Rational design and synthesis of novel 2,5-disubstituted cis- and trans-piperidine derivatives exhibiting differential activity for the dopamine transporter

Article abstract of DOI:10.1016/S0960-894X(01)00443-7

Herein, we report the rational design and synthesis of novel 2,5-disubstituted piperidine derivatives in the cis and trans isomeric forms. Out of these two isomers, the cis-isomer, 7a, was found to exhibit the most potent activity and selectivity for the

Full text of DOI:10.1016/S0960-894X(01)00443-7

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2337–2340
Rational Design and Synthesis of Novel 2,5-Disubstituted
cis- and trans-Piperidine Derivatives Exhibiting Differential
Activity for the Dopamine Transporter
Aloke K. Dutta,a,* Matthew Ca. Davisa,y and Maarten E. A. Reithb
aDepartment of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA
bUniversity of Illinois, College of Medicine, Department of Biomedical and Therapeutic Sciences, Peoria, IL 61605, USA
Received 18 May 2001; accepted 15 June 2001
Abstract—Herein, we report the rational design and synthesis of novel 2,5-disubstituted piperidine derivatives in the cis and trans
isomeric forms. Out of these two isomers, the cis-isomer, 7a, was found to exhibit the most potent activity and selectivity for the
dopamine transporter. These novel derivatives represent conformationally constrained version of piperidine analogue of GBR
compounds. # 2001 Elsevier Science Ltd. All rights reserved.
Widespread abuse of cocaine has become a national and
international problem and discovery of pharmacother-
apeutic agents for potential treatment of cocaine addic-
tion is urgent.1 Cocaine binds to all three monoamine
transporter molecules in the central nervous system
(CNS): the dopamine transporter (DAT), serotonin
transporter (SERT), and norepinephrine transporter
(NET). But the binding of cocaine to the DAT is impli-
cated strongly in its reinforcing effects.2,3 Thus, sig-
nificant effort has been directed towards development of
drugs for the DAT.4aꢀh
result, the structural complexity of the newly designed
compound increases due to introduction of the two
asymmetric centers relative to the parent molecule I.
Our current targets, the cis- and trans-derivatives (7a,b)
are derived from this structural representation and are
shown in Figure 2. These novel 2,5-disubstituted com-
pounds are conformationally constrained compared to
the parent lead I (Fig. 1). In this report, we describe the
rational design, synthesis and biological characteriza-
tion of these molecules.
The synthesis of our target molecules is shown in
Scheme 1 in a linear six-step process. The starting 2-
chloro-5-nitropyridine reacted with diphenylacetonitrile
Our ongoing structure–activity relationship (SAR)
studies of piperidine analogues of GBR 12909 resulted
in the development of many molecules with high affinity
and selectivity for the DAT.5aꢀc In our goal of convert-
ing flexible piperidine analogues into more rigid struc-
tures, we designed a general structural representation of
molecule II resulting from
a transformation of
molecular structure of our previous lead compound,
4-[2-(diphenyl)ethyl]-aminomethyl]-1-[(4-fluorophenyl)-
methyl]-piperidine I which is shown in Figure 1.5c Thus,
formation of a new piperidine ring from the secondary
amine and opening up of the existing piperidine ring of I
led to the formation of a general structure II. As a
*Corresponding author. Tel.: +1-313-577-1064; fax: +1-313-577-
2033; e-mail: adutta@wizard.pharm.wayne.edu
yCurrent address, Naval Air Warfare Center, Code 4T4200D, China
Lake, CA 93555, USA.
Figure 1. Structural transformation of I into relatively conform-
ationally constrained 2,5-disubstituted piperidine derivatives.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00443-7

