Synthesis and biological evaluation of new 4-arylpiperidines and 4-aryl-4-piperidinols: dual Na+ and Ca2+ channel blockers with reduced affinity for dopamine D2 receptors

Article abstract of DOI:10.1016/S0968-0896(01)00288-7

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na⁺ and T-type Ca²⁺ channels and binding affinity for dopamine D₂ receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D₂ receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO method but only 1/20 the affinity for dopamine D₂ receptor of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D₂ receptors since only biphenyl compounds such as 2f had high affinitity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases. Copyright

Full text of DOI:10.1016/S0968-0896(01)00288-7

Bioorganic & Medicinal Chemistry 10 (2002) 371–383
Synthesis and Biological Evaluation of New 4-Arylpiperidines and
4-Aryl-4-piperidinols: Dual Na+ and Ca2+ Channel Blockers with
Reduced Affinity for Dopamine D2 Receptors
Hirokazu Annoura,* Kyoko Nakanishi, Mayumi Uesugi, Atsuko Fukunaga,
Seiichi Imajo, Atsuko Miyajima, Yoshiko Tamura-Horikawa and Shigeki Tamura
Suntory Biomedical Research Limited, 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618–8503, Japan
Received 2 July 2001; accepted 10 August 2001
Abstract—A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a–f, 3a–f and 4a–f) was synthesized and evaluated for
blocking effects on both neuronal Na+ and T-type Ca2+ channels and binding affinity for dopamine D2 receptors. Most of the
compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference
standard. In addition, these compounds had significantly reduced affinity for dopamine D2 receptors which is common in this class
of structure. Compounds 2a–f, 3a–f and 4a–f exhibited potent anticonvulsant effects following systemic (ip) administration on
audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was
also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal
damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold
the potency in this MCAO model but only 1/20 the affinity for dopamine D2 receptors of 1a. The superposition of 2a, 3a and 4a on
the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxy-
propanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that
diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion
channels; however, this is not the case for dopamine D2 receptors since only biphenyl compounds such as 2f had high affinity
similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and
treatment of ischemic diseases. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
in the progressive and delayed death of nerve cells that
occurs in cerebral injury and cerebrovascular diseases
such as stroke and trauma.2,3 It has recently been
demonstrated that the aberrant activation of Na+
and Ca2+ channels is closely involved in the pathway
of Ca2+ overload and the accumulation of intracel-
lular Na+ ions results in a rapid Ca2+ overload by the
reverse operation of the Na+/Ca2+ exchange mechan-
ism.2,3
Calcium ion (Ca2+) is indispensable to the survival of a
cell and works as an almost universal signal messenger,
controlling a diverse range of cellular processes under
physiological conditions.1 However, the rise in the
intracellular concentration of Ca2+ to a pathological
level due to depletion of ATP following the failure of
intracellular energy-dependent ion homeostasis caused
by ischemia is directly connected to cell death or
damage.2 This phenomenon is known as Ca2+ overload
which induces functional disorders in the mitochondria
and randomly activates various Ca2+-dependent enzy-
matic reactions and invites further Ca2+ overload. A
better understanding of cell death and damage has
revealed that Ca2+ overload is a major causative factor
In 1985, van Zwieten advocated that a group of com-
pounds, represented by flunarizine 1a which blocks
Na+ and Ca2+ channels to prevent the overloading of
the cell with Ca2+ ions under pathological and ischemic
conditions, should be defined as Ca2+ overload block-
ers and discriminated from conventional Ca2+ entry
+
blockers.4 Although only a fewtypes of Na
and/or
Ca2+ channel blockers, including 1a,3b,4,5 lomerizine
(KB-2796) 1b,6 U-92032 1c,7 and lifarizine (RS-87476)
1d,8 have been reported as Ca2+ overload blockers and
*Corresponding author. Tel.: +81-75-962-8188; fax: +81-75-962-
6448; e-mail: hirokazu_annoura@suntory.co.jp
0968-0896/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00288-7

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H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
shown to prevent neuronal cell death in animal models
of ischemia, they have in common a diphenylmethylpi-
perazine moiety shown as the general formula (A) which
not only causes the blockade of ion channels but also
has significant affinity for dopamine D2 receptors,
showing a clear link to the clinical risk of extra-
pyramidal side effects9 (Chart 1). To overcome this
problem, there is a need to develop a class of com-
pounds that have significant effects on ischemia but
whose structural features are distinctly different from
those of 1a–d. Consequently, the strategy we have
adopted to achieve this objective is based upon the
molecular modification of the general formula (A), in
expectation of the discovery of a newscaffold. Recently,
we have identified a structurally novel class of arylpi-
peridines having the general formula (B) as neuronal
Na+ and T-type Ca2+ channel blockers with reduced
affinity for dopamine D2 receptors.10 Here we provide a
full account of this study including the structure–activ-
ity relationships (SAR) on the basis of a systematic
conformation search and a similar structure analysis.
8b (67%) and 8c (65%), respectively. Hydrogenation of
8a–c in the presence of a catalytic amount of Pd–C in
methanol yielded 4-arylpiperidines 9a (88%), 9b (87%)
and 9c (89%), respectively. 4-Aryl-4-piperidinols 9d–f
were also prepared by hydrogenation of 7d–f in the
presence of a catalytic amount of palladium hydroxide
in methanol. Reactions between 9a–f and cinnamyl
bromide, and between 9a–f and phenacyl bromide in the
presence of triethylamine in acetonitrile gave 2a–f in 35–
76% yields and 3a–f in 50–96% yields, respectively
(Scheme 2). The coupling reaction of 9a–f with phenyl
glycidyl ether in 2-propanol proceeded smoothly to give
4a–f in 74–96% yields. Compounds 4a–f were essen-
tially prepared in the racemic form. To clarify the effect
of chirality with respect to the secondary alcohol moi-
ety, (S)-4a and (R)-4a, both enantiomers of 4a, were
prepared in similar chemical yields by employing chiral
phenyl glycidyl ethers11 in the final step. Their optical
purities were determined by normal phase HPLC using
a Daicel Chiralpak OD column (n-hexane/2-PrOH/die-
thylamine=500:500:1) and were found to be >98% ee.
Compounds 2a–f, 3a–f and 4a–f were converted into
hydrochloride or fumarate salt in a conventional man-
ner before the biological assays.
Chemistry
Compounds 9a–f were prepared using the pathway
shown in Scheme 1. Treatment of N-tert-butoxy-
carbonyl-4-piperidone or N-benzyl-4-piperidone, 6a or
6b, with the Grignard or lithium reagent prepared from
the corresponding aryl bromides 5a–d in a conventional
manner gave 7a–f in 52–77% yields. Deprotection of the
Boc group in 7a–c by exposure to trifluoroacetic acid
proceeded with dehydration of the tert-hydroxy group
and gave the tetrahydropyridine derivatives, 8a (92%),
Results and Discussion
Although flunarizine 1a is regarded as a potent non-
selective Ca2+ channel blocker, extensive study has
revealed that its mechanisms of action in preventing cell
death is mainly the blockade of Na+ and T-type Ca2+
channels.3 T-type Ca2+ channels act as a trigger for
depolarization, modulating cell excitability and sig-
Chart 1.

