Biarylcarboxylic acids and -amides: Inhibition of phosphodiesterase type IV versus [3H]rolipram binding activity and their relationship to emetic behavior in the ferret

Article abstract of DOI:10.1021/jm9505066

In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea and vomiting. In general, compounds that inhibit PDE-IV also potently displace [³H]rolipram from a high-affinity binding site in rat cortex. While this binding site has not been identified, it has been proposed to be an allosteric binding site on the PDE-IV enzyme. Preliminary studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity. Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing compounds with decreased [³H]rolipram binding affinity while retaining PDE-IV potency. Thus, a novel series of 4-(3-alkoxy-4- methoxyphenyl)benzoic acids and their corresponding carboxamides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy analogues that provided the desired activity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity (IC₅₀ 0.41 μM) and possessed 400 times weaker activity than rolipram for the [³H]rolipram binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced airway obstruction assay (ED₅₀ 8.8 mg/kg, po) and demonstrated a significant reduction in emetic side effects (ferret, 20% emesis at 30 mg/kg, po).

Full text of DOI:10.1021/jm9505066

120
J . Med. Chem. 1996, 39, 120-125
Bia r ylca r boxylic Acid s a n d -a m id es: In h ibition of P h osp h od iester a se Typ e IV
ver su s [3H]Rolip r a m Bin d in g Activity a n d Th eir Rela tion sh ip to Em etic
Beh a vior in th e F er r et
Allen J . Duplantier,* Michael S. Biggers, Robert J . Chambers, J ohn B. Cheng, Kelvin Cooper, David B. Damon,
J ames F. Eggler, Kenneth G. Kraus, Anthony Marfat,* Hiroko Masamune, J oann S. Pillar, J ohn T. Shirley,
J ohn P. Umland, and J ohn W. Watson
Central Research Division, Pfizer Inc, Groton, Connecticut 06340
Received J uly 13, 1995X
In addition to having desirable inhibitory effects on inflammation, anaphylaxis, and smooth
muscle contraction, PDE-IV inhibitors also produce undesirable side effects including nausea
and vomiting. In general, compounds that inhibit PDE-IV also potently displace [3H]rolipram
from a high-affinity binding site in rat cortex.1,2 While this binding site has not been identified,
it has been proposed to be an allosteric binding site on the PDE-IV enzyme.3 Preliminary
studies have suggested that the emetic potency of PDE-IV inhibitors is correlated with affinity
for the brain rolipram binding site rather than potency at inhibiting PDE-IV enzyme activity.
Efforts to eliminate the emetic potential of PDE-IV inhibitors were directed toward developing
compounds with decreased [3H]rolipram binding affinity while retaining PDE-IV potency. Thus,
a novel series of 4-(3-alkoxy-4-methoxyphenyl)benzoic acids and their corresponding carboxa-
mides were prepared and evaluated for their PDE-IV inhibitory and rolipram binding site
properties. Modification of the catechol ether moiety led to phenylbutoxy and phenylpentoxy
analogues that provided the desired actitivity profile. Specifically, 4-[3-(5-phenylpentoxy)-4-
methoxyphenyl]-2-methylbenzoic acid, 18, was found to exhibit potent PDE-IV inhibitory activity
(IC50 0.41 µM) and possessed 400 times weaker activity than rolipram for the [3H]rolipram
binding site. In vivo, compound 18 was efficacious in the guinea pig aerosolized antigen induced
airway obstruction assay (ED50 8.8 mg/kg, po) and demonstrated a significant reduction in
emetic side effects (ferret, 20% emesis at 30 mg/kg, po).
In tr od u ction
dazolidinones (1).12 Following this reasoning, 4 was
modified to reduce its affinity for the [3H]rolipram
binding site, leading to compound 18 which displayed
a greatly reduced emetic liability. The SAR of this novel
series of arenecarboxylic acid and -carboxamide catechol
ethers leading to compound 18 is reported herein.
Inhibition of phosphodiesterase type IV (PDE-IV)
represents a promising therapeutic target for the treat-
ment of various inflammatory diseases such as arthritis
and asthma.4-7 However, the currently known PDE-
IV inhibitors, such as the prototypical agent rolipram,
are hampered by nausea and emetic side effects limiting
their therapeutic potential.8 While it is possible that
PDE inhibitors have peripheral emetic actions, there is
current evidence demonstrating an effect on the area
postrema.9 Therefore it is reasonable to assume that
keeping a PDE-IV inhibitor out of the brain could reduce
its emetic potential. To reduce this side effect liability,
we reasoned that incorporation of an arenecarboxylic
acid would reduce penetration into the brain and, thus,
reduce activity at the emetic center in the central
nervous system (CNS). Compound 4 was designed on
the basis of a previously reported series of catechol
ethers with potent PDE-IV inhibitory activity10 and
synthesized as an initial test of this hypothesis. Al-
though 4 displayed potent PDE-IV inhibitory activity,
it also showed a similar emetic liability to rolipram. As
a follow-up hypothesis, we considered that the affinity
of a compound for the [3H]rolipram binding site might
be a factor in determining its emetic potency. In fact,
[3H]rolipram binding activity has been correlated with
emetic side effects in a study in dogs.11 Furthermore,
a reduction in the ratio of the concentrations required
for inhibition of PDE-IV to [3H]rolipram binding activity
to mouse brain was previously achieved by catechol
ether modifications to a series of rolipram-related imi-
Ch em istr y
All of the biaryl carboxylic acids reported herein were
prepared from 5-bromoguaiacol as presented in Scheme
1. Etherification of 5-bromoguaiacol with the appropri-
ate alcohol under Mitsunobu conditions13 gave the
catechol diethers 2a -h in 80-90% yield. Catechol
diether 2k was synthesized from 5-bromoguaiacol by
acylation with 4-phenylbutyryl chloride followed by
treatment with [bis(cyclopentadienyl)titanium](µ-chloro)-
(µ-methylidene)dimethylaluminum (Tebbe’s reagent)14
to give enol ether 2j (Scheme 2). Subsequent subjection
of 2j to a Simmons-Smith reaction15 readily provided
2k . Catechol diethers 2a -h and 2k were then con-
verted to their corresponding arylzinc chlorides by
treatment with n-butyllithium and zinc chloride (Scheme
1) and were coupled in situ to the desired aryl iodide or
bromide by palladium catalysis.16 The resulting biaryl
X Abstract published in Advance ACS Abstracts, December 1, 1995.
0022-2623/96/1839-0120$12.00/0 © 1996 American Chemical Society

Biarylcarboxylic Acids and -amides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 121
Sch em e 1a
either ip or po.20 Both emetic (vomiting and retching)
as well as prodromal activity (gagging, mouth scratch-
ing, and salivation) were scored.
