Synthesis and structure-activity relationship of 3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane and 3β-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters

Article abstract of DOI:10.1016/j.bmc.2009.05.052

Early studies led to the identification of 3β-(4-methoxyphenyl)tropane-2β-carboxylic acid methyl ester (5) with high affinity at the DAT (IC₅₀ = 6.5 nM) and 5-HTT (K_i = 4.3 nM), while having much less affinity at the NET (K_i

Full text of DOI:10.1016/j.bmc.2009.05.052

Bioorganic & Medicinal Chemistry 17 (2009) 5126–5132
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure–activity relationship of 3b-(4-alkylthio,
-methylsulfinyl, and -methylsulfonylphenyl)tropane and
3b-(4-alkylthiophenyl)nortropane derivatives for monoamine transporters
*
Chunyang Jin , Hernán A. Navarro, F. Ivy Carroll
Organic and Medicinal Chemistry, Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Early studies led to the identification of 3b-(4-methoxyphenyl)tropane-2b-carboxylic acid methyl ester
(5) with high affinity at the DAT (IC50 = 6.5 nM) and 5-HTT (Ki = 4.3 nM), while having much less affinity
at the NET (Ki = 1110 nM). In the present study, we replaced the 40-methoxy group of the 3b-phenyl ring
with a bioisosteric 40-methylthio group to give 7a. We also synthesized a number of 3b-(4-alkylthiophe-
nyl)tropanes 7b–e, 3b-(4-methylsulfinylphenyl) and 3b-(4-methylsulfonylphenyl)tropane analogues
7f–h as well as the 3b-(4-alkylthiophenyl)nortropane derivatives 8–11 to further characterize the
structure–activity relationship of this type of compound for binding at monoamine transporters. With
exception of the 40-methylsulfonyl analogue 7h, all the tested compounds possessed high binding affin-
ities at the 5-HTT. The Ki values ranged from 0.19 nM to 49 nM. The 3b-(4-methylthiophenyl)tropane 7a
and its N-(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the most selective compounds for
the 5-HTT over the NET (NET/5-HTT = 314–364) in the series. However, none of the compounds showed
selectivity similar to 5 for both the DAT and 5-HTT relative to the NET. This study provided useful SAR
information for rational design of potent and selective monoamine transporter inhibitors.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 25 March 2009
Revised 21 May 2009
Accepted 22 May 2009
Available online 29 May 2009
Keywords:
Monoamine transporters
3-Phenyltropanes
3-Phenylnortropanes
Cocaine
Addiction
1. Introduction
much attention as potential pharmacotherapies for treating co-
caine abuse.21–24
Monoamine neurotransmitter transporters are the principle
sites of action for cocaine (1, Fig. 1) and other stimulants.1–5 Com-
pounds with high affinity and selectivity for the dopamine, seroto-
nin, and norepinephrine transporters (DAT, 5-HTT, and NET,
respectively) are all of interest. In the brain, cocaine binds to the
DAT, 5-HTT, and NET, and inhibits presynaptic reuptake of the
respective neurotransmitters. It also has effects on the cholinergic,
The exploration of potent and selective monoamine transporter
inhibitors for cocaine abuse therapy depends on an understanding
of the mechanisms of action and their structure–activity relation-
ships (SAR). This has been accomplished experimentally by
correlation of the structural variation with inhibition of
[3H]WIN35,428, [3H]paroxetine, and [3H]nisoxetine binding at
the DAT, 5-HTT, and NET, respectively.25 The information was used
muscarinic, and
r
receptors as well as sodium channels.6–9 The
behavioral and reinforcing effects of cocaine result primarily from
inhibition of the DAT and subsequent increases in extracellular lev-
els of dopamine (DA), which in turn stimulate postsynaptic DA
receptors.4,7,10–15 Hence, the discovery and development of potent
and selective DAT inhibitors represents one of the promising ap-
proaches for the treatment of cocaine abuse. Several lines of evi-
dence have suggested that inhibition of the 5-HTT can also
modulate the reinforcing properties of cocaine.14,16–18 Animal
behavior studies demonstrated that selective serotonin (5-HT) up-
take inhibitors as well as dopamine uptake inhibitors can attenuate
cocaine-induced stimulant and reinforcing effects.19,20 Accord-
ingly, the mixed action inhibitors of DAT and 5-HTT have received
* Corresponding author. Tel.: +1 919 541 6328; fax: +1 919 541 6499.
E-mail address: cjin@rti.org (C. Jin).
Figure 1. Structures of cocaine (1) and 3b-phenyltropanes.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.052

C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
5127
as an indication of the compound’s potential ability to inhibit up-
CH3
N
CH3
N
take of the DA, 5-HT, and norepinephrine (NE) neurotransmitters.
Over the last decade, we and others have synthesized a large num-
ber of 3-phenyltropane analogues with 3b-phenyltropane-2b-car-
boxylic acid methyl ester (WIN35,065-2, 2) as the lead
compound, and evaluated them for binding at monoamine trans-
porters in order to identify the key structural features required
for potent and selective monoamine transporter inhibitors.6,25–34
Generally, the overall tropane configuration, the substituents and
substitution pattern on the 3-aromatic ring, the nature of the
2b-subsitituents, and the N-substitution are all important for the
ligand recognition site interaction. One of the most studied com-
pounds, the DAT selective inhibitor 3b-(4-chlorophenyl)-2b-[3-
(40-methylphenyl)isoxazol-5-yl]tropane (RTI-336, 6) is currently
in advanced preclinical development.35–37
In order to gain a better understanding of the molecular mech-
anisms of cocaine actions in the brain and find highly potent and
selective monoamine uptake inhibitors, we have continued our
SAR studies of 2. In a recent study, we reported that 3b-(4-
methoxyphenyl)tropane-2b-carboxylic acid methyl ester (5) pos-
sessed high affinity at the DAT (IC50 = 6.5 nM) and 5-HTT
(Ki = 4.3 nM), while having much less affinity at the NET
(Ki = 1110 nM).23 Thus, 5 is a promising lead compound to further
develop ligands with high affinities for both the DAT and 5-HTT,
and low affinity for the NET. In this study, we replaced the 40-meth-
oxy group of the 3b-phenyl ring in 5 with the corresponding bio-
isosteric 40-methylthio group and further characterized the SAR
of this type of compound for binding at the DAT, 5-HTT, and NET.
We report herein the synthesis and monoamine transporter
binding properties of novel 3b-(4-alkylthiophenyl)tropanes 7a–e,
3b-(4-methylsulfinylphenyl) and 3b-(4-methylsulfonylphenyl)tro-
pane analogues 7f–h, and 3b-(4-alkylthiophenyl)nortropane deriv-
atives 8–11 (Fig. 2).