H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
373
Scheme 1. Reagents and conditions: (a) Mg, THF or n-BuLi, THF; (b) TFA–CH2Cl2 (1:1), rt, 12 h; (c) H2, cat Pd–C or Pd(OH)2, MeOH, 12 h.
nificantly contribute to epileptic action.12 Therefore, we
first assessed the effects of a series of synthetic com-
pounds 2a–f, 3a–f and 4a–f on Na+ channels and T-
type Ca2+ channels. The effects on Na+ channels were
evaluated based on the inhibitory action on veratridine-
induced depolarization in rat cerebrocortical synapto-
somes using the voltage-sensitive fluorescent dye Rho-
damine 6G.13 The effects on low-threshold (T-type)
Ca2+ currents in primary cultured rat cerebrocortical
neurons were examined using a whole-cell voltage-
clamp recording technique.3d As shown in Tables 1–3,
most of the compounds were found to block both Na+
and T-type Ca2+ channels with potency greater than or
equal to flunarizine 1a which was adopted as a reference
standard. As for the anti-veratridine effects, 2c, 3c and
4c, possessing a cyclohexyloxy group as the Z sub-
stituent, showed the best results with IC50 values of
<0.1 mM. The compounds in Table 1–3 showed a con-
centration-dependent block of T-type Ca2+ currents
induced by a depolarizing pulse to ꢀ40 mV from a
holding potential (VH) of ꢀ100 mV. Interestingly, 2b
and 4f are the most potent compounds, showing IC50
values of 0.6 mM for the blockade of T-type Ca2+
channels, however, the phenacyl derivative 3d had
markedly decreased activity.
>10 mM). These differences clearly demonstrate that
compounds 2a–e, 3a–e and 4a–e possess structural fea-
tures distinctly different from those of flunarizine 1a and
its analogues.
In addition, our compounds were found to cause rever-
sible inhibition of Na+ currents in a concentration- and
voltage-dependent manner in primary cultured rat cere-
brocortical neurons using a whole-cell voltage-clamp
recording technique. For instance, the IC50 values of 2a,
3a and 4a obtained at a VH of ꢀ100 mV were more than
10, 10 and 5 mM, respectively, whereas these values
dropped to 1.4, 1.5 and 0.7 mM, respectively, at a VH of
ꢀ70 mV. The racemate 4a and both the enantiomers,
(S)-4a and (R)-4a, could not be discriminated with
respect to potency and selectivity in primary assays;
however, (S)-4a showed a voltage-dependent block of
Na+ channels that was slightly greater than that of its
enantiomer (R)-4a. This result may indicate that the
blockade of ion channels strongly depends upon the
membrane potential and state of the channel; resting,
opening or inactivated.15 It should be noted that the
markedly enhanced voltage dependency promises event-
specific inhibition of ion channels without primary hae-
modynamic adverse effects.
The binding affinity for dopamine D2 receptors was
assessed using [3H]-racoplide as a ligand binding to rat
striatum membranes.14 In remarkable contrast to the
potent activity against Na+ and T-type Ca2+ channels,
our compounds exhibited extremely lowaffinity for
dopamine D2 receptors, with the exception of 2f, 3f and
4f having the biphenyl group at the 4-position of the 4-
piperidinol ring system. Surprisingly, 4b practically lost
all binding affinity for dopamine D2 receptors (IC50
Computational chemistry has proved valuable tools in
the study of molecular events and of SAR. To elucidate
the common pharmacophores and/or the special
arrangement of components essential for inhibition of
ion channels, a systematic conformation search and a
similar structure analysis by root-mean-square (rms)
fitting were carried out for compounds 2a, 2f, 3a and 4a.
Structures were minimized with MM2 parameters
implemented by Macromodel.16 Figures 1 and 2 show

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H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
Scheme 2. Reagents and conditions: (a) cinnamyl bromide, Et3N, MeCN, 80 ꢁC, 2 h; (b) phenacyl bromide, Et3N, MeCN, 80 ꢁC, 2 h; (c) phenyl
glycidyl ether, 2-PrOH, reflux, 2 h.
reasonable superposition of 2a, 2f, 3a and 4a the struc-
tures of which were 0.9, 1.5, 4.1 and 3.9 kcal/mol higher
in energy than the lowest energy conformers, respec-
tively. The RMS error for fitting 2f, 3a and 4a to 2a are
0.44, 0.51 and 0.10 A, respectively. All compounds have
the piperidine ring in the chair conformation and the 4-
aryl group in an equatrial position relative to the piper-
idine ring. As depicted in Figure 1, the cinnnamyl group
in 2a (white), the phenacyl group in 3a (red) and the
phenoxypropanol group in 4a (green) closely overlap.
The distance from the center of each benzene ring in the
above lipophilic parts of 3a and 4a to that of 2a is 1.27 and
0.13 A, respectively. From these results, it can be specu-
lated that the three lipophilic parts are structurally and
biologically equivalent and that these compounds
occupy nearly the same area of the ion channels due to
their possible conformational changes. Moreover, as
shown in Figure 2, the diphenyl ether group in 2a
(white) and the biphenyl group in 2f (magenta) occupy
quite similar spatial positions, leading to suggestions
that both the groups are a pair of bioisosteres for the
blockade of ion channels. However, the biphenyl group
does not possess the same profile as that of the diphenyl
ether group since biphenyl compounds 2f, 3f and 4f
showhigh affinity for dopamine D receptors similar to
2
flunarizine 1a, which has 6.7–32.5 times the affinity of
other synthetic compounds. Interestingly, the simpler
known compound (E)-4-phenyl-1-(3-phenyl-2-prope-
nyl)piperidine17 had decreased the inhibitory activity for
Na+ and T-type Ca2+ channels (both IC50 >10 mM)
but increased binding affinity for dopamine D2 recep-
tors (IC50=0.19 mM). These results imply that the Z
substitutent in 2a–f, 3a–f and 4a–f plays a pivotal role in
a hydrophobic interaction, where an optimum size is
required. Therefore, the Z substituent may change cer-
tain interatomic distances and bond angles, which not
only affect the potency for ion channels but also inter-
fere with receptor binding.
Next, we investigated the effects of 2a–f, 3a–f and 4a–f
on audiogenic seizures in DBA/2 mice to confirm their
in vivo activity and permeability into brain.18 Anti-
convulsant and neuroprotective activities are mutually
related in several voltage-dependent Na+ channel
blockers.18c Compounds 2a–f, 3a–f and 4a–f exhibited
potent anticonvulsant effects following systemic (ip)

H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
375
Table 1. Biological activity of 2a–ga
IC50 (mM)
e
Compdb
X
Y
Z
Anti-veratridinec
T-type Ca2+
Currentsd
D2
Anticonvulsant effect in
DBA/2 micef ED50 (mg/kg; ip)
2a
2b
2c
2d
2e
2f
H
H
H
OH
OH
OH
H
H
H
H
H
F
OC6H5
CH2C6H4-4-F
O-cycloC5H9
OC6H5
CH2C6H4-4-F
C6H5
0.32
0.19
<0.1
0.36
0.23
0.28
0.29
0.8
0.6
5.0
1.7
1.5
1.9
2.2
2.68
3.38
5.03
4.80
6.50
0.84
0.228
4.2
2.2
5.0
2.5
2.7
5.8
6.4
1a
aEach value represents multiple determinations (ꢂ2) with a deviation of less than 20%.
bEach assay was carried out after conversion to the hydrochloride or fumarate salt.
cDetermined as inhibitory effects upon the veratridine-induced depolarization in rat cerebrocortical synaptosomes using a membrane potential sen-
sitive fluorescent dye Rhodamine 6G.13
dDetermined as inhibitory effects on low-threshold (T-type) Ca2+ currents in primary cultured rat cerebrocortical neurons using a whole-cell vol-
tage-clamp recording technique.3d
eDetermined in competition experiments with [3H]-raclopride.14
fCompounds were administered intraperitoneally to DBA/2 mice (n=6) 20 min prior to auditory stimulation of at least 90 dB for 1 min.18
Table 2. Biological activity of 3a–ga
IC50 (mM)
Compd
X
Y
Z
Anti-veratridine
T-type Ca2+
Currents
D2
Anticonvulsant effect in
DBA/2 mice ED50 (mg/kg; ip)
3a
3b
3c
3d
3e
3f
H
H
H
OH
OH
OH
H
H
H
H
H
F
OC6H5
CH2C6H4-4-F
O-cycloC5H9
OC6H5
CH2C6H4-4-F
C6H5
0.19
0.25
<0.1
0.45
0.78
3.2
2.3
4.1
1.53
2.69
2.91
1.65
4.12
0.71
3.3
2.5
1.6
3.5
2.5
1.9
>10
1.5
3.0
0.32
aSee footnotes in Table 1.
administration with ED50 values as shown in Tables 1–
3. We also assessed the neuroprotective activity of 2a,
3a and 4a against transient MCAO19 for 60 min in rats
by measuring peripheral type benzodiazepine binding
site (PTBBS) densities5b in ipsilateral cortical and stria-
tal homogenates as a quantitative index for neuronal
damage 10 days after reperfusion. Each compound was
administered immediately after both MCAO and reper-
fusion (each 3 mg/kg, iv). Consequently, 2a, 3a and 4a
significantly reduced PTBBS levels by 47.5, 46.6 and
65.8%, respectively [*p<0.05 vs vehicle; each value
represents multiple determinations (ꢂ6) with a devia-
tion of less than 20%]. In particular, 4a had 1.7-fold the
potency but only 1/20 the affinity for dopamine D2
receptors of flunarizine 1a, which reduces PTBBS levels
by 37.9% (*p<0.05) in this MCAO model. Rectal tem-
perature was found to increase during MCAO up to
38.5 ꢁC. Our compounds did not significantly affect this
ischemic hyperthermia at the doses tested, exhibiting
neuroprotection. These results indicate that 2a, 3a and
4a have a pronounced neuroprotective efficacy against
neuronal damage induced by transient focal ischemia in
rats. Interestingly, compounds 2a, 3a and 4a at the
effective doses had no effects on systemic blood pressure
and heart rate in anesthetized rats.
In conclusion, we described a structurally novel class of
4-arylpiperidines and 4-aryl-4-piperidinols, represented
by 2a, 3a and 4a, that have not only highly potent
blocking effects on both neuronal Na+ and T-type

