Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor

Article abstract of DOI:10.1016/j.bmc.2010.04.052

4-((1H-Imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthesized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have low (or no) affinity for human histamine H3 receptor, where

Full text of DOI:10.1016/j.bmc.2010.04.052

Bioorganic & Medicinal Chemistry 18 (2010) 5441–5448
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and structure–activity relationships of N-aryl-piperidine derivatives
as potent (partial) agonists for human histamine H3 receptor
*
Makoto Ishikawa , Takeshi Furuuchi, Miki Yamauchi, Fumikazu Yokoyama, Nobukazu Kakui, Yasuo Sato
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
4-((1H-Imidazol-4-yl)methyl)-1-aryl-piperazine and piperidine derivatives were designed and synthe-
sized as candidate human histamine type 3 agonists. The piperazine derivatives were found to have
low (or no) affinity for human histamine H3 receptor, whereas the piperidine derivatives showed mod-
erate to high affinity, and their agonistic activity was greatly influenced by substituents on the aromatic
ring. Among the piperidine-containing compounds, 17d and 17h were potent human histamine H3
receptor agonists with high selectivity over the closely related human H4 receptor. Our results indicate
that appropriate conformational restriction, that is, by the piperidine spacer moiety, favors specific bind-
ing to the human histamine H3 receptor.
Received 23 March 2010
Revised 16 April 2010
Accepted 17 April 2010
Available online 21 April 2010
Keywords:
Histamine H3 receptor
Agonists
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
eral lipophilic groups of these ligands occupy a hydrophobic pocket
of the H3 receptor, while the imidazole group is arranged near the
The histamine H3 receptor was discovered in 1983 by Arrang
et al.,1 as a presynaptic autoreceptor belonging to the superfamily
of G-protein coupled receptors, which are inhibitory modulators of
the synthesis and release of histamine in the central nervous sys-
tem.2,3 Further studies have clarified that the H3 receptor also
modulates various neurotransmitters, including acetylcholine,4,5
dopamine,6,7 serotonin,8 and noradrenaline,9 in both the central
and peripheral nervous systems. These characteristics of H3 recep-
tor suggest that H3 agonists could be therapeutic agents for a
broad range of disorders, including myocardial ischemia,10 inflam-
mation,11 migraine,12 sleep disorders,13 and anxiety disorders.14
It has been suggested that the pharmacophore for H3 agonistic
activity consists of an imidazole ring substituted only at the 4-posi-
tion, an alkyl spacer, and a basic moiety.15,16 This basic moiety is ex-
pected to be physiologically protonated and to interact with an
aspartate residue (Asp114) of the receptor’s transmembrane domain
3, which is highly conserved in the histamine receptor family.17,18
The potency and selectivity of agonists of this type for H3 receptor
could be increased by appropriate conformational restriction, for
aspartate residue (Asp114) in transmembrane domain 3.26 The lack
of the basic moiety and incorporation of the lipophilic part would
be expected to improve pharmacokinetic properties, such as absorp-
tion, and penetration of the blood–brain barrier. As an agonist of this
type, we reported 5,25 which possesses a (4-tert-butylphenyl-
thio)ethyl lipophilic moiety at the 4 position of the imidazole ring.
Compound 5 has high affinity and agonist potency at the H3 recep-
tor, and showed a good pharmacokinetic profile following oral
administration in rodents. These features allowed us to establish
that H3 agonists act as anti-stress agents, at least in the resident in-
truder aggression model in mice. Therefore, 5 should be a useful tool
to investigate the roles of the H3 receptor. However, 5 also has high
affinity for human histamine H4 receptor, and improvement of the
selectivity for H3 receptor is required for development of the ligand
as a potential therapeutic agent.
The human histamine H4 receptor was cloned in 2000, using se-
quence information from the human H3 receptor, and identified as
a Gi/o protein coupled receptor like H3 receptor.27–31 The H4
receptor is expressed predominantly in mast cells, eosinophils
and bone marrow and may be involved in immune responses, so
that it is a potential therapeutic target for inflammation.32 The hu-
man H4 receptor shares 31% sequence identity at the protein level
and 54% identity in the transmembrane domains, compared with
human H3 receptor.27,28 The high homology between human H3
receptor and human H4 receptor has complicated the development
of selective H3 receptor ligands.
example, substitution on the alkyl spacer ((R)-a-methylhistamine
11), or incorporation of a (substituted) ring structure (immepip
2,19 methimepip 320 and AEIC 421)(Figure. 1). In addition, H3 ago-
nists of another type, without the basic side chain, have been re-
ported; they consist of an imidazole ring, an alkyl spacer, and a
lipophilic tail.15,16,20,22–26 Although the binding modes have not
been established, De Esch and co-workers hypothesized that periph-
We hypothesized that the flexible thioether spacer of 5 might
allow the ligand to interact strongly with both human H3
receptor and H4 receptor. In other words, we considered that
* Corresponding author. Tel.: +81 45 541 2521; fax: +81 45 541 0667.
E-mail address: makoto_ishikawa@meiji.co.jp (M. Ishikawa).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.04.052

5442
M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
conformational fixation of 5 might yield new types of ligands
with improved selectivity. In the present work, we designed
and synthesized conformationally constrained analogs of 5 based
on piperidine or piperazine as a spacer. Binding affinities, and
functional activities in the [35S]GTP
cS binding assay to human
Scheme 1. Synthesis of compounds 7a–c. Reagents and conditions: (i) 4-formy-
limidazole, Et3N, MeOH-1,4-dioxane, rt, overnight; (ii) NaBH4, MeOH, rt, 1 h—
overnight, 63–94% in two steps.
histamine H3 receptor in vitro were evaluated to assess the po-
tency of the newly designed compounds. The binding affinity of
selected compounds for other human histamine receptor cong-
eners, H1, H2 and H4, was also measured.
were expressed in membranes of CHO cells (H1) and CHO-K1 cells
(H2, H4) for these assays.
2. Chemistry
The synthesis of compounds 7 is outlined in Scheme 1. Com-
mercially available piperazine derivatives were treated with 4-
formylimidazole under basic conditions to form the imine, then re-
duced with NaBH4 to give the target compounds 7a–c in moderate
to high yield (63–94%).
4. Results and discussion
Binding affinity, functional activity and antagonist potency of
the synthesized compounds are summarized in Table 1. Immepip
and 5 exhibited high affinity and agonistic activity (Ki = 0.30 nM,
EC50 = 0.67 nM, ia = 82% and Ki = 0.43 nM, EC50 = 0.75 nM, ia =
76%, respectively). Although the binding manner of 5 to the recep-
tor must be different from that of immepip, the hydrophobic inter-
action might enable 5 to bind with the receptor as strongly as
immepip. All compounds with a piperidine ring (17a–n, R1 = CH)
as a spacer showed moderate to high affinity for human histamine
H3 receptor (Ki = 1.0–127 nM). It is plausible that these ligands
interact with both the imidazole-binding site and with a hydro-
phobic pocket of human histamine H3 receptor like 5 does. On
the other hand, the compounds with a piperazine ring (7a–c,
R1 = N) as a spacer showed a drastic loss of affinity, which is due
to unfavorable interaction of the alkyl-amine part of piperazine
ring with the hydrophobic pocket.
