Design, synthesis and biological evaluation of novel benzopyran sulfonamide derivatives as 5-HT6 receptor ligands

Article abstract of DOI:10.14233/ajchem.2015.17783

On the basis of a known pharmacophore model for 5-HT₆ receptor antagonists (5-HT₆R), we have designed and synthesized a novel series of benzopyran sulfonamide derivatives 9(a-d), 20(a-d) and 21(a-d) and their structures were confirmed by ¹H NMR and mass spectral data. All the synthesized compounds were tested for their antagonistic activity towards 5-HT₆R in a cell based reporter gene in vitro functional assay. Most of the tested compounds showed moderate to potent binding affinities towards 5-HT₆R.

Full text of DOI:10.14233/ajchem.2015.17783

Asian Journal of Chemistry; Vol. 27, No. 6 (2015), 2117-2124
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17783
Design, Synthesis and Biological Evaluation of Novel Benzopyran
Sulfonamide Derivatives as 5-HT
6
Receptor Ligands
1,*
1,2
1
2
RAMAKRISHNA V.S. NIROGI , RAJESHKUMAR BADANGE , VEENA REBALLI and MUKKANTI KHAGGA
1
2
Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad-500 034, India
Institute of Science and Technology, JNTU Hyderabad, Kukatpally, Hyderabad-500 085, India
*
Corresponding author: Fax: +91 40 23541152; Tel: +91 40 23556038/23541142; E-mail: nvsrk@suven.com
Received: 8 April 2014; Accepted: 21 July 2014; Published online: 17 March 2015;
AJC-16975
On the basis of a known pharmacophore model for 5-HT
of benzopyran sulfonamide derivatives 9(a-d), 20(a-d) and 21(a-d) and their structures were confirmed by H NMR and mass spectral
data. All the synthesized compounds were tested for their antagonistic activity towards 5-HT R in a cell based reporter gene in vitro
functional assay. Most of the tested compounds showed moderate to potent binding affinities towards 5-HT R.
6
receptor antagonists (5-HT
6
R), we have designed and synthesized a novel series
1
6
6
Keywords: 5-HT R, Benzopyran, Cognitive impairment, Alzheimer's disease, Structure activity relationship.
6
In general, this model contains four different key elements,
that is, a positively ionizable atom (PI, secondary or tertiary
amine group), a hydrogen bond acceptor (HBA, a sulfone or a
sulfonamide group), a hydrophobic site (HYD) and an aromatic
INTRODUCTION
Cognitive dysfunction is a characteristic feature of many
neurological disorders likeAlzheimer's disease (AD), Schizo-
phrenia, Parkinson's disease (PD) and other neurodegenerative
ring hydrophobic site (AR) (Fig. 1). A few of the reported
1
diseases . Among these, Alzheimer's disease is the leading
10
clinical stage 5-HT
6
R antagonists viz. LuAE 58054 (phase
cause of dementia and affects 36 million people worldwide
and this number is expected to increase with increased life
11
12
II), SB-742457 (phase II) and SUVN-502 (phase I, our own
internally discovered compound) align with above pharmaco-
2
expectancy around the world . The current line of treatments,
phoric model. Based on literature support and in continuation
donepezil and memantine, lose their efficacy over a period of
13
of our research towards identifying potent 5-HT
6
R antagonists,
3
time . The need of the moment is to develop new therapies for
we have designed and synthesized compound I. It contains a
benzopyran central core bearing piperazine and sulfonamide
groups as pendant groups. The methylene group adjacent to
oxygen of benzopyran central core could be a metabolic prone
site by CYP enzymes. To minimize this metabolic issue, we
introduced a cyclobutyl group adjacent to oxygen of compound
I to obtain compound II. This modification could inhibit
unforeseen metabolic issues, if any, associated with compound
I. Compound III were obtained by interchanging the positions
of piperazine and sulfonamide groups of Compounds II.
Compounds I, compounds II and compounds III (Fig. 1) thus
designed contains all the pharmacophoric requirements for 5-
this debilitating disorder and 5-hydroxytryptamine 6 receptor
(
5-HT
6
R) attracted a lot of focus for this purpose. It belongs
to 5-hydroxytryptamine (5-HT, serotonin) super family of
4
receptors which is subdivided into 14 subclasses . 5-HT
6
receptors are exclusively located in brain regions such as
olfactory tubercule, striatum and nucleus accumbens. These
5
areas are known to be involved in cognitive processes . 5-HT
6
receptors are positively coupled to adenylyl cyclase and
receptor antagonism leads to elevation of cAMP and enhances
6
neurotransmission at cholinergic and glutamatergic pathways .
Several atypical antipsychotics and tricyclic antidepressants
7
bind with high affinity to 5-HT
that antagonism of 5-HT
6
receptor . These facts suggest
HT
6
R binding as discussed above and we expect these com-
R.
6
receptor could potentially provide
pounds to show affinity towards 5-HT
6
better treatments for cognitive dysfunction associated with
neurodegenerative disorders.
EXPERIMENTAL
A number of selective 5-HT
in the last decade and a pharmacophoric model was cons-
tructed based on these structurally diverse 5-HT R antagonists .
6
R antagonists were identified
8
All the reagents and chemicals used were of reagent
grade. 2-Bromophenol and 2'-hydroxyacetophenone were
9
6

2
118 Nirogi et al.
Asian J. Chem.
H
HCl
O
N
3
'
N
4
'
2'
R1
O
5
'
S
6
'
N
O
Proton
donor (PI)
H
Hydrophobic
site (HYD)
H
N
Compounds II
HCl
O
N
N'
X
X
3
'
N
S
4
'
4'
2'
O
5'
3'
2'
O
R1
R1
O
Double
acceptor (HBA)
6
'
5
'
S
Hydrophobic
site (AR)
6
'
N
O
O
H
S
HN
O
O
Reported 5-HT receptor
Pharmacophor model
6
Compounds I
HCl
N
HN
Compounds III
Fig. 1. Design of ligands
commercially procured and used as such without further
purification. 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 iodine. Chroma-
tography refers to column chromatography performed using
(400 MHz, DMSO-d ) δ: 12.39 (1H, bs), 7.54-7.56 (1H, dd,
6
J = 7.88, 1.48 Hz), 7.31-7.33 (1H, t, J = 7.16 Hz), 7.11-7.13
(1H, dd, J = 8.12, 0.76 Hz), 6.86-6.90 (1H, t, J = 7.76 Hz),
4.21-4.24 (2H, t, J = 5.97 Hz), 2.69-2.72 (2H, t, J = 6.95 Hz).
