Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter

Article abstract of DOI:10.1021/jm0608614

Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or four-carbon chain. The "inactive" RS/SR diastereomers showed substantial activity when the phenyl substituent was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration of action. The activity of these compounds provides additional evidence for a conformational/superposition model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a previously described vinylogous amide, had activity similar to that of methylphenidate.

Full text of DOI:10.1021/jm0608614

J. Med. Chem. 2007, 50, 219-232
219
Slow-Onset, Long-Duration, Alkyl Analogues of Methylphenidate with Enhanced Selectivity for
the Dopamine Transporter
Mark Froimowitz,*,† Yonghong Gu,† Les A. Dakin,† Pamela M. Nagafuji,† Charles J. Kelley,† Damon Parrish,‡
Jeffrey R. Deschamps,‡ and Aaron Janowsky§
Massachusetts College of Pharmacy and Health Sciences, 179 Longwood AVenue, Boston, Massachusetts 02115, The Laboratory for the
Structure of Matter, NaVal Research Laboratory, 4555 OVerlook AVenue, Washington, D.C. 20375, and Department of Veterans Affairs
Medical Center and Methamphetamine Abuse Research Center, Oregon Health and Science UniVersity, 3710 Southwest U.S. Veterans Hospital
Road, Portland, Oregon 97239
ReceiVed July 21, 2006
Methylphenidate analogues, in which the carbomethoxy has been replaced by an alkyl group and with different
phenyl substituents, have been synthesized and tested in monoamine transporter assays. As predicted from
a pharmacophore model, most of the RR/SS diastereomers showed high potency as dopamine reuptake
inhibitors. Analogues with a 4-chlorophenyl group and an unbranched initial alkyl atom had consistently
enhanced selectivity for the dopamine transporter. The most potent compounds were those with a three- or
four-carbon chain. The “inactive” RS/SR diastereomers showed substantial activity when the phenyl substituent
was 3,4-dichloro. On a locomotor assay, one compound was found to have a slow onset and a long duration
of action. The activity of these compounds provides additional evidence for a conformational/superposition
model of methylphenidate with cocaine-like structures. A ketone analogue, obtained by hydrogenating a
previously described vinylogous amide, had activity similar to that of methylphenidate.
Scheme 1
Introduction
Methylphenidate (Scheme 1), which was first synthesized 60
years ago,1 is still commonly used for the treatment of attention-
deficit hyperactivity disorder. The activity of the compound,
whose primary pharmacological action is to block the reuptake
of dopamine (DA) and norepinephrine (NE) by their respective
transporters in the central nervous system, resides almost entirely
in the threo isomer.2-4 The absolute configuration of the active
(+)-enantiomer has been determined to be R,R from chemical
conversion to compounds with known absolute configuration,5
and this has been confirmed more recently by X-ray crystal-
lography.6
In cases where the three-dimensional structure of the binding
site in a target protein is not well defined, as is the case for the
monoamine transporters, one can perform ligand-based design
to develop a pharmacophore. That is, by studying the confor-
mational properties of a series of pharmacologically similar
compounds, one can formulate hypotheses regarding the phar-
macophore. To that end, conformational analyses were per-
formed on a series of DA reuptake blockers, including cocaine
and CFT (Scheme 1).7 The preferred conformation of the tropane
DA reuptake blockers was found to have an intramolecular
hydrogen bond between the carbonyl oxygen and the axial
ammonium hydrogen. On this basis, a pharmacophore model
was proposed in which the key feature was the orientation of
the ammonium hydrogen. The model could then explain why
some DA reuptake inhibitors, such as 1-amino-4-phenyltetralins
and 3-phenyl-1-aminoindanes, have optimal activity as second-
ary amines whereas others, such as cocaine, have optimal
activity as tertiary amines. That is, an N-substituent in the tertiary
amine of the former is in the position required for the ammonium
hydrogen. This pharmacophore model has been tested by the
synthesis of rigid analogues of cocaine with defined orientations
of the ammonium hydrogen, and different transporter selectivi-
ties were demonstrated that were consistent with its predictions.8
More recently, the pharmacophore model was extended to
methylphenidate by a conformational analysis of the threo and
erythro isomers using the molecular mechanics program MM2-
87, and the preferred conformer of the threo isomer was found
to have an intramolecular hydrogen bond between the carbonyl
oxygen and the equatorial ammonium hydrogen.6 Similar
conformations were observed in a number of crystal structures
of methylphenidate analogues with different phenyl substitu-
ents.9 This model also correctly predicted a decrease of activity
when the secondary amines of methylphenidate analogues were
N-methylated.10
Using these preferred conformers of methylphenidate and
CFT, the compounds were superimposed and an essentially
perfect fit was found for the sequence of atoms from the amine
atom through the ester group (Figure 1).6 This suggests that
methylphenidate and CFT should share similar structure activity
relations with respect to the carbomethoxy side chain. It should
be noted that an ester group is not required for the activity of
tropane-containing DA reuptake blockers and compounds with
a variety of other substitutions retain potent activity.11-20 In
* To whom correspondence should be addressed. Phone: (617) 732-
2851. Fax: (617) 732-2959. E-mail: mfroimowitz@mcphs.edu.
† Massachusetts College of Pharmacy and Health Sciences.
‡ Naval Research Laboratory.
§ Oregon Health and Science University.
10.1021/jm0608614 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/22/2006

220 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
Figure 1. Stereoscopic images of the superposition of the atoms of (R,R)-methylphenidate and CFT from the nitrogen through the ester, showing
an essentially perfect fit for that sequence of atoms.
Scheme 2
particular, replacing the carbomethoxy group in CFT and
cocaine by a simple alkyl group can produce compounds with
good potency in blocking the reuptake of dopamine.8,13,15,18 If
the superposition model of CFT and methylphenidate is correct,
one would expect that similar substitutions in the latter should
produce active compounds. On the basis of this ligand-based
design, we have synthesized methylphenidate analogues in
which the carbomethoxy group is replaced by various alkyl
groups. There has been one previous limited report of alkyl
analogues of methylphenidate from a half-century ago in which
there was apparently no separation of diastereomers.21 This was
also prior to the development of binding and uptake assays so
that it was impossible to determine any kind of selectivity, and
in any case, virtually no in vivo pharmacological data were
reported.
phenyl ring of methylphenidate were found to greatly enhance
activity,32,33 and as with other DA reuptake blockers, halogens
such as chlorine and bromine in the meta and/or para positions
provided the most potent compounds.7 The addition of an
N-methyl or N-allyl group to methylphenidate analogues,
however, consistently reduced potency,10,34 while an N-benzyl
increased potency but appears to change the structure-activity
relationships in the compound.35 Similarly, changing the size
of the nitrogen-containing ring led to less potent compounds,
while replacement of the phenyl ring by a â-napthyl group
enhanced potency.35 More recently, it has been shown that the
presence of the basic nitrogen is not always required for activity
in methylphenidate since its replacement by oxygen or carbon,
as with other dopamine uptake blockers,36 still produces active
compounds,37 though this may require the presence of the
potency-enhancing effect of the 3,4-dichloro group.
It should also be noted that the pharmacophore model for
methylphenidate has been used by others to design novel
methylphenidate analogues22 and that the model has been
successfully extended to the DA reuptake inhibitors bupropion23
and BTCP.24
Synthesis
Most compounds were synthesized following Scheme 2. A
bromobenzene (4) with the required phenyl substituent was
converted into a Grignard reagent which was then allowed to
react with pyridine-2-carboxaldehyde (5) to produce the second-
ary alcohol 6. The alcohol 6 was oxidized with pyridinium
chlorochromate to produce the ketone 7, which was purified in
a Kauffman column38 (Ace Glass, Vineland, NJ). This was then
allowed to react with a Grignard reagent that contains the
required R2 group to produce the tertiary alcohol 8. After
purification, alcohol 8 was dehydrated with refluxing HCl to
produce alkene 9, usually as a mixture of Z and E isomers. For
a few compounds, it was necessary to use stronger HBr for the
dehydration. Dehydration with HCl of alcohols 8 with methoxy
groups on the phenyl ring resulted in considerable demethylation
of the methoxy group. For these compounds, the dehydration
was performed with POCl3/pyridine.39 The alkene mixture 9
was hydrogenated with 10% Pt/C in HOAc containing 3% CF3-
COOH to produce the final compounds 10 with a ratio of about
40:60 of the RR/SS and RS/SR diastereomers. The diastereomers
One less desirable aspect to the clinical use of methylpheni-
date is that it typically must be administered two or three times
per day25 since the ester moiety is rapidly metabolized to
produce the inactive acid.26 Methylphenidate, as a potent DA
reuptake blocker, also has abuse potential. There is evidence
that the abusability of a drug is correlated with a fast onset and
a short duration of action.27-31 Our goal is the synthesis of DA
reuptake blockers with reduced abuse liability as possible
maintenance pharmacotherapies for the treatment of cocaine
dependence. Therefore, to obtain compounds with longer
durations of action, we deemed it advantageous to replace the
carbomethoxy with something more metabolically stable such
as an alkyl group.
Because of the similar pharmacological profiles of cocaine
and methylphenidate, there has been a revival of interest in the
synthesis and testing of analogues of the latter as possible
medications for treating cocaine abuse. Substitutions on the

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 221
Scheme 3
of 10 were generally separable by column chromatography. In
the few instances where this was not easy, fractional crystal-
lization was used to separate the diastereomers. Initially, many
of the relative configurations of the diastereomers of 10 were
determined by X-ray crystallography. However, it was also
possible to distinguish the purified diastereomers by the NMR
chemical shift of the benzylic methine proton. In the RR/SS
diastereomers, that methine proton appeared as a broad doublet
(J ) ca. 12 Hz), usually at 3.2-3.0 ppm, which was 0.2-0.3
ppm downfield from the corresponding resonance in the RS/SR
diastereomer. For the N-methyl analogues, the separated dia-
stereomers were allowed to react with HCHO and HCOOH.
While the reactions in Scheme 2 used to prepare the
methylphenidate analogues look deceptively simple, complica-
tions occurred with the use of the Grignard reagents to prepare
the tertiary alcohols 8. The addition of methyl and ethyl Grignard
to ketone 7a proceeded without difficulty, giving ∼90% yields
of the desired tertiary alcohols 8a and 8b. However, with larger
Grignard reagents, there was considerable reduction of ketones
7 back to the secondary alcohols 6 as is well-known to occur
for some Grignard reactions. For example, the addition of ketone
7a to a preformed solution of isobutyl Grignard at 0° gave 40%
of the reduced secondary alcohol 6a as an isolated side product.
With a rapid, reverse addition of Grignard reagent at -10°, the
yield of 6a was again about 40%. Only when the Grignard
reagent was added dropwise to a cooled (0°) solution of the
ketones 7 did the desired tertiary alcohols 8 predominate over
reduction products 6. The reaction products were also ac-
companied by unexpected ketones 12, resulting from the
apparent 1,6-conjugate addition of the Grignard reagent to C-5
of the pyridine ring and subsequent oxidative loss of the C-5
hydrogen. We did not identify the oxidant in this addition. The
amount of 12 produced in any reaction could be quantitated by
integration of the proton NMR spectra of the crude product
mixtures. The integrated area of the multiplets around δ 8.5
(H-6 on the pyridine rings of both alcohols and the byproduct
ketone) can be compared with the integrated area around 8 ppm
in which overlapping doublets due to three hydrogens deshielded
by the ketone carbonyl appear in 12. No other resonances appear
near 8 ppm in either alcohol. Since we observed no evidence
for the reaction of ketone 12 with a second molecule of Grignard
reagent, we presumed that the ketone function was tied up,
perhaps by chelation with magnesium ion until the Grignard
reagent was consumed.
Figure 2. Crystal structure of the ketone analogue of methylphenidate
(compound 15). The structure shown is the major component in the
crystal which contains some disorder.
analogue of methylphenidate. However, because of the high
stability of vinylogous amides, it was necessary to hydrogenate
for 3 days, and the lengthy hydrogenation also removed the Cl
from the phenyl ring (compound 15). Upon making the HCl
salt of a mixture of diastereomers, only a single isomer was
found, and X-ray crystallography indicated that it was the RR/
SS diastereomer (Figure 2). While this compound was stable
enough to make a salt, to perform elemental analysis, to obtain
a crystal structure, and for pharmacological testing, converting
it back to the free base by treatment with a mild base was
sufficient to cause it to decompose. This was assumed to be
due to the highly acidic proton R to both the phenyl ring and
the carbonyl group that is easily extracted by base. Because of
this difficulty, no further synthetic work was performed on these
kinds of compounds. The two methyl ester containing com-
pounds with a 4-chloro- and 3,4-dichlorophenyl group were
synthesized as before.1,32
Some comments must be made regarding the nomenclature
for the diastereomers of 10. In methylphenidate, the RR/SS
diastereomers are designated as threo because the heteroatomic
groups are on opposite sides when the protons on the two
asymmetric carbons are eclipsed. In the methylphenidate
analogues synthesized here, where an alkyl group replaces the
carbomethoxy group, the diastereomers with the same relative
configuration should be designated as erythro since the new
alkyl chain is on the same side as the alkyl portion of the
piperidine ring. However, due to the ambiguities inherent in
the threo-erythro nomenclature, it is generally preferable to
designate diastereomers using the Cahn-Ingold-Prelog system
of R and S.41 It should also be noted that, while a higher priority
carbomethoxy group has been replaced by a lower priority alkyl
group, the R,R enantiomer of methylphenidate still corresponds
to the R,R enantiomer of the alkyl analogues.
Workups of the Grignard additions for intermediates 8
generally produced mixtures with varying amounts of 6 and
12. To aid in the purification of the tertiary alcohols 8, it proved
beneficial to reflux the crude mixture in ethanol with 1 equiv
of semicarbazide hydrochloride. The fast-running 8 was then
easily separated by silica gel chromatography from the polar
semicarbazone derivatives of ketones 12 and the slow-running
secondary alcohols 6. On TLC, alcohols 8 had Rf values (with
10-25% ethyl acetate in hexanes) equal to or higher than those
of the starting ketones. This unexpected mobility of tertiary
alcohols 8 on silica gel can be explained by an intramolecular
hydrogen bond between the hydroxyl group and pyridine
nitrogen. In the NMR, the hydroxyl hydrogen in the tertiary
alcohols 8 was always present as a sharp singlet at a chemical
shift of 6.0 ( 0.2 ppm. In the secondary alcohols 6, the OH
resonance was broadened, and the compounds had very low Rf
values.
Binding and Uptake Assays
The compounds were tested in binding and uptake assays
utilizing recombinant human DA, NE, and 5HT transporters
stably expressed in human embryonic kidney 293 cells (HEK-
hDAT, -hNET, and -hSERT, respectively) as previously de-
scribed.42 The binding studies measured the potency of the test
compounds in competition experiments with [125I]RTI-55, while
the uptake assays measured the potency in inhibiting the uptake
of the respective tritiated monoamine neurotransmitters.
We previously reported the synthesis of vinylogous amide
analogues (compound 14, Scheme 3) of methylphenidate.40 We
attempted to hydrogenate one of these compounds to the ketone

