Discovery of the first potent and orally available agonist of the orphan G-protein-coupled receptor 52

Article abstract of DOI:10.1021/jm5002919

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D₂ receptor signaling and activates dopamine D₁/N-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds 2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N- (2-methoxyethyl)benzamide 7m showed potent activity (pEC₅₀ = 7.53 ± 0.08) and good pharmacokinetic properties. Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function.

Full text of DOI:10.1021/jm5002919

Article
pubs.acs.org/jmc
Discovery of the First Potent and Orally Available Agonist of the
Orphan G‑Protein-Coupled Receptor 52
Masaki Setoh,*,† Naoki Ishii,† Mitsunori Kono,† Yuhei Miyanohana,† Eri Shiraishi,† Toshiya Harasawa,†,§
Hiroyuki Ota,† Tomoyuki Odani,† Naoyuki Kanzaki,† Kazunobu Aoyama,† Teruki Hamada,†
and Masakuni Kori‡
†Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-higashi-2-chome, Fujisawa, Kanagawa
251-8555, Japan
‡CMC Center, Takeda Pharmaceutical Company Ltd., 17-85, Jusohonmachi-2-chome, Yodogawa-ku, Osaka 532-8686, Japan
S
* Supporting Information
ABSTRACT: G-protein-coupled receptor 52 (GPR52) is an
orphan Gs-coupled G-protein-coupled receptor. GPR52
inhibits dopamine D2 receptor signaling and activates
dopamine D1/N-methyl-D-aspartate receptors via intracellular
cAMP accumulation, and therefore, GPR52 agonists may have
potential as a novel class of antipsychotics. A series of GPR52
agonists with a bicyclic core was designed to fix the
conformation of the phenethyl ether moiety of compounds
2a and 2b. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-
7-yl]-N-(2-methoxyethyl)benzamide 7m showed potent activity (pEC50 = 7.53 0.08) and good pharmacokinetic properties.
Compound 7m significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg
without disturbance of motor function.
highly expressed in the brain. Examination of localization of
GPR52 mRNA in the rat brain using in situ hybridization
showed that GPR52 is highly expressed in the mesolimbic
system which is responsible for positive symptoms and is
colocalized with dopamine D2 receptor. In addition, GPR52 is
partially colocalized with dopamine D1 receptors in the
prefrontal cortex, which is involved in cognitive function. On
the basis of these findings, activation of Gs-coupled GPR52
could inhibit D2 receptor signaling as well as activate D1/
NMDA function via intracellular cAMP accumulation. There-
fore, we expect that GPR52 agonists could be a novel class of
antipsychotics to serve the unmet medical needs.
We conducted high-throughput screening (HTS) for GPR52
agonists and discovered a hit compound 1 with a moderate
potency (pEC50 < 5, 33% at 10 μM). Our initial modifications
of the hit compound 1 afforded N-(2-hydroxyethyl)benzamide
derivatives 2a and 2b with more potent agonistic activity
INTRODUCTION
■
Schizophrenia is a chronic and devastating mental disorder,
which affects approximately 1% of the global population
irrespective of ethnic, economical, or cultural boundaries.1,2
The core symptoms of schizophrenia are broadly classified as
(1) positive symptoms such as delusions, hallucinations, and
paranoia; (2) negative symptoms such as apathy and lack of
social interaction; and (3) cognitive impairment such as
memory and attention deficits.3 Current treatment for
schizophrenia mainly includes atypical antipsychotic agents
including serotonin−dopamine antagonists (SDA, 5-HT2A and
D2 receptors antagonists, e.g., risperidone), multiacting
receptor-targeted antipsychotics (MARTA, e.g., olanzapine),
and dopamine system stabilizers (DSS, e.g., aripiprazole).
These agents are effective against positive symptoms but show
limited efficacy in the treatment of negative symptoms and
cognitive impairment. Moreover, these antipsychotics are
associated with side effects such as weight gain, diabetes, QT
prolongation, hyperprolactinemia, and extrapyramidal syn-
dromes.4−7 Therefore, there are still the unmet medical needs
in the current therapies, and development of a new class of
antipsychotics with efficacy for negative symptoms and/or
cognitive impairment as well as without side effects is required.
G-protein-coupled receptor 52 (GPR52) is an orphan Gs-
coupled G-protein coupled receptor.8 Although its natural
ligand has not been identified, we have recently discovered a
surrogate ligand9 and analyzed GPR52 expression pattern in
human, mouse, and rat tissues and showed that GPR52 is
(pEC50 of 6.19
0.01 and 6.46
0.09, respectively) than
compound 1.10 In an effort to improve the agonistic activity,
new core scaffolds were designed using compounds 2a and 2b
as lead compounds. In this paper, we examined if fixing the
conformation of the phenethyl ether moiety of compounds 2a
and 2b through construction of a bicyclic central core could
lead to enhancement of the agonistic activity. We designed 6−5
ring benzofurans 7a and 7b as the first tool compounds by
Received: February 23, 2014
Published: June 2, 2014
© 2014 American Chemical Society
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Figure 1. Design of fused bicyclic compounds.
cyclization between the 1-position of the pyridine ring and the
α-position of the phenethyl ether moiety (Figure 1). The global
minimum conformations of the designed benzofurans 7a and
7b and compound 2a were calculated using the MNDO-PM3
(MOPAC, version 7.01) method in MOE11 (Figure 2a).11,12
When the central cores of the minimum conformations of 2a,
7a, and 7b were superimposed, a large gap was observed
between the location of the benzene ring in the benzyl group of
7a and 7b and that of the benzene ring in the phenethyl group
of 2a.
On the basis of conformation analysis, we expected that the
conformational restriction of the benzene ring in the benzyl
group by fixing the phenethyl ether moiety would have an effect
on the GPR52 agonistic activity and designed various 6−5 ring
system bicyclic compounds 7a−f. Among them, benzofuran
(7a), benzothiophene (7c), and indazole (7e) derivatives,
which have a heteroatom at the corresponding position of the
oxygen atom of the ether moiety of compounds 2a and 2b,
were designed to examine the effect of the heteroatom at the
position. Benzofuran (7b), benzothiophene (7d), and indazole
(7f) derivatives, in which the corresponding heteroatom was
replaced by carbon and moved to the upper right of the core
template (dotted circles in Figure 1), were synthesized to
investigate the effect on the activity.
We also designed dihydrobenzofurans 7g and 7h. Conforma-
tional analyses of 2a and dihydrobenfuran 7g using MOE
indicated that the location of the benzene ring in the benzyl
group of 7g was located in the vicinity of the benzene ring in
the phenethyl group of compound 2a (Figure 2b). Therefore,
consideration of GPR52 agonistic activity of compounds 2a, 7a,
and 7g would demonstrate the appropriate location of the
benzene ring in the benzyl group for the agonistic activity.
Furthermore, benzofurans 7i and 7j were designed by
introducing the methyl group at the 3-position (Y1 or Y2) of the
benzofurans 7a and 7b to clarify the tolerability for the GPR52
agonistic activity. Especially, introduction of the methyl group
at the Y1 position (3-position of the benzofuran 7i) would
restrict the rotation of the benzamide group at the 4-position
Figure 2. (a) Overlay of compounds 2a (red), 7a (blue), and 7b
(brown). The picture was generated using Moe 2010.10. (b)
Compounds 2a (red), 7a (blue), and 7g (yellow). The picture was
generated using Moe 2010.10.
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a
Scheme 1
a
Reagents and conditions: (a) 3-(R′OCO)phenylboronic acid, Pd(PPh3)4, DME, 2 M Na2CO3 aq, 85 °C; (b) XPhB(OH)2, Pd(PPh3)4, DME, 2 M
Na2CO3 aq, 85 °C; (c) 2 N NaOH, EtOH or THF−MeOH, room temperature; (d) RNH2, HOBt, WSC, DMF, room temperature.
and vary the dihedral angle between the benzofuran and the
benzamide. On the other hand, introduction of the methyl
group at the Y2 position (3-position of the benzofuran 7j) may
suggest the presence of a hydrophobic pocket around the Y2
position.
In this paper, we describe the discovery of the first GPR52
agonists. Synthesis, structure−activity relationship, and phar-
macological effects of representative compounds are also
discussed.
