Synthesis and evaluation of pyrrolin-2-one compounds, a series of plasminogen activator inhibitor-1 inhibitors

Article abstract of DOI:10.1248/cpb.57.979

A novel series of furan-2-one and pyrrolin-2-one derivatives having PAI-1 (plasminogen activator inhibitor-1) inhibitory activity were synthesized and evaluated for their antithrombotic activity in a rat arterial thrombosis model. Among the synthesized co

Full text of DOI:10.1248/cpb.57.979

September 2009
Chem. Pharm. Bull. 57(9) 979—985 (2009)
979
Synthesis and Evaluation of Pyrrolin-2-one Compounds, a Series of
Plasminogen Activator Inhibitor-1 Inhibitors
Hiroshi MIYAZAKI, ,a Tsuyoshi OGIKU,a Hiroshi SAI,a Yasunori MORITANI,a Akio OHTANI,b and
*
a
Hiroshi OHMIZU
a Medicinal Chemistry Laboratory, Mitsubishi Tanabe Pharma Co., Ltd.; 3–16–89 Kashima, Yodogawa, Osaka 532–8505,
Japan: and b Pharmacology Laboratory, Mitsubishi Tanabe Pharma Co., Ltd.; 2–2–50 Kawagishi, Toda, Saitama
335–8505, Japan. Received May 19, 2009; accepted June 16, 2009; published online June 18, 2009
A novel series of furan-2-one and pyrrolin-2-one derivatives having PAI-1 (plasminogen activator inhibitor-
1) inhibitory activity were synthesized and evaluated for their antithrombotic activity in a rat arterial thrombo-
sis model. Among the synthesized compounds, 5f (T-1776Na) was found to have good selectivity for PAI-1 over
other enzymes and high antithrombotic activity.
Key words plasminogen activator inhibitor-1; inhibitor; antithrombotic drug; furan-2-one; pyrrolin-2-one
Plasminogen activator inhibitor-1 (PAI-1) is an effective products 8a (as a minor product) and 8b (as a major product)
fast-acting inhibitor of both tissue-type plasminogen activa- in which the 5-pyridylmethylidene parts were introduced.
tor (t-PA) and two-chain urokinase-type plasminogen activa- Compounds 8a and 8b were separated by silica gel chro-
tor (tcu-PA), and thus plays an important role in regulation of matography and transformed to their HCl salts 1a and 1b, re-
the fibrinolytic system.1) Elevated levels of PAI-1 in plasma spectively.
have been observed in patients with deep vein thrombosis2—4)
and unstable angina.5) Furthermore, a number of animal stud-
ies have shown that PAI-1 is responsible for fibrinolytic ac-
tivity in thrombotic and prethrombotic states.6—8) Thus, inhi-
bition of PAI-1 activity or reduction of its production may
shift the balance between thrombogenesis and thrombolysis
towards thrombolysis. In fact, it has been reported that an an-
tibody against PAI-1 can enhance clot lysis and decrease
thrombus growth in animal models of venous thrombosis9)
and arterial thrombosis.10) Therefore, therapeutic inhibition
of PAI-1 activity or reduction of its production may be useful
for prevention and/or treatment of thrombotic disorders. In-
deed, a number of small molecules that inhibit PAI-1 or re-
duce its production have recently been reported.11—20)
4-Methyllactam (pyrrolin-2-one) compounds were synthe-
High-throughput screening of Mitsubishi Tanabe chemical
libraries led to the discovery of 4-methyl-3-phenyl-5-[1-
pyridin-4-ylmeth-(E)-ylidene]-5H-furan-2-one hydrochloride
(1a) as a weak PAI-1 inhibitor (IC50ꢀ24 mM, Fig. 1). To im-
prove the inhibitory activity of 1a towards PAI-1, we carried
out a series of chemical modifications. In this paper, we de-
scribe the synthesis, structure–activity relationships (SAR),
and antithrombotic activity of a series of furan-2-one and
pyrrolin-2-one derivatives.
Chart 1
Chemistry
The synthetic route of furan-2-one derivatives is shown in
Chart 1. The furan-2-one derivatives 1a and 1b were synthe-
sized from 4-methyl-3-phenyl-2,5-dihydrofuran-2-one 7.21)
Treatment of 7 with lithium diisopropylamide (LDA) fol-
lowed by 4-pyridinecarboxaldehyde and dehydration after
methanesulfonylation of the hydroxyl group afforded the
Chart 2
Fig. 1. Hit Compound 1a
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: miyazaki.hiroshi@me.mt-pharma.co.jp

980
Vol. 57, No. 9
Chart 3
sized as shown in Chart 2. The acidic NH proton of 922) was
first protected with tert-butoxycarbonyl (Boc), and then the
5-pyridylmethylidene parts were introduced under basic con-
ditions. These reactions proceeded with good Z-selectivity in
cases of pyrrolin-2-one as well as furan-2-one, and separa-
tion of E and Z-products by silica gel chromatography fol-
lowed by conversion to their HCl salts gave the 5-pyridyl-
methylidenepyrrolin-2-one compounds 2a—d. Compounds
11b and 11d were then methylated by NaH and MeI, and
converted to their HCl salts 3a and 3b, respectively.
Chart 4
The synthetic route of 4-methoxylactam (pyrrolin-2-one)
compounds is shown in Chart 3. Compounds 4a and 4b were
synthesized from the amide compound 12. After 12 was pro-
tected with Boc, the product 13 was cyclized under basic
conditions and transformed into the intermediate 15. Com-
pound 4a was obtained from 15 by the same method as 2d in
two steps. In the case of compound 4b, methoxymethyl
(MOM)-protected 3-hydroxyphenyl was first introduced and
the product 17 was converted to the 3-carboxymethoxy-
phenyl compound 4b by a conventional method.
The 4-phenyllactam or 4-heteroaryllactam (pyrrolin-2-
one) compounds 5a—j and 6 were synthesized as follows
(Chart 4, 5). 3,4-Diphenyl-1,5-dihydropyrrol-2-one 6 was
synthesized in a similar manner as the literature.23) N-(2-
Oxo-2-phenylethyl)-2-phenylacetamide 20 was cyclized to
give 21 by treatment with acetic anhydride, and cleavage of
the N-acetyl group of 21 provided 3,4-diphenyl-1,5-dihy-
Chart 5
dropyrrol-2-one 6. After various substituents were introduced Biological Results and Discussion
into the 5-position of the N-acetyl compound 21 or N-Boc The inhibitory activity of furan-2-one and pyrrolin-2-one
protected compound 22, several conventional conversions af- derivatives for human PAI-1 is summarized in Tables 1 and 2.
forded the 4-phenyllactam compounds 5a—h. The Z-isomer 1b showed better PAI-1 inhibitory activity than
In the case of 2-furyl at the 4-position of pyrrolin-2-one, 5i the E-isomer 1a. However, these furan-2-one compounds
was obtained by introducing a substituent at the 5-position of (1a, b) were biologically unstable. This instability was be-
2724) without NH-Boc protection. The thienyl compound 5j lieved to be due to their a,b-unsaturated lactone ring. As
was provided in a similar manner as 5i from the commer- such, 1a and 1b were considered inappropriate for inhibition
cially available 28 in three steps.
of thrombus formation in vivo. Thus, we tried to transform

September 2009
981
the lactone ring into a more stable scaffold. The pyrrolin-2- matic ring, which extends from the 5-position, are favorable
one compounds 2a—d, having a 3 or 4-pyridine ring at the 5- for PAI-1 inhibitory activity. Other hydrophilic substituents,
position, were first evaluated. The 3-pyridine compound 2b such as alcohol (5d), dimethylacetal (5e) and carboxylic acid
showed strong inhibitory activity for human PAI-1 (5f), were also examined. Compound 5d did not inhibit
(IC50ꢀ9.8 mM). However, in case of the pyrrolin-2-ones, the human PAI-1, while compound 5e showed a moderate in-
inhibitory activity of the E-isomer 2a and that of the 4-pyri- hibitory activity (IC50ꢀ7.9 mM). Particularly, compound 5f,
dine compounds 2c and 2d was low. Furthermore, the N- having a carboxylic acid group, was found to have potent
methylated compounds 3a and 3b had no PAI-1 inhibitory PAI-1 inhibitory activity (IC50ꢀ9.6 mM).
activity. This led us to examine the SAR of pyrrolin-2-one
derivatives with no subsitituent at the 1-position.
