Benzofuran based PDE4 inhibitors

Article abstract of DOI:10.1016/S0968-0896(99)00038-3

Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzofurans 26 is also presented. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00038-3

Bioorganic & Medicinal Chemistry 7 (1999) 1131±1139
Benzofuran Based PDE4 Inhibitors
D. G. McGarry,a,* J. R. Regan,a,y F. A. Volz,a C. Hulme,a K. J. Moriarty,a,{
S. W. Djuric,a,x J. E. Souness,b B. E. Miller,a,{ J. J. Travisa,{ and D. M. Sweeneya,{
aDepartments of Medicinal Chemistry and In¯ammation Biology, RhoÃne Poulenc Rorer, 500 Arcola Rd, Collegeville, PA 19426, USA
bDepartment of In¯ammation Biology, RhoÃne Poulenc Rorer, Dagenham, Essex RM107XS, England
Received 8 October 1998; accepted 15 December 1998
AbstractÐReplacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-meth-
oxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory
activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzo-
furans 26 is also presented. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
(4) in which the 3,4-dialkoxyphenyl subunit of 3 was
replaced by a benzimidazole ring system. In this paper,
we report the synthesis and PDE4 inhibitory activity of
the related benzofuran system 5. We also describe the
e€ect on PDE4 inhibition of pairing the 2-alkyl-7-
methoxy-benzofuran sca€old with a selection of novel
as well as established pyrrolidinone surrogates to gen-
erate the hybrid structures represented by 6.11
Cyclic nucleotide phosphodiesterases (PDE1-7) are a
family of enzymes that degrade the intracellular sec-
ondary messengers cAMP and cGMP1 thereby limiting
a host cell's response to extracellular signals mediated
by these carriers. In a number of immunological cell
types, elevation of cAMP levels by PDE4 inhibition2
causes activation of negative feedback mechanisms
resulting in suppression of the cell's in¯ammatory
activities.3 In particular, this type of manipulation
brings about a marked reduction in the release of the
proin¯ammatory cytokine TNF-a into the blood.4
These observations have generated considerable interest
in the use of PDE4 inhibitors for the treatment of var-
ious immunological disorders, including asthma and
rheumatoid arthritis.5,6 The discovery of the ®rst PDE4
selective inhibitor, rolipram (1, Fig. 1) more than 2
decades ago,7 provided a benchmark for the develop-
ment of more potent and selective analogues. Initially,
the majority of research in this area focused on repla-
cement of the pyrrolidinone of 1 with a wide range of
other functionality (represented by the general structure
2).8 In our laboratories, this approach led to the dis-
covery of a clinical candidate RP 73401 (3).9 More
recently,10 we reported a new series of PDE4 inhibitors
Chemistry
The substituted benzofurans employed in this study
were prepared by Pd (0)/Cu (I) catalyzed12 coupling of
an appropriate terminal acetylene with either aldehyde 7
or ester 8 (Scheme 1). This approach, although very
direct, does require the use of excess alkyne to achieve
useful conversion. Aldehyde 7 was a superior substrate
for this reaction than ester 8, (63% and 38% yields,
respectively, with 1-hexyne) presumably as a result of
decreased steric crowding around the C-Br bond of 7.
Simple carbonyl transformations of 9 and 10 provided
the carboxylic acids 11 in good yield. Subsequent ela-
boration of these sca€olds (Scheme 2) into the corre-
sponding N-(3,5-dichloropyridin-4-yl) amides (5),10
tetrahydro-pyrimidin-2-one (12),13 pyrrolidinone (13),7b
pyrrolidine carbamate (14)14 and pyrrolidine sulphona-
mide (15)14 derivatives was carried out by adaptation of
the published procedures for the synthesis of their
respective 3,4-dialkoxyphenyl analogues. The 1-phenyl-
2-pyridyl-ethane derivative 1815 was prepared from 9c
as shown in Scheme 3. Addition of phenylmagnesium
bromide followed by oxidation of the resulting secondary
alcohol gave ketone 16. Subsequent addition of pyridin-
4-yl-methyl lithium to 16, followed by dehydration with
TFA, then hydrogenation of the resulting ole®n gave 18
y*Corresponding author. Tel.: 610-454-5624; fax: 610-454-3311.
Present address: Boehringer Ingelheim Pharmaceuticals, Research
and Development Center, 900 Ridgebury Road, Ridge®eld, CT 06877
USA.
Present address: Pharmacopoeia, 101 College Rd. East, Princeton,
N.J. 08540 USA.
Present address: Abbott Laboratories, Immune Sciences Research,
100 Abbott Park Rd, Abbott Park, Illinois, 60064-3500 USA.
In¯ammation Biology, Collegeville.
{
x
{
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00038-3

1132
D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
Figure 1. Evolution of the Rolipram family of PDEA inhibitors.
as a racemic mixture. The 2-(heteroaromatic)-substituted
ethyl derivatives 26a±d, f were prepared by treatment of
9c with an appropriately protected16 heteroaromatic-
substituted-methyl lithium reagent, to give 19, followed
by dehydration (with concomitant deprotection) and
ole®n hydrogenation. N-oxide 26e (Table 4) was derived
from 26a by m-CPBA oxidation. Compound 26g
(Scheme 4) was prepared by Wittig ole®nation of 9c, to
give 20, followed by Heck coupling with 2-methoxy-5-
bromo-pyridine to give 21, reduction of the double
bond and hydrolysis of the 2-methoxy-pyridine to the
corresponding 2-pyridone. Compound 26h was
obtained by hydrogenation of 22, followed by Claisen
condensation with ethyl acetate and reaction of the
resulting b-keto-ester with hydrazine.
Results and Discussion
Biological results are summarized in Tables 1±5. New
compounds were evaluated by measuring their ability to
inhibit guinea pig macrophage PDE4 (IC50) using a
previously published protocol.17 Since there are a number
of di€erent PDE4 inhibitor assays in common use,
comparisons between the activity of the benzofurans,
which are the subject of this article, and certain of the
Scheme 1. Reagents and conditions: (a) (Ph3P)2PdCl2/CuI/Et3N/RCCH/
DMF/110 ꢀC. (b) NaOH/THF/MeOH/rt; (c) NaClO2/NaH2PO4/
2-methyl-2-butene, rt.
Scheme 2. Reagents and conditions: (a) (COCl)2/DMF. (b) 4-Amino-3,5-
dichloro-pyridine/NaEt2AlH2. (c) Cyanoacetic acid/piperidine. (d) H2O2/
Na2CO3. (e) Pb(OAc)4. (f) Ph3PˆCHCO2Me. (g) MeNO2/tetramethyl-
guanidine. (h) Raney Ni. (i) LAH. (j) BOC2O or RSO2Cl/Et3N.
