SAR studies on new bis-aryls 5-HT7 ligands: Synthesis and molecular modeling

Article abstract of DOI:10.1016/j.bmc.2010.01.035

Structure-activity relationships of a series of bis-arylic compounds, investigated as 5-HT₇R ligands, are reported. The main structural modifications involved a central aryl moiety (phenyl, pyridine, diazine, triazine) and the nature and positi

Full text of DOI:10.1016/j.bmc.2010.01.035

Bioorganic & Medicinal Chemistry 18 (2010) 1958–1967
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
SAR studies on new bis-aryls 5-HT7 ligands: Synthesis and molecular modeling
c,
b
Eduard Badarau a,b, Ryszard Bugno c, Franck Suzenet a, , Andrzej J. Bojarski , Adriana-Luminita Finaru ,
*
*
Gérald Guillaumet a
a Institut de Chimie Organique et Analytique, Université d’Orléans, UMR-CNRS 6005, BP 6759, rue de Chartres, 45067 Orléans cedex 2, France
b Centrul de Cercetare ‘Chimie Aplicata˘ ßsi Inginerie de Proces’, Universitatea din Baca˘u, Calea Ma˘ra˘ßsesti, nr. 157, 600115 Baca˘u, Romania
c Institute of Pharmacology, Polish Academy of Sciences, Sme˛tna 12, Kraków 31-343, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationships of a series of bis-arylic compounds, investigated as 5-HT7R ligands, are
reported. The main structural modifications involved a central aryl moiety (phenyl, pyridine, diazine, tri-
azine) and the nature and position of an amine-containing aliphatic chain. The affinity of the synthesized
Received 21 September 2009
Revised 13 January 2010
Accepted 14 January 2010
Available online 18 January 2010
compounds (26 nM–10
arylic ligands and rationalized by a ligand-based pharmacophore approach.
Ó 2010 Elsevier Ltd. All rights reserved.
lM) was systematically correlated with other previously reported series of bis-
Keywords:
5-HT7 receptors
Bis-aryls
SAR
Molecular modeling
1. Introduction
models have been published,3–8 and they are characterized by the
presence of at least four pharmacophore features: a positive ion
(PI, a basic nitrogen proven to interact with an Asp residue in the
binding site), a hydrogen-bond acceptor (HBA, usually an oxygen
or an aromatic nitrogen) and two hydrophobic regions (HYD, aro-
matic or aliphatic, specific to each reported model). Beside the PI fea-
ture (mandatory for all the monoamine-type neurotransmitters or
ligands), it has to be stressed that all the previously 5-HT7 validated
models also included an HBA feature. However, a significant number
of potent ligands do not have hydrogen-bond acceptor groups. Thus,
Due to serotonin’s multiple implications in many physiological
processes in both the CNS and at periphery,1 the discovery of po-
tent and selective serotoninergic ligands keeps motivating the sci-
entific community. Since the crystal structure of its receptors is
still unresolved, many of the newly discovered serotoninergic hits
were identified via a high-throughput screening (HTS) approach.
Subsequently, these hits were improved in terms of their biological
properties by various structural modifications. Identification of the
essential chemical features of ligands, indispensable to their bio-
logical activity seems of crucial importance, as it allows a rational
design of future derivatives. One of the most straightforward
methods consists in conducting different simplifications on more
complex, biologically active, chemical structures. In the case of 5-
HT7 receptors, such simplifications led Rault and co-workers to dis-
cover the bis-aryl compound 3 (Fig. 1).2 Using the same approach,
we are presenting the design, synthesis and SAR studies of new bis-
aryl 5-HT7 receptor ligands.
O
O
O
O
simplification 1
N
N
1
2
One of the several methods for rationalizing SAR data, which has
proven its efficacy in the case of transmembrane receptors, is the
pharmacophore-based approach. This method helps to better
understand ligand-protein interactions through the discovery of a
common binding pattern (a pharmacophore model) of particular
classes of ligands. In the case of 5-HT7Rs, several pharmacophore
simplification 2
O
O
N
3
* Corresponding authors.
E-mail addresses: franck.suzenet@univ-orleans.fr (F. Suzenet), bojarski@if-
pan.krakow.pl (A.J. Bojarski).
Figure 1. Rational simplifications of aporphine-based ligand 1 leading to discovery
of bis-arylic ligand 3.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.01.035

E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
1959
on the basis of a representative group of those ligands, we generated
3 steps
46-69%
5a
N
N
N
N
a pharmacophore model devoid of the HBA feature and used it for
rationalizing the activity of newly synthesized bis-aryl derivatives.
This model, complementary to the classical one, could give a more
general insight into the binding within 5-HT7Rs.
N
N
a or b
Me
O
SMe
Ar
S
O
, X = S, Ar = C6H5, 95%
5b, X = S, Ar = 2,6-diMeC6H3, 91%
2. Results and discussion
2.1. Chemistry
N
N
N
5c
5d
, X = S, Ar = 2,6-diMeOC6H3, 85
%
Ar
N
X
, X = O, Ar = C6H5, 89%
5e, X = O, Ar = 2,6-diMeC6H3, 70%
The first series of compounds were designed on a pyridine scaf-
fold. Starting from the commercially available 2,6-dibromopyri-
5f
, X = O, Ar = 2,6-diMeOC6H3, 81
%
dine,
a first substitution step of one bromine with the
corresponding aminoalkyl chain led to intermediates 4a and 4b.
The resulting derivatives were subsequently engaged in a Suzuki-
coupling reaction with various boronic acids to give the desired fi-
nal compounds 4c–f (Scheme 1).
1) c
2) a
N
N
N
N
N
SMe
Ar
N
SMe
Ar
N
S
6
5g, Ar = 2,6-diMeOC6H3, 67%
Other derivatives built on a triazine and diazine scaffold were
subsequently synthesized. Using the triazine chemistry, we chose
an SNAr approach with a methylsulfonyl function as a leaving
group and the desired aminoalkyl chain as a nucleophile.9 Thus,
3-methylsulfanyl-1,2,4-triazine and 2-methylsulfanyl-1,3-diazine
were arylated at positions C5 and C4, respectively, following proto-
cols previously described in the literature.10,11 The oxidation of
thiomethyl moieties to the corresponding sulfones with m-CPBA
in dichloromethane, and the subsequent substitution of methyl-
sulfones with the aminoalkyl chains led to the desired final deriv-
atives 5a–g (Scheme 2).
Subsequent modulations involved different aryl substituents in
the ortho position to the aliphatic chain. Following the previously
described synthetic route, the desired compounds 8d–i were ob-
tained in two steps: alkylation of the corresponding bromothi-
ophenol or bromophenol with 1-dimethylamino-2-chloroethane,
and subsequent arylation of the halogenated substrate via a palla-
dium-catalyzed cross coupling step (Scheme 3).
Scheme 2. Reagents and conditions: (a) dimethylaminoethanethiol, triethylamine,
DCM, 12 h, 0 to 25 °C; (b) dimethylaminoethanol, NaH, THF, 1 h, 0–25 °C. (c) m-
CPBA, DCM, 3 h, 0 to 25 °C, 85% (7).
a
Br
Br
N
XH
X
8a, 2-Br, X = S, 74%
8b
, 2-Br, X = O, 60%
, 3-Br, X = S, 74%
8c
b
R
N
X
8d
, X = S, R = 2-C6H5, 75%
8e, X = O, R = 2-C6H5, 62%
A last series of compounds were obtained starting with the pre-
viously synthesized methylsulfonyl diazine/triazine intermediates
(described in Scheme 2). Those sulfones reacted with vinylmagne-
sium bromide under anhydrous conditions. The 1,4-addition of
secondary amines to the resulting vinylhetaryl derivatives 9 pro-
ceeded smoothly at room temperature, and led to the desired
derivatives 10a–d in good yields (Scheme 4).
8f
, X = O, R = 2-(2-MeOC6H4), 63%
8g, X = S, R = 2-(2,6-diMeC6H3), 62%
8h, X = S, R = 3-C6H5, 91%
8i
, X = S, R = 3-(2,6-diMeC6H3), 69%
Scheme 3. Reagents and conditions: (a) 1-dimethylamino-2-chloroethane, NaOH,
EtOH, H2O, 3 h, 80 °C; (b) ArB(OH)2, Pd(PPh3)4, satd NaHCO3, toluene/EtOH, 12 h,
110 °C.