222 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
Table 1. Inhibition of [125I]RTI-55 Binding (Ki, nM) and [3H]Monoamine Uptake (IC50, nM) by RR/SS Diastereomers
dopamine
[I125]RTI-55
serotonin
[I125]RTI-55
binding
norepinephrine
DA
5HT
uptake
[I125]RTI-55
binding
NE
uptake
NE/DA NE/DA
binding uptake
R1
R2
COOCH3
R3
binding
uptake
1
2
H
H
110 ( 9
500 ( 65
25 ( 8
180 ( 70
37 ( 10
11 ( 3
79 ( 16 65000 ( 4000 5100 ( 7000 660 ( 50
61 ( 14
210 ( 30
11 ( 3
35 ( 13
210 ( 30
50 ( 15
51 ( 20
26 ( 7
6.0
1.0
4.4
2.0
9.7
18
18
29
53
7.0
230
12
180
32
6.6
75
1.1
2.4
11
6.2
10
4.0
5.2
25
0.77
0.88
1.0
1.6
9.1
6.8
1.6
3.2
14
1.1
15
8.7
15
4.1
7.8
4.3
2.1
1.4
1.6
5.0
0.43
1.8
4.7
1.6
2.2
cocaine
4-chloro
240 ( 15
11 ( 2
340 ( 40
250 ( 40
>9800
500 ( 90
110 ( 40
360 ( 140
360 ( 60
COOCH3
methyl
ethyl
propyl
isopropyl
butyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
6000 ( 100
10a 4-chloro
10b 4-chloro
10c 4-chloro
10d 4-chloro
10e 4-chloro
10f 4-chloro
10g 4-chloro
10h 4-chloro
10i 4-chloro
10j 4-chloro
10k 4-chloro
10l 4-chloro
10m 4-chloro
10n 4-chloro
10o 4-chloro
10p 4-chloro
10q 3-chloro
22 ( 7
4900 ( 500 1900 ( 300
7800 ( 800 2400 ( 400
23 ( 5
7.4 ( 0.4
32 ( 6
2700 ( 600 2900 ( 1100 200 ( 80
46 ( 16
7.8 ( 1.1
16 ( 4
5300 ( 1300 3300 ( 400
4300 ( 400 4000 ( 400
810 ( 170
230 ( 30
8.2 ( 2.1
8.6 ( 2.9
45 ( 14
14 ( 2
isobutyl
pentyl
5900 ( 900
490 ( 80
840 ( 130 120 ( 40
23 ( 7
2200 ( 100 1500 ( 300
160 ( 40
49 ( 16
isopentyl
neopentyl
cyclopentylmethyl
cyclohexylmethyl
benzyl
phenethyl
phenpropyl
3-pentyl
3.6 ( 1.2
120 ( 40
9.4 ( 1.5
130 ( 40
440 ( 110
24 ( 9
5000 ( 470 7300 ( 1400 830 ( 110 210 ( 40
60 ( 2
21 ( 1
3900 ( 500
2900 ( 80
>8300
1400 ( 400 520 ( 110
2100 ( 900 1700 ( 600 310 ( 40
230 ( 70
370 ( 90
160 ( 20
290 ( 90
240 ( 60
27 ( 8.3
2.8 ( 0.4
23 ( 3
900 ( 400 1000 ( 200 4200 ( 200 940 ( 140
1100 ( 200 1100 ( 200 2900 ( 800 2900 ( 600
640 ( 60
700 ( 200 1600 ( 300
>9400
650 ( 210 1800 ( 600 680 ( 240
440 ( 150
400 ( 80
36 ( 10
3.7 ( 1.1
1.4 ( 0.1
0.97 ( 0.31
2.3 ( 0.2
1.0 ( 0.5
6.6 ( 0.9
52 ( 16
22 ( 5
490 ( 100 600 ( 140
970 ( 290 330 ( 80
3900 ( 300
cyclopentyl
isobutyl
5700 ( 1100 4600 ( 800
3200 ( 400 2100 ( 100
380 ( 120
23 ( 6
14 ( 6
3.9 ( 1.4
12 ( 3
25 ( 9
190 ( 60
44 ( 18
14 ( 1
10 ( 1
8.1 ( 3.8
27 ( 10
9.0 ( 1.2
28 ( 3
3,4-dichloro COOCH3
1600 ( 150
1800 ( 500
540 ( 110
560 ( 120
10r 3,4-dichloro propyl
10s 3,4-dichloro butyl
10t 3,4-dichloro isobutyl
4.5 ( 0.4
5.7 ( 0.5
5.5 ( 1.3
13 ( 4
25 ( 9
35 ( 12
1300 ( 300 1400 ( 300
1600 ( 100 1100 ( 300
1300 ( 200 1400 ( 500
11
3,4-dichloro isobutyl
29
60
170
0.76
7.3
10u 4-methoxy isobutyl
10v 3-methoxy isobutyl
10w 4-isopropyl isobutyl
2800 ( 600 3500 ( 500 3100 ( 200 410 ( 90
4200 ( 400 2700 ( 800 3800 ( 500 330 ( 40
16
9.4
1.8
1.2
3300 ( 600 4000 ( 400 3300 ( 600 4700 ( 700 2500 ( 600 7100 ( 1800
370 ( 70
15
H
COCH3
190 ( 50
7800 ( 1200
>9700
2700 ( 400 220 ( 30
Results
the uptake of 5HT, and the RR/SS diastereomers (Table 1) were
considerably more potent in binding to the DA and NE
transporters and in blocking uptake of those neurotransmitters
than the equivalent RS/SR diastereomers (Table 2).
The binding affinity of the alkyl analogues of methylphenidate
for the cloned human monoamine transporters and their potency
at inhibiting the uptake of DA, 5HT, and NE at their respective
transporters are shown in Table 1 for the RR/SS diastereomers
and in Table 2 for the RS/SR diastereomers. Included in Table
1 are results for cocaine and methylphenidate under the same
conditions. As is well-known, cocaine blocks all three monoam-
ine transporter sites. The threo RR/SS diastereomer of meth-
ylphenidate, which contains the therapeutic activity, has con-
siderable potency at the DA and NE transporters, but is much
weaker at the 5HT transporter.
4-Chloro Compounds. A large number of analogues were
made with a 4-chloro substituent, and most of the RR/SS
diastereomers were considerably more potent than the equivalent
ester-containing compound at binding to the DA transporter and
blocking the uptake of DA, indicating that the ester group is
not required for potent activity. The most potent compounds in
blocking the uptake of DA were those where R2 was three or
four carbon atoms long. Branching at the second carbon, as in
isobutyl ((RR/SS)-10f), and at the third carbon, as in isopentyl
((RR/SS)-10h), did not affect potency significantly as compared
with that of the analogue without the additional methyl group.
However, there was a significant decrease in potency with the
neopentyl compound ((RR/SS)-10i). Compounds with phenyl
rings in the side chain were considerably weaker, with the
phenethyl compound appearing to be the optimal substitution.
The most noteworthy aspect to these compounds, however, is
the emergence of considerable selectivity for the DA transporter
relative to the NE transporter in many of the compounds on
the functional uptake assays. However, this only occurred for
compounds with an unbranched first carbon atom since com-
pounds in which the first atom was branched such as isopropyl
((RR/SS)-10d), 3-pentyl ((RR/SS)-10o), and cyclopentyl ((RR/
SS)-10p) showed little selectivity. The compounds with the best
selectivity are R2 ) isobutyl ((RR/SS)-10f), isopentyl ((RR/SS)-
10h), and cyclopentylmethyl ((RR/SS)-10j), which are 53-, 230-,
The greatest discrepancies between the binding and uptake
results occur for the NE transporter, where there is a 10-fold or
greater difference for a number of compounds. As a result, there
are much larger differences in DA/NE selectivity based on the
binding data than on the functional uptake data.
As found previously,32 the addition of a chlorine atom to the
meta and/or para position of the phenyl ring in methylphenidate
increases potency significantly. The RR/SS diastereomer of the
4-chloro ester compound with a carbomethoxy group was 17-
fold more potent than (RR/SS)-methylphenidate in blocking DA
uptake and 3-fold more potent in blocking NE uptake. The ester
compound with a 3,4-dichloro group was 8.3-fold more potent
in blocking the uptake of DA and 3.8-fold in blocking the uptake
of NE. Both compounds were approximately equipotent in
blocking the uptake of DA and NE. As with methylphenidate
itself, none of the synthesized compounds had significant
binding affinity to the 5HT transporter or potency at blocking

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 223
Table 2. Inhibition of [125I]RTI-55 Binding (Ki, nM) and [3H]Monoamine Uptake (IC50, nM) by RS/SR Diastereomers
dopamine
[I125]RTI-55
serotonin
[I125]RTI-55
norepinephrine
[I125]RTI-55
DA
5HT
NE
R1
R2
COOCH3
methyl
ethyl
propyl
isopropyl
butyl
isobutyl
pentyl
isopentyl
neopentyl
cyclopentylmethyl
cyclohexylmethyl
benzyl
phenethyl
phenpropyl
3-pentyl
cyclopentyl
isobutyl
COOCH3
propyl
R3
binding
uptake
binding
uptake
binding
uptake
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
4-chloro
H
2000 ( 600
>3900
2700 ( 1000
1500 ( 700
2800 ( 700
450 ( 60
990 ( 280
170 ( 40
380 ( 130
650 ( 20
680 ( 120
670 ( 260
180 ( 20
410 ( 60
390 ( 60
420 ( 140
1400 ( 400
1200 ( 90
240 ( 30
88 ( 12
5900 ( 200
>9100
4200 ( 400
3200 ( 1100
>10 mM
>10 mM
4700 ( 800
4100 ( 1000
1300 ( 7
>6100
>6300
>9200
1400 ( 400
3200 ( 800
1300 ( 400
200 ( 50
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
1800 ( 300
380 ( 40
900 ( 320
290 ( 70
170 ( 50
870 ( 140
510 ( 170
600 ( 40
310 ( 80
260 ( 30
550 ( 60
700 ( 90
2900 ( 900
>5700
1400 ( 400
>10 mM
1600 ( 300
4500 ( 1500
1500 ( 300
12000 ( 1400
>5500
2600 ( 800
4300 ( 200
4000 ( 800
2400 ( 700
1500 ( 200
4300 ( 200
3300 ( 800
340 ( 50
4200 ( 1900
30 ( 8
31 ( 11
120 ( 30
660 ( 130
16000 ( 2000
12000 ( 2300
3200 ( 600
4800 ( 700
4300 ( 500
3600 ( 1000
6700 ( 500
3500 ( 1000
3200 ( 700
3700 ( 500
4300 ( 800
1800 ( 70
1500 ( 200
4800 ( 1100
4600 ( 700
3200 ( 400
2500 ( 420
450 ( 80
1100 ( 200
450 ( 40
1500 ( 300
950 ( 190
3800 ( 600
1700 ( 500
3300 ( 600
540 ( 150
1700 ( 700
>8300
1800 ( 600
5600 ( 1400
6400 ( 1300
4700 ( 500
210 ( 900
1200 ( 400
>9600
4200 ( 900
870 ( 230
1100 ( 90
180 ( 60
550 ( 80
290 ( 60
180 ( 60
750 ( 170
860 ( 330
3000 ( 540
730 ( 250
730 ( 230
1700 ( 600
>8800
610 ( 150
1700 ( 200
3800 ( 30
1000 ( 300
73 ( 5
190 ( 50
47 ( 22
63 ( 27
19 ( 3
100 ( 19
1600 ( 400
1400 ( 90
>8700
4-chloro
3-chloro
690 ( 140
140 ( 30
90 ( 14
3,4-dichloro
3,4-dichloro
3,4-dichloro
3,4-dichloro
3,4-dichloro
4-methoxy
3-methoxy
4-isopropyl
800 ( 110
88 ( 32
10r
10s
10t
11
10u
10v
10w
43 ( 9
butyl
29 ( 5
67 ( 13
isobutyl
isobutyl
isobutyl
isobutyl
isobutyl
31 ( 11
13 ( 3
44 ( 12
45 ( 4
2400 ( 700
1200 ( 300
2600 ( 300
1700 ( 100
770 ( 220
950 ( 190
>6500
400 ( 120
140 ( 20
>9100
and 180-fold more selective in binding and 14-, 15-, and 15-
fold more selective in blocking uptake at the DA transporter
relative to the NE transporter, respectively. The cyclopentyl-
methyl analogue is closely related to the isobutyl compound in
that the terminal methyl groups of the latter are tied into a
cyclopentyl ring. The cyclohexylmethyl compound ((RR/SS)-
10k), however, was about 10-fold weaker than the cyclopen-
tylmethyl compound, presumably because the latter is smaller
and more flexible. The selectivity for the DA transporter appears
to be due to a decrease in potency at the NE transporter. The
loss of potency as one lengthens the alkyl group parallels what
has been found in methylphenidate analogues in which potency
decreases as the size of the ester group is increased.43
3,4-Dichloro Compounds. These RR/SS diastereomers had
somewhat higher binding affinity and potency at blocking the
uptake of DA than the 4-chloro compounds with the same alkyl
group (Table 1), in line with the previous finding that this phenyl
substitution is optimal or close to optimal in all classes of DA
reuptake blockers.7 The most potent analogue was the propyl
compound ((RR/SS)-10r). However, the selectivity for the
DA transporter relative to the NE transporter has decreased.
As in ester analogues of methylphenidate, an N-methyl sub-
stituent reduced potency.10 However, one unexpected result
with these compounds was that the RS/SR diastereomers that
typically have weak activity at monoamine transporters now
began to show decent potency at blocking uptake of monoam-
ines, with the isobutyl compound ((RS/SR)-10t) having a
potency of 13 nM in blocking the DA transporter and 19 nM
in blocking the NE transporter (Table 2). This RS/SR
compound even has a much higher potency in blocking the 5HT
transporter than any other of the methylphenidate analogues
reported here.
Other Phenyl Substituents. Chlorine and methoxy substit-
uents in the 3- and 4-positions of the phenyl ring enhance
potency in ester analogues of methylphenidate relative to that
of the parent compound.32 Single compounds were made with
a 3-chloro, a 3-methoxy, or a 4-methoxy on the phenyl ring
with the isobutyl side chain that is near optimal in the analogues
with 4-chloro and 3,4-dichloro substituents. These halogen and
methoxy substitutions also produced RR/SS diastereomers with
low nanomolar potency. The 4-methoxy compound ((RR/SS)-
10u) had the best selectivity for DA uptake inhibition with 16-
fold selectivity in blocking uptake and 60-fold selectivity with
respect to binding at the NE transporter. A compound with a
4-isopropyl substituent ((RR/SS)-10w) had little potency. The
RS/SR diastereomers were weak inhibitors at all three monoam-
ine transporter sites.
Ketone Analogue. The ketone analogue of methylphenidate
(Figure 2) had activity comparable to that of methylphenidate.
As was found previously in a number of crystal structures of
ester analogues,9 there was a hydrogen bond between the
carbonyl oxygen and the equatorial ammonium proton in the
crystal structure (Figure 2).
Locomotor Activity. The locomotor activities induced by
various doses of cocaine, methylphenidate, and the 4-chloro,
isobutyl compound ((RR/SS)-10f) over an 8 h period are shown
in Figure 3. As can be seen, both cocaine and methylphenidate
are active by the first 10 min data point and peak activity occurs
during the first 30 min. In contrast, (RR/SS)-10f appears to have
a slow onset of 20-30 min and peak activity occurs between
90 and 120 min. The compound also is active much longer and
lasts for the entire 8 h period at the highest dose. Thus, the
compound has the slow-onset, long-duration profile that is
believed to reduce abuse potential. (RR/SS)-10f does not produce

224 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
Figure 3. Effect of an ip injection of (a, left) cocaine, (b, middle) methylphenidate, and (c, right) (RR/SS)-10f on horizontal locomotor activity
counts per 10 min in mice as a function of dose (top to bottom panels) and time during an 8 h session. Stimulant effects of doses of the compounds
as compared with vehicle at (a) 0-30 min, (b) 0-30 min, and (c) 90-120 min that are statistically significant at p < 0.05 are indicated by an
asterisk.
the maximum stimulation that occurs with cocaine or meth-
ylphenidate, presumably because it enters the brain more slowly
so that its brain concentration increases more slowly.
As these novel alkyl analogues of methylphenidate are not esters,
they would be expected to have longer in vivo half-lives, and
this should make them more suitable as longer duration
maintenance therapies for treating cocaine abuse. The longer
duration of activity can be clearly seen in the locomotor activity
of (RR/SS)-10f as compared with both cocaine and methylpheni-
date (Figure 3). The compound also appears to have an onset
of activity of at least 20 min, whereas methylphenidate and
cocaine have much faster onsets, suggesting that the compound
would have reduced abuse potential (Figure 3). One can
speculate that this is due to the absence of the ester group which
appears to facilitate entry into the brain.
Discussion
As with methylphenidate, the alkyl analogues were potent
blockers at the DA and NE transporters and much weaker at
the 5HT transporter. The optimal side chain substitutions were
alkyl analogues that were three or four carbon atoms long.
However, there were several unexpected structure-activity
features of these compounds. First, the analogues with a
4-chlorophenyl group consistently showed enhanced selectivity
for blocking the DA transporter relative to the NE transporter
as compared with ester-containing compounds as long as the
first carbon of the side chain was unbranched, due to lessened
potency at the NE transporter. It should be noted that meth-
ylphenidate also is branched at this point due to the ester group.
The compounds with a 3-chloro and a 3,4-dichloro group
showed reduced DA transporter selectivity. The compounds with
methoxy groups in the 3- and 4-positions of the phenyl ring
also showed better selectivity for blocking uptake of DA,
particularly when the group was in the 4-position. It seems that
the 4-position is more critical for better DA transporter
selectivity. A second, especially surprising result was the
emergence of potent blocking activity in the “inactive” RS/SR
diastereomers at all three monoamine transporters when the
phenyl substitution was 3,4-dichloro.
Experimental Section
General Information. New compounds were synthesized fol-
lowing Schemes 2 and 3. Reagents were purchased from Lancaster
or Aldrich and used as is. 1H and 13C NMR spectra of most
compounds were taken on a Varian 90 MHz spectrophotometer
equipped with an Anasazi Instrument FT probe in CDCl3 as a
solvent (unless otherwise noted) with TMS as an internal standard.
1H NMR spectra of some salts of compounds 10 were taken in
D2O at 270 MHz using a Jeol-FX-270 spectrometer, while other
salts were taken in d4-methanol at 90 MHz. Mass spectra were
obtained from a Micromass LTC electrospray spectrophotometer.
Catalytic hydrogenations were performed with a Parr shaker in a
500 mL bottle at 50-55 psi of H2. Analytical thin layer chroma-
tography was performed on Analtech 250 µm glass-backed silica
gel plates. Flash chromatography was performed with silica gel 60
(70-230 mesh). HCl salts of the amines were obtained by
dissolving the free base in EtOAc or a mixture of EtOAc and
hexanes, adding HCl dissolved in ether, and filtering the solids.
Recrystallizations to constant mp were from EtOAc that sometimes
contained a little ethanol unless otherwise noted. Melting points
were determined in a Mel-temp apparatus with a Hg thermometer
and are uncorrected. The relative configurations of most of the final
compounds were determined by crystallography of at least one of
the diastereomeric pairs. The diastereomers of 10 could also be
The robust potency of these novel analogues of methylpheni-
date which were designed from a ligand-based analysis of
methylphenidate and CFT provides additional evidence in favor
of the conformation and superposition model of those com-
pounds.6 It also suggests that other substitutions that enhance
blocking potency and selectivity in tropane-containing com-
pounds should also produce potent compounds in analogues of
methylphenidate.
1
As indicated above, methylphenidate must be taken two or
three times per day due to the relatively quick in vivo
metabolism of its ester to the pharmacologically inactive acid.
distinguished by H NMR. On chromatography of free bases 10
with 0.5-1% Et2NH in EtOAc/hexane, the RS/SR diastereomer
always had a higher Rf value than the RR/SS diastereomer, except

