Heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids as leukotriene biosynthesis inhibitors

Article abstract of DOI:10.1021/jm9904102

A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion of an oxime moiety was investigated using REV-5901 as a starting point. A systematic structure- activity optimization showed that the spatial arrangement and stereochemistry of the oxime insertion unit proved to be important for inhibitory activity. The promising lead, S-(E)-11, inhibited LTB₄ biosynthesis in the intact human neutrophil with IC₅₀ of 8 nM and had superior oral activity in vivo, in a rat pleurisy model (ED₅₀ = 0.14 mg/kg) and rat anaphylaxis model (ED₅₀ = 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked LTE₄ biosynthesis (ED₅₀ of 0.1 mg/kg) and eosinophil influx (ED₅₀ of 0.2 mg/kg). S-(E)-11 (A-93178) was selected for further preclinical evaluation.

Full text of DOI:10.1021/jm9904102

690
J . Med. Chem. 2000, 43, 690-705
Heter oa r ylm eth oxyp h en yla lk oxyim in oa lk ylca r boxylic Acid s a s Leu k otr ien e
Biosyn th esis In h ibitor s
Teodozyj Kolasa,* David E. Gunn, Pramila Bhatia, Keith W. Woods, Todd Gane, Andrew O. Stewart,
J ennifer B. Bouska, Richard R. Harris, Keren I. Hulkower, Peter E. Malo, Randy L. Bell, George W. Carter, and
Clint D. W. Brooks*
Immunoscience Research, Abbott Laboratories, D47K, AP10, 100 Abbott Park Road, Abbott Park, Illinois 600064
Received August 12, 1999
A novel series of heteroarylmethoxyphenylalkoxyiminoalkylcarboxylic acids was studied as
leukotriene biosynthesis inhibitors. A hypothesis of structure-activity optimization by insertion
of an oxime moiety was investigated using REV-5901 as a starting point. A systematic
structure-activity optimization showed that the spatial arrangement and stereochemistry of
the oxime insertion unit proved to be important for inhibitory activity. The promising lead,
S-(E)-11, inhibited LTB4 biosynthesis in the intact human neutrophil with IC50 of 8 nM and
had superior oral activity in vivo, in a rat pleurisy model (ED50 ) 0.14 mg/kg) and rat
anaphylaxis model (ED50 ) 0.13 mg/kg). In a model of lung inflammation, S-(E)-11 blocked
LTE4 biosynthesis (ED50 of 0.1 mg/kg) and eosinophil influx (ED50 of 0.2 mg/kg). S-(E)-11
(A-93178) was selected for further preclinical evaluation.
In tr od u ction
of FLAP inhibitors, represented by the clinical candidate
BAY × 1005.10 The quinolylmethoxyphenyl group was
also a recognized pharmacophore for leukotriene recep-
tor antagonists.1
Leukotriene (LT) receptor antagonists and biosyn-
thesis inhibitors have provided a new therapeutic ap-
proach for the treatment of asthma.1 The enzyme
5-lipoxygenase (5-LO) catalyzes the oxidation of arachi-
donic acid and dehydration to the reactive epoxide
intermediate, LTA4.2 Enzyme-catalyzed addition of glu-
tathione to LTA4 provides LTC4 which is subsequently
metabolized by cleavage of amino acids to LTD4 and
LTE4. This group of peptidyl leukotrienes are potent
mediators of smooth airway contraction, vascular per-
meability, and mucus secretion.3 Enzyme-mediated
hydration of LTA4 provides LTB4, a potent mediator of
inflammatory cell recruitment and leukocyte activation.4
The discovery of 5-lipoxygenase-activating protein (FLAP)
by Merck scientists provided a new target for specific
inhibition of leukotriene biosynthesis.5 The 18-kDa
protein FLAP was proposed to act as a carrier protein
that presented arachidonic acid to the enzyme 5-lipoxy-
genase in a manner to specifically induce oxidative
catalysis.6 Merck scientists invented compounds that
blocked the function of FLAP and then verified their
hypothesis by demonstrating effective inhibition of
leukotriene biosynthesis via optimized inhibitors such
as MK-0591.7 Our research centered on developing
clinically useful specific inhibitors of 5-LO such as the
N-hydroxyurea series, represented by zileuton. We also
investigated alternative structural classes of leukotriene
inhibitors. In this context, we were intrigued by the
properties of analogues containing the 2-quinolylmethoxy-
phenyl moiety which originated with REV-5901 (Chart
1), an early reference leukotriene inhibitor,8 subse-
quently shown to block the actions of FLAP.9 Scientists
at Bayer A.G. had built on REV-5901 to create a series
We have previously demonstrated that inserting the
oxime moiety into a substituted indole series provided
analogues with improved oral bioavailability and in vivo
pharmacological properties.11 We also showed subtle
differences in properties depending on the orientation
of the oxime functionality for a given substrate. We
proposed to further examine this hypothesis of inserting
the oxime group into a series of lipophilic quinolyl-
methoxyphenyl derivatives. Our hypothesis derived
from the assumption that the oxime function might
replace an alkyl or alkenyl linking group to achieve
superior biological properties in one or more ways, as
follows: (1) improved potency by restricting the spatial
orientation of binding groups, (2) heteroatom-hydrogen
bonding interactions, (3) improved solvation for absorp-
tion characteristics, or (4) improved resistance toward
metabolism. The hypothesis was readily tested by the
straightforward conversion of hydroxy analogue A (re-
sembling REV-5901) to the corresponding alkoxyamine
B which could be reacted with a variety of carbonyl
units to provide oxime analogues C for biological evalu-
ation (Chart 2).
Ch em istr y
The compounds of this investigation were prepared
by the methods outlined in Schemes 1-11. Scheme 1
illustrates the general method for the preparation of
iminoxy analogues. The 4-phenolic aldehyde 5 or the
quinolylmethoxyphenylcarboxylate 6 were starting points
for the preparation of hydroxy analogues 7 that were
subjected to the Mitsunobu reaction with N-hydroxyph-
thalimide followed by treatment with hydrazine to give
the intermediate alkoxyamine 9. Reaction of the
alkoxyamine 9 with various carbonyl intermediates
provided the alkoxyiminoalkyl acids 10-37. Replacing
* Corresponding authors. T. Kolasa: Exploratory Chemistry, Abbott
Laboratories, D41M, AP10, 100 Abbott Park Rd, Abbott Park, IL 60064;
e-mail, teodozyj.kolasa@abbott.com. C. D. W. Brooks: Chemical Sci-
ences, Abbott Laboratories, D41K, R13, 1401 Sheridan Rd, North
Chicago, IL 60064; fax, 847-937-9249; e-mail, clint.brooks@abbott.com.
10.1021/jm9904102 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/01/2000

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 691
Ch a r t 1. Leukotriene Biosynthesis Inhibitors
Ch a r t 2. Oxime Insertion Hypothesis
method. The preparation of the ether analogue 98 was
accomplished from 2-chloroquinoline and 4-hydroxyben-
zaldehyde by the common Ullman reaction. The syn-
thesis of the quinolinylphenyl analogue (no linker group)
is illustrated in Scheme 5. Palladium-catalyzed coupling
of 4-formylbenzeneboronic acid (99) with 2-bromoquino-
line gave aldehyde 100 that was converted into the
target 102. The ethylene 106 and ethyl 108 analogues
were prepared as outlined in Scheme 6. Reaction of
4-bromobenzaldehyde (103) with cyclohexylmagnesium
chloride followed by protection of the hydroxy group
with tert-butyldimethylsilyl chloride and subsequent
reaction with n-BuLi and DMF afforded the aldehyde
104. Wittig reaction and subsequent silyl deprotection
with HF provided the alcohol 105. The alcohol 105 was
then transformed into target 106 following the standard
reactions shown in Scheme 1. Reduction of 105 with
Raney nickel gave the alcohol 107 that was converted
to the acid 108 by the general method.
cyclohexylmagnesium chloride with different Grignards
provided the compounds 42-62. In the case of acids 59
and 60, the starting alcohol was prepared by the
reduction of cyclohexyl(4-(2-quinolylmethoxy)phenyl)-
acetic acid.10c The compounds 63-84 and 87-93 with
the quinoline moiety replaced by different heterocycles
were prepared by this method using the requisite
heterocyclic variant to replace 2-chloromethylquinoline.
The derivatives 109-116 with a substituted phenyl ring
were prepared by similar methods.
A modification of the previous route starts with
4-hydroxyacetophenone 38 as described in Scheme 2.
Treatment of the 4-hydroxyacetophenone 38 with 2-chlo-
roquinoline gave methyl 4-(2-quinolylmethoxy)phenyl
ketone, which was alkylated with 1-iodobutane and then
reduced with NaBH4 to provide alcohol 39 that was
converted into the target alkoxyiminoalkylcarboxylic
acids 40 and 41 by the general methods of Scheme 1.
An alternative synthetic method (Scheme 3) to pro-
vide analogues with replacement of the quinolylmethoxy
moiety involved reaction of 4-benzyloxybenzaldehyde
(85) with cyclohexylmagnesium chloride followed by the
hydrogenolysis of the benzyl group to give alcohol 86
that was transformed into the quinoxalyliminoxy de-
rivative 87 by the general method.
Synthetic routes to analogues that investigated al-
ternatives to the methoxy link connecting the 2-quinolyl
and phenyl groups are shown in Schemes 4-6. The
preparation of the alternative methoxy link analogue
97 is described in Scheme 4. Mitsunobu reaction of
4-hydroxymethylbenzoic acid methyl ester (94) with
2-hydroxyquinoline provided a mixture of O-alkylated
and N-alkylated products. The O-alkylated derivative
was separated and reduced by the method of Kokotos12
to the alcohol 95. Oxidation of alcohol 95 to the corre-
sponding aldehyde by a modified Pfitzner-Moffatt
procedure13 followed by the reaction with cyclohexyl-
magnesium chloride gave the alcohol 96 that was
converted to the desired analogue 97 by the general
Analogues with replacements for the phenyl ring were
prepared by procedures described in Schemes 7-11. The
naphthyl analogue 119 was prepared as shown in
Scheme 7. Reaction of 6-bromo-2-naphthol (117) with
n-BuLi and DMF gave aldehyde 118, which was con-
verted to the target analogue 119 by the general
method. The benzothiophene analogue 125 was pre-
pared as shown in Scheme 8. Condensation of 5-hy-
droxy-2-nitrobenzyl alcohol (121) with 2-chlorometh-
ylquinoline followed by oxidation with DCC-DMSO-
H3PO4 yielded aldehyde 122. Condensation of 122 with
ethyl thioglycolate and subsequent hydrolysis with
NaOH provided the intermediate acid 123 that was
reduced to the aldehyde 124 and converted to the target
analogue 125. The 6-substituted benzothiophene ana-
logue 129 was synthesized as shown in Scheme 9.
Alkylation of 2-chloro-4-hydroxybenzaldehyde (126) with
2-chloroquinoline followed by condensation with ethyl
mercaptoacetate gave the benzothiophene ester 127.
Hydrolysis followed by reduction of the acid to the
corresponding alcohol and then oxidization provided the
aldehyde 128 that was converted to the target analogue
129. The compounds 130-132 were prepared as previ-
ously described. The benzofuran analogue 135 was
prepared as shown in Scheme 10. Reaction of 2-hydroxy-
5-methoxybenzaldehyde (133) with methyl bromoace-
tate followed by deprotection of the methoxy group with
BBr3 provided ester 134 that was converted to the target
135. The biphenyl analogue 140 was prepared as shown
in Scheme 11. Friedel-Craft reaction of 2-phenylanisole
(137) with cyclohexanecarbonyl chloride and subsequent

692 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Kolasa et al.
Sch em e 1a
a
(a) (1) 2-Chloromethylquinoline, K2CO3, DMF, (2) Grignard compound, THF; (b) (1) ClCO2Et, Et3N, THF, (2) NaBH4, THF-MeOH; (c)
PhtNOH, Ph3P, DEAD (or DIAD), THF; (d) H2NNH2, EtOH-CH2Cl2; (e) (1) keto acid or keto ester, AcOH, 1,4-dioxane-MeOH, (2) 1 N
NaOH, MeOH-1,4-dioxane for hydrolysis of esters.
Sch em e 2a
a
(a) (1) 2-Chloromethylquinoline, K2CO3, DMF, (2) n-BuI, t-BuOK, DME, (3) NaBH4, EtOH; (b) (1) PhtNOH, Ph3P, DIAD, THF, (2)
H2NNH2, EtOH, (3) CHOCO2H (or MeCOCO2Me), AcOH, 1,4-dioxane-MeOH, (4) (in case of ester) NaOH, 1,4-dioxane-MeOH.
Sch em e 3a
a
(a) (1) Cyclohexylmagnesium chloride, THF, (2) H2, 10% Pd-C, EtOH; (b) (1) 2-chloromethylquinoxaline, K2CO3, DMF, (2) PhtNOH,
Ph3P, DIAD, THF, (3) H2NNH2, EtOH, (4) CHOCO2H, AcOH, 1,4-dioxane-MeOH.
Sch em e 4a
a
(a) (1) 2-Hydroxyquinoline, Ph3P, DIAD, THF, (2) NaOH, 1,4-dioxane, MeOH, (3) Et3N, EtO2CCl, THF, (4) NaBH4, MeOH, THF; (b)
(1) DCC, DMSO, H3PO4, (2) cyclohexylmagnesium chloride, THF; (c) (1) PhtNOH, Ph3P, DIAD, THF, (2) H2NNH2, 1,4-dioxane, EtOH, (3)
methyl pyruvate, AcOH, MeOH, 1,4-dioxane, (4) NaOH, 1,4-dioxane, MeOH.
methoxy deprotection with AlBr3 afforded the hydroxy
ketone 138. Alkylation of 138 with 2-chloromethylquin-
oline and then reduction with NaBH4 provided the
alcohol 139 that was converted to the target 140 by the
general method.
insertion. The replacement of the hydroxy group by the
iminoxyalkylcarboxylic group would provide an oxime
insertion analogue 10, and its biological properties could
be compared to the structurally related FLAP inhibitors
2 and 4. The oxime analogue 10 was found to inhibit
LTB4 biosynthesis in a calcium ionophore-stimulated
human neutrophil assay14 with an IC50 of 17 nM
compared to an IC50 of 60 nM for the structurally related
FLAP inhibitor 4. The oxime analogue 10 showed
promising in vivo activity in a rat pleurisy model15 with
an oral ED50 of 2.5 mg/kg. The encouraging activity of
Resu lts a n d Discu ssion
We selected the synthetically accessible cyclohexyl-
(4-(2-quinolylmethoxy)phenyl)methanol (7) as a suitable
template, with structural features similar to REV-5901
and BAY × 1005 to test the hypothesis of oxime