(RNH2) to afford the desired amide derivatives 7a−f and 7i−n.
The benzofuran derivatives 6a and 6b were reduced with
triethylsilane in TFA to yield the 2,3-dihydrobenzofuran
derivatives 6g and 6h.13 Compounds 6g and 6h were
condensed with 2-aminoethanol to afford the desired amide
derivatives 7g and 7h (Scheme 2). The synthesized target
compounds are listed in Table 1.
Synthesis of the benzofurans 3a, 3b, 3i, and 3j described
above is depicted in Scheme 3. By use of Rap−Stoermer
condensation14 from (3-trifluoromethyl)phenacyl bromide 9,
prepared by bromination15 of 3-trifluoromethylacetophenone 8
and commercially available 2-hydroxybenzaldehyde or aceto-
phenone derivatives 10a, 10b, and 10i, and 10j, prepared by
bromination of 1-(2-hydroxyphenyl)ethanone, 2-aroylbenzofur-
ans 11a, 11b, 11i, and 11j were synthesized. Subsequent
Wolff−Kishner reduction of the compounds 11a, 11b, 11i, and
11j afforded the 2-(3-trifluoromethyl)benzylbenzofurans 3a,
3b, 3i, and 3j.
CHEMISTRY
■
Synthesis of the designed compounds is outlined in Schemes 1
and 2. Preparation of starting materials 3a, 3b, 3e, 3f, 3i, 3j, 4c,
4d, and 4n is described in the sections below. Suzuki coupling
reaction of bromides or triflates 3a, 3b, 3e, 3f, 3i, and 3j with 3-
(ethoxycarbonyl)phenylboronic acid gave benzoates 5a, 5b, 5e,
5f, 5i, and 5j (method A). Suzuki coupling reaction of bromides
4c, 4d, and 4n with phenylboronic acids gave benzoates 5c, 5d,
5m, and 5n (method B). Basic hydrolysis of the benzoates 5a−
f, 5i, 5j, 5m, and 5n afforded corresponding carboxylic acids
6a−f, 6i, 6j, 6m, and 6n, which were condensed with amines
Preparation of benzothiophene derivatives 4c, 4d, and 4n is
illustrated in Scheme 4. Carboxylic acids 12c, 12d, and 12n16
were reduced with borane−THF complex to give alcohols 13c,
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a
Scheme 2
a
Reagents and conditions: (a) triethylsilane, TFA, room temperature; (b) 2-aminoethanol, HOBt, WSC, DMF, room temperature.
13d, and 13n. Suzuki coupling reaction of the alcohols 13c,
13d, and 13n with 3-(ethoxycarbonyl)phenylboronic acid gave
benzoates 14c, 14d, and 14n, which in turn provided the
bromides 4c, 4d, and 4n upon reaction with PBr3.
The 2-benzyl-2H-indazole derivatives 3e and 3f were
synthesized by regioselective benzylation at the 2-position of
commercially available bromo-2H-indazoles 15e and 15f under
heating condition (Scheme 5).
because of the steric hindrance, while that between the 3-
nonsubstituted benzofuran core of 7a (blue) and the 4-phenyl
ring was 61°. The difference in the dihedral angle between the
3-methylbenzofuran 7i (green) and 3-nonsubstituted benzofur-
an 7a (blue) significantly affected the potential to exhibit
agonistic activity. Orthogonal configuration of the phenyl group
at 4-position was unfavorable for binding to the GPR52
receptor.
We then modified the amide moiety of the benzothiophene
derivative 7d as a representative compound. GPR52 agonistic
activities of the benzothiophene derivatives (7k−n) are
summarized in Table 3. Conversion of the N-2-hydroxyethyl
group of the lead compound (7d) into an N-2-carbamoyl-
methyl (7k) or an N-2-methoxyethyl group (7l) maintained
potent GPR52 agonistic activity (pEC50 of 7.26 0.19 and 7.37
0.16, respectively). Modification of the amide chain did not
show a significant effect on the activity. GPR52 might not have
the interaction sites with the amide chain. 3-Chloro-5-
BIOLOGICAL RESULTS AND DISCUSSION
■
GPR52 agonistic activities of the synthesized compounds were
determined based on the cAMP production using CHO cells
expressing human GPR52 (Tables 2 and 3). All of the
synthesized compounds exhibited GPR52 agonistic activity. Of
particular note, the benzofuran derivatives (7a, pEC50 = 7.55
0.25; 7b, pEC50 = 7.46 0.16), the benzothiophene derivative
(7c, pEC50 = 7.42 0.20; 7d, pEC50 = 7.43 0.21), and the
indazole derivative (7e, pEC50 = 7.41 0.12) showed potent
GPR52 agonistic activity. The results suggest that the benzene
ring in the benzyl group of compounds 7c−e exists in the same
territory as that of compound 7a (Figure 2).
Compounds 7b, 7d, and 7f showed comparable activity to
7a, 7c, and 7e, respectively, indicating that the position of the
heteroatom on the templates did not have a significant impact
on the activity and GPR52 might not have the sites that interact
with the heteroatom of these compounds.
fluorobenzyl derivative (7m, pEC50 = 7.53
0.08) was as
potent as 3-trifluoromethyl derivative (7l, pEC50 = 7.37
0.16). Introduction of fluorine at the 4-position (7n, pEC50
=
7.08
0.16) also resulted in comparable potent GPR52
activity.
Thus, we identified a series of the benzothiophenes (7d, 7k−
n) as the first potent GPR52 agonists and the representative
compound 7m with good oral pharmacokinetic profile (Cmax
=108.1 ng/mL; AUC0−8h = 613.7 ng·h/mL; F (bioavailability)
= 73%, mouse cassette dosing at 0.1 mg/kg, iv and 1 mg/kg,
po) and good brain penetration (brain/plasma AUC ratio B/P
= 0.94, in mice after oral administration of 30 mg/kg) which
could be used for in vivo pharmacological evaluation.
Compound 7m showed potent activity with pEC50 of 7.53
0.08 and showed no cAMP production using CHO cells
expressing human dopamine D1 receptor (Figure 4).
Compound 7m affects cAMP accumulation through direct
interaction with GPR52. Furthermore, compound 7m did not
interact with other receptor (such as D1, D2, 5-HT2, AMPA,
and NMDA). Antipsychotic activity of 7m was assessed in
methamphetamine (MAP) (2 mg/kg, sc) induced hyper-
locomotion17 test in mice. The compound 7m (3, 10, and 30
mg/kg po) dose-dependently attenuated MAP-induced hyper-
On the other hand, the dihydrobenzofuran derivatives
(compounds 7g [pEC50 = 6.19
0.05] and 7h [pEC50 =
6.68 0.07]) showed much weaker activity than the
benzofuran derivatives 7a and 7b. These results suggested
that the location of the benzene ring in the benzyl group of
compound 7a had a greater impact on the GPR52 agonistic
activity than those of compounds 2a and 7g (Figure 2b).
Substituent effect at the 3-position on the benzofurans 7a
and 7b was examined by introducing a methyl group.
Compound 7j (Y2 = Me) (pEC50 = 7.09
0.14) was fully
tolerated, but compound 7i (Y1 = Me) resulted in a decrease of
activity (pEC50 < 5). Conformational analyses of simple
fragments of 7a and 7i were performed in MOE (Figure 3).
The dihedral angle between 3-methylbenzofuran core of 7i
(green) and the 4-phenyl ring was nearly orthogonal (85°)
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Table 1. Synthesized Compounds 7a−n
CONCLUSIONS
■
The first GPR52 agonists were successfully discovered and
evaluated. Initial modification of the hit compound 1 obtained
using HTS afforded the key lead compounds 2a and 2b. On the
basis of a superimposition study of 2a and the designed
benzofuran derivative 7a, several conformationally constrained
bicyclic derivatives, 7a−j, were synthesized as a novel series of
GPR52 agonists. Further modification of the benzothiophene
derivatives provided the representative GPR52 agonist 7m
(pEC50 = 7.53 0.08) which showed good brain penetration
and pharmacokinetic properties after oral administration in
mice. MAP-induced hyperactivity was suppressed in mice after
oral administration of 3 mg/kg compound 7m. Furthermore,
compound 7m showed low risk of impaired motor function
even at a high dose. The discovery of GPR52 agonists has
potential to lead to a novel class of antipsychotics which could
address the current unmet medical needs.
