Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors

Article abstract of DOI:10.1016/j.ejmech.2012.04.030

A series of arylalkanol-piperidine derivatives was synthesized, and their triple reuptake inhibition and in vivo activities have been evaluated. Among them, compounds 2a, 2j, 2k, 2m and 2n exhibited high potency for 5-HT, NA and DA transporters. Optimized compounds 2j and 2m showed significant reduction of immobility time compared to that of vehicle in the mouse tail suspension test (TST) test at doses ranging from 10 to 50 mg/kg po, and were not generally motor stimulants at 50 mg/kg dose. In addition, compounds 2j and 2m displayed desirable pharmacokinetic properties in SD rats.

Full text of DOI:10.1016/j.ejmech.2012.04.030

European Journal of Medicinal Chemistry 54 (2012) 123e136
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as
triple reuptake inhibitors
,
Yong-Yong Zheng a, Lin Guo b, Xue-Chu Zhen b, Jian-Qi Li a
*
a Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, 1111 North Zhongshan No.1 Road, Shanghai 200437, PR China
b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, PR China
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
< A series of arylalkanol-piperidine
derivatives (2aey) were synthesized.
< Synthesized
compounds
were
tested for triple reuptake inhibition
and antidepressant activities.
< 5 compounds exhibited high
potency for 5-HT, NA and DA
transporters.
< Some compounds showed antide-
pressant activities in TST and dis-
played desirable pharmacokinetic
properties.
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of arylalkanol-piperidine derivatives was synthesized, and their triple reuptake inhibition and
in vivo activities have been evaluated. Among them, compounds 2a, 2j, 2k, 2m and 2n exhibited high
potency for 5-HT, NA and DA transporters. Optimized compounds 2j and 2m showed significant
reduction of immobility time compared to that of vehicle in the mouse tail suspension test (TST) test at
doses ranging from 10 to 50 mg/kg po, and were not generally motor stimulants at 50 mg/kg dose. In
addition, compounds 2j and 2m displayed desirable pharmacokinetic properties in SD rats.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 11 February 2012
Received in revised form
23 April 2012
Accepted 24 April 2012
Available online 30 April 2012
Keywords:
Arylalkanol-piperidine derivatives
Triple reuptake inhibitor
Antidepressant
1. Introduction
neurotransmitter reuptakes of either serotonin (5-HT) (SSRI, e.g.,
fluoxetine) or noradrenalin (NA) (SNRI, e.g., reboxetine) have
Depression has received considerable attention in the last
decades. Notoriously, it is involved in people’s thought, feeling and
behavior, which can eventually lead to suicide [1]. Various chemical
drugs have been developed to treat patients with depression by
interfering with either the uptake or metabolism of aminergic
neurotransmitters [2]. Specifically, drugs that selectively block the
established as effective antideprssants. Furthermore, drugs which
block reuptake at both 5-HT and NA transporters (e.g., venlafaxine
and duloxetine, Fig. 1) or at both NA and dopaminergic (DA)
neurons (e.g., bupropion, Fig. 1), also known as dual reuptake
inhibitors, provide good efficacy and tolerability too [3e5].
Recent research showed that triple reuptake inhibitors are
promising chemical entities for the treatment of depression. New
structures of some triple reuptake inhibitors [6] were revealed to be
DOV-21947 (EB-1010) [7], PRC200-SS [8], and GSK1360707F [9,10]
(Fig. 1), which block the reuptake of 5-HT, NA and DA
* Corresponding author. Tel.: þ86 21 55514600; fax: þ86 21 65312830.
E-mail address: lijianqb@126.com (J.-Q. Li).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.04.030

124
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
Fig. 1. Molecular structures of known clinical and preclinical antidepressants.
transporters. The effectiveness of this class of compounds was
further supported by both preclinical [11] and clinical studies. It is
known that DA agonists themselves (e.g., pergolide, bromocriptine)
showed efficacy as augmenting agents with antidepressant in
clinical studies [7]. It is hypothesized [12,13] that the increase of DA
levels in triple reuptake inhibitors may address the anhedonic
component of depression as well as shorten the time to onset.
Therefore, the triple reuptake inhibitors might result in improved
efficacy toward a broader range of the depressed population [14].
In our previous studies on monoamine transporters, we dis-
good yields (71e89%). Finally, the compounds 5aej were reduced
by sodium borohydride provided the series of target compounds
2aej in excellent yields (85e92%). An alternative synthesis was
employed for those linear-chain analogs of 2keo, where the cor-
responding aryl ketone is unavailable. In this case, ketone deriva-
tives 7aec were prepared with 3-chloropropanoyl chloride and
aromatic ring in the presence of aluminum choride and dichloro-
methane in 75e87% yields. The resulting compounds 7aec were
then treated with 4-benzylpiperidine derivatives 4 via SN2 mech-
anism, yielding 5keo in good yields (76e86%).
closed
a
series of arylalkanol-piperazine compounds (Fig. 2,
According to Scheme 2, target compounds with two chiral
carbon centers on the side-chain analogs, erythro and threo
conformations, were prepared. The relative threo or erythro
configuration were determination by 1H NMR as Solladie reported
[18]. In general, intermediate 9aec were synthesized by Friedel-
Craft acylation of the corresponding aromatic ring in 61e84%
yields, and 9de9e were obtained from commercial suppliers.
Bromination of compounds 9aee with CuBr2 provided compounds
10aee in good yields (74e83%), which were then coupled with 4 to
yield 5pet by nucleophilic substitution in good to excellent yields
(72e90%). Final reduction of ketone 5pet with NaBH4 in methanol
gave a mixture, which were further separated by column chroma-
tography to give threo- and erthro-compounds 2pe2y in 27e38%
yields. All final products were characterized by 1H NMR, MS(ESI)
and elemental analysis.
Compound 1) and reported the biological evaluation of their anti-
depressant activity [15e17]. We have extended our research to the
alternate isostere of piperazine since then.
Herein we reported our synthesis of the arylalkanol-piperidine
derivatives where piperazine in compound 1 was substituted by
piperidine (2j), and investigations of their antidepressant activities
by focusing on both in vitro effect of different arylalkanol substi-
tution on reuptake inhibition and in vivo activity. The results
demonstrate that the arylalkanol structure has great impact on the
antidepressant activity.
2. Results and discussion
2.1. Chemistry
The synthetic routes of all target compounds were outlined in
two schemes. In Scheme 1, a series of linear-chain arylalkanol-
piperidine derivatives (2aeo) was prepared. Briefly, a commercially
available aryl ketone 3 with 4-benzylpiperidine derivatives 4 in the
presence of paraformaldehyde by the Mannich reaction afforded
the intermediate arylalkaneone-piperidine derivatives 5aej in
2.2. Biology
The novel compounds described above were test for their
inhibition of functional uptake of serotonin, noradrenalin and
dopamine. The plasmids were transfected into CHO cells, which
encoded the human serotonin transporter (hSERT), noradrenalin
Fig. 2. Rational design of novel triple reuptake inhibitors.

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
125
Scheme 1. Reagents and conditions: (a) paraformaldehyde, HCl, EtOH, 80; (b) NaBH4, MeOH, rt.; (c) Ar, AlCl3, CH2Cl2, 0e70; (d) CH3CN, DIPEA, rt.
transporter (hNAT), and dopamine transporter (hDAT). Then, the
stably expressed cell strains were selected and used for the uptake
test. 3H-serotonin, 3H-dopamine, 3H-noradrenalin were obtained
from the PerkinElmer Life Sciences, LesUlis, France. The detailed
results were summarized in Table 1.
analog threo-2t was essentially inactive as the triple uptake reup-
take inhibitor, and erythro-2u is only active for 5-HT and NA. Other
side-chain analogs, such as threo-2p, erythro-2q, threo-2v, erythro-
2w, threo-2x and erythro-2y also showed less than 85% inhibition
for 5-HT, NA and DA at the concentration of 10 mM. These results
The role of aromatic ring substitution was first explored. Inter-
estingly, the 3,4-dichlorophenyl substituted compounds 2m and 2n
exhibited higher potency for the three monoamine transporters
than other substituted phenyl compounds, whereas the 3,4-
dimethoxyphenyl 2f and 2,4-difluorophenyl 2h analogs were
weak for all of three transporters. With this information in hand,
the 2,3-dihydrobenzofuran analog 2o was prepared to determine if
fused at the 3,4-positions of phenyl ring would serve to the reup-
take activity. This modification resulted in 2o weak for all of three
transporters. The mono-substituted phenyl compounds 2c, 2d, 2g,
and 2i and the single aromatic ring thiophene derivative 2e did not
show activities, indicating the importance of the 3,4-
dichlorosubstituted in interacting with the monoamine trans-
porters. Increase in hydrophobicity was most prominent with
aromatic substitutions, and any substitution which enhances
aromatic hydrophobic makeup of the molecule will change its
biological activity [19,20]. To explore the effect of enhanced
hydrophobicity of phenyl substitution, the phenyl moiety was
replaced by 5-chloro-6-methoxynaphthalen and benzo[b]thiophen
to produce 2k, 2l, 2a, 2j and 2b, these compounds, with the
exception of benzo[b]thiophen-3-yl (2b), were much potent for all
three transporters.
suggested that the distance of linker chain and the steric effect in
the structure had a great influence on the reuptake activity.
Studies on the chiral side-chain compounds (erythro and threo)
revealed that the erythro compounds were relatively better for 5-
HT and NA reuptake inhibitions (Scheme 2 and Table 1). For
example, the erythro conformation of 2s showed good selectivity
for 5-HT reuptake inhibition, whereas the threo isomer 2r
expressed less than 80% inhibition even at a concentration of
10 mM. The erythro isomer 2u was a dual reuptake inhibitor for 5-
HT and NA, and the threo 2t was inactive.
On the basis of in vitro studies, five compounds 2a, 2j, 2k, 2m
and 2n were selected for profiling in the mouse tail suspension test
(TST) [21], which has predictive value for antidepressant-like
activity. The compounds were administered orally 30 min before
the test in mice. For comparative purposes, venlafaxine (50 mg/kg,
po.) was also included in the experiment. The TST must be validated
by testing the influence of the compounds on motor behavior
because an increase in motor activity might account for changes in
the immobility time in the test. The second in vivo test involves
spontaneous locomotor activity test, venlafaxine was selected as
a positive control. And the results were displayed in Fig. 3.
It is evident that the compounds 2j, 2k and 2m are dose
dependently reduced the immobility time in the TST, which were
statistically significant compared to the vehicle at 20 and 50 mg/kg
dose (Fig. 3aee). The positive control, venlafaxine, also produced
a statistically significant reduction of immobility time at 50 mg/kg
dose. Specifically, the effects of 2j and 2m were statistically
significant even at lower dose of 10 mg/kg, these compounds
induced the marked antidepressant-like effects and were the most
potent ones in the TST model.
The uptake activities of compounds with linear and side-chains
were also explored. In general, the linear-chain analogs exhibited
higher potency for all three monoamine transporters than the side-
chain analogs. As shown in Table 1, compounds 2l and 2n exhibited
potent activities. For the 2l, the IC50 values were determined to be
427, 800 nM for 5-HT and NA, respectively, whereas the corre-
sponding side-chain analogs threo-2r and erythro-2s were
observed active only for 5-HT. In the case of 2n, the side-chain
O
O
O
O
O
a
4
Y
b
d
1)
Ar
N
Br
O
Ar
9a-e
Ar
c
2) e
8
10a-e
5p-t
OH
Y
Ar
N
2p-2y
Scheme 2. Reagents and conditions: (a) Ar, AlCl3, CH2Cl2, 0e70; (b) CuBr2, CH2Cl2, reflux; (c) CH3CN, DIPEA, rt; (d) NaBH4, MeOH, rt; (e) silica gel (200e300 mesh) column
chromatography, dichloromethane/methanol, 20:1 v/v.

