Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)- hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A designed, potent, orally active inhibitor of cholesterol absorption

Article abstract of DOI:10.1021/jm970701f

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]- (4S)-(4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED₅₀ of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.

Full text of DOI:10.1021/jm970701f

973
J . Med. Chem. 1998, 41, 973-980
Discover y of 1-(4-F lu or op h en yl)-(3R)-[3-(4-flu or op h en yl)-(3S)-
h yd r oxyp r op yl]-(4S)-(4-h yd r oxyp h en yl)-2-a zetid in on e (SCH 58235):
A Design ed , P oten t, Or a lly Active In h ibitor of Ch olester ol Absor p tion
Stuart B. Rosenblum,* Tram Huynh, Adriano Afonso, Harry R. Davis, J r., Nathan Yumibe, J ohn W. Clader, and
Duane A. Burnett
Department of Discovery Research, Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, New J ersey 07033-0539
Received October 16, 1997
(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibi-
tor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has
been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism
of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-
lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster
model for the reduction of serum total cholesterol and liver cholesteryl esters versus control.
On the basis of our analysis of the putative metabolite structure-activity relationship (SAR),
SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydrox-
yphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites
of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were
prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe
the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a
series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable
efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day
cholesterol-fed hamster model.
In tr od u ction
none (1, SCH 58235).8 Azetidinone 1 exhibits remark-
able reduction in liver cholesterol ester (LCE) potency
in cholesterol-fed hamsters (LCE ED50 0.04 mg/kg/day)
and was designed to exhibit a simplified metabolic
profile and an improved pharmacokinetic profile relative
to our first-generation lead 2.
Recent clinical trials and extensive epidemiological
studies support the reduction of low-density plasma
lipoproteins (LDL) as a major goal in the treatment and
prevention of coronary heart disease (CHD).1 The
pharmacological reduction of LDL levels has been
achieved in man by the use of cholesterol biosynthesis
inhibitors (e.g., HMG-CoA reductase inhibitors, typified
by the statins), bile acid sequestrates (e.g., resins,
Cholestyramine, Colestipol), and HDL-elevating agents
(e.g., fibrates, nicotinic acid analogues)2 and with cho-
lesterol absorption inhibitors (CAIs; e.g., Tiqueside (6,
CP 88,818; Pfizer3), 2 (SCH 48461; Schering-Plough4))
(Figure 1). Even with the current diverse repertoire of
therapeutic agents and combinations thereof, a signifi-
cant portion of the hypercholesterolemic population is
unable to reach target serum cholesterol levels, or drug
interaction and safety issues preclude the prolonged
treatment regimen needed to reduce CHD risk.5 There-
fore, the discovery of more efficacious, well-tolerated
agents and combinations of agents which regulate
cholesterol homeostasis by complementary mechanisms
of action remains of interest.
The discovery of 2 and the structure-CAI activity
relationship of related first-generation 2-azetidinone
inhibitors of cholesterol absorption have been previously
described.6,10 Azetidinone 2 was found to reduce serum
total cholesterol and liver cholesteryl ester levels in a
dose-dependent fashion in the orally dosed 7-day cho-
lesterol-fed hamster (LCE ED50 2.2 mg/kg),11 7-day rat
(LCE ED50 2 mg/kg),11 and 21-day monkey (LCE ED50
0.2 mg/kg)12 models by inhibiting lumenal cholesterol
absorption. 2 was evaluated in a 8-week human trial
after a 2-week American Heart Association step 1 diet
lead-in regiment and reduced serum LDL levels by 15%
at a 25 mg/day dose.4
Studies with [3H]-2 in a bile duct-diverted rat model
indicated the rapid appearance of a complex metabo-
lite mixture in the bile. Further studies confirmed
that in rats, the metabolite mixture was a more potent
inhibitor of [14C]cholesterol absorption and had a greater
localization in the intestinal lumen than 2.13 In light
of the encouraging but modest activity in humans
and the complex metabolic profile in rats of our first-
generation lead (2), we speculated that a metabolite-
like analogue with improved pharmacokinetic and
pharmacodynamic profiles would have significantly
increased CAI activity.
As part of an extensive synthetic effort to further
explore the structure-activity relationship (SAR) of
2-azetidinone inhibitors of cholesterol absorption,6,7 we
wish to report a new, orally active cholesterol absorption
inhibitor, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-
(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidi-
* Corresponding author: e-mail, stuart.rosenblum@spcorp.com.
S0022-2623(97)00701-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

974 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Rosenblum et al.
Sch em e 1. Putative Sites of Metabolism of 2: Design
of 1 (SCH 58235)a
F igu r e 1. Potency comparison of various agents for the
reduction of liver cholesterol ester levels in cholesterol-fed
hamsters.
Resu lts a n d Discu ssion
The expected modes of primary metabolism of 2 are
dealkylation of the N1- and C4-methoxyphenyl groups
(Scheme 1), para hydroxylation of the pendent C3-side
chain phenyl group, benzylic oxidation (hydroxylation
potentially followed by ketone formation), and 2-azeti-
dinone ring opening.14 Limiting the analysis to these
five sites of metabolism, greater than 40 constitutively
different potential metabolites are predicted. Additional
consideration of the stereochemical consequences of
benzylic hydroxylation and potential intramolecular
cyclization/lactone formation from the benzylic hydroxyl
metabolites15 would make preparation of all possible
metabolites a formidable task. A directed synthetic
effort toward the most probable metabolites was un-
dertaken using the 7-day cholesterol-fed hamster model
as the primary assay to evaluate activity. The CAI
activity of these putative metabolites is summarized in
Table 1.
a
ED50 of reduction of liver cholesterol esters in hamsters.
yl substituent, and a C3-arylalkyl substituent (either
3R or 3S). It has also been previously shown that CAI
activity is maintained with a wide variety of para
substituents (H, halogen, OH, OCH3) on the N1-phenyl
but that the C4-phenyl requires a hydroxyl or alkoxyl
residue for activity.6
The current work focuses on the effect of C3-pendent
aryl ring hydroxylation, C3-side chain benzylic oxida-
tion, and strategic incorporation of fluorine on the CAI
activity of 2-azetidinones in the cholesterol-fed hamster
model. The effect of para hydroxylation of the C3-
pendent aryl ring in both 8 (monohydroxy series) and
13 (dihydroxy series) was deleterious with only marginal
CAI activity (i.e., LCE reduction) at 10 mg/kg. This may
partly be due to the poor solubility of these compounds
in the oral gavage vehicle (i.e., corn oil).
