Synthesis and structure activity relationship of rigidized indolyl pyrrolidine derivatives as 5-HT6 receptor ligands

Article abstract of DOI:10.14233/ajchem.2013.15443

A novel series of rigidized indolyl pyrrolidine derivatives have been designed by constraining the tryptamine nitrogen through a and b carbons. All the synthesized derivatives have shown moderate affinities at 5-HT6R when tested in in vitro binding assay.

Full text of DOI:10.14233/ajchem.2013.15443

Asian Journal of Chemistry; Vol. 25, No. 16 (2013), 9293-9298
http://dx.doi.org/10.14233/ajchem.2013.15443
Synthesis and Structure Activity Relationship of Rigidized
Indolyl Pyrrolidine Derivatives as 5-HT6 Receptor Ligands
1,*
1,2
1
1
2
RAMAKRISHNA NIROGI , ADIREDDY DWARAMPUDI , VENUGOPALARAO BHATTA , LAXMAN KOTA and P.K. DUBEY
1Discovery Research, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad-500 034, India
2Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500 085, India
*Corresponding author: Fax: +91 40 23541152; Tel: +91 40 23556038/23541142; E-mail: nvsrk@suven.com
(Received: 7 March 2013;
Accepted: 20 September 2013)
AJC-14164
A novel series of rigidized indolyl pyrrolidine derivatives have been designed by constraining the tryptamine nitrogen through α and β carbons.
All the synthesized derivatives have shown moderate affinities at 5-HT6R when tested in in vitro binding assay. Synthesis, structure
activity relationship (SAR), pharmacokinetic profile and in vivo efficacy of a selected compound is the subject matter of this communication.
Key Words: 5-HT6R, Structure activity relationship, Pharmacokinetic, Brain penetration, Water maze, Cognition.
ring through α and β carbons. The results of these efforts are
the subject matter of this paper.
INTRODUCTION
Serotonin (5-hydroxytryptamine, 5-HT) plays an important
role in the modulation of neuropsychiatric disorders and exerts
its actions via fourteen classes of receptors, which are involved
in controlling an array of physiological functions and promo-
ting pathophysiological conditions in states of excess or
deficiency. 5-HT6R was identified in 1990 in rat and it has
become a promising target for the treatment of neuropsy-
chological disorders like anxiety, depression, schizophrenia,
epilepsy, obesity, abnormal feeding behaviour and cognitive
dysfunctions1-7.
EXPERIMENTAL
Infrared spectra were recorded on KBr disc and in the
solid state using Perkin-Elmer model 1600 FT-IR spectropho-
tometer (Perkin-Elmer, Norwalk, CT, USA). Electron spray
ionization mass spectra were recorded on a API 4000 triple
quadruple instrument (MDS-SCIEX, Concord, Ontario,
Canada). 1H NMR spectra were obtained on a Bruker proton
NMR spectrometer (Fallanden, Switzerland) at 400 MHz.
Deuterated reagents were used as solvents and were commer-
cially procured. Tetramethylsilane (TMS) was used as internal
standard. Chemical shift values were expressed in parts per
million (δ) and coupling constants were expressed in Hertz
(Hz). Column chromatography was performed using 60-120
mesh silica gel and executed under nitrogen pressure (flash
chromatography) conditions.All the reagents and solvents used
were of reagent grade. Various substituted indoles were
synthesized in-house using literature reported procedures15 and
analytically characterized them thoroughly using spectral data.
2-Bromobenzenesulfonyl chloride was synthesized in-house
from 2-bromoaniline via diazonium salt intermediate16.
3-(1H-Indol-3-yl)-1-methyl pyrrolidine-2,5-dione (5a):
A mixture of indole (4a, 2 g, 17.09 mmol) and maleic acid (2
g, 17.24 mmol) were heated to 50 ºC and stirred until the mass
solidified. The mixture was allowed to stand for 0.5 h and
then diluted with a solution of potassium hydroxide (28.76 g,
51.27 mmol) in 50 mL of water. The reaction mass was heated
to 80 ºC and stirred for 0.5 h. The mass was cooled to room
Scientists from industries and academia evinced enormous
interest in the development of newer ligands for 5-HT6 recep-
tors, which have the capability to address debilitating CNS
related disorders, hitherto a highly unmet clinical field. There
are large number of other publications as well as patents in
the past two decades disclosing variety of scaffolds for 5-HT6R
ligands including N-phenylsulfonyl tryptamine (MS-245)8 and
2-phenyltryptamine (PMDT)9, which demonstrate the potential
of 5-HT6R ligands. A number of 5-HT6 receptor antagonists
like SB-74245710, LuAE5805411, SUVN-50212 and SAM-76013
have entered clinical development.