EXPERIMENTAL SECTION
■
General. Reactions were run using the commercially available
starting materials and solvents without further purification. In the
following experimental, melting points were determined on a Buchi B-
̈
545 and were uncorrected. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a Varian Mercury-300 (300 MHz) or
a Bruker AV-300M spectrometer. Chemical shifts are given in parts per
million (ppm) with tetramethylsilane as an internal standard.
Abbreviations are used as follows: s = singlet, d = doublet, t = triplet,
q = quartet, quin = quintet, m = multiplet, dd = doublets of doublet, dt
= doublets of triplet, dq = doublets of quartet, brs = broad singlet.
Coupling constants (J) are given in hertz (Hz). Liquid chromatog-
raphy−mass spectrometry (LC/MS) analysis was performed on a
Shimadzu LC-20AD, equipped with a L-column 2 ODS (3.0 mm × 50
mm i.d., 3 μm particle size, CERI, Japan), eluting with 5 mM AcONH4
in ultrapure water/acetonitrile = 90/10 (mobile phase A) and 5 mM
AcONH4 in ultrapure water/acetonitrile = 10/90 (mobile phase B),
using the following elution gradient of 5% B to 90% B over 0.9 min
followed by 90% B isocratic over 1.1 min at a flow rate of 1.5 mL/min
(detection at 220 or 254 nm). Mass spectra were recorded using a
Shimadzu LCMS-2020 with electrospray ionization. Thin-layer
chromatography (TLC) was carried out using Merck Kieselgel 60,
63−200 mesh F254 plates or Fuji Silysia Chemical Ltd. 100−200 mesh
NH plates. Chromatographic purification was carried out on Purif-
Pack (SI 60 μm or NH 60 μm, Fuji Silysia Chemical Ltd.). All of the
final products undergoing biological testing were >95% pure as
demonstrated by analysis carried out using analytical high-performance
liquid chromatography (HPLC). The HPLC analyses were performed
using a Shimadzu UFLC instrument equipped with a L-column 2 ODS
(3.0 mm × 50 mm, 2 μm). Elution was with a gradient of 5−90%
solvent B in solvent A (solvent A was 0.1% TFA in water, and solvent
B was 0.1% TFA in acetonitrile) at a flow rate of 1.2 mL/min with UV
detection at 220 nm. All commercially available solvents and reagents
were used without further purification unless otherwise stated. Yields
were not optimized.
Method A. 3-{2-[3-(Trifluoromethyl)benzyl]-1-benzofuran-4-
yl}benzoic Acid (6a). A mixture of 3a (3.40 g, 9.58 mmol), [3-
(ethoxycarbonyl)phenyl]boronic acid (2.23 g, 11.5 mmol), and
Pd(PPh3)4 (553 mg, 0.48 mmol) in 2 N Na2CO3 (30 mL)−DME
(30 mL) was refluxed for 16 h under N2 atmosphere. Then the
reaction mixture was concentrated under reduced pressure, diluted
with water, and extracted with EtOAc. The extract was washed with
brine, then dried over MgSO4 and concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (EtOAc−hexane = 2:3) to give 3.30 g of 5a. To a
solution of this compound was added 2 N NaOH (8 mL, 16 mmol) in
EtOH (50 mL) at room temperature. The mixture was stirred for 2 h
at 60 °C. After concentration, the mixture was diluted with water,
acidified with 1 N HCl, and extracted with EtOAc. The extract was
a
b
Yield from esters (5c, 5d, 5m, and 5n). Racemate.
locomotion (Figure 5). Moreover, compound 7m did not show
significant cataleptogenic effects even at a dose of 100 mg/kg
(Figure 6) and had a low risk of extrapyramidal side effects
(EPS). These data suggest that the downstream functions by
activation of GPR52 could be different from those of D2
receptor blockade.
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a
Scheme 3
a
Reagents and conditions: (a) CuBr2, EtOAc, 80 °C; (b) 9, K2CO3, acetonitrile, 80 °C; (c) (11a, 11b, and 11j) hydrazine hydrate, ethylene
glycol,130 °C, then potassium hydroxide, 160 °C; (11i) (1) hydrazine hydrate, ethylene glycol,130 °C, then potassium hydroxide, 160 °C; (2) boron
tribromide, dichloromethane, room temperature, (3) Tf2O, pyridine, room temperature.
a
Scheme 4
a
Reagents and conditions: (a) 1.2 M borane−THF complex, 60 °C; (b) 3-(ethoxycarbonyl)phenylboronic acid, Pd(PPh3)4, 2 M Na2CO3 aq, DME,
85 °C; (c) PBr3, Et2O, room temperature.
a
described for 6a in 72% yield starting from compound 3b as colorless
crystals. Mp: 169−170 °C (EtOAc−hexane). H NMR (300 MHz,
Scheme 5
1
CDCl3) δ: 4.19 (s, 2H), 6.47 (s, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.38−
7.62 (m, 7H), 8.07 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.60
(t, J = 1.5 Hz, 1H).
3-{2-[3-(Trifluoromethyl)benzyl]-2H-indazol-4-yl}benzoic
Acid (6e). Compound 6e was prepared in a manner similar to that
1
described for 6a in 73% yield starting from compound 3e. H NMR
(300 MHz, DMSO-d6) δ: 5.80 (s, 2H), 7.23 (d, J = 6.4 Hz, 1H), 7.37
(dd, J = 8.7, 6.4 Hz, 1H), 7.54−7.72 (m, 5H), 7.79 (s, 1H), 7.95−8.04
(m, 2H), 8.24 (t, J = 1.6 Hz, 1H), 8.78 (d, J = 0.8 Hz, 1H).
3-{2-[3-(Trifluoromethyl)benzyl]-2H-indazol-7-yl}benzoic
Acid (6f). Compound 6f was prepared in a manner similar to that
a
Reagents and conditions: (a) 3-(trifluoromethyl)benzyl bromide,
DMF, 50 °C.
1
described for 6a in 65% yield starting from compound 3f. H NMR
washed with water and brine and then dried over MgSO4 and
concentrated under reduced pressure. The residue was crystallized
from EtOAc−hexane to give 6a (2.3 g, 61%) as colorless crystals. Mp:
(300 MHz, DMSO-d6) δ: 5.83 (s, 2H), 7.13−7.24 (m, 1H), 7.48−7.82
(m, 7H), 7.91−7.97 (m, 1H), 8.25−8.31 (m, 1H), 8.61−8.68 (m, 2H).
3-{3-Methyl-2-[3-(trifluoromethyl)benzyl]-1-benzofuran-4-
yl}benzoic Acid (6i). Compound 6i was prepared in a manner similar
to that described for 6a in 49% yield starting from compound 3i as
1
138−139 °C (EtOAc−hexane). H NMR (300 MHz, CDCl3) δ: 4.19
(s, 2H), 6.63 (s, 1H), 7.20−7.78 (m, 8H), 7.85 (dd, J = 7.8, 1.2 Hz,
1H), 8.13 (dd, J = 7.8, 1.2 Hz, 1H), 8.37 (s, 1H).
1
colorless crystals. Mp: 169−170 °C (EtOAc−hexane). H NMR (300
3-{2-[3-(Trifluoromethyl)benzyl]-1-benzofuran-7-yl}benzoic
Acid (6b). Compound 6b was prepared in a manner similar to that
MHz, CDCl3) δ: 1.82 (s, 3H), 4.12 (s, 2H), 7.10 (dd, J = 7.2, 1.2 Hz,
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a
Table 2. GPR52 Agonistic Activities of Bicyclic Compounds
a
Data are expressed as the mean SEM from two independent experiments performed in duplicate.
a
Table 3. GPR52 Agonistic Activities of Benzothiophene Derivatives
a
Data are expressed as the mean SEM from two independent experiments performed in duplicate.
Figure 4. cAMP production assay of compound 7m using CHO cells
expressing human GPR52 or dopamine D1 receptor (DRD1). The
data are the mean SD (n = 4).
mmol) in Et2O (13 mL) was added dropwise PBr3 (126 μL, 1.34
mmol). The mixture was stirred at room temperature for 1.5 h, diluted
with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated to give crude product of 4c (448 mg).
