1-(2-alkanamidoethyl)-6-methoxyindole derivatives: A new class of potent indole melatonin analogues

Article abstract of DOI:10.1021/jm960653j

A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the melatonin receptor isolated from quail optic tecta in a series of in

Full text of DOI:10.1021/jm960653j

J . Med. Chem. 1997, 40, 2003-2010
2003
1-(2-Alk a n a m id oeth yl)-6-m eth oxyin d ole Der iva tives: A New Cla ss of P oten t
In d ole Mela ton in An a logu es
Giorgio Tarzia, Giuseppe Diamantini, Barbara Di Giacomo, and Gilberto Spadoni*
Istituto di Chimica Farmaceutica e Tossicologica, Universita` degli Studi di Urbino, Piazza Rinascimento 6,
I-61029 Urbino, Italy
Daniele Esposti
Istituto di Fisiologia Umana, Universita` degli Studi di Milano, Via Manzagalli 32, I-20131 Milano, Italy
Romolo Nonno, Valeria Lucini, Marilou Pannacci, Franco Fraschini, and Bojidar Michaylov Stankov
Cattedra di Chemioterapia, Dipartimento di Farmacologia, Universita` degli Studi di Milano, Via Vanvitelli, 32,
I-20129 Milano, Italy
Received September 17, 1996X
A new series of indole melatonin analogues, bearing the amido ethyl side chain attached at
the N-1 position of the indole nucleus, were synthesized and tested for their affinity for the
melatonin receptor isolated from quail optic tecta in a series of in vitro ligand-binding
experiments using 2-[125I]iodomelatonin as the labeled ligand. The biological activity was
evaluated using two models: effects on the forskolin-stimulated cAMP accumulation in explants
from quail optic tecta and evaluation of the GTPγS index derived from competition experiments
performed in the absence or presence of GTPγS. Compounds 2a and 2k -n , obtained by shifting
the methoxy group and the ethylamido side chain from the C-5 and C-3 positions of melatonin
to the C-6 and N-1 positions of the indole nucleus, exhibited an affinity similar to that of
melatonin itself, as well as full agonist activity. Optimization of the C-2 substituent by
introducing Br, phenyl, or COOCH3 (2b-d ) resulted in a significantly enhanced affinity (in
the picomolar range) and improved agonist biological activity. Compounds lacking the methoxy
group and bearing an N-alicyclic group (2h -j) behaved as partial agonists or antagonists.
In tr od u ction
Melatonin (N-acetyl-5-methoxytryptamine, aMT, 1),
the principal hormone of the pineal gland, has a number
of relevant actions.1 Its activity, mediated through
high-affinity G-protein-coupled receptors, is principally
related to the regulation of the photoperiodic responses,2
the entrainment of the mammalian circadian rhythms,3
the induction of sleep in humans,4 and retinal physiol-
F igu r e 1.
ogy.5 The physiological importance of other claims such
as antioxidant6 and immunomodulatory7 actions has not
macophoric groups of melatonin can be shifted from C-5
and C-3 to the C-6 and N-1 indole positions without loss
of potency.
In order to verify this hypothesis, we studied the
synthesis and biological activity of the new indole
derivatives 2a -n and 6 containing an alkanamido side
chain linked to the N-1 indole position. The rationale
of our design is evident upon comparison of the struc-
tures of both aMT and the new derivative 2a (Figure
1).
Furthermore, considering that melatonin is peripher-
ally metabolized to 6-hydroxymelatonin,13 the com-
pounds of this study might present a distinctly different
metabolic behavior and half-life. However, these latter
points have not been investigated yet. The minor
structural differences of these compounds relative to
melatonin could be sufficient to induce selectivity for
its target sites.
yet been substantiated. Despite its great potential, the
therapeutic use of aMT is limited due to its very short
biological half-life and poor selectivity for its target sites,
Mel1a, Mel1b, Mel1c, and Mel2, although the physiological
role of the latter two receptors is still unclear.8
We9 and other authors10 have shown that the key
elements for high binding affinity to the melatonin
receptor are the methoxy group and the N-alkanamido
side chain linked to an appropriate aromatic spacer, as
well as their relative spatial positions.
If one considers the NH indole unimportant for the
binding to the melatonin receptor (since it can be
replaced by other molecular frames11 without loss of
affinity), it can be assumed that the C-3 and N-1 indole
positions are equivalent, although N-methylmelatonin
is 40 times less potent than aMT itself.12 Thus, as a
working hypothesis, we assumed that the above phar-
Ch em istr y
* Corresponding author: Gilberto Spadoni, Istituto di Chimica
Farmaceutica, Universita` di Urbino, Piazza Rinascimento 6, 61029
Urbino, Italy. (Tel) +39-722-2545. (Fax) +39-722-2737. (E-mail)
chimfarm@chim.uniurb.it.
The novel melatonin analogues 2a -n (Table 1) were
synthesized starting from the corresponding indoles
3a -h as reported in Scheme 1. N-Cyanomethylation
X Abstract published in Advance ACS Abstracts, May 15, 1997.
S0022-2623(96)00653-X CCC: $14.00 © 1997 American Chemical Society

2004 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Tarzia et al.
Ta ble 1. Binding Affinitya and Biological Activity of Compounds 2a -n , 6, and 7
relative
affinityb
GTPγS
cAMP
indexd
compd
aMT (1)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
R
R1
R2
IC50
Ki
indexc
activitye
2.2
12
0.16
0.052
0.83
82
0.61
3.4
0.044
0.014
0.23
1
5.45
0.073
0.024
0.38
38
2450
165
1450
8180
4550
16
40
5
3.2
2.2
3230
0.059
0.028
1.6
1
0.85
1.3
1
0.85
1.2
1.15
1.02
0.98
0.4
A
A
A
A
A
A
PA
CH3
H
Br
6-OCH3
6-OCH3
6-OCH3
6-OCH3
H
5-OCH3
5-OCH3
H
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
cyclopropyl
cyclobutyl
cyclobutyl
CF3
phenyl
COOCH3
phenyl
1.45
0.93
0.95
0.29
0.75
0.14
0.16
0.18
0.97
0.32
1.1
0.98
1.05
0.08
1.02
0.82
0.91
23
1500
99
880
5000
2800
9.6
24
3.0
1.9
1.3
H
I
H
H
5400
360
3200
18000
10000
35
89
11
7.1
4.8
7100
0.8
0.2
A-PA
AN-PA
H
H
0.25
0.25
0.99
0.44
1
0.96
1.06
0
AN-PA
phenyl
AN-PA
H
H
H
H
6-OCH3
6-OCH3
6-OCH3
6-OCH3
A
PA
A
A
A
cyclopropyl
CH2CH2CH3
CH2CH3
6
7
1900
AN
A
A-PA
A
2-Br-melatonin
2-Ph-melatonin
6-Cl-melatonin
0.13
0.062
3.6
0.036
0.017
0.99
1.15
0.78
1.04
a
IC50 and Ki values are expressed in nM and are the means of three to 20 independent determinations, derived from nonlinear fitting
b
strategies. The SEM values were below 15% of the mean. Relative affinity ) (IC50 compound/IC50 aMT) determined in parallel, in the
same experiment. c GTPγS index ) [(IC50 with GTPγS)/(IC50 without GTPγS)] compound/[(IC50 with GTPγS)/(IC50 without GTPγS)] aMT.
cAMP index ) (percent inhibition compound)/(percent inhibition aMT) determined in parallel in the same experiment. e A, agonist; PA,
d
partial agonist; AN, antagonist.
