Synthesis and structure activity relationship of 3-(arylsulfonyl)-8- (piperidin-4-yl amino)quinoline derivatives as 5-HT6 receptor antagonists

Article abstract of DOI:10.14233/ajchem.2014.15904

As part of our efforts to develop better therapies for the treatment of cognitive impairment associated with Alzheimer's disease and Schizophrenia, we have focused our research towards 5-HT₆ receptor (5-HT₆R) in order to identify potent and selective ligands for this purpose. Herein, we report the synthesis, structure activity relationship and biological evaluation of a novel series of 3-(arylsulfonyl)-8- (piperidin-4-yl amino)quinoline derivatives, as 5-HT₆ receptor (5-HT₆R) antagonists. In this work, we have shown that moving from aryl sulfonamide platform to biaryl sulfone platform retains the 5-HT⁶.R affinity when tested in vitro in cell based reporter gene functional assay.

Full text of DOI:10.14233/ajchem.2014.15904

Asian Journal of Chemistry; Vol. 26, No. 13 (2014), 3779-3784
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15904
Synthesis and Structure Activity Relationship of 3-(Arylsulfonyl)-8-
(piperidin-4-yl amino)quinoline Derivatives as 5-HT6 Receptor Antagonists
1,*
1,2
1
2
RAMAKRISHNA V.S. NIROGI , RAJESHKUMAR BADANGE , PARANDHAMA GUDLA and MUKKANTI KHAGGA
1Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad-500 034, India
2Institute of Science and Technology, 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: 12 June 2013;
Accepted: 21 December 2013;
Published online: 23 June 2014;
AJC-15344
As part of our efforts to develop better therapies for the treatment of cognitive impairment associated with Alzheimer's disease and
Schizophrenia, we have focused our research towards 5-HT6 receptor (5-HT6R) in order to identify potent and selective ligands for this
purpose. Herein, we report the synthesis, structure activity relationship and biological evaluation of a novel series of 3-(arylsulfonyl)-8-
(piperidin-4-yl amino)quinoline derivatives, as 5-HT6 receptor (5-HT6R) antagonists. In this work, we have shown that moving from aryl
sulfonamide platform to biaryl sulfone platform retains the 5-HT6R affinity when tested in vitro in cell based reporter gene functional
assay.
Keywords: 5-HT6R, Cognitive impairment, Alzheimer’s disease, Structure Activity Relationship, Pharmacokinetic profile.
SB-7424576 and Lu AE 580547 are in human phase 2 clinical
trials whereas SUVN-502, which is our internally developed
compound, completed human phase 1 clinical trials8.
INTRODUCTION
The occurrence of decline in cognitive performances such
as learning and memory are on a rise all over the world in
elderly population and people with Alzheimer’s disease1. The
current medications, such as donepezil and memantine, used
for the treatment of above neurological disorders have modest
efficacy and lose their action over a period of time2. This poses
a great challenge and requires continuing efforts to develop
symptomatic treatments that have advantage over current
therapies against cognitive impairment andAlzheimer’s disease
based on a novel mechanism of action. In recent years several
experiments have shown that blockade of 5-HT6R function
improves cognition in a number of rodent behavioral models3.
In addition, in vivo microdialysis studies have shown that 5-
HT6R antagonism enhances neurotransmission at cholinergic
and glutamatergic neurons as well as in other pathways4. They
are exclusively located in central nervous system (CNS), espe-
cially in the brain regions known to be associated with learning
and memory3. The brain selective location, together with high
affinity for therapeutically important antipsychotics and anti
depressants, has stimulated significant interest for potential
therapeutic utilities of 5-HT6R in CNS diseases5. Thus, anta-
gonism of the 5-HT6R can potentially provide an effective
treatment for cognitive impairment inAlzheimer’s disease and
Schizophrenia. Few of the reported 5-HT6R antagonists viz.
Our research group is engaged in developing better
therapies for brain related disorders such as Alzheimer's
disease, Schizophrenia and depression, etc. in a multi targeted
approach and 5-HT6R platform is one among them. Majority
of the reported 5-HT6R ligands have a positively ionizable
basic amine moiety, two hydrophobic aryl functionalities and
a hydrogen bond acceptor group, which are thought to be basic
pharmacophoric requirements for 5-HT6R binding9. We have
recently reported a series of piperidin-4-ylamino aryl
sulfonamides, that is, compound I (Fig. 1) which are potent,
selective, orally active and brain penetrant 5-HT6R anta-
gonists10. In continuation to our research towards 5-HT6R for
developing better therapies for unmet medical needs, we then
focused our attention to biaryl sulfones bearing cyclic amines
such as piperidines as they were not much studied and
evaluated. Herein we report the identification of a series of 3-
sulfonyl quinoline derivatives, that is, Compound II (Fig. 1)
obtained by migrating arylsulfonyl group from sulfonamidic
position of Compound I to the 3-position of the quinoline
core. The compound II, thus obtained, contain all the
pharmacophoric requirements for 5-HT6R binding as discussed
above and hence we expect these compound to be potent 5-
HT6R antagonists.

3780 Nirogi et al.
Asian J. Chem.
