Substituted (Pyridylmethoxy)naphthalenes as potent and orally active 5- Lipoxygenase inhibitors: Synthesis, biological profile, and pharmacokinetics of L-739,010

Article abstract of DOI:10.1021/jm970046b

Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox 5-lipoxygenase (5-LO) inhibitors. These bicyclo derivatives were shown to be metabolically more stable than their tetrahydropyranyl counterparts but were not well orally absorbed. Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)- 7-[[6-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]-2- pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE production by human 5-LO and LTB₄ biosynthesis by human PMN leukocytes and human whole blood (IC₅₀s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat pleurisy model (inhibition of LTB₄, ED₅₀ = 0.3 mg/kg) and in the anesthetized dog model (inhibition of ex vivo whole blood LTB₄ and urinary LTB₄, ED₅₀ = 0.45 and 0.23 μg/kg/min, respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases, respectively at 2.5 μg/kg/min, iv infusion) and, more particularly in the conscious antigen sensitive squirrel monkey model (53% inhibition of the increase in R(L) and 76% in the decrease of C(dyn), at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based on its overall biological profile, compound 3g has been selected for preclinical animal toxicity studies.

Full text of DOI:10.1021/jm970046b

2866
J . Med. Chem. 1997, 40, 2866-2875
Su bstitu ted (P yr id ylm eth oxy)n a p h th a len es a s P oten t a n d Or a lly Active
5-Lip oxygen a se In h ibitor s: Syn th esis, Biologica l P r ofile, a n d P h a r m a cok in etics
of L-739,010
Pierre Hamel,† Denis Riendeau,‡ Christine Brideau,§ Chi-Chung Chan,§ Sylvie Desmarais,‡ Daniel Delorme,†,∇
Daniel Dube´,† Yves Ducharme,† Diane Ethier,‡ Erich Grimm,† J ean-Pierre Falgueyret,‡ J ocelyne Guay,‡
Tom R. J ones,§ Elizabeth Kwong,| Malia McAuliffe,§ Cyril S. McFarlane,§ Hanna Piechuta,§ Marie Roumi,|
Philip Tagari,‡ Robert N. Young,† and Yves Girard*,†
Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Received J anuary 21, 1997X
Dioxabicyclooctanyl naphthalenenitriles have been reported as a class of potent and nonredox
5-lipoxygenase (5-LO) inhibitors. These bicyclo derivatives were shown to be metabolically
more stable than their tetrahydropyranyl counterparts but were not well orally absorbed.
Replacement of the phenyl ring in the naphthalenenitrile 1 by a pyridine ring leads to the
potent and orally absorbed inhibitor 3g (L-739,010, 2-cyano-4-(3-furyl)-7-[[6-[3-(3-hydroxy-6,8-
dioxabicyclo[3.2.1]octanyl)]-2-pyridyl]methoxy]naphthalene). Compound 3g inhibits 5-HPETE
production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human
whole blood (IC50s of 20, 1.6, and 42 nM, respectively). Derivative 3g is orally active in the rat
pleurisy model (inhibition of LTB4, ED50 ) 0.3 mg/kg) and in the anesthetized dog model
(inhibition of ex vivo whole blood LTB4 and urinary LTE4, ED50 ) 0.45 and 0.23 µg/kg/min,
respectively, iv infusion). In addition, 3g shows excellent functional activity against ovalbumin-
induced dyspnea in rats (60% inhibition at 0.5 mg/kg, 4 h pretreatment) and Ascaris-induced
bronchoconstriction in conscious sheep (50% and >85% inhibition in early and late phases,
respectively at 2.5 µg/kg/min, iv infusion) and, more particularly in the conscious antigen
sensitive squirrel monkey model (53% inhibition of the increase in RL and 76% in the decrease
of Cdyn, at 0.1 mg/kg, po). In rats and dogs, 3g presents excellent pharmacokinetics (estimated
half-lives of 5 and 16 h, respectively) and bioavailabilities (26% and 73% when dosed as its
hydrochloride salt at doses of 20 and 10 mg/kg, respectively, in methocel suspension). Based
on its overall biological profile, compound 3g has been selected for preclinical animal toxicity
studies.
Sch em e 1
In tr od u ction
Leukotrienes are derived from the biotransformation
of arachidonic acid through the action of 5-lipoxygenase
(5-LO) and are postulated to be implicated in a variety
of disorders.1 Furthermore, it has been recently dem-
onstrated that inhibitors of leukotriene (LT) biosynthe-
sis2 (by either 5-LO or 5-lipoxygenase-activating protein
(FLAP)) or LTD4 receptor antagonists3 possess clinical
efficacy in the treatment of asthma.
We have previously reported a novel class of selective
and nonredox 5-lipoxygenase inhibitors, the naphtha-
lenic lignan lactones.4 These compounds were shown
to be bioavailable and orally active when the open forms
of the lactones were used as prodrugs. More recently
we have described the structure-activity relationship
(SAR) study performed on this series especially directed
toward the improvement of the metabolic stability as
well as the optimization of the in vitro potency.5 From
this SAR study a new class of highly potent and
metabolically more stable inhibitors was identified, the
dioxabicyclooctanyl naphthalenenitriles. One of the
best representatives of this series is (1S,5R)-3-cyano-
1-(3-furyl)-6-[[3-[3-(3-hydroxy-6,8-dioxabicyclo[3.2.1]-
octanyl)]benzyl]oxy]naphthalene (1, L-708,780) which
exhibits an excellent in vitro inhibitory profile. In
addition, compound 1 was shown to be orally active in
animal models of asthma and inflammation. However,
the replacement of the lactone moiety of the lignan
series by a cyano group to prevent the metabolism at
this specific site resulted in very lipophilic derivatives
that were generally shown to be poorly or not absorbed.
In this paper, we describe the continuation of the SAR
investigation with particular emphasis on modifications
to improve the bioavailability of derivatives from this
series. The strategy explored has involved the replace-
ment of the middle phenyl ring by nitrogen-containing
heterocycles. Thus, a series of compounds were pre-
pared leading to the identification of the pyridine
derivative 3g (L-739,010) which presents an improved
* To whom correspondence should be adressed. Phone: (514) 428-
8506. Fax: (514) 695-0693.
† Department of Medicinal Chemistry.
‡ Department of Biochemistry.
§ Department of Pharmacology.
| Department of Pharmaceutical Research and Development.
∇ Present address: Astra Research, 275 Blvd. Armand-Frappier,
Laval, Quebec, Canada H7V 4A7.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0022-2623(97)00046-0 CCC: $14.00 © 1997 American Chemical Society

(Pyridylmethoxy)naphthalenes as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2867
Ta ble 1. Physical and Synthetic Data for Naphthalenes 3a -h
compd
R1
R2
Ar
X
Y
L
methoda
formula
anal.b
mp (°C)
yield (%)c
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
5
6
4e
9
7
7
7
7
7
7
7
10
H
H
H
H
H
H
H
H
H
H
H
H
5,3-Pyr
4,2-Pyr
2,4-Pyr
6,2-Pyr
7,2-Quin
2,4-Tz
CH2OH
CH2OH
CH2OH
CH2OH
CH2Br
CH2Br
CH2OH
Br
OH
OH
OH
OH
OH
OH
OH
CH2OH
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
OCH2
A
A
A
A
B
B
A
C
C26H22N2O4
C26H22N2O4
C26H22N2O4
C26H22N2O4
C30H24N2O4
C24H20N2O4S
C27H22N2O5
C27H22N2O5
C,H,N
d
C,H,N
C,H,N
d
C,H,N,S
C,H,N
C,H,N
176-178
144
57
63
67
43
54
51
70
51
162-165
164-166
192-194
157-159
161-163
159-160
3g
3h
O-CH2
O-CH2
6,2-Pyr
6,2-Pyr
a
b
Method A: PPh3, TBADC, THF. Method B: Cs2CO3, DMF. Method C: NaOH, 18-crown-6, toluene. Elemental analyses were within
(0.4% of the calculated values. c Isolated yield of the final step. High-resolution mass spectrum was obtained for this compound.
d
Sch em e 2
Sch em e 3
overall biological profile over 1. The overall pharma-
cological profile obtained with compound 3g will be
presented.
