Synthesis, monoamine transporter binding, properties, and functional monoamine uptake activity of 3β-[4-methylphenyl and 4-chlorophenyl]- 2β-[5-(substituted phenyl)thiazol-2-yl]tropanes

Article abstract of DOI:10.1021/jm0703035

Synthetic methods were developed for the synthesis of the 3β-(4-substituted phenyl)-2β-[5-(substituted phenyl)thiazol-2-yl] tropanes (4a-s). The compounds were evaluated for their monoamine transporter binding and monoamine uptake inhibition properties using both rat brain tissue and cloned transporter assays. In general, the compounds showed higher dopamine transporter (DAT) affinity relative to the serotonin and norepinephrine transporters (SERT and NET, respectively) and greater [³H]dopamine uptake inhibition potency relative to [³H]serotonin and [ ³H]norepinephrine uptake inhibition. Several compounds were DAT selective relative to the SERT and NET in the monoamine transporter binding assays. The most potent and selective analog in the functional monoamine uptake inhibition test was 3β-(4-methylphenyl-2β-[5-(3-nitrophenyl)thiazol-2- yl]tropane (4p).

Full text of DOI:10.1021/jm0703035

3686
J. Med. Chem. 2007, 50, 3686-3695
Synthesis, Monoamine Transporter Binding, Properties, and Functional Monoamine Uptake
Activity of 3â-[4-Methylphenyl and 4-Chlorophenyl]-2â-[5-(Substituted
phenyl)thiazol-2-yl]tropanes
Paul K. Gong,† Bruce E. Blough,† Lawrence E. Brieaddy,† Xiaodong Huang,† Michael J. Kuhar,‡ Herna´n A. Navarro,† and
F. Ivy Carroll*,†
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194, and Yerkes
National Primate Center of Emory UniVersity, 954 Gatewood Road NE, Atlanta, Georgia 30329
ReceiVed March 16, 2007
Synthetic methods were developed for the synthesis of the 3â-(4-substituted phenyl)-2â-[5-(substituted
phenyl)thiazol-2-yl]tropanes (4a-s). The compounds were evaluated for their monoamine transporter binding
and monoamine uptake inhibition properties using both rat brain tissue and cloned transporter assays. In
general, the compounds showed higher dopamine transporter (DAT) affinity relative to the serotonin and
norepinephrine transporters (SERT and NET, respectively) and greater [3H]dopamine uptake inhibition potency
relative to [3H]serotonin and [3H]norepinephrine uptake inhibition. Several compounds were DAT selective
relative to the SERT and NET in the monoamine transporter binding assays. The most potent and selective
analog in the functional monoamine uptake inhibition test was 3â-(4-methylphenyl-2â-[5-(3-nitrophenyl)-
thiazol-2-yl]tropane (4p).
The neurotransmitter dopamine (DAa) is involved in vital
functions such as locomotion, feeding, emotion, and reward.1
Compounds that inhibit binding to the DA transporter (DAT)
and, thus, block reuptake of DA have been studied as potential
drugs to treat Parkinson’s disease,2-4 attention deficit hyper-
activity disorder (ADHD),5,6 depression,7 obesity,8 and cocaine
(1) addiction.9 One of the most studied classes of DA uptake
inhibitors is the 3-phenyltropanes.10-14 The lead DA uptake
inhibitor in this class was 3â-phenyltropane-2â-carboxylic acid
methyl ester (2, WIN 35,065-2).15,16 Many WIN 35,065-2
analogs have been synthesized and evaluated for their binding
to the DAT.10-14 Replacement of the 2â-carbomethoxy group
with certain heterocyclic groups led to analogues that retained
high affinity for the DAT and, in some cases, were DAT
selective relative to binding at the serotonin and norepinephrine
transporters (SERT and NET, respectively).17-19 One of the most
interesting compounds is the DAT selective inhibitor 3â-(4-
chlorophenyl)-2â-[3-(4-methylphenyl)isoxazol-5-yl]tropane (3,
RTI-336), which is in advanced preclinical development.17,20-22
Another class of DAT selective 2â-heterocyclic analogues
discovered in the initial study of 3â-(aryl)-2â-heterocyclic
tropanes was 3â-(4-chlorophenyl)-2â-(5-phenylthiazol-2-yl)-
tropane (4a, RTI-219).19 In this paper, we describe the synthesis
of a number of new 3â-(4-chloro and 4-methylphenyl)-2â-[5-
(substituted phenyl)thiazol-2-yl]tropanes (4b-s) and report their
monoamine transporter binding properties and their functional
monoamine uptake inhibition activity.
* To whom correspondence should be addressed. Dr. F. Ivy Carroll,
Organic and Medicinal Chemistry, Research Triangle Institute, Post Office
Box 12194, Research Triangle Park, NC 27709-2194, Telephone: 919 541-
6679. Fax: 919 541-8868. E-mail: fic@rti.org.
† Research Triangle Institute.
‡ Yerkes National Primate Center of Emory University.
a Abbreviations: DAT, dopamine transporter; SERT, serotonin trans-
porter; NET, norepinephrine transporter; DA, dopamine; 5HT, serotonin;
NE, norepinephrine; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;
HOAt, 1-hydroxy-7-azabenzotriazole; HEK, human embryonic kidney.
Chemistry
The 4-substituted phenylthiazole analogues 4b-d, 4f, 4h, and
4m were synthesized using a procedure exactly analogous to
10.1021/jm0703035 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/30/2007

2â-Phenylthiazole Analogs of 3â-Phenyltropanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3687
Scheme 2a
Scheme 1
that used to prepare 4a (Scheme 1).19 The acid 5a was treated
with oxalyl chloride, and the resultant acid chloride was
condensed with the appropriate 2-aminoacetophenone to give
the amides 6. Cyclization with Lawesson’s reagent gave the
3â-(4-chlorophenyl)-2â-[5-(substituted phenyl)thiazol-2-yl]tro-
panes (4b-d, 4f, 4h, and 4m). Because the yields obtained by
this procedure were low when attempted for the 3â-(4-
methylphenyl)-2â-[5-(substituted phenyl)thiazol-2-yl]tropane
analogs, a new procedure outlined in Scheme 2 was developed.
Coupling of 5a or 5b with the appropriately protected ami-
noacetophenones (12a-h) using 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDCI) and 1-hydroxy-7-azabenzotriazole
(HOAt) in dimethylformamide afforded the amides (7). Treat-
ment of amides 7 with cold triflic anhydride in the presence of
pyridine formed an intermediate imino triflate that, when
subjected to an excess of hydrogen sulfide gas, yielded the
thioamides 8.23 The thioamides 8 were cyclized to the desired
4e, 4g-l and 4n-s by briefly heating in concentrated hydro-
chloric acid. The protected aminoacetophenones 12a-h needed
to synthesize the amides 7 were produced in a three-step
synthesis from commercially available phenacyl bromides 9a-
h, as outlined in Scheme 3. Heating a solution of 9a-h in
dimethylsulfoxide with sodium azide provided the phenacyl
azides 10a-h. Treatment of 10a-h with ethylene glycol in
chloroform using boron trifluoride etherate as the acid catalyst
yielded the ketone-protected phenacyl azides 11a-h. Reduction
of the azides 11a-h to the protected 2-aminoacetophenones
12a-h was achieved by first converting the azides 11a-h to
the phosphazo intermediate with triphenylphosphine followed
by treatment with water (Staudinger reaction24).
a Reagents and conditions: (a) 12a-h, EDCl, HOAt, DMF; (b) (i) Tf2O,
pyridine, CH2Cl2, -45 to 0 °C, 4 h; (ii) H2S(g), 0 °C, 1 h; (c) (i) 12 N
HCl, 60 °C, 30 min; (ii) 3 M NaOH.
Scheme 3a
a Reagents and conditions: (a) NaN3, DMSO; (b) HOCH2CH2OH,
BF3·Et2O, CHCl3; (c) (i) PPh3, THF; (ii) H2O.
Biological Section
Target compounds were evaluated in two different monoam-
ine transporter binding assays. In one assay, the striata, midbrain,
or frontal cortex of male Sprague-Dawley rats (200-250 g)
were used for competition binding assays at the DAT, SERT,
and NET.25,26 The final concentration of radioligands in the
assays was 0.5 nM [3H]WIN 35,065-2 for the DAT, 0.2 nM

3688 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Gong et al.
Table 1. Monoamine Transporter Binding Properties of 2-Phenylthiazole Analogs Using Rat Brain Tissues
DAT, IC50 (nM)
[3H]WIN35,428
SERT, Ki (nM)
NET, Ki (nM)
cmpd
WIN
Z
X
Y
[3H]Paroxetine
1900
[3H]Nisoxetine
920
23
35,065-2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
4F
H
H
H
H
Br
H
NO2
H
Cl
CH3O
H
H
Br
H
NO2
H
Cl
5.7
6 ( 1
20 ( 3
107 ( 20
18 ( 6
20 ( 3
5 ( 1
14 ( 3
440 ( 100
65 ( 6
12 ( 4
22 ( 3
10 ( 2
41 ( 5
4 ( 1
>2000
8560
371 ( 70
903 ( 320
840 ( 20
280 ( 20
980 ( 100
301 ( 30
800 ( 100
380 ( 30
1510 ( 80
2240 ( 600
1110 ( 70
312 ( 10
1690 ( 240
10,000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>2000
>4300
>2000
>2000
>2000
4Cl
4Br
H
NO2
H
CH3O
Cl
CH3O
F
Cl
H
NO2
H
CH3O
Cl
Cl
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4n
4o
4p
4q
4r
15 ( 6
102 ( 40
83 ( 20
>2000
190 ( 20
>2000
4s
CH3O
CH3O
Table 2. Comparison of Dopamine, Serotonin, and Norepinephrine Transporter Binding and Uptake Studies in C6hDAT, HEK-hSERT, and HEK-hNET
Cells for WIN 35,065-2 Analogsa
binding,b Ki (nM)
uptake,b IC50 (nM)
[3H]5HT
cmpd
Z
X
Y
DAT
SERT
NET
[3H]DA
[3H]NE
cocainec
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
272 ( 60
18 ( 4
601 ( 130
2670 ( 520
653 ( 80
830 ( 147
1840 ( 150
1700 ( 90
2700 ( 400
3290 ( 390
2530 ( 240
2270 ( 380
2510 ( 370
1270 ( 170
2300 ( 70
1910 ( 200
1630 ( 380
2870 ( 190
4240 ( 970
2210 ( 300
1970 ( 660
990 ( 140
3630 ( 810
>6100
267 ( 47
158 ( 63
30 ( 6
41 ( 10
107 ( 22
63 ( 28
30 ( 5
45 ( 11
38 ( 18
416 ( 82
212 ( 85
181 ( 28
400 ( 100
810 ( 290
98 ( 11
197 ( 54
23 ( 5
318 ( 57
385 ( 40
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
F
Cl
Br
H
NO2
H
OCH3
Cl
OCH3
F
Cl
Br
H
NO2
H
OCH3
Cl
H
H
H
H
Br
H
NO2
H
Cl
OCH3
H
H
H
Br
H
NO2
H
2710 ( 500
1010 ( 200
4400 ( 900
8220 ( 830
4000 ( 1000
3600 ( 600
1610 ( 470
6700 ( 700
5300 ( 1700
>6800
750 ( 270
690 ( 190
912 ( 40
12 ( 2
28 ( 3
2390 ( 580
5700 ( 1800
1500 ( 500
1820 ( 140
740 ( 110
5200 ( 1900
2710 ( 340
3590 ( 490
1720 ( 600
1320 ( 300
1870 ( 620
870 ( 320
1640 ( 160
580 ( 160
3670 ( 540
2940 ( 340
7710 ( 410
35 ( 13
39 ( 13
6.1 ( 2.3
7.7 ( 2.1
8.6 ( 2.7
66 ( 8
960 ( 300
2300 ( 200
582 ( 94
650 ( 160
620 ( 130
6500 ( 1000
4210 ( 170
4870 ( 840
1170 ( 60
1820 ( 410
3240 ( 280
1550 ( 210
2040 ( 240
1810 ( 380
4000 ( 2000
>6900
Cl
Cl
234 ( 74
61 ( 18
212 ( 10
130 ( 10
12 ( 3
140 ( 40
14 ( 5
53 ( 20
105 ( 47
529 ( 31
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
3200 ( 1300
377 ( 90
1840 ( 500
3860 ( 500
3170 ( 800
2380 ( 190
6800 ( 1800
4400 ( 1100
>10 000
226 ( 77
469 ( 77
885 ( 57
Cl
OCH3
4s
OCH3
1390 ( 300
a This data was supplied by the NIDA-CTDP program. Details of experimentals for these binding and uptake studies are given in ref 27. b Values for the
mean ( standard error of three independent experiments, each conducted with triplicate determination. c Data taken from ref 27.