Compounds 17 were prepared as shown in Scheme 2. 1-Boc-4-
piperidinemethanol 8 was converted to the aldehyde 9 by Swern
oxidation,33 and coupled with the Grignard reagent derived from
protected 4-iodoimidazole 1034 to give alcohol 11 in good yield
(93%). The alcohol 11 was chlorinated with thionyl chloride to ob-
tain 12 (86%), which was subsequently hydrogenated in the pres-
ence of Pd/C to give 13 (50%). Selective deprotection of the Boc
group with trifluoroacetic acid provided imidazole-protected
immepip 14 (quant.). Compound 14 was coupled with correspond-
ing aryl bromides using active palladium(0) catalyst precursor [Pd-
l
-BrP(t-Bu)3]2,35 to introduce various aryl groups in good yield
(73%-quant.). These reaction conditions worked well even with
an electron-rich aryl bromide that was expected to be inactive in
Pd-catalyzed reactions. Subsequent acid or basic hydrolysis of the
protecting group provided the desired target compounds 17a–n
(29–83%).
In the series of piperidine derivatives, binding affinity and ago-
nistic activity were greatly influenced by the substituents on the
aryl ring. Unsubstituted compound 17a showed moderate affinity
and EC50 value (30 nM and 41 nM, respectively), with low intrinsic
activity (57%), showing a slightly antagonistic profile at high con-
3. Pharmacology
centration (13% at 10À5 M) with the full agonist (R)-
a-methylhista-
mine in the [35S]GTP
c
S binding assay. Conversion of the phenyl
The affinity values for human histamine H3 receptor were mea-
sured in terms of displacement of [3H]-(R)–
a-methylhistamine
ring to a pyridine ring 17n decreased the affinity and EC50 value
(127 nM and 177 nM, respectively), presumably because of unfa-
vorable basic interaction with the hydrophobic pocket, but intrin-
sic activity was increased (74%). A meta or para substituent on the
hydrophobic moiety generally served to increase the affinity,
although the biphenyl derivative (17m), which had the greatest
molecular length, showed decreased affinity (61 nM). This result
indicated that there is a restriction on the molecular length of
the ligand if it is to be accommodated in the hydrophobic pocket
of human H3 receptor. meta-Substituted compounds 17e and 17g
showed dramatically increased affinity, but the intrinsic activity
was reduced. In particular, the bulky isopropyl meta substituent
17g resulted in antagonistic activity (IC50 = 6.6 nM). Hydrophobic
substitution at the meta position was favorable for interaction with
the hydrophobic pocket of human histamine H3 receptor. But, such
binding to membranes of CHO cells expressing the human H3
receptor in the presence of the compounds. Functional activities
of these ligands were measured by means of [35S]GTP
cS binding
assay to membranes of CHO-K1 cells expressing human H3 recep-
tor. Intrinsic activity (ia) is the ratio of the maximum response to
each ligand to the maximum response to (R)-a-methylhistamine.
To avoid overlooking compounds that possess affinity for the
receptor, but exhibit low intrinsic activity, the antagonist potency
of each ligand at 10À5 M was measured as the ability to inhibit the
binding of [35S]GTP
cS in the presence of 10 nM (R)-a-methylhista-
mine. The affinity values for human histamine H1,36 H2,37 and
H438,39 receptors were measured in terms of displacement of
[3H]rilamine (for H1), [125I]aminopotentidine (for H2), and [3H]his-
tamine (for H4) in the presence of the compounds. The receptors
Figure 1. H3 receptor agonists.

M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
5443
Scheme 2. Synthesis of compounds 17a–n. Reagents and conditions: (i) (COCl)2, DMSO, Et3N, CH2Cl2, À78 °C to 2 °C, 30 min; (ii) 10, EtMgBr, CH2Cl2–THF, À40 °C, then 9, rt,
5 h, 93% in two steps based on 10; (iii) SOCl2, Et3N, CH2Cl2, rt, 30 min, 86%; (iv) Pd/C, H2, toluene, rt, overnight, 50%; (v) TFA, H2O, CH2Cl2, rt, 1 h, quant; (vi) 15,
[Pd-l-BrP(t-Bu)3]2, t-BuONa, toluene, reflux, 3 h overnight, 73%-quant; (vii) 47% HBr aq, 100 °C, overnight; and/or KOH, EtOCH2CH2OH, H2O, 120 °C, overnight, 29–83%.
substitution may inhibit the conformational change40 of the recep-
tor to the active form for coupling to G-protein to transmit the ago-
nist signals. The naphthyl compound (17l), which can be classified
as a meta-substituted derivative, also showed diminished agonistic
activity. Comparatively small substituents at the para position in-
creased the affinity and EC50 value. Compounds 17b, 17c, 17d,
17h, and 17j (F–, NO2–, CF3–, OMe and NHMe, respectively) were
partial agonists of H3 with moderate to high affinity. Among them,
17c and 17d exhibited antagonistic potency at high concentration
(12% and 23% at 10À5 M, respectively), because of their moderate
intrinsic activity (69% and 59%). But, the para substituent –OMe
(17h) was found to increase the intrinsic activity (77%) and did
not show antagonistic potency. The high intrinsic activity (74%)
of the 3-pyridyl derivative 17n and 17h suggested that the combi-
nation of weak polarity and proton-accepting ability in the aryl
moiety could influence the intrinsic activity. Bulkier lipophilic para
substituents, such as isopropyl, t-Bu, and Ph (17f, 17i and 17m),
diminished the agonistic activity. The bulkiness of these para sub-
stituents might also hamper the conformational change of human
histamine H3 receptor to the active form, as in the case of meta-
substituted compounds. The slight agonistic activity of 17k, which
had the bulky substituent –NMe2, might again reflect the combina-
tion of weak polarity and proton-accepting ability.
should provide not only highly selective human histamine H3 ago-
nists, but also detailed information about the structural differences
of the hydrophobic pocket between H3 and H4.
5. Conclusion
As a part of our search for selective human histamine H3 receptor
agonists, we designed and synthesized 4-((1H-imidazol-4-yl)-
methyl)-1-aryl-piperazine and piperidine derivatives. These com-
pounds are conformationally constrained by their piperazine or
piperidine spacer moiety. The piperazine derivatives showed low
(or no) affinity for human histamine H3 receptor, whereas the piper-
idine derivatives showed moderate to high affinity. In the piperidine
series, some aromatic para substituents increased the H3 agonist
activity, but meta substituents and bulky para substituents dimin-
ished the agonist activity, or generated an antagonistic profile.
