N-Substituted 3,3-Dimethylpiperidines
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 3945
3,3-Dim et h yl-1-[3-(5-m et h oxyin d a n -1-yl)-n -p r op yl]p i-
p er id in e (18): 89% yield; 1H-NMR δ 0.93 (s, 6H), 1.20 (t, 2H,
J ) 6 Hz), 1.24-1.84 (mm, 7H), 2.03 (br d, 2H), 2.21-2.37
(mm, 5H), 2.72-3.07 (mm, 3H), 3.76 (s, 3H, OCH3), 6.68-7.08
(mm, 3H); GC/MS m/ z 302 (M+ + 1, 3), 301 (M+, 9), 126 (100).
2.26 (mm, 4H), 2.51-2.77 (mm, 3H), 3.80 (s, 3H) 6.63-7.12
(mm, 3H); GC/MS m/z 330 (M+ + 1, 3), 329 (M+, 11), 126 (100).
3,3-Dim eth yl-1-[4-(6-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -bu tyl]p ip er id in e (29): 1H-NMR δ 0.92 (s,
6H), 1.19 (t, 2H, J ) 6 Hz), 1.27-1.88 (mm, 12H), 1.98 (s, 2H),
2.21-2.30 (mm, 4H), 2.65-2.73 (mm, 3H), 3.75 (s, 3H) 6.58-
7.08 (m, 3H); GC/MS m/ z 330 (M+ + 1, 3), 329 (M+, 14), 126
(100).
3,3-Dim eth yl-1-[4-(7-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -bu tyl]p ip er id in e (30): 36% yield; 1H-NMR δ
0.92 (s, 6H), 1.19 (t, 2H, J ) 6 Hz), 1.30-1.85 (mm, 12H), 1.99
(s, 2H), 2.24-2.26 (mm, 4H), 2.64-2.74 (mm, 3H), 3.77 (s, 3H)
6.63-6.99 (mm, 3H); GC/MS m/ z 330 (M+ + 1, 3), 329 (M+,
12), 126 (100).
3,3-Dim eth yl-1-[5-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
n -p en tyl]p ip er id in e (31): 1H-NMR δ 0.92 (s, 6H), 1.19 (t,
2H, J ) 6 Hz), 1.24-1.88 (mm, 14H, (CH2)2CH(CH2)4 and
piperidine CH2), 1.98 (s, 2H), 2.19-2.26 (mm, 4H), 2.67-2.76
(mm, 3H), 7.02-7.17 (mm, 4H); GC/MS m/ z 314 (M+ + 1, 1),
343 (M+, 6), 126 (100).
3,3-Dim eth yl-1-[5-(6-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -p en tyl]p ip er id in e (32): eluted with CHCl3;
1H-NMR δ 0.93 (s, 6H), 1.20 (t, 2H, J ) 6 Hz), 1.24-1.89 (mm,
14H), 2.02 (s, 2H), 2.15-2.27 (mm, 4H), 2.65-2.76 (mm, 3H),
3.75 (s, 3H, OCH3) 6.57-7.08 (mm, 3H); GC/MS m/z 344 (M+
+ 1, 6), 343 (M+, 23), 126 (100).
3,3-Dim eth yl-1-(5-p h en yl-n -p en tyl)p ip er id in e (33). Li-
AlH4 (1.17 g) was added to a stirred solution of amide 15 (8.20
g, 30 mmol) in anhydrous THF (100 mL) under N2. After 1 h,
the reaction mixture was poured on ice, and the organic layer
was dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography (CH2Cl2/
MeOH, 95:5, as eluent) to afford 33 as a colorless oil in
quantitative yield: 1H-NMR δ 0.95 (s, 6H, 2 CH3), 1.22 (t, 2H,
J ) 6 Hz, CH2C(CH3)2), 1.31-1.39 (mm, 2H, piperidine CH2),
1.41-1.71 (mm, 6H, PhCH2(CH2)3), 2.01 (s, 2H, NCH2C(CH3)2),
2.25-2.29 (mm, 4H, CH2NCH2), 2.63 (t, 2H, J ) 8 Hz,
benzylic), 7.16-7.32 (mm, 5H, aromatic); GC/MS m/ z 260 (M+
+ 1, 1), 259 (M+, 3), 126 (100).
