Structure-activity relationships study of two series of leukotriene B4 antagonists: Novel indolyl and naphthyl compounds substituted with a 2- [methyl(2-phenethyl)amino]-2-oxoethyl side chain

Article abstract of DOI:10.1021/jm950699x

N-Methyl-N-phenethylphenylacetamide has been reported to be a key binding domain to LTB₄ receptors. Here we describe the synthesis and structure-activity relationship (SAR) studies of two new series of LTB₄ receptor antagonists in wh

Full text of DOI:10.1021/jm950699x

3756
J . Med. Chem. 1996, 39, 3756-3768
Str u ctu r e-Activity Rela tion sh ip s Stu d y of Tw o Ser ies of Leu k otr ien e B4
An ta gon ists: Novel In d olyl a n d Na p h th yl Com p ou n d s Su bstitu ted w ith a
2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl Sid e Ch a in
Wan K. Chan,*,† Fu-Chih Huang,† Matthew M. Morrissette,† J ames D. Warus,† Kevin J . Moriarty,†
Robert A. Galemmo,‡ William D. Dankulich,† Gregory Poli,† and Charles A. Sutherland§
Departments of Medicinal Chemistry and Inflammation Biology, Rhoˆne-Poulenc Rorer Central Research, 500 Arcola Road,
Collegeville, Pennsylvania 19426
Received September 25, 1995X
N-Methyl-N-phenethylphenylacetamide has been reported to be a key binding domain to LTB4
receptors. Here we describe the synthesis and structure-activity relationship (SAR) studies
of two new series of LTB4 receptor antagonists in which the phenyl ring of this receptor binding
domain is replaced with indole and naphthalene, respectively. Results of these studies indicate
that, in addition to the 2-[methyl(2-phenethyl)amino]-2-oxoethyl moiety, the presence of an
acid group and a lipophilic side chain, as well as the spatial relationship of these three functions,
is crucial for high binding affinity with LTB4 receptors. Our SAR studies also reveal that an
arenecarboxylic acid, or an enoic acid in which the carboxyl group is conjugated with the central
ring, is the preferred polar group. The lipophilic side chain of the naphthyl series was found
to tolerate minor variations, ranging from a phenylmethoxy group to phenyl and alkyloxy
groups. The most active compounds are 2-ethyl-3-[1-[2-[methyl(2-phenethyl)amino]-2-oxoethyl]-
5-(phenylmethoxy)indol-3-yl]propenoic acid (4g) of the indolyl series and 4-[2-[methyl(2-
phenethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)-2-naphthalenecarboxylic acid (2a ) or the
naphthyl series, with IC50 of 8 and 4.7 nM respectively, in the receptor binding assay using
intact human neutrophils.
In tr od u ction
Leukotriene B4 (LTB4, 1) is a metabolite of the
5-lipoxygenase arachidonic acid peroxidation pathway
and has been implicated as a mediator of inflammatory
diseases such as allergic asthma, psoriasis, gout, and
ulcerative colitis. Discovery of specific LTB4 receptor
antagonists as therapeutic agents for treatment of
LTB4-mediated diseases has been a topic of intense
research interest in recent years.1 We have reported
the synthesis RG 14893 (2a ), a potent competitive LTB4
receptor antagonist with oral inhibitory activity of the
chemotaxis of PNMs to the LTB4-induced wheals in
guinea pigs.2 In the preceding paper3 we have also
described the development and structure-activity re-
lationship study of a class of LTB4 antagonists based
on the phenylacetamide 3. Our study established that
three structural features, namely (a) the 2-[methyl(2-
phenethyl)amino]-2-oxoethyl side chain, (b) an acid
function, and (c) an additional lipophilic group, are
required for high binding affinity with LTB4 receptors.3
improved activity in binding assay using intact human
cells. In this report, we describe the synthesis and the
SAR studies of two series of high-affinity LTB4 receptor
antagonists based on the indolyl and naphthyl central
ring. This research effort eventually led to the discovery
of 2a .
In the phenylacetamide series of LTB4 receptor an-
tagonists, the central phenyl ring appears to mimic part
of the triene system of the natural ligand, LTB4, and to
act as template for the attached side chains. Thus, we
decided to investigate if other aromatic systems could
better serve these two functions. Moreover, since the
more active phenylacetamides were found to bind with
human LTB4 receptors with an IC50 of about 50 nM,3 it
was also our objective to develop novel compounds with
Ch em istr y
Most of the indoles listed in Table 1 are synthesized
according to Scheme 1. N-Methyl-N-phenethylbromoac-
etamide (9) was prepared from bromoacetyl bromide or
* Author to whom all correspondence should be addressed.
† Department of Medicinal Chemistry.
chloride and N-methyl-N-phenethylamine in the pres-
ence of triethylamine. Phosphonate esters (10) were
either obtained commercially or prepared from triphenyl
phosphite and the corresponding R-bromo ester.4 The
‡ Current address: Department of Medicinal Chemistry, Dupont-
Merck, Wilmington, DE 19880.
§ Department of Inflammation Biology.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(95)00699-6 CCC: $12.00 © 1996 American Chemical Society

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3757
Ta ble 1. LTB4 Receptor Binding Data of Substituted Indoles
IC50 (SEM (N), nM
compd
4a
4b
4c
4d
6a
7a
4e
4f
4g
4h
4i
R
R1
GP spleen
human intact PMN
3-CHdCHCO2H
3-CHdCHCO2H
3-CHdCHCO2H
3-CHdCHCO2H
3-CHO
3-CHdCHCO2Et
3-(CHdCH)2CO2H
3-CHdC(Me)CO2H
3-CHdC(Et)CO2H
3-CH2CH2CO2H
3-CH2CO2H
5-BnOa
6-BnO
7-BnO
4-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
5-BnO
4-BnO
4-BnO
4-BnO
4-BnO
4-BnO
4.3 ( 0.49 (20)
53 ( 34.5(17)
NTb
>300 (1)
>300 (1)
1.0 ( 0.25 (3)
NAc
16.5 ( 1.5(2)
>300 (1)
NT
80 (1)
>300 (1)
8 (1)
19.0 ( 9(2)
11.0 ( 2.1(6)
7.6 ( 1.7 (6)
NT
5 (1)
1.3 (1)
40 (1)
30 (1)
1.5 ( 0.5 (2)
5 (1)
2.5 ( 0.5 (3)
12 (1)
4.5 (1)
1.5 (1)
2.33 ( 0.34 (4)
1.5 (1)
2.5 (1)
1.45 ( 0.35 (2)
NT
4j
3-CO2H
3-CO2H
2-CO2H
26.3 ( 3.1 (3)
90 (1)
11.2 ( 2.8 (6)
8.5 (1)
19 (1)
4k (2-Me)
4l
4m
4n
4o
4p
4q
4r
4s
3-CO(C6H4-m-CO2H)
3-CHdCH(5-tetrazolyl)
3-(CHdCH)2CO2H
3-CHdC(Me)CO2H
3-CHdC(Et)CO2H
3-CH(Ph)CO2H
3-CO2H
15 (1)
24.5 ( 4.5 (2)
35 ( 5 (2)
19 (1)
20.3 ( 3.2 (3)
a
b
BnO ) phenylmethoxy. NT ) not tested. c NA ) no activity.
Ta ble 2. Binding Data of the Naphthyl Series of LTB4 Receptor Antagonists
IC50 ( SEM (N), nM
compd
R
R1
8-BnOa
7-BnO
1-BnO
8-BnO
8-BnO
8-BnO
8-BnO
GP spleen
human intact PMN
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
CO2H
CO2H
CO2H
0.36 ( 0.03 (25)
1.07 ( 0.33 (3)
6.5 (1)
4.7 ( 0.8 (5)
7.75 ( 1.52 (4)
80 (1)
3.55 ( 0.61 (10)
8 (1)
10 (1)
100 (1)
50 (1)
5 (1)
60 (1)
25 (1)
8.25 ( 1.44 (4)
700 (1)
9.0 ( 1.53 (3)
50 (1)
40 (1)
20 (1)
250 (1)
CHdCHCO2H
(CHdCH)2CO2H
(CH2)2CO2H
(CH2)4CO2H
CHdC(Et)CO2H
CHdCH-(5-tetrazolyl)
CON(Me)OH
CO2H
0.58 ( 0.07 (5)
1 (1)
NTb
2.8 (1)
0.8 (1)
3 (1)
10 (1)
8-BnO
8-BnO
8-BnO
8-OC6H5
8-C6H5
8-OMe
8-O(CH2)4CH3
8-C6H5
8-C6H5
8-OC6H5
8-OC6H5
1.5 (1)
CO2H
CO2H
CO2H
0.45 ( 0.05 (2)
>30 (1)
0.6 (1)
1 (1)
3.5 (1)
2 (1)
20 (1)
CHdCHCO2H
(CH2)2CO2H
CHdCHCO2H
(CH2)2CO2H
a
b
BnO ) phenylmethoxy. NT ) not tested.
only problematic step in Scheme 1 was the hydrolysis
of the esters 7 to the acid 4. This reaction proceeded
slowly at room temperature and gave the diacid side
product at a reaction temperature higher than ∼50 °C.
The R-methyl acids, 4f and 4p , could be synthesized
directly from 6a and 6d , respectively, by treating the
indolecarboxaldehydes with methylmalonic acid in the
presence of morpholine.5
indolecarboxylates with 9 in a manner similar to the
synthesis of 6 from 5 described in Scheme 1. Most of
the starting indolecarboxylates were obtained com-
mercially. The precursors for 4m and 4r were synthe-
sized according to known procedures. These N-alky-
lated indolecarboxylates were then hydrolyzed to the
desired acids.
The syntheses of 2a and 2k -n of the naphthyl series
(Table 2) are illustrated in Scheme 2. The Stobbe
condensation of 11 with dimethyl succinate gave 12 as
The indolecarboxylic acids 4i-m and 4r -s of Table
1 were prepared by N-alkylation of the corresponding

3758 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Chan et al.
Sch em e 1a
mixtures of E and Z isomers, which were cyclized
directly with Ac2O:NaOAc to give the naphthadenecar-
boxylate 13a and 13k .6 The intermediate 13l was
obtained from 13a via a three-step procedure (hydro-
genolysis, conversion of the resulting naphthol to the
triflate, and palladium-catalyzed phenylation of the
triflate with phenylboric acid7). 13 was subjected to
methanolysis, and the product 14 was converted to the
triflate 15. Palladium-catalyzed vinylation of 15 with
vinyltributyltin afforded the 4-vinylnaphthalene 16.8
Hydroboration of 16 with 9-BBN gave the hydroxy
intermediate 17, which was oxidized with J ones reagent
to the naphthaleneacetic acid 18. Coupling of 18 with
N-methylphenethylamine using 1,1'-carbonyldiimida-
zole (CDI) yielded the esters 19a and 19k -l. Hydro-
genolysis of 19a gave the naphthol 20, which was
alkylated to afford the esters 21. Hydrolysis of 19 and
21 yielded the acids 2a and 2k -n as crystalline solid
substances. The hydroxamic acid 2j was prepared from
the acid chloride of 2a .
The reactions described in Scheme 2 proceeded quite
well, with the exception of the oxidation of 17 to the
naphthaleneacetic acid 18. This reaction was rather
slow, and the best yield was only about 60%. We,
therefore, have explored other synthetic routes to the
naphthaleneacetic acid. Two of these alternate ap-