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H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
Table 3. Biological activity of 4a–ga
IC50 (mM)
Compd
X
Y
Z
Anti-veratridine
T-type Ca2+
Currents
D2
Anticonvulsant effect in
DBA/2 mice ED50 (mg/kg; ip)
4a
H
H
H
H
H
OH
OH
OH
H
H
H
H
H
H
H
F
OC6H5
OC6H5
OC6H5
0.22
0.13
0.12
0.36
<0.1
0.39
0.44
0.30
3.5
2.0
2.7
0.8
5.2
2.1
1.3
0.6
4.64
4.34
4.08
5.0
2.5
2.5
7.5
<2.5
3.9
3.7
(S)-4a
(R)-4a
4b
4c
4d
CH2C6H4-4-F
O-cycloC5H9
OC6H5
CH2C6H4-4-F
C6H5
>10
5.40
3.20
7.41
0.16
4e
4f
1.3
aSee footnotes in Table 1.
Ca2+ channels but also extremely lowaffinity for
dopamine D2 receptors. A systematic conformation
search and a similar structure analysis have revealed
that the cinnamyl, phenacyl and phenoxypropanol
groups are likely to be bioisosteres for the blockade of
ion channels. Furthermore, diphenyl ether and biphenyl
groups are considered to act as a bioisostere for the
blockade of ion channels; however, this is not the case
for dopamine D2 receptors since compounds with a
biphenyl group had high affinity similar to flunarizine
1a. The identification of compound 4a (SUN N5030)
may lead to newand more effective neuroprotectant
strategies for ischemic diseases such as stroke and
trauma, one of the leading causes of death and disability
in industrialized societies.
point apparatus and are uncorrected. 1H NMR
spectra were recorded on a Brucker ARX 400 FT
NMR spectrometer. Chemical shifts are expressed in
parts per million (d, ppm) with tetramethylsilane as
an internal standard. IR spectra were recorded on a
Perkin–Elmer 1640 instrument. Optical rotations
were determined on a JASCO DIP-181 polarimeter.
The specific rotation has not been corrected. Ele-
mental analyses of these elements fall withinꢃ0.4%
of the calculated values. Analytical TLC was carried
out using Silica-gel 60 F254 plates (Merck Art
5715) or TLC plate NH (Fuji Silysia Chemical
Ltd.). Column chromatography was performed on
silica-gel 60 (Merck Art 9185, 230–400 mesh) or Chro-
matorex NH-DM1020 (Fuji Silysia Chemical Ltd., 100–
200 mesh).
Experimental
All melting points were determined on a Yanagimoto
micro-melting point apparatus or a Buchi 535 melting
¨
N-tert-Butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol
(7a). A 35-mL volume of 4-phenoxyphenyl magnesium
bromide [0.6 M in tetrahydrofuran (THF)] prepared
from 4-bromodiphenyl ether 5a was added to a stirred
solution of N-tert-buthoxycarbonyl-4-piperidone 6a
(3.5 g, 17.6 mmol) in anhydrous THF (100 mL) at 0 ꢁC
under an argon atmosphere. After being stirred for 1 h
Figure 2. Superposition of diphenyl ether 2a (white) and its biphenyl
derivative 2f (magenta).
Figure 1. Superposition of biologically active compounds 2a (white),
3a (red) and 4a (green).

H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
377
at the same temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl and the pro-
duct was extracted with ether. The extract was washed
with brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromato-
graphy over silica gel using n-hexane/AcOEt=3:1 as an
eluent to give 7a (2.92 g, 45% yield) as a colorless oil. 1H
NMR (CDCl3) d 1.48 (9H, s), 1.73–1.76 (2H, m), 1.99
(2H, m), 3.25 (2H, m), 4.02 (2H, m), 7.00 (3H, m), 7.11
(1H, m), 7.34 (2H, m), 7.43 (2H, d, J=8.8 Hz); IR
(CHCl3) 3094, 3436, 3010, 2980, 2875, 1682, 1589, 1507,
N-tert-Butoxycarbonyl-(4-(4-cyclopentyloxy)phenyl)-4-
piperidinol (7c). The starting material, 4-bromophenyl
cyclopentyl ether 5c, was prepared as follows: a mixture
of p-bromophenol (1.00 g, 5.78 mmol), cyclopentyl bro-
mide (682 mM, 6.36 mmol) and sodium hydroxide
(254 mg, 6.36 mmol) in EtOH (10 mL) was refluxed
overnight. The reaction mixture was concentrated in
vacuo and then diluted with water. The product was
extracted with AcOEt and the extract was washed with
1 N NaOH and water. After being dried over MgSO4
and removal of the solvent in vacuo, the obtained resi-
due was purified by column chromatography over silica
gel using n-hexane as an eluent to give 5c (878 mg, 63%
1489, 1430, 1367, 1242, 1168 cmꢀ1
.
1
N-tert-Butoxycarbonyl-4-[4-(4-fluorobenzyl)phenyl]-4-pi-
peridinol (7b). The starting material, 4-bromo-4a-
fluorodiphenylmethane 5b, was prepared as follows:
13 mL of 4-fluorophenyl magnesium bromide (1.54 M in
THF) prepared from 4-bromofluorobenzene was added
to a stirred solution of 4-bromobenzaldehyde (3.3 g,
18.0 mmol) in anhydrous THF (10 mL) at 0 ꢁC under an
argon atmosphere. After being stirred for 30 min at the
same temperature, the reaction mixture was quenched
with saturated aqueous NH4Cl and the product was
extracted with AcOEt. The extract was washed with
brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography
over silica gel using n-hexane/AcOEt=6:1 as an eluent
to give 4-bromo-40-fluorodiphenylmethanol as a color-
less oil. To a stirred solution of the obtained 4-bromo-
40-fluorodiphenylmethanol in trifluoroacetic acid
(25 mL) was added triethylsilane (5.6 mL, 35 mmol) at
0 ꢁC under an argon atmosphere. After being stirred for
1 h at room temperature, the reaction mixture was made
basic with 10% aqueous NaOH until the pH was 10 at
0 ꢁC and the product was extracted with AcOEt. The
extract was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified
by column chromatography over silica gel using n-
hexane as an eluent to give 5b (3.9 g, 82% yield) as
yield) as a colorless oil. H NMR (CDCl3) d 1.59–1.63
(2H, m), 1.76–1.90 (6H, m), 4.69–4.71 (1H, m), 6.74
(2H, d, J=8.9 Hz), 7.34 (2H, d, J=8.9 Hz); IR (CHCl3)
2965, 1487, 1242, 1170, 986, 824 cmꢀ1
.
Compound 7c was prepared by the same procedure
described for the synthesis of 7b using 5c (1.27 g,
5.27 mmol) and 6a (997 mg, 5.00 mmol) in 65% yield
(1.168 g) as a pale yellowoil. 1H NMR (CDCl3) d 1.48
(9H, s), 1.61–1.63 (2H, m), 1.72–1.99 (10H, m), 3.25
(2H, m), 3.97 (2H, m), 4.75 (1H, m), 6.85 (2H, d,
J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz); IR (CHCl3) 3011,
2971, 1682, 1609, 1509, 1478, 1430, 1367, 1279, 1269,
1086, 1030, 986 cmꢀ1
.
N-Benzyl-4-(4-phenoxyphenyl)-4-piperidinol (7d). This
compound was prepared in 66% yield as a pale orange
oil from commercially available 4-bromodiphenyl ether
5a and N-benzyl-4-piperidone 6b, using the procedure
1
described for 7a. H NMR (CDCl3) d 1.73–1.78 (2H,
m), 2.15 (2H, m), 2.58 (2H, m), 2.77–2.81 (2H, m), 3.58
(2H, s), 6.96–7.02 (4H, m), 7.09 (1H, m), 7.28–7.35 (7H,
m), 7.47 (2H, d, J=8.8Hz); IR (CHCl3) 2946, 2818,
2399, 1704, 1590, 1506, 1490, 1106 cmꢀ1
.
N-Benzyl-4-[4-(4-fluorobenzyl)phenyl]-4-piperidinol (7e).
This compound was prepared in 75% yield as a yellow
oil from 4-bromo-40-fluorodiphenylmethane 5b and N-
benzyl-4-piperidone 6b, using the procedure described
1
a colorless oil. H NMR (CDCl3) d 3.89 (2H, s), 6.97
(2H, t, J=8.6 Hz), 7.03 (2H, d, J=8.3 Hz), 7.10 (2H,
dd, J=8.6, 5.4 Hz), 7.40 (2H, d, J=8.3 Hz); IR (neat)
3039, 1603, 1508, 1488, 1222, 1156, 1069 1011,
1
for 7b. H NMR (CDCl3) d 1.71–1.74 (2H, m), 2.14
797 cmꢀ1
.
(2H, m), 2.44–2.49 (2H, m), 2.74–2.79 (2H, m), 3.58
(2H, s), 3.93 (2H, s), 6.96 (2H, t, J=8.7 Hz), 7.12–7.15
(4H, m), 7.29–7.36 (5H, m), 7.43 (2H, d, J=8.3 Hz); IR
(CHCl3) 2950, 2816, 1711, 1603, 1508, 1367, 1344, 1157,
Next, 6.5 mL of n-BuLi (0.6M in n-hexane) was added
dropw ise to a stirred solution of5b (2.5 g, 9.4 mmol) in
anhydrous ether (25 mL) at ꢀ78ꢁC under an argon atmo-
sphere. The reaction mixture was warmed to ꢀ20ꢁC and
stirred for 1 h. Then, a solution of 6a (3.5g, 17.6 mmol) in
anhydrous THF (100 mL) was added at the same tem-
perature and stirring was continued for 1 h at 0 ꢁC. After
being quenched with saturated aqueous NH4Cl, the
product was extracted with ether, washed with brine
and dried over MgSO4. Removal of the solvent in
vacuo gave a residue, which was chromatographed
over silica gel using n-hexane/AcOEt=4:1 as an eluent
1110, 1043 cmꢀ1
.
N-Benzyl-4-(3-fluoro-4-phenyl)phenyl-4-piperidinol (7f).
This compound was prepared in 62% yield as a reddish
orange oil from 4-bromo-3-fluorobiphenyl 5f and N-
benzyl-4-piperidone 6b, using the procedure described
1
for 7a. H NMR (CDCl3) d 1.74–1.78 (2H, m), 2.18
(2H, m), 2.48 (2H, m), 2.79–2.83 (2H, m), 3.60 (2H, s),
7.29–7.38 (8H, m), 7.40–7.45 (3H, m), 7.54 (2H, d,
J=8.2 Hz); IR (CHCl3) 2946, 2817, 1706, 1483, 1406,
1367, 1345, 1119 cmꢀ1
.
1
to afford 7b (2.69 g, 77% yield) as a colorless oil. H
NMR (CDCl3) d 1.48 (9H, s), 1.70–1.73 (2H, m), 1.97
(2H, m), 3.24 (2H, m), 3.94 (2H, s), 3.99 (2H, m), 6.96
(2H, t, J=8.7 Hz), 7.11–7.17 (4H, m), 7.38 (2H, d,
J=8.3 Hz); IR (CHCl3) 3018, 1682, 1508, 1431, 1367,
4-(4-Phenoxyphenyl)-1,2,3,6-tetrahydropyridine (8a). To
a stirred solution of 7a (10.5 mmol) in CH2Cl2 (40 mL)
was added dropwise trifluoroacetic acid (10 mL) at 0 ꢁC.
After being stirred for 30 min at room temperature, the
1168 cmꢀ1
.