2.2. Biological evaluation and molecular modeling
Our studies into designing new compounds with 5-HT7Rs prop-
erties started from a series of 8-azachromanes 11, previously syn-
Y
N
Y
N
a
N
N
S
Ar
Ar
O
O
a
9a, Y = N, Ar = Ph
91%
96%
N
Br
N
Br
Br
N
X
9b
, Y = N, Ar = 2,6-diMeC6H3
9c, Y = N, Ar = 2,6-diMeOC6H3 96%
4a, X = S, 73%
4b, X = O, 80%
9d
, Y = CH, Ar = 2,6-diMeOC6H3 96%
b
Y
N
b
N
N
X
R
N
Ar
NMe2
4c, X = S, R = 2,6-diMeC6H3, 75%
4d, X = O, R = 2,6-diMeC6H3, 67%
4e, X = S, R = 3-Furyl, 49%
10a
, Y = N, Ar = Ph
10b, Y = N, Ar = 2,6-diMeC6H3
10c
67%
79%
68%
, Y = N, Ar = 2,6-diMeOC6H3
4f, X = S, R = C6H5, 89%
10d, Y = CH, Ar = 2,6-diMeOC6H3 89%
Scheme 1. Reagents and conditions: (a) dimethylaminoethanol/ethanethiol, NaH,
THF, 12 h, 0–25 °C; (b) ArB(OH)2, Pd(PPh3)4, satd NaHCO3, toluene/EtOH, 12 h,
110 °C.
Scheme 4. Reagents and conditions: (a) vinylmagnesium bromide, THF, 30 min,
À78 °C; (b) dimethylamine, MeOH, 1 h, 35 °C.

1960
E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
thesized in our laboratory.12 Those molecules were developed as
analogs of the potent 5-HT7 receptor ligands A and B (Fig. 2), ini-
tially reported by Johansson,13,14 yet with an aryl substituent in
an unexplored position on the central scaffold. Unfortunately, 8-
azachroman bioisosters 11 were found inactive at 5-HT7 receptors
(Ki >10,000 nM).
Table 1
Binding affinities for pyridinic analogs 4
N
R
N
X
Compound
X
R
5-HT7 Kia,b (nM)
5-HT1A Kia,c (nM)
Apart from the similarity to the chromane-based 5-HT7 ligands
A and B,13,14 the 8-azachromanes are also related to the potent 5-
HT7 agent 4f described by Thomson et al. (Fig. 3).15 For instance, in
the particular case of compound 11a, the difference in the 5-HT7R
affinity between these two compounds (11a and 4f) could be ex-
plained by either (i) a more flexible structure allowing different
positioning of the amine inside the protein binding site, or (ii)
the heteroatom change in the ortho position to the aromatic nitro-
gen (O instead of S), or (iii) the di-ortho-methyl substituent on the
aryl. To verify the two latter hypotheses, we synthesized the easily
accessible derivatives 4c and 4d, as intuitively shown in the
Figure 3.
4a
4b
4c
4d
4e
4f
S
O
S
O
S
S
Br
Br
37 (4.1d)
2240
128
133
902
927
7220
28
2,6-diMeC6H3
2,6-diMeC6H3
3-Furyl
1614
26
C6H5
6.2 (0.6d)
43
a
Values are means of three experiments run in triplicate, SEM 6 16%.
Competition binding experiments for cloned human 5-HT7 receptors (stably
expressed in HEK-293 cells).
b
c
Competition binding experiments for native serotonin 5-HT1A receptors (rat
hippocampus).
Values reported in the literature.15
d
The various compounds, synthesized according to Scheme 1,
were tested in competition binding experiments, following the
previously published procedures16 (Table 1).
gen atom may partly explain the decrease in the activity of our ini-
tial 8-azachroman derivatives 11.
In the sulfur series, the hypothesis about the enhanced selectiv-
ity profile over the 5-HT1ARs, induced by an increased torsion angle
between the planes of the two aryl rings (a consequence of the
disubstitution on the aryl substituent)—as stated earlier in the lit-
erature,13 was verified. The selectivity ratio remains constant to a
value of seven when passing from compound 4f to compound 4c,
which suggests that these ligands bind differently compared to
aporphine derivatives and their simplified chroman analogs. Final-
ly, furyl proved to be a good substituent that could be accommo-
dated in the 5-HT7Rs binding site, most probably through a
hydrophobic/aromatic interaction, like in the case of the phenyl
substituent.
A direct comparison between compounds 4a/4b or 4c/4d shows
a 70-fold and a 100-fold decrease in affinity, respectively, caused
by the replacement of sulfur with oxygen. Therefore, the hydro-
phobic zone proves mandatory in this region of the molecule.
The negative impact on binding caused by the presence of an oxy-
NMe2
NMe2
O
OMe
MeO
O
As initially remarked by Thomson,15 the affinity for the 5-HT7
receptors is extremely sensitive to the variation of the central scaf-
fold. Since the nitrogen between meta substituents seemed essen-
tial for good affinity, we introduced supplementary nitrogen atoms
in previously unexplored positions, and synthesized 1,3-diazine
and 1,2,4-triazine analogs (see Scheme 2).
A , Ki = 13.4 nM
B, Ki = 2.55 nM
R"
N
R'
R"
Unfortunately compounds 5a–g were devoid of affinity for 5-
HT7Rs (Ki >10,000 nM), proving that additional nitrogens have a
negative impact on the 5-HT7 binding.
N
O
11
, Ki > 10000 nM
R'
Then, starting with simplification of the rigid skeleton of
Johansson’s chroman 12 (Fig. 4), the importance of the heteroatom
(S or O) in the ortho position to the aryl substituent on 5-HT7R
affinity was analyzed (Scheme 3, Table 2).
Following the same approach, the parent compound 12 was
simplified to bis-aryls 10 (Fig. 5). Since Rault and co-workers had
shown active derivatives in the carbocyclic series,2 taking advan-
tage of the availability of some previously synthesized intermedi-
ates, we explored the affinity profile of their heterocyclic analogs
(Scheme 4, Table 3).
R' = Me, OMe
R"= Me, Et, Pr
Figure 2. Similarity between our derivatives 11 and the previously reported 5-HT7
ligands A and B.
aryl
N
N
variation
N
S
N
S
4f
, Ki = 6.2 nM
4c
simplification
heteroatom
change
NR2
NR2
O
X
simplification
N
N
O
X = O, S
Ar
Ar
N
O
N
8
12
heteroatom
change
4d
11a, Ki > 10000 nM
Figure 4. Design of the simplified bis-aryl structures 8 in correlation with the
ligands of Johansson 12.
Figure 3. An intuitive design of the simplified oxygenated analog 4d.

E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
1961
Table 2
3D conformations for the input ligands, generated via a stochas-
tic research coupled to a polling method as implemented in Dis-
covery Studio19 (the ‘Best’ generation routine), were used in the
‘Common Feature Pharmacophore Generation’ protocol in order
to construct different pharmacophore hypotheses. At least one of
the following features was imposed during the pharmacophore
search: Hydrophobic (HYD), Hydrophobic aromatic (HYD_Ar),
Hydrophobic alifatic (HYD_alif) and Positive ionisable (PI). The
top 10 ranked pharmacophores (energy threshold = 20 Kcal, inter-
site distance = 2.0 Å) were subjected to a careful analysis in order
to comply with the SAR data described in the literature. For exam-
ple, particular attention was devoted to the fitting of one aromatic
methyl substituent of compound 16 to the HYD feature; the
hypothesis that led to the fitting of the aromatic ring substituent
to the HYD area was rejected, since the phenyl analog of 16 was re-
ported by Johansson to be inactive.14 On the basis of internal fitting
scores (see Table 4 for details), we selected the hypothesis (Hyp1)
shown in Figure 7A.
Binding affinities for compounds 8
N
X
R
Compound
X
R
5-HT7 Kia (nM)
8a
8b
8d
8e
8f
S
O
S
O
O
S
Br
Br
C6H5
C6H5
4110
2663
553
156
669
2-MeOC6H4
2,6-diMeC6H3
8g
1429
a
See Table 1 for details.
heteroatom
introduction
A similar hypothesis (Hyp2) was generated with compound 19
excluded from the training set. Because of differences in the 3D
arrangement of the selected features, both hypotheses were fur-
ther used during our study. Matrix distances between the chemical
features are represented in Table 5.
NR2
NR2
N
O
Ar
Ar
simplification
Since the new compounds are related to those from the training
set, they often fit well into the model, showing good scoring values.
