Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: Effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors

Article abstract of DOI:10.1021/jm050694s

4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage similar to that found in the wake-promoting drug modafinil have been synthesized. The transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/ NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand, the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET selectivity. Among them, (+)-cis-5b shows a low nanomolar K _i for the NET with 39-fold and 321-fold lower potency at the DAT and SERT, respectively, thus making it a useful pharmacological research tool for exploring NET-associated behavioral signatures. On the other hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than those selective for SERT or SERT + NET, some of the present compounds will be valuable to study in animal models of depression.

Full text of DOI:10.1021/jm050694s

7970
J. Med. Chem. 2005, 48, 7970-7979
Further Structure-Activity Relationship Studies of Piperidine-Based
Monoamine Transporter Inhibitors: Effects of Piperidine Ring Stereochemistry
on Potency. Identification of Norepinephrine Transporter Selective Ligands
and Broad-Spectrum Transporter Inhibitors
Rong He,†,# Toru Kurome,†,# Kelly M. Giberson,‡ Kenneth M. Johnson,‡ and Alan P. Kozikowski*,†
Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy (M/C781),
University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7230, and Department of Pharmacology and
Toxicology, University of Texas Medical Branch, Galveston, Texas 77555-1031
Received July 20, 2005
4-(4-Chlorophenyl)piperidine analogues each bearing a thioacetamide side chain appendage
similar to that found in the wake-promoting drug modafinil have been synthesized. The
transporter inhibitory activity of both the cis and trans isomers of these 3,4-disubstituted
piperidines in both their (+)- and (-)-enantiomeric forms was determined. These studies reveal
that the (-)-cis analogues exhibit dopamine transporter/norepinephrine transporter (DAT/
NET) selectivity as was previously reported for the (+)-trans analogues. On the other hand,
the (-)-trans and the (+)-cis isomers show serotonin transporter (SERT) or SERT/NET
selectivity. Among them, (+)-cis-5b shows a low nanomolar Ki for the NET with 39-fold and
321-fold lower potency at the DAT and SERT, respectively, thus making it a useful
pharmacological research tool for exploring NET-associated behavioral signatures. On the other
hand, several of the compounds described herein, such as (+)-trans-5c, show comparable activity
at all three transporters. Because broad-spectrum transporter inhibitors have been hypothesized
to exhibit a more rapid onset of action and/or a greater efficacy as antidepressant agents than
those selective for SERT or SERT + NET, some of the present compounds will be valuable to
study in animal models of depression.
Introduction
discovery of serotonin-selective reuptake inhibitors (SS-
RIs) such as fluoxetine, citalopram, paroxetine, and
setraline in the treatment of depression.5 In contrast,
despite the important role of NE in a number of
disorders of the central nervous system (CNS) including
depression and ADHD, a relatively smaller number of
NET selective inhibitors have been developed to date
(e.g., nisoxetine and reboxetine).6 Although a variety of
approaches have been explored to gain insights into the
nature and site of interaction of the transporter inhibi-
tors with their target proteins including binding and
functional analysis using site directed mutagenesis,7
homology-based molecular modeling, and photoaffinity/
electrophile labeling of the binding site,8 precise topo-
graphical details of the inhibitor-transporter complex
are still lacking.
In the course of our studies aimed at identifying
molecules for use in the treatment of cocaine addiction,9
hybrid molecules combining structural features of (+)-
methyl 4â-(4-chlorophenyl)-1-methylpiperidine-3R-car-
boxylate [nocaine, (+)-CPCA, (+)-trans-1], a piperidine-
based analogue of cocaine lacking its tropane skeleton,10
and modafinil,11 a popular non-amphetamine-like wake-
promoting agent, were prepared (Figure 1). The chemi-
cal synthesis and transporter activity of the (+)-trans
isomers in this series were reported recently, and these
compounds were shown to exhibit largely a mixed DAT/
NET selectivity.12 Moreover, comparative molecular
field analysis (CoMFA) contour maps have been gener-
ated for analogues of (+)-trans-CPCA at the DAT.13
These contour maps provide a visual representation of
The biogenic amine neurotransmitters dopamine (DA),
5-hydroxytryptamine (5-HT), and norepinephrine (NE)
are involved inter alia in the regulation of emotions,
reactions to stress, and the physiological drives of
appetite and sleep.1 Chemical imbalances in these
neurotransmitters result in pathological conditions such
as depression, Parkinson’s disease, bipolar disorder, and
attention deficit hyperactivity disorder (ADHD).2 The
reuptake of these monoamine transmitters into nerve
terminals through neuronal plasma membrane mono-
amine dopamine, norepinephrine, and serotonin trans-
porters (DAT, SERT, and NET) provides a mechanism
for modulating the intensity and duration of monoamine
signaling at synapses. The design of agents capable of
inhibiting these transporters continues to represent an
important approach to the treatment of neuropsychiatric
disorders and drug addiction.3
While cocaine, a major drug of abuse, is able to inhibit
all three transporters, its effect at the DAT is believed
to play the major role in its addictive properties. The
dopamine hypothesis of cocaine’s behavior-reinforcing
effects has thus served as a major motivation for
research efforts aimed at the discovery of DAT-selective
inhibitors (GBR 12935, WIN35,428).4 On the other
hand, knowledge of serotonin’s role in mood led to the
* To whom correspondence should be addressed. Phone: 312-996-
7577. Fax: 312-996-7107. E-mail: Kozikowa@uic.edu.
# These authors contributed equally to this work.
† University of Illinois at Chicago.
‡ University of Texas Medical Branch.
10.1021/jm050694s CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/17/2005

Effects of Piperidine Ring Stereochemistry
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7971
which inspired the present series of ligands, the sulfur
atom is present as the sulfoxide.
Biological Results and Discussion
The newly synthesized compounds (-)-trans 4, 5a-
e,g,h, 7, 8a,b, (+)-cis 1, 4, 5b-i, 7, 8a,b, (-)-cis 4, 5a-
e,g, 7, and 8a were tested for the abilities to inhibit
uptake of [3H]DA, [3H]5-HT, and [3H]NE through the
corresponding transporters using rat synaptosomal
nerve endings.9a The ClogP, uptake data, and selectivity
profiles (based on the Ki values) of these compounds are
shown in Table 1. Compounds synthesized from the (+)-
trans isomer were tested earlier.12 For comparison
purposes, data for (+)-, (-)-trans-, and (-)-cis-CPCA
from the previous papers10,12 and for (-)-cocaine12 and
modafinil12 are also listed.
A small set of analogues of each stereoisomer was
prepared using the ester 4 as a common intermediate.
These analogues include the unsubstituted amides,
alkyl- and arylamides, alcohols, and their inverse ester
derivatives. As was found to be the case for the various
analogues prepared in the (+)-trans series, overall, most
of the analogues prepared from the other three stereo-
isomers of 1 also exhibited good inhibitory activities at
the NET. On the other hand, the nature of the stereo-
chemistry of these piperidines did, however, exert a
distinct influence on their DAT and SERT activity,
leading to their overall transporter selectivity profile.
Introduction of the thioacetate group into the side chain
of each of the CPCA isomers led to the esters 4 generally
possessing an improved activity relative to the starting
compounds 1. The (-)-trans-4 isomer exhibits an im-
proved potency at the SERT and the NET with little
change in its DAT activity compared to the (-)-trans-1.
The (-)-cis-4, on the other hand, shows a combined
DAT/NET selectivity. In the case of the (+)-cis-4, NET
selectivity was found, while the (+)-cis-1 exhibits the
best SERT selectivity in this series of analogues. An
improvement in potency at all three transporters is
observed for (+)-trans-4. Conversion of (+)- and (-)-
trans-4 into their unsubstituted amides (+)- and (-)-
trans-5a was not particularly favorable, leading to a
reduction in SERT activity in both cases. Examination
of the data for the amide (-)-cis-5a shows that it is fairly
active at all three transporters but shows little discrimi-
nation among them (Ki ) 21-69 nM).
Among the (+)-trans isomers bearing an N-substitut-
ed amide side chain,12 the monoalkylamides (+)-trans-
5b and -5c show a much improved potency (12- to 159-
fold) at the DAT relative to (+)-trans-5a. Both compounds
are more active than the N,N-disubstituted amides (+)-
trans-5d and -5e at the DAT. For these amides, a larger
N-substitutent appears to favor heightened potency at
both the SERT and the NET. The isopropylamide (+)-
trans-5c and the piperidinylamide (+)-trans-5e, having
groups bulkier than those present in either the methyl-
amide (+)-trans-5b or the dimethylamide (+)-trans-5d,
respectively, have Ki values less than 10 nM for both
the SERT and the NET. In the case of the sterically
smaller alcohol (+)-trans-7, the presence of the free OH
group appears to be particularly advantageous for
interaction with the NET because a Ki of 0.9 nM was
found.
Figure 1. Rational design of nocaine/modafinil hybrid ligands.
the possible binding modes of members in this series
bearing various substituents at the 3-position of the
piperidine ring. The CoMFA analysis facilitates a phar-
macophore-based approach to the design of additional
analogues in the piperidine series. Because most of the
modeling, chemistry, and pharmacology efforts have
been directed to compounds derived from (+)-trans-
CPCA, the effect of alterations in the relative and
absolute stereochemistry of these 3,4-disubstituted
piperidines on transporter inhibitory activity has yet to
be fully elucidated. Comparison of the SAR of the four
stereoisomeric series will provide additional information
of use in the CoMFA analysis while potentially identify-
ing other ligands of therapeutic value. Transporter
selective ligands of high potency are also in considerable
demand for study as diagnostic tools using positron
emission tomography (PET).14 Accordingly, in the present
research all four stereoisomeric piperidines comprising
a sulfur-bearing side chain containing an ester, amide,
or alcohol group were prepared and their transporter
activities were measured.