Scheme 3. Reagents and conditions: (a) PhMgBr. (b) PCC. (c) LDA/
4-methyl-pyridine. (d) TFA. (e) H2/Pd/C. (f) LDA/Me-(heterocycle).

D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
1133
Scheme 4. Reagents and conditions: (a) (Ph3P)CH3Br/Na(NSiMe3)2. (b) Ph3PˆCHCO2Me. (c) (Ph3P)2PdCl2/5-bromo-2-methoxy-pyridine/Et3N/
DMF/100 ꢀC. (d) H2/Pd/C. (e) 1.5 M HCl/80 ꢀC. (f) LDA/CH3CO2Et. (g) NH2NH2.
Table 1. Comparison between benzofuran benzimidazole and di-
alkoxy-phenyl sca€olds
Table 2. Comparison between benzofuran and dialkoxy-phenyl
sca€olds bearing pyrrolidinone and tetrahydropyrimidinone substitu-
ents
Compound
Structure
IC50(nM)a IC50(rolipram)/
IC50(compound)b
Compound
Structure
IC50(nM) IC50 (rolipram)/
IC50 (compound)a
3
1
300
1
300b
1
13
27
300b
1
4a
4b
R=PhCH2
R=Ph(CH2)2
24
25
12
12
200
1.5
12
48
6
5a
5b
5c
R=PhCH2
R=Ph(CH2)2
R=CH3(CH2)3
0.4
0.7
2
750
430
150
aPartially puri®ed PDE4 from guinea pig macrophage.
bActivity relative to rolipram was calculated by dividing the IC50 value
obtained for a test compound into the IC50 value obtained for roli-
pram under the same assay conditions.
aActivity relative to rolipram was calculated by dividing the IC50 value
obtained for a test compound into the IC50 value obtained for roli-
pram under the same assay conditions.
bTest sample was a racemic mixture.
published inhibitor families cited in the following dis-
cussion (which were evaluated under di€erent assay
conditions) were made by referencing all activities relative
to that of the widely used standard inhibitor rolipram.18
Inhibitory activities against other PDE isozymes were
not routinely measured.
pyrrolidinone (Table 2, 1 versus 13) and tetrahydro-
pyrimidin-2-one families (12 versus 27) but breaks down
for the case of the N-BOC-substituted pyrrolidine sys-
tem (Table 3). In this instance, a 60 fold loss in potency
was observed for the benzofuran sca€old relative to the
dialkoxy-phenyl system (28 versus 14). It is not entirely
clear why this loss occurs, particularly in view of the
observation that the benzofuran and dialkoxyphenyl
sca€olds impart similar potency in the related methyl-
sulfonamide system (29 versus 15).
Within the dichloropyridin-4-yl amide series (Table 1),
the benzofuran sca€old appears to be more potent,
in vitro, than the analogous benzimidazole system
(5a,b versus 4a,b),19 imparting activity comparable to
that of the parent 3,4-dialkoxyphenyl core structure 3.
The latter correlation holds reasonably well across the

1134
D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
Table 3. Comparison between benzofuran and dialkoxy-phenyl
sca€olds bearing an N-substituted pyrrolidine
Table 4. Comparison between benzofuran and dialkoxy-phenyl
sca€olds bearing (2-aryl)-ethyl substituents
Compound
Structure
IC50 (nM)
IC50 (rolipram)/
IC50 (compound)a
Compound
Structure
IC50 (nM) IC50 (rolipram)/
IC50(compound)a
R1
R2
28
29
R=CO2t-Bu
R=SO2Me
10b
1b
30
31
Phb
15
11
20
27
H
14
15
R=CO2t-Bu
R=SO2Me
1800c
360c
0.16
1
aActivity relative to rolipram was calculated by dividing the IC50 value
obtained for a test compound into the IC50value obtained for rolipram
under the same assay conditions.
bCalculated using data taken from reference 14.
cTest sample was a racemic mixture.
R1
Phb
R2
18
2000
0.15
Di€erences in activity between the benzofuran and di-
alkoxyphenyl systems were also observed for the triaryl-
ethane series (Table 4). Comparison of 18 and 30
revealed a signi®cant loss of activity in the benzofuran
series. We speculated that increased steric interactions
between the phenyl and benzofuranyl ring systems in 18
could well result in altered conformational preferences
in this molecule (relative to 30) which, in turn, may dis-
favor the bioactive conformer. This idea was subse-
quently supported by the observation that 26a (in which
the phenyl group of 18 has been removed) was highly
active. In fact, 26a was an order of magnitude more
potent than its dialkoxyphenyl analogue 31.20 The level
of activity observed for 26a led us to examine some
simple pyridine ring analogues of this system. The pyr-
idazine 26b was equipotent with 26a suggesting that the
key interactions in this part of the pharmacophore are
not heavily dependent on pKa. Introduction of a nitro-
gen adjacent to the ethylene linker (26c) was deleterious
to activity, while replacement of the ring nitrogen with a
phenolic hydroxyl (26c versus 26d) or an N-oxide (26a
versus 26e) had little e€ect on potency. Surprisingly, the
N-oxide 26e was more than 20 times more potent than
the isosteric pyridone 26f, yet pyridone 26g retained
activity close to that of 26a. Substitution of the six
membered ring with a 5-membered heterocycle, as in
26h, resulted in a further reduction in potency. While
there are clear di€erences in activity among analogues
26a±h, all of these compounds are, in an absolute sense,
tight binding ligands for PDE4. In particular, 26a, b, e
and g, are approximately equipotent, despite the fact
that they contain a variety of di€erent Lewis base con-
®gurations. These results indicate a surprising level of
tolerence to structural variation in this area of the roli-
pram pharmacophore and thus highlight a useful
opportunity for the modi®cation of physical±chemical
26a
26b
H
H
1
1
300
300
26c
26d
H
H
27
15
11
20
26e
26f
H
H
1
300
150
22
26g
26h
H
H
2
14
4
75
aActivity relative to rolipram was calculated by dividing the IC50 value
obtained for a test compound into the IC50 value obtained for roli-
pram under the same assay conditions.
bTest sample was a racemic mixture.

D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
1135
Table 5. TNF-a inhibitory e€ects for a selection of benzofurans in a
mouse endotoxemia model
dried over MgSO4 and concentrated. The residue was
puri®ed by ¯ash chromatography, eluting with 15%
ethyl acetate in hexanes, to give 4.4 g (63%) of 9c as an
Compound
ED50 (mg/Kg p.o.)
1
oil. H NMR (CDCl3) d 0.93 (t, J=7 Hz, 3H), 1.40 (m,
5a
5b
30
50
2H), 1.75 (m, 2H), 2.80 (t, J=7 Hz, 2H), 4.09 (s, 3H),
6.80 (d, J=8 Hz, 1H), 7.14 (s, 1H), 7.60 (d, J=8 Hz,
1H), 10.0 (s, 1H); MS (EI) m/z 232 (M)+. The following
compounds were prepared using essentially the same
procedure:
5c
15
26a
26b
20
>50
>50
>50
2-Benzyl-7-methoxy-benzofuran-4-yl carbaldehyde (9a).