Str u ctu r e-Activity Rela tion sh ip s
As mentioned in the Introduction, biarylcarboxylic
acid 4 was designed to have minimal CNS exposure. We
reasoned that the carboxylic acid functionality would
be polar enough to prohibit any compound migration
into the brain. Furthermore, the PDE-IV inhibitory
activity (IC50 0.52 µM) of compound 4 was enhanced
compared to that of rolipram (Table 1), making 4 an
exciting compound for testing our hypothesis. However,
compound 4 caused emesis in a ferret emesis model
(100% prodromal or emetic behavior at 10 mg/kg, ip),
and this result led us to the redirected strategy of
preparing potent PDE-IV inhibitors with reduced [3H]-
rolipram binding activity.
a
Reagents and conditions: (i) R1OH, DEAD, PPh3, THF, 25
°C; (ii) n-butyllithium, THF, -78 °C; ZnCl2, then warm to 25 °C;
Pd(PPh3)4, aryl iodide or bromide; (iii) NaOH, EtOH, reflux; (iv)
SOCl2; DMF (cat.), NH3(g)/CH2Cl2 or NH4OH/THF.
Sch em e 2a
We chose the cyclopentoxy group and the carboxylic
acid functionality of compound 4 for SAR development.
The corresponding methyl ester 3 did not inhibit PDE-
IV, and this result suggested a hydrogen-bonding in-
teraction between the carboxylic acid moiety in 4 and
the PDE IV isozyme. The m-carboxylic acid 5 also
inhibited PDE-IV, but was 3 times less potent than 4.
Thus, the p-carboxylic acid 4 was chosen for further SAR
studies.
a
Reagents and conditions: (i) 4-phenylbutyryl chloride, 4-
DMAP, pyridine, 0 °C; (ii) Tebbe reagent, pyridine, 1:3 THF/
toluene; (iii) CH2I2, Zn-Cu couple, I2, ether, reflux.
Replacement of the cyclopentyl group with either an
(S)- or (R)-2-exo-norbornyl group10 (6 and 7, respectively)
had no effect on rolipram binding, and to our surprise,
the two enantiomers had equipotent PDE-IV inhibition.
In efforts to reduce the affinity to the [3H]rolipram
binding site, we next applied some of the catechol ether
side chain modifications previously disclosed for com-
pound 1.12 In parallel to the SAR derived for 1, the
2-indanyl analogue 8 was 6 times more potent than 4
against the PDE-IV enzyme and displayed ∼4 times less
[3H]rolipram binding activity. Moreover, the 4-phenyl-
butyl (9) and the (S)- and (R)-5-phenylpent-2-yl ana-
logues (10 and 11, respectively) were 10 times weaker
than 4 for [3H]rolipram binding activity. The 10 times
difference in PDE-IV potency between compound 10 and
its enantiomer, 11, revealed for the first time enan-
tiospecificity at the catechol ether moiety. Interestingly,
the achiral cyclopropyl analogue 12 was equipotent to
10 for both PDE-IV inhibition and rolipram binding
activity.
The COOH group was the next structural moiety that
we modified. We believed that replacement of the
COOH group with CONH2 would still allow for the
required hydrogen bonding at this site to the PDE-IV
enzyme and should therefore provide analogues with
potent PDE-IV inhibition. Thus, replacement of the
carboxylic acid functionality of the acid analogue 8 with
a carboxamide group provided compound 13, displaying
slightly weaker PDE-IV activity and slightly more
potent [3H]rolipram binding affinity. The 4-phenylbu-
toxy analogue 14 was ∼60 times less potent than its
acid homologue as a PDE-IV inhibitor, but most inter-
estingly 14 showed very low affinity for the [3H]rolipram
binding site. More striking was the dramatic difference
in PDE-IV potency between the 5-phenylpent-2-yl enan-
tiomers, 15 and 16. The cyclopropyl analogue 17
showed more potent PDE-IV activity (IC50 0.67 µM)
compared to the 4-phenylbutoxy analogue 14. This
esters (e.g. 3) were then saponified to provide carboxylic
acids 4-12 and 18. Selected carboxylic acids were
subsequently converted to their corresponding amides
by successive treatment with thionyl chloride and either
anhydrous ammonia or ammonium hydroxide.
Biology
Over the last three decades PDEs have evolved into
seven major families (PDE-I, -II, -III, -IV, -V, -VI, and
-VII) according to their substrate sensitivity, Ca2+
/
calmodulin requirement, and inhibitor selectivity.17
PDE-IV, a cAMP-specific and Ca2+-independent enzyme,
was shown to be a key isozyme that controls the
hydrolysis of cAMP in mast cells, basophils, eosinophils,
monocytes, and lymphocytes.17 As a result, inhibitors
of PDE-IV block the activation of various mediators from
these cells and may represent a new class of anti-
inflammatory drugs. Recently, four human cDNA iso-
forms of PDE-IV (PDE-IV-A, -B, -C, and -D) were
identified, and all four were expressed in human lung.18
PDE-IV was isolated from human lung homogenates
by differential centrifugation and ion-exchange chro-
matography.19 Human lung PDE-IV cannot be stimu-
lated by CaCl2 (1 µM to 100 mM) and is activated by
MnCl2 and MgCl2 (EC50 ∼10 µM). The double reciprocal
plot of the results of enzyme kinetic experiments reveal
a Km of 1.0 ( 0.1 µM and a Vmax ) 0.51 ( 0.1 µM/(min/
mg) protein for lung PDE-IV (n ) 4). Except for
rolipram (IC50 ) 3.45 µM), vinpocetine (PDE-I inhibitor),
SKF-94120 (PDE-III inhibitor), zaprinast (PDE-V in-
hibitor), and cGMP are inactive at 100 µM. [3H]-
Rolipram binding activity was evaluated using whole
mouse brain.2,12
The antianaphylactic activity of PDE-IV inhibitors
was determined by the ability to block the airway
obstructive response of anti-OA-IgG1 passively sensi-
tized guinea pigs challenged with aerosolized ovalbu-
men. Emetic activity was determined in ferrets dosed

122 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Duplantier et al.
