1-arylnaphthalene lignan: A novel scaffold for type 5 phosphodiesterase inhibitor

Article abstract of DOI:10.1021/jm9807048

1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iwasaki, was disclosed as a new structural class of PDE5 inhibitors. The structural requirements for potent and specific PDE5 inhibition were revealed in a 1-arylnaphthalene lignan s

Full text of DOI:10.1021/jm9807048

J . Med. Chem. 1999, 42, 1293-1305
1293
1-Ar yln a p h th a len e Lign a n : A Novel Sca ffold for Typ e 5 P h osp h od iester a se
In h ibitor
Tatsuzo Ukita,* Yoshinori Nakamura, Akira Kubo, Yasuo Yamamoto, Masami Takahashi, J un Kotera,† and
Tomohiro Ikeo†
Discovery Research Laboratory, Tanabe Seiyaku Company, Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532-8505, J apan, and
2-2-50, Kawagishi, Toda, Saitama 335-8505, J apan
Received December 14, 1998
1-Arylnaphthalene lignan, which had been reported as a PDE4 inhibitor by Iwasaki, was
disclosed as a new structural class of PDE5 inhibitors. The structural requirements for potent
and specific PDE5 inhibition were revealed in a 1-arylnaphthalene lignan series, in which 1-(3-
bromo-4,5-dimethoxyphenyl)-5-chloro-3-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-2-(methoxy-
carbonyl)naphthalene hydrochloride (27q) showed the most potent and specific inhibition (PDE5
inhibition IC50 ) 6.2 nM, selectivity for PDE5 against PDE1, -2, -3, and -4 >16 000). It is
noteworthy that 27q has the best selectivities against PDE isoforms among PDE5 inhibitors
so far reported. Compound 27q exhibited almost the same relaxant effects on rat aortic rings
as sodium 1-[6-chloro-4-[(3,4-methylenedioxybenzyl)amino]quinazolin-2-yl]piperidine-4-car-
boxylate (35) (27q, EC50 ) 0.10 µM; 35, EC50 ) 0.20 µM) and was selected for further biological
evaluation.
In tr od u ction
fumarate, followed by acid-mediated ring opening of 1,4-
epoxides 8 and subsequent dehydration7 (Scheme 1). As
shown in Scheme 1, the precursors of isobenzofuran (3
and 6) were prepared by the following two methods:
bromoacetals 1 were transformed into cyclic acetals 3
via hydroxy acetals 28 (method A), and lactols 6 were
obtained from phthalides 5 which were converted from
amides 49 (method B). The Diels-Alder adducts 8 were
afforded by the reaction of 3 or 6 with dimethyl
fumarate as a dienophile in the presence of acetic acid
in a one-pot procedure. Aromatization of 8 proceeded
well by treatment with trifluoroacetic acid or BF3‚Et2O
via ring opening of 1,4-epoxides and subsequent dehy-
dration to provide the key intermediates 9 in good
yields.
9a was found to be a seed compound from the random
screening of 1-arylnaphthalene lignans6 on PDE5 inhi-
bition. 9a was divided into three parts (A-C rings), and
the modification of each part was carried out in the
following procedures: (i) transformation of the meth-
oxycarbonyl moiety on 2,3-positions of arylnaphthalene
(B ring); (ii) conversion of 1-aryl group and/or substit-
uents on 1-aryl group as the C ring; and (iii) replace-
ment of substituents on the A ring. The transformation
of substituent on 2,3-positions of 9a is outlined in
Scheme 2. 3-Carboxylactone 11 was prepared by selec-
tive oxidation of the 3-hydroxymethyl group of diol 10
that was obtained from 9a by the reduction of ester
groups with Red-Al. Alkaline hydrolysis of the ester
group of 9a proceeded in a highly selective manner to
provide 2-methoxycarbonyl-3-carboxy compound 12a
because of the steric hindrance of the 1-(3,4,5-tri-
methoxyphenyl) ring. Corresponding 2-carboxylactone
13 was selectively prepared by the reduction of 12a with
sodium borohydride via the activated mixed anhydride.
3-Amino-2-hydroxymethyl compound 14 was obtained
by means of Curtius rearrangement of acyl azide derived
from 12a , followed by reduction of 13 with LiAlH4.
Cyclic nucleotide phosphodiesterases (PDEs) are key
enzymes for catalyzing the hydrolysis of cyclic nucle-
otides, cAMP and cGMP, to their respective 5′-nucleo-
side monophosphates. PDEs have been classified into
at least seven distinct isoenzyme families,1 which have
been distinguished by their substrate specificities, the
mechanisms of regulation, and their sensitivity to
various pharmacological agents. PDE5, cGMP-specific
PDE, is distributed in lung, kidney, spleen, endothelial
cells, smooth muscle cells, etc., and plays a key role for
biological regulations by means of hydrolysis of cGMP
in these tissues. Because cGMP mediates vasorelaxant
actions, the potent and selective PDE5 inhibitor is an
attractive target for treatment of hypertension, angina,
congestive heart failure, and impotence.2
Potent and selective PDE5 inhibitors have been
extensively reported, but a majority of them are clas-
sified into three categories: zaprinast-related inhibi-
tors,3 quinazoline derivatives,4 and phthalazine deriva-
tives.5 Iwasaki et al. in our company reported a series
of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans as
selective PDE4 inhibitors.6 In connection with our
efforts in search of biologically active lignans, we now
disclose 1-arylnaphthalene lignans having potent and
specific PDE5 inhibitory activities. It is noteworthy that
both selective PDE4 and PDE5 inhibitors are derived
from the common scaffold, 1-arylnaphthalene lignan,
and the spectra of PDE inhibitions are entirely altered
by the chemical modification of its substituents.
Ch em istr y
The key intermediates 9, 1-aryl-2,3-bis(methoxycar-
bonyl)naphthalene lignans, were synthesized by the
Diels-Alder reaction of isobenzofurans 7 with dimethyl
† Tanabe Seiyaku Co., Ltd., Saitama.
10.1021/jm9807048 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/23/1999

1294 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ukita et al.
Sch em e 1a
a
Reagents: (a) n-BuLi, R2CHO/THF, or n-BuLi then ClTi(Oi-Pr)3, R2CHO/THF; (b) dimethyl fumarate, AcOH/toluene; (c) s-BuLi,
TMEDA, R2CHO/THF; (d) DIBAL/CH2Cl2; (e) TFA or BF3‚OEt2. 9a -p were prepared by method A. c 9q-s were prepared by method B.
b
Condensation of 12a with ammonia or secondary amines
afforded amides 16, 18-24, and 27a in good yields,
whereas that with methylamine resulted in providing
a mixture of amide 17 and imide 28, which were isolated
by silica gel column chromatography. Alcohols 25 and
26 were obtained from the reduction of ketone 24 and
ester 22 with NaBH4 in good yields, respectively.
Scheme 3 summarizes the synthesis of reduced ana-
logues of 27a . Amine 31, the reduced analogue of the
amide on the 3-position of 27a , was prepared from
2-methoxycarbonyl-3-methyl analogue 29, which was
produced by the Diels-Alder reaction of isobenzofuran
7a with methyl crotonate. Bromination of 29 with
N-bromosuccinimide was followed by substitution with
4-(2-hydroxyethyl)piperazine to provide amine 31 in a
moderate yield. 2-Hydroxymethyl analogue 34, ac-
companied by the excessively reduced amine 33, was
obtained from O-tert-butyldimethylsilyl compound 32 by
treatment with LiAlH4.
on rat aortic rings and additionally investigated for the
two different forms of PDEs isolated from canine
adrenal gland (PDE2) and lung (PDE4) (Table 4). From
the random screening of 1-arylnaphthalene lignans on
PDE inhibition, we found that 9a had a relatively
selective PDE5 inhibitory activity (IC50 ) 2.1 µM,
selectivity for PDE5 over PDE1 and -3 > 50).
Transformation of the substituents on the 2,3-posi-
tions of 9a was first examined (Table 1). The importance
of both or either ester group on the 2,3-positions of 9a
is evident from the comparison of PDE5 inhibitory
activities and isozyme selectivities between 9a and bis-
(hydroxymethyl) compound 10, the corresponding re-
duced product of 9a . Both 2-carboxy and 3-carboxy
lactones 11 and 13, the imide 28, and amides 16-18,
having carbonyl groups on 2- and/or 3-positions, were
synthesized to investigate the structure-activity rela-
tionships (SAR) of 1-arylnaphthalene lignans. 3-Car-
boxylactone 11 was 30 times more potent than 9a (IC50
) 0.068 µM), though it exhibited remarkably worse
selectivities for PDE5 over PDE1 and -3 than 9a .
2-Carboxylactone 13, the corresponding regioisomer of
11, showed drastically changed PDE inhibition spectra
and potent PDE1 and -3 inhibitory activities, with less
PDE5 activity. The imide 28, 2-methoxycarbonyl-3-
amide 16, and 2-methoxycarbonyl-3-methylamide 17
markedly lost PDE5 inhibitory activities (IC50 > 100
µM), whereas 2-methoxycarbonyl-3-dimethylamide 18
Biologica l Resu lts a n d Discu ssion
The compounds reported in this paper were first
evaluated for inhibitory activities against the three
different forms of PDEs isolated from canine cardiac
ventricle (PDE1 and -3) and lung (PDE5) in vitro (Tables
1-3).
Compounds selected on the basis of the PDE5 inhibi-
tory activity were next evaluated for the relaxant effects

1-Arylnaphthalene Lignan
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1295
Sch em e 2a
a
Reagents: (a) Red-Al/THF; (b) AgCO3/benzene; (c) NaOHaq/MeOH; (d) (1) ClCOOEt, NEt3/THF, (2) NaN3, (3) heat/toluene, (4) concd
HCl; (e) LiAlH4/THF; (f) (1) ClCOOEt, NEt3/THF, (2) NaBH4, (3) NaH/DMF; (g) amine, NH3, or CH3NH2, EDCl‚HCl-HOBt or CDI; (h)
NaBH4/EtOH; (i) NaBH4/MeOH-THF.
showed an improved PDE5 inhibitory activity (IC50
0.23 µM) with retained isozyme selectivities.
)
2-hydroxymethyl analogue 34, the reduction product of
methyl ester, exhibited marked loss of PDE1, -3, and
-5 inhibitiory activities (IC50 > 100 µM for PDE1, -3,
and -5). The 2-methoxycarbonyl and 3-[4-(2-hydroxy-
ethyl)piperazino]carbonyl groups were fixed from the
results of the above SAR study about the substituent
on 2,3-positions of 27a .
Next we looked at the replacement of the 1-aryl group,
1-(3,4,5-trimethoxyphenyl) group, with the phenyl group
having a variety of substituents, the heteroaryl group,
or the trans-styryl group (Table 2). Among mono-, di-,
and trisubstituted phenyl compounds, 3-halogeno-4,5-
dimethoxyphenyl derivatives 27c and 27d only pos-
sessed increased potencies compared with 3,4,5-tri-
Next we focused on the synthesis of 3-tertiary amides
19 and 20 based on the above results. Morpholino,
4-oxopiperidino, 4-hydroxypiperidino, and 4-(hydroxy-
methyl)piperidino amides 23-26, having oxygen atom
in, on, or close to the 4-position of the six-membered
ring, exhibited similar PDE5 inhibitory activities to
dimethyl amide 18 and improved isozyme selectivities.
Among the cyclic amides, 3-(2-hydroxyethyl)piperazino
amide 27a showed a potent PDE5 inhibitory activity
(IC50 ) 0.094 µM) and improved selectivities for PDE5
over PDE1 and -3 (selectivity ratios: 436 and 1063,
respectively).
27a was selected as a lead compound, and the
corresponding reduced products of 27a were synthesized
in order to confirm the role of the carbonyl group on 2-
and/or 3-positions toward PDE5 inhibitory activity. 4-(2-
Hydroxyethyl)piperazinomethyl analogue 31, the reduc-
tion product of amide carbonyl, resulted in a consider-
able loss of activity (IC50 ) 2.4 µM). On the other hand,
methoxyphenyl 27a (27c, IC50 ) 0.049 µM; 27d , IC50 )
0.024 µM; 27a , IC50 ) 0.094 µM). Replacement by
heteroaryl groups (27j and 27k ) and the trans-styryl
group (27l) led to remarkable loss of PDE5 inhibitory
activities (IC50 >100 µM).
Finally we investigated the effects of substituent on
the A ring toward PDE5 inhibitory activity (Table 3).

