RETRACTED ARTICLE: 3-Benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists and their efficient synthesis

Article abstract of DOI:10.1016/j.bmc.2011.07.014

A series of novel 3-benzhydryl-4-piperidone derivatives were identified as potent tachykinin neurokinin-1 (NK₁) receptor antagonists. An efficient and versatile synthesis of this series was achieved with a coupling reaction of 1-benzylpiperidon

Full text of DOI:10.1016/j.bmc.2011.07.014

Bioorganic & Medicinal Chemistry 19 (2011) 5175–5182
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
3-Benzhydryl-4-piperidones as novel neurokinin-1 receptor antagonists
and their efficient synthesis
⇑
Junya Shirai , Minoru Nakamura, Naoki Tarui, Tadatoshi Hashimoto, Yoshinori Ikeura
Pharmaceutical Research Division, Takeda Pharmaceutical Co. Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 3-benzhydryl-4-piperidone derivatives were identified as potent tachykinin neurokinin-
1 (NK1) receptor antagonists. An efficient and versatile synthesis of this series was achieved with a cou-
pling reaction of 1-benzylpiperidones with benzhydryl bromides or benzhydrols in the presence of tri-
fluoromethanesulfonate and a condensation reaction of piperidones with benzyl alcohols using ethyl
o-phenylenephosphate. The 3-benzhydryl-4-piperidone skeleton, which has a 1,1-diphenylmethane moi-
ety that is a known privileged substructure targeting G-protein coupled receptors, can be used for chem-
ical library synthesis because of chemical accessibility and diversity.
Received 6 June 2011
Revised 8 July 2011
Accepted 8 July 2011
Available online 19 July 2011
Keywords:
Tachykinin
NK1 receptor
Ó 2011 Elsevier Ltd. All rights reserved.
3-Benzhydryl-4-piperidone
G-Protein coupled receptor (GPCR)
1,1-Diphenylmethane moiety
1. Introduction
of the G-protein coupled receptor (GPCR).5 We have already found
that benzhydryl groups can be easily introduced to the piperidone
Tachykinin peptides, which belong to a neuropeptide family
consisting of five common residues (Phe-X-Gly-Leu-Met-NH2) lo-
cated at the C-terminal of the amino acid sequence, include sub-
stance P (SP), neurokinin A (NKA), and neurokinin B (NKB) in
mammals. SP, NKA, and NKB selectively bind the neurokinin-1
(NK1), neurokinin-2 (NK2), and neurokinin-3 (NK3) receptors,
respectively, to cause a variety of biological responses in both the
central nervous system (CNS) and peripheral tissues.1 Among
them, SP is one of the oldest and most extensively investigated
neuropeptides.2 Animal studies with tachykinin NK1 antagonists
have resulted in several prospective disease treatments, such as
overactive bladder, gastrointestinal disorders, emesis, pain, and
CNS disorders.3
We previously reported the identification of TAK-637 (19,Fig. 1),
a structurally distinct 1,7-naphthyridine-6-carboxamide deriva-
tive, which is a potent and orally active tachykinin NK1 antagonist.4
In the course of a research program to identify a novel series of
tachykinin NK1 antagonists whose structures were different from
that of TAK-637, the 3-benzhydryl-4-piperidone derivative 13r
was found from high-throughput screening (HTS) of Takeda’s
chemical library.
core at the a
-position of the carbonyl group.6 On the basis of struc-
tural attractiveness and synthetic accessibility, we began optimiza-
tion using 13r as the lead compound. The aim of this study was to
elucidate the chemical tractability of the 3-benzhydryl-4-piperi-
done derivatives of tachykinin NK1 antagonists in order to explore
drugs targeting GPCRs. Herein, we describe the efficient and versa-
tile synthesis of 3-benzhydryl-4-piperidone derivatives and their
biological evaluation.
2. Chemistry
The synthesisof the 3-benzhydryl-4-piperidone derivatives 13a–
y was accomplished as illustrated in Scheme 1. The commercially
available 1-benzylpiperidone derivatives 1–3 were treated with
benzhydryl bromide in the presence of trimethylsilyl trifluorometh-
anesulfonate (TMSOTf) and zinc bromide or with benzhydrol deriv-
atives in the presence of TMSOTf and zinc bromide to afford the
3-benzhydryl-4-piperidone derivatives 4–10. Compounds 4 and 7
were converted to the piperidone derivatives 11 and 12 by treat-
ment with hydrochloric acid, which was followed by hydrogenation.
The modifications at the 1-position in compounds 11 and 12 were
carried out by condensation with various benzyl alcohol derivatives
using ethyl o-phenylenephosphate (EPPA).7 EPPA is a useful dehy-
drating reagent because it is easy to handle (simply mix an alcohol,
a nucleophile, and EPPA without intensive care) and it can be used in
a simple procedure for removing reacted reagents by washing with
alkaline. When corresponding benzyl halides are commercially
We were interested in the structural diversity, as well as in the
novelty, of the 3-benzhydryl-4-piperidone core. The benzhydryl
(1,1-diphenylmethane) group is a known privileged substructure
⇑
Corresponding author. Tel.: +81 6 6300 6673; fax: +81 6 6300 6306.
E-mail address: Shirai_Junya@takeda.co.jp (J. Shirai).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.07.014

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J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
Figure 1. Chemical structure of TAK-637 (19), screening hit (13r), and target compounds.
Scheme 1. Synthesis of 3-benzhydryl-4-piperidone derivatives. Reagents and conditions: (a) (for 4–6) benzhydryl bromide, trimethylsilyl trifluoromethanesulfonate, zinc
bromide, CH2Cl2, rt; (b) (for 7–10) benzhydrol derivatives, trimethylsilyl trifluoromethanesulfonate, zinc bromide, CH2Cl2, rt; (c) concentrated HCl, EtOH (then aqueous
NaOH); (d) H2, 5%Pd–C, MeOH, rt; (e) benzyl alcohol derivatives, ethyl o-phenylenephosphate, CH2Cl2, rt (then 4 M HCl/EtOAc); (f) 2-bromomethyl-4-nitroanisole, NaHCO3,
DMF, rt; (g) H2, 5%Pd–C, THF, MeOH, rt then concentrated HCl, EtOH; (h) methanesulfonyl chloride or acetyl chloride, pyridine, rt.
unavailable or chemically unstable, EPPA is suitable for this kind of
reaction, such as for the synthesis of compound 13a (R2 = 2-OH).