Ch em istr y
The pyridine-containing final products 3a -d ,g were
obtained via Mitsunobu-type condensations of py-
ridinemethanols 4a -e with the cyanonaphthalene phe-
nol 75 (Table 1). The quinoline and thiazole derivatives
3e,f resulted from alkylation of 7 with the appropriate
bromides 5 and 6 using cesium carbonate in DMF. The
reverse link analog 3h was arrived at by coupling
bicyclopyridine bromide 9 with the naphthalenemetha-
nol derivative 10 in the presence of 18-crown-6 under
basic conditions.
bromide affording the corresponding ethyl ester which
was efficiently reduced with diisobutylaluminum hy-
dride to 4e. Recently, an optimized approach to 4e,
involving initial condensation of the monolithiated
derivative of 2,6-dibromopyridine with DMF, has been
reported by Cai et al.7
The (bromomethyl)naphthalene 5 (Scheme 3) was
obtained by initial metalation of 7-bromoquinaldine
with n-butyllithium and quenching of the lithiated
species with tetrahydropyran-4-one leading to the tet-
rahydropyranyl adduct. This material was in turn
treated with n-butyllithium and the dianion reacted
with bromine to yield the desired bromide 5. For the
preparation of the (bromomethyl)thiazole 6 (Scheme 4),
5-methylthiazole was metalated at the 2-position with
subsequent quenching with tetrahydropyran-4-one, and
the resulting intermediate was brominated using N-
bromosuccinimide.
The required pyridinemethanols 4a -c were derived
from the appropriate bromopyridinecarboxylic acids
(Scheme 1) via initial esterification, reduction to the
primary alcohols, and protection as tert-butyldiphenyl-
silyl derivatives. After metalation with n-butyllithium,
addition of tetrahydropyran-4-one and subsequent depro-
tection afforded the desired diols 4a -c. Metalation of
2,6-dibromopyridine and condensation with tetrahydro-
pyran-4-one or (1S,5R)-6,8-dioxabicyclo[3.2.1]octan-3-
one5,6 (Scheme 2) led to the bromopyridines 8 and 9. A
further metalation with n-butyllithium with subsequent
quenching by paraformaldehyde led to the pyridinemeth-
anols 4d ,e. A more efficient preparation of 4e was
achieved by carbonylation of bromide 9 in ethanol in
the presence of trans-bis(triphenylphosphine)palladium

2868 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Hamel et al.
Ta ble 2. In Vitro Potency of Naphthalenes 2 and 3a -f
Sch em e 4
Sch em e 5
The naphthalenemethanol intermediate 10 required
for the synthesis of the reverse link analog 3h was
derived from the phenol 7 (Scheme 5) via initial deriva-
tization to the corresponding triflate. Carbonylation in
the presence of palladium acetate and 1,1′-bis(diphe-
nylphosphine)ferrocene in methanolic solution led to the
corresponding methyl ester which was conveniently
reduced to the alcohol 10 by lithium borohydride in
THF.
In Vitr o Stu d ies
The compounds were evaluated for their potency to
inhibit (a) oxidation of arachidonic acid by human
recombinant 5-LO using a spectrophotometric assay
monitoring 5-hydroperoxyeicosatetraenoic acid (5-H(P)-
ETE) production,8 (b) production of leukotriene B4 in
Ca2+-ionophore-activated human polymorphonuclear
(PMN) leukocytes,9 and (c) production of LTB4 in human
whole blood activated with ionophore A23187.9 The
data are reported in Tables 2-4.
Heter ocycle In ser tion . A strategy considered to
improve the bioavailability of derivatives in this series
was to insert a nitrogen-containing heterocycle in the
molecule. These heterocycles could be formulated as
salts, thus improving aqueous solubility and conse-
quently oral absorption.10 We had learned from a
previous SAR study5 that attachment of such groups
directly to the naphthalene ring results in significant
loss of potency. Therefore, we investigated the replace-
ment of the middle phenyl ring by various heterocycles.
The compounds prepared are reported in Table 2.
a
Each IC50 value corresponds to an average of at least two
independent determinations, except those identified with an
asterisk, which are the result of a single titration.
a major metabolite with comparable plasma concentra-
tion (2.5 µM) to the parent compound was also observed.
On the basis of metabolism studies performed in the
previous series,5 this metabolite is presumably the
result of oxidative metabolism of the tetrahydropyran
ring. Other heterocycles such as the quinoline 3e and
thiazole 3f were found to be significantly less potent
inhibitors.
2,6-P yr id in e Op tim iza tion . (A) Tetr a h yd r op y-
r a n Rin g. To prevent the oxidative metabolism on the
tetrahydropyran moiety, this ring was substituted by
the metabolically more stable dioxabicyclooctanyl group.5
As shown in Table 3, such substitution in the phenyl
series (1 versus 2) led to an equipotent compound in
the cellular HPMN assay but resulted in significant loss
of potency in both enzymatic H5-LO and HWB assays
(6-15-fold). However, in the pyridine series, the same
substitution led to compound 3g which was equipotent
to the tetrahydropyranyl analog 3d in all in vitro assays.
Derivative 3g as its hydrochloride salt was also well
absorbed in rats reaching a plasma concentration of 3
µM 2 h after administration of a dose of 20 mg/kg.
Furthermore, in contrast with the extensive metabolism
observed with 3d , no obvious circulating metabolite was
detected (detection limit ) 0.2 µM) after dosing 3g.
Thus, replacement of the middle phenyl ring in struc-
All possible pyridine regioisomer analogs (3a -d )
corresponding to the tetrahydropyranyl derivative 25
were prepared, and the 2,6-disubstituted pyridine 3d
was found not only to be the most potent isomer but
also to possess an overall in vitro profile 2-3-fold
superior to 2. Consequently plasma level studies with
this compound were performed in rats. In contrast to
the results observed with 2 where no drug was detected
in plasma after oral administration, compound 3d as
its hydrochloride salt reached a plasma concentration
of 2 µM 1 h after oral dosing at 20 mg/kg. In addition,

(Pyridylmethoxy)naphthalenes as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2869
Ta ble 3. In Vitro Potency and in Vivo Data of Naphthalenes 1, 2, and 3d ,g,h
a
b
Each IC50 value corresponds to an average of at least two independent determinations. 20 mg/kg po in 0.5% methocel; 5 mg/kg iv
in PEG-400/H2O (3:1). c AUCpo/4 × AUCiv × 100. A major metabolite was also observed at a concentration of 2.5 µM. nd, not determined.
d
Ta ble 4. Comparison of in Vitro Potency of Zileuton, MK-0591,
F u r th er in Vitr o Obser va tion s. Photoaffinity la-
D-2138, and 3g
beling of the active site of 5-lipoxygenase has been
IC50 (nM)a
HPMN
reported previously using the thiopyranoindole inhibitor
L-708,714.8 The labeling by this probe can be inhibited
by arachidonic acid and several structurally unrelated
5-lipoxygenase inhibitors. Similarly, 3g inhibited up to
80% of the labeling of 5-lipoxygenase by [125I]L-708,-
714 in a dose-dependent manner with an IC50 value of
34 nM (Figure 1), a value comparable to that observed
for the inhibition of 5-lipoxygenase activity (IC50 ) 20
nM). In this assay, the IC50 for compound D-2138 is
190 nM. This is in agreement with the lower potency
of D-2138 as an inhibitor of enzymatic activity with IC50
of 330 nM (Table 4). These data are consistent with a
nonredox mechanism of inhibition by 3g involving
competition with arachidonic acid for binding at the
active site of the enzyme.
H5-LO
HWB
Zileuton
MK-0591
D-2138
3g
3700
5000
330
20
1100
3
10
2000
500
80
1.6
42
a
Each IC50 value is an average of at least two independent
determinations.
tures 1 and 2 by the heterocycle pyridine led to in-
creased oral absorption confirming the validity of our
strategy.
(B) Meth ylen eoxy Lin k . Since it has been demon-
strated that the nature of the linkage between the aryl
and the naphthalene groups in the naphthalene series
has a major effect on 5-LO inhibition,4 it became
pertinent to reexamine this modification in the newly
optimized pyridine series. The oxymethylene derivative
3h was found to be slightly less potent then the
methyleneoxy analog 3g, as previously observed for the
naphthalene lactone series.
In Vivo Stu d ies
Bioch em ica l Effica cy. The inhibitory effect of 3g
on the biosynthesis of leukotriene B4 in vivo was
evaluated using the rat pleural cavity model following
carrageenan-induced inflammation.9 In this model, 3g
showed excellent activity with an ED50 of 0.3 mg/kg 6 h
after oral dosing. For comparison, the ED50 for the
FLAP inhibitor MK-0591 under the same conditions is
0.15 mg/kg.
In summary compound 3g (L-739,010) was found to
possess the best in vitro biological profile with IC50s of
1.6, 20, and 42 nM, respectively, in HPMN, H5-LO, and
HWB assays. Derivative 3g was also found to be more
potent in vitro than MK-0591,9 D-2138,11 and Zileuton12
(Table 4).
