IR
cmꢀ1: 3390 (N–H), 3047 (C–H arom.), 2977–2836 (C–H aliph.),
(N–H), 3056 (C–H arom.), 2929–2848 (C–H aliph.), 1750 (C O),
–
1
0
–
1607 (C C). H NMR (CDCl ): 2.11 (q, 2H, H-2 , J ¼ 7.2), 2.73 (t, 2H,
–
3
H-10, J ¼ 7.2 Hz), 3.81 (t, 2H, H-30, J ¼ 7.2 Hz), 6.79–6.89 (m, 2H, H-4
and H-7), 6.99–7.22 (m, 6H, H-2, H-5, H-200, H-300, H-400 and H-500),
8.04 (s, 1H, NH). 13C NMR (CDCl3): 22.1 (CH2, C-10), 27.6 (CH2, C-20),
41.7 (CH2, C-30), 103.4 and 103.7 (CH, C-200), 108.3 (CH, C-7), 110.2
and 110.6 (CH, C-4), 111.7 and 111.9 (CH, C-400), 114.7 (C–C, C-1),
122.4 (CH, C-2), 123.6 (CH, C-500), 123.8 (CH, C-3), 127.6 (C–C, 2.7
(CH, C-600), 131.1 (C–C, C-8), 132.8 (C–C, C-3), 142.7 (C–C, C-100),
–
1
0
–
–
1697 (C O), 1617 (C C arom.). H NMR (CDCl ): 2.12 (q, 2H, H-2 ,
–
–
3
J ¼ 7.2), 2.82 (t, 2H, H-10, J ¼ 7.5 Hz), 3.79 (t, 2H, H-30, J ¼ 7.2 Hz),
7.06–7.17 (m, 3H, H-2, H-5, H-6), 7.30 (d, 1H, H-7, J ¼ 7.8), 7.58 (d,
1H, H-4), 7.67 (m, 2H, H-200 and H-500), 7.81 (m, 2H, H-300 and H-400),
8.02 (s, 1H, NH). 13C NMR (CDCl3): 22.4 (CH2, C-10), 28.5 (CH2, C-20),
37.8 (CH2, C-30), 111.5 (CH, C-40), 115.1 (C–C, C-1), 118.7 (CH, C-7),
119.1 (CH, C-6), 121.4 (CH, C-5), 121.8 (CH, C-2), 123.0 (CH, C-200 and
C-500), 127.2 (C–C, C-8), 132.0 (C–C, C-100 and C-600), 133.8 (CH, C-300
154.6 (C–F, C-6), 169.2 (C O). Anal. calcd. for C18H15FN2O2: C,
–
69.67; H, 4.87; N, 9.03; Found: C, 69.76; H, 4.95; N, 9.08.
and C-400), 136.2 (C–N, C-3), 168.5 (C O). Anal. calcd. for
–
3-[3-(3-{4-Fluorophenyl}-1H-1-pyrazolyl)propyl]-1H-indole
(9a)
–
C19H16N2O2: C, 74.98; H, 5.30; N, 10.51; Found: C, 75.02; H,
5.27; N, 10.41.
Prepared from 3-(4-fluorophenyl)-1H-pyrazole (0.099 g, 0.61 mmol),
anhydrous potassium carbonate (0.083 g, 0.61mmol), and 3-(3-
indolyl)propyl-4-methylbenzenesulfonate derivative 2a (0.200 g,
0.61 mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 31% yield, oil. IR cmꢀ1: 3448 (N–H), 3050 (C–H
2-[3-(5-Fluoro-3-indolyl)propyl]isoindoline-1,3-dione (7b)
Prepared from phthalimide (0.085 g, 0.58 mmol), anhydrous
potassium carbonate (0.080 g, 0.58 mmol), and 3-(5-fluoro-3-
indolyl)propyl-4-methylbenzenesulfonate 2b (0.200 g, 0.58 mmol).
The crude was purified by column chromatography (hexane/AcOEt
2:1); 56% yield, m.p.: 133–135°C. IR cmꢀ1: 3409 (N–H), 3047 (C–H
–
–
arom.), 2959–2919 (C–H aliph.), 1606 (C N), 1507 and 1524 (C C).