Ta ble 1. PDE Inhibition of Biarylcarboxylic Acids and -amides Prepared from 2
PDE-IV IC50 (µM) or % rolipram bind. IC50(µM)
entry
R1
cyclopentyl
cyclopentyl
cyclopentyl
R2
R3
formula
analysisa mp (°C)
inh, conc ( SEM (n)f
or % inh, conc ( SEM (n)f
rolipram
3.45 ( 0.34 (7)
0.004 ( 0.0002 (111)
0.13 ( 0.04 (3)
3
4
5
6
7
8
9
CO2Me
CO2H
H
H
H
C20H22O4
C19H20O4
C, H
C, H
C, H
C, H
C, H
C, Hb
C, Hc
C, H
C, H
C, H
131-2 25.1 ( 3.9%, 100 µM (3)
230-2 0.52 ( 0.18 (3)
149-50 1.64 ( 0.81 (2)
230-2 0.11 ( 0.03 (2)
234-6 0.13 ( 0.04 (2)
244-7 0.081 ( 0.006 (3)
178-9 0.30 ( 0.04 (2)
159-60 0.14 ( 0.01 (3)
159-60 1.42 ( 0.15 (5)
141-2 0.13 ( 0.05 (2)
0.009 ( 0.0005 (3)
0.015 ( 0.002 (3)
0.003 ( 0.0005 (3)
0.003 ( 0.0004 (3)
0.015 ( 0.004 (3)
0.323 ( 0.061 (3)
0.111 ( 0.035 (5)
0.623 ( 0.050 (3)
0.129 ( 0.013 (3)
0.005 ( 0.002 (3)
26 ( 3%, 10 µM (3)
33 ( 5%, 10 µM (3)
41 ( 1%, 100 µM (3)
1.90 ( 0.75 (3)
CO2H C19H20O4
(S)-(+)-2-exo-norbornyl CO2H
(R)-(-)-2-exo-norbornyl CO2H
H
H
H
H
H
H
H
H
H
H
H
H
C21H22O4
C21H22O4
C23H20O4
C24H24O4
C25H26O4
C25H26O4
C26H26O4
2-indanyl
4-phenylbutyl
(i)
(ii)
(iii)
2-indanyl
4-phenylbutyl
(i)
CO2H
CO2H
CO2H
CO2H
10
11
12
13
14
15
16
17
18
CO2H
CONH2
CONH2
CONH2
CONH2
CONH2
CO2H
C23H21NO3 C, H, Nd 237-9 0.16 ( 0.11 (2)
C24H25NO3 C, H, N 178-80 20.3 ( 15.0 (4)
C25H27NO3 C, H, N 182-4 1.94 ( 1.36 (3)
(ii)
(iii)
C25H27NO3
C26H27NO3 C, H, Ne 154-5 0.67 ( 0.17 (3)
C26H28O4 C, H 127-8 0.41 ( 0.02 (2)
183-4 24 ( 10%, 100 µM (3)
5-phenylpentyl
CH3
1.68 ( 0.005 (2)
a
b
Unless indicated, all values were within 0.4%. C: calcd, 76.65; found, 75.93. c C: calcd, 76.56; found, 76.06; H: calcd, 6.43; found,
5.92. N: calcd, 3.90; found, 3.27. e C: calcd, 77.78; found, 74.61. f Number in parentheses denotes number of times tested.
d
Ta ble 2. In Vivo Results for Selected PDE-IV Inhibitors
PDE-IV
IC50, µM
rolipram binding
IC50 or % inh, conc
AAIAO assay
ED50 mg/kg, po
compound
ferret emesis (drug plasma conc)e
rolipram
3.45
1.94
0.67
0.41
0.004 µM
33%, 10 µM
1.90 µM
0.6a
1.1a
2/10b at 0.03 mg/kg, poc (<0.09 µM)f
0/10b at 30 mg/kg, pod (<0.06 µM)f
not tested
15
17
18
26 ( 20% inh at 10 mg/kg
1.68 µM
8.8a
3/15b at 30 mg/kg, pod (24.0 ( 10.2 µM)
a
ED50 based on log linear regression on a minimum of three point dose response curve. Each point is generated by n ) 5 animals.
Number of animals exhibiting emesis or prodromal behavior/total animals tested. c Tween 80/water as vehicle. PEG 400 as vehicle.
b
d
e Corresponding concentration of drug in ferret plasma at 1 h post dose. f HPLC detection limit.
result contrasts with data for compounds 9 and 12
(carboxylic acids) which show similar inhibition of PDE-
IV. Compared to rolipram, the [3H]rolipram binding
affinities for compounds 15 and 17 were more than 400
times less potent and their PDE-IV inhibitory properties
were maintained. Thus, 15 and 17 appeared to be good
compounds for testing the hypothesis correlating rolip-
ram binding with emetic side effects.
In vivo, compound 17 was not very efficacious in the
guinea pig aerosolized antigen-induced airway obstruc-
tion assay (AAIAO) (26% inhibition at 10 mg/kg, po),
but compound 15 showed good activity in this assay
(ED50 1.1 mg/kg, po) (Table 2). Thus, 15 was compa-
rable to rolipram for both inhibition of PDE-IV (IC50’s
1.94 and 3.45 µM, respectively) and efficacy in the
AAIAO assay (ED50’s 1.1 and 0.6 mg/kg, po, respec-
tively), but differed in [3H]rolipram binding affinity
(IC50’s >10 µM and 4 nM, respectively). Moreover, 15
failed to show emetic or prodromal effects in the ferret
at a dose of 30 mg/kg, po, whereas 20% of ferrets dosed
with rolipram at 0.03 mg/kg, po, displayed prodromal
or emetic behavior. However, the presence of 15 was
undetected in the ferret’s plasma at 1 h postdose,
indicating that compound 15 was either not absorbed
or was rapidly metabolized. Thus, we could not con-
clude that there was a relationship between the weak
[3H]rolipram binding activity of carboxamides 15 and
17 and the apparent lack of emetic side effects. As-
suming that the carboxamide moiety was metabolically
labile, we redirected our focus to the corresponding
carboxylic acid functionality.
In efforts to test our hypothesis using the carboxylic
acid functionality, we concentrated on analogues of
compounds 9-12 in which the position ortho to the
carboxylic acid group and the length of the catechol
ether side chain was varied. Specifically, 4-[3-(5-phen-
ylpentoxy)-4-methoxyphenyl]-2-methylbenzoic acid, 18,
was found to exhibit potent PDE-IV inhibitory activity
(IC50 0.41 µM) and possessed 400 times weaker activity
than rolipram for [3H]rolipram binding affinity (Table
1). In vivo, compound 18 was efficacious in the AAIAO
assay (guinea pig, ED50 8.8 mg/kg, po) and demonstrated
a significant reduction in emetic side effects (ferret, 20%
prodromal or emetic behaviors at 30 mg/kg, po) (Table
2). Importantly, the concentration of 18 in the ferret
plasma at this dose was 24.0 µM (1 h postdose). Thus,
the above data for compound 18 provides evidence in
support of the hypothesis that [3H]rolipram binding
affinity is linked to emetic side effects.
Con clu sion s
In conclusion, the above results support the hypoth-
esis that [3H]rolipram binding activity is responsible for
the emetic side effects seen with PDE-IV inhibitors.

Biarylcarboxylic Acids and -amides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 123
determined in a liquid scintillation counter. IC50 values were
determined from semilog graphs of percent inhibition versus
concentration.
Furthermore, the SAR developed for the catechol ether
side chain of the biarylcarboxylic acids in this report
can be used as a means of designing PDE-IV inhibitors
with reduced emetic potency.