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3759
Sch em e 2a
proaches are illustrated in Scheme 3 and 4, which also
depict the syntheses of two of the isomers of 2a (2b and
2c, respectively). Unfortunately these alternate syn-
thetic routes did not offer an advantage over the original
approach described in Scheme 2. More recently, Pen-
drak et al. has reported a new method for the prepara-
tion of the intermediate 18a .9
Thus in Scheme 3, Stobbe condensation of 22 with
methyl succinate afforded an E/Z mixture of 23, which
was reduced directly to 24. Conversion of 24 to its acid
chloride, followed by intramolecular Friedel-Crafts
acylation, afforded the R-tetralone 25. The methoxy
group of 24 was also cleaved during this process. The
phenolic function of 25 was benzylated to afford 26. 26
was reacted with tert-butyl (diethylphosphono)acetate
in a Wittig reaction, and the product was treated with
DDQ to afford the tert-butyl ester 27. The tert-butyl
group of 27 was removed under acidic condition to give
the naphthaleneacetic acid 28. The conversion of 28 to
2b was achieved by using procedures similar to those
used for the preparation of 2a from 19a .
In Scheme 4, benzylation of commercially available
29 gave 4-bromonaphthalene 30. Palladium-catalyzed
ethynylation of 30,10 followed by transesterification,
afforded the 4-ethynylnaphthalene 31. Oxidation of the
geminal diboron intermediate of 31 gave naphthalene-
acetic acid 32.11 Conversion of 32 to 2c following similar
procedures described for the preparation of 2a .
The rest of the compounds listed in Table 2 were
derived by modification of the acid group of 2a and 2k -
l. These compounds were prepared from the corre-
sponding naphthalenecarboxaldehydes. As an illustra-
tion, the synthesis of 2q is shown in Scheme 5. Thus,
a reduction-oxidation reaction sequence converted the
intermediate 17k of Scheme 2 to the naphthalenecar-
boxaldehyde 33. Conversion of 33 to the key intermedi-
ate 36, and the subsequent transformation of 36 to 2q,
followed similar procedures described in Schemes 1 and

3760 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Chan et al.
Sch em e 3a
Sch em e 4a
2. Intermediates 17 were used as the starting material
predominantly because they were available at the time.
All of the compounds bearing an enoic carboxylic acid
side chain consisted of a mixture of cis-trans isomers
(by NMR). No attempts were made to separate these
geometric isomers, and the biological data obtained for
these compounds were those of the isomeric mixtures.
Resu lts a n d Discu ssion
The locations of the phenylmethoxy group of 4a was
found to be crucial for receptor affinity. Thus, the 6-
and 7-phenylmethoxy analogs, 4b and 4c, were less
active, whereas the 4-phenylmethoxy analog 4d was
more active than 4a . These results suggest that the
spatial relationship of the three side chains, which to a
large extend is determined by their substitution pattern
on the central indole ring, is an important factor in
determining the affinity of these molecules with LTB4
receptors.
We have found from SAR study of the phenylacet-
amide series that modification on either the amide or
phenylmethoxy group led to compounds of lower activ-
ity,3 therefore our SAR study of 4a was directed mainly
toward the modification of its acid side chain. The
importance of this carboxylic acid function was demon-
strated by the lower receptor affinity of the aldehyde
6a and ester 7a , and the comparable activity of the
corresponding tetrazole 4n . Varying the length of the
The LTB4 receptor binding data, obtained from ra-
dioligand binding assay using either guinea pig spleen
cell membrane12 or intact human neutrophils13 are
listed in Tables 1 and 2. The lead compound 2a had
IC50 values of 0.36 and 4.7 nM respectively, in the GP
spleen cell membrane and intact human PMN binding
assay.
Our interest in the indole series originated from an
initial observation that both the indoleacrylic acid 3714
and the phenylacetamide 3 bound to LTB4 receptors of
a cell membrane preparation of GP PMNs with similar
activity.15 This result prompted us to replace one of the
two phenylmethyl groups of 37 with the 2-[methyl(2-
phenethyl)amino]-2-oxoethyl moiety of 3. The resulting
hybrid molecule 4a was found to have a high affinity
for LTB4 receptors, with IC50s of 4 and 55 nM in binding
assays using GP spleen cell membrane and intact
human neutrophils, respectively (Table 1).

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3761
Sch em e 5a
carboxylic acid function afforded somewhat more potent
compounds (4e and 4j), especially in the human whole
cell assay. On the other hand, analogs of 4a having a
saturated acid side chain (4h and 4i) were at least 7-fold
less active than 4a . These data suggested that the
length of the acid side chain, at least within the range
of one to five carbon atoms, was not a significant factor
in determining the binding affinity of these compounds.
Instead, conjugation of the carboxyl group with the
central aromatic ring was a prerequisite for strong
binding to LTB4 receptors. The binding affinity of 4a
was also found to improve noticeably, especially in the
human whole cell binding assay, by substituting the
carbon atom next to the carboxyl function with a lower
alkyl group (4f and 4g). In fact, 4g was the lead
compound of the indole series, with an IC50 value of 1.3
and 7.6 nM respectively in the GP spleen cell membrane
and intact human PMN binding assay.
paralleled those obtained for the indole series. Thus,
compounds 2b and 2c again demonstrated the impor-
tance of the substitution pattern on the central ring.
The saturated acids (2f and 2g) were again less active.
The propenoic acid 2d and its tetrazolyl derivative 2i
had binding affinity comparable to that of 2a , whereas
the hydroxamic acid 2j was less active. We also carried
out a limited study on the modification of the phenyl-
methoxy group of 2a . The phenyl (2l) and short chain
alkyloxy (2n ) analogs were found to retain the receptor
affinity of the parent compound, whereas the activities
of the methoxy (2m ) and the phenoxy (2k ) analogs were
significantly reduced.
The guinea pig aggregation assay17 was used to
determine, in vitro, whether compounds active in the
binding assay were LTB4 receptor agonists or antago-
nists. Thus, 4a and 2a were found to inhibit LTB4-
induced (1 nM) aggregation of guinea pig PMNs with
IC50 values of 1.5 and 0.85 nM, respectively. In addi-
tion, these agents were found to be pure LTB4 antago-
nists due to their complete lack of agonist activity in
this assay.18 These results indicated a good correlation
between the binding affinity and functional antagonist
activity of 4a and 2a against LTB4 high-affinity recep-
tors in guinea pigs. In vivo, the po administration of
2a to guinea pigs, 1 h prior to LTB4 challenge, resulted
in a dose-related reduction in LTB4-induced broncho-
constriction with an ED50 value of 1.7 mg/kg.18 This
result confirmed that 2a was a potent, orally active
antagonist of LTB4 high-affinity receptors.
In summary, we have achieved the main objectives
for this study, namely, to develop novel LTB4 receptor
ligands based on central aromatic systems other than
benzene and to improve activity of these compounds in
the intact human neutrophil binding assay. Some of
these compounds, such as 2a ,b,d ,e,i,l,n and 4g,m , were
found to bind to LTB4 receptors of human neutrophil
with IC50 of less than 10 nM. Our SAR studies, based
on in vitro receptor binding assays, established that (1)
the spatial relationship among the three side chains on
the central aromatic ring, as determined by their
substitution pattern, is crucial for receptor binding, (2)
the one-carbon carboxylic and the propenoic acid side
Similar acid group modifications of the 4-(phenyl-
methoxy)indole 4d , however, did not improve activity
(4o-q and 4s, Table 1). It is noteworthy that the
phenylacetic acid derivative 4r was quite active, even
though its carboxylic group was not conjugated with
either the indole or phenyl ring.
Other modifications on the acid side chain of 4a , such
as transposition of the acid group from the 3 to the 2
position on the indole ring (4l), or replacing the enoic
acid group with the carboxybenzoyl moiety found in
LY223982,16 a potent LTB4 receptor antagonist (4m ),
also improved binding affinity. 4m in particular was
one of the two indoles that have IC50 values of less than
10 nM in the intact human PMN binding assay.
The LTB4 receptor binding data of the naphthyl
compounds are shown in Table 2. One of the initial
compounds synthesized in this series, 4-[2-[methyl(2-
phenethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)-2-naph-
thalenecarboxylic acid (2a ) was found to bind with
human neutrophil LTB4 receptors with an IC50 value
of 4.7 nM. By Scatchard analysis, 2a exhibited Kis of
0.14 and 2 nM for guinea pig and human PMN LTB4
receptors, respectively.2
SAR study of 2a was carried out in a manner similar
to that described for 4a , and in general the results