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H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
reaction mixture was made basic with 10% aqueous
NaOH until the pH was 9 at 0 ꢁC and the product was
extracted with CH2Cl2. The extract was washed with
brine and dried over MgSO4. The solvent was con-
centrated in vacuo to give 8a (2.43 g, 92% yield) as an
orange powder. Its hydrochloride was obtained by
treating with 2-PrOH saturated with HCl in a conven-
tional manner followed by recrystallization from
MeOH–ether in 80% yield (2.25 g), and which was used
using CH2Cl2/MeOH=30:1 as an eluent to give 9b
(627 mg, 87% yield) as a white powder. 1H NMR
(CDCl3) d 1.62 (2H, ddd, J=12.9, 12.2, 3.9 Hz), 1.79–
1.82 (2H, m), 2.58 (1H, tt, J=12.2, 3.6 Hz), 2.73 (2H, td,
J=12.2, 2.4 Hz), 3.16–3.19 (2H, m), 3.91 (2H, s), 6.96
(2H, dd, J=8.7, 8.7 Hz), 7.08–7.15 (6H, m); IR (CHCl3)
2930, 2337, 1603, 1508, 1446, 1318, 1016, 862, 820 cmꢀ1
.
4-(4-Cyclopentyloxyphenyl)piperidine (9c). This com-
pound was obtained as a pale yellow powder from 8c
1
in the next step. H NMR (CDCl3) d 2.45 (2H, m), 3.11
1
(2H, t, J=5.7 Hz), 3.53 (2H, m), 6.09 (1H, m), 6.96 (2H,
d, J=8.7 Hz), 7.05 (2H, d, J=7.7 Hz), 7.09 (2H, t,
J=7.4 Hz), 7.30–7.37 (4H, m); IR (CHCl3) 3024, 3018,
using the procedure described for 9b in 89% yield. H
NMR (CDCl3) d 1.56–1.64 (2H, m), 1.77–1.89 (8H, m),
2.54 (1H, tt, J=7.3, 3.6 Hz), 2.72 (2H, td, J=12.2,
2.4 Hz), 3.15–3.18 (2H, m), 4.70–4.74 (1H, m), 6.81 (2H,
d, J=8.6 Hz), 7.10 (2H, d, J=8.6 Hz); IR (CHCl3) 2940,
1610, 1509, 1445, 1364, 1318, 1177, 1138, 1101, 1052,
1674, 1606, 1508, 1489, 1243 cmꢀ1
.
4-[4-(4-Fluorobenzyl)phenyl]-1,2,3,6-tetrahydropyridine
(8b). To a stirred solution of 7b (6.34 mmol) in CH2Cl2
(15 mL) was added dropwise trifluoroacetic acid (5 mL)
at 0 ꢁC. After being stirred overnight at room tempera-
ture, the reaction mixture was concentrated in vacuo.
The residue was chromatographed over NH–silica gel
using CH2Cl2/MeOH=30:1 as an eluent to give 8b
(1.14 g, 67% yield) as a yellowoil. 1H NMR (CDCl3) d
2.41–2.46 (2H, m), 3.09 (2H, t, J=5.8 Hz), 3.50–3.53
(2H, m), 3.93 (2H, s), 6.10 (1H, m), 6.96 (2H, t, J=8.7),
7.10–7.15 (4H, m), 7.31 (2H, d, J=8.2 Hz); IR (CHCl3)
3020, 2926, 2993, 1604, 1508, 1434, 1157, 1016,
989 cmꢀ1
.
General procedure for the synthesis of 4-Aryl-4-
piperidinol (9d–f)
Compounds 7d–f were dissolved in MeOH and hydro-
genated in the presence of Pd(OH)2 (20% w/w of 7d–f)
under 5 atom at room temperature for 2–5 days. After
completion of the reaction, the catalyst was filtered off
and the filtrate was concentrated in vacuo. The residue
was chromatographed over NH–silica gel using
CH2Cl2/MeOH=20:1 as an eluent to give 9d–f.
930 cmꢀ1
.
4-(4 -Cyclopentyloxyphenyl) -1,2,3,6-tetrahydropyridine
(8c). This compound was obtained as a yellow powder
from 7c using the procedure described for 8b in 65%
4-(4-phenoxyphenyl)-4-piperidinol (9d). This compound
1
was obtained as a yellow oil in 75% yield. H NMR
(CDCl3) d 1.73–1.77 (2H, m), 2.02 (2H, td, J=12.5,
4.6 Hz), 2.96–2.99 (2H, m), 3.12 (2H, td, J=12.5,
2.6 Hz), 6.99 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=7.7 Hz),
7.10 (1H, t, J=7.5 Hz), 7.33 (2H, dd, J=7.7, 7.5 Hz),
7.46 (2H, d, J=8.8 Hz); IR (CHCl3) 2949, 1702, 1589,
1
yield. H NMR (CDCl3) d 1.59–1.62 (2H, m), 1.77–1.91
(6H, m), 2.40–2.44 (2H, m), 3.09 (2H, t, J=5.7 Hz), 3.51
(2H, dd, J=5.8, 2.8 Hz), 4.75 (1H, m), 6.03 (1H, m),
6.82 (1H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz); IR
(CHCl3) 2963, 1606, 1509, 1438, 1358, 1317, 1274, 1177,
1507, 1490, 1320, 1170, 1132, 1014 cmꢀ1
.
1114, 1090, 988 cmꢀ1
.
4-[4-(4-fluorobenzyl)phenyl]-4-piperidinol (9e). This com-
pound was obtained as a colorless crystal in 74% yield.
1H NMR (CDCl3) d 1.74–1.78 (2H, m), 2.04 (2H, td,
J=12.5, 4.5 Hz), 2.99–3.01 (2H, m), 3.13 (2H, td,
J=12.5, 2.6 Hz), 7.31–7.32 (1H, m), 7.34 (1H, s), 7.34–
7.38 (1H, m), 7.41–7.46 (3H, m), 7.55 (2H, d,
J=8.3 Hz); IR (CHCl3) 2949, 2842, 1709, 1603, 1508,
4-(4-Phenoxyphenyl)piperidine (9a). The hydrochloride
of 8a (2.25 g, 7.82 mmol) was dissolved in MeOH
(50 mL) and hydrogenated in the presence of 10% Pd–C
(338 mg) under atmospheric pressure for 20 h. The cat-
alyst was filtered off and the filtrate was concentrated in
vacuo. To the residue was added 10% aqueous NaOH
and the product was extracted with AcOEt. The extract
was washed with brine and dried over MgSO4 to give 9a
(1.74 g, 88% yield) as a pale yellowoil. 1H NMR
(CDCl3) d 1.63 (2H, ddd, J=12.7, 12.2, 3.7 Hz),
1.82–1.85 (2H, m), 2.60 (1H, tt, J=12.2, 3.7 Hz),
2.74 (2H, td, J=12.2, 3.7 Hz), 3.17–3.20 (2H, m), 6.95
(2H, d, J=8.5 Hz), 7.00 (2H, d, J=8.0 Hz), 7.08 (1H, t,
J=7.5 Hz), 7.18 (2H, d, J=8.5 Hz), 7.32 (2H, dd,
J=8.0, 7.5 Hz); IR (CHCl3) 3024, 2960, 2712, 1590,
1438, 1320, 1157, 1131, 1018 cmꢀ1
.
4-(3-fluoro-4-phenyl)phenyl-4-piperidinol (9f). This com-
1
pound was obtained as a yellow oil in 64% yield. H
NMR (CDCl3) d 1.75–1.78 (2H, m), 2.01–2.08 (2H, m),
2.99–3.02 (2H, m), 3.10–3.16 (2H, m), 7.31–7.38 (3H,
m), 7.42–7.46 (3H, m), 7.54–7.56 (2H, m); IR (CHCl3)
3589, 2950, 1484, 1406, 1320, 1270, 1134, 1010 cmꢀ1
.
1508, 1489, 1241, 1208 cmꢀ1
.
General procedure for the synthesis of compounds 2a–f
and 3a–f
4-[4-(4-Fluorobenzyl)phenyl]piperidine (9b). To a solu-
tion of 8b (717 mg, 2.68 mmol) in MeOH was added
acetic acid (228 mL, 4.02 mmol) and the mixture was
hydrogenated in the presence of 10% Pd–C (338 mg)
under atmospheric pressure overnight. The catalyst was
filtered off and the filtrate was concentrated in vacuo.
The residue was chromatographed over NH–silica gel
A mixture of 9a–f (2 mmol) and cinnamyl bromide
(394 mg) or 9a–f (2 mmol) and phenacyl bromide
(398 mg) in the presence of Et3N (0.56 mL) in MeCN
(8 mL) was stirred at reflux under a nitrogen atmo-
sphere. After consumption of the starting material, the
reaction mixture was concentrated in vacuo and the

