N-Arylated pyrrolidin-2-ones and morpholin-3-ones as potassium channel openers.

Article abstract of DOI:10.1016/S0968-0896(02)00171-2

Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-3-one (3-5), piperidin-2-one (6), and pyrrolidin-2-one (7-13) was synthesized and evaluated for potassium channel opening activity. In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-on (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demonstrated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder)=7.4 and 6.7 microM, respectively; IC50 ratio (portal vein/bladder)=41 and 51, respectively].

Full text of DOI:10.1016/S0968-0896(02)00171-2

Bioorganic & Medicinal Chemistry 10 (2002) 3267–3276
N-Arylated Pyrrolidin-2-ones and Morpholin-3-ones as
Potassium Channel Openers
Pi-Hui Liang, Ling-Wei Hsin and Chen-Yu Cheng*
Institute of Pharmaceutical Sciences, College of Medicine, National Taiwan University, Taipei 10018, Taiwan
Received 29 January 2002; accepted 6 May 2002
Abstract—Based on the most stable conformation of ZD6169, a series of N-arylated derivatives of oxazolidindione (2), morpholin-
3-one (3–5), piperidin-2-one (6), and pyrrolidin-2-one (7–13) was synthesized and evaluated for potassium channel opening activity.
In the in-vitro assays, N-(4-benzoylphenyl)-piperidin-2-one (6) and N-(4-benzoylphenyl)-3,3-dimethyl-pyrrolidin-2-one (9) demon-
strated potent and selective relaxant activity at the bladder detrusor muscle [IC50, bladder=7.4 and 6.7 mM, respectively; IC50 ratio
(portal vein/bladder)=41 and 51, respectively]. # 2002 Elsevier Science Ltd. All rights reserved.
Introduction
been shown to hyperpolarize membrane potential, thus
decreasing the probability of opening of voltage-depen-
dent Ca2+ channels. This would in turn reduce Ca2+
entry and muscle contraction, and thus relax the hyper-
active bladder.6 Recent study with cromakalim suggest
that KCOs are potential therapeutic agents for the
treatment of detrusor instability and hyperreflexia.
However, full utility of KCOs against urinary incon-
tinence will only be realized with compounds that have
minimal hemodynamic side effects, such as hypotension
and tachycardia.
Urinary incontinence (UI), a widespread and distressing
condition with the elderly population, can be classified
into four types: urge, stress, reflux, and overflow incon-
tinence.1 Urinary urge incontinence (UUI), the most
prevalent category among the four types of incon-
tinence, has been characterized by abnormal sponta-
neous detrusor contractions, which produce a chronic
sensation of urgency, and result in involuntary urine
loss. Depending upon the age of the patients, UUI
accounts for 35–65% of all incontinence cases.2 Con-
ventional medical treatments for UI include anti-
muscarinic, antispasmodic, and mixed antimuscarinic/
antispasmodic agents.3 These treatments have shown
limited success due to their generally low efficacy and/or
high incidence of side effects. Therefore, the search for
more specific and effective pharmacotherapy for UI is
still a worthwhile endeavor from both scientific and
commercial points of view.
Bladder-selective ATP-sensitive KCOs, which may be
useful in the treatment of UI, were not reported until
recently. Investigators at Zeneca Pharmaceuticals dis-
covered a series of anilide tertiary carbinols represented
by ZD6169, which has received considerable attention
following the initial report of its bladder-selective prop-
erties.7 The identification of ZD6169 as a bladder
smooth muscle relaxant and an opener of KATP chan-
nels in the detrusor has been established through a series
of in vitro studies, including tissue function, electro-
physiological evaluations, radioisotope efflux, and
binding assays.8À11 In vivo studies showed that ZD6169
significantly reduced micturition frequency in rats
(ED50=0.16 mg/kg); while its effect on cardiovascular
parameters was minimal (ED20=30 mg/kg).12 Research-
ers were able to show that ZD6169, administered either
orally (3 mg/kg) or intra-arterially (1 mg/kg), inhibited
PGE2-induced bladder overactivity.13,14 At the oral
dose to reduce bladder overactivity in rats, ZD6169 has
been reported to have either no effect12 or minimal
effect14 on mean arterial pressure. ZD6169 was
Several potent ATP-sensitive potassium channel open-
ers (KCOs) such as cromakalim and pinacidil (Chart 1)
have been studied clinically as antihypertensive agents.4
ATP-dependent potassium (KATP) channels also exist in
the bladder and it can be activated by numerous
antihypertensive KCOs.5 Activation of KATP channels
present on the smooth muscle cells of the detrusor has
*Corresponding author at current address: Formosa Laboratories,
Inc., No. 36-1, Hoping Street, Louchu County, Taoyuan 338,
Taiwan. Tel.: +886-3-324-5501; fax: +886-3-324-5492; e-mail: cyc@
formosalab.com
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00171-2

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P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
advanced as far as phase II clinical trail; however, its
development has been reportedly terminated in favor of
ZD0947.15
It has been postulated that ZD6169 exists in two energy-
minimized conformations (I and II, Fig. 1a), both
involving the formation of intra-molecular hydrogen
bond. The OH group eclipses the NH group in con-
former I, whereas the OH group eclipses the carbonyl
group in conformer II. Conformer I was calculated to
have a lower minimized energy (11.7 kcal/mol) than
conformer II (13.3 kcal/mol; Fig. 1c and d).19 Besides,
it can be seen that the X-ray diffraction structure of
More recent examples of bladder-selective KCO’s
16
include ZM244085
and WAY-133537.17 Previous
efforts in this laboratory have resulted in the discovery
of a series of rigid cromakalim analogues with bladder-
selective KCO activity, as represented by HI-21.18
Chart 1.
Figure 1. (a) Conformer I and conformer II resulted from intramolecular hydrogen bonding of ZD6169; (b) X-ray diffraction structure of ZD6169;
(c) energy minimization of conformer I; (d) energy minimization of conformer II.

P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
3269
Chart 2.
ZD6169 (Fig. 1b)7b,20 resembles conformer I rather than
conformer II. This result drove our attention to the
synthesis of N-aryl-oxazolidindione 2 and morpholin-2-
ones 3–5, which mimic conformer I of ZD6169. To fur-
ther study the roles of hetero-atoms and a-substituents
in compounds 2 and 3, piperidin-2-one derivative 6, and
pyrrolidin-2-one derivatives 7–13 were also synthesized
(Chart 2). The KCO activity of compounds 2–13 were
investigated with in-vitro tissue assays.
were synthesized by condensation of 4-aminobenzo-
phenone with the appropriate lactones in the presence
of anhydrous aluminum chloride21 in yields of 92% and
90%, respectively (Scheme 2). However, when 4-amino-
benzophenone was reacted with a-trifluromethyl- or
a-methyl-g-butyrolactone in the presence of AlCl3, only
small amounts of the corresponding amides could be
isolated from a complex mixture of products. Thus,
4-aminobenzophenone was coupled with a-methyl-g-
butyrolactone in the presence of Al(CH3)3, a milder
Lewis acid, to give the g-hydroxyamide intermediate 18,
which then underwent lactam formation under Mitsu-
nobu reaction condition22 to provide N-(4-benzoylphe-
nyl)-3-methylpyrrolidin-2-one (7) as shown in Scheme 3.
Compound 8, the trifluoromethyl analogue of 7, was
prepared in a similar fashion, albeit in lower yield. N-(4-
Benzoylphenyl)-3,3-dimethylpyrrolidin-2-one (9) and N-
(4-benzoylphenyl)-3-hydroxy-3-methylpyrrolidin-2-one
(12) were prepared from 7 via base-catalyzed a-methy-
lation and a-hydroxylation, respectively. When the
chiral Davis’ reagent23 was used in the above hydroxyl-
ation reaction, (À)-12 was obtained in 73% yield.
However, when compound 8 was subjected to the above
reaction conditions, instead of the desired methylation
and hydroxylation products, only the defluorinated
product 10 was obtained. A similar observation has
been documented in the literature.24 Alternatively,
compound 12 and its trifluoromethyl analogue 13 were
synthesized starting from ethyl pyruvates 20 and 21.
Thus compounds 20 and 21 underwent alkylation with
allyl magnesium bromide, followed by basic hydrolysis
to give 2-hydroxy-2-methyl-4-pentenoic acid (22) and its
trifluoromethyl analogue 23 (Scheme 4). Compounds 22
Chemistry
Target compounds 2–13 were synthesized using three
different routes. N-(4-Benzoylphenyl)-5-methyl-5-tri-
fluoromethyl-2,4-oxazolidinedione (2) was prepared
from racemic ZD6169 via treatment with 1,1-carbo-
nyldiimidazole under basic conditions; while N-aryl-2-
methyl-2-trifluoromethylmorpholin-3-ones 3–5 were
obtained from the appropriate aniline tertiary carbinols
by treatment with 1-bromo-2-chloroethane as shown in
Scheme 1. N-(4-Benzoylphenyl)piperidin-2-one (6) and
N-(4-benzoylphenyl)-3-hydroxypyrrolidin-2-one
(11)
Scheme 1. Reagents and conditions: (a) SOCl2, RC6H4NH2, TEA,
DMF, À24 ꢀC to rt; (b) KHMDS (2 equiv), 1,1-carbonyldiimidazole,
THF, À20 ꢀC to rt, 24 h; (c) 1-bromo-2-chloroethane, K2CO3, 18-
crown-6-ether, DMF, 100 ꢀC, 7 days.
Scheme 2. Reagents: (a) AlCl3, 120Æ5 ꢀC, 1 day.

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P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
activity has been shown to reside in ZD6169, thus
making (Æ)-1 about 2-fold less potent than ZD6169.7b
The rigidization of ZD6169 with a carbonyl group
between the amide nitrogen and the teritary hydroxyl
group (2) resulted in a 4-fold decrease in activity at the
detrusor and an 8-fold decrease in activity at the portal
vein. When the above carbonyl group in compound 2
was changed to an ethylene bridge, further decrease in
the activity at the portal vein was observed, which
resulted in compound 3 being a bladder-selective KCO
(IC50 ratio=1.8). The replacement of the benzoyl group
in 3 with a more electron-withdrawing trifluoromethyl
group as in compound 4 resulted in further increase in
bladder selectivity (IC50 ratio=17). Furthermore, it was
surprising to note that the simple piperidone derivative
6 demonstrated potent and selective relaxant activity at
Scheme 3. Reagents and conditions: (a) Al(CH3)3, CH2Cl2, rt; (b)
DEAD, PPh3, CH2Cl2, rt, 24 h; (c) LDA, THF, À78 ꢀC, 30 min; then
MeI, À23 ꢀC to 0 ꢀC, 3 h; (d) LDA, THF, À78 ꢀC, 1 h; then O2, À78 ꢀC
to rt; (e) LDA, THF, À78 ꢀC, 30 min; then Davis reagent, À78 ꢀC, 2 h.
the bladder detrusor (IC50, bladder=7.4 mM ; IC ratio
50
>41). Among the pyrrolidin-2-one analogues 7–13, the
a-methyl analogue 7 showed weak and selective KCO
activity at the detrusor. The replacement of the
a-methyl with a a-trifluoromethyl substituent as in
compound 8 resulted in enhancement of the sponta-
neous contraction on both rat portal vein and detrusor
preparations. The introduction of a second methyl
group as in compound 9 resulted in significant increase
in KCO potency; whereas the effect of an a-hydroxyl
group as in compounds 11–13 was not apparent. Com-
pound 9 was identified as the most potent and bladder-
selective KCO (IC50, detrusor=6.7 mM ; IC ratio=51) in
50
this novel series of conformationally restricted deriva-
tives of ZD6169. It is noteworthy that bladder-selectiv-
ity was not observed with (Æ)-1 in these in vitro assays,
although ZD6169 [(À)-1] was claimed to be a bladder-
selective KCO. However, this is not inconsistent with
the results obtained by Zeneca’s researchers, who have
suggested pharmacokinetic reasons for the in-vivo
selectivity demonstrated by ZD6169.11 When the ben-
zoylphenyl moieties in the X-ray diffraction structures
of compound 9 and ZD6169 are superimposed, the
corresponding amide carbonyl and the methyl groups
are found to occupy different space areas (Fig. 2b). The
unexpected conformational behavior of compound 9
may contribute to its high bladder selectivity, which was
not observed with ZD6169. Compound (À)-12 was
about 2-fold more potent than its recemate [(Æ)-12],
indicating that, as with the case of ZD6169, the KCO
activity of this type of compounds also resides in the
(À)-isomers.
Scheme 4. Reagents and conditions: (a) allyl bromide, Mg, Et2O,
À50 ꢀC to rt, 3 h; (b) 1 N NaOH, MeOH, rt, 1.5 h; (c) SOCl2, À20 ꢀC,
1 h; then 4-aminobenzophenone, DMF, À20 ꢀC to rt, 5 h; (d) O3,
CH2Cl2, À78 ꢀC, 30 min; (e) NaBH4, MeOH, rt, 1 h; (f) PPh3, DEAD,
CH2Cl2, rt, 24 h; (g) MnO2, CH2Cl2, rt, 1 h.
and 23 were coupled with 4-aminobenzophenone to give
the corresponding amide intermediates 24 and 25, which
were then subjected to ozonolysis, followed by NaBH4
reduction, lactam formation under Mitsunobu condi-
tion, and MnO2 oxidation to provide target compounds
12 and 13.
Results and Discussion
The KCO activity and selectivity of target compounds
2–13 were evaluated by in-vitro tissue assays with pre-
parations of male Wistar rat portal vein and rat bladder
detrusor strips based on literature procedures.25 Details
of the pharmacological assays are given in section B of
the Experimental Section. All compounds tested, except
compound 8, demonstrated significant relaxant activity
on both rat portal vein and detrusor strips; however, as
compared to lemakalim and (Æ)-1 (a racemic mixture
of ZD6169 and its (R)-(+)-isomer), these rigid analo-
gues are less potent (Table 1). Although (Æ)-1 or the
racemate of ZD6169 was used as the reference com-
pound in our assay, it may be pointed out that the KCO
The observed relaxant activity was antagonized by the
potassium channel inhibitor glibenclamide, indicating
the direct involvement of potassium channels. However,
the antagonism observed with compounds 6 and 9 was
not as significant as that observed with (Æ)-1
and lemakalim, whose IC50 values increased 60- and
100-fold, respectively, in the presence of glibenclamide.
Whether compounds 6 and 9 act as pure potassium
channel openers at the bladder detrusor cannot be
inferred from this study. Other mechanisms of action,
including a direct interference at the level of voltage-
sensitive Ca2+ channels, could also mediate the relaxant
properties of such compounds.27

P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
3271
Table 1. Mechanoinhibitory activity of compounds 2–13 on rat portal vein and rat detrusor stripsa
Compound
IC50 (mM)b
IC50 (mM)b in the
presence of glibenclamidec
Portal veind
Detrusore
IC50 ratiof
Portal vein
Detrusor
2
3
4
5
6
7
8
9
10
4.8Æ0.12
16Æ0.11
170Æ0.11
52Æ0.15
>300
8.3Æ0.09
9.1Æ0.14
10Æ0.13
15Æ0.03
7.4Æ0.05
35Æ0.02
+
6.7Æ0.23
14Æ0.17
19Æ0.15
33Æ0.10
15Æ0.07
19Æ0.11
2.0Æ0.11
0.34Æ0.07
0.58
1.8
17
3.5
>41
4.0
NDh
51
90Æ0.08
180Æ0.19
240Æ0.17
220Æ0.06
>300
16Æ0.14
320Æ0.15
260Æ0.10
>300
47Æ0.15
49Æ0.11
ND
27Æ0.12
54Æ0.10
25Æ0.16
120Æ0.09
67Æ0.15
>300
140Æ0.13
250Æ0.12
g
+
ND
>300
>300
340Æ0.07
52Æ0.14
84Æ0.18
92Æ0.12
42Æ0.27
160Æ0.13
0.64Æ0.09
0.23Æ0.04
3.7
4.4
2.8
2.8
8.4
0.32
0.68
11
12
150Æ0.07
110Æ0.08
74Æ0.11
>300
(À)-12
13
(Æ)-1
Lemakalim
2.5Æ0.20
120Æ0.08
18Æ0.09
34Æ0.12
aData represents the mean of four experiments each performed in duplicate.
bp <0.05.
c1 mM.
dSpontaneously contracting rat portal vein.
eIsolated rat detrusor strips exposed to extracellular KCl (20 mM).
fIC50, portal vein/IC50, bladder
.
gThe + sign indicates enhancement of the spontaneous contraction.
hND, not determined.
Figure 2. (a) X-ray crystal structure of compound 9; (b) superposition of the X-ray diffraction structures of compound 9 (shown in line) and ZD6169
(shown in stick).
a Bruker DPX-200 NMR spectrometer. Chemical shifts
were recorded in parts per million downfield from
Me4Si. Mass spectra were recorded on a Jeol JMS-D300
mass spectrometer. HRMS were obtained with a Jeol
JMS-HX110 spectrometer. Elemental analysis was per-
formed with a Perkin-Elmer 2400-CHN instrument.
Optical rotation was determined with a Jasco DIP-370
digital polarimeter. TLC was performed on Merck (art.
5715) silica gel plates and visualized under UV light
(254 nm). Flash column chromatography was per-
formed with Merck (art. 9385) 40–63 mm silica gel 60.
Anhydrous tetrahydrofuran (THF) was distilled from
sodium-benzophenone prior to use.
Conclusion
A series of rigid analogues based on the most stable
conformation of ZD6169 was synthesized and evaluated
for potassium channel opening activity. In in-vitro
assays, compounds 6 and 9 emerged as potent and
bladder-selective KCOs, with an IC50, bladder of about
7.0 mMand an IC ratio (portal vein/bladder) of
greater than 40. Further SAR study and in-vivo assays
on selected members of this series are in progress.
50
Experimental
Chemistry
3-(4-Benzoylphenyl)-5-methyl-5-trifluoromethyl-2,4-oxa-
zolidinedione (2). To a solution of (Æ)-126 (470 mg,
1.39 mmol) in THF (20 mL) was added potassium
bis(trimethylsilyl)amide (KHMDS, 7.3 mL of a 0.5 M
solution in hexane), and the mixture was stirred at
IR spectra were determined with a Perkin-Elmer 1760-X
FT-IR spectrometer. NMR spectra were recorded on

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P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
À24 ꢀC for 1 h. A solution of 1,1-carbonyldiimidazole
(300 mg, 1.85 mmol) in THF (5 mL) was added and the
resultant reaction mixture was stirred for 1 day. The
reaction mixture was quenched with 1.0 N HCl (20 mL)
and extracted with CH2Cl2. The organic layer was
separated, dried over MgSO4, and evaporated. The
residue was crystallized from CH2Cl2 and hexane to
afford 2 (300 mg, 59%) as colorless crystals: mp 164–
(d, J=8 Hz, 2H); 13C NMR (50 MHz, CDCl3) d 20.2,
37.1, 50.1, 61.5, 76.6 (q, J=27 Hz), 119.0, 124.8 (q,
J=100 Hz), 128.6, 140.8, 156.9; IR (KBr) cmÀ1 2937,
1671, 1594; MS (EI, 70 eV) m/z 334 (M+, base), 210;
HRMS calcd for C14H17F3N2O+4 : 334.1136, found
334.1139. Anal. calcd for C14H17F3N2O4: C, 50.28; H,
5.12; N, 8.38. Found C, 50.45; H, 5.31; N, 8.19.
166 ꢀC; H NMR (200 MHz, CDCl3) d 1.9 (s, 3H), 7.4–
N-(4-Benzoylphenyl)piperidin-2-one (6). By the proce-
1
7.6 (m, 5H), 7.7–7.9 (m, 4H); 13C NMR (50 MHz,
CDCl3) d 16.5, 81.8 (q, J=32 Hz), 122.3, 124.9 (q,
J=280 Hz), 128.4, 139.9, 130.9, 132.8, 133.3, 136.7,
138.1, 151.1, 166.2, 195.1; IR (KBr) cmÀ1 2959, 1836,
1766, 1660; MS (EI, 70 eV) m/z 363 (M+). Anal. calcd
for C18H12F3NO4: C, 59.49; H, 3.89; N, 3.85. Found C,
59.50; H, 3.90; N, 3.92.
dure for compound 11, compound
6
(128 mg,
0.45 mmol, 90%) was obtained from 4-aminobenzophe-
none (100 mg, 0.51 mmol), d-valerolactone (16, 76.5 mg,
ꢀ
1
0.76 mmol). 6: mp 110 C; H NMR (200 MHz, CDCl3)
d 1.8 (m, 4H), 2.4 (t, J=7 Hz, 2H), 3.5 (t, J=7 Hz, 2H),
7.4–7.5 (m, 3H), 7.6–7.9 (m, 6H); 13C NMR (50 MHz,
CDCl3) d 23.2, 32.6, 37.0, 44.9, 119.3, 128.7, 130.0,
130.3, 132.8, 133.2, 138.2, 142.6, 171.8, 196.4; IR (KBr)
cmÀ1 1700, 1650; MS (EI, 70 eV) m/z 279 (M+); HRMS
calcd for C18H17O2N+: 279.1257, found 279.1259.
Anal. calcd for C18H17NO2: C, 77.40; H, 6.14; N, 5.02.
Found C, 77.68; H, 6.30; N, 4.93.
N-(4-Benzoylphenyl)-2-methyl-2-trifluoromethylmophor-
lin-3-one (3). To
a
mixture of (Æ)-1 (400 mg,
1.18 mmol), potassium carbonate (810 mg, 5.9 mmol),
and 5 mL DMF was added 1-bromo-2-chloroethane
(0.2 mL, 2.37 mmol). The reaction mixture was stirred at
100 ꢀC for 7 days. DMF was removed by Kugel-rohr
distillation and the residue was partitioned between
CH2Cl2 (20 mL) and H2O (20 mL). The organic layer
was collected, dried over MgSO4, and evaporated. The
residue was chromatographed (silica gel; CH2Cl2) to
give a crude product, which was crystallized from
CH2Cl2 and n-hexane to give 3 (202 mg, 47%) as color-
N-(4-Benzoylphenyl)-3-methylpyrrolidin-2-one (7). To a
stirred solution of 18 (2.3 g, 7.75 mmol) and triphenyl-
phosphine (2.4 g, 9.3 mmol) in dry CH2Cl2 (30 mL)
under N2 was slowly added diethylazodicarboxylate
(DEAD, 1.44 mL, 9.30 mmol) and the resulting mixture
was stirred at room temperature for 1 day. The solution
was treated with H2O (20 mL), and the CH2Cl2 layer
was separated. The organic solvent was evaporated and
the residue was chromatographed (silica gel; CH2Cl2) to
afford compound 7 (2.0 g, 93%) as a light yellow solid:
mp 95 ꢀC; 1H NMR (200 MHz, CDCl3) d 1.3 (d,
J=7 Hz, 3H), 1.8 (m, 1H), 2.4 (m, 1H), 2.7 (m, 1H), 3.8
(dd, J=9, 5 Hz, 2H), 7.3–7.5 (m, 3H), 7.7–7.8 (m, 6H);
13C NMR (50 MHz, CDCl3) d 16.5, 27.3, 38.9, 46.8,
118.8, 128.7, 130.3, 131.7, 132.7, 133.2, 138.3, 143.8,
177.7, 196.2; IR (KBr) cmÀ1 2987, 1702, 1652; MS (EI,
70 eV) m/z 279 (M+, base). Anal. calcd for C18H17NO2:
C, 77.40; H, 6.10; N, 5.00. Found C, 77.38; H, 6.13; N,
5.01.
less crystals: mp 96 ꢀC; H NMR (200 MHz, CDCl3) d
1
1.7 (s, 3H), 3.9 (dd, J=5, 4 Hz, 2H), 4.1 (m, 1H), 4.2 (m,
1H), 7.2 (m, 1H), 7.4–7.5 (m, 4H), 7.6–7.8 (m, 4H); 13C
NMR d (50 MHz, CDCl3) 20.2, 50.1, 61.5, 79.6 (q,
J=27 Hz) 120.8 (q, J=105 Hz), 125.0, 128.6, 129.9,
131.5, 133.1, 136.6, 137.7, 145.1, 164.8, 196.0; IR (KBr)
cmÀ1 2925, 1679, 1599; MS (EI, 70 eV) m/z 363 (M+,
base), 266, 210; HRMS calcd for C19H16F3NO+3 :
363.1082,
found
363.1083.
Anal.
calcd
for
C19H16F3NO3: C, 62.75; H, 4.44; N, 3.86. Found C,
62.65; H, 4.45; N, 3.79.
N-(4-Trifluoromethyl)phenyl-2-methyl-2-trifluoromethyl-
mophorlin-3-one (4). By the procedure for compound 3,
compound 4 (60 mg, 0.19 mmol, 47%) was obtained
from N-(4-trifluoromethyl)phenyl-2-hydroxyl-2-trifluoro-
methylpropionamide (14, 121 mg, 0.40 mmol ). 4: mp
N-(4-Benzoylphenyl)-3-trifluoromethylpyrrolidin-2-one (8).
By the procedure for the preparation of 7, crude 8 was
obtained from 19 (110 mg, 0.31 mmol), which was crys-
tallized from CH2Cl2 and n-hexane to afford 8 (80 mg,
77%) as colorless crystals: mp 124 ꢀC; 1H NM R
(200 MHz, CDCl3) d 2.4 (m, 2H), 3.4 (m, 1H), 3.9 (m,
2H), 7.5–7.6 (m, 3H), 7.7–7.9 (m, 6H); 13C NM R
(50 MHz, CDCl3) d 19.5, 46.5, 47.9 (q, J=29 Hz), 110.0,
119.5, 125.3 (q, J=276 Hz), 128.8, 130.3, 131.6, 132.8,
134.4, 138.0, 142.5, 167.0, 195.9; IR (KBr) cmÀ1 2957,
1704, 1646; MS (EI, 70 eV) m/z 333 (M+). Anal. calcd
for C18H14F3NO2: C, 64.78; H, 4.23; N, 4.20. Found C,
64.80; H, 4.25; N, 4.11.
85 ꢀC; H NMR (200 MHz, CDCl3 ) d 1.7 (s, 3H), 3.9
1
(dd, J=9, 5 Hz, 2H), 4.1 (m, 1H), 4.2 (m, 1H), 7.4 (d,
J=8 Hz, 2H), 7.6 (d, J=8 Hz, 2H); 13C NMR (50 MHz,
CDCl3) d 20.2, 50.2, 61.4, 79.6 (q, J=27 Hz), 120.8 (q,
J=105 Hz), 125.7, 126.8, 129.3, 129.9, 144.6, 164.7; IR
(KBr) cmÀ1 2925, 1681, 1600; MS (EI, 70 eV) m/z 327
(M+, base); HRMS calcd for C13H11F6NO+2 : 327.0693,
found 327.0695.
N-[4-(N,N-Dimethylamino)sulfonylphenyl]-2-methyl-2-
trifluoromethylmophorlin-3-one (5). By the procedure
for compound 3, compound 5 (26 mg, 0.08 mmol, 36%)
was obtained from N-[4-(N,N-dimethylamino)sulfonyl-
phenyl]-2-hydroxyl-2-trifluoromethylpropionamide (15,
N-(4-Benzoylphenyl)-3,3-dimethylpyrrolidin-2-one (9). To
a solution of 7 (197 mg, 0.71 mmol) in THF (10 mL) was
added LDA (1.43 mmol) in THF (5 mL) at À23 ꢀC. The
mixture was stirred for 30 min, and then methyl iodide
(0.23 mL, 3.6 mmol) was added. The resulting mixture
was stirred for 3 h at 0 ꢀC. The solvent was evaporated,
and the residue was partitioned between diethyl ether
70 mg, 0.22 mmol). 5: mp 103 ꢀC; H NMR (200 MHz,
1
CDCl3) d 1.6 (s, 3H), 2.6 (s, 6H), 3.9 (dd, J=5, 4 Hz,
2H), 4.1 (m, 1H), 4.2 (m, 1H), 7.5 (d, J=8 Hz, 2H), 7.8

P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
3273
(10 mL) and 1.0 N HCl (10 mL). The organic layer was
separated, and the aqueous layer was extracted with
diethyl ether (10 mL). The organic layers were com-
bined, dried over MgSO4, and evaporated. The crude
product was crystallized from ethyl acetate and n-hex-
ane to give 9 (130 mg, 63%) as a colorless crystal: mp
99 ꢀC; 1H NMR (200 MHz, CDCl3) d 1.2 (s, 6H), 2.0 (t,
J=7 Hz, 2H), 3.8 (t, J=7 Hz, 2H), 7.1–7.3 (m, 3H), 7.6–
7.8 (m, 6H); 13C NMR (50 MHz, CDCl3) d 25.0, 33.7,
42.5, 45.2, 118.9, 128.7, 130.3, 131.6, 132.6, 133.1, 138.3,
143.9, 179.9, 196.0; IR (KBr) cmÀ1 2924, 1700, 1653;
MS (EI, 70 eV) m/z 293 (M+). Anal. calcd for
C19H19NO2: C, 77.79; H, 6.50; N, 4.80. Found C, 77.41;
H, 6.47; N, 4.85.
resulting mixture was evaporated and partitioned
between diethyl ether (20 mL Â 2) and water (10 mL).
The organic layer was collected, and evaporated. The
residue was chromatographed (silica gel; CH2Cl2/
MeOH=30/1) to afford 170 mg of unreacted 7 and
crude 12, which was crystallized from CH2Cl2 and n-
hexane to afford compound 12 (112 mg, 76%) as color-
less crystals: mp 122 ꢀC; H NMR (200 MHz, CDCl3) d
1
1.5 (s, 3H), 2.3 (m, 2H), 2.6 (s, 1H), 3,8 (m, 1H), 3.9 (m,
1H), 7.4–7.5 (m, 3H), 7.7–7.9 (m, 6H); 13C NM R
(50 MHz, CDCl3) d 24.6, 33.6, 44.8, 75.4, 119.0, 128.7,
130.3, 131.7, 132.8, 133.9, 138.1, 143.1, 176.9, 196.0; IR
(KBr) cmÀ1 3365, 1698, 1653; MS (EI, 70 eV) m/z 295
(M+, base). Anal. calcd for C18H17NO3: C, 73.03; H,
5.88; N, 4.70. Found C, 73.20; H, 5.80; N, 4.74.
N-(4-Benzoylphenyl)-3-difluoromethylene-pyrrolidin-2-one
(10). To a stirred solution of compound 8 (100 mg,
0.33 mmol) in THF (20 mL) was added LDA
(0.36 mmol) at À23 ꢀC and the solution was further
stirred for 0.5 h. Then methyl iodide (0.08 mL,
1.3 mmol) was added. The resulting mixture was stirred
for 3 h at 0 ꢀC. The resulting mixture was quenched with
CH2Cl2 (20 mL) and H2O (10 mL). The CH2Cl2 layer
was dried over MgSO4, and evaporated to give a resi-
due, which was crystallized from CH2Cl2 and n-hexane
to afford compound 10 (15 mg, 15%). Compound 10
was also obtained when 8 was treated with NaH
(yield=5%). 10: mp 126 ꢀC; 1H NMR (200 MHz,
CDCl3) d 2.9 (m, 2H), 3.9 (t, J=7 Hz, 2H), 7.4–7.6 (m,
3H), 7.7–7.8 (m, 6H); 13C NMR (50 MHz, CDCl3) d
18.6, 45.6, 88.3 (dd, J=14, 10 Hz), 118.9, 128.7, 130.3,
131.7, 132.7, 133.7, 138.1, 143.3, 156.2 (dd, J=306,
292 Hz), 164.8 (dd, J=14, 10 Hz), 195.9; IR (KBr) cmÀ1
3425, 1683, 1650, 1600; MS (EI, 70 eV) m/z 313 (M+),
236; HRMS calcd for C18H13F2NO+2 : 313.0914, found:
313.0916.
(À)-N-(4-Benzoylphenyl)-3-hydroxy-3-methylpyrrolidin-
2-one (À)-12. To a solution of 7 (80 mg, 0.28 mmol)
in THF (10 mL) at À78 ꢀC and under N2 was added
LDA (0.57 mmol in 10 mL of THF). After 30 min,
(+)-(8,8-dichlorocamphorsulfonyl)-oxaziridine (177 mg,
0.56 mmol) in THF (5 mL) was added, and the resultant
mixture was stirred for 2 h. The solvent was evaporated,
and the residue was partitioned between diethyl ether
(20 mL Â 2) and water (10 mL). The organic layer was
separated, concentrated, and the residue was chromato-
graphed (silica gel; CH2Cl2/MeOH=30/1). The product
was crystallized from CH2Cl2 and n-hexane to give
(À)-12 (60 mg, 73%) as colorless crystals: mp 122 ꢀC;
MS (EI, 70 eV) m/z 295 (M+); HRMS calcd for
C18H19NO+3 : 295.1208, found 295.1208; [a]2D0=À18.1 (c,
1.4, MeOH).
N-(4-Benzoylphenyl)-3-hydroxy-3-trifluoromethylpyrroli-
din-2-one (13). To a solution of 25 (320 mg, 1.04 mmol)
in CH2Cl2 (20 mL) at À78 ꢀC was passed O3 gas pro-
duced from an ozone generator. After 1 h, the color of
solution was changed from colorless to blue. NaBH4
(197 mg, 5.18 mmol) and methanol (5 mL) was then
added to the solution, and the stirring was continued for
1 h. The reaction mixture was evaporated, treated with
1.0 N HCl (10 mL) and extracted with CH2Cl2 (10 mL).
The CH2Cl2 layer was combined, dried over MgSO4,
and evaporated. The residue was chromatographed
(silica gel; EtOAc/n-hexane=13/7) to give 27 (155 mg,
47%) as a yellow liquid. Then, to a solution of 27
(40 mg, 0.11 mmol) and triphenylphosphine (85 mg,
0.34 mmol) in CH2Cl2 (10 mL) at room temperature
under N2 was slowly added DEAD (0.05 mL,
0.34 mmol), and the mixture was stirred for 1 day. The
solution was then washed with H2O (20 mL), and the
organic layer was dried (MgSO4), and evaporated. The
N-(4-Benzoylphenyl)-3-hydroxypyrrolidin-2-one (11). A
mixture of 4-aminobenzophenone (966 mg, 4.90 mmol),
a-hydroxyl-g-butyrolactone (17, 500 mg, 4.90 mmol),
and AlCl3 (130 mg, 0.98 mmol) in a sealed vessel was
stirred at 120 ꢀC for 1 day. The reaction mixture was
then cooled to room temperature and carefully quen-
ched with dilute HCl (20 mL) and extracted with
CH2Cl2 (20 mL Â 2). The organic layers were combined,
dried (MgSO4), and evaporated. The residue was chro-
matographed (silica gel; CH2Cl2/MeOH=20/1) to pro-
vide 11 (1.26 g, 92%) as a yellow solid: mp 161–162 ꢀC;
1H NMR (200 MHz, CDCl3) d 2.1 (m, 2H), 2.6 (q,
J=6 Hz, 1H), 3.9 (m, 2H), 4.5 (dd, J=8, 1 Hz, 1H), 7.3–
7.5 (m, 3H), 7.7–7.8 (m, 6H); 13C NMR (50 MHz,
CDCl3) d 27.9, 44.8, 71.2, 119.0, 128.8, 130.4, 131.8,
132.8, 134.0, 138.0, 142.9, 175.3, 196.1; IR (KBr) cmÀ1
3357, 1700, 1650; MS (EI, 70 eV) m/z 281 (M+); HRMS
calcd for C17H15NO+3 : 281.1052, found 281.1052. Anal.
calcd for C17H15NO3: C, 72.59; H, 5.38; N, 4.98. Found
C, 72.40; H, 5.46; N, 4.92.
residue was dissolved in CH2Cl2.
M n2O (93 mg,
1.1 mmol) was added, and resulting mixture was stirred
for 1 h at room temperature. The mixture was filtered
through a thin pad of Celite, washed with CH2Cl2
(20 mL), and the combined filtrates were evaporated.
The residue was chromatographed (silica gel; CH2Cl2/
MeOH=20/1) to afford 13 (11 mg, 32%) as a light yel-
N-(4-Benzoylphenyl)-3-hydroxy-3-methylpyrrolidin-2-one
(12). To a solution of 7 (310 mg, 1.11 mmol) in THF
(10 mL) was added LDA (2.2 mmol) in THF (22 mL) at
À78 ꢀC. After 1 h, the reaction flask was left open to
atmosphere and stirred vigorously for another 1 h. The
1
low liquid: H NMR (200 MHz, CDCl3) d 2.2–2.8 (m,
2H), 3.1 (s, 1H), 3.7 (m, 1H), 3.9 (m, 1H), 7.2–7.5 (m,
3H), 7.7–7.9 (m, 6H); 13C NMR (50 MHz, CDCl3) d
33.7, 44.7, 75.7 (q, J=29 Hz), 119.1, 123.1 (q,

3274
P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
J=280 Hz), 128.7, 129.5, 130.3, 131.7, 132.8, 133.8,
138.1, 140.5, 143.8, 177.0, 196.0; IR (KBr) cmÀ1 3416,
2923, 1727, 1684; MS (EI, 70 eV) m/z 349 (M+), 197;
HRMS calcd for C18H14F3NO+3 : 349.0926, found
349.0930.
ethyl 2-hydroxy-2-trifluoromethyl-4-pentenoate (420 mg,
30%). A mixture of ethyl 2-hydroxy-2-trifluoromethyl-
4-pentenoate (420 mg, 1.98 mmol), 1.0 N NaOH (5 mL),
and MeOH (5 mL) was stirred at room temperature for
1.5 h. The solvent was evaporated under reduced pres-
sure and residue was treated with H2O (20 mL) and
Et2O (20 mL). The water layer was collected, washed
with Et2O (10 mL), acidified with 3.0 N HCl until the
pH <1, and then extracted with Et2O. The organic
layer was separated, dried over MgSO4, and evapo-
N-(4-Benzoylphenyl)-4-hydroxy-2-methylbutanamide (18).
A
solution of trimethylaluminum (0.6 mL, 15%,
1.52 mmol) in n-hexane was slowly added to a solution
of 4-aminobenzophenone (300 mg, 1.52 mmol) in 5 mL
of CH2Cl2 under nitrogen. The mixture was stirred at
room temperature for 15 min, and a-methyl-g-butyr-
olactone (152 mg, 1.52 mmol) was added. The resulting
mixture was further stirred at room temperature for 3
days. The solution was carefully quenched with 1.0 N
HCl (10 mL) and extracted with CH2Cl2. The organic
layer was dried (MgSO4) and concentrated to afford 18
(390 mg, 92%) as a light yellow liquid: 1H NM R
(200 MHz, CDCl3) d 1.2 (d, J=7 Hz, 3H), 1.7 (dd, J=8,
6 Hz, 1H), 1.9 (dd, J=8, 6 Hz, 1H), 2.7 (m, 1H), 3.7 (t,
J=6 Hz, 2H), 3.9 (s, 1H), 7.1 (m, 2H), 7.4 (m, 4H), 7.7
(m, 3H), 9.3 (s, 1H); 13C NMR (50 MHz, CDCl3) d 18.1,
36.9, 39.1, 60.5, 119.5, 125.7, 128.7, 128.8, 129.5, 130.3,
132.0, 132.9, 138.0, 138.3, 143.2, 176.8, 196.9; IR (KBr)
cmÀ1 3352 (OH, NH), 1675, 1645; MS (EI, 70 eV) m/z
279 (M+), 197, 120 (base); HRMS calcd for
C18H19NO+3 : 297.1376, found 297.1372.
1
rated to give 23 (250 mg, 69%): H NMR (200 MHz,
CDCl3) d 2.7 (m, 2H), 5.2 (m, 2H), 5.7 (m, 1H), 6.3 (s,
2H); 13C NMR (50 MHz, CDCl3) d 36.3, 77.6 (q,
J=29 Hz), 121.5, 123.1 (q, J=284 Hz), 128.8, 172.4; IR
(KBr) cmÀ1 3462, 1731,1645; MS (EI, 70 eV) m/z 184
(M+); HRMS calcd for C6H7O3F+3 : 184.0347, found
184.0347.
N-(4-Benzoylphenyl)-2-hydroxy-2-methyl-4-pentenamide
(24). By the same procedure for compound 25, com-
pound 24 (320 mg, 56%) was obtained from 22 (400 mg,
1
3.08 mmol). H NMR (200 MHz, CDCl3) d 1.8 (s, 3H),
3.0 (m, 2H), 5.2 (m, 2H), 5.7 (m, 1H), 7.5 (m, 3H), 7.7
(m, 6H), 8.1 (s, 1H), 8.3 (s, 1H); 13C NMR (50 MHz,
CDCl3) d 23.3, 41.4, 85.9, 119.8, 120.7, 128.7, 130.3,
131.2, 131.9, 132.7, 134.1, 138.2, 141.2, 158.7, 170.3,
196.0; IR (KBr) cmÀ1 3353, 1732, 1697, 1651; MS (EI,
70 eV) m/z 309 (M+), 291, 279, 197; HRMS calcd for
C18H19NO+3 : 309.1364, found 309.1367.
N-(4-Benzoylphenyl)-4-hydroxy-2-trifluoromethylbutana-
mide (19). By the procedure for the preparation of 18,
crude 19 was obtained from 4-aminobenzophenone
(300 mg, 1.52 mmol) and a-trifluoromethyl-g-butyr-
olactone (281 mg, 1.83 mmol), which was then crystal-
lized from EtOAc and n-hexane to give 19 (282 mg,
53%) as a yellow solid: mp 124 ꢀC; 1H NMR (200 MHz,
CDCl3) d 2.0–2.3 (m, 2H), 3.4 (m, 1H), 3.8 (m, 2H), 7.4–
7.8 (m, 9H), 8.1 (s, 1H); 13C NMR (50 MHz, CDCl3) d
29.2, 48.9 (q, J=25 Hz), 59.6, 119.8, 125.8 (q,
J=149 Hz), 128.8, 130.3, 131.9, 133.1, 133.8, 137.8,
142.0, 166.1, 197.0; IR (KBr) cmÀ1 3331, 1674, 1646;
MS (EI, 70 eV) m/z 351 (M+); HRMS calcd for
C18H16F3NO+3 : 351.1082, found 351.1082.
N-(4-Benzoylphenyl)-2-hydroxy-2-trifluoromethyl-4-pen-
tenamide (25). To a stirred, cooled (À20 ꢀC) solution of
23 (250 mg, 1.35 mmol) in DMF (5 mL) was added
thionyl chloride (224 mg, 0.15 mL, 1.76 mmol), and the
mixture was stirred at À15 to À5 ꢀC for 1 h. 4-Amino-
benzophenone (186 mg, 0.95 mmol) was then added in
one portion, and the mixture was stirred at room tem-
perature for 5 h. DMF was removed via Kugel-rohr
distillation, and the residue was partitioned between
water (10 mL) and CH2Cl2 (20 mL). The cloudy solution
was filtered through a thin pad of Celite. The Celite pad
was washed with CH2Cl2. The organic layers were
combined, dried over MgSO4, and evaporated. The
residue was treated with n-hexane and CH2Cl2. The
precipitate was collected as compound 25 (80 mg, 23%):
1H NMR (200 MHz, CDCl3) d 2.9 (m, 2H), 5.3 (m, 2H),
5.7 (m, 1H), 7.4–7.6 (m, 3H), 7.7–8.0 (m, 6H); 13C
NMR (50 MHz, CDCl3) d 37.1, 89.1 (q, J=28 Hz),
119.2, 120.9, 125.0 (q, J=304 Hz), 128.0, 129.1, 130.9,
132.3, 133.7, 137.5, 140.5, 151.2, 165.4, 195.6; IR (KBr)
cmÀ1 3352, 2961 1728, 1660; MS (EI, 70 eV) m/z 363
(M+), 224; HRMS calcd for C19H16F3NO+3 : 363.1063,
found 363.1062.
2-Hydroxy-2-methyl-4-pentenoic acid (22). By the same
procedure for 23, 22 was obtained from ethyl pyruvate
(20, 370 mg, 3.18 mmol) as colorless crystals (62 mg,
15%). 22: 1H NMR (200 MHz, CDCl3) d 1.4 (s, 3H), 2.4
(m, 2H), 5.1 (m, 2H) 5.7 (m, 1H), 7.1 (s, 2H); 13C NM R
(50 MHz, CDCl3) d 25.5, 44.7, 75.0, 119.9, 132.2, 180.5;
IR (KBr) cmÀ1 3460, 1728, 1644; MS (EI, 70 eV) m/z
130 (M+), 89 (base); HRMS calcd for C6H10O+3 :
130.0630, found 130.0626.
2-Hydroxy-2-trifluoromethyl-4-pentenoic acid (23). A
solution of allyl magnesium bromide (8.6 mmol) in Et2O
(15 mL) was slowly added to a solution of ethyl tri-
fluoropyruvate (21, 1.10 g, 6.47 mmol) in Et2O (10 mL)
at À50 ꢀC under nitrogen. The stirred mixture was let
warm to rt, and poured into a mixture of ice and 1.0 N
HCl (20 mL). The organic layer was separated. The
aqueous layer was extracted with Et2O (20 mL Â 2).
The combined organic layers were dried over MgSO4,
and evaporated. The residue was distilled to provide
Biological assays
Measurements of contractile activity in rat portal vein
and bladder detrusor. The assay was performed with
preparations of portal vein and urinary bladder detru-
sor strips from male Wistar rats (body weight 180–
220 g).25 The portal vein and bladder were isolated, and
excess fat and connective tissue were removed. In the
portal vein assay, each portal vein was cut longitudinally

P.-H. Liang et al. / Bioorg. Med. Chem. 10 (2002) 3267–3276
3275
into four strips approximately 5–7 mm in length and
mounted in 1 mL organ bath containing modified Krebs
buffer of the following composition (in mM): NaCl 118,
KCl 4.7, CaCl2 2.52, MgSO4 1.19, KHPO4 1.19,
NaHCO3 25, and Glucose 11.48. Each strip was tied at
one end to a glass rod and placed in tissue organ baths
containing Krebs solution and maintained at 37 ꢀC. The
other end of the strip was tied via silk thread to a force
displacement transducer (Grass Model 7D) and after
15-min equilibration period, a 0.5 g preload tension was
applied followed by frequent washouts for the next
30–45 min. In the detrusor assay, the middle region of
bladder was cut into four horizontal strips 2–3 mm in
width, 1–1.5 cm in length and mounted in a 5-mL organ
bath, contained Krebs solution, and gassed with a
mixture of O2 (95%) and CO2 (5%). The two ends
of the strips were tied to the glass rod and the trans-
ducer, respectively. Detrusor strips were progressively
stretched to the preload tension 1.0 g. During the
following 30 min of equilibration period, the tissue was
frequently washed with fresh buffer. After the equili-
bration period, 20 mMKCl was added to the bath of
detrusor strips and equilibrated for 20 min before
specific experimental processes were initiated. Vasocon-
traction were recorded isometrically via a force–
displacement transducer connected to a Grass Model
7D polygraph. When the tension had stabilized, the
reference and test compounds were added at increasing
concentrations until maximal relaxation. The same
experiments were repeated in the presence of
glibenclamide (1 mM). The relaxation response was
expressed as the percentage of the contractile response
for either spontaneous contraction of portal vein or
KCl-evoked contraction of detrusor. The IC50 value was
graphically assessed for each dose response curve as the
contraction evoking 50% inhibition of contractile
activity. Results were expressed as the mean (ÆSD) of
6–12 experiments.
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Acknowledgements
We thank Dr. Chien-Shu Chen for his work in compu-
ter-modeling. This research was supported by the
National Science Council of the Republic of China
under Grant No. NSC 88-2314-B002-138.
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