3762 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Chan et al.
2.97, 3.08 (2 s, 3 H), 4.7, 5.1 (2 s, 2 H), 5.21 (bs, 2 H), 6.28,
6.34 (2 d, 1 H), 6.8-8.15 (m, 15 H). Anal. (C29H28N2O4) C, H,
N.
Compounds 4b-g and 4o-q of Scheme 1, and the inter-
mediates leading to them, were prepared according to the
above procedures.
chains are preferred over propanoic or pentadienoic
acids, (3) alkylation on the R carbon of the propenoic
acid can enhance potency, and (4) naphthalene is
preferred over indole as the aromatic central ring.
Exp er im en ta l Section
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-6-(p h en -
1
ylm eth oxy)in d ole-3-ca r boxa ld eh yd e (6b): H NMR δ 2.9
Melting points were determined on a Thomas-Hoover ap-
paratus and were uncorrected. Mass and proton NMR spectra
were recorded for all compounds and were consistent with
assigned structures. 1H NMRs were recorded on a Varian EM-
390 (90 MHz) or a Bruker ACF-300 (300 MHz) spectrometer
in CDCl3 solution unless indicated otherwise.
N-Meth yl-N-(2-p h en eth yl)-2-br om oa ceta m id e (9). To
a solution of 34.7 g (171.95 mmol) of bromoacetyl bromide in
100 mL of CH2Cl2, cooled to -25 °C by an external cooling
bath, was added dropwise a solution of 46.5 g (343.9 mmol) of
N-methylphenethylamine in 50 mL of CH2Cl2 over a period of
1 h. The reaction mixture was stirred at -25 °C for an
additional 15 min and allowed to equilibrate to room temper-
ature. The mixture was diluted with CH2Cl2 and washed
successively with H2O, 1 N aqueous HCl solution, and satu-
rated salt solution. After being dried over MgSO4, the organic
layer was concentrated in vacuo to give quantitatively 9 as a
beige oil: 1H NMR δ 2.86, 2.9 (2 t, 2 H), 2.95, 3.0 (2 s, 3 H),
3.6, 3.64 (2 t, 2 H), 3.7, 4.07 (2 s, 2 H), 7.34 (m, 5 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-5-(p h en -
ylm eth oxy)in d ole-3-ca r boxa ld eh yd e (6a ). A suspension
of NaH (0.9 g of 80% dispersion in mineral oil, 30 mmol) in
120 mL of anhydrous tetrahydrofuran (THF) in a round bottom
flask was cooled in an ice bath, and 7.46 g (29.7 mmol) of
5-(phenylmethoxy)indole-3-carboxaldehyde (5a ) was added in
portions with stirring . The mixture was stirred in the cooling
bath for additional 10 min, and 9.13 g (35.64 mmol) of 9 was
added. The reaction mixture was stirred at room temperature
for 18 h. H2O and EtOAc were added, and the layers were
separated. The aqueous layer was extracted with EtOAc. The
combined extracts were dried (MgSO4) and concentrated in
vacuo to give an oil. This oil was chromatographed on silica
gel using CH2Cl2:EtOAc (2:1) as the eluent to give 12.4 g (29.07
mmol, 97.9% yield) of 6a as a beige solid: 1H NMR δ 1.27 (t,
3 H), 2.88 (m, 2 H), 2.9, 3.04 (2 s, 3 H), 3.6 (m, 2 H), 4.3, 4.77
(2 s, 2 H), 5.18, 5.22 (2 s, 2 H), 6.7-7.73 (m, 13 H), 8.0 (m, 1
H), 10.04, 10.1 (2 s, 1 H). Anal. (C27H26N2O3‚0.25H2O) C, H,
N.
(m, 2 H), 2.91, 3.05 (2 s, 3 H), 3.64 (m, 2 H), 4.26, 4.8 (2 s, 2
H), 5.12, 5.15 (2 s, 2 H), 6.4, 6.86 (2 s, 1 H), 7.0-7.66 (m, 12
H), 7.26 (m, 1 H), 10.0, 10.7 (2 s, 1 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-7-(p h en -
1
ylm eth oxy)in d ole-3-ca r boxa ld eh yd e (6c): H NMR δ 2.4,
2.84 (2 s, 3 H), 2.76 (m, 2 H), 3.4 (m, 2 H), 4.48, 5.04 (2 s, 2 H),
5.05 (s, 2 H), 6.8-8.1 (m, 14 H), 10.0, 10.4 (2 s, 1 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-4-(p h en -
ylm eth oxy)in d ole-3-ca r boxa ld eh yd e (6d ): 1H NMR δ 1.25
(t, 3 H), 2.89 (m, 2 H), 2.89, 3.01 (2 s, 3 H), 3.6 (m, 2 H), 4.31,
4.81 (2 s, 2 H), 5.0, 5.28 (2 bs, 2 H), 6.5-7.85 (m, 14 H), 10.4,
10.6 (2 s, 1 H).
Eth yl 3-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
6-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7b): 1H NMR δ
1.33 (t, 3 H), 2.78 (m, 2 H), 2.8, 3.0 (2 s, 3 H), 3.57 (m, 2 H),
4.25, 4.8 (2 s, 2 H), 4.3 (q, 2 H), 5.1, 5.15 (2 cs, 2 H), 6.4, 6.45
(2 d, 1 H), 6.75-7.6 (m, 13 H), 7.9 (m, 2 H).
Eth yl 3-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
7-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7c): 1H NMR δ
1.34 (t, 3 H), 2.43, 2.87 (2 s, 3 H), 2.7 (m, 2 H), 3.44 (m, 2 H),
4.3 (q, 2 H), 4.53, 5.05 (2 s, 2 H), 5.05, 5.08 (2 s, 2 H), 6.42, 6.5
(2 d, 1 H), 6.64 (m, 2 H), 7.07-7.8 (m, 12 H), 7.94, 8.0 (2 d, 1
H).
Eth yl 3-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
4-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7d ): 1H NMR δ
1.24 (t, 3 H), 2.80 (t, 2 H), 2.84, 3.00 (2 s, 3 H), 3.54 (q, 2 H),
4.15 (q, 2 H), 4.28, 4.70 (2 s, 2 H), 5.17, 5.20 (2 s, 2 H), 6.20,
6.23 (2 d, 1 H), 6.40-7.53 (m, 15 H), 7.27, 8.33 (2 d, 1 H).
Eth yl 5-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
5-(p h en ylm eth oxy)in d ol-3-yl]-2,4-p en ta d ien oa te (7e): 1H
NMR δ 1.27 (t, 3 H), 2.66, 2.86 (2 s, 3 H), 2.70 (m, 2 H), 3.42
(m, 2 H), 3.81-4.53 (m, 4H), 4.99 (bs, 2 H), 5.77 (d, 1 H), 6.0-
8.0 (m, 17 H).
Eth yl 2-m eth yl-3-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-
oxoeth yl]-5-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7f):
1H NMR δ 1.37 (t, 3 H), 2.10,2.14 (2 s, 3 H), 2.80 (m, 2 H),
2.84, 2.99 (2 s, 3 H), 3.54 (m, 2 H), 4.26 (q, 2 H), 4.26, 4.70 (2
s, 2 H), 6.60-7.73 (m, 14 H), 7.88 (d, 1 H).
Eth yl 3-[1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
5-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7a ). A suspen-
sion of NaH (0.84 g of 80% dispersion in mineral oil, 28 mmol)
in 80 mL of anhydrous THF in a round bottom flask was cooled
in a cold water bath (ca. 10 °C), and 5.6 mL (27.2 mmol) of
triethyl phosphonoacetate (10a ) was added dropwise at 0 °C.
After the mixture was stirred for an additional 10 min, a
solution of 7.74 g (18.15 mmol) of 6a in 40 mL of anhydrous
THF was added. The reaction mixture was stirred at room
temperature for 5 h. H2O and EtOAc were added, and the
layers were separated. The organic layer was washed with
saturated salt solution, dried (MgSO4), and concentrated in
vacuo to give 11.7 g of yellow solid substance. This crude
product was chromatographed on silica gel using 10% EtOAc
in CH2Cl2 as the eluent to give 7.93 g of 7a as beige solid
substance: 1H NMR δ 1.34 (t, 3 H), 2.79, 3.00 (2 s, 3 H), 2.81
(m, 2 H), 3.53 (m, 2 H), 4.20, 4.63 (2 s, 2 H), 4.28 (q, 2 H),
5.10, 5.11 (2 s, 2 H), 6.30, 6.34 (2 d, 1 H), 6.67-7.50 (m, 14 H),
7.83, 7.87 (2 d, 1 H). Anal. (C31H32N2O4) C, H, N.
3-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-5-(ph en -
ylm eth oxy)in d ol-3-yl]p r op en oic Acid (4a ). To a mixture
of 7.4 g (14.95 mmol) of 7a and 200 mL of EtOH was added a
solution of 1.26 g (44.4 mmol) of KOH in 20 mL of H2O. The
mixture was heated at 50 °C for 3 days, and the suspension
obtained was concentrated in vacuo. The concentrated reac-
tion mixture was diluted with H2O and extracted with Et2O.
The aqueous layer was acidified with 2 N aqueous HCl solution
to pH ∼7. The precipitate formed was collected and dried in
vacuo to give 2.8 g (5.98 mmol, 40% yield) of 4a as light beige
powder: 1H NMR (5-10% DMSO-d6 in CDCl3) δ 2.9 (m, 2 H),
E t h yl 2-et h yl-3-[1-[2-[m et h yl(2-p h en et h yl)a m in o]-2-
oxoeth yl]-5-(p h en ylm eth oxy)in d ol-3-ly]p r op en oa te (7g):
1H NMR δ 1.20 (m, 6 H), 2.67 (m, 4 H), 2.86, 2.93 (2 s, 3 H),
3.42 (m, 2 H), 4.10 (q, 2 H), 4.17, 4.64 (2 s, 2 H), 4.99, 5.01 (2
s, 2 H), 6.60-7.40 (m, 14 H), 7.80 (d, 1 H).
Eth yl 2-m eth yl-3-[1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-
oxoeth yl]-4-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7p ):
1H NMR δ 1.13 (t, 3 H), 2.11, 2.13 (2 s, 3 H), 2.82 (m, 2 H),
2.88, 3.02 (2 s, 3 H), 3.57 (m, 2 H), 4.1 (q, 2 H), 4.31, 4.8 (2 s,
2 H), 5.16 (bs, 2 H), 6.43-7.6 (m, 14 H), 8.53 (bs, 1 H).
E t h yl 2-et h yl-3-[1-[2-[m et h yl(2-p h en et h yl)a m in o]-2-
oxoeth yl]-4-(p h en ylm eth oxy)in d ol-3-yl]p r op en oa te (7q):
1H NMR δ 0.99 (t, 3 H), 1.20 (t, 3 H), 2.40 (m, 2 H), 2.86 (m,
2 H), 2.82, 2.99 (2 s, 3 H), 3.57 (m, 2 H), 4.20 (q, 2 H), 4.89,
5.20 (2 s, 2 H), 5.26 (bs, 2 H), 6.56-7.73 (m, 12 H), 7.81 (d, 1
H), 8.10 (s, 1 H), 8.70 (d, 1 H).
3-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-6-(ph en -
ylm eth oxy)in d ol-3-yl]p r op en oic a cid (4b): 1H NMR (5-
10% DMSO-d6 in CDCl3) δ 2.96 (m, 2 H), 2.97, 3.1 (2 s, 3 H),
4.74, 5.1 (2 s, 2 H), 6.16, 5.2 (2 s, 2 H), 6.35 (d, 1 H), 6.85-
8.16 (m, 15 H). Anal. (C29H28N2O4) C, H, N.
3-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-7-(ph en -
ylm eth oxy)in d ol-3-yl]p r op en oic a cid (4c): 1H NMR (5-
10% DMSO-d6 in CDCl3) δ 2.48, 2.81 (2 s, 3 H), 2.63 (m, 2 H),
3.3 (m 2 H), 4.52, 5.0 (2 s, 2 H), 5.0 (bs, 2 H), 6.2, 6.26 (2 d, 1
H), 6.6-7.47 (m, 14 H), 7.95, 8.03 (2 d, 1 H). Anal.
(C29H28N2O4‚0.5H2O) C, H, N.
3-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-4-(ph en -
ylm eth oxy)in d ol-3-yl]p r op en oic a cid (4d ): 1H NMR (5-
10% DMSO-d6 in CDCl3) δ 2.86 (m, 2 H), 2.94, 3.0 (2 s, 3 H),

