Structure - Activity relationship studies of 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine derivatives and their N-analogues: Evaluation of behavioral activity of O- and N-analogues and their binding to monoamine transporters

Article abstract of DOI:10.1021/jm000311k

In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the brain as DAT has been implicated strongly in the reinforcing effect of

Full text of DOI:10.1021/jm000311k

J . Med. Chem. 2001, 44, 937-948
937
Str u ctu r e-Activity Rela tion sh ip Stu d ies of
4-[2-(Dip h en ylm eth oxy)eth yl]-1-ben zylp ip er id in e Der iva tives a n d Th eir
N-An a logu es: Eva lu a tion of Beh a vior a l Activity of O- a n d N-An a logu es a n d
Th eir Bin d in g to Mon oa m in e Tr a n sp or ter s
Aloke K. Dutta,*,† Xiang-Shu Fei,† Patrick M. Beardsley,‡ J ennifer L. Newman,‡ and Maarten E. A. Reith#
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, Virginia Commonwealth University,
Richmond, Virginia, and Department of Biomedical and Therapeutic Sciences, College of Medicine, University of Illinois,
Peoria, Illinois
Received J uly 24, 2000
In our effort to develop a pharmacotherapy for the treatment of cocaine addiction, we embarked
on synthesizing novel molecules targeting the dopamine transporter (DAT) molecule in the
brain as DAT has been implicated strongly in the reinforcing effect of cocaine. Our previously
developed DAT-selective piperidine analogue, 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine,
was the basis for our current structure-activity relationship (SAR) studies exploring the
significance of the contribution of the benzhydryl O- and N-atoms in these molecules in
interacting with the DAT. Thus, we replaced the benzhydryl O-atom with an N-atom, altered
the location of the benzhydryl N-atom to an adjacent position, and in one other occasion
converted the benzhydryl O-ether linkage into an oxime-type derivative. Furthermore, we also
evaluated the important contribution of the piperidine N-atom to binding by altering its pKa
value chemically. Novel analogues were tested for potency in inhibiting [3H]WIN 35,428, [3H]-
citalopram, and [3H]nisoxetine binding at the DAT, serotonin transporter (SERT), and
norepinepherine transporter (NET). [3H]DA was used to measure DA reuptake inhibition. The
results indicated that the benzhydryl O- and N-atoms are exchangeable for the most part. On
the other hand, an enhanced interaction with the SERT was observed when the benzhydryl
N-atom moved to an adjacent position (21a ; DAT (IC50) ) 19.7, SERT (IC50) ) 137 nM, NET
(IC50) ) 1111 nM). In either cases, further alkylation of the N-atom reduced the activity for
the transporter. The presence of a powerful electron-withdrawing cyano group in compound
5d expectedly produced the most potent and selective ligand for the DAT (DAT (IC50) ) 3.7
nM, DAT/SERT ) 615). Selected compounds were further analyzed in the dopamine reuptake
inhibition assay. Preliminary behavioral assessment of some of the selected compounds in mice
indicated that these compounds are much less stimulating when compared with cocaine at
comparable doses. In drug-discrimination studies these selected compounds incompletely
generalized from the cocaine stimulus in mice trained to discriminate 10 mg/kg cocaine from
vehicle.
In tr od u ction
Direct-acting DA receptor agonists are also found to
modulate cocaine self-administration.13 Similarly DA
receptor antagonists also change cocaine self-adminis-
tration in a fashion expected from antagonists acting
on these receptors.14 The DA hypothesis for cocaine
addiction was further strengthened by the demonstra-
tion that the destruction of dopaminergic system in the
nucleus accumbens in rats selectively attenuated co-
caine self-administration.15 In a recent DAT knock-out
(KO) mice experiment, it was demonstrated that the
mice without DAT are hyperactive and indifferent to
cocaine.16 Also in another recent PET experiment
involving human subjects, the production of a ‘high’
caused by administration of a psychostimulant cor-
related very well with the increased level of DA in the
limbic region of the brain.17 Recently the roles of the
SERT and the serotonergic systems have also been im-
plicated in modulating some of the effects of cocaine.18-20
However, the correlation of the effect of SERT blockers
and serotonergic receptor agonists in behavior modula-
tion is not very strong.19 In other behavioral experi-
Cocaine is a powerful reinforcer, and its strong
addiction liability leads to widespread drug abuse which
is causing a national crisis.1-5 Currently there is no
medication available for the treatment of cocaine ad-
diction, and the development of a medication for cocaine
abuse is urgently required. Extensive studies in eluci-
dating the mechanism of action of cocaine revealed its
binding to the dopamine transporter (DAT), serotonin
transporter (SERT), and norepinepherine transporter
(NET) systems in the brain.6-8 The role of DAT is
implicated strongly in the powerful reinforcing effect of
cocaine by various experimental evidences.9-12 Thus,
DAT blockers are known to be self-administered readily
in animal studies with a significant correlation between
their behavioral and DA uptake blocking potencies.11,12
* To whom correspondence should be addressed. Tel: 1-313-577-
1064. Fax: 1-313-577-2033. E-mail: adutta@wizard.pharm.wayne.edu.
† Wayne State University.
‡ Virginia Commonwealth University.
#
University of Illinois.
10.1021/jm000311k CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/06/2001

938 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Dutta et al.
in conventional GBR molecules.24,35,36 This led us to
speculate the possible involvement of different binding
domains of these piperidine analogues in comparison
with conventional piperazine GBR molecules.
Ch a r t 1
In one of our latest SAR studies, we have demon-
strated that the benzhydryl O-atom could be replaced
by an N-atom in the piperidine analogues while main-
taining the activity and selectivity for the DAT (1b,
Chart 1).37 We also found that the compound containing
the benzhydrylamine N-atom connected to a carbonyl
group is rather very weak for the DAT. This might
indicate either the need of a basic benzhydryl N-atom
for binding interaction or the production of an unfavor-
able steric or electronic interactions with the DAT due
to the presence of an amide moiety.
The current hypothesis of our work is based on our
previous SAR results in this series of compounds. As a
part of extension of our previous results, our current
study is focused on: (a) evaluating the importance of the
contribution of the benzhydryl O- and N-atoms in
interacting with the DAT by altering their steric and
electronic environments; (b) examining the impact of
replacing the O-atom by an N-atom on activity and
selectivity of several analogues; (c) exploring the effect
of positional isomers created by relocating the benzhy-
dryl N-atom to an adjacent position in the ethylene
chain; and (d) evaluating some selected compounds in
behavioral experiments.
ments the modulation in serotonergic activity was
shown to have an effect in dopaminergic behavior thus
indicating cross-talk between these two systems.21 In
addition, DAT KO mice self-administered cocaine which
might indicate the involvement of a more complex
mechanism in cocaine’s reinforcing effect.22
A great number of structurally diversed compounds
have been developed for DAT with an aim to develop
effective pharmacotherapies for cocaine addiction. Among
some of these compounds developed are tropane, GBR,
and methylphenidate analogues as some of the most
widely studied compounds.23-31 Recently, piperidine-
based nonrigid analogues of cocaine were shown to have
good potency and selectivity for the DAT.32 Our interest
in GBR compounds started with the modification of the
central piperazine ring of GBR 12909 (Chart 1) into a
piperidine moiety which upon extensive structure-
activity relationship (SAR) studies led to the develop-
ment of a series of potent and selective ligands for the
DAT.33-36 In our SAR studies, we established optimal
structural requirements in these molecules required for
their highest selectivity and potency for the DAT. Thus,
the presence of different N-benzyl groups in these
molecules, unlike in conventional GBR molecules, was
best-tolerated for activity at the DAT, while it was not
favored by the SERT as reflected in low affinity binding
for the SERT.35 Interestingly, these SAR results turned
out to be somewhat different from the SAR results found
Ch em istr y
Synthesis of the intermediate 4 in Scheme 1 was
accomplished in two steps from the known starting
material 2 by converting it to the intermediate carbon-
ate 3 by a reaction with methyl chloroformate. This
intermediate carbonate on hydrolysis with KOH pro-
duced amine 4.38,39 Amine 4 was then alkylated with
various benzyl halides in the presence of a base to
produce different benzyl-substituted compounds 5a -d
in good yield. Compound 5e was synthesized by follow-
ing a procedure described by us earlier.37
A convergent synthetic approach was adopted in our
synthesis of O-aralkylhydroxylamine derivative 13.
