Synthesis and biological evaluation of novel (-)-cercosporamide derivatives as potent selective PPARγ modulators

Article abstract of DOI:10.1016/j.ejmech.2012.05.040

Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC₅₀ = 0.94 nM, E_max = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.

Full text of DOI:10.1016/j.ejmech.2012.05.040

European Journal of Medicinal Chemistry 54 (2012) 522e533
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological evaluation of novel (ꢀ)-cercosporamide derivatives as
potent selective PPAR
g
modulators
Akihiro Furukawa a, , Tsuyoshi Arita , Takehiro Fukuzaki , Makoto Mori , Takeshi Honda ,
a
a
a
a
*
b
a
b
a
a
Susumu Satoh , Yumi Matsui , Kenji Wakabayashi , Shinko Hayashi , Kouichi Nakamura ,
Kazushi Araki , Masanori Kuroha , Jun Tanaka , Satoko Wakimoto , Osamu Suzuki , Jun Ohsumi
Shinagawa R&D Center, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140 8710, Japan
Daiichi Sankyo RD Novare Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134 8630, Japan
a
a
a
a
a
a
a
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 April 2012
Received in revised form
Selective peroxisome proliferator-activated receptor gamma (PPAR
g
) modulators are expected to be
a novel class of drugs improving plasma glucose levels without PPAR
a continuation of our studies for (ꢀ)-Cercosporamide derivatives as selective PPAR
synthesized substituted naphthalene type compounds and identified the most potent compound 15
EC50 ¼ 0.94 nM, Emax ¼ 38%). Compound 15 selectively activated PPAR transcription and did not
activate PPAR and PPAR . The potassium salt of compound 15 showed a high solubility and a good oral
g
-related adverse effects. As
g
modulators, we
28 May 2012
Accepted 30 May 2012
Available online 7 June 2012
(
g
a
d
bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose
levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase
or a cardiac enlargement in WistareImamichi rats, even at 100 mg/kg.
Keywords:
PPAR
g
SPPARM
Diabetes
Ó 2012 Elsevier Masson SAS. All rights reserved.
Type 2 diabetes
(ꢀ)-Cercosporamide
1. Introduction
rosiglitazone are the PPARg full agonists used in clinical settings. In
spite of their beneficial effects, the use of these drugs has been
Diabetes is one of the most serious health problems in the
world. The International Diabetes Federation (IDF) estimated that
the number of people living with diabetes has soared to 366
million, representing 8.3% of the global adult population. This
number is projected to increase to 552 million people by 2030, or
limited because of adverse effects such as weight gain, edema, and
anemia [3]. Furthermore, additional concerns that the use of PPAR
g
full agonists elevates the risk of cardiovascular events [4] and
fractures [5] have been raised.
The PPARg is associated with transcriptions of various genes as
9
.9% of adults [1]. Type 2 diabetes, which is the more common type
well as glycometabolism related genes. It is believed that some of
the genes are related to the adverse effects. Therefore, the selective
PPARg modulators (SPPARMs), which partially activate the PPARg
of diabetes, usually develops in adulthood and is related to obesity,
lack of physical activity, and unhealthy diets. For treatment of type
2
diabetes, lifestyle changes and weight loss are recommended. If
transcriptional activity, have been considered to be ideal drug
candidates. They are expected to improve the insulin resistance of
a sufficient control of plasma glucose level cannot be achieved,
several oral medications are available, such as metofolmin, sulfo-
nylureas, DPP-IV inhibitors and peroxisome proliferator-activated
type 2 diabetes with attenuated PPAR
g related adverse effects [6].
Some SPPARMs, such as Fmoc- -Leucine [7], FK614 [8], T2384 [9],
L
receptor gamma (PPAR
g
) agonists.
INT-131 [10], MBX-102 [11], MK-0533 [12], and benzimidazolones
[13] were reported to improve plasma glucose levels in hypergly-
cemic rodent models without several undesired side effects. Thus,
the development of novel SPPARMs as drug candidates has drawn
considerable attention.
Peroxisome proliferator-activated receptor gamma (PPAR
g) is
a member of a large family of ligand-activated nuclear hormone
receptors, and is known to mediate adipocyte differentiation and
improve plasma glucose levels effectively [2]. Pioglitazone and
We also reported that (ꢀ)-Cercosporamide derivative 2 (Scheme
1
) was a novel SPPARM and it showed ideal pharmacological effects
Abbreviations: PPAR
SPPARM, selective peroxisome proliferator-activated receptor gamma modulator.
g, peroxisome proliferator-activated receptor gamma;
in hyperglycemic db/db mice [14]. (ꢀ)-Cercosporamide was origi-
*
Corresponding author. Tel.: þ81 3 3492 3131; fax: þ81 3 5436 8563.
E-mail address: furukawa.akihiro.zy@daiichisankyo.co.jp (A. Furukawa).
nally isolated in 1991 as an antifungal agent and phytotoxin from
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.05.040

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
523
2 3 3 3
Scheme 1. Reagents and conditions: (a) MeI, K CO , DMF, r.t., 24 h; (b) substituted naphthaldehyde, Et SiH, TFA, CH CN, r.t., 1e12d.
Scheme 2. Reagents and conditions: (a) RCH
2
PPh
3
Br, NaH, THF, 0 ꢁC to r.t., 1.5 h; (b) DMF, n-BuLi, THF, ꢀ78 ꢁC to r.t., 1.5 h; (c) PdeC, EtOAc, r.t., 1 h.
a fungal plant pathogen of cassava, Cercosporidium henningsii [15].
In our exploratory campaign for a novel antihyperglycemic agent,
we discovered that (ꢀ)-Cercosporamide had a plasma glucose-
lowering effect in hyperglycemic KK/Ta mice [16]. We tried to
synthesize more potent (ꢀ)-Cercosporamide derivatives and to
clarify the mechanism of action. In the research program, we
identified a potent compound 2 as a novel SPPARM.
2-Alkylated naphthaldehydes 19aec were synthesized from
compound 16 as shown in Scheme 2. Alkyl groups were introduced
by Wittig reaction. Following conversion of the 1-bromo group to
the formyl group and hydrogenation of the double bond gave
naphthaldehydes 19aec.
Syntheses of 6-halo-2-methylnaphthaldehydes 23aeb and 5- or
7-halo-2-methylnaphthaldehydes 28aed were performed as
Here, we report further efforts for enhancing the potency of
compound 2. Compound 15 was found to be the most potent
compound in a full-length human PPARg reporter gene assay. The
detailed pharmacological evaluations of compound 15 revealed
strong in vivo efficacies and attenuated adverse effects.
shown in Scheme 3. b-Tetralones 20aeb were converted to
compound 21aeb via VilsmeiereHaack type reaction [18], followed
by dehydrogenation to give compound 22aeb. The subsequent
MigitaeKosugieStille couplings afforded the naphthaldehydes
23aeb.
the same way as
a
-Tetralones 24aed were converted to compound 26aed in
-tetralones. Subsequent reductions, lithiations,
b
2
. Results and discussions
and formylations gave naphthaldehydes 28aed.
Syntheses of 4-halo-2-alkylnaphthaldehydes were achieved as
shown in Scheme 4. Compound 29 was formylated to give naph-
thaldehyde 30. The ortho lithiation of compound 31 mediated by
2
.1. Chemistry
0
The X-ray crystal structure analysis of the complex of PPAR
g-
N,N,N -trimethylethylenediamine [19] and successive treatment
LBD (ligand binding domain) and compound 2 [14] suggested that
there is a hydrophobic space in front of the naphthalene C2 posi-
tion. Thus, we introduced alkyl substituents at the naphthalene C2
position of compound 2, expecting the alkyl substituents to fill the
space and make the derivatives more potent. We also tested
incorporating halogen substituents into the naphthalene ring.
All of the (ꢀ)-Cercosporamide derivatives 2e15 were synthe-
sized by reductive N-alkylation [17] of amide 1 using trifluoroacetic
acid and triethylsilane with substituted naphthaldehydes as alky-
lating agents in moderate to high yield (61%e89%) as shown in
Scheme 1.
with iodomethane yielded naphthaldehyde 32. The bromination of
lithiated 31 and subsequent Suzuki-Miyaura coupling afforded
naphthaldehyde 34.
2.2. In vitro pharmacology
The effects of these derivatives 2e15 were tested in a full-length
human PPARg reporter gene assay using MG-63 cells. The results
are summarized in Table 1.
Alkyl substituents on the naphthalene C2 position strengthened
the derivatives without large changes of the maximum efficacy. In
Scheme 3. Reagents and conditions: (a) DMF, PBr
3
, CHCl
3
, reflux, 2 h; (b) DDQ, toluene, reflux, 2e4d; (c) Me
4
Sn, Pd(PPh
3
)
4
, toluene, reflux, 9 h; (d) N
H
2 4
eH
2
O, KOH, diethylene
ꢁ
, r.t., 1e4d; (f) DMF, n-BuLi, THF, ꢀ78 ꢁC to r.t., 1 h.
glycol, 180 C, 1.5 h; (e) B(C
6
5
F )
3
, Et
3
SiH, CH
2
Cl
2

524
A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
ꢁ
Scheme 4. Reagents and conditions: (a) MeOCHCl
2
, TiCl
4
ꢁ
, CH
2
Cl
2
0
C to r.t., 4 h.; (b)
CF Br,
BOMe,
0
MeI, N,N,N -trimethylethylenediamine, n-BuLi, THF, ꢀ78 C to r.t., 26 h.; (c) BrCF
2
2
0
ꢁ
N,N,N -trimethylethylenediamine, n-BuLi, THF, ꢀ78 C to r.t., 19 h.; (c) Et
2
ꢁ
PdCl
2
(dppf)･CH
2
Cl
, K
2 2
CO
3
, DMF, 70 C, 2.5 h.
Fig. 1. Crystal structure of the complex of PPARg-LBD and compound 15.
comparison with non-substituted compound 2 (EC50 ¼ 180 nM,
E
max ¼ 47%), methyl-substituted compound 3 (EC50 ¼ 28 nM,
max ¼ 47%) was six times more potent and ethyl-substituted
substituent would change the electrostatic potential of the naph-
thalene ring to strengthen the interaction with PPAR . We
considered these effects made compound 15 two hundred times
more potent than compound 2.
The selectivity on PPAR subtypes of compound 15 was tested in
GAL4-PPAR-LBD reporter gene assays using COS7 cells (Fig. 2). The
E
g
compound 4 (EC50 ¼ 3.7 nM, Emax ¼ 39%) was fifty times more
potent. Compounds 5 and 6, n-propyl and n-butyl substituents, also
showed enhanced potencies, but were inferior to compound 3.
Interestingly, compound 6 was found to have a lower maximal
efficacy (Emax ¼ 22%) than the other alkyl derivatives 3e5. The
reason why the large alkyl substituent decreased the Emax value is
not clear, and is now under investigation.
compound 15 potently induced PPAR
(EC50 ¼ 12 nM, Emax ¼ 64%). On the other hand, only slight and no
induction was observed even at 10 M for the PPAR and PPAR
transactivation, respectively. These results suggested that
compound 15 is a highly selective PPAR partial agonist.
g
transactivation
m
a
d
Regarding the effect of the halogen substituents, we started our
SAR study from 2-methyl compound 3 due to synthetic feasibility.
g
7
-Chloro compound 10 (EC50 ¼ 4.9 nM, Emax ¼ 44%) was the most
potent among the chloro-substituted compounds 7e10. 4-Fluoro
compound 11 (EC50 ¼ 4.8 nM, Emax ¼ 50%) was the most
potent among the fluoro-substituted compounds 11e14. These
compounds were five times more potent than compound 3.
We combined the most potent alkyl substituent of 2-ethyl and the
most potent halogen substituent of 4-fluoro. The resulting 2-ethyl-
2
2
.3. In vivo pharmacology
.3.1. Pharmacokinetics
In consideration of the excellent in vitro profiles, we expected
that compound 15 would show ideal pharmacological effects
in vivo. Prior to detailed in vivo evaluations, we tested the phar-
macokinetic profiles in rats. Since compound 15 had a low solu-
4
-fluoro compound 15 showed an extreme potency
(
EC50 ¼ 0.94 nM, Emax ¼ 38%), which was almost two hundred
times more potent than non-substituted compound 2.
bility (23 mg/mL in JP2 at pH6.8), we tried to administer it as a salt
X-ray crystal structure analysis of the complexes of PPARgeLBD
form. Compound 15 was readily converted to potassium salt by
treatment with aqueous potassium hydroxide in a co-solvent of
ethanol and dichloromethane. The potassium salt 35 showed an
with compound 15 showed that 2-ethyl group sufficiently filled the
hydrophobic space (Fig. 1, PDB ID: 4F9M). 4-Fluoro substituent was
located near the side chain of Lys367 causing a bigger van der Waals
force than that of compound 4. We speculated that 4-fluoro
improved solubility (910
mg/mL in JP2 at pH6.8). The potassium salt
35 was administered to Fischer rats at 10 mg/kg orally and intra-
venously. Compound 15 was metabolically stable in rats: the
elimination terminal half-life after intravenous administration was
estimated to be 4.0 h and the total clearance to be 6.98 mL/min/kg.
Sufficient plasma concentration of compound 15 was observed
after oral administration (Fig. 3), and the bioavailability was esti-
mated to be 58%. These good pharmacokinetic profiles of potassium
salt 35 prompted us to conduct detailed in vivo evaluations.
Table 1
Full-length human PPAR
g
reporter gene assay.
Compound
R
X
Transactivation
EC50 (nM)
E
max (%)
2
3
4
5
6
7
8
9
H
Me
Et
e
180
28
47
47
39
e
3.7a
43
a
e
n-Pr
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Et
e
37
22
57
59
26
44
50
39
28
40
38
e
59
22
4-Cl
5-Cl
6-Cl
7-Cl
4-F
5-F
6-F
7-F
4-F
170
56
4.9
4.8
16
27
65
0.94
11
10
11
12
13
14
15
Rosiglitazone
106
a
The PPARg transcriptional activity in the presence of compound 4 is slightly
different from the previously reported values (EC50 ¼ 3.5 nM, Emax ¼ 27%) [20]
Fig. 2. PPAR subtypes selectivity Footnote: Data are represented as mean ꢂ S.E.M.
(n ¼ 3).
because of a variant assay system.

