Synthesis and pharmacological investigation of aralkyl diamine derivatives as potential triple reuptake inhibitors

Article abstract of DOI:10.1016/j.ejmech.2014.08.045

A series of aralkyl diamine derivatives were designed, synthesized, and evaluated for their triple reuptake inhibitory abilities. Compounds 18c (5-HT, NE, DA, IC₅₀ = 389, 69, 238 nM), 36a (5-HT, NE, DA, IC₅₀ = 378, 477, 247 nM), and

Full text of DOI:10.1016/j.ejmech.2014.08.045

European Journal of Medicinal Chemistry 86 (2014) 219e234
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and pharmacological investigation of aralkyl diamine
derivatives as potential triple reuptake inhibitors
,
, b,
Yong-Yong Zheng a 1, Zhi-Jie Weng a 1, Peng Xie a, Mei-Yu Zhu a, Long-Xuan Xing a,
,
*
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 School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of aralkyl diamine derivatives were designed, synthesized, and evaluated for their triple reup-
take inhibitory abilities. Compounds 18c (5-HT, NE, DA, IC50 ¼ 389, 69, 238 nM), 36a (5-HT, NE, DA,
IC50 ¼ 378, 477, 247 nM), and 36d (5-HT, NE, DA, IC50 ¼ 501, 206, 357 nM) showed in vivo activities in the
rat forced swim test at 5, 10, and 20 mg/kg PO. 36a was identified as the most promising candidate in this
study. Specifically, 36a exhibited high selectivity for monoamine transporters over a number of CNS-
related targets. Furthermore, 36a showed a good pharmacokinetic properties and acceptable safety
profile in preclinical studies.
Received 25 March 2014
Received in revised form
12 August 2014
Accepted 13 August 2014
Available online 14 August 2014
Keywords:
© 2014 Elsevier Masson SAS. All rights reserved.
Aralkyl diamine derivatives
Triple reuptake inhibitory
Monoamine transporters
1. Introduction
Reports suggest that the addition of dopamine (DA) reuptake to 5-
HT and NE reuptake may improve efficacy and reduce the time to
Depression is increasing as a global mental health issue, and this
condition can disturb thoughts, feelings, behaviors, and can
sometimes lead to suicide [1]. Thus, antidepressants to treat these
concerns is of enormous scientific interest [2e5]. Current hypoth-
eses suggest that depression is related to deficiencies of certain
neurotransmitters such as serotonin, (5-HT) and norepinephrine
(NE) [6].
In particular, onset of action and side effects appear to be a
general hurdle, even for the dual reuptake inhibitors. For instance,
5-HT/NE transporters (SNRIs, e.g., venlafaxine, duloxetine and
milnacipran, Fig. 1) were reported to exhibit more benign side ef-
fect profiles than those of mono-reuptake inhibitors, although they
have not been shown to be more efficacious or to have more rapid
onset of antidepressant response [7]. Therefore, high efficacy drugs
with few side effects should be intensively pursued to identify new
therapeutics for treating depression.
onset of antidepressant response [9]. In particular, recent experi-
ments suggest that the triple reuptake inhibitors (TRIs), i.e. DOV-
21947 (EB-1010) [10], PRC200-SS [11], and GSK1360707F [12,13]
(Fig. 1), which block the reuptake of 5-HT, NE and DA trans-
porters, offer more rapid onset of action and possess greater effi-
cacy than traditional antidepressants. Therefore, TRIs may be
applicable for a broader range of the depressed population [14].
Inspired by these works, reuptake of DA with NE and 5-HT was
thought to be a possible solution for producing potent antide-
pressants. In our previous studies of monoamine transporters, a
series of arylalkanol-piperdine derivatives was identified and their
triple reuptake inhibition and antidepressant activities were re-
ported [15]. In this study, we designed and synthesized a new series
of compounds (Fig. 2) by changing the arylalkanol-piperdine scaf-
fold. We then examined whether monoamine transporter reuptake
inhibition was improved by replacing the hydroxyl group at the C1
position in arylalkanol-piperdine derivatives with heterocycles
(such as cyclic amines). Subsequently, we replaced the 3-benzo[b]
thiophene moiety at the C1 position with other aromatic sub-
stituents to understand the effect of different aromatic ring sub-
stitutions on the affinity and selectivity for different monoamine
transporters. Finally, we explored the role of different substituents
at the C3 position to produce aralkyl diamine compounds. From
To enhance drug efficacy while suppressing unwanted effects,
different strategies have been developed, such as the monoamine
hypothesis and non-monoamine-based antidepressants [3,8].
* Corresponding author.
E-mail address: lijianqb@126.com (J.-Q. Li).
Authors Yong-Yong Zheng and Zhi-Jie Weng contributed equally.
1
http://dx.doi.org/10.1016/j.ejmech.2014.08.045
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

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Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
C3 N-methyl-1-phenylmethanamine substitution compounds
23aeb and 27aeb is shown in Schemes 3 and 4. Treating aryl ke-
tone 19 or 8 with N-methyl-1-phenylmethanamine resulted in C3
substitution. Furthermore, the target compounds 23aeb and
27aeb were obtained by reduction, activation and substitution.
Then the N-methylamine derivative 28 was obtained through N-
debenzylation of 23b (81% yield).
Finally, the preparation of the desired N,N-dimethylamine de-
rivatives 32aem is outlined in Scheme 5. The key precursors 30
were obtained via a Mannich reaction of aryl ketone 19 with
dimethylamine, and then reduction. Then, 30 could be activated
with 4-toluenesulfonyl chloride and substituted with cyclic amines
5 to provide target compounds 32aem. The desired compounds
36aee and 40 were offered by substitution, reduction, activation,
and substitution with cyclic amines (Schemes 6 and 7).
Fig. 1. Molecular structures of selected clinical and preclinical antidepressants.
2.2. Biology
these studies, we have discovered a series of compounds that
potently inhibit the reuptake of 5-HT, NE, and DA transporters.
All synthesized compounds were tested for their inhibition of 5-
HT, NE and DA reuptake. The plasmids were transfected into CHO
cells, which encoded the human 5-HT transporter (hSERT), NE
transporter (hNET), and DA transporter (hDAT). Then, the stably
expressed cell strains were selected and used for the uptake test.
3H-5-HT, 3H-DA, 3H-NE were obtained from PerkinElmer Life Sci-
ences (LesUlis, France). All compounds were initially screened at
2. Results and discussion
2.1. Chemistry
Synthetic access to the novel aralkyl diamine derivatives was
achieved by seven synthetic routes as illustrated in Schemes 1e7.
The synthesis of 4-benzyl-1,2,3,6-tetrahydropyridine derivatives 6
and 12 are depicted in Scheme 1. Briefly, a commercially available
4-benzyl-1,2,3,6-tetrahydropyridine 1 with 3-acetylbenzo[b]thio-
phene in the presence of paraformaldehyde by the Mannich reac-
tion afforded the intermediate aryl alkaneone amine derivatives 2
(73% yield). Then compound 2 was reduced with sodium borohy-
dride into the corresponding alcohol 3 (89% yield). A strategy to
introduce a heterocycle at the C1 position was then applied. Acti-
vation of alcohol 3 with 4-toluenesulfonyl chloride in the presence
of N,N-diisopropylethylamine at room temperature provided
compound 4, which was immediately coupled with cyclic amines 5
to yield 6aed by nucleophilic substitution in moderate yields
(47e60% yield). An alternative synthesis was employed for analogs
of 12aeb, for which the corresponding aryl ketone was unavailable.
In this case, ketone 8 was prepared through FriedeleCrafts acyla-
tion reactions. The acylation of the aromatic ring with 3-
chloropropanoyl chloride 7 was catalyzed by aluminum chloride.
Then 8 was treated with 1 via the SN2 mechanism, yielding 9
(77e82% yield), which were then treated successively with sodium
borohydride, 4-toluenesulfonyl chloride and pyrrolidine provided
the target compounds 12aeb.
10 mM concentration, and selective compounds (inhibition >90%)
were then assayed to obtain their IC50 values. The triple reuptake
inhibitor DOV-21947 was used as a reference. Detailed results are
summarized in Table 1.
For the C3 substituent 4-benzyl-1,2,3,6-tetrahydropyridine de-
rivatives, inhibition of 5-HT, NE and DA reuptake were explored
(Table 1, 6aed, 12aeb). Compound 6a bearing pyrrolidine and 3-
benzo[b]thiophene moieties exhibited high potency for all three
monoamine transporters, whereas piperidine (6b), morpholine
(6c) and piperazine (6d) analogs were moderately inhibitory for 5-
HT, DA and NE, respectively. When the pyrrolidine feature
remained, the replacement of the 3-benzo[b]thiophene moiety
with the 5-chloro-6-methoxynaphthalen moiety (compound 12a)
dramatically decreased inhibition of the three transporters. Data
show that the 3,4-dichlorophenyl is a preferred substituent. Thus,
12b was prepared.
In our next series, we investigated the effects of replacing the C3
substituent 4-benzyl-1,2,3,6-tetrahydropyridine moiety with
piperidine and morpholine moieties (Table 1, compounds 18aee).
None of these C3 piperidine or morpholine substituted compounds
were potent except the C1 pyrrolidine substituted compound 18c.
Compound 18c exhibited interesting triple reuptake potency (5-HT,
IC50 ¼ 389 nM; NE, IC50 ¼ 69 nM; DA, IC50 ¼ 238 nM), however the
C1 substituent with morpholine (18a and 18b), 3-methylpiperidine
(18d) and ethyl piperidine-3-carboxylate (18e) were weak reuptake
inhibitors of all three transporters.
The C3 cyclic amine substituted compounds 18aee (Scheme 2)
were obtained by substitution of aryl ketone 13 with cyclic amines
5 in the C3 position, and subsequent reduction, activation, and
substitution with cyclic amines 17. Synthesis of the corresponding
Fig. 2. Rational design of novel triple reuptake inhibitors.

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
221
Scheme 1. Reagents and conditions: (a) 3-aetylbenzo[b]thiophene, paraformaldehyde, HCl, EtOH, 80 ꢀC; (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC;
(e) Ar, AlCl3, CH2Cl2; (f) CH3CN, DIPEA, rt.
Continuing with evaluation of C3 substituent effect on reuptake
inhibition, we introduced an N-methylbenzylamine to the C3 po-
sition. 23a, 23b, 27a, and 27b were all weak inhibitors of three
monoamine transporters. Interestingly, compared with 23b, 28
lacked a benzyl group and was selectively potent for reuptake in-
hibition of the NE transporter. This indicates the importance of C3
substituent interacting with the monoamine transporters.
Based on the above results, dimethylamine substitution was
then utilized at the C3 position to explore monoamine reuptake
inhibition. In the meantime, the influence of aromatic moieties at
the C1 position in this series was systematically studied. For 3,4-
dichlorophenyl substituted compounds 36aeb, 36d exhibited
higher potency for all three monoamine transporters than any
other substituted phenyl compounds. Compound 36c showed
potent inhibition against 5-HT and NE transporters but had
dramatically reduced potency against DA transporter compared to
the other 3,4-dichlorophenyl counterparts. Moreover, the 2,4-
difluorophenyl analog 32i and the mono-substituted phenyl com-
pounds 32aeh had no activity, indicating the necessity of a 3,4-
dichloro substituent that interacts with monoamine transporters.
Compound 40 is structurally identical to 36d except that the C3eN
dimethyl is replaced with diethyl group. This replacement resulted
in its preference for the DA and NE transporters over the 5-HT
transporter.
Increased hydrophobicity was the most prominent outcome
with aromatic substitutions and these substitutions can change its
biological activity. In our exploration to evaluate the effect of
enhanced hydrophobicity of phenyl substitution, the phenyl moiety
was replaced with 5-chloro-6-methoxymaphthalen and benzo[b]
thiophen to produce 32jem and 36e. Compound 32k bearing the
pyrrolidine and 2-benzo[b]thiophene moieties was potent against
all three monoamine transporters (IC50 values ¼ 401, 495 and
Scheme 2. Reagents and conditions: (a) CH3CN, DIPEA, rt. (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC.