1296 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ukita et al.
Sch em e 3a
a
Reagents: (a) (1) n-BuLi, 3,4,5-(OMe)3PhCHO/THF, (2) methyl crotonate, AcOH/toluene, (3) TFA; (b) NBS, (PhCO)2O2/CCl4; (c) 1-(2-
hydroxyethyl)piperazine/THF; (d) TBS-Cl, imidazole/THF; (e) LiAlH4/THF.
Sch em e 4a
a
Reagents: (a) NaOHaq/MeOH; (b) 1-(2-hydroxyethyl)piperazine, DCC, HOBt/CH2Cl2.
Removal of substituents (27o) and introduction of an
alkoxy, alkyl, and/or chloro substituent on 5,6,7-posi-
tions (27m ,q-s) showed potent PDE5 inhibitory activi-
ties similar to 27d . Introduction of the methoxy group
on the 8-position (27n ) resulted in marked loss of not
only PDE5 but also PDE1 inhibitory activity (IC50 > 100
µM). From the modification of the substituent on the A
ring, 5-chloro analogue 27q showed the best inhibitory
activity against PDE5 (IC50 ) 0.0062 µM), with mark-
edly improved selectivities against PDE1 and -3 iso-
forms.
We selected seven compounds on the basis of the

1-Arylnaphthalene Lignan
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1297
Ta ble 2. Structures and PDE Inhibitions
Ta ble 1. Structures and PDE Inhibitions
a
IC50 values were determined from the logarithmic concentra-
tion-inhibition curve (at least four points). The value is given as
the mean of three experiments, where the variation from the mean
value is (20% or less.
a
IC50 values were determined from the logarithmic concentra-
tion-inhibition curve (at least four points). The value is given as
the mean of three experiments, where the variation from the mean
value is (20% or less.
correlated with the inhibitory activities toward PDE5
as shown in Table 4.
PDE5 inhibitory potency and isozyme selectivities for
the evaluation of their relaxant effects on rat aortic
rings and inhibitory activities of two additional and
different forms of PDEs (PDE2 and -4), as shown in
Table 4. Sodium 1-[6-chloro-4-[(3,4-methylenedioxy-
benzyl)amino]quinazolin-2-yl]piperidine-4-carboxylate
(35) was selected as a reference compoud. These com-
pounds were examined for relaxant effects on isolated
rat aortic rings precontracted with phenylephrine (3
µM). The EC50 values of these compounds were well-
It was ascertained that 27q exhibited a highly selec-
tive PDE5 inhibitory activity against not only PDE1 and
-3 but also PDE2 and -4 (>16 000). It is noteworthy that

1298 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ta ble 3. Structures and PDE Inhibitions
Ukita et al.
emental analyses were performed on a Perkin-Elmer 2400II
analyzer. IR spectra were recorded on a Shimadzu IR-420
spectrophotometer. 1H NMR spectra were obtained on a
Bruker AC-200 instrument (200 MHz) with TMS as an
internal standard. Mass spectra were recorded on a Hitachi
M-2000A spectrometer. Column chromatography was per-
formed with silica gel (E. Merck, 70-230 mesh). Reactions
were monitored by TLC using 0.25-mm silica gel F-254 (E.
Merck) glass plates. n-Butyllithium was the 1.6 M solution in
hexane and sec-butyllithium was the 1.3 M solution in cyclo-
hexane supplied by Asia Lithium Co.
Gen er a l P r oced u r e for th e P r ep a r a tion of Dim eth yl
Ester of 1-Ar yln a p h th a len e Der iva tives 9. Meth od A
(Sch em e 1). Compounds 9a ,c-h ,j-p were essentially pre-
pared by the same procedure. The sequence is illustrated for
9a , followed by analytical data for 9c-h ,j-p .
6,7-Dim et h oxy-2,3-b is(m et h oxyca r b on yl)-1-(3,4,5-t r i-
m eth oxyp h en yl)n a p h th a len e (9a ). To a solution of acetal
1 [R1 ) 4,5-(OMe)2] (58.2 g, 0.20 mol) in THF (300 mL) was
added n-BuLi (131 mL, 0.21 mol) at -78 °C under a nitrogen
atmosphere. After the mixture stirred at the same temperature
for 30 min, a solution of the 3,4,5-trimethoxybenzaldehyde
(39.2 g, 0.20 mol) in THF (100 mL) was added, and the reaction
mixture was stirred at the same temperature for 30 min. The
mixture was poured into H2O and extracted with AcOEt. The
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. A mixture of the residue,
dimethyl fumarate (28.8 g, 0.20 mol), and acetic acid (100 mL)
in toluene (100 mL) was heated under reflux for 2 h. After
cooling to room temperature, TFA (5 mL) was added to the
reaction mixture and the mixture was stirred at room tem-
perature overnight. The mixture was poured into saturated
aqueous NaHCO3 and extracted with CHCl3. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. Crystallization of the residue from
Et2O gave 9a (49.8 g, 53%): mp 186-187 °C; 1H NMR (CDCl3)
δ 3.68 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.95 (s, 6H), 4.03 (s,
3H), 6.61 (s, 2H), 6.95 (s, 1H), 7.25 (s, 1H), 8.46 (s, 1H); EIMS
m/z 470 (M+, base), 455, 439, 344.
1-(3-Ch lor o-4,5-d im et h oxyp h en yl)-6,7-d im et h oxy-2,3-
bis(m eth oxyca r bon yl)n a p h th a len e (9c): yield 43%; mp
165-168 °C; 1H NMR (CDCl3) δ 3.69 (s, 3H), 3.80 (s, 3H), 3.85
(s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 4.03 (s, 3H), 6.80-6.90 (m,
2H), 7.02 (d, 1H, J ) 1.9 Hz), 7.25 (s, 1H), 8.47 (s, 1H).
1-(3-Br om o-4,5-d im et h oxyp h en yl)-6,7-d im et h oxy-2,3-
bis(m eth oxyca r bon yl)n a p h th a len e (9d ): yield 37%; mp
178-179 °C; 1H NMR (CDCl3) δ 3.69 (s, 3H), 3.80 (s, 3H), 3.81
(s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 4.03 (s, 3H), 6.86 (s, 1H),
6.68 (d, 1H, J ) 1.9 Hz), 6.89 (d, 1H, J ) 1.9 Hz), 7.25 (s, 1H),
8.46 (s, 1H); EIMS m/z 518/520 (M+, base), 487/489.
a
IC50 values were determined from the logarithmic concentra-
tion-inhibition curve (at least four points). The value is given as
the mean of three experiments, where the variation from the mean
value is (20% or less.
Ta ble 4. PDE Inhibitions and Relaxant Effects on Rat Aorta
for Selected Compounds
PDE inhibition, IC50, µMa
relaxant effect
compd
I
II
III
IV
V
EC50, µMb
27a
27c
27d
27m
27o
27p
27q
35
41
26
11
61
>100 >100 >100
>100 >100 >100
>100 >100 >100
>100 >100 >100
0.094
0.049
0.024
0.017
0.025
0.012
0.0062
2.0
1.3
0.46
0.30
0.79
0.56
0.10
0.20
3.4 >100 >100 >100
13
>100
4.7
>100 >100 >100
>100 >100 >100
15 >100
3.4 0.0016
a
IC50 values were determined from the logarithmic concentra-
tion-inhibition curve (at least four points). The value is given as
the mean of three experiments, where the variation from the mean
value is (20% or less. EC50 values were determined from the
logarithmic concentration-relaxation curve. The value is given
as the average of two experiments, where the variation from the
mean value is (30% or less.
b
6,7-Dim eth oxy-2,3-bis(m eth oxyca r bon yl)-1-(2-m eth yl-
4,5-d im eth oxyp h en yl)n a p h th a len e (9e): yield 63%; mp
162-164 °C; 1H NMR (CDCl3) δ 1.93 (s, 3H), 3.61 (s, 3H), 3.75
(s, 3H), 3.81 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 4.03 (s, 3H),
6.65 (s, 1H), 6.73 (s, 1H), 6.81 (s, 1H), 7.27 (s, 1H), 8.47 (s,
1H); EIMS m/z 454 (M+, base), 422, 407.
27q showed the best selectivities against PDE isoforms
(PDE1, -2, -3, and -4), among PDE5 inhibitors so far
reported.
Con clu sion
We discovered that 1-arylnaphthalene lignans have
potent and specific PDE5 inhibitory activities and
indicated that the spectra of PDE inhibitions are
entirely altered by the chemical modification of substi-
tutents on the common scaffold, 1-arylnaphthalene
lignan. This finding will be beneficial for the design of
specific PDE5 inhibitors in the other structural class.
Among the analogues, 27q showed the most potent and
specific PDE5 inhibitory activity (IC50 ) 6.2 nM, isozyme
selectivities > 16 000) and exhibited potent effects on
relaxation of rat aortic rings (EC50 ) 0.10 µM). 27q was
selected for further evaluation as a treatment of car-
diovascular diseases.
6,7-Dim eth oxy-2,3-bis(m eth oxyca r bon yl)-1-(3,4-m eth -
ylen ed ioxyp h en yl)n a p h th a len e (9f): yield 57%; mp 169-
1
170 °C; H NMR (CDCl3) δ 3.68 (s, 3H), 3.79 (s, 3H), 3.94 (s,
3H), 4.02 (s, 3H), 6.03 (d, 1H, J ) 1.4 Hz), 6.07 (d, 1H, J ) 1.4
Hz), 6.72-6.99 (m, 4H), 7.23 (s, 1H), 8.44 (s, 1H); EIMS m/z
424 (M+, base), 393.
1-(3,4-Dich lor op h e n yl)-6,7-d im e t h oxy-2,3-b is(m e t h -
oxyca r bon yl)n a p h th a len e (9g): yield 75%; mp 185-187 °C;
1H NMR (CDCl3) δ 3.67 (s, 3H), 3.79 (s, 3H), 3.94 (s, 3H), 4.03
(s, 3H), 6.72 (s, 1H), 7.18-7.31 (m, 2H), 7.49 (d, 1H, J ) 2.0
Hz), 7.56 (d, 1H, J ) 8.2 Hz), 8.47 (s, 1H); EIMS m/z 448 (M+,
base), 417.
1-(3,5-Dich lor op h e n yl)-6,7-d im e t h oxy-2,3-b is(m e t h -
oxyca r bon yl)n a p h th a len e (9h ): yield 65%; mp 153-155 °C;
1H NMR (CDCl3) δ 3.69 (s, 3H), 3.81 (s, 3H), 3.94 (s, 3H), 4.03
(s, 3H), 6.72 (s, 1H), 7.20-7.36 (m, 3H), 7.47 (t, 1H, J ) 1.9
Hz), 8.47 (s, 1H); EIMS m/z 448 (M+, base), 417.
1-(2-Br om o-4-p yr id yl)-6,7-d im eth oxy-2,3-bis(m eth oxy-
Exp er im en ta l Section
Gen er a l. Melting points were determined on a Bu¨chi 535
capillary melting point apparatus and are uncorrected. El-