126
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
Table 1
Activity at monoamine transporters of target compounds.
.
Compd.
Stereochemistry
NA
Ar
Y
[3H]5-HT uptake IC50 (nM)
[3H]NA uptake IC50 (nM)
[3H]DA uptake IC50 (nM)
DOV21947
411 ꢀ 34
71 ꢀ 5
159 ꢀ 13
2a
rac
255 ꢀ 31
327 ꢀ 19
491 ꢀ 32
2b
rac
OH
27%a
61%a
64%a
2c
2d
2e
rac
rac
rac
56%a
62%a
78%a
50%a
83%a
82%a
61%a
30%a
52%a
2f
rac
74%a
63%a
61%a
2g
2h
2i
rac
rac
rac
65%a
74%a
78%a
62%a
55%a
66%a
57%a
66%a
768 ꢀ 56
2j
rac
rac
171 ꢀ 15
265 ꢀ 22
385 ꢀ 27
420 ꢀ 30
566 ꢀ 66
346 ꢀ 41
2k
2l
rac
rac
OH
OH
427 ꢀ 38
337 ꢀ 25
800 ꢀ 57
265 ꢀ 33
73%a
2m
564 ꢀ 44

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
127
Table 1 (continued )
Compd.
Stereochemistry
Ar
Y
[3H]5-HT uptake IC50 (nM)
[3H]NA uptake IC50 (nM)
[3H]DA uptake IC50 (nM)
2n
rac
425 ꢀ 33
178 ꢀ 13
689 ꢀ 71
2o
2p
rac
74%a
55%a
88%a
49%a
75%a
a
threo (rac)
78%
2q
erythro (rac)
33%a
34%a
77%a
2r
2s
threo (rac)
OH
OH
80%a
63%a
51%a
22%a
56%a
erythro (rac)
357 ꢀ 30
55%a
2t
threo (rac)
erythro (rac)
threo (rac)
38%a
36%a
a
2u
2v
367 ꢀ 20
531 ꢀ 42
64%
59%a
62%a
70%a
2w
2x
erythro (rac)
threo (rac)
80%a
61%a
55%a
83%a
68%a
35%a
2y
erythro (rac)
63%v
57%a
70%a
a
Percent inhibition measured at a concentration of 10
m
M. rac ¼ racemate.

128
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
Fig. 3. (a) Compound 2a in the mouse TSTat 10, 20 and 50 mg/kg po. (b) Compound 2j in the mouse TSTat 10, 20 and 50 mg/kg po. (c) Compound 2k in the mouse TSTat 10, 20 and 50 mg/
kg po. (d) Compound 2m in the mouse TSTat 10, 20 and 50 mg/kg po. (e) Compound 2n in the mouse TSTat 10, 20 and 50 mg/kg po. (f) Compounds in the mouse locomotor activity assay
at 5 min time point, at 50 mg/kg po. CON ¼ Control, VEN ¼ Venlafaxine, one-way ANOVA followed by Scheffe post hoc test, (*) p<0.05 vs control, (**) p<0.001 vs control.
By the mouse spontaneous locomotor activity test, the effects of
compounds 2a, 2j, 2k, 2m and 2n in the TST were not due to
a general locomotor activation effect. The compounds did not
produce statistically significant increase locomotor activity in vivo
in the first 5 min at the 50 mg/kg dose (Fig. 3f). The 5 min time point
was significant because that is the amount of time the compounds
were evaluated in the TST.
Compounds 2a, 2j, 2k, 2m and 2n were further characterized in
several CNS receptor binding assays to assess the selectivity and
specific interactions of these compounds with the monoamine
Table 2
Binding affinity of compounds 2a, 2j, 2k, 2m and 2n for CNS receptorsa.
Target receptor
Radioligand
Inhibition of 2a (%)
Inhibition of 2j (%)
Inhibition of 2k (%)
Inhibition of 2m (%)
Inhibition of 2n (%)
5-HT1A
5-HT1B
5-HT2A
5-HT2B
5-HT3
5-HT5A
5-HT6
5-HT7
D1
[3H]8eOHeDPAT
65.4
ꢁ15.3
31.5
6.1
10.6
0.2
53.7
43.5
85.6(9650 nM)b
10.8
1.2
33.4
6.5
42.6
14.5
8.3
33.5
16.8
29.7
35.6
4.3
46.5
10.2
15.6
ꢁ30.8
0.5
ꢁ10.6
ꢁ0.9
5.8
27.1
ꢁ0.5
11.3
45.6
32.9
46.7
28.5
10.6
33.2
57.8
12.9
27.3
9.7
0.9
10.3
0.6
4.8
33.5
25.1
ꢁ11.0
1.9
[
125I]CYP
[3H]Ketanserin
[3H]Mesulergine
[3H]BRL 43694
[3H]LSD
4.9
14.1
41.6
14.8
19.2
47.9
19.2
4.6
[3H]LSD
[3H]LSD
0.5
[3H]SCH 23390
[3H]Methylspiperone
[3H]Methylspiperone
[3H]Prazosin
33.3
31.4
10.3
35.6
16.2
58.9
62.3
31.2
15.6
10.7
7.9
D2
D3
3.5
alpha 1
alpha 2
beta 1
beta 2
H 1
H 2
M 1
M 2
0.8
51.2
27.3
33.4
49.8
45.3
14.9
4.3
84.3(8000nM)b
43.5
15.3
14.7
12.5
6.7
[3H]RX 821002
[3H](ꢁ)CGP12177
[3H](ꢁ)CGP12177
[3H]Pyrilamin
32.5
41.2
16.7
0.1
8.2
31.2
6.5
[
125I]APT
[3H]pirenzepine
[3H]AF-DX 384
34.2
16.5
3.7
a
Percent inhibition measured at a concentration of 10
The IC50 when the percent inhibition high than 80%.
mM.
b

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
129
Table 3
Pharmacokinetic properties of compounds 2j and 2m after oral (10 mg/kg) and iv (1 mg/kg) administration to SD rats.
Dose (mg/kg)
1(iv)
Compd
AUC(0-inf) (h$ng/mL)
t1/2 (h)
Tmax (h)
Cmax (ng/mL)
F%
2j
2m
2j
1025 ꢀ 307
1234 ꢀ 511
5720 ꢀ 1234
5439 ꢀ 1834
2.5 ꢀ 0.8
2.3 ꢀ 1.0
3.5 ꢀ 1.4
2.9 ꢀ 0.9
653 ꢀ 231
750 ꢀ 330
923 ꢀ 426
897 ꢀ 356
10(po)
0.5 ꢀ 0.1
0.7 ꢀ 0.1
55.8
44.1
2m
transporters. The assays were performed at CEREP (Celle L’Ev-
escault, France) using a similar procedure as described previously
[22]. The description of all receptors targeted and corresponding
radioligand used, is provided in Table 2. The default concentration
at 254 and/or 265 nm. Uncorrected melting points were deter-
mined on an electrothermal melting point apparatus. Solvents and
reagents were used without any pretreatment.
for primary binding experiments was 10
mM. Compounds with
4.1.1. Procedure A: synthesis of compounds 7aec
inhibition >80% in the primary assay were moved into the
secondary assay with full concentration curves of the test
compound in order to test the IC50 value for inhibition. It is clear
from the results in Table 2 that compounds 2a, 2j, 2k, 2m and 2n
does not potently bind to any of the receptor tested. In cases where
4.1.1.1. 3-Chloro-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-
one (7a). Aluminum chloride (8.4 g, 62.0 mmol) was added drop-
wise to a solution of 3-chloropropanoyl chloride (7.2 g, 57.0 mmol)
in chloroform (70 mL) at room temperature. The reaction mixture
was stirred at the same temperature for 1 h. After cooling to 10,
a solution of 1-chloro-2-methoxynaphthalene (11.0 g, 57.0 mmol)
in chloroform (25 mL) was added dropwise, and then the mixture
was stirred at room temperature for 2.5 h. The reaction was
complete as determined by thin layers chromatography (TLC) with
EtOAc/hexane (1/15, v/v). The reaction mixture was poured slowly
onto ice water, after stirred for 30 min, the organic layer was
washed with water and brine, dried over anhydrous sodium sulfate,
filtered, and concentrated in reduced pressure. the crude product
was purified by silica gel column chromatography with EtOAc/
hexane (1/20, v/v) as mobile phase to give 7a (12.1 g, 75.0%) as
a pale yellow solid. Mp: 74e76. MS (ESI) m/z: 283 (Mþ1).
it exhibited >80% binding in the primary assay at 10 mM, the follow
up secondary binding result revealed little to no potency.
To further evaluate this series of compounds, the pharmacoki-
netic properties of 2j and 2m were measured in male SD rats. After
oral administration of 10 mg/kg of 2j to rats, a Cmax of 923 ng/mL
was obtained at 30 min (Table 3). The elimination half-life of 2j
following oral administration was 3.5 h in rats. Compound 2j
showed a good bioavailability (F ¼ 55.8%) in rats. Compound 2m
also had a good bioavailability (F ¼ 44.1%), rapid absorption with
maximum concentration achieved within 1 h, and a moderate
terminal half-life (t1/2 ¼ 2.9 h).
3. Conclusion
4.1.1.2. 3-Chloro-1-(3,4-dichlorophenyl)propan-1-one (7b). Starting
with 1,2-dichlorobenzene (14.7 g, 0.1 mol), Procedure A was fol-
lowed to afford compound 7b (20.5 g, 87.1%) as a white solid. Mp:
58e60 (Lit. 59e60) [23]. MS (ESI) m/z: 237 (Mþ1).
In summary, a new series of arylalkanol-piperidine derivatives
was investigated, and as our continuing effort to identify novel
compounds targeting 5-HT, NA and DA reuptake inhibition for the
treatment of depressive disorders. We showed the synthesis and
in vitro characterization of a wide range of arylalkanol-piperidine
in this new scaffold and probed the SAR around the 5-HT, NA and
DA transporters. Benzo[b]thiophen and 3,4-dichlorophenyl
emerged as preferred aromatic substituents for developing
potency at the three transporters. In vivo profiling of five candi-
dates (2a, 2j, 2k, 2m and 2n) in the TST confirmed our hypothesis
and showed that this scaffold holds potential for the development
of novel antidepressants. Notably, two lead compounds (2j and 2m)
had good pharmacokinetic profiles and exhibited significant effi-
cacy in the TST. Future studies are ongoing to fully appreciate the
therapeutic potential of such compounds.
4.1.1.3. 3-Chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one
(7c). Starting with 2,3-dihydrobenzofuran (6.0 g, 50.0 mmol),
Procedure A was followed to afford compound 7c (8.4 g, 80.2%) as
a white solid. Mp: 53e55. MS (ESI) m/z: 211 (Mþ1).
4.1.2. Procedure B: synthesis of compounds 10aee
4.1.2.1. 1-(benzo[b]thiophen-3-yl)-2-bromopropan-1-one (10a). To
a stirred solution of benzo[b]thiophene (5.0 g, 37.3 mmol) in CH2Cl2
(60 mL) was added dropwise aluminum chloride (6.5 g, 48.4 mmol)
at room temperature. After completion of addition, the mixture was
stirred at the same temperature for 10 min. The reaction was cooled
to 0, a solution of propionic anhydride (5.8 g, 44.7 mmol) in CH2Cl2
(20 mL) was added dropwise and stirred at the same temperature
for 1 h. Quenched the reaction by the addition of water (30 mL). The
organic layer were washed with water (50 mL), brine (50 mL) and
dried over anhydrous sodium sulfate, and solvent was removed
under reduced pressure. The crude residue was purified by silica gel
column chromatography using EtOAc/hexane (1/20, v/v) as mobile
phase to give 9a (6.2 g, 61.7%) as a white solid. Mp: 78e80 (Lit.
79e81) [24].MS (ESI) m/z: 191 (Mþ1). 1H NMR (400 MHz, CDCl3):
4. Experimental protocols
4.1. Chemistry
Nuclear magnetic resonance (NMR) spectra were recorded on
a Varian INOVA-400 spectrometer with TMS as an internal stan-
dard. Chemical shift (
d values) and coupling constants (J values) are
given in ppm and Hz, respectively. ESI mass spectra were per-
formed on an Agilent 6210 TOF spectrometer. Elemental analyses
were performed on a MOD-1106 instrument and are consistent
with theoretical values within ꢀ0.4%. The progress of all reactions
was monitored using TLC on precoated silica gel plates GF254
(Qingdao Haiyang Chemical, China). Silica gel column chromatog-
raphy was performed with Silica gel 60G (Qingdao Haiyang
Chemical, China). The chromatograms were viewed under UV light
d
8.77 (d, J ¼ 8.0 Hz, 1H, AreH), 8.26 (s, 1H, thiophen-2H), 7.85 (d,
1H, AreH), 7.49 (t, J ¼ 8.0 Hz, 1H, AreH) 7.41 (t, J ¼ 8.0 Hz, 1H,
AreH), 3.02 (q, J ¼ 7.2 Hz, CH2CH3), 1.28 (t, J ¼ 7.2 Hz, CH2CH3).
To a stirred solution of 9a (6.2 g, 32.6 mmol) in EtOAc/CHCl3
(40 mL/40 mL) was added CuBr2 (15.1 g, 65.3 mmol). The reaction
mixture was slowly heated to reflux, and the refluxing was
continued for 4 h. After the mixture was cooled to room temper-
ature, filtered, and the solvent was removed under reduced

