Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3- bis(hydroxymethyl)naphthalene lignans

Article abstract of DOI:10.1021/jm9509096

A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement of the 1-phenyl ring by a pyridone ring led to marked improvement of the

Full text of DOI:10.1021/jm9509096

2696
J . Med. Chem. 1996, 39, 2696-2704
Novel Selective P DE IV In h ibitor s a s An tia sth m a tic Agen ts. Syn th esis a n d
Biologica l Activities of a Ser ies of 1-Ar yl-2,3-bis(h yd r oxym eth yl)n a p h th a len e
Lign a n s
Tameo Iwasaki,* Kazuhiko Kondo,* Tooru Kuroda, Yasunori Moritani, Shinsuke Yamagata, Masaki Sugiura,
Hideo Kikkawa,† Osamu Kaminuma,† and Katsuo Ikezawa†
Lead Optimization Research Laboratory, Tanabe Seiyaku Company, Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532, J apan,
and 2-2-50, Kawagishi, Toda, Saitama 335, J apan
Received December 11, 1995X
A series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans have been synthesized and
evaluated for their ability to selectively inhibit PDE IV isolated from guinea pig. Replacement
of the 1-phenyl ring by a pyridone ring led to marked improvement of their selectivity for PDE
IV over PDE III. The compounds that were most potent and selective involved those bearing
an N-alkylpyridone ring at C-1. These compounds also showed potent antispasmogenic activity
without causing significant changes in heart rate in the guinea pig. The most potent compound
was 6,7-diethoxy-2,3-bis(hydroxymethyl)-1-[1-(2-methoxyethyl)-2-oxo-pyrid-4-yl]naphthalene
(17f), ED50 values of histamine-induced and antigen-induced bronchoconstriction in the guinea
pig being 0.08 and 2.3 mg/kg iv, respectively. This compound was chosen as a candidate for
further pharmacological evaluation.
In tr od u ction
Being too unstable to be isolated, isobenzofurans 4
generated from the cyclic acetals 3 were treated directly
with dimethyl maleate to give the adducts 5. The
adducts 5 were also prepared by the reaction of the
hydroxy acetals 2 with dimethyl maleate in the presence
of acetic acid in a one-pot procedure. Subsequent
aromatization of the adducts 5 with boron trifluoride
etherate or trifluoroacetic acid followed by reduction of
the ester groups with lithium aluminum hydride (LAH)
afforded the diols 7 (method A). The methylsulfonyl
analog 7g was obtained by oxidizing the corresponding
sulfide 7gg with m-chloroperbenzoic acid. The naph-
thalene 7e was prepared by reduction of the corre-
sponding ester 69 with LAH. The preparation of the diol
with a spacer methylene 7d was as follows. Treatment
of the hydroxy acetal 2 with dimethyl acetylenedicar-
boxylate in acetic acid afforded the olefin 8. Subsequent
catalytic hydrogenation of 8 gave the adduct 5 which
was converted to the diol 7d by the same reactions as
described above.
The amino analog 7h was synthesized by deprotection
of the silyl ether 6a , Zincke nitration10 on the resulting
9, and catalytic hydrogenation (method B). The acet-
amide analog 7i was prepared by acylation of the
corresponding amine 6i with acetic anhydride followed
by reduction with LAH. The N,N-dimethylcarbamoyl
analog 7j was obtained by transformation of the diol 7k
to the silyl derivative 11, lithiation followed by carbon-
ation, condensation with dimethylamine, and deprotec-
tion (method C).
Asthma is a complex disease characterized by airways
obstruction and bronchial inflammation. Despite wide-
spread use of antiasthmatic drugs, the mortality and
morbidity due to asthma is increasing worldwide, sug-
gesting the lack of really effective drugs for therapy.
Cyclic nucleotide phosphodiesterases (PDEs) are the
enzymes hydrolyzing purine cyclic nucleotides, cAMP
and cGMP, to form the respective 5′-mononucleotides.
At least seven different gene families of PDEs are
currently known to exist in mammalian tissues.1 In-
hibition of PDE activity results in the increase in
cellular levels of second messengers, cAMP and cGMP.
Elevation of these second messengers has been impli-
cated in relaxation of airway smooth muscle.2 There is
also considerable evidence that elevated levels of cAMP
in proinflammatory cells prevents their activation.3
An area of recent interest has been the search for
selective PDE IV inhibitors as potential antiasthmatic
agents.4 The reported selective PDE IV inhibitors
include catechol ethers, quinazolinediones, and xan-
thines.4c,5 During our continued search for biologically
active lignans, we found that arylnaphthalene lignans
showed consistent PDE IV inhibitory activity as a class.
Since inhibition of PDE III is reported to correlate with
the induction of cardiovascular side effects,6 we under-
took a search for PDE IV inhibitors having minimal
PDE III inhibitory activity in the lignan series. We
report here the synthesis, structure-activity relation-
ships, and biological activities of a series of novel 1-aryl-
2,3-bis(hydroxymethyl)naphthalene lignans.
The diols bearing a pyridone ring 15 and 17 were
prepared by the methods shown in Scheme 2. Acety-
lation of the pyridines 7 prepared via the isobenzofurans
4 provided the acetates 13 which were oxidized with
m-chloroperbenzoic acid to give the N-oxides 14. Treat-
ment of 14 with acetic anhydride followed by selective
removal of the acetyl group of the C-1 substituent with
ammonium hydroxide afforded the pyridones 15 (R2 )
Ac).11 Alkylation of 15 (R2 ) Ac) with alkyl halides and
sodium hydride gave the N-alkyl analogs 16. Removal
of the acetate protecting groups with sodium methoxide
Ch em istr y
The various diols 7, 15, and 17 were synthesized via
either Diels-Alder reactions of isobenzofurans 47
(Scheme 1) or cyclization of lactones 218 (Scheme 3). As
shown in Scheme 1, the bromo acetals 1 were trans-
formed into the cyclic acetals 3 via hydroxy acetals 2.
† Saitama.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
S0022-2623(95)00909-5 CCC: $12.00 © 1996 American Chemical Society

PDE IV Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2697
Sch em e 1a
a
Reagents and conditions: (a) n-BuLi, R2CHO/THF, -70 °C; (b) dimethyl maleate, AcOH/toluene reflux; (c) TFA/CHCl3, 25 °C or
BF3‚OEt2/CH3CN reflux; (d) LAH/THF, 10 °C; (e) 10% aqueous HCl/THF, reflux, overnight; (f) (1) NaNO2/AcOH; (2) Me2SO4, K2CO3/
DMF; (g) (1) H2, 10% Pd-C/THF-MeOH, 25 °C; (2) Ac2O, Et3N/THF, 25 °C; (3) LAH/THF, 10 °C; (h) TBDMSCI/pyridine, 25 °C; (i)
n-BuLi, CO2/Et2O, -70 °C; (j) (1) CDI/THF, HNMe2, 25 °C; (2) 10% aqueous HCl/THF, 25 °C.
provided the N-alkylpyridones 17 (method D). In an
alternative synthesis of 17, the diesters 6 were oxidized
to the N-oxides 18, which were converted into the
pyridones 19. Subsequent alkylation followed by reduc-
tion of the ester groups with sodium borohydride and
methanol in THF12 gave the N-alkylpyridones 17 (method
E). The acetate 17h was obtained by acylation of 17b
with acetic anhydride.
Scheme 3 summarizes the synthesis of the diols 7 via
the lactones 21, which were prepared in three steps from
aldehydes via Stobbe condensation.13 Alkylation of the
lactones 21 with aldehydes and lithium diisopropyl-
amide followed by cyclization with trifluoroacetic acid
gave the tetralins 23. The diols 7 were obtained by
aromatization of 23 with 2,3-dichloro-5,6-dicyanoben-
zoquinone and subsequent reduction with LAH (method
F).
Secondly, we selected a group of compounds on the basis
of the PDE IV inhibitory potency. These compounds
were evaluated for their ability to inhibit intravenous
histamine-induced and antigen-induced bronchospasm
in anesthetized guinea pigs (Table 2). The effects of
these compounds on heart rate were simultaneously
investigated to assess the cardiovascular side effects
reported to be produced by nonselective PDE inhibitors
(Table 2).
P h osp h od iester a se In h ibition . The most potent
inhibitors of PDE IV were found among the compounds
carrying a 3,4,5-trisubstituted phenyl and a N-alkylated
pyridone ring at C-1 (Table 1). In the trisubstituted
phenyl series, the initial lead compound 7a showed
potent inhibitory activity against PDE IV (IC50 ) 0.3
µM), though it exhibited poor selectivity for PDE IV over
PDE III. In an attempt to define the structural param-
eters necessary for activity and selectivity, our strategy
was to systematically change the substituents on the
naphthalene ring of compound 7. Replacement of the
6,7-dimethoxy group of 7a to a 6,7-methylenedioxy
group (7b) led to a decrease of PDE IV inhibitory
activity. A drop in the activity was also observed when
Biologica l Resu lts a n d Discu ssion
The compounds reported in this paper were first
evaluated as inhibitors of the four different forms of
PDE isolated from guinea pig cardiac ventricle (PDE I
and III) and lung (PDE IV and V) in vitro (Table 1).

2698 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Iwasaki et al.