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 693
Sch em e 5a
a
(a) 2-Bromoquinoline, Na2CO3, Pd(Ph3P)2Cl2, benzene; (b) cyclohexylmagnesium chloride, THF; (c) (1) PhtNOH, DIAD, Ph3P, THF,
(2) H2NNH2, 1,4-dioxane, MeOH, (3) CHOCO2H, AcOH, H2O, MeOH, 1,4-dioxane.
Sch em e 6a
a
(a) (1) Cyclohexylmagnesium chloride, THF, (2) TBDMS-Cl, Im, DMF, (3) n-BuLi, DMF, THF; (b) (1) 2-chloromethylquinoline, PPh3,
toluene, (2) t-BuOK, TH, (3) HF, MeCN; (c) (1) PhtNOH, Ph3P, DIAD, THF, (2) H2NNH2, EtOH-dioxane, (3) CHOCOOH, AcOH, MeOH,
dioxane, H2O; (d) Raney Ni, THF; (e) (1) PhtNOH, Ph3P, DIAD, THF, (2) H2NNH2, EtOH-dioxane, (3) CHOCOOH, AcOH, MeOH, dioxane,
H2O.
Sch em e 7a
a
(a) n-BuLi, DMF, THF; (b) (1) 2-chloromethylquinoline, K2CO3, DMF, (2) cyclohexylmagnesium chloride, THF, (3) PhtNOH, Ph3P,
DIAD, THF, (4) H2NNH2, EtOH, 1,4-dioxane, (5) CHOCOOH, AcOH, MeOH, 1,4-dioxane, H2O.
Sch em e 8a
a
(a) (1) 2-Chloroquinoline, Et4NF, DMF, (2) DCC, DMSO, H3PO4; (b) (1) HSCH2CO2Et, K2CO3, DMF, (2) NaOH, 1,4-dioxane, MeOH;
(c) (1) MeNHOMexHCl, Py, CBr4, CH2Cl2, THF, (2) DIBAL, THF; (d) (1) cyclohexylmagnesium chloride, (2) PhtNOH, DIAD, Ph3P, THF,
(3) H2NNH2, EtOH, 1,4-dioxane, (4) MeCOCO2Me, AcOH, MeOH, 1,4-dioxane, (5) NaOH, 1,4-dioxane, MeOH.
this oxime analogue prompted us to conduct an exten-
sive structure-activity (SAR) analysis of this new series
of leukotriene inhibitors.
The first stage of the SAR analysis was to evaluate
substitution R1 on the oxime function as outlined in
Table 1. It was observed that the substitutent effect of
R1 was more pronounced in vivo. The methyl-substi-
tuted derivative 11, with ED50 ) 0.5 mg/kg in the rat
pleurisy model, was 5 times more potent than the
unsubstituted analogue 10. The other substituents
examined gave properties inferior to 11. The E isomer
was the predominate isomer for most cases of R1
substitution examined. However, for R1 ) 2-thienyl,
enough of the Z isomer was formed to allow comparative
evaluation. The E isomer 19 was more effective in vivo
by about 2-fold than the Z isomer 20 although the in

694 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Kolasa et al.
Sch em e 9a
a
(a) (1) 2-Chloromethylquinoline, K2CO3, DMF, (2) HSCH2CO2Et, K2CO3, DMF; (b) (1) NaOH, EtOH, 1,4-dioxane, (2) ClCO2Et, Et3N,
THF, NaBH4, MeOH, (3) DCC, DMSO, H3PO4; (c) (1) cyclohexylmagnesium chloride, THF, (2) PhtNOH, DIAD, Ph3P, THF, (3) H2NNH2,
EtOH, 1,4-dioxane, (4) MeCOCO2Me, AcOH, 1,4-dioxane, MeOH, (5) NaOH, 1,4-dioxane, MeOH.
Sch em e 10a
a
(a) (1) BrCH2CO2Et, K2CO3, DMF, (2) BBr3, CH2Cl2, (3) SOCl2, MeOH; (b) (1) 2-chloromethylquinoline, K2CO3, DMF, (2) NaOH,
1,4-dioxane, MeOH, (3) ClCO2Et, Et3N, THF, NaBH4, MeOH, (4) DCC, DMSO, H3PO4, (5) cyclohexylmagnesium chloride, THF, (5) PhtNOH,
Ph3P, DIAD, THF, (6) H2NNH2, 1,4-dioxane, EtOH, (7) CHOCO2H, AcOH, 1,4-dioxane, MeOH, H2O.
Sch em e 11a
trophil (IC50 ) 40 nM) and in the rat pleurisy model
(ED50 ) 2 mg/kg), comparable to the saturated analogue
22.
Insertion of a phenyl group was examined in com-
pounds 27-29 that exhibited moderate in vitro and low
in vivo activities. The saturated cyclohexyl ring ana-
logue 30 was also a poor inhibitor. These results
suggested that the insertion of a phenyl or cycloalkyl
group likely disrupts the preferred orientation of the
carboxylic group for potent inhibition. For these limited
examples, we postulated that a carboxylic group had a
limited binding domain and that the direct attachment
of a carboxylic group to the oxime group provided the
best activity.
a
(a) (1) Cyclohexanecarbonyl chloride, AlCl3, CH2Cl2, (2) AlBr3,
As the next step we investigated substituents R at
the benzylic site (Table 2). The compounds with R being
primary n-alkyl groups 31-37 generally lacked in vivo
activity. Secondary alkyl substituents (40 and 41) had
good in vitro activity, and 41 had in vivo activity of 40%
at 3 mg/kg. This interesting difference from the n-alkyl
series suggested that a more rigid cycloalkyl group
might provide more favorable activity than the flexible
secondary alkyl group. Replacement of alkyl substitu-
ents with cycloalkyl groups resulted in dramatic im-
provement in in vivo potencies. The cyclopentyl ana-
logues 42 and 43 had 27% and 61% in vivo inhibition
at 3 mg/kg, respectively. The cyclohexyl analogues 10
and 11 gave better in vivo inhibition values, particularly
11 with ED50 ) 0.5 mg/kg. The cycloheptyl (45) and
adamantyl (47) derivatives also had good in vitro and
in vivo activity with ED50 values 0.70 and 0.60 mg/kg,
respectively. The phenylalkyl analogues 50-53 had
good in vitro activity but reduced in vivo activity
compared to the cycloalkyl analogues. The phenyl
analogue 54 lacked in vivo activity. The analogues 55-
57 where R was a heterocyclic group were also inferior
inhibitors. The presence of heteroatoms in the R sub-
stituent had a detrimental effect compared to the
cycloalkyl substituent. Finally, we tested a compound
without any substituent R in the benzylic position (58),
resulting in very poor inhibitory activity, IC50 ) 1400
benzene; (b) (1) 2-chloromethylquinoline, K2CO3, KI, DMF, (2)
NaBH4, MeOH; (c) (1) PhtNOH, Ph3P, DIAD, THF, (2) H2NNH2,
1,4-dioxane, MeOH, (3) CHOCO2H, AcOH, 1,4-dioxane, MeOH,
H2O.
vitro activity of the two isomers was similar. From this
set of analogues we decided to adopt R1 ) H or Me as
we continued the SAR investigation of the series.
The next stage was to evaluate the distance or
composition relationship of the connecting group L to
the oxime sp2 carbon and the carboxylic group as
outlined in Table 1. Adding one methylene unit to 11
resulted in analogue 21 with reduced in vitro activity
(only 40% at 100 nM), although 21 still demonstrated
in vivo activity (68% at 3 mg/kg). Two isomers of the
ethylene analogue were formed, E (22) and Z (23), that
had similar in vitro potency to 11 but suffered at least
a 2-fold loss of in vivo potency. The three-methylene
extension 24 had a 4-fold drop in in vitro activity but
still retained in vivo activity (ED50 ) 3 mg/kg). The five-
methylene homologue had comparable in vitro inhibition
to 11 but lacked in vivo activity (5% at 3 mg/kg). This
result suggested that the four-methylene extension was
likely the limit of added lipophilicity for the extended
alkylcarboxylate to retain adequate oral bioavailability.
The single conjugated double-bond analogue 26 was an
effective inhibitor against the stimulated human neu-

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 695
Ta ble 1. SAR of Substitution on the Iminoxy Linking Group
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
R1
L
mp, °C
formulac
zileuton
2
3
4
10
11
12
13
14
15
16
17
18
19(E)
20(Z)
21
22(E)
23(Z)
24
320
7
8
60
17
15
30
120
181
31
35
43
20
23
21
6.00
1.60
1.60
4.00
2.50
0.50
ntd
H
CH3
CH3CH2
CH2StBu
CH2SCH2CH2OH
Ph
PhCH2
4-HOPhCH2
PhCH2CH2
2-thienyl
2-thienyl
CH3
CH3
CH3
CH3
CH3
bond
bond
bond
bond
bond
bond
bond
bond
bond
bond
bond
CH2
197-198
183-184
105
160-162
146-147
176-178
92-95
139-141
157-159
134-136
178-179
85
115-117
88-91
134-135
105-106
78-80
C25H26N2O4
C26H28N2O4
C27H30N2O4‚H2O
C30H36N2O4S
C28H32N2O5S
C31H30N2O4‚0.5H2O
C32H32N2O4‚H2O*
C32H32N2O5
47%
ntd
41%
ntd
39%
34%
60%
29%
68%
1.00
62%
3.00
5%
C33H34N2O4‚0.5H2O
C29H28N2O4S‚2.5H2O
C29H28N2O4S
40% at 100
17
20
59
C27H30N2O4‚0.5H2O
C28H32N2O4
C28H32N2O4‚0.75H2O
C29H34N2O4
CH2CH2
CH2CH2
(CH2)3
(CH2)5
25
17
C31H38N2O4‚0.25H2O
26
27
28
29
CH3
H
H
H
CHdCH
Ph (1,4)
4-C6H4CHdCH
5-(2-OH)C6H3
40
31
2.00
41%
0%
35%
9%
C28H30N2O4‚0.25H2O
174-175
210-212
134-136
75-77
C31H30N2O4
48% at 100
95% at 100
67
C33H32N2O4‚0.75H2O
C31H30N2O5‚0.25H2O
30
1,4-cyclohexyl
C30H34N2O4
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils.14 The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy.15 The 95% confidence limits were (<50% of the mean value. Dose-response studies
b
were conducted for the more promising compounds, and ED50 values (mg/kg) are reported as the mean of separate dose-response
determinations. c All compounds had CHN analyses (0.4% of the theoretical, except as indicated by an asterisk. nt indicates not tested.
d
nM. This result indicates that the substituent R is
important for effective inhibitory activity.
benzylic positioning of the cyclohexyl group (m and n )
0) was optimized.
These studies showed that the derivatives with R )
cycloalkyl group and R1 ) methyl had the best in vivo
activity. Throughout this series the trend was evident
that the propionic acid derivatives (R1 ) Me) were
generally more potent in vivo than the acetic acid
derivatives (R1 ) H) despite similar in vitro activities.
The next phase of the SAR investigation focused on
the importance of the quinolyl heterocycle in the lead
compound 11. We examined substitution of and replace-
ments for the 2-quinolyl group, and the results are
summarized in Table 4. The 6-fluoro analogue 64 had
similar in vitro (IC50 ) 20 nM) and in vivo (ED50 ) 0.4
mg/kg) activity as the unsubstituted lead compound 11.
This indicated that tolerance of substituents was likely.
Rather than pursuing this in detail we wanted to first
establish if there was a better heterocyclic template
than the 2-quinolyl unit. The 2-pyridyl analogues 65 and
67 had poor activity in both assays. The presence of the
second ring appeared to be important for activity
because fusing a thiazole to the pyridyl moiety as in
analogue 66 restored the in vitro activity and even
showed moderate activity in vivo (47% at 3 mg/kg).
Replacement of quinolyl by thiazolyl alone as in ex-
amples 68-71 resulted in a loss of activity. A set of
4-phenyl-2-thiazole analogues 72-75 showed in vitro
potencies comparable to the lead compound 11 but very
poor in vivo activity. The 2-benzothiazole analogues 76
and 77 had better in vivo activities (ED50 ) 3 mg/kg for
76 and 85% inhibition at 3 mg/kg for 77) than the
4-phenyl-2-thiazole analogues. Since benzothiazoles ap-
peared to be the next best heterocyclic template to the
For the next stage of the SAR investigation, we
selected 11 as the most potent in vivo derivative and
chose to examine the effects of the distance m and n
that position the cyclohexylmethyl group between the
2-quinolylmethoxyphenyl group and the iminoxycar-
boxylate function. The results of this study are sum-
marized in Table 3. Separation of the 2-quinolylmethoxy-
phenyl group from the cyclohexylmethyl substituent by
one methylene unit (61, m ) 1, n ) 0) resulted in a
3-fold loss of potency in vitro and a dramatic reduction
of in vivo activity, 30% at 3 mg/kg. Increasing the
distance by two methylene units (62, m ) 2, n ) 0)
demonstrated further reduction in both in vitro and in
vivo potency. In the opposite direction, separating the
iminoxycarboxylate group from the cyclohexylmethyl
substituent by one methylene unit (60, m ) 0, n ) 1)
showed only a slight decrease of in vitro activity but
dramatic loss of in vivo potency in the rat pleurisy
model. These limited results led us to assume that the

