CHEMMEDCHEM
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stitution at the cyclopropyl ring. The final step involved the ef-
ficient convertion of primary cyclopropylamines 9a–f to the
corresponding N,N-dimethyl analogues using the formalde-
hyde/sodium cyanoborohydride/acetic acid/methanol system
to furnish functionalized tryptamines 4a–f in good yields (82–
97%).[20] This sequence was also applied for the synthesis of 2-
vinyl analogues (5) from 2-vinyl-indol-3-ylacetonitrile (7), pre-
pared according to a well-known method.[21] Cyclopropanation
was found to be compatible with the additional vinyl moiety,
and the corresponding cyclopropylamines 11 a and 11 b were
obtained in 40% and 47% yield, respectively. Reductive amina-
tion with formaldehyde afforded the targeted compounds 5a
and 5b.
All synthesized compounds were evaluated against 5-HT1A,
5-HT4 and 5-HT6 receptors (Table 2). Results were expressed as
a percentage of radioligand binding inhibition in the presence
Scheme 1. Preparation of tryptamine analogues 4a–f and 5a,b. Reagents
and conditions: a) NaOH, CH2Cl2/H2O (2:1), 08C, 15 min; then MeI, BnBr or
ArSO2Cl, RT, 12 h; b) R2(CH2)2MgBr, MeTi(OiPr)3, THF, RT, 1.5 h; then BF3·OEt2,
RT, 30 min; c) NaBH3CN, AcOH, MeOH, 08C, 5 min; then HCHO, 08C, 1.5 h.
of compounds at 10À6 m (1 mm) concentration and at 10À8
(10 nm) for the most potent ones.
m
Initial structure–activity relationship development showed
that all of the N,N-dimethyl arylsulfonyltryptamines bearing
a cyclopropyl ring on the a-position of the ethylamine side
chain (4b–e) exhibited similar activities and selectivities, with
interesting percent inhibition values at 1 mm against the 5-HT6
receptor. The affinities (Ki) of these cyclopropyl analogues for
the 5-HT6 receptor were determined to between 0.12 mm and
0.14 mm (4b–d), except for compound 4e, with a more bulky
naphthyl substituent that exhibited a Ki value of 0.53 mm
(Table 2). Contrary to our initial expectation, the weak affinity
observed could be explained by a more limited conformational
flexibility and an increasing hydrophobic character of the
modified ethylamine side chain.[22] In addition, it could also be
the consequence of a slightly lower pKa value of cyclopropyla-
mines.[23,24] Increasing the hydrophobicity by ethyl substitution
on the three-membered ring (compound 4 f) drastically de-
creased the affinity of 4 f for serotonin receptors.
ates and final compounds are given in Table 1. Firstly, substitu-
tion on the indole nitrogen was performed by treatment of
the nitriles with sodium hydroxide in a biphasic system at
Table 1. Structures and isolated yields of intermediary and final com-
pounds shown in Scheme 1.
Product (Yield [%])
R
R1
R2
Step a
Step b
Step c
(92)
H
H
H
H
H
H
Vinyl
Vinyl
Bn
PhSO2
p-MeC6H4SO2
p-ClC6H4SO2
2-NaphthylSO2
PhSO2
H
H
H
H
H
Et
H
H
8a (72)
8b (39)
8c (37)
8d (60)
8e (45)
9a
(46) 4a
(66) 4b
(59)
9b
9c
9d
9e
(82)
(97)
4c
(53) 4d
(65) 4e
(88)
(94)
4 f[b] (94)
–
–
9 f[a] (58)
Me
Bn
10a (69) 11 a
10b (75) 11 b
(40) 5a
(47) 5b
(76)
(60)
Next, our attention turned to the N-substituent of the indole
ring (R1). An arylsulfonyl moiety in this position was considered
to be optimal as benzyl derivative 4a (Ki =1.38 mm) was ap-
proximately tenfold less potent than the corresponding sulfo-
nylated analogue (4b; Ki =0.12 mm), suggesting that a H-bond
acceptor in this position is essential for affinity. Interestingly,
this functionality can be omitted without significant loss of po-
tency when a vinyl group is present at the 2-position of the
indole system (5b; Ki =0.19 mm). Replacing the benzyl substitu-
ent with a less hydrophobic methyl group dramatically de-
creases the pharmacological effect of the vinyl containing de-
rivatives (5a vs 5b); compound 5a was found to be practically
inactive at concentrations in the micromolar range.
[a] 60:40 Mixture of diastereoisomers. [b] Reaction performed with (cis)-
9 f.
room temperature in the presence of methyl iodide, benzyl
bromide or arylsulfonyl chlorides. The corresponding N-func-
tionalized indolylacetonitriles (8a–e) were isolated in 37–72%
yields after purification by column chromatography or crystalli-
zation. We next turned to the titanium-mediated cyclopropa-
nation step.[17] While this reaction has been previously studied
with a variety of nitriles, including carbohydrates,[18] to the best
of our knowledge, the use of nitriles bearing indole or sulfona-
mide moieties is unprecedented. After initial optimization
steps,[16] we found that the use of 1.5 equivalents of the alkylti-
tanium reagent, MeTi(OiPr)3[19] and 1.5 equivalents of ethylmag-
nesium bromide in tetrahydrofuran (THF), followed by the ad-
dition of boron trifluoride diethyl etherate led to the total con-
sumption of the starting nitriles and gave the corresponding
primary cyclopropylamines 9a–e in 40–66% yields. Use of n-
butylmagnesium bromide instead of ethylmagnesium bromide
afforded the cyclopropylamine 9 f, bearing an additional sub-
The more active cyclopropyl-tryptamine was 4-chlorobenze-
nesulfonyl derivative 4d, exhibiting 87% inhibition of 5-HT6 at
1 mm, with both a Ki and IC50 value of approximately 0.15 mm.
Derivative 4d displayed good selectivity for 5-HT6 over the
other serotonin receptors evaluated (5-HT1A and 5-HT4). How-
ever, 4d is around tenfold less active than the previously de-
scribed benzenesulfonyl-2-vinyltryptamine (1, Ar=Ph).[10]
In conclusion, N,N-dimethyltryptamine analogues bearing
a cyclopropyl ring on the a-position of the tryptamine side
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ChemMedChem 2013, 8, 70 – 73 71