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3763
3.56 (m, 2 H), 4.47, 4.88 (2 s, 2 H), 4.7, 4.75 (2 s, 2 H), 6.14,
6.2 (2 d, 2 H), 6.43-7.74 (m, 14 H), 8.07, 8.15 (2 d, 1 H). Anal.
(C29H28N2O4) C, H, N.
5-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-5-(ph en -
ylm eth oxy)in d ol-3-yl]-2,4-p en ta d ien oic a cid (4e): 1H NMR
(5-10% DMSO-d6 in CDCl3) δ 2.9 (m, 2 H), 2.99, 3.13 (2 s, 3
H), 3.8 (m 2 H), 4.82, 5.17 (2 s, 2 H), 5.3 (s, 2 h), 6.03 (d, 1
H),7.0-7.7 (m, 17 H). Anal. (C31H30N2O4‚0.25H2O) C, H, N.
2-Met h yl-3-[1-[2-[m et h yl(2-p h en et h yl)a m in o]-2-oxo-
eth yl]-5-(p h en ylm eth oxy)in d ol-3-yl]p r op en oic a cid (4f):
1H NMR (5-10% DMSO-d6 in CDCl3) δ 2.06 (m, 3 H), 2.93
(m, 2 H), 2.93, 3.04 (2 s, 3 H), 4.66, 5.05 (2 s, 2 H), 5.05, 5.09
(2 s, 2 H), 6.80-6.90 (m, 2 H), 7.06-7.50 (m, 12 H), 7.70 (bs,
1 H). Anal. (C30H30N2O4) C, H, N.
2-Eth yl-3-[1-[2-[m eth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-
5-(ph en ylm eth oxy)in dol-3-yl]pr open oic acid (4g): 1H NMR
(5-10% DMSO-d6 in CDCl3) δ 1.13-1.47 (m, 6 H), 2.46, 2.87
(2 s, 3 H), 2.56-3.00 (m, 4 H), 3.45 (m, 2 H), 4.27 (m, 2 H),
4.36, 4.76 (2 s, 2 H), 5.16, 5.20 (2 s, 2 H), 6.86-7.65 (m, 14 H),
8.17 (d, 1 H). Anal. (C31H32N2O4‚0.2H2O) C, H, N.
5-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-4-(ph en -
ylm eth oxy)in dol-3-yl]-2,4-pen tadien oic acid (4o): 1H NMR
δ 2.75 (m, 2 H), 2.91, 3.05 (2 s, 3 H), 3.56 (m, 2 H), 4.26, 4.35,
4.81, 4.89 (4 s, 2 H), 5.16, 5.20, 5.23 (3 s, 2 H), 5.59-8.0 (m,
18 H). Anal. (C31H30N2O4‚0.25H2O) C, H, N.
2-Met h yl-3-[1-[2-[m et h yl(2-p h en et h yl)a m in o]-2-oxo-
eth yl]-4-(p h en ylm eth oxy)in d ol-3-yl]p r op en oic a cid (4p ):
1H NMR δ 2.1 (bs, 3 H), 3.65 (t, 2 H), 4.4, 4.9 (2 s, 2 H), 5.22
(bs, 2 H), 6.5-7.7 (m, 14 H), 8.66 (bs, 1 H). Anal. (C30H30N2O4)
C, H, N.
2-Eth yl-3-[1-[2-[m eth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-
4-(ph en ylm eth oxy)in dol-3-yl]pr open oic acid (4q): 1H NMR
δ 2.00, 2.10 (2 s, 3 H), 2.63-3.00 (m, 5 H), 3.50 (m, 2 H), 4.23,
4.29, 4.80, 4.87 (4 s, 2 H), 5.13 (m, 2 H), 6.43-7.54 (m 14 H),
7.76-8.88 (m, 1 H). Anal. (C31H32N2O4) C, H, N.
3-[1-[2-[Me t h y l(2-p h e n e t h y l)a m in o -2-o x o e t h y l]-5-
(p h en ylm eth oxy)in d ol-3-yl]p r op a n oic Acid (4h ). A mix-
ture of 0.93 g of 7a , 0.5 g of 10% palladium on activated carbon,
and 150 mL of EtOH was shaken under 40 psi of hydrogen in
a Parr apparatus for 30 min. The catalyst was removed by
filtration, and the filtrate was concentrated in vacuo. The
residue obtained was chromatographed on silica gel using
EtOAc:hexane (2:1) as the eluent to give in over 90% yield
ethyl 3-[1-[2-[methyl(2-phenethyl)amino-2-oxoethyl]-5-(phenyl-
methoxy)indol-3-yl]propanoate (8) as a white powder: 1H NMR
δ 1.24 (t, 3 H), 2.56-3.14 (m, 6 H), 2.71, 2.95 (2 s, 3 H), 3.5
(m, 2 H), 4.16 (q, 2 H), 4.28, 4.61 (2 a, 2 H), 6.7-7.6 (m, 14 H).
8 was hydrolyzed to 4h according to the procedure described
for the synthesis of 4a , except the reaction was conducted at
room temperature in 6 h: 1H NMR δ 2.75 (m, 4 H), 2.81, 2.03
(2 s, 3 H), 3.0 (m, 2 H), 3.6 (m, 2 H), 4.36, 4.76 (2 s, 2 H), 5.18
(bs, 2 H), 6.72-7.7 (m, ∼13 H), 8.2 (m, ∼1 H). Anal.
(C29H30N2O4) C, H, N.
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-3-(2-tet-
r a zol-5-ylvin yl)-5-(p h en ylm eth oxy)in d ole (4n ). 3-(2-Cy-
anovinyl)-1-[2-[methyl(2-phenethyl)amino]-2-oxoethyl]-5-
(phenylmethoxy)indole (7n ) was prepared from 6a and 10e
according to the procedure for the synthesis of 7a : 1H NMR δ
2.9 (m, 2 H), 2.91, 3.04 (2 s, 3 H), 3.6 (m, 2 H), 4.23, 4.86 (2 s,
2 H), 5.06, 5.12 (2 s, 2 H), 5.49, 5.56 (2 d, 1 H), 6.3-7.5 (m, 15
H). A mixture of 0.845 g (1.88 mmol) of 7n , 0.37 g (5.64 mmol)
of sodium azide, and 0.3 g (5.64 mmol) of ammonium chloride
in 5 mL of DMF was heated in an oil bath of 100 °C for 18 h.
The reaction mixture was cooled and poured into 200 mL of
cold water. Two milliliters of 1 N aqueous NaOH solution was
added, and the aqueous mixture was extracted with Et2O. The
aqeous layer was acidified to pH ∼4 with 1 N HCl solution.
The precipitate formed was collected by filtration and dissolved
in ∼200 mL of EtOAc. The solution was stirred for 0.5 h and
filtered to remove undissolved substances. The filtrate was
concentrated in vacuo, and the residue was triturated in
EtOAc to give 108 mg of 4n as white solid powder: 1H NMR
δ 2.85, 2.96 (2 t, 2 H), 3.02, 3.07 (2s, 3 H), 3.59, 3.69 (2 t, 2 H),
4.5, 4.9 (2 s, 2 H), 5.13, 5.16 (2 s, 2 H), 6.75-7.85 (m, 16 H).
Anal. (C29H28N6O2‚0.5H2O) C, H, N.
Meth yl 1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
5-(p h en ylm eth oxy)-3-in d olea ceta te (ester of 4i): 1H NMR
δ 2.74 (m, 2 H), 2.82, 2.98 (2 s, 3 H), 3.46 (m, 2 H), 3.51-3.71
(m, 5 H), 4.47, 4.71 (2 s, 2 H), 5.08, 5.12 (2 s, 2 H), 6.74-7.5
(m, 13 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-5-(p h en -
ylm eth oxy)-3-in d olea cetic a cid (4i): 1H NMR (C6D6:DMSO-
d6, 9:1) δ 2.62 (m, 2 H), 2.67, 2.69 (2 s, 3 H), 3.36 (m, 2 H),
3.61, 3.62 (2 s, 2 H), 4.45, 4.72 (2 s, 2 H), 4.90, 4.92 (2 s, 2 H),
6.77-7.39 (m, 13 H). Anal. (C27H26N2O4) C, H, N.
Eth yl 1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-5-
(p h en ylm eth oxy)-3-in d oleca r boxyla te (ester of 4j): 1H
NMR δ 1.34 (t, 3 H), 2.80 (m, 2 H), 2.75, 2.94 (2 s, 3 H), 3.46
(m, 2 H), 4.16, 4.57 (2 s, 2 H), 4.28, 4. 30 (2 q, 2 H), 5.04, 5.06
(2 s, 2 H), 6.53-7.90 (m, 14 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoth eyl]-5-(p h en -
1
ylm eth oxy)-3-in d oleca r boxylic a cid (4j): H NMR δ 2.86
(m, 2 H), 3.50 (m, 2 H), 4.40, 4.86 (2 s, 2 H), 5.06 (bs, 2 H),
6.60-7.80 (m, 14 H). Anal. (C27H26N2O4) C, H, N.
E t h yl 2-m et h yl-1-[2-[m et h yl(2-p h en et h yl)a m in o]-2-
oxoeth yl]-5-(p h en ylm eth oxy)-3-in d oleca r boxyla te (ester
1
of 4k ): H NMR δ 1.37, 1.41 (2 t, 3 H), 2.38, 2.56 (2 s, 3 H),
2.84 (m, 2 H), 2.9, 3.01 (2 s, 3 H), 3.65 (t, 2 H), 4.3, 4.61 (2 s,
2 H), 4.41, 4.45 (2 q, 2 H), 6.64 (d, 1 H), 6.6-8.37 (m, 12 H).
2-Meth yl-1-[2-[m eth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-
5-(p h en ylm eth oxy)-3-in d oleca r boxylic a cid (4k ): 1H NMR
δ 2.4, 2.63 (2s, 2 H), 2.87, 2.96 (2 t, 2 H), 3.03, 3.05 (2 s, 3 H),
3.69,3.71 (2 t, 2 H), 4.36, 4.79 (2 s, 2 H), 5.08, 5.11 (2 s, 2 H),
6.52-7.83 (m, 13 H). Anal. (C28H28N2O4) C, H, N.
Eth yl 1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-5-
(p h en ylm eth oxy)-2-in d oleca r boxyla te (ester of 4l): 1H
NMR δ 1.35, 1.39 (2 t, 3 H), 2.94 (m, 2 H), 3.03, 3.06 (2 s, 3
H), 3.74 (m, 2 H), 4.38, 4.42 (2 q, 2 H), 5.2 (s, 2 H), 5.22, 5.46
(2 s, 2 H), 6.8-7.65 (m, 14 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]2-oxoeth yl]-5-(p h en -
ylm eth oxy)-2-in d oleca r boxylic a cid (4l): 1H NMR (5-10%
DMSO-d6 in CDCl3) δ 2.9 (m, 2 H), 2.9, 3.1 (2 s, 3 H), 3.6 (m,
2 H), 5.17 (s, 2 H), 5.23, 5.54 (2 s, 2 H), 6.87-7.6 (m, 13 H),
8.05 (s, 1 H). Anal. (C27H26N2O4‚0.25H2O) C, H, N.
3-(3-Car boxyben zoyl)-1-[2-[m eth yl(2-ph en eth yl)am in o]-
2-oxoeth yl]-5-(p h en ylm eth oxy)in d ole (4m ). To a solution
of 2.23 g (10 mmol) of 5-(phenylmethoxy)indole in 15 mL of
THF, stirred under nitrogen in a round bottom flask that was
cooled in an ice bath, was added 6.15 mL (12 mmol) of a 2 M
solution of CH3MgBr in Et2O. The mixture was stirred in the
ice bath for another 15 min, and a solution of 2.38 g (12 mmol)
of isophthalic acid, monomethyl ester monochloride was added.
The reaction mixture was stirred at room temperature for 18
h and poured into cold water. The aqueous mixture was
extracted with EtOAc. The combined extracts were washed
with saturated salt solution, dried (MgSO4), and concentrated
in vacuo. The residue obtained was chromatographed on silica
gel using 25% EtOAc in hexane as eluent to give 0.4 g of 3-(3-
carbomethoxybenzoyl)-5-(phenylmethoxy)indole. This inter-
mediate was alkylated with reagent 9 to give the methyl ester
of 4m . Alkaline hydrolysis of this ester gave 4m as beige
powder: 1H NMR (5-10% DMSO-d6 in CDCl3) δ 2.90 (m, 2
H), 2.91, 3.03 (2 s, 3 H), 4.06 (m, 2 H), 4.66, 5.1 (2 s, 2 H), 5.1
(s, 2 H), 6.83-8.3 (m, 18 H). Anal. (C34H30N2O5‚0.2H2O) C,
H, N.
2-[1-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-4-(ph en -
ylm eth oxy)in d ol-3-yl]p h en yla cetic Acid (4r ). To a solu-
tion of 1 g (4.48 mmol) of 4-(phenylmethoxy)indole in 10 mL
of Et2O, stirred under nitrogen in an ice bath, was added
dropwise 1.5 mL (4.48 mmol) of a 3 M solution of CH3MgBr in
Et2O, followed by 1.31 g (5.37 mmol) of ethyl 2-bromophenyl-
acetate. The reaction mixture was stirred at room tempera-
ture for 18 h and at reflux for 6 h. The reaction mixture was
poured into cold water, and the aqueous mixture was extracted
with EtOAc. The combined extracts were washed with satu-
rated salt solution, dried (MgSO4), and concentrated in vacuo.
The residue was chromatographed on silica gel using 20%
EtOAc in hexane as eluent to yield 0.45 g of ethyl 2-[4-(phen-
ylmethoxy)indol-3-yl]phenylacetate as an off-while powder:
mp 126-128 °C; 1H NMR δ 1.10 (t, 3 H), 4.10 (q, 2 H), 5.20 (s,
2 H), 5.81 (s, 1 H), 6.60 (d, 2 H), 6.90-7.20 (m, 3 H), 7.40 (s, 5