The potency of 3g on the inhibition of urinary leu-
kotriene E4 (an index of the systemic biosynthesis of
peptidoleukotrienes) and of the ex vivo generation of

2870 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Hamel et al.
F igu r e 1. Inhibition of photoaffinity labeling of 5-LO by 3g.
Soluble extracts from baculovirus-infected insect cells (Sf9)
overexpressing 5-LO were incubated with 10 nM [125I]L-708,-
714 and the indicated concentration of 3g or D2138 prior to
photolysis and electrophoresis as previously described.8
F igu r e 2. Intravenous infusion of 3g at 2.5 µg/kg/min in
allergic sheep: (A) effect on postantigen bronchoconstriction
and (B) effect on postantigen urinary LTE4 excretion.
leukotriene B4 by whole blood stimulated with calcium
ionophore A23187 was measured in anesthetized dogs.13
In a dose-dependent fashion, 3g was demonstrated to
be a very potent leukotriene biosynthesis inhibitor in
vivo with an ED50 of 0.23 µg/kg/min for the inhibition
of the base-line urinary LTE4 excretion over 5-7 h after
the commencement of the infusion and with an ED50 of
0.45 µg/kg/min for the inhibition of ex vivo LTB4 genera-
tion by dog whole blood. For MK-0591, the ED50s were
1.0 and 0.51 µg/kg/min, respectively.
caris antigen (Figure 2A). MK-0591 was also effective
at this dose with >75% and >90% inhibition of both
phases. However, both 3g and MK-0591 showed no
significant activity at a lower dose of 0.8 µg/kg/min.
Urinary LTE4 production was also measured throughout
the experiment (Figure 2B), and 3g was shown to reduce
LTE4 excretion by 94% (0-1.5 h) relative to a vehicle
control.
P la sm a Level Stu d ies. Since the direct leukotriene
inhibitor 3g (L-739,010) possesses an overall biological
profile at least comparable and in some assays or models
superior to our clinical leukotriene biosynthesis inhibi-
tor candidate MK-0591 (Table 5), further pharmacoki-
netic studies have been performed on this compound.
Initial bioavailability studies performed on 3g (Table
3) as its hydrochloride salt have demonstrated that this
compound is also well absorbed when administered in
a 0.5% methocel suspension in rats at a dose of 20 mg/
kg with a bioavailability of 26% (0-24 h) (Figure 3). In
dogs, 3g is also very well absorbed with a bioavailability
of 73% (0-24 h) following oral administration of 3g (HCl
salt) at a 10 mg/kg dose. The half-lives determined from
intravenous administration of 3g (free base) in PEG-
400/water (3:1) were 5 and 16 h in rats and dogs,
respectively.
R esp ir a t or y F u n ct ion a l Mod els. Compound 3g
was evaluated against antigen-induced dyspnea in
hyperreactive rats.14 When 3g was administered orally
at 0.5 mg/kg 4 h before ovalbumin challenge, it produced
a 60% (p < 0.01) inhibition of dyspnea. This result is
comparable to the activity observed with MK-0591 (56%
inhibition) under the same conditions.
The activity of 3g on antigen-induced bronchocon-
striction in allergic conscious squirrel monkeys9 was
determined. After a 4 h pretreatment with an oral dose
of 0.1 mg/kg (n ) 5) followed by a challenge with an
aerosol of Ascaris antigen, 3g produced a 53% inhibition
of the increase in airway resistance (RL) and a 76%
inhibition of decrease in dynamic compliance (Cdyn). For
comparison, MK-0591 shows only comparable activity
at 1 mg/kg with inhibitions of 71% and 70% for RL and
Cdyn, respectively. Thus, 3g is approximately 10 times
more potent than MK-0591 in this model.
Con clu sion
In the conscious allergic sheep model,15 the adminis-
tration of 3g as a bolus dose of 0.2 mg/kg followed by a
constant infusion of 2.5 µg/kg/min (n ) 4) resulted in
inhibition of both the early and late phase bronchocon-
striction (50% and >85% respectively) induced by As-
Replacement of the middle phenyl ring in the dioxa-
bicyclooctanyl naphthalenenitrile 1 by the pyridine
heterocycle leads to the identification of the optimized
5-LO inhibitor 3g (L-739,010). Following oral admin-

(Pyridylmethoxy)naphthalenes as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2871
Ta ble 5. Comparison of in Vivo Potency of 3g and MK-0591
3g
MK-0591
LTB4 inhibition in rat pleural cavity following carageenan-induced inflammation (ED50
)
0.3 mg/kg
0.15 mg/kg
0.5 µg/kg/min
1.0 µg/kg/min
56%
inhibition of ex vivo whole blood LTB4
0.45 µg/kg/min
0.23 µg/kg/min
60%
inhibition of urinary LTE4 in dogs (ED50
)
inhibition of ovalbumin-induced dyspnea in inbred hyperreactive rats at 0.5 mg/kg (% inhibition)
(4 h pretreatment, po, in 1% methocel)
inhibition of Ascaris-induced bronchoconstriction in squirrel monkeys (% inhibition of RL, Cdyn
)
53%, 76%
71%, 70%
(4 h pretreatment, po, in 1% methocel)
(at 0.1 mg/kg)
(at 1.0 mg/kg)
inhibition of Ascaris-induced bronchoconstriction in sheep at 2.5 µg/kg/min iv infusion
(% inhibition in early and late phases)
50%, >85%
>75%, >90%
induced dyspnea in rats, (2) Ascaris-induced broncho-
constriction in sheep, and (3) more particularly, Ascaris-
induced bronchoconstriction in squirrel monkeys, where
3g is significantly more potent than MK-0591. In
addition, 3g presents excellent pharmacokinetics after
intravenous administration and is orally well absorbed
as its hydrochloride salt in both rats and dogs. Conse-
quently 3g has been selected for preclinical toxicity
studies.16
Exp er im en ta l Section
Biology. Activity of Hu m a n 5-Lip oxygen a se (H5-LO).
The activity of 5-LO was measured using a spectrophotometric
assay and soluble extracts from Sf9 insect cells overexpressing
human 5-LO as described by Falgueyret et al.8
Gen er a tion of LTB4 in Hu m a n P er ip h er a l Blood P oly-
m or p h on u clea r Leu k ocytes (HP MN) a n d Hu m a n Wh ole
Blood (HWB). The generation of LTB4 in human peripheral
blood polymorphonuclear leukocytes and human whole blood
was measured as previously described by Brideau et al.9
Leu k otr ien e Biosyn th esis in Ra t P leu r a l Ca vity. LTB4
levels in rat pleural exudates following interpleural injection
of carrageenan followed 16-20 h later by ionophore A23187
were determined as previously described.9
Mea su r em en t of Ur in a r y LTE4 a n d ex Vivo Gen er a tion
of LTE4 in An esth etized Dogs. The measurements of
urinary LTE4 and the ex vivo generation of LTB4 by whole
blood stimulated with calcium ionophore A23187 in anesthe-
tized dogs were carried out as described by Tagari et al.13
An tigen -In d u ced Dysp n ea in Hyp er r ea ctive Ra t. The
inhibition of ovalbumin-induced dyspnea in hyperreactive rats
was assayed as previously described by Piechuta et al.14
An tigen -In du ced Br on ch ocon str iction in Squ ir r el Mon -
k eys. Naturally sensitized male squirrel monkeys were
challenged with an aerosol of Ascaris antigen. Changes in
pulmonary mechanics (airway resistance, RL, and dynamic
compliance, CDyn) were monitored in conscious animals using
airflow measurements from a face mask and measurements
of pleural pressure as previously described.9
An tigen -In d u ced Air w a y Resp on ses in Aller gic Sh eep .
Measurement of bronchoconstriction in conscious allergic
sheep exposed to Ascaris antigen was performed according to
Abraham et al.15
Mea su r em en t of P la sm a Levels a n d Bioa va ila bility.
For po measurements, male Sprague-Dawley rats (2-4) were
starved overnight and then dosed orally with the study
compound as a suspension in 0.5% or 1% aqueous methocel.
