Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists

Article abstract of DOI:10.1002/cmdc.201300240

The 5-HT₇ receptor (5-HT7R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5- HT₇R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT<

Full text of DOI:10.1002/cmdc.201300240

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DOI: 10.1002/cmdc.201300240
Aryl Biphenyl-3-ylmethylpiperazines as 5-HT7 Receptor
Antagonists
Jeeyeon Kim,[a, b] Youngjae Kim,[a, b] Jinsung Tae,[b] Miyoung Yeom,[a, c] Bongjin Moon,[c] Xi-
Ping Huang,[d] Bryan L. Roth,[d] Kangho Lee,[e, f] Hyewhon Rhim,[e, f] Il Han Choo,[g]
Youhoon Chong,[h] Gyochang Keum,[a] Ghilsoo Nam,*[a] and Hyunah Choo*[a, i]
The 5-HT7 receptor (5-HT7R) is a promising therapeutic target
for the treatment of depression and neuropathic pain. The 5-
HT7R antagonist SB-269970 exhibited antidepressant-like activi-
ty, whereas systemic administration of the 5-HT7R agonist AS-
19 significantly inhibited mechanical hypersensitivity and ther-
mal hyperalgesia. In our efforts to discover selective 5-HT7R an-
tagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were
designed, synthesized, and biologically evaluated against the
5-HT7R. Among the synthesized compounds, 1-([2’-methoxy-
(1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28)
was the best binder to the 5-HT7R (pKi =7.83), and its antago-
nistic property was confirmed by functional assays. The selec-
tivity profile of compound 28 was also recorded for the 5-HT7R
over other serotonin receptor subtypes, such as 5-HT1R, 5-
HT2R, 5-HT3R, and 5-HT6R. In a molecular modeling study, the
2-methoxyphenyl moiety attached to the piperazine ring of
compound 28 was proposed to be essential for the antagonis-
tic function.
Introduction
According to sequence similarity and function, the serotonin
receptors are classified into seven families (5-HT1R–5-HT7R).
Among these, the 5-HT7 receptor (5-HT7R) was the most re-
cently cloned one.[1] The 5-HT7R belongs to the group of G-pro-
tein-coupled receptors (GPCRs) and is coupled to the stimula-
tory G protein (Gs), which activates adenylate cyclase, with a re-
sultant increase of the intracellular level of the secondary mes-
senger cyclic adenosine monophosphate (cAMP).[2–4] The 5-
HT7Rs are located in the central nervous system, such as the
thalamus, hypothalamus, hippocampus, and cortex, as well as
in the peripheral tissues.[2–4] Recently, attention has been given
to 5-HT7Rs because of their potential roles in depression, con-
trol of circadian rhythms, migraine, epilepsy, and neuropathic
pain.[5] In particular, observations such as the down regulation
of 5-HT7Rs after chronic antidepressant administration and an-
tidepressant-like behaviors in 5-HT7R-knock-out mice[6] suggest-
ed the use of 5-HT7R antagonists as possible antidepressants.
Thus, it has been reported that SB-269970 (Figure 1), which
had been a well-known selective 5-HT7R antagonist until it was
reported to block a2-adrenoreceptors,[7] exhibited antidepres-
sant-like activity in a forced swimming test and showed fast ef-
fects in an open field test with olfactory bulbectomized rats
(OBX), which is an important indication of the 5-HT7R antago-
nist being a putative fast-acting antidepressant.[8] On the other
hand, there have been several reports that activation of 5-
[a] J. Kim,+ Y. Kim,+ M. Yeom, Dr. G. Keum, Dr. G. Nam,++ Prof. H. Choo++
Center for Neuro-Medicine, Korea Institute of Science and Technology
Seongbuk-gu, Seoul 136-791 (Korea)
E-mail: gsnam@kist.re.kr
hchoo@kist.re.kr
[b] J. Kim,+ Y. Kim,+ Prof. J. Tae
Department of Chemistry, Yonsei University
Seodaemun-gu, Seoul 120-749 (Korea)
[c] M. Yeom, Prof. B. Moon
Department of Chemistry, Sogang University
Mapo-gu, Seoul 121-742 (Korea)
[d] Dr. X.-P. Huang, Prof. B. L. Roth
National Institute of Mental Health Psychoactive Drug Screening Program,
Division of Medicinal Chemistry and Natural Products, and
Department of Pharmacology, School of Medicine
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (USA)
[e] K. Lee, Dr. H. Rhim
Center for Neuroscience, Korea Institute of Science and Technology
Seongbuk-gu, Seoul 136-791 (Korea)
[f] K. Lee, Dr. H. Rhim
Department of Neuroscience, University of Science and Technology
Gajungro 217, Youseong-gu, Daejeon 305-350 (Korea)
[g] Prof. I. H. Choo
School of Medicine, Chosun University
Pilmoondaero 309, Dong-gu, Kwangju 501-759 (Korea)
[h] Prof. Y. Chong
Department of Bioscience and Biotechnology, Konkuk University
Gwangjin-gu, Seoul 143-701 (Korea)
[i] Prof. H. Choo++
Department of Biological Chemistry, University of Science and Technology
Gajungro 217, Youseong-gu, Daejeon 305-350 (Korea)
[+] These authors contributed equally to this work.
[
++] The two corresponding authors contributed equally to this work.
Figure 1. Structures of 5-HT7R modulators.
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HT7Rs is involved in pain processing,[9] and both pronociceptive
and antinociceptive roles have been proposed to be associated
with 5-HT7Rs; activation of 5-HT7Rs exerts antinociceptive ef-
fects in the central nervous system,[9d–g] whereas 5-HT7Rs partic-
ipate in the peripheral pronociceptive effect of serotonin,
a neurotransmitter.[9h,i] Systemic administration of the 5-HT7R
agonist AS-19 (Figure 1) significantly inhibited mechanical hy-
persensitivity and thermal hyperalgesia in the neuropathic-
pain animal model. Therefore, the 5-HT7R is a promising thera-
peutic target for the treatment of depression and neuropathic
pain.
various aryl piperazines, 5, under reductive amination condi-
tions to afford the title compounds 6–28 in 15–78% yields.[12]
In total, 23 aryl biphenyl-3-ylmethylpiperazines, 6–28, were
synthesized.
