Synthesis and biological evaluation of derivatives of 2-{2-fluoro-4-[(2- oxocyclopentyl)methyl]phenyl}propanoic acid: Nonsteroidal anti-inflammatory drugs with low gastric ulcerogenic activity

Article abstract of DOI:10.1021/jm300049g

We previously reported that 2-fluoroloxoprofen has lower gastric ulcerogenic activity than loxoprofen, a nonsteroidal anti-inflammatory drug (NSAID) without selectivity for COX-2. We synthesized derivatives of 2-fluoroloxoprofen and studied their properti

Full text of DOI:10.1021/jm300049g

Article
pubs.acs.org/jmc
Synthesis and Biological Evaluation of Derivatives of
2-{2-Fluoro-4-[(2-oxocyclopentyl)methyl]phenyl}propanoic
Acid: Nonsteroidal Anti-Inflammatory Drugs with Low
Gastric Ulcerogenic Activity
Naoki Yamakawa,†,‡ Shintaro Suemasu,† Yoshinari Okamoto,‡ Ken-ichiro Tanaka,‡ Tomoaki Ishihara,†
Teita Asano,† Keishi Miyata,‡ Masami Otsuka,‡ and Tohru Mizushima*,†
†Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan
‡Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
S
* Supporting Information
ABSTRACT: We previously reported that 2-fluoroloxoprofen has lower
gastric ulcerogenic activity than loxoprofen, a nonsteroidal anti-inflamma-
tory drug (NSAID) without selectivity for COX-2. We synthesized
derivatives of 2-fluoroloxoprofen and studied their properties. Compared
to 2-fluoroloxoprofen, one derivative, 11a, exhibited higher anti-inflamma-
tory activity and an equivalent ulcerogenic effect. These results suggest that
11a could be therapeutically beneficial for use as an NSAID.
Loxoprofen (1) (Figure 1), an NSAID without selectivity for
COX-2, has been used clinically for many years as a standard
INTRODUCTION
■
Nonsteroidal anti-inflammatory drugs (NSAIDs) are an
important family of therapeutic agents, accounting for nearly
5% of all prescribed medications.1 An inhibitory effect of
NSAIDs on cyclooxygenase (COX) activity and a resulting
decrease in prostaglandins (PGs) such as PGE2 have been
shown to be responsible for their anti-inflammatory actions.
One downside of NSAID use is associated with gastrointestinal
side effects.2 Since PGE2 has a strong protective effect on the
gastrointestinal mucosa, it was considered that the adverse
gastrointestinal effects of NSAIDs could also be due to their
inhibitory action on COX activity.
Figure 1. Structures of loxoprofen and 2-fluoroloxoprofen.
COX has two main subtypes, COX-1 and COX-2, that are
responsible for the majority of COX activity at the gastro-
intestinal mucosa and in tissue inflammation, respectively.3,4
Thus, it stands to reason that a greatly reduced incidence of
gastroduodenal lesions has been reported for selective COX-2
inhibitors.5 However, a recently raised issue concerning the use
of selective COX-2 inhibitors is their potential risk for
cardiovascular thrombotic events.6,7 This may be due to the
fact that prostacyclin, a potent antiaggregator of platelets and a
vasodilator, is mainly produced by the action of COX-2.8,9
Thus, it is evident that NSAIDs other than COX-2-selective
inhibitors that do not cause gastrointestinal problems need to
be developed.
We recently suggested that COX-independent NSAID-
induced cell death is also involved in NSAID-induced gastric
lesions and that this direct cytotoxicity of NSAIDs is due to
their membrane permeabilization activity.10,11 Thus, we
proposed that NSAIDs with lower membrane permeabilization
activity would be safer on stomach tissue even if they had a
reduced selectivity for COX-2.11
NSAID in Japan, and clinical studies have suggested that it is
safer to use than other NSAIDs, such as indomethacin.12 Com-
pound 1 is a prodrug that is converted to its active metabolite
(the trans-alcohol form) after absorption in the gastrointestinal
tract.13 We recently reported that 1 has relatively lower mem-
brane permeabilization activity than other NSAIDs14 and
considered that it could be used as a lead compound to obtain
NSAIDs with even lower gastric ulcerogenic activity. We syn-
thesized a series of its derivatives and obtained 2-fluoroloxo-
profen (2) (Figure 1), which has lower gastric ulcerogenic
activity but equivalent anti-inflammatory activity compared
with 1.15 In order to obtain more clinically beneficial NSAIDs
(higher anti-inflammatory activity and/or lower gastric
ulcerogenic activity), we describe here details of the synthesis
of a series of derivatives of 2 and the results of experiments
Received: January 12, 2012
Published: March 12, 2012
© 2012 American Chemical Society
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a
Scheme 1. Synthesis of Key Intermediates 7−9 for the Target Compounds
a
Reagents and conditions: (a) diethyl methylmalonate, NaOH, DMF; (b) conc H2SO4, AcOH, reflux; (c) MeOH, conc HCl, reflux; (d) H2, 10%
Pd/C, MeOH; (e) (i) 6 M H2SO4, NaNO2, H2O, (ii) 3 M H2SO4, reflux, (iii) MeOH, conc HCl, reflux; (f) (i) conc HCl, NaNO2, H2O,
(ii) EtOCSSK, H2O.