In our recent publication14 we have disclosed the effects
of rigidization of phenyl sulfonyl ring in MS-245 through
C-2 of indole (Fig. 1). This series of compounds 1 have shown
moderate binding affinities towards the 5-HT6R and were found
to be selective ligands towards 5-HT6R. In continuation to this
effort, we thought of constraining the tryptamine terminal
nitrogen by its incorporation into a five membered pyrrolidine

9294 Nirogi et al.
Asian J. Chem.
R1
N
R
H3C
CH3
β
H3C
α N
R
N
CH3
Rigidization
O
H3C
β
N
S
O
A
N
S
Ethylamine side
chain constrained
O
N
S
O
2
B
O
O
O
R1
N
MS-245
R
1
α
N
O
S
O
3
Fig. 1. Genesis of ligands 2 and 3
temperature and washed with diethyl ether. The aqueous phase
was acidified using hydrochloric acid and the resulting solids
were filtered, washed with water and dried. 3-Indolylsuccinic
acid (2.6 g, 11.15 mmol), thus obtained, was reacted with 1,3-
dimethyl urea (3 g, 34.09 mmol) at 180 ºC and stirred for 1 h.
The hot mixture was diluted with water, cooled to room
temperature and the resulting solids were filtered and further
purified by flash chromatography (silica gel, EtOAc/hexanes,
2/3) to obtain 5a (1.7 g, 68 %), which was confirmed by IR,
NMR and mass spectral analyses. Similarly compounds 5b-5h
were synthesized.
g, 2.98 mmol) solution in dimethylformamide (5 mL) was
added to a stirred solution of compound 6a (0.5 g, 2.48 mmol)
and sodium hydride (60 %, 0.18 g, 3.73 mmol) in dimethyl
formamide (20 mL) under nitrogen at room temperature. The
reaction mass was stirred for 3 h at room temperature. After
the completion of reaction, the reaction mixture was quenched
with 25 mL ice-cold water and the product was extracted with
ethyl acetate (3 × 15 mL). The combined organic phase was
washed sequentially with water and brine, dried over anhydrous
sodium sulphate and concentrated in vacuo. The resultant
residue was purified by flash chromatography (silica gel,
EtOAc/TEA, 99/1) to afford the title compound 7a (0.83 g, 80
%), which was confirmed by IR, NMR and mass analyses.
Similarly compounds 7b-7h were synthesized.
5a: M.R (ºC): 173.5-175.0; IR (KBr, νmax, cm-1): 3334,
1
1769, 1677, 745; mass (m/z): 229 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 2.75-2.81 (1H, m), 2.91 (3H, s, N-
CH3), 3.15-3.25 (1H, m), 4.33-4.37 (1H, m), 7.10-7.27 (2H,
m), 7.45-7.47 (1H, m), 8.02-8.07 (2H, m), 8.77 (1H, bs).
3-(1-Methyl pyrrolidin-3-yl)-1H-indole (6a): To a stirred
suspension of lithium aluminum hydride (0.85 g, 22.27 mmol)
in tetrahydrofuran (15 mL) was added a solution of compound
5a (1.7 g, 7.42 mmol) in tetrahydrofuran (20 mL) and the
resulting slurry was stirred for 4 h at reflux temperature. After
the completion of reaction, the reaction mixture was cooled to
10 ºC, poured on to chilled water (20 mL) and stirred for 0.5
h. The slurry, thus obtained, was filtered through celite pad
and washed with ethyl acetate. The organic layer was sepa-
rated and the aqueous phase was extracted with ethyl acetate
(2 × 20 mL). The combined organic layer was washed with
brine solution (15 mL) and dried over sodium sulfate. Organic
volatiles were removed under reduced pressure. The residual
mass, thus obtained, was purified by flash chromatography
(silica gel, EtOAc/TEA, 99/1) to afford compound 6a (0.52 g,
70 %), which was confirmed by IR, NMR and mass spectral
analyses. Similarly compounds 6b-6h were synthesized.
6a: M.R (ºC): 85.3-89.6; IR (KBr, νmax cm-1): 3409, 2940,
7a: M.R (ºC): 86.2-88.0; IR (KBr, νmax cm-1): 2777, 1369,
1178, 593; Mass (m/z): 419 [M + 1], 421 [M + 3]; 1H NMR
(400 MHz) (CDCl3) δ (ppm): 1.96-1.98 (1H, m), 2.36-2.40
(1H, m), 2.43 (3H, s), 2.54-2.61 (2H, m), 2.83-2.87 (1H, m),
3.10-3.15 (1H, m), 3.59-3.61 (1H, m), 7.22-7.24 (2H, m), 7.35-
7.40 (1H, m), 7.43-7.48 (1H, m), 7.57-7.62 (2H, m), 7.65-
7.69 (2H, m), 8.02-8.04 (1H, dd, J = 8.72 and 2.16 Hz).