Obtained as a tan solid (78%) 1H NMR (CDCl3) d
4.07 (s, 3H), 4.17 (s, 2H), 6.83 (d, J=8 Hz, 1H), 7.12 (s,
1H), 7.31 (m, 5H), 7.62 (d, J=8 Hz, 1H), 9.99 (s, 1H).
MS (EI) m/z 266 (M)+.
properties of this class of compound without incurring a
severe penalty in inhibitory potency.
Of the benzofurans in this paper tested (5a±c, 15, 26a
and 26b), 5c was the most potent inhibitor of TNF-a
release in vivo, as measured in a murine endotoxemia
model (Table 5). In addition, a number of benzofurans
of general formula 5 produced a pronounced emetic
reaction in dogs when administered i.v. For example, 5a
caused emesis in 3/4 dogs at a dose of 0.3 mg/Kg. These
results precluded further development of this series.
7-Methoxy-2-phenethyl-benzofuran-4-yl carbaldehyde
1
(9b). Obtained as an oil (76%). H NMR (CDCl3) d
3.10 (m, 4H), 4.08 (s, 3H), 6.83 (d, J=8 Hz, 1H), 7.2±7.4
(m, 6H), 7.62 (d, J=8 Hz, 1H), 10.0 (s, 1H). MS (EI)
m/z 280 (M)+.
2-Butyl-7-methoxy-benzofuran-4-carboxylic acid (11c).
To a solution of 9c (700 mg, 3 mmol) in t-butanol
(30 mL) was added of 2-methyl-but-2-ene (3 mL) fol-
lowed by a solution comprised of NaClO2 (3.0 g techni-
cal grade, 27 mmol) and NaH2PO4.H2O (3.0 g, 22 mmol)
in water (30 mL). The resulting mixture was stirred vig-
orously for 3.5 h, diluted with ethyl acetate, washed with
water, then brine, dried over MgSO4 and concentrated.
The residue was triturated with ether and ®ltered to give
741 mg (99%) of 10c as a white solid. 1H NMR (CDCl3)
d 1.0 (t, J=7 Hz, 3H), 1.46 (m, 2H), 1.80 (m, 2H),
2.86 (t, J=7 Hz, 2H), 4.1 (s, 3H), 6.90 (d, J=8 Hz, 1H),
7.10 (s, 1H), 8.0 (d, J=8 Hz, 1H); MS (EI) m/z 249
(M+H)+.
Conclusion
The 7-methoxybenzofuran unit can function as a repla-
cement for the dialkoxyphenyl moiety found in several
classes of PDE4 inhibitor. This substitution is, however,
not universally applicable and can result in enhance-
ment or substantial reductions in potency depending on
the pyrrolidine surrogate employed. An analysis of the
failure of this replacement in the triaryl-ethane system
18 led to the synthesis of a particularly potent group of
compounds represented by 26a±h. These results further
re®ne our understanding of the rolipram pharmaco-
phore and provide an important caveat for researchers
interested in generating new structural classes of PDE4
inhibitors by combining novel analogues of the di-
alkoxyphenyl sca€old with new or established pyrroli-
dine surrogates.
The following compounds were prepared using essen-
tially the same procedure:
2-Benzyl-7-methoxy-benzofuran-4-yl carboxylic acid
(11a). Obtained as a white solid (88%) 1H NMR
(CDCl3) d 4.05 (s, 3H), 4.17 (s, 2H), 6.78 (d, J=8 Hz,
1H), 7.04 (s, 1H), 7.2±7.4 (m, 5H), 7.98 (d, J=8 Hz,
1H). MS (EI) m/z 282 (M)+.
Experimental
1H NMR spectra were recorded at a frequency of 300 M
Hz. Unless otherwise speci®ed, materials were obtained
from commercial suppliers and were used without fur-
ther puri®cation. Melting points were determined using
a Thomas±Hoover capillary melting point apparatus
and are uncorrected. Anhydrous solvents were obtained
from Aldrich. Column chromatography was performed
on Merck silica gel (230±400 mesh).
7-Methoxy-2-phenethyl-benzofuran-4-yl carboxylic acid
(11b). Obtained as white solid (85%). 1H NMR
(CDCl3) d 3.13 (m, 4H), 4.08 (s, 3H), 6.81 (d, J=8 Hz,
1H), 7.09 (s, 1H), 7.2±7.33 (m, 5H), 8.00 (d, J=8 Hz,
1H). MS (EI) m/z 296 (M)+.
2-Butyl-7-methoxy-benzofuran-4-carboxylic acid (3-5-
dichloro-pyridin-4y-l)-amide (5c). To a suspension of
11c (2.7 g, 10.8 mmol) in CH2Cl2 (20 mL) was added 1
drop of DMF followed by oxalyl chloride (10 mL, 2 M
in CH2Cl2). The resulting mixture was stirred for 45 min
(during which time the solid suspension gradually dis-
solved). This solution was then concentrated under
vacuum and the crude product, 2-butyl-7-methoxy-ben-
zofuran-4-carbonyl chloride, used without further puri-
®cation. In a separate ¯ask, 4-amino-3,5-dichloro-
pyridine (3.6 g, 22 mmol) was dissolved in THF/toluene
2-Butyl-7-methoxy-benzofuran-4-yl carbaldehyde (9c). A
solution containing 7 (6.96 g, 30 mmol), (Ph3P)2PdCl2
(1.14 g, 1.6 mmol), CuI (144 mg, 0.75 mmol) in DMF
(80 mL) was degassed, then ¯ushed with argon. To this
solution was added Et3N (21 mL, 152 mmol) followed
by 1-hexyne (12 mL, 105 mmol). The resulting solution
was warmed to 110 ꢀC and stirred at this temperature
for 2 h. The mixture was then cooled to room tempera-
ture, diluted with ether, washed with water, then brine,

1136
D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
(2/1, 60 mL). To this solution was added NaEt2AlH2
(5 mL, 2 M in toluene. CAUTION, pyrophoric reagent).
The resulting mixture was warmed to 50 ꢀC and stirred
at this temperature for 1 h then cooled to room tem-
perature. To this solution was added the crude acid
chloride (prepared above) in THF (15 mL). The result-
ing mixture was warmed to 50 ꢀC and stirred for 2 h.
The reaction mixture was then cooled to room tem-
perature and quenched with sat. sodium tartrate solu-
tion, diluted with ethyl acetate, washed with HCl
(0.25 M), then brine, dried over MgSO4 and con-
centrated. The residue was recrystallized from ethyl
acetate to give 2.38 g (56%) of 5c as a white solid.