CO2CH3
CO2CH3
a
SR
12
7a, R = CH3
7b, R = C2H5
7c, R = CH(CH3)2
7d, R = CF3
Scheme 1. Reagents and conditions: (a) Grignard reagent, ꢀ45 °C, 2 h, then ꢀ78 °C,
TFA.
sired 3b-(3-bromo-4-methylthiophenyl)tropane 7e in 13% yield,
as well as oxidation products 3b-(3-bromo-4-methylsulfinylphe-
nyl)tropane 7f and 3b-(4-methylsulfinylphenyl)tropane 7g in 15%
and 34% yields, respectively (Scheme 2). Use of 1 equiv of bromine
didn’t improve the bromination reaction as judged by TLC analysis.
Oxidation of 7a using 30% hydrogen peroxide in acetic acid pro-
vided the sulfone analogue 7h in 84% yield.
The synthesis of 3b-(4-alkylthiophenyl)nortropane analogues
8–11 is presented in Scheme 3. Treatment of 3-phenyltropanes
7a,b with 1-chloroethyl chloroformate afforded the corresponding
(1-chloroethyl)urethane intermediates, which were converted to
the N-nortropanes 8a,b in 86% and 87% yields, respectively, by sol-
volysis with methanol.39 N-Alkylation of 8a,b with 1-bromo-3-
fluoropropane using potassium carbonate in acetonitrile afforded
N-(3-fluoropropyl)nortropane analogues 9a,b in 94% and 87%
yields, respectively. Using similar conditions, 8a,b were alkylated
with allyl bromide in the presence of catalytic potassium iodide
to provide 10a,b in 79% and 83% yields, respectively. Finally, the
N-propylnortropanes 11a,b were prepared in 60–88% yield by
hydrogenation of the corresponding N-ally analogues 10a,b over
10% palladium on carbon. The 1H NMR data of the target com-
pounds are in agreement with the assigned structures. The chem-
ical shift and coupling pattern of the C(2)–H and C(3)–H are
consistent with previously reported compounds that possess the
2b,3b-stereochemistry.40–42
2. Chemistry
All the 3-phenyltropane compounds described herein were pre-
pared starting from natural (ꢀ)-cocaine, and therefore, they are
optically active and possess the same absolute configuration as
(ꢀ)-cocaine. The synthesis of 3b-(4-alkylthiophenyl)tropanes
7a–e, and 3b-(4-methylsulfinylphenyl) and 3b-(4-methylsulfonyl-
phenyl)tropane analogues 7f–h is outlined in Schemes 1 and 2.
Conjugate addition38 of the appropriate Grignard reagent to anhy-
droecgonine methyl ester (12) at ꢀ45 °C in ethyl ether followed by
the addition of trifluoroacetic acid (TFA) afforded 7a–c in good
yields ranging from 61% to 86% (Scheme 1). The addition of 4-tri-
fluoromethylthiophenyl magnesium bromide to 12 gave only 7%
yield (40% based on the recovered 12) of 7d. Bromination of 3b-
(4-methylthiophenyl)tropane-2b-carboxylic acid methyl ester
(7a) with 2 equivalents of bromine in acetic acid afforded the de-
3. Biology
Binding affinities at the DAT, 5-HTT, and NET represent inhibi-
tion of 0.5 nM [3H]WIN35,428, 0.2 nM [3H]paroxetine, and
0.5 nM [3H]nisoxetine binding, respectively, determined as previ-
ously reported.41,42 The results of the binding studies, along with
binding data of cocaine and 523 for comparison are listed in Tables
1 and 2. The DAT has two binding sites, and thus IC50 values are re-
ported. Since the 5-HTT and NET have only one binding site, Ki val-
ues were calculated for inhibition of binding at these two
transporters.
4. Results and discussion
SAR studies of the 3-phenyltropane class of monoamine uptake
inhibitors from our laboratory, as well as from others, have ad-
dressed the key structural features required for binding to the
DAT, as well as the 5-HTT and NET.25,31,43 The binding affinity
and selectivity of compounds for the monoamine transporter is
highly dependent on the nature and position of the substituents
on the 3b-phenyl ring.25,31,44 Recently, we reported that the 40-
methoxy analogue 5 is selective for both the DAT (IC50 = 6.5 nM)
and 5-HTT (Ki = 4.3 nM) relative to the NET (Ki = 1110 nM).23 In this
study, we replaced the 40-methoxy group of 5 with the bioisosteric
40-methylthio group to give 3b-(4-methylthiophenyl)tropane-2b-
carboxylic acid methyl ester (7a). We also synthesized a number
of 3b-(4-alkylthiophenyl) analogues of 7a and expanded the
Figure 2. Structures of 3b-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphe-
nyl)tropane and 3b-(4-alkylthiophenyl)nortropane derivatives.

5128
C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
Scheme 2. Reagents and conditions: (a) Br2, AcOH, 0 °C; (b) 30% H2O2, AcOH, room temperature.
Scheme 3. Reagents and conditions: (a) 1-chloroethyl chloroformate, 1,2-dichloroethane, reflux; (b) CH3OH, reflux; (c) 1-bromo-3-fluoropropane, K2CO3, CH3CN, reflux; (d)
allyl bromide, KI, K2CO3, CH3CN, room temperature; (e) 10% Pd/C, H2, EtOH.
Table 1
Monoamine transporter binding properties of 3b-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropane derivatives
Compda
R
X
n
DAT, IC50b (nM) [3H]WIN35,428
5-HTT, Kib (nM) [3H]paroxetine
NET, Kib (nM) [3H]nisoxetine
NET/DAT ratio
NET/5-HTT ratio
Cocainec
89.1
6.5 1.3
95
1990
22
171
24
5
21
5c
4.3 0.5
0.7 0.2
4.5 0.5
23
8
0.6 0.2
3.2 0.4
4.3 0.6
208 45
1110 64
220 10
1170 300
258
314
260
7
238
202
216
120
48
7a
7b
7c
7d
7e
7f
7g
7h
CH3
H
H
H
H
Br
Br
H
H
0
0
0
0
0
1
1
2
9
3
C2H5
CH(CH3)2
CF3
CH3
CH3
232 34
16
200 70
10.1
76 18
91 16
>10,000
2
2
2
129
2
8
1900 300
121 12
690 80
515 60
>10,000
10
12
9
6
1
1
CH3
CH3
a
All compounds were tested as the HCl salt.
All values are means standard error of three or four experiments performed in triplicate.
