Synthesis, ligand binding, and quantitative structure-activity relationship study of 3β-(4'-substituted phenyl)-2β-heterocyclic tropanes: Evidence for an electrostatic interaction at the 2β-position

Article abstract of DOI:10.1021/jm960160e

A set of 3β-(4'-substituted phenyl)-2β-heterocyclic tropanes was designed, synthesized, and characterized. We discovered that these compounds can function as bioisosteric replacements for the corresponding WIN 35,065-2 analogs which possess a 2β-carbometh

Full text of DOI:10.1021/jm960160e

J . Med. Chem. 1996, 39, 2753-2763
2753
Syn th esis, Liga n d Bin d in g, a n d Qu a n tita tive Str u ctu r e-Activity Rela tion sh ip
Stu d y of 3â-(4′-Su bstitu ted p h en yl)-2â-h eter ocyclic Tr op a n es: Evid en ce for a n
Electr osta tic In ter a ction a t th e 2â-P osition
Pravin Kotian,† S. Wayne Mascarella,† Philip Abraham,† Anita H. Lewin,† J ohn W. Boja,‡
Michael J . Kuhar,‡ and F. Ivy Carroll*,†
Chemistry and Life Sciences, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, and
Neuroscience Branch, National Institute on Drug Abuse (NIDA) Addiction Research Center, P.O. Box 5180, Baltimore,
Maryland 21224
Received February 26, 1996X
A set of 3â-(4′-substituted phenyl)-2â-heterocyclic tropanes was designed, synthesized, and
characterized. We discovered that these compounds can function as bioisosteric replacements
for the corresponding WIN 35,065-2 analogs which possess a 2â-carbomethoxy group. Several
of the compounds showed high affinity and selectivity for the dopamine transporter (DAT)
relative to the serotonin and norepinephrine transporters. From the structure-activity
relationship study, the 3â-(4′-chlorophenyl)-2â-(3′-phenylisoxazol-5-yl)tropane (5d ) emerged as
the most potent and selective compound. The binding data for 2â-heterocyclic tropanes were
found to show a high correlation with molecular electrostatic potential (MEP) minima near
one of the heteroatoms in the 2â-substituents. In contrast, low correlations were found for
other MEP minima near the 2â-substituent as well as for calculated log P or substituent volume.
These quantitative structure-activity relationship studies are consistent with an electrostatic
contribution to the binding potency of these WIN 35,065-2 analogs at the DAT.
Cocaine (1), which inhibits the presynaptic uptake of
dopamine (DA), serotonin (5-HT), and norepinephrine
(NE) in brain, is one of the most reinforcing and
addictive compounds ever studied.1-3 Interest in co-
caine and dopamine transporter (DAT) research was
greatly stimulated by reports that a binding site on the
DAT might be the site responsible for the reinforcing
properties of cocaine.4,5 Thus, the behaviors associated
with cocaine addiction are believed to result from the
inhibition of DA uptake by the binding of cocaine to
specific recognition site(s) located on the DAT of meso-
limbocorticol neurons which potentiate dopaminergic
neurotransmission leading to reinforcement.
In order to gain information about the pharmacophore
for this binding site, we have examined the effects of
variation in the structure of 3â-phenyl-2â-carbomethox-
ytropane (WIN 35,065-2, 2a ) on the inhibition of radio-
ligand binding of the DAT. The pharmacophore fea-
WIN 35,428, [3H]paroxetine, and [3H]nisoxetine binding
tures identified to be present in 2a analogs which are
at the DA, 5-HT, and NE transporters was used as an
indication of the target compound’s ability to inhibit
uptake of these neurotransmitters. The study demon-
strates that high affinity at the cocaine binding site on
the DAT can be obtained by replacing the 2â-car-
bomethoxy group of 2a with several different heterocy-
clic bioequivalents and that the 2â-isoxazole group
provides high potency and DAT selectivity. A part of
this study was described in a preliminary communica-
tion.9
Structure-activity relationship (SAR) studies di-
rected toward defining the pharmacophore for the
cocaine binding site on the DAT have been the subject
of many reports in the last 6 years.10 These studies
have largely been qualitative in nature and are still in
a speculative stage. Despite the existence of common
features, significant differences in binding may exist
even between compounds which are structurally very
similar. In previous reports, we have applied quantita-
both potent and selective for the dopamine transporter
relative to the 5-HT and NE transporters were a tropane
ring with (a) an N atom at the 8-position, (b) a small to
medium size group possessing at least one heteroatom
on the 2â-position, and (c) a 4′-substituted or 3′,4′-
disubstituted phenyl ring in the 3â-position.
In previous reports we described the synthesis and
biochemical evaluation of several 3â-(4′-substituted
phenyl)-2â-(3′-substituted-1′,2′,4′-oxadiazol-5′-yl)tro-
panes 3. These compounds were found to be excellent
bioisosteres for 3â-(4′-substituted phenyl)tropane-2â-
carboxylic acid esters such as 2b,c.6-8 The primary
objective of the present study was to replace the
metabolically labile 2â-ester group by other stable
bioisosteric heterocyclic groups. The inhibition of [3H]-
† Research Triangle Institute.
‡ NIDA Addiction Research Center.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
S0022-2623(96)00160-4 CCC: $12.00 © 1996 American Chemical Society

2754 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Kotian et al.
Sch em e 1a
a
Reagents: (a) CH3C(dNOH)R, nC4H9Li, THF, 0 °C; (b) H2SO4, THF; (c) H2O; (d) POCl3, RCONHNH2; (e) (COCl)2, CH2Cl2; (f)
C6H5CONHNH2; (g) C6H5COCH2NH2; (h) (4-CH3OC6H4P(O)-S-)2, toluene; (i) POCl3; (j) 2-aminothiophenol, CH2Cl2.
tive structure-activity relationship (QSAR) studies to
gain information about the 3â-aryl group of the WIN
35,065-2 class of compounds.11,12 In this work we now
apply QSAR studies to learn about the effects of the 2â-
substituent on binding potency.
phenone, in tetrahydrofuran at 0 °C, and the reaction
mixture was warmed to 25 °C. After 18 h at 25 °C, the
reaction mixture was added to a tetrahydrofuran solu-
tion containing sulfuric acid and was refluxed for 1 h
to give the 3â-(4′-substituted phenyl)-2â-(3′-substituted
isoxazol-5′-yl)tropanes 5a -f.13 The 3â-(4′-substituted
phenyl)-2â-(5′-substituted 1′,3′,4′-oxadiazol-2′-yl)tro-
panes 7a -c were obtained by refluxing the 3â-(4′-chloro-
or 4′-methylphenyl)tropane-2â-carboxylic acid 6a ,b 8
with N-acetyl or N-benzoyl hydrazide in phosphorus
oxychloride.14 In the case of 7a ,b, a small amount of
the 2R-isomers 8a ,b was obtained.
Ch em istr y
The syntheses of the 2-heterocyclic analogs of 3â-
phenyl-2â-carbomethoxytropanes 5a -f, 7a -c, 11a ,b,
12, 13a -b, and 14 are outlined in Scheme 1. A solution
of the appropriate 3â-(4′-substituted phenyl)tropane-2â-
carboxylic acid methyl esters 4a -c8,11,12 was added to
the dilithium salt of the oxime of acetone, or of aceto-
Acids 6a ,b were treated with oxalyl chloride, and the
resultant acid chlorides were condensed with N-benzoyl

3â-(4′-Substituted phenyl)-2â-heterocyclic Tropanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2755
Ta ble 1. Chemical Shift and Vicinal Coupling Constants for the C-2 and C-3 Protons of the 3â-Substituted-2-heterocyclic Tropanesa
a
b
Spectra were carried out on the free bases of the compounds at 500 mHz. In parts per million downfield from TMS. c J values are
in Hz.
Sch em e 2a
hydrazide and 2-aminoacetophenone to give the hy-
drazides 9a ,b or the amides 10a ,b, respectively. Cy-
clization of 9a ,b and 10a with Lawesson’s reagent15
gave the 3â-(4′-substituted phenyl)-2â-(5′-phenyl-1′,3′,4′-
thiadiazol-2′-yl)tropanes 11a ,b and the 3â-(4′-chloro-
phenyl)-2â-(5′-phenylthiazol-2′-yl)tropane (12), respec-
tively. Cyclodehydration of 10a ,b with phosphorus
oxychloride afforded the 3â-(substituted phenyl)-2â-(5′-
phenyloxazol-2′-yl)tropanes 13a ,b. Condensation of the
acid chloride from 6a with 2-aminothiophenol gave 3â-
(4′-chlorophenyl)-2â-(benzothiozol-2-yl)tropane (14). An
attempt to convert 6a directly to 14 using refluxing
phosphorus oxychloride gave mainly the R-isomer 15.
The synthesis of the 3â-(substituted phenyl)tropane-
2â-tetrazoles 18a ,b is shown in Scheme 2. Dehydration
of 3â-(4′-substituted phenyl)tropane-2â-carboxamides
16a ,b8 with trifluoroacetic anhydride and pyridine in
tetrahydrofuran gave the 2â-nitriles 17a ,b. Subjection
of the nitriles 17a ,b to a cycloaddition reaction using
trimethylsilyl azide13 afforded the tetrazoles 18a ,b.