Previous work6 has shown that the key structural
elements for CAI activity of 2-azetidinones are an N1-
aryl-substituted 2-azetidinone backbone, a (4S)-alkoxyar-
Next, the effect of C3-side chain benzylic hydroxyla-
tion was examined and found to be stereochemistry-
dependent. The 3′S alcohol analogue 10 was found to

New Orally Active Cholesterol Absorption Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 975
Ta ble 2. CAI Dose-Response of 1 (SCH 58235) and 2
Ta ble 1. CAI Activity of 2 and Putative Metabolites 8-18
1 (SCH 58235)
2 (SCH 48461)
dose
liver CEa serum TCb liver CEa serum TCb
(mg/kg/day)
(%)
(%)
(%)
(%)
3
1
0.3
0.1
0.03
-100
-100
-96
-100
-100
-72
-68
-14
NS
-76
NS
NS
-87
-37
-39
-23
a
Percent negation of rise in liver cholesterol esters relative to
b
R1
R2
OCH3 OCH3 2.2
Monohydroxy 2-Azetidinone Series
R3
activitya
control-fed 0.5% cholesterol for 7 days. Percent negation of rise
no.
R
in total serum cholesterol relative to control-fed 0.5% cholesterol
for 7 days. NS, percent reduction was not statistically significant;
all percent values (10%; see Experimental Section for details.
2 (SCH 48461)
H
H
8
9
10
OH
H
H
H
H
H
OCH3 OCH3 -16% @10
OH (R) OCH3 OCH3
OH (S) OCH3 OCH3 0.9
5
an LCE ED50 of 0.04 mg/kg/day in the 7-day cholesterol-
fed hamster model, a 50-fold (50×) increase in potency
relative to 2. The dramatic increase in in vivo potency
is probably due to both an increased intrinsic binding
interaction with the (3′S)-hydroxyl side chain substitu-
ent and a greatly improved ADME (absorption, distri-
bution, metabolism, and excretion) profile which in-
creased lumenal retention time (i.e., the site of biological
action).
11 (SCH 53695)
H
H
OH
OCH3 OH
OCH3 5b,c
-78% @ 10
b
12
Dihydroxy 2-Azetidinone Series
OH
H
H
H
13
14
15
16
H
OH
OCH3 -64% @10
OCH3
OCH3 0.3
OH -68% @10
OH (R) OH
OH (S) OH
3
H
OH
3′-Keto 2-Azetidinone Series
H
H
17
18
dO
dO
OCH3 OCH3
OH OCH3
2
3
A series of congeners of 2 were prepared incorporating
various desirable metabolic transformations into their
structure, while undesired metabolic transformations
were blocked by strategic substitution with fluorine.
Significant increases in CAI activity relative to 2 were
observed in most analogues (Figure 2) which incorpo-
rated p-fluorine substitution on the N1-phenyl and C3-
pendent phenyl rings (compounds 19-27). Dramatic
activity improvements relative to 2 were also observed
with a variety of C4-(4-alkoxyphenyl) substituents (e.g.,
20, 21) and with 3′-acetoxy side chain substitution (e.g.,
25, 26). The SAR in this series confirmed the impor-
tance and stereochemical preference of a C3-(3′S)-
hydroxyl substituent.
Ch em istr y. Our initial approach to the preparation
of the putative 2 metabolites described above (Table 1)
is outlined in Scheme 2. Multigram quantities of
enantiomerically pure 217 were available and served as
the starting material for our initial targets. Treatment
of 2 with N-bromosuccinimide afforded a diastereomeric
mixture of C3-side chain benzylic bromides 28 and 29.
Repeated attempts to prepare C3-side chain benzylic
hydroxyl analogues by direct solvolysis of the corre-
sponding bromides (28, 29) afforded only trace amounts
of 9 and 10 within a complex mixture of non-2-azetidi-
none products.15 Benzylic bromide displacement with
tetra-n-butylammonium trifluoroacetate followed by
mild trifluoroacetate deprotection with ethanolic am-
monia provided the desired putative metabolites 9 and
10. Manganese oxide oxidation of both 9 and 10
afforded ketone 17 in 80% yield.
a
Activity reported as ED50 (mg/kg/day) or percent reduction of
b
liver cholesterol esters (LCE) in cholesterol-fed hamsters. Syn-
thesis described in ref 6. c Isolation of 11 (SCH 53695) from the
bile of 2 (SCH 48461)-dosed rats described in ref 13.
be 5-fold more potent than the 3′R alcohol isomer 9
(LCE ED50 0.9 vs 5 mg/kg) in the monohydroxy series.
More dramatically, in the dihydroxy series (side chain-
3′-OH and C4-phenyl-4-OH) the 3′S alcohol 15 was
found to be 1 order of magnitude more potent than the
3′R alcohol isomer 14 and at least 7-fold more potent
than 2. Attempts to prepare the pendent 4-hydrox-
yphenyl benzyl alcohol (R ) R1 ) OH; R2 ) R3 ) OCH3)
analogue were unsuccessful and highlighted the insta-
bility of this potential metabolite. The CAI profiles of
C3-side chain ketone congeners 17 and 18 were not
significantly different than that of 2. The clear stere-
ochemical preference at the C3-side chain benzylic
position and at the C4-azetidinone position for CAI
activity suggests a well-defined molecular interaction
with an as yet undiscovered target.