10-(1-Methyl pyrrolidin-3-yl)-5-thia-4b-aza-indeno-
[2,1-a]indene-5,5-dioxide (2a): A solution of compound 7a
(0.5 g, 1.19 mmol), potassium acetate (0.23 g, 2.38 mmol)
and tetrakis(triphenyl phosphine) palladium(0) (0.068 g, 0.059
mmole) in N,N-dimethyl acetamide (10 mL) was stirred for
5 h at 125-130 ºC under nitrogen atmosphere. After the comp-
letion of reaction, the resulting solution was partitioned
between water and ethyl acetate. The layers were separated
and the aqueous layer was extracted with ethyl acetate. The
combined organic layer was washed with brine solution and
dried over anhydrous sodium sulphate and the solvent was
removed under reduced pressure. The residual mass, thus
obtained, was purified by flash chromatography (silica gel,
EtOAc/TEA, 99.5/0.5) to give 2a (0.31 g, 78 %), which was
confirmed by IR, NMR and mass spectral analyses. Similarly
compounds 2b-2h were synthesized.
1
1452, 737; mass (m/z): 201 [M + 1]; H NMR (400 MHz)
(CDCl3) δ (ppm): 1.94-1.98 (1H, m), 2.37-2.40 (1H, m), 2.42
(3H, s), 2.52-2.57 (1H, m), 2.60-2.65 (1H, m), 2.82-2.86 (1H,
m), 3.10-3.15 (1H, m), 3.56-3.61 (1H, m), 7.10-7.13 (1H, m),
7.21-7.25 (1H, m), 7.39-7.41 (1H, m), 7.68-7.72 (1H, d, J =
8.04 Hz), 7.77-7.78 (1H, d, J = 7.84 Hz), 8.32 (1H, bs).
1-(2-Bromo benzenesulfonyl)-3-(1-methyl pyrrolidin-
3-yl)-1H-indole (7a ): 2-Bromobenzenesulfonyl chloride (0.76
2a: M.R (ºC): 167.8-173.1; IR (KBr, νmax cm-1): 2940,
1
1325, 1181, 583; Mass (m/z): 339 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 2.20-2.25 (1H, m), 2.33-2.37 (1H,
m), 2.50 (3H, s), 2.83-2.97 (4H, m), 4.02-4.07 (1H, m), 7.24-
7.25 (1H, m), 7.35-7.40 (1H, m), 7.48-7.51 (1H, m), 7.64-

Vol. 25, No. 16 (2013)
Synthesis and Structure Activity Relationship of Rigidized Indolyl Pyrrolidine Derivatives 9295
7.68 (1H, m), 7.70-7.72 (1H, d, J = 7.72 Hz), 7.83-7.85 (1H,
d, J = 8.12 Hz), 7.87-7.89 (1H, d, J = 8.12 Hz), 8.05-8.07
(1H, d, J = 8.00 Hz).
7.48 (2H, m), 7.55-7.59 (1H, d, J = 8.84 Hz), 7.63-7.65 (1H,
m), 7.80-7.81 (1H, d, J = 7.82 Hz), 7.99-8.00 (1H, d, J = 7.90
Hz).
2b: M.R (ºC): 97.7-106.8; IR (KBr, νmax cm-1): 2924, 1334,
3-Bromo-1-(tert-butyl dimethyl silanyl)-1H-indole
(8a): To a cooled solution of indole (4a, 2 g, 17.09 mmol) in
tetrahydrofuran (20 mL) at -78 ºC was added a solution of
n-butyllithium (32 mL, 1.6 M solution in hexane, 51.28 mmol)
dropwise via cannula under nitrogen atmosphere. The reaction
mass was warmed to -10 ºC, stirred for 0.5 h and again cooled
to -50 ºC. Then a solution of tert-butyl dimethyl silyl chloride
(7.7 g, 51.28 mmol) in tetrahydrofuran (30 mL) was added
dropwise to this mixture. The temperature was raised to 0 ºC
and stirred for 3 h at the same temperature. The reaction mixture
was cooled to -78 ºC, freshly crystallized N-bromosuccinimide
(6.06 g, 34.18 mmol) was added via a solid-addition funnel
and the resulting mixture was stirred for 2 h at -78 ºC and then
allowed warm to room temperature. After completion of the
reaction, the mass was poured into a mixture of hexane
(100 mL) and pyridine (1 mL). The resulting suspension was
filtered through a celite pad, the filtrate was concentrated
under reduced pressure. The crude residue was then purified
by flash chromatography (silica gel, 100 % hexane) to obtain
8a (3.4 g, 68 %) as a colourless solid, which was confirmed
by IR, NMR and mass analyses. Similarly compounds 8b-8d
were synthesized.
