Novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors with good ADME-related physicochemical parameters

Article abstract of DOI:10.1016/j.ejmech.2013.08.026

Under physiological conditions healthy bones are maintained by a well tightened balance between osteoclast (OCs) and osteoblast (OBs) activity. Disruption of this balance leads to osteoporosis characterized by decline in bone function and skeletal rigidity. Inhibition of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) could help maintaining the appropriate bone mass density by increasing the level of estradiol and testosterone in bone. Herein, we described the synthesis, the physicochemical properties and the biological evaluation of novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-HSD2 inhibitors showing high potency (compound 10f, IC₅₀ = 23 nM), with a good selectivity toward 17β-HSD1 (the isoenzyme responsible of the reverse reaction), and a likely good in vitro ADME profile. It was also shown that the acidity of the phenolic hydroxy correlates with the inhibitory potency, suggesting pKa as a predictive parameter for the activity of this class of inhibitors.

Full text of DOI:10.1016/j.ejmech.2013.08.026

European Journal of Medicinal Chemistry 69 (2013) 201e215
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel N-methylsulfonamide and retro-N-methylsulfonamide
derivatives as 17 -hydroxysteroid dehydrogenase type 2 (17b-HSD2)
b
inhibitors with good ADME-related physicochemical parameters
,
Enrico Perspicace a, Annalaura Giorgio a b, Angelo Carotti b,
,
a,c,
*
Sandrine Marchais-Oberwinkler a , Rolf W. Hartmann
*
a Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany
b Dipartimento Farmaco-Chimico, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy
c Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Under physiological conditions healthy bones are maintained by a well tightened balance between
osteoclast (OCs) and osteoblast (OBs) activity. Disruption of this balance leads to osteoporosis charac-
Received 14 July 2013
Received in revised form
8 August 2013
Accepted 14 August 2013
Available online 29 August 2013
terized by decline in bone function and skeletal rigidity. Inhibition of 17
b-hydroxysteroid dehydrogenase
type 2 (17 -HSD2) could help maintaining the appropriate bone mass density by increasing the level of
b
estradiol and testosterone in bone. Herein, we described the synthesis, the physicochemical properties
and the biological evaluation of novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives
as 17
toward 17
b
-HSD2 inhibitors showing high potency (compound 10f, IC50 ¼ 23 nM), with a good selectivity
Keywords:
b
-HSD1 (the isoenzyme responsible of the reverse reaction), and a likely good in vitro ADME
17b-Hydroxysteroid dehydrogenase type 2
Enzyme inhibition
Osteoporosis
N-Methylsulfonamide derivatives
Retro-N-methylsulfonamide derivatives
Structureeactivity relationship
Structureeproperty relationship
ADME properties
profile. It was also shown that the acidity of the phenolic hydroxy correlates with the inhibitory potency,
suggesting pKa as a predictive parameter for the activity of this class of inhibitors.
Ó 2013 Elsevier Masson SAS. All rights reserved.
pKa
Log P
Aqueous solubility
1. Introduction
remodeling process. Deregulation in this equilibrium often leads to
diseases like osteopenia [1] or osteoporosis [2].
Bone is formed and maintained by two cell types: osteoblasts
(OB), which are the cells that synthesize and mineralize the bone
matrix and osteoclasts (OC), which resorb or remove the calcified
tissues. OB and OC work together regulating the balance of bone
Osteoporosis is a common systemic bone disease characterized
by a loss or decrease in bone mineral density (osteopenia) and
deterioration of the bone microarchitecture. It comes from an
increased OC activity and/or a decreased OB activity, which leads to
bone fragility and high bone fracture risk [3].
The decrease in active sex steroids level (estradiol E2 and
testosterone T, e.g. in women at menopause) [4,5] has been
described among the factors responsible for the development of
osteoporosis. The antiresorptive bisphosphonates, like alendronate,
are the most frequently administered therapeutic treatment. It is
effective in both postmenopausal women [6] and men [7,8]. How-
ever, it leads to reduction of only 50% of fracture risks.
Osteoporosis is an aged-dependent disease. It is estimated that
40% of all women worldwide over the age of 50 will experience an
osteoporotic fracture during their life time. As the population is
Abbreviation: OB, osteoblast; OC, osteoclast; 17
b-HSD2, 17b-hydroxysteroid
dehydrogenase type 2; 17 -HSD1, 17 -hydroxysteroid dehydrogenase type 1; E2,
b
b
estradiol; T, testosterone; A-dione, androstenedione; SF, selectivity factor; ADME,
absorption, distribution, metabolism and elimination; MW, molecular weight; tPSA,
topological polar surface area.
* Corresponding authors. Pharmaceutical and Medicinal Chemistry, Saarland
University, Campus C23, D-66123 Saarbrücken, Germany. Tel.: þ49 681 302 70300;
fax: þ49 681 302 70308.
E-mail addresses: s.marchais@mx.uni-saarland.de (S. Marchais-Oberwinkler),
rwh@mx.uni-saarland (R.W. Hartmann).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.08.026

202
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
getting older and as this disease is a real issue in public/family care
and health costs, development of new therapeutic strategies for
this disease are urgently needed.
methoxylated 3 and 5 and the hydroxylated 8 show a moderate
17 -HSD2 inhibitory activity with an IC50 around 500 nM, inde-
pendent of the 1,3 or 1,4-substitution pattern of the central core B.
b
17
b
-Hydroxysteroid dehydrogenase type
2
(17
b
-HSD2,
As these derivatives present additionally a good selectivity toward
17b-HSD1 (selectivity factor between 8 and 200, Table 1), they were
considered as interesting hits for further optimization.
EC1.1.1.51 [9]) catalyzes the NADþ-dependent oxidation of the
biologically active sex steroids E2 and T into their less active forms
estrone (E1) and androstenedione (A-dione), respectively (Fig. 1).
The ADME (absorption, distribution, metabolism and elimina-
tion) profile of a compound describes its disposition in the tissues
in vivo. Recently, prediction of ADME parameters has become an
important tool in drug development to anticipate the suitability of a
molecule for in vivo evaluation in order to combat drug attrition
during clinical phase development. As the physical chemical
properties can be controlled through structure modification, ADME
parameters can be adjusted, when necessary, in an early stage of
development in parallel to efficacy optimization.
17b-HSD2 is a membrane-associated protein located in the endo-
plasmic reticulum [10], and the 3D-structure of this enzyme re-
mains unknown. This enzyme is expressed in a broad variety of
tissues such as placenta, liver, small intestine, endometrium, uri-
nary tracts and to a lesser extends also in kidney, pancreas, colon,
uterus, breast and prostate. 17b-HSD2 is also present in OB [10e13].
Inhibition of this enzyme will lead to an intracellular E2 and T in-
crease, which can replenish the reduced endogenous hormone
levels in osteoporotic patients and thus can be beneficial for the
treatment of osteoporosis.
So far, only few 17
literature [14,15]. Bagi et al. have validated the concept of
improving bone quality by inhibiting 17 -HSD2 using a monkey
osteoporosis model [5]. They synthesized several 2,3-disubstituted-
cis-pyrrolidinone derivatives substituted by a thiophene moiety 1
or a phenyl ring 2aeb and evaluated in vivo the activity of the cis-
pyrrolidinone derivative 1 (Fig. 2) [16e18]. However, this com-
pound only led to minor effects on bone mass, which might be due
to its poor pharmacokinetic profile, eventually due to its poor sol-
ubility. Thus, there is a need to develop new potent 17
hibitors with a better pharmacokinetic profile. The new compounds
should not inhibit 17 -HSD1, the isoenzyme catalyzing the reverse
The aim of this project was to develop 17b-HSD2 inhibitors to be
used in vivo for a proof of principle in an animal model and,
hopefully, later in human. Therefore in addition to pursue good
potency and selectivity, acceptable ADME properties of the com-
pounds to be developed are in our focus to increase the success of
in vivo application.
b-HSD2 inhibitors have been described in the
b
In this study, we describe new 17b-HSD2 inhibitors of the
biphenyl class derived from 3 to 8, bearing a sulfonamide moiety
instead of the carboxamide, with improved potency. The design of
the molecules was guided by selection of the ones with favorable
ADME parameters only. The biological evaluation of the synthe-
sized compounds is reported as well as their physicochemical
properties (calculated and experimentally determined). In addition
it will be shown that the acidity of the molecules correlates well
with their biological activity, highlighting the pKa as an important
parameter to be taken into account in the design of inhibitors in
this class.
b-HSD2 in-
b
reaction (reduction of E1 into E2 (Fig. 1) as this would be contra-
productive for the aim to increase E2).
Our group has been working for twenty years on the develop-
ment of inhibitors of steroidogenic enzymes (e.g. 5a-reductase [19],
aromatase [20e23], CYP17 [24,25], CYP11B2 [26e29], CYP11B1
[30,31]) and in the last years a lot of experience was gained in the
2. Rationale and design
design of potent and selective 17b-HSD1 [32e37] and 17b-HSD2
[38e44] inhibitors. Recently, we described [40,44] 3- and 4-phenyl-
N-methyl benzamide derivatives (compound 3e8, Fig. 2) as new
17b-HSD2 inhibitors. These compounds all have a phenyl central
core B. They differ in the substitution pattern of the phenyl B:
compounds 3, 4 are 1,4-disubstituted while compounds 5e8 are
1,3-disubstituted. They differ also in the size of the linker n (n ¼ 0
for 5 and 6, n ¼ 1 for 3, 4, 7 and 8) between the phenyl C and the
amide moiety. They can bear two hydroxy (4, 6 and 8) or two
methoxy groups (3, 5 and 7) on the phenyls A and C. The
Within the most relevant predicting ADME parameters, the
following were selected and calculated for compounds 3e8: mo-
lecular weight (MW), lipophilicity (log P), acidity (pKa), topological
polar surface area (tPSA), number of rotatable bonds and number of
H-bond donors (HD) and acceptors (HA) (Table 1).
According to their calculated ADME profile, molecules 3e8 are
small (MW around 400 Da) with a good lipophilicity (clog P around
3), an adequate polar surface area (tPSA <75 Å2) and a reduced
flexibility (small number of rotatable bounds). They were therefore
Fig. 1. Interconversion of estradiol (E2) to estrone (E1) by 17b-HSD2 and 17b-HSD1, and testosterone (T) to androstenedione (A-dione) by 17b-HSD2 and 17b-HSD3.

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
203
Fig. 2. Described 17b-HSD2 inhibitors.
considered as interesting hits and good starting points for optimi-
zation of their potency.
addition, the length of the linker was also varied (n ¼ 0 or 1) to
explore different areas in the enzyme active site.
The 3- and 4-phenyl-N-methyl benzamide derivatives 3e8
(Fig. 2) present a certain structural similarity to the equipotent
2,3-disubstituted cis-pyrrolidinones 2aeb (Fig. 2) developed by
Bagi et al. sharing the aromatic ring C, the biphenyl moiety A and B
and the N-methyl amide function, which is essential for activity.
2aeb differ from 3e8 for the presence of a secondary hydroxy
group (versus the amide bond in 3e8) and of the pyrrolidinone
moiety. The tetrahedral geometry of the alcohol in 2aeb might
allow different H-bond interactions (HA and HD) compared to the
planar N-methylamido group of 3e8 (only HA), and this might be
more favorable for the stabilization of the enzymeeinhibitor
complex. In this study, a ligand-based strategy was used to design a
The physicochemical properties of compounds 3e8, bearing
either hydroxy or methoxy groups, span a good range. The same
substituents were introduced on the sulfonamide at different po-
sitions on the phenyl A and C to identify the best substitution
pattern. In the previous study of the 2,5-thiophene carboxamide
class (compound 11, Fig. 4), the positive influence of an additional
substituent like a F on the A ring was demonstrated [40,44]. In this
study, we wanted to investigate the influence of an additional
fluorine on the phenyl C ring on the activity, as it will modify the
acidity of the hydroxy group next to it. The phenyl ring A was also
replaced by its bioisostere thiophene and pyridine rings to decrease
the lipophilicity of the molecule.
series of new 17b-HSD2 inhibitors by replacement of the planar
amide for the bioisosteric tetrahedral sulfonamide and retro-
sulfonamide moieties (compounds 9aer and 10aed, Fig. 3).
As both 1,3- and 1,4-substitution pattern on the central phenyl B
(1,4- in case of 3 and 4 and 1,3- in case of 5e8) led to equipotent
compounds, the sulfonamides/retrosulfonamides were designed
with both 1,3-(10aed) and 1,4-(9aer) substitution pattern. In
3. Results
3.1. Chemistry
The synthesis of the sulfonamides 9aep and 10a, 10b was
achieved in a three-step pathway as depicted in Scheme 1 starting
Table 1
Predicted ADME-related physicochemical parameters and biological activities of compounds 3e8.
Cpd
MW
clog Pa
cpKab
tPSAc
Rotat. bonds
HDd
HAe
17
b
-HSD2f
17
b
-HSD1g
SFh
3
4
361
333
4.30
3.14
e
39
61
6
4
0
2
4
4
494 nM
594 nM
>100,000 nM
13,009 nM
>202
22
9.8 (A)
9.6 (C)
e
5
6
347
319
3.94
3.29
39
61
5
3
0
2
4
4
517 nM
>60,000 nM
>115
nd
9.6 (A)
9.6 (C)
e
35%@1
m
M
M
13%@1
m
M
7
8
361
333
4.28
3.08
39
61
6
4
0
2
4
4
13%@1
m
3%@1
m
M
nd
22
9.8 (A)
9.7 (C)
482 nM
3801 nM
a
Calculated log P, values determined with ACD/Labs Percepta 2012 Release using GALAS method.
b
c
d
e
f
Calculated pKa values for the OH phenyl A ring (A) and OH phenyl C ring (C) determined with ACD/Labs Percepta 2012 Release using the classic method.
Total polar surface area (A ), determined with ACD/Labs Percepta 2012 Release.
HA: number of H-bond acceptors.
2
ꢀ
HD: number of H-bond donors.
17
b-HSD2 potency, IC50 or % inhibition@1
m
M, human placental, microsomal fraction, substrate E2 [500 nM], cofactor NADþ [1500 nM], mean value of three de-
terminations, standard deviation less than 15%.
g
17
standard deviation less than 15%.
b-HSD1 potency, IC50 or % inhibition@1 mM human placental, cytosolic fraction, substrate E1 [500 nM], cofactor NADH [500 nM], mean value of three determinations,
h
SF: selectivity factor, ratio IC50 (HSD1)/IC50 (HSD2).