Next we focused our efforts on optimizing compound 5f,
having a phenoxy acetic acid group. However, compounds 5g
Our search for more attractive templates focused on sub- and 5h, having a 4- or 2-phenoxy acetic acid moiety, and
stituents at the 4-position of the pyrrolin-2-one ring (Table compounds 5i and 5j, having a furan or thiophene at the 4-
2). In case of a methoxy group, compounds 4a and 4b exhib- position of pyrrolin-2-one ring, exhibited less potent in-
ited no inhibitory activity. Next, a phenyl group was intro- hibitory activity for human PAI-1 than compound 5f.
duced. The phenylmethylidene compound 5a and the 4-
In order to select the best compound, the synthesized
pyridylmethylidene compounds 5b and 6, having no sub- pyrrolin-2-one compounds were evaluated for their an-
stituent at the 5-position, did not inhibit human PAI-1. How- tithrombotic activity in rat arterial thrombosis model. Com-
ever, 3-pyridylmethylidene 5c showed potent inhibitory ac- pounds 2b, 5c, and 5e could not be intravenously infused to
tivity for human PAI-1 (IC50ꢀ12.6 mM). These findings sug- rats due to their poor solubility. They were thus considered
gest that hydrophilic groups at the meta-position of the aro- not to have the desired features for antithrombotic drug. On
the other hand, compound 5f, possessing a carboxylic acid
Table 1. Inhibitory Effect of Furan-2-one and Pyrrolin-2-one Derivatives group at the 5-position of the pyrrolin-2-one ring, had good
against Human PAI-1 Activitya)
solubility and was found to decrease thrombus weight at a
dose of 0.5 mg/kg/min. Finally, we evaluated the selectivity of
compound 5f for rat PAI-1. Compound 5f inhibited rat PAI-1
with an IC50 value of 10.3 mM, which is almost equal to its in-
hibition of human PAI-1. Compound 5f showed no inhibitory
effect against the serine proteases thrombin, plasmin, and
trypsin, and the serpins antithrombin III, antiplasmin, and
antitrypsin at 30 mM. It shows the antithrombotic activity of
5f is thought to be based on its PAI-1 inhibition.
Configuration at
C-5 position
Inhibitory activitya)
Compound
X
Ar
IC50 (mM)
1a
1b
2a
2b
2c
2d
3a
3b
E
Z
E
Z
E
Z
Z
Z
O
O
NH
NH
NH
NH
4-Pyridyl
4-Pyridyl
3-Pyridyl
3-Pyridyl
4-Pyridyl
4-Pyridyl
24 mM
5.6 mM
7% inhibition at 30 mM
9.8 mM
Conclusion
5% inhibition at 30 mM
24% inhibition at 10 mM
2% inhibition at 30 mM
4% inhibition at 30 mM
In this study, we examined the structure–activity relation-
ships of a series furan-2-one derivatives. Initial modification
led to identification of the pyrrolin-2-one template as a prom-
ising scaffold. Optimization of the pyrrolin-2-one derivatives
resulted in identification of 5f (T-1776Na) as a potent PAI-1
NMe 3-Pyridyl
NMe 4-Pyridyl
a) See Experimental.
Table 2. Inhibitory Effect of Pyrrolin-2-one Derivatives against Human PAI-1 Activitya) and Their Antithrombotic Activityb)
Inhibitory activitya)
IC50 (mM)
% decrease in
Compound
R
Ar
thrombus weightb)
2b
4a
4b
5a
5b
5c
6
5d
5e
5f
Me
OMe
OMe
Ph
Ph
Ph
—
Ph
Ph
Ph
3-Pyridyl
4-Pyridyl (HCl)
3-Carboxymehoxyphenyl
Ph
4-Pyridyl
9.8 mM
ntc)
No effect at 30 mM
No effect at 30 mM
No effect at 15 mM
No effect at 30 mM
12.6 mM
3-Pyridyl
ntc)
—
No effect at 15 mM
No effect at 30 mM
7.9 mM
3-Hydroxyphenyl
3-Dimethoxymethylphenyl
3-Carboxymehoxyphenyl (Na salt)
4-Carboxymehoxyphenyl (Na salt)
2-Carboxymehoxyphenyl (Na salt)
3-Carboxymehoxyphenyl
3-Carboxymehoxyphenyl
ntc)
43.4%
9.6 mM
5g
5h
5i
Ph
Ph
2-Furyl
2-Thienyl
No effect at 30 mM
32% inhibition at 30 mM
30% inhibition at 30 mM
27% inhibition at 30 mM
5j
a) See Experimental. b) Compounds were intravenously infused at 0.5 mg/kg/min during electrical stimulation. See Experimental. c) Not tested due to low solubility.

982
Vol. 57, No. 9
Lithium bis(trimethylsilyl)amide in THF (3.5 ml, 3.5 mmol) was slowly
added to a solution of 10 (800 mg, 2.93 mmol) in THF (12 ml) at ꢁ78 °C.
The mixture was stirred for 30 min at the same temperature and 4-
pyridinecarboxaldehyde (380 mg, 3.5 mmol) in THF (5 ml) was added drop-
wise. After the addition, the mixture was further stirred for 30 min at
inhibitor. Compound 5f was selected for further biological
evaluation and was found to possess good antithrombotic ac-
tivity in rat model. Compound 5f was also found to have
good selectivity for PAI-1 over serine proteases and serpins.
These findings indicate that pyrrolin-2-one derivatives are ꢁ78 °C and for 16 h at room temperature. Water and ethyl acetate were
added to the mixture and the organic layer was separated. The organic layer
was dried and concentrated in vacuo. The resulting residue was chro-
matographed on silica gel to give 80 mg (10%) of 4-methyl-3-phenyl-5-[1-
pyridin-3-ylmeth-(E)-ylidene]-1,5-dihydropyrrol-2-one (11a) and 570 mg
potential candidates for antithrombotic drugs. Accordingly,
compound 5f has been selected as lead compound and fur-
ther research on its antithrombotic effects are on going.
(74%) of 4-methyl-3-phenyl-5-[1-pyridin-3-ylmeth-(Z)-ylidene]-1,5-dihy-
dropyrrol-2-one hydrochloride (11b) as a solid. mp 180—182 °C (11a),
230—231 °C (11b).
Experimental
Melting points were measured using a Büchi 535 capillary melting point
apparatus and are uncorrected. IR spectra were recorded on a PerkinElmer
Spectrum One FT-IR spectrometer. 1H-NMR spectra were recorded on a
Bruker AC-200 spectrometer (200 MHz) or on a Bruker AVANCE 400 spec-
trometer (400 MHz) with Me4Si as internal standard. Mass spectra were ob-
tained on a ThermoFisher FINNIGAN LXQ or Q-TOF Ultima API mass
spectrometer. Elemental analyses were obtained on a PerkinElmer 2400 II
(C, H, N) and Dionex DX-320 (S).