Chemistry
In reference to the druglike properties of the com-
pounds selected for synthesis, most of the analogues
were designed to have a suitable ClogP value (1 < ClogP
< 5) and molecular weight (MW < 500) for penetration
of the blood-brain barrier.15 Scheme 1 shows the
chemical synthesis of our target structures starting from
each pure stereoisomer of CPCA 1, which were prepared
using the known literature procedure.10a These methods
are similar to those we have reported previously.12
Briefly, each isomer of 1 was converted to its corre-
sponding alcohol 2 by lithium aluminum hydride
(LiAlH4) reduction, and the alcohol in turn was trans-
formed to the iodide 3 by reaction with iodine in the
presence of triphenylphosphine and imidazole. The key
intermediate 4 was then obtained by coupling of 3 with
methyl thioglycolate in the presence of cesium carbon-
ate. Treatment of the ester 4 with either liquid ammonia
or various alkylamines afforded the corresponding
amides 5a-e. On the other hand, the arylamines 5f-i
were obtained by reacting the acid 6 with the corre-
sponding arylamines in the presence of N-(3-dimeth-
ylaminopropyl)-N′-ethylcarbodiimide
hydrochloride
(EDCI) and 1-hydroxybenzotriazole (HOBt). The inverse
esters 8a and 8b were prepared from the alcohol 7 by
conventional methods employing acetic anhydride/
pyridine and benzoyl chloride/dimethylaminopyridine
(DMAP), respectively.
To avoid complications from introduction of a new
stereocenter, the sulfur atom was left unoxidized in
these analogues. In the case of the drug modafinil,
In the (-)-trans-amide series, the ligand (-)-trans-
5a is similar in activity to (+)-trans-5a at the SERT and

7972 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25
He et al.
Scheme 1a
a Reagents and conditions: (a) LiAlH4; (b) Ph3P/I2/imidazole; (c) methyl thioglycolate, Cs2CO3; (d) NH3 (liquid), t-BuOH; (e) (for 5b-e)
HNR1R2 in MeOH; (f) LiOH, MeOH; (g) (for 5f-i) H2NR2, EDCI; (h) LiAlH4; (i) Ac2O/pyridine; (j) benzoyl chloride, Et3N, DMAP.
the NET, with the best activity being displayed at the
NET. The N-alkyl-substituted amides (-)-trans-5b-e
show a different transporter potency as found for the
corresponding enantiomeric (+)-trans-amides. They ex-
hibit moderate potency at the SERT and the NET with
little discrimination among them and low potency at the
DAT. The dialkyl-substituted amides (-)-trans-5d and
-5e show strongly diminished activity at the DAT. The
benzylamide (-)-trans-5g also has low activity at the
DAT and the SERT, while it maintains activity at the
NET. In going from (-)-trans-5g to the phenylethyla-
mide (-)-trans-5h, the simple elongation of the side
chain provides an improvement in both the DAT and
the SERT potencies (68-fold and 11-fold, respectively).
This result may support the presence of a specific
π-interaction between the ligand and the DAT and the
SERT. Among the (-)-trans-amides, 5a and 5g had good
NET selectivity over DAT and SERT.
In the (+)-cis-amide series, the monoalkylamides (+)-
cis-5b and -5c show high potency at the NET. The
methylamide 5b exhibits poor activity at the SERT,
while the amide (+)-cis-5c containing the larger isoprop-
ylamide group exhibits an improved SERT potency (49-
fold more potent than 5b). The NET activity of the
phenylamide (+)-cis-5f (Ki ) 1060 nM) was the weakest
among the (+)-cis-amide ligands tested. Introduction of

Effects of Piperidine Ring Stereochemistry
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7973
Table 1. Activity at Monoamine Transporters
reuptake Ki ( SEM (nM)a
[3H]5HT
155 ( 1
uptake ratio (based on Ki)
compd
cocaineb
ClogPf
[3H]DA
[3H]NE
5HT/DA
NE/DA
NE/5HT
423 ( 147
3800
233 ( 62
80 ( 23
159 ( 19
13 ( 3
108 ( 4
>10000
252 ( 43
25 ( 6
39 ( 5
25 ( 2
0.8 ( 0.1
27 ( 7
modafinilc
(+)-trans-1b CPCA
(+)-trans-4
(+)-trans-5a
(+)-trans-5b
(+)-trans-5c
(+)-trans-5d
(+)-trans-5e
(+)-trans-7
(+)-trans-8a
(+)-trans-8b
(-)-trans-1d
(-)-trans-4
(-)-trans-5a
(-)-trans-5b
(-)-trans-5c
(-)-trans-5d
(-)-trans-5e
(-)-trans-5g
(-)-trans-5h
(-)-trans-7
(-)-trans-8a
(-)-trans-8b
(+)-cis-1
3.22
3.15
2.19
2.29
3.13
2.89
3.8
2.81
3.71
5.45
3.22
3.15
2.19
2.29
3.13
2.89
3.8
4.34
4.56
2.81
3.71
5.45
3.22
3.15
2.29
3.13
2.89
3.8
4.31
4.34
4.56
5.49
2.81
3.71
5.45
3.22
3.15
2.19
2.29
3.13
2.89
3.8
8490 ( 1430
208 ( 47
557 ( 150
110 ( 45
1.1 ( 0.4
88 ( 22
4.5 ( 0.7
158 ( 5
57 ( 18
6.7 ( 1.5
930 ( 10
69 ( 15
545 ( 167
116 ( 26
138 ( 19
186 ( 8
190 ( 29
753 ( 81
68 ( 18
129 ( 2
130 ( 14
71 ( 6
36.4
1.08
0.31
0.24
2.0
0.03
0.12
0.07
0.2
2.59
3.5
8.5
1.0 ( 0.2
116 ( 46
83 ( 1
1.11
0.76
0.05
9.81
1.63
0.1
0.8
0.72
0.31
0.15
0.005
0.06
0.67
0.43
0.83
0.09
0.38
0.49
1.17
0.43
0.04
2.63
0.95
0.4
0.79
7.45
0.24
0.003
0.3
0.27
0.23
11.7
2.49
0.83
0.94
9.8
4.88
0.53
0.23
0.12
3.34
0.05
0.1
7.08
0.32
3.76
0.14
0.06
0.23
0.008
0.06
0.1
0.07
0.14
0.02
0.05
0.27
0.1
0.07
0.03
0.02
7.81
0.66
0.09
0.15
0.27
0.16
0.03
0.07
0.27
0.04
13.3
0.18
0.89
0.99
19
0.7 ( 0.3
0.9 ( 0.3
3.6 ( 1.5
4.5 ( 1.2
386 ( 112
57 ( 1
16 ( 5
35 ( 11
68 ( 22
2930 ( 580
2620 ( 390
1100 ( 270
164 ( 6
663 ( 42
> 3000
0.32
0.03
0.49
0.71
0.21
0.06
0.06
0.48
2.97
0.69
0.24
0.19
0.04
0.67
8.23
0.25
0.98
0.19
1.13
0.07
1.08
1.06
1.91
0.71
0.18
5.67
4.88
0.39
1.12
53 ( 1
44 ( 2
67 ( 2
218 ( 35
82 ( 1
> 3000
1570 ( 110
23 ( 3
32 ( 1
178 ( 27
123 ( 29
52 ( 6
185 ( 62
536 ( 126
378 ( 75
1560 ( 370
598 ( 32
215 ( 15
142 ( 5
176 ( 6
>3000
56 ( 14
415 ( 37
98 ( 6
5.5 ( 1.6
11 ( 1
47 ( 8
134 ( 14
1060 ( 190
54 ( 8
100 ( 26
101 ( 18
>3000
56 ( 10
403 ( 9
1770 ( 240
36 ( 4
(+)-cis-4
(+)-cis-5b
(+)-cis-5c
(+)-cis-5d
(+)-cis-5e
173 ( 45
572 ( 46
91 ( 1
(+)-cis-5f
80 ( 5
(+)-cis-5g
302 ( 9
112 ( 18
102 ( 9
160 ( 5
177 ( 55
1470 ( 430
69 ( 8
22 ( 1
(+)-cis-5h
(+)-cis-5i
121 ( 19
108 ( 6
305 ( 30
125 ( 17
270 ( 5
391 ( 27
182 ( 24
21 ( 4
(+)-cis-7
(+)-cis-8a
610 ( 9
143 ( 6
88 ( 3
3.49
0.09
1.28
0.59
1.29
0.06
1.19
3.75
0.38
21.9
0.7
(+)-cis-8b
(-)-cis-1e
(-)-cis-4
38 ( 4
22 ( 1
(-)-cis-5a
54 ( 1.9
311 ( 4
13 ( 5
69 ( 14
18 ( 1
(-)-cis-5b
347 ( 52
154 ( 14
8.8 ( 2.1
42 ( 2
23 ( 5
185 ( 16
469 ( 85
(-)-cis-5c
16 ( 2
11.5
(-)-cis-5d
(-)-cis-5e
17 ( 3
34 ( 5
63 ( 6
0.53
1.22
5.81
5.0
13 ( 1
(-)-cis-5g
4.34
2.81
3.71
3.9 ( 0.8
37 ( 5
85 ( 4
(-)-cis-7
26 ( 4
(-)-cis-8a
46 ( 5
30 ( 7
10.1
0.65
a Data are mean values ( SEM from two to four independent experiments, each consisting of six drug concentrations in triplicate, as
described in ref 9a. b Data for (+)-trans analogues were taken from ref 12. c Data taken from ref 11b. d Data taken from ref 10d. e Data
taken from ref 10c. f ClogP calculated by using the program available at the Web site: http://www.daylight.com/daycgi/clogp.
the slightly larger benzyl group into the amide to give
(+)-cis-5g was found to be favorable and led to a
recovery of activity at the NET relative to the N-
phenylamide (20-fold more potent than 5f). In compari-
son to (+)-cis-5g, analogues (+)-cis-5h and -5i failed to
show any discrimination among the three transporters.
Of considerable interest is the activity displayed by the
methylamide (+)-cis-5b because this compound has a
NET inhibitory activity of 5.5 nM while exhibiting 39-
fold and 321-fold lower activity at the DAT and the
SERT, respectively.