1
1180, 582; Mass (m/z): 353 [M + 1]; H NMR (400 MHz)
(CDCl3) δ (ppm): 1.14-1.17 (3H, t, J = 7.24 Hz), 2.17-2.24
(1H, m), 2.33-2.37 (1H, m), 2.59-2.75 (3H, m), 2.91-3.03 (3H,
m), 4.04-4.07 (1H, m), 7.23-7.29 (1H, m), 7.36-7.40 (1H, m),
7.46-7.50 (1H, m), 7.65-7.70 (1H, m), 7.71-7.73 (1H, d, J =
8.12 Hz), 7.83-7.86 (2H, m), 8.12-8.13 (1H, d, J = 7.92 Hz).
2c: M.R (ºC): 132.3-143.5; IR (KBr, νmax cm-1): 2796,
1
1325, 1165, 580; Mass (m/z): 369 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 2.16-2.21 (1H, m), 2.32-2.35 (1H,
m), 2.48 (3H, s), 2.75-2.77 (1H, m), 2.82-2.87 (1H, m), 2.93-
2.97 (2H, m), 3.86 (3H, s), 3.97-4.01 (1H, m), 6.98-7.01 (1H,
dd, J = 8.80 and 2.48 Hz), 7.44-7.48 (2H, m), 7.58-7.61 (1H,
d, J = 8.80 Hz), 7.63-7.67 (1H, m), 7.81-7.83 (1H, d, J = 7.80
Hz), 8.01-8.03 (1H, d, J = 7.96 Hz).
2d: M.R (ºC): 98.8-108.8; IR (KBr, νmax cm-1): 2967, 1332,
1
1178, 580; Mass (m/z): 383 [M + 1]; H NMR (400 MHz)
(CDCl3) δ (ppm): 1.12-1.16 (3H, t, J = 7.32 Hz), 2.16-2.21
(1H, m), 2.35-2.37 (1H, m), 2.61-3.02 (6H, m), 3.87 (3H, s),
4.03-4.05 (1H, m), 6.99-7.01 (1H, dd, J = 8.84 & 2.44 Hz),
7.44-7.48 (2H, m), 7.59-7.61 (1H, d, J = 8.84 Hz), 7.63-7.66
(1H, m), 7.81-7.83 (1H, d, J = 7.80 Hz), 8.06-8.08 (1H, d, J =
7.92 Hz).
8a: M.R (ºC): 73.2-74.1; IR (KBr, νnax, cm-1): 2931, 1445,
2e: M.R (ºC): 115.9-118.9; IR (KBr, νmax, cm-1): 2922,
1
1329, 1175, 559; mass (m/z): 383 [M + 1]; H NMR (400
1287, 739; Mass (m/z): 310.2 [M + 1], 312.2 [M + 3]; H
1
NMR (400 MHz) (CDCl3) δ (ppm): 0.60 (6H, s), 0.91 (9H, s),
7.16-7.23 (3H, m), 7.47-7.50 (1H, m), 7.55-7.58 (1H, m).
(1H-Indol-3-yl)-(1-methyl pyrrolidin-2-yl)methanone
(9a): To a stirred solution of compound 8a (1 g, 3.41 mmol)
in tetrahydrofuran (15 mL) cooled to -78 ºC was added a solu-
tion of n-butyllithium (6.4 mL, 1.6 M solution in hexane, 10.23
mmol) dropwise via cannula under nitrogen atmosphere. The
resulting solution was stirred for 15 min at -78 ºC, then added
a solution of 1-methyl pyrrolidine-2-carboxylate (0.65 g, 5.10
mmol) in tetrahydrofuran (10 mL). Reaction mass was stirred
for 12 h at room temperature.After completion of the reaction,
the reaction mass was quenched in saturated ammonium
chloride solution and the compound was extracted with ethyl
acetate. The organic layer was washed with brine solution,
dried over anhydrous sodium sulphate and solvent removed
under reduced pressure. The residual mass, thus obtained, was
purified by flash chromatography (silica gel, EtOAc/TEA, 99/1)
to afford the compound 9a (0.46 g, 60 %), which was confir-
med by IR, NMR and mass analyses. Similarly compounds
9b-9d were synthesized.
MHz) (CDCl3) δ (ppm): 1.42-1.47 (3H, t, J = 6.96 Hz), 2.18-
2.22 (1H, m), 2.32-2.43 (1H, m), 2.49 (3H, s), 2.77-2.79 (1H,
m), 2.86-2.88 (1H, m), 2.92-2.95 (2H, m), 3.94-3.99 (1H, m),
4.06-4.11 (2H, q, J = 6.96 Hz), 6.98-7.01 (1H, dd, J = 8.80
and 2.42 Hz), 7.44-7.48 (2H, m), 7.57-7.60 (1H, d, J = 8.80
Hz), 7.62-7.66 (1H, m), 7.80-7.82 (1H, d, J = 7.84 Hz), 8.01-
8.03 (1H, d, J = 7.92 Hz ).
