Novel naphthalene derivatives as inhibitors of human immunoglobulin E antibody production

Article abstract of DOI:10.1021/jm9605041

A series of naphthalene derivatives with a variety of substituents at the 2-position was prepared in order to evaluate their suppressive effect on immunoglobulin E (IgE) antibody production by human peripheral blood mononuclear cells provoked with anti-CD40 antibody (α-CD40), interleukin-4 (IL-4), and interleukin-10 (IL-10). Compounds having a 1,4-phenylene spacer moiety tethered between the 2-naphthyl nucleus and anthranilic acid suppressed IgE antibody production in vitro in preference to that of IgG antibody without affecting cell viability. Deletion of the anthranilic acid moiety diminished the inhibitory activities. Changing the 2-naphthyl to a 1- naphthyl or phenyl nucleus led to no change in the potency, indicating that the aromatic group at this position is indispensable for the inhibitory activities. On the other hand, changing the 1,4-phenylene spacer to a 1,3- phenylene one resulted in reduced potency. Similarly, inhibitory activities were lost when the CO₂H moiety at the 2-position was moved to the 3- or 4- position on the terminal benzene. These observations suggest that the conformation around the anthranilic acid moiety affects the inhibitory activities toward IgE biosynthesis, 2-(4-(2-Naphthyloxy)benzamido)benzoic acid (29) seemed to be a more potent inhibitor of IgE production than of IgG production. Insertion of a methylene between the inter-phenylene and the amide moiety resulted in 2-((4-(2-naphthyloxy)phenyl)acetamido)benzoic acid (31), which provided a stronger inhibition of both IgE and IgG production, although the selectivity toward IgE was lower than that of 29. Introduction of a benzyl group at the 6-position on the naphthalene ring considerably increased the inhibitory activity toward IgE production with an IC₅₀ of 8.3 nM (36). The potency of 31 and 36 was retained when hydrocortisone or lipopolysaccharide was used instead of α-CD40 and IL-10 as costimulatory factors with IL-4, implying that these compounds may interfere with signal transduction between IL-4/IL-4 receptor cognition and genetic transcription that induce class-switching of immunoglobulin in B cells. These novel naphthalene derivatives are thus excellent candidates for further investigation with a view toward a therapeutic remedy against IgE-mediated allergic diseases.

Full text of DOI:10.1021/jm9605041

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J . Med. Chem. 1997, 40, 395-407
395
Articles
Novel Na p h th a len e Der iva tives a s In h ibitor s of Hu m a n Im m u n oglobu lin E
An tibod y P r od u ction †
Masaichi Hasegawa,* Kazuya Takenouchi, Katsushi Takahashi, Takahiro Takeuchi, Keiji Komoriya,
Yasuhide Uejima, and Takashi Kamimura
Teijin Institute for Bio-Medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191, J apan
Received J uly 11, 1996X
A series of naphthalene derivatives with a variety of substituents at the 2-position was prepared
in order to evaluate their suppressive effect on immunoglobulin E (IgE) antibody production
by human peripheral blood mononuclear cells provoked with anti-CD40 antibody (R-CD40),
interleukin-4 (IL-4), and interleukin-10 (IL-10). Compounds having a 1,4-phenylene spacer
moiety tethered between the 2-naphthyl nucleus and anthranilic acid suppressed IgE antibody
production in vitro in preference to that of IgG antibody without affecting cell viability. Deletion
of the anthranilic acid moiety diminished the inhibitory activities. Changing the 2-naphthyl
to a 1-naphthyl or phenyl nucleus led to no change in the potency, indicating that the aromatic
group at this position is indispensable for the inhibitory activities. On the other hand, changing
the 1,4-phenylene spacer to a 1,3-phenylene one resulted in reduced potency. Similarly,
inhibitory activities were lost when the CO2H moiety at the 2-position was moved to the 3- or
4-position on the terminal benzene. These observations suggest that the conformation around
the anthranilic acid moiety affects the inhibitory activities toward IgE biosynthesis. 2-(4-(2-
Naphthyloxy)benzamido)benzoic acid (29) seemed to be a more potent inhibitor of IgE production
than of IgG production. Insertion of a methylene between the inter-phenylene and the amide
moiety resulted in 2-((4-(2-naphthyloxy)phenyl)acetamido)benzoic acid (31), which provided a
stronger inhibition of both IgE and IgG production, although the selectivity toward IgE was
lower than that of 29. Introduction of a benzyl group at the 6-position on the naphthalene
ring considerably increased the inhibitory activity toward IgE production with an IC50 of 8.3
nM (36). The potency of 31 and 36 was retained when hydrocortisone or lipopolysaccharide
was used instead of R-CD40 and IL-10 as costimulatory factors with IL-4, implying that these
compounds may interfere with signal transduction between IL-4/IL-4 receptor cognition and
genetic transcription that induce class-switching of immunoglobulin in B cells. These novel
naphthalene derivatives are thus excellent candidates for further investigation with a view
toward a therapeutic remedy against IgE-mediated allergic diseases.
In tr od u ction
edies such as histamine antagonists and mast cell
stabilizers available on the market at present, they are
not very effective against allergic disorders because they
are unable to prevent immunization against an al-
lergenic antigen. Recent research on suppressive agents
of IgE biosynthesis has gained much attention because
such agents may prevent immunization against the
allergen.1c IgE production by mature B cells is regu-
lated by various cytokines and adhesion molecules.3
Soluble interleukin-4 (IL-4) receptor,4 an IL-4 mutant
protein,5 interleukin-12 (IL-12),6 interferon-γ (IFN-γ),7
anti-lymphocyte function-associated antigen-1 (LFA-1)
antibody,8 anti-CD23 antibody,9 interleukin-8 (IL-8),10
and soluble IgE receptor11 are known to suppress IgE
production in vitro and/or in vivo. Surprisingly, anti-
IgE antibodies down-regulate IgE biosynthesis by in-
ducing apotosis in the B cells.12 These agents are not,
however, regarded as promising orally active ones owing
to their polypeptide structure. Splatast, a low molecular
weight antiallergic agent, was reported to suppress
murine IgE production in vitro and in vivo.13 It was
reported to suppress IgE production by 56% at 2 µM in
human B cells cultured with an antigen-specific T cell
line. Nevertheless, the clinical effect of splatast on IgE
Allergies in humans are characterized by the appear-
ance in serum and tissues of the immunoglobulin E
isotype (IgE) directed toward specific environmental
antigens.1 Binding of antigens to specific IgE on mast
cells or basophiles leads to the cross-linking of IgE
receptors, resulting in cell activation and degranulation
for the release of inflammatory mediators such as
platelet-activating factor (PAF), leukotrienes, and his-
tamine.2 These mediators contribute to bronchocon-
striction and recruitment of inflammatory cells such as
leukocytes and lymphocytes. IgE-mediated allergic
diseases, called atopy, include allergic rhinitis, oph-
thalmia, asthma, dermatitis, drug and food allergy,
anaphylaxis, and hyper-IgE syndrome. The suppression
of undesirable IgE-mediated inflammation and immune
reactions is believed to be useful for treatment of atopic
disorders. Although there are many antiallergic rem-
† A part of this study was presented at the AFMC International
Medicinal Chemistry Symposium 95, Tokyo, J apan, Sept. 3-8, 1995
(PIT052), and at the AAAA&I (American Academy of Allergy, Asthma,
and Immunology) International Conference, New York, NY, Feb. 24-
March 1, 1995 (A345 and A346).
X Abstract published in Advance ACS Abstracts, February 1, 1997.
S0022-2623(96)00504-3 CCC: $14.00 © 1997 American Chemical Society

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396 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Sch em e 1
Hasegawa et al.
Sch em e 2
production seems obscure. It was also reported that
disodium cromoglycate (DSCG) and its derivatives sup-
pressed IgE biosynthesis in vitro.14 Prostaglandin E2
was reported to inhibit IL-4-induced IgE production in
human peripheral blood mononuclear cells (PBMC),7b
whereas it stimulated IgE production by murine sple-
nocytes or B cells.15 Hence, there are no orally active
agents that are recognized to suppress the IgE level
suitable for clinical use.
cyclopropane moiety of TEI-6472 into an inter-phen-
ylene one, considering the homology of molecular rigid-
ity (Scheme 1). This change in drug design was also
favorable in view of the feasibility of preparing diverse
new compounds. Here we report (1) the discovery of
novel low molecular weight inhibitors of IgE production
by PBMC provoked with R-CD40, IL-4, and IL-10 and
(2) the first SAR studies on the inhibition of IgE
biosynthesis.
We previously demonstrated that (7E)-N-(2-carboxy-
ph en yl)-8-(2-n a ph t h yl)-5,6-tr a n s-m et h a n o-7-oct en -
amide L-lysine salt (TEI-6472), which was first discov-
ered as an inhibitor of leukotriene biosynthesis, showed
a suppressive effect on IgE antibody production by
trinitrophenol (TNP)-keyhole limpet hemocyanin (KLH)-
primed murine spleen cells.16 Since the effect of TEI-
6472 on IgE production was not considered to be
optimal, we became interested in the structure-activity
relationship (SAR) of a series of its analogues. However,
the cyclopropane moiety impeded the accessible syn-
thesis of analogues. Therefore, we opted for designing
a new class of inhibitors of IgE production that had no
cyclopropane moiety. Replacement of cyclopropane with
simple methylene afforded TEI-8364, which showed IgE
preferential inhibition of antibody biosynthesis in PBMC
and tonsillar B cells, both stimulated with IL-4, IL-10,17
and anti-CD40 antibody (R-CD40).3d,18 However, the
optimal effective dose was found to be more than 1 µM.
In order to find a promising candidate for a human IgE-
suppressive agent, we decided to change the ene-
Ch em istr y
Naphthalene derivatives were generally prepared as
follows (Scheme 2): Sodium naphthoxide or naphtha-
lenethiolate (1) was coupled with methyl bromobenzoate
or methyl bromophenylacetate (2) with copper(I) chlo-
ride19 followed by hydrolysis to give carboxylic acids
5-10. The same reaction using naphthyl bromide
derivative 3 and sodium phenoxide derivative 4 also
afforded 5-10. After the conversion of 5-10 to acyl
chloride with (COCl)2, condensation of the corresponding
acyl chlorides with aniline derivative 12 provided
amides 44 and 45. When R was methyl in 11, the
products were treated with LiOH to give acids 29, 31,
36, 37, and 47-50 (R4 ) CO2H). Compound 46, having
a benzene moiety instead of the naphthalene ring, was
also prepared by the same procedure using sodium
phenoxide instead of sodium naphthoxide. As shown
in Scheme 3, benzyl ether 13 was hydrogenated followed
by hydrolysis to give 35. Nitrile 14 was converted to
tetrazole derivative 43 with NaN3 and NH4Cl. Com-