1-Arylnaphthalene Lignan
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1299
ca r bon yl)n a p h th a len e (9j):10 yield 60%; mp 192-194 °C; 1H
NMR (CDCl3) δ 3.68 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 4.04 (s,
3H), 6.65 (s, 1H), 7.3-7.37 (m, 2H), 7.55 (d, 1H, J ) 0.7 Hz),
8.48-8.58 (m, 2H); EIMS m/z 459/461 (M+, base), 428/430.
6,7-Dim et h oxy-2,3-b is(m et h oxyca r b on yl)-1-(3,4,5-t r i-
m eth oxystyr yl)n a p h th a len e (9l): yield 57%; mp 166-168
(TMEDA) (22.3 mL, 148 mmol) in THF (30 mL) was added
s-BuLi (125 mL, 163 mmol) at -78 °C under a nitrogen
atmosphere, and the mixture was stirred at the same tem-
perature for 15 min. To this mixture was added dropwise 3,4,5-
trimethoxybenzaldehyde (18.1 g, 73.8 mol) in 300 mL of THF.
After stirring at the same temperature for 30 min, the reaction
mixture was poured into a mixture of H2O and AcOEt. The
organic layer was separated, washed with brine, dried over
MgSO4, and concentrated under reduced pressure. A solution
of the residue in concentrated hydrochloric acid (10 mL)-
dioxane (100 mL) was heated under reflux for 2 h. After
evaporation of the organic solvent, the residue was diluted with
H2O and extracted with CHCl3. The organic layer was washed
successively with saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated under reduced pressure. The
residue was crystallized from Et2O to give 5q (19.2 g, 68%):
mp 165-168 °C; 1H NMR (CDCl3) δ 3.83 (s, 3H), 3.86 (s, 3H),
6.26 (s, 1H), 6.69 (d, 1H, J ) 1.9 Hz), 7.07 (d, 1H, J ) 1.9 Hz),
7,34-7.35 (m, 1H), 7,50-7.60 (m, 1H), 7.90 (d, 1H, J ) 8.2
Hz); EIMS m/z 384/382 (M+, base), 303.
1-(3-Br om o-4,5-d im e t h oxyp h e n yl)-5-ch lor o-2,3-b is-
(m eth oxyca r bon yl)n a p h th a len e (9q). To a stirred solution
of 5q (5.0 g, 13 mmol) in CH2Cl2 (50 mL) was added diisobut-
ylaluminum hydride (DIBAL) (1.5 M in toluene, 9.6 mL, 14.3
mmol) at -78 °C under a nitrogen atmosphere, and the
mixture was stirred at the same temperature for 30 min. After
addition of 1 mL of acetic acid, the reaction mixture was
washed with brine. The organic layer was dried over MgSO4
and concentrated under reduced pressure. A mixture of the
residue, dimethyl fumarate (1.87 g, 13 mmol), and acetic acid
(8 mL) in toluene (24 mL) was refluxed for 3 h. After
evaporation of the solvent, the residue was diluted with AcOEt
and washed successively with aqueous NaHCO3 and brine. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure to give 1-(3-bromo-4,5-dimethoxyphenyl)-5-
chloro-2,3-bis(methoxycarbonyl)-1,4-epoxy-1,2,3,4-tetrahy-
dronaphthalene. The crude product was used in the next step
without further purification. A mixture of the crude product
and boron trifluoride etherate (BF3‚Et2O) (3.2 mL, 26 mmol)
in CH3CN (50 mL) was heated at 50 °C for 5 h. The reaction
mixture was poured into saturated aqueous NaHCO3 and
extracted with AcOEt. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. Crystallization of the residue from i-Pr2O gave 9q
(3.45 g, 54%): mp 133-135 °C; 1H NMR (CDCl3) δ 3.70 (s,
3H), 3.84 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 6.85 (d, 1H, J )
1.9 Hz), 7.13 (d, 1H, J ) 1.9 Hz), 7.41-7.62 (m, 2H), 7.70 (dd,
1H, J ) 7.0, 1.6 Hz), 9.06 (d, 1H, J ) 0.7 Hz); EIMS m/z 492/
494 (M+, base), 461/463.
1
°C; H NMR (CDCl3) δ 3.88 (s, 3H), 3.90 (s, 3H), 3.92 (s, 6H),
3.95 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H), 6.76 (s, 2H), 6.81 (d,
1H, J ) 16.5 Hz), 7.23 (s, 1H), 7.32 (d, 1H, J ) 18.1 Hz), 7.37
(s, 1H), 8.38 (s, 1H); EIMS m/z 496 (M+, base).
1-(3-Br om o-4,5-dim eth oxyph en yl)-6-eth oxy-7-m eth oxy-
2,3-bis(m eth oxyca r bon yl)n a p h th a len e (9m ): yield 42%;
1
mp 171-173 °C; H NMR (CDCl3) δ 1.56 (t, 3H, J ) 7.0 Hz),
3.69 (s, 3H), 3.79 (s, 3H), 3.84 (s, 3H), 3.94 (s, 3H), 3.95 (s,
3H), 4.25 (q, 2H, J ) 7.0 Hz), 6.86 (S, 1H), 6.89 (d, 1H, J )
1.9 Hz), 7.18 (d, 1H, J ) 1.9 Hz),7.23 (s, 1H), 8.44 (s, 1H);
EIMS m/z 532/534 (M+, base).
1-(3-Br om o-4,5-d im et h oxyp h en yl)-6,7,8-t r im et h oxy-
2,3-bis(m eth oxyca r bon yl)n a p h th a len e (9n ): yield 66%;
mp 199-202 °C; 1H NMR (CDCl3) δ 3.36 (s, 3H), 3.61 (s, 3H),
3.83 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H), 4.01 (s,
3H), 6.83 (d, 1H, J ) 1.9 Hz), 7.05-7.15 (m, 2H), 8.46 (s, 1H);
EIMS m/z 548/550 (M+, base), 470.
1-(3-Br om o-4,5-d im eth oxyp h en yl)-2,3-bis(m eth oxyca r -
bon yl)n a p h th a len e (9o): yield 56%; mp 153-156 °C; 1H
NMR (CDCl3) δ 3.70 (s, 3H), 3.84 (s, 3H), 3.96 (s, 3H), 3.97 (s,
3H), 6.88 (d, 1H, J ) 1.9 Hz), 7.16 (d, 1H, J ) 1.9 Hz), 7.50-
7.70 (m, 3H), 7.93-8.09 (m, 1H), 8.63 (s, 1H); EIMS m/z 458/
460 (M+, base), 443/445, 427/429.
1-(3-Br om o-4,5-d im eth oxyp h en yl)-2,3-bis(m eth oxyca r -
bon yl)-6-m eth oxyn a p h th a len e (9p ): yield 22%; mp 151-
1
153 °C; H NMR (CDCl3) δ 3.68 (s, 3H), 3.83 (s, 3H), 3.95 (s,
9H), 6.86 (d, 1H, J ) 1.9 Hz), 7.14 (d, 1H, J ) 1.9 Hz), 7.19-
7.29 (m, 2H), 7.53 (d, 1H, J ) 9.1 Hz), 8.50 (s, 1H); EIMS m/z
488/490 (M+, base), 457/459.
1-(3-Am in o-4,5-d im et h oxyp h en yl)-6,7-d im et h oxy-2,3-
bis(m et h oxyca r bon yl)n a p h t h a len e (9b ):6 yield 81%; mp
196-198 °C; 1H NMR (CDCl3) δ 1.50-1.70 (br s, 2H), 3.68 (s,
3H), 3.80 (s, 6H), 3.91 (s, 3H), 3.93 (s, 3H), 4.02 (s, 3H), 6.33
(d, 1H, J ) 1.8 Hz), 6.39 (d, 1H, J ) 1.9 Hz), 6.70 (s, 1H), 7.22
(s, 1H), 8.42 (s, 1H).
6,7-Dim et h oxy-2,3-b is(m et h oxyca r b on yl)-1-(3-n it r o-
p h en yl)n a p h th a len e (9i). To a solution of acetal 1 [R1 ) 4,5-
(OMe)2] (5.82 g, 20 mmol) in THF (40 mL) was added n-BuLi
(12.5 mL, 20 mmol) at -78 °C under a nitrogen atmosphere.
After stirring at the same temperature for 30 min, ClTi-
(Oi-Pr)3 (1 M in hexane, 20 mL, 20 mmol) was added and the
mixture was stirred at the same temperature for 30 min. After
3-nitrobenzaldehyde (3.02 g, 0.20 mol) in 20 mL of THF was
added, the reaction mixture was warmed to room temperature.
After stirring for 30 min, the mixture was poured into diluted
hydrochloric acid and extracted with AcOEt. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. A mixture of the residue, dimethyl
fumarate (2.88 g, 20 mmol), and acetic acid (10 mL) in toluene
(30 mL) was heated under reflux for 2 h. After evaporation of
the solvent, the residue was dissolved in a mixture of CHCl3
(50 mL) and TFA (10 mL). After stirring at room temperature
overnight, the reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with CHCl3. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was crystallized from
Et2O to afford 9i (4.6 g, 54%): mp 194-196 °C; 1H NMR
(CDCl3) δ 3.62 (s, 3H), 3.74 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H),
6.63 (s, 1H), 7.29 (s, 1H), 7.62-7.80 (m, 2H), 8.25-8.40 (m,
2H), 8.52 (s, 1H); EIMS m/z 425 (M+, base), 394.
1-(3-Br om o-4,5-d im e t h oxyp h e n yl)-7-ch lor o-2,3-b is-
(m eth oxyca r bon yl)n a p h th a len e (9r ): yield 39%; mp 145-
1
148 °C; H NMR (CDCl3) δ 3.69 (s, 3H), 3.85 (s, 3H), 3.96 (s,
3H), 3.97 (s, 3H), 6.84 (d, 1H, J ) 1.9 Hz), 7.13 (d, 1H, J ) 1.9
Hz), 7.50-7.62 (m, 2H), 7.94 (m, 1H), 8.60 (s, 1H); EIMS m/z
492/494 (M+, base).
1-(3-Br om o-4,5-d im eth oxyp h en yl)-2,3-bis(m eth oxyca r -
bon yl)-7-m eth yln a p h th a len e (9s): yield 83%; mp 120-122
1
°C; H NMR (CDCl3) δ 2.47 (s, 3H), 3.69 (s, 3H), 3.84 (s, 3H),
3.96 (s, 3H), 3.97 (s, 3H), 6.86 (d, 1H, J ) 1.8 Hz), 7.14 (d, 1H,
J ) 1.8 Hz), 7.35 (s, 1H), 7.44 (dd, 1H, J ) 8.3, 1.4 Hz), 7.89
(d, 1H, J ) 8.3 Hz), 8.58 (s, 1H); EIMS m/z 472/474 (M+, base),
457/459, 441/443.
2,3-Bis(h yd r oxym e t h yl)-6,7-d im e t h oxy-1-(3,4,5-t r i-
m eth oxyp h en yl)n a p h th a len e (10). To a stirred suspension
of 3a (2.0 g, 4.25 mmol) in THF (20 mL) was added dropwise
Red-Al (70% in toluene, 3.07 g, 10.6 mmol) at -10 °C, and the
mixture was stirred at 0 °C for 1 h. After dropwise addition of
MeOH (1 mL) and 20% aqueous NaOH (6 mL), the mixture
was stirred at 50 °C for 30 min. The reaction mixture was
poured into a mixture of H2O and AcOEt and extracted with
AcOEt. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by silica gel chromatography (CHCl3-MeOH )
10:1) gave 10 (1.47 g, 83%): mp 124-126 °C; 1H NMR (CDCl3)
Gen er a l P r oced u r e for th e P r ep a r a tion of Dim eth yl
Ester of 1-Ar yln a p h th a len e Der iva tives 9. Meth od B
(Sch em e 1). Compounds 9q-s were essentially prepared by
the same procedure. The sequence is illustrated for 9q,
followed by analytical data for 9r ,s.
3-(3-Br om o-4,5-d im et h oxyp h en yl)-7-ch lor op h t h a lid e
(5q). To a stirred mixture of 2-chloro-N-methylbenzamide (4a )
(12.5 g, 73.8 mmol) and N,N,N′,N′-tetramethylethylenediamine