–
–
1H NMR (CDCl3): 2.30 (q, 2H, H-20, J ¼ 7.2), 2.78 (t, 2H, H-10,
J ¼ 7.2 Hz), 4.17 (t, 2H, H-30, J ¼ 7.2 Hz), 6.47 (s, 1H, H-50), 6.95 (s, 1H,
H-7), 7.03–7.22 (m, 4H, H-2, H-4, H-5 and H-6), 7.33 (m, 2H, H-200 and
600), 7.56 (d, 1H, H-40, J ¼ 7.8), 7.77 (m, 2H, H-300 and H-500), 8.10 (s, 1H,
NH). 13C NMR (CDCl3): 21.3 (CH2, C-10), 29.6 (CH2, C-20), 50.8 (CH2,
C-30), 101.4 (CH, C-50), 110.2 (CH, C-4), 114.0 (C–C, C-1), 114.4 (CH,
C-7), 114.4 and 117.8 (CH, C-300 and C-500), 118.3 (CH, C-6), 120.6
(C–H, C-5), 121.1 (CH, C-2), 126.2 and 126.3 (CH, C-200 and C-600), 126.4
(C–C, C-100), 129.0 (C–C, C-8), 129.7 (CH–N, C-40), 135.4 (C–N, C-3), 149.5
(C–N, C-60), 159.8 and 163.1 (C–F, C-400). Anal. calcd. for C20H18FN3:
C, 75.21; H, 5.68; N, 13.16; Found: C, 75.25; H, 5.60; N, 13.21.
–
–
–
arom.), 2979–2859 (C–H aliph.), 1697 (C O), 1627 and 1612 (C C).
–
1H NMR (CDCl3): 2.10 (m, 2H, H-20), 2.77 (t, 2H, H-10, J¼ 7.5 Hz), 3.78
(t, 2H, H-30, J¼ 7.2 Hz), 6.90 (td, 1H, H-5, J¼ 9.0, J ¼ 2.4), 7.12 (s, 1H,
H-7), 7.22 (m, 2H, H-4 and H-2), 7.70 (m, 2H, H-200 and H-500), 7.83
(m, 2H, H-300 and H-400), 8.03 (s, 1H, NH). 13C NMR (CDCl3): 22.8 (CH2,
C-10), 28.8 (CH2, C-20), 38.1 (CH2, C-30), 100.9 and 104.2 (CH, C-5), 110.5
and 110.8 (CH, C-7), 111.9 and 112.1 (CH, C-4), 123.5 (CH, C-200 and
C-500), 123.7 (CH, C-2), 128.1 (C0–0 C, C-8), 132.5 (C–C, C-100 and C-600),
00
–
133.2 (C–N, C-3), 134.3 (CH, C-3 and C-4 ), 168.9 (C O). Anal. calcd.
–
for C19H15FN2O2: C, 70.80; H, 4.69; N, 8.69; Found: C, 70.78; H, 4.71;
N, 8.69.
5-Fluoro-3-[3-(3-(4-fluorophenyl)-1-pyrazolyl)propyl]-1H-
indole (9b)
Prepared from 3-(4-fluorophenyl)-1H-pyrazole (0.080 g, 0.58 mmol),
anhydrous potassium carbonate (0.080 g, 0.58mmol), and 3-(5-
fluoro-3-indolyl)propyl-4-methylbenzenesulfonate derivative 2b
(0.200g, 0.58 mmol). The crude was purified by column chroma-
1-[3-(3-Indolyl)propyl]benzo[c]-3-isoxazolone (8a)
Prepared from 2-benzoxazolinone (0.083 g, 0.61 mmol), anhy-
drous potassium carbonate (0.085 g, 0.61 mmol), and 3-(3-indolyl)-
propyl-4-methylbenzenesulfonate
derivative
2a
(0.200 g,
tography (hexane/AcOEt 2:1), 35% yield, m.p.: 80–81°C. IR cmꢀ1
:
0.61 mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 80% yield, m.p.: 91–93°C. IR cmꢀ1: 3300
–
–
3446 (N–H), 3058 (C–H arom.), 2952–2892 (C–H aliph.), 1603 (C N),
1
0
–
–
–
–
1505 and 1488 (C C). H NMR (CDCl ): 2.22 (q, 2H, H-2 , J ¼ 7.2),
(N–H), 3057 (C–H arom.), 2927–2843 (C–H aliph.), 1750 (C O),
3
1
0
–
2.67 (t, 2H, H-10, J ¼ 7.2 Hz), 4.12 (t, 2H, H-30, J ¼ 7.2 Hz), 6.42 (s, 1H,
H-50), 6.86 (td, 1H, H-50, J ¼ 9.0 and J ¼ 2.4), 6.97–7.03 (m, 3H, H-2,
H-4 and H-7), 7.11–7.20 (m, 2H, H-200 and 600), 7.31 (d, 1H, H-40), 7.68–
7.72 (m, 2H, H-300 and H-500), 7.99 (s, 1H, NH). 13C NMR (CDCl3): 22.4
(CH2, C-10), 30.8 (CH2, C-20), 52.0 (CH2, C-30), 101.4 (CH, C-50), 103.9
and 104.3 (CH, C-5), 110.6 and 111.0 (CH, C-7), 112.1 and 112.2 (CH,
1615 (C C). H NMR (CDCl ): 2.16 (q, 2H, H-2 , J ¼ 7.2), 2.82 (t, 2H,
–
3
H-10, J ¼ 7.2 Hz), 3.84 (t, 2H, H-30, J ¼ 7.2 Hz), 6.82 (d, 1H, H-7,
J ¼ 7.6), 7.00–7.21 (m, 6H, H-2, H-4, H-5, H-6, H-200 and H-400), 7.33
(d, 1H, H-300, J ¼ 8.1), 7.52 (d, 1H, H-500, J ¼ 7.8), 8.30 (s, 1H, NH).