Pharmacology
The pharmacological profiles of compounds 6–28 were deter-
mined for 5-HT7R by [3H]d-lysergic acid diethylamide ([3H]LSD)
radioligand binding assays in transfected CHO-K1 cells.[13] SB-
269970 and AS-19 were used as reference compounds. The se-
lectivity profile of compound 28 for other subtype serotonin
receptors was also obtained by radioligand binding assays
with the corresponding radioligands, namely [3H]8-hydroxy-2-
(dipropylamino)tetralin ([3H]8-OH-DPAT) for the 5-HT1A receptor,
[3H]GR125743 for the 5-HT1B and 5-HT1D receptors,
[3H]ketanserin for the 5-HT2A receptor, [3H]LSD for the 5-
HT2Band 5-HT6 receptors, [3H]mesulergine for the 5-HT2C recep-
tor, and [3H]LY278584 for the 5-HT3 receptor.[13c] Selectivity in-
dexes (SIs) were preliminarily calculated by comparing other
subtype serotonin receptor binding affinities (expressed as in-
hibition constant (Ki) values) with that for 5-HT7R (expressed as
a Ki value). Functional characterization of compound 28 was
carried out by measuring cAMP levels from HEK293 cells transi-
ently transfected with human cloned 5-HT7R, with 5-carboxa-
midotryptamine (5-CT) or SB-269970 as reference com-
pounds.[4]
There have been reports of 5-HT7R ligands with biaryl moiet-
ies by several groups.[10] Recently, 1-[2-(4-methoxyphenyl)phe-
nyl]piperazine (1; Figure 1) was identified as a high-affinity 5-
HT7R ligand.[10c] We have also been involved in the discovery of
novel selective 5-HT7R modulators and focused on the biaryl
moiety for several years.[10d–f] Herein, we report the design, syn-
thesis, binding affinity, and functional in vitro activity at the 5-
HT7R of a series of biphenyl compounds. Based on the pharma-
cological data, such as selectivity over other subtype serotonin
receptors and functional activity, we suggest the most active
compound as a lead compound for the treatment of depres-
sion. In addition, we address a key structural moiety and deter-
mine its antagonistic activity to the 5-HT7R through a molecular
modeling study.
Results and Discussion
Structure–activity relationship analysis
Chemistry
The binding affinity of the designed compound 6 with no sub-
stituents on the biphenyl and piperazinylphenyl moieties was
evaluated, and the pKi value was determined as 6.35 (Table 1).
We then fixed the biphenyl substituent R1 as H to understand
the role of the piperazinylphenyl substituent R2 for the binding
affinity. Compounds 7–24, with the unsubstituted biphenyl
moiety (R1: H) and various aryl piperazines (R2: F, Cl, Me, OMe,
and so on), were tested for 5-HT7R binding affinities (Table 1).
Compounds 7–9, with the R2 group as a fluorine, showed mod-
erate binding affinities to 5-HT7R; compound 7, with the 2-
fluoro substituent, had better binding affinity (pKi =6.48) than
the unsubstituted compound 6. When a chorine atom was at-
tached to the piperazinylphenyl ring, the overall binding affini-
ties of compounds 10–12 were lower than that of the original
compound 6. Compounds 13–15, with methyl substituents,
showed binding affinities with pKi values of 6.01, 6.32, and
5.42, respectively. Compounds 16–19, with two methyl sub-
stituents, showed only marginal binding affinities against 5-
HT7R. Among compounds 20–22, with methoxy substituents,
only the 2-methoxy-substituted compound 20 showed good
binding affinity, with a pKi value of 7.10. Compound 23, with
a 3,4-dimethoxy substituent, showed only marginal binding af-
finity (pKi =5.68). Compound 24, with a 3-CF3 substituent,
showed lower binding affinity (pKi =6.15) than the unsubstitut-
ed compound 6. Taken together, the compounds with the
ortho substituents 2-F, 2-Cl, and 2-OCH3 showed better binding
affinities than the equivalent compounds with meta or para
The title compounds, aryl biphenyl-3-ylmethylpiperazines 6–
28, were synthesized in two steps from commercially available
3-bromobenzaldehyde (2) and aryl boronic acid 3 (Scheme 1).
Suzuki coupling of 3-bromobenzaldehyde (2) with aryl boronic
acids 3 (R1: H, F, Cl, CH3, or OCH3) was performed in the pres-
ence of a catalytic amount of Pd(PPh3)4 and Na2CO3 in DMF
heated at reflux to afford biphenyl-3-carbaldehydes 4 in 37–
81% yields.[11] Biphenyl-3-carbaldehydes 4 were treated with
Scheme 1. Synthesis of aryl biphenyl-3-ylmethylpiperazines 6–28. Reagents
and conditions: a) Pd(PPh3)4, Na2CO3, N,N-dimethylformamide (DMF), reflux,
6 h, 37–81%; b) NaBH(OAc)3, MeOH, RT, 8 h, 15–78%.
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Table 1. Binding affinities to the 5-HT7R.
Table 2. Selectivity profile of compound 28 over other serotonin receptor
subtypes.
Compd
R1
R2
pKi[a]
Ki [nm]
6
7
8
9
10
11
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6.35Æ0.08
6.48Æ0.06
5.85Æ0.07
6.03Æ0.06
5.83Æ0.06
5.24Æ0.08
422
332
1420
930
Receptor
pKi[a]
Ki [nm]
15.0
100
679
225
70.0
43.0
233
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-CH3
3-CH3
4-CH3
2,3-diCH3
2,4-diCH3
2,5-diCH3
3,5-diCH3
2-OCH3
3-OCH3
4-OCH3
3,4-diOCH3
3-CF3
2-OCH3
2-OCH3
2-OCH3
2-OCH3
5-HT7
7.83Æ0.06
7.00Æ0.09
6.17Æ0.04
6.65Æ0.03
7.16Æ0.06
7.37Æ0.07
6.63Æ0.08
6.5Æ0.1
5-HT1A
5-HT1B
5-HT1D
5-HT2A
5-HT2B
5-HT2C
5-HT3
1480
5770
>10000
981
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
SB-269970
AS-19
<5
6.01Æ0.07
6.32Æ0.09
5.42Æ0.07
5.90Æ0.06
5.47Æ0.08
5.64Æ0.07
6.03Æ0.08
7.10Æ0.06
6.16Æ0.08
6.34Æ0.07
5.68Æ0.07
6.15Æ0.07
7.3Æ0.1
479
3760
1250
3390
2310
932
295
>10000
5-HT6
<5
[a] Values are the mean ÆSEM of triplicate binding experiments.
79.0
694
458
2080
711
54
33.0
51.0
15.0
0.34
0.81
rotonin receptors, as well as other GPCRs, the selectivity profile
is very important in drug discovery. Compound 28 was not
binding effectively to the 5-HT6R and was moderately selective
for the 5-HT1R, 5-HT2CR, and 5-HT3R. However, compound 28
was less selective for the 5-HT2AR and 5-HT2BR, with pKi values
of 7.16 and 7.37, respectively.
2-F
2-Cl
2-CH3
2-OCH3
7.48Æ0.08
7.29Æ0.07
7.83Æ0.06
9.47Æ0.05
9.09Æ0.05
In a functional characterization test against the 5-HT7R, com-
pound 28 was evaluated for adenylate cyclase activity by
using HEK293 cells transiently transfected with human 5-
HT7R.[4] For the agonist test, in which the nonselective 5-HT7R
agonist 5-CT was used as positive control, compound 28
showed only a 20% cAMP level, compared with the 100%
cAMP level with 5-CT at 12.5 mm (Figure 2a). On the other
hand, compound 28 blocked the cAMP level increase by 5-HT
(serotonin), with 70% inhibition at 10 mm, compared with
100% inhibition by SB-269970. According to these functional
assays, compound 28 could be defined as a 5-HT7R antagonist.
Overall, compound 28 is a novel 5-HT7R antagonist.
[a] Values are the meanÆSEM of triplicate binding experiments.
substituents, whereas in the case of methyl substituents, com-
pound 14, with a 3-CH3 group, was the better binder to 5-
HT7R. Monosubstituted compounds showed better binding af-
finities than disubstituted compounds (16–19 and 23). Among
compounds 7–24, compound 20, with the 2-methoxy substitu-
ent, was the most active.