carried out to examine their ulcerogenic and anti-inflammatory
activities.
methyl ester precursor of final compounds 10a, 10b, 11a, 11b,
and 12−17 were prepared from the corresponding inter-
mediates 7−9. Finally, these precursors were hydrolyzed with
base to give the final compounds.
CHEMISTRY
■
The synthetic route for type-B target compounds (21a, 21b,
22a, 22b, 23, and 24) having an aromatic heteroring or an
acyclic ketone (Figure 2) is outlined in Scheme 3. Treatment of
8 with trifluoromethanesulfonic anhydride ((CF3SO2)2O)19
provided 18, which was then reacted with dimethylzinc
(Zn(CH3)2)20 to yield 19. The methyl group of 19 was
transformed into an active methylene group by treatment with
N-bromosuccinimide (NBS) to yield the key intermediate 20.
Compound 20 was reacted with four kinds of boronic acid by
the Suzuki−Miyaura coupling method21 to yield the precursors
for 21a, 21b, 22a, and 22b. Finally, these methyl ester pre-
cursors were hydrolyzed with base to give the final compounds.
On the other hand, treatment of 20 with two kinds of aceto-
acetic ester derivatives provided the corresponding precur-
sors for 23 and 24. Finally, these precursors were subjected
to decarboxylation and hydrolysis with acid to give the final
compounds.
The synthetic route for type-C target compounds (33a,
33b, 39, and 40), which were modified at the 5- or 6-position
of the phenyl ring of 2 by halogen (F or Br) or para-phenol
(Figure 2), is outlined in Schemes 4 and 5. Compounds 33a
and 33b were synthesized from the corresponding commer-
cially available starting materials 25a and 25b, respectively, in a
manner similar to that described in Scheme 1. As part of the
process, the amino group of 29a and 29b was transformed into
a bromo group via a Sandmeyer reaction22 and further con-
verted into a methyl group by treatment with Zn(CH3)2 to
yield the intermediates 31a and 31b.
Compounds 1 and 2 were synthesized as described
previously.15,16
The synthetic route for key intermediates 7−9 is outlined
in Scheme 1. The commercially available 1, 2-difluoro-4-nitro-
benzene (3) was converted to propanoic acid 5 via methyl-
malonate 4 as described previously.17 Methyl esterification of 5
under acidic conditions gave methyl propanoate 6 that was sub-
sequently treated with palladium on carbon under atmospheric
H2 pressure to provide key intermediate 7. Another key inter-
mediate 8 was obtained by hydrolyzing the diazonium salt that
was formed by treatment of 7 with sodium nitrite (NaNO2).
On the other hand, the diazonium salt formed by treatment of
7 with NaNO2 was reacted with potassium ethyl xanthate
(EtOCSSK)18 to yield key intermediate 9.
The synthetic route for type-A target compounds (10a, 10b,
11a, 11b, and 12−17) having a heteroatom (O, N or S) bridge
between two rings (Figure 2) is outlined in Scheme 2. The
terminal ring is a cycloketone, cycloalkanol, or cycloalkane. The
On the other hand, 39 was synthesized from 34 according
to a previously described method.15 Compound 40 was syn-
thesized via the Suzuki-Miyaura cross-coupling reaction
Figure 2. Structure of three types of derivative of 2-fluoroloxoprofen.