696 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Ta ble 2. SAR of Benzylic Substituents
Kolasa et al.
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
R
R1
mp, °C
formulac
C25H26N2O4
C26H28N2O4
C23H22N2O4
C23H24N2O4
C24H26N2O4
10
11
31
32
33
34
35
36
37
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
cyclohexyl
cyclohexyl
allyl
n-butyl
n-butyl
n-heptyl
n-heptyl
n-octyl
H
17
15
142
52
45% at 100
100% at 100
96% at 100
92% at 100
54% at 100
10
14
30
16
18
13
21
20
27
29
30
10
22
9
2.50
0.50
ntd
197-198
183-184
123-124
124-126
118-119
93-96
CH3
CH3
H
CH3
H
CH3
CH3
H
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
CH3
H
CH3
CH3
CH3
H
CH3
CH3
CH3
0%
ntd
0%
C26H30N2O4‚0.4H2O
C27H32N2O4‚0.4H2O
C28H34N2O4‚0.4H2O
C31H40N2O4‚0.4H2O
ntd
oil
oil
27%
n-dodecyl
ntd
101-103
109-112
178-180
187-188
153-154
184-186
88-90
187-188
199-200
180-181
152-154
186-187
73-75
137-138
160-162
110-112
144-146
72-74
foam
169-170
di-n-butylmethyl
di-n-butylmethyl
cyclopentyl
7%
C
28H34N2O4
C29H36N2O4‚2H2O
24H24N2O4
40%
27%
61%
ntd
C
cyclopentyl
cycloheptyl
cycloheptyl
C25H26N2O4
C26H28N2O4
C27H30N2O4‚0.5H2O
C29H30N2O4
C30H32N2O4
C26H28N2O4
C27H30N2O4
C27H24N2O4‚0.25H2O
C29H28N2O4
C30H30N2O4‚0.25H2O
C29H27FN2O4*
C27H24N2O5
C24H24N2O5‚2H2O*
C24H20N2O4S
0.70
1.20
0.60
ntd
2-adamantyl
2-adamantyl
cyclohexylmethyl
cyclohexylmethyl
phenylmethyl
2-methyl-2-phenylpropyl
2-methyl-2-phenylpropyl
3-(4-F-phenyl)propyl
4-methoxyphenyl
4-tetrahydropyranyl
2-thienyl
ntd
36%
4.00
2.00
2.60
20%
ntd
58% at 100
-12% at 100
33
20% at 100
1400
6%
3-pyridyl
ntd
C25H21N2O4‚3H2O*
C20H17ClN2O4‚0.25H2O*
He
ntd
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. Dose-response studies
were conducted for the more promising compounds, and ED50 values (mg/kg) are reported as the mean of separate dose-response
determinations. c All compounds had analyses (0.4% of the theoretical, except as indicated by an asterisk. nt indicates not tested.
d
e 2-Chlorophenyl ring was used instead of phenyl ring.
Ta ble 3. SAR of the Oximinoaryl Group Linker
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
R1
m
n
mp, °C
formulac
C26H28N2O4
C26H28N2O4‚0.25H2O
C27H30N2O4
C27H30N2O4
C28H32N2O4‚0.5H2O
11
59
60
61
62
CH3
H
CH3
CH3
CH3
0
0
0
1
2
0
1
1
0
0
15
47
20
50
0.50
73% at 10
33%
30%
6%
183-184
68-70
117-118
72-73
51% at 100
59-60
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. ED50 values (mg/kg) are
reported as the mean of separate dose-response determinations. c All compounds had analyses (0.4% of the theoretical.
quinolyl group, we examined the effect of halogen
substituents in the central phenoxy unit. The chlori-
nated analogues 78 and 79 had good in vivo activities
in rat pleurisy model (ED50 ) 84% at 3 mg/kg and ED50
) 2.6 mg/kg, respectively). The brominated analogue 80
also had good in vivo activity (ED50 ) 1 mg/kg).
vitro activity but poor in vivo activity. Additional
heterocyclic moieties examined were the 2-benzothienyl
analogue 88, 5-phenyl-3-isoxazolyls 89 and 90, 1,4-
benzodioxan-2-yls 91 and 92, and 1-methyl-2-benzimi-
dazolyl analogue 93. All of these compounds showed
such poor activity in vitro that they were not tested in
vivo except 90, which showed no inhibition at 3 mg/kg.
These results indicated that one heterocyclic nitrogen
was required for inhibitory activity. The role of this
The 2-benzoxazolyl analogue 84 was about 2-fold less
potent in vitro than the corresponding 2-benzothiazolyl
analogue 76. The 2-quinoxalyl analogue 87 had good in

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 697
Ta ble 4. SAR of Heterocycle Modifications
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
heterocycle
R1
R2
mp, °C
formulac
C25H26N2O4
C26H28N2O4
C25H25FN2O4
C26H27FN2O4
C21H24N2O4
C22H23N3O4S
C22H25ClN2O4‚0.25H2O
C19H22N2O4S
C20H24N2O4S‚0.25H2O
10
11
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
87
88
89
90
91
92
93
2-quinolyl
2-quinolyl
H
Me
H
Me
H
H
Me
H
Me
H
H
H
Me
H
Me
H
Me
H
Me
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Br
H
Cl
Cl
H
H
H
H
H
H
H
H
17
15
2.50
0.50
39%
0.40
3%
197-198
183-184
165-166
164-165
169-171
194-195
127-129
159-160
156-157
163-164
153-155
88-90
6-fluoro-2-quinolyl
6-fluoro-2-quinolyl
2-pyridyl
pyrido[2,3-b]-2-thiazolyl
6-chloro-2-pyridyl
99% at 1560
20
150
27
7% at 100
62% at 1560
360
380
490
21
20
35
57% at 100
60
60
28
28
22
87
14
48
143
25
94% at 1560
140
61% at 100
65% at 780
78% at 780
820
47%
ntd
4-thiazolyl
4-thiazolyl
ntd
ntd
2-methyl-4-thiazolyl
2-(4-chlorophenyl)-4-thiazolyl
4-phenyl-2-thiazolyl
4-phenyl-2-thiazolyl
4-(4-isopropylphenyl)-2-thiazolyl
4-(4-isopropylphenyl)-2-thiazolyl
2-benzothiazolyl
2-benzothiazolyl
2-benzothiazolyl
2-benzothiazolyl
2-benzothiazolyl
5-fluoro-2-benzothiazolyl
5-fluoro-2-benzothiazolyl
5-fluoro-2-benzothiazolyl
2-benzoxazolyl
2-quinoxalyl
2-benzothienyl
5-phenyl-3-isoxazolyl
5-phenyl-3-isoxazolyl
1,4-benzodioxan-2-yl
1,4-benzodioxan-2-yl
1-methyl-2-benzimidazolyl
4%
30%
0%
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
20H24N2O4S
25H25ClN2O4S
25H26N2O4S‚1.25H2O
26H28N2O4S‚0.5H2O
28H32N2O4S‚2H2O
29H34N2O4S‚2.25H2O
23H24N2O4S*
24H26N2O4S‚0.5H2O
23H23ClN2O4S
24H25ClN2O4S
23H23BrN2O4S
15%
15%
17%
3.00
85%
84%
2.60
1.00
0%
93-95
163-165
161-163
179-180
160-162
187-189
114-116
202-204
171-172
175-177
143-145
111-112
159-162
141-146
114-116
96-99
23H23FN2O4S
1.70
22%
14%
28%
ntd
23H22ClFN2O4S
24H24ClFN2O4S
23H24N2O5‚0.5H2O
24H25N3O4
H
H
Me
H
Me
Me
C24H25NO4S‚0.5H2O
C25H26N2O4
C26H28N2O4‚0.5H2O
C24H27NO6‚0.8H2O
C25H29NO6
ntd
0%
ntd
foam
82-85
190-191
ntd
ntd
C25H29N3O4‚0.25H2O
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. Dose-response studies
were conducted for the more promising compounds, and ED50 values (mg/kg) are reported as the mean of separate dose-response
determinations. c All compounds had analyses (0.4% of the theoretical, except as indicated by an asterisk. nt indicates not tested.
d
Ta ble 5. SAR of the Link Unit for Quinolyl and Phenyl Groups
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
X
R1
mp, °C
formulac
C25H26N2O4
C26H28N2O4
C26H28N2O4
C24H24N2O4‚0.25H2O
C24H24N2O3‚0.25H2O
C26H26N2O3‚0.25H2O
C26H28N2O3‚0.25H2O
10
11
97
CH2O
CH2O
OCH2
O
bond
CHdCH
CH2CH2
H
17
15
2.5
0.5
0%
ntd
ntd
ntd
ntd
197-198
183-184
179-180
192-193
182-184
140-142
foam
Me
Me
H
H
H
81% at 390
160
1200
91
98
102
106
108
H
290
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. c All compounds had
analyses (0.4% of the theoretical. nt indicates not tested.
b
d
nitrogen atom appeared to be more complex than we
anticipated, and the 2-quinolyl group had the best
activity of the heterocycles studied.
Continuing to dissect the SAR of this series of
leukotriene inhibitors, we examined the connecting
group between the 2-quinolyl heterocycle and the cen-
tral phenyl group. These results are summarized in
Table 5. Reversing the methoxy regiochemistry of 11
led to the analogue 97, which had much weaker in vitro
activity and was inactive in vivo. Removal of the
methylene gave the ether analogue 98 that also had
poor in vitro activity. Removing the methoxy group as

698 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Ta ble 6. SAR of Phenyl Substitution
Kolasa et al.
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
R1
R2
R3
mp, °C
formulac
C25H26N2O4
C26H28N2O4
C26H28N2O5
10
11
H
Me
H
Me
H
Me
H
Me
Me
Me
H
H
OMe
OMe
H
H
H
Cl
H
H
H
H
Me
Me
F
H
H
17
15
20
2.50
0.50
41%
32%
15%d
58%
nte
197-198
183-184
87-90
183-185
foam
109
110
111
112
113
114
115
116
98% at 100
20
20
C27H30N2O5‚0.4H2O
C26H28N2O4‚0.4H2O
70-75
C27H30N2O4‚0.1H2O
97% at 100
168-170
153-155
75-77
C25H25FN2O4‚1.5H2O
14
90
27
0.80
C26H27ClN2O4
S-cyclohexyl
H
nte
C32H38N2O4S
C26H27ClN2O4
Cl
1.20
90-92
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. Dose-response studies
were conducted for the more promising compounds, and ED50 values (mg/kg) are reported as the mean of separate dose-response
determinations. c All compounds had analyses (0.4% of the theoretical. Sodium salt showed in vivo 45% at 3 mg/kg. e nt indicates not
d
tested.
Ta ble 7. SAR of the Internal Aryl Group
in vivo ratb
ED50, mg/kg, or
% I at 3 mg/kg
human PMNLa
IC50, nM
compd
Aryl
R1
mp, °C
formulac
C29H28N2O4
C29H28N2O4‚0.25H2O
C28H28N2O4S
C28H28N2O4S
C23H25N3O5
C28H27N3O4S‚0.5H2O*
C24H25N3O4‚0.3H2O
119
120
125
129
130
131
132
135
136
140
2,6-naphthyl
1,4-naphthyl
H
H
CH3
CH3
CH3
H
H
H
H
H
56
24%
ntd
170-175
118-120
91-93
89% at 25
33
40
2,5-benzothienyl
2.6-benzothienyl
3,5-isoxazolyl
2,4-(5-phenyl)thiazolyl
2,5-pyridyl
2,5-benzofuryl
4,4′-biphenyl
2,5-biphenyl
ntd
80%
78-80
490
ntd
175-176
94-96
2% at 100
41% at 6250
52% at 25
55% at 100
160
ntd
ntd
175-178
89-96
31%
10%
ntd
C
C
27H26N2O4‚0.7H2O
25H20N2O4‚0.7H2O
92-95
190-192
C31H30N2O4
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (<50% of the mean value. c All compounds had
analyses (0.4% of the theoretical except as indicated by an asterisk. nt indicates not tested.
b
d
in the directly bonded analogue 102 also resulted in a
weak inhibitor. Replacing the methoxy linker with an
ethylene (106) or ethyl (108) connecting group gave less
potent analogues. It was concluded from this set of
changes that the 2-quinolylmethoxy unit was a key
component for favorable in vitro and in vivo activity.
The final stage of evaluation focused on the central
phenoxy unit in lead compounds 10 and 11. The previ-
ous results of halogen substitution of the central phenyl
ring in the benzothiazolyl series (78 and 79) showed
enhanced inhibitory activity. Therefore we examined the
effect of halogen and other substituents on the central
phenyl ring in the lead quinolyl series of 10 and 11.
These results are summarized in Table 6. Strongly
electron-donating substituents in the 2-position like
methoxy (109 and 110) or thiocyclohexyl (115) resulted
in significant losses of in vivo potency. Electron-
withdrawing substituents such as chlorine (114 and
116) had comparable activity to 11 in both in vitro and
in vivo assays. Methyl substituents (111 and 112)
afforded compounds with good in vitro but lower in vivo
activities. Replacement of the central phenyl ring with
the 2,6-naphthyl group gave 119 (Table 7) which was
about 3 times less potent in vitro and much less active
in vivo. The 1,4-naphthyl analogue 120 had potent in
vitro activity with 89% inhibition at 25 nM. The 2,6-
benzothienyl analogue 129 showed good in vivo activity
with 80% inhibition at 3 mg/kg. The 3,5-isoxazolyl
analogue 130, the 5-phenyl-2,4-thiazolyl analogue 131,
and the 2,5-pyridyl analogue 132 were all weak inhibi-
tors. The 2,5-benzofuryl analogue 135 had only 31%
inhibition at 3 mg/kg. The 4,4′-biphenyl analogue 136
and the 2,5-biphenyl analogue 140 gave only moderate
activity in vitro.
From the set of inhibitors evaluated, 11 was chosen
as a lead compound for more detailed investigation of