To further improve the binding affinity to the 5-HT7R, we
fixed the piperazinylphenyl moiety R2 as the 2-OCH3 group and
modified the biphenyl substituent R1 with 2-F, 2-Cl, 2-CH3, or 2-
OCH3 groups. The binding affinities of the substituted com-
pounds 25–28 against 5-HT7R were improved relative to the
original compound, with pKi values between 7.29 and 7.83,
with the bismethoxy-substituted compound 28 being the
most potent (pKi =7.83). Even though 28 showed 28-fold in-
creased binding affinity over that of the original compound 6,
it is still a relatively weaker binder to the 5-HT7R compared
with the well-known 5-HT7R antagonist SB-269970 (pKi =9.47)
and the agonist AS-19 (pKi =9.09).
Molecular modeling study
The high binding affinity and antagonistic property of com-
pound 28 to 5-HT7R was then tackled by a molecular docking
study. The geometry-optimized structure of 28 was docked to
the modeled structure of the 5-HT7R by Glide 4.0 software im-
plemented in Maestro 7.5 (Schrçdinger Inc.).[10b] In accordance
with the previously reported binding models,[19–23] an ionic in-
teraction between the protonated amino group of compound
28 and Asp162 in the 5-HT7R was shown to constitute a main
essential binding interaction (Figure 3a). Also, the 2-methoxy-
phenyl and 2’-methoxybiphenyl-3-ylmethyl functionalities at-
tached at both ends of the piperazine moiety of compound 28
were found in the two hydrophobic pockets HPP1 (yellow
dotted half-circle in Figure 3b) and HPP2 (red dotted half-circle
in Figure 3b). It is of particular interest that the two aromatic
methoxy substituents on the piperazinylphenyl and the bi-
For compound 28, which had the best binding affinity in
this series, the selectivity profile over other subtype serotonin
receptors was examined, and the results are summarized in
Table 2. Each subtype serotonin receptor is a therapeutic
target for the treatment of central nervous system disorders
such as schizophrenia, anxiety, depression, and cognition.[14–18]
Still, to decrease the side effects caused by action on other se-
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Figure 3b) and HPP2 (Leu232/Ile233/Arg367, Figure 3b), re-
spectively (Figure 3c), and the resulting hydrophobic interac-
tion must be responsible for the high binding affinity of com-
pound 28 to the 5-HT7R. Taken together, the binding interac-
tions of the aryl piperazine ligand 28 with the 5-HT7R can be
characterized as bidirectional hydrophobic interactions anch-
ored at the salt bridge, the binding interaction of which is sig-
nificantly enhanced by additional hydrophobic interactions
around the two aromatic methoxy substituents.
Based on the understanding of the binding mode of com-
pound 28, we then attempted to explain its antagonistic prop-
erty through comparison with the binding modes of SB-
269970 and AS-19, the representative 5-HT7R antagonist and
agonist, respectively. Thus, the geometry-optimized structures
of both SB-269970 and AS-19 were docked to the ligand bind-
ing site of the 5-HT7R by using the same docking protocol, and
their binding modes were compared with that of compound
28 (Figure 4). The three 5-HT7R ligands commonly occupied
one of the two hydrophobic pockets (HPP1; yellow dotted
half-circles in Figure 4), and the 2’-methoxybiphenyl moiety of
compound 28 (Figure 4a), 2-hydroxybenzenesulfonyl moiety of
SB-269970 (Figure 4b), and trimethylpyrazole moiety of AS-19
(Figure 4c) were observed in this pocket. However, the binding
interactions of these ligands to the other hydrophobic pocket
(HPP2; red dotted half-circles in Figure 4) were strikingly differ-
ent. Whereas compound 28 (Figure 4a) and SB-269970 (Fig-
Figure 2. Functional assays against 5-HT7R.
phenyl functionalities of compound 28 were snugly fitted into
the small hydrophobic pockets HPP1 (Val163/Thr214/Phe344,
Figure 3. Docking mode of compound 28 in the ligand binding site of modeled 5-HT7R: a) 2D schematic plot created with the program LIGPLOT; b) molecular
surface representation of the binding pockets HPP1 (yellow dotted half-circle) and HPP2 (red dotted half-circle); c) the two hydrophobic sites, HPP1 and
HPP2, around the aromatic methoxy substituents.
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Figure 4. Docking modes of a) compound 28, b) SB-269970, and c) AS-19 in the ligand binding site of the 5-HT7R and d) their superimposed structures, with
28, SB-269970, and AS-19 shown in gray, magenta, and yellow, respectively. The two hydrophobic pockets HPP1 and HPP2 are shown in molecular surface
representation, respectively highlighted with yellow and red dotted half-circles.
ure 4b) were shown to cover this pocket with their 2-methoxy-
Experimental Section
phenyl and 4-methylpiperidine functionalities, respectively, the
Chemistry
short dimethylamino moiety of AS-19 leaves this pocket
almost unoccupied (Figure 4c). It could be assumed that the
General: All reactions were carried out under dry nitrogen or
argon unless otherwise indicated. Commercially available reagents
were used without further purification. Solvents and gases were
dried according to standard procedures. Organic solvents were
evaporated with reduced pressure by using a rotary evaporator.
Analytical thin layer chromatography (TLC) was performed by
using glass plates pre-coated with silica gel (0.25 mm). TLC plates
were developed by exposure to UV light (UV) and then were vi-
sualized with a KMnO4 stain followed by brief heating on hot plate.
Flash column chromatography was performed by using silica gel
resulting flexibility conferred to the hydrophobic pocket HPP2
of the 5-HT7R upon binding to AS-19 might allow conforma-
tional change to the receptor that would result in agonism of
AS-19, which is not feasible in the binding events with the
antagonists, such as compound 28 and SB-269970.
1
60 (230–400 mesh, Merck) with the indicated solvents. H and 13C
Conclusions
NMR spectra were recorded on Bruker 300, Bruker 400, or Varian
300 NMR spectrometers. 1H NMR spectra are represented as fol-
lows: chemical shift, multiplicity (s: singlet; d: doublet; t: triplet; q:
quartet; m: multiplet; dd: doublet of doublet; td: triplet of dou-
blet; brs: broad singlet; brt: broad triplet), integration, and cou-
Aryl biphenyl-3-ylmethylpiperazines were designed, synthe-
sized, and biologically evaluated against the 5-HT7R. Among
the synthesized compounds, compound 28 was the best
binder to the 5-HT7R, with a pKi value of 7.83, and it was con-
firmed as an antagonist according to the functional assays.
Also, the selectivity profile of compound 28 was reported over
other serotonin receptor subtypes such as the 5-HT1R, 5-HT2R,
5-HT3R, and 5-HT6R. A molecular modeling study was per-
formed in comparison with the known 5-HT7R modulators SB-
269970 and AS-19 to show that the 2-methoxyphenyl moiety
attached to the piperazine ring of compound 28 may be es-
sential to the antagonistic function. Further structure–activity
relationship studies on these biphenyl compounds are in prog-
ress and will be reported in due course.