Data taken from Ref. 23.
b
c
3b-(4-methylthiophenyl)tropane to the corresponding 3b-(4-
methylsulfinylphenyl) and 3b-(4-methylsulfonylphenyl)tropanes
as well as 3b-(4-alkylthiophenyl)nortropanes with variants of the
N-substituents to further characterize the SAR of this type of
compound. The ratio of Ki/IC50 values of NET/DAT and the ratio of
Ki values of NET/5-HTT were calculated as a measure of the
in vitro selectivity of the compounds for the DAT relative to the
NET and the 5-HTT relative to the NET, respectively. As shown in
Table 1, replacement of the 40-methoxy group of 5 with the 40-
methylthio group afforded 7a with a comparable DAT affinity as
that of 5 (9 nM vs 6.5 nM) and enhanced affinities for both the 5-
HTT and NET. The magnitude of increase at the 5-HTT is more than
that of the NET, leading to increased selectivity for the 5-HTT rela-
tive to the NET (NET/5-HTT ratio of 314 of 7a vs 258 of 5). Thus, 7a

C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
5129
Table 2
Monoamine transporter binding properties of 3b-(4-alkylthiophenyl)nortropane derivatives
Compda
R1
R2
DAT, IC50c (nM) [3H]WIN35,428
5-HTT, Kic (nM) [3H]paroxetine
NET, Kic (nM) [3H]nisoxetine
NET/DAT ratio
NET/5-HTT ratio
7a
CH3
CH3
CH3
CH3
CH3
H
FCH2CH2CH2
CH2@CHCH2
CH3CH2CH2
CH3
9
28
112
71 25
3
6
0.7 0.2
0.19 0.01
220 10
24
0.8
9
28
16
5
0.7
2
2
314
110
320
364
211
260
94
74
43
41
8ab
9a
21
6
2
3
1
960 100
2000 500
1200 140
1170 300
118 13
>2000
10a
11a
7b
5.5 0.8
5.7 0.6
4.5 0.5
1.26 0.05
CH3
74 20
C2H5
C2H5
C2H5
C2H5
C2H5
232 34
177 62
1200 200
1100 100
900 300
8bb
9b
H
FCH2CH2CH2
CH2@CHCH2
CH3CH2CH2
27
47
49
2
3
6
10b
11b
>2000
>2000
2
a
Compounds were tested as the HCl salt.
Compounds were tested as the tartrate salt.
All values are means standard error of three or four experiments performed in triplicate.
b
c
is more potent at the 5-HTT and more selective for the 5-HTT over
the NET than 5. Changing the 40-methylthio group of 7a with a
slightly larger 40-ethylthio group resulted in 7b, which had less po-
tency for all three monoamine transporters, with the biggest loss of
affinity at the DAT (232 nM vs 9 nM of 7a). Somewhat surprisingly,
the 40-isopropylthio analogue 7c possessed a similar affinity at the
DAT (16 nM vs 9 nM of 7a) and slightly enhanced affinity at the 5-
HTT (129 nM vs 220 nM of 7a) relative to 7a. Compound 7d with
an electron-withdrawing trifluoromethyl group also had loss of po-
tency compared to 7a. We previously found that a combination of
30-halogen atoms with 40-substituents on the 3b-phenyl ring usu-
ally led to enhanced affinity at the DAT.25 The addition of a bromo
group ortho to the 4’-methylthio group of 7a, however, had almost
no effect on binding affinity at the DAT, 5-HTT, and NET. The 40-
methylsulfinyl compounds 7f and 7g were less potent than the cor-
responding 4’-methylthio analogues 7e and 7a, respectively, while
still having reasonable affinities at all three transporters. The 40-
methylsulfonyl analogue 7h had much less affinity, in particular
respectively, showed less affinities at all three transporters than
the N-methyl substituted 7a, though they still possessed apprecia-
ble affinities at the 5-HTT with Ki values ranging from 3 nM to
5.7 nM. The similar affinities of 10a and 11a at the DAT and 5-
HTT suggest that electronic as well as steric factors of N-substitu-
ents may not play an important role in receptor binding of these
compounds. An analogous effect was observed upon replacement
of the N-methyl group in 3b-(4-ethylthiophenyl)tropane 7b by
hydrogen or alkyl groups to give 8b–11b, while in this case, they
all possessed less affinities than the corresponding 40-methylthio
analogues.
In summary, a new series of 3b-(4-alkylthio, 4-methylsulfinyl,
and 4-methylsulfonylphenyl)tropane and 3b-(4-alkylthiophe-
nyl)nortropane derivatives were synthesized and evaluated for
their monoamine transporter binding affinities. With exception
of the 4’-methylsulfonyl analogue 7h, all the tested compounds
exhibited high binding affinities at the 5-HTT with Ki values rang-
ing from 0.19 nM to 49 nM. The 3b-(4-methylthiophenyl)nortro-
pane 8a had a Ki value of 0.19 nM at the 5-HTT and also
appreciable affinity at the DAT and NET (IC50 = 28 nM and
Ki = 21 nM, respectively), and thus is the most potent compound
for all three transporters in the series. Compound 7a and its N-
(3-fluoropropyl) analogue 9a and N-allyl analogue 10a are the
most selective compounds for the 5-HTT relative to the NET. How-
ever, none of the tested compounds showed good selectivity for
the DAT over the NET. This study provided useful SAR information
for further design of potent and selective monoamine uptake
inhibitors.
for the DAT and NET with IC50 and Ki values >10 lM, respectively.
With the exception of 7c, all the 40-alkylthiol and 40-methylsulfinyl
tropanes 7a, 7b, and 7d–g possessed nanomolar or subnanomolar
affinity at the 5-HTT (Ki = 0.6–4.5 nM) and good selectivity for
the 5-HTT over the NET (NET/5-HTT = 120–314). However, none
of these compounds had selectivity similar to 5 for both the DAT
and 5-HTT relative to the NET.
The tertiary amino nitrogen of cocaine and its 3-phenyltropane
analogues may contribute to the electrostatic or hydrogen-binding
interactions between the ligand and transporter binding site.25
Consequently, N-substituents that change electron density at the
nitrogen atom should affect their binding properties, possibly with
gains in selectivity for specific transporters. In our SAR studies, we
noticed that removing the N-methyl group from 3b-phenyltro-
panes resulted in enhanced affinity for binding at the 5-HTT and
NET with virtually no change in binding affinity at the DAT.25 In
addition, studies from other groups showed that N-substituted
analogues of 3b-(4-iodophenyl)tropane yielded higher 5-HTT affin-
ity.45,46 Replacement of the N-methyl group by hydrogen in 3b-(4-
methylthiophenyl)tropane 7a to give N-nortropane 8a exhibited
approximately 4- and 10-fold increases at the 5-HTT and NET,
respectively, but had threefold less affinity at the DAT (Table 2).
Compound 8a with an IC50 value of 28 nM at the DAT, and Ki values
of 0.19 nM and 21 nM at 5-HTT and NET, respectively, is a potent
and nonselective monoamine uptake inhibitor. N-Substituents of
3-fluoropropyl, allyl, and propyl groups in 9a, 10a, and 11a,
5. Experimental
Melting points were determined using a MEL-TEMP II capillary
melting point apparatus and are uncorrected. Nuclear magnetic
resonance (1H NMR and 13C NMR) spectra were obtained on a Bru-
ker Avance DPX-300 MHz NMR spectrometer. Chemical shifts are
reported in parts per million (ppm) with reference to internal sol-
vent. Mass spectra (MS) were run on a Perkin–Elmer Sciex API 150
EX mass spectrometer equipped with ESI (turbospray) source or on
a Hewlett Packard 5989A instrument by electron impact. Elemen-
tal analyses were performed by Atlantic Microlab Inc., Atlanta, GA.
