6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives: a novel class of endothelin receptor antagonists.

Article abstract of DOI:10.1016/S0968-0896(02)00122-0

Compounds (2-5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity with an IC(50) value of 2.4 nM against (125)I-labeled ET-1 binding to human ET(A) receptors and a 170-fold selectivity for ET(A) over ET(B) receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxyphenyl group led to the identification of a more potent ET(A) selective antagonist 2p with an IC(50) value of 0.87 nM for ET(A) receptors and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD(50): 0.04 mg/kg) in the lethality model.

Full text of DOI:10.1016/S0968-0896(02)00122-0

Bioorganic& Medicinal Chemistry 10 (2002) 2461–2470
6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine Derivatives:
A Novel Class of Endothelin Receptor Antagonists
Kenji Niiyama,* Toshiaki Mase, Hirobumi Takahashi, Akira Naya, Kasumi Katsuki,
Toshio Nagase, Satoshi Ito, Takashi Hayama, Akihiro Hisaka, Satoshi Ozaki,
Masaki Ihara, Mitsuo Yano, Takahiro Fukuroda, Kazuhito Noguchi, Masaru Nishikibe
and Kiyofumi Ishikawa
Tsukuba Research Institute, Banyu Pharmaceutical Co. Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan
Received 7 February 2002; accepted 4 April 2002
Abstract—Compounds (2–5) with a 6-carboxy-5,7-diarylcyclopentenopyridine skeleton were designed, synthesized, and identified as
a new class of potent non-peptide endothelin receptor antagonists. The regio-isomer 2 was found to show potent inhibitory activity
with an IC50 value of 2.4 nM against 125I-labeled ET-1 binding to human ETA receptors and a 170-fold selectivity for ETA over ETB
receptors. Furthermore, 2 displayed more potent in vivo activity than did the indan-type compound 1 in a mouse ET-1 induced
lethality model, suggesting the potential of 2 as a new lead structure. Derivatization on substituted phenyl groups at the 5- and 7-
positions of 2 revealed that a 3,4-methylenedioxyphenyl group at the 5-position and a 4-methoxyphenyl group at the 7-position
were optimal for binding affinity. Further derivatization of 2 by incorporating a substituent into the 2-position of the 4-methoxy-
phenyl group led to the identification of a more potent ETA selective antagonist 2p with an IC50 value of 0.87 nM for ETA receptors
and a 470-fold selectivity. In addition, 2p showed highly potent in vivo efficacy (AD50: 0.04 mg/kg) in the lethality model. # 2002
Elsevier Science Ltd. All rights reserved.
Introduction
antagonists are expected to have clinical potential in the
endothelin-mediated disorders mentioned above.3
Endothelin-1 (ET-1),1 and its closely related isopeptides
(ET-2, ET-3) were identified as potent vasoconstrictor
peptides consisting of 21 amino acids. The endothelins
exert their diverse biological actions through distinct
cell surface G-protein coupled receptors (GPCR)
termed ETA and ETB.2 The ET-1 selective ETA recep-
tors are primarily found on vascular smooth muscle and
mediate vasoconstriction and vascular smooth muscle
proliferation. The non-selective ETB receptors are pri-
marily found in vascular endothelium and can mediate
either vasodilation or vasoconstriction. The diversity of
physiological effects elicited by the endothelins has been
implicated in the pathogenesis of a variety of disease
states such as renal failure, cerebral vasospasm, pul-
monary hypertension, and congestive heart failure. Ele-
vated levels of endothelins have been observed in many
of these disease states. Therefore, endothelin receptor
We initiated exploration of peptide endothelin antago-
nists immediately after the discovery of the endothelins
and identified ETA selective BQ-1234 and ETB selective
BQ-788,5 which have greatly contributed to elucidation
of the physiological roles of endothelin receptors. In
addition, we simultaneously looked for a novel non-
peptide pharmacophore to develop as an orally active
endothelin receptor antagonist.
There are a number of non-peptide endothelin antago-
nists including ETA selective,6 ETB selective,7 and ETA/
ETB mixed agents8 known to date. The common feature
of these antagonists is an acidic functional group such
as carboxylic acid or sulfonamide positioned between
two aromaticrings. Among them, we had an interest in
the highly rigid structure of 1 (Fig. 1) with nano-molar
binding affinity for ETA receptors.8b We speculated that
incorporation of a nitrogen atom into the indan skele-
ton of 1 would change the physicochemical properties,
in particular its hydrophilicity, leading to a new phar-
macophore with a different biological profile from 1.
*Corresponding author. Tel.: +81-298-77-2220; fax: +81-298-77-
2027; e-mail: niiymakj@banyu.co.jp
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00122-0

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K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
obtained in a similar manner by using the 3,4-methyle-
nedioxyphenyl Grignard reagent in place of 4-methox-
yphenyl Grignard reagent in the initial step of the
synthesis of 4.
For the synthesis of derivatives that have a 2-substituted
phenyl group at the 7-positon of 2, an intermediate 18
was prepared as the starting material from 6 in an ana-
logous fashion to the synthesis of 2. Transformation of
18 to substituted derivatives was achieved in a similar
manner to the reported procedure.11 2-O-Alkoxy-4-
methoxyphenyl derivatives (2k–2n) were obtained by
alkylation of 18 with a alkyl bromide followed by
hydrolysis (Scheme 3). Trifluoromethanesulfonylation
of 18 followed by a Heck reaction gave an intermediate
21, which was hydrolyzed to afford the cinnamic acid
analogue 2o. Hydrogenation of 21 followed by hydro-
lysis gave the propionicacid analogue 2p.
Figure 1.
Based on this speculation, we designed and synthesized
four regio-isomers of cyclopentenopyridines (2–5) as
racemates, and compared their biological properties
with that of 1.
In this paper, we describe the synthesis of cyclopente-
nopyridines and their in vitro binding affinity for ETA
and ETB receptors. We also describe the structure–
activity relationships of some derivatives of the selected
pharmacophore 2 to optimize the substituents on the
cyclopentenopyridine skeleton. In addition, we refer to
the identification of a highly potent ETA selective
antagonist through further modification.
Results and Discussion
The synthesized compounds were evaluated in binding
assays (inhibitory activity against 125I-labeled ET-1
binding to both human ETA and ETB receptors).12
Selected compounds were further assessed in isolated
13
tissue assays using rabbit iliacarteries
and in an in
vivo assay using a mouse lethality model.13 A rat in situ
intestinal absorption study was also conducted to esti-
mate the oral absorption of the compounds.