1
pling constant (J) in Hertz (Hz). H NMR chemical shifts are report-
ed relative to CDCl3 (d=7.26 ppm). 13C NMR chemical shifts were
recorded relative to the central line of CDCl3 (d=77.0 ppm). LC–MS
analyses were performed on either a Micromass QUATTRO micro or
an Agilent 6410 Triple Quad system. Purity was checked on
a Waters HPLC e2695 instrument equipped with a UV/Vis 2489 de-
tector and a SunFire C18 (4.6ꢁ150 mm, 5 mm) reversed-phase
column. Standard conditions were as follows: eluents: system A
(CH3CN), system B (H2O/0.1m NH4OAc); a flow rate of 1 mLminÀ1
;
a gradient of 30–100% A over 20 min; detection at l 254 and
280 nm.
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(1,1’-Biphenyl)-3-carbaldehyde (4a): Phenylboronic acid (3a;
395 mg, 3.24 mmol), tetrakis(triphenylphosphine)palladium (31 mg,
0.027 mmol), and Na2CO3 (430 mg, 4.05 mmol) were added to a so-
lution of 3-bromobenzaldehyde (2; 315 mL, 2.70 mmol) in DMF
(20 mL). The resulting solution was stirred and heated at reflux for
6 h. After termination of this reaction, the solution was allowed to
cool to room temperature, partitioned between saturated NaHCO3
solution and EtOAc, and extracted with EtOAc. The combined or-
ganic phases were washed with brine, dried over MgSO4, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/Et2O, 8:1) to afford the product 4a
(380 mg, 2.09 mmol, 77% yield): 1H NMR (300 MHz, CDCl3): d=
10.10 (s, 1H), 8.08 (s, 1H), 7.84 (d, J=7.2 Hz, 2H), 7.62–7.56 (m,
3H), 7.48–7.35 ppm (m, 3H).
0.15 mmol, 18% yield): HPLC: purity 99%, tR =16.9 min; 1H NMR
(300 MHz, CDCl3): d=7.61–7.18 (m, 11H), 6.93–6.81 (m, 3H), 3.63 (s,
2H), 3.20 (brt, J=5.1 Hz, 4H), 2.64 ppm (brt, J=5.1 Hz, 4H);
13C NMR (75 MHz, CDCl3): d=151.4, 141.3, 141.2, 138.5, 129.2,
128.8, 128.3, 128.1, 127.4, 127.3, 126.1, 119.7, 116.1, 115.6, 63.2,
53.2, 49.2 ppm; LC–MS (ESI): m/z calcd for C23H24N2: 329.20
[M+H]+; found: 329.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2-fluorophenyl)piperazine
(7):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(2-fluorophenyl)piperazine (5b; 296 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 7 (191 mg, 0.55 mmol, 67% yield): HPLC:
purity 96%, tR =16.7 min; 1H NMR (300 MHz, CDCl3): d=7.63–7.32
(m, 9H), 6.98–6.84 (m, 4H), 3.64 (s, 2H), 3.13 (brt, J=5.1 Hz, 4H),
2.65 ppm (brt, J=5.1 Hz, 4H); 13C NMR (75 MHz, CDCl3): d=157.2
(d, J=237 Hz), 148.1 (d, J=1.5 Hz), 141.3 (d, J=8.25 Hz), 138.6,
132.0, 130.4, 128.8, 128.2, 128.0, 127.7, 127.4, 127.3, 126.1, 117.8 (d,
J=7.5 Hz), 115.7, 115.4, 63.1, 53.2, 50.2 ppm; LC–MS (ESI): m/z
calcd for C23H23FN2: 347.19 [M+H]+; found: 347.4.
2’-Fluoro-(1,1’-biphenyl)-3-carbaldehyde (4b): Following the
same procedure as that used for the synthesis of 4a, the reaction
of 3-bromobenzaldehyde (2; 315 mL, 2.70 mmol), 2-fluorophenyl-
boronic acid (3b; 454 mg, 3.24 mmol), tetrakis(triphenylphosphi-
ne)palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 mL) gave the title compound 4b (440 mg,
1
2.20 mmol, 81% yield): H NMR (300 MHz, CDCl3): d=10.09 (s, 1H),
8.07 (d, J=1.5 Hz, 1H), 7.90 (dt, J=7.6, 1.3 Hz, 1H), 7.85–7.82 (m,
1H), 7.62 (t, J=7.8, Hz, 1H), 7.48 (td, J=7.9, 2.0 Hz, 1H), 7.39–7.35
(m, 1H), 7.28–7.16 ppm (m, 3H).
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3-fluorophenyl)piperazine
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(3-fluorophenyl)piperazine (5c; 198 mg,
(8):
1.10 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
100 mg,
2’-Chloro-(1,1’-biphenyl)-3-carbaldehyde (4c): Following the
same procedure as that used for the synthesis of 4a, the reaction
of 3-bromobenzaldehyde (2; 277 mL, 2.37 mmol), 2-chlorophenyl-
boronic acid (3c; 446 mg, 2.85 mmol), tetrakis(triphenylphosphine)-
palladium (27 mg, 0.024 mmol), and Na2CO3 (377 mg, 3.56 mmol)
in DMF (20 mL) gave the title compound 4c (189 mg, 0.87 mmol,
37% yield): 1H NMR (400 MHz, CDCl3): d=10.01 (s, 1H), 8.06–7.68
(m, 1H), 7.58–7.50 (m, 2H), 7.43–7.33 ppm (m, 4H).
0.55 mmol), and NaBH(OAc)3 (355 mg, 1.65 mmol) in MeOH (10 mL)
gave the title compound 8 (113 mg, 0.33 mmol, 59% yield): HPLC:
purity 99%, tR =17.1 min; 1H NMR (300 MHz, CDCl3): d=7.67–7.37
(m, 9H), 7.22 (q, J=7.2 Hz, 1H), 6.72–6.55 (m, 3H), 3.67 (s, 2H),
3.26 (brt, J=5.1 Hz, 4H), 2.67 ppm (brt, J=4.8 Hz, 4H); 13C NMR
(75 MHz, CDCl3): d=164.0 (d, J=241.5 Hz), 153.1 (d, J=9.75 Hz),
141.4, 141.2, 138.7, 130.3, 130.1, 128.9, 128.2, 128.0, 127.5, 127.3,
126.1, 111.2, 105.8 (d, J=21 Hz), 102.7 (d, J=24.75 Hz), 63.1, 53.0,
48.7 ppm; LC–MS (ESI): m/z calcd for C23H23FN2: 347.19 [M+H]+;
found: 347.4.
2’-Methyl-(1,1’-biphenyl)-3-carbaldehyde (4d): Following the
same procedure as that used for the synthesis of 4a, the reaction
of 3-bromobenzaldehyde (2; 315 mL, 2.70 mmol), 2-methylphenyl-
boronic acid (3d; 439 mg, 3.24 mmol), tetrakis(triphenylphosphi-
ne)palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 mL) gave the title compound 4d (402 mg,
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(4-fluorophenyl)piperazine
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(4-fluorophenyl)piperazine (5d; 296 mg,
(9):
1
2.05 mmol, 76% yield): H NMR (300 MHz, CDCl3): d=10.08 (s, 1H),
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
7.89–7.84 (m, 2H), 7.61–7.58 (m, 2H), 7.32–7.23 (m, 4H), 2.27 ppm
(s, 3H).