2f: M.R (ºC): 110-115.1; IR (KBr, νmax, cm-1): 2966, 1328,
1
1179, 559; mass (m/z): 397 [M + 1]; H NMR (400 MHz)
(CDCl3) δ (ppm): 1.17-1.21 (3H, t, J = 7.20 Hz), 1.44-1.47
(3H, t, J = 6.96 Hz), 2.18-2.23 (1H, m), 2.32-2.38 (1H, m),
2.59-2.68 (2H, m), 2.74-2.80 (1H, m), 2.88-2.90 (1H, m), 2.95-
2.99 (2H, m), 3.98-4.00 (1H, m), 4.06-4.11 (2H, q, J = 6.96
Hz), 6.98-6.99 (1H, dd, J = 8.80 & 2.36 Hz), 7.44-7.48 (2H,
m), 7.57-7.60 (1H, d, J = 8.80 Hz), 7.62-7.64 (1H, m), 7.80-
7.82 (1H, d, J = 7.80 Hz), 8.05-8.07 (1H, d, J = 7.92 Hz).
2g: M.R (ºC): 141.8-145.7; IR (KBr, νmax, cm-1): 2972,
1
1325, 1180, 586; mass (m/z): 397 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 1.36-1.38 (6H, d, J = 6.40 Hz), 2.17-
2.20 (1H, m), 2.33 (1H, m), 2.48 (3H, s), 2.74-2.76 (1H, m),
2.81-2.83 (1H, m), 2.90-2.94 (2H, m), 3.95-3.97 (1H, m), 4.53-
4.56 (1H, m), 6.97-6.99 (1H, dd, J = 8.80 and 2.40 Hz), 7.46-
7.49 (2H, m), 7.57-7.59 (1H, d, J = 8.80 Hz), 7.62-7.64
(1H, m), 7.81-7.82 (1H, d, J = 7.80 Hz), 8.00-8.01 (1H, d, J =
7.96 Hz).
9a: IR (KBr, νmax, cm-1): 3314, 1769, 1277, 735; mass (m/
1
z): 229.3 [M + 1]; H NMR (400 MHz) (CDCl3) δ (ppm):
1.85-1.90 (1H, m), 1.99-2.04 (2H, m), 2.25-2.28 (1H, m), 2.35-
2.38 (1H, m), 2.40 (3H, s, N-CH3), 3.22-3.26 (1H, m), 3.43-
3.47 (1H, m), 7.27-7.32 (2H, m), 7.42-7.44 (1H, m), 8.37-
8.38 (1H, m), 8.47-8.49 (1H, m), 8.84 (1H, bs).
2h: IR (KBr, νmax, cm-1): 2970, 1335, 1182, 580; mass (m/
z): 411 [M + 1]; 1H NMR (400 MHz) (CDCl3) δ (ppm): 1.19-
1.25 (3H, t, J = 7.24 Hz), 1.37-1.39 (6H, d, J = 6.42 Hz), 2.19-
2.25 (1H, m), 2.32-2.39 (1H, m), 2.59-2.76 (3H, m), 2.84-
2.86 (1H, m), 2.92-2.95 (2H, m), 4.01-4.06 ( 1H, m), 4.45-
4.48 (1H, m), 6.98-7.00 (1H, dd, J = 8.84 & 2.48 Hz), 7.44-
3-(1-Methyl pyrrolidin-2-ylmethyl)-1H-indole (10a):
To a stirred suspension of lithium aluminum hydride (0.11 g,
2.96 mmol) in tetrahydrofuran (10 mL) was added a solution
of compound 9a (0.45 g, 1.97 mmol) in tetrahydrofuran (10
mL) and the resulting slurry was heated at reflux for 4 h.After
the completion of reaction, the reaction mixture was cooled to

9296 Nirogi et al.
Asian J. Chem.
10 ºC, poured on to chilled water (20 mL) and stirred for 0.5 h.
The slurry, thus obtained, was filtered through celite pad and
washed with ethyl acetate (15 mL). The organic layer was
separated and the aqueous phase was extracted with ethyl
acetate (2 × 15 mL). The combined organic layer was washed
with brine solution (15 mL) and dried over anhydrous sodium
sulfate. Organic volatiles were removed under reduced
pressure. The residual mass, thus obtained, was purified by
flash chromatography (silica gel, EtOAc/TEA, 99/1) to afford
compound 10a (0.35 g, 83 %), which was confirmed by IR,
NMR and mass analyses. Similarly compounds 10b-10d were
synthesized.
10a: IR (KBr, νmax, cm-1): 3399, 2920, 1472, 717; mass
(m/z): 215.2 [M + 1]; 1H NMR (400 MHz) (CDCl3) δ (ppm):
1.58-1.61 (2H, m), 1.77-1.80 (2H, m), 2.21-2.23 (1H, m), 2.46-
2.50 (4H, m), 2.58-2.64 (1H, m), 3.13-3.22 (2H, m), 7.02-
7.03 (1H, m), 7.11-7.14 (1H, m), 7.17-7.21 (1H, m), 7.35-
7.37 (1H, m), 7.60-7.62 (1H, d, J = 7.84 Hz), 8.00 (1H, bs).