H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
379
residue was purified by column chromatography over
silica gel using CH2Cl2/MeOH=30:1 as an eluent to
give 2a–f or 3a–f. These compounds were converted to
hydrochloride or fumarate salt using excess 4 N HCl/
dioxane or a suitable molar excess of fumaric acid in
MeOH, and which were subjected to biological assays.
CDCl3) d 1.80 (2H, m), 2.19 (2H, m), 2.51 (2H, m), 2.90
(2H, m), 3.25 (2H, d, J=6.7 Hz), 6.33 (1H, dt, J=15.8,
6.7 Hz), 6.56 (1H, d, J=15.8 Hz), 6.98 (2H, d,
J=8.8 Hz), 7.01 (2H, d, J=7.7 Hz), 7.10 (1H, t,
J=7.4 Hz), 7.23 (1H, t, J=7.6 Hz), 7.29–7.35 (4H, m),
7.39 (2H, d, J=7.2 Hz), 7.47 (2H, d, J=8.8 Hz); IR
(KBr, fumarate salt) 1702, 1589, 1508, 1490, 1372, 1287,
1240, 1171, 984 cmꢀ1; mp (fumarate salt) 93–97 ꢁC.
1-Cinnamyl-4-(4-phenoxyphenyl)piperidine (2a). This
compound was obtained in 76% yield as an oil, which
was subsequently converted to its hydrochloride in 64%
overall yield from the starting material after recrystalli-
zation from ether–MeOH. 1H NMR (400 MHz, CDCl3)
d 1.75–1.87 (4H, m), 2.10 (2H, td, J=11.5, 3.0 Hz),
2.46–2.54 (1H, m), 3.11–3.14 (2H, m), 3.20 (2H, dd,
J=6.7, 0.8 Hz), 6.33 (1H, dt, J=15.8, 6.7 Hz), 6.55 (1H,
d, J=15.8 Hz), 6.94 (2H, d, J=8.6 Hz), 6.99 (2H, d,
J=7.7 Hz), 7.07 (1H, t, J=7.4 Hz), 7.19 (2H, d,
J=8.6 Hz), 7.22 (1H, t, J=7.4 Hz), 7.29–7.34 (4H, m),
7.39 (2H, d, J=7.3 Hz); IR (KBr, hydrochloride salt)
2930, 2526, 1654, 1589, 1504, 1490, 1239, 1170, 978,
869, 749, 693 cmꢀ1; mp (hydrochloride salt) 200–204 ꢁC.
.
.
Anal. calcd for C26H27NO2 C4H4O4 1/2H2O: C, 70.57;
H, 6.32; N, 2.74. Found: C, 70.37; H, 6.26; N, 3.06.
1-Cinnamyl-4-[4-(4-fluorobenzyl)phenyl]-4-piperidinol (2e).
This compound was obtained in 65% yield as an oil,
which was subsequently converted to its fumarate in
39% overall yield from the starting material after
recrystallization from ether–2-PrOH. 1H NMR
(400 MHz, CDCl3) d 1.76 (2H, m), 2.18 (2H, m), 2.51
(2H, m), 2.89 (2H, m), 3.24 (2H, d, J=6.7 Hz), 3.93
(2H, s), 6.32 (1H, dt, J=15.9, 6.7 Hz), 6.55 (1H, d,
J=15.9 Hz), 6.96 (2H, dd, J=8.7, 8.4 Hz), 7.13 (2H, d,
J=8.3 Hz), 7.15 (2H, d, J=8.4 Hz), 7.22 (2H, t,
J=7.3 Hz), 7.31 (2H, dd, J=7.6, 7.3 Hz), 7.39 (2H, d,
J=7.6 Hz), 7.43 (2H, d, J=8.3 Hz); IR (KBr, fumarate
.
Anal. calcd for C26H27NO HCl: C, 76.92; H, 6.95; N,
3.45. Found: C, 76.77; H, 6.95; N, 3.45.
salt) 1700, 1600, 1578, 1508 1364, 1221, 1158, 984 cmꢀ1
;
1-Cinnamyl-4-[4-(4-fluorobenzyl)phenyl]piperidine (2b).
This compound was obtained in 70% yield as an oil,
which was subsequently converted to its hydrochloride
in 55% overall yield from the starting material after
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.77–1.84 (4H, m), 2.09 (2H, td,
J=11.2, 3.6 Hz), 2.48 (1H, m), 3.19–3.12 (2H, m),
3.19 (2H, dd, J=6.9, 0.8 Hz), 3.91 (2H, s), 6.33 (1H,
dt, J=15.9, 6.9 Hz), 6.53 (1H, d, J=15.9 Hz), 6.96 (2H,
dd, J=8.8, 8.7 Hz), 7.07–7.16 (6H, m), 7.22 (1H, t,
J=7.3 Hz), 7.30 (1H, dd, J=7.5, 7.3 Hz), 7.38 (2H, d,
J=7.5 Hz); IR (KBr, hydrochloride salt) 2940, 2488,
mp (fumarate salt) 100–103 ꢁC. Anal. calcd for
.
C27H28FNO C4H4O4: C, 71.94; H, 6.23; N, 2.71.
Found: C, 71.75; H, 6.28; N, 2.90.
1-Cinnamyl-4-(3-fluoro-4-phenyl)phenyl-4-piperidinol (2f).
This compound was obtained in 50% yield as an oil,
which was subsequently converted to its fumarate in
37% overall yield from the starting material after
recrystallization from ether–EtOH. 1H NMR (400 MHz,
CDCl3) d 1.80 (2H, m), 2.20 (2H, dt, J=13.2, 5.3 Hz),
2.51 (2H, m), 2.2 (2H, m), 3.25 (2H, d, J=6.7 Hz), 6.33
(1H, dt, J=15.9, 6.7 Hz), 6.57 (1H, d, J=15.9 Hz), 7.23
(1H, m), 7.29–7.45 (10H, m), 7.54 (2H, d, J=8.2 Hz); IR
(KBr, fumarate salt) 3384, 3030, 2934, 2576, 1701, 1582,
1485, 1449, 1407, 1272 cmꢀ1; mp (fumarate salt) 107–
1600, 1504, 1458, 1221, 1158, 978, 816, 752, 695 cmꢀ1
;
mp (hydrochloride salt) 203–205 ꢁC. Anal. calcd for
.
C27H28FN HCl: C, 76.85; H, 6.93; N, 3.32. Found: C,
76.76; H, 6.86; N, 3.33.
ꢁ
.
.
109 C. Anal. calcd for C26H26FNO C4H4O4 1/4H2O: C,
70.92; H, 6.05; N, 2.76. Found: C, 70.99; H, 5.97; N,
2.83.
1-Cinnamyl-4-(4-cyclopentyloxyphenyl)piperidine
(2c).
This compound was obtained in 35% yield as an oil,
which was subsequently converted to its hydrochloride
in 32% overall yield from the starting material after
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.58–1.62 (2H, m), 1.76–1.93 (10H,
m), 2.24 (2H, m), 2.50 (1H, m), 3.21–3.23 (2H, m), 3.32
(2H, m), 4.69–4.72 (1H, m), 6.38 (1H, dt, J=15.8,
6.9 Hz), 6.58 (1H, d, J=15.8 Hz), 6.80 (2H, d,
J=8.6 Hz), 7.12 (2H, d, J=8.6 Hz), 7.21–7.25 (1H, m),
7.31 (2H, dd, J=7.5, 7.2 Hz), 7.40 (2H, d, J=7.5 Hz);
IR (KBr, hydrochloride salt) 2947, 1612, 1512, 1450,
1244, 1184, 834, 749, 692 cmꢀ1; mp (hydrochloride salt):
1-Phenacyl-4-(4-phenoxyphenyl)piperidine (3a). This
compound was obtained in 96% yield as an oil, which
was subsequently converted to its hydrochloride in 91%
overall yield from the starting material after recrystalli-
zation from ether–MeOH. 1H NMR (400 MHz, CDCl3)
d 1.82–1.94 (4H, m), 2.29 (2H, td, J=11.2, 3.2 Hz), 2.52
(1H, m), 3.13 (2H, m), 3.85 (2H, s), 6.94 (2H, dd,
J=8.6, 1.9 Hz), 7.00 (2H, d, J=8.1 Hz), 7.08 (1H, t,
J=7.4 Hz), 7.19 (2H, d, J=8.6 Hz), 7.32 (2H, dd,
J=8.1, 7.4 Hz), 7.47 (2H, dd, J=7.6, 7.4 Hz), 7.57 (1H,
t, J=7.4 Hz), 8.03 (2H, d, J=7.6 Hz); IR (KBr, hydro-
chloride salt) 3391, 2948, 2537, 1703, 1590, 1508, 1490,
1450, 1248, 755, 691 cmꢀ1; mp (hydrochloride salt) 183–
ꢁ
.
.
243–244 C. Anal. calcd for C25H31NO HCl 1/2H2O: C,
73.78; H, 8.17; N, 3.44. Found: C, 73.62; H, 7.97; N,
3.44.
ꢁ
.
.
185 C. Anal. calcd for C25H25NO2 HCl 1/4H2O: C,
72.80; H, 6.48; N, 3.40. Found: C, 72.75; H, 6.36; N, 3.43.
1-Cinnamyl-4-(4-phenoxyphenyl)-4-piperidinol (2d). This
compound was obtained in 64% yield as an oil, which
was subsequently converted to its hydrochloride in 42%
overall yield from the starting material after recrystalli-
zation from ether–2-PrOH. 1H NMR (400 MHz,
1-Phenacyl-4-[4-(4-fluorobenzyl)phenyl]piperidine (3b).
This compound was obtained in 82% yield as an oil,
which was subsequently converted to its hydrochloride
in 54% overall yield from the starting material after