3764 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Chan et al.
H), 7.50 (s, 5 H), 8.23 (bs, 1 H). This intermediate was
N-alkylated with 9 to afford 0.44 g of the ester of 4r : 1H NMR
δ 1.06 (t, 3 H), 2.69, 2.90 (2 s, 3 H), 2.71 (m, 2 H), 3.42 (m, 2
H), 4.01 (m, 2 H), 4.18, 4.55 (2 s, 2 H), 5.02 (s, 2 H), 5.56, 5.62
(2 s, 1 H), 6.39 (m, 2 H), 6.60-7.25 (m, 17 H). Hydrolysis of
the ester gave 4r as white crystalline substance: 1H NMR δ
2.71 (m, 2 H), 2.31, 2.93 (2 s, 3 H), 3.46, 3.54 (2 t, 2 H), 4.14,
4.18, 4.26, 4,3 (4 s, 2 H), 4.7 (bs, 1 H), 5.04 (m, 2 H), 5.55, 5.63
(2 s, 1 H), 6.31-7.26 (m, 13 H). Anal. (C34H32N2O4) C, H, N.
Eth yl 1-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-4-
(p h en ylm eth oxy)-3-in d oleca r boxyla te (ester of 4s): 1H
NMR δ 1.20 (t, 3 H), 2.73, 2.90 (2 s, 3 H), 2.76 (m, 2 H), 4.17,
4.56 (2 s, 2 H), 4.20 (m, 2 H), 5.14, 5.16 (2 s, 2 H), 6.30-7.60
(m, 14 H).
δ 3.89 (s, 3 H), 5.31 (s, 2 H), 7.03 (d, 1 H), 7.35-7.70 (m, 7 H),
8.02 (s, 1 H), 9.11 (s, 1 H).
Meth yl 8-(P h en ylm eth oxy)-4-vin yl-2-n a p h th a len eca r -
boxyla te (16a ). A mixture of 100.44 g (0.288 mol) of 15a ,
48.34 g (1.14 mol) of lithium chloride, 3.2 g (4.56 mmol) of bis-
(triphenylphosphine)palladium(II) chloride, and ∼600 mL of
anhydrous DMF was stirred at room temperature under an
argon atmosphere for 15 min. Next, 79.55 g (0.251 mol) of
vinyltributyltin was added, and the mixture was stirred at
room temperature for 12 h. The reaction mixture was poured
into 1000 mL of water and extracted with four 200-mL portions
of EtOAc. The organic layers were washed with water, dried
(MgSO4), and concentrated in vacuo. The residue was taken
up in 500 mL of Et2O and treated with 2 equiv of a solution of
KF in water. The precipitate formed (Bu3SnF) was removed
by filtration. The filtrate was washed with H2O, dried
(MgSO4), and concentrated in vacuo. The crude product was
purified by silica gel flash chromatography using 5% EtOAc
in hexane as eluent to yield 57.89 g of 16a : 1H NMR δ 3.93
(s, 3 H), 5.25 (s, 2 H), 5.51 (d, 1 H), 5.88 (d, 1 H), 6.90 (d, 1 H),
7.31-7.52 (m, 6 H), 7.66 (d, 1 H), 8.22 (s, 1 H), 9.05 (s, 1 H).
Meth yl 4-(2-Hyd r oxyeth yl)-8-(p h en ylm eth oxy)-2-n a p h -
th a len eca r boxyla te (17a ). To a solution of 57.89 g (0.182
mol) of 16a in 500 mL of THF, stirred at room temperature
under argon, was added 44.45 g (0.364 mol) of 9-BBN. The
reaction mixture was stirred for 48 h, cooled in an ice bath,
and treated with 100 mL each of H2O and 30% H2O2. The
mixture was stirred for an hour each in the ice bath, and at
room temperature. The mixture was again cooled in an ice
bath and 27.3 mL of 2 N aqueous NaOH solution was added.
After bein stirred in the cooling bath for 4 h, the mixture was
extracted with four 150-mL portions of EtOAc. The organic
extracts were dried (MgSO4) and concentrated in vacuo. The
crude product was chromatographed on a silica gel using a
solvent mixtures of 15-50% ethyl acetate in hexane as the
eluent to afford 40.5 g of 17a : 1H NMR δ 3.32 (t, 2 H), 3.91 (s,
3 H), 3.98 (t, 2 H), 6.90 (d, 1 H), 7.31-7.57 (m, 7 H), 7.61 (d,
1 H), 7.98 (s, 1 H), 9.01 (s, 1 H). Five grams of unreacted
starting material 16a was also recovered.
3-Ca r b om et h oxy-5-(p h en ylm et h oxy)-1-n a p h t h a len e-
a cetic Acid (18a ): To a suspension of 64.03 g (0.19 mol) of
17a in 1500 mL of acetone was added dropwise at 0 °C 50 mL
of J ones reagent. The mixture was stirred at ∼0 °C for 38 h,
and during this period a total of 130 mL of J ones reagent in
three portions was added at intervals. The mixture was then
diluted with H2O and extracted with EtOAc. The organic
extracts were washed with water, dried (MgSO4), and concen-
trated in vacuo. The residue was triturated with Et2O to give
18a as light brown solid substance. The concentrated mother
liquor was triturated again in Et2O. This procedure was
repeated twice to yield additional crops of the product. Total
yield of 18a was 40.2 g (with minor impurities): 1H NMR δ
3.98 (s, 3 H), 4.11 (s, 2 H), 5.32 (s, 2 H), 6.93 (d, 1 H), 7.32-
7.54 (m, 7 H), 8.04 (s, 1 H), 9.10 (s, 1 H).
1-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-4-(p h en -
1
ylm eth oxy)-3-in d oleca r boxylic a cid (4s): H NMR δ 2.86
(m, 2 H), 2.89, 2.98 (2 s, 3 H), 3.55 (m, 2 H), 4.24, 4.75 (2 s, 2
H), 5.20, 5.24 (2 s, 2 H), 6.43 (d, 2 H), 6.80 (m, 2 H), 6.94-7.30
(m, 10 H), 7.46, 7.79 (2 s, 1 H). Anal. (C27H26N2O4) C, H, N.
3-Ca r b om et h oxy-4-[2-(p h en ylm et h oxy)p h en yl]-3-b u -
ten oic Acid (12a ). A solution of 210.7 g (0.99 mol) of
2-(phenylmethoxy)benzaldehyde (11a ) and 173.65 g (1.19 mol)
of dimethyl succinate in 500 mL of t-BuOH was added
dropwise within 3 h to a refluxing mixture of 166.1 g (1.48
mol) of KO-t-Bu and 1000 mL of t-BuOH. Reflux was
continued for another 3 h, and t-BuOH was removed in vacuo.
The residue obtained was dissolved in 1000 mL of 1 N aqueous
HCl, and the aqueous solution was extracted with three 250-
mL portions of EtOAc. The combined organic layers were
dried (MgSO4) and concentrated in vacuo to yield an oily crude
product. This oil was stirred in a solvent mixture of hexane:
Et2O (9:1, v/v) overnight, and the solid substance formed was
collected and dried under reduced pressure to give 275 g (0.848
mol) of 12a : 1H NMR δ 3.55 (s, 2 H), 3.82 (s, 3 H), 5.12 (s, 2
H), 6.60-7.50 (m, 9 H), 8.10 (s, 1 H).
Meth yl 4-Acetoxy-8-(p h en ylm eth oxy)-2-n a p h th a len e-
ca r boxyla te (13a ). A solution of 275 g (0.848 mol) of 12a in
1000 mL of acetic anhydride was heated at reflux for 6 h. After
cooling, the mixture was concentrated in vacuo, and the
residue was dissolved in toluene. The toluene solution was
concentrated in vacuo. This process was repeated one more
time, and the residue was dissolved in Et2O. After the mixture
stood at room temperature overnight, a solid precipitate
formed was collected by filtration to give 75 g of 13a as yellow
solid. The filtrate was concentrated in vacuo and dissolved
in a CH3OH:H2O solvent mixture and cooled to 0 °C. The
crystalline substance formed was collected by filtration to give
another batch of 13a . The filtrate was purified on a short silica
gel column using 10% acetone in hexane as eluent to afford
an additional quantity of the product. The total yield of 13a
was about 127 g: 1H NMR δ 2.41 (s, 3 H), 3.95 (s, 3 H), 5.28
(s, 2 H), 6.92 (d, 1 H), 7.30-7.51 (m, 7 H), 7.85 (s, 1 H), 9.00
(s, 1 H).
Meth yl 4-Hyd r oxy-8-(p h en ylm eth oxy)-2-n a p h th a len e-
ca r boxyla te (14a ). Sodium (12.49 g, 0.543 mol) was added
in portions within 1 h under argon to 1000 mL of anhydrous
CH3OH. To this mixture was added 126.93 g of 13a (0.362
mol) in one portion. The reaction mixture was stirred for 1 h
and acidified to pH ∼3 with 1 N HCl solution (∼800 mL). The
precipitate formed was collected by filtration and dissolved in
EtOAc. The organic solution was dried (MgSO4), and solvent
was removed in vacuo to give 109.38 g of 14a as a pale yellow
solid: 1H NMR δ 3.89 (s, 3 H), 5.30 (s, 2 H), 7.11 (d, 1 H),
7.30-7.59 (m, 7 H), 7.87 (d, 1 H), 8.55 (s, 1 H), 9.40 (bs, 1 H).
3-Ca r bom eth oxy-5-(p h en ylm eth oxy)-1-n a p h th yl Tr i-
flu or om eth a n esu lfon a te (15a ). Pyridine (144 mL, 1.77 mol)
was added to a solution of 109.4 g (0.355 mol) of 14a in 800
mL of anhydrous CH2Cl2. The mixture was cooled in an ice
bath and 71.7 mL (0.426 mol) of triflic anhydride was added
dropwise within 0.5 h. The reaction mixture was stirred in
the cooling bath for an additional 1 h, and solvent was removed
in vacuo. The residue was diluted with 1 N HCl solution and
extracted with three 250-mL portions of EtOAc. The combined
extracts were dried over MgSO4 and concentrated in vacuo to
give 155.1 g of 15a as light brown solid substance: 1H NMR
Meth yl 4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
8-(p h en ylm eth oxy)-2-n a p h th a len eca r boxyla te (19a ). To
a solution of 40.2 g (0.115 mol) of 18a in 100 mL of CH2Cl2
was added 27.91 (0.172 mol) of CDI. The mixture was stirred
at room temperature for 1 h, and 23.27 g (0.172 mol) of
N-methylphenethylamine and a catalytic amount of 4-(dimeth-
ylamino)pyridine (DMAP) were added. The mixture was
stirred at room temperature for 18 h and concentrated in
vacuo. The residue obtained was diluted with EtOAc, and the
organic solution was washed with 1 N HCl solution, saturated
aqueous Na2CO3 solution, and H2O, dried (MgSO4), and
concentrated in vacuo. The residue was chromatographed on
silica gel using 30-50% EtOAc in hexane as the eluent to
afford 30.8 g of 19a as a beige oily substance: 1H NMR δ 2.30,
2.89 (2 t, 2 H), 2.92, 3.02 (2 s, 3 H), 3.59, 3.63 (2 t, 2 H) 3.75,
4.07 (2 s, 2 H), 3.92, 3.94 (2 s, 3 H), 5.25, 5.28 (2 s, 2 H), 6.89,
6.91 (2 d, 1 H), 7.05-7.54 (m, 7 H), 7.78, 7.95 (2 s, 1 H), 9.03,
9.07 (2 s, 1 H).
4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-8-(p h en -
ylm eth oxy)-2-n a p h th a len eca r boxylic Acid (2a ). To a
solution of 30.8 g (65.87 mmol) of 19a in 450 mL of a solvent
mixture of THF:CH3OH:H2O (1:1:1) was added 13.82 (0.329