The structural assignment for the 3â-(substituted
phenyl)-2-heterocyclic tropanes was based largely on the
methods of synthesis and elemental and 1H NMR
analysis. The vicinal couplings J 2eq,3ax ) 5.67-6.13 Hz
and J 2ax,3ax ) 11.73-12.19 Hz for the 2â- and 2R-
heterocyclic, respectively, are in accord with the stere-
ochemical assignments (Table 1).
a
Reagents: (a) (CF3CO)2O, pyridine, THF; (b) (CH3)3SiN3.

2756 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Kotian et al.
Ta ble 2. Comparison of Transporter Binding Potencies for 3â-(Substituted phenyl)-2â-heterocyclic Tropanes
a
b
Data are mean ( standard error of three or four experiments performed in triplicate. Ratios of IC50 values. c The IC50 values are
from ref 7. Cocaine has IC50 values of 89, 3300, and 1050 nM at the DA, NE, and 5-HT transporters (ref 8).
Biologica l Eva lu a tion
[3H]DA uptake data with the [3H]WIN 35,428 binding
data gave the following statistical values: n ) 6, s )
Competitive radioligand binding assays were used to
determine the affinities of target compounds. DA, 5-HT,
and NE transporter binding studies were performed as
previously described7 using [3H]WIN 35,428, [3H]par-
oxetine, and [3H]nisoxetine in striatum, frontal cortex,
and midbrain from rats, respectively. The ratios of IC50
values 5-HT/DA and NE/DA were used as a measure of
the in vitro selectivity of the compounds for the DAT
relative to the 5-HT and NE transporters. This method
of estimating selectivity has been described in previous
reports.8 Ratios above 300 have been shown to correlate
with selectivity of DA uptake relative to 5-HT and NE
uptake. The results of the binding studies are sum-
marized in Tables 2 and 3.
0.21, F ) 24, r2 ) 0.89.
Molecu la r Mod elin g
We have studied the relationship between the elec-
trostatic (molecular electrostatic potential), hydrophobic
(calculated log P), and steric (substituent volume) prop-
erties of the 2â-heterocyclic moiety of several 3â-(4′-chlo-
rophenyl)tropane analogs and their binding affinities at
the DAT. In order to make these calculations feasible,
simplified models of each compound were formed by
replacing the common 3â-(4′-chlorophenyl)tropane with
a methyl group (see model structures I-III). Details
Selected compounds were evaluated for their ability
to inhibit [3H]DA uptake in rat striatal synaptosomes.8
The Ki values, calculated using the Cheng and Prusoff
equation,16 are listed in Table 4. A correlation of the

3â-(4′-Substituted phenyl)-2â-heterocyclic Tropanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2757
Ta ble 3. Comparison of Transporter Binding Potencies for WIN 35,065-2 Ester and Acid Analogs
IC50 (nM)a
ratioa
DA
NE
5-HT
compd
R
X
[3H]WIN 35,428
[3H]nisoxetine
[3H]paroxetine
NE/DA
5-HT/DA
4a b
4bb
2a b
2bb
6a
CH3
CH3
C6H5
C6H5
H
Cl
CH3
Cl
CH3
Cl
1.12 ( 0.1
1.71 ( 0.31
1.98 ( 0.05
3.26 ( 0.06
2070 ( 21
37 ( 2.1
60 ( 0.53
2950 ( 220
5800 ( 373
>200 000
44.5 ( 1.34
240 ( 27
33
35
1490
1779
>96
40
140
1162
7515
29
2300 ( 176
24 500 ( 1500
59 500 ( 4900
a
b
See footnotes a and b from Table 2. The IC50 values are taken from refs 8 and 10.
Ta ble 4. Inhibition of Dopamine Transport by WIN 35,065-2
Analogs
oxazole. When the substituent is a methyl, the rank
order of binding potencies is 1,2-isoxazole > 1,2,4-
oxadiazole = 1,3,5-oxadiazole. It is particularly inter-
esting to note that the 1,2-isoxazoles (5a -e) have the
highest affinity for the DAT and that the isomeric 1,3-
oxazoles (13a ,b) showed markedly lower affinity for the
DAT than 5d ,e. In addition, the bioisosteric 2â-1,2,4-
oxadiazole analogs 3a ,b bind to the DAT with affinities
equal to, or better than, those of the parent esters,
whereas the isomeric 1,3,4-oxadiazole analogs 7a ,b have
much lower affinities for the DAT. Since these mark-
edly different DAT affinities for isomeric compounds are
not likely due to steric or hydrophobic properties, these
results suggested that the differences were due to other
factors.
compd
DA uptakea Ki (nM)b
2a c
3a
5d
7a
13a
5.25 ( 0.76
0.59 ( 0.05
2.08 ( 0.27
18.7 ( 1.2
19 ( 1.6
a
b
Inhibition of [3H]dopamine. Calculated using the Cheng and
Prusoff equation (ref 16); the Km value for dopamine uptake was
105 nM (ref 18). The data ( standard error represent the mean of
three or four independent experiments, each performed in tripli-
cate. c Data taken from ref 8.
of the calculations are presented in the Experimental
Section. All three molecular descriptors were obtained
for 12 model compounds: methyl- and phenyl-substi-
tuted oxazoles (models of 13a ), isoxazoles (5a ,d ), oxa-
diazoles (3a , 7a ), thiazoles (12), thiadiazoles (11a ),
tetrazoles (18a ), benzothiazoles (14a ), phenyl and meth-
yl esters (2b, 4a ), and carboxylic acids (6a ). Substitu-
ents with acidic protons were modeled as the anionic
conjugate bases. The local minimum (Vmin) of the
molecular electrostatic potential (MEP) of the 2â-
substituent models was determined in the vicinity of the
heteroatoms labeled A-C in model structures I-III.
QSAR analysis was then performed using the DAT
binding affinities of the corresponding 2â-heterocyclic-
(4′-chlorophenyl)tropanes as the reference values.
One of the more interesting features of the SAR of
WIN 35,065-2 analogs for the DAT is the number of
different types of 2â-substituents that provide good
affinity.10 Almost any group at C-2 of a 3â-phenyltro-
pane will provide a compound with affinity exceeding
that of cocaine. In contrast, the analog 6a , which has
a 2â-carboxy group, has very low affinity for the DAT.
We also found that 18a , the bioisosteric 2â-tetrazole
analog of the acid 6a , had very low affinity for the DAT,
suggesting that groups possessing negative charge are
not well accommodated at the DAT. The second 2â-
tetrazole studied, 18b, also had low affinity at the DAT,
as expected. A computational analysis of all the 2â-
heterocyclic analogs along with the parent esters and
acids was conducted to gain information on the binding
requirements of 2â-substituents of the DAT. To inves-
tigate the possibility that electrostatic properties may
be important in determining the relative potencies of
the 2â-heterocyclic analogs and their parent compounds,
a series of semiempirical quantum mechanics calcula-
tions using Spartan24 were performed. Semiempirical
methods have been demonstrated to reproduce MEP
values adequate for QSAR studies, especially if relative
minima are used rather than absolute values.25-27
(When considered necessary to verify the accuracy of
the semiempirical calculations, some values were re-
calculated at a higher level of theory using STO-3G and
6-31G* ab initio calculations. In agreement with the
published reports, the AM1 values were found to be
satisfactory.) The resulting relative local minima of the
MEP adjacent to heteroatoms A-C are listed in Table
5. A good correlation between the relative MEP minima
adjacent to heteroatom A [∆Vmin(A)] and the IC50 values
Resu lts a n d Discu ssion
Bioisosteric replacement of ligands containing a car-
bomethoxy group by structurally related heterocyclic
moieties possessing properties similar to those of the
carbomethoxy group has led to compounds potent and
selective for certain receptors.17 In a previous report,
we showed that an analog of 2a in which the 2â-
carbomethoxy group had been replaced by a 1,2,4-
oxadiazole ring was recognized by the cocaine binding
site on the DAT.6,7 This finding, combined with the
recent interest in the SAR of the 2â-position of analogs
of 2a , prompted us to study other 2â-heterocyclic ring
groups.8,18-23 In the present study, we have synthesized
analogs possessing seven different 2â-heterocyclic groups.
Analysis of their affinities at the DAT shows that when
the substituent on the heterocycle is a phenyl group,
the order of DA binding potencies for the bioisosteric
heterocycles is 1,2-isoxazole > 1,2,4-oxadiazole > 1,3-
thiazole > 1,3,5-oxadiazole > 1,3,5-thiadiazole > 1,3-

2758 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Kotian et al.
Ta ble 5. Relative MEP Minima (∆Vmin, kcal/mol), Calculated
log P (ClogP), and Substituent Volume (VOL, Å3)
shown to correlate strongly with the ability to form
increasingly strong hydrogen bonds.29,30 This provides
a convenient physicochemical rationale for several
QSAR studies13,28,31,32 that have observed that increas-
ingly negative Vmin in the vicinity of hydrogen bond
acceptor atoms correlates with increases in receptor
binding affinities. In contrast to these QSAR studies
reported for ligands bearing similar heterocyclic sub-
stituents, increased binding affinity at the DAT cor-
relates with decreasing negative potentials. This sug-
gests a different type of electrostatic interaction
mediating binding at the DAT for the 5-membered ring
heterocylic, ester, and carboxylic acid analogs modeled
in this study. No comparable correlation between
binding affinity and MEP minima at position B or C
was found. Furthermore, neither the calculated log P
(ClogP) nor the substituent volume (VOL) of the 2â-
substituents contributes to satisfactory binding affinity
correlations.