To a solution of 11b (150 mg, 0.57 mmol) in CHCl3 (10 ml) was added 4 N
HCl in ethyl acetate (0.16 ml) and the mixture was stirred for 10 min. The
reaction mixture was concentrated in vacuo, and the resulting residue was
triturated with diethyl ether and filtrated to afford 2b (162 mg, 95%) as a
1
solid. mp 311—314 °C (dec.). H-NMR (400 MHz, DMSO-d6) d: 2.30 (3H,
s), 6.54 (1H, s), 7.37—7.57 (5H, m) 7.95 (1H, dd, Jꢀ8.2, 5.5 Hz), 8.57 (1H,
d, Jꢀ8.5 Hz), 8.73 (1H, d, Jꢀ5.5 Hz), 9.00 (1H, d, Jꢀ1.8 Hz), 10.64 (1H, s).
IR (ATR) cmꢁ1: 3075, 2698, 1683, 1640, 1544, 1387, 1216, 789, 671, 435.
MS (APCI): 263 [MꢃH]ꢃ. HR-MS-ESI Calcd for C17H15N2O ([MꢃH]ꢃ):
263.1184. Found: 263.1175.
4-Methyl-3-phenyl-5-[1-pyridin-4-ylmeth-(E)-ylidene]-5H-furan-2-
one Hydrochloride (1a); 4-Methyl-3-phenyl-5-[1-pyridin-4-ylmeth-(Z)-
ylidene]-5H-furan-2-one Hydrochloride (1b) 1.6 M n-BuLi in hexane
(5.4 ml, 8.6 mmol) was slowly added to a solution of diisopropylamine
(1.2 ml, 8.6 mmol) in tetrahydrofuran (THF) (15 ml) at ꢁ78 °C. The solution
was stirred for 30 min at the same temperature and 4-methyl-3-phenyl-2,5-
dihydrofuran-2-one 721) (1.0 g, 5.7 mmol) in THF (15 ml) was added drop-
wise to the solution. The mixture was stirred for 30 min at ꢁ78 °C and 4-
pyridinecarboxaldehyde (0.92 g, 8.6 mmol) in THF (5 ml) was added drop-
wise to the mixture. After the addition, the mixture was further stirred for
1 h at ꢁ78 °C. Water and ethyl acetate were added to the mixture and the or-
ganic layer was separated. The organic layer was then dried and concentrated
in vacuo. The resulting residue was dissolved in CH2Cl2 (20 ml), and triethyl-
amine (1.2 ml, 8.6 mmol) and methanesulfonyl chloride (0.67 ml, 8.6 mmol)
were added to the solution at 0 °C. The mixture was stirred for 30 min at
0 °C and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (1.3 ml, 8.6 mmol) was
added. After the addition, the reaction mixture was further stirred for 30 min
at 0 °C. Water and CHCl3 were then added to the mixture and the organic
layer was separated. The organic layer was dried and concentrated in vacuo.
The residue was chromatographed on silica gel to give 75 mg (5%) of 4-
2a, prepared from 11a as described in the synthesis of 2b, was obtained as
a solid. Yield 81%. mp 302—304 °C (dec.). 1H-NMR (400 MHz, DMSO-d6)
d: 1.84 (3H, s), 6.60 (1H, s), 7.35—7.60 (5H, m) 7.88 (1H, dd, Jꢀ8.0,
5.5 Hz), 8.43 (1H, d, Jꢀ8.0 Hz), 8.76 (1H, d, Jꢀ5.5 Hz), 8.94 (1H, s), 10.46
(1H, s). IR (ATR) cmꢁ1: 3150, 2479, 1687, 1638, 1205, 832, 598. MS
(APCI): 263 [MꢃH]ꢃ. HR-MS-ESI Calcd for C17H15N2O ([MꢃH]ꢃ):
263.1184. Found: 263.1180.
4-Methyl-3-phenyl-5-[1-pyridin-4-ylmeth-(E)-ylidene]-1,5-dihydropy-
rrol-2-one Hydrochloride (2c); 4-Methyl-3-phenyl-5-[1-pyridin-4-yl-
meth-(Z)-ylidene]-1,5-dihydropyrrol-2-one Hydrochloride (2d) 2c and
2d, prepared from 10 and 4-pyridinecarboxaldehyde as described in the syn-
thesis of 2a and 2b, were obtained as a solid. 2c yield 6%. mp 331—335 °C
(dec.). 1H-NMR (400 MHz, DMSO-d6) d: 1.96 (3H, s), 6.64 (1H, s), 7.38—
7.57 (5H, m) 8.01 (2H, d, Jꢀ6.6 Hz), 8.80 (2H, d, Jꢀ6.6 Hz), 10.59 (1H, s).
IR (ATR) cmꢁ1: 3039, 1697, 1598, 1493, 1196, 1136, 856, 697. MS (APCI):
263 [MꢃH]ꢃ. HR-MS-ESI Calcd for C17H15N2O ([MꢃH]ꢃ): 263.1184.
Found: 263.1173. 2d yield 55%. mp 322—325 °C (dec.). 1H-NMR
(400 MHz, DMSO-d6) d: 2.31 (3H, s), 6.58 (1H, s), 7.40—7.58 (5H, m)
8.09 (2H, d, Jꢀ6.8 Hz), 8.81 (2H, d, Jꢀ6.8 Hz), 10.82 (1H, s). IR (ATR)
cmꢁ1: 3050, 2734, 1698, 1617, 1597, 1205, 868, 802, 547. MS (APCI): 263
[MꢃH]ꢃ. HR-MS-ESI Calcd for C17H15N2O ([MꢃH]ꢃ): 263.1184.
1,4-Dimethyl-3-phenyl-5-[1-pyridin-3-ylmeth-(Z)-ylidene]-1,5-dihy-
dropyrrol-2-one Hydrochloride (3a) 60% Sodium hydride in oil (25 mg,
0.63 mmol) was slowly added to a solution of 11b (150 mg, 0.57 mmol) in
DMF (3 ml). The mixture was stirred for 1 h at room temperature and methyl
iodide (0.04 ml, 0.63 mmol) was added. After the addition, the mixture was
further stirred for 1.5 h at room temperature. Water and ethyl acetate were
added to the mixture and the organic layer was separated. The organic layer
was washed with water, dried and concentrated in vacuo. The resulting
residue was chromatographed on silica gel to give 100 mg (63%) of 1,4-di-
methyl-3-phenyl-5-[1-pyridin-3-ylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2-
one (11e) as a solid. mp 129—130 °C.
methyl-3-phenyl-5-[1-pyridin-4-ylmeth-(E)-ylidene]-5H-furan-2-one
(8a)
and 1.16 g (77%) of 4-methyl-3-phenyl-5-[1-pyridin-4-ylmeth-(Z)-ylidene]-
5H-furan-2-one (8b) as a solid. mp 127—128 °C (8a), 189—190 °C (8b).
To a 8a (200 mg, 0.76 mmol) solution in CHCl3 (10 ml) was added 4 N
HCl in ethyl acetate (0.19 ml) and the mixture was stirred for 10 min. The
reaction mixture was then concentrated in vacuo. The resulting residue was
triturated with diethyl ether and filtrated to afford 1a (212 mg, 93%) as a
solid. mp ꢂ230 °C. 1H-NMR (400 MHz, DMSO-d6) d: 2.03 (3H, s), 7.21
(1H, s), 7.45—7.58 (5H, m), 8.05 (2H, d, Jꢀ6.4 Hz), 8.89 (2H, d,
Jꢀ6.4 Hz). IR (ATR) cmꢁ1: 3045, 2948, 2382, 2117, 2011, 1754, 1652,
1627, 1598, 1494, 1178, 1058, 981, 789, 750, 696, 536, 481. MS (APCI):
264 [MꢃH]ꢃ. HR-MS-ESI Calcd for C17H14NO2 ([MꢃH]ꢃ): 264.1025.