[3H]paroxetine for the SERT, and 0.5 nM [3H]nisoxetine for
the NET. Results from this assay are listed in Table 1. In the
second assay, the competition binding assays were determined
using (h)DAT, (h)SERT, and (h)NET, stably expressed in
HEK293 cells, and the nonselective radioligand [125I]RTI-55
for the analogues 4b-s (Table 2).27 The HEK-(h)DAT, -(h)-
SERT, and -(h)NET cells were also used to evaluate the
compound’s ability to block the reuptake of [3H]dopamine ([3H]-

2â-Phenylthiazole Analogs of 3â-Phenyltropanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3689
DA), [3H]serotonin ([3H]5HT), and [3H]norepinephrine ([3H]-
NE; Table 2).27
> 4b ) 4f > 4h. Thus, for determining activity at the DAT,
binding or uptake yields comparable results.
The most DAT selective analog relative to SERT in the
cloned receptor assay was the 3â-(4-chlorophenyl)-2â-(4-
methoxyphenyl)thiazole analog 4h, which showed a 600-fold
preference for the DAT. The 3â-(4-chlorophenyl)-2â-(4-nitro-
phenyl)thiazole analog 4f showed a 370-fold preference for the
DAT relative to the NET and, thus, was the most DAT selective
analog relative to the NET. In the monoamine uptake inhibition
studies, the 3â-(4-chlorophenyl)-2â-(4-nitrophenyl)thiazole 4f
and the 3â-(4-methylphenyl)-2â-(3-nitrophenyl)thiazole 4p both
had greater than 100-fold selectivity for [3H]DA uptake inhibi-
tion relative to [3H]5HT inhibition. Analog 4p also had 88-
fold selectivity for [3H]DA uptake inhibition relative to [3H]NE
uptake inhibition, whereas 4f possessed only a 19-fold selectivity
for [3H]DA uptake inhibition. Analog 4p was also highly
selective in the rat brain tissue binding assay showing 2400-
and 1000-fold selectivity for the DAT relative to the SERT and
NET.
In summary, using the 3â-(4-chlorophenyl)-2â-phenylthiazole
analog 4a as a lead compound, a number of analogs were
designed, synthesized, and evaluated for their monoamine
transporter binding and monoamine uptake inhibition properties
to gain a better understanding of the structure-activity relation-
ship (SAR) for this class of compounds. While most of the 3â-
(4-chlorophenyl)-2â-(substituted phenyl)thiazole analogs could
be synthesized by standard methods used for the synthesis of
thiazoles, a new method had to be developed to synthesize the
3â-(4-methylphenyl)-2â-(substituted phenyl)thiazole analogs.
The key step in the synthesis was the conversion of an amide
to the thioamide that could be cyclized to the desired target
compounds. In general, the compounds showed higher DAT
affinity relative to the SERT and NET and greater [3H]DA
uptake inhibition potency relative to [3H]5HT and [3H]NE
uptake inhibition. Based on the functional monoamine uptake
data, the most potent and DA selective ligand was the 3â-(4-
methylphenyl)-2â-(3-nitrophenyl)thiazole analog 4p. However,
based on the monoamine transporter binding data, several other
compounds were DAT selective relative to the SERT and NET.
These compounds should not be overlooked as potential DAT
selective compounds, because it is difficult to predict the phar-
macokinetic and pharmacodynamic properties of compounds.
Results and Discussion
In our original studies of 3â-phenyl-2â-heterocyclic tropane
analogs, we reported that the 2â-phenylthiazole 4a could be
easily synthesized using standard methods for preparing thia-
zoles. Specifically, the 3â-(4-chlorophenyl)tropane-2â-(N-
phenacyl)-carboxamide was easily prepared and cyclized to the
desired 4a in good yield by using Lawesson’s reagent. We
anticipated that the aromatic substituted analogs 4b-s could
be prepared by a similar procedure and, indeed, we were able
to obtain the 3â-(4-chlorophenyl) analogs 4b-d, 4f, and 4h in
satisfactory yield (Scheme 1). Surprisingly, when we tried this
procedure on the 3â-(4-methylphenyl) analogs, the reactions
became much more difficult to workup and the yields were
unacceptable. Fortunately, we were able to develop a new
synthesis of this class of compounds, which proceeded with
much less difficulty and higher overall yields (Scheme 2). The
key step in the new synthetic route was the conversion of the
amides 7 to the thioamides 8. This was achieved by first
converting amide 7 to the triflate enolate, followed by treatment
with hydrogen sulfide. Attempts to convert 7 to 8 using
Lawesson’s reagent, or phosphorus pentasulfide under a variety
of conditions, including different solvents, were unsuccessful.
Once the thioamides 8 were in hand, they were easily converted
to the desired 2â-arylthiazole analogs by acid-catalyzed cy-
clization.
The 2â-arylthiazole analogs were evaluated for their mono-
amine transporter binding properties using rat brain tissue (Table
1) or cloned receptors (Table 2). All compounds tested, with
the exception of the 3â-(4-chlorophenyl)-2â-(3,4-dichlorophe-
nyl)thiazole analog 4i, in the rat tissue assay had higher affinity
for the DAT relative to the SERT and NET. With a few
exceptions, the 2â-arylthiazole analogs tended to show lower
IC50s for the DAT in the rat brain tissues test than the Kis for
the DAT in the cloned receptor assay. An analysis of the DAT
affinities in Table 1 shows that 11 of the analogs evaluated in
the rat brain DAT test had IC50s of 20 nM or less. The rank
order for these analogs is: 4p > 4g > 4a > 4b > 4n > 4k >
4h > 4q > 4e > 4c ) 4f. A similar analysis of the DAT
affinities determined using cloned human transporters (Table
2) shows that seven of the same analogs had Kis of 20 nM or
less, although their rank order was different: 4f > 4g > 4h >
4n ) 4b > 4p > 4a. These results show that the highest potency
compounds were identified by either the rat brain tissue or the
cloned receptor assays. The two most potent compounds in the
rat brain tissue DAT test are the 3â-(4-methyl and 3â-4-
chlorophenyl)-2â-(3-nitrophenyl)thiazole analogs 4p and 4g,
which have IC50s of 4 and 5 nM, respectively. In the case of
the cloned transporter test, the 3â-(4-chlorophenyl)-2â-(4-
nitrophenyl) and (4-methoxyphenyl)thiazole analogs 4f and 4g
with Ki of 6.1 and 7.7 nM, respectively, possessed the highest
affinity.
Experimental Section
Nuclear magnetic resonance (1H NMR and 13C NMR) spectra
were recorded on a 300 MHz (Bruker AVANCE 300) spectrometer.
Chemical shift data for the proton resonances were reported in parts
per million (δ) relative to internal (CH3)4Si (δ 0.0). Optical rotations
were measured on an AutoPol III polarimeter purchased from
Rudolf Research. Elemental analyses were performed by Atlantic
Microlab, Norcross, GA. Analytical thin-layer chromatography
(TLC) was carried out on plates precoated with silica gel GHLF
(250 µM thickness). TLC visualization was accomplished with a
UV lamp or in an iodine chamber. All moisture-sensitive reactions
were performed under a positive pressure of nitrogen maintained
by a direct line from a nitrogen source. Anhydrous solvents and
hydrogen sulfide gas were purchased from Aldrich Chemical Co.
3â-(4-Chlorophenyl)-2â-[5-(4-chlorophenyl)thiazol-2-yl]tro-
pane (4c) Hydrochloride. To compound 5a (3.0 g, 0.0107 mol)
in CH2Cl2 (75 mL) was added oxalyl chloride (11.0 mL, 2 M in
CH2Cl2, 0.0214 mol). The reaction mixture was stirred at rt for 2
h and concentrated in vacuo. The resulting acid chloride was
redissolved in CH2Cl2 (50 mL), and 2-amino-4′-chloroacetophenone
hydrochloride (4.93 g, 0.0239 mol) was added, followed by Et3N
(5.47 g, 0.0541 mol) in CH2Cl2 (50 mL). The reaction mixture was
stirred at rt overnight, filtered, and concentrated in vacuo to afford
Similar to the radioligand binding data, all of the compounds
4a-s were better uptake inhibitors at the (h)DAT relative to
the (h)SERT and (h)NET (Table 2). Even though the rank order
of potency in [3H]DA uptake inhibition did not parallel the rank
order in the DAT binding studies, the three most potent analogs,
all of which showed IC50s of less than 30 nM, are also the three
analogs possessing the highest DAT affinity. The most potent
analog in the [3H]DA uptake inhibition study was the 3â-(4-
methylphenyl)2â-(3-nitrophenyl)thiazole analog 4p, with an IC50
of 23 nM. The rank order of the four most potent analogs is 4p

3690 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Gong et al.
5.9 g of a red-orange amorphous solid, which was purified by
column chromatography on silica gel, eluting with CH2Cl2-
CHCl3-MeOH-NH4OH (50:40:9:1) to yield 3.7 g (80%) of 6c as
an orange amorphous solid.
extracted with 125 mL of diethyl ether. The combined organic layers
were washed with water and brine and dried with Na2CO3. The
organic fractions were concentrated to a residue that was purified
by flash chromatography using CH2Cl2 as the eluent to give 700
mg (87%) of 10c as a slightly yellow powder: 1H NMR (CDCl3)
δ 8.35 (d, 2H, J ) 9 Hz), 8.10 (d, 2H, J ) 9 Hz), 4.61 (s, 2H).
4-Fluorophenacyl Azide (10a). Using a procedure similar to
that described for 10c, 1.7 g (0.0078 mol) of 4-fluorophenacyl
bromide was treated with NaN3 to give 1.24 g (88%) of 10a as
yellow crystals: 1H NMR (CDCl3) δ 7.95 (m, 2H), 7.18 (m, 2H),
4.53 (s, 2H).
4-Chlorophenacyl Azide (10b). Using a procedure similar to
that described for 10c, 25 g (0.11 mol) of 4′-chlorophenacyl bromide
was treated with NaN3 to give 10.5 g (50%) of 10b as a white
solid: 1H NMR (CDCl3) δ 7.85 (d, 2H, J ) 8.7 Hz), 7.49 (d, 2H,
J ) 8.7 Hz), 4.53 (s, 2H).
4-Methoxyphenacyl Azide (10d). Using a procedure similar to
that described for 10c, 5.26 g (0.023 mol) of 4-methoxyphenacyl
bromide was treated with sodium azide to give 4.1 g (93%) of 10d
as a light yellow powder: 1H NMR (CDCl3) δ 7.89 (d, 2H, J )
7.2 Hz), 6.96 (d, 2H, J ) 7.2 Hz), 4.54 (s, 2H), 3.89 (s, 3H).
3-Bromophenacyl Azide (10e). Using a procedure similar to
that described for 10c, 2.2 g (0.008 mol) of 3-bromophenacyl
bromide was treated with sodium azide to give 1.3 g (62%) of 10e
as a white powder: 1H NMR (CDCl3) δ 8.05 (m, 1H), 7.84 (d,
1H, J ) 7.5 Hz), 7.77 (d, 1H), 7.37 (dd, 1H), 4.54 (s, 2H).