13C NMR (CDCl3): 22.3 (CH2, C-10), 27.8 (CH2, C-20), 41.8 (CH2, C-30),
108.3 (CH, C-200), 110.0 (CH, C-4), 111.2 (CH, C-7), 114.5 (C–C, C-1),
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Novel Indolalkyl Arenes as Antidepressants
181
C-4), 115.5 and 115.6 (C–C, C-100), 115.7 and 116.0 (CH, C-300 and
C-500), 123.8 (CH, C-2), 127.5 and 127.6 (CH, C-200 and C-600), 128.4 and
128.1 (C–C, C-100), 130.3 (C–C, C-8), 131.0 (CH–N, C-40), 133.2 (C–N,
C-3), 150.9 (C–N, C-60), 156.5 and 159.6 (C–F, C-6), 161.2 and 164.4
(C–F, C-400). Anal. calcd. for C20H17F2N3: C, 71.20; H, 5.08; N, 12.46;
Found: C, 71.12; H, 5.13; N, 12.54.
5-Fluoro-3-[3-(5-{trifluoromethyl}-1H-pyrazolyl)propyl]-1H-
indole (11b)
Prepared from 5-(trifluoromethyl)-1H-pyrazole (0.078 g, 0.58 mmol),
anhydrous potassium carbonate (0.080 g, 0.58 mmol) and 3-(5-
fluoro-3-indolyl)propyl-4-methylbenzenesulfonate derivative 2b
(0.200 g, 0.58 mmol). The crude was purified by column
chromatography (hexane/AcOEt 2:1), 61% yield, oil. IR cmꢀ1
:
3422 (N–H), 3058 (C–H arom.), 2937–2853 (C–H aliph.), 1628
1-[3-(3-Indolyl)propyl]-5-fluoro-1H-indazole (10a)
1
0
–
–
(C N), 1487 (C C), 1239 (CF ). H NMR (CDCl ): 2.17 (q, 2H, H-2 ,
–
–
Prepared from 5-fluoro-1H-indazole (0.083 g, 0.61 mmol), anhy-
drous potassium carbonate (0.083 g, 0.61 mmol), and 3-(3-indolyl)-
3
3
J ¼ 7.0), 2.60 (t, 2H, H-10, J ¼ 7.0 Hz), 4.09 (t, 2H, H-30, J ¼ 6.9 Hz),
6.42 (s, 1H, H-7), 6.83 (t, 1H, H-7, J ¼ 9.0), 6.93 (s, 1H, H-2), 7.07
(d, 1H, H-4, J ¼ 9.6), 7.17 (m, 1H, H-60), 7.30 (s, 1H, H-50), 8.57 (s, 1H,
NH). 13C NMR (CDCl3): 22.2 (CH2, C-10), 30.6 (CH2, C-20), 52.5 (CH2,
C-30), 103.6 and 103.9 (CH, C-50), 104.6 and 104.7 (CH, C-5), 110.4
and 110.7 (CH, C-7), 112.3 and 112.4 (CH, C-4), 114.6 and 114.7
(C–C, C-1), 116.5, 120.0, 123.6 and 127.8 (C–F, CF3), 124.1 (CH, C-2),
127.9 (C–C, C-8), 131.0 (CH–N, C-60), 133.4 (C–N, C-3), 141.8, 142.3,
142.8 and 143.3 (C–CF, C-40), 156.4 and 159.5 (C–F, C-6). Anal.
calcd. for C15H13F4N3: C, 57.88; H, 4.21; N, 13.50; Found: C, 57.71;
H, 4.17; N, 13.44.