Chemistry
The synthetic procedure of 6-carboxy-7-(4-methoxy-
phenyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-
b]pyridine 2 is summarized in Scheme 1. Pyridine-2,3-
dicarboxylic anhydride 6 was reacted with a 4-
methoxyphenyl Grignard reagent to provide a mixture
of regioisomers 7 and 8 (7:8=1:1) in 65% yield,9,10
which was separated by chromatography to give 8 in
33% yield. Transformation of 8 to an enone 9 was
achieved by the following reaction steps: (1) SOCl2, (2)
EtOMgCH(CO2Et)2, and (3) 5% Na2CO3,11 though the
yield was not reproducible (15–63%). The enone 9 was
converted to a tertiary alcohol 10 in 91% yield by
treatment with a 3,4-methylenedioxyphenyl Grignard
reagent. Conversion of 10 to the desired cis–cis isomer
12 was accomplished in 47% yield by catalytic hydro-
genation in the presence of sulfuric acid, while 11 was
obtained in 33% yield as a major by-product. Epimer-
ization and hydrolysis of the ester moiety was simulta-
neously achieved by treatment with NaOH in MeOH to
give 2 in 93% yield. The regio-isomer 5 was obtained in
a similar manner by using the 3,4-methylenedioxy-
phenyl Grignard reagent in place of 4-methoxyphenyl
Grignard reagent in the initial step of the synthesis of 2.
At first, the binding affinities of the cyclopentenopyri-
dine analogues (2–5) were compared with that of the
indan-type compound 1 (Table 1). It is interesting to
note that large differences in the binding affinities were
observed among these four regio-isomers (2–5). The
isomer 2 was most potent and had an IC50 value of 2.4
nM for ETA receptors, which is comparable to that of 1.
The rank order of the binding affinities of the isomers
for ETA receptors was as follows: 2>3>4> >5. The
least potent isomer 5 showed a 200-fold decreased affi-
nity (IC50: 460 nM) compared with 2. On the other
hand, 2 showed a 7-fold reduction in the ETB binding
affinity compared with 1. Thus, the selectivity of 2 for
ETA over ETB receptors was 10-fold greater than that of
1. These results not only indicated that the replacement
of a benzene ring with a pyridine ring was tolerated but
also implied the interaction of the nitrogen atom in the
molecule with the both receptors. Since 2 would have
another interaction site, analogues of 2 were expected to
have different binding profiles from the analogues of 1,
which has no site to interact with the receptors on the
indan ring.
In the mouse lethality model, 2 was effective (AD50: 6
mg/kg iv), while 1 was not effective even at 10 mg/kg in
spite of having comparable binding affinities. From
physicochemical analysis, it was revealed that logP
values of the two compounds were largely different (1:
2.1, 2: 0.12). Judging from a much lower logP value of
2, improvement in the in vivo efficacy was considered to
be due to the increased hydrophilic character of 2. These
results suggested that cyclopentenopyridine analogues
Synthesis of 6-carboxy-5-(4-methoxyphenyl)-7-(3,4-
methylenedioxyphenyl)cyclopenteno[1,2-c]pyridine 4 was
initiated from the addition reaction of 4-methoxyphenyl
Grignard reagent to pyridine-3,4-dicarboxylic anhy-
dride 13 (Scheme 2). This reaction proceeded regiose-
lectively to yield 14 in 65% yield.10 Transformation of
14 to 4 was achieved in a manner similar to that descri-
bed for the preparation of 2. The regio-isomer 3 was

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
2463
Scheme 1. Synthesis of a cyclopenteno[1,2-b]pyridine derivative 2. Reagents: (a) 4-methoxyphenylmagnesium bromide, THF, ꢁ78 ꢀC; (b) (1) SOCl2,
reflux; (2) EtOMgCH(CO2Et)2, rt; (3) 5% aq Na2CO3, reflux; (c) 3,4-(methylenedioxy)phenylmagnesium bromide, THF, ꢁ78 ꢀC; (d) H2, Pd/C,
H2SO4, EtOH, rt; (e) NaOH, MeOH, rt.
Scheme 2. Synthesis of a cyclopenteno[1,2-c]pyridine derivative 4. Reagents: (a) 4-methoxyphenylmagnesium bromide, THF, ꢁ78 ꢀC; (b) (1) SOCl2,
reflux; (2) EtOMgCH(CO2Et)2, rt; (3) 5% aq Na2CO3, reflux; (c) 3,4-(methylenedioxy)phenylmagnesium bromide, THF, ꢁ78 ꢀC; (d) H2, Pd/C,
H2SO4, EtOH, rt; (e) NaOH, MeOH, rt.
Scheme 3. Synthesis of 2-substituted 4-methoxyphenylderivatives 2n, 2o and 2p. Reagents: (a) NaH, BrCH2CO2Et, THF; (b) 4 N NaOH, MeOH, rt;
(c) Tf2O, DMAP, CH2Cl2; (d) methyl acrylate, PdCl2(PPh3)2, NaHCO3, 120 ꢀC; (e) H2, Pd/C, MeOH.

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K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
had different biological as well as physicochemical
properties from indan analogues than were expected.
Therefore, the cyclopenteno[1,2-b]pyridine analogue 2
was selected as a novel pharmacophore for a non-pep-
tide antagonist, and further derivatization of this struc-
ture was performed.
logues (2a–2i) and evaluated them in the binding assay
(Table 2). Replacement of the 3,4-methylenedioxy-
phenyl group at the 5-position with a phenyl group (2a)
resulted in substantial loss of potency for both ETA and
ETB receptors. Introduction of a methoxy group into
the 2-, 3-, and 4-position of the phenyl group [(2b), (2c),
(2d), respectively] resulted in partial recovery of the
binding affinity for ETA receptors. Although 2c was the
most potent analogue of the three, its ETA binding affi-
nity was approximately 10-fold less than that of 2. From
the results, we assumed that an electron-donating group
at the 3-position was necessary for retaining the potent
ETA binding affinity. Based on this assumption, an
indole moiety was introduced in place of the methyl-
enedioxyphenyl group, however, the resulting analogues
(2e and 2f) showed unexpectedly low binding affinity
(2e: IC50 >1100 nM, 2f: IC50=3500 nM) for ETA
receptors. With respect to a substituent on the phenyl
group at the 7-position, it is evident that a 4-methoxy
group in 2 makes a significant contribution to the high
binding affinity for ETA receptors compared to the affi-
nity of unsubstituted (2g), 4-fluoro (2h), and 4-hydroxy
(2i) analogues. These derivatives indicated, based upon
the limited SAR performed, that a 3,4-methylenedioxy-
phenyl group at the 5-position and a 4-methoxyphenyl
group at the 7-position of the cyclopenteno[1,2-b]pyri-
dine were optimal.