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Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
Scheme 3. Reagents and conditions: (a) N-methyl-1-phenylmethanamine, paraformaldehyde, HCl, EtOH, 80 ꢀC; (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3,
70 ꢀC; (e) 5%Pd/C, EtOH, rt.
Scheme 4. Reagents and conditions: (a) N-methyl-1-phenylmethanamine, CH3CN, DIPEA, rt; (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC.
Scheme 5. Reagents and conditions: (a) dimethylamine, paraformaldehyde, HCl, EtOH, 80 ꢀC; (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC.

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
223
Scheme 6. Reagents and conditions: (a) dimethylamine, CH3CN, DIPEA, rt. (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC.
Scheme 7. Reagents and conditions: (a) diethylamine, CH3CN, DIPEA, rt. (b) NaBH4, MeOH, rt.; (c) TsCl, CH3CN, DIPEA, rt.; (d) CH3CN, K2CO3, 70 ꢀC.
863 nM for 5-HT, NE and DA, respectively). Whereas the corre-
sponding morpholine and 2-benzo[b]thiophene moieties 32j was
observed to be active only for 5-HT and NE (5-HT, IC50 ¼ 449 nM;
NE, IC50 ¼ 1456 nM). When the 2-benzo[b]thiophene aromatic was
replaced by 3-benzo[b]thiophene, the pyrrolidine moiety 32m also
had greater potency for all three monoamine transporters than the
morpholine moiety 32l. The 5-chloro-6-methoxynaphthalen and
pyrrolidine moieties 36e, offered potency against the DA trans-
porter that was weaker than the 3,4-dichlorophenyl series 36a (5-
HT, IC50 ¼ 378 nM; NE, IC50 ¼ 477 nM; DA, IC50 ¼ 247 nM) and 36d
(5-HT, IC50 ¼ 501 nM; NE, IC50 ¼ 206 nM; DA, IC50 ¼ 357 nM).
On the basis of in vitro studies, 3,4-dichlorophenyl compounds
18c, 36a and 36d were selected for further profiling in the rat forced
swim test (FST)[16], an assay in which rats are placed into a beaker
of water and the time of animal immobility is recorded. The FST has
been used widely as a preclinical model for screening antidepres-
sant activity and is sensitive to known antidepressant drugs. Thus,
18c, 36a and 36d were dosed at 5,10 and 20 mg/kg (PO) in male rats
for the FST, respectively. For comparative purposes, venlafaxine was
a positive control (30 mg/kg, PO).
even at 5 mg/kg. This compound induced a marked antidepressant-
like effect and was the most potent in the FST model.
In order to validate the changes in motor activity of rats did not
disturb the results obtained in the FST, spontaneous locomotor
activity was measured. The test compounds 18c, 36a and 36d were
administered at higher dose (20 mg/kg, PO), which was efficacious
in the FST. Venlafaxine (30 mg/kg, PO) was selected as a positive
control. As shown in Fig. 3D, compounds 18c, 36a and 36d at the
effective dose (20 mg/kg, PO) produced no significant changes in
locomotor activity compared with the vehicle control and ven-
lafaxine groups.
To conclude that in vivo activities in the FST are caused only by
triple neurotransmitter reuptake inhibition and not by interaction
with other targets, receptor selectivity of these compounds was
tested. Compound 36a was selected for further characterization in
several CNS receptor binding assays to assess the selectivity and
specific interactions of this series of compounds with the mono-
amine transporters. Compound 36a was performed against 55 re-
ceptors at Cerep (Celle L'Evescault, France, Cerep study number
100005534) using a test that has been previously described [17].
The description of all receptors targeted and corresponding
radioligand used is provided in Supplementary material (SM)
Table S1. The default concentration for primary binding experi-
As shown in Fig. 3, the selected compounds 18c, 36a and 36d
reduced immobility times in the FST in a dose-dependent manner
that was statistically significant compared with vehicle at 5, 10 and
20 mg/kg (PO). The positive control, venlafaxine (30 mg/kg, PO), also
produced a similar reduction in immobility with a mid-range dose of
18c (10 mg/kg, PO; Fig. 3A) and a lower dose of 36d (5 mg/kg, PO;
Fig. 3C). Specifically, the effect of 36a was statistically significant
ments was 10 mM. Results indicating inhibition greater than 50%
were considered to represent significant effects test compound
effects. Thus, compound 36a does not potently bind to any re-
ceptors tested except for 5-HT, NE and DA transporters.

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Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
Table 1
Activity at monoamine transporters of target compounds.
Compd.
Ar
R1
R2
X
m
[3H]5-HT uptake IC50 (nM)
[3H]NE uptake IC50 (nM)
[3H]DA uptake IC50 (nM)
DOV21947
6a
411.5 34.1
621.3 41.5
71.4 4.9
157.3 6.4
159.3 13.2
325.4 18.5
CH2
0
6b
6c
CH2
O
1
1
1
0
905.3 87.4
65.4%a
52.7%a
77.4%a
79.1%a
852.3 58.4
83.9%a
6d
12a
NH
CH2
73.9%a
635.4 15.2
73.5%a
79.9%a
79.5%a
12b
CH2
0
79.1%a
425.7 46.7
291.4 15.7
18a
18b
18c
O
1
1
0
59.9%a
74.0%a
68.1%a
O
73.8%a
4.9%a
54.4%a
CH2
389.4 18.8
68.9 5.7
238.1 12.5
18d
18e
30.5%a
34.9%a
35.3%a
19.0%a
54.3%a
36.6%a
23a
23b
Me
Me
Bn
Bn
O
O
1
1
30.3%a
24.1%a
37.8%a
5.3%a
41.9%a
46.2%a
27a
27b
Me
Me
Bn
Bn
O
O
1
1
35.6%a
47.3%a
50.6%a
49.5%a
3.4%a
2.5%a
28
Me
H
O
1
86.1%a
327.9 46.8
42.0%a
32a
32b
32c
32d
32e
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
CH2
O
0
1
1
1
0
70.2%a
50.7%a
62.7%a
46.2%a
57.6%a
68.9%a
74.2%a
87.6%a
83.2%a
77.4%a
46.6%a
6.4%a
CH2
O
40.1%a
8.5%a
CH2
37.1%a

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
225
Table 1 (continued )
Compd.
Ar
R1
R2
X
m
[3H]5-HT uptake IC50 (nM)
[3H]NE uptake IC50 (nM)
[3H]DA uptake IC50 (nM)
32f
32g
32h
32i
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
1
1
1
1
25.9%a
39.2%a
58.5%a
55.6%a
29.3%a
40.4%a
52.5%a
19.4%a
22.9%a
25.8%a
35.7%a
50.7%a
32j
32k
32l
Me
Me
Me
Me
Me
Me
O
1
0
1
449.2 22.9
401.0 16.5
1187.8 122.1
1456.3 151.7
495.0 131.5
2541.5 426.5
66.8%a
CH2
O
863.1 65.2
56.8%a
32m
36a
Me
Me
Me
Me
CH2
O
0
1
425.3 23.2
378.5 4.2
249.9 12.9
477.5 3.5
986.1 61.2
247.2 24.1
36b
36c
36d
36e
Me
Me
Me
Me
Me
Me
Me
Me
CH2
NH
1
1
0
0
546.1 41.4
399.3 51.4
501.4 25.9
337.6 44.3
633.5 63.2
427.6 35.9
205.7 19.9
373.5 112.4
602.1 86.0
80.1%a
CH2
CH2
356.6 17.6
8192.5 482.2
40
Et
Et
CH2
0
76.5%a
136.4 24.5
362.8 15.8
a
Percent inhibition measured at a concentration of 10 mM.
Fig. 3. The effect of compounds 18c, 36a and 36d in the rat test predictive of antidepressant activity.

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Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
Table 2
Acute toxicity of 36a in mice.
Dose (mg/kg)
Mice (N)
Deaths (N)
Survival on day 14 (%)
900
750
600
450
300
150
Vehicle
10
10
10
10
10
10
10
6
4
2
0
0
0
0
40%
60%
80%
100%
100%
100%
100%
To explore the safety profile of these diamine derivatives, the
acute toxicity of 36a was measured in KM mice at a single dose of
150, 300, 450, 600, 750, and 900 mg/kg or vehicle control (n ¼ 10)
by oral administration. Animal death was closely monitored for 14
days (Table 2). Treatment with 36a at 900 mg/kg killed 60% of the
mice, whereas the lower doses (150, 300, and 450 mg/kg) caused no
abnormalities or animal deaths throughout the experiment. These
data suggest that administration of 36a at or below 450 mg/kg (PO)
may be safe for mice.
Fig. 4. Brain and plasma concentrationetime plots of compound 36a after IV (0.5 mg/
kg) in SD rats.
Compound 36a was also tested in a bacteria reversion mutation
assay (Ames test), to ascertain if the compound can cause DNA
mutations. Compound 36a was negative at all dosages tested (3, 10,
4. Experimental protocols
4.1. Chemistry
30, 100, 300, 1000, and 5000
and TA100; SM Table S2).
mg/plate) in two tested strains (TA98
Nuclear magnetic resonance (NMR) spectra were recorded on a
Bruker NMR AVANCE 600 (600 MHz) or a Varian INOVA-400
(400 MHz) spectrometer with TMS as an internal standard.
Next, pharmacokinetics (PK) of 36a were measured in male SD
rats (See Table 3). After administration of 2 mg/kg (PO) 36a to SD
rats, a Cmax of 26.8 ng/mL was obtained at 30 min. Compound 36a
was cleared well (CLz/F ¼ 25.0 L/h/kg) in rats. The elimination half-
life of 36a after oral administration was 4.5 h. Compound 36a also
distributed well (Vz/F ¼ 163.8 L/kg) and had a moderately orally
bioavailable (F ¼ 19.4%) in rats.
Chemical shift (d values) and coupling constants (J values) are given
in ppm and Hz, respectively. Signal multiplicities are characterized
as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and
br (broad). ESI mass spectra and HRMS were performed on an
Agilent 6210 TOF spectrometer. The progress of all reactions was
monitored using TLC on precoated silica gel plates GF254 (Qingdao
Haiyang Chemical, China). Silica gel column chromatography was
performed with Silica gel 60G (Qingdao Haiyang Chemical, China).
The chromatograms were viewed under UV light at 254 and/or
265 nm. Uncorrected melting points were determined on an elec-
trothermal melting point apparatus. Solvents and reagents were
used without any pretreatment. Compounds purity were evaluated
by high performance liquid chromatography (HPLC), and all final
test compounds were >98% purity. The HPLC methods were used a
Because the brain-blood barrier (BBB) is one of the factors
relevant to the success of drugs for CNS disorders [18], compound
36a was also evaluated for brain penetration. After 0.5 mg/kg (ip)
36a to SD rats, brain concentrations of 36a were greater than these
in the plasma. The results are shown in Fig. 4. Compound 36a had a
brain to plasma ratio of 23 at 0.08 h (see SM for detailed results).
3. Conclusion
In the present work, we designed and synthesized a series of
novel aralkyl diamine derivatives, in our continuous effort to find
potent reuptake inhibition of 5-HT, NE, and DA transporters for the
treatment of depressive disorders. Our SAR studies revealed that
the presence of a 3,4-dichlorophenyl moiety at the C1 position was
important for their biological activities. To confirm the potential
in vivo antidepressant effect of this series of compounds, com-
pounds 18c, 36a, and 36d were selected for FST profiling in rats.
These selected compounds showed a dose-dependent reduction of
the immobility time in the FST. The most promising compound,
36a, exhibited high selectivity for monoamine transporters over
other CNS receptors. Compound 36a also had good pharmacoki-
netic properties in rats, was negative in the Ames test, and had an
acceptable safety profile. Our data lay a foundation for successful
future development of novel aralkyl diamine derivatives as next
generation of antidepressants.
Waters XBridge column, C18 (5
m
m, 250 mm ꢁ 4.6 mm); with a
mobile phase A (10 mM NaH2PO4 (pH ¼ 7.0)) and B (CH3CN),
90:10e10:90 v/v; detection at 220 nm; flow: 1.0 mL/min; temp
25 ꢀC.
4.1.1. Procedure A. 1-(Benzo[b]thiophen-3-yl)-3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)propan-1-one (2)hydrochloride [15]
To a stirred mixture of paraformaldehyde (0.74 g, 25.1 mmol), 3-
acetylbenzo[b]thiophen (3.4 g, 19.3 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (4.4 g, 21.2 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 dichloromethane (50 mL) and water
Table 3
Pharmacokinetic parameters of compound 36a.
Dose (mg/kg)
AUC(0et) (ngh/mL)
AUC(0e∞) (ngh/mL)
MRT(0et) (h)
Vz/F (L/kg)
CLz/F (L/h/kg)
T1/2Z (h)
Tmax (h)
Cmax (ng/mL)
F (%)
2 (po)
0.5 (iv)
61.0
78.6
80.0
83.7
3.05
1.06
163.8
8.3
25.0
6.0
4.5
1.0
0.5
26.8
48.5
19.4