∆Vmin
substituent
model
A
B
C
ClogP
VOL
2b
3a
4a
5a
5d
223
244
217
239
240
0
194
193
180
181
290
62
226
152
226
144
144
226
131
133
226
226
226
0
198
197
192
290
290
0
247
290
290
241
187
63
1.49
1.83
0.18
0.66
2.49
-0.17
0.89
1.93
3.08
2.19
2.58
-0.18
116
122.5
66.7
86.1
134.8
42.9
124.8
134.4
140.9
132
119.3
59.6
6a
7a
11a
12
13a
14a
18a
Ta ble 6. Actual and Calculated -log(IC50) Values
compd
actual
calcd
2b
3a
4a
5a
5d
-0.3
-0.47
-0.19
-0.55
-0.25
-0.24
-3.47
-0.86
-0.87
-1.05
-1.03
0.43
-0.21
-0.05
0.23
Considering that a combination of electrostatic, steric,
and hydrophobic factors may be of importance for potent
DAT affinity, the high correlation of binding potency
with only the MEP at position A is noteworthy. Also
noteworthy is the fact that this electrostatic correlation
is observed for a diverse set of compounds spanning
several structural types. Although considering other
factors such as the conformational arrangement of the
2â-substituent may provide a useful refinement of the
model, such factors were not necessary to obtain a good
statistical correlation.
-0.11
-3.32
-1.1
-1.18
-0.76
-1.29
-0.14
-2.96
6a
7a
11a
12
13a
14a
18a
-2.64
In the construction of a pharmacophore for the 2â-
substituent, it was assumed that all of the 2â-hetero-
cyclic analogs and their parent esters or carboxylic acids
interact with the DAT in a similar fashion. Apparently,
heteroatom A in the general model structures I-III is
the essential pharmacophoric contact point for this
entire series of compounds.
Since 2â-substituents not possessing a heteroatom
(and therefore an associated negative MEP minimum)
have been reported to possess high affinity for the
DAT,10 other structural parameters must be considered
in order to formulate a pharmacophore that will encom-
pass these analogs. Although no useful correlation with
hydrophobic or steric effects was observed for the 2â-
heterocylic analogs studied here, it is possible that
relatively weaker steric or hydrophobic effects that also
contribute to binding may become evident for analogs
with nonpolar 2â-substituents.
F igu r e 1. Calculated vs experimental-log(IC50) values for
inhibition of [3H]WIN 35,428 binding to the dopamine trans-
porter for 12 2â-heterocyclic analogs.
Reports from some laboratories have shown that there
are differences between the cocaine binding site(s) on
the DAT and the site(s) for DA uptake.10 These results
suggest that some compound(s) might inhibit radioli-
gand binding without inhibiting the translocation of DA.
The high correlation (r2 ) 0.89) between [3H]WIN
35,428 binding and [3H]DA uptake for selected com-
pounds from this study suggests that these compounds
do not show significant differences between binding and
uptake.
for inhibition of radioligand binding at the DAT [ex-
pressed as -log(IC50)] was obtained from a least-squares
linear regression analysis. The resulting QSAR equa-
tion is:
-log(IC50) ) 0.014Vmin(A) - 3.47
r2 ) 0.91, n ) 12, F ) 101, s ) 0.36
The actual and calculated -log(IC50) values (based on
the QSAR equation shown above) are listed in Table 6
and plotted in Figure 1. As reported in a preliminary
publication,28 the sign of the coefficient for the MEP
minimum is not consistent with the formation of a
hydrogen bond at this site on the ligand. Increasingly
negative Vmin adjacent to nucleophilic atoms has been
In summary, a series of analogs of 3â-phenyl-2â-
carbomethoxytropane (2a ) with eight different types of
heterocyclic rings in the 2-position of the tropane ring
were prepared and evaluated for inhibition of radioli-
gand binding at the DA, 5-HT, and NE transporters.
Several of the compounds showed potent binding at the
DAT combined with low affinities for the 5-HT and NE

3â-(4′-Substituted phenyl)-2â-heterocyclic Tropanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2759
to 5b by a procedure analogous to that described for 5a .
Purification by flash column chromatography (15% CMA in
methylene chloride) gave 0.73 g (62%) of pure isoxazole 5b:
1H NMR (CDCl3) δ 1.73 (m, 3H), 2.11 (m, 3H), 2.17 (s, 3H),
2.23 (s, 3H), 2.25 (s, 3H), 3.20 (m, 2H), 3.32 (m, 2H), 6.13 (s,
1H), 6.97 (m, 4H); IR (CCl4) 2935, 2785, 1590, 1510, 1460,
transporters. 3â-(4′-Chlorophenyl)-2â-(3′-phenylisoxazol-
5-yl)tropane (5d ) with an IC50 value at the DAT of 1.28
nM combined with NE/DA and 5-HT/DA ratios of 393
and 889, respectively, emerged as a potent and selective
compound for the DAT.
The binding data for 2â-heterocyclic tropanes were
found to correlate significantly with the molecular
electrostatic potential of one of the heteroatoms in the
2â-substituents. In contrast, low correlations were
found for MEP of other atoms in the 2â-substituents as
well as for ClogP or substituent volume. These QSAR
studies are consistent with a predominantly electrostatic
interaction of these analogs.
1421, 1350, 1125, 1010, 910 cm-1
.
The free base was converted to the hydrochloride salt: mp
277 °C; [R]D -107.28° (c 0.71, MeOH); 1H NMR (CD3OD) δ
2.01 (s, 3H), 2.24 (s, 3H), 2.32 (m, 2H), 2.42 (m, 4H), 2.81 (s,
3H), 3.61 (m, 1H), 3.78 (m, 1H), 4.03 (m, 1H), 4.15 (m, 1H),
5.45 (s, 1H), 6.96 (m, 4H). Anal. (C19H25ClN2O) C, H, N.
3â-(4′-Io d op h e n yl)-2â-(3′-m e t h yliso xa zo l-5′-y l)t r o -
p a n e (4c) Hyd r och lor id e. A 0.73 g (1.9 mmol) sample of
3â-(4′-iodophenyl)-2â-carbomethoxytropane (4c) was converted
to 5c by a procedure analogous to that described for 5a .
Purification by flash column chromatography [5% CHCl3/CH3-
OH/concentrated NH4OH (40:9:1) in CH2Cl2] gave 0.37 g (49%)
of pure isoxazole 5c: 1H NMR (CDCl3) δ 1.71 (m, 3H), 2.12
(m, 3H), 2.18 (s, 3H), 2.24 (s, 3H), 3.17 (m, 2H), 3.33 (m, 2H),
6.18 (s, 1H), 6.74 (m, 2H), 7.49 (m, 2H); IR (CHCl3) 2940, 1600,
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary tube apparatus. All optical rotations were determined
at the sodium D line using a Rudolph Research Autopol III
polarimeter (1 dm cell). NMR spectra were recorded on a
Bruker WM-250 or AM-500 spectrometer using tetramethyl-
silane as internal standard. Flash chromatography was
carried out using the solvent indicated. Visualization was
accomplished under UV or in an iodine chamber. Since all
the compounds described were prepared starting from natural
cocaine, they are all optically active and have the absolute
configuration of natural cocaine. Microanalyses were carried
out by Atlantic Microlab, Inc. Cocaine was provided by the
National Institute on Drug Abuse. [3H]-3â-(p-Fluorophenyl)-
tropane-2â-carboxylic acid methyl ester ([3H]WIN 35,428) and
[3H]paroxetine were purchased from DuPont-New England
Nuclear (Boston, MA). [3H]Nisoxetine was purchased from
American Radiolabeled Chemicals, Inc. (St. Louis, MO). When
anhydrous conditions were required, solvents were distilled
and dried by standard techniques immediately prior to use.
All air and moisture sensitive reactions were conducted under
a prepurified nitrogen atmosphere in flame-dried glassware
previously dried at 150 °C. Anhydrous solvents were trans-
ferred using conventional syringe or steel cannula techniques
under an inert atmosphere.
3â-(4′-Ch lor op h en yl)-2â-(3′-m et h ylisoxa zol-5′-yl)t r o-
p a n e (5a ) Hyd r och lor id e. A solution of n-butyllithium in
hexane (5.9 mL, 2.5 M, 14.6 mmol) was added to a stirred
solution of acetone oxime (0.55 g, 7.3 mmol) in dry tetrahy-
drofuran (15 mL) at 0 °C under nitrogen. After 1 h, a solution
of 1.65 g (5.62 mmol) of 3â-(4′-chlorophenyl)-2â-carbomethox-
ytropane (4a ) in 10 mL of dry THF was added dropwise with
stirring at 0 °C. The solution was allowed to warm to room
temperature over 18 h. The mixture was poured into a stirred
solution of concentrated sulfuric acid (3.2 g) in THF (15 mL)
and water (4 mL) and heated under reflux for 1 h. The cooled
solution was made basic using saturated aqueous K2CO3 (10
mL) and extracted with methylene chloride (3 × 10 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the solvent was removed in vacuo to give 1.8 g of crude 5a .
Purification by flash column chromatography [10% CHCl3/CH3-
OH/concentrated NH4OH (40:9:1) in CH2Cl2] gave 0.74 g (46%)
of pure isoxazole 5a which was further purified by crystal-
lization from methylene chloride/hexane: mp 154-156 °C; 1H
NMR (CDCl3) δ 1.71 (m, 3H), 2.10 (m, 3H), 2.18 (s, 3H), 2.24
(s, 3H), 3.20 (m, 2H), 3.32 (m, 2H), 6.18 (s, 1H), 6.9 (d, J ) 8
Hz, 2H), 7.14 (d, J ) 8 Hz, 2H); IR (CCl4) 2950, 1590, 1490,
1420, 1350, 1020, 910 cm-1. Anal. (C18H21N2OCl) C, H, N.