1-(2-Bromo benzenesulfonyl)-3-(1-methyl pyrrolidin-
2-ylmethyl)-1H-indole (11a): 2-Bromobenzenesulfonyl
chloride (0.50 g, 1.96 mmol) in dimethylformamide (5 mL)
was added to a stirred solution of compound 10a (0.35 g, 1.63
mmol) and sodium hydride (50 %, 0.098 g, 2.45 mmol) in
dimethylformamide (15 mL) under nitrogen atmosphere at
room temperature and the reaction mass was stirred for 3 h at
room temperature. After the completion of reaction, the
reaction mixture was quenched with 15 mL ice-cold water
and the product was extracted with ethyl acetate (3 × 15 mL).
The combined organic phase was washed sequentially with
water and brine, dried over anhydrous sodium sulphate and
concentrated in vacuo. The resultant residue was purified by
flash chromatography (silica gel, EtOAc/TEA, 99/1) to afford
the title compound 11a (0.56 g, 80 %), which was confirmed
by IR, NMR and mass analyses. Similarly compounds 11b-
11d were synthesized.
3a: M.R (ºC): 200.6-201.9; IR (KBr, νnax, cm-1): 2788,
1
1332, 1177, 547; mass (m/z): 353 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 1.60-1.80 (4H, m), 2.25-2.27 (1H,
m), 2.54-2.62 (4H, m), 2.87-2.93 (1H, m), 3.14-3.20 (1H, m),
3.32-3.35 (1H, m), 7.25-7.28 (1H, m), 7.36-7.38 (1H, m), 7.48-
7.50 (1H, m), 7.59-7.61 (1H, d, J = 8.00 Hz), 7.64-7.68 (1H,
m), 7.69-7.71 (1H, d, J = 8.00 Hz), 7.83-7.85 (1H, d, J = 7.82
Hz), 7.88-7.90 (1H, d, J = 7.84 Hz).
3b: M.R (ºC): 190.7-195.1; IR (KBr, νnax, cm-1): 2769,
1
1322, 1174, 582; mass (m/z): 383 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 1.62-1.65 (2H, m). 1.78-1.80 (2H,
m), 2.27-2.29 (1H, m), 2.55-2.63 (4H, m), 2.86-2.90 (1H, m),
3.14-3.19 (1H, m), 3.28-3.32 (1H, m), 3.86 (3H, s), 6.99-7.01
(1H, dd, J = 8.84 and 2.00 Hz), 7.02-7.05 (1H, m), 7.45-7.49
(1H, m), 7.58-7.60 (1H, d, J = 8.84 Hz), 7.63-7.66 (1H, m),
7.81-7.83 (1H, d, J = 7.83 Hz), 7.81-7.88 (1H, d, J = 7.84
Hz).
3c: M.R (ºC): 113.0-120.0; IR (KBr, νnax, cm-1): 2774,
1334, 1174, 584; mass (m/z): 397 [M+1]; 1H NMR (400 MHz)
(CDCl3) δ (ppm): 1.43-1.46 (3H, t, J = 6.96 Hz), 1.60-1.64
(2H, m). 1.77-1.81 (2H, m), 2.26-2.28 (1H, m), 2.54-2.61 (4H,
m), 2.84-2.90 (1H, m), 3.13-3.18 (1H, m), 3.27-3.31 (1H, m),
4.05-4.10 (2H, q, J = 6.96 Hz), 6.98-7.01 (1H, dd, J = 8.71
and 2.20 Hz), 7.02-7.05 (1H, m), 7.44-7.48 (1H, m), 7.57-
7.59 (1H, d, J = 8.71 Hz), 7.62-7.66 (1H, m), 7.81-7.83 (1H,
d, J = 7.82 Hz), 7.85-7.87 (1H, d, J = 7.86 Hz).
3d: M.R (ºC): 123.6-125.1; IR (KBr, νmax, cm-1): 2777,
1
1326, 1174, 580; mass (m/z): 411 [M + 1]; H NMR (400
MHz) (CDCl3) δ (ppm): 1.35-1.37 (6H, d, J = 6.40 Hz), 1.60-
1.64 (2H, m). 1.77-1.81 (2H, m), 2.26-2.28 (1H, m), 2.55-
2.62 (4H, m), 2.84-2.90 (1H, m), 3.12-3.18 (1H, m), 3.26-
3.31 (1H, m), 4.53-4.56 (1H, m), 6.98-7.00 (1H, dd, J = 8.80
and 2.0 Hz), 7.01-7.04 (1H, m), 7.44-7.48 (1H, m), 7.56-7.58
(1H, d, J = 8.80 Hz), 7.62-7.66 (1H, m), 7.80-7.87 (1H, d, J =
7.80 Hz ), 7.85-7.87 (1H, d, J = 7.80 Hz).
11a: M.R (ºC): 86.2-88.0; IR (KBr, νnax, cm-1): 2765, 1369,
1178, 596; mass (m/z): 433 [M + 1], 435 [M + 3]; 1H NMR
(400 MHz) (CDCl3) δ (ppm): 1.54-1.58 (2H, m), 1.64-1.68
(2H, m), 2.22-2.24 (1H, m), 2.48-2.53 (4H, m), 2.56-2.59 (1H,
m), 3.10-3.14 (2H, m), 7.21-7.25 (2H, m), 7.36-7.41 (1H, m),
7.45-7.49 (1H, m), 7.52-7.57 (1H, m), 7.58 (1H, s), 7.65-7.77
(2H, m), 8.04-8.07 (1H, dd, J = 7.88 and 1.68 Hz).