Sch em e 1

SAR of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 939
Sch em e 2
Thus, as shown in Scheme 2, intermediates 9 and 12
were synthesized separately. Synthesis of 9 was ac-
complished by following a published procedure which
involved a reaction between diphenylbenzhydryl chlo-
ride and N-hydroxyphthalimide to produce intermediate
pthalimide 8, which on hydrolysis with hydrazine in
ethanol furnished O-aralkylhydroxylamine 9.40 The
other intermediate 12 was made from the known ester
10 by reducing it to alcohol 11, which was followed by
oxidation under Swern oxidation condition to aldehyde
12.41 Finally, the target compound 13 was made by
reacting amine 9 and aldehyde 12 under a modified
reductive amination condition in good yield.42
Target compounds 17a ,b, 21a ,b, and 25 were syn-
thesized in good yield by following our previous proce-
dure and are shown in Schemes 3 and 4.37 Thus the
respective starting materials were converted into in-
termediate acids by treatment with a mixture of tri-
fluoroacetic acid, HCl, and water. The acid was then
converted into amides 16a ,b, 20a ,b, and 24 by treat-
ment with water-soluble coupling agent 1-(3-(dimethy-
lamino)propyl)-3-ethylcarbodiimide followed by treat-
ment with the appropriate amine. Reduction of the
amides with borane/THF complex provided the final
compounds.
longer N-alkyl chain connecting the aromatic ring to the
piperidine N-atom in these derivatives produced less
selective compounds for the DAT even though they
maintained strong potencies for the DAT. On the other
hand, the selectivity was enhanced significantly when
the propyl chain length was reduced to a methylene link
connecting the aromatic and the piperidine rings. Ad-
ditionally, we also found that the presence of an
electron-withdrawing group in the aromatic ring of the
benzyl substitution further increased the activity and
selectivity for the DAT indicating the positive influence
of electronic interaction with the transporter. In our
effort to extend our previous findings, and to explore
the effect of electronegative F-atoms and the strong
electron-withdrawing group cyano-substituted in the
aromatic ring, compounds 5a -d were designed and
synthesized. Conforming to our previous results, we
found that these novel compounds exhibited profound
selectivity and potency for the DAT (Table 1). Thus,
compound 5d , with a strongly electron-withdrawing
cyano group located in the phenyl ring, exhibited
remarkable potency and selectivity (IC50 ) 3.7 nM, DAT/
SERT ) 615) for the DAT. On the contrary, we have
previously found an electron-donating -NH2 group
located in the para position of the aromatic ring
decreased activity and selectivity.35 In our current
study, we converted this -NH2 group in compound 5f
into methansulfonamide 5g, which in turn changed it
into an electron-withdrawing-type substituent thus
altering the electronic character in the original 5f
molecule. As expected, we found potent activity in this
compound 5g compared to its parent amino compound
(IC50 ) 26 nM vs 101 nM, Table 1). Compounds 5a -c
containing eletronegative F-atoms at various positions
in the phenyl ring, as expected, showed good activity
and selectivity for the DAT, where the difluoro com-
pound 5b was the most active. The rationale behind
synthesizing 5e lied in evaluation of the importance of
the basic piperidine N-atom in interaction with the
DAT. The weak activity of 5e for the DAT indicated the
N-Methyl analogues 18 and 22 were synthesized by
following a published procedure.43 Compound 27 was
synthesized in good yield by following Willamson ether
synthesis procedure using a phase-transfer catalyst.44
Thus the known alcohol 26 was treated with (1-bromo-
ethyl)benzene in the presence of sodium hydride and
tetrabutylammonium iodide, a phase-transfer catalyst,
to produce 27 in good yield.
Resu lt a n d Discu ssion s
Our previous SAR results have demonstrated that the
nature of the aromatic-alkyl substitution on the pip-
eridine N-atom of these molecules plays a crucial role
in selectivity for the DAT when their binding was
compared to the SERT. As we have demonstrated, a

940 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Dutta et al.
Sch em e 3
Ta ble 1. Affinity and Selectivity of Drugs at the DAT, SERT,
and NET in Rat Striatum
Sch em e 4
IC50, nMa
DAT
[3H]WIN
35,428
SERT
NET
SERT/
compd
cocaine
GBR 12909 10.6 ( 1.9
1a
1b
5a
5b
5c
5d
5e
5g
13
17a
17b
18
21a
21b
22
[3H]citalopram [3H]nisoxetine DAT
266 ( 37
737 ( 160
132 ( 0
3530 ( 550
496 ( 22
2.7
12
113
62
49
122
71
615
6.1
22
19
227
347
7.8
7.0
17
27
3.2
7.8
17.2 ( 4.7b
9.37 ( 2.62c
23.4 ( 3.8
10.1 ( 0.93
32.1 ( 2.1
3.67 ( 0.58
2156 ( 54
26.6 ( 1.4
34.4 ( 4.2
7.00 ( 1.7
4.50 ( 0.64
213 ( 3
1920 ( 233
585 ( 101
1150 ( 40
1220 ( 140
2260 ( 140
2280 ( 470
13200 ( 800
586 ( 29
945 ( 20
921 ( 110
342 ( 66
626 ( 33
691 ( 68
1027 ( 94
2620 ( 170
1590 ( 160
1560 ( 210
1660 ( 470
137 ( 46
19.7 ( 1.4
65.3 ( 3.2
94.0 ( 12.5
295 ( 41
1110 ( 120
1100 ( 250
2520 ( 230
963 ( 38
requirement of the presence of a basic N-atom in
interaction with the DAT.
25
27
751 ( 62
5860 ( 600
In our recent study, we have shown that the benzhy-
dryl O-atom can be replaced by an N-atom in these
piperidine analogues while maintaining the activity and
selectivity for the DAT.37 In our current investigation,
we have extended our initial results by incorporating
more analogues for the comparison of the activity of
N-analogues and the corresponding O-analogues. Thus
compounds 17a ,b and 21b were designed and synthe-
a
The DAT was labeled with [3H]WIN 35, 428, the SERT with
[3H]citalopram, and the NET with [3H]nisoxetine. Results are the
average ( SEM of 3 independent experiments assayed in triplicate.
See ref 35. c See ref 37.
b
sized when their corresponding O-analogue versions
were also synthesized and characterized. Overall the
activities on interchanging the O- and N-atoms in these

SAR of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 941
Ta ble 2. Inhibition of Dopamine Reuptake in Rat Cytosol
analogues correlated pretty well. Compound 17b was
found to be more potent and selective compared to its
previously characterized O-analogue (IC50 ) 4.5 nM vs
15.2 nM, DAT/SERT ) 347 vs 49, Table 1).34 On the
other hand, 21b was found to be less potent than the
corresponding O-analogue characterized earlier,34 which
may reflect more sensitivity toward the alteration of the
alkyl chain length between the bisphenyl moiety and
the piperidine ring in the case of N-analogues compared
to the corresponding O-versions. Future studies will be
done to further investigate this.
IC50, nM
[3H]DA uptake
inhiba
[3H]DA uptake/
compd
[3H]WIN 35,428 binding
GBR 12909
1a
1b
5d
13
5g
21a
17b
17a
6.63 ( 0.43
2.48 ( 0.59
12.0 ( 1.6
4.58 ( 0.80
16.6 ( 2.8
9.73 ( 1.2
49.6 ( 7.2
20.6 ( 2.5
10.7 ( 1.8
0.62
0.14
1.33
1.23
0.48
0.36
2.5
4.5
1.5
In our next effort to explore steric and electronic
effects on the benzhydryl O- and N-atoms, compounds
13 and 18 (Schemes 2 and 3) were designed and
synthesized. In compound 13, we altered the electronic
nature of the benzhydryl O-atom by converting it into
a hydroxylamine-type derivative. The binding results
indicate that compound 13 is still quite potent for the
DAT and has good selectivity, which indicated that the
presence of an adjacent N-atom was not detrimental to
its activity (Table 1). However, the potency of compound
13 when compared with our previous closely related lead
compound 1a (Chart 1)35 was a little less, and was much
less selective for the DAT, reflecting a somewhat nega-
tive impact on selectivity due to the presence of an
adjacent N-atom. This result also corresponds somewhat
with 21a , as explained next, where the N-atom is in the
same location as in 13 and which also demonstrated
much less selectivity. Compound 18, on the other hand,
was weak.
a
Results are the average ( SEM of 3-4 independent experi-
ments assayed in triplicate.
N-analogue versions did not correlate very well. Nev-
ertheless, in both cases the importance of the presence
of a bisphenyl moiety in their interaction with the DAT
was demonstrated.
Some of the selected compounds were tested in a NET
assay. In some instances these analogues were more
active at the NET than at the SERT. Compound 5d in
this regard was the most active compound (IC50 ) 342
nM).
The selected compounds were subsequently tested in
the dopamine reuptake inhibition assay and compared
with the value of the standard compound GBR 12909.
For the most part, compounds which showed appreciable
potency in binding were also active in the uptake
inhibition assay (Table 2). Compounds 21a and 17b
showed relatively weaker uptake inhibition activity and
thus exhibited the highest uptake-to-binding ratios in
this current series of compounds. In this regard, com-
pound 17b was 7-fold less potent than GBR 12909 in
the relative activity measure (4.5 vs 0.62). On the other
hand, compound 1a was found to have a low discrimi-
nation ratio (0.14). These compounds were chosen for
further in vivo testing along with compounds 1a ,b and
GBR 12909.