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 225
in two cases where there was branching at the R-carbon (i.e., 10d
and 10p). Elemental analyses of the final products as HCl salts
were obtained from Atlantic Microlabs, Norcross, GA, and all were
within (0.4% of the theoretical values.
13C NMR δ 193.1, 159.3, 155.1, 148.4, 137.6, 136.9, 129.1, 126.1,
124.4, 123.8, 119.0, 115.5, 55.2.
Data for (4-isopropylphenyl)-2-pyridylmethanone (7f): 1H
NMR δ 8.67 (1H, d, br), 8.08-7.94 (3H, m), 7.79 (1H, dt, J ) 2,
5 Hz), 7.45-7.27 (3H, m), 2.94 (1H, septet, J ) 7 Hz), 1.24 (6H,
d, J ) 7 Hz); 13C NMR δ 193.2, 155.3, 154.3, 148.4, 136.9, 134.0,
131.3 (2C), 126.2 (2C), 125.9, 124.4, 34.2, 23.6 (2C).
General Procedure for Secondary Alcohols 6. (4-Chlorophe-
nyl)-2-pyridylmethanol (6a). A small crystal of iodine was added
to Mg (7.07 g, 291 mmol) in THF (280 mL), and the slurry was
heated. A solution of p-bromochlorobenzene 4 (53.6 g, 280 mmol)
in THF (280 mL) was added slowly, and the mixture was refluxed
for 2 h until almost all of the Mg had dissolved. The solution was
cooled to 0 °C, pyridine-2-carboxaldehyde (5) (25 g, 233 mmol)
in THF (22 mL) was added slowly, and the solution was allowed
to warm to room temperature (rt) over 2 h. The reaction was diluted
with saturated NH4Cl, extracted with EtOAc (3×), washed with
brine, dried (MgSO4), and concentrated under reduced pressure to
an oil. The oil was taken up in 300 mL of hexanes and allowed to
crystallize. Filtration gave alcohol 6a (49 g, 96%) as an off-white
solid: mp 79-80 °C [lit. (Bull. Chem. Soc. Jpn. 1987, 60, 2651-
General Procedure for Synthesizing Tertiary Alcohols 8. 1-(4-
Chlorophenyl)-1-(2-pyridyl)-1-propanol (8b). Ketone 7a (8.0 g,
36.8 mmol) was dissolved in THF (120 mL) and cooled to 0 °C,
and a solution of 2 M EtMgBr (27 mL, 55.1 mmol) was slowly
added via cannula over 2 h at 0 °C. During the addition, the solution
took on a bright red color. The solution was diluted with saturated
aqueous NH4Cl, extracted 3× with EtOAc, washed with brine, and
dried (MgSO4). The EtOAc solution, one spot by TLC, was then
concentrated to an oil (9.2 g, 99% recovery) of 8b: 1H NMR δ
8.48 (1H, d, br), 7.67 (1H, dt, J ) 2,7 Hz), 7.52, (1H, m), 7.45
(2H, d, J ) 9 Hz), 7.27 (2H, d, J ) 9 Hz), 7.20 (1H, m), 5.91 (1H,
s), 2.23 (2H, diastereotopic, 2 q, J ) 7, ∆δ ) 2 Hz), 0.85 (3H, t,
1
2655) mp 82.5-84 °C]; H NMR δ 8.53 (1H, d, br), 7.62 (1H, dt
1
J ) 2, 7 Hz), 7.30 (4H, s), 7.22 (1H, m), 7.15 (1H, apparent td,
br), 6.00 (1H, s), 5.72 (1H, s); 13C NMR δ 160.8, 147.4 (CH),
141.3, 136.5 (CH), 132.7, 128.0 (2C), 127.7 (2C), 122.0 (CH), 120.5
(CH), 74.1.
J ) 7 Hz). Integration of the H NMR spectrum from 8.1 to 7.9
ppm (two doublets) relative to the area of the δ 8.48 multiplet
indicated the presence of about 6% 12b.
Data for 1-(4-chlorophenyl)-1-(2-pyridyl)-1-butanol (8c): yield
85%; 1H NMR δ 8.46 (1H, d, br), 7.57 (1H, td, J ) 2, 7 Hz), 7.49
(2H, d, J ) 8.7 Hz), 7.24 (2H, d, J ) 8.7 Hz), overlapping 7.1-
7.5 (2H, m), 5.84 (1H, s, br), 2.24 (2H, diastereotopic, 2 q, J ) 7,
∆δ ) 2 Hz), 1.30 (m, 2H), 0.88 (3H, t, J ) 7 Hz).
1
Data for (3-chlorophenyl)-2-pyridylmethanol (6b): H NMR
δ 8.34 (1H, ddd, J ) 1, 2, 5 Hz), 7.50 (1H, dt J ) 2, 7 Hz), 7.46-
7.08 (5H, m), 7.02 (1H, ddd, J ) 1, 5, 7 Hz), 5.73 (1H, s); 13C
NMR δ 161.2, 147.9, 145.3, 137.1, 134.2, 129.7, 127.6, 126.8,
125.0, 122.5, 121.0, 74.7.
Data for 1-(4-chlorophenyl)-2-methyl-1-(2-pyridyl)-1-pro-
Data for (3,4-dichlorophenyl)-2-pyridylmethanol (6c): 1H
NMR δ 8.44 (1H, dd, J ) 2, 5 Hz), 7.62 (1H, dt, J ) 2, 7 Hz),
7.59 (1H, d, J ) 3 Hz), 7.55-7.07 (4H, m), 5.81 (1H, s, v br),
5.71 (1H, s); 13C NMR δ 160.2, 148.0 (CH), 143.4, 137.2 (CH),
131.5, 130.4 128.8 (CH), 127.7, 126.2 (CH), 122.8 (CH), 121.1
(CH), 74.0 (CH).
1
panol (8d): H NMR δ 8.45 (1H, d, br), 7.5-7.7 (3H, m), 7.2-
7.4 (4H, 2 d, J ) 9 Hz, overlying 1H, m), 6.05 (1H, s, br), 2.77
(1H, septet, J ) 7 Hz), 0.94 (3H, d, J ) 7 Hz), 0.72 (3H, d, J )
7 Hz).
Data for 1-(4-chlorophenyl)-1-(2-pyridyl)-1-pentanol (8e): oil;
1
yield (after chromatography) 68%; H NMR δ 8.46 (1H, d, br),
(4-Methoxyphenyl)-2-pyridylmethanol (6d) and (3-Methox-
yphenyl)-2-pyridylmethanol (6e). Crude alcohols 6d and 6e were
not characterized, but oxidized directly to ketones 7d and 7e.
Data for (4-isopropylphenyl)-2-pyridylmethanol (6f): 1H NMR
δ 8.44 (1Η, br), 7.6-6.9 (7H, m), 5.73 (1H, s), 2.85 (1H, septet),
1.10 (6H, d, J ) 7 Hz); 13C NMR δ 162.5, 147.8, 140.7, 138.7,
128.3, 127.0 (2C), 126.5 (2C), 122.2, 121.2, 75.1, 33.8, 24.0 (2C).
General Procedure for Synthesizing Ketones 7. (4-Chlo-
rophenyl)-2-pyridylmethanone (7a). Pyridinium chlorochromate
(67 g, 310 mmol) was dissolved in CH2Cl2 (∼600 mL), and 60 g
of Celite was added with stirring. The alcohol 6a (65 g, 296 mmol)
was added and the slurry stirred at rt for 20 min. The solution was
concentrated, 75 g of silica gel was added, and all solvents were
removed. The preadsorbed product was placed atop dry silica gel
(200 g) in a Kauffman column and was extracted with 700 mL of
boiling heptane overnight. After being cooled to rt, the heptane
solution deposited 46 g (71% yield) of crystalline ketone 7a (mp
60-61 °C), which was collected by filtration: 1H NMR δ 8.72
(1H, d, br), 8.02 (2H, d, J ) 9 Hz, overlying 1H, m), 7.88 (1H, dt,
J ) 2, 7 Hz), 7.47 (2H, d, J ) 7 Hz, overlying 1H, m); 13C NMR
δ 192.2, 154.6, 148.4 (CH), 139.2, 137.1(CH), 133.4, 132.4 (2CH),
128.3 (2C), 126.3(CH), 124.5(CH).
7.61 (1H, td, J ) 2, 7 Hz), 7.48 (2H, d, J ) 9 Hz), 7.24 (2H, d,
J ) 9 Hz), 7.0-7.4 (overlapping 2H, m), 5.94 (1H, s, br), 2.30-
2.13 (2H, m), 1.43-1.13 (4H, m), 0.85 (3H, t, J ) 7 Hz); 13C
NMR δ 163.3, 147.3 (CH), 145.3, 137.0 (CH), 132.6, 128.2 (2CH),
127.5 (2CH), 122.1 (CH), 120.2 (CH), 76.9, 41.0, 25.7, 23.0, 14.0.
Data for 1-(4-chlorophenyl)-3-methyl-1-(2-pyridyl)-1-butanol
(8f): mp 69-71 °C (crystallized from pentane); yield 70%; 1H NMR
δ (8.48 1H, d, br), 7.54 (1H, td, J ) 2, 7 Hz), 7.49 (2H, d, J ) 9
Hz), 7.25 (2H, d, J ) 9 Hz), overlapping 7.1-7.5 (2H, m), 5.98
(1H, s, br), 2.20 (1H, dd, J ) 7, 14 Hz), 2.08 (1H, dd, J ) 7, 14
Hz), 1.75 (1H, nonet, J ) 7 Hz), 0.96 (3H, d, J ) 7 Hz), 0.76 (3H,
d, J ) 7 Hz); 13C NMR δ 163.7, 147.2 (CH), 146.0, 137.0 (CH),
132.6, 128.2 (2CH), 127.5 (2CH), 122.1 (CH), 120.5 (CH), 77.3,
49.6, 24.8, 24.4, 24.3.
Data for 1-(4-chlorophenyl)-1-(2-pyridyl)-1-hexanol (8g): yield
67%; 1H NMR δ 8.42 (1H, ddd, J ) 1, 2, 5 Hz), 7.54 (1H, td, J )
2, 7 Hz), 7.49 (2H, d, J ) 9 Hz), 7.33 (1H, td, J ) 2, 7 Hz), 7.22
(2H, d, J ) 9 Hz), 7.04 (1H, ddd, J ) 1, 5, 7 Hz), 5.97 (1H, s, br),
2.23 (2H, t, J ) 7 Hz), 1.46-1.13 (6H, m), 0.82 (3H, t, J ) 7 Hz);
13C NMR δ 163.4, 147.2, 145.4, 137.0, 132.5, 128.2 (2C), 127.5
(2C), 122.0, 120.2, 76.9, 41.2, 32.1, 23.2, 22.5, 14.0.
Data for 1-(4-chlorophenyl)-4-methyl-1-(2-pyridyl)-1-pentanol
(8h): yield 56%; 1H NMR δ 8.42 (1H, ddd, J ) 1, 2, 5 Hz), 7.64-
7.43 (1H, m), 7.49 (2H, d, J ) 9 Hz), 7.35-7.17 (1H, m), 7.22
(2H, d, J ) 9 Hz), 7.04 (1H, ddd, J ) 1, 5, 7 Hz), 5.98 (1H, s, br,
OH), 2.36-2.16 (2H, m), 1.61-1.00 (3H, m), 0.85 (6H, d, J ) 7
Hz); 13C NMR δ 163.4, 147.2, 145.3, 137.0, 132.5, 128.2 (2C),
127.5 (2C), 122.0, 120.2, 76.9, 39.1, 32.4, 28.3, 22.6 (2C).
Data for 1-(4-chlorophenyl)-3,3-dimethyl-1-(2-pyridyl)-1-bu-
tanol (8i): yield (front-running component on silica column) 44%;
1H NMR δ 8.37 (1H, d, br), 7.54 (2H, d, J ) 9 Hz), 7.43-7.38
(2H, m), 7.19 (2H, d, J ) 9 Hz), 6.98 (1H, td, J ) 2, 7 Hz), 6.14
(1H, s, OH), 2.36 (1H, d, J ) 15 Hz), 2.31 (1H, d, J ) 15 Hz),
0.86 (9H, s); 13C NMR δ 164.3, 147.5, 147.0 (CH), 136.9 (CH),
132.4, 128.2 (2CH), 127.3 (2CH), 121.9 (CH), 120.7 (CH), 78.7,
52.3, 32.1, 31.8 (3C).
Data for (3-chlorophenyl)-2-pyridylmethanone (7b): 1H NMR
δ 8.69 (1H, ddd, J ) 1, 2, 5 Hz), 8.11-7.77 (4H, m), 7.64-7.30
(3H, m); 13C NMR δ 192.1, 154.3, 148.5, 137.9, 137.1, 134.2,
132.6, 130.9, 129.4, 129.2, 126.5, 124.6.
Data for (3,4-dichlorophenyl)-2-pyridylmethanone (7c): mp
81-2 °C; 1H NMR δ 8.68 (1H, d, br), 8.25-7.77 (4H, m), 7.56-
7.48 (2H, m); 13C NMR δ 190.7, 154.1, 148.5, 137.2, 135.9, 133.0,
132.5, 130.2, 130.1, 126.7, 124.7.
Data for (4-methoxyphenyl)-2-pyridylmethanone (7d): 1H
NMR δ 8.69 (1H, d, br), 8.13 (2H, d, J ) 9 Hz), 7.85 (1H, m),
7.82 (1H, dt, J ) 2, 8 Hz), 7.42 (1H, ddd, J ) 2, 5, 7 Hz), 6.95
(2H, d, J ) 9 Hz); 13C NMR δ 192.1, 163.6, 155.7, 148.3, 137.0,
133.5 (2C), 129.0, 125.8, 124.4, 113.5 (2C), 55.4.
Data for (3-methoxyphenyl)-2-pyridylmethanone (7e): 1H
NMR δ 8.64 (1H, d, br), 8.01-7.63 (4H, m), 7.44-7.03 (3H, m);