2338
A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2337–2340
under phase-transfer condition consisting of toluene,
tetrabutylammonium fluoride and 50% NaOH to
furnish 2-(diphenyl-cyanomethyl)-5-nitropyridine 2 in
very good yield.6 Acidic hydrolysis of nitrile 2 by brief
treatment with aqueous sulfuric acid produced amide
intermediate 3 in good yield.7 In our initial effort, this
intermediate was hydrolyzed and decarboxylated to 5 in
one step by reaction with sulfuric acid and sodium
nitrite but only in fair yield. We found an alternative
two-step route that improved the yield of 5. The nitro
group of 3 was first reduced by hydrogenation in
presence of 10% Pd/C as a catalyst producing amino-
amide 4 in almost quantitative yield. Then 4 was
hydrolyzed and decarboxylated to 5 by refluxing 37%
HCl in excellent yield.
column chromatography. The reductive alkylation of 6
with less than one equivalent of 4-fluorobenzaldehyde
resulted in cis- and trans-isomers mixture, 7a,b, respec-
tively, which could then be separated by column chro-
matography.8,9 The mixture 6 was also converted into
amide mixtures 8a,b by reaction with 4-fluorobenzoyl
chloride as shown in Scheme 2 and was separated by
column chromatography to isolate pure 8a and 8b.
The assignment of structures of 7a,b and 8a,b was
determined by 1-D and 2-D NMR (400 MHz) experi-
ments (Table 1).8,9 In these compounds, the assumption
that the diphenylmethyl moiety would assume the
equatorial position was borne out by the data. The com-
pound 7a eluted first from the column. The multiplet
at d 2.7 ppm attributed to H-5 is 13 Hz broad (over-
lapping with one half of the H-6 doublet) composed of
Æ (3J5,4+3J5,6). This small Æ3J for H-5 is consistent
In the key step, hydrogenation (60psi) of 5 in the pre-
sence of PtO2 (IV) yielded cis- and trans-isomers 6 in
approximately 3:2 ratio (by NMR), respectively. This
mixture was too difficult to separate using preparative
3
3
with H-5eq orientation having two Jaxeq and two Jeqeq
couplings. The signal attributed to H-2, d 3.28 ppm, is a
Figure 2. Two geometrical isomers of our target compounds.
Scheme 1.
Scheme 2.

A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2337–2340
2339
doublet of triplets (3J 4.4 and 10.8 Hz) where
3J2,3ax=3J2,CH(Ph) . The large coupling of H-2 and
H-3ax is consisten2t with H-2ax orientation (Table 1).
binding activity for the DAT. Recently in another
study, 2,3-disubstituted analogues of piperidine were
developed which exhibited good affinity for the DAT
and the activity resided mainly in the cis-isomeric form
of these compounds.10a In another recent study, 3- and
4-amino derivatives of piperidine molecules were devel-
oped which showed potent affinities for both the DAT
and NET.10b
The compound, 7b, eluting last has the trans configura-
tion. The multiplet at d 2.65 ppm attributed to H-5