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a
Scheme 2. Synthesis of the Type-A Target Compounds (10a, 10b, 11a, 11b, and 12−17)
a
Reagents and conditions: (a) 1,2-epoxycyclopentane or 1,2-epoxycycIohexane, LiBr, CH2Cl2; (b) NaOH, H2O, MeOH, reflux; (c) cyclopentanone
or cyclohexanone, NaBH3CN, AcOH, MeOH; (d) chlorocyclopentanone, K2CO3, DMF; (e) 1,2-epoxycyclopentane, NaH, DMF; (f)
bromocyclopentane, K2CO3,DMF; (g) cyclopentanone, NBS, CH2Cl2; (h) 1,2-epoxycyclopentane, borax, CH2Cl2.
between the methyl ester of 39 and 4-hydroxyphenylboronic
the carrageenan-induced footpad edema assay. We also carried
out a preliminary examination of the gastric ulcerogenic activity
of the derivatives and found that the oral administration of
22b produced more gastric lesions than 2 (data not shown).
This compound was therefore also discounted from further
analysis. The results in Table 1 also highlight the fact that, as
well as 1 and 2, some derivatives (11a, 14, 21a, and 22a) did
not exhibit any apparent selectvity for COX-2 (the COX-1/
COX-2 value of COX-2-selective inhibitor celecoxib was found
to be 22.7, measured using the same methodology as that used
to generate the results presented in Table 123).
We then evaluated the anti-inflammatory effects of selected
derivatives (11a, 14, 21a, and 22a) at various doses. As shown
in Figure 3, the volume of carrageenan-induced footpad edema
was significantly decreased after oral administration of 1 or 2,
confirming their previously described anti-inflammatory
activities.13,15,24 Of the selected derivatives, only 11a showed
a significantly more potent anti-inflammatory activity than 2 for
various doses and at different time-points after the challenge
with carrageenan (Figure 3). This result suggests that 11a
could be more effective than 2 for use as an NSAID. On the
other hand, 21a showed less anti-inflammatory activity than 2
at the lowest dose, 3 h after the administration of carrageenan
(Figure 3).
acid as described previously.16
RESULTS AND DISCUSSION
■
We examined the inhibitory effects of synthesized derivatives of
2 on COX-1 and COX-2 activity using a human whole blood
COX assay. To begin with, we determined COX inhibition at
derivative concentrations of 10 and 100 μM and eliminated
those derivatives that did not have an inhibitory action on
either COX-1 or COX-2 activity when employed at 10 μM
(Table 1). We also examined the anti-inflammatory effects of all
derivatives by employing a rat carrageenan-induced foot-
pad edema assay; derivatives were administered at a dose of
37.3 μM/kg (corresponding to 10 mg/kg for 1), and those that
did not show any anti-inflammatory effect (decrease in the
volume of carrageenan-induced footpad edema) were not
considered as candidates for further analysis (Table 1). We
then examined the inhibitory effects on COX-1 or COX-2 of
the remaining derivatives at various concentrations to deter-
mine IC50 values (concentration of each compound required
for 50% inhibition of COX-1 or COX-2 activity) and selectivity
for COX-2 (Table 1). Among the derivatives, compounds
10a, 12, and 21b were eliminated as candidates for further
analysis because of their low anti-inflammatory activity in
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a
Scheme 3. Synthesis of the Type-B Target Compounds (21a, 21b, 22a, 22b, 23, and 24)
a
Reagents and conditions: (a) (CF3SO2)2O, Et3N, CH2Cl2; (b) Zn(CH3)2, Pd(dppe)Cl2, 1,4-dioxane, reflux; (c) NBS, AIBN, CCl4, reflux; (d) 3 M
Na2CO3, trans-PdBr(N-Succ)(PPh3)2, THF, reflux; (e) KOH, H2O, EtOH, reflux; (f) dry Na2CO3, dry acetone, reflux; (g) conc HCl, AcOH, reflux.
Scheme 4. Synthesis of the Type-C Target Compounds with Modification at the 2 and 5 Positions or 2 and 6 Positions of the
a
Phenyl Ring by Fluorine (33a and 33b)
a
Reagents and conditions: (a) diethyl methylmalonate, NaOH, DMF; (b) conc H2SO4, AcOH, reflux; (c) MeOH, conc HCl, reflux; (d) H2, 10%
Pd/C, MeOH; (e) (i) 40% HBr, NaNO2, CuBr, H2O, (ii) MeOH, conc HCl, reflux; (f) Zn(CH3)2, Pd(dppe)Cl2, 1,4-dioxane, reflux; (g) NBS,
AIBN, CCl4, reflux; (h) dry Na2CO3, methyl 2-oxocyclopentanecarboxylate, dry acetone, reflux; (i) conc HCl, AcOH, reflux.