Sch em e 2a
a
Reagents and conditions: (a) Ac2O, pyridine, 25 °C; (b) m-CPBA/CH2Cl2, 25 °C; (c) (1) Ac2O, reflux; (2) NH4OH/MeOH, 25 °C; (d)
NaH, R3I/DMF, 25 °C; (e) NaOMe/MeOH, 25 °C; (f) NaBH4/THF-MeOH, reflux.
Sch em e 3a
Moreover, for analog 7i, the ratio of the IC50 value for
PDE III to PDE IV increases from 3 to 29. Thus, nature
of the 3-substituent on the 1-phenyl ring had a marked
effect on the potency and selectivity.
From the above results, it may be concluded that the
amide group on the C-1 phenyl ring of 7j plays an
important role in PDE IV inhibitory activity. Therefore,
we next designed the diols bearing a pyridone ring at
C-1 (15a and 17a -i), which has an amide group in the
ring. Among them, N-alkylated pyridones (17d -f)
showed the best inhibitory activity against PDE IV (IC50
) 0.03-0.07 µM) with good selectivity for the PDE I,
III, and V isozymes; the PDE III vs PDE IV selectivity
ratio is between 714 and 1667 for these compounds. It
is evident from Table 1 that in general, the change of
the phenyl ring to the pyridone ring markedly improved
the selectivity ratio. Replacement of the 6,7-diethoxy
groups in 17e and 17f by 6,7-dimethoxy groups resulted
in a severe loss of PDE IV inhibitory activity (17b,c);
however, the 6-methoxy-7-ethoxy analog (17d ) retained
activity. The 2,3-bis(hydroxymethyl) groups seem to be
essential for the activity because replacement of 2,3-
bis(hydroxymethyl) groups with 2,3-bis(acetoxymethyl)
groups resulted in a large loss of activity (17h ).
a
Reagents and conditions: (a) LDA, R2CHO/THF, -70 °C; (b)
TFA, 25 °C; (c) DDQ/PhH, reflux; (d) LAH/THF, 10 °C.
the 7-methoxy group was replaced by a hydrogen atom
(7c). Transformation of the 2,3-bis(hydroxymethyl)
groups into a lactone function (24a )14 retained the
activity. Removal of the 3,4,5-trimethoxyphenyl group
(7e) or introduction of a methylene group between the
naphthalene ring and 1-phenyl ring (7d ) resulted in a
substantial loss in activity. The activity of 7a was
markedly enhanced, however, by changing the 3-meth-
oxy group of the 3,4,5-trimethoxyphenyl moiety to other
functional groups. The optimal activity was obtained
when the 3-methoxy group was substituted with a N,N-
dimethylcarbamoyl group (7j, IC50 ) 0.005 µM) and
either a methylsulfonyl (7g) or acetamido group (7i).
An tisp a sm ogen ic Activity. We selected 11 com-
pounds on the basis of the PDE IV inhibitory potency
for the evaluation of their ability to reverse histamine-
induced bronchoconstriction in anesthetized guinea pigs
when given intravenously. Rolipram4a was selected as
a reference compound (ED50 ) 0.01 mg/kg iv).15 As
shown in Table 2, compounds with the N,N-dimethyl-
carbamoyl (7j) and N-(2-methoxyethyl) (17f) substitu-
ents had excellent antispasmogenic activity with ED50
values of 0.03 and 0.08 mg/kg, respectively. The most
potent compound was N-(2-methoxyethyl) derivative 17f

PDE IV Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2699
Ta ble 1. Physical Properties and PDE Inhibitory Activities of Lignans
4
5
3
6
R1
OH
2
7
OH
1
R2
8
PDE inhibition, IC50, µMe
selectivity
compd
7a
7b
7c
7d
7e
7f
R1
R2
method
formulaa
C23H26O7
C22H22O7
C22H24O6
C24N28O7
C14H16O4
C22H24O6
mp, °C
I
III
IV
V
III/IV
6,7-(OMe)2
6,7-OCH2O- 3,4,5-(OMe)3Ph
6-OMe
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OEt)2
3,4,5-(OMe)3Ph
F
F
F
A
A
F
A
B
124-126
60
0.9
0.3
3
3
3
0.5
2
5
5
254-255 >100 >100
>30
40
5
20
0.2
>30
3,4,5-(OMe)3Ph
3,4,5-(OMe)3PhCH2
H
3,4-(OMe)2Ph
3-MeSO2-4,5-(OMe)2Ph
3-H2N-4,5-(OMe)2Ph‚HCl
124-125
182-184
30
40
20
8
8
20
>100
190-192 >100 >100
186-187
187-189
200-210
70
100
50
1
0.09
20
3
7g
7h
C23H26O8Sb
C24H29NO6‚
HCl‚1.6H2O
C24H27NO7
C25H29NO7
C22H20O6
C19H19NO5
C20H21NO5
C23H27NO4
C22H25NO6
0.05
0.05
53
30
2
400
7i
7j
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
6,7-(OMe)2
3-CH3CONH-4,5-(OMe)2Ph
3-Me2NCO-4,5-(OMe)2Ph
3,4,5-(OMe)3Ph
B
C
F
D
D
E
E
200-201
100
2
0.06
0.3
0.07
0.005
0.5
0.2
0.6
100
30
1
10
20
20
22
29
12
1
100
33
100
28
162-163 >100
24a c
15a
17a
17b
17c
205-206
9
2-oxopyrid-4-yl
242-244 >100
176-178 >100
159-161 >100
124-126 >100
20
N-Me-2-oxopyrid-4-yl
N-Bu-2-oxopyrid-4-yl
N-(2-methoxyethyl)-2-
oxopyrid-4-yl
20
30
14
0.3
0.5
17d
17e
17f
5-OMe-7-OEt N-Bu-2-oxopyrid-4-yl
E
E
E
C
24H29NO5
164-166 >100
149-150 >100
126-127 >100
50
50
57
0.07
0.03
0.057
8
9
22
714
1667
1000
6,7-(OEt)2
6,7-(OEt)2
N-Bu-2-oxopyrid-4-yl
N-(2-methoxyethyl)-2-
oxopyrid-4-yl
C25H31NO5
C24H29NO6
17g
6-OEt-7-OMe N-(2-methoxyethyl)-2-
E
C
23H27NO6
162-164 >100
7
0.45
24
17
oxopyrid-4-yl
17h d
17i
rolipram
6,7-(OMe)2
6,7-(OMe)2
N-Bu-2-oxopyrid-4-yl
N-Me-2-oxopyrid-6-yl
E
D
C27H31NO7
C20H21NO5
134-135 >100
238-240 >100
80
30
20
0.6
1.9
4
30
>100
4
50
>53
>100 >100
a
b
C, H, N, S, and Cl analyses were within (0.4% of the theoretical values, unless otherwise noted. S: calcd, 6.93; found, 7.51. c 6,7-
d
Dimethoxy-9-(3,4,5-trimethoxyphenyl)naphtho[2,3-c]furan-1(3H)-one. 2,3-Bis(acetoxymethyl)-1-(N-butyl-2-oxopyrid-4-yl)-6,7-dimethoxy-
naphthalene. e Data shown are the result of single determination.
Ta ble 2. Bronchial and Cardiovascular Effects of Selected Compounds
PDE inhibition,
histamine-induceda
bronchoconstriction
antigen-inducedc
bronchoconstriction,
ED50, mg/kg
IC50, µMd
dose,
mg/kg iv
heart rateb
∆beats/min
compd
7a
III
0.9
0.09
IV
% reduction
ED50, mg/kg
0.3
0.05
3
89
34
57
71
45
69
90
59
83
69
79
34
70
40
75
92
47
60
92
98
30
76
98
81
79
72
79
3
1
-7
-4
1
2
1
28
50
1
1
3
7
6
4
-5
5
4.6
7g
7h
7j
0.03
0.1
0.3
0.3
1
0.093
20
0.05
0.39
0.03
>10
3
0.06
0.005
0.03
0.1
0.3
3
0.1
0.3
0.3
1
17b
17c
30
14
0.3
0.5
>10
0.16
0.42
17d
50
0.07
3
17e
17f
50
57
0.03
0.057
0.3
0.1
0.3
1
0.3
1
3
3
0.1
1
>10
0.08
0.51
2.3
5
5
4
7
6
11
9
17g
7
0.45
4.1
17i
rolipram
30
>100
0.6
1.9
>10
19
0.01
3
a
b
Precent inhibition of histamine-induced bronchoconstriction in guinea pigs. Difference in heart rate between basal value and the
value observed after test compound administration in guinea pigs. Basal values for heart rate were 230-330 beats/min. c The dose which
inhibits antigen-induced bronchoconstriction in guinea pigs by 50%. Data shown are the result of single determination.
d
which showed a 98% reduction of the histamine re-
sponse at 1 mg/kg, and rolipram exhibited a 72%
reduction at the same dose. The N-butyl analog 17e
was 4-fold less potent than compound 17f in inhibition
of bronchoconstriction despite the fact that 17e was
2-fold more potent than 17f as an inhibitor of PDE IV.

2700 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Iwasaki et al.