380
H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.81–1.96 (4H, m), 2.30 (2H, td,
J=11.5, 2.3 Hz), 2.51 (1H, m), 3.14 (2H, m), 3.88 (2H,
s), 3.92 (2H, m), 6.96 (2H, dd, J=8.8, 8.7 Hz), 7.07–7.17
(6H, m), 7.47 (2H, dd, J=7.5, 7.4 Hz), 7.58 (1H, t,
J=7.4 Hz), 2.30 (2H, td, J=11.5, 2.3 Hz), 8.02 (2H, d,
J=7.5 Hz); IR (KBr, hydrochloride salt) 3402, 2928,
2620, 2544, 1694, 1599, 1508, 1450, 1225, 962, 755,
690 cmꢀ1; mp (hydrochloride salt) 179–181 ꢁC. Anal.
40% overall yield from the starting material after
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.80 (2H, m), 2.29 (2H, m), 2.68
(2H, m), 2.95 (2H, m), 3.90 (2H, s), 7.31–7.37 (3H, m),
7.41–7.49 (5H, m), 7.54–7.60 (3H, m), 8.03 (2H, d,
J=7.6 Hz); IR (KBr, 1/2 fumarate) 3292, 1706, 1582,
1484, 1450, 1407, 1266, 1226, 975, 944 cmꢀ1; mp (1/2
fumarate salt) 172–174 ꢁC. Anal. calcd for
.
.
C25H24FNO2 1/2C4H4O4 3/5H2O: C, 70.76; H, 5.98; N,
3.06. Found: C, 70.85; H, 5.88; N, 3.06.
.
.
calcd for C26H26FNO HCl 1/3H2O: C, 72.63; H, 6.49;
N, 3.26. Found: C, 72.52; H, 6.35; N, 3.30.
General procedure for the synthesis of compounds 4a–f
1-Phenacyl-4-(4-Cyclopentyloxyphenyl)piperidine (3c).
This compound was obtained in 87% yield as an oil,
which was subsequently converted to its hydrochloride
in 68% overall yield from the starting material after
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.59 (2H, m), 1.79–1.90 (10H, m),
2.28 (2H, td, J=11.2, 3.2 Hz), 2.46 (1H, m), 3.11 (2H,
m), 3.83 (2H, s), 4.69–4.72 (1H, m), 6.80 (2H, d,
J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.46 (2H, dd,
J=7.6, 7.4 Hz), 7.56 (1H, t, J=7.4 Hz), 8.03 (2H, d,
J=7.6 Hz); IR (KBr, hydrochloride salt) 2957, 1706,
1512, 1450, 1400, 1358, 1244, 1179, 962, 832, 753,
685 cmꢀ1; mp (hydrochloride salt) 233–235 ꢁC. Anal.
A mixture of 9a–f (2 mmol) and 1,2-epoxy-3-phenoxy-
propane (phenyl glycidyl ether) (507 mg) in 2-PrOH
(10 mL) was refluxed under a nitrogen atmosphere.
After consumption of the starting material, the reaction
mixture was concentrated in vacuo and the residue was
purified by column chromatography over silica gel using
CH2Cl2/MeOH=30:1 as an eluent to give 4a–f. These
compounds were converted into hydrochloride or
fumarate salt in a conventional manner and subjected to
biological assays.
1-(2-Hydroxy-3-phenoxypropyl)-4-(4-phenoxyphenyl)pi-
peridine (4a). This compound was obtained in 96%
yield as an oil, which was subsequently converted to its
hydrochloride in 88% overall yield from the starting
.
calcd for C24H29NO2 HCl: C, 72.07; H, 7.56; N, 3.50.
Found: C, 72.12; H, 7.60; N, 3.56.
1
1-Phenacyl-4-(4-phenoxyphenyl)-4-piperidinol (3d). This
compound was obtained in 50% yield as an oil, which
was subsequently converted to its 1/2 fumarate in 35%
overall yield from the starting material after recrystalli-
zation from ether–MeOH. 1H NMR (400 MHz, CDCl3)
d 1.79 (2H, m), 2.27 (2H, td, J=13.0, 4.3 Hz), 2.67 (2H,
m), 2.92 (2H, m), 3.89 (2H, s), 6.98 (2H, dd, J=8.6,
2.0 Hz), 7.10 (1H, d, J=7.6 Hz), 7.10 (1H, t, J=7.4 Hz),
7.33 (2H, dd, J=7.6, 7.4 Hz), 7.45–7.48 (2H, m), 7.48
(2H, d, J=8.6 Hz), 7.57 (1H, t, J=7.4 Hz), 8.02 (2H, d,
J=7.1 Hz); IR (KBr, 1/2 fumarate salt) 1697, 1589,
1508, 1490, 1450, 1368, 1234, 1171 cmꢀ1; mp (1/2
fumarate salt) 173–175 ꢁC. Anal. calcd for
material after recrystallization from ether–MeOH. H
NMR (400 MHz, CDCl3) d 1.68–1.88 (4H, m), 2.14 (1H,
m), 2.43 (1H, td, J=11.4, 2.8 Hz), 2.50–2.59 (3H, m),
2.98 (1H, m), 3.14 (1H, m), 4.00–4.02 (2H, m), 4.09–4.15
(1H, m), 6.93–6.97 (5H, m), 7.01 (2H, d, J=7.8 Hz),
7.08 (1H, t, J=7.4 Hz), 7.18 (2H, d, J=8.5 Hz), 7.26–
7.34 (4H, m); IR (KBr, hydrochloride salt) 3268, 2657,
1590, 1509, 1490, 1246, 1171, 1050, 755, 693 cmꢀ1; mp
(hydrochloride salt) 151–152 ꢁC. Anal. calcd for
.
C26H29NO3 HCl: C, 70.98; H, 6.87; N, 3.18. Found: C,
70.90; H, 6.82; N, 3.20.
(S)-1-(2-Hydroxy-3-phenoxypropyl)-4-(4-phenoxyphenyl)-
piperidine [(S)-4a]. This compound was obtained by
employing (2S)-1,2-epoxy-3-phenoxypropane11a in 77%
yield as an oil, which was subsequently converted to its
hydrochloride in 67% overall yield from the starting
material after recrystallization from ether–MeOH. The
spectroscopic data of (S)-4a were identical to those of
racemic 4a. The optical purity was estimated to be >98%
ee by HPLC (Daicel Chiralpak OD, flowrate 1.8 mL/
min, n-hexane/2-PrOH/diethylamine=500:500:1). Typi-
cal retention times were 12.3 min for (S)-4a and 9.3 min
for (R)-4a. [a]D ꢀ12.8ꢁ (c 1.02, MeOH; hydrochloride
salt); mp (hydrochloride salt) 177–178 ꢁC. Anal. calcd
.
.
C25H25NO3 1/2C4H4O4 H2O: C, 69.96; H, 6.31; N, 3.02.
Found: C, 70.09; H, 5.98; N, 3.07.
1-Phenacyl-4-[4-(4-fluorobenzyl)phenyl]-4-piperidinol (3e).
This compound was obtained in 63% yield as an oil,
which was subsequently converted to its 1/2 fumarate in
40% overall yield from the starting material after
recrystallization from ether–MeOH. 1H NMR
(400 MHz, CDCl3) d 1.76 (2H, m), 2.26 (2H, td,
J=12.4, 4.4 Hz), 2.65 (2H, td, J=12.4, 2.2 Hz), 2.91
(2H, m), 3.89 (2H, s), 3.94 (2H, s), 6.96 (2H, t,
J=8.7 Hz), 7.12–7.16 (4H, m), 7.44 (2H, d, J=8.3 Hz),
7.57 (1H, t, J=7.3 Hz), 8.02 (2H, d, J=7.5 Hz); IR
(KBr, 1/2 fumarate salt) 1699, 1599, 1582, 1508, 1450,
1372, 1261, 1224, 1158 cmꢀ1; mp (1/2 fumarate salt) 75–
.
for C26H29NO3 HCl: C, 70.98; H, 6.87; N, 3.18. Found:
C, 70.77; H, 6.91; N, 3.05.
ꢁ
.
.
78 C. Anal. calcd for C26H26FNO2 1/2C4H4O4 H2O: C,
70.13; H, 6.31; N, 2.92. Found: C, 70.21; H, 6.19; N,
3.12.
(R)-1-(2-Hydroxy-3-phenoxypropyl)-4-(4-phenoxyphenyl)-
piperidine [(R)-4a]. This compound was obtained by
employing (2R)-1,2-epoxy-3-phenoxypropane11b in 86%
yield as an oil, which was subsequently converted to its
hydrochloride in 72% overall yield from the starting
material after recrystallization from ether–MeOH. The
spectroscopic data of (R)-4a were identical to those of
1-Phenacyl-4-(3-fluoro-4-phenyl)phenyl-4-piperidinol (3f).
This compound was obtained in 76% yield as an oil,
which was subsequently converted to its 1/2 fumarate in