1485, 1450, 1420, 1355 cm-1
.
The free base was converted to the hydrochloride salt: mp
>235 °C dec; [R]D -94.57° (c 0.39, MeOH); 1H NMR (CD3OD)
δ 2.11 (s, 3H), 2.50 (m, 6H), 2.89 (s, 3H), 3.70 (m, 1H), 3.90
(m, 1H), 4.14 (m, 1H), 4.22 (m, 1H), 5.66 (s, 1H), 6.96 (m, 2H),
7.56 (m, 2H). Anal. (C18H22ClIN2O‚0.25H2O) C, H, N.
3â-(4′-Ch lor op h en yl)-2â-(3′-p h en ylisoxa zol-5′-yl)t r o-
p a n e (5d ) Hyd r och lor id e. A 1.18 g (4 mmol) sample of 3â-
(4′-chlorophenyl)-2â-carbomethoxytropane (4a ) was converted
to 5d by a procedure analogous to that described for 5a but
using acetophenone oxime in place of acetone oxime. Purifica-
tion by flash column chromatography [20% ether/triethylamine
(9:1) in hexane] gave 0.75 g (50%) of pure isoxazole 5d which
was further purified by crystallization from ether/petroleum
ether: 1H NMR (CDCl3) δ 1.74 (m, 3H), 2.22 (m, 3H), 2.27 (s,
3H), 3.24 (m, 2H), 3.36 (m, 2H), 6.80 (s, 1H), 6.94 (m, 2H),
7.12 (m, 2H), 7.40 (m, 3H), 7.76 (m, 2H); IR (CHCl3) 2940, 1600,
1590, 1490, 1450, 1405, 1350 cm-1
.
The free base was converted to the hydrochloride salt: mp
1
287 °C; [R]D -97.5° (c 0.28, MeOH); H NMR (CD3OD) δ 2.35
(m, 6H), 2.84 (s, 3H), 3.73 (m, 1H), 4.09 (m, 1H), 4.21 (m, 1H),
6.12 (s, 1H), 7.14 (m, 4H), 7.34 (m, 3H), 7.57 (m, 2H). Anal.
(C23H24Cl2N2O‚0.25H2O) C, H, N.
3â-(4′-Met h ylp h en yl)-2â-(3′-p h en ylisoxa zol-5′-yl)t r o-
p a n e (5e) Hyd r och lor id e. A 1.09 g (4 mmol) sample of 3â-
(4′-methylphenyl)-2â-carbomethoxytropane (4b) was converted
to 5e by a procedure analogous to that described for 5d .
Purification by flash column chromatography [25% ether/
triethylamine (9:1) in hexane] gave 1.1 g (77%) of pure
isoxazole 5e which was further purified by crystallization from
methylene chloride/hexane: 1H NMR (CDCl3) δ 1.76 (m, 3H),
2.23 (m, 3H), 2.24 (s, 3H), 2.27 (s, 3H), 3.23 (m, 2H), 3.36 (m,
2H), 6.74 (s, 1H), 6.93 (m, 4H), 7.41 (m, 3H), 7.76 (m, 2H); IR
(CCl4) 2935, 1590, 1455, 1410, 1215 cm-1
The free base was converted to the hydrochloride salt: mp
1
270 °C dec; [R]D -102.22° (c 0.68, MeOH); H NMR (CD3OD)
δ 2.08 (m, 1H), 2.15 (s, 3H), 2.45 (m, 5H), 2.84 (s, 3H), 3.68
(m, 1H), 3.88 (m, 1H), 4.07 (m, 1H), 4.22 (m, 1H), 5.97 (s, 1H),
7.0 (m, 4H), 7.33 (m, 3H), 7.54 (m, 2H). Anal. (C24H27ClN2O)
C, H, N.
3â-(4′-Io d op h e n yl)-2â-(3′-p h e n y lisox a zo l-5′-y l)t r o -
p a n e (5f) Hyd r och lor id e. A 0.73 g (1.9 mmol) sample of 3â-
(4′-iodophenyl)-2â-carbomethoxytropane (4c) was converted to
5f by a procedure analogous to that described for 5d . Purifica-
tion by flash column chromatography [20% ether/triethylamine
(9:1) in hexane] gave 0.5 g (56%) of pure isoxazole 5f which
was further purified by crystallization from methylene
chloride/hexane: 1H NMR (CDCl3) δ 1.72 (m, 3H), 2.15 (m,
2H), 2.28 (s, 3H), 3.22 (m, 2H), 3.35 (m, 2H), 6.74 (m, 2H),
6.79 (s, 1H), 7.44 (m, 5H), 7.75 (m, 2H); IR (CHCl3) 2940, 1580,
The free base was converted to the hydrochloride salt: mp
>235 °C dec; [R]D -102.89° (c 0.46, MeOH); 1H NMR (CD3-
OD) δ 2.04 (s, 3H), 2.19 (m, 1H), 2.30 (m, 1H), 2.48 (m, 2H),
2.60 (m, 1H), 2.70 (m, 1H), 2.90 (s, 3H), 3.68 (m, 1H), 3.81 (m,
1H), 4.04 (m, 1H), 4.15 (m, 1H), 5.55 (s, 1H), 7.04 (d, J ) 8
Hz, 2H), 7.14 (d, J ) 8 Hz, 2H). Anal. (C18H22Cl2N2O) C, H,
N.
1480, 1475, 1450, 1400, 1355, 1005 cm-1
.
3â-(4′-Met h ylp h en yl)-2â-(3′-m et h ylisoxa zol-5′-yl)t r o-
p a n e (5b) Hyd r och lor id e. A 1.09 g (4 mmol) sample of 3â-
(4′-methylphenyl)-2â-carbomethoxytropane (4b) was converted
The free base was converted to the hydrochloride salt: mp
>267 °C dec; [R]D -91.11° (c 0.43, MeOH); 1H NMR (CD3OD)
δ 2.54 (m, 6H), 2.92 (s, 3H), 3.79 (m, 1H), 4.05 (m, 1H), 4.19

2760 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Kotian et al.
(m, 1H), 4.33 (m, 1H), 6.18 (s, 1H), 7.02 (m, 2H), 7.43 (m, 3H),
7.63 (m, 4H). Anal. (C23H24ClIN2O‚0.5H2O) C, H, N.
3â-(4′-Ch lor op h en yl)-2â-(5′-p h en yl-1′,3′,4′-th ia d ia zol-2′-
yl)tr op a n e (11a ) Hyd r och lor id e. To a solution of the acid
chloride of 6a [prepared from 0.59 g (2 mmol) of 3â-(4′-
chlorophenyl)tropane-2â-carboxylic acid as previously de-
scribed]8 in CH2Cl2 was added benzoyl hydrazide. The mixture
was stirred at room temperature overnight and basified with
concentrated NH4OH, the organic layer separated, and the
aqueous layer extracted with of CHCl3 (3 × 10 mL). The
combined organic layers were dried (Na2SO4) and filtered, and
the solvent was removed in vacuo to give crude product.
Purification by recrystallization from ethyl acetate/ether gave
0.52 g (66%) of pure 3â-(4′-chlorophenyl)-2â-carboxytropane-
N′-benzoylhydrazide (9a ): 1H NMR (CDCl3) δ 1.76 (m, 3H),
2.24 (m, 2H), 2.41 (s, 3H), 2.51 (m, 1H), 2.68 (m, 1H), 3.18 (m,
1H), 3.44 (m, 2H), 7.22 (m, 4H), 7.46 (m, 3H), 7.78 (m, 2H),
9.02 (br s, 1H), 12.97 (br s, 1H); IR (CHCl3) 3385, 3035, 3000,
3â-(4′-Ch lor op h en yl)-2â-(5′-p h en yl-1′,3′,4′-oxa d ia zol-2′-
yl)tr op a n e (7a ) Hyd r och lor id e. To a solution of 0.59 g (2
mmol) of 3â-(4′-chlorophenyl)tropane-2â-carboxylic acid (6a )
in 2 mL of POCl3 was added 0.31 g (2.2 mmol) of N-benzoyl
hydrazide. The reaction mixture was refluxed under a nitro-
gen atmosphere for 2 h, cooled, poured into ice, and rendered
basic to pH 7-8 using concentrated NH4OH. To the ice-cold
aqueous layer was added 10 mL of brine, and the mixture was
extracted with methylene chloride (3 × 10 mL). The organic
layers were combined, dried (NaSO4), and filtered, and the
solvent was removed in vacuo to give 0.9 g of residue.
Purification by flash column chromatography [50% ether/
triethylamine (9:1) in hexane] gave 0.33 g (42%) of 7a which
was recrystallized from ether/petroleum ether: [R]D -106.25°
(c 0.08, CHCl3); 1H NMR (CDCl3) δ 1.81 (m, 3H), 2.18 (s, 3H),
2.26 (m, 2H), 2.66 (m, 1H), 3.33 (m, 2H), 3.51 (m, 2H), 7.16
(m, 4) 7.45 (m, 3H), 7.86 (m, 2H); IR (CHCl3) 2950, 1550, 1490,
1620, 1570, 1485, 1450, 1215 cm-1
.