No protection/deprotection process is needed for synthesizing
target products. Thus, this reaction will be applicable for library
synthesis. Compounds bearing amino groups (13x and 13y) on the
N-benzyl group were synthesized by reaction of compound 11 with

J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
5177
Table 1
Binding affinities of various benzhydryl derivatives for the NK1 receptor in human IM-
9 cells
Compounda Structure
Binding affinityb
%Inh.
(10ꢀ7 M)
IC50
(nM)
Scheme 2. Synthesis of benzhydryl derivatives 16 and 17. Reagents and conditions:
(a) benzhydrol, trimethylsilyl trifluoromethanesulfonate, CH2Cl2, rt; (b) concen-
trated HCl, EtOH.
4, 7, 8
81.7
97
5
6
ꢀ16.2
NCc
Scheme 3. Synthesis of diphenylmethylidene derivative 18. Reagents and condi-
tions: (a) dichlorodiphenylmethane, trimethylsilyl trifluoromethanesulfonate, zinc
bromide, CH2Cl2, rt; (b) concentrated HCl, EtOH then aqueous NaOH.
54.3
NCc
11
16
17
17.6
NCc
NCc
NCc
Scheme 4. Optical resolution of 13r by chiral column chromatography. Reagents:
(a) Chiralpak AD, hexane and 2-propanol (9:1, v/v).
9.7
2-bromomethyl-4-nitroanisole in the presence of NaHCO3, which
was followed by reduction of the nitro group followed by sulfonyla-
tion or acylation.
The 3-piperidone derivatives 16 and the 3-pyrrolidone deriva-
tives 17, which are shown in Scheme 2, were also prepared by sim-
ilar methods as those described in Scheme 1. Diphenylmethylidene
derivative 18, which is shown in Scheme 3, was synthesized by
using dichlorodiphenylmethane instead of benzhydryl bromide
as in Scheme 1.
ꢀ0.6
The optical resolution of the lead compound 13r was performed
by chiral column chromatography to assess the differences in bio-
logical activity between the enantiomers as shown in Scheme 4.
Each of the enantiomers was successfully obtained with high opti-
cal purity. The racemization was not observed under physiological
conditions (data not shown), and the absolute stereochemistry was
not determined.
18
ꢀ2.0
29.8
31.1
NCc
NCc
NCc
9
3. Results and discussion
The compounds thus synthesized were evaluated for their
in vitro inhibitory activity against [125I]Bolton–Hunter (BH)-SP
binding in human IM-9 cells.8 The results are listed in Tables 1–3
as % inhibition at 10ꢀ7 M and/or IC50 values.
10
Since we assumed that the relative location of a benzhydryl
group, a benzyl group, and a nitrogen atom would play an impor-
tant role in the inhibitory activity, the effects of various benzhydryl
derivatives were examined in order to confirm the requisite
structure in compound 13r. As shown in Table 1, N-benzyl piperi-
done 4 displayed inhibitory activity at 10ꢀ7 M, while the N-methyl
a
b
c
All of the compounds are racemic except for 18.
Inhibition of [125I]Bolton–Hunter-SP binding in human IM-9 cells.
NC means ‘not calculable’.

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J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
Table 2
group with 9H-xanthene (9) or a 5H-dibenzo[a,d][7]annulene
(10) group resulted in reduced activity. The linkage of both phenyl
rings prevents the compound from maintaining a preferable con-
formation between these phenyl groups and the N-benzyl analog.
On the basis of the results regarding the core structure and the
benzhydryl group, we conducted further optimization by introduc-
ing various substituents onto the N-benzyl group (Table 2). The
detailed structure–activity relationships were as follows. An intro-
duction at the ortho-position was more preferable than at the
meta- or para-position (13b–g). The ortho introduction of substitu-
ents with or without hydrogen bonding acceptors enhanced the
activity (13b, 13e, 13i–l), whereas ortho substitution with a hydro-
gen bonding donor reduced the activity (13a). In addition, com-
pound 13h containing a 3,5-bis(trifluoromethyl) group showed a
remarkably decreased activity even though the 3,5-bis(trifluoro-
Binding affinities of 1-benzyl-3-benzhydryl derivatives: effects of modification of N-
benzyl group
Compounda
R2
Binding affinityb IC50 (nM)
4
H
97
280
6.6
31
77
4.9
270
220
13a
13b
13c
13d
13e
13f
13g
13h
13i
13j
13k
131
2-OH
2-MeO
3-MeO
4-MeO
2-CF3
3-CF3
4-CF3
3,5-(CF3)2
2-F
methyl) group is
antagonists.
a common substituent in tachykinin NK1
Subsequently, the effects of additional substituents were exam-
ined for 13b-related compounds (Table 3). The introduction of a
methoxyl group at the 4-, 5- or 6-position gave more favorable
results than that at the 3-position. Modification at the 5-position
resulted in the discovery of the trifluoromethoxyl analog 13s,
which had subnanomolar affinity. Since we found that the corre-
sponding phenyl compound 13t exhibited more potency than
13s, further investigation of the phenyl analogs 13u–y was
employed, showing that isopropyl (13u) and methylsulfonamide
(13x) had a similar potency to that of 13t.
32.9% inh. (10ꢀ7 M)
46
6.1
18
14
2-CN
2-NO2
2-Ph
a
All of the compounds were racemic.
See corresponding footnotes in Table 1
b
Furthermore, to reveal the differences in affinity between the
enantiomers, the evaluation of the optically active compounds for
the screening hit 13r was carried out (Table 3). Unexpectedly, the
(ꢀ)-isomer ((ꢀ)-13r) was only 2.4 times more potent than the
(+)-isomer ((+)-13r). To understand the reason for the small
differences in the activities between the enantiomers, the confor-
mational similarity was examined using a molecular modeling
study with molecular operating environment (MOE) software (
Fig. 2).9 The analysis suggested that both enantiomers of 13r ((S)-
13r and (R)-13r) were well superimposed and shared a common
pharmacophore.
Compounds with good affinity, such as 13r, 13t, 13u, and 13x
were evaluated for the inhibition of capsaicin-induced plasma
extravasation in the trachea of guinea pigs upon oral and intrave-
nous administration.10 Unfortunately, the in vivo activities were
weaker than we expected. We suspect that the results involved
pharmacokinetic issues due to the high lipophilicity and low solu-
bility of the compounds. Further optimizations to resolve the is-
sues are being carried out and will be reported in due course.
