Structure-activity relationships of (E)-3-(1,4-benzoquinonyl)-2-[(3- pyridyl)alkyl]-2-propenoic acid derivatives that inhibit both 5-lipoxygenase and thromboxane A2 synthetase

Article abstract of DOI:10.1021/jm950725r

As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4- benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) an

Full text of DOI:10.1021/jm950725r

3148
J . Med. Chem. 1996, 39, 3148-3157
Str u ctu r e-Activity Rela tion sh ip s of (E)-3-(1,4-Ben zoqu in on yl)-2-[(3-p yr id yl)-
a lk yl]-2-p r op en oic Acid Der iva tives Th a t In h ibit Both 5-Lip oxygen a se a n d
Th r om boxa n e A2 Syn th eta se
Shigeki Hibi, Yasushi Okamoto,* Katsuya Tagami, Hirotoshi Numata, Naoki Kobayashi, Masanobu Shinoda,
Tetsuya Kawahara, Koukichi Harada, Kaname Miyamoto, and Isao Yamatsu
Tsukuba Research Laboratories, Eisai Company, Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-26, J apan
Received September 29, 1995X
As part of our research for the development of novel antiinflammatory drug candidates, we
have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-
propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX)
A2 synthetase. In order to increase the absorption after oral administration, we introduced a
carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character.
Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic
acid moiety afforded good to moderate inhibitory activities against the production of leukotriene
(LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced
peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group
influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by
introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity
on LTB4 production. The position of an alkoxy group on the 1,4-benzoquinone skeleton played
an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an
appropriate alkoxy group and proper length of methylene side chain, together with a polar
substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and
possess a variety of pharmacologically beneficial effects.
Ch a r t 1
In tr od u ction
Since the roles of arachidonic acid metabolites, such
as leukotrienes (LTs), prostaglandins (PGs), and throm-
boxanes (TXs), as mediators of the inflammatory reac-
tion were clarified, much effort has been made to
develop inhibitors of the production of these chemical
mediators as antiinflammatory agents.1-4 These me-
diators also play important roles in some inflammatory
or allergic diseases, acting either alone or in combina-
tion,4,5 and inhibitors of 5-lipoxygenase (5-LO) and/or
cyclooxygenase (CO) may be useful for the treatment
of asthma, psoriasis, and rheumatoid arthritis, for
example.6-9 Dual inhibitors of CO and 5-LO have been
under development,6-9 but none has entered clinical use
yet, and only nonsteroidal antiinflammatory drugs
(NSAIDs) are used clinically. It should be noted that
NSAIDs are not effective in some inflammatory diseases
such as asthma and hepatitis, suggesting that inflam-
matory mediators other than PGs may play important
roles in the pathology of these diseases.
Recently we have reported that 3-pyridylmethyl-
substituted 2-amino-6-hydroxybenzothiazole derivatives
showed dual 5-LO and thromboxane A2 (TXA2) syn-
thetase inhibitory activity and were effective for the
treatment of an inflammatory bowel disease model due
to their characteristic distribution.10 However, com-
pounds with better absorption are required to treat a
wide variety of inflammatory diseases. Triple-func-
tional compounds which specifically inhibit both 5-LO
and TXA2 synthetase as well as scavenging active
oxygen species were reported by Terao et al. as candi-
dates for the treatment of inflammatory diseases such
as nephrosis.11-14
In this paper, we describe the design, synthesis, and
pharmacological properties of a novel series of (E)-3-
(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid
derivatives. These compounds have potent inhibitory
activities toward both 5-LO and TXA2 synthetase, and
they showed good absorption into the circulation after
po administration in preclinical and clinical studies.
Design
For the past several years, we have been searching
for superior 5-LO inhibitors among compounds with
redox character, since the enzyme reaction involves oxi-
dation as well as reduction steps of the iron atom. AA-
861, which has a 1,4-benzoquinone skeleton, is a typical
redox-type inhibitor14 (Chart 1). Electronic equivalents
of 1,4-benzoquinone such as 2-amino-6-hydroxyben-
zothiazoles (e.g., E3040) also inhibit 5-LO.10 (Chart 1).
In designing a novel dual inhibitor of 5-LO and TXA2
synthetase, we planned to introduce a 3-pyridyl residue,
which is known to selectively inhibit TXA2 synthetase,15,16
into the 1,4-benzoquinone skeleton, which suppresses
5-LO activity14 (Chart 2). As lipophilicity is important
for 5-LO inhibition, the effects on the 5-LO activity of
various combinations of three substituents attached to
the 1,4-benzoquinone skeleton were examined. In order
to increase the absorption from digestive organs, a
X Abstract published in Advance ACS Abstracts, J uly 1, 1996.
S0022-2623(95)00725-4 CCC: $12.00 © 1996 American Chemical Society

Dual Inhibitors of 5-LO and TXA2 Synthetase
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3149
Ch a r t 2
The coupling of the aldehydes 10, 14, and 17 and the
Wittig-Horner reagents 6a -d was performed in the
presence of an appropriate base such as NaH or t-BuOK,
affording 18 in fairly good yield. After hydrolysis of 18,
the resultant carboxylic acids 19 were oxidized by using
cerium(IV) ammonium nitrate (CAN)23 to afford the 1,4-
benzoquinone derivatives 20. The yields in the oxida-
tion by CAN were somewhat low because the extraction
of the product from the reaction mixture was difficult
(Scheme 3). The reduction of the benzoquinones to
corresponding hydroquinones 21 was easily achieved by
using sodium hydrosulfite (Scheme 3).
P h a r m a cologica l Resu lts a n d Discu ssion
(1) In Vitr o Stu d ies (GP EC). We initially evaluated
the inhibitory activities of the obtained (E)-3-(1,4-
benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid de-
rivatives 20 and 21 by monitoring the inhibition of
both LTB4 and TXB2 production from glycogen-induced
peritoneal cells of rats (GPEC) as we have previously
reported10 (in vitro). The results are summarized in
Table 1.
carboxylic acid moiety was also introduced into the
structure. To synthesize the designed compounds, we
planned to utilize the Wittig-Horner reaction between
1,4-benzoquinone precursors and 3-pyridylalkyl-bearing
phosphonoacetates. The length of the methylene chain
in Wittig-Horner reagents was varied from three to six
to investigate the selectivity in TXA2 synthetase inhibi-
tion and the role of lipophilicity in 5-LO inhibition.
As shown in Table 1, the IC50 values for the inhibition
of LTB4 production by (E)-3-(1,4-benzoquinonyl)-2-[(3-
pyridyl)alkyl]-2-propenoic acid derivatives 20a -q varied
from 0.17 (20n ) to 11.7 (20q) µM, while those for
inhibition of TXB2 production were under 1.0 µM for all
compounds examined, suggesting that the structural
changes greatly affect the inhibition of LTB4 produc-
tion. In general, introduction of a polar substituent
such as carboxylic acid is known to reduce inhibitory
activity against LTB4 production,24 but these (E)-3-
(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid
derivatives exhibit potent inhibition of LTB4 produc-
tion by GPEC. The inhibitory activity of LTB4 produc-
tion generally increased with increasing length of the
alkyl chain, indicating that the lipophilicity of the
compound is also an important factor for the inhibition
of LTB4 production by propenoic acid derivatives 20
(Figure 1).
As shown in Figure 1 and Table 1, the compounds
with a shorter methylene side chain (e.g., 20a ,i) showed
weaker inhibitory activities on LTB4 production, sug-
gesting that the lipophilicity of the alkyl side chain is
important. In contrast, an increase of lipophilicity by
introduction of a longer alkoxy chain residue at R1
(20e,f) reduced the inhibitory activity on LTB4 produc-
tion compared with the corresponding methoxy-substi-
tuted derivative 20c. However, similar lipophilic alkoxy
group substitution on R2 (20j-m ) did not markedly
Ch em istr y
The general synthetic pathways for preparation of the
compounds listed in Table 1 are shown in Schemes 1-3.
The starting materials, Wittig-Horner reagents 6a -
d , and 1,4-dimethoxybenzaldehydes 10, 14, and 17 were
synthesized by known or general procedures outlined
in Schemes 1 and 2, respectively.
The Wittig-Horner reagents 6a -d were prepared
from the corresponding chloride or mesylate of the
alcohol 517 derived from 4 and triethyl phosphonoacetate
in the presence of base (Scheme 1). The alcohol 5 was
obtained by the coupling of 3-bromopyridine (1) and the
lactone 2 in the presence of n-butyllithium or magne-
sium to give keto alcohol 4.18 In an alternative route,
the keto alcohol 4 was also prepared via Claisen
condensation and decarboxylation of methyl nicotinate
(3) and the lactone 2 in good yield.19,20
The trialkoxy-substituted aldehydes 10,21 14,21 and
17 were generally synthesized from the corresponding
1,4-hydroquinone dimethyl ethers 7 and 11 or phenol
15,22 respectively. The 1,4-hydroquinone dimethyl ethers
7 and 11 were subjected to formylation, Bayer-Villiger
rearrangement, and hydrolysis to afford the phenol
derivatives 8 and 12. Phenol derivatives 8, 12, and 15
were alkylated by alkyl halides with base, and the
resulting ethers 9, 13, and 16 were formylated to afford
the aldehydes 10, 14, and 17 (Scheme 2).
Sch em e 1. Synthesis of the Wittig-Horner Reagents 6a -d a
a
Reagents: (a) n-BuLi or Mg; (b) t-BuOK, t-BuOH, then heat; (c) NH2NH2, NaOH; (d) SOCl2 or MsCl; (e) (EtO)2P(O)CH2COOEt, NaI,
NaH.

3150 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Sch em e 2. Synthesis of the Aldehydes 10, 14, and 17a
Hibi et al.
a
Reagents: (a) m-CPBA; (b) NaOH, H2O; (c) Cl2CHOCH3, TiCl4; (d) R3X, base.
Sch em e 3. Synthesis of 1,4-Benzoquinone Derivatives 20 and Hydroquinone Derivatives 21a
a
Reagents: (a) NaH, DMF or t-BuOK, t-BuOH; (b) NaOH, H2O; (c) (NH4)2Ce(NO3)6; (d) Na2S2O4.
reduce the inhibition compared with the corresponding
methoxy-substituted derivative 20g. Among the three
monomethoxy compounds with n ) 5 (20c,g,n ), 20n
showed somewhat stronger inhibition of LTB4 produc-
tion than 20c,g.
inhibitors has already been well established, and the
distance between the carboxylic acid and the nitrogen
atom of pyridine or imidazole is critical.15,16 In the cases
of 20a ,i, this distance may be too short to allow efficient
binding to the enzyme.
It should be noted that none of the compounds
examined inhibited the production of PGE2 at the dose
at which the production of TXB2 is almost completely
suppressed. This can be attributed to the inhibition of
TXA2 synthetase without affecting CO.
Hydroquinones 21c,g,n showed decreased inhibitory
activities on both LTB4 and TXB2 production compared
with the corresponding 1,4-benzoquinones 20c,g,n .
Considering that 21c showed almost the same activities
as 20c in cell-free in vitro experiments (see below), the
observed differences in the activities could be attributed
to differences of transmembrane permeation ability.