Aer osolized An t igen In d u ced Air w a y Ob st r u ct ion
Assa y. This assay tests the ability of a compound to block
the airway obstruction resulting from an aerosolized antigen
induced pulmonary anaphylaxis. Male Hartley guinea pigs
(300-350 g) are passively immunized by subcutaneous injec-
tion of 0.375 mg/kg of purified guinea pig anti-ovalbumin IgG1,
48-72 h prior to antigen challenge. Pyrilamine (5 mg/kg) and
propranolol (2 mg/kg) are administered subcutaneously 30 min
prior to challenge. Test compounds are administered into the
stomach, either one or 2 h prior to challenge, as a suspension
in water and 2% Tween-80 using an Argyle feeding tube.
Guinea pigs (five/test dose + five controls) are then placed
in a Tri-R Airborne infection apparatus (model A42). Oval-
bumin (OA, 0.01-0.03%) is dissolved in 0.9% saline, placed
in the glass nebulizer-venturi unit and aerosol generated for
5 min (main air flow meter set at 10). This is followed by a 8
min cloud decay (vacuum flow set at 7.0).
After removal, animals are sacrificed by ip injection of ∼2
mL of sodium pentobarbital. Animals die within 1 to 2 min
of injection. As soon as they die, the animals’ pleural spaces
are opened by cutting into the xyphoid process allowing the
lungs to collapse. Lungs are then removed, the heart cut away,
and the trachea tied. The volume of air trapped in the lungs
is determined by measuring the upward force exerted on a 20
g anchor, when the lungs and anchor are submerged in saline.
The volume of trapped gas is normalized to the animal’s body
weight and expressed as excised lung gas volume (ELGV) in
mL/kg.
Exp er im en ta l Section
Biology. P h osp h od iesta r a se Typ e IV Activity. Thirty
to forty grams of human lung tissue is placed in 50 mL of pH
7.4 Tris-phenylmethanesulfonyl fluoride (PMSF)/sucrose buffer
and homogenized using a Tekmar Tissumizer (Tekmar Co.,
Cincinnati, OH) at full speed for 30 s. The homogenate is
centrifuged at 48000g for 70 min at 4 °C. The supernatant is
filtered twice through a 0.22 µm filter and applied to a Mono-Q
FPLC column (Pharmacia LKB Biotechnology, Piscataway,
NJ ) preequilibrated with pH 7.4 Tris-PMSF buffer. A flow
rate of 1 mL/min is used to apply the sample to the column,
followed by a 2 mL/min flow rate for subsequent washing and
elution. Sample is eluted using an increasing, stepwise NaCl
gradient in the pH 7.4 Tris-PMSF buffer. Eight 1.0 mL
fractions are collected. Fractions are assayed for specific PDE-
IV activity, determined by [3H]cAMP hydrolysis and the ability
of a known PDE-IV inhibitor (e.g. rolipram) to inhibit that
hydrolysis. Appropriate fractions are pooled, diluted with
ethylene glycol (2 mL ethylene glycol/5 mL of enzyme prep)
and stored at -20 °C until use.
Compounds are dissolved in DMSO at a concentration of
10 mM and diluted 1:25 in water (400 µM compound, 4%
DMSO). Further serial dilutions are made in 4% DMSO to
achieve desired concentrations. The final DMSO concentration
in the assay tube is 1%. In duplicate the following are added,
in order, to a 12 × 75 mm glass tube (all concentrations are
given as final concentrations in assay tube): (i) 25 µL of
compound or DMSO (1%, for control and blank), (ii) 25 µL of
pH 7.5 Tris buffer and 10 mM MgCl2, (iii) [3H]cAMP (1 µM),
(iv) 25 µL of PDE-IV enzyme (for blank, enzyme is preincu-
bated in boiling water for 5 min).
A test compound’s performance is judged by its ability to
reduce the drug-treated group mean ELGV below that of the
control group mean ELGV. A log linear regression is per-
formed on the grouped mean data, and an ED50
is calculated
as the dose necessary to produce a 50% reduction below the
control group ELGV.
The reaction tubes are shaken and placed in a water bath
(37 °C) for 20 min, at which time the reaction is stopped by
placing the tubes in a boiling water bath for 4 min. Washing
buffer (0.5 mL, 0.1 M 4-(2-hydroxyethyl)-1-piperazineethane-
sulfonic acid (HEPES)/0.1 M NaCl, pH 8.5) is added to each
tube on an ice bath. The contents of each tube are applied to
an Affi-Gel 601 column (Biorad Laboratories, Melville, NY)
(boronate affinity gel, 1 mL bed volume) previously equili-
brated with washing buffer. [3H]cAMP is washed with 2 × 6
mL of washing buffer, and [3H]-5′AMP is then eluted with 4
mL of 0.25 M acetic acid. After vortexing, 1 mL of the eluent
is added to 3 mL of scintillation fluid in a suitable vial,
vortexed, and counted for [3H].
F er r et Em esis Assa y. Five male ferrets are dosed with
the test compound (either oral or ip) and then placed in clear
individual Plexiglas cages. The vehicle for the oral dosing is
2% Tween-80 and 3 mL of distilled water. The vehicle for ip
dosing is 3 mL of distilled water.
Animals are watched continuously throughout the study
period (typically 60 min). The following behavioral patterns
are scored as emesis: (1) productive vomiting, (2) nonproduc-
tive vomiting where the animal makes multiple abdominal
pumping movements associated with retching or an open
mouth, (3) gagging which is an abdominal contraction against
a closed glottis with mouth wide open and culminating in an
expiatory cough, and (4) scratching of the roof of the mouth
with a fore paw. For each animal, the number of behavioral
episodes and the time at which they occur is recorded. Data
is expressed as percent of animals exhibiting emesis or
prodromal behaviors. If plasma drug levels are required,
animals are anesthetized with rompun and ketamine and 1
mL of blood is drawn from the heart using standard cardiac
puncture techniques.
% inhibition )
1 - [average cpm (test compound) - average cpm (blank)]/
[average cpm (control) - average cpm (blank)]
IC50 is defined as that concentration of compound which
inhibits 50% of specific hydrolysis of [3H]cAMP to [3H]5′AMP.
The IC50 values for the compounds reported were determined
from concentration-response curves in which concentration
ranged from 0.01 to 100 µM.
Ferrets are not restudied for 7 days. Animals used in this
screen are only exposed to emetic stimuli three times and are
then removed from the colony.
[3H]Rolip r a m Bin d in g Assa y. Fresh mouse brains were
homogenized in 20 volumes of ice-cold 50 mM Tris‚HCl (pH
8.0) buffer containing 1.2 mM MgCl2 in a polytron PT-10
homogenizer (Brinkman Instruments). The resulting homo-
genate was centrifuged at 30000g for 20 min at 4 °C. The
pellet was washed by resuspension in 20 volumes of fresh
buffer and recovered by centrifugation as before. The final
pellet was suspended in Tris buffer (0.5 mg of protein/mL) for
binding experiments. Incubation mixtures in duplicates con-
sisted of 0.1 mL of (()-[3H]rolipram (2 nM final), 0.02 mL of
inhibitor, and 0.9 mL of membrane preparation (added last).