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Naphthalene Inhibitors of IgE Antibody Production
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 397
Sch em e 3
for their effect on the viability of, human PBMC. PBMC
from healthy donors were cultured with R-CD40, IL-4,
and IL-10 with or without the test compounds for 2
weeks.18 IgE and IgG levels were determined by
enzyme-linked immunosorbent assay (ELISA). Sup-
pression (%) was calculated by the following mathemati-
cal equation: (level without compound - level with
compound)/level without compound × 100. The results
are summarized in Table 2, where they are expressed
as suppression (%) of IgE production, IgG production,
and cell viability by each compound tested at 3 µM. In
these columns, a negative number of suppression (%)
means enhancement of antibody biosynthesis or cell
viability. The IC50 (µM) is also given for highly active
compounds. For determination of cell viability, the
alamar blue assay was performed as described in the
instruction manual provided by the manufacturer. This
assay includes an oxidation-reduction indicator that
both fluoresces and changes color in response to chemi-
cal reduction of alamar blue resulting from cell growth
and is generally used, like the MTT assay, to measure
relative cytotoxicity of various compounds. Continued
cell growth causes the redox indicator to change from
the oxidized (nonfluorescent, blue) form to the reduced
(fluorescent, red) form because cell growth maintains a
reduced environment while inhibition of cell growth
maintains an oxidized environment.
pound 42 was obtained from 15 by methylation with
MeI and NaI followed by hydrolysis.
Scheme 4 shows the reactions for the preparation of
30, 34, 40, 41, and 51: Sodium naphthoxide (16) and
ethyl 3-(4-bromophenyl)cinnamate were condensed with
CuCl followed by hydrogenation and hydrolysis to yield
17, which was converted to 34 in the same manner as
in Scheme 2. An attempt was made to invert the order
of the amide moiety. Compound 16 was coupled with
4-nitrophenyl bromide and then hydrogenated over Pd/C
to give 4-(2-naphthyloxy)aniline (18). Condensation of
18 and phthalic anhydride yielded 51. Compound 16
and methyl 4-(bromomethyl)benzoate were condensed
in alkali media without CuCl followed by hydrolysis to
give 19. Similar reaction of methyl 4-chloro-3-nitroben-
zoate with 16 led to 20 in good yield because of the
electron-attracting effect of NO2. Compounds 19 and
20 were treated with methyl anthranilate followed by
hydrolysis in the same manner as in Scheme 2 to
provide 30 and 40, respectively. Reduction of 5 with
LiAlH4 gave alcohol, which was converted to bromide
21 with CBr4 and trioctylphosphine20 and then coupled
with methyl anthranilate with K2CO3 and NaI followed
by hydrolysis to yield benzylamine derivative 41.
As indicated in Scheme 5, methyl 4-(2-naphthyloxy)-
phenylacetate (22) was alkylated with MeI and lithium
diisopropylamide (LDA) followed by hydrolysis to afford
23. Further methylation was accomplished by the
reaction of the methyl ester of 23 with MeI and LDA
followed by hydrolysis to yield 24. Compounds 23 and
24 were then converted to 32 and 33, respectively, as
described above.
Table 2 lists the inhibitory activities of 29-45 toward
IgE and IgG production and their effects on viability.
Suppression of IgE production caused by the lead
compound TEI-6472 was strong, with an IC50 of 1.9 µM
toward PBMC, similar to the result found with TNP-
KLH-primed mouse splenocytes.16 The inhibition of
immunoglobulin production was IgE selective in view
of the minimal effect on the IgG. An attempt to alter
the vinyl and cyclopropane moiety of TEI-6472 to 1,4-
phenylene was successful from the results of 2-(4-(2-
naphthyloxy)benzamido)benzoic acid (29) and 2-((4-(2-
naphthyloxy)phenyl)acetamido)benzoic acid (31). Com-
pound 29 seems to be a potent inhibitor of IgE produc-
tion, with an IC50 of 1.3 µM, in preference to IgG pro-
duction. The presence of a 3 µM concentration of 29 in
the culture did not affect the cell viability. Insertion of
the methylene between the inter-phenylene and the
amide moiety resulted in 31, which was found to be a 3
times more potent inhibitor of IgE (IC50 ) 0.6 µM) than
TEI-6472; however, it also suppressed IgG production
(IC50 ) 4.3 µM). It is quite interesting that the transfer
of the methylene in 31 to the para position (30)
eliminated the potency. Further extension of molecular
size by insertion of an additional methylene moiety to
give 34 diminished the activity. These results indicate
that both the distance between naphthalene and an-
thranilic acid and the relative conformation of the
internal phenylene moiety are responsible for the
inhibitory activity. Compound 29 was thus selected as
the second lead compound in view of its biological
efficacy and synthetic efficiency.
2-Naphthylmagnesium bromide21 from 25 reacted
with methyl 4-formylbenzoate to yield carbinol deriva-
tive 26. Oxidation of 26 with pyridinium chlorochro-
mate (PCC), followed by hydrolysis, gave ketone 27.
Reduction of 26 with triethylsilane in trifluoroacetic acid
(TFA),22 followed by hydrolysis, resulted in the for-
mation of 28. Condensation of 27 and 28 with meth-
yl anthranilate followed by hydrolysis as described
above afforded 39 and 38, respectively (Scheme 6).
Table 1 lists the analytical data of the major compounds
29-45.
Alteration of X to S (37), CH2 (38), or CO (39) resulted
in loss of activity, suggesting that oxygen in X may play
an important role. Methylation and dimethylation of
31, yielding 32 and 33, respectively, considerably re-
duced the inhibitory effect. Steric hindrance of the
methyl or dimethyl moiety in Y restricts the molecular
conformation, which may influence the biological effect.
Resu lts a n d Discu ssion
All the synthesized compounds were evaluated for in
vitro inhibition of total IgE and IgG production by, and

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398 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Sch em e 4
Hasegawa et al.
Sch em e 5
Sch em e 6
Substitution of a hydroxy moiety at R1 provided 35,
which maintained inhibitory activity comparable to that
of 29. It is of great interest, however, that the introduc-
tion of benzyloxy at the 6-position (R1) on the naphtha-
lene ring of 31, affording 36, resulted in a significant
enhancement of IgE inhibitory activity (IC50 ) 8.3 nM)
together with a partial decrease in the cell viability.
Similarly, introduction of NO2 at R2 (40) increased IgE
inhibitory activity without much reduction in cell vi-
ability. Noteworthy is the fact that methylation of the

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Naphthalene Inhibitors of IgE Antibody Production
Ta ble 1. Analytical Data of Naphthalene Derivatives
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 399
compd
R1
X
R2
Y
R3
R4
mp, °C
formulaa
C24H17NO4
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
H
H
H
H
H
H
OH
OBn
H
H
H
H
H
H
H
H
H
O
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
CO
CO
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
2-TETb
CONH2
NH2
213.0-213.5
218.5-219.0
173.5
OCH2
O
C25H19NO4
C25H19NO4
C26H21NO4
C27H23NO4
C26H21NO4
C24H17NO5
C32H25NO5
C24H17NO3S
C25H19NO3
C25H17NO4
C24H16N2O6‚1/2H2O
C24H19NO3
C25H19NO4
C24H17N5O2
C24H18N2O3
C23H18N2O2
CH2CO
CHMeCO
CMe2CO
(CH2)2CO
CO
O
O
O
O
O
S
185.0-185.5
211.5-212.0
168.0-168.5
250.5-251.0
210.0-210.5
238.5-239.0
221.0-222.0
242.0-243.0
241.0-242.0
194.5-195.5
166.0-167.0
223.5-224.0
199.5-200.5
204.5-206.5
CH2CO
CO
CH2
CO
O
CO
CO
CO
O
O
O
O
CH2
CO
CO
CO
CO
O
a
b
C, H, N analyses were within (0.4% of theoretical values. 2-(1H-Tetrazol-5-yl).
Ta ble 2. Inhibition of IgE and IgG Production by PBMC
suppression (%) at 3 µM (IC50, µM)
compd
R1
X
R2
Y
R3
R4
IgE production
IgG production
viability
TEI-6472
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
63.0 (1.88)
64.8 (1.3)
-6.1
-0.5 (>10)
-16.9 (38)
-16.1
-2.6
-7.4
NTa
11.4
-2.1
-11.3
-2.9
5.2
58.2
NT
-1.1
NT
19.1
-1.7
-5.1
-13.6
7.3
H
H
H
H
H
H
OH
OBn
H
H
H
H
H
H
H
H
H
O
OCH2
O
O
O
O
O
O
S
CH2
CO
O
O
O
O
O
O
H
H
H
H
H
H
H
H
H
H
H
NO2
H
H
H
H
H
CO
CO
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
2-TETb
CONH2
NH2
CH2CO
CHMeCO
CMe2CO
(CH2)2CO
CO
CH2CO
CO
CO
CO
CO
CH2
CO
86.6 (0.6)
8.7
31.2 (4.3)
-15.9
-30.4
-5.4
-41.2
8.5
76.6 (1.2)
95.1 (0.0083)
25.8
9.5
10.3
-8.7 (>10)
91.7 (0.042)
-2.8
-21.1
5.4
93.0 (0.29)
21.9
36.9 (2.4)
-4.5
10.1
-18.7
10.8
-27.7
CO
CO
CO
-74.5
8.6
45
31.6 (4.4)
3.3 (>10)
-9.3
a
b
NT ) not tested. 2-(1H-Tetrazol-5-yl).
amide moiety (R3 ) Me, 42) caused loss of activity.
Therefore, the ability of a conformational change in the
two benzene rings, which may prevent hydrogen bond
formation, appears to be crucial for the suppressive
activity toward IgE production. Carboxylic acid at R4
of 29 was converted to tetrazole to give 43. Although
the tetrazole moiety is in general recognized as a
bioisoster of CO2H in view of its pKa value,23 it is quite
intriguing that 43 caused enhancement of IgE produc-
tion. These results demonstrate that the shape and the
size of R4 remarkably affect IgE production. Compari-
son of 44 with 29 showed that CONH2 at R4 should not
be substituted for CO2H, indicating that this hydrogen
bond is responsible for the activity. It is unique that
45, having an amino group at R4, showed modest
potency.
Table 3 lists the inhibitory activities toward IgE and
IgG production and viability effect for the compounds
having a partial structure of 29. Compound 5, lacking
the anthranilic acid moiety, was inactive; this observa-
tion is consistent with the importance of this moiety,
as described above. Conversion of the naphthalene ring
into benzene (46) resulted in retention of the potency.
However, further elimination of this benzene moiety or
replacement of the benzene moiety with a cyclohexane
one virtually abolished the potency (data not shown).
These facts confirm that both the anthranilic acid