Sch em e 1a
a
Reagents: (a) NaH, ClCH2CN, DMF, room temperature, 16 h (method A); (b) Raney nickel, H2, 4 atm, (RCO)2O, THF, 50 °C, 6 h
(method B); (c) Raney nickel, H2, 4 atm, EtOH-NH3, THF, 50 °C, 6 h; (d) (CF3CO)2O or cyclopropanecarbonyl or cyclobutanecarbonyl
chloride, THF, TEA, room temperature.
Sch em e 2a
of indoles 3a -h with sodium hydride and chloroaceto-
nitrile in DMF gave the required 1-(cyanomethyl)indoles
4a -h that were converted to the final compounds 2a -
g,m ,n by hydrogenation over Raney nickel and con-
comitant N-acylation with a suitable anhydride (method
A). Hydrogenation of the nitriles 4a , 4e, and 4h over
Raney nickel in THF and ammonia in ethanol provided
the desired crude amines which were then acylated
(cyclopropane or cyclobutanecarbonyl chloride/TEA) or
trifluoroacylated (CF3CO)2O/TEA) to give the desired
a
Reagents: (a) CH2dCH2CN, NaOCH3, 50 °C; (b) Raney nickel,
amides 2h -l (method B). The 1-(2-cyanoethyl)indole
H2, 4 atm, (EtCO)2O, THF, 50 °C, 6 h.
derivative 5 was prepared by reacting 3d with acrylo-
nitrile at 50 °C in the presence of sodium methoxide
(Scheme 2). Reduction (Raney nickel, H2) of the result-
ing nitrile and concomitant N-acylation with propionic
anhydride gave the desired N-propylpropionamido de-
rivative 6. The indole starting materials 3e,f,h are
commercially available (Aldrich Chemical Co). Indoles
3a ,14 3d ,14 and 3g15 were prepared according to previ-
ously described procedures. 6-Methoxy-2-bromoindole
(3b) was prepared according to a method previously
described for related compounds16 (Scheme 3). A modi-
fied Madelung synthesis17 was adopted for the prepara-
tion of 6-methoxy-2-phenyl-1H-indole (3c)18 (Scheme 4).
The intermediate N-(2-methyl-5-methoxyphenyl)benz-
amide was prepared by condensation of the commercial
2-methyl-5-methoxyaniline with benzoyl chloride/TEA
(toluene, reflux, 3 h, room temperature, 16 h; yield 83%,
mp 123-125 °C). 1-(Cyanomethyl)indole (4h ) was
synthesized according to a literature method.19 Com-
pound 7, N-[(2-phenyl-1H-indol-3-yl)ethyl]cyclobutane-

Potent Indole Melatonin Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2005
Sch em e 3a
was the case with compounds 2i, 2j, and 7. On the basis
of the data obtained, a cAMP index, assigning a rank
of potency for the compounds, was calculated as fol-
lows: percent inhibition compound/percent inhibition
aMT.
(ii) Effects of Coin cu ba tion w ith GTP γS on th e
IC50 Va lu es (GTP γS In d ex). The choice of introducing
the GTPγS index was based on the knowledge that the
aMT receptor is coupled to a regulatory G-protein in its
signal-transduction pathway.21,24 It is well-known that
guanine nucleotides shift a significant part of the
available receptors from the state of high-affinity con-
formation (Rh) to a state of lower affinity conformation
(Rl).25 Agonists possess higher affinity for the Rh form,
while antagonists cannot distinguish between Rh and
Rl or have a higher affinity for Rl.25,26 This is also the
mechanism by which the difference between the efficacy
of agonists and antagonists is explained.27 Assuming
that under basal, unstimulated conditions there is an
existing ratio of Rh/Rl < 1, the system is prevalently
inactive. In that case the agonists, because of their
higher affinity for the Rh, would create a shift in the
equilibrium toward the Rh state, with a consequent
activation of the signal-transduction pathway, while the
antagonists would keep the basal conditions unaltered
or at best change the ratio of Rh/Rl toward values less
than basal values.28 This type of interaction would
allow prediction of the efficacy of a compound after
having measured its affinity for both Rh and Rl.29 The
prediction was that, under conditions of competition
analysis, coincubation with GTPγS would result in
increased IC50 values for an agonist (giving a shift to
the right of the curve), while the IC50 values for an
antagonist would remain unchanged or decrease (the
curve would shift to the left). The series of pilot studies
using melatonin (agonist) and compound 720a (antago-
nist) completely confirmed the prediction of this model.
In the presence of GTPγS, the aMT IC50 values in-
creased by 3-6 times while the IC50 values for com-
pound 7 showed a 2-3-fold decrease. These results
completely justified the application of this new approach
to assess the agonist/antagonist nature of all the
compounds reported in this study.
a
Reagents: (a) n-BuLi, -78 °C; (b) CO2; (c) t-BuLi, -78 °C; (d)
1,2-dibromotetrachloroethane.
Sch em e 4a
a
Reagents: (a) benzoyl chloride, TEA, toluene, reflux, 3 h, room
temperature 16 h; (b) n-BuLi, THF, room temperature, 20 h.
carboxamide, used as reference antagonist, was syn-
thesized as previously described.20a
P h a r m a cology
Bin d in g Stu d ies a n d Deter m in a tion of Affin ity.
The affinity of the analogs at the melatonin binding site
in the quail optic tecta was determined in competition
binding analyses using 2-[125I]iodomelatonin as a la-
beled ligand (100 pM). The IC50 values were determined
and Ki values calculated by using nonlinear fitting
strategies. The source of the animals, the characteriza-
tion of the melatonin receptor, and the isolation of the
crude membrane preparations have been described in
detail elsewhere.21,22
Biologica l Activity Deter m in a tion . Biological ac-
tivity was evaluated using two methods: (i) effects on
the forskolin-stimulated cAMP accumulation in quail
optic tecta explants and (ii) effects of coincubation with
GTPγS (10-4 M) on the IC50 values (GTPγS index).