Rolipram (10 µM) was used for nonspecific binding. After a
60 min incubation at 4 °C the contents of the incubation tubes
were filtered through a Whatman GF/C glass filter. The
membranes were washed three times with 3 mL of ice-cold
buffer, and radioactivity on the separated filter disks was
Ch em istr y. Gen er a l Meth od s. Anhydrous THF and
ether were distilled over Na under a N2
atmosphere. Other
solvents and reagents were of reagent grade and were used
as supplied by the manufacturer. All reactions were run under
a N2 atmosphere. Organic extracts were routinely dried over
anhydrous Na2SO4. Concentration refers to rotory evapora-
ration under reduced pressure. Chromatography refers to
“flash chromatography” on EM Science silica gel (40-63 µm).
Melting points were determined using a Mel-Temp II capillary
melting point apparatus and are uncorrected. Elemental
analyses were performed either by Schwarzkopf Microana-
lytical Lab., Woodside, NY, or by Pfizer Microanalytical Lab.,
Groton, CT.
Gen er a l P r oced u r e A. Eth er ifica tion of 5-Br om ogu a i-
a col. (R)-exo-2-(5-Br om o-2-m et h oxyp h en oxy)b icyclo-
[2.2.1]h ep ta n e (2c). To a stirred solution of 5-bromoguaiacol

124 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Duplantier et al.
(1.50 g, 7.39 mmol), triphenylphosphine (2.13 g, 8.13 mmol),
and (S)-(-)-endo-norborneol (0.83 g, 7.39 mmol) in anhydrous
THF (25 mL) at 25 °C was added diethyl azodicarboxylate (1.4
mL, 8.9 mmol). After 18 h the mixture was diluted with ether
(350 mL) and washed with 1 N NaOH, water, and brine.
Concentration provided a yellow oil which was triturated with
1:1 ether/hexane to remove triphenylphosphine oxide. The
filtrate was concentrated and chromatographed (1:9 ethyl
acetate/hexane) to afford 1.75 g (80%) of a clear colorless oil:
gas evolution had ceased, ether was added and the mixture
was concentrated. Chromatography through a short column
of basic alumina eluted with 1:3 petroleum ether/ether afforded
4.4 g (97%) of a yellow oil: 1H NMR (300 MHz, CDCl3) δ 1.95
(quintet, J ) 7.6 Hz, 2H), 2.33 (t, J ) 7.3 Hz, 2H), 2.72 (t, J )
7.7 Hz, 2H), 3.80 (s, 3H), 3.84 (d, J ) 2.1 Hz, 1H), 4.10 (d, J
) 2.0 Hz, 1H), 6.81 (d, J ) 8.72 Hz, 1H), 7.14-7.32 (m, 7H);
MS m/z 347.
1-(5-Br om o-2-m eth oxyp h en oxy)-1-(3-p h en ylp r op yl)cy-
clop r op a n e (2k ). To a stirred solution of 2j (4.4 g, 12.7 mmol)
in anhydrous ether (8 mL) was added methylene iodide (3.7
g, 14.0 mmol) followed by zinc-copper couple (0.84 g, 14.0
mmol) and iodine (5 mg). After heating at reflux for 17 h, the
mixture was filtered and washed with ether. The combined
ether washings were washed with saturated aqueous am-
monium chloride, sodium bicarbonate, and brine. Concentra-
tion and chromatography (1:9 ethyl acetate/hexane) afforded
3.2 g (71%) of a colorless oil. 1H NMR (300 MHz, CDCl3) δ
0.73 (dd, J ) 5.9, 7.4 Hz, 2H), 1.04 (dd, J ) 5.6, 6.9 Hz, 2H),
1.76-1.87 (m, 4H), 2.63 (t, J ) 7.0 Hz, 2H), 3.81 (s, 3H), 6.73
(d, J ) 8.5 Hz, 1H), 7.02 (dd, J ) 2.2, 8.7 Hz, 1H); HRMS
calcd for C19H21BrO2 360.0725, found 360.0714.
1
[R]D -23.1° (c ) 1.59, CHCl3); H NMR (300 MHz, CDCl3) δ
1.1 (m, 3H), 1.5 (m, 3H), 1.8 (m, 2H), 2.32 (m, 1H), 2.49 (d, J
) 4.6 Hz, 1H), 3.80 (s, 3H), 4.14 (d, J ) 6.5 Hz, 1H), 6.71 (d,
J ) 8.5 Hz, 1H), 6.92 (d, J ) 2.3 Hz, 1H), 6.98 (dd, J ) 8.5,
2.3 Hz, 1H). Anal. (C14H17O2Br) C, H.
1
4-Br om o-2-cyclop en toxya n isole (2a ):21 colorless oil; H
NMR (250 MHz; CDCl3) δ 1.59-1.70 (m, 2H), 1.80-2.06 (m,
6H), 3.85 (s, 3H), 4.65-4.76 (m, 1H), 6.69 (d, J ) 8.4 Hz, 1H),
6.99 (m, 2H).
(S)-exo-2-(5-Br om o- 2-m eth oxyp h en oxy)bicyclo[2.2.1]-
h ep ta n e (2b). See 2c for 1H NMR and purification method:
colorless oil; [R]D +21.8° (c ) 1.42, CHCl3). Anal. (C14H17O2-
Br) C, H.
4-Br om o-2-(2-in d a n yloxy)a n isole (2d ): purified by chro-
matography (95:5 hexane/ethyl acetate) followed by recrystal-
lization from methanol; 76% yield; white solid; mp 116-117
Gen er a l P r oced u r e B. P a lla d iu m -Ca ta lyzed Bia r yl
Cou plin g. (R)-(+)-4-[4-Meth oxy-3-(5-ph en ylpen t-2-yloxy)-
p h en yl]ben zoic Acid (10). To a stirred solution of 2f (2.0 g,
5.7 mmol) in anhydrous THF (30 mL) at -78 °C was added
dropwise a 2.5 M solution of n-BuLi in hexanes (2.80 mL, 7.0
mmol). After 30 min a 1 M solution of ZnCl2 in THF (7.0 mL,
7.0 mmol) was added, and the mixture was warmed to ambient
temperature over 30 min before adding tetrakis(triphenylphos-
phine)palladium(0) (0.42 g, 0.36 mmol) and methyl 4-bro-
mobenzoate (1.32 g, 5.7 mmol). After stirring at ambient
temperature over 3 h, the mixture was concentrated and
chromatographed (1:3 ether/hexane) to give 1.2 g (50%) of a
yellow oil (MS m/z 418). The oil was dissolved in a mixture of
ethanol (15 mL) and 1 N NaOH (12 mL) and heated to reflux.