The selected compounds were tested in mice for their
locomotor activity effects and in mice trained to dis-
criminate 10 mg/kg cocaine from vehicle (Figure 1). The
reference compounds cocaine (F3,27 ) 24.77, P < 0.0001)
and GBR 12909 (F3,28 ) 31.11, P < 0.0001) significantly
altered locomotor activity with 10 and 30 mg/kg, in-
creasing distanced traveled relative to control (Dun-
nett’s, P < 0.05). Compound 1a (F3,28 ) 13.85, P <
0.0001) also significantly altered locomotor activity with
30 mg/kg, increasing distance traveled relative to control
(Dunnett’s, P < 0.05). Compared to the reference
compounds, compound 1a was approximately 3 times
less potent than either cocaine or GBR 12909 in
increasing locomotor activity. On the other hand, the
N-analogue compound 1b did not affect locomotor activ-
ity up to 56 mg/kg, the highest dose tested. The other
N-analogue compounds, 17b (F3,27 ) 10.72, P < 0.0001)
and 21a (F3,28 ) 8.01, P < 0.0005), did affect locomotor
activity but decreased it (Dunnett’s, P < 0.05) at 100
and 30 mg/kg, the highest doses tested, respectively.
These results indicate that a molecule containing a
benzhydryl O-atom, as in compound 1a , can produce
stimulation of locomotor activity, whereas compounds
with either benzhydryl N-atoms, as in 17b and 1b, or
the N-atom relocated to an adjacent position, as in 21a ,
are not stimulatory but inhibitory in this regard. Bind-
In our next design of compound 21a we wanted to
observe the effect of relocation of the benzhydryl N-atom
to an adjacent location which resulted in the formation
of a structural isomer of 1b (Chart 1), our previous
N-analogue lead compound.37 Binding results indicated
that such an alteration resulted in the maintenance of
activity but a decrease in the selectivity for the DAT;
in this regard, it is quite different from 1b (Table 1).
This is quite contrasting in the light of the fact that most
of the active piperidine analogues with N-benzyl sub-
stitutions have exhibited substantial selectivity for the
DAT by exhibiting poor affinity for the SERT. Shifting
the location of the benzhydryl N-atom to an adjacent
position caused a dramatic departure from such selec-
tivity. This might reflect altered molecular interaction
resulting from such modification which enhanced its
affinity for the SERT. This enhanced interaction with
the SERT was lost to a great extent when the N-atom
was methylated, as in compound 22, which may be due
to an unfavorable steric interaction.
In our final series of compounds, we wanted to
evaluate the contribution of the phenyl ring in the
benzhydryl moiety of these molecules in interaction with
the transporters. Thus, the N-analogue 25 and the
O-analogue 27, where one of the phenyl rings is replaced
by a methyl group, were synthesized and biologically
characterized. Compound 27 turned out to be far more
weaker than its corresponding bisphenyl counterpart,
and the N-analogue compound 25 showed modest activ-
ity (Table 1). This illustrated the importance of the
presence of a bisphenyl moiety in interaction with the
monoamine transporters more so in the case of O-
analogues than N-analogues. It is interesting to note
that in this instance the activity between the O- and

942 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Dutta et al.
F igu r e 1. Distance traveled during locomotor activity tests. Each symbol represents the average distance traveled (cm) for each
dosage group (N ) 8; except N ) 7 for the saline group during cocaine tests and for 30 mg/kg 17b) during the entire 60-min test
session expressed as a percentage of each individual drug’s vehicle control. Brackets indicate SEM. ANOVA results with cocaine
(F3,27 ) 24.77, P < 0.0001), GBR 12909 (F3,28 ) 31.11, P < 0.0001), 1a (F3,28 ) 13.85, P < 0.0001), 17b (F3,27 ) 10.72, P < 0.0001),
and 21a (F3,28 ) 8.01, P < 0.0005) indicated significant alterations in distance traveled were produced during tests with these
compounds. Asterisks indicate that post-hoc Dunnett’s tests resulted in a dose producing a significantly different (P < 0.05)
distance traveled, relative to vehicle control.
F igu r e 2. Top: Percentage of lever presses emitted upon cocaine-designated lever. Each symbol represents the mean number of
lever presses emitted upon the cocaine-designated lever expressed as a percentage of total lever presses emitted during the test.
Brackets indicate SEM. If a mouse failed to lever-press sufficiently to obtain at least one pellet delivery during a test, its data
were excluded for calculations of mean drug lever responding for that test (see text): 1b and 17b (N ) 6); 21a (N ) 7); 1a (N )
8); cocaine (N ) 21; except at 3 mg/kg, N ) 20; and at 30 mg/kg, N ) 19). Bottom: Response rate expressed as mean lever
presses/s. Each symbol represents the mean number of lever presses emitted during the 15-min test session. Brackets indicate
SEM: 1b and 17b (N ) 6); 21a (N ) 7); 1a (N ) 8); cocaine (N ) 21; except at 3 and 30 mg/kg, N ) 20).
ing affinities at the three transporters did not predict
these differences in locomotor activity effects, for all four
compounds, 1a ,b, 17b, and 21a , had nanomolar affinity
at the DAT and poor (between 137 and 1920 nM) affinity
at the SERT (Table 1). Compound 1a ’s affinity at the
NET was not evaluated, but compounds 1b, 17b, and
21a had micromolar affinity at this transporter sug-
gesting poor activity as well. Interestingly, compound
1a exhibited a relatively lower discrimination ratio
compared to compounds 17b and 21a .
Similar to the locomotor activity results, tests in
cocaine-discriminating mice showed that the benzhydryl
O-atom-containing compound 1a produced differences
relative to compounds 1b, 17b, and 21a (Figure 2).
Compound 1a produced over 60% cocaine lever selection
at 56 and 75 mg/kg and increased overall rates of lever
pressing relative to vehicle control at 75 and 100 mg/
kg. Compounds 1b, 17b, and 21a , however, produced
less than 50% cocaine lever selection throughout the
dose ranges tested and either had little effect on overall

SAR of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 943
EtOAc was added. The EtOAc solution was washed with brine,
dried over Na2SO4, and evaporated to give crude product which
was purified by flash chromatography (EtOAc/MeOH/Et3N )
response rates (1b and 17b) or modestly decreased them
(21a ). These results indicate that none of the tested
compounds completely generalized from the cocaine-
discriminative stimulus and their effects on overall rates
of responding differed in ways similar to their relative
differences observed during locomotor activity tests.
1
100/5/2) to give a white solid 4: 2.80 g (80% yield); H NMR
(CDCl3) δ 7.35-7.19 (10H, m, Ar-H), 5.31 (1H, s, Ph2CHO),
3.50-3.46 (2H, t, J ) 6.0 Hz, OCH2), 3.08-3.04 (2H, bd, J )
2.3 Hz, NCH2), 2.77-2.68 (2H, t, J ) 12.6 Hz), 2.62-2.54 (2H,
t, J ) 12.3 Hz, NCH2), 1.82-1.57 (5H, m), 1.14-1.02 (2H, m).
Anal. (C20H25NO‚2.0H2O) C, H, N.
Con clu sion
P r oced u r e A: 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(3-flu o-
r op h en yl)m et h yl]p ip er id in e (5a ). A mixture of 4-[2-(di-
phenylmethoxy)ethyl]piperidine (4) (58 mg, 0.19 mmol), 3-fluo-
robenzyl chloride (51 mg, 0.35 mmol), Et3N (0.5 mL), and
anhydrous K2CO3 (0.3 g) in DMF (10 mL) was stirred at 65
°C overnight. The reaction mixture was diluted with 30 mL
water and extracted with Et2O. The combined organic phase
was dried over Na2SO4 and evaporated to give crude product,
which was purified by flash chromatography (EtOAc/hexane
) 1/3) to give 5a , a viscous liquid: 62 mg (79% yield); 1H NMR
(CDCl3) δ 7.34-7.20 (10H, m, 2Ph), 7.11-7.03 (3H, m, m-FPh),
6.95 (1H, m, m-FPh), 5.31 (1H, s, Ph2CH), 3.45-3.44 (2H, t, J
) 6.6 Hz, OCH2), 3.44 (2H, s, m-FPhCH2), 2.84-2.80 (2H, bd,
J ) 11.1 Hz, NCH2), 1.97-1.89 (2H, t, J ) 11.4 Hz, NCH2),
1.63-1.51 (4H, m), 1.49-1.44 (1H, m), 1.29-1.21 (2H, m). Free
base was converted into its oxalate salt: mp 150-151 °C. Anal.
[C27H30NOF‚(COOH)2‚0.3H2O] C, H, N.