3-Nitrophenacyl Azide (10f). Using a procedure similar to that
described for 10c, 3.16 g (0.013 mol) of 3-nitrophenacyl bromide
was treated with NaN3 to give 1.80 g (68%) of 10f as a yellow
powder: 1H NMR (CDCl3) δ 8.74 (d, 1H, J ) 1.8 Hz), 8.49 (dd,
1H, J ) 8.1 Hz), 8.27 (d, 1H, J ) 8.1 Hz), 7.75 (dd, 1H J ) 8.1
Hz), 4.63 (s, 1H).
3,4-Dichlorophenacyl Azide (10g). Using a procedure similar
to that described for 10c, 2.14 g (0.008 mol) of 3,4-dichlorophenacyl
bromide was treated with NaN3 to give 881 mg (48%) of 10g as a
clear oil: 1H NMR (CDCl3) δ 8.00 (d, 1H, J ) 1.8 Hz), 7.73 (dd,
1H, J ) 8.4 Hz), 7.59 (d, 1H, J ) 8.1 Hz), 4.52 (s, 2H).
3,4-Dimethoxyphenacyl Azide (10h). Using a procedure similar
to that described for 10c, 11.1 g (0.043 mol) of 3,4-dimethox-
yphenacyl bromide was treated with NaN3 to give 8.29 g (87%) of
10h as a yellow powder: 1H NMR (CDCl3) δ 7.52 (d, 1H, J ) 2.1
Hz), 7.47 (dd, 1H, J ) 8.4 Hz), 6.89 (d, 1H, J ) 8.4 Hz), 4.53 (s,
2H), 3.96 (s, 3H), 3.95 (s, 3H).
4-Nitrophenacyl Azide Ethylene Ketal (11c). A solution of 473
mg (2.29 mmol) of 10c, 2.3 mL (41.3 mmol) of ethylene glycol,
and 3 mL (23.4 mmol) of BF3‚Et2O in 20 mL of CH2Cl2 was
allowed to stir for 2 days under a N2 atmosphere at room
temperature. Saturated NaHCO3 solution was added, and the mixture
was extracted with CHCl3. The extracts were washed with water
and brine and then dried (Na2SO4). Organic layers were concen-
trated to dryness to leave a residue that was purified by silica gel
chromatography, eluting with a 0-25% EtOAc/hexanes gradient.
Concentration of collected fractions yielded 395 mg (69%) of 11c
as white feathery crystals: 1H NMR (CDCl3) δ 8.23 (d, 2H, J )
8.7 Hz), 7.70 (d, 2H, J ) 8.7 Hz), 4.22 (m, 2H), 3.92 (m, 2H),
3.46 (s, 2H).
4-Fluorophenacyl Azide Ethylene Ketal (11a). Using a pro-
cedure similar to that described for 11c, 1.22 g (0.007 mol) of 10a
was converted to 1.33 g (87%) of 11a as a clear oil: 1H NMR
(CDCl3) δ 7.48 (m, 2H), 7.05 (m, 2H), 4.18 (m, 2H), 3.90 (m,
2H), 3.42 (s, 2H).
4-Chlorophenacyl Azide Ethylene Ketal (11b). Using a
procedure similar to that described for 11c, 10.5 g (0.054 mol) of
10b was converted to 6.2 g (54%) of 11b as a white solid: 1H
NMR (CDCl3) δ 7.44 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4
Hz), 4.17 (m, 2H), 3.89 (m, 2H), 3.41 (s, 2H).
Compound 6c (3.7 g, 0.0086 mol) and Lawesson’s reagent (13.9
g, 0.034 mol) were added to toluene (150 mL) and stirred at reflux
for 6 h. The reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography on silica gel,
eluting with hexane-Et2O-Et3N (10:9:1) to afford 1.28 g (35%)
of 4c as a white solid. The free base was dissolved in CH2Cl2 and
treated with excess 2 M ethereal HCl. The mixture was concentrated
and triturated with warm EtOAc, cooled, and filtered to yield 0.80
g of 4c‚HCl as a white solid: mp 142-143 °C; 1H NMR (CDCl3,
free base) δ 7.57 (s, 1H), 7.51 (d, 2H), 7.34 (d, 2H), 7.08 (d, 2H),
6.80 (d, 2H), 3.50 (bd, 1H), 3.40 (bs, 1H), 3.20-3.53 (m, 2H),
2.55 (q, 1H), 2.10-2.42 (m, 2H), 2.35 (s, 3H), 1.57-1.90 (m, 3H);
[R]D ) -25.3° (c 0.53, MeOH). Anal. (C23H23Cl3N2S‚2H2O) C,
H, N, S.
3â-(4-Chlorophenyl)-2â-[5-(4-fluorophenyl)thiazol-2-yl]tro-
pane (4b) Hydrochloride. Compound 4b was prepared by a
procedure analogous to that described for the preparation of 4c to
afford 23% of 4b as a beige solid: mp (HCl salt) 188-190 °C; 1H
NMR (CDCl3, free base) δ 7.53 (m, 3H), 7.08 (m, 4H), 6.80 (d,
2H), 3.50 (bd, 1H), 3.40 (bs, 1H), 3.23-3.40 (m, 2H), 2.65 (bs,
1H), 2.10-2.42 (m, 2H), 2.35 (s, 3H), 1.60-1.85 (m, 3H); [R]D )
-24.0° (c 0.47, MeOH). Anal. (C23H23Cl2FN2S‚0.5H2O) C, H, N.
3â-(4-Chlorophenyl)-2â-[5-(4-bromophenyl)thiazol-2-yl]tro-
pane (4d) Hydrochloride. Compound 4d was prepared by a
procedure analogous to that described for 4c to give 32% of 4d as
a white solid: mp (HCl salt) 114-116 °C; 1H NMR (CDCl3, free
base) δ 7.60 (s, 1H), 7.46 (q, 4H), 7.08 (d, 2H), 6.80 (d, 2H), 3.50
(bd, 1H), 3.40 (bs, 1H), 3.24-3.42 (m, 2H), 2.30-2.42 (m, 2H),
2.35 (s, 3H), 1.65-1.85 (m, 3H); [R]D -25.9° (c 0.78, MeOH).
Anal. (C23H24Cl3BrN2S‚H2O) C, H, N, S.
3â-(4-Chlorophenyl)-2â-[5-(4-nitrophenyl)thiazol-2-yl]tro-
pane (4f) Hydrochloride. Compound 4f was prepared by a
procedure analogous to that described for 4c to give 23% of 4f as
a light yellow solid: mp (HCl salt) 180-183 °C; 1H NMR (CDCl3,
free base) δ 8.24 (d, 2H), 7.71 (m, 3H), 7.10 (d, 2H), 6.82 (d, 2H),
3.55 (bd, 1H), 3.42 (bs, 1H), 3.27-3.41 (m, 2H), 2.22-2.40 (m,
2H), 2.37 (s, 3H), 1.63-1.87 (m, 3H); [R]D -23.7° (c 0.38, MeOH).
Anal. (C23H23Cl2N3O2S‚1.75H2O) C, H, N, S.
3â-(4-Chlorophenyl)-2â-[5-(4-methoxyphenyl)thiazol-2-yl]tro-
pane (4h) Hydrochloride. Compound 4h was prepared by a
procedure analogous to that described for 4c to give 35% of 4h as
a beige solid: 1H NMR (CDCl3 free base) δ 7.50 (d, 2H J ) 8.7
Hz), 7.49 (s, 1H), 7.08 (d, 2H, J ) 8.5 Hz), 6.91 (d, 2H, J ) 8.7
Hz), 6.82 (d, 2H, J ) 8.5 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 3.38 (m,
1H), 3.32 (m, 1H), 3.24 (m, 1H), 2.34 (s, 3H), 2.17-2.44 (m, 2H),
1.82 (m, 2H), 1.63 (m, 2H); 13C NMR (CDCl3) δ 168.1, 159.3,
140.4, 139.7, 135.2, 131.9, 129.1, 128.1, 127.9, 125.2, 114.3, 65.8,
61.6, 55.4, 52.9, 41.7, 36.9, 35.1, 26.0, 25.5; mp (HCl salt) 171-
173 °C; [R]D -16.4° (c 0.75, MeOH). Anal. (C24H27Cl2N2OS‚2HCl)
C, H, N, S.
3â-(4-Methylphenyl)-2â-[5-(4-bromophenyl)thiazol-2-yl]tro-
pane (4m) Tartrate. Compound 4m was prepared by a procedure
analogous to that described for 4c except the compound was
20
characterized as the tartrate salt: mp 190-193 °C, [R]D -21.1
1
(c 0.5, CH3OH); H NMR (CDCl3 free base) δ 7.58 (s, 1H), 7.49
(d, 2H, J ) 8.8 Hz), 7.44 (d, 2H, J ) 8.8 Hz), 6.93 (d, 2H, J ) 7.9
Hz), 6.76 (d, 2H, J ) 8.0 Hz), 3.51 (m, 1H), 3.49 (m, 1H), 3.31
(m, 1H), 3.23 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.15-2.45 (m,
2H), 1.84 (m, 2H), 1.63 (m, 2H); 13C NMR (CDCl3) δ 170.0, 138.6,
138.5, 136.5, 135.7, 131.9, 131.6, 128.8, 127.9, 127.5, 121.3, 65.8,
61.8, 53.1, 41.7, 37.0, 35.1, 26.0, 25.6, 21.0. Anal. (C28H32BrN206‚
2.5H2O) C, H, N.
4-Nitrophenacyl Azide (10c). Into a 100-mL round-bottom flask
was added 950 mg (3.9 mmol) of 4-nitrophenacyl bromide, 271
mg (4.3 mmol) of sodium azide, and 15 mL of DMSO. The reaction
mixture was allowed to stir at room temperature for at least 30
min, 50 mL of ice water was added, and the aqueous layer was
4-Methoxyphenacyl Azide Ethylene Ketal (11d). Using a
procedure similar to that described for 11c, 1.53 g (0.008 mol) of
10d was converted to 1.32 g (70%) of 11d as a clear oil that
solidified to a white solid upon standing: 1H NMR (CDCl3) δ 7.42

2â-Phenylthiazole Analogs of 3â-Phenyltropanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3691
(d, 2H, J ) 7.2 Hz), 6.88 (d, 2H, J ) 7.2 Hz), 4.15 (m, 2H), 3.90
(m, 2H), 3.81 (s, 3H), 3.42 (s, 2H).
11h was reduced to give 5.1 g (85%) of 12h as a white powder:
1H NMR (CDCl3) δ 7.01 (dd, 1H, J ) 8.1 Hz), 6.97 (d, 1H), 6.85
(d, 1H), 4.07 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (m, 2H),
2.92 (s, 2H), 1.34 (bs, 2H).
3-Bromophenacyl Azide Ethylene Ketal (11e). Using a pro-
cedure similar to that described for 11c, 980 mg (4.1 mmol) of
10e was converted to 923 mg (80%) of 11e as a clear oil: 1H NMR
(CDCl3) δ 7.66 (m, 1H), 7.46 (m, 2H), 7.25 (m, 1H), 4.18 (m,
2H), 3.90 (m, 2H), 3.41 (s, 2H).