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400 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Hasegawa et al.
Ta ble 3. Inhibition of IgE and IgG Production by PBMC for
Compounds Having Partial Structure
Ta ble 5. Comparison of in Vitro Suppressive Effect on IgE
production of 31 and 36
IgE production, IC50 (µM)
human PBMC
IL-4, R-CD40,
mouse B cells
IL-4, LPS
IL-10
IL-4, HC
31
36
0.6
0.0083
1.9
0.63
0.012
NTa
a
NT ) not tested.
Ta ble 6. Comparison of in Vitro Biological Data on 29, 31, 36,
and 30
a
C, H, N analyses were within (0.4% of theoretical values. NT
) not tested.
production, IC50 (µM)
IgE, human PBMC IL-4, LTB4, RBL-1
PGE2, WI-38
A23187, IL-1R
Ta ble 4. Inhibition by Isomers of 29 of IgE and IgG
Production by PBMC
R-CD40, IL-10
A23187
29
31
36
30
1.3
0.6
0.0083
>3.0
0.4
0.7
1.2
NT
10
10
NTa
<1.0
a
NT ) not tested.
of the CD40 ligand expressed on the surface of T cells,
which then costimulates B cells via CD40. These facts
demonstrate that these compounds act on B cells.
DSCG was reported to inhibit the Sµ to Sꢀ deletional
switch recombination and IgE synthesis in human B
cells.14 In addition, we previously reported that TEI-
8364, having the inter-phenylene replaced with a hex-
enyl chain, affected B cell differentiation and IgE
preferential class-switching.18 Since TEI-8364 also pos-
sesses naphthalene and anthranilic acid moieties, the
inhibitory mechanism of these compounds here may be
the same as that of TEI-8364. Table 5 compares the in
vitro suppressive effect on IgE production between 31
and 36. When mouse spleen B cells were stimulated
with IL-4 and lipopolysaccharide (LPS), 31 and 36
inhibited IgE synthesis comparably to the extent found
in the original experiment using IL-4-, R-CD40-, and IL-
10-treated human PBMC; for instance, 36 lowered IgE
production with an IC50 of 0.012 µM. The same ten-
dency was observed with 31 when IL-4 and hydrocor-
tisone (HC) instead of IL-4, R-CD40, and IL-10 were
added to cultures of human PBMC.24 These data
strongly suggest that compounds such as 31 or 36 may
interfere with signal transduction between IL-4/IL-4
receptor cognition25 and genetic transcription, which
induce the class-switching of immunoglobulin in B cells
to release IgE.26
Table 6 summarizes the effects of four compounds on
the production of arachidonic acid metabolites. Since
PGE2 was reported to affect IgE synthesis,7b,15 some of
our representative compounds were evaluated for their
suppressive effect on PGE2 biosynthesis by human lung
fibroblast WI-38 stimulated with interleukin-1R (IL-1R)
and Ca2+ ionophore A23187.27 Compounds 29 and 31
showed weak activity with an IC50 of 10 µM, whereas
30, having little IgE inhibitory effect, was found to be
a relatively strong inhibitor of PGE2 production. These
data demonstrate that PGE2 does not play a pivotal role
in the inhibition of IgE biosynthesis by these com-
pounds. Although TEI-6472 was shown to be an inhibi-
tor of IgE and LTB4 biosynthesis, the relationship
between IgE biosynthesis and LTB4 seems obscure.
Compounds 29, 31, and 36 exhibited a strong suppres-
sive effect on LTB4 production by rat basophilic leuke-
mia cells (RBL-1) stimulated with A23187.28 However,
a
C, H, N analyses were within (0.4% of theoretical values.
moiety and the benzene ring on the opposite side are
essential for the inhibitory activities toward IgE bio-
synthesis.
Table 4 lists five isomers of 29 that were also studied
as inhibitors of IgE production. 1-Substituted naph-
thalene isomer 47 was equally as active as 29, indicating
the importance of the aryloxy moiety on the left side as
was shown by 46. Rearrangement of 29 also gave the
1,3-oriented isomer 48, which completely lost the activ-
ity. This implies that the shape of the molecule is also
responsible for the inhibitory effect on IgE production.
Transfer of carboxylic acid substituents to the 3- or
4-position (49, 50) entirely eliminated the potency. Of
great interest is the fact that inversion of the amide
functionality (51) also resulted in loss of activity. These
results strongly indicate that the anthranilic acid
moiety, including its amide functionality, is a core moie-
ty for the inhibitory activities. Reduction of the carbonyl
moiety of the amide afforded 41, which also showed
absolutely no activity at all (Table 2). These facts
strongly suggest that the carbonyl group in the amide
is essential for the suppressive activity toward IgE
biosynthesis.
The detailed mode of action of IgE inhibition is not
understood. It is well known that IL-4 production by T
cells plays a major role in the induction of IgE produc-
tion by B cells.4,5 R-CD40 is believed to be an equivalent

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Naphthalene Inhibitors of IgE Antibody Production
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 401
compound)/level without compound × 100. After removal of
the medium, alamar blue (Biosource, CA; 20 µL/well) was
added to the cultures, and incubation was carried out for 2 h.
Cell viability was measured by counting the number of
fluorescent (viable) cells (excitation λ ) 530 nm, emission λ )
590 nm). Suppression (%) was calculated as described above.
Biologica l Assa y of in Vitr o Effects of Der iva tives on
IgE P r od u ction by Hu m a n P BMC Stim u la ted w ith IL-4
a n d HC. HC (1 µM) was used instead of IL-10 and R-CD40
according to the same procedure as described above.
the suppressive effect of these compounds on IgE
production did not correlate with that on LTB4 produc-
tion.
Con clu sion
We prepared a series of naphthyloxy-substituted
benzamidobenzoic acids and related derivatives and
conducted the structure-activity relationship studies
on their inhibitory activities toward IgE biosynthesis.
The results may be summarized as follows: (1) 2-(4-(2-
Naphthyloxy)benzamido)benzoic acid (29) was found to
have a suppressive activity for IgE in preference to that
for IgG biosynthesis. (2) The presence of a 2-aryloxy
group at the 4-position on the inter-phenylene was
necessary for the inhibitory activity. (3) A spacer
methylene between the amide and phenylene (31)
enhanced the suppressive activity for IgE and IgG
biosynthesis, whereas it weakened IgE class selectivity.
(4) The anthranilic acid moiety was found to be a core
moiety: The carboxylic acid and amide carbonyl could
not be moved to another position and were not replace-
able with other functional groups. (5) Placement of a
benzyloxy group on the 6-position of the naphthalene
ring (36) provided the optimal potency.
Biologica l Assa y of in Vitr o Effects of Der iva tives on
IgE P r od u ction by Mou se Sp leen B Cells Stim u la ted
w ith IL-4 a n d LP S. Mouse B cells were prepared by treating
DBA/2 splenocytes with anti-mouse T cell serum (Cedarlane,
Canada) followed by incubation with Low-Tox rabbit comple-
ment (Cedarlane, Canada). B cells were fractionated by
gradient centrifugation and cultured in RPMI 1640 medium
(the same as described above) supplemented with 10% FCS
(Whittaker, ML) in 96-well plates. LPS (Sigma, MO) was
added at a final concentration of 2 µg/mL. After incubation
for 1 day, mouse IL-4 (Genzyme, MA) was added at a final
concentration of 50 ng/mL. Cultures was continued for 6 days,
and IgE levels in the media were measured by ELISA.
Biologica l Assa y of in Vitr o Effects of Der iva tives on
LTB4 P r od u ction .28 Rat basophile leukemia cell line RBL-1
(Dainippon Pharmaceutical Co., J apan) was maintained in
Dulbecco’s modified Eagle’s medium containing FCS (10%).
Cells were preincubated with or without test compounds for
10 min at 37 °C. Ca2+ ionophore A23187 was added at a final
concentration of 2 µM. After incubation for 5 min, the reaction
was stopped, and the culture media were harvested. The level
of LTB4 in the supernatant of the centrifuged medium was
determined with an ELISA assay kit (Cayman & Amersham).
Biologica l Assa y of in Vitr o Effects of Der iva tives on
The efficacy of 31 and 36 was maintained when
R-CD40 and IL-10 were replaced by HC or LPS as
costimulatory factors with IL-4, implying that these
compounds may act on IL-4 signal transduction to cause
class-switching of immunoglobulin in B cells. No cor-
relation between IgE production and LTB4/PGE2 pro-
duction was observed in terms of suppressive effect.
P GE2
P r od u ction .27 Human lung fibroblasts, WI-38 (Riken
Cell Bank, J apan), were maintained in Dulbecco’s modified
Eagle’s medium containing penicillin (50 units) and strepto-
mycin (50 mg/mL) and supplemented with 10% FCS. Cell
suspensions (200 µL, 2 × 105 cells/mL) were plated onto 96-
well plates, and the cells were grown to confluence (4 days).
Then they were starved with fresh medium minus serum but
containing 0.5% bovine serum albumin (BSA) overnight. The
medium was aspirated and replaced with that containing 0.5%
BSA and interleukin-1R (IL-1R) (10 ng/mL) with or without
test compound. The cells were then incubated overnight at
37 °C. PGE2 released into the medium was determined with
an ELISA assay kit (Cayman & Amersham).
4-(2-Na p h th yloxy)p h en yla cetic Acid (6). Gen er a l P r o-
ced u r e A.19a To a solution of 2-naphthol (28.83 g, 0.20 mol)
in a mixture of dry benzene (400 mL) and dry MeOH (100 mL)
was added NaOMe (28%, MeOH solution, 36.7 mL, 0.19 mol)
at room temperature. The reaction mixture was stirred for 1
h at room temperature and then concentrated. A mixture of
the residue, methyl 4-bromophenylacetate (45.8 g, 0.20 mol),
and CuCl (5.94 g, 0.06 mol) in dry pyridine (500 mL) was
heated at 120 °C with stirring for 86 h. After cooling, 5 N
HCl (150 mL) was poured into the reaction mixture, and the
products were extracted with EtOAc. The organic layer was
dried over Na2SO4 and evaporated. Purification by silica gel
column chromatography (hexane-EtOAc, 50:1-10:1) gave the
methyl ester of the title compound (22, 27.4 g, 48%). A solution
of this compound (26.7 g, 95 mmol) in MeOH-THF (175/350
mL) was treated with 4 N LiOH (119 mL, 0.48 mol) and stirred
overnight at room temperature. The reaction mixture was
acidified to pH 1 with 5 N HCl (95 mL) and stirred for 1 h at
room temperature. The mixture was extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4,
and evaporated. Recrystallization from CH3CN afforded 6
(20.73 g, 78% yield) as a white prism: 1H NMR (CDCl3) δ 3.67
(s, 2 H), 7.04 (d, J ) 8.6 Hz, 2 H), 7.24-7.34 (m, 4 H), 7.43
(dquint, J ) 1.7, 6.9 Hz, 2 H), 7.71 (d, J ) 8.9 Hz, 1 H), 7.81-
7.85 (m, 2 H), 10.10 (s br, 1 H).
Exp er im en ta l Section
1H and 13C NMR spectra were recorded on a J EOL EX-270
Fourier transform spectrometer at 270 MHz (1H) and 68 MHz
(13C), using tetramethylsilane as an internal standard. The
abbreviations are as follows: s ) singlet, d ) doublet, t )
triplet, q ) quartet, m ) multiplet, br ) broad. For TLC
analysis, Merck precoated TLC (silica gel 60 F254, d ) 0.25
mm) was used. Melting point determinations were performed
on an electrothermal YANACO MP-S3 or METTLER FP62
apparatus. The FT-IR spectra were determined on a J ASCO
FT/IR-5300 in a KBr pellet. Purification by medium-pressure
liquid chromatography was carried out on Daisogel IR-60 silica
gel. Where analyses are indicated only by symbols of the
elements, analytical results are within (0.4% of the theoretical
values. All nonaqueous reactions were carried out under an
inert atmosphere except for hydrogenations, which were
carried out under a hydrogen atmosphere. THF and ether
were distilled from sodium benzophenone ketyl prior to use.
CH2Cl2 was dried over CaH2. Pyridine and MeOH were dried
over molecular sieve 4A and molecular sieve 3A, respectively.
The other commercially available reagents and solvents were
used without further purification unless otherwise stated.
Biologica l Assa y of in Vitr o Effects of th e Der iva tives
on IgE a n d IgG P r od u ction by a n d Via bility of Hu m a n
P BMC Stim u la ted w ith IL-4, IL-10, a n d r-CD40.18 Human
PBMC were obtained by the Ficoll-Paque (Pharmacia, Upp-
sala, Sweden) density gradient centrifugation technique.
PBMC (final: 2 × 106 cells/mL) were cultured in triplicate in
flat-bottomed 96-well plates (Falcon, NJ ) in a final volume of
200 µL of RPMI 1640 supplemented with 10% fetal calf serum
(FCS; Whittaker, ML), 2 mM glutamine, 50 units/mL penicil-
lin, and 50 µg/mL streptomycin. IL-4 (0.1 µg/mL), IL-10 (0.2
µg/mL), and R-CD40 (2 µg/mL), with or without test compound,
were added to the cultures on day 0. After 14 days, the culture
medium was harvested, and human IgG and IgE levels in it
were determined by enzyme-linked immunosorbent assays
(ELISA). Suppression (%) was calculated by the following
mathematical equation: (level without compound - level with
4-(Na p h th yloxy)ben zoic Acid (5). Methyl 4-hydroxy-
benzoate and 2-bromonaphthalene were treated instead of
2-naphthol and methyl 4-bromobenzoate, respectively, accord-
ing to the same procedure as described in the preparation of