8-Bromo-3,4-dihydro-2H-1-benzopyran-4-one (3):
Compound 2 (3.5 g, 14.28 mmol) was added in portions to a
mechanically stirred mass of polyphosphoric acid (17.5 g) at
100-110 °C and stirred for 10-15 min (excessive heating decom-
poses the product). Then the reaction mixture was cooled to
50-60 °C and crushed ice (~150 g) was added to it under vigorous
stirring during which solids precipitated out. The product was
extracted with chloroform (100 mL × 3). Combined organic
extracts were dried over anhydrous sodium sulfate, concen-
trated in vacuo to obtain a dark residue. The resultant residual
mass was chromatographed (silica gel, 2:8 ethyl acetate-
hexanes as eluent) to afford title compound (2.33 g, 72 %
6
0-120 mesh silica gel and executed under nitrogen pressure
(
flash chromatography) conditions. All the mentioned yields
refer to isolated pure products. Electrospray ionization mass
spectra were recorded on aAPI 4000 triple quadrupole instru-
1
ment (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. Tetramethylsilane
(TMS) was used as an internal standard. Chemical shift values
are expressed in parts per million (δ) and coupling constants
are expressed in Hz.
+
1
3
-(2-Bromo phenoxy)propionic acid (2): Powdered
yield). ESI mass: m/e 227.3, 229.1 (M + H) . H NMR (400
MHz, CDCl ) δ: 7.86-7.88 (1H, dd, J = 7.84, 1.53 Hz), 7.72-
KOH (6.16 g, 110 mmol) was added in portions to a stirred
suspension of phenolic compound, 1 (8.65 g, 50 mmol) in
water (250 mL) at 25-50 °C and stirred for 0.5 h, followed by
the addition of 3-bromopropionic acid (8.41 g, 55 mmol) and
then refluxed for 18 h. Then the reaction mixture was cooled
to room temperature, acidified with conc. HCl (pH-2) and
extracted with ethyl acetate (150 mL × 4). The combined organic
extracts were dried over anhydrous sodium sulfate, concen-
trated in vacuo to obtain a dark residue. The resultant residual
mass was chromatographed (silica gel, 1:1 ethyl acetate-
hexanes as eluent) to afford title compound (3.55 g, 29 % yield).
3
7.75 (1H, dd, J = 7.76, 1.55 Hz), 6.90-6.94 (1H, t, J = 7.80
Hz), 4.64-4.68 (2H, t, J = 6.39 Hz), 2.84-2.88 (2H, t, J = 6.49
Hz).
8-Bromo-3,4-dihydro-2H-1-benzopyran (4): NaBH (0.33
4
g, 8.817 mmol) was added in portions to a stirred suspension
of 3 (2 g, 8.81 mmol) in methanol (10 mL) at 25-35 °C. The
reaction mixture was stirred at room temperature for 0.5 h
and then concentrated to obtain a thick residual mass. The
resultant residual mass was diluted with water (25 mL) and
extracted with ethyl acetate (25 mL × 3). The combined organic
extracts were dried over anhydrous sodium sulfate, concen-
+
1
ESI mass of a fragment: m/e 244.1, 245.3 (M-H ). H NMR

Vol. 27, No. 6 (2015)
Design, Synthesis and Biological Evaluation of Novel Benzopyran Sulfonamide Derivatives 2119
O
a
O
b
c, d
OH
Br
29%
O
OH
72%
O
72%
over 2 steps
O
Br
Br
Br
1
2
4
3
5'
4
'
6'
O N
H N
H
2
2
R1
g
N
e
f
3
'
S
2'
O O
O
O
79%
89%
72-76%
O
Br
Br
Br
5
6
7
a-d
5'
5'
4'
4'
6'
6'
H
H
R1
R1 3'
N
N
3
'
h
S
S
i
2'
2'
O O
O O
54-59%
O
90-93%
O
N
N
N
Boc
N
H
HCl
9
a-d
8
a-d
Scheme-I:Reagents and conditions: (a) KOH, water, 3-bromopro-pionic acid, 100-110 °C, 18 h; (b) PPA, 100-110 °C, 15 min; (c) NaBH
d) Et SiH, CF CO H, 60-65 °C, 4 h; (e) KNO , H SO , 0-5 °C, 1 h; (f) Fe, NH Cl, H O:THF-:EtOH, reflux, 3 h; (g) substituted benzenesulfonyl
chlorides, pyridine, DCM, RT, 4 h; (h) 1-Boc piperazine, pd
4
, MeOH, RT, 0.5 h;
(
3
3
2
3
2
4
4
2
2
dba
3
, BINAP, NaOBut, toluene, reflux, 6 h; (i) MeOH.HCl, RT, 3 h
trated in vacuo to afford hydroxy derivative (1.83 g, 91 %
yield). Et SiH (2 g, 17.29 mmol) was added to a solution of
hydroxy derivative (1.8 g, 7.86 mmol) in trifluoroacetic acid
20 mL) at room temperature, then heated and maintained at
0-65 °C for 4 h. The reaction mixture was then poured on to
concentrated in vacuo to obtain a crude residual mass. The
resultant residual mass was chromatographed (silica gel, 2:8
ethyl acetate-hexanes as eluent) to afford title compound (0.95
3
+
1
(
6
g, 79 % yield). ESI mass: m/e 258.14, 260.01 (M + H) . H
NMR (400 MHz, CDCl ) δ: 8.28-8.29 (1H, d, J = 2.45 Hz),
3
water (25 mL), extracted with ethyl acetate (25 mL × 4). The
combined organic extracts were washed with brine (25 mL),
dried over anhydrous sodium sulfate and concentrated in vacuo
to obtain a dark residual mass. The resultant residual mass
was chromatographed (silica gel, 1:9 ethyl acetate-hexanes as
eluent) to afford the title compound (1.2 g, 72 % yield). ESI
7.95-7.95 (1H, d, J = 2.29 Hz), 4.42-4.44 (2H, t, J = 5.32 Hz),
2.89-2.92 (2H, t, J = 6.41 Hz), 2.04-2.13 (2H, m).
6-Amino-8-bromo-3,4-dihydro-2H-1-benzopyran (6):
A mixture of 5 (0.9 g, 3.48 mmol), Fe (0.87 g, 13.95 mmol) and
NH Cl (1.1 g, 17.44 mmol) in EtOH:THF:water (1:1; 4, 20 mL)
4
was refluxed for 3 h, cooled to room temperature, diluted with
chloroform (50 mL) and filtered through celite. The organic
layer was separated, dried over anhydrous sodium sulfate,
concentrated in vacuo to afford the title compound (0.70 g,
+
1
mass: m/e 213.09, 215.01 (M + H) . H NMR (400 MHz,
CDCl ) δ: 7.33-7.35 (1H, d, J = 7.79 Hz), 6.98-7.00 (1H, d,
3
J = 7.45 Hz), 6.69-6.73 (1H, t, J = 7.72 Hz), 4.29-4.32 (2H,
t, J = 5.13 Hz), 2.80-2.83 (2H, t, J = 6.43 Hz), 2.00-2.06
+
1
89 %). ESI mass: m/e 228.30, 230.10 (M + H) . H NMR (400
MHz, CDCl ) δ: 6.76-6.76 (1H, d, J = 2.38 Hz), 6.37-6.37
(
2H, m).