In the (-)-cis series, the majority of the compounds
again show reasonably good activity for the DAT and
the NET. The alkylamides (-)-cis-5b-e show good
potency at the DAT except 5b; all of these analogues
show double-digit activity at the NET. The dialkyl-
amides (-)-cis-5d and -5e were more potent than their
monoalkylamide counterparts (-)-cis-5b and -5c at the
SERT. The dimethylamide (-)-cis-5d shows low nano-
molar affinity for the SERT, although its selectivity is
only 2- to 7-fold over those of the other transporters.
The monomethylamide (-)-cis-5b showed a reasonable
potency of 18 nM at the NET and is 19-fold and 17-fold
selective over the SERT and the DAT, respectively.
Among the alcohols tested, (+)-trans-7 shows excel-
lent potency (Ki ) 0.9 nM) and reasonably good selectiv-
ity (18- to 175-fold) at the NET, while the (+)-cis-7
shows no activity at the concentration tested (Ki > 3000
nM) at the NET. Because the two alcohols (+)-trans-7,
which maintains good activity at the NET, and (+)-cis-7
differ only in the stereochemistry of the sulfur-bearing
side chain, these compounds should be valuable in the
elaboration of a CoMFA map for the NET.
For the inverse esters derived from the isomeric
alcohols 7, the only ones showing low nanomolar affinity
were (+)-trans-8a and -8b. The former compound showed
some NET selectivity, while the latter was more active
at both the SERT and the NET. Derivatization of the

7974 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25
He et al.
pounds occupy the two left quadrants clustering near
the ordinate at 0. Also, as is apparent from Figure 2c,
one of the (+)-cis compounds shows the best NET
selectivity, namely, (+)-cis-5b.
Conclusions
In summary, the present study was undertaken in
order to examine the influence of the stereochemistry
of the piperidine ligands containing a sulfur side chain
on their transporter selectivity. Many of the members
of each of the three new stereoisomeric series reported
herein exhibit reasonably good transporter inhibitory
activity especially at the NET, much like that of the
previously reported (+)-trans isomers. Of some interest
in this study is the 68-fold change in DAT activity that
is observed in going from the benzylamide (-)-trans-5g
to the phenylethylamide (-)-trans-5h and the 20-fold
increase in NET activity that is observed in going from
the phenylamide (+)-cis-5f to the benzylamide (+)-cis-
5g. Moreover, replacement of the monomethylamide
groups of (+)-trans-5b and (+)-cis-5b by the larger, more
hydrophobic isopropylamides as in (+)-trans-5c and (+)-
cis-5c was found to lead to a valuable improvement in
inhibitory potency at the SERT. Of the analogues
studied herein, one of the most NET selective com-
pounds was the alcohol (+)-trans-7. In contrast, the
alcohol (+)-cis-7, which differs from (+)-trans-7 only in
the stereochemistry of the sulfur-bearing side chain,
lacks both potency and selectivity.
In general, the (+)-trans and the (-)-cis analogues
were found to exhibit a mixed DAT/NET selectivity. The
(-)-trans and the (+)-cis analogues show a trend toward
SERT or SERT/NET selectivity. Among the analogues
newly explored in this study, (-)-trans-5g, (+)-cis-5b,
and (-)-cis-5b show relatively good potency and selec-
tivity at the NET. Because the Ki value of (+)-cis-5b at
the NET is 5.5 nM and its selectivity for the NET is
the best among those tested in this study, 321-fold over
the SERT and 39-fold over the DAT, this compound will
be valuable for exploration in animal models to gain a
better understanding of NET-associated behavioral
signatures.17 Because broad-spectrum transporter in-
hibitors have been hypothesized to exhibit a more rapid
onset of action and/or greater efficacy as antidepressant
agents than those selective for SERT or SERT + NET,
some of the present compounds will be valuable for
study in animal models of depression.18
Figure 2. The log-log plots of the transporter activity shown
by the four stereoisomeric series of piperidine analogues. For
compounds showing a Ki value greater than 3000, “3000” was
used for the calculation of the uptake ratio (see Table 1).
alcohol group of (+)-cis-7 was effective in restoring NET
activity as in the case of (+)-cis-8a and -8b. Introduction
of the benzoyl group provided the largest effect on the
activity of the (+)-cis alcohol 7 because its conversion
to (+)-cis-8b led to more than a 21-fold increase in
potency at the NET, while this change caused a 9-fold
decrease in DAT potency.
Overall, the (+)-trans and (-)-cis series of compounds
are more potent than the (-)-trans and the (+)-cis series
at both the DAT and the SERT. The (+)-trans and (-)-
cis series possess the 4S configuration at the 4-position
of the piperidine ring, while the (-)-trans and the (+)-
cis series have the 4R configuration at this position. The
stereochemistry of this ring position thus influences the
overall transporter selectivity profile of this group of
ligands.
Many of the analogues from all four stereoisomeric
series are reasonably well tolerated at the NET. The
improved NET activity of these ligands relative to the
methyl esters 1 may stem in part from the greater
flexibility of the sulfur-bearing side chain in the vicinity
of the piperidine ring as opposed to the sp2-hybridized
carbomethoxy group present in 1.16
Perhaps the best way to view the transporter selectiv-
ity profiles for members of each of these four isomeric
series can be seen from the log(NET/5HT) - log(5HT/
DAT) plots shown in Figure 2. In Figure, compounds
showing the same potency at the two transporters under
comparison (Ki ratio of 1.0) will fall on the zero line,
whereas those falling at 1 or -1 would show a 10-fold
difference in potency (Ki ratio of 10 or 0.1). Visual
inspection of these plots reveals that the (-)-cis ana-
logues (Figure 2d) and the (+)-trans analogues show a
trend toward DAT/NET selectivity (Figure 2a) because
more of the compounds occupy the lower right quadrant.
On the other hand, the plots of the (-)-trans analogues
(Figure 2b) and (+)-cis analogues (Figure 2c) reveal a
trend toward SERT/NET selectivity because these com-
Experimental Section
1H and 13C NMR spectra were obtained with a Bruker
Avance spectrometer at 300 and 75 MHz, respectively. 1H
chemical shifts (δ) were reported in ppm downfield from
internal Me4Si. 13C chemical shifts (δ) are referenced to CDCl3
(central peak, δ ) 77.00 ppm) as the internal standard. Mass
spectra were measured using positive mode electrospray
ionization (ESI). The HRMS data were obtained on a Micro-
mass Q-TOF-2TM instrument. Optical rotations were mea-
sured with an AUTOPOL IV (Rudolph Research Analytical)
instrument. TLC was performed on silica gel 60F254 glass
plates; column chromatography was performed using Merck
silica gel (230-400 mesh). Analytical HPLC was performed
using a Shimadzu LC-10AD system, equipped with a Waters
484 tunable absorbance detector set at 220 nm. Waters
µ-Bondapak C18 column (3.9 mm × 300 mm, 5 µm) and ACE
5 AQ C18 UltraInert column (4.6 mm × 250 mm, 5 µm) were
used. The HPLC data of tested compounds including the
conditions can be seen in the Supporting Information. Starting

Effects of Piperidine Ring Stereochemistry
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7975
materials were obtained from Aldrich, Alfa Aesar, or Acros.
Solvents were obtained from Fisher Scientific or Aldrich and
were used without further purification unless noted otherwise.
(3S,4R)-4-(4-Chlorophenyl)-3-(hydroxymethyl)-1-meth-
ylpiperidine ((-)-trans-2). To a solution of (3S,4R)-4-(4-
chlorophenyl)-1-methylpiperidine-3-carboxylic acid methyl es-
ter (2.0 g, 7.5 mmol) in anhydrous THF (40 mL) that was
cooled to 0 °C was added LiAlH4 (425 mg, 11.25 mmol). The
resulting mixture was warmed to room temperature and
stirred overnight, then the reaction was quenched with a
saturated solution of NH4Cl (30 mL). The mixed solution was
extracted with CH2Cl2 (3 × 25 mL). The combined organic
extract was dried over Na2SO4, concentrated, and purified by
column chromatography with EtOAc/MeOH/Et3N (8/1/1) as the
(c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.30 (dd, J ) 8.45
Hz, 2H), 7.11 (d, J ) 8.4 Hz, 2H), 3.58-3.50 (m, 1H), 3.27-
3.20 (m, 1H), 3.00-2.97 (m, 1H), 2.97-2.83 (m, 2H), 2.30 (s,
3H), 2.22 (d, J ) 10.6 Hz, 2H), 2.10-1.90 (m, 2H), 1.69-1.64
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 141.4, 132.5, 128.9, 128.8,
59.6, 56.8, 46.7, 44.1, 43.8, 25.1, 6.7; MS (ESI) 350.3 [MH+];
HRMS (ESI) calculated for C13H18ClIN+ [MH+] 350.0172, found
350.0168.
[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidine-3-yl-
methylsulfanyl]acetic Acid Methyl Ester ((-)-trans-4).
To a solution of (-)-trans-3 (617 mg, 1.76 mmol) in anhydrous
MeCN (20 mL) was added 316 µL of methyl thioglycolate (374
mg, 3.52 mmol) under nitrogen at room temperature, followed
by the addition of cesium carbonate (1.43 g, 4.40 mmol). After
the mixture was stirred at room temperature overnight, the
solvent was evaporated and the residue was partitioned with
CH2Cl2/H2O (1/1, 40 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 25 mL), and the combined organic layers
were dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The crude product was purified
by column chromatography using the mixture EtOAc/Et3N
(98/2 to 10/1) as the eluent to afford (-)-trans-4 as a colorless
eluent to yield (-)-trans-2 as a white solid (1.61 g, 90%). [R]25
D
1
-28° (c 0.49, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.22 (d, J
) 8.4 Hz, 2H), 7.09 (d, J ) 8.4 Hz, 2H), 3.50 (br s, 1H), 3.34
(dd, J ) 2.7, 11 Hz, 1H), 3.14 (dd, J ) 7.2, 11.1 Hz, 2H), 2.94-
2.84 (m, 1H), 2.29 (s, 3H), 2.24 (td, J ) 6.3, 10.1 Hz, 1H), 2.03-
1.90 (m, 2H), 1.87 (dd, J ) 10.8, 10.5 Hz, 1H), 1.82-1.69 (m,
2H); 13C NMR (CDCl3, 75 MHz) δ 142.9, 132.1, 128.9, 128.8,
63.3, 59.5, 56.2, 46.6, 44.1, 43.9, 34.4.
oil (505 mg, 88%). [R]25 -98.2° (c 0.72, CHCl3); 1H NMR
Compounds (+)-cis-2 and (-)-cis-2 were prepared by the
general procedure described for (-)-trans-2.
