SAR studies of piperidine-based analogues of cocaine. 4. Effect of N-modification and ester replacement

Article abstract of DOI:10.1021/jm0200153

A series of novel N- and 3α-modified piperidine-based analogues of cocaine were synthesized and tested for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE transporters. N-Demethylation of trans-(+)-3α-piperidine-based ligands leads to improved activity at the SERT and NET and modest changes at the DAT. Replacement of the N-methyl group in trans-(+)-ester 1a with phenylalkyl groups leads to a modest 2.3-fold improvement in activity at the SERT (K_i ≤ 3.27 μM), insignificant changes at the NET, and a 3.5-fold loss in activity at the DAT (K_i ≥ 810 nM); however, such replacement in cis-(-)-ester 4, the more potent isomer of 1a, leads, in general, to a significant decrease in activity at all monoamine transporters (K_i > 1 μM). Other N-modified ligands, including the ligands with polar groups incorporated in the N-alkyl substituent (3e-g) and ligands lacking the basic nitrogen (3i and 6d), show decreased activity at all monoamine transporters, though ligands 3e-g are similar in potency at the NET to 1a. N-Norester 2a, a possible metabolite of the lead compound 1a, and alcohol 1c, a compound with a 3α-substituent that is more stable to metabolism than 1a, were selected for further behavioral tests in animals. Alcohol 1c and ester 2a are similar in potency at the DAT to cocaine, ester 1a, and oxadiazole 1b, and both fully substitute for cocaine and have potency similar to that of cocaine in drug discrimination tests. Like cocaine, 1c increased locomotor activity (LMA) monotonically with time, whereas 2a produces biphasic effects consisting of initial locomotor depression followed by delayed locomotor stimulation. An interesting difference between cocaine, ester 1a, alcohol 1c, and N-norester 2a is that 1c and 2a are significantly longer acting in LMA tests. Although this result was anticipated for alcohol 1c, it is rather surprising for 2a which has an ester function susceptible to hydrolysis, a pathway of in vivo deactivation of cocaine and its ester analogues. The present results may have important implications for our understanding of the pharmacological mechanisms underlying the behavioral actions of cocaine and of the structural features needed for the design of the new leads in the discovery of a cocaine abuse medication.

Full text of DOI:10.1021/jm0200153

© Copyright 2002 by the American Chemical Society
Volume 45, Number 15
J uly 18, 2002
Articles
SAR Stu d ies of P ip er id in e-Ba sed An a logu es of Coca in e. 4. Effect of
N-Mod ifica tion a n d Ester Rep la cem en t
Pavel A. Petukhov,† J ianrong Zhang,† Alan P. Kozikowski,*,† Cheng Z. Wang,‡ Yan Ping Ye,‡
Kenneth M. J ohnson,‡ and Srihari R. Tella§
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road, N.W.,
Washington, D.C. 20007, Department of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, Texas 77555-1031, and Department of Pharmacology, Georgetown University Medical Center,
3900 Reservoir Road, N.W., Washington, D.C. 20007
Received J anuary 9, 2002
A series of novel N- and 3R-modified piperidine-based analogues of cocaine were synthesized
and tested for their ability to inhibit reuptake of DA, 5-HT, and NE by the DA, 5-HT, and NE
transporters. N-Demethylation of trans-(+)-3R-piperidine-based ligands leads to improved
activity at the SERT and NET and modest changes at the DAT. Replacement of the N-methyl
group in trans-(+)-ester 1a with phenylalkyl groups leads to a modest 2.3-fold improvement
in activity at the SERT (Ki e 3.27 µM), insignificant changes at the NET, and a 3.5-fold loss
in activity at the DAT (Ki g 810 nM); however, such replacement in cis-(-)-ester 4, the more
potent isomer of 1a , leads, in general, to a significant decrease in activity at all monoamine
transporters (Ki > 1 µM). Other N-modified ligands, including the ligands with polar groups
incorporated in the N-alkyl substituent (3e-g) and ligands lacking the basic nitrogen (3i and
6d ), show decreased activity at all monoamine transporters, though ligands 3e-g are similar
in potency at the NET to 1a . N-Norester 2a , a possible metabolite of the lead compound 1a ,
and alcohol 1c, a compound with a 3R-substituent that is more stable to metabolism than 1a ,
were selected for further behavioral tests in animals. Alcohol 1c and ester 2a are similar in
potency at the DAT to cocaine, ester 1a , and oxadiazole 1b, and both fully substitute for cocaine
and have potency similar to that of cocaine in drug discrimination tests. Like cocaine, 1c
increased locomotor activity (LMA) monotonically with time, whereas 2a produces biphasic
effects consisting of initial locomotor depression followed by delayed locomotor stimulation.
An interesting difference between cocaine, ester 1a , alcohol 1c, and N-norester 2a is that 1c
and 2a are significantly longer acting in LMA tests. Although this result was anticipated for
alcohol 1c, it is rather surprising for 2a which has an ester function susceptible to hydrolysis,
a pathway of in vivo deactivation of cocaine and its ester analogues. The present results may
have important implications for our understanding of the pharmacological mechanisms
underlying the behavioral actions of cocaine and of the structural features needed for the design
of the new leads in the discovery of a cocaine abuse medication.
In tr od u ction
initiating and maintaining abstinence and in preventing
relapse is urgently needed. The complexity of the
mechanisms mediating the addictive properties of co-
Cocaine is a widely abused drug. The development of
pharmacotherapies that could assist the patient in
* To whom correspondence should be addressed. Phone: 202-687-
0686. Fax: 202-687-5065. E-mail: kozikowa@georgetown.edu.
† Department of Neurology, Georgetown University Medical Center.
‡ University of Texas Medical Branch.
§ Department of Pharmacology, Georgetown University Medical
Center.
10.1021/jm0200153 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/17/2002

3162 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15
Petukhov et al.
Ch a r t 1. Cocaine and Its Synethetic Analogues
F igu r e 1. Schematic representation of the key interactions
between monoamine reuptake inhibitors and the binding site
of the monoamine transporters.
caine is such that it is difficult to define appropriate
targets for medication development. Nevertheless, the
predominant model for the origin of the reinforcing and
rewarding properties of cocaine is the blockade of the
dopamine transporter (DAT); most of the drugs gener-
ated to date have targeted either the DA receptors or
DA transporters.1-3 Although the importance of the
interaction of cocaine with the dopaminergic system
(“DA hypothesis”) is strongly supported by experimental
data, cocaine’s effect on the serotonergic system has also
been implicated in the cocaine-seeking behavior ob-
served in rats4-6 and monkeys.7,8 Recent studies of
DAT+SERT knockout mice have shown that the SERT
plays an important role in mediating the behavioral
actions of cocaine,9 although interaction with mGlu5
receptor may be involved as well.10 The DAT, SERT, and
NET are also targets for PCP, amphetamines, and other
drugs of abuse. Thus, investigation of compounds with
various combinations of DAT, SERT, and NET activity
might lead to the development of medications or strate-
gies for the treatment of drug abuse and addiction.
The rational design of ligands with a predetermined
potency at and selectivity for the DA, 5-HT, and NE
transporters is hindered by the lack of knowledge about
their 3D structure.11,12 Most of the potent tropane-based
DAT, SERT, and NET inhibitors, including cocaine, are
believed to have at least three major interactions with
the transporter binding site: one ionic or H-bonding
interaction of the basic nitrogen, one dipole-dipole or
H-bonding interaction of the ester group of the ligand,
and an interaction of the aryl group of the ligand with
a lipophilic binding pocket (Figure 1).13-15 This model
has been successfully used for the design of new
ligands,15,16 though for each particular class of ligands
certain additional requirements may be present.17 Al-
though this pharmacophore model was widely recog-
nized, it was shown later for the case of tropane-based
compounds that neither the basic nitrogen18-20 nor the
ester group, or indeed any polar group,21 is needed for
high-affinity binding and inhibition of reuptake of
monoamines. Therefore, further studies are needed to
clarify and rationalize the differences and similarities
in the properties and structure of monoamine trans-
porters and their inhibitors.
tial medications for cocaine abuse. As previously re-
ported, N-demethylation leads to increased activity of
tropane-based14,26-28 and indanamine-based25 ligands at
the SERT and NET (Chart 1). In the case of tropane-
based29 and indanamine-based ligands,25 large N-alkyl
groups were found to cause reduced activity at the DAT,
SERT, and NET, although, interestingly, N-bromo-
propyl-, chloropropyl-, fluoropropyl-, and N-fluoroethyl-
tropane-based ligands have been found to have a greater
affinity for the SERT and a lower affinity for the DAT
and NET than the corresponding N-methylated ligands.