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
227
(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) and stirred for 1 h at room temperature to give a hydro-
chloride product. The white solid was filtered, washed thoroughly
with ethyl acetate and ethanol, separately, and to give compound 2
hydrochloride (5.6 g, 73.0%) as a white solid. Mp: 213e215 ꢀC. MS
d 25.42, 28.42, 31.45, 32.00, 32.69, 43.29, 44.02, 52.35, 55.33, 58.24,
65.46, 120.31, 121.29, 122.21, 122.34, 124.91, 125.03, 125.14, 126.44,
126.35, 129.36, 130.06, 131.42, 132.87, 136.35. HRMS calcd for
C
27H33N2S (M þ H)þ, 417.2364; found, 417.2365.
4.1.3.2. 1-(3-(Benzo[b]thiophen-3-yl)-3-(piperidin-1-yl)propyl)-4-
benzyl-1,2,3,6-tetrahydropyridine (6b) hydrochloride. Yield 59.7%,
the purity was 98.3% by HPLC analysis. Mp: 164e166 ꢀC. MS (ESI) m/
(ESI) m/z: 362 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.18e2.42
(m, 2H), 3.16e3.51 (m, 2H), 3.38 (s, 2H), 3.47e3.51 (t, J ¼ 7.2 Hz, 2H),
3.68e3.71 (t, J ¼ 7.2 Hz, 2H), 3.74e3.86 (m, 2H), 5.48 (s, 1H),
7.21e7.23 (m, 3H), 7.29e7.33 (t, J ¼ 7.6 Hz, 2H), 7.45e7.55 (m, 2H),
8.08e8.10 (d, J ¼ 8.0 Hz, 1H), 8.58e8.60 (d, J ¼ 8.0 Hz, 1H), 9.04 (s,
1H).
z: 431.3 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.76 (m, 6H),
2.19e2.26 (m, 2H), 2.58 (m, 2H), 2.63e2.79 (m, 4H), 3.03e3.16 (m,
2H), 3.29 (m, 2H), 3.29 (m, 2H), 3.65 (s, 2H), 4.96e4.99 (t, J ¼ 6.8 Hz,
1H), 5.38 (s, 1H), 7.11e7.26 (m, 5H), 7.44e7.51 (m, 2H), 8.04e8.09
(m, 2H), 8.23 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 23.26, 25.45,
26.32, 27.83, 30.24, 32.45, 36.37, 44.01, 45.35, 49.29, 56.36, 65.42,
121.25, 121.47, 122.05, 122.44, 123.99, 124.78, 125.51, 126.10, 129.64,
131.22, 131.48, 132.90, 137.24. HRMS calcd for C28H35N2S (M þ H)þ,
431.2521; found, 431.2527.
4.1.2. Procedure B. 1-(Benzo[b]thiophen-3-yl)-3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)propan-1-ol (3) hydrochloride [15]
Sodium borohydride (0.18 g, 4.8 mmol) was added dropwise to a
stirred solution of 1-(benzo[b]thiophen-3-yl)-3-(4-benzyl-5,6-
dihydropyridin-1(2H)-yl)propan-1-one (2) hydrochloride (1.9 g,
4.8 mmol) in methanol (20 mL), and then the mixture was stirred at
room temperature for 2 h. Quenched with water (5 mL), and stirred
for 10 min, then the solvent was removed under reduced pressure.
The crude residue was extracted with dichloromethane (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) and added hydrogen chloride ethanol solu-
tion (1.25 M, 5 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 afford compound 3 hydrochloride (1.7 g,
89.0%) as a white solid. Mp: 170e172 ꢀC. MS (ESI) m/z: 364
4.1.3.3. 1-(3-(Benzo[b]thiophen-3-yl)-3-(morpholin-4-yl)propyl)-4-
benzyl-1,2,3,6-tetrahydropyridine (6c) hydrochloride. Yield 47.1%,
the purity was 98.8% by HPLC analysis. Mp: 152e154 ꢀC. MS (ESI) m/
z: 433.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.18 (m, 2H),
2.66e2.69 (m, 2H), 2.74 (m, 2H), 3.00e3.10 (m, 4H), 3.13 (m, 2H),
3.29 (m, 4H), 3.64 (m, 2H), 3.83 (s, 2H), 4.98e5.00 (d, J ¼ 9.2 Hz,1H),
5.38 (s, 1H), 7.11e7.27 (m, 5H), 7.42e7.52 (m, 2H), 8.04e8.09 (m,
2H), 8.21 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 26.28, 27.45,
32.16, 44.23, 44.57, 49.79, 52.05, 53.41, 61.24, 67.40, 121.43, 121.87,
123.12, 123.45, 124.35,124.93, 125.43, 126.49, 127.28, 129.48, 131.22,
132.45, 133.11, 137.42. HRMS calcd for C27H33N2OS (M þ H)þ,
433.2314; found, 433.2318.
4.1.3.4. 1-(3-(Benzo[b]thiophen-3-yl)-3-(piperazin-1-yl)propyl)-4-
benzyl-1,2,3,6-tetrahydropyridine (6d) hydrochloride. Yield 48.7%,
the purity was 99.0% by HPLC analysis. Mp: 171e173 ꢀC. MS (ESI) m/
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.11e2.38 (m, 2H),
2.19e2.27 (m, 2H), 3.09e3.38 (m, 2H), 3.24e3.31 (m, 2H), 3.35 (s,
2H), 3.51e3.78 (m, 2H), 5.04e5.07 (q, J ¼ 4.0 Hz, 1H), 5.43 (s, 1H),
5.72 (br, 1H), 7.19e7.23 (t, J ¼ 8.0 Hz, 3H), 7.28e7.32 (t, J ¼ 7.6 Hz,
2H), 7.35e7.41 (m, 2H), 7.60 (s, 1H), 7.96e7.99 (m, 2H).
z: 432.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.08 (m, 1H),
2.30 (m, 1H), 2.63e2.69 (m, 2H), 2.81e2.86 (m, 2H), 3.03e3.06 (m,
2H), 3.14e3.19 (m, 4H), 3.26e3.36 (m, 4H), 3.55 (m, 1H), 3.76e3.78
(m, 1H), 3.87 (s, 2H), 4.79e4.83 (t, J ¼ 6.0 Hz, 1H), 5.39 (s, 1H),
7.12e7.27 (m, 5H), 7.41e7.48 (m, 2H), 8.00e8.05 (m, 3H). 13C NMR
4.1.3. Procedure C. General procedure for the preparation of
compounds 6aed
(100 MHz, DMSO-d6):
d 25.43, 28.24, 30.45, 45.11, 45.67, 47.29,
To a solution of compound 3 (8 mmol) and N,N-diisopropyle-
thylamine (9.6 mmol) in acetonitrile (30 mL), p-toluenesulfonyl
chloride (8.8 mmol) was added, and the resulting mixture was
stirred for 12 h. Then cyclic amines 5 (8.8 mmol) and potassium
carbonate (8 mmol) were added to the reaction mixture, and stirred
at 70 ꢀC for 8 h. After filtering, the filtrate was evaporated to dryness
under reduced pressure. The residue was extracted with dichloro-
methane (60 mL) and water (40 mL), and the organic layer was
washed with brine (30 mL) and dried over anhydrous sodium
sulfate, the solvent was removed under reduced pressure. The
residue was dissolved in ethanol (30 mL) and added hydrogen
chloride ethanol solution (1.25 M, 8 mL) dropwise, and the result-
ing mixture was stirred for 1 h at room temperature to give a hy-
drochloride product. The crude product was purified by
recrystallization from ethanol to yield compounds 6aed.
48.51, 51.46, 52.89, 59.35, 65.27, 120.27, 121.46, 123.10, 123.67,
124.56, 125.59, 126.37, 128.11, 128.46, 131.72, 132.63, 135.29, 137.81.
HRMS calcd for C27H34N3S (M þ H)þ, 432.2473; found, 432.2469.
4.1.4. General procedure for the synthesis of 1-aryl-3-chloropropan-
1-ones (8) [15]
Aluminum chloride (8.4 g, 62.0 mmol) was added dropwise to a
solution of 3-chloropropanoyl chloride (7.2 g, 57.0 mmol) in chlo-
roform (70 mL) at room temperature. The reaction mixture was
stirred at the same temperature for 1 h. After cooling to 10 ꢀC, a
solution of aromatic ring (57.0 mmol) in chloroform (25 mL) was
added dropwise, and then the mixture was stirred at room tem-
perature 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 into 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 compound 8.
4.1.3.1. 1-(3-(Benzo[b]thiophen-3-yl)-3-(pyrrolidin-1-yl)propyl)-4-
benzyl-1,2,3,6-tetrahydropyridine (6a) hydrochloride. Yield 58.9%,
the purity was 98.5% by HPLC analysis. Mp: 168e170 ꢀC. MS (ESI) m/
z: 417.2 (M þ H)þ. 1H NMR (400 MHz, CDCl3):
d 1.96e2.22 (m, 4H),
2.49e2.57 (m, 2H), 2.61e2.78 (m, 2H), 2.85e3.06 (m, 4H),
3.29e3.33 (m, 2H), 3.38e3.45 (m, 2H), 3.60e3.80 (m, 2H), 4.01 (s,
2H), 5.28e5.39 (m,1H), 5.63 (s,1H), 7.11e7.12 (m, 2H), 7.21e7.30 (m,
3H), 7.43e7.47 (m, 1H), 7.53 (m, 1H), 7.93e7.95 (dd, J ¼ 2.0, 8.0 Hz,
1H), 8.23 (s, 1H), 8.72 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
4.1.5. Procedure D. General procedure for the synthesis of aryl
ketone 9 [15]
To a stirred mixture of ketone 8 (7.1 mmol) and 4-benzyl-1,2,3,6-
tetrahydropyridine hydrochloride (1.1 g, 6.4 mmol) in acetonitrile