1300 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ukita et al.
δ 3.59-4.15 (br s, 2H), 3.75 (s, 3H), 3.84 (s, 6H), 3.96 (s, 3H),
4.01 (s, 3H), 4.65 (s, 2H), 4.93 (s, 2H), 6.59 (s, 2H), 6.79 (s,
1H), 7,14 (s, 1H), 7.73 (s, 1H); EIMS m/z 414 (M+, base), 396.
6,7-Dim et h oxy-2-(m et h oxyca r b on yl)-1-(3-n it r op h en -
yl)n a p h th a len e-3-ca r boxylic a cid (12i): yield 93%; mp
1
249-250 °C dec; H NMR (DMSO-d6) δ 3.47 (s, 3H), 3.64 (s,
3H), 3.94 (s, 3H), 6.64 (s, 1H), 7.71 (s, 1H), 7.75-7.90 (m, 2H),
8.08-8.15 (m, 1H), 8.29-8.43 (m, 1H), 8.57 (s, 1H), 13.27 (br
s, 1H); EIMS m/z 411 (M+), 379 (base).
1-(2-Br om o-4-p yr id yl)-6,7-d im et h oxy-2-(m et h oxyca r -
bon yl)n a p h th a len e-3-ca r boxylic a cid (12j): yield 98%; mp
223-225 °C dec; 1H NMR (CDCl3) δ 3.69 (s, 3H), 3.81 (s, 3H),
4.05 (s, 3H), 6.67 (s, 1H), 7.30 (s, 1H), 7.34 (dd, 1H, J ) 5.0,
1.4 Hz), 7.56-7.62 (m, 1H), 8.55 (d, 1H, J ) 5.0 Hz), 8.61 (s,
1H); EIMS m/z 445/447 (M+), 413/415 (base).
2-(H yd r oxym e t h yl)-6,7-d im e t h oxy-1-(3,4,5-t r im e t h -
oxyp h en yl)n a p h th a len e-3-ca r boxylic Acid La cton e (11).
A mixture of 10 (1.5 g, 3.62 mmol) and AgCO3 (3.0 g, 10.9
mmol) in benzene (30 mL) was refluxed for 3 h. The solid was
filtered off and washed with CHCl3. The filtrate was concen-
trated under reduced pressure, and the residue obtained was
crystallized from AcOEt to give 11 (1.1 g, 74%): mp 240-242
1
°C; H NMR (CDCl3) δ 3.86 (s, 3H), 3.87 (s, 3H), 3.98 (s, 3H),
4.06 (s, 3H), 5.27 (s, 2H), 6.60 (s, 2H), 7.14 (s, 1H), 7.32 (s,
1H), 8.33 (s, 1H); EIMS m/z 410 (M+, base), 395, 379.
6,7-Dim eth oxy-2-(m eth oxycar bon yl)-1-(2-th ien yl)n aph -
th a len e-3-ca r boxylic a cid (12k ): yield 99%; mp 225-227 °C
Gen er a l P r oced u r e for th e P r ep a r a tion of 12. Com-
pounds 12a -s were essentially prepared by the same proce-
dure. The sequence is illustrated for 12a , followed by analytical
data for 12b-s.
1
dec; H NMR (DMSO-d6) δ 3.54 (s, 3H), 3.69 (s, 3H), 3.93 (s,
3H), 6.99 (s, 1H), 7.11 (dd, 1H, J ) 3.5, 1.2 Hz), 7.22 (dd, 1H,
J ) 5.1, 3.5 Hz), 7.67 (s, 1H), 7.78 (dd, 1H, J ) 5.1, 1.2 Hz),
8.54 (s, 1H), 13.04-13.45 (br s, 1H); EIMS m/z 372 (M+), 340
(base).
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-tr im eth -
oxyp h en yl)n a p h th a len e-3-ca r boxylic Acid (12a ). A solu-
tion of 3a (30 g, 63.8 mmol) in a mixture of MeOH (200 mL)
and 2 N aqueous NaOH (63.8 mL) was refluxed for 30 min.
After evaporation of the organic solvent, the residue was
acidified with 2 N hydrochloric acid and extracted with CHCl3.
The organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. Crystallization of
the residue from Et2O gave 12a (27.4 g, 94%): mp 222-224
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-tr im eth -
oxystyr yl)n a p h th a len e-3-ca r boxylic a cid (12l): yield 93%;
1
mp 239-240 °C dec; H NMR (DMSO-d6) δ 3.69 (s, 3H), 3.74
(s, 3H), 3.85 (s, 6H), 3.92 (s, 3H), 3.93 (s, 3H), 6.77 (d, 1H, J )
16 Hz), 6.96 (s, 2H), 7.43 (s, 1H), 7.58 (d, 1H, J ) 16 Hz), 7.61
(s, 1H), 8.40 (s, 1H), 13.12 (br s, 1H); SIMS m/z 482 (M+, base),
451.
1
1-(3-Br om o-4,5-dim eth oxyph en yl)-6-eth oxy-7-m eth oxy-
2-(m eth oxycar bon yl)n aph th alen e-3-car boxylic acid (12m ):
yield 86%; mp 223-224 °C dec; 1H NMR (CDCl3) δ 1.57 (t,
3H, J ) 6.9 Hz), 3.70 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H), 3.96 (s,
3H), 4.26 (q, 2H, J ) 7.0 Hz), 6.87 (s, 1H), 6.91 (d, 1H, J ) 1.9
Hz), 7.19 (d, 1H, J ) 1.9 Hz), 7.26 (s, 1H), 8.55 (s, 1H); EIMS
m/z 518/520 (M+), 486/488 (base).
1-(3-Br om o-4,5-d im eth oxyp h en yl)-6,7,8-tr im eth oxy-2-
(m eth oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12n ):
yield 93%; mp 231-232 °C dec; 1H NMR (CDCl3) δ 3.36 (s,
3H), 3.61 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.02
(s, 3H), 6.84 (d, 1H, J ) 1.9 Hz), 7.10 (d, 1H, J ) 1.9 Hz), 7.13
(s, 1H), 8.56 (s, 1H); EIMS m/z 534/536 (M+), 502/504 (base),
424.
1-(3-Br om o-4,5-d im eth oxyp h en yl)-2-(m eth oxyca r bon -
yl)n a p h th a len e-3-ca r boxylic a cid (12o): yield 83%; mp
188-191 °C; 1H NMR (CDCl3) δ 3.72 (s, 3H), 3.85 (s, 3H), 3.97
(s, 3H), 6.90 (d, 1H, J ) 1.9 Hz), 7.17 (d, 1H, J ) 1.9 Hz),
7.54-7.73 (m, 3H), 7.98-8.10 (m, 1H), 8.75 (s, 1H), 10.00-
10.78 (br s, 1H); EIMS m/z 444/446 (M+), 412/414 (base).
1-(3-Br om o-4,5-d im eth oxyp h en yl)-6-m eth oxy-2-(m eth -
oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12p ): yield
93%; mp 206-208 °C; 1H NMR (CDCl3) δ 3.70 (s, 3H), 3.85 (s,
3H), 3.96 (s, 6H), 6.88 (d, 1H, J ) 1.9 Hz), 7.15 (d, 1H, J ) 1.9
Hz), 7.21-7.35 (m, 2H), 7.55 (d, 1H, J ) 9.1 Hz), 8.52 (s, 1H);
EIMS m/z 474/476 (M+), 442/444 (base).
1-(3-Br om o-4,5-d im et h oxyp h en yl)-5-ch lor o-2-(m et h -
oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12q): yield
93%; mp 202-204 °C; 1H NMR (DMSO-d6) δ 3.57 (s, 3H), 3.81
(s, 3H), 3.84 (s, 3H), 7.03 (d, 1H, J ) 1.9 Hz), 7.10 (d, 1H, J )
1.9 Hz), 7.50-7.76 (m, 2H), 7.93 (dd, 1H, J ) 7.3, 1.1 Hz), 8.90
(s, 1H); EIMS m/z 478/480 (M+), 446/448 (base).
°C; H NMR (DMSO-d6) δ 3.54 (s, 3H), 3.70 (s, 3H), 3.758 (s,
3H), 3.762 (s, 6H), 3.93 (s, 3H), 6.61 (s, 2H), 6.97 (s, 1H), 7.65
(s, 1H), 8,48 (s, 1H), 13,14 (br s, 1H); SIMS m/z 456 (M+),425
(base).
1-(3-Am in o-4,5-d im e t h oxyp h e n yl)-6,7-d im e t h oxy-2-
(m eth oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12b):
1
yield 97%; H NMR (CDCl3) δ 3.68 (s, 3H), 3.81 (s, 3H), 3.81
(s, 3H), 3.92 (s, 3H), 4.03 (s, 3H), 5.66 (br s, 3H), 6.36 (d, 1H,
J ) 1.8 Hz), 6.41 (d, 1H, J ) 1.9 Hz), 7.00 (s, 1H), 7.24 (s,
1H), 8.52 (s, 1H); EIMS m/z 441 (M+), 423, 409 (base).
1-(3-Ch lor o-4,5-d im et h oxyp h en yl)-6,7-d im et h oxy-2-
(m eth oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12c):
yield 84%; mp 209-212 °C dec; 1H NMR (DMSO-d6) δ 3.53 (s,
3H), 3.70 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 3.93 (s, 3H), 6.85
(s, 1H), 6.92-7.01 (m, 2H), 7.67 (s, 1H), 8.50 (s, 1H), 13.08-
13.30 (br s, 1H); SIMS m/z 4460 (M+ + 1), 429 (base).
1-(3-Br om o-4,5-d im e t h oxyp h e n yl)-6,7-d im e t h oxy-2-
(m eth oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12d ):
yield 98%; mp 228-230 °C; 1H NMR (DMSO-d6) δ 3.54 (s, 3H),
3.70 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 3.93 (s, 3H), 6.86 (s,
1H), 7.02 (d, 1H, J ) 1.9 Hz), 7.08 (d, 1H, J ) 1.9 Hz), 7.67 (s,
1H), 8.51 (s, 1H), 13.00-13.40 (br s, 1H).
6,7-Dim et h oxy-2-(m et h oxyca r b on yl)-1-(2-m et h yl-4,5-
d im eth oxyp h en yl)n a p h th a len e-3-ca r boxylic a cid (12e):
yield 87%; mp 202-204 °C dec; 1H NMR (CDCl3) δ 1.94 (s,
3H), 3.62 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 3.96 (s, 3H), 4.04
(s, 3H), 6.66 (s, 1H), 6.74 (s, 1H), 6.82 (s, 1H), 7.29 (s, 1H),
8.57 (s, 1H); EIMS m/z 440 (M+), 408 (base).
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-1-(3,4-m eth ylen e-
d ioxyp h en yl)n a p h th a len e-3-ca r boxylic a cid (12f): yield
99%; mp 255-256 °C; 1H NMR (DMSO-d6) δ 3.51 (s, 3H), 3.67
(s, 3H), 3.93 (s, 3H), 6.13 (d, 2H, J ) 2.0 Hz), 6.73 (dd, 1H, J
) 7.9, 1.7 Hz), 6.81 (s, 1H), 6.84 (d, 1H, J ) 1.5 Hz), 7.04 (d,
1H, J ) 7.9 Hz), 7.64 (s, 1H), 8.48 (s, 1H), 13.17 (br s, 1H);
EIMS m/z 410 (M+), 378 (base).
1-(3-Br om o-4,5-d im et h oxyp h en yl)-7-ch lor o-2-(m et h -
oxyca r bon yl)n a p h th a len e-3-ca r boxylic a cid (12r ): yield
71%; mp 215-217 °C dec; 1H NMR (CDCl3) δ 3.70 (s, 3H), 3.86
(s, 3H), 3.98 (s, 3H), 6.86 (d, 1H, J ) 1.9 Hz), 7.14 (d, 1H, J )
1.9 Hz), 7.52-7.65 (m, 2H), 7.97 (d, 1H, J ) 7.9 Hz), 8.71 (s,
1H); EIMS m/z 478/480 (M+), 446/448 (base).
1-(3,4-Dich lor op h en yl)-6,7-d im eth oxy-2-(m eth oxyca r -
bon yl)n a p h th a len e-3-ca r boxylic a cid (12g): yield 98%; mp
1
248-250 °C dec; H NMR (DMSO-d6) δ 3.51 (s, 3H), 3.68 (s,
1-(3-Br om o-4,5-dim eth oxyph en yl)-2-(m eth oxycar bon yl)-
7-m eth yln a p h th a len e-3-ca r boxylic a cid (12s): yield 83%;
3H), 3.93 (s, 3H), 6.70 (s, 1H), 7.32 (dd, 1H, J ) 8.3, 2.0 Hz),
7.57 (d, 1H, J ) 2.0 Hz), 7.69 (s, 1H), 7.78 (d, 1H, J ) 8.3 Hz),
8.53 (s, 1H); EIMS m/z 434 (M+), 402 (base).
1
mp 214-216 °C dec; H NMR (CDCl3) δ 2.48 (s, 3H), 3.70 (s,
3H), 3.85 (s, 3H), 3.98 (s, 3H), 6.88 (d, 1H, J ) 1.9 Hz), 7.15
(d, 1H, J ) 1.9 Hz), 7.36 (s, 1H), 7.46 (dd, 1H, J ) 8.4, 1.4
Hz), 7.93 (d, 1H, J ) 8.3 Hz), 8.70 (s, 1H); EIMS m/z 458/460
(M+), 426/428 (base).
1-(3,5-Dich lor op h en yl)-6,7-d im eth oxy-2-(m eth oxyca r -
bon yl)n a p h th a len e-3-ca r boxylic a cid (12h ): yield 95%; mp
1
239-241 °C; H NMR (DMSO-d6) δ 3.52 (s, 3H), 3.69 (s, 3H),
3.94 (s, 3H), 6.69 (s, 1H), 7.37 (d, 2H, J ) 1.9 Hz), 7.69 (s,
1H), 7.77 (t, 1H, J ) 1.9 Hz), 8.54 (s, 1H), 13.24 (br s, 1H);
EIMS m/z 434 (M+), 402 (base).
3-Am in o-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-
tr im eth oxyp h en yl)n a p h th a len e (13). To a mixture of 12a
(15.0 g, 35 mmol) and triethylamine (21.2 g, 210 mmol) in THF