Optical rotations were measured on an AutoPol III polarimeter,
purchased from Rudolf Research. Analytical thin-layer chromatog-
raphy (TLC) was carried out using EMD Silica Gel 60 F254 TLC plates.
TLC visualization was achieved with a UV lamp or in an iodine

5130
C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
chamber. Flash column chromatography was done on a Combi-
Flash Companion system using Isco prepacked silica gel columns
or using EM Science Silica Gel 60 Å (230–400 mesh). Unless other-
wise stated, reagent-grade chemicals were obtained from commer-
cial sources and were used without further purification. All
moisture- and air-sensitive reactions and reagent transfers were
carried out under dry nitrogen.
(300 MHz; CDCl3) d 7.30 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz,
2H), 3.62–3.53 (m, 1H), 3.48 (s, 3H), 3.42–3.22 (m, 2H), 2.97
(ddd, J = 12.5, 5.1, 5.1 Hz, 1H), 2.92–2.87 (m, 1H), 2.58 (ddd,
J = 12.5, 12.6, 2.4 Hz, 1H), 2.30–2.04 (m, 5H), 1.78–1.54 (m, 3H),
1.26 (d, J = 6.0 Hz, 6H); 13C NMR (75 MHz; CDCl3) d 172.2, 142.2,
132.5, 132.2, 128.0, 65.5, 62.5, 53.0, 51.3, 42.1, 38.6, 34.2, 33.7,
26.1, 25.3, 23.4; MS (ESI) m/z 334.4 (M+1). The free base was con-
verted to the hydrochloride salt: mp 165–166 °C; ½a D20
ꢀ116 (c
ꢂ
5.1. 3b-(4-Methylthiophenyl)tropane-2b-carboxylic acid methyl
ester (7a)
0.38, CH3OH). Anal. Calcd for C19H27NO2SꢃHClꢃ0.75H2O: C, 59.51;
H, 7.75; N, 3.65. Found: C, 59.62; H, 7.89; N, 3.37.
Magnesium (0.72 g, 0.03 mol) was weighed into a 100 mL round
bottom flask. A single crystal of iodine was added and the system
was flushed with nitrogen and flame dried. After cooling to room
temperature, anhydrous Et2O (2 mL) was added. A solution of 4-
bromothioanisole (5.08 g, 0.025 mol) in anhydrous Et2O (20 mL)
was prepared and 2 mL was added. After addition of a catalytic
amount of 1,2-dibromoethane, the orange iodine color disappeared
which indicated the initiation was successful. The rest of the 4-
bromothioanisole solution was added slowly over 30 min while
the solution was kept refluxing. After addition, the reaction mix-
ture was refluxed for 1 h. The fleshly prepared Grignard solution
was then diluted with anhydrous Et2O (76 mL) and cooled to
ꢀ45 °C. A solution of anhydroecgonine methyl ester (12) (1.80 g,
0.01 mol) in 1:1 mixture of CH2Cl2–Et2O (15 mL) was added slowly
and the reaction mixture was stirred at ꢀ45 °C for another 2 h.
After cooling to ꢀ78 °C, the reaction was quenched by slow addi-
tion of a solution of TFA (4.60 mL, 60.0 mmol) in Et2O (6 mL). The
mixture was warmed to room temperature and 6 N HCl (40 mL)
was added. The aqueous layer was separated, made basic to pH
11 using NH4OH, and extracted with EtOAc (3 ꢁ 100 mL). The com-
bined EtOAc extracts were washed with brine (3 ꢁ 50 mL), dried
(Na2SO4), and concentrated under reduced pressure. Flash column
chromatography of the crude product on silica gel using 0?20%
Et2O in hexane with the addition of 5% Et3N afforded 7a (2.60 g,
87%) as an oil. 1H NMR (300 MHz; CDCl3) d 7.18 (s, 4H), 3.60–
3.51 (m, 1H), 3.50 (s, 3H), 3.42–3.34 (m, 1H), 2.96 (ddd, J = 12.8,
5.1, 5.1 Hz, 1H), 2.90–2.84 (m, 1H), 2.57 (ddd, J = 12.6, 12.8,
3.0 Hz, 1H), 2.45 (s, 3H), 2.30–2.01 (m, 5H), 1.78–1.54 (m, 3H);
13C NMR (75 MHz; CDCl3) d 171.6, 139.9, 135.0, 127.6, 126.3,
65.0, 62.0, 52.4, 50.7, 41.7, 33.8, 33.1, 25.6, 24.9, 15.8; MS (EI) m/
z 305 (M+). The free base was converted to the hydrochloride salt:
5.4. 3b-(4-Trifluoromethylthiophenyl)tropane-2b-carboxylic
acid methyl ester (7d)
The procedure for 7a was followed using 900 mg (5.00 mmol) of
12 to give 0.12 g (7%) of 7d as a solid: mp 64–65 °C; 1H NMR
(300 MHz; CDCl3) d 7.60–7.51 (m, 2H), 7.37–6.27 (m, 2H), 3.65–
3.55 (m, 1H), 3.49 (s, 3H), 3.41–3.32 (m, 1H), 3.02 (ddd, J = 12.5,
5.1, 5.1 Hz, 1H), 2.97–2.88 (m, 1H), 2.56 (ddd, J = 12.6, 12.5,
2.7 Hz, 1H), 2.33–2.05 (m, 5H), 1.80–1.54 (m, 3H); 13C NMR
(75 MHz; CDCl3) d 172.0, 146.9, 136.1, 129.9 (q, JC,F = 306 Hz),
128.7, 121.4 (q, JC,F = 1.9 Hz), 65.5, 62.3, 52.8, 51.3, 42.1, 34.0,
33.9, 26.0, 25.4; MS (EI) m/z 359 (M+). The free base was converted
to the hydrochloride salt: mp 169–171 °C; ½a D20
ꢀ113 (c 0.35,
ꢂ
CH3OH). Anal. Calcd for C17H20F3NO2SꢃHClꢃ0.25H2O: C, 51.00; H,
5.41; N, 3.50. Found: C, 50.87; H, 5.52; N, 3.37.