-Bromo-6-nitro-3,4-dihydro-2H-1-benzopyran (5):
(0.71 g, 7.04 mmol) was added to a stirred solution of 4
1 g, 4.69 mmol) in conc. H SO (10 mL) at 0-5 °C and then
3
8
3
(1H, d, J = 2.27 Hz), 4.19-4.22 (2H, t, J = 5.28 Hz), 2.71-2.74
(2H, t, J = 6.35 Hz), 1.95-2.01 (2H, m).
KNO
(
2
4
6-(Benzenesulfonamido)-8-bromo-3,4-dihydro-2H-1-
1
stirred at room temperature for 1 h. The reaction mixture was
poured on to crushed ice (50 g) and extracted with chloroform
benzopyran (7a) (7, R = H): Benzenesulfonyl chloride (0.18
g, 1.05 mmol) was added to a stirred solution of 6 (0.2 g, 0.87
mmol) and pyridine (0.20 g, 2.63 mmol) in dichloromethane
(15 mL) and stirred at room temperature for 4 h. Then reaction
(50 mL × 3). The combined organic extracts were washed with
brine (25 mL), dried over anhydrous sodium sulfate and

2
120 Nirogi et al.
Asian J. Chem.
mixture was poured on to water (10 mL) and extracted with
dichloromethane (15 mL × 3). The combined organic extracts
were dried over anhydrous sodium sulfate, concentrated in
vacuo to obtain a dark residue. The resultant residual mass
was chromatographed (silica gel, 3:7 ethyl acetate-hexanes as
eluent) to afford title compound (0.24 g, 76 % yield). ESI
Hz), 8.11-8.13 (1H, d, J = 7.2 Hz), 8.06-8.08 (1H, d, J = 7.9
Hz), 7.57-7.72 (3H, m), 6.32-6.35 (2H, d, J = 12.24 Hz), 3.99-
4.02 (2H, m), 3.12-3.14 (4H, m), 2.88-2.91 (4H, m), 2.47-
2.49 (2H, m), 1.74-1.76 (2H, m).
6-(2-Fluoro-1-benzenesulfonamido)-8-(piperazin-1-
1
yl)-3,4-dihydro-2H-1-benzopyran hydrochloride (9d) (9, R
-
1
mass: m/e 366.2, 368.3 (M-H) . H NMR (400 MHz, CDCl
3
)
= 2-F): The title compound was prepared using essentially
the same procedure as described for the preparation of 9a.
δ: 7.71-7.73 (2H, d, J = 7.45 Hz), 7.56-7.59 (1H, t, J = 7.30
Hz), 7.45-7.49 (2H, t, J = 7.84 Hz), 6.95-6.96 (1H, d, J = 2.34
Hz), 6.80-6.80 (1H, d, J = 2.09 Hz), 6.21 (1H, bs), 4.25-4.28
+
1
ESI mass: m/e 392.4 (M + H) . H NMR (400 MHz, CD OD)
3
δ: 7.64-7.67 (1H, m), 7.25-7.32 (3H, m), 6.49-6.50 (1H, d,
J = 1.95 Hz), 6.41-6.41 (1H, d, J = 1.96 Hz), 3.91-3.95 (2H, t,
J = 6.37 Hz), 3.31-3.34 (4H, m), 3.15-3.17 (4H, m), 2.39-
2.42 (2H, m), 1.71-1.74 (2H, m).
The target compounds 20a-d and 21a-d were synthesized
according to Scheme-II.
(2H, t, J = 5.09 Hz), 2.71-2.74 (2H, t, J = 6.40 Hz), 1.95-1.98
(
2H, m).
6
-(Benzenesulfonamido)-8-(1-tert butyloxycarbonyl-1
piperazin-4-yl)-3,4-dihydro-2H-1-benzopyran (8a) (8, R
H): pd db (14.9 mg, 0.016 mmol), BINAP (16.8 mg,
.27 mmol) and NaOtBu (78 mg, 0.81 mmol) were added in
sequence to a stirred solution of 7a (0.2 g, 0.54 mmol) and
-boc piperazine (0.12 g, 0.65 mmol) in dry toluene (15 mL)
=
2
3
0
2'-Hydroxy-5'-nitro acetophenone (11a) and 2'-hydroxy-
3'-nitro acetophenone (11b): Nitrating mixture, prepared
1
from conc. HNO
added drop wise to a stirred mixture of 2'-hydroxyaceto-
phenone (10) (5.44 g, 40 mmol) in conc. H SO (16.5 mL) at
3
(60 mmol) and conc. H
2
SO
4
(60 mmol), was
and refluxed for 6 h. Then the reaction mixture was cooled to
room temperature, poured on to water (25 mL) and extracted
2
4
with CHCl
3
(25 mL × 3). The combined organic extracts were
-5 to 0 °C under stirring and maintained at 0 °C for 2 h. The
reaction mixture was then poured on to cold water (100 mL)
and extracted with ethyl acetate (50 mL × 3). The combined
organic extracts were washed with brine (100 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo to obtain
crude yellow residue. The resultant residual mass was chroma-
tographed (silica gel, 2:8 to 4:6 ethyl acetate-hexane as eluent)
to afford title compounds 11a (2.30 g, 31 % yield) and 11b
(2.12 g, 29 % yield). The ESI mass for both compounds 11a
washed with brine (25 mL), dried over anhydrous sodium
sulfate, concentrated in vacuo to obtain a dark residue. The
resultant residual mass was chromatographed (silica gel, 3:7
ethyl acetate-hexanes as eluent) to afford the title compound
+
1
(
(
7
6
0.15 g, 59 % yield). ESI mass: m/e 474.3 (M + H) . H NMR
400 MHz, CDCl ) δ: 7.54-7.70 (2H, d, J = 7.43 Hz), 7.52-
.54 (1H, t, J = 7.54 Hz), 7.41-7.45 (2H, t, J = 7.88 Hz), 6.46-
.46 (1H, d, J = 2.06 Hz), 6.29-6.30 (1H, d, J = 2.32 Hz), 6.11
3
+
1
(
1H, bs), 4.21-4.24 (2H, t, J = 5.02 Hz), 3.53-3.55 (4H, t, J =
and 11b was observed at m/e 180.1 (M-H ). H NMR of 11a
(400 MHz, CDCl ) δ: 8.79-8.79 (1H, d, J = 2.6 Hz), 8.36-8.39
(1H, dd, J = 9.09, 2.48 Hz), 7.11-7.13 (1H, d, J = 9.13 Hz),
4
.78 Hz), 2.80-2.83 (4H, t, J = 4.94 Hz), 2.67-2.70 (2H, t, J =
3
6
.38 Hz), 1.93-1.97 (2H, m), 1.48 (9H, s).