130
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
pressure. The crude residue was purified by column chromatog-
raphy using EtOAc/hexane (1/20, v/v) as mobile phase to give
compound 10a (7.3 g, 83.2%) as a white solid. Mp: 65e66. MS (ESI)
m/z: 269 (Mþ1).
to afford compound 5c (6.2 g, 79.5%) as a white solid. Mp: 191e193.
MS (ESI) m/z: 340 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.16e2.51
(m, 2H, 4Hpy.), 3.11e3.17 (m, 2H, 4Hpy.), 3.38 (s, 2H, AreCH2e),
3.41e3.44 (t, J ¼ 6.8 Hz, 2H, eCOCH2CH2Ne), 3.67e3.70 (t,
J ¼ 6.8 Hz, 2H, eCOCH2CH2Ne), 3.44e3.84 (m, 2H, 4Hpy.), 5.47 (s,1H,
]CH), 7.21e7.24 (m, 3H, AreH), 7.30e7.33 (m, 2H, AreH), 7.62e7.65
(m, 2H, AreH), 8.00e8.03 (m, 2H, AreH), 10.86 (br, 1H, HCl).
4.1.2.2. 2-Bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-
one (10b). Starting with 1-chloro-2-methoxynaphthalene (3.84 g,
20.0 mmol), Procedure B was followed to afford compound 9b
(4.2 g, 84.7%), then 10b (4.1 g, 74.3%) was got as a pale yellow solid.
Mp: 73e75. MS (ESI) m/z: 327 (Mþ1).
4.1.3.4. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-p-tolylpropan-
1-one hydrochloride (5d). Starting with 1-p-tolylethanone (2.7 g,
20.1 mmol) and 4-benzyl-1,2,3,6-tetrahydropyridine hydrochloride
(4.6 g, 22.2 mmol), Procedure C was followed to afford compound
5d (6.1 g, 85.3%) as a white solid. Mp: 180e183. MS (ESI) m/z: 320
4.1.2.3. 2-Bromo-1-(3,4-dichlorophenyl)propan-1-one (10c). Starting
with 1,2-dichlorobenzene (14.6 g, 100.0 mmol), Procedure B was fol-
lowed to afford compound compound 9c (16.2 g, 80.2%), then 10c
(18.6 g, 82.8%) was got as a pale yellow solid. Mp: 49e51 (Lit. 50e51)
[25]. MS (ESI) m/z: 281 (Mþ1).
(Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.15e2.50 (m, 2H, 4Hpy.),
2.39 (s, 3H, AreCH3), 3.10e3.50 (m, 2H, 4Hpy.), 3.37 (s, 2H,
AreCH2e), 3.41e3.44 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.62e3.66
(t, J ¼ 6.8 Hz, 2H, eCOCH2CH2Ne), 3.62e3.83 (m, 2H, 4Hpy.), 5.47 (s,
1H, ]CH), 7.21e7.24 (m, 3H, AreH), 7.29e7.33 (t, J ¼ 7.2 Hz, 2H,
AreH), 7.35e7.37 (d, J ¼ 8.0 Hz, 2H, AreH), 7.89e7.91 (d, J ¼ 8.4 Hz,
2H, AreH), 10.77 (br, 1H, HCl).
4.1.2.4. 2-Bromo-1-(4-methoxyphenyl)propan-1-one (10d). Starting
with 1-(4-methoxyphenyl)propan-1-one (3.3 g, 20.1 mmol), Procedure
B was followed to afford compound 10d (4.0 g, 82.1%) as a pale yellow
solid. Mp: 66e68 (Lit. 66) [26]. MS (ESI) m/z: 243 (Mþ1).
4.1.3.5. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(thiophen-2-yl)
propan-1-one hydrochloride (5e). Starting with 1-(thiophen-2-yl)
ethanone (2.7 g, 21.4 mmol) and 4-benzyl-1,2,3,6-tetrahydropyr
idine hydrochloride (4.8 g, 23.1 mmol), Procedure C was followed to
afford compound 5e (5.6 g, 75.4%) as a white solid. Mp: 166e168. MS
4.1.2.5. 2-Bromo-1-(3-fluorophenyl)propan-1-one
(10e). Starting
with 1-(3-fluorophenyl)propan-1-one (4.5 g, 29.6 mmol), Proce-
dure B was followed to afford compound 10e (5.2 g, 76.3%) as a pale
yellow solid. Mp: 58e59. MS (ESI) m/z: 231 (Mþ1).
(ESI) m/z: 312 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.15e2.44 (m,
4.1.3. Procedure C: synthesis of compounds 5aej
2H, 4Hpy.), 3.12e3.21 (m, 2H, 4Hpy.), 3.41 (s, 2H, AreCH2e),
4.1.3.1. 1-(benzo[b]thiophen-2-yl)-3-(4-benzyl-5,6-dihydropyridin-1
(2H)-yl)propan-1eone hydrochloride (5a). To a stirred mixture of
compounds 1-(benzo[b]thiophen-2-yl)ethanone (3.7 g, 21.0 mmol)
and paraformaldehyde (0.8 g, 27.3 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (4.8 g, 23.1 mmol) in ethanol
(95%, 15 mL) was added concentrated hydrochloric acid (0.2 mL).
The reaction was slowly heated to reflux, and the refluxing was
continued for 5 h. After the mixture was cooled to room temper-
ature, the solvent was removed under reduced pressure. The crude
residue was extracted with CH2Cl2 (50 mL) and water (30 mL). The
organic layer was washed with brine (30 mL) and dried over
anhydrous sodium sulfate, and the solvent was removed under
reduced pressure. The residue was dissolved in ethyl acetate
(20 mL) was added hydrogen chloride ethanol solution (1.25 M,
16 mL) dropwise, and the resulting mixture was stirred for 1 h at
room temperature to give a hydrochloride product. The white solid
was filtered, washed thoroughly with ethyl acetate and ethanol,
separately, and to give compound 5a (6.3 g, 75.4%) as a white solid.
Mp: 200e203. MS (ESI) m/z: 362 (Mþ1). 1H NMR (400 MHz, DMSO-
3.43e3.49 (t,
J
¼
7.2 Hz, 2H, eCOCH2CH2Ne), 3.63e3.66 (t,
J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.49e3.82 (m, 2H, 4Hpy.), 5.47(s, 1H,
]CH), 7.21e7.24 (m, 1H, thiop.), 7.21e7.24 (m, 2H, Ar), 7.28e7.34 (m,
3H, Ar), 8.03e8.06 (m, 2H, thiop.), 10.95 (br, 1H, HCl).
4.1.3.6. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dimethoxy
phenyl)propan-1-one hydrochloride (5f). Starting with 1-(3,4-
dimethoxyphenyl)ethanone (3.6 g, 20.0 mmol) and 4-benzyl-
1,2,3,6-tetrahydropyridine hydrochloride (4.6 g, 22.0 mmol),
Procedure C was followed to afford compound 5f (5.7 g, 71.1%) as
a white solid. Mp: 170e172. MS (ESI) m/z: 366 (Mþ1). 1H NMR
(400 MHz, DMSO-d6): d 2.15e2.51 (m, 2H, 4Hpy.), 3.13e3.44 (m, 2H,
4Hpy.), 3.40 (s, 2H, AreCH2e), 3.41e3.42 (m, 2H, eCOCH2CH2Ne),
3.51e3.76 (m, 2H, 4Hpy.), 3.60e3.67 (m, 2H, eCOCH2CH2Ne),
5.47 (s, 1H, ]CH), 7.09e7.11 (d, J ¼ 8.8 Hz, 1H, AreH), 7.21e7.24
(m, 3H, AreH), 7.29e7.33 (t, J ¼ 7.6 Hz, 2H, AreH), 7.48e7.49 (d,
J ¼ 2.0 Hz, 1H, AreH), 7.67e7.70 (dd, J1 ¼ 2.0 Hz, J2 ¼ 6.4 Hz, 1H,
AreH), 10.70 (br, 1H, HCl).
d6):
d
2.14e2.43 (m, 2H, 4Hpy.(1,2,3,6-tetrahydropyridine)),
4.1.3.7. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-nitrophenyl)
propan-1-one hydrochloride (5g). Starting with 1-(4-nitrophenyl)
ethanone (2.5 g, 15.2 mmol) and 4-benzyl-1,2,3,6-tetrahydro
pyridine hydrochloride (3.5 g, 16.7 mmol), Procedure C was fol-
lowed to afford compound 5g (4.6 g, 78.6%) as pale yellow solid.
Mp: 177e179. MS (ESI) m/z: 351 (Mþ1). 1H NMR (400 MHz, DMSO-
3.15e3.50 (m, 2H, 4Hpy.), 3.38 (s, 2H, AreCH2e), 3.46e3.50 (t,
J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.75e3.78 (t, J ¼ 7.2 Hz, 2H,
-COCH2CH2Ne), 3.69e3.85 (m, 2H, 4Hpy.), 5.49 (s, 1H, ]CH),
7.22e7.33 (m, 5H, AreH), 7.48e7.58 (m, 2H, AreH), 8.05e8.07 (d,
J ¼ 8.0 Hz, 2H, AreH), 8.45 (s, 1H, AreH), 10.85 (br, 1H, HCl).
d6):
2H, AreCH2e), 3.45e3.48 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne),
3.68e3.85 (m, 2H, 4Hpy.), 3.74e3.78 (t, 7.2 Hz, 2H,
d 2.17e2.49 (m, 2H, 4Hpy.), 3.11e3.51 (m, 2H, 4Hpy.), 3.37 (s,
4.1.3.2. 1-(benzo[b]thiophen-3-yl)-3-(4-benzyl-4-hydroxypiperidin-
1-yl)propan-1-one hydrochloride (5b). Starting with 1-(benzo[b]
thiophen-3-yl)ethanone (3.5 g, 20 mmol) and 4-benzylpiperidin-4-
ol hydrochloride (5.0 g, 22 mmol), Procedure C was followed to
afford compound 5b (6.5 g, 78.3%) as a white solid. Mp: 173e175.
MS (ESI) m/z: 380 (Mþ1).
J
¼
eCOCH2CH2Ne), 5.47 (s, 1H, ]CH), 7.21e7.24 (m, 3H, AreH),
7.29e7.33 (m, 2H, AreH), 8.21e8.24 (m, 2H, AreH), 8.36e8.39 (m,
2H, AreH), 10.80 (br, 1H, HCl).
4.1.3.8. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(2,4-difluorophe
nyl)propan-1-one hydrochloride (5h). Starting with 1-(2,4-
difluorophenyl)ethanone (2.1 g, 13.5 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (3.1 g, 14.8 mmol), Procedure C
was followed to afford compound 5h (3.6 g, 71.0%) as a white solid.
4.1.3.3. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-chlorophenyl)
propan-1-one hydrochloride (5c). Starting with 1-(4-chlorophenyl)
ethanone (3.2 g, 20.8 mmol) and 4-benzyl-1,2,3,6-tetrahydro-
pyridine hydrochloride (4.8 g, 23.1 mmol), Procedure C was followed