In order to optimize the substituents on the phenyl
groups at the 5- and 7-positions of 2, we prepared ana-
Table 1. In vitro potency of indan and cyclopentenopyridine derivatives
Compound
IC50, nM (n)
Selectivity
ETB/ETA
ETA
ETB
1
2
3
4
5
3.3ꢂ0.2 (2)
2.4ꢂ0.5 (1)
6.8ꢂ0.3 (2)
30 (1)
56ꢂ6 (3)
17
170
40
From the report of indan-type compounds,8b we expec-
ted that introduction of a substituent into the 2-position
of the 4-methoxyphenyl group would lead to identifica-
tion of a compound that had different biological prop-
erties without losing in vitro potency. Therefore, we
performed derivatization of 2 based on this strategy,
and characterized their biological properties (Table 3).
Introduction of a hydroxyl group (2j) resulted in moder-
ate binding affinity (IC50: 5.3 nM) for ETA receptors. The
ETA receptor affinity of the 2-(2-hydroxyethoxy) analo-
gue 2k was comparable to that of 2. Replacement of the
hydroxylethyl moiety of 2k with a carbamoylmethyl (2m)
410ꢂ110 (3)
270ꢂ37 (2)
690 (1)
23
460ꢂ15 (2)
83000 (1)
180
Table 2. In vitro potency of cyclopenteno[1,2-b]pyridine derivatives
Compound
R1
R2
IC50, nM (n)
Selectivity
ETB/ETA
ETA
ETB
2
3,4-Metylenedioxyphenyl
Phenyl
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
2.4ꢂ0.5 (11)
1500 (1)
310 (1)
42 (1)
270 (1)
1100 (1)
3500 (1)
19 (1)
410ꢂ110 (3)
>100000 (1)
300000 (1)
7000 (1)
170
>67
97
170
16
—
8
130
69
110
2a
2b
2c
2d
2e
2f
2g
2h
2i
2-Methoxyphenyl
3-Methoxyphenyl
4-Methoxyphenyl
Indol-4-yl
4400 (1)
>100000 (1)
28000 (1)
2400 (1)
2700 (1)
11000 (1)
Indol-6-yl
3,4-Methylenedioxyphenyl
3,4-Methylenedioxyphenyl
3,4-Methylenedioxyphentl
F
OH
39 (1)
96 (1)

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
Table 3. Biological properties of cyclopenteno[1,2-b]pyridine derivatives
2465
a
b
Compound
R
IC50, nM (n)
Selectivity
ETB/ETA
AD50 (mg/kg, iv)
pA2
8.0
Absorptionc (%)
ETA
ETB
2
2j
H
OH
2.4ꢂ0.5 (11)
5.3ꢂ1.6 (3)
2.5ꢂ0.3 (3)
28 (1)
410ꢂ110 (3)
680ꢂ77 (2)
540ꢂ32 (3)
6600 (1)
170
130
220
240
330
170
250
470
6
100
47
2k
2l
2m
2n
2o
2p
OCH2CH2OH
OCH2CH2NHMe
OCH2CONH2
OCH2CO2H
CH¼CHCO2H
CH2CH2CO2H
>3
2.0 (1)
660 (1)
>3
0.2
2
17
12
16
7
1.2ꢂ0.02 (3)
1.9ꢂ0.4 (2)
0.87ꢂ0.35 (2)
200ꢂ24 (3)
470ꢂ160 (2)
410ꢂ84 (2)
8.2
8.8
0.04
aET-1 induced mouse lethality.
bIsolated rabbit iliacartery.
cIn situ rat intestinal loop.
Conclusion
or a carboxymethyl group (2n) resulted in maintenance
of the ETA binding affinity, while replacement with a
basic( N-methyamino)ethyl (2l) group reduced the affi-
nity. It is worthy of note that the carboxymethoxy ana-
logue 2n showed much improved in vivo efficacy (AD50:
0.2 mg/kg) in the mouse lethality model as compared
with 2, although the intrinsicantagonisticactivity of 2n
was comparable to 2. Taken together, we assumed that
incorporating an additional carboxylic moiety to the 4-
methoxyphenyl group contributed to improvement in in
vivo efficacy. Based on the structure of 2n, we also
designed and synthesized carbon linked analogues (2o
and 2p). The cinnamic acid analogue 2o showed potent
binding affinity comparable to 2n, but was 10-fold less
active in the lethality model. In contrast, the propionic
acid analogue 2p showed the highest in vitro potency
(IC50: 0.87 nM) for the ETA receptors in this class of
compounds and a 470-fold selectivity for the ETA over
the ETB receptors. In addition, 2p displayed 5-fold
higher in vivo efficacy (AD50: 0.04 mg/kg) than did 2n in
the mouse model. 2p also showed greater antagonistic
activity than 2n in the rabbit isolated tissue assay (pA2:
2p=8.8, 2n=8.2). These results suggested that 2p had
great potential for a highly potent non-peptide endo-
thelin receptor antagonist. However, the rat in situ
intestinal absorption study indicated that the dicar-
boxylicacid analogues ( 2n and 2p) showed low absorp-
tion (2n: 12%, 2p: 7%), while the monocarboxylic acid 2
showed good absorption (100%). We considered that
the poor absorption was caused from highly hydrophilic
character of these compounds. Therefore, further deri-
vatization of this class to identify an orally active
antagonist is focused on increasing the hydrophobicity
of the dicarboxylic acid analogues.
In summary, we have discovered 6-carboxy-7-(4-meth-
oxyphenyl)-5-(3,4-methylenedioxypheny)cyclopenteno
[1,2-b]pyridine 2 with an IC50 value of 2.4 nM for ETA
receptors as a novel pharmacophore of a non-peptide
endothelin antagonist. This compound 2 showed highly
potent antagonisticactivity (p A2: 8.0) in the rabbit iso-
lated tissue assay. In addition, 2 had higher in vivo effi-
cacy in the mouse lethality model than that of the
indan-type compound 1. Derivatization of 2 by intro-
ducing a substituent into the 4-methoxyphenyl group
led to the identification of 2p, which possessed high
binding affinity (IC50: 0.87 nM) for ETA receptors with
a 470-fold selectivity for ETA over ETB receptors. In
addition, 2p showed not only greater intrinsicantag-
onisticatcivity (p A2: 8.8) in the tissue assay but also
greater in vivo efficacy (AD50: 0.04 mg/kg) in compar-
ison with 2 (AD50: 6 mg/kg). These biological properties
indicated that 2p has great potential as a novel potent
non-peptide ETA selective endothelin receptor antago-
nist. In spite of highly potent biological activities, its
intestinal absorption was poor. Therefore, we will focus
our effort on improving absorbability. Further derivati-
zation of 2 directed toward an orally active ETA/ETB
mixed or ETA selective antagonist will be described in
the near future.
