Novel conformationally restricted analogues of serotonin as 5-HT6R ligands 445
intermediates. Substituted benzyl chlorides were
3.21–3.25 (2H, m, CH2CH2NMe2), 3.34–3.44 (2H, m,
CH2CH2NMe2), 5.18 (2H, s, C5-CH2), 6.98–7.04 (1H,
dt, J= 9.23, 2.52 Hz), 7.36–7.42 (1H, dt), 7.43–7.49 (2H,
m), 7.53–7.56 (1H, dd, J= 10.2, 2.44 Hz), 7.60–7.62 (1H,
d, J= 7.44 Hz), 8.04–8.06 (1H, d, J= 7.52 Hz); 13C-NMR
(DMSO-d6): δ 19.41, 41.67, 48.52, 56.26, 100.44, 100.49,
104.27, 104.50, 109.38, 109.64, 110.85, 110.95, 121.48,
124.00, 127.4, 128.11, 130.09, 131.65, 131.70, 131.80,
142.22, 142.27, 155.95, 158.25; HRMS: [M+H]+ C19H19FN2
calc. 295.1610, found. 295.1610.
either commercially obtained or synthesized in-house
from the substituted toluene by N-chlorosuccinimide
reaction. Similarly, substituted benzoyl chlorides were
synthesized in-house from the corresponding benzoic
acids using thionyl chloride.
Synthesis
General procedure for the synthesis of derivatives 6–20
1-(2′-Bromophenylsulphonyl)-N,N-dimethyltryptamine
derivative (0.286 mmol) was taken in
a 100-mL
three-necked round-bottomed flask, along with N,N-
dimethylacetamide (10 mL), potassium acetate (0.343
mmol, 33.6 mg) and tetrakis (triphenyl phosphine)
palladium(0), (0.0143 mmol, 16.5 mg). e reaction
mixture was maintained under nitrogen atmosphere at
125–130°C with stirring for 5 h. After the completion of
reaction (TLC), excess of dimethylacetamide was dis-
tilled off under reduced pressure. e residue obtained
was purified by silica gel column chromatography using
methanol:ethyl acetate (2:8) as an eluent. e com-
pounds 6–20 were characterized by the spectral data.
General procedure for the synthesis of derivatives 31–35
1-(2′-Bromobenzoyl)-N,N-dimethyltryptamine
derivative (0.286 mmol) was taken in
a 100-mL,
three-necked round-bottomed flask, along with N,N-
dimethylacetamide (10 mL), potassium acetate (0.343
mmol, 33.6 mg) and tetrakis (triphenylphosphine)
palladium(0), (0.0143 mmol, 16.5 mg). e reaction
mixture was maintained under nitrogen atmosphere at
125–130°C with stirring for 5 h. After the completion of
reaction (TLC), excess of dimethylacetamide was dis-
tilled off under reduced pressure. e residue obtained
was purified by silica gel column chromatography using
methanol:ethyl acetate (2:8) as an eluent. e com-
pounds 31–35 were characterized by the following spec-
tral data.
2-Methoxy-10-[(2-N,N-dimethylamino-2-methyl)ethyl]
benzo[d]isothiazolo[3,2-a]indol-S,S-dioxide (15). Yield:
68.5%; Mp 202.4–205.3°C; IR (cm−1): 2933, 1461, 1438,
1323, 1174, 582; Mass (m/z): 371.2 (M+H)+; 1H-NMR
(CDCl3): δ 1.00–1.02 (3H, d, J = 6.44 Hz, CHCH3),
2.44 (6H, s, N(CH3)2), 2.81–2.87 (1H, dd, J = 13.44 Hz,
CH2CH(CH3)NMe2), 2.93–3.10 (1H, m, CH(CH3)NMe2),
3.18–3.23 (1H, dd, J = 13.44, 3.20 Hz, CH2CH(CH3)
NMe2), 3.87 (3H, s, OCH3), 6.99–7.02 (2H, m), 7.45–7.59
(1H, m), 7.58–7.62 (1H, m), 7.64–7.69 (1H, m), 7.79–7.85
(2H, m), 13C-NMR (CDCl3): δ 14.12, 28.23, 40.78, 55.75,
60.02, 103.59, 112.50, 114.78, 116.05, 122.26, 122.66,
127.34, 128.22, 128.44, 130.21, 133.91, 134.76, 138.11,
156.28; HRMS: [M+H]+ C20H22N2O3S calc. 371.1429,
found. 371.1422.