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402 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Hasegawa et al.
filtrate was concentrated to give the methyl ester of 17.
6 to afford 5 as a white solid in 20% yield: mp 180-181 °C;
1H NMR (CDCl3) δ 7.04-7.10 (m, 2 H), 7.25-7.29 (m, 1 H),
7.44-7.54 (m, 3 H), 7.76-7.79 (m, 1 H), 7.83-7.90 (m, 2 H),
8.07-8.12 (m, 2 H); 13C NMR (DMSO-d6) δ 115.9, 117.7, 120.5,
125.6, 125.7, 127.0, 127.5, 127.9, 130.6, 131.9, 134.2, 153.2,
161.2, 167.0. Anal. (C17H12O3) C, H, N.
4-((6-(Ben zyloxy)-2-n a p h t h yl)oxy)p h en yla cet ic Acid
(7). Methyl 4-hydroxyphenylacetate and 6-(benzyloxy)-2-
bromonaphthalene were treated instead of 2-naphthol and
methyl 4-bromobenzoate, respectively, according to the same
procedure as described in the preparation of 6 to afford 7 as a
white solid: 8% yield: 1H NMR (DMSO-d6) δ 3.65 (s, 2 H),
5.18 (s, 2 H), 7.00 (d, J ) 8.6 Hz, 2 H), 7.20-7.50 (m, 11 H),
7.64 (d, J ) 9.6 Hz, 1 H), 7.71 (d, J ) 8.9 Hz, 1 H).
A
solution of this compound (275 mg, 0.9 mmol) in MeOH-THF
(5/10 mL) was treated with 4 N LiOH (2.2 mL, 9 mmol) and
stirred overnight at room temperature. The reaction mixture
was acidified to pH 1 with 5 N HCl (3 mL) and stirred for 1 h
at room temperature. The mixture was poured onto water,
and the products were extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and evapo-
rated. Recrystallization from hexane-benzene (3/2 mL) af-
forded 17 as pale yellow needles (219 mg, 83%): 1H NMR
(CDCl3) δ 2.71 (t, J ) 7.6 Hz, 2 H), 2.98 (t, J ) 7.6 Hz, 2 H),
7.00 (d, J ) 8.6 Hz, 2 H), 7.19-7.29 (m, 4 H), 7.36-7.47 (m, 2
H), 7.70 (d, J ) 7.6 Hz, 1 H), 7.82 (d, J ) 8.9 Hz, 2 H).
4-(2-Na p h th yloxy)a n ilin e (18). To a solution of 2-naph-
thol (1.44 g, 10 mmol) in dry DMF (10 mL) was added 60%
NaH (60% in fossil oil, 400 mg, 10 mmol) at 0 °C. After this
mixture had been stirred for 0.3 h, 4-bromonitrobenzene (2.02
g, 10 mmol) was introduced to it, and stirring was continued
overnight at room temperature. The reaction mixture was
poured onto water, and the products were extracted with CH2-
Cl2. The organic layer was washed with brine, dried over Na2-
SO4, and concentrated. The residue was purified by silica gel
column chromatography (hexane-EtOAc, 50:1-10:1) to give
4-(2-naphthyloxy)nitrobenzene as a white solid. To a solution
of this compound (0.49 g, 1.85 mmol) in EtOAc (5 mL) was
added 10% Pd/C (49 mg), and the resulting mixture was stirred
overnight at room temperature under a hydrogen atmosphere.
The mixture was filtered through Celite. Concentration of the
filtrate gave 18 (423 mg, 97%) as a brown solid: 1H NMR
(CDCl3) δ 3.62 (s br, 2 H), 6.72 (d, J ) 8.9 Hz, 2 H), 6.94 (d, J
) 8.6 Hz, 2 H), 7.15 (d, J ) 2.3 Hz, 1 H), 7.22-7.26 (m, 1 H),
7.32-7.44 (m, 2 H), 7.64 (d, J ) 7.9 Hz, 1 H), 7.79 (d, J ) 8.9
Hz, 2 H).
4-((2-Na p h th yloxy)m eth yl)ben zoic Acid (19). To a so-
lution of 2-naphthol (721 mg, 5.0 mmol) in DMF (5 mL) was
added NaH (60% in fossil oil, 220 mg, 5.5 mmol). After the
mixture had been stirred for 1 h at room temperature, methyl
4-(bromomethyl)benzoate was added to it, and stirring con-
tinued for 3.5 h at room temperature. The reaction mixture
was poured onto water, and the products were extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated. Recrystallization from MeOH gave
the methyl ester of the title compound. A solution of this
compound (1.06 g, 3.63 mmol) in MeOH-THF (8/15 mL) was
treated with 4 N LiOH (9 mL, 36 mol) and stirred overnight.
The reaction mixture was acidified to pH 1 with 5 N HCl (10
mL) and stirred for 20 min at room temperature. The mixture
was washed with water, and the products were extracted with
EtOAc. The organic layer was dried over Na2SO4 and evapo-
rated. Recrystallization from CH3CN afforded 19 (0.87 g) as
a white needle in 55% yield: 1H NMR (CDCl3) δ 5.28 (s, 2 H),
7.20-7.27 (m, 2 H), 7.35 (dt, J ) 2.0, 7.9 Hz, 1 H), 7.45 (dt, J
) 1.3, 8.2 Hz, 1 H), 7.61 (d, J ) 8.3 Hz, 2 H), 7.72 (d, J ) 7.9
Hz, 1 H), 7.78 (d, J ) 8.9 Hz, 2 H), 8.15 (d, J ) 8.2 Hz, 2 H).
4-(2-Na p h th yloxy)-3-n itr oben zoic Acid (20). Methyl
4-chloro-3-nitrobenzoate was treated instead of methyl 4-(bro-
momethyl)benzoate according to the same procedure as de-
scribed in the preparation of 19 to give 20 as a white solid:
99% yield; 1H NMR (DMSO-d6) δ 7.20 (d, J ) 8.9 Hz, 1 H),
7.41 (dd, J ) 1.3, 6.0 Hz, 1 H), 7.50-7.60 (m, 2 H), 7.69 (d, J
) 1.3 Hz, 1 H), 7.91 (m, 1 H), 7.98 (m, 1 H), 8.06 (d, J ) 8.9
Hz, 1 H), 8.16 (dd, J ) 2.0, 4.0 Hz, 1 H), 8.53 (d, J ) 2.3 Hz,
1 H).
4-(2-Na p h th ylth io)ben zoic Acid (8). 2-Naphthalenethiol
and ethyl 4-bromobenzoate were treated instead of 2-naphthol
and methyl 4-bromobenzoate, respectively, according to the
same procedure as described in the preparation of 6 to afford
1
8 as amber needles: 60% yield; H NMR (CDCl3) δ 7.23 (s, 2
H), 7.49-7.58 (m, 3 H), 7.81-7.96 (m, 5 H), 8.06 (d, J ) 1.7
Hz, 1 H).
4-(1-Na p h th yloxy)ben zoic Acid (9). Methyl 4-hydroxy-
benzoate and 1-bromonaphthalene were treated instead of
2-naphthol and methyl 4-bromophenylacetate, respectively,
according to the same procedure as described in the prepara-
tion of 6 to afford 9 as a white solid: 14% yield; 1H NMR
(CDCl3) δ 6.94 (d, J ) 7.6 Hz, 2 H), 7.06 (d, J ) 6.3 Hz, 1 H),
7.35-7.55 (m, 3 H), 7.69 (d, J ) 8.9 Hz, 1 H), 7.87 (d, J ) 8.5
Hz, 1 H), 8.0-8.3 (m, 3 H).
3-(2-Na p h th yloxy)ben zoic Acid (10). Methyl 3-hydroxy-
benzoate and 2-bromonaphthalene were treated instead of
2-naphthol and methyl 4-bromophenylacetate, respectively,
according to the same procedure as described in the prepara-
tion of 6 to afford 10 as a white solid: 52% yield; 1H NMR
(CDCl3) δ 7.29 (dt, J ) 9.0, 1.9 Hz, 2 H), 7.40-7.55 (m, 5 H),
7.72 (d, J ) 7.5 Hz, 1 H), 7.83 (d, J ) 7.2 Hz, 1 H), 7.90-8.00
(m, 2 H).
2-(4-(2-Na p h th yloxy)ben za m id o)ben zon itr ile (14). To
a suspension of 5 (264 mg, 1.0 mmol) in dry CH2Cl2 (5 mL)
was added oxalyl chloride (140 mg, 1.1 mmol) followed by
treatment with DMF (1 drop). After having been stirred for
2 h at 35 °C, the reaction mixture was concentrated. To a
solution of the residue in dry CH2Cl2 (7 mL) was added a
solution of anthranilonitrile (118 mg, 1.0 mmol) and trieth-
ylamine (111 mg, 1.1 mmol) in dry CH2Cl2 (1 mL) at 0 °C; this
was stirred for 4 h at 0 °C and then overnight at room
temperature. The reaction mixture was poured onto water,
and the products were extracted with CH2Cl2. The organic
layer was washed with brine, dried over Na2SO4, and concen-
trated. Purification by silica gel column chromatography
(hexane-EtOAc, 20:1-5:1) gave 14 (263 mg, 72% yield) as a
white solid: 1H NMR (CDCl3) δ 7.15 (d, J ) 8.9 Hz, 2 H), 7.18-
7.30 (m, 2 H), 7.46-7.54 (m, 3 H), 7.61-7.69 (m, 2 H), 7.76-
7.79 (m, 1 H), 7.85-7.96 (m, 4 H), 8.34 (s br, 1 H), 8.61 (d, J
) 8.6 Hz, 1 H).
3-(4-(2-Na p h th yloxy)p h en yl)p r op a n oic Acid (17). To
a solution of 2-naphthol (1.44 g, 10 mmol) in dry benzene (20
mL) and dry MeOH (5 mL) was added NaOMe (28%, MeOH
solution, 1.83 mL, 9.5 mmol) at room temperature. The
reaction mixture was stirred for 1 h at room temperature and
then concentrated. A mixture of the resultant solution, ethyl
(E)-4-bromocinnamate (2.55 g, 10 mmol), and CuCl (0.3 g, 3
mmol) in dry pyridine (10 mL) was heated at 120 °C with
stirring for 48 h. After cooling, 5 N HCl (150 mL) was poured
into the reaction mixture, and the products were extracted
with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and evaporated. Purification by silica gel column
chromatography (hexane-EtOAc, 20:1) gave methyl (E)-3-(4-
(2-naphthyloxy)phenyl)propenate (280 mg, 53%): 1H NMR
(CDCl3) δ 3.81 (s, 3 H), 6.37 (d, J ) 15.8 Hz, 1 H), 7.04-7.06
(m, 2 H), 7.24-7.28 (m, 1 H), 7.40-7.54 (m, 5 H), 7.68 (d, J )
15.8 Hz, 1 H), 7.72-7.76 (m, 1 H), 7.83-7.88 (m, 2 H).
To a solution of this compound (280 mg, 0.92 mmol) in
EtOAc (5 mL) was added 10% Pd/C (10 wt %, 30 mg), and this
was stirred for 6 h at room temperature under a hydrogen
atmosphere. The reaction mixture was filtered, and the
4-(2-Na p h th yloxy)ben zyl Br om id e (21).20 To a suspen-
sion of LiAlH4 (76 mg, 2.0 mmol) in dry THF (10 mL) was
added a solution of 5 (264 mg, 1.0 mmol) in dry THF (5 mL)
at 0 °C. The mixture was stirred for 3 h at room temperature
and poured into ether (30 mL) and saturated Na2SO4 solution
(30 mL). The products were extracted with ether. The organic
layer was washed with brine, dried over Na2SO4, and concen-
trated. The residual mixture was chromatographed on silica
gel (using hexane-EtOAc, 3:1) to afford 4-(2-naphthyloxy)-
benzyl alcohol (239 mg, 95% yield) as a white solid: 1H NMR
(CDCl3) δ 4.70 (s, 2 H), 7.07 (d, J ) 8.6 Hz, 2 H), 7.24-7.28
(m, 1 H), 7.31 (d, J ) 2.6 Hz, 1 H), 7.36-7.49 (m, 4 H), 7.70
(d, J ) 7.6 Hz, 1 H), 7.81-7.85 (m, 2 H).