Experimental
General
All reagents and solvents were of commercial quality
and were used without further purification unless

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K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
otherwise noted. Melting points were determined with a
Yanaco MP micromelting point apparatus and were not
corrected. H NMR spectra were recorded on a Varian
6-Ethoxycarbonyl-5-hydroxy-7-(4-methoxyphenyl)-5-(3,
4-methylenedioxyphenyl)cyclopenta-1,3-dieno[2,1-b]pyri-
dine (10). A solution of 9 (1.55 g, 5.01 mmol) in anhy-
drous THF (50 mL) was treated with 3,4-
methylenedioxypheny Grignard reagent prepared from
4-bromo-1,2-methylenedioxybenzene (1.21 g, 6.01
mmol), magnesium turnings (153 mg, 6.29 mmol), and
anhydrous THF (12 mL) at ꢁ78 ꢀC. After 30 min of
stirring at the same temperature, the reaction mixture
was quenched with 1 N HCl (8 mL), and was extracted
with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced
pressure. The residue was triturated with Et2O to give
10 as a pale yellow powder (1.96 g, 91%).1H NMR
(CDCl3) d 1.09 (t, J=7.0 Hz, 3H), 3.88 (s, 3H), 4.02–
4.24 (m, 2H), 4.51 (s, 1H), 5.92 (d, J=1.5 Hz, 1H), 5.94
(d, J=1.5 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.98 (d,
J=1.7 Hz, 1H), 7.03 (d, J=8.9 Hz, 2H), 7.04 (dd,
J=1.7 and 8.1 Hz, 1H), 7.15 (dd, J=4.8 and 7.6 Hz,
1H), 7.56 (dd, J=1.4 and 7.6 Hz, 1H), 7.68 (d, J=8.9
Hz, 2H), 8.54 (dd, J=1.4 and 4.8 Hz, 1H); HRMS calcd
for C25H22NO6 (M+H)+: 432.1447. Found 432.1453.
1
Gemini-300 instrument at 300 MHz. Chemical shifts
were reported in parts per million as d units relative to
tetramethylsilane as an internal standard. Mass spectra
were recorded with fast atom bombardment (FAB)
ionization on a JEOL JMS-SX 102A spectrometer. Thin
layer chromatography was performed with E. Merck
Kieselgel 60 F254 plates (0.25 mm) and visualized with
UV light or phosphomolybdicacid. Column chromato-
graphy was performed on Wako gel C-300.
2-(4-Methoxybenzoyl)pyridine-3-carboxylic acid (8). A
solution of pyridine-2,3-dicaboxylic anhydride 6 (7.46 g,
50.0 mmol) in anhydrous THF (80 mL) was treated with
4-methoxyphenyl Grignard reagent prepared from
4-bromoanisole (6.57 mL, 52.5 mmol), magnesium
turnings (1.34 g, 55.1 mmol), and anhydrous THF (100
mL) at ꢁ78 ꢀC. After 30 min of stirring at the same
temperature, the reaction mixture was quenched with
1 N HCl (55 mL), and was extracted with EtOAc. The
organiclayer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was triturated with Et2O (50 mL) and the
resulting insoluble material was collected by filtration.
The crude product was purified by column chromato-
graphy on silica gel to give 8 as a white foam (4.28 g,
(5RS,6RS,7SR)-6-Ethoxycarbonyl-7-(4-methoxyphenyl)-
5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine
(12). To a solution of 10 (457 mg, 1.06 mmol) and
H2SO4 (0.29 mL) in EtOH (20 mL) was added 10%
palladium on carbon (914 mg) and the mixture was
hydrogenated at atmosphericpressure at room tem-
perature for 70 h. The catalyst was removed by filtration
and washed with EtOAc(50 mL). The filtrate and
washings were combined, washed with saturated
NaHCO3 solution and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel to give
12 as a pale yellow foam (206 mg, 47%) together with a
1
33%). H NMR (CDCl3) d 3.86 (s, 3H), 6.92 (d, J=9.0
Hz, 2H), 7.51 (dd, J=4.9 and 8.1 Hz, 1H), 7.76 (d,
J=9.0 Hz, 2H), 8.37 (dd, J=1.8 and 8.1 Hz, 1H), 8.82
(dd, J=1.8 and 4.9 Hz, 1H); MS m/z 258 (M+H)+.
6-Ethoxycarbonyl-7-(4-methoxyphenyl)-5-oxocyclopenta-
1,3-dieno[2,1-b]pyridine (9). A mixture of 8 (4.12 g, 16.0
mmol) and thionyl chloride (29.2 mL, 400 mmol) was
refluxed for 2 h. After cooling to room temperature, the
mixture was concentrated under reduced pressure, and
the residue was azeotroped with toluene to remove the
residual thionyl chloride and hydrogen chloride to give
the crude acid chloride (4.02 g) as a pale yellow powder.
The powder was dissolved in THF (25 mL) and Et2O
(25 mL) and treated with EtOMgCH(CO2Et)2 prepared
from diethyl malonate (5.03 mL, 33.1 mmol), magne-
sium turnings (875 mg, 36.0 mmol), EtOH (4 mL), and
Et2O (16 mL). After 1 h of stirring at room temperature,
the reaction mixture was quenched with 10% H2SO4
(100 mL) at 0 ꢀC, and was extracted with Et2O. The
organiclayer was washed with brine, dried over
Na2SO4, and concentrated under reduced pressure to
give a pale brown oil. To the residue was added 5%
Na2CO3 solution (100 mL) and the mixture was refluxed
for 10 min. After cooling to room temperature, the
mixture was neutralized with 1 N HCl, and extracted
with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chroma-
tography on silica gel to give 9 as an orange foam (3.11
1
by-product 11 (150 mg, 33%). 11: H NMR (CDCl3) d
1.04 (t, J=7.0 Hz, 3H), 3.63 (d, J=9.7 Hz, 1H), 3.79 (s,
3H), 3.85–3.95 (m, 2H), 4.90 (d, J=9.7 Hz, 1H), 5.93 (d,
J=1.5 Hz, 1H), 5.94 (d, J=1.5 Hz, 1H), 6.63 (dd,
J=1.7 and 8.2 Hz, 1H), 6.71 (d, J=8.2 Hz, 1H), 6.73 (d,
J=1.7 Hz, 1H), 6.88 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8
Hz, 2H), 7.22 (dd, J=4.9 and 7.9 Hz, 1H), 7.58 (dd,
J=1.8 and 7.9 Hz, 1H), 8.59 (dd, J=1.8 and 4.9 Hz,
1H); HRMS calcd for C25H24NO6 (M+H)+: 434.1604.