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 699
Ta ble 8. Comparison of the Biological Activity of Stereoisomers of 11
in vivo rat pleurisyb
ED50, mg/kg, or
% I at mg/kg
in vivo rat
human PMNLa
IC50, nM
anaphylaxisc
ED50, mg/kg
HWBLd
IC50, µM
rate
T1/2, h
monkeye
T1/2, h
doge
T1/2, h
stereoisomer
R
RS-E/ Zg
RS-Z
RS-E
RS-E
R-E
OH
OH
32
170
15
95% at 100
70
8
89% at 30 µM
ntf
0.50
74% at 0.3
29% at 3
43% at 0.3
0.14
1.20
ntf
2.10
59% at 12.5 nM ntf
ntf
1 (iv)
ntf
5.4 (po), 2 (iv)
ntf
OH
1.20
1.80
ntf
1.5 (po) 5.6 (po)
O-Na+
OH
ntf
72% at 1.56 nM ntf
ntf ntf
ntf
63% at 12.5 nM ntf
3.8 (po) 4.5 (po)
11.8 (po) 4 (po) 4.6 (po)
10.3 (iv)
S-E
S-E
OH
ntf
0.84
0.72
O-Na+
34
0.13
1.6 (iv)
5.6 (po), 5.8 (iv)
a
Inhibition of calcium ionophore (A-23187)-stimulated LTB4 formation in human neutrophils. The 95% confidence limits were (<20%
b
of the mean value. Ionophore-induced rat pleurisy. The 95% confidence limits were (< 50% of the mean value. ED50 values (mg/kg) are
reported as the mean of separate dose-response determinations. c Rat anaphylaxis16 leukotriene formation, oral dose. Human whole
d
blood LTB4 assay.21 e Plasma half-life. f nt indicates not tested. E/ Z ratio was 7:1.
g
the biological properties of its stereoisomers. These
results are summarized in Table 8. The racemic Z and
E isomers of 11 inhibited intact stimulated human
neutrophils with IC50 ) 170 and 15 nM, respectively.
Resolution of the optical isomers gave the S-(E) isomer
with IC50 ) 8 nM compared to the R-(E) isomer with
IC50 ) 70 nM. The absolute configuration of the R and
S enantiomers of 11 was assigned by X-ray crystal-
lographic studies previously reported.22 The sodium salt
of S-(E)-11 provided superior oral activity in rat pleu-
risy15 and rat anaphylaxis16 models with ED50 ) 0.14
and 0.13 mg/kg, respectively.17 Further characterization
of S-(E)-11 sodium salt in a mouse granuloma model18
also gave effective inhibition of LTB4 with an oral ED50
) 0.70 mg/kg. In a model of lung inflammation,19 Brown
Norway rats injected with Sephadex G200 developed
increased levels of cysteinyl leukotrienes and eosino-
phils in bronchoalveolar lavage fluid (BAL). The sodium
salt of S-(E)-11 had an oral ED50 ) 0.1 mg/kg for
blocking LTE4 in BAL and an ED50 ) 0.2 mg/kg for
blocking eosinophil influx in BAL. In a guinea pig
model20 of airway obstruction the S-(E)-11 sodium salt
was very effective with an oral ED50 ) 2 mg/kg. Initial
pharmacokinetic studies showed that S-(E)-11 had a
good half-life (t1/2) in dog, rat, and monkey.
linked to the R position of propionic acid with the E
geometry as in 11. The S enantiomer of E-11 had
approximately 10-fold better activity in vitro and in vivo
than its R enantiomer. Heteroarylmethoxyphenylalkoxy-
iminoalkylcarboxylic acids provide a new class of leu-
kotriene biosynthesis inhibitors, and S-(E)-11-Na salt
(A-93178) was selected for additional preclinical evalu-
ation. One of the remaining challenges will be to provide
an efficient synthetic process22 for the large-scale prepa-
ration of this promising leukotriene biosynthesis inhibi-
tor.
Exp er im en ta l Section
Ch em istr y Gen er a l. Melting points were taken on a
Thomas-Hoover melting apparatus and are uncorrected. 1H
NMR spectra were recorded using a Nicolet QE-300 (300 MHz)
instrument. Mass spectra were obtained with a Hewlett-
Packard HP5985 spectrometer. Microanalyses were performed
by the Robertson Microlit Laboratories, Inc., Madison, NJ .
Reagents were obtained from Aldrich and Lancaster Chemical
Companies. The final carboxylic acid products were crystallized
from ethyl acetate and hexane mixtures.
Rep r esen ta tive P r oced u r e a s Ou tlin ed in Sch em e
1. Cycloh exyl(4-(2-qu in olylm eth oxy)p h en yl)m eth oxy-
im in oa cetic Acid (E-(RS)-10, R ) cycloh exyl, m ) 0, n )
0, R1 ) H). To a solution of 4-hydroxybenzaldehyde (5) (3.66
g, 30 mmol) and K2CO3 (8.24 g, 60 mmol) in DMF (75 mL)
was added 2-chloromethylquinoline HCl (6.42 g, 30 mmol), and
the resulting solution was stirred at ambient temperature for
16 h, then poured into water (100 mL), and extracted with
EtOAc. The extract was dried with MgSO4, concentrated in
vacuo, and chromatographed (silica gel, 2:1 hexanes-EtOAc)
to afford 5.8 g (74%) of 4-(2-quinolylmethoxy)benzaldehyde.
To a solution of 4-(2-quinolylmethoxy)benzaldehyde (2.63 g,
10 mmol) in THF (50 mL) at -78 °C was added cyclohexyl-
magnesium chloride (10 mL of a 2 M solution in THF, 20
mmol). The resulting mixture was stirred at ambient temper-
ature for 12 h and then quenched with aqueous saturated NH4-
Cl (25 mL) and the THF was removed in vacuo. To the residue
was added water (50 mL) and the product was extracted with
EtOAc. The extract was dried with MgSO4, concentrated in
vacuo, and purified by chromatography (silica gel, 9:1 CH2-
Cl2-EtOAc) to afford 3.3 g (94%) of cyclohexyl(4-(2-quinolyl-
methoxy)phenyl)methanol (7, R ) cyclohexyl, m ) 0, n ) 0).
To a mixture of cyclohexyl(4-(2-quinolylmethoxy)phenyl)-
methanol (3.47 g, 10 mmol), Ph3P (3.93 g, 15 mmol), and
N-hydroxyphthalimide (1.55 g, 9.5 mmol) in THF (100 mL)
was added dropwise a solution of diethyl azodicarboxylate
Con clu sion
S-(E)-2-Cyclohexyl(4-(2-quinolylmethoxy)phenyl)-
methoxyiminopropionic acid sodium salt (S-(E)-11-Na
salt) was the optimized lead compound arising from our
studies to enhance the leukotriene inhibitory properties
of the 2-quinolylmethoxyphenyl series represented by
REV-591 (1). The hypothesis of insertion of an oxime
group provided a series of leukotriene inhibitors with
optimized in vitro and in vitro activity. The structural
features of this series were examined with respect to
the components in a systematic manner to identify the
key factors responsible for optimized activity in vivo.
The 2-quinolylmethoxyphenyl moiety and the cyclohexyl
group in the benzylic position were important for
superior activity. The presence of the carboxylic group
was particularly important for in vivo activity. The best
results were obtained when the iminoxy moiety was

700 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Kolasa et al.
(DEAD; 2.4 mL, 15 mmol) in THF (15 mL). The mixture was
stirred at room temperature for 14 h and concentrated in
vacuo, and the residue was chromatographed (silica gel, 2:1
hexanes-EtOAc) to provide 4.9 g (99%) of oily N-phthaloyl-
O-(cycloh exyl-4-(2-qu in olin ylm et h oxy)ph en yl)m et h yl-
hydroxylamine (8, R ) cyclohexyl, m ) 0, n ) 0).
A solution of N-phthaloyl-O-(cyclohexyl-4-(2-quinolinyl-
methoxy)phenyl)methylhydroxylamine from above and hydra-
zine hydrate (1.5 mL, 30 mmol) in EtOH-CH2Cl2 (1:1, 80 mL)
was refluxed for 30 min and cooled to room temperature, 10%
Na2CO3 (50 mL) was added, and the mixture was extracted
with EtOAc. The extract was washed with water and brine,
dried with MgSO4, and concentrated in vacuo to provide 3.11
g (86%) of O-(cyclohexyl-4-(2-quinolinylmethoxy)phenyl)meth-
ylhydroxylamine (9, R ) cyclohexyl, m ) 0, n ) 0).
A mixture of O-(cyclohexyl-4-(2-quinolinylmethoxy)phenyl)-
methylhydroxylamine (347 mg, 1 mmol), glyoxylic acid hydrate
(92 mg, 1 mmol), and AcOH (0.06 mL, 1 mmol) in 1,4-dioxane
(15 mL), H2O (5 mL), and MeOH (10 mL) was stirred at
ambient temperature for 8 h, the organics were removed in
vacuo, and the product was extracted with EtOAc. The extract
was dried with MgSO4 and concentrated in vacuo. The residue
was dissolved in DMF (25 mL) and was treated with Na2CO3
(84 mg, 1 mmol) and CH3I (3 mL), and the resulting mixture
was stirred at ambient temperature for 72 h, then poured into
water (50 mL), and extracted with ethyl acetate. The ethyl
acetate extract was washed with water and brine, dried with
MgSO4, and concentrated in vacuo and the residue was
chromatographed (silica gel, 5:2 hexanes-Et2O) to afford 225
mg (51%) of (E)-cyclohexyl(4-(2-quinolylmethoxy)phenyl)-
methoxyiminoacetic acid methyl ester (E-(RS)-10 methyl
ester, R ) cyclohexyl, m ) 0, n ) 0, R1 ) H): 1H NMR (300
MHz, DMSO-d6) δ 1.10 (m, 5 H), 1.28 (m, 1 H), 1.65 (m, 4 H),
1.90 (m, 1 H), 3.69 (s, 3 H), 4.42 (d, J ) 7 Hz, 1 H), 5.36 (s, 2
H), 7.05 (d, J ) 9 Hz, 2 H), 7.20 (d, J ) 9 Hz, 2 H), 7.62 (m, 1
H), 7.78 (m, 2 H), 7.80 (m, 1 H), 8.01 (m, 2 H), 8.42 (d, J ) 9
Hz, 1 H); MS (DCI-NH3) m/z 433 (M + H)+; and 18 mg (4%)
of (Z)-cyclohexyl(4-(2-quinolylmethoxy)phenyl)methoxyimino-
acetic acid methyl ester (Z-(RS)-10 methyl ester, R ) cyclo-
hexyl, m ) 0, n ) 0, R1 ) H): 1H NMR (300 MHz, DMSO-d6)
δ 1.10 (m, 5 H), 1.33 (m, 1 H), 1.56 (m, 4 H), 1.85 (m, 1 H),
3.75 (s, 3 H), 4.84 (d, J ) 7 Hz, 1 H), 5.36 (s, 2 H), 7.03 (d, J
) 9 Hz, 2 H), 7.15 (d, J ) 9 Hz, 2 H), 7.26 (s, 1 H), 7.62 (m, 1
H), 7.78 (d, J ) 9 Hz, 1 H), 7.79 (m, 1 H), 8.01 (t, J ) 9 Hz, 2
H), 8.42 (d, J ) 9 Hz, 1 H); MS (DCI-NH3) m/z 433 (M + H)+.
1 H); MS (DCI-NH3) m/z 447 (M + H)+. Anal. Calcd for
C
27H30N2O4: C, 72.62; H, 6.77; N, 6.27. Found: C, 72.45; H,
7.11; N, 6.09.
To a solution of E-(RS)-11 methyl ester (770 mg, 1.7 mmol)
in 1,4-dioxane-MeOH (2:1) (60 mL) was added 1 N NaOH (1.8
mL) and the mixture was stirred at room temperature for 12
h; the organic solvents were removed in vacuo; the residue
was diluted to 20 mL and acidified to pH 3. The solid product
was collected by filtration, dried in vacuo, and recrystallized
from ethyl acetate-hexane to provide 720 mg (98%) of E-(RS)-
11: mp 183-184 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.12
(m, 5 H), 1.35 (m, 1 H), 1.67 (m, 4 H), 1.86 (m, 1 H), 1.98 (s, 3
H), 4.92 (d, J ) 7 Hz, 1 H), 5.35 (s, 2 H), 7.03 (d, J ) 9 Hz, 2
H), 7.17 (d, J ) 9 Hz, 2 H), 7.62 (m, 1 H), 7.68 (d, J ) 9 Hz, 1
H), 7.78 (m, 1 H), 8.00 (m, 2 H), 8.42 (d, J ) 9 Hz, 1 H); MS
(DCI-NH3) m/z 433 (M + H)+. Anal. Calcd for C26H28N2O4:
C, 72.20; H, 6.53; N, 6.48. Found: C, 71.90; H, 6.75; N, 6.28.
Rep r esen ta tive P r oced u r e a s Ou tlin ed in Sch em e 2.
2-Bu tyl-1-(4-(2-qu in olylm eth oxy)p h en yl)h exyl-1-oxyim i-
n oa cetic Acid (40). A mixture of 4-hydroxyacetophenone (38)
(2.72 g, 20 mmol), anhydrous K2CO3 (5.52 g, 40 mmol), and
2-chloroquinoline HCl (4.28 g, 20 mmol) in DMSO (50 mL) was
stirred at room temperature for 14 h. The mixture was diluted
with water (200 mL) and extracted with ethyl acetate to
provide 5.5 g of crude 4-(2-quinolylmethoxy)acetophenone.
The crude ketone (2.10 g, 7.58 mmol) in anhydrous DME
(70 mL) at room temperature was treated with 1-iodobutane
(2.59 mL, 22.7 mmol) and potassium tert-butoxide (1.91 g, 17.1
mmol). The suspension was warmed to 55 °C, stirred for 16 h,
and concentrated in vacuo and the residue was diluted with
EtOAc and H2O. The pH was adjusted to 5 by adding 10% citric
acid, the organic layer was separated, washed with water and
brine, dried over MgSO4, and concentrated in vacuo, and the
residue was purified by chromatography (silica gel, 8:1 hex-
anes-EtOAc, 6:1 hexanes-EtOAc, 4:1 hexanes-EtOAc) to
give 1.45 g (52%) of 2-nonyl 4-(2-quinolylmethoxy)phenyl
ketone: 1H NMR (300 MHz, CDCl3) δ 0.84 (t, J ) 7.5 Hz, 6
H), 1.24 (m, 8 H), 1.48 (m, 2 H), 1.73 (m, 2 H), 3.30 (m, 1 H),
5.45 (s, 2 H), 7.08 (d, J ) 9 Hz, 2 H), 7.57 (m, 1 H), 7.65 (d, J
) 9 Hz, 1 H), 7.76 (m, 1 H), 7.85 (d, J ) 9 Hz, 1 H), 7.95 (d, J
) 9 Hz, 2 H), 8.10 (d, J ) 9 Hz, 1 H), 8.21 (d, J ) 9 Hz, 1 H);
MS (DCI-NH3) m/z 390 (M + H)+.
The alkylated ketone (0.810 g, 2.08 mmol) was suspended
in EtOH (15 mL) and NaBH4 (0.206 g, 5.2 mmol) was added.
The mixture was stirred at room temperature for 1 h and then
refluxed for 1 h. The ethanol was removed in vacuo, 10% citric
acid was added, and the product was extracted with EtOAc.
The organic layer was washed with water and brine, dried over
MgSO4, and concentrated in vacuo and the residue was
purified by chromatography (silica gel, 1:1 hexane-EtOAc) to
give 750 mg (92%) of 2-butyl-1-(4-(2-quinolylmethoxy)phenyl)-
Hydrolysis of E-(RS)-10 methyl ester with 1 N NaOH in
1,4-dioxane-MeOH at room temperature provided E-(RS)-10
1
(R ) cyclohexyl, m ) 0, n ) 0, R1 ) H): mp 197-198 °C; H
NMR (300 MHz, DMSO-d6) δ 1.10 (m, 5H), 1.68 (m, 1H), 1.65
(m, 4H), 1.90 (m, 1H), 4.89 (d, 1H, J ) 7 Hz), 5.35 (s, 2H),
7.04 (d, 2H, J ) 9 Hz), 7.18 (d, 2H, J ) 9 Hz), 7.56 (s, 1H),
7.62 (m, 1H), 7.78 (d, 1H, J ) 9 Hz), 7.80 (m, 1H), 8.00 (t, 2H,
J ) 9 Hz), 8.41 (d. 1H, J ) 9 Hz), 13.16 (broad s, 1H); MS
(DCI-NH3) m/z 419 (M + H)+. Anal. Calcd for C25H26N2O4:
C, 71.75; H, 6.26; N, 6.69. Found: C, 71.69; H, 6.50; N, 6.63.
1
1-hexanol (39) as a white powder: mp 115-116 °C; H NMR
(300 MHz, CDCl3) δ 0.85 (m, 6 H), 1.24 (m, 12 H), 1.59 (m, 2
H), 4.58 (dd, J ) 6, and 3 Hz, 1 H), 5.38 (s, 2 H), 6.90 (d, J )
9 Hz, 2 H), 7.24 (d, J ) 9 Hz, 2 H), 7.55 (m, 1 H), 7.68 (d, J )
9 Hz, 1 H), 7.74 (m, 1 H), 7.83 (d, J ) 9 Hz, 1 H), 8.10 (d, J )
9 Hz, 1 H), 8.20 (d, J ) 9 Hz, 1 H); MS (DCI-NH3) m/z 392
(M + H)+.
E-(RS)-2-(Cycloh exyl(4-(2-q u in olylm et h oxy)p h en yl)-
m eth oxyim in o)p r op ion ic Acid (E-(RS)-11). The Z and E
isomers of 2-cyclohexyl(4-(2-quinolylmethoxy)phenyl)meth-
oxyiminopropionic acid methyl ester (1.18 g) prepared as
previously described22 were separated by chromatography
(silica gel, hexanes-Et2O 3:1) to afford 140 mg (12%) of
Z-(RS)-11 methyl ester: 1H NMR (300 MHz, DMSO-d6) δ 0.93
(m, 3 H), 1.08 (m, 2 H), 1.32 (m, 1 H), 1.60 (m, 4 H), 1.68 (m,
1 H), 1.91 (s, 3 H), 3.80 (s, 3 H), 4.73 (d, J ) 7 Hz, 1 H), 5.36
(s, 2 H), 7.03 (d, J ) 9 Hz, 2 H), 7.14 (d, J ) 9 Hz, 2 H), 7.62
(m, 1 H), 7.69 (d, J ) 8 Hz, 1 H), 7.78 (m, 1 H), 8.02 (m, 2 H),
8.43 (d, J ) 8 Hz, 1 H); MS (DCI-NH3) m/z 447 (M + H)+.
Anal. Calcd for C27H30N2O4: C, 72.62; H, 6.77; N, 6.27.
Found: C, 72.49; H, 6.61; N, 5.99; and 960 mg (81%) of E-(RS)-
11 methyl ester: mp 105-106 °C; 1H NMR (300 MHz, DMSO-
d6) δ 1.05 (m, 5 H), 1.33 (m, 1 H), 1.67 (m, 4 H), 1.85 (m, 1 H),
2.03 (s, 3 H), 3.68 (s, 3 H), 4.95 (d, J ) 7 Hz, 1 H), 7.04 (d, J
) 9 Hz, 2 H), 7.19 (d, J ) 9 Hz, 2 H), 7.63 (m, 1 H), 7.67 (d, J
) 8 Hz, 1 H), 7.80 (m, 1 H), 8.00 (m, 2 H), 8.42 (d, J ) 8 Hz,
According to the preparation of 10, the hydroxy intermediate
39 (510 mg, 1.3 mmol) afforded 160 mg (66%) of 40 as a white
powder: mp 109-112 °C; 1H NMR (300 MHz, DMSO-d6) δ 0.69
(m, 6 H), 1.15 (m, 12 H), 1.68-1.80 (m, 1 H), 5.02 (d, J ) 7.5
Hz, 1 H), 5.29 (s, 2 H), 6.90 (d, J ) 9 Hz, 2 H), 7.13 (d, J ) 9
Hz, 2 H), 7.51 (s, 1 H), 7.55 (m, 1 H), 7.61 (d, J ) 9 Hz, 1 H),
7.72 (m, 1 H), 7.94 (m, 2 H), 8.34 (d, J ) 9 Hz, 1 H), 13.10 (bs,
1 H); MS (DCI-NH3) m/z 463 (M + H)+. Anal. Calcd for
C
28H34N2O4: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.59; H,
7.43; N, 6.02.
P r oced u r e a s Ou tlin ed in Sch em e 3. Cycloh exyl(4-(2-
qu in oxalylm eth oxy)ph en yl)m eth oxyim in oacetic Acid (87).
To a solution of 4-benzyloxybenzaldehyde (85) (12.0 g, 56.5
mmol) in anhydrous THF (120 mL) at -78 °C was added
dropwise cyclohexylmagnesium chloride (32.51 mL, 65 mmol;
2 M solution in Et2O). After 30 min the mixture was allowed