P h a r m a cologica l Meth od s. Procedures involving use of
small laboratory rodents and their care were conducted in
conformity with institutional guidelines that are in compliance
with national laws and policies (EEC Council Directive 86/
609 and Italian government act 116/J anuary 27, 1992).
σ1 Recep tor Bin d in g Exp er im en ts: [3H]-(+)-SKF 10047
Bin d in g. The method adopted was originally described by
McCann et al.44 In brief, male Sprague Dawley rats (Charles
River, Italy) were sacrificed by decapitation. The brains were
rapidly removed, and whole fresh brain, minus the cerebellum
and pons-medulla oblongata, was homogenized in 30 volumes
of 5 mM Tris-HCl (pH ) 8.0 at 25 °C) containing 10 mM K+-
EDTA with a Brinkmann Polytron (setting 5 for 3 × 15 s).
The homogenate was centrifuged at 48000g for 15 min at 4
°C. The supernatant was discarded, and the pellets were
washed once by resuspension in fresh buffer and then centri-
fuged. The final pellets were either resuspended in the
incubation buffer or stored (for a maximum of 2 days) at -80
°C until assayed. For displacement experiments each sample
received the following in a final volume of 0.5 mL: brain
homogenate, equivalent of 8-10 mg of tissue based on the
original w.w., 4-5 nM [3H]-(+)-SKF 10047 (New England
Nuclear, specific activity 60 Ci/mmol), 300 nM unlabeled MK-
801 to block binding of (+)-SKF 10047 to PCP receptors, and
various concentrations (10-10-10-4 M) of the test substance.
After incubation at 25 °C for 60 min, the reaction was ended
by the addition of 5 mL of ice-cold Tris buffer and rapid
filtration through Whatman GF/B filter paper presoaked in
cold Tris buffer containing 0.5% polyethyleneimine to reduce
nonspecific binding. Filters were then washed with 2 × 5 mL
of cold buffer. Filters were then counted by liquid scintillation
spectrometry using NEN Formula 989 as scintillation cocktail.
Specific [3H]-(+)-SKF 10047 binding was defined as the
difference between binding in the absence or presence of 100
µM cold (+)-SKF 10047, a generous gift of SKB, Italy. The Kd
3,3-Dim et h yl-1-[4-(4-m et h oxyin d a n -1-yl)-n -b u t yl]p ip -
1
er id in e (19): H-NMR δ 0.92 (s, 6H), 1.19 (t, 2H, J ) 6 Hz),
1.35-1.86 (mm, 9H, CH(CH2)3, 1 of endo-CH2 and piperidine
CH2), 2.00 (br s, 2H), 2.21-2.32 (mm, 5H), 2.67-3.13 (m, 3H),
3.81 (s, 3H, OCH3), 6.64-7.16 (mm, 3H); GC/MS m/ z 316 (M+
+ 1, 2), 315 (M+, 8), 126 (100).
3,3-Dim eth yl-1-[2-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
eth yl]p ip er id in e (20): eluted with CHCl3/MeOH, 9:1; 1H-
NMR δ 0.95 (s, 6 H, 2 CH3), 1.23 (t, 2 H, J ) 6 Hz,
CH2C(CH3)2), 1.56-2.11 (mm, 10 H, (CH2)2CH(CH2)2N and
piperidine CH2), 2.26-2.46 (m, 4H, CH2NCH2), 2.74-2.90
(mm, 3H, benzylic), 7.02-7.19 (m, 4H, aromatic); GC/MS m/ z
273 (M+ + 2, 1), 272 (M+ + 1, 1), 271 (M+, 10), 126 (100).
3,3-Dim eth yl-1-[3-(1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
n -p r op yl]p ip er id in e (21): 58% yield; 1H-NMR δ 0.98 (s, 6H,
2 CH3), 1.24-1.25 (m, 2H, CH2C(CH3)2), 1.55-1.86 (mm, 10H,
(CH2)2CH(CH2)2 and piperidine CH2), 1.97-2.67 (mm, 6H,
NCH2C(CH3)2 and CH2NCH2), 2.71-2.74 (mm, 3H, benzylic),
7.02-7.16 (mm, 4H, aromatic); GC/MS m/ z 286 (M+ + 1, 2),
285 (M+, 9), 126 (100).