We then evaluated the gastric ulcerogenic activity of selected
derivatives. Oral administration of 2 produced fewer gastric
lesions in rats than 1 (Figure 4), as described previously.15
All of the selected derivatives showed significantly lower
ulcerogenic activity than 1 (Figure 4). Furthermore, compared
with 2, compounds 11a and 14 showed significantly lower
ulcerogenic activity at the dose of 7.45 mM/kg while 21a and
22a had significantly lower activity at 0.37 and 0.75 mM/kg,
suggesting that these compounds could be more effective than
2 as potential NSAIDs. The mechanism for this lower ulcer-
ogenic activity of 11a and 14, compared to 2 is unknown at
present.
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Scheme 5. Synthesis of the Type-C Target Compounds with Modification at the 2 and 6 Positions of the Phenyl Ring by
a
Fluorine, Bromine, or the 4-Hydroxyphenyl Group (39 and 40)
a
Reagents and conditions: (a) 3 M HCl aq, NaNO2, CuSO4, Na2SO3, AcONa, H2O, 0 °C; (b) NH2OH·HCl, (HCHO)n, AcONa, H2O; (c) conc
HCl, reflux; (d) MeOCH2P(Ph3)Cl, C6H18KNSi2, toluene; (e) 3 M HCl aq, acetone, reflux; (f) PFC (2.0 mol %), H5IO6, acetonitrile; (g) conc HCl,
CH3OH, reflux; (h) 2.0 M LDA, CH3I, dry THF, −78 to −40 °C; (i) NBS, AIBN, CCl4, reflux; (j) dry Na2CO3, methyl 2-
oxocyclopentanecarboxylate, dry acetone, reflux; (k) conc HCl, AcOH, reflux; (l) 4-DMAP, EDC, CH3OH; (m)
, Pd(PPh3)4,
Na2CO3, THF, reflux; (n) KOH, C2H5OH, H2O, reflux.
Table 1. Experimental Results of in Vitro Human Whole Blood Assay for Inhibition of COX-1- and COX-2-Derived PG
a
Biosynthesis, And in Vivo Anti-Inflammatory Assay by Carrageenan-Induced Rat Paw Edema
COX-1 inhibition (%)
COX-2 inhibition (%)
IC50 (μM)
reduction in paw edema (%)
compd
10 μM
100 μM
10 μM
100 μM
COX-1
COX-2
COX-1/COX-2
3 h
6 h
b
b
b
b
b
1
35.0 5.9
32.7 5.1
54.6 0.9
0
87.5 2.4
85.7 2.2
83.4 1.1
0
53.2 5.9
44.2 2.4
45.3 1.7
28.3 3.7
40.7 2.8
0
97.4 1.2
81.8 7.0
77.6 1.7
76.7 1.9
91.9 1.6
30.0 7.2
82.5 0.5
80.2 7.0
96.4 1.1
93.1 3.0
64.4 5.1
80.1 1.8
96.1 2.1
89.2 2.8
90.9 2.2
99.5 0.5
82.2 2.9
0
23.5
4.8
10.1
1.3
6.8
2.3
1.7
0.7
44.0 0.2
41.8 0.4
20.6 9.3
<0
53.1 2.5
54.1 0.4
5.7 0.3
<0
b
b
b
2
24.2
8.6
14.3
10a
10b
11a
11b
12
9.0 0.8
15.6 0.5
1.5 0.1
3.0 0.2
14.0 0.4
21.3 2.8
24.1 6.2
26.3 8.8
34.7 0.6
0
92.0 2.3
0
0.7
0.1
0.1
45.5 1.0
<0
60.1 1.9
19.2 4.3
25.0 4.2
13.3 4.8
51.9 6.1
27.2 7.0
<0
80.6 2.8
10.4 0.7
65.0 5.5
0
82.3 1.5
78.2 2.2
81.4 0.9
60.7 1.7
47.6 4.6
87.9 0.2
79.9 6.0
76.5 1.6
57.5 5.6
87.4 3.4
98.1 0.3
13.5 1.9
81.0 0.4
79.3 5.6
49.7 6.6
7.2 1.0
27.6 3.3
25.4 8.3
39.7 2.0
55.5 7.4
0
30.3 0.3
<0
13
14
40.4 1.9
38.0 1.1
<0
15
16
0
17
4.7 0.7
26.3 2.6
27.4 1.1
30.9 2.0
53.9 2.0
78.0 6.5
0
15.6 3.0
64.1 1.8
45.8 0.6
58.7 6.2
60.2 4.4
0
<0
9.5 0.6
45.8 3.5
28.0 7.3
45.2 0.01
33.4 0.2
20.2 6.7
<0
21a
21b
22a
22b
23
21.6 7.5
19.9 5.7
30.1 8.6
9.5 1.4
4.1 2.8
13.0 1.9
4.0 1.1
8.3 2.8
5.3
1.5
7.6
1.2
38.9 6.6
12.5 8.1
32.7 2.5
40.2 3.1
20.9 6.4
<0
24
0
33a
33b
39
0
15.0 4.9
0
84.8 4.1
70.9 6.7
0
<0
<0
11.3 1.0
13.8 2.6
0
21.6 2.6
<0
17.7 9.6
<0
0
40
15.4 0.3
38.0 3.2
<0
<0
a
The inhibitory effect of each compound on COX-1- and COX-2-derived PG biosynthesis was measured. The relative inhibition of COX-1 or COX-