Among this series of compounds, 17d and 17h are potent human
histamine H3 receptor agonists with 120-fold and 574-fold selectiv-
ity, respectively, over the closely related human H4 receptor. These
results indicate that appropriate conformational fixation by intro-
duction of a suitable spacer permits specific recognition of the
hydrophobic pocket of the receptor, affording highly selective
human histamine H3 receptor ligands.
We evaluated the affinity of two selected compounds, 17d and
17h, for other human histamine receptor congeners, H1, H2 and H4
(Table 2). Compounds 17d and 17h showed low (or no) affinity for
human H1 and H2 receptor, like 5. As for human H4 receptor, 5 had
high affinity, resulting in no selectivity over H3 receptor (H3 Ki/H4
Ki = 2.6). However, 17d and 17h showed significantly reduced H4
receptor affinity (Ki = 216 nM, 3100 nM, respectively), with high
selectivity (H3 Ki/H4 Ki = 120, 574, respectively). Conformational
fixation by the piperidine ring spacer did not greatly influence
the ligand interaction with the hydrophobic pocket of the H3
receptor, but this change appears to disfavor interaction with the
hydrophobic pocket of H4 receptor. In addition, 17h had approxi-
mately the same affinity for human histamine H3 receptor as
17d did, even though 17h showed over 10-fold lower affinity than
17d at human H4 receptor. These results suggested that the config-
uration of the hydrophobic pocket is different between H3 and H4.
In another point of view, the novel agonists could be generated by
introducing the aryl moiety directly to the N-atom of immepip.
And it showed improved selectivity over H3 receptor compared
with immepip without inducing antagonistic activity (immepip:
H3 Ki/H4 Ki = 46). Further SAR-studies on ligands of this type
6. Experimental
6.1. Chemistry
NMR spectra were obtained on JEOL GX-400 FT-NMR spectrom-
eters. The following abbreviations are used: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet, and br = broad. MS were mea-
sured with Hitachi M-80B, Agilent HP5989A and JEOL JMS-700
instruments. Column chromatography was carried out using silica-
gel 60 N 40–50 lm (Kanto Chemical) or NH-Chromatography sili-
cagel 100–200 mesh (Fulisilysia Chemical). Thin layer
chromatography was performed on Silica Gel 60 F254 plates
(Merck).
6.1.1. 1-((1H-Imidazol-4-yl)methyl)-4-phenylpiperazine (7a)
To a mixture of 4-formylimidazole (61.1 mg, 0.64 mmol) and 1-
phenylpiperazine (6a) (100.6 mg, 0.62 mmol) in MeOH (2.5 ml)
and 1,4-dioxane (2.5 ml) was added Et3N (0.17 ml, 1.24 mmol),
and stirred at room temperature over night. Then the solvent

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M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
Table 1
Affinity, functional activity and antagonist potency of the synthesized compounds at human H3 receptor
N
R1
N
HN
R2
Compd
R1
R2
Human histamine H3 receptor
iac SEMb (%)
Kia (nM)
EC50 SEMb (nM)
Antagonist inhibitiond SEMb (%)
7a
N
>1000
>1000
>1000
30
n.c.e
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
n.d.f
7b
N
CF3
n.c.e
7c
N
n.c.e
17a
17b
17c
17d
CH
CH
CH
CH
41 13
1.1 0.2
8.8 5.9
1.1 0.2
57
67
69
59
1
2
2
2
13
3
12
n.d.f
12
F
NO2
CF3
20
1
3
1.8
23
17e
17f
17g
CH
CH
CH
1.0
14
0.21 0.05
36 2
46
52
1
2
CF3
12
3
31
1
1.0
n.c.e
n.d.f
80 1 (IC50 = 6.6 nM)
n.d.f
17h
17i
CH
CH
CH
CH
OMe
5.4
14
7.6 1.7
18
77
37
66
54
2
1
2
1
4
41
5
17j
1.6
1.4
1.7 0.7
2.0 0.7
n.d.f
21
NH
N
17k
5
5
17l
CH
16
1.6 0.6
33
1
38
17m
17n
CH
CH
61
n.c.e
n.d.f
102 1 (IC50 = 347 nM)
n.d.f
N
127
177 29
74 3
Immepip
5
0.30
0.43
0.67 0.10
0.75 0.10
82
76
2
1
n.d.f
n.d.f
a
b
c
d
e
f
Mean of two experiments.
Results are presented as mean SEM of at least three independent experiments.
Intrinsic activity, being the ratio of the maximum response of each ligand to the maximum response of RAMH.
Inhibition of RAMH-induced binding of [35S]GTP
Not calculable.
c
S at the concentration of 10À5 M.
Not detected.
Table 2
Binding affinity of selected compounds for human histamine H1, H2, H3, and H4 receptors
Compd
Human histamine receptors binding affinity Kia (nM)
Selectivity Ki (H4)/Ki (H3)
H1
H2
H3
H4
5
17d
17h
Immepip
>1000
>1000
>1000
>1000
>1000
>1000
>100019
0.43
1.8
1.1
216
2.6
120
574
46
5.4
3100
0.4841
2241
a
Mean of two experiments.
was evaporated to give the crude imine. This imine was used at
next step without further purification.
residue was purified with column chromatography (CHCl3:MeOH:
28% aqueous NH3 = 80:1:0.1–20:1:0.1) to give 7a as a white solid
(94.8 mg, 63%, two steps), mp 182 °C. 1H NMR (CDCl3) d 7.62 (s,
1H), 7.29–7.25 (m, 2H), 6.97 (s, 1H), 6.95–6.90 (m, 2H), 6.85 (m,
1H), 3.60 (br s, 2H), 3.21–3.14 (m, 4H), 2.65 (br s, 4H); MS (FAB+)
m/z 243 (M+H)+; HRMS (FAB+) C14H19N4 (M+H)+ calcd 243.1610,
found 243.1612.
NaBH4 (49.8 mg, 1.32 mmol) was added to a mixture of above
imine in MeOH (2.5 ml), and stirred at room temperature over
night. The reaction was quenched with H2O (20 ml), and extracted
with CHCl3 (30 ml  5). The combined organic layer was washed
with brine (30 ml), dried (Na2SO4), and evaporated. The resulting

M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
5445
6.1.2. 1-((1H-Imidazol-4-yl)methyl)-4-(4-trifluoromethylphenyl)-
piperazine (7b)
over night. The reaction mixture was filtered by a pad of Celite, and
the filtrate was evaporated. The residue was purified with prepara-
tive thin layer chromatography (EtOAc) to give 13 as a clear oil
(42.6 mg, 50%). 1H NMR (CDCl3) d 7.84 (s, 1H), 6.96 (s, 1H), 4.15–
4.11 (m, 2H), 2.88 (s, 6H), 2.68–2.65 (m, 2H), 2.49 (d, 2H,
J = 7.1 Hz), 1.82 (m, 1H), 1.64 (br d, 2H, J = 12.7 Hz), 1.45 (s, 9H),
1.15 (dq, 2H, J = 4.2, 12.7 Hz); MS (FAB+) m/z 373 (M+H)+.
