Novel inhibitor of p38 MAP kinase as an anti-TNF-α drug: Discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent

Article abstract of DOI:10.1021/jm050165o

The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA) and inflammat

Full text of DOI:10.1021/jm050165o

5966
J. Med. Chem. 2005, 48, 5966-5979
Novel Inhibitor of p38 MAP Kinase as an Anti-TNF-r Drug: Discovery of
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715)
as a Potent and Orally Active Anti-Rheumatoid Arthritis Agent
Seiji Miwatashi,* Yasuyoshi Arikawa, Etsuo Kotani, Maki Miyamoto, Ken-ichi Naruo, Hiroyuki Kimura,
Toshimasa Tanaka, Satoru Asahi, and Shigenori Ohkawa
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 17-85 Jusohonmachi 2-chome, Yodogawa-ku,
Osaka, 532-8686, Japan
Received February 21, 2005
The p38 mitogen-activated protein (MAP) kinase has been implicated in the proinflammatory
cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic
inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease. To
develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles
and evaluated their inhibition of p38 MAP kinase, lipopolysaccharide (LPS)-stimulated release
of tumor necrosis factor-R (TNF-R) from human monocytic THP-1 cells in vitro, and LPS-induced
TNF-R production in vivo in mice. During the course of the study, we found that these
compounds risk the inhibition of cytochrome P450 (CYP) isoforms by coordination of the
4-pyridyl nitrogen with heme iron. We therefore investigated the effects of substitution at the
2-position of the pyridyl ring on the inhibitory activity of p38 MAP kinase and CYPs in more
detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (8h,
TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38R, IC50 ) 7.1
nM; LPS-stimulated release of TNF-R from THP-1, IC50 ) 48 nM; LPS-induced TNF-R
production in mice, 87.6% inhibition at 10 mg/kg, po) and no inhibitory activity for major CYPs,
including CYP3A4. This compound also showed good bioavailability in mice and rats and
significant efficacy in a rat adjuvant-induced arthritis model. Compound 8h was selected as a
clinical candidate and is now under clinical investigation for the treatment of RA.
Introduction
inflammatory cytokines and are presently under inves-
tigation in clinical trials.6,7
Rheumatoid arthritis (RA), which affects about 1% of
the world’s population, is a serious, chronic, and sys-
temic inflammatory disease characterized by inflam-
mation and progressive joint destruction. The drug
treatment to date has primarily focused on the use of
nonsteroidal antiinflammatory drugs (NSAIDs) and
disease-modifying antirheumatic drugs (DMARDs). More
recently, novel biological products (the chimeric tumor
necrosis factor-R (TNF-R) antibody infliximab,1-3 the
soluble TNF-R receptor etanercept,4 and interleukin-1
(IL-1)-receptor antagonist anakinra5) that modify pro-
inflammatory cytokines have gained clinical approval.
These biological drugs have shown that lowering pro-
inflammatory cytokine levels is a valid treatment for
RA patients, but there are drawbacks related to patient
cost, production efficiency, and administration by injec-
tion. Therefore, attention in inflammation research has
focused on the development of orally active small
molecular inhibitors of cytokine release. TNF-R and IL-
1â are proinflammatory cytokines implicated as causal
agents in the onset and progression of bone and joint
destruction and are regulated by a mitogen-activated
protein (MAP) kinase known as p38. Indeed, selective
inhibitors of this kinase, such as the prototypical SB
203580, potently suppress the release of these pro-
In a previous paper,8 we reported the development of
p38 MAP kinase inhibitors that contain a pyridyl
thiazole core (Figure 1). Although compound 1 had
desirable p38 MAP kinase and TNF-R inhibitory activ-
ity, it was also a potent inhibitor of cytochrome P450
(CYP) 3A4, CYP2C9 and CYP2C19, a property that
would dramatically complicate its clinical use due to the
potential for serious drug-drug interactions and hepa-
totoxicity.9
It was previously reported that nitrogen-containing
heterocycles, such as imidazole and pyridine, are known
to be good ligands for ferric ion, the heme iron of CYPs,
and compounds with such a heterocyclic moiety are
often potent inhibitors of CYPs.10 The GSK group
reported that the introduction of a methyl group adja-
cent to pyridyl nitrogen in pyridylimidazole derivatives
reduced CYP2D6 affinity, but this modification lowered
the oral activity.11 The Aventis group reported that RPR
203494, a 2-cyclopropylamino-pyrimidine analogue,
showed good potency and had no inhibitory effect on
CYP2D6, CYP1A2, and CYP2C9 up to 50 µM.12 Recently
the Eberhard-Karls University Tu¨bingen and Merckle
GmbH group reported that the combination of substit-
uents at the pyridine C2 and imidazole N1 positions
resulted in almost no interference with CYP1A2,
CYP2C9, CYP2C19, CYP2D6, and CYP3A4.13
* Corresponding author. Tel: +81-6-6300-6872. Fax: +81-6-6300-
6306. E-mail: Miwatashi_Seiji@takeda.co.jp.
10.1021/jm050165o CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/23/2005

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5967
Figure 1. Docking model of compound 1 with p38 MAP kinase.
Scheme 1. Synthesis of 4-Phenyl-5-pyridyl-1,3-thiazoles 7a
a Reagents: (a) LDA, hexane, THF, -78 °C and then -20 °C; (b) nBuLi (2 equiv), hexane, THF, -78 °C and then 0 °C; (c) 3, -78 °C;
(d) Br2, AcOH, 70 °C; (e) 6, DMF, 80 °C; (f) NaOH (aq), EtOH; (g) 150 °C; (h) mCPBA, DMF; (i) POCl3, 100 °C.
Scheme 2. Synthesis of Amides 8 and 11 and
We evaluated a docking experiment between com-
pound 1 and p38 MAP kinase using crystal data of the
Secondary Amines 10a
complex of SB 203580 and p38 MAP kinase (Figure 1).14
This suggested that the space near pyridine is sufficient
to tolerate a substitution adjacent to the pyridyl nitro-
gen, and furthermore, hydrophobic substituents such as
alkyl or phenyl were expected to interact in the groove
between Leu108 and Gly110 of p38 MAP kinase. There-
fore, the introduction of a substituent into the pyridyl
ring seemed a good approach for reducing CYP3A4
inhibitory activity without reducing p38 MAP kinase
inhibitory activity.
In this report, we describe further efforts to elucidate
the in vitro potency, in vitro CYP3A4 inhibition profile,
bioavailability, and in vivo efficacy.
Chemistry
a Reagents: (a) R4COCl, Et3N, DMF or THF; (b) PhCOCl (2
equiv), Et3N, THF; (c) HCl (aq), 40 °C; (d) LiAlH4, AlCl3, THF,
reflux; (e) NaH, DMSO and then CH3I.
The preparation of 4-phenyl-5-pyridyl-1,3-thiazoles 7
from 4-methylpyridines 2, the key intermediate of this
work, is shown in Scheme 1.
The 4-methylpyridines 2 were treated with lithium
diisopropyl amide (LDA) (method A) or 2 equiv of
n-butyllithium (method B) and reacted with 1-benzoyl-
2-methylaziridines 38 to provide the ketones 4. Bromi-
nation of 4 gave R-bromo ketones 5, which were con-
verted into 1,3-thiazoles 7 with various thioamides 6,
except thioacetamide (R3 ) Me). In the case of reacting
5g (R1 ) NH2, R2 ) 3-Me) with thioacetamide, only a
trace of the cyclization product 7r was generated, and
debromination mainly occurred to give the correspond-
ing ketone 4 (R1 ) NH2, R2 ) 3-Me). Alternatively,
treating R-bromo ketone 5g with ethyl 3-amino-3-
thioxopropanoate8 followed by hydrolysis and decar-
boxylation provided the desired 7r via 7o. Oxidation of
7a with m-chloroperbenzoic acid (mCPBA) gave the
N-oxide, which was converted into the 2-chloropyridyl
derivative 7s using phosphorus oxychloride (POCl3).
General modification of the amino group at the 2
position of the pyridyl ring is outlined in Schemes 2 and
3. Direct acylation of 2-aminopyridines 7 was performed
with acyl chlorides with good yields, except for benzoyl
chloride. The use of 1 equiv of benzoyl chloride proved

5968 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Scheme 3. Direct Amination of 2-Fluoropyridine 7da
Miwatashi et al.
We then focused on various amide derivatives in the
hope of obtaining improved interactions with the en-
zyme. Some were identified as having superior activity
compared to the N-monoalkyl analogues. In the series
of alkyl amide derivatives, propionamide 8b induced a
substantial boost in activity compared to acetamide 8a
or butyramide 8c. Compounds with bulky amide groups
on the pyridyl ring, such as cyclohexanecarboxamide 8d,
phenylacetamide 8e, 3-phenylpropionamide 8f, and
benzamide 8h, proved to be as effective as the initial
monoalkylamines (10a, 10c, 10e, 12a). However, N-
methylation of the amide group dramatically reduced
the potency (8h vs 11), as shown by the tertiary amine
analogue 12b. To evaluate the role of the 2-substituent
on the pyridyl ring, we conducted a docking simulation
between compound 8h and p38 MAP kinase (Figure 2).
The phenyl ring of the benzamide moiety interacted
with the hydrophobic groove between Leu108 and
Gly110, and there were two hydrogen bonds between
the amino pyridyl moiety and the kinase backbone
Met109 amide. This hydrophobic interaction with the
enzyme seems to result in increased inhibitory activity.
a Reagents: (a) R5R6NH, reflux.
Scheme 4. Synthesis of Methyl Sulfones 13a
For kinase inhibitors, it is well-known that the SAR
for a cell-based assay does not parallel that for the
corresponding kinase enzymatic assay. These com-
pounds were therefore further evaluated for their
inhibitory activity of TNF-R production in LPS-stimu-
lated THP-1 cells as a secondary screen (Table 2).
Compound 7s, with chloro acting as an electron-
withdrawing group, exhibited weak anti-TNF-R activity
in parallel with its weak p38 MAP kinase inhibitory
activity. The introduction of methyl (7c) adjacent to the
pyridyl nitrogen resulted in diminished activity, as in
the p38 MAP kinase assay. Changing the methyl group
of 7c to an amino group (7h, 10a, 10c, 10e, 12a)
increased the activity, but the activity was sensitive to
the length of the methylene spacer. Cyclopentylamino
12a showed the most potent cellular activity among
them. In contrast to these amino derivatives, amide
derivatives did not vary considerably in activity with
respect to the methylene spacer length. Benzamide 8h
gave slightly reduced cellular activity, but phenyl-
acetamide 8e and 3-phenylpropionamide 8f showed
strong inhibitory activity, suggesting that amide sub-
stituents were preferable to amines.
a Reagents: (a) mCPBA, DMF.
inefficient, providing a mixture of 8 and 9. Therefore,
the amines 7 were converted to dibenzoyl intermediates
9 with 2 equiv of benzoyl chloride, which were subse-
quently cleaved by hydrolysis to give monobenzoyl
derivates 8. The resulting amides 8 were reduced to
amines 10 using a complex of lithium aluminum hydride
and aluminum chloride. The amide 8h (R2 ) 3-Me, R3
) Et, R4 ) Ph) was alkylated with methyl iodide to
afford 11. Secondary and tertiary amine derivatives 12
were obtained by direct amination of 2-fluoropyridyl
derivative 7d (Scheme 3). Sulfonyl derivatives 13 were
synthesized by oxidization of the corresponding sulfide
with 2 equiv of mCPBA in N,N-dimethylformamide
(DMF) (Scheme 4). All synthesized compounds are listed
in Table 1.
Results and Discussion
CYP3A4 is one of the most important enzymes in drug
metabolic processes,15 and the SAR trends for inhibition
of other CYPs such as CYP2C9 and CYP2C19 are
typically similar to that for CYP3A4. We therefore
selected CYP3A4 as a representative CYP, and mea-
sured the percent inhibition as shown in Table 2.
Although compound 7a, which has no substituent on
the pyridyl ring, exhibited moderate to high affinity for
CYP3A4, substitution at the pyridine C2 position elimi-
nated that interaction. In particular, the introduction
of an electron-withdrawing substituent, such as fluoro
(7d) or chloro (7s), into the pyridyl moiety dramatically
reduced CYP3A4 inhibition. This decreased affinity is
most likely due to reduced electron density at the
pyridyl nitrogen, so that coordination to the heme iron
of CYP3A4 is weak. However, this series of compounds
showed poor p38 inhibitory potency, and this approach
did not seem promising. Replacement of the chlorine
atom of 7s by methyl (7c) or amino (7h) (sterically
SAR data for the pyridine 2-substituent of the
4-phenyl-5-pyridyl-1,3-thiazole derivatives are shown in
Table 2. Introduction of a methyl group adjacent to the
pyridyl nitrogen gave slightly diminished activity against
p38 MAP kinase (7a vs 7c), while halogenopyridines 7d
and 7s were also less potent inhibitors. This is presum-
ably due to the reduced electron density at the pyridyl
nitrogen atom, which interacts with the amide NH of
Met109. These results indicate that substitution at the
2-position of the pyridyl ring appears crucial to p38 MAP
kinase inhibitory activity. N-Monoalkylamines 10a, 10c,
10e, and 12a resulted in significant improvements in
potency against p38 MAP kinase inhibitory activity,
whereas the tertiary amine in 12b reduced the activity.
This suggested that the hydrogen atom of the amino
group acts as a hydrogen donor for tight binding at the
linker region of the enzyme. This result triggered a
search for even more suitable substituents at the
2-position of the pyridyl ring.

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5969
Table 1. Physicochemical Properties of 4-Phenyl-5-pyridyl-1,3-thiazoles
compd
R1
R2
R3
formula
17H16N2S
22H18N2S2
18H18N2S‚H2O
17H15FN2S
17H17N3OS
17H17N3OS
17H17N3S
17H17N3S
17H17N3S
16H14ClN3S
16H15N3S
yield (%)a
mp (°C)
anal.b
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
H
3-Me
3-Me
3-Me
3-Me
4-MeO
3-MeO
4-Me
3-Me
2-Me
3-Cl
Et
C
C
C
C
C
C
C
C
C
C
C
C
C
C
59
84
60
38
75
65
73
60
59
81
84
76
72
62
63
91
71
72
81
66
64
56
75
88
75
77
88
52
77
71
88
55
69
75
74
95
68
83
62
56
48
35
54
65
33
75
62
70
54
52
52
70
56-58
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
H
4-MeSPh
101-102
oil
Me
F
Et
Et
oil
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Me
Et
153-154
130-131
126-127
144-146
107-108
131-132
158-159
140-141
117-118
113-115
131-132
119-122
181-183
152-153
oil
Et
Et
Et
Et
Et
H
Et
4-F
Et
16H14FN3S
17H14F3N3S
18H19N3S
3-CF3
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Cl
Et
Pr
CH2CO2Et
C19H19N3O2S
4-MeSPh
C23H20N2S2
C22H19N3S2
C16H15N3S
NH2
NH2
Cl
4-MeSPh
Me
Et
C17H15ClN2S
19H19N3OS
C20H21N3OS
AcNH
Et
C
119-120
103-104
88-89
98-100
107-108
126-127
205-206
113-114
128-129
95-97
135-136
94-95
104-105
116-117
97-98
112-113
145-146
amorphous
180-182
106-107
134-136
97-98
EtCONH
PrCONH
Et
Et
C21H23N3OS
cHexCONH
PhCH2CONH
Ph(CH2)2CONH
PhCH2CONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCH2NH
PhCH2NH
Ph(CH2)2NH
Ph(CH2)2NH
Ph(CH2)3NH
PhCONMe
cPenNH
Et
C24H27N3OS
Et
C25H23N3OS
Et
C26H25N3OS
4-MeSPh
C30H25N3OS2‚0.25H2O
Et
C
C
C
C
C
C
C
C
C
C
C
C
24H21N3OS
23H18ClN3OS
23H19N3OS
Et
H
Et
4-F
Et
23H18FN3OS
24H18F3N3OS‚0. 5H2O
24H21N3OS
3-CF3
2-Me
4-Me
3-MeO
4-MeO
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
3-Me
Et
Et
Et
24H21N3OS
Et
24H21N3O2S
24H21N3O2S
23H19N3OS
8p
8q
8r
Et
Me
Pr
25H23N3OS
8s
4-MeSPh
Et
4-MeSPh
Et
4-MeSPh
Et
29H23N3OS2
10a
10b
10c
10d
10e
11
C24H23N3S
C29H25N3S2
C25H25N3S‚0.25H 2O
C30H27N3S2
137-139
52-53
94-96
C26H27N3S
Et
C25H23N3OS
12a
12b
13a
13b
13c
13d
13e
13f
Et
C22H25N3S
21H23N3S
117-118
108-109
171-174
134-138
212-214
244-245
148-150
174-176
N-pyrrolidinyl
H
Et
C
4-MeSO2Ph
4-MeSO2Ph
4-MeSO2Ph
4-MeSO2Ph
4-MeSO2Ph
4-MeSO2Ph
C22H18N2O2S2
C23H20N2O2S2
C29H23N3O3S2
C30H25N3O3S2
C29H25N3O2S2
C30H27N3O2S2
Me
PhCONH
PhCH2CONH
PhCH2NH
Ph(CH2)2NH
a No attempt was made to optimize yields. Numbers respect the yield for the last step. b Analytical results are within (0.4% of the
theoretical value.
similar, but electronically different) resulted in reduced
CYP3A4 affinity.
Benzamide 8h also showed reduced CYP3A4 affinity,
but phenylacetamide 8e and 3-phenylpropionamide
8f showed increased affinity in proportion to the in-
creasing length of the methylene spacer. The benzyl
derivative 10a showed stronger affinity than the cor-
responding amide 8h. Cyclopentylamine 12a and ter-
tiary amine 12b gave higher affinity than benzyl-
amine 10a. It appears that the CYP3A4 affinity is
related to lipophilicity as well as steric effects of the
substituent.
We attempted to calculate the coordination energy of
pyridine or 2-methylpyridine to heme using D-Mol, an
ab initio method, to determine the energetic contribution
of a having a substituent adjacent to the pyridyl
nitrogen (Figure 3). In this calculation, the pyridine-
heme complex is 15.8 kcal/mol more stable than the
2-methylpyridine-heme complex, and this stability may
be crucial for the CYP interaction.

5970 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Table 2. SAR of Pyridine-2-substitutient
Miwatashi et al.
IC50 (nM)a
TNF-R
CYP3A4
(% inhibn, at 1 µM)
compd
R1
p38R
7a
H
Me
F
15
53
(12-19)
(41-69)
(68-130)
(17-24)
(150-390)
(18-39)
(5.9-13)
(10-18)
(6.3-10)
(4.8-6.5)
(6.3-11)
(6.4-7.7)
(4.3-10)
(3.8-6.8)
(6.2-11)
73
450
NTb
130
890
NTb
(36-150)
48.5
24.0
-5.1
10.2
1.2
17.2
13.0
16.9
-4.3
7.2
12.9
4.3
9.5
17.3
17.9
NTb
15.9
21.9
7c
(170-1200)
7d
7h
7s
8a
8b
8c
8d
8e
8f
8h
10a
10c
10e
11
12a
12b
94
NH2
Cl
20
240
26
(74-230)
(370-2200)
AcNH
EtCONH
8.8
13
7.9
5.6
8.1
7.1
6.7
5.1
8.1
6.1
(4.1-13)
PrCONH
NTb
77
cHexCONH
PhCH2CONH
Ph(CH2)2CONH
PhCONH
(37-150)
(7.1-25)
(13-29)
(35-71)
(22-35)
(25-71)
(61-240)
13
19
48
PhCH2NH
Ph(CH2)2NH
Ph(CH2)3NH
PhCONMe
cPenNH
28
42
120
>1000
3.0
160
NTb
(2.1-4.1)
(110-230)
5.1
NTb
(3.2-8.2)
N-pyrrolidinyl
a 95% Confidence intervals or remarks are in parentheses. b NT means not tested.
Figure 2. Docking model of compound 8h with p38 MAP kinase.
were nearly equipotent in the p38 MAP kinase inhibi-
tion assay, suggesting no significant electronic effect
involved with substitution at this position and that the
strong activity seen with 3-methyl 8h is likely due to
favorable steric interactions.
TNF-R inhibition was relatively insensitive to sub-
stitution on the 4-phenyl ring (8h-8p). Compounds
3-chloro 8i, unsubstituted 8j, 4-fluoro 8k, 3-methoxy 8o,
and 4-methoxy 8p retained relatively constant activity,
except for 3-trifluoromethyl 8l. A comparison of methyl-
substituted derivatives (8h, 8m, 8n) revealed a trend
toward increasing activity from para to ortho to meta.
Variation of the 4-phenyl substituent had little influ-
ence on CYP inhibitory potency. While overall these
compounds showed little CYP3A4 inhibition, the com-
pounds with large electronegative substituents, chloro
8i and trifluoromethyl 8l, did possess the highest
inhibition of the series.
Figure 3. Computation of coordination energy between
pyridine and 2-methylpyridine to heme.
We chose the benzamide group as a representative
substituent on the pyridyl ring for the next SAR study
around the phenyl ring on the 4-position of the thiazole
ring (Table 3). We introduced small substituents into
the phenyl ring, such as fluorine, methyl, and methoxy,
as in our previous studies.8 By comparison, 3-chloro 8i,
unsubstituted 8j, 4-fluoro 8k, and 3-trifluoromethyl 8l
As the introduction of lower alkyl and 4-methyl-
sulfonylphenyl substituents at the 2-position of

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Table 3. SAR of Phenyl Ring Substitutution
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5971
derivatives. Methyl derivative 13b showed no affinity
for CYP3A4, and amide derivatives 13c and 13d gave
good results, suggesting that the introduction of a
substituent adjacent to the pyridyl nitrogen was effec-
tive in reducing CYP3A4 interaction, and amide sub-
stituents gave the best results for 4-phenyl-5-pyridyl-
1,3-thiazoles.
Some potent compounds were tested for their ability
to inhibit LPS-induced TNF-R production in mice with
10 mg/kg oral administration; also examined was the
plasma concentration after the oral administration of
various compounds in mice (Table 5). Benzylamine 10a
and cyclopentylamine 12a inhibited TNF-R levels by
more than 50% at 10 mg/kg; however, they had very
poor oral absorption. In contrast to these amine de-
rivatives, the amide compounds showed significantly
more potent activity. Among these compounds, acetyl
8a and propionyl 8b displayed excellent anti-TNF-R
activities (85.5% and 89.5%, respectively) and good oral
absorption. Cyclohexylcarbonyl 8d also had strong
activity, but lower plasma concentration. Among the
benzoyl compounds, 3-methylphenyl 8h, 3-chlorophenyl
8i, phenyl 8j, and 4-fluorophenyl 8k inhibited TNF-R
levels by more than 80%, but a slightly bulkier sub-
stituent such as trifluoromethylphenyl (8l) gave less
activity. 3-Methylphenyl 8h showed the best overall
results in both the in vivo TNF-R assay and plasma
concentration.
On the basis of their promising in vivo activity,
compounds 8b and 8h were further evaluated in rat
pharmacokinetic studies. Compound 8b showed good
bioavailability (BA) in mice (50.3%), but only 4.6% in
rats (data not shown). In contrast, compound 8h had a
modest mouse BA (18.4%) and a slightly improved rat
BA (21.1%) profile. The rat PK parameters for com-
pound 8h are shown in Table 6.
Compound 8h was further tested to evaluate its
selectivity for p38 MAP kinase over several other
protein kinases (Table 7). Notably, it only significantly
inhibited p38R (IC50 ) 7.1 nM) and p38â (IC50 ) 200
nM) in a concentration-dependent manner and was
approximately 28 times more selective for p38R over
p38â. Compound 8h was also examined for its potential
to inhibit 11 CYP isoforms and was found to have no
significant inhibitory effect at 1-100 µM (Figure 4). To
CYP3A4
IC50 (nM)a
(% inhibn,
compd
R2
p38R
TNF-R
at 1 µM)
8h
8i
8j
8k
8l
3-Me
3-Cl
H
4-F
3-CF3
7.1 (6.4-7.7)
48 (35-71)
130 (78-210)
110 (77-140)
93 (68-130)
690 (n ) 1)
4.3
8.2
-12.5
2.4
10.3
NTb
NTb
NTb
NTb
30 (23-40)
31 (23-43)
31 (21-48)
91 (66-120)
8m 2-Me 110 (77-170)
220 (150-330)
8n
8o
8p
4-Me 210 (140-290) 450 (210-950)
3-MeO 120 (93-160)
4-MeO 130 (96-180)
110 (66-200)
130 (83-200)
a 95% Confidence intervals or remarks are in parentheses. b NT
means not tested.
the thiazole ring was well-tolerated in our previous
studies,8 we examined the effect of substitution at the
thiazole 2-position in this work as well (Table 4). The
lower alkyl compounds, such as methyl 8q and propyl
8r, gave strong inhibition of p38 MAP kinase and TNF-
R. 4-Methylsulfonylphenyl derivatives methyl 13b, ben-
zylamino 13e, and phenethylamino 13f exhibited p38
MAP kinase inhibitory activity as strong as the corre-
sponding 2-ethyl thiazole derivatives (7c, 10a, 10c,
respectively). These results are similar to the previously
reported SAR trend found in a series of pyrimidinyl-
imidazoles.16
In the series of 4-methylsulfonylphenyl derivatives
(13a-f), substitution at the 2-position of the pyridyl ring
had a significant impact on cell-based activity. Methyl
compound 13b and benzylamino compound 13e showed
less potency than unsubstituted 13a. Although the
activity was retained when amide groups (13c, 13d)
were introduced, they led to a decrease relative to the
parent compounds 8h and 8e.
The substituent effects on CYP3A4 inhibition for
these compounds were greater than for the 2-ethyl
Table 4. SAR of Thiazole 2-Substituent
IC50 (nM)a
CYP3A4
(% inhibn, at 1 µM)
compd
R1
R3
p38R
TNF-R
8q
PhCONH
PhCONH
H
Me
Pr
13
13
14
26
37
34
11
9.1
(10-17)
(10-18)
(12-16)
(22-31)
(27-50)
(23-52)
(8.7-15)
(6.9-12)
33
37
(19-60)
NTb
NTb
25.0
-1.7
5.7
8r
(22-62)
13a
13b
13c
13d
13e
13f
4-MeSO2C6H4
4-MeSO2C6H4
4-MeSO2C6H4
4-MeSO2C6H4
4-MeSO2C6H4
4-MeSO2C6H4
49
(29-84)
Me
440
70
61
130
43
(310-630)
(42-120)
(24-150)
(120-150)
(32-57)
PhCONH
PhCH2CONH
PhCH2NH
Ph(CH2)2NH
6.8
11.3
12.0
a 95% Confidence intervals or remarks are in parentheses. b NT means not tested.

5972 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Miwatashi et al.
Table 5. Inhibitory Potencies of 4-Phenyl-5-pyridyl-1,3-thiazoles on LPS-induced TNF-R Production in Mice and Pharmacokinetic
Parameters
LPS mice (10 mg/kg, po)
mice (10 mg/kg, po)d
compd
R1
R2
R3
% inhibna
SE
Cmax (µg/mL)
AUC0-4h (µg‚h/mL)
8a
8b
8d
8f
8h
8i
8j
8k
8l
8q
10a
12a
13b
13c
AcNH
3-Me
3-Me
3-Me
3-Me
3-Me
3-Cl
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
85.5**
89.5**
75.4**
60.7
87.6*
90.9**
86.6**
98.2**
59.6**
64.2
64.6*
66.3
46.8
58.6
2.4
3.2
1.82
1.72
0.06
0.03
0.59
0.15
0.10
0.05
NTb
0.10
NDc
0.06
0.71
0.05
1.70
2.85
0.06
0.07
1.16
0.36
0.16
0.11
NTb
0.25
EtCONH
cHexCONH
Ph(CH2)2CONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCONH
PhCH2NH
cPenNH
7.0
4.5
6.2
3.1
H
3.6
4-F
1.3
3-CF3
3-Me
3-Me
3-Me
3-Me
3-Me
12.2
8.7
11.7
15.0
16.4
15.7
0.09
1.79
0.10
Me
PhCONH
4-MeSO2C6H4
4-MeSO2C6H4
a Dunnett-type test: *p < 0.05, **p < 0.01 vs control. b NT means not tested. c ND means not detected. (<0.01 µg/mL). d Parameters
were calculated from the mean concentration (Balb/c mouse, female, 8 weeks, n ) 3).
Table 6. Pharmacokinetic Parameters of Selected p38 MAP
Kinase Inhibitor 8h in Rata
1 mg/kg, iv
10 mg/kg, po
C5min
(µg/mL)
AUC0-24h
(µg‚h/mL)
Cmax
(µg/mL)
AUC0-24h
(µg‚h/mL)
compd
BA (%)
8h
1.25 ( 0.03 0.55 ( 0.01 0.19 ( 0.05 1.16 ( 0.16 21.1 ( 2.9
a Results are shown as the mean ( SE.
Table 7. Selectivity Profile of 8h for Representative Kinases
kinase
IC50 (µM)
kinase
IC50 (µM)
p38R
p38â
p38γ
p38δ
JNK1
0.0071
0.20
>10
ERK1
IKKâ
MEKK1
TAK1
>10
>10
>10
>10
>10
>10
evaluate its potency as an anti-RA drug, 8h was tested
in a rat adjuvant-induced arthritis (AA) model (3, 10,
and 30 mg/kg, po), as shown in Figure 5, and signifi-
cantly reduced the secondary paw volume (25 ( 6%
inhibition vs vehicle) with no influence on the animal
body weight compared to control animals.
Figure 4. Inhibition of 8h for representative CYP isoforms.
served for several amide derivatives. The most prom-
ising compound in this series, 8h,was a specific inhibitor
of p38R MAP kinase with an IC50 value of 7.1 nM and
exhibited inhibition of TNF-R production by 87.6% in
mice with a 10 mg/kg single oral administration.
Moreover, 8h displayed a markedly reduced inhibition
profile for CYP isoforms with reasonable mouse and rat
pharmacokinetics. Compound 8h was evaluated in a rat
AA model (30 mg/kg, po), providing 25 ( 6% inhibition
of the secondary paw volume, further validating this
class of p38 MAP kinase inhibitors. On the basis of its
overall profile, compound 8h was chosen as a promising
drug candidate for the treatment of inflammatory
diseases mediated by TNF-R, such as rheumatoid
arthritis, and is now under clinical evaluation.
Conclusion
A novel structural class of 4-phenyl-5-pyridyl-1,3-
thiazoles was optimized as inhibitors of p38 MAP kinase
and the proinflammatory cytokine TNF-R. In this series
of compounds, it was shown that the introduction of an
electron-withdrawing substituent or bulky substituent
at the pyridine C2 position was a very effective approach
to reduce the inhibition activity of CYPs such as
CYP3A4. The introduction of an electron-withdrawing
group led to reduced p38 MAP kinase inhibitory activity,
but this effect could be overcome by introducing an
appropriate bulky substituent adjacent to the pyridyl
nitrogen. Among various bulky substituents, good cel-
lular activity and pharmacokinetic profiles were ob-

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5973
tert-Butyl [4-[2-(4-Methoxyphenyl)-2-oxoethyl]-2-pyr-
idyl]carbamate (4d). Under an argon atmosphere, a solution
of 2-tert-butyl (4-methyl-2-pyridyl)carbamate (2d)19,20 (20 g, 97
mmol) in THF (300 mL) was cooled to -78 °C and a 1.6 M
solution of n-butyllithium in hexane (140 mL, 0.23 mol) was
added dropwise to the solution. After the addition, the solution
was stirred for 30 min at 0 °C and cooled to -78 °C. A solution
of 1-(4-methoxybenzoyl)-2-methylaziridine (25 g, 0.13 mol) in
THF (50 mL) was added dropwise to the mixture. The reaction
mixture was allowed to warm to room temperature and stirred
for 2 h at room temperature. Water (100 mL) and isopropyl
ether (300 mL) were added to the reaction mixture, and the
resulting crude crystal was collected by filtration to give crude
crystalline. This crude crystal was recrystallized from THF/
hexane to afford 23 g (yield 69%) of 4d as a solid. Mp: 187-
190 °C. 1H NMR (CDCl3) δ: 1.46 (9H, s), 3.85 (3H, s), 4.37
(2H, s), 6.92 (1H, dd, J ) 5.2, 1.1 Hz), 7.06 (2H, d, J ) 8.8
Hz), 7.72 (1H, s), 8.02 (2H, d, J ) 8.8 Hz), 8.15 (1H, d, J ) 5.2
Hz), 9.70 (1H, brs).
tert-Butyl [4-[2-(3-Methoxyphenyl)-2-oxoethyl]-2-pyr-
idyl]carbamate (4e). This compound was prepared from 1-(3-
methoxybenzoyl)-2-methylaziridine as described in the syn-
thesis of 4d as a solid. Yield: 53%. Mp: 99-100 °C (ethyl
acetate/isopropyl ether). 1H NMR (CDCl3) δ: 1.52 (9H, s), 3.86
(3H, s), 4.27 (2H, s), 6.87 (1H, dd, J ) 5.2, 1.4 Hz), 7.10-7.16
(1H, m), 7.39 (1H, dd, J ) 8.3, 7.7 Hz), 7.50-7.53 (1H, m),
7.55-7.59 (1H, m), 7.66 (1H, brs), 7.91 (1H, s), 8.19 (1H, d, J
) 5.2 Hz).
Figure 5. Antiinflammatory effects in the rat adjuvant-
induced arthritis model of 8h (po, 14 days). **p < 0.01 vs
vehicle (Dunnett-type test; n ) 12).
Experimental Section
Chemistry. The melting points were determined on a
Yanagimoto micro melting point apparatus or a Bu¨che B-545
and are uncorrected. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a Varian Gemini-200 (200
MHz) spectrometer, with tetramethylsilane as the internal
standard. TLC analyses were carried out on Merck Kieselgel
60 F254 plates. Elemental analyses were carried out by Takeda
Analytical Laboratories, Ltd., and were within ( 0.4% of the
theoretical values unless otherwise noted. Tetrahydrofuran
(THF) was distilled over calcium hydride before use and other
solvents and reagents were used without purification. Ex-
tracted solutions were dried over anhydrous Na2SO4 unless
otherwise noted and concentration of the organic solution was
carried out under reduced pressure. Chromatographic purifi-
cation was carried out on silica gel columns (Kieselgel 60,
0.063-0.22 mm, Merck) unless otherwise noted. The yields
reported are not optimized.
tert-Butyl [4-[2-(4-Methylphenyl)-2-oxoethyl]-2-pyridyl]-
carbamate (4f). This compound was prepared from 2-methyl-
1-(4-methylbenzoyl)aziridine as described in the synthesis of
4d as a solid. Yield: 68%. Mp: 137-138 °C (ethyl acetate/
1
isopropyl ether). H NMR (CDCl3) δ: 1.52 (9H, s), 2.42 (3H,
s), 4.26 (2H, s), 6.87 (1H, dd, J ) 5.1, 1.5 Hz), 7.28 (2H, d, J
) 8.1 Hz), 7.66 (1H, brs), 7.89 (2H, d, J ) 8.1 Hz), 7.90 (1H, d,
J ) 0.7 Hz), 8.18 (1H, dd, J ) 5.1, 0.7 Hz).
The 1-benzoyl-2-methylaziridines 3 and thioamides 6 were
prepared according to a previous report.8 The 2-fluoro-4-
methylpyridine 2c17,18 and 2-tert-butoxycarbonylamino-4-
methylpyridine 2d19,20 were synthesized according to previous
reports.
tert-Butyl [4-[2-(3-Methylphenyl)-2-oxoethyl]-2-pyridyl]-
carbamate (4g). This compound was prepared from 2-methyl-
1-(3-methylbenzoyl)aziridine as described in the synthesis of
4d as a solid. Yield: 81%. Mp: 144-146 °C (ethyl acetate/
1
isopropyl ether). H NMR (CDCl3) δ: 1.53 (9H, s), 2.42 (3H,
1-(3-Methylphenyl)-2-(2-methyl-4-pyridyl)ethanone (4a).
Under an argon atmosphere, a solution of diisopropylamine
(110 mL, 0.78 mol) in THF (760 mL) was cooled to -50 °C
and a 1.6 M solution of n-butyllithium in hexane (500 mL, 0.80
mol) was added dropwise to the solution. After the addition,
the solution was stirred for 10 min and a solution of 2,4-
dimethylpyridine (2a) (88 mL, 0.76 mol) in THF (76 mL) was
added dropwise at -30 °C. The reaction mixture was stirred
for 1 h at -10 °C and then the resulting mixture was cooled
to -78 °C. A solution of 1-(3-methylbenzoyl)-2-methylaziridine
(140 g, 0.80 mol) in THF (76 mL) was added dropwise at -78
°C. After the addition, the mixture was stirred for 2 h at -78
°C and then the reaction mixture was allowed to warm to room
temperature. Water (800 mL) was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extracts were washed with water, dried, and concentrated to
give a residue. The residue was crystallized with isopropyl
ether/hexane to afford 156 g (91%) of 4a as a solid. Mp: 56-
57 °C. 1H NMR (CDCl3) δ: 2.42 (3H, s), 2.54 (3H, s), 4.23 (2H,
s), 7.00 (1H, d, J ) 5.1 Hz), 7.07 (1H, s), 7.33-7.45 (2H, m),
7.76-7.83 (2H, m), 8.44 (1H, d, J ) 5.1 Hz).
s), 4.28 (2H, s), 6.87 (1H, d, J ) 5.1 Hz), 7.32-7.43 (2H, m),
7.75-7.83 (2H, m), 7.92 (1H, s), 8.06 (1H, brs), 8.21 (1H, d, J
) 5.1 Hz).
tert-Butyl [4-[2-(2-Methylphenyl)-2-oxoethyl]-2-pyridyl]-
carbamate (4h). This compound was prepared from 2-methyl-
1-(2-methylbenzoyl)aziridine as described in the synthesis of
4d as a solid. Yield: 61%. Mp: 131-132 °C (ethyl acetate/
1
hexane). H NMR (CDCl3) δ: 1.52 (9H, s), 2.50 (3H, s), 4.22
(2H, s), 6.87 (1H, dd, J ) 5.1, 1.5 Hz), 7.23-7.45 (3H, m), 7.65
(1H, brs), 7.73 (1H, d, J ) 7.7 Hz), 7.87 (1H, s), 8.19 (1H, d, J
) 5.1 Hz).
tert-Butyl [4-[2-(3-Chlorophenyl)-2-oxoethyl]-2-pyridyl]-
carbamate (4i). This compound was prepared from 1-(3-
chlorobenzoyl)-2-methylaziridine as described in the synthesis
of 4d as a solid. Yield: 78%. Mp: 152-153 °C (ethyl acetate/
1
isopropyl ether). H NMR (CDCl3) δ: 1.53 (9H, s), 4.26 (2H,
s), 6.85 (1H, dd, J ) 5.2, 1.8 Hz), 7.43 (1H, dd, J ) 8.0, 7.7
Hz), 7.56 (1H, ddd, J ) 8.0, 2.2, 1.1 Hz), 7.86 (1H, ddd, J )
7.7, 1.7, 1.1 Hz), 7.91 (1H, s), 7.95 (1H, brs), 7.97 (1H, dd, J )
2.2, 1.7 Hz), 8.22 (1H, dd, J ) 5.2, 0.6 Hz).
1-(3-Methylphenyl)-2-(4-pyridyl)ethanone (4b). This
compound was prepared from 4-methylpyridine (2b) as
described in the synthesis of 4a as a solid. Yield: 65%.
tert-Butyl [4-(2-Oxo-2-phenylethyl)-2-pyridyl]carbam-
ate (4j). This compound was prepared from 1-benzoyl-2-
methylaziridine as described in the synthesis of 4d as a solid.
Yield: 72%. Mp: 162-163 °C (ethyl acetate/hexane). 1H NMR
(CDCl3) δ: 1.53 (9H, s), 4.29 (2H, s), 6.87 (1H, dd, J ) 5.2, 1.4
Hz), 7.41-7.63 (3H, m), 7.92-8.05 (3H, m), 8.34 (1H, d, J )
5.2 Hz), 8.50 (1H, brs).
1
Mp: 115-116 °C (ethyl acetate/hexane). H NMR (CDCl3) δ:
2.43 (3H, s), 4.28 (2H, s), 7.20 (2H, dd, J ) 4.4, 1.8 Hz), 7.32-
7.46 (2H, m), 7.76-7.83 (2H, m), 8.56 (2H, dd, J ) 4.4, 1.8
Hz).
2-(2-Fluoro-4-pyridyl)-1-(3-methylphenyl)ethanone (4c).
This compound was prepared from 2-fluoro-4-methylpyridine
(2c)17,18 as described in the synthesis of 4a as a solid. Yield:
53%. Mp: 66-67 °C (ethyl acetate/hexane). 1H NMR (CDCl3)
δ: 2.43 (3H, s), 4.32 (2H, s), 6.85 (1H, s), 7.08-7.10 (1H, m),
7.32-7.81 (3H, m), 8.16-8.19 (2H, m).
tert-Butyl [4-[2-(4-Fluorophenyl)-2-oxoethyl]-2-pyridyl]-
carbamate (4k). This compound was prepared from 1-(4-
fluorobenzoyl)-2-methylaziridine as described in the synthesis
of 4d as a solid. Yield: 76%. Mp: 139-141 °C (ethyl acetate/
1
hexane). H NMR (CDCl3) δ: 1.53 (9H, s), 4.26 (2H, s), 6.86

5974 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Miwatashi et al.
(1H, dd, J ) 5.3, 1.7 Hz), 7.16 (2H, t, J ) 6.8 Hz), 7.92 (1H, s),
8.02 (2H, t, J ) 6.8 Hz), 8.18 (1H, d, J ) 5.3 Hz), 8.34 (1H,
brs).
2-(2-Amino-4-pyridyl)-2-bromo-1-phenylethanone Hy-
drobromide (5j). This compound was prepared as described
from 4j in the synthesis of 5a as a solid. Yield: 86%. 1H NMR
(DMSO-d6) δ: 6.98 (1H, dd, J ) 6.8, 1.6 Hz), 7.16 (1H, s), 7.22
(1H, s), 7.60 (2H, t, J ) 7.9 Hz), 7.67-7.80 (1H, m), 7.97 (1H,
d, J ) 6.8 Hz), 8.06-8.28 (4H, m).
tert-Butyl [4-[2-Oxo-2-(3-trifluoromethylphenyl)ethyl]-
2-pyridyl]carbamate (4l). This compound was prepared from
2-methyl-1-(3-trifluoromethylbenzoyl)aziridine as described in
the synthesis of 4d as a solid. Yield: 70%. Mp: 149-150 °C
2-(2-Amino-4-pyridyl)-2-bromo-1-(4-fluorophenyl)etha-
none Hydrobromide (5k). This compound was prepared
from 4k as described in the synthesis of 5a as a solid. Yield:
1
(ethyl acetate/hexane). H NMR (CDCl3) δ: 1.53 (9H, s), 4.32
(2H, s), 6.87 (1H, dd, J ) 5.2, 1.4 Hz), 7.64 (1H, t, J ) 7.7 Hz),
7.85 (1H, d, J ) 7.7 Hz), 7.93 (1H, s), 8.11-8.27 (4H, m).
1
82%. H NMR (DMSO-d6) δ: 6.98 (1H, dd, J ) 6.8, 1.8 Hz),
7.14 (1H, s), 7.21 (1H, s), 7.45 (2H, t, J ) 8.8 Hz), 7.97 (1H, d,
J ) 6.8 Hz), 8.06-8.28 (5H, m).
2-Bromo-1-(3-methylphenyl)-2-(2-methyl-4-pyridyl)-
ethanone Hydrobromide (5a). Bromine (24 mL, 0.46 mol)
was added dropwise to a solution of 4a (150 g, 0.46 mol) in
acetic acid (450 mL) and the mixture was stirred for 3 h at 80
°C. The solvent was removed in vacuo and ethyl acetate was
added to the residue. The resulting crystalline material was
collected by filtration and washed with ethyl acetate to afford
168 g (yield 66%) of 5a as a solid. 1H NMR (DMSO-d6) δ: 2.42
(3H, s), 2.72 (3H, s), 3.39 (1H, brs), 7.26 (1H, s), 7.45-7.59
(2H, m), 7.90-8.01 (3H, m), 8.02 (1H, s), 8.81 (1H, d, J ) 6.2
Hz).
2-Bromo-1-(3-methylphenyl)-2-(4-pyridyl)ethanone Hy-
drobromide (5b). This compound was prepared from 4b as
described in the synthesis of 5a as a crude oil, and this
compound was used in the next reaction without further
purification.
2-Bromo-2-(2-fluoro-4-pyridyl)-1-(3-methylphenyl)eth-
anone Hydrobromide (5c). This compound was prepared
from 4c as described in the synthesis of 5a as a crude oil, and
this compound was used in the next reaction without further
purification.
2-(2-Amino-4-pyridyl)-2-bromo-1-(4-methoxyphenyl)-
ethanone Hydrobromide (5d). This compound was prepared
from 4d as described in the synthesis of 5a as a solid. Yield:
82%. 1H NMR (DMSO-d6) δ: 3.38 (2H, brs), 3.88 (3H, s), 6.97
(1H, dd, J ) 6.8, 1.8 Hz), 7.09 (1H, s), 7.11 (2H, d, J ) 9.0
Hz), 7.19 (1H, s), 7.95 (1H, d, J ) 6.8 Hz), 8.09 (2H, d, J ) 9.0
Hz), 8.15 (1H, brs).
2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methoxyphenyl)-
ethanone Hydrobromide (5e). This compound was prepared
from 4e as described in the synthesis of 5a as a solid. Yield:
58%. 1H NMR (DMSO-d6) δ: 3.39 (2H, brs), 3.84 (3H, s), 6.97
(1H, dd, J ) 6.7, 1.7 Hz), 7.15 (1H, s), 7.18 (1H, s), 7.30 (1H,
dd, J ) 8.0, 1.9 Hz), 7.52 (1H, dd, J ) 8.3, 8.0 Hz), 7.59 (1H,
t, J ) 1.9 Hz), 7.69 (1H, d, J ) 8.3 Hz), 7.96 (1H, d, J ) 6.7
Hz), 8.14 (1H, brs).
2-(2-Amino-4-pyridyl)-2-bromo-1-(4-methylphenyl)-
ethanone Hydrobromide (5f). This compound was prepared
from 4f as described in the synthesis of 5a as a solid. Yield:
75%. 1H NMR (DMSO-d6) δ: 2.41 (3H, s), 3.41 (2H, brs), 6.97
(1H, dd, J ) 6.9, 1.5 Hz), 7.10 (1H, s), 7.19 (1H, d, J ) 1.5
Hz), 7.40 (2H, d, J ) 8.1 Hz), 7.95 (1H, d, J ) 6.9 Hz), 8.01
(2H, d, J ) 8.1 Hz), 8.16 (1H, brs).
2-(2-Amino-4-pyridyl)-2-bromo-1-[3-(trifluoromethyl)-
phenyl]ethanone Hydrobromide (5l). This compound was
prepared from 4l as described in the synthesis of 5a as a solid.
Yield: 93%. 1H NMR (DMSO-d6) δ: 6.95 (1H, dd, J ) 6.8, 1.6
Hz), 7.23 (2H, s), 7.80-7.94 (2H, m), 7.96 (1H, d, J ) 6.8 Hz),
8.10 (2H, d, J ) 7.4 Hz), 8.21 (2H, brs), 8.32-8.44 (1H, m).
4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]pyri-
dine (7a). Propanethioamide (0.53 g, 5.9 mmol) was added to
a solution of 5b (2.0 g, 5.4 mmol) in DMF (6.0 mL), and the
resulting mixture was stirred at room temperature for 14 h.
Aqueous sodium hydrogen carbonate was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extracts were washed with brine, dried, and concentrated to
give a solid. The crude crystalline was recrystallized from
ethanol to afford 8.9 g (yield 59%) of 7a as a solid. Mp: 56-
58 °C. 1H NMR (CDCl3) δ: 1.46 (3H, t, J ) 7.6 Hz), 2.33 (3H,
s), 3.09 (2H, q, J ) 7.6 Hz), 7.11-7.24 (5H, m), 7.37 (1H, s),
8.51 (2H, d, J ) 6.2 Hz). Anal. (C17H16N2S) C, H, N.
4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-thi-
azol-5-yl]pyridine (7b). This compound was prepared from
5b and 4-(methylthio)benzenecarbothioamide as described in
the synthesis of 7a as a solid. Yield: 84%. Mp: 101-102 °C
(ethyl acetate/isopropyl ether). 1H NMR (CDCl3) δ: 2.36 (3H,
s), 2.54 (3H, s), 7.16-7.34 (7H, m), 7.45 (1H, s), 7.94 (2H, d, J
) 8.8 Hz), 8.54 (2H, d, J ) 6.2 Hz). Anal. (C22H18N2S2) C, H,
N.
4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-meth-
ylpyridine (7c). This compound was prepared from 5a and
propanethioamide as described in the synthesis of 7a as an
1
oil. Yield: 60%. H NMR (CDCl3) δ: 1.45 (3H, t, J ) 7.6 Hz),
2.33 (3H, s), 2.51 (3H, s), 3.09 (2H, q, J ) 7.6 Hz), 6.99 (1H,
dd, J ) 5.2, 1.2 Hz), 7.13-7,30 (4H, m), 7.39 (1H, s), 8.38 (1H,
d, J ) 5.2 Hz). Anal. (C18H18N2S‚H2O) C, H, N.
4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-fluo-
ropyridine (7d). This compound was prepared from 5c and
propanethioamide as described in the synthesis of 7a as an
1
oil. Yield: 38%. H NMR (CDCl3) δ: 1.64 (3H, t, J ) 7.6 Hz),
2.34 (3H, s), 3.10 (2H, q, J ) 7.6 Hz), 6.84-6.86 (1H, m), 7.05-
7.09 (1H, m), 7.13-7.25 (3H, m), 7.37 (1H, s), 8.10 (1H, d, J )
5.6 Hz). Anal. (C17H15FN2S) C, H, N.
4-[2-Ethyl-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-
pyridylamine (7e). This compound was prepared from 5d
and propanethioamide as described in the synthesis of 7a as
a solid. Yield: 75%. Mp: 153-154 °C (ethanol). 1H NMR
(CDCl3) δ: 1.44 (3H, t, J ) 7.6 Hz), 3.06 (2H, q, J ) 7.6 Hz),
3.82 (3H, s), 4.41 (2H, brs), 6.45 (1H, d, J ) 1.4 Hz), 6.57 (1H,
dd, J ) 5.4, 1.4 Hz), 6.84 (2H, d, J ) 8.2 Hz), 7.47 (2H, d, J )
8.2 Hz), 7.98 (1H, d, J ) 5.4 Hz). Anal. (C17H17N3OS) C, H, N.
4-[2-Ethyl-4-(3-methoxyphenyl)-1,3-thiazol-5-yl]-2-
pyridylamine (7f). This compound was prepared from
5e and propanethioamide as described in the synthesis of 7a
2-(2-Amino-4-pyridyl)-2-bromo-1-(3-methylphenyl)-
ethanone Hydrobromide (5g). This compound was prepared
from 4g as described in the synthesis of 5a as a solid. Yield:
86%. 1H NMR (DMSO-d6) δ: 2.41 (3H, s), 3.41 (1H, brs), 6.98
(1H, d, J ) 6.8 Hz), 7.12 (1H, s), 7.20 (1H, s), 7.43-7.58 (2H,
m), 7.87-8.00 (3H, m), 8.17 (2H, brs).
2-(2-Amino-4-pyridyl)-2-bromo-1-(2-methylphenyl)-
ethanone Hydrobromide (5h). This compound was prepared
from 4h as described in the synthesis of 5a as a solid. Yield:
1
1
82%. H NMR (DMSO-d6) δ: 2.40 (3H, s), 6.95 (1H, dd, J )
as a solid. Yield: 65%. Mp: 130-131 °C (ethanol). H NMR
6.0, 1.7 Hz), 7.04 (1H, s), 7.18 (1H, s), 7.34-7.42 (2H, m), 7.47-
7.55 (1H, m), 7.96 (1H, d, J ) 6.6 Hz), 8.01 (2H, d, J ) 7.2
Hz), 8.17 (1H, brs).
(CDCl3) δ: 1.45 (3H, t, J ) 7.6 Hz), 3.08 (2H, q, J ) 7.6 Hz),
3.75 (3H, s), 4.41 (2H, brs), 6.45 (1H, d, J ) 0.6 Hz), 6.58 (1H,
dd, J ) 5.5, 1.7 Hz), 6.84-6.89 (1H, m), 7.06-7.11 (2H, m),
7.19-7.26 (1H, m), 7.99 (1H, d, J ) 5.5 Hz). Anal. (C17H17N3-
OS) C, H, N.
2-(2-Amino-4-pyridyl)-2-bromo-1-(3-chlorophenyl)eth-
anone Hydrobromide (5i). This compound was prepared
from 4i as described in the synthesis of 5a as a solid. Yield:
4-[2-Ethyl-4-(4-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridylamine (7g). This compound was prepared from 5f
and propanethioamide as described in the synthesis of 7a as
a solid. Yield: 73%. Mp: 126-127 °C (ethanol). 1H NMR
(CDCl3) δ: 1.44 (3H, t, J ) 7.6 Hz), 2.35 (3H, s), 3.06 (2H, q,
1
64%. H NMR (DMSO-d6) δ: 3.42 (3H, s), 6.98 (1H, dd, J )
6.9, 1.7 Hz), 7.12 (1H, s), 7.20 (1H, s), 7.64 (1H, t, J ) 8.0 Hz),
7.80 (1H, d, J ) 8.0 Hz), 7.96 (1H, d, J ) 6.9 Hz), 8.05 (1H, d,
J ) 8.0 Hz), 8.15 (1H, s).

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5975
J ) 7.6 Hz), 4.45 (2H, brs), 6.44 (1H, d, J ) 0.8 Hz), 6.57 (1H,
dd, J ) 5.2, 1.7 Hz), 7.13 (2H, d, J ) 8.0 Hz), 7.42 (2H, d,
J ) 8.0 Hz), 7.97 (1H, d, J ) 5.2 Hz). Anal. (C17H17N3S) C, H,
N.
7.15-7.23 (3H, m), 7.25-7.34 (3H, m), 7.47 (1H, s), 7.93 (2H,
d, J ) 8.8 Hz), 8.40 (1H, d, J ) 4.9 Hz). Anal. (C23H20N2S2) C,
H, N.
4-[4-(3-Methylphenyl)-2-[4-(methylthio)phenyl]-1,3-thi-
azol-5-yl]-2-pyridylamine (7q). This compound was pre-
pared from 4-(methylthio)benzenecarbothioamide and 5g as
described in the synthesis of 7a as a solid. Yield: 71%. Mp:
181-183 °C (ethanol). 1H NMR (CDCl3) δ: 2.36 (3H, t, J )
7.2 Hz), 2.54 (3H, s), 4.44 (2H, s), 6.50 (1H, s), 6.61 (1H, dd, J
) 5.3, 1.4 Hz), 7.14-7.34 (5H, m), 7.50 (1H, s), 7.99 (2H, d, J
) 8.6 Hz), 8.00 (1H, d, J ) 5.3 Hz). Anal. (C22H19N3S2) C, H,
N.
4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridylamine (7h). This compound was prepared from
5g and propanethioamide as described in the synthesis of 7a
1
as a solid. Yield: 60%. Mp: 144-146 °C (ethanol). H NMR
(CDCl3) δ: 1.44 (3H, t, J ) 7.6 Hz), 2.34 (3H, s), 3.08 (2H, q,
J ) 7.6 Hz), 4.42 (2H, brs), 6.44 (1H, dd, J ) 1.4, 0.8 Hz), 6.56
(1H, dd, J ) 5.2, 1.4 Hz), 7.10-7.28 (3H, m), 7.42 (1H, s), 7.97
(1H, dd, J ) 5.2, 0.8 Hz). Anal. (C17H17N3S) C, H, N.
4-[2-Ethyl-4-(2-methylphenyl)-1,3-thiazol-5-yl]-2-pyrid-
ylamine (7i). This compound was prepared from 5h and
propanethioamide as described in the synthesis of 7a as a solid.
4-[2-Methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridylamine (7r). A mixture of 7o (7.0 g, 20 mmol) in
ethanol (40 mL) and 1 N aqueous sodium hydroxide (40 mL,
40 mmol) was stirred at room temperature for 2 h. The reaction
solution was acidified with 2 N hydrochloric acid and the
precipitate was collected by filtration. The crude crystalline
was washed with water and ethanol. The crystalline material
was dried to afford 6.1 g (yield 95%) of [5-(2-amino-4-pyridyl)-
4-(3-methylphenyl)-1,3-thiazol-2-yl]acetic acid (7t) as a solid.
1
Yield: 59%. Mp: 107-108 °C (ethanol). H NMR (CDCl3) δ:
1.45 (3H, t, J ) 7.6 Hz), 2.12 (3H, s), 3.08 (2H, q, J ) 7.6 Hz),
4.31 (2H, brs), 6.25 (1H, dd, J ) 0.8, 0.6 Hz), 6.40 (1H, dd, J
) 5.5, 1.7 Hz), 7.13-7.32 (4H, m), 7.88 (1H, d, J ) 5.5 Hz).
Anal. (C17H17N3S) C, H, N.
4-[4-(3-Chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-pyridyl-
amine (7j). This compound was prepared from 5i and pro-
panethioamide as described in the synthesis of 7a as a solid.
1
Mp: 132-133 °C. H NMR (DMSO-d6) δ: 2.29 (3H, s), 4.14
(2H, s), 6.11 (2H, brs), 6.33 (1H, dd, J ) 5.4, 1.8 Hz), 6.44 (1H,
s), 7.12-7.29 (3H, m), 7.38 (1H, s), 7.86 (1H, d, J ) 5.4 Hz).
Anal. (C17H15N3O2S‚0.25H2O) C, H, N.
Solid 7t (0.50 g, 1.5 mmol) was heated at 140 °C for 15 min.
The oil was cooled to room temperature. The crude crystalline
material was recrystallized from ethyl acetate/ether to afford
0.31 g (yield 72%) of 7r as a solid. Mp: 152-153 °C. 1H NMR
(CDCl3) δ: 2.34 (3H, s), 2.76 (3H, s), 4.40 (2H, brs), 6.44 (1H,
s), 6.56 (1H, dd, J ) 5.1, 1.5 Hz), 7.10-7.26 (3H, m), 7.42 (1H,
s), 7.97 (1H, d, J ) 5.1 Hz). Anal. (C16H15N3S) C, H, N.
2-Chloro-4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-
pyridine (7s). To a solution of 7a (2.8 g, 10 mmol) in DMF
(50 mL) was added mCPBA (3.0 g, 12 mmol) at 0 °C, and the
resulting mixture was stirred at room temperature for 14 h.
Aqueous sodium hydrogen carbonate was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
extracts were washed with brine, dried, and concentrated to
give a solid. The crude crystalline was washed with hexane to
afford 2.2 g (yield 74%) of 4-[2-ethyl-4-(3-methylphenyl)-1,3-
thiazol-5-yl]pyridine 1-oxide (7u) as a solid. Mp: 143-144 °C.
1H NMR (CDCl3) δ: 1.45 (3H, t, J ) 7.6 Hz), 2.35 (3H, s), 3.09
(2H, q, J ) 7.6 Hz), 7.13-7.26 (5H, m), 7.36 (1H, s), 8.06-
8.10 (2H, m). Anal. (C17H16N2OS) C, H, N.
1
Yield: 81%. Mp: 131-132 °C (ethanol). H NMR (CDCl3) δ:
1.45 (3H, t, J ) 7.4 Hz), 3.07 (2H, q, J ) 7.4 Hz), 4.46 (2H,
brs), 6.45 (1H, s), 6.50 (1H, dd, J ) 5.6, 1.6 Hz), 7.18-7.36
(3H, m), 7.62 (1H, m), 8.01 (1H, d, J ) 5.6 Hz). Anal. (C16H14-
ClN3S) C, H, N.
4-(2-Ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridylamine (7k).
This compound was prepared from 5j and propanethioamide
as described in the synthesis of 7a as a solid. Yield: 84%. Mp:
158-159 °C (ethanol). 1H NMR (CDCl3) δ: 1.45 (3H, t, J )
7.5 Hz), 3.08 (2H, q, J ) 7.5 Hz), 4.44 (2H, brs,), 6.43 (1H, s),
6.56 (1H, dd, J ) 5.2, 1.8 Hz), 7.27-7.39 (3H, m), 7.49-7.57
(2H, m), 7.97 (1H, d, J ) 5.2 Hz). Anal. (C16H15N3S) C, H, N.
4-[2-Ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-pyridyl-
amine (7l). This compound was prepared from 5k and
propanethioamide as described in the synthesis of 7a as a solid.
1
Yield: 76%. Mp: 140-141 °C (ethanol). H NMR (CDCl3) δ:
1.44 (3H, t, J ) 7.5 Hz), 3.07 (2H, q, J ) 7.5 Hz), 4.46 (2H,
brs), 6.42 (1H, s), 6.54 (1H, dd, J ) 5.4, 1.4 Hz), 6.97-7.07
(2H, m), 7.47-7.54 (2H, m), 8.00 (1H, d, J ) 5.4 Hz). Anal.
(C16H14FN3S) C, H, N.
4-[2-Ethyl-4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-
yl]-2-pyridylamine (7m). This compound was prepared from
5l and propanethioamide as described in the synthesis of 7a
A solution of 7u (1.00 g, 3.37 mmol) in POCl3 (6.5 mL) was
stirred at 100 °C for 2 h. The reaction solution was cooled,
and a saturated aqueous sodium hydrogen carbonate solution
was added to the reaction mixture. The resulting mixture was
extracted with ethyl acetate and washed with brine. The
combined organic phase was dried and concentrated to give a
residue. The residue was chromatographed on silica gel,
eluting with hexane/ethyl acetate (2:1) to afford 0.90 g (yield
1
as a solid. Yield: 72%. Mp: 117-118 °C (ethanol). H NMR
(CDCl3) δ: 1.45 (3H, t, J ) 7.8 Hz), 3.19 (2H, q, J ) 7.8 Hz),
4.47 (2H, brs), 6.42 (1H, s), 6.54 (1H, dd, J ) 5.2, 1.6 Hz), 7.41
(1H, dd, J ) 7.8, 7.6 Hz), 7.57 (1H, d, J ) 7.6 Hz), 7.54 (1H,
d, J ) 7.8 Hz), 7.91 (1H, s), 8.00 (1H, d, J ) 5.2 Hz). Anal.
(C17H14F3N3S) C, H, N.
4-[4-(3-Methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-
pyridylamine (7n). This compound was prepared from
butanethioamide and 5g as described in the synthesis of 7a
1
81%) of 7s as an oil. H NMR (CDCl3) δ: 1.42 (3H, t, J ) 7.7
Hz), 2.35 (3H, s), 3.10 (2H, q, J ) 7.7 Hz), 7.09 (1H, dd, J )
5.2, 1.4 Hz), 7.12-7.30 (4H, m), 7.37 (1H, s), 8.22-8.27 (1H,
m). Anal. (C17H15ClN2S) C, H, N.
1
as a solid. Yield: 62%. Mp: 113-115 °C (ethanol). H NMR
(CDCl3) δ: 0.98 (3H, t, J ) 7.3 Hz), 1.76-1.92 (2H, m), 2.34
(3H, s), 3.04 (2H, t, J ) 7.4 Hz), 4.14 (2H, brs), 6.44 (1H, s),
6.56 (1H, dd, J ) 5.4, 1.5 Hz), 7.09-7.26 (3H, m), 7.41 (1H, s),
7.96 (1H, d, J ) 5.4 Hz). Anal. (C18H19N3S) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]acetamide (8a). Acetyl chloride (0.33 mL, 4.6 mmol)
was added to a solution of 7h (1.3 g, 4.4 mmol) in THF (13
mL), and triethylamine (0.64 mL, 4.6 mmol) was added to the
mixture. The resulting mixture was stirred for 1 h at room
temperature and aqueous sodium hydrogen carbonate was
added to the reaction mixture. The resulting mixture was
extracted with ethyl acetate. The extracts were washed with
aqueous sodium hydrogen carbonate, dried, and concentrated
to give a residue. The residue was chromatographed on silica
gel, eluting with hexane/ethyl acetate (2:1), and recrystallized
from ethyl acetate/hexane to afford 0.99 g (yield 66%) of 8a as
a solid. Mp: 119-120 °C. 1H NMR (CDCl3) δ: 1.45 (3H, t, J )
7.7 Hz), 2.21 (3H, s), 2.33 (3H, s), 3.09 (2H, q, J ) 7.7 Hz),
6.86 (1H, dd, J ) 5.1, 1.5 Hz), 7.13-7.24 (3H, m), 7.39 (1H, s),
8.02 (1H, brs), 8.08 (1H, d, J ) 5.1 Hz), 8.27 (1H, s). Anal.
(C19H19N3OS) C, H, N.
Ethyl [5-(2-Amino-4-pyridyl)-4-(3-methylphenyl)-1,3-
thiazol-2-yl]acetate (7o). This compound was prepared from
ethyl 3-amino-3-thioxopropanoate and 5g as described in the
synthesis of 7a as a solid. Yield: 63% (ethanol). Mp: 131-
132 °C. 1H NMR (CDCl3) δ: 1.33 (3H, t, J ) 7.2 Hz), 2.34 (3H,
s), 4.11 (2H, s), 4.27 (2H, q, J ) 7.2 Hz), 4.43 (2H, brs), 6.47
(1H, s), 6.58 (1H, d, J ) 5.3 Hz), 7.10-7.27 (3H, m), 7.41 (1H,
s), 7.99 (1H, d, J ) 5.3 Hz). Anal. (C19H19N3O2S) C, H, N.
2-Methyl-4-[4-(3-methylphenyl)-2-[4-(methylthio)-
phenyl]-1,3-thiazol-5-yl]pyridine (7p). This compound was
prepared from 4-(methylthio)benzenecarbothioamide and 5a
as described in the synthesis of 7a as a solid. Yield: 91%. Mp:
1
119-122 °C (ethyl acetate/hexane). H NMR (CDCl3) δ: 2.36
(3H, s), 2.52 (3H, s), 2.54 (3H, s), 7.04 (1H, d, J ) 4.9 Hz),

5976 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Miwatashi et al.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]propionamide (8b). This compound was prepared
from 7h and propionyl chloride as described in the synthesis
N-[4-[4-(3-Chlorophenyl)-2-ethyl-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8i). This compound was prepared from
7j as described in the synthesis of 8h as a solid. Yield: 52%.
Mp: 128-129 °C (ethanol). 1H NMR (CDCl3) δ: 1.47 (3H, t, J
) 7.6 Hz), 3.10 (2H, q, J ) 7.6 Hz), 7.09 (1H, dd, J ) 5.2, 1.4
Hz), 7.10-7.39 (3H, m), 7.45-7.63 (4H, m), 7.90-7.97 (2H,
m), 8.16 (1H, dd, J ) 5.2, 0.8 Hz), 8.50 (1H, d, J ) 0.8 Hz),
8.67 (1H, brs). Anal. (C23H18ClN3OS) C, H, N.
1
of 8a as a solid. Yield: 64%. Mp: 103-104 °C (ethanol). H
NMR (CDCl3) δ: 1.25 (3H, t, J ) 7.7 Hz), 1.42 (3H, t, J ) 7.7
Hz), 2.33 (3H, s), 2.44 (2H, q, J ) 7.7 Hz), 3.09 (2H, q, J ) 7.7
Hz), 6.83 (1H, dd, J ) 5.1, 1.5 Hz), 7.11-7.23 (3H, m), 7.39
(1H, s), 8.06 (1H, dd, J ) 5.1, 0.7 Hz), 8.08 (1H, brs), 8.34 (1H,
s). Anal. (C20H21N3OS) C, H, N.
N-[4-(2-Ethyl-4-phenyl-1,3-thiazol-5-yl)-2-pyridyl]benz-
amide (8j). This compound was prepared from 7k as described
in the synthesis of 8h as a solid. Yield: 77%. Mp: 95-97 °C
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]butyramide (8c). This compound was prepared from
7h and butyryl chloride as described in the synthesis of 8a as
1
(ethanol). H NMR (CDCl3) δ: 1.47 (3H, t, J ) 7.6 Hz), 3.11
1
(2H, q, J ) 7.6 Hz), 6.88 (1H, dd, J ) 5.2, 1.2 Hz), 7.29-7.39
(3H, m), 7.45-7.63 (5H, m), 7.90-7.96 (2H, m), 8.11 (1H, d, J
) 5.2 Hz), 8.50 (1H, d, J ) 1.2 Hz), 8.65 (1H, brs). Anal.
(C23H19N3OS) C, H, N.
a solid. Yield: 56%. Mp: 88-89 °C (ethyl acetate). H NMR
(CDCl3) δ: 1.01 (3H, t, J ) 7.3 Hz), 1.45 (3H, t, J ) 7.6 Hz),
1.65-1.87 (2H, m), 2.33 (3H, s), 2.38 (2H, t, J ) 7.3 Hz), 3.08
(2H, q, J ) 7.6 Hz), 6.83 (1H, dd, J ) 5.4, 1.7 Hz), 7.10-7.23
(3H, m), 7.39 (1H, s), 7.98 (1H, brs), 8.06 (1H, d, J ) 5.4 Hz),
8.34 (1H, s). Anal. (C21H23N3OS) C, H, N.
N-[4-[2-Ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8k). This compound was prepared from
7l as described in the synthesis of 8h as a solid. Yield: 71%.
Mp: 135-136 °C (ethanol). 1H NMR (CDCl3) δ: 1.46 (3H, t, J
) 7.7 Hz), 3.10 (2H, q, J ) 7.7 Hz), 6.88 (1H, dd, J ) 5.2, 1.6
Hz), 7.03 (2H, t, J ) 8.8 Hz), 7.45-7.63 (5H, m), 7.88-7.95
(2H, m), 8.14 (1H, d, J ) 5.2 Hz), 8.49 (1H, d, J ) 1.6 Hz),
8.67 (1H, brs). Anal. (C23H18FN3OS) C, H, N.
N-[4-[2-Ethyl-4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-
5-yl]-2-pyridyl]benzamide (8l). This compound was pre-
pared from 7m as described in the synthesis of 8h as a solid.
Yield: 88%. Mp: 94-95 °C (ethanol). 1H NMR (CDCl3) δ: 1.47
(3H, t, J ) 7.5 Hz), 3.11 (2H, q, J ) 7.5 Hz), 6.87 (1H, dd, J )
5.2, 1.6 Hz), 7.39-7.73 (6H, m), 7.86-7.96 (3H, m), 8.15 (1H,
d, J ) 5.2 Hz), 8.51 (1H, s), 8.71 (1H, brs). Anal. (C24H18F3N3OS‚
0.5H2O) C, H, N.
N-[4-[2-Ethyl-4-(2-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8m). This compound was prepared from
7i as described in the synthesis of 8h as a solid. Yield: 55%.
Mp: 104-105 °C (ethanol). 1H NMR (CDCl3) δ: 1.47 (3H, t, J
) 7.7 Hz), 2.14 (3H, s), 3.10 (2H, q, J ) 7.7 Hz), 6.62 (1H, dd,
J ) 5.5, 1.8 Hz), 7.18-7.37 (4H, m), 7.45-7.63 (3H, m), 7.88-
7.95 (2H, m), 8.01 (1H, dd, J ) 5.5, 0.9 Hz), 8.46 (1H, d, J )
0.9 Hz), 8.54 (1H, brs). Anal. (C24H21N3OS) C, H, N.
N-[4-[2-Ethyl-4-(4-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8n). This compound was prepared from
7g as described in the synthesis of 8h as a solid. Yield: 69%.
Mp: 116-117 °C (ethanol). 1H NMR (CDCl3) δ: 1.46 (3H, t, J
) 7.5 Hz), 2.36 (3H, s), 3.09 (2H, q, J ) 7.5 Hz), 6.89 (1H, dd,
J ) 5.1, 1.5 Hz), 7.14 (2H, d, J ) 8.1 Hz), 7.45 (2H, d, J ) 8.1
Hz), 7.46-7.62 (3H, m), 7.89-7.96 (2H, m), 8.11 (1H, d, J )
5.1 Hz), 8.50 (1H, d, J ) 1.5 Hz), 8.65 (1H, brs). Anal.
(C24H21N3OS) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]cyclohexanecarboxamide (8d). This compound
was prepared from 7h and cyclohexanecarbonyl chloride as
described in the synthesis of 8a as a solid. Yield: 75%. Mp:
98-100 °C (ethyl acetate). 1H NMR (CDCl3) δ: 1.21-2.08
(13H, m), 2.20-2.31 (1H, m), 2.33 (3H, s), 3.08 (2H, q, J ) 7.5
Hz), 6.82 (1H, dd, J ) 5.3, 1.7 Hz), 7.10-7.35 (3H, m), 7.39
(1H, s), 8.00 (1H, brs), 8.07 (1H, d, J ) 5.3 Hz), 8.37 (1H, s).
Anal. (C24H27N3OS) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]-2-phenylacetamide (8e). This compound was pre-
pared from 7h and phenylacetyl chloride as described in the
synthesis of 8a as a solid. Yield: 88%. Mp: 107-108 °C (ethyl
acetate/hexane). 1H NMR (CDCl3) δ: 1.44 (3H, t, J ) 7.5 Hz),
2.31 (3H, s), 3.08 (2H, q, J ) 7.5 Hz), 3.76 (2H, s), 6.81 (1H,
dd, J ) 5.2, 1.4 Hz), 7.10-7.47 (9H, m), 7.90 (1H, s), 8.02 (1H,
d, J ) 5.2 Hz), 8.33 (1H, s). Anal. (C25H23N3OS) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]-3-phenylpropionamide (8f). This compound was
prepared from 7h and 3-phenylpropionyl chloride as described
in the synthesis of 8a as a solid. Yield: 75%. Mp: 126-127
°C (ethyl acetate). 1H NMR (CDCl3) δ: 1.45 (3H, t, J ) 7.5
Hz), 2.31 (3H, s), 2.70 (2H, t, J ) 7.7 Hz), 3.06 (2H, t, J ) 7.7
Hz), 3.09 (2H, q, J ) 7.5 Hz), 6.83 (1H, dd, J ) 5.4, 1.4 Hz),
7.10-7.47 (9H, m), 7.97 (1H, s), 8.04 (1H, d, J ) 5.4 Hz), 8.32
(1H, s). Anal. (C26H25N3OS) C, H, N.
N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-
thiazol-5-yl]-2-pyridyl]-2-phenylacetamide (8g). This com-
pound was prepared from 7q and phenylacetyl chloride as
described in the synthesis of 8a as a solid. Yield: 77%. Mp:
1
205-206 °C (ethanol). H NMR (CDCl3) δ: 2.34 (3H, s), 2.54
N-[4-[2-Ethyl-4-(3-methoxyphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8o). This compound was prepared from
7f as described in the synthesis of 8h as a solid. Yield: 75%.
Mp: 97-98 °C (ethanol). 1H NMR (CDCl3) δ: 1.46 (3H, t, J )
7.6 Hz), 3.10 (2H, q, J ) 7.6 Hz), 3.76 (3H, s), 6.86-6.92 (2H,
m), 7.06-7.11 (2H, m), 7.23 (1H, d, J ) 8.3 Hz), 7.47-7.62
(3H, m), 7.93 (2H, d, J ) 6.9 Hz), 8.10 (1H, d, J ) 5.5 Hz),
8.52 (1H, dd, J ) 1.7, 0.8 Hz), 8.71 (1H, brs). Anal.
(C24H21N3O2S) C, H, N.
N-[4-[2-Ethyl-4-(4-methoxyphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8p). This compound was prepared from
7e as described in the synthesis of 8h as a solid. Yield: 74%.
Mp: 112-113 °C (ethanol). 1H NMR (CDCl3) δ: 1.46 (3H, t, J
) 7.7 Hz), 3.09 (2H, q, J ) 7.7 Hz), 3.82 (3H, s), 6.87 (2H, d,
J ) 9.1 Hz), 6.91 (1H, dd, J ) 5.2, 1.4 Hz), 7.43-7.63 (5H, m),
7.93 (2H, d, J ) 6.9 Hz), 8.13 (1H, dd, J ) 5.2, 0.6 Hz), 8.50
(1H, dd, J ) 1.4, 0.6 Hz), 8.63 (1H, brs). Anal. (C24H21N3O2S)
C, H, N.
(3H, s), 3.77 (2H, s), 6.86 (1H, dd, J ) 5.3, 1.7 Hz), 7.18-7.45
(11H, m), 7,84 (1H, s), 7.93 (2H, d, J ) 7.0 Hz), 8.04 (1H, d, J
) 5.3 Hz), 8.39 (1H, s). Anal. (C30H25N3OS2‚0.25H2O) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8h). Benzoyl chloride (21.6 mL, 186
mmol) was added to a solution of 7h (50.0 g, 169 mmol) in
THF (500 mL), and triethylamine (28.3 mL, 203 mmol) was
added to the mixture. The resulting mixture was stirred for 3
h at room temperature and aqueous sodium hydrogen carbon-
ate was added to the reaction mixture. The resulting mixture
was extracted with ethyl acetate. The extracts were washed
with aqueous sodium hydrogen carbonate, dried, and concen-
trated to give a residue. Concentrated hydrochloric acid (100
mL) was added to the residue and the mixture was stirred at
40 °C for 14 h. The mixture was basified with 8 N aqueous
sodium hydroxide and extracted with ethyl acetate. The
extracts were dried and concentrated to give a residue. The
residue was chromatographed on silica gel, eluting with
hexane/ethyl acetate (2:1), and recrystallized from ethyl
acetate/hexane to afford 59.8 g (yield 88%) of 8h as a solid.
Mp: 113-114 °C. 1H NMR (CDCl3) δ: 1.46 (3H, t, J ) 7.6
Hz), 2.34 (3H, s), 3.10 (2H, q, J ) 7.6 Hz), 6.87 (1H, dd, J )
5.2, 1.4 Hz), 7.13-7.30 (3H, m), 7.45-7.63 (4H, m), 7.94 (2H,
d, J ) 7.5 Hz), 8.06 (1H, d, J ) 5.2 Hz), 8.52 (1H, s), 8.74 (1H,
brs). Anal. (C24H21N3OS) C, H, N.
N-[4-[2-Methyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8q). This compound was prepared from
7r as described in the synthesis of 8h as a solid. Yield: 95%.
1
Mp: 145-146 °C (ethanol). H NMR (CDCl3) δ: 2.34 (3H, s),
2.78 (3H, s), 6.86-6.89 (1H, m), 7.16-7.22 (3H, m), 7.41 (1H,
s), 7.46-7.59 (3H, m), 7.90-7.91 (2H, m), 8.09 (1H, d, J ) 5.2
Hz), 8.50 (1H, s), 8.69 (1H, brs). Anal. (C23H19N3OS) C, H, N.

Inhibitor of p38 MAP Kinase as an Anti-TNF-R Drug
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19 5977
N-[4-[4-(3-Methylphenyl)-2-propyl-1,3-thiazol-5-yl]-2-
pyridyl]benzamide (8r). This compound was prepared from
7n as described in the synthesis of 8h as an amorphous
(0.17 mL, 2.7 mmol) was added to the reaction mixture, and
the resulting mixture was stirred at room temperature for 1
h. Water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The extract was washed with
brine, dried, and concentrated to give a residue. The residue
was chromatographed on silica gel, eluting with hexane/ethyl
acetate (2:1), and the crude crystalline was washed with
hexane to afford 0.71 g (yield 65%) of 11 as a solid. Mp: 94-
96 °C. 1H NMR (CDCl3) δ: 1.43 (3H, t, J ) 7.6 Hz), 2.36 (3H,
s), 3.07 (2H, q, J ) 7.6 Hz), 3.83 (3H, s), 6.19-6.23 (1H, m),
7.18-7.32 (4H, m), 7.39-7.48 (4H, m), 8.29-8.34 (2H, m), 8.54
(1H, d, J ) 2.2 Hz). Anal. (C25H23N3OS) C, H, N.
1
powder. Yield: 68%. H NMR (CDCl3) δ: 1.08 (3H, t, J ) 7.1
Hz), 1.80-1.99 (2H, m), 2.34 (3H, s), 3.04 (2H, t, J ) 7.7 Hz),
6.88 (1H, dd, J ) 5.2, 1.7 Hz), 7.15-7.63 (7H, m), 7.90-7.95
(2H, m), 8.11 (1H, d, J ) 5.2 Hz), 8.51 (1H, s), 8.61 (1H, brs).
Anal. (C25H23N3OS) C, H, N.
N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-
thiazol-5-yl]-2-pyridyl]benzamide (8s). This compound was
prepared from 7q as described in the synthesis of 8h as a solid.
1
Yield: 83%. Mp: 180-182 °C (ethanol). H NMR (CDCl3) δ:
2.37 (3H, s), 2.54 (3H, s), 5.92 (1H, dd, J ) 5.3, 1.4 Hz), 7.16-
7.40 (5H, m), 7.45-7.64 (4H, m), 7.92-7.97 (4H, m), 8.12 (1H,
d, J ) 5.3 Hz), 8.59 (1H, s), 8.70 (1H, brs). Anal. (C29H23N3OS2)
C, H, N.
N-Cyclopentyl-4-[2-ethyl-4-(3-methylphenyl)-1,3-thi-
azol-5-yl]-2-pyridylamine (12a). A mixture of 7d and cyclo-
pentylamine (1.6 mL, 16 mmol) was heated at 110 °C for 14
h. The mixture was cooled to room temperature, and aqueous
sodium hydrogen carbonate was added to the mixture. The
mixture was extracted with ethyl acetate, and the extracts
were washed with brine. The combined organic phase was
dried and concentrated to give a residue. The residue was
recrystallized from ethyl acetate to afford 0.19 g (yield 33%)
of 12a as a solid. Mp: 117-118 °C. 1H NMR (CDCl3) δ: 1.22-
1.93 (11H, m), 2.33 (3H, s), 3.08 (2H, q, J ) 7.4 Hz), 3.65-
3.81 (1H, m), 4.56 (1H, d, J ) 6.6 Hz), 6.28 (1H, s), 6.48-6.51
(1H, m), 7.10-7.18 (3H, m), 7.41 (1H, s), 7.97 (1H, d, J ) 5.6
Hz). Anal. (C22H25N3S) C, H, N.
4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-(1-pyr-
rolidinyl)pyridine (12b). This compound was prepared from
7d and pyrrolidine as described in the synthesis of 12a as a
solid. Yield: 75%. Mp: 108-109 °C (ethyl acetate/hexane). 1H
NMR (CDCl3) δ: 1.45 (3H, t, J ) 7.5 Hz), 1.94-2.01 (4H, m),
2.34 (3H, s), 3.08 (2H, q, J ) 7.5 Hz), 3.32-3.39 (4H, m), 6.30
(1H, s), 6.40-6.44 (1H, m), 7.09-7.28 (3H, m), 7.45 (1H, s),
8.04 (1H, d, J ) 5.2 Hz). Anal. (C21H23N3S) C, H, N.
4-[4-(3-Methylphenyl)-2-[4-(methylsulfonyl)phenyl]-
1,3-thiazol-5-yl]pyridine (13a). To a solution of 7b (0.80 g,
2.1 mmol) in DMF (8.0 mL) was added mCPBA (0.90 g, 3.7
mmol) at 0 °C and the mixture was stirred at room temper-
ature for 3 h. An 8 N aqueous sodium hydroxide solution was
added to the reaction mixture, and the resulting mixture was
extracted with ethyl acetate. The extracts were washed with
brine, dried, and concentrated to give a residue. The residue
was chromatographed on silica gel, eluting with hexane/ethyl
acetate (3:7) to give crude crystalline material, which was
recrystallized from ethyl acetate/isopropyl ether to afford 0.54
g (yield 62%) of 13a as a solid. Mp: 171-174 °C. 1H NMR
(CDCl3) δ: 2.36 (3H, s), 3.11 (3H, s), 7.18-7.32 (5H, m), 7.45
(1H, s), 8.05 (2H, d, J ) 8.4 Hz), 8.22 (2H, d, J ) 8.4 Hz), 8.58
(2H, d, J ) 6.2 Hz). Anal. (C22H18N2O2S2) C, H, N.
2-Methyl-4-[4-(3-methylphenyl)-2-[4-(methylsulfonyl)-
phenyl]-1,3-thiazol-5-yl]pyridine (13b). This compound was
prepared from 7p as described in the synthesis of 13a as a
solid. Yield: 70%. Mp: 134-138 °C (ethanol). 1H NMR (CDCl3)
δ: 2.37 (3H, s), 2.55 (3H, s), 3.11 (3H, s), 7.07 (1H, d, J ) 5.2
Hz), 7.16-7.31 (4H, m), 7.47 (1H, s), 8.05 (2H, d, J ) 8.5 Hz),
8.22 (2H, d, J ) 8.5 Hz), 8.45 (1H, d, J ) 5.2 Hz). Anal.
(C23H20N2O2S2) C, H, N.
N-Benzyl-N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-
5-yl]-2-pyridyl]amine (10a). Aluminum lithium hydride
(0.18 g, 4.7 mmol) was added to a suspension of aluminum
chloride (0.59 g, 4.4 mmol) in THF (40 mL), and the mixture
was stirred at room temperature for 15 min. A solution of 8h
(0.50 g, 1.3 mmol) in THF (10 mL) was added to the mixture,
and the resulting mixture was heated to reflux for 2 h. After
the reaction mixture was cooled to room temperature, water
was added and the mixture was extracted with ethyl acetate.
The extracts were washed with brine, dried, and concentrated
to give a residue. The residue was recrystallized from ethyl
acetate/hexane to afford 0.31 g (yield 62%) of 10a as a solid.
Mp: 106-107 °C. 1H NMR (CDCl3) δ: 1.43 (3H, t, J ) 7.5
Hz), 2.34 (3H, s), 3.06 (2H, q, J ) 7.5 Hz), 4.38 (2H, d, J ) 5.8
Hz), 4.75-4.95 (1H, m), 6.32 (1H, s), 6.53 (1H, dd, J ) 5.5, 1.4
Hz), 7.12-7.38 (8H, m), 7.40 (1H, s), 8.01 (1H, d, J ) 5.5 Hz).
Anal. (C24H23N3S) C, H, N.
N-Benzyl-N-[4-[4-(3-methylphenyl)-2-(4-methylthio-
phenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (10b). This com-
pound was prepared from 8s as described in the synthesis of
10a as a solid. Yield: 56%. Mp: 134-136 °C (ethyl acetate/
1
hexane). H NMR (CDCl3) δ: 2.36 (3H, s), 2.53 (3H, s), 4.39
(2H, d. J ) 5.8 Hz), 4.86 (1H, d, J ) 5.8 Hz), 6.37 (1H, s), 6.58
(1H, dd, J ) 5.5, 1.5 Hz), 7.13-7.30 (11H, m), 7.48 (1H, s),
7.91 (1H, d, J ) 8.6 Hz), 8.38 (1H, d, J ) 5.5 Hz). Anal.
(C29H25N3S2) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]-N-(2-phenylethyl)amine (10c). This compound
was prepared from 8e as described in the synthesis of 10a as
a solid. Yield: 48%. Mp: 97-98 °C (ethyl acetate/hexane). 1H
NMR (CDCl3) δ: 1.44 (3H, t, J ) 7.5 Hz), 2.32 (3H, s), 2.81
(2H, t, J ) 7.0 Hz), 3.08 (2H, q, J ) 7.5 Hz), 3.36-3.46 (2H,
m), 4.50-4.65 (1H, m), 6.30 (1H, s), 6.51 (1H, dd, J ) 5.2, 1.4
Hz), 7.05-7.35 (8H, m), 7.43 (1H, s), 8.00 (1H, d, J ) 5.2 Hz).
Anal. (C25H25N3S‚0.25H2O) C, H, N.
N-[4-[4-(3-Methylphenyl)-2-(4-methylthiophenyl)-1,3-
thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (10d). This
compound was prepared from 8g as described in the synthesis
of 10a as a solid. Yield: 35%. Mp: 137-139 °C (ethyl acetate/
1
hexane). H NMR (CDCl3) δ: 2.35 (3H, s), 2.54 (3H, s), 2.82
(2H, t, J ) 7.0 Hz), 3.43 (2H, dt, J ) 6.0, 7.0 Hz), 4.57 (1H, t,
J ) 6.0 Hz), 6.34 (1H, s), 6.56 (1H, dd, J ) 5.3, 1.3 Hz), 7.11-
7.35 (10H, m), 7.51 (1H, s), 7.92 (2H, d, J ) 8.4 Hz), 8.02 (1H,
d, J ) 5.3 Hz). Anal. (C30H27N3S2) C, H, N.
N-[4-[4-(3-Methylphenyl)-2-(4-methylsulfonylphenyl)-
1,3-thiazol-5-yl]-2-pyridyl]benzamide (13c). This com-
pound was prepared from 8s as described in the synthesis of
13a as a solid. Yield: 54%. Mp: 212-214 °C (ethanol). 1H
NMR (CDCl3) δ: 2.38 (3H, s), 3.12 (3H, s), 6.95 (1H, dd, J )
5.4, 1.6 Hz), 7.26-7.36 (3H, m), 7.50-7.58 (4H, m), 7.92-7.97
(2H, m), 8.05 (2H, d, J ) 8.6 Hz), 8.18 (1H, d, J ) 5.4 Hz),
8.24 (2H, d, J ) 8.6 Hz), 8.62 (1H, s), 8.67 (1H, s). Anal.
(C29H23N3O3S2) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]-N-(3-phenylpropyl)amine (10e). This compound
was prepared from 8f as described in the synthesis of 10a as
a solid. Yield: 54% (ethyl acetate/hexane). Mp: 52-53 °C. 1H
NMR (CDCl3) δ: 1.45 (3H, t, J ) 7.5 Hz), 1.77-1.95 (2H, m),
2.32 (3H, s), 2.69 (2H, t, J ) 7.7 Hz), 3.00-3.22 (4H, m), 4.47-
4.60 (1H, m), 6.26 (1H, s), 6.49 (1H, dd, J ) 5.2, 1.4 Hz), 7.05-
7.35 (8H, m), 7.42 (1H, s), 7.98 (1H, d, J ) 5.2 Hz). Anal.
(C26H27N3S) C, H, N.
N-[4-[2-Ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-
pyridyl]-N-methylbenzamide (11). Sodium hydride (60%
paraffin dispersion, 0.12 g, 3.0 mmol) was added to a solution
of 8h (1.1 g, 2.7 mmol) in dimethyl sulfoxide (20 mL), and the
mixture was stirred at room temperature for 1 h. Methyl iodide
N-[4-[4-(3-Methylphenyl)-2-(4-methylsulfonylphenyl)-
1,3-thiazol-5-yl]-2-pyridyl]-2-phenylacetamide (13d). This
compound was prepared from 8g as described in the synthesis
1
of 13a as a solid. Yield: 52%. Mp: 244-245 °C (ethanol). H
NMR (CDCl3) δ: 2.36 (3H, s), 3.11 (3H, s), 3.78 (2H, s), 6.95
(1H, dd, J ) 5.0, 1.6 Hz), 7.20-7.45 (9H, m), 7.87 (1H, s), 8.04
(2H, d, J ) 8.4 Hz), 8.05 (1H, d, J ) 5.0 Hz), 8.21 (2H, d, J )
8.4 Hz), 8.43 (1H, s). Anal. (C30H25N3O3S2) C, H, N.

5978 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 19
Miwatashi et al.
Effects of an Engineered Human Antitumor Necrosis Factor
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ylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]amine (13e). This com-
pound was prepared from 10b as described in the synthesis
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1
of 13a as a solid. Yield: 52%. Mp: 148-150 °C (ethanol). H
NMR (CDCl3) δ: 2.39 (3H, s), 3.10 (3H, s), 4.41 (2H, d,
J ) 6.0 Hz), 4.91 (1H, t, J ) 6.0 Hz), 6.38 (1H, s), 6.59 (1H,
dd, J ) 5.2, 1.4 Hz), 7.20-7.33 (8H, m), 7.48 (1H, s), 8.00-
8.10 (3H, m), 8.20 (2H, d, J ) 8.8 Hz). Anal. (C29H25N3O2S2)
C, H, N.
N-[4-[4-(3-Methylphenyl)-2-(4-methylsulfonylphenyl)-
1,3-thiazol-5-yl]-2-pyridyl]-N-(2-phenylethyl)amine (13f).
This compound was prepared from 10d as described in the
synthesis of 13a as a solid. Yield: 70%. Mp: 174-176 °C
1
(ethanol). H NMR (CDCl3) δ: 2.36 (3H, s), 2.84 (2H, t, J )
7.1 Hz), 3.11 (3H, s), 3.33-3.50 (2H, m), 4.43-4.67 (1H, m),
6.36 (1H, s), 6.58 (1H, dd, J ) 5.4, 1.4 Hz), 7.15-7.36 (8H, m),
7.52 (1H, s), 8.02-8.07 (3H, m), 8.22 (2H, d, J ) 8.8 Hz). Anal.
(C30H27N3O2S2) C, H, N.
Biological Methods. p38 MAP Kinase Assay, THP-1
TNF-r Release Assay and Mouse TNF-r Release Assay.
These assays were performed according to the protocols
described previously.8
Measurement of CYP Inhibition Activity. The inhibition
activity of the thiazole derivatives on CYP3A4 was evaluated
by incubating 40 µM 7-benzyloxyquinoline with the mi-
crosomes derived from CYP3A4-expressing insect cell (BD
Biosciences) in the presence of 1 µM compounds. The concen-
tration of 7-benzyloxyquinoline metabolite was measured with
a spectrofluorometer.
The inhibition activity of compound 8h on CYP isoforms was
also evaluated by using specific CYP-expressing human B-
limphoblastoid cells (BD Biosciences). The concentrations of
8h were 1, 10, and 100 µM. The substrates of each CYPs were
4 µM ethoxyresorufin for CYP1A1 and CYP1A2, 400 µM
coumarin for CYP2A6, 400 µM 7-ethoxycoumarin for CYP2B6,
400 µM tolbutamide for CYP2C8 and CYP2C9, 80 µM S-(()-
mephenytoin for CYP2C19, 200 µM (()-bufuralol for CYP2D6,
500 µM 4-nitrophenol for CYP2E1, and 80 µM testosterone for
CYP3A4. The concentration of the marker metabolite for
CYP1A1, CYP1A2, and CYP2A6 was measured with a spec-
trofluorometer, and for the other CYPs it was measured by
HPLC.
Adjuvant-Induced Arthritis Assay. Arthritis was in-
duced in 7-week-old male Lewis rats (n ) 6) by an intradermal
injection of 0.25 mg of Mycobacterium tuberculosis in 0.05 mL
of liquid paraffin at a site on the right hind paw on day 0. The
paw volume of the untreated (left) hind paw was determined
on day 14. Drugs (3, 10, and 30 mg/kg, po) and the vehicle
(saline) were administered from day 0 to day 13.
(12) Collis A. J.; Foster M. L.; Halley F.; Maslen C.; McLay I. M.;
Page K. M.; Redford E. J.; Souness J. E.; Wilsher N. E.
RPR203494
a Pyrimidine Analogue of the p38 Inhibitor
RPR200765A with an Improved in Vitro Potency. Bioorg. Med.
Chem. Lett. 2001, 11, 693-696.
(13) Laufer, S. A.; Wagner, G. K.; Kotschenreuther, D. A.; Albrecht,
W.; Novel Substituted Pyridinyl Imidazoles as Potent Anti-
cytokine Agents with Low Activity against Hepatic Cytochrome
P450 Enzymes. J. Med. Chem. 2003, 46, 3230-3244.
(14) Wang, Z.; Canagarajah, B. J.; Boehm, J. C.; Kassisa`, S.; Cobb,
M. H.; Young, P. R.; Abdel-Meguid, S.; Adams, J. L. Goldsmith,
E. J. Structural Basis of Inhibitor Selectivity in MAP Kinases.
Structure 1998, 6, 1117-1128. (Protein Data Bank Code
1A9U).
(15) Dresser, G. K.; Spence, J. D.; Bailey, D. G. Pharmacokinetic-
pharmacodynamic consequences and clinical relevance of cyto-
chrome P450 3A4 inhibition. Clin. Pharmacokinet. 2000, 38, 41-
57.
(16) Liverton, N. J.; Butcher, J. W.; Claiborne, C. F.; Claremon, D.
A.; Libby, B. E.; Nguyen, K. T.; Pitzenberger, S. M.; Selnick, H.
G.; Smith, G. R.; Tebben, A.; Vacca, J. P.; Varga, S. L.; Agarwal,
L.; Dancheck, K.; Forsyth, A. J.; Fletcher, D. S.; Frantz, B.;
Hanlon, W. A.; Harper, C. F.; Hofsess, S. J.; Kostura, M.; Lin,
J.; Luell, S.; O’Neill, E. A.; Orevillo, C. J.; Pang, M.; Parsons, J.;
Rolando, A.; Sahly, Y.; Visco, D. M.; O’Keefe, S. J. Design and
Synthesis of Potent, Selective, and Orally Bioavailable Tetra-
substituted Imidazole Inhibitors of p38 Mitogen-Activated Pro-
tein Kinase. J. Med. Chem. 1999, 42, 2180-2190.
Acknowledgment. We acknowledge the contribu-
tion of Dr. Tomohiro Kawamoto for the establishment
and measurement of the p38 assay; Dr. Teruaki Okuda,
Mr. Shin-ichi Niwa, and Ms. Miyako Sudo for the CYP
assay; Mr. Koji Ohnishi and Mr. Masashi Yamaguchi
for the pharmacokinetic study; and Mr. Shigeru Morim-
oto, Ms. Keiko Igaki, and Dr. Yasumasa Watanabe for
the in vivo assays.
(17) Roe, A.; Cheek, P. H.; Hawkins, G. F. The Synthesis of 2-Fluoro-
4- and 2-Fluoro-6-pyridinecarboxylic Acid and Derivatives. J.
Am. Chem. Soc. 1949, 71, 4152-4153.
(18) Anderson, W. K.; Dean, D. C.; Endo, T. Synthesis, Chemistry,
and Antineoplastic Activity of R-Halopyridinium Salts: Potential
Pyridone Prodrugs of Acylated Vinylogous Carbinolamine Tumor
Inhibitors. J. Med. Chem. 1990, 33, 1667-1675.
Supporting Information Available: Elemental analyses
for compounds 7-13. This material is available free of charge
via the Internet at http://pubs.acs.org.
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