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3765
mol) of LiOH‚H2O. This mixture was stirred overnight at room
temperature and acidified to pH ∼3 with 1 N HCl solution.
The precipitate formed was extracted into EtOAc. The organic
extracts were washed with H2O, dried (MgSO4), and concen-
trated in vacuo. The solid residue was triturated with Et2O
to afford 26.7 g of 2a as white powder: 1H NMR δ 2.88, 2.91
(2 t, 2 H), 2.98, 3.08 (2 s, 3 H), 3.67 (m, 2 H), 3.79, 4.12 (2 s,
2 H), 5.29, 5.31 (2 s, 2 H), 6.91, 6.93 (2 d, 1 H), 7.12-7.56 (m,
Met h yl 4-(2-h yd r oxyet h yl)-8-p h en yl-2-n a p h t h a len e-
ca r boxyla te (17l): 1H NMR δ 3.4 (t, 2 H), 3.9 (s, 3 H), 4.05 (t,
2 H), 7.26-7.9 (m, 7 H), 8.17 (m, 2 H), 8.66 (bs, 1 H).
3-Ca r bom eth oxy-5-p h en oxy-1-n a p h th a len ea cetic a cid
(18k ): 1H NMR δ 3.95 (s, 3 H), 4.14 (s, 2 H), 6.95 (d, 1 H), 7.13
(d, 2 H), 7.21 (t, 1 H), 7.42 (m, 2 H), 7.6 (t, 1 H), 7.77 (d, 1 H),
8.0 (s, 1 H), 8.86 (s, 1 H).
3-Ca r b om et h oxy-5-p h en yl-1-n a p h t h a len ea cet ic a cid
1
7 H), 7.82, 8.01 (2 s, 1 H), 9.12, 9.14 (2 s, 1 H). Anal. (C29H27
NO4) C, H, N.
-
(18l): H NMR δ 3.87 (s, 3 H), 4.16 (s, 2 H), 7.23-7.74 (m, 8
H), 7.97 (m, 2 H), 8.6 (bs, 1 H).
Meth yl 4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
8-p h en oxy-2-n a p h th a len eca r boxyla te (19k ): 1H NMR δ
2.91 (m, 2 H), 3.06, 3.12 (2 s, 3 H), 3.73 (m, 2 H), 3.86, 4.20 (2
s, 2 H), 4.03 (s, 3 H), 7.07 (d, 1 H), 7.24-7.93 (m, 12 H), 7.91,
8.10 (2 s, 1 H), 9.11, 9.17 (2 s, 1 H).
The 2-naphthalenecarboxylic acids 2k -n , and the interme-
diates leading to them, were prepared by the procedures
described above, with the exception of intermediates 13l, 20,
and 21.
Meth yl 4-a cetoxy-8-p h en oxy-2-n a p h th a len eca r boxy-
Meth yl 4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
8-p h en yl-2-n a p h th a len eca r boxyla te (19l): 1H NMR δ 2.84,
2.86 (2 t, 2 H), 3.0, 3.06 (2 s, 3 H), 3.66 (t, 2 H), 3.87 (s, 3 H),
3.87, 4.13 (2 s, 2 H), 7.0-8.0 (m, 14 H), 8.56 (bs, 1 H).
Meth yl 8-h yd r oxy-4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-
oxoeth yl]-2-n a p h th a len eca r boxyla te (20) was prepared
from 19a in a manner similar to the preparation of methyl
4-acetoxy-8-hydroxy-2-naphthalenecarboxylate from 13a (see
1
la te (13k ): H NMR δ 2.52 (s, 3 H), 4.03 (s, 3 H), 6.98-7.82
(m, 8 H), 8.07 (d, 1 H), 9.18 (d, 1 H).
Meth yl 4-Acetoxy-8-p h en yl-2-n a p h th a len eca r boxyla te
(13l). A mixture of 3.55 g of 13a (10.1 mmol), 1.5 g of 10%
Pd/C, and 240 mL of EtOH was shaken in a Parr apparatus
under 35 psi of H2 for 2.5 h. After removal of the catalyst by
filtration, the filtrate was concentrated in vacuo to give methyl
4-acetoxy-8-hydroxy-2-naphthalenecarboxylate in quantitative
yield: 1H NMR (5-10% DMSO-d6 in CDCl3) δ 2.54 (s, 3 H),
4.02 (s, 3 H), 7.12 (dd, 1 H), 7.50 (m, 1 H), 7.81 (d, 1 H), 7.98
(d, 1 H), 9.16 (d, 1 H), 10.34 (s, 1 H). To a solution of 2.578 g
(9.9 mmol) of methyl 4-acetoxy-8-hydroxy-2-naphthalenecar-
boxylate in 30 mL of pyridine was added dropwise at room
temperature 2 mL (3.35 g, 11.88 mmol) of trifluoromethane-
sulfonic anhydride. The reaction mixture was stirred for 18
h and concentrated in vacuo. The residue was dissolved in
EtOAc, and the organic solution was washed with 1 N aqueous
HCl solution and saturated salt solution, dried (MgSO4), and
concentrated in vacuo. The crude product was chromato-
graphed on silica gel using 20% EtOAc in hexane as the eluent
to give 2.1 g of the triflate as yellow solid: 1H NMR δ 2.47 (s,
3 H), 4.00 (s, 3 H), 7.50-7.60 (m, 2 H), 7.83-7.95 (m, 2 H),
8.69 (d, 1 H). To a solution of 7.32 g (18.7 mmol) of the triflate
in 50 mL of dioxane was added 5.94 g (28 mmol) of K3PO4, 2.5
g (20.5 mmol) of phenylboric acid (97%), and 0.54 g (0.47 mmol)
of tetrakis(triphenylphosphine)palladium(0). The mixture was
stirred in an oil bath of 85 °C for 18 h, cooled, and poured into
∼500 mL of cold H2O. EtOAc was added, and the gray solid
Pd catalyst was removed by filtration. The layers were
separated, and the aqueous layer was extracted with ad-
ditional amount of EtOAc. The combined extracts were
washed with saturated salt solution, dried (MgSO4), and
concentrated in vacuo. The crude product was triturated in
acetone:Et2O to give 13l as grayish powder. The mother liquor
was concentrated, and the residue was purified on a silica gel
column, using 10% EtOAc in hexane as the eluent, to afford
additional amount of product. Total yield of 13l was 5.2 g:
1H NMR δ 2.46 (s, 3 H), 3.86 (s, 3 H), 7.34-7.90 (m, 9 H), 8.50
(d, 1 H).
1
synthesis of 13l from 13a ): H NMR δ 2.99 (t, 2 H), 3.07,
3.14 (2 s, 3 H), 3.74, 4.03 (2 s, 2 H), 3.75 (t, 2 H), 3.94, 3.96 (2
s, 3 H), 6.2 (m, 1 H), 6.78, 6.95 (2 d, 1 H), 7.01 (m, 1 H), 7.21-
7.43 (m, 5 H), 7.6, 7.81 (2 d, 1 H), 7.96, 8.06 (2 bs, 1 H), 8.52,
8.55 (2 d, 1 H).
Meth yl 8-Meth oxy-4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-
oxoeth yl]-2-n a p h th a len eca r boxyla te (21m ). A mixture of
0.125 g (0.33 mmol) of 20, 56 mg (0.397 mmol) of CH3I, 46 mg
(0.33 mmol) of K2CO3, and 25 mL of 2-butanone was heated
to reflux under nitrogen for 18 h. Water and CH2Cl2 were
added to the reaction mixture, and the layers were separated.
The organic layer was washed with saturated salt solution,
dried (MgSO4), and concentrated in vacuo. The residue was
purified by flash silica gel column chromatography, using 10%
EtOAc in CH2Cl2 as the eluent, to give 130 mg (0.33 mmol) of
21m as a yellow oil: 1H NMR δ 2.8, 2.89 (2 t, 2 H), 2.93, 3.04
(2 s, 3 H), 3.58, 3.64 (2 t, 2 H), 3.75, 4.06 (s, 2 H), 3.94, 3.95 (2
s, 3 H), 4.0, 4.02 (2 s, 3 H), 6.85 (t, 1 H), 7.13 (d, 1 H), 7.16-
7.55 (m, 6 H) 7.78, 7.96 (2 s, 1 H), 8.95, 9.02 (2 s, 1 H).
Meth yl 4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
8-(p en tyloxy)-2-n a p h th a len eca r boxyla te (21n ) w a s p r e-
p a r ed a ccor d in g to th e a bove p r oced u r e: 1H NMR δ 0.97
(m, 3 H), 1.5 (m, 4 H), 1.94 (m, 2 H), 2.8, 2.86 (2 t, 2 H), 2.88,
3.0 (2 s, 3 H), 3.59, 3.64 (2 t, 2 H), 3.74, 4.06 (2 s, 2 H), 3.92,
3.93 (2 s, 3 H), 4.11 (m, 2 H), 6.84 (t, 1 H), 7.1-7.54 (m, 7 H),
7.79, 7.94 (2 s, 1 H), 8.97, 9.02 (2 s, 1 H).
4-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-8-p h e-
n oxy-2-n a p h th a len eca r boxylic a cid (2k ): 1H NMR δ 2.79-
3.10 (m, 2 H), 2.98, 3.03 (2 s, 3 H), 3.57-3.84 (m, 3 H), 4.13
(m, 2 H), 6.70-7.66 (m, 13 H), 7.79, 7.98 (2 s, 1 H), 9.02, 9.06
(2 s, 1 H). Anal. (C28H25NO4‚0.25H2O) C, H, N.
4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-8-p h en -
1
Meth yl 4-h yd r oxy-8-p h en oxy-2-n a p h th a len eca r boxy-
yl-2-n a p h th a len eca r boxylic a cid (2l): H NMR δ 2.92 (m,
1
la te (14k ): H NMR δ 3.34 (s, 3 H), 6.95 (d, 1 H), 7.04 (m, 2
2 H), 3.03, 3.09 (2 s, 3 H), 3.70 (t, 3 H), 3.83, 4.17 (2 s, 2 H),
7.18-7.77 (m, 13 H), 7.94 (m, 1 H), 8.63, 8.69 (2 bs, 1 H). Anal.
(C28H25NO3) C, H, N.
H), 7.16 (t, 1 H), 7.34-7.48 (m, 4 H), 7.96 (d, 1 H), 8.31 (bs, 1
H).
8-Meth oxy-4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth -
yl]-2-n a p h th a len eca r boxylic a cid (2m ): 1H NMR δ 2.79 (m,
2 H), 2.9, 2.96 (2 s, 3 H), 3.55 (m, 2 H), 3.66, 4.02 (2 s, 2 H),
3.94, 3.95 (2 s, 3 H), 6.8 (t, 1 H), 7.04-7.48 (m, 7 H), 7.69,
7.88 (2 s, 1 H), 8.86, 8.92 (2 s, 1 H). Anal. (C23H23NO4‚0.2H2O)
C, H, N.
Meth yl 4-h yd r oxy-8-p h en yl-2-n a p h th a len eca r boxyla te
(14l): 1H NMR (5-10% DMSO-d6 in CDCl3) δ 3.85 (s, 3 H),
7.33-7.60 (m, 3 H), 7.33 (s, 5 H), 8.08 (bs, 1 H), 8.28 (d, 1 H).
3-Ca r bom eth oxy-5-p h en oxy-1-n a p h th yl tr iflu or om eth -
a n esu lfon a te (15k ): 1H NMR δ 4.12 (s, 3 H), 7.08-8.05 (m,
8 H), 8.29 (d, 1 H), 9.36 (d, 1 H).
Meth yl 8-p h en oxy-4-vin yl-2-n a p h th a len eca r boxyla te
(16k ): 1H NMR δ 4.02 (s, 3 H), 5.60 (d, 1 H), 5.94 (d, 1 H),
6.96-8.00 (m, 9 H), 8.39 (s, 1 H), 9.19 (s, 1 H).
Met h yl 8-p h en yl-4-vin yl-2-n a p h t h a len eca r b oxyla t e
(16l): 1H NMR (CDCl3) δ 3.95 (s, 3 H), 5.66 (dd, 1 H), 5.95
(dd, 1 H), 7.0-7.87 (m, 8 H), 8.28 (d, 1 H), 8.33 (bs, 1 H).
4-[2-[Met h yl(2-p h en et h yl)a m in o]-2-oxoet h yl]-8-(p en -
tyloxy)-2-n a p h th a len eca r boxylic a cid (2n ): 1H NMR (DM-
SO-d6) δ 0.92 (m, 3 H), 1.44 (m, 4 H), 1.87 (m, 2 H), 2.76, 2.84
(2 t, 2 H), 2.88, 3.04 (2 s, 3 H), 3.53, 3.66 (2 t, 2 H), 3.85, 4.12
(2 s, 2 H), 4.16 (m, 2 H), 7.0 (m, 1 H), 7.15-7.56 (m, 7 H),
7.67, 7.83 (2 s, 1 H), 8.75, 8.78 (2 s, 1 H). Anal. (C27H31
-
NO4‚0.25H2O) C, H, N.
Meth yl 4-(2-h yd r oxyeth yl)-8-p h en oxy-2-n a p h th a len e-
ca r boxyla te (17k ): 1H NMR δ 3.40 (t, 2 H), 4.02 (s, 3 H), 4.06
(t, 3 H), 7.02 (d, 1 H), 7.20-7.70 (m, 7 H), 7.98 (d, 1 H), 8.16
(s, 1 H), 9.16 (s, 1 H).
N-Meth yl-4-[2-[m eth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-
8-(p h en ylm eth oxy)n a p h th a len e-2-h yd r oxa m ic Acid (2j).
To a solution of 0.5 g (1.1 mmol) of 2a in 10 mL of CH2Cl2,
stirred under argon in an ice bath, were added 0.24 mL (2.76