Synthesized as a white solid, using the procedure for 7a from 1-
(4-(trifluoromethyl)phenyl)piperazine (6b) (94%, two steps), mp
179–180 °C. 1H NMR (CDCl3) d 7.63 (s, 1H), 7.48–7.45 (m, 2H),
6.98 (s, 1H), 6.94–6.89 (m, 2H), 3.60 (br s, 2H), 3.29–3.26 (m,
4H), 2.66–2.63 (m, 4H); MS (FAB+) m/z 311 (M+H)+; HRMS
(FAB+) C15H18F3N4 (M+H)+ calcd 311.1484, found 311.1491.
6.1.7. 4-((1-(N,N-Dimethylsulfamoyl)-1H-imidazol-4-yl)methyl)-
piperidine (14)
6.1.3. 1-((1H-Imidazol-4-yl)methyl)-4-(4-tert-butylphenyl)-
piperazine (7c)
TFA (7 ml) and H2O (0.1 ml) was added to a solution of 13
(2.007 g, 5.39 mmol) and stirred at room temperature for 1 h. To
the mixture was added saturated aqueous K2CO3 (50 ml) and di-
luted with brine (50 ml). After the extraction with CHCl3
(50 ml  4), the combined organic layer was dried (Na2SO4). The
solvent was evaporated and the resulting residue was purified with
NH–SiO2 column chromatography (MeOH:CHCl3 = 1:20) to give
amine 14 as a white solid (2.177 g, quant.). 1H NMR (CDCl3) d
7.82 (d, 1H, J = 1.2 Hz), 6.96 (d, 1H, J = 1.2 Hz), 3.07–3.02 (m, 2H),
2.88 (s, 6H), 2.58 (dt, 2H, J = 2.7, 12.1 Hz), 2.49 (d, 2H, J = 7.1 Hz),
1.82 (m, 1H), 1.68–1.64 (m, 2H), 1.14 (dq, 2H, J = 3.9, 12.1 Hz);
MS (FAB+) m/z 273 (M+H)+.
Synthesized as a white solid, using the procedure for 7a from 1-
(4-tert-butylphenyl)piperazine (6c) (83%, two steps), mp 169–
170 °C. 1H NMR (CDCl3) d 7.61 (s, 1H), 7.30–7.26 (m, 2H), 6.96 (s,
1H), 6.88–6.84 (m, 2H), 3.60 (br s, 2H), 3.18–3.15 (m, 4H), 2.66–
2.63 (m, 4H), 1.28 (s, 9H); MS (FAB+) m/z 299 (M+H)+; HRMS
(FAB+) C18H27N4 (M+H)+ calcd 299.2236, found 299.2237.
6.1.4. 1-Boc-4-((1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-yl)-
(hydroxy)methyl)piperidine (11)
To a solution of (COCl)2 (0.92 ml, 10.54 mmol) in CH2Cl2 (50 ml)
was added DMSO (0.99 ml, 13.96 ml) at À78 °C, and stirred for
10 min at the same temperature. A solution of 1-(tert-butoxycar-
bonyl)-4-piperidinemethanol
8 (1.50 g, 6.99 mmol) in CH2Cl2
6.1.8. N,N-Dimethyl-4-((1-phenylpiperidin-4-yl)methyl)-1H-imid-
azole-1-sulfonamide (16a)
(9 ml) was added and stirred for 30 min at À78 °C. Et3N (4.9 ml,
35.15 mmol) was added, then the mixture was warmed to 2 °C,
and stirred for 20 min at that temperature. The reaction mixture
was poured into H2O (100 ml), and extracted with EtOAc
(200 ml). The organic layer was washed with aqueous 1 N HCl
(100 ml), H2O (100 ml), saturated aqueous NaHCO3 (100 ml) and
brine (100 ml), sequentially. The organic layer was dried (MgSO4),
and the solvent was evaporated to give the crude 1-Boc-4-formyl-
piperazine (9).
To a solution of 4-iodo-imidazole-1-sulfonic acid dimethyla-
mide (10) (1.75 g, 5.81 mmol) in CH2Cl2 (12 ml) was added EtMgBr
(0.91 N in THF, 6.4 ml, 5.82 mmol) at À40 °C, and stirred for 5 min.
The solution of above aldehyde 9 in THF (9 ml) was added to the
mixture, and warmed to room temperature. The reaction mixture
was stirred for 5 h at room temperature, and quenched with satu-
rated aqueous NH4Cl (10 ml). The mixture was poured into brine
(50 ml) and extracted with EtOAc (100 ml  2). The organic layer
was dried (MgSO4), evaporated, and the resulting residue was puri-
fied with column chromatography (EtOAc then MeOH:
EtOAc = 1:19) to give 11 as a white solid (2.12 g, 93% based on
10). 1H NMR (CDCl3) d 7.85 (s, 1H), 7.13 (s, 1H), 4.44 (d, 1H,
J = 6.6 Hz), 4.15–4.10 (m, 2H), 2.87 (s, 6H), 2.79–2.51 (m, 3H),
1.93 (m, 1H), 1.85–1.70 (m, 2H), 1.44 (s, 9H), 1.30–1.21 (m, 2H);
MS (ESI+) m/z 389 (M+H)+.
A mixture of 14 (91.0 mg, 0.33 mmol) and bromobenzene
(69.9
l
l, 0.67 mmol) and t-BuONa (66.3 mg, 0.69 mmol) and [Pd-
mol) in toluene (4 ml) was stirred
l-BrP(t-Bu)3]2 (16.6 mg, 21.4
l
under reflux condition for 2 h. The reaction mixture was poured into
H2O (15 ml), and extracted with EtOAc (30 ml). The organic layer
was washed with brine (15 ml), dried (Na2SO4), evaporated, and
purified with column chromatography (MeOH:CHCl3:28% aqueous
NH3 = 1:150:0.1) to give 16a as a pale brown oil (107.4 mg, 92%).
1H NMR (CDCl3) d 7.84 (d, 1H, J = 1.0 Hz), 7.22 (dd, 2H, J = 7.3,
7.8 Hz), 6.99 (d, 1H, J = 1.0 Hz), 6.93 (d, 2H, J = 7.8 Hz), 6.82 (t, 1H,
J = 7.3 Hz), 3.67 (br d, 2H, J = 12.4 Hz), 2.86 (s, 6H), 2.68 (dt, 2H,
J = 2.7, 12.4 Hz), 2.54 (d, 2H, J = 6.8 Hz), 1.87–1.77 (m, 3H), 1.44
(dq, 2H, J = 3.1, 12.4 Hz); MS (EI+) m/z 348 (M+).