204
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
Fig. 3. Chemical structure of the designed compounds 9aer and 10aef.
from 4- and 3-bromobenzenesulfonyl chloride 14a and 15a,
respectively. The synthesis of the retrosulfonamides 9q, 9r and
10cef was performed in a three-step pathway as depicted in
Scheme 2, similar to the synthesis of the sulfonamide but starting
from the 4- and 3-bromo-N-methylaniline 14b and 15b.
Compounds 14a, 15a and 14b, 15b were reacted with
corresponding-methylaniline and chlorosulfonyl derivatives,
respectively, to afford the bromo-N-methylsulfonamide in-
termediates 12aeg and 13aec in very good yields. Then, a Suzukie
Miyaura cross coupling performed under microwave irradiation
with differently substituted phenylboronic acids led to compounds
9aek, 9m, 9o and 9q and 10a, 10c and 10e. Finally, ether cleavage
using boron trifluoride methyl sulfide complex BF3$SMe2 in pres-
ence of triethylamine resulted in the final compounds 9l, 9n, 9p and
9r and 10b, 10d and 10f. Ether cleavage failed when boron tri-
bromide, pyridium hydrochloride salt and boron trifluoride methyl
sulfide complex without triethylamine were used.
indication that the tetrahedral sulfonamide cannot achieve addi-
tional H-bond interactions in case of the methoxylated derivatives
in contrast to the carboxamido group and that compounds with a
sulfonamido group combined with a methoxy group are not
accepted by the enzyme while they are tolerated when they bear
hydroxy groups. An explanation for this could be that the
methoxylated and hydroxylated molecules might not bind in the
same area of the enzyme.
In the 1,3-phenyl series, one moderately active sulfonamide
(10b, IC50 ¼ 540 nM) and two highly active retrosulfonamides (10d
and 10f, IC50 ¼ 159 and 23 nM, respectively) could be identified.
Considering the sulfonamides only, a decrease in activity was
observed with the methoxylated derivatives (10a, 26% inhibition at
1
m
M vs 5, IC50 ¼ 517 nM) compared to the carboxamides while an
increase was found with the hydroxylated compounds (10b,
M). These activity differ-
IC50 ¼ 540 nM vs 6, 35% inhibition at 1
m
ences also support our assumption that in presence of the sulfo-
namido group the hydroxylated and methoxylated compounds
might bind in a different way/area, therefore exhibiting different
structureeactivity relationships.
3.2. Biological results
Independently of the 1,3- or 1,4-substitution pattern the retro-
sulfonamide derivatives are superior to the sulfonamides when the
The synthesized compounds were tested for their ability to
inhibit 17b-HSD2 and 17b-HSD1 enzymes from human placental
source as previously described [45]. Results are reported in Table 2
as percentage of inhibition and as IC50 values for compounds
exceeding 50% inhibition at a concentration of 1 mM. Compounds
showing an inhibitory activity below 10% were considered inactive.
In the 1,4-phenyl class three moderately active compounds
bearing a sulfonamide moiety could be identified, 9n and 9p with
an IC50 around 1 mM and the retrosulfonamide 9r with an IC50 value
of 511 nM. Replacement of the carboxamido by the sulfonamido
compounds are hydroxylated (9r, IC50
¼
511 nM vs 9n,
IC50 ¼ 1179 nM or 10d, IC50 ¼ 159 nM vs 10b, IC50 ¼ 540 nM). In the
case of the methoxylated compounds a weak inhibitory activity
without differences between the sulfonamides or the retro-
sulfonamides was observed.
Comparing the contribution of the substituents, it is clear that
the hydroxylated compounds are always more active than the
methoxylated derivatives independent of the linker size (for n ¼ 0,
9b OMe, 27% inhibition at 1
9o OMe, no inhibition at 1
stitution pattern of the B ring, 1,3-phenyl or 1,4-phenyl, and the
sulfonamide or retrosulfonamide linker (10a OMe, 26% inhibition at
m
M vs 9n OH, IC50 ¼ 1179 nM, for n ¼ 1
group resulted in a loss of activity in both methoxylated (9o, no
mM vs 9p OH, IC50 ¼ 934 nM), the sub-
inhibition at 1
m
M vs 3, IC50 ¼ 494 nM) and hydroxylated com-
pounds (9p, IC50 ¼ 934 nM vs 4, IC50 ¼ 594 nM). This could be an
1
m
M vs 10b OH, IC50 ¼ 540 nM, 9q OMe, 25% inhibition at 1
m
M vs
9r OH, IC50 ¼ 511 nM, 10c OMe, 14% inhibition at 1
IC50 ¼ 159 nM).
mM vs 10d OH,
Introduction of a fluorine substituent in ortho of the hydroxy
group on the phenyl C ring increased the inhibitory activity leading
to highly potent 10f (IC50 ¼ 23 nM). On the other hand a fluorine
substituent had no influence on the activity of the methoxy de-
rivative (10e inactive at 1
mM) highlighting the importance of
acidity of the OH group for activity.
Fig. 4. 2,5-Thiophene amide 11 as 17b-HSD2 inhibitor.

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
205
Scheme 1. Synthesis of compounds 9aep, 10a, 10b, 12aef and 13a. Reagents and conditions: (i) Bu4HSO4, NaOH 50%, CH2Cl2, r.t., 3h. (ii) Boronic acid, Pd(PPh3)4, Cs2CO3, DME/EtOH/
H2O (1:1:1), microwave irradiation (150 ꢀC, 150 W, 20 min). (iii) BF3$SMe2, Et3N, CH2Cl2, 0 ꢀC to r.t.
The influence of the linker length was also investigated: longer
linkers, n ¼ 1, are slightly more favorable than shorter linkers
(n ¼ 0) in case of the hydroxylated compound (9p, n ¼ 1,
respectively for the most potent compounds. Measurements were
performed on a SiriusT3 instrument from Sirius Analytical using an
automated potentiometric titration as described in Table 3.
The molecular weight (355 Da < MW < 373 Da) of the syn-
thesized molecules was small and within the allowed range for
drug-likeness.
IC50 ¼ 934 nM vs 9m, n ¼ 0, 38% inhibition at 1
mM).
The most active compounds identified, i.e., 9n, 9p, 9r, 10b and
10d showed a weak selectivity (selectivity factors, SFs, between 2
and 6) for 17
b
-HSD1 except 10f, which exhibited a SF ¼ 10.
The lipophilicity (characterized by log P), which is an important
parameter as it affects absorption, distribution, metabolism,
excretion, toxicity and in vivo pharmacological properties, was first
calculated for all the compounds during the design step in order to
focus only on the ones with a good profile. As there is a high
variation in the predicted clog P depending on the program used,
the log P of the most interesting compounds was determined
experimentally (elog P). The clog P turned out to be always lower
than the elog P, which was found to be between 3.7 and 4.4
(Table 3), an acceptable range, except for compound 9p, which has a
very high elog P of 5.41. The increase in lipophilicity for this com-
pound comes from the presence of the additional methylene linker
(n ¼ 1) between the sulfonamide function and the phenyl C ring.
This result indicates that compounds from this class with a linker
n ¼ 1 do not have an optimum profile and were therefore not
further investigated. The sulfonamide 10b (elog P ¼ 4.34) was
slightly more lipophilic than the corresponding carboxamide 6
3.3. Physicochemical properties determination
The relevant physicochemical parameters of the most potent
compounds were both calculated and experimentally determined
as shown in Table 3.
In silico predictions of physicochemical parameters were per-
formed using ACD/Labs Percepta 2012 Release software. The loga-
rithm of partition constant P (log P) was used as quantitative
descriptor of lipophilicity. The negative logarithm of the acid
dissociation constant Ka (pKa) were used as the measure of the
acidity. Lipophilicity and acidity calculated parameters are indi-
cated in Table 3 as clog P and cpKa, respectively.
The experimental determination of the physicochemical pa-
rameters log P, log S (S is the aqueous solubility expressed in mmol/
L) and pKa, are reported in Table 3 as elog P, elog S and epKa,
Scheme 2. Synthesis of compounds 9q, 9r, 10cef, 12g, 13b and 13c. Reagents and conditions: (i) Bu4HSO4, NaOH 50%, CH2Cl2, r.t., 3h. (ii) Boronic acid, Pd(PPh3)4, Cs2CO3, DME/EtOH/
H2O (1:1:1), microwave irradiation (150 ꢀC, 150 W, 20 min). (iii) BF3$SMe2, Et3N, CH2Cl2, 0 ꢀC to r.t.

