Meperidine Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 5 1341
base): δ 139.8, 138.1, 127.5, 121.4, 93.7, 52.6, 46.0, 42.0, 36.4.
Anal. (C13H15N2I‚HCl) C, H, N.
as a white solid, mp 247-249 °C. 1H NMR (free base): δ 7.65
(d, J ) 8.8 Hz, 2H), 7.13 (d, J ) 8.4 Hz, 2H), 4.12 (m, J ) 7.2
Hz, 2H), 2.78 (d, J ) 8.4 Hz, 2H), 2.54 (d, J ) 13.2 Hz, 2H),
2.27 (s, 3H), 2.14 (t, J ) 10.8 Hz, 2H), 1.94 (t, J ) 10.4 Hz,
2H), 1.18 (t, J ) 7.6 Hz, 3H). 13C NMR (free base): δ 173.7,
137.5, 127.8, 92.7, 60.9, 53.2, 48.3, 46.1, 33.6, 14.0. Anal.
(C15H20NO2I‚HCl) C, H, N.
4-(4-Methylphenyl)-1-methylpiperidine-4-carboxylic
Acid Ethyl Ester (7d). General Method D. This compound
was obtained as a white solid (0.75.g, 52%) and converted into
a hydrochloride salt (General Method A), which was obtained
as a white solid, mp 196-197 °C (HCl salt). 1H NMR (free
base): δ 7.27 (d, J ) 8.0 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 2H),
4.11 (q, J ) 7.2 Hz, 2H), 2.78 (br s, 2H), 2.57 (d, J ) 13.2 Hz,
2H), 2.30 (s, 3H), 2.26 (s, 3H), 2.13 (t, J ) 11.2 Hz, 2H), 1.96
(t, J ) 11.2 Hz, 2H), 1.17 (t, J ) 7.2 Hz, 3H). 13C NMR (free
base): δ 174.3, 136.4, 129.1, 125.5, 60.6, 53.4, 48.2, 46.1, 33.8,
20.7, 13.9. Anal. (C16H23NO2‚HCl) C, H, N.
4-(3,4-Dichlorophenyl)-1-methylpiperidine-4-carboxy-
lic Acid Ethyl Ester (7e). General Method D. This compound
was obtained as a white solid (1.3 g, 76%) and converted into
a hydrochloride salt (General Method A), which was obtained
as a white solid, mp 195-196 °C. 1H NMR (free base): δ 7.47
(d, J ) 2.0 Hz, 1H), 7.40 (d, J ) 8.8 Hz, 1H), 7.23 (dd, J ) 2.4,
8.4 Hz, 1H), 4.14 (m, J ) 6.8 Hz, 2H), 2.80 (d, J ) 8.4 Hz,
2H), 2.55 (d, J ) 12.8 Hz, 2H), 2.28 (s, 3H), 2.16 (t, J ) 11.6
Hz, 2H), 1.94 (m, J ) 11.2 Hz, 2H), 1.20 (t, J ) 6.8 Hz, 3H).
13C NMR (free base): δ 173.4, 132.6, 131.2, 130.4, 128.2, 125.4,
61.2, 53.2, 48.2, 46.0, 33.6, 14.0. Anal. (C15H19NO2Cl2‚HCl) C,
H, N.
1-Methyl-4-naphthalen-2-yl-piperidine-4-carboxylic
Acid Ethyl Ester (7f). General Method D. This compound was
obtained as a white solid (1.1 g, 73%) and converted into a
hydrochloride salt (General Method A), which was obtained
as a white solid, mp 191-193 °C. 1H NMR (free base): δ 7.80
(m, 4H), 7.55 (dd, J ) 2.0, 8.6 Hz, 1H), 7.44 (m, 2H), 4.12 (m,
J ) 6.8 Hz, 2H), 2.83 (d, J ) 9.2 Hz, 2H), 2.70 (d, J ) 12.4 Hz,
2H), 2.28 (s, 3H), 2.21 (t, J ) 11.6 Hz, 2H), 2.10 (m, 2H), 1.16
(t, J ) 6.8 Hz, 3H). 13C NMR (free base): δ 174.3, 133.3, 132.3,
128.1,128.0, 127.3, 126.0, 125.9, 124.6, 124.0, 60.8, 53.5, 48.7,
46.2, 33.9, 14.0. Anal. (C19H23NO2‚HCl) C, H, N.