In addition, the series of compounds can be used as templates
for chemical library synthesis because of their easy synthetic
accessibility for broad modification. Furthermore, we found that
several related compounds were active toward other GPCRs such
as PAR1, PAR2, GPR100, and orexin receptor 2. Thus, the series of
compounds may serve as drug-like leads for GPCRs because they
have the benzhydryl (1,1-diphenylmethane) group, which is well
known as a privileged substructure for GPCRs.
Table 3
Binding affinities of 1-(di-substituted)benzyl-3-benzhydryl derivatives
Compounda
13b
R1
R2
Binding affinityb
IC50 (nM)
4-F
2-MeO
6.6
13m
13n
13o
13p
13q
13r
4-F
4-F
4-F
4-F
4-F
4-F
4-F
H
H
H
H
H
2,3-(MeO)2
2,4-(MeO)2
2,5-(MeO)2
2,6-(MeO)2
55
9.5
3.1
2.3
4.0
1.1
0.81
0.34
0.42
2.6
5.9
0.26
15
2-MeO, 5-F
2-MeO, 5-Br
2-MeO, 5-CF3O
2-MeO, 5-CF3O
2-MeO, 5-iPr
2-MeO, 5-N02
2-MeO, 5-NH2
2-MeO, 5-NHSO2Me
2-MeO, 5-NHAc
13s
13t
13u
13v
13w
13x
I3y
H
(+)-13r
(ꢀ)-13r
4-F
4-F
2-MeO, 5-Br
2-MeO, 5-Br
1.5
0.62
TAK-637
0.45
a
All of the compounds were racemic except for (+)-13r and (ꢀ)-13r.
b
See corresponding footnotes in Table 1.
4. Conclusion
(5), N-phenylethyl (6), and N-unsubstituted (11) analogs showed
low potencies. These results indicated that a benzyl group is the
best substituent on piperidone nitrogen. The comparison of com-
pounds 16–18 with 4 suggested that the position of the piperidone
nitrogen, the ring size, and the linkage between the piperidine ring
and the benzhydryl group were crucial for the activity. The effect of
the substituents on the benzhydryl group was investigated. The
introduction of a fluorine atom at the 4-position (7) enhanced
the activity slightly, whereas the replacement of the benzhydryl
We revealed that a series of novel 3-benzhydryl-4-piperidone
derivatives are potent tachykinin NK1 receptor antagonists. A cou-
pling reaction of 1-benzylpiperidones with benzhydryl bromides
or benzhydrols in the presence of TMSOTf and a condensation reac-
tion of piperidones with benzyl alcohols using EPPA are useful for
the synthesis of the 3-benzhydryl-4-piperidone skeleton. The
3-benzhydryl-4-piperidone skeleton can be used for a chemical
library synthesis of drug-like lead compounds targeting GPCRs.

J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
5179
Figure 2. Overlapping between the most stable conformations of (S)-13r (gray) and (R)-13r (orange).
5.1.3. 3-(Diphenylmethyl)-1-(2-phenylethyl)piperidin-4-one (6)
Crystals. Mp 73–76 °C. 1H NMR (CDCl3) d: 2.30–3.05 (m, 10H),
4.57 (d, J = 11.4 Hz, 1H), 7.10–7.40 (m, 15H). Anal. Calcd for
5. Experimental
5.1. Chemistry
C26H27NO: C, 84.51; H, 7.37; N, 3.79. Found: C, 84.71; H, 7.44; N,
3.53.
Melting points were determined with a Yanagimoto melting
point apparatus and are uncorrected. 1H NMR spectra were re-
corded on a Varian Gemini-200 spectrometer. Chemical shifts are
given in d values (ppm) using tetramethylsilane as the internal
standard. Reactions were followed by TLC on Silica Gel 60 F 254
precoated TLC plates (E. Merck) or NH TLC plates (Fuji Silysia
Chemical Ltd). Chromatographic separations were carried out on
Silica Gel 60 (0.063–0.200 or 0.040–0.063 mm, E. Merck) or basic
silica gel (ChromatorexÒ NH, 100–200 mesh, Fuji Silysia Chemical
Ltd) using the indicated eluents. Compounds 1–3 and solvents
were commercially available and used as received. Yields are not
optimized. Chemical intermediates were characterized by 1H
NMR. Elemental analysis (C, H, N) were carried out by the Analyt-
ical Department of Takeda Chemical Industries.
5.1.4. 1-Benzyl-3-[bis(4-fluorophenyl)methyl]piperidin-4-one
hydrochloride (7)
To a cooled mixture of 1 (10 g, 50 mmol) in CH2Cl2 (50 mL) was
added TMSOTf (20 mL) in an ice bath, followed by 4,40-difluoro-
benzhydrol (11 g, 55 mmol). The mixture was stirred at room tem-
perature for 14 h. Iced water and sodium acetate (10 g) were added
thereto. The organic layer was washed with water and concen-
trated in vacuo. The resultant oil was dissolved in EtOH (50 mL)
and concentrated HCl (10 mL) and kept in a refrigerator overnight.
The precipitate was collected by filtration and washed with cooled
EtOH to give 7 (16.9 g, 79%) as crystals. Mp 180–182 °C. 1H NMR
(CDCl3) d: 2.30–2.75 (m, 5H), 2.80–2.94 (m, 1H), 3.20–3.30 (m,
1H), 3.42 and 3.57 (q, J = 13.0 Hz, 2H), 4.61 (d, J = 11.0 Hz, 1H),
6.81–7.30 (m, 13H) (as free base). Anal. Calcd for C25H24ClF2NO:
C, 70.17; H, 5.65; N, 3.27. Found: C, 70.08; H, 5.69; N, 3.42.
The following compounds from 8 to 10 were prepared in a man-
ner similar to that described for the synthesis of 7 and desalting
process if needed.
5.1.1. 3-Benzhydryl-1-benzyl-4-piperidone hydrochloride (4)
To a cooled solution of 1 (95 g, 0.50 mol) in CH2Cl2 (250 mL)
was added trimethylsilyl trifluoromethanesulfonate (TMSOTf)
(100 mL) portionwise in an ice water bath at below 25 °C. After
stirring for 30 min, benzhydryl bromide (125 g, 0.50 mol) was
added thereto, followed by zinc bromide (5.0 g). Then, the mixture
was warmed to room temperature overnight and poured into ice
(300 g) and sodium acetate (100 g). The organic layer was washed
with water and concentrated in vacuo. The resultant oil was dis-
solved in EtOH (200 mL). Concentrated HCl (100 mL) was slowly
added and then the mixture was concentrated. The residue was
dissolved in EtOH (500 mL), and cooled in an ice bath. The precip-
itate was collected by filtration to give 4 (144 g, 74%) as crystals.