(+)- a n d (-)-3,3-Dim eth yl-1-[3-(5-m eth oxy-1,2,3,4-tet-
r a h yd r on a p h th a len -1-yl)-n -p r op yl]p ip er id in e [(+)- a n d
(-)-22]. Enantiomeric excess for (+)-22 and (-)-22 was
determined by chiral HPLC in the same conditions as for (+)-
10 and (-)-10, eluting solely with n-hexane/2-propanol 98:2;
both enantiomers displayed ee > 99%; [R]D ) +1.0° and -1.0°,
respectively (c 1.0, CHCl3).
3,3-Dim eth yl-1-[3-(5-h yd r oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -p r op yl]p ip er id in e (23). Compound 22 (1.0
g, 3.2 mmol) was stirred in 80 mL of 48% HBr, and then the
mixture was refluxed for 12 h. After cooling, it was made
alkaline with conc. KOH, and then it was extracted three times
with Et2O. The collected organic layers were dried (Na2SO4)
and evaporated to dryness, affording a residue which was
purified by column chromatography (CHCl3/CH3OH, 9:1, as
eluent). Pure 23 (0.91 g, 93% yield) was a pale yellow oil: 1H-
NMR δ 0.94 (s, 6H, 2 CH3), 1.21 (t, 2H, J ) 6 Hz, CH2C(CH3)2),
1.50-1.91 (mm, 10H, (CH2)2CH(CH2)2 and piperidine CH2),
2.00-2.10 (br s, 2H, NCH2C(CH3)2), 2.25-2.35 (mm, 4H, CH2-
NCH2), 2.55-2.80 (mm, 3H, benzylic), 4.80-5.30 (br s, 1H, OH,
D2O exchanged), 6.56-7.01 (mm, 3H, aromatic); GC/MS m/ z
302 (M+ + 1, 4), 301 (M+, 15), 126 (100).
3,3-Dim eth yl-1-[3-(6-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
1
th a len -1-yl)-n -p r op yl]p ip er id in e (24): H-NMR δ 0.99 (s,
6H, 2 CH3), 1.26 (t, 2H, J ) 6 Hz, CH2C(CH3)2), 1.51-1.84
(mm, 10H, (CH2)2CH(CH2)2 and piperidine CH2), 2.10-2.30 (br
s, 2H, NCH2C(CH3)2), 2.35-2.55 (mm, 4H, CH2NCH2), 2.60-
2.75 (mm, 3H, benzylic), 3.74 (s, 3H, OCH3), 6.56-7.06 (mm,
3H, aromatic); GC/MS m/ z 316 (M+ + 1, 2), 315 (M+, 10), 126
(100).
3,3-Dim eth yl-1-[3-(7-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -p r op yl]p ip er id in e (25): 96% yield; 1H-NMR
δ 0.95 (s, 6H), 1.21 (t, 2H, J ) 6 Hz), 1.46-1.86 (mm, 10H),
1.93-2.15 (br d, 2H), 2.26-2.30 (mm, 4H), 2.66-2.73 (mm,
3H), 3.77 (s, 3H), 6.64-6.97 (mm, 3H); GC/MS m/ z 316 (M+
+ 1, 2), 315 (M+, 8), 126 (100).
3,3-Dim et h yl-1-[4-(1,2-d ih yd r on a p h t h a len -4-yl)-n -b u -
1
tyl]p ip er id in e (26): pale yellow oil, eluted with CHCl3; H-
NMR δ 0.92 (s, 6H, 2 CH3), 1.17-1.22 (mm, 2H, CH2C(CH3)2),
1.35-1.68 (mm, 6H, CH2(CH2)2CH2N and piperidine CH2), 1.99
(s, 2H, NCH2C(CH3)2), 2.20-2.50 (mm, 8H, 2 allyl CH2 and
CH2NCH2), 2.72 (t, 2H, J ) 8 Hz, benzyl CH2), 5.84 (br t, 1H,
vinyl CH), 7.09-7.26 (mm, 4H, aromatic); GC/MS m/ z 298 (M+
+ 1, 5), 297 (M+, 21), 126 (100).
3,3-Dim eth yl-1-[4-(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -bu tyl]p ip er id in e (28): eluted with CHCl3; 1H-
NMR δ 0.92 (s, 6H), 1.19 (t, 2H, J ) 6 Hz), 1.28-1.83 (mm,
12H, (CH2)2CH(CH2)3 and piperidine CH2), 1.99 (s, 2H), 2.21-