D
(CDCl3, 300 MHz) δ 7.27 (d, J ) 8.7 Hz, 2H), 7.12 (d, J ) 8.4
Hz, 2H), 3.60 (s, 3H), 3.28-3.22 (m, 1H), 3.06 (q, J ) 14.7 and
18.0 Hz, 2H), 2.97-2.92 (m, 1H), 2.50 (dd, J ) 2.4 and 7.5 Hz,
1H), 2.34 (s, 3H), 2.28-1.96 (m, 4H), 1.84-1.74 (m, 3H); 13C
NMR (CDCl3, 75 MHz) δ 171.0, 142.8, 132.6, 129.3, 129.2, 61.1,
56.6, 52.7, 47.5, 46.8, 41.6, 35.3, 35.0, 34.3; MS (ESI) 328.2
[MH+]; HRMS (ESI) calculated for C16H23ClNO2S+ [MH+]
328.1138, found 328.1136.
(3R,4R)-4-(4-Chlorophenyl)-3-(hydroxymethyl)-1-me-
1
thylpiperidine ((+)-cis-2). Yield 92%; white solid; H NMR
(CDCl3, 300 MHz) δ 7.29 (d, J ) 8.5 Hz, 2H), 7.24 (d, J ) 8.5
Hz, 2H), 3.76-3.50 (m, 2H), 3.15(br.d, J ) 11 Hz, 1H), 3.10-
3.00 (m, 1H), 2.84 (dt, J ) 12, 4.4 Hz, 1H), 2.65-2.45 (m, 2H),
2.29 (s, 3H), 2.13 (td, J ) 11, 3.0 Hz, 1H), 1.86-1.69 (m, 3H).
(3S,4S)-4-(4-Chlorophenyl)-3-(hydroxymethyl)-1-meth-
1
Compounds (+)-cis-4 and (-)-cis-4 were prepared by the
general procedure described for (-)-trans-4.
ylpiperidine ((-)-cis-2). Yield 100%; white solid; H NMR
(CDCl3, 300 MHz) δ 7.29 (d, J ) 8.5 Hz, 2H), 7.24 (d, J ) 8.5
Hz, 2H), 3.76-3.50 (m, 2H), 3.15 (br.d, J ) 11 Hz, 1H), 3.10-
3.00 (m, 1H), 2.84 (dt, J ) 12, 4.4 Hz, 1H), 2.65-2.45 (m, 2H),
2.29 (s, 3H), 2.13 (td, J ) 11, 3.0 Hz, 1H), 1.86-1.69 (m, 3H).
(3S,4R)-4-(4-Chlorophenyl)-3-(iodomethyl)-1-methyl-
piperidine ((-)-trans-3). To a solution of PPh3 (2.41 g, 9.18
mmol) in anhydrous CH2Cl2 (60 mL) was added iodine (2.33
g, 9.18 mmol) under nitrogen at room temperature. After the
mixture was stirred at room temperature for 15 min, imidazole
(0.71 g, 10.43 mmol) was added in one portion, followed by
the addition of a solution of (-)- trans-2 (1.0 g, 4.17 mmol) in
20 mL of CH2Cl2 at room temperature. The resulting mixture
was refluxed for 3 h and then washed with a 5% aqueous
solution of sodium thiosulfate to remove the excess iodine. The
organic phase was dried over Na2SO4, concentrated, and
purified by column chromatography first with EtOAc as the
eluent to remove all the formed triphenylphosphine oxide and
then with EtOAc/Et3N (98/2 to 95/5) as the eluent to provide
(-)-trans-3 as a colorless oil (1.25 g, 86%). [R]25D -55° (c 0.83,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.28 (d, J ) 8.7 Hz, 2H),
7.17 (d, J ) 8.4 Hz, 2H), 3.17-3.08 (m, 1H), 3.04 (dd, J ) 2.7
and 12.9 Hz, 1H), 2.98-2.90 (m, 1H), 2.75 (dd, J ) 6.9 and
10.1 Hz, 1H), 2.38 (s, 3H), 2.29 (td, J ) 4.5 and 11.3 Hz, 1H),
2.08 (td, J ) 3.0, 13.2 Hz, 1H), 2.01-1.84 (m, 2H), 1.82-1.66
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 141.4, 132.2, 128.8 (2C),
61.9, 55.9, 46.6, 46.1, 41.4, 33.8, 10.7; MS (ESI) 350.1 [MH+];
HRMS (ESI) calculated for C13H18ClIN+ [MH+] 350.0172, found
350.0164.
[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidine-3-yl-
methylsulfanyl]acetic acid Methyl Ester ((+)-cis-4). Yield
88%; colorless oil; [R]25 +70.8° (c 0.72, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 7.30 (d, J ) 8.48 Hz, 2H), 7.11 (d, J )
8.41 Hz, 2H), 3.58 (s, 3H), 3.24-3.17 (m, 1H), 3.08-2.90 (m,
3H), 2.79-2.90 (m, 2H), 2.29 (s, 3H), 2.25-1.98 (m, 5H), 1.78-
1.65 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 171.0, 142.0, 132.2,
128.9, 128.7, 58.3, 56.5, 52.4, 46.7, 43.6, 40.7, 33.9, 30.1, 25.4;
MS (ESI) 328.2 [MH+]; HRMS (ESI) calculated for C16H23-
ClNO2S+ [MH+] 328.1138, found 328.1142.
[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidine-3-yl-
methylsulfanyl]acetic acid Methyl Ester ((-)-cis-4). Yield
74%; colorless oil; [R]25D -70.6° (c 0.5, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.29 (d, J ) 8.4 Hz, 2H), 7.11 (d, J ) 8.3 Hz, 2H),
3.58 (s, 3H), 3.20-3.17 (m, 1H), 3.08-2.90 (m, 3H), 2.90-2.81
(m, 2H), 2.27 (s, 3H), 2.21-1.95(m, 5H), 1.74-1.68 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 171.0, 142.0, 132.2, 128.9, 128.7,
58.3, 56.5, 52.4, 46.7, 43.6, 40.7, 33.9, 30.1, 25.4; MS (ESI)
328.3 [MH+]; HRMS (ESI) calculated for C16H23ClNO2S+ [MH+]
328.1138, found 328.1134.
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]acetamide ((-)-trans-5a). To a solution of
(-)-trans-4 (176 mg, 0.54 mmol) in t-BuOH (3 mL), which was
contained in a tube that was cooled with a dry ice/acetone bath,
was introduced an excess of ammonia gas. The tube was
capped, and the reaction mixture was stirred at room tem-
perature for 72 h (Caution! Use adequate shielding.). The tube
was recooled and opened, and the solvent was evaporated
under vacuum. The residue was purified by column chroma-
tography using EtOAc/MeOH/Et3N (8/1/1) as the eluent to give
Compounds (+)-cis-3 and (-)-cis-3 were prepared by the
general procedure described for (-)-trans-3.
(3R,4R)-4-(4-Chlorophenyl)-3-(iodomethyl)-1-methyl-
(-)-trans-5a as a white solid (160 mg, 95%). [R]25 -105° (c
piperidine ((+)-cis-3). Yield 86%; colorless oil; [R]25 -14°
D
D
1
1
0.53, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.28 (d, J ) 8.1
(c 0.55, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.30 (dd, J )
Hz, 2 H), 7.11 (d, J ) 8.7 Hz, 2 H), 6.46 (brs, 1H), 5.63 (brs,
1H), 3.27-3.22 (m, 1H), 3.07 (dd, J ) 14.4 and 14.7 Hz, 2H),
2.98-2.84 (m, 1H), 2.44 (d, J ) 10.2 Hz, 1H), 2.36 (s, 3H),
2.24-2.06 (m, 4H), 1.87-1.80 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 171.4, 142.5, 132.8, 129.3, 129.2, 61.1, 56.5, 47.4, 46.8,
41.6, 36.7, 35.8, 35.1; MS (ESI) 313.1 [MH+]; HRMS (ESI)
calculated for C15H22ClN2OS+ [MH+] 313.1141, found 313.1156.
8.45 Hz, 2H), 7.11 (d, J ) 8.4 Hz, 2H), 3.58-3.50 (m, 1H),
3.27-3.20 (m, 1H), 2.92-3.04 (m, 1H), 2.81-2.92 (m, 2H), 2.31
(s, 3H), 2.22 (m, 2H), 2.10-1.90 (m, 2H), 1.66-1.82 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 141.7, 132.5, 128.9, 128.8, 59.8,
56.8, 46.7, 44.4, 44.0, 25.1, 6.9; MS (ESI) 350.1 [MH+]; HRMS
(ESI) calculated for C13H18ClIN+ [MH+] 350.0172, found
350.0175.
(3S,4S)-4-(4-Chlorophenyl)-3-(iodomethyl)-1-methyl-
2-[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidine-3-yl-
methylsulfanyl]acetamide ((-)-cis-5a). Compound (-)-cis-
piperidine ((-)-cis-3). Yield 69%; colorless oil; [R]25 +18°
D

7976 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25
He et al.
5a was prepared by the general procedure described for (-)-
trans-5a. Yield:100%; white solid; [R]25D -82.6° (c 1.0, CHCl3);
1HNMR (CDCl3, 300 MHz) δ 7.29 (d, J ) 8.3 Hz, 2H), 7.10 (d,
J ) 8.3 Hz, 2H), 6.89 (brs, 1H), 6.23 (brs, 1H), 3.22 (m, 1H),
3.10-2.98 (m, 3H), 2.90-2.80 (m, 2H), 2.29 (s, 3H), 2.21-1.96
(m, 5H), 1.72-1.69 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 171.9,
141.4, 132.3, 128.8, 58.2, 56.2, 46.5, 43.3, 40.9, 36.2, 30.2, 25.0;
MS (ESI) 313.3 [MH+]; HRMS (ESI) calculated for C15H22ClN2-
OS+ [MH+] 313.1141, found 313.1136.