The highlight of our SAR investigation based on
putative metabolites of 2 was the activity enhancement
of a 3′S-hydroxylated C3-side chain substituent. Cou-
pling this discovery with previous SAR results6 led us
to incorporate in our synthetic targets “productive” (i.e.,
enhanced activity) functional groups and also to block
sites of potential “nonproductive” metabolism. We
postulated that strategically hydroxylated and meta-
bolically blocked analogues would have simpler meta-
bolic and pharmacokinetic profiles and thus increased
CAI potency. The use of a halogen to block sites of
metabolism is well-known,16 and fluorine was chosen
due to its small steric demand and its deactivating effect
to deter P450-mediated aromatic hydroxylation at other
sites on a phenyl ring. This reasoning led directly to
the targeted synthesis of compound 1, a compound whose
structure has been optimized at the putative metabolic
sites for CAI activity as outlined in Scheme 1.
Access to nonhydroxylated 2 congeners was accom-
plished in good yield by the previously disclosed method
B (Scheme 3).6 Compound 1 and a series of fluorinated
analogues (Figure 2) were prepared as summarized in
Scheme 4. Using the trans-stereoselective conditions
developed by Vaccaro et al.,18 racemic ester 35 was
assembled by the cycloaddition of a suitably protected
imine (34) with the ketene derived from methyl 4-(chlo-
roformyl)butyrate (33). Chiral chromatographic separa-
tion of 35 provided enantiomerically pure (>98% ee)
1 was found to have a dose-responsive effect (Table
2) on serum cholesterol and liver cholesterol esters with

976 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Rosenblum et al.
Sch em e 2. Preparation of Putative Metabolites of 2a
a
Reagents: (a) N-bromosuccinimide, CCl4; (b) (n-Bu)4NTFA,
CH2Cl2, H2O; (c) NH3(s) in EtOH; (d) chiral chromatography
(Chiracel OD column); (e) MnO2, dioxane.
Sch em e 3. Preparation of Analogues of 2a
F igu r e 2. CAI activity of SCH 58235 (1) and analogues.
Unless otherwise noted, absolute stereochemistry is shown and
compounds were determined to be >98% ee by chiral chroma-
tography (Chiracel OD). Activity reported as ED50 of reduction
in liver cholesterol esters in 7-day hamster model.
2-azetidinone 36 (3R,4S). Chemoselective ester hy-
drolysis with lithium hydroxide followed by acid chloride
formation afforded acid chloride 38. Introduction of the
C3-pendent 4-fluorophenyl moiety was accomplished
efficiently by application of palladium-mediated arylzinc
acid chloride coupling methodology pioneered by Nege-
shi.19 Stereorandom borane reduction of the benzylic
ketone followed by chromatographic separation affords
the benzylic hydroxy isomers (1, 23, 24) in high enan-
tiomeric purity. A scalable stereospecific synthesis of
azetidinone 1 has been accomplished which will be
reported elsewhere.
a
Reagents: (a) (n-Bu)3N, toluene; (b) optional chiral chroma-
tography (Chiracel OD column); (c) 10% Pd-C, EtOH, H2(g) (60
psi).
animal models suggests a mechanism that interferes
with a fundamental cholesterol-trafficking process. Fur-
ther biological evaluation of 1 has found its CAI activity
to be synergistically potentiated by the HMG-CoA
reductase inhibitor Lovastatin in dogs.20
The integration of synthetic and medicinal chemistry
with metabolic and pharmacological data led to the
design of azetidinone 1, which is being progressed for
the treatment of hypercholesterolemia in humans and
as a mechanistic tool in the study of cholesterol traf-
ficking.
Su m m a r y
The impressive CAI activity of 1 in the cholesterol-
fed hamster (LCE ED50 0.04 mg/kg/day) has been
additionally confirmed in a cholesterol-fed rhesus mon-
key model (LCE ED50 0.0005 mg/kg/day, 400 times more
potent than 2).13 The truly remarkable activity in

New Orally Active Cholesterol Absorption Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 977
Sch em e 4. Synthesis of 1 (SCH 58235) and Analoguesa
(achiral) or Chiracel columns (chiral) with UV detection (254
nm) as detailed. 1H (300 MHz) and 13C (75 MHz) NMR spectra
were recorded in deuterated chloroform (Cambridge Isotope
Laboratories) unless otherwise noted on a Varian Gemini 300
spectrometer. Chemical shifts are reported in ppm (δ) relative
to TMS, and coupling constants (J ) are reported in Hz.
Elemental analyses were within 0.4% of theory, unless oth-
erwise noted. Specific rotation [R]D is reported in degree/dm
at the specified temperature and the concentration (c) ex-
pressed in g/100 mL of specified solvent. Chemical ionization
(CI; CH4 carrier) and electron ionization (EI; ∼70 eV) mass
spectra were recorded on a Hewlett-Packard 5989A spectrom-
eter. Tandem liquid chromatography-electrospray mass spec-
tra were recorded on a SCIEX API-100 spectrometer. Typical
gradient chromatography conditions were acetonitrile/water
(5:95 to 95:5) over 10 min on a Suplecosil LC-18DB (3.3-cm ×
4.6-mm i.d.) column with ion-current detection. High-resolu-
tion mass spectra were recorded on a peak matching J EOL
J MS-HX110A spectrometer.
Meth od A: 1,(4S)-Bis(4-m eth oxyp h en yl)-(3R)-((3R)-h y-
d r oxy-3-p h en ylp r op yl)-2-a zetid in on e (9). To a solution of
1,(4S)-bis(4-methoxyphenyl)-(3R)-(3-phenylpropyl)-2-azetidi-
none17 (2; 5.04 g, 12.6 mmol) in 20 mL of CCl4 at 80 °C were
added N-bromosuccinimide (2.76 g, 15.5 mmol) and benzoyl
peroxide (0.24 g, 1.0 mmol) in three equal portions over 1 h.
After 4 h, the reaction mixture was cooled to 22 °C, and 1 N
NaHSO4 was added. The organic layer was separated, washed
thrice with water, and dried over MgSO4. Purification by
chromatography afforded 28 and 29 as a diastereomeric
1
mixture (3.6 g): H NMR (300 MHz) δ 5.05 (m, 1H, PhCHBr
(isomers a and b)), 4.70 (d, 1H, J ) 2.2 Hz, NCH-Ar (isomer
a)), 4.68 (d, 1H, J ) 2.2 Hz, NCH-Ar (isomer b)); Rf ) 0.4, 4:1
hexane/ethyl acetate; MS (CI) m/e 480 (M+H). Anal. (C26H26
-
NO3Br) C, H, N.