(i) Effects on F or sk olin -Stim u la ted cAMP Ac-
cu m u la tion . The punching technique, the handling of
tissue explants, and cAMP determinations have been
described in detail elsewhere.23 The concentrations of
the compounds to be used were calculated on the basis
of their affinity, as follows: the experimentally derived
maximum effective dose of melatonin was around 10-7
M. Therefore, the relative affinity for each compound
was determined as IC50 compound/IC50 aMT and the
dose of the compound equivalent to that of melatonin
(MED, melatonin equivalent dose) in terms of receptor
occupancy was calculated (MED compound ) relative
affinity compound × 10-7). Afterward, two doses of each
compound were assayed: one that was equal (or closest)
to the calculated MED and another greater by 1 order
of magnitude. For example, a compound with a relative
Briefly, in each experiment aMT was assayed as a
reference standard, GTPγS was used in a constant
concentration of 10-4 M, and the labeled ligand was
always 200 pM. The rest of the conditions of the
experiment were as described elsewhere.21,22 In order
to compare these results with those of the cAMP
analysis, a numerical index was introduced (GTPγS
index), equal to: [(IC50 + GTPγS)/(IC50 - GTPγS)]-
compound/[(IC50 + GTPγS)/(IC50 - GTPγS)] aMT.
As seen in Table 1, the GTPγS index evaluation
thoroughly corresponded to that obtained using the
cAMP data. The final evaluation of the compounds
(agonist, partial agonist, antagonist) was made taking
into consideration both indices (GTPγS index and
cAMP). Compounds with indices having numerical
values >0.8 were considered full agonists; values rang-
ing from 0.2 to 0.8 were indicative of partial agonists
and values <0.2 were considered characteristic for the
antagonists. In the few cases in which the values of
both indices were close to, but not within, the theoreti-
cally determined limits of the range 0.2-0.8, a double
denomination was adopted, i.e. if a compound had a
affinity of 0.025 has a MED value of 2.5 × 10-9
.
Therefore the doses utilized were 10-9 and 10-8 M. This
avoided the use of inadequately high or low doses in the
analyses, as has been the common practice to date. In
all cases the two concentrations employed gave similar
results, thus confirming the validity of the theoretical
assumption regarding the receptor occupancy. In only
a few cases, the higher dose could not be used, due to
problems related to the solubility of the compounds. This

2006 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Tarzia et al.
GTPγS index ) 0.16 and cAMP index ) 0.25, it was
considered as antagonist-partial agonist.
pounds lacking the methoxy substituent and N-acylated
with an alicyclic group (2h -j) showed a dramatic
decrease in biological efficacy, behaving as partial
agonists or antagonists. The indole C-2 phenyl substi-
tution does not appear to influence the biological activ-
ity, as the C-2 substituted (2j) and C-2 unsubstituted
(2i) analogues showed the same efficacy. Therefore, the
biological activity of these new derivatives appears to
be modulated by the presence and the position of the
methoxy substituent and by the nature of the N-acyl
group, and these data are in agreement with recently
reported results,20 using different compounds.
The results of this study are consistent with our initial
hypothesis that it should be possible to shift the phar-
macophoric groups of the aMT moiety to suitable
positions on the indole nucleus, while still retaining high
binding affinity and efficacy. This confirms that the
proton-donor NH indole is not essential to the anchoring
of a ligand to the aMT receptor and that the lower
affinity of the N-methylmelatonin is not due to the lack
of the hydrogen donor, but rather to steric hindrance of
the alkyl substituent in the receptor ligand interaction.
By comparing 2b and 2c with aMT it can be seen that
when the rest of the molecule was optimized by means
of the introduction of a C-2 bromine or a C-2 phenyl,
we obtained compounds which, with ca. 40-fold greater
affinity than aMT itself, represent some of the most
potent melatonin agonists reported to date.
Resu lts a n d Discu ssion
The binding affinities for the melatonin receptor, as
well as the biological activity of the new compounds
2a -n and 6, are reported in Table 1. In accordance
with our working hypothesis, the highest binding af-
finity occurs when the side chain and the methoxy
substituent are in the N-1 and C-6 positions of the
indole, respectively. In these compounds (2a -d and
2k -n ) the distance between the methoxy group and the
amido function is comparable to that of aMT. In our
derivatives the importance of the methoxy substituent
on the benzene nucleus of the indole for melatonin-like
properties was investigated by deleting this group or
by shifting its position. Both deletion of the methoxy
substituent, as in compounds 2e,h -j, and its displace-
ment from the C-6 to the C-5 position, as in compound
2f, led to a dramatic decrease in the binding affinity.
Interestingly, the compound 2f also exhibited a de-
creased biological activity. This indicates that 2f be-
haves like a partial agonist. As in other series of
melatonin analogues, structural variations at the N-
alkanamido group were found to be important in adjust-
ing the binding of the side chain to the receptor.
Replacement of the acetyl group by propanoyl (2n ) or
butanoyl (2m ) led to a sharp increase in the binding
affinity, but a marked drop was observed with cyclo-
propanoyl (2l) substitution. A slight decrease in binding
affinity also occurred when moving from the N-acetyl
(2a ) to the N-trifluoroacetyl (2k ) derivative. While the
compound with a shorter C-3 alkyl chain [N-[(5-meth-
oxy-1H-indol-3-yl)methyl]propanamide]9 exhibited no
affinity to the melatonin receptor (IC50 > 10-5 M),
compound 6, with a longer N-alkyl chain [N-(3-alkan-
amidopropyl)], was slightly less potent than 2d which
has the natural ethyl alkanamido chain. Another
modification concerned the introduction of a suitable
substituent in the C-2 indole position. In fact, our
previous studies9,30,31 and the very high affinity of
2-iodomelatonin demonstrated the importance of this
type of substitution for affinity to the melatonin recep-
tor. As entries 2b-d clearly illustrate, the binding
affinity of the 2-bromo (2b), 2-phenyl (2c), and 2-car-
bomethoxy (2d ) derivatives is much greater than that
found for the corresponding compounds lacking the C-2
indole substituent. This effect is also evident for the
5-methoxy analogues, among which the 2-iodo deriva-
tive 2g has a binding affinity 15 times greater than that
of the C-2 unsubstituted compound 2f, thus confirming
our hypothesis regarding the presence of a secondary
binding site around the C-2 indole position, in agree-
ment with a previous study11b using different com-
pounds.