A solution of 0.4 g (1 mmol) of 9a and 0.8 g (2 mmol) of
Lawesson’s reagent in 10 mL of toluene was refluxed for 4 h
under nitrogen. The reaction mixture was cooled and solvent
removed in vacuo to give a yellow residue. To the residue was
added 3 g of silica gel and 10 mL of methylene chloride, the
resulting slurry was mixed, and the solvent was removed in
vacuo. The crude compound impregnated on silica gel was
loaded on a column and purified by flash column chromatog-
raphy [50% ether/triethylamine (9:1) in hexane] to give 0.23 g
(58%) of 11a which was further purified by recrystallization
from ether: 1H NMR (CDCl3) δ 1.75 (m, 3H), 2.20 (m, 3H),
2.32 (s, 3H), 3.30 (m, 3H), 3.78 (m, 1H), 6.86 (m, 2H), 7.08 (m,
2H), 7.43 (m, 3H), 7.97 (m, 2H); 13C NMR 25.55, 25.88, 34.60,
36.09, 41.55, 49.73, 61.48, 65.33, 127.59, 128.28, 128.78,
128.88, 130.37, 130.88, 132.19, 139.27, 168.29, 169.56; IR
(CCl4) 2940, 1490, 1460, 1340, 1245, 1100, 1010 cm-1
1450, 1340, 1090 cm-1
.
The free base was converted to the hydrochloride salt: mp
160-162 °C; [R]D +84.59° (c 0.36, CH3OH); 1H NMR (CD3OD)
δ 2.08 (m, 1H), 2.57 (m, 5H), 3.0 (s, 3H), 4.01 (m, 2H), 4.15
(m, 1H), 4.39 (m, 1H), 7.24 (m, 4H), 7.52 (m, 5H). Anal.
(C22H23Cl2N3O‚0.75H2O) C, H, N.
Further elution gave as a second fraction 0.1 g (13%) of
white solid which was characterized as 3â-(4′-chlorophenyl)-
2R-(5′-phenyl-1′,3′,4′-oxadiazol-2′-yl)tropane (8a ): mp 168-170
1
°C; [R]D +33.06° (c 0.18, CHCl3); H NMR (CDCl3) δ 1.76 (m,
3H), 2.06 (s, 3H), 2.45 (s, 3H), 3.36 (m, 2H), 3.51 (m, 1H), 3.65
(m, 1H), 7.21 (m, 4H), 7.47 (m, 3H), 7.91 (m, 2H). Anal.
(C22H22ClN3O) C, H, N.
3â-(4′-Meth ylp h en yl)-2â-(5′-p h en yl-1′,3′,4′-oxa d ia zol-2′-
yl)tr op a n e (7b) Hyd r och lor id e. A 0.65 g (2.5 mmol) sample
of 3â-(4′-methylphenyl)tropane-2â-carboxylic acid (6b) was
converted to 7b by a procedure analogous to that described
for 7a . Purification by flash column chromatography [50%
ether/triethylamine (9:1) in hexane] gave 0.36 g (40%) of 7b:
[R]D -163.92° (c 0.2, CHCl3); 1H NMR (CDCl3) 1.83 δ (m, 3H),
2.18 (s, 3H), 2.21 (s, 3H), 2.3 (m, 2H), 2.67 (m, 1H), 3.33 (m,
1H), 3.41 (m, 1H), 3.53 (m, 1H), 3.61 (m, 1H), 7.0 (m, 2H), 7.13
(m, 2H), 7.44 (m, 3H), 7.86 (m, 2H); IR (CHCl3) 2990, 1545,
The free base was converted to the hydrochloride salt: mp
165-170 °C; [R]D -42.81° (c 0.16, MeOH); H NMR (CD3OD)
1
δ 2.06 (m, 1H), 2.53 (m, 5H), 2.97 (s, 3H), 3.92 (m, 1H), 4.17
(m, 2H), 4.39 (m, 1H), 7.11 (m, 2H), 7.26 (m, 2H), 7.51 (m,
3H), 7.79 (m, 2H). Anal. (C22H23Cl2N3S‚0.75H2O) C, H, N.
3â-(4′-Meth ylp h en yl)-2â-(5′-p h en yl-1′,3′,4′-th ia d ia zol-2′-
yl)tr op a n e (11b) Hyd r och lor id e. A 0.65 g (2.5 mmol)
sample of 3â-(4′-methylphenyl)tropane-2â-carboxylic acid (6b)
was converted to 11b as described for 11a . Purification by
flash column chromatography [50% CHCl3/CH3OH/concen-
trated NH4OH (40:9:1) in CH2Cl2] gave 0.48 g (51%) of pure
3â-(4′-m et h ylph en yl)-2â-ca r boxyt r opa n e-N ′-ben zoylh y-
drazide (9b) which was further purified by recrystallization
from ether/petroleum ether: 1H NMR (CDCl3) δ 1.75 (m, 3H),
2.20 (m, 2H), 2.27 (s, 3H), 2.42 (s, 3H), 2.51 (m, 1H), 2.67 (m,
1H), 3.18 (m, 1H), 3.47 (m, 2H), 7.11 (m, 4H), 7.48 (m, 3H),
7.81 (m, 2H), 9.06 (br s, 1H), 13.09 (br s, 1H); IR (CHCl3) 3385,
1505, 1440, 1350 cm-1
.
The free base was converted to the hydrochloride salt: mp
175-178 °C; [R]D +97.22° (c 0.25, CH3OH); 1H NMR (CD3OD)
δ 2.05 (m, 1H), 2.21 (s, 3H), 2.51 (m, 5H), 2.99 (s, 3H), 3.86
(m, 1H), 3.95 (m, 1H), 4.14 (m, 1H), 4.35 (m, 1H), 7.02 (m, 4)
7.53 (m, 5H). Anal. (C23H26ClN3O‚0.75H2O) C, H, N.
Further elution gave as a second fraction 0.18 g (20%) of
solid which was characterized as 3â-(4′-methylphenyl)-2R-(5′-
phenyl-1′,3′,4′-oxadiazol-2-yl)tropane (8b) and recrystallized
from ether/petroleum ether: mp 126-128 °C; [R]D +40.73° (c
0.28, CHCl3); 1H NMR (CDCl3) δ 1.77 (m, 2H), 2.0 (m, 4H),
2.25 (s, 3H), 2.47 (s, 3H), 3.33 (m, 2H), 3.51 (m, 1H), 3.69 (d of
d, J ) 2.6, 12 Hz, 1H), 6.91 (m, 2) 7.03 (m, 2H), 7.45 (m, 2H),
7.45 (m, 3H), 7.89 (m, 2H); IR (CHCl3) 3020, 1540, 1510, 1415,
1250, 1215 cm-1. Anal. (C23H25N3O) C, H, N.
3045, 1625, 1570, 1460, 1420, 1100 cm-1
.
Reaction of 0.29 g (0.75 mmol) of 3â-(4′-methylphenyl)-2â-
carboxytropane-N′-benzoylhydrazide (9b) as described for 9a
gave after workup and purification by flash chromatography
[40% ether/triethylamine (9:1) in hexane] 0.16 g (58%) of pure
11b: 1H NMR (CDCl3) δ 1.70 (m, 1H), 1.88 (m, 2H), 2.20 (s,
3H), 2.23 (m, 2H), 2.21 (s, 3H), 2.38 (m, 1H), 3.21 (m, 1H),
3.32 (m, 1H), 3.39 (m, 1H), 3.78 (m, 1H), 6.81 (m, 2H), 6.92
(m, 2H), 7.43 (m, 3H), 7.97 (m, 2H); 13C NMR 20.98, 25.65,
25.95, 34.79, 36.25, 41.65, 50.05, 61.68, 65.49, 127.32, 127.65,
128.89, 128.95, 130.29, 131.11, 135.94, 137.68, 168.83, 169.45;
3â-(4′-Meth ylp h en yl)-2â-(5′-m eth yl-1′,3′,4′-oxa d ia zol-2′-
yl)tr op a n e (7c) Hyd r och lor id e. A 0.65 g (2.5 mmol) sample
of 6b was converted to 6c by a procedure analogous to that
described for 6a but using 0.21 g (2.75 mmol) of N-acetyl
hydrazide in place of the N-benzyl hydrochloride. Purification
by flash column chromatography [75% ether/triethylamine (9:
1) in hexane] gave 0.29 g (39%) of 7c: [R]D -108.47° (c 0.14,
CHCl3); 1H NMR (CDCl3) δ 1.75 (m, 3H), 2.18 (s, 3H), 2.22 (s,
3H), 2.25 (m, 2H), 2.35 (s, 3H), 2.56 (m, 1H), 3.24 (m, 1H), 3.4
(m, 2H), 3.47 (m, 1H), 7.0 (m, 4H); 13C NMR (CDCl3) 11.06,
20.9, 25.08, 26.32, 34.11, 34.6, 41.83, 45.73, 61.97, 66.21,
127.11, 128.85, 135.85, 138.19, 162.5, 167.44; IR (CHCl3) 2950,
IR (CCl4) 2935, 1510, 1450, 1250, 1120, 1100, 1060 cm-1
.
The free base was converted to the hydrochloride salt: mp
1
180-185 °C; [R]D -33.5° (c 0.2, MeOH); H NMR (CD3OD) δ
1.95 (m, 1H), 2.17 (s, 3H), 2.41 (m, 5H), 2.89 (s, 3H), 3.76 (m,
1H), 4.05 (m, 2H), 4.30 (m, 1H), 4.22 (m, 1H), 6.89 (m, 2H),
6.99 (m, 2H), 7.39 (m, 3H), 7.67 (m, 2H). Anal. (C23H26
-
ClN3S‚H2O) C, H, N.