propyl-4-methylbenzenesulfonate
derivative
2a
(0.200 g,
0.61 mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 36% yield, m.p.: 106–107°C. IR cmꢀ1: 3411
–
–
(N–H), 3058 (C–H arom.), 2931–2873 (C–H aliph.), 1616 (C N),
1
0
–
1504 (C C). H NMR (CDCl ): 2.33 (q, 2H, H-2 , J ¼ 7.2), 2.74 (t, 2H,
–
3
H-10, J ¼ 7.2 Hz), 4.38 (t, 2H, H-30, J ¼ 6.9 Hz), 6.91 (s, 1H, H-7), 7.05–
7.22 (m, 4H, H-2, H-5, H-6 and H-80), 7.32 (m, 2H, H-4 and 100), 7.51
(d, 1H, H-70, J ¼ 7.8), 7.96 (s, 1H, H-40), 8.10 (s, 1H, NH). 13C NMR
(CDCl3): 21.8 (CH2, C-10), 27.6 (CH2, C-20), 50.7 (CH2, C-30), 108.4,
108.6, 110.2, 110.3, 111.5, 111.6, 111.9, 118.8, 119.5, 120.4, 123.1,
125.2, 126.3, 130.3, 136.4, 138.2, 147.5, 154.8. Anal. calcd. for
C18H16FN3: C, 73.70; H, 5.50; N, 14.32; Found: C, 73.68; H, 5.51;
N, 14.28.
1-[3-(3-Indolyl)propyl]-2-(2-nitrophenyl-)1H-benzo[d]-
imidazole (12a)
Prepared from 2-(2-nitrophenyl)-1H-benzo[d]imidazole (0.200 g,
0.84 mmol), anhydrous potassium carbonate (0.116 g, 0.84 mmol),
and 3-(3-indolyl)propyl-4-methylbenzenesulfonate derivative 2a
(0.275 g, 0.84 mmol). The crude was purified by column
chromatography (hexane/AcOEt 2:1), 92% yield, m.p.: 161–
1-(3-(5-Fluoro-1H-indol-3-yl)propyl)- 5-fluoro-1H-indazole
(10b)
Prepared from 5-fluoro-1H-indazole (0.80 g, 0.58 mmol), anhy-
drous potassium carbonate (0.080 g, 0.58 mmol), and 3-(5-fluoro-3-
indolyl)propyl-4-methylbenzenesulfonate derivative 2b (0.200 g,
0.58 mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 36% yield, m.p.: 106–107°C. IR cmꢀ1: 3411
–
162°C. IR cmꢀ1: 3451 (N–H), 3057 (C–H arom.), 2937–2852
1
–
(C–H aliph.), 1530 (NO asim), 1364 (NO sim), 1448 (C C). H NMR
–
2
2
(DMSO-d6): 2.07 (q, 2H, H-20, J ¼ 7.5), 2.64 (t, 2H, H-10, J ¼ 7.2 Hz),
4.21 (t, 2H, H-30, J ¼ 7.5 Hz), 6.92 (m, 2H, H-5 and H-7), 7.05 (t, 1H,
H-6, J ¼ 7.2), 7.29 (m, 4H, H-2, H-4, H-80and 100), 7.64–7.76 (m, 5H,
H-70, H-90, 200, 300 and 400 J ¼ 7.8), 8.13 (d, 1H, H-500, J ¼ 6.9), 10.7 (s,
1H, NH). 13C NMR (DMSO-d6): 21.3 (CH2, C-10), 28.9 (CH2, C-20), 43.2
(CH2, C-30), 110.4 (CH, C-100), 110.8 (CH, C-4), 112.4 (C–C, C-1), 117.6
(CH, C-70), 117.7 (CH, C-7), 118.8 (CH, C-6), 120.4 (C–H, C-5), 121.8
(CH, C-80), 121.7 (CH, C-90), 122.2 (C–C, C-100), 124.1 (CH, C-200), 124.4
(CH, C-2), 126.3 (C–C, C-8), 130.8 (CH, C-500), 131.4 (CH, C300),
132.8 (CH, C-400), 134.4 (C–C, C-3), 135.8 (C–C, C-50), 142.1
(C–C–NO2, C-600), 148.2 (C–C, C-60), 148.4 (N–C–N, C-40). Anal.
calcd. for C24H20N4O2: C, 72.81; H, 5.08; N, 14.23; Found: C, 71.97;
H, 5.11; N, 14.27.