An equal mixture of isomers 28 and 29 (0.423 g) was
dissolved in 5 mL of CH2Cl2, and 40% aqueous (n-BuN)4TFA
(0.25 mL) was added. The biphasic reaction mixture was
refluxed for 12 h and cooled, water and ethyl ether were added,
and the layers were separated. The organic layer was con-
centrated to dryness, immediately redissolved in ethanol
saturated with ammonia (10 mL), and stirred at room tem-
perature. After 1 h the reaction mixture was concentrated to
dryness and the residue applied to a Chiralcel OD chroma-
tography column, eluting with hexane/ethanol (9:1) to obtain
enantiomerically pure (>98% ee) diastereomers 9 and 10. 9:
[R]22 +8.3° (c 3, MeOH); MS (CI) m/e 418 (M+H, 63), 400 (M
D
- 18, 100); 1H NMR (300 MHz) δ 4.82 (dd, 1H, PhCHOH),
4.67 (d, 1H, J ) 2.2 Hz, NCH-Ar). Anal. (C26H27NO4) C, H,
N.
1,(4S)-Bis(4-m eth oxyp h en yl)-(3R)-((3S)-h yd r oxy-3-p h e-
n ylp r op yl)-2-a zetid in on e (10): see experimental for com-
pound 9; oil; [R]22D +33.1° (c 3, MeOH); MS (CI) m/e 418 (M+H,
a
Reagents: (a) (n-Bu)3N, toluene; (b) chiral chromatography
(Chiracel OD column); (c) LiOH, THF; (d) oxalyl chloride, CH2Cl2;
(e) F-4-PhZnBr, (Ph3P)4Pd, THF; (f) BH3-S(CH3)2; (g) chiral
chromatography (Chiracel OD column); (h) 10% Pd/C, EtOH, H2(g)
(60 psi); (i) acetyl chloride, pyridine; (j) pTolSO3H, toluene.
1
52), 400 (M - 18, 100); H NMR (300 MHz) δ 4.70 (dd, 1H,
PhCHOH), 4.57 (d, 1H, J ) 2.2 Hz, NCH-Ar). Anal. (C26H27
-
NO4) C, H, N.
1,(4S)-Bis(4-m eth oxyp h en yl)-(3R)-(3-oxo-3-p h en ylp r o-
p yl)-2-a zetid in on e (17). An equal mixture of alcohols 9 and
10 (0.130 g) was dissolved in 1.8 mL of acetone, and manga-
nese dioxide (0.374 g) was added. The mixture was heated at
reflux for 20 h, cooled, and filtered through silica gel (acetone
wash). Further purification by column chromatography elut-
ing with ethyl acetate/hexane (1:1) afforded 17 (0.102 g): oil;
1H NMR (300 MHz) δ 8.1 (d, 2H, Ar), 7.7-7.3 (m, 7H, Ar),
6.95 (d, 2H, Ar), 6.85 (d, 2H, Ar), 4.78 (d, 1H, J ) 2.1 Hz,
NCH-Ar), 3.9 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.5-3.2 (m,
2H, COCH2), 2.5-2.3 (m, 2H, CH2CH); MS (CI) m/e 416 (M+H,
100), 266 (93). Anal. (C26H25NO4) C, H, N.
Exp er im en ta l Section
All reactions were performed under argon with magnetic
stirring unless otherwise stated. Air- and moisture-sensitive
reagents were transferred with disposable all-polypropylene
syringes available from Aldrich Chemical Co. Anhydrous
ether, tetrahydrofuran, toluene, and methylene chloride were
obtained from Aldrich Chemical Co. and used without further
drying. All commercially available compounds were used
without further purification unless otherwise noted. Melting
points were taken on a Thomas-Hoover melting point ap-
paratus and are uncorrected. Analytical TLC was performed
using Analtech glass-coated plates with fluorescent indicator
(silica gel GF, 250 µm), and visualization was accomplished
with a UV lamp (254 nm). Preparative flash chromatography
utilized Selecto Scientific flash silica gel (32-63 µm) under
medium pressure with compound-to-silica gel weight ratios of
1:10-30. Analytical HPLC was performed on a Rainin HPXL
pump system using either Rainin Dynamax 60A columns
(4S)-(4-Hyd r oxyp h en yl)-(3R)-((3R)-h yd r oxy-3-p h en yl-
p r op yl)-1-(4-m et h oxyp h en yl)-2-a zet id in on e (14): pre-
pared by method A to obtain an equal mixture of compounds
14 and 15, can be further purified on a Chiracel OD column
to obtain 14; mp 87-90 °C; 1H NMR (300 MHz) δ 4.82 (d, 1H,
PhCHOH); HRMS calcd for
C25H25NO4 403.1783, found
403.1797.

978 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Rosenblum et al.
(4S)-(4-Hyd r oxyp h en yl)-(3R)-((3S)-h yd r oxy-3-p h en yl-
p r op yl)-1-(4-m eth oxyp h en yl)-2-a zetid in on e (15): see ex-
perimental for compound 14; H NMR (300 MHz) δ 4.78 (d,
1H, PhCHOH); HRMS calcd for C25H25NO4 403.1783, found
403.1787.
(300 MHz) δ 7.4-7.2 (m, 8H, Ar), 6.92 (d, 2H, Ar), 6.85 (d,
2H, Ar), 5.8 (br s, 1H, OH), 4.65 (d, 1H, J ) 2.1 Hz, NCHAr),
3.82 (s, 3H, OCH3), 3.15 (m, 1H, C(O)CH), 2.65 (t, 2H, CH2-
Ar), 2.1-1.85 (m, 4H, CH2CH2); MS (CI) m/e 404 (M+H, 2),
388 (100); IR (CHCl3, cm-1) 3942 (br, OH), 1734 (CdO). Anal.
(C25H25NO4) C, H, N.