Mp 205–207 °C. 1H NMR (CDCl3) d: 2.20–2.40, 2.50–2.70 and
2.75–2.90 (m, 6H), 3.30–3.40 (m, 1H), 3.44 and 3.54 (q,
J = 13.2 Hz, 2H), 4.64 (d, J = 11.2 Hz, 1H), 7.17–7.27 (m, 15H) (as
free base). Anal. Calcd for C25H26ClNO: C, 76.61; H, 6.69; N, 3.57.
Found: C, 76.52; H, 6.82; N, 3.50.
5.1.5. 1-Benzyl-3-[bis(4-chlorophenyl)methyl]piperidin-4-one
hydrochloride (8)
Crystals. Mp 192–194 °C. 1H NMR (CDCl3) d: 2.30–2.90 (m, 6H),
3.20–3.34 (m, 1H), 3.42 and 3.57(q, J = 12.9 Hz, 2H), 4.56 (d,
J = 11.0 Hz, 1H), 7.00–7.32 (m, 13H) (as free base). Anal. Calcd for
C25H24Cl3NO: C, 65.16; H, 5.25; N, 3.04. Found: C, 64.76; H, 5.33;
N, 3.25.
5.1.6. 1-Benzyl-3-(9H-xanthen-9-yl)piperidin-4-one (9)
Crystals. Mp 124–125 °C. 1H NMR (CDCl3) d: 2.05–2.87 (m, 7H),
3.27 and 3.57(q, J = 13.0 Hz, 2H), 4.91 (d, J = 4.0 Hz, 1H), 6.90–7.35
(m, 13H). Anal. Calcd for C25H23NO2: C, 81.21; H, 6.27; N, 3.79.
Found: C, 81.11; H, 6.19; N, 3.97.
The following compounds 5 and 6 were prepared in a manner
similar to that described for the synthesis of 4 using 2 or 3 instead
of 1. Compounds were obtained as free amine.
5.1.7. 1-Benzyl-3-(5H-dibenzo[a,d][7]annulen-5-yl)piperidin-4-
one (10)
Crystals. Mp 167–169 °C. 1H NMR (CDCl3) d: 2.08–3.20 (m, 7H),
3.39 and 3.47 (q, J = 13.2 Hz, 2H), 4.74 (d, J = 10.8 Hz, 1H), 6.86 (d,
J = 11.8 Hz, 1H), 6.99 (d, J = 11.8 Hz, 1H), 7.10–7.40 (m, 13H). Anal.
Calcd for C27H23NOꢁ0.25H2O: C, 84.67; H, 6.45; N, 3.66. Found: C,
84.73; H, 6.58; N, 3.84.
5.1.2. 3-(Diphenylmethyl)-1-methylpiperidin-4-one (5)
Crystals. Mp 127–128 °C. 1H NMR (CDCl3) d: 2.28 (s, 3H),
2.45–2.60 (m, 4H), 2.70–2.80 (m, 2H), 3.40–3.55 (m, 2H), 4.56 (d,
J = 11.4 Hz, 1H), 7.10–7.35 (m, 10H). Anal. Calcd for C19H21NO: C,
81.68; H, 7.58; N, 5.01. Found: C, 81.55; H, 7.70; N, 4.89.

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J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
5.1.8. 3-Benzhydryl-4-piperidone hydrochloride (11)
(d, J = 11.2 Hz, 1H), 6.80–7.68 (m, 12H). Anal. Calcd for
26H22F5NO: C, 67.97; H, 4.83; N, 3.05. Found: C, 67.93; H, 4.63;
N, 2.95.
A mixture of 4 (210 g, 0.59 mol) and 5%Pd-C (21 g) in MeOH
(2.8 L) and water (280 mL) was stirred under an atmosphere of
H2 (1 atm) at 30–40 °C for 3–4 h. The catalyst was removed by fil-
tration and the filtrate was concentrated in vacuo. The resultant oil
was dissolved in EtOH (300 mL). The solution was kept in a refrig-
erator for 14 h. The precipitate was collected by filtration with
cooled EtOH to give 11 (150 g, 92%) as crystals. Mp 208–210 °C.
1H NMR (DMSO-d6) d: 2.75–3.70 (m, 6H), 4.14 (m, 1H), 4.47 (d,
J = 11.0 Hz, 1H), 7.35 (m, 10H), 9.63 (br s, 2H). Anal. Calcd for
C
5.1.15. 3-[Bis(4-fluorophenyl)methyl]-1-[3-(trifluoromethyl)
benzyl]piperidin-4-one (13f)
Crystals. Mp 150–151 °C. 1H NMR (CDCl3) d: 2.25–3.00 (m, 6H),
3.20 (m, 1H), 3.51 (d, J = 13.0 Hz, 1H), 3.60 (d, J = 13.0 Hz, 1H), 4.59
(d, J = 11.0 Hz, 1H), 6.75–7.35 (12H, m). Anal. Calcd for
C
26H22F5NOꢁ0.1H2O: C, 67.34; H, 5.20; N, 3.14. Found: C, 67.19;
C
18H20ClNO: C, 71.63; H, 6.68; N, 4.64. Found: C, 71.41; H, 6.60;
N, 4.66.
The following compound 12 was prepared in a manner similar
H, 5.72; N, 2.90.
5.1.16. 3-[Bis(4-fluorophenyl)methyl]-1-[4-(trifluoromethyl)
benzyl]piperidin-4-one (13g)
to that described for the synthesis of 11.
Crystals. Mp 126–127 °C. 1H NMR (CDCl3) d: 2.30–2.95 (m, 6H),
3.26 (m, 1H), 3.45 (d, J = 13.2 Hz, 1H), 3.62 (d, J = 13.2 Hz, 1H), 4.56
(d, J = 11.2 Hz, 1H), 6.81–7.59 (m, 12H). Anal. Calcd for
5.1.9. 3-(4,40-Difluorobenzhydryl)-4-piperidone hydrochloride
(12)
Crystals. Mp 122–123 °C. 1H NMR (DMSO-d6) d: 2.70–3.70 (m,
6H), 4.06 (m, 1H), 4.55 (d, J = 11.2 Hz, 1H), 7.00–7.50 (m, 8H),
9.56 (br s, 2H). Anal. Calcd for C18H18F2ClNO: C, 64.00; H, 5.37; N,
4.15. Found: C, 63.81; H, 5.65; N, 4.15.
C26H22F5NO: C, 67.97; H, 4.83; N, 3.05. Found: C, 67.75; H, 4.91;
N, 3.01.