In this report, we have demonstrated the development
of some very potent and selective compounds for the
DAT which includes compound 5d as among one of the
highest selective and potent compounds for DAT known
to date. In general, structurally similar N- and O-
analogues correlated very well in activity. Relocation
of the benzhydryl N-atom to an adjacent position
resulted in an enhancement of potency for the SERT
without altering DAT activity.
Selected compounds were tested in a dopamine re-
uptake assay. On the basis of the binding results, some
compounds were chosen for in vivo locomotor activity
and drug-discrimination studies. In the locomotor as-
sessments, compound 1a was less stimulating than
cocaine and GBR 12909 and did not generalize com-
pletely with the cocaine stimulus in drug-discrimination
tests. On the other hand, the N-analogues 1b, 17b, and
21a did not exhibit any stimulant action despite their
strong potency for the DAT. In drug-discrimination tests
they also incompletely generalized with the cocaine-
discriminative stimulus. Our continuing and future
studies will probe more into differences of in vivo results
between O- and N-analogues of these novel piperidine
compounds.
4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(3,4-d iflu or op h en yl)-
m eth yl]p ip er id in e (5b). 4-[2-(Diphenylmethoxy)ethyl]pip-
eridine (4) (0.12 g, 0.42 mmol) was reacted with 3,4-
difluorobenzyl bromide (0.17 g, 0.82 mmol), Et3N (0.5 mL), and
K2CO3 (0.6 g) in dry DMF (10 mL) to give 5b, 0.15 g (86%
1
yield), as a viscous liquid (procedure A): H NMR (CDCl3) δ
7.34-6.99 (13H, m, Ar-H), 5.31 (1H, s, Ph2CH), 3.49-3.45 (2H,
t, J ) 6.3 Hz, OCH2), 3.85 (s, 2H, NCH2Ph), 2.80-2.77 (2H, d,
J ) 11.4 Hz, NCH2), 1.95-1.87 (2H, t, J ) 11.4 Hz, NCH2),
1.63-1.55 (4H, m), 1.50-1.42 (1H, m), 1.28-1.15 (2H, m). Free
base was converted into its oxalate salt: mp 158-159 °C. Anal.
[C27H29NOF2‚(COOH)2] C, H, N.
Exp er im en ta l Deta ils
4-[2-(Dip h en ylm eth oxy)eth yl]-1-[(4-(tr iflu or om eth yl)-
p h en yl)m eth yl]p ip er id in e (5c). 4-[2-(Diphenylmethoxy)-
ethyl]piperidine (4) (0.11 g, 0.37 mmol) was reacted with
4-trifluoromethylbenzyl chloride (0.14 g, 0.72 mmol), Et3N (0.5
mL) and K2CO3 (0.5 g) in DMF (10 mL) to give 5c, 0.15 g (92%
Analytical silica gel-coated TLC plates (Si 250F) were
purchased from Baker, Inc. and were visualized with UV light
or by treatment with phosphomolybdic acid (PMA). Flash
chromatography was carried out on Baker silica gel 40 mm.
1H NMR spectra were routinely obtained at GE-300 MHz FT
NMR. The NMR solvent used was CDCl3 as indicated. TMS
was used as an internal standard. Elemental analyses were
performed by Atlantic Microlab, Inc. and were within (0.4%
of the theoretical values.
1
yield), as a viscous liquid (procedure A): H NMR (CDCl3) δ
7.64-7.47 (4H, m, CF3Ph), 7.34-7.23 (10H, m, 2Ph), 5.31 (s,
Ph2CH), 3.52 (2H, s, p-FPhCH2), 3.49-3.45 (2H, t, J ) 6.3 Hz,
OCH2), 2.84-2.80 (2H, d, J ) 11.1 Hz, NCH2), 2.00-1.92 (2H,
t, J ) 11.1 Hz, NCH2), 1.63-1.55 (4H, m), 1.49-1.42 (1H, m),
1.27-1.15 (2H, m). Free base was converted into its oxalate
salt: mp 149-150 °C. Anal. [C28H30NOF3‚(COOH)2‚0.70H2O]
C, H, N.
[3H]WIN 35,428 (86 Ci/mmol), [3H]citalopram (82 Ci/mmol),
[3H]nisoxetine (80 Ci/mmol) and [3H]dopamine (60.0 Ci/mmol)
were obtained from DuPont-New England Nuclear (Boston,
MA). Cocaine hydrochloride was purchased from Mallinckrodt
Chemical Corp. (St. Louis, MO). WIN 35,428 naphthalene-
sulfonate was purchased from Research Biochemicals, Inc.
(Natick, MA). (-)-Cocaine HCl was obtained from the National
Institute on Drug Abuse. GBR 12909 dihydrochloride (1-[2-
[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)pipera-
zine) was purchased from SIGMA-Aldrich (#D-052; St. Louis,
MO).
1-(Met h oxyca r b on yl)-4-[2-(d ip h en ylm et h oxy)et h yl]-
p ip er id in e (3). A solution of 4-[2-(diphenylmethoxy)ethyl]-
1-(phenylmethyl)piperidine (234) (4.62 g, 11.82 mmol) and
methyl chloroformate (2.60 g, 23.64 mmol) in benzene (60 mL)
was refluxed for 6 h. After TLC showed the completion of
reaction, the solvent was removed in vacuo to give a viscous
liquid 3: 4.17 g (99% yield); 1H NMR (CDCl3) δ 7.34-7.18 (10H,
m, Ar-H), 5.30 (1H, s, Ph2CHO), 3.67 (3H, s, OCH3), 3.50-
3.46 (2H, t, J ) 6.0 Hz, OCH2), 2.77-2.68 (2H, t, J ) 12.3 Hz,
NCH2), 2.62-2.54 (2H, t, J ) 12.0 Hz, NCH2), 1.67-1.57 (5H,
m), 1.26-1.07 (2H, m).
4-[2-(Dip h e n ylm e t h oxy)e t h yl]-1-[(4-cya n op h e n yl)-
m eth yl]p ip er id in e (5d ). 4-[2-(Diphenylmethoxy)ethyl]pip-
eridine (4) (0.15 g, 0.52 mmol) was reacted with 4-cyanobenzyl
bromide (0.18 g, 0.92 mmol), Et3N (0.5 mL) and K2CO3 (0.7 g)
in 10 mL DMF to give 5d , 0.17 g (84% yield), as a white solid
1
(procedure A): H NMR (CDCl3) δ 7.61-7.58 (2H, d, J ) 7.5
Hz, Ar-H), 7.45-7.42 (2H, d, J ) 7.5 Hz, Ar-H), 7.33-7.22
(10H, m, Ar-H), 5.31 (1H, s, Ph2CHO), 3.51 (2H, s, p-
CNPhCH2), 3.50-3.46 (2H, t, J ) 6.0 Hz, OCH2CH2), 2.81-
2.77 (2H, bd, J ) 10.8 Hz, NCH2), 2.00-1.93 (2H, t, J ) 11.1
Hz, NCH2), 1.65-1.56 (4H, m), 1.52-1.46 (1H, m, OCH2-
CH2CH), 1.30-1.18 (2H, m). Free base was converted into its
oxalate salt: mp 120-121 °C. Anal. [C28H30N2O‚(CO2H)2‚
0.26H2O] C, H, N.
P r oced u r e B: 4-[2-(Dip h en ylm eth oxyl)eth yl]-1-[(p h en -
ylm eth yl)ca r bon yl]p ip er id in e (5e). A solution of phenyl-
acetic acid (0.11 g, 0.82 mmol), 1-[3-(dimethylamino)propyl]-
3-ethylcarbodiimidehydrochloride (EDCI) (0.17 g, 0.88 mmol)
and 1-hydroxybenzotriazole (HOBT) (0.11 g, 0.88 mmol) in
Et3N (1 mL) and dry CH2Cl2 (10 mL) was stirred at room
temperature for 1 h. 4-[2-(Diphenylmethoxy)ethyl]piperidine
(4) (0.12 g, 0.41 mmol) dissolved in CH2Cl2 (5 mL) was added
into the above reaction mixture. The solution was stirred at
4-[2-(Dip h en ylm eth oxy)eth yl]p ip er id in e (4). Compound
3 (4.17 g, 11.81 mmol) was dissolved in ethanol (100 mL) and
KOH (2.5 g) was added into the solution. The reaction mixture
was refluxed for 3 days. The solvent was evaporated and

944 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Dutta et al.
room temperature overnight. The solvent was removed in
vacuo and the residue was dissolved in EtOAc. The organic
phase was washed with 5% citric acid aqueous solution,
followed by saturated NaHCO3 solution and finally dried over
Na2SO4. The organic extract was evaporated to give a crude
product which was purified by flash chromatography (EtOAc/
hexane ) 1/3) to collect a viscous liquid 5e: 0.27 g (96% yield);
1H NMR (CDCl3) δ 7.32-7.25 (15H, m, Ar-H), 5.29 (1H, s, Ph2-
CHO), 4.62-4.58 (1H, d, J ) 12.6 Hz, NCH), 3.84-3.79 (1H,
d, J ) 13.2 Hz, NCH), 3.72 (2H, s, PhCH2), 3.47-3.43 (2H, t,
J ) 6.2 Hz, OCH2), 2.96-2.88 (1H, t, J ) 12.6 Hz, NCH), 2.58-
2.50 (1H, t, J ) 12.3 Hz, NCH), 1.68-1.52 (3H, m), 1.27-1.19
(2H, m), 1.10-1.03 (1H, m), 0.89-0.81 (1H, m). Anal.