228
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
(20 mL) was added diisopropylethylamine (1.7 g, 12.9 mmol). After
being stirred overnight at room temperature, the solvent was
removed under reduced pressure. The crude residue was extracted
with dichloromethane (30 mL) and water (30 mL). The organic
layer was washed with brine (20 mL) and dried over anhydrous
sodium sulfate, and the solvent was removed under reduced
pressure. The residue was dissolved in ethyl acetate (10 mL) and
hydrogen chloride ethanol solution (1.25 M, 8 mL) was added
dropwise, the resulting mixture was stirred for 1 h at room tem-
perature to give a hydrochloride product. The white solid was
filtered, washed thoroughly with ethyl acetate and ethanol, sepa-
rately, and to give compound 9.
4.1.7.1. 4-Benzyl-1-(3-(5-chloro-6-methoxynaphthalen-2-yl)-3-(pyr-
rolidin-1-yl)propyl)-1,2,3,6-tetrahydropyridine (12a) hydrochloride.
Yield 48.0% as a white solid, the purity was 98.9% by HPLC analysis.
Mp: 209e211 ꢀC. MS (ESI) m/z: 475.2 (M þ H)þ. 1H NMR (400 MHz,
CDCl3): d 2.94e2.20 (m, 4H), 2.59e2.63 (m, 2H), 2.71e2.92 (m, 2H),
2.98e3.16 (m, 4H), 3.23e3.25 (m, 2H), 3.27e3.36 (m, 2H),
3.38e3.39 (m, 2H), 3.49 (s, 2H), 4.02 (s, 3H), 5.08e5.10 (m, 1H),
5.28e5.36 (m, 1H), 7.05e7.07 (m, 2H), 7.12e7.25 (m, 3H), 7.36e7.38
(d, J ¼ 8.8 Hz, 1H), 7.90e7.93 (d, J ¼ 8.8 Hz, 1H), 8.06e8.08 (d,
J ¼ 7.2 Hz, 1H), 8.30e8.33 (dd, J ¼ 0.8, 8.8 Hz, 2H). 13C NMR
(100 MHz, DMSO-d6):
d 27.18, 28.30, 30.24, 31.45, 32.34, 45.31,
45.69, 54.13, 55.22, 57.15, 66.34, 115.23, 120.24, 121.35, 122.12,
122.47, 124.30, 124.98, 125.62, 126.47, 126.79, 129.21, 130.23, 131.05,
132.44, 147.47. HRMS calcd for C30H36ClN2O (M þ H)þ, 475.2516;
found, 475.2520.
4.1.5.1. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(5-chloro-6-
methoxynaphthalen-2-yl)propan-1-one
(9a)
hydrochloride.
Yield 81.9% as a white solid. Mp: 183e185 ꢀC. MS (ESI) m/z: 420.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.16e2.43 (m, 2H),
4.1.7.2. 4-Benzyl-1-(3-(3,4-dichlorophenyl)-3-(pyrrolidin-1-yl)pro-
pyl)-1,2,3,6-tetrahydropyridine (12b) hydrochloride. Yield 50.0% as a
white solid, the purity was 98.4% by þHPLC analysis. Mp:
230e232 ꢀC. MS (ESI) m/z: 429.2 (M þ H) . 1H NMR (400 MHz,
3.18e3.56 (m, 2H), 3.38 (s, 2H), 3.50e3.53 (t, J ¼ 7.2 Hz, 2H),
3.74e3.78 (t, J ¼ 7.2 Hz, 2H), 3.74e3.90 (m, 2H), 4.05 (s, 3H), 5.50 (s,
1H), 7.22e7.24 (m, 3H), 7.30e7.34 (t, J ¼ 7.6 Hz, 2H), 7.69e7.71 (d,
J ¼ 9.2 Hz, 1H), 8.10e8.20 (m, 3H), 8.75 (s, 1H).
CDCl3): d 2.01e2.14 (m, 4H), 2.22e2.26 (m, 2H), 2.71e2.82 (m, 2H),
2.83e2.96 (m, 4H), 3.10e3.20 (m, 2H), 3.27e3.33 (m, 2H),
3.36e3.46 (m, 2H), 4.01 (s, 2H), 5.08 (m, 1H), 5.36e5.42 (m, 1H),
7.13e7.15 (d, J ¼ 7.6 Hz, 2H), 7.23e7.34 (m, 3H), 7.58e7.60 (d,
J ¼ 8.4 Hz, 1H), 7.97e8.01 (m, 2H). 13C NMR (100 MHz, DMSO-d6):
4.1.5.2. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-
dichlorophenyl)propan-1-one (9b) hydrochloride. Yield 76.9% as a
white solid. Mp: 190e193 ꢀC. MS (ESI) m/z: 374.1 (M þ H)þ. 1H NMR
d
27.22, 28.35, 31.55, 32.34, 44.31, 44.62, 51.48, 53.26, 57.90, 66.37,
(400 MHz, DMSO-d6):
d 2.15e2.44 (m, 2H), 3.11e3.51 (m, 2H), 3.37
122.45, 122.89, 123.26, 124.83, 125.46, 125.67, 126.17, 126.35, 128.87,
(s, 2H), 3.41e3.45 (t, J ¼ 7.2 Hz, 2H), 3.67e3.71 (t, J ¼ 7.2 Hz, 2H),
3.67e3.84 (m, 2H), 5.47 (s, 1H), 7.20e7.23 (m, 3H), 7.29e7.33 (m,
2H), 7.82e7.84 (d, J ¼ 8.4 Hz, 1H), 7.93e7.96 (m, 1H), 8.20e8.21 (d,
J ¼ 2.4 Hz, 1H).
130.62, 131.31, 133.46, 135.89. HRMS calcd for
C25H31Cl2N2
(M þ H)þ, 429.1864; found, 429.1869.
4.1.8. General procedure for the synthesis of aryl ketone 14
Ketone 13 (50 mmol) was reacted with cyclic amines 5
(50 mmol) in acetonitrile (100 mL) using procedure D. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
14 hydrochloride.
4.1.6. General procedure for the synthesis of aryl alcohol 10 [15]
Aryl ketone 9 (4 mmol) was treated with sodium borohydride
(4 mmol) in methanol (20 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
10 hydrochloride.
4.1.8.1. 1-(3,4-Dichlorophenyl)-3-(piperidin-1-yl)propan-1-one (14a)
hydrochloride. Yield 77.7% as a white solid. MS (ESI) m/z: 286.1
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.92e2.05 (m, 2H),
4.1.6.1. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(5-chloro-6-
methoxynaphthalen-2-yl)propan-1-ol
(10a)
hydrochloride.
2.08e2.35 (m, 4H), 3.11e3.15 (m, 2H), 3.37e3.43 (m, 2H), 3.52e3.54
(d, J ¼ 8.0 Hz, 2H), 3.84e3.86 (t, J ¼ 8.0 Hz, 2H), 7.79e7.81 (d,
J ¼ 8.0 Hz, 1H), 7.93e7.96 (m, 1H), 8.15e8.16 (d, J ¼ 4.0 Hz, 1H).
Yield 88.5% as a white solid. Mp: 164e166 ꢀC. MS (ESI) m/z: 422.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.07e2.26 (m, 2H),
2.29e2.32 (m, 2H), 2.67e3.01 (m, 2H), 3.19e3.24 (m, 2H), 3.36 (s,
2H), 3.39e3.55 (m, 2H), 4.00 (s, 3H), 5.15e5.18 (t, J ¼ 5.2 Hz, 1H),
5.33 (s, 1H), 7.10e7.12 (d, J ¼ 6.8 Hz, 2H), 7.19e7.32 (m, 4H),
7.51e7.54 (d, J ¼ 8.8 Hz, 1H), 7.69e7.71 (d, J ¼ 8.8 Hz, 1H), 7.81 (s,
1H), 8.12e8.15 (d, J ¼ 8.8 Hz, 1H).
4.1.8.2. 1-(3,4-Dichlorophenyl)-3-morpholinopropan-1-one
(14b)
hydrochloride. Yield 81.7% as a white solid. MS (ESI) m/z: 288.1
(M þ H)þ. 1H NMR (600 MHz, DMSO-d6):
d 3.14e3.16 (m, 2H),
3.45e3.46 (m, 2H), 3.51e3.53 (d, J ¼ 12.0 Hz, 2H), 3.73e3.76 (t,
J ¼ 7.8 Hz, 2H), 3.86e3.90 (t, J ¼ 12.0 Hz, 2H), 3.98e3.99 (m, 2H),
7.85e7.86 (d, J ¼ 8.4 Hz, 1H), 7.95e7.97 (dd, J ¼ 1.8, 8.4 Hz, 1H),
8.22e8.23 (d, J ¼ 1.8 Hz, 1H).
4.1.6.2. 3-(4-Benzyl-5,6-dihydropyridin-1(2H)-yl)-1-(3,4-
dichlorophenyl)propan-1-ol (10b) hydrochloride. Yield 8þ2.91 % as a
white solid. Mp: 160e163 ꢀC. MS (ESI) m/z: 376.1 (M þ H) . H NMR
(400 MHz, DMSO-d6):
d
2.01e2.06 (t, J ¼ 8.0 Hz, 2H), 2.10e2.40 (m,
4.1.9. General procedure for the synthesis of aryl alcohol 15
Aryl ketone 14 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (50 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
15 hydrochloride.
2H), 3.05e3.41 (m, 2H), 3.08e3.15 (t, J ¼ 8.0 Hz, 2H), 3.35 (s, 2H),
3.51e3.76 (m, 2H), 4.69e4.72 (q, J ¼ 4.0 Hz, 1H), 5.42 (s, 1H), 5.80
(br, 1H), 7.19e7.23 (m, 3H), 7.28e7.32 (t, J ¼ 7.6 Hz, 2H), 7.35e7.37
(dd, J ¼ 2.0, 6.0 Hz, 1H), 7.58e7.61 (m, 2H), 10.60 (br, 1H).
4.1.7. General procedure for the preparation of compounds 12aeb
Aryl alcohol 10 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), and then
treated with pyrrolidine (8.8 mmol) as procedure C. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
12 hydrochloride.
4.1.9.1. 1-(3,4-Dichlorophenyl)-3-(piperidin-1-yl)propan-1-ol (15a)
hydrochloride. Yield 93.2% as a white solid. MS (ESI) m/z: 288.1
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.94e2.06 (m, 2H),
2.05e2.33 (m, 4H), 3.13e3.17 (m, 2H), 3.25e3.36 (m, 2H), 3.37e3.51
(m, 2H), 3.54e3.62 (m, 2H), 4.75e4.77 (m, 1H), 5.83 (br, 1H),
7.35e7.37 (d, J ¼ 8.0 Hz, 1H), 7.57e7.61 (m, 2H).