5.1.17. 3-[Bis(4-fluorophenyl)methyl]-1-[3,5-bis(trifluoro-
methyl)benzyl]piperidin-4-one (13h)
5.1.10. 3-[Bis(4-fluorophenyl)methyl]-1-(2-hydroxybenzyl)
piperidin-4-one (13a)
Crystals. Mp 205–206 °C. 1H NMR (CDCl3) d: 2.33–2.61 (m, 2H),
2.52 (t, J = 6.0 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 3.31 (m, 1H), 3.52, (d,
J = 13.7 Hz, 1H), 3.65(d, J = 13.7 Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H),
6.78–7.79 (m, 11H). Anal. Calcd for C27H21F8NO: C, 61.48; H,
4.01; N, 2.66. Found: C, 61.42; H, 4.15; N, 2.49.
A cooled mixture of 12 (6.7 g, 20.0 mmol), 2-hydroxybenxyl
alcohol (2.6 g, 20.0 mmol) and diisopropylethylamine (10.2 mL,
58.6 mmol) in CH2Cl2 (50 mL) was added ethyl o-phenylenephos-
phate (EPPA) (4.8 mL) in an ice bath. The mixture was stirred at
room temperature for 60 min, and poured into EtOAc. The solution
was washed with water, dried over magnesium sulfate and con-
centrated in vacuo. The residue was crystallized from diethyl ether
to give 13a (6.9 g, 85%) as crystals. Mp 151–152 °C. 1H NMR (CDCl3)
d: 2.40–2.91 (m, 6H), 3.41 (m. 1H), 3.70 (s, 2H), 4.44 (d, J = 11.0 Hz,
2H), 6.74–7.28 (m, 12H). Anal. Calcd for C25H23FNO2: C, 73.69; H,
5.69; N, 3.44. Found: C, 73.78; H, 5.72; N, 3.43.
5.1.18. 3-[Bis(4-fluorophenyl)methyl]-1-(2-fluorobenzyl)
piperidin-4-one hydrochloride (13i)
Crystals. Mp 162–164 °C. 1H NMR (CDCl3) d: 2.25–3.00 (m, 6H),
3.20 (m, 1H), 3.51 (d, J = 13.0 Hz, 1H), 3.60 (d, J = 13.0 Hz, 1H), 4.59
(d, J = 11.0 Hz, 1H), 6.75–7.35 (m, 12H) (as free base). Anal. Calcd
for C25H23F3ClNO: C, 67.34; H, 5.20; N, 3.14. Found: C, 67.19; H,
5.72; N, 2.90.
The following compounds 13b–u were prepared in a manner
similar to that described for the synthesis of 13a and salt formation
process if needed.
5.1.19. 2-({3-[Bis(4-fluorophenyl)methyl]-4-oxopiperidin-1-yl}
methyl)benzonitrile (13j)
Crystals. Mp 83–84 °C. 1H NMR (CDCl3) d: 2.26–3.10 (m, 6H),
3.20–3.30 (m, 1H), 4.63 (d, J = 11.4 Hz, 1H), 3.57 (d, J = 13.3 Hz,
1H), 3.78 (d, J = 13.3 Hz, 1H), 6.76–7.72 (m, 12H). Anal. Calcd for
5.1.11. 3-[Bis(4-fluorophenyl)methyl]-1-(2-methoxybenzyl)
piperidin-4-one hydrochloride (13b)
Crystals. Mp 163–165 °C. 1H NMR (CDCl3) d: 2.35–3.80 (m, 6H),
3.70 (s, 3H), 4.20–4.40 (m, 3H), 4.90 (m, 1H), 6.80–7.60 (m, 12H)
(as free base). Anal. Calcd for C26H26F2ClNO2: C, 68.19; H, 5.72; N,
3.06. Found: C, 67.98; H, 5.72; N, 3.11.
C26H22F2N2O: C, 74.98; H, 5.32; N, 6.73. Found: C, 74.99; H, 5.24;
N, 6.51.
5.1.20. 3-[Bis(4-fluorophenyl)methyl]-1-(2-nitrobenzyl)
piperidin-4-one (13k)
5.1.12. 3-[Bis(4-fluorophenyl)methyl]-1-(3-methoxybenzyl)
piperidin-4-one hydrochloride (13c)
Crystals. Mp 151–152 °C. 1H NMR (CDCl3) d: 2.15–2.97 (m, 6H),
3.15 (m, 1H), 3.63, (d, J = 13.6 Hz, 1H), 3.95 (d, J = 13.6 Hz, 1H), 4.44
(d, J = 11.4 Hz, 1H), 6.77–7.86 (m, 12H). Anal. Calcd for
Crystals. Mp 161–163 °C. 1H NMR (CDCl3) d: 2.25–2.95 (m, 6H),
3.26 (m, 1H), 3.83 (s, 3H), 4.59 (d, J = 11.0 Hz, 1H), 6.75–7.85 (m,
12H) (as free base). Anal. Calcd for C26H26F2ClNO2: C, 68.19; H,
5.72; N, 3.06. Found: C, 68.05; H, 5.63; N, 2.94.
C25H22F2N2O3: C, 68.80; H, 5.08; N, 6.42. Found: C, 68.66; H,
5.11; N, 6.41.
5.1.21. 1-(Biphenyl-2-ylmethyl)-3-[bis(4-fluorophenyl)methyl]
piperidin-4-one hydrochloride (13l)
5.1.13. 3-[Bis(4-fluorophenyl)methyl]-1-(4-methoxybenzyl)
piperidin-4-one hydrochloride (13d)
Crystals. Mp 144–146 °C. 1H NMR (CDCl3) d: 2.20–2.70 (m, 6H),
3.12 (m, 1H), 3.36 (d, J = 13.2 Hz, 1H), 3.53 (d, J = 13.2 Hz, 1H), 4.48
(d, J = 11.0 Hz, 1H), 6.78–7.45 (m, 17H). (as free base). Anal. Calcd
for C31H28ClF2NO: C, 73.87; H, 5.60; N, 2.78. Found: C, 73.65; H,
5.44; N, 2.59.
Crystals. Mp 187–190 °C. 1H NMR (CDCl3) d: 2.25–2.40 (m, 1H),
2.45–2.70 (m, 4H), 2.80–2.90 (m, 1H), 3.19–3.27 (m, 1H), 3.34 (d,
J = 12.9 Hz, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.82 (s, 3H), 4.58 (d,
J = 11.4 Hz, 1H), 6.80–7.28 (m, 12H) (as free base). Anal. Calcd for
C26H26F2ClNO2: C, 68.19; H, 5.72; N, 3.06. Found: C, 67.98; H,
5.72; N, 3.11.