O
S
concentrated under vacuum to obtain a residual mass. The
residual mass was stirred with water (50 mL), basified with
lye solution (pH-12) and the product was extracted with ethyl
acetate (3 × 50 mL). The combined organic extracts were dried
over anhydrous sodium sulfate and concentrated in vacuo. The
resultant residual mass was chromatographed (silica gel, 2:8
ethyl acetate-hexane as eluent) to afford the 3-bromo-8-quino
quinoline (3) (1.4 g, 65 % yield). IR (KBr, νmax cm-1): 3472,
3361, 1613, 1369, 1126, 757. ESI mass: m/e 223.1, 225.1 (M
+ H)+. 1H NMR (400 MHz, CDCl3) δ: 6.91-6.92 (d, J = 7.56
Hz, 1H), 7.04-7.06 (d, J = 8.1 Hz, 1H), 7.32-7.36 (m, 1H),
8.21-8.21 (d, J = 2.2 Hz, 1H), 8.72-8.72 (d, J = 2.17 Hz, 1H).
8-Acetamino-3-bromoquinoline (4):Acetyl chloride (1.02
g, 13 mmol) was added to a stirred solution of 3-bromo-8-
amino quinoline (2.23 g, 10 mmol) and triethylamine (2.52 g,
25 mmol) in dichloromethane (50 mL) under N2 atmosphere
at 0-5 °C. Then the mass was stirred at RT for 2 h.After comp-
letion of the reaction (TLC), the mixture was poured onto water
(25 mL). The organic layer was separated, dried over anhy-
drous sodium sulfate and concentrated in vacuo to obtain 8-
acetamino-3-bromo quinoline (4) (2.2 g, 85 % yield). IR (KBr,
O
O
O
S
Het
R1
R1
N
HN
HN
N
N
R2
R2
Compound I
Compound II
Fig. 1. Genesis of ligands
EXPERIMENTAL
All the reagents and chemicals used were of reagent grade.
8-Nitroquinoline was commercially procured. Thin layer
chromatography (TLC) was performed on Merck silica gel
60 F254 plates and spots visualization was accomplished with
UV light (254 nm) and/or iodometry. Chromatography refers
to column chromatography performed using 60-120 mesh
silica gel and executed under nitrogen pressure (flash
chromatography) conditions. All the mentioned yields refer
to isolated pure products. Melting points of synthesized
compounds were determined using Electrothermal (model IA
9300 series) open capillary apparatus and are uncorrected.
Infrared spectra were recorded on KBr disc and in solid state
using Perkin-Elmer model 1600 FT-IR spectrophotometer
(Perkin-Elmer, Norwalk, CT, USA). Electrospray ionization
mass spectra were recorded on a API 4000 triple quadrupole
ν
max, cm-1): 3360, 1694, 1524, 1319, 1248, 887. ESI mass:
m/e 265.1, 267.2 (M + H)+. H NMR (400 MHz, CDCl3) δ:
2.35 (s, 3H), 7.40-7.42 (m, 1H), 7.54-7.58 (m, 1H), 8.31-8.31
(d, J = 2.18 Hz, 1H), 8.76- 8.78 (m, 2H).
1
8-Acetamino-3-(4-chloro phenylsulfanyl)quinoline (5b,
R1 = 4-Cl): 4-Chloro thiophenol (2.16 g, 15 mmol) was added
to a stirred suspension of 8-acetamino-3-bromo quinoline (2.65
g, 10 mmol) and K2CO3 (2.76 g, 20 mmol) in DMF (25 mL)
under N2 atmosphere at RT. The mass was heated to 140 °C
and maintained for 8 h.After completion of the reaction (TLC),
the mixture was cooled to room temperature, poured onto cold
water (25 mL) under stirring. The product was extracted with
ethyl acetate (3 × 25 mL). The combined organic extracts were
dried over anhydrous sodium sulfate and concentrated in vacuo
to get dark residue. The resultant residual mass was chromato-
graphed (silica gel, 3:7 ethyl acetate-hexane as eluent) to afford
the title compound (2.26 g, 70 % yield). IR (KBr, νmax, cm-1):
3370, 1691, 1519, 1319, 760. ESI mass: m/e 329.2, 331.2 (M
+ H)+. 1H NMR (400 MHz, CDCl3) δ: 2.33 (s, 3H), 7.18-7.32
(m, 4H), 7.38-7.40 (d, J = 8.19 Hz, 1H), 7.51-7.55 (m, 1H),
8.05-8.06 (d, J = 2.14 Hz, 1H), 8.66-8.67 (d, J = 2.06 Hz,
1H), 8.73-8.75 (d, J = 7.69 Hz, 1H), 9.62 (1H, bs).
1
instrument (MDS-SCIEX, Concord, Ontario, Canada). H
NMR spectra were obtained on a Bruker NMR spectrometer
(Fallanden, Switzerland) at 400 MHz. Deuterated reagents
were used as solvents and were commercially procured. Tetra-
methylsilane (TMS) was used as an internal standard. Chemical
shift values are expressed in parts per million (δ) and coupling
constants are expressed in Hz. Analytical HPLC was routinely
carried out using Agilant systems with auto sampler (Model-
1100 series).