206
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
S > 7.94$10ꢁ2 mM) while was too low for 9p (elog S ¼ ꢁ5.9,
Table 2
S ¼ 1.26$10ꢁ3 mM). As solubility is affected by lipophilicity, the high
elog S value was expected as 9p exhibited a high elog P. This con-
firms that 9p is inappropriate for further development. The solu-
bilities of the sulfonamide 10b and of the corresponding
carboxamide analog 6 were in a similar range. Exchange of the
carboxamido for the sulfonamido moiety should not change
significantly the lipophilicity of the compounds in vivo.
In vitro 17b-HSD2 and 17b-HSD1 inhibitory potencies of substituted N-methyl-
sulfonamide and retro-N-methylsulfonamide derivatives 9aer and 10aef.
Molecular flexibility, polar surface area and hydrogen bond
donor and acceptor counts are important determinants of oral
bioavailability [46]. The tPSA was calculated using the program
Advance Chemistry Development, Inc. (ACD/Labs) Percepta 2012
Release and all values are reported in Table 3. It can be seen that for
all synthesized compounds the tPSA is <140 Å2, the compounds
possess less than 10 rotatable bonds and less than 12 hydrogen
bonds (acceptors and donors), fulfilling the requirements of the
Veber [46]/Lipinski [47] rule for a good oral bioavailability.
Cpd
Central
core
n
R
R2
R3 % Inhibition at 1
(IC50
m
M
SFd
)
17
b
-
17b-
HSD2a,b
HSD1a,c
10
9a
0
2-OMePh
3-OMe
H
23
e
The pKa of a compound is indicative of its ionizability, which is a
major determinant of solubility and permeability. The pKa values of
the most interesting compounds were calculated (cpKa) and
determined experimentally (epKa) for each phenolic group. The
calculated value helped the assignment of the experimental values
obtained. The epKas of the hydroxy groups from the A ring and from
the C ring are differentiated in Table 3 by the letter (A) or (C),
respectively. In addition, to verify the good correlation between
calculated and experimental pKa values and proceed with the
correct acid group assignment (OH in phenyl A or phenyl C ring),
the cpKa and epKa of 9i and of 9m bearing only one OH group,
either on the phenyl A or phenyl C ring, was determined. The OH on
phenyl C ring appears to be more acidic (epKa 9i ¼ 8.9) than the OH
phenyl A ring (epKa 9m ¼ 9.5). This was confirmed in all the sul-
fonamides bearing two OH moieties: 10b, 9n and 9p, where the
epKa of OH on the phenyl C varied between 8.8 and 8.9 whereas the
epKa of OH on the phenyl A varied between 9.2 and 9.4. Within the
retrosulfonamides 9r and 10d, the epKa of OH on the phenyl C
varied between 8.2 and 8.5, resulting slightly more acidic than the
one of the sulfonamides, because of the electron withdrawing effect
of the SO2 moiety directly attached to the C ring. Comparison of the
epKa of the carboxamide 6 with the corresponding sulfonamide
10b indicates that the carboxamido and the sulfonamido groups
have a different effect on the acidity of the OH group of phenyl A
ring or OH group of phenyl C ring. Introduction of the electron
withdrawing fluorine on the retrosulfonamide phenyl C ring
resulted in a stronger increase in acidity of the OH next to the F
atom (epKa of OH on the phenyl C ¼ 6.9 for 10f compared to the
epKa of OH on the phenyl C ¼ 8.2 for 10d).
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
0
0
0
0
0
0
0
0
0
0
0
0
0
3-OMePh
4-OMePh
2-OMePh
3-OMePh
3-OMePh
2-Thienyl
3-Thienyl
3-OMePh
3-MePh
3-OMe
3-OMe
e
H
H
H
H
H
H
H
H
H
H
H
H
H
27
13
10
10
22
32
23
18
22
15
31
38
50
n.i.
n.i.
17
n.i.
n.i.
n.i.
n.i.
15
14
n.i.
15
14
45
e
e
e
e
e
e
e
e
e
e
e
e
2
2-OMe
4-OMe
3-OMe
3-OMe
3-OH
3-OH
3-Pyridinyl 3-OH
2-Thienyl
3-OHPh
3-OHPh
3-OH
3-OMe
3-OH
(1179 nM) (2031 nM)
n.i.
57
(934 nM)
9o
9p
1
1
3-OMePh
3-OHPh
3-OMe
3-OH
H
H
n.i.
18
(4299 nM)
e
5
9q
9r
0
0
3-OMePh
3-OHPh
3-OMe
3-OH
H
H
25
16
e
66
(511 nM)
22
6
(3282 nM)
10a
10b
0
0
3-OMePh
3-OHPh
3-OMe
3-OH
H
H
26
n.i.
e
68
(540 nM)
42
2
(1308 nM)
10c
10d
0
0
3-OMePh
3-OHPh
3-OMe
3-OH
H
H
14
14
e
4. Discussion and conclusion
88
68
3
(159 nM)
(427 nM)
17
80
The main goal of this work was to develop new active and se-
10e
10f
0
0
3-OMePh
3-OHPh
3-OMe 4-F n.i.
3-OH 4-F 96
(23 nM)
e
10
lective 17
Starting from the moderately active biphenylcarboxamides 3e8
and exchanging the amide moiety for sulfonamido/retro-
b-HSD2 inhibitors with a good in vitro ADME profile.
(238 nM)
a
Mean value of three determinations, standard deviation less than 15%.
a
b
Human placental, microsomal fraction, substrate E2 [500 nM], cofactor NADþ
sulfonamido group, a new class of biphenyl derivatives was
designed, prepared and tested. In the 1,4-phenyl class with linker n
= 1, replacement of the carboxamido by a sulfonamido/retro-
sulfonamido group led to a decreased activity for hydroxy com-
pound 9p and a loss of activity for methoxy compound 9o. Three
moderately active compounds 9n, 9c and 9r could be identified
[1500 nM].
c
Human placental, cytosolic fraction, substrate E1 [500 nM], cofactor NADH
[500 nM].
d
SF: selectivity factor, ratio IC50 (17b-HSD1)/IC50 (17b-HSD2).
(elog P ¼ 3.78) but exchange of one moiety for the other should not
have critical effect on the in vivo behavior of the compounds.
The aqueous solubility S of the most interesting compounds,
expressed in mmol/L, was determined experimentally at pH ¼ 7.4
and at 25 ꢀC in KCl 0.15 M solution (elog S, Table 3). It was in a good
range for compounds 9n, 9r, 10b, 10d and 10f (ꢁ2.6 > elog S > ꢁ4.1,
with an IC50 between 500 nM and 1 mM with linker n = 0. In the 1,3-
phenyl class, a reduction of the activity was observed for the
methoxylated sulfonamide 10a while an increase was seen with the
hydroxylated retrosulfonamide 10b.
The retrosulfonamides were superior to the sulfonamides, in-
dependent of their 1,3- or 1,4-substitution pattern, as seen with 10d
corresponding to concentrations in the range: 2.51 mM
>

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
207
Table 3
Physicochemical properties calculated and experimentally determined for compounds 6, 9i, 9m, 9n, 9p, 9r, 10b, 10d and 10f.
Cpd
MW
319
clog Pa
elog Pb
elog Sc
ꢁ2.81
cpKad
epKae
tPSAf
61
Rotat. bondsg
3
HD
2
HA
6
3.29
3.78
9.6 (A)
9.6 (C)
9.4 (A)
9.4 (C)
9.5 (A)
9.4 (C)
9.7 (A)
9.5 (C)
9.7 (A)
8.7 (C)
9.6 (A)
9.4 (C)
9.7 (A)
8.7 (C)
9.7 (A)
7.4 (C)
9.4 (A)
9.0 (C)
9.5 (A)
8.9 (C)
9.5 (A)
8.8 (C)
9.2 (A)
8.8 (C)
9.8 (A)
8.5 (C)
9.4 (A)
8.9 (C)
9.8 (A)
8.2 (C)
9.3 (A)
6.9 (C)
4
9i
9m
9n
369
369
355
3.80
3.80
3.31
n.d.h
n.d.h
4.17
n.d.h
n.d.h
ꢁ4.09
75
75
86
5
5
4
1
1
2
5
5
5
9p
369
355
355
355
373
3.20
3.53
3.32
3.48
3.50
5.41
3.72
4.34
4.08
4.42
ꢁ5.90
ꢁ3.29
ꢁ3.18
ꢁ3.27
ꢁ2.64
86
86
86
86
86
5
4
4
4
4
2
2
2
2
2
5
5
5
5
5
9r
10b
10d
10f
a
Calculated log P, values determined with ACD/Labs Percepta 2012 Release using GALAS method.
Experimental log P using SiriusT3 instrument.
b
c
Experimental log S using SiriusT3 instrument, value of elog S at pH ¼ 7.4.
d
e
f
Calculated pKa values for the OH phenyl A ring (A) and OH phenyl C ring (C) determined with ACD/Labs Percepta 2012 Release using the classic method.
Experimental log P using SiriusT3 instrument.
2
ꢀ
Topological polar surface area (A ) determined with ACD/Labs Percepta 2012 Release.
Rotatable bonds determined with ACD/Labs Percepta 2012 Release.
Not determined due to a too high lipophilicity of the compound.
g
h
and 10f, leading to highly active compounds, the latter being the
most potent 17b-HSD2 inhibitors described in this class of com-
Increasing the acidity of one phenolic OH enhanced the strength
of the hydrogen bond interaction achieved by this group and
therefore might lead to a greater stabilization of the enzymeein-
hibitor complex. In case of compound 10f, it can be assumed that
the OH bond is mostly ionized (epKa ¼ 6.9) because of the com-
bined strong electron withdrawing effects of F and SO2 on the
acidity of the OH on phenyl C. In this case it might participate in
ionic interactions with basic nitrogens of lysines (pKa values be-
tween 10 and 10.5) or arginines (pKa values of 12e13) present in
the active site.
Potency comparison of carboxamides versus sulfonamides sug-
gests that the planar amide bond results in a better stabilization of
the compound than the tetrahedral eSO2Ne moiety, indicating that
the geometry of hydrogen bonding interaction is more favorable in
case of the eCONe. The sulfonamide moiety has one more H-bond
acceptor atom, which is obviously not involved in the stabilization
of the compound. Interestingly, the amides 3, 4 and 5 were more
potent than their sulfonamide analogs 9o, 9p and 10a, respectively,
except 6 which resulted weaker than 10b. This missing correlation
in the activities between the carboxamide and sulfonamide classes
might be explained by a likely different binding mode of these two
series of compounds in the enzyme active site.
pounds. We hypothesized that the SO2 moiety, next to the phenyl C
ring in the retrosulfonamides was responsible for this increased
activity as it caused an enhancement of the acidity of the C ring
hydroxy group. In order to verify this hypothesis, the retro-
sulfonamide bearing an additional electron withdrawing fluorine at
the C ring, compound 10f, was designed and synthesized. This
compound turned out to be even more active, confirming the hy-
pothesis that the retrosulfonamides were superior to the sulfon-
amides because of the electron withdrawing effect of the sulfonyl
group. In addition, the acidity of the OH group of phenyl C corre-
lated well with the potency of the compounds, highlighting the pKa
as an important physicochemical parameter for the design of new
molecular entities and as predicting molecular descriptor for
inhibitory activity. In previous studies [40,44] of 2,5-thiophene
carboxamide class 11, the increased acidity of the OH phenyl on A
was also correlated with an enhanced activity.
Comparison of the new sulfonamides (1,4-: 9ae9r, 1,3-: 10ae
10f) with the Bagi compounds (1,4-: 2a, 1,3-: 2b) highlights striking
similarities: in each of these two compound classes the 1,3-phenyl
substitution is approximately two times better than the 1,4-phenyl,
leading to moderate 17b-HSD2 inhibitors with an IC50 around
500 nM for 2b and 10b. In addition, the tetrahedral eSO2Ne moiety
might mimic the tetrahedral secondary OH of 2b. Superimposition
of these two compounds (Fig. 5) shows that the phenyl C rings do
not cover the same area in both classes and the pyrrolidinone
moiety of 2b overlaps with the N-methyl group of the sulfonamide.
In case that both compounds have the same binding mode, this
might indicate that the cis-pyrrolidinone moiety is not highly
necessary and that the phenyl C ring does not achieve crucial in-
teractions. Interestingly, exchange of the central phenyl B for a 2,5-
thiophene ring in the pyrrolidinone derivative 2b leading to com-
pound 1 and in the carboxamido class 6 to 11 (where R1 ¼ 3-OH,
R2 ¼ 3-OH without F) results in a gain in activity in both classes of
compounds.
Fig. 5. Molecular superimposition of low-energy conformations of compounds 10b
(green) and 2b (gray). The picture was generated using MOE 2010.10. (For interpre-
tation of the references to colour in this figure legend, the reader is referred to the web
version of this article.)

