2-amino-3-substituted-6-[(E)-1-phenyl-2-(N- methylcarbamoyl)vinyl]imidazo-[1,2-a]pyridines as a novel class of inhibitors of human rhinovirus: Stereospecific synthesis and antiviral activity

Article abstract of DOI:10.1021/jm9810405

A series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N- methylcarbamoyl)vinyl]imidazo[1,2-a]-pyridines 1a-i, structurally related to Enviroxime and its analogous benzimidazoles, was designed and prepared for testing as antirhinovirus agents. The imidazo ring in this class of compounds was constructed starting from the aminopyridine after tosylation and subsequent treatment with the appropriate acetamides. The key steps in the synthesis include the development and use of a new Horner-Emmons reagent for the direct incorporation of methyl vinylcarboxamide. The reaction was stereospecific in the substrates 5a-f leading exclusively to the desired E- isomer and avoiding the use of reverse-phase preparative HPLC for the separation of both possible isomers before antiviral activity evaluation. The isopropylsulfonyl group, known as the best substituent at the 1-position in the benzimidazole SAR in terms of activity, was introduced in this new series of imidazo[1,2-a]pyridines via halogen-metal exchange and subsequent treatment with isopropyl isopropanethiolsulfonate. Compounds 1a-i were evaluated in plaque reduction assay and in a cytopathic effect assay. Compounds 1b-d,h exhibited a strong antirhinovirus activity, and no apparent cellular toxicity was visible. The substitution at the 3-position was required for activity. Surprisingly the isopropylsulfonyl in this family of compounds did not enhance the activity as in the case of benzimidazoles. Instead, compound 1i was 4 times less active than its phenyl and sulfide partners. The chemistry as well as the biological evaluation are discussed.

Full text of DOI:10.1021/jm9810405

50
J . Med. Chem. 1999, 42, 50-59
2-Am in o-3-su bstitu ted -6-[(E)-1-p h en yl-2-(N-m eth ylca r ba m oyl)vin yl]im id a zo-
[1,2-a ]p yr id in es a s a Novel Cla ss of In h ibitor s of Hu m a n Rh in ovir u s:
Ster eosp ecific Syn th esis a n d An tivir a l Activity
Chafiq Hamdouchi,*,† J esu´s de Blas,† Mirian del Prado,† J oseph Gruber,‡ Beverly A. Heinz,‡ and Lori Vance‡
Centro de Investigacio´n Lilly, S.A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain, and
Infectious Diseases Research, Lilly Research Laboratories, Indianapolis, Indiana 46285
Received May 29, 1998
A series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]-
pyridines 1a -i, structurally related to Enviroxime and its analogous benzimidazoles, was
designed and prepared for testing as antirhinovirus agents. The imidazo ring in this class of
compounds was constructed starting from the aminopyridine after tosylation and subsequent
treatment with the appropriate acetamides. The key steps in the synthesis include the
development and use of a new Horner-Emmons reagent for the direct incorporation of methyl
vinylcarboxamide. The reaction was stereospecific in the substrates 5a -f leading exclusively
to the desired E-isomer and avoiding the use of reverse-phase preparative HPLC for the
separation of both possible isomers before antiviral activity evaluation. The isopropylsulfonyl
group, known as the best substituent at the 1-position in the benzimidazole SAR in terms of
activity, was introduced in this new series of imidazo[1,2-a]pyridines via halogen-metal
exchange and subsequent treatment with isopropyl isopropanethiolsulfonate. Compounds 1a -i
were evaluated in plaque reduction assay and in a cytopathic effect assay. Compounds 1b-
d ,h exhibited a strong antirhinovirus activity, and no apparent cellular toxicity was visible.
The substitution at the 3-position was required for activity. Surprisingly the isopropylsulfonyl
in this family of compounds did not enhance the activity as in the case of benzimidazoles.
Instead, compound 1i was 4 times less active than its phenyl and sulfide partners. The chemistry
as well as the biological evaluation are discussed.
Ch a r t 1
In tr od u ction
The human rhinoviruses are a group of more than 110
serotypes that are recognized as the most important
etiologic agents of the common cold in adults and
children.1 In addition to causing the common cold, these
viruses also typically precipitate or exacerbate several
chronic conditions such as bronchitis, otitis media,
sinusitis, emphysema, and asthma. Because of their
significant association with disease, the search for an
effective treatment for rhinovirus infections has at-
tracted considerable attention in the scientific com-
munity. Since the large number of serotypes makes the
development of a broad-spectrum vaccine unlikely, most
effort has focused on the development of effective
antivirals. Several antiviral drugs have been studied for
the treatment of rhinovirus colds. Among compounds
that have been studied are those that bind directly to
the virus and inhibit virus uncoating and compounds
that block the attachment of rhinovirus to ICAM-1. A
wide range of compounds have been found to have
antirhinovirus activity. However, despite good in vitro
activity, the majority of the compounds have been
ineffective when given in a manner that would be
acceptable for the treatment of colds, namely, by either
oral or intranasal administration. Others have been
rejected as clinical candidates because of problems with
toxicity, unfavorable pharmacology, or insufficient po-
tency. Thus the treatment of the common cold remains
an elusive goal.
Enviroxime (Chart 1), a benzimidazole derivative with
strong in vitro antirhinoviral activity, is one of the more
extensively studied synthetic agents.2 Enviroxime and
related benzimidazoles3 showed potent broad-spectrum
antiviral activity against a range of both rhinoviruses
and enteroviruses. Noncytotoxic concentrations of En-
viroxime are associated with complete inhibition of
replication of 81 rhinovirus sereotypes. The 50% inhibi-
tory concentration (IC50) ranges from 0.05 to 0.12 µg/
mL for different serotypes. Although the mechanism of
action of Enviroxime is not completely understood, it is
believed that the drug inhibits the formation of the viral
RNA polymerase replication complex.4
† Centro de Investigacio´n Lilly, S.A.
‡ Lilly Research Laboratories.
10.1021/jm9810405 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/22/1998

Novel Class of Inhibitors of Human Rhinovirus
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 51
Sch em e 1
The major handicaps of Enviroxime are the poor oral
bioavailability and undesirable side effects. Studies of
oral Enviroxime showed low levels in blood and nasal
secretions and an unacceptably high frequency of nau-
sea and vomiting.5 Thus, despite its potent in vitro
antirhinovirus activity, significant therapeutic benefit
was not found with either oral or intranasal adminis-
tration, and Enviroxime clinical studies were termi-
nated. Enviradene, a related benzimidazole, showed
improved pharmacokinetics in dogs and caused no
emesis.6 However, the peak plasma levels did not
surpass the antiviral IC50 value, and the studies on
Enviradene were also discontinued. Although the ori-
gins of the poor oral bioavailability and emetic side effect
found in this class of antirhinoviral agents are not
completely understood, considerable efforts are still
devoted to this family of benzimidazoles with the aim
of finding an analogue with improved oral plasma levels
and a better safety profile.7
pounds with Z-double bonds. Our sp2 target was there-
fore an (E)-methyl vinylcarboxamide that would be
expected to participate in the hydrogen-bond formation
with virus-specific target in an analogous way as the
oximes.9 On the other hand, the substitution at the
1-position of benzimidazoles greatly increases the activ-
ity, and both the electron-rich nitrogen at the 3-position
and the free amino group at C-2 were key elements for
activity. On the basis of this information, we undertook
the synthesis of 2-amino-3-substituted-6-[(E)-1-phenyl-
2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines 1a-i
that would offer the following potential advantages: (a)
maintained potency (structurally related to benzimid-
azoles) and (b) enhanced oral bioavailability and fewer
side effects (new nucleus and new sp2 carbon between
aromatic rings).
The synthetic approach to the intermediates 5a -f is
based on classical transformations10 as outlined in
Scheme 1. Friedel-Crafts acylation of benzene with
6-chloronicotinyl chloride and subsequent treatment
with ammonia in ethanol leads to the desired amino-
pyridine. Reaction of the aminopyridine with p-toluene-
sulfonyl chloride in pyridine and subsequent reaction
with the appropriate acetamides in the presence of
Hu¨nig’s base in DMF provided the corresponding car-
bamides 4a -f in good yield. The 2-bromo-2-arylacet-
amides 3b -e required for the latter transformations
were prepared from their corresponding 2-bromo-2-
arylacetic acids after bromination in the presence of
N-bromosuccinimide and subsequent amidation. On the
other hand, the reagent 3f, where the leaving group is
a tosyl, was prepared from the corresponding aryl
aldehyde after treatment with trimethylsilyl cyanide,
hydrolysis, acetylation of the resulting hydroxy acid,
amidation, removal of the acetyl group, and tosylation.
Conversion of 4a -f to the desired 2-(N-trifluoracetyl-
amino)imidazopyridines 5a -f was accomplished by
treatment with trifluoroacetic anhydride.
On the other hand, in an effort to identify structurally
related analogues of Enviroxime that do not belong to
the benzimidazole family, an aza analogue (Chart 1) was
8
designed and synthesized by Kelley et al. However,
the new compound was found to be devoid of antiviral
activity by the plaque reduction assay.
Here we describe the design, execution, and antiviral
activity evaluation of a new class of compounds from
the imidazo[1,2-a]pyridine family which are structurally
related to Enviroxime. The key step of the synthesis is
based on a successful application of a new Horner-
Emmons reagent for the stereospecific incorporation of
methyl vinylcarboxamide.
Ch em istr y
We decided to transfer the information that was
gained from the benzimidazole structure-activity re-
lationship (SAR) to the imidazo[1,2-a]pyridine family.
From the considerable amount of SAR that was per-
formed around the Enviroxime nucleus, it was con-
cluded that an sp2 carbon between aromatic rings was
a key element for activity. Various substituted olefins
and oximes gave active compounds; however, there is a
correlation between double-bond geometry and activity,
and compounds with E-double bonds are much more
active and have a better therapeutic index than com-
As was mentioned above, the detailed analysis of the
sp2 carbon between aromatic rings in the reported
benzimidazole SAR had illustrated the importance of
the geometry of the double bond. These reports also
stressed the difficulties encountered in the separation
and purification of the desired E-isomer. In most of the
cases purification by reverse-phase preparative HPLC

52 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Hamdouchi et al.
Ta ble 1. Reaction of 5a -f with Diethyl [(N-Methylcarbamoyl)methyl]phosphonate (6)
substr
R
base
solvent
time (h)
compd
yield (%)
E:Z
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
H
H
H
H
NaH
KH
THF
THF
THF
DMF
Tol-THF
Tol-THF
Tol-THF
Tol-THF
Tol-THF
Tol-THF
60
24
24
18
60
24
18
15
15
18
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
0
80
0
1:1
1.4:1
1:0
1:0
1:0
1:0
1:0
1:0
1:0
LiHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
63
52
75
86
50
57
79
H
C6H4
2,5-diF-C6H3
2,3,4-triF-C6H2
3-CF3-C6H4
2-CF3-4-F-C6H3
Sch em e 2
During the benzimidazole SAR exploration of the
1-position with a variety of substituents, the authors
came to the conclusion that the isopropylsulfonyl was
the best candidate selected because of its significant
improvement in activity.2,3 In fact, it was suggested that
the presence of internal hydrogen bonding between the
amine hydrogen and the sulfonyl oxygen is important
for enhanced activity. In an attempt to transfer this
information to imidazopyridine SAR, our next target
was 2-amino-3-isopropylsulfonyl-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (1i) and
its isopropyl sulfide analogue 1h .
was required before antiviral activity evaluation.3 We
therefore felt the need of having a stereospecific method
that allows to convert compounds 5a ,b to our target
structures 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines 1a -i.
Peterson olefination was tried unsuccessfully in our
hands. On the other hand, the only known method for
a direct and stereospecific generation of the (E)-(N-
methylcarbamoyl)vinyl function was reported recently
by Mitchell et al.11 They used palladium-catalyzed
hydroarylation of arylpropiolamides to prepare ste-
reospecifically (E)-3,3-diarylacrylamides. Since this
method was not applicable to our substrates, we turned
to the Horner-Emmons reaction. Although this reaction
is widely used for the preparation of unsaturated esters,
to our knowledge there has been no application of this
method for the direct preparation of unsaturated car-
boxamides. Diethyl [(N-methylcarbamoyl)methyl]phos-
phonate (6) for the Horner-Emmons reaction was
readily prepared in large scale from triethyl phospho-
noacetate and methylamine in 88% yield (Scheme 2).
The parameters for the Horner-Emmons reaction
using the reagent 6, which include the nature of base,
the solvent, the temperature, and the concentration,
were first studied with substrate 5a . The most signifi-
cant results are summarized in Table 1. Regarding the
stereospecificity, the best results were achieved using
KHMDS as base either in DMF or in a mixture of
toluene-THF (diluted solution). Under both conditions
compound 7a was isolated in moderate to good yield.
1H NMR analysis of the crude showed only the E-isomer
of the desired product whose geometry was established
by NOE experiments. Because of the low solubility of
5a in the mixture of toluene-THF, DMF turned out to
be the solvent of choice in terms of the chemical yield.
The problem of solubility was not encountered in
substrates 5b-f where the 3-position was occupied by
an aromatic ring. Hence compounds 5b-f were sub-
jected to the Horner-Emmons reaction with 6 using
KHMDS as base and toluene-THF as solvent to give
the corresponding [(N-methylcarbamoyl)vinyl]imidazo-
[1,2-a]pyridines 7b-f with E-selectivity higher than
95% and moderate to good yield (Table 1). With the
exception of compound 7a 12 where the trifluoroacet-
amide group was hydrolyzed using 0.5 N NaOH, the
conversion of 7b-f to their corresponding final products
was performed using Hu¨nig’s base.
The synthesis of these compounds is outlined in
Scheme 4. 2-Trifluoroacetamido-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7a ) was
chemoselectively iodinated at the 3-position using N-
iodosuccinimide in acetonitrile at 0 °C in 98% yield. The
trifluoroacetamide group of the resulting iodo derivative
7g could be hydrolyzed when being supported on silica
gel and kept with MeOH/CH2Cl2 (2:98) to give 1g in 45%
yield. Compound 7g was first deprotonated with PhLi
and then subjected to a halogen-metal exchange reac-
tion with t-BuLi, and the resulting trianion was reacted
with isopropyl isopropanethiolsulfonate to give com-
pound 7h , which was mixed with silica gel in MeOH/
CH2Cl2. The cake was stirred for 2 days yielding the
desired 2-amino-3-isopropylthio-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (1h ) in
73% overall yield from 7g.
The synthesis of 2-amino-3-isopropylsulfonyl-6-[(E)-
1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]-
pyridine (1i) was achieved beginning with similar
reaction sequences. The resulting crude of 7h was
subjected to MCPBA oxidation to give the corresponding
sulfone in 63% yield and subsequent hydrolysis of the
trifluoroacetamide group on silica gel support to provide
1i in 89% yield.
SAR An a lysis
[(Methylcarbamoyl)vinyl]imidazopyridines 1a -i were
subjected to biological evaluation following the proce-
dures described in the Experimental Section. The
compounds were tested taking Enviroxime as a refer-
ence. Human rhinovirus-14 was selected as the routine
and initial virus for testing due to the amount of
information known about this serotype. The plaque
reduction assays were run in order to determine the
antiviral activity IC50 (Table 2). Compounds 1a with
hydrogen and 1g with iodine at the 3-position did not
show antiviral activity. However the substitution of this
position by an aryl, sulfenyl, or sulfonyl group resulted

Novel Class of Inhibitors of Human Rhinovirus
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 53
Sch em e 3
Sch em e 4
in moderate to potent compounds. Hence, it appears
that the substitution at the 3-position is a key element
for activity. In contrast to the results of the benzimid-
azole SAR2 studies where N-sulfonyl compounds have
generally shown the highest activity with the isopro-
pylsulfonyl being the group of choice, this is just the
reverse. The internal hydrogen bonding between the
amine hydrogen and the sulfonyl oxygen does not seem
to enhance the activity as in the case of benzimidazoles.3
Instead, a considerable loss of activity was observed
when the sulfide in compound 1h was replaced with its
corresponding sulfone. Even the phenyl and substituted
fluorophenyl analogues turned out to be more active.
Thus, in this new family of compounds the isopropyl-
sulfonyl is apparently not required for antirhinovirus
activity and could be replaced by an aromatic ring. Di-
and trifluorophenyl analogues 1c,d were found to be
slightly more active than their phenyl partners. This

54 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Ta ble 2. Antiviral Activity Evaluation of Imidazopyridines 1a -i
Hamdouchi et al.
IC50 (µg/mL)
CPE/XTTb
TC50 (µg/mL)
CPE/XTTb
b,c
compd
R
PRAa
TC50b:IC50
1a
1b
1c
1d
1f
1g
1h
1i
H
C6H5
2,5-diF-C6H3
2,3,4-triF-C6H2
2-CF3-4-F-C6H3
I
>10
0.27
0.18
0.17
0.44
>3.2
0.17
0.64
0.30
0.16
0.21
0.48
5.03
4.87
6.98
17
30
33
>10
>21
-S(i-Pr)
-S(O)2(i-Pr)
0.21
10
48
a
b
PRA assay using rhinovirus-14, IC50 (mg/mL). CPE/XTT assay using rhinovirus 14. c Ratio of TC50 over IC50
.
cal shifts (δ values) and coupling constants (J values) are given
in ppm and Hz, respectively. Mass spectra and high-resolution
mass spectra were recorded at an ionizing voltage of 70 eV on
a VG-AutoSpec spectrometer. Mass spectra, elemental analy-
ses, and some NMR spectra were provided by the Servicio
Interdepartamental de Investigacio´n (SIdI) at UAM (Madrid).
1,2-D ih y d r o -2-t o lu e n e s u lfo n im id o -5-b e n zo y lp y r i-
d in e (2). Step 1: 2-Ch lor o-5-ben zoylp yr id in e. Aluminum
chloride (100 g, 0.73 mol) was suspended in 200 mL of benzene
under N2. A solution of chloronicotinoyl chloride (53 g, 0.30
mol) in 100 mL of benzene was added to the rapidly stirring
suspension and then refluxed overnight. The reaction was
cooled to room temperature. Ethyl acetate (1 L) was added,
and the pH was adjusted to 8.5 with 5 N NaOH. Aluminum
salts precipitated and were filtered away. The filtrate was
washed with H2O, dried over Na2SO4, and concentrated in
vacuo. The resulting solid was recrystallized from Et2O/hexane
(3:2) yielding 54.6 g (83%): 1H NMR (300 MHz, CDCl3) δ 8.76
(d, 1H, J ) 2.2), 8.09 (dd, 1H, J ) 2.6, 8.4), 7.78 (d, 2H, J )
6.7), 7.65 (t, 1H, J ) 7.3), 7.53 (d, 2H, J ) 7.8), 7.48 (d, 1H, J
) 8.4); MS (EI+) m/z 220 (42), 219 (23), 218 (100), 182 (3), 140
(2), 105 (4).
suggests the importance of the electronic effect on the
antiviral activity.
The active compounds were selected for evaluation in
a cytopathic effect assay in order to determine the
general cellular toxicity TC50. In general these com-
pounds do not exhibit an apparent cellular toxicity as
could be seen by their ratio of TC50 over IC50, and no
relationship between cellular toxicity and antiviral
activity was visible in these experiments.
Con clu sion
Benzimidazoles with potent broad-spectrum anti-
rhino/enteroviral activity have been studied quite ex-
tensively. These compounds have not yet met the
requirements for a drug to treat the common cold: (1)
potent broad-spectrum antiviral activity, (2) limited
potential for the development of resistance, (3) oral
bioavailability, (4) safety, and (5) human efficacy.
Therefore, the identification of non-benzimidazole struc-
turally related analogues with good antirhinoviral activ-
ity is highly desired. We have designed and synthesized
a series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines, struc-
turally related to Enviroxime. The design of the new
class of compounds was based on information that was
gained from benzimidazole structure-activity relation-
ships. The development of new Horner-Emmons meth-
odology for the direct incorporation of methyl vinylcar-
boxamide permitted the construction of the sp2 region
in a stereospecific manner avoiding the use of reverse-
phase preparative HPLC for the separation of both
possible isomers before antiviral activity evaluation.
Most of these compounds (1b-d ,h ) exhibited a strong
antirhinovirus activity, and no apparent cellular toxicity
was found. The isopropylsulfonyl, which was the best
substituent in the benzimidazole series, did not enhance
the activity in this case. Instead, compound 1i was 4
times less active than its phenyl and sulfide partners.
Finally, compounds 1c,d ,h exhibited a potency compa-
rable to that of Enviradene (0.15 µg/mL), a related
benzimidazole that failed in the clinic.
Step 2: 1,2-Dih ydr o-2-am in o-5-ben zoylpyr idin e. 2-Chlo-
ro-5-benzoylpyridine (50 g, 0.23 mol) was dissolved in 250 mL
of ethanol and 200 mL of anhydrous ammonia, placed in a
reactor, and then heated at 145 °C for 16 h. The solvents were
removed in vacuo, and the remaining solid was recrystallized
from EtOH/H2O yielding 38 g (85%) of product as a white solid.
Step 3: 1,2-Dih yd r o-2-tolu en esu lfon im id o-5-ben zoyl-
p yr id in e (2). 1,2-Dihydro-2-amino-5-benzoylpyridine (77.0
mmol) was dissolved in dry pyridine (60 mL). p-Toluenesulfo-
nyl chloride (85.6 mmol) was added, and the solution was
heated at 80-90 °C under Ar overnight. Pyridine was removed
in vacuo to give a solid. Water (1.5 L) was added, and the
mixture was stirred for 90 min. The white solid was collected,
dried, and crystallized from ethyl acetate (200 mL) to give 2
1
(91%) as a white solid: mp 207-209 °C; H NMR (300 MHz,
DMSO-d6) δ 8.35 (s, 1H, H6), 8.06 (d, 1H, J ) 8.8, H3), 7.84
and 7.52 (AA′BB′ system, 4H, J ) 7.5, tol), 7.70-7.23 (m, 10H,
Ar), 2.31 (s, 3H, Ar); 13C NMR (DMSO-d6) δ 192.7, 155.0, 148.0,
143.4, 140.4, 138.3, 136.9, 132.9, 129.7, 129.6, 128.8, 127.2,
125.4, 112.5, 21.2; MS (EI+) m/z 352 M+ (1), 287 (100), 115
(5), 105 (10), 77 (17), 65 (12); HRMS calcd for C19H16N2O3S
352.0882, found 352.0882.
2-Br om o-2-p h en yla ceta m id e (3b). Step 1: 2-Br om o-2-
p h en yla cetic Acid . Phenylacetic acid (0.13 mol), benzoyl
peroxide (0.54 mmol), and N-bromosuccinimide (0.13 mol) were
combined in 500 mL of carbon tetrachloride under N2 and
refluxed under UV radiation for 5 h. The reaction was cooled
to room temperature, and the succinimide filtered away. The
carbon tetrachloride was removed in vacuo and the remaining
oil recrystallized from hexane yielding the desired product as
a yellow solid (82%).
Step 2: 2-Br om o-2-p h en yla ceta m id e (3b). 2-Bromo-2-
phenylacetic acid (21 g, 100 mmol) in 170 mL of dry CH2Cl2
and 3 drops of DMF were cooled in an ice bath under N2.
Oxalyl chloride (200 mmol) in 25 mL of dry CH2Cl2 was added
dropwise over 25 min. The ice bath was removed and the
reaction stirred for 3 h. The solvents were removed in vacuo
and then azeotroped with toluene (3 × 25 mL). The remaining
Since the antirhinoviral activity found in this new
class of compounds was promising, more biological
evaluations that include broad-spectrum activity and
oral bioavailability will be worthwhile.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents were purchased from
Aldrich and used without further purification unless stated
otherwise. Column chromatography was carried out on flash
silica gel (Merck 230-400 mesh). TLC analysis was conducted
on silica gel plates (Whatman). 1H and 13C NMR spectra were
recorded at 200 or 300 MHz with Bruker instruments. Chemi-

Novel Class of Inhibitors of Human Rhinovirus
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 55
oil was dissolved in 300 mL of toluene and 300 mL of hexane
and stirred vigorously with a mechanical stirrer. Ammonia gas
was then blown through a gas dispersion tube over the top of
this solution for 1 h. The resulting solid was filtered, and the
solvents were removed in vacuo. The solid was dissolved in
EtOAc/H2O and the organic layer washed with 1 N HCl,
saturated NaHCO3, and brine and then dried over Na2SO4.
The solvent was removed in vacuo, and the remaining solid
was recrystallized from EtOAc/hexane to yield 16.8 g (68%) of
the desired product: mp 138-141 °C; 1H NMR (200 MHz,
DMSO-d6) δ 7.80 (br s, 1H, CONH), 7.54 (dd, J ) 7.8, 2.3, 2H,
ArH), 7.41 (br s, 1H, CONH), 7.41-7.30 (m, 3H, ArH), 5.54
(s, 1H, ArCHBrCONH2); 13C NMR (DMSO-d6) δ 169.1, 133.8,
128.9, 128.8, 128.7, 49.9; MS (EI+) m/z 213 M+ (1), 169 (15),
134 (89), 91 (100).
product: 1H NMR (300 MHz, DMSO-d6) δ 7.78 (br s, 1H),
7.67-7.58 (m, 4H), 6.07 (s, 1H), 2.06 (s, 3H); FDMS (MeOH)
m/z 279 (M+). Anal. (C11H9F4NO4) C, H, N.
St ep 4: 2-Tr iflu or om et h yl-4-flu or om a n d elic Am id e.
O-Acetyl-2-trifluoromethyl-4-fluoromandelic amide (50.44 g,
180.8 mmol) was dissolved in 250 mL of MeOH and 84 mL of
diisopropylethylamine and then refluxed under N2 for 3 h.
Solvents were removed in vacuo, and the remaining solid was
recrystallized from EtOAc/hexanes yielding 40.9 g (95%) of a
white solid: 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.49 (m,
4H), 7.40 (br s, 1H),), 6.40 (d, 1H, J ) 5), 5.07 (d, 1H, J ) 5);
FDMS (MeOH) m/z 237 (M+). Anal. (C9H7F4NO2) C, H, N.
Step 5: 2-O-Tolu en esu lfon im id o-2-(2-tr iflu or om eth yl-
4-flu or op h en yl)a ceta m id e (3f). 2-Trifluoromethyl-4-fluoro-
mandelic amide (11.85 g, 50 mmol) was suspended in 400 mL
of CH2Cl2 under N2. Dimethylaminopyridine (500 mg, cata-
lytic), DIPEA (9.6 mL, 55 mmol), and p-toluenesulfonyl
chloride (10.5 g, 55 mmol) were added, and the reaction was
stirred overnight. Solvents were removed in vacuo and re-
maining solids dissolved in EtOAc. EtOAc was then washed
with saturated NaHCO3 (3 × 150 mL) and brine (3 × 150 mL)
and dried over Na2SO4. EtOAc was removed in vacuo and
remaining solid recrystallized from EtOAc/hexane yielding
17.8 g (91%) of a white solid: 1H NMR (300 MHz, DMSO-d6)
δ 7.84 (br s, 1H), 7.71-7.66 (m, 2H), 7.66 (d, 2H, J ) 8.2),
7.52-7.48 (m, 1H), 7.50 (dd, 1H, J ) 9.3, 2.6), 7.34 (d, 2H, J
) 8.2), 5.81 (s, 1H), 2.33 (s, 3H); FDMS (MeOH) m/z 392 (M +
H). Anal. (C16H13F4NO4S) C, H, N.
2-Br om o-2-(2,5-d iflu or op h en yl)a cet a m id e (3c): pre-
pared according to the procedure for 3b; 18.5 g (68%); mp 102-
1
104 °C; H NMR (300 MHz, DMSO-d6 δ 7.95 (br s, 1H), 7.61
(br s, 1H), 7.60-7.52 (m, 1H), 7.38-7.28 (m, 2H), 5.80 (s, 1H);
FDMS (MeOH) m/z 249 (M+).
2-Br om o-2-(2,3,4-tr iflu or op h en yl)a ceta m id e (3d ): pre-
pared according to the procedure for 3b; 10.2 g (76%); mp 82-
84 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.85 (br s, 1H), 7.6 (br
s, 1H), 7.4-7.3 (m, 2H), 5.80 (s, 1H); FDMS (MeOH) m/z 267
(M+).
2-Br om o-2-(3-tr iflu or om eth ylp h en yl)a ceta m id e (3e):
prepared according to the procedure for 3b; 14.25 g (52%); 1H
NMR (300 MHz, DMSO-d6) δ 7.90 (br s, 2H), 7.52-7.82 (m,
3H), 7.50 (s, 1H), 5.66 (s, 1H); FDMS (MeOH) m/z 281 (M+).
1-Ca r b a m oylm e t h yl-1,2-d ih yd r o-2-p -t olu e n e su lfon -
im id o-6-ben zoylp yr id in e (4a ). To a stirred suspension of 2
(11.65 g, 32.10 mmol) in 100 mL of dry DMF was added DIPEA
(6.34 mL, 34.20 mmol). After 15 min, the solution turned clear.
Iodoacetamide (6.74 g, 34.2 mmol) was added. The mixture
was stirred for 24 h and then poured onto water (2 L) and
stirred for an additional hour. Solid was collected and air-dried
2-O-Tolu en esu lfon im id o-2-(2-t r iflu or om et h yl-4-flu o-
r op h en yl)a cet a m id e (3f). St ep 1: 2-Tr iflu or om et h yl-4-
flu or om a n d elic Acid . 2-Trifluoromethyl-4-fluorobenzalde-
hyde (48.4 g, 252 mmol) and a catalytic amount of zinc iodide
(15 mg) were combined under N2. Trimethylsilyl cyanide (25
g, 252 mmol) was added dropwise over 20 min, and the
reaction was stirred overnight; 75 mL of 9 N HCl was then
added dropwise over 20 min and reaction refluxed overnight.
The cooled solution was then extracted with diethyl ether (3
× 500 mL). The combined ether layers were extracted with
saturated NaHCO3 (4 × 200 mL). The combined NaHCO3
layers were acidified to pH 1 with 5 N HCl and extracted with
diethyl ether (3 × 500 mL). The combined ether extracts were
dried over Na2SO4 and concentrated in vacuo. The resulting
white solid was recrystallized from CHCl3/hexanes yielding
50.1 g of a white solid (84%): mp 82-84 °C; 1H NMR (300
MHz, DMSO-d6) δ 7.70-7.66 (m, 1H), 7.57-7.52 (m, 2H), 5.20
(s, 1H); FDMS (MeOH) m/z 238 (M+). Anal. (C9H6F4O3) C, H.
Step 2: O-Acetyl-2-tr iflu or om eth yl-4-flu or om a n d elic
Acid . 2-Trifluoromethyl-4-fluoromandelic acid (49.4 g, 207.6
mmol) was dissolved in 150 mL of 30% HBr/HOAc and stirred
overnight. The reaction was then poured onto 3 L of ice and
immediately extracted with diethyl ether (3 × 500 mL). The
combined ether extracts were then dried over Na2SO4 and
removed in vacuo yielding 58 g of a white solid (quantitative):
1H NMR (300 MHz, DMSO-d6) δ 7.80-7.60 (m, 3H), 6.12 (s,
1H), 2.13 (s, 3H); FDMS (MeOH) m/z 280 (M+). Anal.
(C11H8F4O4) C, H.
Step 3: O-Acetyl-2-tr iflu or om eth yl-4-flu or om a n d elic
Am id e. O-Acetyl-2-trifluoromethyl-4-fluoromandelic acid (58
g, 207.6 mmol) in 150 mL of dry CH2Cl2 and 3 drops of DMF
were cooled in an ice bath under N2. Oxalyl chloride (500
mmol) in 25 mL of dry CH2Cl2 was added dropwise over 25
min. The ice bath was removed and the reaction stirred for 3
h. The solvents were removed in vacuo and then azeotroped
with toluene (3 × 25 mL). The remaining oil was dissolved in
100 mL of toluene and 600 mL of hexane and stirred vigorously
with a mechanical stirrer. Ammonia gas was then blown
through a gas dispersion tube over the top of this solution for
1 h. The resulting solid was filtered, and the solvents were
removed in vacuo. The solid was dissolved in EtOAc/H2O and
the organic layer washed with 1 N HCl, saturated NaHCO3,
and brine and then dried over Na2SO4. The solvent was
removed in vacuo, and the remaining solid was recrystallized
from EtOAc/hexane to yield 52.36 g (90%) of the desired
1
yielding 13.15 g (97%) of a white solid: mp 210-212 °C; H
NMR (200 MHz DMSO-d6) δ 8.54 (d, 1H, J ) 2.0, H6), 8.06
(dd, 1H, J ) 9.5, 2.0, H4), 7.79-7.64 (m, 5H, Ar), 7.57 (AA′BB′
system, 2H, J ) 7.6, tol), 7.47 (d, 1H, J ) 9.5, H3), 7.30 (AA′BB′
system, 2H, J ) 7.8, tol), 4.91 (s, 2H, CH2), 2.35 (s, 3H, CH3);
13C NMR (DMSO-d6) δ 191.0, 167.5, 156.1, 147.4, 142.0, 140.4,
136.6, 133.1, 129.6, 129.5, 129.0, 126.1, 119.9, 115.9, 54.8, 21.1;
MS (EI+) m/z 409 M+ (18), 345 (24), 328 (28), 287 (11), 254
(6), 209 (36), 182 (19), 155 (9), 105 (66), 91 (100), 77 (58); HRMS
calcd for C19H21N3O4S 409.1096, found 409.1105.
1,2-Dih yd r o-2-t olu e n e su lfon im id o-5-b e n zoyl-N -(1-
p h en ylca r ba m oylm eth yl)p yr id in e (4b): prepared accord-
ing to the procedure for 4a ; 14.0 g (96%); 1H NMR (300 MHz,
DMSO-d6) δ 8.17 (br s, 1H), 8.05 (dd, 1H, J ) 9.5, 2.2), 7.78
(s, 1H), 7.76 (d, 2H, J ) 8.2), 7.69 (s, 1H), 7.56 (d, 1H, J )
9.6), 7.55-7.53 (m, 1H), 7.43-7.28 (m, 11H), 6.84 (s, 1H), 2.34
(s, 3H); FDMS (MeOH) m/z 485 (M+). Anal. (C27H23N3O4S) C,
H, N.
1,2-Dih yd r o-2-tolu en esu lfon im id o-5-ben zoyl-N-[1-(2,5-
d iflu or op h en yl)ca r ba m oylm eth yl]p yr id in e (4c): prepared
according to the procedure for 4a ; 14.9 g (95%); 1H NMR (300
MHz, DMSO-d6) δ 8.28 (br s, 1H), 8.11 (dd, 1H, J ) 9.4, 2.3),
7.92 (br s, 1H), 7.81 (s, 1H), 7.75 (d, 2H, J ) 9.5), 7.64-7.60
(m, 2H), 7.53-7.42 (m, 6H), 7.36 (d, 2H, J ) 9.5), 7.12 (s, 1H),
7.06 (m, 1H), 2.38 (s, 3H); FDMS (MeOH) m/z 521 (M+). Anal.
(C27H21F2N3O4S) C, H, N.
1,2-Dih ydr o-2-tolu en esu lfon im ido-5-ben zoyl-N-[1-(2,3,4-
t r iflu or op h en yl)ca r ba m oylm et h yl]p yr id in e (4d ): pre-
pared according to the procedure for 4a ; 11.3 g (78%); 1H NMR
(300 MHz, DMSO-d6) δ 8.20 (br s, 1H), 8.05 (dd, 1H, J ) 9.4,
2.1), 7.90 (br s, 1H), 7.74-7.69 (m, 1H), 7.70 (d, 2H, J ) 8.1),
7.62-7.40 (m, 4H), 7.38-7.35 (m, 3H), 7.31 (d, 2H, J ) 7.4),
7.13 (s, 1H), 7.10 (m, 1H), 2.33 (s, 3H). Anal. (C27H20F3N3O4S)
C, H, N.
1,2-Dih yd r o-2-t olu en esu lfon im id o-5-b en zoyl-N-[1-(3-
t r iflu o r o m e t h y lp h e n y l)c a r b a m o y lm e t h y l]p y r id in e
(4e): prepared according to the procedure for 4a ; 12.7 g (76%);
1H NMR (300 MHz, DMSO-d6) δ 8.17 (br s, 1H), 8.07 (dd, 1H,
J ) 8.0, 3.0), 7.81-7.53 (m, 10H), 7.43-7.40 (m, 2H), 7.36-

56 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Hamdouchi et al.
7.29 (m, 4H), 6.87 (s, 1H), 2.33 (s, 3H); FDMS (MeOH) m/z
553 (M+). Anal. (C28H22F3N3O4S) C, H, N.
was cooled to -78 °C; 8.85 mL of triethyl phosphonoacetate
was added dropwise over a 10-min period. The reaction
mixture was allowed to warm to room temperature, and then
stirred at this temperature for 29 h (TLC: MeOH/CH2Cl2, 1:9).
The solvents were removed in vacuo at 35 °C, and the resulting
colorless liquid was used without further purification for the
Horner-Emmons reactions. The preparation of the Horner
reagent was repeated on a 30-g scale. The time required was
3 days. The colorless liquid was purified by distillation (0.5
mmHg/130 °C), 87% yield: 1H NMR (200 MHz, CDCl3) δ 7.05
(br s, 1H, NH), 4.07 (quintet, 4H, J ) 7.0, 2 × CH2O), 2.79 (d,
2H, J ) 24.9, CH2P), 2.74 (s, 3H, CH3), 1.22 (t, 6H, J ) 7.0, 2
× CH3-CH2O); 13C NMR (CDCl3) δ 164.5, 62.7, 62.6, 36.0, 33.5,
26.5, 16.2, 16.1.
2-Tr iflu or oa ceta m id o-6-[(E)-1-p h en yl-2-(N-m eth ylca r -
ba m oyl)vin yl]im id a zo[1,2-a ]p yr id in e (7a ). Meth od A: Di-
ethyl [(N-methylcarbamoyl)methyl]phosphonate (6) (1.88 g, 9
mmol) in 250 mL of dry THF was placed in a flame-dried flask
under Ar. The solution was cooled to -78 °C before the
dropwise addition of KHMDS (30 mL, 15 mmol; 0.5 M in
toluene). The mixture was stirred for 2 h at -78 °C. A solution
of 2-trifluoroacetamido-6-benzoylimidazo[1,2-a]pyridine (5a )
(2.0 g, 6.0 mmol) in 100 mL of dry THF was added dropwise.
The reaction mixture was stirred at -78 °C for 2 h and then
allowed to warm to room temperature. The resulting brown
solution was stirred at room temperature for 60 h. The THF
was evaporated in vacuo, and the mixture was diluted with
400 mL of EtOAc and washed with saturated NH4Cl (2 × 100
mL) and once with brine. After drying over MgSO4, the
solvents were removed in vacuo to give a red oil. The crude
was purified by column chromatography CH3CN/CH2Cl2 (2:1)
to give pure vinyl carboxamide 7a in 52% yield.
Meth od B: KHMDS (3 g, 15 mmol; solid) was dissolved in
40 mL of dry DMF under Ar at 0 °C. A solution of the diethyl
[(N-methylcarbamoyl)methyl]phosphonate (6) (1.12 g, 5.4 mmol)
in 10 mL of dry DMF was added. The reaction mixture was
stirred at 0 °C for about 1 h. A solution of 2-trifluoroacetamido-
6-benzoylimidazo[1,2-a]pyridine (5a ) (1.5 g, 4.5 mmol) in 10
mL of dry DMF was transferred via cannula. The bath was
removed, and the resulting clear brown solution was allowed
to warm to room temperature. After 18 h the reaction mixture
was quenched with saturated NH4Cl (30 mL) and extracted
with EtOAc (3 × 100 mL). The organic layers were combined
and washed with saturated NH4Cl and then with brine. After
drying over MgSO4, the solvent was removed in vacuo. 1H
NMR analysis of the crude showed only the desired E-isomer
along with traces of starting material. The crude was purified
by column chromatography (CH3CN/CH2Cl2, 1:2 then 1:1 then
2:1) to give 1.1 g (63% yield) of pure vinyl carboxamide 7a and
300 mg (20% yield) of recovered ketone: 1H NMR (200 MHz,
CDCl3) δ 8.02 (s, 1H, H3), 7.81 (s, 1H, H5), 7.49-7.27 (m, 7H,
Ar), 6.42 (s, 1H, CHdC), 5.29 (br d, 1H, J ) 5.0, NHMe), 2.63
(d, 3H, J ) 4.9, CH3); 13C NMR (CDCl3) δ 166.5, 162.2, 154.2,
138.6, 136.8, 129.3, 129.1, 128.5, 127.2, 126.1, 125.1, 123.0,
118.1, 116.0, 106.3, 103.3, 26.3; MS (EI+) m/z 388 M+ (100),
358 (36), 319 (42), 288 (13), 260 (20), 209 (13), 181 (8), 159 (7),
151 (8), 105 (11), 77 (18), 69 (16); HRMS calcd for C19H15N4O2F3
388.1147, found 388.1144.
1,2-Dih yd r o-2-t olu en esu lfon im id o-5-b en zoyl-N-[1-(2-
t r iflu o r o m e t h y l-4-flu o r o p h e n y l)c a r b a m o y lm e t h y l]-
p yr id in e (4f): prepared according to the procedure for 4a ;
14.46 g (84%); 1H NMR (300 MHz, DMSO-d6) δ 8.37 (br s, 1H),
8.06 (dd, 1H, J ) 9.5, 2.1), 7.92 (br s, 1H), 7.83 (dd, 1H, J )
9.1, 2.6), 7.64 (d, 2H, J ) 8.2), 7.58-7.53 (m, 3H), 7.48-7.36
(m, 6H), 7.28 (d, 2H, J ) 8.1), 7.00 (s, 1H), 2.32 (s, 3H); FDMS
(MeOH) m/z 571 (M+). Anal. (C28H21F4N3O4S) C, H, N.
2-Tr iflu or oa ce t a m id o-6-b e n zoylim id a zo[1,2-a ]p yr i-
d in e (5a ). To a suspension of 4a (7.15 g, 17.46 mmol) in 85
mL of dry CH2Cl2 was added trifluoroacetic anhydride (62 mL).
The mixture was stirred for 2.5 h at 30 °C under Ar. The
solvents were removed in vacuo, and the foam was taken up
in EtOAc (600 mL) and washed with NaHCO3 (2 × 250 mL)
and brine (1 × 250 mL). The organic layer was dried (Na2-
SO4), and solvents were removed in vacuo to afford 5.5 g (92%)
of product as a white solid: mp 233-235 °C; 1H NMR (200
MHz, CDCl3) δ 10.80 (br s, 1H, NH), 8.66 (s, 1H, H5), 8.24 (s,
1H, H3), 7.83-7.78 (m, 3H, Ar), 7.71-7.51 (m, 4H, Ar); 13C
NMR (DMSO-d6) δ 192.8, 141.8, 140.6, 137.0, 133.3, 133.1,
132.6, 129.5, 129.3, 128.6, 125.0, 122.5, 115.5, 104.3; MS (EI+)
m/z 333 M+ (100), 314 (9), 264 (49), 256 (37), 236 (7), 228 (7),
209 (8), 159 (8), 146 (6), 105 (52), 77 (53); HRMS calcd for
C
16H10N3O2F3 333.0725, found 333.0725.
2-Tr iflu or oa ceta m id o-3-p h en yl-6-ben zoylim id a zo[1,2-
a ]p yr id in e (5b): prepared according to the procedure for 5a ;
1
9.75 g (94%); mp 202-204 °C; H NMR (200 MHz, CDCl3) δ
10.9 (br s, 1H, NH), 8.69 (s, 1H, H3), 7.78-7.42 (m, 12H, Ar);
13C NMR (CDCl3) δ 192.9, 155.7, 154.9, 142.6, 136.6, 136.3,
133.0, 129.6, 129.4, 128.7, 128.6, 128.1, 127.0, 126.1, 124.3,
118.7, 116.2, 113.0; MS (EI+) m/z 409 M+ (100), 349 (73), 312
(7), 206 (11), 105 (61), 77 (76); HRMS calcd for C22H14F3N3O2
409.1038, found 409.1037. Anal. (C22H14F3N3O2) C, H, N.
2-Tr iflu or oa ce t a m id o-3-(2,5-d iflu or op h e n yl)-6-b e n -
zoylim id a zo[1,2-a ]p yr id in e (5c): prepared according to the
procedure for 5a ; 12.05 g (95%); mp 116-118 °C; 1H NMR (200
MHz, CDCl3) δ 11.1 (br s, 1H, NH), 8.50 (s, 1H, H5), 7.87-
7.78 (m, 3H, Ar), 7.70-7.49 (m, 5H, Ar), 7.30-7.11 (m, 2H,
Ar); 13C NMR (CD3OD) δ 194.4, 162.8, 160.0, 158.0, 155.1,
145.1, 138.9, 138.2, 134.1, 131.0, 130.8, 129.7, 127.7, 125.6,
120.2, 119.7, 119.5, 119.2, 119.0, 118.8, 118.5, 118.3, 118.6;
MS (EI+) m/z 445 M+ (100), 376 (66), 348 (5), 242 (5), 105 (30),
77 (36); HRMS calcd for C22H12F5N3O2 445.0850, found 445.0859.
Anal. (C22H12F5N3O2) C, H, N.
2-Tr iflu or oa ceta m id o-3-(2,3,4-tr iflu or op h en yl)-6-ben -
zoylim id a zo[1,2-a ]p yr id in e (5d ): prepared according to the
1
procedure for 5a ; 8.43 g (87%); mp 78-80 °C; H NMR (200
MHz, CDCl3) δ 9.31 (br s, 1H), 8.42 (s, 1H), 7.87-7.03 (m, 9H,
Ar); 13C NMR (CDCl3) δ 192.5, 162.5, 143.2, 140.4, 137.9, 136.4,
133.3, 130.8, 129.7, 129.1, 128.7, 128.3, 127.1, 124.7, 116.2,
113.3, 113.0; MS (EI+) m/z 463 M+ (100), 374 (71), 359 (10),
260 (6), 105 (49), 77 (52); HRMS calcd for C22H11F6N3O2
463.0755, found: 463.0760. Anal. (C22H11F6N3O2) C, H, N.
2-Tr iflu or oa cet a m id o-3-(3-t r iflu or om et h ylp h en yl)-6-
ben zoylim id a zo[1,2-a ]p yr id in e (5e): prepared according to
the procedure for 5a ; 10.17 g (93%); mp 217 °C; 1H NMR (200
MHz, CDCl3) δ 10.23 (br s, 1H, NH), 8.63 (s, 1H), 7.89-7.52
(m, 11H, Ar); 13C NMR (DMSO-d6) δ 191.5, 155.7, 142.2, 136.2,
132.2, 131.7, 129.9, 129.8, 129.7, 129.3, 129.0, 128.0, 127.7,
125.0, 124.8, 124.7, 124.6, 124.5, 122.4, 117.7, 116.3; MS (EI+)
m/z 477 M+ (100), 408 (69), 105 (36), 77(43); HRMS calcd for
No isomerization of the double bound was noticed when
compound 7a was kept in the presence of a catalytic amount
of TFA overnight or in CDCl3 for several weeks.
2-Tr iflu or oa cet a m id o-3-p h en yl-6-[(E)-1-p h en yl-2-(N-
m eth ylca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr id in e (7b). Tri-
fluoroacetamido-3-phenyl-6-benzoylimidazo[1,2-a]pyridine (5b)
(618 mg, 1.27 mmol) was converted to the desired product 7b
in a substantially analogous manner to 7a to yield 526 mg
(75%) after column chromatography (CH3CN/CH2Cl2, 1:1). 1H
NMR analysis of the crude showed only the E-isomer of the
desired product whose geometry was established by NOE
C
23H13F6N3O2 477.0912, found 477.0915. Anal. (C23H13F6N3O2)
C, H, N.
2-Tr iflu or oa ce t a m id o-3-(2-t r iflu r om e t h yl-4-flu or o-
p h en yl)-6-ben zoylim id a zo[1,2-a ]p yr id in e (5f): prepared
according to the procedure for 5a ; 11.0 g (88%); mp 189-191
°C; 1H NMR (200 MHz, CDCl3) δ 11.2 (br s, 1H, NH), 8.06 (s,
1H, H5), 7.80-7.40 (m, 10H, Ar); MS (EI+) m/z 495 M+ (100),
426 (62), 329 (9), 105 (26), 77 (35); HRMS calcd for C23H12F7N3O2
495.0818, found 495.0817. Anal. (C23H12F7N3O2) C, H, N.
Dieth yl [(N-Meth ylcar bam oyl)m eth yl]ph osph on ate (6).
A solution of 4.12 mL of methylamine in 8.30 mL of methanol
1
experiments: mp 225-227 °C; H NMR (200 MHz, CDCl3) δ
7.98 (s, 1H, H5), 7.58-7.23 (m, 12H, Ar), 6.34 (s, 1H, CHdC),
5.17 (br d, J ) 5.0, NHMe), 2.64 (d, 3H, J ) 5.0, CH3); 13C
NMR (acetone-d6) δ 170.8, 166.3, 145.3, 142.7, 142.2, 138.2,
135.6, 133.0, 129.8, 129.4, 129.0, 128.8, 128.6, 128.7, 126.9,

Novel Class of Inhibitors of Human Rhinovirus
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 57
125.4, 123.6, 123.3, 117.0, 25.5; MS (EI+) m/z 464 M+ (100),
395 (50), 365 (44), 338 (36), 235 (26), 209 (15), 166 (17), 104
(13), 77 (16); HRMS calcd for C25H19N4O2F3 464.1460, found
464.1464.
neutralized to pH 7 with HCl (5% aqueous solution) and
extracted with CHCl3 (3 × 50 mL). The combined organic
extracts were dried (Na2SO4), and the solvent was removed
at reduced pressure to yield 130 mg (58%) as a light-brown
solid: mp 97-99 °C; 1H NMR (200 MHz, CDCl3) δ 7.61 (d,
1H, J ) 1.4, H5), 7.47-7.41 (m, 3H, Ar), 7.33-7.27 (m, 3H,
Ar), 7.12 (dd, 1H, J ) 9.3, 1.8, H7 or H8), 6.77 (s, 1H, H3), 6.36
(s, 1H, CHdC), 5.13 (br d, 1H, J ) 4.9, NHMe), 3.90 (br s, 2H,
NH2), 2.62 (d, 3H, J ) 4.9, CH3NH); 13C NMR (CDCl3) δ 166.8,
151.0, 146.2, 142.4, 137.4, 129.2, 128.7, 128.6, 125.5, 124.6,
122.5, 121.4, 114.1, 94.4, 26.1; MS (EI+) m/z 292 M+ (100), 262
(32), 234 (20), 223 (15), 215 (13), 178 (8), 160 (10), 117 (6), 105
(9), 77 (9); HRMS calcd for C17H16ON4 292.1324, found
292.1328.
2-Tr iflu or oa cet a m id o-3-(2,5-d iflu or op h en yl)-6-[(E)-1-
p h en yl-2-(N-m eth ylca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr i-
d in e (7c). Trifluoroacetamido-3-(2,5-difluorophenyl)-6-ben-
zoylimidazo[1,2-a]pyridine (5c) (500 mg, 1.15 mmol) was
converted to the desired product 7c in a substantially analo-
gous manner to 7a to yield 483 mg (86%) after column
chromatography (CH3CN/CH2Cl2, 1:1). 1H NMR analysis of the
crude showed only the E-isomer of the desired product whose
geometry was established by NOE experiments: mp 134-136
°C; 1H NMR (200 MHz, CDCl3) δ 7.87 (s, 1H, H5), 7.62 (AA′BB′
system, 2H, J ) 9.2, H6 and H7), 7.40-7.28 (m, 8H, Ar), 6.56
(s, 1H, CHdC), 2.65 (s, 3H, CH3); 13C NMR (CD3OD) δ 169.4,
161.2, 148.1, 144.2, 140.3, 138.8, 134.2, 130.5, 129.7, 129.5,
129.4, 128.8, 127.5, 125.6, 123.4, 119.3, 119.0, 118.9, 118.6,
118.1, 117.6, 117.3; MS (EI+) m/z 500 M+ (100), 470 (42), 431
(26), 403 (16), 400 (17), 237 (11), 215 (9), 152 (9), 105 (11), 102
(10), 77 (11); HRMS calcd for C25H17N4O2F5 500.1272, found
500.1279.
2-Tr iflu or oa ceta m id o-3-(2,3,4-tr iflu or op h en yl)-6-[(E)-
1-p h en yl-2-(N-m et h ylca r b a m oyl)vin yl]im id a zo[1,2-a ]-
p yr id in e (7d ). The 2-trifluoroacetamido-3-(2,3,4-trifluoro-
phenyl)-6-benzoylimidazo[1,2-a]pyridine (5d ) (303 mg, 0.67
mmol) was converted to the desired product 7d in a substan-
tially analogous manner to 7a to give 168 mg (50%) after
column chromatography (CH3CN/CH2Cl2, 1:1). 1H NMR analy-
sis of the crude showed only the E-isomer of the desired
product whose geometry was established by NOE experi-
ments: mp 115-117 °C; 1H NMR (200 MHz, CDCl3) δ 7.85 (s,
1H), 7.71-7.15 (m, 10H, Ar), 6.48 (s, 1H, CHdC), 5.21 (m, 1H,
NHMe), 2.65 (d, 3H, CH3). Anal. (C25H16F6N4O2) C, H, N.
2-Am in o-3-p h en yl-6-[(E)-1-p h en yl-2-(N-m eth ylca r ba m -
oyl)vin yl]im id a zo[1,2-a ]p yr id in e (1b). 2-Trifluoroacet-
amido-3-phenyl-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]-
imidazo[1,2-a]pyridine (7b) (0.13 g, 0.26 mmol) was dissolved
in MeOH/DIPEA (4 mL, 1:1) and refluxed under Ar for 2 days.
The solvents were removed in vacuo, and the mixture was
purified by column chromatography (CH2Cl2/CH3CN/MeOH 55:
40:5) affording 1b as a yellow solid in 87% yield: mp 187-189
1
°C; H NMR (200 MHz, CD3OD) δ 2.60 (s, 3H), 6.44 (s, 1H),
7.20-7.42 (m, 12H), 7.91 (br s, 1H). Anal. (C23H20N4O) C, H,
N.
2-Am in o-3-(2,5-d iflu or op h en yl)-6-[(E)-1-p h en yl-2-(N-
m eth ylca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr id in e (1c). The
2-trifluoroacetamido-3-(2,5-difluorophenyl)-6-[(E)-1-phenyl-2-
(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7c) was con-
verted to the desired product 1c in manner substantially
analogous to 1b. After column chromatography (CH3CN/CH2-
Cl2, 1:1), 1c was isolated as a yellow solid in 82% yield: mp
1
162-164 °C; H NMR (200 MHz, CDCl3) δ 7.62 (dd, 1H, J )
2.1, 1.2, H5), 7.45-6.99 (m, 10H, Ar), 6.35 (s, 1H, H vinyl),
5.19 (d, 1H, J ) 4.9, NH), 4.18 (br s, 2H, NH2), 2.63 (d, 3H, J
) 5.0, CH3); 13C NMR (CDCl3) δ 166.8, 156.5, 149.6, 146.0,
143.0, 137.1, 129.2, 128.7, 128.1, 125.9, 124.0, 123.1, 121.8,
118.1, 117.9, 117.4, 116.1, 115.6, 114.2, 99.6, 26.2; MS (EI+)
m/z 404 M+ (100), 374 (17), 345 (12), 207 (9), 152 (7), 140 (7),
105 (7), 77 (11); HRMS calcd for C23H18N4OF2 404.1449, found
404.1448.
2-Tr iflu or oa cet a m id o-3-(3-t r iflu or om et h ylp h en yl)-6-
[(E)-1-p h en yl-2-(N-m eth ylca r ba m oyl)vin yl]im id a zo[1,2-
a ]p yr id in e (7e). 2-Trifluoroacetamido-3-(3-trifluorometh-
ylphenyl)-6-benzoylimidazo[1,2-a]pyridine (5e) (228 mg, 0.49
mmol) was converted to the desired product 7e in a substan-
tially analogous manner to 7a to give 228 mg (57%) after
column chromatography (CH3CN/CH2Cl2, 1:1). 1H NMR analy-
sis of the crude showed only the E-isomer of the desired
product whose geometry was established by NOE experi-
2-Am in o-3-(2,3,4-tr iflu or op h en yl)-6-[(E)-1-p h en yl-2-(N-
m eth ylcar bam oyl)vin yl]im idazo[1,2-a ]pyr idin e (1d). 2-Tri-
fluoroacetamido-3-(2,3,4-trifluorophenyl)-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7d ) was con-
verted to the desired product 1d in a manner substantially
analogous to 1b. After column chromatography (CH3CN/CH2-
Cl2, 1:1), compound 1d was isolated as a yellow solid in 91%
yield: 1H NMR (200 MHz, CDCl3) δ 7.70 (s, 1H), 7.44-7.00
(m, 9H, Ar), 6.63 (s, 1H, CHdC), 5.20 (br s, 1H, NH-CH3)
4.13 (br s, 2H, NH2), 2.62 (d, J ) 4.9, 3H, CH3); 13C NMR
(CDCl3) δ 166.7, 149.6, 137.1, 129.2, 129.1, 128.8, 128.6, 128.1,
128.0, 127.7, 126.1, 125.7, 123.9, 123.8, 123.6, 123.5, 123.1,
122.7, 122.6, 121.9, 121.8, 118.4, 114.4, 114.2, 112.7, 26.2; MS
(EI+) m/z 423 M+ (6), 422 (25), 392 (6), 353 (14), 259 (14), 105
(16), 84 (100); HRMS: (M+ - 1) 422.135830.
1
ments: mp 243 °C; H NMR (200 MHz, DMSO-d6) δ 9.19 (s,
1H), 8.03-7.23 (m, 11H, Ar), 6.57 (s, 1H, CHdC), 3.51 (s, 3H,
CH3); 13C NMR (DMSO-d6) δ 164.9, 160.2, 152.6, 141.5, 137.7,
137.0, 131.4, 129.8, 129.5, 128.8, 128.5, 128.2, 127.9, 127.3,
126.5, 125.2, 123.2, 122.7, 121.1, 116.8, 113.6, 24.8; MS (EI+)
m/z 532 M+ (100), 463 (41), 433 (79), 406 (47), 235 (52), 166
(25), 69 (14); HRMS (M+ - 2) 530.115540.
2-Tr iflu or oa cet a m id o-3-(2-t r iflu or om et h yl-4-flu or o-
p h en yl)-6-[(E)-1-p h en yl-2-(N-m et h ylca r b a m oyl)vin yl]-
im id a zo[1,2-a ]p yr id in e (7f). 2-Trifluoroacetamido-3-(2-tri-
flu or om et h yl-4-flu or op h en yl)-6-ben zoylim id a zo[1,2-
a]pyridine (5f) (500 mg, 1.04 mmol) was converted to the
desired product 7f in substantially analogous manner to 7a
to give 439 mg (79%) after column chromatography (CH3CN/
2-Am in o-3-(3-tr iflu or om eth ylp h en yl)-6-[(E)-1-p h en yl-
2-(N-m eth ylcar bam oyl)vin yl]im idazo[1,2-a ]pyr idin e (1e).
2-Trifluoroacetamido-3-(3-trifluoromethylphenyl)-6-[(E)-1-phen-
yl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7e) was
converted to the desired product 1e in a manner substantially
analogous to 1b. After column chromatography (CH3CN/CH2-
Cl2, 1:1), compound 1e was isolated as a yellow solid in 85%
1
CH2Cl2, 1:1). H NMR analysis of the crude showed only the
E-isomer of the desired product whose geometry was estab-
1
lished by NOE experiments: mp 144-146 °C; H NMR (200
MHz, CDCl3) δ 11.2 (br s, 1H, NH), 7.59-7.34 (m, 7H, Ar),
7.20-7.15 (m, 4H, Ar), 6.23 (s, 1H, CHdC), 5.18 (br d, 1H, J
) 4.8, NHMe), 2.60 (d, 3H, J ) 4.8, CH3-NH); 13C NMR
(CDCl3) δ 166.4, 165.4, 160.4, 155.1, 145.2, 141.8, 137.4, 136.6,
136.5, 136.3, 129.2, 129.1, 128.8, 128.5, 127.9, 126.1, 123.1,
122.8, 122.2, 119.9, 119.4, 115.9, 114.7, 114.4, 111.4, 26.2; MS
(EI+) m/z 550 M+ (100), 520 (37), 492 (10), 481 (14), 450 (11),
422 (12), 209 (6), 191 (6), 178 (9), 105 (7), 102 (7); HRMS calcd
for C26H17N4O2F7 550.1239, found 550.1237.
1
yield: mp 205 °C; H NMR (200 MHz, CDCl3) δ 7.83 (s, 1H),
7.64 (m, 11H, Ar), 6.42 and 6.38 (s, 1H, CHdC), 5.13 (br s,
1H, NH-CH3) 4.11 (br s, 2H, NH2), 2.62 (d, J ) 4.9, 3H, CH3);
13C NMR (CD3OD) δ 169.4, 150.6, 148.2, 143.6, 142.1, 139.0,
132.4, 131.3, 130.3, 129.4, 129.3, 127.7, 124.9, 123.4, 121.8,
118.7, 114.7, 26.1; MS (EI+) m/z 437 M+ (36), 436 (100), 406
(18), 377 (16), 279 (10), 77 (6); HRMS (M+ - 1) 436.151580.
2-Am in o-6-[(E)-1-p h en yl-2-(N-m eth ylca r ba m oyl)vin yl]-
im id a zo[1,2-a ]p yr id in e (1a ). 2-Trifluoroacetamido-6-[(E)-1-
phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7a)
(300 mg, 0.77 mmol) was stirred in the presence of 0.5 N NaOH
(17 mL) at room temperature for 5 h. The solution was
2-Am in o-3-(2-tr iflu or om eth yl-4-flu or op h en yl)-6-[(E)-1-
p h en yl-2-(N-m eth ylca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr i-
d in e (1f). 2-Trifluoroacetamido-3-(2-trifluoromethyl-4-fluoro-
phenyl)-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]-

58 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1
Hamdouchi et al.
pyridine (7f) was converted to the desired product 1f in a
manner substantially analogous to 1b. After column chroma-
tography (CH3CN/CH2Cl2, 1:1), compound 1f was isolated as
a green solid in 78% yield: mp 168-170 °C; 1H NMR (200
MHz, CDCl3) δ 7.52 (dd, 1H, J ) 8.4, H7 or H8), 7.47-7.16 (m,
9H, Ar), 6.94 (d, 1H, J ) 8.9, H7 or H8), 6.16 (s, 1H, CHdC),
5.39 (br d, 1H, J ) 4.6, NHMe), 3.92 (br s, 2H, NH2), 2.55 (d,
3H, J ) 4.7, CH3); 13C NMR (CDCl3) δ 166.7, 165.3, 160.3,
149.3, 146.2, 142.3, 137.1, 129.1, 128.5, 125.6, 123.7, 121.9,
121.7, 120.3, 119.9, 115.5, 114.9, 113.9, 100.4, 26.1; MS (EI+)
m/z 454 M+ (100), 424 (19), 395 (12), 356 (7), 279 (10), 209
(11), 77 (9); HRMS calcd for C24H18N4OF4 454.1416, found
454.1407.
) 6.8, (CH3)2CH); MS (EI+) m/z 366 M+ (33), 323 (100), 293
(18), 237 (15), 196 (10), 178 (7), 102 (6); HRMS calcd for
C
20H22N4OS 366.1514, found 366.1520.
2-Tr iflu or oacetam ido-3-isopr opylsu lfon yl-6-[(E)-1-ph en -
yl-2-(N-m et h ylca r b a m oyl)vin yl]im id a zo[1,2-a ]p yr id in e
(7i). To a solution of 2-trifluoroacetamido-3-iodo-6-[(E)-1-
phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7g)
(70 mg, 0.15 mmol) in 5 mL of THF cooled to -78 °C was added
PhLi (230 µL, 0.33 mmol) under Ar. The reaction mixture was
stirred for 3 min before injecting t-BuLi (310 µL, 0.38 mmol).
After stirring for a 10-min period, a solution of isopropyl
isopropanethiolsulfonate (109 mg, 0.60 mmol) in 5 mL of THF
was added. The reaction mixture was stirred for 30 min at
-78 °C and then quenched with 2 drops of water and 10 mL
of not dried THF. EtOAc (15 mL) was added; the mixture was
allowed to warm to room temperature. The solution was
filtered through Celite, and the solvents were removed in
vacuo. The residue was then dissolved in dry CH2Cl2 (10 mL)
and cooled to 0 °C. Previously dried m-CPBA (208 mg, 5 equiv
excess calculated over 100% theoretical yield of sulfide coupling
product) dissolved in CH2Cl2 (40 mL) was then added dropwise
until the complete oxidation to sulfone had finished (monitored
by TLC). The solution was washed with Na2SO3 (50 mL) and
NaHCO3 (2 × 50 mL). The organic layers were dried (Na2SO4),
and the solvent was evaporated in vacuo. The residue was
purified by flash chromatography in silica gel (CH3CN/CH2-
Cl2, 1:1) to give 47 mg of 7i as a white solid (63% yield): 1H
NMR (200 MHz, CDCl3) δ 9.81 (br s, 1H, NHCOCF3), 8.47 (s,
1H, H5), 7.76 (d, 1H, J ) 8.8, H7 or H8), 7.50-7.23 (m, 6H,
Ar), 6.42 (s, 1H, H vinyl), 5.28 (br d, 1H, J ) 4.8, NHMe), 3.28
(heptet, 1H, J ) 6.8, CH(CH3)2), 1.29 (d, 6H, J ) 6.8, CH3-
CH); MS (EI+) m/z 494 M+ (33), 425 (33), 388 (100), 358 (59),
319 (24), 292 (57), 288 (19), 260 (23), 237 (21), 205 (18), 178
(18), 105 (17), 83 (16), 58 (24); HRMS calcd for C22H21N4O4F3S
494.1235, found 494.1229.
2-Tr iflu or oa ce t a m id o-3-iod o-6-[(E )-1-p h e n yl-2-(N -
m eth ylca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr id in e (7g). To
a solution of 2-trifluoroacetamido-6-[(E)-1-phenyl-2-(N-meth-
ylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7a ) (423 mg, 1.22
mmol) in 20 mL of dry CH3CN cooled at 0 °C was added
N-iodosuccinimide (302 mg, 1.34 mmol) portionwise, and the
mixture was stirred for 10 min. The desired product precipi-
tated as a white solid which was filtered and air-dried
affording 375 mg of crude product. CH3CN was evaporated in
vacuo and the residue dissolved in EtOAc (50 mL) and washed
with (40% p/v) NaHSO3 (2 × 50 mL) and NaHCO3 (2 × 50
mL). The organic layer was dried (Na2SO4) and EtOAc removed
at reduced pressure, affording 240 mg (98% overall yield) of
7g as a white solid: mp 232-234 °C; 1H NMR (200 MHz,
CDCl3) δ 9.52 (br s, 1H, NHCOCF3), 7.83 (d, 1H, J ) 1.4, H5),
7.49-7.22 (m, 7H, Ar), 6.37 (s, 1H, CHdC), 5.21 (br d, 1H, J
) 4.9, NHMe), 2.65 (d, 3H, J ) 4.9, CH3); 13C NMR (DMSO-
d6) δ 165.2, 155.5, 154.8, 144.5, 144.1, 142.0, 137.7, 129.4,
128.3, 127.9, 125.7, 123.5, 118.8, 116.7, 113.0, 107.3, 25.4; MS
(EI+) m/z 514 M+ (49), 484 (11), 445 (7), 388 (100), 358 (54),
319 (18), 288 (23), 260 (37), 233 (6), 205 (16), 179 (16), 159
(14), 126 (13), 105 (13), 77 (15), 69 (18); HRMS calcd for
C19H14N4O2F3I 514.0114, found 514.0117.
2-Am in o-3-iodo-6-[(E)-1-ph en yl-2-(N-m eth ylcar bam oyl)-
vin yl]im id a zo[1,2-a ]p yr id in e (1g). Iodoimidazopyridine 7g
(135 mg, 0.46 mmol) was dissolved in CH2Cl2/MeOH (98:2, 15
mL). SiO2 was added to the solution, and the mixture was
stirred vigorously for 1 day. The conversion to the amine was
followed by TLC (CH2Cl2/CH3CN, 4:1). The residue was filtered
and the silica gel washed with CH3CN (10 mL). Removal of
the solvents gave the unstable compound 1g as a green-yellow
solid in 45% yield: mp 186-188 °C; 1H NMR (200 MHz, CDCl3)
δ 7.68 (d, 1H, J ) 1.7, H5), 7.47-7.41 (m, 3H, Ar), 7.35-7.24
(m, 3H, Ar), 7.06 (dd, 1H, J ) 9.3, 1.9, H7 or H8), 6.40 (s, 1H,
CHdC), 5.25 (br s, 1H, J ) 4.9, NH), 4.40-3.70 (br s, 2H, NH2),
2.64 (d, 3H, J ) 4.9, CH3).
No isomerization of the double bound was noticed when 7h
was kept in the presence of a catalytic amount of TFA
overnight or for several weeks in CDCl3.
2-Am in o-3-isop r op ylsu lfon yl-6-[(E )-1-p h e n yl-2-(N -
m eth ylcar bam oyl)vin yl]im idazo [1,2-a ]pyr idin e (1i). 2-Tri-
fluoroacetamido-3-isopropylsulfonyl-6-[(E)-1-phenyl-2-(N-
methylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7i) (45 mg, 0.09
mmol) was dissolved in a 1:1 mixture of MeOH/CH2Cl2, and
silica gel was added until a cake was obtained. The cake was
vigorously stirred for 2 days. After filtration through Celite,
the compound 1i was obtained as a white solid (33 mg, 89%):
mp 207-209 °C; 1H NMR (200 MHz, CDCl3) δ 8.46 (s, 1H, H5),
7.53-7.30 (m, 7H, Ar), 6.41 (s, 1H, CHdC), 5.30 (d, 1H, J )
4.8, NHMe), 5.17 (br s, 2H, NH2), 3.26 (heptet, 1H, J ) 7.0,
CH(CH3)2), 2.12 (d, 3H, J ) 4.8, CH3NH), 1.34 (d, 6H, J ) 7.0,
(CH3)2CH); MS (EI+) m/z 398 M+ (44), 292 (100), 262 (27), 233
(15), 215 (9), 205 (8), 178 (7), 77 (6), 58 (8); HRMS calcd for
2-Am in o-3-isop r op ylth io-6-[(E)-1-p h en yl-2-(N-m eth yl-
ca r ba m oyl)vin yl]im id a zo[1,2-a ]p yr id in e (1h ). To a solu-
tion of 2-trifluoroacetamido-3-iodo-6-[(E)-1-phenyl-2-(N-meth-
ylcarbamoyl)vinyl]imidazo[1,2-a]pyridine (7g) (72 mg, 0.15
mmol) in 5 mL of THF cooled to -78 °C was added phenyl-
lithium (230 µL, 0.33 mmol) under Ar. The reaction mixture
was stirred for 3 min before injecting t-BuLi (310 µL, 0.38
mmol). After the mixture stirred for a 10-min period, a solution
of isopropyl isopropanethiolsulfonate (109 mg, 0.60 mmol) in
5 mL of THF was added. The reaction mixture was stirred for
30 min at -78 °C and then quenched with 2 drops of H2O and
10 mL of THF. EtOAc (15 mL) was added, and the mixture
was allowed to warm to room temperature. The solution was
filtered through Celite, and the solvents were removed in
vacuo. Radial chromatography afforded the isopropyl sulfide
1h with the trifluoroacetyl group cleaved and the intermediate
7h in pure form. The ratio of intermediate/product depends
on the speed of the radial chromatography. The fraction of
trifluoroacetyl material 7h was mixed with silica gel in MeOH/
CH2Cl2 and the cake was stirred for 2 days. After filtration
the desired product 1h was obtained in 73% overall yield: mp
C
20H22N4O3S 398.1413, found 398.1413.
Dr u g Solu tion s for Biologica l Assa ys. Compounds were
dissolved in DMSO at 1000× concentrations and diluted
1/1000 into culture media (final concentration of DMSO )
0.1%). Although DMSO had no detectable effect on virus
replication, 0.1% DMSO was added to all no-drug control
samples.
Cytop a th ic Effect Assa y. The cytopathic effect (CPE)
assay was performed as described previously13 with a modi-
fication to the method of the quantification of the cytopathic
effect of virus on the cells. Instead of using crystal violet
staining, XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-
tetrazolium-5-carboxanilide) was used as substrate to quantify
the surviving host cells.14
P la qu e Red u ction Assa y. Susceptible H-HeLa cells were
grown in 60-mm diameter tissue culture dishes at 37 °C in
minimum essential medium with 10% newborn calf serum and
1% nonessential amino acids (medium A). When confluent
monolayers were formed, growth medium was removed, and
0.2 mL of medium A containing approximately 150 plaque-
forming units of rhinovirus-14 was added. After adsorption for
30 min at room temperature, the infected cell sheet was
1
112-114 °C; H NMR (200 MHz, CDCl3) δ 8.01 (d, 1H, J )
1.5, H5), 7.47-7.20 (m, 7H, Ar), 6.40 (s, 1H, CHdC), 5.20 (br
s, 1H, J ) 4.9, NHMe), 4.26 (br s, 2H, NH2), 2.97 (heptet, 1H,
J ) 6.8, CH(CH3)2), 2.65 (d, 3H, J ) 4.9, CH3), 1.13 (d, 6H, J

Novel Class of Inhibitors of Human Rhinovirus
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 1 59
(4) Heinz, B. A.; Vance, L. M. The Antiviral Compound Enviroxime
Targets the 3A Coding Region of Rhinovirus and Poliovirus. J .
Virol. 1995, 69, 4189-4197. (b) Heinz, B. A.; Vance, L. M.
Sequence Determinants of 3A-Mediated Resistance to En-
viroxime in Rhinoviruses and Enteroviruses. J . Virol. 1996, 70,
4854-4857.
(5) (a) Phillpotts, R. J .; DeLong, D. C.; Wallace, J .; J ones, R. W.;
Reed, S. E.; Tyrrell, D. A. Rhinovirus Infection in Man. Lancet
1981, 1/ 8234, 1342-1344. (b) Miller, F. D.; Monto, A. S.;
DeLong, D. C.; Exelby, A.; Bryan, E. R.; Srivastava, S. Controlled
Trial of Enviroxime Against Natural Rhinovirus Infections in a
Community. Antimicrob. Agents Chemother. 1985, 27, 102-106.
(6) (a) Enviradene (IND 20204); Virology Section, Summary; p 58,
unpublished results. (b) Enviradene (IND 20204); IND Protocol
No. 3; pp 1457-1461, unpublished results.
overlaid with equal parts of 1.6% sterile agarose solution and
a 2-fold concentration of medium A supplemented with MgSO4
(final concentration, 12 mM). Overlay media also contained
varying concentrations of the compounds to be tested. Plaque
assays were incubated at 35 °C for 48 h. A solution of 10%
formalin was added to each dish to inactivate the virus and
fix the cell sheet to the plastic surface. The fixed cell sheets
were stained with 0.5% crystal violet, and the plaques were
counted. Results from duplicate wells at each concentration
were averaged and compared with DMSO control wells. The
inhibition of plaque formation by 50% (IC50) was calculated
from the linear region of the inhibition-concentration curve
using the method of Reed and Muench.15
Ack n ow led gm en t. This research was supported by
the CDTI program (Plan Concertado 96/0036) and the
Spanish Farma III program (Ministerio de Industria y
Ministerio de Sanidad). We are also grateful to the Lilly
Rhinovirus Action Group for their advice and interest
in this work.
(7) Tebbe, M. J .; Spitzer, W. A.; Victor, F.; Miller, S. C.; Lee, C. C.;
Sattelberg, T. R.; McKinney, E., Sr.; Tang, J . C. Antirhino/
Enteroviral Vinyl Acetylene Benzimidazoles: A Study of Their
Activity and Oral Plasma Levels in Mice. J . Med. Chem. 1997,
40, 3937-3946.
(8) Kelley, J . L.; McLean, W.; Ronda, G. D.; Crouch, R. Synthesis
of 6-[[(Hydroxyimino)phenyl]methyl]-1-[(1-methylethyl)sulfonyl]-
1H-imidazo[4,5-b]pyridin-2-amine. An Aza Analogue of En-
viroxime. J . Heterocycl. Chem. 1990, 27, 1821.
(9) Ogata, M.; Matsumoto, H.; Shimizu, S.; Kida, S.; Wada, T.; Shiro,
M.; Sato, K. Synthesis and Antiviral activity of Sulfonamido-
benzophenon Oximes and Sulfonamidobenzamides. J . Med.
Chem. 1986, 29, 417-423.
(10) (a) Bochis, R. J .; Olen, L. E.; Fisher, M. H.; Reamer, R. A.; Wilks,
G.; Taylor, J . E.; Olson, G. Isomeric Phenylthioimidazo[1,2-a]-
pyridines as Anthelmintics. J . Med. Chem. 1981, 24, 1483. (b)
Montgomery, J . A. Secrist, A. A. In Comprehensive Heterocycle
Chemistry; Katritzky, A. R., Ed.; Pergamon Press: Oxford, 1984;
Chapter 4.10, p 607 and references therein. (c) Gueiffer, A.; Viols,
H.; Blache, Y.; Chavignon, O.; Teulade, J . C.; Aumelas, A.;
Chapat, J . P. Heterocycles 1994, 38, 55.
(11) Hay, L. A.; Mitchell, D. A. Regio and Stereocontrolled Method
for Preparing 3,3-Diarylacrylamides. Tetrahedron Lett. 1997, 38,
6533-6536.
(12) Attempts of N-detrifluoroacetylation of compound 7a using
Hu¨nig’s base failed to yield the desired amine. Instead the
reaction led to imidazo ring opening providing the aminopyridine
as the main product.
(13) Tang, J .; Colacino, J . M.; Larsen, S. H.; Spitzer, W. Virucidal
Activity of Hypericin Against Enveloped and Nonenveloped DNA
and RNA Viruses. Antiviral Res. 1990, 13, 313-326.
(14) Scudiero, D. A.; Shoemaker, R. H.; Paull, K. D.; Monk, A.;
Tierney, S.; Notziger, T. H.; Currens, M. J .; Seniff, D.; Boyd, M.
R. Evaluation of a Soluble Tetrazolium/Formazan Assay for Cell
Growth and Drug Sensitivity in Culture Using Human and
Other Tumor Cell Lines. Cancer Res. 1988, 48, 4827-4833.
(15) Reed, L. J .; Muench, H. A. A Simple Method of Estimating Fifty
Percent Endpoints. J . Am. Hyg. 1938, 27, 493-497.
Refer en ces
(1) (a) Couch, R. B. Rhinoviruses. In Virolgy; Fields, B. N., Ed.;
Raven Press: New York, 1990; Chapter 22, pp 607-629. (b)
Rueckert, R. R. Picornaviruses and their Replication. In Virolgy;
Fields, B. N., Ed.; Raven Press: New York, 1985; Chapter 32,
pp 705-738. (c) Monto, A. S.; Bryan, E. R. Ohmit, S. Rhinovirus
Infections in Tecumseh, Michigan: Frequency of Illness and
Number of Serotypes. J . Infect. Dis. 1987, 154, 43-49. (d) Blaas,
D.; Hofer, F.; Gruenberger, M.; Kowalski, H.; Machat, H.;
Kuechler, E.; Huettinger, M. Entry of Minor Group Human
Rhinoviruses into the Cell. Cellular Receptor for Animal Viruses;
Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY,
1994; pp 129-140. (e) Chapman, M. S.; Rossmann, M. G.
Comparison of the Surface Properties of Picornaviruses. Virology
1993, 195, 745-756.
(2) (a) Wikel, J . H.; Paget, C. J .; DeLong, D. C.; Nelson, J . D.; Wu,
C. Y. E.; Paschal, J . W.; Dinner, A.; Templeton, R. J .; Chaney,
M. O.; J ones, N. D.; Chamberlin, J . W. Synthesis of Syn and
Anti Isomers of 6-[[(Hydroxyimino)phenyl]methyl]-1-[(1-meth-
ylethyl)sulfonyl]-1H-benzimidazol-2-amine. Inhibitors of Rhi-
novirus Multiplication. J . Med. Chem. 1980, 23, 368-372. (b)
DeLong, D. C. Effect of Enviroxime on Rhinovirus Infections in
Humans. In Microbiology; Leive, L., Schlessinger, D., Eds.;
American Society for Microbiology: Washington, DC, 1984; pp
431-434. (c) DeLong, D. C.; Reed, S. E. Inhibition of Rhinovirus
Replication in Organ Culture by a Potential Antiviral Drug. J .
Infect. Dis. 1980, 141, 87-91.
(3) (a) Victor, F.; Loncharich, R.; Tang, J .; Spitzer, A. W. Synthesis
and Antiviral Activity of C2 Analogues of Enviroxime: An
Exploration of the Role of Critical Functionality. J . Med. Chem.
1997, 40, 3478-3483. (b) Victor, F.; Brown, T. J .; Campanale,
K.; Heinz, B. A.; Shipley, L. A.; Su, K. S.; Tang, J .; Vance, L.
M.; Spitzer, W. A. Synthesis, Antiviral Activity, and Biological
Properties of Vinylacetylene Analogues of Enviroxime. J . Med.
Chem. 1997, 40, 1511-1518.
J M9810405