226 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
The trailing component on a silica column was crystallized from
hexane with a trace of diisopropyl ether to give (4-chlorophenyl)-
[5-(2,2-dimethylpropyl)-2-pyridyl]methanone (12i): mp 70-71 °C;
1H NMR δ 8.49 (1H, d, br), 8.05 (2H, d, J ) 9 Hz), 8.01 (1H, d,
J ) 7 Hz), 7.68 (1H, dd, J ) 2, 7), 7.47 (2H, d, J ) 9 Hz), 2.60
(2H, s), 0.95 (9H, s); 13C NMR δ 192.1, 152.3, 149.9 (CH), 139.0,
138.6 (2C, one a CH), 134.8, 132.4 (2CH), 128.3 (2CH), 123.9
(CH), 47.1, 31.6, 29.1 (3C); absolute mass calcd for C17H18ClNaNO
310.0975, obsd 310.0979.
Data for 1-(4-chlorophenyl)-2-cyclopentyl-1-(2-pyridyl)etha-
nol (8j): yield 61%; 1H NMR δ 8.45 (1H, d, br), 7.53 (2H, d, J )
9 Hz), 7.68-7.28 (2H, m), 7.23 (2H, d, J ) 9 Hz), 7.10 (1H, td,
J ) 2, 7 Hz), 5.96 (1H, s, OH), 2.35 (2H, m), 1.87-1.02 (9H, m);
13C NMR δ 163.7, 147.2, 145.8, 136.9, 132.6, 128.2 (2C), 127.6
(2C), 122.0, 120.6, 77.1, 47.0, 36.1, 34.4, 33.9, 24.9, 24.7.
Data for 1-(4-chlorophenyl)-2-cyclohexyl-1-(2-pyridyl)ethanol
(8k): yield 63%; 1H NMR δ 8.43 (1H, ddd, J ) 1.0, 1.8, 4.8 Hz),
7.49 (2H, d, J ) 9.0 Hz), 7.66-7.23 (2H, m), 7.22 (2H, d, J ) 8.7
Hz), 7.07 (1H, ddd, J ) 1.2, 4.9, 6.1 Hz), 6.02 (1H, s, OH), 2.16
(2H, m), 1.54-0.87 (11H, m); 13C NMR δ 163.6, 147.0, 145.8,
136.8, 132.3, 128.0 (2C), 127.3 (2C), 121.8, 120.2, 77.0, 48.2, 35.0,
34.6, 33.4, 26.2 (3C).
Data for 1-(3,4-dichlorophenyl)-1-(2-pyridyl)-1-butanol (8r):
yield 71%; 1H NMR δ 8.44 (1H, ddd, J ) 1, 2, 5 Hz), 7.72-7.50
(2H, m), 7.36-7.27 (3H, m), 7.09 (1H, ddd, J ) 1, 5, 7 Hz), 6.00
(1H, s, br), 2.23 (2H, t, J ) 7 Hz), 1.39-1.19 (2H, m), 0.87 (3H,
t, J ) 7 Hz); 13C NMR δ 162.6 (2C), 147.4, 137.1, 132.2, 130.7,
130.0, 128.3, 125.6, 122.2, 120.1, 76.7, 43.4, 16.8, 14.3.
Data for 1-(3,4-dichlorophenyl)-1-(2-pyridyl)-1-pentanol (8s):
yield 58%; 1H NMR δ 8.43 (1H, ddd, J ) 1, 2, 5 Hz), 7.72-7.49
(2H, m), 7.36-7.26 (3H, m), 7.08 (1H, ddd, J ) 1, 5, 7 Hz), 6.07
(1H, s, br), 2.23 (2H, t, J ) 7 Hz), 1.33-1.20 (4H, m), 0.83 (3H,
t, J ) 7 Hz); 13C NMR δ 162.7, 147.4 (2C), 137.1, 132.2, 130.7,
130.0, 128.3, 125.6, 122.2, 120.1, 76.7, 40.9, 25.7, 23.0, 14.0.
Data for 1-(3,4-dichlorophenyl)-3-methyl-1-(2-pyridyl)-1-bu-
1
tanol (8t): yield 61%; H NMR δ 8.43 (1H, dd, J ) 2, 5 Hz),
7.71-7.34 (5H, m), 7.10 (1H, ddd, J ) 1, 2, 7 Hz), 6.07 (1H, s,
OH), 2.23-2.13 (2H, m), 1.76 (1H, septet, J ) 6 Hz), 0.90 (3H, d,
J ) 6 Hz), 0.75 (3H, d, J ) 6 Hz); 13C NMR δ 162.8, 147.9,
147.2 (CH), 137.1 (CH), 132.2, 130.6, 129.9 (CH), 128.2 (CH),
125.4 (CH), 122.2 (CH), 120.3 (CH), 76.9, 49.3, 24.7, 24.3, 24.1.
Data for 1-(4-methoxyphenyl)-3-methyl-1-(2-pyridyl)-1-bu-
tanol (8u): 1H NMR δ 8.39 (1H, ddd, J ) 1, 2, 5 Hz), 7.65-7.22
(2H, m), 7.46 (2H, d, J ) 9 Hz), 7.05, (1H, ddd, J ) 1.3, 5, 6 Hz),
2.25 (1H, dd, J ) 6, 14 Hz), 2.13 (1H, dd, J ) 6, 14 Hz), 1.78
(1H, nonet, J ) 6 Hz), 0.90 (3H, d, J ) 6.9 Hz), 0.68 (3H, d, J )
6.9 Hz); 13C NMR δ 164.4, 158.3, 147.0 (CH), 139.5, 136.7 (CH),
127.1 (2CH), 121.7 (CH), 120.6 (CH), 113.4 (2CH), 77.2, 55.0,
49.6, 24.8, 24.2.
Data for (4-chlorophenyl)[5-(cyclohexylmethyl)-2-pyridyl]-
1
methanone (12k): H NMR δ 8.47 (1H, d, J ) 1.5 Hz, br), 8.07
(2H, d, J ) 9 Hz), 7.98 (1H, d, J ) 7 Hz), 7.72 (1H, dd, J ) 2, 7
Hz), 7.42 (2H, d, J ) 9 Hz), 2.55 (2H, d, J ) 6.5 Hz), 1.85-1.5
(11H, m); 13C NMR δ 191.7, 152.2, 149.0 (CH), 139.9, 138.8, 137.2
(CH), 134.8, 132.3 (2CH), 128.1 (2CH), 124.1 40.9, 39.3, 32.8 (2C)
26.1, 25.9 (2C); absolute mass calcd for C19H20ClNaNO 336.1131,
obsd 336.1122.
Data for 1-(3-methoxyphenyl)-3-methyl-1-(2-pyridyl)-1-bu-
1
tanol (8v): H NMR δ 8.40 (1H, d, br, J ) 5 (Hz), 7.40 (2H, m),
7.20-6.90 (4H, m), 6.70 (1H, m), 6.05 (1H, s), 3.68 (3H, s), 2.25
(1H, dd, J ) 6, 14 Hz), 2.17 (1H, dd, J ) 6, 14), 1.88 (nonet, J )
6 Hz), 0.90 (3H, d, J ) 6 Hz), 0.77 (3H, d, J ) 6 Hz); 13C NMR
δ 164.0, 159.5, 149.0 147.0 136.8, 129.0, 121.8, 120.5, 118.3, 112.0,
111.8, 77.4, 54.9, 49.5, 24.8, 24.4, 24.2.
Data for 1-(4-chlorophenyl)-2-phenyl-1-(2-pyridyl)ethanol
1
(8l): yield 70%; H NMR δ 8.34 (1H, ddd, J ) 1, 2, 5 Hz), 7.56
(2H, d, J ) 9 Hz), 7.61-7.22 (2H, m), 7.27 (2H, d, J ) 9 Hz),
7.20-6.88 (6H, m), 5.40 (1H, s, OH), 3.68 (1H, d, J ) 13 Hz),
3.50 (1H, d, J ) 13 Hz); 13C NMR δ 162.6, 147.2, 144.7, 136.8,
136.1, 132.9, 130.7 (2C), 128.2 (2C), 127.7 (4C), 126.4, 122.1,
120.7, 77.2, 47.2.
Data for 1-(4-isopropylphenyl)-3-methyl-1-(2-pyridyl)-1-bu-
1
tanol (8w): yield 60%; H NMR δ 8.39 (1H, dd, J ) 2, 5 Hz),
7.48 (2H, d, J ) 9 Hz), 7.51-7.27 (2H, m), 7.13 (2H, d, J ) 9
Hz), 6.98 (1H, dt, J ) 2, 7 Hz), 6.01 (1H, s, OH), 2.83 (1H, septet,
J ) 7 Hz), 2.25 (1H, d, J ) 6 Hz), 2.20 (1H, d, J ) 6 Hz), 2.01-
1.66 (1H, m), 1.17(6H, d, J ) 7 Hz), 0.93 (3H, d, J ) 6 Hz), 0.75
(3H, d, J ) 6 Hz); 13C NMR δ 164.3, 146.9, 144.8, 136.7, 126.1
(2C), 125.8 (2C), 121.7, 120.7, 77.4, 49.7, 33.6, 24.8, 24.3 (2C),
23.9 (2C).
Data for 1-(4-chlorophenyl)-3-phenyl-1-(2-pyridyl)-1-pro-
1
panol (8m): yield 60%; H NMR δ 8.37 (1H, dd, J ) 2, 5 Hz),
7.50 (2H, d, J ) 9 Hz), 7.61-7.07 (overlapping 8H, m), 7.23 (2H,
d, J ) 9 Hz), 6.10 (1H, s, OH), 2.63-2.47 (4H, m); 13C NMR δ
162.9, 147.4, 144.8, 142.3, 137.2, 128.4 (6C), 127.5 (2C), 125.8,
122.3, 120.2, 76.7, 43.3, 30.1.
Data for 1-(4-chlorophenyl)-4-phenyl-1-(2-pyridyl)-1-butanol
(8n): yield 69%; 1H NMR δ 8.44 (1H, dd, J ) 2, 5 Hz), 7.40 (2H,
d, J ) 9 Hz), 7.30-6.93 (overlapping 10H, m), 5.96 (1H, s, OH),
2.66-1.48 (6H, m); 13C NMR δ 163.1, 147.2, 145.1, 142.1, 137.0,
132.6, 128.4 (2C), 128.2(4C), 127.4 (2C), 125.7, 122.0, 120.1, 76.8,
40.6, 35.9, 25.2.
Data for 2-[1-(4-chlorophenyl)ethenyl]pyridine (9a): yield
87%; 1H NMR δ 8.56 (1H, ddd, J ) 1, 2, 5 Hz), 7.50 (1H, dt, J )
2, 7 Hz), 7.32 (2H, d, J ) 9 Hz), 7.17 (2H, d, J ) 9 Hz), 7.22-
6.98 (overlapping 2H, m), 5.97 (1H, d, J ) 1.6 Hz), 5.50 (1H, d,
J ) 1.6 Hz); 13C NMR δ 157.9, 149.3, 148.1, 138.9, 136.2, 133.6,
129.8 (2C), 128.4 (2C), 122.5 (2C), 118.0.
Data for 1-(4-chlorophenyl)-2-ethyl-1-(2-pyridyl)-1-butananol
(8o): yield 57%; 1H NMR δ 8.40 (1H, dd, J ) 2, 5 Hz), 7.60 (2H,
d, J ) 9 Hz), 7.59-7.33 (overlapping 2H, m), 7.24 (2H, d, J ) 9
Hz), 7.04 (1H, ddd, J ) 1, 2, 7 Hz), 6.13 (1H, s), 2.40-2.16 (1H,
m), 1.65-1.07 (4H, m), 0.88 (3H, t, J ) 7 Hz), 0.76 (3H, t, J ) 7
Hz); 13C NMR δ 163.2, 146.9, 145.5, 137.0, 132.3, 128.2 (2C),
127.5 (2C), 121.9, 120.4, 80.7, 49.3, 22.8, 22.3, 13.3, 13.1.
Data for 1-(4-chlorophenyl)-1-cyclopentyl-1-(2-pyridyl)meth-
General Procedure for Synthesizing Intermediates 9. 2-[1-
(4-Chlorophenyl)propenyl]pyridine (9b). Alcohol 8b (9.2 g, 36.7
mmol) was dissolved in 12 N HCl (120 mL) and refluxed for 48 h.
The acidic solution was concentrated and neutralized to pH 9 with
NaOH. The alkaline solution was extracted 3× with EtOAc, washed
with brine, dried (MgSO4), filtered, and concentrated to an oil. After
column chromatography with 10% EtOAc in hexanes as the eluent,
6.2 g (74% yield) of 9b was obtained as a mixture of Z and E
isomers. In some intermediates 9, one isomer was preponderant;
1H NMR (partial for major isomer) δ 8.67 (1H, dd, J ) 2, 5 Hz),
7.68 (1H, dt, J ) 2, 7 Hz), 7.27 (2H, d, J ) 9 Hz), 7.13 (2H, d,
J ) 9 Hz), 6.25 (1H, q, J ) 7 Hz), 1.80 (3H, d, J ) 7 Hz).
Data for 2-[1-(4-chlorophenyl)-1-butenyl]pyridine (9c): yield
85%; 1H NMR (partial for major isomer) δ 8.65 (1H, dd, J ) 2, 5
Hz), 7.66 (1H, dt, J ) 2, 7 Hz), 7.18, 7.16 (4H, central legs of
aromatic doublets), overlapping 7.1-7.5 (2H, m), 6.14 (1H, t, J )
7 Hz), 2.16 (2H, pentet, J ) 7 Hz), 1.04 (3H, t, J ) 7 Hz).
Data for 2-[1-(4-chlorophenyl)-2-methylpropenyl]pyridine
1
anol (8p): yield 63%; H NMR δ 8.41 (1H, ddd, J ) 1, 2, 5 Hz),
7.58 (2H, d, J ) 9 Hz), 7.61-7.29 (2H, m), 7.24 (2H, d, J ) 9
Hz), 7.07 (1H, ddd, J ) 1, 2, 7 Hz), 6.18 (1H, s, OH), 3.05 (1H,
pentet, J ) 8 Hz), 1.62-1.19 (8H, m); 13C NMR δ 163.4, 146.8,
145.6, 137.1, 132.4, 128.2 (2C), 127.7 (2C), 121.9, 120.4, 78.0,
48.0, 27.5, 26.8, 26.5, 26.4.
Data for 1-(3-chlorophenyl)-3-methyl-1-(2-pyridyl)-1-butanol
1
(8q): yield 51%; H NMR δ 8.43 (1H, d, br, J ) 5 Hz), 7.60-
7.00 (7H, m), 6.06 (1H, s, br), 2.41 (1H, dd, J ) 7, 14 Hz), 2.06
(1H, dd, J ) 7, 14 Hz), 1.77 (1H, octet, J ) 7 Hz), 0.91 (3H, d,
J ) 7 Hz), 0.75 (3H, d, J ) 7 Hz); 13C NMR δ 163.3, 149.6,
147.1, 137.0, 134.1, 129.3, 126.8, 126.2, 124.1, 122.1, 120.4, 77.2,
49.4, 24.7, 24.3, 24.2.
1
(9d): H NMR δ 8.60 (1H, dd, J ) 2, 5 Hz), 7.60 (1H, dt, J ) 2,
7 Hz), 7.24 (2H, d, J ) 9 Hz), 7.14 (2H, d, J ) 9 Hz), 7.0-7.3
(2H, m), 1.83 (6H, s).