208
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
The in vitro ADME profile of a compound reflects its in vivo
used as stationary phase. All solvents were HPLC grade. In a
gradient run the percentage of acetonitrile was increased from an
initial concentration of 0% at 0 min to 100% at 15 min and kept at
pharmacokinetic behavior that can be related to its chemical
properties. The prediction of the ADME parameters has become an
accepted strategy in modern drug development to reduce the
number of synthesized molecules and speed up the drug discovery
process reducing the attrition rate during clinical trials. For all
synthesized compounds reported herein, ADME-related physico-
chemical parameters were proved to span a good range. Some of
these parameters were determined experimentally because of the
high variability of the predictions obtained using different in silico
programs. All of the most potent compounds turned out to exhibit
good ADME-related parameters in an acceptable range.
100% for 5 min. The injection volume was 15
mL and flow rate was
set to 800
m
L/min. MS analysis was carried out at a needle voltage of
3000 V and a capillary temperature of 350 ꢀC. Mass spectra were
acquired in positive mode from 100 to 1000 m/z and UV spectra
were recorded at the wave length of 254 nm and in some cases at
360 nm.
GC/MS spectra were measured on a DSQ II Mass SpectrometerÒ
(ThermoFisher) with an Optima-5-MS (0.25
mM, 30 m) column
(MachereyeNagel GmbH, Dühren, Germany).
The best compound identified in this study, 10f, is the most
potent 17b-HSD2 inhibitor described in this class of compounds
Synthesis of compound 6 was made as described in the litera-
ture [40].
with a very good activity (IC50 ¼ 23 nM). Moreover, its calculated
and experimentally determined ADME parameters (MW ¼ 373 Da,
elog P ¼ 4.42, tPSA ¼ 86 Å2, 4 rotatable bonds, 2 HD, 4 HA) are in
very good range, predicting a good bioavailability. Especially its
good solubility (elog S ¼ ꢁ2.64, S ¼ 2.28 mM) makes it appropriate
for in vivo application. It exhibited also a good selectivity toward
5.2. General procedures
5.2.1. General procedure for sulfonamides preparation (method A)
To a solution of substituted N-methylaniline (1 mmol) in CH2Cl2
(5 mL) was added aqueous NaOH 25 M (1 mL) followed by tetra-
butylammonium hydrogen sulfate (0.15 mmol). After 5 min of
vigorous stirring, the substituted benzenesulfonyl chloride
(1 mmol) was added to the reaction mixture. The solution was
stirred either for 3 h or overnight at room temperature. Water was
added to quench the reaction. Aqueous layer was extracted with
CH2Cl2 (3 ꢃ CH2Cl2). The organic layer was washed once with brine
and once with water, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography using a mixture of n-hexane and ethyl acetate as
solvent to afford the desired compound.
17b-HSD1 (SF: 10). The metabolic stability of 10f as well as its
pharmacokinetics will be determined in order to verify whether it
can be successfully tested in animal models of osteoporosis. In this
report we also demonstrated that there was a correlation between
the acidity of the phenolic hydroxy on C ring and the inhibitory
potency, and this suggests that pKa could be used as a useful
parameter to guide the design of new class of inhibitors.
5. Experimental section
5.1. Chemical methods
Chemical names follow IUPAC nomenclature.
Starting materials were purchased from Aldrich, Acros, Combi-
Blocks or Fluka and were used without purification. No attempts
were made to optimize reaction yields.
All microwave irradiation experiments were carried out in a
CEM-Discover microwave apparatus.
Melting points (mp) were measured on a Stuart Scientific SMP3
apparatus and are uncorrected.
Column chromatography was performed on silica gel (70e
200 mm) with hexane/ethyl acetate mixtures as eluents, and the
5.2.2. General procedure for SuzukieMiyaura coupling (method B)
In a sealed tube was introduced the previously prepared bromo-
N-methylsulfonamide derivative (1 eq.) followed by the corre-
sponding boronic acid (1.5 eq.), cesium carbonate (3 eq.), tetra-
kis(triphenylphosphine)palladium (0.02 eq.) and a mixture of DME/
EtOH/H2O (1:1:1, v:v:v, 3 mL) as solvent. The reactor was flushed
with N2 and submitted to microwave irradiation (150 ꢀC, 150 W) for
20 min. After cooling, a mixture of EtOAc/H2O (1:1, v:v, 2 mL) was
added to stop the reaction. The aqueous layer was extracted with
EtOAc (3 ꢃ EtOAc). The organic layer was washed once with brine
and once with water, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by column
chromatography using a mixture of n-hexane and ethyl acetate as
solvent to afford the desired compound.
reaction progress was monitored by thin-layer chromatography
analysis (TLC) on Alugram SIL G/UV254 (MachereyeNagel). Visu-
alization was accomplished with UV light.
1H NMR and 13C NMR spectra were measured on a Bruker DRX-
500 spectrometer (at 500 MHz and 125 MHz, respectively) at 300 K
in acetone-d6. Chemical shifts are reported in
d
(parts per million:
5.2.3. General procedure for ether cleavage (method C)
ppm), by reference to the hydrogenated residues of deuterated
solvent as internal standard: 2.05 ppm (1H NMR) and 29.8 and
206.3 ppm (13C NMR) for acetone-d6. The spectral splitting patterns
are designated as follows: s, singlet; d, doublet; dd, doublet of
doublets; ddd, doublet of doublet of doublets, t, triplet; q, quartet;
m, multiplet; br s, broad singlet.
To a solution of substituted methoxysulfonamide derivative
(1 eq.) in CH2Cl2 (10 mL) at 0 ꢀC was added, Et3N (6 eq. per
methoxy group) followed by boron trifluoride methyl sulfide
complex (6 eq. per methoxy group). The reaction was warmed to
room temperature and stirred overnight. The reaction was
monitored by TLC and when necessary an extra portion of Et3N
and BF3$SMe2 was added to complete the reaction. The reaction
mixture was cooled at 0 ꢀC and methanol was added to quench
the reaction. After warming up to room temperature for 1 h, the
solvent was carefully removed under reduced pressure (temper-
ature of bath was 25 ꢀC). Cold water was added to the residue and
the aqueous layer was extracted with CH2Cl2 (3 ꢃ CH2Cl2). The
organic layer was washed once with water, dried over MgSO4,
filtered and evaporated to dryness under reduced pressure. The
residue was purified by column chromatography using a mixture
of hexanes and ethyl acetate as solvent to afford the desired
compound.
IR spectra were recorded neat on a Perkin Elmer Spectrum 100
FTIR spectrophotometer.
All tested compounds exhibited ꢂ95% chemical purity assessed
by HPLC/MS.
Mass spectrometry measurements were performed on a TSQÒ
Quantum (ThermoFisher, Dreieich, Germany). The triple quadru-
pole mass spectrometer was equipped with an electrospray inter-
face (ESI). The SurveyorÒ-LC-system consisted of a pump, an auto
sampler, and a PDA detector. The system was operated by the
standard software XcaliburÒ. A RP C18 NUCLEODURÒ 100e5
(3 mm) column (MachereyeNagel GmbH, Dühren, Germany) was

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
209
5.3. Detailed synthesis procedure for the preparation of compounds
d 38.9, 55.8, 114.9, 128.9, 129.1, 130.5, 131.1, 133.0, 134.9, 159.9; GCe
MS (EI) m/z: [M]þ 356.20, 358.22.
5.3.1. 4-Bromo-N-methyl-N-phenylbenzenesulfonamide (12b)
The title compound was prepared by reaction of N-methylani-
line (643 mg, 6 mmol) in CH2Cl2 (18 mL) and NaOH 25 M (6 mL)
with 4-bromobenzenesulfonyl chloride (14a) (1.533 g, 6 mmol) and
tetrabutylammonium hydrogen sulfate (306 mg, 0.9 mmol) as
phase transfer catalyst according to method A. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 90:10) to afford 12b (1.91 g,
5.86 mmol, 98%) as colorless crystal. C13H12BrNO2S; mp 98e100 ꢀC;
5.3.5. 4-Bromo-N-(3-hydroxyphenyl)-N-methylbenzenesulfonamide
(12e)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (754 mg,
2.12 mmol) with Et3N (1.77 mL, 12.72 mmol) and BF3$SMe2
(1.34 mL,12.72 mmol) in CH2Cl2 (10 mL) according to method C. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 12e
(693 mg, 2.03 mmol, 96%) as pale brown solid. C13H12BrNO3S; mp
IR (neat): 1346, 1158 cmꢁ1
; d 3.22 (s, 3H),
1H NMR (acetone-d6):
7.15e7.17 (m, 2H), 7.28e7.37 (m, 3H), 7.45e7.48 (m, 2H), 7.75e7.78
;
104e106 ꢀC; IR (neat): 3378, 1331, 1153 cmꢁ1 1H NMR (acetone-
(m, 2H); 13C NMR (acetone-d6):
d
38.6, 127.4, 128.1, 128.2, 129.1,
d6):
d
3.18 (s, 3H), 6.58 (ddd, J ¼ 0.9, 2.2, 8.0 Hz, 1H), 6.67 (t,
129.8, 130.4, 131.2, 133.1, 137.0, 142.4; GCeMS (EI) m/z: [M]þ 326.27,
J ¼ 2.3 Hz, 1H), 6.78 (ddd, J ¼ 1.0, 2.3, 8.2 Hz, 1H), 7.14 (t, J ¼ 8.2 Hz,
1H), 7.49e7.52 (m, 2H), 7.75e7.78 (m, 2H), exchange of hydroxy
328.37.
proton with deuterated solvent; 13C NMR (acetone-d6):
d 38.6,
5.3.2. 4-Bromo-N-(2-methoxyphenyl)-N-methylbenzenesulfonamide
(12c)
114.6, 115.2, 118.0, 128.1, 130.4, 130.5, 133.0, 137.0, 143.5, 158.5; GCe
MS (EI) m/z: [M]þ 342.45, 344.49.
The title compound was prepared by reaction of 2-methoxy-N-
methylaniline (274 mg, 2 mmol) in CH2Cl2 (6 mL) and NaOH 25 M
(2 mL) with 4-bromobenzenesulfonyl chloride (14a) (511 mg,
2 mmol) and tetrabutylammonium hydrogen sulfate (102 mg,
0.3 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 90:10) to afford 12c
(282 mg, 0.79 mmol, 40%) as colorless solid. C14H14BrNO3S; mp
5.3.6. 4-Bromo-N-(3-methoxybenzyl)-N-methylbenzenesulfonamide
(12f)
The title compound was prepared by reaction of 1-(3-
methoxyphenyl)-N-methylmethanamine (558 mg, 3.69 mmol)
in CH2Cl2 (5 mL) and NaOH 25
M
(1 mL) with 4-
bromobenzenesulfonyl chloride (14a) (943 mg, 3.69 mmol) and
tetrabutylammonium hydrogen sulfate (188 mg, 0.55 mmol) as
phase transfer catalyst according to method A. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 12f (1.285 g,
3.47 mmol, 94%) as yellow viscous solid. C15H16BrNO3S; IR (neat):
123e125 ꢀC; IR (neat): 1339, 1152 cmꢁ1
3.20 (s, 3H), 3.44 (s, 3H), 6.93e6.97 (m, 2H), 7.27 (ddd, J ¼ 0.6, 1.6,
5.5 Hz, 1H), 7.31e7.34 (m, 1H), 7.57e7.60 (m, 2H), 7.76e7.79 (m,
;
1H NMR (acetone-d6):
d
2H); 13C NMR (acetone-d6):
d 38.2, 55.4, 113.0, 121.3, 127.4, 129.7,
130.2, 130.7, 132.6, 132.7, 140.1, 157.3; GCeMS (EI) m/z: [M]þ 356.23,
1340, 1157 cmꢁ1; 1H NMR (acetone-d6):
4.18 (s, 2H), 6.86e6.89 (m,1H), 6.90e6.93 (m, 2H), 7.24 (t, J ¼ 7.9 Hz,
1H), 7.81e7.87 (m, 4H); 13C NMR (acetone-d6):
34.9, 55.6, 55.5,
d 2.64 (s, 3H), 3.78 (s, 3H),
358.27.
d
5.3.3. 4-Bromo-N-(3-methoxyphenyl)-N-methylbenzenesulfonamide
(12a)
114.1, 114.7, 121.3, 127.9, 130.0, 130.2, 131.2, 138.0, 138.6, 161.0; GCe
MS (EI) m/z: [M]þ 370.06, 372.12.
The title compound was prepared by reaction of 3-methoxy-
N-methylaniline (274 mg, 2 mmol) in CH2Cl2 (5 mL) and NaOH
5.3.7. N-(4-Bromophenyl)-3-methoxy-N-methylbenzenesulfonamide
(12g)
25
M (1 mL) with 4-bromobenzenesulfonyl chloride (14a)
(511 mg, 2 mmol) and tetrabutylammonium hydrogen sulfate
(102 mg, 0.3 mmol) as phase transfer catalyst according to
method A. The residue was purified by silica gel column chro-
matography using n-hexane and EtOAc as eluent (n-hexane/
EtOAc 90:10) to afford 12a (641 mg, 1.80 mmol, 90%) as brown
solid. C14H14BrNO3S; mp 72e76 ꢀC; IR (neat): 1356, 1165 cmꢁ1; 1H
The title compound was prepared by reaction of 4-bromo-N-
methylaniline (558 mg, 3 mmol) in CH2Cl2 (9 mL) and NaOH 25 M
(3 mL) with 3-methoxybenzenesulfonyl chloride (15a) (425
mL,
3 mmol) and tetrabutylammonium hydrogen sulfate (153 mg,
0.45 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 12g
(985 mg, 2.77 mmol, 92%) as yellow oil. C14H14BrNO3S; IR (neat):
NMR (acetone-d6):
d
3.21 (s, 3H), 3.75 (s, 3H), 6.70 (ddd, J ¼ 0.9,
2.0, 7.9 Hz, 1H), 6.74 (t, J ¼ 2.4 Hz, 1H), 6.87 (ddd, J ¼ 0.9, 2.6,
8.3 Hz, 1H), 7.23 (t, J ¼ 8.1 Hz, 1H), 7.49e7.52 (m, 2H), 7.75e7.79
1350, 1151 cmꢁ1 1H NMR (acetone-d6):
; d 3.19 (s, 3H), 3.79 (s, 3H),
(m, 2H); 13C NMR (acetone-d6):
d
38.6, 55.0, 113.4, 113.8, 119.2,
7.00 (dd, J ¼ 1.7, 2.5 Hz, 1H), 7.11e7.14 (m, 3H), 7.23 (ddd, J ¼ 1.0, 2.6,
128.2, 129.1, 130.4, 130.5, 133.1, 143.5, 160.9; GCeMS (EI) m/z:
8.4 Hz, 1H), 7.48 (t, J ¼ 8.1 Hz, 1H), 7.50e7.53 (m, 2H); 13C NMR
[M]þ 356.21, 358.19.
(acetone-d6): d 38.3, 56.0, 113.3, 120.1, 120.7, 121.1, 129.1, 131.1, 132.7,
138.4, 142.1, 160.8; GCeMS (EI) m/z: [M]þ 356.38, 358.42.
5.3.4. 4-Bromo-N-(4-methoxyphenyl)-N-methylbenzenesulfonamide
(12d)
5.3.8. 3-Bromo-N-(3-methoxyphenyl)-N-methylbenzenesulfonamide
(13a)
The title compound was prepared by reaction of 4-methoxy-N-
methylaniline (274 mg, 2 mmol) in CH2Cl2 (5 mL) and NaOH 25 M
(1 mL) with 4-bromobenzenesulfonyl chloride (14a) (511 mg,
2 mmol) and tetrabutylammonium hydrogen sulfate (102 mg,
0.3 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 90:10) to afford 12d
(697 mg, 1.96 mmol, 98%) as pale brown viscous solid.
The title compound was prepared by reaction of 3-methoxy-N-
methylaniline (823 mg, 6 mmol) in CH2Cl2 (18 mL) and NaOH 25 M
(6 mL) with 3-bromobenzenesulfonyl chloride (15a) (1.533 g,
6 mmol) and tetrabutylammonium hydrogen sulfate (306 mg,
0.9 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 13a
(2.112 g, 5.93 mmol, 99%) as brown oil. C14H14BrNO3S; IR (neat):
C
14H14BrNO3S; IR (neat): 1345, 1154 cmꢁ1
;
1H NMR (acetone-d6):
d
3.17 (s, 3H), 3.79 (s, 3H), 6.86e6.89 (m, 2H), 7.02e7.06 (m, 2H),
1351, 1149 cmꢁ1; 1H NMR (acetone-d6):
6.71 (ddd, J ¼ 0.9, 2.2, 7.9 Hz, 1H), 6.73 (t, J ¼ 2.3 Hz, 1H), 6.89 (ddd,
d 3.22 (s, 3H), 3.75 (s, 3H),
7.44e7.49 (m, 2H), 7.75e7.78 (m, 2H); 13C NMR (acetone-d6-d6):

