Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein

Article abstract of DOI:10.1021/jm020038h

A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead 22, various structural features were explored with respect to inhibition of the CETP-mediated transfer of [³H] cholesterol from high-density cholesterol donor particles to low-density cholesterol acceptor particles. The free hydroxyl group of the propanol was required for high potency, since acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline analogues. Activity was substantially reduced by oxidation or substitution in the methylene of the benzylic group, implying that the benzyl ring orientation was important for activity. In the benzylic group, substitution at the 3-position was preferred over either the 2- or the 4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best 3-benzylic substituents were OCF₂CF₂H (42, IC₅₀ 0.14 μM in buffer, 5.6 μM in human serum), cyclopentyl (39), 3-iso-propoxy (27), SCF₃ (67), and C(CF₃)₂OH (36). Separation of 42 into its enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent (IC₅₀ 0.02 μM in buffer, 0.6 μM in human serum) than the major S(-) enantiomer 1b, demonstrating that the R-chirality at the propanol 2-position is key to high potency in this series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with submicromolar potency in plasma. A chiral synthesis of 1a is reported.

Full text of DOI:10.1021/jm020038h

J . Med. Chem. 2002, 45, 3891-3904
3891
Ch ir a l N,N-Disu bstitu ted Tr iflu or o-3-Am in o-2-P r op a n ols Ar e P oten t In h ibitor s
of Ch olester yl Ester Tr a n sfer P r otein
Richard C. Durley,*,† Margaret L. Grapperhaus,† Brian S. Hickory,† Mark A. Massa,† J ane L. Wang,†
Dale P. Spangler,† Deborah A. Mischke,† Barry L. Parnas,† Yvette M. Fobian,† Nigam P. Rath,‡
Dorothy D. Honda,† Ming Zeng,† Daniel T. Connolly,† Deborah M. Heuvelman,† Bryan J . Witherbee,†
Michele A. Melton,† Kevin C. Glenn,† Elaine S. Krul,† Mark E. Smith,† and J ames A. Sikorski†,§
Pharmacia Discovery Research, 700 Chesterfield Parkway North, St. Louis, Missouri 63198, and Department of Chemistry,
University of Missouri-St. Louis, St. Louis, Missouri 63121
Received J anuary 25, 2002
A novel series of substituted N-benzyl-N-phenyl-trifluoro-3-amino-2-propanols are described
that reversibly inhibit cholesteryl ester transfer protein (CETP). Starting with screening lead
22, various structural features were explored with respect to inhibition of the CETP-mediated
transfer of [3H]cholesterol from high-density cholesterol donor particles to low-density cholesterol
acceptor particles. The free hydroxyl group of the propanol was required for high potency, since
acylation or alkylation reduced activity. High inhibitory potency was also associated with 3-ether
moieties in the aniline ring, and the highest potencies were exhibited by 3-phenoxyaniline
analogues. Activity was substantially reduced by oxidation or substitution in the methylene of
the benzylic group, implying that the benzyl ring orientation was important for activity. In
the benzylic group, substitution at the 3-position was preferred over either the 2- or the
4-positions. Highest potencies were observed with inhibitors in which the 3-benzylic substituent
had the potential to adopt an out of plane orientation with respect to the phenyl ring. The best
3-benzylic substituents were OCF2CF2H (42, IC50 0.14 µM in buffer, 5.6 µM in human serum),
cyclopentyl (39), 3-iso-propoxy (27), SCF3 (67), and C(CF3)2OH (36). Separation of 42 into its
enantiomers unexpectedly showed that the minor R(+) enantiomer 1a was 40-fold more potent
(IC50 0.02 µM in buffer, 0.6 µM in human serum) than the major S(-) enantiomer 1b,
demonstrating that the R-chirality at the propanol 2-position is key to high potency in this
series. The R(+) enantiomer 1a represents the first reported acyclic CETP inhibitor with
submicromolar potency in plasma. A chiral synthesis of 1a is reported.
In tr od u ction
treated with designed antisense oligodeoxynucleotides
also had elevated HDLc and showed significantly re-
duced aortic lesions.13 However, the effects of lowering
of CETP activity in humans are less clear.14 On one
hand, lowering CETP has been shown to be protective.
For example, subjects with a genetic deficiency for CETP
had marked hyperalphalipoproteinemia and were pro-
tected against atherosclerosis,15 and analysis for CETP
polymorphism in the Framingham Offspring Study
identified the Taq 1B-B2 allele in men associated with
significantly reduced CETP activity, elevated HDLc, and
a reduced risk for CHD.16 On the other hand, those
populations exhibiting hyperalphalipoproteinemia were
only protected against atherosclerosis below a certain
level of HDLc,17 and there is evidence to suggest that
elevated HDLc levels in certain populations with a
common CETP amino polymorphism (Ile405Val) are
associated with increased risk for CHD.18-20 Further-
more, CETP has been suggested to participate in the
movement of cholesterol from peripheral cells to the
liver for catabolism, a process known as reverse cho-
lesterol transport.6
Epidemiological1 and clinical2 studies have demon-
strated an inverse relationship between serum high-
density cholesterol (HDLc) levels and the incidence of
coronary heart disease (CHD). Interventions that raise
HDLc have been shown to reduce CHD events,3,4
whether significant lowering of plasma low-density
cholesterol (LDLc) occurs.5
Cholesteryl ester transfer protein (CETP) is a plasma
carrier glycoprotein that transfers cholesteryl ester (CE)
from HDL to very low-density lipoprotein (VLDL) and
LDL in exchange for triglyceride (TG).6-8 There have
been several suggestions that CETP plays a proathero-
genic role, since CETP lowers cardioprotective HDLc.
Thus, inhibiting CETP activity should elevate HDLc
and provide a potential therapeutic benefit for patients
with CHD.7-9 There are numerous animal studies that
support these hypotheses. For example, transgenic mice
expressing simian CETP were observed to develop
severe atherosclerosis,10 rabbits treated with a covalent
modifier of CETP11 had elevated HDLc and exhibited
attenuated atherosclerosis,12 and cholesterol-fed rabbits
Despite the controversy of the role of CETP in the
progression of atherosclerosis, there has been consider-
able interest in finding inhibitors of CETP. Small
molecule CETP inhibitors from a variety of structural
classes including sterols, polycyclic natural products,
and heterocycles are known.7 Each class of known
* To whom correspondence should be addressed. Tel: (636)737-6792.
Fax: (636)737-7425. E-mail: richard.c.durley@pharmacia.com.
† Pharmacia Discovery Research.
‡ University of Missouri-St. Louis.
§ Current Address: AtheroGenics, Inc., 8995 Westside Parkway,
Alpharetta, GA 30004.
10.1021/jm020038h CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/03/2002

3892 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
Sch em e 1a
Sch em e 2a
a
Reagents: (a) 2-Substituted oxirane, Yb(CF3SO3)3, CH3CN, 50
°C, 2 h. R1 and R2 defined in Tables 1-4; R3 ) CF3 or defined in
Table 5.
inhibitors appears to require a central core ring for
activity. Representative members of these classes typi-
cally exhibit modest micromolar IC50 values for inhibit-
ing CETP-mediated transfer of 3H-CE from HDL to LDL
under buffered assay conditions in vitro.7 To date, no
CETP inhibitor class, either reversible or irreversible,
has been described that exhibits submicromolar activity
when this CETP-mediated transfer process is assayed
in the presence of human plasma.7 However, recently,
a series of tetrahydronaphthalene derivatives have been
reported with low nanomolar potency in vitro,21 and a
series of tetrahydoquinoline derivatives have been
reported (activity not given).22
Herein, we describe the identification N,N-disubsti-
tuted trifluoro-3-amino-2-propanols as an unusually
simple class of CETP inhibitors. Subsequent modifica-
tion of these inhibitors led to the chiral R-(+)-trifluoro-
propanol derivative 1a having low nanomolar potency
in vitro under buffered conditions and submicromolar
potency in the presence of human serum. This novel
class thus represents the first alicyclic series exhibiting
significant inhibitory activity for the CETP system. We
also report the contributions of the trifluoromethyl and
alcohol moieties to inhibitor potency and significantly
extend the structure-activity relationship (SAR) based
upon modifications of the benzylic haloalkoxy ether
group. The discovery of 1a was briefly reported in an
earlier communication.23
a
Reagents: (a) Cyclohexane, heat, -H2O. (b) NaBH4, CH3OH.
(c) NaBH(OAc)3, AcOH, DCE, room temperature. (d) NBS, AIBN,
CCl4, heat. (e) Cyclohexane, heat. R1 and R2 defined in Tables 1-4.
appropriate 2-alkyloxiranes. The required N-benzyl-
anilines 3 were conveniently prepared by standard
reductive amination or alkylation sequences (Scheme
2). The aniline 9 (or benzylamine in the case of 10 and
11) was treated with an appropriate benzaldehyde 12
(or ketone in the case of 13) to generate imine 14, which
was then reduced with sodium borohydride to give the
3
N-benzylaniline 3. Reduction of imine 14 to 3 with H-
sodium borohydride provided a convenient entry to
radiolabeled analogues. Alternatively, direct reductive
amination of a mixture of 9 and 12 with sodium
triacetoxyborohydride also gave 3. In cases where the
benzaldehyde 12 was difficult to access, radical bromi-
nation of a suitable toluene 15 gave the bromomethyl-
benzene 16, which could be used to prepare 3 by reaction
with an excess of aniline 9.
Ch em istr y
The benzamide 17 was prepared from 18 by treatment
with hydrogen over Pd/C to give the secondary amine
19 (Scheme 3). Subsequent treatment of 19 with 3-tri-
fluomethylbenzoyl chloride produced the mixed bis-
trifluoromethylbenzoylamide ester 20, which was hy-
drolyzed to the benzamide 17 with methanolic ammonia.
The acetate 21 was synthesized from 22 (see Table 2)
by treatment with acetic anhydride in the presence of
triethylamine. Benzoxazine 23 was obtained from 3-
[(2,5-difluoro-phenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
methyl]amino]-1,1,1-trifluoro-2-propanol, as prepared by
Schemes 1 and 2 (above), by treatment with K2CO3 in
refluxing dimethylformamide (DMF). Aldehydes 24 and
25, used in the preparation of 26 and 27 (see Table 4),
were synthesized from 3-hydroxy benzaldehyde 28 by
N,N-Disubstituted trifluoro-3-amino-2-propanols 2
were readily prepared from the ring-opening reaction
of commercially available 2-trifluoromethyloxirane of
unspecified enantiomeric composition with the ap-
propriate N-benzylaniline 3 (Scheme 1, R3 ) CF3). This
reaction proceeded smoothly in the presence of ytter-
bium(III) triflate in warm acetonitrile. The ytterbium
triflate helps the reaction proceed at lower temperature
and minimizes the need for large excess quantities of
volatile epoxide due to thermal loss. The epoxide ring-
opening reaction proceeded with complete regioselec-
tivity, since none of the isomeric 2-amino-3-propanol
product was detected. Other N,N-disubstituted alkanol-
amines 4-8 (Table 5) were prepared similarly from the