is 36 Hz broad. The H-6ax signal, d 2.33, appears as a
3
3
triplet (2J6ax6eq and J6ax5) with J=10.4 Hz indicating
that H-5 is axially oriented. The Æ3J for H-5 is con-
3
sistent with axial orientation having two Jaxeq and two
3
The binding affinity of 7a,b and 8a for monoamine
transporter systems was evaluated by measuring their
potency in inhibiting binding of [3H]WIN 35,428 to
DAT, [3H]citalopram to SERT, and [3H]nisoxetine to
NET in rat brain tissue (Table 2). Binding results
demonstrated more activity for the cis isomer (ꢁ)-7a
compared to the trans (ꢁ)-7b (IC50 of 30nM vs
212 nM). Thus the cis isomer was 7 times more potent
than the trans isomer for the DAT. The selectivity of the
cis isomer for the DAT was 93 when compared against
SERT and was 45 when compared against NET (Table
3). Furthermore, the cis compound (ꢁ)-7a was much
more potent at DAT than cocaine (IC50 of 30nM vs
266 nM; Table 2) and was also much more selective at
the DAT than cocaine when compared against either
SERT or NET. In addition, the more active cis com-
pound also turned out to be more selective than our
large Jaxax couplings. Unfortunately, the signal attrib-
uted to H-2, d 3.2, overlaps with H-6eq and the expected
triplet (3J2a3a=3J2aCH(Ph)2) could not be confirmed.
However, the peakwidth of H-2 signal is 20Hz broad
indicating H-2 in an axial position. In addition, in a
nuclear Overhouser experiment, irradiation of H-6ax
resulted in an enhancement of (H2,H6eq) peak. There-
fore, H-2 must be axially oriented in order to have this
interaction.
Our previous SAR studies in piperidine analogues of
GBR compounds developed 1,4-disubstituted piperidine
compounds showing selective affinity for the DAT.
These substituted piperidine analogues are also quite
flexible and it is not clear at this point the extent of
contribution of their flexibility in their high affinity
Table 1. Selected NMR data of 7a,b
Compd
Chemical shifts
Multiplicity
Coupling constants
7a
H2ax
H5eq,H6ax
H6eq
3.28
2.65–2.72
2.99
dt
m
dd
J2ax,3ax=J2ax,a=10.8 Hz, J2ax,3eq=4.4 Hz
Peak width=13 Hz
J6eq,6ax=12.9 Hz, J6eq,5eq=6 Hz
7b
H2ax,H6eq
H5ax
H6ax
3.15–3.25
2.60–2.70
2.33
m
m
t
Peak width=20Hz
Peak width=36 HZ
J6ax,5ax=10.4 Hz, J6ax,6eq=10.4 Hz
Table 2. Binding activity of 7a,b and 8a at the dopamine, serotonin and norepinephrine transporters in rat brain tissue
Compd
DAT, IC50 (nM)
[3H]WIN 35, 428a
SERT, IC50 (nM)
[3H]citaloprama
NET, IC50 (nM)
[3H]nisoxetinea
[3H]DA uptake
Inhibition, IC50 (nM)a
Cocaine
I
(ꢁ)-7a
(ꢁ)-7b
(ꢁ)-8a
266ꢁ37
737ꢁ1603520
137ꢁ46
ꢁ554
191ꢁ28
ꢁ7.2
19.7ꢁ1.4b
30.0ꢁ0.5
212ꢁ201330
87.0ꢁ8.8
1110ꢁ12049.6
1349ꢁ19028.9
4470ꢁ1,18010
5610ꢁ445
2810ꢁ411
ꢁ102
ꢁ2.5
6
ꢁ10
6210ꢁ822
aThe DAT was labeled with [3H]WIN 35, 428, the SERT with [3H]citalopram and the NET with [3H]nisoxetine (see ref 5a for procedure). Results are
averageꢁSEM of three independent experiments assayed in triplicate.
bSee ref 5c.