1-Arylnaphthalene Lignan
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1301
(300 mL) was added dropwise ethyl chloroformate (7.6 g, 70
mmol) in 50 mL of THF at -50 °C. After the mixture stirred
at 0 °C for 30 min, 6.8 g of NaN3 in H2O (50 mL) was added to
the mixture in one portion. After the mixture stirred at room
temperature for 30 min, the mixture was diluted with CHCl3
and washed with brine. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. The residue
was dissolved in toluene (100 mL) and refluxed for 1 h. After
cooling to room temperature, 70 mL of concentrated hydro-
chloric acid (70 mL) was added and the mixture was heated
at 100 °C for 10 min. The reaction mixture was extracted with
CHCl3 and washed with brine. The organic layer was dried
over MgSO4 and concentrated under reduced pressure. Puri-
fication of the residue by silica gel chromatography (n-hexane-
AcOEt ) 1:1) gave 13 (8.9 g, 59%): mp 168-170 °C; 1H NMR
(CDCl3) δ 3.47 (s, 3H), 3.73 (s, 3H), 3.83 (s, 6H), 3.94 (s, 6H),
4.21 (br s, 2H), 6.57 (s, 2H), 6.86 (s, 1H), 6.91 (s, 2H); EIMS
m/z 427 (M+).
N-Meth yl-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-
tr im eth oxyp h en yl)-3-n a p h th a len eca r boxa m id e (17) a n d
6,7-Dim eth oxy-2-p h en yl-9-(3,4,5-tr im eth oxyp h en yl)ben z-
[f]isoin d ole-1,3-d ion e (28). To a mixture of 12a (500 mg, 1.1
mmol), EDCI‚HCl (230 mg, 1.2 mmol), and HOBt‚1H2O (184
mg, 1.2 mmol) in DMF (5 mL) was added 40% aqueous MeNH2
(103 µL, 1.2 mmol), and the mixture was stirred at room
temperature for 2 h. The mixture was poured into H2O and
extracted with AcOEt. The organic layer was washed succes-
sively with saturated aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by silica gel chromatography (from CHCl3-
acetone ) 10:1 to CHCl3-MeOH ) 20:1) gave 17 (23 mg, 4%)
and 28 (320 mg, 67%), respectively.
17: mp 219-220 °C; 1H NMR (CDCl3) δ 3.03 (d, 3H, J ) 4.8
Hz), 3.62 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.02
(s, 3H), 6.14-6.32 (br d, 1H), 6.60 (s, 2H), 6.97 (s, 1H), 7.17 (s,
1H), 7.91 (s, 1H); EIMS m/z 469 (M+), 437 (base), 422. Anal.
(C25H27NO7‚1.4H2O) Calcd: C, 60.69; H, 6.07; N, 2.83. Found:
C, 60.67; H, 5.62; N, 2.82.
3-Am in o-2-(h yd r oxym eth yl)-6,7-d im eth oxy-1-(3,4,5-tr i-
m eth oxyp h en yl)n a p h th a len e (14). To a stirred suspension
of lithium aluminum hydride (LiAlH4) (72 mg, 1.88 mmol) in
THF (10 mL) was added 13 (400 mg, 0.94 mmol) in 10 mL of
THF at 5 °C, and the mixture was stirred at the same
temperature for 1 h. H2O (0.07 mL), 15% aqueous NaOH (0.07
mL), and H2O (0.21 mL) were added dropwise to the reaction
mixture successively, and the resultant mixture was stirred
at room temperature overnight. The precipitate was removed
by filtration, and the filtrate was concentrated under reduced
pressure. Crystallization of the residue from n-hexane-AcOEt
(1:1) gave 14 (320 mg, 85%): mp 114-115 °C; 1H NMR (CDCl3)
δ 3.50-4.30 (m, 3H), 3.66 (s, 3H), 3.78 (s, 6H), 3.93 (s, 6H),
4.57 (s, 2H), 6.50 (s, 2H), 6.65 (s, 1H), 6.88 (s, 1H), 6.92 (s,
1H); EIMS m/z 400 (M+), 381.
3-(H yd r oxym e t h yl)-6,7-d im e t h oxy-1-(3,4,5-t r im e t h -
oxyp h en yl)n a p h th a len e-2-ca r boxylic Acid La cton e (15).
To mixture of 12a (2.0 g, 4.38 mmol) and triethylamine (443
mg, 4.38 mmol) in THF (20 mL) was added dropwise ethyl
chloroformate (475 mg, 4.38 mmol) in 10 mL of THF at -5 to
0 °C. After stirring at 0 °C for 10 min, the precipitate was
filtered off and washed with THF. The filtrate was added
dropwise to a solution of NaBH4 (414 mg, 10.6 mmol) in 50%
H2O-THF (v/v) (20 mL) at 0-5 °C. After stirring at room
temperature for 1 h, the reaction mixture was poured into H2O
and extracted with AcOEt. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. To a solution
of the obtained residue in DMF (25 mL) was added NaH (62%
dispersion in mineral oil, 204 mg, 5.26 mmol) at room tem-
perature, and the mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched with the addition
of H2O and extracted with AcOEt. The organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from Et2O gave
15 (1.52 g, 85%): mp 233-235 °C; 1H NMR (CDCl3) δ 3.80 (s,
3H), 3.86 (s, 3H), 3.98 (s, 3H), 4.06 (s, 3H), 5.41 (s, 2H), 6.62
(s, 2H), 7.15 (s, 1H), 7.20 (s, 1H), 7.73 (s, 1H); EIMS m/z 410
(M+, base), 395.
1
28: mp >250 °C; H NMR (CDCl3) δ 3.15 (s, 3H), 3.81 (s,
3H), 3.86 (s, 6H), 3.99 (s, 3H), 4.07 (s, 3H), 6.62 (s, 2H), 7.14
(s, 1H), 7.32 (s, 1H), 8.19 (s, 1H); EIMS m/z 437 (M+ base),
422.
N,N-Dim eth yl-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-1-
(3,4,5-tr im eth oxyph en yl)-3-n aph th alen ecar boxam ide (18).
To a solution of 12a (500 mg, 1.1 mmol) in DMF (5 mL) was
added 1,1′-carbonyldiimidazole (CDI) (213 mg, 1.31 mmol).
After stirring at room temperature for 1 h, 50% aqueous Me2-
NH (118 mg, 1.31 mmol) was added and the mixture was
stirred at room temperature overnight. The mixture was
poured into H2O and extracted with AcOEt. The organic layer
was washed successively with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by silica gel chromatog-
raphy (CHCl3-acetone ) 10:1) afforded 18 (396 mg, 75%): mp
190-192 °C; 1H NMR (CDCl3) δ 3.10 (s, 6H), 3.55 (s, 3H), 3.79
(s, 3H), 3.84 (s, 6H), 3.95 (s, 3H), 4.03 (s, 3H), 6.60 (s, 2H),
7.03 (s, 1H), 7.14 (s, 1H), 7.64 (s, 1H); EIMS m/z 483 (M+),
439 (base).
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 19-24.
Compounds 19-24 were essentially prepared by the same
procedure. The sequence is illustrated for 19, followed by
analytical data for 20-24.
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-3-(1-p yr r olid in yl-
ca r bon yl)-1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (19).
To a mixture of 12a (500 mg, 1.1 mmol), EDCI‚HCl (230 mg,
1.2 mmol), and HOBt‚1H2O (184 mg, 1.2 mmol) in DMF (5
mL) was added pyrrolidine (100 µL,1.2 mmol), and the mixture
was stirred at room temperature overnight. The mixture was
poured into H2O and extracted with AcOEt. The organic layer
was washed successively with saturated aqueous NaHCO3 and
brine, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by silica gel chromatog-
raphy (CHCl3-MeOH ) 20:1) gave 19 (506 mg, 91%): mp 196-
1
198 °C; H NMR (CDCl3) δ 1.83-2.08 (m, 4H), 3.39-3.78 (m,
4H), 3.56 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.03
(s, 3H), 6.59 (s, 2H), 7.02 (s, 1H), 7.15 (s, 1H), 7.69 (s, 1H);
EIMS m/z 509 (M+), 477, 439 (base).
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-tr im eth -
oxyp h en yl)-3-n a p h th a len eca r boxa m id e (16). To a mixture
of 12a (500 mg, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDCI‚HCl) (230 mg, 1.2
mmol), and 1-hydroxybenzotriazole hydrate (HOBt‚1H2O) (184
mg, 1.2 mmol) in DMF (5 mL) was added 28% aqueous NH3
(167 µL, 1.2 mmol), and the mixture was stirred at room
temperature for 3 h. The mixture was poured into H2O and
extracted with AcOEt. The organic layer was washed succes-
sively with saturated aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by silica gel chromatography (CHCl3-MeOH )
20:1) gave 16 (330 mg, 66%): mp 206-207 °C; 1H NMR
(CDCl3) δ 3.63 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.95 (s, 3H),
4.02 (s, 3H), 5.70-6.42 (br s, 2H), 6.61 (s, 2H), 6.97 (s, 1H),
7.20 (s, 1H), 8.02 (s, 1H); SIMS m/z 456 (M+ + 1), 439, 424
(base). Anal. (C24H25NO8) Calcd: C, 60.88; H, 5.75; N, 2.96.
Found: C, 61.05; H, 5.30; N, 2.87.
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-3-(p ip er id in oca r -
bon yl)-1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (20): yield
1
90%; mp 170-172 °C; H NMR (CDCl3) δ 1.50-1.80 (m, 6H),
3.34-3.90 (m, 4H), 3.57 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.94
(s, 3H), 4.03 (s, 3H), 6.60 (s, 2H), 7.03 (s, 1H), 7.14 (s, 1H),
7.61 (s, 1H); EIMS m/z 523 (M+), 491, 439 (base).
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-3-(4-m eth yl-1-p ip -
er a zin ylca r b on yl)-1-(3,4,5-t r im et h oxyp h en yl)n a p h t h a -
len e (21): yield 65%; mp 136-138 °C; 1H NMR (CDCl3) δ
2.31-2.60 (m, 4H), 2.35 (s, 3H), 3.45-3.61 (m, 2H), 3.57 (s,
3H), 3.69-3.90 (m, 2H), 3.79 (s, 3H), 3.84 (s, 6H), 3.94 (s, 3H),
4.03 (s, 3H), 6.59 (s, 2H), 7.02 (s, 1H), 7.15 (s, 1H), 7.62 (s,
1H); EIMS m/z 538 (M+), 455 (base), 439.
6,7-Dim et h oxy-2-(m et h oxyca r b on yl)-3-[4-(et h oxyca r -
b on yl)p ip er id in oca r bon yl]-1-(3,4,5-t r im et h oxyp h en yl)-