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
525
Compound 35 showed almost an equal potency to rosiglitazone
in glucose-lowering effects. Although body weight gains were
increased at the pharmacologically effective doses (over 1 mg/kg),
the degree of body weight gain of compound 35 inclined to be small
in comparison to the same dose of rosiglitazone. These results
indicated that compound 35 had sufficient anti-diabetic effects on
type 2 diabetes at clinically acceptable doses.
2
.3.3. PPAR
The PPAR
g
agonist-related adverse effects
agonists are known to induce several adverse effects
g
such as body weight increase, edema, anemia, and cardiac hyper-
trophy. We tried to evaluate these adverse effects by measuring
body weight gain, plasma volume, and heart weight in normal
WistareImamichi rats. Compound 35 (100 mg/kg/day), rosiglita-
zone (30, 100 and 300 mg/kg/day), and vehicle were administered
for 14 days under the same condition as ZDF rats. The results are
shown in Fig. 5. In comparison with the vehicle treated group, the
compound 35 and rosiglitazone 30 and 100 mg/kg treated groups
were inclined to increase body weight gain without statistically
significant difference. On the other hand, the rosiglitazone 300 mg/
kg treated group did not show an increase of body weight gain.
Thus, we considered that rosiglitazone 300 mg/kg was likely to be
over-dosing. Compound 35 did not increase plasma volume or
heart weight even at 100 mg/kg, although rosiglitazone signifi-
cantly increased plasma volume (p < 0.01) and heart weight
Fig. 3. Plasma concentrations of compound 15 in Fischer rats. Footnote: Data
are represented as mean ꢂ S.D. (n ¼ 4) after oral administration of compound 35 at
10 mg/kg.
2.3.2. Pharmacological effects in type 2 diabetes model
We evaluated the pharmacological effects of compound 35 in
female Zucker diabetic fatty (ZDF) rats by comparing the marketed
PPAR agonist rosiglitazone and vehicle treated groups. Both
g
compounds were suspended in 0.5% (w/v) methylcellulose solution
and administered once daily by oral gavage for 12 days. The
measured parameters are shown in Fig. 4. Both compounds
significantly lowered the non-fasting plasma glucose level below
(p < 0.01) in a dose dependent manner at 30 and 100 mg/kg.
Although compound 35 at 100 mg/kg slightly affected the body
2
00 mg/dL at over 1 mg/kg (p < 0.01). Both compounds also dose-
weight gain of WistareImamichi rats without statistical signifi-
cance, it did not cause an increase of plasma volume or cardiac
hypertrophy. On the other hand, rosiglitazone 30 and 100 mg/kg
significantly increased plasma volume and heart weight in a dose
dependent manner. The increase of plasma volume was associated
with edema and anemia. The increased plasma volume also
stressed the heart and resulted in cardiac enlargement. These
dependently improved plasma lipids profiles. Compound 35
significantly decreased the triglyceride at 100 mg/kg (p < 0.05) and
free fatty acids at over 1 mg/kg (p < 0.01). Rosiglitazone signifi-
cantly decreased the triglyceride at 1 mg/kg (p < 0.05), 10 and
100 mg/kg (p < 0.01) and free fatty acids at over 1 mg/kg (p < 0.01).
Body weight increments were induced in the plasma glucose
lowered groups (p < 0.01) and the slight body weight increase was
also recognized in the rosiglitazone 0.1 mg/kg group (p < 0.05).
results indicated that compound 35 was safer than marketed PPAR
g
full agonist rosiglitazone, in terms of the cardiovascular risks.
Fig. 4. Evaluation of pharmacological effects of compound 35 in Zucker diabetic fatty rats. Footnote: Each group of rats were orally administered (dose indicated in mg/kg/day) for
2 days with compound 35, rosiglitazone, or vehicle. Data are represented as mean ꢂ S.E.M. (n ¼ 5). Statistical significances of differences between the control and treated groups
were analyzed by one-way ANOVA with Dunnett’s multiple comparison test (*P < 0.05, **P < 0.01).
1

526
A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
Fig. 5. Evaluation of PPAR
g
agonist-related adverse effects of compound 35 in WistareImamichi rats. Footnote: Each group of rats were orally administered (dose indicated in mg/
kg/day) for 14 days with compound 35, rosiglitazone, or vehicle. Data are represented as mean ꢂ S.E.M. (n ¼ 5). There was no statistical significance of difference between the
control and the compound 35 treated group analyzed by an unpaired, two-tailed t-test. Statistical significances of differences between the control and rosiglitazone-treated groups
were analyzed by one-way ANOVA with Dunnett’s multiple comparison test (**P < 0.01).
3
. Conclusion
400, Varian Mercury 500, or JEOL JNM-ECA500 with tetrame-
thylsilane as an internal reference. Mass spectra were recorded on
JEOL JMS-GCmate, JEOL JMS-600H, JEOL JMS-Lcmate, JEOL JMS-
T100LC, or Waters Xevo Qtof.
For enhancing the potency of compound 2 as a selective PPAR
g
modulator, we introduced alkyl substituents at C2 position of the
naphthalene ring and halogen substituents at the C4, C5, C6, or C7
position. The most potent 2-ethyl-4-fluoro substituted compound
4.1.1. (9aS)-8-acetyl-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-
9,9a-dihydrodibenzo[b,d]furan-4-carboxamide (1)
1
5 was two hundred times more potent than compound 2 in
full-length human PPAR transactivation reporter assay
EC50 ¼ 0.94 nM, Emax ¼ 38%). Compound 15 selectively induced
PPAR transactivation and did not affect PPAR and PPAR in GAL4-
PPAR-LBD reporter gene assays. Although compound 15 has a low
solubility, the potassium salt 35 has a high solubility (910 g/mL in
a
(
g
(ꢀ)-Cercosporamide (10.49 g, 31.7 mmol) was dissolved in DMF
2 3
(50 mL). Iodomethane (5.0 mL, 80.3 mmol) and K CO (9.03 g,
g
a
d
65.3 mmol) were added, and the mixture was stirred at room
temperature for 36 h. K CO was separated by filtration from the
2
3
m
reaction mixture and 0.1 N hydrochloric acid was added, followed
by extraction with EtOAc. The organic layer was washed with
JP2 at pH6.8) and a good oral bioavailability (58%) at a dose of 10 mg/
kg in Fischer rats. In vivo pharmacological evaluation of compound
2 4
brine, then dried over Na SO . The solvent was removed under
3
5 demonstrated potent anti-diabetic effects on type 2 diabetes
models of ZDF rats, which were almost equivalent to rosiglitazone.
Moreover, compound 35 did not induce PPAR -related adverse
reduced pressure, and the resulting residue was recrystallized
from EtOAc to afford 7.19 g of compound 1 (66% yield) as a yellow
1
g
solid. H NMR (CDCl
3
, 500 MHz)
d: 1.76 (3H, s), 2.65 (3H, s), 3.94
effects such as a plasma volume increase or a cardiac enlargement in
WistareImamichi rats. These results support potassium salt 35 as
a promising anti-diabetic drug candidate.
(3H, s), 5.76 (1H, brs), 6.04 (1H, s), 6.36 (1H,s), 7.10 (1H, brs), 10.79
(1H, s), 18.83 (1H, s). C NMR (CDCl , 500 MHz) d: 28.0, 32.1, 56.7,
3
13
58.7, 96.6, 98.3, 101.6, 105.2, 106.5, 156.1, 157.9, 160.5, 164.8, 180.3,
þ
1
91.9, 198.0, 201.7. MS (ESI) m/z: 346 (M þ H) . HRMS (ESI) m/z:
4
. Experimental section
346.0929 (calcd for
17 7
C H16NO : 346.0927). Anal. Calcd for
17 7
C H15NO : C, 59.13; H, 4.38; N, 4.06; O, 32.43. Found: C, 59.03; H,
4.1. Chemistry
4.42; N, 4.14; O, 32.31.
All reactions were performed under a nitrogen atmosphere,
4.1.2. General procedure to synthesize PPAR
g
modulators (2e15)
unless otherwise indicated. Commercially available chemicals were
used without further purification. Thin-layer chromatography (TLC)
performed on Merck TLC Silica gel 60 F254 glass plates was used
routinely to monitor the progress of the reactions and the purity of
the compounds. For the flash column chromatography, silica gel 60
Compound 1 was suspended in CH CN. Substituted naph-
3
thaldehyde (1e3eq.), triethylsilane (2e3eq.), and trifluoroacetic
acid (2e3eq.) were added, and then the mixture was stirred at
room temperature for 1e12 days. The solvent was evaporated
under reduced pressure, and the resulting residue was purified by
(
Merck, 230e400) was employed. Nuclear magnetic resonance
silica gel column chromatography (CH
to afford the desired product. The product was further purified by
2
Cl
2
/MeOH ¼ 100/1 to 50/1)
1
13
spectra ( H NMR and C NMR) were recorded on Varian Mercury