A solution of the residue, dimethyl maleate (3.46 g, 24 mmol),
and acetic acid (10 mL) in toluene (20 mL) was heated under
reflux for 5 h. The solvent was removed by evaporation to
give 1,4-epoxy-1,2,3,4-tetrahydro-6,7-dimethoxy-1-[3-(meth-
ylthio)-4,5-dimethoxyphenyl]-2,3-bis(methoxycarbonyl)naph-
thalene (5g) as a syrup. This crude product was used in the
next step without purification. To a solution of 5g in CHCl3
(50 mL) was added trifluoroacetic acid (TFA) (10 mL), and the
mixture was stirred at room temperature for 3 h. The reaction
mixture was neutralized with saturated aqueous NaHCO3. The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. Crystallization of the residue from Et2O
gave 6g (4.08 g, 42%): mp 164-166 °C; 1H NMR (CDCl3) δ
2.37 (s, 3H), 3.65 (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.92 (s,
3H), 3.94 (s, 3H), 4.01 (s, 3H), 6.73 (s, 2H), 6.91 (s, 1H), 7.21
(s, 1H), 8.42 (s, 1H); MS m/z 489, 488, 487, 486 (M+). Anal.
(C25H26O8S) C, H, S.
In the guinea pig antigen-induced bronchoconstriction
model, compound 17f (ED50 ) 2.3 mg/kg iv) proved to
have activity greater than rolipram (ED50 ) 19 mg/kg
iv).16 More detailed information on the antispasmogenic
activity of 17f in this model will be published elsewhere.
To assess the cardiovascular side effects, the effects
of selected compounds on heart rate were investigated.
Increasing effects of these compounds on heart rate
correlate with the inhibitory effects of those on PDE III
activity. Among the compounds showing potent anti-
spasmogenic activity, the N-(2-methoxyethyl) analog 17f
exhibited minimal effects on increase in heart rate,
reflecting the high III/IV selectivity ratio (1000). By
contrast, the N,N-dimethylcarbamoyl analog 7j possess-
ing poor selectivity ratio (12) induced significant in-
crease in heart rate. However, this correlation did not
hold for the methylsulfonyl analog 7g (ED50 ) 0.093 mg/
kg iv) having very poor selectivity ratio (2), where it was
found that compound 7g showed negligible changes in
heart rate, though the reason for this is not clear.
2,3-Bis(h yd r oxym et h yl)-6,7-d im et h oxy-1-[3-(m et h yl-
th io)-3,4-d im eth oxyp h en yl]n a p h th a len e (7gg). To a sus-
pension of lithium aluminum hydride (LAH) (340 mg, 8.8
mmol) in THF (40 mL) was added a solution of the 6g (2.14 g,
4.4 mmol) in THF (60 mL) at -20 °C. The mixture was
gradually warmed to 10 °C during 1 h and stirred at the same
temperature for 1 h. To this mixture was added dropwise
water (0.34 mL), 15% aqueous NaOH (0.34 mL), and water
(1.0 mL) successively at 10 °C, and the resulting 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 Et2O
Con clu sion
Novel arylnaphthalene lignans bearing a N-alkylpyr-
idone ring have been shown to be very potent PDE IV
inhibitors with high PDE III vs PDE IV selectivity
1
gave 7gg (1.84 g, 97%): mp 141-142 °C; H NMR (CDCl3) δ
ratios. Of the analogs, compound 17f (PDE IV IC50
)
1.24 (t, J ) 7.1 Hz, 1.5H), 2.03 (s, 1.5H), 2.34 (s, 3H), 3.30-
3.80 (br s, 2H), 3.73 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 3.97 (s,
3H), 4.10 (q, J ) 7.1 Hz, 1H), 4.59 (s, 2H), 4.85 (s, 2H), 6.69
(s, 2H), 6.75 (s, 1H), 7.09 (s, 1H), 7.64 (s, 1H); MS m/z 432,
431, 430 (M+). Anal. (C23H26O6S‚0.5AcOEt) C, H, S.
2,3-Bis(h yd r oxym et h yl)-6,7-d im et h oxy-1-[3-(m et h yl-
su lfon yl)-4,5-d im eth oxyp h en yl]n a p h th a len e (7g). To a
stirred solution of 7gg (2.3 g, 5.3 mmol) in CHCl3 (100 mL)
was added m-chloroperbenzoic acid (m-CPBA) (2.0 g, 11.7
mmol), and the mixture was stirred at room temperature for
1 h. The reaction mixture was washed with 1 N aqueous
NaOH (30 mL), dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from AcOEt-
Et2O gave 7g (1.6 g, 68%): mp 187-189 °C; 1H NMR (CDCl3)
δ 3.27 (s, 3H), 3.40-3.90 (br s, 2H), 3.70 (s, 3H), 3.88 (s, 3H),
3.96 (s, 3H), 4.09 (s, 3H), 4.39 (AB q, J ) 12.0 Hz, 1H), 4.59
(AB q, J ) 12.0 Hz, 1H), 4.63 (AB q, J ) 13.0 Hz, 1H), 4.90
(AB q, J ) 13.0 Hz, 1H), 6.59 (s, 1H), 7.07 (s, 1H), 7.23 (d, J
) 1.5 Hz, 1H), 7.47 (d, J ) 1.5 Hz, 1H), 7.63 (s, 1H); MS m/z
464, 463, 462 (M+). Anal. (C23H26O8S) C, H; S: calcd, 6.93;
found, 7.51.
0.057 µM, PDE III/IV ratio 1000) showed potent anti-
spasmogenic activity (ED50 ) 0.08 mg/kg iv) without
producing the significant changes in heart rate with the
use of histamine-induced bronchospasm assay. Com-
pound 17f was 8-fold less active than rolipram (ED50
)
0.01 mg/kg iv) in the above assay system, whereas in
the guinea pig antigen-induced bronchoconstriction
model, 17f (ED50 ) 2.3 mg/kg iv) was 8-fold more active
than rolipram (ED50 ) 19 mg/kg iv).
On the basis of the potency, selectivity, and favorable
effect on cardiovascular systems, compound 17f was
selected for further evaluation as an antiasthmatic
agent.
Exp er im en ta l Section
Melting points were determined on a Yamato MP-21 capil-
lary melting point apparatus and are uncorrected. 1H NMR
spectra were obtained at 200 MHz with a Bruker AC-200
instrument. Chemical shifts were reported in ppm (δ) using
Me4Si as standard. Mass spectra were obtained on a Hitachi
M-60 mass spectrometer. Elemental analyses were carried out
in this laboratory. Column chromatography was performed
with silica gel (E. Merck, 70-230 mesh). Reactions were
monitored by TLC using 0.25 mm silica gel F254 (E. Merck)
glass plates. n-Butyllithium was the 1.6 M solution in hexane
supplied by Asia Lithium Co.
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 oxyben zyl)n a p h th a len e (7d ): yield 53%; mp 182-184
°C; 1H NMR (CDCl3) δ 3.30 (br s, 2H), 3.65 (s, 3H), 3.75 (s,
6H), 3.82 (s, 3H), 3.93 (s, 3H), 4.43 (s, 2H), 4.83 (s, 4H), 6.30
(s, 2H), 7.03 (s, 1H), 7.18 (s, 1H), 7.53 (s, 1H); MS m/z 428
(M
+). Anal. (C24H28O7) C, H.
6,7-Dim et h oxy-2,3-b is(h yd r oxym et h yl)n a p h t h a len e
1
(7e): yield 53%; mp 190-192 °C; H NMR (CDCl3) δ 3.94 (s,
Gen er a l P r oced u r e for t h e Syn t h esis of Diols 7.
Meth od A (Sch em e 1). Compounds 7d ,e,g were all prepared
by essentially the same procedure (Scheme 1). The sequence
is illustrated for 7g, followed by analytical data for 7d and
7e.
6,7-Dim et h oxy-2,3-b is(m et h oxyca r b on yl)-1-[3-(m et h -
ylt h io)-4,5-d im et h oxyp h en yl]n a p h t h a len e (6g). To a
stirred solution of 1 [R1 ) 4,5-(OMe)2] (5.82 g, 20 mmol) in
THF (40 mL) was added BuLi (13.1 mL, 21 mmol) at -70 °C
under an atmosphere of nitrogen. The mixture was stirred
at the same temperature for 30 min. To this mixture was
added a solution of the 3,4-dimethoxy-5-(methylthio)benzal-
dehyde (4.24 g, 20 mmol) in THF (15 mL). The resulting
mixture was stirred at the same temperature for 2 h and
poured into a mixture of water (50 mL) and AcOEt (100 mL).
The organic layer was separated, washed with water (30 mL),
dried over MgSO4, and concentrated under reduced pressure.
6H), 4.75 (d, J ) 6.0 Hz, 4H), 5.00 (t, J ) 6.0 Hz, 2H), 7.12 (s,
2H), 7.67 (s, 1H); MS m/z 248 (M+). Anal. (C14H16O4) C, H.
1,4-Epoxy-1,4-dih ydr o-6,7-dim eth oxy-1-(3,4,5-tr im eth ox-
yben zyl)-2,3-bis(m eth oxyca r bon yl)n a p h th a len e (8). This
compound was prepared as described for 6g except for using
dimethyl acetylenedicarboxylate in lieu of dimethyl maleate:
1
yield 17%; H NMR (CDCl3) δ 3.65 (d, J ) 1.5 Hz, 2H), 3.69
(s, 6H), 3.72 (s, 3H), 3.80 (s, 3H), 3.84 (s, 6H), 3.88 (s, 3H),
5.90 (s, 1H), 6.55 (s, 2H), 7.17 (d, J ) 1.5 Hz, 2H); MS m/z 500
(M+). Anal. (C26H28O10) C, H.