6.1.9. N,N-Dimethyl-4-((1-(4-fluorophenyl)piperidin-4-yl)methyl)-
1H-imidazole-1-sulfonamide (16b)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-fluorobenzene (82%). 1H NMR (CDCl3) d 7.84 (s,
1H), 6.99 (s, 1H), 6.96–6.92 (m, 2H), 6.91–6.86 (m, 2H), 3.55–
3.51 (m, 2H), 2.86 (s, 6H), 2.63 (dt, 2H, J = 2.2, 12.2 Hz), 2.54 (d,
2H, J = 6.6 Hz), 1.84–1.77 (m, 3H), 1.49–1.37 (m, 2H); MS (FAB+)
m/z 367 (M+H)+.
6.1.10. N,N-Dimethyl-4-((1-(4-nitrophenyl)piperidin-4-yl)methyl)-
1H-imidazole-1-sulfonamide (16c)
6.1.5. 1-Boc-4-(chloro(1-(N,N-dimethylsulfamoyl)-1H-imidazol-
4-yl)methyl)piperidine (12)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-nitrobenzene (96%). 1H NMR (CDCl3) d 8.13–8.08
(m, 2H), 7.85 (d, 1H, J = 1.0 Hz), 6.98 (d, 1H, J = 1.0 Hz), 6.82–6.77
(m, 2H), 3.95 (br d, 2H, J = 13.0 Hz), 2.95 (dt, 2H, J = 2.4, 13.0 Hz),
2.87 (s, 6H), 2.53 (d, 2H, J = 7.1 Hz), 2.02 (m, 1H), 1.82 (br d, 2H,
J = 13.0 Hz), 1.32 (dq, 2H, J = 3.9, 13.0 Hz); MS (FAB+) m/z 394
(M+H)+.
To a solution of alcohol 11 (108.5 mg, 279
added Et3N (0.16 ml, 1.15 mmol) and thionylchloride (25
327 mol) at 0 °C, and stirred at room temperature for 30 min.
The solvent was evaporated, and the residue was purified with
short column chromatography (EtOAc:Hex = 1:2) to give chloride
12 as a clear oil (97.9 mg, 86%). 1H NMR (CDCl3) d 7.85 (d, 1H,
J = 1.0 Hz), 7.21 (d, 1H, J = 1.0 Hz), 4.73 (d, 1H, J = 6.8 Hz), 4.29–
4.05 (m, 2H), 2.88 (s, 6H), 2.78–2.61 (m, 2H), 2.28 (m, 1H), 1.89
(m, 1H), 1.55 (m, 1H), 1.45 (s, 9H), 1.34–1.20 (m, 2H); MS (EI+)
m/z 406 (M+).
l
mol) in CH2Cl2 was
l
l,
l
6.1.11. N,N-Dimethyl-4-((1-(4-(trifluoromethyl)phenyl)piperidin-
4-yl)methyl)-1H-imidazole-1-sulfonamide (16d)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-(trifluoromethyl)benzene (87%). 1H NMR (CDCl3)
d 7.84 (d, 1H, J = 1.2 Hz), 7.45 (d, 2H, J = 8.8 Hz), 6.98 (s, 1H), 6.90
(d, 2H, J = 8.8 Hz), 3.79 (br d, 2H, J = 12.7 Hz), 2.88 (s, 6H), 2.79
(dt, 2H, J = 2.4, 12.7 Hz), 2.53 (d, 2H, J = 7.1 Hz), 1.87 (m, 1H),
6.1.6. 1-Boc-4-((1-(N,N-dimethylsulfamoyl)-1H-imidazol-4-
yl)methyl)piperidine (13)
A suspension of chloride 12 (97.9 mg, 240
lmol) and 10% Pd/C
(209.1 mg) was stirred at room temperature under H2 atmosphere

5446
M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
1.79 (br d, 2H, J = 12.7 Hz), 1.33 (dq, 2H, J = 3.9, 12.7 Hz); MS (ESI+)
m/z 417 (M+H)+.
12H), 2.68–2.54 (m, 2H), 2.52 (d, 2H, J = 6.6 Hz), 1.80–1.76 (m,
3H), 1.52–1.37 (m, 2H); MS (ESI+) m/z 392 (M+H)+.
6.1.12. N,N-Dimethyl-4-((1-(3-(trifluoromethyl)phenyl)piperidin-
4-yl)methyl)-1H-imidazole-1-sulfonamide (16e)
6.1.19. N,N-Dimethyl-4-((1-(naphthalen-2-yl)piperidin-4-yl)-
methyl)-1H-imidazole-1-sulfonamide (16l)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-3-(trifluoromethyl)benzene (81%). 1H NMR (CDCl3)
d 7.84 (d, 1H, J = 1.2 Hz), 7.33 (m, 1H), 7.11–6.99 (m, 4H), 3.73–
3.69 (m, 2H), 2.83 (s, 6H), 2.78 (dt, 2H, J = 2.4, 12.5 Hz), 2.54 (d,
2H, J = 6.8 Hz), 1.91–1.78 (m, 3H), 1.38 (dq, 2H, J = 4.1, 12.5 Hz);
MS (ESI+) m/z 417 (M+H)+.
Synthesized as a pale brown oil, using the procedure for 16a
from 2-bromonaphtalene (quant.). 1H NMR (CDCl3) d 7.85 (d, 1H,
J = 1.2 Hz), 7.70 (d, 2H, J = 9 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.39 (dt,
1H, J = 1.2, 7.0 Hz), 7.36–7.24 (m, 2H),7.11 (d, 1H, J = 1.2 Hz), 7.00
(d, 1H, J = 0.8 Hz), 3.79 (br d, 2H, J = 12.4 Hz), 2.88 (s, 6H), 2.69
(dt, 2H, J = 1.2, 12.4 Hz), 2.56 (d, 2H, J = 6.8 Hz), 1.92–1.84 (m,
3H), 1.53 (dq, 2H, J = 4.0, 12.4 Hz); MS (EI+) m/z 398 M+.
6.1.13. N,N-Dimethyl-4-((1-(4-isopropylphenyl)piperidin-4-yl)-
methyl)-1H-imidazole-1-sulfonamide (16f)
6.1.20. 4-((1-(Biphenyl-4-yl)piperidin-4-yl)methyl)-N,N-dimethyl-
1H-imidazole-1-sulfonamide (16m)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-isopropylbenzene (96%). 1H NMR (CDCl3) d 7.84
(d, 1H, J = 1.2 Hz), 7.11 (d, 2H, J = 8.8 Hz), 6.98 (d, 1H, J = 1.2 Hz),
6.87 (d, 2H, J = 8.8 Hz), 3.61 (br d, 2H, J = 12.2 Hz), 2.86 (s, 6H),
2.82 (m, 1H), 2.65 (dt, 2H, J = 2.0, 12.2 Hz), 2.53 (d, 2H,
J = 6.6 Hz), 1.85–1.76 (m, 3H), 1.49–1.37 (m, 2H), 1.21 (d, 6H,
J = 6.8 Hz); MS (EI+) m/z 390 M+.