(R,S)-4-(2-Butyl-7-methoxy-benzofuran-4-yl)-1-(t-butyl-
oxy-carbonyl)-pyrrolidine (14). Prepared according to
the procedure in reference 14 except starting with 9c
1
instead of 3-cyclopentoxy-4-methoxy-benzaldehyde. H
NMR (CDCl3 The product exists as two conformers in
solution) d 0.94 (t, J=7 Hz, 3H), 1.43 (m, 2H), 1.50,
1.52 (two s, total 9H), 1.76 (bm, 2H), 2.11 (bm, 1H),
2.25 (bm, 1H), 2.79 (bt, J=7 Hz, 2H), 3.33±3.72 (m,
4H), 3.76, 3.88 (two t, J=8 Hz, total 1H), 4.00 (s, 3H),
6.45 (s, 1H), 6.69 (d, J=8 Hz, 1H), 6.95 (d, J=8 Hz,
1H); MS (EI) m/z 373 (M)+. Combustion analysis
C22H31O4N requires C 70.7, H 8.4, N 3.7. Found C
70.8, H 8.2, N 3.6. Using essentially the same proce-
dure, except using methanesulphonyl chloride, the fol-
lowing was prepared
mp. 166±167 ꢀC; H NMR (CDCl3) d 0.91 (t, J=7 Hz,
1
3H), 1.41 (m, 2H), 1.75 (m, 2H), 2.80 (t, J=7 Hz, 2H),
4.10 (s, 3H), 6.80 (d, J=8 Hz, 1H), 6.97 (s, 1H), 7.65
(bs, 1H), 7.70 (d, J=8 Hz, 1H), 8.56 (s, 2H); MS (EI)
m/z 392 (M)+. Combustion analysis C19H18O3N2Cl2
requires C 58.0, H 4.6, N 7.1. Found C 58.0, H 4.6, N
6.9.
(R,S)-1-(methanesulphonyl)-4-(2-butyl-7-methoxy-benzo-
furan-4-yl)-pyrrolidine (15). 1H NMR (CDCl3) d 0.93
(t, J=7 Hz, 3H), 1.40 (m, 2H), 1.73 (m, 2H), 2.20 (m,
1H), 2.33 (m, 1H), 2.76 (t, J=7 Hz, 2H), 2.85 (s, 3H),
3.36±3.50 (m, 2H), 3.60 (m, 2H), 3.78 (m, 1H), 3.96 (s,
3H), 6.40 (s, 1H), 6.66 (d, J=8 Hz, 1H), 6.94 (d,
J=8 Hz, 1H); MS (EI) m/z 351 (M)+. Combustion
analysis C18H25O4NS requires C 61.5, H 7.2, N 4.0.
Found C 61.4, H 7.2, N 3.8.
The following compounds were prepared using essen-
tially the same procedure:
2-Benzyl-7-methoxy-benzofuran-4-carboxylic acid (3-5-
dichloro-pyridin-4-yl)-amide (5a). (67%) mp 214±215 ꢀC;
1H NMR (CDCl3) d 4.08 (s, 3H), 4.16 (s, 2H), 6.82 (d,
J=8 Hz, 1H), 6.94 (s, 1H), 7.2±7.35 (m, 5H), 7.68 (bs,
1H), 7.72 (d, J=8 Hz, 1H), 8.53 (s, 2H); MS (EI) m/z
426 (M)+. Combustion analysis C22H16O3N2Cl2
requires C 61.8, H 3.8, N 6.6. Found C 61.6, H 3.9, N
6.5.
(2-Butyl-7-methoxy-benzofuran-4-yl)-phenyl-ketone (16).
To a cooled (10 ꢀC) solution of phenylmagnesium chlo-
ride in THF (6 mL, 0.66 M) was added a solution con-
taining 9c (580 mg, 2.5 mmol) in THF (2 mL). The
resulting solution was warmed to room temperature
over 10 min then the reaction was quenched by adding
dilute hydrochloric acid (0.1 M). The mixture was dilu-
ted with ether, washed with water, then brine, dried over
MgSO4 and concentrated. The residue was taken up
in CH2Cl2 (7 mL) and pyridinium chlorochromate
(590 mg, 2.75 mmol) added. The resulting mixture was
stirred for 1 h then diluted with CH2Cl2 and poured
onto a column of silica gel. The product was eluted with
10% ethyl acetate in hexanes to give 15, 500 mg (86%)
7-Methoxy-2-phenethyl-benzofuran-4-carboxylic acid (3-
5-dichloro-pyridin-4y-l)-amide(5b). (80%) 1H NMR
(DMSO) d 3.04 (m, 2H), 3.11 (m, 2H), 3.34 (s, 3H), 7.0
(s, 1H), 7.04 (d, J=8 Hz, 1H), 7.20 (m, 1H), 7.28 (m,
4H), 7.91 (d, J=8 Hz, 1H), 8.73 (s, 2H), 10.4 (s, 1H);
MS (EI) m/z 440 (M)+.
1
5-(2-Butyl-7-methoxy-benzofuran-4-yl)-tetrahydro-pyri-
midin-2-one (12). Prepared according to the procedure
in reference 13 except starting with 9c instead of 3-cyclo-
pentoxy-4-methoxy-benzaldehyde. mp 222±223 ꢀC; 1H
NMR (DMSO) d 0.93 (t, J=7 Hz, 3H), 1.37 (m, 2H),
1.67 (m, 2H), 2.75 (d, J=7 Hz, 2H), 3.2±3.4 (m, 5H),
3.89 (s, 3H), 6.27 (bs, 2H), 6.78 (s, 1H), 6.79 (d,
J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H); MS (EI) m/z 303
(M+H)+. Combustion analysis C17H22O3N2 requires C
67.5, H 7.3, N 9.3. Found C 67.4, H 7.4, N 9.1.
as a white solid. H NMR (CDCl3) d 0.95 (t, J=7 Hz,
3H), 1.44 (m, 2H), 1.75 (m, 2H), 2.83 (t, J=7 Hz, 2H),
4.09 (s, 3H), 6.72 (d, J=8 Hz, 1H), 6.96 (s, 1H), 7.5 (m,
4H), 7.77 (m, 2H); MS (EI) m/z 308 (M)+.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-1-phenyl-2-pyridin-
4-yl-ethanol (17).