2340
A. K. Dutta et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2337–2340
Table 3. Selectivity of various ligands for their binding to the
monoamine transporters
4. (a) Neurotransmitter Transporters: Structure, Function, and
Regulation; Carrol, F. I.; Lewin, A. H.; Kuhar, M. J. Reith,
M. E. A., Eds.; Humana: Totowa, NJ, 1997; p 263. (b) Singh,
S. Chem. Rev. 2000, 100, 925. (c) Deutsch, H. M.; Shi, Q.;
Gruszecka-Kowalik, E.; Schweri, M. M. J. Med. Chem. 1996,
39, 1201. (d) Meltzer, P. C.; Liang, A. Y.; Blundell, P.;
Gonzalez, M. D.; Chen, Z.; George, C.; Madras, B. K. J. Med.
Chem. 1997, 40, 2661. (e) Matecka, D.; Lewis, D.; Rothman,
R. B.; Dersch, C. M.; Wojnicki, F. H. E.; Glowa, J. R.;
DeVries, C.; Pert, A.; Rice, K. C. J. Med. Chem. 1997, 40, 705.
(f) Agoston, G. E.; Wu, J. H.; Izenwasser, S.; George, C.;
Katz, J.; Kline, R. H. J.; Newman, A.-H. J. Med. Chem. 1997,
40, 4329. (g) Zhang, C.; Izenwasser, S.; Katz, J. L.; Terry,
P. D.; Trudell, M. L. J. Med. Chem. 1998, 41, 2430. (h)
Davies, H. M. L.; Saikali, E.; Huby, N. J. S.; Gilliatt, V. J.;
Matasi, J. J.; Sexton, T.; Childers, S. R. J. Med. Chem. 1994,
37, 1262.
Compd
SERT/DAT
NET/DAT
Cocaine
I
2.7
6.9
6.36
56
(ꢁ)-7a
(ꢁ)-7b
(ꢁ)-8a
93.7
6.28
71.4
44.9
21
64.4
previous lead I for binding to the DAT (93 vs 6.9; Table
3). Interestingly, the cis amide (ꢁ)-8a was moderately
potent and quite selective at the DAT which might
indicate relative less importance of a basic N-atom at
the 5-position in binding interaction. This result is in
contrast to our earlier findings where we have
demonstrated both exocyclic and piperidine N-atoms
are important for binding interactions with the
DAT.5b,c
5. (a) Dutta, A. K.; Coffey, L. L.; Reith, M. E. A. J. Med.
Chem. 1997, 40, 35. (b) Dutta, A. K.; Xu, C.; Reith, M. E. A.
J. Med. Chem. 1998, 41, 3293. (c) Dutta, A. K.; Fei, X.-S.;
Beardsley, P.; Newman, J.; Reith, M. E. A. J. Med. Chem.
2001, 44, 937.
6. Makosza, M.; Wojciechowski, K.; Jawdosiuk, M. Polish J.
Chem. 1978, 52, 1173.
7. Sury, E.; Hoffmann, K. Helv. Chem. Acta. 1954, 247–248,
2133.
To the best of our knowledge, these newly designed
molecules represent a novel structural class of com-
pounds evaluated for activity for the monoamine trans-
porter systems in the CNS. It is evident from these
results that the stereochemistry at the 5-position played
a significant role in activity. Our ongoing work is look-
ing into extensive SAR studies of these newly developed
molecules to understand more about the dynamics of
interaction of these molecules with the monoamine
transporter systems.
8. Racemic
cis-2-diphenylmethyl-5-(4-fluorobenzylamino)-
1
piperidine, 7a, H NMR (CDCl3; 400 MHz) d 1.3–1.4 (2H, m,
H-3), 1.49 (1H, tt, 2J and 3J3a=13.6 Hz; 3J3e and 3J5e=4.0Hz,
H-4ax), 1.65–1.85 (3H, m, H-4eq, 2NH), 2.65–2.72 (2H, m, H-
5eq, H-6ax), 2.99 (1H, dd, 3J=12.9 Hz, J5eq=6 Hz, H-6eq),
3.28 (1H, dt, 3J=4.4 and 10.8 Hz, H-2ax), 3.71 (2H, s,
CH2C6H4F), 3.81 (1H, d, 3J=9.6 Hz, CH(C6H5)2), 6.99 (2H, t,
3J=8.4 Hz, ArH ortho F), 7.12–7.39 (12H, m, ArH). Pre-
cipitated as bis-hydrochloride salt. Mp 240–261 ꢂC. EA calcd
.
for C25H29N2FCl2 0.5 H2O: C, 65.93; H, 6.59; N, 6.15. Found:
C, 65.62; H, 6.78; N, 6.49.
9. Racemic trans-2-diphenylmethyl-5-(4-fluorobenzylamino)-
1
Acknowledgements
piperidine, 7b, H NMR (CDCl3; 400 MHz) d 1.17 (2H, qm,
3J=10Hz, H-3ax and H-4ax), 1.57–1.65 (1H, m, H-3eq), 1.4–
1.7 (bs, NH), 1.9–1.96 (1H, m, H-4eq), 2.33 (1H, t, 2J and
3J=10.4 Hz, H-6ax), 2.65 (1H, m, Æ3J=36 Hz, H-5ax), 3.15–
3.25 (2H, m, H-2ax, H-6eq), 3.68 (1H, d, 2J=9.6 Hz,
CH(C6H5)2), 3.76 (2H, s, CH2C6H4F), 6.97 (2H, t, 3J=8.8 Hz,
ArH ortho F), 7.1–7.3 (10H, m, ArH), 7.36 (2H, d, 3J=7.6 Hz,
ArH meta F). Precipitated as bis-hydrochloride salt, mp 291–
295 C. EA calcd for C25H29N2FCl2 0.5 H2O: C, 65.93; H,
6.59; N, 6.15. Found: C, 65.56; H, 6.89; N, 6.14.
10. (a) Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.;
Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah,
E. J. Med. Chem. 1998, 41, 1962. (b) Choi, S.-W.; Elmaleh,
D. R.; Hanson, R. N.; Fischman, A. J. Med. Chem. 2000, 43,
205.
This work was supported by the National Institute on
Drug Abuse/NIH (DA 12449).
References and Notes
ꢂ
ꢃ
1. Carroll, F. I.; Howell, L. L.; Kuhar, M. J. J. Med. Chem.
1999, 42, 2721.
2. Reith, M. E. A.; Meisler, B. E.; Sershen, H.; Lajtha, A.
Biochem. Pharmacol. 1986, 35, 1123.
3. Ritz, M. C.; Lamb, R. J.; Goldberg, R.; Kuhar, M. J.
Science 1987, 237, 1219.