3766 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Chan et al.
mmol) of oxalyl chloride and a drop of DMF. The reaction
mixture was stirred in the cooling bath for 1 h and was allowed
to warm to room temperature. This mixture was added with
stirring to a cooled (ice bath) mixture of 0.38 g (98% reagent,
4.41 mmol) of N-methylhydroxylamine hydrochloride, 0.9 mL
of triethylamine, 5 mL of THF, and 1 mL of H2O. The reaction
mixture was stirred at room temperature for 2 h and poured
into 100 mL of a 1 N aqueous HCl solution. CH2Cl2 was added,
and the layers were separated. The organic layer was washed
with H2O, dried (MgSO4), and concentrated in vacuo. The
residue was purified on a silica gel column, using 20-30%
EtOAc in CH2Cl2 as the eluent, to yield 210 mg of 2j as an
off-white foam: 1H NMR δ 2.85 (m, 2 H), 2.85, 2.98 (2 s, 3 H),
3.61 (m, 1 H), 3.74, 4.00 (2 s, 2 H), 5.27 (s, 2 H), 6.97-8.10 (m,
14 H), 8.74 (bs, 1 H). Anal. (C30H30N2O4‚0.5H2O) C, H, N.
3-Car bom eth oxy-4-(3-m eth oxyph en yl)bu tyr ic Acid (24).
3-Carbomethoxy-4-(3-methoxyphenyl)-3-butenoic acid (23) was
prepared from m-anisaldehyde and methyl succinate according
to the procedure described for the preparation of 12a . Next,
21.1 g (∼84.4 µmol) of crude 23, a yellow oil, was dissolved in
100 mL of HOAc, and 2.11 g of 10% Pd/C was added. The
mixture was shaken under 50 psi of H2 for 4 h and filtered to
remove the catalyst. The filtrate was concentrated in vacuo
to give 17.6 g of 24 as yellow oil: 1H NMR δ 2.25-3.24 (m, 5
H), 3.63 (s, 3 H), 3.73 (s, 3 H), 6.67-7.25 (m, 4 H).
3-Ca r b om et h oxy-6-h yd r oxy-3,4-d ih yd r o-1(2H )-n a p h -
th a len on e (25). A solution of 27 g (106.8 mmol) of 24 and
15.6 mL (213.6 mmol) of thionyl chloride in CH2Cl2 was heated
to reflux for 18 h. After being cooled to room temperature,
the reaction mixture was concentrated in vacuo. The residue
was dissolved in 100 mL of 1,2-dichloroethane, and this
solution was added dropwise to a suspension of 57 g (427.3
mmol) as AlCl3 in 300 mL of 1,2-dichloroethane. The reaction
mixture was stirred at room temperature for 18 h and poured
into cold water. The aqueous mixture was acidified with 150
mL of concentrated HCl and filtered. The filtrate was washed
with H2O, dried (MgSO4), and concentrated in vacuo. The
residue was chromatographed on silica gel using 50% EtOAc
in hexane as the eluent to give 5.3 g of 25 as a brown
crystalline solid: 1H NMR δ 2.8 and 3.15 (m, 5 H), 3.7 (s, 3
H), 6.73 (d, 1 H), 6.81 (dd, 1 H), 7.95 (d, 1 H).
3-Car bom eth oxy-6-(ph en ylm eth oxy)-3,4-dih ydr o-1(2H)-
n a p h th a len on e (26). A solution of 5.3 g (24.1 mmol) of 25
and 4.3 mL (35.1 mmol) of benzyl bromide in 30 mL of DMF
was heated at 75 °C with 6.65 g (48.1 mmol) of anhydrous K2-
CO3 for 18 h. EtOAc and H2O were added, and the layers were
separated. The organic layer was washed with H2O, dried
(MgSO4), and concentrated in vacuo. The residue was chro-
matographed on silica gel using 25% EtOAc in hexane as the
eluent to give 5.8 g of 26 as a brown solid: 1H NMR δ 2.88 (m,
2 H), 3.17 (m, 3 H), 3.73 (s, 3 H), 5.12 (s, 2 H), 6.8 (d, 1 H),
6.92 (dd, 1 H), 7.4 (m, 5 H), 8.0 (d, 1 H).
ter t-Bu tyl 3-Car bom eth oxy-6-(ph en ylm eth oxy)-1-n aph -
th a len ea ceta te (27). To a solution of 17.03 mL (72.5 mmol)
of tert-butyl (diethylphosphono)acetate in 100 mL of THF was
added in portions 2.17 g of NaH (72.5 mmol, 80% oil disper-
sion). After the mixture was stirred for 2 h at room temper-
ature, 4.5 g (14.5 mmol) of 26 was added, and the reaction
mixture was stirred at room temperature for 18 h. Water and
EtOAc were added, and the layers were separated. The
organic layer was washed with saturated salt solution, dried
(MgSO4), and concentrated in vacuo. The residue was purified
by silica gel flash chromatography, using 6% EtOAc in hexane
as the eluent, to afford 4.95 g (12.1 mmol) of the Wittig product
as a yellow oil. This material and 4.13 g (18.18 mmol) of DDQ
were dissolved in 20 mL of benzene, and the solution was
heated at 60 °C for 2 h. After cooling, the reaction mixture
was concentrated in vacuo. The residue was purified by flash
silica gel chromatography, using 6% EtOAc in hexane as
eluent, to give 2.75 g of 27 as yellow oil. The product was
contaminated by a small amount of the ethyl ester formed via
transesterification during the workup: 1H NMR δ 1.43 (s, 9
H), 3.94 (s, 3 H), 5.21 (s, 2 H), 7.86 (m, 7 H), 7.84 (s, 1 H), 7.95
(d, 1 H), 8.41 (s, 1 H).
of trifluoroacetic acid in 30 mL of CH2Cl2 was stirred at room
temperature for 6 h. The reaction mixture was concentrated
in vacuo to afford 0.9 g of 28 as a white solid: 1H NMR δ 3.94
(s, 3 H), 4.03 (s, 2 H), 5.16 (s, 2 H), 7.42 (m, 6 H), 7.85 (m, 2
H), 8.4 (s, 1 H).
4-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-7-(p h en yl-
m eth oxy)-2-n a p h th a len eca r boxylic a cid (2b) was pre-
pared from 28 according to the procedure described for the
preparation of 2a from 18a (Scheme 2): 1H NMR δ 2.9 (m, 2
H), 3.0 and 3.06 (s, 3 H), 3.64 (q, 2 H), 3.77 and 4.12 (s, 2 H),
5.18 and 5.2 (s, 2 H), 7.15-7.91 (m, 14 H), 8.42 and 8.47 (s, 1
H). Anal. (C29H27NO4) C, H, N.
Ben zyl 4-Br om o-1-(p h en ylm et h oxy)-2-n a p h t h a len e-
ca r boxyla te (30). A solution of 5 g (14.57 mmol) of benzyl
4-bromo-1-hydroxy-2-naphthalenecarboxylate (29) (Alfred Bad-
er Chemicals) and 2.08 mL (17.48 mmol) of benzyl bromide in
45 mL of a solvent mixture of acetone:DMF (8:1, v/v) was
heated to reflux in the presence of 4.03 g (29.14 mmol) of
anhydrous K2CO3 for 2 h. Water and EtOAc were added to
the reaction mixture, and the layers were separated. The
organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash silica gel chromatography,
using 5% EtOAc in hexane as eluent, to give 1.9 g of 30 as a
white solid. 1H NMR δ 5.13 (s, 2 H), 7.2 (m, 12 H), 8.08 (m, 2
H), 8.26 (s, 1 H).
Meth yl 3-Eth yn yl-1-(p h en ylm eth oxy)-2-n a p h th a len e-
ca r boxyla te (31). A mixture of 1.9 g (4.38 mmol) of 30, 1
mL (0.686 g, 7.02 mmol) of (trimethylsilyl)acetylene, 33 mg
(0.044 mmol) of bis(triphenylphosphine)palladium(II) acetate,
and 25 mL of triethylamine was heated at 100 °C for 4 h and
then was stirred at room temperature overnight. The reaction
mixture was concentrated in vacuo, and the residue was
partitioned between ethyl acetate and saturated NaHCO3
solution. The organic layer was washed with saturated NH4-
Cl solution, dried (MgSO4), and concentrated in vacuo. The
residue was dissolved in 50 mL of CH3OH, and the solution
was stirred at room temperature in the presence of 1 g of K2-
CO3 for 3 h. The mixture was concentrated in vacuo, and the
residue was partitioned between EtOAc and H2O. The organic
layer was dried (MgSO4) and concentrated in vacuo. The
residue was purified by silica gel flash chromatography, using
5% EtOAc in hexane as eluent, to afford 0.2 g of 31 as an
orange oil, which solidified after standing at room temperature
for a few hours: 1H NMR δ 3.34 (s, 1 H), 3.86 (s, 3 H), 5.08 (s,
2 H), 7.34 (m, 7 H), 8.04 (s, 1 H), 8.13 (m, 2 H).
3-Ca r b om et h oxy-4-(p h en ylm et h oxy)-1-n a p h t h a len e-
a cetic Acid (32). To a solution of 1.25 mL (1.25 mmol) of
2,3-dimethyl-2-butene in 20 mL of THF was added dropwise
at 0 °C 1.25 mL (1.25 mmol) of a 1.0 M solution of borane-
THF complex in THF. The mixture was stirred at 0 °C for 2
h, and a solution of 0.36 g (1.13 mmol) of 31 in 10 mL of THF
was added. The mixture was stirred at 0 °C for another 2 h,
and a solution of 0.88 g (5.12 mmol) of 3-chloroperoxybenzoic
acid in 10 mL of THF was added. After being stirred for an
additional 18 h at room temperature, the reaction mixture was
treated with 2 N aqueous NaOH solution, H2O, and Et2O, and
the layers were separated. The organic layer was dried
(MgSO4) and concentrated in vacuo. The residue was dissolved
in 30 mL of acetone, and J ones reagent was added at 0 °C
until a green precipitate occurred. The reaction mixture was
stirred in the cooling bath for another hour and then treated
with EtOAc and H2O, and the layers were separated. The
organic layer was dried (MgSO4) and concentrated in vacuo.
The residue was partitioned between EtOAc and saturated
aqueous Na2CO3 solution. The aqueous layer was acidified
with 1 N HCl to pH ∼1. The precipitate that occurred was
collected by filtration and dried to afford ∼70 mg of crude 32
as a yellow solid. This substance was used for the preparation
of 2c without further purification.
4-[2-Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-1-(p h en -
ylm eth oxy)-2-n a p h th a len eca r boxylic a cid (2c) was pre-
pared from 32 according to the procedures described for the
synthesis of 2a from 18a (Scheme 2). Methyl ester of 2c: 1H
NMR δ 2.87 (m, 2 H), 3.0, 3.05 (2 s, 3 H), 3.66 (m, 2 H), 3.72,
4.05 (2 s, 2 H), 3.9 (s, 3 H), 5.13, 5.16 (2 s, 2 H), 7.15-7.65 (m,
11 H), 7.78 (s, 1 H), 7.9 (d, 1 H), 8.29 (d, 1 H), 8.34 (d, 1 H).
3-Ca r b om et h oxy-6-(p h en ylm et h oxy)-1-n a p h t h a len e-
a cetic a cid (28). A solution of 1 g (2.5 mmol) of 27 and 3 mL