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 9 (75 mg, 0.22 mmol, 27% yield): HPLC:
purity 96%, tR =17.2 min; 1H NMR (300 MHz, CDCl3): d=7.64–7.33
(m, 9H), 7.05–6.89 (m, 4H), 3.65 (s, 2H), 3.13 (brt, J=4.8 Hz, 4H),
2.68 ppm (brt, J=4.8 Hz, 4H); 13C NMR (75 MHz, CDCl3): d=155.9
(d, J=244.5 Hz), 141.3 (d, J=6 Hz), 140.4 (d, J=8.25 Hz), 138.7,
128.9, 128.3, 128.1, 127.4, 127.3, 126.1, 124.6 (d, J=3 Hz), 119.0 (d,
J=3 Hz), 116.2 (d, J=20.25 Hz), 63.2, 53.3, 50.7 ppm; LC–MS (ESI):
m/z calcd for C23H23FN2: 347.19 [M+H]+; found: 347.4.
2’-Methoxy-(1,1’-biphenyl)-3-carbaldehyde (4e): Following the
same procedure as that used for the synthesis of 4a, the reaction
of 3-bromobenzaldehyde (2; 315 mL, 2.70 mmol), 2-methoxyphenyl-
boronic acid (3e; 492 mg, 3.24 mmol), tetrakis(triphenylphosphi-
ne)palladium (31 mg, 0.027 mmol), and Na2CO3 (430 mg,
4.05 mmol) in DMF (20 mL) gave the title compound 4e (447 mg,
1
2.11 mmol, 78% yield): H NMR (300 MHz, CDCl3): d=10.07 (s, 1H),
8.04 (brt, J=1.5 Hz, 1H), 7.86–7.79 (m, 2H), 7.57 (t, J=7.6 Hz, 1H),
7.39–7.33 (m, 2H), 7.08–7.00 (m, 2H), 3.83 ppm (s, 3H).
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2-chlorophenyl)piperazine (10):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(2-chlorophenyl)piperazine (5e; 382 mg,
1-([1,1’-Biphenyl]-3-ylmethyl)-4-phenylpiperazine (6): (1,1’-Bi-
phenyl)-3-carbaldehyde (4a; 150 mg, 0.82 mmol) was added to
a solution of 1-phenylpiperazine (5a; 266 mg, 1.64 mmol) in MeOH
(10 mL). The reaction mixture was stirred at room temperature for
2 h, then NaBH(OAc)3 (529 mg, 2.46 mmol) was added, and the re-
sulting mixture was stirred for 8 h. After termination of the reac-
tion, the solution was partitioned between saturated NaHCO3 solu-
tion and CH2Cl2 and was extracted with CH2Cl2. The combined or-
ganic phases were washed with brine, dried over MgSO4, and con-
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/Et2O, 8:1) to afford product 6 (49 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 10 (200 mg, 0.55 mmol, 67% yield):
HPLC: purity 99%, tR =18.3 min; 1H NMR (300 MHz, CDCl3) 7.59–
7.62 (m, 3H), 7.30–7.50 (m, 7H), 7.15–7.20 (m, 1H), 7.01 (dd, J=8.0,
1.3 Hz, 1H), 6.92 (td, J=7.6, 1.3 Hz, 1H), 3.63 (s, 2H), 3.07 (brs, 4H),
2.66 ppm (brs, 4H); 13C NMR (75 MHz, CDCl3): d=149.5, 141.3,
141.3, 138.8, 130.7, 128.8, 128.8, 128.3, 128.1, 127.7, 127.4, 127.3,
126.0, 123.7, 120.5, 63.3, 53.4, 51.3 ppm; LC–MS (ESI): m/z calcd for
C23H23ClN2: 363.16 [M+H]+; found: 363.4.
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1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3-chlorophenyl)piperazine (11):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(3-chlorophenyl)piperazine (5 f; 382 mg,
2.40 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=162.3, 149.4, 142.9,
141.5, 135.7, 130.3, 130.1, 129.7, 129.7, 129.1, 128.0, 127.2, 127.0,
116.4, 59.9, 52.9, 49.9, 20.5 ppm; LC–MS (ESI): m/z calcd for
C24H26N2: 343.22 [M+H]+; found: 343.2.
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 11 (159 mg, 0.44 mmol, 53% yield):
HPLC: purity 99%, tR =18.6 min; 1H NMR (300 MHz, CDCl3): d=
7.41–7.44 (m, 1H), 7.13–7.30 (m, 8H), 6.98 (t, J=8.1 Hz, 1H), 6.58–
6.72 (m, 3H), 3.33 (s, 2H), 2.97 (brt, J=4.9 Hz, 4H), 2.34 ppm (brt,
J=5.0 Hz, 4H); 13C NMR (75 MHz, CDCl3): d=152.6, 142.9, 141.6,
135.6, 135.0, 130.3, 130.1, 129.7, 128.0, 127.3, 127.1, 127.1, 119.2,
115.7, 113.9, 59.9, 52.7, 48.8 ppm; LC–MS (ESI): m/z calcd for
C23H23ClN2: 363.16 [M+H]+; found: 363.1.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2,3-dimethylphenyl)piperazine
(16): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(2,3-dimethylphenyl)piperazine (5k; 312 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 16 (58 mg, 0.16 mmol, 20% yield): HPLC:
purity 99%, tR =19.2 min; 1H NMR (300 MHz, CDCl3): d=7.63–7.34
(m, 9H), 7.09–6.88 (m, 3H), 3.65 (s, 2H), 2.92 (brt, J=4.8 Hz, 4H),
2.66 (brs, 4H), 2.26 (s, 3H), 2.21 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=151.8, 141.3, 138.9, 138.0, 131.3, 128.8, 128.8, 128.4,
128.2, 127.4, 127.3, 126.0, 125.9, 125.0, 116.8, 63.4, 53.9, 52.3, 20.7,
14.1 ppm; LC–MS (ESI): m/z calcd for C25H28N2: 357.23 [M+H]+;
found: 357.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(4-chlorophenyl)piperazine (12):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(4-chlorophenyl)piperazine (5g; 382 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 12 (192 mg, 0.53 mmol, 64% yield):
HPLC: purity 99%, tR =18.4 min; 1H NMR (300 MHz, CDCl3): d=
7.40–7.43 (m, 1H), 7.12–7.29 (m, 8H), 6.99–7.04 (m, 2H), 6.60–6.64
(m, 2H), 3.32 (s, 2H), 2.92 (brt, J=4.8 Hz, 4H), 2.34 ppm (brt, J=
4.9 Hz, 4H); 13C NMR (75 MHz, CDCl3): d=150.2, 143.0, 141.6, 135.6,
130.4, 130.2, 129.7, 128.1, 127.4, 127.2, 127.1, 124.4, 117.3, 60.0,
52.8, 49.3 ppm; LC–MS (ESI): m/z calcd for C23H23ClN2: 363.16
[M+H]+; found: 363.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2,4-dimethylphenyl)piperazine