(m, 5H), 1.69 (br.d, 1H), 1.07 (d, J ) 6.3 Hz, 3H), 1.05 (d, J )
6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 167.4, 141.6, 132.4,
128.8, 128.7, 67.1, 58.3, 56.4, 46.6, 43.4, 41.6, 40.5, 36.3, 29.7,
25.1, 22.7; MS (ESI) 355.1 [MH+]; HRMS (ESI) calculated for
C18H28ClN2OS+ [MH+] 355.1611, found 355.1614.
2-[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N-isopropylacetamide ((-)-cis-5c). Yield
90%; white solid; [R]25D -81.3° (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.28 (d, J ) 8.3 Hz, 2H), 7.08 (d, J ) 8.3 Hz, 2H),
6.78 (d, J ) 7.0 Hz, 1H), 3.97 (m, 1H), 3.19 (d, J ) 11.5 Hz,
1H), 3.02 (s, 2H), 2.89-2.75 (m, 2H), 2.28 (s, 3H), 2.05-1.95
(m, 5H), 1.69 (br.d, 1H), 1.07 (d, J ) 6.3 Hz, 3H), 1.05 (d, J )
6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 167.4, 141.6, 132.4,
128.8, 128.7, 58.3, 56.4, 46.6, 43.4, 41.6, 40.5, 36.3, 29.7, 25.1,
22.7; MS (ESI) 355.5 [MH+]; HRMS (ESI) calculated for C18H28-
ClN2OS+ [MH+] 355.1611, found 355.1614.
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-methylacetamide ((-)-trans-5b). (-)-
trans-4 (124 mg, 0.378 mmol) was dissolved in a 2.0 M solution
of methylamine in MeOH (5.0 mL). The resulting mixture was
stirred at room temperature for 24 h. The solvent was then
evaporated under vacuum. The residue was purified by
preparative TLC using EtOAc/Et3N (10/1) as the developing
solvent to afford (-)-trans-5b as a white solid (88.5 mg, 72%).
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N,N-dimethylacetamide ((-)-trans-5d).
(-)-trans-4 (92.0 mg, 0.281 mmol) was dissolved in a 2.0 M
solution of dimethylamine in MeOH (4.0 mL). The resulting
mixture was stirred at room temperature until TLC analysis
showed that the starting material had almost disappeared. The
solvent was then evaporated under vacuum. The crude product
was purified by preparative TLC using EtOAc/Et3N (10/1) as
the developing solvent to afford (-)-trans-5d as a colorless oil
[R]25 -75.7° (c 0.66, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.29 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 8.2 Hz, 2H), 6.48 (brs,
1H), 3.22-3.16 (m, 1H), 3.15-2.95 (m, 2H), 2.94-2.82 (m, 1H),
2.70 (d, J ) 5.1 Hz, 3H), 2.34 (s, 3H), 2.32-1.90 (m, 5H), 1.82-
1.65 (m, 3H); 13C NMR δ (CDCl3, 75 MHz) 168.9, 142.4, 132.5,
129.1, 60.9, 56.3, 47.1, 46.6, 41.4, 36.8, 35.5, 34.8, 26.6; MS
(ESI) 327.2 [MH+]; HRMS (ESI) calculated for C16H24ClN2OS+
[MH+] 327.1298, found 327.1307.
(87 mg, 91%). [R]25 -72° (c 0.47, CHCl3); 1H NMR (CDCl3,
Compounds (+)-cis-5b and (-)-cis-5b were prepared by the
same general procedure described for (-)-trans-5b.
D
300 MHz) δ 7.26 (d, J ) 8.4 Hz, 2H), 7.12 (d, J ) 8.4 Hz, 2H),
3.28-3.20 (m, 1H), 3.18 and 3.12 (ABq, J ) 13.5 Hz, 2H), 2.98
(s, 3H), 2.97-2.88 (m, 1H), 2.87 (s, 3H), 2.49 (dd, J ) 2.7, 12.8
Hz, 1H), 2.34 (s, 3H), 2.28-2.20 (m, 2H), 2.16-2.04 (m, 1H),
2.03-1.97 (m, 1H), 1.87-1.75 (m, 3H); 13C NMR (CDCl3, 75
MHz) δ 168.9, 142.5, 132.1, 129.0, 128.8, 60.7, 56.2, 47.0, 46.5,
41.4, 37.9, 35.8, 34.7, 34.6, 34.5; MS(ESI) 341.2 [MH+]; HRMS
(ESI) C17H26ClN2OS+ [MH+] 341.1454, found 341.1446.
2-[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N-methylacetamide ((+)-cis-5b). Yield
90%; colorless oil; [R]25D +81°(c 0.35, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.30 (d, J ) 8.31 Hz, 2H), 7.09 (d, J ) 8.3 Hz,
2H), 6.90 (s, 1H), 3.21-3.16 (m, 1H), 3.05-2.99 (m, 3H), 2.90-
2.82 (m, 1H), 2.78-2.67 (m, 4H), 2.29 (s, 3H), 2.05-1.85 (m,
5H), 1.73-1.61 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 168.0,
142.4, 132.5, 128.7, 58.3, 56.4, 46.5, 43.2, 40.5, 36.3, 30.1, 26.8,
25.1; MS (ESI) 327.1 [MH+]; HRMS calculated for C16H24ClN2-
OS+ [MH+] 327.1298, found 327.1295.
2-[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N-methylacetamide ((-)-cis-5b). Yield
84%; colorless oil; [R]25D -88.7° (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.29 (d, J ) 8.3 Hz, 2H), 7.09 (d, J ) 8.3 Hz, 2H),
6.90 (br.s, 1H), 3.20-3.16 (m, 1H), 3.05-2.98 (m, 3H), 2.90-
2.82 (m, 1H), 2.79-2.72 (m, 4H), 2.29 (s, 3H), 2.17-1.97 (m,
5H), 1.72-1.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.0,
141.6, 132.3, 128.7, 58.3, 56.4, 46.5, 43.2, 40.5, 36.3, 30.1, 26.5,
25.1; MS (ESI) 327.4 [MH+]; HRMS calculated for C16H24ClN2-
OS+ [MH+] 327.1298, found 327.1294.
Compounds (+)-cis-5d and (-)-cis-5d were prepared by the
general procedure described for (-)-trans-5d.
2-[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N,N-dimethylacetamide ((+)-cis-5d). Yield
82%; colorless oil; [R]25D +68° (c 0.75, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.28 (d, J ) 8.33 Hz, 2H), 7.13 (d, J ) 8.32 Hz,
2H), 3.22-3.18 (m, 1H), 3.11 (q, J ) 2.7 Hz, 14 Hz, 2H), 3.00-
2.96 (m, 1H), 2.94 (s, 3H), 2.93-2.89 (m, 2H), 2.87 (s, 3H), 2.27
(s, 3H), 2.20-2.11 (m, 2H), 2.05-1.80 (m, 3H), 1.71-1.67 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 169.5, 142.2, 132.3, 129.2,
128.8, 58.6, 56.6, 46.8, 43.7, 41.0, 38.1, 36.1, 34.9, 30.5, 25.6;
MS (ESI) 341.2 [MH+]; HRMS (ESI) C17H26ClN2OS+ [MH+]
341.1454, found 341.1445.
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-isopropylacetamide ((-)-trans-5c). (-)-
trans-4 (116 mg, 0.354 mmol) was dissolved in a mixture of
1.0 mL of MeOH and 2.0 mL of isopropylamine. The resulting
solution was stirred at room temperature until TLC indicated
that the starting material had almost disappeared. The solvent
was then evaporated under vacuum. The crude product was
purified by preparative TLC using EtOAc/Et3N (10/1) as the
2-[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N,N-dimethylacetamide ((-)-cis-5d). Yield
70%; colorless oil; [R]25D -76.2° (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.29 (d, J ) 8.1 Hz, 2H), 7.13 (d, J ) 8.3 Hz, 2H),
3.22-3.18 (m, 1H), 3.11 (d, J ) 2.9 Hz, 2H), 3.00-2.96 (m,
1H), 2.95 (s, 3H), 2.88 (s, 3H), 2.28 (s, 3H), 2.21-1.99 (m, 5H),
1.70-1.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.5, 142.2,
132.3, 129.2, 128.8, 58.6, 56.6, 46.8, 43.7, 41.0, 38.1, 36.1, 34.9,
30.5, 25.6; MS (ESI) 341.2 [MH+]; HRMS (ESI) C17H26ClN2-
OS+ [MH+] 341.1454, found 341.1455.
developing solvent to afford (-)-trans-5c as a white solid (103
1
mg, 82%). [R]25 -72.7° (c, 1.0, CHCl3); H NMR (CDCl3, 300
D
MHz) δ 7.28 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 8.4 Hz, 2H), 6.40
(d, J ) 7.8 Hz, 1H), 4.02-3.85 (m, 1H), 3.25-3.19 (m, 1H),
3.05 and 2.98 (ABq, J ) 8.4 Hz, 2H), 2.90-2.84 (m, 1H), 2.34
(s, 3H), 2.25-1.90 (m, 5H), 1.80-1.75 (m, 3H), 0.98 (d, J )
6.6 Hz, 3H), 0.94 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 167.1, 142.3, 132.6, 129.1, 129.0, 61.0, 56.3, 47.3, 46.5,
41.7, 41.2, 36.8, 35.3, 34.8, 22.6; MS (ESI) 355.3 [MH+]; HRMS
(ESI) calculated for C18H28ClN2OS+ [MH+] 355.1611, found
355.1612.
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-1-(piperidin-1-yl)ethanone ((-)-trans-
5e). (-)-trans-4 (117 mg, 0.357 mmol) was dissolved in a
mixture of 1.0 mL of MeOH and 2.0 mL of piperidine. The
resulting solution was stirred at room temperature until TLC
analysis indicated that the starting material had been con-
sumed. The solvent was then evaporated under vacuum. The
crude product was purified by preparative TLC using EtOAc/
Et3N (10/1) as the developing solvent to afford (-)-trans-5e
as a pale-yellow oil (125 mg, 92%). [R]25 -75.2° (c 0.43,
Compounds (+)-cis-5c and (-)-cis-5c were prepared by the
general procedure described for (-)-trans-5c.