1
6-(Benzenesulfonamido)-8-(piperazin-1-yl)-3,4-dihydro-
2.75 (3H, s). H NMR of 11b (400 MHz, CD OD) δ: 8.17-
3
1
2
H-1-benzopyran hydrochloride (9a) (9, R = H): Com-
8.20 (1H, dd, J = 7.08, 1.05 Hz), 8.04-8.06 (1H, dd, J = 7.58,
1.27 Hz), 7.02-7.06 (1H, t, J = 7.97 Hz), 2.70 (3H, s).
pound 8a (0.15 g, 0.31 mmol) was stirred in methanolic HCl
20 % w/v solution, 5 mL) for 3 h and then solvent was removed
in vacuo to obtain the title compound (0.12 g, 93 % yield).
(
6-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane]-4-one (12a): Cyclobutanone (0.91 g, 13 mmol)
was added to a solution of 11a (1.81 g, 10 mmol) in benzene
(35 mL) and pyrrolidine (0.71 g, 10 mmol) at room temperature
and the resulting mixture was refluxed for 3 h. Then the
reaction mixture was concentrated in vacuo to obtain a dark
residue. The resultant residual mass was chromatographed
(silica gel, 1:9 ethyl acetate-hexanes as eluent) to afford title
compound (1.54 g, 66 % yield). ESI mass: m/e 234.1 (M +
+
1
ESI mass: m/e 374.4 (M + H) . H NMR (400 MHz, DMSO-
) δ: 9.84 (1H, s), 8.86 (2H, bs), 7.69-7.71 (2H, d, J = 7.45
d
6
Hz), 7.58-7.62 (1H, t, J = 7.24 Hz), 7.51-7.55 (2H, t, J = 7.65
Hz), 6.43 (1H, d, J = 2.01 Hz), 6.42 (1H, d, J = 1.97 Hz),
4
2
.05-4.08 (2H, t, J = 4.60 Hz), 3.31 (4H, bs), 3.15 (4H, bs),
.56-2.59 (2H, t, J = 5.98 Hz), 1.80-1.82 (2H, m).
6
-(3-Fluoro-1-benzenesulfonamido)-8-(piperazin-1-1
yl)-3,4-dihydro-2H-1-benzopyran hydrochloride (9b) (9, R
3-F): The title compound was prepared using essentially
the same procedure as described for the preparation of 9a.
+
1
H) . H NMR (400 MHz, CDCl ) δ: 8.74-8.75 (1H, d, J = 2.6
3
=
Hz), 8.32-8.34 (1H, dd, J = 9.0, 2.6 Hz), 7.09-7.12 (1H, d, J =
9.12 Hz), 2.98 (2H, s), 2.35-2.41 (2H, m), 2.19-2.25 (2H, m),
1.97-2.00 (1H, m), 1.74-1.80 (1H, m).
+
1
ESI mass: m/e 392.4 (M + H) . H NMR (400 MHz, CD OD)
3
δ: 7.47-7.49 (2H, m), 7.29-7.35 (2H, m), 6.59-6.60 (1H, d,
J = 1.98 Hz), 6.47-6.47 (1H, d, J = 1.97 Hz), 3.95-3.99 (2H, t,
J = 6.37 Hz), 3.35-3.39 (4H, m), 3.19-3.21 (4H, m), 2.41-
6-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane]-4-ol (13a): NaBH (0.15 g, 4.07 mmol) was added
4
in portions to a stirred suspension of 12a (0.95 g, 4.07 mmol)
in methanol (10 mL) at 25-35 °C. The reaction mixture was
stirred at room temperature for 0.5 h and then concentrated to
obtain a thick residual mass. Then the reaction mixture was
concentrated to get a thick residual mass. The resultant residual
mass was diluted with water (25 mL), extracted with ethyl
acetate (25 mL × 3) and the combined organic extracts were
dried over anhydrous sodium sulfate, concentrated in vacuo
to afford the title compound (0.91 g, 95 % yield). ESI mass:
2
.43 (2H, m), 1.71-1.74 (2H, m).
-(1-Naphthalenesulfonamido)-8-(piperazin-1-yl)-3,4-
6
1
dihydro-2H-1-benzopyran hydrochloride (9c) (9, R together
with benzene ring is 1-naphthyl): The title compound was
prepared using essentially the same procedure as described
for the preparation of 9a. ESI mass: m/e 424.3 (M + H) . H
NMR (400 MHz, DMSO-d ) δ:10.28 (1H, s), 8.78-8.79 (2H,
bs), 8.66-8.68 (1H, d, J = 8.36 Hz), 8.19-8.21 (1H, d, J = 8.2
+
1
6

Vol. 27, No. 6 (2015)
Design, Synthesis and Biological Evaluation of Novel Benzopyran Sulfonamide Derivatives 2121
O
O
O
6
5
5
4
6
7
a
O N
O N
2
2
b
2
OH
2
OH
O
3
8
1
1
1a
1b
(
(
5-NO
3-NO
2
, 31%
)
)
1
1
2a
2b
(6-NO , 66%)
2
1
0
2
, 29%
(
8-NO , 59%)
2
OH
5
8
5
8
6
7
6
c
d
e
O N
2
2
O N
2
2
O
7
O
1
1
4a
4b
(6-NO , 94%)
2
1
1
3a
3b
(
(
6-NO , 95%
)
)
2
(8-NO , 82%)
8-NO , 91%
2
2
5
5
5
6
7
6
6
7
O N
H N
2
2
2
2
O N
2
2
7
f
O
g
O
8
8
O
8
Br
N
N
N
N
Boc
Boc
1
1
5a
5b
(6-NO , 8-Br, 84%)
2
16a
16b
(6-NO , 8-(1-Boc-4-piperazinyl), 65%)
2
17a
17b
(6-NH , 8-(1-Boc-4-piperazinyl), 95%)
2
(
8-NO , 6-Br, 79%)
2
(8-NO , 6-(1-Boc-4-piperazinyl), 57%)
2
(8-NH , 6-(1-Boc-4-piperazinyl), 92%)
2
R1 2'
'
R1 2'
'
5
5
3
3
O
S
6
O
S
6
7
H
N
H
h
i
4
'
4'
2
N
2
7
O
O
O
O
5
'
6'
8
5'
6'
8
N
N
N
Boc
N
HCl
H
1
1
8a-d
9a-d
(
(
6-NHSO Ar, 8-(1-Boc-4-piperazinyl), 70-85%
)
)
20a-d
21a-d
(
(
6-NHSO
8-NHSO
2
2
Ar, 8-piperazinyl, 82-90%
Ar, 6-piperazinyl,79-88%)
)
2
8-NHSO Ar, 6-(1-Boc-4-piperazinyl), 70-85%
2
Scheme-II: Reagents and conditions: (a) HNO
Et SiH, TFA, 60-65 °C, 4 h; (e) Br , CH
RT, 2 h; (h) Substituted benzenesulfonyl chlorides, pyridine, RT, 4 h; (i) MeOH.HCl, RT, 3 h
3
:H
2
SO
4
, 0-5 °C, 2 h; (b) cyclobutanone, pyrrolidine, benzene, reflux, 3 h; (c) NaBH
4
, MeOH, RT, 0.5 h; (d)
(g),
3
2
3
CO
2
H, RT, 4 h; (f) 1-Boc piperazine, pd dba , BINAP, NaOBut, toluene, reflux, 6 h; (g) 10 % Pd-C, H
2
3
2
+
1
m/e 236.1 (M + H) . H NMR (400 MHz, CDCl
(
6
3
) δ: 8.37-8.38
2.82-2.86 (2H, t, J = 6.47 Hz), 2.30-2.38 (2H, m), 2.07-2.13
(2H, m), 1.99-2.02 (2H, t, J = 6.46 Hz), 1.68-1.73 (1H, m),
1.54-1.57 (1H, m).