3â-(4′-Ch lor op h e n yl)-2â-(5′-p h e n ylt h ia zol-2′-yl)t r o-
p a n e (12) Hyd r och lor id e. A 0.73 g (0.0025 mol) sample of
6a was converted to 3â-(4′-chlorophenyl)tropane-2â-N-phen-
acylcarboxamide (10a ) by a procedure analogous to that
described for the synthesis of 9a except 2-aminoacetophenone
was used in place of benzoyl hydrazide. Purification by flash
column chromatography [15% CHCl3/CH3OH/concentrated
NH4OH (40:9:1) in CH2Cl2] gave 0.8 g (81%) of 10a : 1H NMR
1590, 1510, 1450, 1350, 1215 cm-1
.
The free base was converted to the hydrochloride salt: mp
1
146 °C dec; [R]D -43.05° (c 0.15, CH3OH); H NMR (CD3OD)
δ 1.99 (m, 1H), 2.23 (s, 3H), 2.27 (s, 3H), 2.47 (m, 5H), 2.94 (s,
3H), 3.72 (m, 1H), 3.79 (m, 1H), 4.10 (m, 1H), 4.23 (m, 1H),
7.05 (m, 4H). Anal. (C18H24ClN3O‚0.5H2O) C, H, N.

3â-(4′-Substituted phenyl)-2â-heterocyclic Tropanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2761
(CDCl3) δ 1.71 (m, 3H), 2.19 (m, 2H), 2.39 (s, 3H), 2.46 (m,
1H), 2.58 (m, 1H), 3.13 (m, 1H), 3.43 (m, 2H), 4.74 (m, 2H),
7.13 (m, 4H), 7.49 (m, 2H), 7.59 (m, 1H), 7.96 (m, 2H), 10.57
(br s, 1H); IR (CHCl3) 3135, 3010, 2930, 1695, 1650, 1590, 1530,
boxylic acid (6a ) as previously described]8 in 10 mL of CH2Cl2
under a nitrogen atmosphere was added 0.45 mL (0.0042 mol)
of 2-aminothiophenol. After 16 h, the reaction mixture was
concentrated. The residue was basified (3 N NaOH) and then
extracted with CH2Cl2. Concentrates of the dried (Na2SO4)
extract gave 0.94 g. Purification of the product by flash column
chromatography [50% CHCl3/CH3OH/concentrated NH4OH
(40:9:1) in CH2Cl2] gave 0.3 g (41%) of 14 which was further
purified by recrystallization from ether/hexane: [R]D -233.89°
(c 0.09, CHCl3); 1H NMR (CDCl3) δ 1.65 (m, 1H), 1.87 (m, 2H),
2.24 (m, 2H), 2.34 (s, 3H), 2.41 (m, 1H), 3.28 (m, 2H), 3.40 (m,
1H), 3.62 (m, 1H), 6.8 (m, 2H), 6.81 (m, 2H), 7.29 (m, 2H), 7.70
(m, 1H), 7.84 (m, 1H); 13C NMR (CDCl3) δ 25.58, 26.07, 35.40,
36.95, 41.56, 53.09, 61.57, 65.47, 120.95, 122.42, 124.11,
125.20, 128.05, 129.03, 131.87, 136.72, 139.91, 151.33, 171.11;
IR (CHCl3) 2940, 2795, 1495, 1445, 1305, 1130, 1105, 1015,
1485, 1450, 1355, 1220 cm-1
.
A solution of 0.74 g (0.001 86 mol) of 10a and 1.51 g
(0.007 45 mol) of Lawesson’s reagent in 18 mL of toluene was
refluxed under N2 for 5 h. The reaction mixture was cooled
and solvent removed in vacuo to give crude residue. To the
residue were added 3 g of silica gel and 10 mL of methylene
chloride, the resulting slurry was mixed properly, and the
solvent was removed in vacuo. The crude compound impreg-
nated on silica gel was loaded on a column and purified by
flash column chromatography [40% ether/triethylamine (9:1)
in hexane] to give 0.21 g (30%) of 12: 1H NMR (CDCl3) δ 1.61
(m, 1H), 1.82 (m, 2H), 2.22 (m, 2H), 2.34 (s, 3H), 2.39 (m, 1H),
3.28 (m, 2H), 3.39 (m, 1H), 3.49 (m, 1H), 6.8 (m, 2H), 7.07 (m,
2H), 7.32 (m, 3H), 7.57 (m, 2H), 7.60 (s, 1H); 13C NMR (CD3-
OD) 25.51, 25.99, 35.01, 36.92, 41.72, 52.97, 61.58, 65.70,
126.45, 127.60, 128.13, 128.89, 129.05, 131.91, 132.43, 136.11,
139.91, 140.27, 168.97; IR (CHCl3) 2945, 1590, 1485, 1445,
907 cm-1
.
The free base was converted to the hydrochloride salt: mp
140-150 °C dec; [R]D -172.49° (c 0.28, MeOH); 1H NMR (CD3-
OD) δ 2.02 (m, 1H), 2.43 (m, 4H), 2.89 (m, 1H), 2.98 (s, 3H),
3.90 (m, 2H), 4.23 (m, 1H), 4.34 (m, 1H), 7.02 (m, 2H), 7.13
(m, 2H), 7.45 (m, 2H), 7.81 (m, 1H), 8.16 (m, 1H). Anal.
(C21H22Cl2N2S‚0.75H2O) C, H, N.
1350, 1125, 1090 cm-1
.
The free base was converted into the hydrochloride salt: mp
228-230 °C; [R]D +27.43° (c 0.11, CH3OH); 1H NMR (CD3OD)
δ 1.99 (m, 1H), 2.51 (m, 5H), 2.93 (s, 3H), 3.79 (m, 2H), 4.15
(m, 1H), 4.28 (m, 1H), 7.02 (d, J ) 8.5 Hz, 2H), 7.21 (d, J )
In a separate run, 0.59 g (0.002 mol) of 6a and 1.1 equiv of
2-aminothiophenol in 5 mL of POCl3 were refluxed under N2
for 30 min. The reaction mixture was cooled, poured into ice,
and basified to pH 7-8 using concentrated NH4OH. To the
aqueous layer was added 10 mL of brine, and the mixture was
extracted with methylene chloride (3 × 10 mL). The combined
organic layers were dried (NaSO4), and filtered, and the solvent
was removed in vacuo to give 0.77 g of residue. Purification
of this residue by flash column chromatography [50% ether/
triethylamine 9:1)] in hexane gave as a first fraction 0.08 g
(11%) of 14. Further elution gave 0.42 g (57%) of 3â-(4′-
chlorophenyl)-2R-(benzothiazol-2′-yl)tropane (15): mp 127-
129 °C; [R]D +114.65° (c 0.19, CHCl3); 1H NMR (CDCl3) δ 1.86
(m, 4H), 2.17 (m, 2H), 2.46 (s, 3H), 3.32 (m, 1H), 3.45 (m, 1H),
3.56 (m, 1H), 3.88 (m, 1H), 7.14 (m, 2H), 7.26 (m, 3H), 7.39
(m, 1H), 7.73 (m, 1H), 7.94 (m, 1H). Anal. (C21H21ClN2S) C,
H, N.
8.5 Hz, 2H), 7.39 (m, 5H), 8.06 (s, 1H). Anal. (C23H24
-
ClN2S‚H2O) C, H, N.
3â-(4′-Ch lor op h e n yl)-2â-(5′-p h e n yloxa zol-2′-yl)t r o-
p a n e (13a ) Ta r tr a te. A solution of 0.725 g (0.001 83 mol) of
10a (prepared as described for the synthesis of 12) in 6 mL of
POCl3 was heated at 125 °C under nitrogen for 2 h. The
reaction mixture was cooled, poured into ice, and rendered
basic to pH 7-8 using concentrated NH4OH. To the ice-cold
aqueous layer was added 10 mL of brine, and the mixture was
extracted with methylene chloride (3 × 10 mL). The organic
layers were combined, dried (NaSO4), and filtered, and the
solvent was removed in vacuo to give 0.63 g of 13a . Purifica-
tion by flash column chromatography [40% ether/triethylamine
(9:1) in hexane] gave 0.34 g (49%) of 13a which was further
purified by recrystallization from ether/petroleum ether: [R]D
1
-70.37° (c 0.19, CHCl3); H NMR (CDCl3) 1.79 (m, 3H), 2.22
3â-(4′-Ch lor op h en yl)tr op a n e-2â-n itr ile (17a ). To a solu-
tion of 0.95 g (0.0035 mol) of 3â-(4′-chlorophenyl)tropane-2â-
carboxamide (16a )8 in 20 mL of dry tetrahydrofuran was added
0.56 mL (7 mmol) of pyridine. To the resulting solution at
room temperature was added dropwise with stirring under
nitrogen 0.35 mL (4.2 mmol) of trifluoroacetic anhydride. The
reaction mixture was stirred at room temperature for 30 min
and the reaction quenched with 10 mL of water. The solvent
was removed in vacuo, and the residue was dissolved in 10
mL of saturated aqueous K2CO3 and extracted with CHCl3 (3
× 10 mL). The organic layers were combined and washed with
20 mL of brine, dried (NaSO4), and filtered, and the solvent
was removed in vacuo to give 0.26 g of product. Purification
by flash column chromatography (10% CMA in methylene
chloride) gave 0.68 g (77%) of 17a which was recrystallized
from methylene chloride and hexane: mp 167-173 °C; [R]D
-73.33° (c 0.48, MeOH); 1H NMR (CDCl3) δ 1.70 (m, 3H), 2.22
(m, 3H), 2.35 (s, 3H), 2.80 (m, 1H), 3.04 (m, 1H), 3.34 (m, 1H),
3.43 (m, 1H), 7.26 (m, 4H); IR (CHCl3) 3700, 2950, 2225, 1490,
1470, 1090, 900 cm-1. Anal. (C15H18Cl2N2‚0.75H2O) C, H, N.