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
131
Mp: 171e173. MS (ESI) m/z: 342 (Mþ1). 1H NMR (400 MHz, DMSO-
4.1.4.3. 3-(4-Benzyl-4-hydroxypiperidin-1-yl)-1-(3,4-dichlorophenyl)
d6):
d
2.15e2.50 (m, 2H, 4Hpy.), 3.13e3.45 (m, 2H, 4Hpy.), 3.36 (s,
propan-1-one hydrochloride (5m). Starting with 3-chloro-1-(3,4-
dichlorophenyl)propan-1-one (2.4 g, 10.2 mmol) and 4-
benzylpiperidin-4-ol hydrochloride (1.8 g, 9.3 mmol), Procedure D
was followed to afford compound 5m (3.0 g, 75.9%) as a white solid.
Mp: 202e204. MS (ESI) m/z: 392 (Mþ1). 1H NMR (400 MHz, DMSO-
2H, AreCH2e), 3.40e3.43 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne),
3.57e3.60 (t, J ¼ 7.2 Hz, 2H, -COCH2CH2Ne), 3.65e3.79 (m, 2H,
4Hpy.), 5.46 (s, 1H, ]CH), 7.20e7.39 (m, 6H, AreH), 7.40e7.45 (m,
1H, AreH), 7.96e8.02 (m, 1H, AreH), 10.59 (br, 1H, HCl).
d6):
d 1.60e1.63 (m, 2H, NCH2CH2CeOH), 1.77e1.85 (m, 2H,
4.1.3.9. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-methoxyphe
NCH2CH2CeOH), 2.75 (s, 2H, AreCH2e), 3.14 (m, 2H, NCH2CH2CeOH),
3.35 (m, 2H, NCH2CH2CeOH), 3.39 (m, 2H, COCH2CH2N), 3.54e3.57 (t,
J ¼ 7.6 Hz, 2H, COCH2CH2N), 7.21e7.30 (m, 5H, AreH), 7.78e7.80 (d,
J ¼ 8.4 Hz,1H, AreH), 7.91e7.93 (dd, J1 ¼ 2.0 Hz, J2 ¼ 8.8 Hz,1H, AreH),
8.15 (d, J ¼ 2.0 Hz, 1H, AreH).
nyl)propan-1-one
hydrochloride
(5i). Starting
with
1-(4-
methoxyphenyl)ethanone (1.5 g, 10.0 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (2.3 g, 11.0 mmol), Procedure C
was followed to afford compound 5i (3.3 g, 88.9%) as a white solid.
Mp: 182e184. MS (ESI) m/z: 336 (Mþ1).
4.1.4.4. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichloroph
enyl)propan-1-one hydrochloride (5n). Starting with 3-chloro-1-
(3,4-dichlorophenyl)propan-1-one (2.4 g, 10.2 mmol) and 4-benzyl-
1,2,3,6-tetrahydropyridine hydrochloride (1.6 g, 9.2 mmol), Procedure
D was followed to afford compound 5n (3.2 g, 76.9%) as a white solid.
Mp: 190e193. MS (ESI) m/z: 374 (Mþ1). 1H NMR (400 MHz, DMSO-
4.1.3.10. 1-(benzo[b]thiophen-3-yl)-3-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)propan-1-one hydrochloride (5j). Starting with 1-(benzo
[b]thiophen-3-yl)ethanone (3.4 g,19.3 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (4.4 g, 21.2 mmol), Procedure C
was followed to afford compound 5j (5.6 g, 73.0%) as a white solid.
Mp: 213e215. MS (ESI) m/z: 362 (Mþ1). 1H NMR (400 MHz, DMSO-
d6): d 2.15e2.44 (m, 2H, 4Hpy.), 3.11e3.51 (m, 2H, 4Hpy.), 3.37 (s, 2H,
d6):
d
2.18e2.42 (m, 2H, 4Hpy.), 3.16e3.51 (m, 2H, 4Hpy.), 3.38 (s, 2H,
AreCH2e), 3.41e3.45 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.67e3.71 (t,
J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.67e3.84 (m, 2H, 4Hpy.), 5.47 (s, 1H,
]CH), 7.20e7.23 (m, 3H, AreH), 7.29e7.33 (m, 2H, AreH), 7.82e7.84
(d, J ¼ 8.4 Hz, 1H, AreH), 7.93e7.96 (m, 1H, AreH), 8.20e8.21 (d,
J ¼ 2.4 Hz, 1H, AreH), 10.88 (br, 1H, HCl).
AreCH2e), 3.47e3.51 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.68e3.71
(t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.74e3.86 (m, 2H, 4Hpy.), 5.48
(s, 1H, ]CH), 7.21e7.23 (m, 3H, AreH), 7.29e7.33 (t, J ¼ 7.6 Hz, 2H,
AreH), 7.45e7.55 (m, 2H, AreH), 8.08e8.10 (d, J ¼ 8.0 Hz,1H, AreH),
8.58e8.60 (d, J ¼ 8.0 Hz, 1H, AreH), 9.04 (s, 1H, AreH).
4.1.4.5. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(2,3-dihydroben
4.1.4. Procedure D: synthesis of compounds 5keo
zofuran-5-yl) propan-1-one hydrochloride (5o). Starting with 3-
4.1.4.1. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(5-chloro-6-met
hoxynaphthalen -2-yl)propan-1-one hydrochloride (5k). To a stirred
mixture of compounds 3-chloro-1-(5-chloro-6-methoxynaph
thalen-2-yl)propan-1-one (2.0 g, 7.1 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (1.1 g, 6.4 mmol) in CH3CN (20 mL)
was added N,N-Diisopropylethylamine (1.7 g, 12.9 mmol). After being
stirred overnight at room temperature, the solvent was removed under
reduced pressure. The crude residuewas extracted with CH2Cl2 (30 mL)
and water (130 mL). The organic layer was washed with brine (20 mL)
and dried overanhydrous sodium sulfate, and the solvent was removed
under reduced pressure. The residue was dissolved in ethyl acetate
(10 mL) was added hydrogen chloride ethanol solution (1.25 M, 8 mL)
dropwise, and the resulting mixture was stirred for 1 h at room
temperature to give a hydrochloride product. The white solid was
filtered, washed thoroughly with ethyl acetate and ethanol, separately,
and to give compound 5k (2.4 g, 81.9%) as a white solid. Mp: 183e185.
chloro-1-(2,3-dihydrobenzofuran-5-yl)propan-1-one
(2.1
g,
10.0 mmol) and 4-benzyl-1,2,3,6-tetrahydropyridine hydrochloride
(1.6 g, 9.2 mmol), Procedure D was followed to afford compound 5o
(3.0 g, 86.2%) as a white solid. Mp: 190e192. MS (ESI) m/z: 348
(Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.11e2.49 (m, 2H, 4Hpy.),
3.13e3.51 (m, 2H, 4Hpy.), 3.23e3.27 (t, J ¼ 8.8 Hz, 2H, eOCH2CH2e),
3.38 (s, 2H, AreCH2e), 3.40.3.43 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne),
3.59e3.63 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.66e3.83 (m, 2H,
4Hpy.), 4.63e4.67 (t, J ¼ 8.8 Hz, 2H, eOCH2e), 5.47 (s, 1H, ]CH),
6.88e6.90 (d, 1H, J ¼ 8.4 Hz, AreH), 7.21e7.24 (m, 3H, AreH),
7.30e7.34 (m, 2H, AreH), 7.83e7.86 (d, 1H, J ¼ 8.4 Hz, AreH), 7.91
(s, 1H, AreH), 10.98 (br, 1H, HCl).
4.1.4.6. 1-(benzo[b]thiophen-3-yl)-2-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)propan-1-one hydrochloride (5p). Starting with 1-(benzo
[b]thiophen-3-yl)-2-bromopropan-1-one (3.0 g, 11.2 mmol) and 4-
benzyl-1,2,3,6-tetrahydropyridine hydrochloride (1.7 g,10.2 mmol),
Procedure D was followed to afford compound 5p (3.2 g, 79.2%) as
a white solid. Mp: 217e218. MS (ESI) m/z: 362 (Mþ1). 1H NMR
MS (ESI) m/z: 420 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.16e2.43
(m, 2H, 4Hpy.), 3.18e3.56 (m, 2H, 4Hpy.), 3.38 (s, 2H, AreCH2e),
3.50e3.53 (t, J ¼ 7.2 Hz, 2H, eCOCH2CH2Ne), 3.74e3.78 (t, J ¼ 7.2 Hz,
2H, eCOCH2CH2Ne), 3.74e3.90 (m, 2H, 4Hpy.), 4.05 (s, 3H, eOCH3),
5.50 (s, 1H, ]CH), 7.22e7.24 (m, 3H, AreH), 7.30e7.34 (t, J ¼ 7.6 Hz,
2H, AreH), 7.69e7.71 (d, J ¼ 9.2 Hz, 1H, AreH), 8.10e8.20 (m, 3H,
AreH), 8.75 (s, 1H, AreH).
(400 MHz, DMSO-d6):
d
1.57e1.59 (d, J ¼ 7.2 Hz, 3H, COCHCH3), 2.32
(m, 2H, 4Hpy.), 3.30 (m, 2H, 4Hpy.), 3.37 (s, 2H, AreCH2e),
3.57e3.86 (m, 2H, 4Hpy.), 5.22e5.24 (d, J ¼ 7.2 Hz, 1H, COCHCH3),
5.48 (s, 1H, ]CH), 7.20e7.22 (d, J ¼ 7.6 Hz, 3H, AreH), 7.29e7.33 (t,
J ¼ 7.6 Hz, 2H, AreH), 7.49e7.58 (m, 2H, AreH), 8.09e8.11 (d,
J ¼ 7.6 Hz,1H, AreH), 8.56e8.58 (d, J ¼ 8.4 Hz,1H, AreH), 9.10 (s,1H,
AreH).
4.1.4.2. 3-(4-Benzyl-4-hydroxypiperidin-1-yl)-1-(5-chloro-6-methox
ynaphthalen-2-yl)propan-1-one hydrochloride (5l). Starting with 3-
chloro-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (2.9 g,
18.7 mmol) and 4-benzylpiperidin-4-ol hydrochloride (1.8 g,
9.3 mmol), Procedure D was followed to afford compound 5l (4.0 g,
82.3%) as awhite solid. Mp: 211e213. MS (ESI) m/z: 438 (Mþ1).1HNMR
4.1.4.7. 2-(4-Benzyl-4-hydroxypiperidin-1-yl)-1-(5-chloro-6-methox
ynaphthalen-2-yl)propan-1-one hydrochloride (5q). Starting with 2-
bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one
(3.26 g, 10.0 mmol) and 4-benzylpiperidin-4-ol hydrochloride
(2.06 g, 9.1 mmol), Procedure D was followed to afford compound
5q (3.4g, 79.3%) as a white solid. Mp: 229e230. MS (ESI) m/z: 438
(Mþ1).
(400 MHz, DMSO-d6):
d 1.61e1.65 (m, 2H, NCH2CH2COH), 1.88e1.94
(m, 2H, NCH2CH2COH), 2.77 (s, 2H, ArCH2e), 3.12e3.18 (m, 2H,
NCH2CH2COH), 3.40 (m, 2H, NCH2CH2COH), 3.43e3.45 (m, 2H,
COCH2CH2N), 3.74e3.77 (t, J ¼ 6.8 Hz, 2H, COCH2CH2N), 4.06 (s, 3H,
eOCH3), 4.84 (s, 1H, eOH), 7.23e7.32 (m, 5H, AreH), 7.69e7.71 (d,
J¼ 9.2 Hz,1H, AreH), 8.10e8.12 (d, J ¼ 8.8 Hz,1H, AreH), 8.17e8.21 (dd,
J1 ¼6.0 Hz, J2 ¼ 9.2 Hz, 2H, AreH), 8.77 (s,1H, AreH),10.23 (br,1H, HCl).
4.1.4.8. 2-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichloroph
enyl)propan-1-one hydrochloride (5r). Starting with 2-bromo-1-