1H, d, J = 2.51 Hz), 8.05-8.08 (1H, dd, J = 8.99, 2.70 Hz),
.87-6.89 (1H, d, J = 9.02 Hz), 4.87-4.91 (1H, m), 2.30-2.45
(
4H, m), 2.14-2.15 (1H, m), 1.94-2.07 (3H, m), 1.75-1.77 (1H, m).
-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane] (14a): Et SiH (0.97 g, 8.4 mmol) was added to a
8-Bromo-6-nitro-3,4-dihydro spiro[2H-1-benzopyran-
2,1'-cyclobutane] (15a): Bromine (0.82 g, 5.1 mmol) was
added at room temperature to a stirred solution of 14a (0.75 g,
3.4 mmol) in acetic acid and maintained for 4 h. The reaction
6
3
solution of 13a (0.9 g, 3.8 mmol) in trifluoroacetic acid (9 mL)
at room temperature and then heated and maintained at 60-
mixture was poured on to saturated Na
2
SO solution (10 mL)
3
6
5 °C for 4 h. Then the reaction mixture was poured on to
and extracted with ethyl acetate (25 mL × 3). The combined
organic extracts were washed with brine (25 mL), dried over
anhydrous sodium sulfate and concentrated in vacuo to afford
title compound (0.86 g, 84 % yield). ESI mass: m/e 298.9,
water (25 mL), extracted with ethyl acetate (25 mL × 4). The
combined organic extracts were washed with brine (25 mL),
dried over anhydrous sodium sulfate, concentrated in vacuo
to obtain dark residual mass. The resultant residual mass was
chromatographed (silica gel, 1:9 ethyl acetate-hexane as eluent)
to afford the title compound (0.79 g, 94 % yield). ESI mass:
+
1
300.6 (M + H) . H NMR (400 MHz, CDCl ) δ: 8.28-8.28
3
(1H, d, J = 2.43 Hz), 7.94-7.94 (1H, d, J = 2.17 Hz), 2.86-
2.89 (2H, t, J = 6.48 Hz), 2.41-2.44 (2H, m), 2.12-2.16 (2H,
m), 2.02-2.05 (2H, t, J = 6.52 Hz), 1.96-1.99 (1H, m), 1.70-
1.75 (1H, m).
+
1
m/e 220.1 (M + H) . H NMR (400 MHz, CDCl
3
) δ: 7.96-7.99
(2H, d, J = 9.23 Hz), 6.82-6.84 (1H, dd, J = 6.77, 3.04 Hz),

2
122 Nirogi et al.
Asian J. Chem.
8
-(1-tert butyloxycarbonyl piperazin-4-yl)-6-nitro-3,4-
dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane] (16a):
pd db (78.2 mg, 0.085 mmol), BINAP (88.7 mg, 0.14 mmol)
6.65 (1H, d, J = 1.81 Hz), 6.47-6.47 (1H, d, J = 1.75 Hz),
3.40-3.42 (4H, m), 3.28-3.31 (4H, m), 2.65-2.68 (2H, t, J =
6.48 Hz), 2.23-2.30 (2H, m), 2.06-2.12 (2H, m), 1.90-1.93
(2H, t, J = 6.33 Hz), 1.84-1.88 (1H, m), 1.69-1.76 (1H, m).
6-(3-Fluoro-1-benzenesulfonamido)-8-(piperazin-1-
yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
hydrochloride (20b): The title compound was prepared using
essentially the same procedure as described for the preparation
2
3
and NaOtBu (0.41 g, 4.27 mmol) were added in sequence to a
stirred solution of 15a (0.85 g, 2.85 mmol) and 1-boc pipe-
razine (0.58 g, 3.13 mmol) in dry toluene (50 mL) and refluxed
for 6 h. Then the reaction mixture was cooled to room tempe-
rature, poured on to water (50 mL) and extracted with CHCl
50 mL × 3). The combined organic extracts were washed with
brine (25 mL), dried over anhydrous sodium sulfate and con-
centrated in vacuo to get a dark residue. The resultant residual
mass was chromatographed (silica gel, 2:8 ethyl acetate-hexane
as eluent) to afford the title compound (0.75 g, 65 % yield).
ESI mass: m/e 404.2 (M + H) . H NMR (400 MHz, CDCl
.71-7.71 (1H, d, J = 2.17 Hz), 7.58-7.59 (1H, d, J = 2.53 Hz),
.62-3.64 (4H, t, J = 4.81 Hz), 3.04-3.06 (4H, t, J = 4.64 Hz),
.83-2.86 (2H, t, J = 6.45 Hz), 2.30-2.35 (2H, m), 2.11-2.18
2H, m), 2.00-2.04 (2H, t, J = 6.49 Hz), 1.92-1.94 (1H, m),
3
+
1
(
of 20a. ESI mass: m/e 432.4 (M + H) . H NMR (400 MHz,
CD OD) δ: 7.50-7.53 (2H, m), 7.31-7.40 (2H, m), 6.61-6.61 (1H,
3
d, J = 2.02 Hz), 6.43-6.43 (1H, d, J = 1.63 Hz), 3.37-3.39
(4H, m), 3.22-3.27 (4H, m), 2.66-2.69 (2H, t, J = 6.44 Hz),
2.21-2.29 (2H, m), 2.07-2.13 (2H, m), 1.91-1.94 (2H, t, J =
6.43 Hz), 1.87-1.88 (1H, m), 1.69-1.76 (1H, m).
+
1
3
) δ:
7
3
2
(
1
6-(1-Naphthalenesulfonamido)-8-(piperazin-1-yl)-3,4-
dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane] hydro-
chloride (20c): The title compound was prepared using
essentially the same procedure as described for the preparation
+
1
.72-1.75 (1H, m), 1.49 (9H, s).
