Tetrasubstituted imidazole inhibitors of cytokine release: Probing substituents in the N-1 position

Article abstract of DOI:10.1021/jm0496584

We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory activity by using our previously described regiospecific synthesis. Systematic optimization of the imidazole N-1 substituent resulted in compound 9b that potently

Full text of DOI:10.1021/jm0496584

J. Med. Chem. 2004, 47, 6311-6325
6311
Tetrasubstituted Imidazole Inhibitors of Cytokine Release: Probing
Substituents in the N-1 Position†
Stefan A. Laufer,* Werner Zimmermann, and Kathrin J. Ruff
Department of Pharmacy, Institute of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tu¨bingen,
Auf der Morgenstelle 8, 72076 Tu¨bingen, Germany
Received May 6, 2004
We prepared novel 1,2,4,5-tetrasubstituted imidazole derivatives with high anti-inflammatory
activity by using our previously described regiospecific synthesis. Systematic optimization of
the imidazole N-1 substituent resulted in compound 9b that potently inhibited the mitogen-
activated protein kinase p38 (p38 IC50 ) 0.218 µM) as well as the release of the proinflammatory
cytokines interleukin-1â (ΙL-1â) and tumor necrosis factor R (TNFR) from human whole blood
after stimulation with LPS. Furthermore, compound 9b exhibited reduced cytochrome P450
interaction in comparison with SB203580. This result is particularly important, since
cytochrome P450 interaction is observed for some p38 inhibitors and in turn can potentially
cause drug-drug interaction or lead to other hepatic changes such as P450 enzyme induction.
Introduction
sequently, anti-cytokine treatments can be efficiently
used in the therapy of chronic inflammatory rheumatic
diseases. Biological cytokine inhibitors, such as soluble
TNFR receptors (Etanercept), IL-1 receptor antagonists
(Anakinra), or anti-TNF antibodies (Infliximab, Adali-
mumab), provide new therapeutic strategies for these
diseases.6,7 However, limitations of these biologicals are
adverse immunological reactions,6,8 and the therapy is
associated with high costs.9 There is still a lack of new
and effective small molecule disease modifying agents
that are orally active and more safe.
Inflammation is a defense reaction initiated by tissue
damage, injury, or infectious pathogens. The primary
objective of inflammation is to localize and eradicate the
irritant and to repair the surrounding tissue. Acute
inflammation exhibits a rapid onset and is maintained
only for a short duration. On the other hand, chronic
inflammation is an inflammatory response of prolonged
duration often leading to severe tissue damage. In some
cases, the stimulus to chronic inflammation may be an
endogenous tissue component, giving rise to a so-called
autoimmune disease.
A new therapeutic drug target for the treatment of
inflammatory disorders is the mitogen-activated protein
kinase (MAPK) p38.10-13 P38 is a serine/threonine
kinase that is part of the stress-activated signal trans-
duction cascade that transduces extracellular signals to
intracellular response, e. g. cytokine production.11,14,15
The p38-MAPK is activated through bis-phosphoryla-
tion of Thr and Tyr within a Thr-Gly-Tyr motif, which
is located in an activation or phosphorylation loop near
the active site. Activated p38 phosphorylates other
kinases or transcription factors, leading to mRNA
stabilization or expression of certain target genes.10,16-18
Pyridinylimidazoles (i.e. SB203580) are potent and
selective inhibitors of p38-MAPK7,19,20 by competing
with ATP for binding to the ATP pocket (Figure 1).21-23
In contrast to ATP, which only interacts with the
activated (bis-phosphorylated) kinase, pyridinylimida-
zoles also bind to the inactive form. The pyridinylimi-
dazole pharmacophore is defined as the 4-aryl-5-(pyridin-
4-yl)imidazole.24 The 4-aryl substituent occupies an
additional hydrophobic pocket generated mainly by the
Thr106 side chain, which is replaced by a bulky hydro-
phobic residue in most other protein kinases. Therefore,
this small hydrophobic pocket near the ATP-binding site
is responsible for the selectivity of SB203580 for p38
compared to most other kinases.22,25,26 The pyridin-4-yl
moiety is essential for the inhibitory potency and
generates a pivotal hydrogen bond with the amino
backbone of Met109 through its pyridinium nitro-
gen.27
Elevated levels of proinflammatory cytokines, espe-
cially tumor necrosis factor R (TNFR) and interleukin-
1â (IL-1â), are associated with several autoimmune
diseases1, including rheumatoid arthritis (RA)2, toxic
shock syndrome, osteoarthritis, and inflammatory bowel
disease. For example, RA is a chronic inflammatory and
destructive joint disease of unknown etiology. It affects
about 1% of the population worldwide and is character-
ized by a chronic inflammation of the synovium (syno-
vitis), which often leads to joint and bone destruction,
to significant disability, and consequently to a reduction
in quality of life. The cytokines mediate the inflamma-
tory response in association with other related mol-
ecules.3,4 It is well-established that TNFR and IL-1â are
key cytokines in the process of chronic inflammation and
the resulting tissue and bone destruction. Therefore, the
regulation of proinflammatory cytokines, mainly TNFR
and IL-1â, is of crucial importance in chronic inflam-
matory diseases such as RA.5 The ongoing evaluation
of the cytokine cascade and the steadily growing knowl-
edge about cytokine-mediated processes seem to open
striking therapeutical options in the fields of sepsis and
autoimmune and chronic inflammatory diseases via
modulation or inhibition of the cytokine cascade. Sub-
† Dedicated to Prof. Dr. Dannhardt on the occasion of his 60th
birthday.
* To whom correspondence should be addressed. Phone: +49 7071
2972459. Fax:
uni-tuebingen.de.
+49 7071 295037. E-mail:
stefan.laufer@
10.1021/jm0496584 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/10/2004

6312 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
Figure 2. Pyridinylimidazole inhibitors of p38-MAP kinase.
The piperidin-4-yl residue of SB235699 is supposed to interact
with Lys53, whereas the cyclopropylmethyl residue is assumed
to interact with Val30 and Val38.22
Figure 1. Representation of the active site interactions
between SB203580 and p38-MAPK. (modified from refs 19, 24,
and 27). The predicted hydrogen bonds and π-π-interaction
are indicated by broken lines.
Chemistry
In general, substitutions at the imidazole N-1 (adja-
cent to the azaheteroaryl) and the C-2 position are both
tolerated. However, substitution at the imidazole N-3
(adjacent to the aryl group) is not tolerated and causes
a loss of potency.24
The general synthesis of regiospecific tetrasubstituted
pyridin-4-ylimidazoles has previously been described
(Scheme 1).31-33 The starting material for all syntheses
was R-hydroximinoketone 6. Compound 6 was obtained
in three steps from nitrile 3. Condensation of activated
2-acetyl isonicotinic acid 1 with 4-fluorophenyl aceto-
nitrile 2 in DMF produced 3 with 62% yield. The nitrile
residue was hydrolyzed using 48% HBr. Due to this
acidic environment, decarboxylation of 3 occurred con-
currently with the cleavage of the acetyl moiety at the
aminopyridine, producing compound 4. Reintroduction
of the acetyl group was achieved by refluxing 4 in acetic
anhydride. Compound 6 was prepared by using isoamyl
nitrite, sodium methoxide, and methanol at room tem-
perature based on a standard procedure used in our
laboratory. In the following step, different residues at
the imidazole N-1 were introduced by using several
substituted triazines. The triazines were prepared ac-
cording to literature procedures.34-36 (For example, we
added paraformaldehyde to the stirred liquid primary
amine. The resulted clear solution could be used without
any purification step.) Depending on the corresponding
residues at the triazines, the imidazole N-oxides 7a-s
were obtained, which were converted into the thiones
8a-s by using 2,2,4,4-tetramethylcyclobutane-1,3-
dithione37 as sulfur donor. At this step, a second source
of diversity was introduced by substituting the thiones
8a-s. To generate compounds 9a-q, iodomethane was
used for the S-methylation. For compounds in the 10
series, 1-chloromethyl-4-methanesulfinylbenzene was
used. In both cases, Na2CO3 catalyzed the S-substitu-
tion. To synthesize compounds 11a-e starting from the
thiones 8a-c, tetramethylammonium iodide was uti-
lized as catalytic agent in THF (Scheme 2).
The major drawback of the therapeutical use of some
pyridinylimidazoles is the occurrence of severe adverse
effects. Some pyridinylimidazoles inhibitors have been
associated with CYP450 inhibition.24,28 Both the imi-
dazole ring itself and the pyridinyl substituent seem to
contribute to this adverse effect.29 Thus, the work
presented here aims to modify the pyridinylimidazole
SB203580 at the N-1 position to enhance its inhibitory
effects on p38-MAPK and to minimize its interference
with the CYP450 pathway. The low CYP450 interaction
potential can in theory be attained by changing elec-
tronic properties of both nitrogen heterocycles while
retaining all essential interactions with the active site
of p38. In a previous study,30 we identified a methyl-
sulfanyl residue as favorable substituent at the C-2
position. This group contributes low sterical hindrance,
thus allowing deep penetration of the inhibitor into the
ATP binding pocket and thereby leading to tighter
binding. Nevertheless, we tested different residues at
the imidazole C-2 in combination with our novel N-1
substituents to determine the importance of the C-2
substituent in combination with different N-1 substi-
tutents. Acetylation of 2-aminopyridine increases the
affinity of pyridinylimidazoles for p38-MAPK. This
higher affinity is not detected for a simple amino group
at the pyridine ring, suggesting that the amino group
of the 2-acetylaminopyridine generates a second hydro-
gen bond with the carbonyl group of Met109.31 There-
fore, we used acetylated 2-aminopyridines in our study.
The key objective of our study was the synthesis of
compounds with higher affinity for the p38-MAPK and
improved in vitro and in vivo potency combined with
reduced CYP450 interaction. We describe our investiga-
tion on the structure-activity relation of tetrasubsti-
tuted imidazoles, which led to the identification of the
methoxyethyl moiety as an optimal N-1 substituent,
combining significantly decreased CYP450 interference
and highly efficient inhibition of p38-MAPK activity
regardless of its C-2 substituent.
Biological Results and Discussion
Recently, 1,4,5-trisubstituted imidazoles have been
synthesized to demonstrate the effects of substitution
at imidazole N-1 [i.e. piperidin-4-yl (SB235699) and
cyclopropylmethyl (SB216995)] (Figure 2). The piperi-
din-4-yl residue was envisioned to interact with the
carboxyl group of Asp168,19 whereas the cyclopropylm-
ethyl residue was assumed to interact with the phos-

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6313
Scheme 1a
a Reagents: (a) carbonyldiimidazole, absolute DMF, potassium tert-butoxide, 120 °C; (b) 48% hydrobromic acid, reflux; (c) acetic anhydride,
4-(dimethylamino)pyridine, reflux; (d) isoamyl nitrite, sodium methoxide, methanol, rt; (e) substituted triazine, ethanol, reflux; (f) 2,2,4,4-
tetramethylcyclobutane-1,3-dithione, DCM, rt; (g) iodomethane, Na2CO3, ethanol, reflux; (h) 1-chloromethyl-4-methylsulfinylbenzene,
Na2CO3, ethanol, reflux.
Scheme 2a
phate-binding ribbon in a cavity formed by Val30 and
Val38.27 Previous work has demonstrated that tetra-
substituted imidazoles that were substituted with a
methyl group at N-1 of the imidazole have improved
selectivity and oral bioavailability.38 Therefore, we
studied the effects of substitution at N-1 in a much
wider range. We analyzed both inhibitions of p38-MAPK
and CYP450 and compared them to the inhibitory
functions of SB203580. It has been demonstrated that
1,4,5-trisubstituted imidazoles can interact with Asp168
a Reagents: (i) Na2CO3, THF, chloro-1-morpholin-4-ylalkan-1-
one, tetrabutylammonium iodide.
of p38-MAPK through the residue positioned at imida-
zole N-1.19,22 Thus, a variety of substituents were

6314 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
Table 1. Inhibition of P38-MAP Kinase by
Acetylaminopyridinesa
Figure 3. Model of 9c bound to the ATP-binding side of p38-
MAP kinase. The predicted hydrogen-bond interactions be-
tween 9c, Met109, Lys53, and Asp168 are displayed by yellow
dashed lines.
Figure 4. Model of a spatially unfavorable conformation of
9c, hindering the compound to bind to the p38-MAPK. The
expected intramolecular hydrogen bond is depicted by a yellow
dashed line.
conformation than 9a because of its elongated flexible
alkyl side chain; hence, it has a lower inhibitory activity.
Compound 9e presumably lost its potency due to its
elongated spacer, corroborating the assumption that
biological activity depends on the length of the side
chain in the case of our tetrasubstituted imidazoles. A
possible explanation for the loss in potency of 9f could
be the sterical conformation of this branched residue
at the imidazole N-1, thus hindering the compound to
penetrate deeply into the ATP binding pocket. However,
this conflicts with literature data, in which branching
was tolerated in the case of some other pyridinylimi-
dazoles.39 Substitution of the hydroxyl groups of 9a and
9c with a methoxy group provided 9b and 9d, respec-
tively. This resulted in a 2-fold improvement of p38
inhibition (Table 1) compared to SB203580. We assumed
that the ether was not able to take the same spatial
conformation as the alcohol (Figure 4) and could there-
fore possibly take a sterical conformation allowing the
interaction of its oxygen atom with the hydroxyl hydro-
gen of Asp168. Contrarily, this improved inhibitory
potency could not be observed in the whole blood assay
in comparison to SB203580 (Table 2). Compounds 9a-d
inhibited the release of both cytokines with similar IC50
values. The different trends in the enzyme assay and
a Results are given as mean of two independent experiments
except stated otherwise.
introduced at N-1 (10a-q) and the the C-2 substituent
(a methylsulfanyl group) was kept constant. Theoreti-
cally, substitution at the imidazole N-1 position with
hydroxyalkyl residues (9a,c,e,f) should result in en-
hanced inhibitory potency compared to SB203580. This
is due to the fact that alcohols could interact via a
hydrogen bond to the carboxyl group of Asp168. Com-
pound 9a displayed a considerable inhibition of p38-
kinase activity comparable to SB203580, whereas 9c
showed a decrease. Compounds 9e and 9f showed a loss
of inhibitory potency (Table 1) compared to the reference
compound SB203580. On one hand, it can be assumed
that 9a and 9c have the ability to interact with Asp168
(Figure 3). On the other hand, the hydroxyalkyl sub-
stituent could force these compounds into a spatially
unfavorable conformation hindering an optimal interac-
tion of the compounds with the active side of the kinase
(Figure 4). 9c was more likely to take the unfavorable

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6315
Table 2. Inhibition of Cytokine Release by
Table 3. Inhibition of P38-MAP Kinase by
Methylsulfinylbenzylmethylsulfanyl-Substituted Imidazole
Compoundsa
Acetylaminopyridinesa
a Results are given as mean of two independent experiments
except stated otherwise.
the whole blood assay could be ascribed to differences
in transport, membrane penetration, intracellular dis-
tribution, or metabolic effects. Given the benefit in
potency gained from the presence of the methoxyethyl
residue in 9b, we wanted to determine whether the
oxygen atom was necessary for the improved inhibitory
potency. Comparing 9b and 9k, we came to the conclu-
sion that the loss of potency of 9k (Table 1) can be
attributed to the reduced electronegativity around the
sulfur atom, leading to a weaker hydrogen bond with
Asp168. In addition, it can also be explained by the
larger atom radius of sulfur. The decreased inhibitory
potency compared to SB203580 was not seen in the
whole blood assay (Table 2) in which 9b and 9k showed
comparable inhibition of cytokine release (Table 2).
Substitution of the hydroxyl group of 9a with an allyloxy
residue (9i) led to decreased activity (Table 1), presum-
ably due to sterical hindrance. In contrast, hydroxyl
substitution in 9a with a propynyloxy residue (com-
pound 9j) resulted in a 3-fold increased inhibition of p38
kinase compared to 9i and only moderately decreased
inhibition compared to SB203580 (Table 1). This could
result from π-π interactions immobilizing the flexible
side chain in a favorable spatial conformation, thereby
causing a tighter binding to the kinase. Similar to the
p38 kinase values, 9i showed less potency in the whole
blood assay than 9j, which was comparable to 9a-d in
the whole blood assay (Table 2). Compound 9g was
expected to be capable of forming two hydrogen bonds
with Asp168. However, contrary to theory, there was
a Results are given as mean of two independent experiments
except stated otherwise.
no improvement noted in p38 kinase inhibitory potency
(Table 1). We supposed that this could be due to a
sterical handicap that prevents the tight binding to p38
kinase. The compounds 9l and 9m possessed a branched
side chain at imidazole N-1 and, in accordance with
their assumed sterical hindrance, demonstrated de-
creased p38 kinase inhibitory potency (Table 1). The
morpholinopropyl residue at imidazole N-1 in trisub-
stituted imidazoles has been described to give margin-
ally better results than the morpholinoethyl residue.40
In contrast, we found that the 2-carbon spacer in 9n
led to a 3-fold better result than the three-carbon spacer
in compound 9o (Table 1). Accordingly, compound 9p,
containing a two-carbon spacer, had approximately the
same inhibitory potency as compound 9n (Table 1). On
the basis of the comparison between compounds 9p and
9n, it can be assumed that the oxygen in the morpholine
ring is not necessary for the inhibitory potency. The
compound with the weakest activity was 9q (Table 1)
substituted at N-1 with a piperidine-1-carboxylic acid
ethyl ester. In an overall perspective, we found in-
creased inhibitory potency in vitro only for the com-
pounds 9b and 9d.
In the next step, we synthesized compounds in the
10 series with a 4-methylsulfinylbenzylsulfanyl residue
at the C-2 position of the imidazole ring to analyze

6316 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
Table 4. Inhibition of P38-MAP Kinase by
CYP450 enzymes were predominantly inhibited by
lipophilic compounds. Hence, the decreased inhibition
demonstrated by 9e (below 40%) for all the five tested
isoforms was attributed to the increase in polarity
resulting from the introduction of the hydroxyethoxy-
ethyl side chain. Introduction of the more lipophilic
methoxyethyl residue 9b showed high affinity for only
two of the five tested isoforms (Table 5) in contrast to
SB203580, which is a potent inhibitor of all five tested
isoforms.
Morpholine-Substituted Imidazolesa
Conclusion
A novel structural class of tetrasubstituted imidazoles
of p38-MAPK was optimized by imidazole N-1 substitu-
tions. We have shown that branched substituents, as
well as spatially dispersed substituents, at the N-1
position resulted in reduced inhibitory potency. This is
somewhat incongruent with literature data from Jack-
son.39 A hypothetical explanation could be an unfavor-
able spatial conformation, which was suggested to
hinder the compounds to fit deeply into the ATP pocket
for tight binding. However, further investigations such
as X-ray studies are necessary to clarify this point.
Furthermore, our results demonstrate that in this class
of compounds the unbranched hydroxyalkyl 9a and 9c
and methoxyalkyl 9b and 9d containing two- or three-
carbon spacers led to significant inhibition of cytokine
release in comparison to SB203580. The methoxyethyl
residue, assumed to build a hydrogen bond to Asp168,
had good inhibitory potency independent from C-2
substitution. In addition, introduction of the methoxy-
ethyl side chain caused loss of interaction with three of
five tested CYP450 isoforms. Large polar substituents
at imidazole N-1 (i.e. compound 9e) were in this case
unfavorable for p38-inhibition but showed diminished
CYP450 interaction for all tested CYP450 isoforms.
In conclusion, we have synthesized novel tetrasub-
stituted imidazoles with higher inhibitory potency for
p38-MAPK in vitro and lower inhibition of CYP450
isoforms than SB203580.
a Results of a single experiment are given except stated other-
wise.
Table 5. Inhibition (%) of Five CYP450 Isoforms by Selected
Compounds at 10 µM
compd
1A2
2C9
2C19
2D6
3A4
SB203580
61
0
75
85
67
61
62
38
97
9b
9e
9p
23.5
18.5
5
70.5
19
3.5
0
0
12
41
77.5
whether the combination of a large residue at C-2 and
different residues at N-1 contributed to increased p38
inhibition. The result was a loss in potency for all tested
substances, except for the methoxyethyl-substituted
compound 10b (Table 3).
In the last part of this study, we focused on novel
residues at the C-2 position of the imidazole ring and
synthesized the morpholin-4-ylalkan-1-ones 11a-e. This
moiety was reported to interact via a hydrogen bond
with Arg173. The effect was the same as for the
compounds in the 10 series. All compounds except 11d
presented a decreased inhibitory potency (Table 4). In
conclusion, N-1 methoxyethyl substitution is superior,
regardless of C-2 residues.
CYP450 Affinity. Both pyridine and imidazole ring
systems are known to be ligands for ferric heme iron in
cytochrome P450. Compounds possessing these hetero-
cyclic rings are often inhibitors of P450 enzymes. The
reference compound SB203580 is a potent inhibitor of
human liver P450 isozymes. At a concentration of 10
µM, it displayed more than 60% inhibition of five
isoforms of cytochrome P450 (Table 5). Recently, suc-
cessful modifications of the 4-pyridyl group have been
described which established p38 inhibitors with signifi-
cantly decreased CYP450 inhibition, including our (2-
acetylaminopyridin-4-yl)imidazole.33 Further modifica-
tions were made in this study to reduce affinity for
CYP450 compared to SB203580. Therefore, we tested
the most active compounds, 9b, 9e, 9p, at a concentra-
tion of 10 µM for their inhibition of five CYP450
isoforms. These novel compounds showed on average
significantly lower inhibition of CYP450. In general,
Experimental Section
Biological Evaluation. Biological profiles of compounds
in this paper were evaluated according to the methods
described as follows.
Whole Blood Assay.41 Test compounds were prepared by
serial dilution in Cremophor EL/ethanol (1:1). Blood of healthy
human contributors was preincubated for 15 min (37 °C, 5%
CO2) with test compounds or 1% Cremophor EL/ethanol as
control samples. Cytokine production was stimulated by
addition of LPS (1 µg/mL) to each sample and adjacent
incubation for 4 h (37 °C, 5% CO2). The reaction was termi-
nated by cooling in an ice bath. The concentrations of the
proinflammatory cytokines TNFR and Il-1â were determined
(after centrifugation) in the supernatant by using commercial
ELISA (Beckman Coulter Immunotech). Anticytokine activity
was determined by comparing the percent reduction of cytok-
ine concentration in test samples to control samples. Results
are given as IC50 values (µM).
p38-MAPK Assay.42 The inhibitors were dissolved in
DMSO, and the final maximal DMSO concentration was kept
below 1%. An Immulon 4HBX plate was coated with ATF-2
(activating transcription factor 2) by filling each well with 50
µL of an ATF-2 solution (10 µg/mL) followed by incubation for
90 min (37 °C). The plate was thoroughly washed with
ultrapure H2O, then free capacities were blocked with blocking
buffer (BB) containing Tween 20 (0.05%), BSA (0.25%), and
NaN3 (0.02%) in TBS and then washed again with ultrapure
H2O. A KB p38 solution was prepared by solution of p38-MAP

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6317
8.5-8.55 (m, 2H, 4-Pyr), 10.72 (s, 1H, NH); IR (ATR) 1682
kinase (10 µL p38 parent solution) in KB1 buffer (8990 µL).
The KB1 buffer contains 50 mM Tris (pH 7.5), 10 mM MgCl2,
10 mM â-glycerophosphate, 100 µg/mL BSA, 1 mM DTT, 10
µM rATP, and 0.1 mM Na3VO4. Different concentrations of
the test compounds were preincubated for 2 min (37 °C) in
KB p38 buffer. The preincubated samples were transferred to
the wells of the coated plate and incubated for 1 h (37 °C).
The plate was thoroughly washed with ultrapure H2O, blocked
with BB, and washed with ultrapure H2O. The wells were then
incubated for 1 h with phospho-ATF-2-antibody solution (NEB
Cell Signaling) composed of 7 mL of BB and 3.5 µL of antibody.
The plate was washed with ultrapure H2O and incubated for
1 h (37 °C) with anti-rabbit IgG-AP-antibody solution (Santa
Cruz Biotechnology) containing 7 mL of BB and 3.5 µL of
antibody. The plate was thoroughly washed with ultrapure
H2O. In each well, 100 µL of 4-nitrophenol phosphate was
added and the plate was incubated for about 1.5 h. The optical
density was measured at 405 nm. Inhibition of p38-MAP
kinase was determined by comparing the percent reduction
of the phospho-ATF-2 concentration in test samples to control
samples. Control samples contained only KB p38 buffer
without an inhibitor. Results are given as IC50 values (µM).
Cytochrome P450 Assay. The inhibition of cytochrome
P450 isoenzymes by selected compounds was determined at a
concentration of 10 µM in phosphate buffer (pH 7.4, 0.1%
DMSO) as reported previously.43
General. All reagents and solvents were of commercial
quality and used without further purification as received,
unless noted otherwise. Melting points were measured on a
Bu¨chi B-545 melting point apparatus and were thermo-
dynamically corrected. 1H NMR spectra were collected on a
Bruker Advance 200 Spectrospin at 200 MHz. Chemical shifts
were reported in parts per million relative to TMS as internal
standard. Infrared spectra were recorded by ATR technique
on a Perkin-Elmer Spectrum One spectrometer.
(NHCdO), 1224 (C-F), cm-1
.
N-{4-[2-(4-Fluorophenyl)-2-hydroxyiminoacetyl]pyri-
din-2-yl}acetamide (6). A 30% sodium methoxide solution
(8.4 g) was diluted with methanol (120 mL). Isoamyl nitrite
(4.8 g, 41.0 mmol) was added to the solution. The reaction
mixture was stirred at room temperature, at which point, 5
(12.0 g, 44.06 mmol) was added over 2 h in portions. After
stirring the mixture for 2 h at room temperature, the reaction
solvent was removed in vacuo and the resulting residue was
dissolved in ice water. The aqueous solution was neutralized
with 10% HCl to precipitate 6. The precipitate was filtered,
washed with diethyl ether, and dried in vacuo to give 6 (6.5 g,
1
54%): mp 162.5 °C; H NMR (DMSO-d6) δ 2.11 (s, 3H, CO-
CH3), 7.24-7.33 (m, 2H, 4-F-Ph), 7.39-7.42 (m, 1H, 4-Pyr),
7.51-7.58 (m, 2H, 4-F-Ph), 8.39 (s, 1H, 4-Pyr), 8.42-8.45 (m,
1H, 4-Pyr), 10.68 (s, 1H, -NH)
Preparation of N-{4-[5-(4-Fluorophenyl)-1-oxy-3-alkyl-
3H-imidazol-4-yl]pyridin-2-yl}acetamides 7a-n, General
Procedure A. A solution of 6 (1 equiv) and a 1,3,5-trialkyl-
[1,3,5]triazinane (1 equiv) in absolute ethanol was heated
under reflux for ca. 6 h. After cooling to room temperature,
the mixture was evaporated in vacuo. Trituration with Et2O
gave compounds 7a-n.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(2-hydroxyethyl)-3H-
imidazol-4-yl]pyridin-2-yl}acetamide (7a). This compound
was prepared from 6 (2.0 g, 6.64 mmol) and 3-[3,5-bis(2-
hydroxyethyl)[1,3,5]triazinan-1-yl]ethan-1-ol (1.45 g, 6.64 mmol)
according to general procedure A. Trituration with Et2O
yielded 7a (1.69 g, 71%): mp 206.6 °C; 1H NMR (DMSO-d6) δ
2.06 (s, 3H, CO-CH3), 3.37 (t, 2H, J ) Hz, O-CH2), 3.91 (t,
2H, J ) 5.06 Hz, N-CH2), 7.04-7.27 (m, 3H, 4-F-Ph, 4-Pyr),
7.46-7.53 (m, 2H, 4-F-Ph), 8.03 (s, 1H, 4-Pyr), 8.35-8.37 (m,
1H, 4-Pyr), 8.53 (s, 1H, C2-H), 10.69 (s, 1H, NH); IR (ATR)
1694 (HNCdO), 1220 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(2-methoxyethyl)-3H-
imidazol-4-yl]pyridin-2-yl}acetamide (7b). This compound
was prepared from 6 (2.0 g, 6.64 mmol) and 1,3,5-tris(2-
methoxyethyl)[1,3,5]triazinane (2.61 g, 6.64 mmol) according
to general procedure A. Trituration with Et2O yielded 7b (2.03
g, 82%): mp 222.3 °C; 1H NMR (DMSO-d6) δ 2.06 (s, 3H, CO-
CH3), 3.17 (s, 3H, O-CH3), 3.50 (t, 2H, J ) 4.98 Hz, O-CH2),
4.01 (t, 2H, J ) 4.98 Hz, N-CH2), 7.02-7.05 (m, 1H, 4-Pyr),
7.10-7.19 (m, 2H, 4-F-Ph), 7.47-7.54 (m, 2H, 4-F-Ph), 8.04
(s, 1H, 4-Pyr), 8.35-8.37 (m, 1H, 4-Pyr), 8.53 (s, 1H, C2-H),
10.69 (s, 1H, N-H)
N-{4-[2-Cyano-2-(4-fluorophenyl)acetyl]pyridin-2-yl}-
acetamide (3). To a stirred solution of 2-acetylaminoisonico-
tinic acid 1 (18.0 g, 0.1 mol) in THF (50 mL) was added
carbonyldiimidazole (17.0 g, 0.1 mol) over 30 min. The reaction
was stirred at room temperature for 45 min. 4-Fluoropheny-
lacetonitrile 2 (14.9 g, 0.11 mol) was added to the solution. At
this point, potassium tert-butoxide (14.6 g, 0.13 mol) was
added. The reaction was heated to 120 °C for 2 h, cooled to
room temperature, and then stirred for an additional 12 h at
room temperature. The addition of ice and neutralization with
concentrated HCl led to the precipitation of crude 3. The
precipitate was collected by filtration; washed with cold H2O,
cold methanol, and petroleum ether; and dried to give 3 (8.43
N-{4-[5-(4-Fluorophenyl)-3-(hydroxypropyl)-1-oxy-3H-
imidazol-4-yl]pyridin-2-yl}acetamide (7c). This compound
was prepared from 6 (5.0 g, 16.6 mmol) and 1-[3,5-bis(3-
hydroxypropyl)[1,3,5]triazinan-1-yl]propan-1-ol (4.38 g, 16.6
mmol) according to general procedure A. Trituration with Et2O
1
g, 62%): mp 257 °C; H NMR (DMSO-d6) δ 2.12 (s, 3H, CO-
CH3), 7.19-7.31 (m, 3H, 4-Pyr und 4-F-Ph), 7.75-7.82 (m, 2H,
4-F-Ph), 8.27 (s, 1H, 4-Pyr), 8.42-8.45 (m, 1H, 4-Pyr); IR (ATR)
1707 (NHCdO), 1234 (C-F) cm-1. C16H12FN3O2 (Mr 297.29)
1
yielded 7c (4.5 g, 73%): mp 214.2 °C; H NMR (DMSO-d6) δ
1.81 (quint, 2H, J ) 6.43 Hz, -CH2-), 2.08 (s, 3H, CO-CH3),
3.19 (t, 2H, J ) 5.98 Hz, O-CH2), 3.92 (t, 2H, J ) 6.94 Hz,
N-CH2), 7.01-7.07 (m, 1H, 4-Pyr), 7.09-7.19 (m, 2H, 4-F-
Ph), 7.49-7.52 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.36-8.37
(m, 1H, 4-Pyr), 8.35 (s, 1H, C2-H), 10.69 (s, 1H, N-H)
1-(2-Aminopyridin-4-yl)-2-(4-fluorophenyl)ethanone (4).
A solution of 3 (27.9 g, 93.9 mmol) in hydrobromic acid (48%)
(500 mL) was heated under reflux for about 30 h. After cooling
to room temperature, the reaction mixture was poured on ice
and made basic with concentrated NH3. The precipitated solids
were filtered; washed with cold H2O, cold methanol, and
petroleum ether; and dried to give 4 (10.81 g, 50%): mp 157.0
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(3-methoxypropyl)-
3H-imidazol-4-yl]pyridin-2-yl}acetamide (7d). This com-
pound was prepared from 6 (2.0 g, 6.64 mmol) and 1,3,5-tris(3-
methoxypropyl)[1,3,5]triazinane (2.01 g, 6.64 mmol) according
to general procedure A. Trituration with Et2O yielded 7d (1.82
g, 71%): mp 213.2 °C; 1H NMR (DMSO-d6) δ 1.82 (quint, 2H,
J ) 6.42 Hz, -CH2-), 2.06 (s, 3H, CO-CH3), 3.09 (s, 3H,
O-CH3), 3.21 (t, 2H, J ) 5.90 Hz, O-CH2), 3.92 (t, 2H, J )
6.94 Hz, N-CH2), 7.03-7.06 (m, 1H, 4-Pyr), 7.10-7.19 (m, 2H,
4-F-Ph), 7.47-7.54 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.36-
8.38 (m, 1H, 4-Pyr), 8.61 (s, 1H, C2-H), 10.71 (s, 1H, N-H); IR
(ATR) 2867 (O-CH3), 1682 (HNCdO), 1555 (HNCdO), 1215
1
°C; H NMR (DMSO-d6) δ 4.31 (s, 2H, -CH2-), 6.32 (s, 2H,
-NH2), 6.94-6.99 (m, 2H, 4-Pyr), 7.09-7.18 (m, 2H, 4-F-Ph),
7.23-7.30 (m, 2H, 4-F-Ph), 8.06-8.09 (m, 1H, 4-Pyr); IR (ATR)
1697 (NHCdO), 1243 (C-F) cm-1
.
N-{4-[2-(4-Fluorophenyl)acetyl]pyridin-2-yl}acet-
amide (5). To suspension of 4 (12.0 g, 52.2 mmol) in acetic
anhydride (100 mL) was added a catalytic amount of 4-DMAP.
The suspension was heated under reflux for 7 h. After cooling
to room temperature, ice water was added to the suspension.
The pH was adjusted with concentrated NH3 to pH 8 with
subsequent precipitation of 5. The precipitate was filtered,
washed with cold water and petroleum ether, and then dried
to give 5 (12.79 g: 90%): mp 140.9 °C; 1H NMR (DMSO-d6) δ
2.11 (s, 3H, CO-CH3), 4.41 (s, 2H, -CH2-), 7.09-7.17 (m, 2H,
4-F-Ph), 7.26-7.33 (m, 2H, 4-F-Ph), 7.61-7.64 (m, 1H, 4-Pyr),
(C-F), 1157 (O-CH3) cm-1
.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-[2-(2-hydroxyethoxy-
)ethyl]-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7e). This
compound was prepared from 6 (5.0 g, 16.61 mmol) and 2-(2-
{3,5-bis[2-(2-hydroxyethoxy)ethyl][1,3,5]triazinan-1-yl}ethoxy)-

6318 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
ethanol (5.0 g, 14.42 mmol) according to general procedure A.
Trituration with Et2O yielded 7e (5.97 g, 89%): mp 210.3 °C;
1H NMR (DMSO-d6) δ 2.06 (s, 3H, CO-CH3), 2.54 (t, 2H, J )
5.88 Hz, O-CH2-), 3.44 (t, 2H, J ) 4.82 Hz, -CH2-O), 3.61
(t, 2H, J ) 4.78 Hz, -CH2-O) 4.00 (t, 2H, J ) 4.68 Hz,
N-CH2-), 7.04-7.07 (m, 1H, 4-Pyr), 7.10-7.20 (m, 2H, 4-F-
Ph), 7.47-7.55 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.35-8.37
(m, 1H, 4-Pyr), 8.58 (s, 1H, C2-H), 10.70 (s, 1H, N-H); IR (ATR)
according to general procedure A. Trituration with diethyl
ether yielded 7k (4.5 g, 70%): mp 189.7 °C; 1H NMR (DMSO-
d6) δ 2.04 (s, 3H, CO-CH3), 3.19 (s, 3H, S-CH3), 3.48 (t, 2H,
J ) 4.95 Hz, S-CH2), 4.05 (t, 2H, J ) 4.98 Hz, N-CH2), 7.00-
7.05 (m, 1H, 4-Pyr), 7.09-7.21 (m, 2H, 4-F-Ph), 7.46-7.55 (m,
2H, 4-F-Ph), 8.06 (s, 1H, 4-Pyr), 8.35-8.37 (m, 1H, 4-Pyr), 8.51
(s, 1H, C2-H), 10.70 (s, 1H, N-H)
N-{4-[3-(2,2-Dimethoxyethyl)-5-(4-fluorophenyl)-1-oxy-
3H-imidazol-4-yl]pyridin-2-yl}acetamide (7l). This com-
pound was prepared from 6 (3.0 g, 9.97 mmol) and 1,3,5-
tris(2,2-dimethoxyethyl)[1,3,5]triazinane (3.5 g, 9.97 mmol)
according to general procedure A. Trituration with Et2O
1699 (HNCdO), 1237 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxypropyl)-1-oxy-
3H-imidazol-4-yl]pyridin-2-yl}acetamide (7f). This com-
pound was prepared from 6 (3.0 g, 9.97 mmol) and 1-[3,5-bis(2-
hydroxypropyl)[1,3,5]triazinan-1-yl]propan-2-ol (2.6 g, 9.97 g)
according to general procedure A. Trituration with Et2O
1
yielded 7l (2.5 g, 63%): mp 205.7 °C; H NMR (DMSO-d6) δ
2.06 (s, 3H, CO-CH3), 3.20 (s, 6H, -C(O-CH3)2), 3.95 (d, 2H,
J ) 2.5 Hz, >N-CH2-), 4.37 (t, 1H, J ) 5.41 Hz, >CH-),
7.04-7.07 (m, 1H, 4-Pyr), 7.10-7.20 (m, 2H, 4-F-Ph), 7.46-
7.53 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.36-8.38 (m, 1H,
4-Pyr), 8.52 (s, 1H, C2-H), 10.67 (s, 1H, N-H); IR (ATR) 1693
1
yielded 7f (2.5 g, 63%): mp 180.5 °C; H NMR (DMSO-d6) δ
1.21 (d, 3H, J ) 5.98 Hz, -CH3), 2.0 (s, 1H, -OH), 2.02 (s,
3H, CO-CH3), 3.4 (quint, 1H, J ) 6.43 Hz, -CH-),3.88 (t,
2H, J ) 6.94 Hz, N-CH2), 7.00-7.06 (m, 1H, 4-Pyr), 7.10-
7.19 (m, 2H, 4-F-Ph), 7.49-7.51 (m, 2H, 4-F-Ph), 8.05 (s, 1H,
4-Pyr), 8.36-8.37 (m, 1H, 4-Pyr), 8.33 (s, 1H, C2-H), 10.69 (s,
1H, N-H)
(NHCdO), 1222 (C-F) cm-1
.
N-{4-[3-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-5-(4-
fluorophenyl)-1-oxy-3H-imidazol-4-yl]pyridin-2-yl}-
acetamide (7m). This compound was prepared from 6 (3.0 g,
9.97 mmol) and 1,3,5-tris(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)-
[1,3,5]triazinane (4.28 g, 9.97 mmol) according to general
procedure A. Trituration with Et2O yielded 7m (2.1 g, 49%):
mp 220 °C; 1H NMR (DMSO-d6) δ 1.13 (d, 6H, J ) 3.7 Hz,
>C(CH3)2), 2.06 (s, 3H, CO-CH3), 3.59-3.65 (m, 1H, >CH-),
3.80-4.24 (m, 4H, >N-CH2, -CH2-O), 7.03-7.07 (m, 1H,
4-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.47-7.57 (m, 2H, 4-F-Ph),
8.01 (s, 1H, 4-Pyr), 8.25-8.35 (m, 1H, 4-Pyr), 8.55 (s, 1H, C2-
H), 10.64 (s, 1H, N-H); IR (ATR) 1694 (NHCdO), 1214 (C-
N-{4-[3-(2-Acetylaminoethyl)-5-(4-fluorophenyl)-3-oxy-
3H-imidazol-4-yl]pyridin-2-yl}acetamide (7g). This com-
pound was prepared from 6 (3.0 g, 9.97 mmol) and N-{2-[3,5-
bis(2-acetylaminoethyl)[1,3,5]triazinan-1-yl]ethyl}acetamide
(3.41 g, 9.97 mmol) according to general procedure A. Tritu-
ration with Et2O yielded 7g (1.4 g, 35%): mp 137.3 °C; 1H
NMR (DMSO-d6) δ 1.64 (s, 3H, CO-CH3), 2.06 (s, 3H, CO-
CH3), 3.15 (q, 2H, -CH2-N), 3.91 (t, 2H, N-CH2-), 7.00-
7.03 (m, 1H, 4-Pyr), 7.10-7.18 (m, 2H, 4-F-Ph), 7.48-7.59 (m,
2H, 4-F-Ph), 8.04 (s, 1H, NH-CO), 8.35-8.37 (m, 1H, 4-Pyr),
8.54 (s, 1H, 4-Pyr), 8.59 (s, 1H, C2-H), 10.77 (s, 1H, N-H); IR
F) cm-1
.
(ATR) 1223 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(2-morpholin-4-yleth-
yl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7n). This
compound was prepared from 6 (5.0 g, 16.6 mmol) and 1,3,5-
tris(2-morpholin-4-ylethyl)[1,3,5]triazinane (6.0 g, 14.1 mmol)
according to general procedure A. Trituration with Et2O
N-{4-[3-(2-Dimethylaminoethyl)-5-(4-fluorophenyl)-1-
oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7h). This
compound was prepared from 6 (5.0 g, 16.59 mmol) and {2-
[3,5-bis(2-(dimethylamino)ethyl)[1,3,5]triazinan-1-yl]ethyl}-
dimethylamine (5.0 g, 16.64 mmol) according to general
procedure A. Trituration with Et2O yielded 7h (4.4 g, 69%):
mp 149.3 °C; 1H NMR (DMSO-d6) δ 2.02 (s, 6H, N(CH3)2), 2.07
(s, 3H, CO-CH3), 2.98 (q, 2H, -CH2-N), 3.83 (t, 2H, N-CH2-
), 6.99-7.04 (m, 1H, 4-Pyr), 7.10-7.17 (m, 2H, 4-F-Ph), 7.50-
7.59 (m, 2H, 4-F-Ph), 8.02 (s, 1H, NH-CO), 8.34-8.36 (m, 1H,
4-Pyr), 8.52 (s, 1H, 4-Pyr), 8.61 (s, 1H, C2-H), 10.79 (s, 1H,
1
yielded 7n (5.2 g, 73%): mp 226.5 °C; H NMR (DMSO-d6) δ
2.06 (s, 3H, CO-CH3), 2.27 (t, 4H, J ) 3.82 Hz, -CH2-O-
CH2-) 3.44 (t, 4H, J ) 4,32 Hz, -CH2-N-CH2-), 3.53 (t, 2H,
J ) 5,94 Hz, N-CH2), 3.96 (t, 2H, J ) 5,88 Hz, N-CH2-),
7.04-7.06 (m, 1H, 4-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.48-
7.55 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.36-8.38 (m, 1H,
4-Pyr), 8.58 (s, 1H, C2-H), 10.69 (s, 1H, NH), IR (ATR) 1691
N-H); IR (ATR) 1222 (C-F) cm-1
.
(HNCdO), 1224 (C-F) cm-1
.
N-{4-[3-(2-Allyloxyethyl)-5-(4-fluorophenyl)-1-oxy-3H-
imidazol-4-yl]pyridin-2-yl}acetamide (7i). This compound
was prepared from 6 (5.0 g, 16.6 mmol) and 1,3,5-tris(2-
allyloxyethyl)[1,3,5]triazinane (5.64 g, 16.61 mmol) according
to general procedure A. Trituration with Et2O yielded 7i (4.9
g, 74%): mp 151.6 °C; 1H NMR (DMSO-d6) δ 2.06 (s, 3H, CO-
CH3), 3.49 (t, 2H, J ) 6.16 Hz, -CH2-O), 3.85-3.87 (m, 2H,
-O-CH2-), 4.04 (t, 2H, J ) 5.81 Hz, N-CH2-), 5.07-5.17
(m, 2H, dCH2), 5.69-5.87 (m, 1H, H-C)), 7.03-7.05 (m, 1H,
4-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.47-7.60 (m, 2H, 4-F-Ph),
8.04 (s, 1H, 4-Pyr), 8.35-8.38 (m, 1H, 4-Pyr), 8.58 (s, 1H, C2-
H), 10.69 (s, 1H, N-H); IR (ATR) 1698 (HNCdO), 1605, 1226
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(3-morpholin-4-yl-
propyl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7o). This
compound was prepared from 6 (4.0 g, 13.0 mmol) and 1,3,5-
tris(2-morpholin-4-ylpropyl)[1,3,5]triazinane (6.14 g, 13.0 mmol)
according to general procedure A. Trituration with Et2O
1
yielded 7o (3.8 g, 65%): mp 232.3 °C; H NMR (DMSO-d6) δ
1.72 (quint, 2H, J ) 6.1 Hz, -CH2-), 2.07 (s, 3H, CO-CH3),
2.14-2.20 (m, 6H, N(CH2)3), 3.41 (t, 4H, J ) 4.26 Hz, -CH2-
O-CH2-), 3.92 (t, 2H, J ) 6,48 Hz, N-CH2), 7.03-7.06 (m,
1H, 4-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.49-7.56 (m, 2H, 4-F-
Ph), 8.05 (s, 1H, 4-Pyr), 8.36-8.38 (m, 1H, 4-Pyr), 8.62 (s, 1H,
C2-H), 10.71 (s, 1H, NH); IR (ATR) 1680 (NHCdO), 1222
(C-F) cm-1
.
(C-F) cm-1
.
N-{4-[5-(4-fluorophenyl)-1-oxy-3-(2-prop-2-ynyloxyeth-
yl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7j). This com-
pound was prepared from 6 (4.0 g, 13.29 mmol) and 1,3,5-
tris(2-prop-2-ynyloxyethyl)[1,3,5]triazinane (4.43 g, 13.29 mmol)
according to general procedure A. Trituration with Et2O
yielded 7j (3.9 g, 75%): mp 163.4 °C; H NMR (DMSO-d6) δ
2.06 (s, 3H, CO-CH3), 3.59 (t, 2H, J ) 6.16 Hz, -CH2-O),
3.94-4.10 (m, 4H, N-CH2-, -O-CH2-), 7.03-7.05 (m, 1H,
4-Pyr), 7.10-7.19 (m, 2H, 4-F-Ph), 7.47-7.60 (m, 2H, 4-F-Ph),
8.04 (s, 1H, 4-Pyr), 8.35-8.38 (m, 1H, 4-Pyr), 8.58 (s, 1H, C2-
H), 10.69 (s, 1H, N-H); IR (ATR) 1679 (NHCdO), 1226 (C-
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(2-piperidin-1-ylethyl)-
3H-imidazol-4-yl]pyridin-2-yl}acetamide (7p). This com-
pound was prepared from 6 (4.0 g, 13.29 mmol) and 1,3,5-
tris(2-piperidin-1-ylethyl)[1,3,5]triazinane (5.59 g, 13.29 mmol)
according to general procedure A. Trituration with Et2O
yielded 7p (4.3 g, 76%): mp 204.5 °C; 1H NMR (CDCl3) δ 1.37-
1.52 (m, 2H, -CH2-), 1.54-1.73 (m, 4H, -CH2-), 2.08 (s, 3H,
CO-CH3), 2.45-2.61 (m, 4H, -CH2-N-CH2-), 3.15 (t, 2H, J
) 6.52 Hz, -CH2-N<), 3.92 (t, 2H, J ) 6.12 Hz, N-CH2-),
7.00-7.04 (m, 1H, 4-Pyr), 7.09-7.15 (m, 2H, 4-F-Ph), 7.47-
7.57 (m, 2H, 4-F-Ph), 8.04 (s, 1H, NH), 8.38-8.40 (m, 1H,
4-Pyr), 8.53 (s, 1H, 4-Pyr),8.58 (s, 1H, C2-H); IR (ATR) 1685
F) cm-1
.
(NHCdO), 1230 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-methylsulfanylethyl)-1-
oxy-3H-imidazol-4-yl]pyridin-2-yl}acetamide (7k). This
compound was prepared from 6 (5.0 g, 16.6 mmol) and 1,3,5-
tris(2-methylsulfanylethyl)[1,3,5]triazinane (5.2 g, 16.8 mmol)
4-[5-(2-Acetylaminopyridin-4-yl)-4-(4-fluorophenyl)-3-
oxyimidazol-1-yl]piperidin-1-carbonic Acid Ethyl Ester
(7q). This compound was prepared from 6 (2.3 g, 7.6 mmol)

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6319
and tris(4-[1,3,5]triazinan-1-yl)piperidin-1-carbonic acid ethyl
ester 7q (6.9 g, 12.4 mmol) according to general procedure A.
Trituration with Et2O yielded 7q (2.4 g, 67%): mp 254.8 °C;
1H NMR (DMSO-d6) δ 1.18 (t, 3H, J ) 7.08 Hz, -CH3), 1.75-
1.87 (m, 4H, 2(CH2)Pip), 2.07 (s, 3H, CO-CH3), 2.77-2.86 (m,
2H, CH2 Pip), 3.94-4.08 (m, 5H, CHPip, CH2Pip, O-CH2),
7.00-7.03 (m, 1H, 4-Pyr), 7.09-7.18 (m, 2H, 4-F-Ph), 7.44-
7.56 (m, 2H, 4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.35-8.38 (m, 1H,
4-Pyr), 8.85 (s, 1H, C2-H), 10.71 (s, 1H, N-H)
2,2,4,4-tetramethylcyclobutan-1,3-dithione (0.80 g, 4.66 mmol)
according to general procedure B. Trituration with Et2O
1
yielded 8d (1.8 g, 95%): mp 227.4 °C; H NMR (DMSO-d6) δ
1.79 (quint, 2H, J ) 5.84 Hz, -CH2-), 2.08 (s, 3H, CO-CH3),
3.05 (s, 3H, O-CH3), 3.19 (t, 2H, J ) 6.04 Hz, O-CH2), 3.94
(t, 2H, J ) 6.18 Hz, N-CH2), 7.12-7.29 (m, 5H, 4-F-Ph, 4-Pyr),
8.07 (s, 1H, 4-Pyr), 8.40-8.43 (m, 1H, 4-Pyr), 10.71 (s, 1H, CO-
NH), 12.96 (s, 1H, NH); IR (ATR) 1695 (NHCdO), 1220 (C-
F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-methyl-3H-imidazol-
4-yl]pyridin-2-yl}acetamide (7r). This compound was pre-
pared from 6 (4.68 g, 15.5 mmol) and 1,3,5-trimethyl[1,3,5]-
triazinane (2.0 g, 15.5 mmol) according to general procedure
A. Trituration with Et2O yielded 7r (3.5 g, 69%): mp 182.3
°C; 1H NMR (CDCl3) δ 2.26 (s, 3H, CO-CH3), 3.66 (s, 3H,
N-CH3), 6.74-6.77 (m, 1H, 4-Pyr), 6.98-7.07 (m, 2H, 4-F-
Ph), 7.47-7.54 (m, 2H, 4-F-Ph), 8.16 (s, 1H, C2-H), 8.22-8.25
(m, 1H, 4-Pyr), 8.28 (s, 1H, 4-Pyr), 10.69 (s, 1H, NH), IR (ATR)
N-{4-[5-(4-Fluorophenyl)-3-[2-(2-hydroxyethoxy)ethyl]-
2-thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8e). This compound was prepared from 7e (5.9
g, 14.66 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(2.51 g, 14.67 mmol) according to general procedure B. Tritu-
1
ration with Et2O yielded 8e (4.7 g, 77%): 232.5 °C; H NMR
(DMSO-d6) δ 2.07 (s, 3H, CO-CH3), 3.22 (t, 2H, J ) 4.62 Hz,
O-CH2-), 3.44 (t, 2H, J ) 5.18 Hz, -CH2-O), 3.58 (t, 2H, J
) 4.18 Hz, -CH2-O), 4.01 (t, 2H, J ) 4.2 Hz, N-CH2-), 7.05-
7.19 (m, 3H, 4-F-Ph, 4-Pyr), 7.24-7.37 (m, 2H, 4-F-Ph), 8.04
(s, 1H, 4-Pyr), 8.37-8.40 (m, 1H, 4-Pyr), 10.67 (s, 1H, CO-
NH), 12.96 (s, 1H, NH); IR (ATR) 1699 (NHCdO), 1122
1225 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-1-oxy-3-(2,2,6,6-tetrameth-
ylpiperidin-4-yl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide
(7s). This compound was prepared from 6 (1.0 g, 3.32 mmol)
and 1,3,5-tris(2,2,6,6-tetramethylpiperidin-4-yl)[1,3,5]triazinane
(1.67 g, 3.32 mmol) according to general procedure A. Tritu-
ration with Et2O yielded 7s (1.2 g, 80%): mp 48.30 °C; 1H NMR
(DMSO-d6) δ 0.83 (s, 6H, C((CH3)2), 1.02 (s, 6H, C((CH3)2),
1.44-1.70 (m, 4H, -CH-(CH2)2-), 2.05 (s, 3H, CO-CH3)
4.18-4.30 (m, 1H, N-CH<), 6.96-7.12 (m, 2H, 4-F-Ph, 4-Pyr)
7.42-7.49 (m, 2H, 4-F-Ph), 8.06 (s, 1H, 4-Pyr), 8.30-8.33 (m,
1H, 4-Pyr), 8.65 (s, 1H, C2-H), 10.65 (s,1H, NH), IR (ATR) 1697
(C-F), 1112 cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxypropyl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}acetamide (8f).
This compound was prepared from 7f (3.5 g, 9.45 mmol) and
2,2,4,4-tetramethylcyclobutan-1,3-dithione (1.63 g, 9.45 mmol)
according to general procedure B. Trituration with Et2O
1
yielded 8f (2.8 g, 77%): mp 224.8 °C; H NMR (DMSO-d6) δ
0.88 (d, 3H, J ) 5.96 Hz, C-CH3), 2.06 (s, 3H, CO-CH3), 3.55-
3.68 (m, 1H, -CH-), 3.90-4.02 (m, 2H, N-CH2), 7.10-7.29
(m, 5H, 4-F-Ph, 4-Pyr), 8.01 (s, 1H, 4-Pyr), 8.36-8.39 (m, 1H,
4-Pyr), 10.65 (s, 1H, CO-NH), 12.85 (s, 1H, NH); IR (ATR)
(NHCdO), 1225 (C-F) cm-1
.
Preparation of N-{4-[5-(4-Fluorophenyl)-3-(2-alkyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide 8a-m, General Procedure B. A solution of
2,2,4,4-tetramethylcyclobutan-1,3-dithione (1 equiv) in DCM
(100 mL) was added dropwise to a stirred solution of 7a-m
(1 equiv) in DCM. The mixture was stirred for 2 h at room
temperature. The solvent was evaporated in vacuo, and the
solid residue was triturated with Et2O.
1710 (NHCdO), 1228 (C-F) cm-1
.
N-{4-[3-(2-Acetylaminoethyl)-5-(4-fluorophenyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8g). This compound was prepared from 7g (1.2
g, 3.00 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(0.52 g, 3.0 mmol) according to general procedure B. Tritura-
tion with Et2O yielded 8g (1.2 g, 97%): mp 266.8 °C; 1H NMR
(DMSO-d6) δ 1.44 (s, 3H, CO-CH3), 2.05 (s, 3H, CO-CH3),
3.22 (q, 2H, -CH2-N), 3.95 (t, 2H, N-CH2-), 7.10-7.29 (m,
5H, 4-F-Ph, 4-Pyr), 7.87 (t, 1H, NH-CO), 8.01 (s, 1H, 4-Pyr),
8.37-8.40 (m, 1H, 4-Pyr), 10.67 (s, 1H, CO-NH), 12.85 (s, 1H,
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxyethyl)-2-thioxo-
2,3-dihydro-1H-imid azol-4-yl]pyridin-2-yl}acetamide (8a).
This compound was prepared from 7a (1.6 g, 4.46 mmol) and
2,2,4,4-tetramethylcyclobutan-1,3-dithione (0.77 g, 4.46 mmol)
according to general procedure B. Trituration with Et2O
NH); IR (ATR) 1222 (C-F) cm-1
.
1
yielded 8a (1.5 g, 90%): mp 222.1 °C; H NMR (DMSO-d6) δ
N-{4-[3-(2-Dimethylaminoethyl)-5-(4-fluorophenyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8h). This compound was prepared from 7h (4.7
g, 12.19 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(2.1 g, 12.19 mmol) according to general procedure B. Tritu-
ration with Et2O yielded 8h (4.0 g, 82%): mp 234.7 °C; 1H
NMR (DMSO-d6) δ 1.94 (s, 6H, N(CH3)2), 2.07 (s, 3H, CO-
CH3), 2.35 (t, 2H, J ) 7.06 Hz, N-CH2), 3.97 (t, 2H, J ) 7.1
Hz, N-CH2), 7.10-7.19 (m, 3H, 4-F-Ph, 4-Pyr), 7.24-7.32 (m,
2H, 4-F-Ph), 8.07 (s, 1H, 4-Pyr), 8.39-8.41 (m, 1H, 4-Pyr),
10.67 (s, 1H, CO-NH), 12.73 (s, 1H, NH); IR (ATR) 1698
2.08 (s, 3H, CO-CH3), 3.50 (t, 2H, J ) Hz, O-CH2), 3.92 (t,
2H, J ) Hz, N-CH2), 7.11-7.32 (m, 5H, 4-F-Ph, 4-Pyr), 8.09
(s, 1H, 4-Pyr), 8.39-8.42 (m, 1H, 4-Pyr), 10.73 (s, 1H, CO-
NH), 12.99 (s, 1H, NH); IR (ATR) 1226 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-methoxyethyl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}acetamide (8b).
This compound was prepared from 7b (2.0 g, 5.37 mmol) and
2,2,4,4-tetramethylcyclobutan-1,3-dithione (0.93 g, 5.37 mmol)
according to general procedure B. Trituration with Et2O
1
yielded 8b (1.7 g, 82%): mp 196.4 °C; H NMR (DMSO-d6) δ
(NHCdO) 1226 (C-F) cm-1
.
2.07 (s, 3H, CO-CH3), 3.03 (s, 3H, O-CH3), 3.50 (t, 2H, J )
5.54 Hz, O-CH2), 4.02 (t, 2H, J ) 5.36 Hz, N-CH2), 7.10-
7.31 (m, 5H, 4-F-Ph, 4-Pyr), 8.07 (s, 1H, 4-Pyr), 8.38-8.40 (m,
1H, 4-Pyr), 10.67 (s, 1H, CO-NH), 12.85 (s, 1H, NH); IR (ATR)
N-{4-[3-(2-Allyloxyethyl)-5-(4-fluorophenyl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}acetamide (8i).
This compound was prepared from 7i (4.9 g, 12.36 mmol) and
2,2,4,4-tetramethylcyclobutan-1,3-dithione (2.12 g, 12.36 mmol)
according to general procedure B. Trituration with Et2O
yielded 8i (4.3 g, 84%): mp 193.7; 1H NMR (DMSO-d6) δ 2.06
(s, 3H, CO-CH3), 3.55 (t, 2H, J ) 6.16 Hz, -CH2-O), 3.72-
3.74 (m, 2H, -O-CH2-), 4.04 (t, 2H, J ) 5.81 Hz, N-CH2-),
4.99-5.07 (m, 2H, dCH2), 5.59-5.75 (m, 1H, HC)), 7.02-7.37
(m, 5H, 4-F-Ph, 4-Pyr), 8.04 (s, 1H, 4-Pyr), 8.37-8.39 (m, 1H,
4-Pyr), 10.67 (s, 1H, CO-NH), 12.85 (s, 1H, NH); IR (ATR)
1224 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}acetamide (8c).
This compound was prepared from 7c (4.0 g, 10.74 mmol) and
2,2,4,4-tetramethylcyclobutan-1,3-dithione (1.85 g, 10.74 mmol)
according to general procedure B. Trituration with Et2O
1
yielded 8c (2.2 g, 52%): mp 224.6 °C; H NMR (DMSO-d6) δ
1.59 (quint, 2H, J ) 5.90 Hz, -CH2-), 2.07 (s, 3H, CO-CH3),
3.27 (t, 2H, J ) 5.8 Hz, O-CH2), 3.94 (t, 2H, J ) 6.68 Hz,
N-CH2), 7.01-7.31 (m, 5H, 4-F-Ph, 4-Pyr), 8.06 (s, 1H, 4-Pyr),
8.39-8.41 (m, 1H, 4-Pyr), 10.71 (s, 1H, CO-NH), 12.96 (s, 1H,
NH)
1699 (NHCdO), 1223 (C-F), 1085 cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-prop-2-ynyloxyethyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8j). This compound was prepared from 7j (3.9 g,
9.94 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(1.71 g, 9.94 mmol) according to general procedure B. Tritu-
ration with Et2O yielded 8j (3.5 g, 86%): mp 207.8 °C; 1H NMR
N-{4-[5-(4-Fluorophenyl)-3-(3-methoxypropyl)-2-thioxo-
2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}acetamide (8d).
This compound was prepared from 7d (1.8 g, 4.66 mmol) and

6320 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
(DMSO-d6) δ 2.05 (s, 3H, CO-CH3), 3.53 (t, 2H, J ) 6.16 Hz,
-CH2-O), 4.00-4.80 (m, 4H, N-CH2-, O-CH2-), 7.02-7.37
(m, 5H, 4-F-Ph, 4-Pyr), 8.04 (s, 1H, 4-Pyr), 8.37-8.39 (m, 1H,
4-Pyr), 10.67 (s, 1H, CO-NH), 12.85 (s, 1H, NH); IR (ATR)
(s, 1H, 4-Pyr), 8.40-8.42 (m, 1H, 4-Pyr), 10.74 (s, 1H, CO-
NH), 12.97 (s, 1H, NH); IR (ATR) 1695 (NHCdO), 1224 (C-
F) cm-1
.
4-[5-(2-Acetylaminopyridin-4-yl)-4-(4-fluorophenyl)-2-
thioxo-2,3-dihydroimidazol-1-yl]piperidin-1-carbonic Acid
Ethyl Ester (8q). This compound was prepared from 7q (2.4
g, 5.11 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(0.88 g, 5.11 mmol) according to general procedure B. Tritu-
1693 (HNCdO), 1218 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-methylsulfanylethyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8k). This compound was prepared from 7k (5.1
g, 13.2 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(2.27 g, 13.2 mmol) according to general procedure B. Tritu-
ration with Et2O yielded 8k (3.6 g, 68%): mp 184.9 °C; 1H
NMR (DMSO-d6) δ 2.07 (s, 3H, CO-CH3), 2.09 (s, 3H, S-CH3),
2.70 (t, 2H, J ) 5.44 Hz, S-CH2), 3.82 (t, 2H, J ) 5.36 Hz,
N-CH2), 7.09-7.30 (m, 5H, 4-F-Ph, 4-Pyr), 8.05 (s, 1H, 4-Pyr),
8.38-8.41 (m, 1H, 4-Pyr), 10.67 (s, 1H, CO-NH), 12.83 (s, 1H,
1
ration with Et2O yielded 8q (1.19 g, 48%): mp 225.5 °C; H
NMR (DMSO-d6)δ 1.16 (t, 3H, J ) 7.17 Hz, -CH3), 1.75-1.86
(m, 4H, 2(CH2)Pip), 2.07 (s, 3H, CO-CH3), 2.76-2.86 (m, 2H,
CH2 Pip), 3.94-4.06 (m, 5H, CHPip, CH2Pip, O-CH2), 6.82-
6.84 (m, 1H, 4-Pyr), 7.06-7.28 (m, 5H, 4-F-Ph, 4-Pyr), 8.09 (s,
1H, 4-Pyr), 8.39-8.42 (m, 1H, 4-Pyr), 10.68 (s, 1H, CO-NH),
12.99 (s, 1H, NH); IR (ATR) 1228 (C-F) cm-1
.
NH); IR (ATR) 1222 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-methyl-2-thioxo-2,3-dihydro-
1H-imidazol-4-yl]pyridin-2-yl}acetamide (8r). This com-
pound was prepared from 7r (2.0 g, 6.13 mmol) and 2,2,4,4-
tetramethylcyclobutan-1,3-dithione (1.1 g, 6.39 mmol) according
to general procedure B. Trituration with Et2O yielded 8r (1.36
g, 65%): mp 266.10 °C; 1H NMR (DMSO-d6) δ 2.09 (s, 3H, CO-
CH3), 3,38 (s, 3H, N-CH3), 6.83-6.86 (m, 1H, 4-Pyr), 7.08-
7.27 (m, 5H, 4-F-Ph, 4-Pyr), 8.10 (s, 1H, 4-Pyr), 8.39-8.44 (m,
1H, 4-Pyr), 10.69 (s, 1H, CO-NH), 12.96 (s, 1H, NH), IR (ATR)
N-{4-[3-(2,2-Dimethoxyethyl)-5-(4-fluorophenyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8l). This compound was prepared from 7l (2.5 g,
6.24 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(1.07 g, 6.24 mmol) according to general procedure B. Tritu-
ration with Et2O yielded 8l (2.1 g, 81%): mp 209.7 °C; 1H NMR
(DMSO-d6) δ 2.06 (s, 3H, CO-CH3), 3.32 (s, 6H, >C(O-CH3)2),
3.96 (d, 2H, J ) 2.61 Hz, >N-CH2-), 4.65 (t, 1H, J ) 5.40
Hz, >CH-), 7.07-7.35 (m, 5H, 4-F-Ph, 4-Pyr), 8.01 (s, 1H,
4-Pyr), 8.37-8.39 (m, 1H, 4-Pyr), 10.57 (s, 1H, CO-NH), 12.85
(s, 1H, NH)
1711(HNCdO), 1228 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2,2,6,6-tetramethylpiperi-
din-4-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-
2-yl}acetamide (8s). This compound was prepared from 8s
(1.2 g, 2.66 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-
dithione (0.46 g, 2.66 mmol) according to general procedure
B. Trituration with Et2O yielded 8s (1.16 g, 93%): mp 212.5
N-{4-[3-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-5-(4-
fluorophenyl)-2-thioxo-2,3-dihydro-1H-imidazol-4-yl]-
pyridin-2-yl}acetamide (8m). This compound was prepared
from 7m (2.1 g, 4.92 mmol) and 2,2,4,4-tetramethylcyclobutan-
1,3-dithione (0.85 g, 4.92 mmol) according to general procedure
B. Trituration with Et2O yielded 8m (2.1 g, 96%): mp 251.0
°C; 1H NMR (DMSO-d6) δ 0.9 (s, 3H, CH3), 1.10 (s, 3H, S-CH3),
2.06 (s, 3H, CO-CH3), 3.50-3.59 (m, 1H, >CH-), 3.62-3.97
(m, 2H, -CH2-O-), 4.23-4.39 (m, 2H, >N-CH2-), 7.03-7.28
(m, 5H, 4-F-Ph, 4-Pyr), 8.01 (s, 1H, 4-Pyr), 8.38-8.40 (m, 1H,
4-Pyr), 10.55 (s, 1H, CO-NH), 12.85 (s, 1H, NH); IR (ATR)
1
°C; H NMR (DMSO-d6) δ 0.97 (s, 6H, C(CH3)2), 1.08 (s, 6H,
C(CH3)2), 1.51-1.84 (m, 4H, -(CH2)2-), 2.08 (s, 3H, CO-CH3),
4.26-4.38 (m, 1H, N-CH<), 7.10-7.29 (m, 5H, 4-F-Ph, 4-Pyr),
8.12 (s, 1H, 4-Pyr), 8.41-8.43 (m, 1H, 4-Pyr), 10.70 (s, 1H, CO-
NH), 12.96 (s, 1H, NH), IR (ATR) 1683 (HNCdO), 1557
(HNCdO), 1239 (C-F) cm-1
.
Preparation of N-{4-[5-(4-Fluorophenyl)-3-alkyl-2-me-
thylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide 9a-
m, General Procedure C. To a solution of 8a-m (1 equiv)
in ethanol were added a catalytic amount of Na2CO3 and
iodomethane. This mixture was heated under reflux for about
3 h under an inert atmosphere of argon. The solution was
cooled to room temperature and filtered. The filtrate was
concentrated in vacuo. The solid residue was purified by
column chromatography or recrystallization.
1699 (NHCdO), 1222 (C-F), cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-morpholin-4-ylethyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8n). This compound was prepared from 7n (5.0
g, 11.7 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(2.0 g, 11.7 mmol) according to general procedure B. Tritura-
tion with Et2O yielded 8n (4.9 g, 95%): mp 230.5 °C; 1H NMR
(CDCl3) δ 2.24 (s, 3H, CO-CH3), 2.37 (t, 4H, J ) 4.48 Hz,
-CH2-O-CH2-), 2.64 (t, 2H, J ) 6.84 Hz, -CH2-N-), 3.55
(t, 4H, J ) 4.56 Hz, -CH2-N-CH2-), 4.19 (t, 2H, J ) 7.32
Hz, N-CH2-), 6.87-6.90 (m, 1H, 4-Pyr), 6.93-7.02 (m, 2H,
4-F-Ph), 7.17-7.27 (m, 2H, 4-F-Ph), 8.16-8.19 (m, 1H, 4-Pyr),
8.30 (s, 1H, 4-Pyr), 8.74 (s, 1H, NH-CO), IR (ATR) 1696
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxyethyl)-2-methyl-
sulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9a).
According to the general procedure C, compound 9a was
obtained from 8a (0.8 g, 2.15 mmol) and iodomethane (0.31 g,
2.20 mmol). Purification by column chromatography (SiO2 60,
DCM/EtOH 9:1) yielded 9a (0.12 g, 14%): mp 195.7 °C; 1H
NMR (CDCl3) δ 2.24 (s, 3H, CO-CH3), 2.73 (s, 3H, S-CH3),
3.92 (t, 2H, J ) 5.01 Hz, O-CH2), 4.04 (t, 2H, J ) 5.33 Hz,
N-CH2), 6.90-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.27-7.45 (m, 2H,
4-F-Ph), 8.19-8.26 (m, 2H, 4-Pyr), 8.34 (s, 1H, CO-NH); IR
(NHCdO), 1225 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(3-morpholin-4-ylpropyl)-
2-thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8o). This compound was prepared from 7o (3.75
g, 8.3 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(1.43 g, 8.3 mmol) according to general procedure B. Tritura-
tion with Et2O yielded 8o (2.46 g, 65%): mp 210.2 °C; 1H NMR
(DMSO-d6) δ 1.86 (quint, 2H, J ) 7.02 Hz, -CH2-), 2.08 (s,
3H, CO-CH3), 2.16-2.22 (m, 6H, N(CH2)3), 3.59 (t, 4H, J )
4.50 Hz, -CH2-O-CH2-), 3,92 (t, 2H, J ) 7.46 Hz, N-CH2),
7.11-7.32 (m, 5H, 4-F-Ph, 4-Pyr), 8.09 (s, 1H, 4-Pyr), 8.39-
8.42 (m, 1H, 4-Pyr), 10.73 (s, 1H, CO-NH), 12.99 (s, 1H, NH),
(ATR) 1665 (HNCdO), 1542 (HNCdO), 1223 (C-F) cm-1
Anal. (C19H19FN4O2S) C, H, N.
.
N-{4-[5-(4-Fluorophenyl)-3-(2-methoxyethyl)-2-methyl-
sulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9b).
According to the general procedure C, compound 9b was
obtained from 8b (0.6 g, 1.55 mmol) and iodomethane (0.43 g,
3.05 mmol). Purification by column chromatography (SiO2 60,
DCM/EtOH 9:1) yielded 9b (0.24 g, 38%): mp 154.5 °C; H
NMR (CDCl3) δ 2.24 (s,3H, CO-CH3), 2.74 (s, 3H, S-CH3),
3.26 (s, 3H, O-CH3), 3.52 (t, 2H, J ) 5.89 Hz, O-CH2), 4.10
(t, 2H, J ) 6.07 Hz, N-CH2), 6.89-6.99 (m, 3H, 4-F-Ph, 4-Pyr),
7.39-7.46 (m, 2H, 4-F-Ph), 8.16 (s, 1H, CO-NH), 8.27-8.30
(m, 2H, 4-Pyr); IR (ATR) 1667 (HNCdO), 1542 (HNCdO), 1120
(C-F) cm-1. Anal. (C20H21FN4O2S) C, H, N.
IR (ATR) 1699 (HNCdO), 1229 (C-F) cm-1
.
N-{4-[5-(4-Fluorophenyl)-3-(2-piperidin-1-ylethyl)-2-
thioxo-2,3-dihydro-1H-imidazol-4-yl]pyridin-2-yl}-
acetamide (8p). This compound was prepared from 7p (4.3
g, 10.12 mmol) and 2,2,4,4-tetramethylcyclobutan-1,3-dithione
(1.74 g, 10.12 mmol) according to general procedure B. Tritu-
ration with Et2O yielded 8p (4.0 g, 90%): mp 104.5 °C; 1H
NMR (CDCl3) δ 1.40-1.52 (m, 2H, -CH2-), 1.57-1.72 (m, 4H,
-CH2-), 2.07 (s, 3H, CO-CH3), 2.42-2.54 (m, 4H, -CH2-
N-CH2-), 2.45 (t, 2H, J ) 6.84 Hz, -CH2-N<), 3.93 (t, 2H,
J ) 6.01 Hz, N-CH2-), 7.10-7.30 (m, 5H, 4-F-Ph, 4-Pyr), 8.08
N-{4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-2-meth-
ylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9c).
According to the general procedure C, compound 9c was
obtained from 8c (2.15 g, 5.56 mmol) and iodomethane (0.99

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6321
g, 7.0 mmol). Purification by column chromatography (SiO2
60, DCM/EtOAc/EtOH 9:2.5:0.5) yielded 9c (0.45 g, 20%): mp
101,3 °C; 1H NMR (CDCl3) δ 2.12 (quint, 2H, J ) 5.13 Hz,
-CH2-), 2.26 (s, 3H, CO-CH3), 2.75 (s, 3H, S-CH3), 3.70 (t,
2H, J ) 5.67 Hz, O-CH2), 4.04 (t, 2H, J ) 5.808 Hz, N-CH2),
6.87-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.37-7.44 (m, 2H, 4-F-Ph),
8.18-8.24 (m, 2H, 4-Pyr), 8.81 (s, 1H, CO-NH); IR (ATR) 1675
(HNCdO), 1550 (HNCdO), 1217 (C-F) cm-1. Anal. (C20H21-
FN4O2S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-(3-methoxypropyl)-2-meth-
ylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9d).
According to the general procedure C, compound 9d was
obtained from 8d (0.8 g, 2.0 mmol) and iodomethane (0.28 g,
1.98 mmol). Purification by column chromatography (SiO2 60,
DCM/EtOH 9:1) yielded 9d (0.45 g, 54%): mp 164.3 °C; 1H
NMR (CDCl3) δ 1.86 (quint, 2H, J ) 5.80 Hz, -CH2-), 2.23
(s, 3H, CO-CH3), 2.73 (s, 3H, S-CH3), 3.21 (s, 3H, O-CH3),
3.27 (t, 2H, J ) 5.86 Hz, O-CH2), 4.01 (t, 2H, J ) 6.64 Hz,
N-CH2), 6.88-6.96 (m, 3H, 4-F-Ph, 4-Pyr), 7.39-7.45 (m, 2H,
4-F-Ph), 8.26-8.28 (m, 3H, 4-Pyr, CO-NH); IR (ATR) 1693
(HNCdO), 1547 (HNCdO), 1214 (C-F) cm-1. Anal. (C21H23-
FN4O2S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-[2-(2-hydroxyethoxy)ethyl]-
2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acet-
amide (9e). According to the general procedure C, compound
9e was obtained from 8e (4.0 g, 9.6 mmol) and iodomethane
(1.5 g, 10.56 mmol). Purification by recrystallization (EtOH)
yielded 9e (2.6 g, 63%): mp 181.5 °C; 1H NMR (CDCl3) δ 2.24
(s, 3H, CO-CH3), 2.74 (s, 3H, S-CH3), 3.13 (t, 2H, J ) 6.23
Hz, O-CH2-), 3.52 (t, 2H, J ) 5.5 Hz, -CH2-O), 3.76 (t, 2H,
J ) 5.6 Hz, -CH2-O), 4.10 (t, 2H, J ) 5.66 Hz, N-CH2-),
6.87-6.97 (m, 3H, 4-F-Ph, 4-Pyr), 7.38-7.45 (m, 2H, 4-F-Ph),
8.21-8.23 (m, 1H, 4-Pyr), 8.38-8.40 (m, 2H, 4-Pyr, CO-NH);
IR (ATR) 1693 (HNCdO), 1219 (C-F) cm-1. Anal. (C21H23-
FN4O3S) C, H, N.
cording to the general procedure C, compound 9i was obtained
from 8i (2.5 g, 6.06 mmol) and iodomethane (0.9 g, 6.33 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
1
9:1) yielded 9i (0.7 g, 27%): mp 127.5 °C; H NMR (CDCl3) δ
2.23 (s, 3H, CO-CH3), 2.73 (s, 3H, S-CH3), 3.55 (t, 2H, J )
5.93 Hz, -CH2-O), 3.87 (dt, 2H, J1 ) 1.36 Hz, J2 ) 2.73 Hz,
J3 ) 4.14 Hz, 4.11 (t, 2H, J ) 6.19 Hz, N-CH2), 5.09-5.20
(m, 2H, dCH2), 5.70-5.83 (m, 1H, HCd), 6.87-6.98 (m, 3H,
4-F-Ph, 4-Pyr), 7.38-7.45 (m, 2H, 4-F-Ph), 7.98 (s, 1H, NH),
8.25-8.31 (m, 2H, 4-Pyr); IR (ATR) 1698 (NHCdO), 1217 (C-
F) cm-1. Anal. (C22H23FN4O2S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3-(2-prop-
2-ynyloxyethyl)-3H-imidazol-4-yl]pyridin-2-yl}acet-
amide (9j). According to the general procedure C, compound
9j was obtained from 8j (1.8 g, 4.39 mmol) and iodomethane
(0.7 g, 4.93 mmol). Purification by recrystallization (EtOH)
yielded 9j (0.7 g, 38%): mp 163.3 °C; 1H NMR (CDCl3) δ 2.18
(s, 3H, CO-CH3), 2.38 (t, 1H, J ) 2.4 Hz, C-H), 2.73 (s, 3H,
S-CH3), 3.62 (t, 2H, J ) 6.04 Hz, -CH2-O), 4.06 (d, 2H, J )
2.38 Hz, O-CH2-), 4.12 (t, 2H, J ) 5.8 Hz, N-CH2-), 6.87-
6.99 (m, 3H, 4-F-Ph, 4-Pyr), 7.39-7.46 (m, 2H, 4-F-Ph), 8.02
(s, 1H, NH), 8.26-8.31 (m, 2H, 4-Pyr); IR (ATR) 1683 (NH-
CdO), 1216 (C-F) cm-1. Anal. (C22H21FN4O2S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3-(2-meth-
ylsulfanylethyl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide
(9k). According to the general procedure C, compound 9k was
obtained from 8k (2.5 g, 6.21 mmol) and iodomethane (0.89 g,
6.26 mmol). Purification by recrystallization (EtOH) yielded
9k (1.5 g, 58%): mp 160.6 °C; 1H NMR (CDCl3) δ 1.97 (s, 3H,
S-CH3), 2.18 (s, 3H, CO-CH3), 2.64 (t, 2H, J ) 7.6 Hz, -CH2-
S), 2.74 (s, 3H, S-CH3), 4.06 (t, 2H, J ) 7.74 Hz, >N-CH2-),
6.82-6.97 (m, 3H, 4-F-Ph, 4-Pyr), 7.35-7.45 (m, 2H, 4-F-Ph),
8.20 (s, 1H, NH), 8.27-8.42 (m, 2H, 4-Pyr); IR (ATR) 1696
(NHCdO), 1212 (C-F) cm-1. Anal. (C20H21FN4OS2) C, H, N.
N-{4-[3-(2,2-Dimethoxyethyl)-5-(4-fluorophenyl)-2-me-
thylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9l).
According to the general procedure C, compound 9l was
obtained from 8l (2.1 g, 5.04 mmol) and iodomethane (0.71 g,
5.04 mmol). Purification by recrystallization (EtOH) yielded
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxypropyl)-2-meth-
ylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9f).
According to the general procedure C, compound 9f was
obtained from 8f (2.0 g, 5.18 mmol) and iodomethane (0.8 g,
5.63 mmol). Purification by recrystallization yielded 9f (0.9 g,
1
9l (0.9 g, 41%): mp 146.8 °C; H NMR (CDCl3) δ 2.16 (s, 3H,
1
43%): mp 239.1 °C; H NMR (DMSO-d6) δ 0.87 (d, 3H, J )
CO-CH3), 2.72 (s, 3H, S-CH3), 3.28 (s, 6H, >C(O-CH3)2), 4.01
(d, 2H, J ) 2.69 Hz, >N-CH2-), 4.43 (t, 1H, J ) 5.46 Hz,
>CH-), 6.87-6.99 (m, 3H, 4-F-Ph, 4-Pyr), 7.37-7.47 (m, 2H,
4-F-Ph), 7.98 (s, 1H, NH), 8.22-8.30 (m, 2H, 4-Pyr); IR (ATR)
1692 (NHCdO), 1212 (C-F) cm-1. Anal. (C21H23FN4O3S) C,
H, N.
5.86 Hz, C-CH3), 2.07 (s, 3H, CO-CH3), 2.63 (s, 3H, S-CH3),
3.64-3.74 (m, 3H, -CH-, N-CH2), 4.98 (d, 1H, J ) 4.62 Hz,
-OH), 7.02-7.13 (m, 3H, 4-F-Ph, 4-Pyr), 7.32-7.40 (m, 2H,
4-F-Ph), 8.04 (s, 1H, 4-Pyr), 8.38-8.40 (m, 1H, 4-Pyr), 8.66 (s,
1H, NH), IR (ATR) 1671 (HNCdO), 1216 (C-F) cm-1. Anal.
(C20H21FN4O2S) C, H, N.
N-{4-[3-(2,2-Dimethyl[1,3]dioxolan-4-ylmethyl)-5-(4-
fluorophenyl)-2-methylsulfanyl-3H-imidazol-4-yl]pyridin-
2-yl}acetamide (9m). According to the general procedure C,
compound 9m was obtained from 8m (2.1 g, 4.75 mmol) and
iodomethane (0.67 g, 4.75 mmol). Purification by column
chromatography (SiO2 60, DCM/EtOH 9:1) yielded 9m (0.4 g,
N-{4-[3-(2-Acetylaminoethyl)-5-(4-fluorophenyl)-2-me-
thylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9g).
According to the general procedure C, compound 9g was
obtained from 8g (0.8 g, 1.93 mmol) and iodomethane (0.3 g,
2.11 mmol). Purification by recrystallization (EtOH) yielded
9g (0.3 g, 36%): mp 206.7 °C; 1H NMR (CDCl3) δ 1.88 (s, 3H,
CO-CH3), 2.20 (s, 3H, CO-CH3), 2.73 (s, 3H, S-CH3), 3.52
(q, 2H, J ) 6.5 Hz, -CH2-N), 4.05 (t, 2H, J ) 6.54 Hz,
N-CH2-), 6.32 (t, 1H, J ) 5.72 Hz, NH-CO), 6.62-6.99 (m,
3H, 4-F-Ph, 4-Pyr), 7.36-7.46 (m, 2H, 4-F-Ph), 8.17 (s, 1H,
4-Pyr), 8.24-8.27 (m, 1H, 4-Pyr), 8.71 (s, 1H, NH); IR (ATR)
1214 (C-F), cm-1. Anal. (C21H22FN5O2S) C, H, N.
1
18%): mp 142.4 °C; H NMR (CDCl3) δ 1.23 (d, 6H, J ) 2.38
Hz, >C(CH3)2), 2.18 (s, 3H, CO-CH3), 2.73 (s, 3H, S-CH3),
3.73 (quint, 1H, J ) 5.98 Hz, >CH-), 3.92-3.99 (m, 2H,
-CH2-O), 4.07-4.22 (m, 2H, >N-CH2), 6.88-6.99 (m, 3H,
4-F-Ph, 4-Pyr), 7.37-7.44 (m, 2H, 4-F-Ph), 7.98 (s, 1H, NH),
8.21 (s, 1H, 4-Pyr), 8.26-8.29 (m, 1H, 4-Pyr); IR (ATR) 1708
(NHCdO), 1225 (C-F) cm-1. Anal. (C23H25FN4O3S) C, H, N.
N-{4-[3-(2-Dimethylaminoethyl)-5-(4-fluorophenyl)-
2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acet-
amide (9h). According to the general procedure C, compound
9h was obtained from 8h (4.5 g, 11.26 mmol) and iodomethane
(1.6 g, 11.27 mmol). Purification by column chromatography
(SiO2 60, DCM/EtOH 9:1) yielded 9h (0.8 g, 17%): mp 159.3
N-{4-[5-(4-Fluorophenyl)-3-(2-morpholin-4-ylethyl)-2-
methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acet-
amide (9n). According to the general procedure C, compound
9n was obtained from 8n (4.5 g, 10.19 mmol) and iodomethane
(1.48 g, 10.49 mmol). Purification by column chromatography
(SiO2 60, DCM/EtOH 9:1) yielded 9n (1.6 g, 34%): mp 218.3
°C; 1H NMR (CDCl3) δ 2.23 (s, 3H, CO-CH3), 2.39 (t, 4H, J )
3.78 Hz, -CH2-O-CH2-), 2.54 (t, 2H, J ) 7.12 Hz, -CH2-
N<), 2.73 (s, 3H, S-CH3), 3.62 (t, 4H, J ) 4.26 Hz, -N(CH2)2),
4.03 (t, 2H, J ) 7.16 Hz, >N-CH2-), 6.88-6.96 (m, 3H, 4-F-
Ph, 4-Pyr), 7.36-7.44 (m, 2H, 4-F-Ph),8.06 (s, 1H, CO-NH)
8.26-8.34 (m, 2H, 4-Pyr), IR (ATR) 1698 (HNCdO), 1214 (C-
F) cm-1. Anal. (C23H26FN5O2S) C, H, N.
1
°C; H NMR (DMSO-d6) δ 1.97 (s, 6H, N(CH3)2), 2.07 (s, 3H,
CO-CH3), 2.31 (t, 2H, J ) 6.88 Hz, -CH2-N<), 2.63 (s, 3H,
S-CH3), 3.85 (t, 2H, J ) 6.68 Hz, N-CH2), 7.02-10 (m, 3H,
4-F-Ph, 4-Pyr), 7.33-7.40 (m, 2H, 4-F-Ph), 8.05 (s, 1H, 4-Pyr),
8.38-8.41 (m, 1H, 4-Pyr), 10.64 (s, 1H, CO-NH); IR (ATR)
1694 (NHCdO), 1219 (C-F) cm-1. Anal. (C21H24FN5OS) C, H,
N.
N-{4-[3-(2-Allyloxyethyl)-5-(4-fluorophenyl)-2-methyl-
sulfanyl-3H-imidazol-4-yl]pyridin-2-yl}acetamide (9i). Ac-
N-{4-[5-(4-Fluorophenyl)-3-(3-morpholin-4-ylpropyl)-
2-methylsulfanyl-3H-imidazol-4-yl]pyridin-2-yl}-

6322 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
acetamide (9o). According to the general procedure C,
compound 9o was obtained from 8o (2.4 g, 5.27 mmol) and
iodomethane (1.48 g, 10.49 mmol). Purification by column
chromatography (SiO2 60, DCM/EtOH 9:1) yielded 9o (0.45 g,
IR (ATR) 1695 (HNCdO), 1535 (HNCdO), 1264 (C-F), 1050
(SdO) cm-1. Anal. (C27H27FN4O3S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(3-methoxypropyl)-3H-imidazol-4-yl]pyridin-
2-yl}acetamide (10d). According to the general procedure D,
compound 10d was obtained from 8d (0.6 g, 1.49 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.3 g, 1.59 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 10d (0.25 g, 30%): mp 149.2 °C; 1H NMR (CDCl3),
δ 1.66 (quint, 2H, J ) 5.93 Hz, -CH2-), 2.23 (s, 3H, CO-
CH3), 2.73 (s, 3H, SO-CH3), 3.16 (t, 2H, J ) 6.53 Hz, O-CH2),
3.17 (s, 3H, O-CH3), 3.81 (t, 2H, J ) 7.41 Hz, N-CH2), 4.45
(s, 2H, S-CH2), 6.88-6.99 (m, 3H, 4-F-Ph, 4-Pyr), 7.38-7.45
(m, 2H, 4-F-Ph), 7.50-7.65 (m, 4H, 4-MeS(O)-Ph, AA′BB′), 8.15
(s, 1H, 4-Pyr), 8.22 (s, 1H, CO-NH), 8.27-8.29 (m, 1H, 4-Pyr);
IR (ATR) 1694 (HNCdO), 1543 (HNCdO), 1219 (C-F), 1047
(SdO) cm-1. Anal. (C28H29FN4O3S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-[2-(2-hydroxyethoxy)ethyl]-
2-(4-methylsulfinylbenzylsulfanyl-3H-imidazol-4-yl]py-
ridin-2-yl}acetamide (10e). According to the general proce-
dure D, compound 10e was obtained from 8e (0.5 g, 1.2 mmol)
and 1-chloromethyl-4-methylsulfinylbenzene (0.48 g, 2.6 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 10e (0.30 g, 44%): mp 113.5 °C; 1H NMR (CDCl3)
δ 2.24 (s, 3H, CO-CH3), 2.72 (s, 3H, SO-CH3), 3.41 (t, 2H, J
) 4.77 Hz, O-CH2-), 3.60 (t, 2H, J ) 4.14 Hz, -CH2-OH),
3.72 (t, 2H, J ) 4.52 Hz, -CH2-O-), 3.92 (t, 2H, J ) 5.34 Hz,
N-CH2-), 4.48 (s, 2H, S-CH2-), 6.84-6.88 (m, 1H, 4-Pyr),
6.90-6.99 (m, 2H, 4-F-Ph), 7.38-7.45 (m, 2H, 4-F-Ph), 7.50-
7.64 (m, 4H, 4-MeS(O)-Ph, AA′BB′), 8.22-8.25 (m, 1H, 4-Pyr),
8.28 (s, 1H, 4-Pyr), 8.38 (s, 1H, CO-NH); IR (ATR) 1690
(HNCdO), 1219 (C-F), 1085 (SdO), cm-1. Anal. (C28H29-
FN4O4S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxypropyl)-2-(4-me-
thylsulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridin-2-
yl}acetamide (10f). According to the general procedure D,
compound 10f was obtained from 8f (0.7 g, 1.81 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.48 g, 2.6 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 10f (0.3 g, 31%): mp 140.4 °C; 1H NMR (CDCl3) δ
1.07 (d, 3H, J ) 6.00 Hz, C-CH3), 2.23 (s, 3H, CO-CH3), 2.71
(s, 3H, SO-CH3), 3.65-3.74 (m, 3H, N-CH2-, -CH-), 4.39
(s, 2H, S-CH2-), 6.87-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.36-7.43
(m, 2H, 4-F-Ph), 7.47-7.63 (m, 4H, 4-MeS(O)-Ph, AA ′BB′),
8.15 (s, 1H, 4-Pyr), 8.22-8.25 (m, 1H, 4-Pyr), 8.31 (s, 1H, CO-
NH); IR (ATR) 1689 (HNCdO), 1219 (C-F), cm-1. Anal.
(C27H27FN4O3S2) C, H, N.
1
18%): mp 215.1 °C; H NMR (CDCl3) δ 1.81 (quint, 2H, J )
7.44 Hz, -CH2-), 2.23 (s, 3H, CO-CH3), 2.30-2.36 (m, 6H,
N(CH2)3), 2.73 (s, 3H, S-CH3), 3.66 (t, 2H, J ) 6.79 Hz,
O-CH2), 3.98 (t, 2H, J ) 7.73 Hz, N-CH2), 6.85-6.96 (m, 3H,
4-F-Ph, 4-Pyr), 7.37-7.44 (m, 2H, 4-F-Ph), 8.28-8.35 (m, 2H,
4-Pyr), 8.54 (s, 1H, CO-NH), IR (ATR) 1694 (HNCdO), 1544
(HNCdO), 1220 (C-F) cm-1, Anal. (C24H28FN5O2S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-methylsulfanyl-3-(2-piperi-
din-1-ylethyl)-3H-imidazol-4-yl]pyridin-2-yl}acetamide
(9p). According to the general procedure C, compound 9p was
obtained from 8p (2.0 g, 4.55 mmol) and iodomethane (0.7 g,
4.39 mmol). Purification by column chromatography (SiO2 60,
DCM/EtOH 9:1) yielded 9p (0.67 g, 32%): mp 104.5 °C; 1H
NMR (CDCl3) δ 1.42-1.58 (m, 2H, -CH2-), 1.61-1.79 (m, 4H,
-CH2-), 2.19 (s, 3H, CO-CH3), 2.52-2.65 (m, 4H, -CH2-
N-CH2-), 2.73 (s, 3H, S-CH3), 2.78 (t, 2H, J ) 6.52 Hz,
-CH2-N<), 4.19 (t, 2H, J ) 6.12 Hz, N-CH2-), 6.86-6.97
(m, 3H, 4-F-Ph, 4-Pyr), 7.37-7.45 (m, 2H, 4-F-Ph), 8.14 (s, 1H,
NH), 8.28-8.31 (m, 2H, 4-Pyr), IR (ATR) 1689 (NHCdO), 1218
(C-F) cm-1. Anal. (C24H28FN5OS) C, N, H.
4-[5-(2-Acetylaminopyridin-4-yl)-4-(4-fluorophenyl)-2-
methylsulfanylimidazol-1-yl]piperidin-1-carbonic Acid
Ethyl Ester (9q). According to the general procedure C,
compound 9q was obtained from 8q (0.3 g, 0.62 mmol) and
iodomethane (0.2 g, 1.41 mmol). Purification by recrystalliza-
1
tion (EtOH) yielded 9q (0.01 g, 3%): mp 190.1 °C; H NMR
(CDCl3) δ 1.28 (t, 3H, J ) 7.10 Hz, -CH3), 1.82-1.88 (m, 2H,
-CH2-Pip), 2.24 (s, 3H, CO-CH3), 2.41-2.58 (m, 2H, -CH2-
Pip), 2.65-2.78 (m, 4H, (CH2)2Pip) 2.75 (s, 3H, S-CH3), 4.03-
4.18 (m, 1H, N-CH), 4.15 (q, 2H, J ) 7.12 Hz, CO-CH2),
6.87-6.95 (m, 3H, 4-F-Ph, 4-Pyr), 7.32-7.39 (m, 2H, 4-F-Ph),
8.11 (s, 1H, CO-NH), 8.17 (s, 1H, 4-Pyr), 8.27-8.29 (m, 1H,
4-Pyr), IR (ATR) 1673 (NHCdO), 1228 (C-F) cm-1. Anal.
(C25H28FN5O3S) C, H, N.
Preparation of N-{4-[5-(4-Fluorophenyl)-2-(4-methyl-
sulfinylbenzylsulfanyl)-3-alkyl-3H-imidazol-4-yl]pyridin-
2-yl}acetamide 10a,b,d-g,i-k,o,p,r,s. General Procedure
D. To a solution of 8 (1 equiv) in EtOH (100 mL) were added
a catalytic amount of Na2CO3 and 1-chloromethyl-4-methyl-
sulfinylbenzene. This mixture was heated under reflux for
about 3 h under an inert atmosphere of argon. The solution
was cooled to room temperature and filtered. The filtrate was
concentrated in vacuo. The solid residue was purified by
column chromatography or recrystallization.
N-{4-[3-(2-Acetylaminoethyl)-5-(4-fluorophenyl)-2-(4-
(methylsulfinyl)benzylsulfanyl)-3H-imidazol-4-yl]pyridin-
2-yl}acetamide (10 g). According to the general procedure
D, compound 10g was obtained from 8g (0.4 g, 0.97 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.2 g, 1.06 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxyethyl)-2-(4-me-
thylsulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridin-2-
yl}acetamide (10a). According to the general procedure D,
compound 10a was obtained from 8a (0.6 g, 1.61 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.32 g, 1.69 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
1
9:1) yielded 10g (0.2 g, 37%): mp 245.8 °C; H NMR (CDCl3)
1
9:1) yielded 10a (0.1 g, 12%): mp 159.5 °C; H NMR (CDCl3)
δ 1.86 (s, 3H, CO-CH3), 2.24 (s, 3H, CO-CH3), 2.72 (s, 3H,
SO-CH3), 3.35 (q, 2H, J ) 6.3 Hz, -CH2-N), 3.85 (t, 3H, J )
6.68 Hz, N-CH2-), 4.46 (s, 2H, S-CH2-), 6.21 (t, 1H, J )
6.16 Hz, NH-CO), 6.86-6.89 (m, 1H, 4-Pyr), 6.91-7.00 (m,
2H, 4-F-Ph), 7.38-7.43 (m, 2H, 4-F-Ph), 7.46-7.63 (m, 4H,
4-MeS(O)-Ph, AA′BB′), 8.09 (s, 1H, 4-Pyr), 8.25-8.28 (m, 1H,
4-Pyr), 8.39 (s, 1H, CO-NH); IR (ATR) 1691 (CdO-NH), 1214
(C-F) cm-1. Anal. (C28H28FN5O3S2) C, H, N.
δ 2.22 (s, 3H, CO-CH3), 2.71 (s, 3H, SO-CH3), 3.71 (t, 2H, J
) 5.84 Hz, -O-CH2), 3.79 (t, 2H, J ) 5.72 Hz, N-CH2), 4.42
(s, 2H, S-CH2), 6.83-6.86 (m, 1H, 4-Pyr), 6.90-6.99 (m, 2H,
4-F-Ph), 7.35-7.45 (m, 2H, 4-F-Ph), 7.48-7.62 (m, 4H, 4-MeS-
(O)-Ph, AA′BB′), 8.14 (s, 1H, 4-Pyr), 8.19-8.22 (m, 1H, 4-Pyr),
8.46 (s, 1H, CO-NH); IR (ATR) 1690 (HNCdO), 1224 (C-F),
1056 (SdO), 838 cm-1. Anal. (C26H25FN4O3S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(2-methoxyethyl)-3H-imidazol-4-yl]pyridin-2-
yl}acetamide (10b). According to the general procedure D,
compound 10b was obtained from 8b (0.5 g, 1.29 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.48 g, 2.6 mmol).
Purification by recrystallization (EtOH) yielded 10b (0.07 g,
10%): mp 130.0 °C; 1H NMR (CDCl3) δ 2.21 (s, 3H, CO-CH3),
2.71 (s, 3H, SO-CH3), 3.14 (s, 3H, O-CH3), 3.31 (t, 2H, J )
5.92 Hz, O-CH2), 3.86 (t, 2H, J ) 5.86 Hz, N-CH2), 4.41 (s,
2H, S-CH2-), 6.88-6.96 (m, 3H, 4-F-Ph, 4-Pyr), 7.36-7.43
(m, 2H, 4-F-Ph), 7.46-7.63 (m, 4H, 4-MeS(O)-Ph, AA′BB′), 8.15
(s, 1H, 4-Pyr), 8.25-8.28 (m, 1H, 4-Pyr), 8.53 (s, 1H, CO-NH);
N-{4-[3-(2-Allyloxyethyl)-5-(4-fluorophenyl)-2-(4-meth-
ylsulfinylbenzylsulfanyl)-3H-imidazol-4-yl]pyridin-2-yl}-
acetamide (10i). According to the general procedure D,
compound 10i was obtained from 8i (1.8 g, 4.36 mmol) and
1-chloromethyl-4-methylsulfinylbenzene (0.9 g, 5.34 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
1
9:1) yielded 10i (0.9 g, 37%): mp 68.4 °C; H NMR (CDCl3) δ
2.23 (s, 3H, CO-CH3), 2.73 (s, 3H, SO-CH3), 3.38 (t, 2H, J )
5.84 Hz, -CH2-O), 3.79 (dt, 2H, J1 ) 1.35 Hz, J2 ) 2.83 Hz,
J3 ) 4.19 Hz, dCH2), 3.90 (t, 2H, J ) 6.02 Hz, N-CH2), 4.44
(s, 2H, S-CH2-), 5.06-5.15 (m, 2H, dCH2), 5.64-5.78 (m, 1H,
HC)), 6.90-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.38-7.43 (m, 2H,

Imidazole Inhibitors of Cytokine Release
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25 6323
4-F-Ph), 7.45-7.52 (m, 2H, 4-MeS(O)-Ph, AA′), 7.61-7.65 (m,
2H, MeS(O)-Ph, BB′), 8.04 (s, 1H, CO-NH) 8.14 (s, 1H, 4-Pyr),
8.27-8.30 (m, 1H, 4-Pyr); IR (ATR) 1694 (NHCdO), 1219 (C-
F) cm-1. Anal. (C29H29FN4O3S2) C, H, N.
4-Pyr), 7.32-7.42 (m, 4H, 4-F-Ph, 4-MeS(O)-Ph), 7.53-7.57 (m,
2H, 4-MeS(O)-Ph), 8.09 (s, 1H, 4-Pyr), 8.16-8.19 (m, 1H,
4-Pyr), 9.05 (s, 1H, CO-NH); IR (ATR) 1698 (HNCdO), 1546
(HNCdO), 1220 (C-F), 1035 (SdO) cm-1. Anal. (C25H23-
FN4O2S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(2-prop-2-ynyloxyethyl)-3H-imidazol-4-yl]py-
ridin-2-yl}acetamide (10j). According to the general proce-
dure D, compound 10j was obtained from 8j (1.6 g, 3.90 mmol)
and 1-chloromethyl-4-methylsulfinylbenzene (0.7 g, 4.15 mmol).
Purification by recrystallization (EtOH) yielded 10j (0.6 g,
27%): mp 136.0 °C; 1H NMR (CDCl3) δ 2.23 (s, 3H, CO-CH3),
2.35 (t, 1H, J ) 2.34 Hz, C-H), 2.73 (s, 3H, SO-CH3), 3.48 (t,
2H, J ) 5.82 Hz, -CH2-O), 3.92 (t, 2H, J ) 5.52 Hz, N-CH2-
), 3.98 (d, 2H, J ) 1.18 Hz, O-CH2-), 4.44 (s, 2H, S-CH2-),
6.75-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.38-7.45 (m, 2H, 4-F-Ph),
7.49-7.56 (m, 2H, 4-MeS(O)-Ph, AA′), 7.61-7.65 (m, 2H, MeS-
(O)-Ph, BB′), 8.03 (s, 1H, CO-NH), 8.16 (s, 1H, 4-Pyr), 8.28-
8.31 (m, 1H, 4-Pyr); IR (ATR) 1693 (NHCdO), 1213 (C-F)
cm-1. Anal. (C29H27FN4O3S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(2-methylsulfanylethyl)-3H-imidazol-4-yl]py-
ridin-2-yl}acetamide (10k). According to the general pro-
cedure D, compound 10k was obtained from 8k (2.0 g, 4.97
mmol) and 1-chloromethyl-4-methylsulfinylbenzene (1.0 g, 5.93
mmol). Purification by column chromatography (SiO2 60, DCM/
EtOH 9:1) yielded 10k (1.6 g, 58%): mp 119.3 °C; 1H NMR
(CDCl3) δ 1.77 (s, 3H, S-CH3), 2.23 (CO-CH3), 2.39 (t, 2H, J
) 7.82 Hz, -CH2-S), 2.74 (s, 3H, SO-CH3), 3.87 (t, 2H, 7.24
Hz, >N-CH2-), 4.38 (s, 2H, S-CH2-), 6.90-6.99 (m, 3H, 4-F-
Ph, 4-Pyr), 7.39-7.47 (m, 2H, 4-F-Ph), 7.51-7.55 (m, 2H,
4-MeS(O)-Ph, AA′), 7.61-7.66 (m, 2H, MeS(O)-Ph, BB′), 8.09
(s, 1H, CO-NH), 8.16 (s, 1H, 4-Pyr), 8.22-8.25 (m, 1H, 4-Pyr);
IR (ATR) 1707 (NHCdO), 1219 (C-F) cm-1. Anal. (C27H27-
FN4O2S3) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(3-morpholin-4-yl-propyl)-3H-imidazol-4-yl]-
pyridin-2-yl}acetamide (10o). According to the general
procedure D, compound 10o was obtained from 8o (1.2 g, 2.63
mmol) and 1-chloromethyl-4-methylsulfinylbenzene (0.67 g,
3.55 mmol). Purification by column chromatography (SiO2 60,
DCM/EtOH 9:1) yielded 10o (0.2 g, 13%): mp 120.9 °C; 1H
NMR (CDCl3) δ 1.56 (quint, 2H, J ) 7.56 Hz, -CH2-), 2.12-
2.23 (m, 6H, N(CH2)3), 2.23 (s, 3H, CO-CH3), 2.73 (s, 3H, SO-
CH3), 3.55-3.60 (m, 4H, -CH2-O-CH2-), 3.77 (t, 2H, J )
7.63 Hz, N-CH2), 6.86-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.37-
7.45 (m, 2H, 4-F-Ph), 7.48-7.65 (m, 4H, 4-MeS(O)-Ph, AA′BB′),
8.17 (s, 1H, 4-Pyr), 8.26-8.29 (m, 1H, 4-Pyr), 8.43 (s, 1H, CO-
NH); IR (ATR) 1694 (HNCdO), 1544 (HNCdO), 1218 (C-F),
1035 (SdO) cm-1. Anal. (C31H34FN5O3S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzylsu-
fanyl)-3-(2,2,6,6-tetramethyl-piperidin-4-yl)-3H-imidazol-
4-yl]pyridin-2-yl}acetamide (10s). According to the general
procedure D, compound 10s was obtained from 8s (0.6 g, 1.55
mmol) and 1-chloromethyl-4-methylsulfinylbenzene (0.33 g,
1.70 mmol). Purification by column chromatography (SiO2 60,
1
DCM/EtOH 9:1) yielded 10s (0.15 g, 16%): mp 218.8 °C; H
NMR (CDCl3) δ 0.97 (s, 6H, C(CH3)2), 1.08 (s, 6H, C(CH3)2),
1.52-1.57 (m, 2H, -CH2- equatorial), 1.84-1.97 (m, 2H,
-CH2-axial), 2.21 (s, 3H, CO-CH3), 2.79 (s, 3H, SO-CH3),
4.26-4.38 (m, 1H, NCH<), 4.55 (s, 2H, S-CH2), 6.88-6.97 (m,
3H, 4-F-Ph, 4-Pyr), 7.36-7.52 (m, 2H, 4-F-Ph), 7.57-7.64 (m,
4H, 4-MeS(O)-Ph, AA′BB′), 8.07 (s, 1H, CO-NH), 8.22 (s, 1H,
4-Pyr), 8.31-8.33 (s, 1H, 4-Pyr); IR (ATR) 1699 (HNCdO),
1546 (HNCdO), 1231 (C-F), 1037 (SdO) cm-1. Anal. (C33H38-
FN5O2S2) C, H, N.
Preparation of 11a-e. General Procedure E. To a
solution of 8 (1 equiv) in THF (30 mL) was added Na2CO3 (1
equiv), tetrabutylammonium iodide (1 equiv), and 4-chloro-1-
morpholin-4-yl-alkan-1-one (1 equiv). This mixture was heated
under reflux for about 6 h under an inert atmosphere of argon.
The solution was cooled to room temperature and filtered. The
filtrate was concentrated in vacuo. The solid residue was
purified by column chromatography or recrystallization.
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxyethyl)-2-(3-mor-
pholin-4-yl-3-oxopropylsulfanyl)-3H-imidazol-4-yl]pyri-
din-2-yl}acetamide (11a). According to the general procedure
E, compound 11a was obtained from 8a (0.6 g, 1.61 mmol) and
3-chloro-1-morpholin-4-ylpropan-1-one (0.3 g, 1.69 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 11a (0.09 g, 11%): mp 219.6 °C; 1H NMR (CDCl3)
δ 2.24 (s, 3H, CO-CH3), 2.95 (t, 2H, J ) 6.62 Hz, -CH2-CON),
3.45-3.66 (m, 10H, morpholino, S-CH2-), 3.88 (t, 2H, J )
6.08 Hz, -CH2-O), 4.07 (t, 2H, J ) 5.98 Hz, N-CH2), 6.89-
6.97 (m, 3H, 4-F-Ph, 4-Pyr), 7.35-7.42 (m, 2H, 4-F-Ph), 8.07
(s, 1H, CO-NH), 8.24-8.26 (m, 2H, 4-Pyr); IR (ATR) 1693
(NHCdO), 1112 (C-F) cm-1. Anal. (C25H28FN5O4S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-(2-hydroxyethyl)-2-(4-mor-
pholin-4-yl-4-oxobutylsulfanyl)-3H-imidazol-4-yl]pyridin-
2-yl}acetamide (11b). According to the general procedure E,
compound 11b was obtained from 8a (0.5 g, 1.34 mmol) and
4-chloro-1-morpholin-4-ylbutan-1-one (0.3 g, 1.56 mmol). Pu-
rification by column chromatography (SiO2 60, DCM/EtOH 9:1)
1
yielded 11b (0.08 g, 11%): mp 169.7 °C; H NMR (CDCl3) δ
2.15 (quint, 2H, J ) 7.4 Hz, -CH2-), 2.25 (s, 3H, CO-CH3),
2.55 (t, 2H, J ) 7.28 Hz, -CH2-CON<), 3.31 (t, 2H, J ) 7.02
Hz, S-CH2-), 3.47 (t, 2H, J ) 4.9 Hz, -CH2-morpholino),
3.61-3.65 (m, 6H, -CH2-morpholino), 3.90 (t, 2H, J ) 5.52
Hz, -CH2-O), 4.09 (t, 2H, J ) 5.62 Hz, N-CH2-), 6.90-6.98
(m, 3H, 4-F-Ph, 4-Pyr), 7.36-7.43 (m, 2H, 4-F-Ph), 8.16 (s, 1H,
CO-NH), 8.23-8.25 (m, 2H, 4-Pyr); IR (ATR) 1682 (NH-
CdO), 1217 (C-F) cm-1. Anal. (C26H30FN5O4S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-(3-hydroxypropyl)-2-(4-mor-
pholin-4-yl-3-oxopropylsulfanyl)-3H-imidazol-4-yl]pyri-
din-2-yl}acetamide (11c). According to the general procedure
E, compound 11c was obtained from 8c (0.5 g, 1.29 mmol) and
3-chloro-1-morpholin-4-ylpropan-1-one (0.3 g, 1.69 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 11c (0.12 g, 18%): mp 193.9 °C; 1H NMR (CDCl3)
δ 2.05 (quint, 2H, J ) 7.45 Hz, -CH2-), 2.25 (s, 3H, CO-
CH3), 2.96 (t, 2H, J ) 6.97 Hz, -CH2-CON), 3.50-3.67 (m,
12H, morpholino, S-CH2-, -CH2-O), 4.03 (t, 2H, J ) 7.43
Hz, N-CH2), 6.86-6.98 (m, 3H, 4-F-Ph, 4-Pyr), 7.33-7.40 (m,
2H, 4-F-Ph), 8.15 (s, 1H, CO-NH), 8.22-8.24 (m, 2H, 4-Pyr);
IR (ATR) 1683 (NHCdO), 1220 (C-F) cm-1. Anal. (C26H30-
FN5O4S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-(2-piperidin-1-ylethyl)-3H-imidazol-4-yl]pyri-
din-2-yl}acetamide (10p). According to the general proce-
dure D, compound 10p was obtained from 8p (1.9 g, 4.32
mmol) and 1-chloromethyl-4-methylsulfinylbenzene (0.8 g, 4.75
mmol). Purification by column chromatography (SiO2 60, DCM/
EtOH 9:1) yielded 10p (0.7 g, 27%): mp 121.2 °C; 1H NMR
(CDCl3) δ 1.19 (m, 6H, -CH2-CH2-CH2-), 2.09-2.21 (m, 4H,
-CH2-N-CH2-), 2.23 (s, 3H, CO-CH3), 2.27 (t, 2H, J ) 7.5
Hz, -CH2-N), 2.73 (s, 3H, SO-CH3), 3.78 (t, 2H, J ) 7.2 Hz,
N-CH2-), 4.44 (s, 2H, S-CH2-), 6.87-6.98 (m, 3H, 4-F-Ph,
4-Pyr), 7.38-7.43 (m, 2H, 4-F-Ph), 7.45-7.52 (m, 2H, 4-MeS-
(O)-Ph, AA′), 7.60-7.65 (m, 2H, MeS(O)-Ph, BB′), 8.04 (s, 1H,
CO-NH), 8.15 (s, 1H, 4-Pyr), 8.27-8.30 (m, 1H, 4-Pyr); IR
(ATR) 1694 (NHCdO), 1219 (C-F) cm-1. Anal. (C31H34-
FN5O2S2) C, H, N.
N-{4-[5-(4-Fluorophenyl)-2-(4-methylsulfinylbenzyl-
sulfanyl)-3-methyl-3H-imidazol-4-yl]pyridin-2-yl}acet-
amide (10r). According to the general procedure D, compound
10r was obtained from 8r (1.0 g, 2.92 mmol) and 1-chloro-
methyl-4-methylsulfinylbenzene (0.5 g, 2.92 mmol). Purifica-
tion by column chromatography (SiO2 60, DCM/EtOH 9:1)
1
yielded 10r (0.25 g, 17%): mp 190.5 °C; H NMR (CDCl3) δ
N-{4-[5-(4-Fluorophenyl)-3-(2-methoxyethyl)-2-(3-mor-
pholin-4-yl-3-oxopropylsulfanyl)-3H-imidazol-4-yl]pyri-
din-2-yl}acetamide (11d). According to the general proce-
2.15 (s, 3H, CO-CH3), 2.65 (s, 3H, SO-CH3), 3.18 (s, 3H,
N-CH3), 4.30 (s, 2H, S-CH2-), 6.77-6.90 (m, 3H, 4-F-Ph,

6324 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 25
Laufer et al.
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dure E, compound 11d was obtained from 8b (0.6 g, 1.55 mmol)
and 3-chloro-1-morpholin-4-ylpropan-1-one (0.3 g, 1.69 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
9:1) yielded 11d (0.11 g, 13%): mp 171.5 °C; 1H NMR (CDCl3)
δ 2.23 (CO-CH3), 2.96 (t, 2H, J ) 7.11 Hz, -CH2-CON), 3.22
(s, 3H, O-CH3), 3.44-3.67 (m, 12H, morpholino, S-CH2-,
-CH2-O), 4.07 (t, 2H, J ) 6.01 Hz, N-CH2), 6.87-6.99 (m,
3H, 4-F-Ph, 4-Pyr), 7.33-7.41 (m, 2H, 4-F-Ph), 8.10 (s, 1H,
CO-NH), 8.26-8.30 (m, 2H, 4-Pyr); IR (ATR) 1696 (NH-
CdO), 1224 (C-F) cm-1. Anal. (C26H30FN5O4S) C, H, N.
N-{4-[5-(4-Fluorophenyl)-3-(3-methoxypropyl)-2-(3-mor-
pholin-4-yl-3-oxopropylsulfanyl)-3H-imidazol-4-yl]pyri-
din-2-yl}acetamid (11e). According to the general procedure
E, compound 11e was obtained from 8d (0.6 g, 1.5 mmol) and
3-chloro-1-morpholin-4-ylpropan-1-one (0.3 g, 1.69 mmol).
Purification by column chromatography (SiO2 60, DCM/EtOH
1
9:1) yielded 11e (0.1 g, 12%): mp 145.5 °C; H NMR (CDCl3)
δ 1.81 (quint, 2H, J ) 7.53 Hz, -CH2-), 2.23 (s, 3H, CO-
CH3), 2.95 (t, 2H, J ) 7.20 Hz, -CH2-CON), 3.18 (s, 3H,
O-CH3), 3.24 (t, 2H, J ) 5.92 Hz, O-CH2), 3.51 (t, 2H, J )
7.22 Hz, S-CH2-), 3.56-3.66 (m, 8H, morpholino), 3.98 (t, 2H,
J ) 6.27 Hz, N-CH2-), 6.87-6.96 (m, 3H, 4-F-Ph, 4-Pyr),
7.33-7.40 (m, 2H, 4-F-Ph), 8.06 (s, 1H, NHCdO), 8.23 (s, 1H,
4-Pyr), 8.26-8.29 (m, 1H, 4-Pyr); IR (ATR) 1225 (C-F) cm-1
Anal. (C27H32FN5O4S) C, H, N.
.
Acknowledgment. We want to thank the Merckle
GmbH, Blaubeuren, Germany, and the Fond der Che-
mischen Industrie, Germany, for financial support. In
addition, we want to acknowledge D. Domeyer for the
molecular modeling; C. Greim, K.Tollmann, and W.
Albrecht for CYP-450 testing; and K. Bauer for technical
assistance.
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Supporting Information Available: Analysis data for
compounds 9-11. This material is available free of charge via
the Internet at http://pubs.acs.org.
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