1
(4S)-(4-Hyd r oxyp h en yl)-(3R)-(3-oxo-3-p h en ylp r op yl)-
1-(4-m et h oxyp h en yl)-2-a zet id in on e (18): prepared by
method A; 1H NMR (300 MHz) δ 8.05 (d, 2H, Ar), 7.65 (t, 1H,
Ar), 7.55 (t, 2H, Ar), 7.3 (m, 3H, Ar), 6.95 (d, 2H, Ar), 6.85 (d,
2H, Ar), 4.75 (d, 1H, J ) 1.98 Hz, CHAr), 3.82 (s, 3H, OCH3),
3.4 (m, 1H) 3.3 (m, 1H), 3.2 (m, 1H), 2.5 (m, 1H), 2.35 (m, 1H);
HRMS calcd for C25H23NO4 401.1627, found 401.1610.
Gen er a l Meth od B: 1-(4-F lu or op h en yl)-(3R)-[3-(4-flu o-
r op h en yl)p r op yl]-(4S)-(4-m et h oxyp h en yl)-2-a zet id in o-
n e (19). A round-bottomed flask was charged with 4-fluor-
oiodobenzene (8.63 mL, 75 mmol), palladium acetate (2.24 g,
10 mmol), triphenylphosphine (2.53 g, 10 mmol), potassium
acetate (29.4 g, 300 mmol), tetrabutylammonium chloride (20.9
g, 75 mmol), 50 mL of dimethylformamide, and 4-pentenoic
acid (5.1 mL, 50 mmol). The reaction mixture was heated at
80 °C for 24 h, cooled, and poured into 1 N NaOH. Ethyl
acetate was added, and the layers were separated. The organic
layer was dried over magnesium sulfate, filtered, and concen-
trated to afford 5-(4-fluorophenyl)-(3E)-pentenoic acid (4.5 g).
A Parr hydrogenation vessel was charged with 5-(4-fluo-
rophenyl)-(3E)-pentenoic acid (4.2 g, 21 mmol) and 30 mL of
ethanol, and 10% palladium on carbon (0.5 g) was added. The
mixture was shaken under hydrogen pressure (50 psi) for 3 h
at room temperature and filtered through Celite and the
filtrate concentrated to afford 5-(4-fluorophenyl)pentanoic acid
(4.1 g).
1,(4S)-Bis(4-h yd r oxyp h en yl)-(3R)-(3-p h en ylp r op yl)-2-
a zetid in on e (16): prepared by method B using the imine
derived from 4-(benzyloxy)benzaldehyde and 4-(benzyloxy)-
aniline; 1H NMR (300 MHz) δ 7.4-7.2 (m, 4H, Ar), 7.0-6.8
(4d, 8H, Ar), 5.7 (br s, 2H, OH), 4.65 (d, 1H, J ) 2.1 Hz,
NCHAr), 3.15 (m, 1H, C(O)CH), 2.63 (t, 2H, CH2Ar), 2.1-1.85
(m, 4H, CH2CH2); MS (CI) m/e 374 (M+H). Anal. (C24H23NO3)
C, H, N.
1-(4-F lu or op h en yl)-(3R)-[3-(4-flu or op h en yl)p r op yl]-
(4S)-(4-m eth oxyp h en yl)-2-a zetid in on e (20): prepared by
1
method B using 4-fluorophenyl iodide; H NMR (300 MHz) δ
7.4-7.0 (m, 12H, Ar), 4.60 (d, 1H, J ) 2.2 Hz, NCHAr), 3.9 (s,
3H, OCH3), 3.2 (m, 1H, C(O)CH), 2.70 (t, 2H, CH2Ar), 2.1-
1.85 (m, 4H, CH2CH2); IR (CHCl3, cm-1) 1741 (CdO); MS (CI)
m/e 408 (M+H, 100). Anal. (C25H23F2NO2) C, H, N.
Gen er a l Meth od C: Keten e-Im in e Gen er a l P r oce-
d u r e. A solution of an appropriate imine (prepared from the
corresponding benzaldehyde and an aniline)18 (100 mol %) in
heptane and tributylamine (220 mol %) was heated to 80 °C
under argon. A solution of an acid chloride (110 mol %) in
toluene was added dropwise to the reaction solution over 0.5
h. The solution was stirred at 80-90 °C for 18-30 h. The
reaction mixture was then cooled, ethyl acetate was added,
and the layers were separated. The organic layer was washed
successively with 1 N HCl (3×), H2O, and saturated NH4Cl,
then dried with MgSO4, and concentrated in vacuo. The crude
product mixture was purified by flash chromatography, eluting
with hexane/ethyl acetate (ca. 9:1) to afford 2-azetidinones.
1-(4-F lu or op h en yl)-(3R)-[3-(4-flu or op h en yl)-3-oxop r o-
p yl]-(4S)-[4-(p h en ylm eth oxy)p h en yl]-2-a zetid in on e (21).
Using the general ketene-imine procedure above, 4-(benzy-
loxy)benzylidine 4-fluoroanisidine (10.5 g, 34.4 mmol), tribu-
tylamine (18 mL, 75.5 mmol), and methyl 4-(chloroformyl)-
butyrate (5 mL, 36.1 mmol) were reacted to prepare racemic
methyl ester 35 (9.7 g, 64%). Chromatographic resolution on
a Chiralcel OD column using hexane/2-propanol (83:17) eluent
afforded optically pure 36 (>98% ee).
To a solution of methyl ester 36 (1.6 g, 3.7 mmol) in 3.5 mL
of CH3OH were added 1.5 mL of water and LiOH‚H2O (0.155
g, 3.7 mmol). After 1 h additional LiOH‚H2O (54 mg, 1.3
mmol) was added. After a total of 2 h, 1 N HCl and ethyl
acetate were added, and the organic layer was separated and
dried. Concentration in vacuo afforded carboxylic acid 37 (1.5
g, 97% yield) which was used without purification.
To a solution of the 37 (1.03 g, 2.46 mmol) in CH2Cl2 at 22
°C, oxalyl chloride (0.32 mL, 3.67 mmol) was added and the
reaction mixture stirred at 22 °C. After 16 h the reaction
mixture was concentrated to dryness in vacuo to afford acid
chloride 38 (1.08 g, 100%) which was used without further
purification.