Blood was taken from the jugular vein prior to dosing and then
0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing. For iv studies,
compounds were dissolved in PEG-400/water (3:1) and injected
intravenously in the jugular vein at a dose of 5 mg/kg at a
dose volume of 0.1 mL/100 g of body weight. Blood was taken
from the jugular vein at 0, 5, 15, and 30 min and 1, 2, 4, 6, 8,
and 24 h after dosing. The blood was centrifuged and plasma
collected. To 100 µL of each plasma sample was added an
equal volume of acetonitrile to precipitate protein. After
centrifugation an aliquot of the supernatant was subjected to
reverse-phase HPLC analysis. The parent compound was
quantitated from the area of the pertinent peak relative to
standardization curves obtained by spiking rat plasma with
F igu r e 3. Mean plasma levels after intravenous administra-
tion of 3g (free base) in PEG-400/water (3:1) and after oral
administration of 3g (HCl salt) in 0.5% methocel suspension
in rats (A) and dogs (B) with dosing volumes of 10 and 5 mL/
kg, respectively.
istration of 3g in rats, no circulating metabolites were
detected. Compound 3g also shows excellent oral activ-
ity in inhibiting (1) LTB4 production from carageenan-
induced inflammation in rat pleural cavity and (2)
urinary LTE4 excretion and ex vivo generation of LTB4
by whole blood in anesthetised dogs. In functional
models, 3g is orally potent to inhibit (1) ovalbumin-

2872 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Hamel et al.
varying concentrations of the compound. The bioavailability
is calculated using the following equation: (AUCpo × doseiv)/
(AUCiv × dosepo) × 100.
Step 3: 2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-4-br o-
m op yr id in e. Silylation as described above afforded the
TBDPS derivative in 93% yield: 1H NMR (CDCl3) δ 1.15 (s,
9H), 4.85 (s, 2H), 7.30-7.48 (m, 7H), 7.64-7.73 (m. 4H), 7.82
(br s, 1H), 8.27 (d, 1H).
Ch em istr y. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a Bruker 300 spectrometer, and
proton chemical shifts are reported relative to tetramethylsi-
lane as internal standard. Melting points were obtained on
either a Buchi 510 or an Electrothermal 9100 apparatus in
open capillary tubes and are uncorrected. Elemental analyses
were performed by Galbraith Laboratories Inc., Knoxville, TN,
Oneida Research Services, Whitesboro, NY, or Guelph Chemi-
cal Laboratories Ltd., Guelph, Ontario. Where reported only
by symbols the results were within 0.4% of theoretical values.
High-resolution mass spectra were recorded at the Biomedical
Mass Spectrometry Unit, McGill University, Montreal, Quebec.
P r ep a r a tion of Alcoh ols. 3-[4-(4-Hyd r oxytetr a h yd r o-
p yr a n yl)]-5-p yr id ylm eth a n ol (4a ). Step 1: 5-Br om o-3-
p yr id ylm eth a n ol. To a solution of methyl 5-bromonicotinate
(14.5 g, 67.1 mmol) in THF (400 mL) under N2 atmosphere
was added in portions over 15 min LAH (2.85 g, 75 mmol).
The slightly warm mixture was stirred at room temperature
for 1 h; then the reaction was quenched carefully with
saturated aqueous NH4Cl (80 mL). After stirring for a further
hour, the organic supernatant was decanted, and the insoluble
aluminum salts were extracted (3×) with EtOAc (100 mL) with
decantation. The combined organic fractions were dried over
MgSO4 and evaporated. The yellow oil obtained (12.3 g) was
used as such in the next step: 1H NMR (CDCl3) δ 1.8 (br s,
OH), 4.74 (s, 2H), 7.90 (dd, 1H), 8.49 (dd, 1H), 8.59 (dd, 1H).
St ep 2: 5-Br om o-3-[[(ter t-b u t yld ip h en ylsilyl)oxy]-
m eth yl]p yr id in e. To a solution of alcohol from step 1 (29 g,
154 mmol) and tert-butyldiphenylchlorosilane (47.5 g, 173
mmol) in CH2Cl2 (500 mL) was added imidazole (15.8 g, 232
mmol). After stirring at room temperature for 1 h, the mixture
was filtered, and the filtrate material was chromatographed
on silica gel eluting with a 1:7 mixture of EtOAc and hexane
to afford the product (67 g, quantitative) as a colorless oil: 1H
NMR (CDCl3) δ 1.08 (s, 9H), 4.72 (s, 2H), 7.33-7.48 (m, 6H),
7.62-7.75 (m, 4H), 7.80 (dd, 1H), 8.45 (dd, 1H), 8.57 (dd, 1H).
Step 3: 3-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-5-[4-
(4-h yd r oxytetr a h yd r op yr a n yl)]p yr id in e. To a solution of
silyl derivative from step 2 (1.28 g, 3 mmol) in THF (10 mL)
at -78 °C was added n-BuLi in hexanes (1.12 M, 3 mL, 3.36
mmol). The mixture was stirred in the cold for 10 min, and a
solution of tetrahydropyran-4-one (360 mg, 3.6 mmol) in THF
(1 mL) was added slowly. After 1.25 h at -78 °C the reaction
was quenched with saturated aqueous NH4Cl and the mixture
allowed to warm up to room temperature. After dilution with
EtOAc (200 mL) the organic phase was washed (4×) with
brine, dried, and evaporated. The residue was chromato-
graphed on silica gel eluting with EtOAc to yield the desired
product (784 mg, 58%) as a colorless oil which solidified: 1H
NMR (CDCl3) δ 1.10 (s, 9H), 1.69 (d, 2H), 2.07-2.25 (m, 2H),
3.80-4.02 (m, 4H), 4.80 (s, 2H), 7.33-7.50 (m, 6H), 7.60-7.75
(m, 5H), 8.49 (dd, 1H), 8.68 (dd, 1H).
Step 4: 2-[[(ter t-Bu tyld ip h en ylsilyl)oxy]m eth yl]-4-[4-
(4-h ydr oxytetr ah ydr opyr an yl)]pyr idin e. The product from
step 3 was condensed with tetrahydropyran-4-one as described
above to afford the hydroxy THP derivative in 20% yield as a
colorless oil: 1H NMR (CDCl3) δ 1.64 (d, 2H), 2.05 (s, 1H, OH),
2.09-2.21 (m, 2H), 3.85-4.00 (m, 4H), 4.91 (s, 2H), 7.23 (m,
1H), 7.30-7.47 (m, 6H), 7.62-7.70 (m, 4H), 7.73 (br s, 1H),
8.48 (d, 1H).
Step 5: 4-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-2-p yr id yl-
m eth a n ol (4b). The desilylation was done as described above
to afford the product in 71% yield as a white solid: 1H NMR
(acetone-d6) δ 1.61 (d, 2H), 2.00-2.12 (m, 2H), 3.69-3.93 (m,
4H), 4.34 (s, 1H, OH), 4,50 (t, 1H, OH), 4.69 (br s, 2H), 7.35
(m, 1H), 7.61 (br s 1H), 8.44 (d, 1H).
2-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-4-p yr id ylm eth a -
n ol (4c). The same sequence of steps as in the preparation
of 4b, starting with 2-bromoisonicotinic acid,18 afforded 4c as
an oil: 1H NMR (CDCl3) δ 1.58 (d, 2H), 2.09-2.20 (m, 2H),
2.25 (br s, OH), 3.85-4.07 (m, 4H), 4.80 (s, 2H), 5.25 (br s,
OH), 7.22 (d, 1H), 7.40 (s, 1H), 8.50 (d, 1H).
2-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-6-p yr id ylm eth a -
n ol (4d ). Step 1: 2-Br om o-6-[4-(4-h yd r oxytetr a h yd r op y-
r a n yl)]p yr id in e (8). A solution of 2,6-dibromopyridine (15
g, 63.3 mmol) in Et2O (225 mL) was cooled to -78 °C. To the
resulting suspension was added n-BuLi (2.0 M) in hexanes
(28.5 mL, 57 mmol), and a yellow solution resulted. After the
mixture stirred for 15 min, a solution of tetrahydropyran-4-
one (6.98 g, 69.8 mmol) in Et2O (15 mL) was added, and a
white solid precipitated out of solution. After a further 15 min,
the reaction was quenched with saturated aqueous NH4Cl and
the mixture allowed to warm up to room temperature. Parti-
tion of the mixture between EtOAc and H2O and evaporation
of the organic phase afforded
a white solid which was
triturated with Et2O and filtered to yield 8 (11.43 g, 78%) as
a white solid: mp 130-132 °C; 1H NMR (CDCl3) δ 1.60 (d,
2H), 2.04-2.19 (m, 2H), 3.84-4.03 (m, 4H), 4.20 (br s, OH),
7.35 (d, 1H), 7.42 (d, 1H), 7.60 (t, 1H).
