Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: Synthesis and biological activities of a series of 1- pyridylnaphthalene derivatives

Article abstract of DOI:10.1021/jm980314l

The structural requirements for potent and selective PDE4 inhibition were revealed in a 1-pyridylnaphthalene series, and the best compound (3kg, T-2585·HCl) was chosen for further biological evaluation (PDE4 inhibition IC₅₀ = 0.13 nM, selectivi

Full text of DOI:10.1021/jm980314l

1088
J . Med. Chem. 1999, 42, 1088-1099
Novel, P oten t, a n d Selective P h osp h od iester a se-4 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-P yr id yln a p h th a len e
Der iva tives
Tatsuzo Ukita,* Masakatsu Sugahara, Yoshihiro Terakawa, Tooru Kuroda, Kazuteru Wada, Aya Nakata,
Yasushi Ohmachi,† Hideo Kikkawa,† Katsuo Ikezawa,† and Kazuaki Naito†,‡
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 May 18, 1998
The structural requirements for potent and selective PDE4 inhibition were revealed in a
1-pyridylnaphthalene series, and the best compound (3k g, T-2585‚HCl) was chosen for further
biological evaluation (PDE4 inhibition IC50 ) 0.13 nM, selectivity PDE3/4 ratio ) 14 000).
Compound 3k g showed potent antispasmogenic activities (ED50 ) 0.063 mg/kg for reduction
of antigen-induced bronchoconstriction, intravenously; ED50 ) 0.033 mg/kg for reduction of
histamine-induced bronchoconstriction, intraduodenally) in guinea pigs with little cardiovas-
cular effects. Furthermore, 3k g induced significantly weaker emetic effects than RP73401 after
oral administration in ferrets and intravenous administration in dogs (3k g, none of 4 ferrets
vomited at a dose of 10 mg/kg, po and none of 8 dogs vomited at a dose of 0.3 mg/kg, iv; RP73401,
4 of 8 ferrets vomited at a dose of 3 mg/kg, po and 6 of 8 dogs vomited at a dose of 0.3 mg/kg,
iv); that is compatible with the lower affinity for the high-affinity rolipram binding site (3k g,
2.6 nM; RP73401, 0.85 nM). This may imply that 3k g has an improved therapeutic ratio because
of a broad margin between the Ki value of binding affinity and the IC50 value of PDE4 inhibition
(ratio ) 0.050).
In tr od u ction
et al. as a new structural class.6 In connection with our
efforts in search of new naphthalene derivatives with
an improved therapeutic ratio, we now disclose 1-py-
ridylnaphthalene derivatives having potent antispas-
mogenic activities with low emetic and cardiovascular
effects.
Asthma is a chronic inflammatory disease of the
airways, with the most characteristic symptoms being
a variable airway obstruction and hyperresponsiveness.
The development of highly effective drugs would be
beneficial, because the mortality and morbidity due to
asthma is increasing worldwide despite extensive treat-
ment.
Cyclic nucleotide phosphodiesterases (PDEs) play a
key role in the metabolism of purine cyclic nucleotides,
cAMP and cGMP. PDEs have been classified into seven
structurally, biochemically, and pharmacologically dis-
tinct families.1 Among them, cAMP-PDE (PDE4), con-
sisting of four gene products (PDE4A to PDE4D), is
characterized by selective, high-affinity hydrolysis of
cAMP.2 Inhibition of PDE4 results in the increase in
cellular levels of cAMP, which contributes to both the
relaxation of airway smooth muscle and the prevention
of proinflammatory cell activation.3
With a considerable amount of interest and excite-
ment, a large number of selective PDE4 inhibitors have
been reported.4 The majority of them are classified into
three categories: rolipram-related compounds, xanthine
derivatives exemplified by theophilline, and nitraqua-
zone analogues.4a Despite significant efforts to discover
potential antiasthmatic agents based on selective PDE4
inhibition, side effects including emesis and cardiovas-
cular effects have limited their therapeutic potential.5
A series of 1-arylnaphthalene lignans having a selec-
tive PDE4 inhibitory activity was reported by Iwasaki
Ch em istr y
1 (T-440), compound 2, and rolipram-related com-
pounds 4-87 possess both an aromatic moiety and a
carbonyl group (Scheme 1). A topological model of the
PDE4 pharmacophore was reported by Marivet.8 We
envisaged that the three-dimensional space location of
a carbonyl group relative to an aromatic ring is also
desirable for the expression of PDE4 inhibitory activity
in the 1-arylnaphthalene series.
To enhance the potency of PDE4 inhibition and
improve the isozyme selectivity against the other types
of PDEs, we designed compound 3 as a hybrid compound
of 1 (T-440) and compound 2, as shown in Scheme 1.6
In this approach, (1) the naphthalene part (A,B-ring)
was fixed, (2) the heterocyclic compound having a
carbonyl group (D-ring) was introduced, and (3) the
pyridyl group (C-ring) was selected on the basis of the
scope of chemical modification.
Compound 3 was divided into four parts (A-D-rings),
and the modification of each part was carried out in the
following procedures: (i) introduction of heterocyclic
compounds containing a carbonyl group as the D-ring,
(ii) preparation of regioisomers of the pyridyl ring for
the C-ring, (iii) conversion of substituents on the B-ring,
and (iv) transformation of substituents on the A-ring.
The desired compound 3 was obtained by means of the
catalytic Ullmann reaction (method A, Scheme 3) or
† Saitama.
‡ Present position: Licensing Division.
10.1021/jm980314l CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/05/1999

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1089
Sch em e 1
On the other hand, compounds having a phthalazi-
none moiety were effectively synthesized by method B.
Compounds 3eg,gg-k g having alkoxy substituents on
the C-6 and C-7 positions were obtained by reduction
of the corresponding esters 11e,g-k with Red-Al, fol-
lowed successively by the reaction with hydrazine
hydrate and by cyclization with 2-(3-pyridinoyl)benzoic
acid (Scheme 4). 3-Hydroxymethyl and 2-hydroxymethyl
analogues 18lg,m g were prepared by the same reactions
as described above.
Biologica l Resu lts a n d Discu ssion
The compounds reported in this paper were evaluated
by inhibitory activities to the five different forms of
PDEs isolated from guinea pig cardiac ventricle (PDE1,
-2, and -3) and lung (PDE4 and -5) in vitro (Table 1).
Selected compounds on the basis of the PDE4 inhibitory
activity were next evaluated for their potency to inhibit
antigen-induced bronchoconstriction (intravenously) and
histamine-induced bronchoconstriction (intraduodenal-
ly) 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). Third, further selected compounds based on
antispasmogenic activities were evaluated for their
affinity for the high-affinity rolipram binding site
isolated from guinea pig brain and for emetic effects in
ferrets and dogs after oral and intravenous administra-
tion, respectively (Table 3).
P h osp h od iester a se In h ibition . In the transforma-
tion of the D-ring, PDE4 inhibitory activity increased
in the order of monocyclic pyridone 3a a , bicyclic qui-
nolone 3a b, and tricyclic phenanthridinone 3a c (IC50:
3a a 80 nM, 3a b 2.8 nM, 3a c 0.20 nM; Table 1). The
importance of the position of the carbonyl group in the
D-ring is evident from the comparison of the potency of
PDE4 inhibitory activity between 3a b and 3a d . 2-Qui-
nolone derivative 3a b was 14 times more potent than
4-quinolone derivative 3a d (Table 1). The lead com-
pound 3a e having a phthalazinone moiety showed
potent inhibitory activity against PDE4 (IC50 ) 0.68 nM)
and exhibited a moderate selectivity for PDE4 over
PDE3 (selectivity ratio ) 370).
Introduction of the pyridyl group on the 4-position of
the phthalazinone moiety of the lead compound 3a e
afforded three regioisomeric 4-pyridylphthalazinone
derivatives (3a f-a h ). 4-(3-Pyridyl)phthalazinone de-
rivative 3a g showed potent PDE4 inhibitory activity
(IC50 ) 0.63 nM) similar to 4-(2-pyridyl)phthalazinone
and 4-(4-pyridyl)phthalazinone derivatives 3a f,a h (IC50
) 0.55, 0.49 nM) and exhibited virtually the same
selectivity for PDE4 over PDE3 as 3a f,a h (Table 1). It
was difficult to select a compound for further chemical
modification among three regioisomers based on PDE
inhibitions. From antispasmogenic activities and car-
diovascular effects of 3a f-a h discussed in the next
section (Table 2), 3a g was chosen for further chemical
modifications; that is, the 4-(3-pyridyl)phthalazinone
moiety was fixed as the D-ring.
phthalazinone cyclization (method B, Scheme 4) from
the key intermediate 1-(halogenopyridyl)naphthalene
(Scheme 2).
As shown in Scheme 2, hydroxy acetals 10 were
prepared by the usual method from the bromo acetals
9.9 1-(Halogenopyridyl)naphthalenes 11a -e,h -m were
synthesized by the Diels-Alder reaction of isobenzo-
furans generated from 10 with dimethyl fumarate or
methyl acrylate, followed by aromatization with BF3‚
Et2O.10
Compounds 3a a -a h were synthesized by reduction
of the corresponding ester 11a with NaBH4-MeOH,
followed by the Ullmann condensation with heterocyclic
compounds having an -NH- moiety in the presence of
a catalytic amount of CuI (Scheme 3).11 Bis(methoxy-
carbonyl) analogue 13 was obtained from the corre-
sponding 11a by the catalytic Ullmann reaction. Bis-
(acetoxymethyl) analogue 14 was prepared by acetylation
of the corresponding bis(hydroxymethyl) 3a g with acetic
anhydride. Regioisomers of pyridine (C-ring) (15 and 16)
and 3d g having no substituents on the C-6 and C-7
positions of naphthalene were prepared in a similar
manner as described above. Method A is widely ap-
plicable to the synthesis of various compounds contain-
ing an -NH- moiety in the D-ring.
Bis(methoxycarbonyl) derivative 13 and bis(acetoxym-
ethyl) derivative 14 showed remarkably reduced PDE4
inhibitory activities (IC50 ) 150, 190 nM), compared
with 3a g (IC50 ) 0.63 nM). Next, 3-hydroxymethyl