1302 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ukita et al.
n a p h th a len e (22): yield 96%; mp 137-139 °C; 1H NMR
(CDCl3) δ 1.28 (t, 3H, J ) 7.13 Hz), 1.50-2.10 (m, 5H), 2.50-
2.70 (m, 1H), 2.95-3.32 (m, 2H), 3.57 (s, 3H), 3.79 (s, 3H), 3.84
(s, 6H), 3.94 (s, 3H), 4.03 (s, 3H), 4.17 (q, 2H, J ) 7.13 Hz),
4.46-4.68 (m, 1H), 6.59 (s, 2H), 7.03 (s, 1H), 7.15 (s, 1H), 7.60
(s, 1H); EIMS m/z 595 (M+), 563, 439 (base).
mp 113-117 °C dec; 1H NMR (CDCl3) δ 1.54-2.30 (br s, 2H),
2.40-2.72 (m, 7H), 3.40-4.18 (m, 4H), 3.57 (s, 3H), 3.65 (t,
2H, J ) 5.4 Hz), 3.80 (s, 3H), 3.81 (s, 3H), 3.91 (s, 3H), 4.02 (s,
3H), 6.33 (d, 1H, J ) 1.8 Hz), 6.38, (d, 1H, J ) 1.8 Hz), 7.09
(s, 1H), 7.12 (s, 1H), 7.58 (s, 1H); SIMS m/z 554 (M+ + 1), 522,
424 (base).
1-(3-Ch lor o-4,5-dim eth oxy)-3-[4-(2-h ydr oxyeth yl)-1-pip-
er a zin ylca r bon yl]-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-
1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (27c): yield 87%;
mp 155-158 °C; 1H NMR (CDCl3) δ 1.50-2.41 (m, 2H), 2.58-
2.84 (m, 5H), 3.47-3.93 (m, 6H), 3.57 (s, 3H), 3.80 (s, 3H), 3.85
(s, 3H), 3.97 (s, 3H), 4.03 (s, 3H), 6.83 (d, 1H, J ) 1.8 Hz),
6.91 (s, 1H), 6.97 (d, 1H, J ) 1.8 Hz), 7.15 (s, 1H), 7.62 (s,
1H); SIMS m/z 573 (M+ + 1), 541, 443 (base).
1-(3-Br om o-4,5-dim eth oxy)-3-[4-(2-h ydr oxyeth yl)-1-pip-
er a zin ylca r bon yl]-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-
1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (27d ): yield 78%;
mp 167-168 °C; 1H NMR (CDCl3) δ 2.45-2.80 (m, 7H), 3.40-
4.00 (m, 6H), 3.59 (s, 3H), 3.80 (s, 3H), 3.85 (s, 3H), 3.95 (s,
3H), 4.03 (s, 3H), 6.88 (d, 1H, J ) 1.9 Hz), 6.91 (s, 1H), 7.13-
7.15 (m, 2H), 7.62 (s, 1H); EIMS m/z 616/618 (M+), 585/587,
487/489, 99 (base).
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im eth oxy-2-(m eth oxyca r bon yl)-1-(2-m eth yl-4,5-d im eth -
oxyp h en yl)n a p h th a len e (27e): yield 55%; mp 120-122 °C;
1H NMR (CDCl3) δ 1.95 (s, 3H), 2.45-2.71 (m, 7H), 3.41-4.01
(m, 6H), 3.54 (s, 3H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H),
4.03 (s, 3H), 6.67 (s, 1H), 6.69 (s, 1H), 6.82 (s, 1H), 7.15 (s,
1H), 7.63 (s, 1H); EIMS m/z 552 (M+), 534, 521, 439, 423 (base).
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im e t h oxy-2-(m e t h oxyca r b on yl)-1-(3,4-m e t h yle n e d i-
oxyp h en yl)n a p h th a len e (27f): yield 94%; mp 186-188 °C;
1H NMR (CDCl3) δ 2.43-2.78 (m, 7H), 3.40-4.00 (m, 6H), 3.59
(s, 3H), 3.79 (s, 3H), 4.02 (s, 3H), 6.03 (d, 1H, J ) 1.3 Hz),
6.07 (d, 1H, J ) 1.3 Hz), 6.71-7.01 (m, 4H), 7.14 (s, 1H), 7.61
(s, 1H); EIMS m/z 522 (M+), 504, 491, 409, 393 (base).
1-(3,4-Dich lor op h en yl)-3-[4-(2-h yd r oxyeth yl)-1-p ip er -
azin ylcar bon yl]-6,7-dim eth oxy-2-(m eth oxycar bon yl)n aph -
th a len e (27g): yield 69%; mp 179-180 °C; 1H NMR (CDCl3)
δ 2.43-2.72 (m, 7H), 3.49-3.94 (m, 6H), 3.58 (s, 3H), 3.78 (s,
3H), 4.03 (s, 3H), 6.76 (s, 1H), 7.15 (s, 1H), 7.21 (dd, 1H, J )
8.2, 2.0 Hz), 7.46 (d, 1H, J ) 1.9 Hz), 7.56 (d, 1H, J ) 8.2 Hz),
7.65 (s, 1H); EIMS m/z 546 (M+), 528, 515, 417 (base).
1-(3,5-Dich lor op h en yl)-3-[4-(2-h yd r oxyeth yl)-1-p ip er -
azin ylcar bon yl]-6,7-dim eth oxy-2-(m eth oxycar bon yl)n aph -
th a len e (27h ): yield 67%; mp 126-128 °C; 1H NMR (CDCl3)
δ 2.43-2.72 (m, 7H), 3.39-4.00 (m, 6H), 3.59 (s, 3H), 3.80 (s,
3H), 4.03 (s, 3H), 6.75 (s, 1H), 7.15 (s, 1H), 7.26 (s, 2H), 7.46
(t, 1H, J ) 1.9 Hz), 7.65 (s, 1H); EIMS m/z 546 (M+), 528, 515,
417 (base).
6,7-Dim eth oxy-2-(m eth oxycar bon yl)-3-(m or ph olin ocar -
bon yl)-1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (23): yield
88%; mp 196-198 °C; H NMR (CDCl3) δ 3.45-3.61 (m, 2H),
3.57 (s, 3H), 3.62-3.90 (m, 6H), 3.79 (s, 3H), 3.84 (s, 6H), 3.95
(s, 3H), 4.03 (s, 3H), 6.59 (s, 2H), 7.03 (s, 1H), 7.15 (s, 1H),
7.61 (s, 1H); EIMS m/z 525 (M+), 439 (base).
1
6,7-Dim et h oxy-2-(m et h oxyca r b on yl)-3-(4-oxop ip er i-
d in oca r b on yl)-1-(3,4,5-t r im et h oxyp h en yl)n a p h t h a len e
1
(24): yield 92%; mp 188-190 °C; H NMR (CDCl3) δ 2.50-
2.70 (m, 4H), 3.53 (s, 3H), 3.70-4.11 (m, 4H), 3.80 (s, 3H), 3.84
(s, 6H), 3.95 (s, 3H), 4.04 (s, 3H), 6.59 (s, 2H), 7.05 (s, 1H),
7.16 (s, 1H), 7.68 (s, 1H); EIMS m/z 537 (M+), 439 (base). Anal.
(C29H33NO9) Calcd: C, 64.80; H, 5.81; N, 2.61. Found: C, 64.77;
H, 5.98; N, 3.05.
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-3-(4-h yd r oxyp ip -
er id in oca r b on yl)-1-(3,4,5-t r im et h oxyp h en yl)n a p h t h a -
len e (25). To a stirred suspension of 24 (2.0 g, 3.72 mmol) in
EtOH (20 mL) was added NaBH4 (70 mg, 1.86 mmol) at 0 °C,
and the mixture was stirred at the same temperature for 30
min. The mixture was poured into H2O and extracted with
AcOEt. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Crystal-
lization of the residue from AcOEt gave 25 (1.80 g, 90%): yield
1
90%; mp 224-227 °C; H NMR (CDCl3) δ 1.52-2.09 (m, 5H),
3.21-3.59 (m, 2H), 3.55 (s, 3H), 3.62-3.92 (m, 2H), 3.79 (s,
3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.03 (s, 3H), 4.09-4.34 (m, 1H),
6.59 (s, 2H), 7.03 (s, 1H), 7.14 (s, 1H), 7.61 (s, 1H); EIMS m/z
539 (M+), 507, 439 (base).
6,7-Dim eth oxy-2-(m eth oxyca r bon yl)-3-(4-h yd r oxym e-
th ylpiper idin ocar bon yl)-1-(3,4,5-tr im eth oxyph en yl)n aph -
th a len e (26). To a stirred mixture of 22 (2.0 g, 3.36 mmol)
and NaBH4 (254 mg, 6.72 mmol) in THF (5 mL) was added
dropwise MeOH (2.1 mL) under reflux over 1 h. The reaction
mixture was allowed to cool to room temperature and concen-
trated under reduced pressure. The residue was poured into
H2O and extracted with CH2Cl2. The organic layer was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by silica gel chromatog-
raphy (CHCl3-acetone ) 2:1) gave 26 (1.45 g, 78%): mp 218-
1
220 °C; H NMR (CDCl3) δ 1.23-1.49 (m, 2H), 1.61-1.99 (m,
3H), 2.70-3.28 (m, 2H), 3.48-3.68 (m, 3H), 3.56 (s, 3H), 3.79
(s, 3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.03 (s, 3H), 4.62-4.89 (m,
1H), 6.59 (s, 2H), 7.02 (s, 1H), 7.14 (s, 1H), 7.61 (s, 1H); EIMS
m/z 553 (M+), 521, 439 (base).
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 27a -n .
Compounds 27a -n were essentially prepared by the same
procedure. The sequence is illustrated for 27a , followed by
analytical data for 27b-n .
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im eth oxy-2-(m eth oxyca r bon yl)-1-(3-n itr op h en yl)n a p h -
th a len e (27i): yield 52%; mp 147-150 °C; 1H NMR (CDCl3) δ
2.26-2.90 (m, 7H), 3.47-4.15 (m, 6H), 3.52 (s, 3H), 3.72 (s,
3H), 4.04 (s, 3H), 6.65 (s, 1H), 7.19 (s, 1H), 7.62-7.80 (m, 3H),
8.23 (d, 1H, J ) 1.0 Hz), 8.28-8.41 (m, 1H); EIMS m/z 523
(M+), 505, 492, 394 (base).
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im e t h oxy-2-(m e t h oxyca r b on yl)-1-(3,4,5-t r im e t h oxy-
p h en yl)n a p h th a len e (27a ). To a mixture of 12a (59.4 g, 0.13
mol), 1-(2-hydroxyethyl)piperazine (17.5 mL, 0.143 mol), and
HOBt‚1H2O (21.9 g, 0.143 mol) in CH2Cl2 (300 mL) was added
1,3-dicyclohexylcarbodiimide (DCC) (29.5 g, 0.143 mol), and
the mixture was stirred at room temperature overnight. The
precipitate was filtered off and washed with CH2Cl2. The
filtrate was washed successively with saturated aqueous
NaHCO3 and brine. The organic layer was dried over MgSO4
and concentrated under reduced pressure. Purification of the
residue by silica gel chromatography (CHCl3-MeOH ) 20:1)
gave 27a (32.0 g, 88%): mp 173-176 °C;1H NMR (CDCl3) δ
2.45-2.74 (m, 7H), 3.42-4.00 (m, 6H), 3.57 (s, 3H), 3.79 (s,
3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.03 (s, 3H), 6.59 (s, 2H), 7.03
(s, 1H), 7.15 (s, 1H), 7.61 (s, 1H); SIMS m/z 569 (M+ + 1, base),
537, 469.
1-(2-Br om o-4-p yr id yl)-3-[4-(2-h yd r oxyet h yl)-1-p ip er -
azin ylcar bon yl]-6,7-dim eth oxy-2-(m eth oxycar bon yl)n aph -
1
th a len e (27j): yield 59%; mp 204-205 °C; H NMR (CDCl3)
δ 2.46-2.74 (m, 7H), 3.40-3.99 (m, 6H), 3.59 (s, 3H), 3.78 (s,
3H), 4.04 (s, 3H), 6.66 (s, 1H), 7.16 (s, 1H), 7.21-7.35 (m, 1H),
7.51 (s, 1H), 7.68 (s, 1H), 9.51 (d, 1H, J ) 5.0 Hz); EIMS m/z
557/559 (M+), 539/541, 526/528, 428/430 (base).
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im et h oxy-2-(m et h oxyca r b on yl)-1-(2-t h ien yl)n a p h t h a -
len e (27k ): yield 83%; mp 190-192 °C; 1H NMR (CDCl3) δ
2.46-2.74 (m, 7H), 3.43-3.93 (m, 6H), 3.59 (s, 3H), 3.82 (s,
3H), 4.03 (s, 3H), 7.05-7.22 (m, 4H), 7.49 (dd, 1H, J ) 5.1,
1.2 Hz), 7.64 (s, 1H); SIMS m/z 485 (M+ + 1), 453, 355 (base).
3-[4-(2-H yd r oxye t h yl)-1-p ip e r a zin ylca r b on yl]-6,7-
d im eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-tr im eth oxystyr -
1-(3-Am in o-4,5-d im eth oxy)-3-[4-(2-h yd r oxyeth yl)-1-pip -
er a zin ylca r bon yl]-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-
1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (27b): yield 38%;
1
yl)n a p h th a len e (27l): yield 73%; mp 123-125 °C; H NMR
(CDCl3) δ 2.42-2.74 (m, 7H), 3.41-3.60 (m, 2H), 3.65 (t, 1H,