3-Bromo-8-nitro quinoline (2): N-Bromosuccinimide
(0.84 g, 4.74 mmol) was added in portions to a stirred solution
of 8-nitro quinoline (1 g, 3.95 mmol) in acetic acid (10 mL) at
25 °C. The mass was then stirred at 65-70 °C for 6 h under N2
atmosphere.After completion of reaction (TLC), the mass was
cooled to RT and poured onto cold water (25 mL) under
stirring. The product was extracted with ethyl acetate (3 × 25
mL). The combined organic extracts were dried over anhydrous
sodium sulfate and concentrated in vacuo to obtain the crude
mass. The resultant crude mass was chromatographed (silica
gel, 1:9 ethyl acetate-hexane as eluent) to give 3-bromo-8-
nitro quinoline (2) (1.09 g, 75 % yield). IR (KBr, νmax, cm-1):
3065, 1535, 1348, 792. ESI mass: m/e 253.1, 255.2 (M + H)+.
1H NMR (400 MHz, CDCl3) δ: 7.65-7.69 (m, 1H), 7.97-7.99
(dd, J = 8.4, 1.2 Hz, 1H), 8.06-8.08 (dd, J = 8.4, 1.2 Hz, 1H),
8.44-8.44 (d, J = 2 Hz, 1H), 9.06-9.06 (d, J = 2.4 Hz, 1H).
3-Bromo-8-aminoquinoline (3): Concentrated hydro-
chloric acid (5.2 mL, 50 mmol) was added to a stirred suspen-
sion of 3-bromo-8-nitroquinoline (2.53 g, 10 mmol), iron
powder (2.75 g, 50 mmol) and ethanol-water (40 mL: 20 mL)
mixture. The mixture was refluxed for 3 h. After completion
of the reaction (TLC), the mixture was cooled to room tempe-
rature and filtered to remove inorganics. The filtrate was
8-Acetamino-3-(4-chloro phenylsulfonyl)quinoline (6b,
R1 = 4-Cl): A solution of 8-acetamino-3-(4-chloro phenyl-
sulfanyl)quinoline (1.64 g, 5 mmol) in dichloromethane (30
mL) was added to a solution of magnesium monoperoxy-
phthalate hexahydrate (9.8 g, 20 mmol) in methanol (20 mL)
at 25-30 °C. Then the mixture was stirred overnight at RT,
during which white solids precipitated. After completion of
the reaction (TLC), the mixture was poured onto water (50 mL)
and the product was extracted with dichloromethane (3 × 25
mL). The combined organic extracts were dried over anhydrous
sodium sulfate and concentrated in vacuo to obtain crude
compound. The resultant residual mass was chromatographed
(silica gel, 3:7 ethyl acetate-hexane as eluent) to afford the
title compound (1.4 g, 78 % yield). ESI mass: m/e 361.4, 363.2
(M + H)+. 1H NMR (400 MHz, CDCl3) δ: 2.35 (s, 3H), 7.62-
7.64 (m, 2H), 7.84-7.90 (m, 1H), 7.94-7.96 (d, J = 8.4 Hz,

Vol. 26, No. 13 (2014) Synthesis and Structure Activity Relationship of 3-(Arylsulfonyl)-8-(piperidin-4-yl amino)quinoline Derivatives 3781
8b. IR (KBr, νmax, cm-1): 3402, 2932, 1572, 1517, 1318, 1155.
2H), 8.07-8.09 (d, J = 8.8 Hz, 1H), 8.14-8.16 (d, J = 8.4 Hz,
ESI mass: m/e 382.5 (M + H)+. 1H NMR (400 MHz, CDCl3)
1H), 8.78-8.78 (d, J = 2.4 Hz, 1H), 9.15-9.15 (d, J = 2.4 Hz,
1H).
8-Amino-3-(4-chloro phenylsulfonyl)quinoline (7b, R1
δ: 1.64-1.71 (m, 2H), 2.11-2.21 (m, 4H), 2.32 (s, 3H), 2.82-
2.85 (m, 2H), 3.46-3.47 (m, 1H), 6.11-6.13 (d, J = 7.80 Hz,
1H), 6.77-6.79 (d, J = 7.76 Hz, 1H), 7.10-7.12 (d, J = 8.09
Hz, 1H), 7.44-7.59 (m, 4H), 7.99-8.01 (m, 2H), 8.67-8.67 (d,
J = 2.21 Hz, 1H), 9.01-9.01 (d, J = 2.22 Hz, 1H). HPLC purity:
98.3 %.