That phenomenon was observed, for example, for 8-azachroman
derivatives, (Fig. 8A), and for disubstituted phenyl triazine or dia-
zine derivatives (5b, 5c, 5e, 5f, 5g). However, the latter derivatives
10
12
Figure 5. Design of the simplified heteroaromatic bis-aryls in correlation with the
ligands of Johansson13 and Rault.2
Table 3
Binding affinities for compounds 10
Y
N
15
13
14
Ar
N
NMe2
O
Compound
Y
R
5-HT7 Kia (nM)
NPr2
NPr2
NPr2
O
10a
10b
10c
10d
N
N
N
CH
C6H5
>10,000
>10,000
>10,000
1485
2,6-diMeC6H3
2,6-diMeOC6H3
2,6-diMOeC6H3
a
NMe2
N
See Table 1 for details.
N
S
N
N
16
The above-mentioned compounds were synthesized following
4f
the steps described in Schemes 3 and 4 and were tested for their
affinity for the 5-HT7 receptors (Tables 2 and 3).
N
S
Interestingly, unlike S over O preference in the case of meta-
substituted compounds (see Table 1), for the ortho derivatives
the affinity of the oxygenated compounds was higher than that
of their sulfur analogs (see couples 8a/8b or 8d/8e, Table 2). Unex-
pectedly, the affinity of the simplified structures 8e and 8f de-
creased dramatically (approx. 100-fold) compared to the data
published for the reference ligands.13 Furthermore, the poly-nitro-
genated compounds 10a–d showed a strong decrease in their
activity.
N
S
17
S
18
N
19
Figure 6. Compounds selected for the training set.
Taking account of all the affinity results and the data reported in
the literature, at this stage of our study we decided to develop a
pharmacophore model to rationalize the structure–activity
relationships.
One of the most important steps in designing a ligand-based
pharmacophore model is the choice of compounds for the ‘training
set’. The vast majority of derivatives with 5-HT7 activity described
in the literature17,18 include oxygen or aromatic nitrogen atoms
that could act as potential HBA features. However, as already men-
tioned in the Section 1, there are also potent ligands devoid of this
pharmacophore feature. Consequently, we selected a representa-
tive training set from among three classes of 5-HT7 agents (Fig. 6).
Table 4
Affinities and fitting scores for the training set
Compound
Ki (5-HT7)
FitValue (Hyp1)
FitValue (Hyp2)
13
14
15
16
4f
17
18
19
3.38
2.91
0.3
13.4
0.6
0.7
12.0
7.6
3.94
3.99
3.89
3.80
3.55
3.51
3.41
2.28
3.13
3.13
2.84
3.38
3.91
3.31
3.99
—

1962
E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
Figure 7. Compound 16 fitted to the selected hypotheses Hyp1 (A) and Hyp2 (B).
Table 5
Matrix distances for the selected hypothesis: Hyp1 and Hyp2
Figure 10. The mapping of compounds 8h (green) and 8i (magenta) with the
pharmacophore. Hydrogen atoms were omitted for clarity
Distances
PI
—
HYD
HYD_Ar
HYD_Alif
PI
HYD
HYD_Ar
HYD_Alif
6.65a
—
4.58a
5.39a
—
2.57a
5.71a
3.23a
—
6.67b
Table 6
6.25b
3.46b
4.99b
6.74b
Binding affinities for compounds 11a–c
3.89b
a
values obtained for Hyp1
Values obtained for Hyp2
N
b
R
X
S
Compound
X
R
5-HT7 Kia (nM)
5-HT1A Kia (nM)
4a
4f
8c
8h
8i
N
N
CH
CH
CH
Br
C6H5
Br
C6H5
2,6-diMeC6H3
37
6.2
511
116
284
133
43
676
516
2350
a
See Table 1 for details.
Figure 8. The mapping of the inactive 8-azachromans (A) and triazines 5b and 5c
(B) using hypothesis Hyp1.
were mapped differently (Fig. 8B), because the central polynitro-
gen ring cannot be accommodated to an HYD_Ar feature.
Since both 8-azachromans and triazine analogs were found to
be experimentally inactive, further tuning of the models was
necessary.
Figure 11. The superposition of the new pharmacophore model (gray centers) over
Rault’s7 (A, red centers) and Kolaczkowski’s8 (B, green centers) models.
The previously obtained pharmacophores were therefore sub-
mitted to a ‘Steric Refinement with Excluded Volumes’ step, using
as inactive compounds our pyrano-pyridine derivatives and tria-
zines (5b and 5c), as well as ligands 20 and 21 previously reported
by Thomson (Fig. 9). Default parameters, as implemented under DS
v2.1,19 were used. Of the two optimized models, Hyp2 with 16 ex-
cluded volumes was able to correctly discriminate between active
and inactive derivatives. In consequence, Hyp2 was the only model
used for the rest of our study.
New derivatives were designed in order to validate the newly
defined pharmacophore. As appears from the model analysis, the
central pyridine could be replaced with a phenyl moiety (Fig. 10),
thus compounds 8c, 8h and 8i were subsequently synthesized
(see Scheme 3, vide supra) and biologically evaluated (Table 6).
The 5-HT7 affinity of the new derivatives was well correlated with
the obtained fit values (2.46, 3.32 and 3.13 for 8c, 8h and 8i,
respectively). As can be seen in Figure 10, steric restrictions are lo-
cated in the vicinity of PI and outside HYD and HYD_Ar features.
Finally, the new pharmacophore model was compared with two
others, previously reported by Rault and Kolaczkowski (which
were regenerated following the same protocols as originally de-
scribed). In the first case (Fig. 11A), HYD1 and PI features are over-
lapping, while the other two hydrophobic regions of the new
hypothesis are well differentiated from Rault’s HYD2 feature. Inter-
estingly, these two hydrophobic regions and the PI feature are very
well superposed on similar features from the receptor-based phar-
macophore model proposed by Kolaczkowski (Fig. 11B). However,
our third HYD feature has a different spatial arrangement.
3. Conclusions
The present study describes interesting SAR data of new 5-HT7
ligands built on a bis-arylic structure. Their biological properties
were systematically correlated with the activity of other classes
of ligands already described in the literature. A new pharmaco-
phore model was generated in order to identify a common binding
pattern for the synthesized compounds. This model devoid of the
N
S
N
N NH
S
N
S
N
20
21
Figure 9. Thomson’s derivatives included in the inactive set.15

E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
1963
HBA feature was designed complementarily to the previously re-
ported 5-HT7 pharmacophores and should give a more general in-
sight into the interaction between the 5-HT7Rs and its ligands.
58.2 (CH2), 64.3 (CH2), 109.9 (2CH), 120.3 (2CH), 138.4 (C), 140.4
(CH), 163.4 (C). MS m/z = 245 [M+H]+ for 79Br, 247 [M+H]+ for 81Br.
4.3. General procedure employed for the Suzuki palladium
coupling reaction
4. Experimental section
4.1. General
To a solution of the corresponding bromide (0.77 mmol) in tolu-
ene (12 mL) were added the appropriate boronic acid (0.92 mmol),
ethanol (6 mL) and satd NaHCO3 (4 mL). The mixture was degassed
andflushedwithnitrogenseveraltimesbeforeaddingpalladiumtet-
rakis(triphenylphosphine) (0.08 mmol) in one portion. The mixture
was degassed one more time and then refluxed under nitrogen
atmosphere for 20 h. The organic solvent was removed, the residue
hydrolyzed with water (15 mL) and the aqueous phase extracted
with DCM (3 Â 25 mL). The combined organic layers were dried over
MgSO4, the solvent evaporated and the crude product purified by
flash chromatography (petroleum ether/ethyl acetate 7/3) to give
the desired coupling derivatives 4c–f.
1H NMR and 13C NMR were recorded on a Bruker Avance
DPX250 spectrometer (250.131 MHz) and a Bruker Avance II
(400 MHz), in CDCl3 and using tetramethylsilane as internal stan-
dard, multiplicities were determined by the DEPT 135 sequence,
chemical shifts (d) were reported in parts per million (ppm). Cou-
pling constants were reported in units of hertz (Hz) if applicable.
Infrared (IR) spectra were recorded on Perkin–Elmer Paragon
1000 PC FTIR using NaCl films or KBr pellets, and on a ATR Nicolet
iS10 equipped with a diamond crystal (ATR-D). Low-resolution
mass spectra (MS) were recorded on a Perkin–Elmer SCIEX AOI
300 spectrometer. High-resolution mass spectra were recorded
on a Q-Tof micro Waters spectrometer. Melting points were deter-
mined in open capillary tubes and are uncorrected. Flash chroma-
tography was performed on Merck 40–70 nM (230–400 mesh)
silica gel under nitrogen pressure. Thin layer chromatography
(TLC) was carried out on Merck silica gel 60 F254 precoated plates.