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 701
to warm to room temperature, the reaction was quenched with
aqueous saturated NH4Cl, and the THF was removed in vacuo.
The product was extracted with EtOAc; the organic layer was
washed with water and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was triturated with hexane; the
solids were collected by filtration and washed with hexane to
give 15.0 g (90%) of (4-benzyloxyphenyl)cyclohexylmethanol
as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.11 (m, 6 H),
1.60 (m, 3 H), 1.77 (m, 1 H), 2.01 (m, 1 H), 4.30 (d, J ) 9 Hz,
1 H), 5.05 (s, 2 H), 6.95 (d, J ) 9 Hz, 2 H), 7.21 (d, J ) 9 Hz,
2 H), 7.39 (m, 5 H); MS (DCI-NH3) m/z 279 (M - H2O + H)+.
To the (4-benzyloxyphenyl)cyclohexylmethanol (13.98 g, 47.0
mmol) in EtOH (250 mL) at room temperature was added 10%
Pd/C (10 mol %) and the mixture was hydrogenated for 4 h.
The catalyst was filtered and the solvent was removed in vacuo
to give 9.24 g (95%) of (cyclohexyl)4-hydroxyphenylmethanol
(86) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.85
(m, 2 H), 1.10 (m, 3 H), 1.33 (m, 2 H), 1.62 (m, 3 H), 1.85 (m,
1 H), 4.08 (dd, J ) 9 and 7.5 Hz, 1 H), 4.82 (d, J ) 7.5 Hz, 1
H), 6.57 (d, J ) 9 Hz, 2 H), 7.02 (d, J ) 9 Hz, 2 H), 9.16 (s, 1
H); MS (DCI-NH3) m/z 206 (M)+, 189 (M - H2O + H)+.
Trichloroisocyanuric acid (3.55 g, 15.3 mmol) was added in
portions to a refluxing solution of 2-methylquinoxaline (5.0 g,
34.7 mmol) in CHCl3 (20 mL) over a period of 90 min. After
the addition was complete, the mixture was refluxed for 30
min, the mixture was cooled to room temperature and quenched
with ice-water, and 50% NaOH was added to adjust to pH 8.
The mixture was extracted with CHCl3, the organic layer was
dried over Na2SO4 and concentrated in vacuo, and the residue
was triturated with hexane to give 2-chloromethylquinoxa-
line: 1H NMR (300 MHz, CDCl3) δ 4.89 (s, 2 H), 7.80 (m, 2
H), 8.11 (m, 2 H), 9.03 (s, 1 H).
and the product was collected by filtration and dried in vacuo
to afford 2.4 g (80%) of crude acid.
To a mixture of the acid (2.4 g, 8.6 mmol) and Et3N (1.25
mL, 8.9 mmol) in THF (80 mL) at -10 °C was added dropwise
a solution of ethyl chloroformate (0.9 mL, 8.8 mmol) in THF
(5 mL). The mixture was stirred at -10 °C for the next 20
min and then warmed to 0 °C. NaBH4 (950 mg, 25 mmol) was
added followed by dropwise addition of methanol (30 mL).
Stirring was continued at 0 °C for 20 min and then allowed to
warm to room temperature. 10% Citric acid was added and
the mixture was concentrated in vacuo. The residue was
extracted with EtOAc, and the extract was washed with water
and brine, dried with MgSO4, and concentrated in vacuo and
the residue was chromatographed (silica gel, 9:1 CH2Cl2-
EtOH) to provide 2.2 g (96%) of alcohol 95: 1H NMR (300 MHz,
DMSO-d6) δ 4.50 (d, J ) 6 Hz, 2 H), 4.65 (t, J ) 6 Hz, 1 H),
5.5 (s, 2 H), 7.06 (d, J ) 9 Hz, 1 H), 7.34 (d, J ) 9 Hz, 2 H),
7.48 (m, 3 H), 7.68 (m, 1 H), 7.80 (m, 1 H), 7.90 (m, 1 H), 8.26
(d, J ) 8 Hz, 1 H); MS (DCI-NH3) m/z 266 (M + H)+.
To a solution of alcohol 95 (2.2 g, 8.3 mmol) in DMSO (25
mL) was added DCC (5.15 g, 25 mmol) followed by addition of
1 M H3PO4 in DMSO (4.2 mL) and the mixture was stirred at
room temperature for 3 h. EtOAc (75 mL) was added, the
dicyclohexylurea was filtered off, and the filtrate was washed
with water and brine, dried with MgSO4, and concentrated in
vacuo and the residue was chromatographed (silica gel, 3:1
CH2Cl2-EtOAc) to afford 2 g (95%) of 4-(2-quinolyloxymethyl)-
benzaldehyde: 1H NMR (300 MHz, CDCl3) δ 5.65 (s, 2 H), 7.01
(d, J ) 9 Hz, 1 H), 7.40 (m, 1 H), 7.70 (m, 4 H), 7.85 (m, 1 H),
7.91 (m, 2 H), 8.04 (d, J ) 8 Hz, 1 H), 10.03 (s, 1 H); MS (DCI-
NH3) m/z 264 (M + H)+.
Cyclohexylmagnesium chloride (2 M inEt2O, 3 mL, 6 mmol)
was added dropwise at -78 °C to a solution of the aldehyde
from above (1.32 g, 5 mmol) in THF (35 mL) and the mixture
was allowed to warm to ambient temperature and stirred for
12 h. The mixture was quenched with aqueous saturated NH4-
Cl, extracted with EtOAc, concentrated in vacuo, and chro-
matographed (silica gel, 3:1 CH2Cl2-EtOAc) to afford 1.25 g
(68%) of cyclohexyl(4-(2-quinolyloxymethyl)phenyl)methanol
(96): 1H NMR (300 MHz, CDCl3) δ 1.15 (m, 5 H), 1.41 (m, 1
H), 1.65 (m, 3 H), 1.80 (d + m, J ) 3 Hz, 2 H), 2.00 (m, 1 H),
4.40 (d-d, J ) 7 and 3 Hz, 1 H), 5.54 (s, 2 H), 6.96 (d, J ) 9
Hz, 1 H), 7.36 (m, 3 H), 7.50 (d, J ) 9 Hz, 2 H), 7.64 (m, 1 H),
7.72 (m, 1 H), 7.87 (m, 1 H), 8.01 (d, J ) 8 Hz, 1 H); MS (DCI-
NH3) m/z 348 (M + H)+.
According to the preparation of 11 using the intermediate
96 from above afforded 97: 315 mg (30%); mp 179-180 °C;
1H NMR (300 MHz, DMSO-d6) δ 1.12 (m, 5 H), 1.40 (m, 1 H),
1.70 (m, 5 H), 5.00 (d, J ) 7 Hz, 1 H), 5.49 (s, 2 H), 7.07 (d, J
) 9 Hz, 1 H), 7.27 (d, J ) 9 Hz, 2 H), 7.48 (m, 3 H), 7.68 (m,
1 H), 7.81 (m, 1 H), 7.90 (m, 1 H), 8.26 (d, J ) 8 Hz, 1 H),
12.91 (broad s, 1 H); MS (DCI-NH3) m/z 433 (M + H)+. Anal.
Calcd for C26H28N2O4: C, 72.20; H, 6.53; N, 6.48. Found: C,
72.06; H, 6.59; N, 6.17.
The intermediate alcohol 86 (2.0 g, 9.71 mmol) was dissolved
in DMF (100 mL) and K2CO3 (1.48 g, 10.7 mmol) was added
to this solution followed by 2-chloromethylquinoxaline (1.73
g, 9.71 mmol). The mixture was stirred at room temperature
for 48 h, quenched with H2O, and extracted with EtOAc. The
organic layer was washed with a 1 N NaOH, water, and brine,
dried over MgSO4, and concentrated in vacuo and the residue
was triturated with hexane to give 2.9 g of cyclohexyl(4-(2-
quinoxalylmethoxy)phenyl)methanol: mp 134-136 °C; 1H
NMR (300 MHz, DMSO-d6) δ 1.00 (m, 5 H), 1.36 (m, 2 H), 1.62
(m, 3 H), 1.73 (m, 1 H), 4.15 (dd, J ) 9 and 7.5 Hz, 1 H), 4.92
(d, J ) 7.5 Hz, 1 H), 7.03 (d, J ) 9 Hz, 2 H), 7.20 (d, J ) 9 Hz,
2 H), 7.89 (m, 1 H), 8.12 (m, 2 H), 9.10 (s, 1 H); MS (DCI-
NH3) m/z 349 (M + H)+.
According to the preparation of 10 using the intermediate
cyclohexyl(4-(2-quinoxalylmethoxy)phenyl)methanol (209 mg,
0.6 mmol) afforded 87: 192 mg, 39% yield; mp 159-162 °C;
1H NMR (DMSO-d6) δ 300 MHz) δ 1.04 (m, 6 H), 1.26 (m, 1
H), 1.68 (m, 4 H), 1.91 (m, 1 H), 4.91 (d, J ) 9 Hz, 1 H), 5.46
(s, 2 H), 7.09 (d, J ) 9 Hz, 2 H), 7.21 (d, J ) 9 Hz, 2 H), 7.57
(s, 1 H), 7.90 (m, 2 H), 8.13 (m, 2 H), 9.12 (s, 1 H), 13.18 (bs,
1 H); MS (DCI-NH3) m/z 420 (M + H)+.
P r oced u r e a s Ou tlin ed in Sch em e 4. 2-(Cycloh exyl(4-
( 2 -q u i n o l y l o x y m e t h y l ) p h e n y l ) m e t h o x y i m i n o ) -
p r op ion ic Acid (97). To a solution of 2-hydroxyquinoline (4.35
g, 30 mmol), methyl 4-hydroxymethylbenzoate (94) (4.98 g,
30 mmol), and Ph3P (13.1 g, 50 mmol) in THF (100 mL) was
added dropwise a solution of DIAD (8.3 mL, 50 mmol) in THF
(15 mL) and the resulting mixture was stirred at ambient
temperature for the next 14 h. The solution was then concen-
trated in vacuo and the residue was chromatographed (silica
gel, 3:1 hexanes-EtOAc) to obtain 3.1 g (35%) of methyl 4-(2-
quinolyloxymethyl)benzoate: 1H NMR (300 MHz, DMSO-d6)
δ 3.86 (s, 3 H), 5.61 (s, 2 H), 7.12 (d, J ) 9 Hz, 1 H), 7.46 (m,
1 H), 7.68 (m, 3 H), 7.79 (m, 1 H), 7.91 (m, 1 H), 8.00 (m, 2 H),
8.40 (d, J ) 8 Hz, 1 H); MS (DCI-NH3) m/z 294 (M + H)+.
P r oced u r e a s Ou tlin ed in Sch em e 5. Cycloh exyl(4-(2-
qu in olyl)p h en yl)m eth oxyim in oa cetic Acid (102). A mix-
ture of 2-bromoquinoline (1.0 g, 4.83 mmol), 4-formylben-
zeneboronic acid (99) (0.8 g, 5.31 mmol), 2 M Na2CO3 (4.8 mL,
9.7 mmol), and Pd(Ph3P)2Cl2 (0.17 g, 0.24 mmol) was dissolved
in benzene and refluxed for 24 h. The reaction was allowed to
cool to room temperature before adding more Pd(Ph3P)2Cl2
(0.17 g, 0.24 mmol) and refluxing for another 24 h. The reaction
was cooled, filtered through Celite, and concentrated in vacuo,
and the crude oil was purified by chromatography (silica gel,
1:9 EtOAc-CH2Cl2) to yield 0.37 g (32%) of aldehyde 100.
The aldehyde 100 (125 mg, 0.54 mmol) was dissolved in THF
(5 mL) and cooled to -78 °C, cyclohexylmagnesium chloride
(2.0 M solution in hexane, 0.3 mL, 0.6 mmol) was added, and
the mixture was allowed to warm to room temperature. An
equal volume of 1 M citric acid was then added and the
mixture was extracted with EtOAc, washed with water and
brine, dried over MgSO4, filtered, and evaporated. The mate-
rial was recrystallized from Et2O-hexane to yield 70 mg (42%)
of alcohol 101.
A solution of the ester (3.1 g, 10.6 mmol) in 1,4-dioxane (75
mL) and MeOH (25 mL) was treated with 1 N NaOH (12 mL)
for 16 h at ambient temperature and at 50 °C for 1 h. The
solution was diluted with water (30 mL) and the organics were
removed in vacuo. The aqueous solution was acidified to pH 3