210
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
J ¼ 0.9, 2.5, 8.4 Hz, 1H), 7.25 (t, J ¼ 8.0 Hz, 1H), 7.53e7.60 (m, 2H),
7.65 (t, J ¼ 2.1 Hz, 1H), 7.86e7.88 (m, 1H); 13C NMR (acetone-d6):
0.63 mmol), cesium carbonate (411 mg, 1.26 mmol) and tetrakis(-
triphenylphosphine)palladium (10 mg, 8.65 ꢃ 10ꢁ3 mmol) in DME/
EtOH/H2O (3 mL) according to method B. The residue was purified
by silica gel column chromatography using n-hexane and EtOAc as
eluent (n-hexane/EtOAc 80:20) to afford 9b (79 mg, 0.21 mmol,
48%) as yellow oil. C21H21NO4S; IR (neat): 1338, 1160, 1147 cmꢁ1; 1H
d
38.7, 55.8, 113.4, 114.1, 119.3, 123.1, 125.8, 127.5, 130.5, 131.1, 132.0,
136.8, 143.4, 161.0; GCeMS (EI) m/z: [M]þ 356.18, 358.25.
5.3.9. N-(3-Bromophenyl)-3-methoxy-N-methylbenzenesulfonamide
(13b)
NMR (acetone-d6): d 3.23 (s, 3H), 3.74 (s, 3H), 3.88 (s, 3H), 6.72e6.76
The title compound was prepared by reaction of 3-bromo-N-
methylaniline (558 mg, 3 mmol) in CH2Cl2 (9 mL) and NaOH 25 M
(m, 2H), 6.87 (ddd, J ¼ 1.0, 2.5, 8.4 Hz, 1H), 7.01 (ddd, J ¼ 0.9, 2.6,
8.3 Hz, 1H), 7.24 (t, J ¼ 8.0 Hz, 1H), 7.27 (t, J ¼ 1.9 Hz, 1H), 7.29 (ddd,
J ¼ 0.9, 1.6, 7.7 Hz, 1H), 7.42 (t, J ¼ 8.1 Hz, 1H), 7.64e7.66 (m, 2H),
(3 mL) with 3-methoxybenzenesulfonyl chloride (15a) (425
mL,
3 mmol) and tetrabutylammonium hydrogen sulfate (153 mg,
0.45 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 13b
(880 mg, 2.47 mmol, 82%) as yellow oil. C14H14BrNO3S; IR (neat):
7.84e7.87 (m, 2H); 13C NMR (acetone-d6):
d 38.6, 55.68. 55.70,113.3,
113.6, 113.7, 115.0, 119.2, 120.3, 128.2, 129.2, 130.3, 131.1, 136.7, 141.4,
143.9, 146.1, 160.9, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ 383.65.
5.3.13. 40-Methoxy-N-(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9c)
1351, 1152 cmꢁ1; 1H NMR (acetone-d6):
d 3.21 (s, 3H), 3.79 (s, 3H),
6.99 (dd, J ¼ 1.7, 2.5 Hz, 1H), 7.15 (ddd, J ¼ 1.0, 2.2, 7.6 Hz, 1H), 7.18
(ddd, J ¼ 1.0, 2.2, 8.2 Hz,1H), 7.24 (ddd, J ¼ 1.0, 2.6, 8.4 Hz,1H), 7.30 (t,
J ¼ 8.0 Hz, 1H), 7.36 (t, J ¼ 2.1 Hz, 1H), 7.46e7.51 (m, 2H); 13C NMR
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (150 mg,
0.43 mmol) with 4-methoxyphenylboronic acid (96 mg,
0.63 mmol), cesium carbonate (411 mg, 1.26 mmol) and tetrakis(-
triphenylphosphine)palladium (10 mg, 8.65 ꢃ 10ꢁ3 mmol) in DME/
EtOH/H2O (3 mL) according to method B. The residue was purified
by silica gel column chromatography using n-hexane and EtOAc as
eluent (n-hexane/EtOAc 80:20) to afford 9c (104 mg, 0.27 mmol,
63%) as colorless crystal. C21H21NO4S; mp 130e132 ꢀC; IR (neat):
(acetone-d6): d 38.4, 56.1,113.2,120.3,120.7,122.4,126.1,130.2,131.0,
131.1,131.3,138.4,144.2,160.8; GCeMS (EI) m/z: [M]þ 356.20, 358.22.
5.3.10. N-(3-Bromophenyl)-4-fluoro-3-methoxy-N-
methylbenzenesulfonamide (13c)
The title compound was prepared by reaction of 3-bromo-N-
methylaniline (744 mg, 4 mmol) in CH2Cl2 (12 mL) and NaOH 25 M
1342, 1159, 1148 cmꢁ1; 1H NMR (acetone-d6):
d 3.22 (s, 3H), 3.74 (s,
(4 mL) with 2-fluoro-3-methoxybenzenesulfonyl chloride (899
m
L,
3H), 3.87 (s, 3H), 6.72e6.76 (m, 2H), 6.87 (ddd, J ¼ 0.9, 2.5, 8.3 Hz,
4 mmol) and tetrabutylammonium hydrogen sulfate (204 mg,
0.6 mmol) as phase transfer catalyst according to method A. The
residue was purified by silica gel column chromatography using n-
hexane and EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 13c
(1.00 g, 2.68 mmol, 67%) as pale yellow solid. C14H13BrFNO3S; mp
1H), 7.06e7.09 (m, 2H), 7.23 (t, J ¼ 8.2 Hz, 1H), 7.60e7.63 (m, 2H),
7.68e7.72 (m, 2H), 7.79e7.82 (m, 2H); 13C NMR (acetone-d6):
d 38.6,
55.66, 55.72, 113.3, 113.6, 115.4, 119.2, 127.4, 129.25, 129.27, 130.3,
132.1, 135.7, 143.9, 145.9, 160.9, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ
384.21.
94e98 ꢀC; IR (neat): 1348, 1152 cmꢁ1; 1H NMR (acetone-d6):
d 3.22
(s, 3H), 3.85 (s, 3H), 7.12 (dd, J ¼ 2.2, 7.9 Hz, 1H), 7.19e7.22 (m, 2H),
5.3.14. 20-Methoxy-N-methyl-N-phenyl-[1,10-biphenyl]-4-
sulfonamide (9d)
7.33 (t, J ¼ 8.0 Hz, 1H), 7.35 (t, J ¼ 8.5 Hz, 1H), 7.38 (t, J ¼ 2.0 Hz, 1H),
7.50 (ddd, J ¼ 0.9, 1.8, 8.0 Hz, 1H); 13C NMR (acetone-d6):
d
38.4,
The title compound was prepared by reaction of 4-bromo-N-
methyl-N-phenylbenzenesulfonamide (12b) (326 mg, 1 mmol)
with 2-methoxyphenylboronic acid (228 mg, 1.5 mmol), cesium
carbonate (978 mg, 3 mmol) and tetrakis(triphenylphosphine)
palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O (3 mL)
according to method B. The residue was purified by silica gel col-
umn chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 80:20) to afford 9d (239 mg, 0.68 mmol, 68%) as
56.8, 113.74, 113.76, 117.1, 117.3, 122.09, 122.15, 122.4, 126.3, 130.4,
131.1, 131.4, 133.50, 133.53, 144.2, 148.9, 149.0, 154.9, 156.9; GCeMS
(EI) m/z: [M]þ 374.48, 376.51.
5.3.11. 20-Methoxy-N-(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9a)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (150 mg,
0.43 mmol) with 2-methoxyphenylboronic acid (96 mg,
0.63 mmol), cesium carbonate (411 mg, 1.26 mmol) and tetrakis(-
triphenylphosphine)palladium (10 mg, 8.65 ꢃ 10ꢁ3 mmol) in DME/
EtOH/H2O (3 mL) according to method B. The residue was purified
by silica gel column chromatography using n-hexane and EtOAc as
eluent (n-hexane/EtOAc 80:20) to afford 9a (84 mg, 0.22 mmol,
51%) as pale brown crystal. C21H21NO4S; mp 82e83 ꢀC; IR (neat):
yellow oil. C20H19NO3S; IR (neat): 1347, 1172, 1152 cmꢁ1
(acetone-d6):
;
1H NMR
d
3.24 (s, 3H), 3.84 (s, 3H), 7.07 (dt, J ¼ 1.0, 7.6 Hz, 1H),
7.15 (dd, J ¼ 0.9, 8.4 Hz, 1H), 7.18e7.20 (m, 2H), 7.27e7.31 (m, 1H),
7.33e7.42 (m, 4H), 7.56e7.59 (m, 2H), 7.69e7.72 (m, 2H); 13C NMR
(acetone-d6):
d 38.5, 56.0, 112.7, 121.8, 127.3, 128.0, 128.3, 129.4,
129.7, 130.7, 130.8, 131.5, 136.0, 142.8, 144.3, 157.5; HPLCeMS (ESI)
m/z: [M]þ 353.78.
1347, 1165, 1150 cmꢁ1; 1H NMR (acetone-d6):
d
3.23 (s, 3H), 3.74 (s,
5.3.15. 30-Methoxy-N-(2-methoxyphenyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9e)
3H), 3.84 (s, 3H), 6.23 (t, J ¼ 2.2 Hz, 1H), 6.76 (ddd, J ¼ 0.9, 2.0,
7.9 Hz,1H), 6.87 (ddd, J ¼ 0.9, 2.5, 8.3 Hz,1H), 7.07 (dt, J ¼ 1.2, 7.6 Hz,
1H), 7.14 (dd, J ¼ 1.0, 8.4 Hz, 1H), 7.24 (t, J ¼ 8.1 Hz, 1H), 7.36 (dd,
J ¼ 1.6, 7.6 Hz, 1H), 7.38e7.42 (m, 1H), 7.59e7.62 (m, 2H), 7.70e7.72
The title compound was prepared by reaction of 4-bromo-N-(2-
methoxyphenyl)-N-methylbenzenesulfonamide (12c) (270 mg,
0.76 mmol) with 3-methoxyphenylboronic acid (173 mg,
1.14 mmol), cesium carbonate (743 mg, 2.28 mmol) and tetrakis(-
triphenylphosphine)palladium (18 mg, 15.58 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 9e (275 mg,
0.72 mmol, 94%) as yellow oil. C21H21NO4S; IR (neat): 1342, 1171,
(m, 2H); 13C NMR (acetone-d6):
d 38.7, 55.7, 56.0, 112.6, 113.1, 113.8,
119.4, 121.9, 128.3, 129.4, 130.3, 130.7, 130.8, 131.5, 136.0, 143.9,
144.4, 157.5, 160.9; HPLCeMS (ESI) m/z: [M þ H]þ 383.85.
5.3.12. 30-Methoxy-N-(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9b)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (150 mg,
0.43 mmol) with 2-methoxyphenylboronic acid (96 mg,
1152 cmꢁ1; 1H NMR (acetone-d6):
d 3.22 (s, 3H), 3.39 (s, 3H), 3.88 (s,
3H), 6.92e6.96 (m, 2H), 7.01 (ddd, J ¼ 0.9, 2.6, 8.3 Hz, 1H), 7.27e7.33
(m, 4H), 7.43 (t, J ¼ 8.2 Hz, 1H), 7.71e7.73 (m, 2H), 7.82e7.85 (m,