A mixture of this compound, [3-(trifluoromethyl)phenyl]boronic acid
(272 mg, 1.43 mmol), and Pd(PPh3)4 (55 mg, 0.048 mmol) in 2 M
Na2CO3 solution (2.4 mL)-DME (15 mL) was refluxed for 12 h under
N2 atmosphere. Then the reaction mixture was concentrated under
reduced pressure, diluted with water, and extracted with EtOAc. The
extract was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane−EtOAc = 95:5 to 80:20) to give 5c (392 mg, 70%, two
steps). 1H NMR (300 MHz, CDCl3) δ: 1.40 (t, J = 7.1 Hz, 3H), 4.26
(s, 2H), 4.40 (q, J = 7.2 Hz, 2H), 7.14 (d, J = 0.8 Hz, 1H), 7.29−7.53
(m, 6H), 7.53−7.58 (m, 1H), 7.70−7.78 (m, 2H), 8.05−8.10 (m, 1H),
8.21−8.24 (m, 1H).
Figure 3. Minimized structures: fragments of benzofuran 7a (blue)
and 3-methylbenzofuran 7i (green). The picture was generated using
Moe 2010.10.
1H), 7.23−7.30 (m, 1H), 7.37−7.57 (m, 6H), 7.67 (dt, J = 7.5, 1.5 Hz,
1H), 8.13 (dd, J = 7.8, 1.5 Hz, 1H), 8.17 (t, J = 1.5 Hz, 1H).
3-{3-Methyl-2-[3-(trifluoromethyl)benzyl]-1-benzofuran-7-
yl}benzoic Acid (6j). Compound 6j was prepared in a manner similar
to that described for 6a in 70% yield starting from compound 3j as
1
colorless crystals. Mp: 200−201 °C (EtOAc−hexane). H NMR (300
MHz, CDCl3) δ: 2.28 (s, 3H), 4.17 (s, 2H), 7.32 (t, J = 7.8 Hz, 1H),
7.40−7.60 (m, 7H), 8.05 (dt, J = 7.5, 1.5 Hz, 1H), 8.11 (dt, J = 7.8, 1.5
Hz, 1H), 8.58 (t, J = 1.5 Hz, 1H).
Method B. Ethyl 3-{2-[3-(Trifluoromethyl)benzyl]-1-benzo-
thiophen-4-yl}benzoate (5c). To a solution of 14c (399 mg, 1.28
5232
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89−90 °C. H NMR (300 MHz, CDCl3) δ: 1.41 (t, J = 7.1 Hz, 3H),
1.95 (t, J = 6.0 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.94 (dd, J = 6.2, 1.0
Hz, 2H), 7.12 (dd, J = 9.6, 8.2 Hz, 1H), 7.31 (dd, J = 8.1, 4.8 Hz, 1H),
7.40−7.42 (m, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.86 (dq, J = 7.7, 1.0 Hz,
1H), 8.09 (dt, J = 7.9, 1.4 Hz, 1H), 8.31 (t, J = 1.8 Hz, 1H).
3-{2-[3-(Trifluoromethyl)benzyl]-2,3-dihydro-1-benzofuran-
7-yl}benzoic Acid (6h). To a mixture of 6b (1.00 g, 2.52 mmol) in
TFA (10 mL) was added triethylsilane (0.8 mL, 5.0 mmol) at room
temperature, and the mixture was refluxed for 3 h. The reaction
mixture was concentrated at reduced pressure, diluted with water, and
extracted with EtOAc. The extract was washed with saturated aqueous
NaHCO3 and brine, then dried over MgSO4 and concentrated under
reduced pressure. The residue was crystallized from hexane to give 6h
(0.8 g, 80%). Mp: 156−157 °C (hexane). 1H NMR (300 MHz,
CDCl3) δ: 2.99−3.11 (m, 2H), 3.20−3.40 (m, 2H), 4.90 (br s, 1H),
5.00−5.12 (m, 1H), 6.95 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H),
7.34 (d, J = 8.1 Hz, 1H), 7.38−7.54 (m, 5H), 7.95 (d, J = 7.8 Hz, 1H),
8.05 (d, J = 7.8 Hz, 1H), 8.46 (s, 1H).
3-{2-[3-(Trifluoromethyl)benzyl]-2,3-dihydro-1-benzofuran-
4-yl}benzoic Acid (6g). Compound 6g was prepared in a manner
similar to that described for 6h in 79% yield starting from compound
6a. 1H NMR (300 MHz, CDCl3) δ: 2.98−3.16 (m, 2H), 3.19 (dd, J =
15.2, 7.5 Hz, 1H), 3.39 (dd, J = 15.3, 8.7 Hz, 1H), 5.00−5.40 (m, 2H),
6.81 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 8.1 Hz,
1H), 7.38−7.57 (m, 5H), 7.66 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.5 Hz,
1H), 8.19 (s, 1H).
Figure 5. Dose-dependent inhibition of MAP-induced hyperlocomo-
tion by compound 7m in mice. Mice were administered compound
7m (1−30 mg/kg, po) and placed in activity chambers for 60 min.
After this period, MAP (2 mg/kg, sc) was injected and measurement
was started. Data are expressed as the mean SEM (n = 6−7 per
group). Data were analyzed by Williams test: (∗) P < 0.025 vs the
control group treated with vehicle and MAP.
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-ben-
zofuran-4-yl}benzamide (7a). A mixture of 6a (200 mg, 0.50
mmol), HOBt (75 mg, 0.56 mmol), WSC (106 mg, 0.56 mmol) in
DMF (3 mL) was stirred at room temperature overnight. The mixture
was poured into water and extracted with EtOAc. The extract was
washed with saturated aqueous NaHCO3 and water, dried over
MgSO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc−hexane = 2:8 to
10:0) to give 7a (154 mg, 70%) as colorless crystals. Mp: 135−136 °C
(EtOAc−hexane). 1H NMR (300 MHz, CDCl3) δ: 2.43 (t, J = 4.8 Hz,
1H), 3.66 (q, J = 4.8 Hz, 2H), 3.86 (q, J = 4.8 Hz, 2H), 4.18 (s, 2H),
6.60 (s, 1H), 6.64 (br s, 1H), 7.26−7.32 (m, 2H), 7.38−7.60 (m, 6H),
7.68−7.81 (m, 2H), 8.01 (s, 1H). LC/MS m/z 440.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-ben-
zofuran-7-yl}benzamide (7b). Compound 7b was prepared in a
manner similar to that described for 7a in 52% yield starting from
compound 6b as colorless crystals. Mp: 140−141 °C (EtOAc−
hexane). 1H NMR (300 MHz, CDCl3) δ: 2.54 (t, J = 5.1 Hz, 1H), 3.65
(q, J = 5.1 Hz, 2H), 3.85 (q, J = 5.1 Hz, 2H), 4.19 (s, 2H), 6.45 (s,
1H), 6.63 (br s, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.38−7.61 (m, 7H),
7.77 (dt, J = 7.8, 1.5 Hz, 1H), 7.95 (dt, J = 7.8, 1.5 Hz, 1H), 8.20 (t, J =
1.5 Hz, 1H). LC/MS m/z 440.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-2H-in-
dazol-4-yl}benzamide (7e). Compound 7e was prepared in a
manner similar to that described for 7a in 74% yield starting from
compound 6e as colorless crystals. Mp: 136−137 °C (EtOAc−
hexane). 1H NMR (300 MHz, DMSO-d6) δ: 3.31−3.41 (m, 2H),
3.50−3.58 (m, 2H), 4.74 (t, J = 5.7 Hz, 1H), 5.79 (s, 2H), 7.26 (d, J =
6.2 Hz, 1H), 7.33−7.42 (m, 1H), 7.53−7.72 (m, 5H), 7.79 (s, 1H),
7.85−7.94 (m, 2H), 8.18 (t, J = 1.6 Hz, 1H), 8.57 (t, J = 5.7 Hz, 1H),
8.80 (d, J = 0.8 Hz, 1H). LC/MS m/z 440.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-2H-in-
dazol-7-yl}benzamide (7f). Compound 7f was prepared in a
manner similar to that described for 7a in 78% yield starting from
compound 6f as colorless crystals. Mp: 136−137 °C (EtOAc−
hexane). 1H NMR (300 MHz, DMSO-d6) δ: 3.33−3.41 (m, 2H), 3.54
(q, J = 6.0 Hz, 2H), 4.75 (t, J = 6.0 Hz, 1H), 5.83 (s, 2H), 7.19 (dd, J =
8.3, 7.2 Hz, 1H), 7.49−7.65 (m, 4H), 7.64−7.73 (m, 1H,), 7.74−7.87
(m, 3H), 8.27 (d, J = 8.3 Hz, 1H), 8.40 (s, 1H), 8.52 (t, J = 6.0 Hz,
1H), 8.65 (s, 1H). LC/MS m/z 440.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-2,3-di-
hydro-1-benzofuran-4-yl}benzamide (7g). Compound 7g was
prepared in a manner similar to that described for 7a in 59% yield
starting from compound 6g as colorless crystals. Mp: 120−121 °C
Figure 6. Low cataleptogenic potential of compound 7m in mice.