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3893
Sch em e 3a
Sch em e 6a
a
Reagents: (a) CyclopropylMgBr, Pd(PPh3)4, THF, reflux. (b)
((CH3)2CHCH2)MgBr, Pd(PPh3)4, THF, reflux. (c) Cyclopentyl-
MgBr, Pd(PPh3)4, THF, reflux.
a
Reagents: (a) H2, 5% Pd/C, CH3OH. (b) 3-CF3PhCOCl, CHCl3.
Inhibitors 35 and 36 were prepared from the methyl
benzoate 37 either by treatment with excess CH3MgCl
or with excess CF3Si(CH3)3 in the presence of tetra-
butylammonium fluoride (Scheme 5). The 3-alkyl ana-
logues 38-40 were synthesized from the bromo inter-
mediate 41 by reaction with the appropriate alkyl-
magnesium bromide in the presence of catalyst,
Pd(PPh3)4 (Scheme 6).
(c) NH3, CH3OH.
Sch em e 4a
Unexpectedly, the potent N,N-disubstituted trifluoro-
3-amino-2-propanol 42 (see Table 4) was shown by
analytical chiral chromatography to consist of a 7:1
mixture of enantiomers. Independent chiral gas chro-
matography (GC) analysis of the corresponding di-
ethylamine adducts confirmed that the commercial
2-trifluoromethyloxirane reagent also contained a 7:1
mixture of the individual S(-)- and R(+)-enantiomers.
The individual enantiomers of 42 were conveniently
isolated by standard preparative chiral chromatography.
The activity24 was shown to reside in the minor (+)-
isomer, 1a , which was prepared independently from the
reaction of N-(3-phenoxyphenyl)-[[3-(1,1,2,2-tetrafluoro-
ethoxy)phenyl]methyl]amine with the known chiral
epoxide, R-(+)-2-trifluoromethyloxirane.25 To confirm
the (R)-configuration at the chiral carbon in (+)-1a , a
crystalline analogue 43 was prepared from the reaction
of N-(3,4,5-trimethoxyphenyl)-[[3-(trifluoromethyl-thio)-
phenyl]methyl]amine with R-(+)-1,1,1-trifluoro-2,3-
epoxypropane, and its structure was determined by
X-ray crystallography (Figure 1).
a
Reagents: (a) (CH3)2CHI, K2CO3, i-propanol, reflux, 8 h. (b)
CH3CH2I, NaOCH3, CH3OH, reflux, 16 h. (c) (i) NaOCH3/MeOH;
(ii) CF3CH2OSO2PhCH3, NMP, 90 °C, 24 h. (d) CCl3C(NH)OC(CH3)3,
BF3‚(CH3CH2)2O, cyclohexane. (e) 2-Trifluoromethyloxirane, 95 °C,
30 h.
Sch em e 5a
a
Reagents: (a) CH3MgCl, THF, 0 °C, room temperature, 2 h.
(b) CF3Si(CH3)3, tetrabutylammonium fluoride, toluene, 40 °C, 18
h.
Resu lts a n d Discu ssion
treatment with the alkyl iodides in the presence of base
(Scheme 4). For 29, the aldehyde 30 was prepared
similarly, using the more reactive alkyl p-toluene-
sulfonate. To form the 3-tert-butyloxybenzaldehyde 31
used in the preparation of 32 (see Table 4), tert-butyl-
2,2,2-trichloroacetimidate in the presence of BF3-Et2O
was required (Scheme 4). Epoxide ring opening by both
the secondary amino and the phenolic hydroxyl func-
tions of 33 afforded the diol 34 (Scheme 4).
An initial chemical lead 22, identified through screen-
ing a combinatorial library, had promising activity (IC50
40 µM) as a CETP inhibitor in a simple buffer as-
say.24,26,27 In a similar assay, but in the presence of
human serum, which provided the source of the LDL,
VLDL, and human CETP, the inhibitory activity (IC50
> 200 µM) was markedly reduced.26,27 The IC50 value
in human serum is indicative of the inhibitory activity
in the target tissue, human blood, when other plasma

3894 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
Ta ble 2. Benzyl Ring Modifications of
N-(3-Fluoro)phenyl-N-benzyl-trifluoro-3-amino-propanols
in-
hibitor
IC50 (µm)
in-
hibitor
IC50 (µm)
R2
in buffera
R2
in buffera
22
50
51
52
53
54
3-CF3
H
3-CH3
4-CH3
2-CF3
2-CH3
37
>100
>100
65
>100
>100
55
56
57
58
59
3-OPh
4-Ph
3-[(3-CF3)-OPh
3-OCF3
15
20
>100
12
4.5
3-OCF2CF2H
a
Ref 24.
Ta ble 3. Aniline Ring Modifications of N-Phenyl-N-
(3-trifluoromethoxy)benzyl-trifluoro-3-amino-propanols
F igu r e 1. Projection plot of 43 with 30% thermalellipsoids
for nonhydrogen atoms confirming the (R)-configuration at the
C2 alcohol center.
Ta ble 1. Aniline Ring Modifications of N-Phenyl-N-
(3-trifluoromethy)benzyl-trifluoro-3-amino-propanols
IC50 (µM)
IC50 (µM)
in plasmaa,b
inhibitor
R1
3-F
3-OCF3
3-OPh
4-OPh
in buffera
58
60
61
62
12
ND
46
40
1.5
1.0
25
IC50 (µM)
IC50 (µM)
ND
inhibitor
R1
3-F
3-Cl
3-CF3
3-CH3
in buffera
inhibitor
R1
in buffera
a
b
Ref 24. ND, not determined.
22
44
45
46
37
12
10
10
47
48
49
H
15
>100
>100
2-CH3
4-CH3
(53 and 54), possibly for the same reason suggested
above for the 2-position in the aniline ring. The benzylic
3-phenoxy (55) and 4-phenyl (56) analogues were twice
as potent as the 3-CF3 analogue, indicating that larger
groups could be accommodated at this position. How-
ever, the 3-(3-CF3-phenoxy) analogue 57 was less potent
suggesting that a defined size or steric constraint
existed at this position. Other analogues were prepared
with various substituents in the benzylic 3-phenoxy
ring, but none of these enhanced potency, so the
3-phenoxy approach was not pursued. However, an
analogue of 22 with a 3-OCF3 substituent in the benzylic
ring (58) was potent, and even more potent was the
extended 3-OCF2CF2H analogue 59. Both the acetate
21 (buffer IC50 70 µM) and the constrained benzoxazine
analogue 23 (buffer IC50 15 µM) were less potent than
their free hydroxyl counterparts (22 and 59, respec-
tively) implying that a free hydroxyl group was impor-
tant for high potency in this series.
A second round of aniline ring modifications was
conducted, this time utilizing the more potent inhibitor
58 containing a 3-OCF3 substituent in the benzylic ring
(Table 3). An analogue with a 3-OCF3 group in the
aniline ring (60) identified the first low micromolar
inhibitor, and more importantly, 60 now exhibited some
inhibitory activity in the presence of human serum (IC50
46 µM). Even more potent was the aniline 3-phenoxy
analogue 61. The preferred meta orientation for this
aniline 3-phenoxy group was demonstrated by preparing
the corresponding 4-positional isomer as in 62, which
exhibited 25-fold lower activity in buffer.
a
Ref 24.
lipoproteins are present. We suspect that this value is
lower than that in buffer due to nonspecific binding of
the inhibitors to nontarget blood proteins. The simplicity
of the chemistry needed to prepare 22 suggested that a
wide variety of structural modifications could be readily
incorporated to explore the SAR within this interesting
new class.
As summarized below, several key structural changes
provided insights into the SAR and suggested a direc-
tion for further modifications. Replacing the aniline 3-F
group of 22 with Cl (44), CF3 (45), or CH3 (46) increased
potency 3-4-fold (Table 1). Removal of the 3-F substitu-
ent altogether (47) retained the potency, implying that
the aniline 3-substituent was open to broad modifica-
tion. However, substitution in the 2-position with CH3
(48) dramatically reduced activity. Ortho substituents
would likely effect the respective orientation of the two
phenyl rings, and this in turn may be critical for
potency. Moving the CH3 group to the 4-position (49)
also reduced activity. Next, keeping the 3-fluoro group
in the aniline ring and the trifluoropropanol chain
constant, various modifications to the benzylic group
were examined. If the benzylic methylene was replaced
by CO, as in the benzamide 12, activity was reduced
significantly (buffer IC50 > 100 µM). Removal of the
benzylic 3-CF3 group (50) or a change to a CH3 group
in either the 3-position (51) or the 4-position (52) also
significantly reduced activity (Table 2), implying that
the benzylic 3-substituent was critical for potency. Also,
substitution in the benzylic 2-position lowered potency
On the basis of the aniline 3-phenoxy analogue 61, a
second round of benzyl ring modifications was carried
out (Table 4). Substitution in the benzylic methylene