H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
381
racemic 4a. The optical purity was estimated to be
>98% ee by HPLC (Daicel Chiralpak OD, flowrate
1.8 ml/min, n-hexane:2-PrOH:diethylamine=500:500:1).
[a]D +12.8ꢁ (c=1.39, MeOH; hydrochloride salt); mp
(hydrochloride salt) 177–178 ꢁC. Anal. calcd for
(2H, m), 2.92 (1H, m), 3.94 (2H, s), 4.01 (2H, d,
J=5.0 Hz), 4.14 (1H, m), 6.92–6.99 (5H, m), 7.12–7.17
(4H, m), 7.26–7.30 (2H, m), 7.42 (2H, d, J=8.3 Hz); IR
(KBr, 1/2 fumarate salt) 1600, 1574, 1508, 1450, 1368,
1245, 1043, 984 cmꢀ1; mp (1/2 fumarate salt) 160–
161 C. Anal. calcd for C27H30FNO3 1/2C4H4O4: C,
70.57; H, 6.53; N, 2.84. Found: C, 70.34; H, 6.36; N,
2.87.
ꢁ
.
.
C26H29NO3 HCl: C, 70.98; H, 6.87; N, 3.18. Found: C,
70.74; H, 6.86; N, 3.09.
1-(2-Hydroxy-3-phenoxypropyl)-4-[4-(4-fluorobenzyl)phe-
nyl]piperidine (4b). This compound was obtained in
92% yield as an oil, which was subsequently converted
to its hydrochloride in 82% overall yield from the
starting material after recrystallization from ether–
1-(2-Hydroxy-3-phenoxypropyl)-4-(3-fluoro-4-phenyl)-
phenyl-4-piperidinol (4f). This compound was obtained
in 96% yield as an oil, which was subsequently con-
verted to its 1/2 fumarate in 78% overall yield from the
starting material after recrystallization from ether–
1
MeOH. H NMR (400 MHz, CDCl3) d 1.70–1.86 (4H,
1
m), 2.16 (1H, m), 2.44 (1H, td, J=11.3, 3.3 Hz), 2.50–
2.64 (3H, m), 3.10 (1H, m), 3.16 (1H, m), 3.95 (2H, s),
3.99–4.06 (2H, m), 4.12–4.16 (1H, m), 6.95–7.01 (4H,
m), 7.11–7.18 (5H, m), 7.28–7.33 (4H, m); IR (KBr,
hydrochloride salt) 3306, 2930, 2646, 1599, 1508,
1250, 1222, 812, 762, 694 cmꢀ1; mp (hydrochloride
MeOH. H NMR (400 MHz, CDCl3) d 1.82 (2H, m),
2.11–2.25 (2H, m), 2.56 (1H, m), 2.64 (2H, d,
J=6.8 Hz), 2.81–2.86 (2H, m), 2.95 (1H, m), 4.02 (2H,
d, J=5.0 Hz), 4.15 (1H, m), 6.93–6.99 (3H, m), 7.26–
7.38 (5H, m), 7.42–7.46 (3H, m), 7.55 (2H, d,
J=8.1 Hz); IR (KBr, 1/2 fumarate salt) 3188, 2935,
1577, 1372, 1450, 1242, 1048, 989 cmꢀ1; mp (1/2 fuma-
rate salt) 193–194 ꢁC. Anal. (C26H28FNO3 1/
.
.
2C4H4O4 1/5H2O: C, 69.61; H, 6.34; N, 2.90. Found:
69.95; H, 6.35; N, 2.89.
ꢁ
.
salt) 160–161 C. Anal. calcd for C27H30FNO2 HCl: C,
71.12; H, 6.85; N, 3.07. Found: C, 71.02; H, 6.78; N,
3.16.
1-(2-Hydroxy-3-phenoxypropyl)-4-(4-cyclopentyloxyphe-
nyl)piperidine (4c). This compound was obtained in
78% yield as an oil, which was subsequently converted
to its hydrochloride in 73% overall yield from the
starting material after recrystallization from ether–
Systematic conformation search and similar structure
analysis of compounds 2a, 2f, 3a and 4a. A conforma-
tion search of three structures, compounds 2a, 3a and
4a, was carried out in two steps. First, a conformation
analysis was performed on the common structural unit,
4-(40-phenoxy)phenylpiperadine (i). Two stable con-
formations were obtained by the energy minimization of
their conformers generated by the rotation of three
bonds at angle values of ꢃ30, ꢃ90, ꢃ150ꢁ using the
MM2 parameters in Macromodel. Next, energetically
favored conformations of whole structure were identi-
fied by the energy minimization of initial conformers
generated by the rotation of the bonds of the angle
values. In this step, initial torsion angles of 4-(40-phen-
oxy)-phenylpiperidine moiety were set to afford stable
conformations. Calculated stable conformations of
substructure i are (t1=90, t2=90, t3=60ꢁ) and (t1=90,
t2=ꢀ90, t3=60ꢁ). Energetically favored conformations
were also obtained by the energy minimization of initial
conformers of 2f generated in the same manner.
Through this search, 12, 56, 22 and 72 distingished
conformers of 2a, 3a, 4a and 2f, respectively, were
obtained within 5 kcal/mol from the most stable con-
formers. Similar structures of 3a, 4a and 2f to 2a were
identified in the energetically favored conformations of
these molecules by RMS fitting of three centers of the
phenyl group (a, b and d) and six atoms of the piper-
idine ring (g).
1
MeOH. H NMR (400 MHz, CDCl3) d 1.58–1.61 (2H,
m), 1.69–1.90 (10H, m), 2.12 (1H, td, J=11.9, 2.3 Hz),
2.38–2.48 (2H, m), 2.53–2.58 (2H, m), 2.96 (1H, m), 3.12
(1H, m), 3.99–4.01 (2H, m), 4.08–4.14 (1H, m), 4.70–
4.73 (1H, m), 6.81 (2H, d, J=8.6 Hz), 6.93–6.97 (3H,
m), 7.11 (2H, d, J=8.6 Hz), 7.23–7.30 (3H, m); IR
(KBr, hydrochloride salt) 2961, 1600, 1512, 1497, 1290,
1244, 1175, 831, 754, 691 cmꢀ1; mp (hydrochloride salt)
ꢁ
.
184–187 C. Anal. calcd for C25H33NO3 HCl: C, 69.51;
H, 7.93; N, 3.24. Found: C, 69.78; H, 7.91; N, 3.29.
1-(2-Hydroxy-3-phenoxypropyl)-4-(4-phenoxyphenyl)-4-
piperidinol (4d). This compound was obtained in 74%
yield as an oil, which was subsequently converted to its
1/2 fumarate in 53% overall yield from the starting
1
material after recrystallization from ether–MeOH. H
NMR (400 MHz, CDCl3) d 1.81 (2H, m), 2.08–2.22 (2H,
m), 2.55 (1H, m), 2.63 (2H, d, J=6.8 Hz), 2.79–2.83
(2H, m), 2.93 (1H, m), 4.01 (2H, dd, J=5.0, 0.7 Hz),
4.14 (1H, m), 6.93 (2H, d, J=8.9 Hz), 6.97–7.05 (4H,
m), 7.10 (1H, t, J=7.4 Hz), 7.26–7.35 (5H, m), 7.46 (2H,
d, J=8.9 Hz); IR (KBr, 1/2 fumarate salt) 1588, 1508,
1490, 1368, 1292, 1240, 1172, 1044, 984 cmꢀ1; mp (1/2
fumarate salt) 180–182 ꢁC. Anal. calcd for
.
.
C26H29NO4 1/2C4H4O4 1/3H2O: C, 69.55; H, 6.60; N,
2.90. Found: C, 69.54; H, 6.64; N, 2.96.
Inhibitory effect of veratridine-induced sodium channel
activity
1-(2-Hydroxy-3-phenoxypropyl)-4-[4-(4-fluorobenzyl)phe-
nyl]-4-piperidinol (4e). This compound was obtained in
88% yield as an oil, which was subsequently converted
to its 1/2 fumarate in 66% overall yield from the start-
ing material after recrystallization from ether–MeOH.
1H NMR (400 MHz, CDCl3) d 1.78 (2H, m), 2.14 (2H,
m), 2.55 (1H, m), 2.62 (2H, d, J=6.7 Hz), 2.78–2.85
The membrane potential of the synaptosomes prepared
from the brain membrane of Wister rats (male, 10–12
weeks old) was measured as reported13 using a mem-
brane potential sensitive fluorescent dye Rhodamine 6G
to evaluate the effects of suppression of the compound
on the veratridine-inducing depolarization response.