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
527
reverse phase column chromatography (COSMOSIL 75C18-PREP,
CH CN/H
O ¼ 1/1 to 4/1) when necessary.
6.01 (1H, s), 6.22 (1H,s), 7.01 (1H, brs), 7.36 (1H, d, J ¼ 8.3 Hz),
7.45e7.48 (1H, m), 7.53e7.56 (1H, m), 7.77 (1H, d, J ¼ 8.3 Hz), 7.84
3
2
(
1H, d, J ¼ 7.8 Hz), 8.11 (1H, d, J ¼ 8.8 Hz), 10.63 (1H, s), 18.83 (1H, s).
1
3
4.1.2.1. (9aS)-8-acetyl-1,7-dihydroxy-3-methoxy-9a-methyl-N-(nap-
3
C NMR (CDCl , 500 MHz) d: 14.1, 25.3, 28.0, 32.0, 35.9, 37.2, 56.4,
hthalen-1-ylmethyl)-9-oxo-9,9a-dihydrodibenzo[b,d]furan-4-carbox-
amide (2). In accordance with the general procedure, compound 1
58.8, 96.4, 98.3, 102.4, 105.2, 106.3, 123.9, 125.1, 126.6, 128.4, 128.58,
128.62, 129.7, 132.4, 132.6, 139.8, 155.7, 157.4, 160.1, 162.3, 180.5,
þ
(
5.04 g, 14.6 mmol) and 1-naphthaldehyde (4.00 mL, 29.5 mmol)
191.9, 198.0, 201.6. MS (FAB) m/z: 528 (M þ H) . HRMS (FAB) m/z:
1
provided 5.46 g of compound 2 (77% yield) as a yellow solid. H
NMR (CDCl , 400 MHz) : 1.75 (3H, s), 2.64 (3H, s), 3.71 (3H, s), 5.06
7
528.2048 (calcd for C31H30NO : 528.2022).
3
d
(
6
1H, dd, J ¼ 14.7, 5.2 Hz), 5.12 (1H, dd, J ¼ 14.7, 5.2 Hz), 6.00 (1H, s),
4.1.2.5. (9aS)-8-acetyl-N-[(2-butylnaphthalen-1-yl)methyl]-1,7-dih-
ydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo[b,d]furan-
4-carboxamide (6). In accordance with the general procedure,
compound 1 (303 mg, 0.877 mmol) and aldehyde 19c (509 mg,
.27 (1H, s), 7.29 (1H, brs), 7.43e7.59 (4H, m), 7.83 (1H, d,
J ¼ 8.3 Hz), 7.90 (1H, d, J ¼ 8.3 Hz), 8.12 (1H, d, J ¼ 8.3 Hz), 10.66 (1H,
s), 18.82 (1H, s). 13C NMR (CDCl
, 500 MHz) : 28.0, 32.0, 41.9, 56.6,
8.8, 96.5, 98.2, 102.3, 105.2, 106.3, 123.6, 125.5, 125.9, 126.4, 126.6,
28.5,128.8,131.4,133.6, 133.9,155.7,157.4, 160.1,162.4,180.4, 191.9,
3
d
5
1
1
4
C
4
2.40 mmol) provided 391 mg of compound 6 (82% yield) as a yellow
1
solid. H NMR (CDCl
3
, 500 MHz)
d
: 0.95 (3H, t, J ¼ 7.3 Hz), 1.41e1.48
þ
98.0, 201.6. MS (FAB) m/z: 486 (M þ H) . HRMS (FAB) m/z:
86.1551 (calcd for 486.1553). Anal. Calcd for
: C, 69.27; H, 4.78; N, 2.89; O, 23.07. Found: C, 68.95; H,
.80; N, 2.91; O, 23.00.
(2H, m), 1.62e1.68 (2H, m), 1.75 (3H, s), 2.64 (3H, s), 2.92 (2H, td,
J ¼ 7.8, 2.8 Hz), 3.60 (3H, s), 5.06 (1H, dd, J ¼ 14.2, 4.4 Hz), 5.11 (1H,
dd, J ¼ 14.4, 4.6 Hz), 6.01 (1H, s), 6.22 (1H, s), 7.00 (1H, brs), 7.36 (1H,
d, J ¼ 8.8 Hz), 7.44e7.48 (1H, m), 7.52e7.56 (1H, m), 7.77 (1H, d,
J ¼ 8.3 Hz), 7.84 (1H, d, J ¼ 7.8 Hz), 8.11 (1H, d, J ¼ 8.8 Hz), 10.63 (1H,
28 7
C H24NO :
28 7
H23NO
13
4
.1.2.2. (9aS)-8-acetyl-1,7-dihydroxy-3-methoxy-9a-methyl-N-[(2-
3
s), 18.83 (1H, s). C NMR (CDCl , 500 MHz) d: 14.1, 22.8, 28.0, 32.0,
methylnaphthalen-1-yl)methyl]-9-oxo-9,9a-dihydrodibenzo[b,d]fu-
33.8, 34.4, 37.2, 56.5, 58.8, 96.4, 98.3,102.4,105.2,106.3,123.8, 125.1,
ran-4-carboxamide (3). In accordance with the general procedure,
126.6, 128.4, 128.6 (ꢃ2), 129.6, 132.4, 132.6, 140.1, 155.7, 157.4, 160.1,
þ
compound
1
(304 mg, 0.880 mmol) and 2-methyl-1-
162.3, 180.5, 191.9, 198.0, 201.6. MS (FAB) m/z: 542 (M þ H) . HRMS
naphthaldehyde (448 mg, 2.63 mmol) provided 379 mg of
7
(FAB) m/z: 542.2185 (calcd for C32H32NO : 542.2179). Anal. Calcd for
C H31NO : C, 70.97; H, 5.77; N, 2.59; O, 20.68. Found: C, 70.69; H,
32 7
5.62; N, 2.66; O, 20.62.
1
compound 3 (86% yield) as a yellow solid. H NMR (CDCl
00 MHz) : 1.74 (3H, s), 2.63 (3H, s), 2.64 (3H, s), 3.62 (3H, s), 5.05
1H, dd, J ¼ 14.4, 4.6 Hz), 5.12 (1H, dd, J ¼ 14.4, 4.6 Hz), 6.00 (1H, s),
.23 (1H, s), 7.02 (1H, brs), 7.35 (1H, d, J ¼ 8.3 Hz), 7.44e7.48 (1H,
m), 7.53e7.57 (1H, m), 7.75 (1H, d, J ¼ 8.8 Hz), 7.84 (1H, d,
3
,
5
d
(
6
4.1.2.6. (9aS)-8-acetyl-N-[(4-chloro-2-methylnaphthalen-1-yl)meth-
yl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo
[b,d]furan-4-carboxamide (7). In accordance with the general
procedure, compound 1 (250 mg, 0.724 mmol) and aldehyde 30
13
J ¼ 7.8 Hz), 8.12 (1H, d, J ¼ 8.3 Hz), 10.63 (1H, s), 18.82 (1H, s).
NMR (CDCl , 500 MHz) : 20.2, 28.0, 32.0, 37.4, 56.5, 58.8, 96.4,
8.2, 102.4, 105.2, 106.3, 123.5, 125.0, 126.6, 128.2, 128.6, 129.2,
30.3, 132.3, 132.6, 135.1, 155.6, 157.3, 160.0, 162.5, 180.4, 191.9,
C
3
d
9
(150 mg, 0.733 mmol) provided 298 mg of compound 7 (77% yield)
1
1
as a yellow solid. H NMR (CDCl
3
, 500 MHz)
d: 1.73 (3H, s), 2.61 (3H,
þ
1
98.0, 201.6. MS (FAB) m/z: 500 (M þ H) . HRMS (FAB) m/z:
00.1711 (calcd for 500.1709). Anal. Calcd for
: C, 69.73; H, 5.04; N, 2.80; O, 22.42. Found: C, 69.41; H,
.02; N, 2.98; O, 22.57.
s), 2.64 (3H, s), 3.62 (3H, s), 5.01 (1H, dd, J ¼ 14.6, 3.9 Hz), 5.08 (1H,
dd, J ¼ 14.4, 4.2 Hz), 6.00 (1H, s), 6.23 (1H, s), 7.07 (1H, brs), 7.48
(1H, s), 7.56e7.62 (2H, m), 8.13 (1H, d, J ¼ 8.3 Hz), 8.29 (1H, d,
5
C
5
29 7
C H26NO :
29 7
H25NO
1
3
J ¼ 8.3 Hz), 10.65 (1H, s), 18.82 (1H, s). C NMR (CDCl
3
, 500 MHz) d:
2
0.0, 28.0, 32.0, 37.2, 56.5, 58.8, 96.5, 98.3, 102.1, 105.2, 106.4, 123.9,
4
.1.2.3. (9aS)-8-acetyl-1,7-dihydroxy-3-methoxy-9a-methyl-N-[(2-
ethylnaphthalen-1-yl)methyl]-9-oxo-9,9a-dihydrodibenzo[b,d]furan-
-carboxamide (4). In accordance with the general procedure,
compound 1 (273 mg, 0.791 mmol) and aldehyde 19a (280 mg,
.52 mmol) provided 323 mg of compound 4 (80% yield) as a yellow
125.1, 126.1, 127.4, 129.2, 129.76, 129.81, 131.8, 133.4, 135.5, 155.8,
157.4, 160.0, 162.5, 180.3, 191.9, 198.0, 201.6. MS (ESI)
þ
4
m/z: 534 (M þ H) . HRMS (ESI) m/z: 534.12937 (calcd for
29 7
C H25ClNO : 534.13195).
1
1
solid. H NMR (CDCl
3H, s), 2.64 (3H, s), 2.96 (2H, q, J ¼ 7.6 Hz), 3.61 (3H, s), 5.06 (1H, dd,
J ¼ 14.4, 4.6 Hz), 5.12 (1H, dd, J ¼ 14.4, 4.6 Hz), 6.01 (1H, s), 6.22
3
, 500 MHz)
d
: 1.31 (3H, t, J ¼ 7.6 Hz), 1.74
4.1.2.7. (9aS)-8-acetyl-N-[(5-chloro-2-methylnaphthalen-1-yl)meth-
yl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo
[b,d]furan-4-carboxamide (8). In accordance with the general
procedure, compound 1 (210 mg, 0.608 mmol) and aldehyde 28a
(
(
1H, s), 7.03 (1H, brs), 7.38 (1H, d, J ¼ 8.8 Hz), 7.45e7.48 (1H, m),
7
8
5
.53e7.57 (1H, m), 7.79 (1H, d, J ¼ 8.3 Hz), 7.84 (1H, d, J ¼ 8.3 Hz),
(125 mg, 0.611 mmol) provided 259 mg of compound 8 (80% yield)
13
1
.11 (1H, d, J ¼ 8.8 Hz), 10.63 (1H, s), 18.83 (1H, s). C NMR (CDCl
00 MHz) : 16.5, 27.1, 28.0, 32.0, 37.1, 56.5, 58.8, 96.4, 98.3, 102.3,
05.2, 106.3, 123.7, 125.1, 126.6, 128.0, 128.60, 128.63, 129.4, 132.4,
3
,
as a yellow solid. H NMR (CDCl
3
, 500 MHz)
d: 1.74 (3H, s), 2.64 (3H,
d
s), 2.64 (3H, s), 3.62 (3H, s), 5.04 (1H, dd, J ¼ 14.4, 4.2 Hz), 5.11 (1H,
1
dd, J ¼ 14.2, 4.9 Hz), 6.01 (1H, s), 6.23 (1H, s), 7.06 (1H, brs),
132.6, 141.5, 155.7, 157.3, 160.1, 162.3, 180.5, 191.9, 198.0, 201.6. MS
7.43e7.48 (2H, m), 7.55 (1H, d, J ¼ 6.8 Hz), 8.06 (1H, d, J ¼ 8.3 Hz),
þ
13
(
C
FAB) m/z: 514 (M þ H) . HRMS (FAB) m/z: 514.1848 (calcd for
8.21 (1H, d, J ¼ 8.8 Hz), 10.65 (1H, s), 18.82 (1H, s). C NMR (CDCl
3
,
30
H
28NO
7
: 514.1866). Anal. Calcd for C30
7
H27NO : C, 70.16; H, 5.30;
500 MHz)
106.4, 122.7, 124.6, 125.4, 126.4, 129.9, 130.3, 130.8, 132.7, 133.6,
36.1, 155.8, 157.4, 160.0, 162.5, 180.4, 191.9, 198.0, 201.6. MS (ESI) m/
d: 20.2, 28.0, 32.0, 37.5, 56.5, 58.8, 96.5, 98.3, 102.1, 105.2,
N, 2.73; O, 21.81. Found: C, 70.04; H, 5.23; N, 2.82; O, 21.68.
1
þ
4.1.2.4. (9aS)-8-acetyl-1,7-dihydroxy-3-methoxy-9a-methyl-N-[(2-
z: 534 (M H) . HRMS (ESI) m/z: 534.12980 (calcd for
þ
propylnaphthalen-1-yl)methyl]-9-oxo-9,9a-dihydrodibenzo[b,d]fur-
an-4-carboxamide (5). In accordance with the general procedure,
compound 1 (304 mg, 0.880 mmol) and aldehyde 19b (523 mg,
C
29
H
25ClNO : 534.13195).
7
4.1.2.8. (9aS)-8-acetyl-N-[(6-chloro-2-methylnaphthalen-1-yl)meth-
yl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo
[b,d]furan-4-carboxamide (9). In accordance with the general
procedure, compound 1 (470 mg, 1.36 mmol) and aldehyde 23a
(283 mg,1.38 mmol) provided 445 mg of compound 9 (61% yield) as
2
.64 mmol) provided 415 mg of compound 5 (89% yield) as a yellow
1
solid. H NMR (CDCl
J ¼ 7.8 Hz),1.75 (3H, s), 2.64 (3H, s), 2.91 (2H, td, J ¼ 7.8, 2.8 Hz), 3.60
3H, s), 5.06 (1H, dd, J ¼ 14.4, 4.6 Hz), 5.12 (1H, dd, J ¼ 14.2, 4.4 Hz),
3
, 500 MHz)
d: 1.02 (3H, t, J ¼ 7.3 Hz),1.71 (2H, q,
(