1,4-Ep oxy-1,2,3,4-tetr a h yd r o-6,7-d im eth oxy-1-(3,4,5-tr i-
m e t h ox yb e n zy l)-2,3-b is(m e t h o xyc a r b o n yl)n a p h t h a -
len e (5d ). A solution of 8 (300 mg, 0.6 mmol) in AcOEt (20
mL) was hydrogenated over 10% Pd-C (150 mg) at atmo-
spheric pressure and 25 °C for 5 h. The catalyst was filtered
off, and the filtrate was concentrated under reduced pressure
to give 5d as an oil (280 mg, 93%): 1H NMR (CDCl3) δ 3.30-

PDE IV Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2701
4.20 (m, 4H), 3.47 (s, 6H), 3.49 (s, 6H), 3.80 (s, 3H), 3.86 (s,
6H), 5.38 (d, J ) 5.0 Hz, 1H), 6.53 (s, 2H), 6.86 (s, 2H); MS
m/z 502 (M+). Anal. (C26H30O10) C, H.
amine (1.4 mL, 10 mmol) in THF (50 mL) was added acetic
anhydride (570 mg, 5.0 mmol) at 10 °C. The mixture was
stirred at room temperature overnight and concentrated under
reduced pressure. The residue was dissolved in AcOEt (100
mL), washed with water, dried over MgSO4, and concentrated
under reduced pressure. Purification of the residue by silica
gel chromatography (CHCl3:acetone ) 10:1) gave 1-(3-acet-
amido-4,5-dimethoxyphenyl)-6,7-dimethoxy-2,3-bis(methoxy-
carbonyl)-6,7-dimethoxynaphthalene (6ii) as a yellow foam
which was reduced with LAH as in the case of 7h . Crystal-
lization of the products from AcOEt gave 7i (4.80 g, 75%): mp
200-201 °C; 1H NMR (CDCl3) δ 2.19 (s, 3H), 3.36-3.70 (br s,
2H), 3.75 (s, 3H), 3.85 (s, 3H), 4.00 (s, 6H), 4.60 (s, 2H), 4.83
(d, J ) 12.0 Hz, 1H), 4.96 (d, J ) 12.0 Hz, 1H), 6.72 (d, J )
1.7 Hz, 1H), 6.85 (s, 1H), 7.13 (s, 1H), 7.71 (s, 1H), 7.88 (br s,
2H); MS m/z 427 (M+). Anal. (C24H27NO7) C, H, N.
Meth od B (Sch em e 1). 1-(3-Br om o-4-h yd r oxy-5-m eth -
oxyp h en yl)-6,7-d ieth oxy-2,3-bis(m eth oxyca r bon yl)n a p h -
th a len e (9h ). To a solution of 6h (5.3 g, 8.2 mmol) in THF
(45 mL) was added 10% aqueous HCl (30 mL), and the mixture
was heated at 70 °C overnight. The reaction mixture was
allowed to cool to room temperature and extracted with AcOEt.
The organic layer was washed with saturated aqueous NaH-
CO3, dried over MgSO4, and concentrated under reduced
pressure. Crystallization of the residue from Et2O gave 9h
(1.8 g, 41%): mp 165-167 °C; 1H NMR (CDCl3) δ 1.44 (t, J )
7.0 Hz, 3H), 1.54 (t, J ) 7.0 Hz, 3H), 3.69 (s, 3H), 3.88 (s, 3H),
3.93 (s, 3H), 3.96-4.04 (m, 2H), 4.24 (t, J ) 7.0 Hz, 2H), 6.05
(s, 1H), 6.83 (d, J ) 2.0 Hz, 1H), 6.84 (s, 1H), 7.13 (d, J ) 2.0
Hz, 1H), 7.23 (s, 1H), 8.42 (s, 1H); MS m/z 533 (M+). Anal.
(C25H25BrO8) C, H; Br: calcd, 14.98; found, 14.35.
Met h od
C (Sch em e 1). 1-(3-Br om o-4,5-d im et h oxy-
ph en yl)-6,7-dim eth oxy-2,3-bis[(ter t-bu tyldim eth ylsiloxy)-
m eth yl]n a p h th a len e (11). To a stirred solution of 7k (4.1
g, 8.9 mmol) in pyridine (10 mL) was added tert-butyldimeth-
ylsilyl chloride (3.44 g, 22.8 mmol) at 10 °C, and the mixture
was stirred at room temperature overnight. The reaction
mixture was concentrated under reduced pressure, and a
solution of the residue in Et2O (50 mL) was washed with 5%
aqueous citric acid and brine, dried over MgSO4, and concen-
trated under reduced pressure. Crystallization of the residue
6,7-Dieth oxy-2,3-bis(m eth oxyca r bon yl)-1-(3-n itr o-4,5-
d im eth oxyp h en yl)n a p h th a len e (10h ). To a stirred sus-
pension of 9h (14 g, 26 mmol) in AcOH (90 mL) was added
NaNO2 (5.4 g, 78 mmol) portionwise so that the reaction
temperature does not exceed 20 °C over 1 h, and the mixture
was stirred at room temperature for 30 min. The reaction
mixture was poured into water (100 mL), and the precipitate
was collected by filtration and washed with water. The
precipitate was dissolved in CHCl3 (100 mL), dried over
MgSO4, and concentrated under reduced pressure. To a
solution of the residue in DMF (150 mL) were added Me2SO4
(4.4 mL, 47 mmol) and K2CO3 (7.1 g, 52 mmol), and the
mixture was stirred at room temperature overnight. The
resulting precipitate was removed by filtration, and the filtrate
was concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 (100 mL), washed with 2 N aqueous
NaOH, followed by water and brine, dried over MgSO4, and
concentrated under reduced pressure. Crystallization of the
residue from diisopropyl ether gave 10h (7.74 g, 58%): mp
183-184 °C; 1H NMR (CDCl3) δ 1.44 (t, J ) 7.0 Hz, 3H), 1.54
(t, J ) 7.0 Hz, 3H), 3.69 (s, 3H), 3.88 (s, 3H), 3.93 (s, 3H),
3.96-4.04 (m, 2H), 4.05 (s, 3H), 4.24 (t, J ) 7.0 Hz, 2H), 6.81
(s, 1H), 7.15 (d, J ) 2.0 Hz, 1H), 7.26 (s, 1H), 7.38 (d, J ) 2.0
1
from hexane gave 11 (4.5 g, 74%): mp 132-134 °C; H NMR
(CDCl3) δ 0.03 (s, 6H), 0.21 (s, 6H), 0.90 (s, 9H), 1.05 (s, 9H),
3.76 (s, 3H), 3.86 (s, 3H), 3.96 (s, 3H), 4.03 (s, 3H), 4.53 (br s,
2H), 5.09 (br s, 2H), 6.72 (s, 1H), 6.85 (d, J ) 1.5 Hz, 1H), 7.17
(s, 1H), 7.18 (d, J ) 1.5 Hz, 1H), 7.90 (s, 1H); MS m/z 692
(M+). Anal. (C34H51BrO6Si2) C, H, Br.
2,3-Bis[(ter t-bu tyldim eth ylsiloxy)m eth yl]-1-(3-car boxy-
4,5-d im eth oxyp h en yl)-6,7-d im eth oxyn a p h th a len e (12).
To a stirred solution of 11 (2.0 g, 2.9 mmol) in Et2O (50 mL)
was added BuLi (2.0 mL, 3.2 mmol) at -70 °C under an
atmosphere of nitrogen, and the mixture was stirred at the
same temperature for 20 min. The mixture was bubbled with
CO2 gas (200 mL/min, 20 min) and stirred at the same
temperature for 2 h. The reaction mixture was poured into a
mixture of water (20 mL) and AcOEt (30 mL), and the organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. Crystallization of the residue
Hz, 1H), 8.50 (s, 1H); MS m/z 513 (M+). Anal. (C26H27NO10
)
C, H, N.
1-(3-Am in o-4,5-d im eth oxyp h en yl)-6,7-d ieth oxy-2,3-bis-
(h yd r oxym eth yl)n a p h th a len e Hyd r och lor id e (7h ).