(s, 3H), 2.27 (m, 2H), 2.66 (m, 1H), 3.27 (m, 1H), 3.40 (m, 2H),
3.53 (m, 1H), 7.11 (s, 1H), 7.16 (s, 4H), 7.31 (m, 5H); IR (CHCl3)
2950, 1540, 1490, 1445, 1350, 1120, 1090 cm-1
.
The free base was converted to the tartrate salt: mp 126
°C dec; [R]D +101.43° (c 0.21, CH3OH); 1H NMR (CD3OD) 2.14
(m, 1H), 2.54 (m, 5H), 2.96 (s, 3H), 3.75 (m, 2H), 4.12 (m, 1H),
4.25 (m, 1H), 4.41 (s, 2H), 7.05 (m, 2H), 7.29 (m, 7H), 7.45 (s,
1H), 7.43 (s, 1H). Anal. (C27H29ClN2O7‚0.75H2O) C, H, N.
3â-(4′-Me t h ylp h e n yl)-2â-(5′-p h e n yloxa zol-2′-yl)t r o-
p a n e (13b) Ta r tr a te. A 0.52 g (0.02 mol) sample of 3â-(4′-
methylphenyl)tropane-2â-carboxylic acid (6b) was converted
to 0.54 g (72%) of pure 3â-(4′-methylphenyl)tropane-2â-N-
phenacylcarboxamide (10b) by a procedure analogous to that
described for 10a : 1H NMR (CDCl3) δ 1.73 (m, 3H), 2.14 (m,
2H), 2.26 (s, 3H), 2.40 (s, 3H), 2.47 (m, 1H), 2.59 (m, 1H), 3.14
(m, 1H), 3.42 (m, 2H), 4.74 (m, 2H), 7.05 (m, 4H), 7.48 (m,
2H), 7.59 (m, 2H), 7.97 (m, 2H), 10.62 (br s, 1H); IR (CHCl3)
3155, 3005, 2930, 1690, 1650, 1520, 1450, 1355, 1215 cm-1
.
Cyclization of 0.5 g (1.33 mmol) of 10b as described above
for the synthesis of 13a after workup and purification by flash
column chromatography [40% ether/triethylamine (9:1)] gave
0.19 g (42%) of 13b: 1H NMR (CDCl3) 1.8 (m, 3H), 2.18 (m,
2H), 2.21 (s, 3H), 2.22 (s, 3H), 2.67 (m, 1H), 3.28 (m, 1H), 3.42
(m, 2H), 3.53 (m, 1H), 6.98 (m, 2H), 7.11 (m, 3H), 7.30 (m,
5H).
The free base was converted to the tartrate salt: mp 175-
181 °C; [R]D -104.04° (c 0.6, CH3OH); 1H NMR (CD3OD) 1.99
(m, 1H), 2.19 (s, 3H), 2.54 (m, 5H), 2.95 (s, 3H), 3.74 (m, 2H),
4.13 (m, 1H), 4.26 (m, 1H), 4.4 (s, 2H), 6.91 (m, 2H), 7.0 (m,
2H), 7.25 (m, 2H), 7.33 (m, 3H), 7.43 (s, 1H). Anal.
(C28H32N2O7‚1H2O) C, H, N.
3â-(4′-Meth ylp h en yl)tr op a n e-2â-n itr ile (17b) Hyd r o-
ch lor id e. Reaction of 0.26 g (0.001 mol) of 3â-(4′-methylphen-
yl)tropane-2â-carboxamide as described for 17a gave after
workup and purification 0.16 g (67%) of 17b: 1H NMR (CDCl3)
δ 1.68 (m, 3H), 2.18 (m, 3H), 2.32 (s, 3H), 2.35 (s, 1H), 2.82
(m, 1H), 3.02 (m, 1H), 3.36 (m, 1H), 3.43 (m, 1H), 7.18 (m,
4H); IR (CHCl3) 3675, 3000, 2950, 2200, 1600, 1510, 1450,
1350, 1220, 1100 cm-1
.
The product was converted to the HCl salt: mp 270 °C (dec.);
[R]D -76.4° (c 0.5, MeOH); 1H NMR (CD3OD) δ 2.08-2.58 (m,
9H), 2.92 (s, 3H), 3.54 (m, 1H), 3.69 (br s, 1H), 4.12 (br s, 1H),
4.29 (m, 1H), 7.21 (m, 4H). Anal. (C16H21ClN2) C, H, N.
3â-(4′-Ch lor oph en yl)-2â-(ben zoth iazol-2′-yl)tr opan e (14)
Hyd r och lor id e. To a solution of 6a acid chloride [prepared
from 0.59 g (2 mmol) of 3â-(4′-chlorophenyl)tropane-2â-car-
3â-(4′-Ch lor op h en yl)-2â-tetr a zolyltr op a n e (18a ). To a
solution of 130 mg (0.5 mmol) of 17a in 5 mL of dry

2762 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Kotian et al.
(6) Carroll, F. I.; Abraham, P.; Kuzemko, M. A.; Gray, J . L.; Lewin,
A. H.; Boja, J .W.; Kuhar, M. J . Synthesis and cocaine receptor
affinities of 3-phenyl-2-(3′-methyl-1,2,4-oxadiazole-5′-yl)tropane
Isomers. J . Chem. Soc., Chem. Commun. 1993, 44-46.
(7) 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 norepi-
nephrine transporters. J . Med. Chem. 1993, 36 (20), 2886-2890.
(8) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J . L.; Kuzemko,
M. A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J . W.;
Kuhar, M. J . Cocaine and 3â-(4′-substituted phenyl)tropane-2â-
carboxylic acid ester and amide analogues. New high-affinity
and selective compounds for the dopamine transporter. J . Med.
Chem. 1995, 38, 379-388.
tetrahydrofuran was added 0.28 mL (5 mmol) of azidotri-
methylsilane, and the mixture was placed in a PTFE-lined
autoclave. The solution was heated to 150 °C for 24 h in an
oil bath, cooled, and transferred to a flask using MeOH, and
the solvent was removed in vacuo to give a brownish residue.
Purification by flash column chromatography (20-50% CMA
in methylene chloride) gave 0.05 g (33%) of 18a : mp 296-
300 °C; [R]D -124.94° (c 0.39, MeOH); 1H NMR (CDCl3 + 1
drop of CD3OD) δ 1.73 (m, 1H), 2.44-2.02 (m, 4H), 2.6 (m,
1H), 2.68 (s, 3H), 3.33 (m, 1H), 3.65 (m, 1H), 3.73 (m, 1H),
3.97 (m, 1H), 6.68 (d, J ) 8 Hz, 2H), 7.07 (d, J ) 8 Hz, 2H).
Anal. (C15H18ClN5‚0.75H2O) C, H, N.
3â-(4′-Meth ylp h en yl)-2â-tetr a zolyltr op a n e (18b) Hy-
d r och lor id e. Reaction of 0.12 g (0.5 mmol) of 17b as
described above for 17a gave after workup and purification
by flash column chromatography [CHCl3/CH3OH/concentrated
NH4OH (40:9:1)] 0.14 g (88%) of 18b: 1H NMR (CDCl3 + 1
drop of CD3OD) δ 1.8 (m, 1H), 2.14 (s, 3H), 2.35 (m, 5H), 2.71
(s, 3H), 3.36 (m, 1H), 3.75 (m, 2H), 4.02 (m, 1H), 6.48 (d, J )
8 Hz, 2H), 6.82 (d, J ) 8 Hz, 2H).
(9) 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 (18), 3451-3453.
(10) Carroll, F. I.; Lewin, A. H.; Kuhar, M. J . Dopamine Transporter
Uptake Blockers: Structure Activity Relationships. In Neu-
rotransmitter Transporters: Structure and Function; Reith, M.
E. A., Eds.; Human Press Publishers: Totowa, NJ , in press.
(11) Carroll, F. I.; Gao, Y.; Rahman, M. A.; Abraham, P.; Lewin, A.
H.; Boja, J . W.; Kuhar, M. J . Synthesis, ligand binding, QSAR,
and CoMFA study of 3â-(p-substituted phenyl)tropan-2â-car-
boxylic acid methyl esters. J . Med. Chem. 1991, 34, 2719-2927.
(12) Carroll, F. I.; Mascarella, S. W.; Kuzemko, M. A.; Gao, Y.;
Abraham, P.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . Synthesis,
ligand binding, and QSAR (CoMFA and classical) study of 3â-
(3′-substituted phenyl)-, 3â-(4′-substituted phenyl)-, and 3â-(3′,4′-
disubstituted phenyl)tropane-2â-carboxylic acid methyl esters.
J . Med. Chem. 1994, 37, 2865-2873.