1090 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ukita et al.
Sch em e 2a
a
Reagents and conditions: (a) n-BuLi, R3CHO/THF, -70 °C; (b) (1) dimethyl fumarate or methyl acrylate, AcOH/toluene or xylene,
reflux, (2) BF3‚Et2O/CH3CN, reflux or 25 °C.
derivative 18lg and 2-hydroxymethyl derivative 18m g
were synthesized to identify which hydroxymethyl group
is necessary for the activity. 18lg retained the activity
(IC50 ) 0.70 nM), though 18m g resulted in a significant
loss in activity (IC50 ) 31 nM). From the above results,
it is concluded that the 3-hydroxymethyl group of 3a g
plays an important role in PDE4 inhibitory activity.
Next we paid attention to regioisomers of the C-ring
because of the importance of three-dimensional rela-
tionships between the carbonyl group in the D-ring and
the 3-hydroxymethyl group on the B-ring. 2,5-Disubsti-
tuted pyridine derivative 15, having the naphthyl and
phthalazinyl groups in a para position to each other,
showed a great decrease of activity (IC50 ) 40 nM)
compared with 2,4-disubstituted pyridine derivative
3a g, having the naphthyl and phthalazinyl groups in a
meta position to each other (IC50 ) 0.63 nM). It was
unexpected that a significant drop of activity was
observed in 2,6-disubstituted pyridine derivative 16
(IC50 ) 15 nM). This suggests that the conformation of
3a g is very important to exert the potent activity, and
the three-dimensional locations of the carbonyl group
in the D-ring and the 3-hydroxymethyl group on the
B-ring are properly controlled by both hydrogens on the
3- and 5-positions of the pyridine ring of 3a g.
Finally we investigated the effects of substituents of
the A-ring on PDE4 inhibitory activity. Removal of
alkoxy substituents on the A-ring (3d g) resulted in a
marked loss in activity (IC50 ) 5000 nM), compared with
6,7-dimethoxy compound 3a g (IC50 ) 0.63 nM). Re-
placement of the 6,7-dimethoxy group of 3a g with a
6-benzyloxy-7-methoxy group (3eg), a 6-cyclopentyloxy-
7-methoxy group (3gg), which is a typical group of
rolipram-related compounds, or a 6-methoxy-7-benzy-
loxy group (3h g) led to a significant decrease of PDE4
inhibitory activity. 6-Ethoxy-7-methoxy analogue 3ig
retained PDE4 inhibitory activity (IC50 ) 0.90 nM),
though it exhibited poor selectivity for PDE4 over PDE3
(selectivity ratio ) 38). 6-Methoxy-7-ethoxy analogue
3jg showed 4 times as much potent activity (IC50 ) 0.16
nM) as 3a g, and the ratio of the IC50 value for PDE3 to
PDE4 increased from 460 to 3100. Among lower alkoxy
analogues, 6,7-diethoxy compound 3k g showed the best
inhibitory activity against PDE4 (IC50 ) 0.13 nM) with
markedly improved selectivity against PDE1, -2, -3, and
-5 isoforms; the PDE3 versus PDE4 selectivity is 14 000.
An tisp a sm ogen ic Activity. We selected 10 com-
pounds on the basis of the PDE4 inhibitory potency (IC50
< 3 nM) for the evaluation of their ability to inhibit
antigen-induced bronchoconstriction (iv) and histamine-
induced bronchoconstriction (id) in anesthetized guinea
pigs. RP7340112 was selected as a reference compound
(ED50 ) 0.033 mg/kg for antigen response, iv; 0.20 mg/
kg for histamine response, id). Among 3a f-a h having
equipotent PDE4 inhibitions, 3a g exhibited the best
inhibitory activity on intravenously administered antigen-
induced bronchoconstriction (ED50 (mg/kg): 3a f 0.18,
3a g 0.022, 3a h 0.17) with the least effect on heart rate
(Table 2). 3a b,k g also had excellent antispasmogenic
activities for intravenously administered antigen re-
sponse, with ED50 values of 0.12 and 0.063 mg/kg,
respectively. 3-Hydroxymethyl analogue 18lg showed
a very weak reduction of antigen response (a 33%
reduction at 1 mg/kg, iv), despite the fact that 18lg had
equipotent PDE4 inhibitory activity to 3,4-bis(hydroxym-
ethyl) analogue 3a g (IC50 ) 0.70 nM). To assess the
cardiovascular side effects, the effects of selected com-
pounds on heart rate were simultaneously investigated,
and it was confirmed that 3a b,a g,k g induced little
increase in heart rate at a dose of 0.1 mg/kg when
administered intravenously (0, 1, and 3 beats/min,
respectively). In the histamine-induced bronchoconstric-
tion model, compound 3k g proved to have the most
potent antispasmogenic activity (ED50 ) 0.033 mg/kg,
id) among the selected compounds and greater activity
than RP73401 (ED50 ) 0.20 mg/kg, id). More detailed
information on the antispasmogenic activity of 3k g will
be published elsewhere.

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1091
Sch em e 3a
a
Reagents and conditions: (a) NaBH4/THF-MeOH, reflux; (b) (1) RH or 4-(3-pyridyl)-1(2H)-phthalazinone, CuI, K2CO3/DMF, 120 °C,
(2) 2 N aqueous HCl/CHCl3-MeOH; (c) (1) Ac2O, Et3N/CH2Cl2, (2) 2 N aqueous HCl/CHCl3-MeOH.

1092 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ukita et al.
Sch em e 4a
a
Reagents and conditions: (a) H2, 10% Pd-C/AcOH-dioxane, 45 psi, 25 °C; (b) cyclopentyl bromide, NaH/DMF, 25 °C; (c) Red-Al/
THF, 0 °C; (d) NH2NH2‚H2O, reflux; (e) (1) 2-(3-pyridinoyl)benzoic acid/ethylene glycol, 150 °C, (2) 2 N aqueous HCl/CHCl3-MeOH.
Affin ity for th e High -Affin ity Rolip r a m Bin d in g
Site a n d Em etic Effects. We finally selected three
compounds (3a b,a g,k g) on the basis of antispasmogenic
activity for the evaluation of emetic effects in ferrets
and dogs and affinity for the high-affinity rolipram
binding site. As shown in Table 3, 3a b,a g,k g did not
induce emetic effects at a dose of 10 or 30 mg/kg, po,
though RP73401 clearly caused emesis at a dose of 3
mg/kg, po. 3k g also showed a considerably weaker
emetic effect than RP73401 in dogs when administered
intravenously at a dose of 0.3 mg/kg (3k g, none of 8
tested animals vomited; RP73401, 6 animals of 8 tested
animals vomited).
The affinities for the high-affinity rolipram binding
site of selected compounds (3a b,a g,k g) and RP73401
were investigated and compared with emetic effects
(Table 3). 3a b,a g,k g exhibited comparatively lower
affinities than RP73401 for the high-affinity rolipram
binding site (Ki value (nM): 3a b 6.2, 3a g 3.5, 3k g 2.6,
RP73401 0.85). It is important that 3k g showed the
broadest margin between the Ki value of binding affinity
and the IC50 value of PDE4 inhibition (ratio ) 0.050),

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1093
Ta ble 1. PDE Inhibitory Activities of Pyridylnaphthalene Derivatives
b
PDE inhibition, IC50 (nM)
selectivity
3/4
compd
methoda
1
2
3
4
5
3a a
3a b
3a c
3a d
3a e
3a f
3a g
3a h
13
A
A
A
A
A
A
A
A
A
A
B
B
A
A
A
B
B
B
B
B
B
50000
2000
2000
80
40000
2000
25
120
210
10
370
310
460
200
190
18
120
23
2000
370
330 ( 90
41 ( 4
400
250 ( 80
170 ( 50
290 ( 40
100 ( 10
29000
3500
81 ( 11
700
80000
5600
2.8 ( 0.3
0.20 ( 0.04
40
0.68 ( 0.26
0.55 ( 0.16
0.63 ( 0.04
0.49 ( 0.06
150
190
0.70 ( 0.04
31
40
15
5000
700
9000
5000
4000
2000
2000
20000
20000
9000
4000
4000
14
18lg
18m g
15
200
40000
10000
>100000
>100000
16
3d g
3eg
3gg
3h g
3ig
3jg
50000
>100000
690
10
>140
30
17
23
16000
940
38
3100
14000
>600
>320000
20000
3000
10000 ( 1100
34 ( 1
0.90 ( 0.24
0.16 ( 0.05
0.13 ( 0.016
500 ( 60
0.31 ( 0.017
1000
800
200 ( 5.8
>100000
14000 ( 3800
490 ( 60
3k g (T-2585‚HCl)
(()-rolipram
RP73401
1300 ( 220
>100000
40000
1800 ( 290
>100000
>100000
>300000
>100000
a
b
Method A: Ullmann reaction. Method B: phthalazinone cyclization. Values given ( SEM are the means of three experiments.
Ta ble 2. Bronchial and Cardiovascular Effects of Selected Compounds
antigen-induced bronchoconstriction
histamine-induced bronchoconstriction
dose
(mg/kg, iv)
heart ratec
(∆beats/min)
b
d
compd
n
% reductiona
ED50 (mg/kg)
ED50 (mg/kg, id)
n
3a b
0.03
0.1
1
3
1
3
0.1
1
2
2
2
1
2
2
2
2
2
3
3
3
2
4
4
4
3
3
2
4
2
5
4
4
4
3
2
2
3
4
-11
68
86
90
38
91
25
87
91
-25
40
78
87
34
61
73
15
82
92
23
77
39
69
37
57
84
33
24
56
63
0.12
(0.013-1.13)
3
0
-4
27
18
15
16
11
0.40
(0.12-1.35)
4
3a c
3a e
1.2
(1.09-1.34)
0.24
(0.10-0.58)
3
55
3a f
0.03
0.1
0.3
1
0.01
0.03
0.1
0.1
0.3
1
0.1
0.3
0.1
0.3
0.03
0.1
0.3
1
0.18
(0.022-1.44)
3 ( 2
5 ( 1
7 ( 4
22
1 ( 2
3 ( 2
1 ( 5
12 ( 4
10 ( 4
29
3a g
3a h
0.022
(0.0098-0.050)
1.1
4
(0.44-2.80)
0.17
(0.014-2.08)
3ig
3jg
0.17
(0.073-0.41)
0.18
(0.059-0.37)
0.063
(0.037-0.107)
7 ( 4
18
3 ( 5
7 ( 3
4 ( 1
3 ( 5
2 ( 3
3k g (T-2585‚HCl)
0.033
(0.01-0.11)
3
3
18lg
RP73401
0.01
0.03
0.1
0.033
(0.0090-0.12)
4
0.20
(0.11-0.34)
3 ( 3
2 ( 5
a
Percent inhibition of antigen-induced bronchoconstriction in guinea pigs. b The dose which inhibits antigen-induced bronchoconstriction
in guinea pigs by 50%. ED50 values were determined from the dose-inhibition curve. The values in parentheses are 95% confidence
limits. c Changes in heart rate between basal value and the value observed after administration of test compounds in guinea pigs. Basal
d
values for heart rate were 230-330 beats/min. The dose which inhibits histamine-induced bronchoconstriction in guinea pigs by 50%.
ED50 values were determined from the dose-inhibition curve (at least three doses). The values in parentheses are 95% confidence limits.
which may imply an improved therapeutic ratio among
the PDE4 inhibitors reported so far.4b
PDE4 inhibitors. Among the analogues, compound 3k g
(PDE4 inhibition IC50 ) 0.13 nM, PDE3/4 ratio )
14 000) showed potent antispasmogenic activities (ED50
) 0.063 mg/kg for reduction of antigen-induced bron-
choconstriction, iv; ED50 ) 0.033 mg/kg for reduction of
histamine-induced bronchoconstriction, id) without sig-
Con clu sion
Novel 1-pyridylnaphthalene derivatives were dis-
closed as a new structural class of potent and selective