5.1.22. 3-[Bis(4-fluorophenyl)methyl]-1-(2,3-dimethoxybenzyl)
piperidin-4-one hydrochloride (13m)
5.1.14. 3-[Bis(4-fluorophenyl)methyl]-1-[2-(trifluoromethyl)
benzyl]piperidin-4-one (13e)
Crystals. Mp 138–140 °C. 1H NMR (CDCl3) d: 2.25–2.40 (m, 1H),
2.45–2.58 (m, 3H), 2.64–2.76 (m, 1H), 2.86–2.96 (m, 1H), 3.16–3.26
(m, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.58 (d, J = 12.9 Hz, 1H), 3.81 (3H,
Crystals. Mp 102–103 °C. 1H NMR (CDCl3) d: 2.30–2.95 (m, 6H),
3.28(m, 1H), 3.59 (d, J = 14.0 Hz, 1H), 3.73 (d, J = 14.0 Hz, 1H), 4.59

J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
5181
s), 3.88 (3H, s), 4.60 (d, J = 11.1 Hz, 1H), 6.80–7.12 (m, 9H), 7.18–
5.1.30. 3-(Diphenylmethyl)-1-[2-methoxy-5-(1-methylethyl)
7.27 (m, 2H) (as free base). Anal. Calcd for C27H28ClF2NO3ꢁH2O: C,
benzyl]piperidin-4-one (13u)
64.09; H, 5.98; N, 2.77. Found: C, 63.99; H, 6.15; N, 2.80.
Amorphous powder. 1H NMR (CDCl3) d: 1.23–1.25 (m, 6H),
2.41–2.52 (m, 3H), 2.64–2.68 (m, 1H), 2.77–2.90 (m, 3H), 3.41–
3.42 (m, 1H), 3.56 (s, 2H), 3.74 (s, 3H), 4.59 (d, J = 10.8 Hz, 1H),
6.79 (d, J = 8.0 Hz, 1H), 7.09–7.31 (m, 12H).
5.1.23. 3-[Bis(4-fluorophenyl)methyl]-1-(2,4-dimethoxy-
benzyl)piperidin-4-one hydrochloride (13n)
Crystals. Mp 127–129 °C. 1H NMR (CDCl3) d: 2.25–2.60 (m, 4H),
2.65–2.76 (m, 1H), 2.82–2.95 (m, 1H), 3.18–3.28 (m, 1H), 3.46 (d,
J = 12.9 Hz, 1H), 3.51 (d, J = 12.9 Hz, 1H), 3.75 (s, 3H), 3.83 (s, 3H),
4.57 (d, J = 11.4 Hz, 1H), 6.38–6.50 (m, 2H), 6.80–7.00 (m,4H),
7.03–7.15 (m, 3H), 7.18–7.30 (m, 2H) (as free base). Anal. Calcd
for C27H28ClF2NO3ꢁ0.5H2O: C, 65.25; H, 5.88; N, 2.82. Found: C,
65.20; H, 6.11; N, 2.70.
5.1.31. 3-(Diphenylmethyl)-1-(2-methoxy-5-nitrobenzyl)
piperidin-4-one (13v)
A mixture of 11 (9.1 g, 30 mmol), 2-methoxy-5-nitrobenzylbro-
mide (7.4 g, 30 mmol), NaHCO3 (5.0 g, 60 mmol) and DMF (40 mL)
was stirred at room temperature for 30 h. After diluting with EtOAc
(250 mL), hexane (50 mL) and H2O (400 mL), the phases were sep-
arated. The organic phase was washed with H2O, dried and concen-
trated. The residue was treated with EtOH to give 13v as colorless
crystals (12.0 g, 93%). Mp 119–120 °C. 1H NMR (CDCl3) d: 2.42–4.50
(m, 2H), 2.54–2.67 (m, 2H), 2.78–2.82 (m, 2H), 3.44–3.50 (m, 1H),
3.56 (s, 2H), 3.87 (s, 3H), 4.56 (d, J = 11.2 Hz, 1H), 6.87 (d, J = 8.8 Hz,
1H), 7.05–7.32 (m, 10H), 8.14–8.17 (m, 1H), 8.33 (d, J = 2.8 Hz, 1H).
Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51. Found: C,
72.37; H, 5.92; N, 6.41.
5.1.24. 3-[Bis(4-fluorophenyl)methyl]-1-(2,5-dimethoxybenzyl)
piperidin-4-one hydrochloride (13o)
Crystals. Mp 195–198 °C. 1H NMR (CDCl3) d: 2.35–2.41 (m,
1H), 2.44–2.35 (m, 2H), 2.58, 2.61 (dd, J = 12.0, 4.0 Hz, 1H),
2.72–2.78 (m, 1H), 2.86–2.90 (m, 1H), 3.23–3.29 (m, 1H), 3.53
(s, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 4.59 (d, J = 10.8 Hz, 1H),
6.78 (s, 2H), 6.84–6.95 (m, 5H), 7.08, 7.10 (dd, J = 8.8, 5.2 Hz,
2H), 7.22–7.26 (m, 2H) (as free base). Anal. Calcd for
C
27H28ClF2NO3ꢁH2O: C, 64.09; H, 5.98; N, 2.77. Found: C, 64.11;
5.1.32. 1-(5-Amino-2-methoxybenzyl)-3-(diphenylmethyl)
piperidin-4-one dihydrochloride (13w)
H, 6.18; N, 2.79.
To a solution of 13v (1.8 g, 4.3 mmol) in THF (10 mL) was added
a suspension of 5% Pd–C (520 mg) in MeOH (15 mL). The mixture
was stirred under an atmosphere of hydrogen at room tempera-
ture. The catalyst was removed by filtration. After the filtrate
was diluted with concentrated HCl (0.71 mL), toluene (40 mL),
EtOH (50 mL), the mixture was evaporated. The residue was trea-
ted with EtOH–EtOAc (4:1, v/v, 50 mL) to give 13w as colorless
crystals (1.8 g, 88%). Mp 198–200 °C. 1H NMR (CDCl3) d: 2.40–
4.60 (m, 13H), 7.06–7.56 (m, 13H), 10.30 (br, 2H) (as free base).
Anal. Calcd for C26H30Cl2N2O2ꢁ0.5H2O: C, 64.73; H, 6.48; N, 5.81.
Found: C, 64.90; H, 6.48; N, 5.71.