To a solution of 5-(4-fluorophenyl)pentanoic acid (1.2 g, 6.3
mmol) in 10 mL of CH2Cl2 was added oxalyl chloride (1.0 mL,
12 mmol), and the solution was heated to mild reflux. After 2
h the reaction mixture was concentrated in vacuo to afford
the acid chloride as an oil (1.3 g).
In a separate flask containing the imine (1.75 g, 5.73 mmol)
derived from 4-(benzyloxy)benzaldehyde and 4-fluoroaniline
were added 10 mL of toluene and tributylamine (2.75 mL, 12
mmol), and the solution was heated to 80 °C. A solution of
the acid chloride above (1.3 g, 6 mmol) was dissolved in 10
mL of toluene and added dropwise over 0.5 h to the hot solution
of imine. After 30 h the reaction mixture was cooled, acidified
with 1 N HCl (20 mL), and diluted with ethyl acetate. The
organic layer was separated, washed twice with 1 N HCl and
twice with water, dried over magnesium sulfate, and concen-
trated to afford crude azetidinone (2.7 g). Purification by flash
chromatography using hexane/ethyl acetate (4:1) eluent af-
forded analytically pure rel-(4S)-[4-(benzyloxy)phenyl]-1-(4-
fluorophenyl)-(3R)-[(4-fluorophenyl)propyl]-2-azetidinone (1.8
g). Optional chiral chromatographic separation on a Chiralcel
OD column using 9:1 hexane/ethanol eluent afforded the abs-
3R,4S isomer (later eluting peak) in >98% ee (0.8 g).
The benzyl-protected phenol (0.166 g) was charged in a Parr
hydrogenation vessel with 10% palladium on carbon (16 mg)
and shaken under hydrogen (60 psi) for 4 h at room temper-
ature. Filtration through Celite followed by concentration
afforded the desired pure C4-phenol analogue 19 (0.130 g): 1H
NMR (300 MHz) δ 7.4-6.9 (m, 12H, Ar), 5.73 (br s, 1H, OH),
4.70 (d, 1H, J ) 2.1 Hz, NCHAr), 3.22 (m, 1H, C(O)CH), 2.75
(t, 2H, CH2Ar), 2.1-1.85 (m, 4H, CH2CH2); MS (CI) m/e 394
(M+H, 5), 257 (16), 138 (100); IR (CHCl3, cm-1) 1738. Anal.
Calcd for C24H21F2NO2: C, 73.27; H, 5.38; N, 3.56. Found: C,
72.59; H, 5.78; N, 3.47.
To suspension of 4-fluorophenylzinc bromide (2.1 mmol)
prepared fresh from flamed zinc chloride and 4-fluorophenyl-
magnesium bromide in THF (4 mL) at 10 °C was added
tetrakis(triphenylphosphonium)palladium (118 mg, 0.1 mmol).
After 5 min a solution of acid chloride 38 (0.9 g, 2.0 mmol) in
2 mL of THF was added, and the ice bath was removed. After
1 h, 1 N HCl and ethyl acetate were added, and the organic
layer was separated and dried. Concentration followed by
flash chromatography afforded ketone 21 (0.79 g, 80%): 1H
NMR (300 MHz) δ 8.0 (2d, 2H, Ar), 7.4-7.1 (m, 11H, Ar), 6.95
(2d, 4H, Ar), 5.1 (s, 2H, CH2Ph), 4.70 (d, 1H, J ) 2.2 Hz,
NCHAr), 3.3 (m, 1H, C(O)CH), 3.2 (m, 2H, CH2CO), 2.4-2.2
(m, 2H, CH2); HRMS calcd for C31H25F2NO3 498.1880, found
498.1877.
1,(4S)-Bis(4-m eth oxyph en yl)-(3R)-[3-(4-h ydr oxyph en yl)-
p r op yl]-2-a zetid in on e (8): prepared by method B starting
1
with 4-(benzyloxy)phenyl iodide; H NMR (300 MHz) δ 7.5-
6.9 (m, 12H, Ar), 4.75 (d, 1H, J ) 2.1 Hz, NCHAr), 3.3 (m,
1H, C(O)CH), 2.75 (t, 2H, CH2Ar), 2.1-1.85 (m, 4H, CH2CH2);
MS (EI) m/e 417 (M+, 48), 268 (100); IR (CHCl3, cm-1) 3381
(br, OH), 1730 (CdO). Anal. (C26H27NO4) C, H, N.
1-(4-F lu or op h en yl)-(3R)-[3-(4-flu or op h en yl)-3-oxop r o-
p yl]-(4S)-(4-h yd r oxyp h en yl)-2-a zetid in on e (22). To a so-
lution of 21 (0.5 g, 1.0 mmol) in 10 mL of ethanol was added
10% Pd/C (0.05 g), and the reaction mixture stirred under a
(3R)-[3-(4-Hydr oxyph en yl)pr opyl]-1-(4-m eth oxyph en yl)-
(4S)-(4-h yd r oxyp h en yl)-2-a zetid in on e (13): prepared by
1
method B starting with 4-(benzyloxy)phenyl iodide; H NMR

New Orally Active Cholesterol Absorption Inhibitor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 979
pressure of hydrogen gas (60 psi) for 12 h. The reaction
mixture was filtered and concentrated to obtain compound
22: 1H NMR (300 MHz) δ 7.4-6.8 (m, 12H, Ar), 6.05 (br s,
1H, OH), 4.75 (d, 1H, J ) 2.2 Hz, NCHAr), 4.60 (m, 1H
CHOH), 3.15 (m, 1H, C(O)CH), 2.6 (br s, 1H, OH), 2.1-1.9
(m, 4H, CH2CH2). Anal. (C24H19F2NO3) C, H, N.
Hz, NCHAr), 3.4 (m, 1H, C(O)CH), 3.0-2.75 (m, 2H, CH2); MS
(CI) m/e 392 (M+H). Anal. (C24H19F2NO2) C, H, N.