702 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Kolasa et al.
According to the preparation of 10 using the intermediate
alcohol 101 afforded 102: 23% yield; mp 182-184 °C; 1H NMR
(DMSO-d6) δ 1.37 (m, 11 H), 5.10 (d, J ) 9 Hz, 1 H), 7.45 (m,
2 H), 7.60 (m, 2 H), 7.68 (s, 1 H), 7.80 (m, 1 H), 8.05 (m, 2 H),
8.20 (m, 2 H), 8.47 (d, J ) 9 Hz, 1 H), 13.20 (bs, 1 H); MS
(DCI-NH3) m/z 389 (M + NH4)+. Anal. Calcd for C24H24N2O3‚
0.25H2O: C, 73.35; H, 6.28; N, 7.12. Found: C, 73.31; H, 6.27;
N, 7.35.
P r oced u r e a s Ou tlin ed in Sch em e 6. Cycloh exyl(4-(2-
q u in ol-2-ylet h en yl)p h en yl)m et h oxyim in oa cet ic Acid
(106). A solution of 4-bromobenzaldehyde (103) (5.13 g, 27.7
mmol) was dissolved in THF (30 mL) and cooled to 0 °C.
Cyclohexylmagnesium chloride (2 M solution in ether, 15 mL,
30 mmol) was added and the reaction was stirred at 0 °C for
0.5 h then overnight at room temperature. The reaction was
quenched with aqueous saturated NH4Cl and extracted with
ethyl acetate. The extracts were washed with NH4Cl, water,
and brine, dried over MgSO4, and evaporated and the residue
was chromatographed (silica gel, 1:9 Et2O-hexane) to yield
3.45 g (46%) of (4-bromophenyl)cyclohexylmethanol.
A mixture of (4-bromophenyl)cyclohexylmethanol (3.44 g,
12.8 mmol), tert-butyldimethylsilyl chloride (2.02 g, 13.4
mmol), and imidazole (915 mg, 13.4 mmol) in DMF (15 mL)
was stirred at room for 14 h, then diluted with water, and
extracted with EtOAc. The extracts were washed with water
and brine, dried over MgSO4, and concentrated in vacuo, and
the residue was chromatographed (silica gel, hexane) to afford
4.54 g (93%) of O-tert-butyldimethylsilyl ether of cyclohexyl-
(4-bromophenyl)methanol.
monitored by TLC and additional Raney Ni was added
periodically. After 6 h the reaction was filtered through Celite,
the solids were washed with ether, and the filtrate was dried
with MgSO4 and concentrated in vacuo to give cyclohexyl(4-
(2-quinol-2-ylethyl)phenyl)methanol (107) (542 mg, 82%).
According to the preparation of 10 using the intermediate
1
alcohol 107 afforded 108: 33% yield; H NMR (DMSO-d6) δ
1.43 (m, 11 H), 3.1 (m, 2 H), 3.25 (m, 2 H), 4.9 (d, J ) 7 Hz, 1),
7.15 (d, J ) 9 Hz, 2 H), 7.25 (d, J ) 9 Hz, 2 H), 7.55 (m, 2 H),
7.60 (s, 1 H), 7.75 (m, 1 H), 8.00 (m, 2 H), 8.30 (bd, J ) 9 Hz,
1 H), 13.20 (bs, 1 H); MS (DCI-NH3) m/z 417 (M + H)+. Anal.
Calcd for C26H28N2O3‚0.25H2O: C, 74.17; H, 6.82; N, 6.65.
Found: C, 73.99; H, 7.01; N, 6.52.
P r oced u r e a s Ou tlin ed in Sch em e 7. Cycloh exyl(6-(2-
qu in olylm eth oxy)n a p h th -2-yl)m eth oxyim in oa cetic Acid
(119). A THF solution of n-BuLi (68.12 mL, 170 mmol) was
added dropwise to 6-bromo-2-naphthol (117) (18.09 g, 81 mmol)
in anhydrous THF at -78 °C; after 15 min DMF (18.82 mL,
243 mmol) was added and the mixture was stirred 15 min.
The mixture was then allowed to warm to room temperature
and water was added. The resulting mixture was acidified to
pH 5 with 10% citric acid and the product was extracted with
EtOAc. The organic layer was washed with water and brine,
dried with MgSO4, filtered, and concentrated in vacuo, the
residue was triturated with hexane, and the precipitate was
filtered to give 11.45 g (82%) of 6-hydroxy-2-naphthaldehyde
(118): 1H NMR (300 MHz, DMSO-d6) δ 7.22 (m, 2 H), 7.80
(m, 2 H), 8.02 (d, J ) 9 Hz, 1H), 8.43 (s, 1 H), 10.04 (s, 1 H),
10.33 (s, 1 H); MS (DCI-NH3) m/z 173 (M + H)+.
This silyl ether (2.0 g, 5.2 mmol) was treated with n-
butyllithium (2.5 M solution in hexane, 2.5 mL, 6.25 mmol)
at -78 °C for 30 min. DMF (2 mL, 25.8 mmol) was added and
the reaction mixture was allowed to warm to room tempera-
ture for 1 h. The reaction was then quenched with 1 M citric
acid and extracted with EtOAc. The extracts were washed with
water and brine, dried over MgSO4, and evaporated and the
residue was chromatographed (silica gel, 1:19 Et2O-hexane)
to provide 1.3 g (77%) of O-tert-butyldimethylsilyl ether of
cyclohexyl(4-formylphenyl)methanol (104).
A solution of 2-chloromethylquinoline (3.8 mmol) and tri-
phenylphosphine (3.8 mmol) in toluene was stirred overnight
to provide 1.65 g of the corresponding phosphonium salt which
was suspended in THF (12 mL) and treated with t-BuOK (410
mg, 3.7 mmol). The bright yellow mixture was refluxed for 15
min, then cooled to room temperature and aldehyde 104 (208
mg, 0.62 mmol) in THF (8 mL) was added. The reaction
mixture was refluxed for 1.5 h, then cooled to room temper-
ature, acidified with 1 M citric acid, and extracted with EtOAc.
The extracts were washed with 1 M citric acid, water, and
brine, dried over MgSO4, and concentrated in vacuo, and the
residue was chromatographed (silica gel, 1:19 Et2O-hexane)
to yield 850 mg (61%) of O-tert-butyldimethylsilyl ether of
cyclohexyl(4-(2-quinol-2-ylethenyl)phenyl)methanol.
The alcohol intermediate from above (117 mg, 0.26 mmol)
was dissolved in acetonitrile (3 mL) and approximately 50
drops of HF were added. After stirring for 3 h at room
temperature the reaction was diluted with water and solid K2-
CO3 was added until the solution was basic. The mixture was
extracted with EtOAc. The extracts were washed with water
and brine, dried over MgSO4, evaporated, and chromato-
graphed (silica gel, 1:4 Et2O-hexane) to yield 81 mg (92%) of
cyclohexyl(4-(2-quinol-2-ylethenyl)phenyl)methanol (105).
According to the preparation of 10 using the intermediate
alcohol 105 afforded 106: 31% yield; mp 140-142 °C; 1H NMR
(DMSO-d6) δ 1.43 (m, 11 H), 5.05 (d, J ) 7 Hz, 1, 7.30 (d, J )
9 Hz, 2 H), 7.52 (m, 2 H), 7.65 (s, 1 H), 7.75 (d, J ) 9 Hz, 2 H),
7.85 (m, 5 H), 8.40 (d, J ) 9 Hz, 1 H), 13.30 (bs, 1 H); MS
(DCI-NH3) m/z 415 (M + H)+. Anal. Calcd for C26H26N2O3‚
0.25H2O: C, 74.53; H, 6.37; N, 6.68. Found: C, 74.45; H, 6.34;
N, 6.61.
According to the preparation of 10 using intermediate 118
afforded 119: 40% yield; mp 170-175 °C; 1H NMR (300 MHz,
DMSO-d6) δ 1.15 (m, 6 H), 1.64 (m, 3 H), 1.88 (m, 2 H), 5.08
(d, J ) 9 Hz, 1 H), 5.51 (s, 2 H), 7.35 (m, 2 H), 7.46 (d, J ) 3
Hz, 1 H), 7.63 (m, 2 H), 7.77 (m, 4 H), 7.88 (d, J ) 9 Hz, 1 H),
8.03 (m, 2 H), 8.43 (d, J ) 9 Hz, 1 H); MS (DCI-NH3) m/z 469
(M + H)+. Anal. Calcd for C29H28N2O4: C, 74.34; H, 6.02; N,
5.98. Found: C, 74.38; H, 6.24; N, 5.83.
P r oced u r e a s Ou tlin ed in Sch em e 8. 2-(Cycloh exyl(5-
(2-qu in olylm eth oxy)ben zo[2,3-b]th ien -2-yl)m eth oxyim i-
n o)p r op ion ic Acid (125). A mixture of 5-hydroxy-2-nitroben-
zyl alcohol (121) (5.1 g, 30 mmol), tetraethylammonium
fluoride hydrate (8.94 g, 60 mmol), and 2-chloromethylquino-
line (5.31 g, 30 mmol) in DMF (90 mL) was stirred at room
temperature for 72 h. The mixture was then poured into water
and extracted with EtOAc. The extract was dried with
anhydrous MgSO4 and concentrated in vacuo. To the residue
was added CH2Cl2 (25 mL) and the solid was filtered to provide
3.1 g of 2-nitro-5-(2-quinolylmethoxy)benzyl alcohol.
To the above alcohol (1.74 g, 5.6 mmol) and DCC (3.71 g,
18 mmol) in DMSO (25 mL) was added 1 M solution of H3PO4
in DMSO (2.7 mL), the resulting mixture was stirred at room
temperature for 1 h, EtOAc (100 mL) was added, and the
precipitated dicyclohexylurea was removed by filtration. The
filtrate was washed with water and brine, dried over anhy-
drous MgSO4, and concentrated in vacuo and the residue was
chromatographed (silica gel, 15:1 CH2Cl2-EtOAc) to afford
1.25 g of 2-nitro-5-(2-quinolylmethoxy)benzaldehyde (122).
To a mixture of 122 (1.24 g, 4 mmol) and K2CO3 (700 mg, 5
mmol) in DMF (15 mL) was added dropwise ethyl thioglycolate
(0.46 mL, 4 mmol), and the resulting mixture was stirred at
room temperature for 16 h, then poured into ice-water, and
extracted with EtOAc. The organic extract was washed with
water 122brine, dried with anhydrous MgSO4, 122concen-
trated in vacuo and the residue was chromatographed (silica
gel, 24:1 CH2Cl2-EtOAc) to provide 480 mg (39%) of ethyl 5-(2-
quinolylmethoxy)benzo[2,3-b]thiophene-2-carboxylate, which
was immediately hydrolyzed with 1 N NaOH (1.5 mL, 1.5
mmol) in 1,4-dioxane (15 mL) and MeOH (10 mL) for 8 h. The
mixture was concentrated in vacuo, the residue was acidified
to pH 3, and the solid product was collected by filtration to
provide 440 mg (99%) of 5-(2-quinolylmethoxy)benzo[2,3-b]-
thiophene-2-carboxylic acid (123).
Cycloh exyl(4-(2-qu in ol-2-yleth yl)p h en yl)m eth oxyim i-
n oa cet ic Acid (108). Cyclohexyl(4-(2-quinol-2-ylethenyl)-
phenyl)methanol (105) (660 mg, 1.44 mmol) in THF (10 mL)
was treated with Raney Ni. The progress of the reaction was
To a mixture of 123 (440 mg, 1.3 mmol), N-methyl-O-
methylhydroxylamine HCl (146 mg, 1.5 mmol), pyridine (0.122