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 227
Data for 2-[1-(4-chlorophenyl)-1-pentenyl]pyridine (9e): yield
(after chromatography) 81%; H NMR (one isomer) δ 8.64 (1H,
dd, J ) 2, 5 Hz), 7.63 (1H, dt, J ) 2, 7 Hz), 7.28-7.06 (6H, m),
6.25 (1H, t, J ) 7 Hz), 2.14 (2H, q, J ) 7 Hz), 1.42 (2H, sextet,
J ) 7 Hz), 0.87 (3H, t, J ) 7 Hz); 13C NMR δ 158.7, 149.6 (CH),
140.3, 136.1 (CH), 132.8 (CH), 132.5, 128.5 (2C), 128.3 (2C), 125.0
(CH), 121.9 (CH), 31.7, 22.9, 13.9 (1C overlapped).
Data for 2-[1-(3-chlorophenyl)-3-methyl-1-butenyl]pyridine
(9q): yield 86%; 1H NMR (70:30 mixture of isomers) δ 8.64 (1H,
m), 7.70-6.70 (6H, m), 6.78 (0.7H, d, J ) 10 Hz), 5.99 (0.3H, d,
J ) 10 Hz), 2.63-2.28 (1H, m), 1.04 (6H, d, J ) 7 Hz).
Data for 2-[1-(3,4-cichlorophenyl)butenyl]pyridine (9r): yield
85%; 1H NMR (60:40 mixture of isomers) δ 8.60 (1H, br), 7.86-
6.76 (6.6H, m), 6.17 (0.4H, t, J ) 7 Hz), 2.15 (2H, q, J ) 7 Hz),
1.04 (3H, t, J ) 7 Hz).
1
Data for 2-[1-(4-chlorophenyl)-3-methyl-1-butenyl]pyridine
1
(9f): oil; yield 79%; H NMR (partial for major isomer) δ 8.65
Data for 2-[1-(3,4-dichlorophenyl)-1-pentenyl]pyridine (9s):
1
(1H, dd, J ) 2, 5 Hz, Py H-6), 7.68 (1H, td, 7,2 Hz, Py-H4), 7.19,
7.17 (4H, central legs of aromatic doublets), 5.95 (1H, d, J ) 10
Hz, vinyl), 2.54 (1H, overlapping septets), 1.04 (6H, d, J ) 8 Hz);
13C NMR (protonated carbons of major isomer) δ 149.7, 139.6,
136.1, 128.4 (2C), 128.3 (2C), 124.8, 121.9, 28.6, 23.0 (2C).
Data for 2-[1-(4-chlorophenyl)-1-hexenyl]pyridine (9g): yield
93%; 1H NMR (partial for major isomer) δ 8.64 (1H, dd, J ) 2, 5
Hz), 7.60 (1H, dt, J ) 2, 7 Hz), 7.28-7.03 (6H, m), 6.15
(1H, t, J ) 7 Hz), 2.17 (2H, m), 1.52-1.25 (4H, m), 0.83 (3H, t,
J ) 7 Hz).
yield 92%; H NMR (ca. 60:40 mixture of isomers) δ 8.67 (1H,
minor, dd, J ) 2, 5 Hz), 8.55 (1H, major, ddd, J ) 1, 2, 5 Hz)
7.69-6.98 (6H, m), 6.19 (1H, minor, t, J ) 7 Hz), 2.11 (2H, m),
1.48 (2H, sextet, br), 0.89 (3H, t, J ) 7 Hz).
Data for 2-[1-(3,4-dichlorophenyl)-3-methyl-1-butenyl]pyri-
dine (9t): yield 99%; 1H NMR (80:20 mixture of isomers) δ 8.67
(0.2H, m), 8.57 (0.8H, ddd, J ) 1, 2, 5 Hz), 7.64-6.85 (6H, m),
6.71 (0.8H, d, J ) 10 Hz), 5.99 (0.2H, d, J ) 10 Hz), 2.42 (1H,
m), 1.04 (6H, d, J ) 7 Hz).
Data for 2-[1-(4-methoxyphenyl)-3-methyl-1-butenyl]pyridine
(9u): 1H NMR (ca. 60:40 mixture of isomers) δ 8.52 (1H, m), 7.54
(1H, m), 7.3-6.3 (6.6H, m), 5.89 (0.4H, d, J ) 10 Hz), 3.75 (1.8H,
s), 3.67 (1.2H, s), 2.46 (1H, m), 1.02 (6H, d, J ) 7 Hz).
Data for 2-[1-(3-methoxyphenyl)-3-methyl-1-butenyl]pyridine
Data for 2-[1-(4-chlorophenyl)-4-methyl-1-pentenyl]pyridine
1
(9h): yield 99%; H NMR (partial for major isomer) δ 8.62 (1H,
dd, J ) 2, 5 Hz), 7.60 (1H, dt, J ) 2, 7 Hz), 7.41-6.89 (6H, m),
6.18 (1H, t, J ) 7 Hz), 2.03 (2H, t, J ) 7 Hz), 1.99-1.58 (1H, m),
0.88 (6H, d, J ) 7 Hz).
1
(9v): H NMR (ca. 60:40 mixture of isomers) δ 8.71 (1H, d, br),
Data for 2-[1-(4-chlorophenyl)-3,3-dimethyl-1-butenyl]pyri-
7.84 (1H, t, br, J ) 8 Hz), 7.55-6.70 (7.6H, m), 6.05 (0.4H, d,
J ) 10 Hz), 3.80 (1.8H, s), 3.74 (1.2H, s), 2.44 (1H, m), 1.10 (6H,
2 d, J ) 7 Hz).
1
dine (9i): yield 95%; H NMR (partial for major isomer) δ 8.65
(1H, dd, J ) 2, 5 Hz), 7.64 (1H, dt, J ) 2, 7 Hz), 7.25-7.04
(overlapping 2H, m), 7.20 (2H, d, J ) 9 Hz), 7.09 (2H, d, J ) 9
Hz), 6.21 (1H, s), 0.95 (9H, s); 13C NMR (major isomer only) δ
159.3, 149.2, 142.0, 141.3, 137.4, 135.8, 132.7, 128.1 (4C), 125.6,
122.0, 30.9 (3C).
Data for 2-[1-(4-isopropylphenyl)-3-methyl-1-butenyl]pyri-
dine (9w): yield 90%; 1H NMR (60:40 mixture of isomers) δ 8.65
(1H, m), 7.64-7.02 (7H, m), 6.72 (0.4H, d, J ) 10 Hz), 5.95 (0.6H,
d, J ) 10 Hz), 2.85 (1H, septet, J ) 7 Hz), 2.62-2.25 (1H, m),
1.20 (6H, d, J ) 7 Hz), 1.03 (6H, d, J ) 7 Hz).
Data for 2-[1-(4-chlorophenyl)-2-cyclopentylvinyl]pyridine
(9j): yield 97%; 1H NMR (mostly one isomer) δ 8.62 (1H, d, br),
7.75-6.76 (7H, m), 6.06 (1H, d, J ) 9 Hz), 2.52 (1H, m), 1.90-
1.10 (8H, m); 13C NMR δ 158.9, 149.7 (CH), 149.2, 138.7, 137.9
(CH), 136.0 (CH), 132.6, 128.5 (2CH), 128.3 (2CH), 125.0 (CH),
121.9 (CH), 40.3, 34.0 (2C), 25.6 (2C).
Data for (RS/SR)-2-[1-(4-chlorophenyl)ethyl]piperidinium
1
chloride ((RS/SR)-10a): yield 56%; H NMR (free base) δ 7.24
(2H, d, J ) 8.6 Hz), 7.13 (2H, d, J ) 8.6 Hz), 2.98-2.80 (1H, m),
2.63-2.29 (3H, m), 2.00-1.01 (overlapping 6H, m), 1.19 (3H, d,
J ) 6.4 Hz); 13C NMR (free base) δ 143.7, 132.0, 129.0 (2C),
128.6 (2C), 62.5, 47.4, 45.7, 30.4, 26.1, 25.0, 18.4. Anal. (C13H19-
Cl2N) C, H, Cl, N.
Data for 2-[1-(4-chlorophenyl)-2-cyclohexylvinyl]pyridine (9k):
1
yield 99%; H NMR (partial for major isomer) δ 8.66 (1H, dd,
J ) 2, 5 Hz), 7.65 (1H, ddd, J ) 1 2, 7 Hz), 7.44-7.05 (overlapping
2H, m), 7.22 (2H, d, J ) 9 Hz), 7.12 (2H, d, J ) 9 Hz), 5.98 (1H,
d, J ) 10 Hz), 2.31 (1H, m), 1.90-0.98 (10H, m); 13C NMR δ
158.8, 149.7 (CH), 149.1, 139.6, 138.2 (CH), 136.0 (CH), 132.6,
128.6 (2CH), 128.4 (2CH), 124.7 (CH), 121.9 (CH), 38.2, 33.1
(2C), 25.9, 25.5 (2C).
Data for (RR/SS)-2-[1-(4-chlorophenyl)ethyl]piperidinium
1
chloride ((RR/SS)-10a): yield 38%; H NMR (free base) δ 7.24
(2H, d, J ) 8.6 Hz), 7.08 (2H, d, J ) 8.6 Hz), 3.16-2.99 (1H, m),
2.71-2.42 (3H, m), 1.91-1.10 (overlapping 6H, m), 1.26 (3H, d,
J ) 6.7 Hz); 13C NMR (free base) δ 143.6, 131.9, 129.2 (2C),
128.5 (2C), 62.5, 47.5, 45.3, 30.9, 26.6, 25.1, 17.2. Anal. (C13H19-
Cl2N) C, H, Cl, N.
Data for 2-[1-(4-chlorophenyl)-2-phenylvinyl]pyridine (9l):
yield 99%; 1H NMR (partial for major isomer) δ 8.59 (1H, d, br),
7.83 (1H, s), 7.46-6.88 (12H, m).
General Procedure for Synthesizing Final Compounds 10.
2-[1-(4-Chlorophenyl)propyl]piperidine (10b). The E/Z mixture
of alkene 9b (8.0 g, 34.8 mmol) was dissolved in glacial acetic
acid (110 mL) inside the Parr bottle. Trifluoroacetic acid (2.5 mL)
was added, followed by the addition of 1.60 g of Pt/C. The reaction
mixture was shaken for 24 h and determined to be complete by
TLC. The reaction mixture was filtered through Celite and
concentrated in vacuo. The crude residue was diluted with EtOAc
(∼200 mL), and the organic phase was carefully washed 3× with
saturated aqueous NaHCO3 and 1× with brine. The organic phase
was dried with Na2SO4, filtered, and concentrated in vacuo to yield
a mixture of the RS/SR and RR/SS isomers 10a, which were
separable via SiO2 chromatography using 99.5% EtOAc/0.5% Et2-
NH f 10% MeOH/89.5% EtOAc/0.5% Et2NH as the eluent, giving
2.9 g of (RS/SR)-10b (35%) eluting first followed by 2.0 g of (RR/
SS)-10b (24%).
Data for (RS/SR)-2-[1-(4-chlorophenyl)propyl]piperidinium
chloride ((RS/SR)-10b): needle crystals; mp 239 °C; 1H NMR (270
MHz, D2O) δ 7.46 (2H, d, J ) 8.3 Hz), 7.28 (2H, d, J ) 8.3 Hz),
3.30 (1H, t, J ) 9.5 Hz), 3.24 (1H, d, J ) 11.7 Hz), 2.85 (1H, dt,
J ) 3.4, 8.0 Hz), 2.68 (1H, m), 2.30 (1H, d, br, J ) 6.8 Hz), 2.00-
1.75 (3H, m), 1.70-1.40 (4H, m), 0.65 (3H, t, J ) 3.4 Hz); 13C
NMR (free base) δ 141.9, 132.7, 130.4 (2C), 129.1 (2C), 61.9, 54.3,
48.0, 31.4, 26.9, 25.6, 25.2, 12.6. Anal. (C14H21Cl2N) C, H, Cl, N.
Data for 2-[1-(4-chlorophenyl)-3-phenylpropenyl]pyridine
1
(9m): yield 87%; H NMR (one major isomer) δ 8.69 (1H, ddd,
J ) 1, 2, 5 Hz), 7.64 (1H, dt, J ) 2, 7 Hz), 7.45-6.75 (11 H, m),
6.31 (1H, t, J ) 7 Hz), 3.52 (2H, d, J ) 7 Hz); 13C NMR δ 158.2,
149.8, 140.7, 140.2, 139.9, 136.2, 133.1, 130.7, 128.6 (2C), 128.53
(2C), 128.48 (2C), 128.4 (2C), 126.2, 125.0, 122.2, 35.7.
Data for 2-[1-(4-chlorophenyl)-4-phenylbutenyl]pyridine (9n):
yield 88%; 1H NMR (60:40 mixture of isomers) δ 8.63 (0.6H, ddd,
J ) 1, 2, 5 Hz), 8.57 (0.4H, ddd, J ) 1, 2, 5 Hz), 7.54 (0.6H, dt,
J ) 2, 5 Hz), 7.42-6.76 (11.4 H, m), 6.15 (0.6 H, t, J ) 7 Hz),
2.75 (2H, t. J ) 7 Hz), 2.44 (2H, q, J ) 7 Hz).
Data for 2-[1-(4-chlorophenyl)-2-ethyl-1-butenyl]pyridine (9o):
1
yield 97%; H NMR δ 8.53 (1H, ddd, J ) 1, 2, 5 Hz), 7.44 (1H,
dt, J ) 2, 7 Hz), 7.40-6.97 (5H, m), 2.18 (4H, q, J ) 7 Hz), 2.15
(2H, q, J ) 7 Hz), 1.00 (6H, t, J ) 7 Hz); 13C NMR δ 161.1,
149.3, 145.2, 140.6, 136.0, 132.4, 130.9 (2C), 128.3 (2C), 127.6,
124.2, 121.1, 24.9, 24.6, 13.2 (2C).
Data for 2-[(4-chlorophenyl)cyclopentylidenemethyl]pyridine
(9p): yield 89%; 1H NMR δ 8.58 (1H, dd, J ) 2, 5 Hz), 7.52 (1H,
dt, J ) 2, 7 Hz), 7.28 (2H, d, J ) 9 Hz), 7.21-6.98 (overlapping
2H, m), 7.14 (2H, d, J ) 9 Hz), 2.56-2.31 (m, 4H), 1.75-1.59
(4H, m); 13C NMR δ 160.7, 149.0, 148.2, 140.7, 135.9, 132.1,
131.5, 130.7 (2C), 128.3 (2C), 124.0, 120.9, 33.8, 33.2, 26.9, 26.5.