1094 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ukita et al.
Ta ble 3. Rolipram Binding Affinity, PDE4 Inhibitory Activity, and Emetic Effects of Selected Compounds
emesis (vomiting/tested)
ferret (po)
[3H]rolipram binding,
PDE4 inhibition,
dog (iv)
a
Kia (nM),
IC50 (nM),
ratio
B/A
compd
GPb brain (A) (n ) 4) GPb lung (B) (n ) 3)
0.3
1
3
10 30 100 (mg/kg) 0.1 0.3 1 (mg/kg)
3a b
3a g
6.2 ( 1.2
3.5 ( 0.9
2.6 ( 0.4
0.85 ( 0.09
3.8 ( 1.1
2.8 ( 0.3
0.63 ( 0.04
0.13 ( 0.02
0.31 ( 0.02
500 ( 60
0.45
0.18
0.050
0.36
0/4
0/6 0/4
0/4c 4/4
1/4
3/4
3k g (T-2585‚HCl)
RP73401
(()-rolipram
0/8
3/4
0/4d 1/8 4/8 6/6
0/4 6/8
130
a
b
c
Mean ( SEM. Guinea pig. Cmax and AUC0-4h of 3k g at a threshold dose which did not induce the emetic effect: Cmax ) 18.4
d
ng/mL, AUC0-4h ) 50.0 ng/mL [mean value (n ) 4)]. Cmax and AUC0-4h of RP73401 at a threshold dose which did not induce the emetic
effect: Cmax ) 9.2 ng/mL, AUC0-4h ) 25.5 ng/mL [mean value (n ) 4)].
2,3-Bis(m et h oxyca r b on yl)-1-(2-b r om o-5-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (11b): yield 48%; mp 186-188 °C;
IR (KBr) 1730, 1712, 1251, 1135 cm-1; 1H NMR (CDCl3) δ 3.67
(s, 3H), 3.79 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H), 6.64 (s, 1H),
7.28 (s, 1H), 7.58-7.68 (m, 2H), 8.37-8.42 (m, 1H), 8.51 (s,
1H); EIMS m/z 461/459 (M+, base), 430/428.
nificant changes in heart rate. Compound 3k g-induced
weak emetic effects on both orally administered ferrets
and intravenously administered dogs correlated with
the affinity for the high-affinity rolipram binding site
(binding affinity Ki ) 2.6 nM).
On the basis of the potency, selectivity, and low side
effects, compound 3k g (T-2585‚HCl) was selected for
further evaluation as an antiasthmatic agent.
2,3-Bis(m et h oxyca r b on yl)-1-(2-b r om o-6-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (11c): yield 51%; mp 199-200 °C;
1
IR (KBr) 1727, 1254, 1161 cm-1; H NMR (CDCl3) δ 3.72 (s,
3H), 3.82 (s, 3H), 3.94 (s, 3H), 4.03 (s, 3H), 6.93 (s, 1H), 7.24
(s, 1H), 7.48 (dd, 1H, J ) 7.5, 1.0 Hz), 7.57 (dd, 1H, J ) 7.9,
1.0 Hz), 7.71 (dd, 1H, J ) 7.9, 7.5 Hz), 8.46 (s, 1H); EIMS m/z
461/459 (M+, base), 430/428.
Exp er im en ta l Section
Melting points were determined on a Bu¨chi 535 capillary
melting point apparatus and are uncorrected. Elemental
analyses were performed on a Perkin-Elmer 2400II analyzer.
IR spectra were recorded on a Perkin-Elmer 1640 spectropho-
2,3-Bis(m eth oxyca r bon yl)-1-(2-br om o-4-p yr id yl)n a p h -
th a len e (11d ): yield 43%; mp 162-163 °C; IR (KBr) 1732,
1
1711, 1278, 1136 cm-1; H NMR (CDCl3) δ 3.69 (s, 3H), 3.98
(s, 3H), 7.23-7.32 (m, 1H), 7.40-7.52 (m, 1H), 7.58 (s, 1H),
7.58-7.70 (m, 2H), 8.03 (dd, 1H, J ) 6.0, 2.4 Hz), 8.50 (dd,
1H, J ) 6.0, 0.6 Hz), 8.67 (s, 1H); EIMS m/z 401/399 (M+, base),
370/368.
1
tometer. H NMR spectra were obtained on a Bruker AC-200
(200 MHz) spectrometer with Me4Si as an internal standard.
Mass spectra were obtained on a Hitachi M-2000A double-
focusing mass spectrometer. 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.
Gen er a l P r oced u r e for t h e Syn t h esis of 2,3-Bis-
(m eth oxyca r bon yl)-1-p yr id yln a p h th a len es 11a -e,h -m
(Sch em e 2). Compounds 11a -e,h -m were all prepared by
essentially the same procedure (Scheme 1). The sequence is
illustrated for 11a , followed by analytical data for 11b-e,h -
m .
6-Ben zyloxy-2,3-b is(m et h oxyca r b on yl)-1-(2-ch lor o-4-
p yr id yl)-7-m et h oxyn a p h t h a len e (11e): yield 16%; mp
260-261 °C dec; IR (KBr) 1730, 1715, 1237, 1137 cm-1 1H
;
NMR (DMSO-d6) δ 3.54 (s, 3H), 3.70 (s, 3H), 3.88 (s, 3H), 5.28
(s, 2H), 6.70 (s, 1H), 7.37-7.58 (m, 7H), 7.87 (s, 1H), 8.53-
8.60 (m, 2H); EIMS m/z 493/491 (M+, 48), 402/400, 91 (base).
7-Ben zyloxy-2,3-b is(m et h oxyca r b on yl)-1-(2-ch lor o-4-
p yr id yl)-6-m eth oxyn a p h th a len e (11h ): yield 40%; mp
1
149-153 °C; IR (KBr) 1735, 1721, 1252, 1132 cm-1; H NMR
(CDCl3) δ 3.64 (s, 3H), 3.93 (s, 3H), 4.05 (s, 3H), 5.10 (s, 2H),
6.60 (s, 1H), 7.04 (dd, 1H, J ) 5.0, 1.4 Hz), 7.13-7.42 (m, 7H),
8.41-8.52 (m, 2H); EIMS m/z 493/491 (M+, 8), 402/400, 91
(base).
2,3-Bis(m et h oxyca r b on yl)-1-(2-b r om o-4-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (11a ). To a stirred solution of 9
(R1,R2dOMe) (86.1 g, 0.296 mol) in THF (500 mL) was added
n-BuLi (194 mL, 0.310 mol) 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 2-bromo-
isonicotinaldehyde (55.0 g, 0.296 mol) in THF (100 mL). The
resulting mixture was stirred at the same temperature for 30
min and poured into a mixture of water and AcOEt. The
organic layer was separated, washed with brine, dried over
MgSO4, and concentrated under reduced pressure. A solution
of the residue 10 (R1,R2dOMe), dimethyl fumarate (42.7 g,
0.296 mol), and acetic acid (100 mL) in xylene (200 mL) was
heated under reflux for 2 h. The solvent was removed by
evaporation to give 2,3-bis(methoxycarbonyl)-1-(2-bromo-4-
pyridyl)-6,7-dimethoxy-1,4-epoxy-1,2,3,4-tetrahydronaphtha-
lene as a syrup. This crude product was used in the next step.
A solution of the crude products and BF3‚Et2O (110 mL, 0.894
mol) in CH3CN (200 mL) was heated under reflux for 3 h. The
reaction mixture was allowed to cool to room temperature and
poured into a mixture of saturated aqueous NaHCO3 and
CHCl3. The organic layer was separated, washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
Crystallization of the residue from MeOH gave 11a (81.7 g,
2,3-Bis(m e t h oxyca r b on yl)-1-(2-ch lor o-4-p yr id yl)-6-
eth oxy-7-m eth oxyn a p h th a len e (11i): yield 54%; mp 205-
1
208 °C; IR (KBr) 1723, 1245, 1135 cm-1; H NMR (CDCl3) δ
1.57 (t, 3H, J ) 7.0 Hz), 3.67 (s, 3H), 3.78 (s, 3H), 3.95 (s, 3H),
4.26 (q, 2H, J ) 7.0 Hz), 6.64 (s, 1H), 7.26 (s, 1H), 7.28 (dd,
1H, J ) 5.0, 1.4 Hz), 7.39 (d, 1H, J ) 0.6 Hz), 8.48 (s, 1H),
8.53 (d, 1H, J ) 5.0 Hz); EIMS m/z 431/429 (M+, base), 372/
370.
2,3-Bis(m e t h oxyca r b on yl)-1-(2-ch lor o-4-p yr id yl)-7-
eth oxy-6-m eth oxyn a p h th a len e (11j): yield 58%; mp 196-
1
198 °C; IR (KBr) 1728, 1248, 1130 cm-1; H NMR (CDCl3) δ
1.45 (t, 3H, J ) 7.0 Hz), 3.67 (s, 3H), 3.95 (s, 3H), 3.96 (q, 2H,
J ) 7.0 Hz), 4.03 (s, 3H), 6.63 (s, 1H), 7.21-7.32 (m, 2H), 7.37-
7.42 (m, 1H), 8.49 (s, 1H), 8.52 (dd, 1H, J ) 5.0, 0.5 Hz); EIMS
m/z 431/429 (M+, base), 372/370.
2,3-Bis(m et h oxyca r b on yl)-1-(2-ch lor o-4-p yr id yl)-6,7-
d ieth oxyn a p h th a len e (11k ): yield 56%; mp 154-156 °C; IR
1
(KBr) 1745, 1712, 1249, 1130 cm-1; H NMR (CDCl3) δ 1.44
(t, 3H, J ) 7.0 Hz), 1.55 (t, 3H, J ) 7.0 Hz), 3.67 (s, 3H), 3.94
(s, 3H), 3.95 (q, 2H, J ) 7.0 Hz), 4.23 (q, 2H, J ) 7.0 Hz), 6.63
(s, 1H), 7.24 (s, 1H), 7.27 (dd, 1H, J ) 5.0, 1.4 Hz), 7.39 (s,
1H), 8.46 (s, 1H), 8.52 (d, 1H, J ) 5.0 Hz); EIMS m/z 445/443
(M+, base), 358/356.
60%): mp 192-194 °C; IR (KBr) 1732, 1720, 1248, 1133 cm-1
;
1H NMR (CDCl3) δ 3.68 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 4.04
(s, 3H), 6.65 (s, 1H), 7.27 (s, 1H), 7.31 (dd, 1H, J ) 5.0, 1.4
Hz), 7.55 (s, 1H), 8.50 (s, 1H), 8.51 (d, 1H, J ) 5.0 Hz); EIMS
m/z 461/459 (M+, base), 430/428.
1-(2-Ch lor o-4-p yr id yl)-6,7-d im eth oxy-3-m eth oxyca r bo-
n yln a p h th a len e (11l): yield 2%; mp 203-206 °C; IR (KBr)
1
1706, 1246, 1123 cm-1; H NMR (CDCl3) δ 3.88 (s, 3H), 3.98