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 7.26 (d, J ) 8.4 Hz, 2
2-[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-N-isopropylacetamide ((+)-cis-5c). Yield
82%; white solid; [R]25D +72° (c 0.41, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.28 (d, J ) 8.3 Hz, 2H), 7.08 (d, J ) 8.3 Hz, 2H),
6.78 (d, J ) 7.0 Hz, 1H), 3.97 (m, 1H), 3.19 (d, J ) 11.5 Hz,
1H), 3.02 (s, 2H), 2.89-2.75 (m, 2H), 2.28 (s, 3H), 2.05-1.95
H), 7.28 (d, J ) 8.4 Hz, 2H), 7.14 (d, J ) 8.4 Hz, 2H), 3.46 (m,
2H), 3.38-3.25 (m, 2H), 3.24-3.20 (m, 1H), 3.16 (ABq, J )
13.8 Hz, 2H), 2.93-2.85 (m, 1H), 2.50 (dd, J ) 2.7, 12.6 Hz,
1H), 2.34 (s, 3H), 2.28-2.20 (m, 2H), 2.16-1.95 (m, 2H), 1.88-
1.70 (m, 3H), 1.66-1.40 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ
167.2, 142.7, 132.3, 129.2, 128.9, 61.0, 56.2, 47.6, 47.2, 46.6,

Effects of Piperidine Ring Stereochemistry
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7977
43.1, 41.4, 34.9, 34.7, 26.5, 25.6, 24.5; MS (ESI) 381.3 [MH+];
HRMS (ESI) calculated for C20H30ClN2OS+ [MH+] 381.1767,
found 381.1768.
Compounds (+)-cis-5e and (-)-cis-5e were prepared by the
general procedure described for (-)-trans-5e.
2-[(3R,4R)-4-(Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-1-(piperidne-1-yl)ethanone ((+)-cis-5e).
Yield 87%; white solid; [R]25D +77° (c 0.875, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ 7.30 (d, J ) 8.1 Hz, 2H), 7.14 (d, J ) 8.3
Hz, 2H), 3.45 (t, J ) 5.39 Hz, 2H), 3.32 (t, J ) 5.3 Hz, 2H),
3.24-3.08 (m, 3H), 3.01-2.94 (m, 1H), 2.90-2.75 (m, 2H), 2.28
(s, 3H), 2.20-1.98 (m, 5H), 1.74-1.31 (m, 7H); 13C NMR
(CDCl3, 75 MHz) δ 167.5, 142.0, 132.1, 129.0, 128.6, 67.1, 58.4,
56.5, 47.6, 46.7, 43.5, 43.1, 40.6, 34.7, 30.2, 26.5, 25.7, 25.4,
24.6; MS (ESI) 381.2 [MH+]; HRMS (ESI) calculated for C20H30-
ClN2OS+ [MH+] 381.1767, found 381.1778.
Cl2 (4 mL) was added benzylamine (11 mg, 0.10 mmol) under
nitrogen at room temperature, followed by the addition of
EDCI (28 mg, 0.15 mmol) and HOBt (5 mg, 0.01 mmol). After
the mixture was stirred at room temperature overnight, the
solvent was evaporated and the residue was diluted with ethyl
acetate and washed with a saturated NaCl solution. The
organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The crude product
was purified by preparative TLC using the mixture EtOAc/
Et3N/MeOH (8/1/1) as the developing solvent to afford (-)-
trans-5g as a white solid (25.4 mg, 63%). [R]25 -74° (c 0.55,
D
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.34-7.19 (m, 7H), 7.10
(d, J ) 7.5 Hz, 2H), 6.95-6.82 (brs, 1H), 4.35 (d, J ) 5.52 Hz,
2H), 3.19-3.12 (m, 3H), 2.83-2.99 (m, 1H), 2.39-2.35 (m, 1H),
2.33 (s, 3H), 2.28-1.95 (m, 4H), 1.90-1.70 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 168.2, 142.0, 138.1, 132.3, 129.1, 129.0,
128.9, 127.8, 127.8, 60.8, 56.2, 47.2, 46.5, 43.9, 41.1, 36.8, 35.5,
34.8; MS (ESI) 403.1 [MH+]; HRMS (ESI) calculated for
C22H28ClN2OS+ [MH+] 403.1611, found 403.1606.
2-[(3S,4S)-4-(Chlorophenyl)-1-methylpiperidin-3-yl-
methylsulfanyl]-1-(piperidne-1-yl)ethanone ((-)-cis-5e).
1
Yield 90%; white solid; [R]25 -83.7° (c 1.0, CHCl3); H NMR
D
Compounds (+)-cis-5g and (-)-cis-5g were prepared by the
general procedure described for (-)-trans-5g.
(CDCl3, 300 MHz) δ 7.27 (d, J ) 8.3 Hz, 2H), 7.14 (d, J ) 8.3
Hz, 2H), 3.43 (t, J ) 5.3 Hz, 2H), 3.29 (t, J ) 5.2 Hz, 2H),
3.22-3.12 (m, 3H), 3.06-2.97 (m, 1H), 2.88-2.80 (m, 2H), 2.26
(s, 3H), 2.17-1.99 (m, 5H), 1.69-1.44 (m, 7H); 13C NMR
(CDCl3, 75 MHz) δ 167.5, 142.0, 132.1, 129.0, 128.6, 58.4, 56.5,
47.6, 46.7, 43.5, 43.1, 40.6, 34.7, 30.2, 26.5, 25.7, 25.4, 24.6;
MS (ESI) 381.4 [MH+]; HRMS (ESI) calculated for C20H30ClN2-
OS+ [MH+] 381.1767, found 381.1760.
2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-benzylacetamide ((+)-cis-5g). Yield 62%;
white solid; [R]25D +76° (c 0.60, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.50 (brs, 1H), 7.38-7.25 (m, 6H), 7.01 (d, J ) 8.32
Hz, 2H), 4.45 (ABq, J ) 5.8, 14.6 Hz, 1H), 4.33 (ABq, J ) 5.5,
14.6 Hz, 1H), 3.18-3.10 (m, 3H), 2.83-2.71 (m, 3H), 2.19 (s,
3H), 2.11-1.88 (m, 5H), 1.87-1.79 (m, 1H), 1.60-1.55 (m, 1H);
13C NMR (CDCl3, 75 MHz) δ 168.5, 141.6, 138.2, 132.4, 128.9,
128.8, 128.7, 128.1, 127.8, 58.4, 56.4, 46.4, 43.4, 41.0, 36.5, 29.7,
24.9; MS (ESI) 403.1 [MH+]; HRMS (ESI) calculated for C22H28-
ClN2OS+ [MH+] 403.1611, found 403.1616.
(3S,4R)-[4-Chlorophenyl]-1-methylpieridin-3-ylmeth-
ylsulfanyl]acetic Acid ((-)-trans-6). To a solution of (-)-
trans-2 (400 mg, 1.22 mmol) in THF/H2O (1/1, 20 mL) was
added LiOH‚2H2O (100 mg, 2.38 mmol) under nitrogen at room
temperature. After being stirred at room temperature until
the reaction was complete, as judged by TLC analysis, the
mixture was neutralized with 10% aqueous HCl solution and
then extracted with CH2Cl2 (3 × 25 mL). The combined
extracts were dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum to give (-)-trans-6 as a yellow
oil (352 mg, 92%). [R]25D -72° (c 1.1, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 7.32 (d, J ) 8.1 Hz, 2H), 7.20 (d, J ) 8.2 Hz, 2H),
3.99 (br d, J ) 10 Hz, 1H), 3.58 (br d, J ) 11 Hz, 1H), 3.13 (q,
J ) 15, 15 Hz, 2H), 2.88 (s, 3H), 2.88-2.70 (m, 3H), 2.69-
2.45 (m, 3H), 2.24 (m, 1H), 2.00-1.96 (m, 1H);
(3R,4R)-[4-Chlorophenyl]-1-methylpieridin-3-ylmeth-
ylsulfanyl]acetic Acid HCl Salt ((+)-cis-6). Compound (+)-
cis-6 was prepared by the general procedure described for (-)-
trans-6. Yield 90%; white solid; [R]25D +125.8 ° (c 0.80, MeOH);
1H NMR (CDCl3, 300 MHz) δ 7.35 (d, J ) 8.5 Hz, 2H), 7.24 (d,
J ) 8.4 Hz, 2H), 4.00 (br d, J ) 11 Hz, 1H), 3.61 (br d, J )
11.5 Hz, 1H), 3.17-3.02 (m, 5H), 2.89 (s, 3H), 2.60-2.52 (m,
1H), 2.44-2.32 (m, 3H), 2.02-1.96 (m, 1H);
2-[[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-benzylacetamide ((-)-cis-5g). Yield 58%;
white solid; [R]25D -71.4° (c 1.0, CHCl3); 1H NMR (CDCl3, 300
MHz) δ 7.51 (brs, 1H), 7.37-7.27 (m, 6H), 7.02 (d, J ) 8.2 Hz,
2H), 4.47 (ABq, J ) 5.9, 14.6 Hz, 1H), 4.34 (ABq, J ) 5.4, 14.6
Hz, 1H), 3.18-3.12 (m, 3H), 2.85-2.72 (m, 3H), 2.20 (s, 3H),
2.11-1.88 (m, 5H), 1.87-1.76 (m, 1H), 1.60-1.56 (m, 1H); 13
C
NMR (CDCl3, 75 MHz) δ 168.5, 141.5, 138.3, 132.3, 128.9,
128.7, 128.7, 128.1, 127.8, 58.4, 56.3, 46.4, 43.9, 43.4, 41.0, 36.5,
29.7, 24.9; MS (ESI) 403.1 [MH+]; HRMS (ESI) calculated for
C22H28ClN2OS+ [MH+] 403.1611, found 403.1615.