Synthesized as a pale brown oil, using the procedure for 16a
from 4-bromobiphenyl (90%). 1H NMR (CDCl3) d 7.49 (d, 1H,
J = 1.2 Hz), 7.57–7.52 (m, 2H), 7.50–7.47 (m, 2H), 7.42–7.37 (m,
2H), 7.29–7.25 (m, 1H), 7.00–6.98 (m, 3H), 3.74 (br d, 2H,
J = 12.2 Hz), 2.86 (s, 6H), 2.75 (dt, 2H, J = 2.2, 12.2 Hz), 2.56 (d,
2H, J = 6.6 Hz), 1.89–1.78 (m, 3H), 1.44 (dq, 2H, J = 3.4, 12.2 Hz);
MS (EI+) m/z 424 M+.
6.1.14. N,N-Dimethyl-4-((1-(3-isopropylphenyl)piperidin-4-yl)-
methyl)-1H-imidazole-1-sulfonamide (16g)
6.1.21. N,N-Dimethyl-4-((1-(pyridin-3-yl)piperidin-4-yl)methyl)-
1H-imidazole-1-sulfonamide (16n)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-3-isopropylbenzene (quant.). 1H NMR (CDCl3) d
7.84 (d, 1H, J = 1.0 Hz), 7.18 (t, 1H, J = 7.8 Hz), 6.99 (d, 1H,
J = 1.0 Hz), 6.82 (m, 1H), 6.76–6.71 (m, 2H), 3.65 (br d, 2H,
J = 12.2 Hz), 2.84 (s, 6H), 2.81 (m, 1H), 268 (dt, 2H, J = 2.2,
12.2 Hz), 2.54 (d, 2H, J = 6.6 Hz), 1.87–1.80 (m, 3H), 1.49–1.38 (m,
2H), 1.22 (d, 6H, J = 6.8 Hz); MS (EI+) m/z 390 M+.
Synthesized as a pale brown oil, using the procedure for 16a
from 3-bromopyridine (92%). 1H NMR (CDCl3) d 8.31 (d, 1H,
J = 1.2 Hz), 8.06 (d, 1H, J = 3.6 Hz), 7.84 (d, 1H, J = 1.0 Hz), 7.20–
7.11 (m, 2H), 6.99 (d, 1H, J = 1.0 Hz), 3.68 (br d, 2H, J = 12.2 Hz),
2.87 (s, 6H), 2.71 (dt, 2H, J = 2.4, 12.2 Hz), 2.54 (d, 2H, J = 6.8 Hz),
1.91–1.84 (m, 3H), 1.46 (dq, 2H, J = 4.1, 12.2 Hz); MS (ESI+) m/z
350 (M+H)+.
6.1.15. N,N-Dimethyl-4-((1-(4-methoxyphenyl)piperidin-4-yl)-
methyl)-1H-imidazole-1-sulfonamide (16h)
6.1.22. 4-((1H-Imidazol-4-yl)methyl)-1-(4-tert-butylphenyl)piper-
idine (17i)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-methoxybenzene (82%). 1H NMR (CDCl3) d 7.84
(s, 1H), 6.99 (s, 1H), 6.93–6.90 (m, 2H), 6.85–6.80 (m, 2H), 3.76
(s, 3H), 3.49 (br d, 2H, J = 12.0 Hz), 2.86 (s, 6H), 2.64–2.55 (m,
2H), 2.52 (d, 2H, J = 6.6 Hz), 1.80–1.76 (m, 3H), 1.49–4.42 (m,
2H); MS (FAB+) m/z 378 M+.
The solution of 16i (80 mg, 0.20 mmol) in 48% aqueous HBr
(1 ml) was stirred at 100 °C over night. The reaction mixture was
basified with 5 N aqueous NaOH, and diluted with brine (10 ml).
The mixture was extracted with CHCl3 (30 ml  3), and organic
layer was dried (Na2SO4), evaporated, purified with preparative
thin layer chromatography (MeOH:CHCl3 = 1:9) to give 17i as a
pale brown solid (44 mg, 75%), mp 168 °C. 1H NMR (CDCl3) d 7.56
(s, 1H), 7.28–7.24 (m, 2H), 6.93–6.82 (m, 2H), 6.79 (s, 1H), 3.71
(br d, 2H, J = 12.2 Hz), 2.64 (dt, 2H, J = 2.2, 12.2 Hz), 2.57 (d, 2H,
J = 6.9 Hz), 1.80–1.67 (m, 3H), 1.44–1.35 (m, 2H), 1.28 (s, 9H); MS
(FAB+) m/z 298 (M+H)+; HRMS (FAB+) C19H28N3 (M+H)+ calcd
298.2283, found 298.2282.
6.1.16. N,N-Dimethyl-4-((1-(4-tert-butylphenyl)piperidin-4-yl)-
methyl)-1H-imidazole-1-sulfonamide (16i)
Synthesized as a pale brown oil, using the procedure for 16a
from 1-bromo-4-tert-butylbenzene (73%). 1H NMR (CDCl3) d 7.88
(s, 1H), 7.29–7.25 (m, 2H), 6.90–6.86 (m, 3H), 3.73 (br d, 2H,
J = 12.2 Hz), 2.89 (s, 6H), 2.72 (d, 2H, J = 6.3 Hz), 2.67 (dt, 2H,
J = 2.2, 12.2 Hz), 1.82–1.74 (m, 3H), 1.40 (dq, 2H, J = 3.8, 12.2 Hz),
1.29 (s, 9H); MS (ESI+) m/z 404 M+.
6.1.23. 4-((1H-Imidazol-4-yl)methyl)-1-phenylpiperidine (17a)
Synthesized as a white solid, using the procedure for 17i from
16a (70%), mp 176 °C. 1H NMR (CDCl3) d 7.58 (s, 1H), 7.26–7.22
(m, 2H), 6.95–6.94 (m, 2H), 6.92–6.80 (m, 2H), 3.69–3.65 (m,
2H), 2.68 (dt, 2H, J = 2.0, 12.2 Hz), 2.58 (d, 2H, J = 6.6 Hz), 1.82–
1.73 (m, 3H), 1.42 (dq, 2H, J = 4.0, 12.2 Hz); MS (FAB+) m/z 242
(M+H)+; HRMS (FAB+) C15H20N3 (M+H)+ calcd 242.1657, found
242.1657.