3-Nitrophenacyl Azide Ethylene Ketal (11f). Using a procedure
similar to that described for 11c, 1.65 g (0.008 mol) of 10f was
converted to 1.29 g (64%) of 11f as a yellow oil that solidified
upon standing: 1H NMR (CDCl3) δ 8.39 (d, 1H, J ) 1.8 Hz), 8.22
(dd, 2H, J ) 8.1 Hz), 7.83 (d, 1H, J ) 1.8 Hz), 7.58 (dd, 1H, J )
1.8 Hz), 4.23 (m, 2H), 3.93 (m, 2H), 4.46 (s, 2H).
3â-(4-Methylphenyl)tropane-2â-N-4′-fluorophenacylcarboxa-
mide Ethylene Ketal (7k). To a cooled solution (0 °C) of 260 mg
(1 mmol) of 5b and 198 mg (1 mmol) of 12a in dry DMF was
added 6 mL of a 3 M (1.8 mmol) HOAt followed by 650 mg (3.4
mmol) of EDCI. After stirring 2 days under N2 at 25 °C, the reaction
mixture was diluted with EtOAc and washed with saturated
NaHCO3 solution, water, and brine. The organic layer was dried
(Na2SO4), filtered, and concentrated. The resulting residue was
purified by flash chromatography on silica gel using 25-50% CMA
solvent in CH2Cl2 as the eluent. Isolated fractions produced 341
mg (78%) of 7k as a pure white solid: 1H NMR (CDCl3) δ 9.86
(bt, 1H), 7.53 (dd, 2H), 7.07-6.96 (m, 6H), 4.11 (m, 2H), 3.91
(m, 2H), 3.59 (m, 2H), 3.23 (t, 2H), 3.05 (m, 1H), 2.45 (dd, 1H),
2.26 (s, 3H), 2.20 (s, 3H), 2.14 (m, 3H), 1.72-1.56 (m, 3H); 13C
NMR (CDCl3) δ 129.3, 128.3, 128.0, 115.4, 65.5, 65.3, 64.3, 61.8,
54.9, 46.7, 41.5, 36.1, 35.6, 26.5, 25.4, 21.5; LCMS (ESI) m/z 439.7
(M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-4′-fluorophenacylcarboxthio-
amide (8k). To a chilled (dry ice/acetonitrile) solution of 294 mg
(0.67 mmol) of 7k in 7 mL of CH2Cl2 containing 190 µL (2.38
mmol) of pyridine under N2 was added 140 µL (0.84 mmol) of
Tf2O. The reaction mixture was slowly warmed to 0 °C and allowed
to stir for 4 h in an ice bath. Hydrogen sulfide gas was bubbled
through the solution. The reaction mixture was diluted with EtOAc,
washed with NaHCO3 solution, water, and brine, and dried (Na2-
SO4). The organic fractions were concentrated to dryness, and the
residue was subjected to column chromatography on silica gel using
25-50% CMA solution in CH2Cl2 gradient. Recrystallization of
dried product fractions from EtOAc/heptanes afforded 200 mg
(66%) of 8k as a tan solid: 1H NMR (CDCl3) δ 12.21 (bs, 1H),
7.56 (dd, 2H), 7.08 (dd, 2H, J ) 8.1 Hz), 7.03 (d, 2H, J ) 8.1
Hz), 6.92 (d, 2H, J ) 8.1 Hz), 4.17 (m, 2H), 3.95 (m, 2H), 3.95
(d, 1H), 3.77 (d, 1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.20 (d, 1H),
3.10 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.19 (m, 3H), 1.75 (m,
2H), 1.61 (dt, 1H); LCMS (ESI) m/z 455.4 (M + 1)+.
3,4-Dichlorophenacyl Azide Ethylene Ketal (11g). Using a pro-
cedure similar to that described for 11c, 720 mg (3.13 mmol) of
10g was converted to 606 mg (71%) of 11g as a clear oil: 1H NMR
(CDCl3) δ 7.60 (d, 1H, J ) 2.1 Hz), 7.45 (d, 1H, J ) 8.4 Hz),
7.32 (d, 1H, J ) 9 Hz), 4.18 (m, 2H), 3.90 (m, 2H), 3.41 (s, 2H).
3,4-Dimethoxyphenacyl Azide Ethylene Ketal (11h). Using a
procedure similar to that described for 11c, 7.97 g (0.036 mol) of
10h was converted to 7.6 g (80%) of 11h as a white powder: 1H
NMR (CDCl3) δ 7.06 (dd, 1H, J ) 8.1 Hz), 7.01 (d, 1H, J ) 1.8
Hz), 6.89 (d, 1H, J ) 8.1 Hz), 4.17 (m, 2H), 3.92 (m, 2H), 3.90 (s,
3H), 3.88 (s, 3H), 3.43 (s, 2H).
4-Nitrophenacylamine Ethylene Ketal (12c). A solution of 1.20
g (0.0048 mol) of 11c was stirred with 1.36 g (0.0053 mol) of
PPh3 in 75 mL of dry THF for 1 day. The reaction mixture was
concentrated to 10 mL, ∼150 µL of water (an excess) was added,
and the reaction mixture was allowed to stir overnight. The reaction
mixture was evaporated to dryness, and the resulting residue was
purified by flash chromatography on silica gel using 0-25% CMA
gradient solution in CH2Cl2 (where CMA refers to 80:18:2 ratio of
CHCl3/MeOH/NH4OH elution solvent). Isolated fractions provided
804 mg (75%) of 12c as a pure, slightly yellow powder: 1H NMR
(CDCl3) δ 8.21 (d, 1H, J ) 7.2 Hz), 7.65 (d, 1H, J ) 7.2 Hz),
4.11 (m, 2H), 3.84 (m, 2H), 2.92 (s, 2H), 1.39 (bs, 2H).
4-Fluorophenacylamine Ethylene Ketal (12a). Using a pro-
cedure similar to that described for 12c, 1.32 g (0.006 mol) of 11a
was reduced to give 847 mg (73%) of 12a as a clear oil: 1H NMR
(CDCl3) δ 7.42 (m, 2H), 7.3 (m, 2H), 4.05 (m, 2H), 3.84 (m, 2H),
2.89 (s, 2H), 1.40 (bs, 2H).
4-Chlorophenacylamine Ethylene Ketal (12b). Using a pro-
cedure similar to that described for 12c, 10.5 g (0.054 mol) of 11b
was reduced to give 6.06 g (54%) of 12b as a white solid: 1H
NMR (CDCl3) δ 7.44 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4
Hz), 4.17 (m, 2H), 3.89 (m, 2H), 3.41 (s, 2H), 1.34 (bs, 2H).
4-Methoxyphenacylamine Ethylene Ketal (12d). Using a
procedure similar to that described for 12c, 1.13 g (0.0048 mol) of
11d was reduced to give 617 mg (61%) of 12d as a white waxy
solid: 1H NMR (CDCl3) δ 7.37 (d, 2H, J ) 8.7 Hz), 6.88 (d, 2H,
J ) 8.7 Hz), 4.05 (m, 2H), 3.85 (m, 2H), 3.80 (s, 3H), 2.90 (s,
2H), 1.38 (bs, 2H).
3-Bromophenacylamine Ethylene Ketal (12e). Using a pro-
cedure similar to that described for 12c, 923 mg (3.25 mmol) of
11e was reduced to give 793 mg (95%) of 12e as a clear oil: 1H
NMR (CDCl3) δ 7.61 (m, 2H), 7.43 (d, 1H), 7.38 (d, 1H), 7.21
(dd, 1H), 4.07 (m, 2H), 3.84 (m, 2H), 2.89 (s, 2H), 1.37 (bs, 2H).
3-Nitrophenacylamine Ethylene Ketal (12f). Using a procedure
similar to that described for 12c, 1.10 g (0.0042 mol) of 11f was
reduced to give 593 mg (60%) of 12f as a white solid: 1H NMR
(CDCl3) δ 8.34 (dd, 1H, J ) 1.8 Hz), 8.19 (dd, 1H, J ) 8.1 Hz),
7.80 (d, 1H, J ) 8.1 Hz), 7.55 (dd, 1H, J ) 8.1 Hz), 4.13 (m, 2H),
3.86 (m, 2H), 2.94 (s, 2H), 1.40 (bs, 2H).
3â-(4-Methylphenyl)-2â-[5-(4′-fluorophenyl)thiazol-2-yl]tro-
pane (4k) Hydrochloride. A solution of 155 mg (0.354 mmol) of
8k dissolved in 3 mL of 12 N HCl was heated to 65 °C for 0.5 h
in a hot water bath. Ice was added directly to the solution, and the
mixture was basified with 12 mL of 3 N NaOH. The basified
solution was extracted with 3 × 25 mL EtOAc, and the combined
organic layers were washed with saturated NaHCO3, water, and
brine and dried (Na2SO4). Solvent was evaporated to yield 122 mg
(88%) of yellowish solid. To a solution of 53 mg (0.135 mol) of
the solid in 2 mL of dry CHCl3 was added an excess amount (3 to
6 equiv) of 1 M HCl in ether. The acidified solution was
concentrated to remove any excess solvent and HCl. The final
residue was washed once with dry diethyl ether and dried to give
48 mg (81%) of the hydrochloride salt of 4k as a light tan solid:
1H NMR (CDCl3 free base) δ 7.52 (m, 3H), 7.06 (dd, 2H, J ) 6.9
Hz), 6.92 (d, 1H, J ) 8.1 Hz), 6.77 (d, 2H, J ) 8.1 Hz), 3.50 (d,
1H), 3.38 (m, 1H), 3.29 (t, 1H), 3.25 (t, 1H), 2.38 (m, 1H), 2.34
(s, 3H), 2.24 (m, 2H), 2.21 (s, 3H), 1.83 (q, 2H), 1.62 (dt, 1H); 13
C
NMR (CDCl3) δ 136.40, 129.18, 128.57, 127.97, 116.32, 66.25,
62.16, 53.56, 42.16, 37.42, 35.58, 26.41, 25.98, 21.40; LCMS (ESI)
m/z 393.7 (M + 1)+. The hydrochloride salt had a mp of 220-
222 °C; [R]20 -18.5° (c 0.20, CH3OH). Anal. (C24H27ClFN2S‚
D
0.5H2O) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-4′-chlorophenacylcarboxa-
mide Ethylene Ketal (7l). Using a procedure similar to that
described for 7k, 2.82 g (0.011 mol) of 5b was coupled with 2.34
g (0.011 mol) of 12b to give 3.24 g (65%) of 7l as a white
powder: 1H NMR (CDCl3) δ 9.87 (bt, 1H), 7.47 (d, 2H, J ) 8.4
Hz), 7.34 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H, J ) 8.1 Hz), 6.96 (d,
2H, J ) 8.1 Hz), 4.10 (m, 2H), 3.90 (m, 2H), 3.58 (d, 2H, J ) 5.1
Hz), 3.24 (m, 2H), 3.03 (m, 1H), 2.45 (d, 1H), 2.26 (s, 3H), 2.19
(s, 3H), 2.14 (m, 3H), 1.75-1.55 (m, 3H); 13C NMR (CDCl3) δ
3,4-Dichlorophenacylamine Ethylene Ketal (12g). Using a
procedure similar to that described for 12c, 606 mg (2.21 mmol)
of 11g was reduced to give 522 mg (95%) of 12g as a clear oil:
1H NMR (CDCl3) δ 7.55 (d, 1H, J ) 1.8 Hz), 7.42 (d, 1H, J ) 8.1
Hz), 7.27 (d, 1H, J ) 8.4 Hz), 4.07 (m, 2H), 3.84 (m, 2H), 2.81 (s,
2H), 1.35 (bs, 2H).
3,4-Dimethoxyphenacylamine Ethylene Ketal (12h). Using a
procedure similar to that described for 12c, 6.63 g (0.025 mol) of

3692 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Gong et al.
129.34, 128.76, 128.01, 65.51, 65.32, 64.32, 61.85, 54.84, 46.58,
41.49, 36.03, 35.60, 26.51, 25.37, 21.50; LCMS (ESI) m/z 456.1
(M + 1)+.