RESULTS AND DISCUSSION
The target compounds were synthesized according to the
representative Schemes I and II.
Indole-3-substituted pyrrolidine diones (5a-5h) were
synthesized by reacting equimolar amounts of indole and
maleic acid at 50 ºC. The resulting indole-3-succinic acid
derivatives were further reacted with dialkyl ureas at 180 ºC.
The diones, thus obtained, were reduced using lithium aluminum
hydride to the corresponding pyrrolidine compounds (6a-6h).
The intermediates (6a-6h) were reacted with 2-bromobenzene-
sulfonyl chloride in the presence of a base to obtain the
intermediates (7a-7h), which were further subjected to Heck
cyclization reaction to obtain the desired series of compounds
(2a-2h).
10-(1-Methyl pyrrolidin-2-ylmethyl)-5-thia-4b-aza
indeno[2,1-a]indene-5,5-dioxide (3a):A solution of compound
11a (0.55 g, 1.27 mmol), potassium acetate (0.25 g, 2.55 mmol)
and tetrakis(triphenyl phosphine) palladium(0) (0.073 g, 0.063
mmol) in N,N-dimethyl acetamide (10 mL) was stirred for 5 h
at 125-130 ºC under nitrogen atmosphere. After the comple-
tion of reaction, the resulting solution was partitioned between
water and ethyl acetate. The organic layer was separated and
the aqueous phase was extracted with ethyl acetate. The com-
bined organic layer was washed with brine solution and dried
over anhydrous sodium sulphate and the solvent was removed
under reduced pressure. The residual mass, thus obtained was
purified by flash chromatography (silica gel, EtOAc/TEA,
99.5/0.5) to give 3a (0.35 g, 80 %), which was confirmed by
IR, NMR and mass analyses. Similarly compounds 3b-3d were
synthesized.
N-Silylated-3-bromo indole derivatives (8a-8d) were
synthesized by protection of indoles with substituted silyl chlo-
rides in the presence of n-butyllithium, followed by bromi-
nation at C-3 of indole position using N-bromo succinimide.
The intermediates 8a-8d were reacted with N-methyl proline
esters in the presence of n-butyl lithium resulting in indole-3-
methanone derivatives (9a-9d). These methanone derivatives
were reduced by using lithium aluminum hydride to obtain

Vol. 25, No. 16 (2013)
Synthesis and Structure Activity Relationship of Rigidized Indolyl Pyrrolidine Derivatives 9297
O
R1
R1
N
N
O
R
c
a,b
R
R
N
H
N
H
N
H
(6a-h)
(4a-d)
(5a-h)
R1
R1
N
N
R
R
e
d
N
S
N
S
O
O
O
O
Br
(2a-h)
(7a-h)
R = H, OCH3, OCH2CH3, OCH(CH3)2
R1 = CH3, CH2CH3
Scheme-I: (a) Maleic acid, 50 ºC, 1h; (b) 1,3-Dialkylurea, 180-190 ºC, 1h, 68 %; (c) LAH, THF, reflux, 4 h, 70 %; (d) 2-Bromo benzenesulfonyl chloride,
NaH, DMF, RT, 3 h, 80 %; (e) CH3COOK, Pd(PPh3)4, DMA, 130 ºC, 5 h, 78 %
R1
O
Br
N
R
R
R
b
c
a
N
N
H
CH3
N
H
H3C
Si
CH3
CH3
CH3
(4a-d)
(8a-d)
(9a-d)
R1
N
R1
R1
N
N
R
R
R
e
d
N
S
N
S
N
H
O
O
(10a-d)
(11a-d)
O
O
(3a-d)
Br
R = H, OCH3, OCH2CH3, OCH(CH3)2
R1 = CH3
Scheme-II: (a) n-BuLi, tert-butyl dimethyl silyl chloride, NBS, THF, -78 ºC, 6 h, 68 %; (b) n-BuLi, 1-alkyl pyrrolidine-2-carboxylic acid methyl ester,
THF, -78 ºC, 12 h, 60 %; (c) LAH, THF, reflux, 4 h, 83 %; (d) 2-Bromo benzenesulfonyl chloride, NaH, DMF, RT, 3 h, 80 %; (e) CH3COOK,
Pd(PPh3)4, DMA, 130 ºC, 5 h, 80 %
corresponding amines (10a-10d). The intermediates (10a-10d)
were reacted with 2-bromo benzenesulfonyl chloride in the
presence of base to afford the intermediates (11a-11d), which
were further subjected to the familiar Heck reaction to obtain
the target compounds (3a-3d). All the intermediates and final
compounds were fully characterized by IR, NMR and mass
spectral data.