528
A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
1
1
a yellow solid. H NMR (CDCl
3
, 400 MHz)
d: 1.74 (3H, s), 2.61 (3H, s),
as a yellow solid. H NMR (CDCl
3
, 400 MHz)
d: 1.74 (3H, s), 2.61 (3H,
2
.63 (3H, s), 3.63 (3H, s), 5.00 (1H, dd, J ¼ 14.5, 4.6 Hz), 5.08 (1H, dd,
s), 2.64 (3H, s), 3.63 (3H, s), 5.02 (1H, dd, J ¼ 14.3, 4.4 Hz), 5.10 (1H,
dd, J ¼ 14.5, 4.6 Hz), 6.01 (1H, s), 6.23 (1H, s), 7.04 (1H, brs),
7.29e7.34 (1H, m), 7.37 (1H, d, J ¼ 8.3 Hz), 7.44 (1H, d, J ¼ 9.1 Hz),
J ¼ 14.5, 5.0 Hz), 6.00 (1H, s), 6.22 (1H, s), 7.02 (1H, brs), 7.36 (1H, d,
J ¼ 8.7 Hz), 7.45 (1H, dd, J ¼ 9.1, 2.4 Hz), 7.64 (1H, d, J ¼ 8.7 Hz), 7.79
(
1H, d, J ¼ 2.4 Hz), 8.05 (1H, d, J ¼ 9.1 Hz), 10.63 (1H, s), 18.78 (1H, s).
7.68 (1H, d, J ¼ 8.3 Hz), 8.13 (1H, dd J ¼ 9.1, 5.2 Hz), 10.65 (1H, s),
1
3
13
C NMR (CDCl
3
, 500 MHz)
d
: 20.1, 28.0, 32.0, 37.3, 56.6, 58.8, 96.5,
18.82 (1H, s). C NMR (CDCl
3
, 500 MHz)
d: 20.0, 28.0, 32.0, 37.5,
9
8.3, 102.1, 105.2, 106.4, 125.4, 127.2, 127.31, 127.35, 130.4, 130.6
56.5, 58.8, 96.5, 98.3, 102.2, 105.2, 106.4, 111.5 (d, JCF ¼ 20 Hz), 116.6
(d, JCF ¼ 25 Hz), 126.1 (d, JCF ¼ 8 Hz), 127.5 (d, JCF ¼ 5 Hz), 129.3,
130.4, 130.7, 133.4 (d, JCF ¼ 8 Hz), 134.3, 155.8, 157.4, 160.0
(
2
ꢃ2), 130.8, 133.3, 135.5, 155.8, 157.4, 160.0, 162.5, 180.4, 191.9, 198.0,
þ
01.6. MS (ESI) m/z: 534 (M þ H) . HRMS (ESI) m/z: 534.13247
(
calcd for C29
7
H25ClNO : 534.13195).
(d, JCF ¼ 247 Hz),160.0,162.5,180.4,191.9,198.0, 201.6. MS (ESI) m/z:
þ
540 (M
þ
Na) . HRMS (ESI) m/z: 540.14208 (calcd for
4.1.2.9. (9aS)-8-acetyl-N-[(7-chloro-2-methylnaphthalen-1-yl)meth-
C
29
7
H24FNNaO : 540.14345).
yl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo
b,d]furan-4-carboxamide (10). In accordance with the general
procedure, compound 1 (450 mg, 1.30 mmol) and aldehyde 28b
330 mg, 1.61 mmol) provided 540 mg of compound 10 (78% yield)
[
4.1.2.13. (9aS)-8-acetyl-N-[(7-fluoro-2-methylnaphthalen-1-yl)met-
hyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodiben-
zo[b,d]furan-4-carboxamide (14). In accordance with the general
procedure, compound 1 (265 mg, 0.767 mmol) and aldehyde 28d
(
1
as a yellow solid. H NMR (CDCl
s), 3.68 (3H, s), 4.94e5.04 (2H, m), 5.99 (1H, s), 6.22 (1H, s), 7.04
1H, brs), 7.32 (1H, d, J ¼ 8.3 Hz), 7.38 (1H, d, J ¼ 8.7 Hz), 7.68 (1H, d,
J ¼ 8.3 Hz), 7.75 (1H, d, J ¼ 8.7 Hz), 8.05 (1H, s), 10.61 (1H, s), 18.77
1H, s). 13C NMR (CDCl
, 500 MHz) : 20.3, 28.0, 32.0, 37.5, 56.5,
8.8, 96.4, 98.3, 102.3, 105.2, 106.3, 122.5, 125.9, 128.0, 129.6, 129.7,
30.3, 130.8, 132.6, 133.1, 136.5, 155.7, 157.3, 160.1, 162.6, 180.4, 191.9,
3
, 400 MHz) d: 1.73 (3H, s), 2.63 (6H,
(147 mg, 0.781 mmol) provided 242 mg of compound 14 (61% yield)
1
(
as a yellow solid. H NMR (CDCl
3
, 400 MHz)
d: 1.74 (3H, s), 2.62 (3H,
s), 2.63 (3H, s), 3.67 (3H, s), 4.97 (1H, dd, J ¼ 14.1, 4.6 Hz), 5.03 (1H,
dd, J ¼ 14.3, 4.8 Hz), 6.00 (1H, s), 6.23 (1H, s), 6.97 (1H, brs), 7.21
(1H, dd, J ¼ 8.7, 2.4 Hz), 7.30 (1H, d, J ¼ 8.3 Hz), 7.69e7.72 (2H, m),
(
3
d
5
13
1
7.81 (1H, dd, J ¼ 8.7, 5.9 Hz), 10.61 (1H, s), 18.78 (1H, s). C NMR
þ
198.0, 201.6. MS (ESI) m/z: 534 (M þ H) . HRMS (ESI) m/z:
3
(CDCl , 500 MHz) d: 20.3, 28.0, 32.0, 37.7, 56.5, 58.8, 96.4, 98.3,
5
34.12981 (calcd for C29
7
H25ClNO : 534.13195).
102.3, 105.2, 106.3, 107.3 (d, JCF ¼ 22 Hz), 115.2 (d, JCF ¼ 25 Hz), 128.1,
1
28.5, 129.6, 129.8 (d, JCF ¼ 6 Hz), 131.0 (d, JCF ¼ 8 Hz), 133.4 (d,
4.1.2.10. (9aS)-8-acetyl-N-[(4-fluoro-2-methylnaphthalen-1-yl)met-
J
CF ¼ 8 Hz), 136.4, 155.7, 157.3, 160.0, 161.3 (d, JCF ¼ 246 Hz), 162.6,
þ
hyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodiben-
zo[b,d]furan-4-carboxamide (11). In accordance with the general
procedure, compound 1 (250 mg, 0.724 mmol) and aldehyde 32
180.4, 191.9, 198.0, 201.7. MS (ESI) m/z: 518 (M þ H) . HRMS (ESI) m/
7
z: 518.15792 (calcd for C29H25FNO : 518.16151).
(
137 mg, 0.728 mmol) provided 295 mg of compound 11 (79% yield)
4.1.2.14. (9aS)-8-acetyl-N-[(2-ethyl-4-fluoronaphthalen-1-yl)meth-
yl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodibenzo
[b,d]furan-4-carboxamide (15). In accordance with the general
procedure, compound 1 (700 mg, 2.03 mmol) and aldehyde 34
1
3
as a yellow solid. H NMR (CDCl , 400 MHz) d: 1.74 (3H, s), 2.61 (3H,
s), 2.64 (3H, s), 3.62 (3H, s), 4.99 (1H, dd, J ¼ 14.5, 4.6 Hz), 5.07 (1H,
dd, J ¼ 14.7, 4.8 Hz), 6.01 (1H, s), 6.23 (1H, s), 7.03e06 (2H, m), 7.52
(
1
1H, t, J ¼ 7.5 Hz), 7.60 (1H, t, J ¼ 7.5 Hz), 8.11 (2H, d, J ¼ 8.3 Hz),
(410 mg, 2.03 mmol) provided 782 mg of compound 15 (72% yield)
13
1
0.66 (1H, s), 18. 83 (1H, s). C NMR (CDCl
3
, 500 MHz)
d
: 20.2, 28.0,
as a yellow solid. H NMR (CDCl
3
, 400 MHz)
d
: 1.31 (3H, t, J ¼ 7.7 Hz),
3
2.0, 37.0, 56.5, 58.8, 96.4, 98.3, 102.2, 105.2, 106.3, 112.4 (d,
1.75 (3H, s), 2.64 (3H, s), 2.94 (2H, q, J ¼ 7.4 Hz), 3.61 (3H, s), 5.01
(1H, dd, J ¼ 14.5, 4.6 Hz), 5.07 (1H, dd, J ¼ 14.5, 4.6 Hz), 6.02 (1H, s),
6.23 (1H, s), 7.00 (1H, brs), 7.07 (1H, d, J ¼ 11.5 Hz), 7.51e7.55 (1H,
J
1
CF ¼ 19 Hz), 121.1 (d, JCF ¼ 5 Hz), 122.7 (d, JCF ¼ 6 Hz), 123.5, 125.3,
26.4 (d, JCF ¼ 4 Hz), 127.6, 133.6 (d, JCF ¼ 5 Hz), 135.7 (d, JCF ¼ 8 Hz),
1
2
55.7, 157.4, 158.2 (d, JCF ¼ 253 Hz), 160.0, 162.5, 180.4, 191.9, 198.0,
m), 7.58e7.63 (1H, m), 8.10e8.13 (2H, m),10.66 (1H, s),18.83 (1H, s).
þ
13
01.6. MS (ESI) m/z: 518 (M þ H) . HRMS (ESI) m/z: 518.16034 (calcd
3
C NMR (CDCl , 500 MHz) d: 16.2, 27.1, 28.0, 32.0, 36.7, 56.5, 58.8,
for C29
7
H25FNO : 518.16151).
96.4, 98.3, 102.2, 105.2, 106.4, 111.0 (d, JCF ¼ 19 Hz), 121.0 (d,
J
CF ¼ 5 Hz), 122.8 (d, JCF ¼ 17 Hz), 123.8 (d, JCF ¼ 2 Hz), 125.4, 125.5
4
.1.2.11. (9aS)-8-acetyl-N-[(5-fluoro-2-methylnaphthalen-1-yl)met-
(d, JCF ¼ 5 Hz), 127.5, 133.8 (d, JCF ¼ 4 Hz), 142.1 (d, JCF ¼ 7 Hz), 155.7,
157.4, 158.5 (d, JCF ¼ 252 Hz), 160.0, 162.4, 180.4, 191.9, 198.0, 201.6.
hyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodiben-
zo[b,d]furan-4-carboxamide (12). In accordance with the general
procedure, compound 1 (330 mg, 0.956 mmol) and aldehyde 28c
þ
MS (ESI) m/z: 532 (M þ H) . HRMS (ESI) m/z: 532.17768 (calcd for
30 7 7
C H27FNO : 532.17716). Anal. Calcd for C30H26FNO : C, 67.79; H,
(
181 mg, 0.962 mmol) provided 400 mg of compound 12 (81%
4.93; N, 2.64; F, 3.57. Found: C, 67.74; H, 4.92; N, 2.83; F, 3.68.
1
yield) as a yellow solid. H NMR (CDCl
.64 (6H, s), 3.63 (3H, s), 5.03 (1H, dd, J ¼ 14.3, 4.4 Hz), 5.11 (1H, dd,
J ¼ 14.3, 4.8 Hz), 6.02 (1H, s), 6.24 (1H, s), 7.06e7.15 (2H, m),
.41e7.49 (2H, m), 7.90 (1H, d, J ¼ 8.7 Hz), 8.03 (1H, d, J ¼ 8.7 Hz),
3
, 400 MHz) d: 1.74 (3H, s),
2
4.1.3. 1-Bromo-2-ethenylnaphthalene (17a)
To a suspension of sodium hydride (>55%, 970 mg, 22.2 mmol)
in THF (200 mL), methyltriphenylphosphonium bromide (7.66 g,
7
1
3
13
ꢁ
0.66 (1H, s), 18.83 (1H, s). C NMR (CDCl
3
, 500 MHz)
d: 20.3, 28.0,
21.4 mmol) was slowly added at 0 C. The mixture was stirred at
ꢁ
2.0, 37.5, 56.5, 58.8, 96.5, 98.3, 102.2, 105.2, 106.4, 108.6
0 C for 30 min, then compound 16 (2.01 g, 8.55 mmol) was added.
(
d, JCF ¼ 19 Hz), 119.3 (d, JCF ¼ 4 Hz), 120.6 (d, JCF ¼ 6 Hz), 122.8
The mixture was stirred at room temperature for 1.5 h. A saturated
(
d, JCF ¼ 17 Hz), 126.3 (d, JCF ¼ 10 Hz), 129.5, 130.4, 134.0 (d,
aqueous NH
layer was extracted with hexane. The combined organic layer was
washed with brine, and then dried over Na SO . The solvent was
4
Cl was added to the reaction mixture. The aqueous
JCF ¼ 4 Hz), 136.2, 155.7, 157.4, 159.2 (d, JCF ¼ 252 Hz), 160.0, 162.5,
þ
1
80.4, 191.9, 198.0, 201.6. MS (ESI) m/z: 518 (M þ H) . HRMS (ESI) m/
2
4
z: 518.15972 (calcd for C29
7
H25FNO : 518.16151).
removed under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane) to give
1
4.1.2.12. (9aS)-8-acetyl-N-[(6-fluoro-2-methylnaphthalen-1-yl)met-
1.18 g of compound 17a (59% yield) as a colorless oil. H NMR
hyl]-1,7-dihydroxy-3-methoxy-9a-methyl-9-oxo-9,9a-dihydrodiben-
zo[b,d]furan-4-carboxamide (13). In accordance with the general
procedure, compound 1 (420 mg, 1.22 mmol) and aldehyde 23b
(CDCl
3
, 500 MHz)
d
: 5.49 (1H, dd, J ¼ 10.7, 1.0 Hz), 5.83 (1H, dd,
J ¼ 17.1, 1.0 Hz), 7.39 (1H, dd, J ¼ 17.3, 11.0 Hz), 749e7.52 (1H, m),
7.57e7.60 (1H, m), 7.67 (1H, d, J ¼ 8.8 Hz), 7.76 (1H, d, J ¼ 8.3 Hz),
7.80 (1H, d, J ¼ 8.8 Hz), 8.35 (1H, d, J ¼ 8.8 Hz).
(
230 mg, 1.22 mmol) provided 495 mg of compound 13 (78% yield)