Another important contribution of this study was the
introduction of the GTPγS index. This approach com-
pletely confirmed the cAMP data. Moreover, it allows
rapid and reliable screening of a large number of aMT
analogues for their efficacy, allowing the estimation of
their potency and the assigning of the order of efficacy
derived from structure-activity studies.
Exp er im en ta l Section
Solvents and reagents were of the highest commercial grade
available and were used without additional purification.
Melting points were determined on a Bu¨chi SMP-510 capillary
melting point apparatus and are uncorrected. 1H-NMR spec-
tra were recorded on a Bruker AC 200 spectrometer; chemical
shifts are reported in ppm and given in δ units. EI-MS spectra
(70 eV) were taken on a Fisons Trio 1000. Only molecular
ions (M+) and base peaks are given. Infrared spectra were
obtained on a Bruker FT-48 spectrometer; absorbances are
reported in ν (cm-1). Elemental analyses were performed on
a Carlo Erba analyzer.
2-Br om o-6-m eth oxyin d ole (3b). n-Butyllithium (4.2 mL
of 2.5 M solution in hexane, 10.5 mmol) was added dropwise
over 15 min to a solution of 6-methoxyindole (1.47 g, 10 mmol)
in dry THF (20 mL) at -70 °C, under a nitrogen atmosphere.
After 30 min of stirring at -68 °C, CO2 gas was bubbled
through the solution for 10 min, and the clear solution was
allowed to reach room temperature. The excess of CO2 was
removed under vacuum (10 °C, 1 mmHg), and the solvent was
concentrated to ca. 5 mL. An additional 15 mL of dry THF
was added, and the suspension was cooled to -70 °C. tert-
Butyllithium (6.2 mL of 1.7 M solution in pentane, 10.5 mmol)
was then added dropwise over 10 min, and the mixture was
stirred for 2 h at -68 °C. A solution of 1,2-dibromotetrachlo-
roethane (3.26 g, 10 mmol) in dry THF (7 mL) was added
dropwise, and the mixture was stirred at -68 °C for 1.5 h.
The mixture was then poured into ice-water (30 g), and a
saturated aqueous NH4Cl solution was added to acidic pH. The
aqueous solution was extracted with ether (3 × 30 mL), and
the combined extracts were washed with brine, dried (Na2-
SO4), and evaporated in vacuo at room temperature. The semi-
solid residue was purified by flash chromatography (silica gel,
cyclohexane/ethyl acetate, 9:1) and crystallization from CHCl3/
The potential agonist or antagonist properties of the
synthesized compounds were evaluated by using the
GTPγS index (Figure 2) or by measuring their influence
on the cAMP synthesis (Figure 3) (see Pharmacology
section). The analogues bearing a 6-methoxy substitu-
ent and N-acylated with alkyl or trifluoromethyl groups
(2a -d ,k ,m ,n ) exhibited evident agonistic activity. On
the contrary, the 6-methoxy-N-cyclopropylamido deriva-
tive 2l showed a decreased efficacy and appeared to be
a partial agonist. All of the 2-substituted N-propanoyl
derivatives (2b -e) behaved as full agonists. Com-

Potent Indole Melatonin Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2007
F igu r e 2. Examples of the evaluation of the biological activity of the compounds by using the GTPγS index: competition
experiments performed with a fixed concentration of the labeled ligand (200 pM 2-[125I]iodomelatonin) and varying concentrations
of the competing drug, in the absence or presence of GTPγS (10-4 M). Ratio ) IC50 + GTPγS/IC50. GTPγS index ) ratio compound/
ratio aMT. IC50 values are expressed in nM. Activity: when GTPγS index <0.2 ) AN (antagonist); between 0.2 and 0.8 ) PA
(partial agonist); >0.8 ) A (agonist).
6-Meth oxy-2-p h en ylin d ole (3c). n-Butyllithium (13.75
mL of 1.6 M solution in hexane, 22 mmol) was added dropwise
to an ice-cooled stirred solution of N-(2-methyl-5-methoxyphen-
yl)benzamide (2.41 g, 10 mmol) in dry THF (20 mL), under a
nitrogen atmosphere. The stirred mixture was kept at room
temperature for 20 h, then cooled to 0 °C, and treated dropwise
with 2 N HCl (11 mL). The organic layer was separated and
the aqueous layer extracted with ether (3 × 20 mL). The
combined organic layers were washed with brine, dried (Na2-
SO4), and concentrated in vacuo to obtain a black residue
which was then purified by flash chromatography (silica gel,
toluene as eluent) and crystallization from toluene to give 3c
as a white solid (0.45 g, 20%): mp 177-178 °C (lit.18 mp 168-
1
170 °C); H NMR (CDCl3) δ 3.88 (s, 3H), 6.76 (m, 1H), 6.79-
7.66 (m, 8H), 6.26 (br s, 1H); MS (EI) m/ z 223 (M+), 208 (100).
Gen er a l P r oced u r e for th e Syn th esis of 1-(Cya n o-
F igu r e 3. Examples of the evaluation of the biological activity
m eth yl)in d ole Der iva tives (4a -h ). A solution of the ap-
propriate indole 3a -h (10 mmol) in dry DMF (10 mL) was
added dropwise to a stirred ice-cooled suspension of sodium
hydride (0.42 g of an 80% dispersion in mineral oil, 14 mmol)
in dry DMF (30 mL) under a N2 atmosphere. After the
addition, the mixture was stirred at 0 °C for 30 min, then
chloroacetonitrile (1.06 g, 14 mmol) was added dropwise, and
the resulting mixture was stirred at room temperature for 16
h, then poured into ice-water (250 g), and extracted with ethyl
acetate (3 × 70 mL). The organic phase was washed with
brine, dried over sodium sulfate, and concentrated under
reduced pressure to give a residue which was purified by flash
column chromatography (silica gel; cyclohexane/ethyl acetate,
7:3) and crystallization.
of the compounds by measuring the effect on forskolin (10-5
M)-stimulated cAMP accumulation in explants from quail optic
tecta. C, control; F, forskolin. Agonist: ratio of percent
inhibition compound/percent inhibition aMT > 0.8. Partial
agonist: ratio of percent inhibition compound/percent inhibi-
tion aMT is between 0.8 and 0.2. Antagonist: ratio of percent
inhibition compound/percent inhibition aMT < 0.2.
hexane, yielding 0.68 g (30%) of the title compound: mp 69-
71 °C dec; 1H NMR (CDCl3) δ 3.84 (s, 3H), 6.46 (m, 1H), 6.77,
6.82 (dd, 1H, J ) 2.24 Hz and J ) 8.3 Hz), 6.81 (br s, 1H),
7.40 (dd, 1H, J ) 0.64 Hz and J ) 8.26 Hz), 7.95 (br s, 1H); IR
3370, 1440 cm-1; MS (EI) m/ z 225, 227 (M+), 210, 212 (100).