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Naphthalene Inhibitors of IgE Antibody Production
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 403
Tri-n-octylphosphine (708 mg, 1.91 mmol) was added to a
solution of 4-(2-naphthyloxy)benzyl alcohol (239 mg, 0.95
mmol) and CBr4 (633 mg, 1.91 mmol) in dry ether (5 mL) at
room temperature, and the resulting mixture was stirred for
40 min at room temperature. Water was poured into the
reaction mixture, and the products were extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4,
and concentrated. Purification by silica gel column chroma-
tography (hexane-EtOAc, 50:1) gave 21 (300 mg, 100% yield)
as a white solid: 1H NMR (CDCl3) δ 4.61 (s, 2 H), 7.02-7.06
(m, 2 H), 7.23-7.26 (m, 2 H), 7.35-7.49 (m, 4 H), 7.71-7.74
(m, 1 H), 7.82-7.86 (m, 2 H).
2-(4-(2-Na p h th yloxy)p h en yl)p r op ion ic Acid (23). n-
BuLi (1.66 M in hexane, 0.72 mL, 1.2 mmol) was added to a
solution of diisopropylamine (121 mg, 1.2 mmol) in THF (5
mL) at -70 °C. After the mixture stirred at -70 °C for 1 h, a
solution of 22 (292 mg, 1.0 mmol) in THF (3 mL) was added
to the reaction mixture followed by stirring for 1.5 h at -70
°C. The reaction mixture was treated with MeI (170 mg, 1.2
mmol) and stirred for 2 h at -70 °C. It was allowed to warm
to -10 °C. Stirring was continued until the reaction was
completed. The resulting reaction was quenched with satu-
rated NH4Cl, and the products were extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4,
and evaporated. The resultant mixture was purified by
column chromatography on silica gel (hexane-EtOAc, 100:1-
20:1) to give the methyl ester of 23 as a pale yellowish oil (226
mg, 74% yield). A solution of this compound (138 mg, 0.45
mmol) in MeOH-THF (4/8 mL) was treated with 4 N LiOH
(1.1 mL, 4.5 mmol) and stirred overnight at room temperature.
The reaction mixture was acidified to pH 1 with 5 N HCl (2
mL) and stirred for 30 min at room temperature. The mixture
was poured onto water, and the products were extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated. Purification by silica gel column
chromatography (hexane-EtOAc-AcOH, 100:100:1) gave 23
as a foam (103 mg) in a total 58% yield from 22: 1H NMR
(CDCl3) δ 1.53 (d, J ) 7.3 Hz, 3 H), 3.76 (q, J ) 7.3 Hz, 1 H),
7.03 (d, J ) 8.6 Hz, 2 H), 7.23-7.33 (m, 4 H), 7.43 (dquint, J
) 1.6, 6.9 Hz, 2 H), 7.71 (d, J ) 7.6 Hz, 1 H), 7.80-7.85 (m, 2
H).
2-Meth yl-2-(4-(2-n a p h th yloxy)p h en yl)p r op ion ic Acid
(24). To a solution of diisopropylamine (92 mg, 0.91 mmol) in
THF (5 mL) was added n-BuLi (1.66 M in hexane, 0.55 mL,
0.91 mmol) at -70 °C. After the mixture had been stirred at
-70 °C for 0.5 h, a solution of the methyl ester of 23 (233 mg,
0.76 mmol) in THF (3 mL) was added to the reaction mixture
followed by stirring for 1 h at -70 °C. The reaction mixture
was then treated with MeI (130 mg, 0.91 mmol) and stirred
for 2 h at -70 °C. It was allowed to warm to -15 °C, and
stirring was continued at this temperature for 2 h. The
resulting reaction was subsequently quenched with saturated
NH4Cl; then the products were extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
evaporated. The residue was purified by column chromatog-
raphy on silica gel (hexane-EtOAc, 100:1-50:1) to give the
methyl ester of 24 (194 mg, 80% yield) as a pale yellow oil. A
solution of this compound (248 mg, 0.77 mmol) in MeOH-THF
(4/8 mL) was treated with 4 N LiOH (1.9 mL, 7.7 mmol) and
stirred overnight at room temperature. The reaction mixture
was acidified to pH 1 with 5 N HCl and stirred for 45 min at
room temperature. The mixture was poured onto water, and
the products were extracted with EtOAc. The organic layer
was washed with brine, dried over Na2SO4, and evaporated.
Purification by silica gel column chromatography (hexane-
EtOAc-AcOH, 100:100:1) gave 24 (203 mg) as a white solid
in a total 69% yield from the methyl ester of 23: 1H NMR
(CDCl3) δ 1.63 (s, 6 H), 7.03 (d, J ) 8.9 Hz, 2 H), 7.24-7.28
(m, 1 H), 7.34-7.49 (m, 5 H), 7.72 (d, J ) 8.9 Hz, 1 H), 7.81-
7.85 (m, 2 H).
it was treated with methyl 4-formylbenzoate (2.95 g, 18 mmol)
and stirred overnight at room temperature. The reaction was
quenched with saturated NH4Cl, and the products were
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and evaporated. Purification by
silica gel column chromatography (hexane-EtOAc, 10:1-5:1)
gave 26 (4.67 g, 89%) as a slightly yellowish liquid: 1H NMR
(CDCl3) δ 2.38 (d, J ) 3.6 Hz, 1 H), 3.90 (s, 3 H), 6.05 (d, J )
3.3 Hz, 1 H), 7.39-7.53 (m, 5 H), 7.79-7.86 (m, 4 H), 8.01 (d,
J ) 8.6 Hz, 2 H).
4-(2-Na p h th oyl)ben zoic Acid (27). To a solution of 26
(496 mg, 1.70 mmol) in dry CH2Cl2 was added pyridinium
chlorochromate (PCC) (0.55 g, 2.5 mmol), and the mixture was
stirred for 2 h at room temperature. The reaction mixture was
filtered on short-pass column chromatography on silica gel
using CH2Cl2 as an eluent. A mixture of ether (10 mL) and
hexane (10 mL) was poured into the concentrated filtrate. The
precipitate was collected on the filter to afford the methyl ester
of 27 (312 mg, 63%). A solution of this compound (290 mg,
1.0 mmol) in MeOH-THF (2/4 mL) was treated with 4 N LiOH
(2.5 mL, 10 mmol) and stirred overnight at room temperature.
The reaction mixture was acidified to pH 1 with 5 N HCl and
stirred for 30 min at room temperature. The mixture was
poured onto water and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and evapo-
rated. Recrystallization from CH3CN gave 27 (191 mg, total
43% yield from 26) as a white crystal: 1H NMR (CDCl3) δ
7.55-7.68 (m, 2 H), 7.92-8.00 (m, 6 H), 8.25-8.28 (m, 3 H).
4-(2-Na p h th ylm eth yl)ben zoic Acid (28).22 To a solution
of 26 (292 mg, 1.0 mmol) in CF3CO2H (1.2 mL) was added
triethylsilane (349 mg, 3.0 mmol), and the mixture was stirred
overnight at room temperature. The reaction mixture was
poured onto aqueous NaHCO3, and the products were ex-
tracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and evaporated. Purification by silica gel
column chromatography (using hexane-EtOAc, 30:1, as an
eluent) gave the methyl ester of 28 (250 mg, 90%) as a white
solid. A solution of this compound (249 mg, 0.9 mmol) in
MeOH-THF (3/6 mL) was treated with 4 N LiOH (2.3 mL,
9.0 mmol) and stirred overnight. The reaction mixture was
acidified to pH 1 with 5 N HCl and stirred for 30 min at room
temperature. The mixture was poured onto water and ex-
tracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and evaporated. Recrystallization from
CH3CN gave 28 (196 mg, total 75% yield from 26) as a white
crystal: 1H NMR (CDCl3) δ 4.21 (s, 2 H), 7.25-7.35 (m, 3 H),
7.42-7.49 (m, 2 H), 7.64 (s, 1 H), 7.76-7.83 (m, 3 H), 8.03 (d,
J ) 8.3 Hz, 2 H).
P r ep a r a tion of 2-((4-(2-Na p h th yloxy)p h en yl)a ceta m i-
d o)ben zoic Acid (31). Gen er a l P r oced u r e B. To a solution
of 6 (19.49 g, 70 mmol) in CH2Cl2 (350 mL) was added oxalyl
chloride (9.8 g, 77 mmol) dropwise at room temperature. After
the addition of DMF (10 drops), stirring was continued for 1 h
at 35 °C. The reaction mixture was concentrated, and to a
solution of the residue in dry CH2Cl2 (200 mL) was added a
solution of methyl anthranilate (10.6 g, 70 mmol) and triethyl-
amine (7.8 g, 77 mmol) in dry CH2Cl2 (200 mL) at 0 °C. The
reaction mixture was stirred for 1.5 h at 0 °C and then
overnight at room temperature. After the reaction mixture
had been poured onto water, the products were extracted with
CH2Cl2. The organic layer was washed with brine, dried over
Na2SO4, and concentrated. Purification by silica gel column
chromatography (hexane-EtOAc, 20:1-5:1) gave the methyl
ester of 31 (23.5 g, 57 mmol) as a yellow liquid. A solution of
this compound (23.5 g, 82%) in MeOH/THF (100/200 mL) was
treated with 4 N LiOH (71 mL, 290 mmol) and stirred
overnight at room temperature. The reaction mixture was
acidified to pH 1 with 5 N HCl and stirred for 30 min at room
temperature. The mixture was poured onto water and ex-
tracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and evaporated. Recrystallization from
CH3CN gave 31 (10.0 g, total 37% yield from 6) as white
needles: mp 173.5 °C; 1H NMR (DMSO-d6) δ 3.80 (s, 2 H),
7.04 (t, J ) 7.6 Hz, 1 H), 7.09-7.14 (m, 2 H), 7.21-7.29 (m, 2
H), 7.34-7.45 (m, 4 H), 7.54-7.65 (m, 2 H), 7.76 (d, J ) 8.6
Hz, 2 H), 8.07 (dd, J ) 1.7, 7.9 Hz, 1 H), 8.76 (dd, J ) 1.0, 8.6
Meth yl 4-(Hyd r oxy(2-n a p h th yl)m eth yl)ben zoa te (26).21
A mixture of Mg (0.53 g, 22 mmol) in dry THF (20 mL) was
heated at 50 °C with stirring. To the mixture was added a
solution of 2-bromonaphthalene (4.14 g, 20 mmol) in THF (20
mL) over a period of 1 h. The reaction mixture was heated to
reflux with stirring for 3 h. After cooling to room temperature,