= 4-Cl): A solution of 8-acetamino-3-(4-chloro phenylsul-
fonyl)quinoline (1.8 g, 5 mmol) in a mixture of ethanol-conc.
hydrochloric acid (40 mL, 1:1) was refluxed for 6 h. After
completion of the reaction (TLC), the mass was cooled and
concentrated in vacuo. The residual mass was diluted with
cold water (25 mL), basified with aq. NaOH (pH-12) and
extracted the product with chloroform (3 × 50 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate and concentrated in vacuo. The resultant residual mass
was chromatographed (silica gel, 3:7 ethyl acetate-hexane as
eluent) to afford the title compound (1.09 g, 69 % yield). IR
(KBr, νmax, cm-1): 3386, 3296, 1498, 1149, 1086. ESI mass:
3-(4-Fluoro phenylsulfonyl)-8-(1-methyl piperidin-4-
yl amino)quinoline (8d): The title compound was prepared
using essentially the same procedure as described for the
preparation of 8b. IR (KBr, νmax, cm-1): 3391, 2935, 1582, 1518,
1
1374, 1152. ESI mass: m/e 400.1 (M + H)+. H NMR (400
MHz, CDCl3) δ: 1.69-1.72 (m, 2H), 2.11-2.23 (m, 4H), 2.32
(s, 3H), 2.82-2.85 (m, 2H), 3.46-3.48 (m, 1H), 6.11-6.13 (d, J
= 7.79 Hz, 1H), 6.78-6.80 (d, J = 7.7 Hz, 1H), 7.10-7.12 (d, J
= 7.76 Hz, 1H), 7.17-7.26 (m, 2H), 7.45-7.49 (m, 1H), 8.00-
8.04 (m, 2H), 8.65 (d, J = 2.19 Hz, 1H), 9.02 (d, J = 2.21 Hz,
1H). HPLC purity: 96 %.
1
m/e 319.5, 321.4 (M + H)+. H NMR (400 MHz, CDCl3) δ:
7.04-7.06 (m, 1H), 7.24-7.26 (m, 1H), 7.44-7.51 (m, 3H), 7.94-
7.96 (d, J = 6.8 Hz, 2H), 8.68-8.68 (d, J = 2.4 Hz, 1H), 9.06-
9.07 (d, J = 2.4 Hz, 1H).
3-(3-Methyl phenylsulfonyl)-8-(1-methyl piperidin-4-
yl amino)quinoline (8e): The title compound was prepared
using essentially the same procedure as described for the
preparation of 8b. IR (KBr, νmax, cm-1): 3418, 2953, 1574, 1375,
3-(4-Chloro phenylsulfonyl)-8-(1-methyl piperidin-4-
ylamino)quinoline (8b, R1 = 4-Cl, R2 = CH3): Sodium
triacetoxy borohydride (0.6 g, 2.83 mmol) was added in por-
tions to a stirred suspension of 8-amino-3-(4-chloro
phenylsulfonyl)quinoline (0.3 g, 0.94 mmol), 1-methyl-4-
piperidone (0.31 g, 2.83 mmol) and sodium sulfate (1.33 g,
9.4 mmol) in glacial acetic acid (6 mL) at room temperature
under N2 atmosphere. The mass was stirred overnight at room
temperature.After completion of the reaction (TLC), the mix-
ture was poured onto cold water (15 mL), basified with aq.
NaOH solution (pH-12) and extracted with chloroform (3 ×
25 mL). The combined organic extracts were dried over anhy-
drous sodium sulfate and concentrated in vacuo to obtain an
oily residue. The mass was chromatographed (neutral silica
gel, 80:20 ethyl acetate-hexane and then 5:95 methanol-ethyl
acetate) to afford the title product (0.2 g, 51 % yield). IR (KBr,
1
1149, 1089. ESI mass: m/e 396.3 (M + H)+. H NMR (400
MHz, DMSO-d6) δ: 1.83-1.89 (m, 2H), 2.15-2.19 (m, 2H),
2.37 (s, 3H), 2.75 (s, 3H), 3.07-3.09 (m, 2H), 3.43-3.46 (m,
2H), 3.47-3.48 (m, 1H), 6.99-7.01 (d, J = 7.72 Hz,1H), 7.34-
7.36 (d, J = 7.99 Hz, 1H), 7.51-7.56 (m, 3H), 7.84-7.88 (m,
2H), 8.95 (d, J = 1.98 Hz, 1H), 9.09-9.10 (d, J = 1.98 Hz, 1H).
HPLC purity: 98.3 %.