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
211
2H); 13C NMR (acetone-d6):
d
38.3, 55.4, 55.7, 113.0, 113.7, 114.7,
0.39 mmol), cesium carbonate (258 mg, 0.79 mmol) and tetra-
kis(triphenylphosphine)palladium (6 mg, 5.19 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 50:50) to afford 9i (87 mg,
0.24 mmol, 91%) as pale brown solid. C20H19NO4S; mp 125e126 ꢀC;
120.4,121.3,128.0,128.9,130.0,130.5,131.1,132.7,139.6,141.8,145.6,
157.5, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ 383.89.
5.3.16. 30-Methoxy-N-(4-methoxyphenyl)-N-methyl-[1,10-
biphenyl]-4-sulfonamide (9f)
The title compound was prepared by reaction of 4-bromo-N-(4-
methoxyphenyl)-N-methylbenzenesulfonamide (12d) (356 mg,
1 mmol) with 3-methoxyphenylboronic acid (228 mg, 1.5 mmol),
cesium carbonate (978 mg, 3 mmol) and tetrakis(triphenylphos-
phine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O
(3 mL) according to method B. The residue was purified by silica gel
column chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 80:20) to afford 9f (305 mg, 0.80 mmol, 80%) as pale
brown solid. C21H21NO4S; mp 86e87 ꢀC; IR (neat): 1345, 1170,
IR (neat): 3377, 1342, 1167, 1148 cmꢁ1; 1H NMR (acetone-d6):
d 3.19
(s, 3H), 3.87 (s, 3H), 6.60 (ddd, J ¼ 0.9, 2.2, 8.1 Hz, 1H), 6.70 (t,
J ¼ 2.3 Hz, 1H), 6.76 (ddd, J ¼ 0.9, 2.3, 8.2 Hz, 1H), 7.00 (ddd, J ¼ 0.9,
2.6, 8.3 Hz, 1H), 7.14 (t, J ¼ 8.1 Hz, 1H), 7.27 (t, J ¼ 1.8 Hz, 1H), 7.29
(ddd, J ¼ 1.0, 1.7, 7.7 Hz, 1H), 7.42 (t, J ¼ 8.0 Hz, 1H), 7.62e7.65 (m,
2H), 7.83e7.86 (m, 2H), 8.49 (s, 1H); 13C NMR (acetone-d6):
d 38.6,
55.7, 113.5, 114.6, 115.0, 115.1, 117.9, 120.3, 128.2, 129.2, 130.3, 131.1,
136.7, 141.4, 143.8, 146.0, 158.5, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ
369.91.
1153 cmꢁ1; 1H NMR (acetone-d6):
d 3.19 (s, 3H), 3.79 (s, 3H), 3.88 (s,
3H), 6.85e6.89 (m, 2H), 7.02 (ddd, J ¼ 1.0, 2.6, 8.3 Hz, 1H), 7.04e7.07
5.3.20. N-(3-Hydroxyphenyl)-N,30-dimethyl-[1,10-biphenyl]-4-
sulfonamide (9j)
(m, 2H), 7.27e7.28 (m,1H), 7.29e7.31 (m,1H), 7.42 (t, J ¼ 8.1 Hz,1H),
7.60e7.63 (m, 2H), 7.83e7.86 (m, 2H); 13C NMR (acetone-d6):
d
38.9,
The title compound was prepared by reaction of 4-bromo-N-(3-
hydroxyphenyl)-N-methylbenzenesulfonamide (12e) (200 mg,
0.58 mmol) with 3-tolylboronic acid (118 mg, 0.87 mmol), cesium
carbonate (567 mg, 1.74 mmol) and tetrakis(triphenylphosphine)
palladium (13 mg, 11.25 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O (3 mL)
according to method B. The residue was purified by silica gel col-
umn chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 70:30) to afford 9j (98 mg, 0.28 mmol, 48%) as brown
55.7, 55.8, 113.6, 114.8, 115.0, 120.4, 128.2, 128.9, 129.3, 131.1, 135.3,
136.7, 141.4, 146.0, 159.7, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ
383.97.
5.3.17. N-(3-Methoxyphenyl)-N-methyl-4-(thiophen-2-yl)
benzenesulfonamide (9g)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (356 mg,
1 mmol) with 2-thiopheneboronic acid (192 mg, 1.5 mmol), cesium
carbonate (978 mg, 3 mmol) and tetrakis(triphenylphosphine)
palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O (3 mL)
according to method B. The residue was purified by silica gel col-
umn chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 80:20) to afford 9g (253 mg, 0.70 mmol, 70%) as pale
oil. C20H19NO3S; IR (neat): 3376, 1341, 1163, 1147 cmꢁ1
(acetone-d6):
;
1H NMR
d
2.42 (s, 3H), 3.20 (s, 3H), 6.60 (ddd, J ¼ 0.9, 2.2,
8.0 Hz, 1H), 6.70 (t, J ¼ 2.3 Hz, 1H), 6.77 (ddd, J ¼ 1.0, 2.5, 8.2 Hz, 1H),
7.13 (t, J ¼ 8.1 Hz, 1H), 7.25e7.28 (m, 1H), 7.39 (t, J ¼ 7.7 Hz, 1H),
7.51e7.54 (m, 1H), 7.56e7.57 (m, 1H), 7.64 (dt, J ¼ 2.0, 8.7, 2H), 7.84
(dt, J ¼ 2.0, 8.7, 2H), 8.70 (br s, 1H); 13C NMR (acetone-d6):
d 21.4,
38.6, 114.6, 115.1, 117.9, 125.2, 128.0, 128.8, 129.2, 129.9, 130.1, 130.3,
136.5, 139.6, 139.9, 143.8, 146.2, 158.6; HPLCeMS (ESI) m/z:
[M þ H]þ 353.90.
brown solid.
C
18H17NO3S2; mp 79e81 ꢀC; IR (neat): 1341,
3.22 (s, 3H), 3.74 (s, 3H), 6.73
1153 cmꢁ1 1H NMR (acetone-d6):
;
d
(ddd, J ¼ 0.9, 2.1, 8.1 Hz, 1H), 6.76 (t, J ¼ 2.3 Hz, 1H), 6.87 (ddd,
J ¼ 0.9, 2.6, 8.4 Hz, 1H), 7.19 (dd, J ¼ 3.8, 5.1 Hz, 1H), 7.23 (t,
J ¼ 8.1 Hz,1H), 7.58e7.61 (m, 3H), 7.65 (dd, J ¼ 1.0, 3.6 Hz,1H), 7.83e
5.3.21. N-(4-Hydroxyphenyl)-N-methyl-4-(pyridin-3-yl)
benzenesulfonamide (9k)
7.86 (m, 2H); 13C NMR (acetone-d6):
d
37.7, 54.7, 112.4, 112.7, 118.2,
The title compound was prepared by reaction of 4-bromo-N-(3-
hydroxyphenyl)-N-methylbenzenesulfonamide (12e) (200 mg,
0.58 mmol) with pyridine-3-boronic acid (107 mg, 0.87 mmol),
cesium carbonate (567 mg, 1.74 mmol) and tetrakis(-
triphenylphosphine)palladium (13 mg, 11.25 ꢃ10ꢁ3 mmol) in DME/
EtOH/H2O (3 mL) according to method B. The residue was purified
by silica gel column chromatography using EtOAc as eluent to
afford 9k (134 mg, 0.39 mmol, 69%) as colorless crystal.
125.4, 125.5, 127.1, 128.58, 128.63, 129.4, 135.2, 138.5, 141.8, 142.9,
159.9; GCeMS (EI) m/z: [M]þ 359.35.
5.3.18. N-(3-Methoxyphenyl)-N-methyl-4-(thiophen-3-yl)
benzenesulfonamide (9h)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (300 mg,
0.84 mmol) with 3-thiopheneboronic acid (162 mg, 1.26 mmol), ce-
sium carbonate (821 mg, 3 mmol) and tetrakis(triphenylphosphine)
palladium (19 mg, 16.44 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O (3 mL)
according to method B. The residue was purified by silica gel column
chromatography using n-hexane and EtOAc as eluent (n-hexane/
EtOAc 80:20) to afford 9h (144 mg, 0.40 mmol, 48%) as pale brown
solid.C18H17NO3S2;mp92e94ꢀC;IR(neat): 1344,1156cmꢁ1;1H NMR
C
18H16N2O3S; mp 165e168 ꢀC; IR (neat): 3380, 1341, 1165,
1152 cmꢁ1; 1H NMR (acetone-d6):
d
3.21 (s, 3H), 6.61 (ddd, J ¼ 0.9,
2.1, 8.0 Hz, 1H), 6.71 (t, J ¼ 2.3 Hz, 1H), 6.78 (ddd, J ¼ 0.9, 2.5, 8.2 Hz,
1H), 7.14 (t, J ¼ 8.1 Hz,1H), 7.51 (ddd, J ¼ 0.9, 4.9, 8.1 Hz,1H), 7.70 (dt,
J ¼ 1.9, 8.5 Hz, 2H), 7.92 (dt, J ¼ 1.9, 8.5 Hz, 2H), 8.12 (ddd, J ¼ 1.7, 2.4,
4.1 Hz, 1H), 8.64 (dd, J ¼ 1.5, 4.8 Hz, 1H), 8.94 (d, J ¼ 2.1 Hz, 1H),
exchange of hydroxyl proton with deuterated solvent; 13C NMR
(acetone-d6):
d
3.22 (s, 3H), 3.74 (s, 3H), 6.72 (ddd, J ¼ 0.9, 2.0, 7.9 Hz,
(acetone-d6): d 38.6, 114.6, 115.2, 117.9, 124.7, 128.3, 129.4, 130.4,
1H), 6.76 (t, J ¼ 2.4 Hz, 1H), 6.87 (ddd, J ¼ 0.9, 2.5, 8.4 Hz, 1H), 7.23 (t,
135.3, 135.4, 137.4, 143.1, 143.7, 149.1, 150.5, 158.6; HPLCeMS (ESI)
J ¼ 8.1 Hz,1H), 7.58e7.64 (m, 4H), 7.89e7.92 (m, 2H), 7.96 (dd, J ¼ 1.6,
m/z: [M þ H]þ 340.98.
2.7 Hz, 1H); 13C NMR (acetone-d6):
d 38.6, 55.7, 113.3, 113.6, 119.2,
123.8, 127.0, 127.3, 128.1, 129.4, 130.3, 136.0, 140.8, 141.2, 143.4, 160.9;
5.3.22. N-(3-Hydroxyphenyl)-N-methyl-4-(thiophen-2-yl)
benzenesulfonamide (9l)
GCeMS (EI) m/z: [M]þ 359.24.
The title compound was prepared by reaction of 4-bromo-N-(3-
hydroxyphenyl)-N-methylbenzenesulfonamide (12e) (200 mg,
0.58 mmol) with 2-thiopheneboronic acid (111 mg, 0.87 mmol),
cesium carbonate (567 mg, 1.74 mmol) and tetrakis(-
triphenylphosphine)palladium (13 mg, 11.25 ꢃ10ꢁ3 mmol) in DME/
EtOH/H2O (3 mL) according to method B. The residue was purified
5.3.19. N-(3-Hydroxyphenyl)-30-methoxy-N-methyl-[1,10-
biphenyl]-4-sulfonamide (9i)
The title compound was prepared by reaction of 4-bromo-N-(3-
hydroxyphenyl)-N-methylbenzenesulfonamide (12e) (90 mg,
0.26 mmol) with 3-methoxyphenylboronic acid (59 mg,