Ch olest er ol-F ed H a m st er Assa y. All animals were
housed, treated, and cared for according to NIH guidelines for
humane treatment of laboratory animals and the Animal
Welfare Act in a program accredited by the American Associa-
tion for Accreditation of Laboratory Animal Care. Male golden
Syrian hamsters (Charles River Labs, Wilmington, MA),
weighing between 100 and 125 g, were fed rodent chow and
provided water ad libitum. Treatment protocols consisted of
feeding chow which had been supplemented with 0.5% cho-
lesterol for 7 days. During this period the animals were
gavaged once daily with test compounds dissolved in 0.2 mL
of corn oil. On day 7, liver samples were taken for lipid
analyses. Samples of liver were extracted for neutral lipid
analysis. Hepatic neutral lipid composition was determined
subsequently using a HPLC method which has been described
previously.6 Data are reported as percent change in hepatic
cholesterol ester content versus control animals receiving the
high-cholesterol diet (oral gavaged in 0.2 mL of corn oil/day)
without drug.
1-(4-F lu or op h en yl)-(3R)-[(3S)-(4-flu or op h en yl)-3-h y-
d r oxyp r op yl]-(4S)-[4-(p h en ylm eth oxy)p h en yl]-2-a zetid i-
n on e (24). To a solution of ketone 21 (0.35 g, 0.71 mmol) in
3 mL of THF was added borane-dimethyl sulfide complex (2
M, 0.4 mL, 0.8 mmol). The reaction mixture was stirred for 3
h at 22 °C and the reaction quenched by the addition of 2 mL
of methanol. The resulting solution was filtered through Celite
to afford an equal mixture of diastereomeric alcohols. Chro-
matographic purification on a Chiracel OD column using
hexane/2-propanol (9:1) eluent afforded the desired 3S alcohol
isomer 24 (>98% ee, 0.141 g) as the slower eluting peak: MS
1
(CI) m/e 500 (M+H, 9), 482 (100); H NMR (300 MHz) δ 7.5-
6.8 (m, 17H, Ar), 5.1 (s, 2H, CH2Ph), 4.75 (m, 1H, CHOH),
4.60 (d, 1H, J ) 2.2 Hz, NCHAr), 3.15 (m, 1H, C(O)CH), 2.4
(br s, 1H, OH), 2.1-1.8 (m, 4H, CH2CH2). Anal. (C31H27F2-
NO3) C, H, N.
Ack n ow led gm en t. We gratefully acknowledge Drs.
A. K. Ganguly, Edmund J . Sybertz, and Michael J .
Green for their support during the course of this project.
We also thank Dan McGregor, Lizbeth Hoos, Keith
Huie, and Robert Clement for their help in obtaining
the biological data.
1-(4-F lu or op h en yl)-(3R)-[(3S)-(4-flu or op h en yl)-3-h y-
d r oxyp r op yl]-(4S)-(4-h yd r oxyp h en yl)-2-a zetid in on e (1).
To a solution of 24 (0.4 g, 0.8 mmol) in 10 mL of ethanol was
added 10% Pd/C (0.03 g), and the reaction mixture stirred
under a pressure of hydrogen gas (60 psi) for 16 h. The
reaction mixture was filtered and concentrated to obtain
compound 1 as a white solid: mp 164-166 °C; MS (CI) m/e
410 (M+H); IR (CHCl3) 1739 (CdO); [R]22D -33.9° (c 3, MeOH);
1H NMR (300 MHz) δ 7.5-7.2 (m, 6H, Ar), 7.1-6.80 (m, 6H,
Ar), 5.2 (s, 1H, OH), 4.80 (m, 1H, CHOH), 4.65 (d, 1H, J ) 2.2
Hz, NCHAr), 3.15 (m, 1H, C(O)CH), 2.1-1.9 (m, 2H, CH2).
Anal. (C24H21F2NO3) C, H, N.
Refer en ces
(1) The Expert Panel. Summary of the Second Report of the
National Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation, and Treatment of High Blood Choles-
terol in Adults (Adult Treatment Panel II). J . Am. Med. Assoc.
1993, 269, 3015-3023.
(2) (a) Wirebaugh, S. R.; Shapiro, M. L.; McIntyre, T. H.; Whitney,
E. J . A Retrospective Review of the Use of Lipid-Lowering Agents
in Combination, Specifically, Gemfibrozil and Lovastatin. Phar-
macotherapy 1992, 12, 445-450. (b) Krause, B. R.; Sliskovic, D.
R.; Bocan, T. M. A. Emerging Therapies in Atherosclerosis. Exp.
Opin. Invest. Drugs 1995, 4, 353-387.
(3) Dujovne, C. A.; Harris, W. S.; Gelfand, R. A.; Morehouse, L. A.;
McCarthy, P. A.; Chandler, C. E.; DeNinno, M. P.; Harwood, H.
J ., J r.; Newton, F. A.; Shear, C. L. Investigations of the Effects
of Synthetic Saponons on Cholesterol Absorption and Serum
Cholesterol Levels. In Atherosclerosis X; Woodford, F. P., Davi-
gnon, J ., Sniderman, A., Eds.; Elsevier Science: New York, 1995;
pp 298-306.
(4) Bergman, M.; Morales, H.; Mellars, L.; Kosoglou, T.; Burrier,
R.; Davis, H. R.; Sybertz, E. J .; Pollare, T. The Clinical Develop-
ment of a Novel Cholesterol Absorption Inhibitor. Proceedings
of the XII International Symposium on Drugs Affecting Lipid
Metabolism, Nov. 7-10, 1995, Houston, TX.
(5) Marcelino, J . J .; Feingold, K. R. Inadequate Treatment with
HMG-CoA Reductase Inhibitors by Health Care Providers. Am.
J . Med. 1996, 100, 605-610.
(6) Clader, J . W.; Burnett, D. A.; Caplen, M. A.; Domalski, M. S.;
Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.; Zhao, H.;
Burrier, R. E.; Salisbury, B.; Davis, H. R., J r.; 2-Azetidinone
Cholesterol Absorption Inhibitors: Structure-Activity Relation-
ships on the Heterocyclic Nucleus. J . Med. Chem. 1996, 39,
3684-3693.