The free base was converted to the HCl salt: mp 212 °C
1
dec; [R]D -110.97° (c 0.16, MeOH); H NMR (CD3OD) δ 2.01
(m, 1H), 2.27 (s, 3H), 2.69 (m, 5H), 2.97 (s, 3H), 3.81 (m, 2H),
4.18 (m, 2H), 5.5 (s, 1H), 6.76 (d, J ) 8 Hz, 2H), 7.02 (d, J )
8 Hz, 2H). Anal. (C16H21ClN5‚0.75H2O) C, H, N.
Bin d in g Assa ys. Inhibition of 0.5 nM [3H]WIN 35,428, 0.5
nM [3H]nisoxetine, and 0.2 nM [3H]paroxetine binding was
carried out as described previously.7
(13) Saunders, J .; Cassidy, M.; Freedman, S. B.; Harley, E. A.;
Iversen, L. L.; Kneen, C.; MacLeod, A. M.; Merchant, K. J .; Snow,
R. J .; Baker, R. Novel quinuclidine-based ligands for the mus-
carinic cholinergic receptor. J . Med. Chem. 1990, 33, 1128-1138.
(14) Afanasiadi, L. S.; Tur, I. N.; Kurapov, P. B. Chem. Heterocycl.
Compd. 1985, 397-400.
[3H]Neu r otr a n sm itter Up ta k e Assa y. [3H]Dopamine
uptake into rat striatal synaptosomes was carried out as
preiously described.8
Molecu la r Mod elin g. Structures for the model compounds
were built on a Silicon Graphics 4D/310 VGX workstation
using standard bond lengths and angles in the SYBYL (version
6.03) software package.33 Geometry optimization was carried
out using the semiempirical AM1 method in the MOPAC
(version 6.0) software package.
(15) El-Barbary, A. A.; Scheibyl, S.; Lawesson, S. O.; Fritz, H. Acta
Chem. Scand. 1980, 597-601.
(16) Cheng, Y.-C.; Prusoff, W. H. Relationship between the inhibition
constant (Ki) and the concentration of inhibitor which cause 50
percent inhibition (I50) of an enzyme reaction. Biochem. Phar-
macol. 1973, 22, 3099-3108.
(17) Burger, A. Isosterism and bioisosterism in drug design. Prog.
Drug Res. 1991, 37, 287-371.
Model structures of the 2â-substituents of compounds 5a ,d ,
6a , 7a , 11a , 12, 13a , 14a , 18a , 2b, 3a , and 4a were constructed
with methyl groups replacing the constant 2â-(4′-chlorophen-
yl)tropane moiety using the SYBYL modeling package running
on Silicon Graphics 4D/310 VGX and Indigo2 workstations.
Geometry optimizations were first performed using the SYBYL
MAXIMIN force field followed by further geometry optimiza-
tion with Spartan semiempirical quantum mechanics calcula-
tions based on the AM1 Hamiltonian. MEPs were then
obtained by Spartan electrostatic potential calculations (“elpot”
at medium resolution). Relative Vmin values adjacent to
heteroatoms A-C were then calculated by substracting the
(18) Boja, J . W.; McNeill, R. M.; Lewin, A. H.; Abraham, P.; Carroll,
F. I.; Kuhar, M. J . Selective dopamine transporter inhibition by
cocaine analogs. NeuroReport 1992, 3 (11), 984-986.
(19) Carroll, F. I.; Abraham, P.; Lewin, A. H.; Parham, K. A.; Boja,
J . W.; Kuhar, M. J . Isopropyl and phenyl esters of 3â-(4-
substituted phenyl)tropan-2â-carboxylic acids. Potent and selec-
tive compounds for the dopamine transporter. J . Med. Chem.
1992, 35, 2497-2500.
(20) Carroll, F. I.; Kotian, P.; Gray, J . L.; Abraham, P.; Kuzemko,
M. A.; Lewin, A. H.; Boja, J . W.; Kuhar, M. J . 3â-(4′-Chloro-
phenyl)tropan-2â-carboxamides and cocaine amide analogues:
new high affinity and selective compounds for the dopamine
transporter. Med. Chem. Res. 1993, 3, 468-472.
(21) Kelkar, S. V.; Izenwasser, S.; Katz, J . L.; Klein, C. L.; Zhu, N.;
Trudell, M. L. Synthesis, cocaine receptor affinity, and dopamine
uptake inhibition of several new 2â-substituted 3â-phenyltro-
panes. J . Med. Chem. 1994, 37, 3875-3877.
(22) Kozikowski, A. P.; Roberti, M.; Xiang, L.; Bergmann, J . S.;
Callahan, P. M.; Cunningham, K. A.; J ohnson, K. M. Structure-
activity relationship studies of cocaine: Replacement of the C-2
ester group by vinyl argues against H-bonding and provides an
esterase-resistant, high-affinity cocaine analogue. J . Med. Chem.
1992, 35, 4764-4766.
(23) Kozikowski, A. P.; Saiah, M. K. E.; J ohnson, K. M.; Bergmann,
J . S. Chemistry and biology of the 2â-alkyl-3â-phenyl analogues
of cocaine: Subnanomolar affinity ligands that suggest a new
pharmacophore model at the C-2 position. J . Med. Chem. 1995,
38, 3086-3093.
(24) Spartan 3.1, 1994; Wavefunction, Inc., 18401 Von Karman Ave.,
Suite 370, Irvine, CA 92715.
(25) Luque, F. J .; Illas, F.; Orozco, M. Comparative study of the
molecular electrostatic potential obtained from different wave-
functions. Reliability of the semiempirical MNDO wavefunction.
J . Comput. Chem. 1990, 11 (4), 416-430.
most negative value in each case from the remaining Vmin
.
Substituent volumes were calculated using the SYBYL VOL-
UME command. Calculated log P values were obtained by
generating SMILES strings using ChemDraw Pro for input
into the Macintosh version of ClogP. Statistical analysis was
performed using the J MP34 statistics package.
Ack n ow led gm en t. This work was supported in part
by the National Institute on Drug Abuse, Grant No.
DA05477.
Refer en ces
(1) Fischman, M. W.; Schuster, C. R. Cocaine self administration
in humans. Fed. Proc. 1988, 41, 241-246.
(2) J ohanson, C. E.; Fischman, M. W. The pharmacology of cocaine
related to its abuse. Pharmacol. Rev. 1989, 41, 3-52.
(3) Koob, G. F.; Bloom, F. E. Cellular and molecular mechanisms
of drug dependence. Science 1988, 242, 715-723.
(4) Ritz, M. C.; Lamb, R. J .; Goldberg, S. R.; Kuhar, M. J . Cocaine
receptors on dopamine transporters are related to self-admin-
istration of cocaine. Science 1987, 237, 1219-1223.
(26) Rodriguez, J .; Manaut, F.; Sanz, F. Quantitative comparison of
molecular electrostatic potential distributions from several
semiempirical and ab initio wave functions. J . Comput. Chem.
1993, 14 (8), 922-927.
(27) Finn, P. W. The Calculation, Representation and Analysis of
Molecular Fields. In Molecular Modelling and Drug Design;
Vinter, J . G., Gardner, M., Eds.; CRC Press: Boca Raton, FL,
1994; pp 266-304.
(5) Bergman, J .; Madras, B. K.; J ohnson, S. E.; Spealman, R. D.
Effects of cocaine and related drugs in nonhuman primates. III.
Self-administration by squirrel monkeys. J . Pharmacol. Exp.
Ther. 1989, 251, 150-155.

3â-(4′-Substituted phenyl)-2â-heterocyclic Tropanes
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2763
(28) Wadsworth, H. J .; J enkins, S. M.; Orlek, B. S.; Cassidy, F.; Clark,
M. S. G.; Brown, F.; Riley, G. J .; Graves, D.; Hawkins, J .; Naylor,
C. B. Synthesis and muscarinic activities of quinuclidin-3-
yltriazole and -tetrazole derivatives. J . Med. Chem. 1992, 35,
1280-1290.
(31) MacLeod, A. M.; Baker, R.; Freedman, S. B.; Patel, S.; Merchant,
K. J .; Roe, M.; Saunders, J . Synthesis and muscarinic activities
of 1,2,4-thiadiazoles. J . Med. Chem. 1990, 33, 2052-2059.
(32) Fang, J .-Y.; Thomson, C. Hydrogen-bonding effects, electrostatic
potential, and the antitumor activity of flavone acetic acid and
related compounds. I. Ab initio studies on the first stable
conformations. Int. J . Quant. Chem. 1995, 54, 313-324.
(33) SYBYL, 6.03, Tripos Associates, Inc., 1699 S. Hanley Rd., Suite
303, St. Louis, MO 63144-2913.
(29) Kollman, P.; McKelvey, J .; J ohansson, A.; Rothenberg, S.
Theoretical studies of hydrogen-bonded dimers. Complexes
involving HF, H2O, NH3, HCl, H2S, PH3, HCN, HNC, HCP, CH2-
NH, H2CS, H2CO, CH4, CF3H, C2H2, C2H4, C6H6, F-, and H3O+.
J . Am. Chem. Soc. 1975, 97 (3), 955-965.
(34) J MP, 3.0, 1994; SAS Institute Inc., Cary, NC 27513.
(30) Murray, J . S.; Ranganathan, S.; Politzer, P. Correlations between
the solvent hydrogen bond acceptor parameter
calculated molecular electrostatic potential. J . Org. Chem. 1991,
56, 3734-3737.
â and the
J M960160E