132
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
(3,4-dichlorophenyl)propan-1-one (2.8 g, 10.0 mmol) and 4-
benzyl-1,2,3,6-tetrahydropyridine hydrochloride (1.6 g,
4.1.5.2. 1-(3-(benzo[b]thiophen-3-yl)-3-hydroxypropyl)-4-benzylpip
eridin-4-ol hydrochlorid (2b). Starting with 1-(benzo[b]thiophen-
3-yl)-3-(4-benzyl-4-hydroxypiperidin-1-yl)propan-1-one hydro-
chloride (4.2 g, 10.6 mmol), procedure E was followed to afford
compound 2b (3.7 g, 87.6%) as a white solid. Mp: 104e106. MS (ESI)
9.2 mmol), Procedure D was followed to afford compound 5r (3.0 g,
80.7%) as a white solid. Mp: 208e211. MS (ESI) m/z: 374 (Mþ1). 1H
NMR (400 MHz, DMSO-d6): d 1.52 (s, 3H, COCHCH3), 2.44e2.55 (m,
2H, 4Hpy.), 3.29 (m, 2H, 4Hpy.), 3.37 (s, 2H, AreCH2e), 3.79e4.05
(m, 2H, 4Hpy.), 5.23e5.29 (q, J ¼ 14.4 Hz, 1H, COCHCH3), 5.47 (s,
1H, ]CH), 7.23e7.35 (m, 5H, AreH), 7.89e7.93 (d, J ¼ 8.4 Hz, 1H,
AreH), 8.00e8.02 (d, J ¼ 8.4 Hz, 1H, AreH), 8.29 (s, 1H, AreH),
10.42e10.62 (dbr, 1H, HCl).
m/z: 382 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 1.58e1.61 (m, 2H,
NCH2CH2CeOH), 1.73-1.80 (m, 2H, NCH2CH2CeOH), 2.11e2.21 (m,
2H, CHOHCH2CH2N), 2.74 (s, 2H, AreCH2e), 3.05e3.11 (m, 2H,
NCH2CH2CeOH), 3.18e3.22 (m, 2H, CHOHCH2CH2N), 3.30 (m, 2H,
NCH2CH2CeOH), 5.01e5.04 (dd, J1 ¼ 3.6 Hz, J2 ¼ 8.0 Hz, 1H,
CHOHCH2CH2N), 7.19e7.41 (m, 7H, AreH), 7.57 (s, 1H, AreH),
7.93e7.96 (m, 2H, AreH). Anal. Calcd for C23H28ClNO2S: C,
66.09%; H, 6.75%; N, 3.35%. Found: C, 66.00%; H, 6.70%; N, 3.31%.
4.1.4.9. 2-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-methoxyphe
nyl)propan-1-one hydrochloride (5s). Starting with 2-bromo-1-(4-
methoxyphenyl)propan-1-one (3.5 g, 14.5 mmol) and 4-benzyl-
1,2,3,6-tetrahydropyridine hydrochloride (2.3 g, 13.1 mmol),
Procedure D was followed to afford compound 5s (4.4 g, 90.0%) as
a white solid. Mp: 202e205. MS (ESI) m/z: 336 (Mþ1). 1H NMR
4.1.5.3. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-chloropheny
l)propan-1-ol hydrochloride (2c). Starting with 3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(4-chlorophenyl)propan-1-one hydro-
chloride (3.5 g, 9.3 mmol), procedure E was followed to afford
compound 2c (3.0 g, 85.3%) as a white solid. Mp: 128e130. MS (ESI)
(400 MHz, DMSO-d6):
d
1.78e1.80 (d, J ¼ 7.2 Hz, 3H, COCHCH3),
1.73e2.15 (m, 2H, 4Hpy.), 3.09e3.44 (m, 2H, 4Hpy.), 3.34 (s, 2H,
AreCH2e), 3.67e3.74 (m, 2H, 4Hpy.), 3.89 (s, 3H, eOCH3),
5.14e5.20 (q, J ¼ 7.6 Hz, 1H, COCHCH3), 5.41 (s, 1H, ]CH),
6.96e6.98 (d, J ¼ 8.8 Hz, 2H, AreH), 7.16e7.23 (m, 3H, AreH),
7.25e7.31 (m, 2H, AreH), 7.91e7.94 (dd, J1 ¼ 3.2 Hz, J2 ¼ 6.0 Hz,
2H, Ar-H).
m/z: 342 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 1.99e2.09 (m, 2H,
eCHOHCH2CH2Ne), 2.06e2.40 (m, 2H, 4Hpy.), 3.07e3.40 (m, 2H,
4Hpy.), 3.10e3.14 (m, 2H, eCHOHCH2CH2Ne), 3.35 (s, 2H,
AreCH2e), 3.50e3.75 (m, 2H, 4Hpy.), 4.66e4.69 (q, J ¼ 4.0 Hz, 1H,
eCHOHCH2CH2Ne), 5.42 (s,1H, ]CH), 5.65 (br,1H, eOH), 7.19e7.21
(m, 3H, AreH), 7.23e7.32 (m, 2H, AreH), 7.39e7.48 (m, 4H, AreH),
10.53 (br,1H, HCl). Anal. Calcd for C21H25Cl2NO: C, 66.67%; H, 6.66%;
N, 3.70%. Found: C, 66.84%; H, 6.60%; N, 3.74%.
4.1.4.10. 2-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3-fluorophenyl)
propan-1-one hydrochloride (5t). Starting with 2-bromo-1-(3-
fluorophenyl)propan-1-one (3.8 g, 16.5 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (3.8 g, 15.0 mmol), procedure D
was followed to afford compound 5t (3.9 g, 72.3%) as a white solid.
Mp: 219e222. MS (ESI) m/z: 324 (Mþ1). 1H NMR (400 MHz, CDCl3-d):
4.1.5.4. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-p-tolylpropan-1-ol
hydrochloride (2d). Starting with 3-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)-1-p-tolylpropan-1-one hydrochloride (3.6 g, 10.1 mmol),
procedure E was followed to afford compound 2d (3.3 g, 91.2%) as
a white solid. Mp: 140e143. MS (ESI) m/z: 322 (Mþ1). 1H NMR
d
1.67-1.69 (d, J ¼ 6.4 Hz, 3H, COCHCH3), 2.28-2.52 (m, 2H, 4Hpy.),
3.24-3.32 (m, 2H, 4Hpy.), 3.36 (s, 2H, AreCH2e), 3.63-3.98 (m, 2H,
4Hpy.), 5.01 (s, 1H, COCHCH3), 5.39 (s, 1H, ]CH), 7.16e7.23 (m, 3H,
AreH), 7.26e7.37 (m, 3H, AreH), 7.46e7.52 (m, 1H, AreH), 7.68e7.71
(d, J ¼ 9.2 Hz, 1H, AreH), 7.79-7.81 (d, J ¼ 8.0 Hz, 1H, AreH).
(400 MHz, DMSO-d6):
d 1.99e2.07 (m, 2H, eCHOHCH2CH2Ne),
2.09e2.40 (m, 2H, 4Hpy.), 2.28 (s, 3H, AreCH3), 3.05e3.17 (m, 2H,
eCHOHCH2CH2Ne), 3.16e3.40 (m, 2H, 4Hpy.), 3.35 (s, 2H, AreCH2e),
3.51e3.74 (m, 2H, 4Hpy.), 4.60e4.63 (t,
J
¼
6.0 Hz, 1H,
4.1.5. Procedure E: synthesis of compounds 2aeo
eCHOHCH2CH2Ne), 5.42 (s, 1H, ]CH), 5.42 (br, 1H, eOH), 7.13e7.15
(d, J ¼ 8.0 Hz, 2H, AreH), 7.19e7.25 (m, 5H, AreH), 7.28e7.32 (m,
2H, AreH), 10.59 (br, 1H, HCl). Anal. Calcd for C22H28ClNO: C, 73.83%;
H, 7.89%; N, 3.91%. Found: C, 73.61%; H, 7.94%; N, 3.86%.
4.1.5.1. 1-(benzo[b]thiophen-2-yl)-3-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)propan-1-ol hydrochloride (2a). To a stirred solution of 1-
(benzo[b]thiophen-2-yl)-3-(4-benzyl-5,6-dihydropyridin-1(2H)-
yl)propan-1eone hydrochloride (3.0 g, 7.2 mmol) in methanol
(30 mL) was added NaBH4 (0.27 g, 7.2 mmol) dropwise, and then
the mixture was stirred at room temperature for 2 h. Quenched by
the addition of water (5 mL), and stirred for 10 min, then the
solvent was removed under reduced pressure. The crude residue
was extracted with CH2Cl2 (50 mL) and water (30 mL). The organic
layer was washed with brine (30 mL) and dried over anhydrous
sodium sulfate, and the solvent was removed under reduced
pressure. The residue was dissolved in ethyl acetate (20 mL) was
added hydrogen chloride ethanol solution (1.25 M, 10 mL) drop-
wise, and the resulting mixture was stirred for 1 h at room
temperature to give a hydrochloride product. The white solid was
filtered, washed thoroughly with ethyl acetate and ethanol,
separately, and to give compound 2a (2.6 g, 86.2%) as a white
solid. Mp: 174e177. MS (ESI) m/z: 364 (Mþ1). 1H NMR
4.1.5.5. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(thiophen-2-yl)
propan-1-ol hydrochloride (2e). Starting with 3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(thiophen-2-yl)propan-1-one hydro-
chloride (3.5 g, 10.1 mmol), procedure E was followed to afford
compound 2e (3.0 g, 85.2%) as a white solid. Mp: 141e143. MS (ESI)
m/z: 314 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.12e2.20 (m, 2H,
eCHOHCH2CH2Ne), 2.20e2.49 (m, 2H, 4Hpy.), 3.09e3.16 (m, 2H,
eCHOHCH2CH2Ne), 3.16e3.40 (m, 2H, 4Hpy.), 3.40 (s, 2H,
AreCH2e), 3.51e3.76 (m, 2H, 4Hpy.), 4.90e4.93 (q, J ¼ 4.8 Hz, 1H,
eCHOHCH2CH2Ne), 5.43 (s, 1H, ]CH), 5.93 (br, 1H, eOH),
6.96e6.70 (m, 2H, AreH), 7.20e7.23 (m, 3H, AreH), 7.28e7.32 (m,
2H, AreH), 7.39e7.40 (dd, J1 ¼ 1.6 Hz, J2 ¼ 2.8 Hz, 1H, AreH), 10.64
(br, 1H, HCl). Anal. Calcd for C22H28ClNO: C, 65.22%; H, 6.91%; N,
4.00%. Found: C, 65.38%; H, 6.98%; N, 3.95%.
(400 MHz, DMSO-d6):
d 2.06e2.40 (m, 2H, 4Hpy.), 2.21-2.32 (m,
2H, eCHOHCH2CH2Ne), 3.08-3.42 (m, 2H, 4Hpy.), 3.14e3.23 (m,
2H, eCHOHCH2CH2Ne), 3.35 (s, 2H, AreCH2e), 3.59e3.78 (m, 2H,
4Hpy.), 5.02e5.05 (q, J ¼ 4.8 Hz, 1H, eCHOHCH2CH2Ne), 5.43 (s,
1H, ]CH), 6.15 (br, 1H, eOH), 7.19e7.23 (t, J ¼ 7.6 Hz, 3H, AreH),
7.27e7.37 (m, 5H, AreH), 7.76e7.78 (d, J ¼ 7.6 Hz, 1H, AreH),
7.90e7.92 (d, J ¼ 7.6 Hz, 1H, AreH), 10.73 (br, 1H, HCl). Anal.
Calcd for C23H26ClNOS: C, 69.07%; H, 6.55%; N, 3.50%. Found: C,
69.23%; H, 6.50%; N, 3.53%.
4.1.5.6. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dimethoxy
phenyl)propan-1-ol hydrochloride (2f). Starting with 3-(4-benzyl-
5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dimethoxyphenyl)propan-1-
one hydrochloride (4.2 g, 10.5 mmol), procedure E was followed to
afford compound 2f (3.9 g, 92.4%) as a white solid. Mp: 147e149.
MS (ESI) m/z: 368 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.06
(m, 2H, eCHOHCH2CH2Ne, 2.06e2.40 (m, 2H, 4Hpy.), 3.03e3.14
(m, 2H, eCHOHCH2CH2Ne), 3.21e3.41 (m, 2H, 4Hpy.), 3.35 (s, 2H,