-Amino-8-(1-tert butyloxycarbonyl piperazin-4-yl)-
,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
of 20a. ESI mass: m/e 464.4 (M + H) . H NMR (400 MHz,
CD OD) δ: 8.63-8.65 (1H, d, J = 7.88 Hz), 8.10-8.13 (2H, m),
6
3
3
(
1
7.98-8.00 (1H, m), 7.59-7.66 (2H, m), 7.48-7.52 (1H, t, J =
7.83 Hz), 6.43-6.44 (1H, d, J = 2.05 Hz), 6.32-6.33 (1H, d,
J = 1.87 Hz), 3.31-3.35 (4H, m), 3.08-3.13 (4H, m), 2.52-
2.56 (2H, t, J = 6.44 Hz), 2.16-2.24 (2H, m), 2.01-2.07 (2H,
m), 1.83-1.85 (2H, t, J = 6.39 Hz), 1.86-1.89 (1H, m), 1.67-
1.72 (1H, m).
17a): 10 % Pd-C (21 mg) was added to a stirred solution of
6a (0.7 g, 1.73 mmol) in methanol (15 mL) and maintained
at room temperature under H (g) balloon pressure for 2 h.
Then the reaction mixture was filtered and the filtrate was
concentrated in vacuo to afford title compound (0.61 g, 95 %
yield). ESI mass: m/e 374.3 (M + H) . H NMR (400 MHz,
CDCl ) δ: 6.13 (1H, d, J = 2.12 Hz), 6.10 (1H, d, J = 1.98 Hz),
.60-3.61 (4H, m), 3.32-3.38 (2H, bs), 2.97-2.99 (4H, m), 2.68-
.71 (2H, t, J = 6.51 Hz), 2.19-2.24 (2H, m), 2.04-2.10 (2H,
2
+
1
6-(2-Fluoro-1-benzenesulfonamido)-8-(piperazin-1-
yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
hydrochloride (20d): The title compound was prepared using
essentially the same procedure as described for the preparation
3
3
2
+
1
m), 1.91-1.95 (2H, t, J = 6.50 Hz), 1.65-1.68 (1H, m), 1.51-
.56 (1H, m), 1.48 (9H, s).
-(Benzenesulfonamido)-8-(1-tert butyloxycarbonyl
of 20a. ESI mass: m/e 432.4 (M + H) . H NMR (400 MHz,
CD OD) δ: 7.49-7.51 (1H, m), 7.32-7.39 (3H, m), 6.58-6.59
1
3
6
(1H, d, J = 2.00 Hz), 6.39-6.40 (1H, d, J = 1.79 Hz), 3.39-
3.41 (4H, m), 3.26-3.31 (4H, m), 2.69-2.71 (2H, t, J = 6.49
Hz), 2.19-2.23 (2H, m), 2.04-2.09 (2H, m), 1.89-1.91 (2H, t,
J = 6.49 Hz), 1.89-1.91 (1H, m), 1.65-1.71 (1H, m).
piperazin-4-yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane] (18a): Benzenesulfonyl chloride (0.1 g, 0.59
mmol) was added to a stirred solution of 17a (0.2 g, 0.53 mmol)
and pyridine (0.13 g, 1.6 mmol) in dichloromethane (15 mL)
and stirred at room temperature for 4 h. Then the reaction
mixture was poured on to water (10 mL) and extracted with
dichloromethane (15 mL × 3). The combined organic extracts
were dried over anhydrous sodium sulfate and concentrated
in vacuo to obtain a dark residue. The resultant residual mass
was chromatographed (silica gel, 3:7 ethyl acetate-hexane as
eluent) to afford the title compound (0.2 g, 72 % yield). ESI
8-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane]-4-one (12b): The title compound was prepared
using essentially the same procedure as described for the
+
1
preparation of 12a. ESI mass: m/e 234.3 (M + H) . H NMR
(400 MHz, CDCl ) δ: 8.07-8.13 (2H, m), 7.08-7.12 (1H, t, J =
3
7.92 Hz), 3.07 (2H, s), 2.40-2.50 (2H, m), 2.19-2.24 (2H, m),
1.97-2.00 (1H, m), 1.72-1.77 (1H, m).
8-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane]-4-ol (13b): The title compound was prepared
using essentially the same procedure as described for the
+
1
mass: m/e 514.5 (M + H) . H NMR (400 MHz, CDCl
3
) δ:
.66-7.68 (2H, d, J = 8.00 Hz), 7.51-7.55 (1H, t, J = 7.09 Hz),
.40-7.44 (2H, t, J = 7.64 Hz), 6.44 (1H, s), 6.26-6.26 (1H, d,
7
7
+
1
preparation of 13a. ESI mass: m/e 236.3 (M + H) . H NMR
(400 MHz, CDCl ) δ: 7.73-7.76 (1H, dd, J = 8.02, 0.92 Hz),
J = 2.05 Hz), 3.54-3.61 (4H, t, J = 4.56 Hz), 2.84-2.86 (4H, t,
J = 4.85 Hz), 2.66-2.69 (2H, t, J = 6.42 Hz), 2.20-2.25 (2H,
m), 2.04-2.09 (2H, m), 1.87-1.94 (3H, m), 1.66-1.71 (1H, m),
3
7.64 - 7.66 (1H, d, J = 7.46 Hz), 6.93-6.97 (1H, d, J = 8.36
Hz), 4.87-4.90 (1H, m), 2.33-2.57 (4H, m), 2.09-2.16 (2H,
m), 1.95-1.96 (1H, m), 1.71-1.78 (2H, m).
1
.48 (9H, s).