Step 2: 2-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-6-p yr id yl-
m eth a n ol (4d ). To n-BuLi (2.0 M) in hexanes (65 mL, 130
mmol) cooled to -78 °C was added a solution of bromide from
step 1 (16 g, 62 mmol) in THF (350 mL), keeping the
temperature below -60 °C. The resulting dark yellow solution
was stirred for a further 10 min. Solid paraformaldehyde (5
g, 166 mmol) was added, the mixture was stirred for 15 min,
and more paraformaldehyde was added (5 g). After a further
15 min of stirring at -78 °C, the mixture was warmed to 0 °C
and the reaction quenched with saturated aqueous NH4Cl.
Partition between EtOAc and H2O and chromatography of the
organic material on silica gel eluting with a 1:1 mixture of
EtOAc and hexane afforded 4d (3.8 g, 29%) as a thick yellow
oil: 1H NMR (CDCl3) δ 1.59 (d, 2H), 2.09-2.25 (m, 2H), 3.04
(t, 1H, OH), 3.75-4.05 (m, 4H), 4.62 (s, 1H, OH), 4.80 (d, 2H),
7.24 (d, 1H), 7.33 (d, 1H), 7.78 (t, 1H).
Step 4: 5-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-3-p yr id yl-
m eth a n ol (4a ). To a solution of THP derivative from step 3
(20.35 g, 45.5 mmol) in THF (350 mL) was added TBAF (1 M)
in THF (52 mL). After 1 h at room temperature the mixture
was evaporated and the residue chromatographed on silica gel
eluting with a 1:4 mixture of EtOH and EtOAc to afford the
product (6.74 g, 71%) as a white solid: mp 143-145 °C; 1H
NMR (CDCl3) δ 1.74 (d, 2H), 2.10-2.32 (m, 2H), 3.83-4.03
(m, 4H), 4.78 (s, 2H), 7.86 (dd, 1H), 8.50 (dd, 1H), 8.68 (dd,
1H).
4-[4-(4-Hyd r oxytetr a h yd r op yr a n yl)]-2-p yr id ylm eth a -
n ol (4b). Step 1: Meth yl 4-Br om op icolin a te. A suspen-
sion of 4-bromopicolinic acid17 (1 g) in EtOAc (25 mL) was
esterified with excess ethereal diazomethane. After chroma-
tography (1:1 EtOAc/hexane) the ester was obtained (785 mg)
as a solid.
6-[3-(3-Hyd r oxy-6,8-d ioxa bicyclo[3.2.1]octa n yl)]-2-p y-
r id ylm eth a n ol (4e). Meth od 1, Step 1: 2-Br om o-6-[3-(3-
h yd r oxy-6,8-d ioxa bicyclo[3.2.1]octa n yl)]p yr id in e (9). The
procedure described above for the preparation of 8 was applied
using (1S,5R)-6,8-dioxabicyclo[3.2.1]octan-3-one5,6 as starting
material to yield 9 in 46% yield as a white solid: mp 161-
1
163 °C; H NMR (CDCl3) δ 1.81-1.98 (m, 2H), 2,43 (d, 1H),
2.66 (m, 1H), 3.70 (m, 1H), 4.41 (s, 1H, OH), 4.50 (d, 1H), 4.70
(m, 1H), 5.77 (s, 1H), 7.35 (dd, 1H), 7.51-7.62 (m, 2H).
Step 2: 6-[3-(3-Hydr oxy-6,8-dioxabicyclo[3.2.1]octan yl)]-
2-p yr id ylm eth a n ol (4e). The procedure of step 2 in the
preparation of 4d was followed using the product from step 1
as starting material to afford 4e in 20% yield as a white solid:
Step 2: 4-Br om o-2-p yr id ylm eth a n ol. The ester from
step 1 was reduced with LAH as described above to afford the
alcohol in 71% yield as a yellow-brown oil: 1H NMR (CDCl3)
δ 3.55 (br s, OH), 4.75 (s, 2H), 7.38 (m, 1H), 7.50 (br s, 1H),
8.39 (d, 1H).
1
mp 163-164 °C; H NMR (CDCl3) δ 1.86-1.99 (m, 2H), 2.44
(d, 1H), 2.68 (m, 1H), 3.57 (t, 1H, OH), 3.82 (m, 1H), 4.54 (d,
2H), 4.65 (s, 1H, OH), 4.70-4.77 (m, 2H), 5.78 (s, 1H), 7.14 (d,
1H), 7.53 (d, 1H), 7.72 (t, 1H).

(Pyridylmethoxy)naphthalenes as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2873
Met h od 2, St ep 1: E t h yl 6-[3-(3-H yd r oxy-6,8-d ioxa -
bicyclo[3.2.1]octa n yl)]-2-p yr id in eca r boxyla te. A mixture
of 9 (5.0 g, 17.5 mmol), trans-bis(triphenylphosphine)palladium
bromide (500 mg, 0.63 mmol), triethylamine (4.9 mL, 35
mmol), and EtOH (50 mL) was placed under an atmosphere
of carbon monoxide using a balloon and heated at 75 °C for 2
days. The solvent was evaporated, and the residue was
chromatographed on silica gel eluting with a mixture of EtOAc
and hexane (2:1) to yield the ester (4.23 g, 87%) as a light
yellow solid: 1H NMR (CDCl3) δ 1.42 (t, 3H), 1.89-2.03 (m,
2H), 2.39 (d, 1H), 2.63 (m, 1H), 3.83 (m, 1H), 4.44 (q, 2H), 4.59
(d, 1H), 4.72 (m, 1H), 5.23 (s, 1H, OH), 5.78 (s, 1H), 7.72 (d,
1H), 7.86 (t, 1H), 8.00 (d, 1H).
mixture of EtOAc and hexane to afford 6 (175 mg, 13%) as an
oil which solidified: 1H NMR (CDCl3) δ 1.82 (m, 2H), 2.16-
2.35 (m, 2H), 2.94 (s, 1H, OH), 3.82-3.96 (m, 4H), 4.55 (s, 2H),
7.25 (s, 1H).
P r ep a r a tion of 2-Cya n o-4-(3-fu r yl)-7-(h yd r oxym eth yl)-
n a p h t h a len e (10). St ep 1: 2-Cya n o-4-(3-fu r yl)-7-[[(t r i-
flu or om eth yl)su lfon yl]oxy]n a p h th a len e. To a suspension
of phenol 75 (9.4 g, 40 mmol) in CH2Cl2 (100 mL) was added
pyridine (4.85 mL, 60 mmol). After the mixture cooled to 0
°C, trifluoromethanesulfonic anhydride (13.54 g, 48 mmol) was
added slowly, and the mixture was stirred in the cold for 2 h.
After dilution with CH2Cl2 (200 mL) the mixture was washed
(2×) with H2O, dried, and evaporated, and the residue was
chromatographed on silica gel eluting with hexane/EtOAc (1:
5) to afford the triflate (14 g) as a yellow oil.
Step 2: Meth yl 2-Cya n o-4-(3-fu r yl)-7-n a p h th oa te. Car-
bon monoxide gas was bubbled for a few minutes into a
mixture of triflate from step 1 (4.5 g, 12.26 mmol), palladium
acetate (275 mg, 1.22 mmol), 1,1′-bis(diphenylphosphino)-
ferrocene (1.36 g, 2.5 mmol), and triethylamine (2.72 g, 26.9
mmol) in MeOH (40 mL) and DMSO (70 mL). A balloon filled
with carbon monoxide was placed over the flask, and the
mixture was stirred at 60 °C for 3 h. After dilution with H2O,
the mixture was extracted (3×) with EtOAc, and the combined
extracts were washed (4×) with H2O, dried, and evaporated.
The residue was stirred with a small volume of Et2O and
filtered to yield the methyl ester (3.32 g, 97%) as a light brown
solid, used as such in the next step.
Step 3: 2-Cya n o-4-(3-fu r yl)-7-(h yd r oxym eth yl)n a p h -
th a len e (10). To a solution of ester from step 2 (840 mg, 3.03
mmol) in THF (25 mL) at room temperature was added in
portions LiBH4 (330 mg, 15 mmol). The mixture was stirred
at room temperature for 24 h, the reation quenched with
saturated aqueous NH4Cl, and the mixture extracted with
EtOAc. The organic fraction was washed (3×) with H2O, dried,
and evaporated, and the crude product was chromatographed
on silica gel eluting with hexane/EtOAc (1:1) leading to the
desired alcohol 10 (440 mg, 58%) as a white solid: mp 131-
134 °C.
