Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(Aminomethyl)-3-phenylbicyclo [2.2.2]- and - [2.2.1] alkane dopamine uptake inhibitors

Article abstract of DOI:10.1021/jm980566m

As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [³H]WIN 35,428 binding and [³H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC₅₀ = 223 nM) to the cocaine binding site as marked by [³H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N,N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC₅₀ = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [³H]-dopamine uptake than [³H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2.2.2] 3,4-dichloro derivatives, which all had n(H) values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.

Full text of DOI:10.1021/jm980566m

882
J . Med. Chem. 1999, 42, 882-895
Syn th esis a n d P h a r m a cology of Site-Sp ecific Coca in e Abu se Tr ea tm en t Agen ts:
2-(Am in om eth yl)-3-p h en ylbicyclo[2.2.2]- a n d -[2.2.1]a lk a n e Dop a m in e Up ta k e
In h ibitor s
Howard M. Deutsch,* David M. Collard, Liang Zhang, Kikue S. Burnham, Abhay K. Deshpande,
Stephan G. Holtzman,† and Margaret M. Schweri‡
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, Department of
Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30032-3090, and Mercer University School of Medicine,
Macon, Georgia 31207-0001
Received October 6, 1998
As part of a program to develop site-specific medications for cocaine abuse, a series of
2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and
tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using
rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in
rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions,
using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene
and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of
the compounds bound with high affinity (median IC50 ) 223 nM) to the cocaine binding site as
marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine
atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding
methoxy groups. In the [2.2.2] series there was little difference in potency between cis and
trans compounds or between N,N-dimethylamines and primary amines. In the [2.2.1] series
the trans exo compounds tended to be least potent against binding, whereas the cis exo
compounds were the most potent (4-Cl cis exo: IC50 ) 7.7 nM, 27-fold more potent than 4-Cl
trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays
were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]-
dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimina-
tion ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the
trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients
approaching unity, except for the [2.2.2] 3,4-dichloro derivatives, which all had nH values of
about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug
discrimination tests in rats, and one had a very long duration of action.
In tr od u ction
In 1978 a small series of 2-(aminomethyl)-3-phenylbi-
cyclo[2.2.2]octane analogues were synthesized17 and
tested for biological activity.17-20 The most potent of
these compounds (4, LR5182) was shown to be selective
for the dopamine transporter, with IC50 values of 3, 58,
and 1700 nM for inhibition of [3H]DA, [3H]norepine-
phrine (NE), and [3H]5-hydroxytryptamine (5-HT, sero-
tonin) transport, respectively. Except for methylpheni-
date (2), GBR 12783 (3), and certain WIN 35,065-2 (1)
derivatives, the potency of most uptake inhibitors at the
Abuse of stimulant drugs such as cocaine, and in-
creasingly methamphetamine, is a major continuing
problem in the United States.1,2 The focus of our work
is to develop treatment agents directed toward the
stimulant recognition site on the dopamine transport
(DAT) complex, where the reinforcing effect of these
agents is thought to be mediated.3-5 Cocaine acts at this
site by blocking the reuptake of dopamine (DA) into the
presynaptic neuron, thus increasing the concentration
of DA in the synapse. However, the importance of sero-
tonergic mechanisms is increasingly being recognized.6-8
Therapeutic drugs could act as replacement agonists,
partial agonists, or antagonists. This would include
drugs which would be long acting, slow onset agonists
as replacement agents9-11 or ones that could, at least
in part, block the binding of cocaine, yet allow DA
uptake. Our recent work in this area12-14 supports this
latter possibility and provides a summary of recent
literature (also see refs 15 and 16). Taken together,
these studies support the possibility that a drug could
be developed which can block the cocaine binding site
but have a lower potential to interfere with DA uptake.
† Emory University School of Medicine.
‡ Mercer University School of Medicine.
10.1021/jm980566m CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/11/1999

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 883
NE transporter is equal to or greater than that at the
DA transporter. Lowering the relative impact on nora-
drenergic systems might make these drugs more useful,
as it would lower sympathetic side effects and alerting/
arousal functions. Whereas methylphenidate (2) con-
tains a phenylethylamine subunit in a partially re-
stricted conformation, both WIN 35,065-2 (1) and
analogues of LR5182 (4) are conformationally more
restricted analogues of phenylpropylamine.
The structural analogy of WIN 35,065-2 (1) deriva-
tives to cocaine is obvious, but most other dopamine
uptake inhibitors, such 2-4, do not contain the tropane
core. However, examination of molecular models sug-
gests a high degree of analogy between the three-
dimensional spatial arrangement of structural features
(phenyl substituents, basic nitrogen) of these series with
the structure of WIN 35,065-2 (and cocaine). Derivatives
of LR5182 are of interest because they might combine
the potency and selectivity of the GBR class of drugs in
a molecular structure bearing more similarity to co-
caine. Modification of the structure (stereochemistry,
substituents on the bicyclic and phenyl rings, type of
amine, etc.) of 3-(aminomethyl)-2-phenylbicycloalkanes
is readily achieved through standard Diels-Alder chem-
istry.17,21 This introduces the possibility of an easily
synthesized rigid framework onto which myriad sub-
stituents can be placed. Thus, this framework might be
used to fine-tune the activity of these compounds to
provide agents ranging from cocaine agonists to antago-
nists.
2, respectively. trans-Disubstituted bicycloalkanes were
prepared by Diels-Alder [4+2] cycloaddition of substi-
tuted (E)-cinnamonitriles 18 or (E)-cinnamoyl chlorides
23 with 1,3-cyclodienes. Reactions of cyclic alkenes with
cinnamonitriles17 were performed in a sealed tube at
140-180 °C, whereas the more reactive cinnamoyl
chlorides were treated with cyclopentadiene at reflux.21
A convenient route to the cis-bicyclo[2.2.2]octane series
required use of (E)-3-cyanopropenonitriles, 18, Scheme
1. Knoevenagal condensation of substituted benzalde-
hydes 16 with cyanoacetic acid gave only (E)-2-cyano-
3-phenylpropenoic acids which when heated with copper-
(I) oxide (decarboxylation)22 gave E/ Z mixtures (approxi-
mately 1:4) of 3-phenylpropenonitriles 18. Diels-Alder
reactions with 1,3-cyclohexadiene gave mixtures of trans
endo and trans exo adducts 19 and the cis endo isomers
20 (the cis exo isomers were not detected in these
reaction mixtures; note that in all cases the endo/exo
designation relates to the substituent with the higher
Cahn-Ingold-Prelog priority in relation to the larger
bridge). The cis endo isomers were separated from the
trans isomers by column chromatography and hydro-
genated to afford cis-2-cyano-3-phenylbicyclo[2.2.2]-
octanes 22. The exo/ endo mixtures of trans isomers 19
were hydrogenated to give the trans-disubstituted bi-
cyclooctanes 21. 2-Cyano-3-phenylbicyclo[2.2.2]octanes
were reduced with borane-THF or Red-Al and treated
with aqueous HCl to afford 5 and 7. N,N-(Dimethylami-
no)methyl analogues 6 and 8 were prepared by Esch-
weiler-Clark methylation of the primary amines.
On the basis of the above information, we initiated a
program to synthesize and evaluate congeners of these
bicyclic amines. The aim was to produce compounds
which, because of their unique interactions with the
dopamine uptake complex, would be either agonists,
partial agonists, or antagonists for the reinforcing
properties of cocaine. This paper describes the synthesis
of both bicyclo[2,2,2]octanes and bicyclo[2,2,1]heptanes,
5-15, in which the relative stereochemistry and the
substitution pattern on the aromatic ring are varied.
We compare their potency in the inhibition of [3H]WIN
35,428 binding with their ability to inhibit [3H]DA
uptake. In addition, the ability of selected compounds
to substitute for cocaine in a drug discrimination
procedure in rats was assessed.
Cinnamoyl chlorides are more reactive dienophiles
than corresponding acids, esters, or nitriles.21 Diels-
Alder reactions of trans-cinnamoyl chlorides 23 and
cyclopentadiene, followed by hydrolysis, gave mixtures
of trans-5-carboxyl-6-phenylbicyclo[2.2.1]hept-2-enes
(approximately 1:1 mixture of compounds with the
carboxyl group occupying the exo and endo positions)
as shown in Scheme 2. The mixtures were treated with
aqueous iodine, and the iodolactones 26 derived from
the endo isomers 24 were separated from unreacted exo
acids 25 and treated with zinc to regenerate the pure
endo acids. Hydrogenation of the separated acids 24 and
25, conversion to the primary amides, followed by
reduction and acidification, gave hydrochloride salts 9
and 11. Methylation gave the hydrochloride salts of the
tertiary amines 10 and 12.
The cis endo analogues 13 and 14 were prepared by
reaction of the E/ Z mixture of cinnamonitriles 18 (see
above) with cyclopentadiene to form a mixture of ste-
reoisomers (small amounts of the cis exo isomers were
detected but were difficult to isolate). The cis endo
isomers were isolated by column chromatography and
converted to the amine hydrochlorides by the same
sequence of reactions used for the bicyclo[2.2.2]octane
series.
The cis-trans relationship of the substituents on the
bicycloalkanes was clearly demonstrated by determi-
nation of coupling constants between protons on C2 and
C3 in the 1H NMR spectra. The coupling constant
between protons in the trans-bicyclo[2.2.2]octane series
is approximately 8 Hz, whereas the cis isomers have a
12-Hz coupling.
Resu lts
Ch em istr y. Synthetic routes to bicyclo[2.2.2]octanes
(Z)-4-Chlorocinnamic acid, 34c, was prepared by
and bicyclo[2.2.1]heptanes are shown in Schemes 1 and
photochemical isomerization of the commercially avail-