5.5. 3b-(3-Bromo-4-methylthiophenyl)tropane-2b-carboxylic
acid methyl ester (7e), 3b-(3-bromo-4-methylsulfinylphenyl)
tropane-2b-carboxylic acid methyl ester (7f), and 3b-(4-
methylsulfinylphenyl)tropane-2b-carboxylic acid methyl ester
(7g)
To a stirred solution of 7a (153 mg, 0.50 mmol) in AcOH (2 mL)
at room temperature under nitrogen was added Br2 (0.056 mL,
1.00 mmol). After stirring for 1 h, the reaction mixture was poured
into a mixture of NaHCO3 and ice. The resultant solution was ex-
tracted with CH2Cl2 (3 ꢁ 30 mL). The combined CH2Cl2 extracts
were washed with 20% Na2S2O3 (30 mL), brine (30 mL), dried
(Na2SO4), and concentrated under reduced pressure. Flash column
chromatography of the crude product on silica gel using 0?5%
Et2O in hexane with the addition of 5% Et3N followed by 0?30%
CH3OH in CH2Cl2 with the addition of 1% NH4OH afforded 7e
(25.0 mg, 13%), 7f (30.0 mg, 15%), and 7g (55.0 mg, 34%).
mp 157–158 °C; ½a D20
ꢀ128 (c 0.29, CH3OH). Anal. Calcd for
ꢂ
C17H23NO2SꢃHClꢃ1.75H2O: C, 54.68; H, 7.42; N, 3.75. Found: C,
54.79; H, 7.50; N, 3.77.
Compound 7e: oil; 1H NMR (300 MHz; CDCl3) d 7.39 (d,
J = 1.5 Hz, 1H), 7.23 (dd, J = 8.1, 1.5 Hz, 1H), 7.05 (d, J = 8.1 Hz,
1H), 3.64–3.54 (m, 1H), 3.53 (s, 3H), 3.42–3.33 (m, 1H), 2.94
(ddd, J = 12.4, 4.8, 4.8 Hz, 1H), 2.88–2.81 (m, 1H), 2.53 (ddd,
J = 12.4, 12.3, 2.7 Hz, 1H), 2.44 (s, 3H), 2.30–2.02 (m, 5H), 1.80–
1.57 (m, 3H); 13C NMR (75 MHz; CDCl3) d 172.1, 141.7, 136.6,
132.0, 127.1, 125.6, 121.8, 65.5, 62.4, 52.8, 51.4, 42.1, 34.2, 33.4,
26.1, 25.4, 16.1; MS (ESI) m/z 384.3 (M+1) (79Br), 386.2 (M+1)
5.2. 3b-(4-Ethylthiophenyl)tropane-2b-carboxylic acid methyl
ester (7b)
The procedure for 7a was followed using 1.80 g (0.01 mol) of 12
to give 1.98 g (62%) of 7b as a solid: mp 55–56 °C; 1H NMR
(300 MHz; CDCl3) d 7.30–7.17 (m, 4H), 3.63–3.53 (m, 1H), 3.49 (s,
3H), 3.40–3.32 (m, 1H), 3.05–2.85 (m, 4H), 2.57 (ddd, J = 12.6,
12.6, 3.0 Hz, 1H), 2.28–2.00 (m, 5H), 1.80–1.55 (m, 3H), 1.28 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz; CDCl3) d 171.6, 140.7, 133.1,
128.7, 127.6, 65.0, 62.0, 52.4, 50.7, 41.7, 33.7, 33.2, 27.6, 25.6,
24.9, 14.2; MS (ESI) m/z 320.2 (M+1). The free base was converted
(
81Br). The free base was converted to the hydrochloride salt: mp
148–150 °C; –90 (c 0.30, CH3OH). Anal. Calcd for
½ ꢂ
a 2D0
C17H22BrNO2SꢃHClꢃ0.5H2O: C, 47.51; H, 5.63; N, 3.26. Found: C,
47.64; H, 5.99; N, 3.00.
Compound 7f: solid; mp 63–66 °C; 1H NMR (300 MHz; CDCl3) d
7.82 (dd, J = 8.7, 2.4 Hz, 1H), 7.50–7.40 (m, 2H), 3.68–3.58 (m, 1H),
3.54 (s, 3H), 3.47–3.37 (m, 1H), 3.10–2.90 (m, 2H), 2.79 (s, 3H),
2.68-2.52 (m, 1H), 2.32–2.03 (m, 5H), 1.80–1.55 (m, 3H); 13C
NMR (75 MHz; CDCl3) d 171.8, 148.8, 142.4, 132.0, 127.7, 125.2,
118.2, 65.3, 62.2, 52.5, 51.4, 42.1, 41.9, 33.9, 33.7, 25.8, 25.2; MS
(ESI) m/z 400.3 (M+1) (79Br), 402.2 (M+1) (81Br). The free base
to the hydrochloride salt: mp 155–157 °C; ½a D20
ꢂ
–120° (c 0.35,
CH3OH). Anal. Calcd for C18H25NO4SꢃHClꢃ1.5H2O: C, 56.46; H,
7.63; N, 3.66. Found: C, 56.70; H, 7.61; N, 3.65.
5.3. 3b-(4-Isopropylthiophenyl)tropane-2b-carboxylic acid
methyl ester (7c)
was converted to the hydrochloride salt: mp 148–150 °C; ½a D20
ꢂ
The procedure for 7a was followed using 850 mg (4.68 mmol) of
12 to give 0.96 g (61%) of 7c as a solid: mp 103–105 °C; 1H NMR
ꢀ91 (c 0.28, CH3OH). Anal. Calcd for C17H22BrNO3SꢃHClꢃ1.5H2O: C,
44.02; H, 5.65; N, 3.02. Found: C, 43.75; H, 5.65; N, 2.99.

C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
5131
Compound 7g: solid; mp 94–97 °C; 1H NMR (300 MHz; CDCl3) d
7.55 (d, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 3.70–3.60 (m, 1H),
3.50 (s, 3H), 3.47–3.37 (m, 1H), 3.10-3.02 (m, 1H), 2.98–2.90 (m,
1H), 2.70 (s, 3H), 2.69–2.52 (m, 1H), 2.32–2.05 (m, 5H), 1.86–1.60
(m, 3H); 13C NMR (75 MHz; CDCl3) d 171.8, 146.7, 142.7, 128.4,
123.2, 65.2, 62.1, 52.5, 51.2, 43.8, 41.9, 33.8, 25.8, 25.1; MS (ESI)
m/z 322.3 (M+1). The free base was converted to the hydrochloride
m/z 306.1 (M+1). The free base was converted to the tartrate salt:
mp 108–110 °C;
½
a 2D0
ꢂ
ꢀ79 (c 0.21, CH3OH); Anal. Calcd for
C21H29NO8Sꢃ0.25H2O: C, 54.83; H, 6.46; N, 3.04. Found: C, 54.69;
H, 6.45; N, 3.02.