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
229
4.1.9.2. 1-(3,4-Dichlorophenyl)-3-morpholinopropan-1-ol (15b) hy-
drochloride. Yield 93.5% as a white solid. MS (ESI) m/z: 290.2
z: 429.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d
1.16e1.20 (t,
J ¼ 8.0 Hz, 3H), 1.43e1.46 (m, 2H), 1.73e2.11 (m, 4H), 2.51e3.15 (m,
11H), 3.39 (m, 4H), 4.05e4.10 (q, J ¼ 8.0 Hz, 2H), 4.78e4.84 (m, 1H),
7.64e7.71 (m, 2H), 8.03 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
(M þ H)þ. 1H NMR (600 MHz, DMSO-d6):
d 2.01e2.06 (m, 1H),
2.11e2.16 (m, 1H), 3.04 (m, 2H), 3.14 (m, 2H), 3.40e3.42 (d,
J ¼ 12.0 Hz, 1H), 3.83e3.87 (t, J ¼ 12.0 Hz, 2H), 3.91e3.93 (m, 2H),
4.72e4.74 (q, J ¼ 3.6 Hz, 1H), 5.85 (s, 1H), 7.37e7.39 (dd, J ¼ 1.8,
8.4 Hz, 1H), 7.61e7.62 (m, 2H).
d
16.78, 20.25, 21.78, 22.66, 25.57, 49.87, 51.24, 51.95, 52.36, 53.47,
61.25, 66.45, 128.66, 131.47, 131.82, 132.35, 132.37, 137.28, 170.25.
HRMS calcd for C21H31Cl2N2O3 (M þ H)þ, 429.1712; found, 429.1719.
4.1.10. General procedure for the preparation of compounds 18aee
Aryl alcohol 15 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with cyclic amines 17 (8.8 mmol) as procedure C. The crude product
was converted into the corresponding hydrochloride salt and pu-
rified by recrystallization from ethanol to yield compound 18
hydrochloride.
4.1.11. General procedure for the synthesis of aryl ketone 20
Aryl ketone 19 (20 mmol) was treated with paraformaldehyde
(22 mmol) and N-methyl-1-phenylmethanamine hydrochloride
(22 mmol) in ethanol (15 mL) as procedure A. The crude product
was purified by recrystallization from ethanol.
4.1.12. General procedure for the synthesis of aryl alcohol 21
Aryl ketone 20 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (30 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
21 hydrochloride.
4.1.10.1. 4-(1-(3,4-Dichlorophenyl)-3-(piperidin-1-yl)propyl)mor-
pholine (18a) hydrochloride. Yield 60.3% as a white solid, the purity
was 99.0% by HPLC analysis. Mp: 229e231 ꢀC. MS (ESI) m/z: 357.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.20e1.26 (m, 6H),
2.06e2.11 (m, 2H), 2.28e2.33 (m, 6H), 2.80e3.03 (m, 4H),
3.35e3.56 (m, 4H), 3.61e3.63 (d, J ¼ 8.0 Hz, 1H), 7.26e7.29 (m, 1H),
7.55 (s,1H), 7.37e7.39 (d, J ¼ 8.4 Hz,1H). 13C NMR (100 MHz, DMSO-
4.1.12.1. 1-(Benzo[b]thiophen-2-yl)-3-(benzyl(methyl)amino)propan-
1-ol (21a) hydrochloride. Yield 92.0% as a white solid. MS (ESI) m/z:
d6):
d
22.45, 22.94, 25.87, 26.17, 50.21, 51.43, 52.37, 52.62, 63.31,
312.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.65 (s, 3H),
66.79, 127.21, 130.88, 131.21, 132.42, 132.83, 135.45. HRMS calcd for
2.75e2.91 (m, 2H), 3.75e3.80 (m, 2H), 4.25 (m, 2H), 5.01 (m, 1H),
5.75 (br, 1H), 7.31e7.35 (m, 3H), 7.38e7.43 (m, 2H), 7.56e7.59 (m,
2H), 7.73 (s, 1H), 7.89 (m, 1H), 7.98e8.03 (m, 1H).
C
18H27Cl2N2O (M þ H)þ, 357.1500; found, 357.1508.
4.1.10.2. 4,40-(1-(3,4-Dichlorophenyl)propane-1,3-diyl)dimorpholine
(18b) hydrochloride. Yield 58.3% as a white solid, the purity was
98.9% by HPLC analysis. Mp: 248e250 ꢀC. MS (ESI) m/z: 359.1
4.1.12.2. 3-(Benzyl(methyl)amino)-1-(2,4-difluorophenyl)propan-1-
ol (21b) hydrochloride. Yield 90.2% as a white solid. MS (ESI) m/z:
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d
2.68e2.71 (m, 2H),
292.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.45e2.75 (m, 2H),
2.92e3.12 (m, 6H), 3.40e3.46 (m, 2H), 3.55e3.61 (m, 2H),
3.77e4.05 (m, 8H), 4.12 (m, 1H), 7.64e7.66 (d, J ¼ 8.0 Hz, 1H),
7.77e7.79 (d, J ¼ 8.0 Hz,1H), 7.97 (s, 1H). 13C NMR (100 MHz, DMSO-
2.66 (s, 3H), 2.87e3.03 (m, 2H), 4.25 (s, 2H), 4.57 (m, 1H), 5.73 (br,
1H), 7.11e7.15 (m, 1H), 7.23e7.27 (m, 1H), 7.35e7.39 (m, 2H), 7.41
(m, 1H), 7.43e7.48 (m, 2H), 7.66e7.71 (m, 1H).
d6):
d 23.18, 25.23, 26.33, 29.52, 51.12, 51.44, 52.39, 53.27, 61.23,
66.37, 127.43, 130.25, 131.78, 131.81, 133.24, 135.16. HRMS calcd for
C
4.1.13. General procedure for the preparation of compounds 23aeb
Aryl alcohol 21 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with morpholine (8.8 mmol) as procedure C. The crude product was
converted into the corresponding hydrochloride salt and purified
by recrystallization from ethanol to yield compound 23
hydrochloride.
17H25Cl2N2O2 (M þ H)þ, 359.1293; found, 359.1290.
4.1.10.3. 4-(3-(3,4-Dichlorophenyl)-3-(pyrrolidin-1-yl)propyl)mor-
pholine (18c) hydrochloride. Yield 48.3% as a white solid, the purity
was 99.1% by HPLC analysis. Mp: 206e208 ꢀC. MS (ESI) m/z: 343.3
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.99e2.03 (m, 4H),
2.60e2.66 (m, 1H), 2.73e2.80 (m, 2H), 2.80e3.00 (m, 5H), 3.20 (m,
1H), 3.36 (m, 2H), 3.79e3.85 (m, 3H), 3.92e3.94 (m, 2H), 4.67e4.69
(d, J ¼ 7.6 Hz, 1H), 7.77e7.83 (m, 2H), 8.14 (s, 1H). 13C NMR
4.1.13.1. 3-(Benzo[b]thiophen-2-yl)-N-benzyl-N-methyl-3-
morpholinopropan-1-amine (23a) hydrochloride. Yield 43.2% as a
white solid, the purity was 98.1% by þHPLC analysis. Mp:
205e207 ꢀC. MS (ESI) m/z: 381.2 (M þ H) . 1H NMR (400 MHz,
(100 MHz, DMSO-d6):
d 22.90, 26.00, 51.09, 51.32, 52.20, 52.72,
63.38, 64.77, 129.49, 131.35, 131.63, 132.17, 132.86, 135.03. HRMS
calcd for C17H25Cl2N2O (M þ H)þ, 343.1338; found, 343.1338.
DMSO-d6): d 2.67 (s, 3H), 2.78e2.93 (m, 2H), 2.98e3.16 (m, 4H),
3.79e3.81 (m, 2H), 3.91e4.02 (m, 4H), 4.23e4.31 (m, 2H), 5.03 (s,
1H), 7.32e7.35 (m, 3H), 7.40e7.46 (m, 2H), 7.56e7.58 (m, 2H), 7.75
(s, 1H), 7.87e7.90 (m, 1H), 7.99e8.02 (m, 1H). 13C NMR (100 MHz,
4.1.10.4. 4-(3-(3,4-Dichlorophenyl)-3-(3-methylpiperidin-1-yl)pro-
pyl)morpholine (18d) hydrochloride. Yield 28.2% as a white solid,
the purity was 98.5% by HPLC analysis. Mp: 224e226 ꢀC. MS (ESI)
DMSO-d6):
d 27.87, 37.82, 42.15, 42.19, 48.23, 50.12, 50.23, 62.45,
m/z: 371.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d
0.90e0.92 (d,
65.19, 120.45, 121.58, 123.10, 123.17, 123.82, 124.15, 125.21, 126.24,
128.43, 132.14, 133.79, 135.67, 138.96, 145.10. HRMS calcd for
J ¼ 8.0 Hz, 3H), 0.93 (m,1H),1.78e1.84 (t, J ¼ 12.0 Hz, 2H),1.93e2.05
(m, 1H), 2.16e2.21 (m, 2H), 2.27e2.35 (m, 6H), 2.44e2.46 (m, 1H),
2.65 (m, 2H), 2.84 (m, 1H), 3.28e3.34 (t, J ¼ 12.0 Hz, 1H), 3.73e3.75
(t, J ¼ 4.0 Hz, 1H), 4.20 (s, 1H), 7.46e7.48 (d, J ¼ 8.0 Hz, 1H),
7.52e7.56 (t, J ¼ 8.0 Hz, 1H), 8.12 (s, 1H). 13C NMR (100 MHz, DMSO-
C
23H29N2OS (M þ H)þ, 381.2001; found, 381.2009.
4.1.13.2. N-Benzyl-3-(2,4-difluorophenyl)-N-methyl-3-
morpholinopropan-1-amine (23b) hydrochloride. Yield 60.0% as a
white solid, the purity was 98.4% by þHPLC analysis. Mp:
229e231 ꢀC. MS (ESI) m/z: 361.2 (M þ H) . 1H NMR (400 MHz,
d6):
d 20.52, 21.46, 22.94, 25.89, 50.17, 51.24, 52.37, 52.82, 55.49,
61.40, 66.79, 129.13, 130.27, 131.35, 132.10, 132.89, 136.17. HRMS
calcd for C19H29Cl2N2O (M þ H)þ, 371.1657; found, 371.1662.
DMSO-d6): d 2.40e2.79 (m, 2H), 2.67 (s, 3H), 2.86e3.05 (m, 2H),
3.47e3.67 (m, 4H), 3.74e3.75 (m, 4H), 4.27 (s, 2H), 4.45 (s, 1H),
7.12e7.17 (m, 1H), 7.23e7.28 (m, 1H), 7.37e7.41 (m, 3H), 7.42e7.50
(m, 2H), 7.65e7.71 (q, J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO-
4.1.10.5. Ethyl 1-(1-(3,4-dichlorophenyl)-3-morpholinopropyl)piperi-
dine-3-carboxylate (18e) hydrochloride. Yield 30.2% as a white solid,
the purity was 98.0% by HPLC analysis. Mp: 181e183 ꢀC. MS (ESI) m/
d6):
d 28.46, 37.59, 42.13, 42.25, 47.09, 50.24, 51.36, 61.57, 66.26,