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3895
Ta ble 4. Benzyl Ring Modifications of
N-(3-Phenoxy)phenyl-N-benzyl-trifluoro-3-amino-propanols
3-alkoxy analogues 26, 29, and 65, which would be
expected to adopt a more coplanar orientation.28
In an effort to explore the contribution of this out-of-
plane spatial orientation (Figure 2)29 to the potency of
61, additional ether analogues were prepared to replace
the 3-OCF3 group with other nonplanar 3-substituents.
Whereas the 3-phenoxy analogue 66 had lower potency
than 61, the more hindered 3-tert-butyloxy and 3-i-
propyloxy analogues 32 and 27 were extremely potent,
exhibiting submicromolar buffer IC50 values and im-
proved potency vs 61 in the presence of serum. The
highest potency, however, was exhibited by the extended
3-(1,1,2,2-tetrafluoroethoxy) analogue 42 (IC50 0.14 µM)
with submicromolar potency in buffer and significant
low micromolar potency in the presence of human serum
(IC50 5.6 µM). Compound 42 therefore represents a more
than 250-fold potency increase over the original screen-
ing lead 22.
The presence of a free hydroxyl on the benzylic 3-ether
substituent as in 34 did not improve potency vs 61, and
34 was 10-fold less potent than 42. Changing the
benzylic 3-OCF3 group to the corresponding thioether
SCF3 analogue 67 improved potency slightly vs 61, but
67 showed no advantage over 42. A heteroatom was not
required for potency as a linking group at the benzylic
3-position. For example, replacing the oxygen linker
from the potent 3-isopropoxy analogue 27 gave the
carbon-linked iso-butyl analogue 38 with activity com-
parable to 27. The related carbocyclic analogue 39
incorporating a cyclopentyl ring also exhibited potency
similar to 27 and 38, but the smaller cyclopropyl system
as in 40 had somewhat reduced activity. Heteroaryl
replacements were also examined,30 and of these, the
2-furyl analogue was the most potent (IC50 0.48 µM).
Interestingly, the activity of the hindered tertiary
alcohol 35 was nearly 8-fold weaker than 61, but the
related bis-trifluoromethyl carbinol 36 had 15-fold
higher potency than 35. Thus, 36 exhibited submicro-
molar potency in the buffer assay and low micromolar
potency (IC50 4.9 µM) comparable to 42 in the serum
assay. The intermediate carboxy ester (37) had 16-fold
lower potency than 61. Thus, numerous modifications
were examined to replace the extended benzylic 3-
(1,1,2,2-tetrafluoroethoxy) moiety in 42, and no func-
tional group was identified that dramatically improved
activity at this position.
IC50 (µm)
IC50 (µm)
inhibitor
R2
in buffera
in plasmaa,b
61
63
64
65
26
29
66
32
27
42
34
67
38
39
40
35
36
37
3-OCF3
4-OCF3
3,4-(OCF2CF2O)
3-OCH3
3-OCH2CH3
3-OCH2CF3
3-OPh
1.0
3.5
12
15
1.6
40
120
ND
>200
70
1.0
5.2
65
70
29
21
5.6
62
24
ND
ND
ND
ND
4.9
ND
3-O-t-Bu
0.66
0.35
0.14
1.3
0.39
0.54
0.30
1.0
3-OPri
3-OCF2CF2H
3-OCH2CH(OH)CF3
3-SCF3
3-[(2-CH3)-Pr]
3-cyclopentyl
3-cycloPr
3-C(CH3)2OH
3-C(CF3)2OH
3-CO2CH3
7.8
0.42
16
a
b
Ref 24. ND, not determined.
F igu r e 2. Negative electrostatic potential for PhOCF3 show-
ing electron dense areas out of plane on the ring.29
with a methyl group as in 13 voided the activity (buffer
IC50 > 100 µM) (compare with 17), again implying that
the orientation of the benzyl group to the phenyl ring
was important for activity. Moving the benzylic 3-OCF3
group in 61 to the 4-position as in 63 reduced activity.
The fluorinated benzodioxane analogue 64 also had less
potency. The 3-CH3O analogue 65 was 15-fold less
potent than 61, indicating that meta-haloalkoxy groups
were preferred for activity. Interestingly, the 3-OCH2CH3
and 3-OCH2CF3 analogues (26 and 29) were more potent
than 65 but not more so than 61. Ab initio calculations
with Gaussian 94 predicted that the 3-OCF3 group is
nearly perpendicular (about 90°) to the plane of the
phenyl ring in PhOCF3 at the lowest torsional energy
conformation (Figure 2).28,29 This out of plane orienta-
tion with respect to the phenyl ring is due to the
electron-withdrawing effect of the fluorine atoms, which
causes the oxygen to have sp3 character. This unusual
substituent orientation would not be expected in the
Changing the terminal trifluoropropanol moiety in 61
with various aromatic and aliphatic groups did not
result in analogues with improved potency (Table 5,
4-8). Also, the N,N-dibenzyl series was found to be less
potent than the N-benzyl aniline counterparts. For
example, 10 had a buffer IC50 of 23 µM as compared
with an IC50 of 1.5 µM for 60, and 11 had a buffer IC50
of 30 µM as compared to an IC50 of 1.0 µM for 61.
When 42 was analyzed by chiral chromatography, an
unexpected 7:1 ratio of enantiomers was observed. The

3896 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
Ta ble 5. Aminopropanol Chain Modifications in the
N-(3-Phenoxy)phenyl-N-(3-trifluoromethoxy)Benzyl Series
in-
hibitor
IC50 (µm)
in-
hibitor
IC50 (µm)
R3
in buffera
R3
in buffera
61
4
5
CF3
CH2CH2CH3
Ph
1.0
3.6
>50
6
7
8
4-CF3Ph
CH2Ph
CHdCH2
18
>50
>50
a
Ref 24.
F igu r e 3. Inhibition of CETP-mediated tranfer ex vivo by
42 at 30 mpk iv after 30 min in hCEPT mouse.
Ta ble 6. CETP Inhibitory Properties of Chiral
N,N-Disubstituted Trifluoro-3-amino-2-propanols
IC50 (µM)
IC50 (µM)
inhibitor
in buffera
in plasmaa,b
1a
1b
43
0.02
0.8
5.0
0.6
20
ND
a
b
Ref 24. ND, not determined.
individual enantiomers were obtained by preparative
chiral chromatography and analyzed for CETP inhibi-
tory activity. The minor (+)-enantiomer 1a had an IC50
of 0.02 µM while the major (-)-enantiomer 1b exhibited
much less activity (IC50 0.8 µM) (Table 6). The minor
(+)-enantiomer 1a also displayed submicromolar activ-
ity (IC50 0.6 µM) in the presence of human serum.
Moreover, 1a could be prepared independently from the
known chiral epoxide, R-(+)-2-trifluoromethyloxirane,25
suggesting that the (+)-1a enantiomer contained the
(R)-configuration. Because no unequivocal structural
data have been presented for such compounds, we
prepared a related crystalline analogue 43 from the
same sample of chiral R-(+)-2-trifluoromethyloxirane,25
determined its structure by X-ray analysis (Figure 1),
and confirmed that the alcohol configuration in 43 was
indeed (R). From these data, we concluded that the
structure of (+)-1a also has the (R)-configuration.
More detailed biochemical binding studies comparing
the relative affinities and binding properties of 42 and
1a ,b have been reported.24 The results of these efforts
demonstrate that inhibitors 42 and 1a reversibly block
both CETP-mediated TG and CE transfer. They associ-
ate with HDL and LDL but do not disrupt the structure
of these lipoproteins. Their CETP inhibitory activity is
highly specific, since they do not inhibit phospholipid
transfer protein or lecithin cholesterol acyl transferase.
Competition experiments showed that the potent re-
versible inhibitor 1a prevented CE binding to CETP and
that 1a bound approximately 5000-fold more efficiently
to CETP than CE.
F igu r e 4. Inhibition of CETP-mediated tranfer ex vivo by
42 at 30 mpk iv after 30 min in hampster.
F igu r e 5. HDL elevation by treatment with 42 in cholesterol-
fed hCEPT mice in vivo 30 mpk po, qd, 5 days. Size exclusion
chromatography using two Superose 6 columns of a plasma
fraction with and without treatment with 42.
vivo by only 30% after 4 h in cholesterol-fed hamsters.
Under these conditions, the observed plasma concentra-
tions of 1a were more than 10-fold greater than the
experimentally determined IC50 values for 1a in either
human or hamster serum (IC50 0.6 µM). Thus, the
increased in vitro potency of 1a did not translate into a
higher level of ex vivo inhibition of CETP activity.
Although compound 42 exhibited a fairly poor oral
bioavailability (<10%) in mice, the plasma concentra-
tions 24 h after administration of a single 30 mg/kg dose
exceeded the serum IC50 levels. Oral dosing of 42 qd
for 5 days at 30 mg/kg raised HDLc by 20% in hCETP
transgenic mice (Figure 5).
In preliminary animal studies, the potent inhibitors
42 and 1a provided the first in vivo proof of concept for
this class. For example, iv administration of a single
dose of 42 at 30 mg/kg inhibited CETP-mediated
transfer ex vivo by 50% after 30 min in hCETP trans-
genic mice (Figure 3) and by 30% after 3 h in cholesterol-
fed hamsters (Figure 4). Compound 42 showed similar
potency for inhibiting CETP-mediated transfer in cho-
lesterol-fed hamster serum (IC50 12 µM) as in human
serum. Surprisingly, administration of a single dose of
1a at 33 mg/kg inhibited CETP-mediated transfer ex
When radiolabeled 42 (with tritium labeling at the
benzylic center24) was added to human plasma and the
plasma was subjected to size exclusion chromatography,