3-(2-Bromo phenylsulfonyl)-8-(1-methyl piperidin-4-
yl amino)quinoline (8f): The title compound was prepared
using essentially the same procedure as described for the prepa-
ration of 8b. IR (KBr, νmax, cm-1): 3383, 2931, 1570, 1518,
1373, 1157. ESI mass: m/e 460, 462 (M + H)+. 1H NMR (400
MHz, CDCl3) δ: 1.65-1.72 (m, 2H), 2.04-2.23 (m, 4H), 2.32
(s, 3H), 2.83-2.86 (m, 2H), 3.46-3.48 (m, 1H), 6.12-6.14 (d, J
= 7.80 Hz, 1H), 6.80-6.82 (d, J = 7.66 Hz, 1H), 7.12-7.14 (d,
J = 7.55 Hz, 1H), 7.43-7.48 (m, 2H), 7.57-7.61 (m, 1H), 7.64-
7.66 (dd, J = 7.88, 1.02 Hz, 1H), 8.48-8.50 (dd, J = 7.95, 1.62
Hz, 1H), 8.74-8.75 (d, J = 2.25 Hz, 1H), 8.99-8.99 (d, J =
2.26 Hz, 1H). HPLC purity: 97.4 %.
ν
max, cm-1): 3388, 2938, 1573, 1515, 1376, 1151. ESI mass:
m/e 416.5 (M + H)+. 1H NMR (400 MHz, CDCl3) δ: 1.63-1.71
(m, 2H), 2.11-2.23 (m, 4H), 2.32 (s, 3H), 2.82-2.85 (m, 2H),
3.47-3.48 (m, 1H), 6.11-6.13 (d, J = 7.68 Hz, 1H), 6.78-6.80
(d, J = 7.76 Hz, 1H), 7.10-7.12 (d, J = 8.08 Hz, 1H), 7.48-
7.52 (m, 3H), 7.92-7.94 (dd, J = 8.61, 1.71 Hz, 2H), 8.64-
8.65 (d, J = 2.32 Hz, 1H), 9.01-9.02 (d, J = 2.22 Hz, 1H).
HPLC purity: 98.0 %.
3-(4-Chloro phenylsulfonyl)-8-(1-tert butoxycarbonyl
piperidin-4-yl amino)quinoline (9b, R1 = 4-Cl): Sodium
triacetoxyborohydride (0.6 g, 2.83 mmol) was added in
portions to a stirred suspension of 8-amino-3-(4-chloro phenyl-
sulfonyl)quinoline (0.3 g, 0.94 mmol), 1-boc-4-piperidone
(0.56 g, 2.83 mmol) and sodium sulfate (1.33 g, 9.4 mmol) in
glacial acetic acid (6 mL) at room temperature under N2 atmos-
phere. The mass was stirred overnight at room temperature.
After completion of the reaction (TLC), the mixture was poured
onto cold water (15 mL), basified with aq. NaOH solution
(pH~12) and extracted with chloroform (3 × 25 mL). The
combined organic extracts were dried over anhydrous sodium
sulfate and concentrated in vacuo to obtain an oily residue.
The mass was chromatographed (neutral silica gel, 20:80 ethyl
acetate-hexane) to afford the title product (0.42 g, 90 % yield).
3-(3-Fluoro phenylsulfonyl)-8-(1-methyl piperidin-4-
yl amino)quinoline (8a): The title compound (8a) was prepared
using essentially the same procedure as described for the prepa-
ration of 8b. IR (KBr, νmax, cm-1): 3411, 2934, 1570, 1516,
1
1371, 1150. ESI mass: m/e 400.5 (M + H)+. H NMR (400
MHz, CDCl3) δ: 1.62-1.72 (m, 2H), 2.11-2.23 (m, 4H), 2.32
(s, 3H), 2.83-2.85 (m, 2H), 3.46-3.49 (m, 1H), 6.12-6.14 (d,
J = 7.76 Hz, 1H), 6.79-6.81 (d, J = 7.74 Hz, 1H), 7.11-7.13
(d, J = 8.08 Hz, 1H), 7.26-7.30 (m, 1H), 7.46-7.54 (m, 2H),
7.69-7.72 (m, 1H), 7.79-7.81 (d, J = 7.88 Hz, 1H), 8.67-8.67
(d, J = 2.22 Hz, 1H), 9.03-9.04 (d, J = 2.20 Hz, 1H). HPLC
purity: 98.9 %.
8-(1-Methyl piperidin-4-yl amino)-3-(phenylsulfonyl)-
quinoline (8c): The title compound was prepared using essen-
tially the same procedure as described for the preparation of
1
ESI mass: m/e 502.7, 504.1 (M + H)+. H NMR (400 MHz,
DMSO-d6) δ: 1.47 (s, 9H), 1.52-1.57 (m, 2H), 2.08-2.17 (m,

3782 Nirogi et al.
Asian J. Chem.
2H), 3.00-3.06 (m, 2H), 3.61-3.63 (m, 1H), 4.01-4.15 (m, 2H),
6.12-6.14 (d, J = 7.99 Hz, 1H), 6.80-6.82 (d, J = 7.74 Hz,
1H), 7.13-7.15 (d, J = 8.07 Hz, 1H), 7.46-7.52 (m, 3H), 7.93-
7.95 (d, J = 9.27 Hz, 2H), 8.65-8.66 (d, J = 2.23 Hz, 1H),
9.01-9.01 (d, J = 2.21 Hz, 1H). HPLC purity: 97.8 %.
3.75-3.78 (m, 1H), 6.99-7.01 (d, J = 7.72 Hz,1H), 7.33-7.35
(d, J = 8.00 Hz, 1H), 7.51-7.55 (m, 3H), 7.84-7.92 (m, 2H),
8.65-8.67 (m, 1H), 8.87-8.88 (m, 1H), 8.94-8.95 (d, J = 2.10
Hz, 1H), 9.09-9.10 (d, J = 2.13 Hz, 1H). HPLC purity: 95 %.
M.R = 129.5-135.3 °C.
3-(4-Chloro phenylsulfonyl)-8-(piperidin-4-yl amino)-
quinoline dihydrochloride (10b, R1 = 4-Cl, R2 = H): 3-(4-
Chloro phenylsulfonyl)-8-(1-tert butoxycarbonyl piperidin-4-
yl amino)quinoline (0.42 g, 0.83 mmol) was stirred in isopro-
panolic HCl (20 % w/v solution, 5 mL) for 2 h.After completion
of the reaction (TLC), the solvent was removed in vacuo to
obtain the title compound as white solids (0.36 g, 93% yield).