230
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
116.54, 121.57, 122.35, 124.38, 125.18, 127.90, 129.21, 130.25, 132.36,
134.58, 155.24, 156.35. HRMS calcd for C21H27F2N2O (M þ H)þ,
361.2091; found, 361.2085.
4.1.16. 3-(2,4-Difluorophenyl)-N-methyl-3-morpholinopropan-1-
amine (28) hydrochloride
A 100 mL hydrogenation reactor was charged with Pd/C (5% Pd
content, 0.1 g), methanol (20 mL) and 23b hydrochloride (1.3 g,
3 mmol). The reactor was pressurized with hydrogen (0.1 MPa), and
then stirred at room temperature for 6 h. The reaction mixture was
filtered to remove catalyst, and the solvent was concentrated under
reduced pressure (~30 mmHg) to give a light white solid. The solid
was purified by recrystallization from ethanol (10 mL) to yield
compound 28 hydrochloride (0.83 g, 80.9% yield) as a white solid.
The purity was 99.3% by HPLC analysis. Mp: 202e204 ꢀC. MS (ESI)
4.1.14. General procedure for the synthesis of aryl alcohol 25
Aryl ketone
8 (50 mmol) was treated with N-methyl-1-
phenylmethanamine hydrochloride (50 mmol) in acetonitrile
(100 mL) as procedure D. The crude product was purified by
recrystallization from ethanol to give compound 24.
Aryl ketone 24 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (30 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
25 hydrochloride.
m/z: 271.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.52e2.55 (m,
4H), 2.62e2.67 (m, 2H), 2.79e2.82 (m, 2H), 3.03e3.06 (m, 4H), 3.89
(s, 3H), 4.69e4.73 (dd, J ¼ 4.4, 10.8 Hz, 1H), 7.21e7.25 (m, 1H),
7.30e7.35 (m, 1H), 7.82e7.88 (dd, J ¼ 8.4, 14.8 Hz, 1H). 13C NMR
4.1.14.1. 3-(Benzyl(methyl)amino)-1-(3,4-dichlorophenyl)propan-1-
(100 MHz, DMSO-d6): d 27.26, 38.43, 42.25, 49.21, 50.38, 52.01,
ol (25a) hydrochloride. Yield 92.2% as a white solid. MS (ESI) m/z:
61.34, 63.18, 115.39, 119.65, 121.34, 132.27, 154.31, 155.29. HRMS
324.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d
2.66 (s, 3H),
calcd for C14H21F2N2O (M þ H)þ, 271.1622; found, 271.1616.
2.77e2.93 (m, 2H), 3.73e3.81 (m, 2H), 4.27 (s, 2H), 5.08 (m, 1H),
5.79 (br, 1H), 7.32e7.37 (m, 4H), 7.38e7.42 (m, 1H), 7.52e7.54 (m,
1H), 7.64e7.66 (d, J ¼ 8.0 Hz, 1H), 7.79 (m, 1H).
4.1.17. General procedure for the synthesis of aryl alcohol 30
Aryl ketone 19 (20 mmol) was treated with paraformaldehyde
(22 mmol) and dimethylamine hydrochloride (22 mmol) in ethanol
(15 mL) as procedure A. The crude product was purified by
recrystallization from ethanol to yield aryl ketone 29.
Compound 29 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (30 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
30 hydrochloride.
4 .1.14 . 2 . 3 - ( B e n z y l ( m e t h y l ) a m i n o ) - 1 - ( 5 - c h l o r o - 6 -
methoxynaphthalen-2-yl)propan-1-ol
(25b)
hydrochloride.
Yield 85.4% as a white solid. MS (ESI) m/z: 370.2 (M þ H)þ. 1H NMR
(400 MHz, DMSO-d6)
d 2.64 (s, 3H), 2.74e2.88 (m, 2H), 3.72e3.79
(m, 2H), 4.03 (s, 3H), 4.23 (m, 2H), 5.04 (m, 1H), 5.73 (br, 1H),
7.27e7.31 (m, 3H), 7.38e7.40 (m, 2H), 7.61e7.63 (d, J ¼ 8.0 Hz, 1H),
7.76e7.78 (m, 1H), 7.94e7.96 (d, J ¼ 8.4 Hz, 1H), 8.07e8.11 (m, 2H).
4.1.15. General procedure for the preparation of compounds 27aeb
Aryl alcohol 25 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with morpholine (8.8 mmol) as procedure C. The crude product was
converted into the corresponding hydrochloride salt and purified
by recrystallization from ethanol to yield compound 27
hydrochloride.
4.1.17.1. 3-(Dimethylamino)-1-(4-fluorophenyl)propan-1-ol
(30a)
hydrochloride. Yield 82.1% as a white solid. MS (ESI) m/z: 198.1
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.84e1.96 (m, 2H), 2.35
(s, 6H),3.01e3.03 (m, 2H), 4.55 (m, 1H), 5.81 (br, 1H), 7.29e7.31 (d,
J ¼ 8.0 Hz, 2H), 7.63e7.65 (d, J ¼ 8.0 Hz, 2H).
4.1.17.2. 3-(Dimethylamino)-1-(4-(trifluoromethyl)phenyl)propan-1-
ol (30b) hydrochloride. Yield 86.5% as a white solid. MS (ESI) m/z:
4.1.15.1. N-Benzyl-3-(3,4-dichlorophenyl)-N-methyl-3-
morpholinopropan-1-amine (27a) hydrochloride. Yield 48.5% as a
white solid, the purity was 98.3% by þHPLC analysis. Mp:
257e259 ꢀC. MS (ESI) m/z: 393.2 (M þ H) . 1H NMR (400 MHz,
248.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.81e1.91 (m, 2H),
2.36 (s, 6H),3.00e3.03 (m, 2H), 4.51 (m, 1H), 5.79 (br, 1H), 7.26e7.31
(d, J ¼ 8.0 Hz, 2H), 7.72e7.76 (d, J ¼ 8.0 Hz, 2H).
DMSO-d6):
d
2.45e2.58 (m, 2H), 2.49e2.58 (m, 2H), 2.69 (s, 3H),
4.1.17.3. 3-(Dimethylamino)-1-(4-methoxyphenyl)propan-1-ol (30c)
hydrochloride. Yield 92.9% as a white solid. MS (ESI) m/z: 210.1
2.87e2.95 (m, 2H), 3.08e3.15 (m, 2H), 3.73e3.79 (m, 4H), 4.24 (s,
2H), 4.31e4.33 (d, J ¼ 6.4 Hz, 1H), 7.36e7.48 (m, 6H), 7.66e7.68 (d,
J ¼ 8.4 Hz, 1H), 7.77 (d, J ¼ 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO-
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.01e2.12 (m, 2H), 2.43
(s, 6H), 2.87e2.89 (m, 2H), 3.45 (s, 3H), 4.73 (m, 1H), 5.65 (m, 1H),
6.53e6.55 (d, J ¼ 8.4 Hz, 2H), 7.27e7.29 (d, J ¼ 8.0 Hz, 2H).
d6):
d 26.37, 33.42, 43.17, 43.29, 49.13, 51.21, 51.32, 61.33, 66.24,
121.20, 121.69, 122.38, 123.02, 123.54, 123.89, 125.09, 126.15, 127.36,
130.25, 132.82, 135.58. HRMS calcd for C21H27Cl2N2O (M þ H)þ,
393.1500; found, 393.1508.
4.1.17.4. 3-(Dimethylamino)-1-(p-tolyl)propan-1-ol (30d) hydro-
chloride. Yield 90.2% as a white solid. MS (ESI) m/z: 194.1 (M þ H)þ.
1H NMR (400 MHz, DMSO-d6)
d 2.12e2.26 (m, 2H), 2.37 (s, 3H),
4.1.15.2. N-Benzyl-3-(5-chloro-6-methoxynaphthalen-2-yl)-N-
2.670 (s, 6H), 2.84e2.89 (m, 2H), 4.57e4.60 (m, 1H), 5.67 (br, 1H),
7.28e7.30 (d, J ¼ 8.0 Hz, 2H), 7.55e7.57 (d, J ¼ 8.0 Hz, 2H).
methyl-3-morpholinopropan-1-amine
(27b)
hydrochloride.
Yield 44.3% as a white solid, the purity was 98þ.9% by HPLC analysis.
Mp: 248e250 ꢀC. MS (ESI) m/z: 439.2 (M þ H) . 1H NMR (400 MHz,
4.1.17.5. 1-(4-Chlorophenyl)-3-(dimethylamino)propan-1-ol
(30e)
DMSO-d6):
d
2.46e2.74 (m, 2H), 2.68 (s, 3H), 2.84e2.94 (m, 2H),
hydrochloride. Yield 93.2% as a white solid. MS (ESI) m/z: 214.1
2.96e3.01 (m, 4H), 3.86 (m, 4H), 4.01 (s, 3H), 4.26 (s, 2H), 4.59e4.61
(d, J ¼ 8.8 Hz, 1H), 7.26e7.29 (t, J ¼ 6.4 Hz, 3H), 7.39e7.40 (d,
J ¼ 6.0 Hz, 2H), 7.62e7.64 (d, J ¼ 9.2 Hz, 1H), 7.76e7.79 (dd, J ¼ 0.8,
8.0 Hz, 1H), 7.96e7.99 (d, J ¼ 8.8 Hz, 1H), 8.09e8.13 (t, J ¼ 8.8 Hz,
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.93e2.03 (m, 2H), 2.69
(s, 6H), 2.79e2.84 (m, 2H), 4.51e4.64 (m,1H), 5.79 (s,1H), 7.25e7.27
(d, J ¼ 8.0 Hz, 2H), 7.40e7.42 (d, J ¼ 8.0 Hz, 2H).
2H). 13C NMR (100 MHz, DMSO-d6):
d
28.43, 38.29, 42.18, 48.31,
4.1.17.6. 1-(2,4-Difluorophenyl)-3-(dimethylamino)propan-1-ol (30f)
hydrochloride. Yield 85.2% as a white solid. MS (ESI) m/z: 216.1
49.67, 50.17, 51.24, 63.35, 67.18, 117.09, 120.18, 121.24, 122.15, 122.36,
124.49, 125.81, 126.57, 126.92, 128.43, 130.16, 131.25, 136.90, 142.13,
156.27. HRMS calcd for C26H32ClN2O2 (M þ H)þ, 439.2152; found,
439.2158.
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.24e2.45 (m, 2H), 2.72
(s, 6H), 2.79e2.83 (m, 2H), 4.67e4.69 (m, 1H), 5.73 (br, 1H),
7.23e7.27 (m, 1H), 7.38e7.41 (m, 1H), 8.02e8.03 (m, 1H).