Hz), 4.15 (m, 2H), 3.89 (m, 2H), 3.60 (dd, 2H), 3.25 (m, 2H), 3.00
(m, 1H), 2.47 (d, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 2.15 (m, 3H),
1.72-1.66 (m, 3H); 13C NMR (CDCl3) δ 129.33, 127.88, 127.68,
123.79, 65.75, 65.56, 64.34, 61.85, 54.73, 46.31, 41.57, 35.96,
35.42, 26.49, 25.36, 21.47; LCMS (ESI) m/z 466.7 (M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-4-nitrophenacylthiocar-
boxthioamide Ethylene Ketal (8o). Using a procedure similar to
that described for 8k, 328 mg (0.70 mmol) of 7o was converted to
163 mg (48%) of 8o as a tan solid: 1H NMR (CDCl3) δ 12.30 (bs,
1H), 8.26 (d, 2H, J ) 9.3 Hz), 7.77 (d, 2H, J ) 9.3 Hz), 7.02 (d,
2H, J ) 8.4 Hz), 6.91 (d, 2H, J ) 8.4 Hz), 4.23 (m, 2H), 3.98 (m,
3H), 3.86 (m, 1H), 3.45 (m, 1H), 3.33 (m, 1H), 3.24 (m, 1H), 3.15
(m, 1H), 2.27 (s, 3H), 2.25 (s, 3H), 2.21 (m, 3H), 1.70-1.56 (m,
3H); 13C NMR (CDCl3) δ 129.24, 128.19, 127.70, 124.04, 65.67,
65.57, 62.06, 61.43, 53.36, 41.37, 35.53, 35.66, 26.59, 25.42, 21.51;
LCMS (ESI) m/z 482.6 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(4′-nitrophenyl)thiazol-2-yl]tro-
pane (4o) Hydrochloride. Using a procedure similar to that
described for 4k, 144 mg (0.30 mmol) of 8o was cyclized to give
122 mg (97%) of 4o free base, which was converted to the
hydrochloride salt: 1H NMR (CDCl3 free base) δ 8.15 (d, 2H, J )
9.3 Hz), 7.65 (d, 2H, J ) 9.3 Hz), 7.62 (s, 1H), 6.85 (d, 2H, J )
8.4 Hz), 6.69 (d, 2H, J ) 8.4 Hz), 3.48 (m, 1H), 3.34 (m, 1H),
3.22 (m, 2H), 2.35 (m, 1H), 2.29 (s, 3H), 2.11 (s, 3H), 2.10 (m,
2H), 1.60 (m, 2H), 1.56 (m, 1H); 13C NMR (CDCl3) δ 137.49,
127.80, 126.43, 125.58, 123.30, 64.67, 60.67, 52.23, 40.72, 35.91,
33.89, 24.92, 24.57, 19.97; LCMS (ESI) m/z 420.8 (M + 1)+. The
hydrochloride salt had a mp of 170-176 °C; [R]20D -16.5° (c 0.20,
CH3OH). Anal. (C24H26ClN3O2S‚2.5H2O) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-3-nitrophenacylcarboxa-
mide Ethylene Ketal (7p). Using a procedure similar to that
described for 8k, 244 mg (1.09 mmol) of 5b was coupled with 12f
to give 318 mg (63%) of 7p as a white solid: 1H NMR (CDCl3) δ
9.99 (bt, 1H), 8.43 (s, 1H), 8.18 (d, 1H, J ) 8.1 Hz), 7.87 (d, 1H,
J ) 8.1 Hz), 7.56 (dd, 1H, J ) 8.1 Hz), 7.99 (d, 2H, J ) 8.1 Hz),
6.90 (d, 2H, J ) 8.1 Hz), 4.16 (m, 2H), 3.92 (m, 2H), 3.68 (dd,
1H), 3.58 (dd, 1H), 3.28 (m, 1H), 3.21 (m, 1H), 3.00 (m, 1H),
2.42 (dd, 1H), 2.26 (s, 3H), 2.25 (s, 3H), 2.12 (m, 3H), 1.72 (m,
2H), 1.61 (dt, 1H); 13C NMR (CDCl3) δ 132.90, 129.80, 129.32,
127.87, 123.90, 121.71, 65.74, 65.61, 64.25, 61.82, 54.70, 46.63,
41.48, 35.89, 35.43, 26.48, 25.36, 21.47; LCMS (ESI) m/z 466.7
(M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-(3-nitrophenacyl)carboxthio-
amide Ethylene Ketal (8p). Using a procedure similar to that
described for 8k, 303 mg (0.70 mmol) of 7p was converted to 141
mg (45%) of 8p as a tan solid: 1H NMR (CDCl3) δ 9.99 (bt, 1H),
8.49 (dd, 1H, J ) 1.8 Hz), 8.25 (dd, 1H, J ) 1.8, 8.4 Hz), 7.94
(dd, 1H, J ) 1.8, 8.4 Hz), 7.62 (dd, 1H, J ) 8.4 Hz), 7.99 (d, 2H,
J ) 8.4 Hz), 6.83 (d, 2H, J ) 8.4 Hz), 4.23 (m, 2H), 3.99 (m, 2H),
3.85 (d, 1H), 3.80 (d, 1H), 3.45 (d, 1H), 3.31 (m, 1H), 3.19 (m,
1H), 3.07 (m, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 2.14 (m, 3H), 1.76
(m, 2H), 1.61 (dt, 1H); 13C NMR (CDCl3) δ 132.81, 130.09, 129.22,
128.15, 124.24, 121.65, 65.76, 65.11, 65.61, 62.03, 61.38, 53.79,
41.26, 36.46, 35.54, 26.51, 25.41, 21.48; LCMS (ESI) m/z 482.6
(M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-4-chlorophenacylcarboxthio-
amide Ethylene Ketal (8l). Using a procedure similar to that
described for 8k, 3.23 g (0.007 mol) of 7l was converted to 1.58 g
(47%) of 8l as a beige solid: 1H NMR (CDCl3) δ 12.23 (bs, 1H),
7.53 (d, 2H, J ) 8.4 Hz), 7.38 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H,
J ) 8.5 Hz), 6.91 (d, 2H, J ) 8.5 Hz), 4.17 (m, 2H), 3.97 (m, 3H),
3.75 (d, 1H), 3.43 (m, 1H), 3.29 (m, 1H), 3.21 (m, 1H), 3.10 (m,
1H), 2.27 (s, 3H), 2.22 (s, 3H), 2.10 (m, 3H), 1.73 (m, 2H), 1.58
(m, 1H); 13C NMR (CDCl3) δ 129.23, 128.98, 128.29, 127.99,
65.55, 65.44, 62.06, 61.41, 53.75, 41.27, 36.59, 35.61, 26.57, 25.42,
21.52; LCMS (ESI) m/z 472.1 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(4-chlorophenyl)thiazol-2-yl]tro-
pane (4l) Hydrochloride. Compound 8l was cyclized using a
procedure similar to that described for 4k to give 750 mg of 4l
free base, which was converted to 739 mg (89%) of the hydro-
chloride salt as an off-white powder: 1H NMR (CDCl3 free base)
δ 7.57 (s, 1H), 7.49 (d, 2H, J ) 8.4 Hz), 7.34 (d, 2H, J ) 8.4 Hz),
6.92 (d, 2H, J ) 8.4 Hz), 6.76 (d, 2H, J ) 8.4 Hz), 3.51 (m, 1H),
3.39 (m, 1H), 3.29 (m, 1H), 3.24 (t, 1H), 2.38 (m, 1H), 2.34 (s,
3H), 2.22 (s, 3H), 2.19 (m, 2H), 1.84 (m, 2H), 1.65 (m, 1H); 13C
NMR (CDCl3) δ 136.82, 129.40, 129.19, 128.04, 127.95, 66.22,
62.14, 53.58, 42.15, 37.39, 35.53, 26.39, 25.97, 21.40; LCMS (ESI)
m/z 446.5 (M + 1)+. The hydrochloride salt had a mp of 192-
195 °C; [R]20 -22.5° (c 0.20, CH3OH). Anal. (C24H26Cl2N2S‚
D
0.5H2O) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-3′-bromophenylacylcar-
boxamide Ethylene Ketal (7n). Using a procedure similar to that
described for 7k, 5b (1 mmol) was coupled to 260 mg (1 mmol)
of 12e to give 255 mg (52%) of 7n as a white solid: 1H NMR
(CDCl3) δ 9.88 (bt, 1H), 7.73 (dd, 1H, J ) 1.8 Hz), 7.49-7.46
(m, 2H, J ) 8.1 Hz), 7.28 (d, 1H, J ) 8.1 Hz), 6.99 (d, 2H, J )
8.1 Hz), 6.91 (d, 2H, J ) 8.1 Hz), 4.12 (m, 2H), 3.92 (m, 2H),
3.58 (m, 2H), 3.27 (m, 2H), 3.00 (m, 1H), 2.44 (dd, 1H), 2.26 (s,
3H), 2.21 (s, 3H), 2.13 (m, 3H), 1.74-1.55 (m, 3H); 13C NMR
(CDCl3) δ 131.91, 130.35, 129.77, 129.32, 128.00, 125.26, 65.53,
65.40, 64.29, 61.82, 54.84, 46.96, 41.44, 35.95, 35.61, 26.49, 25.39,
21.49; LCMS (ESI) m/z 499.6 (M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-3′-bromophenylacylcar-
boxthioamine Ethylene Ketal (8n). Using a procedure similar to
that described for 8k, 268 mg (0.54 mmol) of 7n was converted to
107 mg (68%) of 8n as a tan solid: 1H NMR (CDCl3) δ 12.23 (bs,
1H), 7.78 (d, 1H, J ) 1.8 Hz), 7.51 (m, 2H), 7.30 (dd, 1H, J ) 7.8
Hz), 7.00 (d, 2H, J ) 8.1 Hz), 6.82 (d, 2H, J ) 8.1 Hz), 4.16 (m,
2H), 3.97 (m, 3H), 3.72 (dd, 1H), 3.42 (m, 1H), 3.32 (m, 1H),
3.16 (dd, 1H), 3.00 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.12 (m,
3H), 1.75 (m, 2H), 1.57 (m, 1H); 13C NMR (CDCl3) δ 131.89,
130.17, 129.29, 128.83, 127.86, 124.86, 65.19, 65.13, 61.62, 61.07,
53.83, 40.87, 36.16, 35.13, 26.16, 25.06, 21.11; LCMS (ESI) m/z
515.7 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(3′-bromophenyl)thiazol-2-yl]tro-
pane (4n) Hydrochloride. Using a procedure similar to that
described for 4k, 107 mg (0.208 mmol) of 8n was cyclized to give
64 mg (67%) of 4n free base: 1H NMR (CDCl3) δ 7.72 (dd, 1H,
J ) 1.8 Hz), 7.58 (s, 1H), 7.50 (dd, 1H, J ) 1.8, 7.8 Hz), 7.38 (dd,
1H, J ) 7.8 Hz), 7.22 (dd, 2H, J ) 8.1 Hz), 6.92 (d, 2H, J ) 8.1
Hz), 6.72 (d, 2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.38 (m, 1H), 3.25
(m, 2H), 2.43 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.17 (m, 2H),
1.83 (m 2H), 1.59 (m, 1H); 13C NMR (CDCl3) δ 137.20, 130.72,
130.69, 129.67, 129.21, 127.93, 125.38, 66.19, 62.14, 53.62, 42.17,
37.41, 35.50, 26.39, 25.99, 21.40; LCMS (ESI) m/z 453.0 (M +
1)+. The hydrochloride salt had a mp of 223-224 °C; [R]20D -20.0°
(c 0.20, CH3OH). Anal. (C24H26BrClN2S) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-4-nitrophenacylcarboxa-
mide Ethylene Ketal (7o). Using a procedure similar to that
described for 7k, 260 mg (1 mmol) of 5b was coupled to 225 mg
(1 mmol) of 12c to give 415 mg (89%) of 7o as a white solid: 1H
NMR (CDCl3) δ 9.92 (bt, 1H), 8.21 (d, 2H, J ) 9.3 Hz), 7.72 (d,
2H, J ) 9.3 Hz), 7.01 (d, 2H, J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4
3â-(4-Methylphenyl)-2â-[5-(3-nitrophenyl)thiazol-2-yl]tro-
pane (4p) Hydrochloride. Using a procedure similar to that
described for 4k, 132 mg (0.274 mmol) of 8p was cyclized to give
88 mg (76%) of 4p free base, which yielded 65 mg (65%) of the
hydrochloride salt as a white solid: 1H NMR (CDCl3 free base) δ