Found: 264.1024.
1b, prepared from 8b as described in the synthesis of 1a, was obtained as
a solid. Yield 94%. mp 279—280 °C (dec.). 1H-NMR (400 MHz, DMSO-d6)
d: 2.41 (3H, s), 6.90 (1H, s), 7.45—7.70 (5H, m), 8.22 (2H, d, Jꢀ6.7 Hz),
8.88 (2H, d, Jꢀ6.7 Hz). IR (ATR) cmꢁ1: 3059, 2969, 1772, 1651, 1629,
1584, 1496, 1478, 1445, 1186, 1153, 953, 871, 797, 786, 692, 546. MS
(APCI): 264 [MꢃH]ꢃ. HR-MS-ESI Calcd for C17H14NO2 ([MꢃH]ꢃ):
264.1025. Found: 264.1022.
4-Methyl-2-oxo-3-phenyl-2,5-dihydropyrrole-1-carboxylic Acid tert-
Butyl Ester (10) To a solution of 4-methyl-3-phenyl-1,5-dihydropyrrol-2-
one 922) (5.1 g, 29.4 mmol) in CH2Cl2 (50 ml) were added (Boc)2O (9.6 g,
44.2 mmol) and N,N-dimethyl-4-aminopyridine (72 mg, 0.59 mmol) and the
mixture was stirred at 40 °C for 30 min. After the reaction mixture was con-
centrated in vacuo, the resulting residue was chromatographed on silica gel
to give 5.8 g (72%) of 10. mp 127—128 °C. 1H-NMR (400 MHz, DMSO-d6)
d: 1.49 (9H, s), 2.11 (3H, s), 4.34 (2H, s), 7.34—7.40 (3H, m), 7.41—7.47
(2H, m). IR (ATR) cmꢁ1: 2980, 1748, 1362, 1302, 1161, 1093, 695. MS
(APCI): 274 [MꢃH]ꢃ. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N,
5.12. Found: C, 70.28; H, 7.05; N, 5.09.
To a solution of 11e (90 mg, 0.33 mmol) in CHCl3 (10 ml) was added 4 N
HCl in ethyl acetate (0.09 ml) and the mixture was stirred for 10 min. The
reaction mixture was then concentrated in vacuo. The resulting residue was
triturated with diethyl ether and filtrated to afford 3a (97 mg, 95%) as a
solid. mp 213—215 °C. 1H-NMR (400 MHz, DMSO-d6) d: 2.30 (3H, s),
2.84 (3H, s), 6.68 (1H, s), 7.37—7.55 (5H, m) 7.87 (1H, dd, Jꢀ8.0, 5.6 Hz),
8.34 (1H, d, Jꢀ8.0 Hz), 8.75 (1H, d, Jꢀ4.6 Hz), 8.90 (1H, d, Jꢀ1.5 Hz). IR
(ATR) cmꢁ1: 3415, 2515, 1683, 1633, 1554, 1438, 788, 682, 547. MS
(APCI): 277 [MꢃH]ꢃ. HR-MS-ESI Calcd for C18H17N2O ([MꢃH]ꢃ):
277.1341. Found: 277.1330.
1,4-Dimethyl-3-phenyl-5-[1-pyridin-4-ylmeth-(Z)-ylidene]-1,5-dihy-
dropyrrol-2-one Hydrochloride (3b) This compound, prepared from 11d
as described in the synthesis of 3a, was obtained as a solid. Yield 65%. mp
1
239—241 °C. H-NMR (400 MHz, DMSO-d6) d: 2.31 (3H, s), 2.90 (3H, s),
6.74 (1H, s), 7.40—7.56 (5H, m) 7.94 (2H, d, Jꢀ6.5 Hz), 8.82 (2H, d,
Jꢀ6.5 Hz). IR (ATR) cmꢁ1: 3499, 3374, 2615, 2073, 1689, 1621, 1606,
1505, 1385, 1242, 856, 632, 547. MS (APCI): 277 [MꢃH]ꢃ. HR-MS-ESI
Calcd for C18H17N2O ([MꢃH]ꢃ): 277.1341. Found: 277.1330.
4-Methyl-3-phenyl-5-[1-pyridin-3-ylmeth-(E)-ylidene]-1,5-dihydro-
pyrrol-2-one Hydrochloride (2a); 4-Methyl-3-phenyl-5-[1-pyridin-3-
ylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2-one Hydrochloride (2b) 1 M
tert-Butoxycarbonylphenylacetylaminoacetic Acid Methyl Ester (13)

September 2009
983
To a solution of phenylacetylaminoacetic acid methyl ester 12 (500 mg,
2.41 mmol) in acetonitrile (20 ml) were added (Boc)2O (630 mg, 2.89 mmol)
and N,N-dimethyl-4-aminopyridine (15 mg, 0.12 mmol) at 0 °C and the mix-
ture was stirred at room temperature for 2 h. After the reaction mixture was
concentrated in vacuo, water and ethyl acetate were added to the residue.
The organic layer was separated, washed with brine, dried and concentrated
in vacuo. The resulting residue was chromatographed on silica gel to give
(1H, d, Jꢀ7.9 Hz), 7.32—7.47 (3H, m), 7.52—7.56 (2H, m), 10.09 (1H, s).
IR (ATR) cmꢁ1: 3174, 1674, 1656, 1626, 1594, 1349, 1224, 1149, 1009,
780, 682, 647, 448. MS (APCI): 338 [MꢃH]ꢃ.
To a 17 (2.8 g, 8.3 mmol) solution in THF (100 ml) was added 6 N aqueous
HCl solution (10 ml) and the mixture was stirred at 50 °C for 2 h. After
water and ethyl acetate were added to the mixture, the organic layer was sep-
arated, dried and concentrated in vacuo. The resulting residue was triturated
with diethyl ether and filtrated to give 2.1 g (86%) of 5-[1-(3-hydroxy-
phenyl)meth-(Z)-ylidene]-4-methoxy-3-phenyl-1,5-dihydropyrrol-2-one (18)
as a solid. mp 188—189 °C. 1H-NMR (400 MHz, DMSO-d6) d: 3.73 (3H, s),
6.22 (1H, s), 6.72 (1H, dd, Jꢀ8.0, 2.3 Hz), 6.94 (1H, s), 7.06 (1H, d,
Jꢀ8.0 Hz), 7.19 (1H, t, Jꢀ8.0 Hz), 7.32—7.46 (3H, m), 7.50—7.57 (2H,
m), 9.46 (1H, s), 9.94 (1H, s). IR (ATR) cmꢁ1: 3314, 1656, 1594, 1451,
1361, 1231, 965, 738, 639. MS (APCI): 294 [MꢃH]ꢃ.
1
405 mg (55%) of 13 as an oil. H-NMR (200 MHz, CDCl3) d: 1.48 (9H, s),
3.73 (3H, s), 4.30 (2H, s), 4.47 (2H, s), 7.15—7.40 (5H, m). MS (SIMS):
308 [MꢃH]ꢃ.