228 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
Data for (RR/SS)-2-[1-(4-chlorophenyl)propyl]piperidinium
chloride ((RR/SS)-10b): mp 238-239 °C; H NMR (270 MHz,
br), 2.65-2.30 (3H, m), 1.96-1.03 (14H, m), 0.80 (3H, t, J ) 7.2
Hz); 13C NMR (free base) δ 141.7, 132.1, 129.8 (2C), 128.6 (2C),
61.7, 51.9, 47.4, 31.8 (2C), 30.9, 27.1, 26.3, 25.1, 22.5, 14.0. Anal.
(C17H27Cl2N) C, H, Cl, N.
1
D2O) δ 7.42 (2H, d, J ) 8.3 Hz), 7.23 (2H, d, J ) 8.3 Hz), 3.37
(2H, t, br, J ) 6.5 Hz), 3.05 (1H, t, J ) 2.5 Hz), 2.80 (1H, m),
1.90-1.65 (4H, m), 1.58-1.20 (4H, m), 0.72 (3H, t, J ) 7.0 Hz);
13C NMR (free base) δ 138.5, 133.1, 129.9 (2C), 129.2 (2C), 61.6,
50.5, 45.9, 28.0, 25.5, 22.6, 22.3, 11.9. Anal. (C14H21Cl2N) C, H,
Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)hexyl]piperidinium
1
chloride ((RR/SS)-10g): yield 34%; H NMR (free base) δ 7.20
(2H, d, J ) 8.6 Hz), 7.04 (2H, d, J ) 8.6 Hz), 3.20-2.95 (1H, d,
br), 2.73-2.35 (3H, m), 1.97-0.99 (14H, m), 0.80 (3H, t, J ) 7.2
Hz); 13C NMR (free base) δ 141.7, 131.9, 129.9 (2C), 128.4 (2C),
61.6, 51.8, 47.5, 31.9, 31.5, 30.9, 27.3, 26.9, 25.1, 22.5, 14.1. Anal.
(C17H27Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)butyl]piperidinium
chloride ((RS/SR)-10c): mp 211-2 °C; 1H NMR (270 MHz, D2O)
δ 7.45 (2H, d, J ) 8.3 Hz), 7.29 (2H, d, J ) 8.3 Hz), 3.36-3.22
(2H, m), 2.89-2.75 (2H, m), 1.92-1.72 (4H, m), 1.67-1.45 (4H,
m), 1.07-0.94 (2H, m), 0.78 (3H, t, J ) 7.3 Hz). Anal. (C15H23-
Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)butyl]piperidinium
chloride ((RR/SS)-10c): mp 234 °C; 1H NMR (270 MHz, D2O) δ
7.43 (2H, d, J ) 8.3 Hz), 7.25 (2H, d, J ) 8.3 Hz), 3.45-3.30
(2H, m), 3.07-2.85 (2H, m), 1.83-1.71 (4H, m), 1.50-1.32 (4H,
m), 1.12-1.05 (2H, m), 0.82 (3H, t, J ) 7.3 Hz). Anal. (C15H23-
Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-4-methylpentyl]pip-
eridinium chloride ((RS/SR)-10h): yield 56%; mp 207-209 °C;
1H NMR (free base) δ 7.23 (2H, d, J ) 8.6 Hz), 7.12 (2H, d, J )
8.6 Hz), 3.03-2.78 (1H, d, br), 2.65-2.25 (3H, m), 1.99-1.04
(12H, m), 0.70 (6H, d, J ) 7 Hz); 13C NMR (free base) δ 141.7,
132.1, 129.8 (2C), 128.6 (2C), 61.7, 52.1, 47.5, 36.7, 30.9, 29.6,
28.0, 26.3, 25.1, 22.9, 22.1. Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-4-methylpentyl]pip-
eridinium chloride ((RR/SS)-10h): yield 37%; 1H NMR (free base)
δ 7.24 (2H, d, J ) 8.6 Hz), 7.05 (2H, d, J ) 8.6 Hz), 3.20-2.96
(1H, d, br), 2.72-2.35 (3H, m), 1.99-1.06 (12H, m), 0.79 (6H, d,
J ) 7 Hz); 13C NMR (free base) δ 141.5, 131.9, 129.9 (2C), 128.4
(2C), 61.7, 52.0, 47.5, 36.9, 30.8, 29.1, 28.1, 26.8, 25.0, 22.9, 22.3.
Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-2-methylpropyl]pip-
1
eridinium chloride ((RS/SR)-10d): mp 305-306 °C; H NMR
(270 MHz, D2O) δ 7.44 (2H, d, J ) 8.3 Hz), 7.23 (2H, d, J ) 8.3
Hz), 3.64-3.55 (1H, m), 3.30 (1H, dd, J ) 1.6, 12.2 Hz), 3.05
(1H, dt, J ) 3.0, 7.2 Hz), 2.65 (1H, dt, J ) 2.4, 6.0 Hz), 2.15 (1H,
septet, J ) 7 Hz), 2.03 (1H, d, J ) 12 Hz), 1.91-1.70 (2H, m),
1.61-1.24 (3H, m), 0.99 (3H, t, J ) 6.6 Hz), 0.71 (3H, t, J ) 6.6
Hz); 13C NMR (free base) δ 138.9, 132.0, 131.1 (2C), 128.1 (2C),
57.7, 57.3, 47.4, 29.9, 27.4, 27.2, 25.0, 21.5, 18.9. Anal. (C15H23-
Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-3,3-dimethylbutyl]-
piperidinium chloride ((RS/SR)-10i): yield 56%; mp, sublimes
1
above 270 °C; H NMR (free base) δ 7.24 (2H, d, J ) 8.6 Hz),
7.16 (2H, d, J ) 8.6 Hz), 3.01-2.87 (1H, m), 2.59-2.28 (3H, m),
1.97-0.93 (8H, m), 0.74 (9H, s); 13C NMR (free base) δ 143.5,
131.8, 130.3 (2C), 128.5 (2C), 62.6, 48.2, 47.5, 45.9, 31.2, 30.9,
30.1 (3C), 26.2, 25.2. Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-2-methylpropyl]pip-
1
eridinium chloride ((RR/SS)-10d): mp 309 °C; H NMR (270
MHz, D2O) δ 7.46 (2H, d, J ) 8.3 Hz), 7.27 (2H, d, J ) 8.3 Hz),
3.68 (1H, m), 3.25 (1H, m), 2.95 (1H, m), 2.75 (1H, m), 2.24 (2H,
m), 1.91 (2H, m), 1.70-1.32 (3H, m), 0.79 (3H, d, J ) 6.6 Hz),
0.74 (3H, d, J ) 6.6 Hz); 13C NMR (free base) δ 138.8, 132.2,
131.1 (2C), 128.1 (2C), 57.6 (2C), 47.5, 31.1, 27.5, 26.5, 25.2, 21.8,
18.3. Anal. (C15H23Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-3,3-dimethylbutyl]-
piperidinium chloride ((RR/SS)-10i): yield 36%; mp 319-320
1
°C; H NMR (free base) δ 7.25 (2H, d, J ) 8.6 Hz), 7.10 (2H, d,
J ) 8.6 Hz), 3.20-2.96 (1H, d, br), 2.67-2.37 (3H, m), 1.79-
0.88 (8H, m), 0.75 (9H, s); 13C NMR (free base) δ 143.1, 131.7,
130.3 (2C), 128.3 (2C), 62.8, 47.9, 47.5, 45.3, 31.6, 31.2, 30.2 (3C),
26.8, 25.1. Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)pentyl]piperidinium
1
chloride ((RS/SR)-10e): H NMR (free base) δ 7.26 (2H, d, J )
Data for (RS/SR)-2-[1-(4-chlorophenyl)-2-cyclopentylethyl]-
9 Hz), 7.13 (2H, d, J ) 9 Hz), 2.90 (1H, d, J ) 12 Hz, br), 2.65-
2.3 (3H, m), 1.95-0.95 (12H, m), 0.79 (3H, t, J ) 7 Hz); 13C
NMR (free base) δ 141.7, 132.1, 129.8 (2C), 128.6 (2C), 61.7, 51.9,
47.5, 31.5, 30.9, 29.7, 26.3, 25.1, 22.7, 13.9. Anal. (C16H25Cl2N)
C, H, Cl, N.
1
piperidinium chloride ((RS/SR)-10j): yield 54%; H NMR (free
base) δ 7.25 (2H, d, J ) 8.6 Hz), 7.16 (2H, d, J ) 8.6 Hz), 3.04-
2.78 (1H, m), 2.58-2.28 (3H, m), 1.97-0.95 (17H, m); 13C NMR
(free base) δ 141.8, 132.0, 129.9 (2C), 128.6 (2C), 61.9, 50.9, 47.4,
38.5, 37.5, 33.7, 31.7, 30.8, 26.2, 25.1 (3C). Anal. (C18H27Cl2N)
C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)pentyl]piperidinium
1
chloride ((RR/SS)-10e): H NMR (free base) δ 7.26 (2H, d, J )
Data for (RR/SS)-2-[1-(4-chlorophenyl)-2-cyclopentylethyl]-
8.6 Hz), 7.06 (2H, d, J ) 8.6 Hz), 3.08 (1H, dd, br, J ) 1, 12 Hz),
2.72-2.32 (3H, m), 2.00-1.9 (12H, m), 0.80 (3H, t, J ) 7.5 Hz);
13C NMR (free base) δ 141.6, 131.8, 129.9 (2C), 128.4 (2C), 61.6,
51.7, 47.5, 31.2, 30.8, 29.9, 26.8, 25.0, 22.7, 14.0. Anal. (C16H25-
Cl2N) C, H, Cl, N.
1
piperidinium chloride ((RR/SS)-10j): yield 36%; H NMR (free
base) δ 7.26 (2H, d, J ) 8.6 Hz), 7.07 (2H, d, J ) 8.6 Hz), 3.22-
2.98 (1H, d, br), 2.71-2.40 (3H, m), 1.86-0.96 (17H, m); 13C NMR
(free base) δ 141.6, 131.8, 129.9 (2C), 128.3 (2C), 61.9, 50.6, 47.4,
38.1, 37.6, 33.6, 31.6, 30.8, 26.7, 25.1 (2C), 25.0. Anal. (C18H27-
Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-2-cyclohexylethyl]-
piperidinium chloride ((RS/SR)-10k): yield 55%; 1H NMR (free
base) δ 7.28 (2H, d, J ) 8.6 Hz), 7.11 (2H, d, J ) 8.6 Hz), 3.01-
2.80 (1H, m), 2.61-2.35 (3H, m), 1.84-0.88 (19H, m); 13C NMR
(free base) δ 141.6, 132.0, 129.8 (2C), 128.6 (2C), 62.1, 48.4, 47.3,
39.5, 34.6 (2C), 32.0, 30.6, 26.6, 26.2, 26.0 (2C), 25.0. Anal.
(C19H29Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-3-methylbutyl]pip-
eridinium chloride ((RS/SR)-10f): mp 276-7 °C; 1H NMR (270
MHz, D2O) δ 7.45 (2H, d, J ) 8.3 Hz), 7.32 (2H, d, J ) 8.3 Hz),
3.32-3.15 (2H, m), 2.94-2.76 (2H, m), 2.29 (1H, d, br, J ) 8.8
Hz), 1.96-1.76 (2H, m), 1.74-1.40 (5H, m), 1.18-1.02 (1H, m),
0.79 (3H, d, J ) 8.8 Hz), 0.77 (3H, d, J ) 8.8 Hz); 13C NMR (free
base) δ 141.6, 132.0, 129.8 (2C), 128.6 (2C), 62.0, 49.5, 47.4, 41.1,
30.8, 26.3, 25.2, 25.0 24.1, 21.0. Anal. (C16H25Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-3-methylbutyl]pip-
eridinium chloride ((RR/SS)-10f): mp 296-7 °C; 1H NMR (free
base) δ 7.26 (2H, d, J ) 8.3 Hz), 7.08 (2H, d, J ) 8.3 Hz), 3.09
(1H, dd, br, J ) 3, 12 Hz), 2.85-2.38 (3H, m), 1.75-0.98 (10H,
m), 0.81 (3H, d, J ) 7 Hz), 0.73 (3H, d, J ) 7 Hz); 13C NMR
(free base) δ 141.4, 131.8, 129.9 (2C), 128.3 (2C), 61.9, 49.2, 47.4,
40.7, 30.8, 26.7, 25.3, 25.0, 24.4, 21.1. Anal. (C16H25Cl2N) C, H,
Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-2-cyclohexylethyl]-
piperidinium chloride ((RR/SS)-10k): yield 37%; 1H NMR (CD3-
OD) δ 7.40 (2H, d, J ) 9 Hz), 7.24 (2H, d, J ) 9 Hz), 3.48-2.92
(4H, m), 1.86-0.77 (19H, m); 13C NMR (CD3OD) δ 139.2, 134.3,
131.5 (2C), 130.3 (2C), 62.5, 49.0 (2C), 40.1, 35.8, 35.5, 32.8, 28.0,
27.5, 27.2, 27.0, 23.34, 23.26. Anal. (C19H29Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-2-phenylethyl]pip-
eridinium chloride ((RS/SR)-10l): yield 56%; 1H NMR (free base)
Data for (RS/SR)-2-[1-(4-chlorophenyl)hexyl]piperidinium
1
chloride ((RS/SR)-10g): yield 51%; H NMR (free base) δ 7.27
δ 7.25-6.78 (9H, m), 3.25-2.33 (6H, m), 2.02-1.02 (6H, m); 13
NMR (free base) δ 140.4, 140.0, 132.1, 130.0 (2C), 129.0 (2C),
C
(2H, d, J ) 8.6 Hz), 7.11 (2H, d, J ) 8.6 Hz), 3.03-2.78 (1H, d,