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1095
(s, 3H), 4.04 (s, 3H), 7.07 (s, 1H), 7.29 (s, 1H), 7.40 (dd, 1H, J
) 5.0, 1.4 Hz), 7.48- 7.56 (m, 1H), 7.86 (d, 1H, J ) 1.4 Hz),
8.45- 8.58 (m, 2H); EIMS m/z 359/357 (M+, base), 328/326.
1-(2-Ch lor o-4-p yr id yl)-6,7-d im eth oxy-2-m eth oxyca r bo-
n yln a p h th a len e (11m ): yield 53%; mp 141-143 °C; IR (KBr)
(d, 1H, J ) 5.0 Hz); EIMS m/z 418 (M+, 48), 400 (base). Anal.
(C24H22N2O5) C, H, N.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-[2-(2(1H)-qu i-
n olon -1-yl)-4-p yr id yl]n a p h th a len e (3a b): yield 58%; mp
>250 °C; IR (KBr) 3386, 1646 cm-1 1H NMR (DMSO-d6) δ
;
1
1723, 1265, 1118 cm-1; H NMR (CDCl3) δ 3.69 (s, 3H), 3.74
3.69 (s, 3H), 3.89 (s, 3H), 4.30 (dd, 1H, J ) 11.6, 5.5 Hz), 4.53
(dd, 1H, J ) 11.6, 5.5 Hz), 4.87 (d, 2H, J ) 5.5 Hz), 4.92 (t,
1H, J ) 5.5 Hz), 5.31 (t, 1H, J ) 5.5 Hz), 6.60-6.80 (m, 3H),
7.28 (dd, 1H, J ) 7.3, 6.8 Hz), 7.39 (s, 1H), 7.40-7.55 (m, 1H),
7.54 (s, 1H), 7.66 (dd, 1H, J ) 5.0, 1.4 Hz), 7.80 (d, 1H, J )
6.8 Hz), 7.93 (s, 1H), 8.07 (d, 1H, J ) 9.6 Hz), 8.89 (d, 1H, J
) 5.0 Hz); EIMS m/z 468 (M+, 26), 450 (base). Anal.
(C28H24N2O5‚0.25H2O) C, H, N.
(s, 3H), 4.04 (s, 3H), 6.59 (s, 1H), 7.19 (s, 1H), 7.21 (dd, 1H, J
) 5.0, 1.4 Hz), 7.31 (s, 1H), 7.80 (d, 1H, J ) 8.6 Hz), 7.93 (d,
1H, J ) 8.6 Hz), 8.52 (d, 1H, J ) 5.0 Hz); EIMS m/z 359/357
(M+, base), 328/326.
Gen er a l P r oced u r e for Syn th esis of 2,3-Bis(h yd r oxy-
m et h yl)-1-p yr id yl-6,7-d im et h oxyn a p h t h a len es 12a -d .
Meth od A (Sch em e 3). Compounds 12a -d were all prepared
by essentially the same procedure (Scheme 2). The sequence
is illustrated for 12a , followed by analytical data for 12b-d .
2,3-Bis(h yd r oxym e t h yl)-1-(2-b r om o-4-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (12a ). To a stirred suspension of
11a (266 g, 0.578 mol) and NaBH4 (65.5 g, 1.73 mol) in THF
(1.5 L) was added MeOH (350 mL) dropwise under reflux over
1 h, and the mixture was stirred under reflux for another 1 h.
The reaction mixture was allowed to cool to room temperature
and concentrated under reduced pressure. The residue was
poured into a mixture of aqueous NaHCO3 and CHCl3, and
the organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. Crystallization of
the residue from AcOEt gave 12a (168 g, 72%): mp 190-192
2,3-Bis(h yd r oxym e t h yl)-6,7-d im e t h oxy-1-[2-(6(5H )-
ph en an th r idin on -5-yl)-4-pyr idyl]n aph th alen e (3ac): yield
36%; mp 245-248 °C dec; IR (KBr) 3381, 1637 cm-1; 1H NMR
(CDCl3) δ 3.47 (br s, 1H), 3.88 (br s, 1H), 3.89 (s, 3H), 4.00 (s,
3H), 4.65 (s, 2H), 4.92 (s, 2H), 6.78 (dd, 1H, J ) 7.3, 2.2 Hz),
6.84 (s, 1H), 7.13 (s, 1H), 7.25-7.42 (m, 2H), 7.52 (s, 1H), 7.58
(dd, 2H, J ) 5.0, 1.4 Hz), 7.75 (s, 1H), 7.69-7.89 (m, 1H), 8.22-
8.39 (m, 2H), 8.46 (dd, 1H, J ) 8.0, 1.4 Hz), 8.91 (d, 1H, J )
5.0 Hz); EIMS m/z 518 (M+, base). Anal. (C32H26N2O5‚0.75H2O)
C, H, N.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-[2-(4(1H)-qu i-
n olon -1-yl)-4-p yr id yl]n a p h th a len e (3a d ): yield 61%; mp
113-115 °C; IR (KBr) 3379, 1625 cm-1 1H NMR (CDCl3) δ
;
1
°C; IR (KBr) 3440 cm-1; H NMR (DMSO-d6) δ 3.61 (s, 3H),
3.22 (br s, 2H), 3.77 (s, 3H), 4.01 (s, 3H), 4.51, 4.70 (ABq, 2H,
J ) 11.6 Hz), 4.88, 5.05 (ABq, 2H, J ) 11.6 Hz), 6.35 (d, 1H,
J ) 8.0 Hz), 6.60 (s, 1H), 7.17 (s, 1H), 7.29 (dd, 1H, J ) 8.0,
6.2 Hz), 7.39-7.60 (m, 3H), 7.68 (s, 1H), 7.79 (s, 1H), 7.98 (d,
1H, J ) 8.0 Hz), 8.28 (d, 1H, J ) 6.2 Hz), 8.81 (d, 1H, J ) 5.0
Hz); SIMS m/z 469 (M+ + 1, base). Anal. (C28H24N2O5‚1.75H2O)
Calcd: C, 67.26; H, 5.54; N, 5.60. Found: C, 66.90; H, 5.08;
N, 5.26.
3.89 (s, 3H), 4.21 (dd, 1H, J ) 11.7, 5.0 Hz), 4.32 (dd, 1H, J )
11.7, 5.0 Hz), 4.84 (d, 2H, J ) 5.0 Hz), 4.87 (t, 1H, J ) 5.0
Hz), 5.30 (t, 1H, J ) 5.0 Hz), 6.47 (s, 1H), 7.40 (s, 1H), 7.44
(dd, 1H, J ) 5.0, 1.3 Hz), 7.66 (s, 1H), 7.94 (s, 1H), 8.54 (d,
1H, J ) 5.0 Hz); EIMS m/z 405/403 (M+, base), 387/385.
2,3-Bis(h yd r oxym e t h yl)-1-(2-b r om o-5-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (12b): yield 84%; mp 197-199 °C;
1
IR (KBr) 3185 cm-1; H NMR (DMSO-d6) δ 3.61 (s, 3H), 3.89
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-[2-(1(2H)-p h -
th a la zin on -2-yl)-4-p yr id yl]n a p h th a len e (3a e): yield 75%;
(s, 3H), 4.27 (s, 2H), 4.72-5.02 (m, 3H), 5.30 (t, 1H, J ) 5.3
Hz), 6.49 (s, 1H), 7.40 (s, 1H), 7.74 (dd, 1H, J ) 8.1, 1.7 Hz),
7.83 (d, 1H, J ) 8.1 Hz), 7.93 (s, 1H), 8.35 (d, 1H, J ) 1.7 Hz);
EIMS m/z 405/403 (M+, base), 387/385.
mp 201-203 °C; IR (KBr) 3426, 3375, 1672 cm-1 1H NMR
;
(CDCl3) δ 3.49 (br s, 1H), 3.82 (s, 3H) 3.87 (br s, 1H), 4.02 (s,
3H), 4.50-4.79 (m, 2H), 4.79-4.99 (m, 1H), 4.99-5.15 (m, 1H),
6.85 (s, 1H), 7.17 (s, 1H), 7.47 (dd, 1H, J ) 5.0, 1.4 Hz), 7.71-
7.98 (m, 5H), 8.42 (s, 1H), 8.46 (d, 1H, J ) 8.4 Hz), 8.85 (d,
1H, J ) 5.0 Hz); EIMS m/z 469 (M+, 79), 340 (base). Anal.
(C27H23N3O5) C, H, N.
2,3-Bis(h yd r oxym e t h yl)-1-(2-b r om o-6-p yr id yl)-6,7-
d im eth oxyn a p h th a len e (12c): yield 80%; mp 107-108 °C;
1
IR (KBr) 3424 cm-1; H NMR (CDCl3) δ 2.85 (br s, 2H), 3.78
(s, 3H), 4.01 (s, 3H), 4.30-4.70 (m, 2H), 4.79-5.09 (m, 2H),
6.76 (s, 1H), 7.14 (s, 1H), 7.55 (dd, 1H, J ) 7.9, 0.9 Hz), 7.61
(dd, 1H, J ) 7.9, 0.9 Hz), 7.71-7.85 (m, 2H); EIMS m/z 405/
403 (M+, 62), 359/357 (base).
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(2-p yr id yl)-2-yl]-4-p yr id yl}n a p h th a len e Hy-
d r och lor id e (3a f). To a solution of the free base of 3a f (1.0
g, 1.8 mmol) in CHCl3 (50 mL) and MeOH (30 mL) was added
a solution of 2 N aqueous HCl (0.9 mL, 1.8 mmol), and the
mixture was concentrated under reduced pressure. Crystal-
lization of the residual hydrochloride from EtOH gave 3a f (1.0
2,3-Bis(h yd r oxym et h yl)-1-(2-b r om o-4-p yr id yl)n a p h -
th a len e (12d ): yield 94%; mp 108-109 °C; IR (KBr) 3388
cm-1; 1H NMR (CDCl3) δ 3.60 (br s, 2H), 4.53, 4.61 (ABq, 2H,
J ) 12.1 Hz), 4.98 (s, 2H), 7.21-7.38 (m, 2H), 7.33-7.60 (m,
3H), 7.87 (dd, 1H, J ) 7.5, 1.4 Hz), 7.92 (s, 1H), 8.49 (dd, 1H,
J ) 5.0, 0.5 Hz); EIMS m/z 345/343 (M+, 56), 327/325 (base).
Gen er a l P r oced u r e for Ullm a n n Rea ction s. Meth od A
(Sch em e 3). Compounds 3a a -a h ,d g, 13, 15, and 16 were all
prepared by essentially the same procedure (Scheme 3). The
sequence is illustrated for 3a a , followed by analytical data for
3a b-a h ,d g, 13, 15, and 16.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-[2-(2(1H)-p y-
r id on -1-yl)-4-p yr id yl]n a p h th a len e (3a a ). A mixture of 12a
(2.0 g, 4.95 mmol), 2-hydroxypyridine (518 mg, 5.44 mmol),
CuI (95 mg, 0.50 mmol), and K2CO3 (752 mg, 5.44 mmol) in
DMF (20 mL) was heated at 120 °C for 5 h. The reaction
mixture was allowed to cool to room temperature and poured
into a mixture of concentrated NH4OH and AcOEt. The organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. Purification of the residue by
silica gel chromatography (CHCl3:MeOH ) 10:1), followed by
crystallization from AcOEt, gave 3a a (1.3 g, 63%): mp 205-
208 °C; IR (KBr) 3373, 1655 cm-1; 1H NMR (CDCl3) δ 3.80 (br
s, 1H), 3.82 (s, 3H), 4.01 (s, 3H), 4.38 (br s, 1H), 4.45 (d, 1H,
J ) 13.0 Hz), 4.52-4.71 (m, 1H), 4.71-4.90 (m, 1H), 5.04 (d,
1H, J ) 13.0 Hz), 6.37 (ddd, 1H, J ) 6.9, 6.7, 1.2 Hz), 6.61 (d,
1H, J ) 9.2 Hz), 6.84 (s, 1H), 7.16 (s, 1H), 7.31-7.52 (m, 2H),
7.77 (s, 1H), 7.96 (s, 1H), 8.05 (dd, 1H, J ) 7.1, 1.7 Hz), 8.73
1
g, 95%): mp 162-164 °C dec; IR (KBr) 3405, 1683 cm-1; H
NMR (DMSO-d6) δ 3.70 (s, 3H), 3.91 (s, 3H), 4.30, 4.50 (ABq,
2H, J ) 11.7 Hz), 4.47 (br s, 3H), 4.87 (s, 2H), 6.76 (s, 1H),
7.41 (s, 1H), 7.53-7.70 (m, 2H), 7.77 (s, 1H), 7.85-8.15 (m,
5H), 8.30-8.52 (m, 2H), 8.81 (d, 2H, J ) 5.3 Hz); SIMS m/z
547 (M+ + 1 - HCl, 90), 529 (base). Anal. (C32H26N4O5‚HCl‚
0.5H2O) C, H, N.
In the same manner, other pyridylnaphthalene hydrochlo-
rides 3a g,a h ,d g, 13, 15, and 16 were obtained.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h th a len e h y-
d r och lor id e (3a g): yield 87%; mp 212-215 °C dec; IR (KBr)
1
3380, 1677 cm-1; H NMR (DMSO-d6) δ 3.69 (s, 3H), 3.91 (s,
3H), 4.31, 4.49 (ABq, 2H, J ) 11.6 Hz), 4.88 (s, 2H), 5.42 (br
s, 3H), 6.74 (s, 1H), 7.42 (s, 1H), 7.62 (dd, 1H, J ) 5.0, 1.4
Hz), 7.76 (s, 1H), 7.75-7.90 (m, 1H), 7.92-8.19 (m, 4H), 8.41-
8.56 (m, 1H), 8.71 (dd, 1H, J ) 6.5, 1.4 Hz), 8.81 (d, 1H, J )
5.0 Hz), 9.04 (dd, 1H, J ) 5.0, 1.4 Hz), 9.18 (d, 1H, J ) 1.4
Hz); SIMS m/z 547 (M+ + 1 - HCl, 64), 529 (base). Anal.
(C32H26N4O5‚HCl‚2H2O) C, H, N.
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(4-p yr id yl)-2-yl]-4-p yr id yl}n a p h th a len e h y-
d r och lor id e (3a h ): yield 44%; mp 220-223 °C dec; IR (KBr)
1
3408, 1674 cm-1; H NMR (DMSO-d6) δ 3.69 (s, 3H), 3.91 (s,