(C28H31O2N‚0.12H2O) C, H, N.
13.38 mmol) was added dropwise into oxalyl chrolide solution.
The reaction mixture was stirred for 5 min. The alcohol 11
(0.99 g, 4.46 mmol) dissolved in CH2Cl2 (20 mL) was added
dropwise into the reaction solution. Stirring was continued for
an additional 20 min. Triethylamine (8.0 mL) was added and
the reaction mixture was stirred for 10 min and then allowed
to warm to room temperature. Water (50 mL) was added and
the mixture was extracted with CH2Cl2. The combined CH2-
Cl2 solution was dried over Na2SO4. The evaporation of solvent
gave an oil: 0.77 g (79% yield); 1H NMR (CDCl3) δ 9.65 (1H, s,
CHO), 7.30-7.24 (2H, m, Ar-H), 7.00-6.97 (2H, m, Ar-H), 3.46
(2H, s, p-FPhCH2), 2.81-2.76 (2H, m, NCH2), 2.30-2.20 (1H,
m, CHCHO), 2.14-2.06 (2H, dt, J ) 2.1, 11.3 Hz, NCH2), 1.92-
1.86 (2H, dd, J ) 3.5, 13.5 Hz), 1.74-1.62 (2H, m).
4-[2-(Dip h en ylm et h oxy)et h yl]-1-[(4-(m et h ylsu lfon yl-
a m in o)p h en yl)m et h yl]p ip er id in e (5g). 4-[2-(Diphenyl-
methoxy)ethyl]-1-[(4-aminophenyl)methyl]piperidine (5f) (0.11
g, 0.29 mmol) was dissolved in CH2Cl2 (5 mL). Methanesulfonyl
chloride (0.04 g, 0.35 mmol) and Et3N (0.1 mL) were added.
The reaction mixture was stirred at room temperature over-
night. The solvent was evaporated and EtOAc (50 mL) was
added. The organic phase was washed by saturated NaHCO3/
H2O and brine, and dried over Na2SO4. After evaporation, the
crude product was purified by flash chromatography (EtOAc/
MeOH ) 100/1) to give pure compound: 26 mg (20% yield); 1H
NMR (CDCl3) δ 7.41-7.14 (14H, m, Ar-H), 5.31 (1H, s, Ph2-
CHO), 3.49-3.45 (4H, m, OCH2CH2, NCH2Ph), 3.40 (1H, s,
NH), 2.98(3H, s, CH3SO2), 2.85-2.81 (2H, bd, J ) 10.8 Hz,
NCH2), 1.97-1.90 (2H, t, J ) 10.8 Hz, NCH2), 1.64-1.51 (4H,
m), 1.50-1.45 (1H, m, O(CH2)2CH), 1.28-1.17 (2H, m). Free
base was converted into its oxalate salt: mp 122-124 °C. Anal.
(C28H34N2O3S‚COOH‚1.15H2O) C, H, N.
N-Ben zh yd r yloxyp h th a lim id e (8). A solution of chloro-
diphenylmethane (6) (3.42 g, 16.93 mmol), N-hydroxyphthal-
imide (7) (2.30 g, 14.11 mmol) and Et3N (3.0 mL) in DMF (50
mL) was stirred at 60 °C under N2 for 8 h. After the reaction
mixture was cooled to room temperature, water (100 mL) was
added. The mixture was extracted with Et2O. The combined
organic phase was dried over Na2SO4. After the evaporation
of the solvent, the crude product was purified by flash
chromatography (hexane/benzene/EtOAc ) 20/10/3) to give a
white solid: 3.95 g (85% yield); 1H NMR (CDCl3) δ 7.72-7.63
(1H, m), 7.56-7.53 (1H, m), 7.40-7.24 (12H, m), 5.85 (1H, s,
Ph2CH).
P r oced u r e C: 4-[((Dip h en ylm eth oxy)a m in o)m eth yl]-
1-[(4-flu or op h en yl)m eth yl]p ip er id in e (13). Into the solu-
tion of O-benzyhydrylhydroxylamine (9) (0.25 g, 1.27 mmol)
and aldehyde 12 (0.28 g, 1.27 mmol) in ClCH2CH2Cl (20 mL)
was added Na(OAc)3BH (0.54 g, 2.55 mmol). The reaction
mixture was stirred at room temperature overnight. EtOAc
(80 mL) was added and the solution was washed by saturated
NaHCO3/H2O and brine. The organic phase was dried over Na2-
SO4 and evaporated to give crude product, which was purified
by chromatography (EtOAc/hexane ) 1/2) to give a colorless
oil: 0.43 g (84% yield); 1H NMR (CDCl3) δ 7.36-7.23 (12H, m,
Ar-H), 7.01-6.95 (2H, t, J ) 7.4 Hz, Ar-H), 3.41 (2H, s,
p-FPhCH2), 2.82-2.78 (2H, bd, J ) 11.1 Hz, NCH2), 2.25-
2.21 (1H, m, NH), 2.00-1.93 (2H, t, J ) 10.8 Hz, NCH2), 1.71-
1.47 (7H, m). Free base was converted into its oxalate salt:
mp 154-155 °C. Anal. (C26H29FN2O‚COOH‚0.10H2O) C, H, N.
P r oced u r e D: 4-[[(Dip h en ylm eth yl)a m in oca r bon yl]-
m eth yl]-1-[(3,4-d iflu or op h en yl)m eth yl]p ip er id in e (16a ).
1-[(3,4-Difluorophenyl)methyl]-4-[(ethoxycarbonyl)methyl]pi-
peridine (14) (0.94 g, 3.16 mmol) was dissolved in 10 mL of a
CF3CO2H/HCl/H2O (1:1:1) mixture. The solution was refluxed
for 2 h, and the solvent was removed in vacuo to give a solid
which was dissolved in 10 mL of CH2Cl2 containing excess of
Et3N to liberate the free amine. Into this solution were added
EDCI (0.73 g, 3.80 mmol) and HOBT (0.55 g, 4.07 mmol). The
solution was stirred for 1 h, and into it was added diphenyl-
aminomethane (0.75 g, 4.10 mmol). The solution was stirred
at room temperature overnight. After workup and purification
(procedure B) a white solid, 1.03 g (75% yield), was produced:
1H NMR (CDCl3) δ 7.34-6.99 (13H, m, Ar-H), 6.27-6.25 (1H,
d, J ) 7.8 Hz, Ph2CH), 6.04-6.02 (1H, d, J ) 7.8 Hz, NH),
3.40 (2H, s, F2PhCH2), 2.82-2.78 (2H, d, J ) 11.4 Hz, NCH2),
2.18-2.15 (2H, d, J ) 7.2 Hz, COCH2), 2.04-1.96 (2H, t, J )
12.0 Hz, NCH2), 1.92-1.83 (1H, m, COCH2CH), 1.72-1.67 (2H,
bd, J ) 11.8 Hz), 1.35-1.23 (2H, m).
P r oced u r e E: 4-[2-((Dip h en ylm eth yl)a m in o)eth yl]-1-
[(3,4-d iflu or op h en yl)m eth yl]p ip er id in e (17a ). Into the
solution of 16a (0.12 g, 0.28 mmol) in 20 mL dry THF was
added 1 M BH3/THF (1.0 mL, 1 mmol). The reaction mixture
was refluxed for 6 h. After the solution was cooled to room
temperature, methanol (5 mL) was added slowly. The solvent
was removed under reduced pressure and 10% HCl/MeOH (10
mL) was added into the residue and the solution was refluxed
for 1 h. Solid NaHCO3 was added and the methanol was
removed in vacuo. The mixture was extracted with EtOAc. The
combined organic phase was dried over Na2SO4 and evaporated
to give the crude product which was purified by flash chro-
matography (hexane/EtOAc/Et3N, 1/2/1%) to give a white solid:
0.11 g (90% yield); 1H NMR (CDCl3) δ 7.39-6.99 (13H, m, Ar-
H), 4.79 (1H, s, Ph2CH), 3.39 (2H, s, F2PhCH2), 2.80-2.76 (2H,
d, J ) 11.1 Hz, NCH2), 2.60-2.55 (2H, t, J ) 7.0 Hz, NCH2),
1.93-1.86 (2H, t, J ) 11.1 Hz, NCH2), 1.62-1.58 (2H, d, J )
12 Hz), 1,49-1.42 (2H, q, J ) 6.3 Hz, NCH2CH2), 1.35-1.31
(1H, m, NCH2CH2CH(CH2)2), 1.26-1.19 (2H, t, J ) 12.0 Hz).