Compound 7m (10−100 mg/kg, po) and haloperidol (0.1 mg/kg, ip)
were evaluated for cataleptic potential in mice. All animals were tested
1 and 2 h after dosing. Data are expressed as the mean SEM (n = 6
per group). Data were analyzed by Williams (compound 7m) or
Student’s t-test (haloperidol): (∗) P < 0.05 vs the corresponding
vehicle control.
Ethyl 3-{2-[3-(Trifluoromethyl)benzyl]-1-benzothiophen-7-
yl}benzoate (5d). A mixture of 4d (1.61 g, 4.29 mmol), [3-
(trifluoromethyl)phenyl]boronic acid (0.98 g, 5.15 mmol), Pd(PPh3)4
(0.15 g, 0.13 mmol), Na2CO3 (0.91 g, 8.58 mmol), water (10 mL),
and DME (30 mL) was refluxed for 14 h under N2 atmosphere. Then
the reaction mixture was concentrated under reduced pressure, diluted
with water, and extracted with EtOAc. The extract was washed with
water, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(hexane−EtOAc = 10:1) to give 5d (1.36 g, 72%) as an oil. 1H NMR
(300 MHz, CDCl3) δ: 1.39 (t, J = 6.9 Hz, 3H), 4.27 (s, 2H), 4.93 (d, J
= 6.9 Hz, 2H), 7.10 (s, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.40−7.60 (m,
6H), 7.68 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 8.06 (d, J = 6.3
Hz, 1H), 8.33 (s, 1H).
Ethyl 3-{2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl}-
benzoate (5m). Compound 5m was prepared in a manner similar to
1
that described for 5d in 79% yield starting from compound 4d. H
NMR (300 MHz, CDCl3) δ: 1.39 (t, J = 7.1 Hz, 3H), 4.18 (s, 2H),
4.40 (q, J = 7.1 Hz, 2H), 6.85−6.91 (m, 1H), 6.93−6.99 (m, 1H), 7.06
(s, 1H), 7.13 (s, 1H), 7.31−7.35 (m, 1H), 7.44 (t, J = 7.7 Hz, 1H),
7.54 (t, J = 7.7 Hz, 1H), 7.70 (dd, J = 8.0, 1.1 Hz, 1H), 7.85−7.90 (m,
1H), 8.05−8.09 (m, 1H), 8.32−8.35 (m, 1H).
Ethyl 3-{4-Fluoro-2-(hydroxymethyl)-1-benzothiophen-7-
yl}benzoate (5n). Compound 5n was prepared in a manner similar
to that described for 5d in 80% yield starting from compound 4n. Mp:
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(EtOAc−hexane). H NMR (300 MHz, CDCl3) δ: 2.42 (br s, 1H),
N-(2-Methoxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-ben-
zothiophen-7-yl}benzamide (7l). Compound 7l was prepared in a
manner similar to that described for 7d in 90% yield starting from
compound 5d as colorless crystals. Mp: 113−114 °C (EtOAc−
hexane). 1H NMR (300 MHz, CDCl3) δ: 3.37 (s, 3H), 3.56 (d, J = 5.0
Hz, 2H), 3.67 (q, J = 5.0 Hz, 2H), 4.27 (s, 2H), 6.53 (br s, 1H), 7.10
(s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.40−7.60 (m, 6H), 7.69 (d, J = 7.8
Hz, 1H), 7.75−7.85 (m, 2H), 8.04 (s, 1H). LC/MS m/z 470.3 (M +
H).
3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-N-(2-
methoxyethyl)benzamide (7m). Compound 7m was prepared in a
manner similar to that described for 7d in 63% yield starting from
compound 5m as colorless crystals. Mp: 94−95 °C (hexane−Et2O).
1H NMR (300 MHz, CDCl3) δ: 3.37 (s, 3H), 3.53−3.60 (m, 2H),
2.94−3.06 (m, 2H), 3.17 (dd, J = 14.7, 7.5 Hz, 1H), 3.34 (dd, J = 15.3,
8.4 Hz, 1H), 3.65 (q, J = 5.1 Hz, 2H), 3.85 (br s, 2H), 4.98−5.05 (m,
1H), 6.62 (br s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 7.5 Hz,
1H), 7.20 (t, J = 8.1 Hz, 1H), 7.38−7.57 (m, 6H), 7.72 (d, J = 7.2 Hz,
1H), 7.85 (s, 1H). LC/MS m/z 442.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-2,3-di-
hydro-1-benzofuran-7-yl}benzamide (7h). Compound 7h was
prepared in a manner similar to that described for 7a in 55% yield
starting from compound 6h as colorless crystals. Mp: 161−162 °C
1
(EtOAc−hexane). H NMR (300 MHz, CDCl3) δ: 2.60 (br s, 1H),
2.97−3.08 (m, 2H), 3.18−3.38 (m, 2H), 3.63 (q, J = 5.1 Hz, 2H), 3.83
(q, J = 5.1 Hz, 2H), 5.00−5.13 (m, 1H), 6.60 (br s, 1H), 6.93 (t, J =
7.5 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.32 (d, J = 7.8 Hz,,1H), 7.28−
7.52 (m, 5H), 7.70 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 6.9 Hz, 1H), 8.08
(s, 1H). LC/MS m/z 442.4 (M + H).
3.63−3.71 (m, 2H), 4.17 (s, 2H), 6.53 (br s, 1H), 6.85−6.91 (m, 1H),
6.93−6.99 (m, 1H), 7.04−7.07 (m, 1H), 7.12−7.14 (m, 1H), 7.31−
7.35 (m, 1H), 7.39−7.47 (m, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.70 (dd, J
= 7.7, 1.1 Hz, 1H), 7.78−7.85 (m, 2H), 8.03−8.07 (m, 1H). LC/MS
m/z 454.2 (M + H).
N-(2-Hydroxyethyl)-3-{3-methyl-2-[3-(trifluoromethyl)-
benzyl]-1-benzofuran-4-yl}benzamide (7i). Compound 7i was
prepared in a manner similar to that described for 7a in 54% yield
starting from compound 6i as colorless crystals. Mp: 139−141 °C
(EtOAc−hexane). 1H NMR (300 MHz, CDCl3) δ: 1.79 (s, 3H), 2.40
(br s, 1H), 3.65 (q, J = 5.4 Hz, 2H), 3.85 (t, J = 5.4 Hz, 2H), 4.11 (s,
2H), 6.63 (br s, 1H), 7.08 (d, J = 7.5 Hz, 1H), 7.21−7.28 (m, 1H),
7.37−7.60 (m, 7H), 7.79−7.83 (m, 2H). LC/MS m/z 454.4 (M + H).