5.9. 3b-(4-Methylthiophenyl)-8-(3-fluoropropyl)nortropane-2b-
carboxylic acid methyl ester (9a)
salt: mp 115 °C (fusion); ½a D20
ꢀ115 (c 0.31, CH3OH). Anal. Calcd for
ꢂ
C17H23NO3SꢃHClꢃ1.5H2O: C, 53.05; H, 7.07; N, 3.64. Found: C, 53.30;
To a stirred mixture of 8a (146 mg, 0.50 mmol) and K2CO3
(138 mg, 1.00 mmol) in CH3CN (5 mL) at room temperature under
nitrogen was added 1-bromo-3-fluoro-propane (93.0 mg,
0.60 mmol). After refluxing for 2 h, the reaction mixture was
cooled to room temperature and diluted with EtOAc (50 mL). The
mixture was washed with brine (3 ꢁ 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. Flash column chromatogra-
phy of the crude product on silica gel using 0?5% Et2O in hexane
with the addition of 5% Et3N afforded 9a (165 mg, 94%) as an oil: 1H
NMR (300 MHz; CDCl3) d 7.18 (s, 4H), 4.60 (t, J = 6.0 Hz, 1H), 4.44 (t,
J = 6.0 Hz, 1H), 3.71–3.64 (m, 1H), 3.49 (s, 3H), 3.43–3.37 (m, 1H),
2.98 (ddd, J = 12.6, 4.8, 4.8 Hz, 1H), 2.93–2.87 (m, 1H), 2.56 (ddd,
J = 12.6, 12.6, 2.7 Hz, 1H), 2.45 (s, 3H), 2.43–2.30 (m, 2H), 2.18–
1.92 (m, 2H), 1.86–1.58 (m, 5H); 13C NMR (75 MHz; CDCl3) d
172.0, 140.5, 135.3, 128.0, 126.7, 82.4 (d, JC,F = 162 Hz), 63.4,
61.6, 52.9, 51.0, 49.4 (JC,F = 5.7 Hz), 34.1 (d, JC,F = 18.5 Hz), 30.4,
30.1, 26.2, 26.1, 16.3; MS (ESI) m/z 352.6 (M+1). The free base
H, 7.01; N, 3.78.
5.6. 3b-(4-Methylsulfonylphenyl)tropane-2b-carboxylic acid
methyl ester (7h)
To a stirred solution of 7a (500 mg, 1.60 mmol) in AcOH (13 mL)
at room temperature was added 30% H2O2 (4.66 mL). After stirring
at room temperature for 20 h, the reaction mixture was poured
into a mixture of NaHCO3 and Na2SO3 in water, and extracted with
EtOAc (3 ꢁ 50 mL). The combined EtOAc extracts were washed
with brine (3 ꢁ 50 mL) and dried (Na2SO4). Removal of the solvent
under reduced pressure afforded 7h (470 mg, 84%) as a solid: mp
123–124 °C; 1H NMR (300 MHz; CDCl3) d 7.89–7.80 (m, 2H),
7.50–7.42 (m, 2H), 3.67–3.58 (m, 1H), 3.52 (s, 3H), 3.43–3.34 (m,
1H), 3.02–2.92 (m, 5H), 2.61 (ddd, J = 12.3, 12.3, 2.7 Hz, 1H),
2.30–2.07 (m, 5H), 1.80–1.56 (m, 3H); 13C NMR (75 MHz; CDCl3)
d 171.6, 150.1, 137.7, 128.1, 126.8, 65.2, 62.0, 52.4, 51.1, 44.4,
41.8, 33.8, 33.6, 25.6, 25.1; MS (EI) m/z 337 (M+). The free base
was converted to the hydrochloride salt: mp 85–87 °C; ½a D20
ꢂ
ꢀ120 (c 0.53, CH3OH). Anal. Calcd for C19H26FNO2SꢃHClꢃ1.5 H2O:
was converted to the hydrochloride salt: mp 159–162 °C; ½a D20
ꢂ
C, 54.99; H, 7.29; N, 3.38. Found: C, 55.09; H, 7.14; N, 3.43.
ꢀ106 (c 0.74, CH3OH); Anal. Calcd for C17H23NO4SꢃHClꢃ1.25H2O:
C, 51.51; H, 6.74; N, 3.53. Found: C, 51.65; H, 6.58; N, 3.42.
5.10. 3b-(4-Ethylthiophenyl)-8-(3-fluoropropyl)nortropane-2b-
carboxylic acid methyl ester (9b)
5.7. 3b-(4-Methylthiophenyl)nortropane-2b-carboxylic acid
methyl ester (8a)
The procedure for 9a was followed using 100 mg (0.33 mmol) of
8b to give 105 mg (87%) of 9b as an oil: 1H NMR (300 MHz; CDCl3)
d 7.26–7.14 (m, 4H), 4.60 (t, J = 6.0 Hz, 1H), 4.44 (t, J = 6.0 Hz, 1H),
3.71–3.63 (m, 1H), 3.48 (s, 3H), 3.43–3.38 (m, 1H), 3.02–2.85 (m,
4H), 2.57 (ddd, J = 12.6, 12.6, 2.7 Hz, 1H), 2.44–2.31 (m, 2H),
2.26–1.92 (m, 2H), 1.86–1.57 (m, 5H), 1.28 (t, J = 7.4 Hz, 3H); 13C
NMR (75 MHz; CDCl3) d 172.0, 141.3, 133.5, 129.3, 128.1, 82.4 (d,
JC,F = 162 Hz), 63.4, 61.6, 53.0, 51.0, 49.4 (d, JC,F = 5.7 Hz), 34.1 (d,
JC,F = 14.6 Hz), 30.4, 30.1, 28.2, 26.2, 26.1, 14.6; MS (ESI) m/z
366.5 (M+1); The free base was converted to the hydrochloride
A mixture of 7a (310 mg, 1.00 mmol) and 1-chloroethyl chloro-
formate (0.43 mL, 4.00 mmol) in 1,2-dichloroethane (3 mL) was re-
fluxed under nitrogen for 20 h. The reaction mixture was
concentrated under reduced pressure and the residue was dis-
solved in MeOH (10 mL). After refluxing for 5 h, the mixture was
cooled to room temperature and concentrated under reduced pres-
sure. The residue was made basic using NaHCO3 and extracted
with CH2Cl2 (3 ꢁ 50 mL). The combined CH2Cl2 extracts were dried
(Na2SO4) and concentrated under reduced pressure. Flash column
chromatography of the crude product on silica gel using 0?5%
CH3OH in CH2Cl2 with the addition of 1% NH4OH afforded 8a
(250 mg, 86%) as a solid: mp 48–49 °C; 1H NMR (300 MHz; CDCl3)
d 7.25–7.09 (m, 4H), 3.78–3.68 (m, 2H), 3.38 (s, 3H), 3.20 (ddd,
J = 12.3, 5.4, 5.4 Hz, 1H), 2.73 (s, 2H), 2.52–2.33 (m, 4H), 2.20–
1.97 (m, 2H), 1.85–1.55 (m, 3H); 13C NMR (75 MHz; CDCl3) d
173.8, 139.4, 136.2, 127.9, 126.7, 56.4, 53.7, 51.2, 35.3, 33.8, 29.1,
27.7, 16.0; MS (ESI) m/z 292.1 (M+1). The free base was converted
salt: mp 165–167 °C; ½a D20
ꢀ118 (c 0.28, CH3OH). Anal. Calcd for
ꢂ
C20H28FNO2SꢃHCl: C, 59.76; H, 7.27; N, 3.48. Found: C, 59.76; H,
7.23; N, 3.26.