6.1.17. N,N-Dimethyl-4-((1-(4-(N-Boc,N-methylamino)phenyl)-
piperidin-4-yl)methyl)-1H-imidazole-1-sulfonamide (16j)
Synthesized as a pale brown oil, using the procedure for 16a
from 4-bromo-(N-Boc, N-methyl)aniline (quant.). 1H NMR (CDCl3)
d 7.84 (s, 1H), 7.07 (d, 2H, J = 8.8 Hz), 6.99 (s, 1H), 6.87 (d, 2H,
J = 8.8 Hz), 3.63 (br d, 2H, J = 12.0 Hz), 3.20 (s, 3H), 2.86 (s, 6H),
2.70–2.64 (m, 2H), 2.52 (d, 2H, J = 6.6 Hz), 1.86–1.80 (m, 3H),
1.49–1.37 (m, 2H), 1.44 (s, 9H); MS (ESI+) m/z 478 (M+H)+.
6.1.24. 4-((1H-Imidazol-4-yl)methyl)-1-(4-fluorophenyl)piper-
idine (17b)
6.1.18. N,N-Dimethyl-4-((1-(4-dimethylaminophenyl)piperidin-
4-yl)methyl)-1H-imidazole-1-sulfonamide (16k)
Synthesized as a pale brown oil, using the procedure for 16a
from 4-bromo-(N,N-dimethyl)aniline (87%). 1H NMR (CDCl3) d
7.84 (d, 1H, J = 1.0 Hz), 6.99 (d, 1H, J = 1.0 Hz), 6.91 (d, 2H,
J = 8.0 Hz), 6.74 (d, 2H, J = 8.0 Hz), 3.49–3.48 (m, 2H), 2.86 (s,
Synthesized as a pale brown solid, using the procedure for 17i
from 16b (29%), mp 156 °C. 1H NMR (CD3OD) d 7.57 (s, 1H),
6.98–6.91 (m, 4H), 6.79 (s, 1H), 3.53–3.52 (m, 2H), 2.62 (dt, 2H,
J = 2.2, 12.2 Hz), 2.56 (d, 2H, J = 7.1 Hz), 1.78–1.65 (m, 3H), 1.37
(dq, 2H, J = 3.8, 12.2 Hz); MS (FAB+) m/z 260 (M+H)+; HRMS
(FAB+) C15H19FN3 (M+H)+ calcd 260.1563, found 260.1562.

M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
5447
6.1.25. 4-((1H-Imidazol-4-yl)methyl)-1-(4-nitrophenyl)piperidine
(17c)
(m, 3H), 1.52–1.42 (m, 2H); MS (FAB+) m/z 292 (M+H)+; HRMS
(FAB+) C19H22N3 (M+H)+ calcd 292.1814, found 292.1818.
Synthesized as a pale brown solid, using the procedure for 17i
from 16c (69%), mp 198 °C. 1H NMR (CD3OD) d 8.08–8.04 (m,
2H), 7.58 (s, 1H), 6.95–6.90 (m, 2H), 6.80 (s, 1H), 4.03 (br d, 2H,
J = 13.2 Hz), 2.94 (dt, 2H, J = 2.4, 13.2 Hz), 2.54 (d, 2H, J = 7.1 Hz),
1.94 (m, 1H), 1.77 (br d, 2H, J = 12.8 Hz), 1.27 (dq, 2H, J = 3.9,
12.8 Hz); MS (FAB+) m/z 287 (M+H)+; HRMS (FAB+) C15H19N4O2
(M+H)+ calcd 287.1508, found 287.1508.
6.1.32. 4-((1H-Imidazol-4-yl)methyl)-1-(biphenyl-4-yl)piper-
idine (17m)
Synthesized as a white solid, using the procedure for 17i from
16m (75%), mp 233 °C. 1H NMR (CDCl3) d 7.57–7.49 (m, 6H),
7.42–7.38 (m, 2H), 7.03–7.00 (m, 2H), 6.76 (s, 1H), 3.73–3.69 (m,
2H), 2.75–2.69 (m, 2H), 2.58–2.56 (m, 2H), 1.83–1.75 (m, 3H),
1.46–1.41 (m, 2H); MS (FAB+) m/z 318 (M+H)+; HRMS (FAB+)
6.1.26. 4-((1H-Imidazol-4-yl)methyl)-1-(4-(trifluoromethyl)-
phenyl)piperidine (17d)
C
21H24N3 (M+H)+ calcd 318.1970, found 318.1970.
Synthesized as a white solid, using the procedure for 17i from
16d (70%), mp 160 °C. 1H NMR (CDCl3) d 7.59 (s, 1H), 7.44 (d, 2H,
J = 9.0 Hz), 6.90 (d, 2H, J = 9.0 Hz), 6.80 (s, 1H), 3.78 (br d, 2H,
J = 12.4 Hz), 2.80 (dt, 2H, J = 2.2, 12.4 Hz), 2.57 (d, 2H, J = 6.6 Hz),
1.89–1.79 (m, 3H), 1.41–1.31 (m, 2H); MS (FAB+) m/z 310
(M+H)+; HRMS (FAB+) C16H19F3N3 (M+H)+ calcd 310.1531, found
310.1531.
6.1.33. 3-(4-((1H-Imidazol-4-yl)methyl)piperidin-1-yl)pyridine
(17n)
Synthesized as a white solid, using the procedure for 17i from
16n (65%), mp 144 °C. 1H NMR (CDCl3) d 8.27 (d, 1H, J = 2.7 Hz),
8.04 (dd, 1H, J = 1.4, 4.4 Hz), 7.59 (s, 1H), 7.20–7.12 (m, 2H), 6.81
(s, 1H), 3.75 (br d, 2H, J = 12.4 Hz), 2.75–2.71 (m, 2H), 2.68 (d,
2H, J = 6.6 Hz), 1.83–1.74 (m, 3H), 1.44–1.33 (m, 2H); MS (FAB+)
m/z 243 (M+H)+; HRMS (FAB+) C14H19N4 (M+H)+ calcd 243.1610,
found 243.1614.
6.1.27. 4-((1H-Imidazol-4-yl)methyl)-1-(3-(trifluoromethyl)-
phenyl)piperidine (17e)
Synthesized as a white solid, using the procedure for 17i from
16e (83%), mp 97–98 °C. 1H NMR (CDCl3) d 7.60 (s, 1H), 7.32 (t,
1H, J = 12.0 Hz), 7.10 (br s, 1H), 7.07–7.01 (m, 2H), 6.81 (s, 1H),
3.70 (br d, 2H, J = 12.3 Hz), 2.74 (dt, 2H, J = 2.2, 12.3 Hz), 2.59 (d,
2H, J = 6.6 Hz), 1.83–1.76 (m, 3H), 1.38 (dq, 2H, J = 3.4, 12.3 Hz);
MS (FAB+) m/z 310 (M+H)+; HRMS (FAB+) C16H19F3N3 (M+H)+ calcd
310.1531, found 310.1531.