1
from hexane gave 12 (1.8 g, 93%): mp 156-157 °C; H NMR
A
(CDCl3) δ -0.08 (s, 3H), -0.05 (s, 3H), 0.16 (s, 3H), 0.18 (s,
3H), 0.82 (s, 9H), 1.02 (s, 9H), 3.70 (s, 3H), 3.87 (s, 3H), 4.00
(s, 3H), 4.13 (s, 3H), 4.40 (br s, 2H), 4.58 (br s, 2H), 6.60 (s,
1H), 7.13 (s, 1H), 7.15 (s, 1H), 7.66 (s, 1H), 7.90 (s, 1H), 12.25
(br s, 1H); MS m/z 656 (M+). Anal. (C35H52O8Si2) C, H.
solution of 10i (8.0 g, 15 mmol) in THF (150 mL) and MeOH
(75 mL) was hydrogenated over 10% Pd-C (2.0 g) at 40 psi
and 25 °C for 7 h. The catalyst was filtered off, and the filtrate
was concentrated under reduced pressure to give an oil. To a
suspension of LAH (1.1 g, 29 mmol) in THF (100 mL) was
added a solution of the oil in THF (500 mL) at 10 °C, and the
mixture was stirred at the same temperature for 1 h. To this
reaction mixture were added dropwise water (1.1 mL), 15%
aqueous NaOH (1.1 mL), and water (3.3 mL) successively at
10 °C, and the mixture was stirred at room temperature for 2
h. The resulting precipitate was removed by filtration, and
the filtrate was concentrated under reduced pressure. Crys-
tallization of the residue from Et2O gave a solid. To a solution
of the solid in AcOEt (50 mL) and MeOH (2 mL) was added a
solution of HCl in 1,4-dioxane (24.1%, 3.8 mL, 15 mmol), and
the mixture was concentrated under reduced pressure. Re-
crystallization of the residual hydrochloride from MeOH-Et2O
gave 7h (3.7 g, 53%): mp 200-210 °C; 1H NMR (CDCl3) δ 1.21
(t, J ) 7.0 Hz, 3H), 1.40 (t, J ) 7.0 Hz, 3H), 3.30-4.00 (m,
4H), 3.78 (s, 3H), 3.91 (s, 3H), 3.93 (q, J ) 7.0 Hz, 2H), 4.19
(q, J ) 7.0 Hz, 2H), 4.59 (d, J ) 12.0 Hz, 1H), 4.66 (d, J )
12.0 Hz, 1H), 6.28 (d, J ) 2.0 Hz, 1H), 6.35 (d, J ) 2.0 Hz,
1H), 6.82 (s, 1H), 7.10 (s, 1H), 7.84 (s, 1H); MS m/z 427 (M+).
Anal. (C24H29NO6‚HCl‚1.6H2O) C, H, N, Cl.
2,3-Bis(h yd r oxym et h yl)-6,7-d im et h oxy-1-[3-(N,N-d i-
m eth ylcar bam oyl)-4,5-dim eth oxyph en yl]n aph th alen e (7j).
To a stirred solution of 12 (2.6 g, 4.0 mmol) in THF (30 mL)
was added carbonyldiimidazole (CDI) (771 mg, 4.8 mmol) at
10 °C, and the mixture was stirred at room temperature for
20 min. To the mixture was added dimethylamine (50%
MeOH solution, 2.0 mL, 20 mmol), and the mixture was stirred
at room temperature overnight. The reaction mixture was
concentrated under reduced pressure. To the residue was
added a mixture of brine (20 mL) and CHCl3 (30 mL). The
organic layer was dried over MgSO4 and concentrated under
reduced pressure. Purification of the residue by silica gel
chromatography (hexane:AcOEt ) 1:1) gave 1.7 g of a foam.
To a stirred solution of the foam in THF (20 mL) was added
10% aqueous HCl (10 mL), and the mixture was stirred at
room temperature for 30 min. The reaction mixture was
concentrated under reduced pressure, and the solution of the
residue in CHCl3 (50 mL) was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Purifica-
tion of the residue by silica gel chromatography (hexane:AcOEt
) 1:1) and crystallization from Et2O gave 7j (850 mg, 47%):
mp 162-163 °C; 1H NMR (CDCl3) δ 2.95 (s, 3H), 3.07 (s, 3H),
3.30-3.80 (br s, 2H), 3.70 (s, 3H), 3.83 (s, 3H), 3.93 (s, 3H),
3.96 (s, 3H), 4.55 (s, 2H), 4.82 (s, 2H), 6.73 (s, 1H), 6.82 (s,
1H), 6.96 (s, 1H), 7.10 (s, 1H), 7.65 (s, 1H); MS m/z 455 (M+).
Anal. (C25H29NO7) C, H, N.
1-(3-Ac e t a m id o -4,5-d im e t h o x y p h e n y l)-2,3-b is (h y -
d r oxym eth yl)-6,7-d im eth oxyn a p h th a len e (7i). A solution
of 10i (8.0 g, 15 mmol) in THF (150 mL) and MeOH (75 mL)
was hydrogenated with H2/Pd-C as in the case of 7h and gave
1-(3-amino-4,5-dimethoxyphenyl)-6,7-dimethoxy-2,3-bis(methox-
ycarbonyl)-6,7-dimethoxynaphthalene (6i) as a syrup. To a
solution of 6i, 4-(dimethylamino)pyridine (0.1 g), and triethyl-

2702 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Iwasaki et al.
Meth od D (Sch em e 2). 2,3-Bis(a cetoxym eth yl)-6,7-
d im eth oxy-1-(4-p yr id yl)n a p h th a len e (13a ). To a stirred
solution of 7l (6.5 g, 20 mmol) in CH2Cl2 (50 mL) were added
acetic anhydride (6.12 g, 60 mmol) and triethylamine (6.1 g,
60 mmol) at 10 °C. The mixture was stirred at room temper-
ature overnight. The reaction mixture was washed with water,
dried over MgSO4, and concentrated under reduced pressure.
Crystallization of the residue from AcOEt/hexane gave 13a
(6.7 g, 82%): mp 112-114 °C; 1H NMR (CDCl3) δ 1.99 (s, 3H),
2.10 (s, 3H), 3.67 (s, 3H), 3.98 (s, 3H), 4.98 (s, 2H), 5.30 (s,
2H), 6.49 (s, 1H), 7.14 (s, 1H), 7.20-7.70 (m, 2H), 7.80 (s, 1H),
8.50-8.70 (m, 2H); MS m/z 409 (M+). Anal. (C23H23NO6) C,
H, N.
2,3-Bis(a cet oxym et h yl)-6,7-d im et h oxy-1-(4-p yr id yl)-
n a p h th a len e N-Oxid e (14a ). To a stirred solution of 13a
(61.4 g, 0.15 mol) in CH2Cl2 (500 mL) was added m-CPBA (31.4
g, 0.18 mol) at 10 °C, and the mixture was stirred at room
temperature for 3 h. The reaction mixture was successively
washed with 10% aqueous NaHSO3, saturated aqueous K2-
CO3, and brine, dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from Et2O
gave 14a (60.56 g, 95%): mp 210-212 °C; 1H NMR (CDCl3) δ
2.03 (s, 3H), 2.12 (s, 3H), 3.75 (s, 3H), 4.02 (s, 3H), 5.04 (s,
2H), 5.34 (s, 2H), 6.54 (s, 1H), 7.18 (s, 1H), 7.20-7.40 (m, 2H),
7.85 (s, 1H), 8.30-8.50 (m, 2H); MS m/z 425 (M+). Anal.
(C23H23NO7) C, H, N.
2,3-Bis(a cetoxym eth yl)-6,7-d im eth oxy-1-(2-oxop yr id -4-
yl)n a p h th a len e (15b). A mixture of 14a (62.0 g, 0.146 mol)
and acetic anhydride (300 mL) was heated under reflux
overnight. The acetic anhydride was removed by evaporation.
To a solution of the residue in MeOH (500 mL) was added 28%
aqueous NH3 (20 mL), and the mixture was stirred at room
temperature for 30 min. The reaction mixture was concen-
trated under reduced pressure, and the residue was poured
into a mixture of water (500 mL) and CHCl3 (1 L). The organic
layer was dried over MgSO4 and concentrated under reduced
pressure. Crystallization of the residue from AcOEt gave 15b
(47.2 g, 76%): mp 241-243 °C; 1H NMR (CDCl3) δ 2.04 (s,
3H), 2.12 (s, 3H), 3.79-3.95 (m, 1H), 3.83 (s, 3H), 4.01 (s, 3H),
5.16 (s, 2H), 5.34 (s, 2H), 6.32 (s, 1H), 6.63 (s, 1H), 6.81 (s,
1H), 7.18 (s, 1H), 7.58 (s, 1H), 7.83 (br s, 1H); MS m/z 425
(M+). Anal. (C23H23NO7) C, H, N.
mg, 5 mmol), and the solution was concentrated under reduced
pressure. Purification of the residue by silica gel chromatog-
raphy (CHCl3:MeOH ) 10:1) followed by crystallization from
AcOEt gave 17a (227 mg, 32%): mp 176-178 °C; 1H NMR
(CDCl3) δ 3.60 (s, 3H), 3.73 (s, 3H), 3.95 (s, 3H), 4.23 (br s,
2H), 4.57 (br s, 2H), 4.84 (br s, 2H), 6.10 (m, 1H), 6.41 (br s,
1H), 6.70 (s, 1H), 7.00 (s, 1H), 7.35 (s, 1H), 7.62 (s, 1H); MS
m/z 355 (M+). Anal. (C20H21NO5) C, H, N.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-(1-m eth yl-2-
oxop yr id -6-yl)n a p h th a len e (17i): yield 54%; mp 177-178
1
°C; H NMR (CDCl3) δ 3.13 (s, 3H), 3.75 (s, 3H), 3.97 (s, 3H),
4.50 (br s, 2H), 4.61 (s, 2H), 4.88 (s, 2H), 6.25 (d, J ) 7.0 Hz,
1H), 6.50 (s, 1H), 6.63 (d, J ) 9.0 Hz, 1H), 7.13 (s, 1H), 7.43
(dd, J ) 7.0, 9.0 Hz, 1H), 7.79 (s, 1H); MS m/z 355 (M+). Anal.
(C20H21NO5) C, H, N.