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3897
(15.3 mmol) were dissolved in 60 mL of 1,2-dichloroethane.
Acetic acid (16.05 mmol) and solid NaBH(OAc)3 (19.5 mmol)
were added. The mixture was stirred at room temperature for
3 h and then acidified with 1 N HCl solution. Alternatively,
the amine (15 mmol) and the aldehyde (15 mmol) in cyclo-
hexane were heated to reflux using a Dean-Stark trap to
remove water. The recovered resultant imine was stirred with
NaBH4 (20 mmol) in methanol for 3 h, and the mixture was
acidified with 1 N HCl solution. After the pH was neutralized
to 7.5 with 2.5 N NaOH, the mixture was extracted with
CH2Cl2. The organic layer was washed with brine and water,
then dried over anhydrous MgSO4, and concentrated in vacuo
to give the desired product as a brown oil, which was examined
for purity by reverse phase HPLC analysis.
P r oced u r e B. Alter n a tive Am in e Alk yla tion P r oce-
d u r e. To a solution of toluene (24 mmol) and N-bromosuccin-
imide (24 mmol) in 100 mL of CCl4 under nitrogen was added
2,2′-azobisisobutyronitrile (4 mmol). The resultant mixture was
refluxed for 2 h and then cooled to room temperature and
quenched with 300 mL of water. The organic layer was
collected, washed with water and brine, dried over MgSO4, and
concentrated in vacuo to give a yellow oil. The oil, dissolved
in cyclohexane (100 mL), was added dropwise under nitrogen
to a solution of the amine (60 mmol) in 500 mL of cyclohexane.
The reaction mixture was refluxed overnight and then cooled
to room temperature and diluted with water and Et2O. The
layers were separated, and the aqueous layer was extracted
with Et2O. The combined organic layers were dried over
MgSO4 and concentrated in vacuo to a dark oil. The crude
product was purified by column chromatography on silica
eluting with EtOAc/hexane (1:4) to separate the mono- and
dialkylated amines and examined for purity by reverse phase
HPLC analysis.
P r oced u r e C. Op en in g of a n Ep oxid e w ith a Secon d -
a r y Am in e to Give a â-Hyd r oxy Am in e. The secondary
amine prepared either in procedure A or B (4 mmol) and
2-trifluoromethyloxirane (6 mmol) (TCI America, catalog no.
T1557) or another oxirane (6 mmol) were dissolved in 1.5 mL
of MeCN. Ytterbium(III) trifluoromethanesulfonate (0.13 g, 0.2
mmol) was added, and the stirred solution was warmed to 50
°C for 2 h (or overnight, if indicated) under an atmosphere of
nitrogen. The reaction was quenched with water and extracted
with Et2O. The Et2O was washed with water and brine and
then dried over MgSO4. The crude product was purified by
flash column chromatography on silica gel eluting with EtOAc/
hexane (1:16 to 1:7) or by semipreparative reverse phase HPLC
(if indicated) using C18 packing and mobile phase CH3CN/H2O
(6:4 to 10:0 in 5 min) at a flow rate of 20 mL/min to give the
desired product. Purity was checked by reverse phase HPLC
analysis.
1-[(3-P h en oxyp h en yl)[[3-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]p en ta n -2-ol (4). The title compound was
prepared from 3-phenoxyaniline and 3-(trifluoromethoxy)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 251), followed by treatment with
2-propyloxirane by procedure C (overnight and purifying
product by reverse phase) to give 4 as a light amber oil (yield
51%). HRMS: m/z [M + H]+ 446.1940 (C25H27F3NO3 requires
446.1944). Anal. (C25H26F3NO3) C, H, N.
1-P h en yl-2-[(3-p h en oxyp h en yl)[[3-(tr iflu or om eth oxy)-
p h en yl]m eth yl]a m in o]eth a n -1-ol (5). The title compound
was prepared from 3-phenoxyaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 251), followed by treatment with
2-phenyloxirane by procedure C (overnight and purifying
product by reverse phase) to give 5 as a light amber oil (yield
49%). HRMS: m/z [M + H]+ 480.1792 (C28H25F3NO3 requires
480.1786). Insufficient material for C, H, and N analysis.
F igu r e 6. Association of [3H]42 with plasma lipoproteins and
albumin. Size exclusion chromatography on two Superose 6
columns of 0.5 mL of human plasma after the addition of
[3H]42. The elution positions of VLDL, LDL, HDL, and
albumin were determined by chromatographing standards
under the same conditions.
the radioactivity was found to elute in five major peaks
(Figure 6). The first three peaks coeluted with high
molecular weight particles containing cholesterol. These
corresponded to the elution positions of VLDL, LDL, and
HDL. The elution of the fourth peak was identical to
the elution position of albumin. The fifth peak to elute
was low molecular weight and probably represented an
unbound compound. Approximately 90% of the radio-
activity was found in the high molecular weight frac-
tions, and only 10% of the radioactivity was found in
the low molecular weight unbound fraction. Similar
results were observed using radiolabeled 1a .
In conclusion, we have discovered chiral N,N-disub-
stituted trifluoro-3-amino-2-propanols as a new simple
class of potent CETP inhibitors. The most potent inhibi-
tor 1a also exhibited submicromolar activity in the
presence of human serum. In hCETP transgenic mice,
42 showed moderate potency ex vivo in the inhibition
of CETP. Similar potencies were observed with ham-
sters for both 42 and 1a . Although 42 exhibited poor
bioavailability in hCETP transgenic mice, it did raise
HDLc moderately after oral dosing qd for 5 days at 30
mg/kg.
Exp er im en ta l Section
1H NMR, 13C NMR, 19F NMR spectra were collected on a
Varian VXR-400 or VXR-300 spectrometer. The samples were
dissolved in CDCl3, C6D6, or dimethyl sulfoxide (DMSO)-d6 100
atom % (MSD Isotopes, St. Louis, MO) at a concentration of
0.3-0.7 wt % and placed in 5 mm NMR tubes (Wilmad Glass,
Buena, NJ ). Mass spectrometry was performed using a SCIEX
(Thornhill, Ontario, Canada) API-III mass spectrometer utiliz-
ing an electrospray interface. High-resolution mass spectra
were obtained by electron impact on a MAT 90 instrument
using Electro Calibration with poly(ethylene glycol) (PEG), and
samples were dissolved in H2O/CH3CN (50:50). UV absorption
spectra were taken on a Hewlett-Packard 8451A diode array
spectrophotometer. Optical rotation was obtained on a Perkin-
Elmer 241 polarimeter using a 1.0 mL microcell and CH3OH
as solvent. All isolated final purified products were routinely
analyzed for purity by reverse-phase high-performance liquid
chromatography (HPLC) and were generally found to be >95%
pure. Yield data on products generated via the general
procedures A and C are not optimized (except in some specific
cases) since these products were made on a parallel synthesis
basis.
2-[(3-P h en oxyp h en yl)[[3-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]-1-[4-(tr iflu or om eth yl)p h en yl]eth a n -1-ol
(6). To a methylene chloride (40 mL) solution of 4-(trifluoro-
methyl)styrene (1.50 g, 8.72 mmol) was added m-chloroper-
oxybenzoic acid (4.50 g, 13.0 mmol). The resulting slurry was
stirred for 18 h at room temperature under nitrogen. The
P r oced u r e A. Red u ctive Alk yla tion of a n Am in e w ith
a Ben za ld eh yd e. The amine (15 mmol) and the benzaldehyde

3898 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
reaction mixture was quenched with aqueous sodium hydrogen
sulfite (approximately 2 g in 20 mL). Methylene chloride (50
mL) was added, and the mixture was shaken. Insoluble solids
were removed by filtration. The organic layer was separated,
washed with saturated sodium bicarbonate, dried over MgSO4,
and evaporated to give 4-(trifluoromethyl)styrene oxide as a
pale yellow oil (1.62 g, 98%).
amino]-1,1,1-trifluoro-2-propanol 19 as an oil, 99% pure by
HPLC analysis. MS: m/z [M + H]+ 224.
The oil (446 mg, 2.0 mmol) and Et3N (544 mg) were
dissolved in anhydrous CHCl3 (30 mL) and cooled to 0 °C.
3-Trifluoromethylbenzoyl chloride (1.04 g, 5.0 mmol) dissolved
in anhydrous CHCl3 (6 mL) was added over a period of 15 min.
The solution was stirred at room temperature. After 14 h, the
solution was washed with 5% NaHCO3 solution (2 × 20 mL)
and brine (2 × 10 mL) and then dried over anhydrous MgSO4.
Removal of the solvent in vacuo gave 3-[3-fluorophenyl[3-
(trifluoromethyl)benzoyl]amino]-1,1,1-trifluoro-2-propyl ben-
zoate 20 as an amber oil (832 mg, 73%), which was greater
than 95% pure by reverse phase HPLC analysis. HRMS: m/z
[M + H]+ 568.0968 (C25H16F10NO3 requires 568.0970).
The amber oil (600 mg, 1.06 mmol) was dissolved in CH3OH
and treated with 28% NH3 solution (122 µL). The solution was
stirred at room temperature for 10 h. The reaction was
quenched with water and extracted with Et2O. The Et2O layer
was washed with brine and water and then dried over
anhydrous MgSO4. The crude product was purified by flash
column chromatography on silica gel eluting with EtOAc/
hexane (1:8) to give 17 as a white powder (255 mg, 61%), 97%
pure by HPLC analysis. HRMS: m/z [M + H]+ 396.0821
(C17H13F7NO2 requires 396.0854). Anal. (C17H12F7NO2) C, H,
N.
3-[(3-Flu or oph en yl)[[3-(tr iflu or om eth yl)ph en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol Aceta te Ester (21). 3-[3-
Fluorophenyl[[3-(3-trifluoromethyl)phenyl]methyl]amino]-1,1,1-
trifluoro-2-propanol (22) (200 mg, 0.52 mmol) prepared below
was dissolved in triethylamine (0.6 mL) and acetic anhydride
(0.5 mL). The solution was stirred and heated to 80 °C for 1
h. The mixture was cooled and diluted with water (20 mL)
and extracted into ether (2 × 40 mL), which was washed with
0.1 N NaOH and water. The ether solution was dried over
anhydrous MgSO4. The ether was removed in vacuo giving the
required product as an amber oil (191 mg, 87%), 98% pure by
HPLC analysis. HRMS: m/z [M + H]+ 424.1159 (C19H17F7NO2
requires 424.1148). Anal. (C19H16F7NO2) C, H, N.
The title compound was prepared from 3-phenoxyaniline
and 3-trifluoro-methoxybenzaldehyde by procedure A to afford
the secondary amine as a yellow oil (MS m/z M+ 359.4). To a
methylene chloride (5 mL) solution of this amine (1.34 g, 3.7
mmol) and 4-(trifluoromethyl)styrene oxide (0.70 g, 3.7 mmol)
was added Yb(OTf)3 (461 mg, 0.74 mmol). The resulting slurry
was stirred for 18 h at room temperature under nitrogen. The
reaction was quenched with water and extracted with Et2O.
The Et2O was washed with water and brine and then dried
over MgSO4. The crude product, containing a mixture of the
two regioisomers, was purified by flash column chromatogra-
phy on silica gel eluting with 15% EtOAc/hexane. The faster
eluting product was isolated and evaporated to an oil. The oil
was taken up in EtOH, evaporated, and dried in vacuo for 24
h to give 6 as an amber oil (546 mg, yield 27%). Anal. (C29H23F6-
NO3‚2EtOH) C, H, N. The second eluting band was also
isolated and identified as the unwanted regioisomer.
3-P h en yl-1-[(3-p h en oxyp h en yl)[[3-(tr iflu or om eth oxy)-
p h en yl]m eth yl]a m in o]p r op a n -2-ol (7). The title compound
was prepared from 3-phenoxyaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 251), followed by treatment with
2-benzyloxirane by procedure C (overnight and purifying
product by reverse phase) to give 7 as a light amber oil (yield
38%). HRMS: m/z [M + H]+ 494.1935 (C29H27F3NO3 requires
494.1944).
1-[(3-P h en oxyp h en yl)[[3-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]bu t-3-en -2-ol (8). The title compound was
prepared from 3-phenoxyphenylaniline and 3-(trifluorometh-
yl)benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 269), which was treated with
2-vinyloxirane by procedure C (overnight and purifying prod-
uct by reverse phase) to give 8 as an amber oil (yield 38%).
HRMS: m/z [M + H]+ 430.1621 (C24H23F3NO3 requires
430.1630).
3-[(3-Flu or oph en yl)[[3-(tr iflu or om eth yl)ph en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (22). The title compound
was prepared from 3-fluoroaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 269), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 22 as an
amber oil (62% yield). HRMS: m/z [M + H]+ 382.1032
(C17H15F7NO requires 382.1042). Anal. (C17H14F7NO) C, H, N.
6-F lu or o-3,4-d ih yd r o-4-[[(3-(1,1,2,2-tetr a flu or oeth oxy)-
p h e n y l]m e t h y l]-2-(t r iflu o r o m e t h y l)-2H -1,4-b e n zo x -
azin e (23). 2,5-Difluoroaniline and 3-(1,1,2,2-tetrafluoroethoxy)-
benzaldehyde were reacted by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 335), which was
treated with 2-trifluoromethyloxirane by procedure C to give
3-[(2,5-difluorophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
methyl]amino]-1,1,1-trifluoro-2-propanol as a light yellow oil
3-[Bis-[3-(3-tr iflu or om eth oxy)ben zyl]a m in o]-1,1,1-tr i-
flu or o-2-p r op a n ol (10). The title compound was prepared
from 3-(trifluoromethoxy)benzylamine and 3-(trifluoromethoxy)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 365), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 10 as a light
yellow oil (yield 65%). HRMS: m/z [M+H]+ 478.1057 (C19H17F9-
NO3 requires 478.1064). Anal. (C19H16F9NO3) C, H, N.
3-[(3-P h en oxyben zyl)[3-(tr iflu or om eth oxy)ben zyl]am i-
n o]-1,1,1-tr iflu or o-2-p r op a n ol (11). The title compound was
prepared from 3-phenoxybenzylamine and 3-(trifluoromethoxy)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 373), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 11 as yellow
oil (61%). HRMS: m/z [M + H]+ 486.1475 (C24H22F6NO3
requires 486.1504). Anal. (C24H21F6NO3) C, H, N.
1
(1.2 g, 69%). H NMR δ (CDCl3): 2.79 (bs, 1H), 3.30 (dd, 1H),
3.61 (dd, 1H), 4.16 (m, 1H), 4.43 (ABq, 2H), 5.88 (tt, 1H), 6.64
(m, 2H), 7.01 (m, 1H), 7.15 (m, 3H), 7.34 (t, 1H). 19F NMR δ
(CDCl3): -137.1 (d, 2F), -128.3 (m, 1F), -117.1 (m, 1F),-88.5
(s, 2F), -79.3 (d, 3F). HRMS: m/z [M + H]+ 448.0940
(C18H15F9NO2 requires 448.1059). Anal. Calcd for C18H14F9-
NO2: C, 48.33; H, 3.16; N, 3.13. Found: C, 48.69; H, 3.40; N,
2.90.
3-[(3-P h en oxyp h en yl)[1-[3-(tr iflu or om eth oxy)p h en yl]-
eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (13). The title com-
pound was prepared from 3′-(trifluoromethoxy)acetophenone
and 3-phenoxy-aniline following procedure A, and the resulting
oil was treated with 2-trifluoromethyloxirane according to
procedure C giving 13 as an amber oil (14% yield). HRMS:
[M + H]+ 485.1442 (C24H22F6NO3 requires 485.1426). Anal.
(C24H21F6NO3) C, H, N.
To the propanol (500 mg, 1.12 mmol) in DMF (20 mL) was
added finely powdered K2CO3 (500 mg). The mixture was
stirred and heated under reflux at 145 °C for 18 h. The mixture
was diluted with water (200 mL) and extracted with diethyl
ether (3 × 150 mL). The ether was washed with brine and
dried (anhydrous MgSO4). The crude product was purified by
flash column chromatography on silica gel eluting with EtOAc/
hexane (1:15) to give the desired product as a light yellow oil
(48% yield). HRMS: m/z [M + H]+ 428.0910 (C18H14F8NO2
requires 428.0898). Anal. (C18H13F8NO2) C, H, N.
N-(3-Flu or oph en yl)-N-(3,3,3-tr iflu or o-2-h ydr oxypr opyl)-
3-(tr iflu or om eth yl)ben zam ide (17). 3-[3-Fluorophenyl(phen-
ylmethyl)amino]-1,1,1-trifluoro-2-propanol (50) (2.56 g, 8.2
mmol), prepared below, was dissolved in CH3OH (30 mL) and
hydrogenated over 5% Pd on charcoal for 3 h. The mixture
was filtered through Celite, and the solvent and volatiles were
removed in vacuo to give 1.8 g (98%) of 3-[(3-fluorophenyl)-
3-[(3-P h en oxyph en yl)[(3-eth oxyph en yl)m eth yl]am in o]-
1,1,1-tr iflu or o-2-p r op a n ol (26). 3-Hydroxybenzaldehyde (28)