Found 434.1598. 12: 1H NMR (CDCl3) d 0.69 (t, J=7.2
Hz, 3H), 3.46 (q, J=7.2 Hz, 2H), 3.78 (s, 3H), 3.88 (t,
J=7.6 Hz, 1H), 4.70 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6
Hz, 1H), 5.94 (d, J=1.5 Hz, 1H), 5.95 (d, J=1.5 Hz,
1H), 6.76–6.88 (m, 5H), 7.17 (dd, J=4.8 and 7.6 Hz,
1H), 7.34 (d, J=8.9 Hz, 2H), 7.52 (d, J=7.6 Hz, 1H),
8.51 (d, J=4.8 Hz, 1H); MS m/z 418 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-7-(4-methoxyphenyl)-5-(3,4-
methylenedioxyphenyl)cyclopenteno[1,2 - b]pyridine (2).
To a solution of 12 (271 mg, 0.65 mmol) in MeOH (4.9
mL) was added 4 N NaOH (1.63 mL) and the mixture
was stirred at room temperature for 16.5 h. The mixture
was neutralized with 4 N HCl (1.63 mL) and con-
centrated under reduced pressure. To the residue was
added water (3 mL), the insoluble material was collected
by filtration, washed with Et2O, and dried in vacuo to
give 2 (236 mg, 93%) as a white solid. Mp 230–233 ꢀC
1
g, 63%). H NMR (CDCl3) d 1.29 (t, J=7.0 Hz, 3H),
3.90 (s, 3H), 4.33 (q, J=7.0 Hz, 2H), 7.03 (d, J=9.0 Hz,
2H), 7.28 (dd, J=5.1 and 7.3 Hz, 1H), 7.83 (dd, J=1.8
and 7.3 Hz, 1H), 7.96 (d, J=9.0 Hz, 2H), 8.62 (dd,
J=1.8 and 5.1 Hz, 1H); MS m/z 310 (M+H)+.

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
2467
(dec.); 1H NMR (DMSO-d6) d 3.15 (t, J=10.2 Hz, 1H),
3.74 (s, 3H), 4.51 (d, J=10.2 Hz, 1H), 4.53 (d, J=10.2
Hz, 1H), 6.01 (s, 2H), 6.77 (dd, J=1.5 and 8.0 Hz, 1H),
6.84 (d, J=1.5 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 6.89
(d, J=8.0 Hz, 1H), 7.16 (d, J=8.7 Hz, 2H), 7.14–7.26
(m, 2H), 8.30–8.34 (m, 1H); HRMS calcd for
C23H20NO5 (M+H)+: 390.1341. Found 390.1366.
(5RS,6SR,7SR)-6-Carboxy-5-(4-methoxyphenyl)-7-(3,
4-methylenedioxyphenyl)cyclopenteno[1,2-c]pyridine (4).
This compound was prepared from 17 by a similar pro-
cedure as described for the preparation of 2. White
solid; mp 190–192 ꢀC; H NMR (DMSO-d6) d 3.18 (t,
1
J=10.2 Hz, 1H), 3.75 (s, 3H), 4.54 (d, J=10.2 Hz, 1H),
4.60 (d, J=10.2 Hz, 1H), 6.02 (s, 2H), 6.79–6.82 (m,
2H), 6.88–6.94 (m, 2H), 6.93 (d, J=8.4 Hz, 2H), 7.23 (d,
J=8.4 Hz, 2H), 8.00 (s, 1H), 8.38 (d, J=4.8 Hz, 1H);
HRMS calcd for C23H20NO5 (M+H)+: 390.1341.
Found 390.1354.
(5RS,6SR,7SR)-6-Carboxy-5-(4-methoxyphenyl)-7-(3,4-
(5).
methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine
This compound was prepared by a similar procedure as
described for the preparation of 2. White foam; 1H
NMR (CDCl3) d 3.30 (t, J=9.9 Hz, 1H), 3.82 (s, 3H),
4.61 (d, J=9.9 Hz, 1H), 4.69 (d, J=9.9 Hz, 1H), 5.92 (s,
2H), 6.68 (d, J=1.3 Hz, 1H), 6.74 (dd, J=1.3 and 7.7
Hz, 1H), 6.79 (d, J=7.7 Hz, 1H), 6.90 (d, J=8.8 Hz,
2H), 7.13 (dd, J=4.9 and 7.7 Hz, 1H), 7.18 (d, J=8.8
Hz, 2H), 7.28 (d, J=7.7 Hz, 1H), 8.48 (d, J=4.9 Hz,
1H); HRMS calcd for C23H20NO5 (M+H)+: 390.1341.
Found 390.1338.
(5RS,6SR,7SR)-6-Carboxy-7-(4-methoxyphenyl)-5-(3,
4-methylenedioxyphenyl)cyclopenteno[1,2-c]pyridine (3).
This compound was prepared by a similar procedure as
described for the preparation of 4. Pale brown solid; mp
187 ꢀC (dec.); H NMR (DMSO-d6) d 3.18 (t, J=10.6
1
Hz, 1H), 3.76 (s, 3H), 4.55 (d, J=10.6 Hz, 1H), 4.59 (d,
J=10.6 Hz, 1H), 6.01 (s, 2H), 6.79 (dd, J=1.7 and 8.1
Hz, 1H), 6.82–6.90 (m, 3H), 6.93 (d, J=8.5 Hz, 2H),
7.26 (d, J=8.5 Hz, 2H), 7.96 (s, 1H), 8.38 (d, J=4.6 Hz,
1H); HRMS calcd for C23H20NO5 (M+H)+: 390.1341.
Found 390.1347.
4 -(4 - Methoxybenzoyl)pyridine - 3 -carboxylic acid (14).
This compound was prepared from pyridine-3,4-dicar-
boxylicanhydride 13 by a similar procedure as descri-
1
bed for the preparation of 8. White foam; H NMR
The following compounds (2a–2i) were prepared in a
similar manner to that described for the preparation of
2.
(DMSO-d6) d 3.83 (s, 3H), 7.03 (d, J=9.1 Hz, 2H), 7.45
(dd, J=1.2 and 4.8 Hz, 1H), 7.61 (d, J=9.1 Hz, 2H),
8.87 (d, J=4.8 Hz, 1H), 9.13 (d, J=1.2 Hz, 1H), MS
m/z 258 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-7-(4-methoxyphenyl)-5-phe-
nylcyclopenteno[1,2-b]pyridine (2a). White solid; mp
164–165 ꢀC; 1H NMR (CDCl3) d 3.38 (t, J=9.8 Hz,
1H), 3.78 (s, 3H), 4.68 (d, J=9.8 Hz, 1H), 4.73 (d,
J=9.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.12 (dd,
J=4.9 and 7.5 Hz, 1H), 7.19 (d, J=8.8 Hz, 2H), 7.20–
7.40 (m, 6H), 8.47 (d, J=4.9 Hz, 1H); HRMS calcd for
C22H20NO3 (M+H)+: 346.1443. Found 346.1444.