P r ep a r a tion of F in a l P r od u cts: 2-Cya n o-4-(3-fu r yl)-
7-[[5-[4-(4-h y d r o x y t e t r a h y d r o p y r a n y l)]-3-p y r id y l]-
m eth oxy]n a p h th a len e (3a ). To a mixture of pyridine alco-
hol 4a (157 mg, 0.75 mmol), cyanophenol 7 (176 mg, 0.75
mmol), and triphenylphosphine (236 mg, 0.9 mmol) in THF
(8 mL) was added di-tert-butyl azodicarboxylate (207 mg, 0.9
mmol). The mixture was stirred at room temperature for 2 h,
evaporated to dryness, and chromatographed on silica gel.
Elution with EtOAc afforded 3a as a yellow oil. Trituration
with hexane led to a yellow solid which was filtered, affording
pure 3a (183 mg, 57%) as a cream-colored solid: 1H NMR
(CDCl3) δ 1.65-1.82 (m, 3H), 2.14-2.33 (m, 2H), 3.85-4.02
(m, 4H), 5.25 (s, 2H), 6.68 (s, 1H), 7.28-7.42 (m, 2H), 7.50 (d,
1H), 7.62 (m, 1H), 7.68 (s, 1H), 7.99 (m, 1H), 8.05-8.17 (m,
2H), 8.67 (m, 1H), 8.78 (d, 1H).
Step 2: 6-[3-(3-Hydr oxy-6,8-dioxabicyclo[3.2.1]octan yl)]-
2-p yr id ylm eth a n ol (4e). To a solution of ester from step 1
(8.6 g, 30.8 mmol) in THF (150 mL) at 0 °C was added
diisobutylaluminum hydride (1.5 M) in toluene (68 mL, 102
mmol). The resulting red mixture was stirred in the cold for
1 h, and then the reaction was quenched with saturated
aqueous NH4Cl resulting in a slurry which was diluted with
EtOAc (150 mL) and filtered. The organic portion of the
filtrate was retained. The solids were suspended in EtOAc
(200 mL), and 5 N aqueous NaOH was added in portions until
the solids became a paste. The organic layer was decanted,
washed (4×) with brine, dried, and filtered. The filtrate was
combined with the first organic filtrate, and the solution was
dried and evaporated to an oil which solidified. The solid was
triturated with Et2O and filtered to afford 4e (5.42 g, 74%).
P r ep a r a tion of Ha lid es. 2-(Br om om eth yl)-7-[4-(4-h y-
d r oxytetr a h yd r op yr a n yl)]qu in olin e (5). Step 1: 7-[4-(4-
Hyd r oxytetr a h yd r op yr a n yl)]-2-m eth ylqu in olin e. To a
solution of 7-bromoquinaldine (444 mg, 2 mmol) in THF (10
mL) at -70 °C was added n-BuLi (1.1 M) in hexanes (2 mL,
2.2 mmol). The resulting purple solution was stirred for 10
min, and a solution of tetrahydropyran-4-one (250 mg, 2.5
mmol) in THF (1.5 mL) was added slowly resulting in a green
solution which was stirred in the cold for a further 20 min;
then the reaction was quenched with saturated aqueous NH4-
Cl and the mixture allowed to warm up. The mixture was
partitioned between EtOAc and H2O, and the organic fraction
was evaporated to an oily residue which solidified. Trituration
with Et2O afforded the desired THP product (126 mg, 26%) as
a white crystalline solid: mp 179-180 °C; 1H NMR (CDCl3) δ
1.72 (s, 1H, OH), 1.82 (d, 2H), 2.30 (m, 2H), 2.76 (s, 3H), 3.87-
4.06 (m, 4H), 7.27 (dd, 1H), 7.68 (dd, 1H), 7.80 (dd, 1H), 8.03
(d, 1H), 8.11 (s, 1H).
Step 2: 2-(Br om om eth yl)-7-[4-(4-h yd r oxytetr a h yd r o-
p yr a n yl)]qu in olin e (5). To a solution of THP quinaldine
from step 1 (121 mg, 0.5 mmol) in THF (2 mL) at -70 °C was
added n-BuLi (1.1 M) in hexanes (1 mL, 1.1 mmol). The
resulting dark red solution was stirred for a further 10 min,
and then it was added via cannula to a -70 °C solution of
bromine (120 mg, 0.75 mmol) in THF (2 mL). A yellow solution
resulted which was stirred in the cold for 30 min and the
reaction quenched with saturated aqueous NH4Cl. Partition
of the mixture between EtOAc and H2O and evaporation of
the organic phase led to a mixture which was chromatographed
on silica gel eluting with EtOAc to yield 5 (33 mg, 22%) as a
syrup: 1H NMR (CDCl3) δ 1.79 (m, 2H), 1.97 (s, 1H, OH), 2.30
(m, 2H), 3.86-4.05 (m, 4H), 4.71 (s, 2H), 7.58 (d, 1H), 7.75
(dd,1H), 7.84 (d, 1H), 8.15 (s, 1H), 8.17 (d, 1H).
A similar procedure was used to prepare the following
compounds (3b-d ,g).
2-Cya n o-4-(3-fu r yl)-7-[[4-[4-(4-h yd r oxytetr a h yd r op yr a -
n yl)]-2-p yr id yl]m eth oxy]n a p h th a len e (3b): from 4b and
7 (63% yield), yellow solid; 1H NMR (CDCl3) δ 1.64 (br d, 2H),
1.71 (s, OH), 2.04-2.22 (m, 2H), 3.89-3.93 (m, 4H), 5.35 (s,
2H), 6.68 (s, 1H), 7.30 (d, 1H), 7.37-7.41 (m, 1H), 7.43 (d, 1H),
7.47 (s, 1H), 7.60 (m, 1H), 7.68 (d, 1H), 8.05 (s, 1H), 8.11 (d,
1H), 8.63 (d, 1H); HRMS (C26H22N2O4 + H+) calcd 427.16578,
found 427.16569.
4-(Br om om eth yl)-2-[4-(4-h yd r oxytetr a h yd r op yr a n yl)]-
th ia zole (6). Step 1: 2-[4-(4-Hyd r oxytetr a h yd r op yr a -
n yl)]-4-m eth ylth ia zole. The procedure of step 1 in the
preparation of 5 was applied using 4-methylthiazole as starting
material and yielded after chromatography on silica gel eluting
with a 1:1 mixture of EtOAc and hexane the desired THP
product in 52% yield as a light yellow solid: mp 98-100 °C;
1H NMR (CDCl3) δ 1.80 (m, 2H), 2.15-2.31 (m, 2H), 2.42 (s,
3H), 3.14 (s, 1H, OH), 3.81-3.98 (m, 4H), 6.83 (s, 1H).
Step 2: 4-(Br om om eth yl)-2-[4-(4-h yd r oxytetr a h yd r o-
p yr a n yl)]th ia zole (6). A mixture of THP product from step
1 (995 mg, 5 mmol), NBS (979 mg, 5.5 mmol), and AIBN (50
mg) in CCl4 (10 mL) was refluxed for 30 min. The cooled
mixture was diluted with Et2O and filtered, and the filtrate
material was chromatographed on silica gel eluting with a 1:1
2-Cya n o-4-(3-fu r yl)-7-[[2-[4-(4-h yd r oxytetr a h yd r op yr a -
n yl)]-4-p yr id yl]m eth oxy]n a p h th a len e (3c): from 4c and
1
7 (67% yield), yellow solid; H NMR (CDCl3) δ 1.55-1.62 (m,
2H), 2.04-2.22 (m, 2H), 3.88-4.05 (m, 4H), 5.14 (s, OH), 5.27
(s, 2H), 6.68 (s, 1H), 7.25 (d, 1H), 7.32 (d, 1H), 7.40 (dd, 1H),
7.44-7.57 (m, 2H), 7.62 (m, 1H), 7.69 (s, 1H), 8.06 (s, 1H), 8.14
(d, 1H), 8.57 (d, 1H).
2-Cya n o-4-(3-fu r yl)-7-[[6-[4-(4-h yd r oxytetr a h yd r op yr a -
n yl)]-2-p yr id yl]m eth oxy]n a p h th a len e (3d ): from 4d and
7 (43% yield), light yellow solid; 1H NMR (CDCl3) δ 1.55-1.62
(br d, 2H), 2.05-2.22 (m, 2H), 3.93-4.03 (m, 4H), 5.17 (s, OH),
5.36 (s, 2H), 6.67 (s, 1H), 7.28 (d, 1H), 7.35 (d, 1H), 7.40 (dd,

2874 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Hamel et al.
1H), 7.47-7.51 (m, 2H), 7.61 (s, 1H), 7.68 (s, 1H), 7.79 (t, 1H),
8.05 (s, 1H), 8.11 (d, 1H).