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404 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Hasegawa et al.
Hz, 1 H), 10.74 (br s, 1 H); 13C NMR (DMSO-d6) δ 43.8, 113.4,
116.4, 119.1, 119.6, 119.9, 122.7, 124.7, 126.6, 127.0, 127.6,
129.7, 130.0, 130.1, 131.0, 131.3, 133.9, 134.0, 140.7, 154.7,
155.5, 169.3, 169.6; IR (neat) 2922, 1671, 1586, 1505, 1451,
2.5 mmol) in MeOH-THF (40/40 mL) was treated with 4 N
LiOH solution (8 mL, 32 mmol) and stirred overnight at room
temperature. The reaction mixture was acidified to pH 1 with
5 N HCl and stirred for 30 min at room temperature. The
mixture was then poured onto water and extracted with
EtOAc. The organic layer was washed with brine, dried over
1402, 1296, 1250, 1227, 1165, 1088, 963, 754 cm-1
(C25H19NO4) C, H, N.
. Anal.
2-(4-(2-Naph th yloxy)ben zam ido)ben zoic Acid (29). Fol-
lowing the same procedure as described for the preparation
of 31, but using 5 instead of 6, compound 29 was prepared via
15 as while needles recrystallized from CH3CN in 74% yield:
mp 213.0-213.5 °C; 1H NMR (DMSO-d6) δ 7.16-7.25 (m, 3
H), 7.36 (dd, J ) 2.3, 8.9 Hz, 1 H), 7.45-7.68 (m, 4 H), 7.87-
8.08 (m, 6 H), 8.69 (d, J ) 7.6 Hz, 1 H), 12.15 (br s, 1 H), 13.75
(br s, 1 H); 13C NMR (DMSO-d6) δ 115.4, 116.5, 118.1, 119.9,
120.1, 122.8, 125.3, 126.8, 127.2, 127.7, 129.2, 129.4, 130.3,
130.4, 131.2, 133.9, 134.3, 141.2, 153.1, 160.2, 164.0, 170.0;
IR (KBr) 1663, 1611, 1505, 1393, 1302, 1223, 1173, 847, 748,
685, 530, 469 cm-1. Anal. (C24H17NO4) C, H, N.
Na2SO4, and evaporated. Recrystallization from CH3CN gave
35 (784 mg, total 73% yield from 13) as a white crystal: mp
250.5-251.0 °C; 1H NMR (DMSO-d6) δ 7.05-7.20 (m, 6 H),
7.24 (s, 1 H), 7.60 (dt, J ) 2.0, 9.0 Hz, 1 H), 7.74 (dd, J ) 9.0,
13.0 Hz, 2 H), 7.95 (d, J ) 8.9 Hz, 2 H), 8.03 (dd, J ) 1.7, 8.0
Hz, 1 H), 8.28 (d, J ) 9.0 Hz, 1 H), 9.70 (s, 1 H), 12.2 (br s, 1
H), 13.7 (br s, 1 H); 13C NMR (DMSO-d6) δ 108.8, 116.2, 116.4,
117.4, 119.4, 119.8, 120.5, 122.8, 128.2, 128.4, 128.7, 128.8,
129.3, 131.3, 132.0, 134.3, 141.2, 150.3, 155.0, 160.9, 164.0,
170.0. Anal. (C24H17NO5) C, H, N.
2-((4-((6-(Ben zyloxy)-2-n a p h th yl)oxy)p h en yl)a ceta m i-
d o)ben zoic Acid (36). Following the same procedure as
described for the preparation of 31, but using 7 instead of 6,
compound 36 was prepared as pale yellow granules recrystal-
lized from CH3CN in 56% yield: mp 210.0-210.5 °C; 1H NMR
(DMSO-d6) δ 3.74 (s, 2 H), 5.20 (s, 2 H), 7.02 (d, J ) 8.6 Hz, 2
H), 7.12 (t, J ) 7.3 Hz, 1 H), 7.20-7.27 (m, 2 H), 7.30-7.58
(m, 10 H), 7.75 (d, J ) 8.9 Hz, 1 H), 7.83 (d, J ) 8.9 Hz, 1 H),
7.95 (dd, J ) 1.3, 7.9 Hz, 1 H), 8.50 (d, J ) 7.9 Hz, 1 H), 12.0
(br s, 1 H); 13C NMR (DMSO-d6) δ 43.8, 69.3, 107.5, 114.2,
116.4, 118.6, 119.4, 119.8, 120.2, 122.7, 127.7, 127.8, 127.9,
128.4, 128.6, 128.8, 129.2, 129.7, 130.9, 131.0, 131.2, 134.0,
2-(4-((2-Na p h th yloxy)m eth yl)ben za m id o)ben zoic Acid
(30). Following the same procedure as described for the
preparation of 31, but using 19 instead of 6, compound 30 was
prepared as white granules recrystallized from CH3CN in 51%
1
yield: mp 218.5-219.0 °C; H NMR (CDCl3) δ 5.28 (s, 2 H),
7.17-7.45 (m, 5 H), 7.63-7.80 (m, 6 H), 8.07 (d, J ) 8.6 Hz, 2
H), 8.15 (dd, J ) 1.7, 7.9 Hz, 1 H), 8.95-8.99 (m, 1 H), 11.90
(s, 1 H); 13C NMR (DMSO-d6) δ 68.6, 107.4, 116.5, 118.7, 119.9,
122.9, 123.7, 126.4, 126.7, 127.2, 127.4, 127.5, 127.9, 128.6,
129.4, 131.3, 134.0, 134.1, 134.3, 141.1, 141.2, 141.3, 156.0,
164.4, 170.0. Anal. (C25H19NO4) C, H, N.
136.9, 140.7, 152.7, 155.5, 156.0, 169.3, 169.6. Anal. (C32H25
NO5) C, H, N.
-
2-(2-(4-(2-Na p h t h yloxy)p h e n yl)p r op ion a m id o)b e n -
zoic Acid (32). Following the same procedure as described
for the preparation of 31, but using 23 instead of 6, compound
32 was prepared as white needles recrystallized from CH3CN
in 36% yield: mp 185.0-185.5 °C; 1H NMR (DMSO-d6) δ 1.48
(d, J ) 6.9 Hz, 3 H), 3.88 (q, J ) 6.9 Hz, 1 H), 7.04-7.14 (m,
3 H), 7.28 (dd, J ) 2.3, 8.9 Hz, 1 H), 7.39-7.59 (m, 6 H), 7.80
(d, J ) 7.6 Hz, 1 H), 7.90 (dd, J ) 1.3, 7.6 Hz, 1 H), 7.95 (d, J
2-(4-(2-Naph th ylth io)ben zam ido)ben zoic Acid (37). Fol-
lowing the same procedure as described for the preparation
of 31, but using 8 instead of 6, compound 37 was obtained as
white needles recrystallized from 2-propanol in 76% yield: mp
1
238.5-239.0 °C; H NMR (CDCl3) δ 7.15 (t, J ) 7.6 Hz, 1 H),
7.34 (d, J ) 8.6 Hz, 2 H), 7.49-7.65 (m, 4 H), 7.80-7.92 (m, 5
H), 8.04 (s, 1 H), 8.13 (dd, J ) 2.0, 8.3 Hz, 1 H), 8.93 (d, J )
8.3 Hz, 1 H), 11.84 (br s, 1 H); 13C NMR (DMSO-d6) δ 116.6,
119.9, 122.9, 126.9, 127.0, 127.6, 127.7, 128.0, 128.4, 129.2,
129.5, 129.6, 131.2, 132.2, 132.3, 132.4, 133.4, 134.2, 141.0,
141.7, 164.0, 170.0. Anal. (C24H17NO3S) C, H, N.
) 8.2 Hz, 2 H), 8.52 (d, J ) 7.6 Hz, 1 H), 11.28 (br s, 1 H); 13
C
NMR (DMSO-d6) δ 18.5, 47.2, 114.0, 116.5, 119.3, 119.9, 120.0,
122.9, 125.1, 126.9, 127.3, 127.9, 129.5, 130.1, 130.4, 131.4,
134.2, 134.4, 136.5, 141.2, 154.7, 155.9, 169.8, 172.8. Anal.
(C26H21NO4) C, H, N.
2-(4-(2-Na p h th ylm eth yl)ben za m id o)ben zoic Acid (38).
Following the same procedure as described for the preparation
of 31, but using 28 instead of 6, compound 38 was obtained
as white needles recrystallized from CH3CN in 79% yield: mp
2-(2-Met h yl-2-(4-(2-n a p h t h yloxy)p h en yl)p r op ion a m i-
d o)ben zoic Acid (33). Following the same procedure as
described for the preparation of 31, but using 24 instead of 6,
compound 33 was prepared as white needles recrystallized
from CH3CN in 65% yield: mp 211.5-212.0 °C; 1H NMR
(DMSO-d6) δ 1.61 (s, 6 H), 7.07 (d, J ) 8.6 Hz, 2 H), 7.11 (t, J
) 7.3 Hz, 1 H), 7.28 (dd, J ) 1.6, 8.9 Hz, 1 H), 7.40-7.52 (m,
5 H), 7.58 (dt, J ) 1.7, 6.9 Hz, 1 H), 7.80 (d, J ) 7.9 Hz, 1 H),
7.90-7.97 (m, 3 H), 8.62 (d, J ) 8.6 Hz, 1 H), 11.25 (br s, 1
H), 13.62 (br s, 1 H); 13C NMR (DMSO-d6) δ 26.6, 47.5, 113.7,
115.6, 118.8, 119.2, 119.7, 122.4, 124.8, 126.6, 127.0, 127.6,
127.8, 129.8, 130.1, 131.1, 133.9, 134.2, 139.8, 141.3, 154.4,
155.3, 169.9, 175.3. Anal. (C27H23NO4) C, H, N.
2-(3-(4-(2-Na p h t h yloxy)p h e n yl)p r op ion a m id o)b e n -
zoic Acid (34). Following the same procedure as described
for the preparation of 31, but using 17 instead of 6, compound
34 was prepared as white needles recrystallized from CH3CN
in 62% yield: mp 168.0-168.5 °C; 1H NMR (CDCl3) δ 2.78 (t,
J ) 7.9 Hz, 2 H), 3.09 (t, J ) 7.9 Hz, 2 H), 6.97-7.02 (m, 2 H),
7.12 (dt, J ) 1.0, 7.3 Hz, 1 H), 7.20-7.27 (m, 4 H), 7.41 (dquint,
J ) 1.3, 6.9 Hz, 2 H), 7.57-7.68 (m, 2 H), 7.80 (d, J ) 8.9 Hz,
2 H), 8.10 (dd, J ) 1.7, 7.9 Hz, 1 H), 8.76 (dd, J ) 1.0, 8.6 Hz,
1 H), 10.87 (br s, 1 H); 13C NMR (DMSO-d6) δ 29.9, 39.0, 113.1,
116.4, 118.7, 119.0, 119.5, 119.9, 122.5, 124.7, 126.6, 127.0,
127.6, 129.6, 129.9, 130.0, 130.2, 131.0, 133.9, 134.0, 136.1,
140.7, 154.6, 154.8, 169.5, 170.4. Anal. (C26H21NO4) C, H, N.
2-(4-((6-Hyd r oxy-2-n a p h t h yl)oxy)b en za m id o)b en zoic
Acid (35). Compound 7 was converted to 13 by reaction with
methyl anthranilate in the same procedure as described for
the preparation of 31. A solution of 13 (1.35 g, 2.7 mmol) in
THF (50 mL) was hydrogenated in the presence of 10% Pd/C
(330 mg) at room temperature. Stirring overnight, filtration
through Celite, and concentration provided the methyl ester
of 35 (1.04 g, 2.5 mmol). A solution of this compound (1.04 g,
1
221.0-222.0 °C; H NMR (CDCl3) δ 4.22 (s, 2 H), 7.15 (t, J )
8.3 Hz, 1 H), 7.24-7.50 (m, 5 H), 7.63-7.69 (m, 2 H), 7.77-
7.83 (m, 3 H), 7.96 (d, J ) 8.6 Hz, 2 H), 8.14 (dd, J ) 1.7, 7.9
Hz, 1 H), 8.96 (d, J ) 7.9 Hz, 1 H), 11.80 (br s, 1 H); 13C NMR
(DMSO-d6) δ 40.9, 116.3, 119.8, 122.8, 125.5, 126.1, 126.8,
127.3, 127.4, 127.5, 128.1, 129.3, 131.2, 131.6, 132.3, 132.4,
133.1, 134.3, 138.1, 141.2, 145.7, 164.4, 169.8. Anal. (C25H19
NO3) C, H, N.
-
2-(4-(2-Na p h th oyl)ben za m id o)ben zoic Acid (39). Fol-
lowing the same procedure as described for the preparation
of 31, but using 27 instead of 6, compound 39 was prepared
as pale yellow needles recrystallized from CH3CN in 62%
1
yield: mp 242.0-243.0 °C; H NMR (CDCl3) δ 7.18-7.24 (m,
1 H), 7.58-7.70 (m, 3 H), 7.92-8.01 (m, 6 H), 8.17 (d, J ) 8.6
Hz, 3 H), 8.28 (s, 1 H), 8.99 (d, J ) 8.3 Hz, 1 H), 12.04 (br s,
1 H); 13C NMR (DMSO-d6) δ 116.9, 120.1, 123.3, 125.1, 127.1,
127.3, 127.7, 128.5, 128.8, 129.7, 130.1, 131.3, 131.8, 131.9,
133.7, 134.2, 134.3, 134.9, 137.5, 140.3, 140.6, 140.8, 164.0,
169.9, 195.2. Anal. (C25H17NO4) C, H, N.
2-(3-Nitr o-4-(2-n a p h th yloxy)ben za m id o)ben zoic Acid
Hem ih yd r a te (40). Following the same procedure as de-
scribed for the preparation of 31, but using 20 instead of 6,
compound 40 was prepared as a white solid recrystallized from
1
CH3CN in 33% yield: mp 241.0-242.0 °C; H NMR (DMSO-
d6) δ 7.24 (t, J ) 7.2 Hz, 1 H), 7.34 (d, J ) 8.5 Hz, 1 H), 7.43
(dd, J ) 2.6, 4.5 Hz, 1 H), 7.50-7.60 (m, 2 H), 7.60-7.70 (m,
2 H), 7.95 (dd, J ) 8.1, 14.6 Hz, 2 H), 8.06 (dd, J ) 7.6, 8.0
Hz, 2 H), 8.20-8.25 (m, 1 H), 8.60-8.70 (m, 2 H), 12.3 (br s,
1 H); 13C NMR (DMSO-d6) δ 115.9, 117.5, 119.9, 120.6, 120.7,
121.0, 123.8, 125.2, 126.0, 127.3, 127.7, 128.1, 129.8, 131.0,