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
133
AreCH2e), 3.55e3.57 (m, 2H, 4Hpy.), 3.73 (s, 3H, eOCH3), 3.76 (s,
3H, eOCH3), 4.57-4.60 (t, J ¼ 6.4 Hz,1H, eCHOHCH2CH2Ne), 5.42 (s,
1H, ]CH), 5.42 (br, 1H, eOH), 6.85e6.89 (m, 2H, AreH), 6.97 (m,
1H, AreH), 7.19e7.23 (m, 3H, AreH), 7.28e7.32 (t, J ¼ 7.2 Hz, 2H,
AreH), 10.60 (br, 1H, HCl). Anal. Calcd for C23H30ClNO3: C, 68.39%;
H, 7.49%; N, 3.47%. Found: C, 68.21%; H, 7.42%; N, 3.43%.
4.1.5.11. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(5-chloro-6-me
thoxynaphthalen-2-yl)propan-1-ol hydrochloride (2k). Starting with
3-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(5-chloro-6-methoxy
naphthalen-2-yl)propan-1-one hydrochloride (1.8 g, 3.9 mmol),
procedure E was followed to afford compound 2k (1.6 g, 88.5%) as
a white solid. Mp: 164e166. MS (ESI) m/z: 422 (Mþ1). 1H NMR
(400 MHz, DMSO-d6):
d 2.07e2.26 (m, 2H, 4Hpy.), 2.29e2.32 (m,
4.1.5.7. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-nitrophenyl)
propan-1-ol hydrochloride (2g). Starting with 3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(4-nitrophenyl)propan-1-one hydro-
chloride (4.0 g, 10.4 mmol), procedure E was followed to afford
compound 2g (3.6 g, 89.5%) as a white solid. Mp: 145e147. MS (ESI)
2H, eCHOHCH2CH2Ne, 2.67e3.01 (m, 2H, 4Hpy.), 3.19-3.24 (m, 2H,
eCHOHCH2CH2Ne), 3.36 (s, 2H, AreCH2e), 3.39e3.55 (m, 2H,
4Hpy.), 4.00 (s, 3H, eOCH3), 5.15e5.18 (t,
J
¼
5.2 Hz, 1H,
CHOHCH2CH2Ne), 5.33 (s, 1H, ]CH), 7.10e7.12 (d, J ¼ 6.8 Hz, 2H,
AreH), 7.19e7.32 (m, 4H, AreH), 7.51e7.54 (d, J ¼ 8.8 Hz, 1H, AreH),
7.69e7.71 (d, J ¼ 8.8 Hz, 1H, AreH), 7.81 (s, 1H, AreH), 8.12e8.15 (d,
J ¼ 8.8 Hz, 1H, AreH). Anal. Calcd for C26H29Cl2NO2: C, 68.12%; H,
6.38%; N, 3.06%. Found: C, 68.29%; H, 6.44%; N, 3.01%.
m/z: 353 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 1.98e2.05 (m, 2H,
eCHOHCH2CH2Ne), 2.12e2.40 (m, 2H, 4Hpy.), 3.06e3.40 (m, 2H,
4Hpy.), 3.15e3.20 (m, 2H, eCHOHCH2CH2Ne), 3.35 (s, 2H,
AreCH2e), 3.43e3.81 (m, 2H, 4Hpy.), 4.83e4.86 (q, J ¼ 4.0 Hz, 1H,
eCHOHCH2CH2Ne), 5.43 (s, 1H, ]CH), 5.90 (br, 1H, eOH),
7.19e7.23 (m, 3H, AreH), 7.28e7.32 (m, 2H, AreH), 7.64e7.67 (m,
2H, AreH), 8.19e8.23 (m, 2H, AreH), 10.43 (br, 1H, HCl). Anal. Calcd
for C21H25ClN2O3: C, 64.86%; H, 6.48%; N, 7.20%. Found: C, 64.99%;
H, 6.42%; N, 7.14%.
4.1.5.12. 4-Benzyl-1-(3-(5-chloro-6-methoxynaphthalen-2-yl)-3-hyd
roxypropyl)piperidin-4-ol hydrochloride (2l). Starting with 3-(4-
benzyl-4-hydroxypiperidin-1-yl)-1-(5-chloro-6-methoxynaphtha
len-2-yl)propan-1-one hydrochloride (3.5 g, 7.4 mmol), procedure
E was followed to afford compound 2l (3.1 g, 88.2%) as a white solid.
Mp: 171e173. MS (ESI) m/z: 440 (Mþ1). 1H NMR (400 MHz, DMSO-
4.1.5.8. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(2,4-difluorophe
nyl)propan-1-ol hydrochloride (2h). Starting with 3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(2,4-difluorophenyl)propan-1-one hyd
rochloride (3.2 g, 8.5 mmol), procedure E was followed to afford
compound 2h (2.8 g, 87.0%) as a white solid. Mp: 148e150. MS (ESI)
d6): d 1.55-1.59 (m, 2H, NCH2CH2COH), 1.86e1.92 (m, 2H,
NCH2CH2COH), 2.08e2.20 (m, 2H, CHOHCH2CH2N), 2.73 (s, 2H,
ArCH2e), 3.06 (m, 2H, CHOHCH2CH2N), 3.06e3.13 (m, 4H,
NCH2CH2COH), 4.00 (s, 3H, eOCH3), 4.78 (s, 1H, CHOHCH2CH2N),
4.84 (br,1H, NCH2CH2COH), 5.69 (br,1H, CHOHCH2CH2N), 7.21e7.30
(m, 5H, AreH), 7.54e7.56 (d, J ¼ 8.8 Hz, 1H, AreH), 7.64e7.67 (d,
J ¼ 8.8 Hz,1H, AreH), 7.90 (s,1H, AreH), 7.94e7.90 (d, J ¼ 8.8 Hz,1H,
AreH), 8.07e8.09 (d, J ¼ 8.8 Hz, 1H, AreH), 10.21 (br, 1H, HCl). Anal.
Calcd for C26H31Cl2NO3: C, 65.54%; H, 6.56%; N, 2.94%. Found: C,
65.68%; H, 6.54%; N, 2.95%.
m/z: 344 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.06e2.07 (m, 2H,
eCHOHCH2CH2Ne), 2.07e2.38 (m, 2H, 4Hpy.), 3.07e3.22 (m, 2H,
4Hpy.), 3.09e3.19 (m, 2H, eCHOHCH2CH2Ne), 3.39 (s, 2H,
AreCH2e), 3.49e3.75 (m, 2H, 4Hpy.), 4.86e4.89 (q, J ¼ 6.0 Hz, 1H,
eCHOHCH2CH2Ne), 5.43 (s, 1H, ]CH), 5.75 (br, 1H, eOH),
7.04e7.08 (m, 2H, AreH), 7.09e7.20 (m, 3H, AreH), 7.22e7.31 (m,
2H, AreH), 7.49e7.55 (m, 1H, AreH), 10.55 (br, 1H, HCl). Anal. Calcd
for C21H24ClF2NO: C, 66.40%; H, 6.37%; N, 3.69%. Found: C, 66.31%;
H, 6.42%; N, 3.64%.
4.1.5.13. 4-Benzyl-1-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)piper-
idin-4-ol hydrochloride (2m). Starting with 3-(4-benzyl-4-
hydroxypiperidin-1-yl)-1-(3,4-dichlorophenyl)propan-1-one hydro-
chloride (2.5 g, 5.8 mmol), procedure E was followed to afford
compound 2m (2.0 g, 79.6%) as a white solid. Mp: 137e139. MS (ESI)
4.1.5.9. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-methoxyphe
nyl)propan-1-ol hydrochloride (2i). Starting with 3-(4-benzyl-
5,6-dihydropyridin-1(2H)-yl)-1-(4-methoxyphenyl)propan-1-one
hydrochloride (3.3 g, 8.9 mmol), procedure E was followed to afford
compound 2i (2.9 g, 87.4%) as a white solid. Mp: 126e128. MS (ESI)
m/z: 394 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 1.57e1.60 (m, 2H,
NCH2CH2CeOH), 1.74e1.81 (m, 2H, NCH2CH2CeOH), 1.92e2.03 (m,
2H, CHOHCH2CH2N), 2.73 (s, 2H, AreCH2e), 3.08 (m, 2H,
NCH2CH2CeOH), 3.08 (m, 2H, CHOHCH2CH2N), 3.26 (m, 2H,
NCH2CH2CeOH), 4.64(dd, J1 ¼3.2Hz, J2 ¼ 8.4Hz,1H, CHOHCH2CH2N),
7.19e7.29 (m, 5H, AreH), 7.32e7.34 (m, 1H, AreH), 7.55e7.57 (dd,
J1 ¼ 3.2 Hz, J2 ¼ 4.8 Hz, 2H, AreH). Anal. Calcd for C21H26Cl3NO2: C,
58.55%; H, 6.08%; N, 3.25%. Found: C, 58.69%; H, 6.14%; N, 3.21%.
m/z: 338 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 1.96e2.01 (m, 2H,
CHOHCH2CH2Ne), 2.21 (m, 2H, 4Hpy.), 3.07e3.10 (m, 2H,
CHOHCH2CH2Ne), 3.11e3.18 (m, 2H, 4Hpy.), 3.33 (s, 2H, ArCH2e),
3.65e3.67 (m, 2H, 4Hpy.), 3.71 (s, 3H, eOCH3), 4.57e4.60 (d,
J ¼ 6.4 Hz, 1H, CHOHCH2CH2Ne), 5.42 (s, 1H, eNCH2CH]C),
6.87e6.89 (d, J ¼ 8.8 Hz, 2H, AreH), 7.17e7.31 (m, 7H, AreH).
Anal. Calcd for C22H28ClNO2: C, 70.67%; H, 7.55%; N, 3.75%. Found:
C, 70.50%; H, 7.48%; N, 3.79%.
4.1.5.14. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichlorop
henyl)propan-1-ol hydrochloride (2n). Starting with 3-(4-benzyl-
5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichlorophenyl)propan-1-one
hydrochloride (3.0 g, 7.3 mmol), procedure E was followed to afford
compound 2n (2.5 g, 82.9%) as a white solid. Mp: 160e163. MS (ESI)
4.1.5.10. 1-(benzo[b]thiophen-3-yl)-3-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)propan-1-ol hydrochloride (2j). Starting with 1-(benzo[b]
thiophen-3-yl)-3-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)propan-
1-one hydrochloride (1.9 g, 4.8 mmol), procedure E was followed to
afford compound 2j (1.7 g, 89.0%) as a white solid. Mp: 170e172. MS
m/z: 376 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.01e2.06 (t,
J ¼ 8.0 Hz, 2H, eCHOHCH2CH2Ne), 2.10e2.40 (m, 2H, 4Hpy.),
3.05e3.41 (m, 2H, 4Hpy.), 3.08e3.15 (t,
J
¼
8.0 Hz, 2H,
eCHOHCH2CH2Ne), 3.35 (s, 2H, AreCH2e), 3.51e3.76 (m, 2H, 4Hpy.),
4.69e4.72 (q, J ¼ 4.0 Hz,1H, CHOHCH2CH2N), 5.42 (s,1H, ]CH), 5.80
(br, 1H, eOH), 7.19e7.23 (m, 3H, AreH), 7.28e7.32 (t, J ¼ 7.6 Hz, 2H,
AreH), 7.35e7.37 (dd, J1 ¼ 2.0 Hz, J2 ¼ 6.0 Hz, 1H, AreH), 7.58e7.61
(m, 2H, AreH), 10.60 (br, 1H, HCl). Anal. Calcd for C21H24Cl3NO: C,
61.10%; H, 5.86%; N, 3.39%. Found: C, 61.24%; H, 5.81%; N, 3.34%.
(ESI) m/z: 364 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
d 2.11e2.38
(m, 2H, 4Hpy.), 2.19e2.27 (m, 2H, eCHOHCH2CH2Ne), 3.09e3.38
(m, 2H, 4Hpy.), 3.24-3.31 (m, 2H, eCHOHCH2CH2Ne), 3.35 (s, 2H,
AreCH2e), 3.51e3.78 (m, 2H, 4Hpy.), 5.04e5.07 (q, J ¼ 4.0 Hz, 1H,
CHOHCH2CH2Ne), 5.43 (s, 1H, ]CH), 5.72 (br, 1H, eOH), 7.19e7.23
(t, J ¼ 8.0 Hz, 3H, AreH), 7.28e7.32 (t, J ¼ 7.6 Hz, 2H, AreH),
7.35e7.41 (m, 2H, AreH), 7.60 (s, 1H, AreH), 7.96e7.99 (m, 2H,
AreH). Anal. Calcd for C23H26ClNOS: C, 69.07%; H, 6.55%; N, 3.50%.
Found: C, 68.91%; H, 6.50%; N, 3.50%.
4.1.5.15. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(2,3-dihydrobe
nzofuran-5-yl)propan-1-ol hydrochloride (2o). Starting with 3-(4-
benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(2,3-dihydrobenzofuran-5-yl)