A solution of diisopropylamine
(345 mL, 2.5 mmol) in THF (6 mL) was cooled to 10 ꢀC
and a solution of n-butyl lithium (0.96 mL, 2.5 M in
hexanes) added dropwise. The resulting solution was
stirred for 15 min then cooled to 78 ꢀC and 4-picoline
(235 mL, 2.4 mmol) in THF (1 mL) added dropwise. This
solution was stirred for 30 min then a solution of 16
(500 mg, 1.6 mmol) in THF (1 mL) added. The resulting
solution was stirred for 15 min then a sat. solution of
ammonium chloride added. The reaction mixture was
diluted with ether, washed with water, then brine, dried
over MgSO4 and concentrated. The residue was puri®ed
by ¯ash chromatography, eluting with 60% ethyl ace-
tate in hexanes, to give 605 mg of 17 as a white solid
(R,S)-4-(2-Butyl-7-methoxy-benzofuran-4-yl)-pyrrolidin-
2-one (13). Prepared according to the procedure in
reference 7b except starting with 9c instead of 3-cyclo-
1
pentoxy-4-methoxy-benzaldehyde. H NMR (CDCl3) d
0.96 (t, J=7 Hz, 3H), 1.42 (m, 2H), 1.75 (m, 2H), 2.63
(dd, J=17, 8 Hz, 1H), 2.77 (dd, J=17, 8 Hz, 1H), 2.80
(t, J=7 Hz, 2H), 3.53 (t, J=8 Hz, 1H), 3.81 (bt,
J=8 Hz, 1H), 3.90 (bt, J=8 Hz, 1H), 4.0 (s, 3H), 6.40 (s,
1H), 6.5 (bs, 1H), 6.69 (d, J=8 Hz, 1H), 6.99 (d,
J=8 Hz, 1H); MS (EI) m/z 287 (M)+. Combustion
analysis C17H21O3N requires C 71.0, H 7.4, N 4.9.
Found C 70.9, H 7.4, N 4.8.
1
(93%). H NMR (CDCl3) d 0.90 (t, J=7 Hz, 3H), 1.32
(m, 2H), 1.60 (m, 2H), 2.35 (bs, 1H), 2.65 (t, J=7 Hz,
2H), 3.60 (d, J=15 Hz, 1H), 3.66 (d, J=15 Hz, 1H), 4.00

D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
1137
(s, 3H), 6.06 (s, 1H), 6.65 (d, J=8 Hz, 1H), 6.76 (d,
J=5 Hz, 2H), 7.18 (d, J=8 Hz, 1H), 7.3 (m, 5H), 8.30
(d, J=5 Hz, 2H); MS (EI) m/z 401 (M)+.
d 0.93 (t, J=7 Hz, 3H), 1.40 (m, 2H), 1.72 (m, 2H), 2.75
(t, J=7 Hz, 2H), 3.10 (bs, 4H), 3.95 (s, 3H), 6.46 (s, 1H),
6.60 (d, J=8 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 7.02 (d,
J=8 Hz, 1H), 7.21 (dd, J=8, 3 Hz, 1H), 8.26 (d,
J=3 Hz, 1); MS (EI) m/z 325 (M)+. Combustion ana-
lysis C20H23O3N requires C 73.8, H 7.1, N 4.3. Found C
73.5, H 7.0, N 4.2.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-1-phenyl-2-pyridin-
4-yl-ethane (18). To
a solution of 17 (375 mg,
0.93 mmol) in CH2Cl2 (8 mL) was added TFA (1.5 mL).
The resulting dark red solution was stirred for 10 min
then a further portion of TFA (1.5 mL) added. This
solution was stirred for 20 min then diluted with ether,
washed with sodium bicarbonate, then brine, dried over
MgSO4 and concentrated. The residue was taken up in a
solution of THF/MeOH (6 mL, 1/1). This solution was
added to 10% Pd/C (60 mg) and the resulting suspen-
sion placed under an atmosphere of hydrogen. The
reaction mixture was then heated to 55 ꢀC and stirred at
this temperature for 2.5 h then cooled to room tem-
perature and ®ltered through Celite. The catalyst was
washed with CH2Cl2 and the combined ®ltrates con-
centrated. The residue was puri®ed by ¯ash chromato-
graphy eluting with 40% ethyl acetate in hexanes to give
276 mg of 18 (77%). 1H NMR (CDCl3) d 0.90 (t,
J=7 Hz, 3H), 1.36 (m, 2H), 1.65 (m, 2H), 2.70 (t,
J=7 Hz, 2H), 3.39 (m, 2H), 3.94 (s, 3H), 4.41 (t,
J=7 Hz, 1H), 6.20 (s, 1H), 6.65 (d, J=8 Hz, 1H), 6.89
(bd, J=5 Hz, 2H), 7.00 (d, J=8 Hz, 1H), 7.2 (m, 5H),
8.37 (bs, 2H); MS (EI) m/z 385 (M)+. Combustion
analysis C26H27O2N requires C 81.0, H 7.0, N 3.6.
Found C 81.0, H 6.9, N 3.5.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-[2-hydroxy-pyri-
din-4-yl]-ethane (26g). 1H NMR (CDCl3) d 0.95 (t,
J=7 Hz, 3H), 1.42 (m, 2H), 1.75 (m, 2H), 2.80 (m, 4H),
3.03 (t, J=7 Hz, 2H), 4.00 (s, 3H), 6.10 (d, J=5 Hz,
1H), 6.35 (s, 1H), 6.37 (s, 1H) 6.65 (d, J=8 Hz, 1H),
6.85 (d, J=8 Hz, 1H), 7.25 (d, J=5 Hz, 1H); MS (EI)
m/z 325 (M)+. Combustion analysis C20H23O3N
requires C 73.8, H 7.1, N 4.3. Found C 73.9, H 7.1, N
4.3.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-pyridin-N-oxide-
4-yl-ethane (26e). To a cooled (0 ꢀC) solution of 26a
(788 mg, 2.5 mmol) in CH2Cl2 (12 mL) was added m-
CPBA (615 mg, 75% technical grade). The resulting
solution was stirred for 30 min then a further batch of
m-CPBA (615 mg) added. This solution was stirred for
30 min then the reaction mixture poured onto a column
of silica gel and the product eluted with 15% MeOH/
25% CH2Cl2 in EtOAc to give 359 mg (44%) of 26e as
white solid. mp 73±75 ꢀC; H NMR (Acetone) d 0.92 (t,
1
J=7 Hz, 3H), 1.41 (m, 2H), 1.72 (m, 2H), 2.78 (t,
J=7 Hz, 2H), 2.95 (m, 2H), 3.05 (m, 2H), 3.91 (s, 3H),
6.60 (s, 1H), 6.71 (d, J=8 Hz, 1H), 6.87 (d, J=8 Hz,
1H), 7.18 (bd, J=5 Hz, 2H), 8.00 (bd, J=5 Hz, 2H); MS
(EI) m/z 325 (M)+.