(17): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(2,4-dimethylphenyl)piperazine (5l; 312 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 17 (156 mg, 0.44 mmol, 54% yield):
HPLC: purity 98%, tR =19.5 min; 1H NMR (300 MHz, CDCl3): d=
7.87–7.53 (m, 9H), 7.22–7.16 (m, 3H), 3.85 (s, 2H), 3.14 (brt, J=
4.8 Hz, 4H), 2.86 (brs, 4H), 2.51 (s, 3H), 2.50 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=149.4, 141.4, 139.0, 132.7, 132.6, 132.0, 129.0,
128.9, 128.4, 128.2, 127.5, 127.4, 127.2, 126.1, 119.2, 63.5, 54.0, 52.2,
20.9, 18.0 ppm; LC–MS (ESI): m/z calcd for C25H28N2: 357.23
[M+H]+; found: 357.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2-methylphenyl)piperazine (13):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(2-methylphenyl)piperazine (5h; 289 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 13 (41 mg, 0.12 mmol, 15% yield): HPLC:
purity 99%, tR =18.5 min; 1H NMR (300 MHz, CDCl3): d=7.73–7.70
(m, 3H), 7.61–7.43 (m, 6H), 7.30–7.03 (m, 4H), 3.74 (s, 2H), 3.04
(brt, J=4.5 Hz, 4H), 2.75 (brs, 4H), 2.40 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=151.7, 141.3, 138.8, 132.7, 131.1, 128.8, 128.8,
128.3, 128.1, 127.4, 127.3, 126.7, 126.0, 123.1, 119.1, 63.4, 53.8, 51.8,
18.0 ppm; LC–MS (ESI): m/z calcd for C24H26N2: 343.22 [M+H]+;
found: 343.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2,5-dimethylphenyl)piperazine
(18): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(2,5-dimethylphenyl)piperazine (5m;
312 mg, 1.64 mmol), (1,1’-biphenyl)-3-carbaldehyde (4a; 150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 18 (62 mg, 0.17 mmol, 21% yield): HPLC:
purity 98%, tR =19.6 min; 1H NMR (300 MHz, CDCl3): d=7.62–7.30
(m, 9H), 7.07 (d, J=7.5 Hz, 1H), 6.89–6.80 (m, 2H), 3.51 (s, 2H),
2.90 (brt, J=4.5 Hz, 4H), 2.56 (brs, 4H), 2.33 (s, 3H), 2.25 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=141.4, 139.1, 138.0, 136.2, 131.4,
131.1, 129.5, 128.9, 128.4, 128.2, 127.4, 126.1, 125.1, 123.9, 120.0,
116.9, 63.5, 54.0, 52.0, 21.5, 17.7 ppm; LC–MS (ESI): m/z calcd for
C25H28N2: 357.23 [M+H]+; found: 357.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3-methylphenyl)piperazine (14):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(3-methylphenyl)piperazine (5i; 289 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 14 (119 mg, 0.35 mmol, 42% yield):
HPLC: purity 98%, tR =17.6 min; 1H NMR (300 MHz, CDCl3): d=
7.80–7.77 (m, 3H), 7.69–7.47 (m, 6H), 7.31 (t, J=7.8 Hz, 1H), 6.91–
6.83 (m, 3H), 3.78 (s, 2H), 3.36 (brt, J=4.8 Hz, 4H), 2.79 (brt, J=
4.8 Hz, 4H), 2.48 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=151.7,
141.4, 141.3, 138.9, 138.8, 129.2, 129.0, 128.4, 128.1, 127.5, 127.4,
126.2, 120.7, 117.1, 113.4, 63.3, 49.4, 22.1 ppm; LC–MS (ESI): m/z
calcd for C24H26N2: 343.22 [M+H]+; found: 343.2.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3,5-dimethylphenyl)piperazine
(19): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(3,5-dimethylphenyl)piperazine (5n; 312 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 19 (139 mg, 0.39 mmol, 48% yield):
HPLC: purity 97%, tR =18.4 min; 1H NMR (300 MHz, CDCl3): d=
7.81–7.78 (m, 3H), 7.70–7.48 (m, 6H), 6.74–6.70 (m, 3H), 3.79 (s,
2H), 3.36 (brt, J=4.8 Hz, 4H), 2.79 (brs, 4H), 2.45 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=151.7, 141.4, 141.3, 138.8, 138.7,
128.9, 128.9, 128.3, 128.1, 127.5, 127.4, 126.1, 121.8, 114.3, 63.3,
53.4, 49.5, 21.9 ppm; LC–MS (ESI): m/z calcd for C25H28N2: 357.23
[M+H]+; found: 357.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(4-methylphenyl)piperazine (15):
Following the same procedure as that used for the synthesis of 6,
the reaction of 1-(4-methylphenyl)piperazine (5j; 155 mg,
0.88 mmol), (1,1’-biphenyl)-3-carbaldehyde (4a; 80 mg, 0.44 mmol),
and NaBH(OAc)3 (284 mg, 1.32 mmol) in MeOH (10 mL) gave the
title compound 15 (54 mg, 0.16 mmol, 36% yield): HPLC: purity
99%, tR =18.3 min; 1H NMR (300 MHz, CDCl3): d=7.71–7.69 (m,
1H), 7.58–7.40 (m, 8H), 7.19 (d, J=8.1 Hz, 2H), 6.95 (d, J=8.4 Hz,
2H), 3.61 (s, 2H), 3.22 (brt, J=5.1 Hz, 4H), 2.65 (brt, J=5.1 Hz, 4H),
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(2-methoxyphenyl)piperazine
(20): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(2-methoxyphenyl)piperazine (5o; 209 mg,
1.09 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
100 mg,
0.55 mmol), and NaBH(OAc)3 (355 mg, 1.65 mmol) in MeOH (10 mL)
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gave the title compound 20 (47 mg, 0.13 mmol, 24% yield): HPLC:
purity 98%, tR =16.2 min; 1H NMR (300 MHz, CDCl3): d=7.67–7.63
(m, 3H), 7.56–7.37 (m, 6H), 7.03–6.84 (m, 4H), 3.88 (s, 3H), 3.69 (s,
2H), 3.14 (brs, 4H), 2.74 ppm (brs, 4H); 13C NMR (75 MHz, CDCl3):
d=152.3, 141.5, 141.3, 141.2, 138.7, 128.8, 128.8, 128.3, 128.2,
127.3, 126.0, 122.9, 121.0, 118.3, 111.2, 63.3, 55.4, 53.4, 50.8 ppm;
LC–MS (ESI): m/z calcd for C24H26N2O: 359.21 [M+H]+; found:
359.4.