SAR of Two Series of Leukotriene B4 Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3767
2c: 1H NMR δ 2.9 (m, 2 H), 3.03, 3.06 (2 s, 3 H), 3.68 (m, 2
H), 3.73, 4.08 (2 s, 2 H), 5.15, 5.2 (2 s, 2 H), 7.14-7.93 (m, 13
H), 7.91 (s, 1 H), 8.29 (m, 1 H).
(m, 4 H), 2.98, 3.10 (2 s, 3 H), 3.44-3.80 (m, 2 H), 3.80, 4.20
(2 s, 2 H), 7.13-7.86 (m, 14 H), 8.03 (m, 1 H).
3-[4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-8-p h e-
1
4-(2-Hyd r oxyeth yl)-8-p h en oxy-2-n a p h th a ld eh yd e (33).
To a solution of 4.86 g (15.1 mmol) of 17k in 120 mL of THF
cooled in a cold water bath (ca. 5-10 °C) was added in portions
1.2 g of LAH. The mixture was stirred in the cooling bath for
1 h, and 4.5 mL of H2O was added slowly, followed by ∼1 mL
of 1 N aqueous HCl. The solid substance occurred was
removed by filtration. The filtrate was washed with saturated
salt solution, dried (MgSO4), and concentrated in vacuo to
afford 4.4 g of 4-(2-hydroxyethyl)-8-phenoxy-2-naphthalene-
methanol as a solid substance. Then 4.16 g (14.14 mmol) of
the naphthalenemethanol was dissolved in 800 mL of CH2-
Cl2, and 7.25 g (83.43 mmol) of activated MnO2 was added.
The mixture was stirred at room temperature for 18 h and
filtered. The filtrate was concentrated in vacuo to afford 2.5
g of 33: 1H NMR δ 3.16 (bs, 1 H), 3.40 (t, 2 H), 4.04 (t, 2 H),
7.03-8.06 (m, 9 H), 8.88 (s, 1 H), 10.26 (d, 1 H).
Eth yl 3-[4-(2-h ydr oxyeth yl)-8-ph en oxy-2-n aph th yl]pr o-
p en oa te (34) was prepared from 33 according to the procedure
described for the synthesis of 7a from 6a (Scheme 1), with the
exception that 2.5 molar equiv of the reagent 10a was used:
1H NMR δ 1.35 (t, 3 H), 3.4 (t, 2 H), 4.1 (t, 2 H), 4.34 (q, 2 H),
6.7 (d, 1 H), 7.04-8.1 (m, 10 H), 8.54 (s, 1 H).
3-(2-Ca r b et h oxyvin yl)-5-p h en oxy-1-n a p h t h a len ea ce-
tic a cid (35) was prepared from 34 according to the procedure
described for the synthesis of 18a from 17a (Scheme 2): 1H
NMR δ 1.4 (t, 3 H), 4.2 (s, 2 H), 4.36 (q, 2 H), 6.68 (d, 1 H),
7.04-8.1 (m, 10 H), 8.56 (bs, 1 H).
Eth yl 3-[4-[2-[m eth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-
8-p h en oxy-2-n a p h th yl]p r op en oa te (36) was prepared from
35 according to the procedure described for the synthesis of
19a from 18a (Scheme 2): 1H NMR δ 1.35 (t, 3 H), 2.94 (m, 2
H), 3.02, 3.11 (2 s, 3 H), 3.71 (m, 2 H), 3.84, 4.13 (2 s, 2 H),
4.34 (q, 2 H), 6.6, 6.64 (2 d, 1 H), 6.97-7.75 (m, 14 H), 7.94,
7.98 (2 d, 1 H), 8.46, 8.53 (2 bs, 1 H).
The following naphthyl carboxylic acids were prepared from
the corresponding esters according to the procedure described
for the synthesis of 2a from 19a (Scheme 2).
3-[4-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-8-(ph en -
ylm eth oxy)-2-n a p h th yl]p r op en oic a cid (2d ): 1H NMR δ
2.76 (t, 2 H), 2.91, 3.03 (2 s, 3 H), 3.56 (t, 2 H), 3.72, 4.02 (2 s,
2 H), 5.2 (s, 2 H), 6.46, 6.49 (2 d, 1 H), 6.8-7.54 (m, 14 H), 7.8,
7.84 (2 d, 1 H), 8.34, 8.38 (2 s, 1 H).
5-[4-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-8-(ph en -
ylm eth oxy)-2-n a p h th yl]-2,4-p en ta d ien oic a cid (2e): 1H
NMR δ 2.90 (m, 2 H), 2.98, 3.10 (2 s, 3 H), 3.60 (m, 2 H), 3.86,
4.14 (2 s, 2 H), 5.35 (s, 2 H), 6.10 (d, 1 H), 7.06-7.60 (m, 17
H), 8.46 (m, 1 H).
n oxy-2-n a p h th yl]p r op en oic a cid (2q): H NMR δ 2.9 (m,
2 H), 3.03, 3.1 (2 s, 3 H), 3.68 (m, 2 H), 3.77, 4.1 (2 s, 2 H), 6.5,
6.55 (2 d, 1 H), 6.92 (t, 1 H), 7.03-7.6 (m, 14 H), 7.85, 8.0 (2
d, 1 H), 8.3, 8.36 (2 s, 1 H).
3-[4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-8-p h e-
n oxy-2-n a p h th yl]p r op a n oic a cid (2r ): 1H NMR δ 2.65 (m,
2 H), 2.83, 2.9 (2 t, 2 H), 3.0, 3.11 (2 s, 3 H), 3.06 (m, 2 H),
3.54, 3.61 (2 t, 2 H), 3.79, 4.12 (2 s, 2 H), 6.9 (m, 1 H), 7.0-
7.62 (m, 13 H), 7.96, 8.1 (2 s, 1 H).
LTB4 Recep tor Liga n d Bin d in g Assa ys. For the proto-
cols of the guinea pig spleen and human PMN whole cell
binding assays, please see ref 3.
Gu in ea P ig P MN Aggr ega tion Assa y. Guinea pigs were
injected ip with 6 mL of 6% sodium caseinate. Twenty-four
hours later peritoneal PMNs were recovered by lavage with
7% sodium citrate in physiological saline. Cells were washed
once in Hank's balanced salt solution and maintained at 1 ×
105/mL on a rocking platform at room temperature in the
absence of Ca2+ or Mg2+ (10 mM), preincubation at 37 °C for
5 min followed by addition of antagonist and, 2 min later,
agonist (LTB4). The ensuing aggregation was monitored for
5 min.
LTB4-In d u ced Br on ch ocon str iction in Gu in ea P igs.
Male Hartley guinea pigs (350-400 g) were anesthetized with
pentobartital (50 mg/kg, ip) and surgically prepared for
measurement of airway function. A tracheal cannula was
inserted, and a catheter was placed in the jugular vein to allow
intravenous administration of drugs. Each animal was placed
in a whole body plethysmograph and ventilated at the rate of
80 breaths/min and a tidal volume of 8 mL/kg. Changes in
dynamic compliance (Cdyn) were measured using a Buxco
pulmonary mechanics computer and Vlidyn differential pres-
sure transducers. Spontaneous breathing was inhibited with
gallamine triethiodide (15 mg/kg, iv) and sympatheitc modula-
tion of airway tone was blocked with propranolol (1 mg/kg,
iv). LTB4 antagonist or vehicle was given orally 1 h before
challenge with LTB4. A DeVilbiss Pulmo-Sonic nebulizer,
placed in-line between the ventilator and the animal, was used
to give a continuous aerosol of LTB4 for 3 min. Peak changes
in Cdyn are measured at the 3 min time point. Mean (( SEM)
values of the maximal responses for drug- and vehicle-treated
groups were compared statistically using Student’s t-test.
Refer en ces
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3-[4-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-8-(ph en -
ylm eth oxy)-2-n a p h th yl]p r op a n oic a cid (2f): 1H NMR δ
2.51 (m, 4 H), 2.9, 3.04 (2 s, 3 H), 2.9, 3.1 (2 t, 2 H), 3.54, 3.68
(2 t, 2 H), 3.76, 4.06 (2 s, 2 H), 5.24, 5.25 (2 s, 2 H), 6.89 (m,
1 H), 6.97-7.56 (m, 13 H), 8.1, 8.14 (2 s, 1 H).
5-[4-[2-Me t h y l(2-p h e n e t h y l)a m in o ]-2-o x o e t h y l]-8-
(ph en ylm eth oxy)-2-n aph th yl]pen tan oic acid (2g): 1H NMR
δ 1.7 (m, 4 H), 2.3 (m, 2 H), 2.75 (t, 2 H), 2.76-2.91 (m, 2 H),
2.9, 3.05 (2 s, 3 H), 3.51, 3.67 (2 t, 2 H), 3.78, 4.06 (2 s, 2 H),
5.28, 5.3 (2 s, 2 H), 6.88 (m, 1 H), 7.04 (m, 1 H), 7.18-7.53 (m,
12 H), 8.06 (d, 1 H).
2-Eth yl-3-[4-[2-[m eth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-
8-(p h en ylm eth oxy)-2-n a p h th yl]p r op en oic a cid (2h ): 1H
NMR δ 1.24 (t, 2 H), 2.50-3.03 (m, 4 H), 2.97, 3.12 (2 s, 3 H),
3.64 (q, 2 H), 3.88, 4.16 (2 s, 2 H), 5.36 (s, 2 H), 7.07-7.80 (m,
14 H), 8.06 (d, 1 H), 8.64 (bs, 1 H).
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4-[2-[Meth yl(2-p h en eth yl)a m in o]-2-oxoeth yl]-8-(p h en -
ylm eth oxy)-2-(2-tetr a zol-5-ylvin yl)n a p h th a len e (2i): 1H
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(m, 2 H), 6.45 (d, 1 H), 6.5-7.55 (m, 15 H), 7.86 (d, 1 H).
3-[4-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-8-ph en -
yl-2-n a p h th yl]p r op en oic a cid (2o): 1H NMR δ 2.85 (t, 2 H),
3.00, 4.13 (2 s, 3 H), 3.64 (t, 2 H), 3.80, 4.13 (2 s, 2 H), 6.36
(dd, 1 H), 6.94-7.64 (m, 15 H), 7.90 (m, 1 H).
3-[4-[2-[Meth yl(2-ph en eth yl)am in o]-2-oxoeth yl]-8-ph en -
1
yl-2-n a p h th yl]p r op a n oic a cid (2p ): H NMR δ 2.54-3.04

3768 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
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