After 1.5 h the ethanol was removed under reduced pressure,
water (20 mL) was added, and the mixture was extracted with
ether before being acidified to pH ∼2 with 6 N HCl. The
resulting suspension was extracted with methylene chloride,
and the combined organics were washed with water and brine.
Concentration provided 1.04 g (45% from 2f) of a white solid:
mp 159-160 °C; [R]D +33.3° (CHCl3); 1H NMR (250 MHz;
CDCl3) δ 1.34 (d, J ) 6.2 Hz, 3H), 1.59-1.94 (m, 4H), 2.67 (t,
J ) 7.1 Hz, 2H), 3.89 (s, 3H), 4.38-4.50 (m, 1H), 6.94 (d, J )
8.3 Hz, 1H), 7.10-7.29 (m, 7H), 7.59 (d, J ) 8.2 Hz, 2H), 8.15
(d, J ) 8.2 Hz, 2H). Anal. (C25H26O4) C, H.
1
°C; H NMR (300 MHz, CDCl3) δ 3.23 (dd, J ) 3.7, 16.7 Hz,
2H), 3.40 (dd, J ) 6.6, 16.7 Hz, 2H), 3.78 (s, 3H), 5.15 (m, 1H),
6.74 (d, J ) 9.1 Hz, 1H), 7.05 (m, 2H), 7.21 (m, 4H). Anal.
(C16H15BrO2) C, H.
4-Br om o-2-(4-p h en ylbu toxy)a n isole (2e): purified by
chromatography (4:1 hexane/ethyl acetate); 95% yield; yellow
oil; 1H NMR (250 MHz, CDCl3) δ 1.75-1.92 (m, 4H), 2.70 (t, J
) 7.0 Hz, 2H), 3.84 (s, 3H), 3.99 (t, J ) 6.3 Hz, 2H), 6.73 (d, J
) 8.5 Hz, 1H), 6.95-7.10 (m, 2H), 7.19-7.39 (m, 5H). Anal.
(C17H19BrO2) C, H.
(R)-4-Br om o-2-(5-p h en yl-2-p en toxy)a n isole (2f): puri-
fied by chromatography (4:1 hexane/ethyl acetate); 80% yield;
colorless oil; [R]D +9.05° (CHCl3); 1H NMR (250 MHz, CDCl3)
δ 1.31 (d, J ) 6.1 Hz, 3H), 1.61-1.98 (m, 4H), 2.62-2.69 (m,
2H), 3.82 (s, 3H), 4.28-4.38 (m, 1H), 6.73 (d, J ) 8.6 Hz, 1H),
6.96-7.05 (m, 2H), 7.16-7.21 (m, 3H), 7.24-7.32 (m, 2H).
Anal. (C18H21BrO2): H; C: calcd, 61.90; found, 59.77.
(S)-4-Br om o-2-(5-p h en yl-2-p en toxy)a n isole (2g): color-
less oil; [R]D -9.0° (CHCl3); 1H NMR identical with 2f. Anal.
(C18H21BrO2) H; C: calcd, 61.90; found, 61.18.
4-Br om o-2-(5-p h en ylp en toxy)a n isole (2h ): purified by
chromatography (4:1 hexane/ethyl acetate); 98% yield; 1H NMR
(300 MHz, CDCl3) δ 1.51 (m, 2H), 1.71 (m, 2H), 1.88 (m, 2H),
2.66 (t, J ) 7.6 Hz, 2H), 3.84 (s, 3H), 3.98 (t, J ) 6.8 Hz, 2H),
6.73 (d, J ) 8.5 Hz, 1H), 7.01 (m, 2H), 7.19 (m, 3H), 7.31 (m,
2H). Anal. (C18H21BrO2) C, H.
5-Br om o-2-m eth oxyp h en yl 4-p h en ylbu tyr a te (2i). To
a stirred solution of 5-bromoguaiacol (5.0 g, 24.6 mmol) and
4-DMAP (10 mg) in pyridine (25 mL) at 0 °C was added
phenylbutyryl chloride (6.7 g, 36.9 mmol) dropwise over 10
min. An exotherm was observed, and a white precipitate
formed during the addition. After stirring for 2 h at room
temperature, the reaction was quenched with water (5 mL)
and the mixture diluted with a 1:3 mixture of ethyl acetate/
hexane (250 mL). The mixture was then washed with 1 N
HCl (100 mL × 3), saturated aqueous bicarbonate, and brine,
dried over sodium sulfate, and filtered. Concentration and
chromatography (1:5 ethyl actetate/hexane) provided 8.3 g
(97%) of a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 2.09
(quintet, J ) 7.5 Hz, 2H), 2.60 (t, J ) 7.3 Hz, 2H), 2.77 (t, J )
7.6 Hz, 2H), 3.81 (s, 3H), 6.84 (d, J ) 8.8 Hz, 1H), 7.16-7.35
(m, 7H); MS m/z 348 and 350.
2-(5-Br om o-2-m eth oxyph en oxy)-5-ph en yl-1-pen ten e (2j).
Tebbe reagent (prepared from titanocene dichloride and tri-
methyl aluminum) (30 mL of a 0.55 M solution in toluene) was
added dropwise to a stirred solution of 5-bromo-2-methoxy-
phenyl 4-phenylbutyrate (2i) (4.55 g, 13.0 mmol) and pyridine
(0.25 mL) in a mixture of anhydrous THF (10 mL) and
anhydrous toluene (30 mL) at 0 °C. The reaction mixture was
warmed to ambient temperature for 2 h and recooled to 0 °C,
and the reaction was quenched with 3N NaOH (6 mL). After
4-(4-Meth oxy-3-cyclop en toxyp h en yl)ben zoic a cid (4):
recrystallized from ethyl acetate/hexane; 31% yield from 2a ;
1
white crystalline solid; mp 230-232 °C; H NMR (250 MHz;
CDCl3) δ 1.58-1.69 (m, 2H), 1.80-2.06 (m, 6H), 3.91 (s, 3H),
4.81-4.93 (m, 1H), 6.96 (d, J ) 8.3 Hz, 1H), 7.16-7.23 (m,
2H), 7.65 (d, J ) 8.5 Hz, 2H), 8.16 (d, J ) 8.5 Hz, 2H). Anal.
(C19H20O4) C, H.
3-(4-Meth oxy-3-cyclop en toxyp h en yl)ben zoic a cid (5):
recrystallized from ethyl acetate/hexane; 35% yield from 2a ;
1
white crystalline solid; mp 149-151 °C; H NMR (250 MHz;
CDCl3) δ 1.60-1.71 (m, 2H), 1.81-2.09 (m, 6H), 3.91 (s, 3H),
4.86-4.91 (m, 1H), 6.96 (d, J ) 8.2 Hz, 1H), 7.12-7.18 (m,
2H), 7.48-7.55 (m, 1H), 7.75-7.81 (m, 1H), 8.05-8.10 (m, 1H),
8.30 (m, 1H). Anal. (C19H20O4) C, H.