884 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
Sch em e 1a
a
Reagents: (a) NCCH2CO2H, NaOH; (b) Cu2O, ∆; (c) cyclohexadiene, 180 °C; (d) H2, Pd/C; (e) (i) BH3/THF, (ii) HCl; (f) (i) NaHCO3, (ii)
H2CO, HCO2H, (iii) HCl.
able E-isomer 33c in order to synthesize the cis,exo-
bicyclo[2.2.1]heptane Diels-Alder adducts. The Z-iso-
mer was easy to separate from the photostationary E/ Z
mixture of acids by trituration with hot water.23 Diels-
Alder reaction of the Z-isomer with cyclopentadiene
gave a mixture of the two cis isomers (cis exo, 35c, and
cis endo) and two trans isomers (24c and 25c). The
crude reaction mixture contained approximately 5% of
the desired cis exo isomer. The mixture was treated with
I2 to convert the cis endo and trans endo acids to the
neutral iodolactones which were separated from the
mixture of cis exo and trans exo acids. The cis exo acid
was separated from the trans endo acid by column
chromatography and converted, via reduction of the
amide, to the cis exo isomer of the hydrochloride salt of
cis,exo- 2-(aminomethyl)-3-(4-chlorophenyl)bicyclo[2.2.1]-
heptane, 15c.
The unsubstituted (Z)-cinnamic acid, 34a , could not
be separated from the E-isomer by the simple trituration
procedure used for the 4-chloro analogue, so another
route was devised for the preparation of the unsubsti-
tuted cis exo ammonium chloride 15a . The trans endo
acid 24a was treated with an excess of lithium diiso-
propylamide at -78 °C to afford the dianion, which was
quenched with aqueous ammonium chloride at room
temperature to afford the trans endo isomer 24a and
the cis exo isomer 35a in a 9:1 mixture (determined by
1H NMR spectroscopy). Conversion of the trans endo
isomer to the neutral iodolactone allowed for the sepa-
ration of the cis endo acid 35a . Conversion of the acid
via the amide to the amine hydrochloride gave the
unsubstituted cis exo ammonium chloride 15a .
isomers have a corresponding coupling constant of about
3.5 Hz (dihedral angle ∼50°).
P h a r m a cology. All of the compounds that were
synthesized in this study were tested for their ability
to inhibit the binding of [3H]WIN 35,428 to rat striatal
tissue membrane preparations and the uptake of [3H]-
DA into rat striatal synaptosomes. These results are
summarized in Table 1. In addition, the ability of
selected members to substitute for cocaine, in rats
trained to discriminate 10 mg/kg of cocaine from saline,
was measured. These data are summarized in Figure
1.
[3H]WIN 35,428 Bin d in g. In terms of binding po-
tency some trends are clear (in general the same
statements can be made for uptake inhibition). As a
group, all of the 3,4-dichloro compounds are more potent
than the corresponding unsubstituted compounds, by a
factor of 9-89-fold (average increase, 30-fold). Similarly,
a 4-chloro substituent makes all the compounds more
potent, by a factor of 7-21-fold (average increase, 13-
fold). Substitution by chlorine in the 3-position also
always increased potency, but less efficiently than in
the 4-position (average increase, 5-fold). In contrast, a
4-methoxy substituent has little effect on binding
potency. A small number of compounds, with methoxy
groups in the 2- and 3-positions, show variable effects.
In one series (trans endo [2.2.1]), both the 2- and
3-methoxy compounds 9e and 9f are much less potent
(34- and 26-fold, respectively). However, the 2- and
3-methoxy trans exo [2.2.1] compounds 11e and 11f are
a little different than the corresponding unsubstituted
compounds.
The 1H NMR spectrum of the cis exo isomers 15 shows
a 9.5-Hz coupling constant between the protons on C2
and C3, consistent with the cis-stereochemistry. In
addition, the spectrum is distinct from that of the cis
endo ammonium salts 13. The cis exo isomers have a
coupling constant of about 1.8 Hz between the protons
on C2 (and C3) and the neighboring bridgehead (the
dihedral angle between these protons, calculated by
MM2, is approximately 85°), whereas the cis endo
The trans [2.2.2] tertiary amines 6 are all more potent
(2-5-fold) than the corresponding primary amines 5, but
in most other cases (cis [2.2.2] endo and exo [2.2.1]) there
were only small differences between amine types.
Except for a few cases, amine type (primary versus
tertiary) is not an important factor in determining
binding potency.
In terms of cis-trans isomerism, the trends are less
clear and not very dramatic. In the [2.2.2] series, all cis

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 885
Sch em e 2a
a
Reagents: (a) (i) cyclopentadiene, ∆, (ii) NaOH, H2O, (iii) HCl; (b) I2, KI, NaHCO3; (c) Zn, AcOH; (d) H2, Pd/C; (e) (i) SOCl2, (ii)
NH4OH; (f) (i) BH3‚THF, (ii) HCl, H2O; (g) (i) NaHCO3, (ii) H2CO, HCO2H, (iii) HCl; (h) 254 nm, dioxane; (i) cyclopentadiene, 140 °C; (j)
(i) LDA, THF, -78 °C, (ii) H3O+.
primary amines 7 are more potent than the correspond-
ing trans primary amines 5 by factors of 1.7-5.5. The
tertiary amines show no consistent difference between
the cis and trans isomers. In general, the stereochemical
arrangement of the phenyl ring and the aminomethyl
substituent is not a large factor in influencing potency
in the [2.2.2] series.
trends are clear: The cis exo compounds 15 are the most
potent, and the trans exo 11 are the least potent. The
cis endo, 13, and the trans endo, 9, compounds differ
little in potency. Two of the most potent compounds in
this study are 15c and 7c with IC50 values of 7.7 and
12.9 nM, respectively. Both of these are cis-4-chloro
isomers.
In the [2.2.1] series, in addition to cis-trans isomer-
ism, we addressed the issue of endo-exo isomerism.
With both cis-trans and endo-exo isomerism the dif-
ferences are usually, but not always, fairly small. Two
Discr im in a tion Ra tio (DR). The discrimination
ratio (DR), defined as the ratio of the IC50 value of a
given compound against [3H]DA uptake to its corre-
sponding IC50 value against [3H]WIN 35,428 binding,

886 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
Ta ble 1. Inhibitory Properties of Test Compounds against [3H]WIN 35,428 Binding and [3H]Dopamine Uptakea
inhibition of [3H]WIN 35,428 binding
phenyl
subst X
N
inhibition of
discrimination
ratio (DR)b
compd
subst R
IC50 (nM)
nH
[3H]dopamine uptake IC50 (nM)
Trans [2.2.2]
1.03 ( 0.08
1.18 ( 0.04
1.20 ( 0.04
1.85 ( 0.31
0.99 ( 0.10
1.33 ( 0.03
2.19 ( 0.30
1.21 ( 0.06
5a
5b
5c
5d
6a
6b
6d
6h
H
H
H
H
H
CH3
CH3
CH3
CH3
1195 ( 15
5930 ( 420 (3)
960 ( 120
375 ( 18
5.0
4.7
5.2
2.6
4.4
5.1
2.6
4.4
3-Cl
4-Cl
3,4-Cl2
H
3-Cl
3,4-Cl2
4-NH2
204 ( 4.0
71.4 ( 7.0 (3)
37.5 ( 3.3 (3)
191 ( 19 (3)
36.8 ( 1.3
21.3 ( 0.80
160 ( 28 (5)
97.5 ( 0.50
840 ( 49
186 ( 38
56.3 ( 14
704 ( 130 (5)
Cis [2.2.2]
1.02 ( 0.03
1.25 ( 0.01
1.21 ( 0.09
2.29 ( 0.23
1.08 ( 0.07
1.01 ( 0.16
1.14 ( 0.07
1.58 ( 0.11
1.01 ( 0.04
7a
7b
7c
7d
7g
8a
8b
8d
8g
H
3-Cl
4-Cl
3,4-Cl2
4-OMe
H
3-Cl
3,4-Cl2
4-OMe
H
H
H
H
270 ( 20
1480 ( 80
430 ( 60
68.3 ( 0.5
34.0 ( 5.0 (3)
1500 ( 100
980 ( 20
283 ( 23
29.3 ( 1.7
1430 ( 50
5.5
3.7
5.3
1.6
6.0
3.1
3.3
2.1
3.8
117 ( 8.0
12.9 ( 0.60 (3)
21.5 ( 0.50
249 ( 36.4 (3)
313 ( 18
86.0 ( 7.0
14.2 ( 1.6 (3)
380 ( 20
H
CH3
CH3
CH3
CH3
Trans Endo [2.2.1]
1.05 ( 0.06
1.12 ( 0.12
1.36 ( 0.10
1.22 ( 0.03
1.35 ( 0.15
1.12 ( 0.08
0.98 ( 0.07
0.98 ( 0.01
9a
9b
9c
9d
9e
9f
9g
10a
H
3-Cl
4-Cl
3,4-Cl2
2-OMe
3-OMe
4-OMe
H
H
H
H
H
H
H
H
CH3
340 ( 32
149 ( 12
2220 ( 180 (3)
758 ( 64 (3)
230 ( 11 (3)
58.0 ( 0.30
36600 ( 400
29300 ( 400
5550 ( 460
1100 ( 25
6.5
5.1
5.0
5.0
3.1
3.3
4.8
2.1
46.0 ( 3.3 (3)
11.6 ( 1.3
11600 ( 560
8820 ( 1500
1160 ( 310
515 ( 80
Trans Exo [2.2.1]
1.05 ( 0.09
1.13 ( 0.07
1.31 ( 0.07
1.13 ( 0.00
0.91 ( 0.00
1.14 ( 0.05
0.93 ( 0.05
1.01 ( 0.00
11a
11b
11c
11d
11e
11f
11g
12a
H
3-Cl
4-Cl
3,4-Cl2
2-OMe
3-OMe
4-OMe
H
H
H
H
H
H
H
H
CH3
2900 ( 100
239 ( 68
8850 ( 950
780 ( 120
3.1
3.3
2.9
2.9
5.3
3.3
4.2
1.7
207 ( 18 (3)
32.7 ( 5.8
593 ( 34 (3)
93.6 ( 5.2
1480 ( 76
7860 ( 400
6560 ( 150
7120 ( 980
4330 ( 530
2010 ( 460 (4)
1700 ( 120
2510 ( 110
Cis Endo [2.2.1]
1.04 ( 0.04
1.11 ( 0.10
1.25 ( 0.09
0.99 ( 0.10
0.89 ( 0.02
13a
13c
13d
13g
14a
H
H
H
H
H
816 ( 50 (4)
65.3 ( 11
3500 ( 32
348 ( 10
98.7 ( 2.3
2260 ( 240
2750 ( 370
4.3
5.3
4.6
4.6
1.3
4-Cl
3,4-Cl2
4-OMe
H
21.3 ( 3.6 (3)
495 ( 140
CH3
2140 ( 160
Cis Exo [2.2.1]
1.06 ( 0.01
1.16 ( 0.13
15a
15c
H
4-Cl
H
H
251 ( 11
7.70 ( 0.60
875 ( 41
34.9 ( 1.5
3.5
4.5
Tropanes
(-)-cocaine
WIN 35,428
160 ( 15 (3)
20.4 ( 1.7 (5)
1.03 ( 0.01
1.07 ( 0.05
404 ( 26
51.3 ( 0.30
2.5
2.5
a
b
Values are expressed as the mean ( standard error of the mean; N ) 2 except where shown (N). Discrimination ratio ) (IC50
against [3H]dopamine uptake):(IC50 against [3H]WIN 35,428 binding).
is an empirical measure utilized in our laboratories to
predict whether a test compound will behave as a
cocaine agonist or antagonist.11 In this model, a com-
pound which is equipotent as an inhibitor of [3H]-
dopamine uptake and [3H]WIN 35,428 binding would
have a DR of 1 and would be expected to resemble
cocaine in its pharmacological properties. On the other
hand, a compound which could inhibit the binding of
cocaine to the reuptake complex (measured with [3H]-
WIN 35,428), but have little or no effect on DA uptake,
would have a high DR (see discussion) and would be
expected to act as a cocaine antagonist. Probably due
to differences in the conditions under which the two
assays are run, cocaine itself has a DR value of 2.5
(instead of 1) using our methodology. The test com-
pounds (5-15) exhibited low DR values ranging from
1.3 to 6.5. The 3,4-dichloro-substituted compounds have
DR values which are 0-71% lower (average 40%) than
the corresponding unsubstituted analogues. No clear
trends are evident for 3- or 4-chloro or 2-, 3-, or
4-methoxy compounds. In most cases trans compounds
show a higher DR than the corresponding cis isomers
(average of 37% higher). Also, the primary amines have
higher DR values than the corresponding tertiary
amines (increasing by an average of 25%). The exo
bicylo[2.2.1] compounds (11, 12, 15) have lower DR
values than either the corresponding endo [2.2.1] (9, 10,
13, 14; 26% lower) or the [2.2.2] (5-8; 32% lower).
Dr u g Discr im in a tion . Compounds 8d and 9a were
tested in the drug discrimination procedure (see Figure