4-Hydroxy-2-oxo-3-phenyl-2,5-dihydropyrrole-1-carboxylic Acid tert-
Butyl Ester (14) Potassium tert-butoxide (88 mg, 0.78 mmol) was slowly
added to a solution of 13 (200 mg, 0.65 mmol) in DMF (10 ml) and the mix-
ture was stirred for 10 min at room temperature. Aqueous saturated ammo-
nium chloride solution, water and ethyl acetate were added to the reaction
mixture. The organic layer was separated, washed with water, dried and con-
centrated in vacuo. The resulting residue was triturated with diethyl ether
and filtrated to afford 14 (120 mg, 68%) as a solid. mp 152 °C. 1H-NMR
(400 MHz, DMSO-d6) d: 1.48 (9H, s), 4.27 (2H, s), 7.21 (1H, t, Jꢀ7.4 Hz),
7.35 (2H, t, Jꢀ7.6 Hz), 7.85 (2H, d, Jꢀ7.2 Hz), 12.36 (1H, br). IR (ATR)
cmꢁ1: 3144, 1718, 1663, 1640, 1349, 1312, 1153, 694. MS (APCI): 276
[MꢃH]ꢃ. Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.46; H, 6.22; N, 5.13.
60% Sodium hydride in oil (300 mg, 7.5 mmol) was slowly added to a so-
lution of 18 (1.8 g, 6.1 mmol) in DMF (50 ml). The mixture was stirred at
room temperature for 1 h and bromoacetic acid tert-butyl ester (2.3 g,
11.8 mmol) was added. After the addition, the mixture was further stirred at
room temperature for 16 h. Water and ethyl acetate were added to the mix-
ture and the organic layer was separated. The organic layer was washed with
water, dried and concentrated in vacuo. The resulting residue was chro-
matographed on silica gel to give 1.2 g (43%) of {3-[3-methoxy-5-oxo-4-
phenyl-1,5-dihydropyrrol-(2Z)-ylidenemethyl]phenoxy}acetic acid tert-butyl
1
4-Methoxy-2-oxo-3-phenyl-2,5-dihydropyrrole-1-carboxylic Acid tert-
Butyl Ester (15) Potassium carbonate (30 g, 217.5 mmol) and dimethyl
sulfate (27 ml, 290 mmol) were added to a solution of 14 in acetone (1 l) and
the mixture was stirred for 3 h at reflux. Water and ethyl acetate were then
added to the mixture and the organic layer was separated. The organic layer
was dried and concentrated in vacuo. The resulting residue 15 (39 g, 93%)
ester (19) as a solid. mp 167—168 °C. H-NMR (200 MHz, CDCl3) d: 1.49
(9H, s), 3.78 (3H, s), 4.53 (2H, s), 6.34 (1H, s), 6.83 (1H, dd, Jꢀ8.2,
2.5 Hz), 6.95 (1H, br), 7.05 (1H, d, Jꢀ7.7 Hz), 7.32 (1H, d, Jꢀ8.2 Hz),
7.34—7.56 (5H, m), 7.71 (1H, br).
Trifluoroacetic acid (1 ml) was added to a solution of 19 (900 mg,
2.21 mmol) in CH2Cl2 (1 ml) and the reaction mixture was stirred at room
temperature for 2 h. After the mixture was concentrated in vacuo, the result-
ing residue was triturated with diethyl ether and filtrated to give 720 mg
(93%) of 4b as a solid. mp 224—226 °C. 1H-NMR (400 MHz, DMSO-d6) d:
3.73 (3H, s), 4.79 (2H, s), 6.29 (1H, s), 6.86 (1H, dd, Jꢀ8.2, 2.3 Hz), 7.09
(1H, s), 7.20 (1H, d, Jꢀ7.9 Hz), 7.30 (1H, t, Jꢀ7.9 Hz), 7.33—7.39 (1H, m),
7.43 (2H, t, Jꢀ7.0 Hz), 7.54 (2H, d, Jꢀ7.0 Hz), 10.14 (1H, s). IR (ATR)
cmꢁ1: 3240, 2861, 2503, 1884, 1702, 1658, 1618, 1590, 1299, 1228, 973,
655, 506. MS (APCI): 352 [MꢃH]ꢃ. HR-MS-ESI Calcd for C20H18NO5
([MꢃH]ꢃ): 352.1185. Found: 352.1169. Anal. Calcd for C20H17NO5: C,
68.37; H, 4.88; N, 3.99. Found: C, 68.28; H, 4.77; N, 4.05.
3,4-Diphenyl-1,5-dihydropyrrol-2-one (6) Triethylamine (150 ml,
1.08 mol) was slowly added to a suspension of N-(2-oxo-2-phenylethyl)-2-
phenylacetamide 20 (32.4 g, 128 mmol) in acetic anhydride (150 ml) at 0 °C.
After the reaction mixture was stirred at room temperature for 13 h, the mix-
ture was concentrated in vacuo. Water and ethyl acetate were added to the
residue, and the organic layer was separated, washed with aqueous saturated
citric acid solution, aqueous saturated NaHCO3 solution and brine, dried and
concentrated in vacuo. Toluene (100 ml) was then added to the resulting
residue, and the mixture was concentrated in vacuo. The residue was tritu-
rated with diethyl ether and filtrated to give 28.2 g (80%) of 1-acetyl-3,4-
diphenyl-1,5-dihydropyrrol-2-one (21) as a solid. mp 154—155 °C. 1H-
NMR (400 MHz, DMSO-d6) d: 2.51 (3H, s), 4.81 (2H, s), 7.25—7.45 (10H,
m). IR (ATR) cmꢁ1: 3059, 1707, 1688, 1639, 1371, 1333, 1291, 691. MS
(APCI): 278 [MꢃH]ꢃ.
1
was used for the next reaction without further purification. mp 152 °C. H-
NMR (400 MHz, DMSO-d6) d: 1.50 (9H, s), 4.01 (3H, s), 4.62 (2H, s), 7.25
(1H, t, Jꢀ7.4 Hz), 7.37 (2H, t, Jꢀ7.6 Hz), 7.76 (2H, d, Jꢀ7.2 Hz). IR (ATR)
cmꢁ1: 2982, 1707, 1629, 1315, 1153, 1012, 781, 697. MS (APCI): 290
[MꢃH]ꢃ. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C,
66.46; H, 6.62; N, 4.91.
4-Methoxy-3-phenyl-5-[1-pyridin-4-ylmeth-(Z)-ylidene]-1,5-dihy-
dropyrrol-2-one Hydrochloride (4a) 0.5 M Potassium hexamethyldisi-
lazide in toluene (8.9 ml, 4.45 mmol) was slowly added to a solution of 15
(1.0 g, 2.98 mmol) in THF (20 ml) at ꢁ78 °C and the reaction mixture was
stirred for 20 min at the same temperature, then at 0 °C for 10 min. 4-
Pyridinecarboxaldehyde (0.43 ml, 4.47 mmol) was slowly added to the reac-
tion mixture at ꢁ78 °C and the mixture was stirred at 0 °C for 2 h. After
aqueous saturated ammonium chloride solution was added to the reaction
mixture, CHCl3 was added. The organic layer was separated, washed with
water and brine, dried and concentrated in vacuo. The resulting residue was
triturated with diethyl ether and filtrated. The crystals obtained were recrys-
tallized from THF to give 120 mg (14%) of 4-methoxy-3-phenyl-5-[1-
pyridin-4-ylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2-one (16) as crystals. mp
232—234 °C (dec.).
To a solution of 16 (120 mg, 0.43 mmol) in THF (20 ml) was added 4 N
HCl in dioxane (0.15 ml) and the mixture was stirred for 10 min. The reac-
tion mixture was then concentrated in vacuo. The resulting residue was tritu-
rated with diethyl ether and filtrated to afford 4a (50 mg, 37%) as a solid. mp
227—228 °C (dec.). 1H-NMR (400 MHz, DMSO-d6) d: 3.78 (3H, s), 6.47
(1H, s), 7.35—7.55 (5H, m), 8.11 (2H, d, Jꢀ6.8 Hz), 8.81 (2H, d,
Jꢀ6.8 Hz), 10.72 (1H, s). IR (ATR) cmꢁ1: 3354, 3046, 2742, 2056, 1702,
1620, 1596, 1493, 1348, 1193, 1019, 870, 803, 698, 522. MS (APCI): 279
[MꢃH]ꢃ. HR-MS-ESI Calcd for C17H15N2O2 ([MꢃH]ꢃ): 279.1134. Found:
279.1126.