(S)-(+)-exo-4-[3-(Bicyclo[2.2.1]h ep t -2-yloxy)-4-m et h -
oxyph en yl]ben zoic acid (6): recrystallized from ethyl acetate/
hexane; 47% yield from 2b; white silvery crystals; mp 230-
232 °C; [R]D +23.5° (c ) 1.05, THF); 1H NMR (250 MHz;
DMSO-d6) δ 1.1 (m, 3H), 1.5 (m, 3H), 1.61 (m, 1H), 1.8 (m,
1H), 2.28 (m, 1H), 2.38 (m, 1H), 3.79 (s, 3H), 4.39 (d, J ) 5.9
Hz, 1H), 7.05 (d, J ) 8.4 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.26
(dd, J ) 8.3, 2.0 Hz, 1H), 7.75 (d, J ) 8.3 Hz, 2H), 7.98 (d, J
) 8.2 Hz, 2H), 12.9 (br s, 1H). Anal. (C21H22O2) C, H.
(R)-(-)-exo-4-[3-(Bicyclo[2.2.1]h ep t -2-yloxy)-4-m et h -
oxyph en yl]ben zoic acid (7): recrystallized from ethyl acetate/
hexane; 42% yield from 2c; silvery white crystals; mp 234-
236 °C; [R]D -25.1° (c ) 0.89, THF). Anal. (C21H22O2) C, H.
4-[4-Meth oxy-3-(2-in d a n yloxy)p h en yl]ben zoic a cid (8):
recrystallized from ethanol; 54% yield from 2d ; white crystal-

Biarylcarboxylic Acids and -amides
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 125
1
line solid; mp 244-247 °C; H NMR (300 MHz; DMSO-d6) δ
7.90-8.02 (m, 3H, including d at 7.93, J ) 8.4 Hz); MS m/z
3.08 (d, J ) 17.1 Hz, 2H), 3.38 (dd, J ) 6.0, 17.1 Hz, 2H), 3.74
(s, 3H), 5.37 (m, 1H), 7.07 (d, J ) 8.5 Hz, 1H), 7.15-7.35 (m,
6H), 7.80 (d, J ) 8.2 Hz, 2H), 7.99 (d, J ) 8.3 Hz, 2H); MS m/z
360. Anal. (C23H20O4) H; C: calcd, 76.65; found, 75.93.
4-[4-Meth oxy-3-(4-p h en ylbu toxy)p h en yl]ben zoic a cid
(9): recrystallized from ethyl acetate/hexane; 40% yield from
402. Anal. (C26H27NO3): H, N; C: calcd, 77.78; found, 74.61.
Ack n ow led gm en t. The authors would like to thank
Dr. J ohn Lowe, III, for helpful discussions and com-
ments during the preparation of the manuscript.
1
2e; silvery white crystals; mp 178-9 °C; H NMR (300 MHz;
DMSO-d6) δ 1.8-2.0 (m, 4H), 2.71 (t, J ) 7.4 Hz, 2H), 3.92 (s,
3H), 4.13 (t, J ) 7.4 Hz, 2H), 6.97 (d, J ) 8.4 Hz, 1H), 7.15-
7.35 (m, 9H), 7.64 (d, J ) 6.5 Hz, 1H), 8.15 (d, J ) 8.5 Hz,
1H); MS m/z 376.
Refer en ces
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between behavioural response and binding in vivo for inhibitors
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(2) Schneider, H. H.; Schmiechen, R.; Brezinski, M.; Seidler, J .
Stereospecific binding of the antidepressant rolipram to brain
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Human cAMP-specific Phosphodiesterase Activity and High
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(4) Duplantier, A. J .; Cheng, J . B. Emerging Opportunities in the
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(5) Nicholson, C. D.; Shahid, M. Inhibitors of Cyclic Nucleotide
Phosphodiesterase Isozymes - their Potential Utility in the
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(7) Lowe, J . A., III; Cheng, J . B. The PDE IV family of calcium-
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(8) Zeller, E; Stief, H. J .; Pflug, B; Sastre, Y.; Hernandez, M. Results
of a phase II study of the antidepressant effect of rolipram.
Pharmacopsychiatry 1984, 17, 188-190.
(9) Carpenter, D. O.; Briggs, D. B.; Knox, A. P.; Strominger, N.
Excitation of Area Postrema Neurons by Transmitters, Peptides,
and Cyclic Nucleotides. J . Neurophysiol. 1988, 59, 358-369.
(10) Saccomano, N. A.; Vinick, F. J .; Koe, K.; Nielsen, J . A.; Whalen,
W. M.; Meltz, M.; Phillips, D.; Thadieo, P. F.; J ung, S.; Chapin,
D. S.; Lebel, L. A.; Russo, L. L.; Helweg, D. A.; J ohnson, J . L.;
Ives, J . L.; Williams, I. H. Calcium-Independent Phosphodi-
esterase Inhibitors as Putative Antidepressants: [3-(Bicyclo-
alkyloxy)-4-methoxyphenyl]-2-imidazolidinones. J . Med. Chem.
1991, 34, 291-298.
(S)-(-)-4-[4-Meth oxy-3-(5-p h en ylp en t-2-yloxy)p h en yl]-
ben zoic a cid (11): recrystallized from ethyl acetate/hexane;
25% yield from 2g; white solid; mp 159-160 °C; [R]D -33.5°
1
(CHCl3); H NMR identical with 10. Anal. (C25H26O4) C, H.
4-[4-Met h oxy-3-[[1-(3-p h en ylp r op yl)-1-cyclop r op yl]-
oxy]p h en yl]ben zoic a cid (12): recrystallized from ethanol;
50% yield from 2k ; white crystalline solid; mp 141-142 °C;
1H NMR (300 MHz; DMSO-d6) δ 0.78 (m, 2H), 0.91 (m, 2H),
1.75 (m, 4H), 2.57 (t, J ) 7.0 Hz, 2H), 3.76 (s, 3H), 7.04-7.26
(m, 7H), 7.38 (d, J ) 2.1 Hz, 1H), 7.66 (d, J ) 8.4 Hz, 2H),
7.98 (d, J ) 8.4 Hz, 2H), 12.95 (s, 1H). Anal. (C26H26O4) C,
H.
4-[4-Met h oxy-3-(5-p h en ylp en t oxy)p h en yl]-2-m et h yl-
ben zoic a cid (18): recrystallized from ethyl acetate/hexane;
50% yield from 2h ; white crystalline solid; mp 130-131 °C;
1H NMR (300 MHz; CDCl3) δ 1.55 (m, 2H), 1.73 (m, 2H), 1.93
(m, 2H), 2.66 (t, J ) 7.5 Hz, 2H), 2.74 (s, 3H), 3.92 (s, 3H),
4.10 (t, J ) 6.8 Hz, 2H), 6.96 (d, J ) 8.4 Hz, 1H), 7.13-7.31
(m, 7H), 7.46 (d, J ) 7.3 Hz, 2H), 8.13 (d, J ) 8.9 Hz, 1H);
COOH proton was not assigned; MS m/z 404. Anal. (C26H28O4)
C, H.