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
529
4
.1.4. 1-Bromo-2-(prop-1-en-1-yl)naphthalene (17b)
m), 7.84 (1H, d, J ¼ 7.8 Hz), 7.99 (1H, d, J ¼ 8.8 Hz), 9.00 (1H, d,
þ
Compound 17b was prepared in a similar manner to as
J ¼ 8.8 Hz), 10.93 (1H, s). MS (EI) m/z: 184 (M ).
1
described for 17a as a colorless oil (94% yield). H NMR (CDCl
3
,
4
1
00 MHz)
.6 Hz), 5.92e6.01 (0.5H, m), 6.29e6.38 (0.5H, m), 6.70 (0.5H, d,
J ¼ 11.3 Hz), 7.06 (0.5H, d, J ¼ 15.6 Hz), 7.41e7.62 (3H, m), 7.71e7.83
2H, m),8.33 (0.5H, d, J ¼ 8.2 Hz), 8.34 (0.5H, d, J ¼ 8.2 Hz).
d
: 1.81 (1.5H, dd, J ¼ 7.0, 1.5 Hz), 2.00 (1.5H, dd, J ¼ 6.6,
4.1.10. 2-Propylnaphthalene-1-carbaldehyde (19b)
Compound 19b was prepared in a similar manner to as
described for 19a as a colorless oil (94% yield). H NMR (CDCl
1
3
,
(
500 MHz)
d
: 1.03 (3H, t, J ¼ 7.3 Hz), 1.72e1.79 (2H, m), 3.10 (2H, t,
J ¼ 7.8 Hz), 7.36 (1H, d, J ¼ 8.8 Hz), 7.49e7.52 (1H, m), 7.60e7.64 (1H,
4.1.5. 1-Bromo-2-(but-1-en-1-yl)naphthalene (17c)
m), 7.83 (1H, d, J ¼ 8.3 Hz), 7.97 (1H, d, J ¼ 8.3 Hz), 9.02 (1H, d,
þ
Compound 17c was prepared in a similar manner to as described
J ¼ 8.8 Hz), 10.91 (1H, s). MS (EI) m/z: 198 (M ).
1
for 17a as a colorless oil (quant.). H NMR (CDCl
3
, 500 MHz)
d
: 1.05
(
2
1.5H, t, J ¼ 7.3 Hz), 1.17 (1.5H, t, J ¼ 7.3 Hz), 2.18e2.24 (1H, m),
4.1.11. 2-Butylnaphthalene-1-carbaldehyde (19c)
Compound 19c was prepared in a similar manner to as
described for 19a as a colorless oil (68% yield). H NMR (CDCl
.32e2.38 (1H, m), 5.84 (0.5H, dt, J ¼ 11.2, 7.3 Hz), 6.36 (0.5H, dt,
1
J ¼ 15.6, 6.3 Hz)., 6.64 (0.5H, d, J ¼ 11.2 Hz), 7.04 (0.5H, d,
3
,
J ¼ 16.1 Hz), 7.38e7.63 (3H, m), 7.71e7.82 (2H, m), 8.34e8.32
500 MHz)
d
: 0.96 (3H, t, J ¼ 7.3 Hz), 1.41e1.48 (2H, m), 1.67e1.73
(
1H, m).
(2H, m), 3.12 (2H, t, J ¼ 8.1 Hz), 7.36 (1H, d, J ¼ 8.3 Hz), 7.50 (1H,
t, J ¼ 7.6 Hz), 7.60e7.63 (1H, m), 7.83 (1H, d, J ¼ 7.8 Hz), 7.96 (1H, d,
J ¼ 8.8 Hz), 9.02 (1H, d, J ¼ 8.8 Hz), 10.91 (1H, s). MS (EI) m/z: 212
4
.1.6. 2-Ethenylnaphthalene-1-carbaldehyde (18a)
To a solution of compound 17a (1.17 g, 5.02 mmol) in THF
þ
(M ).
(
25 mL), n-butyllithium (2.44 mol/L in hexane, 2.50 mL, 6.10 mmol)
ꢁ
ꢁ
was added dropwise at ꢀ78 C. The mixture was stirred at ꢀ78 C
for 30 min. DMF (0.78 mL, 10.0 mmol) was slowly added, and the
mixture was stirred with warming to room temperature for 1 h. A
4.1.12. 2-Bromo-6-chloro-3,4-dihydronaphthalene-1-carbaldehyde
(21a)
To a solution of phosphorus tribromide (1.35 mL, 14.2 mmol) in
saturated aqueous NH
aqueous layer was extracted with EtOAc. The combined organic
layer was washed with brine, and then dried over MgSO . The
4
Cl was added to the reaction mixture. The
CHCl
3
(30 mL), DMF (1.30 mL, 16.7 mmol) was added dropwise at
ꢁ
ꢁ
0
C. The mixture was stirred at 0 C for 2 h. Then, a solution of
4
compound 20a (1.00 g, 5.54 mmol) in CHCl
the mixture at 0 C. The resulting mixture was stirred with heating
3
(10 mL) was added to
ꢁ
solvent was removed under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (hexane/
to reflux for 2 h. A saturated aqueous NaHCO
reaction mixture. The aqueous layer was extracted with CH
combined organic layer was washed with brine, and then dried
over MgSO . The solvent was removed under reduced pressure, and
the resulting light yellow oil (1.11 g) was directly used for the next
reaction.
3
was added to the
EtOAc ¼ 30/1 to 10/1) to give 475 mg of compound 18a (52% yield)
2
Cl . The
2
1
as a light yellow oil. H NMR (CDCl
3
, 400 MHz)
d: 5.69 (1H, d,
J ¼ 10.9 Hz), 5.74 (1H, d, J ¼ 17.2 Hz), 7.47 (1H, dd, J ¼ 17.2, 10.9 Hz),
4
7
.52e7.67 (3H, m), 7.86 (1H, d, J ¼ 8.2 Hz), 8.02 (1H, d, J ¼ 8.6 Hz),
8
.97 (1H, d, J ¼ 8.2 Hz), 10.86 (1H, s).
4.1.7. 2-(Prop-1-en-1-yl)naphthalene-1-carbaldehyde (18b)
4.1.13. 2-Bromo-6-chloronaphthalene-1-carbaldehyde (22a)
Compound 18b was prepared in a similar manner to as
To a solution of compound 21a (1.11 g) in toluene (30 mL), 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (2.80 g, 12.3 mmol) was
added. The mixture was stirred with heating to reflux for 3 days.
The reaction mixture was filtered through Celite, and the solvent
was evaporated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (hexane/
1
described for 18a as a light yellow oil (88% yield). H NMR (CDCl
3
,
4
1
00 MHz)
d
: 1.66 (1.5H, dd, J ¼ 6.8, 1.8 Hz), 2.02 (1.5H, dd, J ¼ 6.6,
.6 Hz), 6.10e6.22 (1H, m), 6.91 (0.5H, d, J ¼ 11.3 Hz), 7.10 (0. 5H, d,
J ¼ 15.6 Hz), 7.34 (0.5H, d, J ¼ 8.6 Hz), 7.49e7.67 (2.5H, m), 7.84 (1H,
t, J ¼ 9.8 Hz), 7.96 (0. 5H, d, J ¼ 8.6 Hz), 8.01 (0.5H, d, J ¼ 8.2 Hz), 9.00
(
(
0.5H, d, J ¼ 8.6 Hz), 9.24 (0.5H, d, J ¼ 8.6 Hz), 10.62 (0.5H, s), 10.77
toluene ¼ 10/1) to give 410 mg of compound 22a (27% yield, two
1
0.5H, s).
steps) as a white solid. H NMR (CDCl
3
, 400 MHz)
d: 7.58 (1H, dd,
J ¼ 9.2, 1.4 Hz), 7.69e7.80 (3H, m), 9.04 (1H, d, J ¼ 9.0 Hz), 10.69
4.1.8. 2-(But-1-en-1-yl)naphthalene-1-carbaldehyde (18c)
(1H, s).
Compound 18c was prepared in a similar manner to as described
1
for 18a as a light yellow oil (81% yield). H NMR (CDCl
0
2
3
, 500 MHz)
d:
4.1.14. 2-Bromo-6-fluoronaphthalene-1-carbaldehyde (22b)
Compound 22b was prepared in a similar manner to as
described for 22a as a white solid (34% yield, two steps). H NMR
.98 (1.5H, t, J ¼ 7.6 Hz), 1.17 (1.5H, t, J ¼ 7.3 Hz), 2.01e2.07 (1H, m),
1
.34e2.40 (1H, m), 6.02 (0.5H, dt, J ¼ 11.7, 7.3 Hz), 6.21 (0.5H, dt,
J ¼ 15.6, 6.3 Hz), 6.86 (0.5H, d, J ¼ 11.7 Hz), 7.08 (0.5H, d, J ¼ 15.6 Hz),
.33 (0.5H, d, J ¼ 8.3 Hz), 7.50e7.56 (1.5H, m), 7.60e7.67 (1H, m),
.83 (0.5H, d, J ¼ 8.3 Hz), 7.85 (0.5H, d, J ¼ 8.3 Hz), 7.96 (0.5H, d,
J ¼ 8.8 Hz), 8.01 (0.5H, d, J ¼ 8.8 Hz), 9.01 (0.5H, d, J ¼ 8.3 Hz), 9.24
0.5H, d, J ¼ 8.3 Hz), 10.66 (0.5H, s), 10.77 (0.5H, s).
(CDCl
3
, 400 MHz)
d
: 7.38e7.45 (2H, m), 7.70 (1H, d, J ¼ 9.0 Hz), 7.79
7
7
(1H, d, J ¼ 8.6 Hz), 9.12 (1H, dd, J ¼ 9.4, 5.5 Hz), 10.70 (1H, d,
J ¼ 1.2 Hz).
(
4.1.15. 6-Chloro-2-methylnaphthalene-1-carbaldehyde (23a)
To a solution of 22a (405 mg, 1.50 mmol) in toluene (15 mL),
4.1.9. 2-Ethylnaphthalene-1-carbaldehyde (19a)
4 3 4
Me Sn (0.625 mL, 4.51 mmol) and Pd(PPh ) (52 mg, 0.045 mmol)
To a solution of compound 18a (228 mg, 1.25 mmol) in EtOAc
12 mL), 10% palladium-carbon (58 mg) was added. The mixture
were added. The mixture was stirred with heating to reflux for 9 h.
The reaction mixture was filtered through Celite, and the solvent
was evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (hexane/
(
was stirred under a hydrogen (1 atm) atmosphere for 1 h.
Palladiumecarbon was separated by filtration. The solvent was
removed under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane/EtOAc ¼ 30/
toluene ¼ 10/1) to give 285 mg of compound 23a (93% yield) as
1
a light yellow solid. H NMR (CDCl
3
, 500 MHz)
d
: 2.80 (3H, s), 7.36
1
to 10/1) to give 222 mg of compound 19a (96% yield) as a colorless
(1H, d, J ¼ 8.3 Hz), 7.53 (1H, dd, J ¼ 9.3, 2.0 Hz), 7.78 (1H, s), 7.83 (1H,
1
oil. H NMR (CDCl
3
, 500 MHz)
d
: 1.37 (3H, t, J ¼ 7.6 Hz), 3.16 (2H, q,
d, J ¼ 8.3 Hz), 8.96 (1H, d, J ¼ 9.3 Hz), 10.89 (1H, s). MS (EI) m/z: 204
þ
J ¼ 7.6 Hz), 7.38 (1H, d, J ¼ 8.8 Hz), 7.50e7.53 (1H, m), 7.61e7.64 (1H,
(M ).