Therefore, manipulation of the nature of the N-sub-
stituent seems to be a reasonable approach for the
design of new monoamine blockers.
The above considerations led us to the design and
synthesis of novel piperidine-based analogues of cocaine
that, while remaining potent DAT and NET inhibitors,
also exhibit increased activity at the SERT. Recently,
the synthesis, pharmacology, and LMA studies of some
3,4-disubstituted piperidine-based ligands and novel
bivalent compounds based on these ligands have been
reported from our laboratory.30-32 Most of these com-
pounds represent a series of potent DA and NE reuptake
inhibitors with Ki values in the nanomolar range that
are less potent inhibitors of the SERT. The results of
different animal behavioral tests strongly suggest that
ester 1a , a modestly DAT/NET selective compound,
could be used during the treatment of cocaine addiction
to prevent relapse.33 Other piperidine-based ligands
have also been found to attenuate the behavioral effects
of cocaine.32 Therefore, ester 1a was used as the lead
compound.
Although the in vivo metabolism of lead compound
1a is also likely to involve N-demethylation, metabolism
of 1a to the corresponding acid, a compound that is
inactive at all monoamine transporters, through es-
terase action probably will be the dominant pathway
in vivo.34 We reasoned that metabolism via esterase
action could be avoided by replacement of the ester
group with a bioisosteric group that is more stable to
metabolic degradation. In fact, in our previous studies
we found that oxadiazole 1b, although completely
cocaine-like, exhibits a significantly longer duration of
action,17b probably because of its slower rate of metabo-
lism. Therefore, exploration of the effect of N-alkylation
and ester replacement on biogenic amine transport in
vitro and, for certain selected compounds, on in vivo
behavior appears to be a reasonable approach to im-
proving our lead compound.
It is widely recognized that the pharmacodynamics
of a drug of abuse and the abuse potential of a drug are
closely related.22 The development of LAAM, a slow
onset-of-action drug for treating heroin addiction which
is metabolized in vivo to a more active N-demethylated
compound, is an excellent example of how N-demethy-
lation could be used for drug development.23,24 A similar
approach has been used for the development of cocaine
analogues possessing a slow onset of action25 as poten-

Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3163
Sch em e 1a
a
(a) R-chloroethyl chloroformate, proton sponge; (b) MeOH, reflux; (c) RBr; (d) LiAlH4, THF; (e) 4-hydroxybenzaldehyde; (f) NaBH3CN,
KOH, MeOH; (g) CH3COCl, NEt3, CH2Cl2; (h) PhSO2Cl, NEt3, CH2Cl2.
Herein, we describe the synthesis of novel N- and 3R-
modified piperidine-based analogues of cocaine, and we
also report the results of preliminary behavioral studies
of 1c and 2a .
tocols described earlier.16,31 The results of reuptake
assays for the monoamine transporters and selectivity
ratios derived from the Ki values are shown in Table 1.
To explore the behavioral consequences of function-
alization of lead compound 1a , we examined compounds
1c and 2a in the LMA test in mice and in a drug
discrimination paradigm in rats. Locomotor activity of
male Swiss-Webster mice was recorded using a Truscan
activity monitor (Coulbourn Instruments, Allentown,
PA) and a computer, according to a procedure described
elsewhere.16 Following 1 h of habituation to test arenas,
several groups of mice were injected intraperitoneally
(ip) with different doses of cocaine, test drugs, or
appropriate vehicles in a volume of 10 mL/kg. Locomotor
activity was measured in 10 min bins for 2 h. The raw
data were converted to 30 min totals, which are pre-
sented as a function of dose and time in Figure 3.
The drug discrimination study was conducted using
Sprague-Dawley rats according to the procedure de-
scribed earlier.16 Rats were trained to discriminate
cocaine (10 mg/kg, ip) from saline. All drugs were
administered intraperitoneally. Cocaine and 2a were
administered 10 min prior to the testing. The LMA tests
revealed delayed peak locomotor responses to 1c occur-
ring about 90 min after its injection. Therefore, 1c was
given 90 min prior to the drug discrimination testing
so as to coincide with the time of its peak effect. The
response rate on both keys and the percent of cocaine
lever-appropriate responding were calculated for each
rat. The response rates following the test drug injections
were presented as the percent of its corresponding
vehicle control response rates. The results are provided
in Figure 4.
Ch em istr y
The synthesis of N- and 3R-modified compounds is
outlined in Scheme 1. Trans-(+)-ester 1a and cis-(-)-
ester 4 were used as the starting materials. The reaction
of ester 1a with R-chloroethyl chloroformate in the
presence of 1,8-bis(dimethylamino)naphthalene and re-
flux of the resulting intermediate in methanol gave the
N-demethylated ester 2a .35 This N-demethylation pro-
cedure was found to be compatible with the oxadiazole
moiety, and oxadiazole 2b was synthesized from oxa-
diazole 1b using the same procedure as described for
ester 1a . Alcohols 1c and 2c were synthesized by
reduction of esters 1a and 2a with lithium aluminum
hydride. N-Norester 2a was further alkylated by various
alkyl bromides in the presence of potassium carbonate
using DMF as a solvent to give the corresponding
N-substituted esters 3a -g (Scheme 1 and Table 1). The
same conditions as above were used to synthesize cis-
3,4-disubstituted ligands 6a -c from ester 4. Amides 3i
and 6d were obtained from N-noresters 2a and 5,
respectively, and the corresponding acid chlorides.
Because of the insufficient solubility of the N-benzyl
compound 3b for pharmacological tests, we decided to
synthesize the more soluble analogue 3h . Reductive
alkylation of the N-norester 2a with 4-hydroxybenzal-
dehyde and sodium cyanoborohydride gave the N-(4-
hydroxybenzyl)piperidine ester 3h in good yield.
P h a r m a cologica l a n d Biologica l Eva lu a tion
Resu lts a n d Discu ssion
Compounds 2a -c, 3a , 3c-i, and 6a -d were tested
for their ability to inhibit high-affinity uptake of [3H]-
DA, [3H]5-HT, and [3H]NE using rat nerve endings
(synaptosomes) obtained from brain regions enriched in
DAT, SERT, and NET, respectively, according to pro-
In general, relative to the corresponding N-methyl
compounds (1a -c), the N-norpiperidines 2a -c exhib-
ited an increased activity at the SERT and NET and
only modest changes at the DAT. N-Norester 2a is 20-

3164 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15
Petukhov et al.
Ta ble 1. Ki’s for the Inhibition of Reuptake of Monoamines, and Ratios of Ki’s for N-modified Piperidine-based Ligands 1a -c, 2a -c,
3a ,c-i, 4, 6a -d , and Cocaine
a
Ki ( SE, nM
[3H]DA
uptake
[3H]5-HT
uptake
[3H]NE
uptake
ratio of Ki’s
compd
R
X
5-HT/DA NE/DA NE/5-HT
cocaineb
(+)-1a b
(+)-1bb
-
-
259 ( 20
233 ( 62
187 ( 3
155 ( 1
108 ( 4
0.60
36.4
31.8
0.42
1.08
1.37
0.70
0.03
0.04
CH3
CH3
COOCH3
8490 ( 1430
5960 ( 80
252 ( 43
256 ( 17
3-methyl-1,2,4-
oxadiazol-5-yl
CH2OH
(+)-1c
(+)-2a
(+)-2b
CH3
H
H
497 ( 58
279 ( 98
189 ( 24
1550 ( 360
434 ( 50
373 ( 4
198 ( 53
7.9 ( 3.0
34 ( 6
3.12
1.56
1.97
0.40
0.03
0.18
0.13
0.02
0.09
COOCH3
3-methyl-1,2,4-
oxadiazol-5-yl
CH2OH
(+)-2c
(+)-3a
(+)-3bc
(+)-3c
(+)-3d
(+)-3e
(+)-3f
(+)-3g
(+)-3h
(+)-3i
(-)-4d
(-)-6a
(-)-6b
(-)-6c
(-)-6d
H
836 ( 35
6980 ( 130
-
1080 ( 30
810 ( 78
4280 ( 220 >10000
3150 ( 420 >10000
>10000
1620 ( 30
>10000
69 ( 8
3280 ( 50
1020 ( 150
4290 ( 120
19500
239 ( 28
3740 ( 600
-
2890 ( 80
3270 ( 160
69 ( 6
1840 ( 260
-
0.29
0.54
-
2.68
4.04
0.08
0.26
-
0.13
0.60
0.08
0.14
<0.21
0.67
-
1.28
0.91
0.23
1.01
0.83
0.29
0.49
-
0.05
0.15
<0.03
<0.04
<0.21
0.41
-
0.23
1.36
0.12
1.61
0.45
isopropyl
PhCH2
COOCH3
COOCH3
PhCH2CH2
COOCH3
142 ( 22
488 ( 30
335 ( 74
441 ( 86
2100 ( 650
1080 ( 60
PhCH2CH2CH2
CH2CH2CH2F
CH2CH2CH2Cl
COOCH3
COOCH3
>2.3
COOCH3
>3.17
-
CH2CH2COOCH2CH3 COOCH3
p-HOPhCH2
CH3CO
CH3
PhCH2
PhCH2CH2
Ph2CHCH2CH2
PhSO2
>10000
2650 ( 150
>10000
391 ( 27
2190 ( 50
1880 ( 160
2690 ( 40
36100
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
1.64
-
>10000
88 ( 3
2980 ( 120
233 ( 30
4340 ( 230
16100
5.67
0.67
1.84
0.63
1.85
a
b
Data are mean ( standard error of at least three experiments as described in ref 31. Data taken from ref 17b. c Insoluble, not
d
tested. Data taken from ref 31.
