4-Aryl/cycloalkyl-5-phenyloxazole derivatives as selective COX-2 inhibitors

Article abstract of DOI:10.1016/S0960-894X(01)00670-9

A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2 inhibitors.

Full text of DOI:10.1016/S0960-894X(01)00670-9

Bioorganic & Medicinal Chemistry Letters 12 (2002) 65–68
4-Aryl/cycloalkyl-5-phenyloxazole Derivatives as Selective
COX-2 Inhibitors
Hiromasa Hashimoto,* Kimiya Maeda, Koichi Ozawa, Jun-ichi Haruta
and Korekiyo Wakitani
Central Pharmaceutical Research Institute, JT, Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan
Received 6 August 2001; accepted 2 October 2001
Abstract—A series of 4-aryl/cycloalkyl-5-phenyloxazole derivatives was synthesized and evaluated for their ability to inhibit
cyclooxygenase-2(COX-2) and cyclooxygenase-1 (COX-1). These compounds were found to be potent and selective COX-2inhi-
bitors. # 2001 Elsevier Science Ltd. All rights reserved.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such
as aspirin and indomethacin have been widely used for
the treatment of inflammatory diseases. However, the
clinical use of these drugs has been limited by unfavor-
able side effects such as gastrointestinal damage.1 Both
the anti-inflammatory effect and the side effects of
NSAIDs are known to be due to inhibition of cyclo-
oxygenase (COX) which converts arachidonic acid to
prostanoids (PGs) that are important mediators of
inflammation but also keep physiological functions such
as gastric mucosal protection and platelet aggregation.2
class.8 Our work led to the discovery of JTE-522,9 which
is now under clinical investigation. In this paper, we
report the synthesis and SAR study of a series of 4-aryl/
cycloalkyl-5-phenyloxazoles 1 as selective COX-2inhi-
bitors.
In 1991, it was discovered that there are two isoforms of
COX.3 One isoform, COX-1, is constitutively expressed
and produces physiologically important PGs. On the
other hand, the second isoform, COX-2, is induced sig-
nificantly under inflammatory conditions. The classical
NSAIDs inhibit COX-1 more strongly than COX-2.
These findings led to a scenario that a selective COX-2
inhibitor may offer a new generation of NSAIDs with
diminished side effects.4
Many efforts have been made to find COX-2selective
inhibitors and now vicinal diaryl heterocyclic com-
pounds bearing methylsulfonyl or sulfonamide group
Synthesis
5
are known to be selective COX-2inhibitors. From this
A series of 5-(4-alkylsulfonylphenyl)-4-aryl/cycloalkyl
oxazoles were synthesized as shown in Scheme 1.10 4-
(Alkylsulfonyl)benzylbromides 2 were coupled with an
appropriate acid chloride 3 in the presence of zinc pow-
der and catalytic amount of tetrakis(triphenylphos-
phin)palladium(0) in 1,2-dimethoxyethane to give
benzyl ketones 4.11 The benzyl ketones were converted
to a-acetoxy ketones 5 (R3=Me) by the reaction with
class of compounds, two drugs, celecoxib6 and rofe-
coxib,7 are now on the market. We and another group
have independently found oxazole derivatives of this
*Corresponding author. Tel.: +81-726-81-9700; fax: +81-726-81-
9725; e-mail: hiromasa.hashimoto@ims.jti.co.jp
0960-894X/02/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00670-9

66
H. Hashimoto et al. / Bioorg. Med. Chem. Lett. 12 (2002) 65–68
Scheme 1. Reagents and conditions: (a) R1COCl (3), Zn, 5–10 mol%
Pd(PPh3)4, DME, 0 ꢀC to rt; (b) Pb(OAc)4, AcOH reflux; (c) Br2, tol-
uene–CHCl3, rt; (d) R3COONa, EtOH reflux; (e) NH4OAc, AcOH
reflux.
Scheme 3. Reagents and conditions: (a) 5-chloro-2-thiophenecarbonyl
chloride, Zn, 5–10 mol% Pd(PPh3)4, DME, 0 ꢀC to rt; (b) Pb(OAc)4,
AcOH reflux; (c) NH4OAc, AcOH reflux; (d) CF3COOH, 50 ꢀC.
lead tetraacetate in refluxing acetic acid.12 Other a-acyl-
oxy ketones were prepared from 4 in two steps; first,
bromination by Br2 in toluene–CHCl3, and second,
reaction with the corresponding acid sodium salt in
refluxing EtOH. Heating the a-acyloxy ketones 5 in
refluxing AcOH in the presence of NH4OAc13 afforded
oxazoles 1 and its regio isomers 6. These isomers were
separable by flash chromatography. When R1 is phenyl
or thienyl ring, 1 was obtained as a major isomer with 6
as a minor isomer (<10%), but in the case that R1 is
cycloalkyl group, only one isomer 1 was observed.
Results and Discussion
The compounds synthesized in this study were tested for
their ability to inhibit human COX-2and COX-1
enzymes in vitro.14 The results of 2-methyloxazoles are
summarized in Table 1. First, we examined 2-methy-5-
(4-methylsulfonyl)phenyl-4-phenyl oxazole 1a as a vici-
nal diaryl type of compound and found that it is a very
potent COX-2inhibitor (IC 50=0.09 mM) with high
selectivity (COX-1: IC50 >100 mM). Introduction of a
fluorine atom on the 4-position of the phenyl group (1b)
also showed high potency for COX-2but reduced
selectivity. Changing the position of the two aromatic
rings on the oxazole, the regioisomer 6b showed reduced
activity. This was also observed in the case of thienyl
derivatives, 1c versus 6c. To see the substituent effect of
the 4-position on the oxazole, other rings instead of
phenyl ring were examined.15 Thienyl compounds (1c–e)
showed high potency. It seems that thienyl type is more
potent. Cyclohexyl (1g) imparts as much activity as
phenyl ring, whereas cycloheptyl (1f) is less active and
cyclopentyl (1h) is weakly active. Notably, cycloalkyls
are highly selective for COX-2. It is interesting to note
Preparation route for 5-(4-aminosulfonyl)phenyl-4-
cyclohexyl or phenyl oxazoles 1j, l, m is shown in Scheme
2. Starting from benzylbromide 7, oxazoles 8 were
obtained by using the same procedure for the prepara-
tion of 1 shown in Scheme 1. The oxazoles 8 were reac-
ted with chlorosulfonic acid in refluxing CHCl3
followed the treatment with 28% ammonia in THF to
give sulfonamides 1j and 1l. N-Methylsulfonamide 1m
was obtained by treating with MeNH2 instead of
ammonia in the last step.
5-(Aminosulfonyl)phenyl-4-(5-chloro-thien-2-yl)-2-methyl
oxazole 1k was prepared as shown in Scheme 3. Ben-
zylbromide 9 was converted to an oxazole 10 in three
steps by the same method as shown in Scheme 1.
Deprotection of the N-tert-butyl group of sulfonamide
was performed by treating the oxazole 10 with
trifluoroacetic acid to give 4-thienyl oxazole 1k.
Table 1. In vitro human COX-2a and COX-1b enzyme inhibitory
concentrations of 2-methyl oxazole derivatives
Compd
R1
R2
COX-2COX-1
IC50 (mM)c
IC50 (mM)c
1a
1b
6b
1c
6c
1d
1e
1f
Ph
4-F-Ph
4-F-Ph
Me
Me
Me
Me
Me
Me
Me
Me
0.09
0.07
2.1
0.03
1.2
0.04
0.14
18
0.07
0.28
38
>100
42
>100
5-Cl-2-thienyl
5-Cl-2-thienyl
5-Me-2-thienyl
5-Et-2-thienyl
Cyclopentyl
Cyclohexyl
Cycloheptyl
4-F-Ph
12.5
93
47.5
>100
>100
>100
>100
>100
1g
1h
1i
Me
Me
Et
1j
1k
1l
4-F-Ph
NH2
NH2
NH2
NHMe
0.024
0.020.6
0.07
3.1
4.7
5-Cl-2-thienyl
Cyclohexyl
Cyclohexyl
47.5
>100
0.15
1m
Indomethacin
2.4
aHuman recombinant COX-2enzyme.
bHuman COX-1 enzyme from human platelets.
cValues are means of at least three experiments.
Scheme 2. Reagents and conditions: (a)–(c) same as shown in Scheme
1; (d) ClSO3H, CHCl3, reflux; (e) 28% NH4OH, THF, rt; (f)
.
MeNH2 HCl, Et3N, dioxane–H2O, rt.

H. Hashimoto et al. / Bioorg. Med. Chem. Lett. 12 (2002) 65–68
67
Table 2. In vitro human COX-2a and COX-1b enzyme inhibitory
concentration of 4-cyclohexyl-5-(4-methylsulfonylphenyl) oxazole
derivatives
Zweifel, B. S.; Manning, P. T.; Hauser, S. D.; Leahy, K. M.;
Smith, W. G.; Isakson, P. C.; Seibert, K. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 3228. (c) Griswold, D. E.; Adams, J. L. Med.
Res. Rev. 1996, 16, 181.
Compd
R3
COX-2COX-1
IC50 (mM)c
5. (a) Prasit, P.; Reondeau, D. Ann. Rep. Med. Chem. 1997,
32, 211. (b) Carter, J. S. Exp. Opin. Ther. Pat. 1998, 8, 21. (c)
Dannhardt, G.; Kiefer, W. Eur. J. Med. Chem. 2001, 36, 109.
6. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Doctor, S.; Graneto, M. J.; Lee, L. F.; Mal-
echa, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu,
S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gre-
gory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med.
Chem. 1997, 40, 1347.
IC50 (mM)c
1g
1n
1o
Me
Et
Ph
0.07
0.27
>100
>100
60
>100
aHuman recombinant COX-2enzyme.
bHuman COX-1 enzyme from human platelets.
cValues are means of at least three experiments.
7. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson,
A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.;
Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.;
O’Neill, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vikers, P.;
Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Boyce, S.;
Rupniak, N.; Forrest, M.; Visco, D.; Patrick, D. Bioorg. Med.
Chem. Lett. 1999, 9, 1773.
8. (a) Haruta, J.; Hashimoto, H.; Matsushita, M. JP 8-
325249, 1996; Chem. Abstr. 1996, 125, 167967. (b) Norman,
B. H.; Lee, L. F.; Masferrer, J. L; Talley, J. J. WO 9427980,
1994; Chem. Abstr. 1995, 122, 314540.
that cyclohexyl ring successfully worked as a bioisostere
of pheny ring in this case.
Both methylsulfone and sulfonamide are well recog-
nized to be important moieties for COX-2inhibition, 6,16
and it is generally seen that sulfonamides are more
potent than methylsulfones, but less selective COX-2
inhibitors.16,17 This phenomenon was also seen in our
oxazole derivatives as shown in Table 1. Sulfonamides
1j–l were equally or slightly more potent for COX-2
compared to the corresponding methysulfones but the
selectivities are reduced. To investigate the effect of
steric bulkiness in this moiety, ethylsulfone 1i and
N-methylsulfonamide 1m were examined. Both com-
pounds exhibit markedly reduced activity. Therefore,
the COX-2activity is very sensitive to the steric
bulkiness of R2.
9. Haruta, J.; Hashimoto, H.; Matsushita, M. WO 9619463,
1996; Chem. Abstr. 1996, 125, 167971.
10. Syntheses of these compounds were performed by the
method described in ref 5 as follows.
Cyclohexyl (4-methylsulfonyl)benzyl ketone 4g. To a solution
of cyclohexanecarbonyl chloride (6.18 g), 2.32 g of tetra-
kis(triphenylphosphine)palladium(0) and zinc powder (3.42g)
in 1,2-DME (200 mL) was added a solution of (4-methyl-
sulfonyl)benzylbromide (10.00 g) in DME (100 mL) drop-
wise at room temperature. After stirring for 2h, the
insoluble material was removed by filtration. The filtrate
was concentrated in vacuo and the residue dissolved in
AcOEt. The solution was washed with 2N aq HCl and brine
and was dried over Na2SO4. The solvent was removed by
evaporation in vacuo. The residue was precipitated in AcOEt–
iPr2O. The precipitates were collected by filtration to give
5.42g (48%) of 4g. 1H NMR (300 MHz, CDCl3): d 1.2–1.4
(m, 5H), 1.7 (m, 1H), 1.8–1.9 (m, 4H), 2.47 (m, 1H), 3.05
(s, 3H), 3.85 (s, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.90 (d,
J=8.3 Hz, 2H).
Next, we examined the effect of the substituent size at
the 2-position of the oxazole. As shown in Table 2, ethyl
group (1n) instead of methyl showed reduced activity
and phenyl (1o) is no more active. COX-2activity is
very sensitive to the bulkiness of the substituent at this
position.
Conclusion
We have designed and synthesized a series of 4-aryl/
cycloalkyl-5-phenyl oxazole derivatives and showed that
they are potent and selective COX-2inhibitors. The
structure–activity relationship study suggests that (1) a
phenyl ring of vicinal diaryl heterocyclic compound can
be replaced by cyclohexyl or thienyl ring in the oxazole
case, (2) sulfonamides are slightly more potent but less
selective inhibitors than methylsulfones, and (3) COX-2
activity is very sensitive to the substituent size at sulfo-
nyl moiety and 2-position of the oxazole ring.
2-Cyclohexyl-1-(4-methylsulfonylphenyl)-2-oxo ethyl acetate
5g. A solution of 4g (1.48 g) and lead tetraacetate (2.50 g) in
AcOH (20 mL) was heated at reflux for 3 h. The solvent was
removed by evaporation in vacuo. The residue was diluted
with AcOEt and washed with water and brine and dried over
Na2SO4. After evaporation of the solvent in vacuo, the residue
was purified by flash chromatography (SiO2, hexane/
1
AcOEt=5/2) to give 0.52 g (29%) of 5g. H NMR (300 MHz,
CDCl3): d 1.1–1.4 (m, 5H), 1.6–2.0 (m, 5H), 2.19 (s, 3H), 2.47
(m, 1H), 3.07 (s, 3H), 6.16 (s, 1H), 7.63 (d, J=8.3 Hz, 2H),
7.98 (d, J=8.3 Hz, 2H).
4-Cyclohexyl-2-methyl-5-(4-methylsulfonyl)phenyl
1g. A solution of 5g (0.52g) and NH Cl (0.29 g) in AcOH (10
oxazole
References and Notes
4
mL) was heated at reflux for 4 h. The solvent was removed by
evaporation in vacuo. The residue was purified by flash chro-
matography (SiO2, hexane/AcOEt=1/1) to give 0.38 g (77%)
of 1g. mp 110 ꢀC. 1H NMR (300 MHz, CDCl3): d 1.20–1.98
(m, 10H), 2.51 (s, 3H), 2.82 (m, 1H), 3.08 (s, 3H), 7.72 (d,
J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H). IR (cmÀ1): 2927,
2853, 1602, 1578, 1308, 1152. MS (FAB+): 320 (MH). Anal.
(C17H21NO3S): calcd: C; 63.92, H; 6.63, N; 4.39. Found: C;
63.83, H; 6.69, N; 4.19.
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