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 229
128.4 (2C), 128.0 (2C), 125.7, 60.7, 53.8, 47.4, 38.6, 31.1, 26.3,
25.0. Anal. (C19H23Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(3-chlorophenyl)-3-methylbutyl]pip-
eridinium chloride ((RR/SS)-10q): yield 32%; 1H NMR (free base)
δ 7.32-6.96 (4H, m), 3.21-2.97 (1H, d, br, J ) 2, 12), 2.73-
2.45 (3H, m), 1.81-1.02 (9H, m), 0.81 (6H, d, J ) 6 Hz); 13C
NMR (free base) δ 145.2, 134.1, 129.4, 128.6, 126.9, 126.4, 61.9,
49.7, 47.4, 40.7, 30.9, 26.7, 25.3, 25.0, 24.1, 21.1. Anal. (C16H25-
Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-2-phenylethyl]pip-
eridinium chloride ((RR/SS)-10l): yield 36%; mp 250-2 °C; 1H
NMR (free base) δ 7.16-6.75 (9H, m), 3.27-2.45 (6H, m), 1.78-
1.08 (6H, m); 13C NMR (free base) δ 140.4, 140.0, 131.6, 129.8
(2C), 128.7 (2C), 127.9 (2C), 127.8 (2C), 125.5, 60.5, 53.3, 47.1,
38.0, 30.5, 26.6, 24.7. Anal. (C19H23Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-3-phenylpropyl]pip-
Data for (RS/SR)-2-[1-(3,4-dichlorophenyl)butyl]piperidinium
chloride ((RS/SR)-10r): yield 53%; recrystallized from CH3CN/
1
1
EtOH, 9:1; H NMR (free base) δ 7.36 (1H, d, J ) 8.1 Hz), 7.30
eridinium chloride ((RS/SR)-10m): yield 53%; H NMR (CD3-
(1H, d, J ) 2.1 Hz), 7.05 (1H, dd, J ) 2.1, 8.1 Hz), 3.03-2.80
(1H, d, br), 2.70-2.27 (3H, m), 2.01-0.93 (10H, m), 0.81 (3H, t,
J ) 7.2 Hz); 13C NMR (free base) δ 143.8 (2C), 132.5, 130.3 (2C),
127.9, 61.4, 51.7, 47.4, 33.9, 30.9, 26.3, 25.1, 20.6, 14.0. Anal.
(C15H22Cl3N) C, H, Cl, N.
OD) δ 7.48 (2H, d, J ) 9 Hz), 7.31 (2H, d, J ) 9 Hz), 7.29-7.00
(5H, m), 3.48-3.12 (2H, m), 3.01-2.68 (2H, m), 2.47-1.46 (10H,
m); 13C NMR (CD3OD) δ 142.3, 138.6, 134.7, 131.6 (2C), 130.5
(2C), 129.4 (4C), 127.0, 62.6, 49.3, 46.9, 34.0, 33.4, 27.8, 23.3,
23.2. Anal. (C20H25Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(3,4-dichlorophenyl)butyl]piperidinium
chloride ((RR/SS)-10r): yield 36%; recrystallized from CH3CN/
Data for (RR/SS)-2-[1-(4-chlorophenyl)-3-phenylpropyl]pip-
1
eridinium chloride ((RR/SS)-10m): yield 36%; H NMR (CD3-
1
EtOH, 6:1; H NMR (free base) δ 7.34 (1H, d, J ) 8.2 Hz), 7.24
OD) δ 7.43 (2H, d, J ) 9 Hz), 7.26 (2H, d, J ) 9 Hz), 7.22-7.04
(5H, m), 3.48-3.25 (2H, m), 3.18-2.81 (2H, m), 2.49-1.27 (10H,
m); 13C NMR (CD3OD) δ 142.3, 138.7, 134.4, 131.6 (2C), 130.1
(2C), 129.4 (4C), 127.0, 62.1, 49.2, 46.7, 34.2 (2C), 27.9, 23.2 (2C).
Anal. (C20H25Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-4-phenylbutyl]pip-
eridinium chloride ((RS/SR)-10n): yield 56%; 1H NMR (free base)
δ 7.30-6.99 (9H, m), 2.96-2.74 (1H, d, br), 2.67-2.23 (5H, m),
1.99-0.81 (10H, m); 13C NMR (free base) δ 142.1, 141.3, 132.1,
129.8 (2C), 128.6 (2C), 128.3 (2C), 128.2 (2C), 125.7, 61.6, 51.6,
47.3, 35.8, 31.2, 30.7, 29.1, 26.2, 25.0. Anal. (C21H27Cl2N) C, H,
Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-4-phenylbutyl]pip-
eridinium chloride ((RR/SS)-10n): yield 37%; 1H NMR (free base)
δ 7.27-6.96 (9H, m), 3.14-2.90 (1H, m), 2.69-2.28 (5H, m),
1.99-0.81 (10H, m); 13C NMR (free base) δ 142.1, 141.2, 131.9,
129.8 (2C), 128.4 (2C), 128.3 (2C), 128.2 (2C), 125.6, 61.4, 51.6,
47.3, 35.8, 31.0, 30.7, 29.3, 26.6, 24.9. Anal. (C21H27Cl2N) C, H,
Cl, N.
(1H, d, J ) 2.0 Hz), 6.98 (1H, dd, J ) 2.0, 8.2 Hz), 3.21-2.98
(1H, d, br), 2.75-2.32 (3H, m), 1.95-0.96 (10H, m), 0.83 (3H, t,
J ) 7.2 Hz); 13C NMR (free base) δ 143.6 (2C), 132.2, 130.4,
130.1, 128.0, 61.3, 51.5, 47.4, 33.6, 30.8, 26.7, 24.9, 20.7, 14.0.
Anal. (C15H22Cl3N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(3,4-dichlorophenyl)pentyl]piperidin-
ium chloride ((RS/SR)-10s): yield 55%; recrystallized from CH3-
CN; 1H NMR (free base) δ 7.37 (1H, d, J ) 8.5 Hz), 7.30 (1H, d,
J ) 1.4 Hz), 7.04 (1H, dd, J ) 1.4, 8.5 Hz), 3.05-2.72 (1H, m),
2.56-2.27 (3H, m), 2.02-0.99 (12H, m), 0.80 (3H, t, J ) 7.2 Hz);
13C NMR (free base) δ 143.7 (2C), 132.5, 130.4 (2C), 127.9, 61.5,
51.9, 47.4, 31.4, 30.8, 29.7, 26.3, 25.0, 22.7, 13.9. Anal. (C16H24-
Cl3N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(3,4-dichlorophenyl)pentyl]piperidin-
ium chloride ((RR/SS)-10s): yield 37%; recrystallized from CH3-
CN; 1H NMR (free base) δ 7.35 (1H, d, J ) 8.3 Hz), 7.24 (1H, d,
J ) 2.0 Hz), 6.98 (1H, dd, J ) 2.0, 8.3 Hz), 3.21-2.98 (1H, m),
2.75-2.32 (3H, m), 1.95-0.96 (12H, m), 0.80 (3H, t, J ) 7.2 Hz);
13C NMR (free base) δ 143.6 (2C), 132.2, 130.4, 130.1, 128.0, 61.4,
51.7, 47.4, 31.1, 30.8, 29.8, 26.7, 24.9, 22.7, 14.0. Anal. (C16H24-
Cl3N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-chlorophenyl)-2-ethylbutyl]piperi-
1
dinium chloride ((RS/SR)-10o): yield 53%; H NMR (free base)
δ 7.25 (2H, d, J ) 8.6 Hz), 7.12 (2H, d, J ) 8.6 Hz), 3.05-2.78
(2H, m), 2.66-2.40 (2H, m), 1.82-1.06 (11H, m), 0.89 (3H, t, J
) 6 Hz), 0.86 (3H, t, J ) 6 Hz); 13C NMR (free base) δ 139.3,
132.1, 131.0 (2C), 128.1 (2C), 57.6, 52.8, 47.5, 41.2, 31.3, 26.6,
25.2, 22.6 (2C), 11.9, 11.4. Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-chlorophenyl)-2-ethylbutyl]piperi-
Data for (RS/SR)-2-[1-(3,4-dichlorophenyl)-3-methylbutyl]-
piperidinium chloride ((RS/SR)-10t): recrystallized from CH3-
1
CN/EtOH, 9:1; H NMR (free base) δ 7.37 (1H, d, J ) 8 Hz),
7.31 (1H, d, J ) 2 Hz), 7.06 (1H, dd, J ) 2, 7 Hz), 3.02-2.81
(1H, m), 2.60-2.32 (3H, m), 1.95-1.75 (2H, m), 1.60-1.13 (6H,
m), 0.80 (6H, d, J ) 6 Hz); 13C NMR (free base) δ 143.7 (2C),
132.5, 130.3 (2C), 127.9, 61.8, 49.6, 47.4, 41.0, 30.8, 26.3, 25.3,
25.0, 24.0, 21.0. Anal. (C16H24Cl3N) C, H, Cl, N.
1
dinium chloride ((RR/SS)-10o): yield 35%; H NMR (free base)
δ 7.24 (2H, d, J ) 8.6 Hz), 7.06 (2H, d, J ) 8.6 Hz), 3.20-2.51
(4H, m), 1.80-1.03 (11H, m), 0.90 (3H, t, J ) 7 Hz), 0.84 (3H, t,
J ) 6 Hz); 13C NMR (free base) δ 138.9, 131.6, 130.8 (2C), 127.6
(2C), 56.8, 52.5, 47.1, 40.0, 29.4, 26.8, 24.7, 22.0, 21.7, 11.0, 10.6.
Anal. (C17H27Cl2N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(3,4-dichlorophenyl)-3-methylbutyl]-
piperidinium chloride ((RR/SS)-10t): recrystallized from CH3-
CN; 1H NMR (free base) δ 7.36 (1H, d, J ) 8 Hz), 7.24 (1H, d, J
) 2 Hz), 6.99 (1H, dd, J ) 2, 7 Hz), 3.21-2.97 (1H, m), 2.72-
2.42 (3H, m), 1.74-1.01 (8H, m), 0.82 (3H, d, J ) 6 Hz), 0.77
(3H, d, J ) 6 Hz); 13C NMR (free base) δ 143.5 (2C), 132.2, 130.4,
130.1, 128.0, 61.8, 49.2, 47.4, 40.6, 30.8, 26.6, 25.3, 24.9, 24.0,
21.1. Anal. (C16H24Cl3N) C, H, Cl, N.
Data for (RS/SR)-2-[(4-chlorophenyl)cyclopentylmethyl]-
piperidinium chloride (RS/SR)-10p): yield 57%; mp 233-4 °C
1
(from CH3CN); H NMR (free base) δ 7.25 (2H, d, J ) 8.6 Hz),
7.10 (2H, d, J ) 8.6 Hz), 3.14-2.94 (1H, m), 2.89-2.68 (4H, m),
1.92-0.89 (14H, m); 13C NMR (free base, CDCl3) δ 140.4, 131.9,
130.8 (2C), 128.0 (2C), 59.4, 56.6, 47.6, 41.4, 32.0, 31.7, 30.9,
26.8, 25.3, 24.9, 24.7. Anal. (C17H25Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-methoxyphenyl)-3-methylbutyl]pi-
peridinium chloride ((RS/SR)-10u): the free base of this diaste-
reomer could be selectively precipitated as an oxalate salt; 1H NMR
(free base) δ 7.12 (2H, d, J ) 8 Hz), 6.84 (2H, d, J ) 2 Hz), 3.78
(3H, s), 3.05-2.80 (1H, d, br), 2.64-2.28 (3H, m), 1.94-1.05 (10H,
m), 0.80 (6H, d, J ) 7 Hz). Anal. (C17H28ClNO) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-methoxyphenyl)-3-methylbutyl]pi-
Data for (RR/SS)-2-[(4-chlorophenyl)cyclopentylmethyl]-
piperidinium chloride ((RR/SS)-10p): yield 32%; mp 250-1 °C
1
(from CH3CN); H NMR (free base) δ 7.25 (2H, d, J ) 8.6 Hz),
7.08 (2H, d, J ) 8.6 Hz), 3.16-2.93 (1H, m), 2.92-2.43 (4H, m),
2.09-0.85 (14H, m); 13C NMR (free base) δ 140.1, 131.9, 130.9
(2C), 128.0 (2C), 59.3, 56.8, 47.4, 41.4, 31.6 (2C), 28.4, 27.4, 25.2,
25.1, 24.6. Anal. (C17H25Cl2N) C, H, Cl, N.
1
peridinium chloride ((RR/SS)-10u): mp 238-40 °C; H NMR
(free base) δ 7.05 (2H, d, J ) 8 Hz), 6.82 (2H, d, J ) 2 Hz), 3.79
(3H, s), 3.23-3.01 (1H, d, br), 2.65-2.25 (3H, m), 1.90-0.98 (10H,
m), 0.80 (6H, d, J ) 7 Hz); 13C NMR (free base) δ 157.4, 134.0,
128.8 (2C), 113.0 (2C), 61.6, 54.5, 48.0, 46.7, 40.2, 29.9, 25.8,
24.7, 24.3, 23.5, 20.5. Anal. (C17H28ClNO) C, H, Cl, N.
Data for (RS/SR)-2-[1-(3-chlorophenyl)-3-methylbutyl]pip-
eridinium chloride ((RS/SR)-10q): yield 58%; 1H NMR (free base)
δ 7.32-7.02 (4H, m), 3.05-2.80 (1H, m), 2.63-2.30 (3H, m),
2.03-1.05 (9H, m), 0.80 (6H, d, J ) 6 Hz); 13C NMR (free base)
δ 145.5, 134.4, 129.7, 128.4, 126.9, 126.7, 61.9, 50.0, 47.4, 41.0,
30.8, 26.3, 25.2, 25.0, 24.1, 21.1. Anal. (C16H25Cl2N) C, H, Cl, N.
Data for (RS/SR)-2-[1-(3-methoxyphenyl)-3-methylbutyl]pi-
peridinium chloride ((RS/SR)-10v): 1H NMR (salt in CD3OD) δ
7.33 (1H, t, J ) 9), 6.96-6.78 (3H, m), 4.82 (2H, s), 3.82 (3H, s),

230 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
3.5-3.1 (1H, m), 3.08-2.76 (2H, m). 2.35-2.1 (1H, m), 2.0-
1.05 (9H, m), 0.84 (6H, d, J ) 7 Hz); 13C NMR (salt in CD3OD)
δ 161.9, 141.7, 131.4, 121.8, 115.5, 114.2, 62.2, 55.8, 48.5, 47.0,
41.0, 28.2, 26.2, 24.2, 23.4, 23.3, 21.3. Anal. (C17H28ClNO) C, H,
Cl, N.
Data for (RR/SS)-2-[1-(3-methoxyphenyl)-3-methylbutyl]pi-
peridinium chloride ((RR/SS)-10v): 1H NMR (salt in CD3OD) δ
7.30 (1Η, t, J ) 9 Hz), 6.93-6.77 (3H, m), 4.83 (2H, s, br), 3.80
(3H, s), 3.5-2.8 (3H, m), 1.95-1.05 (12H, m), 0.88 (6H, d, br, J
) 6 Hz); 13C NMR (salt in CD3OD) δ 161.6, 141.8, 131.0, 121.9,
115.8, 113.6, 62.6, 55.7, 48.2, 46.7, 41.6, 28.0, 26.3, 24.2, 23.4,
23.3, 21.3. Anal. (C17H28ClNO) C, H, Cl, N.
Data for (RS/SR)-2-[1-(4-isopropylphenyl)-3-methylbutyl]pi-
peridinium chloride ((RS/SR)-10w): 1H NMR (free base) δ 7.12
(4H, s), 3.03-2.72 (2H, m), 2.64-2.29 (3H, m), 1.98-1.07 (9H,
m), 1.24 (6H, d, J ) 7 Hz), 0.80 (6H, d, J ) 6 Hz); 13C NMR
(free base) δ 146.6, 140.2, 128.3 (2C), 126.4 (2C), 62.2, 49.6, 47.5,
41.2, 33.6, 30.9, 26.4, 25.2 (2C), 24.2, 24.0 (2C), 21.1. Anal.
(C19H32ClN) C, H, Cl, N.
Data for (RR/SS)-2-[1-(4-isopropylphenyl)-3-methylbutyl]pi-
peridinium chloride ((RR/SS)-10w): 1H NMR (free base) δ 7.12
(2H, d, J ) 9 Hz), 7.08 (2H, d, J ) 9 Hz), 3.20-2.96 (1H, m),
2.88 (1H, heptet, J ) 7 Hz), 2.68-2.45 (3H, m), 1.78-1.04 (9H,
m), 1.24 (6H, d, J ) 7 Hz), 0.81 (6H, d, J ) 6 Hz); 13C NMR
(free base) δ 146.5, 140.0, 128.4 (2C), 126.1 (2C), 62.1, 49.2, 47.5,
40.7, 33.6, 30.8, 26.8, 25.3, 25.1, 24.1, 24.0 (2C), 21.2. Anal.
(C19H32ClN) C, H, Cl, N.
(RS/SR)-2-[1-(3,4-Dichlorophenyl)-3-methylbutyl]-1-methylpi-
peridinium chloride ((RS/SR)-11). A solution of (RS/SR)-10t (0.18
g, 0.60 mmol) and HCHO (37% in H2O, 0.14 mL) in formic acid
(7 mL) was refluxed for 18 h. The reaction mixture was neutralized
with 2 N NaOH to pH 8. The aqueous layer was extracted with
CH2Cl2 (3×), and the organic layers were dried (Na2SO4) and
concentrated to give 0.18 g (95%) of 11: 1H NMR (free base) δ
7.36 (1H, d, J ) 8 Hz), 7.26 (1H, d, J ) 2 Hz), 7.02 (1H, dd, J )
2, 7 Hz), 3.22 (1H, dt, J ) 12, 6), 3.04-2.79 (1H, m), 2.35 (3H,
s), 2.20-1.17 (11H, m), 0.85 (6H, pseudo-t, J ) 6 Hz); 13C NMR
(free base) δ 143.2, 132.1, 131.2, 130.6, 129.9, 128.5, 70.1, 58.3,
43.2, 43.0, 33.4, 25.9, 25.4, 24.7, 24.4 (2C), 21.0. Anal. (C17H26-
Cl3N) C, H, Cl, N.
Data for (RR/SS)-2-[1-(3,4-dichlorophenyl)-3-methylbutyl]-
1-methylpiperidinium chloride ((RR/SS)-11): yield 95%; 1H NMR
(free base) δ 7.34 (1H, d, J ) 8 Hz), 7.26 (1H, d, J ) 2 Hz), 7.03
(1H, dd, J ) 2, 8 Hz), 3.07-2.80 (2H, m), 2.52-2.05 (2H, m),
2.37 (3H, s), 1.64-1.12 (9H, m), 0.84 (6H, d, J ) 6 Hz); 13C NMR
(free base) δ 143.5, 132.0, 131.2, 130.7, 129.9, 128.3, 67.5, 56.6,
43.7, 41.7, 39.8, 25.3, 24.6, 24.1, 23.8, 22.5, 21.4. Anal. (C17H26-
Cl3N) C, H, Cl, N.
The assays contained an aliquot of membrane preparation
(approximately 12-30 µg of protein, depending on the cell line,
which resulted in binding <10% of the total radioactivity), drug,
and [125I]RTI-55 (40-80 pM final concentration) in a final volume
of 250 µL. Krebs-HEPES assay buffer (25 mM HEPES, 122 mM
NaCl, 5 mM KCl, 1.2 mM MgSO4, 2.5 mM CaCl2, 1 µM pargyline,
100 µM tropolone, 2 mg of glucose/mL, 0.2 mg of ascorbic acid/
mL, pH 7.4) was used for all assays. Specific binding was defined
as the difference in binding observed in the presence and absence
of 5 µM mazindol (HEK-hDAT and -NET) or 5 µM imipramine
(HEK-hSERT). The membranes were preincubated with the drugs
at rt for 10 min before the addition of [125I]RTI-55. The reaction
was incubated for 90 min at rt in the dark and terminated by
filtration through Wallac Filtermat A filters using a 96-well Tomtec
cell harvester. Scintillation fluid (50 µL) was added to each filtered
spot, and the radioactivity remaining on the filter was determined
using a Wallac 1205 Betaplate or 1405 microBeta scintillation
counter. Competition experiments were conducted with duplicate
determinations of each point, and the experiments were repeated
at least two additional times.
(c) Uptake Assays. As previously described,42 HEK-hDAT,
-hSERT, and -hNET cells were grown on 150 mm diameter tissue
culture dishes. The medium was removed, and the plates were
washed twice with Ca2+- and Mg2+-free PBS. Fresh Ca2+- and
Mg2+-free PBS (2.5 mL) was then added, and the plates were placed
in a 25 °C water bath for 5 min. The cells were gently scraped
from the plates and were separated by trituration with a pipet for
5-10 aspirations and ejections. Aliquots (50 µL) of the suspended
cells were added to assay tubes containing the drugs and Krebs-
HEPES assay buffer in a final assay volume of 0.5 mL. After a 10
min preincubation in a 25 °C water bath, [3H]neurotransmitter (20
nM final concentration; [3H]DA, [3H]5-HT, or [3H]NE, 56, 26.9,
or 60 Ci/mmol, respectively) was added, and the assay was
incubated for 10 min. The reaction was terminated by filtration
through Wallac Filtermat A filters, presoaked in 0.05% polyeth-
ylenimine, using a Tomtec cell harvester. Scintillation fluid was
added to each filtered spot, and the radioactivity remaining on the
filters was determined as described above. The specific uptake was
defined as the difference in uptake observed in the absence and
presence of 5 µM mazindol (hDAT and hNET) or 5 µM imipramine
(hSERT). Competition experiments were run in triplicate for each
point, and the experiments were repeated at least two additional
times.
(d) Data Analysis. Prism software (GraphPad Software, San
Diego, CA) was used to analyze all kinetic, saturation, and
competition binding data. IC50 values were converted to Ki values
using the Cheng-Prusoff equation.
Locomotor Assays. These were conducted using 40 Digiscan
testing chambers (40.5 cm × 40.5 cm × 30.5 cm) housed in sets
of two within sound-attenuating enclosures. A panel of 16 infrared
beams and photodetectors were located in the horizontal direction
of each activity chamber. A 7.5 W incandescent light above each
chamber provided dim illumination, and fans provided an 80 dB
ambient noise level. Separate groups of eight nonhabituated, male
Swiss-Webster mice (Hsd:ND4, aged 2-3 months) were injected
via the intraperitoneal route with vehicle, cocaine, methylphenidate,
or the test compound immediately prior to locomotor testing. The
vehicle was 0.9% saline for cocaine and methylphenidate and
deionized water for (RR/SS)-10f. Horizontal activity (interruption
of photocell beams) was measured for 8 h within 10 min periods
beginning at 0800 h (2 h after lights on). Testing was conducted
with one mouse per activity chamber. ED50 values, doses producing
half-maximal stimulant activity ((maximum - mean control)/10
min), were estimated from a linear regression against log doses of
the ascending portion of the dose-response curves.
Data for (RR/SS)-1-Phenyl-1-(2-piperidinium)-2-propanone
chloride ((RR/SS)-15): yield 79%; mp 171-3 °C; 13C NMR
(CDOD3) δ 206.1, 133.1, 128.9 (2C), 128.4 (2C), 127.9, 60.3, 56.2,
44.7, 27.7, 25.5, 21.4, 21.1. Anal. (C14H20ClNO) C, H, Cl, N.
Binding and Uptake Assays. (a) Materials. Radioactive
compounds were purchased from Perkin-Elmer Life Sciences
(Boston, MA). Most other reagents were purchased from Sigma
Chemical Co. (St. Louis, MO).
(b) Radioligand Binding Assays. As previously described,42
HEK-hDAT and -hSERT cells were incubated in Dulbecco’s
modified Eagle’s medium supplemented with 5% fetal bovine
serum, 5% calf bovine serum, 0.05 U of penicillin/streptomycin,
and puromycin (2 µg/mL). HEK-hNET cells were incubated in
Dulbecco’s modified Eagle’s medium supplemented with 10% fetal
bovine serum, 0.05 U of penicillin/streptomycin, and Geneticin (300
µg/mL). Cells were grown until confluent on 150 mm diameter
tissue culture dishes in a humidified 10% CO2 environment at 37
°C. The medium was removed from the plates, the cells were
washed with 10 mL of PBS, lysis buffer (10 mL, 2 mM HEPES,
1 mM EDTA) was added, and the plates were placed on ice for 10
min. The cells were scraped from the plates and centrifuged for 20
min at 30000g. The pellet was resuspended in 6-24 mL of 0.32
M sucrose with a Polytron homogenizer at setting 7 for 5 s.
X-ray Crystallography. Crystallographic data for the structural
analysis have been deposited with the Cambridge Crystallographic
Data Centre, CCDC deposition no. 615455.
Acknowledgment. This work was supported by Grant
DA015795 from the National Institute on Drug Abuse and a