IR (KBr, νmax cm-1): 3366, 2957, 1582, 1323, 1156, 1066. ESI
mass: m/e 402.4 (M + H)+. 1H NMR (400 MHz, CD3OD) δ:
1.77-1.85 (m, 2H), 2.32-2.35 (m, 2H), 3.16-3.22 (m, 2H), 3.43-
3.46 (m, 2H), 3.87-3.92 (m, 1H), 7.08-7.10 (d, J = 7.69 Hz,1H),
7.35-7.37 (d, J = 8.1 Hz, 1H), 7.54-7.58 (m, 1H), 7.61-7.64
(d, J = 8.41 Hz, 2H), 8.04-8.06 (d, J = 8.36 Hz, 2H), 8.86 (s,
1H), 9.09 (s, 1H). HPLC purity: 99.5 %. M.R = 295.2-297.0 °C.
3-(3-Fluoro phenylsulfonyl)-8-(piperidin-4-yl amino)-
quinoline dihydrochloride (10a): The title compound was
prepared using essentially the same procedure as described
for the preparation of 10b. IR (KBr, νmax, cm-1): 3389, 2954,
3-(2-Bromo phenylsulfonyl)-8-(piperidin-4-yl amino)-
quinoline dihydrochloride (10f): The title compound was
prepared using essentially the same procedure as described
for the preparation of 10b. IR (KBr, νmax, cm-1): 3383, 2935,
1571, 1517, 1374, 1157. ESI mass: m/e 446.4, 448 (M + H)+.
1H NMR (400 MHz, DMSO-d6) δ: 1.69-1.77 (m, 2H), 2.11-
2.14 (m, 2H), 3.01-3.06 (m, 2H), 3.30-3.33 (m, 2H), 3.76-
3.79 (m, 1H), 7.02-7.04 (m,1H), 7.34-7.36 (d, J = 8.03 Hz,
1H), 7.52-7.56 (m, 1H), 7.64-7.67 (m, 1H), 7.74-7.78 (m, 1H),
7.81-7.83 (d, J = 7.74 Hz, 1H), 8.41-8.43 (d, J = 7.70 Hz,
1H), 8.66-8.68 (m, 1H), 8.86-8.88 (m, 1H), 8.93-8.94 (d, J =
1.57 Hz, 1H), 9.03-9.03 (d, J = 1.49 Hz, 1H). HPLC purity:
98.47 %. M.R = 130.2-133.1 °C.
RESULTS AND DISCUSSION
The target compounds 8 and 10 were prepared as according
to Scheme-I.
The general synthetic strategy for the proposed targets 8
and 10 was achieved as shown in Scheme-I. Electrophilic
bromination of 8-nitroquinoline (1) with N-bromosuccinimide
(NBS) provided intermediate 2. Reduction of nitro functional
group of intermediate 2 with Fe/HCl followed by acetylation
under basic conditions afforded intermediate 4. The inter-
mediate 4 was further reacted with substituted thiophenols to
get the biarylsulfide intermediates 5. Oxidation of interme-
diates 5 using appropriate oxidizing reagents provided interme-
diates 6. Hydrolysis of intermediates 6 with conc. HCl in
ethanol under reflux yielded intermediates 7. The intermediates
7 were reacted with 1-methyl-4-piperidone in the presence of
acetic acid, sodium sulfate and sodium triacetoxyborohydride
to afford targeted compound 8. 1-Boc-4-piperidone was
reacted with 7 under reductive amination conditions to obtain
Boc protected intermediates 9. These on deprotection with
IPA·HCl yielded targeted compound 10 as HCl salts.
1
1590, 1373, 1152, 701. ESI mass: m/e 386.4 (M + H)+. H
NMR (400 MHz, DMSO-d6) δ: 1.70-1.78 (m, 2H), 2.10-2.13
(m, 2H), 2.97-3.05 (m, 2H), 3.28-3.31 (m, 2H), 3.79-3.81 (m,
1H), 7.02-7.04 (d, J = 7.71 Hz, 1H), 7.33-7.35 (d, J = 8.02
Hz, 1H), 7.52-7.61 (m, 2H), 7.67-7.72 (m, 1H), 7.90-7.97 (m,
2H), 8.89-8.91 (m, 1H), 9.01-9.14 (m, 3H). HPLC purity: 98.4
%. M.R = 250.2-252.5 °C.