(2) In Vitr o Stu d ies (Hu m a n cells).10 We next
conducted in vitro assays using human whole blood,
human neutrophils, and human platelets for 20c and
21c. In these experiments the representative 5-LO and
Introduction of an extra methoxy group into the
benzoquinone skeleton (20q) resulted in decreased
inhibition of LTB4 production compared with the cor-
responding monomethoxy compounds 20c,g,n . These
results could also be attributable to the decrease in the
lipophilicity of the molecules. Thus, we conclude that
the positions of alkoxy substituents on the 1,4-benzo-
quinone skeleton markedly affected the inhibitory activ-
ity on LTB4 production, probably due to steric and
electronic interactions, while lipophilic character around
the propenoic acid residue generally increased the
inhibitory activity.
As shown in Table 1 and Figure 1, the inhibition of
TXB2 production decreased only when the length of the
methylene side chain was short (n ) 3) in this series.
The structure-activity relationship of TXA2 synthetase

Dual Inhibitors of 5-LO and TXA2 Synthetase
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3151
Ta ble 1. Inhibitory Activity against Eicosanoid Production by Glycogen-Induced Peritoneal Cells of Rat (GPEC)a
IC50 (mM)b
compd
R1
MeO
MeO
MeO
MeO
EtO
n-C7H15
Me
Me
Me
Me
Me
R2
R3
n
LTB4
TXB2
0.48
0.09
0.07
0.12
0.32
0.16
0.18
PGE2
mp (°C)c
formulad
20a
20b
20c
20d
20e
20f
20g
20h
20i
Me
Me
Me
Me
Me
Me
MeO
MeO
n-C4H9O
n-C4H9O
EtO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3
4
5
6
5
5
5
6
3
5
5
5
5
5
6
5
5
5
5
5
3.2
1.4
0.82
0.59
4.4
100 (75%)e
>100f
140-142
124-125
134-135
C20H21NO5‚0.5H2O
C21H23NO5‚0.4H2O
C22H25NO5‚0.3H2O
C23H27NO5‚0.5H2O
C23H27NO5‚0.3H2O
19g
100 (100%)e 119-121
100 (76%)e
>100e
116-118
oil
128-130
h
O
3.2
0.54
C28H37NO5
>100g
C22H25NO5‚0.3H2O
0.18 <0.1 (55%) 100 (100%)e 108-110
C23H27NO5‚0.1H2O
h,i
1.8
1.0
0.84
0.89
NT
92-95
C23H27NO5
20j
20k
20l
<0.1 (61%) 100 (100%)e 97-100
C25H31NO5‚0.5H2O
0.12
100 (93%)g
105-108
oil
oil
C23H27NO5,h,j
h
Me
Me
Me
Me
n-C7H15
O
0.27 <0.1 (77%) NT
0.27 <0.1
0.17
0.22
0.75
C28H37NO5
C28H35NO5
>100f
h
20m
20n
20o
20p
20q
21c
21g
21n
(cyclohexylmethyl)oxy Me
Me
Me
Me
MeO
Me
MeO
0.11
NT
NT
NT
148-149
64-66
110-112
oil
C22H25NO5‚0.5AcOEth,k
MeO
MeO
Me
Me
Me
0.42
0.50
0.41
0.40
1.5
C23H27NO5‚0.7H2Oh,l
h
H
C21H23NO5
C22H25NO6
>100f
>100f
>100f
>100f
h
MeO
MeO
Me
11.7
4.9
>3.0
2.1
amorphous C22H27NO5‚HClm
h
MeO
Me
amorphous C22H27NO5
h
Me
MeO
0.14
amorphous C22H27NO5
a
Aliquots (5 × 105 cells) of rat peritoneal leukocytes were incubated (5 min, 37 °C) with test compounds prior to addition of A23187
(4 µM, 10 min, 37 °C). Aliquots of the supernatant were analyzed for LTB4, TXB2, and PGE2. See the Experimental Section for details.
b
IC50 values were derived from inhibition experiments in which data points were measured in duplicate, and concentration-effect curves
were calculated by the probit method. Values in parentheses indicate the inhibition (%) at the dose. c The solid was recrystallized from
n-hexane-AcOEt. Elemental analyses for C, H, and N are within (0.4% of the theoretical values. e The production of PGE2 was potentiated
d
at 0.1-1 µM. f The production of PGE2 was potentiated at 0.1-10 µM. g The production of PGE2 was potentiated at 0.1-100 µM. Formula
h
i
j
k
was obtained by high-resolution mass spectroscopy. C: calcd, 69.50; found, 65.83. C: calcd, 69.50; found, 67.57. H: calcd, 6.84; found,
l
m
6.33. H: calcd, 6.98; found, 6.44. Elemental analysis by using HCl salt. NT: not tested.
Ta ble 2. In Vitro Activities in Human Cells (IC50, µM)a
human
neutrophils,c
LTB4
human
platelets,d
TXB2
human whole bloodb
LTB4 TXB2
5.8 3.2
>100 3.0
1.3 >100
>100 <0.1
compd
20c
21c
Zileuton
Ozagrel
0.90
1.9
0.42
0.39
1.9
NT
1.9
>100
a
IC50 values were derived from inhibition experiments in which
data points were measured in duplicate, and concentration-effect
curves were calculated by the probit method. b Human whole blood
(0.4 mL) was incubated (5 min, 37 °C) with test compounds prior
to addition of A23187 (40 µM, 20 min, 37 °C). Aliquots of plasma
were analyzed for LTB4, TXB2, and PGE2. c Human PMNs (1 ×
105 cells) were incubated (5 min, 37 °C) with test compounds prior
to addition of A23187 (4 mM, 10 min, 37 °C). Aliquots of the
d
supernatant were analyzed for LTB4. Human platelets (6 × 107
F igu r e 1. Relationship between the length of the methylene
chain and IC50
cells) were incubated (5 min, 25 °C) with test compounds prior to
addition of PGH2 (1 µg/mL, 3 min, 25 °C). Aliquots of the
supernatant were analyzed for TXB2. NT: not tested.
.
TXA2 synthetase inhibitors Zileuton25 and Ozagrel,26
respectively, were also evaluated (Table 2).
(3) In Vitr o Stu d ies (Cell-fr ee en zym e a ssa y).10
The cell-free in vitro assay of 5-LO from RBL-1 and
TXA2 synthetase from microsome human platelets was
performed to confirm that the biological activities were
due to direct enzyme inhibition (Table 3).
As shown in Table 3, 20c and 21c exhibited both 5-LO
and TXA2 synthetase inhibitory activities. In contrast
to the in vitro cell studies (Tables 1 and 2), 21c exhibited
more potent inhibition than 20c against 5-LO in mi-
crosomes of RBL-1 cells. Thus, the observed difference
of in vitro activity might be attributed to a difference of
transmembrane permeation ability but not to a differ-
As shown in Table 2, both 20c and the corresponding
hydroquinone 21c inhibited LTB4 and TXB2 production,
except for LTB4 production in human whole blood in the
case of 21c. The selective 5-LO inhibitor Zileuton
exhibited 2-4 times higher activity than 20c in the
inhibition of LTB4 production. Ozagrel selectively
inhibited TXA2 production in human whole blood as
compared with 20c and 21c. However, the inhibition
of TXB2 production by both 20c and 21c in human
plateletes was almost as potent as that of the selective
TXA2 inhibitor Ozagrel.

3152 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Hibi et al.
Ta ble 3. In Vitro Cell-Free Enzyme Assay (IC50, µM)a
1.55-2.04 (m, 4H), 2.05-2.30 (m, 2H), 2.57 (t, J ) 7.6 Hz, 2H),
2.89 (ddd, J ) 22.4, 10.8, 4.0 Hz, 1H), 4.07-4.24 (m, 6H), 7.19
(dd, J ) 8.0, 4.8 Hz, 1H), 7.44-7.48 (m, 1H), 8.38-8.43 (m,
2H).
Eth yl 2-(Dieth ylp h osp h on o)-5-(3-p yr id yl)p en ta n oa te
(6a ). 5-(3-Pyridyl)propanol (5a ) (6.9 g, 50.3 mmol) was treated
according to the same procedure described for the preparation
of 6c to afford 6a (7.0 g, 20.4 mmol, 41%) as a dark brown oil:
1H NMR (CDCl3) δ 1.22-1.40 (m, 11H), 1.60-2.10 (m, 4H),
2.65 (t, J ) 7.6 Hz, 2H), 2.89-3.02 (m, 1H), 4.07-4.30 (m, 6H),
7.20 (dd, J ) 8.0, 4.8 Hz, 1H), 7.42-7.50 (m, 1H), 8.40-8.46
(m, 2H).
enzyme source
microsome of
microsome of human platelets,c
TXA2 synthetase
compd
20c
21c
Zileuton
Ozagrel
RBL-1 cells,b 5-LO
16.3
4.8
0.41
NT
0.026
0.033
NT
0.006
a
IC50 values were derived from inhibition experiments in which
data points were measured in duplicate, and concentration-effect
b
curves were calculated by the probit method. Homogenates of
E t h yl 2-(Diet h ylp h osp h on o)-6-(3-p yr id yl)h exa n oa t e
(6b). 5-(3-Pyridyl)butanol (5b) (15.0 g, 99.1 mmol) was treated
according to the same procedure described for the preparation
of 6c to afford 6b (7.9 g, 22.4 mmol, 23%) as a dark brown oil.
Eth yl 2-(Dieth ylph osph on o)-8-(3-pyr idyl)octan oate (6d).
5-(3-Pyridyl)heptanol (5d ) (25.5 g, 0.142 mol) was treated
according to the same procedure described for the preparation
of 6c to afford 6d (25.0 g, 0.066 mol, 46%) as a dark brown oil.
Gen er a l P r oced u r e for th e Syn th esis of th e Ald eh yd es
10, 14, a n d 17: Rep r esen ta tive Rou te to th e Ald eh yd e
10a . 2,5-Dim eth oxy-3,6-d im eth ylp h en ol (8a ). m-Chloro-
perbenzoic acid (70%, 130 g, 0.53 mol) was added portionwise
to a solution of 2,5-dimethoxy-3,6-dimethylbenzaldehyde (7a )
(94 g, 0.48 mol) in dichloromethane (660 mL) with stirring at
room temperature. The mixture was heated to reflux for 30
min, then ice (200 g) and a saturated solution of sodium
thiosulfate (200 mL) were added. The resulting solid were
RBL-1 cells were incubated (5 min, 37 °C) with test compounds
prior to addition of arachidonic acid (0.2 mM, 10 min, 37 °C).
Aliquots of the reaction mixtures were analyzed for 5-HETE.
c Microsomes fraction (20 µg of protein) from human platelets was
incubated (5 min, 25 °C) with test compounds prior to addition of
PGH2 (1 µg/mL, 1 min, 25 °C). Aliquots of the reaction mixtures
were analyzed for TXB2. NT: not tested.
ence of intrinsic inhibitory potency toward 5-LO. These
two compounds (20c and 21c) did not show any signifi-
cant difference in inhibitory activity against cell-free in
vitro TXA2 synthetase in microsomes of human plate-
lets.