Alkyl Analogues of Methylphenidate
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2 231
(16) Kotian, P.; Mascarella, S. W.; Abraham, P.; Lewin, A. H.; Boja, J.
W.; Kuhar, M. J.; Carroll, F. I. Synthesis, Ligand Binding, and
Quantitative Structure-Activity Relationships Study of 3â-(4′-
Substituted phenyl)-2â-heterocyclic Tropanes: Evidence for an
Electrostatic Interaction at the 2â-Position. J. Med. Chem. 1996, 39,
2753-2763.
(17) Xu, L.; Kelkar, S. V.; Lomenzo, S. A.; Izenwasser, S.; Katz, J. L.;
Kline, R. H.; Trudell, M. L. Synthesis, Dopamine Transporter
Affinity, Dopamine Uptake Inhibition, and Locomotor Stimulant
Activity of 2-Substituted 3â-Phenyltropane Derivatives. J. Med.
Chem. 1997, 40, 858-863.
grant from DNAPrint Genomics of Sarasota, FL, to M.F.
Pharmacological assays were provided by the National Institute
on Drug Abuse as follows: monoamine transporter binding and
uptake studies under Interagency Agreement Contract Y1 DA
0107-05 to A.J. and mouse locomotor activities under Contracts
N01DA-2-9305 and N01DA-7-8076 to Michael J. Forster. X-ray
crystallographic studies were provided by Contract Y1-DA1002-
04 from the National Institute on Drug Abuse. We thank Jitendra
Belani for the mass spectra.
(18) Kozikowski, A. P.; Araldi, G. L.; Prakash, K. R. C.; Zhang, M.;
Johnson, K. M. Synthesis and Biological Properties of New 2â-Alkyl-
and 2â-Aryl-3-(substituted phenyl)tropane Derivatives: Stereochem-
ical Effect of C-3 on Affinity and Selectivity for Neuronal
Dopamine and Serotonin Transporters. J. Med. Chem. 1998, 41,
4973-4982.
Supporting Information Available: X-ray crystallographic data
and results from elemental analysis. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Xu, L.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.; Klein-Stevens, C.;
Zhu, N.; Lomenzo, S. A.; Winfield, L.; Trudell, M. L. Synthesis and
Biological Evaluation of 2-Substituted 3â-Tolyltropane Derivatives
at Dopamine, Serotonin, and Norepinephrine Transporters. J. Med.
Chem. 2002, 45, 1203-1210.
(20) Xu, L.; Kulkarni, S. S.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.;
Lomenzo, S. A.; Newman, A. H.; Trudell, M. L. Synthesis and
Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3â-
aryltropane Derivatives. J. Med. Chem. 2004, 47, 1676-1682.
(21) Sury, E.; Hoffman, K. Uber Alkylenimin-Derivate. 11. Mitteilung.
Piperidin-derivate mit Zentralerregender Wirkung I. HelV. Chim. Acta
1954, 37, 2133-2145.
(22) Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. A Stereoselective
Synthesis of dl-threo-Methylphenidate: Preparation and Biological
Evaluation of Novel Analogues. J. Org. Chem. 1998, 63, 9628-
9629.
(23) Froimowitz, M.; George, C. Conformational Analysis and a Crystal
Structure of Bupropion, an Antidepressant with Dopamine
Reuptake Blocking Activity. J. Chem. Inf. Comput. Sci. 1998, 38,
506-510.
(24) Froimowitz, M.; Wu, K.-M.; Rodrigo, J.; George, C. Conformational
Preferences of the Potent Reuptake Blocker BTCP and Its Analogs
and Their Incorporation into a Pharmacophore Model. J. Comput.-
Aided Mol. Des. 2000, 14, 135-146.
(25) Wolraich, M. L.; Doffing, M. A. Pharmacokinetic Considerations in
the Treatment of Attention-Deficit Hyperactivity Disorder with
Methylphenidate. CNS Drugs 2004, 18, 243-250.
(26) Patrick, K. S.; Kilts, C. D.; Breese, G. R. Synthesis and Pharmacology
of Hydroxylated Metabolites of Methylphenidate. J. Med. Chem.
1981, 24, 1237-1240.
(27) Oldendorf, W. H. Some Relationships between Addiction and Drug
Delivery to the Brain. In BioaVailability of Drugs to the Brain and
Blood-Brain Barrier; Frankenheim, J., Brown, R. M., Eds.; NIDA
Monograph 120; NIDA: Rockville, MD, 1992.
(28) Volkow, N. D.; Ding, Y.-S.; Fowler, J. S.; Wang, G.-J.; Logan, J.;
Gatley, J. S.; Dewey, S.; Ashby, C.; Liebermann, J.; Hitzemann, R.;
Wolf, A. P. Is Methylphenidate Like Cocaine? Studies on Their
Pharmacokinetics and Distribution in the Human Brain,” Arch. Gen.
Psychiatry 1995, 52, 456-463.
(29) Froimowitz, M.; Wu, K.-M.; Moussa, A.; Haidar, R. M.; Jurayji, J.;
George, C.; Gardiner, E. L. Slow-Onset, Long-Duration 3-(3′,4′-
Dichlorophenyl)-1-indanamine Monoamine Reuptake Blockers as
Potential Medications to Treat Cocaine Abuse. J. Med. Chem. 2000,
43, 4981-4992.
(30) Woolverton, W. L.; Wang, Z. Relationship Between Injection
Duration, Transporter Occupancy and Reinforcing Strength of
Cocaine. Eur. J. Pharmacol. 2004, 486, 251-257.
(31) Gardner, E. L.; Liu, X.; Paredes, W.; Giordano, A.; Spector, J.;
Lepore, M.; Wu, K.-M.; Froimowitz, M. A Slow-Onset, Long-
Duration Indanamine Monoamine Reuptake Inhibitor as a Potential
Maintenance Pharmacotherapy for Psychostimulant Abuse: Effects
in Laboratory Rat Models Relating to Addiction. Neuropharmacology
2006, 51, 993-1003.
(32) Deutsch, H. M.; Shi, Q.; Gruszecka-Kowalik, E.; Schweri, M. M.
Synthesis and Pharmacology of Potential Cocaine Antagonists. 2.
Structure-Activity Relationship Studies of Aromatic Ring-Substituted
Methylphenidate Analogs. J. Med. Chem. 1996, 39, 1201-1209.
(33) Gately, S. J.; Pan, D.; Chen, R.; Chaturvedi, G.; Ding, Y.-S. Affinities
of Methylphenidate Derivatives for Dopamine, Norepinephrine and
Serotonin Transporters. Life Sci. 1996, 58, PL 231-239.
(34) Deutsch, H. M. Structure-Activity Relationships for Methylphenidate
Analogs and Comparisons to Cocaine and Tropanes. Med. Chem.
Res. 1998, 8, 91-99.
References
(1) Panizzon, L. La Preparazione di Piridil- e Piperdil-Arilacetonitrili e
di Alcuni Prodotti di Transformazione (Parte I). HelV. Chim. Acta
1944, 27, 1748-1756.
(2) Maxwell, R. A.; Chaplin, E.; Eckhardt, S. B.; Soares, J. R.; Hite, G.
Conformational Similarities between Molecular Models of Phen-
ethylamine and of Potent Inhibitors of the Uptake of Tritiated
Norepinephrine by Adrenergic Nerves in Rat Aorta. J. Pharm. Exp.
Ther. 1970, 173, 158-165.
(3) Ferris, R. M.; Tang, F. L. M.; Maxwell, R. A. A Comparison of the
Capacities of Isomers of Amphetamine, Deoxypipradrol and Meth-
ylphenidate to Inhibit the Uptake of Tritiated Catecholamines into
Rat Cerebral Cortex Slices, Synaptosomal Preparations of Rat
Cerebral Cortex, Hypothalamus and Striatum and into Adrenergic
Nerves of the Rabbit Aorta. J. Pharm. Exp. Ther. 1972, 181, 407-
416.
(4) Solanto, M. V. Neuropsychopharmacological Mechanisms of Stimu-
lant Drug Action in Attention-Deficit Hyperactivity Disorder:
Review and Integration. BehaV. Brain Res. 1998, 94, 127-152.
(5) Shafi’ee, A.; Hite, G. The Absolute Configurations of the Phe-
niramines, Methyl Phenidates, and Pipradrols. J. Med. Chem. 1969,
12, 266-270.
A
(6) Froimowitz, M.; Patrick, K. S.; Cody, V. Conformational Analysis
of Methylphenidate and Its Structural Relationship to Other Dopamine
Reuptake Blockers such as CFT. Pharm. Res. 1995, 12, 1430-1434.
(7) Froimowitz, M. Conformational Analysis of Cocaine, the Potent
Analog 2â-Carbomethoxy-3â-(4-flurophenyl)tropane (CFT), and
Other Dopamine Reuptake Blockers. J. Comput. Chem. 1993, 14,
934-943.
(8) Miles, M. P.; Johnson, K. M.; Zhang, M.; Flippen-Anderson, J. L.;
Kozikowski, A. P. Tuning the Selectivity of Monoamine Transporter
Inhibitors by the Stereochemistry of the Nitrogen Lone Pair. J. Am.
Chem. Soc. 1998, 120, 9072-9073.
(9) Froimowitz, M.; Wu, K.-M.; George, C.; VanDerveer, D.; Shi, Q.;
Deutsch, H. M. Crystal Structures of Analogs of threo-Methylpheni-
date. Struct. Chem. 1998, 9, 295-303.
(10) Froimowitz, M.; Deutsch, H. M.; Shi, Q.; Wu, K.-M.; Glaser, R.;
Adin, I.; George, C.; Schweri, M. M. Further Evidence for a
Dopamine Reuptake Pharmacophore. The Effect of N-Methylation
on threo-Methylphenidate and its Analogs. Bioorg. Med. Chem. Lett.
1997, 7, 1213-1218.
(11) Kozikowski, A. P.; Xiang, L.; Tanaka, J.; Bergmann, J. S.; Johnson,
K. M. Use of Nitrile Oxide Cycloaddition (NOC) Chemistry in the
Synthesis of Cocaine Analogues; Mazindol Binding and Dopamine
Uptake Studies. Med. Chem. Res. 1991, 1, 312-321.
(12) Kozikowski, A. P.; Roberti, M.; Xiang, L.; Bergmann, J. S.; Callahan,
P. M.; Cunningham, K. A.; Johnson, K. M. Structure-Activity
Relationship Studies of Cocaine: Replacement of the C-2 Ester Group
by Vinyl Argues Against H-Bonding and Provides an Esterase-
Resistant, High Affinity Cocaine Analogue. J. Med. Chem. 1992,
35, 4764-4766.
(13) Kozikowski, A .P.; Roberti, M.; Johnson, K. M.; Bergmann, J. S.;
Ball, R. G. SAR of Cocaine: Further Exploration of Structural
Variations at the C-2 Center Provides Compounds of Subnanomolar
Binding Potency. Bioorg. Med. Chem. Lett. 1993, 3, 1327-1332.
(14) Kelkar, S. V.; Izenwasser, S.; Katz, J. L.; Klein, C. L.; Zhu, N.;
Trudell, M. L. Synthesis, Cocaine Receptor Affinity, and Dopamine
Uptake Inhibition of Several New 2â-Substituted 3â-Phenyltropanes.
J. Med. Chem. 1994, 37, 3875-3877.
(15) Kozikowski, A. P.; Saiah, M. K. E.; Johnson, K. M.; Bergmann, J.
S. Chemistry and Biology of the 2â-Alkyl-3â-phenyl Analogues of
Cocaine: Subnanomolar Affinity Ligands that Suggest a New
Pharmacophore Model at the C-2 Position. J. Med. Chem. 1995, 38,
3086-3093.

232 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 2
Froimowitz et al.
(35) Deutsch, H. M.; Ye, X.; Shi, Q.; Liu, Z.; Schweri, M. M. Synthesis
and Pharmacology of Site Specific Cocaine Abuse Treatment
Agents: A New Synthetic Methodology for Methylphenidate Analogs
Based on the Blaise Reaction. Eur. J. Med. Chem. 2001, 36, 303-
311.
(36) Madras, B. K.; Pristupa, Z. B.; Niznik, H. B.; Liang A. Y.; Blundell,
P.; Gonzalez, M. D.; Meltzer, P. C. Nitrogen-based Drugs are not
Essential for Blockade of Monoamine Transporters. Synapse 1996,
24, 340-348.
(37) Meltzer, P. C.; Wang, P.; Blundell, P.; Madras, B. K. Synthesis and
Evaluation of Dopamine and Serotonin Transporter Inhibition by
Oxacyclic and Carbacyclic Analogues of Methylphenidate. J. Med.
Chem. 2003, 46, 1538-1545.
(38) Kauffman, J. K.; Bjorkman, C. O. Improved Apparatus for Continuous
Column Chromatography. J. Chem. Educ. 1976, 53, 33.
(39) Giner, J.-L.; Margot, C.; Djerassi, C. Stereospecificity and Re-
giospecificity of the Phosphorus Oxychloride Dehydration of Sterol
Side Chain Alcohols. J. Org. Chem. 1989, 54, 369-373.
(40) Froimowitz, M.; Gu, Y.; Dakin, L. A.; Kelley, C. J.; Parrish, D.;
Deschamps, J. R. Vinylogous Amide Analogs of Methylphenidate.
Bioorgan. Med. Chem. Lett. 2005, 15, 3044-3047.
(41) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley-Interscience: New York, 1994; Chapter 5.
(42) Eshleman, A. J.; Carmolli, M.; Cumbay, M.; Martens, C. R.; Neve,
K. A.; Janowsky, A. Characteristics of Drug Interactions With
Recombinant Biogenic Amine Transporters Expressed in the Same
Cell Type. J. Pharmacol. Exp. Ther. 1999, 289, 877-885.
(43) Schweri, M. M.; Skolnick, P.; Rafferty, M. F.; Rice, K. C.; Janowsky,
A. J.; Paul, S. M. [3H]Threo-(()-Methylphenidate Binding to 3.4-
Dihydroxyphenethylamine Uptake Sites in Corpus Striatum: Cor-
relation with the Stimulant Properties of Ritalinic Acid Esters. J.
Neurochem. 1985, 45, 1062-1070.
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