{3-[3-Methoxy-5-oxo-4-phenyl-1,5-dihydropyrrol-(2Z)-ylidene-
methyl]phenoxy}acetic Acid (4b) 0.5 M Potassium hexamethyldisilazide
in toluene (72 ml, 36 mmol) was slowly added to a solution of 15 (7.0 g,
24 mmol) in THF (200 ml) at ꢁ78 °C and the reaction mixture was stirred at
ꢁ5 °C for 30 min. 3-Methoxymethoxybenzaldehyde (3.7 g, 22.3 mmol) was
added slowly to the reaction mixture at ꢁ70 °C and the mixture was stirred
at 0 °C for 2 h and at room temperature for 2 h. After aqueous saturated am-
monium chloride solution was added to the reaction mixture, ethyl acetate
was added. The organic layer was separated, dried and concentrated in
vacuo. The resulting residue was triturated with diethyl ether and filtrated.
The crystals obtained were recrystallized from ethyl acetate to give 3.3 g
(44%) of 4-methoxy-5-[1-(3-methoxymethoxyphenyl)meth-(Z)-ylidene]-3-
phenyl-1,5-dihydropyrrol-2-one (17) as crystals. mp 170—171 °C. 1H-NMR
(400 MHz, DMSO-d6) d: 3.39 (3H, s), 3.73 (3H, s), 5.27 (2H, s), 6.28 (1H,
s), 6.96 (1H, dd, Jꢀ7.9, 2.3 Hz), 7.21 (1H, s), 7.24 (1H, d, Jꢀ7.9 Hz), 7.30
28% Sodium methoxide in MeOH (13.6 ml, 65.1 mmol) was slowly added
to a suspension of 21 (17.19 g, 62 mmol) in MeOH (400 ml) at 0 °C and the
reaction mixture was stirred at the same temperature for 1 h. After slow ad-
dition of acetic acid (3.71 ml, 65.1 mmol) to the mixture, the mixture was
concentrated in vacuo. Water and CH2Cl2 were added to the residue, and the
organic layer was separated, washed with brine, dried and concentrated in
vacuo. The resulting residue was triturated with diethyl ether and filtrated to
1
give 14.01 g (96%) of 6 as a solid. mp 184—185 °C. H-NMR (400 MHz,
DMSO-d6) d: 4.37 (2H, s), 7.25—7.40 (10H, m), 8.52 (1H, s). IR (ATR)
cmꢁ1: 3189, 3059, 1681, 1444, 1368, 762, 743, 702, 689. MS (APCI): 236
[MꢃH]ꢃ. HR-MS-ESI Calcd for C16H14NO ([MꢃH]ꢃ): 236.1075. Found:
236.1067.
2-Oxo-3,4-dipenyl-2,5-dihydropyrrole-1-carboxylic Acid tert-Butyl-
ester (22) (Boc)2O (12.44 g, 57 mmol) and N,N-dimethyl-4-amino-
pyridine (348 mg, 2.85 mmol) were added to a suspension of 6 (6.71 g,
28.5 mol) in acetonitrile (300 ml) at 0 °C and the mixture was stirred at room
temperature for 3 h. Water and ethyl acetate were then added to the mixture,
and the organic layer was separated. The organic layer was washed with
brine, dried and concentrated in vacuo. The resulting residue was chro-
matographed on silica gel to give 2.44 g (26%) of 22 as a solid. mp 144—
146 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.52 (9H, s), 4.78 (2H, s), 7.22—

984
Vol. 57, No. 9
7.27 (2H, m), 7.32—7.43 (8H, m). IR (ATR) cmꢁ1: 2978, 1764, 1349, 1297, (ATR) cmꢁ1: 3163, 1672, 1583, 1421, 1246, 1181, 1044, 691. MS (APCI):
1160, 913, 691. MS (APCI): 336 [MꢃH]ꢃ. Anal. Calcd for C21H21NO3: C,
75.20; H, 6.31; N, 4.18. Found: C, 74.90; H, 6.29; N, 3.99.
396 [MꢁNa]ꢁ. HR-MS-ESI Calcd for C25H20NO4 ([MꢃH]ꢃ): 398.1392.
Found: 398.1392.
3,4-Diphenyl-5-[1-phenylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2-one
(5a) 0.5 M Potassium hexamethyldisilazide in toluene (7.2 ml, 3.6 mmol)
{2-[5-Oxo-3,4-diphenyl-1,5-dihydropyrrol-(2Z)-ylidenemethyl]phe-
noxy}acetic Acid Sodium Salt (5h) This compound, prepared from 22
was slowly added to a solution of 21 (500 mg, 1.8 mmol) and benzaldehyde and 2-formylphenoxyacetic acid tert-butyl ester as described in the synthesis
(0.27 ml, 2.7 mmol) in THF (20 ml) at ꢁ78 °C and the reaction mixture was of 16 and 5f, was obtained as a solid. Yield 67%. mp 357—360 °C (dec.).
stirred at ꢁ78 °C for 30 min and at room temperature for 12 h. After aque-
1H-NMR (400 MHz, DMSO-d6) d: 4.52 (2H, s), 5.92 (1H, s), 6.86—6.94
ous saturated ammonium chloride solution was added to the reaction mix- (2H, m), 7.17—7.35 (9H, m), 7.40—7.47 (3H, m), 11.66 (1H, s). IR (ATR)
ture, ethyl acetate was added. The organic layer was separated, dried and cmꢁ1: 3196, 1683, 1624, 1576, 1495, 1442, 798, 744, 731, 695, 639. MS
concentrated in vacuo. The resulting residue was triturated with diisopropyl (APCI): 396 [MꢁNa]ꢁ. HR-MS-ESI Calcd for C25H20NO4 ([MꢃH]ꢃ):
ether and filtrated. The crystals obtained were recrystallized from ethyl ac- 398.1392. Found: 398.1377.
etate, THF and diisopropyl ether to give 156 mg (27%) of 5a as crystals. mp
{3-[3-Furan-2-yl-5-oxo-4-phenyl-1,5-dihydropyrrol-(2Z)-ylidene-
243—244 °C. 1H-NMR (400 MHz, DMSO-d6) d: 5.84 (1H, s), 7.23—7.34 methyl]phenoxy}acetic Acid (5i) This compound, prepared from 4-(2-
(8H, m), 7.38 (2H, t, Jꢀ7.5 Hz), 7.44—7.49 (3H, m), 7.54 (2H, d, furyl)-3-phenyl-1,5-dihydropyrrol-2-one 2724) and 3-formylphenoxyacetic
Jꢀ7.5 Hz), 10.63 (1H, s). IR (ATR) cmꢁ1: 3217, 1682, 1635, 1222, 795, acid tert-butyl ester as described in the synthesis of 5j, was obtained as a
730, 683, 641, 517. MS (APCI): 324 [MꢃH]ꢃ. HR-MS-ESI Calcd for solid. Yield 60%. mp 214—216 °C. 1H-NMR (400 MHz, DMSO-d6) d: 4.80
C23H18NO ([MꢃH]ꢃ): 324.1388. Found: 324.1379.