Visualization was made with ultraviolet light at 254 nm and, if
necessary, an ethanolic solution of potassium permanganate. Reac-
tions requiring anhydrous conditions were performed under nitro-
gen. Toluene and tetrahydrofuran were freshly distilled from
sodium/benzophenone under argon prior to use. Dichloromethane
was distilled from calcium hydride under argon prior to use.
4.3.1. 2-(6-(2,6-Dimethylphenyl)pyridin-2-ylthio)-N,N-
dimethylethanamine (4c)
C17H22N2S; yield 75%; light-yellow oil; IR (ATR-D) cmÀ1 2914,
2770, 1571, 1556, 1439, 1416, 1154, 1139, 1046, 798; 1H NMR
(400 MHz, CDCl3, 25 °C) d = 2.08 (s, 6H), 2.23 (s, 6H), 2.59 (t, 2H,
J = 7.2 Hz), 3.28 (t, 2H, J = 7.2 Hz), 6.89 (d, 1H, J = 7.4 Hz), 7.09 (d,
2H, J = 7.5 Hz), 7.14 (d, 1H, J = 7.4 Hz), 7.18 (dd, 1H, J = 7.5 Hz,
J = 8.2 Hz), 7.52 (t, 1H, J = 7.4 Hz); 13C NMR (100.7 MHz, CDCl3,
25 °C) d = 20.4 (CH), 27.7 (CH2), 45.4 (CH), 58.9 (CH2), 120.2 (CH),
120.3 (CH), 127.5 (2CH), 127.8 (CH), 135.9 (C), 136.1 (CH), 140.6
(C), 158.4 (C), 159.6 (C); MS m/z = 287.5 [M+H]+; HRMS calculated
for C17H22N2S 287.1582, found 287.1575.
4.2. General procedure employed for the synthesis of
compounds 4a–b
4.3.2. 2-(6-(2,6-Dimethylphenyl)pyridin-2-yloxy)-N,N-
dimethylethanamine (4d)
C17H22N2O; yield 67%; light-yellow oil; IR (ATR-D): cmÀ1 2946,
2767, 1588, 1571, 1446, 1309, 1239, 1026, 805, 769; 1H NMR
(250 MHz, CDCl3, 25 °C) d = 2.09 (s, 6H), 2.32 (s, 6H), 2.69 (t, 2H,
J = 5.6 Hz), 4.40 (t, 2H, J = 5.6 Hz), 6.76 (t, 2H, J = 7.3 Hz), 7.10 (m,
2H) , 7.18 (dd, 1H, J = 6.0 Hz, J = 8.8 Hz), 7.61 (dd, 1H, J = 7.3 Hz,
J = 8.3 Hz); 13C NMR (62.9 MHz, CDCl3, 25 °C) d = 20.4 (CH), 45.9
(CH), 58.5 (CH2), 63.7 (CH2), 109.2 (CH), 117.4 (CH), 127.6 (2CH),
127.7 (CH), 136.0 (C), 138.6 (CH), 140.6 (C), 157.1 (C), 163.6 (C);
MS m/z = 271.0 [M+H]+; HRMS calculated for C17H22N2O
271.1810, found 271.1795.
Under nitrogen atmosphere, sodium hydride (10.13 mmol) was
added at 0 °C to a solution of dimethylaminoetanol or dimethylam-
inoetanthiol (9.29 mmol) in anhydrous tetrahydrofuran (25 mL).
After 30 min of steering at 0 °C, 2,6-dibromopyridine (8.44 mmol)
dissolved in anhydrous tetrahydrofurane (5 mL) was added, and
the mixture was allowed to return to room temperature and con-
tinued stirring until the complete consumption of the starting
material. Then, the reaction was quenched by slowly adding water
(35 mL). Subsequently, the aqueous layer was separated and ex-
tracted with ethyl acetate (3 Â 30 mL), the combined organic lay-
ers ware dried over magnesium sulfate, filtrated and
concentrated under reduced pressure. The crude product was puri-
fied by flash chromatography to give the desired compounds.
4.3.3. 2-(6-(Furan-3-yl)pyridin-2-yloxy)-N,N-dimethyl-ethan-
amine (4e)
C13H16N2OS; yield 49%; yellow oil; IR (ATR-D): cmÀ1 2970,
2769, 1556, 1433, 1158, 1139, 1061, 1009, 781; 1H NMR
(400 MHz, CDCl3, 25 °C) d = 2.23 (s, 6H), 2.68 (t, 2H), 3.37 (t, 2H),
6.87–6.88 (m, 1H), 7.03 (d, 1H, J = 7.8 Hz), 7.12 (d, 1H, J = 7.8 Hz),
7.45 (t, 1H, J = 7.8 Hz), 7.47–7.48 (m, 1H), 8.02 (s, 1H); 13C NMR
(100.7 MHz, CDCl3, 25 °C) d = 27.6 (CH2), 45.5 (CH), 59.1 (CH2),
108.7 (CH), 115.4 (CH), 120.4 (CH), 127.2 (C), 136.5 (CH), 141.5
(CH), 143.9 (CH), 151.5 (C), 158.5 (C); MS m/z = 249.0 [M+H]+;
HRMS calculated for C13H16N2OS 249.1062, found 249.1056.
4.2.1. 2-(6-Bromopyridin-2-ylthio)-N,N-dimethylethanamine
(4a)
C9H13N2SBr; Yield 69%; colorless oil; IR (ATR-D) cmÀ1 2940,
2770, 1567, 1537, 1408, 1156, 1114, 769. 1H NMR (400 MHz, CDCl3,
25 °C) d = 2.28 (s, 6H), 2.58 (t, 2H, J = 7.2 Hz), 3.25 (t, 2H, J = 7.2 Hz),
7.08 (ta, 2H, J = 7.6 Hz), 7.25 (t, 1H, J = 7.6 Hz). 13C NMR
(100.7 MHz, CDCl3, 25 °C) d = 28.0 (CH2), 45.4 (CH3), 58.5 (CH2),
120.9 (CH), 123.0 (CH), 137.9 (CH), 141.6 (C), 160.3 (C). MS m/
z = 216.0 [M-NMe2] for 79Br, 218.0 [MÀNMe2] for 81Br, 261.0
[M+H]+ for 79Br, 263.0 [M+H]+ for 81Br.
4.3.4. 2-(6-Phenylpyridin-2-ylthio)-N,N-dimethylethan-amine (4f)
C15H18N2S; Yield 89%; colorless oil; IR (ATR-D): cmÀ1 2939,
2767, 1557, 1427, 1140, 755, 691. 1H NMR (400 MHz, CDCl3,
25 °C) d = 2.33 (s, 6H), 2.71 (t, 2H, J = 7.3 Hz), 3.44 (t, 2H,
J = 7.3 Hz), 7.12 (dd, 1H, J = 0.9 Hz, J = 7.7 Hz), 7.40–7.56 (m, 5H),
8.03–8.07 (m, 2H). 13C NMR (100.7 MHz, CDCl3, 25 °C) d = 27.7
(CH2), 45.6 (CH3), 59.1 (CH2), 115.8 (CH), 120.8 (CH), 126.8 (2CH),
128.8 (2CH), 129.2 (CH), 136.7 (CH), 139.1 (C), 156.7 (C), 158.5
(CH). MS m/z = 214.0 [MÀNMe2]+, 259.0 [M+H]+.
4.2.2. 2-(6-Bromopyridin-2-yloxy)-N,N-dimethylethan-amine (4b)
C9H13N2OBr; Yield 80%; colorless oil; IR (ATR-D) cmÀ1 2945,
1585, 1553, 1433, 1402, 1295, 1156, 784. 1H NMR (400 MHz,
CDCl3, 25 °C) d = 2.27 (s, 6H), 2.63 (t, 2H, J = 5.5 Hz), 4.34 (t, 2H,
J = 5.5 Hz), 6.68 (d, 1H, J = 7.8 Hz), 6.98 (d, 1H, J = 7.8 Hz), 7.35 (t,
1H, J = 7.8 Hz). 13C NMR (100.7 MHz, CDCl3, 25 °C) d = 45.8 (CH3),

1964
E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
4.4. General protocol used for the synthesis of compounds 5a–c
and 5g
of steering at 0 °C, the corresponding triazine (0.85 mmol) dis-
solved in anhydrous tetrahydrofurane (3 mL) was added, and the
mixture was allowed to return to room temperature and continued
stirring until the complete consumption of the starting material.