-(Benzenesulfonamido)-8-(piperazin-1-yl)-3,4-dihydro
spiro[2H-1-benzopyran-2,1'-cyclobutane]-hydrochloride
20a): Compound 18a (0.2 g, 0.37 mmol) was stirred in
6
8-Nitro-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane] (14b): The title compound was prepared using
essentially the same procedure as described for the preparation
(
+
1
methanolic HCl (20 % w/v solution, 5 mL) for 3 h and then
solvent was removed in vacuo to obtain the title compound
0.15 g, 85 % yield). ESI mass: m/e 414. (M + H) . H NMR
400 MHz, CD OD) δ: 7.69-7.71 (2H, d, J = 7.60 Hz), 7.56-
.60 (1H, t, J = 7.33 Hz), 7.46-7.50 (2H, t, J = 7.74 Hz), 6.65-
of 14a. ESI mass: m/e 220.1 (M + H) . H NMR (400 MHz,
CDCl ) δ: 7.62-7.64 (1H, d, J = 8.04 Hz), 7.22-7.24 (1H, d,
3
+
1
(
J = 7.41 Hz), 6.82-6.86 (1H, t, J = 7.77, 7.83 Hz), 2.83-2.86
(2H, t, J = 6.52 Hz), 2.35-2.40 (2H, m), 2.07-2.12 (2H, m), 2.02-
2.06 (2H, t, J = 6.71 Hz), 1.91-1.94 (1H, m), 1.60-1.69 (1H, m).
(
3
7

Vol. 27, No. 6 (2015)
Design, Synthesis and Biological Evaluation of Novel Benzopyran Sulfonamide Derivatives 2123
6
-Bromo-8-nitro-3,4-dihydro spiro[2H-1-benzopyran- essentially the same procedure as described for the preparation
+
1
2
,1'-cyclobutane] (15b): The title compound was prepared
using essentially the same procedure as described for the
of 21a. ESI mass: m/e 464.2 (M + H) . H NMR (400 MHz,
CD OD) δ: 8.79-8.82 (1H, d, J = 8.57 Hz), 8.09-8.11 (1H, d,
3
+
1
preparation of 15a. ESI mass: m/e 298.0, 300.1 (M + H) . H
NMR (400 MHz, CDCl
J = 8.18 Hz), 7.99-8.01 (2H, m), 7.68-7.72 (1H, t, J = 7.29
Hz), 7.62-7.65 (1H, t, J = 7.61 Hz), 7.41-7.45 (1H, t, J = 7.75
Hz), 7.10-7.11 (1H, d, J = 1.98 Hz), 6.53-6.53 (1H, d, J =
1.97 Hz), 3.31-3.40 (8H, m), 2.47-2.50 (2H, t, J = 6.34 Hz),
1.51-1.54 (2H, t, J = 6.40 Hz), 1.47-1.48 (2H, m), 1.26-1.32
(2H, m), 1.05-1.13 (2H, m).
3
) δ: 7.77 (1H, d, J = 2.15 Hz), 7.36
1H, d, J = 2.27 Hz), 2.82-2.85 (2H, m), 2.34-2.42 (2H, m),
(
2
.02-2.10 (4H, m), 1.89-1.94 (1H, m), 1.64-1.71 (1H, m).
-(1-tert butyloxycarbonyl piperazin-4-yl)-8-nitro-3,4-
6
dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane] (16b):
The title compound was prepared using essentially the same
procedure as described for the preparation of 16a. ESI mass:
m/e 404.4 (M + H) . H NMR (400 MHz, CDCl
1H, d, J = 2.72 Hz), 6.87-6.87 (1H, d, J = 2.52 Hz), 3.55-
.57 (4H, m), 3.01-3.03 (4H, m), 2.80-2.83 (2H, t, J = 6.47
Hz), 2.33-2.36 (2H, m), 2.01-2.10 (4H, m), 1.89-1.92 (1H,
m), 1.65-1.70 (1H, m).
8-(2-Fluoro-1-benzenesulfonamido)-6-(piperazin-1-
yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
hydrochloride (21d): The title compound was prepared using
essentially the same procedure as described for the preparation
+
1
3
) δ: 7.22-7.22
(
3
+
1
of 21a. ESI mass: m/e 432.2 (M + H) . H NMR (400 MHz,
CD OD) δ: 7.53-7.55 (1H, m), 7.31-7.36 (3H, m), 6.59-6.598
3
(1H, d, J = 2.07 Hz), 6.45-6.46 (1H, d, J = 1.71 Hz), 3.30-
3.32 (4H, m), 3.21-3.26 (4H, m), 2.51-2.56 (2H, t, J = 6.44
Hz), 2.15-2.19 (2H, m), 1.97-1.98 (2H, m), 1.81-1.84 (2H, t,
J = 6.43 Hz), 1.79-1.82 (1H, m), 1.65-1.71 (1H, m).
8
-Amino-6-(1-tert butyloxycarbonyl piperazin-4-yl)-
,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
17b): The title compound was prepared using essentially the
same procedure as described for the preparation of 17a. ESI
3
(
+
1
RESULTS AND DISCUSSION
mass: m/e 374.4 (M + H) . H NMR (400 MHz, CDCl
.29 (1H, d, J = 2.31 Hz), 6.16 (1H, d, J = 2.23 Hz), 3.47-3.48
4H, m), 2.82-2.84 (4H, m), 2.58-2.61 (2H, m), 1.97-2.14 (4H,
m), 1.81-1.85 (2H, m), 1.62-1.78 (2H, m), 1.39 (9H, s).
-(Benzenesulfonamido)-6-(1-tert butyloxycarbonyl
3
) δ:
6
(
The synthesis of target compounds 9a-d, 20a-d and 21a-d
was achieved as given in Schemes-I and II. Condensation of
2-bromophenol (1) with 3-bromopropionic acid gave inter-
mediate 2 which upon treatment with polyphosphoric acid
underwent cyclization and yielded intermediate 3. Reduction
of 3 followed by dehydroxylation gave intermediate 4. Nitration
of 4 with nitrating mixture gave intermediate 5. The reduction
8
piperazin-4-yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-
cyclobutane] (19a): The title compound was prepared using
essentially the same procedure as described for the preparation
of 18a. ESI mass: m/e 514.4 (M + H) . H NMR (400 MHz,
CDCl ) δ: 7.73-7.75 (2H, d, J = 7.58 Hz), 7.47-7.51 (1H, t,
J = 8.03 Hz), 7.37-7.40 (1H, t, J = 7.50 Hz), 7.04 (1H, bs),
.90 (1H, bs), 6.35 (1H, bs), 3.55 (4H, m), 2.97 (4H, m), 2.57-
.60 (2H, m), 1.85-1.88 (4H, m), 1.72-1.75 (2H, m), 1.55-
.60 (2H, m), 1.48 (9H, s).
+
1
of intermediate 5 with Fe/NH Cl yielded intermediate 6 which
4
3
upon treatment with various substituted benzenesulfonyl chlo-
rides gave intermediates 7a-d. The intermediates 7a-d were
treated with 1-Boc-piperazine under Buchwald coupling condi-
tions and obtained intermediates 8a-d which upon deprotection
with methanolic HCl gave targeted compounds 9a-d (Scheme-
I). Nitration of 2′-hydroxyaceto-phenone (10) with nitrating
mixture gave the isomeric compounds 11a and 11b. Conden-
sation of 11a with cyclobutanone gave intermediate 12a. The
intermediate 12a upon reduction gave intermediate 13a which
was subjected to dehydroxylation to obtain intermediate 14a.