8.41 (s, 1H), 8.12 (dd, 1H, J ) 1.8, 7.5 Hz), 7.88 (d, 1H, J ) 7.5
Hz), 7.70 (s, 1H), 7.54 (dd, 1H, J ) 7.5 Hz), 6.94 (d, 2H, J ) 8.1
Hz), 6.77 (d, 2H, J ) 8.1 Hz), 3.54 (m, 1H), 3.42 (m, 1H), 3.30
(m, 1H), 3.26 (m, 1H), 2.43 (s, 3H), 2.29 (m, 3H), 2.23 (s, 3H),
1.85 (m, 2H), 1.64 (dt, 1H); 13C NMR (CDCl3) δ 138.03, 132.42,
130.19, 129.24, 127.89, 122.33, 121.49, 66.15, 62.13, 53.64, 42.17,
37.35, 35.36, 26.37, 26.00, 21.40; LCMS (ESI) m/z 420.9 (M +
1)+. The hydrochloride salt had a mp of 208-211 °C; [R]20D -10.5°
(c 0.20, CH3OH). Anal. (C24H26ClN3O2S‚1H2O) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-4-methoxyphenacyl)car-
boxamide Ethylene Ketal (7q). Using a procedure similar to that

2â-Phenylthiazole Analogs of 3â-Phenyltropanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3693
described for 7k, 250 mg (1 mmol) of 5b was coupled with 250
mg (1 mmol) of 12d to give 286 mg (53%) of 7q as a clear oil:
1H NMR (CDCl3) δ 9.87 (bt, 1H), 7.47 (d, 2H, J ) 8.1 Hz), 7.02
(d, 2H, J ) 8.1 Hz), 6.98 (d, 2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1
Hz), 4.11 (m, 2H), 3.92 (m, 2H), 3.81 (s, 3H), 3.59 (d, 2H, J ) 5.1
Hz), 3.24 (m, 2H), 3.00 (m, 1H), 2.44 (dd, 1H), 2.28 (s, 3H), 2.19
(s, 3H), 2.15 (m, 3H), 1.70 (m, 2H), 1.60 (dt, 1H); 13C NMR
(CDCl3) δ 129.33, 128.10, 127.76, 113.93, 65.37, 65.19, 64.31,
61.85, 55.71, 54.90, 46.77, 41.49, 36.08, 35.71, 26.53, 25.38, 21.50;
LCMS (ESI) m/z 451.5 (M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-(4-methoxyphenacyl)car-
boxthioamide Ethylene Ketal (8q). Using a procedure similar to
that described for 8k, 280 mg (0.62 mmol) of 7q was converted to
83 mg (29%) of 8q as a tan solid: 1H NMR (CDCl3) δ 12.14 (bs,
1H), 7.50 (d, 2H, J ) 8.1 Hz), 7.02 (d, 2H, J ) 8.1 Hz), 6.92 (d,
4H, J ) 8.4 Hz), 4.14 (m, 2H), 3.96 (m, 3H), 3.81 (s, 3H), 3.75 (d,
1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.20 (dd, 1H), 3.09 (m, 1H), 2.27
(s, 3H), 2.21 (s, 3H), 2.14 (m, 3H), 1.72 (m, 2H), 1.57 (dt, 1H);
13C NMR (CDCl3) δ 129.21, 128.35, 127.76, 114.11, 65.57, 65.32,
65.27, 62.09, 61.32, 55.77, 53.98, 41.23, 36.62, 35.56, 26.55, 25.41,
21.51; LCMS (ESI) m/z 467.6 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(4-methoxyphenyl)thiazol-2-yl]tro-
pane (4q) Hydrochloride. Using a procedure similar to that
described for 4k, 110 mg (0.24 mmol) of 8q was cyclized to give
72 mg (75%) of 4q free base, which was converted to the
hydrochloride salt: 1H NMR (CDCl3) δ 7.50 (d, 2H J ) 8.7 Hz),
7.49 (s, 1H), 6.92 (d, 2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1 Hz),
6.77 (d, 2H, J ) 8.1 Hz), 3.83 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H),
3.30 (m, 1H), 3.22 (m, 1H), 2.41 (m, 1H), 2.33 (s, 3H), 2.25 (m,
2H), 2.21 (s, 3H), 1.83 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3)
δ 135.55, 129.15, 128.13, 128.01, 114.72, 66.31, 62.18, 55.79,
53.55, 42.15, 37.46, 35.69, 26.42, 25.95, 21.39; LCMS (ESI) m/z
405.7 (M + 1)+. The hydrochloride salt had a mp of 155-160 °C;
[R]20D -14.5° (c 0.20, CH3OH). Anal. (C25H30ClN2OS‚1.5H2O) C,
H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-(3,4-dichlorophenacyl)car-
boxamide Ethylene Ketal (7r). Using a procedure similar to that
described for 7k, 1.04 g (0.004 mol) of 5b was coupled with 1.0 g
(0.004 mol) of 12g to give 1.33 g (67%) of 7r as a white powder:
1H NMR (CDCl3) δ 9.86 (bt, 1H), 7.66 (d, 1H, J ) 1.8 Hz), 7.45
(d, 1H, J ) 8.1 Hz), 7.36 (d, 1H, J ) 8.1 Hz), 7.01 (d, 2H, J ) 8.4
Hz), 6.95 (d, 2H, J ) 8.4 Hz), 4.10 (m, 2H), 3.91 (m, 2H), 3.57
(d, 2H, J ) 5.4 Hz), 3.29 (m, 1H), 3.23 (m, 1H), 3.03 (m, 1H),
2.45 (dd, 1H, J ) 6.9 Hz), 2.26 (s, 3H), 2.21 (s, 3H), 2.15 (m,
3H), 1.65 (m, 3H); 13C NMR (CDCl3) δ 130.77, 129.34, 128.81,
127.94, 126.08, 65.62, 65.46, 64.30, 61.83, 54.78, 46.65, 41.47,
35.91, 35.51, 26.91, 25.37, 21.51; LCMS (ESI) m/z 489.3 (M +
1)+.
3â-(4-Methylphenyl)tropane-2â-N-(3,4-dichlorophenacyl)car-
boxthioamide Ethylene Ketal (8r). Using a procedure similar to
that described for 8k, 977 mg (2.0 mmol) of 7r was converted to
597 mg (59%) of 8r as a beige crystalline powder: 1H NMR
(CDCl3) δ 12.24 (bs, 1H), 7.71 (d, 1H, J ) 1.8 Hz), 7.49 (d, 1H,
J ) 8.4 Hz), 7.41 (dd, 1H, J ) 2.1 Hz, 8.4 Hz), 7.02 (d, 2H, J )
7.8 Hz), 6.87 (d, 2H, J ) 7.8 Hz), 4.17 (m, 2H), 3.95 (m, 3H),
3.75 (dd, 1H, J ) 15 Hz), 3.42 (m, 1H), 3.32 (m, 1H), 3.21 (m,
1H), 3.08 (m, 1H), 2.27 (s, 3H), 2.23 (s, 3H), 2.15 (m, 3H), 1.68
(m, 3H); 13C NMR (CDCl3) δ 130.57, 128.82, 128.33, 127.80,
125.62, 65.19, 65.17, 65.13, 61.61, 61.03, 53.42, 40.86, 36.11,
35.13, 26.14, 26.02, 21.09; LCMS (ESI) m/z 505.6 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(3,4-dichlorophenyl)thiazol-2-yl]-
tropane (4r) Hydrochloride. Using a procedure similar to that
described for 4k, 567 mg (1.18 mmol) of 8r was cyclized to give
505 mg of 4r free base, which was converted to 410 mg (75%) of
the hydrochloride salt: 1H NMR (CDCl3 free base) δ 7.65 (d, 1H,
J ) 1.5 Hz), 7.56 (s, 1H), 7.40 (m, 2H), 6.92 (d, 2H, J ) 8.1 Hz),
6.75 (d, 2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.39 (m, 1H), 3.25 (m,
2H), 2.42 (m, 1H), 2.35 (s, 3H), 2.22 (s, 3H), 2.19 (m, 2H), 1.84
(m, 2H), 1.64 (m, 1H); 13C NMR (CDCl3) δ 137.43, 131.11, 129.21,
128.43, 127.90, 125.95, 66.16, 62.13, 53.60, 42.16, 37.37, 35.43,
26.37, 25.99, 21.40; LCMS (ESI) m/z 443.8 (M + 1)+. The
hydrochloride salt had a mp of 214-216 °C; [R]20D -13.0° (c 0.20,
CH3OH). Anal. (C24H25Cl3N2S) C, H, N, S.
3â-(4-Methylphenyl)tropane-2â-N-3,4-dimethoxyphenacyl-
carboxamide Ethylene Ketal (7s). Using a procedure similar to
that described for 7k, 893 mg (3.44 mmol) of 5b was coupled to
825 mg (3.44 mmol) of 12h to give 1.42 g (86%) of 7s as a clear
viscous oil: 1H NMR (CDCl3) δ 9.86 (bt, 1H), 7.11 (dd, 1H, J )
2.1, 8.1 Hz), 7.05 (d, 1H, J ) 2.1 Hz), 6.99 (d, 2H, J ) 9 Hz),
6.98 (d, 2H, J ) 9 Hz), 6.86 (d, 1H, J ) 8.1 Hz), 4.10 (m, 2H),
3.94 (m, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.61 (d, 2H, J ) 5.1 Hz),
3.25 (m, 2H), 3.03 (m, 1H), 2.46 (dd, 1H, J ) 6.6 Hz), 2.26 (s,
3H), 2.15 (s, 3H), 2.10 (m, 3H), 1.70 (m, 3H); 13C NMR (CDCl3)
δ 129.32, 128.08, 118.85, 111.11, 109.69, 65.44, 65.22, 65.36,
61.87, 56.37, 54.91, 46.61, 41.51, 36.12, 35.68, 26.53, 25.37, 21.50;
LCMS (ESI) m/z 481.5 (M + 1)+.
3â-(4-Methylphenyl)tropane-2â-N-3,4-dimethoxyphenacyl-
carboxthioamide Ethylene Ketal (8s). Using a procedure similar
to that described for 4k, 1.05 g (0.0021 mol) of 7s was converted
to 520 mg (47%) of 8s as a tan crystalline solid: 1H NMR (CDCl3)
δ 12.21 (bs, 1H), 7.15 (dd, 1H, J ) 2.1, 8.1 Hz), 7.08 (d, 1H, J )
2.1 Hz), 7.02 (d, 2H, J ) 7.8 Hz), 6.95 (d, 2H, J ) 7.8 Hz), 6.90
(d, 1H, J ) 8.1 Hz), 4.16 (m, 2H), 3.99 (m, 2H), 3.98 (m, 1H),
3.93 (s, 3H), 3.89 (s, 3H), 3.81 (d, 1H), 3.43 (d, 1H), 3.27 (m,
1H), 3.20 (m, 1H), 3.09 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.10
(m, 3H), 1.70 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3) δ 129.92,
129.05, 119.62, 111.196, 110.37, 66.27, 66.09, 66.04, 62.80, 62.21,
57.16, 54.59, 42.02, 37.35, 36.35, 27.30, 26.14, 22.23; LCMS (ESI)
m/z 497.8 (M + 1)+.
3â-(4-Methylphenyl)-2â-[5-(3,4-dimethoxyphenyl)thiazol-2-yl]-
tropane (4s) Dihydrochloride. Using a procedure similar to that
described for 4k, 520 mg (1.03 mmol) of 8s was cyclized to 450
mg of 4s free base, which was converted to 450 mg (82%) of the
dihydrochloride salt: 1H NMR (CDCl3 free base) δ 7.50 (s, 1H),
7.14 (dd, 1H, J ) 2.1, 8.1 Hz), 7.05 (d, 1H, J ) 2.1 Hz), 6.92 (d,
2H, J ) 7.8 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 6.77 (d, 2H, J ) 7.8
Hz), 3.95 (s, 3H), 3.90 (s, 3H), 3.50 (m, 1H), 3.39 (m, 1H), 3.31
(m, 1H), 3.23 (m, 1H), 2.42 (m, 1H), 2.34 (s, 3H), 2.22 (s, 3H),
2.16 (m, 2H), 1.82 (m, 2H), 1.63 (m, 1H); 13C NMR (CDCl3) δ
135.72, 129.17, 128.02, 119.61, 111.99, 110.31, 66.31, 62.17, 56.51,
56.45, 53.56, 42.17, 37.45, 35.70, 26.43, 25.85, 21.40; LCMS (ESI)
m/z 435.7 (M + 1)+. The dihydrochloride salt had a mp of 140-
148 °C; [R]20 -7.5° (c 0.20, CH3OH). Anal. (C25H32Cl2N2O2S‚
D
1.25H2O) C, H, N, S.