5.1.25. 3-[Bis(4-fluorophenyl)methyl]-1-(2,6-dimethoxybenzyl)
piperidin-4-one (13p)
Crystals. Mp 125–126 °C. 1H NMR (CDCl3) d: 2.35–2.41 (m, 1H),
2.44–2.35 (m, 2H), 2.58, 2.61 (dd, J = 12.0, 4.0 Hz, 1H), 2.72–2.78
(m, 1H), 2.86–2.90 (m, 1H), 3.23–3.29 (m, 1H), 3.53 (s, 2H), 3.73
(s, 3H), 3.80 (s, 3H), 4.59 (d, J = 10.8 Hz, 1H), 6.78 (s, 2H), 6.84–
6.95 (m, 5H), 7.08, 7.10 (dd, J = 8.8, 5.2 Hz, 2H), 7.22–7.26 (m,
2H). Anal. Calcd for C27H27F2NO3: C, 71.05; H, 6.19; N, 3.19. Found:
C, 70.93; H, 5.93; N, 3.17.
5.1.26. 3-[Bis(4-fluorophenyl)methyl]-1-(5-fluoro-2-methoxy-
benzyl)piperidin-4-one (13q)
5.1.33. N-(3-{[3-(Diphenylmethyl)-4-oxopiperidin-1-yl]
methyl}-4-methoxyphenyl)methanesulfonamide (13x)
To a solution of 13x (473 mg, 1.0 mmol) in pyridine (5 mL) was
added methanesulfonyl chloride (150 mg, 1.3 mmol) at room tem-
perature, and then the mixture was stirred for 1 h and poured into
H2O (0.2 mL). The mixture was concentrated and the residue was
diluted with EtOAc (40 mL) and aqueous NaHCO3 (30 mL). The or-
ganic phase was dried and concentrated. The residue was purified
by silica gel column chromatography using EtOAc–hexane (1:1, v/
v) as an eluent to give 13x as amorphous powder (408 mg, 85%). 1H
NMR (CDCl3) d: 2.36–2.43 (m, 1H), 2.54–2.63 (m, 3H), 2.71–2.77
(m, 1H), 2.85–2.91 (m, 1H), 2.94 (s, 3H), 3.39–3.44 (m, 1H), 3.49–
3.59 (m, 2H), 3.77 (s, 3H), 4.64 (d, J = 11.2 Hz, 1H), 6.20 (br, 1H),
6.81 (d, J = 8.8 Hz, 1H), 7.11–7.31 (m, 12H).
Amorphous power. 1H NMR (CDCl3) d: 2.38–2.61 (m, 4H), 2.74–
2.78 (m, 1H), 2.85–2.90 (m, 1H), 3.26–3.31 (m, 1H), 3.52 (s, 2H),
3.74 (s, 3H), 4.58 (d, J = 11.2 Hz, 1H), 6.75 (m, 1H), 6.86–6.96 (m,
5H), 7.09–7.12 (m, 3H), 7.23–7.26 (m, 2H).
5.1.27. 3-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-methoxy-
benzyl)piperidin-4-one (13r)
Crystals. Mp 129–130 °C. 1H NMR (CDCl3) d: 2.35–3.29 (m, 6H),
3.29 (m, 1H), 3.50 (s, 2H), 3.74(s, 3H), 4.55 (d, J = 11.0 Hz, 1H),
6.68–7.47 (m, 11H). Anal. Calcd for C26H24BrF2NO2: C, 71.05; H,
6.19; N, 3.19. Found: C, 70.93; H, 5.93; N, 3.17.
5.1.28. 3-[Bis(4-fluorophenyl)methyl]-1-[2-methoxy-5-
(trifluoromethoxy)benzyl]piperidin-4-one hydrochloride (13s)
Amorphous powder. 1H NMR (CDCl3) d: 2.40–2.45 (m, 2H),
2.49–2.61 (m, 4H), 3.30 (m, 1H), 3.53 (s, 2H), 3.77 (s, 3H), 4.56
(d, J = 11.2 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 6.87 (dd, J = 8.8,
8.6 Hz, 2H), 6.94 (dd, J = 8.8, 8.6 Hz, 2H), 7.07–7.12 (m, 3H), 7.22–
7.25 (m, 3H) (as free base).
The following compound 13y was prepared in a manner similar
to that described for the synthesis of 13x using acetyl chloride in-
stead of methanesulfonyl chloride.
5.1.34. N-(3-{[3-(Diphenylmethyl)-4-oxopiperidin-1-yl]methyl}
-4-methoxyphenyl)acetamide (13y)
Amorphous powder. 1H NMR (CDCl3) d: 2.19 (s, 3H), 2.37–2.43
(m, 1H), 2.49–2.55 (m, 2H), 2.62–2.66 (m, 1H), 2.72–2.78 (m,
1H), 2.82–2.88 (m, 1H), 3.38–3.43 (m, 1H), 3.49–3.59 (m, 2H),
3.74 (s, 3H), 4.62 (d, J = 11.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 7.01
(br, 1H), 7.11–7.42 (m, 12H).
5.1.29. 3-(Diphenylmethyl)-1-[2-methoxy-5-(trifluoromethoxy)
benzyl]piperidin-4-one hydrochloride (13t)
Crystals. Mp 174–175 °C. 1H NMR (CDCl3) d: 2.39–2.55 (m, 3H),
2.63–2.66 (m, 1H), 2.72–2.78 (m, 1H), 2.82–2.86 (m, 1H), 3.39–3.45
(m, 1H), 3.53 (s, 2H), 3.76 (s, 3H), 4.59 (d, J = 11.2 Hz, 1H), 6.80 (d,
J = 8.8 Hz, 1H), 7.08–7.32 (m, 12H) (as free base). Anal. Calcd for
5.1.35. (+)-3-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-
methoxybenzyl)piperidin-4-one ((+)-13r)
See Section 5.1.36.
C27H27ClF3NO3: C, 64.09; H, 5.38; N, 2.77. Found: C, 64.11; H,
5.53; N, 2.65.