(N–H), 3056 (C–H arom.), 2933–2875 (C–H aliph.), 1613 (C N),
–
1
0
–
–
1505 (C C). H NMR (CDCl ): 2.33 (q, 2H, H-2 , J ¼ 7.2), 2.74 (t, 2H,
3
H-10, J ¼ 7.2 Hz), 4.38 (t, 2H, H-30, J ¼ 6.9 Hz), 6.91 (s, 1H, H-7), 7.05–
7.22 (m, 4H, H-2, H-5, H-6 and H-80), 7.32 (m, 2H, H-4 and 100), 7.51
(d, 1H, H-70, J ¼ 7.8), 7.96 (s, 1H, H-40), 8.10 (s, 1H, NH). 13C NMR
(CDCl3): 21.8 (CH2, C-10), 28.8 (CH2, C-20), 51.4 (CH2, C-30), 106.4,
109.6, 109.9, 110.0, 112.5, 112.6, 120.4, 123.1, 125.7, 130.3, 133.3,
132.5, 136.4, 136.5, 144.8, 146.8, 154.3, 154.8. Anal. calcd. for
C18H15F2N3: C, 69.44; H, 4.86; N, 13.50; Found: C, 69.33; H, 4.90;
N, 13.62.
3-[3-(5-{Trifluoromethyl}-1H-pyrazolyl)propyl]-1H-indole
(11a)
1-[3-(5-Fluoro-3-indolyl)propyl]-2-(2-nitrophenyl)-1H-
benzo[d]imidazole (12b)
Prepared from 5-(trifluoromethyl)-1H-pyrazole 0.083 g, 0.61mmol),
anhydrous potassium carbonate (0.083 g, 0.61mmol), and 3-(3-
indolyl)propyl-4-methylbenzenesulfonate derivative 2a (0.200g,
0.61mmol). The crude was purified by column chromatography
(hexane/AcOEt 2:1), 55% yield, oil. IR cmꢀ1: 3415 (N–H), 3057 (C–H
Prepared from 2-(2-nitrophenyl)-1H-benzo[d]imidazole (0.200 g,
0.84 mmol), anhydrous potassium carbonate (0.116 g, 0.84 mmol),
and 3-(5-fluoro-3-indolyl)propyl-4-methylbenzenesulfonate deriv-
ative 2b (0.150 g, 0.36 mmol). The crude was purified by column
chromatography (hexane/AcOEt 2:1), 57% yield, m.p.: 161.5–
162°C. IR cmꢀ1: 3453 (N–H), 3064 (C–H arom.), 2957–2860 (C–H
–
–
–
–
arom.), 2939–2852 (C–H aliph.), 1619 (C N), 1493 (C C), 1239
1
(CF3). H NMR (CDCl3): 2.17 (q, 2H, H-20, J ¼ 7.0), 2.60 (t, 2H, H-10,
J ¼ 1H NMR (CDCl3): 2.30 (q, 2H, H-20, J ¼ 7.2), 2.76 (t, 2H, H-10,
J ¼ 7.2 Hz), 4.19 (t, 2H, H-30, J ¼ 7.2 Hz), 6.50 (s, 1H, H-7), 6.97 (s, 1H,
H-5), 7.09–7.24 (m, 2H, H-2 and H-6), 7.35 (d, 2H, H-4 and 60, J ¼ 8.1),
7.54 (d, 1H, H-50, J ¼ 7.8), 8.01 (s, 1H, NH). 13C NMR (CDCl3): 21.8
(CH2, C-10), 30.3 (CH2, C-20), 52.2 (CH2, C-30), 104.1 (CH, C-50), 111.1
(CH, C-4), 114.4 (C–C, C-1), 118.6 (CH, C-7), 119.3 (CH, C-6), 121.6
(C–H, C-5), 122.1 (CH, C-2), 127.1 (C–C, C-8), 130.4 (CH, C-60), 136.3
(C–N, C-3), 141.9 and 142.4 (C–F, C-40). Anal. calcd. for C15H14F3N3:
C, 61.43; H, 4.81; N, 14.33; Found: C, 61.50; H, 4.79; N, 14.30.
aliph.), 1533 (NO2 asym), 1366 (NO2 sym), 1486 (C C). 1H NMR
–
–
(DMSO-d6): 2.03 (q, 2H, H-20, J ¼ 7.5), 2.60 (t, 2H, H-10, J ¼ 7.5 Hz),
4.19 (t, 2H, H-30, J ¼ 7.5 Hz), 6.87 (m, 2H, H-5 and H-7), 7.32 (m, 4H,
H-2, H-4, H-80 and 100), 7.60–7.75 (m, 5H, H-70, H-90, 200, 300 and 400),
8.14 (d, 1H, H-500, J ¼ 6.9), 10.9 (s, 1H, NH). 13C NMR (DMSO-d6): 21.8
(CH2, C-10), 29.1 (CH2, C-20), 44.2 (CH2, C-30), 110.6, 110.8, 112.4,
116.6, 118.7, 120.8, 121.9, 121.5, 122.3, 124.1, 125.0, 126.9, 130.8,
131.8, 132.8, 134.4, 135.8, 142.6, 148.2, 146.7, 149.4, 152.6. Anal.