1096 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ukita et al.
3H), 4.31, 4.48 (ABq, 2H, J ) 11.6 Hz), 4.87 (s, 2H), 5.18 (br
s, 3H), 6.74 (s, 1H), 7.42 (s, 1H), 7.62 (dd, 1H, J ) 5.0, 1.4
Hz), 7.75 (s, 1H), 7.78-7.90 (m, 1H), 7.95 (s, 1H), 7.98-8.18
(m, 4H), 8.41-8.55 (m, 1H), 8.80 (d, 1H, J ) 5.0 Hz), 8.97 (s,
1H), 9.00 (s, 1H); SIMS m/z 547 (M+ + 1 - HCl, base). Anal.
(C32H26N4O5‚HCl‚2.5H2O) Calcd: C, 61.19; H, 5.14; N, 8.92.
Found: C, 61.72; H, 4.84; N, 8.28.
2,3-Bis(h yd r oxym et h yl)-{2-[1(2H )-p h t h a la zin on -4-(3-
p yr id yl)-2-yl]-4-p yr id yl}n a p h t h a len e d ih yd r och lor id e
(3d g): yield 67%; mp 242-243 °C dec; IR (KBr) 3442, 1674
cm-1; 1H NMR (DMSO-d6) δ 4.32-4.56 (m, 2H), 4.95 (br s, 4H),
4.93 (s, 2H), 7.33 (d, 1H, J ) 8.0 Hz), 7.40-7.65 (m, 3H), 7.71-
7.90 (m, 2H), 7.92-8.11 (m, 4H), 8.12 (s, 1H), 8.42-8.55 (m,
1H), 8.67 (d, 1H, J ) 8.0 Hz), 8.79 (d, 1H, J ) 5.0 Hz), 8.95-
9.10 (m, 1H), 9.10-9.28 (m, 1H); SIMS m/z 487 (M+ + 1 -
2HCl, base). Anal. (C30H22N4O3‚2HCl‚3.25H2O) C, H, N.
2,3-Bis(m et h oxyca r bon yl)-6,7-d im et h oxy-1-{2-[1(2H)-
p h t h a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h t h a -
len e h yd r och lor id e (13): yield 17%; mp 184-186 °C; IR
(KBr) 1723, 1675, 1253, 1120 cm-1; 1H NMR (DMSO-d6) δ 3.60
(s, 3H), 3.78 (s, 3H), 3.89 (s, 3H), 3.95 (s, 3H), 4.13 (br s, 1H),
6.93 (s, 1H), 7.50 (dd, 1H, J ) 5.0, 1.5 Hz), 7.65-7.83 (m, 3H),
7.86 (dd, 1H, J ) 7.8, 5.0 Hz), 8.00 (d, 1H, J ) 3.5 Hz), 8.02
(d, 1H, J ) 3.5 Hz), 8.31-8.55 (m, 2H), 8.60 (s, 1H), 8.79 (d,
1H, J ) 5.0 Hz), 8.90 (d, 1H, J ) 3.5 Hz), 9.02 (d, 1H, J ) 1.4
Hz); SIMS m/z 603 (M+ + 1 - HCl, base). Anal. (C34H26N4O7‚
HCl‚2.75H2O) C, H, N.
25 °C for 20 h. The catalyst was filtered off, and the filtrate
was concentrated under reduced pressure. The residue was
dissolved in a mixture of aqueous NaHCO3 and CHCl3, and
the organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. Crystallization of
the residue from EtOH gave 11f (3.4 g, 63%): mp 231-233
°C dec; IR (KBr) 3401, 1726, 1711, 1236, 1128 cm-1; 1H NMR
(DMSO-d6) δ 3.53 (s, 3H), 3.71 (s, 3H), 3.87 (s, 3H), 6.66 (s,
1H), 7.40 (dd, 1H, J ) 5.0, 1.4 Hz), 7.48 (s, 2H), 8.45 (s, 1H),
8.57 (d, 1H, J ) 5.0 Hz), 10.24 (br s, 1H); EIMS m/z 403/401
(M+, base), 372/370.
2,3-Bis(m eth oxyca r bon yl)-1-(2-ch lor o-4-p yr id yl)-6-cy-
clop en tyloxy-7-m eth oxyn a p h th a len e (11g). To a solution
of 11f (890 mg, 2.2 mmol) in DMF (20 mL) was added NaH
(60%, 106 mg, 2.6 mmol) at 0 °C, and the mixture was stirred
at room temperature for 30 min. Cyclopentyl bromide (0.28
mL, 2.6 mmol) was added to the mixture at 0 °C, and the
mixture was stirred overnight at room temperature. The
reaction mixture was concentrated under reduced pressure.
The residue was dissolved in a mixture of aqueous NH4Cl and
CHCl3, and the organic layer was washed with brine, dried
over MgSO4, and concentrated under reduced pressure. Puri-
fication of the residue by silica gel chromatography (CHCl3:
MeOH ) 10:1), followed by crystallization from AcOEt, gave
11g (680 mg, 65%): mp 179-181 °C; IR (KBr) 1732, 1714,
1
1238, 1133 cm-1; H NMR (CDCl3) δ 1.45-2.20 (m, 8H), 3.67
(s, 3H), 3.75 (s, 3H), 3.95 (s, 3H), 4.88-5.00 (m, 1H), 6.62 (s,
1H), 7.24 (s, 1H), 7.27 (dd, 1H, J ) 5.0, 1.4 Hz), 7.38 (s, 1H),
8.47 (s, 1H), 8.52 (d, 1H, J ) 5.0 Hz); EIMS m/z 471/469 (M+,
11), 403/401 (base).
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(3-p yr id yl)-2-yl]-5-p yr id yl}n a p h th a len e h y-
d r och lor id e (15): yield 42%; mp 212-213 °C dec; IR (KBr)
1
3422, 1671 cm-1; H NMR (DMSO-d6) δ 3.61 (s, 3H), 3.91 (s,
Gen er a l P r oced u r e for Syn th esis of 2,3-Bis(h yd r oxym -
et h yl)-1-p yr id yl-6,7-d im et h oxyn a p h t h a len es 12e,g-m .
3H), 4.34 (s, 2H), 4.88 (s, 2H), 5.13 (br s, 3H), 6.58 (s, 1H),
7.43 (s, 1H), 7.82 (dd, 1H, J ) 6.0, 3.0 Hz), 7.55-8.15 (m, 6H),
8.45-8.55 (m, 3H), 8.93 (d, 1H, J ) 4.3 Hz), 9.09 (s, 1H); SIMS
m/z 547 (M+ + 1 - HCl, base). Anal. (C32H26N4O5‚HCl‚
0.75H2O) C, H, N.
Meth od
B (Sch em e 4). Compounds 12e,g-m were all
prepared by essentially the same procedure (Scheme 4). The
sequence is illustrated for 12e, followed by analytical data for
12g-m .
6-Ben zyloxy-2,3-bis(h yd r oxym eth yl)-1-(2-ch lor o-4-p y-
r id yl)-7-m eth oxyn a p h th a len e (12e). To a solution of 11e
(3.0 g, 6.1 mmol) in THF (30 mL) was added Red-Al (34%,
sodium bis(2-methoxyethoxy)aluminum hydride in toluene, 5.0
mL, 17 mmol) in THF (10 mL) dropwise at 0 °C, and the
mixture was stirred at room temperature for 1 h. To the
reaction mixture were added dropwise MeOH (2 mL) and 2 N
aqueous NaOH (20 mL) at 10 °C, and the resulting mixture
was stirred at 40 °C for 30 min. The mixture was poured into
a mixture of H2O and CH2Cl2, and the organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. Crystallization of the residue from EtOH-
Et2O gave 12e (1.6 g, 60%): mp 215-217 °C dec; IR (KBr)
3356 cm-1; 1H NMR (CDCl3) δ 2.85 (br s, 1H), 3.09 (br s, 1H),
3.75 (s, 3H), 4.53 (s, 2H), 4.93 (s, 2H), 5.29 (s, 2H), 6.55 (s,
1H), 7.18 (s, 1H), 7.22-7.58 (m, 7H), 7.70 (s, 1H), 8.55 (dd,
1H, J ) 5.0, 0.5 Hz); SIMS m/z 438/436 (M+ + 1, 9), 420/418,
91 (base).
2,3-Bis(h yd r oxym eth yl)-1-(2-ch lor o-4-p yr id yl)-6-cyclo-
p en t yloxy-7-m et h oxyn a p h t h a len e (12g): yield 61%; mp
200-201 °C; IR (KBr) 3410 cm-1; 1H NMR (DMSO-d6) δ 1.45-
1.92 (m, 6H), 1.85-2.19 (m, 2H), 3.59 (s, 3H), 4.20 (dd, 1H, J
) 11.6, 5.0 Hz), 4.31 (dd, 1H, J ) 11.6, 5.0 Hz), 4.71-4.92 (m,
3H), 4.89-5.07 (m, 1H), 5.28 (t, 1H, J ) 5.5 Hz), 6.47 (s, 1H),
7.36 (s, 1H), 7.40 (dd, 1H, J ) 5.0, 1.4 Hz), 7.52 (s, 1H), 7.92
(s, 1H), 8.57 (d, 1H, J ) 5.0 Hz); EIMS m/z 415/413 (M+, 34),
347/345, 329/327 (base).
2,3-Bis(h yd r oxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(3-p yr id yl)-2-yl]-6-p yr id yl}n a p h th a len e h y-
d r och lor id e (16): yield 26%; mp 225-229 °C dec; IR (KBr)
1
3428, 1672 cm-1; H NMR (DMSO-d6) δ 3.56 (s, 3H), 3.88 (s,
3H), 3.93 (br s, 3H), 4.25, 4.50 (ABq, 2H, J ) 11.6 Hz), 4.85
(s, 2H), 6.77 (s, 1H), 7.36 (s, 1H), 7.68-7.81 (m, 3H), 7.84 (d,
1H, J ) 7.4 Hz), 7.91 (s, 1H), 7.95-8.10 (m, 2H), 8.18-8.31
(m, 2H), 8.45 (dd, 1H, J ) 6.0, 3.0 Hz), 8.84 (dd, 1H, J ) 5.0,
1.4 Hz), 8.93 (d, 1H, J ) 1.4 Hz); SIMS m/z 547 (M+ + 1 -
HCl, 68), 529 (base). Anal. (C32H26N4O5‚HCl‚1.5H2O) C, H, N.
2,3-Bis(a cetoxym eth yl)-6,7-d im eth oxy-1-{2-[1(2H)-p h -
th a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h th a len e Hy-
d r och lor id e (14). To a stirred solution of the free base of 3a g
(1.5 g, 2.7 mmol) in CH2Cl2 (20 mL) were added acetic
anhydride (1.6 mL, 17.0 mmol) and triethylamine (3.1 mL, 22.2
mmol) at 0 °C. The mixture was stirred overnight at room
temperature. The reaction mixture was washed with saturated
aqueous NaHCO3 and brine, dried over MgSO4, and concen-
trated under reduced pressure. Purification of the residue by
silica gel chromatography (CHCl3:MeOH ) 20:1), followed by
crystallization from AcOEt, gave the free base of 14 (1.3 g,
75%). To a solution of the free base of 14 (932 mg, 1.5 mmol)
in CHCl3 (15 mL) and MeOH (5 mL) was added a solution of
2 N aqueous HCl (0.74 mL, 1.5 mmol), and the mixture was
concentrated under reduced pressure. Crystallization of the
residual hydrochloride from EtOH gave 14 (893 mg, 91%): mp
161-163 °C dec; IR (KBr) 1733, 1674 cm-1; 1H NMR (DMSO-
d6) δ 1.94 (s, 3H), 2.10 (s, 3H), 3.68 (s, 3H), 3.92 (s, 3H), 4.92,
5.03 (ABq, 2H, J ) 12.2 Hz), 5.34 (s, 2H), 5.53 (br s, 1H), 6.71
(s, 1H), 7.48 (s, 1H), 7.54 (dd, 1H, J ) 5.0, 1.4 Hz), 7.70-7.89
(m, 2H), 7.89-8.10 (m, 4H), 8.40-8.58 (m, 2H), 8.81 (d, 1H, J
) 5.0 Hz), 8.94 (dd, 1H, J ) 5.0, 1.4 Hz), 9.07 (d, 1H, J ) 1.4
Hz); SIMS m/z 631 (M+ + 1 - HCl, 74), 571 (base). Anal.
(C36H30N4O7‚HCl‚1.5H2O) C, H, N.
7-Ben zyloxy-2,3-bis(h yd r oxym eth yl)-1-(2-ch lor o-4-p y-
r id yl)-6-m eth oxyn a p h th a len e (12h ): yield 59%; mp 146-
148 °C; IR (KBr) 3331 cm-1 1H NMR (CDCl3) δ 2.48 (br s,
;
2H), 4.03 (s, 3H), 4.49 (s, 2H), 4.91 (s, 2H), 5.07 (s, 2H), 6.48
(s, 1H), 7.06 (dd, 1H, J ) 5.0, 1.4 Hz), 7.10-7.48 (m, 7H), 7.74
(s, 1H), 8.46 (d, 1H, J ) 5.0 Hz); EIMS m/z 437/435 (M+, 44),
91 (base).
Meth od B (Sch em e 4). 2,3-Bis(m eth oxyca r bon yl)-1-(2-
ch lor o-4-pyr idyl)-6-h ydr oxy-7-m eth oxyn aph th alen e (11f).
A solution of 11e (6.6 g, 13.4 mmol) in AcOH (1 L) and dioxane
(1 L) was hydrogenated over 10% Pd-C (2.0 g) at 45 psi and
2,3-Bis(h ydr oxym eth yl)-1-(2-ch lor o-4-pyr idyl)-6-eth oxy-
7-m eth oxyn a p h th a len e (12i): yield 59%; mp 150-153 °C;
1
IR (KBr) 3318 cm-1; H NMR (CDCl3) δ 1.54 (t, 3H, J ) 7.0
Hz), 3.14 (br s, 1H), 3.29 (br s, 1H), 3.73 (s, 3H), 4.23 (q, 2H,