1-Arylnaphthalene Lignan
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1303
J ) 5.1 Hz), 3.78-3.90 (m, 2H), 3.81 (s, 3H), 3.89 (s, 3H), 3.92
(s, 6H), 3.97 (s, 3H), 4.03 (s, 3H), 6.68 (d, 1H, J ) 16 Hz), 6.76
(s, 2H), 7.13 (s, 1H), 7.42 (s, 1H), 7.51 (d, 1H, J ) 16 Hz), 7.55
(s, 1H); EIMS m/z 594 (M+), 99 (base).
1-(3-Br om o-4,5-d im eth oxyp h en yl)-6-eth oxy-3-[4-(2-h y-
d r oxyeth yl)-1-p ip er a zin ylca r bon yl]-7-m eth oxy-2-(m eth -
oxyca r bon yl)n a p h th a len e (27m ): yield 85%; mp 110-112
°C; 1H NMR (CDCl3) δ 1.56 (t, 3H, J ) 7.0 Hz), 2.42-2.73 (m,
7H), 3.41-4.02 (m, 6H), 3.59 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H),
3.95 (s, 3H), 4.25 (q, 2H, J ) 7.0 Hz), 6.88 (d, 1H, J ) 1.8 Hz),
6.91 (s, 1H), 7.13 (s, 1H), 7.14 (s, 1H), 7.60 (s, 1H); EIMS m/z
630/632 (M+), 599/601, 501/503, 99, 56 (base).
°C dec; 1H NMR (DMSO-d6) δ 2.43 (s, 3H), 2.90-4.06 (m, 11H),
3.52 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 4.40-4.68 (m, 1H), 5.40
(br s, 1H), 7.02 (s, 1H), 7.06 (d, 1H, J ) 1.6 Hz), 7.40 (s, 1H),
7.56 (d, 1H, J ) 8.4 Hz), 8.01 (d, 1H, J ) 8.4 Hz), 8.10 (s, 1H),
11.24 (br s, 1H); SIMS m/z 571/573 (M+ + 1 - HCl), 539/541,
441/443 (base).
3-Meth yl-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-
tr im eth oxyp h en yl)n a p h th a len e (29). To a solution of acetal
1 [R1 ) 4,5-(OMe)2] (169 g, 0.58 mol) in THF (400 mL) was
added dropwise n-BuLi (400 mL, 0.64 mol) at -78 °C under a
nitrogen atmosphere, and the mixture was stirred at the same
temperature for 30 min. A solution of 3,4,5-trimethoxybenz-
aldehyde (114 g, 0.58 mol) in THF (300 mL) was added
dropwise at -70 °C over 30 min. After stirring at the same
temperature for 1 h, the mixture was poured into H2O and
extracted with AcOEt. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. A mixture of the obtained residue, methyl crotonate
(67.7 mL, 0.64 mol), and acetic acid (180 mL) in toluene (180
mL) was heated under reflux for 1 h. After the addition of TFA
(30 mL), the mixture was further refluxed for 2 h. The reaction
mixture was poured into saturated aqueous NaHCO3 and
extracted with CHCl3. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by silica gel chromatog-
raphy (n-hexane-CHCl3-AcOEt ) 10:5:1) gave 29 (10.7 g,
4.3%): mp 175-183 °C dec;1H NMR (CDCl3) δ 2.47 (s, 3H),
3.60 (s, 3H), 3.78 (s, 3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.01 (s,
3H), 6.63 (s, 2H), 6.99 (s, 1H), 7.09 (s, 1H), 7.54 (s, 1H); EIMS
m/z 426 (M+, base), 411.
3-(Br om om eth yl)-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-
1-(3,4,5-tr im eth oxyp h en yl)n a p h th a len e (30). A mixture of
29 (8.4 g, 19.7 mmol), N-bromosuccinimide (NBS) (3.86 g, 21.7
mmol), and benzoyl peroxide (200 mg) in CCl4 (300 mL) was
heated under reflux overnight. The mixture was poured into
H2O and extracted with AcOEt. The organic layer was washed
successively with saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated under reduced pressure. Puri-
fication of the residue by silica gel chromatography (n-hexane-
AcOEt ) 5:3) gave 30 (1.45 g, 14.6%): mp 180-181 °C; 1H
NMR (CDCl3) δ 3.59 (s, 3H), 3.79 (s, 3H), 3.85 (s, 6H), 3.95 (s,
3H), 4.03 (s, 3H), 4.78 (s, 2H), 6.61 (s, 2H), 7.02 (s, 1H), 7.14
(s, 1H), 7.76 (s, 1H); EIMS m/z 504/506 (M+), 425 (base), 410,
94.
3-[4-(2-Hydr oxyeth yl)piper azin om eth yl]-6,7-dim eth oxy-
2-(m et h oxyca r b on yl)-1-(3,4,5-t r im et h oxyp h en yl)n a p h -
th a len e Dih yd r och lor id e (31). To a stirred suspension of
30 (0.82 g, 1.62 mmol) in THF (10 mL) was added 1-(2-
hydroxyethyl)piperazine (0.40 mL, 3.24 mmol) at room tem-
perature, and the mixture was stirred at room temperature
for 4.5 h. The reaction mixture was concentrated under
reduced pressure. The residue was diluted with CH2Cl2 and
washed successively with saturated aqueous NaHCO3 and
brine. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. Purification of the residue by
silica gel chromatography (CHCl3-MeOH ) 10:1) gave 3-[4-
(2-hydroxyethyl)piperazinomethyl]-6,7-dimethoxy-2-(methoxy-
carbonyl)-1-(3,4,5-trimethoxyphenyl)naphthalene (0.85 g,
95%): 1H NMR (CDCl3) δ 2.32-2.61 (m, 10H), 3.42-3.80 (m,
5H), 3.52 (s, 3H), 3.80 (s, 3H), 3.85 (s, 6H), 3.94 (s, 3H), 4.02
(s, 3H), 6.62 (s, 2H), 7.05 (s, 1H), 7.13 (s, 1H), 7.59 (s, 1H);
EIMS m/z 554 (M+), 536, 523, 425 (base).
After addition of 4 N HCl-dioxane (0.94 mL, 3.76 mmol) to
a solution of the above free base (0.85 g, 1.5 mmol) in 10 mL
of dioxane, the mixture was concentrated under reduced
pressure. The residue was triturated with ether and the
product 31 (0.86 g) was collected in 82% yield: mp 123-130
°C dec; 1H NMR (D2O) δ 2.44-4.02 (s, 13H), 3.21-3.37 (m,
2H), 3.62 (s, 3H), 3.68 (s, 3H), 3.73 (s, 6H), 3.80 (s, 2H), 3.94
(s, 3H), 3.98 (s, 3H), 6.47 (s, 2H), 6.76 (s, 1H), 7.04 (s, 1H),
7.40 (s, 1H); EIMS m/z 554 (M+ - 2HCl), 536, 523, 425 (base).
1-(3-Br om o-4,5-dim eth oxyph en yl)-3-[4-(2-h ydr oxyeth yl)-
1-p ip er a zin ylca r bon yl]-6,7,8-tr im eth oxy-2-(m eth oxyca r -
1
bon yl)n a p h th a len e (27n ): yield 81%; mp 148-150 °C; H
NMR (CDCl3) δ 2.41-2.76 (m, 7H), 3.30-4.10 (m, 4H), 3.35
(s, 3H), 3.50 (s, 3H), 3.64 (t, 2H, J ) 5.2 Hz), 3.83 (s, 3H), 3.89
(s, 3H), 3.91 (s, 3H), 4.00 (s, 3H), 6.84 (d, 1H, J ) 1.8 Hz),
6.98 (s, 1H), 7.07 (d, 1H, J ) 1.8 Hz), 7.61 (s, 1H); EIMS m/z
646/648 (M+), 615/618, 517/519 (base), 439.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 27o-s.
Compounds 27o-s were essentially prepared by the same
procedure. The sequence is illustrated for 27o, follwed by
analytical data for 27p -s.
1-(3-Br om o-4,5-dim eth oxyph en yl)-3-[4-(2-h ydr oxyeth yl)-
1-p ip er a zin ylca r b on yl]-2-(m et h oxyca r b on yl)n a p h t h a -
len e Hyd r och lor id e (27o). To a mixture of 12o (2.0 g, 4.49
mmol), 1-(2-hydroxyethyl)piperazine (660 µL, 4.94 mol), and
HOBt‚1H2O (668 mg, 4.94 mmol) in CH2Cl2 (40 mL) was added
DCC (1.02 g, 4.94 mmol), and the mixture was stirred at room
temperature overnight. The precipitate was filtered off and
washed with CH2Cl2. The filtrate was washed successively
with saturated aqueous NaHCO3 and brine. The organic layer
was dried over MgSO4 and concentrated under reduced pres-
sure. Purification of the residue by silica gel chromatography
(CHCl3-MeOH ) 20:1) gave 1-(3-bromo-4,5-dimethoxyphenyl)-
3-[4-(2-hydroxyethyl)piperazinocarbonyl]-2-(methoxycarbonyl)-
naphthalene. After addition of 2 N hydrochloric acid (2.05 mL,
4.1 mmol) to a solution of the obtained free base (1.9 g, 3.41
mmol) in CHCl3 (40 mL), the mixture was concentrated under
reduced pressure. Crystallization of the residual salt from
AcOEt gave 27o (1.76 g, 66%): mp 173-175 °C dec; 1H NMR
(DMSO-d6) δ 2.90-3.96 (m, 11H), 3.54 (s, 3H), 3.82 (s, 3H),
3.85 (s, 3H), 4.40-4.59 (m, 1H), 5.39 (br s, 1H), 7.04 (s, 1H),
7.07 (s, 1H), 7.59-7.81 (m, 3H), 8.07-8.18 (m, 1H), 8.33 (s,
1H), 11.04 (br s, 1H); SIMS m/z 557/559 (M+ + 1-HCl), 525/
527, 427/429 (base).
1-(3-Br om o-4,5-dim eth oxyph en yl)-3-[4-(2-h ydr oxyeth yl)-
1-p ip er a zin ylca r bon yl]-7-m eth oxy-2-(m eth oxyca r bon yl)-
n a p h th a len e h yd r och lor id e (27p ): yield 57%; mp 159-162
1
°C; H NMR (DMSO-d6) δ 2.91-4.08 (m, 11H), 3.52 (s, 3H),
3.81 (s, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 4.41-4.69 (m, 1H), 5.41
(br s, 1H), 7.00 (s, 1H), 7.04 (s, 1H), 7.29 (dd, 1H, J ) 9.2, 2.6
Hz), 7.44-7.61 (m, 2H), 8.00 (s, 1H), 10.97 (br s, 1H); EIMS
m/z 586/588 (M+ - HCl), 568/570, 555/557, 457/459 (base).
1-(3-Br om o-4,5-d im eth oxyp h en yl)-5-ch lor o-3-[4-(2-h y-
d r oxyeth yl)-1-p ip er a zin ylca r bon yl]-2-(m eth oxyca r bon -
yl)n a p h th a len e h yd r och lor id e (27q): yield 67%; mp 230-
1
235 °C dec; H NMR (DMSO-d6) δ 2.96-4.06 (m, 11H), 3.56
(s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 4.35-4.67 (m, 1H), 5.38 (br
s, 1H), 7.06 (s, 1H), 7.11 (d, 1H, J ) 1.5 Hz), 7.58-7.71 (m,
2H), 7.88-8.01 (m, 1H), 8.31 (s, 1H), 11.15 (br s, 1H); SIMS
m/z 591/593 (M+ + 1 - HCl, base), 559/561, 491/493.
1-(3-Br om o-4,5-d im eth oxyp h en yl)-7-ch lor o-3-[4-(2-h y-
d r oxyeth yl)-1-p ip er a zin ylca r bon yl]-2-(m eth oxyca r bon -
yl)n a p h th a len e h yd r och lor id e (27r ): yield 66%; mp 156-
1
158 °C dec; H NMR (DMSO-d6) δ 2.89-4.01 (m, 11H), 3.53
(s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 4.40-4.70 (m, 1H), 5.40 (br
s, 1H), 7.06 (s, 1H), 7.11 (s, 1H), 7.56 (d, 1H, J ) 1.9 Hz), 7.77
(dd, 1H, J ) 8.7, 2.1 Hz), 8.10-8.26 (m, 2H), 10.77 (br s, 1H);
SIMS m/z 591/593 (M+ + 1 - HCl, base), 559/561, 461/463.
1-(3-Br om o-4,5-dim eth oxyph en yl)-3-[4-(2-h ydr oxyeth yl)-
1-p ip er a zin ylca r bon yl]-2-(m et h oxyca r b on yl)-7-m et h yl-
n a p h th a len e h yd r och lor id e (27s): yield 77%; mp 230-231
3-[4-(2-t er t -B u t y ld i m e t h y ls i ly lo x y e t h y l)p i p e r a -
zin om eth yl]-6,7-d im eth oxy-2-(m eth oxyca r bon yl)-1-(3,4,5-
tr im eth oxyp h en yl)n a p h th a len e (32). To a stirred suspen-