Refer en ces
(1) Brooks, C. D. W.; Summers, J . B. Modulators of Leukotriene
Biosynthesis and Receptor Activation. J . Med. Chem. 1996, 39,
2629-2654.
2-Cyan o-4-(3-fu r yl)-7-[[6-[3-(3-h ydr oxy-6,8-dioxabicyclo-
[3.2.1]oct a n yl)]-2-p yr id yl]m et h oxy]n a p h t h a len e
(3g,
1
L-739,010): from 4e and 7 (70% yield), light yellow solid; H
NMR (CDCl3) δ 1.89-2.05 (br d, 2H), 2.40 (d, 1H), 2.65 (dd,
1H), 3.86 (t, 1H), 4.59 (d, 1H), 4.73 (t, 1H), 5.08 (s, 1H), 5.34
(s, 2H), 5.80 (s, OH), 6.67 (s, 1H), 7.30 (d, 1H), 7.39 (dd, 1H),
7.42-7.46 (m, 2H), 7.50 (d, 1H), 7.60 (t, 1H), 7.67 (s, 1H), 7.77
(t, 1H), 8.05 (s, 1H), 8.09 (d, 1H).
(2) 5-LO or FLAP inhibitors, recent clinical results: (a) Israel, E.;
Rubin, P.; Kemp, J . P.; Grossman, J .; Pierson, W.; Siegel, S. C.;
Tinkelman, D.; Murray, J . J .; Busse, W.; Segal, A. T.; Fish, J .;
Kaiser, H. B.; Ledford, D.; Wenzel, S.; Rosenthal, R.; Cohn, J .;
Lanni, C.; Perlman, H.; Karahalios, P.; Drasen, J . M. The Effect
of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate
Asthma. Ann. Intern. Med. 1993, 119, 1059-1066. (b) Friedman,
B. S.; Bel, E. H.; Buntinx, A.; Tanaka, W.; Han, Y. H.; Shingo,
S.; Spector, R.; Sterk, P. Oral Leukotriene Inhibitor (MK-886)
Blocks Allergen-Induced Airway Responses. Am. Rev. Respir.
Dis. 1993, 147, 839-844. (c) Diamant, Z.; Timmers, M. C.; van
der Veen, H.; Friedman, B. S.; De Smet, M.; Depre´, M.; Hilliard,
2-Cya n o-4-(3-fu r yl)-7-[[7-[4-(4-h yd r oxytetr a h yd r op yr a -
n yl)]-2-qu in olin yl]m eth oxy]n a p h th a len e (3e). A mixture
of bromide 5 (30 mg, 0.093 mmol), 7 (26 mg, 0.11 mmol), and
Cs2CO3 (65 mg, 0.2 mmol) in DMF (2 mL) was stirred at room
temperature for 20 h. The mixture was diluted with H2O and
extracted (2×) with EtOAc, and the extracts were washed (3×)
with H2O, dried, and evaporated. Chromatography on silica
gel eluting with EtOAc led to 3e (24 mg, 54%) as a light yellow
solid: 1H NMR (CDCl3) δ 1.77 (s, OH), 1.83 (br d, 2H), 2.29-
2.40 (m, 2H), 3.96-4.02 (m, 4H), 5.53 (s, 2H), 6.67 (s, 1H), 7.31
(d, 1H), 7.42-7.46 (m, 2H), 7.59 (m, 1H), 7.66-7.70 (m, 2H),
7.85 (dd, 1H), 7.87 (d, 1H), 8.02 (s, 1H), 8.10 (d, 1H), 8.19-
8.21 (m, 1H); HRMS (C30H24N2O4 + H+) calcd 477.18143, found
477.18147.
D.; Bel, E.; Sterk, P. J . The Effect of MK-0591,
a Novel
5-Lipoxygenase Activating Protein Inhibitor, on Leukotriene
Biosynthesis and Allergen-Induced Airway Responses In Asth-
matic Subjects In Vivo. J . Allergy Clin. Immunol. 1995, 95, 42-
51.
(3) LTD4 antagonists, recent clinical results: (a) Margolskee, D.;
Bodman, S.; Dockborn, R.; Israel, E.; Kemp, J .; Mansmann, H.;
Minotti, D. A.; Spector, S.; Stricker, W.; Tinkelman, D.; Townley,
R.; Winder, J .; Williams, V. The Therapeutic Effects of MK-571.
A Potent and Selective LTD4 Receptor Antagonist in Patients
with Chronic Asthma. J . Clin. Allergy Immunol. 1991, 87, 309.
(b) Impens, N.; Reiss, T. F.; Teahan, J . A.; Desmet, M.; Rossing,
T. H.; Shingo, S.; Zhang, J .; Schandevyl, W.; Verbesselt, R.;
Dupont, A. G. Acute Bronchodilation with an Intravenously
Administered Leukotriene D4 Antagonist MK-679. Am. Rev.
Respir. Dis. 1993, 147, 1442-1446. (c) Reiss, T. F.; Bronsky, E.;
Hendeles, L.; Hill, J .; Harman, E.; Guerreiro, D.; Zhang, J . MK-
0476, A Potent Leukotriene D4 Receptor Antagonist, Inhibits
Exercise Induced Bronchoconstriction is Asthmatics at the End
of a Once Daily Dosing Interval. Am. J . Respir. Crit. Care Med.
1995, 151, A377. (d) Dahlen, B.; Zetterstrom, O.; Bjorck, T.;
Dahlen, S. E. The Leukotriene-Antagonist ICI-204,219 Inhibits
the Early Airway Reaction to Cumulative Bronchial Challenge
with Allergen in Atopic Asthmatics. Eur. Respir. J . 1994, 7, 324-
331. (e) Taniguchi, Y.; Tamura, G.; Honma, M.; Aizawa, T.;
Maruyama, N.; Shirato, K.; Takishima, T. The Effect of an Oral
Leukotriene Antagonist, ONO-1078, on Allergen-Induced Im-
mediate Bronchoconstriction in Asthmatic Subjects. J . Allergy
Clin. Immunol. 1993, 92, 507-512.
(4) Ducharme, Y.; Brideau, C.; Dube´, D.; Chan, C.-C.; Falgueyret,
J .-P.; Gillard, J . W.; Guay, J .; Hutchinson, J . H.; McFarlane, C.
S.; Riendeau, D.; Scheigetz, J .; Girard, Y. Naphthalenic Lignan
Lactones as Selective, Non-redox 5-Lipoxygenase Inhibitors.
Synthesis and Biological Activity of (Methoxyalkyl) Thiazole and
Methoxytetrahydropyran Hybrids. J . Med. Chem. 1994, 37, 512-
518.
(5) Delorme, D.; Ducharme, Y.; Brideau, C.; Chan, C.-C.; Chauret,
N.; Desmarais, S.; Dube´, D.; Falgueyret, J .-P.; Fortin, R.; Guay,
J .; Hamel, P.; J ones, T. R.; Le´pine, C.; Li, C.; McAuliffe, M.;
McFarlane, C. S.; Nicoll-Griffith, D. A.; Riendeau, D.; Yergey,
J . A.; Girard, Y. Dioxabicyclooctanyl Naphthalenenitriles as Non-
redox 5-Lipoxygenase Inhibitors. Structure-Activity Relationship
Study Directed toward the Improvement of Metabolic Stability.
J . Med. Chem. 1996, 39, 3951-3970.
2-Cya n o-4-(3-fu r yl)-7-[[2-[4-(4-h yd r oxytetr a h yd r op yr a -
n yl)]-4-th ia zolyl]m eth oxy]n a p h th a len e (3f). The preced-
ing procedure was used starting with 7 and halide 6 to afford
1
3f in 51% yield as a cream-colored solid; H NMR (CDCl3) δ
1.85 (br d, 2H), 2.28-2.37 (m, 2H), 2.91 (s, OH), 3.91-3.94
(m, 4H), 5.32 (s, 2H), 6.68 (s, 1H), 7.32-7.40 (m, 3H), 7.47 (s,
1H), 7.61 (s, 1H), 7.68 (s, 1H), 8.07-8.12 (m, 2H).
2-Cyan o-4-(3-fu r yl)-7-[[[6-[3-(3-h ydr oxy-6,8-dioxabicyclo-
[3.2.1]octa n yl)]-2-p yr id yl]oxy]m eth yl]n a p h th a len e (3h ).