2 (%) at 10 and 100 μM, IC50 values (concentration of each compound required for 50% inhibition of COX-1 or COX-2), and the COX-1/COX-2
ratio of IC50 values are shown. The values of IC50 were estimated from the sigmoid-like dose−response curve (four-parameter logistic curve model)
drawn with the aid of logistic-curve fitting software (ImageJ, version 1.43u; National Institutes of Health, U.S.). Values are the mean SEM (n = 3−
6). For the in vivo anti-inflammatory assay, rats were orally administered 37.3 μM/kg test compound and 1 h later received an intradermal injection
of carrageenan (1%) into the left hindpaw. Footpad edema was measured 3 and 6 h after the administration of carrageenan, and the relative
b
inhibition of the increase in edema volume by each compound was determined. Values are the mean SEM (n = 3−6). Data from our previous
report.15
Finally, the orientation of the selected derivatives in COX-2
and the interaction between these derivatives and amino acid
residues in the active site of COX-2 were examined by molec-
ular modeling and docking studies. Since 2 is a prodrug,15 the
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Figure 3. Anti-inflammatory activities of loxoprofen (1), 2-fluoroloxoprofen (2), and the latter’s derivatives (11a, 14, 21a, and 22a). Rats were orally
administered 3.73, 11.2, or 37.3 μM/kg test compound and 1 h later received an intradermal injection of carrageenan (1%) into the left hindpaw.
Footpad edema was measured 3 h (A) and 6 h (B) after the administration of carrageenan, and the relative inhibition of the increase in edema
volume by each compound was determined. Values are the mean SEM (n = 3−6): (∗) P < 0.05.
For type-B derivatives, 21a and 22a showed COX-inhibition
and anti-inflammatory effects equivalent to 2, suggesting that
the furan ring can become a bioisostere of the cyclopentanone
ring of 2. On the other hand, 23 and 24 showed very weak
COX-inhibition and anti-inflammatory effects, suggesting that
the closed circular ring in 2 is important for its COX-inhibition
and anti-inflammatory effects.
We previously reported that, as well as 2, oral administration
into rats of 2-bromoloxoprofen or 2-p-hydroxyphenylloxopro-
fen produced fewer gastric lesions but showed an equivalent
anti-inflammatory effect compared to 1.15,16 Therefore, we
examined here the effect of a similar modification of the aro-
matic ring of 2 by F, Br, or p-phenol on the anti-inflammatory
effect of 2 (type-C derivatives). However, 33a, 33b, 39, and 40
Figure 4. Production of gastric lesions in the presence of loxoprofen
showed weaker COX inhibition and anti-inflammatory effects
(1), 2-fluoroloxoprofen (2), and the latter’s derivatives (11a, 14, 21a,
than 2, suggesting that the introduction of a substituted group
and 22a). Rats were orally administered 0.37, 0.75, 1.12, 1.86, 3.73,
into the aromatic ring of 1 should be restricted to one position
in order to maintain its anti-inflammatory activity.
and 7.45 mM/kg test compound, and their stomachs were removed
after 8 h. Stomachs were scored for hemorrhagic damage. Values are
the mean SEM (n = 3−6): (∗) P < 0.05 (vs 1); (#) P < 0.05 (vs 2).
CONCLUSION
■
active metabolite (2-[2-fluoro-4-{(2-hydroxycyclopentyl)-
methyl}phenyl]propanoic acid) was subjected to the analysis.
We recently reported results for 1 by this analysis, which
showed that the cyclopentanone ring interacts with Y385 and
S530, whereas propanoic acid interacts with R120 and Y355.16
All of these amino acids were reported to be important for
the interaction between COXs and NSAIDs.25,26 Similar orien-
tation and interactions were observed for 2 and its selected
derivatives in this study (Figure 5).
Compound 11a was found to have a more potent anti-inflam-
matory effect and an equivalent gastric ulcerogenic activity
compared with 2. Furthermore, as for 2, 11a has no apparent
selectivity for COX-2. Thus, we consider that 11a could be
therapeutically beneficial for clinical use as an NSAID.
EXPERIMENTAL SECTION
The purity of the final compounds was greater than 95% as judged by
HPLC (for details, see Supporting Information).
■
We have thus not only identified here interesting and bene-
ficial NSAIDs (see Conclusion) but also suggested structure−
activity relationships of 2 for COX inhibition and anti-inflam-
matory effects, as follows:
For type-A derivatives, as described above, 2 is a prodrug and
the trans-alcohol form of 2 showed a more potent inhibitory
effect on both COX-1 and COX-2 activity than 2.15 However,
13 and 16, corresponding to the trans-alcohol form of 12 and
15, respectively, showed a weaker inhibitory effect on both
COX-1 and COX-2 than 12 and 15, respectively (Table 1).
Thus, the alteration in bridge heteroatom (O or S) between the
two rings may result in the disappearance of 2’s property as a
prodrug.
2-[4-(Cyclopentylamino)-2-fluorophenyl]propanoic Acid
(11a). To a solution of 7 (1.50 g, 7.6 mmol) in a mixture of
MeOH (10 mL) and AcOH (0.2 mL) were added cyclopentanone
(1.4 mL, 15.2 mmol) and sodium cyanoborohydride (NaBH3CN)
(0.96 g, 15.2 mmol). The solution was stirred at room temperature for
12 h. The reaction mixture was evaporated to dryness, extracted with
CH2Cl2, dried over anhydrous Na2SO4, and filtered. The filtrate was
evaporated to dryness and the residue was purified on silica gel
chromatography (n-hexane/AcOEt, 3:2) to afford the methyl ester
precursor of 11a. Hydrolysis with NaOH was done to give final
1
compound 11a as a brown powder solid (1.09 g, 54%). H NMR
(CDCl3) δ: 1.28 (6H, d, J = 7.0 Hz), 1.33−1.68 (6H, m), 1.79−1.91
(2H, m), 3.56−3.64 (1H, m), 3.70 (1H, q, J = 7.3 Hz), 6.17−6.30
(2H, m), 6.90 (1H, t, J = 8.8 Hz). 13C NMR (CDCl3) δ: 18.1, 25.0,
33.9, 39.0, 55.7, 100.3, 110.4, 116.1, 116.3, 129.8, 130.0, 150.8, 161.2
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Figure 5. Potential binding mode of the active metabolite of 2 (A), 11a (B), 14 (C), 21a (D), and 22a (E) to the active site of murine COX-2.
Hydrogen atoms of the amino acid residues and the ligand have been removed.
(d, JC−F = 242 Hz), 178.4. HR-FAB-MS (m/z): 251.1324 (M+, calcd
for C14H18FNO2, 251.1322). Anal. Calcd for C14H18FNO2: C, 66.91;
H, 7.22; N, 5,57. Found: C, 67.05; H, 7.24; N, 5,46.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and characterization results. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(5) FitzGerald, G. A.; Patrono, C. The coxibs, selective inhibitors of
cyclooxygenase-2. N. Engl. J. Med. 2001, 345, 433−442.
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*Phone and fax: 81-3-5400-2628. E-mail: mizushima-th@
pha.keio.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research from the Ministry of Health, Labour, and Welfare of
Japan, Grants-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan, and Grants-in-Aid of the Japan Science and Technology
Agency.
ABBREVIATIONS USED
■
NSAID, nonsteroidal anti-inflammatory drug; COX, cyclo-
oxygenase; PG, prostaglandin; NBS, N-bromosuccinimide;
DMF, N,N-dimethylformamide; THF, tetrahydrofuran
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