5.11. 3b-(4-Methylthiophenyl)-8-allylnortropane-2b-carboxylic
acid methyl ester (10a)
To a stirred mixture of 8a (582 mg, 2.00 mmol), K2CO3 (552 mg,
4.00 mmol), and KI (10.0 mg) in CH3CN (10 mL) at room tempera-
ture under nitrogen was added allyl bromide (0.21 mL, 2.40 mmol).
After stirring at room temperature for 3 h, the reaction mixture
was diluted with EtOAc (50 mL). The mixture was washed with
brine (3 x 30 mL), dried (Na2SO4), and concentrated under reduced
pressure. Flash column chromatography of the crude product on
silica gel using 0?5% Et2O in hexane with the addition of 5%
Et3N afforded 10a (520 mg, 79%) as a solid: mp 46–48 °C; 1H
NMR (300 MHz; CDCl3) d 7.21–7.15 (m, 4H), 5.86–5.68 (m, 1H),
5.18–4.94 (m, 2H), 3.71–3.64 (m, 1H), 3.49 (s, 3H), 3.47–3.41 (m,
1H), 3.08–2.96 (m, 2H), 2.92–2.78 (m, 2H), 2.60 (ddd, J = 12.6,
12.6, 2.7 Hz, 1H), 2.45 (s, 3H), 2.18–1.97 (m, 2H), 1.82–1.58 (m,
3H); 13C NMR (75 MHz; CDCl3) d 171.8, 140.2, 136.6, 135.2,
127.9, 126.5, 116.2, 61.9, 61.1, 56.6, 52.7, 50.8, 34.0, 33.8, 26.0,
25.8, 16.0; MS (ESI) m/z 332.5 (M+1). The free base was converted
to the tartrate salt: mp 118–121 °C; ½a D20
ꢀ103 (c 0.26, CH3OH).
ꢂ
Anal. Calcd for C20H27NO8S: C, 54.41; H, 6.16; N, 3.17. Found: C,
54.27; H, 6.15; N, 3.09.
5.8. 3b-(4-Ethylthiophenyl)nortropane-2b-carboxylic acid
methyl ester (8b)
The procedure for 8a was followed using 640 mg (2.00 mmol) of
7b to give 530 mg (87%) of 8b as a solid: mp 49–51 °C; 1H NMR
(300 MHz; CDCl3) d 7.24 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz,
2H), 3.80–3.68 (m, 2H), 3.37 (s, 3H), 3.34–3.15 (m, 2H), 2.90 (q,
J = 7.3 Hz, 2H), 2.80–2.70 (m, 1H), 2.40 (ddd, J = 12.9, 12.9, 2.4 Hz,
1H), 2.25–1.94 (m, 2H), 1.87–1.56 (m, 3H), 1.27 (t, J = 7.3 Hz, 3H);
13C NMR (75 MHz; CDCl3) d 173.7, 140.0, 134.4, 129.2, 127.8,
56.3, 53.7, 51.1, 51.0, 35.2, 33.6, 29.0, 27.8, 27.6, 14.3; MS (ESI)
to the hydrochloride salt: mp 82–84 °C; ½a D20
ꢀ78 (c 0.29, CH3OH).
ꢂ

5132
C. Jin et al. / Bioorg. Med. Chem. 17 (2009) 5126–5132
Anal. Calcd for C19H25NO2SꢃHClꢃ0.5H2O: C, 60.54; H, 7.22; N, 3.72.
References and notes
Found: C, 60.36; H, 7.32; N, 3.44.
1. Reith, M. E. A.; Meisler, B. E.; Sershen, H.; Lajtha, A. Biochem. Pharmacol. 1986,
35, 1123.
5.12. 3b-(4-Ethylthiophenyl)-8-allylnortropane-2b-carboxylic
acid methyl ester (10b)
2. Riddle, E. L.; Fleckenstein, A. E.; Hanson, G. R. AAPS J. 2005, 7, E847.
3. Heikkila, R. E.; Manzino, L. Eur. J. Pharmacol. 1984, 103, 241.
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6. Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med. Chem. 1992, 35, 969.
7. Kuhar, M. J.; Ritz, M. C.; Boja, J. W. Trends Neurosci. 1991, 14, 299.
8. Kalivas, P. W. Am. J. Addict. 2007, 16, 71.
9. Howell, L. L.; Kimmel, H. L. Biochem. Pharmacol. 2008, 75, 196.
10. Rocha, B. A.; Fumagalli, F.; Gainetdinov, R. R.; Jones, S. R.; Ator, R.; Giros, B.;
Miller, G. W.; Caron, M. G. Nat. Neurosci. 1998, 1, 132.
The procedure for 10a was followed using 270 mg (0.89 mmol)
of 8b to give 255 mg (83%) of 10b as a solid: mp 71–72 °C; 1H NMR
(300 MHz; CDCl3) d 7.29–7.14 (m, 4H), 5.85–5.68 (m, 1H), 5.18–
4.95 (m, 2H), 3.73–3.66 (m, 1H), 3.49 (s, 3H), 3.46–3.40 (m, 1H),
3.08–2.78 (m, 6H), 2.60 (ddd, J = 12.6, 12.6, 2.7 Hz, 1H), 2.19–2.04
(m, 2H), 1.80–1.55 (m, 3H), 1.28 (t, J = 7.5 Hz, 3H); 13C NMR
(75 MHz; CDCl3) d 171.9, 141.1, 136.7, 133.4, 129.1, 128.0, 116.3,
62.1, 61.2, 56.7, 52.8, 51.0, 34.1, 34.0, 28.0, 26.1, 25.9, 14.5; MS
(ESI) m/z 346.3 (M+1). The free base was converted to the hydro-
11. Wilcox, K. M.; Rowlett, J. K.; Paul, I. A.; Ordway, G. A.; Woolverton, W. L.
Psychopharmacology (Berl) 2000, 153, 139.
12. Wise, R. A.; Leeb, K.; Pocock, D.; Newton, P.; Burnette, B.; Justice, J. B.
Psychopharmacology (Berl) 1995, 120, 10.
13. Volkow, N. D.; Wang, G.-J.; Fischman, M. W.; Foltin, R. W.; Fowler, J. S.;
Abumrad, N. N.; Vitkun, S.; Logan, J.; Gatley, S. J.; Pappas, N.; Hitzemann, R.;
Shea, C. E. Nature 1997, 386, 827.