3â-(4-Chlorophenyl)tropane-2â-N-3-bromophenacylcarboxa-
mide Ethylene Ketal (7e). Using a procedure similar to that
described for 7k, 279 mg (1 mmol) of 5a was coupled with 259
mg (1 mmol) of 12e to give 145 mg (28%) of 7e as a white solid:
1H NMR (CDCl3) δ 9.89 (bt, 1H), 7.73 (dd, 1H, J ) 1.8 Hz), 7.48
(dd, 2H, J ) 1.8, 7.8 Hz), 7.28 (dd, 1H, J ) 7.8 Hz), 7.14 (d, 2H,
J ) 8.4 Hz), 6.95 (d, 2H, J ) 8.4 Hz), 4.11 (m, 2H), 3.91 (m, 2H)
3.65 (dd, 1H), 3.55 (dd, 1H), 3.30 (m, 1H), 3.24 (dd, 1H), 3.00
(m, 1H), 2.43 (dd, 1H), 2.20 (s, 3H), 2.11 (m, 3H), 1.70-1.59 (m,
3H); 13C NMR (CDCl3) δ 131.96, 130.42, 129.76, 129.53, 128.69,
125.25, 65.53, 65.40, 64.19, 61.69, 54.62, 47.00, 41.39, 35.85,
35.50, 26.46, 25.35; LCMS (ESI) m/z 521.7 (M + 1)+.
3â-(4-Chlorophenyl)tropane-2â-N-3-bromophenacylcarboxthio-
amide Ethylene Ketal (8e). Using a procedure similar to that
described for 8k, 140 mg (0.270 mmol) of 7e was converted to 61
mg (42%) of 8e as a tan solid: 1H NMR (CDCl3) δ 12.23 (bs,
1H), 7.77 (dd, 1H), 7.51 (dd, 2H, J ) 1.5, 7.8 Hz), 7.31 (dd, 1H
J ) 7.8 Hz), 7.16 (d, 2H, J ) 8.4 Hz), 6.86 (d, 2H, J ) 8.4 Hz),
4.16 (m, 2H), 3.96 (m, 3H), 3.67 (d, 1H), 3.43 (d, 1H), 3.33 (m,
1H), 3.15 (d, 1H), 3.07 (m, 1H), 2.23 (s, 3H), 2.08 (m, 3H), 1.74-
1.55 (m, 3H); 13C NMR (CDCl3) δ 131.93, 130.22, 129.33, 129.26,
128.21, 124.84, 65.18, 65.13, 61.46, 60.81, 53.82, 40.80, 35.95,
35.92, 26.12, 25.00; LCMS (ESI) m/z 535.3 (M + 1)+.
3â-(4-Chlorophenyl)-2â-[5-(3-bromo-2-thiazol)-2-yl]tro-
pane (4e) Hydrochloride. Using a procedure similar to that
described for 4k, 61 mg (0.114 mmol) of 8e was cyclized to give
36 mg (67%) of 4e free base, which was converted to the
hydrochloride salt as a tan solid: 1H NMR (CDCl3 free base) δ

3694 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Gong et al.
7.72 (dd, 1H), 7.59 (s, 1H), 7.50 (dd, 1H, J ) 1.5, 6.9 Hz), 7.41(d,
1H, J ) 1.5, 6.9 Hz), 7.21 (dd, 1H, J ) 7.8 Hz), 7.08 (d, 2H, J )
8.4 Hz), 6.80 (d, 2H, J ) 8.4 Hz), 3.50 (dd, 1H), 3.40 (m, 1H),
3.31 (t, 1H), 3.24 (t, 1H), 2.35 (s, 3H), 2.23 (m, 3H), 1.82 (m,
2H), 1.64 (dt, 1H); 13C NMR (CDCl3) δ 137.24, 130.83, 130.76,
129.71, 129.41, 128.58, 125.36, 66.08, 62.00, 53.39, 42.13, 37.27,
35.32, 26.38, 25.93; LCMS (ESI) m/z 475.8 (M + 1)+. The
hydrochloride salt had a mp of 185-200 °C; [R]20D -26.5° (c 0.20,
CH3OH). Anal. (C23H23BrCl2N2S‚2.0H2O) C, H, N, S.
3â-(4-Chlorophenyl)tropane-2â-N-(3-nitrophenacyl)carboxa-
mide Ethylene Ketal (7g). Using a procedure similar to that
described for 7k, 321 mg (1.15 mmol) of 5a was coupled with 257
mg (1.15 mmol) of 12f to give 128 mg (23%) of 7g as a white
solid: 1H NMR (CDCl3) δ 9.98 (bt, 1H), 8.42 (dd, 1H, J ) 2.1
Hz), 8.20 (dd, 1H, J ) 2.1, 7.5 Hz), 7.87 (dd, 1H, J ) 2.1, 7.5
Hz), 7.56 (dd, 1H, J ) 7.5 Hz), 7.14 (d, 1H, J ) 8.7 Hz), 6.97 (d,
2H, J ) 8.7 Hz), 4.16 (m, 2H), 3.92 (m, 2H) 3.64 (dd, 1H), 3.56
(dd, 1H), 3.29 (m, 1H), 3.23 (dd, 1H), 3.00 (m, 1H), 2.43 (dd,
1H), 2.25 (s, 3H), 2.14 (m, 3H), 1.67 (m, 3H); LCMS (ESI) m/z
486.5 (M + 1)+.
3â-(4-Chlorophenyl)tropane-2â-N-(3-nitrophenacyl)carboxthio-
amide Ethylene Ketal (8g). Using a procedure similar to that
described for 8k, 256 mg (0.53 mmol) of 7g was converted to 155
mg (54%) of 8g as a tan solid: 1H NMR (CDCl3) δ 12.34 (bs,
1H), 8.48 (dd, 1H, J ) 2.1 Hz), 8.25 (dd, 1H, J ) 2.1, 7.5 Hz),
7.91 (dd, 1H, J ) 2.1, 7.5 Hz), 7.62 (dd, 1H, J ) 7.8 Hz), 7.15 (d,
2H, J ) 8.1 Hz), 6.89 (d, 2H, J ) 8.1 Hz), 4.22 (m, 2H), 3.97 (m,
3H), 3.82 (d, 1H), 3.44 (d, 1H), 3.31 (m, 1H), 3.18 (d, 1H), 3.10
(m, 1H), 2.27 (s, 3H), 2.10 (m, 3H), 1.75 (m, 2H), 1.54 (m, 1H);
13C NMR (CDCl3) δ 132.82, 130.16, 129.63, 128.60, 124.28,
121.61, 65.74, 65.72, 65.46, 61.86, 61.17, 53.76, 41.25, 36.31,
35.42, 26.52, 25.37; LCMS (ESI) m/z 503.0 (M + 1)+.
3â-(4-Chlorophenyl)-2â-[5-(3,4-dichlorophenyl)thiazol-2-yl]-
tropane (4i) Hydrochloride. Using a procedure similar to that
described for 4k, 619 mg (1.18 mmol) of 8i was cyclized to give
501 mg (92%) of 4i free base, which was converted to the
hydrochloride salt as a white solid: 1H NMR (CDCl3 free base) δ
7.65 (d, 1H, J ) 1.8 Hz), 7.58 (s, 1H), 7.42 (d, 1H, J ) 8.4 Hz),
7.38 (dd, 1H, J ) 1.8, 8.4 Hz), 7.08 (d, 2H, J ) 8.1 Hz), 6.79 (d,
2H, J ) 8.1 Hz), 3.51 (m, 1H), 3.40 (m, 1H), 3.29 (m, 1H), 3.25
(m, 1H), 2.38 (m, 1H), 2.35 (s, 3H), 2.21 (m, 2H), 1.83 (m, 2H),
1.63(m, 1H); 13C NMR (CDCl3) δ 25.93, 26.37, 35.25, 37.22, 42.12,
53.38, 61.98, 66.04, 125.93, 128.46, 128.60, 129.39, 131.16, 137.48;
LCMS (ESI) m/z 465.4 (M + 1)+. The hydrochloride salt had a
mp of 164-172 °C; [R]20D -20.5° (c 0.20, CH3OH). Anal. (C23H22-
Cl4N2S‚2.25H2O) C, H, N, S.
3â-(4-Chlorophenyl)tropane-2â-N-(3,4-dimethoxyphenacyl)-
carboxamide Ethylene Ketal (7j). Using a procedure similar to
that described for 7k, 1.19 g (0.0043 mol) of 5a was coupled to
1.02 g (0.0043 mol) of 12h to give 1.16 g (55%) of 7j as a white
solid: 1H NMR (CDCl3) δ 9.80 (bt, 1H), 7.17 (d, 2H, J ) 8.4 Hz),
7.12 (dd, 1H, J ) 1.8, 8.4 Hz), 7.05 (d, 2H, J ) 8.4 Hz), 7.03 (d,
1H, J ) 8.4 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 4.10 (m, 2H), 3.95 (m,
2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.63 (dq, 2H), 3.26 (d, 2H), 3.03
(m, 1H), 2.46 (dd, 1H), 2.21 (s, 3H), 2.10 (m, 3H), 1.70 (m, 3H);
13C NMR (CDCl3) δ 129.21, 128.28, 118.43, 110.68, 109.18, 65.02,
64.81, 63.83, 61.31, 55.97, 54.25, 46.24, 41.06, 35.60, 35.16, 26.08,
24.92; LCMS (ESI) m/z 501.8 (M + 1)+.
3â-(4-Chlorophenyl)tropane-2â-N-(3,4-dimethoxyphenacyl)-
carboxthioamide Ethylene Ketal (8j). Using a procedure similar
to that described for 8k, 1.16 g (0.0023 mol) of 7j was converted
to 617 mg (51%) 8j as a tan solid: 1H NMR (CDCl3) δ 12.20 (bs,
1H), 7.17 (d, 2H, J ) 8.4 Hz), 7.08 (dd, 1H, J ) 1.8, 8.4 Hz), 7.07
(d, 1H, J ) 1.8 Hz), 6.97 (d, 2H, J ) 8.4 Hz), 6.90 (d, 1H, J ) 8.4
Hz), 4.15 (m, 2H), 3.01 (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.77
(dd, 1H), 3.44 (d, 1H), 3.28 (m, 1H), 3.19 (m, 1H), 3.10 (m, 1H),
2.21 (s, 3H), 2.10 (m, 3H), 1.71 (m, 2H), 1.56 (m, 1H); 13C NMR
(CDCl3) δ 129.83, 128.57, 118.89, 111.27, 109.62, 65.43, 65.36,
65.34, 61.93, 61.26, 56.45, 53.89, 41.27, 36.45, 35.47, 26.57, 25.37;
LCMS (ESI) m/z 517.7 (M + 1)+.
3â-(4-Chlorophenyl)-2â-[5-(3,4-dimethoxyphenyl)thiazol-2-yl]-
tropane (4j) Hydrochloride. Using a procedure similar to that
described for 4k, 620 mg (1.2 mmol) of 8j was cyclized to give
515 mg (96%) of 4j free base, which was converted to the
hydrochloride salt: 1H NMR (CDCl3, free base) δ 7.50 (s, 1H),
7.15 (dd, 1H, J ) 1.8, 8.4 Hz), 7.10 (d, 2H, J ) 8.4 Hz), 7.05 (d,
1H, J ) 1.8 Hz), 6.86 (d, 1H, J ) 8.4 Hz), 6.83 (d, 2H, J ) 8.4
Hz), 3.95 (s, 3H), 3.91 (s, 3H), 3.50 (m, 1H), 3.40 (m, 1H), 3.31
(m, 1H), 3.24 (m, 1H), 2.36 (m, 1H), 2.35 (s, 3H), 2.23 (m, 2H),
1.65 (m, 2H), 1.60 (m, 1H); 13C NMR (CDCl3) δ 135.74, 129.50,
128.54, 119.64, 111.99, 110.24, 66.17, 62.02, 56.51, 56.45, 53.35,
42.14, 37.33, 35.49, 26.43, 25.91; LCMS (ESI) m/z 455.6 (M +
1)+. The hydrochloride salt had a mp of 159-168 °C; [R]20D -9.0°
(c 0.20, CH3OH). Anal. (C25H28.5Cl2.5N2O2S‚1.75H2O) C, H, N, S.