compared to that of the lead compound 1a . The N-
isopropyl ligand 3a and the N-phenylalkyl ligands
3c,d ,h are 2.3-3.2-fold more active at the SERT than
the parent N-methyl compound 1a , while they are 3.5-
29.9-fold less potent at the DAT than 1a . A loss of
activity at the DAT and the SERT was observed for the
N-modified esters 3e,f with polar groups incorporated
F igu r e 2. (A) Overlay of cis-(-)-piperidine 4 in blue on
tropane-based compound RTI-55 in red; (B) overlay of trans-
into the N-substituents, which gave rise to especially
high activity at the SERT and low activity at the DAT
and NET in the case of the corresponding tropane-based
ligands. To explore the importance of equatorial (trans-
series) versus axial (cis-series) orientation of the ester
group, the cis-(-)-piperidine-based ligands 6a -d were
also synthesized. Even though ligands from the cis-
piperidine series mimic the structure of cocaine more
precisely and are usually more potent than ligands from
the trans-piperidine series,31 compounds 6a -c show
lower activity at all monoamine transporters than the
N-methyl ester 4. Moreover, phenylalkyl-substituted
ligands 6a -c from the cis-(-)-series are almost equally
inactive at the DAT and SERT as the phenylalkyl-
substituted ligands 3c,d from the trans-(+)-series.
Interestingly, N-phenylpropyl and N-phenylpentyltro-
pane-based compounds were significantly more potent
for the DAT and the SERT compared to the correspond-
ing N-methyl ligand WIN35428, whereas N-benzyltro-
pane-based ligands were less potent at these transport-
ers.14
(+)-piperidine 1a in green on tropane-based compound RTI-
55 in red; (C) overlay of trans-(+)-piperidine 1a in green on
trans-N,N-dimethyl[3-(3′,4′-dichlorophenyl)indan-1-yl]amine in
magenta. The lowest-energy conformations of the ligands were
minimized using the “Tripos” force field and were overlaid on
each other using the “Fit atoms” menu in SYBYL (Tripos, Inc).
and 32-fold more active, oxadiazole 2b is 16.0- and 7.5-
fold more active, and alcohol 2c is 6.5- and 2.9-fold more
active in blocking the reuptake at the SERT and NET,
respectively, than the corresponding N-methyl ligands
1a -c. The activity at the DAT of N-norester 2a is not
different from the activity of the N-methyl ester 1a . The
DAT activity of oxadiazole 2b is almost unchanged,
whereas the activity of alcohol 2c is 1.7-fold lower than
the activity of 1c. The increase of activity at the SERT
and NET is in agreement with the previously reported
increase of activity at the SERT and NET of N-
demethylated tropane-based26,27 and indanamine-based
ligands.25 Therefore, these results suggest that N-
demethylation could provide a rather universal tool for
increasing the blocking ability at the SERT and NET,
irrespective of the other functional groups of the ligands.
In general, the monoamine-blocking ability of most
of the N-alkyl compounds in the trans-series of piperi-
dine-based ligands without a polar group incorporated
into the N-substituent is lower at the DAT and higher
at the SERT, with insignificant changes at the NET,
The difference between the NET-blocking activity of
ligands trans-(+)-3c-f and cis-(-)-6b and the corre-
sponding N-methyl ligands trans-(+)-1a and cis-(-)-4
is insignificant. Interestingly, trans-(+)-ligands 3a , 3g,
and 3h were 7.3-, 8.3-, and 4.3-fold less active than
N-methyl ligand 1a , respectively, whereas cis-(-)-

Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3165
F igu r e 3. Locomotor effect of cocaine (A, B), 1c (C, D), and 2a (E, F) as a function of dose and time during 120-min sessions in
male Swiss-Webster mice. *P < 0.05 and **P < 0.01 as compared to the corresponding saline control responses.
piperidine ring, because 3a , 3h , and 6a show Ki values
greater than 1.0 µM at the NET. In contrast, the activity
at the NET of tropane-based and indanamine-based
ligands is very sensitive to the overall size of the
N-substituent.14,25,26,28,29
Ligands 3i and 6d , with an amido nitrogen instead
of a basic amino nitrogen, were found to be very weak
blockers with Ki values greater than 10 µM at all
monoamine transporters. This suggests that for piperi-
dine-based ligands protonation of the basic nitrogen may
be required for the effective blockade of the monoamines
at the DAT, SERT, and NET, although for tropane-
based ligands the presence of the basic nitrogen is not
essential for high activity.18-20
On the basis of the models shown in Figure 2, the
dissimilarity in the SAR pattern of the N-modified
piperidine-based and indanamine-based compounds
could be a result of their different, poorly superimposing
scaffolds (Figure 2C). It is, however, quite surprising
that the perfectly superimposing N-modified cis-(-)-
piperidine-based and tropane-based compounds (Figure
2A) also display a nonmatching SAR pattern. The trans
orientation of the ester group (Figure 2B) may be
responsible for a different SAR pattern in the case of
the N-modified trans-(+)-piperidine-based compounds.
An increased flexibility of the piperidine-based ligands
compared to the flexibility of the indanamine-based and
tropane-based ligands may also be a reason the SAR
patterns of these compounds are different.
F igu r e 4. Discriminative stimulus effects of cocaine, 1c, and
2a in Sprague-Dawley rats trained to discriminate cocaine (10
mg/kg) from saline.
Despite the fact that alcohol 1c has only one electron
donor atom in its 3R-substituent, it exhibits reuptake-
blocking properties comparable to those of ester 1a and
oxadiazole 1b, compounds with two and three electron
donor atoms, respectively. Moreover, alcohol 1c shows
even 5.5-fold higher activity at the SERT (Ki ) 1550
nM) than the lead compound 1a , while alcohol 1c is 2.1-
fold less active at the DAT and 1.3-fold more active at
the NET. The fact that N-noralcohol 2c also exhibits a
ligands 6a and 6c were 33.9- and 49.3-fold less active
than N-methyl ligand 4, respectively. Thus, the NET is
much less tolerant to N-substitution in the cis-(-)-series
than in the trans-(+)-series of ligands. Moreover, it
appears that the NET is more tolerant to the overall
size of the N-substituent, especially if it contains an aryl
or polar group, although it might be more sensitive to
the bulk of the N-substituent in close proximity to the

3166 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15
Petukhov et al.
Ta ble 2. Effect of the Presence of Functional Groups on the Pharmacological Profiles and Behavioral Effects of 1a -c and 2a in LMA
and Drug Discrimination Tests
drug
functional groups
pharm.
profile selectivity
locomotor test,
cocaine-like
discrimination test,
cocaine-like
prolonged
actionb
compd
N-Ra
Xa
1a c
1be
1c
N-CH3
N-CH3
N-CH3
N-H
COOCH3
oxadiazolyl
CH2OH
DAT+NET
DAT+NET
DAT+NET
NET
reduced
yes
yes
yes
yes
yes
nod
yes
yes
yesf
yes
2a
COOCH3
yesf,g
a
b
d
For definition of N-R and X see general structure 3. Prolonged action when compared to ester 1a . c Data taken from ref 33. When
compared to cocaine. e Data taken from ref 17b. f At 10 and 30 mg/kg. Significant depressant action at 30 and 60 min.
g
3-fold decrease in DAT activity, a 1.8-fold increase in
SERT activity, and an 8.7-fold decrease in NET activity
compared to N-norester 2a indicates that the presence
of an ester or oxadiazole group as the 3R-substituent is
important for blocking reuptake at the DAT, whereas
the presence of an alcohol group favors inhibition of
reuptake at the SERT.