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1097
J ) 7.0 Hz), 4.53 (s, 2H), 4.93 (s, 2H), 6.52 (s, 1H), 7.14 (s,
1H), 7.29 (dd, 1H, J ) 5.0, 1.4 Hz), 7.40 (d, 1H, J ) 0.5 Hz),
7.74 (s, 1H), 8.53 (dd, 1H, J ) 5.0, 0.5 Hz); EIMS m/z 375/373
(M+, base), 357/355.
5.26 (t, 1H, J ) 5.0 Hz), 6.52 (dd, 1H, J ) 5.0, 1.4 Hz), 6.62 (s,
1H), 6.67 (s, 1H), 7.33 (s, 1H), 7.51 (s, 1H), 7.84 (s, 1H), 8.11
(d, 1H, J ) 5.0 Hz); EIMS m/z 369 (M
+, 33), 351 (base).
2,3-Bis(h yd r oxym eth yl)-7-eth oxy-1-(2-h yd r a zin o-4-p y-
2,3-Bis(h ydr oxym eth yl)-1-(2-ch lor o-4-pyr idyl)-7-eth oxy-
6-m eth oxyn a p h th a len e (12j): yield 87%; mp 123-126 °C;
r id yl)-6-m eth oxyn a p h th a len e (17j): yield 86%; 197-200
1
°C; IR (KBr) 3311 cm-1; H NMR (DMSO-d6) δ 1.28 (t, 3H, J
1
IR (KBr) 3414 cm-1; H NMR (CDCl3) δ 1.42 (t, 3H, J ) 7.0
) 6.9 Hz), 3.79 (q, 2H, J ) 6.9 Hz), 3.89 (s, 3H), 4.14 (s, 2H),
4.34 (d, 2H, J ) 4.7 Hz), 4.75 (t, 1H, J ) 4.7 Hz), 4.83 (d, 2H,
J ) 5.3 Hz), 5.26 (t, 1H, J ) 5.3 Hz), 6.51 (dd, 1H, J ) 5.1, 1.4
Hz), 6.61 (s, 1H), 6.65 (s, 1H), 7.35 (s, 1H), 7.52 (s, 1H), 7.85
(s, 1H), 8.10 (d, 1H, J ) 5.1 Hz); EIMS m/z 369 (M+, 27), 351
(base).
Hz), 3.24 (br s, 1H), 3.40 (br s, 1H), 3.90 (q, 2H, J ) 7.0 Hz),
3.99 (s, 3H), 4.52 (d, 2H, J ) 4.5 Hz), 4.92 (d, 2H, J ) 4.5 Hz),
6.52 (s, 1H), 7.14 (s, 1H), 7.28 (dd, 1H, J ) 5.0, 1.4 Hz), 7.40
(dd, 1H, J ) 1.4, 0.5 Hz), 7.74 (s, 1H), 8.53 (dd, 1H, J ) 5.0,
0.5 Hz); EIMS m/z 375/373 (M+, base), 357/355.
2,3-Bis(h yd r oxym et h yl)-1-(2-ch lor o-4-p yr id yl)-6,7-d i-
eth oxyn a p h th a len e (12k ): yield 97%; mp 148-150 °C; IR
(KBr) 3268 cm-1; 1H NMR (CDCl3) δ 1.41 (t, 3H, J ) 7.0 Hz),
1.53 (t, 3H, J ) 7.0 Hz), 3.25 (br s, 1H), 3.40 (br s, 1H), 3.90
(q, 2H, J ) 7.0 Hz), 4.21 (q, 2H, J ) 7.0 Hz), 4.52 (s, 2H), 4.91
(s, 2H), 6.52 (s, 1H), 7.13 (s, 1H), 7.28 (dd, 1H, J ) 5.0, 1.4
Hz), 7.39 (d, 1H, J ) 0.5 Hz), 7.71 (s, 1H), 8.52 (dd, 1H, J )
5.0, 0.5 Hz); EIMS m/z 389/387 (M+, base), 371/369.
2,3-Bis(h yd r oxym eth yl)-6,7-d ieth oxy-1-(2-h yd r a zin o-4-
p yr id yl)n a p h th a len e (17k ): yield 62%; mp 225-230 °C dec;
1
IR (KBr) 3277 cm-1; H NMR (DMSO-d6) δ 1.28 (t, 3H, J )
6.9 Hz), 1.40 (t, 3H, J ) 6.9 Hz), 3.81 (q, 2H, J ) 6.9 Hz), 4.14
(s, 2H), 4.16 (q, 2H, J ) 6.9 Hz), 4.34 (d, 2H, J ) 4.6 Hz), 4.74
(t, 1H, J ) 4.6 Hz), 4.82 (d, 2H, J ) 5.3 Hz), 5.25 (t, 1H, J )
5.3 Hz), 6.51 (d, 1H, J ) 5.0 Hz), 6.61 (s, 1H), 6.66 (s, 1H),
7.34 (s, 1H), 7.52 (s, 1H), 7.83 (s, 1H), 8.10 (d, 1H, J ) 5.0
Hz); EIMS m/z 383 (M+, 26), 365 (base).
1-(2-Ch lor o-4-p yr id yl)-6,7-d im eth oxy-3-h yd r oxym eth -
yln a p h th a len e (12l): yield 24%; mp 115-118 °C; IR (KBr)
6,7-Dim et h oxy-1-(2-h yd r a zin o-4-p yr id yl)-3-h yd r oxy-
m eth yln a p h th a len e (17l): yield 69%; mp 139-144 °C; IR
(KBr) 3329 cm-1; 1H NMR (CDCl3) δ 3.73 (s, 3H), 3.90 (s, 3H),
4.18 (s, 2H), 4.64 (d, 2H, J ) 5.6 Hz), 5.28 (t, 1H, J ) 5.6 Hz),
6.69 (dd, 1H, J ) 5.0, 1.4 Hz), 6.83 (s, 1H), 7.21 (s, 1H), 7.23
(d, 1H, J ) 1.4 Hz), 7.38 (s, 1H), 7.52 (s, 1H), 7.72 (s, 1H),
8.10 (d, 1H, J ) 5.0 Hz); SIMS m/z 326 (M+ + 1, base).
6,7-Dim et h oxy-1-(2-h yd r a zin o-4-p yr id yl)-2-h yd r oxy-
m eth yln a p h th a len e (17m ): yield 96%; mp 84-88 °C; IR
(KBr) 3346 cm-1; 1H NMR (CDCl3) δ 3.75 (s, 3H), 4.00 (s, 3H),
4.52 (s, 2H), 6.00 (br s, 1H), 6.65 (dd, 1H, J ) 5.0, 1.4 Hz),
6.69 (s, 1H), 6.72 (s, 1H), 7.14 (s, 1H), 7.53 (d, 1H, J ) 8.4
Hz), 7.74 (d, 1H, J ) 8.4 Hz), 8.21 (d, 1H, J ) 5.0 Hz); EIMS
m/z 325 (M+, base).
3422 cm-1 1H NMR (CDCl3) δ 1.93 (br s, 1H), 3.86 (s, 3H),
;
4.02 (s, 3H), 4.86 (s, 2H), 7.05 (s, 1H), 7.19 (s, 1H), 7.28 (d,
1H, J ) 1.4 Hz), 7.40 (dd, 1H, J ) 5.0, 1.4 Hz), 7.51 (s, 1H),
7.76 (s, 1H), 8.50 (d, 1H, J ) 5.0 Hz); EIMS m/z 331/329 (M+,
base), 302/300.
1-(2-Ch lor o-4-p yr id yl)-6,7-d im eth oxy-2-h yd r oxym eth -
yln a p h th a len e (12m ): yield 83%; mp 132-135 °C; IR (KBr)
1
3373 cm-1; H NMR (CDCl3) δ 1.64 (t, 1H, J ) 5.5 Hz), 3.75
(s, 3H), 4.02 (s, 3H), 4.51 (d, 2H, J ) 5.5 Hz), 6.56 (s, 1H),
7.18 (s, 1H), 7.20-7.32 (m, 1H), 7.38 (s, 1H), 7.55 (d, 1H, J )
8.4 Hz), 7.80 (d, 1H, J ) 8.4 Hz), 8.55 (dd, 1H, J ) 5.0, 0.6
Hz); EIMS m/z 331/329 (M+, base), 302/300.
Gen er a l P r oced u r e for Syn th esis of Hyd r a zin op y-
r id yln a p h th a len es 17e,g-m . Meth od B (Sch em e 4). Com-
pounds 17e,g-m were all prepared by essentially the same
procedure (Scheme 4). The sequence is illustrated for 17e,
followed by analytical data for 17g-m .
Gen er a l P r oced u r e for Syn th esis of P h th a la zin op y-
r id yln a p h th a len es 3eg,gg-k g a n d 18lg,m g. Meth od B
(Sch em e 4). Compounds 3eg,gg-k g and 18lg,m g were all
prepared by essentially the same procedure (Scheme 4). The
sequence is illustrated for 3eg, followed by analytical data for
3gg-k g and 18lg,m g.
6-Ben zyloxy-2,3-bis(h yd r oxym eth yl)-1-(2-h yd r a zin o-4-
p yr id yl)-7-m eth oxyn a p h th a len e (17e). A mixture of 12e
(1.6 g, 3.6 mmol) and NH2NH2‚H2O (20 mL) was heated under
reflux for 2 h. The reaction mixture was allowed to cooled to
room temperature and poured into water. The precipitate was
collected by filtration and washed with water and successive
EtOH to give 17e (1.4 g, 88%): mp 155-157 °C dec; IR (KBr)
3324 cm-1; 1H NMR (DMSO-d6) δ 3.61 (s, 3H), 4.15 (br s, 2H),
4.34 (d, 2H, J ) 4.3 Hz), 4.76 (t, 1H, J ) 5.1 Hz), 4.83 (d, 2H,
J ) 5.1 Hz), 5.23 (s, 2H), 5.27 (t, 1H, J ) 5.1 Hz), 6.52 (dd,
1H, J ) 5.0, 1.4 Hz), 6.62 (s, 1H), 6.69 (s, 1H), 7.28-7.52 (m,
7H), 7.83 (s, 1H), 8.11 (d, 1H, J ) 5.0 Hz); SIMS m/z 432 (M+
+ 1, 22), 91 (base).
2,3-Bis(h ydr oxym eth yl)-6-cyclopen tyloxy-1-(2-h ydr azi-
n o-4-p yr id yl)-7-m eth oxyn a p h th a len e (17g): yield 99%; mp
127-130 °C; IR (KBr) 3312 cm-1; 1H NMR (DMSO-d6) δ 1.48-
1.90 (m, 6H), 1.85-2.21 (m, 2H), 3.58 (s, 3H), 4.14 (s, 2H), 4.34
(d, 2H, J ) 5.0 Hz), 4.75 (t, 1H, J ) 5.0 Hz), 4.83 (d, 2H, J )
5.0 Hz), 4.85-5.08 (m, 1H), 5.26 (t, 1H, J ) 5.0 Hz), 6.52 (d,
1H, J ) 5.1 Hz), 6.62 (s, 1H), 6.66 (s, 1H), 7.32 (s, 1H), 7.52 (s,
1H), 7.84 (s, 1H), 8.11 (d, 1H, J ) 5.1 Hz); EIMS m/z 409 (M+,
33), 293 (base).
6-Ben zyloxy-2,3-b is(h yd r oxym et h yl)-7-m et h oxy-1-{2-
[1(2H )-p h t h a la zin o n -4-(3-p y r id y l)-2-y l]-4-p y r id y l}-
n a p h th a len e Dih yd r och lor id e (3eg). A mixture of 17e (1.3
g, 3.0 mmol) and 2-(3-pyridinoyl)benzoic acid (710 mg, 3.1
mmol) in ethylene glycol (10 mL) was heated at 120 °C for 4
h. The reaction mixture was allowed to cool to room temper-
ature and poured into water. The precipitate was collected by
filtration and washed with water and MeOH successively to
give the free base of 3eg (1.0 g, 55%). To a solution of the free
base of 3eg (250 mg, 0.4 mmol) in CHCl3 (3 mL) and MeOH
(1 mL) was added a solution of 2 N aqueous HCl (0.4 mL, 0.8
mmol), and the mixture was concentrated under reduced
pressure. Crystallization of the residual dihydrochloride from
EtOH gave 3eg (144 mg, 55%): mp 219-221 °C dec; IR (KBr)
1
3426, 1629 cm-1; H NMR (DMSO-d6) δ 3.69 (s, 3H), 4.13 (br
s, 4H), 4.29, 4.48 (ABq, 2H, J ) 11.7 Hz), 4.86 (s, 2H), 5.25 (s,
2H), 6.76 (s, 1H), 7.29-7.69 (m, 7H), 7.69-7.88 (m, 2H), 7.87-
8.12 (m, 4H), 8.40-8.59 (m, 2H), 8.80 (d, 1H, J ) 5.0 Hz), 8.94
(d, 1H, J ) 4.3 Hz), 9.08 (s, 1H); SIMS m/z 623 (M+ + 1 -
2HCl, 18), 91 (base). Anal. (C38H30N4O5‚2HCl‚2.5H2O) C, H,
N.
7-Ben zyloxy-2,3-bis(h yd r oxym eth yl)-1-(2-h yd r a zin o-4-
p yr id yl)-6-m eth oxyn a p h th a len e (17h ): yield 83%; mp
1
199-202 °C; IR (KBr) 3352 cm-1; H NMR (DMSO-d6) δ 3.89
2,3-Bis(h yd r oxym eth yl)-6-cyclop en tyloxy-7-m eth oxy-
1-{2-[1(2H )-p h t h a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}-
n a p h th a len e h yd r och lor id e (3gg): yield 73%; mp 215-217
°C dec; IR (KBr) 3422, 1674 cm-1; 1H NMR (DMSO-d6) δ 1.51-
1.90 (m, 6H), 1.89-2.21 (m, 2H), 3.66 (s, 3H), 4.05 (br s, 3H),
4.29, 4.48 (ABq, 2H, J ) 11.7 Hz), 4.86 (s, 2H), 4.88-5.07 (m,
1H), 6.73 (s, 1H), 7.38 (s, 1H), 7.60 (dd, 1H, J ) 5.0, 1.4 Hz),
7.73 (s, 1H), 7.75-7.88 (m, 1H), 7.88-8.12 (m, 4H), 8.42-8.60
(m, 2H), 8.79 (d, 1H, J ) 5.0 Hz), 8.94 (dd, 1H, J ) 5.0, 1.4
Hz), 9.08 (d, 1H, J ) 1.4 Hz); SIMS m/z 601 (M+ + 1 - HCl,
17), 61 (base). Anal. (C36H32N4O5‚HCl‚2H2O) C, H, N.
(s, 3H), 4.13 (br s, 2H), 4.34 (s, 2H), 4.78 (br s, 1H), 4.83 (s,
2H), 4.91 (s, 2H), 5.27 (br s, 1H), 6.41 (d, 1H, J ) 5.1 Hz), 6.56
(s, 1H), 6.75 (s, 1H), 7.20-7.45 (m, 6H), 7.54 (s, 1H), 7.85 (s,
1H), 8.10 (d, 1H, J ) 5.1 Hz); SIMS m/z 432 (M+ + 1, 74), 91
(base).
2,3-Bis(h yd r oxym eth yl)-6-eth oxy-1-(2-h yd r a zin o-4-p y-
r id yl)-7-m eth oxyn a p h th a len e (17i): yield 89%; mp 130-
134 °C; IR (KBr) 3350 cm-1 1H NMR (DMSO-d6) δ 1.39 (t,
;
3H, J ) 6.9 Hz), 3.60 (s, 3H), 4.05-4.28 (m, 4H), 4.35 (d, 2H,
J ) 5.0 Hz), 4.75 (t, 1H, J ) 5.0 Hz), 4.83 (t, 2H, J ) 5.0 Hz),