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3899
(1.81 g, 14.8 mmol), sodium methoxide (0.822 g, 15.2 mmol),
and ethyl iodide (2.70 g, 17.3 mmol) were refluxed in 25 mL
of CH3OH overnight. Ethyl acetate was added, and the solution
was washed with water and dried over MgSO4. Evaporation
gave crude 3-ethoxybenzaldehyde (24) (1.78 g), which was
vacuum-distilled to a pale yellow oil (1.47 g 66%).
3-t-Butoxybenzaldehyde (31) (585 mg, 3.27 mmol) and
3-phenoxyaniline (595 mg, 3.21 mmol) by procedure A, followed
by treatment of the product with 2-trifluoromethyloxirane (515
mg, 4.6 mmol) as in procedure C to give 32 as an amber oil
(823 mg, 56%). HRMS: m/z [M + H]+ 460.2103 (C26H29F3NO3
requires 460.2100). Anal. (C26H28F3NO3) C, H, N.
3-[[(3-P h en oxyph en yl)[3-(3,3,3-tr iflu or o-2-h ydr oxy-pr o-
p oxy)p h en yl]m et h yl]a m in o]-1,1,1-t r iflu or o-2-p r op a n ol
(34). 3-Hydroxybenzaldehyde and 3-phenoxyaniline were re-
acted following procedure A to afford the secondary amine (33)
as a yellow oil (yield 83%) (MS m/z M+ 291). This amine (200
mg, 0.65 mmol) was stirred with 2-trifluoromethyloxirane (522
mg, 3 mmol) for 30 h at 95 °C in a sealed vial to give a dark
amber oil, which was purified on silica eluting with ethyl
acetate/hexane (1:6) to give 34 as a brown oil (251 mg, 75%).
HRMS: m/z [M + H]+ 516.1638 (C25H24F6NO4 requires
516.1610). Anal. (C25H23F6NO4) C, H, N.
r,r-Dim eth yl-3-[[(3-p h en oxyp h en yl)(3,3,3-tr iflu or o-2-
h yd r oxyp r op yl)a m in o]m eth yl]ben zen em eth a n ol (35). To
a solution of 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxy-
propyl)amino]methyl] benzoic acid, methyl ester (37) (218 mg,
0.49 mmol) in 0.7 mL of tetrahydrofuran (THF) at 0 °C was
slowly added a 3.0 M THF solution of methylmagnesium
chloride (650 µL, 2.0 mmol). The reaction mixture was warmed
to room temperature, stirred for 2 h, and then diluted with
diethyl ether and quenched with saturated aqueous am-
monium chloride. The aqueous layer was extracted with
dichloromethane, and the combined organic layers were dried
over anhydrous MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
eluting with 1:4 ethyl acetate:hexane to afford 35 as a light
yellow oil (174 mg, 80%). HRMS: m/z [M + H]+ 446.1938.
(C25H27F3NO3 requires 466.1943). Anal. (C25H26F3NO3‚0.5H2O)
C, H, N.
The title compound was prepared from 3-ethoxybenzalde-
hyde (24) (420 mg, 2.80 mmol) and 3-phenoxy-aniline (526 mg,
2.84 mmol) by procedure A, and the resulting oil was treated
with 2-trifluoromethyloxirane (392 mg, 3.5 mmol) according
to procedure C giving 26 as an amber oil (732 mg, 61%).
HRMS: m/z [M + H]+ 432.1770 (C24H25F3NO3 requires
432.1780). Anal. (C24H24F3NO3) C, H, N.
3-[(3-P h en oxyp h en yl)[[3-(isop r op oxy)p h en yl]m eth yl]-
a m in o]-1,1,1-t r iflu or o-2-p r op a n ol (27). 3-Hydroxybenz-
aldehyde (5.60 g, 45.9 mmol) and 2-iodopropane (7.86 g, 46.2
mmol) were dissolved in 2-propanol (50 mL). Potassium
carbonate (20 g, 145 mmol) was added, and the mixture was
heated to reflux for 8 h, at which time thin-layer chromatog-
raphy (TLC) analysis indicated that the reaction had gone to
completion. Water was added to dissolve all solids, and the
mixture was extracted with ether (3×). The combined ether
layer was washed with water, 2 M NaOH, again with water
until clear (4×), and finally with brine. The solution was dried
over MgSO4, filtered, and evaporated to give 3-isopropoxy-
benzaldehyde (25) (5.03 g, 67%) as a pale oil. MS: m/z [M +
H] 165.
The title compound was prepared from 3-isopropoxybenz-
aldehyde (25) (780 mg, 4.75 mmol) and 3-phenoxyaniline (881
mg, 4.76 mmol) by procedure A, followed by treatment of the
product with 2-trifluoromethyloxirane (764 mg, 6.8 mmol) as
in procedure C to give the desired product an amber oil (1.31
g, 62%). HRMS: m/z [M + H]+ 446.1936 (C25H27F3NO3 requires
446.1943). Anal. (C25H26F3NO3) C, H, N.
3-[[(3-P h en oxyp h en yl)(3,3,3-t r iflu or o-2-h yd r oxyp r o-
p yl)a m in o]m e t h yl]-r,r-b is(t r iflu or om e t h yl)b e n ze n e -
m eth a n ol (36). To a solution of 3-[[(3-phenoxyphenyl)(3,3,3-
trifluoro-2-propanol)amino]methyl] benzoic acid, methyl ester
(37) (331 mg, 0.74 mmol), and trimethyl(trifluoromethyl)silane
(423 mg, 3.0 mmol) in 3.0 mL of toluene at room temperature
was added a 1.0 M in THF solution of tetrabutylammonium
fluoride (150 µL, 0.15 mmol), which had been dried over
molecular sieves. The reaction mixture was heated at 40 °C
for 18 h. HPLC indicated incomplete reaction; therefore,
additional trimethyl(trifluoromethyl)silane (440 µL, 3.0 mmol)
and tetrabutylammonium fluoride (150 µL, 0.15 mmol) was
added and the reaction mixture was heated to 50 °C in a sealed
glass vial. After 2 h, HPLC analysis indicated that no starting
material remained. The reaction mixture was quenched with
water and extracted with dichloromethane. The organic layer
was dried over MgSO4 and concentrated in vacuo. The crude
product was purified on silica gel eluting with 1:9 ethyl acetate:
hexane to afford 36 (46 mg) as a yellow-brown oil. HRMS: m/z
[M + H]+ 554.1385. (C25H21F9NO3 requires 554.1378). Insuf-
ficient material was avaliable for C, H, and N analysis.
3-[(3-P h en oxyph en yl)[[3-(2,2,2-tr iflu or oeth oxy)ph en yl]-
m et h yl]a m in o]-1,1,1-t r iflu or o-2-p r op a n ol (29). NaOCH3
(21.61 g, 0.10 mol) in anhydrous CH3OH was slowly added to
3-hydroxybenzaldehyde (12.22 g, 0.10 mol) in anhydrous
CH3OH (100 mL). The solvent was removed in vacuo. After
the flask was purged with N2, 2,2,2-trifluoroethyl p-toluene-
sulfonate (25.42 g, 0.10 mol) and 100 mL of N-methyl pyrroli-
dine were added. The solution was stirred for 24 h at 90 °C
under N2, quenched with water, and extracted with Et2O (3×).
The combined Et2O layer was washed with 1 N NaOH (2×),
water, and brine, dried over MgSO4, filtered, and evaporated
to give 11.72 g of crude product. Chromatography from silica
with 5-10% EtOAc in hexane followed by a second chroma-
tography on silica with toluene gave 3-(2,2,2-trifluoroethoxy-
benzaldehyde) (30) (5.24 g, 26%) as a pale oil. 19F NMR δ
(C6D6): (t, 3F). MS: m/z [M + H] 205.
The title compound was prepared from 3-(2,2,2-trifluoro-
ethoxybenzaldehyde (30) (360 mg, 1.76 mmol) and 3-phenoxy-
aniline (326 mg, 1.76 mmol) by procedure A, followed by
treatment with 2-trifluoromethyloxirane (314 mg, 2.8 mmol)
as in procedure C to give 29 as a clear colorless oil (572 mg,
67%). HRMS: m/z [M + H]+ 486.1498 (C24H22F6NO3 requires
486.1504). Anal. (C24H21F6NO3) C, H, N.
3-[[(3-P h en oxyp h en yl)(3,3,3-t r iflu or o-2-h yd r oxyp r o-
p yl)a m in o]m eth yl]ben zoic Acid , Meth yl Ester (37). 3-[[(3-
Phenoxyphenyl) amino]methyl]benzoic acid, methyl ester was
prepared from 3-phenoxyaniline (25.0 g, 135.0 mmol) and
3-(bromomethyl)benzoic acid, methyl ester (8.8 g, 38.4 mmol)
as in procedure B to afford the desired trifluoroacetyl (TFA)
3-[[[3-(1,1-Dim eth yleth oxy)p h en yl]m eth yl](3-p h en oxy-
p h en yl)a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (32). 3-Hydroxy-
benzaldehyde (28) (4.08 g, 33.4 mmol) as slurry in 50 mL of
anhydrous CH2Cl2 was added to tert-butyl-2,2,2-trichloro-
acetimidate (25.0 g, 114 mmol) in 200 mL of anhydrous
cyclohexane with an additional 50 mL of CH2Cl2 used in
transfer. The mixture was stirred under N2 until uniform and
then, BF3‚Et2O (0.50 mL, 4 mmol) was added via syringe and
stirring was continued for 1 h. Powdered Na2CO3 (50 g, 0.6
mol) was added, and the solution was filtered through a silica
gel plug, washing the plug with hexane. The solvent was
removed to give crude product 3.54 g (59%) as an amber oil
(85% by GC). Chromatography on silica with 6-10% EtOAc
in hexane gave 3-t-butoxybenzaldehyde (31) as a colorless oil
(1.88 g, 32%), which was 98% pure by HPLC analysis. MS:
m/z [M + H] 179.
1
salt as a yellow oil (10.2 g, 59%). H NMR (CDCl3): δ 8.04 (s,
1H), 8.00 (d, 1H), 7.10-6.92 (m, 7H), 6.84 (t, 1H), 6.47 (d, 1H),
6.22 (s, 1H), 6.08 (d, 1H), 3.72 (d, 2H), 3.48 (s, 3H), 3.30 (bt,
1H). HRMS: m/z [M + H]+ 334.1442 (C21H19NO3 requires
334.1443). The title compound was prepared from this amine
salt (6.2 g, 18.6 mmol) and 2-trifluoromethyloxirane (3.4 g, 30
mmol) by procedure C to give 37 as a pale yellow oil (4.9 g,
79%). HRMS: m/z [M + H]+ 446.1596 (C24H23NO4F3 requires
446.1579). Anal. (C24H22F3NO4‚1.4H2O) C, H, N.
3-[[[3-(2-Meth ylpr opyl)ph en yl]m eth yl](3-ph en oxyph en -
yl)a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (38). A 1.0 M THF
solution of 3-{[(3-bromophenyl)methyl](3-phenoxyphenyl)-
amino}-1,1,1-trifluoropropan-2-ol (41) (0.5 g, 1.0 mmol) (pre-