5182
J. Shirai et al. / Bioorg. Med. Chem. 19 (2011) 5175–5182
5.1.36. (ꢀ)-3-[Bis(4-fluorophenyl)methyl]-1-(5-bromo-2-
methoxybenzyl)piperidin-4-one ((ꢀ)-13r)
centrifugation for 5 min at 500g to obtain a cell pellet. The pellet
was washed once with PBS crushed using a Polytron homogenizer
(Kinematika, Germany) in 30 mL of 50 mM Tris–HC1 buffer (pH
An optical resolution of 13r (1.0 g) was carried out by prepara-
tive high-performance liquid chromatography (HPLC) using
Chiralpak AD (50.0 mmID ꢂ 500 mmL, DAICEL Chemical Industries,
Ltd, Japan) under detection at 254 nm with a mixture of hexane
and 2-propanol (9:1, v/v) as the eluent at a flow rate of 70 mL/min
at 28 °C to give (+)-13r (0.41 g, 41%, 99.9%ee) and (ꢀ)-13r (0.43 g,
7.4) containing NaCl (120 mM), KC1 (5 mM), chymostatin (2
mL), bacitracin (40 g/mL), (p-amidinophenyl)methanesulfonyl
fluoride (40 g/mL), and ethylenediaminetetraacetic acid (EDTA)
lg/
l
l
(1 mM), and then centrifuged at 40,000g for 20 min. The residue
was suspended in 30 mL of a reaction buffer [50 mM Tris–HC1 buf-
fer (pH 7.4), 0.02% bovine serum albumin, (p-amidinophe-
43%, 99.9%ee) as colorless powders: (+)-13r, [a]D = +93.0 (c 1.049,
MeOH); (ꢀ)-13r, [ D = ꢀ94.3 (c 1.049, MeOH).
a
]
nyl)methanesulfonyl fluoride (40
lg/mL), chymostatin (2 lg/mL),
bacitracin (40 g/mL) and MnCl2 (3 mM)] and then preserved fro-
l
5.1.37. 1-Benzyl-4-(diphenylmethyl)piperidin-3-one
hydrochloride (16)
zen (ꢀ80 °C) as a receptor specimen.
Compound 14 (10 g, 44 mmol) was dissolved in CH2Cl2
(150 mL) and then saturated aqueous NaCl (50 mL) and potassium
bicarbonate (6 g) were added thereto. The organic layer was dried
over anhydrous magnesium sulfate and concentrated in vacuo. The
resultant oil was dissolved in CH2Cl2 (150 mL). The mixture was
cooled in an ice bath and TMSOTf (18 mL) was added, followed
by benzhydrol (8.2 g, 44 mmol). The mixture was stirred at room
temperature for 14 h. Cooled water (100 mL) and sodium acetate
(20 g) were added thereto. The organic layer was washed with
water and concentrated in vacuo. The resultant oil was dissolved
in EtOH (5 mL) and concentrated HCl (5 mL) and kept in a refriger-
ator overnight. The precipitate was collected by filtration with
cooled EtOH to give 16 (12.4 g, 72%) as crystals. Mp 169–171 °C.
1H NMR (CDCl3) d: 1.50–3.30 (m, 6H), 2.92 and 3.16 (q,
J = 13.0 Hz, 1H), 3.59 (s, 2H), 4.40 (d, J = 9.8 Hz, 1H), 7.28 (m,
15H). Anal. Calcd for C25H26ClNO: C, 76.61; H, 6.69; N, 3.57. Found:
C, 76.52; H, 6.70; N, 3.33.
5.2.2. Radioligand binding assay
The above specimen was suspended in the reaction buffer, and a
50
l
L portion of the suspension was used in the reaction. After
addition of the sample and
[
125I]BH-SP (final concentration
130 pM), the reaction was allowed to proceed in 0.2 mL of reaction
mixture at room temperature for 30 min. The amount of nonspe-
cific binding was determined by adding SP at a final concentration
of 2 ꢂ 10ꢀ6 M. After the reaction, a cell harvester (Filtermate
Harvester PerkinElmer, USA) was used, and the reaction was termi-
nated by rapid filtration through a glass filter (GF/C) (PerkinElmer,
USA). After washing three times with 50 mM Tris–HC1 buffer (pH
7.4) containing 0.02% bovine serum albumin, the radioactivity
remaining on the filter was measured with TopCount Microplate
Scintillation Counter (Packard BioScience). Before use, the filter
was immersed in 0.3% poly(ethy1enimine) for 2–24 h.
Acknowledgments
The following compound 17 was prepared in a manner similar
to that described for the synthesis of 16.
We appreciate the great contribution of Mr. M. Yamaoka and
Mr. E. Imamiya for their investigation of the structure–activity
relationship information. We also thank Dr. T. Tanaka for the
molecular modeling studies.
5.1.38. 1-Benzyl-4-benzhydryl-3-pyrrolidone hydrochloride (17)
Amorphous powder. 1H NMR (CDCl3) d: 2.47–3.50 (m, 5H), 3.49
and 3.70 (q, J = 13.0 Hz, 2H), 4.50 (1H, d, J = 7.0 Hz), 7.00–7.36 (m,
15H). Anal. Calcd for C24H23ClNO: C, 76.28; H, 6.40; N, 3.71. Found:
C, 76.51; H, 6.55; N, 3.27.
References and notes
The following compound 18 was prepared in a manner similar
to that described for the synthesis 4 using dichlorodiphenylme-
thane instead of benzhydryl bromide. The compound was obtained
as free amine.
1. Chang, M. M.; Leeman, S. E.; Niall, H. D. Nat. New Biol. 1971, 232, 86.
2. (a) Otsuka, M.; Yoshioka, K. Physiol. Rev. 1993, 73, 229; (b) Maggi, C. A.;
Patacchini, R.; Rovero, P.; Giachetti, A. J. Auton. Pharmacol. 1993, 13, 23; (c)
Regoli, D.; Boudon, A.; Fauchere, J. L. Pharmacol. Rev. 1994, 46, 551; (d)
MacLean, S. Med. Res. Rev. 1996, 16, 297; (e) Lowe, J. A., III Med. Res. Rev. 1996,
16, 527.
5.1.39. 1-Benzyl-3-(diphenylmethylidene)piperidin-4-one (18)
Crystals. Mp 135–137 °C. 1H NMR (CDCl3) d: 2.67 (t, J = 5.8 Hz,
2H), 2.90 (t, J = 5.8 Hz, 2H), 3.50 (s, 2H), 3.61 (s, 2H), 7.06–7.25
(m, 15H). Anal. Calcd for C25H23NO: C, 84.93; H, 6.56; N, 3.96.
Found: C, 83.93; H, 6.62; N, 3.94.
3. (a) Elliott, J.; Seward, E. M. Exp. Opin. Ther. Pat. 1997, 7, 43; (b) Hokfelt, T.;
Pernow, B.; Wahren, J. J. Intern. Med. 2001, 249, 27.
4. Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.; Fujishima, A.;
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