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 887
F igu r e 1. Dose-response curves for the discriminative stimulus effects of 8d (b) (n ) 5), 9a (3) (n)4), and cocaine (0) (n ) 10)
in rats trained on 33 µmol/kg (10 mg/kg) cocaine. Rats (n rats at each dose level) were injected with the test compound 30 min
before testing for generalization to cocaine (see Experimental Section for details).
1). Both compounds 8d and 9a were as efficacious as
cocaine but were less potent (ED50 values of 9.2 µmol/
kg (3.2 mg/kg) and 41 µmol/kg (9.7 mg/kg), respectively)
than might be predicted based on their potency in vitro.
The ED50 for cocaine is 8.9 µmol/kg (3.0 mg/kg). To
compare behavioral potencies relative to potency in
vitro, the ratio of IC50 for inhibition of 3[H]WIN 35,426
binding (nM) to ED50 (µmol/kg) in drug discrimination
was calculated. Compounds with high ratios are very
potent behaviorally at a given binding potency. For
compounds 8d and 9a the ratios are 1.6 and 8.4,
respectively. This compares to cocaine with a ratio of
18 (160/8.9). Although neither of these compounds
appeared to cause unusual overt behavioral effects,
several incidents should be noted. Compound 8d might
have a long duration of action as judged by the fact that
animals receiving the highest dose (30 mg/kg) were still
largely selecting the cocaine-appropriate lever the next
day in a training session with saline (data not shown).
One of the four rats given the highest dose of 9a was
observed to undergo a convulsion and was found dead
in his cage the following morning.
Discu ssion
Str u ctu r e-Activity Rela tion sh ip s. The inhibitory
potency of the compounds in this series against [3H]WIN
35,428 binding ranged from an IC50 of 7.7 nM for 15c
to 11.6 µM for 9e. In the [3H]dopamine uptake assay,
IC50’s of 29.3 nM (8d ) to 36.6 µM (9e) were obtained.
As the data in Table 1 indicate, the inhibitory potencies
of the compounds in the two assays were highly cor-
related (R2 ) 0.978 for a log-log plot of the IC50 values
for the two assays). Despite this excellent correlation,
the potencies of the compounds did not always covary
to the same degree in both assays; thus, DR values of
1.3 (14a ) to 6.5 (9a ) were obtained. Although assay con-
ditions can make a huge difference,24,25 high DRs should
theoretically identify potential cocaine antagonists,
because they can detect compounds which are propor-
tionally better at displacing cocaine binding rather than
blocking dopamine uptake. The highest DR values
obtained for this series of compounds, however, appar-
ently showed insufficient separation in inhibitory po-
tency between the two functions for antagonist activity
to emerge. Thus, compound 9a (DR ) 6.5) acted as an
agonist in the drug discrimination assay, substituting
fully for cocaine. Theoretically,26 a DR of 36 is the value
obtained when 80% of the [3H]WIN 35,428 binding sites
and 10% of substrate sites are occupied (the IC50 values
were used as an approximation of the Ki and KD in these
calculations). If 90% of the [3H]WIN 35,428 binding sites
are occupied, a DR of 81 is required to only have 10%
of the dopamine uptake inhibited. Thus, it is likely that
large values of the DR are required before antagonism
could be observed. Despite this, there are indications
(see Results, Discrimination Ratio) that the DR values
are related to some structural features of these ana-
logues; these may be useful in future investigations
aimed at the development of cocaine antagonists.
Hill Coefficien ts. Except for the 3,4-dichloro-sub-
stituted bicyclo[2.2.2] compounds, all of the compounds
in this study had nH values close to unity, ranging from
0.89 to 1.36 (average ) 1.11 ( 0.02; Table 1). The 3,4-
dichloro-substituted bicyclo[2.2.2] compounds 5d , 6d ,
7d , and 8d had Hill coefficients of approximately 2,
ranging from 1.58 to 2.29 (average ) 1.97 ( 0.16
(SEM)). The increase in nH did not appear to be a
function only of dichloro substitution, however, as the
3,4-dichloro substituted bicyclo[2.2.1] compounds 9d ,
11d , and 13d had an average nH of 1.20 ( 0.04, which
was significantly lower than the values obtained for the
3,4-dichloro bicyclo[2.2.2] group (p < 0.01, 2-tailed
t-test).

888 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
To provide some rationale for the variation in biologi-
cal screening data of the bicyclic (2-aminomethyl)-3-
phenyl analogues 5-15, we have considered their
structural homology with WIN 35,065-2 and drawn
analogy with the SAR of substituted analogues of
methylphenidate recently synthesized in our laborato-
ries.12,27 WIN 35,065-2 and the bicyclic compounds
synthesized here are conformationally restricted ana-
logues of 3-phenylpropylamine. Compounds 5-15 lack
the methyl ester functionality of WIN 35,065-2 and
possess additional conformational flexibility around the
C2-exocyclic methylene bond. In addition to the effects
of substituents on the phenyl ring, analysis of the SAR
should also explain the effect of cis-trans and endo-
exo stereochemistry on uptake and binding. It must be
noted that all of the compounds synthesized in this
study (5-15) are racemic and have not been resolved
into the individual enantiomers. The earlier work on
the bicyclo[2.2.2] series17,20 indicated that there was
little difference in the inhibition of either DA, NE, or
5-HT uptake between the enantiomers (enantioselec-
tivities of 3, 2, and 5, respectively).
F igu r e 2. Energy-minimized (MM2) conformation 15 (2S);
H atoms omitted for clarity.
the molecule and in particular by extending the planar
ring structure into a hydrophobic binding pocket. For
example, 3- and 4-halogen-substituted analogues (and
3,4-dichloro analogues) of methylphenidate, WIN, and
5-15 have higher potencies than the unsubstituted
compounds. In the case of compounds 5-15, the 4-chloro
compounds have greater potency than the 3-substituted
analogues, in common with the effect of the position of
substituents in the WIN series,35 but different than the
methylphenidate12 series where the 3-substituted ana-
logues are more potent. The effect of methoxy groups is
inconsistent in these bicyclic compounds. In the trans
endo series, a methoxy group in the 2-, 3-, or 4-position
lowered activity (34-, 26-, and 4-fold, respectively),
whereas the same substituents had no effect in the trans
exo series. In a few other cases, a 3- or 4-methoxy group
had little effect. In the methylphenidate and WIN series,
methoxy groups usually have little effect, except in the
2-position12 where all substituents tend to lower po-
tency.
In the following discussion, we have arbitrarily chosen
one enantiomer (the 2S) for both the cis exo series 15
and the trans exo series 11 to illustrate the arguments
being presented. Although we also studied the other
enantiomer, these results are not discussed as they do
not shed any additional light on the matter. In the
highly active cis exo series, 15, rotation around the C3-
phenyl bond is restricted by the bicyclic ring structure.
Two conformations around the C2-exocyclic methylene
bond lead to low-energy structures, with the minimum
shown in Figure 2. In this conformation the N-phenyl-
C4 distance, 6.1 Å, is not large enough to provide a good
overlap with the structure of WIN with coplanar phenyl
rings and overlap of the nitrogen atoms. The other low-
energy conformations of 15 have much shorter N-C4
distances. Overlay of the carbon atoms of the phenyl
rings and nitrogen atoms of 15 and WIN (rms fit of
seven atoms in each structure29) is best achieved by
tilting the molecules relative to each other, as shown
in Figure 3. In this overlay most of the atoms of the
unsubstituted bicyclic portion are in the area of the
methyl ester of WIN 35,065-2. Studies of the SAR of the
methyl ester of WIN and cocaine36 have shown that
although a â configuration is required, there is great
latitude in the nature and size of groups in this position.
For 15, alternate overlays (not shown) produced similar
results in terms of the way the phenyl rings overlap but
differ in where the atoms of the bicyclic structure were
In a number of studies of dopamine reuptake inhibi-
tors (e.g., methylphenidates,12 tropanes,28 and others29)
the distance between the N and C4 (or the centroid) of
the phenyl ring is often correlated with potency, with
the suggestion that this is a gauge of the fit of this
portion of the molecule into the binding site. The N-C4
distance in WIN 35,065-2 is approximately 7.0 Å
(determined by MM230). Recent data on WIN analogues
in which this distance is extended31 indicate that even
longer distances (ca. 9 Å) may be optimal. In the bicyclic
structures 5-15, this distance varies depending on the
conformation about the C2-exocyclic methylene bond.
However, in the more potent cis exo series, the maxi-
mum N-C4 distance obtainable by rotation around the
C2-exocyclic methylene bond is only approximately 6.1
Å, and some energy-minimized structures have consid-
erably shorter distances. In energy-minimized confor-
mations of the least active trans exo series, 11, the
N-C4 distances are generally longer than in the cis
series; in one conformer (discussed in more detail later)
this distance is about 7.0 Å. Other factors than just this
distance obviously are important in determining binding
potency in these series.
Analogues of WIN in which the nitrogen is replaced
with oxygen and the phenyl ring is optimally substituted
(e.g., 3,4-dichloro) retain relatively high potency.32 In
addition, some cocaine analogues without a basic nitro-
gen (e.g., 8-(trifluoromethylsulfonyl)norcocaine) retain
high affinity.33 This suggests that interaction of the
nitrogen with the binding site is through hydrogen
bonding rather than by ionic interactions of an am-
monium cation. Recently published data have shown
that in WIN analogues in which the phenyl ring is
optimally substituted (e.g., 3,4-dichloro), replacement
of the nitrogen with carbon34 can lead to compounds
with relatively high affinity indicating that a fit of this
atom into a pocket may be all that is required. These
observations indicate that the exact mode of binding of
tropanes, and presumably all other DA uptake inhibi-
tors, is far from clear.
Substituents on the phenyl ring, however, can have
dramatic effects on binding, presumably by lengthening

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 889
F igu r e 3. Overlay of 15 (2S) and WIN 35,065-2 (black); H
atoms omitted for clarity.
F igu r e 5. Overlay of 11 (2S) and WIN 35,065-2 (black); H
atoms omitted for clarity.
it is not obvious why 11 would be less active as
compared to 15. However, it should be noted that the
overlapping phenyl rings of 11 and WIN 35,065-2
assume a different orientation with respect to the
bicycles.
Dr u g Discr im in a tion Stu d ies. Compounds 8d and
9a substituted fully for cocaine in drug discrimination
studies, suggesting that they might ultimately have
utility as replacement therapy for the treatment of
cocaine abuse. The in vivo potency of compound 9a could
be predicted by comparison of its in vitro potency in the
[3H]DA uptake assay with that of cocaine (i.e., 9a is
5-fold less potent than cocaine both as a dopamine
uptake inhibitor and in the drug discrimination assay).
The same correlation was not seen with 8d ; it was 14-
fold more potent than cocaine as a [3H]DA uptake
inhibitor but equipotent as a substitute for cocaine in
the drug discrimination assay. It is possible that phar-
macokinetic factors dictated by the varying lipophilicity
of these agents may account for the divergence between
the in vivo and in vitro potency of these agents. The
calculated values of log P29 for cocaine, 9a , and 8d are
1.91, 2.50, and 4.20, respectively. If the more lipophilic
8d is absorbed more slowly after ip injection or is bound
to a greater extent to plasma proteins, its concentration
in the brain could be relatively lower than that of a more
rapidly absorbed, unbound drug. Studies of more hy-
drophilic analogues of bicyclic amines related to 5-15
are in progress.
F igu r e 4. Overlay of 15 (2S) and WIN 35,065-2 (black); H
atoms omitted for clarity.
placed relative to WIN 35,065-2. Until more information
in available about the SAR of the bicylic amines, it is
not possible to predict which overlay might be more
appropriate. However, because of the relatively poor
overlap of the phenyl rings, this very simple picture
would not seem to predict the high potency of the cis
exo series based on these presumed pharmacophores
(nitrogen atom and phenyl).
Given the uncertainty of the mode of binding of
phenyltropanes to the DAT, it is also worth considering
other ways of drawing analogies to the structure of 15.
A good overlay of the phenyl rings of low-energy
conformations of WIN 35,065-2 and 15 can be achieved
by placement of the primary amine of 15 in the same
area as the methyl ester carbonyl oxygen of WIN 35,-
065-2 and is shown as Figure 4. This also provides a
good overlap of the bicyclic structures of the two series.
In the energy-minimized conformations of the least
active trans exo series 11, the N-C4 distance is about
7.0 Å. A similar overlay to that shown in Figure 3, using
this conformation of 11 and WIN 35,065-2, is shown in
Figure 5. Because of the apparent better overlap of the
phenyl rings in these overlays of 11 and WIN 35,065-2,
Con clu sion s
Analogues of 2-(aminomethyl)-3-phenylbicycloalkanes
have been prepared and tested for their binding to the
DAT and their ability to inhibit DA uptake. Many of
these were potent inhibitors of both binding and uptake.
Several alternate explanations of the SAR of these com-
pounds are offered in terms of known pharmacophores.
In addition, two compounds were tested for their ability
to substitute for cocaine in drug discrimination tests in
rats. Both of these compounds did fully substitute for
cocaine, proving the behavioral efficacy of this class of
drugs. These, and other related analogues, may be
promising candidates for development as cocaine abuse

890 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
1 h. The solution was filtered, and the solvent was removed
under reduced pressure to give of cis-2-cyano-3-phenylbicyclo-
[2.2.2]octane (22a ) as a brown oil (91 mg, 99%): 1H NMR
(CDCl3) δ 7.22-7.41(m, 5H), 3.34 (d, 11.0 Hz, 1H, H-C2), 3.24
(d, 11.0 Hz, 1H, H-C3), 2.15 (m, 4H), 1.50-1.81(m, 6H); IR
treatment agents, due to their likely slow onset and long
duration of action. Further testing of these and other
related compounds is in progress.
Exp er im en ta l Section
3066, 3025, 2954, 2870, 2239, 1705 cm-1
.
1
tr a n s-2-Cya n o-3-p h en ylbicyclo[2.2.2]octa n e (21a ): 1H
NMR (CDCl3) δ 7.21-7.40 (m, 5H), 3.19 (d, 8.3 Hz, 1H, H-C2),
2.96 (d, 8.3 Hz, 1H, H-C3), 1.40-2.10 (m, 10H); IR 3065, 3032,
Gen er a l Meth od s. H NMR spectra were obtained at 300
MHz on a Varian Gemini spectrometer. Infrared spectra were
obtained using KBr pellets on a Nicolet 520FT spectrometer.
Melting points were determined on a Mel-Temp apparatus
and are uncorrected. All starting materials were used as
received from Aldrich Chemical Co. Tetrahydrofuran (THF)
was dried over sodium benzophenone ketyl prior to distillation
under nitrogen. Elemental analyses were obtained from
Atlantic Microlabs, Atlanta, GA. Representative procedures
for the synthesis of hydrochlorides of 2-(aminomethyl)-3-
phenylbicycloalkanes are given below. Spectral data are
presented for representative synthetic intermediates and
products.
2940, 2871, 2243, 1671 cm-1
.
cis- a n d tr a n s-2-(Am in om eth yl)-3-p h en ylbicyclo[2.2.2]-
a lk a n e Hyd r och lor id e Sa lts 5 a n d 7. BH3-THF (1.34 mL
of a 1 M BH3 solution in THF, 1.34 mmol) was added to a
solution of cis-2-cyano-3-phenylbicyclo[2.2.2]octane (22a ) (71
mg, 0.33 mmol) in 2 mL THF, and the mixture was heated at
reflux overnight under N2. The solution was added to 2 mL
concentrated HCl, the THF was removed under reduced
pressure, a few NaOH pellets were added, and the mixture
was extracted with CH2Cl2 (3 × 30 mL). The combined extracts
were dried over MgSO4, and the solvent was removed under
reduced pressure to afford a brown oil. Concentrated HCl was
added, and the precipitate was filtered and dried to afford cis-
2-(aminomethyl)-3-phenylbicyclo[2.2.2]octane hydrochloride
(7a ) as a white solid: mp 220 °C dec; 1H NMR (D2O) δ 7.12-
7.38 (m, 5H), 3.15 (d, 11.9 Hz, 1H, H-C3), 2.64 (t, 11.9 Hz,
1H, diastereotopic H-C9), 2.42 (dd, 11.9 Hz, 4.2 Hz, 1H,
diastereotopic H-C9), 2.25-2.33 (m, 1H, H-C2), 1.30-2.06
Syn th esis of cis- a n d tr a n s-2-(Am in om eth yl)-3-p h en -
ylbicyclo[2.2.2]a lk a n e Hyd r och lor id e Sa lts 5-8. (E)-2-
Cya n o-3-p h en ylp r op en oic Acid s 17. Knoevenagal conden-
sation of cyanoacetic acid with substituted benzaldehydes 16
was performed under basic conditions according to the method
of Lapworth and Baker.37 Cyanoacetic acid (57.7 g, 680 mol)
was dissolved in a solution of Na2CO3 (72.0 g, 680 mol) in 500
mL H2O with gentle warming. A solution of NaOH (3.39 g,
85.0 mol) in 250 mL H2O was added, and the mixture was
warmed to 40 °C. Benzaldehyde 16a (60 mL, 0.54 mol) was
added, with vigorous shaking. After standing for 1 h, concen-
trated HCl was added until the solution was strongly acidic.
The mixture was shaken vigorously and allowed to stand for
1 h at room temperature. The precipitate was filtered, washed
with cold water and toluene, and dried under vacuum to give
(E)-2-cyano-3-phenylacrylic acid (17a ) as an off-white solid
(50.0 g, 53%): mp 186-188 °C (lit.38 mp 185 °C); 1H NMR
(acetone-d6) δ 8.48 (s, 1H, H-C3), 8.08-8.13 (m, 2H), 7.60-
(m, 10H); IR 3447, 3033, 2934, 2868, 1604, 1499, 1453 cm-1
Anal. (C15H22NCl) C, H, N, Cl.
.
Alternatively, the 2-cyano-3-phenylbicyclo[2.2.2]alkanes were
treated with Redal (5 equiv, 65 wt % solution in toluene) in
dry THF overnight at room temperature. Workup and acidi-
fication as above gave the hydrochloride salts as white solids.
tr a n s-2-(Am in om eth yl)-3-ph en ylbicyclo[2.2.2]octan e h y-
d r och lor id e (5a ): mp 269 °C dec; 1H NMR (D2O) δ 7.18-
7.35 (m, 5H), 2.94 (dd, 9.8 Hz, 13.0 Hz, 1H, diastereotopic
H-C9), 2.77 (dd, 5.7, 13.0 Hz, 1H, diastereotopic H-C9), 2.43
(d, 8.1 Hz, 1H, H-C3), 2.24 (m, 1H, H-C2), 1.20-1.66 (m,
10H); IR 3439, 3039, 2947, 2870, 1607, 1473, 1453 cm-1. Anal.
(C15H22NCl) C, H, N, Cl.
7.68 (m, 3H); IR 3104, 2841, 2210, 1690, 1604 cm-1
.
(E/Z)-3-P h en ylp r op en on itr iles 18. Decarboxylation of
(E)-2-cyano-3-phenylpropenoic acids with Cu2O was performed
according to the method of Fairhurst.22 (E)-2-Cyano-3-phenyl-
acrylic acid (17a ) (2.00 g, 11.6 mmol) was mixed with 80 mg
cuprous oxide in a horizontally clamped round-bottom flask
equipped with a tube leading to a cooled receiver. The solid
was heated in vacuo (0.5 mmHg) with a Bunsen burner. The
product (0.89 g, 60%) was collected by distillation and consisted
of a mixture of E- and Z-isomers 18a (ca. 1:5 by 1H NMR
cis- a n d tr a n s-2-(N,N-Dim eth yla m in om eth yl)-3-p h en -
ylbicyclo[2.2.2]a lk a n e Hyd r och lor id e Sa lts 6 a n d 8. The
hydrochloride salt of cis-2-(aminomethyl)-3-phenylbicyclo-
[2.2.2]octane 7a (62.9 mg, 0.25 mmol) was dissolved in 5 mL
5% Na2CO3. The solution was extracted with CH2Cl2 (3 × 5
mL), the extacts were combined, and the solvent was removed
under reduced pressure; 37% formaldehyde (1.5 mL, 20 mmol)
and formic acid (0.85 mL, 20 mmol) were added to the residue,
and the mixture was heated at reflux overnight; 2 N NaOH
solution (15 mL) was added, and the aqueous solution was
extracted with CH2Cl2 (3 × 30 mL). The combined organic
extracts were dried over MgSO4, and the solvent was removed
under reduced pressure to give a brown oil. The residue was
dissolved in 3 mL ethanol, and excess concentrated HCl was
added. The solution was evaporated to dryness to give cis-2-
(N,N-dimethylaminomethyl)-3-phenylbicyclo[2.2.2]octane hy-
drochloride (8a ) as a colorless solid (16 mg, 19%): mp 218-
220 °C; 1H NMR (D2O) δ 7.20-7.30 (m, 5H), 3.39 (d, 11.2 Hz,
1H, diastereotopic H-C9), 3.05 (t, 11.2 Hz, 1H, diastereotopic
H-C9), 2.73 (s, 3H, NCH3), 2.70 (s, 3H, NCH3), 2.64 (m, 1H,
H-C2), 2.57 (dd, 12.6 Hz, 4.5 Hz, 1H, H-C3), 1.60-2.00 (m,
analysis): IR 3071, 3032, 2971, 2219, 1628, 1481 cm-1 1H
;
NMR (CDCl3) the Z-isomer showed characteristic absorbances
at δ 7.82 (m, 2H), 7.46 (m, 3H), 7.14 (d, 12.2 Hz, 1H, H-C3),
5.46 (d, 12.2 Hz, 1H, H-C2); the E-isomer showed absorbances
at δ 7.82 (m, 5H), 7.40 (d, 16.6 Hz, 1H, H-C3), 5.89 (d, 16.5
Hz, 1H, H-C2).
tr a n s,exo/en d o- a n d cis,en d o-5-Cya n o-6-p h en ylbicyclo-
[2.2.2]oct-2-en es 19 a n d 20. A mixture of (E)- and (Z)-3-
phenylpropenonitrile, 18a (1.26 g, 12.0 mmol), 1,3-cyclohexa-
diene (1.40 mL, 14.9 mmol), benzene (1 mL), and a few crystals
of hydroquinone was heated in a sealed tube at 180 °C for 6
days. The mixture was cooled, and the solvent was removed
under reduced pressure. Chromatography (SiO2, 30% v/v
diethyl ether in hexane) afforded a mixture of the trans exo
and trans endo nitriles 19a (110 mg, 7.0%) as a colorless oil
and endo-5-cyano-endo-6-phenylbicyclo[2.2.2]oct-2-ene (20a )
(707 mg, 28.0%) as a white solid: mp 96-97 °C (lit.39 mp 98
°C); 1H NMR (CDCl3) δ 7.16-7.34 (m, 5H), 6.70 (t, 7.2 Hz, 1H,
H-C2), 6.48 (t, 7.2 Hz, 1H, H-C3), 3.30 (dd, 10.5 Hz, 2.7 Hz,
1H, H-C5), 3.25 (d, 10.5 Hz, 1H, H-C6), 3.06 (bs, 1H, H-C1),
2.87-2.83 (m, 1H, H-C4), 1.78-1.25 (m, 4H, H-C7,8); IR
10H); IR 3441, 3019, 2954, 2892, 2868, 1677, 1473, 1400 cm-1
Anal. (C17H28NCl) C, H, N, Cl.
.
tr a n s-2-(N,N-Dim eth yla m in om eth yl)-3-p h en ylbicyclo-
1
[2.2.2]octa n e h yd r och lor id e (6a ): mp 219-228 °C dec; H
NMR (D2O) δ 7.12-7.32 (m, 5H), 3.16 (dd, 9.3 Hz, 13.3 Hz,
1H, diastereotopic H-C9), 2.79 (dd, 4.8 Hz, 13.3 Hz, 1H,
diastereotopic H-C9), 2.62 (s, 6H, N(CH3)2), 2.28-2.42 (m, 2H,
H-C2,3), 1.10-1.62 (m, 10H); IR 3454, 3065, 3033, 2940, 2868,
1618, 1486, 1420 cm-1. Anal. (C17H28NCl) C, H, N, Cl.
3070, 3052, 3026, 2908, 2861, 2236, 1648 cm-1
.
tr a n s- a n d cis-2-Cya n o-3-p h en ylbicyclo[2.2.2]octa n es
21 a n d 22. Substituted bicyclo[2.2.2]oct-2-enes 19 and 20 were
separately hydrogenated over 10% palladium on carbon or
PtO2 under 40 psi of H2. A mixture of endo-5-cyano-endo-6-
phenylbicyclo[2.2.2]oct-2-ene (20a ) (90 mg, 0.43 mmol), 5.3 mg
10% Pd/C, and 1.0 mL ethyl acetate was shaken under H2 for
Syn th esis of tr a n s,exo- a n d tr a n s,en d o-2-(Am in om eth -
yl)-3-p h en ylb icyclo[2.2.1]Alk a n e H yd r och lor id e Sa lt s
9-12. tr a n s,exo- a n d tr a n s,en d o-5-Ca r boxy-6-p h en ylbi-
cyclo[2.2.1]h ep t -2-en es 24 a n d 25. A mixture of trans-

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 891
cinnamoyl chloride (16.0 g, 96 mmol) and freshly distilled
cyclopentadiene (25.0 mL, 303 mmol) was heated at reflux for
18 h. Excess cyclopentadiene was removed under reduced
pressure. The residue was dispersed in 120 mL 10% NaOH
containing a small amount of detergent (Alconox), and the
mixture was heated at 50 °C for 18 h. The mixture was
acidified with concentrated HCl and extracted with CH2Cl2 (3
× 100 mL). The combined extracts were washed with saturated
NaCl (2 × 50 mL) and dried over MgSO4, and the solvent was
evaporated to give a brown solid (16 g) containing a mixture
of exo and endo Diels-Alder adducts 24a and 25a .
1H, H-C3), 2.57 (br s, 1H, H-C4 or C1), 1.82 (d, 9.9 Hz, 1H,
Ha-C7), 1.54 (d, 9.9 Hz, 1H, Hb-C7), 1.25-1.41 (m, 3H,
H-C5,6); IR 3100-3500, 3072, 3040, 2973, 2840, 1710, 1680
cm-1
.
tr a n s,en d o- a n d tr a n s,exo-2-Am id o-3-p h en ylbicyclo-
[2.2.1]h ep ta n es 29 a n d 30. Thionyl chloride (0.57 mL, 8.2
mmol) was added dropwise to a stirred suspension of endo-2-
carboxy-exo-3-phenylbicyclo[2.2.1]heptane (27a ) (345 mg, 1.50
mmol) in 5 mL chloroform containing 0.1 mL DMF at room
temperature. The solution was cooled to 0 °C and cannulated
into a flask containing 15 mL concentrated NH4OH at 0 °C.
The resulting mixture was stirred at 0 °C for 10 min and at
room temperature for 1 h. The mixture was extracted with
chloroform (3 × 30 mL), the combined extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
The residue was recrystallized from a mixture of hexane and
CH2Cl2 (10:1) to give exo-2-amido-endo-3-phenylbicyclo[2.2.1]-
heptane (30a ) as a colorless solid (296 mg, 92%): mp 149-
A solution of iodine (33 g, 130 mmol) and KI (66 g, 400
mmol) in 250 mL water was added dropwise to a solution
containing the mixture of Diels-Alder adducts in 250 mL
saturated NaHCO3, and the mixture was stirred for 20 min.
The precipitate was filtered and washed with 50 mL water,
and the filtrate was saved to recover the exo acid 24a (see
later). The solid was washed with 40 mL 1% Na2S2O3 and 40
mL water and dried under vacuum to afford the iodolactone
26a as an off-white solid: mp 118-120 °C (lit.21 mp 118.5-
1
150 °C (lit.21 mp 153-154 °C); H NMR (CDCl3) δ 7.18-7.34
(m, 5H), 5.54 (br s, 1H, NH), 5.36 (br s, 1H, NH), 3.53-3.56
(m, 1H, H-C3), 2.57 (d, 3.6 Hz, 1H, H-C1), 2.48 (br s, 1H,
H-C4), 2.39 (d, 6.0 Hz, 1H, H-C2), 1.89 (d, 9.9 Hz, 1H, Ha-
C7), 1.59-1.71 (m, 2H), 1.41 (d, 9.9 Hz, 1H, Hb-C7), 1.28-
1.36 (m, 2H); IR 3421, 3191, 3065, 3031, 2973, 2940, 1657,
1
120 °C); H NMR (CDCl3) δ 7.13-7.40 (m, 5 H), 5.21 (d, 5.1
Hz, 1H, H-C3), 4.05 (d, 5.1 Hz, 1H, H-C2), 3.32 (s, 1H,
H-C5), 3.23 (t, 4.8 Hz, 1H, H-C6), 2.87 (br s, 2H, H-C1,4),
2.30 (d, 12.0 Hz, 1H, Ha-C7), 2.11 (d, 12.0 Hz, 1H, Hb-C7); IR
1651 cm-1
.
3066, 3032, 2975, 2891, 1796, 1607, 1497, 1453, 1178 cm-1
.
en d o-2-Am id o-exo-3-p h en ylbicyclo[2.2.1]h ep ta n e (29a ):
mp 141-142 °C (lit.39 mp 138-141 °C); 1H NMR (CDCl3) δ
7.14-7.25 (m, 5H), 5.98 (br s, 1H, NH), 5.23 (br s, 1H, NH),
3.21 (d, 6.0 Hz, 1H, H-C2), 2.69-2.74 (m, 1H, H-C3), 2.54
(br s, 1H, H-C1), 2.50 (d, 3.9 Hz, 1H, H-C4), 1.79 (d, 9.9 Hz,
1H, Ha-C7), 1.41-1.66 (m, 5H, H-C5,6 and Hb-C7); IR 3407,
A mixture of iodolactone 26a (20.0 g, 58.8 mmol), zinc dust
(40 g, 0.66 mol), and 600 mL glacial acetic acid was stirred
for 18 h, and the mixture was filtered through a bed of Celite.
Most of the acetic acid was removed under reduced pressure,
and 2 N NaOH was added until the pH was approximately
13. The mixture was filtered, and the filtrate was washed with
Et2O (2 × 50 mL). The aqueous phase was neutralized with
concentrated HCl and extracted with CH2Cl2 (3 × 50 mL). The
combined extracts were dried over MgSO4, and the solvent was
removed under reduced pressure to afford endo-5-carboxy-exo-
6-phenylbicyclo[2.2.1]hept-2-ene (24a ) as a colorless solid (7.2
g, 56% from the iodolactone): mp 113-113.5 °C (lit.40 mp 113-
3210, 3049, 3007, 2960, 2871, 1657, 1650 cm-1
.
tr a n s,en d o- a n d tr a n s,exo-2-(Am in om eth yl)-3-p h en yl-
b icyclo[2.2.1]h ep t a n e H yd r och lor id e Sa lt s 9 a n d 11.
trans-2-amido-3-phenylbicyclo[2.2.1]heptanes 29 and 30 were
treated with BH3-THF (3 equiv, 1 M BH3 in THF) followed
by aqueous acid according to the procedure given above (for
the synthesis of 5 and 7) to afford 9 and 11.
1
114 °C); H NMR (CDCl3) δ 7.18-7.35 (m, 5H), 6.44 (dd, 5.6
Hz, 3.2 Hz, 1H, H-C3), 6.19 (dd, 5.6 Hz, 2.9 Hz, 1H, H-C2),
3.49 (s, 1H, H-C4), 3.03-3.32 (m, 3H, H-C4,5,6), 1.80 (d, 8.8
Hz, 1H, Ha-C7), 1.60 (dd, 8.8 Hz, 1.7 Hz, 1H, Hb-C7); IR 2700-
en d o-2-(Am in om eth yl)-exo-3-p h en ylbicyclo[2.2.1]h ep -
ta n e h yd r och lor id e (9a ): mp 210-211 °C; 1H NMR (D2O) δ
7.10-7.27 (m, 5H), 2.93-3.07 (m, 2H, H-C8), 2.28 (br s, 1H,
H-C3), 2.11 (br s, 3H, H-C1,2,4), 1.64 (d, 10.5 Hz, 1H, Ha-
C7), 1.45-1.56 (m, 1H), 1.33-1.39 (m, 2H), 1.28 (d, 10.5 Hz,
1H, Hb-C7), 1.14-1.23 (m, 1H); IR 2800-3500, 2993, 2960,
2875, 1640 cm-1. Anal. (C14H20NCl) C, H, N, Cl.
3300, 3072, 3032, 2986, 2881, 1703, 1680 cm-1
.
The exo isomer 25a was isolated from the filtrate from the
iodolactonization reaction described above. The basic filtrate
was acidified with concentrated HCl. The precipitate was
collected by filtration and dissolved in boiling cyclohexane. The
solution was cooled and filtered to remove unreacted cinnamic
acid. The solvent was removed, and the residue was recrystal-
lized from methanol-water to give exo-5-carboxy-endo-6-
phenylbicyclo[2.2.1]hept-2-ene (25a ) as colorless blades: mp
114-114.5 °C (lit.41 mp 113-114 °C); 1H NMR (CDCl3) δ 7.16-
7.28 (m, 5H), 6.33 (dd, 3.2 Hz, 5.6 Hz, 1H, H-C2 or 3), 6.05
(dd, 2.8 Hz, 5.6 Hz, 1H, H-C3 or 2), 3.73 (dd, 3.4 Hz, 5.2 Hz,
1H, H-C5), 3.22 (s, 2H, H-C1,4), 2.55 (dd, 1.6 Hz, 5.4 Hz,-
1H,H-C6), 1.89 (d, 8.7 Hz, 1H, Ha-C7), 1.57 (d, 8.7 Hz, 1H,
Hb-C7); IR 3100-3500, 3073, 3039, 2975, 2919, 1705, 1650
exo-2-(Am in om eth yl)-en d o-3-p h en ylbicyclo[2.2.1]h ep -
ta n e h yd r och lor id e (11a ): mp 218-220 °C dec; 1H NMR
(D2O) δ 7.10-7.26 (m, 5H), 2.81 (dd, 9.3 Hz, 12.6 Hz, 1H,
diastereotopic H-C8), 2.72 (d, 6.0 Hz, 12.6 Hz, 1H, diaste-
reotopic H-C8), 2.64-2.67 (m, 1H, H-C3), 2.26 (br s, 1H,
H-C4), 2.11 (d, 4.5 Hz, 1H, H-C2), 1.85-1.92 (m, 1H, H-C1),
1.52 (d, 9.9 Hz, 1H, Ha-C7), 1 43-1.49 (m, 1H), 1.28 (d, 9.9
Hz, 1H, Hb-C7), 1.01-1.16 (m, 3H); IR 3467, 3025, 2954, 2877,
1614, 1508, 1442 cm-1. Anal. (C14H20NCl) C, H, N, Cl.
tr a n s,en d o- a n d tr a n s,exo-2-(N, N-Dim et h yla m in o-
m et h yl)-3-p h en ylb icyclo[2.2.1]h ep t a n e H yd r och lor id e
Sa lts 10 a n d 12. 2-(Aminomethyl)-3-phenylbicyclo[2.2.1]-
heptane hydrochlorides 9 and 11 were neutralized and treated
with formaldehyde and formic acid according to the method
above (for the synthesis of 6 and 8) to afford 10 and 12.
en d o-2-(N,N-Dim et h yla m in om et h yl)-exo-3-p h en ylb i-
cyclo[2.2.1]h ep ta n e h yd r och lor id e (10a ): mp 218-220 °C
dec; 1H NMR (D2O) δ 7.11-7.27 (m, 5H), 3.25 (dd, 12.6 Hz,
9.9 Hz, 1H, diastereotopic H-C8), 3.09 (dd, 12.6 Hz, 4.8 Hz,
1H, diastereotopic H-C8), 2.66 (s, 6H, N(CH3)2), 2.21-2.28
(m, H-C2,3, 2H,), 2.12 (br s, 2H, H-C1,4), 1.70 (d, 10.5 Hz,
1H, Ha-C7), 1.34-1.56 (m, 3H), 1.29 (d, 10.5 Hz, 1H, Hb-C7),
1.18-1.26 (m, 1H); IR 3432, 3102, 3067, 3010, 2968, 2919,
2884, 1607, 1481, 1403 cm-1. Anal. (C15H26NCl) C, H, N, Cl
exo-2-(N,N-Dim et h yla m in om et h yl)-en d o-3-p h en ylb i-
cyclo[2.2.1]h ep ta n e h yd r och lor id e (12a ): mp 186-187 °C
dec; 1H NMR (D2O) δ 7.13-7.28 (m, 5H), 3.08 (dd, 9.3 Hz, 13.2
Hz, 1H, diastereotopic H-C8), 2.85 (dd, 6.0 Hz, 13.2 Hz, 1H,
diastereotopic H-C8), 2.71 (br s, 1H, H-C3), 2.66 (s, 6H,
cm-1
.
tr a n s,en d o- a n d tr a n s,exo-2-Ca r boxy-3-p h en ylbicyclo-
[2.2.1]h ep ta n es 27 a n d 28. Substituted bicyclo[2.2.1]hept-
2-enes 24 and 25 were hydrogenated in quantitative yield over
10% palladium on carbon or PtO2 under 40 psi of H2 according
to the procedure given above (for the synthesis of 21 and 22)
to afford 27 and 28, respectively.
en do-2-Car boxy-exo-3-ph en ylbicyclo[2.2.1]h eptan e (27a):
mp 104.5-106.5 °C (lit.21 mp 105 °C); 1H NMR (CDCl3) δ 11.2
(br s, 1H, COOH), 7.14-7.31 (m, 5H), 3.16 (d, 6.0 Hz, 1H,
H-C2), 2.89-2.93 (m, 1H, H-C3), 2.72 (br s, 1H, H-C1),
2.49-2.51 (m, 1H, H-C4), 1.80 (d, 10.2 Hz, 1H, H-C7), 1.39-
70 (m, 5H, H-C5,6,7); IR 2800-3500, 3066, 3052, 2964, 2887,
1697, 1649 cm-1
.
exo-2-Car boxy-en do-3-ph en ylbicyclo[2.2.1]h eptan e (28a):
1
mp 105-105.5 °C (lit.23 mp 105 °C); H NMR (CDCl3) δ 8.90
(br s, 1H, CO2H), 7.18-7.34 (m, 5H), 3.56 (dd, 3.9 Hz, 6.3 Hz,
1H, H-C2), 2.66 (d, 3.9 Hz, 1H, H-C1 or C4), 2.61 (d, 6.3 Hz,

892 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
N(CH3)2), 2.24 (br s, 1H, H-C1), 2.09 (br s, 1H, H-C4), 1.96-
2.06 (m, 1H, H-C2), 1.08-1.56 (m, 6H, H-C5,6,7); IR 3375,
concentrated under reduced pressure, 100 mL 10% Na2CO3
was added, and the solution heated at 70 °C for 3 h. The
solution was cooled to room temperature and washed with CH2-
Cl2 (3 × 50 mL). The aqueous solution was acidified with
concentrated HCl and extracted with CH2Cl2 (2 × 30 mL). The
combined extracts were washed with saturated NaCl (2 × 40
mL) and dried over MgSO4, and the solvent was removed
under reduced pressure to give a brown solid (3.1 g). Analysis
3026, 2960, 2927, 2881, 2855, 1650, 1485, 1466, 1407 cm-1
Anal. (C16H26NCl) C, H, N, Cl.
.
Syn th esis of cis,en d o-2-(Am in om eth yl)-en d o-3-p h en yl-
bicyclo[2.2.1]a lk a n e Hyd r och lor id e Sa lts 13 a n d 14.
en d o-5-Cya n o-en d o-6-p h en ylbicyclo[2.2.1]h ep t-2-en es 31.
Diels-Alder reaction of cyclopentadiene and a mixture of (E)-
and (Z)-18 (approximately 1:4 by 1H NMR analysis) according
to the procedure given above (for the synthesis of 19 and 20)
gave a mixture of 31 and the corresponding trans isomers
which were separated by column chromatography (SiO2, 1/10
EtOAc/hexane).
1
of the solid by H NMR showed that it consisted of a mixture
of cis endo, cis exo (35c), trans endo (27c), and trans exo (28c)
adducts in a ratio of approximately 3:1:1:1. The mixture was
dissolved in 235 mL 10% NaCO3, and a solution of KI3
(prepared from 2.0 g I2 and 4.0 g KI in 20 mL H2O) was added
until no more precipitate formed. The mixture was extracted
with CH2Cl2 (4 × 30 mL), and the aqueous solution was
acidified with concentrated HCl. The aqueous solution was
extracted with CH2Cl2 (3 × 30 mL), the combined extracts were
washed with saturated NaCl (2 × 40 mL), dried over MgSO4,
and filtered, and the solvent was removed under reduced
en d o-5-Cya n o-en d o-6-p h en ylb icyclo[2.2.1]h ep t -2-en e
1
(31a ): H NMR (CDCl3) δ 7.22-7.33 (m, 5H), 6.44-6.50 (m,
2H, H-C2,3), 3.67 (dd, 3.0 Hz, 9.7 Hz, 1H, H-C6), 3.46 (dd,
3.9 Hz, 9.7 Hz, 1H, H-C5), 3.36 (br s, 1H, H-C4), 3.25 (br s,
1H, H-C1), 1.67 (dt, 1.8 Hz, 9.1 Hz, Ha-C7), 1.52 (d, 9.1 Hz,
1H, Hb-C7); IR 3065, 3033, 2973, 2875, 2243, 1661, 1491, 1438
1
cm-1
.
pressure to give an off-white solid (0.61 g). H NMR showed
that the solid contained a mixture of cis exo (35c) and trans
exo (28c) acids (approximately 1:1). Column chromatography
(SiO2; CHCl3:EtOAc, 6:1) gave the cis exo acid 35c as a white
solid (140 mg, 46% yield from mixture of 35c and 28c): mp
98-99 °C (lit.23 mp 103 °C); 1H NMR (300 MHz, CDCl3) δ
7.12-7.22 (m, 4H), 6.39 (dd, 3.3 Hz, 5.6 Hz, 1H, H-C3), 6.24
(dd, 2.7 Hz, 5.6 Hz, 1H, H-C2), 3.06-3.10 (m, 2H, H-C4 and
C6), 3.00 (br s, 1H, H-C1), 2.70 (dd, 1.8 Hz, 9.5 Hz, 1H,
H-C5), 2.29 (d, 9.0 Hz, 1H, Ha-C7), 1.64 (d, 9.0 Hz, 1H, Hb-
en d o-2-Cya n o-en d o-3-p h en ylbicyclo[2.2.1]h ep ta n es 32.
Substituted bicyclo[2.2.1]hept-2-enes 31 were hydrogenated in
quantitative yield over 10% palladium on carbon or PtO2 under
40 psi of H2 according to the procedure given above (for the
synthesis of 21 and 22) to afford 32.
en do-2-Cyan o-en do-3-ph en ylbicyclo[2.2.1]h eptan e (32a):
1H NMR (CDCl3) δ 7.23-7.39 (m, 5H), 3.41 (d, 13.0 Hz, 1H,
H-C2), 3.30 (ddd, 2.1 Hz, 4.5 Hz, 13.0 Hz, 1H, H-C3), 2.69
(br s, 1H, H-C4), 2.57 (br s, 1H, H-C1), 1.47-1.97 (m, 6H,
C7); IR 2700-3300, 3063, 2987, 2948, 1713, 838, 730 cm-1
.
H-C5,6,7); IR 3065, 3033, 2970, 2888, 2243, 1652 cm-1
.
exo-2-Car boxy-exo-3-(4-ch lor oph en yl)bicyclo[2.2.1]h ep-
ta n e (36c). exo-5-Carboxyl-exo-6-(4-chlorophenyl)bicyclo[2.2.1]-
hept-2-ene (35c) (135 mg, 0.54 mmol) was hydrogenated in
quantitative yield over 30 mg 10% palladium on carbon in 15
mL ethyl acetate under 40 psi of H2 according to the procedure
given above (for the synthesis of 21 and 22) to afford exo-2-
carboxy-exo-3-(4-chlorophenyl)bicyclo[2.2.1]heptane (36c) as an
off-white solid: mp 129-130 °C; 1H NMR (CDCl3) δ 7.07-7.20
(m, 4H), 3.12 (d, 9.7 Hz, 1H, H-C3), 2.83 (d, 9.7 Hz, 1H,
H-C2), 2.50 (br s, 1H, H-C1), 2.47 (br s, 1H, H-C4), 2.22 (d,
10.5 Hz, 1H, Ha-C7), 1.57-1.70 (m, 2H), 1.41 (d, 10.5 Hz, 1H,
Hb-C7), 1.24-1.37 (m, 2H); IR 2700-3300, 3051, 2954, 2881,
en do-2-(Am in om eth yl)-en do-3-ph en ylbicyclo[2.2.1]h ep-
ta n e Hyd r och lor id e Sa lts 13. endo-2-Cyano-endo-3-phenyl-
bicyclo[2.2.1]heptanes 32 were treated with BH3-THF (3
equiv, 1 M BH3 in THF) followed by aqueous acid according
to the procedure given above (for the synthesis of 5 and 7) to
afford 13.
en do-2-(Am in om eth yl)-en do-3-ph en ylbicyclo[2.2.1]h ep-
1
ta n e h yd r och lor id e (13a ): mp 259-262 °C; H NMR (D2O)
δ 7.13-7.18 (m, 5H), 3.30 (dd, 3.9 Hz, 12.0 Hz, 1H, diaste-
reotopic H-C8), 2.79-2.82 (m, 2H, diastereotopic H-C8 and
H-C3), 2.36-2.46 (m, 1H, H-C2), 2.30 (br s, 2H, H-C1 and
C4), 1.34-1.63 (m, 6H, H-C5, C6 and C7); IR 3441, 3033,
2947, 2871, 1611, 1482, 1426 cm-1. Anal. (C14H20NCl) C, H,
N, Cl.
1703, 841, 742 cm-1
.
exo-2-Am id o-exo-3-(4-ch lor op h en yl)bicyclo[2.2.1]h ep -
ta n e (37c). Thionyl chloride (1.0 mL, 13 mmol) was added to
a solution of exo-2-carboxy-exo-3-(4-chlorophenyl)bicyclo[2.2.1]-
heptane (36c) (120 mg, 0.48 mmol) in 10 mL CHCl3 containing
0.1 mL DMF. The mixture was stirred for 30 min at room
temperature, cooled to 0 °C, and added dropwise to concen-
trated NH3 (15 mL). The mixture was stirred at 0 °C for 20
min and then at room temperature for 18 h. The organic layer
was separated, and the aqueous layer was extracted with CH2-
Cl2 (2 × 10 mL). The organic fractions were combined, washed
with saturated NaCl (2 × 20 mL), and dried over MgSO4. The
solvent was removed under reduced pressure to give exo-2-
amido-exo-3-(4-chlorophenyl)bicyclo[2.2.1]heptane (37c) as a
white solid (120 mg, 100%): mp 192-194 °C; 1H NMR (CDCl3)
δ 7.13-7.22 (m, 4H), 4.89 (br s, 2H, N-H), 3.07 (d, 9.5 Hz,
1H, H-C2), 2.67 (d, 9.5 Hz, 1H, H-C3), 2.58 (br s, 1H, H-C4),
2.42 (br s, 1H, H-C1), 2.35 (d, 10.5 Hz, 1H, Ha-C7), 1.63-
1.68 (m, 2H), 1.44 (d, 10.5 Hz, 1H, Hb-C7), 1.23-1.38 (m, 2H);
en d o-2-(N,N-Dim eth yla m in om eth yl)-en d o-3-p h en ylbi-
cyclo[2.2.1]h ep ta n e Hyd r och lor id e Sa lts 14. endo-2-(Ami-
nomethyl)-endo-3-phenylbicyclo[2.2.1]heptane hydrochlorides
13 were neutralized and treated with formaldehyde and formic
acid according to the method provided above (for the synthesis
of 6 and 8) to afford 14.
en d o-2-(N,N-Dim eth yla m in om eth yl)-en d o-3-p h en ylbi-
cyclo[2.2.1]h ep ta n e h yd r och lor id e (14a ): mp 270 °C dec;
1H NMR (D2O) δ 7.11-7.25 (m, 5H), 3.33 (dd, 1H, 13.2 Hz,
3.3 Hz, diastereotopic H-C8), 2.96 (d, 1H, 10.8 Hz, H-C3),
2.86 (dd, 1H, 13.2 Hz, 6.0 Hz, diastereotopic H-C8), 2.63 (s,
3H, NCH3), 2.57 (s, 3H, NCH3), 2.30 (br s, 3H, H-C1,2,4),
1.32-1.65 (m, 6H); IR 3421, 3059, 3032, 3019, 2953, 2868,-
1611, 1448, 1400 cm-1. Anal. (C22H26NCl) C, H, N, Cl.
Syn th esis of cis,exo-2-(Am in om eth yl)-exo-3-(4-ch lor o-
p h en yl)bicyclo[2.2.1]a lk a n e Hyd r och lor id e Sa lt (15c).
(Z)-4-Ch lor ocin n a m ic Acid (34c). A solution of (E)-4-chlo-
rocinnamic acid (33c) (8.00 g, 43.8 mmol) in 300 mL dioxane
was irradiated at 254 nm in a quartz tube for 24 h. The solvent
was removed under reduced pressure, and the residue was
triturated with boiling water. Upon cooling, (Z)-4-chlorocin-
namic acid (34c) precipitated as a colorless crystalline solid
(1.1 g, 14%): mp 109-110 °C (lit.23 mp 111 °C); 1H NMR
(CDCl3) δ 7.40-7.42 (m, 4H), 6.90 (d, 12.6 Hz, 1H, H-C3),
5.96 (d, 12.6 Hz, 1H, H-C2); IR 2500-3300, 3053, 2947, 1691,
IR 3493, 3330, 3011, 2964, 2879, 1659, 1612, 830, 768 cm-1
.
exo-2-(Am in om et h yl)-exo-3-(4-ch lor op h en yl)b icyclo-
[2.2.1]h ep ta n e Hyd r och lor id e Sa lt (15c). exo-2-Amido-exo-
3-(4-chlorophenyl)bicyclo[2.2.1]heptane (37c) was treated with
BH3-THF (3 equiv, 1.0 M BH3 in THF) followed by aqueous
acid according to the procedure given above (for the synthesis
of 5 and 7) to afford 15c as a white crystalline solid (60%
1
yield): mp 260 °C dec; H NMR (D2O) δ 7.07-7.19 (m, 4H),
1635, 849, 765 cm-1
.
2.88 (br d, 6.0 Hz, 1H, H-C8), 2.29 (br s, 1H, H-C4), 2.04-
2.13 (m, 4H, H-C1,2,3,8), 1.62 (d, 10.5 Hz, 1H, Ha-C7), 1.42-
1.57 (m, 2H), 1.25 (d, 10.5 Hz, 1H, Hb-C7), 1.11-1.21 (m, 2H);
IR 3447, 3031, 2960, 2875, 1604, 834, 769 cm-1. Anal.
(C14H19N2Cl) C, H, N, Cl.
exo-5-Car boxyl-exo-6-(4-ch lor oph en yl)bicyclo[2.2.1]h ept-
2-en e (35c). A mixture of (Z)-4-chlorocinnamic acid (34c) (2.6
g, 14.2 mmol) and cyclopentadiene (7 mL, 85 mmol) was heated
in a sealed tube at 140 °C for 4 days. The mixture was

Site-Specific Cocaine Abuse Treatment Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 893
5-exo-Carboxy-6-exo-phenylbicyclo[2.2.1]hept-2-ene (35a).
A solution of 5-endo-carboxy-6-exo-phenylbicyclo[2.2.1]hept-2-
ene (24a ) (1.27 g, 5.92 mmol) in 10.0 mL dry THF was added
dropwise to a solution of LDA‚THF (8.0 mL of 1.5 M solution
in hexane, 12.0 mmol, 2 equiv) in 10 mL dry THF at -78 °C
under N2. The mixture was warmed to room temperature and
stirred for 5 h. Ice-cold saturated NH4Cl solution was added,
followed by concentrated HCl until the solution was strongly
acidic. The mixture was extracted with CH2Cl2 (3 × 25 mL),
and the combined extracts were washed with brine and dried
over MgSO4. The solvent was removed under reduced pressure
to give a mixture (1.20 g) of 24a (90% by 1H NMR analysis)
and 5-exo-carboxy-6-exo-phenylbicyclo[2.2.1]hept-2-ene, 35a
(10%). The solid was dissolved in 40 mL 10% Na2CO3, and a
solution of KI3 (2 g I2 and 4 g KI in 20 mL H2O) was added
until no more precipitate formed. The mixture was washed
with CH2Cl2 (3 × 30 mL), and concentrated HCl was added to
the aqueous solution until it was strongly acidic. The white
precipitate was filtered and dried under vacuum. Recrystalli-
zation from CH3OH/H2O gave 5-exo-carboxy-6-exo-phenylbicyclo-
[2.2.1]hept-2-ene, 35a (65 mg, plus 50 mg from a second crop),
as colorless blades: mp 138-139 °C (lit.42 mp 136 °C); 1H NMR
(CDCl3) δ 7.12-7.25 (m, 5H, H-Ph), 6.38 (dd, 3.6 Hz, 5.7 Hz,
1H, H-C3), 6.22 (dd, 3.3 Hz, 5.4 Hz, 1H, H-C2), 3.11 (dd, 1.5
Hz, 9.9 Hz, H-C5), 3.02-3.04 (m, 2H, H-C1 and C4), 2.70
(dd, 1.8 Hz, 9.9 Hz, H-C6), 2.34 (d, 9.0 Hz, 1H, H-C7), 1.63
(dt, 1.5 Hz, 9.0 Hz, H-C7); IR 3098, 3065, 3026, 2980, 2736,
CH3OH/AcOEt to afford the hydrochlorde salt of 2-exo-(ami-
nomethyl)-3-exo-phenylbicyclo[2.2.1]heptane, 15a , as a white
crystalline solid (35 mg, 53% yield from 35): mp 258 °C dec;
1H NMR (D2O) δ 7.10-7.23 (m, 5H, H-Ph), 2.91 (br d, 7.2
Hz, 1H, H-C3), 2.33 (br s, 1H, H-C1), 2.06-2.11 (m, 4H,
H-C8,5,4), 1.67 (d, 9.9 Hz, H-C7), 1.16-1.57 (m, 5H,
H-C2,3,7); MS (EI) M+ 201.2 (100%); IR 3425, 3061, 2937,
2892, 1606, 1506, 1463, 99, 802, 740, 730 cm-1. Anal. (C14H20
NCl) C, H, N, Cl.
-
P h a r m a cology. [3H]]WIN 35,428 Bin d in g. The synthe-
sized compounds were screened for activity in a striatal tissue
preparation using a modification of the [3H]WIN 35,428
binding assay described by Reith and Selmeci.43 Male Spra-
gue-Dawley rats (Harlan Sprague-Dawley, Indianapolis, IN)
weighing 150-300 g were anesthetized using CO2 gas and
sacrificed by decapitation. (Preliminary experiments demon-
strated no difference in the KD or Bmax of [3H]WIN 35,428
binding in unanesthetized rats versus anesthetized rats; data
not shown.) Their brains were quickly removed and placed in
ice-cold 0.32 M sucrose. The striatal tissue was removed and
homogenized in 20 volumes of 0.32 M sucrose, using 10 up/
down strokes of a motorized Potter-Elvejhm homogenizer. The
supernatant obtained after centrifugation for 10 min at 0 °C
(S1 fraction) was removed and centrifuged for 20 min at 20000g
and 0 °C to obtain the P2 fraction, which was then resuspended
in 50 volumes (original wet weight) of ice-cold 25 mM sodium
phosphate buffer (pH 7.7) using a Tekmar tissuemizer. Samples
containing 750 µL phosphate buffer, 150 µL P2 suspension,
50 µL test compound, 25 µL water or amfonelic acid (to define
nonspecific binding; final concentration, 10 µM), and 25 µL
[3H]WIN 35,428 (final concentration, 2 nM) were incubated
for 2 h at 0 °C. The incubation was terminated by vacuum
filtration through Whatman GF/B filters presoaked with 0.05%
(w/v) poly(ethylenimine), mounted in Millipore filtration mani-
folds. A 5-mL aliquot of assay buffer was added to the sample
immediately before filtering it, and a second 5-mL aliquot of
assay buffer was used to wash the filter. The filters were
transferred to scintillation vials, shaken vigorously in the
presence of 8 mL Beckman Ready-Safe scintillation fluid for
30 min, and counted in a liquid scintillation counter.
1776, 1705, 1492, 1427, 1262, 1203, 926, 709 cm-1
.
2-exo-Car boxy-3-exo-ph en ylbicyclo[2.2.1]h eptan e (36a).
5-exo-Carboxy-6-exo-phenylbicyclo[2.2.1]hept-2-ene, 35a (60
mg, 0.28 mmol), was hydrogenated in quantitative yield over
30 mg 10% palladium on carbon in 15 mL ethyl acetate under
42 psi of H2 according to the procedure given above (for the
synthesis of 21 and 22) to afford 2-exo-carboxy-3-exo-phenylbi-
cyclo[2.2.1]heptane, 36a , as a light brown oil: 1H NMR (CDCl3)
δ 7.16-7.26 (m, 5H, H-Ph), 3.22 (d, 10.2 Hz, H-C2), 2.54-
2.58 (m, 2H, H-C1 and C4), 2.90 (dd, 1.8 Hz, 10.2 Hz, H-C3),
2.54-2.58 (m, 2H, H-C1 and C4), 2.35 (dt, 1.8 Hz, 10.2 Hz,
1H, H-C7), 1.67-1.73 (m, 2H, H-C5 and C6), 1.47 (dt, 1.8H
z, 10.2 Hz, H-C7), 1.30-1.41 (m, 2H, H-C5 and C6); IR 3094,
3071, 3033, 2964, 2872, 1782, 1713, 1475, 1298, 1244, 699
IC50 values (that concentration of test compound required
to inhibit 50% of the control specific binding of [3H]WIN 35,-
428) were determined from dose-response curves usually
containing a range of six concentrations of the test drug, with
triplicate determinations made at each concentration. The IC50
for WIN 35,428 was 22.2 ( 4.7 nM (average ( SEM) under
these conditions.
cm-1
.
2-exo-(Am in om et h yl)-3-exo-p h en ylb icyclo[2.2.1]h ep -
ta n e Hyd r och lor d e Sa lt (15a ). SOCl2 (0.20 mL, 2.7 mmol)
was added to a solution of 5-exo-carboxy-6-exo-phenylbicyclo-
[2.2.1]heptane, 36a , and 0.3 mL N,N-dimethylformamide in
10.0 mL CHCl3, and the mixture was stirred under N2 for 30
min. The mixture was cooled to 0 °C, added dropwise to ice-
cold concentrated ammonium hydroxide, and stirred at 0 °C
for 30 min and at room temperature for 2 h. The CHCl3 layer
was separated, and the aqueous solution was extracted with
CH2Cl2 (3 × 10 mL). The organic portions were combined,
washed with brine, dried over MgSO4, and evaporated to give
2-exo-amido-3-exo-phenylbicyclo[2.2.1]heptane, 37a , as a light
brown solid: 1H NMR (CDCl3) δ 7.20-7.34 (m, 5H, H-Ph),
4.86 (br s, 1H, H-N), 3.17 (d, 9.9 Hz, H-C3), 2.75 (d, 9.9 Hz,
1H, H-C2), 2.67 (br s, 1H, H-C4), 2.52 (br s, 1H, H-C1), 2.42
(dt, 2.1 Hz, 9.9 Hz, 1H, H-C7), 1.66-1.74 (m, 2H, H-C5 and
C6), 1.51 (dt, 1.8 H z, 10.2 Hz, H-C7), 1.31-1.43 (m, 2H,
H-C5 and C6).
A solution of 1.0 M BH3 in THF (1.5 mL, 1.5 mmol) was
added dropwise to a solution of 2-exo-amido-3-exo-phenylbicyclo-
[2.2.1]heptane, 37a , in 10 mL THF at 0 °C. The mixture was
heated at reflux for 18 h and cooled to 0 °C, and concentrated
HCl was added until the solution was strongly acidic. THF
was removed under reduced pressure, the mixture was washed
with CH2Cl2 (3 × 20 mL), 20% NaOH solution was added to
the aqueous solution until it was strongly basic, and the
mixture was extracted with Et2O (3 × 15 mL). The combined
extracts were washed with brine, dried over MgSO4 and
evaporated to give 2-exo-(aminomethyl)-3-exo-phenylbicyclo-
[2.2.1]heptane as a colorless oil. The oil was dissolved in 0.5
mL CH3OH and 1 drop 12 M HCl added. The solvent was
evaporated, and the resulting solid was recrystallized from
[3H]Dop a m in e Up ta k e. Accumulation of [3H]DA was
determined as previously described.44 Briefly, 250 µL S1
fraction prepared as described above from striatal tissue of
anesthetized rats was diluted 4-fold with a modified Krebs-
phosphate buffer (120 mM NaCl, 4.9 mM KCl, 1.2 mM MgSO4,
11 mM glucose, 0.16 mM Na2EDTA, 1.1 mM ascorbic acid, 0.01
mM pargyline, and 15.5 mM Na2PO4, equilibrated with 95%
O2-5% CO2 and adjusted to pH 7.4 with NaOH) and prein-
cubated with 1100 µL Krebs-phosphate buffer and 100 µL
vehicle or drug for 10 min at 37 °C. A solution of [3H]DA
hydrochloride (50 µL, DuPont/NEN, Boston, MA, or Amersham
Corp., Arlington Heights, IL) which had been previously
diluted with sufficient unlabeled DA‚HCl to bring the specific
activity to approximately 5 Ci/mmol was added to give a final
concentration of DA of about 30 nM. The samples were exposed
to the [3H]DA for exactly 2.0 min. Nonspecific dopamine
transport was determined by following the same protocol at 0
°C. Accumulation of [3H]dopamine was terminated by the rapid
addition of 5 mL of the chilled Krebs-phosphate buffer to each
sample, followed by filtration through a Whatman GF/C filter
under vacuum, after which the filter was washed with an
additional 5-mL aliquot of buffer. The filters were extracted,
and the trapped radioactivity was quantified as described for
the [3H]WIN 35,428 binding assay.
The IC50 values were determined from dose-response curves
usually containing a range of five concentrations of test drug,

894 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Deutsch et al.
with [3H]dopamine uptake measured in duplicate samples at
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Ack n ow led gm en t. This work was supported in part
by grants from the National Institute of Drug Abuse,
RO1 DA06305 (H.M.D.) and KO5 DA00008 (S.G.H.).
The authors wish to thank Mr. Adam Eason and Ms.
Monica Stafford for their assistance in the biochemical
assays and Ms. Christine Engels who performed the
drug discrimination experiments. The authors would
also like to thank Dr. Carol Venanzi, New J ersey
Institute of Technology, for many helpful discussions.
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