134
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
propan-1-one hydrochloride (3.9 g, 10.2 mmol), procedure E was fol-
lowed to afford compound 2o (3.2 g, 81.6%) as a white solid. Mp:
153e155. MS (ESI) m/z: 350 (Mþ1). 1H NMR (400 MHz, DMSO-d6):
7.21e7.31 (m, 5H, AreH), 7.36 (d, J ¼ 8.8 Hz, 1H, AreH), 7.83 (d,
J ¼ 8.4 Hz, 1H, AreH), 7.81 (d, J ¼ 8.8 Hz, 1H, AreH), 8.12 (s, 1H,
AreH), 8.15 (d, J ¼ 8.8 Hz, 1H, AreH), 11.1 (s, 1H, HCl). Anal. Calcd for
C26H31Cl2NO3: C, 65.54%; H, 6.56%; N, 2.94%. Found: C, 65.33%; H,
6.51%; N, 2.93%.
d
2.02-2.04 (m, 2H, eCHOHCH2CH2Ne), 2.04e2.40 (m, 2H, 4Hpy.),
3.06e3.08 (m, 2H, eCHOH CH2CH2Ne), 3.12-3.17 (t, J ¼ 8.8 Hz, 2H,
ArCH2CH2Oe), 3.21e3.24 (m, 2H, 4Hpy.), 3.35 (s, 2H, AreCH2e),
3.55e3.74 (m, 2H, 4Hpy.), 4.47e4.52 (t, J ¼ 8.8 Hz, 2H, ArCH2CH2Oe),
4.55e4.58 (t, J ¼ 6.0 Hz, 1H, CHOHCH2CH2N), 5.42 (s, 1H, ]CH), 5.42
(s, 1H, eOH), 6.68e6.70 (d, J ¼ 8.4 Hz, 1H, AreH), 7.04e7.06 (d,
J ¼ 8.4 Hz,1H, AreH), 7.20e7.23 (m, 4H, AreH), 7.28e7.32 (t, J ¼ 7.2 Hz,
2H, AreH),10.62 (br,1H, HCl). Anal. Calcd for C23H28ClNO2: C, 71.58%; H,
7.31%; N, 3.63%. Found: C, 71.32%; H, 7.37%; N, 3.67%.
Spectral for 2s. Mp: 276e278. MS (ESI) m/z: 440 (Mþ1). 1H NMR
(400 MHz, CDCl3):
d
0.87 (d, J ¼ 7.2 Hz, 3H, ]CHeCH3), 1.51e1.61
(m, 4H, (eCH2e)2eCeOH), 2.52e2.57 (m, 2H, eNeCH2e),
2.69e2.73 (m, 2H, eNeCH2e), 2.81 (s, 2H, eCH2ePh), 2.94 (m,
1H, eOH), 4.03 (s, 3H, eOCH3), 4.15 (q, 1H, CHCH3), 4.41 (d,
J ¼ 1.6 Hz, 1H, CHOH), 7.18e7.36 (m, 6H, AreH), 7.59 (dd, J1 ¼1.6 Hz,
J2 ¼ 8.8 Hz, 1H, AreH), 7.76 (m, 2H, AreH), 8.20 (d, J ¼ 8.8 Hz, 1H,
AreH). Anal. Calcd for C26H31Cl2NO3: C, 65.54%; H, 6.56%; N, 2.94%.
Found: C, 65.36%; H, 6.58%; N, 2.95%.
4.1.6. Procedure F: synthesis of compounds 2pey
4.1.6.1. Threo-1-(benzo[b]thiophen-3-yl)-2-(4-benzyl-5,6-dihydropyr
idin-1(2H)-yl)propan-1-ol hydrochloride (2p) and erythro-1-(benzo
[b]thiophen-3-yl)-2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)propan-
1-ol hydrochloride (2q). To a stirred solution of aluminum isoprop-
oxide (1.3 g, 6.4 mmol) in isopropanol (30 mL) was added aluminum
chloride (0.11 g, 0.9 mmol) dropwise, and then the mixture was stirred
at 50 for 4 h. To the reaction solution 1-(benzo[b]thiophen-3-yl)-2-(4-
4.1.6.3. Threo-2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichl
orophenyl)propan-1-ol hydrochloride (2t) and erythro-2-(4-benzyl-
5,6-dihydropyridin-1(2H)-yl)-1-(3,4-dichlorophenyl)propan-1-ol
hydrochloride (2u). Starting with 2-(4-benzyl-5,6-dihydropyridin-
1(2H)-yl)-1-(3,4-dichlorophenyl)propan-1-one
hydrochloride
(2.8 g, 6.8 mmol), procedure F was followed to afford compound 2t
(1.0 g, 35.5%) as a white solid and 2u (0.8 g, 28.4%) as a white solid,
separately. Spectral for 2t. Mp: 203e205. MS (ESI) m/z: 376 (Mþ1).
benzyl-5,6-dihydropyridin-1(2H)-yl)propan-1-one
hydrochloride
(2.1 g, 5.3 mmol) was added, and then the mixture was heated to 65 for
12 h. The solvent was removed under reduced pressure. The crude
residue was extracted with CH2Cl2 (50 mL) and water (30 mL). The
organic layer was washed with brine (30 mL) and dried over anhydrous
sodium sulfate, and the solvent was removed under reduced pressure.
The crude residue was purified by silica gel column chromatography
using CH2Cl2/MeOH (30/1, v/v) as mobile phase to give threo and erthro
conformation, which was treated with hydrogen chloride ethanol
solution and got compound 2p (0.8 g, 37.9%) as a white solid and 2q
(0.7 g, 33.2%) as a white solid, separately. Spectral for 2p. Mp: 207e209.
1H NMR (400 MHz, DMSO-d6):
d
1.05e1.07 (d, J ¼ 8.0 Hz, 3H,
eNCHCH3), 2.15e2.19 (m, 1H, 4Hpy.), 2.93e3.09 (m, 2H, 4Hpy.),
3.23e3.3.42 (m, 2H, 4Hpy.), 3.49e3.75 (m, 2H, AreCH2e),
3.94e3.99 (m, 1H, 4Hpy.), 4.10e4.14 (m, 1H, eNCHCH3), 4.51e4.54
(d, J ¼ 10.4 Hz, 1H, CHOH), 4.74e4.77 (d, J ¼ 9.6 Hz, 1H, ]CH),
5.41 (br, 1H, eOH), 7.12e7.14 (d, J ¼ 6.8 Hz, 2H, AreH), 7.21e7.37 (m,
3H, AreH), 7.40e7.45 (m, 2H, AreH), 7.55e7.58 (m,1H, AreH),10.25
(br, 1H, HCl). Anal. Calcd for C21H24Cl3NO: C, 61.10%; H, 5.86%; N,
3.39%. Found: C, 61.25%; H, 5.91%; N, 3.36%.
MS (ESI) m/z: 364 (Mþ1). 1H NMR (400 MHz, CDCl3):
d
1.08e1.10 (d,
Spectral for 2u. Mp: 215e217. MS (ESI) m/z: 376 (Mþ1). 1H NMR
J ¼ 6.4 Hz, 3H, eNCHCH3), 2.90e3.17 (m, 2H, 4Hpy.), 3.24e3.3.39 (m,
2H, 4Hpy.), 3.57e3.66 (m, 2H, AreCH2e), 4.09e4.27 (m, 2H, 4Hpy.),
4.33e4.36 (m, 1H, -NCHCH3), 5.07e5.09 (d, J ¼ 10.4 Hz, 1H, CHOH),
5.28e5.32 (m, 1H, ]CH), 5.41 (br, 1H, eOH), 7.05e7.11 (m, 2H, AreH),
7.20e7.31 (m, 3H, AreH), 7.34e7.38 (t, J ¼ 7.6 Hz, 1H, AreH), 7.40e7.44
(t, J ¼ 7.6 Hz, 1H, AreH), 7.73e7.75 (d, J ¼ 9.6 Hz, 1H, AreH), 7.84e7.86
(d, J¼ 8.0 Hz,1H, AreH), 8.09e8.15 (q, J ¼ 8.0 Hz,1H, AreH). Anal. Calcd
for C23H26ClNOS: C, 69.07%; H, 6.55%; N, 3.50%. Found: C, 69.24%; H,
6.59%; N, 3.54%.
(400 MHz, DMSO-d6):
d
1.01e1.02 (d, J ¼ 5.2 Hz, 3H, eNCHCH3),
2.13e2.57 (m, 2H, 4Hpy.), 3.11e3.45 (m, 2H, 4Hpy.), 3.31 (s, 2H,
AreCH2e), 3.81e3.87 (m, 2H, 4Hpy.), 3.81e3.87 (m, 1H, eNCHCH3),
5.42e5.44 (d, J ¼ 1.2 Hz, 1H, CHOH), 5.53 (s, 1H, ]CH), 6.22e6.34
(br, 1H, eOH), 7.21e7.25 (t, J ¼ 7.2 Hz, 3H, AreH), 7.30e7.34 (m,
2H, AreH), 7.40e7.42 (d, J ¼ 8.4 Hz, 1H, AreH), 7.63e7.65 (m, 2H,
Ar-H), 10.00e10.25 (dbr, 1H, HCl). Anal. Calcd for C21H24Cl3NO: C,
61.10%; H, 5.86%; N, 3.39%. Found: C, 61.29%; H, 5.88%; N, 3.35%.
Spectral for 2q. Mp: 227e230. MS (ESI) m/z: 364 (Mþ1). 1H NMR
4.1.6.4. Threo-2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(4-methoxy
phenyl)propan-1-ol hydrochloride (2v) and erythro-2-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(4-methoxyphenyl)propan-1-ol hydrochlo-
ride (2w). Starting with 2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-
(4-methoxyphenyl)propan-1-one hydrochloride (3.1 g, 8.3 mmol),
procedure F was followed to afford compound 2v (1.1 g, 35.3%) as
a white solid and 2w (0.9, 28.9%) as a white solid, separately. Spectral
(400 MHz, DMSO-d6):
d
1.14e1.16 (d, J ¼ 6.4 Hz, 3H, eNCHCH3),
2.18e2.57 (m, 2H, 4Hpy.), 3.17e3.48 (m, 2H, 4Hpy.), 3.40 (s, 2H,
AreCH2e), 3.84e3.97 (m, 2H, 4Hpy.), 3.84e3.97 (m, 1H, eNCHCH3),
5.54 (s, 1H, CHOH), 5.83 (s, 1H, ]CH), 6.20e6.31 (br, 1H, eOH),
7.22e7.26 (m, 3H, AreH), 7.31e7.35 (m, 2H, AreH), 7.37e7.41 (m,
2H, AreH), 7.98e8.00 (d, J ¼ 6.8 Hz, 1H, AreH), 8.06e8.15 (dbr,
J ¼ 33.6 Hz, 1H, AreH). Anal. Calcd for C23H26ClNOS: C, 69.07%; H,
6.55%; N, 3.50%. Found: C, 69.22%; H, 6.58%; N, 3.55%.
1
for 2v. Mp: 195e197.MS (ESI) m/z: 338 (Mþ1). H NMR (400 MHz,
DMSO-d6):
d
0.93e0.94 (q, J ¼ 6.4 Hz, 3H, eNCHCH3), 2.07e2.64 (m,
2H, 4Hpy.), 3.22e3.45 (m, 2H, 4Hpy.), 3.38 (s, 2H, AreCH2e),
3.57e3.93 (m, 2H, 4Hpy.), 3.75 (s, 3H, eOCH3), 3.83e3.93 (m, 1H,
-NCHCH3), 4.59e4.61 (d, J ¼ 9.2 Hz, 1H, CHOH), 5.52 (s, 1H, ]CH),
6.94e6.96 (d, J ¼ 8.8 Hz, 2H, AreH), 7.21e7.34 (m, 7H, AreH). Anal.
Calcd for C22H28ClNO2: C, 70.67%; H, 7.55%; N, 3.75%. Found: C, 70.50%;
H, 7.48%; N, 3.79%.
4.1.6.2. Threo-4-benzyl-1-(1-(5-chloro-6-methoxynaphthalen-2-yl)-
1-hydroxypropan-2-yl)piperidin-4-ol hydrochloride (2r) and erythro-
4-benzyl-1-(1-(5-chloro-6-methoxynaphthalen-2-yl)-1-
hydroxypropan-2-yl)piperidin-4-ol hydrochloride (2s). Starting with
2-(4-benzyl-4-hydroxypiperidin-1-yl)-1-(5-chloro-6-
methoxynaphthalen-2-yl)propan-1-one hydrochloride (3.4 g,
7.2 mmol), procedure F was followed to afford compound 2r (1.2 g,
35.1%) as a white solid and 2s (1.3 g, 38.0%) as a white solid, sepa-
rately. Spectral for 2r. Mp: 272e275. MS (ESI) m/z: 440 (Mþ1). 1H
Spectral for 2w. Mp: 215e217. MS (ESI) m/z: 338 (Mþ1). 1H NMR
(400 MHz, DMSO-d6):
d
1.03e1.05 (q, J ¼ 3.2 Hz, 3H, eNCHCH3),
2.12e2.54 (m, 2H, 4Hpy.), 3.17e3.46 (m, 2H, 4Hpy.), 3.39 (s, 2H,
AreCH2e), 3.57e3.80 (m, 2H, 4Hpy.), 3.75 (s, 3H, eOCH3),
3.81e3.93 (m, 1H, eNCHCH3), 5.39 (s, 1H, CHOH), 5.53 (s, 1H, ]
CH), 6.92e6.94 (d, J ¼ 8.0 Hz, 2H, AreH), 7.22e.35 (m, 7H, AreH).
Anal. Calcd for C22H28ClNO2: C, 70.67%; H, 7.55%; N, 3.75%. Found:
C, 70.55%; H, 7.50%; N, 3.71%.
NMR (400 MHz, CDCl3):
d
1.20 (d, J ¼ 7.2 Hz, 3H, ]CHeCH3),
1.72e1.77 (m, 2H, eCH2COH), 2.35e2.47 (m, 2H, eCH2COH), 2.88
(s, 2H, eCH2Ph), 3.27e3.44 (m, 4H, eN(CH2)2), 3.77 (d, J ¼ 10.4 Hz,
1H, CHOH), 4.02 (s, 3H, eOCH3), 4.16 (s, 1H, eOH), 5.79 (s, 1H, eOH),