In conclusion, in spite of the introduction of a polar
carboxylic acid moiety into the 1,4-benzoquinone skel-
eton, compounds 20c,g,n exhibited well-balanced inhi-
bition of the production of both LTB4 and TXB2 but did
not inhibit production of PGE2 in in vitro screening. The
compounds showed good absorption into the systemic
circulation after po administration in preclinical studies
(data not shown). Dual-function compounds such as 20c
(E6700) that specifically inhibit both 5-LO and TXA2
synthetase could possess a variety of pharmacologically
beneficial effects, and clinical studies are in progress.
filtered off and washed with
a small amount of dichlo-
romethane. The combined organic layer was washed succes-
sively with 1 N sodium hydroxide and brine, dried, and
evaporated. The residue was dissolved in methanol (250 mL).
To the solution was added 28% sodium methoxide in methanol
(120 mL, 0.59 mol), and the mixture was stirred at room
temperature for 30 min. Ice-water (300 mL) was added to the
reaction mixture, and then the mixture was neutralized with
2 N hydrochloric acid affording white precipitates. The solid
was collected by filtration, washed with water, and dried to
afford crude 8a (75 g, 0.41 mol, 81%) as a white solid, which
was used for the next step without further purification: 1H
NMR (400 MHz, CDCl3) δ 2.13 (s, 3H), 2.27 (s, 3H), 3.75 (s,
3H), 3.77 (s, 3H), 5.73 (br s, 1H), 6.29 (s, 1H).
4-H yd r oxy-2,5-d im et h oxy-3,6-d im et h ylb en za ld eh yd e
(9a ). To the solution of 2,5-dimethoxy-3,6-dimethylphenol (8a )
(31 g, 0.28 mol) in dichloromethane (330 mL) was added
titanium(IV) chloride (40 mL, 0.36 mol) under 10 °C, and the
resulting deep purple solution was stirred for an additional
15 min at 0 °C. R,R-Dichloromethyl methyl ether (39 mL, 0.43
mol) was added to the solution under 15 °C, and the mixture
was stirred at room temperature for 2.5 h. The reaction was
quenched carefully with 300 mL of ice-water and the mixture
extracted with ethyl acetate twice. The organic layer was
washed successively with saturated sodium hydrogen carbon-
ate and brine, dried, and evaporated. The residue was treated
with ether, and the resulting solid was collected by filtration
and washed with a small amount of ethanol and n-hexane (1:
1) to afford 9a (38 g, 0.18 mol, 65%) as a white solid, which
was used for the next step without further purification: mp
168-169 °C (EtOH-n-hexane); 1H NMR (400 MHz, CDCl3) δ
2.20 (s, 3H), 2.52 (s, 3H), 3.75 (s, 3H), 3.81 (s, 3H), 6.40 (s,
1H), 10.39 (s, 1H).
2,4,5-Tr im eth oxy-3,6-d im eth ylben za ld eh yd e (10a ). To
the solution of 4-hydroxy-2,5-dimethoxy-3,6-dimethylbenzal-
dehyde (9a ) (38 g, 0.18 mol) in N,N-dimethylformamide (300
mL) was added sodium hydride (60% oil suspension, 8.0 g, 0.20
mol) with stirring in an ice bath. After 15 min, iodomethane
(12.5 mL, 0.20 mol) was added dropwise to the reaction
mixture at room temperature. The mixture was stirred for
an additional 3 h, the reaction was quenched with water, and
the mixture was extracted with ethyl acetate twice. The
organic layer was washed with brine, dried, and evaporated.
The crude residue was purified by flash column chromatog-
raphy on silica gel (solvent: ethyl acetate-n-hexane ) 1:9) to
afford 10a (41 g, 0.18 mol, >99%) as a yellow solid: mp 29-
30 °C (ethyl acetate-n-hexane); 1H NMR (400 MHz, CDCl3) δ
Exp er im en ta l Section
Ch em istr y. Reagents and solvents were purchased from
the usual commercial sources. Silica gel (Kieselgel 60, Merck)
was used for column chromatography and silica gel (Kieselgel
60 F254, Merck) for analytical thin layer chromatography (TLC).
Compounds were detected on TLC plates by exposure to UV
light (254 nm). Melting points were measured on a Yanagi-
moto micromelting point apparatus without correction. 1H and
13C NMR spectra were recorded on a Varian Unity 400
spectrometer, and chemical shifts are expressed in ppm
downfield from tetramethylsilane (TMS) as an internal refer-
ence. Infrared spectra were recorded on a J asco FT/IR-330E
spectrometer. Mass spectra (MS) were obtained on a J EOL
J MS-HX100 mass spectrometer. All organic extracts were
dried over anhydrous MgSO4, and the solvent was removed
with a rotary evaporator under reduced pressure.
Eth yl 2-(Dieth ylp h osp h on o)-7-(3-p yr id yl)h ep ta n oa te
(6c). Mesyl chloride (161 g, 1.41 mol) was added dropwise to
a mixture of 5-(3-pyridyl)pentanol (5c) (221 g, 1.34 mol) and
triethylamine (142 g, 1.40 mol) in dichloromethane (2 L) under
cooling with ice. The mixture was stirred for 1 h at the same
temperature; then the organic layer was separated, washed
with brine twice, dried, and evaporated to give the chloride
as a pale red oil. Triethyl phosphonoacetate (300 g, 1.34 mol)
was added dropwise to a suspension of sodium hydride (55%
oil suspension, 59 g, 1.35 mol) in N,N-dimethylformamide (500
mL) under 60 °C, and the mixture was stirred at room
temperature for 1 h. To this mixture was added dropwise a
solution of the above chloride in N,N-dimethylformamide (500
mL) at 60 °C. The reaction mixture was stirred for 12 h at 60
°C, and then ethyl acetate (3 L) was added. The organic layer
was washed with brine, dried, and evaporated. The crude
residue was purified by flash column chromatography on silica
gel (solvent: ethyl acetate-n-hexane ) 1:2-1:1, ethyl acetate-
methanol (5%)) to afford 6c (226 g, 0.61 mol, 45%) as a pale
red oil: 1H NMR (400 MHz, CDCl3) δ 1.20-1.50 (m, 11H),

Dual Inhibitors of 5-LO and TXA2 Synthetase
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3153
2.20 (s, 3H), 2.48 (s, 3H), 3.75 (s, 3H), 3.79 (s, 3H), 3.92 (s,
3H), 10.43 (s, 1H).
2,5-dimethoxy-3,6-dimethylbenzaldehyde (10b) (1.34 g, 5.6
mmol) and Wittig-Horner reagent 6c (2.1 g, 5.6 mmol) were
treated according to the procedure described for the prepara-
tion of 19c to afford 19e (400 mg, 0.94 mmol, 17%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.23 (m, 2H), 1.39
(t, J ) 7.0 Hz, 3H), 1.46 (m, 2H), 1.52 (m, 2H), 2.08 (s, 3H),
2.17 (s, 3H), 2.20 (t, J ) 8.0 Hz, 2H), 2.53 (t, J ) 8.0 Hz, 2H),
3.56 (s, 3H), 3.78 (s, 3H), 4.03 (t, J ) 7.0 Hz, 2H), 7.21 (br s,
1H), 7.46 (d, J ) 8.0 Hz, 1H), 7.58 (s, 1H), 8.43 (br s, 2H).
(E )-3-[4-(n -H e p t y lo x y )-2,5-d im e t h o x y -3,6-d im e t h -
ylp h en yl]-2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (19f).
4-(n-Heptyloxy)-2,5-dimethoxy-3,6-dimethylbenzaldehyde (10c)
(1.0 g, 3.2 mmol) and Wittig-Horner reagent 6c (1.2 g, 3.2
mmol) were treated according to the procedure described for
the preparation of 19c to afford 19f (350 mg, 0.7 mmol, 22%)
as a colorless oil.
(E)-3-(2,3,5-Tr im eth oxy-4,6-d im eth ylp h en yl)-2-[5-(3-p y-
r id yl)p en t yl]-2-p r op en oic Acid (19g). 2,3,5-Trimethoxy-
4,6-dimethylbenzaldehyde (14a ) (1.4 g, 6.2 mmol) and Wittig-
Horner reagent 6c (2.3 g, 6.2 mmol) were treated according to
the procedure described for the preparation of 19c to afford
19g (390 mg, 2.2 mmol, 34%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.21 (tt, J ) 8.0, 8.0 Hz, 2H), 1.35 (t, J ) 7.2
Hz, 3H), 1.40 (t, J ) 8.0 Hz, 2H), 1.48 (tt, J ) 8.0, 8.0 Hz,
2H), 2.07 (s, 3H), 2.15 (t, J ) 8.0 Hz, 2H), 2.21 (s, 3H), 2.49 (t,
J ) 8.0 Hz, 2H), 3.65 (s, 3H), 3.70 (s, 3H), 3.77 (s, 3H), 4.28
(q, J ) 7.2 Hz, 2H), 7.16 (dd, J ) 4.8, 7.6 Hz, 1H), 7.39 (d, J
) 8.0 Hz, 1H), 7.44 (s, 1H), 8.36 (d, J ) 1.6 Hz, 1H), 8.40 (dd,
J ) 1.6, 4.8 Hz, 1H).
(E)-3-(2,3,5-Tr im eth oxy-4,6-d im eth ylp h en yl)-2-[6-(3-p y-
r id yl)h exyl]-2-p r op en oic Acid (19h ). 2,3,5-Trimethoxy-4,6-
dimethylbenzaldehyde (14a ) (1.4 g, 5.1 mmol) and Wittig-
Horner reagent 6d (2.0 g, 5.3 mmol) were treated according
to the procedure described for the preparation of 19c to afford
19h (220 mg, 0.52 mmol, 10%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.20-1.27 (m, 4H), 1.42 (tt, J ) 8.0, 8.0 Hz,
2H), 1.55 (tt, J ) 8.0, 8.0 Hz, 2H), 2.11 (s, 3H), 2.19 (t, J ) 8.0
Hz, 2H), 2.23 (s, 3H), 2.58 (t, J ) 8.0 Hz, 3H), 3.69 (s, 3H),
3.71 (s, 3H), 3.82 (s, 3H), 7.26 (d, J ) 7.6 Hz, 1H), 7.54 (d, J
) 7.6 Hz, 1H), 7.58 (s, 1H), 8.50 (br s, 2H).
(E)-3-[3-(n-Butyloxy)-2,5-dimethoxy-4,6-dimethylphenyl]-
2-[3-(3-p yr id yl)p r op yl]-2-p r op en oic Acid (19i). 3-(n-Bu-
tyloxy)-2,5-dimethoxy-4,6-dimethylbenzaldehyde (14b) (2.8 g,
11.2 mmol) and Wittig-Horner reagent 6a (3.8 g, 11.2 mmol)
were treated according to the procedure described for the
preparation of 19c to afford 19i (1.3 g, 3.0 mmol, 27%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J ) 8.0 Hz,
3H), 1.51 (q, J ) 7.6 Hz, 2H), 1.71-1.85 (m, 4H), 2.04 (s, 3H),
2.22 (br s, 5H), 2.52 (t, J ) 7.6 Hz, 2H), 3.66 (s, 6H), 3.90 (t,
J ) 8.0 Hz, 2H), 7.16 (br s, 1H), 7.39 (d, J ) 7.6 Hz, 1H), 7.56
(s, 1H), 8.42 (br s, 1H), 8.51 (br s, 1H).