1304 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ukita et al.
sion of 27a (11.4 g, 20 mmol) in THF (40 mL) were added
imidazole (2.04 g, 30 mmol) and tert-butyldimethylsilyl chlo-
ride (4.52 g, 30 mmol), and the mixture was stirred at room
temperature overnight. The mixture was poured into H2O and
extracted with AcOEt. The organic layer was washed succes-
sively with saturated NaHCO3 and brine, dried over MgSO4,
and concentrated under reduced pressure. The residue was
triturated with n-hexane, and the product 32 (13.1 g) was
obtained in 96% yield: mp 95-98 °C; 1H NMR (CDCl3) δ 0.06
(s, 6H), 0.89 (s, 9H), 2.43-2.72 (m, 6H), 3.40-3.93 (m, 6H),
3.57 (s, 3H), 3.79 (s, 3H), 3.84 (s, 6H), 3.94 (s, 3H), 4.03 (s,
3H), 6.59 (s, 2H), 7.02 (s, 1H), 7.15 (s, 1H), 7.61 (s, 1H); EIMS
m/z 682 (M+), 537, 439 (base).
3-[4-(2-H yd r oxyet h yl)p ip er a zin om et h yl]-2-(h yd r oxy-
methyl)-6,7-dimethoxy-1-(3,4,5-trimethoxyphenyl)naphtha-
len e (33) a n d 3-[4-(2-Hyd r oxyeth yl)p ip er a zin oca r bon yl]-
2-(h yd r oxym et h yl)-6,7-d im et h oxy-1-(3,4,5-t r im et h oxy-
p h en yl)n a p h th a len e (34). To a stirred suspension of LiAlH4
(2.67 g, 70.3 mmol) in THF (50 mL) was added dropwise 32
(12.0 g, 17.6 mmol) in 20 mL of THF at room temperature,
and the mixture was stirred for 3 h. H2O (8.5 mL) and 2 N
aqueous NaOH (5.7 mL) were added dropwise successively,
and the resultant mixture was stirred at room temperature
for 30 min. The precipitate was removed through a Celite pad,
and the filtrate was concentrated under reduced pressure.
Purification of the residue by silica gel chromatography (from
CHCl3-MeOH ) 20:1 to CHCl3-MeOH ) 1:2) gave 33 (3.5 g,
38%) and 34 (1.5 g, 16%), respectively.
tissues, and cut into rings with special care not to damage the
endothelium. The rings were longitudinally opened and mounted
in organ baths containing 10 mL of Krebs-Henseleit solution
(37 °C, pH 7.4, bubbled with 95% O2-5% CO2). The coronary
arterial strips were allowed to equilibrate under a resting
tension of 1 g. The presence of intact endothelial cells was
confirmed by bradykinin (final concentration, 7 × 10-9 M)-
induced relaxation of strips precontracted with KCl (final
concentration, 50 mM). The strips were contracted with
phenylephrine (final concentration, 3 × 10-6 M), and after the
attainment of a plateau contraction, cumulative concentra-
tion-relaxation curves for
a tested compound were con-
structed. Relaxation was calculated as a percentage of the
contractile response to papaverine.
Ack n ow led gm en t. We express our great gratitude
to Drs. K. Matsumoto, K. Kawashima, and T. Iwasaki
of Tanabe Seiyaku Co., Ltd. for their encouragement
and interest.
Refer en ces
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33: 1H NMR (CDCl3) δ 1.51-1.92 (br s, 1H), 2.31-2.90 (m,
10H), 3.50-3.90 (m, 5H), 3.75 (s, 3H), 3.85 (s, 6H), 3.96 (s,
3H), 4.01 (s, 3H), 4.50 (s, 2H), 6.61 (s, 2H), 6.85 (s, 1H), 7.13
(s, 1H), 7.60 (s, 1H); EIMS m/z 526 (M+), 396, 131 (base).
1
34: mp 188-191 °C; H NMR (CD3OD) δ 2.64 (t, 2H, J )
(3) (a) Dumaitre, B.; Dodic, N. Synthesis and Cyclic GMP Phos-
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5.8 Hz), 2.68-3.00 (m, 8H), 3.64-3.78 (m, 2H), 3.70 (s, 3H),
3.83 (s, 3H), 3.84 (s, 6H), 3.95 (s, 3H), 3.97 (s, 2H), 6.77 (s,
2H), 6.95 (s, 1H), 7.25 (s, 1H), 7.82 (s, 1H); SIMS m/z 541 (M+
+ 1, base), 411.
Biologica l Meth od s. Isola tion of P h osp h od iester a se
Isozym es. The method of Reeves et al.11 was modified to
isolate PDE isozymes: 1.0 g of lung, heart, or adrenal gland
of 56-week-old beagle dog was homogenized in 10 mL ice-cold
homogenization buffer (20 mM Tris/HCl, pH 7.8, 2 mM
magnesium acetate, 0.3 mM CaCl2, 1 mM dithiothreitol, 40
µM leupeptin, 1.3 mM benzamidine, 0.2 mM phenylmethane-
sulfonyl fluoride, and 1 mM NaN3) in a Polytron homogenizer
for 1 min at medium speed. The homogenate was centrifuged
at 6000g for 20 min, and the supernatant was recentrifuged
at 100000g for 60 min. The cytosolic fraction isolated above
was applied to a DEAE-Sephadex column (Pharmacia) equili-
brated in elution buffer (20 mM Tris/HCl, pH 7.8, 1 mM
dithiothreitol, 1 mM CaCl2, 2 µM leupeptin, and 5 mM
benzamidine). The column was washed with 10 mL of elution
buffer, and the PDEs were then eluted from the column by
running a linear NaCl gradient (0-400 mM, 50 mL; 400-2000
mM, 10 mL) in elution buffer. Fractions (1 mL each) were
collected on ice and assayed for cGMP and cAMP hydrolytic
PDE activity.
Assa y of P h osp h od iester a se Activity. PDE activity was
determined by a modification of the method of Thompson et
al.12 The assay buffer contained 50 mM Tris-HCl, pH 8.0, 5
mM MgCl2, 4 mM 2-mercaptoethanol, 1 µM unlabeled cGMP
or cAMP, and 22 nM [3H]cGMP or [3H]cAMP. The reaction was
started by mixing 0.1-10 µM enzyme solution into 500 µL of
assay buffer, and tubes were incubated at 37 °C for 30 min.
After boiling for 1.5 min, the mixture was added to 100 µL of
1 mg/mL Crotalus atrox snake venom and incubated at 37 °C
for 30 min. The reaction was quenched by the addition of 500
µL of methanol, and the resultant solution was applied to a
Dowex (1 × 8-400) column. Aqueous scintillation cocktails were
added to each elute, and the radioactivity was measured.
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(8) Plaumann, H. P.; Smith, J . G.; Rodigo, R. Potential Isobenzo-
furans: their Use in the Synthesis of Naturally Occurring
1-Arylnaphthalide Lignans. J . Chem. Soc. Chem. Commun.
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(9) Weeratunga, G.; Rajapaksa, D.; Rodrigo, R. The Synthesis and
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