To determine how the behavioral pharmacology of 1c
and 2a differs from that of cocaine, lead compound 1a ,
and oxadiazole 1b, we have used LMA tests in mice and
drug discrimination tests in rats. The small structural
modifications in the lead molecule, ester 1a , resulted
in intriguing behavioral properties that are summarized
in Table 2. The behavioral effects of lead compound 1a
and oxadiazole 1b were studied earlier,17b,33 and it has
been shown that ester 1a and oxadiazole 1b are
completely cocaine-like in LMA and drug discrimination
tests when tested alone, though 1a has lower efficacy
than cocaine in increasing LMA.
Cocaine (5.6-30 mg/kg) produced rapid and dose-
dependent enhancements in the distance traveled (F4,58
) 20.44, P < 0.001) and stereotypic movements (F4,58
) 5.1, P ) 0.001) in mice (panels A and B of Figure 3).
The duration of locomotor effects of cocaine lasted about
2 h at the maximal dose (30 mg/kg) tested. A two-way
analysis revealed significant effects for cocaine-induced
changes in the distance traveled (F(dose)1,61 ) 55.4, P
< 0.001; F(time)3,183 ) 0.5, P ) 0.68; F(dose × time)3,183
) 34.2, P < 0.001) and in the stereotypic movements
(F(dose)1,61 ) 28.3, P < 0.001; F(time)3,183 ) 17.1, P <
0.001; F(dose × time)3,183 ) 4.6, P < 0.01). Although 1c
is almost 2-fold less potent at the DAT than cocaine,
the parent compound 1a , and oxadiazole 1b, it produced
significant and dose-dependent enhancements in the
distance traveled (F5,72 ) 7.7, P < 0.001) and stereotypic
movements (F5,72 ) 31.6, P < 0.001) (panels C and D of
Figure 3). A two-way analysis revealed significant
effects for 1c-induced changes in distance traveled
(F(dose)5,72 ) 9.98, P < 0.001; F(time)3,216 ) 3.64, P )
0.014; F(dose × time)15,216 ) 5.89, P < 0.001) and
stereotypic movements (F(dose)5,72 ) 52.1, P < 0.001;
Figure 3). A two-way analysis revealed significant
changes in the distance traveled (F(dose)1,45 ) 0.441, P
< 0.51; F(time)3,135 ) 37.32, P < 0.001; F(dose ×
time)3,135 ) 23.18, P < 0.001) and in the stereotypic
movements (F(dose)1,45 ) 9.3, P < 0.01; F(time)3,135
)
60.8, P < 0.001; F(dose × time)3,135 ) 54.4, P < 0.001).
There were initial and significant reductions in both
distance traveled and stereotypic movements compared
to the vehicle control responses 30 and 60 min following
10 and 30 mg/kg doses. Following these initial reduc-
tions, there were significant delayed enhancements in
the distance traveled and stereotypic movements 90 and
120 min after the administration of 10 and 30 mg/kg
doses of 2a . Doses of 2a greater than 30 mg/kg produced
convulsions (locomotor data are not shown for high
doses).
Cocaine produced dose-dependent (1.56-10 mg/kg)
and full substitution for cocaine in cocaine-trained
animals in a drug discrimination test (Figure 4). Despite
some differences in the locomotor effects of 2a and 1c,
these compounds completely substituted for cocaine in
the drug discrimination test. The doses (95% confidence
limits) of cocaine, 2a , and 1c that produced 50% (ED50)
cocaine-appropriate lever responding were 3.48 (2.47-
4.65), 3.55 (2.85-4.77), and 2.42 (1.65-3.11) mg/kg,
respectively. There were no significant differences in the
rates of responding following cocaine injection (F5,60
)
0.46, P ) 0.83) and 2a (F5,30 ) 0.45, P ) 0.8). However,
both 2a (10 mg/kg) and 1c (30 mg/kg) at high doses
produced either partial (failure to complete all 20 trials
of the session) or complete suppression of the responding
in 3 out of 10 and 4 out of 12 animals, respectively.
Analysis of the data after the exclusion of the above
missing data points confirmed that neither 2a (F5,30
0.45, P ) 0.8) nor 1c (F5,35 ) 1.5, P ) 0.2) had any
significant effects on the rates of responding.
)
An interesting difference between cocaine, ester 1a ,
alcohol 1c, and N-norester 2a is that the latter two
compounds are substantially longer acting than cocaine
in LMA tests (Figure 3). Although prolonged action is
anticipated from compounds lacking the 3R-ester group,
such as alcohol 1c and oxadiazole 1b, this is a surprising
and intriguing fact for N-norester 2a , because the 3R-
ester group 2a should be equally susceptible to hydroly-
sis as the ester group of cocaine and 1a . Another
interesting result of N-demethylation is the initial
depressant action of 2a followed by delayed locomotor
stimulation (panels E and F of Figure 3). We hypoth-
esize that 2a may initially act on an unidentified
pharmacological target that counteracts the LMA pro-
duced by 2a . The initial depression may be a result of
the different population of DA, 5-HT, and NE receptors
by corresponding monoamines due to the decreased ratio
F(time)3,216 ) 12.76, P < 0.001; F(dose × time)15,216
)
20.84, P ) 0.001). However, the locomotor effects of 1c
were relatively prolonged compared to cocaine and
lasted at least 2 h following 30-56 mg/kg doses of 1c.
This may be due to its slower metabolism relative to
cocaine, as 1c lacks an ester group and, thus, will not
be subjected to rapid hydrolysis in vivo. The onset of
action for 1c was relatively slower as compared to
cocaine, especially on stereotypic movements, which
peaked about 90 min after the injection.
In contrast to cocaine and alcohol 1c, N-norester 2a
produced biphasic effects on LMA (panels E and F of

Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3167
were visualized with UV light or an ammonium molybdate/
H2SO4 solution. Ester 3h was synthesized according to a
procedure published in ref 41. The synthesis of esters 1a and
4 is described in ref 30.
of Ki values of 5-HT to DA (36.4, 31.8, 3.12, and 1.56
for 1a , 1b, 1c, and 2a , respectively) and/or the decreased
ratio of Ki values of NE to DA (1.08, 1.37, 0.4, and 0.03,
respectively), though in that case it is not clear what
causes the delayed locomotor stimulation. This hypoth-
esis is supported by the fact that norcocaine, which is,
like 2a , more active at the SERT and NET than cocaine,
produced locomotor inhibition when injected intraperi-
toneally.36 However, we cannot exclude a direct action
of 2a on other pharmacological systems, such as sodium
channels36 or GABA37-40 receptors, that have been
reported to selectively reduce LMA while leaving intact
discriminative stimulus effects. Thus, further investiga-
tion of the pharmacological activity of these compounds
is clearly warranted.
Gen er a l P r oced u r e A: N-Dem eth yla tion . To a solution
of N-methylated compound (3.73 mmol) in CH2Cl2 (50 mL)
were added 1,8-bisdimethylaminonaphthalene (0.44 g, 2.1
mmol, 0.55 equiv) and R-chloroethyl chloroformate (4.16 g, 29.1
mmol, 3.14 mL, 7.8 eq). The resulting solution was heated at
reflux for 1.5 h. After the mixture had cooled to room
temperature, 1 M anhydrous hydrogen chloride solution in
ether (200 mL) was added; the suspension was filtered though
a silica gel plug, and the residue was rinsed with CH2Cl2 (2 ×
25 mL). The filtrate was concentrated under a flow of argon
and mixed with methanol (50 mL). The resulting mixture was
stirred at reflux for 1 h, concentrated, mixed with a 0.5 M
solution of KOH (30 mL), and extracted with EtOAc (3 × 25
mL). The combined organic extracts were washed with brine
(10 mL), concentrated, and purified by column chromatogra-
phy.