3900 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
pared as in 40) was syringed into a two-neck round-bottom
flask containing 2-methylpropylmagnesium bromide (0.33 g,
2.0 mmol) under nitrogen equipped with a stir bar. To the
resulting solution was added Pd(PPh3)4 (57.0 mg, 0.05 mmol).
The reaction was allowed to reflux for 18 h at which time TLC
indicated desired product. The reaction was cooled, washed
with saturated ammonium chloride (2 × 25 mL), dried
(anhydrous MgSO4), and concentrated. The crude product was
purified by flash column chromatography on silica gel eluting
with EtOAc/hexane (1:9) to give 38 as a yellow oil (201 mg,
45%). MS: m/z M+ 443. HRMS: m/z [M + H]+ 444.2157
(C26H29F3NO2 requires 444.2152). Anal. (C26H28F3NO2) C, H,
N.
3-[[(3-Cyclop en tylp h en yl)m eth yl](3-p h en oxyp h en yl)-
a m in o]-1,1,1-tr iflu or op r op a n -2-ol (39). The title compound
was prepared from 3-phenoxyaniline and 3-cyclopentylbenz-
aldehyde31 by procedure A to afford the secondary amine as a
yellow oil, followed by treatment with 2-trifluoromethyloxirane
by procedure C to give 39 as an amber oil (yield 43%). HRMS:
m/z [M + H]+ 456.2143 (C27H29F3NO2 requires 456.2150). Anal.
(C27H28F3NO2‚0.4EtOH) C, H, N.
3-[[(3-Cyclop r op ylp h en yl)m eth yl](3-p h en oxyp h en yl)-
a m in o]-1,1,1-t r iflu or op r op a n -2-ol (40). 3-Phenoxyaniline
and 3-bromobenzaldehyde were reacted by procedure A to
afford the secondary amine as a yellow oil (MS m/z M+ 354),
which was treated with 2-trifluoromethyloxirane by procedure
C to give 3-[[(3-bromophenyl)methyl]-(3-phenoxyphenyl)amino]-
1,1,1-trifluoro-2-propanol (41) as an amber oil (yield 63%).
HRMS: m/z [M + H]+ 466.0598 (C22H20F3NO2Br requires
466.0629). A THF (5 mL) solution of cyclopropylmagnesium
bromide was prepared from bromocyclopropane (1.45 g, 12.0
mmol) and magnesium (314 mg, 12.9 mmol).31 To this solution
was added 3-[[(3-bromophenyl)methyl](3-phenoxyphenyl)-
amino]-1,1,1-trifluoropropan-2-ol (1.4 g, 3.0 mmol) and Pd-
(PPh3)4 (0.16 mmol). The resulting solution was refluxed for
18 h under nitrogen, and the reaction mixture was poured into
saturated NH4Cl and extracted with EtOAc. The EtOAc was
washed with water and brine and then dried over MgSO4. The
crude product was purified by flash column chromatography
on silica gel eluting with 15% EtOAc/hexane to give 40 as an
amber oil (452 mg, 35%). HRMS: m/z [M + H]+ 428.1806
(C25H24F3NO2 requires 428.1837). Anal. (C25H24F3NO2) C, H,
N.
give 26 as an amber oil (66% yield). HRMS: m/z [M + H]+
432.1026 (C18H15F9NO requires 432.1010). Insufficient mate-
rial was available for C, H, and N analysis.
3-[3-Meth ylp h en yl[[3-(tr iflu or om eth yl)p h en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (46). The title compound
was prepared from 3-methylaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a brown oil (MS m/z M+ 265), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 46 as a light
brown oil (51% yield). HRMS: m/z [M + H]+ 378.1254
(C18H18F6NO requires 378.1288). Anal. (C18H17F6NO) C, H, N.
3-[P h en yl[[3-(tr iflu or om eth yl)p h en yl]m eth yl]a m in o]-
1,1,1-tr iflu or o-2-p r op a n ol (47). The title compound was
prepared from 3-(trifluoromethyl)aniline and 3-(trifluoro-
methyl)benzaldehyde by procedure A to afford the secondary
amine as a yellow oil (MS m/z M+ 251), followed by treatment
with 2-trifluoromethyloxirane by procedure C to give 47 as a
light amber oil (63% yield). HRMS: m/z [M + H]+ 364.1122
(C17H16F6NO requires 364.1136). Anal. (C17H15F6NO) C, H, N.
3-[2-Meth ylp h en yl[[3-(tr iflu or om eth yl)p h en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (48). The title compound
was prepared from 3-methylaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a dark brown oil (MS m/z M+ 265), followed by treatment
with 2-trifluoromethyloxirane by procedure C to give 48 as a
brown oil (42% yield). HRMS: m/z [M + H]+ 378.1254
(C18H18F6NO requires 378.1288). Anal. (C18H17F6NO) C, H, N.
3-[4-Meth ylp h en yl[[3-(tr iflu or om eth yl)p h en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (49). The title compound
was prepared from 3-methylaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 265), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 49 as an
amber oil (48% yield). HRMS: m/z [M + H]+ 378.1267
(C18H18F6NO requires 378.1288). Anal. (C18H17F6NO) C, H, N.
3-[(3-F lu or op h en yl)[(p h en yl)m et h yl]a m in o]-1,1,1-t r i-
flu or o-2-p r op a n ol (50). The title compound was prepared
from 3-fluoroaniline and benzaldehyde by procedure A to afford
the secondary amine as a brown oil (MS m/z M+ 201), followed
by treatment with 2-trifluoromethyloxirane by procedure C to
give 50 as a yellow oil (44% yield). HRMS: m/z [M + H]+
314.1178 (C16H16F4NO requires 314.1168). Insufficient mate-
rial was available for C, H, and N analysis.
3-[(3-P h en oxyp h en yl)[[3-(1,1,2,2-t et r a flu or oet h oxy)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (42). The
title compound was prepared from 3-phenoxyaniline and
3-(1,1,2,2-tetra-fluoroethoxy)benzaldehyde by procedure A to
afford (3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
methyl]amine as a yellow oil (MS m/z M+ 391), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
42 as a light amber oil (yield 63%). HRMS: m/z [M + H]+
504.1425 (C24H21F7NO3 requires 504.1410). Anal. (C24H20F7NO3)
C, H, N. To separate this compound into its enantiomers, a
further preparation of this material was made from 3-
phenoxyaniline and 3-(1,1,2,2-tetra-fluoroethoxy)toluene by
procedure B to give the secondary amine (MS m/z M+ 391),
followed by treatment with 2-trifluoromethyloxirane by pro-
3-[(3-F lu or op h en yl)[[3-m eth ylp h en yl]m eth yl]a m in o]-
1,1,1-tr iflu or o-2-p r op a n ol (51). The title compound was
prepared from 3-fluoroaniline and 3-methylbenzaldehyde by
procedure A to afford the secondary amine as a yellow oil (MS
m/z M+ 215), followed by treatment with 2-trifluoromethyl-
oxirane by procedure C to give 51 as a light yellow oil (32%
yield). HRMS: m/z [M + H]+ 328.1300 (C17H18F4NO requires
328.1325). Anal. (C17H17F4NO) C, H, N.
3-[(3-F lu or op h en yl)[[4-m eth ylp h en yl]m eth yl]a m in o]-
1,1,1-tr iflu or o-2-p r op a n ol (52). The title compound was
prepared from 3-fluoroaniline and 4-methylbenzaldehyde by
procedure A to afford the secondary amine as a yellow oil (MS
m/z M+ 215), followed by treatment with 2-trifluoromethyl-
oxirane by procedure C to give 52 as an amber oil (44% yield).
HRMS: m/z [M + H]+ 328.1333 (C17H18F4NO requires
328.1325). Anal. (C17H17F4NO) C, H, N.
1
cedure C to give 42 as a light amber oil (yield 69%). H NMR,
19F NMR, and HRMS were identical to previously prepared
material.
3-[(3-Flu or oph en yl)[[2-(tr iflu or om eth yl)ph en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (53). The title compound
was prepared from 3-fluoroaniline and 2-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 269), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 53 as a brown
oil (37% yield). HRMS: m/z [M + H]+ 382.1053 (C17H15F7NO
requires 382.1042). Anal. (C17H14F7NO) C, H, N.
3-[(3-Ch lor oph en yl)[[3-(tr iflu or om eth yl)ph en yl]m eth yl]-
a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (44). The title compound
was prepared from 3-chloroaniline and 3-(trifluoromethyl)-
benzaldehyde by procedure A to afford the secondary amine
as a yellow oil (MS m/z M+ 231), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 25 as an
amber oil (54% yield). HRMS: m/z [M + H]+ 398.0727 (C17H15
-
ClF6NO requires 398.0746). Anal. (C17H14ClF6NO) C, H, N.
3-[3-(Tr iflu or om e t h yl)p h e n yl[[3-(t r iflu or om e t h yl)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (45). The
title compound was prepared from 3-(trifluoromethyl)aniline
and 3-(trifluoromethyl)benzaldehyde by procedure A to afford
the secondary amine as a brown oil (MS m/z M+ 319), followed
by treatment with 2-trifluoromethyloxirane by procedure C to
3-[(3-F lu or op h en yl)[[2-m eth ylp h en yl]m eth yl]a m in o]-
1,1,1-tr iflu or o-2-p r op a n ol (54). The title compound was
prepared from 3-fluoroaniline and 2-methylbenzaldehyde by
procedure A to afford the secondary amine as a dark yellow
oil (MS m/z M+ 215), followed by treatment with 2-trifluoro-
methyloxirane by procedure C to give 54 as a yellow oil (44%