Free base was converted into its HCl salt: mp 280-281 °C.
Anal. (C27H30N2F2‚2HCl‚0.25H2O) C, H, N.
O-Ben zh ydr ylh ydr oxylam in e (9). N-Benzhydryloxyphthal-
imide (8) (1.03 g, 3.14 mmol) was dissolved in EtOH (20 mL).
Hydrazine (0.3 mL, 9.37 mmol) was added into EtOH solution.
After the reaction mixture was stirred at room temperature
for 0.5 h, EtOH was removed in vacuo and EtOAc (60 mL)
was added into the mixture. The mixture was filtered. The
solution was collected and dried over Na2SO4. After the
evaporation of solvent, the crude product was purified by flash
chromatography (hexane/EtOAc ) 5/1) to give a viscous oil:
0.31 g (50% yield); 1H NMR (CDCl3) δ 7.34-7.26 (10H, m, Ar-
H), 5.65 (1H, s, Ph2CH).
1-[(4-F lu or op h en yl)m eth yl]-4-(h yd r oxym eth yl)p ip er i-
d in e (11). Dry THF (50 mL) was added dropwise into lithium
aluminum hydride (0.7 g, 19 mmol) under N2 in an ice bath.
1-[(4-Fluorophenyl)methyl]-4-(ethoxylcarbonyl)piperidine (10)
(1.21 g, 4.57 mmol) dissolved in dry THF (10 mL) was added
dropwise into the cooled LAH suspension solution. The reac-
tion mixture was refluxed for 2 h and was brought to room
temperature followed by cooling in an ice water bath. Satu-
rated NaOH/H2O (3 mL) was added dropwise into the cold
solution. The mixture was filtered. The solution was dried over
1
Na2SO4 and evaporated to produce 11: 0.98 g (98% yield); H
NMR (CDCl3) δ 7.36-7.26 (2H, m, Ar-H), 7.07-6.96 (2H, m,
Ar-H), 4.66 (1H, s, OH), 3.50-3.48 (2H, d, J ) 6.0 Hz, CH2-
OH), 3.46 (2H, s, F-PhCH2), 2.90-2.87 (2H, bd, J ) 11.1 Hz,
NCH2), 1.99-1.91 (2H, dt, J ) 1.8, 11.8 Hz, NCH2), 1.73-1.68
(3H, m), 1.34-1.22 (2H, m).
1-[(4-F lu or op h en yl)m et h yl]p ip er id in e-4-ca r b oxa ld e-
h yd e (12). A solution of oxalyl chloride (0.59 mL, 3.95 mmol)
in CH2Cl2 (20 mL) was cooled to -78 °C. DMSO (0.95 mL,
4-[[(Dip h en ylm eth yl)a m in oca r bon yl]m eth yl]-1-(p h en -
ylm eth yl)p ip er id in e (16b). 1-(Phenylmethyl)-4-[(ethoxycar-
bonyl)methyl]piperidine (15) (0.65 g, 2.51 mmol) was refluxed
in a CF3COOH/HCl/H2O (1:1:1) mixture to give the intermedi-

SAR of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 945
ate acid, which reacted with aminodiphenylmethane (0.18 g,
3.10 mmol), EDCI (0.58 g, 2.97 mmol), and HOBT (0.41 g, 3.04
mmol) to produce 16b: 0.74 g (72% yield) (procedure D); 1H
NMR (CDCl3) δ 7.35-7.19 (15H, m, Ar-H), 6.27-6.24 (1H, d,
J ) 7.8 Hz, 2PhCH), 6.01-5.98 (1H, d, J ) 7.1 Hz, NHCO),
3.48 (2H, s, PhCH2), 2.87-2.83 (2H, d, J ) 11.4 Hz, N(CH)2),
2.17-2.15 (2H, d, J ) 7.2 Hz, NCOCH2), 2.00-1.93 (2H, t, J
) 11.4 Hz, NCH2), 1.90-1.83 (1H, m, NCOCH2CH), 1.71-1.67
(2H, d, J ) 10.8 Hz), 1.36-1.23 (2H, m).
4-[2-((Dip h en ylm eth yl)a m in o)eth yl]-1-(p h en ylm eth yl)-
p ip er id in e (17b). Compound 16b (0.54 g, 1.31 mmol) was
reacted with 1 M BH3/THF (5.0 mL, 5 mmol) in THF (10 mL)
to produce 17b: 0.44 g (84% yield) (procedure E); 1H NMR
(CDCl3) δ 7.39-7.19 (15H, m, Ar-H), 4.79 (1H, s, Ph CH), 3.47
(2H, s, PhCH2), 2.86-2.82 (2H, d, J ) 11.1 Hz, NCH2), 2.59-
2.55 (2H, t, J ) 7.2 Hz, NCH2), 1.94-1.87 (2H, t, J ) 11.1 Hz,
NCH2), 1.61-1.58 (2H, m), 1.48-1.42 (2H, m), 1.34-1.20 (3H,
m). Free base was converted into its HCl salt: mp 172-174
°C. Anal. (C27H32N2‚2HCl‚1.06H2O) C, H, N.
P r oced u r e F : 4-[2-((Dip h en ylm eth yl)-N-m eth yla m i-
n o)eth yl]-1-(4-p h en ylm eth yl)p ip er id in e (18). A solution of
4-[(2-diphenylethyl)aminomethyl]-1-[(4-fluorophenyl)methyl]-
piperidine (1b) (0.23 g, 0.59 mmol), formaldehyde (1.0 g, 37%/
H2O) and formic acid (2.0 g, 88%/H2O) was refluxed for 3 h.
After the reaction solution was cooled to room temperature,
the solvent was removed in vacuo. The crude product was
purified by flash chromatography (EtOAc/hexane ) 1/2) to
give a white solid: 0.17 g (71% yield); 1H NMR (CDCl3) δ
7.40-7.16 (12H, m, Ar-H), 7.05-6.95 (2H, t, J ) 7.4 Hz, Ar-
H), 4.31 (1H, s, Ph2CHN), 3.41 (2H, s, p-FPhCH2N), 2.80-
2.76 (2H, d, J ) 11.8 Hz, NCH2), 2.36-2.30 (2H, t, J ) 7.5
Hz, NCH2), 2.11 (3H, s, NCH3), 1.91-1.83 (2H, t, J ) 11.4 Hz,
NCH2), 1.54-1.50 (2H, d, J ) 11.4 Hz), 1.47-1.40 (3H, m,
NCH2CH2CH), 1.32-1.10 (2H, m). Free base was converted
into its HCl salt: mp 260-261 °C. Anal. (C28H33N2F‚2HCl‚
0.50H2O) C, H, N.
4-[(2-Dip h en yleth yl)a m in oca r bon yl]-1-[(4-flu or op h en -
yl)m eth yl]p ip er id in e (20a ). 1-[(4-Fluorophenyl)methyl]-4-
(ethoxycarbonyl)piperidine (19a ) (0.68 g, 2.72 mmol) was
converted into carboxylic acid and was reacted with 2,2-
diphenylethylamine (0.67 g, 3.40 mmol), EDCI (0.76 g, 3.95
mmol), and HOBT (0.62 g, 4.59 mmol) to produce 20a : 0.84 g
(75% yield) (procedure D); 1H NMR (CDCl3) δ 7.36-7.20 (12H,
m, Ar-H), 7.01-6.95 (2H, m, Ar-H), 5.39 (1H, bs, NH), 4.21-
4.15 (1H, t, J ) 7.8 Hz, Ph2CH), 3.91-3.86 (2H, t, J ) 7.5 Hz,
CH2NH), 3.41 (2H, s, p-FPhCH2), 2.84-2.80 (2H, d, J ) 11.4
Hz, NCH2), 1.96-1.87 (3H, m, NHCOCH, NHCH2), 1.65-1.58
(4H, m).
4-[(Bis(4-flu or oph en yl)m eth ylam in o)m eth yl]-1-(2-ph en -
yleth yl)p ip er id in e (21b). Compound 20b (0.30 g, 0.71 mmol)
was reacted with 1 M BH3/THF (4 mL, 4 mmol) in THF (25
mL) to produce a white solid 21b: 0.28 g (96% yield) (procedure
1
E); H NMR (CDCl3) δ 7.35-7.18 (10H, m, Ar-H), 7.00-6.95
(3H, m, Ar-H), 4.74 (1H, s, (p-FPh)2CH), 3.02-2.99 (2H, d, J
) 10.8 Hz, NCH2), 2.83-2.78 (2H, m), 2.60-2.55 (2H, m),
2.45-2.43 (2H, d, J ) 6.2 Hz, NHCH2CH), 2.04-1.96 (2H, t,
J
) 11.4 Hz, NCH2), 1.78-1.26 (5H, m). Free base was
converted into its HCl salt: mp 214-215 °C. Anal. (C27H30F2N2‚
2HCl‚0.50H2O) Calcd: C, 64.58; H, 6.61; N, 5.57. Found: C,
64.61; H, 6.65; N, 5.43.