pyrrolidin-2-ylmethyl)-5-thia-4b-aza-indeno[2,1-a]indene-
5,5-dioxide (3a-3d) derivatives were tested for their 5-HT6R
in vitro binding affinity at 100 nM concentration. All the
compounds were tested as racemates and the results are given
in Table-1.As part of our structure activity relationship studies,
initially we regidized the tryptamine side chain into the
pyrrolidine ring through β carbon i.e., 10-(1-methyl pyrrolidin-
3-yl)-5-thia-4b-aza-indeno[2,1-a]indene-5,5-dioxide (unsubs-
tituted indole 2a) and the % inhibition at 100 nM concen-
tration was found to be 54.65 percent. Later, we introduced
Structure activity relationship (SAR):Analytically well
characterized 10-(1-methyl pyrrolidin-3-yl)-5-thia-4b-aza-
indeno[2,1-a]indene-5,5-dioxide (2a-2h) and 10-(1-methyl

9298 Nirogi et al.
Asian J. Chem.
TABLE-2
PHARMACOKINETIC PROFILE OF COMPOUND 2ca
Route
Oral
i.v.
n
3
3
Dose (mg/kg)
Cmax (ng/mL)
107 49
Tmax (h)
1.3 0.6
0.08 0.0
AUCt (ng h/mL)
946 563
t1/2 (h)
F (%)
34
10
10
7.48 0.85
4.13 0.31
1476 455
2769 307
aFasted male wistar rats, Vehicle used: water for injection for both oral and i.v. routes. Dosing Volumes: 10 mL/kg for oral and 2 mL/kg for i.v.
the substitution on phenyl ring of indole with electron donating
groups like methoxy (2c, 95.52 %), ethoxy (2e, 58.54 %),
isopropoxy (2g, 53 %) at second position (R) and these were
found to have moderate affinities at 5-HT6R and it appears
that there is a slight preference for lower alkoxy (methoxy)
substitution. Replacement of methyl with ethyl on the amine
had little effect on 5-HT6R binding affinities as can be seen by
comparing 2c (95.52 %) with 2d (66.63 %) and 2e (58.54 %)
with 2f (41.97 %). Based on these results, we evaluated the
effect of rigidization of the tryptamine side chain into the
pyrrolidine ring through α carbon. This change resulted in
compounds with less potency compared to their respective
counterparts as can be seen by comparing 2c (95.52 %) vs 3b
(63.42 %) and 2e (58.54 %) vs 3c (52.36 %)). The overall
result indicates that rigidization through α and β carbons are
tolerated for 5-HT6R binding. Among all the synthesized
compounds, 2c (95.52 %) has shown highest percent of inhibition
at 5-HT6R, when tested at 100 nM concentration, indicating
that regidization of the tryptamine side chain into the
pyrrolidine ring through β carbon was more favorable than
rigidization through α carbon.
deficit at 10 mg/kg p.o. dose in Morris water maze model,
which was apparent from lesser target latency (Fig. 2).
55000
50000
PEG400 50 %(1 mL/kg, p.o.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
45000
Donepezil (0.3 mg/kg, i.p.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
40000
Compound 2c (10 mg/kg, p.o.) + Scopolamine (0.6-0.8 mg/kg, i.p.)
35000
30000
25000
20000
15000
10000
5000
Day 1
Day 2
Day 3
Day 4
Day 5
Fig. 2. Morris water maze test data for compound 2c in rats. Data represents
Mean SEM of latency to target, **p < 0.01, *p < 0.05, (one way
ANOVA, Dunnett’s post hoc analysis)
Conclusion
In summary, a novel series of compounds 2 and 3 were
designed by constraining the tryptamine side chain into a
pyrrolidine ring through α and β carbons and were found to
have moderate affinities at 5-HT6R. The most active compound
2c has shown the acceptable pharmacokinetic profile along
with the cognition potential at 10 mg/kg (Watermaze). The
overall results indicated that these compounds have the
potential to be 5-HT6R ligands. Hence further efforts for their
chiral separation and detailed profiling are under progress and
constitute subject matter of our next publication.
TABLE-1
5-HT6R BINDING AFFINITIES OF
COMPOUND 2 AND 3 DERIVATIVESa
Compound
R
H
R1
Inhibition % at 100 nM
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
CH3
CH3
54.65
43.76
95.52
66.63
58.54
41.97
53.00
31.93
58.61
63.42
52.36
49.07
2a
2b
2c
2d
2e
2f
H
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