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 703
mL, 1.5 mmol), and CBr4 (497 mg, 1.5 mmol) in CH2Cl2 (25
mL) and THF (15 mL) was added Ph3P (393 mg, 1.5 mmol) in
portions. The mixture was stirred at room temperature for 60
min and concentrated in vacuo and the residue was chromato-
graphed (silica gel, 9:1 CH2Cl2-EtOAc) to afford 470 mg (97%)
of 5-(2-quinolylmethoxy)benzo[2,3-b]thiophene-2-carboxylic acid
N-methyl-N-methoxyamide.
7.71 (m, 2 H), 7.80 (m, 1 H), 8.00 (m, 2 H), 8.41 (d, J ) 8 Hz,
1 H); MS (DCI-NH3) m/z 489 (M + H)+.
P r oced u r e a s Ou tlin ed in Sch em e 10. Cycloh exyl(5-
(2-qu in olylm eth oxy)ben zofu r a n -2-yl)m eth oxyim in oa ce-
tic Acid (135). To a solution of 2-hydroxy-5-methoxybenzal-
dehyde (133) (20.0 g, 131.0 mmol) and K2CO3 (45.26 g, 328.0
mmol) in DMF was added methyl bromoacetate (12.44 mL,
131.0 mmol) dropwise and the mixture was allowed to stir at
room temperature for 4 h then warmed to 80 °C and stirred
overnight. The reaction was quenched with H2O and the
precipitate was collected by filtration to give 11.0 g (41%) of
methyl 5-methoxy-2-benzofurancarboxylate as a pale yellow
solid: 1H NMR (300 MHz, DMSO-d6) δ 3.81 (s, 3 H), 3.89 (s,
3 H), 7.13 (dd, J ) 9 Hz and 3 Hz, 1 H), 7.28 (d, J ) 3 Hz, 1
H), 7.63 (d, J ) 9 Hz, 1 H), 7.69 (s, 1 H).
The ester from above (9.26 g, 50.0 mmol) was dissolved in
anhydrous CH2Cl2 at -15 °C and BBr3 (45 mL, 50.0 mmol)
was added to the solution. The mixture was stirred at this
temperature for 3 h and then allowed to warm to room
temperature and stirred overnight. The reaction was quenched
with MeOH, brine was added, and the mixture was extracted
with ethyl acetate, dried with MgSO4, and concentrated in
vacuo. The solid residue was triturated with hexane and the
solid collected by filtration to give 9.24 g of a yellow solid which
was immediately dissolved in MeOH and treated with SOCl2
(3.79 mL, 52.0 mmol). The reaction was allowed to stir at room
temperature for 70 h. Water was added to the mixture and
the resulting solid was collected by filtration to give 7.30 g
(76%) of 5-hydroxy-2-benzofurancarboxylic acid methyl ester
(134): 1H NMR (300 MHz, DMSO-d6) δ (3.87 s, 3 H), 6.96 (dd,
J ) 9 Hz and 3 Hz, 1 H), 7.06 (d, J ) 3 Hz, 1 H), 7.52 (d, J )
9 Hz, 1H), 7.62 (s, 1 H), 9.49 (s, 1 H).
The amide from above was treated at -78 °C with DIBAL
(1 N in THF, 1.5 mL, 1.5 mmol) and stirred at room temper-
ature for 18 h. More DIBAL (1.5 mL) was added and the
mixture was stirred for 15 h. Additional DIBAL (3 mL) was
added, stirred 12 h, and then quenched with aqueous saturated
NH4Cl. The mixture was extracted with ethyl acetate, dried
with anhydrous MgSO4, and concentrated in vacuo and the
residue was chromatographed (silica gel, 9:1 CH2Cl2-EtOAc)
to give 100 mg of 5-(2-quinolylmethoxy)benzo[2,3-b]thiophene-
2-carbaldehyde (124).
According to the preparation of 11 using the intermediate
124 afforded 125: 12% yield; mp 91-93 °C; 1H NMR (300
MHz, DMSO-d6) δ 1.18 (m, 6 H), 1.44 (m, 1 H), 1.63 (m, 3 H),
1.92 (m, 1 H), 2.00 (s, 3 H), 5.30 (d, J ) 7 Hz, 1 H), 5.43 (s, 2
H), 7.11 (d-d, J ) 9 and 3 Hz, 1 H), 7.25 (s, 1 H), 7.48 (d, J )
3 Hz, 1 H), 7.62 (m, 1 H), 7.70 (d, J ) 9 Hz, 1 H), 7.80 (m, 2
H), 8.01 (m, 2 H), 8.42 (d, J ) 9 Hz, 1 H), 13.05 (broad s, 1 H);
MS (DCI-NH3) m/z 489 (M + H)+.
P r oced u r e a s Ou tlin ed in Sch em e 9. 2-(Cycloh exyl(6-
(2-qu in olylm eth oxy)ben zo[2,3-b]th ien -2-yl)m eth oxyim i-
n o)p r op ion ic Acid (129). A mixture of 2-chloro-4-hydroxy-
benzaldehyde (126) (7.8 g, 50 mmol), K2CO3 (8.28 g, 60 mmol),
and 2-chloroquinoline (9.8 g, 55 mmol) in DMF (120 mL) was
stirred at room temperature for 36 h. The mixture was poured
into water (400 mL) and extracted with EtOAc to afford 14 g
(99%) of crude 2-chloro-4-(2-quinolylmethoxy)benzaldehyde.
According to the preparation of 129 using intermediate 134
1
afforded 135: 27% yield; mp 89-96 °C; H NMR (300 MHz,
Ethyl mercaptoacetate (5.65 mL, 50 mmol) was added to a
mixture of the aldehyde from above and K2CO3 (11 g, 80 mmol)
in DMF (150 mL). The resulting mixture was stirred at room
temperature for 72 h, water (500 mL) was added, and the
mixture was extracted with EtOAc. The organic layer was
washed with water and brine, dried with anhydrous MgSO4,
and concentrated in vacuo and the residue was chromato-
graphed (silica gel, 3:1 hexanes-EtOAc) to provide 14 g (80%)
of ethyl 6-(2-quinolylmethoxy)benzo[2,3-b]thiophene-2-car-
boxylate (127).
DMSO-d6) δ 1.12 (m, 5 H), 1.37 (m, 1 H), 1.66 (m, 3 H), 1.98
(m, 2 H), 5.11 (d, J ) 9 Hz, 1 H), 5.49 (s, 2 H), 6.82 (s, 1 H),
7.04 (dd, J ) 9 and 3 Hz, 1 H), 7.26 (d, J ) 3 Hz, 1 H), 7.50 (d,
J ) 9 Hz, 1 H), 7.62 (m, 2 H), 7.69 (d, J ) 9 Hz, 1 H), 7.79 (m,
1 H), 8.01 (m, 2 H), 8.41 (d, J ) 9 Hz, 1 H); MS (DCI-NH3)
m/z 459 (M + H)+. Anal. Calcd for C27H26N2O4‚0.70H2O: C,
68.83; H, 5.86; N, 5.95. Found: C, 68.74; H, 6.04; N, 5.86.
Cycloh exyl(5-(2-q u in olylm et h oxy)b en zofu r a n -2-yl)-
m eth oxyim in oa cetic a cid sod iu m sa lt (135 Na ): 1H NMR
(300 MHz, DMSO-d6) δ 1.12 (m, 5 H), 1.40 (m, 1 H), 1.64 (m,
3 H), 1.91 (m, 2 H), 4.90 (d, J ) 9 Hz, 1 H), 5.28 (s, 2 H), 6.68
(s, 1 H), 7.0 (dd, J ) 9 and 3 Hz, 1 H), 7.24 (d, J ) 9 Hz, 1 H),
7.35 (s, 1 H), 7.47 (d, J ) 9 Hz, 1 H), 7.62 (m, 1 H), 7.69 (d, J
) 9 Hz, 1 H), 7.79 (m, 1 H), 8.01 (m, 2 H), 8.41 (d, J ) 9 Hz,
1 H); MS (FAB) m/z 481 (M + Na)+.
P r oced u r e a s Ou t lin ed in Sch em e 11. Cycloh exyl-
(3-p h en yl-4-(2-qu in olylm eth oxy)p h en yl)m eth oxyim in o-
a cetic Acid (140). To 2-phenylanisole (137) (1.0 g, 5.55 mmol)
in CH2Cl2 (50 mL) was added AlCl3 (7.4 g, 55.48 mmol) at room
temperature. After 5 min, cyclohexanecarbonyl chloride (855
mg, 5.83 mmol) was added and the mixture was allowed to
stir for 4 h at room temperature. Water was added to the
reaction; the mixture was extracted with CH2Cl2. The com-
bined extracts were washed with aqueous saturated NaHCO3
and brine, dried over MgSO4, and evaporated to yield 1.6 g
(98%) of cyclohexyl 4-methoxyphenyl ketone as a yellow oil.
The product was carried on without further purification.
A solution of the ketone (1.6 g, 5.44 mmol) was dissolved in
benzene (100 mL) and AlBr3 (5.0 g, 18.75 mmol) was added
and refluxed for 2 h. After cooling to room temperature, 3 M
HCl was added and the mixture was extracted with Et2O. The
combined extracts were washed with water and brine, dried
over MgSO4, and evaporated and the crude product was
triturated with hexane and filtered to yield 1.5 g (60%) of
cyclohexyl (4-hydroxy-3-phenyl)phenyl ketone (138).
To 127 from above (7.3 g, 20 mmol) in 1,4-dioxane (75 mL)
and EtOH (75 mL) was added 1 N NaOH (30 mL) and the
resulting solution was stirred at room temperature for 24 h.
The solution was concentrated in vacuo, then diluted with H2O
(100 mL), and acidified to pH 3. The solid was collected by
filtration and dried under reduced pressure to provide 6.8 g
(99%) of crude 6-(2-quinolylmethoxy)benzo[2,3-b]thiophene-2-
carboxylic acid which was dissolved in THF (40 mL) and
treated with Et3N (3 mL, 21 mmol) and ethyl chloroformate
(2.1 mL, 21 mmol) at -20 to -15 °C for 25 min, then the
mixture was warmed to 0 °C, and NaBH4 (2.28 g, 60 mmol)
was added followed by dropwise addition of MeOH (30 mL).
The reaction was allowed to warm to room temperature and
acidified to pH 4. The solid was collected by filtration and dried
in vacuo to afford 4.64 g (72%) of 6-(2-quinolylmethoxy)benzo-
[2,3-b]thien-2-ylmethanol.
A solution of alcohol from above and DCC (12.36 g, 60 mmol)
in DMSO (50 mL) was treated with 1 M phosphoric acid in
DMSO (10 mL) for 2 h at ambient temperature. EtOAc (150
mL) was added and the dicyclohexylurea was removed by
filtration. The filtrate was washed with water and brine, dried
with anhydrous MgSO4, and concentrated in vacuo and the
residue was chromatographed (silica gel, 9:1 CH2Cl2-EtOAc)
to afford 3.8 g of 6-(2-quinolylmethoxy)benzo[b]thien-2-yl-
carbaldehyde (128).
According to the preparation of 11 using intermediate 128
afforded 129: 27% yield; mp 78-80 °C; H NMR (300 MHz,
DMSO-d6) δ 1.16 (m, 6 H), 1.45 (m, 1 H), 1.68 (m, 3 H), 1.90
(m, 1 H), 1.98 (s, 3 H), 5.25 (d, J ) 7 Hz, 1 H), 5.42 (s, 2 H),
7.12 (dd, J ) 9 Hz, 3 Hz, 1 H), 7.24 (s, 1 H), 7.62 (m, 2 H),
To a solution of 138 (1.5 g, 5.36 mmol) in DMF (50 mL) were
added K2CO3 (2.4 g, 17.14 mmol), 2-chloromethylquinoline HCl
(1.2 g, 5.36 mmol), and KI (100 mg, 0.60 mmol). The reaction
was allowed to stir for 24 h at room temperature. An equal
volume of 1 M citric acid was added and the mixture was
1