A mixture of bicyclobromopyridine 9 (99 mg, 0.35 mmol),
benzyl alcohol 10 (135 mg, 0.54 mmol), powdered NaOH (70
mg, 1.5 mmol), and 18-crown-6 (4.4 mg, 0.017 mmol) in toluene
(7 mL) was refluxed with azeotropic removal of H2O for 2 h.
The mixture was poured into saturated aqueous NH4Cl and
extracted (3×) with EtOAc; the extracts were washed with
brine, dried, and evaporated. Because the final product 3h
and starting material 10 coeluted on silica gel, the crude
mixture was dissolved in DMF (4 mL), triethylamine (0.028
mL, 0.2 mmol) and tert-butyldimethylchlorosilane (30 mg, 0.2
mmol) were added, and the mixture was stirred at room
temperature for 4 h. After the reaction quenched with
saturated aqueous NH4Cl, the mixture was extracted (3×) with
EtOAc. These extracts were washed with brine, dried, and
evaporated, and the residue was chromatographed on silica
gel eluting with hexane/EtOAc (1:1) to afford the product 3h
1
(80 mg, 51%); H NMR (acetone-d6) δ 1.75 (m, 2H), 2.40 (m,
1H), 2.55 (m, 1H), 3.65 (m, 1H), 4.35 (s, 1H), 4.48 (m, 1H),
4.60 (m, 1H), 5.60 (br s, 3H), 6.70 (d, 1H), 6.85 (br s, 1H), 7.30
(d, 1H), 7.68 (m, 2H), 7.85 (m, 2H), 7.95 (s, 1H), 8.22 (m, 2H),
8.42 (s, 1H).
(6) Leger, S.; Omeara, J .; Wang, Z. Lewis Acid-Catalyzed Intramo-
lecular Reaction between Silyl Enol Ethers and Ortho Esters:
An Efficient Approach to 1,6-Anhydropyranoses. Synlett 1994,
829-830.
(7) Cai, D.; Hughes, D. L.; Verhoven, T. R. A Study of the Lithiation
of 2,6-Dibromopyridine with Butyllithium, and its Application
to Synthesis of L-739,010. Tetrahedron Lett. 1996, 37, 2537-
2540.
(8) Falgueyret, J .-P.; Denis, D.; Macdonald, D.; Hutchinson, J . H.;
Riendeau, D. Characterization of the Arachidonate and ATP
Binding Sites of Human 5-Lipoxygenase Using Photoaffinity
Labeling and Enzyme Immobilization. Biochemistry 1995, 34,
13603-13611.
P r ep a r a tion of th e Hyd r och lor id e Sa lt of 3g. To a
solution of 3g (6.245 g) in dry EtOAc (450 mL) was added
slowly a dilute solution of HCl in EtOAc with care to avoid
excess of the HCl. When no more precipitation occurred on
further addition, the white microgranular solid was filtered
under nitrogen atmosphere and washed with dry EtOAc. The
hydrochloride salt was obtained (6.27 g, 93%) as a stable, white
solid: mp 155 °C dec. Anal. C, H, N, Cl. HPLC analysis on
reverse phase column indicated >99.5% purity with only traces
(0.15%) of an impurity resulting from opening of the bicyclooc-
tanyl ring.
(9) Brideau, C.; Chan, C.; Charleson, S.; Denis, D.; Evans, J . F.;
Ford-Hutchinson, A. W.; Fortin, R.; Gillard, J . W.; Guay, D.;
Gue´vremont, D.; Hutchinson, J . H.; J ones, T. R.; Le´ger, S.;
Mancini, J . A.; McFarlane, C. S.; Pickett, C.; Piechuta, H.; Prasit,
P.; Riendeau, D.; Rouzer, C. A.; Tagari, P.; Vickers, P. J .; Young,
R. N.; Abraham, W. M. Pharmacology of MK-0591 (3-[1-(4-
Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-yl-methoxy)indol-2-
yl]-2,2-dimethyl propanoic acid), a Potent Orally Active Leukot-
riene Biosynthesis Inhibitor. Can. J . Physiol. Pharmacol. 1992,
70, 799-807.
Ack n ow led gm en t. We warmly acknowledge the
contributions of Dr. W. M. Abraham, Mount Sinai
Medical Center, University of Miami School of Mede-
cine, for the sheep study and the personnel of Merck
Frosst Laboratory Animal Resources for their technical
support.
(10) An excellent discussion of the effect of solubility on absorption
can be found in: Rowland, M.; Tozer, T. N. Clinical Pharmaco-

(Pyridylmethoxy)naphthalenes as 5-LO Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2875
kinetics Concepts and Applications; Lea and Febiger Publish-
ers: Philadelphia, PA, 1980; Chapter 3.
have revealed the formation of reactive intermediates at both
the dioxabicyclooctanyl group and the furan ring.20 (b) In
preclinical animal toxicity studies, 3g has shown induction of
lipidosis in the dog gallbladder.21
(11) Crawley, G. C.; Dowell, R. I.; Edwards, P. N.; Foster, S. J .;
McMillan, R. M.; Walker, E. R. H.; Waterson, D. Methoxytet-
rahydropyrans. A New Series of Selective and Orally Potent
5-Lipoxygenase Inhibitors. J . Med. Chem. 1992, 35, 2600-2609.
(12) 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.
(13) Tagari, P.; Becker, A.; Brideau, C.; Frenette, R.; Sadl, V.;
Thomas, E.; Vickers, P.; Ford-Hutchinson, A. Leukotriene
Generation and Metabolism in Dogs: Inhibition of Biosynthesis
by MK-0591. J . Pharmacol. Exp. Ther. 1993, 265, 416-425.
(14) Piechuta, H.; Ford-Hutchinson, A. W.; Letts, L. G. Inhibition of
Allergen-Induced Bronchoconstriction in Hyperreactive Rats as
a Model for Testing 5-Lipoxygenase Inhibitors and Leukotriene
D4 Receptor Antagonists. Agents Actions 1987, 22, 69-74.
(15) Abraham, W. M.; Ahmed, A.; Cortes, A.; Sielczak, M. W.; Hinz,
W.; Bouska, J .; Lanni, C.; Bell, R. L. The 5-Lipoxygenase
Inhibitor Zileuton Blocks Antigen-Induced Late Airway Re-
sponses, Inflammation and Airway Hyperresponsiveness in
Allergic Sheep. Eur. J . Pharmacol. 1992, 217, 119-126.
(16) (a) In preclinical studies, compound 3g (L-739,010) has shown,
after intravenous administration of [14C]L-739,010 in rats and
Rhesus monkeys, very long terminal half-lives of radioactivity
in plasma (64 and 95 h, respectively).19 These findings suggest
the formation of reactive metabolite(s) which covalently bind to
plasma proteins. Microsomal metabolism studies on L-739,010
(17) Deady, L. W.; Shanks, R. A.; Campbell, A. D.; Chooi, S. Y. The
Synthesis of Some Substituted Methyl-pyridinecarboxylates.
Aust. J . Chem. 1971, 24, 385-392.
(18) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;
Watanabe, M.; Yokoyama, K. Novel 1,4-Dihydropyridine Cal-
cium Antagonists. Synthesis and Hypotensive Activity of 4-(Sub-
stituted Pyridyl)-1,4-dihydropyridine Derivatives. Chem. Pharm.
Bull. 1990, 38, 2446-2458.
(19) Zhang, K. E.; Naue, J .; Vyas, K. P. The Disposition of L-739,-
010, a Potent 5-Lipoxygenase Inhibitor in the Rat and Rhesus
Monkey. ISSX Proc. 1994, 6, 83.
(20) (a) Chauret, N.; Nicoll-Griffith, D.; Friesen, R.; Li, C.; Trimble,
L.; Dube, D.; Fortin, R.; Girard, Y.; Yergey, J . Microsomal
Metabolism of the 5-Lipoxygenase Inhibitors L-746,530 and
L-739,010 to Reactive Intermediates that Covalently Bind to
Protein: The Role of the 6,8-Dioxabicyclo[3.2.1]octanyl Moiety.
Drug Metab. Dispos. 1995, 23, 1325-1334. (b) Zhang, K. E.;
Naue, J .; Vyas, K. P. Metabolism of the 5-Lipoxygenase Inhibitor
L-739,010: Evidence of Furan Bioactivation. Chem. Res. Toxicol.
1996, 9, 547-554.
(21) Molon-Noblot, S.; Gillet, J .-P.; Durand-Cavagna, G.; Huber, A.
C.; Patrick, D. H.; Duprat, P. Lipidosis Induced in the Dog
Gallbladder by
a Direct 5-Lipoxygenase Inhibitor. Toxicol.
Pathol. 1996, 24, 231-237.
J M970046B