N-(2-Hydroxyethyl)-3-{3-methyl-2-[3-(trifluoromethyl)-
benzyl]-1-benzofuran-7-yl}benzamide (7j). Compound 7j was
prepared in a manner similar to that described for 7a in 62% yield
starting from compound 6j as colorless crystals. Mp: 158−159 °C
(EtOAc−hexane). 1H NMR (300 MHz, CDCl3) δ: 2.26 (s, 3H), 2.57
(br s, 1H), 3.63 (q, J = 5.7 Hz, 2H), 3.83 (q, J = 5.7 Hz, 2H), 4.17 (s,
2H), 6.61 (br s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.40−7.56 (m, 7H),
7.75 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 8.18 (t, J = 1.5 Hz,
1H). LC/MS m/z 454.3 (M + H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-ben-
zothiophen-7-yl}benzamide (7d). To a solution of ethyl 3-{2-[3-
(trifluoromethyl)benzyl]-1-benzothiophen-7-yl}benzoate (5d) (0.25 g,
0.57 mmol) in MeOH (5 mL)−THF (2 mL) was added 1 N NaOH
(1.70 mL, 1.70 mmol) in EtOH (50 mL). The mixture was stirred for
30 min at 60 °C. After concentration, the mixture was diluted with
water, acidified with 1 N HCl, and extracted with EtOAc. The extract
was washed with water and brine and then dried over MgSO4 and
concentrated under reduced pressure. The residue was dissolved in
DMF (5 mL). To the solution were added 2-aminoethanol (0.041 mL,
0.68 mmol), WSC (0.15 g, 0.85 mmol), and HOBt (0.12 g, 0.85
mmol). The mixture was stirred for 15 h at room temperature. The
reaction solution was diluted with water and extracted with EtOAc.
The extract was washed with water, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane−EtOAc = 1:1) to give 7d
(0.25 g, 97%) as an oil. 1H NMR (300 MHz, CDCl3) δ: 2.24 (t, J = 4.8
Hz, 1H), 3.65 (q, J = 5.1 Hz, 1H), 3.85 (q, J = 5.1 Hz, 1H), 4.27 (s,
2H), 6.62 (br s, 1H), 7.11 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.40−7.60
(m, 6H), 7.69 (d, J = 7.5 Hz, 1H), 7.78−7.85 (m, 2H), 8.05 (s, 1H).
LC/MS m/z 456.3 (M + H).
N-(2-Amino-2-oxoethyl)-3-{4-fluoro-2-[3-(trifluoromethyl)-
benzyl]-1-benzothiophen-7-yl}benzamide (7n). Compound 7n
was prepared in a manner similar to that described for 7d in 37% yield
starting from compound 5n as a solid. Mp: 157−158 °C (EtOAc−
1
hexane). H NMR (300 MHz, CDCl3) δ: 4.20 (d, J = 4.9 Hz, 2H),
4.27 (s, 2H), 5.53 (br s, 1H), 6.20 (br s, 1H), 7.03−7.14 (m, 2H), 7.22
(s, 1H), 7.23−7.29 (m, 1H), 7.39−7.58 (m, 5H), 7.75−7.86 (m, 2H),
8.04−8.09 (m, 1H). LC/MS m/z 487.3 (M + H).
2-Bromo-1-[3-(trifluoromethyl)phenyl]ethanone (9). A mix-
ture of 1-[3-(trifluoromethyl)phenyl]ethanone (8) and CuBr2 in
AcOEt (50 mL) was refluxed for 16 h. The solid was filtered off. The
filtrate was washed with saturated aqueous NaHCO3, dried, and
concentrated. The residue was used without further purification.
1-(3-Bromo-2-hydroxyphenyl)ethanone (10j). To a mixture of
1-(2-hydroxyphenyl)ethanone (4.00 g, 29.5 mmol) and diisopropyl-
amine (0.42 mL, 2.95 mmol) in CS2 (50 mL) was added NBS (5.25 g,
29.5 mmol) at 0 °C. The mixture was stirred for 1 h at room
temperature, taken up in water, and extracted with EtOAc. The extract
was washed with saturated aqueous NaHCO3 and water, then dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (EtOAc−hexane =
0:10 to 2:8) to give 10j (1.60g, 25%). 1H NMR (300 MHz, CDCl3) δ:
2.66 (s, 3H), 6.82 (t, J = 7.8 Hz, 1H), 7.69−7.75 (m, 2H), 12.9 (s,
1H).
(4-Bromo-1-benzofuran-2-yl)[3-(trifluoromethyl)phenyl]-
methanone (11a). To a solution of 2-bromo-6-hydroxybenzaldehyde
(10a) (4.0 g, 19.9 mmol) in acetonitrile (50 mL) were added 9 (6.38
g, 23.9 mmol) and K2CO3 (3.30 g, 23.9 mmol) at room temperature.
The mixture was refluxed for 16 h and taken up in water and extracted
with EtOAc. The combined organic extracts were washed with water
and brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane−EtOAc = 90:10 to 40:60) to give 11a (4.4 g, 60%).
Mp: 91−92 °C (MeOH). 1H NMR (300 MHz, CDCl3) δ: 7.39 (t, J =
8.1 Hz, 1H), 7.49−7.62 (m, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.91 (d, J =
7.8, 1.2 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H).
N-(2-Hydroxyethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-ben-
zothiophen-4-yl}benzamide (7c). Compound 7c was prepared in a
manner similar to that described for 7d in 85% yield starting from
(7-Bromo-1-benzofuran-2-yl)[3-(trifluoromethyl)phenyl]-
methanone (11b). Compound 11b was prepared in a manner similar
to that described for 11a in 69% yield starting from compound 10b as
colorless crystals. Mp: 75−78 °C (MeOH). 1H NMR (300 MHz,
CDCl3) δ: 7.24 (t, J = 7.5 Hz, 1H), 7.66−7.74 (m, 4H), 7.90 (d, J =
7.8 Hz, 1H), 8.36 (d, J = 7.8 Hz, 1H), 8.50 (s, 1H).
1
compound 5c as an oil. H NMR (300 MHz, CDCl3) δ: 2.41 (t, J =
4.9 Hz, 1H), 3.61−3.72 (m, 2H), 3.81−3.91 (m, 2H), 4.27 (s, 2H),
6.62 (br s, 1H), 7.13 (d, J = 0.8 Hz, 1H), 7.28−7.59 (m, 7H), 7.66−
7.71 (m, 1H), 7.73−7.78 (m, 1H), 7.79−7.84 (m, 1H), 7.93−7.96 (m,
1H). LC/MS m/z 456.3 (M + H).
( 4 - M e t h o x y - 3 - m e t h y l - 1 - b e n z o f u r a n - 2 - y l ) [ 3 -
(trifluoromethyl)phenyl]methanone (11i). Compound 11i was
prepared in a manner similar to that described for 11a in 69% yield
starting from compound 10i as colorless crystals. Mp: 91−92 °C
(MeOH). 1H NMR (300 MHz, CDCl3) δ: 2.82 (s, 3H), 3.96 (s, 3H),
6.66 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.1 Hz,
1H), 7.64 (t, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 8.24 (dd, J =
7.8 Hz, 1H), 8.31 (s, 1H).
N-(2-Amino-2-oxoethyl)-3-{2-[3-(trifluoromethyl)benzyl]-1-
benzothiophen-7-yl}benzamide (7k). Compound 7k was prepared
in a manner similar to that described for 7d in 94% yield starting from
compound 5d as a solid. Mp: 147−148 °C (EtOAc−hexane). 1H
NMR (300 MHz, CDCl3) δ: 4.18 (d, J = 4.8 Hz, 2H), 4.27 (s, 1H),
5.45 (br s, 1H), 6.00 (br s, 1H), 6.90−7.00 (m, 1H), 7.10 (s, 1H), 7.31
(d, J = 7.2 Hz, 1H), 7.40−7.60 (m, 6H), 7.68 (d, J = 8.1 Hz, 1H),
7.80−7.90 (m, 2H), 8.10 (m, 1H). LC/MS m/z 469.3 (M + H).
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(7-Bromo-3-methyl-1-benzofuran-2-yl)[3-(trifluoromethyl)-
phenyl]methanone (11j). Compound 11j was prepared in a manner
similar to that described for 11a in 88% yield starting from compound
10j as colorless crystals. Mp: 97−98 °C (MeOH). H NMR (300
crystallized from hexane−EtOAc to give 13d (0.41 g, 83%). Mp:
1
82−83 °C. H NMR (300 MHz, CDCl3) δ: 1.94 (t, J = 6.0 Hz, 1H),
4.94 (d, J = 6.0 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.31 (s, 1H), 7.47
(d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.8 Hz, 1H).