Con clu sion s
We have demonstrated that N-demethylation can be
successfully used to improve SERT and NET activity
of the trans-(+)-piperidine-based ligands, and the effect
of N-demethylation is independent of the nature of the
3R-substituent. Although N-alkylation can also be used
for improving SERT activity in the case of the trans-
(+) ligands, there appear to be restrictions for the size
of the N-substituent and the presence of functional
groups in it. The results of the preliminary behavioral
tests of 1c and 2a are consistent with the DA hypoth-
esis. The prolonged duration of action for oxadiazole 1b
and alcohol 1c suggests that cleavage of the ester group
in 1a could be one of the pathways of metabolic
deactivation of 1a in vivo. We hypothesize that 2a has
an additional pharmacological action that may be
responsible for its initial depressant effects, while its
metabolites may be responsible for the delayed locomo-
tor stimulation, although thorough and systematic
studies of the neurotransmitter activity of these com-
pounds have yet to be performed. The present results
may have important implications for our understanding
of the pharmacological mechanisms underlying the
behavioral actions of cocaine and of the structural
features needed for the design of new leads in the
discovery of a cocaine abuse medication.
Gen er a l P r oced u r e B: N-Alk yla t ion . To a solution of
N-norester 2a (0.39 mmol) in dry DMF (2 mL) were added
alkyl bromide (0.49 mmol, 1.25 equiv) and K2CO3 (1.22 mmol,
3.1 equiv) at room temperature. The resulting suspension was
stirred in a sealed tube at 90 °C for the amount of time
indicated for each compound. The reaction mixture was cooled
to room temperature, mixed with water (10 mL), and extracted
with ether (3 × 10 mL). The combined organic solutions were
washed with brine, concentrated, and purified by column
chromatography.
Gen er a l P r oced u r e C: N-Alk yla t ion . To a solution of
ester 4 (0.15 mmol) in acetone (9 mL) were added alkyl
bromide (0.5 mmol), NEt3 (0.11 mL, 0.77 mmol), and KI (0.043
g, 0.26 mmol) at room temperature. The resulting suspension
was heated under reflux for 2 h. The reaction mixture was
cooled to room temperature, concentrated, diluted with CH2-
Cl2 (30 mL), washed with brine, dried, and again concentrated.
The residue was purified by column chromatography.
(3R,4S)-4-(4-Ch lor oph en yl)piper idin e-3-car boxylic Acid
Meth yl Ester (2a ). Following general procedure A, ester 1a
(1.00 g, 3.73 mmol), 1,8-bisdimethylaminonaphthalene (0.44
g, 2.1 mmol), and R-chloroethyl chloroformate (4.16 g, 29.1
mmol, 3.14 mL) gave crude N-norester 2a . Column chroma-
tography with EtOAc/NEt3/MeOH (8:1:1) as eluent afforded
pure N-norester 2a as a colorless glass (0.63 g, 67%): [R]D
+54.0 (c 1.33, CHCl3); IR (film) 3331, 2946, 1731, 1493, 1432,
1197, 1171, 1143, 821 cm-1; 1H NMR (CDCl3) δ 1.62 (H5ax, qd,
J ) 12.0, 4.2 Hz, 1H), 1.81 (H5eq, ddt, J ) 13.2, 3.9, 2.7 Hz,
1H), 2.68 (H3, td, J ) 11.1, 3.6 Hz, 1H), 2.76 (H6ax, td, J )
12.6, 3.0 Hz, 1H), 2.83 (H2ax, dd, J ) 12.0, 11.1 Hz, 1H), 2.91
(H4, td, J ) 11.4, 3.9 Hz, 1H), 3.18 (H6eq, brd, J ) 12.9 Hz,
1H), 3.34 (H2eq, ddd, J ) 12.0, 3.6, 0.9 Hz, 1H), 3.45 (s, 3H),
7.14 (d, J ) 8.7 Hz, 2H), 7.25 (d, J ) 8.7 Hz, 2H); 13C NMR
(CDCl3) δ 33.86 (CH2), 44.51 (CH), 46.34 (CH2), 49.36 (CH2),
50.04 (CH), 51.26 (CH3), 128.40 (CH2), 128.40 (CH2), 132.00
(C), 142.07 (C), 173.30 (C); MS m/z (%) 57 (100), 87 (31), 115
(63), 128 (12), 165 (10), 180 (10), 194 (55), 222 (7), 253 (M+,
32). 2a ‚HCl: anal. (C13H16ClNO2‚1.1HCl) C, H, N.
(3R,4S)-4-(4-Ch lor oph en yl)-3-(3-m eth yl-1,2,4-oxadiazol-
5-yl)p ip er id in e (2b). Following general procedure A, oxa-
diazole 1b (90 mg, 309 µmol), 1,8-bisdimethylaminonaphtha-
lene (364 mg, 170 µmol), and R-chloroethyl chloroformate (2.4
mmol, 260 µL) gave crude oxadiazole 2b. Column chromatog-
raphy with EtOAc/NEt3/MeOH (8:1:1) as eluent afforded pure
oxadiazole 2b as a colorless glass (82 mg, 95%): IR (film) 3319,
2932, 1578, 1493, 1437, 1394, 1364, 1088, 821 cm-1; 1H NMR
(CDCl3) δ 1.73 (qd, J ) 12.3, 3.9 Hz, 1H), 1.91 (brd, J ) 11.7
Hz, 1H), 2.27 (s, 3H), 2.84 (td, J ) 12.0, 2.1 Hz, 1H), 2.91-
3.14 (m, 2H), 3.20-3.46 (m, 3H), 7.09 (d, J ) 8.4 Hz, 2H), 7.20
(d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 11.28, 34.24, 42.43,
45.97, 46.22, 50.51, 128.28, 128.58, 132.36, 140.91, 166.55,
178.93; MS m/z (%) 59 (100), 82 (19), 98 (11), 111 (28), 138
(15), 165 (9), 190 (24), 221 (8), 235 (4). 2b‚HCl: [R]D +71.1 (c
0.76, CHCl3); anal. (C14H16ClN3O‚1.2HCl) C, H, N.
Exp er im en ta l P r oced u r es
Gen er a l Meth od s. Reagent-grade solvents were used
without further purification. All reagents were purchased from
commercial sources and were used as received. All reactions
1
were conducted under an atmosphere of nitrogen. H and 13C
NMR spectra were acquired at nominal frequencies of 300 and
75 MHz, respectively, on a Varian Unity Inova 300 spectrom-
eter. 1H NMR spectra are referenced to internal TMS, and 13C
NMR spectra are referenced to the signal of CDCl3 (δ 77.00
ppm). 1H NMR splitting patterns are designated as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).
NMR assignments were made with the help of COSY and
DEPT experiments. Melting points were determined in Pyrex
capillaries with a Thomas-Hoover Unimelt apparatus and are
not corrected. Mass spectra were recorded via direct inlet in
the EI mode at an ionization potential of 70 eV on a Shimadzu
QP-5000 mass spectrometer. Optical rotation was measured
on an Rudolph AUTOPOL III polarimeter. IR spectra were
recorded on an ATI Mattson Genesis Series FTIR spectrom-
eter. Combustion analyses were performed by Micro-Analysis,
Inc. (Wilmington, DE). Merck silica gel 60 Geduran (No.
110832-1) with a particle size of 32-63 µm was used for
column chromatography. Merck silica gel 60 F254 (No. 5715-7)
with a layer thickness of 250 µm was used for TLC; the spots

3168 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15
Petukhov et al.