2008 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13
Tarzia et al.
6-Meth oxy-1-(cya n om eth yl)in d ole (4a ): white solid, 0.56
g (30%); mp 104-5 °C (ether/hexane); 1H NMR (CDCl3) δ 3.91
(s, 3H), 4.96 (s, 2H), 6.54 (dd, 1H, J ) 0.86 Hz and J ) 3.3
Hz), 6.82, 6.85 (dd, 1H, J ) 8.57 Hz and J ) 2.2 Hz), 6.89 (d,
1H, J ) 2.2 Hz), 6.99 (d, 1H, J ) 3.3 Hz), 7.53 (d, 1H, J )
8.57 Hz); IR (Nujol) 2249, 1626 cm-1; MS (EI) m/ z 186 (M+),
171 (100).
N-[2-(2-Br om o-6-m eth oxy-1H-in d ol-1-yl)eth yl]p r op a n -
a m id e (2b): white crystalline solid, 0.15 g (45%); mp 97-98
1
°C (ether); H NMR (CDCl3) δ 1.09 (t, 3H), 2.12 (q, 2H), 3.61
(q, 2H), 3.86 (s, 3H), 4.33 (t, 2H), 5.48 (br s, 1H), 6.52 (s, 1H),
6.75, 6.80 (dd, 1H, J ) 8.37 Hz and J ) 2.22 Hz), 6.84 (d, 1H,
J ) 2.22 Hz), 7.40 (d, 1H, J ) 8.58 Hz); IR (Nujol) 3230, 1634
cm-1; MS (EI) m/ z 324, 326 (M+), 189 (100). Anal. (C14H17
-
BrN2O2) C, H, N.
2-Br om o-6-m eth oxy-1-(cya n om eth y)lin d ole (4b): white
solid, 1.99 g (75%); mp 68-70 °C dec (methanol); 1H NMR
(CDCl3) δ 3.90 (s, 3H), 5.04 (s, 2H), 6.61 (d, 1H, J ) 0.64 Hz),
6.80 (br s, 1H), 6.83, 6.88 (dd, 1H, J ) 8.58 Hz and J ) 2.23
Hz), 7.42, 7.46 (dd, 1H, J ) 8.58 Hz and J ) 0.64 Hz); IR
(Nujol) 2250, 1620 cm-1; MS (EI) m/ z 264, 266 (M+), 249, 251
(100).
6-Meth oxy-2-p h en yl-1-(cya n om eth yl)in d ole (4c): amor-
phous solid, 0.21 g (8%); 1H NMR (CDCl3) δ 3.80 (s, 3H), 4.70
(s, 2H), 6.43 (br s, 1H), 6.60-6.90 (m, 3H), 7.10-7.60 (m, 5H);
MS (EI) m/ z 262 (M+), 247 (100).
2-Ca r b om et h oxy-6-m et h oxy-1-(cya n om et h yl)in d ole
(4d ): 1.7 g (70%); mp 178-80 °C (methanol); 1H NMR (CDCl3)
δ 3.92 (s, 3H), 3.93 (s, 3H), 5.58 (s, 2H), 6.80 (br s, 1H), 6.89,
6.93 (dd, 1H, J ) 8.88 Hz and J ) 2.22 Hz), 7.33 (br s, 1H),
7.58 (d, 1H, J ) 8.57 Hz); IR (Nujol) 1707, 1624 cm-1; MS (EI)
m/ z 244 (M+), 229 (100).
N-[2-(6-Meth oxy-2-p h en yl-1H-in d ol-1-yl)eth yl]p r op a n -
a m id e (2c): white crystalline solid, 0.19 g (58%); mp 106-
107 °C (ether/hexane); H NMR (CDCl3) δ 0.96 (t, 3H), 1.93
1
(q, 2H), 3.41 (q, 2H) 3.91 (s, 3H), 4.35 (t, 2H), 5.20 (br s, 1H),
6.49 (d, 1H, J ) 0.64 Hz), 6.80, 6.85 (dd, 1H, J ) 8.57 Hz and
J ) 2.22 Hz), 6.97 (d, 1H, J ) 2.22 Hz), 7.46-7.53 (m, 6H); IR
(Nujol) 3190, 1678 cm-1; MS (EI) m/ z 322 (M+), 236 (100).
Anal. (C20H22N2O2) C, H, N.
N-[2-(2-Ca r bom eth oxy-6-m eth oxy-1H-in d ol-1-yl)eth yl]-
p r op a n a m id e (2d ): white crystalline solid, 0.21 g (68%); mp
133 °C (ethyl acetate/hexane); 1H NMR (CDCl3) δ 1.06 (t, 3H),
2.10 (q, 2H), 3.68 (q, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.65 (t,
2H), 6.02 (br s, 1H), 6.80, 6.84 (dd, 1H, J ) 8.37 Hz and J )
2.22 Hz), 6.87 (br s, 1H), 7.27 (s, 1H), 7.52 (d, 1H, J ) 8.9 Hz);
IR (Nujol) 3262, 1707, 1638 cm-1; MS (EI) m/ z 304 (M+), 231
(100). Anal. (C16H20N2O4) C, H, N.
N-[2-(2-P h en yl-1H-in d ol-1-yl)eth yl]p r op a n a m id e (2e):
oil, overall yield (starting from 2-phenylindole) 7%; H NMR
2-P h en yl-1-(cya n om eth yl)in d ole (4e). This compound
was used as a crude intermediate because it is difficult to
separate from the starting unreacted 2-phenylindole.
5-Meth oxy-1-(cya n om eth yl)in d ole (4f): 0.62 g (33%); mp
1
(CDCl3) δ 0.96 (t, 3H), 1.92 (q, 2H), 3.42 (q, 2H), 4.40 (t, 2H),
5.19 (br s, 1H), 6.57 (s, 1H), 7.15-7.66 (m, 9H); IR (Nujol) 3155,
1683 cm-1; MS (EI) m/ z 292 (M+), 206 (100). Anal.
(C19H20N2O) C, H; N: calcd, 9.58; found, 9.11.