(E)-3-[3-(n -Bu tyloxy)-2,5-d im eth oxy-4,6-d im eth ylp h e-
n yl]-2-[5-(3-pyr id yl)p en tyl]-2-p r open oic Acid (19j). 3-(Bu-
tyloxy)-2,5-dimethoxy-4,6-dimethylbenzaldehyde (14b) (3.0 g,
12.0 mmol) and Wittig-Horner reagent 6c (4.4 g, 12.0 mmol)
were treated according to the procedure described for the
preparation of 19c to afford 19j (1.1 g, 2.4 mmol, 20%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J ) 8.0 Hz,
3H), 1.13 (br s, 2H), 1.40-1.55 (m, 4H), 1.71 (tt, J ) 7.6, 7.6
Hz, 2H), 2.05 (s, 3H), 2.13 (t, J ) 7.6 Hz, 2H), 2.19 (s, 3H),
2.48 (t, J ) 7.6 Hz, 2H), 3.62 (br s, 6H), 3.86 (t, J ) 8.0 Hz,
2H), 7.17 (d, J ) 7.6 Hz, 1H), 7.40 (d, J ) 7.6 Hz, 1H), 7.51 (s,
1H), 8.44 (s, 2H).
(E)-3-(3-Eth oxy-2,5-d im eth oxy-4,6-d im eth ylp h en yl)-2-
[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (19k ). 3-Ethoxy-
2,5-dimethoxy-4,6-dimethylbenzaldehyde (14c) (5.5 g, 23.1
mmol) and Wittig-Horner reagent 6c (9.3 g, 25.4 mmol) were
treated according to the procedure described for the prepara-
tion of 19c to afford 19k (5.0 g, 11.7 mmol, 51%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 1.24 (tt, J ) 8.0, 8.0 Hz,
2H), 1.35 (t, J ) 8.0 Hz, 3H), 1.40-1.52 (m, 4H), 2.08 (s, 3H),
2.18 (t, J ) 8.0 Hz, 2H), 2.21 (s, 3H), 2.53 (t, J ) 8.0 Hz, 2H),
3.66 (s, 3H), 3.69 (s, 3H) 3.99 (q, J ) 8.0 Hz, 2H), 7.24 (dd, J
) 4.8, 7.6 Hz, 1H), 7.49 (d, J ) 7.6 Hz, 1H), 7.58 (s, 1H), 8.43
(s, 1H), 8.46 (s, 1H).
Eth yl (E)-3-(2,4,5-Tr im eth oxy-3,6-d im eth ylp h en yl)-2-
[5-(3-p yr id yl)p en tyl]-2-p r op en oa te (18c). A solution of
ethyl 2-(diethylphosphono)-7-(3-pyridyl)heptanoate (6c) (222
g, 0.60 mol) in N,N-dimethylformamide (300 mL) was added
dropwise to a suspension of sodium hydride (60% oil suspen-
sion, 24 g, 0.6 mol) in N,N-dimethylformamide (200 mL) at 0
°C. After completion of the dropping, the mixture was stirred
at room temperature for 1 h; then
a solution of 2,4,5-
trimethoxy-3,6-dimethylbenzaldehyde (10a ) (122 g, 0.54 mol)
in N,N-dimethylformamide (200 mL) was added dropwise. The
reaction mixture was stirred overnight under heating at 50
°C and then poured onto 1 L of ice-water. The whole mixture
was extracted with 1 L of ethyl acetate twice. The organic
layer was separated, dried, and evaporated. The crude residue
was purified by flash column chromatography on silica gel
(solvent: n-hexane-ethyl acetate ) 1:9-3:7) to afford 18c (177
g, 0.40 mol, 74%) as a pale yellow oil: 1H NMR (400 MHz,
CDCl3) δ 1.21 (tt, J ) 7.5, 7.5 Hz, 2H), 1.35 (t, J ) 7.1 Hz,
3H), 1.38 (tt, J ) 7.5, 7.5 Hz, 2H), 1.46 (tt, J ) 7.5, 7.5 Hz,
2H), 2.07 (s, 3H), 2.16 (t, J ) 7.5 Hz, 2H), 2.16 (s, 3H), 2.48 (t,
J ) 7.5 Hz, 2H), 3.54 (s, 3H), 3.76 (s, 3H), 3,82 (s, 3H), 4.12
(q, J ) 7.1 Hz, 2H), 7.16 (dd, J ) 5.5, 7.8 Hz, 1H), 7.39 (dt, J
) 1.5, 7.8 Hz, 1H), 7.45 (s, 1H), 8.36 (d, J ) 1.5 Hz, 1H), 8.39
(dd, J ) 1.5, 5.5 Hz, 1H).
(E)-3-(2,4,5-Tr im eth oxy-3,6-d im eth ylp h en yl)-2-[5-(3-p y-
r id yl)p en tyl]-2-p r op en oic Acid (19c). A solution of ethyl
(E)-3-(2,4,5-trimethoxy-3,6-dimethylphenyl)-2-[5-(3-pyridyl)-
pentyl]-2-propenoate (18c) (177 g, 0.39 mol) in ethanol (500
mL) was treated with 5 N sodium hydroxide solution (100 mL).
The mixture was heated under reflux for 1 h followed by the
addition of 1 L of ice. The whole was neutralized with 6 N
hydrochloric acid and extracted with 1 L of ethyl acetate twice.
The organic layer was washed with brine, dried, and evapo-
rated to afford 19c (159 g, 0.39 mol, >99%) as a colorless oil:
1H NMR (400 MHz, CDCl3) δ 1.24 (tt, J ) 7.6, 7.6 Hz, 2H),
1.47 (tt, J ) 7.6, 7.6 Hz, 2H), 1.52 (tt, J ) 7.6, 7.6 Hz, 2H),
2.09 (s, 3H), 2.17 (s, 3H), 2.20 (t, J ) 7.6 Hz, 2H), 2.54 (t, J )
7.6 Hz, 2H), 3.57 (s, 3H), 3.78 (s, 3H), 3,83 (s, 3H), 7.23 (dd, J
) 5.0, 7.6 Hz, 1H), 7.48 (br d, J ) 7.6 Hz, 1H), 7.59 (s, 1H),
8.46 (br s, 2H).
(E)-3-(2,4,5-Tr im eth oxy-3,6-d im eth ylp h en yl)-2-[3-(3-p y-
r id yl)p r op yl]-2-p r op en oic Acid (19a ). 2,4,5-Trimethoxy-
3,6-dimethylbenzaldehyde (10a) (2.2 g, 10.0 mmol) and Wittig-
Horner reagent 6a (3.4 g, 10.0 mmol) were treated according
to the same procedure described for the preparation of 19c to
afford 19a (800 mg, 2.2 mmol, 22%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 1.84 (tt, J ) 7.6, 7.6 Hz, 2H), 2.10 (s, 3H),
2.23 (s, 3H), 2.25 (t, J ) 7.6 Hz, 2H), 2.57 (t, J ) 7.6 Hz, 2H),
3.56 (s, 3H), 3.80 (s, 3H), 3.87 (s, 3H), 7.21 (t, J ) 7.6 Hz, 1H),
7.46 (d, J ) 7.6 Hz, 1H), 7.60 (s, 1H), 8.46 (br s, 1H), 8.58 (br
s, 1H).
(E)-3-(2,4,5-Tr im eth oxy-3,6-d im eth ylp h en yl)-2-[4-(3-p y-
r id yl)bu tyl]-2-p r op en oic Acid (19b). 2,4,5-Trimethoxy-3,6-
dimethylbenzaldehyde (10a ) (1.6 g, 7.1 mmol) and Wittig-
Horner reagent 6b (2.5 g, 7.1 mmol) were treated according
to the procedure described for the preparation of 19c to afford
19b (1.0 g, 2.5 mmol, 35%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.41-1.58 (m, 4H), 2.08 (s, 3H), 2.18 (s, 3H),
2.25 (t, J ) 7.2 Hz, 2H), 2.53 (t, J ) 7.2 Hz, 2H), 3.55 (s, 3H),
3.78 (s, 3H), 3.85 (s, 3H), 7.21 (t, J ) 7.6 Hz, 1H), 7.44 (d, J )
7.6 Hz, 1H), 7.59 (s, 1H), 8.44 (br s, 2H).
(E)-3-(2,4,5-Tr im eth oxy-3,6-d im eth ylp h en yl)-2-[6-(3-p y-
r id yl)h exyl]-2-p r op en oic Acid (19d ). 2,4,5-Trimethoxy-3,6-
dimethylbenzaldehyde (10a ) (1.4 g, 6.3 mmol) and Wittig-
Horner reagent 6d (2.4 g, 6.3 mmol) were treated according
to the same procedure described for the preparation of 19c to
afford 19d (1.4 g, 3.3 mmol, 52%) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 1.22 (t, J ) 3.5 Hz, 4H), 1.41 (t, J ) 7.6
Hz, 2H), 1.53 (t, J ) 7.6 Hz, 2H), 2.10 (s, 3H), 2.18 (s, 3H),
2.19 (t, J ) 7.6 Hz, 2H), 2.55 (t, J ) 7.6 Hz, 2H), 3.57 (s, 3H),
3.79 (s, 3H), 3.85 (s, 3H), 7.23 (t, J ) 8.0 Hz, 1H), 7.51 (d, J )
8.0 Hz, 1H), 7.58 (s, 1H), 8.47 (br s, 2H).
(E)-3-(4-Eth oxy-2,5-d im eth oxy-3,6-d im eth ylp h en yl)-2-
[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (19e). 4-Ethoxy-

3154 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Hibi et al.
(E )-3-[3-(n -H e p t yloxy)-2,5-d im e t h oxy-4,6-d im e t h yl-
p h en yl]-2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (19l).
3-(n-Heptyloxy)-2,5-dimethoxy-4,6-dimethylbenzaldehyde (14d)
(2.4 g, 7.8 mmol) and Wittig-Horner reagent 6c (2.9 g, 7.8
mmol) were treated according to the procedure described for
the preparation of 19c to afford 19l (560 mg, 1.1 mmol, 14%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.90 (t, J )
8.0 Hz, 3H), 1.20-1.38 (m, 10H), 1.41-1.54 (m, 4H), 1.76 (tt,
J ) 7.6, 7.6 Hz, 2H), 2.08 (s, 3H), 2.18 (t, J ) 7.6 Hz, 2H),
2.21 (s, 3H), 2.53 (t, J ) 7.6 Hz, 2H), 3.67 (s, 3H), 3.69 (s, 3H),
3.90 (t, J ) 8.0 Hz, 3H), 7.23 (t, J ) 7.6 Hz, 1H), 7.47 (d, J )
7.6 Hz, 1H), 7.58 (s, 1H), 8.46 (br s, 2H).
lized from an ethanol-water mixture to afford 20c (90 g, 0.24
mol, 62%) as a yellow solid: mp 122-128 °C (EtOH-H2O);
1H NMR (400 MHz, CDCl3) δ 1.26 (tt, J ) 7.0, 7.0 Hz, 2H),
1.50 (tt, J ) 7.0, 7.0 Hz, 2H), 1.61 (tt, J ) 7.0, 7.0 Hz, 2H),
1.95 (s, 3H), 1.96 (s, 3H), 2.12 (t, J ) 7.0 Hz, 2H), 2.60 (t, J )
7.0 Hz, 2H), 4.01 (s, 3H), 7.26 (s, 1H), 7.27 (dd, J ) 5.0, 8.5
Hz, 1H), 7.55 (br d, J ) 8.5 Hz, 1H), 8.44 (br d, J ) 5.0 Hz,
1H), 8.50 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 8.9, 13.4,
27.9, 28.8, 29.1, 30.7, 32.7, 60.9, 123.8, 128.9, 131.1, 137.3,
138.6, 139.0, 139.7, 139.8, 145.5, 148.3, 155.6, 169.8, 183.3,
186.7; IR (KBr) 1700, 1650, 1635, 1600 cm-1. Anal. (C22H25
-
NO5‚0.3H2O) C, H, N.