212
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
by silica gel column chromatography using n-hexane and EtOAc as
eluent (n-hexane/EtOAc 70:30) to afford 9l (124 mg, 0.36 mmol,
62%) as pale brown crystal. C17H15NO3S2; mp 146e148 ꢀC; IR (neat):
137.5, 138.8, 141.5, 146.0, 161.0, 161.3; HPLCeMS (ESI) m/z: [M þ H]þ
397.79.
3379, 1336, 1158, 1138 cmꢁ1
;
1H NMR (acetone-d6):
d
3.19 (s, 3H),
5.3.26. 30-Hydroxy-N-(3-hydroxybenzyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9p)
6.61 (ddd, J ¼ 0.9, 2.2, 8.1 Hz, 1H), 6.70 (t, J ¼ 2.3 Hz, 1H), 6.77 (ddd,
J ¼ 0.9, 2.4, 8.2 Hz,1H), 7.13 (t, J ¼ 8.1 Hz,1H), 7.19 (dd, J ¼ 3.6, 5.1 Hz,
1H), 7.57e7.61 (m, 3H), 7.65 (dd, J ¼ 1.0, 3.6 Hz, 1H), 7.85 (dt, J ¼ 2.0,
The title compound was prepared by reaction of 30-methoxy-N-
(3-methoxybenzyl)-N-methyl-[1,10-biphenyl]-4-sulfonamide (9o)
(240 mg, 0.6 mmol) with Et3N (1.67 mL, 12 mmol) and with
BF3$SMe2 (1.26 mL, 12 mmol) in CH2Cl2 (10 mL) according to
method C. The residue was purified by silica gel column chroma-
tography using n-hexane and EtOAc as eluent (n-hexane/EtOAc
60:40) to afford 9p (202 mg, 0.55 mmol, 91%) as pale brown solid.
8.7 Hz, 2H), 8.53 (br s, 1H); 13C NMR (acetone-d6):
d 38.6, 114.6,
115.2, 118.0, 126.3, 126.4, 128.0, 129.5, 129.6, 130.3, 136.2, 139.4,
142.8, 143.8, 158.5; HPLCeMS (ESI) m/z: [M]þ 345.92.
5.3.23. 30-Hydroxy-N-(3-methoxyphenyl)-N-methyl-[1,10-
biphenyl]-4-sulfonamide (9m)
C
20H19NO4S; mp 180e181 ꢀC; IR (neat): 3285, 2976, 2923, 2880,
2856, 1590, 1483, 1453, 1321, 1304, 1296, 1148, 1085, 835, 768, 694,
584 cmꢁ1 1H NMR (acetone-d6):
2.65 (s, 3H), 4.15 (s, 2H), 6.78
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (12a) (356 mg,
1 mmol) with 3-hydroxyphenylboronic acid (207 mg, 1.5 mmol),
cesium carbonate (978 mg, 3 mmol) and tetrakis(triphenylphos-
phine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O
(3 mL) according to method B. The residue was purified by silica gel
column chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 60:40) to afford 9m (246 mg, 0.67 mmol, 67%) as
colorless crystal. C20H19NO4S; mp 109e112 ꢀC; IR (neat): 3378,
;
d
(ddd, J ¼ 0.8, 2.5, 8.2 Hz, 1H), 6.80e6.83 (m, 1H), 6.87e6.89 (m, 1H),
6.94 (ddd, J ¼ 0.9, 2.4, 8.2 Hz, 1H), 7.18 (t, J ¼ 7.9 Hz, 1H), 7.21 (t,
J ¼ 2.1 Hz, 1H), 7.22 (ddd, J ¼ 0.9, 1.6, 7.6 Hz, 1H), 7.33e7.37 (m, 1H),
7.89 (dt, J ¼ 2.2, 8.7 Hz, 2H), 7.94 (dt, J ¼ 2.2, 8.7 Hz, 2H), 8.37 (br s,
1H), 8.58 (br s, 1H); 13C NMR (acetone-d6):
d 34.9, 54.6, 114.9, 115.6,
115.9, 116.4, 119.3, 120.2, 128.5, 128.9, 130.5, 131.1, 137.5, 138.8, 141.6,
146.1, 158.6, 159.0; HPLCeMS (ESI) m/z: [M þ 1]þ 369.77.
1339, 1162, 1147 cmꢁ1; 1H NMR (acetone-d6):
d 3.22 (s, 3H), 3.73 (s,
3H), 6.71e6.74 (m, 2H), 6.86 (ddd, J ¼ 0.9, 2.5, 8.4 Hz,1H), 6.91 (ddd,
5.3.27. 3-Methoxy-N-(30-methoxy-[1,10-biphenyl]-4-yl)-N-
methylbenzenesulfonamide (9q)
J ¼ 0.9, 2.5, 8.2 Hz, 1H), 7.16e7.19 (m, 2H), 7.20e7.24 (m, 1H), 7.30e
7.34 (m, 1H), 7.62e7.65 (m, 2H), 7.78e7.81 (m, 2H), 8.55 (s, 1H); 13
C
The title compound was prepared by reaction of N-(4-
NMR (acetone-d6):
d
38.6, 55.7, 113.3, 113.7, 114.9, 116.4, 119.2, 119.3,
bromophenyl)-3-methoxy-N-methylbenzenesulfonamide
(12g)
128.0, 129.2, 130.3, 131.1, 136.5, 141.4, 143.9, 146.2, 158.9, 160.9; GCe
(356 mg, 1 mmol) with 3-methoxyphenylboronic acid (228 mg,
1.5 mmol), cesium carbonate (978 mg, 3 mmol) and tetrakis(-
triphenylphosphine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 50:50) to afford 9q (237 mg,
0.62 mmol, 62%) as orange oil. C21H21NO4S; IR (neat): 1349, 1171,
MS (EI) m/z: [M]þ 369.29.
5.3.24. 30-Hydroxy-N-(3-hydroxyphenyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9n)
The title compound was prepared by reaction of 30-methoxy-N-
(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-4-sulfonamide (9b)
(254 mg, 0.66 mmol) with Et3N (1.47 mL, 10.56 mmol) and with
BF3$SMe2 (1.11 mL, 10.56 mmol) in CH2Cl2 (10 mL) according to
method C. The residue was purified by silica gel column chroma-
tography using n-hexane and EtOAc as eluent (n-hexane/EtOAc
60:40) to afford 9n (230 mg, 0.65 mmol, 98%) as colorless crystal.
1151 cmꢁ1; 1H NMR (acetone-d6):
d 3.23 (s, 3H), 3.76 (s, 3H), 3.87 (s,
3H), 6.94 (ddd, J ¼ 0.9, 2.6, 8.2 Hz, 1H), 7.01 (dd, J ¼ 1.7, 2.5 Hz, 1H),
7.17e7.23 (m, 4H), 7.24 (dt, J ¼ 2.1, 8.7 Hz, 2H), 7.36 (t, J ¼ 7.9 Hz,1H),
7.48 (t, J ¼ 8.0 Hz, 1H), 7.64 (dt, J ¼ 2.1, 8.7 Hz, 2H); 13C NMR
(acetone-d6):
d 38.4, 55.6, 56.0, 113.2, 114.0, 120.01, 120.05, 120.7,
C
19H17NO4S; mp 120e124 ꢀC; IR (neat): 3380, 1335, 1160,
127.5, 128.1, 130.8, 131.0, 138.8, 140.5, 142.1, 142.3, 160.7, 161.2;
1146 cmꢁ1; 1H NMR (acetone-d6):
d
3.20 (s, 3H), 6.61 (ddd, J ¼ 0.9,
HPLCeMS (ESI) m/z: [M]þ 383.83.
2.0, 8.0 Hz, 1H), 6.70 (t, J ¼ 2.3 Hz, 1H), 6.77 (ddd, J ¼ 0.8, 2.4, 8.1 Hz,
1H), 6.92 (ddd, J ¼ 1.0, 2.3, 8.1 Hz, 1H), 7.13 (t, J ¼ 8.1 Hz, 1H), 7.17e
7.20 (m, 2H), 7.33 (t, J ¼ 7.8 Hz, 1H), 7.62e7.65 (m, 2H), 7.79e7.81
5.3.28. 3-Hydroxy-N-(30-hydroxy-[1,10-biphenyl]-4-yl)-N-
methylbenzenesulfonamide (9r)
(m, 2H), 8.50 (s, 1H), 8.57 (s, 1H); 13C NMR (acetone-d6):
d
38.6,
The title compound was prepared by reaction of 3-methoxy-N-
(30-methoxy-[1,10-biphenyl]-4-yl)-N-methylbenzenesulfonamide
(9q) (200 mg, 0.52 mmol) with Et3N (1.67 mL, 12 mmol) and with
BF3$SMe2 (1.26 mL, 12 mmol) in CH2Cl2 (10 mL) according to
method C. The residue was purified by silica gel column chroma-
tography using n-hexane and EtOAc as eluent (n-hexane/EtOAc
60:40) to afford 9r (157 mg, 0.44 mmol, 85%) as pale brown crystal.
114.6, 114.9, 115.1, 116.4, 118.0, 119.3, 128.0, 129.2, 130.3, 131.1, 136.5,
141.4, 143.8, 146.1, 158.5, 158.9; GCeMS (EI) m/z: [M]þ 355.26.
5.3.25. 30-Methoxy-N-(3-methoxybenzyl)-N-methyl-[1,10-biphenyl]-
4-sulfonamide (9o)
The title compound was prepared by reaction of 4-bromo-N-(3-
methoxybenzyl)-N-methylbenzenesulfonamide (12f) (356 mg,
1 mmol) with 3-methoxyphenylboronic acid (228 mg, 1.5 mmol),
C
19H17NO4S; mp 150e154 ꢀC; IR (neat): 3376, 2973, 2939, 2880,
2814, 1739, 1690, 1602, 1592, 1478, 1450, 1338, 1306, 1260, 1210,
1168, 1146, 1088, 837, 785, 685, 588 cmꢁ1 1H NMR (acetone-d6):
cesium carbonate (978 mg,
3
mmol) and tetrakis(-
;
triphenylphosphine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 9o (254 mg,
0.64 mmol, 64%) as orange oil. C22H23NO4S; IR (neat): 1338,
d
3.22 (s, 3H), 6.85 (ddd, J ¼ 1.0, 2.2, 8.2 Hz, 1H), 7.02 (t, J ¼ 1.9 Hz,
1H), 7.08 (ddd, J ¼ 1.0, 1.7, 7.7 Hz, 1H), 7.11e7.14 (m, 3H), 7.23 (dt,
J ¼ 2.2, 8.7 Hz, 2H), 7.28 (t, J ¼ 8.2 Hz,1H), 7.39 (t, J ¼ 7.7 Hz,1H), 7.59
(dt, J ¼ 2.2, 8.7 Hz, 2H), 8.72 (br s, 2H); 13C NMR (acetone-d6):
d 38.5,
114.5, 115.2, 115.5, 118.9, 119.7, 120.9, 127.5, 127.9, 130.9, 131.0, 138.8,
1158 cmꢁ1; 1H NMR (acetone-d6):
d
2.65 (s, 3H), 3.77 (s, 3H), 3.90 (s,
140.4, 142.0, 142.3, 158.6, 158.8; HPLCeMS (ESI) m/z: [M]þ 355.82.
3H), 4.20 (s, 2H), 6.87 (ddd, J ¼ 0.6, 2.5, 8.2 Hz, 1H), 6.91e6.95 (m,
2H), 7.03 (ddd, J ¼ 0.9, 2.6, 8.3 Hz, 1H), 7.28 (t, J ¼ 7.7 Hz, 1H), 7.30 (t,
J ¼ 1.7 Hz, 1H), 7.32 (ddd, J ¼ 1.0, 1.6, 7.6 Hz, 1H), 7.45 (t, J ¼ 8.1 Hz,
5.3.29. 30-Methoxy-N-(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-
3-sulfonamide (10a)
The title compound was prepared by reaction of 3-bromo-N-(3-
methoxyphenyl)-N-methylbenzenesulfonamide (13a) (356 mg,
1H), 7.92e7.97 (m, 4H); 13C NMR (acetone-d6):
d
35.0, 54.7, 55.5,
55.7, 113.6, 114.1, 114.6, 115.0, 120.4, 121.3, 128.6, 128.9, 130.5, 131.1,