704 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4
Kolasa et al.
(3) Israel, E. Moderating the Inflammation of Asthma: Inhibiting
the Production or Action of Products of the 5-Lipoxygenase
Pathway. Ann. Allergy 1994, 72, 279-284.
(4) Henderson, J r., W. R. The Role of Leukotrienes in Inflammation.
Ann. Intern. Med. 1994, 121, 684-697.
(5) Young, R. N.; Gillard, J . W.; Hutchinson, J . H.; Leger, S.; Prasit,
P. Discovery of inhibitors of the 5-lipoxygenase-activating protein
(FLAP). J . Lipid Mediators 1993, 6, 233-238.
(6) (a) Mancini, J . A.; Abramovitz, M.; Cox, M. E.; Wong, E.;
Charleson, S.; Perrier, H.; Wang, Z.; Prasit, P.; Vickers, P. J .
5-Lipoxygenase-Activating Protein is an Arachidonic Acid Bind-
ing Protein. FEBS Lett. 1993, 318, 277-281. (b) Abramovitz,
M.; Wong, E.; Cox, M. E.; Richardson, C. D.; Li, C.; Vickers, P.
J . 5-Lipoxygenase-Activating Protein Stimulates the Utilization
of Arachidonic Acid by 5-Lipoxygenase. Eur. J . Biochem. 1993,
215, 105-111. (c) Vickers, P. J . 5-Lipoxygenase-Activating
Protein (FLAP). J . Lipid Mediators Cell Signal. 1995, 12, 185-
194.
(7) Brideau, C.; Chan, C.; Denis, D.; Evans, J . F.; Ford-Hutchinson,
A. W.; Fortin, R.; Gillard, J . W.; Guay, J .; Hutchinson, J .; J ones,
T.; Leger, S.; Mancini, J . A.; McFarlane, C. S.; Pickett, C.;
Piechuta, H.; Prasit, P.; Riendau, D.; Rouzer, C. A.; Tagari, P.;
Vickers, P. J .; Young, R. N. Pharmacology of MK0591 (3-[1-(4-
Chlorobenzyl)-3-(tert-Butylthio)-5-(Quinolin-2-yl-methoxy)indol-
2-yl]-2,2-dimethylpropanoic Acid), a Potent, Orally Active Leu-
kotriene Biosynthesis Inhibitor. Can. J . Physiol. Pharmacol.
1992, 70, 799-807.
extracted with EtOAc. The combined extracts were washed
with water and brine, dried over MgSO4, and evaporated. The
crude product was triturated with hexane and collected by
filtration to yield 1.8 g (79%) of the quinolylmethoxy ketone,
which was immediately reduced with NaBH4 (323 mg, 8.54
mmol) in methanol. The reaction was stirred for 1 h at room
temperature. Water (50 mL) was added and extracted with
EtOAc. The combined extracts were washed with water and
brine, dried over MgSO4, filtered, and evaporated. The crude
product was triturated with hexane and collected by filtration
to yield 1.4 g (78%) of 139.
According to the preparation of 10 using intermediate 139
1
afforded 140: 35% yield; mp 190-192 °C; H NMR (DMSO-
d6) δ 1.47 (m, 11 H), 4.97 (d, J ) 9 Hz, 1 H), 5.39 (s, 2 H), 7.86
(m, 15 H), 13.3 (bs, 1 H); MS (DCI-NH3) m/z 495 (M + H)+.
Anal. Calcd for C31H30N2O4: C, 75.30; H, 6.07; N, 5.66.
Found: C, 74.69; H, 6.23; N, 5.46.
Biologica l Meth od s. Percent inhibition was computed by
comparing individual values in treatment groups to the mean
value of the control group. Statistical significance was deter-
mined using one-way analysis of variance and Tukey’s multiple
comparison procedure. Linear regression was used to estimate
IC50 and ED50 values.
Ra t P leu r a l In fla m m a tion Mod el. Pleural inflammation
was induced in male rats according to the method of Rao et
al.15a Animals were dosed with experimental compounds in
0.2% HPMC 1 h before the intrapleural injection of the calcium
ionophore A-23187. The rats were lightly anesthetized with
Penthrane and injected intrapleurally with 0.5 mL of 2%
ethanol in injectable saline containing 20 µg of A-23187. Thirty
minutes later, the animals were killed, and the pleural cavities
were lavaged with ice-cold saline. The lavage fluid was then
added to ice-cold methanol (final methanol concentration, 30%)
to lyse cells and precipitate protein. Leukotrienes were deter-
mined by enzyme immunoassay.
Ra t P er iton ea l An a p h yla xis Mod el. This assay was
performed as described by Young et al.16a Rats were passively
sensitized to bovine serum albumin, and 3 h later they were
challenged in the peritoneal cavity with antigen. The perito-
neal cavity was lavaged 15 min later, and the fluids were
analyzed for leukotriene content by enzyme immunoassay.
Mou se Gr a n u lom a Mod el. Polyacrylamide gel-induced
inflammation in mice was conducted according to the method
of Harris et al.18 Anesthetized mice were injected with poly-
acrylamide gel (Bio-Gel P4) in the back. At various times after
the injection of the gel, the animals were euthanized, the
injection sites were lavaged, and the level of LTB4 was
determined.
Lu n g In fla m m a tion Mod el. A model of lung inflammation
in Brown Norway rats was conducted according to the method
of Namovic et al.19 Brown Norway rats were orally dosed with
inhibitors in 0.2% methylcellulose and then injected in the
central tail vein with Sephadex G-200. For the next 3 days,
the rats were dosed either once or twice a day with either
inhibitor or the vehicle control, 0.2% methylcellulose. The rats
were anesthetized and the airways were lavaged with phos-
phate-buffered saline and analyzed for leukotriene content by
enzyme immunoassay.
(8) Musser, J H.; Chakraborty, U.; Sciortino, S.; Gordon, R. J .;
Khandwala, A.; Neiss, E. S.; Pruss, T. P.; Van Inwegen, R.;
Weinryb, I.; Coutts, S. M. Substituted Arylmethyl Phenyl Ethers.
Part 1. A Novel Series of 5-Lipoxygenase Inhibitor and Leuko-
triene Antagonists. J . Med. Chem. 1987, 30, 96-104.
(9) (a) Musser, J . H.; Kreft, A. F. 5-Lipoxygenase: Properties,
Pharmacology and the Quinolyl(bridged)aryl class of inhibitors.
J . Med. Chem. 1992, 35, 2502-2524. (b) Kreft, A. F.; Marshall,
L. A.; Wong, A. Structure-Activity Relationships in the Quino-
line-Containing Class of Inhibitors of 5-Lipoxygenase (5-LO)
Enzyme Translocation and Activation. Drugs Future 1994, 19,
255-264.
(10) (a) Muller-Peddinghaus, R.; Raddatz, S. BAY x 1005. Drugs
Future 1995, 20, 996-1000. (b) Matzke, M.; Beckermann, B.;
Fruchtmann, R.; Fugmann, B.; Gardiner, P. J .; Goossens, J .;
Hatzelmann, A.; J unge, B.; Keldenich, J .; Konsdorfer, C.; Mohrs,
K.-H.; Muller-Peddinghaus, R.; Raddatz, S. Leukotriene Syn-
thesis Inhibitors of the Quinoline Type: Parameters for the
Optimization of Efficacy. Eur. J . Med. Chem. 1995, 30, 442-
443. (c) Hatzelmann, A.; Goossens, J .; Fruchtmann, R.; Mohrs,
K.-H.; Raddatz, S.; Muller-Peddinghaus, R. Inversely-Correlated
Inhibition of Human 5-Lipoxygenase Activity by BAY × 1005
and Other Quinoline Derivatives in Intact Cells and a Cell-Free
System-Implications for the Function of 5-Lipoxygenase Activat-
ing Protein. Biochem. Pharmacol. 1994, 47, 2259-2268.
(11) (a) Woods, K. W.; Brooks, C. D. W.; Maki, R. G.; Rodriques, K.
E.; Bouska, J . B.; Young, P.; Bell, R. L.; Carter, G. W. O-
Alkylcarboxylate Oxime and N-Hydroxyurea Analogues of Sub-
stituted Indole Leukotriene Biosynthesis Inhibitors. Bioorg. Med.
Chem. Lett. 1996, 6, 1545-1552. (b) Kolasa, T.; Bhatia, P.;
Brooks, C. D. W.; Hulkower, K. I.; Bouska, J . B.; Harris, R. R.;
Bell, R. L. Synthesis of Indolylalkoxyiminoalkylcarboxylates as
Leukotriene Biosynthesis Inhibitors. Bioorg. Med. Chem. 1997,
5, 507-514. (c) Brooks, C. D. W.; Stewart, A. O.; Kolasa, T.;
Basha, A.; Bhatia, P.; Ratajczyk, J . D.; Craig, R. A.; Gunn, D.;
Harris, R. R.; Bouska, J . B.; Malo, P. E.; Bell, R. L.; Carter, G.
W. Design of Inhibitors of Leukotriene Biosynthesis and Their
Therapeutic Potential. Pure Appl. Chem. 1998, 70, 271-274.
(12) Kokotos, G. Convenient One-Pot Conversion of N-Protected
Amino Acids into Alcohols. Synthesis 1990, 299-301.
(13) Schobert, R. Oxidation von sec-1,2-Diolen zu 1,2-Diketonen unter
Pfitzner-Moffatt-Bedingungen. Synthesis 1987, 741-742.
(14) Carter, G. W.; Young, P. R.; Albert, D. H.; Bouska, J .; Dyer, R.;
Bell, R. L.; Summers, J . B.; Brooks, D. W. 5-Lipoxygenase
Inhibitory Activity of Zileuton. J . Pharmacol. Exp. Ther. 1991,
256, 929-937.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data for the final compounds shown in
the tables that are not described in the published version. This
material is available free of charge via the Internet at http://
www.pubs.acs.org.
(15) (a) Rao, T. S.; Currie, J . L.; Shaffer, A. F.; Isakson, P. C.
Evaluation of 5-Lipoxygenase Inhibitors, Zileuton, A78773 and
ICI-D2138 in an Ionophore (A23187)-induced Pleural Inflam-
mation Model in the Rat. Life Sci. 1993, 53, 147-152. (b) Bell,
R. L.; Harris, R. R.; Malo, P. E.; Bouska, J . B.; Shaughnessy, T.
K.; Hulkower, K. I.; Brooks, C. D. W.; Carter, G. W. ABT-761
Attenuates Bronchoconstriction and Pulmonary Inflammation
in Rodents. J . Pharmacol. Exp. Ther. 1997, 280, 1366-1373.
(16) (a) Young, P. R.; Bell, R. L.; Lanni, C.; Summers, J . B.; Brooks,
D. W.; Carter, G. W. Inhibition of Leukotriene Biosynthesis in
the Rat Peritoneal Cavity. Eur. J . Pharmacol. 1991, 205, 259-
Refer en ces
(1) (a) Brooks, C. D. W.; Summers, J . B. Modulators of Leukotriene
Biosynthesis and Receptor Activation. J . Med. Chem. 1996, 39,
2629-2654. (b) Bell, R. L.; Summers, J . B.; Harris, R. R.
Leukotriene Modulators as Therapeutic Agents in Asthma and
Other Inflammatory Diseases. Annu. Rep. Med. Chem. 1997, 32,
91-100.
(2) Ford-Hutchinson, A. W.; Gresser, M.; Young, R. N.; 5-Lipoxy-
genase. Annu. Rev. Biochem. 1994, 63, 383-417.

Leukotriene Biosynthesis Inhibitors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 4 705
266. (b) Malo, P. E.; Bell, R. L.; Shaughnessy, T. K.; Summers,
J . B.; Brooks, C. D. W.; Carter, G. W. The 5-Lipoxygenase
Inhibitory Activity of Zileuton in in vitro and in vivo Models of
Antigen-Induced Airway Anaphylaxis. Pulmon. Pharmacol.
1994, 7, 73.
J . Pharmacol. 1996, 315, 81-88.
(20) Malo, P. E.; Bell, R. L.; Shaughnessy, T. K.; Brooks, D. W.;
Carter, G. W. The Use of Two Guinea Pig Pulmonary Models to
Differentiate Leukotriene Inhibitors with Different Mechanisms
of Action. Am. Rev. Resp. Dis. 1993, 147, A447.
(17) Bell, R. L.; Harris, R. R.; Bouska, J . B.; Hulkower, K. I.; Moore,
J .; Bhatia, P.; Malo, P. E.; Kolasa, T.; Brooks, C. D. W.; Carter,
G. W. Characterization of A-93178, an Iminoxy-Quinoline In-
hibitor of Leukotriene Biosynthesis. In Recent Advances in
Prostaglandin, Thromboxane, and Leukotriene Research; Sin-
zinger et al., Eds.; Plenum Press: New York, 1998; pp 91-98.
(18) Harris, R. R.; Wilcox, D.; Bell, R. L.; Brooks, D. W.; Carter, G.
W. The Role of Mast Cells in Polyacrylamide Gel Induced
Inflammation in Mice. Inflamm. Res. 1998, 47, 104-108.
(19) Namovic, M. T.; Walsh, R. E.; Goodfellow, C.; Harris, R. R.;
Carter, G. W.; Bell, R. L. Pharmacological Modulation of
Eosinophil Influx into the Lungs of Brown Norway Rats. Eur.
(21) Bell, R. L.; Bouska, J . B.; Malo, P. E.; Lanni, C.; Harris, R. R.;
Otis, E. R.; Stewart, A. O.; Brooks, D. W.; Carter, G. W.
Optimization of the Potency and Duration of Action of N-
Hydroxyurea 5-Lipoxygenase Inhibitors. J . Pharmacol. Exp.
Ther. 1995, 272, 724.
(22) Kolasa, T.; Gunn, D. E.; Stewart, A. O.; Brooks, C. D. W.
Synthesis and Resolution of 2-(Cyclohexyl-4-(2-quinolylmeth-
oxy)phenyl)methoxyiminopropionic Acid, Leukotriene Biosyn-
thesis Inhibitors. Tetrahedron Asymmetry 1996, 7, 2645-2654.
J M9904102