(E )-3-[3-(Cycloh e xyloxy)-2,5-d im e t h oxy-4,6-d im e t h -
ylp h en yl]-2-[5-(3-p yr id yl)pen tyl]-2-p r op en oic Acid (19m ).
3-(Cyclohexyloxy)-2,5-dimethoxy-4,6-dimethylbenzaldehyde (14e)
(1.0 g, 3.3 mmol) and Wittig-Horner reagent 6c (1.8 g, 4.9
mmol) were treated according to the procedure described for
the preparation of 19c to afford 19m (380 mg, 0.8 mmol, 24%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.09 (dq, J )
4.0, 12.0 Hz, 2H), 1.17-1.34 (m, 4H), 1.42-1.55 (m, 4H), 1.67-
1.82 (m, 5H), 1.90 (br d, J ) 12.0 Hz, 2H), 2.10 (s, 3H), 2.18 (t,
J ) 8.0 Hz, 2H), 2.20 (s, 3H), 2.54 (t, J ) 8.0 Hz, 2H), 3.67 (s,
3H), 3.68 (s, 3H), 3.70 (d, J ) 4.0 Hz, 2H), 7.22 (t, J ) 7.6 Hz,
1H), 7.46 (d, J ) 7.6 Hz, 1H), 7.58 (s, 1H), 8.43 (br s, 2H).
(E)-3-(2,5,6-Tr im eth oxy-3,4-d im eth ylp h en yl)-2-[5-(3-p y-
r id yl)p en tyl]-2-p r op en oic Acid (19n ). 2,5,6-Trimethoxy-
3,4-dimethylbenzaldehyde (17a ) (2.0 g, 9.0 mmol) and Wittig-
Horner reagent 6c (3.7 g, 10.0 mmol) were treated according
to the procedure described for the preparation of 19c to afford
19n (1.9 g, 4.6 mmol, 51%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.30 (tt, J ) 7.6, 7.6 Hz, 2H), 1.42-1.52 (m,
4H), 2.15 (s, 3H), 2.19 (s, 3H), 2.28 (t, J ) 7.6 Hz, 2H), 2.64 (t,
J ) 7.6 Hz, 2H), 3.56 (s, 3H), 3.72 (s, 3H), 3.76 (s, 3H), 7.24
(m, 1H), 7.49 (d, J ) 7.2 Hz, 1H), 7.64 (s, 1H), 8.43 (br s, 2H).
(E)-3-(2,5,6-Tr im eth oxy-3,4-d im eth ylp h en yl)-2-[6-(3-p y-
r id yl)h exyl]-2-p r op en oic Acid (19o). 2,5,6-Trimethoxy-3,4-
dimethylbenzaldehyde (17a ) (1.3 g, 5.9 mmol) and Wittig-
Horner reagent 6d (2.5 g, 6.5 mmol) were treated according
to the procedure described for the preparation of 19c to afford
19o (1.3 g, 3.0 mmol, 51%) as a colorless oil.
(E)-3-(2,5,6-Tr im eth oxy-3-m eth ylp h en yl)-2-[5-(3-p yr id -
yl)p en t yl]-2-p r op en oic Acid (19p ). 2,5,6-Trimethoxy-3-
methylbenzaldehyde (17b) (2.1 g, 9.8 mmol) and Wittig-
Horner reagent 6c (4.0 g, 10.7 mmol) were treated according
to the procedure described for the preparation of 19c to afford
19p (2.5 g, 6.3 mmol, 64%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.28 (t, J ) 8.0 Hz, 2H), 1.30-1.55 (m, 4H),
2.25 (s, 3H), 2.30 (t, J ) 8.0 Hz, 2H), 2.53 (t, J ) 8.0 Hz, 2H),
3.58 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H), 6.60 (s, 1H), 7.21 (dd, J
) 5.0, 7.0 Hz, 1H), 7.47 (dd, J ) 1.0, 9.0 Hz, 1H), 7.64 (s, 1H),
8.43 (br s, 2H).
(E)-3-[2,3,4-Tr im eth oxy-5-(m eth oxym eth oxy)-6-m eth -
ylp h en yl]-2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (19q).
2,3,4-Trimethoxy-5-(methoxymethoxy)-6-methylbenzalde-
hyde (1.0 g, 3.7 mmol) and Wittig-Horner reagent 6c (1.4 g,
3.7 mmol) were treated according to the procedure described
for the preparation of 19c to afford 19q (760 mg, 1.6 mmol,
43%) as a colorless oil: 1H NMR (90 MHz, CDCl3) δ 1.09-
1.86 (m, 6H), 2.00-2.34 (m, 2H), 2.09 (s, 3H), 2.37-2.71 (m,
2H), 3.56 (s, 3H), 3.69 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 5.03
(s, 2H), 5.57-6.31 (m, 2H), 7.03-7.57 (m, 3H), 8.29-8.51 (m,
2H).
(E)-3-(2-Meth oxy-3,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[3-(3-p yr id yl)p r op yl]-2-p r op en oic Acid (20a ). Com-
pound 19a (800 mg, 2.2 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20a
(300 mg, 0.8 mmol, 38%) as a yellow solid: mp 105-108 °C
1
(n-hexane-AcOEt); H NMR (400 MHz, CDCl3) δ 1.90 (tt, J
) 8.0, 8.0 Hz, 2H), 1.95 (s, 3H), 1.97 (s, 3H), 2.17 (t, J ) 8.0
Hz, 2H), 2.63 (t, J ) 8.0 Hz, 2H), 4.04 (s, 3H), 7.26 (s, 1H),
7.28 (dd, J ) 4.5, 7.5 Hz, 1H), 7.56 (br d, J ) 7.5 Hz, 1H), 8.47
(br d, J ) 4.5 Hz, 1H), 8.64 (br s, 1H). Anal. (C20H21
NO5‚0.5H2O) C, H, N.
-
(E)-3-(2-Meth oxy-3,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[4-(3-p yr id yl)bu tyl]-2-p r op en oic Acid (20b). Compound
19b (1.0 g, 2.5 mmol) was treated according to the procedure
described for the preparation of 20c to afford 20b (390 mg,
1.1 mmol, 44%) as a yellow solid: mp 124-125 °C (n-hexane-
AcOEt); 1H NMR (400 MHz, CDCl3) δ 1.42-1.63 (m, 4H), 1.95
(s, 6H), 2.17 (t, J ) 7.0 Hz, 2H), 2.62 (t, J ) 7.0 Hz, 2H), 4.03
(s, 3H), 7.25 (s, 1H), 7.31 (dd, J ) 5.0, 8.0 Hz, 1H), 7.60 (d, J
) 8.0 Hz, 1H), 8.46 (br d, J ) 5.0 Hz, 1H), 8.48 (br s, 1H).
Anal. (C21H23NO5‚0.4H2O) C, H, N.
(E)-3-(2-Meth oxy-3,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[6-(3-p yr id yl)h exyl]-2-p r op en oic Acid (20d ). Compound
19d (1.4 g, 3.3 mmol) was treated according to the procedure
described for the preparation of 20c to afford 20d (480 mg,
1.2 mmol, 36%) as a yellow solid: mp 119-121 °C (n-hexane-
AcOEt); 1H NMR (400 MHz, CDCl3) δ 1.15-1.34 (m, 4H), 1.44
(tt, J ) 7.5, 7.5 Hz, 2H), 1.58 (tt, J ) 7.5, 7.5 Hz, 2H), 1.95 (s,
6H), 2.12 (t, J ) 7.5 Hz, 2H), 2.60 (t, J ) 7.5 Hz, 2H), 4.03 (s,
3H), 7.25 (s, 1H), 7.32 (dd, J ) 5.5, 8.0 Hz, 1H), 7.60 (d, J )
8.0 Hz, 1H), 8.47 (dd, J ) 1.0, 5.5 Hz, 1H), 8.50 (d, J ) 1.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 8.9, 13.5, 28.0, 28.7, 29.2,
30.8, 33.0, 60.9, 123.9, 128.9, 131.1, 137.5, 138.8, 139.1, 139.71,
139.74, 145.3, 148.0, 155.6, 169.9, 183.4, 186.8. Anal. (C23H27
-
NO5‚0.5H2O) C, H, N.
(E)-3-(2-Eth oxy-3,6-d im eth yl-1,4-ben zoqu in on -5-yl)-2-
[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20e). Compound
19e (400 mg, 0.94 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20e
(125 mg, 0.31 mmol, 34%) as a yellow solid: mp 116-118 °C
1
(n-hexane-AcOEt); H NMR (400 MHz, CDCl3) δ 1.23-1.29
(m, 2H), 1.38 (t, J ) 7.0 Hz, 3H), 1.46-1.55 (m, 2H), 1.56-
1.64 (m, 2H), 1.95 (s, 3H), 1.96 (s, 3H), 2.12 (t, J ) 8.0 Hz,
2H), 2.60 (t, J ) 8.0 Hz, 2H), 4.28 (q, J ) 7.0 Hz, 2H), 7.25-
7.29 (m, 2H), 7.55 (dt, J ) 1.0, 8.0 Hz, 1H), 8.45 (dd, J ) 1.0,
5.0 Hz, 1H), 8.50 (d, J ) 1.0 Hz, 1H). Anal. (C23H27
NO5‚0.3H2O) C, H, N.
-
(E)-3-[2-(n -Hep tyloxy)-3,6-d im eth yl-1,4-ben zoqu in on -5-
yl]-2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20f). Com-
pound 19f (350 mg, 0.7 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20f
(100 mg, 0.21 mmol, 31%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 0.76 (t, J ) 7.0 Hz, 3H), 1.20-1.40 (m, 8H), 1.40-
1.55 (m, 4H), 1.60 (tt, J ) 7.0, 7.0 Hz, 2H), 1.74 (tt, J ) 7.0,
7.0 Hz, 2H), 1.95 (s, 3H), 1.99 (s, 3H), 2.13 (t, J ) 7.0 Hz, 2H),
2.60 (t, J ) 7.0 Hz, 2H), 4.20 (t, J ) 7.0 Hz, 2H), 7.23 (s, 1H),
7.25 (dd, J ) 5.0, 8.0 Hz, 1H), 7.53 (br d, J ) 8.0 Hz, 1H), 8.43
(d, J ) 5.0 Hz, 1H), 8.49 (br s, 1H); HRMS (C28H37NO5) calcd
468.2750 (MH+), found, 468.2740.