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3901
yield). HRMS: m/z [M + H]+ 328.1353 (C17H18F4NO requires
328.1325). Anal. (C17H17F4NO) C, H, N.
compound was prepared from 3-phenoxyaniline and 4-(tri-
fluoromethoxy)benzaldehyde by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 359), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
63 as a light amber oil (42%). HRMS: m/z [M + H]+ 472.1344
(C23H20F6NO3 requires 472.1347). Anal. (C23H19F6NO3) C, H,
N.
3-[(3-P h en oxyp h en yl)[(2,2,3,3-tetr a flu or o-2,3-d ih yd r o-
1,4-ben zod ioxin -6-yl)m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r o-
p a n ol (64). The title compound was prepared from 3-phe-
noxyaniline and 2,2,3,3-tetrafluorobenzo-1,4-dioxin-6-carb-
aldehyde by procedure A to afford the secondary amine as a
yellow oil (MS m/z M+ 236), followed by treatment with
2-trifluoromethyloxirane by procedure C to give 64 as a light
amber oil (44%). HRMS: m/z [M + H]+ 527.1925 (C24H19F7-
NO4 requires 527.1906). Anal. (C24H18F7NO4) C, H, N.
3-[(3-P h en oxyph en yl)[[3-(m eth oxy)ph en yl]m eth yl]am i-
n o]-1,1,1-tr iflu or o-2-p r op a n ol (65). The title compound was
prepared from 3-methoxybenzaldehyde and 3-phenoxy-aniline
following procedure A, and the resulting oil was reacted with
2-trifluoromethyloxirane according to procedure C giving 65
as an amber oil (50%). HRMS: m/z [M + H]+ 417.1548
(C23H23F3NO3 requires 417.1552). Anal. (C23H22NF3O3) C, H,
N.
3-[(3-P h en oxyp h en yl)[[3-p h en oxyp h en yl]m eth yl]a m i-
n o]-1,1,1-tr iflu or o-2-p r op a n ol (66). The title compound was
prepared from 3-phenoxyaniline and 3-phenoxybenzaldehyde
by procedure A to afford the secondary amine as a brown oil
(MS m/z M+ 367), followed by treatment with 2-trifluoro-
methyloxirane by procedure C to give 66 as a brown oil (yield
39%). HRMS: m/z [M + H]+ 480.1772 (C28H25F3NO3 requires
480.1788). Anal. (C28H24F3NO3) C, H, N.
3-[(3-P h en oxyp h en yl)[[3-(tr iflu or om eth ylth io)p h en yl]-
m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (67). The title
compound was prepared from 3-trifluoromethylthiobenzalde-
hyde and 3-phenoxyaniline by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 375), followed by
treatment of this product with 2-trifluoromethyloxirane as in
procedure C to give 67 as an amber oil (yield 57%). HRMS:
m/z [M + H]+ 488.1116 (C23H20F6NO2S requires 488.1119).
Anal. (C23H19F6NO2S) C, H, N.
3-[(3-F lu or op h en yl)[[3-(p h en oxy)p h en yl]m eth yl]a m i-
n o]-1,1,1-tr iflu or o-2-p r op a n ol (55). The title compound was
prepared from 3-fluoroaniline and 3-(phenoxy)benzaldehyde
by procedure A to afford the secondary amine as a yellow oil
(MS m/z M+ 293), followed by treatment with 2-trifluoro-
methyloxirane by procedure C to give 55 as an amber oil.
HRMS: m/z [M + H]+ 406.1418 (C22H20F4NO2 requires
406.1430). Anal. (C22H19F4NO2) C, H, N.
3-[(3-Flu or oph en yl)[[4-(ph en yl)ph en yl] m eth yl]am in o]-
1,1,1-tr iflu or o-2-p r op a n ol (56). The title compound was
prepared from 3-fluoroaniline and 4-phenylbenzaldehyde by
procedure A to afford the secondary amine as an amber oil,
followed by treatment with 2-trifluoromethyloxirane by pro-
cedure C to give 56 as a brown oil (yield 41%). HRMS: m/z
[M + H]+ 390.1468 (C22H20F4NO requires 390.1481). Anal.
(C22H19F4NO) C, H, N.
3-[(3-F lu or op h en yl)[[3-(3-t r iflu or om et h ylp h en oxy)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (57). The
title compound was prepared from 3-fluoroaniline and 3-(3-
trifluoromethylphenoxy)benzaldehyde by procedure A to afford
the secondary amine as a yellow oil (MS m/z M+ 361), followed
by treatment with 2-trifluoromethyloxirane by procedure C to
give 57 as a brown oil (40% yield). HRMS: m/z [M + H]+
474.1338 (C23H19F7NO2 requires 474.1305). Anal. (C23H18F7-
NO2) C, H, N.
3-[(3-F lu or op h e n yl)[[3-(t r iflu or om e t h oxy)p h e n yl]-
m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (58). The title
compound was prepared from 3-fluoroaniline and 3-(trifluo-
romethoxy)benzaldehyde by procedure A to afford the second-
ary amine as a yellow oil (MS m/z M+ 285), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
58 as a light yellow oil (yield 52%). HRMS: m/z [M + H]+
398.0987 (C17H15F7NO2 requires 398.0991). Anal. (C17H14F7-
NO2) C, H, N.
3-[(3-F lu or op h e n yl)[[3-(1,1,2,2-t e t r a flu or oe t h oxy)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (59). The
title compound was prepared from 3-fluoroaniline and 3-(1,1,2,2-
tetrafluoroethoxy)benzaldehyde by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 317), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
59 as a light yellow oil (61% yield). HRMS: m/z [M + H]+
430.1042 (C18H16F8NO2 requires 430.1053). Anal. (C18H15F8-
NO2) C, H, N.
3-[(3-Tr iflu or om eth oxy)p h en yl[[3-(tr iflu or om eth oxy)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (60). The
title compound was prepared from 3-trifluoromethoxyaniline
and 3-(trifluoromethoxy)benzaldehyde by procedure A to afford
the secondary amine as a yellow oil (MS m/z M+ 351), followed
by treatment with 2-trifluoromethyloxirane by procedure C to
give 60 as a light yellow oil (yield 43%). HRMS: m/z [M +
H]+ 464.0898 (C18H15F9NO3 requires 464.0909). Anal. (C18H14F9-
NO3) C, H, N.
3-[(3-P h en oxyp h en yl)[[3-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n ol (61). The title
compound was prepared from 3-phenoxyaniline and 3-(tri-
fluoromethoxy)benzaldehyde by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 359), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
61 as a light amber oil (yield 37%). HRMS: m/z [M + H]+
472.1342 (C23H20F6NO3 requires 472.1347). Anal. (C23H19F6-
NO3) C, H, N.
Sep a r a tion of 3-[(3-P h en oxyp h en yl)[[3-(1,1,2,2-tetr a -
flu or oet h oxy)p h en yl]m et h yl]a m in o]-1,1,1-t r iflu or o-2-
p r op a n ol (42) in to Its En a n tiom er s. On a Chiralpak AD
HPLC column, using mobile phase 2-propanol/hexane (1:9) and
UV absorption detection at 250 nm, was injected 3-[(3-phenoxy-
phenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl], methyl]amino]-
1,1,1-trifluoro-2-propanol (42) (12.2 g, 24 mmol). Two peaks
were observed at 6.36 and 8.43 min. Collection of the com-
pound eluting at 8.43 min gave (2R)-3-[(3-phenoxyphenyl)[[3-
(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-
2-propanol (1a ) (1.4 g, 11%); [R]589 ) +16.8° (c 0.125 g/dL,
1
CH3CN), [R]365 ) +84.0° (c 0.125 g/dL, CH3CN). H NMR and
19F NMR were identical to 42. HRMS: m/z [M + H]+ 504.1388
(C24H21F7NO3 requires 504.1410). Anal. (C24H20F7NO3) C, H,
N.
Collection of the compound eluting at 6.36 min gave (2S)-
3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-
methyl]amino]-1,1,1-trifluoro-2-propanol (1b) (10.5 g, 86%);
[R]589 ) -17.0° (c 0.125 g/dL, CH3CN), [R]365 ) -85.7° (c 0.125
g/dL, CH3CN). 1H NMR and 19F NMR were identical to 42.
HRMS: m/z [M + H]+ 504.1431 (C24H21F7NO3 requires
504.1410). Anal. (C24H20F7NO3) C, H, N.
R-(+)-2-Tr iflu or om eth yloxir a n e.25 (+)-DIP-Cl (1.2 kg,
3.74 mol) was transferred to a 5 L three neck flask containing
5 L of ether under nitrogen. Anhydrous ether (5 L) was added,
and the mixture was stirred until the solids dissolved and the
temperature equilibrated to 0 °C. 3-Bromotrifluoroacetone (326
mL, 3.14 mol) was added, and the reaction was stirred for 72
h, while maintaining the temperature between -4 and 5 °C.
The reaction was followed with 19F NMR by removing an
aliquot (20 µL), quenching with anhydrous methanol (0.6 mL),
and referencing to external D2O. The reduction was 68%
complete at 48 h. The ether was removed under vacuum (100
3-[(4-P h en oxyp h en yl)[[3-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n -ol (62). The title
compound was prepared from 4-phenoxyaniline and 3-(tri-
fluoromethoxy)benzaldehyde by procedure A to afford the
secondary amine as a yellow oil (MS m/z M+ 359), followed by
treatment with 2-trifluoromethyloxirane by procedure C to give
62 as a light amber oil (42%). HRMS: m/z [M + H]+ 472.1334
(C23H20F6NO3 requires 472.1347). Anal. (C23H19F6NO3) C, H,
N.
3-[(3-P h en oxyp h en yl)[[4-(t r iflu or om et h oxy)p h en yl]-
m eth yl]a m in o]-1,1,1-tr iflu or o-2-p r op a n -ol (63). The title

