Synthesis and discovery of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines as a novel class of potent cholesteryl ester transfer protein inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.12.096

2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC₅₀ = 26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F = 53%) and long human liver microsome stability (t_1/2 = 62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.

Full text of DOI:10.1016/j.bmcl.2009.12.096

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1432–1435
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and discovery of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines as a
novel class of potent cholesteryl ester transfer protein inhibitors
*
Aihua Wang , Catherine P. Prouty, Patricia D. Pelton, Maria Yong, Keith T. Demarest,
William V. