Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1- [2- [bis (4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents

Article abstract of DOI:10.1021/jm990291q

An investigation into the preparation of potential extended-release cocaine-abuse therapeutic agents afforded a series of compounds related to 1- [2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a) and 1-[2-[bis(4- fluorophenyl)methoxy]ethyl]-4-(

Full text of DOI:10.1021/jm990291q

J . Med. Chem. 1999, 42, 5029-5042
5029
Oxygen a ted An a logu es of 1-[2-(Dip h en ylm eth oxy)eth yl]- a n d
1-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-4-(3-p h en ylp r op yl)p ip er a zin es (GBR
12935 a n d GBR 12909) a s P oten tia l Exten d ed -Action Coca in e-Abu se Th er a p eu tic
Agen ts
David B. Lewis,†,∇ Dorota Matecka,†,| Ying Zhang,†, Ling-Wei Hsin,† Christina M. Dersch,‡ David Stafford,§
J ohn R. Glowa,§ Richard B. Rothman,‡ and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, Maryland 20892, Clinical Psychopharmacology
Section, IRP, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, and
Department of Pharmacology and Therapeutics, LSUMC-Shreveport, 1501 Kings Highway, P.O. Box 33932,
Shreveport, Louisiana 71130-3932
Received J une 8, 1999
An investigation into the preparation of potential extended-release cocaine-abuse therapeutic
agents afforded a series of compounds related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpro-
pyl)piperazine (1a ) and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine
(1b) (GBR 12935 and GBR 12909, respectively), which were designed, synthesized, and
evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake
of [3H]-labeled dopamine (DA). The addition of hydroxy and methoxy substituents to the benzene
ring on the phenylpropyl moiety of 1a -1d resulted in a series of potent and selective ligands
for the DAT (analogues 5-28). The hydroxyl groups were included to incorporate a medium-
chain carboxylic acid ester into the molecules, to form oil-soluble prodrugs, amenable to “depot”
injection techniques. The introduction of an oxygen-containing functionality to the propyl side
chain provided ketones 29 and 30, which demonstrated greatly reduced affinity for the DAT
and decreased potency in inhibiting the uptake of [3H]DA, and benzylic alcohols 31-36, which
were highly potent and selective at binding to the DAT and inhibiting [3H]DA uptake. The
enantiomers of 32 (34 and 36) were practically identical in biological testing. Compounds 1b,
32, 34, and 36 all demonstrated the ability to decrease cocaine-maintained responding in
monkeys without affecting behaviors maintained by food, with 34 and 36 equipotent to each
other and both more potent in behavioral tests than the parent compound 1b. Intramuscular
injections of compound 41 (the decanoate ester of racemate 32) eliminated cocaine-maintained
behavior for about a month following one single injection, without affecting food-maintained
behavior. The identification of analogues 32, 34, and 36, thus, provides three potential
candidates for esterification and formulation as extended-release cocaine-abuse therapeutic
agents.
In tr od u ction
(e.g. pneumonia).10 Additionally, there is evidence that
cocaine abuse plays a part in decreased performance in
several neuropsychological (NP) parameters, including
attention and concentration, learning and verbal memory,
reaction time, visuo-spatial skills, calculating ability,
and abstracting ability. These NP decrements seem to
last beyond the period of actual cocaine use, in that
several NP functions are measurably impaired, after up
to 3 months of abstinence from cocaine.10 Although the
estimated potential worldwide production of cocaine
declined slightly in 1997, U.S. cocaine abuse seems to
have stabilized at a high level from data on price,
availability, cocaine-related emergency room episodes,
and other indicators. The extent of this abuse is
reflected by U.S. Federal seizures of about 100 metric
tons of cocaine during 1997, while the abuse of crack
cocaine remained high and stable and continued to
spread to smaller cities and towns.11
Cocaine is one of the most widely abused drugs
today.1-7 In addition to affecting the lives of those who
abuse it, it has also had enormous effects on public
health worldwide, through the increased spread of
infectious diseases8 (e.g. HIV-1, hepatitis B and C, and
drug-resistant tuberculosis9), which are transmitted via
behavioral practices commonly associated with cocaine
abuse. Furthermore, cocaine abusers show an increased
incidence of cerebrovascular accident (stroke), myocar-
dial infarction (heart attack), and pulmonary diseases
* Requests for reprints should be addressed to Kenner C. Rice, Chief,
Laboratory of Medicinal Chemistry, NIDDK, NIH, 8 Center Dr., MSC
0815, Bethesda, MD 20892-0815. Fax: (301) 402-0589. E-mail: KR21F@
NIH.gov.
† Laboratory of Medicinal Chemistry, NIDDK.
§ LSUMC-Shreveport.
‡ National Institute on Drug Abuse.
∇ Present address: DMEDP, ONDC, CDER, FDA, 5600 Fishers Ln.,
Rockville, MD 20857.
| Present address: ONDC, CDER, FDA, 5600 Fishers Ln., Rockville,
MD 20857.
Numerous studies have indicated that the reinforcing
effects of cocaine are largely mediated by the mesolimbic
dopaminergic system according to the dopamine (DA)
Present address: ArQule, Inc., 200 Boston Ave., Medford, MA
02155.
10.1021/jm990291q CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/05/1999

5030 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
hypothesis of reinforcement.12 According to this hypoth-
esis, cocaine interacts with a site on the dopamine
transporter protein (DAT),13 lowering DA reuptake into
dopaminergic neurons, resulting in increased synaptic
DA levels. The resultant elevated synaptic DA levels
interact with DA receptors on postsynaptic neurons and
result in a variety of clinically observable effects,
including reinforcement and locomotor stimulation.14
Based on these observations, a great deal of emphasis
has been directed toward the development of selective
and potent DA reuptake inhibitors as putative thera-
peutic agents for the treatment of cocaine abuse.15
Ch a r t 1. Parent Compounds GBR 12935, 12909, 12783,
and 13069 (Analogues 1a -1d )
However, as reviewed in detail elsewhere,16 the ability
of the DA hypothesis to explain the acute euphoric
effects of cocaine in humans is unclear. For example,
schizophrenic patients who are on therapeutic doses of
antipsychotic medication abuse cocaine and experience
cocaine-induced euphoria.17 Controlled studies in hu-
mans also fail to support the DA hypothesis.18
GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-
(3-phenylpropyl)piperazine (1b)] (Chart 1).32 Tritiated
piperazine 1a is commonly used as a standard radioli-
gand for binding studies involving the DAT,33 and 1b
has been shown to decrease cocaine-maintained re-
sponding in rhesus monkeys without affecting similar
responding maintained by food.34 We have previously
demonstrated that modifications in the piperazine ring
of 1b can lead to greatly enhanced affinity and selectiv-
ity in binding to the DAT and in the ability to inhibit
the uptake of radiolabeled DA.35 Additionally, modifica-
tions in the 3-phenylpropyl moiety of 1a or 1b have
resulted in another series of potent and selective ligands
for the DAT.36
The scope of our research and that of others on the
development of potential cocaine treatment medications
has focused in large part on the development of DAT-
selective ligands, which exhibit enhanced selectivity
and/or potency for binding to the DAT and for inhibiting
the uptake of DA.37 However, the development of potent
and selective DAT ligands suitable for the treatment of
cocaine abuse alone is insufficient for a successful drug-
abuse treatment agenda. Such an agenda requires strict
patient compliance to suppress the extremely potent
reinforcing and euphorigenic effects of cocaine. Thus,
we have examined methodology designed to address the
potential future problem of patient noncompliance and
relapse to cocaine abuse.
One approach that has successfully been employed
in the treatment of neuroleptic disorders is the use of
controlled-release dosage forms of therapeutic agents.38
The duration of action of a parenterally administered
pharmaceutical can be increased by changing the sol-
vent to a nonaqueous medium, such as a fixed oil of
vegetable origin (e.g. castor, cottonseed, olive, peanut,
or sesame oil), which serves to reduce the release rate
into the plasma.39 The half-life can be increased yet
again by the preparation of an oil-soluble prodrug; this
can be accomplished by the conversion of an aliphatic
alcohol to an ester, using a medium-chain alkanoic acid
(e.g. hexanoic, heptanoic, decanoic, cyclopentylpropionic,
or phenylpropionic acid).40 The esterified alcohol is then
formulated in an oily vehicle and administered by
intramuscular injection, forming a “depot” of the pro-
drug. The esterified prodrug then diffuses to the surface
of the oil droplet, partitions into the aqueous (plasma)
phase, and is hydrolyzed to the parent compound,
presumably at the interface.41 This “depot” approach has
been used successfully for formulating phenothiazines
in the treatment of schizophrenic patients, effecting a
much longer duration of clinical action for these antip-
Recent studies showed that DAT knockout mice self-
administer cocaine19 and demonstrate cocaine-condi-
tioned place preference,20 indicating that in the absence
of the DAT, cocaine can still establish rewarding effects.
Although these data suggest that the DAT is not critical
for mediating cocaine reward, the data do not rule out
a role for mesolimbic DA as a mediator of cocaine
reward. Since DA is a substrate of the norepinephrine
(NE) transporter,21 DA could be accumulated by NE
nerves. This has been shown to occur in both the medial
frontal cortex22 and nucleus accumbens, but not in the
striatum of rats,23 which lacks noradrenergic innerva-
tion.24 The inability of cocaine to elevate extracellular
DA in the striatum of DAT knockout mice is consistent
with the lack of NE transporters in this brain region.18
Thus, in the absence of the DAT, it is reasonable to
assume that some of the extracellular DA in the nucleus
accumbens would be accumulated by NE nerves. Since
cocaine is a potent inhibitor of the NE transporter,25
administration of cocaine would block DA accumulation
and increase extracellular DA, triggering the cocaine
reward. Viewed collectively, these data indicate the need
to further test the clinical relevance of the DA hypoth-
esis of cocaine reward. One approach to testing the DA
hypothesis is to develop appropriate pharmacological
tools such as high-affinity slowly dissociating DAT
ligands with low intrinsic activity.14,26 The DA hypoth-
esis predicts that such an agent would have efficacy in
treating cocaine addiction. The present study focuses
on developing potential medications for testing the DA
hypothesis as opposed to evaluating the clinical rel-
evance of the hypothesis. The medications required for
testing the DA hypothesis must have high selectivity
for the DAT, and thus there is a need to determine their
Ki values at the serotonin transporter protein (SERT)
and their serotonin (5-HT) reuptake inhibition.
A variety of structural classes of DA uptake blockers
(which bind to the DAT with varying affinities) have
been used as templates for the synthesis of potential
cocaine-abuse treatment agents, including cocaine ana-
logues,27 tropanes,28 benztropines,29 mazindol,30 and
disubstituted piperazines.31 Research in this laboratory
has focused on the development of novel analogues of
the disubstituted piperazines GBR 12935 [1-[2-(diphen-
ylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (1a )] and

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5031
group was connected at various sites on the phenylpro-
pyl moiety (Figure 1). A series of phenolic derivatives
of 1a -1d (5-16, Chart 2) were synthesized, along with
their methoxy congeners (17-28, Chart 2). The corre-
sponding methoxy-bearing analogues were utilized as
synthetic precursors to several of the hydroxy analogues
and were also subjected to biological evaluation (DAT
and SERT binding; DA and 5-HT uptake inhibition), to
compare the biological activity of the methoxy analogues
with that for their phenolic congeners. In addition, the
aliphatic benzylic hydroxy analogues 31-36 were syn-
thesized. The racemates (31, 32) were synthesized
initially, followed by the R- and S-enantiomers (33-36).
Based on biological evaluation in DAT and SERT
binding, along with DA and 5-HT uptake inhibition, the
most promising hydroxylated analogues (16 and 32,
Chart 2) were then administered to rhesus monkeys in
drug self-administration studies, to assess behavioral
activity. The racemic benzylic alcohol 32 was chosen for
formulation as a decanoate ester (41, Scheme 1), based
on its behavioral profile in monkeys (decrease in drug-
maintained performance, without a concurrent decrease
in food-maintained responding). When a single injection
of a sufficient dose of the decanoate ester formulation
41 was given to monkeys responding under schedules
of food and cocaine self-administration, cocaine-main-
tained responding decreased more than 80% within
several days of the injection while food-maintained
responding was unaffected. This selective effect on
cocaine-maintained responding lasted almost 30 days
pursuant to a single injection, and was followed by a
return to control levels of responding.43 These results
F igu r e 1. Potential sites for the incorporation of the hydroxyl
group.
sychotic drugs and allowing discharge of patients from
institutional settings. This methodology has also been
used for antipsychotics (haloperidol, fluphenazine, clo-
phenthixol), sex hormones (testosterone, estradiol), and
other steroids (nandrolone, methylprednisolone).42
We sought to apply this approach toward the develop-
ment of extended-action formulations of 1a and 1b
analogues. Previous work in this laboratory had deter-
mined that 1b eliminated cocaine-maintained respond-
ing without affecting similar behavior maintained by
food and could maintain these effects for at least 12 days
via repeated administration without developing toler-
ance.34 Furthermore, when administration of 1b was
discontinued, cocaine-maintained responding reverted
to the previously established (predrug) levels. Resump-
tion of administration of 1b again abolished cocaine-
maintained responding, without affecting food-main-
tained responding.34 Since none of the parent compounds
1a -1d contained a hydroxyl group to serve as the
“anchor” for the ester functionality, we designed a series
of analogues of compounds 1a -1d , in which a hydroxyl
Ch a r t 2. Analogues 5-36, Along with the Common Intermediates 3 and 4

5032 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
Sch em e 1a
a
Synthetic methods A-H: (A) (a) 2′-, 3′-, or 4′-TBDMS-protected hydroxycinnamoyl chloride, CHCl3-aq NaHCO3; (b) TBAF, THF, rt;
(c) aluminum hydride, THF. (B) H2, 10% Pdm-C, MeOH. (C) (a) 2′-, 3′-, or 4′-Methoxycinnamic acid, DCC, CH2Cl2; (b) aluminum hydride,
THF. (D) L-Selectride, THF. (E) 3-Chloropropiophenone, acetone. (F) LAH, THF. (G) (R)-(+)- or (S)-(-)-3-Chloro-1-phenyl-1-propanol,
NaI, K2CO3, 80 °C. (H) C9H19COCl, CHCl3.
Sch em e 2a
a
(a) TBDMSCl, imidazole, DMF; (b) oxalyl chloride, DMF (cat.), CH2Cl2; (c) 3 or 4, aq NaHCO3-CHCl3; (d) TBAF, THF; (e) AlH3, THF.
suggest that a similar formulation, if proven safe for
human use, should be tested as a potential medication
for cocaine abuse. In addition, the R- and S-enantiomers
of analogue 16 (34 and 36) were administered to test
subjects (monkeys), to compare their efficacy as poten-
tial cocaine-abuse treatment agents (with comparison
to the racemic compound 16). Herein, we report the
binding affinities of analogues 5-36 to the DAT and
SERT, along with the ability to inhibit the reuptake of
DA and 5-HT. In addition, behavioral (cocaine and food
self-administration) studies are reported for analogues
15, 16, 32, and the enantiomers of 32 (34 and 36) to
allow comparison with previously published data on 41
(the decanoate ester of alcohol 32).43
Ch em istr y
The monosubstituted piperazines 1-[2-(diphenyl-
methoxy)ethyl]piperazine (3) and 1-[2-[bis(4-fluorophen-
yl)methoxy]ethyl]piperazine (4) were synthesized as
previously described32 by a two-step sequence: conver-
sion of either benzhydrol or 4,4′-difluorobenzhydrol to
the diarylmethoxyethyl chloride, followed by reaction
with an excess of piperazine, affording the key inter-
mediates 3 and 4 in ca. 70% yield (Scheme 1). The alkyl

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5033
Sch em e 3a
a
(a) H2, Pd-C, MeOH.
Sch em e 4a
a
(a) 3 or 4, DCC, CH2Cl2; (b) AlH3, THF; (c) H2, Pd-C, MeOH; (d) L-Selectride, THF.
chlorides were purified by distillation in vacuo, and the
monosubstituted piperazines 3 and 4 were purified by
partition between aqueous citric acid and chloroform.44
Analogues 8-10 were prepared by coupling either 3
or 4 with 3′- or 4′-tert-butyldimethylsiloxycinnamoyl
chloride (37), employing Schotten-Baumann condi-
tions, affording amides 38 (method A, Scheme 2). The
required acid chlorides 37 were prepared by a two-step
process: diprotection of the appropriate hydroxycin-
namic acid with tert-butyldimethylsilyl chloride (TB-
DMS chloride), followed by selective conversion of the
silyl ester to the acid chloride by treatment with oxalyl
chloride in the presence of dimethylformamide (DMF).45
The silyl protecting groups were removed by treatment
with tetrabutylammonium fluoride (TBAF), and the
resultant phenolic amides 39 were reduced with alu-
minum hydride46 in THF, affording the unsaturated
analogues 8-10.
Analogues 5 and 6 (see Scheme 4), however, were
unavailable by this method, as the presence of the
o-hydroxy group on the phenyl ring of the 1-phenylpro-
penyl moiety caused the hydride reduction step to give
a mixture of the desired product and the product
resulting from the reduction of the olefinic bond, which
were not separable by chromatography or crystalliza-
tion. The saturated analogues 11-16 were prepared by
catalytic reduction of the double bond in compounds
5-10 by hydrogenation over palladium-on-carbon (Pd-
C) (method B, Scheme 3). The unsaturated methoxy-
containing analogues (anisoles 17-22) were synthesized
by coupling the monosubstituted piperazines 3 and 4
with either 2′-, 3′-, or 4′-methoxycinnamic acid, using

5034 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
Sch em e 5a
a
(a) 3-Chloropropiophenone, acetone; (b) LAH, THF; (c) C9H19COCl, CHCl3.
Sch em e 6a
a
(a) (R)-(+)-3-Chloro-1-phenyl-1-propanol, NaI, K2CO3, DMF, 70 °C; (b) (S)-(-)-3-chloro-1-phenyl-1-propanol, NaI, K2CO3, DMF, 70
°C.
dicyclohexylcarbodiimide (DCC), affording the meth-
unsaturated methoxy analogue 19, using this same
method. Analogues 23-28 were synthesized via cata-
lytic reduction of 17-22 over Pd-C (method B, Scheme
4).
The ketones 29 and 30 were synthesized by treatment
of piperazines 3 and 4 with 3-chloropropiophenone
(method E, Scheme 5). Lithium aluminum hydride
(LAH) reduction of 29 and 30 afforded the racemic
benzylic alcohols 31 and 32 (method F, Scheme 5).
oxyamides 40 and subsequently reducing the amide
functionality by treatment with aluminum hydride,
affording the amines 17-22 (method C, Scheme 4).
Analogues 5 and 6 were prepared by treating the
unsaturated methoxy analogues 17 and 18 with L-
Selectride, resulting in O-demethylation47 without re-
duction of the double bond (method D, Scheme 4).
Analogue 7 was also prepared from the corresponding

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5035
Ta ble 1. Physical Properties of the Final Amines (Ligands
5-36)
crystn
solvent
%
synth
compd
salta
mp (°C)
yieldb method
5
6
7
8
9
2 maleate 168-169 2-PrOH-EtOH
2 maleate 175-176 2-PrOH-EtOH
2 maleate 168-169 2-PrOH-EtOH
2 maleate 158-159 MeOH
2 maleate 156-158 MeOH
2 maleate 150-153 MeOH
2 maleate 162-164 MeOH
2 maleate 166-167 MeOH
2 maleate 155-157 MeOH
2 maleate 159-160 MeOH
2 maleate 164-166 MeOH
2 maleate 177-178 MeOH
2 maleate 176-178 MeOH
2 maleate 173-174 MeOH
2 maleate 183-185 MeOH
2 maleate 188-190 MeOH
2 maleate 194-196 MeOH
2 maleate 195-198 MeOH
2 maleate 181-182 MeOH
2 maleate 182-183 MeOH
2 maleate 175-176 2-PrOH-EtOH
2 maleate 170-171 MeOH
2 maleate 192-194 MeOH
2 maleate 188-190 MeOH
2 maleate 171-174 MeOH
2 maleate 165-166 MeOH
2 maleate 169-170 MeOH
74
79
68
41
36
32
82
77
86
80
76
79
69
63
55
44
64
47
81
84
52
34
56
62
65
64
88
93
39
58
59
D
D
D
A
A
A
B
B
B
B
B
B
C
C
C
C
C
C
B
B
B
B
B
B
E
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
36
F igu r e 2. Dose-response curves are shown for 1b and for
34 and 36 (the enantiomers of 32), with cocaine-maintained
responding shown on the horizontal axis. The baseline (un-
medicated, control) response is 1.
decreased affinity for the SERT among the des-fluoro
analogues. Among the phenolic analogues 5-10 (con-
taining an unsaturated side chain), the ortho- and meta-
substituted compounds 5-8 showed greater affinity for
the DAT than the para-substituted compounds 9 and
10. A similar relationship was seen among analogues
17-22, which contain a methoxy-substituted cinnamyl
side chain, in that the ortho- and meta-substituted
analogues 17-20 displayed a greater affinity for the
DAT than the para-substituted analogues 21 and 22.
Among the analogues with a saturated (propyl) side
chain (11-16 and 23-28), the meta-substituted (13, 14,
25, 26) and para-substituted (15, 16, 27, 28) analogues
displayed a greater affinity for the DAT than the ortho-
substituted (11, 12, 23, 24) analogues in these series.
There was no significant difference in either DAT
affinity/selectivity or DA uptake inhibition potency/
selectivity between the hydroxy-substituted analogues
and the corresponding methoxy-substituted congeners.
Table 2 also displays the binding and uptake inhibition
data for the propyl-chain-substituted analogues 29-36.
The two benzylic ketones 29 and 30 displayed greatly
decreased affinity for the DAT and were less potent in
the ability to inhibit the uptake of DA, when compared
with the parent compounds 1a -1d , and when compared
with compounds 5-28 with one exception. (Analogue
12 displayed DAT binding affinity, which was practi-
cally identical to that for 30.) When ketones 29 and 30
were reduced to the racemic benzylic alcohols 31 and
32, the DAT binding affinity and the ability to inhibit
DA uptake were both restored to values quite similar
to those for the parent compounds 1a -1d . On the basis
of the preliminary behavioral results in rhesus monkeys
for the decanoate ester 41 of racemic alcohol 32,43 we
decided to synthesize and test the two enantiomers of
32. The R- and S-benzylic carbinols (34 and 36, respec-
tively) were found to be practically identical, in terms
of DAT affinity and DA uptake inhibition, to their
racemic congener 32. In the des-fluoro series, the
racemic benzylic alcohol 31 was found to have practi-
cally identical biological properties (in vitro and ex vivo
biological test results) to the R-enantiomer 33. The
S-enantiomer 35 was not prepared, based on the com-
parison of the biological results for 32, 34, and 36,
E
F
F
G
G
G
2 HCl
216-218 2-PrOH
2 maleate 170-171 MeOH
2 maleate 175-176 MeOH
2 maleate 175-176 MeOH
a
The CI mass spectra of all the final amines and precursor
amides contained the predicted (M + 1) peaks. All compounds gave
CHN analysis within (0.4 of calculated values. The yields for
compounds 5-7, 11-16, and 23-28 are for the final synthetic step;
the yields for compounds 8-10, 17-22, and 29-36 are for the
steps from the intermediate 3 or 4.
b
Analogues 33 and 34 were synthesized by alkylating
piperazines 3 and 4 with R-(+)-3-chloro-1-phenyl-1-
propanol, and analogue 36 was prepared from S-(-)-3-
chloro-1-phenyl-1-propanol (method G, Scheme 6).48 The
decanoate ester 41 was prepared by treating alcohol 32
with a slight molar excess of decanoyl chloride, as
previously described (method H, Scheme 5).43 This oily
“prodrug” was purified by conversion to the bis-maleate
salt in a concentrated methanolic solution, followed by
careful conversion back to the free base, to eliminate
ester hydrolysis.
Resu lts a n d Discu ssion
The binding data shown in Table 2 indicate that the
addition of a hydroxy or methoxy substituent to the
phenyl ring of the propylphenyl (or propenylphenyl)
moiety of compounds 1a -1d resulted in a novel series
of disubstituted piperazines (5-28) with generally high
affinity and selectivity for the DAT and a high degree
of potency and selectivity for the inhibition of DA uptake
versus SERT binding and 5-HT uptake inhibition.
As previously observed in this laboratory, the bis-
fluoro analogues (even-numbered compounds from 6 to
28) generally displayed greater affinity in binding to the
DAT and were more potent at inhibiting the uptake of
DA, while the des-fluoro analogues (odd numbered
compounds from 5 to 27) were usually more selective
for binding to the DAT and for inhibiting the uptake of
DA.35,36 This trend seems to be due, in part, to a

5036 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
Ta ble 2. Binding Affinities at the DAT and SERT Labeled with [125I]RTI-55 and DA and 5-HT Reuptake Inhibition of Analogues
5-36 (IC50 ( SD, NM)a
binding
reuptake
5-HT/DA ratios
ligand
DAT
SERT
[3H]DA
[3H]5-HT
binding
168
34.1
158
70.0
29.3
78.3
11.2
19.6
5.0
35.0
4.2
45.4
13.0
59.6
6.2
uptake
1a
1b
1d
5
6
7
3.7 ( 0.3
3.7 ( 0.4
0.9 ( 0.1
2.90 ( 0.14
0.92 ( 0.05
2.3 ( 0.22
4.2 ( 0.1
22.8 ( 2.5
13.7 ( 0.6
24.8 ( 0.84
41 ( 1.5
623 ( 13
126 ( 5
135 ( 7
203 ( 16
27 ( 1.2
180 ( 5
47 ( 2
448 ( 24
68 ( 3
869 ( 53
174 ( 5
449 ( 10
74 ( 3
894 ( 56
72.2 ( 2.4
339 ( 15
157 ( 7
461 ( 10
112 ( 4.4
701 ( 25
90 ( 3.4
232 ( 7
191 ( 7
101 ( 2
100 ( 3.5
550 ( 19
96 ( 4
3.7 ( 0.4
7.3 ( 0.2
11 ( 0.6
298 ( 29
73 ( 2
80.5
10.0
52.4
225
56.7
96.2
23.3
33.1
19.6
161
19.8
101
19.8
50.1
22.6
211
576 ( 32
1580 ( 85
397 ( 18
866 ( 72
226 ( 14
1430 ( 116
391 ( 37
1090 ( 40
297 ( 15
881 ( 27
113 ( 7.6
872 ( 31
258 ( 10
1180 ( 93
499 ( 17
1690 ( 109
473 ( 17
1920 ( 159
392 ( 17
494 ( 17
342 ( 13
1180 ( 44
265 ( 13
982 ( 52
219 ( 7
7 ( 0.2
7 ( 0.63
9 ( 0.6
8
9
9.7 ( 0.3
43 ( 0.8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
36
20 ( 1.5
6.8 ( 0.3
15 ( 0.6
9.9 ( 0.3
5.7 ( 0.3
15 ( 0.8
8.7 ( 0.2
5.7 ( 0.12
17.4 ( 0.5
11.4 ( 0.3
5.6 ( 0.28
7.4 ( 0.4
5.1 ( 0.4
6.7 ( 1.0
37 ( 1.3
11.6 ( 0.3
7.1 ( 0.4
2.69 ( 0.1
4.9 ( 0.3
2.5 ( 0.3
28.7 ( 3.6
15.1 ( 0.9
28 ( 0.9
47.7
58.4
94.0
44.8
24.4
6.0
67.4
331
70.6
51.8
40.0
76.0
39.3
295
40.8
133
23.3
9.0
10.9
211
12.4
202
28.8
49.4
9.8 ( 1.4
6.5 ( 0.25
8.7 ( 0.33
4 ( 0.35
6.5 ( 0.6
7.4 ( 1.2
9.4 ( 0.16
329 ( 13
41.6 ( 1.9
7.03 ( 0.24
5.57 ( 0.13
5.4 ( 0.10
3.5 ( 0.16
3.6 ( 0.16
8
19 ( 0.7
10.1
40.4
26.3
44.4
19.7
6.3
2.5 ( 0.005
3.8 ( 0.1
12.4 ( 1.0
4.87 ( 0.35
208 ( 4
1310 ( 34
215 ( 6.14
700 ( 51
117 ( 7
939 ( 27
85 ( 3
2990 ( 135
452 ( 17
1480 ( 45
69 ( 17
1090 ( 77
101 ( 3
178 ( 7
47.8 ( 1.7
6.09 ( 0.2
2.14 ( 0.05
8.4 ( 0.4
3 ( 28
4.5
114
54.7
112
28.3
30.7
4.4 ( 0.45
135 ( 5
a
The IC50 values of the test agents were determined in the above assays as described in Biological Methods (see Experimental Section).
coupled with a comparison of the biological data for 31
and 33. Attempts to evaluate the DAT binding affinity
of the decanoate ester 41 gave Ki values of 18.2 ( 0.9
nM (bis-maleate salt) and 1.73 ( 0.06 nM (free base).
While the results of these studies indicate that the ester
41 does potently inhibit DAT binding, it is not possible
to distinguish between inhibition produced by 41 and
32, as the parent alcohol 32 may be produced by the
action of membrane-associated esterases or by hydroly-
sis by the aqueous buffer utilized in the assay. The
unexpectedly high DAT affinity is presumably due to
the hydrolysis of the ester during the performance of
the assay. Since the alcohol 32 has demonstrated a high
affinity for the DAT and is a potent inhibitor of DA
uptake, even a relatively small percent amount of
hydrolysis would lead to a biological result quite similar
to that for the alcohol itself. Studies are ongoing,
involving the preparation and biological testing of a
nonhydrolyzable isostere of the decanoate ester 41, to
estimate the DAT binding and DA uptake inhibition
potency of the ester prodrug 41.
Compound 1b and the enantiomers 34 and 36 were
studied for behavioral effects on modulation of food- and
cocaine-maintained responding in rhesus monkeys.
These drugs all decreased cocaine-maintained respond-
ing to a greater extent than food-maintained respond-
ing, and none of these analogues significantly increased
responding during the fixed interval (FI) components.
Figure 2 shows the effects of different doses of 1b and
enantiomers 34 and 36, relative to the effects of vehicle
pretreatment (i.e. the horizontal line at y ) 1 indicates
no effect relative to that of vehicle), on cocaine-
maintained responding. Each drug dose-dependently
decreased cocaine-maintained responding, with the
highest doses tested decreasing cocaine-maintained
responding almost completely. Enantiomers 34 and 36
were approximately equipotent, and both were more
potent than 1b in this behavioral test.
These results show that enantiomers 34 and 36 not
only retained the ability to selectively decrease cocaine-
maintained responding much in the same way that 1b
had been shown to affect these behaviors previously,49
but also both compounds were more potent than 1b. The
lack of difference in potency between 34 and 36 was
consistent with their similar abilities in inhibiting DA
reuptake and in their similar affinities for the DAT and
supports the notion that this could be the primary
mechanism by which they reduce cocaine-maintained
responding. However, additional studies examining
factors such as the possibility that their enhanced in
vivo potency may be the result of bioavailability are
warranted.
In summary, compounds with an oxygen-containing
substituent on the benzene ring of the phenylpropyl or
phenylpropenyl moiety generally displayed potent and
selective binding to the DAT, with respect to the SERT,
as did compounds containing a hydroxyl group at the
benzylic position of the phenylpropyl moiety. There were
small differences in potency and affinity among the
phenols and anisoles, based on the isomeric position of

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5037
the hydroxy or methoxy group. Among the benzylic
alcohols, there seemed to be little difference in biological
activity in DAT and SERT binding and DA and 5-HT
uptake inhibition between the racemates, the R-enan-
tiomers, and the S-enantiomers with the same aromatic
substitution patterns. The results indicate that the use
of the racemic compound 32 for further in vivo inves-
tigations in live animals is warranted. Ketones 29 and
30 showed reduced DAT affinity and also displayed a
greatly decreased ability to inhibit DA uptake, relative
to the corresponding benzylic alcohols 31 and 32. The
SERT affinity and the ability to inhibit 5-HT uptake
were affected to a much smaller extent. In rhesus
monkey behavioral studies, the bis-fluoro para-phenolic
analogue 16 decreased both cocaine- and food-main-
tained responding equally. The des-fluoro para-phenolic
analogue 15 displayed some behavioral selectivity, in
that cocaine-maintained responding was decreased to
a significantly greater extent than food-maintained
responding. The racemic benzylic alcohol 32 exhibited
the greatest promise among the preliminary analogues,
regarding separation of cocaine- and food-maintained
response. On the basis of the behavioral activity com-
parisons of 15, 16, and 32, analogue 32 was converted
to the decanoate ester 41 and formulated as a “depot”
that was then administered to monkeys via intramus-
cular injection, affording 24 days of activity pursuant
to a single injection.43 Further studies now in progress
of 41 in multiple animals appear to be promising and
will be reported in due course.50 Compounds 34 and 36,
which decreased cocaine-maintained responding with
high degrees of potency and selectivity over food-
maintained responding, have not yet been converted to
the corresponding decanoate esters. Studies are ongoing
at this time to evaluate the behavioral effects of the
decanoate ester 41 and hopefully detect blood levels of
the putative active compound 32, and these will be
reported in a future communication.
potential cocaine-abuse therapeutic agents, all ame-
nable to conversion to an oil-soluble “prodrug” which
should (as in the case of compound 41) provide the
desired pharmaceutical effect for a greatly extended
time period following a single injection. This choice of
alternative drug substances affords the possibility of
singling out the specific molecular entity possessing the
optimal therapeutic and toxicological properties within
the defined set consisting of compounds 32, 34, and 36.
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary apparatus and are uncorrected. Elemental analyses were
performed by Atlantic Microlabs, Atlanta, GA, and were within
(0.4% for the elements indicated. Chemical ionization mass
spectra (CIMS) were obtained using a Finnegan 1015 mass
spectrometer. Electron ionization mass spectra (EIMS) were
obtained using a V.G. Micro Mass 7070F mass spectrometer.
Optical rotations were obtained using a Perkin-Elmer 341
polarimeter and are reported at the sodium D-line (589 nm).
1H NMR spectra were recorded on the free bases in CDCl3 or
CDCl3 plus D2O using a Varian XL-300 spectrometer. 19F NMR
spectra were utilized in determination of enantiomeric excess
in chiral compounds and were determined at 282 MHz in
CDCl3. Chemical shifts are expressed in parts per million
(ppm) on the δ scale relative to a TMS internal standard. Thin-
layer chromatography (TLC) was performed on 250-µm Anal-
tech GHLF silica gel plates. No attempt was made to optimize
the yields reported.
1-[2-(Dip h en ylm eth oxy)eth yl]p ip er a zin e (3) was syn-
thesized from 2a by a modification of the method described
by van der Zee.32 To a stirred solution of 2b (159 g, 663 mmol)
in 1.2 L of toluene were added piperazine (357 g, 4.11 mol,
6.4 equiv) and anhydrous K2CO3 (180 g, 1.3 mol, 99+%; ACS
Reagent, granular). The reagents were rinsed into the reaction
vessel with an additional 100 mL of toluene, and the reaction
was run at reflux for 12 h and then cooled to room tempera-
ture. The organic mixture was washed with water (4 × 500
mL) and brine, dried over Na2SO4, and concentrated to ca. 190
g of a yellow oil. The crude monosubstituted piperazine was
dissolved in ca. 2 L of chloroform and divided into four 500-
mL portions. Each portion was extracted with 10% aq citric
acid (500 + 250 + 100 mL), and the organic layer was
discarded. The acidic aqueous portions were combined, and
made alkaline with concentrated NH4OH solution, and ex-
tracted into CHCl3. The organic solutions from the four initial
portions of the crude piperazine were combined, dried over Na2-
SO4, and concentrated to 168 g of a pale yellow oil, which was
dissolved in 2.5 L of MeOH, heated to boiling, and treated with
169 g of maleic acid (1.45 mol, 2.2 equiv, based on the amount
of the starting material 2b). The bis-maleate salt crystallized
upon cooling, was collected by filtration, and was washed with
MeOH and Et2O, affording 224 g (424 mmol, 64% yield) of
snow-white crystals: mp 168-169 °C (lit.32 mp 169-170 °C).
1-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]p ip er a zin e (4)
was synthesized from 2b in an analogous procedure to that
used for 3. The yield was 69% of snow-white crystals: mp 157-
159 °C (lit.32 mp 158-159 °C).
Con clu sion s
The addition of hydroxyl or methoxyl substituents to
the phenyl ring of the phenylpropyl moiety of 1a and
1b analogues resulted in retention of DAT affinity and
DA uptake inhibition potency for the new compounds.
Likewise, addition of a benzylic hydroxyl group to the
phenylpropyl side chain resulted in retention of DAT
binding affinity and selectivity (when compared with
SERT binding affinity) and DA uptake inhibition po-
tency. The stereochemistry at the benzylic position did
not affect the biological activity to any significant extent.
This finding suggested that the use of racemic com-
pound 32 for esterification and formulation as a “depot”
injection was warranted. Among the two potential
candidates for esterification and formulation as a “de-
pot” injection, the phenolic compound 16 inhibited both
food- and cocaine-maintained responding almost equally,
and the benzylic compound 32 selectively decreased
cocaine-maintained responding with respect to those
behaviors maintained by food. All available data (bind-
ing, neurotransmitter uptake, and primate behavior) for
compounds 32, 34, and 36 (the optically pure enanti-
omers of 32) suggest that these analogues are promising
candidates for esterification and formulation as poten-
tial extended-release dosage forms. The identification
of analogues 32, 34, and 36 provides the choice of three
Syn th etic Meth od A. i. To a stirred solution of 2-, 3-, or
4-hydroxycinnamic acid (ca. 10 g, 60 mmol) in dimethylfor-
mamide (DMF; 80 mL) were added tert-butyldimethylsilyl
chloride (TBDMSCl; 140 mmol) and imidazole (260 mmol). The
mixture was stirred for 12-24 h at room temperature, poured
into water, and extracted into ether (3 × 100 mL). The ethereal
solution was dried (MgSO4) and concentrated at reduced
pressure, affording the ester ether, which was not purified
further (reaction product analyzed by TLC, MS, NMR).
ii. The bis-silyl-protected hydroxycinnamic acid (ca. 12 g,
30 mmol of the ester ether) was dissolved in 100 mL of dry
dichloromethane, cooled to ca. 0 °C with a water-ice bath, and
treated with oxalyl chloride (1.2 equiv of a 2.0 M solution in
dichloromethane) and DMF (4-5 drops). The reaction was
stirred at 0 °C for 1 h and at room temperature for 1 h and

5038 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
concentrated, affording the TBDMS ether-protected hydroxy-
cinnamoyl chloride as a pale yellow oil. This intermediate,
being relatively unstable, was then used directly without
further purification.
2H), 3.62 (t, J ) 5.9 Hz, 2H), 5.38 (s, 1H), 6.80-6.89 (m, 4H),
7.05-7.14 (m, 3H), 7.22-7.29 (m, 4H), 7.32-7.36 (m, 4H); MS
(CI-NH3) m/z 431 (MH+). Anal. 11‚2 maleate (C28H34N2O2‚
2C4H4O4‚CH3OH) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[3-(2′-hydroxy-
p h en yl)p r op yl]p ip er a zin e (12) was synthesized from 6
according to synthetic method B (Scheme 2): 1H NMR (CDCl3)
δ 1.78-1.82 (m, 2H), 2.34-2.37 (m, 2H), 2.51-2.59, (m, 10H),
2.67 (t, J ) 6.0 Hz, 2H), 3.54-3.58 (m, 2H), 5.32 (s, 1H), 6.62
(d, J ) 6.8 Hz, 1H), 6.97-7.03 (m, 4H), 7.09-7.14 (m, 1H),
7.24-7.29 (m, 5H); MS (CI-NH3) m/z 467 (MH+). Anal. 12‚2
maleate (C28H32N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[3-(3′-h yd r oxyp h en yl)-
p r op yl]p ip er a zin e (13) was synthesized from 7 according to
synthetic method B (Scheme 3): 1H NMR (CDCl3) δ 1.74-1.84
(m, 2H), 2.36 (t, J ) 7.8 Hz, 2H), 2.49-2.57, (m, 8H), 2.68 (t,
J ) 5.9 Hz, 2H), 3.59 (t, J ) 5.9 Hz, 2H), 5.36 (s, 1H), 6.60 (s,
1H), 6.61 (d, J ) 7.5 Hz, 1H), 6.70 (d, J ) 7.5 Hz, 1H), 7.08-
7.35 (m, 11H); MS (CI-NH3) m/z 431 (MH+). Anal. 13‚2
maleate (C28H34N2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[3-(3′-hydroxy-
p h en yl)p r op yl]p ip er a zin e (14) was synthesized from 8
according to synthetic method B (Scheme 3): 1H NMR (CDCl3)
δ 1.77-1.82 (m, 2H), 2.34-2.37 (m, 2H), 2.51-2.59, (m, 10H),
2.67 (t, J ) 5.9 Hz, 2H), 3.54-3.58 (m, 2H), 5.32 (s, 1H), 6.62
(d, J ) 6.8 Hz, 1H), 6.97-7.03 (m, 4H), 7.09-7.14 (m, 1H),
7.24-7.29 (m, 5H); MS (CI-NH3) m/z 467 (MH+). Anal. 14‚2
maleate (C28H32N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[3-(4′-h yd r oxyp h en yl)-
p r op yl]p ip er a zin e (15) was synthesized from 9 according to
synthetic method B (Scheme 3): 1H NMR (CDCl3) δ 1.78-1.89
(m, 2H), 2.51 (t, J ) 7.5 Hz, 2H), 2.67, (m, 8H), 2.64 (t, J )
5.9 Hz, 2H), 3.60 (t, J ) 6.0 Hz, 2H), 5.35 (s, 1H), 6.65 (d, J )
8.7 Hz, 2H), 6.96 (d, J ) 8.7 Hz, 2H), 7.23-7.32 (m, 10H); MS
(CI-NH3) m/z 431 (MH+). Anal. 15‚2 maleate (C28H34N2O2‚
2C4H4O4(1CH3OH) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[3-(3′-hydroxy-
p h en yl)p r op yl]p ip er a zin e (16) was synthesized from 10
according to synthetic method B (Scheme 3): 1H NMR (CDCl3)
δ 1.81-1.87 (m, 2H), 2.48-2.45 (m, 4H), 2.66-2.73, (m, 10H),
3.55 (t, J ) 5.4 Hz, 2H), 5.30 (s, 1H), 6.61 (d, J ) 8.4 Hz, 2H),
6.99 (d, J ) 8.4 Hz, 2H), 6.90-7.01 (m, 4H), 7.22-7.27 (m,
4H); MS (CI-NH3) m/z 467 (MH+). Anal. 16‚2 maleate
(C28H32N2F2O2‚2C4H4O4) C, H, N.
Syn th etic Meth od C. i. To a stirred solution of 2-, 3-, or
4-methoxycinnamic acid (ca. 10 g, 55 mmol) in dichlo-
romethane (30 mL) was added dicyclohexylcarbodiimide (DCC;
80 mmol, in 20 mL of dichloromethane). The mixture was
stirred until a copious white precipitate formed (5-10 min)
and was then treated with a solution of 3 or 4 (25 mmol, in 30
mL of dichloromethane). The reaction was stirred until TLC
analysis showed no further starting material (3 or 4), at which
time the mixture was filtered through a bed of Celite and
concentrated at reduced pressure. The crude amide was
purified by chromatography (EtOAc to elute dicyclohexylcar-
bonylurea, DCU, generated in the reaction; followed by
chloroform-methanol, 20:1, to elute the amide).
ii. The amide from step i was dissolved in 20 mL of THF
and treated with alane (ca. 2 equiv of a 1 M solution in THF)
for 15-30 min. The reaction mixture was worked up and
purified as in synthetic method A (bis-maleate salt, from
methanol).
1-[2-(Diph en ylm eth oxy)eth yl]-4-[1-(2′-m eth oxyph en yl)-
p r op en yl]p ip er a zin e (17) was synthesized from 3 according
to synthetic method C (Scheme 4): 1H NMR (CDCl3) δ 2.58
(m, 8H), 2.70 (t, J ) 6.1 Hz, 2H), 3.19 (d, J ) 6.7 Hz, 2H),
3.61 (t, J ) 6.1 Hz, 2H), 3.84 (s, 3H), 5.37 (s, 1H), 6.29 (dt, J
) 16.0, 6.8 Hz, 1H), 6.82-6.94 (m, 3H), 7.19-7.36 (m, complex,
11H), 7.44 (dd, J ) 7.6, 1.8 Hz, 1H); MS (CI-NH3) m/z 443
(MH+). Anal. 17‚2 maleate (C29H34N2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[1-(2′-m eth -
oxyp h en yl)p r op en yl]p ip er a zin e (18) was synthesized from
4 according to synthetic method C (Scheme 4): 1H NMR
(CDCl3) δ 2.56 (m, 8H), 2.88 (t, J ) 5.9 Hz, 2H), 3.18 (d, J )
iii. Monosubstituted piperazine 3 or 4 (ca. 3 g, 10 mmol)
was dissolved in a biphasic mixture of chloroform and satu-
rated solution of sodium bicarbonate and treated with the
appropriate TBDMS-protected hydroxycinnamoyl chloride
(crude, ca. 15 mmol, 1.5 equiv, dissolved in 10-15 mL of dry
ethanol-free chloroform). After 10 min, brine was added to
the reaction, the layers were separated, and the organic portion
was dried (Na2SO4) and concentrated to a yellow oil. The crude
TBDMS-protected phenolic amide was dissolved in tetrahy-
drofuran (THF; 40 mL) and treated with tetrabutylammonium
fluoride (TBAF; trihydrate, ca. 20 mmol, 2 equiv). The THF
solution was stirred for 20 min and poured into 40 mL of brine,
and the layers were separated. The solvent was removed under
reduced pressure; the residue was taken up in chloroform,
washed with brine, dried (Na2SO4), and concentrated to a
yellow oily solid, which was purified either by chromatography
(chloroform-methanol, 20:1) or by precipitation from ethyl
acetate.
iv. To a stirred 1 M solution of alane (AlH3) in THF (ca. 3
mL, 3 mmol, 9 mequiv) was added a solution of the deprotected
product from step iii (2-3 mmol, in 20 mL of THF). The
reaction was stirred at room temperature for 15-30 min and
poured into 100 mL of dilute aqueous sodium hydroxide. The
crude product was extracted into chloroform (3 × 50 mL); the
organic portions were combined, washed with brine, dried (Na2-
SO4), and concentrated at reduced pressure. The R,â-unsatur-
ated phenolic analogue was purified by conversion to the bis-
maleate salt, followed by recrystallization from methanol.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[1-(3′-hydroxy-
p h en yl)p r op en yl]p ip er a zin e (8) was synthesized from 4
according to synthetic method A (Scheme 2): 1H NMR (CDCl3)
δ 2.58 (m, 8H), 2.68 (t, J ) 5.9 Hz, 2H), 3.14 (d, J ) 6.8 Hz,
2H), 3.56 (t, J ) 5.9 Hz, 2H), 5.32 (s, 1H), 6.17-6.27 (m, 1H),
6.44 (d, J ) 15.6 Hz, 1H), 6.67-6.71 (m, 1H), 6.80 (s, 1H),
6.89 (d, J ) 7.8 Hz, 1H), 6.96-7.02 (m, 4H), 7.16 (t, J ) 7.8
Hz, 1H), 7.24-7.29 (m, 4H); MS (CI-NH3) m/z 465 (MH+).
Anal. 8‚2 maleate (C28H30N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[1-(4′-h yd r oxyp h en yl)-
p r op en yl]p ip er a zin e (9) was synthesized from 3 according
to synthetic method A (Scheme 2): 1H NMR (CDCl3) δ 2.65
(m, 8H), 2.72 (t, J ) 5.7 Hz, 2H), 3.17 (d, J ) 6.6 Hz, 2H),
3.61 (t, J ) 6.0 Hz, 2H), 5.37 (s, 1H), 5.96-6.08 (m, 1H), 6.42
(d, J ) 15.6 Hz, 1H), 6.71 (d, J ) 8.7 Hz, 2H), 7.12 (d, J ) 8.7
Hz, 1H), 7.22-7.35 (m, 11H); MS (CI-NH3) m/z 429 (MH+).
Anal. 9‚2 maleate (C28H32N2O2‚2C4H4O4‚0.5CH3OH) C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[1-(4′-hydroxy-
p h en yl)p r op en yl]p ip er a zin e (10) was synthesized from 4
according to synthetic method A (Scheme 2): 1H NMR (CDCl3)
δ 2.57 (m, 8H), 2.68 (t, J ) 6.0 Hz, 2H), 3.14 (d, J ) 6.6 Hz,
2H), 3.57 (t, J ) 6.0 Hz, 2H), 5.33 (s, 1H), 6.08-6.18 (m, 1H),
6.47 (d, J ) 16.2 Hz, 1H), 6.73 (d, J ) 8.7 Hz, 2H), 6.97-7.04
(m, 4H), 7.25-7.28 (m, 4H), 7.31 (d, J ) 8.7 Hz, 2H); MS (CI-
NH3) m/z 465 (MH+). Anal. 10‚2 maleate (C28H30N2F2O2‚
2C4H4O4‚CH3OH) C, H, N.
Syn th etic Meth od B. A solution of the hydroxyphenylpro-
penylpiperazine (analogues containing an unsaturated cin-
namoyl side chain, 5-10 and 17-22, 1-3 mmol, in ca. 50 mL
of methanol) was added to a Parr bottle, treated with ca. 10-
20 wt % of 10% Pd-C catalyst, and hydrogenated at 45-50
psi for 2-4 h. The reaction was stopped and filtered through
a bed of Celite, the filter cake was washed with more methanol,
and the organic solutions were combined and concentrated to
an oily residue. The crude product was taken up in chloroform,
washed with aqueous ammonia and brine, dried (Na2SO4),
concentrated at reduced pressure, and purified by conversion
to the bis-maleate salt and recrystallization from methanol.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[3-(2′-h yd r oxyp h en yl)-
p r op yl]p ip er a zin e (11) was synthesized from 5 according to
synthetic method B (Scheme 3): 1H NMR (CDCl3) δ 1.87 (m,
2H), 2.28 (t, J ) 6.3 Hz, 2H), 2.67 (m, 8H), 2.73 (t, J ) 6.0 Hz,

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5039
6.7 Hz, 2H), 3.56 (t, J ) 6.1 Hz, 2H), 3.84 (s, 3H), 5.34 (s, 1H),
6.26-6.34 (m, 1H), 6.82-6.88 (m, 3H), 6.92-7.04 (m, 3H),
7.19-7.30 (m, 6H), 7.44 (d, J ) 5.9 Hz, 1H); MS (CI-NH3) m/z
479 (MH+). Anal. 18‚2 maleate (C29H32N2F2O2‚2C4H4O4) C, H,
N.
1.81 (m, 2H), 2.36 (t, J ) 7.8 Hz, 2H), 2.48-2.55 (m, 8H), 2.57
(t, J ) 7.5 Hz, 2H), 3.56 (t, J ) 6.0 Hz, 2H), 3.79 (s, 3H), 5.33
(s, 1H), 6.81-6.83 (d, J ) 7.8 Hz, 3H), 7.08-7.11 (d, J ) 8.1
Hz, 2H), 7.16-7.35 (m, 10H); MS (CI-NH3) m/z 445 (MH+).
Anal. 27‚2 maleate (C29H36N2O2‚2C4H4O4) C, H, N.
1-[2-(Diph en ylm eth oxy)eth yl]-4-[1-(3′-m eth oxyph en yl)-
p r op en yl]p ip er a zin e (19) was synthesized from 3 according
to synthetic method C (Scheme 4): 1H NMR (CDCl3) δ 2.57
(m, 8H), 2.70 (t, J ) 6.0 Hz, 2H), 3.15 (d, J ) 6.6 Hz, 2H),
3.60 (t, J ) 6.0 Hz, 2H), 3.81 (s, 3H), 5.37 (s, 1H), 6.24-6.32
(m, 1H), 6.49 (d, J ) 16.5 Hz, 1H), 6.78-6.81 (m, 1H), 6.92-
6.98 (m, 2H), 7.20-7.35 (m, 6H); MS (CI-NH3) m/z 443 (MH+).
Anal. 19‚2 maleate (C29H34N2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[1-(3′-m eth -
oxyp h en yl)p r op en yl]p ip er a zin e (20) was synthesized from
4 according to synthetic method C (Scheme 4): 1H NMR
(CDCl3) δ 2.56 (m, 8H), 2.68 (t, J ) 5.7 Hz, 2H), 3.15 (d, J )
6.0 Hz, 2H), 3.57 (t, J ) 6.0 Hz, 2H), 3.81 (s, 3H), 5.34 (s, 1H),
6.22-6.31 (m, 1H), 6.49 (d, J ) 15.3 Hz, 1H), 6.78-6.81 (m,
1H), 6.92-7.04 (m, 5H), 7.20-7.30 (m, 6H); MS (CI-NH3) m/z
479 (MH+). Anal. 20‚2 maleate (C29H32N2F2O2‚2C4H4O4) C, H,
N.
1-[2-(Diph en ylm eth oxy)eth yl]-4-[1-(4′-m eth oxyph en yl)-
p r op en yl]p ip er a zin e (21) was synthesized from 3 according
to synthetic method C (Scheme 4): 1H NMR (CDCl3) δ 2.59
(m, 8H), 2.71 (t, J ) 6.0 Hz, 2H), 3.15 (d, J ) 6.6 Hz, 2H),
3.61 (t, J ) 6.0 Hz, 2H), 3.81 (s, 3H), 5.37 (s, 1H), 6.08-6.18
(m, 1H), 6.47 (d, J ) 15.3 Hz, 1H), 6.84 (d, J ) 8.7 Hz, 2H),
7.21-7.36 (m, complex, 12H); MS (CI-NH3) m/z 443 (MH+).
Anal. 21‚2 maleate (C29H34N2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[1-(4′-m eth -
oxyp h en yl)p r op en yl]p ip er a zin e (22) was synthesized from
4 according to synthetic method C (Scheme 4): 1H NMR
(CDCl3) δ 2.57 (m, 8H), 2.68 (t, J ) 6.0 Hz, 2H), 3.14 (d, J )
6.6 Hz, 2H), 3.57 (t, J ) 6.0 Hz, 2H), 3.81 (s, 3H), 5.33 (s, 1H),
6.08-6.18 (m, 1H), 6.47 (d, J ) 16.2 Hz, 1H), 6.86 (d, J ) 8.7
Hz, 2H), 6.97-7.04 (m, 4H), 7.25-7.28 (m, 4H), 7.31 (d, J )
8.7 Hz, 2H); MS (CI-NH3) m/z 479 (MH+). Anal. 22‚2 maleate
(C29H32N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Diph en ylm eth oxy)eth yl]-4-[3-(2′-m eth oxyph en yl)-
p r op yl]p ip er a zin e (23) was synthesized from 17 according
to synthetic method B (Scheme 4): 1H NMR (CDCl3) δ 1.69-
1.83 (m, 4H), 2.39 (t, J ) 7.8 Hz, 2H), 2.49-2.64 (m, 8H), 2.66-
2.71 (m, 2H), 3.60 (t, J ) 5.9 Hz, 2H), 3.81 (s, 3H), 5.37 (s,
1H), 6.82-6.90 (m, 2H), 7.12-7.35 (m, complex, 12H); MS (CI-
NH3) m/z 445 (MH+). Anal. 23‚2 maleate (C29H36N2O2‚2C4H4O4)
C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[3-(2′-m eth -
oxyp h en yl)p r op yl]p ip er a zin e (24) was synthesized from 18
according to synthetic method B (Scheme 4): 1H NMR (CDCl3)
δ 1.69-1.78 (m, 2H), 2.29 (t, J ) 7.5 Hz, 2H), 2.44-2.55 (m,
8H), 2.61 (t, J ) 6.0 Hz, 2H), 3.53 (t, J ) 6.0 Hz, 2H), 3.72 (s,
3H), 5.30 (s, 1H), 6.65-6.72 (m, 3H), 7.09-7.30 (m, complex,
11H); MS (CI-NH3) m/z 481 (MH+). Anal. 24‚2 maleate
(C29H34N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Diph en ylm eth oxy)eth yl]-4-[3-(3′-m eth oxyph en yl)-
p r op yl]p ip er a zin e (25) was synthesized from 19 according
to synthetic method B (Scheme 4): 1H NMR (CDCl3) δ 1.79-
1.85 (m, 4H), 2.38 (t, J ) 7.8 Hz, 2H), 2.49-2.64 (m, 8H), 2.66-
2.71 (m, 2H), 3.60 (t, J ) 5.9 Hz, 2H), 3.79 (s, 3H), 5.37 (s,
1H), 6.74-6.79 (m, 4H), 7.19-7.35 (m, complex, 10H); MS (CI-
NH3) m/z 445 (MH+). Anal. 23‚2 maleate (C29H36N2O2‚2C4H4O4)
C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[3-(3′-m eth -
oxyp h en yl)p r op yl]p ip er a zin e (26) was synthesized from 20
according to synthetic method B (Scheme 4): 1H NMR (CDCl3)
δ 1.77-1.86 (m, 2H), 2.37 (t, J ) 7.8 Hz, 2H), 2.48-2.55 (m,
8H), 2.66 (t, J ) 6.0 Hz, 2H), 3.56 (t, J ) 6.0 Hz, 2H), 3.79 (s,
3H), 5.33 (s, 1H), 6.72-6.78 (m, 3H), 6.97-7.04 (m, 4H), 7.16-
7.29 (m, 5H); MS (CI-NH3) m/z 481 (MH+). Anal. 26‚2 maleate
(C29H34N2F2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-flu or op h en ylm eth oxy)eth yl]-4-[3-(4′-m eth -
oxyp h en yl)p r op yl]p ip er a zin e (28) was synthesized from 22
according to synthetic method B (Scheme 4): 1H NMR (CDCl3)
δ 1.73-1.81 (m, 2H), 2.36 (t, J ) 7.8 Hz, 2H), 2.48-2.55 (m,
8H), 2.57 (t, J ) 7.5 Hz, 2H), 3.56 (t, J ) 6.0 Hz, 2H), 3.79 (s,
3H), 5.33 (s, 1H), 6.81-6.83 (d, J ) 7.8 Hz, 3H), 6.97-7.04
(m, 4H), 7.08-7.11 (d, J ) 8.1 Hz, 2H), 7.16-7.29 (m, 5H);
MS (CI-NH3) m/z 481 (MH+). Anal. 28‚2 maleate (C29H34
-
N2F2O2‚2C4H4O4) C, H, N.
Syn th etic Meth od D. A 1 M solution of L-Selectride in
THF (15 mL) was added to the methyl ether (3-5 mmol,
product from synthetic method C). The reaction mixture was
heated at reflux for 18-24 h and then cooled to room
temperature. Water was added, and the layers were separated.
The aqueous portion was extracted with chloroform, and the
organic portions were combined, washed (water, brine), dried
(Na2SO4), and concentrated, affording a bright yellow oil. The
phenolic analogues were purified by silica gel column chro-
matography (chloroform-methanol, 20:1), followed by conver-
sion to the bis-maleate salt and recrystallization from 2-pro-
panol-ethanol.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[1-(2′-h yd r oxyp h en yl)-
p r op en yl]p ip er a zin e (5) was synthesized from 17 according
to synthetic method D: 1H NMR (CDCl3) δ 2.60 (m, 8H), 2.70
(t, J ) 5.8 Hz, 2H), 3.18 (d, J ) 6.8 Hz, 2H), 3.60 (t, J ) 5.8
Hz, 2H), 5.35 (s, 1H), 6.35 (m, 1H), 6.73-6.88 (m, 2H), 6.86
(m, 1H), 7.08 (m, 1H), 7.20-7.34 (complex m, 11H); MS (CI-
NH3) m/z 429 (MH+). Anal. 5‚2 maleate (C28H32N2O2‚2C4H4O4)
C, H, N.
1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[1-(2′-hydroxy-
p h en yl)p r op en yl]p ip er a zin e (6) was synthesized from 18
according to synthetic method D (Scheme 4): 1H NMR (CDCl3)
δ 2.60 (m, 8H), 2.69 (t, J ) 5.9 Hz, 2H), 3.19 (d, J ) 6.8 Hz,
2H), 3.57 (t, J ) 5.9 Hz, 2H), 5.32 (s, 1H), 6.27-6.37 (m, 1H),
6.74-6.80 (m, 2H), 6.87 (m, 1H), 6.97-7.04 (m, 4H), 7.10 (m,
1H), 7.24-7.29 (m, 4H), 7.35 (m, 1H); MS (CI-NH3) m/z 465
(MH+). Anal. 6‚2 maleate (C28H30N2F2O2‚2C4H4O4) C, H, N.
1-[2-(Dip h en ylm eth oxy)eth yl]-4-[1-(2′-h yd r oxyp h en yl)-
p r op en yl]p ip er a zin e (7) was synthesized from 19 according
to synthetic method D (Scheme 4): 1H NMR (CDCl3) δ 2.59
(m, 8H), 2.70 (t, J ) 5.8 Hz, 2H), 3.15 (d, J ) 6.8 Hz, 2H),
3.60 (t, J ) 5.8 Hz, 2H), 5.36 (s, 1H), 6.16-6.26 (m, 1H), 6.41-
6.47 (m, 1H), 6.60 (m, 1H), 6.68-6.71 (m, 1H), 6.79 (bs, 1H),
6.87-6.90 (m, 1H), 7.20-7.34 (complex m, 11H); MS (CI-NH3)
m/z 429 (MH+). Anal. 7‚2 maleate (C28H32N2O2‚2C4H4O4‚
0.25H2O) C, H, N.
Syn th etic Meth od E. To a stirred solution of 3-chloropro-
piophenone (100 g, 581 mmol) in 1.0 L of acetone was added
piperazine 3 or 4 (ca. 400 mmol, in 800 mL of acetone). The
reaction was stirred at room temperature for 12-18 h (over-
head mechanical stirrer) and concentrated at reduced pressure.
The resultant residue was partitioned between 1 L of chloro-
form and 500 mL of dilute aqueous ammonia. The layers were
separated; the organic portion was washed with brine, dried
(Na2SO4), and concentrated to a yellow oil. The crude ketone
was purified by conversion to the bis-maleate salt and recrys-
tallization from methanol.
1-[2-(Diph en ylm eth oxy)eth yl]-4-(3-oxo-3-ph en ylpr opyl)-
p ip er a zin e (29) was synthesized from 3 according to synthetic
method E (Scheme 5): 1H NMR (CDCl3) δ 2.63 (m, 8H), 2.73
(t, J ) 6.0 Hz, 2H), 2.90 (t, J ) 7.5 Hz, 2H), 3.23 (t, J ) 7.5
Hz, 2H), 3.62 (t, J ) 6.3 Hz, 2H), 5.37 (s, 1H), 6.97-7.03 (m,
4H), 7.25-7.29 (m, 4H), 7.43-7.49 (m, 2H), 7.53-7.59 (m, 1H),
7.95 (d, J ) 7.8 Hz, 1H); MS (CI-NH3) m/z 429 (MH+). Anal.
29‚2 maleate (C28H32N2O2‚2C4H4O4) C, H, N.
1-[2-[Bis(4-flu or oph en ylm eth oxy)eth yl]-4-(3-oxo-3-ph en -
ylp r op yl)p ip er a zin e (30)51 was synthesized from 4 according
to synthetic method E (Scheme 5)T 30‚2 maleate, mp 165-
166 °C,(lit.32 mp 165-166 °C); 1H NMR (CDCl3) δ 2.55 (m, 8H),
1-[2-(Diph en ylm eth oxy)eth yl]-4-[3-(4′-m eth oxyph en yl)-
p r op yl]p ip er a zin e (27) was synthesized from 21 according
to synthetic method B (Scheme 4): 1H NMR (CDCl3) δ 1.73-

5040 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Lewis et al.
2.67 (t, J ) 6.0 Hz, 2H), 2.84 (t, J ) 7.5 Hz, 2H), 3.18 (t, J )
7.5 Hz, 2H), 3.56 (t, J ) 6.3 Hz, 2H), 5.33 (s, 1H), 7.24-7.33
(m, 10H), 7.43-7.49 (m, 2H), 7.53-7.59 (m, 1H), 7.95 (d, J )
7.8 Hz, 1H); MS (CI-NH3) m/z 465 (MH+). Anal. 30‚2 maleate
(C28H30N2F2O2‚2C4H4O4) C, H, N.
(trifluoromethyl)phenylacetyl chloride (MTPA-Cl; 30 µL; Fluka
ChiraSelect Reagent, 99% [99+% ee/GLC]). After reaction
completion (TLC analysis), 3-(dimethylamino)propylamine (0.2
mL) was added, and the mixture stirred for an additional 15
min. Silica gel was added and the solvent removed at reduced
pressure. The residue was loaded onto a short silica gel column
and eluted with 50-100% ethyl acetate/n-hexane to afford the
purified Mosher ester. The diastereomeric ratio was deter-
mined by spectral comparison of the optically active compound
(ester of 34 or 36) with the product derived from the racemic
compound (32).
Syn th etic Meth od F . Lithium aluminum hydride (ca. 3 g,
95% powder, 80 mmol) was added carefully to 200 mL of dry
THF at room temperature. The flask was cooled with a water-
ice bath, and the ketone (100 mmol, in 200 mL of THF) was
added via an addition funnel over 30-40 min. The reaction
was stirred for an additional 30 min and quenched using the
basic workup.52 The precipitated aluminum salts were removed
by filtration of the quenched reaction mixture through a pad
of Celite. The cake was washed three times with portions of
THF and the organic portions were combined and concentrated
at reduced pressure. The alcohol was purified by conversion
to either the bis-maleate salt (see synthetic methods A, B, C)
or the bis-HCl salt (recrystallized from 2-propanol).
(()-1-[2-(Diph en ylm eth oxy)eth yl]-4-(3-h ydr oxy-3-ph en -
ylp r op yl)p ip er a zin e (31) was synthesized from 29 according
to synthetic method F (Scheme 5): 1H NMR (CDCl3) δ 1.84-
1.88 (m, 2H), 2.59 (m, complex, 10H), 2.71 (t, J ) 5.9 Hz, 2H),
3.60 (t, J ) 6.0 Hz, 2H), 4.93 (t, J ) 6.6 Hz, 1H), 5.37 (s, 1H),
7.25-7.39 (m, complex, 15H); MS (CI-NH3) m/z 431 (M+). Anal.
31‚2 maleate (C28H34N2O2‚2C4H4O4) C, H, N.
(()-1-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]-4-(3-h y-
d r oxy-3-p h en ylp r op yl)p ip er a zin e (32)43 was synthesized
from 30 according to synthetic method F (Scheme 5): 32‚2HCl,
mp 216-218 °C (lit.43 mp 216-218 °C); 1H NMR (CDCl3) δ
1.84-1.88 (m, 2H), 2.59 (m, complex, 10H), 2.68 (t, J ) 5.7
Hz, 2H), 3.57 (t, J ) 6.0 Hz, 2H), 4.93 (t, J ) 6.6 Hz, 1H), 5.34
(s, 1H), 6.98-7.04 (m, 4H), 7.25-7.39 (m, complex, 9H); MS
(CI-NH3) m/z 467 (M+). Anal. 32‚2HCl (C28H32N2F2O2‚2HCl)
C, H, N.
Syn th etic Meth od G. R-(+)- or S-(-)-3-Chloro-1-phenyl-
1-propanol (10 mmol; Aldrich, 99% ee/gc) was added to a
stirred solution of 3 or 4 (7 mmol, in 30 mL of DMF). Potassium
carbonate (20-25 mmol) was added, followed by sodium iodide
(11 mmol). The reaction was stirred at 70-80 °C for 18-24 h,
cooled to room temperature, and poured into 200 mL of water.
The resultant creamy suspension was extracted into ether (3
× 100 mL) and the organic portions were combined, washed
with brine, dried (MgSO4), and concentrated. The product was
purified by conversion to the bis-maleate salt and recrystal-
lization from methanol.
(()-1-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]-4-(3-h y-
d r oxy-3-p h en ylp r op yl)p ip er a zin e d eca n oa te (41)43,51 was
synthesized according to synthetic method H, Scheme 5). To
a stirred solution of 96.5 g of 32 (207 mmol) in 800 mL of
pentene-stabilized, ethanol-free CHCl3 was added decanoyl
chloride (70 mL, 330 mmol) over 20-30 min. The reaction was
stirred for 12 h at room temperature and then concentrated
in vacuo. The crude decanoyl ester 41 was converted to the
bis-maleate salt in portions. A 24-g portion of crude 41 (39
mmol) was dissolved in 75 mL of MeOH, and the solution was
heated to boiling and treated with 11.7 g of maleic acid (100
mmol, 2.5 equiv). The salt crystallized and was collected on a
filter. The snow-white crystalline product was washed twice
with petroleum ether and air-dried, affording 29.4 g of 41‚2
maleate (34 mmol, 87% from the free base): mp 152-154 °C
(lit.43 mp 154-155 °C). Several batches of the bis-maleate salt
(102 g, 120 mmol) were combined and partitioned between 500
mL of CHCl3 and 500 mL of dilute aq NaHCO3. The aqueous
portion was discarded, and the organic fraction was washed
with water and brine, dried over Na2SO4, concentrated at
reduced pressure, and dried in vacuo (0.1 mmHg) to constant
weight, affording 67 g of 41 (free base), as an almost colorless,
viscous oil (108 mmol, 90% from the bis-maleate salt): 1H
NMR (CDCl3) δ 0.87 (3H, t, J ) 6.7 Hz), 1.24 (12H, bs), 1.60
(2H, t, J ) 6.9 Hz), 1.87-1.95 (1H, m), 2.03-2.18 (1H, m),
2.31 (2H, t, J ) 7.5 Hz), 2.43 (4H, m), 2.53 (4H, m), 2.66 (2H,
t, J ) 6.0 Hz), 3.55 (2H, t, J ) 6.0 Hz), 5.33 (1H, s), 5.81 (1H,
t, J ) 6.9 Hz), 7.00 (4H, m), 7.24-7.34 (9H, m, ar); MS (CI-
NH3) m/z 621 (M+). Anal. 41‚2 maleate (C38H50N2F2O3‚
2C4H4O4‚1CH3OH) C, H, N.
(()-1-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]-4-(3-h y-
d r oxy-3-p h en ylp r op yl)p ip er a zin e Deca n oa te (41) (50%
solu tion in sesa m e oil).43,51 The purified free base 41 (67 g)
was dissolved in 400 mL of Et2O and combined with 67 g of
sesame oil (Sigma Catalog No. S-7131), and the resultant
solution was stirred for 1 h, concentrated on the rotovap, and
dried in vacuo (0.1 mmHg) for 16 h, at which time constant
mass was reached (134.1 g, calculated as a 49.9% w/w solution
in sesame oil).
(R)-(+)-1-[2-(Dip h en ylm eth oxy)eth yl]-4-(3-h yd r oxy-3-
p h en ylp r op yl)p ip er a zin e (33) was synthesized from 3 ac-
cording to synthetic method G (Scheme 6): 1H NMR (CDCl3)
δ 1.84-1.88 (m, 2H), 2.59 (m, complex, 10H), 2.71 (t, J ) 5.9
Hz, 2H), 3.60 (t, J ) 6.0 Hz, 2H), 4.93 (t, J ) 6.6 Hz, 1H), 5.37
(s, 1H), 7.25-7.39 (m, complex, 15H); MS (CI-NH3) m/z 431
Biologica l Meth od s. Binding assays for the DAT and
(M+); [R]D ) +10.0° (c 0.86, DMF). Anal. 33‚2 maleate
20
SERT followed published procedures36 and used 0.01 nM
[
125I]RTI-5553 (s.a. ) 2200 Ci/mmol). Briefly, 12- × 75-mm
(C28H34N2O2‚2C4H4O4) C, H, N.
(R)-(+)-1-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-4-(3-
h yd r oxy-3-p h en ylp r op yl)p ip er a zin e (34) was synthesized
from 4 according to synthetic method G (Scheme 6): 1H NMR
(CDCl3) δ 1.84-1.88 (m, 2H), 2.59 (m, complex, 10H), 2.68 (t,
J ) 5.7 Hz, 2H), 3.57 (t, J ) 6.0 Hz, 2H), 4.93 (t, J ) 6.6 Hz,
1H), 5.34 (s, 1H), 6.98-7.04 (m, 4H), 7.25-7.39 (m, complex,
9H); MS (CI-NH3) m/z 467 (M+); [R]D20 ) +12.5 (c 1.59, MeOH).
Anal. 34‚2 maleate (C28H32N2F2O2‚2C4H4O4) C, H, N.
(S)-(-)-1-[2-[Bis(4-flu or op h en yl)m et h oxy]et h yl]-4-(3-
h yd r oxy-3-p h en ylp r op yl)p ip er a zin e (36) was synthesized
from 4 according to synthetic method G (Scheme 6): 1H NMR
(CDCl3) δ 1.84-1.88 (m, 2H), 2.59 (m, complex, 10H), 2.68 (t,
J ) 5.7 Hz, 2H), 3.57 (t, J ) 6.0 Hz, 2H), 4.93 (t, J ) 6.6 Hz,
1H), 5.34 (s, 1H), 6.98-7.04 (m, 4H), 7.25-7.39 (m, complex,
polystyrene test tubes were prefilled with 100 µL of drug, 100
µL of radioligand ([125I]RTI-55), and 50 µL of a “blocker” or
buffer. Drugs and blockers were made up in 55.2 mM sodium
phosphate buffer, pH 7.4 (BB), containing 1 mg/mL bovine
serum albumin (BB/BSA). Radioligands were made up in a
protease inhibitor cocktail containing 1 mg/mL BSA [BB
containing chymostatin (25 µg/mL), leupeptin (25 µg/mL),
EDTA (100 µM), and EGTA (100 µM)]. The samples were
incubated in triplicate for 18-24 h at 4 °C (equilibrium) in a
final volume of 1 mL. Brandel cell harvesters were used to
filter the samples over Whatman GF/B filters, which were
presoaked in wash buffer (ice-cold 10 mM Tris-HCl/150 mM
NaCl, pH 7.4) containing 2% poly(ethylenimine).
The [3H]DA and [3H]5-HT uptake assays also proceeded
according to published procedures.54 Briefly, synaptosomes
were prepared by homogenization of rat caudate (for [3H]DA
reuptake) or whole rat brain minus cerebellum (for [3H]5-HT
reuptake) in ice-cold 10% sucrose, using a Potter-Elvehjem
homogenizer. After a 1000g centrifugation for 10 min at 4 °C,
the supernatants were retained on ice. The uptake assays were
initiated by the addition of 100 µL of synaptosomes to 12- ×
20
9H); MS (CI-NH3) m/z 467 (M+); [R]D ) -12.4° (c 1.60,
MeOH). Anal. 36‚2 maleate (C28H32N2F2O2‚2C4H4O4) C, H, N.
The optical purity of compounds 34 and 36 was determined
by 19F and 1H NMR spectral analysis of the Mosher esters of
these compounds. To a stirred solution of 34 or 36 (15 mg),
triethylamine (0.2 mL), and 4-(dimethylamino)pyridine (DMAP;
20 mg) in CH2Cl2 (3 mL) was added (R)-(-)-R-methoxy-R-

Oxygenated Analogues of GBR 12935 and GBR 12909
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 5041
75-mm polystyrene test tubes prefilled with 750 µL of [3H]-
ligand (5 nM final concentration) in a Krebs-phosphate buffer
(pH 7.4), which contained ascorbic acid (1 mg/mL) and par-
gyline (50 µM) (buffer), 100 µL of test drugs made up in buffer,
and 50 µL of buffer. The nonspecific uptake of each [3H]ligand
was measured by incubations in the presence of 1 µM 1a ([3H]-
DA) and 10 µM fluoxetine ([3H]5-HT). The incubations were
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Beh a vior a l Meth od s. Three individually housed, adult
male rhesus monkeys (Macaca mulatta), weighing between 7.8
and 9.2 kg, served as subjects in these studies. Each monkey
was maintained at about 90% of its free-feeding weight to allow
the use of food-maintained responding as a control perfor-
mance. These monkeys had been previously equipped with a
chronically indwelling catheter/port system.49 Experimental
sessions were conducted 5 days a week in separate sound- and
light-attenuating chambers, in a manner similar to previous
reports.34,43 Lever pressing was maintained by a multiple
chained fixed-interval (FI) 10-min FR 30 (food) chained FI 10-
min FR 30 (cocaine) schedule. Completion of the FI chain
component produced the second component of the chain
schedule, availability of food or cocaine under an FR schedule.
In the FR component, a maximum of 10 reinforcers could be
delivered. Each (FI and FR) component of the multiple
schedule included a 60-s limited hold (LH) period: in the FI,
if no responses occurred within 60 s after 10 min, the stimuli
were extinguished and the FR component was started; in the
FR component, the availability of that reinforcer was canceled
and the ratio requirements and the LH period were reset. Each
session was composed of four repetitions of the following
sequence: FI 10 min, FR 30 (food), FI 10 min, FI 30 (cocaine).
Green lights were illuminated during the food-availability
periods, and red lights were illuminated during the cocaine-
availability periods. The unit dose of cocaine used as a
reinforcer was 5.6 µg/kg/injection throughout the experiment.
The effects of 4-5 doses of 34, 36, and 1b or vehicle (a
mixture of distilled water and saline) were examined for five
consecutive sessions for each drug. For each drug, the effects
of the vehicle were assessed first, and then an ascending series
of doses were tested. The range of doses was chosen to include
a dose large enough to decrease responding substantially. The
order of drug testing was mixed among the animals, except
1b was always tested last. Doses of each drug or vehicle were
infused intravenously over about 15 min starting 30 min prior
to session onset. The dependent measures collected were the
average response rates in the food and cocaine components of
each session. For each subject, data from the last three
sessions for each dose of pretreatment drug or vehicle phase
were averaged and represented a stable effect.
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Ack n ow led gm en t. We thank Noel Whittaker and
Wesley White of the Laboratory of Analytical Chemistry
for mass spectral data and acknowledge the National
Institute on Drug Abuse, Medications Development
Division, for partial financial support of this work.
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