(3R,4S)-4-(4-Ch lor op h en yl)-3-(h yd r oxym eth yl)p ip er i-
d in e (2c). To a solution of N-norester 2a (0.45 g, 1.8 mmol)
in anhydrous THF (10 mL) that was cooled to 0 °C was added
LiAlH4 (0.07 g, 1.8 mmol). The resulting mixture was warmed
to room temperature and stirred for 2 h, mixed with a
saturated solution of NH4Cl (15 mL), and extracted with CH2-
Cl2 (3 × 10 mL). The combined organic extract was concen-
trated and purified by column chromatography on SiO2 with
EtOAc/NEt3/MeOH (6:2:2) as eluent to yield pure alcohol 2c
as a colorless glass (0.36 g, 89%): [R]D +34.6 (c 1.36, CHCl3);
1-bromo-3-phenylpropane (75 µL, 490 µmol) gave crude ester
3d after 30 h. Column chromatography with EtOAc/hexanes/
NEt3 (4:6:1) as eluent afforded pure ester 3d as a colorless
solid (140 mg, 96%): [R]D +20.9 (c 0.575, CHCl3); IR (film)
1
2946, 1735, 1494, 1157, 1123, 823 cm-1; H NMR (CDCl3) δ
1.72-1.92 (m, 4H), 2.10-2.12 (m, 1H), 2.16 (t, J ) 10.8 Hz,
1H), 2.43 (dd, J ) 6.6, 1.1 Hz, 2H), 2.65 (t, J ) 7.5 Hz, 2H),
2.70-2.81 (m, 1H), 2.86 (td, J ) 11.4, 3.6 Hz, 1H), 3.00 (brd,
J ) 11.4 Hz, 1H), 3.16 (ddd, J ) 11.1, 3.6, 1.5 Hz, 1H), 3.44 (s,
3H), 7.13 (brd, J ) 8.7 Hz, 2H), 7.16-7.31 (m, 7H); 13C NMR
(CDCl3) δ 28.51, 32.96, 33.48, 44.41, 48.89, 51.32, 53.50, 56.02,
57.60, 125.63, 128.16, 128.22, 128.41, 128.50, 132.04, 141.85,
141.89, 173.34; MS m/z (%) 55 (11), 70 (9), 91 (27), 115 (10),
128 (7), 163 (7), 223 (20), 252 (11), 266 (100), 236 (38), 371
(M+, 11). 3d ‚HCl: anal. (C22H26ClNO2‚1.2HCl) C, H, N.
IR (film) 3290, 2914, 1492, 1090, 1014, 820 cm-1 1H NMR
;
(CDCl3) δ 1.59 (qd, J ) 12.3, 3.9 Hz, 1H), 1.68-1.86 (m, 2H),
3.02-3.16 (m, 2H), 3.20-3.36 (m, 4H), 7.11 (d, J ) 8.4 Hz,
2H), 7.25 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 34.73 (CH2),
44.32 (CH), 44.44 (CH), 46.43 (CH2), 49.66 (CH2), 62.52 (CH2),
128.43 (CH), 128.54 (CH), 131.66 (C), 142.79 (C); MS m/z (%)
56 (72), 69 (18), 86 (45), 103 (8), 115 (15), 125 (14), 138 (7),
152 (14), 194 (37), 225 (M+, 30). 2c‚HCl: anal. (C12H17ClNO‚
HCl) C, H, N.
(3R,4S)-4-(4-Ch lor op h en yl)-1-(3-flu or op r op yl)p ip er i-
d in e-3-ca r boxylic Acid Meth yl Ester (3e). Following gen-
eral procedure B, N-norester 2a (120 mg, 470 µmol) and
1-bromo-3-fluoropropane (54 µL, 590 µmol) gave crude ester
3e after 20 h. Column chromatography with EtOAc/hexanes
(4:6) as eluent afforded pure ester 3e as a colorless oil (130
mg, 88%): [R]D +31.9 (c 1.04, CHCl3) IR (film): 2952, 2815,
1731, 1494, 1157, 824 cm-1; 1H NMR (CDCl3) δ 1.68-2.00 (m,
4H), 2.08-2.18 (m, 1H), 2.20 (t, J ) 10.8 Hz, 1H), 2.54 (brt, J
) 7.8 Hz, 2H), 2.72-2.84 (m, 1H), 2.87 (td, J ) 11.4, 3.6 Hz,
1H), 3.00 (brd, J ) 11.4 Hz, 1H), 3.15 (ddd, J ) 10.8, 3.6, 1.8
Hz, 1H), 3.45 (s, 3H), 4.40 (dt, J ) 47.4, 6.0 Hz, 2H), 7.14 (d,
J ) 8.4 Hz, 2H), 7.25 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ
27.92 (CH2, d, J C-C-F ) 19.6 Hz), 32.99 (CH2), 44.43 (CH),
48.95 (CH), 51.44 (CH3), 53.58 (CH2), 53.98 (CH2, d, J C-C-C-F
) 5.0 Hz), 56.12 (CH2), 82.26 (CH2, d, J C-F ) 164.0 Hz), 128.51
(CH2), 128.58 (CH2), 132.16 (C), 141.89 (C), 173.34 (C); MS
m/z (%) 70 (10), 90 (25), 102 (13), 115 (12), 128 (8), 163 (8),
(3R,4S)-4-(4-Ch lor op h en yl)-1-isop r op ylp ip er id in e-3-
ca r boxylic Acid Meth yl Ester (3a ). Following general
procedure B, N-norester 2a (100 mg, 390 µmol) and 2-bro-
mopropane (46 µL, 490 µmol) gave crude ester 3a after 60 h.
Column chromatography with EtOAc/hexanes/NEt3 (4:15:1) as
eluent afforded pure ester 3a as a colorless oil (130 mg, 92%):
IR (film) 2964, 1735, 1493, 1173, 1157, 824 cm-1 1H NMR
;
(CDCl3) δ 1.09 (dd, J ) 6.6, 2.7 Hz, 6H), 1.76-1.90 (m, 2H),
2.24-2.40 (m, 1H), 2.38 (t, J ) 10.8 Hz, 1H), 2.68-2.90 (m,
3H), 2.95 (bd, J ) 11.1 Hz, 1H), 3.11 (ddd, J ) 10.8, 3.0, 1.8
Hz, 1H), 3.45 (s, 3H), 7.14 (d, J ) 8.7 Hz, 2H), 7.24 (d, J ) 8.7
Hz, 2H); 13C NMR (CDCl3) δ 17.87, 18.15, 33.09, 44.75, 48.73,
49.10, 51.38, 51.43, 54.67, 128.45, 128.57, 132.10, 141.87,
173.60; MS m/z (%) 56 (42), 72 (6), 110 (5), 115 (8), 280 (100),
236 (38), 295 (M+, 9). 3a ‚HCl: [R]D +43.7 (c 0.49, CHCl3); anal.
(C16H22ClNO2‚HCl) C, H, N.
223 (25), 266 (100), 268 (34), 313 (M+, 9). 3e‚HCl: anal. (C16H21
ClFNO2‚1.1HCl) C, H, N.
-
(3R,4S)-1-Ben zyl-4-(4-ch lor op h en yl)p ip er id in e-3-ca r -
boxylic Acid Meth yl Ester (3b). Following general proce-
dure B, N-norester 2a (100 mg, 390 µmol) and benzyl bromide
(58 µL, 490 µmol) gave crude ester 3b after 30 h. Column
chromatography with EtOAc/hexanes/NEt3 (4:6:1) as eluent
afforded pure ester 3b as a colorless oil (110 mg, 81%): [R]D
+16.4 (c 1.07, CHCl3); IR (film) 2946, 2804, 1735, 1493, 1156,
(3R,4S)-4-(4-Ch lor op h en yl)-1-(3-ch lor op r op yl)p ip er i-
d in e-3-ca r boxylic Acid Meth yl Ester (3f). Following gen-
eral procedure B, N-norester 2a (100 mg, 390 µmol) and
1-bromo-3-chloropropane (53 µL, 490 µmol) gave crude ester
3f after 20 h. Column chromatography with EtOAc/hexanes
(4:6) as eluent afforded pure ester 3f as a colorless oil (105
mg, 81%): [R]D +20.9 (c 0.555, CHCl3); IR (film) 2950, 1734,
1494, 1158, 1130, 824 cm-1; 1H NMR (CDCl3) δ 1.70-1.86 (m,
2H), 1.97 (brt, J ) 7.2 Hz, 2H), 2.13 (td, J ) 10.8, 3.6 Hz, 1H),
2.21 (t, J ) 10.8 Hz, 1H), 2.55 (t, J ) 6.9 Hz, 2H), 2.77 (td, J
) 11.1, 5.1 Hz, 1H), 2.85 (td, J ) 11.7, 3.6 Hz, 1H), 2.99 (brd,
J ) 10.8 Hz, 1H), 3.14 (brd, J ) 10.8 Hz, 1H), 3.46 (s, 3H),
3.62 (t, J ) 6.6 Hz, 2H), 7.14 (d, J ) 8.7 Hz, 2H), 7.25 (d, J )
8.7 Hz, 2H); 13C NMR (CDCl3) δ 29.92 (CH2), 33.08 (CH2), 43.10
(CH2), 44.50 (CH), 49.05 (CH), 51.54 (CH3), 53.71 (CH2), 55.14
(CH2), 56.24 (CH2), 128.60 (CH), 128.65 (CH), 132.28 (C),
141.93 (C), 173.32 (C); MS m/z (%) 70 (14), 98 (6), 106 (8), 115
(9), 128 (5), 223 (17), 266 (71), 268 (24), 329 (M+, 3). 3f‚HCl:
anal. (C16H21Cl2NO2‚1.1HCl) C, H, N.