(4-Bromo-1-benzothiophen-2-yl)methanol (13c). Compound
1
MHz, CDCl3) δ: 2.70 (s, 3H), 7.20−7.27 (m, 1H), 7.63−7.71 (m,
3H), 7.87 (d, J = 7.8 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 8.57 (s, 1H).
4-Bromo-2-[3-(trifluoromethyl)benzyl]-1-benzofuran (3a). A
mixture of 11a (4.4 g, 11.9 mmol) and hydrazine monohydrate (2.38
g, 47.6 mmol) in ethylene glycol (50 mL) was heated to 130 °C for 2
h. After the mixture was cooled to room temperature, potassium
hydroxide (2.00 g, 35.7 mmol) was added to the mixture. The mixture
was heated to 160 °C for 2 h. The reaction solution was taken up in
water and extracted with EtOAc. The extract was washed with water
and brine, then dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane−EtOAc = 95:5 to 30:70) to give 3a (3.4 g, 80%) as an
oil. 1H NMR (300 MHz, CDCl3) δ: 4.16 (s, 2H), 6.46 (s, 1H), 7.09 (t,
J = 8.1 Hz, 1H), 7.31−7.36 (m, 2H), 7.40−7.61 (m, 4H).
13c was prepared in a manner similar to that described for 13d in 68%
1
yield starting from compound 12c. H NMR (300 MHz, CDCl3) δ:
1.91−2.00 (m, 1H), 4.95 (dd, J = 6.0, 0.8 Hz, 2H), 7.13−7.19 (m,
1H), 7.36−7.38 (m, 1H), 7.50 (dd, J = 7.4, 0.8 Hz, 1H), 7.74 (d, J =
8.0 Hz, 1H).
(7-Bromo-4-fluoro-1-benzothiophen-2-yl)methanol (13n).
Compound 13n was prepared in a manner similar to that described
for 13d in 60% yield starting from compound 12n. Mp: 80−81 °C. 1H
NMR (300 MHz, DMSO-d6) δ: 2.01 (t, J = 6.0 Hz, 1H), 4.95 (dd, J =
6.0, 0.9 Hz, 2H), 6.92 (dd, J = 9.6, 8.1 Hz, 1H), 7.34−7.42 (m, 2H).
Ethyl 3-[2-(Hydroxymethyl)-1-benzothiophen-7-yl]benzoate
(14d). A mixture of 13d (1.8 g, 7.40 mmol), [3-(ethoxycarbonyl)-
phenyl]boronic acid (1.72 g, 8.88 mmol), Pd(PPh3)4 (0.26 g, 0.22
mmol), Na2CO3 (1.57 g, 14.8 mmol), water (10 mL), and DME (30
mL) was refluxed for 16 h under N2 atmosphere. Then the reaction
mixture was concentrated under reduced pressure, diluted with water,
and extracted with EtOAc. The extract was washed with water, dried
over MgSO4, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane−EtOAc =
3:1) to give 14d (2.20 g, 95%) as an oil. 1H NMR (300 MHz, CDCl3)
δ: 1.41 (t, J = 7.2 Hz, 3H), 1.93 (t, J = 6.0 Hz, 1H), 4.41 (q, J = 7.2 Hz,
2H), 4.93 (d, J = 6.0 Hz, 2H), 7.30 (s, 1H), 7.36 (d, J = 6.9 Hz, 1H),
7.45 (t, J = 7.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 7.8 Hz,
1H), 7.91 (d, J = 7.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.36 (s, 1H).
Ethyl 3-[2-(Hydroxymethyl)-1-benzothiophen-4-yl]benzoate
(14c). Compound 14c was prepared in a manner similar to that
described for 14d in 91% yield starting from compound 13c. 1H NMR
(300 MHz, CDCl3) δ: 1.39 (t, J = 7.1 Hz, 3H), 2.13 (br s, 1H), 4.39
(q, J = 7.1 Hz, 2H), 4.89 (br s, 2H), 7.25 (d, J = 3.3 Hz, 1H), 7.30−
7.43 (m, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.68−7.75 (m, 1H), 7.82 (d, J =
7.7 Hz, 1H), 8.04−8.09 (m, 1H), 8.21 (t, J = 1.6 Hz, 1H).
7-Bromo-2-[3-(trifluoromethyl)benzyl]-1-benzofuran (3b).
Compound 3b was prepared in a manner similar to that described
1
for 3a in 74% yield starting from compound 11b as an oil. H NMR
(300 MHz, CDCl3) δ: 4.20 (s, 2H), 6.40 (s, 1H), 7.06 (t, J = 7.5 Hz,
1H), 7.35−7.59 (m, 6H).
7-Bromo-3-methyl-2-[3-(trifluoromethyl)benzyl]-1-benzo-
furan (3j). Compound 3j was prepared in a manner similar to that
described for 3a in 75% yield starting from compound 10j as an oil. 1H
NMR (300 MHz, CDCl3) δ: 2.20 (s, 3H), 4.18 (s, 2H), 7.08 (t, J = 7.5
Hz, 1H), 7.34−7.53 (m, 6H).
4-Methoxy-3-methyl-2-[3-(trifluoromethyl)benzyl]-1-benzo-
furan. This compound was prepared in a manner similar to that
described for 3a in 74% yield starting from compound 11i as an oil. 1H
NMR (300 MHz, CDCl3) δ: 2.37 (s, 3H), 3.89 (s, 3H), 4.08 (s, 2H),
6.59 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz,
1H), 7.35−7.50 (m, 4H).
3-Methyl-2-[3-(trifluoromethyl)benzyl]-1-benzofuran-4-ol.
To a solution of 4-methoxy-3-methyl-2-[3-(trifluoromethyl)benzyl]-1-
benzofuran (1.51 g, 4.68 mmol) in dichloromethane (30 mL) was
added dropwise boron tribromide (1.0 M dichloromethane solution,
5.0 mL, 5.0 mmol) at 0 °C in Ar atmosphere. The mixture was stirred
at ambient temperature for 3 h. The reaction mixture was quenched
with saturated aqueous NaHCO3. The organic layer was separated,
and the aqueous layer was extracted with dichloromethane. The
combined organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane−EtOAc = 90:10 to 20:80)
to give the titled compound (1.38 g, 96%). Mp: 91−92 °C (EtOAc−
Ethyl 3-[4-Fluoro-2-(hydroxymethyl)-1-benzothiophen-7-
yl]benzoate (14n). Compound 14n was prepared in a manner
similar to that described for 14d in 80% yield starting from compound
13n. Mp: 89−90 °C. 1H NMR (300 MHz, CDCl3) δ: 1.41 (t, J = 7.1
Hz, 3H), 1.95 (t, J = 6.0 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 4.94 (dd, J
= 6.2, 1.0 Hz, 2H), 7.12 (dd, J = 9.6, 8.2 Hz, 1H), 7.31 (dd, J = 8.1, 4.8
Hz, 1H), 7.40−7.42 (m, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.86 (dq, J =
7.7, 1.0 Hz, 1H), 8.09 (dt, J = 7.9, 1.4 Hz, 1H), 8.31 (t, J = 1.8 Hz,
1H).
Ethyl 3-[2-(Bromomethyl)-1-benzothiophen-7-yl]benzoate
(4d). To a solution of 14d (2.2 g, 7.04 mmol) in Et2O (20 mL)
was added dropwise PBr3 (0.7 mL, 7.39 mmol). The mixture was
stirred at room temperature for 2 h, diluted with EtOAc, washed with
saturated aqueous NaHCO3 and brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane−EtOAc = 10:1) to give 4d
1
hexane). H NMR (300 MHz, CDCl3) δ: 2.41 (s, 3H), 4.09 (s, 2H),
5.05 (s, 1H), 6.50 (d, J = 8.4 Hz, 1H), 6.92−7.05 (m, 2H), 7.30−7.51
(m, 4H).