3902 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Durley et al.
to 0.1 Torr), leaving a pale, viscous oil. A 5 L three neck flask
equipped with a stirrer, dropping funnel, and short-path
distillation head with chilled receiver was charged with the
50% (w/w) NaOH and heated to 40 °C. With external heat
removed, the mixture was added dropwise to the NaOH, with
the rate controlled to maintain the pot temperature below 65
°C. Stirring broke up a yellow-orange solid byproduct. The
product epoxide formed immediately, distilling over with a
head temperature of 32-42 °C to give a colorless liquid (145
g, 43%). 1H NMR δ (C6D6): 2.50 (m, 1H, CF3CH), 2.15 (dd,
1H, J ) 2.10, 5.01 Hz), 1.75 (m, 1H). 19F NMR δ (C6D6): -75.4
(d, J ) 4.7 Hz).
Ch ir a l GC An a lysis of 2-Tr iflu or om eth yloxir a n e Di-
eth yla m in e Ad d u cts. Chiral GC/MS analysis was performed
on the diethylamine adduct from R-(+)-2-trifluoromethyl-
oxirane using a γ-cyclodextrin column: 4 drops of epoxide and
4 drops of diethylamine were heated briefly in a sealed vial,
diluted with MTBE, and analyzed. Two peaks were found as
follows: 10.97 and 11.11 min (ratio 1:230; 99% ee). M + H+
calcd, 186; found, 186, both peaks. Commercially available
2-trifluoromethyloxirane from TCI lot OGH01 gave two peaks,
10.96 and 11.12 min (ratio 8.5:1; 79% ee).
flush the catheter and replace blood volume. Subsequent blood
samples were taken at 2 and 4 h by the same method. Blood
samples were mixed well and kept on ice until the completion
of the experiment. Plasma was obtained by centrifugation of
the blood samples at 4 °C. The plasma (50 µL) was treated
with 5 µL of precipitating reagent (dextran sulfate, 10 g/L; 0.5
M magnesium chloride) to remove VLDL/LDL. After the
plasma was centrifuged, the resulting supernatant (25 µL)
containing the HDL was analyzed for radioactivity using a
liquid scintillation counter.
The percentage of [3H]CE transferred from HDL to LDL and
VLDL (% transfer) was calculated based on the total radio-
activity in equivalent plasma samples before precipitation.
Typically, the amount of transfer from HDL to LDL and VLDL
in control animals was 20-35% after 4 h. The PEG vehicle
was determined to have no effect on CETP activity in this
model.
Alternatively, inhibition of CETP activity by a test com-
pound was determined by administering the compound to mice
that have been selected for expression of human CETP
(hCETP) by transgenic manipulation (hCETP mice). Test
compounds were administered by intravenous injection, and
the amount of transfer of [3H]CE from HDL to VLDL and LDL
particles was determined and compared to the amount of
transfer observed in control animals. C57Bl/6 mice that were
homozygous for the hCETP gene were maintained on a high
fat chow diet, such as TD 88051, as described by Nishina et
al. (J . Lipid Res. 1990, 31, 859-869) for at least 2 weeks prior
to the study. Mice received an intravenous bolus injection of
test compound in 10% ethanol and 90% PEG. Control animals
received the vehicle solution without test compound by oral
gavage or by an intravenous bolus injection. At the start of
the experiment, all animals received 0.05 mL of a solution
containing [3H]CE-HDL into the tail vein. [3H]CE-HDL is a
preparation of human HDL containing [3H]CE and was
prepared according to the method of Glenn et al.33 After 30
min, the animals were exsanguinated and blood was collected
in standard microtainer tubes containing ethylenediamine
tetraacetic acid. Blood samples were mixed well and kept on
ice until the completion of the experiment. Plasma was
obtained by centrifugation of the blood samples at 4 °C. The
plasma was separated and analyzed by gel filtration chroma-
tography, and the relative proportion of [3H]CE in the VLDL,
LDL, and HDL regions was determined.
(2R)-3-[(3-P h en oxyph en yl)[[3-(1,1,2,2-tetr aflu or oeth oxy)-
ph en yl]m eth yl]am in o]-1,1,1-tr iflu or o-2-pr opan ol (1a). The
title compound was prepared from 3-phenoxyaniline and
3-(1,1,2,2-tetrafluoroethoxy)toluene by procedure B to afford
the secondary amine as a yellow oil (MS m/z M+ 391), followed
by treatment with R-(+)-2-trifluoromethyloxirane by procedure
1
C to give 1a as an light amber oil (yield 66%). H NMR and
19F NMR were identical to 42. [R]589/[R]365 were the same as
observed above. HRMS: m/z [M + H]+ 504.1431 (C24H21O3-
NF7 requires 504.1410). Anal. (C24H20F7NO3) C, H, N.
(2R,+)-1,1,1-Tr iflu or o-3-[(3,4,5-tr im eth oxyp h en yl)[[(3-
t r iflu or om et h ylt h io)p h en yl]m et h yl]a m in o]p r op a n -2-ol
(43). The title compound was prepared from 3,4,5-trimethoxy-
aniline and 3-(trifluoromethylthio)benzaldehyde by procedure
A to afford the secondary amine as a brown oil (MS m/z M+
285), followed by treatment with (R+)-2-trifluoromethyloxirane
by procedure C to give 43 as an oil, which was triturated with
hexanes to give a white solid. The precipitate was isolated by
filtration and dried in vacuo to give the desired product as
white crystals; mp 88.9-89.1 (yield 52%); [R] (CHCl3) +26.8
at 589 nm; mp 88.9-89.1. HRMS: m/z [M + H]+ 486.1158
(C20H22F6NO4S requires 486.1174). Anal. (C20H21F6NO4S) C,
H, N. Chiral HPLC: 97.59% at 250 nm (Chiralpak-AD normal
phase column, heptane/2-propanol).
In h ibition of CETP Ex Vivo. Inhibition of CETP activity
with either compound 42 or 1a was determined by administer-
ing the compound to an animal by intravenous injection,
measuring the amount of transfer of tritium-labeled CE
([3H]CE) from HDL to VLDL and LDL particles, and compar-
ing this amount of transfer with the amount of transfer
observed in control animals.
The percentage of [3H]CE transferred from HDL to LDL and
VLDL (% transfer) was calculated based on the total radio-
activity in equivalent plasma samples before precipitation.
Typically, the amount of transfer from HDL to LDL and
VLDL in control animals was 20-35 after 30 min. The PEG
was determined to have no effect on CETP activity in this
model.
Effect of 42 on VLDLc, LDLc, a n d HDLc In Vivo. A
strain of C57bl mouse was made to transgenically express
human CETP. Plasma concentrations of hCETP ranged from
2 to 20 µg/mL. The hCETP mice were made hypercholester-
olemic by feeding cholesterol- and fat-supplemented chow for
a minimum of 2 weeks, as described above. Test compounds
were administered orally in selected aqueous- or oil-based
vehicles for up to 1 week. The animals were sacrificed. Serum
was obtained and analyzed by size exclusion chromatography
(see below) for the relative abundance of VLDLc, LDLc, and
HDLc.
Bin d in g of [3H]-La beled 42 With P la sm a Lip op r otein s
a n d Albu m in . [3H]4224 (33 000 dpm in 20 µL of 16% DMSO)
was mixed with 0.5 mL of human plasma. The mixture was
then subjected to size exclusion chromatography using two
Superose 6 columns and TSE buffer as eluant. One milliliter
fractions were collected and analyzed for cholesterol to locate
the lipoproteins32 or for liquid scintillation counting to locate
[3H]SC-75744. The elution positions of VLDL, LDL, HDL, and
albumin were determined by chromatographing standards32
under the same conditions.
Male golden Syrian hamsters were maintained on a diet of
chow containing 0.24% cholesterol for at least 2 weeks prior
to the study. For animals receiving intravenous dosing im-
mediately before the experiment, animals were anesthetized
with pentobarbital. Anesthesia was maintained throughout the
experiment. In-dwelling catheters were inserted into the
jugular vein and carotid artery. At the start of the experiment,
all animals received 0.2 mL of a solution containing [3H]CE-
HDL into the jugular vein. [3H]CE-HDL is a preparation of
human HDL containing [3H]CE and was prepared according
to the method of Glenn et al.33 Test compound was dissolved
as a 80 mM stock solution in vehicle (2% ethanol:98% PEG
400, Sigma Chemical Company, St. Louis, MO) and adminis-
tered either by bolus injection or by continuous infusion. Two
minutes after the [3H]CE-HDL dose was administered, ani-
mals received 0.1 mL of the test solution injected into the
jugular vein. Control animals received 0.1 mL of the intrave-
nous vehicle solution without test compound. After 5 min, the
first blood samples (0.5 mL) were taken from the carotid artery
and collected in standard microtainer tubes containing ethyl-
enediamine tetraacetic acid. Saline (0.5 mL) was injected to

Inhibitors of Cholesteryl Ester Transfer Protein
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18 3903
(17) Hirano, K.; Yamashita, S.; Nakajima, N. Genetic Cholesteryl
Ester Transfer Protein Deficiency is Extremely Frequent in
Omagari Area of J apan; Marked Hyperalphalipoproteinemia
Caused by Cholesteryl Ester Transfer Protein Gene Mutation
is Not a Longevity Syndrome. Arterioscler., Thromb., Vasc. Biol.
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(18) Bruce, C.; Sharp, D. S.; Tall, A. R. Relationship of HDL and
Coronary Heart Desease to a Common Amino Acid Polymor-
phism in the Cholesteryl Ester Transfer Protein in Men with
and without Hyperalphalipoproteinemia. J . Lipid Res. 1998, 39,
1071-1078.
Ack n ow led gm en t . We thank Shengtian Yang,
Claude R. J ones, and J ohn Likos for NMR assistance
and J ames Doom and Gary Mappes for mass spectral
analysis. We also thank Anne Daiss for elemental
analysis. We are grateful to Brad McKinnis for chiral
chromatography analysis and radiolabel synthesis. This
paper is dedicated to Prof. Herbert C. Brown on the
occasion of his 90th birthday.
(19) Agerholm-Larsen, B.; Nordestgaard, B. G.; Steffensen, R.;
J ensen, G.; Tybjaerg-Hansen, A. Elevated HDL cholesterol is a
risk factor for ischemic heart disease in white women when
caused by a common mutation in the cholesteryl ester transfer
protein gene. Circulation 2000, 101, 1907-1912.
Su p p or tin g In for m a tion Ava ila ble: Details of the X-ray
structure for 43. These materials are available free of charge
via the Internet at http://pubs.acs.org.
(20) Tall, A. R.; J iang, X.-C.; Luo, Y.; Silver, D. 1999 George Lyman
Duff Memorial Lecture: Lipid transfer proteins, HDL metabo-
lism, and atherogenesis. Arterioscler., Thromb., Vasc. Biol. 2000,
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