(2H, s), 6.45 (1H, s), 6.68 (1H, dd, Jꢀ3.4, 1.8 Hz), 6.77 (1H, d, Jꢀ3.4 Hz),
3,4-Diphenyl-5-[1-pyridin-4-ylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2- 6.90 (1H, dd, Jꢀ8.1, 2.4 Hz), 7.10—7.45 (8H, m), 7.82 (1H, d, Jꢀ1.8 Hz),
one (5b) This compound, prepared from 22 and 4-pyridinecaeboxaldehyde 10.69 (1H, s). IR (ATR) cmꢁ1: 3237, 2504, 1702, 1641, 1300, 682. MS
as described in the synthesis of 16, was obtained as crystals. Yield 46%. mp (APCI): 388 [MꢃH]ꢃ. HR-MS-ESI Calcd for C23H18NO5 ([MꢃH]ꢃ):
236—237 °C (dec.). 1H-NMR (400 MHz, DMSO-d6) d: 5.78 (1H, s), 7.25— 388.1185. Found: 388.1184.
7.35 (7H, m), 7.45—7.52 (5H, m), 8.54 (2H, d, Jꢀ6.1 Hz), 10.80 (1H, s). IR
{3-[5-Oxo-4-phenyl-3-thiophen-2-yl-1,5-dihydropyrrol-(2Z)-ylidene-
(ATR) cmꢁ1: 3199, 3056, 1699, 1636, 1598, 1440, 1207, 692, 639, 481. MS methyl]phenoxy}acetic Acid (5j) 1,1ꢄ-Carbonyldiimidazole (12.16 g,
(APCI): 325 [MꢃH]ꢃ. HR-MS-ESI Calcd for C22H17N2O ([MꢃH]ꢃ):
75 mmol) was added to
a suspension of phenylacetic acid (9.72 g,
325.1341. Found: 325.1346.
71.4 mmol) in CH2Cl2 (70 ml) at room temperature and the mixture was
3,4-Diphenyl-5-[1-pyridin-3-ylmeth-(Z)-ylidene]-1,5-dihydropyrrol-2- stirred for 30 min. Triethylamine (11.94 ml, 85.68 mmol) and 2-amino-1-(2-
one (5c) This compound, prepared from 22 and 3-pyridinecaeboxaldehyde thiophenyl)ethanone hydrochloride 28 (12.68 g, 71.4 mmol) were then added
as described in the synthesis of 16, was obtained as crystals. Yield 29%. mp to the mixture at 0 °C. After the reaction mixture was stirred at room tem-
239—240 °C. 1H-NMR (400 MHz, DMSO-d6) d: 5.86 (1H, s), 7.23—7.37 perature for 14 h, aqueous 5% citric acid solution was added. The organic
(7H, m), 7.40 (1H, dd, Jꢀ7.5, 4.7 Hz), 7.43—7.52 (3H, m), 8.00 (1H, d, layer was separated, washed with aqueous saturated NaHCO3 solution and
Jꢀ8.2 Hz), 8.46 (1H, d, Jꢀ4.1 Hz), 8.66 (1H, s), 10.77 (1H, s). IR (ATR)
brine, dried and concentrated in vacuo. The residue was triturated with
cmꢁ1: 3199, 1677, 1442, 1217, 796, 731, 691, 515. MS (APCI): 325 EtOH and filtrated to give 12.34 g (67%) of N-[2-oxo-2-(2-thiophenyl)-
[MꢃH]ꢃ. HR-MS-ESI Calcd for C22H17N2O ([MꢃH]ꢃ): 325.1341. Found: ethyl]-2-phenylacetamide 29 as a solid. mp 90—92 °C. 1H-NMR (400 MHz,
325.1339.
DMSO-d6) d: 3.53 (2H, s), 4.54 (2H, d, Jꢀ5.6 Hz), 7.19—7.34 (6H, m),
5-[1-(3-Hydroxyphenyl)meth-(Z)-ylidene]-3,4-diphenyl-1,5-dihydro- 8.04 (2H, d, Jꢀ4.6 Hz), 8.48 (1H, t, Jꢀ5.6 Hz). IR (ATR) cmꢁ1: 3380, 3097,
pyrrol-2-one (5d) This compound, prepared from 22 and 3-methoxy- 1650, 1512, 1415, 1236, 723, 513, 478. MS (APCI): 260 [MꢃH]ꢃ. Anal.
methoxybenzaldehyde as described in the synthesis of 18, was obtained as a Calcd for C14H13NO2S: C, 64.84; H, 5.05; N, 5.40; S, 12.37. Found: C,
solid. Yield 38%. mp 226—227 °C. 1H-NMR (400 MHz, DMSO-d6) d: 5.75 64.46; H, 5.00; N, 5.36; S, 12.31.
(1H, s), 6.71 (1H, dd, Jꢀ7.9, 2.1 Hz), 6.86 (1H, s), 6.99 (1H, d, Jꢀ7.9 Hz),
7.18 (1H, t, Jꢀ7.9 Hz), 7.22—7.34 (7H, m), 7.43—7.49 (3H, m), 9.48 (1H, 57.6 mmol) in EtOH (50 ml) and the mixture was stirred at reflux for 30 min.
s), 10.51 (1H, s). IR (ATR) cmꢁ1: 3419, 3259, 3061, 1683, 1578, 1216, 727,
After slow addition of acetic acid (6.57 ml, 115.2 mmol) to the mixture at
683, 642. MS (APCI): 340 [MꢃH]ꢃ. HR-MS-ESI Calcd for C23H18NO2 0 °C, the mixture was concentrated in vacuo. Water and CH2Cl2 were then
([MꢃH]ꢃ): 340.1338. Found: 340.1324.
added to the residue, and the organic layer was separated, washed with brine,
95% Sodium methoxide (6.55 g, 115.2 mmol) was added to 29 (14.94 g,
5-[1-(3-Dimethoxymethylphenyl)meth-(Z)-ylidene]-3,4-diphenyl-1,5- dried and concentrated in vacuo. The resulting residue was triturated with
dihydropyrrol-2-one (5e) This compound, prepared from 22 and 3- MeOH and filtrated to give 7.91 g (57%) of 3-phenyl-4-(2-thiophenyl)-1,5-
dimethoxymethylbenzaldehyde as described in the synthesis of 16, was ob- dihydropyrrol-2-one 30 as a solid. mp 224—227 °C. 1H-NMR (400 MHz,
tained as crystals. Yield 55%. mp 235—236 °C. 1H-NMR (400 MHz,
DMSO-d6) d: 4.42 (2H, s), 7.07 (1H, dd, Jꢀ5.1, 3.8 Hz), 7.29—7.36 (3H,
DMSO-d6) d: 3.25 (6H, s), 5.39 (1H, s), 5.85 (1H, s), 7.23—7.35 (8H, m), m), 7.38—7.48 (3H, m), 7.56 (1H, d, Jꢀ5.1 Hz), 8.38 (1H, s). IR (ATR)
7.40 (1H, t, Jꢀ7.8 Hz), 7.44—7.50 (4H, m), 7.57 (1H, d, Jꢀ7.8 Hz), 10.67 cmꢁ1: 3170, 3050, 1677, 725, 697. MS (APCI): 242 [MꢃH]ꢃ.
(1H, s). IR (ATR) cmꢁ1: 3209, 2948, 1682, 1361, 1049, 794, 734, 693, 642.
A solution of NaOH (260 mg, 6.5 mmol) in water (1 ml) was added to a
suspension of 30 (145 mg, 0.6 mmol) and 3-formylphenoxyacetic acid tert-
MS (APCI): 398 [MꢃH]ꢃ. HR-MS-ESI Calcd for C26H24NO3 ([MꢃH]ꢃ):
398.1756. Found: 398.1737. Anal. Calcd for C26H23NO3: C, 78.57; H, 5.83; butyl ester (118 mg, 0.5 mmol) in MeOH (2.5 ml). After stirring the mixture
N, 3.52. Found: C, 78.55; H, 5.94; N, 3.62. at room temperature for 16 h, 2 N HCl aqueous solution (3.25 ml) was added,
{3-[5-Oxo-3,4-diphenyl-1,5-dihydropyrrol-(2Z)-ylidenemethyl]phe- and the reaction mixture was concentrated in vacuo. Water and CHCl3 were
noxy}acetic Acid Sodium Salt (5f) Following the synthetic method of 4b, then added to the residue. The organic layer was separated, washed with
{3-[5-oxo-3,4-diphenyl-1,5-dihydropyrrol-(2Z)-ylidenemethyl]phenoxy}acetic
acid (free form) was prepared from 5d as crystals. Yield 61%. mp 247—
248 °C. To a 397.5 mg (1 mmol) of free form solution in MeOH (10 ml) was
added 2 N NaOH aqueous solution (0.5 ml). After the reaction mixture was
stirred for 10 min at room temperature, the mixture was concentrated in
aqueous 5% citric acid solution, dried and concentrated in vacuo. The
residue was triturated with MeOH and filtrated to give 175 mg (87%) of 5j
as a solid. mp 261—263 °C. 1H-NMR (400 MHz, DMSO-d6) d: 4.79 (2H, s),
6.17 (1H, s), 6.88 (1H, dd, Jꢀ8.2, 2.3 Hz), 7.08 (1H, s), 7.16 (1H, d,
Jꢀ7.6 Hz), 7.18—7.38 (8H, m), 7.75 (1H, d, Jꢀ4.9 Hz), 10.75 (1H, s). IR
vacuo. The resulting residue was triturated with diethyl ether and filtrated to (ATR) cmꢁ1: 3218, 2499, 1890, 1705, 1646, 1622, 1307, 793, 687, 652, 442.
give 419 mg (quant.) of 5f as a solid. mp ꢂ320 °C. 1H-NMR (400 MHz,
DMSO-d6) d: 4.16 (2H, s), 5.78 (1H, s), 6.76 (1H, dd, Jꢀ8.1, 2.2 Hz), 6.90
(1H, s), 7.02 (1H, d, Jꢀ7.7 Hz), 7.21 (1H, t, Jꢀ8.1 Hz), 7.23—7.35 (7H, m),
7.42—7.49 (3H, m), 10.59 (1H, s). IR (ATR) cmꢁ1: 3242, 1690, 1601, 1426,
MS (APCI): 404 [MꢃH]ꢃ. HR-MS-ESI Calcd for C23H18NO4S ([MꢃH]ꢃ):
404.0957. Found: 404.0960. Anal. Calcd for C23H17NO4S: C, 68.47; H, 4.25;
N, 3.47; S, 7.95. Found: C, 68.17; H, 4.33; N, 3.67.
Inhibitory Effect on the Reaction of Human PAI-1 with t-PA The ex-
1219, 687. MS (APCI): 396 [MꢁNa]ꢁ. HR-MS-ESI Calcd for C25H20NO4 periment was performed according to the method of Keijer et al.25) Inhibi-
([MꢃH]ꢃ): 398.1392. Found: 398.1396.
{4-[5-Oxo-3,4-diphenyl-1,5-dihydropyrrol-(2Z)-ylidenemethyl]phe- residual t-PA activity. Twenty-five microliters of t-PA solution (final conc.
tion of the interaction between t-PA and PAI-1 was determined by measuring
noxy}acetic Acid Sodium Salt (5g) This compound, prepared from 22
and 4-formylphenoxyacetic acid tert-butyl ester as described in the synthesis
of 16 and 5f, was obtained as a solid. Yield 46%. mp 270—275 °C (dec.).
0.2 nM) and 25 ml of assay buffer or PAI-1 solution (PAI-1 was added so as to
inhibit t-PA activity by 75% in the absence of test compound) were mixed
and incubated with 2.5 ml of a test compound solution (dissolved in DMSO)
1H-NMR (400 MHz, DMSO-d6) d: 4.09 (2H, s), 5.78 (1H, s), 6.78 (2H, d, at 25 °C for 15 min. Two hundred microliters of a chromogenic substrate so-
Jꢀ8.7 Hz), 7.21—7.32 (7H, m), 7.42—7.49 (5H, m), 10.53 (1H, s). IR lution (S-2288: H-D-iie-Pro-Arg-pNA) was then added to the mixture, and

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the whole was incubated at 37 °C. The increase in absorbance at 405 nm was 10) Biemond B. J., Levi M., Coronel R., Janse M. J., Ten Cate J. W., Pan-
continuously (every 5 min) monitored for 2 h with a microplatereader and nekoek H., Circulation, 91, 1175—1181 (1995).
DA/D min was calculated. The IC50 value was estimated as the concentration 11) Folkes A., Roe M. B., Sohal S., Golec J., Faint R., Brooks T., Charlton
that inhibits PAI-1 activity by 50%. P., Bioorg. Med. Chem. Lett., 11, 2589—2592 (2001).
Antithrombotic Activity of 5f (T-1776Na) in a Rat Model of Arterial 12) Folkes A., Brown S. D., Canne L. E., Chan J., Engelhardt E., Epshteyn
Thrombosis Thrombus was induced in the abdominal aorta by electrical
stimulation.26) On the day before the experiment, a catheter-type platinum
electrode was implanted into the abdominal aorta through the left femoral
artery under Nembutal (Abbot, 50 mg/kg, ip) anesthesia. After the end of the
S., Faint R., Golec J., Hanel A., Kearney E., Leahy J. W., Mac M.,
Matthews D., Prisbylla M. P., Sanderson J., Simon R. J., Tesfai Z.,
Vicker N., Wang S., Webb R. R., Charlton P., Bioorg. Med. Chem.
Lett., 12, 1063—1066 (2002).
electrode was exteriorized at the back of the neck, a plate-type silver–silver 13) Wang S., Golec J., Miller W., Milutinovic S., Folkes A., Williams S.,
chloride was implanted subcutaneously at the back of the neck at the oppo-
site pole. After suturing the incisions, an electric cell and a variable resist-
Brooks T., Hardman K., Charlton P., Wren S., Spencer J., Bioorg. Med.
Chem. Lett., 12, 2367—2370 (2002).
ance were placed on the back, each secured by adhesive tape, to act as a 14) De Nanteuil G., Lila-Ambroise C., Rupin A., Vallez M. O., Verbeuren
power source and fine-tuning the current, respectively. The rats were allowed T. J., Bioorg. Med. Chem. Lett., 13, 1705—1708 (2003).
to recover overnight in individual cages. In the experiment, each electrode 15) Ye B., Bauer S., Buckman B. O., Ghannam A., Griedel B. D., Khim S.
was connected to the electric cell and a direct current (200 mA) was applied
continuously for 4 h. Test compound or its vehicle was intravenously infused
at the dose indicated during electrical stimulation. After current application
was stopped, the rats were anesthetized again, and the thrombus formed was
removed and its wet weight was measured with an electronic balance. Re-
sults are expressed as the meansꢅS.E. of 10 rats.
K., Lee W., Sacchi K. L., Shaw K. J., Liang A., Wu Q., Zhao Z.,
Bioorg. Med. Chem. Lett., 13, 3361—3365 (2003).
16) Ye B., Chou Y. L., Karanjawala R., Lee W., Lu S. F., Shaw K. J., Jones
S., Lentz D., Liang A., Tseng J. L., Wu Q., Zhao Z., Bioorg. Med.
Chem. Lett., 14, 761—765 (2004).
17) Gopalsamy A., Kincaid S. L., Ellingboe J. W., Groeling T. M., Antrilli
T. M., Krishnamurthy G., Aulabaugh A., Friedrichs G. S., Crandall D.
L., Bioorg. Med. Chem. Lett., 14, 3477—3480 (2004).
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