[3H]WIN 35,428 Binding Assay. Male Sprague-Dawley
rats (200-250 g, Taconic, Germantown, NY) were decapitated
and their brains removed to an ice-cooled dish for dissection
of the caudate-putamen. The tissue was homogenized in 30
volumes of ice-cold modified Krebs-HEPES buffer (15 mM
HEPES, 127 mM NaCl, 5 mM KCl, 1.2 mM MgSO4, 2.5 mM
CaCl2, 1.3 mM NaH2PO4, 10 mM glucose, pH adjusted to 7.4)
using a Teflon/glass homogenizer and centrifuged at 20 000g
for 10 min at 4 °C. The resulting pellet was then washed two
more times by resuspension in ice-cold buffer and centrifuga-
tion at 20,000g for 10 min at 4 °C. Fresh homogenates were
used in all experiments. Binding assays were conducted in
modified Krebs-HEPES buffer on ice, essentially as previously
described.23 The total volume in each tube was 0.5 mL, and
the final concentration of membrane after all additions was
approximately 0.3% (w/v) corresponding to 150-300 g of
protein/sample. Increasing concentrations of the drug being
tested were added to triplicate samples of membrane suspen-
sion. Five minutes later, [3H]WIN 35 428 (final concentration
1.5 nM) was added and the incubation was continued for 1 h
on ice. The incubation was terminated by the addition of 3
mL of ice-cold buffer and rapid filtration through Whatman
GF/B glass fiber filter paper (presoaked in 0.1% BSA in water
to reduce nonspecific binding) using a Brandel Cell Harvester
(Gaithersburg, MD). After filtration, the filters were washed
with three additional 3 mL washes and transferred to scintil-
lation vials. Absolute ethanol (0.5 mL) and Beckman Ready
Value Scintillation Cocktail (2.75 mL) were added to the vials
which were counted the next day at an efficiency of about 36%.
Under these assay conditions, an average experiment yielded
approximately 6000 dpm total binding per sample and ap-
proximately 250 dpm nonspecific binding. Nonspecific binding
was defined as binding in the presence of 100 µM cocaine. Ki
4-(4-Methylphenyl)-1-methylpiperidine-4-carboni-
trile (6d). General Method C. This compound was obtained
as an oil (0.63 g, 39%) and converted into a hydrochloride salt
(General Method A), which was obtained as a white solid, mp
198-200 °C (HCl salt). 1H NMR (free base): δ 7.38 (d, J ) 8.4
Hz, 2H), 7.20 (d, J ) 8.4 Hz, 2H), 2.96 (m, 2H), 2.48 (m, 2H),
2.38 (s, 3H), 2.35 (s, 3H), 2.10 (m, 4H). 13C NMR (free base):
δ 137.8, 137.2, 129.6, 125.4, 122.0, 52.7, 46.0, 41.7, 36.6, 20.8.
Anal. (C14H18N2‚HCl‚1/3H2O) C, H, N.
4-(3,4-Dichlorophenyl)-1-methylpiperidine-4-carboni-
trile (6e). General Method C. This compound was obtained
as an orange oil (0.79 g, 39%) and converted into a hydro-
chloride salt (General Method A), which was obtained as a
white solid, mp 266-268 °C. 1H NMR (free base): δ 7.56 (d, J
) 2.0 Hz, 1H), 7.45 (d, J ) 8.4 Hz, 1H), 7.31 (dd, J ) 2.4, 8.4
Hz, 1H), 2.95 (m, 2H), 2.46 (m, 2H), 2.36 (s, 3H), 2.07 (m, 4H).
13C NMR (free base): δ 140.2, 133.2, 132.4, 130.9, 127.9, 125.0,
121.0, 52.4, 45.8, 41.6, 36.3. Anal. (C13H14N2Cl2‚HCl‚1/4 H2O)
C, H, N.