Bromination of intermediate 14a gave intermediate 15a which
upon reaction with 1-Boc piperazine under Buchwald coupling
conditions yielded intermediate 16a. The reduction of nitro
group with 10 % Pd-C in methanol yielded intermediate 17a.
The intermediate 17a was treated with substituted benzene-
sulfonyl chlorides in presence of an appropriate base and
obtained intermediates 18a-d. The deprotection of 18a-d with
methanolic HCl gave targeted compounds 20a-d as HCl salts.
A similar strategy was followed for the synthesis of targeted
compounds 21a-d starting from intermediate 11b with some
non-critical variations.
6
2
1
8
-(Benzenesulfonamido)-6-(piperazin-1-yl)-3,4-dihydro
spiro[2H-1-benzopyran-2,1'-cyclobutane] hydrochloride
21a): Compound 19a (0.2 g, 0.38 mmol) was stirred in metha-
(
nolic HCl (20 % w/v solution, 5 mL) for 3 h.After completion
of the reaction (TLC), the solvent was removed in vacuo to
obtain the title compound (0.15 g, 85 % yield). ESI mass: m/e
+
1
4
14.1 (M + H) . H NMR (400 MHz, CD OD) δ: 7.71-7.72
3
(
(
(
2
(
2H, d, J = 7.76 Hz), 7.55-7.58 (1H, t, J = 7.40 Hz), 7.43-7.47
2H, t, J = 7.69 Hz), 7.09-7.09 (1H, d, J = 2.19 Hz), 6.66-6.66
1H, d, J = 1.86 Hz), 3.48-3.54 (4H, m), 3.41-3.42 (4H, m),
.62-2.65 (2H, t, J = 6.31 Hz), 1.81-1.85 (4H, m), 1.69-1.75
3H, m), 1.53-1.62 (1H, m).
-(3-Fluoro-1-benzenesulfonamido)-6-(piperazin-1-
8
yl)-3,4-dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane]
hydrochloride (21b): The title compound was prepared using
essentially the same procedure as described for the preparation
+
1
of 21a. ESI mass: m/e 431.7 (M + H) . H NMR (400 MHz,
CD
Structure activity relationship (SAR): All the synthe-
sized compounds, belonging to compounds I, II and III, were
3
OD) δ: 7.41-7.43 (2H, m), 7.29-7.31 (2H, m), 6.57-6.58
1H, d, J = 2.02 Hz), 6.41-6.41 (1H, d, J = 1.63 Hz), 3.34-
(
tested for their antagonistic activity towards 5-HT R at 1 µM
6
3
.37 (4H, m), 3.26-3.29 (4H, m), 2.56-2.59 (2H, t, J = 6.44
concentration (Table-1). For the exploration of SAR, we intro-
1
Hz), 2.18-2.25 (2H, m), 2.01-2.08 (2H, m), 1.87-1.91 (2H, t,
J = 6.43 Hz), 1.82-1.86 (1H, m), 1.69-1.76 (1H, m).
duced selective substitutions at R position of compounds I,
1
II and III. We initially tested compound 9a where R = H and
8-(1-Naphthalenesulfonamido)-6-(piperazin-1-yl)-3,4-
its inhibition at 5-HT R was found to be 73 %. Among
6
dihydro spiro[2H-1-benzopyran-2,1'-cyclobutane] hydro-
chloride (21c): The title compound was prepared using
compounds I, compound 9c bearing 1-naphthylsulfonamide
group was found to be most potent with an inhibition of 89 %.

2
124 Nirogi et al.
Asian J. Chem.
TABLE-1
-HT RECEPTOR BINDING DATA OF COMPOUNDS I, II AND III
TABLE-2
4
1
5
HUMAN CYP450 INHIBITORY DATA AND
6
a
MICROSOMAL METABOLIC STABILITY
1
% Inhibition at 1 µM
Compound
R
a
concentration
% Metabolism in
liver microsomes
IC (µM)
50
9
a
H
3-F
73
39
Compound
9b
CYP 3A4
1.5
CYP 2D6
7.5
>10
Human
Rat
1
R together with benzene ring
9
c
30.16
35.14
33.42
40.09
9
c
89
is 1-naphthyl
20c
3.2
9
d
2-F
H
3-F
18
69
42
a
Cytochrome P450 inhibitory potential was determined using isoform-
20a
selective assays and heterologously expressed human CYP 2D6 and
CYP 3A4. These values are the mean of duplicate determinations.
Microsomal metabolic stability in Wistar Rat and Human at 0.5 h, con.
2.5 µM
20b
1
R together with benzene ring
2
0c
0d
1a
1b
1c
1d
92
is 1-naphthyl
2
2
2
2-F
H
3-F
11
9
8
Conclusion
1
We have reported a set of new compounds belonging to
three different platforms obtained by rational medicinal chemistry
approach. These compounds have shown moderate to potent
R together with benzene ring
2
13
is 1-naphthyl
2
2-F
6
a
%
inhibition towards 5-HT R was measured using cell based reporter
in vitro binding affinities towards 5-HT
6
R. Both the compounds
6
gene functional assay. Values are mean of two experiments
9
c and 20c were found to be metabolically stable when tested
in liver microsomes. Compound 20c was shown more resis-
tance to metabolism by CYP3A4 enzyme compared to 9c,
proving the fact that the insertion of cyclobutyl group, in general,
could improve metabolic stability of the compound II, in
addition to maintaining the potency. Based on these findings,
the novel series of compounds I and II, could be further opti-
1
The other compounds from the series i.e. compound 9b (R =
3
1
-F) and compound 9d (R = 2-F) have shown 39 and 18 % of
inhibition, respectively towards 5-HT R. These compounds
were almost 3 to 4 fold less potent compared 9a and 9c.Among
compound II, compound 20a (R = H) has shown an inhibition
of 69 % whereas compound 20c with a 1-naphthylsulfon-amide
group was found to be most potent among all compounds with
R. The compound 20b
R = 3-F) has shown moderate antagonistic activity with an
inhibition of 42 % towards 5-HT R. compound 20d (R = 2-F)
was inactive which showed an inhibition of 11 %. Compounds
1a-d which represent compound III were all inactive towards
-HT R with poor antagonistic activity. More over these comp-
ounds were 8-9 folds less potent compared to the most potent
compounds 9c and 20c. In general, all the tested compounds
belonging to compound I and compound II have shown
moderate to potent antagonistic activities where as derivatives
belonging to compound III were inactive.
6
1
mized to obtain potent 5-HT R antagonists with a balanced
6
biological profile, for the treatment of neurological disorders.
an inhibition of 92 % towards 5-HT
(
6
1
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