1098 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6
Ukita et al.
7-Ben zyloxy-2,3-b is(h yd r oxym et h yl)-6-m et h oxy-1-{2-
[1(2H )-p h t h a la zin o n -4-(3-p y r id y l)-2-y l]-4-p y r id y l}-
n a p h th a len e h yd r och lor id e (3h g): yield 71%; mp 205-208
°C dec; IR (KBr) 3414, 1672 cm-1; 1H NMR (DMSO-d6) δ 3.91
(s, 3H), 4.02 (br s, 3H), 4.29, 4.47 (ABq, 2H, J ) 11.7 Hz), 4.86
(s, 2H), 4.96, 5.14 (ABq, 2H, J ) 11.7 Hz), 6.83 (s, 1H), 7.19-
7.40 (m, 5H), 7.42 (s, 1H), 7.48 (dd, 1H, J ) 5.0, 1.4 Hz), 7.75
(s, 1H), 7.72-8.13 (m, 5H), 8.41-8.53 (m, 2H), 8.79 (d, 1H, J
) 5.0 Hz), 8.92 (dd, 1H, J ) 5.0, 1.4 Hz), 9.08 (d, 1H, J ) 1.4
Hz); SIMS m/z 623 (M+ + 1 - HCl, 60), 91 (base). Anal.
(C38H30N4O5‚HCl‚1.75H2O) C, H, N.
mM EDTA/5 mM 2-mercaptoethanol/2 mM benzamidine/10
µM leupeptin/10 µM pepstatin A, pH 6.5, by using a Polytron
PT-20. Phenylmethanesulfonyl fluoride (PMSF) dissolved in
dimethyl sulfoxide (DMSO) was added to the buffer im-
mediately before homogenization to give a final concentration
of 0.1 mM. The homogenate was then centrifuged for 45 min
at 35000g and the resulting supernatant applied to a column
of Resource-Q. The PDEs were eluted from the column by
using a continuous 50-1000 mM sodium acetate gradient (pH
6.5, containing 20 mM Bis-Tris, 2 mM EDTA, 5 mM 2-mer-
captoethanol, 2 mM benzamidine, 0.1 mM PMSF). Fractions
were collected and assayed for cAMP and cGMP PDE activity.
Fractions containing high levels of type 1, 2, or 3 PDE activity
from cardiac ventricle and type 4 or 5 PDE activity from lung
were pooled. The combined PDE fractions were diluted to 77%
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.14 The reaction mixture contained 50 mM Tris-HCl, pH 8.0,
5 mM MgCl2, 4 mM 2-mercaptoethanol. In evaluation of the
inhibitor effects of the different agents examined in types 1-5
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 an inhibitor. The concentration 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 30 min at 30 °C. Assays were performed in
triplicate at three to four different inhibitor concentrations,
the mean of the determinations at each concentration was
plotted, and the IC50 values were determined graphically. IC50
values presented are from representative experiments.
2,3-Bis(h ydr oxym eth yl)-6-eth oxy-7-m eth oxy-1-{2-[1(2H)-
p h t h a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h t h a -
len e h yd r och lor id e (3ig): yield 55%; mp 204-207 °C dec;
1
IR (KBr) 3416, 1672 cm-1; H NMR (DMSO-d6) δ 1.40 (t, 3H,
J ) 6.9 Hz), 3.68 (s, 3H), 4.17 (q, 2H, J ) 6.9 Hz), 4.30, 4.48
(ABq, 2H, J ) 11.7 Hz), 4.86 (s, 2H), 5.13 (br s, 3H), 6.73 (s,
1H), 7.40 (s, 1H), 7.61 (dd, 1H, J ) 5.0, 1.4 Hz), 7.75 (s, 1H),
7.81 (dd, 1H, J ) 6.0, 3.0 Hz), 7.93 (s, 1H), 7.95-8.21 (m, 3H),
8.47 (dd, 1H, J ) 6.0, 3.0 Hz), 8.60-8.73 (m, 1H), 8.80 (d, 1H,
J ) 5.0 Hz), 9.02 (dd, 1H, J ) 5.0, 1.4 Hz), 9.16 (d, 1H, J )
1.4 Hz); SIMS m/z 561 (M+ + 1 - HCl, base). Anal. (C33H29N4O5‚
HCl‚2H2O) C, H, N.
2,3-Bis(h ydr oxym eth yl)-7-eth oxy-6-m eth oxy-1-{2-[1(2H)-
p h t h a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h t h a -
len e h yd r och lor id e (3jg): yield 44%; mp 211-215 °C dec;
1
IR (KBr) 3389, 1677 cm-1; H NMR (DMSO-d6) δ 1.26 (t, 3H,
J ) 6.9 Hz), 3.70-4.10 (m, 2H), 3.90 (s, 3H), 4.31, 4.47 (ABq,
2H, J ) 11.7 Hz), 4.87 (s, 2H), 5.40 (br s, 3H), 6.70 (s, 1H),
7.41 (s, 1H), 7.59 (d, 1H, J ) 5.0 Hz), 7.75 (s, 1H), 7.80 (dd,
1H, J ) 6.0, 3.0 Hz), 7.94 (s, 1H), 7.95-8.18 (m, 3H), 8.47 (dd,
1H, J ) 6.0, 3.0 Hz), 8.65 (d, 1H, J ) 8.0 Hz), 8.79 (d, 1H, J
) 5.0 Hz), 9.00 (d, 1H, J ) 5.0 Hz), 9.14 (s, 1H); SIMS m/z
561 (M+ + 1 - HCl, 82), 543 (base). Anal. (C33H28N4O5‚HCl‚
0.75H2O) C, H, N.
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/stroke of air at
a rate of 60 strokes/min (Harvard model 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 intra-
venous 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.
2,3-Bis(h yd r oxym et h yl)-6,7-d iet h oxy-1-{2-[1(2H )-p h -
th a la zin on -4-(3-p yr id yl)-2-yl]-4-p yr id yl}n a p h th a len e h y-
d r och lor id e (3k g): yield 80%; mp 207-211 °C dec; IR (KBr)
1
3426, 1680 cm-1; H NMR (DMSO-d6) δ 1.26 (t, 3H, J ) 6.9
Hz), 1.40 (t, 3H, J ) 6.9 Hz), 3.75-4.08 (m, 2H), 4.18 (q, 2H,
J ) 6.9 Hz), 4.31, 4.47 (ABq, 2H, J ) 11.6 Hz), 4.86 (s, 2H),
6.02 (br s, 3H), 6.70 (s, 1H), 7.40 (s, 1H), 7.59 (dd, 1H, J ) 5.0,
1.4 Hz), 7.75 (s, 1H), 7.80 (dd, 1H, J ) 6.0, 3.0 Hz), 7.93 (s,
1H), 7.93-8.13 (m, 3H), 8.47 (dd, 1H, J ) 6.0, 3.0 Hz), 8.56-
8.70 (m, 1H), 8.79 (d, 1H, J ) 5.0 Hz), 9.00 (dd, 1H, J ) 5.0,
1.4 Hz), 9.14 (d, 1H, J ) 1.4 Hz); SIMS m/z 575 (M+ + 1 -
HCl, 45), 557 (base). Anal. (C34H30N4O5‚HCl‚2H2O) C, H, N.
6,7-Dim eth oxy-3-h ydr oxym eth yl-1-{2-[1(2H)-ph th alazi-
n on -4-(3-pyr idyl)-2-yl]-4-pyr idyl}n aph th alen e h ydr och lo-
r id e (18lg): yield 63%; mp >250 °C; IR (KBr) 3419, 1679 cm-1
;
1H NMR (DMSO-d6) δ 3.81 (s, 3H), 3.91 (s, 3H), 4.00 (br s,
2H), 4.68 (s, 2H), 7.33 (s, 1H), 7.38 (d, 1H, J ) 1.4 Hz), 7.43
(s, 1H), 7.65-7.93 (m, 4H), 7.93-8.18 (m, 3H), 8.32-8.47 (m,
1H), 8.50 (dd, 1H, J ) 6.0, 3.0 Hz), 8.78 (d, 1H, J ) 5.0 Hz),
8.90 (dd, 1H, J ) 5.0, 1.4 Hz), 9.01 (d, 1H, J ) 1.4 Hz); EIMS
m/z 516 (M+ - HCl, base). Anal. (C31H24N4O4‚HCl‚1.5H2O) C,
H, N.
An tigen -In d u ced Br on ch ocon str iction in An esth e-
tized Gu in ea P igs. Anti-ovalbumin (OA) rabbit antiserum
was prepared from rabbits (2.0-2.5 kg; J apan KBL) which had
been immunized by injecting 10 mg of OA emulsified with
Freund’s complete adjuvant intramuscularly 4 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 >10 000 times as determined
by the guinea pig 4-h PCA reaction test. Male Hartley guinea
pigs (J apan SLC, Inc.) weighing 250-700 g were used. Guinea
pigs were sensitized by iv administration of anti-OA rabbit
antiserum (0.5 mL/kg); 20-28 h later, animals were challenged
by antigen (30 µg/kg, iv). Guinea pigs were cannulated in the
trachea under anesthesia with R-chloralose (120 mg/kg, iv) and
ventilated with 10 mL/kg/stroke of air at a rate of 60 strokes/
min (Harvard model 683). Spontaneous breathing was abol-
ished with gallamine triethiodide (5 mg/kg, iv). The changes
of pulmonary mechanics were measured by the method of
Konzett and Ro¨ssler15 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
6,7-Dim eth oxy-2-h ydr oxym eth yl-1-{2-[1(2H)-ph th alazi-
n on -4-(3-pyr idyl)-2-yl]-4-pyr idyl}n aph th alen e h ydr och lo-
r id e (18m g): yield 50%; mp 200-213 °C dec; IR (KBr) 3412,
1
1682 cm-1; H NMR (DMSO-d6) δ 3.69 (s, 3H), 3.90 (s, 3H),
4.40 (br s, 2H), 4.41 (s, 2H), 6.79 (s, 1H), 7.41 (s, 1H), 7.52-
7.70 (m, 2H), 7.70-8.18 (m, 6H), 8.40-8.58 (m, 2H), 8.79 (d,
1H, J ) 5.0 Hz), 8.93 (dd, 1H, J ) 5.0, 1.4 Hz), 9.06 (d, 1H, J
) 1.4 Hz); SIMS m/z 517 (M+ + 1 - HCl, base). Anal.
(C31H24N4O4‚HCl‚1.25H2O) C, H, N.
Biologica l Meth od s. Isola tion of P h osp h od iester a se
Isozym es. The method of Reeves et al.13 was modified to
isolate PDE isozymes. Briefly, male guinea pigs were killed
with pentobarbital, and the hearts and lungs were im-
mediately 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 3 volumes of 20 mM Bis-Tris/2