6-Ethoxycarbonyl-5-(4-methoxyphenyl)-7-oxocyclopenta-
1,3-dieno[1,2-c]pyridine (15). This compound was pre-
pared from 14 by a similar procedure as described for
the preparation of 9. Yellow foam; 1H NMR (CDCl3) d
1.26 (t, J=7.1 Hz, 3H), 3.91 (s, 3H), 4.29 (q, J=7.1 Hz,
2H), 7.05 (d, J=8.9 Hz, 2H), 7.31 (d, J=4.9 Hz, 1H),
7.57 (d, J=8.9 Hz, 2H), 8.77 (d, J=4.9 Hz, 1H), 8.79 (s,
1H); MS m/z 310 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-5-(2-methoxyphenyl)-7-(4-
methoxyphenyl)cyclopenteno[1,2-b]pyridine (2b). White
solid; mp 194–197 ꢀC; 1H NMR (CDCl3) d 3.48 (t,
J=9.6 Hz, 1H), 3.67 (s, 3H), 3.75 (s, 3H), 4.73 (d,
J=9.6 Hz, 1H), 4.94 (d, J=9.6 Hz, 1H), 6.84 (d, J=9.1
Hz, 2H), 6.87–6.97 (m, 2H), 7.09 (dd, J=5.0 and 7.6
Hz, 1H), 7.15 (d, J=9.1 Hz, 2H), 7.15–7.20 (m, 1H),
7.24–7.31 (m, 2H), 8.43 (d, J=5.0 Hz, 1H); HRMS
calcd for C23H22NO4 (M+H)+: 376.1549. Found
376.1547.
6-Ethoxycarbonyl-7-hydroxy-5-(4-methoxyphenyl)-7-(3,
4-methylenedioxyphenyl)cyclopenta-1,3-dieno[1,2-c]pyri-
dine (16). This compound was prepared from 15 by a
similar procedure as described for the preparation of 10.
1
Yellow foam; H NMR (CDCl3) d 1.05 (t, J=7.1 Hz,
3H), 3.90 (s, 3H), 4.00–4.21 (m, 2H), 4.42 (s, 1H), 5.93
(d, J=1.5 Hz, 1H), 5.95 (d, J=1.5 Hz, 1H), 6.76 (d,
J=8.6 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 7.02–7.07 (m,
1H), 7.03 (d, J=8.9 Hz, 2H), 7.20 (dd, J=0.9 and 5.2
Hz, 1H), 7.47 (d, J=8.9 Hz, 2H), 8.52 (d, J=0.9 Hz,
1H), 8.56 (d, J=5.2 Hz, 1H); MS m/z 432 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-5-(3-methoxyphenyl)-7-(4-
methoxyphenyl)cyclopenteno[1,2-b]pyridine (2c). White
solid; mp 193–195 ꢀC; 1H NMR (CDCl3) d 3.36 (t,
J=9.6 Hz, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 4.65 (d,
J=9.6 Hz, 1H), 4.72 (d, J=9.6 Hz, 1H), 6.80–6.90 (m,
3H), 6.88 (d, J=8.8 Hz, 2H), 7.11–7.15 (m, 1H), 7.17 (d,
J=8.8 Hz, 2H), 7.28–7.33 (m, 2H), 8.47 (d, J=4.8 Hz,
1H); HRMS calcd for C23H22NO4 (M+H)+: 376.1549.
Found 376.1541.
(5RS,6RS,7SR)-6-Ethoxycarbonyl-5-(4-methoxyphenyl)-
7-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-c]pyridine
(17). This compound was prepared from 15 by a simi-
lar procedure as described for the preparation of 12.
1
Pale yellow foam; H NMR (CDCl3) d 0.70 (t, J=7.2
Hz, 3H), 3.47 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 3.83 (t,
J=7.5 Hz, 1H), 4.71 (d, J=7.5 Hz, 1H), 4.78 (d, J=7.5
Hz, 1H), 5.94 (d, J=1.7 Hz, 1H), 5.95 (d, J=1.7 Hz,
1H), 6.78 (d, J=8.7 Hz, 1H ), 6.84–6.89 (m, 2H), 6.87
(d, J=8.4 Hz, 2H), 7.19 (dd, J=1.4 and 5.2 Hz, 1H),
7.27 (d, J=8.4 Hz, 2H), 8.47 (d, J=1.4 Hz, 1H), 8.53
(d, J=5.2 Hz, 1H); MS m/z 418 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-5,7-bis(4-methoxyphenyl)cy-
clopenteno[1,2-b]pyridine (2d). Pale yellow solid; mp
185–187 ꢀC; 1H NMR (CDCl3) d 3.33 (t, J=9.8 Hz,
1H), 3.79 (s, 3H), 3.82 (s, 3H), 4.63 (d, J=9.8 Hz, 1H),
4.71 (d, J=9.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.90

2468
K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
1
(d, J=8.8 Hz, 2H), 7.12 (dd, J=4.8 and 7.7 Hz, 1H),
7.19 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 7.21–
7.30 (m, 1H), 8.46 (d, J=4.8 Hz, 1H); HRMS calcd for
C23H22NO4 (M+H)+: 376.1549. Found 376.1536.
White powder; H NMR (CDCl3) d 1.20 (t, J=7.1 Hz,
3H), 3.68 (t, J=9.8 Hz, 1H), 3.78 (s, 3H), 4.17 (q,
J=7.1 Hz, 2H), 4.62 (d, J=9.8 Hz, 1H), 5.08 (d, J=9.8
Hz, 1H), 5.98 (s, 2H), 6.45 (dd, J=2.7 and 8.6 Hz, 1H),
6.66 (d, J=1.8 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 6.71
(dd, J=1.8 and 7.9 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H),
7.07 (d, J=8.6 Hz, 1H), 7.18 (dd, J=5.0 and 7.6 Hz,
1H), 7.36 (d, J=7.6 Hz, 1H), 8.38 (d, J=5.0 Hz, 1H);
MS m/z 434 (M+H)+.