N-[2-(5-Meth oxy-1H-in d ol-1-yl)eth yl]p r op a n a m id e (2f):
white crystalline solid, 0.14 g (55%); mp 80-81 °C (ethyl
acetate/hexane); 1H NMR (CDCl3) δ 1.10 (t, 3H), 2.12 (q, 2H),
3.61 (q, 2H) 3.85 (s, 3H), 4.26 (t, 2H), 5.50 (br s, 1H), 6.43 (dd,
1H, J ) 3.16 Hz and J ) 0.65), 6.86, 6.90 (dd, 1H, J ) 8.9 Hz
and J ) 2.22 Hz), 7.03 (d, 1H, J ) 3.18 Hz), 7.10 (d, 1H, J )
2.22 Hz), 7.25 (dd, 1H, J ) 8.9 Hz and J ) 0.64 Hz); IR (Nujol)
3312, 1647 cm-1; MS (EI) m/ z 246 (M+), 160 (100). Anal.
(C14H18N2O2) C, H, N.
1
97-98 °C (ethyl acetate/hexane); H NMR (CDCl3) δ 3.87 (s,
3H), 4.95 (s, 2H), 6.53, 6.54 (dd, 1H, J ) 0.94 Hz and J ) 3.18
Hz), 6.95, 7.00 (dd, 1H, J ) 8.9 Hz and J ) 2.54 Hz), 7.06 (d,
1H, J ) 3.18 Hz), 7.12 (d, 1H, J ) 2.22 Hz), 7.27 (dd, 1H, J )
8.9 Hz and J ) 2.2 Hz); IR (Nujol) 1611, 1577 cm-1; MS (EI)
m/ z 186 (M+), 171 (100).
2-Iod o-5-m eth oxy-1-(cya n om eth yl)in d ole (4g): 2.18 g
(70%); mp 126-127 °C (ethyl acetate/hexane); 1H NMR (CDCl3)
δ 3.85 (s, 3H), 5.04 (s, 2H), 6.79 (br s, 1H), 6.88, 6.93 (dd, 1H,
J ) 8.9 Hz and J ) 2.23 Hz), 7.01 (d, 1H, J ) 2.22 Hz), 7.26
(d, 1H, J ) 8.9 Hz); IR (Nujol) 2255, 1621 cm-1; MS (EI) m/ z
312 (M+), 76 (100).
N-[2-(2-Iod o-5-m et h oxy-1H -in d ol-1-yl)et h yl]p r op a n -
a m id e (2g): white crystalline solid, 0.093 g (25%); mp 129-
130 °C (ether/hexane); H NMR (CDCl3) δ 1.08 (t, 3H), 2.09
1
2-Car bom eth oxy-6-m eth oxy-1-(2-cyan oeth yl)in dole (5).
Sodium methoxide (0.054 g, 1 mmol) was added to a 50 °C
preheated solution of 3d (0.205 g, 1 mmol) in acrylonitrile (3
mL). The reaction mixture was stirred for 0.5 h at room
temperature, then poured into ice-water, and extracted (3×)
with CHCl3; the combined extracts were washed with brine
and dried (Na2SO4). After removal of the solvent the crude
residue was chromatographed over silica gel (cyclohexane/ethyl
acetate, 8:2, as eluent) to give a white crystalline solid: yield,
0.23 g (88%). Crystallization from ethanol: mp 114-116 °C;
1H NMR (CDCl3) δ 2.92 (t, 2H), 3.91 (s, 3H), 3.92 (s, 3H), 4.81
(t, 2H), 6.84, 6.89 (dd, 1H, J ) 8.3 Hz and J ) 2.44 Hz), 7.27
(s, 1H), 7.30 (br s, 1H), 7.54, 7.58 (dd, 1H, J ) 8.3 Hz and J )
0.98 Hz); IR (Nujol) 2249, 1696 cm-1; MS (EI) m/z 258 (M+),
218 (100).
(q, 2H), 3.55 (q, 2H), 3.82 (s, 3H), 4.28 (t, 2H), 5.65 (br s, 1H),
6.69 (s, 1H), 6.76, 6.81 (dd, 1H, J ) 8.9 Hz and J ) 2.55 Hz),
6.96 (d, 1H, J ) 2.54 Hz), 7.24 (d, 1H, J ) 8.9 Hz); IR (CDCl3)
3445, 1668 cm-1; MS (EI) m/ z 372 (M+), 245 (100). Anal.
(C14H17IN2O2) C, H, N.
N-[2-(6-Meth oxy-1H-in d ol-1-yl)eth yl]bu ta n a m id e (2m ):
white crystalline solid, 0.19 g (72%); mp 93-94 °C (ether/
hexane); 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.60 (m, 2H), 2.08 (t,
2H), 3.63 (q, 2H), 3.87 (s, 3H), 4.24 (t, 2H), 5.43 (br s, 1H),
6.44, 6.45 (dd, 1H, J ) 3.18 Hz and J ) 0.63 Hz), 6.77 (d, 1H,
J ) 2.23 Hz), 6.82 (br s, 1H), 6.95 (d, 1H, J ) 3.18 Hz), 7.48,
7.52 (dd, 1H, J ) 8.26 Hz and J ) 0.95 Hz); IR (Nujol) 3252,
1640 cm-1; MS (EI) m/ z 260 (M+), 173 (100). Anal.
(C15H20N2O2) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Acyla m in o-
N-[2-(1H-in dol-1-yl)eth yl] Der ivatives (2a-g,m ,n ). Meth od
A. A solution of the suitable 1-(cyanomethyl)indole 4a -g (1
mmol) in THF (5 mL) and acetic, propionic, or butyric
anhydride (2 mL) was hydrogenated over Raney nickel at 4
atm of H2 for 6 h at 50 °C. The catalyst was filtered on Celite,
and the filtrate was concentrated in vacuo and partitioned
between ethyl acetate and 2 N NaOH. The organic layer was
washed with brine, dried (Na2SO4), and evaporated under
reduced pressure to give the crude title compounds (2a -g,m ,n )
which were purified by flash chromatography (silica gel;
cyclohexane/ethyl acetate, 3:7) and crystallization.
N-[2-(6-Met h oxy-1H -in d ol-1-yl)et h yl]a cet a m id e (2a ):
white crystalline solid, 0.17 g (73%); mp 118-119 °C (ethyl
acetate/hexane); 1H NMR (CDCl3) δ 1.92 (s, 3H), 3.61 (q, 2H),
3.87 (s, 3H), 4.24 (t, 2H), 5.50 (br s, 1H), 6.45 (d, 1H, J ) 3.16
Hz), 6.78, 6.82 (dd, 1H, J ) 8.37 Hz and J ) 2.22 Hz), 6.83 (d,
1H, J ) 2.22 Hz), 6.96 (d, 1H, J ) 3.17 Hz), 7.50 (d, 1H, J )
8.35 Hz); IR (Nujol) 3303, 1639 cm-1; MS (EI) m/ z 232 (M+),
160 (100). Anal. (C13H16N2O2) C, H, N.