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-(2-phenylethyl)acetamide ((-)-trans-
5h). To a solution of (-)-trans-6 (30 mg, 0.10 mmol) in
anhydrous CH2Cl2 (4 mL) was added 2-phenylethylamine (13
mg, 0.10 mmol) under nitrogen at room temperature, followed
by the addition of EDCI (28 mg, 0.15 mmol) and HOBt (5 mg,
0.01 mmol). After the mixture was stirred at roomtemperature
overnight, the solvent was evaporated and the residue was
diluted with ethyl acetate and washed with a saturated NaCl
solution. The organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum. The crude
product was purified by TLC using the mixture EtOAc/Et3N/
MeOH (8/1/1) as the developing solvent to afford (-)-trans-5h
as a colorless oil (23 mg, 56%). [R]25D -68° (c 0.42, CHCl3); 1H
NMR (CDCl3, 300 MHz) δ 7.34-7.22 (m, 5H), 7.16 (d, J ) 7.0
Hz, 2H), 7.09 (d, J ) 8.3 Hz, 2H), 6.65-6.58 (m, 1H), 3.44 (dd,
J ) 13.1, 6.7 Hz, 2H), 3.21-3.19 (m, 1H), 3.11 (dd, J ) 11.4,
16 Hz, 2H), 2.99-2.94 (m, 1H), 2.72 (t, J ) 7.42 Hz, 2H), 2.35
(s, 3H), 2.30-2.08 (m, 2H), 2.05-1.98 (m, 3H), 1.80-1.75 (m,
3H); 13C NMR (CDCl3, 75 MHz) δ 168.2, 142.3, 138.8, 132.6,
129.1, 129.0, 128.9, 128.8, 126.8, 60.7, 56.2, 47.1, 46.5, 41.2,
40.9, 36.9, 35.7, 35.4, 34.7; MS (ESI) 417.3 [MH+]; HRMS (ESI)
calculated for C23H30ClN2OS+ [MH+] 417.1767, found 417.1776.
2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-phenylacetamide ((+)-cis-5f). To a so-
lution of (+)-cis-6 (30 mg, 0.10 mmol) in anhydrous CH2Cl2 (4
mL) was added aniline (18 mg, 0.15 mmol) under nitrogen at
room temperature, followed by the addition of EDCI (28 mg,
0.15 mmol) and HOBt (5 mg, 0.01 mmol). After the mixture
was stirred at room temperature overnight, the solvent was
evaporated and the residue was diluted with ethyl acetate and
washed with a saturated NaCl solution. The organic layer was
dried over anhydrous sodium sulfate, filtered, and concen-
trated under vacuum. The crude product was purified by TLC
using the mixture EtOAc/Et3N/MeOH (8/1/1) as the developing
solvent to afford (+)-cis-5f as a colorless oil (30 mg, 73%). [R]25
D
+70° (c 0.72, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.53-7.21
(m, 6H), 7.20-7.10 (m, 1H), 7.08 (d, J ) 8.3 Hz, 2H), 3.30-
3.21 (m, 3H), 3.15-3.00 (m, 1H), 2.94-2.86 (m, 2H), 2.34 (s,
3H), 2.26-2.00 (m, 5H), 1.88-1.67 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 166.8, 141.3, 137.7, 132.4, 129.3, 128.8, 128.7, 124.7,
120.1, 58.5, 56.6, 46.5, 43.4, 41.1, 37.4, 29.8, 25.0; MS (ESI)
389.2 [MH+]; HRMS (ESI) C21H26ClN2OS+ [MH+] 389.1454,
found 389.1452.
2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-(2-phenylethyl)acetamide ((+)-cis-
5h). Compound (+)-cis-5h was prepared by the general
procedure described for (-)-trans-5h. Yield 58%; colorless oil;
[R]25D +65° (c 0.63, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.35-
7.23 (m, 5H), 7.18 (d, J ) 7.13 Hz, 2H), 7.07 (d, J ) 8.3 Hz,
2H), 6.93 (brs, 1H), 3.49-3.44 (m, 2H), 3.17-3.13 (m, 1H), 3.04
(s, 2H), 2.98-2.95 (m, 1H), 2.88-2.84 (m, 1H), 2.77-2.72 (m,
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-benzylacetamide ((-)-trans-5g). To a
solution of (-)-trans-6 (30 mg, 0.10 mmol) in anhydrous CH2-

7978 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25
He et al.
3H), 2.25 (s, 3H), 2.14-1.93 (m, 5H), 1.72-1.66 (m, 1H); 13C
NMR (CDCl3, 75 MHz) δ 168.4, 141.6, 139.0, 132.3, 128.9,
128.8, 128.78, 128.7, 126.7,58.3, 56.5, 46.6, 43.3, 41.0, 40.7,
36.4, 35.8, 30.0, 25.2; MS (ESI) 417.1 [MH+]; HRMS (ESI)
calculated for C23H30ClN2OS+ [MH+] 417.1767, found 417.1776.
(8 mL) was added 2.0 mL of Ac2O under nitrogen at room
temperature, followed by 1.0 mg of 4-(dimethylamino)pyridine
(DMAP). After the mixture was stirred at room temperature
for 2 h, the solvent was evaporated and the residue was diluted
with ethyl acetate and washed with saturated NaHCO3
aqueous solution (2 × 15 mL). The organic layer was dried
over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The crude product was purified by preparative
TLC using EtOAc/Et3N (10/1) as the developing solvent to
afford (-)-trans-8a as a colorless oil (74 mg, 70%). [R]25D -83.0°
(c 1.05, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.29 (d, J ) 8.3
Hz, 2H), 7.14 (d, J ) 8.4 Hz, 2H), 4.04-4.03 (m, 2H), 3.24-
3.30 (m, 1H), 2.98-2.92 (m, 1H), 2.57 (t, J ) 6.9 Hz, 2H), 2.43
(dd, J ) 1.5, 10.2 Hz, 1H), 2.35 (s, 3H), 2.31-2.19 (m, 1H),
2.17-2.05 (m, 3H), 2.01 (s, 3H), 1.81-1.78 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ 171.1, 142.9, 132.6, 129.3, 129.2, 63.7, 61.2,
56.6, 47.4, 46.8, 42.0, 35.1, 31.4, 21.2; MS (ESI) 342.3 [MH+];
HRMS (ESI) calculated for C17H25ClNO2S+ [MH+] 342.1295,
found 342.1287.
2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]-N-naphthylacetamide ((+)-cis-5i). To a
solution of (+)-cis-6 (30 mg, 0.10 mmol) in anhydrous CH2Cl2
(4 mL) was added â-naphthylamine (22 mg, 0.15 mmol) under
nitrogen at room temperature, followed by the addition of
EDCI (28 mg, 0.15 mmol) and HOBt (5 mg, 0.01 mmol). After
the mixture was stirred at room temperature overnight, the
solvent was evaporated and the residue was diluted with ethyl
acetate and washed with a saturated NaCl solution. The
organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The crude product
was purified by TLC using the mixture EtOAc/Et3N/MeOH
(8/1/1) as the developing solvent to afford (+)-cis-5i as a white
solid (29 mg, 65%). [R]25 +70° (c 0.47, CHCl3); 1H NMR
D
(CDCl3, 300 MHz) δ 9.16 (s, 1H), 8.19 (s, 1H), 7.86-7.81 (m,
3H), 7.52-7.40 (m, 3H), 7.28-7.23 (m, 1H), 7.07 (d, 2H), 3.33-
3.26 (m, 3H), 3.09 (d, 1H), 2.98-2.90 (m, 2H), 2.37 (s, 3H),
2.28-1.99 (m, 5H), 1.71 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
167.1, 141.2, 135.2, 134.0, 132.5, 131.0, 129.0, 128.8, 128.7,
127.9, 127.8, 126.7, 125.3, 119.9, 116.9, 77.7, 77.2, 76.8, 58.5,
56.6, 46.6, 43.4, 41.2, 37.5, 29.8, 25.0; MS (ESI) 439.1 [MH+];
HRMS (ESI) calculated for C25H28ClN2OS+ [MH+] 439.1611,
found 439.1613.
Compounds (+)-cis-8a and (-)-cis-8a were prepared by the
general procedure described for (-)-trans-8a.
Acetic Acid 2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methyl-
piperidin-3-yl]methylsulfanyl]ethyl Ester ((+)-cis-8a).
1
Yield 64%; colorless oil; [R]25 +73° (c 1.1, CHCl3); H NMR
D
(CDCl3, 300 MHz) δ 7.29 (d, J ) 8.4 Hz, 2H), 7.12 (d, J ) 8.31
Hz, 2H), 4.02-3.95 (m, 2H), 3.22-3.18 (m, 1H), 3.00-2.97 (m,
1H), 2.88-2.74 (m, 2H), 2.54-2.48 (m, 2H), 2.28 (s, 3H), 2.20-
1.80 (m, 5H), 2.00 (s, 3H), 1.70-1.67 (m, 1H); 13C NMR (CDCl3,
75 MHz) δ 170.9, 142.0, 132.2, 128.8, 128.7, 63.6, 58.3, 56.5,
46.6, 43.6, 41.4, 30.8, 29.5, 25.3, 21.0; MS (ESI) 342.1 [MH+];
HRMS (ESI) calculated for C17H25ClNO2S+ [MH+] 342.1295,
found 342.1289 [MH+].
2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]ethanol ((-)-trans-7). To a solution of
[(3S,4R)-4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethyl-
sulfanyl]acetic acid methyl ester (271 mg, 0.827 mmol) in
anhydrous THF (10 mL) that was cooled to 0 °C was added
LiAlH4 (47.1 mg, 1.24 mmol). The resulting mixture was
warmed to room temperature and stirred overnight, and then
the reaction was quenched with a saturated solution of NH4-
Cl (10 mL). The solution was extracted with CH2Cl2 (3 × 25
mL). The combined organic extracts were dried over Na2SO4,
concentrated, and purified by column chromatography on silica
gel with EtOAc/Et3N (10:1) to EtOAc/MeOH/Et3N (8:1:1) as
the eluent to yield (-)-trans-7 as a colorless oil (203 mg, 82%).