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182
C. Ojeda-Gómez et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
arom.), 2973–2870 (C–H aliph.), 1488 (C C). 1H NMR (DMSO-d6):
–
calcd. for C24H19FN4O2: C, 69.55; H, 4.62; N, 13.52; Found: C, 69.37;
H, 4.55; N, 13.51.
–
1.45 (d, 3H, CH3, J ¼ 6.7), 2.80–3.05 (m, 2H, H-10), 3.35 (m, 1H, H-20),
6.78–7.30 (m, 5H, H-2, H-4, H-5, H-6 and H-7), 7.36–7.45 (m, 3H,
H-300, H-400 and H-500), 9.80 (s, 1H, NH). 13C NMR (DMSO-d6): 18.9
(CH3), 31.5 (CH2, C-20), 36.0 (CH2, C-10), 113.2, 116.6, 118.9, 120.9,
–
3-(1H-Indol-3-yl)-2-methylpropanal (13a)
A mixture of indole (0.500 g, 4.23 mmol) and methacrolein
(0.440 g, 2.35 mmol) was dissolved in dry CH2Cl2 (30 mL) in the
presence of molecular iodine as a catalyst. The reaction mixture
was stirred at room temperature for 1 h. The solvent was
evaporated in vacuo to obtain a crude, which was purified by
column chromatography (hexane/AcOEt 2:3), to produce pure 13a
as an oil (0.110 g, 55%). IR cmꢀ1: 3408 (N–H), 3051 (C–H arom.),
–
122.7, 126.5, 128.4, 128.5, 135.9, 136.1, 136.8, 161.8 (C N). Anal.
–
calcd. for C18H16ClN3: C, 69.79; H, 5.21; N, 13.56; Found: C, 70.01;
H, 5.24; N, 13.60.
2-(1-(5-Fluoro-1H-indol-3-yl)propan-2-yl)-5-chloro-1H-
benzo[d]imidazole (15b)
2959–2926 (C–H aldehyde), 1717 (C O), 1372 (sym) and 1457
Prepared from 3-(5-fluoro-1H-indol-3-yl)-2-methylpropanal 13b
(0.300 g, 1.46 mmol) and 4-chloro-o-phenylenediamine (0.210 g,
1.47 mmol) in ethanol. The crude was purified by column
chromatography (hexane/AcOEt 2:1), 18% yield, oil. IR cmꢀ1: 3413
–
(asym) (CH3). 1H NMR (DMSO-d6): 1.40 (d, 3H, CH3, J ¼ 7.2), 2.98 and
3.45 (m, 2H, H-10), 3.16 (m, 1H, H-20), 6.90 (m, 3H, H-2, H-5 and H-7),
–
7.00 (m, 2H, H-4 and H-6), 8.02 (s, 1H, NH). 9.50 (s, 1H, H–C O).
–
13C NMR (DMSO-d6): 13.8, 31.7, 46.9, 111.2, 118.7, 119.5, 122.1,
(N–H), 3052 (C–H arom.), 2979–2889 (C–H aliph.), 1495 (C C).
–
–
122.4, 136.2, 205.5.
1H NMR (DMSO-d6): 1.48 (d, 3H, CH3, J ¼ 7.0), 2.85–3.02 (m, 2H,
H-10), 3.34 (m, 1H, H-20), 6.82–7.29 (m, 3H, H-2, H-4, H-5 and H-7),
7.31–7.45 (m, 3H, H-300, H-400 and H-600), 9.98 (s, 1H, NH). 13C NMR
(DMSO-d6): 19.1 (CH3), 29.8 (CH2, C-20), 36.2 (CH2, C-10), 109.2,
109.3, 110.8, 111.0, 112.5, 112.7 113.5, 113.9, 114.0, 116.9, 120.7,
112.5, 122.9, 130.5, 130.9, 135.9, 136.8, 136.9, 148.5, 154.6, 161.5
–
General procedure for the preparation of
indolylbenzimidazoles 14a,b, 15a,b, and 16a,b
2-{1-(1H-Indol-3-yl)propan-2-yl}-1H-benzo[d]imidazole
(14a)
(C N). Anal. calcd. for C18H15ClFN3: C, 65.96; H, 4.61; N, 12.82;
–
A mixture of 3-(1H-indol-3-yl)-2-methylpropanal (13a) (0.220 g,
1.17 mmol) and o-phenylenediamine (0.127 g, 1.17 mmol) was
stirred in ethanol (50 mL) for 24 h under reflux. The solvent was
evaporated in vacuo to give an oily crude, which was purified by
column chromatography (hexane/AcOEt 1:2) to produce pure 14a
in 42% yield as a pale brown oil. IR cmꢀ1: 3420 (N–H), 3055 (C–H
Found: C, 66.06; H, 4.65; N, 12.80.