4-[(2-Dip h e n yle t h yl)-N -m e t h yla m in om e t h yl]-1-[(4-
flu or op h en yl)m eth yl]p ip er id in e (22). 4-[(2-Diphenylethyl)-
aminomethyl]-1-[(4-fluorophenyl)methyl]piperidine (21a ) (45
mg, 0.11 mmol) was refluxed in formaldehyde (1.0 g) and
formic acid (2.0 g, 37%/H2O) to produce 22: 44 mg (88% yield)
1
(procedure F); H NMR (CDCl3) δ 7.28-7.13 (12H, m, Ar-H),
7.02-6.96 (2H, t, J ) 8.4 Hz, Ar-H), 4.15-4.10 (1H, t, J ) 7.5
Hz, Ph2CH), 3.46 (2H, s, F-PhCH2), 2.91-2.88 (2H, d, J ) 7.5
Hz, Ph2CHCH2N), 2.81-2.77 (2H, d, J ) 11.1 Hz, NCH2), 2.20
(3H, s, CH3), 2.20-2.17 (2H, d, J ) 7.5 Hz, NCH2CH), 1.90-
1.83 (2H, t, J ) 11.4 Hz, NCH2), 1.52-1.47 (2H, d, J ) 12.9
Hz), 1.54-1.28 (1H, m, NCH2CH), 1.14-1.06 (2H, t, J ) 12.4
Hz). Free base was converted into its oxalate salt: mp 144-
145 °C. Anal. [C28H33N2F‚2(COOH)2‚1.47H2O]] C, H, N.
4-[[(1-P h en yleth yl)a m in oca r bon yl]m eth yl]-1-[(4-flu o-
r op h en yl)m eth yl]p ip er id in e (24). 1-[(4-Fluorophenyl)meth-
yl]-4-[(ethoxycarbonyl)methyl]piperidine (23) (0.55 g, 1.97
mmol) was refluxed in 10 mL of CF3CO2H/HCl/H2O (1:1:1) to
give acid which reacted with 1-phenylethylamine (0.29 g, 2.40
mmol), EDCI (0.56 g, 2.97 mmol) and HOBT (0.40 g, 2.96
mmol) in CH2Cl2 (10 mL) to produce 24 as a solid: 0.33 g (50%
yield) (procedure D); 1H NMR (CDCl3) δ 7.35-7.23 (7H, m,
Ar-H), 7.00-6.94 (2H, t, J ) 8.4 Hz, Ar-H), 5.83-5.80 (1H,
bd, J ) 7.5 Hz, NH), 5.15-5.10 (m, 1H, PhCHMe), 3.42 (s,
2H, p-PhCH2N), 2.83-2.78 (m, 2H, N(CH)2), 2.07-2.05 (2H,
d, J ) 7.2 Hz, CH2CO), 1.99-1.89 (2H, m), 1.86-1.78 (1H,
m), 1.71-1.61 (2H, t, J ) 15 Hz), 1.48-1.45 (3H, d, J ) 6.9
Hz, Me), 1.33-1.21 (2H, m).
4-[2-[(1-P h en yleth yl)a m in o]eth yl]-1-[(4-flu or op h en yl)-
m eth yl]p ip er id in e (25). Compound 24 (0.33 g, 0.93 mmol)
was reacted with 1 M BH3/THF (5.0 mL, 5 mmol) to produce
25 as a viscous oil: 0.23 g (95% yield) (procedure E); 1H NMR
(CDCl3) δ 7.34-7.21 (5H, m, Ar-H), 7.01-6.95 (2H, t, J ) 8.4
Hz, Ar-H), 4.09-4.07 (1H, d, J ) 6.0 Hz, NH), 3.77-3.71 (1H,
q, J ) 6.3 Hz, PhCHMe), 3.42 (2H, s, p-FPhCH2), 2.82-2.78
(2H, d, J ) 10.8 Hz, NCH2), 2.55-2.37 (2H, m, NCH2), 1.91-
1.83 (2H, t, J ) 11.4 Hz, NCH2), 1.59-1.53 (4H, m), 1.44-
1.38 (1H, m), 1.36-1.34 (3H, d, J ) 6.0 Hz, CH3), 1.25-1.14
(2H, m). Free base was converted into its oxalate salt: mp
172-173 °C. Anal. [C22H29FN2‚2(COOH)2] C, H, N.
4-[(2-Dip h en yleth yl)a m in om eth yl]-1-[(4-flu or op h en yl-
)m eth yl]p ip er id in e (21a ). Compound 20a (0.32 g, 1.3 mmol)
was reacted with 1 M BH3/THF (4.0 mL, 4 mmol) in THF (20
mL) to produce 21a : 0.25 g (81% yield) (procedure E); 1H NMR
(CDCl3) δ 7.32-7.19 (12H, m, Ar-H), 7.00-6.95 (2H, m, Ar-
H), 4.21-4.17 (1H, t, J ) 7.7 Hz, (Ph)2CH), 3.67 (1H, s, NH),
3.41 (2H, s, p-FPhCH2), 3.22-3.19 (2H, d, J ) 7.8 Hz, NHCH2-
CH(Ph)2), 2.83-2.79 (2H, bd, J ) 11.1 Hz, NCH2), 2.52-2.50
(2H, d, J ) 6.6 Hz, NHCH2CH), 1.91-1.84 (2H, t, J ) 11.1
Hz), 1.58-1.54 (2H, d, J ) 12 Hz), 1.45-1.39 (1H, m,
NHCH2CH), 1.21-1.14 (2H, t, J ) 12 Hz). Free base was
4-[2-(1-P h en yleth oxy)eth yl]-1-[(4-flu or op h en yl)m eth -
yl]p ip er id in e (27). Alcohol 26 (0.21 g, 0.82 mmol) was
dissolved in dry THF (10 mL). n-Bu4NI (0.33 g, 0.89 mmol)
and 60% NaH (0.20 g) were added. After the reaction mixture
was stirred for 3 h, 1-bromoethylbenzene (0.50 g, 2.70 mmol)
was added. The mixture was stirred at room temperature
overnight. The solvent was removed in vacuo and water (5 mL)
was added. The mixture was extracted with EtOAc. The
combined organic phase was dried over Na2SO4 and evaporated
to give crude product, which was purified by chromatography
(EtOAc/hexane ) 1/3) to give 27 as a viscous oil: 0.15 g (54%
yield); 1H NMR (CDCl3) δ 7.35-7.23 (7H, m, Ar-H), 7.01-6.95
(2H, t, J ) 8.4 Hz, Ar-H), 4.39-4.32 (1H, q, J ) 6.3 Hz,
PhCHMe), 3.42 (2H, s, p-FPhCH2N), 3.33-3.28 (2H, t, J )
6.2 Hz, OCH2), 2.84-2.80 (2H, m, NCH2), 1.95-1.84 (2H, dq,
J ) 2.1, 11.1 Hz, NCH2), 1.64-1.33 (5H, m), 1.43-1.41 (3H,
d, J ) 6.0 Hz, CH3), 1.28-1.13 (2H, m). Free base was
converted into its HCl salt: mp 126-127 °C. Anal. (C27H31
FN2O‚2HCl) C, H, N.
-
4-[(Bis(4-flu or op h en yl)eth yla m in o)ca r bon yl]-1-(p h en -
yleth yl)p ip er id in e (20b). 1-(Phenylethyl)-4-(ethoxycarbon-
yl)piperidine (19b) (0.25 g, 0.95 mmol) was converted into
carboxylic acid which was then reacted with bis(4-fluorophen-
yl)methylamine (0.25 g, 1.14 mmol), EDCI (0.25 g, 1.28 mmol),
HOBT (0.20 g, 1.48 mmol) in Et3N (1.5 mL) in CH2Cl2 (20 mL)
to produce 20b: 0.32 g (74% yield) (procedure E); 1H NMR
(CDCl3) δ 7.29-7.03 (10H, m, Ar-H), 7.05-6.99 (3H, m, Ar-
H), 6.22-6.20 (1H, d, J ) 7.8 Hz, p-FPh2CH), 6.00-5.97 (1H,
d, J ) 7.5 Hz, NH), 3.08-3.04 (2H, bd, J ) 11.4 Hz, NCH2),
2.83-2.78 (2H, d), 2.62-2.57 (2H, m), 2.25-2.15 (1H, m,
NCOCH), 2.10-2.03 (2H, t, J ) 11.4 Hz, NCH2), 1.96-1.81
(4H, m).
converted into its oxalate salt: mp 155-157 °C. Anal. [C22H28
FNO‚(COOH)2‚0.40H2O] C, H, N.