530
A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
4
.1.16. 6-Fluoro-2-methylnaphthalene-1-carbaldehyde (23b)
Compound 23b was prepared in a similar manner to as
described for 23a as a light yellow solid (95% yield). 1H NMR
CDCl , 500 MHz) : 2.80 (3H, s), 7.35e7.43 (3H, m), 7.86 (1H, d,
4.1.23. 7-Chloro-2-methylnaphthalene-1-carbaldehyde (28b)
Compound 28b was prepared in a similar manner to as
described for 28a as a yellow solid (33% yield, two steps) H NMR
1
(
3
d
(CDCl
3
, 400 MHz)
d
: 2.82 (3H, s), 7.34 (1H, d, J ¼ 8.6 Hz), 7.45 (1H,
J ¼ 8.3 Hz), 9.04 (1H, dd, J ¼ 9.3, 5.9 Hz), 10.90 (1H, s). MS (EI) m/
dd, J ¼ 8.6, 2.0 Hz), 7.75 (1H, d, J ¼ 8.6 Hz), 7.91 (1H, d, J ¼ 8.2 Hz),
þ
þ
z: 188 (M ).
9.10 (1H, d, J ¼ 2.3 Hz), 10.88 (1H, s). MS (EI) m/z: 204 (M ).
4
.1.24. 1-Bromo-5-fluoro-2-methylnaphthalene (27c)
To a solution of compound 26c (925 mg, 3.66 mmol) in CH Cl
2 2
4
.1.17. 1-Bromo-5-chloronaphthalene-2-carbaldehyde (26a)
Compound 26a was prepared in a similar manner to as
1
(40 mL), tris(pentafluorophenyl)borane (2.06 g, 4.02 mmol) and
triethylsilane (5.90 mL, 36.5 mmol) were added. The mixture was
stirred at room temperature for 4 days. The reaction solution
was evaporated under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane) to give
4
described for 22a as a white solid (15% yield, two steps). H NMR
(
CDCl
J ¼ 7.4 Hz), 8.01 (1H, d, J ¼ 8.6 Hz), 8.33 (1H, d, J ¼ 9.0 Hz), 8.46
1H, d, J ¼ 8.2 Hz), 10.64 (1H, s).
3
, 400 MHz)
d
: 7.58 (1H, dd, J ¼ 8.6, 7.4 Hz), 7.76 (1H, d,
(
1
28 mg of compound 27c (49% yield) as a colorless oil. H NMR
4
.1.18. 1-Bromo-7-chloronaphthalene-2-carbaldehyde (26b)
Compound 26b was prepared in a similar manner to as
(
(
(
CDCl
3
, 400 MHz)
d: 2.63 (3H, s), 7.12 (1H, dd, J ¼ 10.4, 7.6 Hz), 7.38
1H, d, J ¼ 8.6 Hz), 7.43e7.48 (1H, m), 7.96 (1H, d, J ¼ 8.2 Hz), 8.05
1H, d, J ¼ 8.6 Hz).
1
described for 22a as a white solid (30% yield, two steps). H NMR
(
CDCl
J ¼ 8.3 Hz), 7.85 (1H, d, J ¼ 8.3 Hz), 7.94 (1H, d, J ¼ 8.8 Hz), 8.51
1H, d, J ¼ 2.0 Hz), 10.65 (1H, s).
3
, 500 MHz)
d
: 7.63 (1H, dd, J ¼ 8.5, 2.2 Hz), 7.83 (1H, d,
4.1.25. 5-Fluoro-2-methylnaphthalene-1-carbaldehyde (28c)
(
To a solution of compound 27c (428 mg, 1.79 mmol) in THF
(
20 mL), n-butyllithium (2.71 mol/L in hexane, 1.00 mL, 2.71 mmol)
was added dropwise at ꢀ78 C. The mixture was stirred at ꢀ78 C for
0 min. DMF (0.70 mL, 9.04 mmol) was slowly added, and the
mixture was stirred with warming to room temperature for 1 h. A
saturated aqueous NH Cl was added to the reaction mixture. The
aqueous layer was extracted with EtOAc. The combined organic layer
was washed with brine, and then dried over MgSO . The solvent was
4
.1.19. 1-Bromo-5-fluoronaphthalene-2-carbaldehyde (26c)
Compound 26c was prepared in a similar manner to as
ꢁ
ꢁ
3
1
described for 22a as a white solid (19% yield, two steps). H NMR
(
(
(
CDCl
3
, 400 MHz)
d: 7.36 (1H, ddd, J ¼ 9.8, 7.8, 0.8 Hz), 7.58e7.64
4
1H, m), 7.96 (1H, d, J ¼ 8.6 Hz), 8.13 (1H, d, J ¼ 8.2 Hz), 8.29
1H, d, J ¼ 8.6 Hz), 10.63 (1H, d, J ¼ 0.8 Hz).
4
removed under reduced pressure, and the resulting residue was
4.1.20. 1-Bromo-7-fluoronaphthalene-2-carbaldehyde (26d)
purified by silica gel column chromatography (hexane/EtOAc ¼ 10/1
Compound 26d was prepared in a similar manner to as
to 5/1) to give 181 mg of compound 28c (54% yield) as a white solid.
1
1
described for 22a as a white solid (26% yield, two steps). H NMR
H NMR (CDCl
3
, 500 MHz)
d: 2.79 (3H, s), 7.14 (1H, dd, J ¼ 10.3, 7.8 Hz),
(
CDCl
3
, 400 MHz)
.16 (1H, dd, J ¼ 10.6, 2.3 Hz), 10.66 (1H, s).
d
: 7.46 (1H, td, J ¼ 8.5, 2.5 Hz), 7.86e7.92 (3H, m),
7.36 (1H, d, J ¼ 8.8 Hz), 7.49e7.53 (1H, m), 8.19 (1H, d, J ¼ 8.8 Hz), 8.70
þ
8
(1H, d, J ¼ 8.8 Hz), 10.90 (1H, s). MS (EI) m/z: 188 (M ).
4
.1.21. 1-Bromo-5-chloro-2-methylnaphthalene (27a)
To a solution of compound 26a (546 mg, 2.01 mmol) in dieth-
4
.1.26. 7-Fluoro-2-methylnaphthalene-1-carbaldehyde (28d)
Compound 28d was prepared in a similar manner to as
1
ylene glycol (20 mL), hydrazine monohydrate (0.28 mL, 5.14 mmol)
and KOH (340 mg, 6.06 mmol) were added. The mixture was stirred
at 180 C for 1.5 h. After the reaction solution was cooled to room
temperature, water was added. The aqueous layer was extracted
with Et
described for 28c as a yellow solid (21% yield, two steps) H NMR
(CDCl , 400 MHz)
3
d
: 2.83 (3H, s), 7.25 (1H, dd, J ¼ 11.0, 8.6 Hz), 7.28
ꢁ
(
1H, d, J ¼ 8.2 Hz), 7.79 (1H, dd, J ¼ 9.0, 5.9 Hz), 7.91 (1H, d,
J ¼ 8.2 Hz), 8.78 (1H, dd, J ¼ 12.1, 2.3 Hz), 10.85 (1H, s). MS (EI) m/z:
þ
2
O. The combined organic layer was washed with brine, and
. The solvent was removed under reduced
1
88 (M ).
then dried over MgSO
4
pressure, and the resulting residue was purified by silica gel column
4
.1.27. 4-Chloro-2-methylnaphthalene-1-carbaldehyde (30)
To a solution of compound 29 (460 mg, 2.60 mmol) and
chromatography (hexane) to give 340 mg of compound 27a (66%
1
yield) as a white solid. H NMR (CDCl
3
, 400 MHz)
d
: 2.63 (3H, s),
2 2
dichloromethyl methyl ether (0.29 mL, 3.20 mmol) in CH Cl
7
.42e7.46 (2H, m), 7.54 (1H, dd, J ¼ 7.4, 0.8 Hz), 8.14 (1H, d,
(30 mL), titanium tetrachloride (0.35 mL, 3.19 mmol) was added
dropwise at 0 C. The mixture was stirred at room temperature for
h. Water was added to the reaction mixture. The aqueous layer was
J ¼ 8.6 Hz), 8.23 (1H, d, J ¼ 8.6 Hz).
ꢁ
4
4.1.22. 5-Chloro-2-methylnaphthalene-1-carbaldehyde (28a)
extracted with Et O. The combined organic layer was washed with
brine, and then dried over MgSO . The solvent was removed under
reduced pressure, and the resulting residue was purified by silica gel
2
To a solution of compound 27a (340 mg, 1.33 mmol) in THF
4
(
20 mL), n-butyllithium (2.71 mol/L in hexane, 0.80 mL, 2.17 mmol)
ꢁ
ꢁ
was added dropwise at ꢀ78 C. The mixture was stirred at ꢀ78 C
for 30 min. DMF (0.42 mL, 5.40 mmol) was slowly added, and the
mixture was stirred with warming to room temperature for 1 h. A
column chromatography (hexane/EtOAc ¼ 10/1 to 5/1) to give
1
385 mg of compound 30 (72% yield) as a brown solid. H NMR (CDCl ,
3
400 MHz) d: 2.79 (3H, s), 7.47 (1H, s), 7.57e7.61 (1H, m), 7.64e7.68
(1H, m), 8.29 (1H, d, J ¼ 8.2 Hz), 8.96 (1H, d, J ¼ 8.6 Hz), 10.88 (1H, s).
saturated aqueous NH
aqueous layer was extracted with EtOAc. The combined organic
layer was washed with brine, and then dried over MgSO . The
4
Cl was added to the reaction mixture. The
4
4.1.28. 4-Fluoro-2-methylnaphthalene-1-carbaldehyde (32)
solvent was removed under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (hexane/
EtOAc ¼ 10/1 to 5/1) to give 126 mg of compound 28a (46% yield) as
0
To a solution of N,N,N -trimethylethylenediamine (0.78 mL,
6.00 mmol) in THF (40 mL), n-butyllithium (2.71 mol/L in hexane,
2
mixture was stirred for 15 min. Compound 31 (800 mg, 4.59 mmol)
ꢁ
.20 mL, 5.96 mmol) was added dropwise at ꢀ20 C and the
a light yellow oil. 1H NMR (CDCl
d
: 2.83 (3H, s),
3
, 400 MHz)
7
.44e7.52 (2H, m), 7.58 (1H, dd, J ¼ 7.4, 0.8 Hz), 8.42 (1H, d,
ꢁ
was added to the mixture at ꢀ20 C, and the mixture was stirred for
J ¼ 8.6 Hz), 8.87 (1H, d, J ¼ 9.0 Hz), 10.92 (1H, s). MS (EI) m/z: 204
30 min. After cooling to ꢀ78
ꢁ
C, n-butyllithium (2.71 mol/L in
þ
(
M ).
hexane, 5.10 mL, 13.8 mmol) was added dropwise, and the mixture