Gen er a l P r oced u r e C. Con ver sion of Ca r boxylic Acid
to Am id e. 4-[4-Meth oxy-3-(4-p h en ylbu toxy)p h en yl]ben -
za m id e (14). A solution of 9 (0.58 g, 1.44 mmol) in thionyl
chloride (10 mL) was heated to reflux over 1.5 h and concen-
trated to a golden oil. The oil was dissolved in methylene
chloride (10 mL), cooled to 0 °C, and treated with 2 drops of
DMF followed by excess anhydrous ammonia gas.22 After
stirring for 16 h the mixture was concentrated under reduced
pressure and filtered. Recrystallization from methanol (20
1
mL) gave 0.30 g (53%) of a beige solid: mp 178-180 °C; H
(11) Barnette, M. S. Challenges for drug discovery. New Drugs for
Asthma-III, Montebello, Quebec, J uly, 1994.
NMR (250 MHz; CDCl3) δ 1.63 (broad s, 2H), 1.80-2.02 (m,
4H), 2.68-2.74 (m, 2H), 3.91 (s, 3H), 4.08-4.13 (m, 2H), 6.95
(d, J ) 8.1 Hz, 1H), 7.10-7.28 (m, 7H), 7.62 (d, J ) 8.1 Hz,
2H), 7.86 (d, J ) 8.1 Hz, 2H). Anal. (C24H25NO3) C, H, N.
4-[4-Meth oxy-3-(2-in d a n yloxy)p h en yl]ben za m id e (13):
purified by chromatography (ethyl acetate) to give 49% yield;
(12) Koe, B. K.; Lebel, L. A.; Nielsen, J . A.; Russo, L. L.; Saccomano,
N. A.; Vinick, F. J .; Williams, I. H. Effects of Novel Catechol
Ether Imidazolidinones on Calcium-Independent Phosphodi-
esterase Activity, [3H]Rolipram Binding, and Reserpine-Induced
Hypothermia in Mice. Drug Dev. Res. 1990, 21, 135-142.
(13) Mitsunobu, O. The use of diethyl azodicarboxylate and triph-
enylphosphine in synthesis and transformation of natural
products. Synthesis 1981, 1-28.
(14) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. Olefin homologation
with titanium methylene compounds. J . Am. Chem. Soc. 1978,
100, 3611-3613.
(15) Smith, R. D.; Simmons, H. E. Org. Synth. 1961, 41, 72-75.
(16) Erdik, E. Transition metal catalyzed reactions of organozinc
reagents. Tetrahedron 1992, 48, 9577-9648.
(17) Cavalla, D.; Frith, R. Phosphodiesterase IV Inhibitors: Struc-
tural Diversity and Therapeutic Potential in Asthma. Curr. Med.
Chem. 1995, 2, 561-572.
(18) Engels, P.; Fichtel, K.; Lubbert, H. Expression and regulation
of human and rat phosphodiesterase type IV isogenes. FEBS
Lett. 1994, 350, 291-295.
(19) Reeves, M. L.; Leigh, B. K.; England, P. J . The identification of
a new cyclic nucleotide phosphodiesterase activity in human and
guinea-pig cardiac ventricle. Biochem. J . 1987, 241, 535-541.
(20) Watson, J . W.; Gonsalves, S. F.; Fossa, A. A.; McLean, S.; Seeger,
T.; Obach, S.; Andrews, P. L. R. The anti-emetic effects of CP-
99, 994 in the ferret and the dog: role of the NK1 receptor. Br.
J . Pharmacol. 1995, 115, 84-94.
(21) The preparation of 2a has been reported: Meyers, A. I.; Snyder,
L. The Synthesis of Aracemic 4-Substituted Pyrrolidinones and
3-Substituted Pyrrolidines. An Asymmetric Synthesis of (-)-
Rolipram. J . Org. Chem. 1993, 58, 36-42.
1
yellow solid; mp 237-239 °C; H NMR (300 MHz, DMSO-d6)
δ 3.06 (d, J ) 17.0 Hz, 2H), 3.37 (dd, J ) 6.1, 17.0 Hz, 2H),
3.73 (s, 3H), 5.37 (m, 1H), 7.05 (d, J ) 8.4 Hz, 1H), 7.15-7.62
(m, 7H), 7.74 (d, J ) 8.5 Hz, 2H), 7.93 (d, J ) 8.4 Hz, 2H),
8.00 (s, 1H). Anal. (C23H21NO3) C, H; N: calcd, 3.90; found,
3.27.
(R)-(+)-4-[4-Meth oxy-3-[(5-ph en ylpen t-2-yl)oxy]ph en yl]-
ben za m id e (15): purified by chromatography (20:1 methylene
chloride/methanol) followed by recrystallization from ethyl
acetate/hexane; 57% yield; white solid; mp 182-184 °C; [R]D
+30.9° (CHCl3); 1H NMR (250 MHz; CDCl3) δ 1.35 (d, J ) 6.1
Hz, 3H), 1.61-1.95 (m, 4H), 2.62-2.70 (t, J ) 7.16 Hz, 2H),
3.89 (s, 3H), 4.42-4.50 (m, 1H), 5.99 (broad d, 2H), 6.96 (d, J
) 8.4 Hz, 1H), 7.12-7.30 (m, 7H), 7.60 (d, J ) 8.3 Hz, 2H),
7.86 (d, J ) 8.3 Hz, 2H). Anal. (C25H27NO3) C, H, N.
(S)-(-)-4-[4-Meth oxy-3-[(5-ph en ylpen t-2-yl)oxy]ph en yl]-
ben za m id e (16): purified by chromatography (20:1 methylene
chloride/methanol) followed by recrystallization from ethyl
acetate/hexane; 63% yield; white fluffy solid; mp 183-184 °C;
1
[R]D -30.7° (CHCl3); H NMR identical with 15.
4-[4-Met h oxy-3-[1-(3-p h en ylp r op yl)-1-cyclop r op oxy]-
p h en yl]ben za m id e (17): recrystallized from ethyl acetate/
hexane; 75% yield; tan powder; mp 154-155 °C; 1H NMR (250
MHz; DMSO-d6) δ 0.79 (m, 2H), 0.92 (m, 2H), 1.77 (m, 4H),
2.59 (t, J ) 6.9 Hz, 2H), 3.77 (s, 3H), 7.03-7.26 (m, 7H), 7.37
(d, J ) 2.0 Hz, 1H), 7.40 (s, 1H), 7.62 (d, J ) 8.3 Hz, 2H),
(22) The substrate may also be disolved in THF and treated with
ammonium hydroxide to give a similar result.
J M9505066