1-Methyl-4-naphthalen-2-yl-piperidine-4-carboni-
trile (6f). General Method C. This compound was obtained
as an orange oil (1.0 g, 45%). The compound was converted
into a hydrochloride salt (General Method A), which was
obtained as a white solid, mp 256-258 °C. 1H NMR (free
base): δ 7.97 (d, J ) 1.6 Hz, 1H), 7.85 (m, 3H), 7.57 (dd, J )
2.0, 8.4 Hz, 1H), 7.50 (m, 2H), 2.99 (d, J ) 12.0, 2H), 2.53 (m,
2H), 2.40 (s, 3H), 2.22 (m, 4H). 13C NMR (free base): δ 137.3,
133.1, 132.7, 128.9, 128.1, 127.5, 126.6, 126.5, 124.6, 123.3,
121.9, 52.7, 46.0, 42.3, 36.5. Anal. (C17H18N2‚HCl‚1/3H2O) C,
H, N.
General Method D. 4-Aryl-1-methylpiperidine-4-car-
boxylic Acid Ethyl Ester (7). The nitriles 6 (5.2 mmol) in
an aqueous solution of sulfuric acid (6.5 mL H2SO4:H2O, 1:1)
was heated in an oil bath at 120 °C for 1.5 h. The flask was
then equipped with a Dean-Stark trap with a stopcock. The
water was azeotropically removed by distillation with con-
tinual drainage of the solvent collected in the trap over 4.5 h,
and alcohol was added as needed. The reaction was then
heated at reflux overnight. The reaction was allowed to cool
to room temperature. The solvent was removed under reduced
pressure. The residue was then cooled in an ice bath, and the
acid was neutralized to a pH of 10 with 1 N NaOH. The
aqueous layer was extracted with Et2O (3 × 75 mL). The
combined organic fractions were dried (Na2SO4), and the
solvent was removed under reduced pressure. The crude
product was purified by chromatography (MeOH:CHCl3, 2.5:
97.5) to afford the esters 7.
4-(4-Fluorophenyl)-1-methylpiperidine-4-carboxylic
Acid Ethyl Ester (7a). General Method D. This compound
was obtained as a white solid (1.0 g, 75%) and converted into
a hydrochloride salt (General Method A), which was obtained
as a white solid, mp 137-138 °C (HCl salt). 1H NMR (free
base): δ 7.36 (m, 2H), 7.00 (m, 2H), 4.12 (q, J ) 6.8 Hz, 2H),
2.78 (br s, 2H), 2.57 (d, J ) 10.2 Hz, 2H), 2.26 (s, 3H), 2.13 (t,
J ) 10.8 Hz, 2H), 1.94 (m, 2H), 1.18 (t, J ) 7.2 Hz, 3H). 13C
NMR (free base): δ 174.1, 161.7 (JC-F ) 245 Hz), 138.7, 127.5,
115.3, 60.8, 53.4, 48.1, 46.2, 34.0, 14.0. Anal. (C15H20NO2F‚
HCl‚1/3H2O) C, H, N.
4-(4-Chlorophenyl)-1-methylpiperidine-4-carboxylic
Acid Ethyl Ester (7b). General Method D. This compound
was obtained as a white solid (1.0 g, 69%) and converted into
a hydrochloride salt (General Method A), which was obtained
as a white solid, mp 168-169 °C (HCl salt). 1H NMR (free
base): δ 7.31 (m, 4H), 4.12 (m, J ) 6.8 Hz, 2H), 2.77 (br s,
2H), 2.56 (d, J ) 12.8 Hz, 2H), 2.27 (s, 3H), 2.13 (t, J ) 11.2
Hz, 2H), 1.93 (m, J ) 10.4 Hz, 2H), 1.18 (t, J ) 7.2 Hz, 3H).
13C NMR (free base): δ 174.0, 141.5, 132.9, 128.6, 127.3, 60.9,
53.4, 48.3, 46.2, 33.9, 14.0. Anal. (C15H20NO2Cl‚HCl) C, H, N.
4-(4-Iodophenyl)-1-methylpiperidine-4-carboxylic Acid
Ethyl ester (7c). General Method D. This compound was
obtained as a white solid (1.3 g, 68%) and converted into a
hydrochloride salt (General Method A), which was obtained