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
531
ꢁ
J ¼ 4.9 Hz), 13.32 (1H, s). 13C NMR (DMSO-d
was stirred with warming to 0 C for 6 h. Iodomethane (2.30 mL,
3
6
, 500 MHz)
d
: 15.7, 26.1,
ꢁ
6.9 mmol) was further added at 0 C, and the mixture was warmed
to room temperature and stirred for 20 h 1 N hydrochloric acid was
added to the reaction mixture. The aqueous layer was extracted
31.8, 32.5, 35.9, 54.4, 55.7, 94.2, 102.1, 102.7, 106.6, 110.1, 110.7,
(d, JCF ¼ 18 Hz), 119.8 (d, JCF ¼ 6 Hz), 121.6 (d, JCF ¼ 17 Hz), 124.8,
125.5, 126.6 (d, JCF ¼ 4 Hz), 127.1, 133.6 (d, JCF ¼ 4 Hz), 141.7 (d,
with Et
2
O. The combined organic layer was washed with brine, and
. The solvent was removed under reduced
JCF ¼ 7 Hz), 154.6, 155.2, 157.3 (d, JCF ¼ 250 Hz), 158.6, 162.4, 172.4,
then dried over MgSO
4
7
185.7, 191.3, 196.3. Anal. Calcd for C30H25FNKO : C, 63.26; H, 4.42; N,
pressure, and the resulting residue was purified by silica gel column
chromatography (hexane/EtOAc ¼ 10/1). Then, the resulting crude
2.46; F, 3.34; K, 6.86. Found: C, 63.27; H, 4.39; N, 2.55; F, 3.33; K, 7.14.
purified product was recrystallized from hexane to give 146 mg of
4.2. Full-length human PPAR
g reporter gene assay
1
compound 32 (17% yield) as white needles. H NMR (CDCl
3
,
4
00 MHz)
d
: 2.82 (3H, s), 7.02 (1H, d, J ¼ 10.6 Hz), 7.53e7.57 (1H, m),
MG-63 cells culture and preparation of plasmids were described
in a previous report [20].
7.64e7.69 (1H, m), 8.09 (1H, d, J ¼ 8.2 Hz), 9.04 (1H, d, J ¼ 8.6 Hz),
þ
10.85 (1H, s). MS (EI) m/z: 188 (M ).
Transiently transfected MG-63 cells were prepared using Lip-
ofectamineÔ (Invitrogen Corporation) reagent according to the
4
.1.29. 2-Bromo-4-fluoronaphthalene-1-carbaldehyde (33)
To a solution of N,N,N -trimethylethylenediamine (2.90 mL,
manufacturer’s protocol. The transfection mixture for each
0
2
5
0
00 cm -cell tray (Sumitomo Bakelite Co., Ltd.) containing
2
8
2.3 mmol) in THF (150 mL), n-butyllithium (2.67 mol/L in hexane,
.0504 mg of pSG5-hPPARg, 0.0504 mg of pGV-P2-PPRE, and Lip-
ꢁ
.40 mL, 22.4 mmol) was added dropwise at ꢀ30 C and the
ofectamine reagent at a ratio of 1.4 (ml of reagent/mg of DNA) was
exposed for 4 h in serum-, antibiotics-free medium. The cells were
trypsinized and replated onto 96-well plates at 40,000 cells/well.
After 24 h of incubation and the replacement of the medium,
various concentrations of the test compound were added to the
culture medium of the transfected cells for 20 h. A luciferase assay
was performed using a Picagene LT 2.0 Luminescence Reagent
mixture was stirred for 30 min. Compound 31 (3.00 g, 17.2 mmol)
ꢁ
ꢁ
was added to the mixture at ꢀ30 C, and the mixture was stirred for
3
0 min. After cooling to ꢀ78 C, n-butyllithium (2.67 mol/L in
hexane, 16.0 mL, 42.7 mmol) was added dropwise, and the mixture
was stirred with warming to 0 C for 3 h 1,2-Dibromo-1,1,2,2-
tetrafluoroethane (8.30 mL, 69.0 mol) was further added at 0 C,
and the mixture was warmed to room temperature and stirred for
ꢁ
ꢁ
(TOYO INK, Co., Ltd.). The luciferase activity was measured with
1
6 h 1 N hydrochloric acid was added to the reaction mixture. The
aqueous layer was extracted with Et O. The combined organic layer
was washed with brine, and then dried over MgSO . The solvent
a luminometer Analyst (Molecular Devices, Inc.).
2
The median effective concentration values (EC50) of partial
agonists were defined as follows: The transcriptional activity in the
presence of 3.3 nM in-house thiazolidinedione compound, 5-(4-
4
was removed under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane/
{
[6-(4-hydroxy-3,5-dimethylphenoxy)-1-methyl-1H-benzimida-
EtOAc ¼ 20/1 to 10/1) to give 2.35 g of compound 33 (54% yield) as
zol-2-yl]methoxy}benzyl)-1,3-thiazolidine-2,4-dione, was defined
as 100%, while that in the vehicle alone was defined as zero. The
maximum transcriptional activity of the test compound alone was
defined as the maximum efficacy (Emax, %). The concentration of the
test compound indicating a half value of Emax was defined as the
EC50 value in the transcriptional activity. Values of each parameter
were determined by nonlinear curve fitting using GraphPad Prism
1
a yellow solid. H NMR (CDCl
3
, 400 MHz)
d: 7.44 (1H, d, J ¼ 9.4 Hz),
7
9
.65 (1H, t, J ¼ 7.6 Hz), 7.72e7.76 (1H, m), 8.12 (1H, d, J ¼ 8.2 Hz),
.22 (1H, d, J ¼ 8.6 Hz), 10.70 (1H, s).
4.1.30. 2-Ethyl-4-fluoronaphthalene-1-carbaldehyde (34)
To a solution of compound 33 (38.0 g, 150 mmol) in DMF
(
500 mL), diethylmethoxyborane (30.0 mL, 228 mmol),
PdCl (dppf)･CH Cl (3.70 g, 4.53 mmol), and K CO (52.0 g,
76 mmol) were added. The mixture was stirred at 70 C for 2.5 h
N hydrochloric acid was added to the reaction mixture. The
aqueous layer was extracted with Et O. The combined organic layer
was washed with brine, and then dried over MgSO . The solvent
4.0 (GraphPad Software Inc.).
2
2
2
2
3
ꢁ
3
2
4.3. Evaluations of PPAR subtypes selectivity
2
4
GAL4-human PPAR
g
chimera receptor expression vector, pM-
as a fusion
was removed under reduced pressure, and the resulting residue
hPPAR , expressed the ligand-binding domain of PPARg
g
was purified by silica gel column chromatography (hexane/
protein with the DNA-binding domain of yeast transcription factor
GAL4. The pG5luc vector (included in CheckMate Mammalian Two-
Hybrid System, Promega Corporation), which contains five tandem
repeats of a GAL4-binding DNA sequence upstream of minimal
TATA to facilitate the detection of firefly luciferase activity induced
EtOAc ¼ 10/1) to give 27.4 g of compound 34 (90% yield) as a light
1
yellow solid. H NMR (CDCl
3
7
(
3
, 400 MHz)
d
: 1.38 (3H, t, J ¼ 7.6, Hz),
.16 (2H, q, J ¼ 7.6 Hz), 7.06 (1H, dd, J ¼ 10.9, Hz), 7.55e7.59 (1H, m),
.66e7.71 (1H, m), 8.12 (1H, d, J ¼ 8.2 Hz), 9.07e9.10 (1H, m), 10.83
þ
1H, s). MS (EI) m/z: 202 (M ).
by a GAL4-hPPARg fusion protein, was used as a GAL4-dependent
reporter vector. Dulbecco’s Modified Eagle Medium (DMEM, Invi-
trogen Corporation) containing 10% (v/v) heat-inactivated fetal
bovine serum (FBS, Invitrogen Corporation) was prepared as
4
1
.1.31. Potassium (9bS)-2-acetyl-6-{[(2-ethyl-4-fluoronaphthalen-
-yl)methyl]carbamoyl}-9-hydroxy-7-methoxy-9b-methyl-1-oxo-
1
,9b-dihydrodibenzo[b,d]furan-3-olate (35)
a culture medium. The COS7 cells were cultured in the culture
ꢁ
To
Cl
a
solution of compound 15 (8.17 g, 15.4 mmol) in
medium at 37 C with 5% CO
cultured to the confluent in 75 cm culture flasks. Cells were
transfected with 4.8 g of the pM-hPPAR and 19.2 g of pG5luc
2
(5% CO
2
, 95% air). The COS7 cells were
2
CH
2
2
eEtOH (1:1, 150 mL), 1 N aqueous potassium hydroxide
(
15.4 mL, 15.4 mmol) was added slowly. The mixture was stirred at
m
g
m
room temperature for 30 min. The solvent was removed under
reduced pressure, and the resulting residue was purified by
using Lipofectamine 2000 (Invitrogen Corporation) in Opti-MEM I
reduced serum medium (Opti-MEM I, Invitrogen Corporation)
according to the manufacturer’s instruction. After the transfection,
the COS7 cells were harvested and re-seeded in 96-well
recrystallization from EtOAc/toluene to afford 4.10 g of compound
1
3
5 (47% yield) as a light yellow solid. H NMR (DMSO-d
6
, 500 MHz)
d
: 1.26 (3H, t, J ¼ 7.6 Hz), 1.46 (3H, s), 2.17 (3H, s), 2.93 (2H, q,
J ¼ 7.6 Hz), 3.60 (3H, s), 4.81 (2H, d, J ¼ 4.9 Hz), 5.23 (1H, s), 6.07
1H, s), 7.26 (1H, d, J ¼ 12.2 Hz), 7.60 (1H, t, J ¼ 7.3 Hz), 7.67 (1H, t,
J ¼ 7.6 Hz), 8.03 (1H, d, J ¼ 8.3 Hz), 8.18 (1H, d, J ¼ 8.3 Hz), 8.38 (1H, t,
white plates and cultured for about 24 h in a CO
pM-PPAR and pM-PPAR expression vectors were used for the
GAL4-PPAR -LBD and GAL4-PPAR -LBD reporter gene assays,
respectively.
2
incubator. The
a
d
(
a
d