Meth od E (Sch em e 2). 6,7-Dieth oxy-2,3-bis(m eth oxy-
ca r bon yl)-1-(4-p yr id yl)n a p h th a len e N-Oxid e (18f). This
compound was prepared as described for 14: yield 94%; mp
177-178 °C; 1H NMR (CDCl3) δ 1.46 (t, J ) 7.0 Hz, 3H), 1.56
(t, J ) 7.0 Hz, 3H), 3.70 (s, 3H), 3.95 (s, 3H), 3.96 (q, J ) 7.0
Hz, 2H), 4.25 (q, J ) 7.0 Hz, 2H), 6.65 (s, 1H), 7.26 (s, 1H),
7.31 (s, 1H), 7.34 (s, 1H), 8.34 (s, 1H), 8.38 (s, 1H), 8.47 (s,
1H); MS m/z 425 (M+). Anal. (C23H23NO7) C, H, N.
6,7-Dieth oxy-2,3-bis(m eth oxyca r bon yl)-1-(2-oxop yr id -
4-yl)n a p h th a len e (19f). This compound was prepared as
described for 15: yield 60%; mp 234-235 °C dec; 1H NMR
(CDCl3) δ 1.48 (t, J ) 7.0 Hz, 3H), 3.79 (s, 3H), 3.94 (s, 3H),
3.90-4.20 (m, 2H), 4.25 (q, J ) 7.0 Hz, 2H), 6.36 (dd, J ) 1.5,
6.6 Hz, 1H), 6.65 (d, J ) 1.0 Hz, 2H), 6.89 (s, 1H), 7.24 (s,
1H), 7.51 (d, J ) 6.6 Hz, 1H), 8.44 (s, 1H); MS m/z 425 (M+).
Anal. (C22H23NO7) C, H, N.
6,7-Diet h oxy-2,3-b is(m et h oxyca r b on yl)-1-[1-(2-m et h -
oxyeth yl)-2-oxop yr id -4-yl]n a p h th a len e (20f). This com-
pound was prepared as described for 16: yield 55%; mp 103-
1
104 °C dec; H NMR (CDCl3) δ 1.45 (t, J ) 7.0 Hz, 3H), 1.55
(t, J ) 6.9 Hz, 3H), 3.36 (s, 3H), 3.75 (s, 6H), 3.65-3.85 (m,
2H), 3.98-4.33 (m, 6H), 6.17 (dd, J ) 1.9, 6.9 Hz, 1H), 6.59
(d, J ) 1.6 Hz, 1H), 6.91 (s, 1H), 7.22 (s, 1H), 7.44 (d, J ) 7.0
Hz, 1H), 8.42 (s, 1H); MS m/z 483 (M+). Anal. (C26H29NO8)
C, H, N.
6,7-Dieth oxy-2,3-bis(h yd r oxym eth yl)-1-[1-(2-m eth oxy-
eth yl)-2-oxop yr id -4-yl]n a p h th a len e (17f). To a stirred
suspension of 20f (2.56 g, 5.3 mmol) and NaBH4 (1.0 g, 26.5
mmol) in THF (42 mL) was added MeOH (8.5 mL) dropwise
under reflux over 1 h, and the mixture was stirred under reflux
for another 1 h. The reaction mixture was allowed to cooled
to room temperature and concentrated under reduced pres-
sure. The residue was poured into a mixture of 10% aqueous
HCl (50 mL) and CHCl3 (100 mL), and the organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from Et2O
followed by recrystallization from EtOH-H2O gave 17f as
colorless needles (1.97 g, 87%): mp 126-127 °C dec; 1H NMR
(CDCl3) δ 1.42 (t, J ) 7.0 Hz, 3H), 1.54 (t, J ) 7.0 Hz, 3H),
3.37 (s, 3H), 3.75 (t, J ) 5.0 Hz, 2H), 3.79-4.34 (m, 7H), 4.61-
4.71 (m, 2H), 4.78-4.97 (m, 3H), 6.13 (dd, J ) 1.8, 6.8 Hz,
1H), 6.49 (d, J ) 1.8 Hz, 1H), 6.71 (s, 1H), 7.06 (s, 1H), 7.45
(d, J ) 6.8 Hz, 1H), 7.66 (s, 1H); MS m/z 427 (M+). Anal.
(C24H29NO6) C, H, N.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-(2-oxop yr id -
4-yl)n a p h th a len e (15a ). To a solution of 10% NH3 in MeOH
(200 mL) was added 15b (2.88 g, 6.8 mmol), and the mixture
was stirred at room temperature overnight. The resulting
mixture was concentrated under reduced pressure, and crys-
tallization of the residue from Et2O gave 15a (1.5 g, 65%): mp
1
242-244 °C; H NMR (DMSO-d6) δ 3.74 (s, 3H), 3.93 (s, 3H),
4.20-4.60 (m, 2H), 4.52 (s, 2H), 4.86 (s, 2H), 6.16 (dd, J ) 1.5,
7.0 Hz, 1H), 6.42 (d, J ) 1.5 Hz, 1H), 6.80 (s, 1H), 7.21 (s,
1H), 7.43 (d, J ) 7.0 Hz, 1H), 7.82 (s, 1H), 11.43-11.70 (m,
1H); MS m/z 341 (M+). Anal. (C19H19NO5) C, H, N.
2,3-Bis(a cet oxym et h yl)-6,7-d im et h oxy-1-(1-m et h yl-2-
oxop yr id -4-yl)n a p h th a len e (16a ). To a suspension of NaH
(60%, 440 mg, 11 mmol) in DMF (30 mL) was added a solution
of 15b (4.25 g, 10 mmol) in DMF (70 mL) at 10 °C, and the
mixture was stirred at room temperature for 30 min. Methyl
iodide (2.13 g, 15 mmol) was added to the mixture at 10 °C,
and the mixture was stirred at room temperature overnight.
The reaction mixture was concentrated under reduced pres-
sure, and the residue was poured into a mixture of water (50
mL) and AcOEt (100 mL). The organic layer was dried over
MgSO4 and concentrated under reduced pressure. Purification
of the residue by silica gel chromatography (CHCl3:acetone )
10:1) gave 16a as a syrup (2.24 g, 51%): 1H NMR (CDCl3) δ
2.04 (s, 3H), 2.12 (s, 3H), 3.13 (s, 3H), 3.75 (s, 3H), 4.01 (s,
3H), 4.55 (s, 2H), 4.84 (s, 2H), 6.13 (dd, J ) 1.5, 7.0 Hz, 1H),
6.47 (d, J ) 1.5 Hz, 1H), 6.80 (s, 1H), 7.11 (s, 1H), 7.45 (d, J
1-(1-Bu t yl-2-oxop yr id -4-yl)-6,7-d im et h oxy-2,3-b is(h y-
d r oxym eth yl)n a p h th a len e (17b): yield 36%; mp 159-161
°C; 1H NMR (CDCl3) δ 0.99 (t, J ) 7.3 Hz, 3H), 1.33-1.90 (m,
4H), 3.75 (s, 3H), 3.90-4.12 (m, 5H), 3.99 (s, 3H), 4.20-4.43
(m, 2H), 4.58-5.00 (m, 2H), 6.38 (dd, J ) 1.8, 6.8 Hz, 1H),
6.42 (d, J ) 1.8 Hz, 1H), 6.61 (s, 1H),7.03 (s, 1H), 7.35 (d, J )
6.8 Hz, 1H), 7.67 (s, 1H); MS m/z 397 (M+). Anal. (C23H27
-
NO4) C, H, N.
2,3-Bis(h yd r oxym et h yl)-6,7-d im et h oxy-1-[1-(2-m et h -
oxyeth yl)-2-oxop yr id -4-yl]n a p h th a len e (17c): yield 33%;
mp 124-126 °C; 1H NMR (DMSO-d6) δ 3.31 (s, 3H), 3.57-
3.80 (m, 2H), 3.68 (s, 3H), 3.91 (s, 3H), 4.10-4.55 (m, 4H),
4.80-4.93 (m, 3H), 5.29 (t, J ) 5.2 Hz, 2H), 6.17 (d, J ) 6.8
Hz, 1H), 6.39 (s, 1H), 6.76 (s, 1H), 7.38 (s, 1H), 7.74 (d, J )
) 7.0 Hz, 1H), 7.81 (s, 1H); MS m/z 439 (M+). Anal. (C24H25
NO7) C, H, N.
-
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-(1-m eth yl-2-
oxop yr id -4-yl)n a p h th a len e (17a ). To a solution of 16a (878
mg, 2 mmol) in MeOH (30 mL) was added NaOMe (270 mg, 5
mmol), and the mixture was stirred at room temperature for
30 min. To the reaction mixture was added acetic acid (300
6.8 Hz, 1H), 7.90 (s, 1H); MS m/z 399 (M+). Anal. (C22H25
-
NO6) C, H, N.

PDE IV Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2703
1-(1-Bu t yl-2-oxop yr id -4-yl)-7-et h oxy-2,3-b is(h yd r oxy-
m eth yl)-6-m eth oxyn a p h th a len e (17d ): yield 88%; mp 164-
166 °C dec; 1H NMR (CDCl3) δ 0.94 (t, J ) 7.3 Hz, 3H), 1.21-
1.44 (m, 2H), 1.30 (t, J ) 6.9 Hz, 3H), 1.59-1.82 (m, 2H), 3.80-
4.08 (m, 4H), 3.89 (s, 3H), 4.29-4.53 (m, 2H), 4.76-4.89 (m,
3H), 5.27 (t, J ) 10.8 Hz, 1H), 6.15 (dd, J ) 1.8, 6.8 Hz, 1H),
6.34 (d, J ) 1.8 Hz, 1H), 6.72 (s, 1H), 7.36 (s, 1H), 7.78 (d, J
) 6.8 Hz, 1H), 7.87 (s, 1H); MS m/z 411 (M+), 393 (M - 18).