822 cm-1 1H NMR (CDCl3) δ 1.72-1.88 (m, 2H), 2.08-2.20
;
(m, 1H), 2.21 (t, J ) 10.8 Hz, 1H), 2.70-2.84 (m, 1H), 2.86
(td, J ) 11.7, 3.6 Hz, 1H), 2.97 (brd, J ) 11.4 Hz, 1H), 3.13
(ddd, J ) 11.1, 3.6, 1.8 Hz, 1H), 3.40 (s, 3H), 3.50-3.62 (m,
2H), 7.13 (d, J ) 8.7 Hz, 2H), 7.23 (d, J ) 8.7 Hz, 2H), 7.24-
7.35 (m, 5H); 13C NMR (CDCl3) δ 32.92 (CH2), 44.43 (CH),
48.95 (CH), 51.28 (CH3), 53.41 (CH2), 55.82 (CH2), 62.74 (CH2),
127.00 (CH), 128.13 (CH), 128.40 (CH), 128.51 (CH), 128.91
(CH), 132.04 (C), 137.76 (C), 141.88 (C), 173.35 (C); MS m/z
(%) 91 (100), 120 (20), 132 (13), 146 (12), 190 (6), 252 (28), 284
(10), 343 (M+, 11). 3b‚HCl: anal. (C20H22ClNO2‚1.1HCl) C, H,
N.
(3R,4S)-4-(4-Ch lor oph en yl)-1-(2-ph en yleth yl)piper idin e-
3-ca r boxylic Acid Meth yl Ester (3c). Following general
procedure B, N-norester 2a (100 mg, 390 µmol) and (2-
bromoethyl)benzene (67 µL, 490 µmol) gave crude ester 3c
after 30 h. Column chromatography with EtOAc/hexanes/NEt3
(4:6:1) as eluent afforded pure ester 3c as a colorless solid (130
mg, 92%): [R]D +26.8 (c 0.605, CHCl3); IR (film) 2947, 1735,
1493, 1193, 1157, 823 cm-1; 1H NMR (CDCl3) δ 1.76-1.84 (m,
1H), 1.84 (dd, J ) 7.8, 3.3 Hz, 1H), 2.12-2.24 (m, 1H), 2.28 (t,
J ) 11.1 Hz, 1H), 2.62-2.72 (m, 2H), 2.75-2.96 (m, 4H), 3.10
(brd, J ) 11.1 Hz, 1H), 3.26 (ddd, J ) 11.1, 3.3, 1.8 Hz, 1H),
3.46 (s, 3H), 7.15 (d, J ) 8.4 Hz, 2H), 7.18-7.34 (m, 7H); 13C
NMR (CDCl3) δ 32.96, 33.49, 44.43, 48.93, 51.42, 53.52, 55.98,
60.23, 125.99, 128.30, 128.48, 128.54, 128.55, 132.15, 139.97,
141.82, 173.36; MS m/z (%) 91 (6), 105 (100), 163 (6), 223 (19),
266 (100), 326 (3). 3c‚HCl: anal. (C21H24ClNO2‚0.9HCl) C, H,
N.
(3R,4S)-4-(4-Ch lor op h en yl)-1-(2-eth oxyca r bon yleth yl)-
p ip er id in e-3-ca r boxylic Acid Meth yl Ester (3g). Following
general procedure B, N-norester 2a (100 mg, 390 µmol) and
ethyl 3-bromopropionate (63 µL, 490 µmol) gave crude ester
3g after 20 h. Column chromatography with EtOAc/hexanes
(4:6) as eluent afforded pure ester 3g as a colorless oil (103
mg, 74%): [R]D +22.0 (c 1.29, CHCl3); IR (film) 2950, 1733,
1
1494, 1190, 1158, 825 cm-1; H NMR (CDCl3) δ 1.27 (t, J )
7.2 Hz, 3H), 1.66-1.84 (m, 2H), 2.17 (td, J ) 10.8, 3.9 Hz,
1H), 2.25 (t, J ) 10.8 Hz, 1H), 2.51 (t, J ) 7.5 Hz, 2H), 2.70-
2.90 (m, 4H), 3.00 (brd, J ) 11.1 Hz, 1H), 3.14 (ddd, J ) 10.8,
3.3, 1.8 Hz, 1H), 3.45 (s, 3H), 4.15 (q, J ) 7.2 Hz, 2H), 7.12 (d,
J ) 8.4 Hz, 2H), 7.24 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ
14.15 (CH3), 32.32 (CH2), 32.92 (CH2), 44.33 (CH), 48.88 (CH),
51.43 (CH3), 53.24 (CH2), 53.32 (CH2), 55.83 (CH2), 60.36 (CH2),
128.51 (CH), 128.57 (CH), 132.18 (C), 141.83 (C), 172.28 (C),
173.28 (C); MS m/z (%) 115 (12), 130 (14), 163 (7), 222 (21),
266 (100), 294 (9), 353 (M+, 8). 3g‚HCl: anal. (C18H24ClNO4‚
1.1HCl) C, H, N.
(3R,4S)-4-(4-Ch lor op h en yl)-1-(3-p h en ylp r op yl)p ip er i-
d in e-3-ca r boxylic Acid Meth yl Ester (3d ). Following gen-
eral procedure B, N-norester 2a (100 mg, 390 µmol) and

Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 15 3169
(3R,4S)-4-(4-Ch lor op h en yl)-1-(4-h yd r oxyben zyl)p ip er i-
d in e-3-ca r boxylic Acid Meth yl Ester (3h ). To a solution
of the hydrochloride of N-norester 2a (100 mg, 340 µmol) in
methanol (3 mL) was added 4-hydroxybenzaldehyde (46 mg,
379 µmol). The resulting suspension was stirred at room
temperature for 15 min before a solution of sodium cyanoboro-
hydride (3.9 mg, 103 µmol) and potassium hydroxide (6 mg,
103 µM) in methanol (0.5 mL) was added dropwise, and the
stirring was continued for 2 h. The solvent was removed, and
the residue was mixed with water (10 mL) and extracted with
CH2Cl2 (3 × 10 mL). The organic extract was concentrated and
purified by column chromatography (EtOAc/hexanes/NEt3, 4.5:
4.5:1) to give pure ester 3h as a colorless oil (85 mg, 69%): IR
(film) 3409, 2949, 1732, 1515, 1493, 1203, 823 cm-1; 1H NMR
(CDCl3) δ 1.74-1.88 (m, 2H), 2.10-2.22 (m, 1H), 2.22 (dd, J
) 10.8, 10.8 Hz, 1H), 2.70-2.84 (m, 1H), 2.91 (td, J ) 11.1,
3.6 Hz, 1H), 3.06 (brd, J ) 12.3 Hz, 1H), 3.17 (m, 1H), 3.43 (s,
3H), 3.46-3.60 (m, 2H), 6.68 (d, J ) 8.1 Hz, 2H), 7.10 (d, J )
8.7 Hz, 2H), 7.13 (d, J ) 8.1 Hz, 2H), 7.22 (d, J ) 8.7 Hz, 2H);
13C NMR (CDCl3) δ 32.53 (CH2), 44.38 (CH), 48.61 (CH), 51.55
(CH3), 53.21 (CH2), 55.46 (CH2), 62.24 (CH2), 115.37 (CH),
128.48 (CH), 128.54 (CH), 130.82 (CH), 132.19 (C), 141.60
(CH), 155.44 (C), 173.72 (C); MS m/z (%) 42 (23), 56 (18), 77
(18), 107 (100), 148 (9), 162 (5), 194 (9), 252 (30), 300 (6), 328
(3), 359 (M+, 10). 3h ‚HCl: [R]D +29.2 (c 0.39, CHCl3); anal.
(C20H22ClNO3‚1.2HCl) C, H, N.
