Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: A novel class of potent and selective human enterovirus 71 inhibitors

Article abstract of DOI:10.1021/jm010536a

When skeletons of Win compounds were used as templates, computer-assisted drug design led to the identification of a novel series of imidazolidinone derivatives with significant antiviral activity against enterovirus 71 (EV 71), the infection of which had

Full text of DOI:10.1021/jm010536a

1644
J . Med. Chem. 2002, 45, 1644-1655
Design , Syn th esis, a n d Str u ctu r e-Activity Rela tion sh ip of P yr id yl
Im id a zolid in on es: A Novel Cla ss of P oten t a n d Selective Hu m a n En ter ovir u s 71
In h ibitor s
Kak-Shan Shia,*,† Wen-Tai Li,† Chung-Ming Chang,† Ming-Chu Hsu,† J yh-Haur Chern,† Max K. Leong,†
Sung-Nien Tseng,‡ Chung-Chi Lee,† Yen-Chun Lee,† Shu-J en Chen,† Kuan-Chang Peng,† Huan-Yi Tseng,†
Yi-Ling Chang,† Chia-Liang Tai,† and Shin-Ru Shih*,‡
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei 11529, Taiwan, R.O.C.,
and School of Medical Technology, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.
Received November 26, 2001
When skeletons of Win compounds were used as templates, computer-assisted drug design led
to the identification of a novel series of imidazolidinone derivatives with significant antiviral
activity against enterovirus 71 (EV 71), the infection of which had resulted in about 80 fatalities
during the 1998 epidemic outbreak in Taiwan. In addition to inhibiting all the genotypes (A,
B, and C) of EV 71 in the submicromolar to low micromolar range, compounds 1 and 8 were
extensively evaluated against a variety of viruses, showing potent activity against coxsackievirus
A9 (IC50 ) 0.47-0.55 µM) and coxsackievirus A24 (IC50 ) 0.47-0.55 µM) as well as moderate
activity against enterovirus 68 (IC50 ) 2.13 µM) and echovirus 9 (IC50 ) 2.6 µM). Our SAR
studies revealed that imidazolidinone analogues with an aryl substituent at the para position
of the phenoxyl ring, such as compounds 20, 21, 27, 57, 58, and 61, in general exhibited the
highest activity against EV 71. Among them, compound 20 and its corresponding hydrochloride
salt 57, in terms of potency and selectivity index, appear to be the most promising candidates
in this series for further development of anti-EV-71 agents. Preliminary results of the study
on the mode of action by a time-course experiment suggest that test compounds 1 and 8 can
effectively inhibit the virus replication at the early stages, referring to virus attachment or
uncoating. This indicates that the surface protein may be the target for this type of compounds.
Ba ck gr ou n d a n d Sign ifica n ce
urgency and significance for developing anti-EV-71
agents.
Enteroviruses comprise nearly 70 distinct serotypes
within the family of piconaviridae. The subgroups
include the polioviruses, coxsackieviruses A and B,
echoviruses, and the newer “numbered enteroviruses”.1
Well-documented clinical manifestations associated with
enterovirus infection range from the mild “common cold”
to fatal neurological and cardiovascular disorders. To
date, there is no effective antiviral agent available for
the treatment or prevention of enterovirus disease.2
Since April 1998, many children in Taiwan fell victim
to hand-foot-and-mouth disease, aseptic meningitis/
encephalitis, or acute flaccid paralysis, which resulted
in almost 80 fatalities.3 Several independent laborato-
ries have isolated enteroviruses from different speci-
mens taken from the above patients, including fatal
cases; enterovirus 71 (EV 71) was identified as a major
factor in the etiology of the aforementioned cases.3 After
the 1998 epidemic outbreak of EV 71 infection, EV 71
has been continually isolated throughout the whole
island all year round, and many severe cases caused by
EV 71 have also been reported. This highlights the
Enterovirus consists of a simple virus capsid and a
single strand of positive-sense RNA. The capsid contains
60 copies each of four coat proteins, namely, VP1, VP2,
VP3, and VP4. Variations within capsid proteins VP1
to VP3 are responsible for the antigenic diversity among
the enteroviruses, and neutralization sites are most
densely clustered on VP1.4 Replication of RNA viruses
is directed by viral RNA polymerase of relatively low
fidelity with characteristic error frequencies of 10-3 to
10-4 misincorporated nucleotides per round of replica-
tion.5,6 This means that the replication of the enterovi-
rus genome, consisting of about 7500 nucleotides, results
in a population of molecules having, on the average, at
least one mutation. Moreover, recombination occurs
with very high frequency in picornaviruses.7 Because
of the prevalent multiple serotypes and the genetic
heterogeneity, development of antiviral agents for re-
gional enterovirus infection is therefore warranted.
Pleconaril (Figure 1), a capsid-binding molecule, has
been shown to have a broad spectrum of activities
against rhinoviruses and enteroviruses by interfering
with the capsid-receptor binding site, resulting in the
inhibition of the virus attachment to the cells and
uncoating of viral RNA.8-13 This potential drug candi-
date is currently undergoing clinical trials, and its
successful phase III results for the treatment of viral
respiratory infection (VRI),8 often referred to as the
common cold, were announced by Viropharma, Inc.
* To whom correspondence should be addressed. For K.-S.S.: e-mail,
shia@nhri.org.tw; fax, +886-2-26953759; phone, +886-2-26954246, ext
304; address, Division of Biotechnology and Pharmaceutical Research,
National Health Research Institutes, 128 Yen-Chiu-Yuan Road,
Sec 2, Taipei 11529, Taiwan, R. O. C. For S.-R.S.: e-mail,
srshih@mail.cgu.edu.tw; fax, +886-3-3283031; phone, +886-3-3283016,
ext 5497.
† National Health Research Institutes.
‡ Chang Gung University.
10.1021/jm010536a CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/13/2002

Pyridyl Imidazolidinones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1645
F igu r e 1. Structure of pleconaril.
F igu r e 3. Molecular volume of compound 1.
Sch em e 1
F igu r e 2. General structure of imidazolidinones.
Unfortunately, we observed that pleconaril could not
neutralize the cytopathic effect (CPE) of cultured cells
induced by enterovirus isolates from the 1998 outbreak
in Taiwan.14 Presumably, this is due to the fact that
pleconaril is deficient in specificity toward the local
strain of enterovirus. This fact further reinforces an
argument of developing the antienterovirus agents
using materials from local strains.
When the skeletons of pleconaril and its related
molecules, so-called WIN compounds, are used as tem-
plates, the rational design, synthesis, and structure-
activity relationship (SAR) studies led to the develop-
ment of a novel class of imidazolidinones with significant
antiviral activity, the general structure of which is
illustrated in Figure 2. These synthetic compounds were
evaluated for anti-EV-71 activity. Some analogues were
found, in addition to inhibiting all of the genotypes of
EV 71, to possess antiviral activity against coxsackievi-
ruses A9, A24, B1, B3, and B5, echovirus 9, and
enterovirus 68. Details of this investigation will be
described herein.
and geometrical rigidity, like fusing a heteroaryl or aryl
group to a monocyclic, bicyclic, spiro, or cage system.
A vast number of virtual compounds were generated
on the basis of the above design, the structures of which
were further optimized by the semiempirical method
AM1. Three-dimensional molecular volumes of these
compounds were then estimated by calculating van der
Waals’ radii. This calculation process disclosed, unex-
pectedly, a series of virtual compounds with molecular
pictures extremely similar to the shape of the VP1 cavity
of picornaviruses. Interestingly, a common feature of
these virtual compounds was the presence of a pyridyl
imidazolidinone functionality as the terminal. A typical
molecular volume picture of these derivatives, which we
refer to as “socklike” molecules, is illustrated by com-
pound 1 as shown in Figure 3. According to Giranda,30
a molecule with this structural feature might be an ideal
receptor-binding inhibitor in that not only can it insert
into the hydrophobic pocket within the capsid protein
VP1 but it can also extend outside the pocket to the
canyon floor, which is the binding site of cellular
receptors. This statement along with the discovery of
these “socklike” molecules strongly motivated us to
realize the synthesis of this class of virtual compounds.
2. Syn th esis. The above computer-generated pyridyl
imidazolidinone compounds were experimentally real-
ized according to a general synthetic method shown in
Scheme 1 with compound 1 as a specific example.31,32
4-Aminopyridine was first coupled with 2-chloroethyl
isocyanate to give the corresponding urea intermediate
2 in 80% yield. Subsequent intramolecular cyclization
of intermediate 2 by treatment with sodium hydride in
the THF/DMF (1:1) cosolvent system at room temper-
ature resulted in the formation of cyclic urea 332 in
virtually quantitative yield (98%). Compound 3 thus
obtained was allowed to react with 6-(4-bromophenoxy)-
hexyl bromide in DMF using sodium hydride as a base
to afford the expected product 1 in excellent yield (96%).
Serving as a key synthetic intermediate, compound 3
underwent substitution reactions with a variety of
Ch em istr y
1. Design . It is well recognized that the capsid
structures between rhinoviruses and enteroviruses are
relatively conserved,8,15-18 although it is highly conceiv-
able that subtle differences in the sizes and shapes of
their hydrophobic VP1 pockets do exist. This, along with
the fact that Win compounds are good VP1-binding
molecules, made us begin our studies on the develop-
ment of anti-EV-71 agents based on the backbone of Win
compounds.
Closer examination of Win compounds19-24 and other
antipicornavirus agents25-29 that also exhibit an inhibi-
tory effect on the early stages of viral replication
revealed that a structural feature of two terminal
aromatic rings linked by an aliphatic chain was con-
stantly recurrent. This structural feature may be critical
for the inhibitors to fit into the hydrophobic VP1 pocket,
which has a “socklike” shape. Although this property is
quite obvious, how to bring it into effect is problematic
in practice. Therefore, for the purpose of simplicity and
feasibility, we adopted a fixed theme with a terminal
phenoxyl moiety linked to an alkyl chain of five to seven
carbon atoms to generate a virtual library. The com-
puter was asked to create a library of virtual molecules
by ending the linker with an aromatic ring-containing
group; this terminal group, however, was elaborated as
a functionality possessing a certain degree of complexity

1646 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Shia et al.
Sch em e 2
3-aminopyridine, and 4-aminopyrimidine, a series of key
intermediates 4, 5, 6, and 732,38 have also been synthe-
sized (see Chart 1). These intermediates were then
individually subjected to alkylation reactions to give the
corresponding imidazolidinone derivatives 36-56 in
good to high yields. Their structures as well as biological
activity evaluation are illustrated in Table 3.
To improve water solubility, pyridyl imidazolidinones
20-24, containing a biphenyl moiety, were converted
to their corresponding hydrochloride salts 57-61, re-
spectively, in almost 100% yield by treatment with an
excess of hydrochloric acid (Aldrich, 1.0 M solution in
diethyl ether). As far as the structure is concerned, the
most likely protonation site should be the nitrogen in
the pyridine ring.
Ch a r t 1
Resu lts a n d Discu ssion
Antiviral activity testing was initiated with “socklike”
molecules 1 and 8. The compounds were individually
subjected to evaluation against a variety of viruses,
including coxsackieviruses (10 serotypes), echoviruses
(2 serotypes), human enteroviruses 68 and 71, influenza
A and B viruses, herpes simplex virus 1 (HSV-1), and
human rhinoviruses 2 (HRV 2) and 14 (HRV 14). The
results of this extensive biological evaluation are il-
lustrated in Table 1.39 As shown, compounds 1 and 8
exhibit significant activities against human enterovirus
68 (IC50 ) 2.13-4.67 µM), human enteroviruses 71 (IC50
) 0.30-1.37 µM), echovirus 9 (IC50 ≈ 2.6 µM), coxsackie-
virus A24 (IC50 ) 0.47-0.55 µM) as well as coxsackie-
virus A9 (IC50 ) 0.77-1.44 µM). However, they show
weak potency (IC50 ≈ 11 µM) against HRV 14 and no
activity against HRV 2, influenza viruses A and B, HSV-
1, and coxsackieviruses B1-B6 up to the concentration
tested (25 µM). In comparison with the Win series, a
distinct difference in antiviral activity was observed. As
alkylating agents to provide compounds 8-35 (Table 2)
in high to excellent yields. Alkylating agents employed
in the alkylation reactions were readily prepared by use
of commercially available phenols as well as dibromo-
alkanes via nucleophilic substitution reactions under
standard conditions.24,33-35 Alternatively, where neces-
sary, the alkylating agents were prepared via a two-
step procedure making use of the Suzuki coupling
process as a key operation.36,37 This is demonstrated by
a typical experiment shown in Scheme 2.
In a similar fashion, starting with various aromatic
amines including aniline, 2-chloro-4-aminopyridine,
Ta ble 1. Antiviral Activity of Compounds 1 and 8 against Various Viruses
compound 1
IC50 (µM)
compound 8
IC50 (µM)
a
a
virus
EV 71(2086) genotype C
EV 71(2231) genotype C
EV 71(BrCr) genotype A
EV 71(1743) genotype B
enterovirus 68
0.31 ( 0.023
1.15 ( 0.052
1.26 ( 0.052
0.60 ( 0.016
2.13 ( 0.190
2.82 ( 0.013
>25
0.51 ( 0.003
1.35 ( 0.038
1.37 ( 0.069
0.75 ( 0.005
4.67 ( 0.046
2.61 ( 0.130
>25
echovirus 9
echovirus 29
coxsackievirus A9
coxsackievirus A10
coxsackievirus A16
coxsackievirus A24
coxsackievirus B1
coxsackievirus B2
coxsackievirus B3
coxsackievirus B4
coxsackievirus B5
coxsackievirus B6
human rhinovirus 14
human rhinovirus 2
influenza A (WSN)
influenza B (WSN)
herpes simplex virus 1
0.77 ( 0.049
5.88 ( 0.340
>25
1.44 ( 0.009
15.71 ( 0.770
>25
0.55 ( 0.063
5.10 ( 0.045
>25
0.47 ( 0.120
5.60 ( 0.034
>25
>25
>25
>25
>25
>25
>25
>25
>25
11.60 ( 0.120
>25
>12.5
>25
>25
>25
>25
>25
>25
>25
a
Mean of triplicate well values. All experiments were performed at least twice. Plaque reduction assay was employed.

Pyridyl Imidazolidinones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1647
Ta ble 2. Anti-EV-71 Activity and Cytotoxicity of 3-(4-Pyridyl)-2-imidazolidinones
a
b
Mean of triplicate well values. All experiments were performed at least twice. Neutralization test was employed. Mean of triplicate
well values. All experiments were performed at least twice. c Not determined because of poor solubility. Not determined because of
d
amorphous solid.
in the case of pleconaril,8-10 it exhibits effective antiviral
activities against an equal number of serotypes of
rhinoviruses and enteroviruses with a slight preference,
if any, for inhibiting the former. However, compounds
1 and 8 provide remarkable evidence that they are much
more specific for human enteroviruses, in particular,
enterovirus 71 (EV 71). Both of these compounds are
highly active against EV 71 with IC50 values for three
genotypes (A, B, and C) of EV 71 in the submicromolar
to low micromolar range and also possess a very low
cytotoxic effect on the uninfected rhabdomyosarcoma
(RD) host cells with IC50 values of more than 25 µM
(Table 2). Therefore, for our purposes, imidazolidinones
1 and 8 are well qualified to serve as lead compounds
for the further development of anti-EV-71 agents.
On the basis of these encouraging results, a series of
structurally related imidazolidinones were thus syn-
thesized according to Scheme 1. The resulting com-
pounds 9-56 were then submitted for anti-EV-71
testing as well as cytotoxicity evaluation in the RD cell
line, results of which are compiled in Tables 2 and 3.
Table 2 summarizes the structure-activity relation-
ship study of the phenyl ring and methylene linker
portions of the molecule. It was found that with the
exception of compound 29, para-monosubstituted de-
rivatives (1, 8-28) showed moderate to high anti-EV-
71 activity (0.04-6.4 µM), irrespective of the electronic
character of the substituent. Compound 29 with a cyano
group located at the para position was found to be
devoid of anti-EV-71 activity but instead exhibited a
potent cytotoxic effect (0.39 µM) on the host cells. The
underlying cause of this effect is not fully understood
and worthy of further study. Biaryl analogues 20, 21,
and 27 with either a phenyl or thienyl moiety at the
para position bestowed the best potency to this class of
compounds, results of which are quite similar to those
observed for the Win compounds.23,24 This is probably
due to the fact that the strongest hydrophobic interac-

1648 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Shia et al.
Ta ble 3. Anti-EV-71 Activity and Cytotoxicity of
3-Heteroaryl-2-imidazolidinones and 3-Aryl-2-imidazolidinones:
Modification of Pyridine Ring
3-(3-Pyridyl)-2-imidazolidinones 40-45, when com-
pared to their corresponding 4-pyridyl isomers, showed
a reduction in antiviral activity by 3- to 7-fold. 4-Py-
rimidyl derivatives 48-52 were also synthesized and
tested but found to be devoid of any antiviral activity.
Interestingly, phenyl derivatives 53-56 were found to
exhibit weak antiviral activity against EV 71. These
observations appear to indicate that, apart from a
required hydrophobic interaction provided by the aro-
matic unit itself, a suitably placed hydrogen bonding
acceptor is necessary for effective antiviral activity. As
for the 4-pyrimidyl derivatives 48-52, the presence of
the N-3 nitrogen apparently counteracts the hydrogen
bonding acceptor capability of the N-1 nitrogen to such
an extent as to render these compounds completely
inactive against EV 71.
Compounds with unsatisfactory or poor water solubil-
ity such as 20-24 were acidified to form their corre-
sponding hydrochloride salts 57-61. The results of their
antiviral activity and selectivity index calculated for RD,
D551, and WI38 cell lines are outlined in Table 4. It is
worth noting that when compared to their neutral
parent compounds 20, 21, and 24, compounds 57-59,
with lower lipophilicity and weaker ability to penetrate
the cells, not only retained antiviral potency against EV
71 but also exhibited lower cytotoxicity. This suggests
that the surface protein may be the target for this type
of compound. This is consistent with the observation of
our preliminary mechanistic studies in which inhibition
of the virus replication at the early stages, referring to
attachment or uncoating, by the test compounds 1 and
8 can be demonstrated by a time-course experiment.39
In all cases examined, imidazolidinone 20 and its
corresponding salt 57, in terms of potency and selectiv-
ity index, appear to be the most promising candidates
for further development as anti-EV-71 agents.
a
b
IC50
(µM)
CC50
compd
n
X
Y
Z
R
R1 mp (°C)
(µM)
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
6
6
5
6
5
6
7
6
6
6
6
6
5
6
6
6
7
5
6
6
6
N
N
N
N
C
C
C
C
C
C
C
C
N
N
N
N
N
C
C
C
C
C
C
C
C
N
N
N
N
N
N
N
N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
C
C
C
C
Br
CF3
Br
Cl 83-85
Cl 77-79
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
>25
Cl 126-128 >25
SCH3 Cl 81-83
Cl
Cl
Cl
CF3
F
Br
CH3
t-Bu
CF3
CF3
Cl
Br
Br
Br
Br
Cl
CF3
>25
121-123 4.65 ( 0.170
76-78 2.52 ( 0.175
116-118 1.43 ( 0.025
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
74-76
81-83
84-86
73-75
53-55
77-79
72-74
2.10 ( 0.410
9.33 ( 0.192
2.07 ( 0.573
>25
>25
>25
>25
125-127 >25
93-95
81-83
90-92
73-75
72-74
59-62
>25
>25
10.66 ( 0.731 >25
10.60 ( 0.480 >25
10.83 ( 1.842 >25
12.04 ( 0.776 >25
a
Mean of triplicate well values. All experiments were performed
b
at least twice. Neutralization test was employed. Mean of
triplicates well values. All experiments were performed at least
twice.
tion could be provided by an aryl or heteroaryl ring at
this position in the binding site. Moreover, in addition
to exhibiting the most potent antiviral activity (IC50
)
0.04 µM), compound 20 also has an excellent selectivity
index of greater than 1250, 1250, and 625 for the D551,
WI38, and RD cell lines, respectively (Table 4). Accord-
ingly, further studies based on this biaryl motif are
currently under active investigation in our laboratories.
For the series of imidazolidinone compounds illustrated
in Table 2, para substitution seems to play an essential
role in antiviral activity, and this is also evidenced by
the fact that compounds with substitution at the meta
and/or ortho position such as compounds 30-35 lead
to a complete loss of antiviral activity.
In summary, on the basis of the skeleton of Win
compounds, the computer-assisted drug design has
resulted in the discovery and experimental realization
of a novel series of imidazolidinone derivatives showing
significant anti-EV-71 activity. According to an SAR
investigation, an aryl substituent at the para position
and a pyridine-containing imidazolidinone ring are two
key structural requirements for potency and selectivity.
Some of the compounds described, such as 20, 57, 58,
and 61, exhibit high antiviral potency and have an
excellent selectivity index. Further SAR studies as well
as pharmacokinetic and mechanistic studies on this
class of compounds are currently under active investiga-
tion and will be reported in due course.
As exemplified by compounds 1, 11, and 12, the length
of the alkyl linker does not appear to contribute
significantly to antiviral activity. As such, all subse-
quently synthesized derivatives were maintained at
these lengths (n ) 5, 6, or 7).
Exp er im en ta l Section
With the para substitution of the phenoxyl ring
maintained, modifications of the other aryl functionality
were carried out. As shown in Table 3, compared to their
parent compounds 1, 8, 11, and 19, the corresponding
2-chloro derivatives 36-39 showed a decrease in activity
by about 100-fold! This effect might be due to a strict
steric requirement on the 4-pyridyl moiety or a reduc-
tion of the basicity of the pyridine nitrogen resulting
from the electron-withdrawing effect of the 2-chloro
group. Such a dramatic decrease in activity as a result
of a minor modification motivated us to further explore
the apparent profound effect of the pyridine ring on
antiviral activity in this series.
A. Ch em istr y. For anhydrous reactions, glassware was
dried overnight in an oven at 120 °C and cooled in a desiccator
over anhydrous CaSO4 or silica gel. Reagents were purchased
from Aldrich, Sigma Chemical Co., and Life Technology.
Solvents, including dry ether and tetrahydrofuran (THF), were
obtained by distillation from the sodium ketyl of benzophenone
under nitrogen. Other solvents, including chloroform, dichlo-
romethane, ethyl acetate, and hexane were distilled over CaH2
under nitrogen. Absolute methanol and ethanol were pur-
chased from Merck and used as received.
Melting points were obtained with a Yanaco (MP-500D)
melting point apparatus. Infrared (IR) spectra were recorded
on a Perkin-Elmer (Spectrum RX1) spectrophotometer. The
wavenumbers reported are referenced to the 1601 cm-1

Pyridyl Imidazolidinones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1649
Ta ble 4. Selectivity Index of Imidazolidinones with Potent Anti-EV-71 Activity
a
b
Mean of triplicate well values. All experiments were performed at least twice. Neutralization test was employed. RD: human
rhabdomyosarcoma cells. c D551: human normal skin fibroblast cells. WI38: human normal lung fibroblast cells.
d
absorption of polystyrene. The proton NMR spectra were
obtained on a Varian Mer-Vx-300 (300 MHz) spectrometer.
Chloroform-d and dimethyl sulfoxide-d6 were used as solvent;
Me4Si (δ 0.00 ppm) was used as an internal standard. All NMR
chemical shifts are reported as δ values in parts per million
(ppm), and coupling constants (J ) are given in hertz (Hz). The
splitting pattern abbreviations are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; br, broad; m, unresolved multiplet
due to the field strength of the instrument; and dd, doublet of
doublet. Mass spectra were carried out on a Hewlett-Packard
(model 1100 MSD) mass spectrometer. Microanalyses were
performed on a Heraeus CHN-O rapid microanalyzer.
Purification on silica gel refers to flash column chromatog-
raphy on Merck silica gel 60 (particle size 230-400 mesh).
Analytical TLC was performed on precoated plates purchased
from Merck (silica gel 60 F254). Compounds were visualized
by using UV light, I2 vapor, or 2.5% phosphomolybdic acid in
ethanol with heating.
collected by filtration and washed with toluene (10 mL) to
afford N-(2-chloroethyl)-N′-(4-pyridyl)urea 2 (5.08 g, 80%).
N-(2-chloroethyl)-N′-(4-pyridyl)urea 2 (5.08 g, 0.26 mmol)
was dissolved in a mixed solvent of dry tetrahydrofuran (20
mL) and dimethylformamide (20 mL) and cooled in an ice bath.
NaH (60% dispersion in mineral oil, 1.07 g, 0.27 mmol) was
then added slowly. The resulting mixture was stirred at room
temperature for 2 h followed by addition of MeOH (10 mL) to
quench the reaction. The solvent was removed under reduced
pressure, and the crude residue thus obtained was extracted
with chloroform (2 × 30 mL) and washed with brine (15 mL).
The organic layer was dried over MgSO4, filtered, and con-
centrated. The resulting solid was recrystallized from MeOH
to give compound 3 as a white solid (4.07 g, 98%). IR vmax
1
(KBr): 1709, 1483, 1266 cm-1. H NMR (CDCl3): δ 8.44 (d, J
) 5.4 Hz, 2H), 7.45 (d, J ) 5.4 Hz, 2H), 3.91 (t, J ) 7.2 Hz,
2H), 3.61 (t, J ) 7.2 Hz, 2H). 13C NMR (CDCl3): δ 159.0, 150.2,
146.6, 111.1, 40.0, 37.1. ESMS m/z: 164.4 (MH+).
A.1. Gen er a l P r oced u r e for th e Syn th esis of Com -
p ou n d s 3-6. 1-(4-P yr id yl)-2-im id a zolid in on e (3). To a
solution of 4-aminopyridine (3.00 g, 31.9 mmol) in 15 mL of
toluene cooled in an ice bath was added 2-chloroethyl isocy-
anate (5.31 g, 47.9 mmol) dropwise over 30 min. The mixture
was stirred at room temperature for 5 h. The precipitate was
1-(2-Ch lor o-4-pyr idyl)-2-im idazolidin on e (4). Yield: 72%.
1
White solid. IR vmax (KBr): 1714, 1592, 1476, 1261 cm-1. H
NMR (CDCl3): δ 8.20 (d, J ) 6.6 Hz, 1H), 7.47 (d, J ) 6.6 Hz,
1H), 7.46 (S, 1H), 3.90 (t, J ) 7.2 Hz, 2H), 3.63 (t, J ) 7.2 Hz,
2H). 13C NMR (CDCl3): δ 158.2, 152.3, 149.8, 148.7, 110.8,
110.2, 42.6, 37.0. ESMS m/z: 198.5 (MH+).

1650 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
1-(3-P yr id yl)-2-im id a zolid in on e (5). Yield: 76%. White
Shia et al.
1.84-1.79 (m, 2H), 1.68-1.60 (m, 2H), 1.53-1.47 (m, 2H). 13
NMR (CDCl3): δ 158.0, 156.7, 150.0, 146.9, 132.1, 116.2, 112.6,
110.7, 67.7, 43.6, 41.3, 41.2, 28.6, 27.0, 23.1. ESMS m/z: 404.4
(MH+). Anal. (C19H22BrN3O2) C, H, N.
C
solid. IR vmax (KBr): 1706, 1476, 1264 cm-1
.
1H NMR
(CDCl3): δ 8.58 (d, J ) 2.7 Hz, 1H), 8.27 (dd, J ) 4.5, 1.2 Hz,
1H), 8.15 (ddd, J ) 8.7, 2.7, 1.2 Hz, 1H), 7.25 (dd, J ) 8.7, 4.5
Hz, 1H), 7.12 (br, 1H), 3.95 (t, J ) 7.2 Hz, 2H), 3.60 (t, J ) 7.2
Hz, 2H). 13C NMR (CDCl3): δ 159.7, 143.5, 138.5, 136.7, 124.9,
123.3, 44.4, 37.5. ESMS m/z: 164.1 (MH+).
1-[7-(4-Br om oph en oxy)h eptyl]-3-(4-pyr idyl)-2-im idazol-
id in on e (12). Yield: 88%. White solid. IR vmax (KBr): 1698,
1598, 1480, 1243 cm-1 1H NMR (CDCl3) δ 8.41 (d, J ) 5.7
.
1-(4-P yr im id in yl)-2-im id a zolid in on e (6). Yield: 78%.
Hz, 2H), 7.46 (d, J ) 5.7 Hz, 2H), 7.32 (d, J ) 8.4 Hz, 2H),
6.73 (d, J ) 8.4 Hz, 2H), 3.88 (t, J ) 6.3 Hz, 2H), 3.77 (t, J )
7.5 Hz, 2H), 3.50 (t, J ) 7.5 Hz, 2H), 3.28 (t, J ) 7.2 Hz, 2H),
1
White solid. IR vmax (KBr): 1693, 1495, 1277 cm-1. H NMR
(CDCl3): δ 8.82 (s, 1H), 8.44 (d, J ) 6.3 Hz, 1H), 8.21 (d, J )
6.3 Hz, 1H), 5.45 (br, 1H), 4.15 (t, J ) 8.1 Hz, 2H), 3.60 (t, J
) 8.1 Hz, 2H). 13C NMR (CDCl3): δ 158.1, 157.6, 156.2, 109.0,
43.2, 37.2. ESMS m/z: 165.2 (MH+).
1.79-1.68 (m, 2H), 1.60-1.55 (m, 2H), 1.50-1.24 (m, 6H). 13
C
NMR (CDCl3): δ 158.2, 156.7, 149.9, 147.2, 132.2, 116.2, 112.6,
110.8, 68.2, 43.8, 41.3, 29.0, 28.9, 27.2, 26.6, 25.9. ESMS m/z:
432.5 (MH+). Anal. (C21H26BrN3O2) C, H, N.
A.2. Gen er a l P r oced u r e for t h e Syn t h esis of 1 a n d
8-35. 1-[6-(4-Br om op h en oxy)h exyl]-3-(4-p yr id yl)-2-im id -
a zolid in on e (1). To a solution of 1-(4-pyridyl)-2-imidazolidi-
none (0.10 g, 0.62 mmol) in 10 mL of dimethylformamide was
added NaH (60% dispersion in mineral oil, 27.2 mg, 0.68 mmol)
in one portion at 0 °C. The resulting mixture was stirred at
room temperature for an additional 30 min and then cooled
in an ice bath. 1-Bromo-6-(4-bromophenoxy)hexane (0.21 g,
0.62 mmol) was added, and the mixture was stirred at room
temperature for 4 h. The reaction was quenched with MeOH
(3 mL), and the solvent was pumped off. Saturated NH4Cl
aqueous solution (5 mL) and dichloromethane (20 mL) were
added to the residue. The dichloromethane layer was separated
and dried over MgSO4, filtered, and evaporated to give the
crude residue, which was subjected to purification by flash
chromatography on silica gel (EA/MeOH ) 10:1) to give
compound 1 as a white solid (0.25 g, 96%). IR vmax (KBr): 1708,
1-[5-(4-Ch lor oph en oxy)pen tyl]-3-(4-pyr idyl)-2-im idazol-
id in on e (13). Yield: 93%. Yellow solid. IR vmax (KBr): 1699,
1595, 1480, 1252 cm-1 1H NMR (CDCl3): δ 8.41 (d, J ) 6.3
.
Hz, 2H), 7.46 (d, J ) 6.3 Hz, 2H), 7.18 (d, J ) 9.0 Hz, 2H),
6.78 (d, J ) 9.0 Hz, 2H), 3.90 (t, J ) 6.3 Hz, 2H), 3.77 (t, J )
9.0 Hz, 2H), 3.51 (t, J ) 9.0 Hz, 2H), 3.31 (t, J ) 6.9 Hz, 2H),
1.84-1.75 (m, 2H), 1.64-1.53 (m, 2H), 1.52-1.46 (m, 2H). 13
C
NMR (CDCl3): δ 157.5, 156.7, 149.9, 147.1, 129.2, 125.4, 115.7,
110.8, 67.8, 43.6, 41.4, 41.6, 28.7, 27.0, 23.2. ESMS m/z: 360.4
(MH+). Anal. (C19H22ClN3O2) C, H, N.
1-[6-(4-Ch lor op h en oxy)h exyl]-3-(4-p yr id yl)-2-im id a zol-
id in on e (14). Yield: 94%. White solid. IR vmax (KBr): 1699,
1480, 1252 cm-1. 1H NMR (CDCl3): δ 8.42 (d, J ) 5.7 Hz, 2H),
7.51 (d, J ) 5.7 Hz, 2H), 7.18 (d, J ) 6.6 Hz, 2H), 6.78 (d, J )
6.6 Hz, 2H), 3.90 (t, J ) 6.3 Hz, 2H), 3.80 (t, J ) 7.5 Hz, 2H),
3.53 (t, J ) 7.5 Hz, 2H), 3.30 (t, J ) 7.2 Hz, 2H), 1.81-1.71
(m, 2H), 1.63-1.35 (m, 6H). 13C NMR (CDCl3): δ 157.6, 156.5,
148.9, 147.8, 129.3, 125.4, 115.7, 110.9, 68.4, 43.8, 41.4, 41.3,
1594, 1500, 1269 cm-1 1H NMR (CDCl3): δ 8.42 (d, J ) 6.3
.
Hz, 2H), 7.45 (d, J ) 6.3 Hz, 2H), 7.32 (d, J ) 8.7 Hz, 2H),
6.73 (d, J ) 8.7 Hz, 2H), 3.89 (t, J ) 6.3 Hz, 2H), 3.78 (t, J )
9.0 Hz, 2H), 3.51 (t, J ) 9.0 Hz, 2H), 3.30 (t, J ) 7.5 Hz, 2H),
1.78-1.71 (m, 2H), 1.64-1.38 (m, 6H). 13C NMR (CDCl3): δ
158.2, 156.8, 150.3, 147.0, 132.2, 116.3, 112.7, 110.8, 68.0, 43.7,
41.4, 41.3, 29.0, 27.3, 26.4, 25.7. ESMS m/z: 418.4 (MH+).
Anal. (C20H24BrN3O2) C, H, N.
29.2, 27.2, 26.4, 25.7. ESMS m/z: 374.5 (MH+). Anal. (C20H24
-
ClN3O2) C, H, N.
1-[7-(4-Ch lor oph en oxy)h eptyl]-3-(4-pyr idyl)-2-im idazol-
id in on e (15). Yield: 84%. White solid. IR vmax (KBr): 170,
1600, 1479, 1243 cm-1 1H NMR (CDCl3): δ 8.40 (d, J ) 6.6
.
Hz, 2H), 7.46 (d, J ) 6.6 Hz, 2H), 7.18 (d, J ) 6.9 Hz, 2H),
6.77 (d, J ) 6.9 Hz, 2H), 3.87 (t, J ) 6.3 Hz, 2H), 3.76 (t, J )
7.2 Hz, 2H), 3.49 (t, J ) 7.2 Hz, 2H), 3.27 (t, J ) 7.2 Hz, 2H),
1-(4-P yr id yl)-3-{6-[4-(tr iflu or om eth yl) p h en oxy]h exyl}-
2-im id a zolid in on e (8). Yield: 89%. White solid. IR vmax
(KBr): 1709, 1593, 1328, 1110 cm-1. 1H NMR (CDCl3): δ 8.42
(d, J ) 6.3 Hz, 2H), 7.49 (d, J ) 9.0 Hz, 2H), 7.47 (d, J ) 6.3
Hz, 2H), 6.91 (d, J ) 9.0 Hz, 2H), 3.97 (t, J ) 6.6 Hz, 2H),
3.79 (t, J ) 7.2 Hz, 2H), 3.51 (t, J ) 7.2 Hz, 2H), 3.31 (t, J )
7.2 Hz, 2H), 1.82-1.75 (m, 2H), 1.64-1.37 (m, 6H). 13C NMR
(CDCl3): δ 161.5, 156.8, 150.3, 147.0, 126.9, 126.8, 114.4, 110.8,
68.0, 43.7, 41.4, 41.3, 28.9, 27.3, 26.4, 25.7. ESMS m/z: 408.5
(MH+). Anal. (C21H24F3N3O2) C, H, N.
1.76-1.71 (m, 2H), 1.57-1.52 (m, 2H), 1.43-1.35 (m, 6H). 13
C
NMR (CDCl3): δ 157.6, 156.5, 149.8, 147.2, 129.2, 125.2, 115.7,
110.8, 68.1, 43.7, 41.3, 29.0, 28.9, 27.2, 26.6, 25.8. ESMS m/z:
388.3 (MH+). Anal. (C21H26ClN3O2) C, H, N.
1-[6-(4-F lu or op h en oxy)h exyl]-3-(4-p yr id yl)-2-im id a zol-
id in on e (16). Yield: 90%. White solid. IR vmax (KBr): 1707,
1595, 1505, 1268 cm-1 1H NMR (CDCl3): δ 8.42 (d, J ) 6.0
.
Hz, 2H), 7.46 (d, J ) 6.0 Hz, 2H), 6.96-6.90 (m, 2H), 6.81-
6.77 (m, 2H), 3.89 (t, J ) 6.3 Hz, 2H), 3.79 (t, J ) 7.2 Hz, 2H),
3.51 (t, J ) 7.2 Hz, 2H), 3.30 (t, J ) 6.9 Hz, 2H), 1.78-1.73
(m, 2H), 1.61-1.23 (m, 6H). 13C NMR (CDCl3): δ 158.7, 156.8,
150.3, 147.0, 115.9, 115.6, 115.3, 110.8, 68.4, 43.7, 41.4, 41.3,
1-(4-P yr idyl)-3-{5-[4-(tr iflu or om eth yl)ph en oxy]pen tyl}-
2-im id a zolid in on e (9). Yield: 91%. White solid. IR vmax
1
(KBr): 1711, 1594, 1329, 1259, 1110 cm-1. H NMR (CDCl3):
δ 8.42 (d, J ) 6.3 Hz, 2H), 7.52-7.49 (m, 4H), 6.90 (d, J ) 8.7
Hz, 2H), 3.98 (t, J ) 6.0 Hz, 2H), 3.80 (t, J ) 7.4 Hz, 2H), 3.55
(t, J ) 7.4 Hz, 2H), 3.34 (t, J ) 6.6 Hz, 2H), 1.86-1.79 (m,
2H), 1.67-1.48 (m, 4H). 13C NMR (CDCl3): δ 161.4, 156.6,
149.0, 147.8, 126.9, 114.4, 111.0, 67.8, 43.7, 41.1, 29.7, 28.7,
27.0, 23.2. ESMS m/z: 394.1 (MH+). Anal. (C20H22F3N3O2) H,
N; C: calcd, 61.06; found, 60.43.
29.1, 27.3, 26.4, 25.7. ESMS m/z: 358.4 (MH+). Anal. (C20H24
-
FN3O2) C, H, N.
1-[6-(4-Meth ylp h en oxy)h exyl]-3-(4-p yr id yl)-2-im id a zol-
id in on e (17). Yield: 93%. White solid. IR vmax (KBr): 1713,
1593, 1509, 1269 cm-1 1H NMR (CDCl3): δ 8.42 (d, J ) 6.3
.
Hz, 2H), 7.45 (d, J ) 6.3 Hz, 2H), 7.04 (d, J ) 8.1 Hz, 2H),
6.76 (d, J ) 8.1 Hz, 2H), 3.91 (t, J ) 6.3 Hz, 2H), 3.78 (t, J )
10.2 Hz, 2H), 3.51 (t, J ) 10.2 Hz, 2H), 3.30 (t, J ) 7.5 Hz,
2H), 2.26 (s, 3H), 1.78-1.30 (m, 8H). 13C NMR (CDCl3): δ
156.9, 156.8, 150.3, 147.0, 129.9, 129.8, 114.4, 110.9, 67.8, 43.8,
41.4, 27.3, 26.5, 25.8, 23.8. ESMS m/z: 354.5 (MH+). Anal.
(C21H27N3O2) C, H, N.
1-(4-P yr idyl)-3-{7-[4-(tr iflu or om eth yl)ph en oxy]h eptyl}-
2-im id a zolid in on e (10). Yield: 92%. Yellow solid. IR vmax
1
(KBr): 1713, 1593, 1329, 1260, 1110 cm-1. H NMR (CDCl3):
δ 8.41 (d, J ) 6.3 Hz, 2H), 7.59 (d, J ) 6.3 Hz, 2H), 7.50 (d, J
) 8.4 Hz, 2H), 6.91 (d, J ) 8.4 Hz, 2H), 3.96 (t, J ) 6.3 Hz,
2H), 3.84 (t, J ) 7.4 Hz, 2H), 3.55 (t, J ) 7.4 Hz, 2H), 3.31 (t,
J ) 7.2 Hz, 2H), 1.80-1.73 (m, 2H), 1.60-1.36 (m, 8H). 13C
NMR (CDCl3): δ 161.5, 156.2, 148.8, 147.4, 126.9, 114.4, 111.1,
68.8, 43.9, 41.5, 41.3, 29.0, 27.2, 26.6, 25.9. ESMS m/z: 422.2
(MH+). Anal. (C22H26F3N3O2) C, H, N.
1-[6-(4-Met h oxyp h en oxy)h exyl]-3-(4-p yr id yl)-2-im id -
a zolid in on e (18). Yield: 94%. White solid. IR vmax (KBr):
1711, 1594, 1508, 1231 cm-1. 1H NMR (CDCl3): δ 8.41 (d, J )
5.7 Hz, 2H), 7.48 (d, J ) 5.7 Hz, 2H), 6.79 (s, 4H), 3.87 (t, J )
6.3 Hz, 2H), 3.78 (t, J ) 7.2 Hz, 2H), 3.73 (s, 3H), 3.51 (t, J )
7.2 Hz, 2H), 3.30 (t, J ) 7.2 Hz, 2H), 1.79-1.70 (m, 2H), 1.63-
1.23 (m, 6H). 13C NMR (CDCl3): δ 156.8, 153.7, 153.2, 150.1,
147.4, 115.4, 114.6, 110.9, 68.4, 55.7, 43.8, 41.3, 29.2, 27.3, 26.5,
25.8. ESMS m/z: 370.2 (MH+). Anal. (C21H27N3O3) C, H, N.
1-[5-(4-Br om oph en oxy)pen tyl]-3-(4-pyr idyl)-2-im idazol-
id in on e (11). Yield: 95%. White solid. IR vmax (KBr): 1701,
1598, 1474, 1248 cm-1 1H NMR (CDCl3) δ 8.41 (d, J ) 5.7
.
Hz, 2H), 7.72 (d, J ) 5.7 Hz, 2H), 7.33 (d, J ) 9.0 Hz, 2H),
6.73 (d, J ) 9.0 Hz, 2H), 3.91 (d, J ) 6.0 Hz, 2H), 3.84 (d, J )
7.5 Hz, 2H), 3.55 (d, J ) 7.5 Hz, 2H), 3.36 (t, J ) 7.2 Hz, 2H),

Pyridyl Imidazolidinones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1651
1-{(6-[4-(Meth ylsu lfa n yl)p h en oxy]h exyl}-3-(4-p yr id yl)-
2-im id a zolid in on e (19). Yield: 88%. White solid. IR vmax
(KBr): 1698, 1600, 1495, 1252 cm-1. 1H NMR (CDCl3): δ 8.40
(d, J ) 6.6 Hz, 2H), 7.50 (d, J ) 6.6 Hz, 2H), 7.21 (d, J ) 9.0
Hz, 2H), 6.80 (d, J ) 9.0 Hz, 2H), 3.90 (t, J ) 6.3 Hz, 2H),
3.79 (t, J ) 7.4 Hz, 2H), 3.51 (t, J ) 7.4 Hz, 2H), 3.30 (t, J )
7.2 Hz, 2H), 2.41 (s, 3H), 1.80-1.71 (m, 2H), 1.63-1.34 (m,
6H). 13C NMR (CDCl3): δ 157.6, 156.5, 148.9, 147.7, 130.1,
128.6, 115.2, 110.9, 67.9, 43.7, 41.4, 41.3, 29.1, 27.2, 26.4, 25.7,
18.0. ESMS m/z: 386.5 (MH+).
1709, 1589, 1501, 1255 cm-1. 1H NMR (CDCl3): δ 8.42 (d, J )
4.8 Hz, 2H), 7.51-7.46 (m, 4H), 7.24-7.16 (m, 2H), 7.02 (dd,
J ) 5.1, 3.6 Hz, 1H), 6.86 (d, J ) 6.6 Hz, 2H), 3.97 (t, J ) 6.3
Hz, 2H), 3.79 (t, J ) 8.9 Hz, 2H), 3.52 (t, J ) 8.9 Hz, 2H), 3.33
(t, J ) 6.9 Hz, 2H), 1.86-1.77 (m, 2H), 1.65-1.50 (m, 4H). 13
C
NMR (CDCl3): δ 158.6, 156.8, 150.3, 150.1, 147.1, 144.3, 127.9,
127.2, 123.8, 122.0, 114.8, 110.9, 67.7, 43.7, 41.4, 41.3, 28.8,
27.1, 23.3. ESMS m/z: 408.4 (MH+).
1-(4-P yr id yl)-3-{6-[4-(2-th ien yl)p h en oxy]h exyl}-2-im id -
a zolid in on e (27). Yield: 88%. Yellow solid. IR vmax (KBr):
1706, 1608, 1522, 1404 cm-1. 1H NMR (CDCl3): δ 8.41 (d, J )
6.6 Hz, 2H), 7.50-7.45 (m, 4H), 7.19-7.15 (m, 2H), 7.02 (dd,
J ) 5.1, 3.9 Hz, 1H), 6.86 (d, J ) 9.0 Hz, 2H), 3.96 (t, J ) 6.3
Hz, 2H), 3.77 (t, J ) 7.5 Hz, 2H), 3.50 (t, J ) 7.5 Hz, 2H), 3.30
1-[5-(Bip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-im id a zol-
id in -2-on e (20). Yield: 88%. White solid. IR vmax (KBr): 1701,
1628, 1474, 1268 cm-1 1H NMR (CDCl3): δ 8.43 (br, 2H),
.
7.54-7.47 (m, 6H), 7.39 (t, J ) 7.2 Hz, 2H), 7.29 (d, J ) 7.2
Hz, 1H), 6.93 (d, J ) 7.2 Hz, 2H), 4.00 (t, J ) 6.3 Hz, 2H),
3.79 (t, J ) 7.2 Hz, 2H), 3.53 (t, J ) 7.2 Hz, 2H), 3.34 (t, J )
6.9 Hz, 2H), 1.89-1.80 (m, 2H), 1.70-1.50 (m, 4H). 13C NMR
(CDCl3): δ 158.6, 156.8, 149.9, 147.2, 140.8, 133.7, 128.7, 128.1,
126.7, 114.8, 110.9, 67.7, 43.8, 41.5, 41.4, 28.9, 27.1, 23.3.
ESMS m/z: 402.5 (MH+). Anal. (C25H27N3O2) C, H, N.
(t, J ) 7.2 Hz, 2H), 1.81-1.75 (m, 2H), 1.59-1.39 (m, 6H). 13
C
NMR (CDCl3): δ 158.6, 156.7, 150.0, 147.2, 144.3, 127.9, 127.2,
123.8, 122.0, 114.8, 110.9, 67.8, 43.7, 41.3, 29.1, 27.3, 26.4, 25.7.
ESMS m/z: 422.5 (MH+).
1-{5-[4-(3-F u r yl)p h en oxy]p en tyl}-3-(4-p yr id yl)-2-im id -
a zolid in on e (28). Yield: 87%. Yellow solid. IR vmax (KBr):
1702, 1592, 1480, 1271 cm-1. 1H NMR (CDCl3): δ 8.39 (d, J )
6.3 Hz, 2H), 7.60 (dd, J ) 1.5, 0.9 Hz, 1H), 7.46 (d, J ) 6.3 Hz,
2H), 7.41 (t, J ) 1.5 Hz, 1H), 7.35 (d, J ) 8.7 Hz, 2H), 6.85 (d,
J ) 8.7 Hz, 2H), 6.01 (dd, J ) 1.5, 0.9 Hz, 1H), 3.94 (t, J ) 6.3
Hz, 2H), 3.75 (t, J ) 7.5 Hz, 2H), 3.49 (t, J ) 7.5 Hz, 2H), 3.30
1-[5-(4′-Ch lor obip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-
im id a zolid in -2-on e (21). Yield: 92%. White solid. IR vmax
1
(KBr): 1702, 1605 cm-1. H NMR (CDCl3): δ 8.41 (d, J ) 5.7
Hz, 2H), 7.60 (d, J ) 5.7 Hz, 2H), 7.44 (dd, J ) 8.7, 1.5 Hz,
4H), 7.34 (d, J ) 8.7 Hz, 2H), 6.92 (d, J ) 8.7 Hz, 2H), 3.99 (t,
J ) 6.3 Hz, 2H), 3.85 (t, J ) 7.2 Hz, 2H), 3.57 (t, J ) 7.2 Hz,
2H), 3.35 (t, J ) 6.9 Hz, 2H), 1.89-1.80 (m, 2H), 1.72-1.51
(m, 4H). 13C NMR (CDCl3): δ 158.7, 156.2, 148.9, 147.2, 139.2,
132.7, 132.5, 128.8, 128.0, 127.9, 114.8, 111.0, 67.6, 43.8, 41.4,
(t, J ) 6.9 Hz, 2H), 1.83-1.75 (m, 2H), 1.65-1.46 (m, 4H). 13
C
NMR (CDCl3): δ 158.1, 156.7, 149.8, 147.1, 143.4, 138.1, 137.5,
126.9, 126.0, 124.9 114.7, 110.8, 108.7, 67.6,43.6, 41.3, 28.8,
27.0, 23.2. ESMS m/z: 392.4 (MH+).
41.3, 28.8, 27.0 23.3. ESMS m/z: 436.1 (MH+). Anal. (C25H26
-
4-{6-[2-Oxo-3-(4-p yr id yl)-1-im id a zolid in yl]h exyl}oxy)-
ben zon itr ile (29). Yield: 88%. White solid. IR vmax (KBr):
ClN3O2) C, H, N.
1
1-[5-(4′-Br om obip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-
im id a zolid in -2-on e (22). Yield: 91%. White solid. IR vmax
1697, 1605, 1511, 1427, 1269 cm-1. H NMR (CDCl3): δ 8.42
(d, J ) 6.6 Hz, 2H), 7.54 (d, J ) 9.0 Hz, 2H), 7.50 (d, J ) 6.6
Hz, 2H), 6.89 (d, J ) 9.0 Hz, 2H), 3.97 (t, J ) 6.3 Hz, 2H),
3.81 (t, J ) 7.5 Hz, 2H), 3.53 (t, J ) 7.5 Hz, 2H), 3.31 (t, J )
7.2 Hz, 2H), 1.84-1.75 (m, 2H), 1.64-1.36 (m, 6H). 13C NMR
(CDCl3): δ 162.3, 156.6, 149.2, 147.6, 133.9, 119.2, 115.4, 110.9,
103.8, 68.1, 43.7, 41.4, 41.3, 28.9, 27.2, 26.4, 25.6. ESMS m/z:
365.1 (MH+).
1
(KBr): 1706 cm-1. H NMR (CDCl3): δ 8.43 (br, 2H), 7.50 (d,
J ) 8.4 Hz, 4H), 7.44 (d, J ) 8.4 Hz, 2H), 7.37 (d, J ) 8.4 Hz,
2H), 6.92 (d, J ) 8.7 Hz, 2H), 3.99 (t, J ) 6.3 Hz, 2H), 3.81 (t,
J ) 7.2 Hz, 2H), 3.55 (t, J ) 7.2 Hz, 2H), 3.34 (t, J ) 6.3 Hz,
2H), 1.93-1.80 (m, 2H), 1.70-1.49 (m, 4H). 13C NMR
(CDCl3): δ 158.8, 156.6, 149.3, 147.6, 139.4, 132.8, 132.4, 131.8,
128.2, 128.0, 120.8, 114.8, 110.9, 67.7, 43.7, 41.4, 28.8, 27.1,
23.3. ESMS m/z: 480.5 (MH+). Anal. (C25H26BrN3O2) C, H, N.
1-[5-(4′-Meth oxybip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-
yl-im id a zolid in -2-on e (23). Yield: 91%. White solid. IR vmax
(KBr): 1711, 1606, 1501, 1273 cm-1. 1H NMR (CDCl3): δ 8.43
(br, 2H), 7.54 (d, J ) 5.1 Hz, 2H), 7.45 (d, J ) 8.7 Hz, 2H),
7.43 (d, J ) 8.7 Hz, 2H), 6.92 (t, J ) 8.7 Hz, 4H), 3.99 (t, J )
6.0 Hz, 2H), 3.82 (t, J ) 7.2 Hz, 2H), 3.82 (s, 3H), 3.55 (t, J )
7.2 Hz, 2H), 3.35 (t, J ) 7.2 Hz, 2H), 1.87-1.52 (m, 6H). 13C
NMR (CDCl3): δ 158.7, 158.1, 156.4, 148.2, 133.4, 127.7, 114.7,
114.2, 67.6, 55.3, 43.8, 41.4, 41.3, 28.9, 27.0, 23.3. ESMS m/z:
432.5 (MH+). Anal. (C26H29N3O3) C, H, N.
1-[6-(3-Br om op h en oxy)h exyl]-3-(4-p yr id yl)-2-im id a zol-
id in on e (30). Yield: 95%. White solid. IR vmax (KBr): 1712,
1592, 1479, 1269 cm-1 1H NMR (CDCl3): δ 8.42 (d, J ) 6.3
.
Hz, 2H), 7.46 (d, J ) 6.3 Hz, 2H), 7.12-7.01 (m, 3H), 6.78 (d,
J ) 8.1 Hz, 1H), 3.91 (t, J ) 6.3 Hz, 2H), 3.79 (t, J ) 7.7 Hz,
2H), 3.52 (t, J ) 7.7 Hz, 2H), 3.30 (t, J ) 7.2 Hz, 2H), 1.81-
1.72 (m, 2H), 1.64-1.36 (m, 6H). 13C NMR (CDCl3): δ 159.8,
156.8, 150.2, 147.0, 130.5, 123.6, 122.7, 117.7, 113.5, 110.8,
67.9, 43.7, 41.2, 28.9, 27.2, 26.4, 25.7. ESMS m/z: 418.2 (MH+).
Anal. (C20H24BrN3O2) C, H, N.
1-{6-[3-(Dim eth yla m in o)p h en oxy]h exyl}-3-(4-p yr id yl)-
2-im id a zolid in on e (31). Yield: 82%. White solid. IR vmax
1
1-[5-(4′-Nit r ob ip h en yl-4-yloxy)p en t yl]-3-p yr id in -4-yl-
im id a zolid in -2-on e (24). Yield: 86%. Yellow solid. IR vmax
(KBr): 1709, 1595, 1479, 1426, 1268 cm-1. H NMR (CDCl3):
δ 8.41 (d, J ) 6.0 Hz, 2H), 7.47 (d, J ) 6.0 Hz, 2H), 7.09 (t, J
) 8.7 Hz, 1H), 6.31 (d, J ) 8.7 Hz, 1H), 6.25-6.23 (m,2H),
3.92 (t, J ) 6.3 Hz, 2H), 3.77 (t, J ) 7.2 Hz, 2H), 3.50 (t, J )
7.2 Hz, 2H), 3.27 (t, J ) 6.9 Hz, 2H), 2.90 (s, 6H), 1.78-1.61
(m, 2H), 1.61-1.38 (m, 6H). 13C NMR (CDCl3): δ 160.1, 156.7,
152.0,149.9, 147.2, 129.7, 110.9, 105.7, 102.0, 99.7, 67.5, 43.8,
41.3, 40.5, 29.2, 27.3, 26.5, 25.8. ESMS m/z: 383.5 (MH+).
Anal. (C22H30N4O2) C, H, N.
1
(KBr): 1708, 1594, 1512, 1342, 1253 cm-1. H NMR (CDCl3):
δ 8.43 (br, 2H), 8.24 (d, J ) 8.7 Hz, 2H), 7.65 (d, J ) 8.7 Hz,
2H), 7.54 (d, J ) 8.7 Hz, 2H), 7.47 (d, J ) 5.1 Hz, 2H), 6.96 (d,
J ) 8.7 Hz, 2H), 4.00 (t, J ) 6.3 Hz, 2H), 3.80 (t, J ) 8.6 Hz,
2H), 3.54 (t, J ) 8.6 Hz, 2H), 3.34 (t, J ) 6.9 Hz, 2H), 1.88-
1.83 (m, 2H), 1.68-1.53 (m, 4H). 13C NMR (CDCl3): δ 159.8,
156.8, 149.9, 147.2, 147.1, 146.5, 130.9, 128.5, 127.0, 124.1,
115.1, 110.9, 67.8, 43.7, 41.4, 41.3, 28.8, 27.0, 23.3. ESMS
m/z: 447.5 (MH+). Anal. (C25H26N4O4) C, H, N.
1-[6-(2,6-Dich lor op h en oxy)h exyl]-3-(4-p yr id yl)-2-im id -
a zolid in on e (32). Yield: 91%. Yellow solid. IR vmax (KBr):
4′-[5-(2-Oxo-3-pyr idin -4-yl-im idazolidin -1-yl)pen tyloxy]-
1713, 1595, 1439, 1269 cm-1 1H NMR (CDCl3): δ 8.41 (br,
.
bip h en yl-4-ca r bon itr ile (25). Yield: 92%. White solid. IR
2H), 7.50 (d, J ) 5.7 Hz, 2H), 7.25 (d, J ) 8.1 Hz, 1H), 7.23 (d,
J ) 8.1 Hz, 1H), 6.95 (t, J ) 8.1 Hz, 1H), 3.99 (t, J ) 6.3 Hz,
2H), 3.80 (t, J ) 7.5 Hz, 2H), 3.54 (t, J ) 7.5 Hz, 2H), 3.32 (t,
J ) 7.2 Hz, 2H), 1.86-1.81 (m, 2H), 1.64-1.43 (m, 6H). 13C
NMR (CDCl3): δ 156.6, 151.7, 149.2, 147.7, 129.5, 128.9, 124.9,
110.9, 73.4, 43.8, 41.3, 29.9, 27.2, 26.5, 25.6. ESMS m/z: 408.1
(MH+). Anal. (C20H23Cl2N3O2) C, H, N.
1
v
max (KBr): 1704, 1601, 1494, 1267 cm-1. H NMR (CDCl3): δ
8.44 (br, 2H), 7.67 (d, J ) 8.4 Hz, 2H), 7.61 (d, J ) 8.4 Hz,
2H), 7.50 (d, J ) 8.4 Hz, 4H), 6.95 (d, J ) 8.4 Hz, 2H), 4.00 (t,
J ) 6.0 Hz, 2H), 3.82 (t, J ) 7.2 Hz, 2H), 3.54 (t, J ) 7.2 Hz,
2H), 3.35 (t, J ) 6.9 Hz, 2H), 1.90-1.83 (m, 2H), 1.69-1.51
(m, 4H). 13C NMR (CDCl3): δ 159.6, 156.7, 149.4, 147.4, 145.2,
132.6, 131.4, 128.3, 127.1, 119.1,1 115.1, 111.1, 110.0, 67.8,
43.7, 41.4, 28.8, 27.1, 23.3. ESMS m/z: 427.5 (MH+).
1-[6-(2-Ch lor o-4-m eth oxyp h en oxy)h exyl]-3-(4-p yr id yl)-
2-im id a zolid in on e (33). Yield: 93%. White solid. IR vmax
(KBr): 1712, 1591, 1499, 1281 cm-1. 1H NMR (CDCl3): δ 8.33
(d, J ) 5.1 Hz, 2H), 7.37 (d, J ) 5.1 Hz, 2H), 6.83 (d, J ) 3.0
1-(4-P yr idyl)-3-{5-[4-(2-th ien yl)ph en oxy]pen tyl}-2-im id-
a zolid in on e (26). Yield: 84%. White solid. IR vmax (KBr):

1652 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Shia et al.
Hz, 1H), 6.75 (d, J ) 9.0 Hz, 1H), 6.63 (dd, J ) 9.0, 3.0 Hz,
1H), 3.86 (t, J ) 6.3 Hz, 2H), 3.69-3.63 (m, 5H), 3.41 (t, J )
7.0 Hz, 2H), 3.21 (t, J ) 7.2 Hz, 2H), 1.76-1.67 (m, 2H), 1.56-
1.41 (m, 4H), 1.37-1.29 (m, 2H). 13C NMR (CDCl3): δ 156.5,
153.6, 149.8, 148.6, 146.8, 123.4, 115.7, 114.8, 112.6, 110.6,
69.7, 55.6, 43.4, 41.4, 28.9, 27.0, 26.2, 25.5. ESMS m/z: 404.1
(MH+). Anal. (C21H26ClN3O3) C, H, N.
8.18 (d, J ) 6.0 Hz, 1H), 7.49-7.47 (m, 2H), 7.23 (d, J ) 8.7
Hz, 2H), 6.81 (d, J ) 8.7 Hz, 2H), 3.92 (t, J ) 6.3 Hz, 2H),
3.77 (t, J ) 8.4 Hz, 2H), 3.53 (t, J ) 8.4 Hz, 2H), 3.30 (t, J )
7.2 Hz, 2H), 2.42 (s, 3H), 1.81-1.72 (m, 2H), 1.64-1.38 (m,
6H). 13C NMR (CDCl3): δ 157.9, 156.5, 152.1, 149.6, 149.5,
130.4, 128.9, 115.4, 110.6, 110.1, 68.1, 44.0, 41.7, 41.5, 29.3,
27.4, 26.6, 25.9, 18.3. ESMS m/z: 420.4 (MH+). Anal. (C21H26
-
ClN3O2S) C, H; N: calcd, 10.01; found, 9.59.
1-[6-(1-Na p h th yloxy)h exyl]-3-(4-p yr id yl)-2-im id a zolid i-
n on e (34). Yield: 88%. Yellow solid. IR vmax (KBr): 1713, 1594,
1427, 1270 cm-1. 1H NMR (CDCl3): δ 8.39 (d, J ) 6.0 Hz, 2H),
8.26-8.21 (m, 1H), 7.78-7.74 (m, 1H), 7.45-7.29 (m, 6H), 6.75
(dd, J ) 7.2, 0.9 Hz, 1H), 4.10 (t, J ) 6.3 Hz, 2H), 3.67 (t, J )
7.1 Hz, 2H), 3.43 (t, J ) 7.1 Hz, 2H), 3.29 (t, J ) 7.2 Hz, 2H),
A.4. Gen er a l P r oced u r e for th e Syn th esis of 40-47.
1-[5-(4-Ch lor op h en oxy)p en tyl]-3-(3-p yr id yl)-2-im id a zoli-
d in on e (40). To a solution of 1-(3-pyridyl)-2-imidazolidinone
(73.4 mg, 0.45 mmol) in 10 mL of dimethylformamide was
added NaH (75% dispersion in mineral oil, 21.8 mg, 0.68 mmol)
in one portion at 0 °C. The mixture was stirred at room
temperature for 30 min and then was cooled in ice bath. 1-[(5-
Bromopentyl)oxy]-4-chlorobenzene (124.9 mg, 0.45 mmol) was
added, and the mixture was stirred at room temperature for
4 h. The reaction was quenched with MeOH (2 mL), and the
solvent was concentrated in vacuo. Saturated NH4Cl aqueous
solution (5 mL) and dichloromethane (15 mL) were added to
the residue. The dichloromethane layer was separated and
dried over MgSO4, filtered, evaporated, and purified by flash
chromatography (MeOH/EtOAc ) 1:10) to give compound 40
as a white solid (136.2 mg, 84%). IR vmax (KBr): 1710, 1488,
1.95-1.86 (m, 2H), 1.65-1.54 (m, 4H), 1.48-1.40 (m, 2H). 13
C
NMR (CDCl3): δ 156.5, 154.7, 149.2, 147.4, 134.4, 127.4, 126.2,
125.9, 125.6, 125.0, 121.9, 120.0, 110.8, 104.5, 67.8, 43.7, 41.2,
29.1, 27.2, 26.4, 25.9. ESMS m/z: 390.5 (MH+). Anal.
(C24H27N3O2) H, N; C: calcd, 74.01; found, 73.20.
1-(4-P yr id yl)-3-[6-(8-qu in olyloxy)h exyl]-2-im id a zolid i-
n on e (35). Yield: 89%. Yellow solid. IR vmax (KBr): 1716, 1598,
1428 cm-1. 1H NMR (CDCl3): δ 8.90 (dd, J ) 4.2, 1.8 Hz, 1H),
8.40 (d, J ) 4.2 Hz, 2H), 8.09 (dd, J ) 8.4, 1.8 Hz, 1H), 7.45-
7.32 (m, 5H), 7.01 (dd, J ) 7.5, 1.2 Hz, 1H), 4.21 (t, J ) 6.6
Hz, 2H), 3.75 (t, J ) 7.2 Hz. 2H), 3.48 (t, J ) 7.2 Hz, 2H), 3.29
1
1431, 1245 cm-1. H NMR (CDCl3): δ 8.56 (bs, 1H), 8.21 (bs,
(t, J ) 6.9 Hz, 2H), 2.06-1.97 (m, 4H), 1.64-1.40 (m, 4H). 13
C
1H), 8.10 (d, J ) 8.4 Hz, 1H), 7.20-7.11 (m, 1H), 7.15 (d, J )
9.0 Hz, 2H), 6.73 (d, J ) 9.0 Hz, 2H), 3.85 (t, J ) 6.3 Hz, 2H),
3.74 (t, J ) 7.2 Hz, 2H), 3.45 (t, J ) 7.2 Hz, 2H), 3.25 (t, J )
6.9 Hz, 2H), 1.80-1.71 (m, 2H), 1.60-1.42 (m, 4H). 13C NMR
(CDCl3): δ 157.5, 157.4, 143.0, 137.9, 137.1, 129.1, 125.1, 124.2,
123.2, 115.6, 67.8, 43.6, 41.6, 41.5, 28.6, 27.0, 22.5. ESMS
m/z: 360.4 (MH+). Anal. (C19H22ClN3O2) C, H, N.
NMR (CDCl3): δ 156.7, 154.8, 149.6, 149.2, 147.4, 136.0, 129.5,
126.7, 121.5, 119.4, 111.2, 110.9, 108.7, 68.8, 43.7, 41.3, 28.9,
27.2, 26.5, 25.8. ESMS m/z: 391.2 (MH+).
A.3. Gen er a l P r oced u r e for t h e Syn t h esis of 36-39.
1-[6-(4-Br om op h en oxy)h exyl]-3-(2-ch lor o-4-p yr id yl)-2-
im id a zolid in on e (36). To a solution of 1-(2-chloro-4-pyridyl)-
2-imidazolidinone 4 (0.11 g, 0.55 mmol) dissolved in 10 mL of
dimethylformamide cooled in ice bath was added NaH (75%
dispersion in mineral oil, 26.6 mg, 0.83 mmol) in one portion.
The mixture was stirred at room temperature for 30 min and
then was cooled in ice bath. 1-Bromo-6-(4-bromophenoxy)-
hexane (0.18 g, 0.55 mmol) was added, and the mixture was
stirred at room temperature for 4 h. The reaction was
quenched with MeOH, and the solvents were pumped off.
Saturated NH4Cl aqueous solution (5 mL) and dichloromethane
(10 mL) were added to the residue. The dichloromethane layer
was dried over MgSO4, filtered, evaporated, and purified by
column chromatography to give 36 as a yellow solid (0.23 g,
1-[6-(4-Ch lor op h en oxy)h exyl]-3-(3-p yr id yl)-2-im id a zol-
id in on e (41). Yield: 85%. Yellow solid. IR vmax (KBr): 1703,
1
1492, 1433, 1244 cm-1. H NMR (CDCl3): δ 8.56 (s, 1H), 8.25
(d, J ) 4.2 Hz, 1H), 8.20 (d, J ) 8.4 Hz, 1H), 7.26-7.21 (m,
1H), 7.18 (d, J ) 9.0 Hz, 2H), 6.78 (d, J ) 9.0 Hz, 2H), 3.89 (t,
J ) 6.3 Hz, 2H), 3.82 (t, J ) 7.4 Hz, 2H), 3.52 (t, J ) 7.4 Hz,
2H), 3.30 (t, J ) 7.2 Hz, 2H), 1.80-1.71 (m, 2H), 1.61-1.36
(m, 6H). 13C NMR (CDCl3): δ 157.5, 157.3, 142.9, 137.9, 137.1,
129.0, 125.1, 124.2, 123.2, 115.8, 67.9, 43.6, 41.6, 41.5, 28.9,
27.1, 26.3, 25.5. ESMS m/z: 374.5 (MH+). Anal. (C20H24ClN3O2)
C, H, N.
92%). IR vmax (KBr): 1714, 1590, 1488, 1245 cm-1 1H NMR
.
1-[7-(4-Ch lor oph en oxy)h eptyl]-3-(3-pyr idyl)-2-im idazol-
(CDCl3): δ 8.18 (d, J ) 5.7 Hz, 1H), 7.48 (dd, J ) 5.4, 1.8 Hz,
1H), 7.43 (d, J ) 1.8 Hz, 1H), 7.32 (d, J ) 9.0 Hz, 2H), 6.73 (d,
J ) 9.0 Hz, 2H), 3.89 (t, J ) 6.3 Hz, 2H), 3.77 (t, J ) 7.2 Hz,
2H), 3.52 (t, J ) 7.2 Hz, 2H), 3.30 (t, J ) 6.9 Hz, 2H), 1.81-
1.71 (m, 2H), 1.61-1.35 (m, 6H). 13C NMR (CDCl3): δ 158.1,
156.2, 152.0, 149.5, 149.0, 132.1, 116.2, 112.6, 110.3, 109.8,
67.9, 43.7, 41.4, 41.2, 28.9, 27.1, 26.4, 25.6. ESMS m/z: 452.0
(MH+). Anal. (C20H23BrClN3O2) C, H, N.
id in on e (42). Yield: 83%. Yellow solid. IR vmax (KBr): 1704,
1
1494, 1246 cm-1. H NMR (CDCl3): δ 8.56 (bs, 1H), 8.16 (d, J
) 3.3 Hz, 1H), 8.02 (d, J ) 8.1 Hz, 1H), 7.25-7.22 (m, 1H),
7.18 (d, J ) 8.7 Hz, 2H), 6.70 (d, J ) 8.7 Hz, 2H), 3.79 (t, J )
6.3 Hz, 2H), 3.69 (t, J ) 6.9 Hz, 2H), 3.39 (t, J ) 6.9 Hz, 2H),
3.18 (t, J ) 7.2 Hz, 2H), 1.68-1.64 (m, 2H), 1.49-1.30 (m, 8H).
13C NMR (CDCl3): δ 157.4, 157.2, 142.7, 137.8, 137.1, 128.9,
124.9, 124.0, 123.0, 115.5, 67.9, 43.6, 41.4, 41.4, 28.8, 28.7, 27.0,
26.4, 25.6. ESMS m/z: 388.5 (MH+). Anal. (C21H26ClN3O2) C,
H, N.
1-(2-Ch lor o-4-pyr idyl)-3-{6-[4-(tr iflu or om eth yl)ph en oxy]-
h exyl}-2-im id a zolid in on e (37). Yield: 88%. White solid. IR
1
v
max (KBr): 1719, 1593, 1477, 1257 cm-1. H NMR (CDCl3): δ
1-(3-P yr id yl)-3-{6-[4-(tr iflu or om eth yl)p h en oxy]h exyl}-
2-im id a zolid in on e (43). Yield: 91%. White solid. IR vmax
8.14 (d, J ) 5.4 Hz, 1H), 7.50-7.41 (m, 4H), 6.89 (d, J ) 8.4
Hz, 2H), 3.95 (t, J ) 6.3 Hz, 2H), 3.74 (t, J ) 8.4 Hz, 2H), 3.50
(t, J ) 8.4 Hz, 2H), 3.28 (t, J ) 6.9 Hz, 2H), 1.80-1.60 (m,
2H), 1.57-1.37 (m, 6H). 13C NMR (CDCl3): δ 161.4, 156.2,
152.0, 149.5, 149.1, 126.8, 126.7, 114.3, 110.3, 109.7, 67.9, 43.6,
41.4, 41.2, 28.9, 27.1, 26.3, 25.6. ESMS m/z: 442.5 (MH+).
Anal. (C21H23ClF3N3O2) C, H; N: calcd, 9.51; found, 9.04.
(KBr): 1705, 1615, 1484, 1329, 1260, 1110 cm-1 1H NMR
.
(CDCl3): δ 8.56 (bs, 1H), 8.25 (d, J ) 4.2 Hz, 1H), 8.18 (d, J )
8.4 Hz, 1H), 7.49 (d, J ) 8.4 Hz, 2H), 7.23 (dd, J ) 8.7, 4.2 Hz,
1H), 6.91 (d, J ) 8.4 Hz, 2H), 3.83 (t, J ) 6.6 Hz, 2H), 3.66 (t,
J ) 7.2 Hz, 2H), 3.36 (t, J ) 7.2 Hz, 2H), 3.19 (t, J ) 6.9 Hz,
2H), 1.84-1.77 (m, 2H), 1.64-1.39 (m, 6H). 13C NMR
(CDCl3): δ 161.2, 157.0, 142.4, 137.8, 137.3, 126.3, 123.8, 123.6,
122.9, 114.0, 67.6, 43.3, 41.2, 41.1, 28.5, 26.5, 26.0, 25.4. ESMS
m/z: 408.5 (MH+). Anal. (C21H24F3N3O2) C, H, N.
1-[5-(4-Br om op h en oxy)p en tyl]-3-(2-ch lor o-4-p yr id yl)-
2-im id a zolid in on e (38). Yield: 91%. Yellow solid. IR vmax
1
(KBr): 1707, 1597, 1479 cm-1. H NMR (CDCl3): δ 8.19 (d, J
) 5.4 Hz, 1H), 7.48 (d, J ) 5.4 Hz, 1H), 7.46 (s, 1H), 7.33 (d,
J ) 9.0, 2H), 6.73 (d, J ) 9.0 Hz, 2H), 3.91 (t, J ) 6.3 Hz, 2H),
3.78 (t, J ) 7.2 Hz, 2H), 3.53 (t, J ) 7.2 Hz, 2H), 3.32 (t, J )
6.9 Hz, 2H), 1.83-1.76 (m, 2H), 1.66-1.49 (m, 4H). 13C NMR
(CDCl3): δ 158.5, 156.6, 149.7, 132.7, 116.7, 113.2, 110.9, 110.3,
68.2, 44.2, 41.9, 41.7, 30.1, 29.2, 27.4. ESMS m/z: 438.0 (MH+).
1-[6-(4-F lu or op h en oxy)h exyl]-3-(3-p yr id yl)-2-im id a zol-
id in on e (44). Yield: 88%. White solid. IR vmax (KBr): 1695,
1484, 1250 cm-1. 1H NMR (CDCl3): δ 8.54 (d, J ) 2.7 Hz, 1H),
8.11 (d, J ) 4.8 Hz, 1H), 7.95 (dd, J ) 8.4, 2.7 Hz, 1H), 7.08
(dd, J ) 8.4, 4.8 Hz, 1H), 6.82 (d, J ) 9.0 Hz, 2H), 6.66 (d, J
) 9.0 Hz, 2H), 3.74 (t, J ) 6.3 Hz, 2H), 3.62 (t, J ) 7.4 Hz,
2H), 3.31 (t, J ) 7.4 Hz, 2H), 3.14 (t, J ) 7.2 Hz, 2H), 1.67-
1.57 (m, 2H), 1.47-1.22 (m, 6H). 13C NMR (CDCl3): δ 158.2,
157.0, 155.0, 154.8, 142.5, 137.7, 137.0, 123.8, 122.9, 114.9,
1-(2-Ch lor o-4-pyr idyl)-3-{6-[4-(m eth ylsu lfan yl)ph en oxy]-
h exyl}-2-im id a zolid in on e (39). Yield: 86%. Yellow solid. IR
1
v
max (KBr): 1714, 1590, 1493, 1243 cm-1. H NMR (CDCl3): δ

Pyridyl Imidazolidinones
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8 1653
67.9, 43.4, 41.3, 41.2, 28.7, 26.9, 26.0, 25.3. ESMS m/z: 358.5
7.2 Hz, 2H), 1.81-1.72 (m, 2H), 1.64-1.39 (m, 6H). 13C NMR
(CDCl3): δ 157.9, 157.8, 156.1, 155.8, 129.4, 129.3, 125.4, 115.8,
108.8, 68.1, 43.7, 41.5, 40.5, 29.1, 27.2, 26.4, 25.9. ESMS m/z:
375.1 (MH+).
1-[6-(4-Br om oph en oxy)h exyl]-3-(4-pyr im idin yl)-2-im id-
a zolid in on e (51). Yield: 89%. White solid. IR vmax (KBr):
1714, 1583, 1487, 1244 cm-1. 1H NMR (CDCl3): δ 8.79 (s, 1H),
8.41 (d, J ) 5.1 Hz, 1H), 8.22 (d, J ) 5.1 Hz, 1H), 7.31 (d, J )
7.8 Hz, 2H), 6.72 (d, J ) 7.8 Hz, 2H), 4.01 (t, J ) 7.5 Hz, 2H),
3.89 (t, J ) 7.8 Hz, 2H), 3.49 (t, J ) 7.8 Hz, 2H), 3.30 (t, J )
6.9 Hz, 2H), 1.78-1.72 (m, 2H), 1.64-1.36 (m, 6H). 13C NMR
(CDCl3): δ 158.1, 158.0, 156.2, 156.0, 132.2, 132.1, 116.2, 112.6,
108.8, 68.0, 43.6, 41.4, 40.4, 29.0, 27.2, 26.4, 25.7. ESMS m/z:
419.1 (MH+).
(MH+). Anal. (C20H24FN3O2) C, H, N.
1-[6-(4-Br om op h en oxy)h exyl]-3-(3-p yr id yl)-2-im id a zol-
id in on e (45). Yield: 89%. Yellow solid. IR vmax (KBr): 1703,
1
1578, 1481, 1242 cm-1. H NMR (CDCl3): δ 8.55 (s, 1H), 8.18
(d, J ) 4.5 Hz, 1H), 8.02 (d, J ) 8.4 Hz, 1H), 7.23 (d, J ) 9.3
Hz, 2H), 7.14 (dd, J ) 8.4, 4.5 Hz, 1H), 6.65 (d, J ) 9.3 Hz,
2H), 3.80 (t, J ) 6.3 Hz, 2H), 3.69 (t, J ) 8.1 Hz, 2H), 3.41 (t,
J ) 8.1 Hz, 2H), 3.20 (t, J ) 7.2 Hz, 2H), 1.72-1.63 (m, 2H),
1.55-1.27 (m, 6H). 13C NMR (CDCl3): δ 157.9, 157.2, 142.8,
137.9, 137.4, 131.9, 124.0, 123.1, 116.0, 112.3, 67.8, 43.6, 41.5,
41.4, 28.8, 27.1, 26.2, 25.4. ESMS m/z: 418.1 (MH+). Anal.
(C20H24BrN3O2) C, H, N.
1-[6-(4-Meth ylp h en oxy)h exyl]-3-(3-p yr id yl)-2-im id a zol-
id in on e (46). Yield: 85%. White solid. IR vmax (KBr): 1707,
1-[7-(4-Br om oph en oxy)h eptyl]-3-(4-pyr im idin yl)-2-im id-
a zolid in on e (52). Yield: 83%. White solid. IR vmax (KBr):
1720, 1581, 1488, 1244 cm-1. 1H NMR (CDCl3): δ 8.80 (s, 1H),
8.40 (d, J ) 6.0 Hz, 1H), 8.25 (d, J ) 6.0 Hz, 1H), 7.32 (d, J )
8.7 Hz, 2H), 6.72 (d, J ) 8.7 Hz, 2H), 4.02 (t, J ) 7.5 Hz, 2H),
3.87 (t, J ) 6.3 Hz, 2H), 3.49 (t, J ) 6.3 Hz, 2H), 3.29 (t, J )
6.9 Hz, 2H), 1.74-1.71 (m, 2H), 1.58-1.25 (m, 8H). 13C NMR
(CDCl3): δ 158.1, 157.9, 157.5, 155.9, 155.1, 132.1, 116.2, 112.5,
108.7, 68.1, 43.7, 41.4, 40.4, 29.0, 28.9, 27.1, 26.6, 25.9. ESMS
m/z: 433.1 (MH+). Anal. (C20H25BrN4O2) C, H, N.
1
1488, 1248 cm-1. H NMR (CDCl3): δ 8.57 (bs, 1H), 8.19 (d, J
) 3.3 Hz, 1H), 8.05 (d, J ) 8.4 Hz, 1H), 7.15 (dd, J ) 8.4, 3.3
Hz, 1H), 6.97 (d, J ) 8.1 Hz, 2H), 6.70 (d, J ) 8.1 Hz, 2H),
3.84 (t, J ) 6.3 Hz, 2H), 3.67 (t, J ) 7.2 Hz, 2H), 3.39 (t, J )
7.2 Hz, 2H), 3.22 (t, J ) 7.2 Hz, 2H), 2.19 (s, 3H), 1.72-1.65
(m, 2H), 1.54-1.30 (m, 6H). 13C NMR (CDCl3): δ 157.1, 156.6,
142.7, 137.8, 137.0, 129.5, 129.3, 123.9, 123.0, 114.0, 67.5, 43.5,
41.4, 41.3, 29.3, 27.1, 26.2, 25.6, 20.1. ESMS m/z: 354.5 (MH+).
Anal. (C21H27N3O2) C, H, N.
1-{6-[4-(ter t-Bu tyl)ph en oxy]h exyl}-3-(3-pyr idyl)-2-im id-
a zolid in on e (47). Yield: 82%. Yellow solid. IR vmax (KBr):
A.6. Gen er a l P r oced u r e for t h e Syn t h esis of 53-56.
1-[5-(4-Br om op h en oxy)p en t yl]-3-p h en yl-2-im id a zolid i-
n on e (53). To a solution of 1-phenyl-2-imidazolidinone (94.1
mg, 0.58 mmol) in 10 mL of dimethylformamide cooled in an
ice bath was added NaH (75% dispersion in mineral oil, 27.8
mg, 0.87 mmol). The mixture was stirred at room temperature
for 30 min and then was cooled in ice bath. 1-Bromo-4-[(5-
bromopentyl)oxy]benzene (186.8 mg, 0.58 mmol) was added,
and the mixture was stirred at room temperature for 4 h. The
reaction was quenched with MeOH, and the solvent was
pumped off. Saturated NH4Cl aqueous solution (5 mL) and
dichloromethane (15 mL) were added to the residue. The
dichloromethane layer was dried over MgSO4, filtered, evapo-
rated, and purified by flash chromatography to furnish com-
pound 53 as a white solid (215.1 mg, 92%). IR vmax (KBr): 1701,
1699, 1513, 1484, 1431 cm-1 1H NMR (CDCl3): δ 8.60 (bs,
.
1H), 8.24-8.21 (m, 2H), 7.29-7.25 (m, 3H), 6.81 (d, J ) 6.9
Hz, 2H), 3.93 (t, J ) 6.3 Hz, 2H), 3.82 (t, J ) 8.6 Hz, 2H), 3.51
(t, J ) 8.6 Hz, 2H), 3.30 (t, J ) 6.9 Hz, 2H), 1.80-1.73 (m,
2H), 1.62-1.37 (m, 6H), 1.28 (s, 9H). 13C NMR (CDCl3): δ
157.2, 156.5, 142.8, 142.7, 137.8, 137.6, 125.9, 124.2, 123.1,
113.6, 67.4, 43.6, 41.5, 33.7, 31.3, 28.9, 27.1, 26.2, 25.5. ESMS
m/z: 396.5 (MH+). Anal. (C24H33N3O2) C, H, N.
A.5. Gen er a l P r oced u r e for th e Syn th esis of 48-52.
1-(4-P yr im id in yl)-3-{5-[4-(tr iflu or om eth yl)p h en oxy]p en -
tyl}-2-im id a zolid in on e (48). To a solution of 1-(4-pyrimidi-
nyl)-2-imidazolidinone (106.7 mg, 0.65 mmol) in 10 mL of
dimethylformamide was added NaH (75% dispersion in min-
eral oil, 0.98 mmol) at 0 °C. The mixture was stirred at room
temperature for 30 min and then was cooled in ice bath. 1-[(5-
Bromopentyl)oxy]-4-(trifluoromethyl)benzene (202.2 mg, 0.65
mmol) was added, and the resulting mixture was stirred at
room temperature for 4 h. The reaction was quenched with
MeOH (3 mL), and the solvent was concentrated in vacuo.
Saturated NH4Cl aqueous solution (5 mL) and dichloromethane
(20 mL) were added to the residue. The dichloromethane layer
was separated and dried over MgSO4, filtered, and evaporated.
The crude product thus obtained was purified by flash chro-
matography on silica gel (MeOH/EtOAc ) 1:6) to give com-
pound 48 as a yellow solid (231.1 mg, 90%). IR vmax (KBr):
1599, 1487, 1244 cm-1 1H NMR (CDCl3): δ 7.50 (d, J ) 7.2
.
Hz, 2H), 7.31-7.26 (m, 4H), 6.97 (t, J ) 7.2 Hz, 1H), 6.70 (d,
J ) 9.3 Hz, 2H), 3.85 (t, J ) 6.6 Hz, 2H), 3.69 (t, J ) 7.8 Hz,
2H), 3.37 (t, J ) 7.8 Hz, 2H), 3.25 (t, J ) 6.9 Hz, 2H), 1.81-
1.72 (m, 2H), 1.60-1.43 (m, 4H). 13C NMR (CDCl3): δ 158.0,
157.7, 140.4, 132.0, 128.5, 122.0, 117.0,116.1, 112.4, 67.7, 43.6,
42.2, 41.5, 28.7, 27.0, 23.0. ESMS m/z: 403.1 (MH+). Anal.
(C20H23BrN2O2) C, H, N.
1-[6-(4-Br om op h en oxy)h exyl]-3-p h en yl-2-im id a zolid i-
n on e (54). Yield: 90%. White solid. IR vmax (KBr): 1697, 1489,
1246 cm-1. 1H NMR (CDCl3): δ 7.53 (d, J ) 7.5 Hz, 2H), 7.33-
7.26 (m, 4H), 7.01 (t, J ) 7.5 Hz, 1H), 6.72 (d, J ) 9.0 Hz,
2H), 3.85 (t, J ) 6.3 Hz, 2H), 3.69 (t, J ) 7.2 Hz, 2H), 3.37 (t,
J ) 7.2 Hz, 2H), 3.25 (t, J ) 6.9 Hz, 2H), 1.76-1.72 (m, 2H),
1.57-1.37 (m, 6H). 13C NMR (CDCl3): δ 158.0, 157.6, 140.5,
131.9, 128.5, 121.8, 116.9, 116.1, 112.3, 67.8, 43.6, 42.1, 41.5,
1
1714, 1583, 1479 cm-1. H NMR (CDCl3): δ 8.80 (s, 1H), 8.41
(d, J ) 6.0 Hz, 1H), 8.23 (d, J ) 6.0 Hz, 1H), 7.49 (d, J ) 8.4
Hz, 2H), 6.90 (d, J ) 8.4 Hz, 2H), 4.06-3.96 (m, 4H), 3.51 (t,
J ) 7.2 Hz, 2H), 3.34 (t, J ) 7.2 Hz, 2H), 1.88-1.79 (m, 2H),
1.67-1.48 (m, 4H). 13C NMR (CDCl3): δ 161.4, 157.8, 156.1,
155.7, 126.9, 126.8, 123.0, 114.4, 108.8, 67.8, 43.6, 41.5, 40.5,
28.7, 27.0, 23.2. ESMS m/z: 395.1 (MH+).
28.8, 27.2, 26.2, 25.5. ESMS m/z: 418.1 (MH+). Anal. (C21H25
-
BrN2O2) C, H, N.
1-[6-(4-Ch lor op h en oxy)h exyl]-3-p h en yl-2-im id a zolid i-
n on e (55). Yield: 93%. White solid. IR vmax (KBr): 1701, 1597,
1492, 1245 cm-1. 1H NMR (CDCl3): δ 7.53 (d, J ) 7.5 Hz, 2H),
7.28 (t, J ) 7.5 Hz, 2H), 7.18 (d, J ) 9.3 Hz, 1H), 6.99 (t, J )
7.5 Hz, 2H), 6.78 (d, J ) 9.3 Hz, 2H), 3.87 (t, J ) 6.3 Hz, 2H),
3.69 (t, J ) 7.4 Hz, 2H), 3.39 (t, J ) 7.4 Hz, 2H), 3.26 (t, J )
6.9 Hz, 2H), 1.80-1.70 (m, 2H), 1.61-1.35 (m, 6H). 13C NMR
(CDCl3): δ 157.7, 157.5, 140.5, 129.1, 128.6, 125.1, 122.0, 117.0,
115.6, 67.9, 43.7, 42.2, 41.5, 28.9, 27.2, 26.3, 25.6. ESMS m/z:
373.1 (MH+). Anal. (C21H25ClN2O2) C, H, N.
1-P h en yl-3-{6-[4-(t r iflu or om et h yl)p h en oxy]h exyl}-2-
im id a zolid in on e (56). Yield: 89%. White solid. IR vmax
(KBr): 1703, 1615, 1329, 1260 cm-1. 1H NMR (CDCl3): δ 7.50
(d, J ) 7.2 Hz, 2H), 7.45 (d, J ) 8.7 Hz, 2H), 7.27 (t, J ) 7.2
Hz, 2H), 6.99 (t, J ) 7.2 Hz, 1H), 6.88 (d, J ) 8.7 Hz, 2H),
3.93 (t, J ) 6.3 Hz, 2H), 3.72 (t, J ) 7.5 Hz, 2H), 3.39 (t, J )
7.5 Hz, 2H), 3.25 (t, J ) 6.9 Hz, 2H), 1.78-1.73 (m, 2H), 1.57-
1-(4-P yr im id in yl)-3-{6-[4-(t r iflu or om et h yl)p h en oxy]-
h exyl}-2-im id a zolid in on e (49). Yield: 88%. Yellow solid. IR
1
v
max (KBr): 1722, 1584, 1475, 1402 cm-1. H NMR (CDCl3): δ
8.81 (d, J ) 1.2 Hz, 1H), 8.42 (d, J ) 6.3 Hz, 1H), 8.25 (dd, J
) 6.3, 1.2 Hz, 1H), 7.50 (d, J ) 8.4 Hz, 2H), 6.91 (d, J ) 8.4
Hz, 2H), 4.06-3.95 (m, 4H), 3.51 (t, J ) 7.7 Hz, 2H), 3.32 (t,
J ) 7.2 Hz, 2H), 1.84-1.72 (m, 2H), 1.65-1.37 (m, 6H). 13C
NMR (CDCl3): δ 161.5, 157.3, 155.9, 154.8, 126.8, 122.7, 122.5,
114.4, 108.8, 68.0, 43.7, 41.4, 40.5, 29.0, 27.2, 26.6. ESMS
m/z: 409.1 (MH+).
1-[6-(4-Ch lor oph en oxy)h exyl]-3-(4-pyr im idin yl)-2-im id-
a zolid in on e (50). Yield: 92%. White solid. IR vmax (KBr):
1718, 1581, 1474, 1244 cm-1. 1H NMR (CDCl3): δ 8.80 (s, 1H),
8.42 (d, J ) 5.7 Hz, 1H), 8.23 (d, J ) 5.7 Hz, 1H), 7.18 (d, J )
8.7 Hz, 2H), 6.78 (d, J ) 8.7 Hz, 2H), 4.02 (t, J ) 7.8 Hz, 2H),
3.90 (t, J ) 8.1 Hz, 2H), 3.50 (t, J ) 8.1 Hz, 2H), 3.31 (t, J )

1654 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 8
Shia et al.
1.37 (m, 6H). 13C NMR (CDCl3): δ 161.5, 157.8, 140.6, 128.7,
126.8, 126.7, 122.1, 117.1, 114.4, 68.0, 43.8, 42.3, 41.6, 28.9,
27.3, 26.4, 25.6. ESMS m/z: 407.3 (MH+). Anal. (C22H25F3N2O2)
C, H, N.
(hand-foot-and-mouth disease) patient. RD cells (rhabdomyo-
sarcoma cells), Vero cells (African green monkey kidney cells;
ATCC accession no. CCL-81), and MRC-5 cells (normal fetal
lung cells; ATCC accession no. CCL-171) were used for virus
isolation and propagation.
A.7. Gen er a l P r oced u r e for t h e Syn t h esis of 57-61.
1-[5-(Bip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-im id a zoli-
d in -2-on e Hyd r och lor id e (57). To a solution of 1-[5-(biphen-
yl-4-yloxy)pentyl]-3-pyridin-4-yl-imidazolidin-2-one (92.3 mg,
0.23 mmol) in 10 mL of tetrahydrofuran was added HCl‚Et2O
(1.0 M solution in diethyl ether, 1.2 mmol) dropwise. The
resulting mixture was stirred at room temperature for 30 min
and then was filtered. The white precipitate was washed with
Et2O (3 × 7 mL) and dried in vacuo to give compound 57 as a
white solid (90.8 mg, 98%). Mp > 200 °C. IR vmax (KBr): 1715,
B.2. Neu tr a liza tion Test.41 This assay measured the
ability of a test compound to inhibit the cytopathic effect
induced by a picornavirus on RD cells. The 96-well tissue
culture plates were seeded with 200 µL of RD cells at a
concentration of 3 × 105 cells/mL in DMEM with 10% FBS.
The plates were incubated for 24-30 h at 37 °C and were used
at about 90% confluency. Virus (100 TCID50) mixed with
different concentrations of test compounds was added to the
cells and incubated at 37 °C for 1 h. After adsorption, the
infected cell plates were overlayed with 50 µL of DMEM plus
5% FBS and 2% DMSO. The plate was wrapped in Parafilm
and incubated at 37 °C for 64 h. At the end of incubation, the
plates were fixed by the addition of 100 µL of 0.5% glutaral-
dehyde for 1 h at room temperature. After the removal of
glutaldehyde, the plates were stained with 0.1% crystal violet
for 15 min at room temperature. The plates were washed and
dried, and the density of the well was measured at 570 nm.
The concentration required for a test compound to reduce the
virus-induced cytopathic effect (CPE) by 50% relative to the
virus control was expressed as IC50. All assays were performed
in triplicate and at least twice.
1636, 1571, 1269 cm-1 1H NMR (DMSO-d6): δ 8.59 (d, J )
.
7.2 Hz, 2H), 8.00 (br, 2H), 7.58 (d, J ) 7.2 Hz, 2H), 7.56 (d, J
) 8.7 Hz, 2H), 7.41 (t, J ) 7.2 Hz, 2H), 7.29 (t, J ) 7.2 Hz,
1H), 6.99 (d, J ) 8.7 Hz, 2H), 4.02-3.95 (m, 4H), 3.59 (t, J )
7.5 Hz, 2H), 3.32-3.27 (m, 2H), 1.79-1.74 (m, 2H), 1.63-1.58
(m, 2H), 1.49-1.1.40(m, 2H). 13C NMR (DMSO-d6): δ 158.3,
154.9, 153.0, 141.0, 139.8, 132.4, 128.8, 127.7, 126.7, 114.9,
111.3, 67.3, 43.0, 41.6, 28.2, 26.1, 22.6. ESMS m/z: 402.5 (M+).
1-[5-(4′-Ch lor obip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-
im id a zolid in -2-on e Hyd r och lor id e (58). Yield: 98%. Mp
> 208 °C. White solid. IR vmax (KBr): 1715, 1636, 1571, 1269
cm-1 1H NMR (DMSO-d6): δ 8.59 (d, J ) 7.2 Hz, 2H), 8.00
.
B.3. P la qu e Red u ction Assa y.20 Antiviral activity of test
compounds was determined by a standard plaque reduction
assay. In brief, Vero cells in monolayers were infected at a
virus concentration to give approximately 50-100 plaques per
monolayer in the virus control containing no test compound.
Test compounds were diluted and included in the agar-medium
overlay. Plates were incubated at 35 °C for 96 h and then
stained with crystal violet and plaques counted. All assays
were performed in triplicate and at least twice. The concentra-
tion required for a test compound to reduce the number of
plaques by 50% relative to the virus control was expressed as
(br, 2H), 7.58 (d, J ) 7.2 Hz, 2H), 7.56 (d, J ) 8.7 Hz, 2H),
7.41 (t, J ) 7.2 Hz, 2H), 7.29 (t, J ) 7.2 Hz, 1H), 6.99 (d, J )
8.7 Hz, 2H), 4.02-3.95 (m, 4H), 3.59 (t, J ) 7.5 Hz, 2H), 3.32-
3.27 (m, 2H), 1.79-1.74 (m, 2H), 1.63-1.58 (m, 2H), 1.49-
1.1.40 (m, 2H). 13C NMR (DMSO-d6): δ 158.5, 155.0, 153.0,
141.2, 138.6, 131.5, 131.0, 128.8, 127.5, 115.0, 111.4, 67.4, 43.0,
41.6, 28.2, 26.1, 22.7. ESMS m/z: 436.4 (M+).
1-[5-(4′-Nit r ob ip h en yl-4-yloxy)p en t yl]-3-p yr id in -4-yl-
im id a zolid in -2-on e Hyd r och lor id e (59). Yield: 97%. Mp
> 199 °C. Yellow solid. IR vmax (KBr): 1718, 1628, 1509, 1265
cm-1 1H NMR (DMSO-d6): δ 8.59 (d, J ) 8.7 Hz, 2H), 8.25
.
IC50
.
(d, J ) 8.7 Hz, 2H), 8.00 (br, 2H), 7.90 (d, J ) 9.0 Hz, 2H),
7.73 (d, J ) 8.7 Hz, 2H), 7.05 (t, J ) 9.0 Hz, 2H), 4.06-3.95
(m, 4H), 3.59 (t, J ) 7.2 Hz), 3.41-3.27 (m, 2H), 1.80-1.73
(m, 2H), 1.64-1.56 (m, 2H), 1.49-1.41 (m, 2H). 13C NMR
(DMSO-d6): δ 159.6, 155.0, 153.0, 146.3, 146.0, 141.0, 130.0,
128.6, 127.0, 124.1, 115.2, 111.4, 67.5, 43.0, 41.6, 28.2, 26.1,
22.6. ESMS m/z: 447.5 (M+).
B.4. Cytotoxicity Assa y.42 Test compounds at various
concentrations were added to four different cell lines, including
RD, Vero, D551 (human normal skin fibroblast cells), and
WI38 (human normal lung fibroblast cells). The cells were then
incubated at 37 °C for 96 h. After incubation, the cells were
harvested and viable cells were counted by trypan blue
staining. All experiments were performed in triplicate and at
least twice. The concentration of a test compound required to
reduce cell viability to 50% of the tested control culture was
1-[5-(4′-Meth oxybip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-
yl-im id a zolid in -2-on e Hyd r och lor id e (60). Yield: 98%. Mp
> 204 °C. White solid. IR vmax (KBr): 1719, 1628, 1497, 1238
expressed as CC50
.
cm-1 1H NMR (DMSO-d6): δ 8.59 (d, J ) 7.5 Hz, 2H), 8.00
.
(br, 2H), 7.52 (d, J ) 3.6 Hz, 2H), 7.48 (d, J ) 3.6 Hz, 2H),
6.99 (d, J ) 3.0 Hz, 2H), 6.95 (d, J ) 3.0 Hz, 2H), 4.01-3.94
(m, 4H), 3.59 (t, J ) 7.2 Hz), 3.46-3.39 (m, 2H), 1.87-1.71
(m, 2H), 1.66-1.56 (m, 2H), 1.48-1.40 (m, 2H). 13C NMR
(DMSO-d6): δ 158.4, 155.4, 153.2, 148.5, 146.3, 141.5, 134.2,
134.1, 127.2, 114.8, 114.3, 111.3, 65.0, 54.9, 45.6, 41.3, 28.2,
26.1, 22.3. ESMS m/z: 432.5 (M+).
Ack n ow led gm en t. We are grateful to the National
Health Research Institutes of the Republic of China for
financial support.
Refer en ces
(1) Melnick, J . L. Enteroviruses: polioviruses, coxsackieviruses,
echoviruses, and newer enteroviruses. In Virology, 3rd ed.;
Fields, B. N., Knipe, D. M., Howley, P. M., Chanock, R. M.,
Melnick, J . L., Monath, T. P., Roizman, B., Straus, S. E., Eds.;
Lippincott-Raven: Philadelphia, PA, 1996; pp 655-712.
(2) Muir, P.; Kammerer, U.; Korn, K.; Mulders, M. N.; Poyry, T.;
Weissbrich, B.; Kandolf, R.; Cleator, G. M.; van Loon A. M.
Molecular typing of enteroviruses: current status and future
requirements. The European Union Concerted Action on Virus
Meningitis and Encephalitis. Clin. Microbiol. Rev. 1998, 11,
202-227.
(3) Ho, M.; Chen, E. R.; Hsu K. H.; Twu, S. J .; Chen, K. T.; Tsai, S.
F.; Wang, J . R.; Shih, S. R. An epidemic of enterovirus 71
infection in Taiwan. Taiwan Enterovirus Epidemic Working
Group. N. Engl. J . Med. 1999, 341, 929-935.
(4) Rueckert, R. R. Picornaviruses and their replication. In Virology;
Fields, B. N., Knipe, D. M., Eds.; Lippincott-Raven: New York,
1990; p 507.
1-[5-(4′-Br om obip h en yl-4-yloxy)p en tyl]-3-p yr id in -4-yl-
im id a zolid in -2-on e Hyd r och lor id e (61). Yield: 99%. Mp
> 196 °C. White solid. IR vmax (KBr): 1720, 1628, 1479, 1264
cm-1 1H NMR (DMSO-d6): δ 8.60 (d, J ) 6.3 Hz, 2H), 8.00
.
(br, 2H), 7.58-7.56 (m, 6H), 7.00 (d, J ) 8.1 Hz, 2H), 4.00-
3.95 (m, 4H), 3.64-3.61 (m, 2H), 3.36-3.29 (m, 2H), 1.76-
1.74 (m, 2H), 1.61-1.58 (m, 2H), 1.46-1.43 (m, 2H). 13C NMR
(DMSO-d6): δ 157.9, 154.7, 153.0, 141.0, 138.7, 131.7, 128.2,
127.7, 120.4, 115.0, 111.4, 67.4, 43.0, 41.6, 28.2, 26.1, 22.6.
ESMS m/z: 480.4 (M+).
B. Biologica l Eva lu a tion . The following test methods were
followed in generating the data in Tables 1-4.
B.1. Cells a n d Vir u ses. EV 71 isolates in 1998 outbreak
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