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
213
1 mmol) with 3-methoxyphenylboronic acid (228 mg, 1.5 mmol),
cesium carbonate (978 mg, 3 mmol) and tetrakis(triphenylphos-
phine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in DME/EtOH/H2O
(3 mL) according to method B. The residue was purified by silica gel
column chromatography using n-hexane and EtOAc as eluent (n-
hexane/EtOAc 80:20) to afford 10a (271 mg, 0.71 mmol, 71%) as
chromatography using n-hexane and EtOAc as eluent (n-hexane/
EtOAc 60:40) to afford 10d (136 mg, 0.38 mmol, 53%) as orange oil.
C19H17NO4S; IR (neat): 3379, 2941, 2873, 2814, 2696, 1690, 1598,
1590,1577, 1474,1450,1418,1338,1306, 1259,1231,1164,1146,1088,
1072, 996, 937, 900, 856, 782, 751, 699, 685, 607, 582 cmꢁ1; 1H NMR
(acetone-d6):
d
3.26 (s, 3H), 6.85 (ddd, J ¼ 0.9, 2.5, 8.1 Hz, 1H), 7.02e
yellow oil. C21H21NO4S; IR (neat): 1349, 1165, 1149 cmꢁ1
;
1H NMR
7.05 (m, 3H), 7.08 (ddd, J ¼ 1.0, 1.6, 7.6 Hz, 1H), 7.11e7.14 (m, 2H),
7.26 (dt, J ¼ 0.5, 7.3 Hz, 1H), 7.37e7.42 (m, 3H), 7.53 (ddd, J ¼ 1.0, 1.8,
7.8 Hz, 1H), 8.62 (br s, 1H), 8.84 (br s, 1H); 13C NMR (acetone-d6):
(acetone-d6): 3.22 (s, 3H), 3.73 (s, 3H), 3.85 (s, 3H), 6.74e6.76 (m,
d
2H), 6.89 (ddd, J ¼ 1.0, 2.3, 8.3 Hz, 1H), 6.97 (ddd, J ¼ 0.9, 2.6, 8.2 Hz,
1H), 7.06 (t, J ¼ 2.0 Hz, 1H), 7.11 (ddd, J ¼ 0.9, 1.6, 7.6 Hz, 1H), 7.26 (t,
J ¼ 8.1 Hz, 1H), 7.39 (t, J ¼ 8.1 Hz, 1H), 7.61e7.68 (m, 3H), 7.95 (ddd,
d
38.6, 114.7, 115.2, 115.6, 119.0, 119.7, 120.9, 125.9, 126.0, 126.4,
130.0, 130.8, 131.0, 138.8, 142.5, 142.6, 143.3, 158.6, 158.8; HPLCeMS
(ESI) m/z: [M]þ 355.88.
J ¼ 1.3, 1.9, 7.6 Hz, 1H); 13C NMR (acetone-d6):
d 38.6, 55.71, 55.72,
113.36, 113.38, 113.7, 114.7, 119.3, 120.2, 126.9, 127.4, 130.35, 130.43,
131.0, 132.4, 138.0, 141.5, 142.6, 143.9, 160.9, 161.3; HPLCeMS (ESI)
m/z: [M þ H]þ 383.85.
5.3.33. 4-Fluoro-3-methoxy-N-(30-methoxybiphenyl-3-yl)-N-
methylbenzenesulfonamide (10e)
The title compound was prepared by reaction of N-(3-
bromophenyl)-4-fluoro-3-methoxy-N-methylbenzenesulfonamide
(13c) (374 mg, 1 mmol) with 3-methoxyphenylboronic acid
(228 mg, 1.5 mmol), cesium carbonate (978 mg, 3 mmol) and tet-
rakis(triphenylphosphine)palladium (23 mg,19.90 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 10e (308 mg,
0.77 mmol, 77%) as yellow oil. C21H20FNO4S; IR (neat): 1345, 1169,
5.3.30. 30-Hydroxy-N-(3-hydroxyphenyl)-N-methyl-[1,10-biphenyl]-
3-sulfonamide (10b)
The title compound was prepared by reaction of 30-methoxy-N-
(3-methoxyphenyl)-N-methyl-[1,10-biphenyl]-3-sulfonamide (10a)
(261 mg, 0.68 mmol) with Et3N (1.67 mL, 12 mmol) and with
BF3$SMe2 (1.26 mL,12 mmol) in CH2Cl2 (10 mL) according to method
C. The residue was purified by silica gel column chromatography
using n-hexane and EtOAc as eluent (n-hexane/EtOAc 60:40) to
afford 10b (221 mg, 0.62 mmol, 91%) as orange oil. C19H17NO4S; IR
(neat): 3380, 2961, 2934, 2863, 2816, 1699, 1594, 1484, 1462, 1457,
1412, 1338, 1308, 1206, 1161, 1146, 1083, 1065, 999, 944, 910, 865,
1150 cmꢁ1; 1H NMR (acetone-d6):
d 3.27 (s, 3H), 3.78 (s, 3H), 3.85 (s,
3H), 6.94 (ddd, J ¼ 0.7, 2.5, 8.3 Hz, 1H), 7.05e7.08 (m, 1H), 7.10e7.14
(m, 2H), 7.20 (ddd, J ¼ 0.8, 2.0, 8.0 Hz, 1H), 7.22e7.25 (m, 1H), 7.31e
7.40 (m, 3H), 7.45 (t, J ¼ 7.9 Hz, 1H), 7.58e7.61 (m, 1H); 13C NMR
779, 692, 637, 593, 576 cmꢁ1; 1H NMR (acetone-d6):
d 3.21 (s, 3H),
6.61 (ddd, J ¼ 1.0, 2.2, 8.1 Hz, 1H), 6.71 (t, J ¼ 2.2 Hz, 1H), 6.78 (ddd,
J ¼ 0.9, 2.5, 8.2 Hz, 1H), 6.89 (ddd, J ¼ 0.9, 2.5, 8.2 Hz, 1H), 7.03e7.06
(m, 2H), 7.15 (t, J ¼ 8.1 Hz,1H), 7.29 (dt, J ¼ 0.4, 7.7 Hz,1H), 7.57 (ddd,
J ¼ 1.2, 1.8, 7.8 Hz, 1H), 7.65 (dt, J ¼ 0.6, 7.9 Hz, 1H), 7.69 (t, J ¼ 1.9 Hz,
1H), 7.91 (ddd, J ¼ 1.3, 1.9, 7.8 Hz, 1H), 8.52 (br s, 1H), 8.53 (br s, 1H);
(acetone-d6): d 38.6, 55.6, 56.7, 113.3, 113.85. 113.88, 114.2, 117.0,
117.2, 120.1, 122.06, 122.13, 126.0, 126.6, 126.8, 130.2, 130.8, 133.76,
133.79,142.4,142.6,143.2,148.7,148.8,154.7,156.7,161.2; HPLCeMS
(ESI) m/z: [M]þ 401.76.
13C NMR (acetone-d6):
d
38.6, 116.66, 116.75, 115.2, 116.1, 117.9, 119.1,
5.3.34. 4-Fluoro-3-hydroxy-N-(30-hydroxybiphenyl-3-yl)-N-
methylbenzenesulfonamide (10f)
126.7, 127.3, 130.32, 130.35, 131.1, 132.1, 138.2, 141.5, 142.6, 143.8,
158.6, 158.9; HPLCeMS (ESI) m/z: [M]þ 355.95.
The title compound was prepared by reaction of 4-fluoro-3-
methoxy-N-(30-methoxybiphenyl-3-yl)-N-methyl-
5.3.31. 3-Methoxy-N-(30-methoxy-[1,10-biphenyl]-3-yl)-N-
methylbenzenesulfonamide (10c)
benzenesulfonamide (10e) (308 mg, 0.77 mmol) with Et3N
(1.67 mL, 12 mmol) and with BF3$SMe2 (1.26 mL, 12 mmol) in
CH2Cl2 (10 mL) according to method C. The residue was purified by
silica gel column chromatography using n-hexane and EtOAc as
eluent (n-hexane/EtOAc 70:30) to afford 10f (204 mg, 0.55 mmol,
71%) as colorless solid. C19H16FNO4S; mp 148e150 ꢀC; IR (neat):
The title compound was prepared by reaction of N-(3-
bromophenyl)-3-methoxy-N-methylbenzenesulfonamide
(13b)
(356 mg, 1 mmol) with 3-methoxyphenylboronic acid (228 mg,
1.5 mmol), cesium carbonate (978 mg, 3 mmol) and tetrakis(-
triphenylphosphine)palladium (23 mg, 19.90 ꢃ 10ꢁ3 mmol) in
DME/EtOH/H2O (3 mL) according to method B. The residue was
purified by silica gel column chromatography using n-hexane and
EtOAc as eluent (n-hexane/EtOAc 80:20) to afford 10c (302 mg,
0.79 mmol, 79%) as yellow oil. C21H21NO4S; IR (neat): 1349, 1166,
3380, 2959, 2868, 1348, 1310, 1231, 1171, 1151 cmꢁ1
(acetone-d6):
;
1H NMR
d
3.26 (s, 3H), 6.85 (ddd, J ¼ 0.9, 2.5, 8.1 Hz, 1H), 7.03e
7.06 (m, 2H), 7.10e7.15 (m, 2H), 7.18 (dd, J ¼ 2.3, 8.1 Hz, 1H), 7.25e
7.33 (m, 2H), 7.39e7.43 (m, 2H), 7.54 (ddd, J ¼ 1.0, 1.8, 7.6 Hz, 1H),
8.48 (br s, 1H), 9.36 (br s, 1H); 13C NMR (acetone-d6):
d 38.5, 114.7,
1150 cmꢁ1; 1H NMR (acetone-d6):
d
3.27 (s, 3H), 3.75 (s, 3H), 3.85 (s,
115.6, 117.35, 117.51, 118.24, 118.27, 119.0, 121.06, 121.12, 125.96,
126.1, 126.5, 130.1, 130.9, 133.96, 133.99, 142.4, 142.6, 143.1, 146.1,
146.2, 154.1, 156.1, 158.8; HPLCeMS (ESI) m/z: [M]þ 373.91.
3H), 6.94 (ddd, J ¼ 0.9, 2.6, 8.3 Hz, 1H), 7.00 (dd, J ¼ 1.8, 2.5 Hz, 1H),
7.06 (t, J ¼ 1.8 Hz, 1H), 7.11 (ddd, J ¼ 1.0, 1.6, 7.6 Hz, 1H), 7.17e7.21
(m, 2H), 7.23 (ddd, J ¼ 0.9, 2.6, 8.3 Hz,1H), 7.33e7.35 (m, 1H), 7.36 (t,
J ¼ 7.9 Hz, 1H), 7.43 (t, J ¼ 7.9 Hz, 1H), 7.50 (t, J ¼ 8.0 Hz, 1H), 7.58
5.4. Physicochemical properties determination
(ddd, J ¼ 1.0, 1.7, 7.8 Hz, 1H); 13C NMR (acetone-d6):
d 38.6, 55.6,
56.0, 113.3, 113.4, 114.1, 120.0, 120.1, 120.8, 125.8, 126.6, 126.7, 130.1,
130.8, 131.0, 138.7, 142.4, 142.6, 143.3, 160.7, 161.2; HPLCeMS (ESI)
m/z: [M þ H]þ 383.88.
The log P and pKa values were calculated from ACD/Labs Per-
cepta 2012 Release program and experimentally determined using
SiriusT3 apparatus from Sirius Analytical Instruments.
The logarithm of partition constant P (log P) was calculated
using the “GALAS” method (Global, Adjusted Locally According to
Similarity). The program predicts clog P by comparing the molecule
with structurally similar molecules where experimental data are
known. The logarithm of dissociation constant Ka (pKa) was ob-
tained using the classical method where Hammet-type equations
5.3.32. 3-Hydroxy-N-(30-hydroxy-[1,10-biphenyl]-3-yl)-N-
methylbenzenesulfonamide (10d)
The title compound was prepared by reaction of 3-methoxy-N-
(30-methoxy-[1,10-biphenyl]-3-yl)-N-methylbenzenesulfonamide
(10c) (275 mg, 0.72 mmol) with Et3N (1.67 mL, 12 mmol) and with
BF3$SMe2 (1.26 mL, 12 mmol) in CH2Cl2 (10 mL) according to
method C. The residue was purified by silica gel column
and electronic substituent constants (
values for ionizable groups.
s) are used to calculate pKa

214
E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
The solubility elog S was experimentally determined using Sir-
026. These data include MOL files and InChiKeys of the most
important compounds described in this article.
iusT3 apparatus from Sirius Analytical Instruments at 25 ꢀC in a
solution of in KCl 1.15 M solution. Solubility S was given in mol/L
and it was obtained using the following equation: S ¼ 10logS
.
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Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2013.08.

E. Perspicace et al. / European Journal of Medicinal Chemistry 69 (2013) 201e215
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2
3
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3
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