2-(1-(1H-Indol-3-yl)propan-2-yl)-6-nitro-1H-benzo[d]-
imidazole (16a)
Prepared from 3-(1H-indol-3-yl)-2-methylpropanal (13a) (0.500 g,
2.75mmol) and 4-nitro-o-phenylenediamine (0.420 g, 2.75 mmol)
in ethanol. The crude was purified by column chromatography
(hexane/AcOEt (2:1), 18% yield, oil. IR cmꢀ1: 3450 (N–H), 3058 (C–H
arom.), 2930–2890 (C–H aliph.), 1495 (C C). 1H NMR (DMSO-d6):
–
–
1.44 (d, 3H, CH3, J ¼ 6.7), 2.83–3.12 (m, 2H, H-10), 3.33 (m, 1H, H-20),
6.90–7.28 (m, 5H, H-2, H-4, H-5, H-6 and H-7), 7.30–7.44 (m, 4H,
H-300, H-400, H-500 and H-600), 9.77 (s, 1H, NH). 13C NMR (DMSO-d6):
18.3 (CH3), 30.2 (CH2, C-20), 35.5 (CH2, C-10), 110.2, 112.4, 113.9,
114.0, 118.9, 120.7, 120.8, 121.2, 122.7, 122.8, 127.5, 135.8, 136.1,
–
arom.), 2937–2865 (C–H aliph.), 1532 (NO2 asym), 1360 (NO2 sym),
1
–
1452 (C C). H NMR (DMSO-d ): 1.46 (d, 3H, CH , J¼ 6.9), 2.83–3.12
–
6
3
(m, 2H, H-10), 3.38 (m, 1H, H-20), 6.70–7.30 (m, 5H, H-2, H-4, H-5, H-6
and H-7), 7.50 (d, 1H, H-300, J ¼ 7.5), 7.71 (dd, 1H, H-400, J ¼ 7.8), 8.43
(s, 1H, H-600), 9.85 (s, 1H, NH). 13C NMR (DMSO-d6): 19.2 (CH3), 31.8
(CH2, C-20), 35.9 (CH2, C-10), 111.2, 112.5, 116.6, 118.8, 118.9, 120.9,
–
136.8, 160.5 (C N). Anal. calcd. for C18H17N3: C, 78.52; H, 6.22;
–
N, 15.26; Found: C, 78.48; H, 6.34; N, 15.32.
122.7, 126.5, 128.4, 128.5, 135.9, 136.1, 136.8, 144.5, 161.8 (C N).
–
2-(1-(5-Fluoro-1H-indol-3-yl)propan-2-yl)-1H-benzo[d]-
imidazole (14b)
Anal. calcd. for C18H16N4O2: C, 67.49; H, 5.03; N, 17.49; Found: C,
67.54; H, 4.99; N, 17.54.