N-[2-(6-Meth oxy-1H-in dol-1-yl)eth yl]pr opan am ide (2n ):
white crystalline solid, 0.14 g (55%); mp 105-106 °C (ethyl
acetate/hexane); 1H NMR (CDCl3) δ 1.10 (t, 3H), 2.13 (q, 2H),
3.62 (q, 2H), 3.87 (s, 3H), 4.24 (t, 2H), 5.43 (br s, 1H), 6.45 (d,
1H, J ) 3.16 Hz), 6.78, 6.82 (dd, 1H, J ) 8.34 Hz and J )
2.22 Hz), 6.83 (d, 1H, J ) 2.22 Hz), 6.95 (d, 1H, J ) 3.16 Hz),
7.52 (d, 1H, J ) 8.34 Hz); IR (Nujol) 3253, 1641 cm-1; MS (EI)
m/ z 246 (M+), 160 (100). Anal. (C14H18N2O2) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Acyla m in o-
N-[2-(1H-in d ol-1-yl)eth yl] Der iva tives (2h -l). Meth od B.
A solution of the suitable 1-(cyanomethyl)indole (4a ,e,h ) (1
mmol) in THF (10 mL) and an ammonia-saturated solution
in ethanol (1 mL) was hydrogenated over Raney nickel at 4
atm of H2 for 6 h at 50 °C. The catalyst was filtered on Celite
and the filtrate concentrated in vacuo and dissolved in dry
THF (3 mL). To this ice-cooled solution were added TEA (0.14
mL, 1 mmol) and trifluoroacetic anhydride (0.14 mL, 1 mmol)
[or cyclopropanecarbonyl chloride or cyclobutanecarbonyl chlo-
ride (1 mmol)]. The ice bath was removed and the solution
stirred for 1-3 h (until the amine disappeared in time course

Potent Indole Melatonin Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 13 2009
(6) (a) Reiter, R. J .; Melchiorri, D.; Sewerynek, E.; Poeggeler, B.;
Barlow-Walden, L.; Chuang, J . I.; Ortiz, G. G.; Acuna-Castro-
viejo, D. A review of the evidence supporting melatonin’s role
as an antioxidant. J . Pineal. Res. 1995, 18, 1-11. (b) Huether,
G. Melatonin as an antiaging drug: between facts and fantasy.
Gerontology 1996, 42, 87-96. (c) Giusti, P.; Lipartiti, M.;
Franceschini, D.; Schiavo, N.; Floreani, M.; Manev, H. Neuro-
protection by melatonin from kainate-induced exitotoxicity in
rats. FASEB J . 1996, 10, 891-895.
TLC analysis, CHCl3 ammonia saturated-MeOH, 95:5, as
eluent). The solvent was evaporated in vacuo, and the residue
was taken up in ethyl acetate, washed with a saturated
aqueous solution of NaHCO3 followed by brine, dried (Na2SO4),
and evaporated again. Purification by flash chromatography
(silica gel; cyclohexane/ethyl acetate, 4:6) and crystallization
gave the required compounds 2h -l.
N-[2-(1H -In d ol-1-yl)et h yl]cyclop r op a n eca r b oxa m id e
(2h ): white crystalline solid, 0.13 g (55%); mp 91-92 °C (ethyl
acetate/hexane); 1H NMR (CDCl3) δ 0.73 (m, 2H), 0.99 (m, 2H),
1.21 (m, 1H), 3.66 (q, 2H), 4.31 (t, 2H), 5.59 (br s, 1H), 6.54 (d,
1H, J ) 3.1 Hz), 7.09-7.27 (m, 3H), 7.38 (d, 1H, J ) 8.04 Hz),
7.66 (d, 1H, J ) 7.93 Hz); IR (Nujol) 3304, 1640 cm-1; MS (EI)
m/ z 228 (M+), 143 (100). Anal. (C14H16N2O) C, H, N.
N-[2-(1H-In dol-1-yl)eth yl]cyclobu tan ecar boxam ide (2i):
white crystalline solid, 0.18 g (74%); mp 103 °C (ethyl acetate/
(7) Maestroni, G. J . M. The immunoneuroendocrine role of mela-
tonin. J . Pineal. Res. 1993, 14, 1-10.
(8) (a) Reppert, S. M.; Weaver, D. R.; Godson, C. Melatonin receptors
step into the light: cloning and classification of subtypes. Trends
Pharmacol. Sci. 1996, 17, 100-102. (b) Dubocovic, M. L. Mela-
tonin receptors: are there multiple subtypes? Trends Pharmacol.
Sci. 1995, 16, 50-56.
(9) Spadoni, G.; Balsamini, C.; Diamantini, G.; Di Giacomo, B.;
Tarzia, G.; Mor, M.; Plazi, P. V.; Rivara, S.; Lucini, V.; Nonno,
R.; Pannacci, M.; Fraschini, F.; Stankov, B. M. Conformationally
restrained melatonin analogues: synthesis, binding affinity for
the melatonin receptor, evaluation of the biological activity and
molecular modeling study. J . Med. Chem. 1997, 40, 1990-2002.
(10) Sugden, D.; Chong N. W. S.; Lewis, D. F. V. Structural require-
ments at the melatonin receptor. Br. J . Pharmacol. 1995, 114,
618-623.
1
hexane); H NMR (CDCl3) δ 1.84-2.22 (m, 6H), 2.87 (m, 1H)
3.62 (q, 2H), 4.31 (t, 2H), 5.31 (br t, 1H), 6.51, 6.52 (dd, 1H, J
) 2.93 Hz and J ) 0.98 Hz), 7.05-7.27 (m, 3H), 7.34, 7.39
(dd, 1H, J ) 8.3 Hz and J ) 0.97 Hz), 7.65 (d, 1H); IR (Nujol)
3264, 1647 cm-1; MS (EI) m/ z 242 (M+), 143 (100). Anal.
(C15H18N2O) C, H, N.
(11) (a) Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell,
H. E.; Renard, P.; Caignard, D. H.; Pfeiffer, B.; Delagrange, P.;
Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J .
Synthesis and structure-activity relationships of novel naftha-
lenic and bioisosteric related amidic derivatives as melatonin
receptor ligands. J . Med. Chem. 1994, 37, 3231-3239. (b)
Langlois, M.; Bremont, B.; Shen, S.; Poncet, A.; Andrieux, J .;
Sicsic, S.; Serraz, I.; Mathe´-Allainmat, M.; Renard, P.; Dela-
grange, P. Design and synthesis of new napthalenic derivatives
as ligands for 2-[125I]Iodomelatonin binding sites. J . Med. Chem.