Then, the reaction was quenched by slowly adding sodium hydro-
genocarbonate (10% aqueous solution, 15 mL). Subsequently, the
aqueous layer was separated and extracted with dichloromethane
(3 Â 20 mL), the combined organic layers ware dried over magne-
sium sulfate, filtrated and concentrated under reduced pressure.
The crude product was purified by flash chromatography to give
the desired compounds 5d–f.
To a solution of the corresponding arylsulfone (0.85 mmol) in
dichloromethane (4 mL) were successively added dimethylamino-
ethanthiol (0.144 g, 1.02 mmol) and triethylamine (0.48 mL,
3.40 mmol). After stirring the mixture for 1 h at room temperature,
the reaction was quenched by addition of a solution of sodium
bicarbonate (10%, 15 mL). The aqueous layer was extracted with
dichloromethane (3 Â 20 mL). The combined organic layers were
dried over MgSO4, the solvent evaporated and the crude product
purified by flash chromatography (dichloromethane/methanol
95/5) to give the derivatives 5a–c or 5g.
4.5.1. N,N-Dimethyl-2-(5-phenyl-1,2,4-triazin-3-yloxy)-ethan-
amine (5d)
4.4.1. N,N-Dimethyl-2-(5-phenyl-1,2,4-triazin-3-ylthio)-ethan-
amine (5a)
C13H16N4O; yield 89%; red oil; IR (NaCl): cmÀ1 2972 et 2824,
1540, 1520, 1288, 768, 754; 1H NMR (250 MHz, CDCl3, 25 °C)
d = 2.30 (s, 6H), 2.79 (t, 2H, J = 5.9 Hz), 4.65 (t, 2H, J = 5.9 Hz),
7.42–7.52 (m, 3H), 8.08–8.12 (m, 2H), 9.34 (s, 1H); 13C NMR
(62.9 MHz, CDCl3, 25 °C) d = 46.8 (CH), 57.7 (CH2), 66.3 (CH2),
127.8 (2CH), 129.2 (2CH), 132.6 (CH), 133.0 (C), 141.4 (CH), 157.8
(C), 165.3 (C); MS m/z = 244.5 [M+H]+; HRMS calculated for
C13H16N4O 245.1402, found 245.1402.
C13H16N4S; yield 95%; dark-yellow oil; IR (NaCl): cmÀ1 2946,
2774, 1536, 1502, 1134; 1H NMR (250 MHz, CDCl3, 25 °C) d = 2.25
(s, 6H), 2.66 (t, 2H, J = 7.2 Hz), 3.35 (t, 2H, J = 7.2 Hz), 7.39–7.52
(m, 3H), 8.02–8.06 (m, 2H), 9.27 (s, 1H); 13C NMR (62.9 MHz, CDCl3,
25 °C) d = 28.4 (CH2), 45.2 (CH), 58.0 (CH2), 127.4 (2CH), 129.2
(2CH), 132.5 (CH), 132.9 (C), 141.8 (CH), 154.3 (C), 173.2 (C); MS
m/z = 260.5 [M+H]+.
4.5.2. 2-(5-(2,6-Dimethylphenyl)-1,2,4-triazin-3-yloxy)-N,N-
dimethylethanamine (5e)
4.4.2. 2-(5-(2,6-Dimethylphenyl)-1,2,4-triazin-3-ylthio)-N,N-
dimethylethanamine (5b)
C15H20N4O; yield 70%; beige oil; IR (NaCl): cmÀ1 2968, 2770,
1544, 1506, 1293, 775; 1H NMR (250 MHz, CDCl3, 25 °C) d = 2.12
(s, 6H), 2.37 (s, 6H), 2.85 (t, 2H, J = 5.8 Hz), 4.69 (t, 2H, J = 5.8 Hz),
7.14 (d, 2H, J = 7.6 Hz), 7.28 (dd, 1H, J = 6.8 Hz, J = 8.3 Hz), 8.91 (s,
1H); 13C NMR (62.9 MHz, CDCl3, 25 °C) d = 20.2 (CH), 46.0 (CH),
57.8 (CH2), 66.8 (CH2), 128.1 (2CH), 129.7 (CH), 133.9 (C), 135.7
(C), 145.9 (CH), 162.4 (C), 165.4 (C); MS m/z = 273.0 [M+H]+; HRMS
calcd for C15H20N4O 273.1715, found 273.1709.
C15H20N4S; yield 91%; light-yellow oil; IR (NaCl): cmÀ1 2950,
2820, 1531, 1486, 1237, 1127; 1H NMR (250 MHz, CDCl3, 25 °C)
d = 2.13 (s, 6H), 2.32 (s, 6H), 2.74 (t, 2H, J = 7.1 Hz), 3.43 (t, 2H,
J = 7.1 Hz), 7.14 (d, 2H, J = 7.6 Hz), 7.28 (dd, 1H, J = 6.8 Hz,
J = 8.3 Hz), 8.87 (s, 1H); 13C NMR (62.9 MHz, CDCl3, 25 °C)
d = 20.2 (CH), 28.6 (CH2), 45.3 (CH), 58.0 (CH2), 128.2 (2CH),
129.7 (CH), 133.9 (C), 135.7 (C), 146.4 (CH), 159.2 (C), 173.8 (C);
MS m/z = 289.0 [M+H]+; HRMS calculated for C15H20N4S
289.1487, found 289.1487.
4.5.3. 2-(5-(2,6-Dimethoxyphenyl)-1,2,4-triazin-3-yloxy)-N,N-
dimethylethanamine (5f)
4.4.3. 2-(5-(2,6-Dimethoxyphenyl)-1,2,4-triazin-3-ylthio) N,N-
dimethylethanamine (5c)
C15H20N4O3; yield 81%; orange solid; mp 111–113 °C; IR (KBr):
cmÀ1 2950, 2774, 1599, 1514, 1255, 784, 746; 1H NMR (250 MHz,
CDCl3, 25 °C) d = 2.32 (s, 6H), 2.81 (t, 2H, J = 5.9 Hz), 3.72 (s, 6H),
4.64 (t, 2H, J = 5.9 Hz), 6.60 (d, 2H, J = 8.4 Hz), 7.35 (t, 1H,
J = 8.4 Hz), 8.89 (s, 1H); 13C NMR (62.9 MHz, CDCl3, 25 °C)
d = 46.0 (CH), 56.0 (2CH), 57.8 (CH2), 66.5 (CH2), 104.1 (2CH),
112.6 (C), 132.2 (CH), 147.4 (CH), 158.2 (C), 158.3 (C), 165.3 (C);
MS m/z = 305.0 [M+H]+; HRMS calcd for C15H20N4O3 305.1614,
found 305.1611.
C15H20N4O2S; yield 85%; yellow solid; mp 73–75 °C; IR (KBr):
cmÀ1 2946, 2778, 1599, 1537, 1242, 1113, 754; 1H NMR
(250 MHz, CDCl3, 25 °C) d = 2.28 (s, 6H), 2.71 (t, 2H, J = 7.2 Hz),
3.36 (t, 2H, J = 7.2 Hz), 3.73 (s, 6H), 6.61 (d, 2H, J = 8.4 Hz), 7.36
(t, 1H, J = 8.4 Hz), 8.86 (s, 1H); 13C NMR (62.9 MHz, CDCl3, 25 °C)
d = 28.5 (CH2), 45.3 (CH), 56.0 (CH), 58.2 (CH2), 104.2 (2CH),
112.7 (C), 132.3 (CH), 147.9 (CH), 155.1 (C), 158.3 (C), 173.0 (C);
MS m/z = 321.0 [M+H]+; HRMS calculated for C15H20N4O2S
321.1385, found 321.1379.