(E)-3-(3-Meth oxy-2,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (20g). Com-
pound 19g (390 mg, 2.2 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20g
(280 mg, 0.73 mmol, 33%) as a yellow solid: mp 128-130 °C
(E)-3-(2-Meth oxy-3,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20c). An aque-
ous solution (700 mL) of cerium(IV) ammonium nitrate (527
g, 0.96 mol) was added to a solution of (E)-3-(2,4,5-trimethoxy-
3,6-dimethylphenyl)-2-[5-(3-pyridyl)pentyl]-2-propenoic acid
(19c) (159 g, 0.39 mol) in an acetonitrile (800 mL)/water (400
mL) mixture with cooling in an ice bath. The mixture was
stirred for 30 min, and the pH thereof was adjusted to 5 with
a saturated solution of sodium hydrogen carbonate followed
by the addition of 3 L of water. The whole was extracted with
6 L of ethyl acetate twice. The organic layer was washed with
brine, dried, and evaporated. The obtained oil was crystallized
from a small amount of ethyl acetate to give crude 20c (114 g,
0.29 mol, 74%) as yellow crystals. This product was recrystal-

Dual Inhibitors of 5-LO and TXA2 Synthetase
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3155
1
(n-hexane-AcOEt); H NMR (400 MHz, CDCl3) δ 1.27 (tt, J
1.49 (tt, J ) 8.0, 8.0 Hz, 2H), 1.59 (tt, J ) 8.0, 8.0 Hz, 2H),
1.65-1.85 (m, 7H), 1.95 (s, 3H), 1.98 (s, 3H), 2.12 (t, J ) 8.0
Hz, 2H), 2.59 (t, J ) 8.0 Hz, 2H), 3.99 (d, J ) 8.0 Hz, 2H),
7.23 (s, 1H), 7.27 (d, J ) 7.2 Hz, 1H), 7.53 (d, J ) 7.2 Hz, 1H),
8.45 (br s, 1H), 8.49 (br s, 1H); HRMS (C28H35NO5) calcd
466.2593 (MH+), found 466.2572.
) 7.6, 7.6 Hz, 2H), 1.51 (tt, J ) 7.6, 7.6 Hz, 2H), 1.61 (tt, J )
7.6, 7.6 Hz, 2H), 1.97 (s, 3H), 1.98 (s, 3H), 2.13 (t, J ) 7.2 Hz,
2H), 2.61 (t, J ) 8.0 Hz, 2H), 3.98 (s, 3H), 7.23 (s, 1H), 7.28
(dd, J ) 2.4, 7.2 Hz, 1H), 8.45 (d, J ) 4.8 Hz, 1H), 8.90 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 9.0, 14.0, 27.9, 28.9, 29.2,
30.7, 32.7, 61.0, 123.8, 128.6, 130.4, 137.4, 138.8, 139.2, 141.8,
(E)-3-(6-Meth oxy-2,3-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (20n ). Com-
pound 19n (1.9 g, 4.6 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20n
(150 mg, 0.36 mmol, 8%) as a yellow solid: mp 148-149 °C
145.3, 148.1, 155.5, 169.6, 182.0, 188.0. Anal. (C22H25
NO5‚0.3H2O) C, H, N.
-
(E)-3-(3-Meth oxy-2,6-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[6-(3-p yr id yl)h exyl]-2-p r op en oic Acid (20h ). Compound
19h (220 mg, 0.52 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20h
(31 mg, 0.08 mmol, 15%) as a yellow solid: mp 108-110 °C
1
(n-hexane-AcOEt); H NMR (400 MHz, CDCl3) δ 1.28 (tt, J
) 7.5, 7.5 Hz, 2H), 1.51 (tt, J ) 7.5, 7.5 Hz, 2H), 1.60 (tt, J )
7.5, 7.5 Hz, 2H), 2.03 (s, 3H), 2.04 (s, 3H), 2.18 (t, J ) 7.5 Hz,
2H), 2.59 (t, J ) 7.5 Hz, 2H), 3.96 (s, 3H), 7.27 (dd, J ) 5.0,
8.0 Hz, 1H), 7.30 (s, 1H), 7.55 (br d, J ) 8.0 Hz, 1H), 8.45 (dd,
J ) 1.5, 5.0 Hz, 1H), 8.48 (d, J ) 1.5 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 12.1, 12.7, 27.7, 28.8, 29.4, 30.6, 32.7, 61.1,
120.3, 123.8, 129.3, 137.5, 138.8, 139.1, 139.3, 141.2, 145.3,
148.1, 154.6, 170.0, 183.3, 186.5; HRMS (C22H25NO5) calcd
383.1733 (M+), found 383.1748. Anal. (C22H25NO5‚0.5AcOEt)
C, N; H: calcd, 6.84; found, 6.33.
1
(n-hexane-AcOEt); H NMR (400 MHz, CDCl3) δ 1.19-1.33
(m, 4H), 1.45 (tt, J ) 7.2, 7.2 Hz, 2H), 1.58 (tt, J ) 6.8, 6.8
Hz, 2H), 1.97 (s, 3H), 1.98 (s, 3H), 2.13 (t, J ) 7.6 Hz, 2H),
2.60 (t, J ) 8.0 Hz, 2H), 4.99 (s, 3H), 7.24 (d, J ) 1.2 Hz, 1H),
7.29 (dd, J ) 2.4, 7.2 Hz, 1H), 7.57 (d, J ) 8.0 Hz, 1H), 8.46
(d, J ) 4.8 Hz, 1H), 8.49 (s, 1H). Anal. (C23H27NO5‚0.1H2O)
C, H, N.
(E)-3-[3-(n -Bu tyloxy)-2,6-d im eth yl-1,4-ben zoqu in on -5-
yl]-2-[3-(3-p yr id yl)p r op yl]-2-p r op en oic Acid (20i). Com-
pound 19i (1.3 g, 3.0 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20i
(460 mg, 1.2 mmol, 39%) as a yellow solid: mp 92-95 °C (n-
hexane-AcOEt); 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J ) 6.8
Hz, 3H), 1.45 (q, J ) 7.2 Hz, 2H), 1.70 (tt, J ) 4.8, 4.8 Hz,
2H), 1.90 (br s, 2H), 1.95 (s, 3H), 1.99 (s, 3H), 2.13-2.27 (m,
2H), 2.53-2.66 (m, 2H), 4.12 (t, J ) 7.6 Hz, 2H), 7.25 (br s,
2H), 7.53 (d, J ) 6.0 Hz, 1H), 8.43 (br s, 1H), 8.61 (br s, 1H);
HRMS (C23H27NO5) calcd 397.1889 (M+), found 397.1904.
Anal. (C23H27NO5) H, N; C: calcd, 69.50; found, 65.83.
(E)-3-[3-(n -Bu tyloxy)-2,6-d im eth yl-1,4-ben zoqu in on -5-
yl]-2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20j). Com-
pound 19j (1.1 g, 2.4 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20j
(410 mg, 0.96 mmol, 40%) as a yellow solid: mp 97-100 °C
(n-hexane-AcOEt); 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J )
7.4 Hz, 3H), 1.26 (tt, J ) 7.6, 7.6 Hz, 2H), 1.40-1.52 (m, 4H),
1.60 (tt, J ) 7.6, 7.6 Hz, 2H), 1.70 (tt, J )7.6, 7.6 Hz, 2H),
1.99 (s, 3H), 2.00 (s, 3H), 2.13 (t, J ) 8.0 Hz, 2H), 2.60 (t, J )
8.0 Hz, 2H), 4.20 (t, J ) 8.0 Hz, 2H), 7.24 (s, 1H), 7.28 (dd, J
) 2.4, 7.6 Hz, 1H), 7.55 (d, J ) 6.4 Hz, 1H), 8.45 (d, J ) 4.0
Hz, 1H), 8.49 (s, 1H). Anal. (C25H31NO5‚0.5H2O) C, H, N.
(E)-3-(3-Eth oxy-2,6-d im eth yl-1,4-ben zoqu in on -5-yl)-2-
[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20k ). Compound
19k (5.0 g, 11.7 mmol) was treated according to the procedure
described for the preparation of 20c to afford 20k (2.0 g, 5.0
mmol, 43%) as a yellow solid: mp 105-108 °C (n-hexane-
AcOEt); 1H NMR (400 MHz, CDCl3) δ 1.26 (tt, J ) 7.6, 7.6
Hz, 2H), 1.34 (t, J ) 6.8 Hz, 3H), 1.50 (tt, J ) 7.6, 7.6 Hz,
2H), 1.59 (tt, J ) 7.6, 7.6 Hz, 2H), 1.97 (s, 3H), 1.98 (s, 3H),
2.13 (t, J ) 7.2 Hz, 2H), 2.59 (t, J ) 8.0 Hz, 2H), 4.26 (q, J )
7.2 Hz, 2H), 7.24 (s, 1H), 7.29 (dd, J ) 2.8, 7.6 Hz, 1H), 7.56
(d, J ) 7.6 Hz, 1H), 8.46 (d, J ) 4.8 Hz, 1H), 8.48 (s, 1H);
HRMS (C23H27NO5) calcd 397.1889 (M+), found 397.1886. Anal.
(C23H27NO5) H, N; C: calcd, 69.50; found, 67.57.
(E)-3-[3-(H ep t yloxy)-2,6-d im et h yl-1,4-b en zoq u in on -5-
yl]-2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20l). Com-
pound 19l (560 mg, 1.1 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20l
(100 mg, 0.21 mmol, 19%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 0.87 (t, J ) 8.0 Hz, 3H), 1.22-1.36 (m, 8H), 1.39 (tt,
J ) 7.6, 7.6 Hz, 2H), 1.49 (tt, J ) 7.6, 7.6 Hz, 2H), 1.60 (tt, J
) 7.6, 7.6 Hz, 2H), 1.70 (q, J ) 8.0 Hz, 2H), 1.97 (s, 3H), 1.99
(s, 3H), 2.14 (t, J ) 7.6 Hz, 2H), 2.60 (t, J ) 7.6 Hz, 2H), 4.08
(t, J ) 8.0 Hz, 2H), 7.24 (t, J ) 4.8 Hz, 1H), 7.28 (s, 1H), 7.54
(d, J ) 7.6 Hz, 1H), 8.44 (d, J ) 4.8 Hz, 1H), 8.48 (s, 1H);
HRMS (C28H37NO5) calcd 468.2750 (MH+), found 468.2746.