532
A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
The serial dilutions of the test compounds and the control solu-
tion (0.1% DMSO) were added into the individual wells in the 96-well
plates and the cells were further incubated for about 24 h in a CO
incubator. A luciferase assay was performed using a Picagene LT 2.0
Luminescence Reagent (TOYO INK, Co., Ltd.) according to the
manufacturer’s instruction. The light intensity in each well was
measured using a Multimode Microplate Reader (Analyst GT,
Molecular Devices, Inc.). Rosiglitazone, 2-(4-tert-Butylphenoxy)-3-
Laboratories Japan, Inc. and Institute of Animal Reproduction,
respectively. The rats were acclimatized for over 1 week and
provided with water and MR-DBT containing 10% lard (Nosan
Corporation) for ZDF rats and FR2 (Funabashi Farms Co., Ltd.) for
WistareImamichi rats ad libitum, respectively. All experimental
procedures were performed in accordance with the guideline of the
Institutional Animal Care and Use Committee of Daiichi Sankyo Co.,
Ltd.
2
[
[
4-[2-[(4-pyridin-2-ylbenzoyl)amino]ethoxy]phenyl]propionic acid
21], and GW501516 [22] (Enzo Life Sciences, Inc.) were used as
4.6.2. Pharmacological effects in type 2 diabetes model
positive references for the PPAR
g
, PPAR
a
, and PPAR
d
tests, respec-
Body weight (BW), plasma glucose (PG), insulin, hematocrit
(Hct), hemoglobin (Hb), the number of red blood cells (RBC) and
mean corpuscular volume (MCV) of ZDF rats were used for
randomization into treatment groups on Day-1. Rats (n ¼ 5 per
treatment group) were treated once daily by oral gavages with
vehicle (0.5% methylcellulose), compound 35 (0.01, 0.1, 1, 10,
100 mg/kg), or rosiglitazone (0.01, 0.1, 1, 10, 100 mg/kg) from Day
tively. The maximum transcriptional activity of the test compound
alone was defined as the maximum efficacy (Emax, %). The concen-
tration of the test compound indicating a half value of Emax was
defined as the EC50 value. Values of each parameter were deter-
mined by nonlinear curve fitting using GraphPad Prism 4.0
(
GraphPad Software Inc.).
.4. X-ray crystallography
Crystals of PPAR -LBD complexed with a peptide derived from
0
to Day 11 for a total of 12 days. Body weight was recorded daily.
4
Blood was collected from a tail vein into a heparinized capillary
tube on Day 12 and plasma samples were obtained after centrifu-
gation at 11000 rpm for 5 min (MC-150 [rotor: TH-1, TH-2 or TH-
11], Tomy Seiko Co., Ltd.).
PG (plasma glucose) (Glucoroder-GXT, Shino-Test Corporation),
TG (triglyceride) (TG E-test Wako, Wako Pure Chemical Industries,
Ltd.), Insulin (High range speedy Insulin ELISA, Morinaga Institute
of Biomedical Science Inc.) and, FFA (free fatty acid) (NEFA C-test
Wako, Wako Pure Chemical Industries, Ltd.) were determined
according to manufacturer’s protocol.
g
SRC-1(RHKILHRLLQEGSPS) and compound 15 were obtained using
hanging drop vapor diffusion at 22 C. The well solution contained
ꢁ
2
4% (w/v) PEG4000, 0.2 M sodium thiocyanate, and 0.1 M TriseHCl
(
pH 8.5). The crystal was transferred to the well solution containing
an additional 8% PEG400 as a cryoprotectant, and was flash frozen.
X-ray diffraction data were collected using in-house X-ray gener-
ator FR-E with detector R-AXIS VII (RIGAKU Corporation) and pro-
cessed with HKL2000 (HKL Research, Inc.) [23]. The structure of
PPARg-LBD derived from 3LMP.pdb was used as an initial model.
4.6.3. PPAR
g agonist-related adverse effects
Several rounds of manual rebuilding with O [24] followed by
refinement with CNX (Accerlys K.K.) [25] were carried out.
BW was used for randomization into treatment groups on Day-1.
Rats (n ¼ 5 per treatment group) were treated once daily by oral
gavages with vehicle (0.5% methylcellulose), compound 35
(100 mg/kg) or rosiglitazone (30,100, 300 mg/kg) from Day 0 to Day
4.5. Pharmacokinetics
13 for a total of 14 days. BW was recorded daily. On Day 14, after the
Male F344/DuCrlCrlj (Fischer) rats were purchased at 7 weeks
animals were retained in a holder, 0.05% Evans blue (EB) solution
prepared with physiological saline (OTSUKA NORMAL SALINE:
Otsuka Pharmaceutical Industries) was administered to unanes-
thetized rats via a tail vein at a volume of 0.1 mL/100 g body weight
using a syringe (1 mL: Terumo Corporation) and a wing-type needle
(27G or 25G, Terumo Corporation). Seven minute later, the animals
were anesthetized with ether. Blood was sampled from the
abdominal aorta using a wing-type needle (19G, Terumo Corpora-
tion) at 10 min after the EB administration. The heart was removed
and the weight was measured. The collected blood samples were
placed in separating agent-containing spitz tubes (Coagulation
Rapid Tube S: Shino-Test Corporation). The plasma samples were
obtained by centrifuging the blood with a heparin sodium injection
old from Charles River Laboratories Japan, Inc. For acclimation, they
were housed in stainless steel cages for 7e11 days in the controlled
animal area. The rats were allowed free access to FR2 laboratory
food (Funabashi Farm Co., Ltd.) and tap water.
ꢁ
NIKKOL HCO-60 (Nikko Chemicals Co., Ltd.) was melted at 60 C
and mixed well in saline to make a 20% (v/v) HCO-60 solution. A 5%
v/v) HCO-60 solution was prepared to dilute a 20% (v/v) HCO-60
solution with saline. Compound 35 was dissolved in a 20% (v/v)
HCO-60 solution for oral administration and a 5% (v/v) HCO-60
solution for intravenous administration. For the administration,
(
2
mL/kg of the solution at a concentration of 5 mg/mL was used. The
solutions of compound 35 were administered to male Fischer rats,
after overnight fasting. A blood sample of approximately 0.2 mL
was collected from the jugular vein with a heparinized syringe. The
ꢁ
solution at 3000 rpm at 4 C for 10 min with a refrigerated
centrifuge (CF7D2: [rotar T3S6-A006] Hitachi Koki Co., Ltd.). To
deproteinize, the obtained plasma samples were mixed and stirred
with 100% (w/v) trichloroacetic acid solution (1:1), and stood at
room temperature for 10 min or more. Furthermore, to release the
EB bound with plasma proteins, the samples were sonicated
(OUTPUT 2, DUTY CONT., TIME 2 min) on ice using a sonicator
(UD-201: Tomy Seiko Co., Ltd.). Then, the samples were centrifuged
ꢁ
blood was centrifuged at 14,000 rpm for 3 min at 4 C (himac
CR15D, Hitachi Koki Co., Ltd. rotor: RT15A2) to obtain the plasma.
ꢁ
The plasma was stored frozen at ꢀ20 C until use for measurement
of plasma concentration. The determination of the plasma
concentration of compound 15 was performed by LC-MS/MS
method using API 4000QTRAP (Applied Biosystems/MDS SCIEX).
PK parameters were calculated using a non-compartmental model
by the computer software WinNonlin Professional version 4.0.1.
ꢁ
at 3000 rpm at 4 C for 10 min using the refrigerated centrifuge. The
supernatant was used for the measurement. The absorbance
(620 nm) of the obtained supernatant was measured using a spec-
trophotometer (DU7500: Beckman-Coulter Co., Ltd.). The circu-
lating plasma volume (P.V.) was calculated from the following
calibration curve: Concentrations of quality control (QC) samples:
0, 0.0001, 0.0002, 0.0004 and 0.0008% (w/v) EB solution (dissolved
in saline) mixed and stirred with 100% (w/v) trichloroacetic acid
solution (1:1).
(
Pharsight Corporation).
4
4
.6. In vivo pharmacology
.6.1. Animals
Five-week-old female ZDF rats and 7-week-old female
WistareImamichi rats were obtained from Charles River

A. Furukawa et al. / European Journal of Medicinal Chemistry 54 (2012) 522e533
533
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Z. Fang, H. Fuentes, M. Lindstrom, J. Liu, D.H.T. Biermann, J. Jaen, N.P.C. Walker,
Equation of calibration curve : Y ¼ aX þ b
R.M. Learned, J.-L. Chen, Y. Li, INT131: a selective modulator of PPARg, J. Mol.
where Y: absorbance at 620 nm, a: slope, b: Y intercept, X:
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12] J.J. Acton III, T.E. Akiyama, C.H. Chang, L. Colwell, S. Debenham, T. Doebber,
M. Einstein, K. Liu, M.E. McCann, D.E. Moller, E.S. Muise, Y. Tan, J.R. Thompson,
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Acknowledgments
We thank Mr. Takashi Suzuki and his co-workers at Onahama
Plant, Daiichi Sankyo Propharma Co. Ltd., for providing the purified
1H-indol-1-yl}phenoxy)butanoic acid (MK-0533): a novel selective peroxi-
some proliferator-activated receptor modulator for the treatment of type 2
g
(ꢀ)-Cercosporamide.
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Supplementary data
[13] W. Liu, F. Lau, K. Liu, H.B. Wood, G. Zhou, Y. Chen, Y. Li, T.E. Akiyama,
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C.H. Chang, L. McNamara, B. McKeever, R.T. Mosley, J.P. Berger, P.T. Meinke,
Benzimidazolones: a new class of selective peroxisome proliferator-activated
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.ejmech.2012.05.
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[
0
40. These data include MOL files and InChiKeys of the most
g
important compounds described in this article.
(
2
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