Anal. (C24H29NO5) C, H, N.
7.30 (m, 3H), 7.50-7.80 (m, 2H); MS m/z 380 (M+). Anal.
(C22H20O6) C, H.
6,7-Dim eth oxy-9-(3,4,5-tr im eth oxyp h en yl)n a p h th o[2,3-
c]fu r a n -1(3H)-on e (24a ). This compound was prepared as
described for 24c: yield 64%; mp 228-229 °C (reported14 mp
238-239 °C); 1H NMR (DMSO-d6) δ 3.70 (s, 3H), 3.79 (s, 3H),
3.80 (s, 6H), 3.96 (s, 3H), 6.70 (s, 2H), 7.12 (s, 2H), 7.50 (s,
1H), 7.95 (s, 1H), 8.31 (s, 1H); MS m/z 410 (M+). Anal.
(C22H20O6) C, H.
1-(1-Bu t yl-2-oxop yr id -4-yl)-6,7-d ie t h oxy-2,3-b is(h y-
d r oxym eth yl)n a p h th a len e (17e): yield 88%; mp 149-150
°C dec; 1H NMR (CDCl3) δ 0.94 (t, J ) 7.3 Hz, 3H), 1.21-1.44
(m, 2H), 1.30 (t, J ) 6.9 Hz, 3H), 1.54 (t, J ) 7.0 Hz, 3H),
1.59-1.82 (m, 4H), 3.80-4.08 (m, 4H), 4.29-4.53 (m, 2H),
4.76-4.89 (m, 4H), 5.27 (t, J ) 10.8 Hz, 1H), 6.15 (dd, J )
1.8, 6.8 Hz, 1H), 6.34 (d, J ) 1.8 Hz, 1H), 6.72 (s, 1H), 7.36 (s,
1H), 7.78 (d, J ) 6.8 Hz, 1H), 7.87 (s, 1H); MS m/z 425 (M+).
Anal. (C25H31NO5) C, H, N.
2,3-Bis(h yd r oxym eth yl)-6-m eth oxy-1-(3,4,5-tr im eth ox-
yp h en yl)n a p h th a len e (7c). This compound was prepared
as described for 7gg: yield 60%; mp 124-125 °C; 1H NMR
(DMSO-d6) δ 3.25 (s, 3H), 3.70 (s, 6H), 3.80 (s, 3H), 4.28 (d, J
) 6.0 Hz, 2H), 4.63 (t, J ) 6.0 Hz, 1H), 4.80 (d, J ) 6.0 Hz,
2H), 5.20 (t, J ) 6.0 Hz, 1H), 6.46 (s, 2H), 6.80-7.00 (m, 1H),
7.00-7.30 (m, 2H), 7.76 (s, 1H); MS m/z 384 (M+). Anal.
(C22H24O6) C, H.
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-
6-E t h oxy-2,3-b is(h yd r oxym et h yl)-7-m et h oxy-1-[1-(2-
m eth oxyp h en yl)n a p h th a len e (7a ): yield 79%; mp 124-126
1
m eth oxyeth yl)-2-oxop yr id -4-yl]n a p h th a len e (17g): yield
°C; H NMR (CDCl3) δ 3.30-4.10 (m, 2H), 3.70 (s, 3H), 3.80
1
87%; mp 162-164 °C dec; H NMR (CDCl3) δ 1.40 (t, J ) 7.0
(s, 6H), 3.93 (s, 3H), 3.96 (s, 3H), 4.60 (s, 2H), 4.85 (s, 2H),
6.55 (s, 2H), 6.76 (s, 1H), 7.08 (s, 1H), 7.64 (s, 1H); MS m/z
410 (M+). Anal. (C23H26O7) C, H.
2,3-Bis(h yd r oxym eth yl)-6,7-(m eth ylen ed ioxy)-1-(3,4,5-
tr im eth oxyp h en yl)n a p h th a len e (7b): yield 85%; mp 254-
255 °C dec; 1H NMR (DMSO-d6) δ 3.68 (s, 9H), 4.10-4.40 (m,
2H), 4.50-4.87 (m, 3H), 5.00-5.23 (m, 1H), 5.92 (s, 2H), 6.44
(s, 3H), 7.16 (s, 1H), 7.67 (s, 1H); MS m/z 398 (M+), 380 (M -
18). Anal. (C22H22O7) C, H.
Hz, 3H), 3.29 (s, 3H), 3.60-3.75 (m, 2H), 3.66 (s, 3H), 4.06-
4.24 (m, 4H), 4.30-4.55 (m, 2H), 4.77-4.92 (m, 3H), 5.27 (t, J
) 5.3 Hz, 1H), 6.15 (dd, J ) 1.8, 6.8 Hz, 1H), 6.38 (d, J ) 1.8
Hz, 1H), 6.75 (s, 1H), 7.35 (s, 1H), 7.72 (d, J ) 6.8 Hz, 1H),
7.86 (s, 1H); MS m/z 413 (M+), 355. Anal. (C23H27NO6) C, H,
N.
2,3-Bis(a cetoxym eth yl)-1-(1-bu tyl-2-oxop yr id -4-yl)-6,7-
d im eth oxyn a p h th a len e (17h ). This compound was pre-
pared as described for 16a : yield 77%; mp 134-135 °C; 1H
NMR (CDCl3) δ 1.01 (t, J ) 7.3 Hz, 3H), 1.33-1.56 (m, 2H),
1.73-1.95 (m, 2H), 1.92 (s, 3H), 2.04 (s, 3H), 3.82 (s, 3H), 4.01
(s, 3H), 3.96-4.12 (m, 2H), 5.03 (d, J ) 12.2 Hz, 1H), 5.20 (d,
J ) 12.2 Hz, 1H), 5.33 (s, 2H), 6.13 (dd, J ) 1.8, 6.8 Hz, 1H),
6.57 (d, J ) 1.8 Hz, 1H), 6.79 (s, 1H), 7.16 (s, 1H), 7.38 (d, J
2,3-Bis(h ydr oxym eth yl)-6,7-dim eth oxy-1-(3,4-dim eth ox-
1
yp h en yl)n a p h th a len e (7f): yield 69%; mp 186-187 °C; H
NMR (CDCl3) δ 2.80-3.50 (m, 2H), 3.62 (s, 3H), 3.75 (s, 3H),
3.88 (s, 6H), 4.50 (br s, 2H), 4.80 (br s, 2H), 6.50-7.10 (m, 5H),
7.50 (s, 1H); MS m/z 384 (M+). Anal. (C22H24O6) C, H.
Biologica l Meth od s. Isola tion of P h osp h od iester a se
Isozym es. The method of Reeves et al.17 was modified to
isolate PDE isozymes. Briefly, male guinea pigs were killed
by decapitation, and the hearts and lungs were immediately
excised and rinsed in ice-cold saline. Samples of cardiac
ventricle and lung were frozen on solid CO2 after removal and
stored at -80 °C until use. Tissue samples were minced and
homogenized in 4 volumes of 20 mM Bis-tris/5 mM 2-mercap-
toethanol/50 mM sodium acetate/2 mM benzamidine/3 mM
EDTA/2 mM EGTA/2000 units/mL aprotinin/10 µM leupeptin/
10 µM pepstatin A, pH 6.5, by using a Polytron PT-20.
Phenylmethanesulfonyl fluoride dissolved in dimethyl sulfox-
ide (DMSO) was added to the buffer immediately before
homogenization to give a final concentration of 0.2 mM. The
homogenate was then centrifuged for 30 min at 25000G and
the resulting supernatant applied to a column of DEAE-
Sepharose CL-6B. The PDEs were eluted from the column
by using a continuous 50-1000 mM sodium acetate gradient
(pH 6.5, containing 2-mercaptoethanol). Fractions were col-
lected and assayed for cAMP and cGMP PDE activity. Frac-
tions containing high levels of type I or type III PDE activity
from cardiac ventricle, and type IV or type V PDE activities
from lung were pooled. The combined PDE fractions were
diluted to 70% with ethylene glycol and stored at -20 °C.
Assa y of P h osp h od iestr a se Activity. PDE activity was
determined by a modification of the method of Thompson et
al.18 The reaction mixture contained 40 mM Tris-HCl, pH 8.0,
5 mM MgCl2, and 4 mM 2-mercaptoethanol. In evaluation of
the inhibitor effects of the different agents examined in type
I, type III, type IV, and type V PDE, the protein concentration
in the assay was adjusted to ensure that hydrolysis of
substrate ([3H]cAMP or [3H]cGMP) did not exceed 20% of the
available substrate in the absence of inhibitor. The concentra-
tion of substrate was 1.0 µM for these studies. All agents
examined were dissolved in DMSO. Following addition of the
substrate, the contents were mixed and incubated for 20 min
at 30 °C. Assays were performed in triplicate at three to four
different inhibitor concentrations, the mean of the determina-
tions at each concentration was plotted, and the IC50 values
were determined graphically. IC50 values presented are from
representative experiments.
) 6.8 Hz, 1H), 7.81 (s, 1H); MS m/z 481 (M+). Anal. (C27H31
-
.