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Naphthalene Inhibitors of IgE Antibody Production
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4 405
131.5, 133.8, 134.1, 134.6, 140.6, 140.7, 152.7, 152.9, 162.4,
170.2. Anal. (C24H16N2O6‚0.5H2O) C, H, N.
treatment with DMF (1 drop). After the reaction mixture had
been stirred for 2 h at 35 °C, it was concentrated. To a solution
of the residue in dry CH2Cl2 (7 mL) was added a solution of
2-aminobenzamide (68 mg, 0.5 mmol) and triethylamine (56
mg, 0.55 mmol) in dry CH2Cl2 (5 mL). It was stirred overnight
at room temperature. The reaction mixture was poured onto
water, and the products were extracted with CH2Cl2. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. The residue was recrystallized from CH3CN to
afford 44 (144 mg, 75%) as white crystals: mp 199.5-200.5
°C; 1H NMR (CDCl3) δ 5.66 (br s, 1 H), 6.22 (br s, 1 H), 7.09-
7.16 (m, 3 H), 7.29-7.30 (m, 1 H), 7.42-7.61 (m, 5 H), 7.74-
7.77 (m, 1 H), 7.84-7.90 (m, 2 H), 8.01-8.06 (m, 2 H), 8.87
(dd, J ) 1.3, 8.9 Hz, 1 H), 12.22 (br s, 1 H); 13C NMR (DMSO-
d6) δ 115.2, 118.2, 119.1, 120.0, 120.1, 122.5, 125.2, 126.7,
127.2, 127.7, 128.7, 129.3, 129.4, 130.2, 130.3, 132.5, 133.9,
140.2, 153.2, 160.0, 163.7, 171.2. Anal. (C24H18N2O3) C, H,
N.
2-((4-(2-Na p h th yloxy)ben zyl)a m in o)ben zoic Acid (41).
To a solution of 21 (313 mg, 1.0 mmol) in dry DMF (3 mL)
were added methyl anthranilate (151 mg, 1.0 mmol), K2CO3
(207 mg, 1.5 mmol), and NaI (225 mg, 1.5 mmol) at room
temperature. The reaction mixture was heated at 120 °C with
stirring overnight. Water was poured into the reaction
mixture, and the products were extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. Purification by silica gel column chromatogra-
phy (hexane-EtOAc, 100:1-50:1) gave the methyl ester of 41
(222 mg, 58%). A solution of this compound (220 mg, 0.57
mmol) in MeOH-THF (3/6 mL) was treated with 4 N LiOH
solution (1.4 mL, 5.7 mmol) and stirred overnight at room
temperature. The reaction mixture was acidified to pH 1 with
5 N HCl and stirred for 30 min at room temperature. The
mixture was poured onto water and extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
evaporated. Recrystallization from CH3CN gave 41 (166 mg,
total 44% yield from 21) as a pale yellow crystal: mp 194.5-
195.5 °C; 1H NMR (CDCl3) δ 4.46 (s, 2 H), 6.66 (t, J ) 8.6 Hz,
2 H), 7.02-7.14 (m, 2 H), 7.23-7.54 (m, 7 H), 7.70 (d, J ) 7.6
Hz, 1 H), 7.76-7.92 (m, 3 H), 7.99 (d, J ) 7.9 Hz, 1 H); 13C
NMR (DMSO-d6, 600 MHz) δ 45.9, 112.3, 114.2, 114.3, 115.4,
119.1, 119.5, 120.3, 125.7, 127.5, 127.7, 128.3, 129.6, 130.4,
130.9, 132.4, 133.5, 134.5, 135.0, 135.3, 151.1, 155.1, 156.2,
170.9. Anal. (C24H19NO3) C, H, N.
2-(N-Meth yl-4-(2-n aph th yloxy)ben zam ido)ben zoic Acid
(42). To a solution of 29 (77 mg, 0.20 mmol) in CH2Cl2 and
MeOH (3/3 mL) was added (trimethylsilyl)diazomethane (in
hexane, 2 M) with stirring at room temperature until the color
of the reaction mixture turned yellow. After concentration, a
solution of the residue (15) in THF (5 mL) was treated with
MeI (86 mg, 0.60 mmol) and NaH (60% in fossil oil, 12 mg,
0.30 mmol) at room temperature. Stirring was continued for
4.5 h at room temperature. The reaction mixture was poured
onto water, and the products were extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4, and
concentrated. Purification by silica gel column chromatogra-
phy (hexane-EtOAc, 3:1-2:1) gave the methyl ester of 42 (42
mg, 51% yield) as colorless liquid. A solution of this compound
(42 mg, 0.10 mmol) in MeOH-THF (2/4 mL) was treated with
4 N LiOH (0.3 mL, 1.2 mmol) and stirred for 2.5 h at room
temperature and for 2.5 h at 50 °C. The reaction mixture was
acidified to pH 1 with 5 N HCl and stirred for 30 min at room
temperature. The mixture was poured onto water, and the
products were extraced with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated. Ether
was added to the residue, and the resulting solid was collected
to give 42 (total 28% yield from 29, 22 mg) as a white solid:
mp 166.0-167.0 °C; 1H NMR (CDCl3) δ 3.45 (s, 3 H), 6.79 (br
s, 1 H), 7.13-7.57 (m, 10 H), 7.67 (d, J ) 6.9 Hz, 1 H), 7.79 (d,
J ) 7.6 Hz, 2 H), 7.90-8.00 (m, 1 H); 13C NMR (DMSO-d6) δ
37.7, 114.2, 117.5, 119.7, 125.0, 126.7, 127.0, 127.3, 127.6,
129.1, 129.9, 130.0, 130.1, 130.2, 130.9, 131.3, 132.8, 132.9,
133.8, 144.2, 153.8, 157.2, 166.7. Anal. (C25H19NO4) H, N; C:
calcd, 75.6; found, 75.1.
2-(4-(2-Na p h th yloxy)ben za m id o)a n ilin e (45). To a sus-
pension of 5 (132 mg, 0.50 mmol) in dry CH2Cl2 (5 mL) was
added oxalyl chloride (70 mg, 0.55 mmol) followed by treatment
with DMF (1 drop). The reaction mixture was concentrated
after having been stirred for 2 h at 35 °C. A solution of the
residue in dry CH2Cl2 (7 mL) was added to a solution of 1,2-
phenylenediamine (162 mg, 1.5 mmol) and triethylamine (56
mg, 0.55 mmol) in dry CH2Cl2 (5 mL) over a period of 3 min.
After having been stirred overnight at room temperature, the
reaction mixture was poured onto water, and the products
were extracted with CH2Cl2. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. The residue
was purified by column chromatography on silica gel (hexane-
EtOAc, 3:1-2:1) to afford 45 (35 mg, 20%) as a pale yellow
solid: mp 204.5-206.5 °C; 1H NMR (DMSO-d6) δ 4.98 (br s, 2
H), 6.69 (t, J ) 7.9 Hz, 1 H), 6.87 (d, J ) 7.9 Hz, 1 H), 7.06 (t,
J ) 7.9 Hz, 1 H), 7.25 (d, J ) 8.9 Hz, 3 H), 7.43 (dd, J ) 2.6,
8.9 Hz, 1 H), 7.54-7.64 (m, 3 H), 7.96 (d, J ) 8.9 Hz, 1 H),
8.05 (d, J ) 8.9 Hz, 1 H), 8.08-8.15 (m, 3 H), 9.73 (s, 1 H); 13
C
NMR (DMSO-d6) δ 114.9, 116.1, 116.2, 117.8, 120.0, 123.3,
125.2, 126.5, 126.7, 126.8, 127.2, 127.7, 129.5, 130.1, 130.2,
130.3, 133.9, 143.2, 153.6, 159.5, 164.5. Anal. (C23H18N2O2)
C, H, N.
2-(4-P h en oxyben za m id o)ben zoic Acid (46). Following
the same procedure as described for the preparation of 31, but
using 4-(phenyloxy)benzoic acid instead of 6, compound 46 was
prepared as white needles recrystallized from CH3CN in 48%
1
yield: mp 197.0-197.5 °C; H NMR (DMSO-d6) δ 7.12-7.26
(m, 6 H), 7.42-7.50 (m, 2 H), 7.65 (t, J ) 8.6 Hz, 1 H), 7.97 (d,
J ) 8.9 Hz, 2 H), 8.05 (dd, J ) 1.7, 7.9 Hz, 1 H), 8.69 (d, J )
7.9 Hz, 1 H), 12.13 (br s, 1 H), 13.77 (br s, 1 H); 13C NMR
(DMSO-d6) δ 116.26, 116.37, 117.74, 119.75, 122.79, 124.55,
128.97, 129.29, 130.28, 131.25, 134.29, 141.24, 155.26, 160.31,
163.94, 170.5. Anal. (C20H15NO4) C, H, N.
2-(4-(1-Naph th yloxy)ben zam ido)ben zoic Acid (47). Fol-
lowing the same procedure as described for the preparation
of 31, but using 9 instead of 6, compound 47 was prepared as
white needles recrystallized from CH3CN in 37% yield: mp
1
217.5-218.5 °C; H NMR (DMSO-d6) δ 7.00 (t, J ) 7.2 Hz, 1
H), 7.11 (d, J ) 8.9 Hz, 2 H), 7.18 (d, J ) 8.0 Hz, 1 H), 7.34 (t,
J ) 8.3 Hz, 1 H), 7.50-7.61 (m, 3 H), 7.82 (d, J ) 8.2 Hz, 1
H), 7.90-8.10 (m, 5 H), 8.64 (d, J ) 8.3 Hz, 1 H), 12.2 (br s, 1
H); 13C NMR (DMSO-d6) δ 115.5, 117.1, 118.4, 121.3, 121.6,
123.6, 124.6, 126.2, 126.6, 126.8, 128.1, 129.4, 129.9, 130.7,
1-(4-(2-Na p h t h yloxy)b en za m id o)-2-(1H-t et r a zol-5-yl)-
ben zen e (43). A suspension of 14 (109 mg, 0.3 mmol), NH4-
Cl (48 mg, 0.9 mmol), and NaN3 (59 mg, 0.9 mmol) in dry DMF
(3 mL) was heated with stirring at 80 °C for 24 h. The reaction
mixture was poured onto iced aqueous HCl. The products were
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, and concentrated. Recrystallization
from CH3CN yielded 43 (92 mg, 75%) as a colorless crystal:
131.4, 134.7, 141.0, 150.8, 160.4, 163.5, 170.9. Anal. (C24H17
NO4) C, H, N.
-
2-(3-(2-Naph th yloxy)ben zam ido)ben zoic Acid (48). Fol-
lowing the same procedure as described for the preparation
of 31, but using 10 instead of 6, compound 48 was prepared
1
mp 223.5-224.0 °C; H NMR (CD3OD) δ 7.15-7.21 (m, 2 H),
1
7.27-7.35 (m, 2 H), 7.43-7.53 (m, 3 H), 7.57-7.63 (m, 1 H),
7.78-8.01 (m, 4 H), 8.14-8.19 (m, 2 H), 8.76-8.81 (m, 1 H);
13C NMR (DMSO-d6) δ 114.1, 115.7, 118.3, 120.5, 122.4, 124.5,
125.6, 127.1, 127.6, 128.0, 128.9, 129.4, 130.0, 130.6, 130.7,
132.1, 134.2, 137.5, 153.4, 160.6, 164.6. Anal. (C24H17N5O2)
C, H, N.
as a white solid in 43% yield: mp 180.0-181.0 °C; H NMR
(DMSO-d6) δ 7.01 (t, J ) 7.4 Hz, 1 H), 7.20-7.40 (m, 3 H),
7.40-7.55 (m, 3 H), 7.58 (t, J ) 7.9 Hz, 1 H), 7.69 (s, 1 H),
7.85 (d, J ) 7.6 Hz, 1 H), 7.92 (d, J ) 1.7 Hz, 1 H), 7.95 (s, 1
H), 8.00 (d, J ) 8.9 Hz, 1 H), 8.05 (d, J ) 8.6 Hz, 1 H), 8.62 (d,
J ) 7.9 Hz, 1 H), 12.1 (br s, 1 H); 13C NMR (DMSO-d6) δ 114.1,
117.5, 118.5, 119.8, 121.8, 121.9, 122.0, 123.5, 125.0, 126.7,
127.2, 127.7, 130.0, 130.3, 130.5, 130.9, 131.4, 133.9, 137.4,
140.8, 154.1, 157.1, 163.3, 170.6. Anal. (C24H17NO4) C, H, N.
2-(4-(2-Na p h th yloxy)ben za m id o)ben za m id e (44). To a
suspension of 5 (132 mg, 0.50 mmol) in dry CH2Cl2 (5 mL)
was added oxalyl chloride (70 mg, 0.55 mmol) followed by