14. Ritz, M. C.; Lamb, R. J.; Goldberg, S. R.; Kuhar, M. J. Science 1987, 237, 1219.
15. Bergman, J.; Madras, B. K.; Johnson, S. E.; Spealman, R. D. J. Pharmacol. Exp. Ther.
1989, 251, 150.
chloride salt: mp 71–73 °C; ½a D20
ꢂ
–72 (c 0.29, CH3OH). Anal. Calcd
for C20H27NO2SꢃHClꢃ0.25H2O: C, 62.16; H, 7.43; N, 3.62. Found: C,
62.28; H, 7.65; N, 3.49.
16. Carroll, F. I.; Howell, L. L.; Kuhar, M. J. J. Med. Chem. 1999, 42, 2721.
17. Howell, L. L.; Carroll, F. I.; Votaw, J. R.; Goodman, M. M.; Kimmel, H. L. J.
Pharmacol. Exp. Ther. 2007, 320, 757.
5.13. 3b-(4-Methylthiophenyl)-8-propylnortropane-2b-
carboxylic acid methyl ester (11a)
18. Ritz, M. C.; Kuhar, M. J. J. Pharmacol. Exp. Ther. 1989, 248, 1010.
19. Howell, L. L.; Byrd, L. D. J. Pharmacol. Exp. Ther. 1995, 275, 1551.
20. Spealman, R. D. Psychopharmacology (Berl) 1993, 112, 93.
21. Blough, B. E.; Abraham, P.; Lewin, A. H.; Kuhar, M. J.; Boja, J. W.; Carroll, F. I. J.
Med. Chem. 1996, 39, 4027.
22. Blough, B. E.; Abraham, P.; Mills, A. C.; Lewin, A. H.; Boja, J. W.; Scheffel, U.;
Kuhar, M. J.; Carroll, F. I. J. Med. Chem. 1997, 40, 3861.
23. Jin, C.; Navarro, H. A.; Carroll, F. I. J. Med. Chem. 2008, 51, 8048.
24. Carey, R. J.; Huston, J. P.; Müller, C. P. Prog. Brain Res. 2008, 172, 347.
25. Carroll, F. I. J. Med. Chem. 2003, 46, 1775.
A mixture of 10a (130 mg, 0.40 mmol) and 10 wt% Pd/C
(26.0 mg) in EtOH was hydrogenated at 1 atm for 16 h. The mixture
was filtered through a short pad of Celite and the filtrate was con-
centrated under reduced pressure. Flash column chromatography
of the crude product on silica gel using 0?10% Et2O in hexane with
the addition of 3% Et3N afforded 11a (115 mg, 88%) as an oil: 1H
NMR (300 MHz; CDCl3) d 7.21–7.15 (m, 4H), 3.76–3.66 (m, 1H),
3.49 (s, 3H), 3.43–3.34 (m, 1H), 2.97 (ddd, J = 12.5, 5.1, 5.1 Hz,
1H), 2.93–2.87 (m, 1H), 2.57 (ddd, J = 12.5, 12.3, 2.7 Hz, 1H), 2.44
(s, 3H), 2.28–1.94 (m, 4H), 1.80–1.58 (m, 3H), 1.50–1.30 (m, 2H),
0.87 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz; CDCl3) d 172.2, 140.7,
135.3, 128.1, 126.8, 62.8, 62.0, 55.8, 53.0, 51.1, 34.3, 34.1, 26.3,
26.0, 22.4, 16.3, 11.9; MS (ESI) m/z 334.3 (M+1). The free base
26. Davies, H. M. L.; Saikali, E.; Huby, N. J. S.; Gilliat, V. J.; Matasi, J. J.; Sexton, T.;
Childers, S. R. J. Med. Chem. 1994, 37, 1262.
27. Xu, L.; Kelkar, S. V.; Lomenzo, S. A.; Izenwasser, S.; Katz, J. L.; Kline, R. H.;
Trudell, M. L. J. Med. Chem. 1997, 40, 858.
28. Carroll, F. I.; Lewin, A. H.; Mascarella, S. W. In Neurotransmitter Transporters:
Structure, Function, and Regulation; Reith, M. E. A., Ed., 2nd ed.; Humana Press:
Totowa, NJ, 2001.
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was converted to the hydrochloride salt: mp 83–85 °C; ½a D20
ꢂ
ꢀ115 (c 0.34, CH3OH); Anal. Calcd for C19H27NO2SꢃHClꢃ0.75H2O:
C, 59.51; H, 7.75; N, 3.65. Found: C, 59.78; H, 8.03; N, 3.27.
5.14. 3b-(4-Ethylthiophenyl)-8-propylnortropane-2b-carboxylic
acid methyl ester (11b)
The procedure for 11a was followed using 140 mg (0.41 mmol)
of 10b to give 85.0 mg (60%) of 11b as an oil: 1H NMR (300 MHz;
CDCl3) d 7.25–7.05 (m, 4H), 3.68–3.55 (m, 1H), 3.41 (s, 3H), 3.34–
3.23 (m, 1H), 2.94–2.75 (m, 4H), 2.50 (ddd, J = 12.5, 12.5, 2.7 Hz,
1H), 2.22–1.82 (m, 4H), 1.70–1.43 (m, 3H), 1.42–1.20 (m, 2H),
1.20 (t, J = 7.4 Hz, 3H), 0.79 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz;
CDCl3) d 172.1, 141.5, 133.4, 129.3, 128.1, 62.8, 61.9, 55.8, 53.0,
51.0, 34.3, 34.1, 28.2, 26.3, 26.0, 22.4, 14.6, 11.9; MS (ESI) m/z
348.0 (M+1). The free base was converted to the hydrochloride
salt: mp 78–80 °C; ½a D20
ꢀ124 (c 0.39, CH3OH). Anal. Calcd for
ꢂ
42. Carroll, F. I.; Gao, Y.; Rahman, M. A.; Abraham, P.; Parham, K.; Lewin, A. H.; Boja,
J. W.; Kuhar, M. J. J. Med. Chem. 1991, 34, 2719.
43. Singh, S. Chem. Rev. 2000, 100, 925.
C20H29NO2SꢃHClꢃ1.25H2O: C, 59.09; H, 8.06; N, 3.45. Found: C,
59.11; H, 8.15; N, 3.49.
44. Carroll, F. I.; Blough, B. E.; Nie, Z.; Kuhar, M. J.; Howell, L. L.; Navarro, H. A. J.
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45. Neumeyer, J. L.; Tamagnan, G.; Wang, S.; Gao, Y.; Milius, R. A.; Kula, N. S.;
Baldessarini, R. J. J. Med. Chem. 1996, 39, 543.
Acknowledgment
46. Tamagnan, G.; Neumeyer, J. L.; Gao, Y.; Wang, S.; Kula, N. S.; Baldessarini, R. J.
Bioorg. Med. Chem. Lett. 1997, 7, 337.
This research was supported by the National Institute on Drug
Abuse, Grant No. DA05477.