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
231
4.1.17.7. 1-(Benzo[b]thiophen-2-yl)-3-(dimethylamino)propan-1-ol
4.1.18.5. N,N-Dimethyl-3-(pyrrolidin-1-yl)-3-(4-(trifluoromethyl)
phenyl)propan-1-amine (32e) hydrochloride. Yield 35.6% as a white
solid, the purity was 98.1% by HPLC analysis. Mp: 231e233 ꢀC. MS
(ESI) m/z: 301.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
(30g) hydrochloride. Yield 95.0% as a white solid. MS (ESI) m/z:
236.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.15e2.23 (m, 2H),
2.69 (s, 6H), 2.81e2.85 (m, 2H), 4.83e4.86 (m, 1H), 5.69 (br, 1H),
7.41e7.46 (m, 2H), 7.75 (s, 1H), 7.89e7.93 (m, 1H), 8.00e8.02 (m,
1H).
d
1.65e2.01 (m, 4H), 2.55e2.60 (m, 2H), 2.68 (s, 6H), 2.78e2.88 (m,
2H), 3.16e3.80 (m, 4H), 4.78e4.79 (m, 1H), 7.23e7.25 (d, J ¼ 8.0 Hz,
2H), 7.71e7.73 (d, J ¼ 8.0 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
d
26.41, 30.87, 45.26, 45.79, 57.24, 57.38, 67.41, 125.31, 127.40,
4.1.17.8. 1-(Benzo[b]thiophen-3-yl)-3-(dimethylamino)propan-1-ol
129.00, 131.42, 132.11, 137.44, 137.13. HRMS calcd for C16H24F3N2
(30h) hydrochloride. Yield 90.5% as a white solid. MS (ESI) m/z:
(M þ H)þ, 301.1892; found, 301.1884.
236.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 2.13e2.24 (m, 2H),
2.67 (s, 6H), 2.83 (m, 2H), 4.87 (m, 1H), 5.72 (br, 1H), 7.45e7.61 (m,
2H), 7.85e7.96 (m, 1H), 8.19 (s, 1H), 8.57 (m, 1H).
4.1.18.6. 3-(4-Methoxyphenyl)-N,N-dimethyl-3-morpholinopropan-
1-amine (32f) hydrochloride. Yield 40.0% as a white solid, the purity
was 98.2% by HPLC analysis. Mp: 194e196 ꢀC. MS (ESI) m/z: 279.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.14e2.36 (m, 2H), 2.41
4.1.18. General procedure for the preparation of compounds 32aem
Aryl alcohol 30 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with cyclic amines 5 (8.8 mmol) as procedure C. The crude product
was converted into the corresponding hydrochloride salt and pu-
rified by recrystallization from ethanol to yield compound 32
hydrochloride.
(s, 6H), 2.47e2.74 (m, 4H), 3.29e3.87 (m, 4H), 3.41 (s, 3H),
3.52e3.54 (m, 2H), 4.29e4.31 (m, 1H), 6.55e6.58 (d, J ¼ 8.4 Hz, 2H),
7.25e7.29 (d, J ¼ 8.4 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
d 25.01,
42.12, 42.24, 48.36, 51.53, 53.02, 54.90, 61.43, 67.09, 121.45, 122.38,
133.51, 133.62, 145.43, 161.47. HRMS calcd for C16H27N2O2 (M þ H)þ,
279.2073; found, 279.2079.
4.1.18.1. 3-(4-Fluorophenyl)-N,N-dimethyl-3-(pyrrolidin-1-yl)
propan-1-amine (32a) hydrochloride. Yield 16.7% as a white solid,
the purity was 98.0% by HPLC analysis. Mp: 245e247 ꢀC. MS (ESI)
4.1.18.7. N,N-Dimethyl-3-morpholino-3-(p-tolyl)propan-1-amine
(32g) hydrochloride. Yield 50.0% as a white solid, the purity was
98.7% by HPLC analysis. Mp: 234e236 ꢀC. MS (ESI) m/z: 263.2
m/z: 251.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d
1.80e1.98 (m,
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.35 (s, 3H), 2.62e2.65
4H), 2.51e2.53 (m, 2H), 2.67 (s, 6H), 2.80e2.84 (m, 2H), 3.04e3.75
(m, 4H), 4.55e4.57 (m, 1H), 7.26e7.28 (dd, J ¼ 8.0, 12.0 Hz, 2H),
(t, J ¼ 6.4 Hz, 2H), 2.70 (s, 6H), 2.80e2.84 (t, J ¼ 6.4 Hz, 2H),
2.87e2.94 (m, 4H), 3.66e3.87 (m, 4H), 4.51e4.53 (d, J ¼ 8.0 Hz, 1H),
7.30e7.32 (d, J ¼ 8.0 Hz, 2H), 7.57e7.59 (d, J ¼ 8.0 Hz, 2H). 13C NMR
7.74e7.83 (m, 2H). 13C NMR (100 MHz, DMSO-d6):
d 26.58, 30.46,
30.52, 32.67, 46.43, 55.57, 57.94, 69.87, 122.34, 122.57, 134.37,
134.69, 142.87, 162.53. HRMS calcd for C15H24FN2 (M þ H)þ,
251.1924; found, 251.1929.
(100 MHz, DMSO-d6): d 21.42, 26.18, 42.58, 42.73, 47.57, 51.24,
52.59, 54.21, 61.38, 65.10, 122.31, 122.42, 132.35, 132.44, 145.24,
148.37. HRMS calcd for C16H27N2O (M þ H)þ, 263.2123; found,
263.2128.
4.1.18.2. 3-(4-Fluorophenyl)-N,N-dimethyl-3-morpholinopropan-1-
amine (32b) hydrochloride. Yield 39.8% as a white solid, the purity
was 99.0% by HPLC analysis. Mp: 251e253 ꢀC. MS (ESI) m/z: 267.2
4.1.18.8. 3-(4-Chlorophenyl)-N,N-dimethyl-3-morpholinopropan-1-
amine (32h) hydrochloride. Yield 50.5% as a white solid, the purity
was 98.4% by HPLC analysis. Mp: 178e180 ꢀC. MS (ESI) m/z: 283.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.51e2.61 (m, 2H), 2.72
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.01e2.06 (m, 1H),
(s, 6H), 3.01e3.08 (m, 2H), 3.87 (m, 8H), 4.49 (m, 1H), 7.31e7.35 (t,
J ¼ 8.0 Hz, 2H), 7.65e7.69 (t, J ¼ 8.0 Hz, 2H). 13C NMR (100 MHz,
2.29e2.37 (m, 4H), 2.39e2.42 (m, 1H), 2.69 (s, 6H), 2.79e2.86 (m,
1H), 3.01e3.08 (m, 1H), 3.51e3.55 (m, 4H), 3.57e3.61 (t, J ¼ 7.2 Hz,
DMSO-d6):
d 25.38, 42.23, 42.68, 47.59, 51.24, 52.27, 52.35, 64.37,
1H), 7.28e7.30 (d, J ¼ 8.0 Hz, 2H), 7.41e7.43 (d, J ¼ 8.0 Hz, 2H). 13
C
67.06, 123.03, 123.18, 134.12, 134.34, 144.93, 165.65. HRMS calcd for
15H24FN2 (M þ H)þ, 267.1873; found, 267.1865.
NMR (100 MHz, DMSO-d6): d 23.47, 43.05, 43.15, 46.81, 51.41, 52.09,
C
52.24, 65.68, 128.41, 128.67, 133.73, 134.25, 138.41, 141.24. HRMS
calcd for C15H24ClN2O (M þ H)þ, 283.1577; found, 283.1568.
4.1.18.3. 3-(4-Fluorophenyl)-N,N-dimethyl-3-(piperidin-1-yl)propan-
1-amine (32c) hydrochloride. Yield 54.2% as a white solid, the purity
was 99.3% by HPLC analysis. Mp: 226e228 ꢀC. MS (ESI) m/z: 265.2
4.1.18.9. 3-(2,4-Difluorophenyl)-N,N-dimethyl-3-morpholinopropan-
1-amine (32i) hydrochloride. Yield 55.0% as a white solid, the purity
was 98.1% by HPLC analysis. Mp: 246e248 ꢀC. MS (ESI) m/z: 285.2
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.24e2.01 (m, 6H),
(M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.61e2.66 (m, 2H), 2.71
(s, 6H), 2.78e2.84 (m, 2H), 2.93e3.03 (m, 4H), 3.90 (m, 4H),
4.67e4.69 (m, 1H), 7.25e7.30 (m, 1H), 7.37e7.43 (m, 1H), 8.02e8.03
2.51e2.53 (m, 2H), 2.67 (s, 6H), 2.80e2.84 (m, 2H), 3.04e3.75 (m,
4H), 4.55e4.57 (m, 1H), 7.26e7.30 (t, J ¼ 8.0 Hz, 2H), 7.74e7.78 (t,
J ¼ 8.0, 2H). 13C NMR (100 MHz, DMSO-d6):
d 23.56, 25.79, 28.34,
(d, J ¼ 6.4 Hz, 1H). 13C NMR (100 MHz, DMSO-d6):
d 24.15, 42.35,
36.23, 43.98, 45.43, 47.69, 55.21, 64.43, 122.77, 122.95, 133.32,
134.45, 145.95, 167.23. HRMS calcd for C16H26FN2 (M þ H)þ,
265.2080; found, 265.2074.
43.62, 47.33, 50.14, 53.00, 53.14, 57.24, 64.17, 118.19, 121.68, 123.24,
134.58, 154.10, 157.28. HRMS calcd for C15H23F2N2O (M þ H)þ,
285.1778; found, 285.1785.
4.1.18.4. N,N-Dimethyl-3-morpholino-3-(4-(trifluoromethyl)phenyl)
propan-1-amine (32d) hydrochloride. Yield 25.8% as a white solid,
the purity was 98.6% by HPLC analysis. Mp: 236e238 ꢀC. MS (ESI)
4.1.18.10. 3-(Benzo[b]thiophen-2-yl)-N,N-dimethyl-3-
morpholinopropan-1-amine (32j) hydrochloride. Yield 45.9% as a
white solid, the purity was 98.8% by þHPLC analysis. Mp:
221e223 ꢀC. MS (ESI) m/z: 305.2 (M þ H) . 1H NMR (400 MHz,
m/z: 317.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.51e2.62 (m,
2H), 2.64 (s, 6H), 2.86e2.88 (m, 4H), 3.53 (m, 2H), 3.84e4.03 (m,
4H), 4.79 (m, 1H), 7.25e7.27 (d, J ¼ 8.0 Hz, 2H), 7.74e7.76 (d,
DMSO-d6):
d 2.49e2.51 (m, 1H), 2.75 (s, 6H), 2.75e2.83 (m, 2H),
J ¼ 8.0 Hz, 2H). 13C NMR (100 MHz, DMSO-d6):
d
24.45, 42.23, 42.79,
3.07 (m, 1H), 3.07e3.28 (m, 4H), 3.85e3.92 (m, 4H), 4.95e4.98 (m,
1H), 7.43e7.47 (m, 2H), 7.79 (s, 1H), 7.90e7.93 (m, 1H), 8.00e8.03
49.57, 51.44, 52.27, 63.76, 65.16, 128.51, 129.32, 129.41, 131.43,
132.09, 135.11, 138.24. HRMS calcd for C16H24F3N2O (M þ H)þ,
317.1841; found, 317.1833.
(m, 1H). 13C NMR (100 MHz, DMSO-d6):
d
25.21, 44.07, 44.20, 49.29,
50.13, 52.32, 53.00, 56.81, 61.42, 121.35, 123.62, 124.14, 127.26,

232
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
129.30, 133.50, 139.44, 147.27. HRMS calcd for C17H25N2OS
4.1.20. General procedure for the preparation of compounds 36aee
Aryl alcohol 34 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with cyclic amines 5 (8.8 mmol) as procedure C. The crude product
was converted into the corresponding hydrochloride salt and pu-
rified by recrystallization from ethanol to yield compound 36
hydrochloride.
(M þ H)þ, 305.1688; found, 305.1680.
4.1.18.11. 3-(Benzo[b]thiophen-2-yl)-N,N-dimethyl-3-(pyrrolidin-1-
yl)propan-1-amine (32k) hydrochloride. Yield 45.6% as a white
solid, the purity was 98.6% by HPLC analysis. Mp: 205e207 ꢀC. MS
(ESI) m/z: 289.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.93 (m,
4H), 2.52e2.60 (m, 2H), 2.75 (s, 6H), 2.76 (m, 2H), 3.05e3.11 (m,
2H), 3.20 (m, 2H), 4.96e5.00 (m, 1H), 7.41e7.45 (m, 2H), 7.79 (s, 1H),
7.88e7.90 (m, 1H), 7.99e8.02 (m, 1H). 13C NMR (100 MHz, DMSO-
4.1.20.1. 3-(3,4-Dichlorophenyl)-N,N-dimethyl-3-morpholinopropan-
1-amine (36a) hydrochloride. Yield 52.2% as a white solid, the pu-
rity was 99.7% by HPLC analysis. Mp: 172e174 ꢀC. MS (ESI) m/z:
d6):
d 25.62, 30.45, 32.18, 47.24, 55.34, 55.62, 58.29, 68.38, 120.76,
317.1 (M þ H)þ. 1H NMR (600 MHz, DMSO-d6):
d 2.66e2.69 (m, 2H),
122.31,124.22,126.31,128.35,132.41,139.79,145.63. HRMS calcd for
17H25N2S (M þ H)þ, 289.1738; found, 289.1746.
2.11e2.16 (m, 1H), 2.70 (s, 6H), 2.82e2.94 (m, 5H), 3.74e3.85 (m,
1H), 3.85 (m, 2H), 3.99e4.04 (m, 2H), 4.67 (s, 1H), 7.75 (s, 1H),
7.79e7.81 (d, J ¼ 7.8 Hz,1H), 8.07 (s, 1H). 13C NMR (150 MHz, DMSO-
C
4.1.18.12. 3-(Benzo[b]thiophen-3-yl)-N,N-dimethyl-3-
morpholinopropan-1-amine (32l) hydrochloride. Yield 46.8% as a
white solid, the purity was 99.3% by þHPLC analysis. Mp:
229e231 ꢀC. MS (ESI) m/z: 305.2 (M þ H) . 1H NMR (400 MHz,
d6):
d 24.36, 42.05, 42.63, 49.61, 51.01, 53.25, 63.50, 66.11, 130.78,
131.82, 132.42, 132.71, 133.36. HRMS calcd for
C15H23Cl2N2O
(M þ H)þ, 317.1182; found, 317.1191.
CDCl3-d):
d 2.82e2.85 (m, 2H), 2.87e2.91 (m, 2H), 2.87e3.01 (m,
4.1.20.2. 3-(3,4-Dichlorophenyl)-N,N-dimethyl-3-(piperidin-1-yl)
propan-1-amine (36b) hydrochloride. Yield 51.8% as a white solid,
the purity was 99.5% by HPLC analysis. Mp: 169e171 ꢀC. MS (ESI) m/
2H), 3.26e3.30 (s, 6H), 3.86e3.93 (t, J ¼ 4.8 Hz, 2H), 3.99e4.05 (t,
J ¼ 4.8 Hz, 2H), 4.11e4.17 (t, J ¼ 11.6 Hz, 1H), 4.28e4.34 (t,
J ¼ 12.0 Hz, 1H), 5.48e5.50 (d, J ¼ 6.4 Hz, 1H), 7.44e7.63 (m, 2H),
7.87e7.99 (m, 1H), 8.20 (s, 1H), 8.62 (s, 1H). 13C NMR (100 MHz,
z: 315.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.46 (m, 2H),1.76
(m, 4H), 2.54e2.57 (m, 2H), 2.57e2.72 (m, 2H), 2.75 (s, 6H),
2.95e3.06 (m, 4H), 4.42e4.45 (d, J ¼ 10.8 Hz, 1H), 7.53e7.55 (d,
J ¼ 8.4 Hz, 1H), 7.71e7.73 (t, J ¼ 4.4 Hz, 1H), 7.83 (s, 1H). 13C NMR
DMSO-d6):
d 23.17, 42.35, 42.67, 47.24, 50.14, 51.46, 55.45, 56.41,
65.14, 122.21, 123.31, 123.84, 126.32, 126.58, 131.49, 134.27, 139.33.
HRMS calcd for C17H25N2OS (M þ H)þ, 305.1688; found, 305.1694.
(100 MHz, DMSO-d6):
d 23.62, 26.58, 27.83, 36.27, 44.36, 45.27,
47.57, 54.28, 62.39, 127.62, 129.32, 132.45, 132.57, 133.61, 134.27.
HRMS calcd for C16H25Cl2N2 (M þ H)þ, 315.1392; found, 315.1387.
4.1.18.13. 3-(Benzo[b]thiophen-3-yl)-N,N-dimethyl-3-(pyrrolidin-1-
yl)propan-1-amine (32m) hydrochloride. Yield 43.2% as a white
solid, the purity was 98.0% by HPLC analysis. Mp: 206e208 ꢀC. MS
4.1.20.3. 3-(3,4-Dichlorophenyl)-N,N-dimethyl-3-(piperazin-1-yl)
propan-1-amine (36c) hydrochloride. Yield 50.2% as a white solid,
the purity was 99.1% by HPLC analysis. Mp: 257e259 ꢀC. MS (ESI) m/
(ESI) m/z: 289.2 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.91 (m,
4H), 2.62e2.70 (m, 2H), 2.73 (s, 6H), 2.97e3.02 (m, 2H), 3.12 (m,
4H), 4.98e5.01 (d, J ¼ 9.6 Hz, 1H), 7.44e7.52 (m, 2H), 8.05e8.09 (t,
z: 316.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 2.26e2.50 (m,
J ¼ 8.4 Hz, 2H), 8.22 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 27.32,
1H), 2.26e2.50 (m, 1H), 2.74 (s, 6H), 2.78e2.83 (m, 1H), 2.96e3.06
(m, 4H), 3.08e3.12 (m, 1H), 3.25e3.27 (m, 4H), 4.19e4.23 (t,
J ¼ 8.0 Hz, 1H), 7.43e7.46 (dd, J ¼ 2.0, 8.0 Hz, 1H), 7.75e7.77 (t,
30.09, 32.58, 45.21, 54.61, 54.74, 55.28, 57.36, 64.30, 121.90, 122.35,
122.45, 125.58, 126.31, 130.14, 132.47, 137.22. HRMS calcd for
C
17H25N2S (M þ H)þ, 289.1738; found, 289.1747.
J ¼ 3.2 Hz, 1H), 7.92 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d
28.44,
37.42, 42.56, 43.69, 49.28, 54.10, 54.35, 64.23,127.32,129.00,131.05,
132.44, 132.87, 135.62. HRMS calcd for C15H24Cl2N3 (M þ H)þ,
316.1345; found, 316.1353.
4.1.19. General procedure for the synthesis of aryl alcohol 34
Aryl ketone 8 (50 mmol) was treated with dimethylamine hy-
drochloride (50 mmol) in acetonitrile (100 mL) as procedure D. The
crude product was purified by recrystallization from ethanol to give
compound 33.
Aryl ketone 33 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (30 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
34 hydrochloride.
4.1.20.4. 3-(3,4-Dichlorophenyl)-N,N-dimethyl-3-(pyrrolidin-1-yl)
propan-1-amine (36d) hydrochloride. Yield 47.0% as a white solid,
the purity was 99.8% by HPLC analysis. Mp: 256e258 ꢀC. MS (ESI)
m/z: 301.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6):
d 1.82e1.99 (m,
4H), 2.52e2.57 (m, 3H), 2.70 (s, 6H), 2.89e2.92 (m, 3H), 3.18 (m,
1H), 3.43 (m, 1H), 4.67 (s, 1H), 7.77e7.80 (d, J ¼ 8.4 Hz, 2H), 8.14 (s,
1H). 13C NMR (100 MHz, DMSO-d6):
d 27.79, 31.73, 47.28, 57.75,
57.83, 69.65, 134.34, 136.22, 136.67, 137.21, 137.92, 139.79. HRMS
calcd for C15H23Cl2N2 (M þ H)þ, 301.1233; found, 301.1237.
4.1.19.1. 1-(3,4-Dichlorophenyl)-3-(dimethylamino)propan-1-ol
(34a) hydrochloride. Yield 93.6% as a white solid. MS (ESI) m/z:
4.1.20.5. 3-(5-Chloro-6-methoxynaphthalen-2-yl)-N,N-dimethyl-3-
(pyrrolidin-1-yl)propan-1-amine (36e) hydrochloride. Yield 44.9% as
a white solid, the purity was 99.5% by HPLC analysis. Mp:
215e217 ꢀC. MS (ESI) m/z: 347.2 (M þ H)þ. 1H NMR (400 MHz,
248.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
d 1.82e1.93 (m, 2H),
2.37 (s, 6H), 3.06 (m, 2H), 4.56 (s, 1H), 5.83 (br, 1H), 7.35e7.37 (d,
J ¼ 8.4 Hz, 1H), 7.63e7.65 (m, 2H).
DMSO-d6):
d 1.93 (m, 4H), 2.51e2.62 (m, 2H), 2.63e2.74 (m, 2H),
4.1.19.2. 1-(5-Chloro-6-methoxynaphthalen-2-yl)-3-(dimethyla-
mino)propan-1-ol (34b) hydrochloride. Yield 90.3% as a white solid.
MS (ESI) m/z: 294.1 (M þ H)þ. 1H NMR (400 MHz, DMSO-d6)
2.68 (s, 6H), 2.91e2.97 (m, 2H), 3.07 (m, 2H), 4.02 (s, 3H), 4.66e4.70
(dd, J ¼ 4.0, 9.6 Hz, 1H), 7.64e7.66 (d, J ¼ 9.2 Hz, 1H), 7.98e8.00 (d,
J ¼ 8.8 Hz,1H), 8.05e8.07 (d, J ¼ 8.8 Hz, 1H), 8.17e8.19 (d, J ¼ 8.8 Hz,
d
1.85e1.97 (m, 2H), 2.35 (s, 6H), 3.07e3.09 (m, 2H), 3.98 (s, 3H),
1H), 8.25 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d 23.66, 26.57,
4.59 (s, 1H), 5.79 (br, 1H), 7.52e7.54 (d, J ¼ 8.0 Hz, 1H), 7.64e7.66 (d,
J ¼ 8.0 Hz, 1H), 7.89 (s, 1H, AreH), 7.90e7.92 (d, J ¼ 8.0 Hz, 1H),
8.05e8.07 (d, J ¼ 8.8 Hz, 1H).
27.68, 43.24, 52.77, 52.98, 57.24, 58.92, 64.98, 117.35, 121.21, 123.35,
125.67, 125.81, 125.92, 126.53, 127.02, 139.26, 158.32. HRMS calcd
for C20H28ClN2O (M þ H)þ, 347.1885; found, 347.1893.

Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
233
4.1.21. 3-(3,4-Dichlorophenyl)-N,N-diethyl-3-(pyrrolidin-1-yl)
propan-1-amine (40) hydrochloride
immobile (seconds over the 6 min trial) as the dependent variable.
Significant main effects were followed up with the post hoc Fisher's
test.
3-Chloro-1-(3,4-dichlorophenyl)propan-1-one 13 (50 mmol)
was treated with diethylamine hydrochloride (50 mmol) in aceto-
nitrile (100 mL) as procedure D. The crude product was purified by
recrystallization from ethanol to give compound 37. MS (ESI) m/z:
274.1 (M þ H)þ.
4.2.3.2. Measurement of locomotor activity. Locomotor activity was
assessed with an animal activity monitoring apparatus (Shanghai
Jiliang Software Technology Co. Ltd.). 60 min after administration,
rats were placed individually in 40 cm ꢁ 40 cm ꢁ 50 cm plastic
cages, to which they had not been previously exposed, under dim
light and sound-attenuated conditions. Locomotor activity was
monitored at 5 min intervals for up to 30 min. The results of the
locomotor activity tests were expressed as mean SEM.
Aryl ketone 37 (10 mmol) was treated with sodium borohydride
(10 mmol) in methanol (30 mL) using procedure B. The crude
product was converted into the corresponding hydrochloride salt
and purified by recrystallization from ethanol to yield compound
38 hydrochloride. MS (ESI) m/z: 276.1 (M þ H)þ.
Aryl alcohol 38 (8 mmol) was first reacted with p-toluene-
sulfonyl chloride (8.8 mmol) in acetonitrile (30 mL), then treated
with pyrrolidine (8.8 mmol) as procedure C. The crude product was
converted into the corresponding hydrochloride salt and purified
by recrystallization from ethanol to yield compound 40 hydro-
chloride. Yield 53.1% as a white solid, the purity was 99.3% by HPLC
analysis. Mp: 249e251 ꢀC. MS (ESI) m/z: 329.2 (M þ H)þ. 1H NMR
4.2.4. Pharmacokinetic study
Male SD rats (SLRC Laboratory Animal Inc., Shanghai, China)
were used. For intravenous administration, prepared dosing solu-
tion was injected via the femoral vein. The rats were fasted over-
night before drug administration and until 6 h after dosing. For the
PO experiment, rats (24 in each group) were given a single dose of
2 mg/kg, and heparinized samples of blood were collected at 5, 15,
30 min, 1, 2, 4, 8, and 24 h postdose. For the iv experiment, rats (24
in each group) were given a single 0.5 mg/kg dose, and blood
samples were collected at 5, 15, 30 min, 1, 2, and 4 h postdose.
Plasma was harvested after centrifugation and stored frozen
at ꢂ40 ꢀC until analyzed. The concentrations of compounds in
plasma were determined by LC/MS/MS (Shimadzu LC-30AD). 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).
(400 MHz, DMSO-d6):
d
1.13e1.16 (t, J ¼ 7.2 Hz, 6H), 1.85e1.98 (m,
4H), 2.58e2.61 (m, 2H), 2.61e2.83 (m, 2H), 2.91e2.96 (m, 2H), 3.06
(m, 4H), 3.19 (m, 1H), 3.74 (m, 1H), 4.63 (m, 1H), 7.75e7.81 (dd,
J ¼ 3.2, 8.4 Hz, 2H), 8.10 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
d
15.28, 24.45, 35.72, 48.54, 48.92, 49.35, 51.22, 53.15, 62.45, 67.28,
130.65, 132.01, 132.68, 133.45, 133.79, 135.25. HRMS calcd for
C
17H27Cl2N2 (M þ H)þ, 329.1551; found, 329.1557.
4.2. Biology evaluation
4.2.1. Inhibition of [3H] neurotransmitter uptake in HEK293 cells
expressing the hSERT, hNET and hDAT
Assays were conducted using procedures identical to those
described by Eshleman [19]. The cells were seeded in 24-well
cluster plates at a density of 1.5 million cells per well. On the sec-
ond day, the cells were incubated with HBSS buffer containing the
tested compound and 3H-serotonin (3 nM) for ten minutes at 37 ꢀC.
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
4.2.5. Acute toxicity test
Male and female KM mice (18e22 g) were purchased from SLRC
Laboratory Animal Inc., Shanghai, China. Mice were randomly
divided into seven groups with ten mice each (five males, five fe-
males). Mice were orally given 36a with a single dose 150, 300,450,
600,750, and 900 mg/kg or vehicle control, respectively. The mouse
death was monitored daily and recorded up to 14 days after
treatment. All animals were euthanized and necropsied for gross
lesion examination for possible damage to the heart, liver, and
kidneys.
counter. Nonspecific uptake was defined with 10 mM DOV 21947.
The protocols for dopamine and epinephrine uptake were the same
with that for serotonin.
4.2.6. Ames test
4.2.2. CNS receptor screening
The TA98 and TA100 strains of Salmonella typhimurium were
utilized for mutagenicity assay. Compound 36a was dissolved in
DMSO and added to bacterial cultures at concentrations up to
Compound 36a was characterized in 55 CNS receptor binding
assays to assess the selectivity and specific interactions of 36a with
the monoamine transporters. The test was carried by Cerep (Celle
L'Evescault, France, Cerep study number 100005534), the test using
a similar procedure as described previously [17].
5000 mg/plate in the presence or absence of rat liver S9 metabolic
activating system. Each dose level, vehicle, and positive control was
plated in triplicate. The test methodology was based on established
procedures as reported [20].
4.2.3. In vivo pharmacology
4.2.3.1. Measurement of antidepressants activity in rat forced swim
test (FST). To evaluate the antidepressants activity of the com-
pounds, the inhibitory effects on immobility in forced swim test in
rats were measured according to the methods described by Porsolt
et al. [16]. Rats were individually placed into clear glass cylinders
(40 cm tall ꢁ 18 cm in diameter) containing 25 1 ꢀC water 15 cm
deep. Rats were administered vehicle, venlafaxine (30 mg/kg) as a
positive control, or test compounds 18c, 36a, or 36d (5, 10 and
20 mg/kg). 1 h following PO administration, rats were placed in the
water, and the time of the animal spent immobile was recorded
over a 6 min trial. Immobility was defined as the postural position
of floating in the water. Data were analyzed by one way analysis of
variance (ANOVA) with treatment group (vehicle, venlafaxine, or
test compounds) as the between group variable and total time
Acknowledgments
This work is supported by National Natural Science Foundation
of China (Grant No. 81302631), Shanghai Rising-Star Program
(Grant No. 13QB1403800), Key Technologies R&D Program of
Shanghai Municipal Science and Technology Commission (Grant
No. 14431901500), and the National Science and Technology Major
Project (Grant No. 2012ZX09103101-038). We thank Professor Lei
Fu (Shanghai Jiao Tong University, China) for helpful discussion.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.08.045.

234
Y.-Y. Zheng et al. / European Journal of Medicinal Chemistry 86 (2014) 219e234
2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS), J. Pharmacol. Exp.
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