(E)-3-[3-(Cycloh exyloxy)-2,6-dim eth yl-1,4-ben zoqu in on -
5-yl]-2-[5-(3-pyr idyl)pen tyl]-2-pr open oic Acid (20m ). Com-
pound 19m (380 mg, 0.8 mmol) was treated according to the
procedure described for the preparation of 20c to afford 20m
(100 mg, 0.22 mmol, 27%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 1.02 (dq, J ) 4.0, 12.0 Hz, 2H), 1.20-1.30 (m, 4H),
(E)-3-(6-Meth oxy-2,3-d im eth yl-1,4-ben zoqu in on -5-yl)-
2-[6-(3-p yr id yl)h exyl]-2-p r op en oic Acid (20o). Compound
19o (1.3 g, 3.0 mmol) was treated according to the procedure
described for the preparation of 20c to afford 20o (175 mg,
0.44 mmol, 15%) as a yellow solid: mp 64-66 °C (n-hexane-
AcOEt); 1H NMR (400 MHz, CDCl3) δ 1.20-1.31 (m, 4H), 1.43
(tt, J ) 7.5, 7.5 Hz, 2H), 1.56 (tt, J ) 7.5, 7.5 Hz, 2H), 2.01 (s,
3H), 2.03 (s, 3H), 2.15 (t, J ) 7.5 Hz, 2H), 2.55 (t, J ) 7.5 Hz,
2H), 3.94 (s, 3H), 7.25 (t, J ) 8.0 Hz, 1H), 7.27 (s, 1H), 7.53 (d,
J ) 8.0 Hz, 1H), 8.46 (br s, 2H); HRMS (C23H27NO5) calcd
397.1889 (M+), found 397.1904. Anal. (C23H27NO5‚0.7H2O) C,
N; H: calcd, 6.98; found, 6.44.
(E)-3-(6-Meth oxy-3-m eth yl-1,4-ben zoqu in on -5-yl)-2-[5-
(3-p yr id yl)p en tyl]-2-p r op en oic Acid (20p ). Compound 19p
(2.5 g, 6.3 mmol) was treated according to the procedure
described for the preparation of 20c to afford 20p (100 mg,
0.27 mmol, 4%) as a yellow solid: mp 110-112 °C (n-hexane-
AcOEt); 1H NMR (400 MHz, CDCl3) δ 1.14 (tt, J ) 8.0, 8.0
Hz, 2H), 1.34 (tt, J ) 8.0, 8.0 Hz, 2H), 1.45 (tt, J ) 8.0, 8.0
Hz, 2H), 1.93 (s, 3H), 2.03 (t, J ) 8.0 Hz, 2H), 2.48 (t, J ) 8.0
Hz, 2H), 3.91 (s, 3H), 6.67 (s, 1H), 6.99 (s, 1H), 7.24 (dd, J )
4.0, 7.0 Hz, 1H), 7.53 (dt, J ) 1.0, 4.0 Hz, 1H), 8.34 (br s, 2H);
HRMS (C21H23NO5) calcd 370.1654 (MH+), found 370.1650.
(E)-3-(2,3-Dim eth oxy-6-m eth yl-1,4-ben zoqu in on -5-yl)-
2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (20q ). A solu-
tion of (E)-3-[2,3,4-trimethoxy-5-(methoxymethoxy)-6-methyl-
phenyl]-2-[5-(3-pyridyl)pentyl]-2-propenoic acid (19q) (760 mg,
1.6 mmol) in acetone (20 mL) was treated with concentrated
HCl (5 mL) with cooling in an ice bath. The mixture was
stirred for 1 h, and the pH thereof was adjust to 5 with a
saturated solution of sodium hydrogen carbonate. The mixture
was extracted with ethyl acetate, and the organic layer was
washed with brine, dried, and evaporated to afford (E)-3-(2,3,4-
trimethoxy-5-hydroxy-6-methylphenyl)-2-[5-(3-pyridyl)pentyl]-
2-propenoic acid (760 mg, 1.6 mmol, >99%) as a colorless oil.
To a solution of this product in ethyl acetate (30 mL) was added
iron(III) chloride hexahydrate (3 g) at room temperature. The
mixture was stirred for 1 h followed by the addition of water,
and the whole was extracted with ethyl acetate twice. The
organic layer was washed with brine, dried, and evaporated.
The crude residue was purified by flash column chromatog-
raphy on silica gel (solvent: ethyl acetate-n-hexane ) 1:2-
1:1) to afford 20q (200 mg, 0.5 mmol, 31%) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 1.07-1.86 (m, 6H), 1.94 (s, 3H),
1.95-2.77 (m, 4H), 3.97 (s, 3H), 4.00 (s, 3H), 6.77-7.60 (m,
3H), 8.29-8.57 (m, 2H); HRMS (C22H25NO6) calcd 400.1760
(MH+), found 400.1747.
(E)-3-(2,5-Dih yd r oxy-4-m eth oxy-3,6-d im eth ylp h en yl)-
2-[5-(3-p yr id yl)p en tyl]-2-p r op en oic Acid (21c). (E)-3-(2-
Methoxy-3,6-dimethyl-1,4-benzoquinon-5-yl)-2-[5-(3-pyridyl)-
pentyl]-2-propenoic acid (20c) (1.0 g, 2.6 mmol) was suspended
in ethyl acetate (150 mL), and the suspension was well mixed
with a solution of sodium hydrosulfite (2 g) in water (50 mL).
The organic layer was separated, dried, and evaporated to give

3156 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16
Hibi et al.
the hydroquinone 21c (660 mg, 1.7 mmol, 66%) as a white
amorphous substance: 1H NMR (400 MHz, CDCl3) δ 1.21 (tt,
J ) 7.0, 7.0 Hz, 2H), 1.44 (tt, J ) 7.0, 7.0 Hz, 2H), 1.51 (tt, J
) 7.0, 7.0 Hz, 2H), 2.06 (s, 3H), 2.17 (s, 3H), 2.23 (t, J ) 7.0
Hz, 2H), 2.54 (t, J ) 7.0 Hz, 2H), 3.76 (s, 3H), 5.22 (br s, 2H),
7.26 (dd, J ) 5.5, 7.0 Hz, 1H), 7.43 (s, 1H), 7.51 (dd, J ) 1.5,
7.0 Hz, 1H), 8.40-8.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
9.5, 12.9, 27.7, 27.8, 28.3, 30.3, 32.6, 60.8, 114.9, 118.4, 119.6,
123.9, 134.0, 137.8, 139.0, 139.4, 140.7, 143.6, 144.9, 145.5,
0.1% BSA) in the presence of 2 mM glutathione. The reaction
was initiated by addition of arachidonic acid (0.2 mM). After
incubation for 10 min at 37 °C, the reaction was stopped by
adding 0.05 µL of 2 N formic acid. Then, 0.2 mL of CHCl3/
MeOH (4:1) and 0.2 mL of saturated NaCl solution were added.
The samples were centrifuged for 5 min at 110g, and the
organic phases were analyzed for 5-HETE by HPLC (C18ODS,
Nucleosil, MeOH:H2O:AcOH (75:25:0.01), 1.5 mL/min).
Hu m a n P la telets. Platelet-rich plasma was obtained from
citrated whole blood by centrifugation (110g, 10 min) and
mixed with anticoagulant solution (ACD-A solution, Terumo
Co., Ltd., J apan). The platelet suspension was centrifuged
(1000g, 10 min) and resuspended in Tris-HCl-saline, pH 7.4,
containing 10 µM indomethacin at a concentration of 3 × 108
cells/mL. Aliquots (0.2 mL) of the platelet suspension were
preincubated with test compound or vehicle alone (0.1%
DMSO/0.1% BSA) for 5 min at 25 °C before addition of PGH2
(1 µg/mL). After 3 min at 25 °C, the reaction was terminated
by adding 0.8 mL of 55 mM citrate/100% ethanol solution. The
cell suspensions were centrifuged (110g, 10 min), and the
supernatants were assayed for TXB2 by radioimmunoassay.
147.6, 171.1. IR (KBr) 3340, 1690, 1635 cm-1. Anal. (C22H27
-
NO5‚HCl) C, H, N (elemental analysis by using HCl salt).
(E)-3-(2,5-Dih yd r oxy-3-m eth oxy-4,6-d im eth ylp h en yl)-
2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (21g). Com-
pound 20g (220 mg, 0.57 mmol) was treated according to the
procedure described for the preparation of 21c to afford 21g
(180 mg, 0.45 mmol, 79%) as a white amorphous substance:
1H NMR (400 MHz, CDCl3) δ 1.06 (tt, J ) 7.0, 7.0 Hz, 2H),
1.38-1.52 (m, 4H), 2.03 (s, 3H), 2.22 (t, J ) 7.0 Hz, 2H), 2.23
(s, 3H), 2.49 (t, J ) 7.0 Hz, 2H), 3.73 (s, 3H), 7.21 (dd, J ) 5.2,
8.0 Hz, 1H), 7.45 (br d, J ) 8.0 Hz, 1H), 7.56 (br s, 2H), 8.24
(d, J ) 2.0 Hz, 1H), 8.40 (dd, J ) 1.6, 4.8 Hz, 1H); HRMS
(C22H27NO5) calcd 385.1889 (M+), found 385.1928.
Hu m a n P la telet Th r om boxa n e Syn th eta se. Platelets
were separated from platelet-rich plasma by centrifugation
(1000g, 10 min, 4 °C), as described above, and resuspended in
phosphate-buffered saline (Dulbecco’s PBS), pH 7.4. Platelets
were homogenized by sonication (Branson Sonifier 185, 5
microtip setting) at 0 °C. The microsome fraction was sepa-
rated by centrifugation (105000g, 60 min) and resuspended
in 50 mM Tris-HCl-saline, pH 7.4, containing 10 µM in-
domethacin. Aliquots (20 µg of protein) of the enzyme prepa-
ration were preincubated for 5 min at 25 °C with test
compound or vehicle (0.1% DMSO/0.1% BSA). The reaction
was initiated by adding PGH2 (1 µg/mL). After incubation for
1 min at 25 °C, the reaction was terminated by adding 0.8
mL of 55 mM citric acid/100% ethanol solution. The incubation
mixture was assayed for TXB2 by radioimmunoassay.
(E)-3-(2,5-Dih yd r oxy-6-m eth oxy-3,6-d im eth ylp h en yl)-
2-[5-(3-p yr id yl)p en t yl]-2-p r op en oic Acid (21n ). Com-
pound 20n (100 mg, 0.26 mmol) was treated according to the
procedure described for the preparation of 21c to afford 21n
(80 mg, 0.21 mmol, 80%) as a white amorphous substance: 1H
NMR (400 MHz, DMSO-d6) δ 1.14 (tt, J ) 7.0, 7.0 Hz, 2H),
1.30-1.40 (m, 4H), 2.00 (s, 3H), 2.02 (s, 3H), 2.13 (t, J ) 7.0
Hz, 2H), 2.41 (t, J ) 7.0 Hz, 2H), 3.46 (s, 3H), 7.26 (dd, J )
5.5, 7.0 Hz, 1H), 7.34 (s, 1H), 7.50 (dd, J ) 1.5, 7.0 Hz, 1H),
7.64 (s, 1H), 8.03 (s, 1H), 8.31-8.36 (m, 2H); HRMS (C22H27
-
NO5) calcd 385.1889 (M+), found 385.1916.