(7) (a) Dugar, S.; Kirkup, M. P.; Clader, J . W.; Lin, S. I.; Rizvi, R.;
Snow, M. E.; Davis, H. R., J r.; McCombie, S. W. Gamma-Lactams
and Related Compounds as Cholesterol Absorption Inhibitors:
Homologs of the Beta-Lactam Cholesterol Absorption Inhibitor
SCH 48461. Bioorg. Med. Chem. Lett. 1995, 5, 2947-2952. (b)
Dugar, S.; Yumibe, N.; Clader, J . W.; Viziano, M.; Huie, K.; Van
Heek, M.; Compton, D. S.; Davis, H. R., J r. Metabolism and
Structure Activity Data Based Drug Design: Discovery of (-)
SCH 53079 an Analogue of the Potent Cholesterol Absorption
Inhibitor (-) SCH 48461. Bioorg. Med. Chem. Lett. 1996, 6,
1271-1274. (c) McKittrick, B. A.; Ma, K.; Dugar, S.; Clader, J .
W.; Davis, H., J r.; Czarniecki, M.; McPhail, A. T. Stereoselective
Synthesis and Biological Activity of cis Azetidinones as Choles-
terol Absorption Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6,
1947-1950.
1-(4-F lu or op h en yl)-(3R)-[(3R)-(4-flu or op h en yl)-3-h y-
d r o x y p r o p y l)]-4S -(4-h y d r o x y p h e n y l)-2-a ze t id in o n e
(23): prepared from 21 by borane reduction, chiral chromato-
graphic separation, and debenzylation; MS (CI) m/e 410 (M+H,
7), 392 (7), 133 (100); IR (CHCl3, cm-1) 1739 (CdO); 1H NMR
(300 MHz) δ 7.5-7.2 (m, 6H, Ar), 7.1-6.80 (m, 6H, Ar), 5.3 (s,
1H, OH), 4.80 (m, 1H, CHOH), 4.65 (d, 1H, J ) 2.2 Hz,
NCHAr), 3.15 (m, 1H, C(O)CH), 2.5 (br s, 1H, OH), 2.1-1.9
(m, 2H, CH2). Anal. (C24H21F2NO3) C, H, N.
(4S)-[4-(Acetyloxy)p h en yl]-(3R)-[(3R)-(a cetyloxy)-3-(4-
flu or op h en yl)p r op yl)]-1-(4-flu or op h en yl)-2-a zet id in o-
n e (25). To a solution of the compound 23 (0.09 g, 0.2 mmol)
in CH2Cl2 were added acetyl chloride (0.08 g, 1.0 mmol) and
pyridine (8 mg, 0.1 mmol) at 22 °C. After 1 h water was added
and the organic layer separated, concentrated, and applied to
a silica gel column to afford diacetoxy analogue 25: 1H NMR
(300 MHz) δ 7.5-7.0 (m, 12H, Ar), 5.84 (dd, 1H, J ) 5.4, 9
Hz, CHOAc), 4.70 (d, 1H, J ) 2.2 Hz, NCHAr), 3.15 (m, 1H,
C(O)CH), 2.4 (s, 3H, OCH3), 2.25 (m, 1H, CHCH2), 2.15 (s, 3H,
OCH3), 2.10-1.8 (m, 3H, CHCH2); MS (FAB) 493.4; HRMS
calcd for C28H25F2NO5 493.1701, found 493.1695.
(4S)-[4-(Acet yloxy)p h en yl]-(3R)[(3S)-(a cet yloxy)-3-(4-
flu or op h en yl]p r op yl)-1-(4-flu or op h en yl)-2-a zet id in on e
(26). 1 (0.25 g, 0.6 mmol) was reacted with acetyl chloride as
above to obtain 26 (0.260 g): 1H NMR (300 MHz) δ 7.5-7.0
(m, 12H, Ar), 5.80 (dd, 1H, J ) 5.4, 9 Hz, CHOAc), 4.70 (d,
1H, J ) 2.2 Hz, NCHAr), 3.15 (m, 1H, C(O)CH), 2.4 (s, 3H,
OCH3), 2.15 (s, 3H, OCH3), 2.20-1.8 (m, 4H, CHCH2); MS
(FAB) m/e 493.4; HRMS calcd for C28H25F2NO5 493.1701, found
493.1694.
1-(4-F lu or op h en yl)-(3R)-[(4-flu or op h en yl)-(2E)-p r op e-
n yl]-(4S)-(4-h yd r oxyp h en yl)-2-a zetid in on e (27). A solu-
tion of 1 (0.1 g, 0.24 mmol) in 5 mL of toluene and p-toluene-
sulfonic acid monohydrate (0.01 g, 0.05 mmol) was heated for
6 h at 80 °C. The reaction mixture was then concentrated to
dryness and 27 isolated by column chromatography with
hexane/ethyl acetate (1:1): 1H NMR (300 MHz) δ 7.4-7.2 (m,
6H, Ar), 7.2-7.0 (m, 6H, Ar), 6.7 (d, 1H, J ) 15.9, CH)CHCH2),
6.3 (m, 1H, CHdCHCH2), 5.8 (s, 1H, OH), 4.75 (d, 1H, J ) 2.0
(8) Rosenblum, S. B.; Dugar, S.; Burnett, D. A.; Clader, J . W.;
McKittrick, B. A. Hydroxy-Substituted Azetidinone Compounds
Useful as Hypocholesterolemic Agents. U.S. Patent 5 631 365,
1997; World (PCT) Patent WO9508532-A1, 1995.

980 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Rosenblum et al.
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Hypocholesterolemic Activity of a Novel Inhibitor of Cholesterol
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were tested as a mixture and had no detectable activity at 50
mg/kg/day in the cholesterol-fed hamster model.
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a Convenient Route to Ketones.
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J . The Hypocholesterolemic Activity of the Potent Cholesterol
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(13) Van Heek, M.; France, C. F.; Compton, D. S.; Mcleod, R. L.;
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(14) The amino acid hydrolysis product of SCH 48461 is described
in ref 6 and had no detectable activity (i.e., LCE reduction) at
50 mg/kg/day in the cholesterol-fed hamster model.
J M970701F