Selective PDE4 Inhibitors as Antiasthmatic Agents
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 6 1099
Contemporary Cardiovascular Medicine. Am. J . Cardiol. 1989,
63, 46-53A. (d) Heaslip, R. J .; Buckley, S. K.; Sickels, B. D.;
Grimes, D. Bronchial vs Cardiovascular Activities of Selective
Phosphodiesterase Inhibitors in the Anesthetized Beta-blocked
Dog. J . Pharmacol. Exp. Ther. 1991, 257, 741-747.
antigen challenge. The effects of drugs are expressed as the
dose which suppressed antigen-induced bronchoconstriction by
50% (ED50).
Rolip r a m Bin d in g Stu d ies. Male Hartley guinea pig
brains were homogenized in 10 volumes of ice-cold 20 mM Tris
HCl (pH 7.4) buffer containing 2 mM MgCl2 and 0.1 mM DTT
in a Polytron PT-10 homogenizer (Kinematica). The resulting
homogenate was centrifuged at 45000g for 30 min at 4 °C. The
pellet was washed by resuspension in 10 mL of buffer and
recovered by centrifugation as before. The final pellet was
suspended in Tris buffer and stored at -80 °C until use.
Competition binding assays were performed after incubation
of the mixture with 3 nM [3H]-(()-rolipram (Amersham),
drugs, and 200 mg of membrane preparation for 60 min at 30
°C in reaction buffer (25 mM Tris HCl (pH 7.4), 5 mM MgCl2,
0.05 mM 5′-AMP). Bound and free radioligand were separated
by rapid filtration of mixture onto Unifilter Plate GF/B 96
(Packard Instrument). The membranes were washed four
times with ice-cold buffer (25 mM Tris HCl (pH 7.4), 5 mM
MgCl2). Plates were dried immediately, and the bound radio-
activity was counted via a TopCount microplate scintillation
counter. Nonspecific binding was determined in the presence
of 10 µM (()-rolipram.
(6) Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yamagata, S.;
Sugiura, M.; Kikkawa, H.; Kaminuma, O.; Ikezawa, K. Novel
Selective PDE IV Inhibitors as Anti-asthmatic Agents. Synthesis
and Biological Activities of a Series of 1-Aryl-2,3-bis(hydroxym-
ethyl)naphthalene Lignans. J . Med. Chem. 1996, 39, 2696-2704.
(7) (a) Torphy, T. J .; Undem, B. J . Phosphodiesterase Inhibitors:
New Opportunities for the Treatment of Asthma. Thorax 1991,
46, 512-523. (b) Heaslip, R. J .; Lombardo, L. J .; Golankiewicz,
J . M.; Ilsemann, B. A.; Evans, D. Y.; Sickels, B. D.; Mudrick, J .
K.; Bagli, J .; Weichman, B. M. Phosphodiesterase-IV Inhibition,
Respiratory Muscle Relaxation and Bronchodilation by WAY-
PDA-641. J . Pharmacol. Exp. Ther. 1994, 268, 888-896. (c)
Stafford, J . A.; Veal, J . M.; Feldman, P. L.; Valvano, N. L.; Bear,
P. G.; Brackeen, M. F.; Brawley, E. S.; Connolly, K. M.;
Domanico, P. L.; Han, B.; Rose, D. A.; Rutkowske, R. D.; Sekut,
L.; Stimpson, S. A.; Strickland, A. B.; Verghese, M. W. Introduc-
tion of a Conformational Switching Element on a Pyrrolidine
Ring. Synthesis and Evaluation of (R*, R*)-(()-Methyl 3-acetyl-
4-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-methyl-1-pyrrolidine-
carboxylate, a Potent and Selective Inhibitor of cAMP-Specific
Phosphodiesterase. J . Med. Chem. 1995, 38, 4972-4975. (d)
Christensen, S. B.; Guider, A.; Forster, C. J .; Gleason, J . G.;
Bender, P. E.; Karpinski, J . M.; DeWolf, W. E., J r.; Barnette,
M. S.; Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.;
Burman, M.; Bochnowicz, S.; Osborn, R. R.; Manning, C. D.;
Grous, M.; Hillegas, L. M.; Bartus, J . O.; Ryan, M. D.; Eggleston,
D. S.; Haltiwanger, R. C.; Torphy, T. J . 1,4-Cyclohexanecarboxy-
lates: Potent and Selective Inhibitors of Phosphodiesterase 4
for the Treatment of Asthma. J . Med. Chem. 1998, 41, 821-
835. (e) Chambers, R. J .; Marfat, A.; Cheng, J . B.; Cohan, V. L.;
Damon, D. B.; Duplantier, A. J .; Hibbs, T. A.; J enkinson, T. H.;
J ohnson, K. L. Biarylcarboxamide Inhibitors of Phosphodi-
esterase IV and Tumor Necrosis factor-R. Bioorg. Med. Chem.
Lett. 1997, 7, 739-744.
(8) Marivet, M. C.; Bourguignon, J .-J .; Lugnier, C.; Mann, A.;
Stoclet, J .-C.; Wermuth, C.-G. Inhibition of Cyclic Adenosine-
3’,5’-phosphate Phosphodiesterase from Vascular Smooth Muscle
by Rolipram Analogues. J . Med. Chem. 1989, 32, 1450-1457.
(9) (a) Rodrigo, R. A Stereo- and Regiocontrolled Synthesis of
Podophyllum Lignans. J . Org. Chem. 1980, 45, 4538-4540. (b)
Forsey, S. P.; Rajapaksa, D.; Taylor, N. J .; Rodrigo, R. Compre-
hensive Synthetic Route to Eight Diastereomeric Podophyllum
Lignans. J . Org. Chem. 1989, 54, 4280-4290.
(10) Sugahara, M.; Moritani, Y.; Terakawa, Y.; Ogiku, T.; Ukita, T.;
Iwasaki, T. A Synthesis of 1-Pyridylnaphthalene Lignan Ana-
logues. Tetrahedron Lett. 1998, 39, 1377-1380.
(11) Sugahara, M.; Ukita, T. A Facile Copper-Catalyzed Ullmann
Condensation: N-Arylation of Heterocyclic Compounds Con-
taining an -NHCO- Moiety. Chem. Pharm. Bull. 1997, 45,
719-721.
Ack n ow led gm en t. We express great gratitude to
Drs. K. Matsumoto, K. Kawashima, and T. Iwasaki of
Tanabe Seiyaku Co., Ltd. for their encouragement and
interest.
Refer en ces
(1) (a) Weishaar, R. E.; Cain, M. H.; Bristol, J . A. A New Generation
of Phosphodiesterase Inhibitors: Multiple Molecular Forms of
Phosphodiesterase and the Potential for Drug Selectivity. J .
Med. Chem. 1985, 28, 537-545. (b) Beavo, J . A.; Reifsnyder, D.
H. Primary Sequence of Cyclic Nucleotide Phosphodiesterase
Isozymes and the Design of Selective Inhibitors. Trends Phar-
macol. Sci. 1990, 11, 150-155. (c) Beavo, J . A. Cyclic Nucleotide
Phosphodiesterases: Functional Implications of Multiple Iso-
forms. Physiol. Rev. 1995, 75, 725-748.
(2) Mu¨ller, T.; Engels, P.; Fozard, J . R. Subtypes of the Type 4 cAMP
Phosphodiesterases: Structure, Regulation and Selective Inhibi-
tion. Trends Pharmacol. Sci. 1996, 17, 294-298.
(3) (a) Torphy, T. J . Action of Mediators on Airway Smooth Muscle
Functional Antagonism as a Mechanism for Bronchodilator
Drugs. Agents Actions 1988, 23 (Suppl.), S37-53. (b) Giembycz,
M. A.; Dent, G. Prospects for Selective Cyclic Nucleotide Phos-
phodiesterase Inhibitors in the Treatment of Bronchial Asthma.
Clin. Exp. Allergy 1992, 22, 337-344. (c) Torphy, T. J .; Livi, G.
P.; Christensen, S. B. Novel Phosphodiesterase Inhibitors for
the Therapy of Asthma. Drug News Perspect. 1993, 6, 203-214.
(4) (a) Christensen, S. B.; Torphy, T. Isozyme-selective Phosphodi-
esterase Inhibitors as Antiasthmatic Agents. Annu. Rep. Med.
Chem. 1994, 29, 185-194. (b) Hughes, B.; Owens, R.; Perry, M.;
Warrellow, G.; Allen, R. PDE 4 Inhibitors: the Use of Molecular
Cloning in the Design and Development of Novel Drugs. Drug
Discov. Today 1997, 2, 89-101. (c) Palfreyman, M. N. Phos-
phodiesterase Type IV Inhibitors as Antiinflammatory Agents.
Drugs Future 1995, 20, 793-804.
(12) Ashton, M. J .; Cook, D. C.; Fenton, G.; Karlsson, J .-A.; Palfrey-
man, M. N.; Raeburn, D.; Ratcliff, A. J .; Souness, J . E.;
Thurairatnam, S.; Vicker, N. Selective Type IV Phosphodi-
esterase Inhibitors as Antiasthmatic Agents. The Syntheses and
Biological Activities of 3-(Cyclopentyloxy)-4-methoxybenzamides
and Analogues. J . Med. Chem. 1994, 37, 1696-1703.
(13) Reeves, M. L.; Leigh, B. K.; England, P. J . The Identification of
a
New Cyclic Nucleotide Phosphodiesterase Activity in the
Human and Guinea-pig Cardiac Ventricle. Biochem. J . 1987,
241, 535-541.
(5) (a) Hebenstriet, G. F.; Fellerer, K.; Fichte, K.; Fischer, G.; Geyer,
N.; Meya, U.; Sastre-y-Herna´ndez, M.; Scho¨ny, W.; Schratzer,
M.; Soukop, W.; Trampitsch, E.; Varosanec, S.; Zawada, E.;
Zo¨chling, R. Rolipram in Major Depressive Disorder: Results
of a Double-Blind Comparative Study with Imipramine Phar-
macopsychiatry 1989, 22, 156-160. (b) Carpenter, D. O.; Briggs,
D. B.; Knox, A. P.; Strominger, N. Excitation of Area Postrema
Neurons by Transmitters, Peptides, and Cyclic Nucleotides. J .
Neurophys. 1988, 59, 358-369. (c) Hood, W. B. Controlled and
Uncontrolled Studies of Phosphodiesterase III Inhibitors in
(14) Thompson, W. J .; Terasaki, W.; Epstein, P. M.; Strada, S. J .
Assay of Cyclic Nucleotide Phosphodiesterase and Resolution of
Multiple Molecular Forms of the Enzyme. Adv. Cycl. Nucleotide
Res. 1979, 10, 69-72.
(15) Konzett, H.; Ro¨ssler, R. Experimental Procedure for the Inves-
tigation of Bronchial Muscle. Naunyn-Schmiedeberg's Arch. Exp.
Pathol. Pharmacol. 1940, 195, 71-74.
J M980314L