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406 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 4
Hasegawa et al.
J .-Y.; Lecoanet-Henchoz, S.; Aubry, J .-P.; Gauchat, J .-F.; Graber,
P. CD23 and B-cell Activation. Curr. Opin. Immunol. 1995, 7,
355-359. (f) Nonoyama, S.; Hollenbaugh, D.; Aruffo, A.; Led-
better, J . A.; Ochs, H. D. B Cell Activation via CD-40 is Required
for Specific Antibody Production by Antigen-Stimulated Human
B Cells. J . Exp. Med. 1993, 178, 1097-1102. (g) Hollenbaugh,
D.; Ochs, H. D.; Noelle, R. J .; Ledbetter, J . A.; Aruffo, A. The
Role of CD40 and Its Ligand in the Regulation of the Immune
Response. Immunol. Rev. 1994, 138, 23-37.
3-(4-(2-Naph th yloxy)ben zam ido)ben zoic Acid (49). Fol-
lowing the same procedure as described for the preparation
of 31, but using 5 instead of 6 and methyl 3-aminobenzoate
instead of methyl anthranilate, compound 49 was prepared
in 48% yield as a white crystal (recrystallized from CH3CN-
1
2-propanol, 1:5): mp 278.0-279.0 °C; H NMR (DMSO-d6) δ
7.19 (d, J ) 8.6 Hz, 2 H), 7.35 (dd, J ) 2.3, 8.6 Hz, 1 H), 7.43-
7.56 (m, 4 H), 7.67 (d, J ) 7.3 Hz, 1 H), 7.87 (d, J ) 7.6 Hz, 1
H), 7.96 (d, J ) 7.6 Hz, 1 H), 8.01-8.08 (m, 4 H), 8.41 (s, 1 H),
10.37 (br s, 1 H); 13C NMR (DMSO-d6) δ 115.1, 117.8, 120.0,
121.1, 124.4, 125.2, 126.8, 127.2, 127.7, 128.8, 129.4, 130.0,
130.2, 130.3, 131.2, 133.9, 139.4, 153.4, 159.8, 164.8, 167.2.
Anal. (C24H17NO4) C, H, N.
(4) (a) Sato, T. A.; Widmer, M. B.; Finkelman, F. D.; Madani, H.;
J acobs, C. A.; Grabstein, K. H.; Maliszewski, C. R. Recombinant
Soluble Murine IL-4 Receptor Can Inhibit or Enhance IgE
Responses in Vivo. J . Immunol. 1993, 150, 2717-2723. (b)
Garrone, P.; Djossou, O.; Galizzi, J .-P.; Banchereau, J . A.
Recombinant Extracellular Domain of the Human Interleukin
4 Receptor Inhibits the Biological Effects of Interleukin 4 on T
and B Lymphocytes. Eur. J . Immunol. 1991, 21, 1365-1369.
(c) Rentz, H.; Enssle, K.; Lauffer, L.; Kurrle, R.; Galfand, E. W.
Inhibition of Allergen-Induced IgE and IgG1 Production by
Soluble IL-4 Receptor. Int. Arch. Allergy Immunol. 1995, 106,
46-54.
(5) (a) Carballido, J . M.; Schols, D.; Namikawa, R.; Zurawski, S.;
Zurawski, G.; Roncarolo, M.-G.; de Vries, J . E. IL-4 Induces
Human B Cell Maturation and IgE Synthesis in Scid-hu Mice.
Inhibition of Ongoing IgE Production by In Vivo Treatment with
an IL-4/IL-13 Receptor Antagonist. J . Immunol. 1995, 155,
4162-4170. (b) Aversa, G.; Punnonen, J .; Cocks, B. G.; Malefyt,
R. de W.; Vega, F., J r.; Zurawski, S. M.; Zurawski, G.; de Vries,
J . E. An Interleukin 4 (IL-4) Mutant Protein Inhibits both IL-4
or IL-13-Induced Human Immunoglobulin G4 (IgG4) and IgE
Synthesis and B Cell Proliferation: Support for a Common
Component Shared by IL-4 and IL-13 Receptors. J . Exp. Med.
1993, 178, 2213-2218.
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C.; Delespesse, G. Recombinant Interleukin-12 Suppresses the
Synthesis of Immunoglobulin E by Interleukin-4 Stimulated
Human Lymphocytes. J . Clin. Invest. 1992, 90, 262-266. (b)
Morris, S. C.; Madden, K. B.; Adamovicz, J . J .; Gause, W. C.;
Hubbard, B. R.; Gately, M. K.; Finkelman, F. D. Effects of IL-
12 on in Vivo Cytokine Gene Expression and Ig Isotype Selection.
J . Immunol. 1994, 152, 1047-1056.
(7) (a) Boguniewicz, M.; J affe, H. S.; Izu, A.; Sullivan, M. J .; York,
D.; Geha, R. S.; Leung, D. Y. M. Recombinant γ Interferon in
Treatment of Patients with Atopic Dermatitis and Elevated IgE
Level. Am. J . Med. 1990, 88, 365-370. (b) Pe´ne, J .; Rousset,
F.; Brie´re, F.; Chretien, I.; Bonnefoy, J .-Y.; Spits, H.; Yokota,
T.; Arai, N.; Banchereau, J .; De Vries, J . E. IgE Production by
Normal Human Lymphocytes Is Induced by Interleukin 4 and
Suppressed by Interferon γ and R and Prostaglandin E2. Proc.
Natl. Acad. Sci. U.S.A. 1988, 85, 6880-6884.
4-(4-(2-Na p h th yloxy)ben zoic Acid (50). Following the
same procedure as described for the preparation of 31, but
using 5 and methyl 4-aminobenzoate instead of 6 and methyl
anthranilate, respectively, compound 50 was prepared in 65%
yield as a white crystal: mp 293.5-294.5 °C; 1H NMR (DMSO-
d6) δ 7.19 (d, J ) 8.6 Hz, 2 H), 7.35 (d, J ) 8.9 Hz, 1 H), 7.46-
7.56 (m, 3 H), 7.86-8.06 (m, 9 H), 10.46 (s, 1 H); 13C NMR
(DMSO-d6) δ 115.1, 117.7, 119.4, 119.7, 120.0, 125.2, 125.4,
126.8, 127.2, 127.7, 129.3, 130.2, 130.3, 130.6, 130.7, 133.9,
143.3, 153.3, 159.9, 165.1, 166.9. Anal. (C24H17NO4) C, H, N.
2-((4-(2-Na p h t h yloxy)p h e n yl)a m in oc a r b on yl)b e n -
zoic Acid (51). To a solution of 18 (37 mg, 0.157 mmol) in
dry CH2Cl2 (5 mL) was added phthalic anhydride (23.5 mg,
0.157 mmol), and the mixture was stirred overnight at room
temperature. The reaction mixture was poured onto water,
and the products were extracted with CH2Cl2. The organic
layer was washed with brine, dried over Na2SO4, and concen-
trated. The residue was recrystallized from CH3CN to afford
51 (29 mg, 48%) as light brown needles: mp 176.0-178.0 °C;
1H NMR (DMSO-d6) δ 7.11 (d, J ) 8.8 Hz, 2 H), 7.29-7.31
(m, 2 H), 7.40-7.49 (m, 2 H), 7.55-7.60 (m, 2 H), 7.66 (d, J )
7.3 Hz, 1 H), 7.75 (d, J ) 9.3 Hz, 2 H), 7.82 (d, J ) 7.8 Hz, 1
H), 7.89 (t, J ) 6.8 Hz, 2 H), 7.95 (d, J ) 8.3 Hz, 1 H), 10.39
(br s, 1 H), 13.01 (br s, 1 H); 13C NMR (DMSO-d6) δ 112.3,
119.2, 119.8, 121.2, 124.6, 126.6, 127.0, 127.6, 127.7, 129.3,
129.5, 130.0, 131.6, 133.9, 135.7, 138.8, 151.5, 155.4, 167.2,
167.4. Anal. (C24H17NO4) C, H, N.
Ack n ow led gm en t. The authors wish to thank Dr.
Toshiaki Harada and Dr. Atsuo Hazato for helpful
discussions. We also acknowledge Dr. Takashi Kawa-
mura, Ms. Atsuko Mizumoto, and Mr. Naoki Hase for
their technical support.
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Inhibition of an in vivo Antigen-Specific IgE Response by
Antibodies to CD23. Science 1993, 261, 1038-1041.
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