Prepared from 3-(5-fluoro-1H-indol-3-yl)-2-methylpropanal (13b)
(0.380 g, 0.203 mmol) and o-phenylenediamine (0.220 g, 0.200 mmol)
in ethanol. The crude was purified by column chromatography
(hexane/AcOEt 1:2), 30% yield, oil. IR cmꢀ1: 3418 (N–H), 3056 (C–H
2-(1-(5-Fluoro-1H-indol-3-yl)propan-2-yl)-6-nitro-1H-
benzo[d]imidazole (16b)
Prepared from 3-(5-fluoro-1H-indol-3-yl)-2-methylpropanal 13b
(0.250 g, 1.22 mmol) and 4-nitro-o-phenylenediamine (0.190 g,
1.23 mmol) in ethanol. The crude was purified by column
chromatography (hexane/AcOEt 1:1), 14% yield, oil. 3448 (N–H),
arom.), 2932–2891 (C–H aliph.), 1492 (C C). 1H NMR (DMSO-d6):
–
–
1.45 (d, 3H, CH3, J ¼ 6.8), 2.84–3.04 (m, 2H, H-10), 3.32 (m, 1H, H-20),
6.92–7.30 (m, 4H, H-2, H-4, H-5 and H-7), 7.31–7.45 (m, 4H, H-300,
H-400, H-500 and H-600), 9.80 (s, 1H, NH). 13C NMR (DMSO-d6): 18.5
(CH3), 30.3 (CH2, C-20), 35.5 (CH2, C-10), 108.2, 108.3, 110.4, 110.8,
112.5, 112.7 113.8, 113.9, 114.0, 118.9, 120.7, 112.5, 122.9, 130.8,
–
3056 (C–H arom.), 2939–2896 (C–H aliph.), 1528 (NO2 asym), 1358
1
–
(NO sym), 1452 (C C). H NMR (DMSO-d ): 1.49 (d, 3H, CH , J¼ 6.9),
–
2
6
3
2.84–3.12 (m, 2H, H-10), 3.36 (m, 1H, H-20), 6.86–7.32 (m, 3H, H-2, H-4,
H-5 and H-7), 7.52 (d, 1H, H-300, J¼ 7.2), 7.75 (dd, 1H, H-400, J¼ 7.4), 8.48
(s, 1H, H-600) 9.87 (s, 1H, NH). 13C NMR (DMSO-d6): 18.7 (CH3), 30.3
(CH2, C-20), 35.9 (CH2, C-10), 108.2, 108.3, 111.8, 111.9, 112.5, 112.6,
113.5, 113.6, 120.7, 122.5, 122.9, 130.5, 130.9, 135.9, 136.8, 136.9,
–
130.9, 135.9, 136.8, 136.9, 147.7, 154.2, 160.5 (C N). Anal. calcd. for
–
C18H16FN3: C, 73.70; H, 5.50; N, 14.32; Found: C, 73.88; H, 5.55;
N, 14.40.
144.8, 147.9, 154.6, 161.8 (C N). Anal. calcd. for C H FN O : C,
–
2-(1-(1H-Indol-3-yl)propan-2-yl)-5-chloro-1H-benzo[d]-
imidazole (15a)
18 15
4 2
63.90; H, 4.47; N, 16.56; Found: C, 64.02; H, 4.42; N, 16.56.
Prepared from 3-(1H-indol-3-yl)-2-methylpropanal 13a (0.420 g,
2.25 mmol) and 4-chloro-o-phenylenediamine (0.320 g, 2.25 mmol)
in ethanol. The crude was purified by column chromatography
(hexane/AcOEt 1:1), 15% yield, oil. IR cmꢀ1: 3415 (N–H), 3050 (C–H
Pharmacological assays
Binding experiments for SERT was determined using [3H]-
paroxetine as radioligand and the clonal cell line HEK-293 that
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Arch. Pharm. Chem. Life Sci. 2014, 347, 174–184
Novel Indolalkyl Arenes as Antidepressants
183
overexpresses SERT (PerkinElmer). Briefly, assays were carried
out in a total volume of 0.5 mL, containing 50 mM Tris–HCl
buffer, pH 7.4, 120 mM NaCl, 5 mM KCl, membrane solution
(100 mL; 9.0 mg/per tube assay) and (50 mL, 2 nM) of [3H]paroxetine
T. F. Molski, M. T. Taber, N. J. Lodge, R. J. Mattson, J. E. Macor,
Bioorg. Med. Chem. Lett. 2009, 19, 4031–4033.
[16] U. Funke, S. Fischer, A. Hiller, M. Scheunemann, W. Deuther-
Conrad, P. Brust, J. Steinbach, Bioorg. Med. Chem. Lett. 2008, 18,
4727–4730.
and the compound to be tested at different concentrations (10ꢀ9
–
10ꢀ4 M). After 30 min at 27°C, incubations were terminated
by rapid filtration, with two 5-mL washes of buffer, through
Whatman GF/C filters that were presoaked with buffer containing
0.01% of polyethyleneimine, using a cell harvester (Brandel
Instruments, Gaithersburg, MD). Radioactivity was counted in a
Packard 1300 liquid scintillation counter with an efficiency of
approximately 50%. Nonspecific binding for [3H]paroxetine was
defined in the presence of 0.1 mM of naphthyl-isopropylamine
hydrochloride.
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Mattson, T. F. Molski, R. G. Krause, M. T. Taber, N. J. Lodge,
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