4.6. 4-(2,6-Dimethoxyphenyl)-2-(methylthio)-pyrimidine (6)
4.4.4. 2-(4-(2,6-Dimethoxyphenyl)pyrimidin-2-ylthio)-N,N-
dimethylethanamine (5g)
C13H14N2O2S; yield 73%; yellow solid; mp 84–86 °C; IR (ATR-D):
cmÀ1 2929, 1590, 1560, 1530, 1420, 1320, 1250, 1208, 1106, 826;
1H NMR (400 MHz, CDCl3, 25 °C) d = 2.56 (s, 3H), 3.72 (s, 6H),
6.61 (d, 2H, J = 8.4 Hz), 6.97 (d, 1H, J = 5.1 Hz), 7.31 (t, 1H,
J = 8.4 Hz), 8.51 (d, 1H, J = 5.1 Hz); 13C NMR (100.7 MHz, CDCl3,
25 °C) d = 14.3 (CH), 56.0 (2CH), 104.3 (2CH), 116.8 (C), 119.0
(CH), 130.7 (CH), 156.4 (CH), 157.9 (C), 163.1 (C), 172.1 (C); MS
m/z = 263.0 [M+H]+.
C16H21N3O2S; yield 67%; colorless oil; IR (ATR-D): cmÀ1 2939,
2772, 1592, 1559, 1533, 1471, 1332, 1250, 1200, 1108, 725; 1H
NMR (400 MHz, CDCl3, 25 °C) d = 2.28 (s, 6H), 2.68 (t, 2H,
J = 7.4 Hz), 3.25 (t, 2H, J = 7.4 Hz), 3.71 (s, 6H), 6.60 (d, 2H), 6.95 (d,
1H, J = 5.0 Hz), 7.31 (t, 1H, J = 8.4 Hz), 8.48 (d, 1H, J = 5.0 Hz); 13C
NMR (100.7 MHz, CDCl3, 25 °C) d = 28.5 (CH2), 45.3 (2CH), 56.0
(2CH), 58.7 (CH2), 104.2 (2CH), 116.8 (C), 119.1 (CH), 130.7 (CH),
156.5 (CH), 157.9 (C), 163.1 (C), 171.4 (C); MS m/z = 320.0 [M+H]+;
HRMS calculated for C16H21N3O2S 320.1433, found 320.1427.
4.7. 4-(2,6-Dimethoxyphenyl)-2-(methylsulfonyl)-pyrimidine
(7)
4.5. General procedure employed for the synthesis of
compounds 5d–f
Under nitrogen atmosphere, meta-chloroperbenzoic acid (tech.
70–75%, 0.41 g, 1.68 mmol) was added at 0 °C to a solution of
pyrimidine 6 (0.20 g, 0.76 mmol) in anhydrous dichloromethane
(10 mL). After 1 h of reaction at room temperature, the suspension
was filtered on a glass sintered funnel and the filtrate washed with
satd NaHCO3 and Na2S2O3. The organic phase was then concen-
Under nitrogen atmosphere, sodium hydride (1.02 mmol) was
added at 0 °C to a solution of dimethylaminoetanol (0.09 mL,
0.094 mmol) in anhydrous tetrahydrofuran (3 mL). After 30 min

E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
1965
trated under vacuum and the obtained crude product purified by
flash chromatography (petroleum ether/ethyl acetate 5/5) to con-
duct to the desired sulfone 7. C13H14N2O4S; yield 85%; yellow solid;
mp 159–161 °C; IR (ATR-D): cmÀ1 2936, 1603, 1572, 1474, 1300,
1132, 1112, 780, 755; 1H NMR (400 MHz, CDCl3, 25 °C) d = 3.32
(s, 3H), 3.71 (s, 6H), 6.62 (d, 2H, J = 8.4 Hz), 7.36 (t, 1H,
J = 8.4 Hz), 7.54 (d, 1H, J = 5.1 Hz), 8.85 (d, 1H, J = 5.1 Hz); 13C
NMR (100.7 MHz, CDCl3, 25 °C) d = 39.3 (CH), 56.0 (2CH), 104.3
(2CH), 115.0 (C), 126.6 (CH), 131.9 (CH), 157.5 (CH), 157.9 (C),
164.8 (C), 165.5 (C); MS m/z = 295.0 [M+H]+.
yield 75%; slightly green oil; IR (ATR-D): cmÀ1 2963, 2768, 1460,
1258, 1039, 1008, 791, 746; 1H NMR (400 MHz, CDCl3, 25 °C)
d = 2.21 (s, 6H), 2.45–2.49 (m, 2H), 2.85–2.89 (m, 2H), 7.24–7.44
(m, 9H); 13C NMR (100.7 MHz, CDCl3, 25 °C) d = 31.3 (CH2), 45.4
(2CH), 58.5 (CH2), 125.7 (CH), 127.5 (CH), 128.0 (CH), 128.2
(2CH), 129.5 (2CH), 130.5 (2CH), 135.3 (C), 140.8 (C), 142.5 (C);
MS m/z = 213.0 [M-NMe2]+, 258.5 [M+H]+; HRMS calcd for
C16H19NS 258.1316, found 258.1310.
4.12. 2-(Biphenyl-2-yloxy)-N,N-dimethylethanamine (8e)
4.8. 2-(2-Bromophenylthio)-N,N-dimethylethanamine (8a)
The compound 8e was obtained following the Suzuki palladium
coupling protocol used for the synthesis of derivative 4c.
C16H19NO; yield 62%; beige oil; IR (ATR-D): cmÀ1 2941, 2769,
1596, 1480, 1433, 1261, 1229, 1122, 1030, 751, 731, 697; 1H
NMR (400 MHz, CDCl3, 25 °C) d = 2.27 (s, 6H), 2.69 (t, 2H, J = 6.0),
4.08 (t, 2H, J = 6.0 Hz), 7.0 (d, 1H, J = 7.0 Hz), 7.05 (td, 1H,
J = 1.0 Hz, J = 7.5 Hz), 7.29–7.35 (m, 3H), 7.38–7.42 (m, 2H), 7.55–
7.57 (m, 2H); 13C NMR (100.7 MHz, CDCl3, 25 °C) d = 46.1 (2CH),
58.2 (CH2), 67.3 (CH2), 113.0 (CH), 121.2 (CH), 126.9 (CH), 127.9
(2CH), 128.7 (CH), 129.7 (2CH), 131.0 (CH), 131.3 (C), 138.6 (C),
155.9 (C); MS m/z = 242.0 [M+H]+; HRMS calcd for C16H19NO
242.1545, found 242.1537.
To a solution of 2-bromothiophenol (3.00 g, 15.87 mmol) in eth-
anol (30 mL) were added sodium hydroxide (1.46 g, 36.50 mmol)
and
a solution of 2-chrolorethylamine chlorhydrate (2.29 g,
15.87 mmol) in ethanol (10 mL). The mixture was refluxed for
2 h, allowed to return to room temperature and then extracted
with diethyl ether (3 Â 30 mL). The organic phase was subse-
quently extracted with 2 N HCl (2 Â 40 mL), the pH of the com-
bined aqueous phases was adjusted at 9 with 4 N NaOH, and
then the extracted with diethyl ether (2 Â 100 mL). The recovered
organic phases were dried over MgSO4, filtered and the solvent
evaporated under reduced pressure to give the derivative 8a,
which was used further without any supplementary purification.
C10H14BrNS; yield 74%; colorless liquid; IR (ATR-D): cmÀ1 2791,
2767, 1447, 1298, 1247, 1018, 741; 1H NMR (250 MHz, CDCl3,
25 °C) d = 2.29 (s, 6H), 2.61 (dd, 2H, J = 6.3 Hz, J = 8.4 Hz), 3.05
(dd, 2H, J = 6.3 Hz, J = 8.4 Hz), 7.01 (dt, 1H, J = 4.5 Hz, J = 4.5 Hz,
J = 8.0 Hz), 7.26 (d, 2H, J = 4.5 Hz), 7.53 (d, 1H, J = 8.0 Hz); 13C
NMR (62.9 MHz, CDCl3, 25 °C) d = 31.0 (CH2), 45.4 (2CH), 58.0
(CH2), 123.5 (C), 126.5 (CH), 127.8 (2CH), 133.1 (CH), 138.2 (C);
MS m/z = 260.0 [M+H]+ for 79Br, 262.0 [M+H]+ for 81Br; HRMS calcd
for C10H14BrNS 260.0109, found 260.0104.
4.13. 2-(2’-Methoxybiphenyl-2-yloxy)-N,N-dimethyl-ethan
amine (8f)
The compound 8f was obtained following the Suzuki palladium
coupling protocol used for the synthesis of derivative 4c.