1-([2’-Fluoro-(1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)pi-
perazine (25): Following the same procedure as that used for the
synthesis of 6, the reaction of 1-(2-methoxyphenyl)piperazine (5o;
192 mg, 1.00 mmol), 2’-fluoro-(1,1’-biphenyl)-3-carbaldehyde (4b;
100 mg, 0.50 mmol), and NaBH(OAc)3 (322 mg, 1.50 mmol) in
MeOH (10 mL) gave the title compound 25 (164 mg, 0.44 mmol,
87% yield): HPLC: purity 98%, tR =16.2 min; 1H NMR (300 MHz,
CDCl3): d=7.61 (brs, 1H), 7.52–7.41 (m, 4H), 7.36–7.30 (m, 1H),
7.26–7.15 (m, 2H), 7.06–6.95 (m, 3H), 6.91 (dd, J=8.1, 1.2 Hz, 1H),
3.88 (s, 3H), 3.70 (s, 2H), 3.16 (brs, 4H), 2.75 ppm (brs, 4H);
13C NMR (75 MHz, CDCl3): d=159.9 (d, J=246.8 Hz), 152.4, 141.5,
138.4, 135.8, 130.9 (d, J=3.75 Hz), 130.0 (d, J=3.0 Hz), 129.3, 129.0
(d, J=8.25 Hz), 128.7, 128.4, 127.9 (d, J=3 Hz), 124.4 (d, J=
3.75 Hz), 122.9, 121.1, 118.3, 116.2 (d, J=22.5 Hz), 111.3, 63.2, 55.4,
53.4, 50.8 ppm; LC–MS (ESI): m/z calcd for C24H25FN2O: 377.2
[M+H]+; found: 377.1.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3-methoxyphenyl)piperazine
(21): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(3-methoxyphenyl)piperazine (5p; 315 mg,
1.64 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
150 mg,
0.82 mmol), and NaBH(OAc)3 (529 mg, 2.46 mmol) in MeOH (10 mL)
gave the title compound 21 (126 mg, 0.35 mmol, 43% yield):
HPLC: purity 96%, tR =16.5 min; 1H NMR (300 MHz, CDCl3): d=
7.78–7.45 (m, 8H), 7.33–7.27 (m, 1H), 6.69–6.53 (m, 3H), 3.90 (s,
3H), 3.75 (s, 2H), 3.34 (brs, 4H), 2.76 ppm (brs, 4H); 13C NMR
(100 MHz, CDCl3): d=160.8, 153.0, 141.4, 141.3, 138.8, 129.9, 128.9,
128.9, 128.3, 128.1, 127.5, 127.3, 126.1, 109.0, 104.5, 102.6, 63.2,
55.3, 53.3, 49.2 ppm; LC–MS (ESI): m/z calcd for C24H26N2O: 359.21
[M+H]+; found: 359.4.
1-([2’-Chloro-(1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)pi-
perazine (26): Following the same procedure as that used for the
synthesis of 6, the reaction of 1-(2-methoxyphenyl)piperazine (5o;
177 mg, 0.92 mmol), 2’-chloro-(1,1’-biphenyl)-3-carbaldehyde (4c;
100 mg, 0.46 mmol), and NaBH(OAc)3 (297 mg, 1.38 mmol) in
MeOH (10 mL) gave the title compound 26 (61 mg, 0.16 mmol,
34% yield): HPLC: purity 98%, tR =16.9 min; 1H NMR (300 MHz,
CDCl3): d=7.46–7.44 (m, 2H), 7.42–7.23 (m, 6H), 7.00–6.87 (m, 3H),
6.84 (d, J=7.8 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 2H), 3.10 (brs, 4H),
2.70 ppm (brs, 4H); 13C NMR (100 MHz, CDCl3): d=152.3, 141.5,
140.6, 139.4, 137.8, 132.6, 131.5, 130.4, 130.0, 128.6, 128.6, 128.2,
128.0, 126.9, 122.9, 121.0, 118.3, 111.2, 63.1, 55.3, 53.3, 50.7 ppm;
LC–MS (ESI): m/z calcd for C24H25ClN2O: 393.17 [M+H]+; found:
393.9.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(4-methoxyphenyl)piperazine
(22): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(4-methoxyphenyl)piperazine (5q; 212 mg,
1.10 mmol),
(1,1’-biphenyl)-3-carbaldehyde
(4a;
100 mg,
0.55 mmol), and NaBH(OAc)3 (355 mg, 1.65 mmol) in MeOH (5 mL)
gave the title compound 22 (128 mg, 0.36 mmol, 65% yield):
HPLC: purity 99%, tR =16.0 min; 1H NMR (300 MHz, CDCl3): d=
7.67–7.63 (m, 3H), 7.56–7.37 (m, 6H), 6.96–6.87 (m, 4H), 3.80 (s,
3H), 3.68 (s, 2H), 3.15 (brt, J=4.5 Hz, 4H), 2.70 ppm (brt, J=
4.8 Hz, 4H); 13C NMR (75 MHz, CDCl3): d=153.9, 145.9, 141.3, 141.2,
138.7, 129.0, 128.9, 128.4, 128.1, 127.5, 127.3, 126.1, 118.3, 114.5,
63.2, 55.6, 53.4, 50.7 ppm; LC–MS (ESI): m/z calcd for C24H26N2O:
359.21 [M+H]+; found: 359.4.
1-([2’-Methyl-(1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)-
piperazine (27): Following the same procedure as that used for
the synthesis of 6, the reaction of 1-(2-methoxyphenyl)piperazine
(5o; 196 mg, 1.02 mmol), 2’-methyl-(1,1’-biphenyl)-3-carbaldehyde
(4d; 100 mg, 0.51 mmol), and NaBH(OAc)3 (329 mg, 1.53 mmol) in
MeOH (50 mL) gave the title compound 27 (77 mg, 0.21 mmol,
41% yield): HPLC: purity 99%, tR =17.1 min; 1H NMR (300 MHz,
CDCl3): d=7.36–7.30 (m, 3H), 7.26–7.19 (m, 5H), 6.99–6.81 (m, 4H),
3.82 (s, 3H), 3.62 (s, 2H), 3.09 (brs, 4H), 2.69 (brs, 4H), 2.27 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=152.4, 142.0, 141.9, 141.6, 138.0,
135.4, 130.4, 130.2, 129.9, 128.1, 128.0, 127.8, 127.3, 125.8, 122.9,
121.1, 118.3, 111.3, 63.2, 55.4, 53.4, 50.8, 20.6 ppm; LC–MS (ESI):
m/z calcd for C25H28N2O: 373.23 [M+H]+; found: 373.4.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3,4-dimethoxyphenyl)piperazine
(23): Following the same procedure as that used for the synthesis
of 6, the reaction of 1-(3,4-dimethoxyphenyl)piperazine (5r;
245 mg, 1.10 mmol), (1,1’-biphenyl)-3-carbaldehyde (4a; 100 mg,
0.55 mmol), and NaBH(OAc)3 (355 mg, 1.65 mmol) in MeOH (5 mL)
gave the title compound 23 (167 mg, 0.43 mmol, 78% yield):
HPLC: purity 99%, tR =16.0 min; 1H NMR (300 MHz, CDCl3): d=
7.66–7.61 (m, 1H), 7.45–7.30 (m, 9H), 6.83–6.80 (m, 1H), 6.59–6.58
(m, 1H), 6.46 (dd, J=8.7, 2.7 Hz, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.54
(s, 2H), 3.10 (brs, 4H), 2.58 ppm (brs, 4H); 13C NMR (75 MHz,
CDCl3): d=162.3, 149.5, 146.5, 143.4, 142.9, 141.5, 135.6, 130.2,
130.1, 129.7, 128.0, 127.2, 127.0, 112.0, 107.9, 102.9, 59.9, 56.3, 55.9,
53.0, 50.9 ppm; LC–MS (ESI): m/z calcd for C25H28N2O2: 389.22
[M+H]+; found: 389.3.