The following compounds were prepared using essen-
tially the same procedures.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-pyridin-4-yl-
ethane (26a). 1H NMR (CDCl3) d 0.95 (t, J=7 Hz,
3H), 1.41 (m, 2H), 1.74 (m, 2H), 2.79 (t, J=7 Hz, 2H),
2.94 (m, 2H), 3.05 (m, 2H), 4.00 (s, 3H), 6.31 (s, 1H),
6.62 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 7.07 (d,
J=5 Hz, 2H), 8.46 (bd, J=5 Hz, 2H); MS (EI) m/z 309
(M)+. Combustion analysis C20H23O2N requires C
77.6, H 7.5 N 4.5. Found C 77.7, H 7.5, N 4.5.
(2-Butyl-7-methoxy-benzofuran-4-yl)-ethene (20). To a
cooled (0 ꢀC) suspension of (Ph3P)CH3Br (1.28 g,
3.6 mmol) THF (7 mL) was added NaN(SiMe3)2
(3.3 mL, 1 M in THF). The resulting yellow mixture was
stirred for 25 min, then a solution of 9c (690 mg,
3 mmol) in THF (3 mL) added in one portion. This sus-
pension was stirred for 10 min then concentrated under
vacuum. The residue was puri®ed by ¯ash chromato-
graphy, eluting with 20% ethyl acetate in hexanes to
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-pyridazin-4-yl-
ethane (26b). 1H NMR (CDCl3) d 0.93 (t, J=7 Hz,
3H), 1.40 (m, 2H), 1.70 (m, 2H), 2.75 (t, J=7 Hz, 2H),
2.95 (m, 2H), 3.05 (m, 2H), 3.95 (s, 3H), 6.25 (s, 1H),
6.60 (d, J=8 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 7.09 (m,
1H), 8.95 (m, 2H); MS (EI) m/z 310 (M)+. Combustion
analysis C19H22O2N2 requires C 73.5, H 7.1 N 9.0.
Found C 73.5, H 7.4, N 8.8.
1
give 676 mg (98%) of 20 as a pale yellow oil. H NMR
(CDCl3) d 0.95 (t, J=7 Hz, 3H), 1.42 (m, 2H), 1.76 (m,
2H), 2.81 (t, J=7 Hz, 2H), 4.00 (s, 3H), 5.26 (d,
J=10 Hz, 1H), 5.70 (d, J=17 Hz, 1H), 6.59 (s, 1H), 6.71
(d, J=8 Hz, 1H), 6.88 (dd, J=17, 10 Hz, 1H), 7.22 (d,
J=8 Hz, 1H); MS (EI) m/z 230 (M)+.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-(2-methoxy-pyri-
din-5-yl)-ethene (21). To a solution of 20 (676 mg,
2.94 mmol) in DMF (9 mL) was added 5-bromo-2-
methoxy-pyridine (620 mg, 3.3 mmol), (Ph3P) PdCl2
(90 mg, 0.13 mmol) and Et3N (1.5 mL, 11 mmol). The
resulting solution was degassed, ¯ushed with argon,
then heated to 118 ꢀC and stirred at this temperature for
4.5 h. The reaction mixture was then cooled to room
temperature, diluted with ether, washed with water,
then brine, dried over MgSO4 and concentrated under
vacuum. The residue was puri®ed by ¯ash chromato-
graphy, eluting with 10% ethyl acetate in hexanes, to
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-pyrimidin-4-yl-
ethane (26c). 1H NMR (CDCl3) d 0.93 (t, J=7 Hz,
3H), 1.40 (m, 2H), 1.70 (m, 2H), 2.75 (t, J=7 Hz, 2H),
3.09 (m, 2H), 3.15 (m, 2H), 3.95 (s, 3H), 6.32 (s, 1H),
6.60 (d, J=8 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 6.98 (dd,
J=5,1 Hz, 1H), 8.50 (d, J=5 Hz, 1H), 9.12 (d, J=1 Hz,
1H); MS (EI) m/z 310 (M)+. Combustion analysis
C19H22O2N2 requires C 73.5, H 7.1, N 9.0. Found C
73.5, H 7.2, N 8.8.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-[5-hydroxy-pyri-
din-2-yl]-ethane (26d). mp 127±128 ꢀC; 1H NMR (CDCl3)
1
give 369 mg (38%) of 21. H NMR (CDCl3) d 0.96 (t,

1138
D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
J=7 Hz, 3H), 1.43 (m, 2H), 1.77 (m, 2H), 2.83 (t,
J=7 Hz, 2H), 3.97 (s, 3H), 4.03 (s, 3H), 6.65 (s, 1H),
6.78 (m, 2H), 7.00 (d, J=16 Hz, 1H), 7.15 (d, J=16 Hz,
1H), 7.30 (d, J=8 Hz, 1H), 7.83 (dd, J=9, 3 Hz, 1H),
8.23 (d, J=3 Hz, 1H); MS (EI) m/z 337 (M)+.
added and the mixture diluted with ether, washed with
water, then brine, dried over MgSO4 and concentrated.
The residue was puri®ed by ¯ash chromatography,
eluting with 20% ether in hexanes, to give 527 mg of 25
1H NMR (CDCl3) d 0.92 (t, J=7 Hz, 3H), 1.25 (t,
J=7 Hz, 3H) 1.44 (m, 2H), 1.76 (m, 2H), 2.80 (t,
J=7 Hz, 2H), 2.90 (m, 2H), 3.03 (m, 2H), 3.45 (s, 2H),
4.00 (s, 3H), 4.17 (q, J=7 Hz, 2H), 6.40 (s, 1H), 6.63 (d,
J=8 Hz, 1H), 6.88 (d, J=8 Hz, 1H); MS (EI) m/z 346
(M)+.
1-(2-Butyl-7-methoxy-benzofuran-4-yl)-2-(2-hydroxy-pyri-
din-5-yl)-ethane (26f). To a solution of 21 (369 mg,
1.1 mmol) in THF/MeOH (4 mL, 1/1) was added 10%
Pd/C (60 mg). The resulting suspension was stirred
under an atmosphere of hydrogen for 4 h then ®ltered
through Celite. The catalyst was washed with CH2Cl2
and the combined ®ltrates concentrated under vacuum.
The residue was puri®ed by ¯ash chromatography,
eluting with 10% ethyl acetate in hexanes, to give
309 mg of 23 (83%). 1H NMR (CDCl3) d 0.95 (t,
J=7 Hz, 3H), 1.42 (m, 2H), 1.74 (m, 2H), 2.77 (t,
J=7 Hz, 2H), 2.87 (m, 2H), 3.00 (m, 2H), 3.90 (s, 3H),
4.00 (s, 3H), 6.30 (s, 1H), 6.64 (d, J=8 Hz, 1H), 6.64 (d,
J=8 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 7.3 (dd, J=8, 3 Hz,
1H), 7.93 (d, J=3 Hz, 1H); MS (EI) m/z 339 (M)+).