NO7 0.3 AcOEt) C, H, N.
Meth od F (Sch em e 3). 3a ,4,9,9a -Tetr a h yd r o-6-m eth -
oxy-9-(3,4,5-tr im eth oxyph en yl)n aph th o[2,3-c]fu r an -1(3H)-
on e (23c). To a stirred solution of lithium diisopropylamide
(LDA) in tetrahydrofuran (THF) [prepared from diisopropyl-
amine (6.34 g, 58.2 mmol) and BuLi (36.4 mL, 58.2 mmol) in
THF (30 mL)] was added a solution of 21 (R1 ) 2-MeO, 10.0 g,
48.5 mmol) in THF (30 mL) at -70 °C under an atmosphere
of nitrogen. The mixture was stirred at the same temperature
for 10 min. To this mixture was added a solution of 3,4,5-
trimethoxybenzaldehyde (9.51 g, 48.5 mmol) in THF (30 mL),
and the resulting mixture was stirred at the same temperature
for 30 min. The reaction mixture was poured into a mixture
of 10% aqueous HCl (100 mL) and AcOEt (200 mL). The
organic layer was separated, washed with water (100 mL),
dried over MgSO4, and concentrated under reduced pressure.
To the solution of the residue in CH2Cl2 (300 mL) was added
trifluoroacetic acid (TFA) (30 mL), and the mixture was stirred
at room temperature overnight. The reaction mixture was
washed with water (100 mL) and saturated aqueous NaHCO3
(100 mL), dried over MgSO4, and concentrated under reduced
pressure. Crystallization of the residue from AcOEt gave 23c
(7.08 g, 38%): mp 195-196 °C; 1H NMR (CDCl3) δ 2.30-2.80
(m, 2H), 2.80-3.20 (m, 2H), 3.72, (s, 6H), 3.80-4.20 (m, 2H),
3.90 (s, 6H), 4.30-4.70 (m, 1H), 6.30 (s, 2H), 6.40-6.80 (m,
3H), MS m/z 384 (M+). Anal. (C22H24O6) C, H.
6-Meth oxy-9-(3,4,5-tr im eth oxyp h en yl)n a p h th o[2,3-c]-
fu r a n -1(3H)-on e (24c). A mixture of 23c (7.68 g, 20 mmol)
and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (10.0 g,
44 mmol) in benzene (100 mL) was heated under reflux for 8
h. After cooling, the mixture was concentrated under reduced
pressure. To the residue was added a mixture of CHCl3 (300
mL) and water (150 mL), and resulting precipitate was
removed by filtration through celite. The organic layer was
washed with saturated aqueous NaHCO3 (100 mL × 3) and
water (100 mL), dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from MeOH
gave 24c (3.88 g, 51%): mp 189-190 °C; 1H NMR (DMSO-d6)
δ 3.75 (s, 6H), 3.88 (s, 6H), 5.30 (s, 2H), 6.45 (s, 1H), 6.90-

2704 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Iwasaki et al.
Karlsson, J .-A. Isozyme-selective Cyclic Nucleotide Phosphodi-
esterase Inhibitors: Biochemistry, Pharmacology and Thera-
peutic Potential in Asthma. Prog. Drug Res. 1993, 40, 9-32. (c)
Christensen, S. B.; Torphy, T. Isozyme-selective Phosphodi-
esterase Inhibitors as Antiasthmatic Agents. Annu. Rep. Med.
Chem. 1994, 29, 185-194.
Hista m in e-In d u ced Br on ch ocon str iction in An esth e-
tized Gu in ea P igs. Male Hartley guinea pigs (J apan SLC,
Inc.) weighing 250-700 g were used. Guinea pigs were
cannulated in the trachea under anesthesia with R-chloralose
(120 mg/kg, iv) and ventilated with 10 mL/kg per stroke of air
at a rate of 60 strokes/min (Harvard 683). Spontaneous
breathing was abolished with gallamine triethiodide (5 mg/
kg, iv). Pulmonary inflation pressure (PIP), an index of
bronchospasm, was measured with a pressure transducer
(Nihonkoden TP-400T) and recorded on a Linearcorder (Graph-
tec WR3701). At the same time, heart rate was monitored by
cardiotachography utilizing the R wave of ECG (standard limb
lead II) as trigger. Bronchoconstriction was induced by
intravenous injection of histamine dihydrochloride (2 µg/kg)
via the lateral saphenous vein at 10 min intervals. Test
compounds were suspended in saline with the aid of Tween
80 and administered intravenously 1 min before histamine
injection.
An tigen -In d u ced Br on ch ocon str iction in An esth e-
tized Gu in ea P igs. Anti-ovalbumin (anti-OA) rabbit anti-
serum was prepared from rabbits (2.0-2.5 kg, J apan KBL)
which had been immunized by injecting an 10 mg of OA
emulsified with Freund’s complete adjuvant intramuscularly
four times weekly. The serum was obtained 7 days after the
last immunization and frozen at <-70 °C until use. The
antibody titers of antiserum thus obtained were >104 times
as determined by the guinea pig 4 h PCA reaction test. Guinea
pigs were sensitized by iv administration of anti-OA rabbit
antiserum (0.5 mL/kg). Twenty to 28 h later, animals were
challenged by antigen (30 µg/kg, iv).
The animals were anesthetized, cannulated, and immobi-
lized in the same way as for histamine challenge except that
they were ventilated at a rate of 15 mL/kg per stroke. The
changes of pulmonary mechanics were measured by the
method of Konzett and Ro¨ssler19 using a differential pressure
transducer (Nihon Kohden, model TP-602) connected to the
tracheal cannula. The increase in the respiratory overflow
volume provoked by antigen challenge was expressed as a
percentage of the maximum overflow volume obtained by
clamping off the trachea. Test compounds were administered
iv 2 min before antigen challenge. The effects of drugs were
expressed as the dose which suppressed antigen-induced
bronchoconstriction by 50% (ED50).
(5) (a) Ashton, M. J .; Cook, D. C.; Fenton, G.; Karlsson, J .-A.;
Palfreyman, M. N.; Raeburn, D.; Ratcliffe, A. J .; Souness, J . E.;
Thurairatnam, S.; Vicker, N. Selective Type IV Phosphodi-
esterase Inhibitors as Antiasthmatic Agents. The Synthesis and
Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides
and Analogs. J . Med. Chem. 1994, 37, 1696-1703. (b) Feldman,
P. L.; Brackeen, M. F.; Cowan, D. J .; Marron, B. E.; Schoenen,
F. J .; Stafford, J . A.; Suh, E. M.; Domanico, P. L.; Rose, D.;
Leesnitzer, M. A.; Brawley, E. S.; Strickland, A. B.; Verghese,
M. W.; Connolly, K. M.; Bateman-Fite, R.; Noel, L. S.; Sekut,
L.; Stimpson, S. A. Phosphodiesterase Type IV Inhibition.
Structure-activity Relationships of 1,3-Disubstituted Pyrrori-
dones. J . Med. Chem. 1995, 38, 1505-1510.
(6) (a) Hood, W. B. Controlled and Uncontrolled Studies of Phos-
phodiesterase III Inhibitors in Contemporary Cardiovascular
Medicine. Am. J . Cardiol. 1989, 63, 46-53A. (b) Heaslip, R. J .;
Buckley, S. K.; Sickels, B. D.; Grimes, D. Bronchial vs Cardio-
vascular Activities of Selective Phosphodiesterase Inhibitors in
the Anesthetized Beta-blocked Dog. J . Pharmcol. Exp. Ther.
1991, 257, 741-747.
(7) Rodrigo, R. Progress in the Chemistry of Isobenzofurans; Ap-
plications to the Synthesis of Natural Products and Polyaromatic
Hydrocarbons. Tetrahedron 1988, 44, 2093-2135.
(8) Ward, R. S. The Synthesis of Lignans and Neolignans. Chem.
Soc. Rev. 1982, 11, 75-125.
(9) Keay, B. A.; Lee, D. K. W.; Rodrigo, R. A New Method for the
Generation of Isobenzofurans: A Simple Entry to Substituted
Naphthalenes. Tetrahedron Lett. 1980, 21, 3663-3666.
(10) Raiford, L. C.; LeRossen, A. L. The Nitration of Brominated
Fluorophenols by the Zincke Method. J . Am. Chem. Soc. 1944,
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(11) Katada, R. Reaction between Pyridine-N-oxide and Acid Anhy-
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(15) It has been reported by Underwood et al. that rolipram is
essentially inactive in the inhibition of histamine-induced bron-
choconstriction in guinea pigs. The apparent discrepancy in the
efficacy of rolipram is probably due to the differences in
experimental conditions. See: Underwood, D. C.; Osborn, R. R.;
Novak, L. B.; Matthews, J . K.; Newsholme, S. J .; Undem, B. J .;
Hand, J . M.; Torphy, T. J . Inhibition of Antigen-Induced Bron-
choconstriction and Eosinophil Infiltration in the Guinea Pig by
the Cyclic AMP-Specific Phosphoesterase Inhibitor, Rolipram.
J . Pharmacol. Exp. Ther. 1993, 266, 306-313.
Ack n ow led gm en t. We express our thanks to Drs.
T. Tosa, K. Matsumoto, and T. Sato of Tanabe Seiyaku
Co., Ltd. for their encouragement and interest.
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