6.1.34. 4-((1H-Imidazol-4-yl)methyl)-1-(4-methoxyphenyl)piper-
idine (17h)
To a mixture of 16h (78.5 mg, 0.21 mmol) in 2-ethoxyethanol
(2.4 ml) and H2O (2.4 ml) was added KOH (322 mg, 4.87 mmol),
and stirred at 120 °C over night. The reaction mixture was ex-
tracted with CHCl3 (20 ml), and organic layer was washed with
brine (10 ml), dried (Na2SO4), and evaporated. The resulting resi-
due was purified with preparative thin layer chromatography
(MeOH:CHCl3:28% aqueous NH3 = 1:5:0.1) to give 17h as a pale
brown solid (40 mg, 71%), mp 139–140 °C. 1H NMR (CDCl3) d
7.56 (s, 1H), 6.91–6.85 (m, 2H), 6.85–6.80 (m, 3H), 3.76 (s, 3H),
3.48 (br d, 2H, J = 12.0 Hz), 2.61–2.54 (m, 4H), 1.81–1.66 (m, 3H),
1.43 (dq, 2H, J = 3.9, 12.0 Hz); MS (FAB+) m/z 272 (M+H)+; HRMS
(FAB+) C16H22N3O (M+H)+ calcd 272.1763, found 272.1766.
6.1.28. 4-((1H-Imidazol-4-yl)methyl)-1-(4-isopropylphenyl)piper-
idine (17f)
Synthesized as a pale brown solid, using the procedure for 17i
from 16f (69%), mp 139 °C. 1H NMR (CDCl3) d 7.57 (s, 1H), 7.12–
7.09 (m, 2H), 6.89–6.85 (m, 2H), 6.80 (s, 1H), 3.58 (br d, 2H,
J = 12.2 Hz), 2.84 (m, 1H), 2.66 (dt, 2H, J = 2.2, 12.2 Hz), 2.57 (d,
2H, J = 6.6 Hz), 1.80–1.68 (m, 3H), 1.39 (dq, 2H, J = 4.4, 12.2 Hz),
1.20 (d, 6H, J = 6.8 Hz); MS (FAB+) m/z 284 (M+H)+; HRMS (FAB+)
6.1.35. 4-(4-((1H-Imidazol-4-yl)methyl)piperidin-1-yl)-N-methyl-
aniline (17j)
C
18H26N3 (M+H)+ calcd 284.2127, found 284.2127.
A mixture of 16j (190 mg, 0.38 mmol) in 48% aqueous HBr
(4 ml) was stirred at 100 °C for 7 h. The solvent was evaporated
and diluted with saturated aqueous K2CO3 (20 ml). The mixture
was extracted with EtOAc (50 ml), and organic layer was washed
with brine (20 ml), dried (Na2SO4), evaporated. The resulting resi-
due was dissolved in 2-ethoxyethanol (3.5 ml), and H2O (3.5 ml),
KOH (605 mg, 9.17 mmol) was added. The mixture was stirred
for 120 °C over night, then extracted with CHCl3 (20 ml). The or-
ganic layer was washed with brine (10 ml), dried (Na2SO4), and
evaporated. The resulting residue was purified with preparative
6.1.29. 4-((1H-Imidazol-4-yl)methyl)-1-(3-isopropylphenyl)piper-
idine (17g)
Synthesized as a brown oil, using the procedure for 17i from
16g (65%). 1H NMR (CDCl3) d 7.58 (d, 1H, J = 2.0 Hz), 7.17 (t, 1H,
J = 8.0 Hz), 6.82–6.80 (m, 2H), 6.76–6.70 (m, 2H), 3.64 (br d, 2H,
J = 12.2 Hz), 2.86 (m, 1H), 2.68 (dt, 2H, J = 2.2, 12.2 Hz), 2.58 (d,
2H, J = 6.6 Hz), 1.83–1.72 (m, 3H), 1.42 (dq, 2H, J = 3.7, 12.2 Hz),
1.23 (d, 6H, J = 7.1 Hz); MS (FAB+) m/z 284 (M+H)+; HRMS (FAB+)
C
18H26N3 (M+H)+ calcd 284.2127, found 284.2127.
thin
layer
chromatography
(MeOH:CHCl3:28%
aqueous
6.1.30. 4-(4-((1H-Imidazol-4-yl)methyl)piperidin-1-yl)-N,N-di-
methylaniline (17k)
NH3 = 1:5:0.1) to give 17j as a brown solid (32 mg, 30%), mp
126 °C. 1H NMR (CDCl3) d 7.55 (s, 1H), 6.93–6.86 (m, 2H), 6.78 (s,
1H), 6.60–6.56 (m, 2H), 3.56–3.53 (m, 2H), 2.79 (br s, 3H), 2.59–
2.44 (m, 4H), 1.80–1.64 (m, 3H), 1.48–144 (m, 2H); MS (ESI+) m/z
271 (M+H)+; HRMS (FAB+) C16H22N4 (M+H)+ calcd 271.1923, found
271.1917.
Synthesized as a brown solid, using the procedure for 17i from
16k (80%), mp 137 °C. 1H NMR (CDCl3) d 7.57 (1H, s), 7.00–6.89 (m,
2H), 6.79 (s, 1H), 6.74–6.72 (m, 2H), 3.45–3.29 (m, 2H), 3.00–2.45
(m, 10H), 1.80–1.62 (m, 3H), 1.49–1.38 (m, 2H); MS (FAB+) m/z
284 (M+); HRMS (FAB+) C17H25N4 (M+H)+ calcd 285.2079, found
285.2081.
6.2. Pharmacology
6.1.31. 4-((1H-Imidazol-4-yl)methyl)-1-(naphthalen-2-yl)piper-
idine (17l)
Profiling of binding affinity for receptors other than H3 receptor
was done by MDS Pharma Services.
Synthesized as a pale brown solid, using the procedure for 17i
from 16l (54%), mp 179 °C. 1H NMR (CDCl3) d 7.70–7.66 (m, 3H),
7.58 (d, 1H, J = 1.0 Hz), 7.39–7.37 (m, 1H), 7.28–7.24 (m, 2H),
7.10 (d, 1H, J = 2.2 Hz), 6.82 (s, 1H), 3.78 (br d, 2H, J = 12.2 Hz),
2.74 (dt, 2H, J = 2.2, 12.2 Hz), 2.60 (d, 2H, J = 6.6 Hz), 1.86–1.76
6.2.1. H3 Receptor binding assay
Membranes prepared from CHO cells stably expressing human
recombinant histamine H3 receptors were incubated with [3H]
(R)-a-methylhistamine (3 nM, PerkinElmer Life Sciences) and test

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M. Ishikawa et al. / Bioorg. Med. Chem. 18 (2010) 5441–5448
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6.2.2. [35S]GTP
cS Binding assay
Membranes prepared from CHO cells stably expressing human
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[
35S]GTP
cS (200 pM, GE Healthcare Bio-Sciences) and test com-
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a
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