3-(Phenylsulfonyl)-8-(piperidin-4-yl amino)quinoline
dihydrochloride (10c): The title compound was prepared
using essentially the same procedure as described for the
preparation of 10b. IR (KBr, νmax cm-1): 3380, 2958, 1585,
1317, 1155, 1028. ESI mass: m/e 368.5 (M + H)+. 1H NMR
(400 MHz, DMSO-d6) δ: 1.70-1.72 (m, 2H), 2.10-2.17 (m,
2H), 2.87-3.02 (m, 2H), 3.27-3.36 (m, 2H), 3.73-3.81 (m, 1H),
7.01-7.03 (d, J = 7.74 Hz, 1H), 7.34-7.36 (d, J = 8.04 Hz,
1H), 7.51-7.55 (m, 1H), 7.61-7.65 (m, 2H), 7.69-7.72 (m, 1H),
8.05-8.07 (d, J = 7.44 Hz, 2H), 8.90-8.92 (m, 1H), 8.97 (d, J =
2.02 Hz, 1H), 9.09-9.10 (d, J = 2.08 Hz, 1H), 9.13-9.15 (m,
1H). HPLC purity: 95.3 %. M.R = 159.6-161.9 °C.
Structure activity relationship (SAR): We used various
substituents at R1 and R2 positions of compound II and explored
their antagonistic activity at 5-HT6R at 1 µM concentration
(Table-1). We initially tested compound 8c where R1 = H, R2
= CH3 and inhibition at 5-HT6R was found to be 43 %. Later,
we introduced various substituents like halogen, alkyl and
alkoxy at R1 position and H, CH3 at R2 position of compound
II. Among these derivatives, compound 8f (R1 = 2'-Br, R2 =
CH3) with an inhibition of 89 % was found to be most potent.
Other derivatives from the series, like compound 8a (R1 = 3'-
F, R2 = CH3) has shown 62 % inhibition whereas compound
8d (R1 = 4'-F, R2 = CH3) and compound 8b (R1 = 4'-Cl, R2 =
CH3) have shown an inhibition 7 and 9 %, respectively. These
compounds, 8b and 8d are almost 7- to 9- fold less potent
compared to compound 8a. Compound 8e (R1 = 3'-CH3, R2 =
CH3) with 76 % inhibition is found to be equipotent compared
to 8f. From the above structure activity relationship, it can be
observed that the presence of halo and alkyl derivatives at 2',
3' position of compound II are more preferable compared to
those substituted at 4' position. Later, we made compounds
3-(4-Fluoro phenylsulfonyl)-8-(piperidin-4-yl
amino)quinoline dihydrochloride (10d): The title compound
was prepared using essentially the same procedure as described
for the preparation of 10b. IR (KBr, νmax, cm-1): 3408, 2958,
1
1585, 1326, 1155, 1105. ESI mass: m/e 386.4 (M + H)+. H
NMR (400 MHz, CD3OD) δ: 1.79-1.87 (m, 2H), 2.31-2.34
(m, 2H), 3.12-3.21 (m, 2H), 3.49-3.50 (m, 2H), 4.08-4.09 (m,
1H), 7.12-7.14 (d, J = 7.62 Hz, 1H), 7.32-7.40 (m, 3H), 7.55-
7.59 (m, 1H), 8.11-8.15 (m, 2H), 8.86-8.87 (d, J = 1.90 Hz, 1H),
9.10 (m, 1H). HPLC purity: 96.2 %. M.R = 245.4-250.9 °C.
3-(3-Methyl phenylsulfonyl)-8-(piperidin-4-yl
amino)quinoline dihydrochloride (10e): The title compound
was prepared using essentially the same procedure as described
for the preparation of 10b. IR (KBr, νmax, cm-1): 3409, 2958,
1
1588, 1374, 1150, 1105. ESI mass: m/e 382.4 (M + H)+. H
NMR (400 MHz, DMSO-d6) δ: 1.68-1.72 (m, 2H), 2.10-2.13
(m, 2H), 2.37 (s, 3H), 2.97-3.06 (m, 2H), 3.29-3.32 (m, 2H),

Vol. 26, No. 13 (2014) Synthesis and Structure Activity Relationship of 3-(Arylsulfonyl)-8-(piperidin-4-yl amino)quinoline Derivatives 3783
Br
Br
a
b
c
N
N
N
72%
68%
82%
NO2
NO2
NH2
1
2
3
O O
S
S
Br
R1
R1
d
e
N
O
N
N
O
70-83%
69-78%
HN
HN
O
HN
5
4
6
O O
S
2'
5'
O O
S
3'
R1
1'
g
R1
f
61-69%
4'
6'
N
N
51-64%
HN
NH2
N
7
R2
8
h
83-90%
O
O
O
O
2'
S
S
3'
R1
1'
R1
i
4'
6'
N
N
5'
89-93%
HN
HN
2HCl
N
N
O
R2
O
9
10
Scheme-Ia: aReagents and conditions: (a) NBS, CH3CO2H, 65-70 °C; (b) Fe/HCl, H2O:EtOH, reflux; (c) CH3COCl, Et3N, DCM; (d) substituted thiophenols,
K2CO3, DMF, 140 °C; (e) Magnesium monoperoxyphthalate hexahydrate, MeOH:DCM, RT; (f) Conc.HCl, Ethanol, reflux; (g) 1-methyl-4-
piperidone, NaBH(OAc)3, AcOH, Na2SO4, 25-30 °C; (h) 1-Boc-4-piperidone, NaBH(OAc)3, AcOH, Na2SO4, 25-30 °C; (i) IPA·HCl, RT, 2-4 h
10a-10f with R2 = H. These compound could be the possible
metabolites of compounds 8a-8f, respectively. Among these,
compound 10f (R1 = 2'-Br, R2 = H), compound 10a (R1 = 3'-F,
R2 = H), compound 10e (R1 = 3'-CH3, R2 = H) and compound
10c (R1 = H, R2 = H) have shown an inhibition of 66, 51, 64
and 49 % towards 5-HT6R. The activities of these compounds
follow a similar trend when compared with their parent comp-
ounds, that is, 8f, 8a, 8e and 8c, respectively. In general, all
the tested compounds 8a-8f and 10a-10f were showing
moderate to potent inhibitory affinity towards 5-HT6R. This
proves the concept that moving from aryl sulfonamides
(compound I) to biaryl sulfones (compound II) retains binding
affinities towards 5-HT6R.