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 54 (2012) 123e136
135
4.1.6.5. Threo-2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3-fluoroph
enyl)propan-1-ol hydrochloride (2x) and erythro-2-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)-1-(3-fluorophenyl)propan-1-ol hydrochloride
(2y). Starting with 2-(4-benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3-
fluorophenyl)propan-1-one hydrochloride (3.6 g, 10.0 mmol), proce-
dure F was followed to afford compound 2x (1.4, 38.7%) as a white
solid and 2y (1.0 g, 27.6%) as a white solid, separately. Spectral for 2x.
Mp: 177e179. MS (ESI) m/z: 326 (Mþ1). 1H NMR (400 MHz, CDCl3):
intervals for up to 30 min. The results of the locomotor activity
tests were expressed as mean ꢀ SEM.
4.3. Pharmacokinetic study
Male SD rats (B&K Universal Group Ltd, China) were used. For
intravenous administration, prepared dosing solution was injected
via the femoral vein. The rats were fasted overnight before drug
administration and until 6 h after dosing. For the po experiment, rats
(three in each group) were given a single dose of 10 mg/kg, and
heparinized samples of blood were collected at 5,15, 30 min,1, 2, 4, 6,
8, 12, and 24 h postdose. For the iv experiment, rats (three in each
group) were given a single 1 mg/kg dose, and blood samples were
collected at 5, 15, 30 min, 1, 2, 4, and 6 h postdose. Plasma was har-
vested after centrifugation and stored frozen at ꢁ40 until analyzed.
The concentrations of compounds inplasmawere determined by LC/
MS/MS (API3200). The results are shown as the maximum plasma
concentration (Cmax), the time to reach peak plasma concentration
(Tmax), terminal half-life ( t1/2), and the area under the plasma
concentration-time curve from zero to time infinity (AUC0-inf).
d
1.06e1.07 (d, J ¼ 5.6 Hz, 3H, eNCHCH3), 2.15e2.19 (m, 1H, 4Hpy.),
2.94e3.08 (m, 2H, 4Hpy.), 3.25e3.29 (m, 1H, 4Hpy.), 3.40e3.43 (m,
2H, AreCH2e), 3.56e3.78 (m, 2H, 4Hpy.), 3.98e4.02 (m, 1H,
eNCHCH3), 5.50e5.53 (d, J ¼ 10.0 Hz, 1H, CHOH), 4.72e4.74 (d,
J ¼ 9.6 Hz, 1H, ]CH), 5.42 (br, 1H, eOH), 6.99e7.03 (m, 1H, AreH),
7.13e7.15 (m, 2H, AreH), 7.20e7.26 (m, 2H, AreH), 7.28e7.37 (m,
4H, AreH), 10.33 (br, 1H, HCl). Anal. Calcd for C21H25ClFNO: C, 69.70%;
H, 6.96%; N, 3.87%. Found: C, 69.84%; H, 6.99%; N, 3.84%.
Spectral for 2y. Mp: 241e243. MS (ESI) m/z: 326 (Mþ1). 1H NMR
(400 MHz, DMSO-d6):
d
1.02e1.04 (d, J ¼ 6.8 Hz, 3H, eNCHCH3),
2.12e2.57 (m, 2H, 4Hpy.), 3.11e3.58 (m, 2H, 4Hpy.), 3.36 (s, 2H,
AreCH2e), 3.59e3.78 (m, 2H, 4Hpy.), 3.90e3.95 (m, 1H, eNCHCH3),
5.46e5.48 (d, J ¼ 1.6 Hz,1H, CHOH), 5.53 (s,1H, ]CH), 6.15e6.27 (dbr,
J ¼ 48.4 Hz, 1H, eOH), 7.07e7.12 (t, J ¼ 8.4 Hz, 1H, AreH), 7.23e7.30
(m, 5H, AreH), 7.32e7.39 (m, 2H, AreH), 7.41e7.44 (t, J ¼ 8.0 Hz, 1H,
AreH), 10.22e10.50 (dbr, 1H, HCl). Anal. Calcd for C21H25ClFNO: C,
69.70%; H, 6.96%; N, 3.87%. Found: C, 69.86%; H, 6.91%; N, 3.84%.
Acknowledgments
The authors acknowledge the financial support from National
Natural Science Foundation of China (Grant No. 30772623) and the
Chinese National Science and Technology Major Project (Grant No.
2012ZX09103-101-038). Authors are really grateful to Professor Lei
Fu (Shanghai Jiao Tong University, China) for helpful discussion. We
would also like to thank Dr. Jun Du (Shanghai Medicilon Incorpo-
ration Limited, China) for in vivo studies.
4.2. Biology evaluation
4.2.1. Inhibition of [3H] neurotransmitter uptake in HEK293 cells
expressing the hSERT, hNAT and hDAT
Assays were conducted using procedures identical to those
described by Eshleman [2]. The cells were seeded in 24-well cluster
plates at a density of 1.5 million cells per well. On the second day, the
cells were incubated with HBSS buffer containing the tested compound
and 3H-serotonin(3 nM) for 10 min at 37. Then, serotonin uptake was
terminated by rinsing three times with ice-cold PBS buffer and cells
were lysed using 0.1 ml of 2 M NaOH. Cell lysate was analyzed for
radioactivity using a scintillation counter. Nonspecific uptake was
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi: 10.1016/j.ejmech.2012.04.030. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
defined with 10 mM DOV 21947. The protocols for dopamine and
epinephrine uptake were the same with that for serotonin.
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