3â-(4-Chlorophenyl)-2â-[5-(3-nitrophenylthiazol)-2-yl]tro-
pane (4g) Hydrochloride. Using a procedure similar to that
described for 4k, 155 mg (0.31 mmol) of 8g was cyclized to give
104 mg (76%) of 4g free base, which was converted to the
hydrochloride salt as a tan solid: 1H NMR (CDCl3 free base) δ
8.41 (dd, 1H, J ) 1.8 Hz), 8.13 (dd, 1H, J ) 1.8 Hz), 7.89 (dd,
1H, J ) 1.8, 8.4 Hz), 7.70 (s, 1H, J ) 7.5 Hz), 7.57 (dd, 1H, J )
7.5 Hz), 7.10 (d, 2H, J ) 6.9 Hz), 6.82 (d, 2H, J ) 6.9 Hz), 3.54
(dd, 1H), 3.43 (m, 1H), 3.31 (m, 1H), 3.27 (t, 1H), 2.37 (s, 3H),
2.22 (m, 3H), 1.85 (m, 2H), 1.65 (m, 1H); 13C NMR (CDCl3) δ
138.06, 132.36, 130.24, 129.37, 127.62, 122.45, 121.55, 66.03,
61.98, 53.42, 42.15, 37.19, 35.18, 26.36, 25.95; LCMS (ESI) m/z
440.6 (M + 1)+. The hydrochloride salt had a mp of 160-162 °C;
[R]20 -25.5° (c 0.20, CH3OH). Anal. (C23H24Cl3N3O2S‚1.5H2O)
D
C, H, N, S.
3â-(4-Chlorophenyl)tropane-2â-N-(3,4-dichlorophenacyl)car-
boxamide Ethylene Ketal (7i). Using a procedure similar to that
described for 7k, 1.19 g (0.0043 mol) of 5a was coupled with 1.04
g (0.0043 mol) of 12g to give 0.83 g (39%) of 7i as a white
powder: 1H NMR (CDCl3) δ 9.88 (bt, 1H), 7.65 (d, 1H, J ) 1.8
Hz), 7.46 (d, 1H, J ) 8.1 Hz), 7.36 (dd, 1H, J ) 2.1 Hz, 8.1 Hz),
7.17 (d, 2H, J ) 8.4 Hz), 7.00 (d, 2H, J ) 8.4 Hz), 4.12 (m, 2H),
3.90 (m, 2H), 3.58 (m, 2H), 3.29 (m, 1H), 3.24 (m, 1H), 3.03 (m,
1H), 2.45 (dd, 1H, J ) 9 Hz), 2.21 (s, 3H), 2.13 (m, 3H), 1.65 (m,
3H); 13C NMR (CDCl3) δ 130.45, 129.10, 128.42, 128.33, 125.68,
65.23, 65.07, 63.83, 61.32, 54.19, 46.28, 41.03, 35.46, 35.04, 26.08,
24.96; LCMS (ESI) m/z 511.3 (M + 1)+.
Acknowledgment. This research was supported by the
National Institute on Drug Abuse under projects DA05477 and
DA-1-8815. We thank the NIDA (CTDP, Division of Pharma-
cotherapies and Medical Consequences of Drug Abuse) for the
data in Table 2.
3â-(4-Chlorophenyl)tropane-2â-N-(3,4-dichlorophenacyl)car-
boxthioamide Ethylene Ketal (8i). Using a procedure similar to
that described for 8k, 835 mg (1.64 mmol) of 7i was converted to
366 mg (42%) of 8i as a beige crystalline solid: 1H NMR (CDCl3)
δ 12.22 (bs, 1H), 7.70 (d, 1H, J ) 1.8 Hz), 7.50 (d, 1H, J ) 8.1
Hz), 7.41 (dd, 1H, J ) 1.8, 8.1 Hz), 7.16 (d, 2H, J ) 8.4 Hz), 6.92
(d, 2H, J ) 8.4 Hz), 4.17 (m, 2H), 3.9 (m, 3H), 3.72 (dd, 1H, J )
2.4, 15 Hz), 3.43 (bd, 1H), 3.41 (m, 1H), 3.20 (bd, 1H), 3.10 (m,
1H), 2.22 (s, 3H), 2.10(m, 3H), 1.7 (m, 3H); 13C NMR (CDCl3) δ
131.03, 129.70, 128.71, 128.60, 126.01, 65.58, 65.43, 61.87, 61.21,
53.81, 41.21, 36.34, 35.37, 26.52, 25.38; LCMS (ESI) m/z 527.6
(M + 1)+.
Supporting Information Available: Elemental analysis. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) Sotnikova, T. D.; Beaulieu, J. M.; Barak, L. S.; Wetsel, W. C.; Caron,
M. G.; Gainetdinov, R. R. Dopamine-independent locomotor actions
of amphetamines in a novel acute mouse model of Parkinson disease.
PLoS Biol. 2005, 3, e271.
(2) Uhl, G. R. Dopamine transporter: basic science and human variation
of a key molecule for dopaminergic function, locomotion, and
parkinsonism. MoVement Disorders 2003, 18, S71-S80.

2â-Phenylthiazole Analogs of 3â-Phenyltropanes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15 3695
(3) Uhl, G. R. Hypothesis: The role of dopaminergic transporters in
selective vulnerability of cells in Parkinsons disease. Ann. Neurol.
1998, 43, 555-560.
(18) Kotian, P.; Abraham, P.; Lewin, A. H.; Mascarella, S. W.; Boja, J.
W.; Kuhar, M. J.; Carroll, F. I. Synthesis and ligand binding study
of 3â-(4′-substituted phenyl)-2â-(heterocyclic)tropanes. J. Med.
Chem. 1995, 38, 3451-3453.
(19) Kotian, P.; Mascarella, S. W.; Abraham, P.; Lewin, Anita H.; Boja
, John W.; Kuhar, Michael J.; Carroll, F. I. Synthesis, ligand binding,
and quantitative structure-activity relationship study of 3â-(4′-
substituted phenyl)-2â-(heterocyclic)tropanes: Evidence for an elec-
trostatic interaction at the 2â-position. J. Med. Chem. 1996, 39,
2753-2763.
(20) Carroll, F. I.; Howard, J. L.; Howell, L. L.; Fox, B. S.; Kuhar, M. J.
Development of the dopamine transporter selective RTI-336 as a
pharmacotherapy for cocaine abuse. AAPS J. 2006, 8, E196-203.
(21) Carroll, F. I.; Fox, B. S.; Kuhar, M. J.; Howard, J. L.; Pollard, G.
T.; Schenk, S. Effects of dopamine transporter selective 3-phenyl-
tropane analogs on locomotor activity, drug discrimination, and
cocaine self-administration after oral administration. Eur. J. Phar-
macol. 2006, 553, 149-156.
(22) Howell, L. L.; Carroll, F. I.; Votaw, J. R.; Goodman, M. M.; Kimmel,
H. L. Effects of combined dopamine and serotonin transporter
inhibitors on cocaine self-administration in rhesus monkeys. J.
Pharmacol. Exp. Ther. 2006, 320, 757-765.
(23) Charette, A. B.; Chua, P. Thiolysis and hydrolysis of imino and
iminium triflates: Synthesis of secondary and tertiary thioamides and
O18-labelled amides. Tetrahedron Lett. 1998, 39, 245-248.
(24) Staudinger, H.; Meyer, J. Synthesis of phosphazo compounds by the
reaction of tertiary phosphines with organic azides. HelV. Chim. Acta
1919, 2, 635.
(25) Boja, J. W.; Rahman, M. A.; Philip, A.; Lewin, A. H.; Carroll, F. I.;
Kuhar, M. J. Isothiocyanate derivatives of cocaine: Irreversible
inhibition of ligand binding at the dopamine transporter. Mol.
Pharmacol. 1991, 39, 339-345.
(26) Carroll, F. I.; Gray, J. L.; Abraham, P.; Kuzemko, M. A.; Lewin, A.
H.; Boja, J. W.; Kuhar, M. J. 3-Aryl-2-(3′-substituted-1′,2′,4′-
oxadiazol-5′-yl)tropane analogues of cocaine: Affinities at the
cocaine binding site at the dopamine, serotonin, and norepinephrine
transporters. J. Med. Chem. 1993, 36, 2886-2890.
(27) Eshleman, A. J.; Carmolli, M.; Cumbay, M.; Martens, C. R.; Neve,
K. A.; Janowsky, A. Characteristics of drug interactions with
recombinant biogenic amine transporters expressed in the same cell
type. J. Pharmacol. Exp. Ther. 1999, 289, 877-885.
(4) Johnston, T. H.; Brotchie, J. M. Drugs in development for Parkinson’s
disease. Curr. Opin. InVest. Drugs 2004, 5, 720-726.
(5) Glase, S. A.; Dooley, D. J. Attention deficit hyperactivity disorder:
Pathophysiology and design of new treatments. Annual Reports in
Medicinal Chemistry; Academic Press: New York, 2004; Vol 39.
(6) DiMaio, S.; Grizenko, N.; Joober, R. Dopamine genes and attention-
deficit hyperactivity disorder: A review. J. Psychiatry Neurosci.
2003, 28, 27-38.
(7) Dailly, E.; Chenu, F.; Renard, C. E.; Bourin, M. Dopamine,
depression and antidepressants. Fundam. Clin. Pharmacol. 2004, 18,
601-607.
(8) Neurosearch, press release, 2004.
(9) Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. Cocaine
receptor: Biochemical characterization and structure-activity rela-
tionships for the dopamine transporter. J. Med. Chem. 1992, 35, 969-
981.
(10) Carroll, F. I.; Lewin, A. H.; Mascarella, S. W. Dopamine transporter
uptake blockers: Structure-activity relationships. Neurotransmitter
Transporters: Structure, Function, and Regulation, 2nd ed.; Humana
Press: Totowa, NJ, 2001; pp 381-432.
(11) Dutta, A. K.; Zhang, S.; Kolhatkar, R.; Reith, M. E. Dopamine
transporter as target for drug development of cocaine dependence
medications. Eur. J. Pharmacol. 2003, 479, 93-106.
(12) Reith, M. E. A. Neurotransmitter Transporters. Structure, Function,
and Regulation; Humana Press: Totowa, NJ, 2002.
(13) Runyon, S. P.; Carroll, F. I. Dopamine transporter ligands: Recent
developments and therapeutic potential. Curr. Top. Med. Chem. 2006,
6, 1825-1843.
(14) Runyon, S. P.; Carroll, F. I. Tropane-based dopamine transporter
uptake inhibitors. Dopamine Transporters, Chemistry, Biology and
Pharmacology; Wiley: New York, 2007.
(15) Clarke, R. L. The Tropane Alkaloids. The Alkaloids; Academic
Press: New York, 1977.
(16) Clarke, R. L.; Daum, S. J.; Gambino, A. J.; Aceto, M. D.; Pearl, J.;
Levitt, M.; Cumiskey, W. R.; Bogado, E. F. Compounds affecting
the central nervous system. 3â-Phenyltropane-2-carboxylic esters and
analogs. J. Med. Chem. 1973, 16, 1260-1267.
(17) Carroll, F. I.; Pawlush, N.; Kuhar, M. J.; Pollard, G. T.; Howard, J.
L. Synthesis, monoamine transporter binding properties, and behav-
ioral pharmacology of a series of 3â-(substituted phenyl)-2â-(3′-
substituted isoxazol-5-yl)tropanes. J. Med. Chem. 2004, 47, 296-
302.
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