382
H. Annoura et al. / Bioorg. Med. Chem. 10 (2002) 371–383
T-Type calcium channel inhibitory effect
cation of the common carotid artery into the internal
carotid artery after ligation of the ipsilateral common
and external carotid arteries. The measurement of per-
ipheral type benzodiazepine binding site (PTBBS) den-
sities5b in ipsilateral cortical and striatal homogenates
was carried out as an index for quantification of neuro-
nal damage 10 days after reperfusion. Compounds and
flunarizine were administered intravenously immedi-
ately after MCAO and immediately after reperfusion
(each 3 mg/kg).
The hippocampal CA1 pyramidal cells were isolated
from Wister rats (female, 1 week old) according to a
reported method3e and the T-type calcium current was
measured under conditions of a fixed membrane poten-
tial using the whole-cell configuration of the patch
clamp technique. The effects of the compounds were
evaluated from the rate of suppression of the peak cur-
rent after 1 min of application using the concentration
clamp method.
Acknowledgements
Dopamine D2 receptor blocking action
A 57 mL volume of the membrane fraction prepared
from the striatum of rats (male, 6 weeks old) was incu-
bated together with the compound and 1.0 nM
[3H]raclopride in a buffer at 25 ꢁC for 1 h. A GF/C glass
filter (0.1% polyethylene imine treatment) was used for
B/F separation. A betaplate was used for measurement
of the radioactivity to evaluate the effect of the com-
pound.14
We thank Dr. T. Ohno for his helpful suggestions. We
also thank Drs. T. Tanaka and T. Nakanishi for their
encouragement throughout this study.
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