3-Methyl-2-[3-(trifluoromethyl)benzyl]-1-benzofuran-4-yl
Trifluoromethanesulfonate (3i). To a solution of 3-methyl-2-[3-
(trifluoromethyl)benzyl]-1-benzofuran-4-ol (1.38 g, 4.50 mmol) in
pyridine (15 mL) was added dropwise trifluoromethanesulfonic
anhydride (0.83 mL, 4.95 mmol) at 0 °C, and the mixture was stirred
for 4 h at room temperature. The reaction mixture was quenched with
water, and crude product was extracted with EtOAc. The organic layer
was washed with 1 N HCl and saturated aqueous NaHCO3, then dried
over MgSO4 and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane−EtOAc =
90:10 to 50:50) to give 3i (1.40 g, 71%) as an oil. 1H NMR (300 MHz,
CDCl3) δ: 2.40 (s, 3H), 4.13 (s, 2H), 7.13 (d, J = 7.2 Hz, 1H), 7.23 (t,
J = 8.1 Hz, 1H), 7.30−7.51 (m, 5H).
(7-Bromo-1-benzothiophen-2-yl)methanol (13d). To a 1.2 M
borane−THF solution (6.86 mL, 8.10 mmol) was added 7-bromo-1-
benzothiophene-2-carboxylic acid (12d) (0.52 g, 2.02 mmol) at 0 °C,
and the mixture was then stirred for 3 h at 60 °C. The reaction mixture
was quenched by the slow addition of 1 N HCl and extracted with
EtOAc. The extract was washed with water, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane−EtOAc = 4:1) and
1
(1.91 g, 72%) as colorless crystals. Mp: 96−97 °C. H NMR (300
MHz, CDCl3) δ: 1.41 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H),
4.77 (s, 2H), 7.38−7.45 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 7.54 (t, J =
7.8 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 8.10
(d, J = 7.5 Hz, 1H), 8.35 (s, 1H).
Ethyl 3-[2-(Bromomethyl)-4-fluoro-1-benzothiophen-7-yl]-
benzoate (4n). Compound 4n was prepared in a manner similar to
that described for 4d in 42% yield starting from compound 14n. Mp:
139−140 °C. 1H NMR (300 MHz, CDCl3) δ: 1.41 (t, J = 7.1 Hz, 3H),
4.41 (q, J = 7.1 Hz, 2H), 4.75 (s, 2H), 7.12 (dd, J = 9.3, 8.1 Hz, 1H),
7.33 (dd, J = 8.1, 4.8 Hz, 1H), 7.50 (s, 1H), 7.56 (t, J = 7.8 Hz, 1H),
7.84 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.30 (d, J = 1.8 Hz,
1H).
7-Bromo-2-[3-(trifluoromethyl)benzyl]-2H-indazole (3e). A
mixture of 7-bromo-1H-indazole (15e) (1.00 g, 5.08 mmol) and 1-
(bromomethyl)-3-(trifluoromethyl)benzene (1.16 mL, 7.61 mmol) in
DMF (2.0 mL) was heated at 50 °C for 20 h. The reaction solution
was poured into water and extracted with EtOAc. The extract was
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Journal of Medicinal Chemistry
Article
washed with water, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc−hexane = 1:9) to give 3e (983 mg, 58%) as
ABBREVIATIONS USED
■
cAMP, 3′,5′-cyclic adenosine monophosphate; EC50, half
maximal effective concentration; 5-HT, 5-hydroxytryptamine
(serotonin); mRNA, messenger ribonucleic acid; NMDA, N-
methyl-D-aspartate; MNDO, modified neglect of diatomic
overlap; PM3, parametrized model number 3; TFA, trifluoro-
acetic acid; Pd(PPh3)4, tetrakis(triphenylphosphine)palladium-
(0); DME, 1,2-dimethoxyethane; Na2CO3, sodium carbonate;
NaOH, sodium hydroxide; EtOH, ethyl alcohol; THF,
tetrahydrofuran; MeOH, methyl alcohol; WSC, 1-(3-dimethy-
laminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt, 1-
hydroxybenzotriazole; DMF, N,N-dimethylformamide; CuBr2,
copper(II) bromide; EtOAc, ethyl acetate; K2CO3, potassium
carbonate; Tf2O, trifluoromethanesulfonic anhydride; PBr3,
phosphorus tribromide; CHO, Chinese hamster ovary; SEM,
standard error of the mean; AMPA, 2-amino-3-(3-hydroxy-5-
methyl-4-isoxazolyl)propionic acid; AUC, area under the curve;
AcONH4, ammonium acetate; mp, melting point; NaHCO3,
sodium hydrogen carbonate; MgSO4, magnesium sulfate; HCl,
hydrochloric acid; HEPES, 2-[4-(2-hydroxyethyl)-1-
piperazinyl]ethanesulfonic acid; BSA, bovine serum albumin;
IBMX, 3-isobutyl-1-methylxanthine
1
an oil. H NMR (300 MHz, CDCl3) δ: 5.72 (s, 2H), 6.91−7.00 (m,
1H), 7.42−7.56 (m, 3H), 7.56−7.65 (m, 3H), 7.96 (s, 1H).
4-Bromo-2-[3-(trifluoromethyl)benzyl]-2H-indazole (3f).
Compound 3f was prepared in a manner similar to that described
for 3e in 55% yield starting from compound 15f. 1H NMR (300 MHz,
CDCl3) δ: 5.64 (s, 2H), 7.12−7.19 (m, 1H), 7.22−7.28 (m, 1H),
7.42−7.54 (m, 2H), 7.57−7.70 (m, 3H), 7.97 (s, 1H).
Evaluation of GPR52 Agonistic Activities. CHO cells
expressing human GPR52 (10 000 cells) were incubated with test
compounds for 30 min at 37 °C in 30 μL/well assay buffer (Hanks’
balanced salt solution (HBSS) containing 5 mM HEPES (pH7.6),
0.5% BSA, 100 μM IBMX, and 100 μM Ro20-1724). Then 10 μL/well
of 0.1 U/μL anti cAMP acceptor beads (PerkinElmer) and 10 μL/well
of 0.1 U/μL biotinylated cAMP donor beads (PerkinElmer) were
added and incubated overnight at room temperature. cAMP
concentrations were determined by measuring AlphaScreen signal
with Envision (PerkinElmer). pEC50 values were calculated by using
nonlinear regression analysis with XLfit (IDBS). pEC50 is the
concentration of the compounds that produces a response that is
50% of its maximal effect, expressed as negative logarithm. Emax (%) is
the efficacy maximum of the compounds in the cAMP assay relative to
1 μM 7a as 100% and DMSO as 0%.
MAP-Induced Hyperlocomotion Test. All animal protocols
were approved by the Experimental Animal Care and Use Committee
of Takeda Pharmaceutical Company Ltd. Male ICR mice (7−8 weeks)
were used for all experiments. The locomotor activity in mice was
measured using a locomotor activity monitor, MDC-LT (Brain
Science Idea Co., Ltd.). Mice were individually placed in transparent
polycarbonate cages (30 cm × 40 cm × 20 cm). After habituation for
60 min, compound 7m (1−30 mg/kg, po) was administered. MAP (2
mg/kg, sc) was injected 60 min after the drug treatment. Activity
counts were monitored for 150 min after administration of 7m.
Catalepsy Test. Male ICR mice (6−7 weeks old) were used. All
animals were tested 1 and 2 h after administration of compound 7m
(10−100 mg/kg, po) or haloperidol (0.1 mg/kg, ip). The mice were
lifted by the tail and placed with their front paws on a steel bar and the
hind legs on the plane surface. The time spent for the mice to show a
cataleptic posture, which was defined as an immobile posture while
keeping both forelimbs on the bar, was measured with a maximum
limit of 30 s. The procedure was repeated twice more, and the
cataleptic response time was averaged for each mouse.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Elemental analysis results of the synthesis of compounds 7a, 7b,
and 7e−n. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Phone: +81-466-32-1122. Fax: +81-466-29-4454. E-mail:
masaki.setoh@takeda.com.
■
Present Address
§T.H.: Shiga University of Medical Science, Seta Tsukinowa-
cho, Otsu, Shiga 520-2192, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Takanobu Kuroita and Dr. Kazuyoshi Aso for
helpful discussions during the preparation of the manuscript,
and Yuji Shimizu for generation of data in the GPR52 agonistic
activities.
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