1-([2’-Methoxy-(1,1’-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)-
piperazine (28): Following the same procedure as that used for
the synthesis of 6, the reaction of 1-(2-methoxyphenyl)piperazine
(5o; 181 mg, 0.94 mmol), 2’-methoxy-(1,1’-biphenyl)-3-carbalde-
hyde (4e; 100 mg, 0.47 mmol), and NaBH(OAc)3 (303 mg,
1.41 mmol) in MeOH (10 mL) gave the title compound 28 (103 mg,
0.27 mmol, 56% yield): HPLC: purity 99%, tR =15.5 min; 1H NMR
(300 MHz, CDCl3): d=7.51 (brs, 1H), 7.45–7.27 (m, 5H), 7.04–6.87
(m, 5H), 6.83 (dd, J=7.8, 0.9 Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.63
(s, 2H), 3.09 (brs, 4H), 2.69 ppm (brs, 4H); 13C NMR (100 MHz,
CDCl3): d=156.6, 152.4, 141.6, 138.5, 137.7, 131.0, 130.8, 130.6,
128.7, 128.4, 128.0, 128.0, 122.9, 121.1, 120.9, 118.3, 111.3, 111.2,
63.3, 55.6, 55.4, 53.4, 50.8 ppm; LC–MS (ESI): m/z calcd for
C25H28N2O2: 389.22 [M+H]+; found: 389.1.
1-([1,1’-Biphenyl]-3-ylmethyl)-4-(3-trifluoromethylphenyl)pipera-
zine (24): Following the same procedure as that used for the syn-
thesis of 6, the reaction of 1-(3-trifluoromethylphenyl)piperazine
(5s; 252.7 mg, 1.01 mmol), (1,1’-biphenyl)-2-carbaldehyde (4a;
100 mg, 0.55 mmol), and NaBH(OAc)3 (353.9 mg, 1.65 mmol) in
MeOH (10 mL) gave the title compound 24 (132.1 mg, 0.33 mmol,
60% yield): HPLC: purity 98%, tR =17.7 min; 1H NMR (300 MHz,
CDCl3): d=7.62–7.30 (m, 10H), 7.10–7.02 (m, 3H), 3.64 (s, 2H), 3.25
(brt, J=4.8 Hz, 4H), 2.64 ppm (brt, J=4.8 Hz, 4H); 13C NMR
(75 MHz, CDCl3): d=162.3, 151.5, 141.2 (d, J=12.75 Hz), 138.5,
129.5, 128.8, 128.1, 127.9, 127.3, 127.2, 126.1, 118.7, 115.7, 115.7,
112.2, 112.1, 63.0, 52.9, 48.7 ppm; LC–MS (ESI): m/z calcd for
C24H23F3N2: 397.19 [M+H]+; found: 396.9.
Biology
Serotonin receptor binding affinity assay:[13c] Eleven dilutions (5ꢁ
assay concentration) of the test and reference compounds were
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prepared in standard binding buffer (50 mm tris(hydroxymethyl)-
aminomethane–HCl (Tris-HCl), 10 mm MgCl2, 1 mm ethylenediami-
netetraacetate (EDTA), pH7.4) by serial dilution: 0.05 nm, 0.5 nm,
1.5 nm, 5 nm, 15 nm, 50 nm, 150 nm, 500 nm, 1.5 mm, 5 mm, and
50 mm. The radioligand, which was mentioned in the text and was
properly chosen for each serotonin subtype receptor, was diluted
to five times the assay concentration in standard binding buffer.
Aliquots (50 mL) of the appropriate radioligand were dispensed
into the wells of a 96-well plate containing standard binding buffer
(100 mL). Triplicate aliquots (50 mL) of the test and reference com-
pound dilutions were added. Finally, crude membrane fractions
(50 mL) of cells expressing recombinant target were dispensed into
each well. The reaction mixtures (250 mL in total) were incubated
at room temperature and shielded from light for 1.5 h, then har-
vested by rapid filtration onto Whatman GF/B glass fiber filters pre-
soaked with 0.3% polyethyleneimine, by using a 96-well Brandel
harvester. Four rapid washes (500 mL) were performed with chilled
standard binding buffer to decrease nonspecific binding. Filters
were placed in 6 mL scintillation tubes and allowed to dry over-
night. The next day, EcoScint scintillation cocktail (4 mL; National
Diagnostics) was added to each tube. The tubes were capped, la-
beled, and counted by liquid scintillation counting. The filter mats
were dried, then the scintillant was melted onto the filters, and the
radioactivity retained on the filters was counted in a Microbeta
scintillation counter. The IC50 values were obtained by using the
Prism 4.0 program (GraphPad Software) and converted into Ki
values.
sion mode of the GLIDE program was employed for the docking,
and up to ten poses were saved for analysis.
Acknowledgements
Binding affinity data were generously provided by the US Nation-
al Institute of Mental Health (NIMH) Psychoactive Drug Screening
Program (contract: HHSN-271-2008-00025-C). This research was
supported by two programs of the National Research Foundation
of Korea (NRF) funded by the Korean Ministry of Education, Sci-
ence and Technology: the Basic Science Research Program (NRF-
2013-R1A1A2A10009907) and the Priority Research Centers Pro-
gram (2012-0006686). Additional funding was provided by the
Korea Institute of Science and Technology (KIST) Institutional Pro-
gram (2E23770).
Keywords: antagonists · biaryls · aryl piperazines · receptors ·
structure–activity relationships
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Molecular docking
The previously constructed model structure of the human 5-HT7
serotonin receptor[10b] was used. Three dimensional structures of
aryl biphenyl-3-ylmethylpiperazines were sketched by the “Build”
module of the Maestro 7.5 software (Schrçdinger Inc.). Energy min-
imization was performed by using a conjugate gradient minimiza-
tion (0.05 convergence criteria), the OPLS-AA force field, and the
GB/SA continuum water model. A torsional scan along every rotat-
able bond was then performed for the minimized structures. The
“Conformational search” module implemented in the Maestro 7.5
software was used with the automatic setup. With the modeled
structure, docking of the aryl biphenyl-3-ylmethylpiperazines was
carried out. The protein preparation utilities in Maestro 7.5 were
used to assign the charge state of ionizable residues, add hydro-
gen atoms, and carry out energy minimization. The ligands were
then docked into the comparative model structure of the 5-HT7R
by using the GLIDE 4.0 program (http://www.schrodinger.com),
with H-bond constraint between Asp162 and the protonated nitro-
gen atoms of the ligands. The default setting of the extreme preci-
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Received: May 27, 2013
Revised: August 5, 2013
Published online on && &&, 0000
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Vacancies filled: 2’-Methoxybiphenyl-3-
ylmethyl(2-methoxyphenyl)piperazine
(28) is shown to serve as a selective 5-
HT7 receptor antagonist. From a compar-
ison with the docking modes of other
known 5-HT7 receptor agonists and an-
tagonists, it is suggested that occupan-
cy of both hydrophobic ligand binding
sites of the 5-HT7 receptor by the ligand
is crucial for its antagonistic property.
J. Kim, Y. Kim, H. Choo*
&& – &&
Aryl Biphenyl-3-ylmethylpiperazines
as 5-HT7 Receptor Antagonists
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