receptors and transporters. In general, these compounds have
shown excellent selectivity over all the receptors examined
(data not shown). The most potent compound of the series,
that is, compound 8f was further evaluated for its CYP liabi-
lities, microsomal metabolic stability (Table-2) and pharma-
cokinetic profile (Table-3). Compound 8f was moderately
metabolized in both rat liver microsomes (54.5 %) and human
liver microsomes (56.9 %). The IC50 value for compound 8f at
CYP 3A4 was found to be 33.88 µM whereas the IC50 value at
CYP 2D6 enzymes were found to be 17.46 µM. These results
show that the compounds from this series have lower potential
for drug-drug interaction, thereby maximizing the safety.
The pharmacokinetic profile of compound 8f was assessed
in male Wister rats (Table-3). Compound 8f at an oral dose of
3 mg/kg was rapidly absorbed in rats with a half-life of 1.9
0.1 h with an oral bioavailability of 20 5 %. The observed
A number of compounds that displayed satisfactory inhi-
bitory potential towards 5-HT6R in functional assay were
profiled for their selectivity against a panel of closely related

3784 Nirogi et al.
Asian J. Chem.
TABLE-1
5-HT6 RECEPTOR BINDING DATA OF COMPOUNDS
of 20 5.4 L/kg for i.v. dose. Importantly, compound 8f was
selectively partitioned in brain with a Cb/Cp value of 8.18,
which would be one of the requirements for achieving in vivo
activity against neuropsychiatric indications.
O
O
2'
S
3'
R1
1'
6'
4'
N
Conclusion
5'
HN
We have disclosed a new series of compound II, i.e., 3-
(arylsulfonyl)-8-(piperidin-4-yl amino)quinoline derivatives,
obtained by moving arylsulfonyl group from 'N' in compound
I to 'C' in compound II (using C/N functional group flip
strategy)12 .The new series of compound II, thus disclosed
herein, have moderate to potent in vitro binding affinities towards
5-HT6R. The lead compound 8f from this series has shown
excellent inhibitory affinity with adequate pharmacokinetic
profile, acceptable selectivity over other closely related receptors.
Based on the above findings, the novel series of compound II,
in general, could be used for further optimization to obtain
potent 5-HT6R antagonists.
N
R2
Compound R1
R2
% inhibition at 1 µM concentrationa
3’-F
CH3
CH3
CH3
CH3
8a
8b
62
9
4’-Cl
H
43
7
8c
4’-F
8d
3’-CH3 CH3
76
89
51
10
49
12
64
66
8e
2’-Br
3’-F
CH3
H
8f
10a
10b
10c
10d
10e
10f
4’-Cl
H
H
H
4’-F
H
3’-CH3
2’-Br
H
ACKNOWLEDGEMENTS
H
a% Inhibition towards 5-HT6R was measured using cell based reporter
gene functional assay. Values are mean of two experiments
The support received from Discovery Analytical, DMPK
Department and Mr. Venkateswarlu Jasti, CEO, Suven Life
Sciences Ltd., Hyderabad is gratefully acknowledged.
TABLE-2
HUMAN CYP45011 INHIBITORY DATA AND
MICROSOMAL METABOLIC STABILITY(a)
REFERENCES
% Metabolism in
liver microsomes
Compound
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33.88
CYP 2D6
17.46
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56.9
Rat
54.5
8f
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TABLE-3
PHARMACOKINETIC PROFILE OF
COMPOUND 8f IN MALE WISTER RATSa
Compound
8f
i.v.
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Dose
t1/2 (h)
1 mg/kg
1.9 0.1
20.0 5.4
120 27
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Vz (L/kg)
CL (mL/min/kg)
p.o.
Dose
Cmax (ng/mL)
Tmax (h)
3 mg/kg
36 12
10. R. Nirogi, A. Shinde, A. Daulatabad, R. Kambhampati, P. Gudla, M.
Shaik, M. Gampa, S. Balasubramaniam, P. Gangadasari, V. Reballi, R.
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1.00 0.00
104 19
AUCt (ng h/mL)
F (%)
20
5
11. D.F.V. Lewis, Cytochromes P450: Structure, Function and Mechanism;
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oral Cmax was 36 12 ng/mL and occurred at 1 h. The compound
displayed an oral exposure of 104 19 ng h/mL. It had a
clearance of 120 27 mL/min/kg and a volume of distribution