(5RS,6SR,7SR)-6-Carboxy-5-(indol-4-yl)-7-(4-methoxy-
1
phenyl)cyclopenteno[1,2-b]pyridine (2e). White foam; H
NMR (CD3OD) d 3.51 (t, J=10.1 Hz, 1H), 3.79 (s,
3H), 4.75 (d, J=10.1 Hz, 1H), 5.04 (d, J=10.1 Hz,
1H), 6.12–6.18 (m, 1H), 6.90–6.96 (m, 1H), 6.93 (d,
J=8.8 Hz, 2H), 7.10 (dd, J=7.3 and 8.1 Hz, 1H),
7.16–7.25 (m, 2H), 7.20 (d, J=8.8 Hz, 2H),7.30–7.34
(m, 1H), 7.36 (d, J=8.1 Hz, 1H), 8.32–8.36 (m, 1H);
HRMS calcd for C24H21N2O3 (M+H)+: 385.1552.
Found 385.1540.
The following compounds (2j–2p) were prepared from
the intermediate 18 in a similar manner to that descri-
bed in the literature.11
(5RS,6SR,7SR)-6-Carboxy-7-(2-hydroxy-4-methoxyphe-
nyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyr-
idine (2j). White solid; mp 128–130 ꢀC; 1H NMR
(CDCl3) d 3.64 (t, J=9.3 Hz, 1H), 3.73 (s, 3H), 4.62
(d, J=9.3 Hz, 1H), 5.10 (d, J=9.3 Hz, 1H), 5.97 (s,
2H), 6.46 (dd, J=2.5 and 8.6 Hz, 1H), 6.59 (d,
J=2.5 Hz, 1H), 6.67 (d, J=1.4 Hz, 1H), 6.73 (dd,
J=1.4 and 8.1 Hz, 1H), 6.79 (d, J=8.1 Hz, 1H),
7.01 (d, J=8.6 Hz, 1H), 7.19 (dd, J=5.1 and 8.0 Hz,
1H), 7.37 (d, J=8.0 Hz, 1H), 8.38 (d, J=5.1 Hz,
1H); HRMS calcd for C23H20NO6 (M+H)+:
406.1291. Found 406.1302.
(5RS,6SR,7SR)-6-Carboxy-5-(indol-6-yl)-7-(4-methoxy-
phenyl)cyclopenteno[1,2-b]pyridine (2f). White foam mp;
1H NMR (CD3OD) d 3.27–3.35 (m, 1H), 3.79 (s, 3H),
4.69 (d, J=9.8 Hz, 1H), 4.73 (d, J=9.6 Hz, 1H), 6.43
(dd, J=0.9 and 3.2 Hz, 1H), 6.90 (dd, J=1.6 and 8.1
Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 7.18 (d, J=8.8 Hz,
2H), 7.22–7.28 (m, 1H), 7.22 (d, J=3.2 Hz, 1H), 7.33 (s,
1H), 7.37–7.43 (m, 1H), 7.55 (d, J=8.1 Hz, 1H), 8.30–
8.34 (m, 1H); HRMS calcd for C24H21N2O3 (M+H)+:
385.1552. Found 385.1570.
(5RS,6SR,7SR)-6-Carboxy-5-(3,4-methylenedioxyphe-
nyl)-7-phenylcyclopenteno[1,2-b]pyridine (2g). White
solid; mp 243–245 ꢀC; 1H NMR (CDCl3) d 3.35 (t,
J=9.7 Hz, 1H), 4.63 (d, J=9.7 Hz, 1H), 4.75 (d, J=9.7
Hz, 1H), 5.97 (d, J=1.5 Hz, 1H), 5.98 (d, J=1.5 Hz,
1H), 6.72 (d, J=1.7 Hz, 1H), 6.77 (dd, J=1.7 and 7.8
Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 7.14 (dd, J=5.1 and
8.2 Hz, 1H), 7.25–7.40 (m, 6H), 8.48 (d, J=5.1 Hz, 1H);
HRMS calcd for C22H18NO4 (M+H)+: 360.1236.
Found 360.1225.
(5RS,6SR,7SR)-6-Carboxy-7-[2-(2-hydroxyethoxy)-4-
methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopen-
teno[1,2-b]pyridine (2k). White; mp 125–128 ꢀC; 1H
NMR (CDCl3) d 3.26 (t, J=9.9 Hz, 1H), 3.71–4.04 (m,
4H), 3.77 (s, 3H), 4.58 (d, J=9.9 Hz, 1H), 5.16 (d,
J=9.9 Hz, 1H), 5.95 (d, J=1.5 Hz, 1H), 5.96 (d, J=1.5
Hz, 1H), 6.44 (d, J=2.4 Hz, 1H), 6.49 (dd, J=2.4 and
8.4 Hz, 1H), 6.70 (d, J=1.3 Hz, 1H), 6.74 (dd, J=1.3
and 8.0 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 7.04 (d,
J=8.4 Hz, 1H), 7.13 (dd, J=4.8, and 7.8 Hz, 1H), 7.32
(d, J=7.8 Hz, 1H), 8.46 (d, J=4.8 Hz, 1H); HRMS
calcd for C25H24NO7 (M+H)+: 450.1553. Found
450.1555.
(5RS,6SR,7SR)-6-Carboxy-7-(4-fluorophenyl)-5-(3,4-me-
thylenedioxyphenyl)cyclopenteno[1,2-b]pyridine
(2h).
White solid; mp 234–236 ꢀC; H NMR (CDCl3) d 3.29
(t, J=10.0 Hz, 1H), 4.62 (d, J=10.0 Hz, 1H), 4.75 (d,
J=10.0 Hz, 1H), 5.98 (s, 2H), 6.71 (d, J=1.3 Hz, 1H),
6.77 (dd, J=1.3 and 7.9 Hz, 1H), 6.81 (d, J=7.9 Hz,
1H), 7.03–7.30 (m, 5H), 7.33 (d, J=7.6 Hz, 1H), 8.49 (d,
J=4.7 Hz, 1H); HRMS calcd for C22H17FNO4
(M+H)+: 378.1142. Found 378.1139.
1
(5RS,6SR,7SR)-6-Carboxy-7-[2-[2-(methylamino)eth-
oxy]-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cy-
clopenteno[1,2-b]pyridine (2l). White solid; mp 130–
132 ꢀC; 1H NMR (CDCl3) d 2.58 (s, 3H), 2.84 (t, J=9.9
Hz, 1H), 3.00–3.13 (m, 2H), 3.75 (s, 3H), 4.01–4.19 (m,
2H), 4.61 (d, J=9.9 Hz, 1H), 5.17 (d, J=9.9 Hz, 1H),
5.92 (d, J=1.4 Hz, 1H), 5.94 (d, J=1.4 Hz, 1H), 6.33
(d, J=2.3 Hz, 1H), 6.50 (dd, J=2.3 and 8.4 Hz, 1H),
6.68–6.79 (m, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.10 (dd,
J=5.0 and 7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 8.47 (d,
J=5.0 Hz, 1H); HRMS calcd for C26H27N2O6
(M+H)+: 463.1869. Found 463.1881.
