Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes

Article abstract of DOI:10.1021/jm030766k

A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment of chronic inflammatory diseases. The contribution of sub

Full text of DOI:10.1021/jm030766k

3230
J . Med. Chem. 2003, 46, 3230-3244
Novel Su bstitu ted P yr id in yl Im id a zoles a s P oten t An ticytok in e Agen ts w ith
Low Activity a ga in st Hep a tic Cytoch r om e P 450 En zym es
Stefan A. Laufer,*,† Gerd K. Wagner,†,§ Dunja A. Kotschenreuther,†, and W. Albrecht‡
Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tu¨bingen,
Auf der Morgenstelle 8, 72076 Tu¨bingen, Germany, and Merckle GmbH, Dr. Georg Spohn Strasse, 89143 Blaubeuren, Germany
Received J anuary 15, 2003
A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated
protein) kinase was prepared as small molecular anticytokine agents and drug candidates for
the treatment of chronic inflammatory diseases. The contribution of substituents at the pyridinyl
and imidazole moiety to selective inhibition of p38 without concomitant cytochrome P450
interaction was evaluated. Placement of a 1-phenylethyl (7e, p38: IC50 0.38 µM) or acetyl
substituent at the exocyclic nitrogen of several 2-aminopyridine imidazoles led to the
identification of potent p38 inhibitors which exceeded the starting lead ML 3375 (p38: IC50
0.63 µM) in potency. A preliminary modeling study related the enhanced bioactivity of 7e to a
novel interaction between its 1-phenylethylamino side chain and a hydrophobic pocket close
to the linker region of p38. The most active p38 inhibitors in this series maintained their efficacy
in functional PBMC (peripheral blood mononuclear cells) and whole blood assays. Moreover,
cytochrome P450 interaction, which has been linked to the liver toxicity observed for model
p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine
substituent at the 1 position of the imidazole nucleus. Combination of both structural features
provided 14c (p38: 0.34 µM, inhibition of CYP1A2 0%, 2C9 2.6%, 2C19 7.6% at 10 µM), which
was selected for further development.
In tr od u ction
The stress-induced signal transduction cascade which
regulates the biosynthesis and release of the proinflam-
matory cytokine tumor necrosis factor R (TNF-R) and
interleukin 1â (IL-1â) in various cell types of the
mononuclear lineage requires a dual specifity Ser/Thr
kinase, termed p38 MAP kinase, as an essential com-
ponent.1 TNF-R and IL-1â mediate a multitude of
cellular events underlying chronic inflammatory condi-
tions such as rheumatoid arthritis (RA) and inflamma-
tory bowel disease (IBD).2,3 In addition to its important
role for the secretion of proinflammatory cytokines, p38
is also involved in the activation of matrix metallopro-
teinases (MMP)4 and the induction of cyclooxygenase 2
(COX-2) transcription,5 proteins that are involved in the
process of tissue destruction and inflammation. Because
of its multiple functions in modulating the inflammatory
response, p38 has become a most rewarding molecular
target for the development of novel small molecular
drugs for the treatment of chronic inflammatory dis-
eases.6,7 Several inhibitors of p38 MAP kinase have been
demonstrated to efficiently reduce cytokine levels in
functional assays as well as in animal tests.8,9 Many of
these compounds were derived from the prototypical
pyridin-4-yl imidazole SB 203580 (Table 1), and the
structural requirements for p38 inhibition have been
F igu r e 1. Schematic drawing of important interactions
between the prototypical pyridin-4-yl imidazole inhibitor SB
203580 and the ATP binding site of p38 (modified from ref
11). The hydrophobic area below the linker region is not
occupied by SB 203580.
extensively discussed.8-12 Crystallographic studies13-15
facilitated the acquisition of SAR and together with
biochemical investigations16,17 revealed compounds of
the pyridinyl imidazole class as competitive inhibitors
at the ATP site of p38 (Figure 1).
The general architecture of the ATP site in protein
kinases has recently been reviewed.18 The linker region
between the N- and C-terminal domain, surrounded by
two hydrophobic regions, serves as a highly significant
anchor for the binding of ATP-site directed kinase
inhibitors (Figure 1).18 A common feature observed in
all crystal structures of p38 in complex with respective
pyridin-4-yl imidazole derivatives is the formation of a
* To whom correspondence should be addressed. Telephone
++49-7071-2972459, Telefax ++49-7071-295037, e-mail stefan.laufer@
uni-tuebingen.de.
† Eberhard-Karls-University Tu¨bingen.
‡ Merckle GmbH.
Current address: ratiopharm GmbH, Department of Patent
Affairs, Graf-Arco-Strasse 3, 89079 Ulm, Germany.
§ Current address: Department of Pharmacy and Pharmacology,
University of Bath, Claverton Down, Bath BA2 4QN, United Kingdom.
10.1021/jm030766k CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/24/2003

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3231
Ta ble 1. Pyridinyl Imidazole Inhibitors of P38 MAP Kinase and Cytokine Release
IC50 ( SEM (µM)
IC50 ( SEM (µM) PBMC
compd
X
p38a
TNF-Ra
IL-1âa
SB 203580
ML 3163
ML 3375
bond
-S-CH2-
-
0.29 ( 0.03 (7)
4.0 ( 1.0 (2)
0. 63 ( 0.08 (2)
0.59 ( 0.09 (21)
1.1 ( 0.4 (4)
0.90 ( 0.19 (6)
0.037 ( 0.006 (20)
0.38 ( 0.13 (4)
0.044 ( 0.009 (4)
a
Number in brackets denotes number of experiments.
Sch em e 1a
a
Reagents: (a) LDA, 4-fluoro-N-methoxy-N-methylbenzamide, THF, -85 °C then 0 °C; (b) NaNO2, acetic acid, 10 °C then rt; (c) saturated
2-propanolic hydrogen chloride, reflux; (d) H2, Pd-C 10%, 1 atm, 2-propanolic hydrogen chloride, rt, all yields: 100%; (e) H2, Pd-C 10%,
1 atm, methanolic hydrogen chloride, rt, yield: 100%; (f) Zn°, H2SO4, ethanol, -10 °C then rt; (g) KSCN, DMF, reflux; (h) KSCN, 10%
HCl, reflux, yields: 5b, 31%; 5c, 13%.
hydrogen bond between the backbone NH of Met109 in
the linker region and the pyridine nitrogen of the
inhibitor, thus underlining the crucial importance of this
pyridine ring for biological activity (Figure 1).13-15 While
the 4-fluorophenyl ring of SB 203580 binds to a hydro-
phobic region which in p38 is represented by an unusu-
ally spacious pocket, a second hydrophobic area below
the linker region is left unoccupied by simple pyridin-
4-yl imidazole inhibitors.13,15
The clinical development of first generation p38
inhibitors has been obstructed by their severe liver
toxicity.19 This has been attributed to interference with
hepatic cytochrome P450 enzymes,19 as both pyridine
and imidazole are known ligands for the heme iron of
cytochrome P450.20 It remains unclear to date if one or
both of these heterocycles are responsible for the
observed liver toxicity of pyridin-4-yl imidazoles, and
various strategies have been applied to separate p38
inhibition from cytochrome P450 interaction. The pyri-
dine9,19 as well as the imidazole21-24 ring have been
replaced with other suitable heterocycles, and sterically
demanding substituents have been introduced at the
imidazole N110 or the 2 position of the pyridine.9
reduced basicity of their thioimidazole core as compared
to 2-carba analogues such as SB 203580 might lead to
reduced cytochrome P450 interaction. However, in the
present study we describe that contrary to this initial
concept, only against cytochrome P450 1A2 does ML
3163 show decreased inhibition, while various other
isoforms of cytochrome P450 are still inhibited by ML
3163 and those alkylsulfanyl imidazole analogues bear-
ing a simple pyridin-4-yl ring. To dissect their desired
p38 inhibitory potency from potential liver toxic side
effects, we prepared a set of ML 3163 and ML 3375
analogues substituted at the pyridine C2 and imidazole
N1 positions. To this end we further extended the scope
of our novel synthetic method for the regioselective
preparation of N-substituted imidazoles.26 Suitable
combination of substituents at both heterocycles yielded
several compounds which displayed a highly promising
profile for development as antiinflammatory agents due
to their enhanced anticytokine activity and reduced
affinity for cytochrome P450.
Ch em istr y
The general synthesis of target compounds 6-9
(Schemes 2 and 3) was built around imidazole thiones
5a -f as the key intermediates (Scheme 1). The syn-
thetic pathway devised for 5a -f started from ketones
2a -c and pursued a nitrosation/reduction/cyclization
Previously we have reported about alkylsulfanyl
imidazole derivatives ML 3163 and ML 3375 as potent
inhibitors of p38 and cytokine release (Table 1).25 During
the design of these compounds, it was hoped that the

3232 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Laufer et al.
Sch em e 2
Sch em e 3a
a
Reagents: (a) R2-hal, ethanol/THF 8+2, reflux; (b) iodomethane (7f) or 1-chloromethyl-4-methanesulfinylbenzene (9b), NaH (55-
65%), THF, rt; (c) excess R1-NH2, neat, 160-180 °C.
strategy. 2a -c were obtained according to the low-
temperature protocol described by Liverton for the
synthesis of structurally related ketones (Scheme 1).9
2-Halogeno-4-methylpyridines 1a -c were deprotonated
with LDA and the resulting picolyllithium derivatives
reacted with 4-fluoro-N-methoxy-N-methylbenzamide.8
Upon treatment with sodium nitrite in acetic acid
ketones 2a -c were readily converted into the corre-
sponding R-oximinoketones 3a -c. The TLC and 1H
NMR data for the material thus obtained indicated that
in each instance only a single oxime regioisomer had
been formed. This is in marked contrast to previously
reported findings where R-nitrosation of ketones with
sodium nitrite in aqueous acetic acid/THF has led to a
mixture of oxime regioisomers.9 Heating of fluoropyri-
dine 3a in 2-propanolic hydrogen chloride afforded the
corresponding isopropanoxy pyridine 3d .
The conversion of R-oximinoketones 3a -d into the
corresponding R-aminoketones was required prior to the
ring closure reaction with potassium thiocyanate. Nu-
merous methods for the transformation of oximes into
amines have been disclosed,27,28 the vast majority of
which does not avoid concomitant reduction of the
oxo functionality. Thus, the treatment of an R-oximino-
ketone similar to 3a -d with H2/Pd-C under neutral
conditions has been reported to afford the corresponding
amino alcohol.29 However, preliminary studies sug-
gested Pd-catalyzed hydrogenation as a suitable ap-
proach toward the selective reduction of the oxime group
when carried out under acidic conditions. In alcoholic
hydrogen chloride, the oxime functionality in R-oximino-
ketones 3a -d was reduced to the corresponding amine
after 6 h, while simultaneous hydrogenation of the
ketone group to the corresponding alcohol was never
observed under these conditions. Using this protocol, we
prepared R-aminoketones 4a , 4c, and 4f. In the case of
3a , the successful and selective hydrogenation of the
oxime group was accompanied by the premature acid-
catalyzed nucleophilic replacement of the fluorine sub-
stituent at the pyridine nucleus by the solvent alcohol.
In saturated methanolic hydrogen chloride, 3a was
completely converted into alkoxypyridine 4b during the
hydrogenation reaction. Efforts directed at the optimi-
zation of this reaction step revealed that use of the
sterically less demanding methanol, saturation of the
alcohol with hydrogen chloride, and elevated tempera-
tures favored nucleophilic substitution. In 2-propanolic
hydrogen chloride, the formation of the corresponding
alkoxypyridine 4f occurred only as a side reaction of
negligible proportions. However, treatment of R-oximi-
noketone 3c according to this protocol effected the
hydrogenolytic cleavage of the bromine-carbon bond
and resulted in the formation of the unsubstituted
pyridin-4-yl derivative 4d . We obtained the desired
R-aminoketone 4e by using zinc powder as an alterna-
tive reducing agent, but the general applicability of this
method was limited by the variable yields obtained and
the tedious workup procedure required.30
R-Aminoketones 4a , 4c, and 4f were employed in the
key cyclization step with potassium thiocyanate in DMF
to yield the corresponding imidazole thiones 5a , 5d , and
5f. However, this general method failed in the case of
bromopyridine 4e where only the rapid decomposition
of the starting material, but not the formation of

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3233
Sch em e 4a
synthetic protocol to the preparation of analogues bear-
ing an acetylamino group at the 2 position of the
pyridine ring (Scheme 5). A preliminary account of the
reaction sequence starting from R-oximinoketone 11 and
leading to N-methyl imidazole 17a via the intermediate
imidazole-N-oxide 12a , imidazole-2-thione 13a and
2-methylsulfanyl imidazole 14a has appeared.31 In
addition to N1-methyl imidazole 14a , analogues 14b
and 14c were prepared following the established syn-
thetic procedures. LiAlH4 reduction of the acetylamino
group in 14a -c provided the respective ethylamino
pyridines 15a -c. Finally, the aminopyridine 16a re-
sulted from the desacetylation of acetylamino pyridine
14a and was reacted with appropriate alkyl or acyl
halides to yield target compounds 17a -d . The N-
substituted imidazoles 18a and 18b (Scheme 6) were
obtained from their N-unsubstituted precursors 6 and
7a by direct alkylation as described previously.31 Upon
treatment with (RS)-1-phenylethylamine, fluoropyridine
18b was converted into phenylethylamino pyridine
18c.31
a
Reagents: (a) excess 4-methoxybenzylamine, neat, reflux; (b)
excess (RS)-1-phenylethylamine, neat, reflux.
imidazole-2-thione 5e was observed. On the other hand,
the ring closure reaction of methoxypyridine 4b with
KSCN presumably afforded imidazole-2-thione 5b ,
though we were not able to isolate this putative primary
reaction product. Instead, the aprotic reaction medium
permitted 5b to undergo an unexpected in-situ intra-
or intermolecular transfer reaction of the methyl group
which led to the formation of 2-methylsulfanyl imidazole
6 as the sole reaction product (Scheme 2). The structure
assigned to 6 is strongly supported by the characteristic
singulets for the pyridone (δ ) 11.38 ppm) and meth-
ylsulfanyl protons (δ ) 2.61 ppm) in the 1H NMR
spectrum as well as by the presence of the strong NH
bending in the IR spectrum (λ-1 ) 1634 cm-1). We
conclude that this rearrangement reaction largely de-
pends on the nature of the solvent, as imidazole-2-thione
5b could be prepared from 4b and KSCN in 10%
hydrochloric acid. The synthesis of 5b under aqueous
conditions was accompanied by the formation of its
hydrolysis product 5c, while not even traces of 6 were
isolated. It should be pointed out that following its
formation from 4f and KSCN in DMF, the sterically
more demanding isopropanoxy pyridine 5f did not
rearrange in this fashion.
Methylation or benzylation of the exocyclic sulfur
atom in 5a , 5b, 5d , and 5f according to the procedure
previously described25 furnished the corresponding alkyl-
sulfanyl imidazole derivatives 7a -b, 7e-f, 8a ,b, and
9a ,b (Scheme 3). Target compounds 7c-9c, 7d -9d , and
7g-7o, bearing a substituted nitrogen functionality at
the pyridine ring, were prepared from the corresponding
fluoropyridine precursors 7a -9a by nucleophilic re-
placement with an appropriate amine (Scheme 3).9 This
synthetic procedure allowed for the ready variation of
substituents at the pyridine ring as well as for the
synthesis of enantiomerically pure benzylethylamines
7g and 7h . The racemic analogue 9c, which contains a
second center of chirality at the sulfoxide, was obtained
as a mixture of diastereoisomers. In general, the fluo-
ropyridine analogues 7a -9a proved to be better suited
for the nucleophilic replacement reaction than the
corresponding chloropyridines. Under otherwise identi-
cal conditions, the reaction of chloropyridine 8b with
4-methoxybenzylamine could not be driven to comple-
tion even after a prolonged reaction time and afforded
8e in only 24% yield (Scheme 4). In turn, this prolonged
reaction time promoted the base-catalyzed cleavage of
the benzylsulfanyl side chain when 8b was reacted with
1-phenylethylamine. After 22 h imidazole-2-thione 10
was isolated as the only product from this reaction.
Previously we have developed a general method to
regiospecifically prepare N1-substituted pyridin-4-yl
imidazoles from suitable R-oximinoketones.26 During the
course of this study we extended the scope of this
Biologica l Resu lts a n d Discu ssion
It has been demonstrated in two different series of
p38 inhibitors that p38 inhibitory potency correlates
with the electron density at the respective heterocyclic
ring nitrogen, which forms the crucial hydrogen bond
to the enzyme backbone at Met109.32,33 Starting from
parent compound ML 3375,25 placement of small electron-
withdrawing substituents at the 2 position of the
pyridin-4-yl moiety resulted in an up to 10-fold decrease
in activity for halogenopyridines 7a and 7b in the
functional assay (Table 2). 7a also showed diminished
activity in the p38 assay. We presume that it is mainly
the poor inhibition of p38 which is responsible for poor
activity in the cellular assay. In the case of halogenopy-
ridines 7a and 7b, the loss of potency can be attributed
to the reduced electron density at the pyridine ring
nitrogen and the subsequent weakening of the hydrogen
bond to the amide NH of Met109. Similarly, the weak
activity of the oxygen-containing analogue 6, which
predominantly exists in the pyridone form, can be
explained by its completely altered hydrogen bonding
properties. The reversed donor/acceptor pattern of py-
ridone 6 presumably interferes with tight binding at the
linker region of the enzyme. Formally replacing the
hydroxyl group of 6 with a methoxy group reconstituted
the sp2 hybridization of the pyridine nitrogen and led
to slightly enhanced potency (7e). However, isopropan-
oxy pyridine 7f surpassed the methoxy analogue 7e in
activity by 1 order of magnitude. 7f inhibited p38 and
IL-1â release with similar efficacy as ML 3375 and
reduced TNF-R release twice as effectively. This result
triggered the search for even better suited substituents
at the 2 position of the pyridine ring.
Regarding the benefit gained from the presence of the
isopropanoxy residue in 7f, the superiority of 7f over
7e suggests that the branched hydrocarbon side chain
rather than the oxygen atom is responsible for the
improved inhibitory potency. We hoped to enhance
bioactivity further by extending the lipophilic portion
of the substituent at the 2 position of the pyridine.
Formal replacement of the oxygen in 7f with a nitrogen
and attachment of an aromatic ring at the hydrocarbon

3234 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Laufer et al.
Sch em e 5a
a
Reagents: (a) substituted triazinane, ethanol, reflux; (b) 2,2,4,4-tetramethylcyclobutane-1,3-dithione, DCM, ice bath then rt; (c)
iodomethane, Na2CO3, THF/ethanol 8+2, reflux; (d) LiAlH4, THF, reflux; (e) 10% HCl, reflux; (f) R2-hal, NaH (55-65%), DMF, reflux;
bTMP: 2,2,6,6-tetramethylpiperidin-4-yl.
Sch em e 6a
stituents at the benzyl moiety to bioactivity by applica-
tion of the Topliss strategy.35 These structural modifi-
cations were expected to affect the interaction between
the aromatic portion of the side chain and the putative
hydrophobic binding site. There was, however, no
outstanding difference in activity between compounds
bearing electron rich (7i, 7j) or electron poor (7k , 7l)
substituents. Anilino derivative 7m and 2-phenylethyl-
amine 7n were prepared to elucidate the optimum
distance between the aryl group and the pyridine
nucleus. Compared to 7d , both extending and shorten-
ing this distance led to improved results in the PBMC
and enzyme assay. A possible explanation for these
results may be provided by the putative binding site
stretching both above and below the pyridine ring
(Figure 2). The length of the side chain in 7m and 7n
may be ideal for the respective phenyl ring to interact
with either one of both areas. This model also accounts
for the similar activities of 7i-l as substituents at the
3 and 4 position of the phenyl ring do not interact with
the enzyme but point toward the solvent. The loss of
activity for the tertiary amine 7o illustrates the steric
constraints at this position rather than the importance
of the exocyclic NH functionality. A hydrogen donor at
this position is no prerequisite to activity as is demon-
strated by the potency of oxygen analogue 7f.
a
Reagents: (a) iodomethane, methanol, reflux (18a ); (b) DMF-
DMA, toluene, reflux (18b); (c) excess (RS)-1-phenylethylamine,
neat, reflux
side chain indeed yielded the highly potent 1-phenyl-
ethylamino pyridine 7c, which clearly exceeded lead
compound ML 3375 with regard to p38 and TNF-R
release inhibition (Table 2). The efficacy of 7c confirmed
the view that the nature of the heteroatom which serves
as a linker between the hydrocarbon side chain and the
pyridine ring is of minor importance.
On the basis of the molecular modeling of 7g (i.e., the
R-enantiomer of 7c) into the ATP cleft of p38 (Figure
2),34 the contribution of the hydrocarbon side chain to
increased enzyme inhibition can be attributed to its
interaction with a hydrophobic area in close proximity
to the linker region, which cannot be occupied by simple
pyridinyl imidazoles such as SB 203580 and ML 3375.
This finding prompted us to explore the structural
requirements for interaction with this putative binding
site. The stereochemistry in the side chain seems to
exert a considerable influence on binding at this posi-
tion, as the R-enantiomer 7g displayed higher activity
against p38 than the S-enantiomer 7h . However, this
difference disappeared in the cellular assay. Similar
inconsistent correlations between stereochemistry and
bioactivity have been described for other imidazole
inhibitors of p38.9 Eradication of the stereocenter (7d )
led to a notable decrease in activity in all test assays.
Next we sought to determine the contribution of sub-
Appropriate substituents at the 2 position of the
imidazole nucleus have been associated with the im-
proved binding properties8,15 and enhanced cellular
activity9 of several p38 inhibitors. Most notably it has
been reported that imidazole inhibitors of p38 bearing
no substituent at both the 1 and 2 position are devoid
of cellular and whole blood anticytokine activity.9 With
this in mind we investigated how replacement of the
comparatively small methylsulfanyl substituent with a
benzylsulfanyl or substituted benzylsulfanyl moiety

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3235
Ta ble 2. Methylsulfanylimidazoles
F igu r e 2. Modeling of 7g into the ATP cleft of p38 MAP
kinase (color code: red ) hydrophobic regions, blue ) hydro-
philic regions). The arrows denote the hydrophobic area in
close proximity to the linker region which stretches bot above
and below the pyridine ring.
Ta ble 3. Benzylsulfanylimidazoles
a
Results are of one experiment except where otherwise stated.
b
Tests were carried out in duplicate except where otherwise
stated. c 6 predominantly exists in the pyridone form. Not de-
d
termined.
present in ML 3163 affected biological activity. Imida-
zole derivatives bearing larger substituents at the 2
position were generally less active than the methylsul-
fanyl analogues in both the p38 and PBMC assay (Table
3). The unfavorable influence of electron withdrawing
substituents at the pyridine was confirmed in the
benzylsulfanyl series (8a , 8b, 9a , 9b). With respect to
inhibition of TNF-R release, this effect was partially
overcome by the presence of the polar methylsulfinyl
moiety at the 4 position of the benzylsulfanyl substitu-
ent (9a , 9b). However, as soon as there were more
effective substituents attached to the pyridine the
importance of substituents at the 2 position dwindled.
Larger groups were better tolerated at the 2 position of
the imidazole if at the same time the most effective
1-phenylethylamine (8c, 9c) or a benzylamine substitu-
ent (8d , 9d ) was placed at the pyridine ring. For these
two pairs of compounds the benefits of the methyl-
sulfinyl moiety for inhibition of TNF-R release also
a
Results are of one experiment except where otherwise stated.
b
Tests were carried out in duplicate except where otherwise
stated. c Not determined.
disappeared. Modification of the benzylamine substitu-
ent at the 4 position was unexpectedly deleterious for
bioactivity (8e).
In the second part of this study we focused on the
interdependency of biological effects exerted by substit-
uents at the imidazole N1 and at the pyridine ring
(Tables 4, 5). In full accordance with data for other p38
inhibitors8 the presence of a substituent at the imidazole
ring nitrogen adjacent to the 4-fluorophenyl moiety was
detrimental for bioactivity (18a , 18c) (Table 4). This

3236 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Ta ble 4. Regioisomers
Laufer et al.
Ta ble 5. Combination of Substituents at the Imidazole and
Pyridine Moiety
a
Results are of one experiment except where otherwise stated.
b
Tests were carried out in duplicate except where otherwise
stated. c 18a predominantly exists in the pyridone form. Not
d
determined.
observation was ascribed to the repulsive interaction of
the respective substituent with the side chain of Lys
53 which otherwise interacts with the lone pair of the
imidazole ring nitrogen (Figure 1).15 In various com-
plexes of p38 with imidazole inhibitors substituents at
the imidazole ring nitrogen adjacent to the pyridin-4-yl
ring do not cause any unfavorable contact between
inhibitor and p38 but are exposed to solvent13 or interact
with the side chain of Asp 168.14,15 The excellent potency
of compound 17a compared to its regioisomer 18c
strongly supported the validity of this concept in the
methylsulfanyl imidazole series presented herein. Pre-
viously we have found that small lipophilic substituents
(CH3, C3H7) at N1 of the core imidazole are suited best
for inhibition of cytokine release in a series of N1-
substituted pyridin-4-yl imidazoles.26 N-Substituted
compounds bearing a simple pyridin-4-yl ring at the 5
position of the imidazole (19-21) were less active
though than the nonsubstituted analogue ML 3375
(Table 5).26 Formal introduction of a simple amino
functionality at the pyridine ring (16a , 16b) did not lead
to enhanced potency in this series. However, acetylation
(14a , 14b), alkylation (15a , 15b), or benzylation (17b)
of the exocyclic nitrogen of aminopyridines 16a and 16b
clearly increased anticytokine activity with 17b being
equipotent to its N-unsubstituted analogue 7d . In the
series of N-substituted imidazoles this effect was most
pronounced when the simple alkyl side chain at the
imidazole nitrogen was replaced with the sterically
demanding and basic tetramethylpiperidinyl substitu-
ent of compounds 14c and 15c. Compared to the
corresponding pyridine 21, a more than 50-fold better
inhibition of p38 was observed in the case of substituted
pyridines 14c and 15c although most of this beneficial
effect was lost in the PBMC assay. Placement of an
aromatic ring at the acetyl group of 14a resulted in only
moderate cellular activity for 17c. The complete inactiv-
ity of dibenzylamine 17d illustrates the limited space
available at the putative binding site.
a
Results are of one experiment except where otherwise stated.
b
Tests were carried out in duplicate except where otherwise
stated. c Not determined.
moiety of ML 3163 with a simple methyl group proved
to be favorable for TNF-R inhibition. N-Substituted and
nonsubstituted imidazole analogues displayed equipo-
tency in the pyridine (19 vs ML 3375) as well as in the
substituted pyridine series (17a vs 7c). However, the
acetylamino functionality present in 14a led to an
exceptional loss of activity in whole blood compared to
the PBMC results. In the tetramethylpiperidine series
(14c, 15c, 21) conflicting results were obtained, al-
though this substituent was seemingly unfavorable for
whole blood activity.
Cytoch r om e P 450 Affin ity. Reference compound
ML 3163 at a concentration of 10 µM displayed more
than 50% inhibition of four isoforms of cytochrome P450
(Table 7). At the same molar concentration ML 3375
exhibited moderate to high affinity for all isoforms
included in the assay. It was expected that the reduced
electron density of the 2-chloropyridine in 7b may
reduce coordination to the cytochrome heme iron if the
pyridine was predominantly responsible for this interac-
tion. However, introduction of electron-withdrawing or
large lipophilic substituents at the pyridin-4-yl moiety
merely shifted selectivity for reduced cytochrome inter-
action from CYP1A2 toward CYP2D6 but did not
improve the overall affinity profile (7b, 7c, 7f). The same
pattern of P450 inhibition was observed for 17a , the
N-methylated analogue of 7c. Combination of the N-
methyl imidazole core with an acetylamino pyridine led
In the whole blood screen even structurally diverse
compounds inhibited the release of both cytokines with
similar IC50 values in the low micromolar range (Table
6). In general, replacement of the methylsulfanyl benzyl

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3237
IC50 ( SEM (µM)
Ta ble 6. Whole Blood Results for Selected Compoundsa
IC50 ( SEM (µM)
compd
TNF-R
IL-1â
compd
TNF-R
IL-1â
SB 203580
ML 3163
ML 3375
7c
7f
14a
0.94 ( 0.14 (12)
20.3 ( 4.8
0.35 ( 0.09 (12)
2.78 ( 0.13
1.2 ( 0.6
14c
15a
15c
17a
19
5.4 ( 3.6
5.0 ( 1.3
2.15 (1)
2.0 ( 0.6
2.7 ( 1.9
4.1 ( 1.0 (2)
1.08 ( 0.73
18.5 ( 13.1 (3)
4.2 ( 0.7
11.0 (5.5
2.7 ( 0.3
0.99 ( 0.46
2.2 ( 0.8
3.0 ( 1.7 (4)
5.1 ( 0.4
19.1 ( 8.6 (4)
7.2 ( 1.8
12.5 ( 6.4 (4)
10.8 ( 6.9 (4)
21
a
Results are given as the mean of two experiments except where otherwise stated.
Ta ble 7. Inhibition [%] of Five CYP450 Isoforms by Selected
Compounds at 10 µM
position of the imidazole contribute to bioactivity only
to a lesser extent. However, this site of interaction
becomes more important and can be exploited for
enhanced binding if the crucial hydrogen bond between
pyridine and Met109 is weakened (9a , 9b). Large
substituents at the N1 of the imidazole are unfavorable
for inhibition of p38. On the other hand these same
substituents at the imidazole N1 (14c, 21) practically
eliminated interaction with cytochrome P450 while
compounds solely substituted at the pyridine (7b, 7c,
7f) only displayed moderately decreased affinity for the
single P450 isoform 2D6. Therefore we conclude that
in this series of pyridinyl imidazoles the substituted
pyridine moiety is of critical importance for activity
while the imidazole ring is responsible for interference
with cytochrome P450. By optimum combination of
substituents at both heterocycles we have identified a
set of efficient anticytokine agents with considerably
reduced P450 interaction. The most promising candi-
dates are currently investigated in animal models of
inflammation.
compd
1A2
2C9
2C19
2D6
3A4
SB 2035019
61
75
85
67
61
ML 3163
ML 3375
7b
7c
7f
14a
14c
17a
21
8.4
72.7
72.4
65.0
79.0
67.5
27.6
2.6
73.6
79.5
41.4
83.5
62.6
20.3
7.6
71.8
39.8
18.6
31.1
<0
13.4
14.6
12.4
19.1
87.1
81.4
48.8
79.2
49.6
16.5
79.0
85.8
49.6
43.5
92.6
66.7
83.2
32.4
<0
57.1
9.0
83.3
7.9
90.9
15.3
to promising results with acetylamino pyridine 14a
showing only low to moderate affinity for all tested P450
isoforms. Introduction of the tetramethylpiperidinyl
moiety at the imidazole nucleus further minimized the
inhibition of P450. Acetylamino pyridine 14c did practi-
cally not interfere with cytochrome P450 isoforms 1A2,
2C9, 2C19, and 2D6, although 3A4 was considerably
affected. Similar results for pyridine compound 21
suggest that this beneficial effect primarily has to be
attributed to the tetramethylpiperidinyl rather than the
acetylamino moiety.
Exp er im en ta l Section
Gen er a l. All reagents and solvents were of commercial
quality and used without further purification. Melting points
were determined on a Buchi Melting Point B-545 apparatus
and are thermodynamically corrected. 1H and 13C NMR spectra
were collected on a Bruker Spectrospin AC 200 at 200 MHz.
Chemical shifts are reported in parts per million relative to
TMS as internal standard. Infrared spectra were recorded by
ATR technique on a Perkin-Elmer Spectrum One spectrom-
eter. GC/MS analyses were carried out on a HP 6890 series
GC-system equipped with a HP-5MS capillary column (0.25
µm film thickness, 30 m × 0.25-mm i.d.) and a HP 5973 mass
selective detector (70 eV). Helium was used as carrier gas, and
the following temperature program was employed: initial
isothermal period of 1.0 min at 100 °C, then an increase at
15.0 °C/min to 225 °C with an isothermal period of 1.0 min at
290 °C, then an increase at 25.0 °C/min to 270 °C with an
isothermal period of 10.0 min at 270 °C. GC data are presented
as retention times (min) and MS results as m/z ratio and
intensity (%) relative to the base peak. Mass spectra were
recorded on a Finnigan Triple-Stage-Quadrupol (TSQ-70).
Enantiomeric purity of chiral compounds was determinded by
HPLC on a Chiralpak AD column (10 µm, 250 × 4.6 mm)
which was eluted isocratically with a n-hexane/2-propanol
system at a flow rate of 1.0 mL/min (UV detection at 254 or
215 nm). HPLC results are given as retention times (min) and
relative purity (%). TLC analyses were performed on fluores-
cent silica gel 60 plates (Macherey-Nagel Art.-Nr. 805021).
Spots were visualized under UV illumination at 254 and 365
nm. Microanalyses were carried out on a Perkin-Elmer EA
2400 instrument. The following compounds were prepared
according to literature procedures: SB 203580,8 1b,36 and 1c.37
The syntheses and analytical properties of ML 3163, ML 3375
and compounds 11, 12a -14a , 16a , 17a , 18a -c, and 19-21
have been reported elsewhere.25,26,31
Con clu sion
The polysubstituted pyridinyl imidazole inhibitors of
p38 presented herein efficiently suppressed the release
of TNF-R and IL-1â from PBMC. Different structural
features seem to be responsible for efficient inhibition
of p38 and cytokine release and unwanted coordination
to cytochrome P450. Weakening the crucial hydrogen
bond between the ring nitrogen and the amide NH of
Met109 led to reduced anticytokine activity (6, 7a , 7b)
but scarcely affected P450 inhibition (7b). The presence
of an additional aromatic (e.g., 7c) or aliphatic (7f) side
chain linked to the pyridine ring via an electron-
donating heteroatom enhanced inhibitory potency. While
in the present study the issue of the optimum nature
of the heteroatom linker has not been systematically
addressed, we suggest that with their (aryl-)alkyl part
these side chains fit into a hydrophobic region present
in all protein kinases.18 In the case of p38 this hydro-
phobic region seems to be capable of accommodating
large and electronically diverse (7c, 7d , 7g-m ) substit-
uents. Introduction of large substituents at the 1 and 2
position of the core imidazole resulted in a general loss
of activity. This effect could be overcome by introducing
appropriate substituents at the pyridinyl moiety.
These findings corroborate and refine our previously
proposed model of a hierarchy of interaction sites:25 It
is predominantly modifications at the pyridine which
affect inhibition of p38 and anticytokine activity in this
series of compounds. Substituents placed at the 2
1-(4-F lu or op h en yl)-2-(2-flu or op yr id in -4-yl)et h a n on e
(2a ). Starting from 1a (13.9 g, 125 mmol), 28.7 g (99%) of

3238 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Laufer et al.
2a was obtained according to the method described for
the synthesis of 2b : mp 116 °C; 1H NMR (CDCl3) δ 4.32
(s, 2H, CH2), 6.85-6.86 (m, 1H, C3-H 2-F-Pyr), 7.08-7.19
(m, 3H, C5-H 2-F-Pyr and 4-F-Ph), 8.00-8.07 (m, 2H, 4-F-Ph),
8.18 (d, 1H, 5.1 Hz, C6-H 2-F-Pyr); IR 1684 (CdO), 1235 cm-1
(C-F); GC 8.77 min; MS m/z (%) 233 (6, M+), 123 (100),
95 (94), 75 (56).
5.2 Hz, C6-H 2-Br-Pyr), 12.72 (bs, 1H, exchangeable, OH); IR
1673 (CdO), 1238 cm-1 (C-F).
1-(4-Flu or oph en yl)-2-(2-isopr opoxypyr idin -4-yl)eth an e-
1,2-d ion e 2-Oxim e (3d ). A solution of 3a (200 mg, 0.76 mmol)
in saturated 2-propanolic hydrogen chloride was heated to
reflux for 2.5 h. The solvent was evaporated, and the slightly
yellow residue was triturated with ethanol to yield 0.11 g (48%)
1
2-(2-Ch lor op yr id in -4-yl)-1-(4-flu or op h en yl)et h a n on e
(2b). Under an argon atmosphere, n-butyllithium (15% in
n-hexane, 45 mL, 104 mmol) was added to a solution of
diisopropylamine (15 mL, 106 mmol) in THF absol (150 mL)
at -85 °C. The slightly yellow solution was stirred at -85 °C
for 55 min. Upon dropwise addition of a solution of 1b (8.6 g,
68 mmol) in THF absol (75 mL) at -85 °C, the color of the
reaction immediately turned purple. After the addition was
complete, the mixture was stirred at -85 °C for 1 h. Within 3
min a solution of 4-fluoro-N-methoxy-N-methylbenzamide8
(12.4 g, 68 mmol) in THF absol (75 mL) was added at -85 °C.
The purple slurry was stirred at -85 °C for 1 h and warmed
to 0 °C during 1 h. The reaction was poured onto a bilayer
system of saturated brine (300 mL) and ethyl acetate (300 mL).
The aqueous phase was extracted with ethyl acetate (2 × 250
mL). The combined organic extracts were washed with satu-
rated brine, dried over NaSO4, and concentrated in vacuo. The
oily residue was dissolved in tert-butyl methyl ether, and the
ethereal solution was kept at 4 °C overnight, after which period
11.2 g (66%) of 2b had precipitated as a crystalline solid: mp
of 3d : mp 227 °C; H NMR (DMSO-d6) δ 1.24 (d, 6H, 6.2 Hz,
2 × CH3), 5.15-5.27 (m, 1H, methine-H), 6.54 (s, 1H, C3-H
2-Iso-O-Pyr), 7.08 (dd, 1H, 1.2/5.3 Hz, C5-H 2-Iso-O-Pyr), 7.36-
7.49 (m, 2H, 4-F-Ph), 7.88-7.97 (m, 2H, 4-F-Ph), 8.19 (d, 1H,
5.4 Hz, C6-H 2-Iso-O-Pyr), 12.44 (bs, 1H, exchangeable, OH);
IR 1672 (CdO), 1226 cm-1 (C-F).
2-Am in o-2-(2-flu or op yr id in -4-yl)-1-(4-flu or op h en yl)-
eth a n on e Hyd r och lor id e (4a ). With gentle heating, 3a (5.0
g, 19 mmol) was dissolved in saturated 2-propanolic hydrogen
chloride/2-propanol (1+1, 60 mL). The yellow solution was
cooled to room temperature. Pd-C 10% (1.5 g) was added, and
the reaction was flushed with hydrogen gas (4×). The slurry
was agitated at room temperature under an atmosphere of
hydrogen at atmospheric pressure until no starting material
was detected by TLC (SiO2 60, DCM/ethanol 9+1; 6.5 h). The
catalyst was filtered off and washed with methanol. The
combined filtrates were concentrated in vacuo to yield 5.4 g
(100%) of crude 4a as an amorphous solid which was employed
in the subsequent reaction step without further purification:
1
mp 248 °C; H NMR (DMSO-d6) δ 6.58 (bs, 1H, methine-H),
1
7.33-7.41 (m, 2H, 4-F-Ph), 7.54 (m, 2H, C3-/C5-H 2-F-Pyr),
8.14-8.25 (m, 2H, 4-F-Ph), 8.30 (d, 1H, 5.5 Hz, C6-H 2-F-Pyr),
9.40 (bs, 3H, exchangeable, NH3+); 13C NMR (DMSO-d6) δ 56.7
(methine), 110.4 (d, 39.3 Hz, C3 2-F-Pyr), 116.8 (d, 22.1 Hz,
C2/C6 4-F-Ph), 122.2 (d, 4.3 Hz, C5 2-F-Pyr), 129.9 (d, 2.8 Hz,
C4 4-F-Ph), 132.8 (d, 9.9 Hz, C3/C5 4-F-Ph), 147.3 (d, 8.3 Hz,
C4 2-F-Pyr), 149.2 (d, 15.2 Hz, C6 2-F-Pyr), 163.4 (d, 236.6 Hz,
C2 2-F-Pyr), 166.2 (d, 255.1 Hz, C1 4-F-Ph), 191.3 (carbonyl);
IR 2811 (NH3+), 1695 (CdO), 1240 cm-1 (C-F).
109 °C; H NMR (CDCl3) δ 4.26 (s, 2H, CH2), 7.11-7.26 (m,
4H, C3-/C5-H 2-Cl-Pyr and 4-F-Ph), 7.99-8.06 (m, 2H, 4-F-Ph),
8.35 (dd, 1H, 0.6/5.1 Hz, C6-H 2-Cl-Pyr); IR 1685 (CdO), 1232
cm-1 (C-F); GC 10.29 min; MS m/z (%) 249 (3, M+), 123 (100),
95 (44), 75 (11).
2-(2-Br om op yr id in -4-yl)-1-(4-flu or op h en yl)et h a n on e
(2c). Starting from 1c (9.6 g, 56 mmol), 15.5 g (94%) of 2c
was obtained according to the method described for the
1
synthesis of 2b: mp 112 °C; H NMR (CDCl3) δ 4.35 (s, 2H,
CH2), 7.17-7.37 (m, 3H, 2-Br-Pyr and4-F-Ph), 7.50 (s, 1H, C3-H
2-Br-Pyr), 8.07-8.15 (m, 2H, 4-F-Ph), 8.42 (d, 1H, 5.1 Hz, C6-H
2-Br-Pyr); IR 1685 (CdO), 1228 cm-1 (C-F); GC 11.05 min;
MS m/z (%) 293 (2, M+), 123 (100), 95 (43), 75 (12).
2-Am in o-1-(4-flu or op h en yl)-2-(2-m eth oxyp yr id in -4-yl)-
eth a n on e Hyd r och lor id e (4b). Upon treatment of 3a (7.5
g, 29 mmol) under the conditions decribed for the preparation
of 4c, 8.5 g (100%) of 4b was obtained as the only product:
mp 252 °C; 1H NMR (DMSO-d6) δ 3.83 (s, 3H, CH3), 6.44 (bs,
1H, methine-H), 7.13-7.16 (m, 2H, C3-/C5-H 2-MeO-Pyr),
7.34-7.46 (m, 2H, 4-F-Ph), 8.16-8.25 (m, 3H, C6-H 2-MeO-
Pyr and 4-F-Ph), 9.29 (bs, 3H, exchangeable, NH3+); 13C NMR
(DMSO-d6) δ 53.4 (CH3), 56.6 (methine), 110.8 (C3 2-MeO-Pyr),
116.2 (d, 22.1 Hz, C2/C6 4-F-Ph), 120.4 (C5 2-MeO-Pyr), 129.5
(d, 2.9 Hz, C4 4-F-Ph), 132.3 (d, 9.9 Hz, C3/C5 4-F-Ph), 143.9
(C4 2-MeO-Pyr), 147.3 (C6 2-MeO-Pyr), 163.8 (C2 2-MeO-Pyr),
165.7 (d, 254.7 Hz, C1 4-F-Ph), 191.2 (carbonyl); IR 1693 (Cd
O), 1235 cm-1 (C-F).
2-Am in o-2-(2-ch lor op yr id in -4-yl)-1-(4-flu or op h en yl)-
eth a n on e Hyd r och lor id e (4c). 3b (1.5 g, 5.4 mmol) was
dissolved in methanol (15 mL) and treated, under the condi-
tions as described for the preparation of 4a , with saturated
methanolic hydrogen chloride (20 mL) in place of the mixture
of 2-propanol and 2-propanolic hydrogen chloride. Thus 1.6 g
(100%) of 4c was obtained: mp 215°C; 1H NMR (DMSO-d6) δ
6.53 (bs, 1H, methine-H), 7.35-7.45 (m, 2H, 4-F-Ph), 7.59 (dd,
1H, 1.5/5.2 Hz, C5-H 2-Cl-Pyr), 7.85 (d, 1H, 0.9 Hz, C3-H 2-Cl-
Pyr), 8.17-8.25 (m, 2H, 4-F-Ph), 8.49 (d, 1H, 4.9 Hz, C6-H 2-Cl-
Pyr), 9.33 (bs, 3H, exchangeable, NH3+); 13C NMR (DMSO-d6)
δ 56.6 (methine), 116.8 (d, 22.2 Hz, C2/C6 4-F-Ph), 123.3 (C5
2-Cl-Pyr), 124.7 (C3 2-Cl-Pyr), 129.9 (d, 2.8 Hz, C4 4-F-Ph),
132.8 (d, 9.9 Hz, C3/C5 4-F-Ph), 145.0 (C4 2-Cl-Pyr), 151.2 (C6
2-Cl-Pyr), 151.3 (C2 2-Cl-Pyr), 166.2 (d, 255.2 Hz, C1 4-F-Ph),
191.2 (carbonyl); IR 2801 (NH3+), 1693 (CdO), 1240 cm-1 (C-
F).
1-(2-F lu or op yr id in -4-yl)-2-(4-flu or op h en yl)eth a n e-1,2-
d ion e 1-Oxim e (3a ). Starting from 2a (10.0 g, 43 mmol), 9.7
g (86%) of 3a was obtained according to the method described
for the synthesis of 3b: mp 174 °C; 1H NMR (DMSO-d6) δ
7.19-7.20 (m, 1H, C3-H 2-F-Pyr), 7.35-7.47 (m, 3H, C5-H 2-F-
Pyr and 4-F-Ph), 7.91-7.98 (m, 2H, 4-F-Ph), 8.29 (d, 1H, 5.3
Hz, C6-H 2-F-Pyr), 12.69 (s, 1H, exchangeable, OH); IR 1669
(CdO), 1263 (C-F), 1235 cm-1 (C-F); 13C NMR (DMSO-d6) δ
105.4 (d, 40.0 Hz, C3 2-F-Pyr), 116.7 (d, 22.4 Hz, C2/C6 4-F-
Ph), 118.2 (d, 4.1 Hz, C5 2-F-Pyr), 130.8 (d, 2.7 Hz, C4 4-F-
Ph), 132.2 (d, 10.1 Hz, C3/C5 4-F-Ph), 144.3 (d, 8.5 Hz, C4 2-F-
Pyr), 148.8 (d, 15.6 Hz, C6 2-F-Pyr), 151.9 (d, 4.1 Hz, oximino),
163.5 (d, 235.8 Hz, C2 2-F-Pyr), 166.0 (d, 254.9 Hz, C1 4-F-
Ph), 192.1 (carbonyl).
1-(2-Ch lor op yr id in -4-yl)-2-(4-flu or op h en yl)eth a n e-1,2-
d ion e 1-Oxim e (3b). A solution of NaNO2 (0.85 g, 12.3 mmol)
in H2O (10 mL) was added dropwise to a solution of 2b (3.0 g,
12 mmol) in glacial acetic acid at 10 °C. After the addition
was complete, the reaction was stirred at room temperature
for 30 min. The mixture was diluted with H2O (60 mL), and
the cream-colored slurry was stirred at room temperature for
another 3 h. The precipitate was collected by filtration, washed
with H2O, and dried in vacuo over CaCl2 to yield 3.0 g (91%)
1
of 3b: mp 200 °C; H NMR (DMSO-d6) δ 7.34-7.52 (m, 4H,
C3-/C5-H 2-Cl-Pyr and 4-F-Ph), 7.93-8.00 (m, 2H, 4-F-Ph), 8.47
(d, 1H, 5.2 Hz, C6-H 2-Cl-Pyr), 12.71 (bs, 1H, exchangeable,
OH); IR 1673 (CdO), 1239 cm-1 (C-F).
1-(2-Br om op yr id in -4-yl)-2-(4-flu or op h en yl)eth a n e-1,2-
d ion e 1-Oxim e (3c). Starting from 2c (5.0 g, 17 mmol), 4.2 g
(76%) of 3c was obtained according to the method described
for the synthesis of 3b: mp 214 °C; 1H NMR (DMSO-d6) δ
7.40-7.48 (m, 3H, C3-H 2-Br-Pyr and 4-F-Ph), 7.65 (d, 1H, 0.8
Hz, C5-H 2-Br-Pyr), 7.93-8.01 (m, 2H, 4-F-Ph), 8.45 (d, 1H,
2-Am in o-1-(4-flu or oph en yl)-2-pyr idin -4-yl-eth an on e Hy-
d r och lor id e (4d ). Upon treatment of 3c (4.0 g, 12.4 mmol)
under the conditions decribed for the preparation of 4c, 3.3 g
(100%) of 4d was obtained as the only product: mp 198 °C;
1H NMR (DMSO-d6) δ 6.78 (bs, 1H, methine-H), 7.32-7.38 (m,
2H, 4-F-Ph), 8.07-8.13 (m, 2H, 4-Pyr), 8.17-8.27 (m, 2H, 4-F-

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3239
Ph), 8.92-8.95 (m, 2H, 4-Pyr), 9.43 (bs, 3H, exchangeable,
NH3+); IR 2801 (NH3+), 1686 (CdO), 1237 cm-1 (C-F).
Hz, C4 4-F-Ph), 128.5, 131.5 (d, 8.7 Hz, C3/C5 4-F-Ph), 139.3,
150.5 (C6 2-Cl-Pyr), 151.2 (C2 2-Cl-Pyr), 162.9 (d, 247.3 Hz, C1
4-F-Ph), 162.9 (C2 imidazole); IR 1515 (C(S)NH), 1219 cm-1
(C-F).
4-(4-F lu or op h en yl)-5-(2-isop r op oxyp yr id in -4-yl)-1,3-d i-
h yd r oim id a zole-2-th ion e (5f). Starting from 4f (2.5 g, 7.6
mmol), 1.8 g (70%) of 5f was obtained according to the method
described for the synthesis of 5d : mp 217 °C; 1H NMR (DMSO-
d6) δ 1.24 (d, 6H, 6.2 Hz, 2 × CH3), 5.10-5.19 (m, 1H, methine-
H), 6.69-6.76 (m, 2H, 2-Iso-O-Pyr), 7.24-7.32 (m, 2H, 4-F-
Ph), 7.42-7.49 (m,2H, 4-F-Ph), 8.02 (d, 1H, 5.5 Hz, C6-H 2-Iso-
O-Pyr), 12.68 (bs, 2H, exchangeable, 2 × NH); IR 1518
(C(S)NH), 1226 cm-1 (C-F).
2-Am in o-2-(2-b r om op yr id in -4-yl)-1-(4-flu or op h en yl)-
eth a n on e Hyd r ogen su lfa te (4e). To a solution of 3c (1.8 g,
5.6 mmol) in ethanol absol (30 mL) at -10 °C was added
concentrated sulfuric acid (1.3 mL). In small portions zinc
powder (1.1 g) was added while the temperature was kept at
-10 °C. After the addition was complete, the mixture was
stirred for 30 min at -10 °C and then warmed to room
temperature. The gray-green colored slurry was filtered, and
the residue of ZnSO4 was thoroughly washed with ethanol.
The combined yellow filtrate was concentrated in vacuo, and
the solid residue was dried to give 2.0 g (91%) of 4e: 1H NMR
(DMSO-d6) δ 6.39 (bs, 1H, methine-H), 7.35-7.44 (m, 2H, 4-F-
Ph), 7.56 (dd, 1H, 1.4/5.1 Hz, C5-H 2-Br-Pyr), 7.91 (s, 1H, C3-H
2-Br-Pyr), 8.12-8.19 (m, 2H, 4-F-Ph), 8.46 (d, 1H, 5.1 Hz, C6-H
2-Br-Pyr), 8.94 (bs, 3H, exchangeable NH3+).
2-Am in o-1-(4-flu or op h en yl)-2-(2-isop r op oxyp yr id in -4-
yl)eth a n on e Hyd r och lor id e (4f). Starting from 3d (2.0 g,
7.6 mmol), 2.5 g (100%) of 4f was obtained according to the
method described for the synthesis of 4a : mp 271 °C; 1H NMR
(DMSO-d6) δ 1.23 (d, 6H, 5.6 Hz, 2 × CH3), 5.09-5.22 (m, 1H,
methine-H CH(CH3)2), 6.38-6.41 (bs, 1H, methine-H CH-
NH3+), 7.00-7.08 (m, 2H, 2-Iso-O-Pyr), 7.33-7.46 (m, 2H, 4-F-
Ph), 8.14-8.23 (m, 3H, 2-Iso-O-Pyr and 4-F-Ph), 9.21 (bs, 3H,
exchangeable, NH3+); IR 2703 (NH3+), 1696 (CdO), 1237 cm-1
(C-F).
4-(4-F lu or op h en yl)-5-(2-flu or op yr id in -4-yl)-1,3-d ih y-
d r oim id a zole-2-th ion e (5a ). Starting from 4a (6.1 g, 20
mmol), 5.0 g (91%) of 5a was obtained according to the method
described for the synthesis of 5d : mp 303 °C; 1H NMR (DMSO-
d6) δ 7.12-7.16 (m, 2H, C3-/C5-H 2-F-Pyr), 7.28-7.27 (m, 2H,
4-F-Ph), 7.46-7.55 (m, 2H, 4-F-Ph), 8.13 (d, 1H, 5.1 Hz, C6-H
2-F-Pyr), 12.85 (bs, 2H, exchangeable, 2 × NH); 13C NMR
(DMSO-d6) δ 106.0 (d, 40.3 Hz, C3 2-F-Pyr), 116.5 (d, 21.9 Hz,
C2/C6 4-F-Ph), 118.9 (d, 3.7 Hz, C5 2-F-Pyr), 121.3, 124.7 (C4
4-F-Ph), 128.5, 131.5 (d, 8.6 Hz, C3/C5 4-F-Ph), 141.5 (d, 9.4
Hz, C4 2-F-Pyr), 148.4 (d, 16.1 Hz, C6 2-F-Pyr), 162.9 (d, 247.2
Hz, C1 4-F-Ph), 162.9 (C2 imidazole), 163.9 (d, 234.0 Hz, C2
2-F-Pyr); IR 1497 (C(S)NH), 1223 cm-1 (C-F).
4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-4-
yl]-1H-p yr id in -2-on e (6). Upon treatment of 4b (8.8 g, 31
mmol) under the conditions decribed for the preparation of 5d ,
4.2 g (45%) of 6 was obtained as the only product: mp 314 °C
(decomp.); 1H NMR (DMSO-d6) δ 2.61 (s, 3H, SCH3), 6.16 (bs,
1H, C3-H pyridone), 6.34 (s, 1H, C5-H pyridone), 7.25-7.33 (m,
3H, C6-H pyridone and 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph),
11.38 (bs, 1H, exchangeable, pyridone-NH), 12.71 (bs, 1H,
exchangeable, imidazole-NH); 13C NMR (DMSO-d6) δ 14.8
(CH3), 103.7 (C5 pyridone), 114.6 (C3 pyridone), 115.8 (d, 21.9
Hz, C2/C6 4-F-Ph), 121.7, 124.5 (d, 3.3 Hz, C4 4-F-Ph), 127.4,
130.7 (d, 8.3 Hz, C3/C5 4-F-Ph), 134.9 (C6 pyridone), 139.7 (C4
pyridone), 161.8 (d, 245.3 Hz, C1 4-F-Ph), 162.1 (C2 imidazole),
162.4 (C2 pyridone); IR 1634 (pyridone I), 1557 (pyridone II),
1220 cm-1 (C-F); MS m/z (%) 301 (93, M+), 300 (100, M+
-
1), 285.1 (13, M+ - CH3), 268.0 (40, M+ - S), 228.1 (20), 121.1
(16), 95.1 (10). Anal. (C15H12FN3OS) C, H, N.
Gen er a l P r oced u r e A: P r ep a r a tion of 2-(Ar yl-)Alk yl-
su lfa n ylim id a zoles. Under an inert atmosphere of argon a
mixture of the respective imidazole-2-thione and the respective
benzyl- or methylhalogenide in ethanol/THF (8+2) was heated
to reflux until the imidazole-2-thione had been consumed
completely (TLC: SiO2 60, DCM/ethanol 9+1). The slurry was
cooled to room temperature and filtered. The red or orange
filtrate was concentrated in vacuo, and the residue was
purified by trituration or column chromatography as appropri-
ate.
4-(4-F lu or op h en yl)-5-(2-m eth oxyp yr id in -4-yl)-1,3-d ih y-
d r oim id a zole-2-th ion e (5b). To a solution of 4b (3.2 g, 10.8
mmol) in 10% hydrochloric acid (50 mL) was added potassium
thiocyanate (2 g, 20.6 mmol). The reaction was heated to reflux
for 30 min. The mixture was cooled to room temperature and
neutralized with 10% aqueous NaHCO3 solution. The precipi-
tate was collected by filtration, washed with H2O, and dried
in vacuo over CaCl2. The crude product was triturated with
ethanol. The insoluble residue (5c) was filtered off. Upon
leaving the filtrate at room temperature 1.0 g (31%) of 5b
2-F lu or o-4-[5-(4-flu or op h en yl)-2-m et h ylsu lfa n yl-3H -
im id a zol-4-yl]p yr id in e (7a ). According to general procedure
A, the title compound was obtained from 5a (0.95 g, 3.3 mmol)
and iodomethane (1.4 g, 9.9 mmol) after 40 h. The crude
reaction product was extracted with hot DCM/ethyl acetate
(1+1). The color was removed from the organic extract by
treatment with Al2O3. The basic alumina was filtered off, and
the filtrate was concentrated in vacuo. The solid residue was
triturated with a small volume of ethanol to yield 0.30 g (30%)
1
of 7a : mp 224 °C; H NMR (DMSO-d6) δ 2.62 (s, 3H, CH3),
1
precipitated: mp 250 °C; H NMR (DMSO-d6) δ 3.81 (s, 3H,
7.08 (s, 1H, C3-H 2-F-Pyr), 7.26-7.35 (m, 3H, C5-H 2-F-Pyr
and 4-F-Ph), 7.46-7.54 (m, 2H, 4-F-Ph), 8.08 (d, 1H, 5.3 Hz,
C6-H 2-F-Pyr), 12.85 (bs, 1H, exchangeable, NH); 13C NMR
(DMSO-d6) δ 15.3 (CH3), 105.4 (d, 39.3 Hz, C3 2-F-Pyr), 116.3
(d, 21.8 Hz, C2/C6 4-F-Ph), 118.9 (d, 3.5 Hz, C5 2-F-Pyr), 119.8,
120.4, 131.2 (d, 8.4 Hz, C3/C5 4-F-Ph), 143.6 (C4 2-F-Pyr), 148.1
(d, 16.1 Hz, 2-F-Pyr), 150.3, 151.1, 162.5 (d, 246.1 Hz, C1 4-F-
Ph), 164.1 (d, 233.3 Hz, C2 2-F-Pyr); IR 1219 cm-1 (C-F); Anal.
(C15H11F2N3S) C, H, N.
OCH3), 6.79-6.82 (m, 2H, C3-/C5-H 2-MeO-Pyr), 7.26-7.50 (m,
4H, 4-F-Ph), 8.06 (d, 1H, 5.3 Hz, C6-H 2-MeO-Pyr), 12.65 (bs,
2H, exchangeable, 2 × NH).
4-[5-(4-F lu or op h en yl)-2-th ioxo-2,3-d ih yd r o-1H-im id a -
zol-4-yl]-1H-p yr id in -2-on e (5c). 5c (0.4 g, 13%) was obtained
as a side product in the preparation of 5b: 1H NMR (DMSO-
d6) δ 5.88 (d, 1H, 6.0 Hz, C5-H pyridone), 6.41 (s, 1H, C3-H
pyridone), 7.26-7.50 (m, 5H, C6-H pyridone and 4-F-Ph), 11.50
(bs, 1H, exchangeable, pyridone-NH), 12.73 (bs, 2H, exchange-
able, 2 × imidazole-NH).
2-Ch lor o-4-[5-(4-flu or op h en yl)-2-m et h ylsu lfa n yl-3H -
im id a zol-4-yl]p yr id in e (7b). According to general procedure
A, the title compound was obtained from 5d (0.5 g, 1.6 mmol)
and iodomethane (0.35 g, 2.5 mmol) after 12 h. Purification
by column chromatography (basic alumina, DCM/ethyl acetate
1+1) yielded 0.16 g (31%) of 7b: mp 236 °C; 1H NMR (DMSO-
d6) δ 2.62 (s, 1H, CH3), 7.27-7.36 (m, 3H, 2-Cl-Pyr and 4-F-
Ph), 7.45-7.55 (m, 3H, 2-Cl-Pyr and 4-F-Ph), 8.24 (d, 1H, 5.1
Hz, C6-H 2-Cl-Pyr), 12.85 (bs, 1H, exchangeable, NH); IR 1231
cm-1 (C-F); Anal. (C15H11ClFN3S) C, H, N.
Gen er a l P r oced u r e B: P r ep a r a tion of N-Su bstitu ted
2-Am in op yr id in es. Under an inert atmosphere of argon, the
respective 5-(2-halogenopyridin-4-yl)imidazole (1 equiv) was
suspended in an excess volume of the respective amine (approx
10 equiv). The mixture was stirred at the appropriate tem-
4-(2-Ch lor op yr id in -4-yl)-5-(4-flu or op h en yl)-1,3-d ih y-
d r oim id a zole-2-th ion e (5d ). With gentle heating 4c (2.9 g,
ca. 9.6 mmol) was dissolved in DMF absol (75 mL). To the clear
orange solution was added potassium thiocyanate (1.9 g, 19.6
mmol). The slurry was heated to reflux for 1.5 h. The reaction
was cooled to room temperature and diluted dropwise with
H2O (140 mL). The yellow precipitate was collected by filtra-
tion, washed with H2O, and dried in vacuo over CaCl2 to afford
2.14 g (74%) of 5d : mp 275 °C (decomp.); 1H NMR (DMSO-d6)
δ 7.12-7.52 (m, 6H, C3-/C5-H 2-Cl-Pyr and 4-F-Ph), 8.27 (d,
1H, 5.2 Hz, C6-H 2-Cl-Pyr), 12.82 (bs, 2H, exchangeable, 2 ×
NH); 13C NMR (DMSO-d6) δ 116.5 (d, 21.8 Hz, C2/C6 4-F-Ph),
119.8 (C5 2-Cl-Pyr), 120.7 (C3 2-Cl-Pyr), 121.0, 124.6 (d, 3.3

3240 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Laufer et al.
perature until the imidazole starting material had been
consumed completely (TLC: SiO2 60, DCM/ethanol 9+1). The
reaction was cooled to room temperature and suspended in
an aqueous solution of citric acid (10%), which had been
brought to pH 5 with an aqueous solution of NaOH (20%)
before. The emulsion was extracted with ethyl acetate (3×).
The combined organic extract was washed with citric acid
(10%, pH 5), an aqueous solution of Na2CO3 (10%), and
saturated brine, dried over Na2SO4, and concentrated in vacuo.
The oily residue was purified by column chromatography.
was triturated with tert-butyl methyl ether to yield the title
compound. A second crop of 7f was obtained from the ethereal
mother liquor by column chromatography (SiO2 60, DCM/ethyl
acetate 1+1), combined yield 2.1 g (50%): mp 141 °C; 1H NMR
(CD3OD) δ 1.28 (d, 6H, 6.1 Hz, 2 × CH3), 2.63 (s, 3H, SCH3),
5.08-5.14 (m, 1H, methine-H), 6.76 (s, 1H, C3-H 2-Iso-O-Pyr),
6.88 (dd, 1H, 1.4/5.4 Hz, C5-H 2-Iso-O-Pyr), 7.10-7.19 (m, 2H,
4-F-Ph), 7.40-7.47 (m, 2H, 4-F-Ph), 7.95 (dd, 1H, 0.7/5.4 Hz,
C6-H 2-Iso-O-Pyr); IR 1222 cm-1 (C-F); MS m/z (%) 343.1 (83,
M+), 328 (62), 300 (100), 284.9 (79), 268 (47), 228.1 (22), 205.2
(23), 199.1 (23), 121.2 (24), 43.1 (51); Anal. (C18H18FN3OS) C,
H, N.
(RS)-{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im i-
d a zol-4-yl]p yr id in -2-yl}-(1-p h en yleth yl)a m in e (7c). Ac-
cording to general procedure B, the title compound was
obtained from 7a (0.2 g, 0.7 mmol) and (RS)-1-phenylethyl-
amine (0.80 g, 6.6 mmol) after 7 h at 160 °C. The crude product
was purified by column chromatography (SiO2 60, DCM/ethyl
(R)-{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a -
zol-4-yl]p yr id in -2-yl}-(1-p h en yleth yl)a m in e (7g). Accord-
ing to general procedure B, the title compound was obtained
from 7a (0.2 g, 0.7 mmol) and (R)-1-phenylethylamine (0.80
g, 6.6 mmol) after 7 h at 170 °C. The crude product was
purified by column chromatography (SiO2 60, DCM/ethyl
1
acetate 1+1) to yield 0.11 g (41%) of 7c: mp 117-119 °C; H
NMR (DMSO-d6) δ 1.37 (d, 3H, 5.5 Hz, CH3), 2.58 (s, 3H,
SCH3), 4.82-5.03 (m, 1H, methine-H), 6.39-7.74 (m, 12H, Ph,
2-Amino-Pyr and 4-F-Ph), 12.57 (bs, 1H, exchangeable, NH);
13C NMR (CD3OD) δ 16.9 (SCH3), 24.5 (CH3), 52.6 (methine),
107.1 (C3 2-Amino-Pyr), 112.1 (C5 2-Amino-Pyr), 116.7 (d, 22.2
Hz, C2/C6 4-F-Ph), 126.9 (C4 Ph), 127.8 (C2/C6 Ph), 128.1, 129.5
(C3/C5 Ph), 131.6 (d, 8.3 Hz, C3/C5 4-F-Ph), 145.5, 147.4 (C1
Ph), 149.3, 160.8 (C2 2-Amino-Pyr), 165.0 (d, 246.3 Hz, C1 4-F-
Ph); IR 1221 cm-1 (C-F); MS m/z (%) 406.2 (16, M + 1+), 403.9
(68, M+), 389.1 (42), 299.1 (12), 285.1 (20), 267.1 (10), 202.2
(15), 178.2 (15), 120.1 (100), 105.3 (48), 79.1 (13), 77.0 (13);
HPLC (254 nm) 18.2 min (48.2%), 28.5 min (51.8%); Anal.
(C23H21FN4S) C, H, N.
1
acetate 1+1) to yield 0.10 g (36%) of 7g: mp 117-119 °C; H
NMR (CD3OD) δ 1.44 (d, 3H, 6.9 Hz, CH3), 2.59 (s, 3H, SCH3),
4.62-4.69 (m, 1H, methine-H), 6.47-6.57 (m, 2H, C3-/C5-H
2-Amino-Pyr), 7.05-7.42 (m, 9H, Ph and 4-F-Ph), 7.80 (d, 1H,
5.5 Hz, C6-H 2-Amino-Pyr); IR 1221 cm-1 (C-F); MS m/z (%)
406.2 (13, M + 1+), 403.9 (70, M+), 389.0 (43), 299.0 (13), 285.1
(16), 267.0 (9), 202.2 (12), 178.2 (12), 120.1 (100), 105.2 (48),
79.1 (12), 77.0 (13); HPLC (254 nm) ee 92.4%; Anal. (C23H21
FN4S) C, H, N.
-
(S)-{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a -
zol-4-yl]p yr id in -2-yl}-(1-p h en yleth yl)a m in e (7h ). Accord-
ing to general procedure B, the title compound was obtained
from 7a (0.2 g, 0.7 mmol) and (S)-1-phenylethylamine (0.80 g,
6.6 mmol) after 13 h at 170 °C. The crude product was purified
by column chromatography (SiO2 60, DCM/ethyl acetate 1+1)
Ben zyl-{4-[5-(4-flu or op h en yl)-2-m eth ylsu lfa n yl-3H-im -
id a zol-4-yl]p yr id in -2-yl}a m in e (7d ). According to general
procedure B, the title compound was obtained from 7a (0.2 g,
0.7 mmol) and benzylamine (0.8 g, 7.5 mmol) after 5 h at 160
°C. The crude product was purified by column chromatography
(basic alumina, DCM/ethyl acetate 1+1) to yield 0.11 g (41%)
1
to yield 0.10 g (36%) of 7g: mp 117-119 °C; H NMR (CD3-
OD) δ 1.44 (d, 3H, 6.9 Hz, CH3), 2.59 (s, 3H, SCH3), 4.62-
4.69 (m, 1H, methine-H), 6.47-6.57 (m, 2H, C3-/C5-H 2-Amino-
Pyr), 7.05-7.42 (m, 9H, Ph and 4-F-Ph), 7.80 (dd, 1H, 0.5/5.5
Hz, C6-H 2-Amino-Pyr); IR 1221 cm-1 (C-F); MS m/z (%) 406.2
(13, M + 1+), 403.9 (58, M+), 389.0 (33), 299.0 (10), 285.1 (15),
267.0 (8), 202.2 (11), 178.2 (12), 120.1 (100), 105.2 (47), 79.1
(12), 77.0 (13); HPLC (254 nm) ee 96.8%; Anal. (C23H21FN4S)
C, H, N.
1
of 7d : mp 152 °C (decomp.); H NMR (CD3OD) δ 2.59 (s, 3H,
CH3), 4.37 (s, 2H, CH2), 6.56-6.59 (m, 2H, C3-/C5-H 2-Amino-
Pyr), 7.04-7.44 (m, 9H, Ph and 4-F-Ph), 7.83 (d, 1H, 5.6 Hz,
C6-H 2-Amino-Pyr); IR 3234 (NH), 1225 cm-1 (C-F); MS m/z
(%) 390.1 (100, M+), 373.0 (5), 313.0 (10), 285.1 (55), 251.9 (7.5),
212.1 (9.7), 106.0 (87), 91.0 (63); Anal. (C22H19FN4S) C, H, N.
{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-
4-yl]p yr id in -2-yl}-(4-m eth oxyben zyl)a m in e (7i). According
to general procedure B, the title compound was obtained from
7a (0.44 g, 1.5 mmol) and 4-methoxybenzylamine (2.0 g, 14.6
mmol) after 7 h at 160 °C. The crude product was purified by
column chromatography (SiO2 60, DCM/ethanol 9+1) to yield
4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-4-
yl]-2-m eth oxyp yr id in e (7e). A methanolic solution of 5b (1.0
g, 3.3 mmol) and iodomethane (5.6 g, 39 mmol) was heated to
reflux for 3 h. The reaction was cooled to room temperature
and filtered. The filtrate was concentrated in vacuo, and the
residue was suspended in ethanol. The insoluble residue was
filtered off, and the solvent was removed from the filtrate in
vacuo. The residue was suspended in DCM/ethanol (9+1). The
insoluble residue was filtered off, and the filtrate was purified
by column chromatography (SiO2 60, DCM/ethanol 9+1) to
yield 0.27 g (26%) of 7e: mp 158 °C; 1H NMR (CD3OD) δ 2.67
(s, 3H, SCH3), 3.90 (s, 3H, OCH3), 6.87-6.89 (m, 1H, C3-H
2-MeO-Pyr), 6.98 (dd, 1H, 1.5/5.5 Hz, C5-H 2-MeO-Pyr), 7.16-
7.24 (m, 2H, 4-F-Ph), 7.46-7.53 (m, 2H, 4-F-Ph), 8.03 (dd, 1H,
0.7/5.5 Hz, C6-H 2-MeO-Pyr); IR 1222 cm-1 (C-F); Anal.
(C16H14FN3OS) C, H, N.
4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-4-
yl]-2-isop r op oxyp yr id in e (7f). To a solution of 5f (4.0 g,
13.8 mmol) in THF absol (60 mL) was added NaH (55-65%,
1.0 g, approx 23 mmol), and the mixture was stirred at
room temperature for 5 min. A solution of iodomethane (2.2
g, 17.3 mmol) in THF absol (5 mL) was added dropwise
and with cooling in a water bath. The reaction was stirred at
room temperature for 1 h. The clear, brown solution was
concentrated in vacuo, and the residue was suspended in H2O.
The aqueous solution was neutralized with 10% hydrochloric
acid and extracted with ethyl acetate. The combined organic
extract was washed with saturated brine and dried over
Na2SO4 and the solvent evaporated. The semisolid residue
was extracted with hot tert-butyl methyl ether (2×). The
organic extract was cooled to room temperature and filtered.
The filtrate was concentrated in vacuo, and the solid residue
1
0.30 g (48%) of 7i: mp 207 °C; H NMR (CD3OD) δ 2.61 (s,
3H, SCH3), 3.75 (s, 3H, OCH3), 4.30 (s, 2H, CH2), 6.56-6.59
(m, 2H, C3-/C5-H 2-Amino-Pyr), 6.81-7.30 (m, 6H, 4-MeO-Ph
and 4-F-Ph), 7.39-7.46 (m, 2H, 4-F-Ph), 7.84 (d, 1H, 6.0 Hz,
C6-H 2-Amino-Pyr); IR 1217 cm-1 (C-F); MS m/z (%) 420.1
(28, M+), 405.1 (5), 285.1 (8), 210.1 (7), 136.1 (63), 121.1 (100),
71.1 (8); Anal. (C23H21FN4OS) C, H, N.
{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-
4-yl]p yr id in -2-yl}-(4-m eth ylben zyl)a m in e (7j). According
to general procedure B, the title compound was obtained from
7a (0.2 g, 0.7 mmol) and 4-methylbenzylamine (0.85 g, 7.0
mmol) after 6 h at 160 °C. The crude product was purified by
column chromatography (SiO2 60, DCM/ethanol 9+1) to yield
0.05 g (18%) of 7j: mp 185 °C; 1H NMR (CD3OD) δ 2.29 (s,
3H, CH3), 2.60 (s, 3H, SCH3), 4.32 (s, 2H, CH2), 6.57-6.60 (m,
2H, C3-/C5-H 2-Amino-Pyr), 7.05-7.50 (m, 8H, 4-Me-Ph and
4-F-Ph), 7.83 (d, 1H, 5.3 Hz, C6-H 2-Amino-Pyr); IR 1218 cm-1
(C-F); MS m/z (%) 404.2 (54, M+), 389.1 (4), 285.1 (24), 221.1
(22), 120.2 (100), 105.1 (56), 77.1 (12); Anal. (C23H21FN4S) C,
H, N.
(4-Ch lor oben zyl)-{4-[5-(4-flu or op h en yl)-2-m eth ylsu lfa -
n yl-3H-im id a zol-4-yl]p yr id in -2-yl}a m in e (7k ). According
to general procedure B, the title compound was obtained from
7a (0.2 g, 0.7 mmol) and 4-chlorobenzylamine (1.0 g, 7.0 mmol)
after heating to reflux for 5.5 h. The crude product was purified
by column chromatography (SiO2 60, DCM/ethanol 9+1) to

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3241
yield 0.12 g (40%) of 7k : mp 195 °C; 1H NMR (CD3OD) δ 2.60
(s, 3H, SCH3), 4.38 (s, 2H, CH2), 6.57-6.60 (m, 2H, C3-/C5-H
2-Amino-Pyr), 7.05-7.14 (m, 2H, 4-F-Ph), 7.22-7.30 (m, 4H,
4-Cl-Ph), 7.38-7.45 (m, 2H, 4-F-Ph), 7.83 (d, 1H, 5.7 Hz, C6-H
2-Amino-Pyr); 13C NMR (CD3OD) δ 16.9 (CH3), 45.6 (CH2),
106.9 (C3 2-Amino-Pyr), 112.2 (C5 2-Amino-Pyr), 116.7 (d, 22.0
Hz, C2/C6 4-F-Ph), 129.5 (C3/C5 4-Cl-Ph), 129.6 (C4 4-F-Ph),
129.7 (C2/C6 4-Cl-Ph), 130.3 (C6 2-Amino-Pyr), 131.7 (d, 8.3
Hz, C3/C5 4-F-Ph), 133.6, 138.9, 140.0, 144.6, 148.4, 160.4 (C2
2-Amino-Pyr), 163.7 (C2 imidazole), 164.1 (d, 246.9 Hz, C1 4-F-
Ph); IR 1218 cm-1 (C-F); MS m/z (%) 424.1 (77, M+), 409.1
(4), 313 (10), 284.8 (100), 251.9 (7), 212.1 (17), 195.0 (12), 178.1
(12), 140.0 (45), 125.0 (44), 89.0 (10); Anal. (C22H18ClFN4S) C,
H, N.
(3,4-Dich lor oben zyl)-{4-[5-(4-flu or op h en yl)-2-m eth yl-
su lfa n yl-3H -im id a zol-4-yl]p yr id in -2-yl}a m in e (7l). Ac-
cording to general procedure B, the title compound was
obtained from 7a (0.2 g, 0.7 mmol) and 3,4-dichlorobenzyl-
amine (1.2 g, 6.8 mmol) after 7.5 h at 160 °C. The crude
product was purified by column chromatography (SiO2 60,
DCM/ethanol 9+1) to yield 0.12 g (38%) of 7l: mp 212 °C; 1H
NMR (CD3OD) δ 2.60 (s, 3H, SCH3), 4.39 (s, 2H, CH2), 6.56-
6.62 (m, 2H, C3-/C5-H 2-Amino-Pyr), 7.06-7.50 (m, 7H, 3,4-
Di-Cl-Ph and 4-F-Ph), 7.84 (d, 1H, 5.5 Hz, C6-H 2-Amino-Pyr);
IR 1225 cm-1 (C-F); MS m/z (%) 460.0 (29, M + 1+), 458.0
(44, M - 1+), 343.0 (24), 328.1 (19), 300.0 (35), 285.1 (100),
268.1 (16), 212.1 (21), 174.0 (22), 158.9 (59), 121.1 (17); Anal.
(C22H17Cl2FN4S) C, H, N.
{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-
4-yl]p yr id in -2-yl}p h en yla m in e (7m ). According to general
procedure B, the title compound was obtained from 7a (0.2 g,
0.7 mmol) and aniline (0.65 g, 7.0 mmol) after heating to reflux
for 6 h. The crude product was purified by column chroma-
tography (SiO2 60, DCM/ethanol 9+1) to yield 0.03 g (12%) of
7m : mp 228 °C; 1H NMR (DMSO-d6) δ 2.62 (s, 3H, CH3), 5.95-
6.13 (m, 2H, C3-/C5-H 2-Amino-Pyr), 6.68-7.60 (m, 9H, Ph and
4-F-Ph), 7.97-8.01 (m, 1H, C6-H 2-Amino-Pyr), 8.99 (bs, 1H,
exchangeable, anilino-NH), 12.68 (bs, 1H, exchangeable, imi-
dazole-NH); IR 1225 cm-1 (C-F); MS m/z (%) 377.2 (20, M +
1+), 375.1 (100, M-1+), 360.1 (11), 326.9 (7), 302.1 (14), 194.0
(8), 187.8 (24), 171.2 (44), 151.0 (25), 137.1 (10), 95.1 (4), 77.1
(9); Anal. (C21H17FN4S) C, H, N.
{4-[5-(4-F lu or op h en yl)-2-m eth ylsu lfa n yl-3H-im id a zol-
4-yl]p yr id in -2-yl}p h en eth yla m in e (7n ). According to gen-
eral procedure B, the title compound was obtained from 7a
(0.2 g, 0.7 mmol) and 2-phenylethylamine (0.85 g, 7.0 mmol)
after 5.5 h at 160 °C. The crude product was purified by column
chromatography (SiO2 60, DCM/ethanol 9+1) to yield 0.12 g
(38%) of 7n : mp 99 °C; 1H NMR (CD3OD) δ 2.61 (s, 3H, SCH3),
2.81 (t, 2H, 7.7 Hz, NCH2), 3.41 (t, 2H, 7.7 Hz, CH2Ph), 6.55-
6.57 (m, 2H, C3-/C5-H 2-Amino-Pyr), 7.08-7.26 (m, 7H, Ph and
4-F-Ph), 7.42-7.49 (m, 2H, 4-F-Ph), 7.82 (d, 1H, 6.1 Hz, C6-H
2-Amino-Pyr); IR 1220 cm-1 (C-F); Anal. (C23H21FN4S) C,
H, N.
C3-H 2-F-Pyr), 7.25-7.51 (m, 10H, C5-H 2-F-Pyr, Ph and 4-F-
Ph), 8.10 (d, 1H, 5.3 Hz, C6-H 2-F-Pyr), 12.93 (bs, 1H,
exchangeable, NH); IR 1228 cm-1 (C-F); Anal. (C21H15F2N3S)
C, H, N.
4-[2-Ben zylsu lfa n yl-5-(4-flu or op h en yl)-3H-im id a zol-4-
yl]-2-ch lor op yr id in e (8b). According to general procedure
A, the title compound was obtained from 5d (0.3 g, 1.0 mmol)
and benzyl chloride (0.12 g, 1.0 mmol) after 6 h. The crude
product was purified by column chromatography (SiO2 60,
DCM/ethanol 9+1) to yield 0.12 g (30%) of 8b: mp 223 °C; 1H
NMR (DMSO-d6) δ 4.43 (s, 2H, CH2), 7.27-7.47 (m, 11H, 2-Cl-
Pyr, Ph and 4-F-Ph), 8.26 (d, 1H, 5.2 Hz, C6-H 2-Cl-Pyr), 12.94
(bs, 1H, exchangeable, NH); 13C NMR (DMSO-d6) δ 36.6 (CH2),
116.0 (d, 21.4 Hz, C2/C6 4-F-Ph), 119.3 (C5 2-Cl-Pyr), 119.9 (C3
2-Cl-Pyr), 126.1, 127.2 (Ph), 128.4 (Ph), 128.8 (Ph), 130.9 (d,
8.1 Hz, C3/C5 4-F-Ph), 131.4, 132.7, 137.6 (Ph), 141.2, 147.6
(d, 245.6 Hz, C1 4-F-Ph), 148.6 (C2 imidazole), 149.9 (C6 2-Cl-
Pyr), 150.6 (C2 2-Cl-Pyr); IR 1233 cm-1 (C-F); Anal. (C21H15
ClFN3S) C, H, N.
-
(RS)-{4-[2-Ben zylsu lfa n yl-5-(4-flu or op h en yl)-3H -im i-
d a zol-4-yl]p yr id in -2-yl}-(1-p h en yleth yl)a m in e (8c). Ac-
cording to general procedure B the title compound was
obtained from 8a (0.2 g, 0.53 mmol) and (RS)-1-phenylethyl-
amine (0.65 g, 5.4 mmol) after 15 h at 150 °C. The crude
product was purified by column chromatography (SiO2 60,
DCM/ethyl acetate 1+1) to yield 0.07 g (28%) of 8c: mp 145
°C; 1H NMR (CD3OD) δ 1.44 (d, 3H, 6.8 Hz, CH3), 4.22 (s, 2H,
CH2), 4.61-4.71 (m, 1H, methine-H), 6.44-6.54 (m, 2H, C3-/
C5-H 2-Amino-Pyr), 7.04-7.35 (m, 9H, Ph and 4-F-Ph), 7.80
(d, 1H, 5.4 Hz, C6-H 2-Amino-Pyr); IR 1221 cm-1 (C-F); HPLC
(215 nm) 7.6 min (49.8%), 11.5 min (50.2%); Anal. (C29H25FN4S)
C, H, N.
Ben zyl-{4-[2-ben zylsu lfa n yl-5-(4-flu or op h en yl)-3H-im i-
d a zol-4-yl]p yr id in -2-yl}a m in e (8d ). According to general
procedure B, the title compound was obtained from 8a (0.2 g,
0.53 mmol) and benzylamine (0.60 g, 5.6 mmol) after 6 h at
180 °C. The crude product was purified by column chroma-
tography (SiO2 60, DCM/ethyl acetate 1+1) to yield 0.14 g
(56%) of 8d : mp 185 °C; 1H NMR (CD3OD) δ 4.21 (s, 2H,
NCH2), 4.38 (s, 2H, SCH2), 6.52-6.55 (m, 2H, C3-/C5-H
2-Amino-Pyr), 7.03-7.38 (m, 9H, Ph and 4-F-Ph), 7.83 (d, 1H,
5.7 Hz, C6-H 2-Amino-Pyr); IR 3407 (NH), 1220 cm-1 (C-F);
Anal. (C28H23FN4S) C, H, N.
{4-[2-Ben zylsu lfa n yl-5-(4-flu or op h en yl)-3H -im id a zol-
4-yl]p yr id in -2-yl}-(4-m eth oxyben zyl)a m in e (8e). Accord-
ing to general procedure B, the title compound was obtained
from 8b (0.2 g, 0.5 mmol) and 4-methoxybenzylamine (2.0 g,
14.6 mmol) after heating to reflux for 22 h. The crude product
was purified by column chromatography (basic alumina, DCM/
ethyl acetate 1+1) to yield 0.06 g (24%) of 8e: mp 196-200
°C; 1H NMR (DMSO-d6) δ 4.29 (s, 2H isomers “A” + “B”,
NCH2), 4.35 (s, 2H “A” + “B”, SCH2), 6.43-6.47 (m, 1H “A” +
2H “B”, C5-H “A” and C3-/C5-H “B” 2-Amino-Pyr), 6.65 (s, 1H
“A”, C3-H 2-Amino-Pyr), 6.80-6.84 (m, 2H “A” + “B”, 4-MeO-
Ph),7.14-7.51 (m, 11H “A” + “B”, 4-MeO-Ph, Ph and 4-F-Ph),
7.79 (d, 1H “B”, 5.4 Hz, C6-H 2-Amino-Pyr), 7.91 (d, 1H “A”,
5.4 Hz, C6-H 2-Amino-Pyr), 12.67 (bs, 1H, exchangeable,
imidazole-NH), amino-NH not detected; IR 1225 cm-1(C-F);
MS m/z (%) 495.7 (67, M - 1+), 481.0 (4), 406.2 (9), 360.7 (15),
270.0 (5), 211.0 (7), 136.0 (21), 121.0 (100), 90.7 (20), 77.4 (4),
65.0 (4); Anal. (C29H25FN4OS) C, H, N.
Ben zyl-{4-[5-(4-flu or op h en yl)-2-m eth ylsu lfa n yl-3H-im -
id a zol-4-yl]p yr id in -2-yl}m et h yla m in e (7o). According to
general procedure B the title compound was obtained from 7a
(0.2 g, 0.7 mmol) and N-methylbenzylamine (0.85 g, 7.0 mmol)
after 7 h at 180 °C. The crude product was purified twice by
column chromatography (SiO2 60, DCM/ethyl acetate 1+1) to
1
yield 0.13 g (46%) of 7o: mp 79 °C; H NMR (CD3OD) δ 2.60
(s, 3H, SCH3), 2.97 (s, 3H, NCH3), 4.64 (s, 2H, CH2), 6.64-
6.66 (m, 2H, C3-/C5-H 2-Amino-Pyr), 7.02-7.45 (m, 9H, Ph and
4-F-Ph), 7.96 (d, 1H, 5.0 Hz, C6-H 2-Amino-Pyr); IR 1219 cm-1
(C-F); MS m/z (%) 404.0 (44, M+), 389.1 (57), 375.1 (11), 313.0
(42), 285.1 (7), 210.1 (44), 202.2 (13), 178.3 (9), 120.1 (35), 106.1
(26), 91.1 (100), 65 (13); Anal. (C23H21FN4S) C, H, N.
2-F lu or o-4-[5-(4-flu or op h en yl)-2-(4-m et h a n esu lfin yl-
ben zylsu lfa n yl)-3H-im id a zol-4-yl]p yr id in e (9a ). According
to general procedure A, the title compound was obtained from
5a (4.2 g, 14.5 mmol) and 1-chloromethyl-4-methanesulfinyl-
benzene38 (4.1 g, 22 mmol) after 2 h. The crude product was
purified twice by column chromatography (1. basic alumina,
DCM/ethyl acetate 1+1; 2. SiO2 60, DCM/ethanol 9+1) to yield
4-[2-Ben zylsu lfa n yl-5-(4-flu or op h en yl)-3H-im id a zol-4-
yl]-2-flu or op yr id in e (8a ). According to general procedure A,
the title compound was obtained from 5a (5.1 g, 17.6 mmol)
and benzyl bromide (9.2 g, 54 mmol) after 1.5 h. The crude
product was purified by column chromatography (basic alu-
mina, DCM/ethyl acetate 1+1) to yield 0.88 g (12%) of 8a : mp
1
2.5 g (39%) of 9a : mp 150 °C; H NMR (DMSO-d6) δ 2.71 (s,
3H, CH3), 4.49 (s, 2H, CH2), 7.10 (s, 1H, C3-H 2-F-Pyr), 7.30-
7.37 (m, 3H, C5-H 2-F-Pyr and 4-F-Ph), 7.47-7.67 (m, 6H, 4-F-
Ph and 4-MeS(O)-Ph), 8.11 (d, 1H, 4.8 Hz, C6-H 2-F-Pyr), 12.95
(bs, 1H, exchangeable, NH); IR 1227 (C-F), 1030 cm-1 (SdO);
Anal. (C22H17F2N3OS2) C, H, N.
1
174 °C; H NMR (DMSO-d6) δ 4.43 (s, 2H, CH2), 7.11 (s, 1H,

3242 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Laufer et al.
2-Ch lor o-4-[5-(4-flu or op h en yl)-2-(4-m et h a n esu lfin yl-
ben zylsu lfa n yl)-3H-im id a zol-4-yl]p yr id in e (9b). To a solu-
tion of 5d (0.31 g, 1.0 mmol) in THF absol (15 mL) was added
NaH (55-65%, 0.1 g, appr. 2 mmol), and the mixture was
stirred at room temperature for 5 min. 1-Chloromethyl-4-
methanesulfinylbenzene38 (0.19 g, 1.0 mmol) was added, and
the reaction was stirred at room temperature for 2 h. The
yellow-brown solution was diluted with H2O and neutralized
with 10% citric acid. The organic solvent was removed under
reduced pressure, and the aqueous solution was extracted with
ethyl acetate (2×). The combined organic extract was washed
with saturated brine, dried over Na2SO4, and concentrated in
vacuo. The solid residue was purified by column chromatog-
raphy (SiO2 60, DCM/ethanol 9.5+0.5) to yield 0.10 g (22%) of
9b: mp 179 °C; 1H NMR (DMSO-d6) δ 2.71 (s, 3H, CH3), 4.48
(s, 2H, CH2), 7.25-8.24 (m, 10H, 2-Cl-Pyr, 4-MeS(O)-Ph and
4-F-Ph), 8.26 (d, 1H, 5.3 Hz, C6-H 2-Cl-Pyr), 12.94 (bs, 1H,
exchangeable, NH); IR 1224 (C-F), 1030 (SdO), 781 cm-1 (C-
Cl); Anal. (C22H17ClFN3OS2) C, H, N.
8.35-8.37 (m 1H, 2-Amino-Pyr), 8.64 (s, 1H, C2-H imidazole),
10.73 (s, 1H, exchangeable, NH); IR 1225 cm-1 (C-F).
N-{4-[5-(4-F lu or op h en yl)-1-oxy-3-(2,2,6,6-tetr a m eth yl-
p ip e r id in -4-yl)-3H -im id a zol-4-yl]p yr id in -2-yl}a ce t a -
m id e (12c). Starting from 1131 (1.2 g, 4.1 mmol) and 1,3,5-
tris(2,2,6,6-tetramethylpiperidin-4-yl)-[1,3,5]-triazinane (2.4 g,
4.7 mol), 1.5 g (82%) of 12c was obtained according to the
1
method described for the preparation of 12b: mp 248 °C; H
NMR (DMSO-d6) δ 0.83 (s, 6H, 2 × CH3), 1.02 (s, 6H, 2 × CH3),
1.44-1.70 (m, 4H, 2 × CH2), 1.98 (s, 3H, C(O)CH3), 4.18-4.30
(m, 1H, methine-H), 6.96-7.12 (m, 3H, 4-F-Ph and 2-Amino-
Pyr), 7.42-7.49 (m, 2H, 4-F-Ph), 8.06 (s, 1H, 2-Amino-Pyr),
8.30-8.33 (m, 2H, 2-Amino-Pyr), 8.65 (s, 1H, C2-H imidazole),
10.65 (bs, 1H, exchangeable, NH); IR 1224 cm-1 (C-F).
N-{4-[5-(4-Flu or oph en yl)-3-pr opyl-2-th ioxo-2,3-dih ydr o-
1H-im id a zol-4-yl]p yr id in -2-yl}a ceta m id e (13b). A solution
of 12b (0.7 g, 2.0 mmol) in DCM (12 mL) was cooled in an ice
bath. A solution of 2,2,4,4-tetramethylcyclobutane-1,3-dithione
(0.35 g, 2.1 mmol) in DCM (6 mL) was added dropwise. After
the addition was complete, the mixture was stirred for 30 min
in the ice bath, and for another 60 min at room temperature.
The solvent was evaporated, and the solid residue was
triturated with diethyl ether. Recrystallization from 2-propanol
(RS)-{4-[5-(4-F lu or op h en yl)-2-(4-m eth a n esu lfin ylben -
zylsu lfa n yl)-3H-im id a zol-4-yl]p yr id in -2-yl}-(1-p h en yleth -
yl)a m in e (9c). According to general procedure B, the title
compound was obtained from 9a (0.3 g, 0.68 mmol) and (RS)-
1-phenylethylamine (0.85 g, 7.0 mmol) after 10 h at 170 °C.
The crude product was purified by column chromatography
(SiO2 60, DCM/ethanol 9+1) to yield 0.08 g (22%) of 9c: mp
1
yielded 0.67 g (90%) of 13b: mp 240 °C; H NMR (DMSO-d6)
δ 0.69 (t, 3H, 7.3 Hz, CH3), 1.43-1.60 (m, 2H, CH2), 2.07 (s,
3H, C(O)CH3), 3.84 (t, 2H, 7.1 Hz, NCH2), 7.07-7.37 (m, 5H,
4-F-Ph and 2-Amino-Pyr), 8.07 (s, 1H, 2-Amino-Pyr), 8.38-
8.40 (m, 1H, 2-Amino-Pyr), 10.73 (s, 1H, exchangeable, aceta-
mido NH), imidazole NH not detected; IR 1490 (C(S)NH), 1228
cm-1 (C-F).
1
193 °C; H NMR (CD3OD) δ 1.45 (d, 3H diastereoisomers “A”
+ “B”, 6.8 Hz, CH3), 2.67 (s, 3H diastereoisomer “A”, S(O)-
CH3), 2.69 (s, 3H diastereoisomer “B”, S(O)CH3), 4.28 (s, 2H
diastereoisomers “A” + “B”, CH2), 4.62-4.73 (m, 1H diastereo-
isomers “A” + “B”, methine-H), 6.39-6.61 (m, 2H diastereo-
isomers “A” + “B”, C3-/C5-H 2-Amino-Pyr), 7.09-7.44 (m, 9H
diastereoisomers “A” + “B”, Ph and 4-MeS(O)-Ph, 2H diaste-
reoisomer “A” 4-F-Ph and 4H diastereoisomer “B” 4-F-Ph), 7.80
(d, 1H diastereoisomer “B”, 5.1 Hz, C6-H 2-Amino-Pyr), 7.94-
8.05 (m, 2H diastereoisomer “A” 4-F-Ph), 8.21 (d, 1H diaste-
reoisomer “A”, 5.0 Hz, C6-H 2-Amino-Pyr); IR 1221 (C-F), 1031
cm-1 (SdO); HPLC (215 nm) 34.9 min (25.2%), 40.2 min
(24.5%), 62.3 min (24.6%), 64.3 min (25.7%); Anal. (C30H27FN4-
OS2) C, H, N.
N-{4-[5-(4-F lu or op h en yl)-3-(2,2,6,6-tetr a m eth ylp ip er i-
d in -4-yl)-2-th ioxo-2,3-d ih yd r o-1H-im id a zol-4-yl]p yr id in -
2-yl}a ceta m id e (13c). Starting from 12c (1.4 g, 3.1 mmol)
and 2,2,4,4-tetramethyl-cyclobutane-1,3-dithione (0.55 g, 3.2
mmol), 1.35 g (93%) of 13c was obtained according to the
1
method described for the preparation of 13b: mp 193 °C; H
NMR (DMSO-d6) δ 1.03 (s, 6H, 2 × CH3), 1.28 (s, 6H, 2 × CH3),
1.44-1.65 (m, 4H, 2 × CH2), 2.01 (s, 3H, C(O)CH3), 6.97-7.31
(m, 5H, 4-F-Ph and 2-Amino-Pyr), 8.00 (s, 1H, 2-Amino-Pyr),
8.25-8.36 (m, 1H, 2-Amino-Pyr), 10.65 (bs, 1H, exchangeable,
acetamido NH), methine-H and imidazole NH not detected;
IR 1513 (C(S)NH), 1239 cm-1 (C-F).
Ben zyl-{4-[5-(4-flu or op h en yl)-2-(4-m et h a n esu lfin yl-
ben zylsu lfan yl)-3H-im idazol-4-yl]pyr idin -2-yl}am in e (9d).
According to general procedure B, the title compound was
obtained from 9a (0.3 g, 0.68 mmol) and benzylamine (0.75 g,
7.0 mmol) after 7 h at 170 °C. The crude product was purified
by column chromatography (SiO2 60, DCM/ethanol 19+1) to
yield 0.07 g (20%) of 9d : mp 149 °C; 1H NMR (CD3OD) δ 2.70
(s, 3H, CH3), 4.21 (s, 2H, NCH2), 4.32 (s, 2H, SCH2), 6.51-
6.55 (m, 2H, C3-/C5-H 2-Amino-Pyr), 7.03-7.42 (m, 13H, Ph,
4-MeS(O)-Ph and 4-F-Ph), 7.82 (d, 1H, 5.5 Hz, C6-H 2-Amino-
Pyr); IR 1227 (C-F), 1034 cm-1 (SdO); Anal. (C29H25FN4OS2)
C, H, N.
N-{4-[5-(4-F lu or op h en yl)-2-m et h ylsu lfa n yl-3-p r op yl-
3H-im id a zol-4-yl]p yr id in -2-yl}a ceta m id e (14b). Starting
from 13b (0.6 g, 1.6 mmol) and iodomethane (0.4 g, 2.8 mmol),
and after addition of a catalytic amount of Na2CO3, the title
compound was prepared according to general procedure A. The
crude product was purified by column chromatography (SiO2
60, DCM/ethyl acetate 1+1) to yield 0.23 g (37%) of 14b: mp
1
164 °C; H NMR (CDCl3) δ 0.83 (t, 3H, 7.4 Hz, CH3), 1.57-
1.65 (m, 2H, CH2), 2.24 (s, 3H, C(O)CH3), 2.73 (s, 3H, SCH3),
3.85 (t, 2H, 7.7 Hz, NCH2), 6.88-6.96 (m, 3H, 4-F-Ph and
2-Amino-Pyr), 7.37-7.44 (m, 2H, 4-F-Ph), 8.25-8.28 (m, 2H,
2-Amino-Pyr), NH not detected; IR 1213 cm-1 (C-F); Anal.
(C20H21FN4OS) C, H, N.
4-(4-F lu or op h en yl)-5-[2-(1-p h en yleth yla m in o)p yr id in -
4-yl]-1,3-d ih yd r oim id a zole-2-th ion e (10). Upon treatment
of 8b (0.2 g, 0.5 mmol) with (RS)-1-phenylethylamine (2.0 g,
16.5 mmol) under the conditions described in the preparation
of 8e, 0.03 g (16%) of 10 was isolated as the only reaction
N-{4-[5-(4-F lu or op h en yl)-2-m et h ylsu lfa n yl-3-(2,2,6,6-
tetr a m eth yl-p ip er id in -4-yl)-3H-im id a zol-4-yl]p yr id in -2-
yl}a ceta m id e (14c). Starting from 13c (1.2 g, 2.6 mmol) and
iodomethane (0.65 g, 4.6 mmol), and after addition of a
catalytic amount of Na2CO3, the title compound was prepared
according to general procedure A. The crude product was
purified by column chromatography (SiO2 60, DCM/ethyl
acetate 1+1) to yield 0.23 g (18%) of 14c: mp 229 °C; 1H NMR
(CDCl3) δ 0.78-0.93 (m, 12H, 4 × CH3), 1.47-1.52 (m, 2H,
equatorial CH2), 1.81-1.87 (m, 2H, axial CH2), 2.00 (s, 3H,
C(O)CH3), 2.61 (s, 3H, SCH3), 4.03-4.19 (m, 1H, methine-H),
6.95-7.04 (m, 3H, 4-F-Ph and 2-Amino-Pyr), 7.26-7.33 (m,
2H, 4-F-Ph), 8.01 (s, 1H, 2-Amino-Pyr), 8.35-8.38 (m, 2H,
2-Amino-Pyr), 10.62 (s, 1H, exchangeable, NH); IR 1255 cm-1
(C-F); Anal. (C26H32FN5OS) C, H, N.
1
product: mp 204 °C; H NMR (DMSO-d6) δ 1.37 (d, 3H, 6.9
Hz, CH3), 4.86 (m, 1H, methine-H), 6.33-6.37 (m, 2H, C3-/
C5-H 2-Amino-Pyr), 7.02-7.43 (m, 9H, Ph and 4-F-Ph), 7.83
(d, 1H, 5.3 Hz, C6-H 2-Amino-Pyr), 12.55 (bs, 1H, exchange-
able, NH), amino-NH not detected; IR 1512 (C(S)NH), 1223
cm-1 (C-F).
N-{4-[5-(4-F lu or op h en yl)-1-oxy-3-p r op yl-3H-im id a zol-
4-yl]p yr id in -2-yl}a ceta m id e (12b). A solution of 1131 (1.2
g, 4.1 mmol) and 1,3,5-tripropyl-[1,3,5]-triazinane (1.0 g, 4.7
mmol) in ethanol absol (20 mL) was heated to reflux for 10 h.
The solvent was evaporated in vacuo. The oily residue was
triturated with diethyl ether to yield 0.74 g (51%) of 12b: mp
203 °C; 1H NMR (DMSO-d6) δ 0.72-0.86 (m, 3H, CH3), 1.58-
1.62 (m, 2H, CH2), 2.05 (s, 3H, C(O)CH3), 3.83 (t, 2H, 7.2 Hz,
NCH2), 6.99-7.02 (m, 1H, 2-Amino-Pyr), 7.10-7.19 (m, 2H,
4-F-Ph), 7.47-7.55 (m, 2H, 4-F-Ph), 8.06 (s, 1H, 2-Amino-Pyr),
Eth yl-{4-[5-(4-flu or oph en yl)-3-m eth yl-2-m eth ylsu lfan yl-
3H-im id a zol-4-yl]p yr id in -2-yl}a m in e (15a ). Starting from
14a (1.0 g, 2.8 mmol) the title compound was prepared
according to the procedure described for the synthesis of 15b.

Pyridinyl Imidazole Anticytokine Agents
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15 3243
Purification of the crude product by column chromatography
yielded 0.67 g (70%) of 15a : mp 150 °C; H NMR (CDCl3) δ
6.24 (s, 1H, 2-Amino-Pyr), 6.50-6.53 (m, 1H, 2-Amino-Pyr),
6.86-6.95 (m, 2H, 4-F-Ph), 7.26-7.47 (m, 7H, Ph and 4-F-
Ph), 8.12-8.16 (m, 1H, 2-Amino-Pyr); IR 1219 cm-1 (C-F);
Anal. (C23H21FN4S) C, H, N.
1
1.23 (t, 3H, 7.1 Hz, CH3), 2.70 (s, 3H, SCH3), 3.23-3.29 (m,
2H, CH2), 3.47 (s, 3H, NCH3), 4.59 (t, 1H, 4.5 Hz, exchangeable,
NH), 6.26-6.27 (m, 1H, 2-Amino-Pyr), 6.49-6.52 (m, 1H,
2-Amino-Pyr), 6.89-6.98 (m, 2H, 4-F-Ph), 7.46-7.53 (m, 2H,
4-F-Ph), 8.15-8.17 (m, 1H, 2-Amino-Pyr); IR 1221 cm-1 (C-
F); Anal. (C18H19FN4S) C, H, N.
17d : mp 163 °C; 1H NMR (CDCl3) δ 2.66 (s, 3H, SCH3), 3.17
(s, 3H, NCH3), 4.80 (s, 4H, 2 × CH2), 6.31 (s, 1H, 2-Amino-
Pyr), 6.48-6.51 (m, 1H, 2-Amino-Pyr), 6.86-6.95 (m, 2H, 4-F-
Ph), 7.19-7.45 (m, 12 H, 2 × Ph and 4-F-Ph), 8.24-8.27 (m,
1H, 2-Amino-Pyr); IR 1219 cm-1 (C-F); Anal. (C30H27FN4S)
C, H, N.
Eth yl-{4-[5-(4-flu or oph en yl)-2-m eth ylsu lfan yl-3-pr opyl-
3H-im id a zol-4-yl]p yr id in -2-yl}a m in e (15b). In small por-
tions LiAlH4 (0.5 g, 11.9 mmol) was added to a solution of 14b
(1.0 g, 2.6 mmol) in THF absol (30 mL). The reaction was
heated to reflux for 4 h. The slurry was cooled to room
temperature, and the reaction was quenched by dropwise
addition of H2O. The aqueous solution was extracted with
DCM. The combined organic extract was washed with satu-
rated brine, dried over Na2SO4, and concentrated in vacuo. The
crude product was purified by column chromatography to yield
0.2 g (21%) of 15b: mp 110 °C; 1H NMR (CDCl3) δ 0.83 (t, 3H,
7.4 Hz, propyl CH3), 1.24 (t, 3H, 7.2 Hz, ethyl CH3), 1.54-
1.66 (m, 2H, propyl CH2), 2.71 (s, 3H, SCH3), 3.22-3.28 (m,
2H, ethyl CH2), 3.79 (t, 2H, 7.7 Hz, imidazole-NCH2), 4.61 (t,
1H, 4.3 Hz, exchangeable, NH), 6.27 (s, 1H, 2-Amino-Pyr),
6.50-6.53 (m, 1H, 2-Amino-Pyr), 6.87-6.98 (m, 2H, 4-F-Ph),
7.43-7.51 (m, 2H, 4-F-Ph), 8.14-8.17 (m, 1H, 2-Amino-Pyr);
IR 1219 cm-1 (C-F); Anal. (C20H23FN4S) C, H, N.
N-{4-[5-(4-F lu or op h en yl)-3-m et h yl-2-m et h ylsu lfa n yl-
3H-im idazol-4-yl]pyr idin -2-yl}-4-m eth oxyben zam ide (17c).
To a solution of 16a (0.5 g, 1.6 mmol) in THF absol (15 mL)
was added triethylamine (0.16 g, 1.6 mmol), and the mixture
was cooled in an ice bath. A solution of 4-methoxybenzoyl
chloride (0.38 g, 2.2 mmol) was added dropwise. After the
addition was complete, the reaction was stirred for 1 h with
cooling and for an additional 1 h at room temperature. The
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was purified by column chro-
matography to yield 0.11 g (15%) of 17c: mp 182 °C; 1H NMR
(CDCl3) δ 2.72 (s, 3H, SCH3), 3.58 (s, 3H, NCH3), 3.90 (s, 3H,
OCH3), 6.90-6.95 (m, 5H, 4-MeO-Ph, 4-F-Ph and 2-Amino-
Pyr), 7.42-7.49 (m, 2H, 4-F-Ph), 7.89-7.94 (m, 2H, 4-MeO-
Ph), 8.28-8.30 (m, 1H, 2-Amino-Pyr), 8.44 (s, 1H, 2-Amino-
Pyr), 8.66 (s, 1H, exchangeable, NH); IR 1253 cm-1 (C-F);
Anal. (C24H21FN4O2S) C, H, N.
Eth yl-{4-[5-(4-flu or oph en yl)-2-m eth ylsu lfan yl-3-(2,2,6,6-
tetr a m eth yl-p ip er id in -4-yl)-3H-im id a zol-4-yl]p yr id in -2-
yl}a m in e (15c). Starting from 14c (0.1 g, 0.2 mmol), the title
compound was prepared according to the procedure described
for the synthesis of 15b. Purification of the crude product by
column chromatography yielded 0.03 g (32%) of 15c: mp 141
°C; 1H NMR (CDCl3) δ 0.90-1.12 (m, 15H, ethyl CH3 and 4 ×
CH3), 1.52-1.59 (m, 2H, equatorial CH2), 1.91-2.11 (m, 2H,
axial CH2), 2.66 (s, 3H, SCH3), 3.21-3.27 (m, 2H, ethyl CH2),
4.14-4.30 (m, 1H, methine-H), 6.37 (s, 1H, 2-Amino-Pyr),
6.41-6.44 (m, 1H, 2-Amino-Pyr), 6.64 (t, 1H, 4.8 Hz, exchange-
able, NH), 7.03-7.12 (m, 2H, 4-F-Ph), 7.40-7.47 (m, 2H, 4-F-
Ph), 8.07-8.10 (m, 2H, 2-Amino-Pyr); IR 1217 cm-1 (C-F);
Anal. (C26H34FN5S) C, H, N.
4-[5-(4-F lu or op h en yl)-2-m et h ylsu lfa n yl-3-p r op yl-3H -
im id a zol-4-yl]p yr id in -2-yla m in e (16b). A solution of 14b
(1.0 g, 2.6 mmol) in 10% hydrochloric acid (30 mL) was heated
to reflux for 14 h. The reaction was cooled to room temperature
and neutralized with an aqueous solution of NaOH (20%). A
precipitate formed which was collected by filtration, washed
with H2O, and dried in vacuo. Recrystallization from 2-pro-
panol yielded 0.6 g (67%) of 16b: mp 145 °C; 1H NMR (CDCl3)
δ 0.80 (t, 3H, 7.4 Hz, CH3), 1.52-1.63 (m, 2H, CH2), 2.70 (s,
3H, SCH3), 3.77 (t, 2H, 7.7 Hz, NCH2), 4.67 (bs, 2H, exchange-
able, NH2), 6.38 (s, 1H, 2-Amino-Pyr), 6.57-6.60 (m, 1H,
2-Amino-Pyr), 6.87-6.96 (m, 2H, 4-F-Ph), 7.40-7.48 (m, 2H,
4-F-Ph), 8.13-8.15 (m, 2H, 2-Amino-Pyr); IR 1226 cm-1 (C-
F); Anal. (C18H19FN4S) C, H, N.
Biologica l Eva lu a tion : P BMC, Wh ole Blood , a n d p 38
Assa y. Test compounds were assayed in concentrations from
10-4 to 10-8 M according to the protocols described previ-
ously.23,25
Cytoch r om e P 450 Assa y. The inhibition of cytochrome
P450 isoenzymes by selected compounds at a concentration of
10 µM in phosphate buffer (pH 7.4, 0.1% DMSO) was deter-
mined as reported.39,40
Ack n ow led gm en t. This work was supported finan-
cially by Merckle GmbH, Blaubeuren, Germany, and
the Fonds der Chemischen Industrie, Germany. We
thank C. Greim for establishing the p38 test assay, D.
Domeyer for the molecular modeling, T. Kammermeier
for the HPLC results and W. Zimmermann for helpful
discussions and valuable advice.
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{4-[5-(4-F lu or op h en yl)-3-m eth yl-2-m eth ylsu lfa n yl-3H-
im id a zol-4-yl]p yr id in -2-yl}-(1-p h en yleth yl)a m in e (17a ).
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Ben zyl-{4-[5-(4-flu or op h en yl)-3-m eth yl-2-m eth ylsu lfa -
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im id a zol-4-yl]p yr id in -2-yl}a m in e (17d ). To a suspension of
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17b: mp 138 °C; 1H NMR (CDCl3) δ 2.68 (s, 3H, SCH3), 3.32
(s, 3H, NCH3), 4.47 (d, 2H, 5.8 Hz, CH2), 5.30 (bs, 1H, NH),

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J M030766K