2-Phenyl-10-(2-N,N-dimethylaminoethyl)isoindolo[2,1-a]
indol-5-one (31). Yield; 56.1 %; Mp 148–151°C; IR (cm−1):
2939, 1716, 1606, 1458, 1361, 885, 758; Mass (m/z):
1
367.3 (M+H)+; H-NMR (CDCl3): δ 2.39 (6H, s, N(CH3)2),
3.07–3.11 (2H, m, CH2CH2NMe2), 3.65–3.70 (2H, m,
CH2CH2NMe2), 7.32–7.39 (2H, m), 7.44–7.48 (2H, m),
7.52–7.55 (2H, m), 7.57–7.64 (4H, m), 7.77–7.80 (1H,
dd), 7.91–7.93 (1H, d, J= 7.84 Hz); 13C-NMR (DMSO-
d6): δ 27.33, 50.18, 63.86, 117.91, 123.93, 124.31, 126.94,
130.21, 130.68, 131.91, 132.32, 133.93, 134.02, 137.34,
138.02, 139.18, 139.50, 139.99, 140.54, 141.32, 145.41,
166.52; HRMS: [M+H]+ C25H22N2O calc 367.1810, found.
367.1801.
General procedure for the synthesis of derivatives 21–30
1-(2′-Bromobenzyl)-N,N-dimethyltryptamine derivative
(0.286mmol)wastakenina100-mL,three-neckedround-
bottomed flask, along with N,N-dimethylacetamide
(10 mL), potassium acetate (0.343 mmol, 33.6 mg) and
tetrakis (triphenyl phosphine) palladium(0), (0.0143
mmol, 16.5 mg). e reaction mixture was maintained
under nitrogen atmosphere at 125–130°C with stirring
for 5 h. After the completion of reaction (TLC), excess of
dimethylacetamide was distilled off under reduced pres-
sure. e residue obtained was purified by silica gel col-
umn chromatography using methanol:ethyl acetate (2:8)
as an eluent. e compounds 21–30 were characterized
by the spectral data.
Radioligand-binding assay for human 5-HT6 receptor
Compounds were investigated by the reported proce-
dure. In brief, receptor source and radioligand used were
human recombinant expressed in HEK-293 cells and [3H]
LSD (60–80 Ci/mmol), respectively. e final ligand con-
centration was 1.5 nM and non-specific determinant was
methiothepin mesylate (0.1 SYMBOL 109\f “Symbol”M).
e reference compound and positive control is methio-
thepin mesylate.
Reactions were carried out in 50 mM Tris–HCl (pH
7.4) containing 10 mM MgCl2, 0.5 mM EDTA for 60 min
at 37°C. e reaction was terminated by rapid vacuum
filtration onto glass fibre filters. Radioactivity trapped
onto the filters was determined and compared with
control values in order to ascertain any interactions of
test compound(s) with the cloned serotonin–5-HT6-
binding site.
2-Fluoro-10-(2-N,N-dimethylaminoethyl)isoindolo[2,1-a]
indole (24). Light brown syrupy mass. Yield: 66.2%;
IR (cm−1): 2952, 2458, 1483, 1189, 791, 720; Mass (m/z):
1
295.3 (M+H)+; H-NMR (CDCl3): δ 2.86 (6H, s, N(CH3)2),
© 2012 Informa UK, Ltd.