(5RS,6SR,7SR)-6-Carboxy-7-(4-hydroxyphenyl)-5-(3,4-
methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine (2i).
White solid; mp 226 ꢀC (dec.); 1H NMR (CDCl3) d
3.25 (t, J=9.9 Hz, 1H), 4.60 (d, J=9.9 Hz, 1H), 4.65 (d,
J=9.9 Hz, 1H), 5.96 (s, 2H), 6.71–6.82 (m, 3H), 6.73 (d,
J=8.5 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H), 7.15 (dd, J=
5.0 and 7.6 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 8.42 (d,
J=5.0 Hz, 1H); HRMS calcd for C22H18NO5
(M+H)+: 376.1185. Found 376.1201.
(5RS,6SR,7SR)-7-(2-Carbamoylmethoxy-4-methoxyphe-
nyl)-6 - carboxy - 5 - (3,4 - methylenedioxyphenyl)cyclopen-
teno[1,2-b]pyridine (2m). White solid; mp 138–140 ꢀC;
1H NMR (DMSO-d6) d 3.37 (t, J=10.0 Hz, 1H), 3.74
(s, 3H), 4.40 (s, 2H), 4.53 (d, J=10.0 Hz, 1H), 4.90 (d,
J=10.0 Hz, 1H), 6.00 (s, 2H), 6.51 (d, J=2.9 Hz, 1H),
6.52 (dd, J=2.9 and 8.2 Hz, 1H), 6.77 (dd, J=1.6 and
7.8 Hz, 1H), 6.83 (d, J=1.6 Hz, 1H), 6.89 (d, J=7.8 Hz,
1H), 7.10 (d, J=8.2 Hz, 1H), 7.17 (dd, J=4.6 and 7.5
(5RS,6SR,7SR)-6-Ethoxycarbonyl-7-(2-hydroxy-4-meth-
oxyphenyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,
2-b]pyridine (18). This compound was prepared from 6
and 2-benzyloxy-4-methoxy-1-bromobenzene in a simi-
lar manner to that described for the preparation of 2.

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 2461–2470
2469
Hz, 1H), 7.23 (dd, J=1.9 and 7.5 Hz, 1H), 7.26 (br s,
1H), 7.41 (br s, 1H), 8.25 (dd, J=1.9 and 4.6 Hz, 1H);
HRMS calcd for C25H23N2O7 (M+H)+: 463.1505.
Found 463.1501.
thank Mr. Shinnosuke Abe for analytical support (Mass
spectra).
References and Notes
(5RS,6SR,7SR) - 6 - Carboxy - 7- (2 -carboxymethoxy - 4 -
methoxyphenyl)-5 - (3,4 - methylenedioxyphenyl)cyclopen-
teno[1,2-b]pyridine (2n). White solid; mp 154–156 ꢀC;
1H NMR (CD3OD) d 3.64 (t, J=10.3 Hz, 1H), 3.77 (s,
3H), 4.37 (d, J=16.1 Hz, 1H), 4.58 (d, J=16.1 Hz,
1H), 4.66 (d, J=10.3 Hz, 1H), 4.91 (d, J=10.3 Hz,
1H), 5.93 (s, 2H), 6.50 (d, J=2.3 Hz, 1H), 6.56 (dd,
J=2.3 and 8.1 Hz, 1H), 6.75–6.86 (m, 3H), 7.18 (d,
J=8.1 Hz, 1H), 7.31 (dd, J=5.4 and 7.5 Hz, 1H), 7.48
(d, J=7.5 Hz, 1H), 8.27 (d, J=5.5 Hz, 1H); HRMS
calcd for C25H22NO8 (M+H)+: 464.1345. Found
464.1356.
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(5RS,6SR,7SR)-6-Carboxy-7-[2-(2-carboxyethenyl)-4-
methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopen-
teno[1,2-b]pyridine (2o). Pale yellow solid; mp 180 ꢀC
(decomp.); 1H NMR (CDCl3) d 3.03 (t, J=10.2 Hz,
1H), 3.83 (s, 3H), 4.77 (d, J=10.2 Hz, 1H), 5.27 (d,
J=10.2 Hz, 1H), 5.95 (d, J=1.9 Hz, 1H), 5.96 (d,
J=1.9 Hz, 1H), 6.29 (d, J=15.4 Hz, 1H), 6.68 (d,
J=1.8 Hz, 1H), 6.76 (dd, J=1.8 and 7.9 Hz, 1H), 6.79
(d, J=7.9 Hz, 1H), 7.00 (dd, J=2.3 and 8.9 Hz, 1H),
7.03 (d, J=8.9 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.20
(dd, J=4.9 and 7.9 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H),
8.32 (d, J=15.4 Hz, 1H), 8.54 (d, J=4.9 Hz, 1H);
HRMS calcd for C26H22NO7 (M+H)+: 460.1397.
Found 460.1393.
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5RS,6SR,7SR)-6-Carboxy-7-[2-(2-carboxyethyl)-4-meth-
oxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,
2-b]pyridine (2p). White foam; 1H NMR (CDCl3) d
2.60–2.80 (m, 2H), 2.98–3.26 (m, 2H), 3.43 (t, J=9.9
Hz, 1H), 3.76 (s, 3H), 4.64 (d, J=9.9 Hz, 1H), 5.04 (d,
J=9.9 Hz, 1H), 5.98 (d, J=2.3 Hz, 1H), 5.99 (d, J=2.3
Hz, 1H), 6.72–6.83 (m, 5H), 6.90 (d, J=8.2 Hz, 1H),
7.19 (dd, J=5.0 and 8.1 Hz, 1H), 7.39 (d, J=8.1 Hz,
1H), 8.38 (d, J=5.0 Hz, 1H); HRMS calcd for
C26H24NO7 (M+H)+: 462.1553. Found 462.1549.
Endothelin receptor binding assay. According to the
reported method,12 binding affinities were determined
by inhibition of specific binding of [125I]ET-1 using
membranes prepared from human neuroblastoma-
derived SK-N-MC cells and Girardi heart cells that
were reported to possess only ETA and ETB receptors,
respectively.5
Antagonism of ET-1-induced contractile response in rab-
bit iliac artery. The antagonism study was conducted
according to the reported experimental protocol13 using
isolated rabbit iliacarteries. The p A2 values were
obtained by analysis of Schild plots.14
Acknowledgements
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We are grateful to Ms. Regina Stamatis, Merck & Co.,
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2470
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