This material was then suspended in aqueous HCl
(3 mL, 1.5 M) and the mixture heated to 80 ꢀC and stir-
red at this temperature for 5.5 h. The resulting mixture
was cooled to room temperature, diluted with ethyl
acetate, washed with water, then brine, dried over
MgSO4 and concentrated under vacuum. The residue
was puri®ed by ¯ash chromatography, eluting with
ethyl acetate to give 248 mg (70% based on 20) of 26g as
5-[2-(2-butyl-7-methoxy-benzofuran-4-yl)-ethyl]-1,2-di-
hydro-pyrazol-3-one (26h). To a solution of 25 (440 mg,
1.27 mmol) in MeOH/H2O (5.5 mL 10/1) was added
hydrazine hydrate (89 mL, 2.54 mmol). The resulting
mixture was stirred for 15 min, then neutralized with
1 M HCl. This mixture was diluted with water and ®l-
tered to give 283 mg (71%) of 26h as a solid. mp 222
ꢀ
1
223 C; H NMR (DMSO) d 0.93 (t, J=7 Hz, 3H), 1.37
(m, 2H), 1.69 (m, 2H), 2.75 (m, 4H), 2.95 (m, 2H), 3.34
(s, 1H), 3.89 (s, 3H), 5.27 (s, 1H), 6.67 (s, 1H), 6.74 (d,
J=8 Hz, 1H), 6.90 (d, J=8 Hz, 1H); MS (EI) m/z 314
(M)+. Combustion analysis C18H22O3N2 requires C
68.8, H 7.0, N 8.9. Found C 68.5, H 7.0, N 8.8.
Biological assays
Inhibition of guinea pig PDE4 in vitro was measured
according to the published procedure.17
1
an oil. H NMR (CDCl3) d 0.95 (t, J=7 Hz, 3H), 1.42
(m, 2H), 1.74 (m, 2H), 2.68±2.81 (m, 4H), 2.92 (t,
J=7 Hz, 2H), 4.00 (s, 3H), 6.30 (s, 1H), 6.50 (d,
J=9 Hz, 1H), 6.61 (d, J=8 Hz, 1H), 6.77 (d, J=8 Hz,
1H), 7.04 (d, J=2 Hz, 1H), 7.28 (dd, J=9, 2 Hz, 1H);
MS (EI) m/z 325 (M)+. Combustion analysis C20H23
O3N requires C 73.8, H 7.1, N 4.3. Found C 74.0, H 7.2,
N 4.2.
Murine endotoxemia model. Compounds were adminis-
tered orally in a vehicle of 0.5% methylcellulose/0.2%
Tween-80 in water to male, Balb/c mice (20±25 g, Taco-
nic Labs.) 4 h prior to challenge with LPS (E. coli
055:B5, Sigma Chemical Co., St. Louis, MO, 30 mg/
mouse by intraperitoneal injection). Ninety minutes
following LPS challenge, mice were anesthetized with
Iso¯urane and blood was collected by cardiac puncture.
The whole blood was allowed to clot on ice and serum
was prepared by centrifugation at 200Âg for 10 min.
Serum was assayed for TNF-a by ELISA (Genzyme
Corp., Cambridge, MA). Dose response curves were
generated in duplicate from n=4±6 mice per dose.
3-(2-Butyl-7-methoxy-benzofuran-4-yl)-propionic acid
methyl ester (24). A solution of 22 (2.4 g, 8.3 mmol) in
THF/MeOH (20 mL, 1/1) was added to 10% Pd/C
(350 mg) and the resulting suspension stirred under a
hydrogen atmosphere for 3 h then ®ltered through
Celite. The catalyst was washed with CH2Cl2 and the
combined ®ltrates concentrated under vacuum. The
residue was puri®ed by ¯ash chromatography, eluting
with 10% ethyl acetate in hexanes to give 2.31 g of 24
Acknowledgements
The authors are grateful to Dr. Sheng-Yuh and Mrs J.
Dreibelbis for providing the mass spectral data cited in
this article.
1
(96%). H NMR (CDCl3) d 0.92 (t, J=7 Hz, 3H), 1.40
(m, 2H), 1.73 (m, 2H), 2.65 (t, J=7 Hz, 2H), 2.77 (t,
J=7 Hz, 2H), 3.05 (t, J=7 Hz, 2H), 3.65 (s, 3H), 3.98 (s,
3H), 6.39 (s, 1H), 6.64 (d, J=8 Hz, 1H), 6.90 (d,
J=8 Hz, 1H); MS (EI) m/z 290 (M)+.
References and Notes
1. Beavo, J. A. Phys. Rev. 1995, 75, 725.
5-(2-Butyl-7-methoxy-benzofuran-4-yl)-3-oxo-pentanoic
acid ethyl ester (25). To a cooled ( 78 ꢀC) solution of
LDA (5.8 mL, 1.5 M in cyclohexane) in THF (15 mL)
was added, dropwise, a solution of ethyl acetate
(0.85 mL, 8.7 mmol) in THF (5 mL). The resulting solu-
tion was stirred for 20 min then a solution of 23 (2.26 g,
7.8 mmol) in THF (5 mL) was added. The reaction
mixture was stirred for 15 min then the cold bath
removed and stirring continued until the reaction mix-
ture reached ambient temperature. Water was then
2. Bourne, H. R.; Lichtenstein, L. M.; Melmon, K. L.; Henry,
C. S.; Weinstein, Y.; Shearer, G. M. Science 1974, 184, 19.
3. Verghese, M. W.; McConnell, R. T.; Strickland, A. B.;
Gooding, R. C.; Stimpson, S. A.; Yarnall, D. P.; Taylor, J. D.;
Furdon, P. J. J. Pharmacol. Exp. Ther. 1995, 272, 1313.
4. (a) Schade, F. U.; Schudt, C. Eur. J. Pharmacol. 1993, 230,
9. (b) Semmler, J.; Endres, S. Int. J. Immunopharmac. 1993, 15,
409. (c) Prabhakar, U.; Lipschutz, D.; O'Leary, J.; Slivjak, M.
J.; Smith III, E. F.; Lee, J. C.; Esser, K. M. Int. J. Immuno-
pharmac. 1994, 16, 805.

D. G. McGarry et al. / Bioorg. Med. Chem. 7 (1999) 1131±1139
1139
5. (a) de Brito, F. B.; Souness, J. E.; Warne, P. J. Emerging
Drugs 1997, 2, 249. (b) Marriot, J. B.; Westby, M.; Dalgleish,
A. G. Drug Develop. Today 1997, 2, 273. (c) Nyman, U.;
Mussener, A; Larsson, E.; Lorentzen, J.; Klareskog, L. Clin.
Exp. Immunol. 1997, 108, 415.
6. Palfreyman, M. N. Drugs of the Future 1995, 20, 793.
7. (a) Schwabe, U.; Miyake, M.; Ohaga, Y.; Daly, J. W. Mol.