-
Tr a n sp or ter Bin d in g Assa ys. The affinity of test com-
pounds for the rat DAT, SERT, and NET was assessed by
inhibition of binding of [3H]WIN 35,428, [3H]citalopram, and

946 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6
Dutta et al.
[3H]nisoxetine, respectively. The general conditions for prepar-
ing membrane fractions from brain tissue and conducting the
binding assays were as described in our previous studies.35-37
Briefly, rat striatum was used for [3H]WIN 35,428 (5.5 nM)
binding assays and cerebral cortex for [3H]citalopram (4.5 nM)
and [3H]nisoxetine (1.1 nM) binding assays. The incubation
buffer for [3H]WIN 35,428 and [3H]citalopram assays was a
sodium phosphate buffer at a final [Na+] of 30 mM, pH 7.4 at
room temperature; for [3H]nisoxetine assays the same buffer
contained, additionally, 225 mM NaCl and 4.5 mM KCl. All
binding assays were conducted at 0-4 °C, for a period of 2 h
for [3H]WIN 35,428 and [3H]citalopram binding and for 3 h
for [3H]nisoxetine binding. The total volume of the binding
mixtures was 0.2 mL in all cases, and the average amount of
protein per assay was 75 µg for [3H]WIN 35,428 and [3H]-
citalopram measurements and 150 µg for [3H]nisoxetine
determinations. Nonspecific binding of [3H]WIN 35,428 and
[3H]citalopram binding was defined with 100 µM cocaine and
that of [3H]nisoxetine binding with 1 µM desipramine. Binding
never exceeded 10% of the totally available radioligand. Assays
were terminated by filtration with a MACH3-96 Tomtec
harvester (Wallac Inc., Gaithersburg, MD) through 0.05% (v/
v) polyethylenimine-presoaked glass fiber filtermats (Wallac
Inc.). Filters were assayed for radioactivity in a Microbeta Plus
liquid scintillation counter (Wallac Inc.).
Test compounds were dissolved in dimethyl sulfoxide (DMSO)
and diluted out in 10% (v/v) DMSO. Additions from the latter
stocks resulted in a final concentration of DMSO of 0.5%,
which by itself did not interfere with radioligand binding. At
least five triplicate concentrations of each test compound were
studied, spaced evenly around the IC50 value. The separation
between individual points on the inhibition curves represented
an approximately 3-fold difference in drug concentration. The
IC50 value was estimated by nonlinear computer curve fitting
to an equation for sigmoidal inhibition as described by us
previously.34
placed into the test chambers where their activity was then
measured for 60 min. A separate vehicle-control group was
tested during tests with each compound. During tests, total
distance traveled (cm) during the entire 60-min session was
recorded for each mouse. A one-factor (dose) analysis of
variance (ANOVA) was conducted for each drug and its vehicle
accompanied by Dunnett’s post-hoc tests when the initial
ANOVA results were statistically significant. Comparisons
between dosage groups were considered significant if P ) 0.05.
Dr u g Discr im in a tion . Su bjects: The subjects used in the
drug-discrimination studies were male adult Swiss-Webster
mice (Harlan Sprague Dawley, Inc., Indianapolis, IN). Mice
were individually housed in an AALAC-accredited animal
facility with a controlled temperature (22-24 °C) on a 12-h
light-dark cycle and provided continuous access to water
except when in the operant chambers. Mice were brought into
the laboratory and tested during the light cycle. The mice were
maintained on a restricted diet by post-session feeding of
rodent chow (Ralston-Purina, St. Louis, MO) in sufficient
amounts to maintain their body weights at 35 ( 5 g.
Ap p a r a tu s a n d p r oced u r e: Experimental sessions were
conducted in eight, light- and sound-attenuated operant
chambers equipped with two response levers separated by a
trough into which a 0.01-mL dipper cup could be presented
(Med Associates, Inc., St. Albans, VT; model ENV-307A). A
triple cue lamp was positioned above each lever, and a house
light was centered at the top of the front panel. Scheduling of
dipper presentations, illumination of lights, and recording of
lever presses were accomplished by a microcomputer system
operating MED-PC software (Med Associates, Inc., St. Albans,
VT; model SOF-700W). The drugs were administered ip in a
volume equivalent to 10 mL/kg prior to the start of drug-
discrimination sessions at the following times: cocaine, 10 min;
compound 21a , 20 min; all other compounds, 30 min. Solvents
used were as described for the locomotor activity studies.
DAT Up ta k e Assa ys. Measurement of uptake of [3H]DA
into rat striatal synaptosomes was based on our previously
reported procedures.45 Briefly, rat striatal P2 membrane frac-
tions were incubated with test drug for 8 min in uptake buffer
(for composition see ref 45) followed by the additional presence
of [3H]DA (4 nM radiolabeled plus 46 nM unradioactive DA)
for 4 min at 25 °C. The total volume was 0.4 mL, and
nonspecific uptake was defined with 100 µM cocaine. The
uptake assay was terminated by filtration through Watman
GF/C glass fiber filters with a 24-pin Brandel cell harvester
(Brandel Inc., Gaithersburg, MD), and filters were assayed for
radioactivity with a liquid scintillation counter (Beckman
model LS 6000IC). Construction of inhibition curves, dissolve-
ment of test compounds, and calculation of IC50 values were
as described above.
Locom otor Activity. Su bjects: Adult male Swiss-Webster
mice (Harlan Sprague Dawley, Inc., Indianapolis, IN) weighing
30-40 g were used. Mice were housed 5/cage and were
provided continuous access to water and food except when in
the activity chambers. All mice were drug-naive at the start
of the study and did not have prior experience with the test
chambers. The mice were housed in an AALAC-accredited
animal facility with a controlled temperature (22-24 °C) on a
12-h light-dark cycle, and all testing occurred during the light
component.
Subjects were initially trained to press one of the two levers
under an FR 1 schedule of reinforcement in which the dipper
cup filled with sweetened condensed milk (1 part granulated
table sugar, 1 part powdered skim milk, and 2 parts water by
volume) was presented following each lever press. The dipper
cup remained raised into the trough except during refilling
cycles. The response requirement was gradually increased to
FR 20. Subsequently, and only during the next few sessions,
the mice were reinforced for pressing the opposite lever until
they pressed reliably under FR 20 conditions. Drug-discrimi-
nation training then began during the daily (Monday-Friday)
15-min experimental sessions. Cocaine-trained mice were
injected with 10 mg/kg cocaine or saline ip 10 min prior to
session start. For each subject, one lever was designated
correct after training drug administration and the other as
correct after saline administration. The lever upon which the
mice initially acquired the lever press response was designated
the saline-correct lever. Lever pressing produced milk delivery
only on the injection-appropriate lever for that day; incorrect
presses reset the response requirement on the correct lever.
A pseudo-random sequence was used to determine which
injection was administered, with the restriction that the same
injection was not given on more than two consecutive sessions,
and during each of the 30 training session blocks the number
of saline and training drug injections was approximately equal.
Generalization testing began once a subject met the follow-
ing criteria: (1) the first completed fixed-ratio (FFR) occurred
on the lever designated correct on at least 8 of 10 consecutive
training sessions; and (2) at least 80% of the total responses
were made on the correct lever during those 8 sessions. After
these initial training conditions were met, tests could occur
on Tuesdays and Fridays provided that the subject completed
the FFR on the correct lever during the most recent training
drug and saline sessions; otherwise, a training session was
administered. Test days were identical to training days except
completions of the fixed ratio contingencies at either lever
resulted in milk delivery. Dose-response curves were collected
first with cocaine (0.3-30 mg/kg) followed by the test com-
Ap p a r a tu s a n d p r oced u r e: Four, commercially obtained,
automated activity monitoring devices each enclosed in sound-
and light-attenuating enclosures were used (AccuScan Instru-
ments, Inc., Columbus, OH). The interior of each activity
device was divided permitting the independent and simulta-
neous recording of two mice.46 The solvents for the drugs were
as follows: cocaine, GBR 12909, and compound 1b: 0.05%
sterile saline; compound 1a : Alkamuls EL-620 (Rhone-Pou-
lenc, North American Chemicals, Cranbury, NJ ):water in 1:6
ratio; compound 17b: Alkamuls EL-620:ethanol:water in 1:1:
18 ratio; compound 21a : sterile water. All drugs were admin-
istered ip in a volume equivalent to 10 mL/kg. The mice were
injected ip with either vehicle or test compound and then

SAR of 4-[2-(Diphenylmethoxy)ethyl]-1-benzylpiperidines
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 947
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