1995, 38, 2050-2060. (c) Copinga, S.; Tepper, P. G.; Grol, C. J .;
Horn, A. S.; Dubocovich, M. L. 2-Amido-8-methoxytetralins: A
series of nonindolic melatonin-like agents. J . Med. Chem. 1993,
36, 2891-2898.
(12) Garrat, P. J .; Vonhoff, S.; Rowe, S. J .; Sugden, D. Mapping the
melatonin receptor. 2. Synthesis and biological activity of indole
derived melatonin analogues with restricted conformations of
the C-3 amidoethane side chain. Bioorg. Med. Chem. Lett. 1994,
4, 1559-1564.
(13) Taborsky, R. G.; Delvigs, P.; Page, I. H. 6-Hydroxyindoles and
the metabolism of melatonin. J . Med. Chem. 1965, 8, 855-858.
(14) Allen, M. S.; Hamaker, L. K.; La Loggia, A. J .; Cook, J . M. Entry
into 6-methoxy-D(+)-tryptophans. Stereospecific synthesis of
1-benzensulfonyl-6-methoxy-D(+)-tryptophan ethyl ester. Synth.
Commun. 1992, 22, 2077-2102.
N-[2-(2-P h en yl-1H-in dol-1-yl)eth yl]cyclobu tan ecar box-
a m id e (2j): white crystalline solid, 0.032 g, total yield (starting
from 2-phenylindole) 10%; mp 118-119 °C (ethyl acetate/
hexane); 1H NMR (CDCl3) δ 1.70-2.11 (m, 6H), 2.70 (m, 1H),
3.42 (q, 2H), 4.39 (t, 2H), 5.12 (br t, 1H), 6.57 (s, 1H), 7.12-
7.44 (m, 9H); IR (Nujol) 3258, 1643 cm-1; MS (EI) m/ z 318
(M+), 206 (100). Anal. (C21H22N2O) C, H, N.
N -[2-(6-Me t h oxy-1H -in d ol-1-yl)e t h yl]t r iflu or oa ce t -
a m id e (2k ): white crystalline solid, 0.17 g (58%); mp 101-
1
102 °C (ether/hexane); H NMR (CDCl3) δ 3.76 (q, 2H), 3.87
(s, 3H), 4.32 (t, 2H), 6.35 (br s, 1H), 6.48 (d, 1H, J ) 3.05 Hz),
6.82 (d, 1H), 6.82, 6.84 (dd, 1H), 6.94 (d, 1H, J ) 3.17 Hz),
7.52 (d, 1H, J ) 8.39 Hz); IR (Nujol) 3310, 1705 cm-1; MS (EI)
m/ z 286 (M+), 160 (100). Anal. (C13H13F3N2O2) C, H, N.
N-[2-(6-Meth oxy-1H-in d ol-1-yl)eth yl]cyclop r op a n eca r -
boxa m id e (2l): white crystalline solid, 0.15 g (60%); mp 121-
123 °C (ethyl acetate/hexane); 1H NMR (CDCl3) δ 0.74 (m, 2H),
0.98 (m, 2H), 1.22 (m, 1H), 3.63 (q, 2H), 3.87 (s, 3H), 4.23 (t,
2H), 5.68 (br s, 1H), 6.46 (d, 1H, J ) 2.44 Hz), 6.80 (m, 2H),
7.98 (dd, 1H, J ) 2.92 Hz and J ) 1.46 Hz), 7.51 (d, 1H, J )
8.3 Hz); IR (Nujol) 3309, 1637 cm-1; MS (EI) m/ z 258 (M+),
41 (100). Anal. (C15H18N2O2) C, H, N.
(15) Kline, T. Preparation of 2-Iodotryptamine and 2-Iodo-5-meth-
oxytryptamine. J . Heterocycl. Chem. 1985, 22, 505-509.
(16) Bergman, J .; Venemalm, L. Efficient synthesis of 2-chloro-,
2-bromo-, and 2-iodoindole. J . Org. Chem. 1992, 57, 2495-2497.
(17) Houlihan, W. J .; Parrino, V. A.; Uike, Y. Lithiation of N-(2-
alkylphenyl)alkanamides and related compounds. A modified
Madelung indole synthesis. J . Org. Chem. 1981, 46, 4511-4515.
(18) Kasahara, A.; Izumi, T.; Kikuchi, T.; Lin, X. Synthesis of indole
derivatives from 2-bromoanilines by a palladium-assisted reac-
tion. J . Heterocycl. Chem. 1987, 24, 1555-1556.
N-[2-[2-(Ca r boxym eth yl)-6-m eth oxy-1H-in d ol-1-yl]p r o-
p yl]p r op a n a m id e (6) was prepared by method A, as de-
scribed above, starting from 6-methoxy-2-carbomethoxy-1-(2-
cyanoethyl)indole (5): white solid, 0.21 g (66%); mp 115-116
°C (ethanol); 1H NMR (CDCl3) δ 1.18 (t, 2H), 2.09 (m, 3H),
2.24 (q, 2H), 3.26 (q, 2H), 3.90 (s, 6H), 4.59 (t, 2H), 6.34 (br t,
1H), 6.76 (d, 1H), 6.82, 6.86 (dd, 1H, J ) 8.79 Hz and J ) 1.95
Hz), 7.27 (d, 1H, J ) 2.93 Hz), 7.55 (d, 1H, J ) 8.79 Hz); IR
(Nujol) 3307, 1701, 1646 cm-1; MS (EI) m/ z 318 (M+), 174
(100). Anal. (C17H22N2O4) C, H, N.
(19) Gatta, F.; Chiavarelli, S. Pirazino(1,2-a)- E 1,4-diazepino(1,2-
a)indoli. Il Farmaco Ed. Sc. 1975, 30, 631-641.
(20) (a) Garrat, P. J .; J ones, R.; Tocher, D. A.; Sugden, D. Mapping
the melatonin receptor. 3. Design and synthesis of melatonin
agonists and antagonists derived from 2-phenyltryptamines. J .
Med. Chem. 1995, 38, 1132-1139. (b) Ying, S. W.; Rusak, B.;
Delagrange, P.; Mocaer, E.; Renard, P.; Guardiola-Lemaitre, B.
Melatonin analogues as agonists and antagonists in the circa-
dian system and other brain areas. Eur. J . Pharmacol. 1996,
296, 33-42.
Ack n ow led gm en t. The authors thank Francesco
Palazzi for skillful technical assistance. This work was
supported by grants from Ministero della Ricerca Sci-
entifica e Tecnologica (MURST) and Consiglio Nazionale
delle Ricerche (CNR).
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