Pharmacol. 1976, 12, 900. (b) Marivet, M. C.; Bourguignon, J-
J.; Lugnier, C.; Mann, A.; Stoclet, J-C.; Wermuth, C-G. J.
Med. Chem. 1989, 32, 1450.
L.; Brawley, E. S.; Leesnitzer, M. A.; Rose, D. A.; Dougherty,
R. W. Bioorg. Med. Chem. Lett. 1994, 4, 1855. More recently,
a number of groups have published patent applications
describing the use of benzofurans and dihydrobenzofurans for
this purpose. For a short summary of the patent literature in
this area see Exp. Opin. Ther. Patents 1998, 8, 899. See also
Gutterer, B.; Flockerzi, D.; Amschler, H.; Ulrich, W.; Bar, T.;
Martin, T.; Hatzelmann, A.; Boss, H.; Beume, R.; Hafner, D.;
Kley, H-P. Byk Gulden Lomberg: European patent application
819688, 1998; Chem. Abst. 1998, 128, 140616.
8. Reviews: (a) Sta€ord, J. A.; Feldman, P. L. Ann. Rep. Med.
Chem.; Academic Press; 1996, Chapter 8. (b) Burnouf, C.;
Pruniaux, M-P.; Szilagyi, C. M. Ann. Rep. Med. Chem.; Aca-
demic Press; 1998, Chapter 10. (c) Davidsen, S. K.; Summers,
J. B. Exp. Opin. Ther. Patents 1995, 5, 1087±1100. (d) Pal-
freyman, M. N.; Souness J. E. Prog. Med. Chem. 1996, 33, 1.
For some more recent papers in this area see: (a) Kleinmann,
E. F.; Campbell, E.; Giordano, L. A.; Cohan, V. L.; Jenkin-
son, T. H.; Cheng, J. B.; Shirley, J. T.; Pettipher, E. R.; Salter,
E. D.; Hibbs, T. A.; DiCapua, F. M.; Bordner, J. J. Med.
Chem. 1998, 41, 266. (b) Duplantier, A. J.; Andersen, C. J.;
Cheng, J. B.; Cohan, V. L.; Decker, C.; DiCapua, F. M.;
Kraus, K. G.; Johnson, K. L.; Turner, C. R.; Umland, J. P.;
Watson, J. W.; Wester, R. T.; Williams, A. L.; Williams J. A.
J. Med. Chem. 1998, 41, 2268. (c) Christensen, S. B.; Guider,
A.; Forster, C. J.; Gleaseon, J. G.; Bender, P. E.; Karpinski, J.
M.; DeWolf, Jr. W. E.; Barnette, M. S.; Underwood, D. C.;
Griswold, D. E.; Cieslinsky, L. B.; Burman, M.; Bochnowitz,
S.; Osborne, R. R.; Manning, C. D.; Grous, M.; Hillegas, L.
M.; O'Leary Bartus, J. ; Ryan, M. D.; Eggleston, D. S.; Halt-
wanger, R. C.; Torphy, T. J. J. Med. Chem. 1998, 41, 821. (e)
Hulme, C.; Moriarty, K.; Miller, B.; Mathew, R.; Ramanjulu,
M.; Cox, P.; Souness, J.; Page, K.; Uhl, J.; Travis, J.; Huang,
Fu-Chih; Labaudiniere, R.; Djuric, S. W. Bioorg. Med. Chem.
Lett. 1998, 8, 1867 and references therein.
9. Ashton, M. J.; Cook, D. C.; Fenton, G.; Karlsson, J-A.;
Palfreyman, M. N.; Raeburn, D.; Ratcli€e, A. J.; Souness, J.
E.; Thurairatman, S.; Vicker, N. J. Med.. Chem. 1994, 37,
1696.
10. Regan, J. R.; Bruno, J.; McGarry, D.; Poli, G.; Hanney,
B.; Miller, B.; Souness, J.; Djuric S. Bioorg. Med. Chem. Lett.
1998, 8, 2736.
11. The ®rst use of a benzofuran ring system to replace the
3,4-dialkoxy-phenyl subunit of rolipram was reported by the
Glaxo group: Sta€ord, J. A.; Feldman, P. L.; Marron, B. E.;
Schoenen, F. J.; Valvano, N. L.; Unwalla, R. J.; Domanico, P.
12. Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Int.
1995, 27, 127.
13. Duplantier, A. J.; Eggler, J. F.; Marfat, A.; Masamune, H.
P®zer PCT Int. Appl., WO 9412461, 1994; Chem. Abst. 1994,
121, 255409. See also Cohan, V. L.; Showell, D. A.; Fisher, C.;
Pazoles, J. Watson, J. W.; Turner, C. R.; Cheng, J. B. J.
Pharmac. Exp. Ther. 1996, 278, 1356.
14. Feldman, P. L.; Brackeen, M. F.; Cowan. D. J.; Marron,
B. E.; Schoenen, F. J.; Sta€ord, J. A.; Suh, E. M.; Domanico,
P. L.; Rose, D.; Leesnitzer, M. A.; Sloan Brawley, E.; Strick-
land. A. B.; Verghese, M. W.; Connolly, K. M.; Bateman-Fite,
R.; Staton Noel, L.; Sekut, L.; Stimpson, S. A. J. Med. Chem.
1995, 38, 1505±1510.
15. Compound 18 is the 2-alkyl-7-methoxy-benzofuranyl
analogue of the Celltech clinical candidate CDP 840 (structure
30) (a) Warrellow, G. J.; Alexander, R. P.; Boyd, E. C.; Eaton,
M. A.; Head, J. C.; Higgs, G. A. presented at the 8th RSC-SCI
Medicinal Chemistry Symposium, Cambridge, U. K. 1995. (b)
Lynch, J. E.; Choi, W.-B.; Churchill, H. R. O.; Volante, R. P.;
Reamer, R. A.; Ball, R. G. J. Org. Chem. 1997, 62, 9223 and
references therein.
16. For the synthesis of 26d and 26g, the required hetero-
cycles, 5-hydroxy-2-methyl-pyridine and 2-hydroxy-4-methyl-
pyridine, were protected as their t-butyldiphenylsilyl ethers.
17. Turner, N. C.; Wood, L. J.; Burns, F. M.; Gueremy, T.;
Souness, J. E. Br. J. Pharmacol. 1993, 108, 876.
18. Activity relative to that of rolipram was calculated by
dividing the IC50 obtained for a given compound into the IC50
obtained for rolipram under the same assay conditions.
19. The most potent compound we prepared in the benzo-
furan series was 5, R=CH2CH3 (IC50=0.2 nM). This com-
pound we prepared from 2-allyl-3-hydroxy-4-methoxy-benzoic
acid methyl ester in 9 steps.
20. This compound was prepared in the same way as 26a,
except using 3-cyclopentoxy-4-methoxy-benzaldehyde as
starting material instead of 9c.