Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy) alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives

Article abstract of DOI:10.1021/jm050033v

A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in markedly improved antiviral activity toward EV71 with IC₅₀ values of 5.0 nM (24b) and 9.3 nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive decrease in activity, while inserting different heteroatoms entirely rendered the compound only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71 activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of picornaviruses to determine their spectrum of antiviral activity.

Full text of DOI:10.1021/jm050033v

3522
J. Med. Chem. 2005, 48, 3522-3535
Design, Synthesis, and Antipicornavirus Activity of
1-[5-(4-Arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one Derivatives
Chih-Shiang Chang,† Ying-Ting Lin,† Shin-Ru Shih,‡ Chung-Chi Lee,† Yen-Chun Lee,† Chia-Liang Tai,†
Sung-Nien Tseng,‡ and Jyh-Haur Chern*,†
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan Town,
Miaoli County 350, Taiwan, R.O.C., and School of Medical Technology, Chang Gung University, Taoyuan 333, Taiwan, R.O.C.
Received January 13, 2005
A series of pyridylimidazolidinone derivatives was synthesized and tested in vitro against
enterovirus 71 (EV71). On the basis of compound 33 (DBPR103), introduction of a methyl group
at the 2- or 3-position of the linker between the imidazolidinone and the biphenyl resulted in
markedly improved antiviral activity toward EV71 with IC50 values of 5.0 nM (24b) and 9.3
nM (14a), respectively. Increasing the branched chain to propyl resulted in a progressive
decrease in activity, while inserting different heteroatoms entirely rendered the compound
only weakly active. The introduction of a bulky group (cyclohexyl, phenyl, or benzyl) led to
loss of activity against EV71. The 4-chlorophenyl moiety in 14a was replaced with bioisosteric
groups such as oxadiazole (28a-d) or tetrazole (32a,b), dramatically improving anti-EV71
activity and selectivity indices. Compounds 14a, 24b, 28b, 28d, and 32a exhibited a strong
activity against lethal EV71, and no apparent cellular toxicity was observed. Three of the more
potent imidazolidinone compounds, 14a, 28b, and 32b, were subjected to a large group of
picornaviruses to determine their spectrum of antiviral activity.
Introduction
Human enterovirus 71 (EV71), a genus of the Picor-
naviridae family first isolated in 1969,1 is most often
associated with outbreaks of the mild childhood exan-
thema, herpangina, and hand-foot-mouth disease (HF-
MD). It is also associated with the cause of acute
neurologic disease including aseptic meningitis, en-
cephalitis, and poliomyelitis-like paralysis.2 It is trans-
mitted by fecal-oral contamination and less commonly
via respiratory droplets and has the potential to cause
outbreaks or epidemics. EV71 has been associated with
sporadic cases of outbreaks in various parts of the world,
including the United States,3 Australia,4 and Europe.5,6
Since 1997 there has been a significant increase in EV71
Figure 1. The anti-enterovirus 71 Compounds.
epidemic activity in the Asia-Pacific region,7-11 often
associated with severe encephalitis and high mortality.
study, the spinal cord and brain stem were the main
During the past 5 years severe outbreaks have occurred
targets of EV71 in the fatal cases of these outbreaks;21
in Malaysia (30 deaths in 1997)12 and in Taiwan (34
however, heart and pancreas might also be involved.22
deaths in 1998, 25 deaths in 2000, and 26 deaths in
After the eradication of poliomyelitis, EV71 will become
2001).13-16 A seroepidemiological study in Taiwan dem-
the most important enterovirus that affects children.
onstrated that the epidemic EV71 seroprevalence rates
EV71 consists of a nonenveloped capsid surrounding
in adults and children older than 6 years ranged from
a core of single-stranded, positive-polarity RNA ap-
57% to 67%, in children younger than 3 years old ranged
proximately 7.5 kb in size. The viral capsid is icosahe-
from 0% to 36%, and for 3-6-year-old children ranged
dral (T ) 1) in symmetry and is composed of 60 identical
units, each consisting of the four structural proteins
VP1-VP4.23 Although a number of promising antiviral
agents with activity against enteroviruses are currently
being developed,24-27 including the potent and broad
antiviral WIN compounds,28-32 rare published papers
reveal activity against EV71.33 In literature research,
the structure-activity relationships (SAR) of EV71
inhibitors is still limited. There are only three kinds of
small molecules that possess activity against EV71, as
shown in Figure 1. Additionally, both the large mol-
ecules of lactoferrin34 and allophycocyanin35 also reveal
anti-EV71 activity by cytopathic effect assay.
from 26% to 51%.17 The EV71 seropositive rate among
12-15-year-old Brazilian children was 69.2%.18 A se-
roepidemiological study in Singapore also shown that
the EV71 seroprevalence rate in the general population
was as high as 60%-70%.19 Therefore, outbreaks of
EV71 infection could spread to other parts of the world
and cause substantial illness and death. EV71 infection
may have a fulminant clinical course, and fatal cases
were in children <5 years of age.20 According to the
* To whom correspondence should be addressed. Tel: 886-37-246-
166, ext. 35716. Fax: 886-37-586-456. E-mail: jhchen@nhri.org.tw.
† National Health Research Institutes.
‡ Chang Gung University.
10.1021/jm050033v CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3523
Scheme 1a
a Reaction conditions: (a) toluene, rt; (b) NaH, DMF/THF (1:1), rt.
Scheme 2a
a Reaction condition: (a) K2CO3, KI, NMP, 60 °C; (b) 4, NaH, DMF, rt.
Therein, oxazolinylisoflavan36 is more active against
rhinovirus 1B (IC50 ) 1.01 µM) than against EV71 (IC50
) 4.56 µM). 4′-Chloro-6-cyanoflavan37 possesses moder-
ate activities against coxsackievirus B4 (IC50 ) 0.32
Chemistry
Considerable efforts to develop structure-activity
relationships have been made over the past several
years to investigate the distance between the imidazo-
lidinone and the substituted phenyl rings.38 The five-
carbon chain is an appropriate length for anti-EV71
activity. Currently, we focus on the modification of the
hydrophobic linker between the heterocyclic and aro-
matic moieties based on the skeleton of compound 33.
The following substituents were adopted as linkers: (1)
an aromatic ring, (2) a heteroatom aliphatic spacer, and
(3) a branched hydrophobic chain. Furthermore, the use
of a heteroaromatic ring surrogated the biphenyl moiety
to improve activity against EV71.
Several methods were developed to synthesize ana-
logues in this series, depending upon the substitution
pattern. The preparation of the core structure of pyridyl
imidazolidinone is outlined in Scheme 1. Compound 438
was synthesized starting with the coupling of 4-ami-
nopyridine and 2-chloroethyl isocyanate to give urea 3,
followed by cyclization by the treatment with NaH in a
mixture of DMF/THF (1:1) at room temperature. Serv-
ing as a key synthetic intermediate, compound 4 un-
derwent substitution reactions with a variety of alky-
lating agents to provide compounds in high to excellent
yields. Compounds 8a-f were synthesized by combining
several kinds of commercially available dibromo com-
pounds 5 and 4′-chloro-4-hydroxybiphenyl as starting
materials with K2CO3 and KI in N-methylpyrolidinone
at 60 °C to give monosubstituted 7 followed by N-
alkylation with 4 (Scheme 2).
µM), echovirus 6 (IC50 ) 0.48 µM), and EV71 (IC50
)
0.45 µM). Lactoferrin is an iron-binding glycoprotein
presented in milk, saliva, mucous secretions, and other
biological fluids of mammals. Allophycocyanin is a red
fluorescent protein that can be isolated from the marine
algae Spirulina platensis. Compound 33 is an imidazo-
lidinone derivative with broad-spectrum antiviral activ-
ity against EV71 (IC50 ) 38 nM),38 coxsackieviruses, and
echoviruses. The series of imidazolidinone compounds
has been found to effectively inhibit the EV71 activity
by directly targeting the VP1 capsid protein through
analysis of the resistant EV71.39 These compounds are
able to block viral uncoating and/or attachment to host
cell receptors and then inhibit the viral infection. The
X-ray crystallographic structure of the capsid for EV71
has not been solved yet. Till now, there is no effective
antiviral treatment for severe EV71 infections, and no
vaccine is available. This fact further reinforces the need
to develop antiviral agents against EV71.
As the result of our previous work, the imidazolidi-
none derivatives demonstrated antiviral activity. Therein,
compound 33 possessed good anti-EV71 activity and
moderate selectivity index.38 Moreover, our preliminary
study showed that compound 33 displayed good oral
efficacy and low cytotoxicity in animal models. It
brought an opportunity to develop more portent anti-
EV71 agents. On the basis of compound 33, we at-
tempted to modify the linker and the biphenyl moiety
to improve the anti-EV71 activity, selectivity index, and
oral bioavailability. Herein, we report the discovery of
more active agents against EV71 that dramatically
increase activity against all serotypes of EV71, possess
broad antiviral spectrum, and have significantly de-
creased cytotoxicity.
The synthesis of the linker replaced with an aliphatic
chain containing a nitrogen atom (11a-d) is illustrated
in Scheme 3. The bis(2-chloroethyl)amine hydrochloride
was treated with formaldehyde and formic acid at 100
°C to introduce the methyl group at the nitrogen atom
(10a). Treatment of 9 with substituted benzyl bromide
in the presence of K2CO3 in acetonitrile at 60 °C gave

3524 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
Scheme 3a
a Reaction conditions: (a) formaldehyde, formic acid, 100 °C or RBr, K2CO3, CH3CN, 60 °C; (b) 6, KOH, KI, CH3CN, 60 °C; (c) 4, NaH,
DMF, 40 °C.
Scheme 4a
the modified Kent’s method (Scheme 5).41 Condensation
of cyanoacetamide and trifluoroacetaldehyde ethyl hemi-
acetal in the presence of piperidine/H2O followed by
hydrolysis of intermediate 17 by heating with concen-
trated HCl at 130 °C gave acid 18. The dicarboxylic acid
18 was subjected to the same sequential reactions as
in the preparation of 14a-h (Scheme 4) to afford the
desired trifluoromethyl compound 19.
The position variation of the branched methyl group
of the linker is illustrated in Scheme 6. The com-
mercially available 20 was tosylated with p-toluene-
sulfonyl chloride in pyridine at room temperature to
provide 21. Due to one tosyl group being less hindered,
21 was reacted with 6 to afford biphenyl 22, which was
coupled with 4 in the presence of NaH to yield 24a-c.
Similarly, compound 21 was N-alkylated primarily with
imidazolidinone 4 to give 23 and then O-alkylated with
biphenyl 6 to afford 25a-c.
a Reaction conditions: (a) LAH, THF, reflux; (b) p-tosyl chloride,
pyridine, rt; (c) 6, K2CO3, CH3CN, 60 °C; (d) 4, NaH, DMF, rt.
the N-substituted 10b-d. The O-alkylation of biphenyl
6 with 10a-d in the presence of KOH and KI afforded
monosubstituted intermediates, which were coupled
with 4 to give 11a-d.
The syntheses of oxadiazoles 28a-d and tetrazoles
32a,b are described in Schemes 7 and 8, respectively.
The tosylate 13a was treated with 4-cyanophenol fol-
lowed by N-alkylation with 4 to give 27 (Scheme 7).
Treatment of 27 with hydroxylamine hydrochloride and
K2CO3 gave amidoxime intermediate, which was acy-
lated with the appropriate acid anhydride in pyridine
at reflux followed by cyclization to give the correspond-
ing 5-substituted oxadiazoles 28a-d. The protection of
phenolic 26 with methyl iodide followed by treatment
with sodium azide in the presence of ammonium chlo-
ride42 generated tetrazole 29 (Scheme 8), which was
treated with the appropriate alkyl iodide to give 2-sub-
stituted tetrazoles 30. The demethylation of 30 with
boron tribromide and then O-alkylation with 13a pro-
vided 31. Finally, compound 31 was reacted with
imidazolidinone 4 in the presence of NaH at room
temperature to give the corresponding tetrazole 32a,b.
The synthesis of the linker replaced with a branched
hydrophobic chain (14a-h) is shown in Scheme 4.
Compounds 14a-h were synthesized by using the
commercially available ester 12a and acids 12f-h as
starting materials or using the Michael addition to
prepare 3-substituted glutarate diesters 12b-e. Com-
pounds 12b-e were prepared by reacting dimethyl
glutaconate with the appropriate Grignard reagents in
the presence of catalytic CuI and excess TMSCl at -78
°C following Welmaker’s synthetic method.40 Reduction
of 12a-h with lithium aluminum hydride gave the
corresponding alcohols, which were tosylated with p-
tosyl chloride to afford 13a-h. Reaction of tosylates
13a-h with biphenyl 6 in the presence of K2CO3 at 60
°C followed by coupling with imidazolidinone 4 gave
14a-h. The construction of trifluoromethyl 18 adopted
Scheme 5a
a Reaction conditions: (a) piperidine, H2O, rt; (b) concd HCl, H2O, 130 °C; (c) LAH, THF, reflux; (d) p-tosyl chloride, pyridine, rt; (e) 6,
K2CO3, CH3CN, 60 °C; (f) 4, NaH, DMF, r.t.

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3525
Scheme 6a
a Reaction conditions: (a) p-tosyl chloride, pyridine, rt; (b) 6, K2CO3, CH3CN, 60 °C; (c) 4, NaH, DMF, rt.
Scheme 7a
a Reaction conditions: (a) K2CO3, CH3CN, 60 °C; (b) 4, NaH, DMF, rt; (c) NH2OH.HCl, K2CO3, EtOH, reflux; (d) RCOOCOR, pyridine,
reflux.
Scheme 8a
a Reaction conditions: (a) CH3I, K2CO3, acetone, reflux; (b) NaN3, DMF, NH4Cl, 110 °C; (c) RI, K2CO3, CH3CN, reflux; (d) BBr3, CH2Cl2,
rt; (e) 13a, K2CO3, CH3CN, 60 °C; (f) 4, NaH, DMF, rt.
Results and Discussion
from a patient with mild HFMD and EV71-4643 strain
was isolated from the spinal cord of a fatal case. Human
neurons are vulnerable to EV71-4643 infection and are
Compounds were tested against two EV71 serotypes
in a neutralization test. EV71-2231 strain was isolated

3526 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
Table 1. Anti-EV71 Activity and Cytotoxicity of Imidazolidinones 8a-f and 11a-d
a Mean of triplicate well values. All experiments were performed against each EV strain at least twice. Neutralization test was employed.
b Both EV71-2231 and EV71-4643 strains were isolated from patients in Taiwan. c Cellular toxicity/RD cell.
consistent with the clinical observation that EV71-4643
targets mainly neuronal cells but is also found in many
organs in conjunction with an inflammatory reaction.43
The concentration of a test compound required to reduce
cell viability to 50% of the tested control culture was
expressed as CC50.
We inserted different heteroatoms (N in 8e or 11a-
d, O in 8f) in the aliphatic linker to explore whether
the active sites exhibited hydrogen-bonding interaction
with the linker of imidazolidinones. Both 8f and 11a
exhibited less potent antiviral activity in comparison to
that of compound 33, with IC50 values of 0.83 and 0.40
µM, respectively (Table 1). This effect was understand-
able when considering the hydrophobic nature of the
drug-binding site. In addition, several hydrophobic
moieties were introduced on the nitrogen atom to
increase hydrophobic characteristics. Derivatives 11b-
d, with a benzyl group at the nitrogen of the linker, lost
the inhibitory activity. It appeared that there were no
strong hydrogen bonding and π-π interactions with the
active binding site due to the linker, and the steric bulk
of the branched moiety was not tolerated in the binding
site. Particularly, the introduction of the methyl group
(11a) at the nitrogen resulted in a moderately active
To investigate an appropriate orientation between the
imidazolidinone and the biphenyl ring of compound 33,
the results of varying the substituents with rigid
moieties on the linker are shown in Table 1. The data
revealed that either an ortho (8a) or a para (8b)
substitution on the phenyl ring resulted in inactivity
while the meta substitution (8c) demonstrated moderate
activity against both the EV71-2231 strain (IC50 ) 1.17
µM) and the EV71-4643 strain (IC50 ) 0.16 µM).
However, an additional methyl group on the phenyl ring
(8d) or a replacement with pyridine as a spacer (8e) led
to the loss of antiviral activity.

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3527
Table 2. Anti-EV71 Activity and Cytotoxicity of Imidazolidinones 14a-h and 19
a Mean of triplicate well values. All experiments were performed against each EV strain at least twice. Neutralization test was employed.
b Both EV71-2231and EV71-4643 strains were isolated from patients in Taiwan. c Cellular toxicity/RD cell.
compound. The results appeared to indicate that the
small aliphatic group might be a key element for
activity.
introduction of the methyl group at the 2-position (24b)
of the linker improved the activity against both the 2231
and 4643 strains, with IC50 values of 20 and 5 nM,
respectively, while shifting the methyl group in the
direction of the imidazolidinone ring (24a) or the bi-
phenyl moiety (25a) resulted in a decrease in activity
toward EV71. A methyl group introduced at the 4-posi-
tion (25b) resulted in comparable activity to 14a. Both
24b and 25b were significantly less cytotoxic than the
corresponding analogues of 24a and 25a. Replacement
of the methyl group of 24b and 25b with a dimethyl
group to form 24c and 25c, respectively, dramatically
reduced activity. However, the dimethyl 14f still pos-
sessed anti-EV71 activity comparable to that of lead
compound 33. The above results revealed that the
introduction of the methyl group at the 2- or 3-position
of the linker significantly improved activity against
EV71. The bulky group substitution on the linker
rendered the compound only weakly active.
The effects of introducing aliphatic chains to the
central position of linker were also examined. Substitu-
tion of a methyl group at the central hydrophobic linker
(14a) exhibited 4-fold increased inhibitory potency (IC50
) 9.3 nM) in the 4643 strain and 2-fold greater in the
2231 strain (IC50 ) 38 nM) as compared to compound
33 (Table 2). However, a decrease in activity was found
in the continuing increase of the branched chain length
from one carbon to three carbons (14a-c). The dimeth-
yl-substituted derivative 14f exhibited a potency com-
parable to that of compound 33. The trifluoromethyl
group (19) reduced the inhibitory activity toward EV71.
Similarly, the compounds employing a bulky group like
isopropyl (14d), cyclohexyl (14g), phenyl (14h), or benzyl
(14e) were devoid of any antiviral activity. The results
indicated that a methyl group might undergo a hydro-
phobic interaction with a small pocket located at the
VP1 binding site to enhance the affinity, while bulkier
groups at the linker might suffer from steric hindrance
with the pocket, leading to the loss in antiviral activity.
The effect on anti-EV71 activity of introducing the
methyl group at different positions of the linker is
identified in Table 3. The results indicated that the
The pyridylimidazolidinone derivatives effectively
inhibit virus replication in the early stages, implying
that these compounds can inhibit viral adsorption and/
or viral RNA uncoating. The virological investigation
demonstrated that the compounds of this series target
EV71 capsid protein VP1.39 It is also very interesting
to note that pleconaril44 developed by Viropharma Inc.

3528 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
Table 3. Anti-EV71 Activity and Cytotoxicity of Imidazolidinones 24a-c and 25a-c
a Mean of triplicate well values. All experiments were performed against each EV strain at least twice. Neutralization test was employed.
b Both EV71-2231and EV71-4643 strains were isolated from patients in Taiwan. c Cellular toxicity/RD cell.
has been shown to have a broad spectrum of activities
against rhinoviruses and enteroviruses. Moreover, it can
occupy the hydrophobic binding pocket within VP1 as
a capsid-binder inhibitor.45 On one hand, we retain the
methyl group attached to the center of the linker in
order to improve activity and simplify synthesis; on the
other hand, we attempt to modify the biphenyl moiety
with the oxadiazole based on pleconaril to enhance
antiviral spectrum. The results are shown in Table 4.
The oxadiazole analogues 28a-d exhibited good activi-
ties against both EV71 strains. Interestingly, we have
found that both the 5-methyl- and 5-ethyloxadiazoles
(28a, 28b) display excellent antiviral activity against
the lethal EV71-4643 strain with subnanomolar potency
(28a, IC50 ) 0.9 nM; 28b, IC50 ) 0.5 nM). Although 28a
possessed good inhibitory activity, it demonstrated a
considerable cytotoxic effect. However, compound 28b
possessed 18-fold and 2.5-fold potency in 4643 strain and
in 2231 strain, respectively, compared to 14a. Replace-
ment of the ethyl group in 28b with a trifluoromethyl
(28d) was only slightly less active (IC50 ) 1.4 nM).
Compounds 28b and 28d dramatically improved the
antiviral activity against lethal EV71-4643 strain and
enjoy low cytotoxicity (CC50 > 25 µM). Moreover,
increasing the size of the chain to n-propyl (28c)
resulted in decreased activity against EV71.
nM) and higher selectivity index (SI > 13 888) than 14a.
Indeed, a considerably increased activity was observed
when the 4′-chlorophenyl in compound 14a was replaced
with its corresponding oxadiazole or tetrazole ring. In
all cases examined, 28b in the oxadiazole series and 32b
in the tetrazole series, in terms of potency and selectiv-
ity index, appeared to be the most promising candidates
for further development as anti-EV71 agents.
In addition to screening imidazolidinones against
EV71 (2 serotypes), we examined the broad-spectrum
activity of this scaffold. The three kinds of different
chemical platforms in 14a, 28b, and 32b were selected
and individually subjected to bioevaluation against a
variety of viruses, including human enteroviruses 68
and 71 (five serotypes), coxsackieviruses (CV; 10 sero-
types), echoviruses (Echo; two serotypes), and human
rhinoviruses (HRV; two serotypes). The results are
illustrated in Table 5. As shown, all of these compounds
exhibited significant activity against EV71 (IC50
)
0.0005-0.32 µM), CVA10 (IC50 ) 0.24-1.71 µM), CVA16
(IC50 ) 0.09-0.90 µM), CVA24 (IC50 ) 0.14-0.25 µM),
CVB1 (IC50 ) 0.035-2.89 µM), CVB4 (IC50 ) 1.24-2.74
µM), CVB5 (IC50 ) 1.32-10.4 µM), Echo9 (IC50 ) 0.28-
2.63 µM), Echo29 (IC50 ) 0.04-3.23 µM), as well as
HRV14 (IC50 ) 0.83-7.91 µM). Moreover, compound
14a showed extended potency against CVA9 (IC50
)
Compounds 32a,b illustrated that the tetrazole moi-
ety acts as a metabolically stable bioisostere for the
oxadiazole functionality (Table 4).46 Both 32a and 32b
exhibited good activity comparable to that of the corre-
sponding oxadiazole derivatives. The ethyl tetrazole 32b
had better activity against EV71-4643 strain (IC50 ) 0.9
0.033 µM). In addition, both 28b and 32b also possessed
inhibitory activity toward HRV2. We were pleased to
find that these compounds exhibited dramatic potency
against all serotypes of EV71 and broad-spectrum
inhibitory activity compared to lead compound 33.

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3529
Table 4. Anti-EV71 Activity and Cytotoxicity of Imidazolidinones 28a-d and 32a,b
a Mean of triplicate well values. All experiments were performed against each EV strain at least twice. Neutralization test was employed.
b Both EV71-2231and EV71-4643 strains were isolated from patients in Taiwan. c Cellular toxicity/RD cell. d Selectivity index is the value
of CC50/IC50
Table 5. Comparative Evaluation of DBPR103, 28b, and 32b against Picornavirus
IC50 (µM)a
.
picornavirus
33
14a
28b
32b
EV71 (1743) genotype B
EV71 (2086) genotype C
EV71 (2231) genotype C
EV71 (4643) genotype C
EV71 (BrCr) genotype A
EV68
coxsackievirus A9
coxsackievirus A10
coxsackievirus A16
coxsackievirus A24
coxsackievirus B1
coxsackievirus B2
coxsackievirus B3
coxsackievirus B4
coxsackievirus B5
coxsackievirus B6
echovirus 9
0.092 ( 0.010
0.043 ( 0.013
0.076 ( 0.004
0.038 ( 0.001
0.130 ( 0.004
0.016 ( 0.001
0.015 ( 0.003
0.004 ( 0.001
0.015 ( 0.001
0.0005 ( 0.0001
0.010 ( 0.002
5.46 ( 0.69
0.018 ( 0.006
0.003 ( 0.001
0.014 ( 0.001
0.0009 ( 0.0005
0.015 ( 0.001
2.87 ( 0.32
-
0.038 ( 0.003
0.0093 ( 0.0001
0.069 ( 0.0004
2.68 ( 0.01
>12.5
0.071 ( 0.004
>12.5
>12.5
1.30 ( 0.94
0.033 ( 0.013
1.71 ( 0.04
>25
>25
0.56 ( 0.07
0.087 ( 0.013
0.15 ( 0.02
0.046 ( 0.005
4.79 ( 0.51
0.24 ( 0.03
0.13 ( 0.03
0.14 ( 0.01
0.035 ( 0.004
0.90 ( 0.02
0.25 ( 0.09
>12.5
>12.5
>12.5
2.89 ( 0.14
>12.5
>12.5
1.24 ( 0.22
1.32 ( 0.06
>25
>25
2.74 ( 0.62
10.4 ( 1.96
>25
>25
1.30 ( 0.79
1.14 ( 0.56
1.27 ( 0.16
4.50 ( 1.41
>12.5
>12.5
>25
1.31 ( 0.13
0.39 ( 0.06
2.63 ( 0.21
0.50 ( 0.05
2.63 ( 0.33
1.58 ( 0.20
0.83 ( 0.10
0.28 ( 0.02
3.23 ( 0.38
1.45 ( 0.15
0.85 ( 0.11
echovirus 29
human rhinovirus 2
human rhinovirus 14
0.040 ( 0.001
>12.5
>12.5
>12.5
7.91 ( 0.62
a Mean of triplicate well values. All experiments were performed at least twice. Neutralization test was employed.
Conclusion
Increasing the length of the branched chain on the
linker resulted in a progressive decrease in activity,
while replacement with the hydrophobic aromatic moi-
ety rendered the compound only weakly active or
inactive. The methyl group was the right substitution
on the linker. Moreover, introducing the methyl group
on the 2- or 3-position of the linker substantially
improved activity against EV71. Furthermore, the
replacement of the chlorophenyl ring of 12a with the
oxadiazole ring or the tetrazole ring resulted in dra-
The pyridylimidazolidinone derivative is the first
compound reported to possess the potent activity against
EV71. On the basis of the SAR studies, we successfully
explored the linked spacer between imidazolidinone and
biphenyl on the basis of lead compound 33. The linker
replacement with the aromatic ring should be meta-
substituted orientation. The results of introducing an
oxygen atom or the nitrogenated side chain on the linker
were detrimental to the antiviral activity against EV71.

3530 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
A suspension of 1-(4-pyridyl)-2-imidazolidinone (0.50 mmol)
and sodium hydride (75% dispersion in mineral oil, 0.55 mmol)
in anhydrous DMF (7 mL) was reacted for 30 min under
nitrogen followed by addition of a solution of 7 (0.50 mmol) in
anhydrous DMF (5 mL). After 12 h, the suspension was
quenched with water followed by extraction with ethyl acetate
(100 mL × 3). The organic layers were combined, washed with
brine, dried over anhydrous magnesium sulfate, and concen-
trated under vacuum. The crude residue was subjected to flash
chromatography on silica gel to afford the target 8.
matically improved inhibitory activity. The 5-ethyloxa-
diazole 28b possessed excellent activity against lethal
EV71-4643 strain with significant low cytotoxicity.
Compounds 14a, 28b, and 32b provided remarkable
evidence that they were much more specific for human
enteroviruses, in particular, EV71. These compounds
were dramatically active against EV71 with a broad
spectrum of potent activity against three genotypes (A,
B, and C) of EV71. Therefore, imidazolidinone com-
pounds 14a, 28b, and 32b are well-qualified to serve
as drug candidates for the further development of anti-
EV71 agents.
1-[2-(4′-Chlorobiphenyl-4-yloxymethyl)benzyl]-3-pyri-
din-4-ylimidazolidin-2-one (8a): yield 87%; white solid; mp
209-211 °C; IR νmax (neat) 2889, 1710, 1594, 1482, 1260 cm-1
;
1H NMR (CDCl3) δ 8.22 (br, 2H), 7.25-7.41 (m, 12H), 6.85 (d,
J ) 8.7 Hz, 2H), 4.99 (s, 2H), 4.52 (s, 2H), 3.59-3.64 (m, 2H),
3.27-3.32 (m, 2H); 13C NMR (CDCl3) δ 157.8, 155.9, 149.7,
146.5, 138.8, 135.0, 134.8, 132.7, 132.5, 130.3, 129.6, 128.7,
128.6, 128.3, 127.8, 127.7, 114.7, 110.7, 67.9, 45.7, 41.4, 40.9;
ESMS m/z 470.1 (MH+). Anal. (C28H24ClN3O2) C, H, N.
Experimental Section
A. Synthetic Methods and Spectroscopic Details.
Reagents were purchased from Aldrich, Acros, TCI, and
Lancaster. Solvents, including dry ether and tetrahydrofuran
(THF), were obtained by distillation from the sodium ketyl of
benzophenone under nitrogen. Other solvents, including chlo-
roform, dichloromethane, ethyl acetate, and hexane, were
distilled over CaH2 under nitrogen. Absolute methanol and
ethanol were purchased from Merck and used as received. A
commercial sample of CuI was obtained from Fisher Scientific
Co. The colored impurities were removed from these salts by
dissolving them in a saturated aqueous solution of KI followed
by treatment with charcoal, filtration, and dilution with cold
water to reprecipitate CuI halide. Analytical TLC was per-
formed 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.
Melting points were obtained with a Yanaco (MP-500D)
melting point apparatus. Fourier transform IR (FTIR) spectra
were recorded on a Perkin-Elmer RX-I instrument (neat; ν,
cm-1). The proton NMR spectra were obtained on a Varian
Mer-Vx-300 (300 MHz) spectrometer. Chloroform-d was used
as solvent and the spectra were referenced to the residual
protonated solvent signal. All NMR chemical shifts are re-
ported as δ values in parts per million (ppm), and coupling
constants (J) are given in hertz (Hz). Mass spectra were carried
out on a Hewlett-Packard (model 1100 MSD) mass spectrom-
eter. Microanalyses were performed on a Heraeus CHN-O
rapid microanalyzer. Purification on silica gel refers to flash
column chromatography on Merck silica gel 60 (particles size
230-400 mesh).
A.1. Preparation of 1-(4-Pyridyl)-2-imidazolidinone
(4). To a stirred solution of 4-aminopyridine (5.0 g, 53.12 mmol)
dissolved in toluene (20 mL) was added 2-chloroethyl isocy-
anate (9.69 g, 79.68 mmol) dropwise over 30 min in an ice bath.
The mixture was reacted at room temperature for 12 h. The
precipitate was collected by filtration and washed with toluene
(20 mL) to afford N-(2-chloroethyl)-N′-(4-pyridyl)urea 3 (9.49
g, 83%).
To an ice-cooled solution of 3 (9.0 g, 41.73 mmol) in a
mixture of dry THF (40 mL) and DMF (40 mL) was added
slowly NaH (1.05 g, 43.82 mmol). The resulting mixture was
stirred at room temperature for 5 h under argon and then
quenched with MeOH (20 mL). After evaporation under
vacuum, the crude residue was extracted with chloroform (30
mL × 2). The organic layer was washed with brine, dried over
MgSO4, and concentrated under vacuum. The solid residue was
recrystallized from MeOH to give compound 4 as a white solid
(6.51 g, 96%).
1-[4-(4′-Chlorobiphenyl-4-yloxymethyl)benzyl]-3-pyri-
din-4-ylimidazolidin-2-one (8b): yield 93%; white solid; mp
1
215-216 °C; IR νmax (neat) 2895, 1704, 1596, 1482 cm-1; H
NMR (CDCl3) δ 8.44 (d, J ) 6.0 Hz, 2H), 7.54 (d, J ) 6.3 Hz,
2H), 7.42-7.48 (m, 6H), 7.24-7.37 (m, 4H), 7.02 (d, J ) 8.7
Hz, 2H), 5.10 (s, 2H), 4.52 (s, 2H), 3.78-3.83 (m, 2H), 3.41-
3.46 (m, 2H); 13C NMR (CDCl3) δ 158.1, 156.4, 150.0, 146.6,
138.9, 136.3, 135.9, 132.6, 132.5, 128.6, 128.3, 127.9, 127.8,
127.7, 115.0, 110.8, 69.7, 47.8, 41.4, 41.0; ESMS m/z 470.1
(MH+). Anal. (C28H24ClN3O2) C, H, N.
1-[3-(4′-Chlorobiphenyl-4-yloxymethyl)benzyl]-3-pyri-
din-4-ylimidazolidin-2-one (8c): yield 88%; white solid; mp
1
171-172 °C; IR νmax (neat) 1704, 1597, 1481, 1252 cm-1; H
NMR (CDCl3) δ 8.43 (br, 2H), 7.42-7.52 (m, 6H), 7.34-7.39
(m, 6H), 7.0 (d, J ) 8.7 Hz, 2H), 5.09 (s, 2H), 4.51 (s, 2H),
3.75-3.81 (m, 2H), 3.39-3.44 (m, 2H); 13C NMR (CDCl3) δ
158.0, 156.4, 150.0, 146.6, 138.8, 137.3, 136.4, 132.6, 132.5,
128.9, 128.7, 127.8, 127.7, 127.7, 127.0, 126.8, 115.1, 110.8,
69.8, 47.9, 41.4, 41.0; ESMS m/z 470.1 (MH+). Anal. (C28H24-
ClN3O2) C, H, N.
1-[3-(4′-Chlorobiphenyl-4-yloxymethyl)-5-methylbenzyl]-3-
pyridin-4-ylimidazolidin-2-one (8d): yield 85%; white solid; mp
170-172 °C; IR νmax (neat) 2918, 1713, 1595, 1483, 1262 cm-1
;
1H NMR (CDCl3) δ 8.43 (d, J ) 6.0 Hz, 2H), 7.34-7.49 (m,
7H), 7.17 (d, J ) 15.0 Hz, 2H), 7.04 (d, J ) 15.0 Hz, 2H), 7.0
(d, J ) 8.4 Hz, 2H), 5.04 (s, 2H), 4.45 (s, 2H), 3.73-3.78 (m,
2H), 3.36-3.42 (m, 2H), 2.37 (s, 3H); 13C NMR (CDCl3) δ 158.1,
156.4, 150.0, 146.6, 138.8, 137.2, 136.4, 136.4, 132.5, 132.5,
128.7, 128.5, 127.8, 127.7, 127.6, 124.2, 115.1, 110.8, 69.9, 47.9,
41.4, 41.0, 21.5; ESMS m/z 484.4 (MH+). Anal. (C29H26ClN3O2)
C, H, N.
1-[6-(4′-Chlorobiphenyl-4-yloxymethyl)-pyridin-2-yl-
methyl]-3-pyridin-4-ylimidazolidin-2-one (8e): yield 82%;
yellow solid; mp 210-212 °C; IR νmax (neat) 2906, 1708, 1593,
1480, 1278 cm-1; 1H NMR (CDCl3) δ 8.44 (d, J ) 6.3 Hz, 2H),
7.25-7.74 (m, 11H), 7.02 (d, J ) 8.7 Hz, 2H), 5.21 (s, 2H),
4.62 (s, 2H), 3.79-3.85 (m, 2H), 3.58-3.63 (m, 2H); 13C NMR
(CDCl3) δ 157.8, 156.6, 156.6, 155.8, 150.0, 146.6, 138.8, 137.6,
132.8, 132.6, 128.7, 127.9, 127.7, 121.0, 120.1, 115.1, 110.8,
70.7, 49.6, 41.8, 41.6; ESMS m/z 471.4 (MH+). Anal. (C27H23-
ClN4O2) C, H, N.
1-{2-[2-(4′-Chlorobiphenyl-4-yloxy)ethoxy]ethyl}-3-py-
ridin-4-ylimidazolidin-2-one (8f): yield 75%; white solid; mp
128-130 °C; IR νmax (neat) 2976, 1710, 1594, 1483, 1276 cm-1
;
A.2. General Procedure for the Synthesis of Com-
pounds 8a-f. To a stirred suspension of desired dibromo
compound (2.0 mmol), potassium bicarbonate (1.9 mmol), and
potassium iodide (0.1 mmol) in N-methylpyrolidinone (3 mL)
was added 4-chloro-4′-hydroxybiphenyl (1.0 mmol) at 60 °C
for 2.5 h under argon. After cooling, the mixture was quenched
with water (30 mL) followed by extraction with ethyl acetate
(30 mL × 3). The organic layers were collected, washed with
brine, and then concentrated under vacuum. The residue was
subjected to flash chromatography on silica gel to give 1-sub-
stituted 7 (yield 50-85%).
1H NMR (CDCl3) δ 8.31 (d, J ) 5.4 Hz, 2H), 7.27-7.34 (m,
8H), 6.84 (d, J ) 8.4 Hz, 2H), 4.03-4.06 (m, 2H), 3.74-3.76
(m, 2H), 3.60-3.68 (m, 2H), 3.54-3.59 (m, 4H), 3.41-3.44 (m,
2H); 13C NMR (CDCl3) δ 158.1, 156.4, 149.9, 146.6, 138.7 132.5,
132.4, 128.6, 127.7, 127.6, 114.7, 110.6, 70.0, 69.4, 67.5, 43.8,
42.9, 41.6; ESMS m/z 438.5 (MH+). Anal. (C24H24ClN3O3) C,
H, N.
A.3. General Procedure for the Synthesis of Com-
pounds 11a-d. 1-{2-[2-(4′-Chlorobiphenyl-4-yloxy)ethyl-N-
methylamino]ethyl}-3-pyridin-4-ylimidazolidin-2-one (11a).

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3531
A mixture of bis(2-chloroethyl)amine hydrochloride (2.0 g,
11.21 mmol), 37% formaldehyde (0.54 g, 16.82 mmol), and
formic acid (1 mL) was heated at 75 °C for 18 h in a sealed
bottle. After cooling, the mixture was taken up in ethyl ether
and washed with saturated NaHCO3 solution until basic pH.
The organic layer was washed with water and dried over
MgSO4, and the solvent was removed in vacuo. The crude
product was purified by flash chromatography on silica gel
using hexanes/ethyl acetate (9:1) as eluant to give 10a (1.6 g,
91%).
To a stirred solution of 10a (0.16 g, 1.0 mmol) dissolved in
dry CH3CN was added compound 6 (0.20 g, 1.0 mmol), KOH
(0.11 g, 2.0 mmol), and catalytic KI (17 mg, 0.1 mmol) under
argon. The mixture was heated at 60 °C for 12 h. After cooling,
the suspension was concentrated to remove CH3CN and then
partitioned with CH2Cl2/H2O. The organic layer was collected
and concentrated. The residue was subjected to chromatogra-
phy on silica gel to give monosubstituted intermediate (0.22
g, 68%). Sequentially, this intermediate (0.20 g, 0.61 mmol)
was treated with a mixture of 4 (0.10 g, 0.61 mmol) and NaH
(44 mg, 1.83 mmol) in dry DMF (2 mL). The suspension was
reacted at 40 °C under argon. After cooling, the suspension
was quenched with distilled water (20 mL) and then extracted
with ethyl acetate (20 mL × 3). The organic layer was collected,
washed with brine, dried over MgSO4, and concentrated under
vacuum. The residue was subjected to flash chromatograph
on silica gel to give 11a as a yellow solid (0.23 g, 85%): mp
yield 67%; yellow oil; 1H NMR (CDCl3) δ 8.38 (dd, J ) 5.0, 1.3
Hz, 2H), 7.34-7.42 (m, 8H), 7.19 (d, J ) 7.8 Hz, 2H), 7.05 (d,
J ) 7.8 Hz, 2H), 6.88 (d, J ) 8.7 Hz, 2H), 4.06 (t, J ) 5.4 Hz,
2H), 3.70 (s, 2H), 3.52-3.53 (m, 2H), 3.48-3.50 (m, 2H), 3.37
(t, J ) 5.7 Hz, 2H), 2.95 (t, J ) 5.4 Hz, 2H), 2.79 (t, J ) 5.7
Hz, 2H), 2.27 (s, 3H); 13C NMR (CDCl3) δ 158.2, 156.4, 149.9,
146.7, 138.8, 136.5, 135.9, 132.5, 132.2, 128.7, 128.7, 128.7,
127.8, 127.6, 114.5, 110.6, 66.9, 59.5, 53.1, 52.3, 42.1, 41.5, 31.1,
21.2; ESMS m/z 541.1 (M+). Anal. (C32H33ClN4O2) C, H, N.
1-{2-[N-(4-Chlorobenzyl)-2-(4′-chlorobiphenyl-4-yloxy)-
ethylamino]ethyl}-3-pyridin-4-ylimidazolidin-2-one (11d):
yield 72%; yellow solid; mp 118-119 °C; IR νmax (neat) 2927,
1711, 1594, 1483, 1271 cm-1; 1H NMR (CDCl3) δ 8.41 (dd, J )
5.1, 1.2 Hz, 2H), 7.29-7.44 (m, 6H), 7.22-7.29 (m, 6H), 6.89
(d, J ) 8.7 Hz, 2H), 4.08 (t, J ) 5.3 Hz, 2H), 3.74 (s, 2H), 3.56-
3.61 (m, 2H), 3.44-3.48 (m, 2H), 3.40 (t, J ) 5.9 Hz, 2H), 2.97
(t, J ) 5.3 Hz, 2H), 2.81 (t, J ) 5.9 Hz, 2H); ESMS m/z 561.3
(M+). Anal. (C31H30Cl2N4O2) C, H, N.
A.4. General Procedure for the Synthesis of Com-
pounds 14a-h. (1) Preparation of 3-Substituted Glut-
arate Diesters (12a-e). To a stirred suspension of CuI (0.3
mmol) in THF (0.1 M) was added dropwise a desired Grignard
reagent (4.0 mmol) under argon. The resulting mixture was
stirred at room temperature until a dark color persisted (5
min). The mixture then was cooled to -78 °C, and TMSCl (4.0
mmol) and the glutarate diester (1.0 mmol) were introduced
sequentially. The mixture was stirred at -78 °C for 2 h and
then allowed to warm to ambient temperature over 4 h. The
reaction then was quenched with saturated aqueous NH4Cl
and diluted with ethyl acetate. The phases were separated,
and the aqueous phase was extracted with ethyl acetate. The
combined organic phases were washed with brine, dried over
MgSO4, and concentrated under vacuum. The crude product
was purified by flash chromatograph on silica gel to give
3-substituted glutarate diester 12a-e (yield about 56-85%).
130-131 °C; IR νmax (neat) 2933, 1704, 1598, 1485, 1274 cm-1
;
1H NMR (CDCl3) δ 8.37 (br, 2H), 7.32-7.42 (m, 8H), 6.90 (d,
J ) 8.7 Hz, 2H), 4.06 (t, J ) 5.3 Hz, 2H), 3.61-3.68 (m, 4H),
3.42 (t, J ) 6.4 Hz, 2H), 2.86 (t, J ) 5.3 Hz, 2H), 2.70 (t, J )
6.4 Hz, 2H), 2.40 (s, 3H); 13C NMR (CDCl3) δ 158.2, 156.5,
149.7, 146.7, 138.8, 132.5, 132.3, 128.6, 127.7, 127.6, 114.6,
110.7, 66.3, 56.5, 55.5, 42.9, 42.1, 41.7, 41.5; ESMS m/ z 451.2
(M+). Anal. (C25H27ClN4O2) C, H, N.
1-{2-[N-Benzyl-2-(4′-chlorobiphenyl-4-yloxy)ethylami-
no]ethyl}-3-pyridin-4-ylimidazolidin-2-one (11b). To a
stirred suspension of bis(2-chloroethyl)amine hydrochloride
(0.18 g, 1.0 mmol) and K2CO3 (0.42 g, 3.0 mmol) in CH3CN
(10 mL) was added benzyl bromide (0.17 g, 1.0 mmol) at reflux
for 8 h. After cooling, the solid material was filtered out and
the filtrate was concentrated in a vacuum. The residue was
subjected to flash chromatography on silica gel to afford 10b
(0.20 g, 87%). To a stirred solution of 10b (0.15 g, 0.65 mmol)
dissolved in dry CH3CN were added 6 (0.13 g, 0.65 mmol),
KOH (73 mg, 1.30 mmol), and catalytic KI (11 mg, 0.065 mmol)
at 60 °C for 24 h under argon. After cooling, the mixture was
concentrated, diluted with distilled water (20 mL), and par-
titioned with CH2Cl2 (20 mL × 3). The organic layer was
collected, washed with brine, dried over MgSO4, and concen-
trated under vacuum. The oil residue was subjected to chro-
matography on silica gel to give monosubstituted intermediate
(0.13 g, 51%). Sequentially, the intermediated (0.10 mg, 0.25
mmol) was treatment with the mixture of 4 (41 mg, 0.25 mmol)
and NaH (18 mg, 0.75 mmol) in dry DMF (1.5 mL). The
suspension was reacted at 40 °C for 24 h under argon. After
cooling, the suspension was quenched with distilled water (15
mL) with vigorous stirring and extracted with ethyl acetate
(15 mL × 3). The organic layer was collected, washed with
brine, dried over MgSO4, and concentrated under vacuum. The
oil residue was subjected to flash chromatography on silica
gel to afford 11b as a colorless oil (95 mg, 72%). IR νmax (neat)
(2) General Procedure of the Synthesis of 14a-h from
12a-h. To a stirred solution of the synthetic diester (1.0 mmol,
i.e., 12a-e) or the commercially available acid (1 mmol, i.e.,
12f-h) dissolved in THF (20 mL) was added lithium alumi-
num hydride (3 mmol) at reflux for 24 h. After cooling the
mixture was quenched with distilled water (50 mL) under
vigorous stirring and the precipitate filtered out. The filtrate
was concentrated under vacuum and extracted with ethyl
acetate (30 mL × 3). The organic layer was collected, washed
with brine, dried over MgSO4, and concentrated under vacuum.
The oil residue was subjected to flash chromatograph on silica
gel to give pure diol as a colorless oil. The diol (1.0 mmol) was
treated with p-tosyl chloride (2.0 mmol) in pyridine (3 mL) at
room temperature for 2 h. The resulting mixture was concen-
trated under vacuum and subjected to flash chromatography
on silica gel to afford an appropriately tosylated 13 as a white
powder (yield about 90-95%). Compound 13 (2.0 mmol)
dissolved in CH3CN (10 mL) was treated with 6 (1.0 mmol)
and K2CO3 (1.0 mmol) at 60 °C for 24 h. After cooling, the
mixture was concentrated under vacuum and diluted with
CH2Cl2/H2O (1:1). The organic layer was washed with brine,
dried over MgSO4, and concentrated under vacuum. The
residue was subjected to flash chromatography on silica gel
to give the 3-substituted 5-(4′-chlorobiphenyl-4-yloxy)pentyl
p-toluenesulfonate (yield about 65-82%). The intermediate
(1.0 mmol) was treated with the mixture of 4 (1.0 mmol) and
NaH (1.5 mmol) in dry DMF (2 mL) at room temperature. After
reaction for 24 h, the mixture was quenched with distilled
water (20 mL) and extracted with ethyl acetate (20 mL × 3).
The organic layer was collected, washed with brine, dried over
MgSO4, and concentrated under vacuum. The residue was
subjected to flash chromatography on silica gel to give the
target 14a-h.
1
2926, 1714, 1596, 1482, 1274 cm-1; H NMR (CDCl3) δ 8.36
(d, J ) 5.1 Hz, 2H), 7.25-7.41 (m, 13H), 6.86 (d, J ) 8.4 Hz,
2H), 4.06 (t, J ) 5.3 Hz, 2H), 3.73 (s, 2H), 3.50-3.55 (m, 2H),
3.34-3.43 (m, 4H), 2.95 (t, J ) 5.3 Hz, 2H), 2.78 (t, J ) 5.9
Hz, 2H); 13C NMR (CDCl3) δ 158.2, 156.4, 149.8, 146.7, 139.1,
138.8, 132.5, 132.2, 128.7, 128.6, 128.0, 127.8, 127.6, 126.9,
114.5, 110.6, 66.9, 59.8, 53.1, 52.3, 42.0, 41.9, 41.4; ESMS m/z
527.4 (M+). Anal. (C31H31ClN4O2) C, H, N.
The desired compounds 11c-d were prepared using the
similar manner as described in the synthetic method of 11b.
1-{2-[2-(4′-Chlorobiphenyl-4-yloxy)-N-(4-methylbenzyl-
)ethylamino]ethyl}-3-pyridin-4-ylimidazolidin-2-one (11c):
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-methylpentyl]-3-py-
ridin-4-ylimidazolidin-2-one (14a): yield 92%; white solid;
mp 166-167 °C; IR νmax (neat) 2931, 1704, 1482 cm-1; 1H NMR
(CDCl3) δ 8.41 (d, J ) 5.7 Hz, 2H), 7.43-7.46 (m, 6H), 7.34-
7.36 (m, 2H), 6.92 (d, J ) 8.4 Hz, 2H), 4.01-4.06 (m, 2H),
3.75-3.80 (m, 2H), 3.48-3.55 (m, 2H), 3.34-3.42 (m, 2H), 1,-

3532 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
75-1.90 (m, 2H), 1.69-1.73 (m, 2H), 1.44-1.48 (m, 1H), 1.03-
1.05 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3) δ 158.4, 156.5,
149.9, 146.7, 139.0, 132.5, 132.2, 128.6, 127.8, 127.7, 114.7,
110.7, 65.9, 42.0, 41.5, 41.5, 36.2, 34.4, 27.7, 19.7; ESMS m/z
450.5 (MH+). Anal. (C26H28ClN3O2) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-phenylpentyl]-3-py-
ridin-4-ylimidazolidin-2-one (14h). yield 67%; white solid;
mp 175-177 °C; IR νmax (neat) 2933, 1712, 1594, 1482, 1271
cm-1; 1H NMR (CDCl3) δ 8.41 (dd, J ) 5.0, 1.3 Hz, 2H), 7.32-
7.91 (m, 7H), 7.17-7.28 (m. 6H), 6.83 (d, J ) 8.7 Hz, 2H),
3.69-3.87 (m, 2H), 3.51-3.67 (m, 2H), 3.31-3.48 (m, 2H),
3.19-3.29 (m, 2H), 2.88-3.0 (m, 1H), 2.17-2.28 (m, 2H), 1.95-
2.08 (m, 2H); 13C NMR (CDCl3): δ 158.3, 156.2, 149.9, 146.6,
143.2, 139.0, 132.4, 132.2, 128.6, 128.5, 127.7, 127.7, 127.3,
126.4, 114.7, 110.7, 65.6, 42.7, 41.5, 41.3, 40.5, 36.5, 34.2;
ESMS m/z 512.2 (MH+). Anal. (C31H30ClN3O2) C, H, N.
A.5. General Procedure for the Synthesis of Com-
pounds 19. 1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-trifluoro-
methylpentyl]-3-pyridin-4-ylimidazolidin-2-one (19). To
a stirred solution of cyanoacetamide (5.38 g, 64.0 mmol)
dissolved in water (35 mL) was added successively trifluoro-
acetaldehyde ethyl hemiacetal (4.60 g, 32.0 mmol) and pip-
eridine (0.2 mL, 2.1 mmol) at 10 °C. After stirring for 3 h at
room temperature, the reaction mixture was cooled in an ice
bath and stirred for another 1 h. After 15 min, the mixture
was allowed to come to room temperature and then filtered
with suction and washed thoroughly with cold distilled water
to yield R,R′-dicyano-â-trifluoromethylglutamide 17 as a white
solid (2.10 g, 27%).
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-ethylpentyl]-3-pyri-
din-4-ylimidazolidin-2-one (14b): yield 86%; white solid; mp
141-142 °C; IR νmax (neat) 2933, 1710, 1594, 1483, 1248 cm-1
;
1H NMR (CDCl3) δ 8.41 (d, J ) 4.8 Hz, 2H), 7.42-7.45 (m,
6H), 7.34-7.36 (m, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 4.03 (t, J )
6.5 Hz, 2H), 3.74-3.79 (m, 2H), 3.49-3.55 (m, 2H), 3.36 (t, J
) 7.2 Hz, 2H), 1.81-1.84 (m, 2H), 1.59-1.65 (m, 3H), 1.44-
1.48 (m, 2H), 0.93 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3) δ
158.4, 156.4, 149.9, 146.7, 139.0, 132.4, 132.2, 128.6, 127.8,
127.7, 114.7, 110.7, 66.0, 41.9, 41.5, 41.5, 33.8, 32.6, 30.8, 26.0,
10.8; ESMS m/z 464.1 (MH+). Anal. (C27H30ClN3O2) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-propylpentyl]-3-py-
ridin-4-ylimidazolidin-2-one (14c): yield 80%; white solid;
mp 142-143 °C; IR νmax (neat) 2930, 1710, 1595, 1483, 1249
cm-1; 1H NMR (CDCl3) δ 8.41 (dd, J ) 5.1, 1.8 Hz, 2H), 7.42-
7.45 (m, 6H), 7.34-7.37 (m, 2H), 6.91-6.94 (d, J ) 8.7 Hz,
2H), 4.03 (t, J ) 6.5 Hz, 2H), 3.73-3.78 (m, 2H), 3.49-3.54
(m, 2H),3.36 (t, J ) 7.4 Hz, 2H), 1.81-1.84 (m, 2H), 1.59-
1.64 (m, 3H), 1.36-1.39 (m, 4H), 0.90-0.94 (m, 3H); 13C NMR
(CDCl3) δ 158.4, 156.4, 150.0, 146.7, 139.0, 132.4, 132.1, 128.6,
127.8, 127.7, 114.7, 110.7, 66.0, 41.9, 41.5, 41.5, 36.0, 33.1, 32.4,
31.3, 19.8, 14.6; ESMS m/z 478.1 (MH+). Anal. (C28H32ClN3O2)
C, H, N.
To a stirred suspension of diamide (2.0 g, 8.1 mmol) was
added concentrated HCl (4.4 mL) at room temperature. The
suspension was warmed to 50 °C, and distilled water (4.4 mL)
was added. The mixture was heated at 130 °C for 8 h. After
cooling, the resulting solution was saturated with NaCl and
extracted with ethyl ether (30 mL × 3). The organic layer was
collected, dried over MgSO4 and concentrated under vacuum.
The residue was recrystallized from cosolvent (ethyl acetate
and ethanol) to obtain trifluoromethylglutaric acid 18 as a pale
yellow solid (0.62 g, 39%). Compound 19 was prepared using
the similar manner as described in method A.4, employing the
required 18 as a starting material: yield 25%; colorless oil;
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3-isopropylpentyl]-3-
pyridin-4-ylimidazolidin-2-one (14d): yield 75%; white
solid; mp 141-142 °C; IR νmax (neat) 2957, 1710, 1594, 1483,
1
1268 cm-1; H NMR (CDCl3) δ 8.40 (d, J ) 6 Hz, 2H), 7.40-
7.45 (m, 6H), 7.34-7.37 (m, 2H), 6.91-6.93 (d, J ) 8.7 Hz, 2
H), 4.02 (t, J ) 6.6 Hz, 2H), 3.71-3.76 (m, 2H), 3.49-3.54 (m,
2H), 3.35 (t, J ) 7.2 Hz, 2H), 1.83-1.87 (m, 2H), 1.66-1.73
(m, 2H), 1.49-1.54 (m, 2H),0.91 (d, J ) 6.6 Hz, 6H); 13C NMR
(CDCl3) δ 158.4, 156.4, 149.9, 146.6, 138.9, 132.4, 132.1, 128.6,
127.8, 127.6, 114.6, 110.7, 66.7, 42.6, 41.5, 41.4, 38.2, 30.2, 29.7,
28.4, 19.1; ESMS m/z 478.1 (MH+). Anal. (C28H32ClN3O2) C,
H, N.
IR νmax (neat) 2943, 1713, 1594, 1483, 1262 cm-1 1H NMR
;
(CDCl3) δ 8.39 (d, J ) 6.3 Hz, 2H), 7.33-7.42 (m, 8H), 6.90 (d.
J ) 8.7 Hz, 2H), 4.07-4.11 (m, 2H), 3.64-3.71 (m, 2H), 3.35-
3.54 (m, 4H), 2.49-2.52 (m, 1H), 2.18-2.45 (m, 1H), 1.91-
2.00 (m, 2H), 1.77-1.84 (m, 1H); 13C NMR (CDCl3) δ 157.9,
1-[3-Benzyl-5-(4′-chlorobiphenyl-4-yloxy)pentyl]-3-py-
ridin-4-yl-imidazolidin-2-one (14e): yield 59%; colorless oil;
1H NMR (CDCl3) δ 8.41 (dd, J ) 5.1, 1.2 Hz, 2H), 7.34-7.45
(m, 8H), 7.16-7.29 (m, 5H), 6.90 (d, J ) 8.7 Hz, 2H), 4.05 (t,
J ) 6.3 Hz, 2H), 3.64-3.70 (m, 2H), 3.31-3.41 (m, 2H), 3.21-
3.30 (m, 2H), 2.61-2.76 (m, 2H), 1.94-2.03 (m, 1H), 1.84-
1.90 (m, 2H), 1.57-1.64 (m, 2H); 13C NMR (CDCl3) δ 158.3,
156.4, 149.9, 146.7, 140.2, 138.9, 132.5, 132.2, 129.0, 128.6,
128.2, 127.8, 127.7, 125.9, 114.7, 110.7, 66.0, 41.7, 41.4, 41.1,
40.7, 34.8, 33.0, 29.9; ESMS m/z 526.2 (M+). Anal. (C32H32-
ClN3O2) C, H, N.
156.5, 149.1, 146.4, 138.7, 132.5, 132.5, 128.6, 128.0 (JCF
)
277.1 Hz), 127.8, 127.6, 114.5, 110.7, 64.7, 42.0, 41.8, 41.4, 37.4
(JCF ) 25.6 Hz), 28.0, 26.1; ESMS m/z 504.1 (MH+). Anal.
(C26H25ClF3N3O2) C, H, N.
A.6. General Procedure for the Synthesis of Com-
pounds 24a-c and 25a-c. 1-[5-(4′-Chlorobiphenyl-4-
yloxy)-1-methylpentyl]-3-pyridin-4-ylimidazolidin-2-
one (24a). To a stirred solution of 20a (1.00 g, 8.46 mmol)
dissolved in pyridine (10 mL) was added p-toluenesulfonyl
chloride (3.55 g, 18.61 mmol) at 0 °C under argon. After
reaction for 3 h, the mixture was evaporated off under vacuum.
The oil residue was subjected to flash chromatograph on silica
gel to give 21a as a white solid (3.48 g, 96%). Compound 21a
(0.85 g, 2 mmol) was treated with 6 (0.20 g, 1 mmol) and K2-
CO3 (0.14 g, 1 mmol) in CH3CN (20 mL) at 60 °C for 6 h. After
cooling the mixture was concentrated to remove solvent and
partitioned with CH2Cl2/H2O (1:1). The organic layer was
washed with brine, dried over MgSO4, and concentrated under
vacuum. The residue was subjected to flash chromatography
on silica gel to give 22a as a white solid (0.42 g, 91%).
Compoound 22a (0.27 g, 0.59 mmol) was treated with the
mixture of 4 (96 mg, 0.59 mmol) and NaH (42 mg, 1.77 mmol)
in dry DMF (1 mL). The resulting mixture was reacted at room
temperature for 12 h under argon and then quenched with
distilled water (10 mL) and extracted with ethyl acetate (10
mL × 3). The organic layers were collected, washed with brine,
dried over MgSO4, and concentrated under vacuum. The
residue was subjected to flash chromatography on silica gel
to give 24a as a white solid (0.23 g, 80%): mp 127-128 °C; 1H
NMR (CDCl3) δ 8.41 (d, J ) 5.4 Hz, 2H), 7.21-7.47 (m, 6H),
7.33-7.36 (m, 2H), 6.91 (d, J ) 8.4 Hz, 2H), 4.10-4.17 (m,
2H), 3.96-4.00 (m, 2H), 3.77-3.82 (m, 2H), 3.37-3.53 (m, 4H),
1.75-1.90 (m, 2H), 1.48-1.64 (m, 2H), 1.20 (d, J ) 6.6 Hz,
1-[5-(4′-Chlorobiphenyl-4-yloxy)-3,3-dimethylpentyl]-
3-pyridin-4-ylimidazolidin-2-one (14f): yield 85%; white
solid; mp 150-152 °C; IR νmax (neat) 2927, 1704, 1606, 1482
1
cm-1; H NMR (CDCl3) δ 8.42 (d, J ) 5.1 Hz, 2H), 7.44-7.46
(m, 6H), 7.34-7.37 (m, 2H), 6.94 (d, J ) 8.7 Hz, 2H), 4.07 (t,
J ) 6.9 Hz, 2H), 3.77-3.82 (m, 2H), 3.51-3.56 (m, 2H), 3.35-
3.41 (m, 2H), 1.81 (t, J ) 6.9 Hz, 2H), 1.55-1.60 (m, 2H), 1.06
(s, 6H); 13C NMR (CDCl3) δ 158.3, 156.3, 149.9, 146.7, 138.9,
132.4, 132.1, 128.6, 127.8, 127.7, 114.7, 110.6, 64.8, 41.4, 40.6,
40.4, 40.2, 39.0, 32.0, 27.6; ESMS m/z 464.1 (MH+). Anal.
(C27H30ClN3O2) C, H, N.
1-{2-{1-[2-(4′-Chlorobiphenyl-4-yloxy)ethyl]cyclohexyl}-
ethyl}-3-pyridin-4-ylimidazolidin-2-one (14g): yield 91%;
white solid; mp 162-163 °C; IR νmax (neat) 2929, 1713, 1594,
1483, 1248 cm-1; 1H NMR (CDCl3) δ 8.42 (d, J ) 6.3 Hz, 2H),
7.43-7.46 (m, 6H), 7.34-7.37 (m, 2H), 6.95 (d, J ) 8.4 Hz,
2H), 4.08 (t, J ) 6.9 Hz, 2H), 3.75-3.81 (m, 2H), 3.51-3.57
(m, 2H), 3.34-3.39 (m, 2H), 1.88 (t, J ) 6.9 Hz, 2H), 1.61-
1.66 (m, 2H), 1.24-1.49 (m, 10H); 13C NMR (CDCl3) δ 158.4,
156.3, 150.0, 146.7, 139.0, 132.5, 132.2, 128.6, 127.8, 127.7,
114.7, 110.7, 64.3, 41.6, 41.5, 39.5, 36.2, 35.9, 34.5, 34.3, 26.4,
21.7; ESMS m/z 504.2 (MH+). Anal. (C30H34ClN3O2) C, H, N.

Antipicornavirus Pyridin-4-ylimidazolidinones
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3533
3H); 13C NMR (CDCl3) δ 158.4, 156.1, 149.9, 146.7, 139.0,
132.4, 132.1, 128.6, 127.8, 127.7, 114.6, 110.7, 67.6, 47.8, 41.6,
36.4, 33.6, 29.0, 23.2, 18.1; ESMS m/z 450.2 (MH+). Anal.
(C26H28ClN3O2) C, H, N.
The desired compounds 24b,c were prepared using a similar
manner as described for the synthesis of 24a. The synthetic
procedure of 25a-c employed the same starting material 20
but primarily N-alkylation with 4 in the presence of NaH and
then coupling with 6 by K2CO3.
subjected to flash chromatography to provide 5-(4-cyanophe-
noxy)-3-methylpentyl p-toluenesulfonate (0.83 g, 2.23 mmol).
The material was treated with NaH in a similar manner as
described in method A.4 to provide 27 (0.38 g, 91%). To a
mixture of hydroxylamine hydrochloride (0.40 g, 5.80 mmol)
and K2CO3 (0.81 g, 5.80 mmol) in ethanol (35 mL) was added
27 (0.62 g, 1.70 mmol) at reflux for 2 h. After cooling, the
resulting mixture was concentrated in vacuo, and the solid
residue was triturated with distilled water (5 mL). The
resulting mixture was filtered, and the cake was washed with
CH2Cl2/MeOH (8:1) to provide crude amidoxime as a white
solid (0.52 g, 77%). The material (0.17 g, 0.43 mmol) was
dissolved in pyridine (7 mL) and acetic anhydride (0.1 mL, 1.08
mmol) was added. The mixture was heated at 110 °C for 1 h.
After cooling the mixture was concentrated in vacuo to give
the crude solid. The residue was subjected to flash chroma-
tography to yield 28a as a colorless oil (0.12 g, 67%): 1H NMR
(CDCl3) δ 8.42 (d, J ) 6.0 Hz, 2H), 7.94 (d, J ) 8.7 Hz, 2H),
7.47 (d, J ) 6.0 Hz, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 4.03-4.09
(m, 2H), 3.75-3.80 (m, 2H), 3.48-3.54 (m, 2H), 3.31-3.43 (m,
2H), 2.62 (s, 3H), 1.76-1.93 (m, 2H), 1.63-1.74 (m, 2H), 1.39-
1.51 (m, 1H), 1.03 (d, J ) 6.3 Hz, 3H); ESMS m/z 422.2 (MH+).
Anal. (C23H27N5O3) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-2-methylpentyl]-3-pyridin-
4-ylimidazolidin-2-one (24b):
yield 86%; white solid; mp 145-146 °C; IR νmax (neat) 2947,
1
1706, 1604, 1483, 1425, 1273 cm-1; H NMR (CDCl3) δ 8.42
(dd, J ) 4.9, 1.7 Hz, 2H), 7.41-7.47 (m, 6H), 7.32-7.37 (m,
2H), 6.92 (d, J ) 8.7 Hz, 2H), 3.98 (t, J ) 6.3 Hz, 2H), 3.55-
3.81 (m, 2H), 3.49-3.53 (m, 2H), 3.11-3.23 (m, 2H), 1.77-
1.99 (m, 3H), 1.57-1.64 (m, 1H), 1.30-1.33 (m, 1H), 0.98 (d,
J ) 6.6 Hz, 3H); 13C NMR (CDCl3) δ 158.4, 156.8, 150.0, 146.6,
139.0, 132.4, 132.1, 128.6, 127.8, 127.7, 114.6, 110.7, 68.0, 50.4,
42.3, 41.5, 31.7, 30.6, 26.8, 17.6; ESMS m/z 450.2 (MH+). Anal.
(C26H28ClN3O2) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-2,2-dimethylpentyl]-
3-pyridin-4-ylimidazolidin-2-one (24c). yield 83%; colorless
oil; IR νmax (neat) 2946, 1698, 1593, 1483, 1420, 1388, 1248
1-{5-[4-(5-Ethyl-1,2,4-oxadiazol-2-yl)phenoxy]-3-meth-
ylpentyl}-3-pyridin-4-ylimidazolidin-2-one (28b): yield
62%; yellow oil; IR νmax (neat) 2928, 1713, 1613, 1594, 1481,
1
cm-1; H NMR (CDCl3) δ 8.43 (d, J ) 6.3 Hz, 2H), 7.42-7.48
(m, 6H), 7.33-7.37 (m, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 3.96-
4.00 (m, 2H), 3.78-3.83 (m, 2H), 3.61-3.66 (m, 2H), 3.11 (s,
2H), 1.82-1.87 (m, 2H), 1.42-1.47 (m, 2H), 0.99 (s, 6H); 13C
NMR (CDCl3) δ 158.4, 157.7, 149.9, 146.6, 139.0, 132.4, 132.1,
128.6, 127.7, 127.6, 114.6, 110.8, 68.6, 56.0, 45.3, 41.5, 36.5,
35.8, 25.8, 24.2; ESMS m/z 464.1 (MH+). Anal. (C27H30ClN3O2)
C, H, N.
1426, 1377, 1253 cm-1 1H NMR (CDCl3) δ 8.40 (d, J ) 6.0
;
Hz, 2H), 7.95 (d, J ) 9.0 Hz, 2H), 7.44 (d, J ) 6.0 Hz, 2H),
6.93 (d, J ) 9.0 Hz, 2H), 4.01-4.08 (m, 2H), 3.74-3.79 (m,
2H), 3.47-3.53 (m, 2H), 3.33-3.41 (m, 2H), 2.94 (q, J ) 7.6
Hz, 2H), 1.76-1.93 (m, 2H), 1.62-1.74 (m, 2H), 1.41-1.48 (m,
1H), 1.43 (t, J ) 7.6 Hz, 3H), 1.03 (d, J ) 6.3 Hz, 3H); 13C
NMR (CDCl3) δ 180.1, 167.6, 160.9, 156.4, 149.8, 146.7, 128.7,
119.1, 114.5, 110.7, 65.9, 41.9, 41.4, 41.4, 36.0, 34.3, 27.7, 20.5,
19.6, 11.1; ESMS m/z 436.2 (MH+). Anal. (C24H29N5O3) C, H,
N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-5-methylpentyl]-3-py-
ridin-4-ylimidazolidin-2-one (25a): yield 79%; white solid;
mp 143-144 °C; IR νmax (neat) 2935, 1710, 1593, 1482, 1425,
1268 cm-1; 1H NMR (CDCl3) δ 8.41 (d, J ) 6.0 Hz, 2H), 7.41-
7.46 (m, 6H), 7.32-7.37 (m, 2H), 6.91 (d, J ) 9.0 Hz, 2H),
4.36-4.42 (m, 1H), 3.74-3.80 (m, 2H), 3.47-3.53 (m, 2H),
3.29-3.33 (m, 2H), 1.78-1.83 (m, 2H), 1.59-1.75 (m, 2H),
1.41-1.56 (m, 2H), 1.32 (d, J ) 6.0 Hz, 3H); 13C NMR (CDCl3)
δ 157.5, 156.4, 149.8, 146.7, 139.0, 132.4, 132.0, 128.6, 127.8,
127.6, 115.9, 110.7, 73.6, 43.8, 41.5, 41.4, 36.2, 27.9, 22.9, 19.9;
ESMS m/z 450.2 (MH+). Anal. (C26H28ClN3O2) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-4-methylpentyl]-3-py-
ridin-4-ylimidazolidin-2-one (25b): yield 89%; white solid;
mp 140-142 °C; IR νmax (neat) 2916, 1712, 1598, 1485, 1427,
1-{3-Methyl-5-[4-(5-n-propyl-1,2,4-oxadiazol-2-yl)phen-
oxy]pentyl}-3-pyridin-4-ylimidazolidin-2-one (28c): yield
57%; yellow oil; IR νmax (neat) 2933, 1714, 1593, 1481, 1426,
1
1254 cm-1; H NMR (CDCl3) δ 8.42 (d, J ) 5.7 Hz, 2H), 7.96
(d, J ) 9.0 Hz, 2H), 7.47 (d, J ) 5.7 Hz, 2H), 6.93 (d, J ) 9.0
Hz, 2H), 4.03-4.09 (m, 2H), 3.75-3.81 (m, 2H), 3.48-3.54 (m,
2H), 3.33-3.42 (m, 2H), 2.89 (t, J ) 7.5 Hz, 2H), 1.83-1.95
(m, 2 H), 1.76-1.91 (m, 2H), 1.63-1.74 (m, 2H), 1.39-1.51
(m, 1H), 1.04 (t, J ) 7.4 Hz, 3H), 1.04 (d, J ) 6.3 Hz, 3H); 13
C
NMR (CDCl3) δ 179.2, 167.6, 160.9, 156.4, 149.5, 147.0, 128.8,
119.2, 114.5, 110.7, 65.9, 42.0, 41.5, 41.5, 36.0, 34.3, 28.6, 27.7,
20.4, 19.6, 13.9; ESMS m/z 450.2 (MH+). Anal. (C25H31N5O3)
C, H, N.
1276 cm-1 1H NMR (CDCl3) δ 8.42 (br, 2H), 7.43-7.45 (m,
;
6H), 7.34-7.36 (m, 2H), 6.91-6.94 (m, 2H), 3.77-3.82 (m, 4H),
3.50-3.56 (m, 2H), 3.31-3.35 (m, 2H), 1.99-2.01 (m, 2H),
1.56-1.70 (m, 2H), 1.25-1.31 (m, 1H), 1.05 (d, J ) 6.0 Hz,
3H); 13C NMR (CDCl3) δ 158.6, 156.5, 149.9, 146.7, 139.0,
132.4, 132.1, 128.6, 127.8, 127.7, 114.7, 110.8, 72.9, 44.2, 41.5,
41.5, 33.1, 30.6, 25.0, 17.2; ESMS m/z 450.2 (MH+). Anal.
(C26H28ClN3O2) C, H, N.
1-{3-Methyl-5-[4-(5-trifluoromethyl-1,2,4-oxadiazol-2-
yl)phenoxy]pentyl}-3-pyridin-4-ylimidazolidin-2-one(28d):
yield 58%; colorless oil; IR νmax (neat) 2928, 1713, 1608, 1596,
1
1481, 1427, 1259, 1161 cm-1; H NMR (CDCl3) δ 8.41 (d, J )
6.3 Hz, 2H), 8.00 (d, J ) 9.0 Hz, 2H), 7.45 (d, J ) 6.3 Hz, 2H),
6.96 (d, J ) 9.0 Hz, 2H), 4.04-4.09 (m, 2H), 3.75-3.90 (m,
2H), 3.49-3.54 (m, 2H), 3.34-3.41 (m, 2H), 1.81-1.94 (m, 2H),
1.65-1.74 (m, 2H), 1.43-1.50 (m, 1H), 1.04 (d, J ) 6.3 Hz,
3H); 13C NMR (CDCl3) δ 168.4, 165.1 (q, JCF ) 44.6 Hz), 161.8,
156.4, 149.9, 146.6, 129.2, 117.0, 115.8 (q, JCF ) 270.8 Hz),
114.8, 110.7, 66.1, 41.9, 41.5, 41.5, 35.9, 34.4, 27.7, 19.6; ESMS
m/z 476.1 (MH+). Anal. (C23H24F3N5O3) C, H, N.
1-[5-(4′-Chlorobiphenyl-4-yloxy)-4,4-dimethylpentyl]-
3-pyridin-4-ylimidazolidin-2-one (25c): yield 85%; colorless
oil; IR νmax (neat) 2963, 1704, 1602, 1485, 1425, 1252 cm-1; 1H
NMR (CDCl3) δ 8.42 (s, 2H), 7.43-7.49 (m, 6H), 7.34-7.36 (m,
2H), 6.93 (d, J ) 8.7 Hz, 2H), 3.76-3.81 (m, 2H), 3.64 (s, 2H),
3.48-3.53 (m, 2H), 3.28-3.33 (m, 2H), 1.56-1.61 (m, 2H),
1.40-1.46 (m, 2H), 1.02 (s, 6H); 13C NMR (CDCl3) δ 158.8,
156.4, 149.4, 147.1, 139.0, 132.4, 132.1, 128.6, 127.8, 127.7,
114.7, 110.8, 76.0, 44.5, 41.5, 41.4, 35.9, 34.4, 24.8, 22.1; ESMS
m/z 464.1 (MH+). Anal. (C27H30ClN3O2) C, H, N.
A.7. General Procedure for the Synthesis of Com-
pounds 28a-d. 1-{3-Methyl-5-[4-(5-methyl-1,2,4-oxadia-
zol-2-yl)phenoxy]pentyl}-3-pyridin-4-ylimidazolidin-2-
one (28a). To a stirred solution of 13a (2.0 g, 4.69 mmol)
dissolved in dried CH3CN were added 4-cyanophenol (0.28 g,
2.35 mmol) and K2CO3 (0.65 g, 4.69 mmol) at 60 °C for 24 h.
After cooling, the solvent was removed in vacuo and the
residue was diluted with distilled water and then extracted
with CH2Cl2. The organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo. The residue was
A.8. General Procedure for the Synthesis of Com-
pounds 32a,b. 1-{3-Methyl-5-[4-[5-(2-methyl-2H-tetrazolyl)]-
phenoxy]pentyl}-3-pyridin-4-ylimidazolidin-2-one (32a).
To a stirred solution of 26 (1.19 g, 10 mmol) dissolved in dry
acetone (30 mL) was added K2CO3 (1.67 g, 12 mmol) at room
temperature for 10 min under argon. Methyl iodide (1.70 g,
12 mmol) was added dropwise, and the mixture was heated
at reflux for 3 h. After cooling the mixture was concentrated
in vacuo and partitioned between distilled water and ethyl
ether. The organic layer was collected, washed with 10% NaOH
and brine, dried over MgSO4, and concentrated in vacuo. The
residue was subjected to flash chromatography to give 4-meth-
oxybenzonitrile as a white solid (1.21 g, 91%). The material

3534 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10
Chang et al.
(1.0 g, 7.51 mmol) was dissolved in DMF (10 mL) and NaN3
(0.54 g, 8.26 mmol), and NH4Cl (0.10 g, 1.88 mmol) was added
under argon. The mixture was heated at 110 °C for 16 h. After
cooling, the reaction mixture was poured into crashed ice with
vigorous stirring and extracted with CH2Cl2 (30 mL × 3). The
aqueous solution was acidified carefully with 6 N HCl. A white
solid precipitate was filtered and recrystallized from CH3CN
to give 29 (0.71 g, 54%). To a stirred suspension of 29 (0.60 g,
3.41 mmol) in CH3CN (20 mL) were added CH3I (0.58 g, 4.09
mmol) and K2CO3 (0.57 g, 4.09 mmol), and the mixture was
heated at reflux for 1 h. After cooling, the mixture was
concentrated in vacuo, and the residue was partitioned be-
tween ethyl acetate and distilled water. The organic layers
were collected, washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was subjected to flash
chromatography to give 30a (0.37 g, 57%). To a stirred solution
of 30a (0.32 g, 1.68 mmol) dissolved in dry CH2Cl2 (15 mL)
was added dropwise BBr3 (5.04 mmol, 1 M solution in CH2-
Cl2) at room temperature under argon. After 3 h the mixture
was poured into ice-water with vigorous stirring and the
resultant white precipitate was collected and recrystallized
from ethanol to give 4-[5-(2-methyl-2H-tetrazolyl)]phenol (0.28
g, 94%). The phenol material was O-alkylation by treatment
with 13a to provide tosylate 31, which was coupled with
imidazolidine 4 to give target 32a (the procedure was similar
to the synthesis of 14 from 13 as described in method A.4):
addition of 100 µL of 0.5% glutaraldehyde 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.
B.3. Cytotoxicity Assay. Twenty-three test compounds at
various concentrations were added to RD 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
expressed as CC50.
Acknowledgment. We are grateful to the National
Health Research Institutes of the Republic of China for
financial support.
Supporting Information Available: Protocols for bio-
logical assays, synthetic procedures, and spectral data for 8a-
f, 11a-d, 14a-h, 19, 24a-c, 25a-c, 28a-d, 32a-b and
elemental analysis data. This material is available free of
charge via the Internet at http://pubs.acs.org.
yield 45%; yellow oil; 1H NMR (CDCl3) δ 8.41 (d, J ) 5.4
Hz, 2H), 8.01 (d, J ) 9.0 Hz, 2H), 7.45 (d, J ) 5.4 Hz, 2H),
6.95 (d, J ) 9.0 Hz, 2H), 4.36 (s, 3H), 4.03-4.10 (m, 2H), 3.74-
3.80 (m, 2H), 3.42-3.54 (m, 2H), 3.34-3.39 (m, 2H), 1.79-
1.92 (m, 2H), 1.64-1.73 (m, 2H), 1.40-1.51 (m, 1H), 1.04 (d,
J ) 6.3 Hz, 3H); 13C NMR (CDCl3) δ 164.8, 160.3, 156.4, 149.9,
146.7, 128.1, 119.7, 114.6, 110.8, 65.9, 41.9, 41.5, 41.5, 39.5,
36.1, 34.3, 27.7, 19.7; ESMS m/z 422.2 (MH+). Anal. (C22H27-
N7O2) C, H, N.
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