In h ibition of Eicosa n oid P r od u ction (in Vitr o). Gly-
cogen -In d u ced P er iton ea l Cells of Ra ts. Mixed peritoneal
leukocytes, including polymorphonuclear leukocytes (PMNs)
and mononuclear leukocytes, were elicited from male F344 rats
(Charles River) by an ip injection of 10 mL of 6% glycogen
solution (type II; Sigma), according to Moroney et al.27 The
cells were suspended in Hanks balanced salt solution (HBSS)
free of Ca2+ and Mg2+ at a concentration of 5 × 106 cells/mL.
Aliquots (0.1 mL) of the cell suspensions were preincubated
for 5 min at 37 °C with test compound or vehicle (0.1% DMSO/
0.1% BSA) in 96-well plates (Costar). The reaction was
initiated by adding A23187 (4 µM). At the end of incubation
(10 min at 37 °C), the reaction was terminated by adding
BW755C (100 µM). The incubation mixtures were centrifuged
(110g, 5 min), and aliquots of the supernatants were analyzed
for LTB4, TXB2, and PGE2 by radioimmunoassay (Amersham,
NEM).
Hu m a n Wh ole Blood . Fresh blood was obtained from
healthy volunteers and anticoagulated with heparin (10
U/mL). Aliquots (0.4 mL) were preincubated with test com-
pound or vehicle (0.1% DMSO/0.1% BSA) for 5 min at 37 °C.
A23187 (40 µM; Calbiochem, CA) was added, and the blood
samples were incubated for an additional 20 min. Plasma was
separated by centrifugation and analyzed for LTB4, TXB2, and
PGE2 by radioimmunoassay.
Hu m a n P er ip h er a l Blood Neu tr op h ils. Human blood
was anticoagulated with heparin (10 U/mL). Red cells were
first removed by dextran sedimentation (6% dextran, 37 °C,
60 min). Neutrophils were sedimented by Percoll (Sigma)
density gradient centrifugation and resuspended in Hanks
balanced salt solution (HBSS) free of Ca2+ and Mg2+ at a
concentration of 1 × 106 cells/mL. Aliquots (0.1 mL) were
preincubated with test compound or vehicle (0.1% DMSO/0.1%
BSA) for 5 min at 37 °C. Eicosanoid synthesis was induced
by adding A23187 (4 µM). After 10 min, the cells were pelleted
by centrifugation (110g, 10 min). Cell-free supernatants were
assayed for LTB4 by radioimmunoassay.
Refer en ces
(1) Samuelsson, B. Leukotrienes: Mediators of Immediate Hyper-
sensitivity Reaction and Inflammation. Science 1983, 220, 568-
575.
(2) Hanley, S. P. Prostaglandins and Lung. Lung 1986, 164, 65-
77.
(3) Newcombe, D. S. Leukotrienes: Regulation of Biosynthesis,
Metabolism, and Bioactivity. J . Clin. Pharmacol. 1988, 28, 530-
549.
(4) Filep, J . Leukotrienes; Prostanoids in Health and Disease.
(Highlights of 2nd International Conference on Leukotrienes and
Prostanoids in Health and Disease, Oct. 9-14, 1988, J erusalem).
Drugs Today 1989, 25 (2), 140-142.
(5) Forman, H. J .; Torres, M. Inflammation: an Overview. Oxid.
Damage Repair [Int. Soc. Free Radical Res. Bienn. Meet.], 5th
1990 (published 1991), 634-641.
(6) Bonne, C.; Muller, A.; Latour, E.; Tissie, G.; Emerit, I.; Modat,
G.; Dornand, J .; Roch, M.; Giroud, J . P.; Grisworld, D. E.;
Marshall, P. J .; Coquelet, C. 2-(2-Hydroxy-4-methylphenyl)-
aminothiazole Hydrochloride as a Dual Inhibitor of Cyclooxy-
genase/Lipoxygenase and a Free Radical Scavenger. Arzneim.
Forsch./ Drug Res. 1989, 39, 1242.
(7) Marshall, P. J .; Grisword, D. E.; Breton, J .; Webb, E. F.;
Hillegass, L. M.; Sarau, H. M.; Newton, J ., J r.; Lee, J . C.; Bender,
P. E.; Hanna, N. Pharmacology of the Pyrrolimidazole, SK&F
105809-I. Inhibition of Inflammatory Cytokine Production and
of 5-Lipoxygenase- and Cyclooxygenase-Mediated Metabolism
of Arachidonic Acid. Biochem. Pharmacol. 1991, 42, 813-824.
(8) Grisword, D. E.; Marshall, P. J .; Lee, J . C.; Webb, E. F.;
Hillegass, L. M.; Wartell, J .; Newton, J ., J r.; Hanna, N.
Pharmacology of the Pyrrolimidazole, SK&F 105809-II. Antiin-
flammatory Activity and Inhibition of Mediator Production in
vivo. Biochem. Pharmacol. 1991, 42, 825-831.
(9) Mylari, B. L.; Carty, T. J .; Moore, P. F.; Zembrowski, W. J . 1,2-
Dihydro-1-oxopyrrolo[3,2,1-kl]phenothiazine-2-carboxamides and
Congeners, Dual Cyclooxygenase/5-Lipoxygenase Inhibitors with
Antiinflammatory Activity. J . Med. Chem. 1990, 33, 2019-2024.
(10) Hibi, S.; Okamoto, Y.; Tagami, K.; Numata, H.; Kobayashi, N.;
Shinoda, M.; Kawahara, T.; Murakami, M.; Oketani, K.; Inoue,
T.; Shibata, H.; Yamatsu, I. Novel Dual Inhibitors of 5-Lipoxy-
genase and Thromboxane A2 Synthetase: Synthesis and Struc-
ture-Activity Relationships of 3-Pyridylmethyl-substituted,
2-Amino-6-hydroxy-benzothiazole Derivatives. J . Med. Chem.
1994, 37, 3062-3070.
RBL-1 Cell 5-Lip oxygen a se. RBL-1 cells (2 × 106 cells/
mL), suspended in 50 mM phosphate buffer, pH 7.4, containing
0.25 M sucrose and 1 mM EDTA, were homogenized by
sonication (Branson Sonifier 185, 5 microtip setting) at 0 °C.
Aliquots (0.5 mL) of the homogenates were preincubated for
5 min at 37 °C with test compound or vehicle (0.1% DMSO/

Dual Inhibitors of 5-LO and TXA2 Synthetase
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 16 3157
(11) Ohkawa, S.; Terao, S.; Terashita, Z.; Shibouta, Y.; Nishikawa,
K. Dual Inhibition of Thromboxane A2 Synthetase and 5-Lipoxy-
genase with Scavenging Activity of Active Oxygen Species.
Synthesis of a Novel Series of (3-Pyridylmethyl)benzoquinone
Derivatives. J . Med. Chem. 1991, 34, 267-276.
(12) Terao, S.; Ohkawa, S.; Terashita, Z.; Shibouta, Y.; Nishikawa,
K. Synthesis and Biological Evaluation of 2,3,5-Trimethyl-6-(3-
pyridylmethyl)-1,4-benzoquinone (CV-6504), a Dual Inhibitor of
TXA2 Synthetase and 5-Lipoxygenase with Scavenging Activity
of Active Oxygen Species (AOS). Adv. Prostaglandin, Throm-
boxane, Leukotriene Res. 1990, 21A (Prostaglandins Relat.
Compd.), 173-176.
(13) Terao, S. Eicosanoid Antagonists. Med. Immunol. 1988, 16 (5),
637-641.
(14) Terao, S.; Shiraishi, M.; Kato, K.; Ohkawa, S.; Ashida, Y.; Maki,
Y. J . Chem. Soc. Perkin Trans. 1 1982, 2909.
(15) Iizuka, K.; Akahane, K.; Momose, D.; Nakazawa, M. Highly
Selective Inhibitors of Thromboxane Synthetase. 1. Imidazole
Derivatives. J . Med. Chem. 1981, 24, 1139-1148.
(16) Tanouchi, T.; Kawamura, M.; Ohyama, I.; Kajiwara, I.; Iguchi,
Y.; Okada, T.; Miyamoto, T.; Taniguchi, K.; Hayashi, M.; Iizuka,
K.; Nakazawa, M. Highly Selective Inhibitors of Thromboxane
Synthetase. 2. Pyridine Derivatives. J . Med. Chem. 1981, 24,
1149-1155.
(17) Mayer, J . M.; Testa, B. Structural Factors Affecting the Basicity
of ω-Pyridylalkanols, ω-Pyridylalkanamides and ω-Pyridylalkyl-
amines. Helv. Chim. Acta 1982, 65, 1868-1884.
(18) Terao, S.; Nishikawa, K. New 2-Heterocyclyl-methyl-1,4-benzo-
quinone derivs. - Useful for Improving Polyunsaturated Fatty
Acid Metabolism. J P 88/45257, 1988.
(20) Shimizu, T.; Tsurumaki, T.; Yamagishi, Y.; Ichino, T. Prepn. of
Pyridyl-alcohol by Reducing Pyridyl-keto-alcohol - Useful as
Intermediate for Agents Treating Asthma and Liver Disease.
J P 94/199790, 1994.
(21) Tyer, S.; Liebskind, L. S. Regiospecific Synthesis of 2-Methoxy-
3-methyl-1,4-benzoquinones from Maleoylcobalt Complexes and
Alkynes via Lewis Acid Catalysis. A Highly Convergent Route
to Isoquinoline Quinones. J . Am. Chem. Soc. 1987, 109, 2759-
2770.
(22) Burnell, R. B.; Ringuet, M. Synthesis of Dehydrocycloroyleanone.
Can. J . Chem. 1978, 56, 517-522.
(23) Syper, L.; Kloc, K.; Mlochowski, J .; Szulc, Z. An Improved
Synthesis of Benzo- and Naphto-quinones from Hydroquinone
Dimethyl Ethers. Synthesis 1979, 521-522.
(24) Hammond, M. L.; Kopka, I. E.; Zambias, R. A.; Caldwell, C. G.;
Boger, J .; Baker, F.; Bach, T.; Luell, S.; MacIntyre, D. E. 2,3-
Dihydro-5-benzofuranols as Antioxidant-based Inhibitors of Leu-
kotriene Biosynthesis. J . Med. Chem. 1989, 32, 1006-1020.
(25) Carter, G. W.; Young, R. P.; 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.
(26) Morita, K.; Iizuka, K.; Arikawa, S.; Akahara, K.; Watanabe, M.
Imidazole derivative and pharmaceutical composition containing
it. J P 81/18488, 1981.
(27) Moroney, M.-A.; Alcaraz, M. J .; Forder, R. A.; Carey, F.; Hoult,
J . R. S. Selectivity of Neutrophil 5-Lipoxygenase and Cyclooxy-
genase Inhibition by an Anti-inflammatory Flavonoid Glycoside
and Related Aglycone Flavonoids. J . Pharm. Pharmacol. 1988,
40, 787-792.
(19) Shimizu, T.; Tsurumaki, T.; Yamagishi, Y.; Ichino, T. Prepn. of
Pyridyl Keto-alcohol by Reacting Pyridine Carboxylate with
Lactone and Decarboxylation - Useful as Intermediates for
Antihypertensives, Anti-asthmatics, etc. J P 94/157459, 1994.
J M950725R