(3R,4S)-1-Acet yl-4-(4-ch lor op h en yl)p ip er id in e-3-ca r -
boxylic Acid Meth yl Ester (3i). To a solution of N-norester
2a (200 mg, 790 µmol) in dry CH2Cl2 (3 mL) were added acetyl
chloride (73 µL, 1.02 mmol) and NEt3 (142 µL, 1.02 mmol) at
room temperature. The resulting mixture was stirred at room
temperature for 2 h. A saturated solution of NH4Cl (10 mL)
was added, and the mixture was extracted with ether (3 × 10
mL). The combined organic solutions were washed with brine,
concentrated, and purified by column chromatography with
EtOAc as eluent. Evaporation of the solvent gave pure
compound 3i as a colorless glass (mixture of Z and E isomers,
220 mg, 94%): [R]D +12.9 (c 0.84, CHCl3); IR (film) 2950, 1733,
1494, 1190, 1158, 825 cm-1; 1H NMR (CDCl3) δ 1.54-1.74 (m,
2H), 1.80-1.96 (m, 2H), 2.15 (s, 3H, NCOCH3, Z or E isomer),
2.16 (s, 3H, NCOCH3, E or Z isomer), 2.58-2.78 (m, 4H), 2.94-
3.08 (m, 2H), 3.14-3.34 (m, 2H), 3.94 (brd, J ) 13.8 Hz, 1H),
4.04 (bd, J ) 11.7 Hz, 1H), 4.77 (brd, J ) 13.8 Hz, 1H), 4.88-
5.20 (m, 1H), 7.11 (brd, J ) 8.1 Hz, 4H), 7.27 (brd, J ) 8.1 Hz,
4H); 13C NMR (CDCl3) δ 21.27, 21.30, 31.95, 33.04, 41.61,
43.67, 44.58, 44.81, 46.43, 47.92, 48.55, 49.20, 51.50, 51.65,
128.36, 128.39, 128.59, 132.54, 140.57, 168.74, 172.35; MS m/z
(%) 82 (11), 114 (11), 151 (3), 194 (6), 236 (21), 252 (15), 295
(M+, 12). 3i‚HCl: anal. (C15H18ClNO3) C, H, N.
13C NMR (CDCl3) δ 26.7, 42.1, 46.5, 51.3, 54.3, 56.2, 62.7, 127.2,
128.3, 128.9, 129.3, 132.0, 138.7, 142.0, 172.6; MS m/z (%) 91
(100), 252 (26), 343 (M+, 7). Anal. (C20H22ClNO2) C, H, N.
(3S,4S)-4-(4-Ch lor oph en yl)-1-(2-ph en yleth yl)piper idin e-
3-ca r boxylic Acid Meth yl Ester (6b). Following general
procedure B, ester 4 (52 mg, 210 µmol) and (2-bromoethyl)-
benzene (34 µL, 250 µmol) gave crude ester 6b after 12 h.
Column chromatography with EtOAc/hexanes/NEt3 (4:6:1) as
eluent afforded pure ester 6b as a colorless oil (54 mg, 73%):
[R]D -15.3 (c 0.43, CHCl3); IR (film) 2950, 1744, 1493, 1167
cm-1; 1H NMR (CDCl3) δ 1.83 (dd, J ) 12.6, 3.0 Hz, 1H), 2.23
(dt, J ) 11.1, 2.7 Hz, 1H), 2.44 (dd, J ) 11.4, 3.3 Hz, 1H),
2.50-2.90 (m, 6H), 2.96-3.03 (m, 1H), 3.07 (d, J ) 10.8 Hz,
1H), 3.38 (dd, J ) 11.1, 1.5 Hz, 1H), 3.50 (s, 3H), 7.15-7.31
(m, 9H); 13C NMR (CDCl3) δ 26.9, 33.7, 42.0, 46.4, 51.5, 54.3,
56.3, 60.4, 126.2, 128.3, 128.5, 129.0, 129.2, 132.0, 140.7, 141.9,
172.7; MS m/z (%) 223 (43), 266 (M+, 100). Anal. (C21H24ClNO2)
C, H, N.
(3S,4S)-4-(4-Ch lor op h en yl)-1-(3,3-d ip h en ylp r op yl)p ip -
er id in e-3-ca r boxylic Acid Meth yl Ester (6c). Following
general procedure B, amine 4 (32 mg, 130 µmol) and Ph2-
CHCH2I (50 mg, 150 µmol) gave crude ester 6c after 12 h.
Column chromatography with EtOAc/hexanes/NEt3 (4:6:1) as
eluent afforded pure ester 6c as a colorless oil (0.045 g, 80%):
[R]D -35.1 (c 0.57, CHCl3); IR (film) 2948, 1742, 1493, 1165
cm-1; 1H NMR (CDCl3) δ 1.78 (dd, J ) 12.3, 3.3 Hz, 1H), 2.04-
2.38 (m, 6H), 2.64 (dq, J ) 11.4, 3.9 Hz, 1H), 2.78 (dt, J )
12.0, 4.2 Hz, 1H), 2.86-3.00 (m, 2H), 3.27 (dd, J ) 11.4, 1.5
Hz, 1H), 3.52 (s, 3H), 4.06 (t, J ) 7.5 Hz, 1H), 7.12-7.32 (m,
14H); 13C NMR (CDCl3) δ 26.8, 32.9, 42.1, 46.5, 48.4, 51.4, 54.3,
56.3, 126.2, 126.3, 128.1, 128.2, 128.3, 128.5, 128.6, 129.2,
132.0, 142.0, 145.0, 145.2, 172.7; MS m/z (%) 266 (100), 447
(M+, 15). Anal. (C28H30ClNO2) C, H, N.
(3S,4S)-1-Ben zen esu lfon yl-4-(4-ch lor op h en yl)p ip er i-
d in e-3-ca r boxylic Acid Meth yl Ester (6d ). Following the
procedure described for 3i, amine 4 (42 mg, 170 µmol) and
PhSO2Cl (25 µL, 200 µmol) gave crude amide 6d after 2 h.
Column chromatography with EtOAc/hexanes (4:6) as eluent
afforded pure amide 6d as a white solid (51 mg, 82%): mp
76-78 °C; [R]D -9.8 (c 0.44, CHCl3); IR (film) 2853, 1740, 1493,
1
1236, 1169 cm-1; H NMR (CDCl3) δ 1.82-1.92 (m, 1H), 2.58
(td, 1H, J ) 11.1, 2.7 Hz, 1H), 2.72 (qd, J ) 12.0, 3.6 Hz, 1H),
2.56-2.87 (m, 2H), 2.97-3.04 (m, 1H), 3.55 (s, 3H), 3.86 (dd,
J ) 11.7, 1.8 Hz, 1H), 4.09 (qd, J ) 12.0, 1.8 Hz, 1H), 7.14 (d,
J ) 8.4 Hz, 2H), 7.24 (d, J ) 8.4 Hz, 2H), 7.52-7.66 (m, 3H),
7.77-7.84 (m, 2H); 13C NMR (CDCl3) δ 26.1, 41.5, 45.3, 46.3,
48.7, 51.9, 127.8, 128.6, 129.1, 129.3, 132.6, 133.1, 136.7, 140.4,
171.0; MS m/z (%) 220 (15), 252 (M+, 100). Anal. (C19H20
-
ClNO4S) C, H, N.
(3S,4S)-4-(4-Ch lor oph en yl)piper idin e-3-car boxylic Acid
Meth yl Ester (5). Following general procedure A, ester 4 (300
mg, 1.18 mmol), 1,8-bisdimethylaminonaphthalene (140 mg,
660 µmol), and R-chloroethyl chloroformate (9.26 mmol, 1.0
mL) gave crude N-norester 5. Column chromatography with
EtOAc/NEt3/MeOH (8:1:1) as eluent afforded pure N-norester
5 as a colorless glass (210 mg, 74%): [R]D -143.0 (c 1.30,
Ack n ow led gm en t. We are indebted to the NIH
National Institute of Drug Abuse (DA11548 and 10458)
for their support of this work. We thank Dr. Werner
Tueckmantel for proofreading of the manuscript.
Refer en ces
1
CHCl3); H NMR (CDCl3) δ 1.62-1.73 (m, 1H), 2.34 (qd, J )
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12.6, 3.9 Hz, 1H), 2.68-2.84 (m, 2H), 2.93-3.16 (m, 3H), 3.34
(t, J ) 13.5 Hz, 2H), 3.45 (s, 3H), 7.12 (d, J ) 8.4 Hz, 2H),
7.26 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3) δ 26.7, 42.9, 45.7,
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(3S,4S)-1-Ben zyl-4-(4-ch lor op h en yl)p ip er id in e-3-ca r -
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3.9 Hz, 1H), 2.78-2.85 (m, 1H), 2.90-2.96 (m, 1H), 3.06 (d, J
) 11.1 Hz, 1H), 3.22 (d, J ) 11.4 Hz, 1H), 3.42 (d, J ) 13.5
Hz, 1H), 3.49 (s, 3H), 3.67 (d, J ) 13.2 Hz, 1H), 7.30 (m, 9H);

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