C17H21NO2; yield 63%; greenish oil; IR (ATR-D): cmÀ1 2939, 2769,
1593, 1503, 1445, 1259, 1233, 1110, 1028, 748; 1H NMR (400 MHz,
CDCl3, 25 °C) d = 2.19 (s, 6H), 2.59 (t, 2H, J = 6.0 Hz), 3.75 (s, 3H),
4.05 (t, 2H, J = 6.0 Hz), 6.93–7.02 (m, 4H), 7.22–7.25 (m, 2H), 7.28–
7.32 (m, 2H); 13C NMR (100.7 MHz, CDCl3, 25 °C) d = 46.0 (2CH),
55.6 (CH), 58.2 (CH2), 67.3 (CH2), 110.7 (CH), 112.7 (CH), 120.3
(CH), 120.8 (CH), 128.0 (C), 128.5 (C), 128.6 (CH), 128.7 (CH), 131.6
(CH), 131.7 (CH), 156.4 (C), 157.1 (C); MS m/z = 272.5 [M+H]+; HRMS
calcd for C16H19NO2 272.1651, found 272.1635.
4.9. 2-(2-Bromophenoxy)-N,N-dimethylethanamine (8b)
The compound 8b was obtained following the same experimen-
tal procedure employed for the synthesis of compound 8a.
C10H14BrNO; yield 60%; colorless liquid; IR (ATR-D): cmÀ1 2941,
2770, 1586, 1477, 1277, 1246, 1029, 745, 663; 1H NMR
(250 MHz, CDCl3, 25 °C) d = 2.38 (s, 6H), 2.81 (t, 2H, J = 5.9 Hz),
4.13 (t, 2H, J = 5.9 Hz), 6.82 (td, 1H, J = 1.4 Hz, J = 7.8 Hz), 6.90
(dd, 1H, J = 1.2 Hz, J = 8.2 Hz), 7.21–7.28 (m, 1H), 7.53 (dd, 1H,
J = 1.6 Hz, J = 7.9 Hz); 13C NMR (62.9 MHz, CDCl3, 25 °C) d = 46.4
(2CH), 58.1 (CH2), 68.0 (CH2), 112.4 (C), 113.4 (CH), 122.1 (CH),
128.5 (CH), 133.5 (CH), 155.4.2 (C); MS m/z = 244.0 [M+H]+ for
79Br, 246.0 [M+H]+ for 81Br.
4.14. 2-(Biphenyl-3-ylthio)-N,N-dimethylethanamine (8h)
The compound 8h was obtained following the Suzuki palladium
coupling protocol described above for the derivative 4c. C16H19NS;
yield 91%; colorless oil; IR (ATR-D): cmÀ1 2939, 2768, 1587, 1461,
752, 695; 1H NMR (250 MHz, CDCl3, 25 °C) d = 2.30 (s, 6H), 2.61 (t,
2H, J = 7.4 Hz), 3.10 (t, 2H, J = 7.4 Hz), 7.33–7.48 (m, 6H), 7.56–7.59
(m, 3H); 13C NMR (62.9 MHz, CDCl3, 25 °C) d = 31.6 (CH2), 45.5
(2CH), 58.7 (CH2), 125.0 (CH), 127.3 (2CH), 127.7 (2CH), 127.8
(CH), 128.9 (2CH), 129.4 (CH), 137.1 (C), 140.7 (C), 142.1 (C); MS
m/z = 258.5 [M+H]+; HRMS calcd for C16H19NS 258.1316, found
258.1304.
4.10. 2-(3-Bromophenylthio)-N,N-dimethylethanamine (8c)
The compound 8c was obtained following the same experimen-
tal procedure employed for the synthesis of compound 8a
C10H14BrNS; yield 74%; colorless oil; IR (ATR-D) : cmÀ1 2970,
2767, 1574, 1555, 1458, 1053, 753, 676; 1H NMR (250 MHz, CDCl3,
25 °C) d = 2.27 (s, 6H), 2.56 (t, 2H, J = 7.2 Hz), 3.03 (t, 2H, J = 7.2 Hz),
7.12 (t, 1H, J = 8.3 Hz), 7.26 (dd, 2H, J = 8.3 Hz, J = 10.1 Hz), 7.45 (s,
1H); 13C NMR (62.9 MHz, CDCl3, 25 °C) d = 31.4 (CH2), 45.4 (2CH),
58.4 (CH2), 122.9 (C), 127.1 (CH), 128.8 (CH), 130.0 (CH), 131.0
(CH), 139.3 (C); MS m/z = 260.0 [M+H]+ for 79Br, 262.0 [M+H]+ for
81Br; HRMS calcd for C10H14BrNS 260.0109, found 260.0102.
4.15. 2-(2,6-Dimethylbiphenyl-3-ylthio)-N,N-dimethyl-
ethanamine (8i)
The compound 8i was obtained following the Suzuki palladium
coupling protocol described above for the derivative 4c. C18H23NS;
yield 69%; colorless oil; IR (ATR-D): cmÀ1 2939, 2768, 1587, 1461,
752, 695; 1H NMR (250 MHz, CDCl3, 25 °C) d = 2.05 (s, 6H), 2.27 (s,
6H), 2.58 (t, 2H, J = 7.4 Hz), 3.04 (t, 2H, J = 7.4 Hz), 6.95–6.99 (m,
1H), 7.09–7.21 (m, 4H), 7.30–7.38 (m, 2H); 13C NMR (62.9 MHz,
CDCl3, 25 °C) d = 20.9 (2CH), 31.4 (CH2), 45.5 (2CH), 58.7 (CH2),
126.7 (CH), 127.2 (CH), 127.3 (CH), 127.4 (2CH), 129.1 (CH),
129.2 (CH), 136.0 (2C), 136.7 (C), 141.3 (C), 141.9 (C); MS m/
z = 286.5 [M+H]+; HRMS calcd for C18H23NS 286.1629, found
286.1621.
4.11. 2-(Biphenyl-2-ylthio)-N,N-dimethylethanamine (8d)
The compound 8d was obtained following the Suzuki palladium
coupling protocol used for the synthesis of derivative 4c. C16H19NS;

1966
E. Badarau et al. / Bioorg. Med. Chem. 18 (2010) 1958–1967
4.16. General procedure employed for the synthesis of vinylic
derivatives 9a–d
4.17.1. N,N-Dimethyl-2-(5-phenyl-1,2,4-triazin-3-yl)-
ethanamine (10a)
C13H16N4; yield 67%; orange oil; IR (NaCl): cmÀ1 3446, 2942,
2770, 1548, 764; 1H NMR (250 MHz, CDCl3, 25 °C) d = 2.32 (s,
6H), 2.94 (t, 2H, J = 7.4 Hz), 3.33 (t, 2H, J = 7.4 Hz), 7.50–7.57 (m,
3H), 8.13–8.17 (m, 2H), 9.52 (s, 1H); 13C NMR (62.9 MHz, CDCl3,
25 °C) d = 35.5 (CH2), 45.4 (2CH), 57.7 (CH2), 127.7 (C), 129.4 (C),
132.4 (C), 133.7 (C), 144.3 (CH), 155.2 (C), 168.6 (C); MS m/
z = 229.0 [M+H]+; HRMS calcd for C13H16N4 229.1453, found
229.1447.
Under nitrogen atmosphere, the corresponding sulfone was dis-
solved in anhydrous tetrahydrofuran (30 mL) and the mixture was
cooled to À78 °C. Then, vinyl magnesium bromide was added (1 M
solution in hexane, 10.2 mL, 10.2 mmol) and the mixture was stir-
red at low temperature 1 h, before quenching it with sat. NaCl
(30 mL). The aqueous phase was separated and extracted with
ethyl acetate (3 Â 50 mL) and the combined organic layers dried
over MgSO4, filtrated and concentrated under reduced pressure.
The final compounds 9a–d were isolated by flash chromatography
(petroleum ether/ethyl acetate 9/1).
4.17.2. 2-(5-(2,6-Dimethylphenyl)-1,2,4-triazin-3-yl)-N,N-
dimethylethanamine (10b)
C15H20N4; yield 79%; beige oil; IR (NaCl): cmÀ1 3450, 2976,
2766, 1597 et 1544, 1505, 1462, 1296, 1051, 780; 1H NMR
(250 MHz, CDCl3, 25 °C) d = 2.09 (s, 6H), 2.29 (s, 6H), 2.90 (t, 2H,
J = 7.4 Hz), 3.36 (t, 2H, J = 7.4 Hz), 7.15 (d, 2H, J = 7.6 Hz), 7.28
(dd, 1H, J = 6.7 Hz, J = 8.4 Hz), 9.06 (s, 1H); 13C NMR (62.9 MHz,
CDCl3, 25 °C) d = 20.3 (2CH), 35.6 (CH2), 45.4 (2CH), 57.9 (CH2),
128.3 (2CH), 129.8 (CH), 134.4 (C), 135.9 (C), 148.6 (CH), 159.8
(C), 169.1 (C); MS m/z = 257.0 [M+H]+; HRMS calcd for C15H20N4
257.1766, found 257.1766.