Acetic Acid 2-[[(3S,4S)-4-(4-Chlorophenyl)-1-methyl-
piperidin-3-yl]methylsulfanyl]ethyl Ester ((-)-cis-8a).
1
Yield 92%; [R]25 -66.9° (c 1.0, CHCl3); H NMR (CDCl3, 300
D
MHz) δ 7.29 (d, J ) 8.3 Hz, 2H), 7.11 (d, J ) 8.3 Hz, 2H),
4.05-3.91 (m, 2H), 3.21-3.17 (m, 1H), 3.00-2.97 (m, 1H),
2.88-2.74 (m, 2H), 2.54-2.48 (m, 2H), 2.27 (s, 3H), 2.13-2.00
(m, 5H), 2.00 (s, 3H), 1.70-1.67 (m, 1H); 13C NMR (CDCl3, 75
MHz) δ 170.9, 142.0, 132.2, 128.8, 128.7, 63.6, 58.3, 56.5, 46.6,
43.6, 41.4, 30.8, 29.5, 25.3, 21.0; MS (ESI) 342.4 [MH+]; HRMS
(ESI) calculated for C17H25ClNO2S+ [MH+] 342.1295, found
342.1288 [MH+].
[R]25 -80.5° (c 0.65, CHCl3); 1H NMR (CDCl3, 300 MHz) δ
D
7.28 (d, J ) 8.3 Hz, 2 H), 7.13 (d, J ) 8.3 Hz, 2H), 3.57-3.40
(m, 3H), 3.35-3.24 (m, 1H), 2.98-2.88 (m, 1H), 2.54 (t, J )
5.4 Hz, 2H), 2.35 (s, 3H), 2.31-2.20 (m, 2H), 2.08-2.04 (m,
3H), 1.81-1.70 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 142.7,
132.7, 129.2 (2), 61.0, 60.5, 56.4, 47.3, 46.6, 41.8, 36.2, 34.7,
34.3; MS(ESI) 300.2 [MH+]; HRMS (ESI) calculated for C15H23-
ClNOS+ [MH+] 300.1189, found 300.1186.
Benzoic Acid 2-[[(3S,4R)-4-(4-Chlorophenyl)-1-meth-
ylpiperidin-3-yl]methylsulfanyl]ethyl Ester ((-)-trans-
8b). To a solution of (-)-trans-7 (89.0 mg, 0.297 mmol) in
anhydrous THF (8 mL) were added Et3N (83 µL) and DMAP
(1.0 mg) under nitrogen at 0 °C, followed by benzoyl chloride
(52 µL, 63 mg, 0.45 mmol). After the mixture was stirred at 0
°C to room temperature overnight, the solvent was evaporated
and the residue was diluted with ethyl acetate and washed
with saturated aqueous NaHCO3 solution (2 × 10 mL). The
organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The crude product
was purified by preparative TLC using EtOAc/Et3N (10/1) as
Compounds (+)-cis-7 and (-)-cis-7 were prepared by the
general procedure described for (-)-trans-7.
2-[[(3R,4R)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]ethanol ((+)-cis-7). Yield 78%; colorless oil;
[R]25D +85.5° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.29
(d, J ) 8.5 Hz, 2H), 7.10 (d, J ) 8.4 Hz, 2H), 3.68-3.63 (m,
2H), 3.48-3.40 (m, 1H), 3.07-2.98 (m, 1H), 2.96-2.82 (m, 2H),
2.69-2.42 (m, 2H), 2.31 (s, 3H), 2.23-1.95 (m, 6H), 1.76-1.62
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 141.8, 132.2, 128.8, 128.7,
62.6, 58.1, 56.4, 46.5, 43.4, 41.0, 36.0, 28.5, 24.9; MS (ESI)
300.2 [MH+]; HRMS (ESI) calculated for C15H23ClNOS+ [MH+]
300.1189, found 300.1190.
2-[[(3S,4S)-4-(4-Chlorophenyl)-1-methylpiperidin-3-yl]-
methylsulfanyl]ethanol ((-)-cis-7). Yield 68%; colorless oil;
[R]25D -87.3° (c 1.0, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.29
(d, J ) 8.4 Hz, 2H), 7.09 (d, J ) 8.3 Hz, 2H), 3.68-3.63 (m,
2H), 3.46-3.41 (m, 1H), 3.07-2.98 (m, 1H), 3.03-2.83 (m, 2H),
2.64-2.45 (m, 2H), 2.30 (s, 3H), 2.23-1.95 (m, 6H), 1.69-1.67
(m, 1H); 13C NMR (CDCl3, 75 MHz) δ 141.8, 132.2, 128.8, 128.7,
62.6, 58.1, 56.4, 46.5, 43.5, 41.0, 35.9, 28.5, 24.9; MS (ESI)
300.3 [MH+]; HRMS (ESI) calculated for C15H23ClNOS+ [MH+]
300.1189, found 300.1189.
the developing solvent to afford (-)-trans-8b as a colorless oil
1
(81 mg, 68%). [R]25 -63.7° (c 0.72, CHCl3); H NMR (CDCl3,
D
300 MHz) δ 7.96-7.91 (m, 2H), 7.52-7.46 (m, 1H), 7.39-7.34
(m, 2H), 7.18 (d, J ) 8.1 Hz, 2H), 7.05 (d, J ) 8.7 Hz, 2H),
4.28-4.16 (m, 2H), 3.22-3.17 (m, 1H), 2.87-2.84 (m, 1H), 2.63
(t, J ) 6.6 Hz, 2H), 2.52-2.40 (m, 1H), 2.27 (s, 3H), 2.20-1.88
(m, 4H), 1.81-1.68 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.4,
142.6, 133.2, 132.3, 129.8, 129.1, 128.6, 63.8, 61.1, 56.3, 47.2,
46.4, 41.8, 35.0, 34.9, 31.5; MS (ESI) 404.2 [MH+]; HRMS (ESI)
calculated for C22H27ClNO2S+ [MH+] 404.1446, found 404.1459.
Benzoic Acid 2-[[(3R,4R)-4-(4-Chlorophenyl)-1-meth-
ylpiperidin-3-yl]methylsulfanyl]ethyl Ester ((+)-cis-8b).
Compound (+)-cis-8b was prepared by the general procedure
described for (-)-trans-8b. Yield 68%; colorless oil; [R]25D +62°
(c 0.33, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 8.04 (d, J ) 7.34
Hz, 2H), 7.61-7.56 (m, 1H), 7.49-7.44 (m, 2H), 7.29 (d, J )
8.3 Hz, 2H), 7.13 (d, J ) 8.3 Hz, 2H), 4.34-4.22 (m, 2H), 3.26-
3.22 (m, 1H), 3.02-2.99 (m, 1H), 2.90-2.82 (m, 2H), 2.76-
2.63 (m, 2H), 2.30 (s, 3H), 2.20-1.96 (m, 5H), 1.72-1.69 (m,
Acetic Acid 2-[[(3S,4R)-4-(4-Chlorophenyl)-1-methyl-
piperidin-3-yl]methylsulfanyl]ethyl Ester ((-)-trans-8a).
To a solution of (-)-trans-7 (92.0 mg, 0.307 mmol) in pyridine

Effects of Piperidine Ring Stereochemistry
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 25 7979
1H); 13C NMR (CDCl3, 75 MHz) δ 166.5, 142.0, 133.2, 132.1,
130.2, 129.9, 128.8, 128.7, 128.6, 64.1, 58.3, 56.5, 46.6, 43.6,
41.5, 31.1, 29.6, 25.4; MS (ESI) 404.2 [MH+]; HRMS (ESI)
calculated for C22H27ClNO2S+ [MH+] 404.1446, found 404.1463.
nephrine reuptake inhibitors: synthesis and evaluation of their
uptake inhibition at monoamine transporter sites. J. Med. Chem.
2003, 46, 1997-2007. (b) Zhou, J.; Kla¨ss, T.; Zhang, A.; Johnson,
K. M.; Wang, C. Z.; Ye, Y.; Kozikowski, A. P. Synthesis and
pharmacological evaluation of (Z)-9-(heteroarylmethylene)-7-
azatricyclo[4.3.1.0(3,7)]decanes: thiophene analogues as potent
norepinephrine transporter inhibitors. Bioorg. Med. Chem. Lett.
2003, 13, 3565-3569.
Acknowledgment. We are indebted to the National
Institute on Drug Abuse (Grant DA10458) for their
support of these studies.
(10) (a) Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.;
Johnson, K. M.; Flippen-Aderson, J. L.; George, C.; Saiah, E.
Chemistry and pharmacology of the piperidine-based analogues
of cocaine. Identification of potent DAT inhibitors lacking the
toropane skeleton. J. Med. Chem. 1998, 41, 1, 1962-1969. (b)
Tamiz, A. P.; Zhang, J.; Flippen-Anderson, J. L.; Zhang, M.;
Johnson, K. M.; Deschaux, O.; Tella, S. R.; Kozikowski, A. P.
Further SAR studies of piperidine-based analogues of cocaine.
2. Potent dopamine and serotonine reuptake inhibitors. J. Med.
Chem. 2000, 43, 1215-1222. (c) Kozikowski, A. P.; Johnson, K.
M.; Deschaux, O.; Bandyopadhyay, B. C.; Araldi, G. L.; Carmona,
G.; Munzar, P.; Simth, M. P.; Balster, R. L.; Beardsley, P. M.;
Tella, S. R. Mixed cocaine agonist/antagonist properties of (+)-
methyl 4-(4-chlorophenyl)-1-methylpiperidine-3-carboxylate, a
piperidine-based analog of cocaine. J. Pharmacol. Exp. Ther.
2003, 305, 143-150. (d) Petukhov, P. A.; Zhang, M.; Johnson,
K. M.; Tella, S. R.; Kozikowski, A. P. SAR studies of piperidine-
based analogues of cocaine. Part 3: Oxadiazoles. Bioorg. Med.
Chem. Lett. 2001, 11, 2079-2083.
Supporting Information Available: HPLC analysis data
and NMR charts (1H and 13C) for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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