4.16.1. 5-Phenyl-3-vinyl-1,2,4-triazine (9a)
C11H9N3; yield 91%; orange solid; mp 85–87 °C; IR (KBr): cmÀ1
3060, 1548, 1506, 987, 942, 772; 1H NMR (400 MHz, CDCl3, 25 °C)
d = 5.92 (dd, 1H, J = 1.7 Hz, J = 10.5 Hz), 6.88 (dd, 1H, J = 1.7 Hz,
J = 17.4 Hz), 7.14 (dd, 1H, J = 10.5 Hz, J = 17.4 Hz), 7.51–7.60 (m,
3H), 8.18–8.22 (m, 2H), 9.52 (s, 1H); 13C NMR (100.7 MHz, CDCl3,
25 °C) d = 126.0 (CH2), 127.7 (CH), 129.5 (CH), 132.6 (CH), 133.7
(C), 134.0 (CH), 144.5 (CH), 155.1 (C), 163.2 (C); MS m/z = 184.0
[M+H]+, 206.0 [M+Na]+.
4.17.3. 2-(5-(2,6-Dimethoxyphenyl)-1,2,4-triazin-3-yl)-N,N-
dimethylethanamine (10c)
4.16.2. 5-(2,6-Dimethylphenyl)-3-vinyl-1,2,4-triazine (9b)
C13H13N3; yield 96%; yellow solid; mp 38–40 °C; IR (KBr): cmÀ1
3038, 1598, 1544, 1498, 1322, 1066, 774; 1H NMR (250 MHz,
CDCl3, 25 °C) d = 2.13 (s, 6H), 5.92 (dd, 1H, J = 1.5 Hz, J = 10.6 Hz),
6.82 (dd, 1H, J = 1.5 Hz, J = 17.4 Hz), 7.09–7.21 (m, 3H), 7.30 (dd,
1H, J = 6.7 Hz, J = 8.4 Hz), 9.04 (s, 1H); 13C NMR (62.9 MHz, CDCl3,
25 °C) d = 20.3 (2CH), 126.4 (CH2), 128.4 (2CH), 129.9 (CH), 133.9
(CH), 134.4 (C), 135.9 (C), 148.8 (CH), 159.8 (C), 163.6 (C); MS m/
z = 212.0 [M+H]+, 206.0 [M+Na]+.
C15H20N4O2; yield 68%; dark-yellow oil; IR (NaCl): cmÀ1 3442,
2942, 2778, 1599, 1472, 1253, 1109, 784; 1H NMR (250 MHz,
CDCl3, 25 °C) d = 2.32 (s, 6H), 2.94 (t, 2H, J = 7.6 Hz), 3.33 (t, 2H,
J = 7.6 Hz), 3.74 (s, 6H), 6.65 (d, 2H, J = 8.4 Hz), 7.39 (t, 1H,
J = 8.4 Hz), 9.06 (s, 1H); 13C NMR (62.9 MHz, CDCl3, 25 °C)
d = 35.6 (CH2), 45.4 (2CH), 56.1 (2CH), 57.9 (CH2), 104.4 (2CH),
113.1 (C), 132.2 (CH), 150.0 (CH), 155.5 (C), 158.3 (C), 168.4 (C);
MS m/z = 289.0 [M+H]+; HRMS calcd for C15H20N4O2 289.1665,
found 289.1658.
4.16.3. 5-(2,6-Dimethoxyphenyl)-3-vinyl-1,2,4-triazine (9c)
C13H13N3O2; yield 96%; yellow solid; mp 162–164 °C; IR (KBr):
cmÀ1 2972, 1599, 1250, 1108, 782; 1H NMR (250 MHz, CDCl3,
25 °C) d = 3.74 (s, 6H), 5.84 (dd, 1H, J = 1.7 Hz, J = 10.6 Hz), 6.65
(d, 2H, J = 8.4 Hz), 6.77 (dd, 1H, J = 1.7 Hz, J = 17.4 Hz), 7.09 (dd,
1H, J = 10.5 Hz, J = 17.4 Hz), 7.39 (t, 1H, J = 8.4 Hz), 9.03 (s, H6);
13C NMR (62.9 MHz, CDCl3, 25 °C) d = 56.1 (2CH), 104.4 (2CH),
113.3 (C), 125.5 (CH2), 132.2 (CH), 134.2 (CH), 150.1 (CH), 155.6
(C), 158.4 (C), 163.4 (C); MS m/z = 244.0 [M+H]+.
4.17.4. 2-(4-(2,6-Dimethoxyphenyl)pyrimidin-2-yl)-N,N-
dimethylethanamine (10d)
C16H21N3O2; yield 89%; yellow oil; IR (ATR-D): cmÀ1 2939, 1597,
1570, 1545, 1471, 1433, 1248, 1108, 727; 1H NMR (250 MHz,
CDCl3, 25 °C) d = 2.36 (s, 6H, H16), 2.96 (t, 2H, H14, J = 7.7 Hz),
3.24 (t, 2H, H13, J = 7.7 Hz), 3.73 (s, 6H, H12), 6.64 (d, 2H, H9,
J = 8.4 Hz), 7.14 (d, 1H, H5, J = 5.1 Hz), 7.33 (t, 1H, H10, J = 8.4 Hz),
8.66 (d, 1H, H4, J = 5.1 Hz); 13C NMR (62.9 MHz, CDCl3, 25 °C)
d = 37.3 (C13), 45.2 (C16), 55.9 (C12), 58.1 (C14), 104.3 (C9), 116.9
(Cq), 121.1 (C5), 130.6 (C10), 156.3 (C4), 157.8 (C8), 162.9 (Cq),
169.1 (Cq); MS m/z = 288.0 [M+H]+; HRMS calcd for C16H21N3O2
288.1712, found 288.1712.
4.16.4. 4-(2,6-Dimethoxyphenyl)-2-vinylpyrimidine (9d)
C14H14N2O2; yield 96%; white solid; mp 141–143 °C; IR (ATR-
D): cmÀ1 2930, 1597, 1560, 1534, 1468, 1428, 1243, 1108, 844,
780; 1H NMR (250 MHz, CDCl3, 25 °C) d = 3.71 (s, 6H), 5.67–5.70
(m, 1H), 6.59–6.64 (m, 3H), 6.95 (dd, 1H, J = 10.6, J = 17.3 Hz),
7.13 (dd, 1H, J = 0.9 Hz, J = 5.0 Hz), 7.32 (dt, 1H, J = 1.4 Hz,
J = 8.4 Hz), 8.69 (dd, 1H, J = 0.9 Hz, J = 5.0 Hz); 13C NMR
(62.9 MHz, CDCl3, 25 °C) d = 56.0 (2CH), 104.4 (2CH), 117.1 (C),
121.7 (CH), 123.3 (CH2), 130.7 (CH), 137.2 (CH), 156.3 (CH), 157.9
(C), 163.0 (C), 164.3 (C); MS m/z = 243.0 [M+H]+.
4.18. Binding experiments
Membrane preparation and general assay procedures for 5-HT7
and 5-HT1A receptors were performed exactly as previously
described.16
For 5-HT7 binding assay, membranes from HEK-293 cells, stably
expressing human 5-HT7b receptor and [3H]-5-CT (93.0 Ci/mmol,
Hartmann) as radioligand were used.
The 5-HT1A receptor affinity was determined for selected com-
pounds, with the use of native rat hippocampal membranes and
[3H]-8-OH-DPAT (170 Ci/mmol, PerkinElmer). For both 5-HT7 and 5-
HT1A binding experiments 7–9 sample concentrations, each run in
triplicate, were used to determine inhibition constant (Ki), whereas
4.17. General procedure employed for the synthesis of
compounds 10a–d
Dimethylamine (solution 40% in water, 0.18 mL, 2.46 mmol)
was added to a solution of the corresponding compound 9a–d
(0.82 mmol) in methanol (2 mL). The reaction mixture was stirred
at room temperature until the total consumption of the starting
material (approx. 1 h). Then, the solvents were evaporated in vacuo
and the residue purified by flash chromatography (dichlorometh-
ane/methanol 95/5) to give the desired corresponding compounds
10a–d.
nonspecific binding was defined in the presence of 10 lM 5-HT.
References and notes
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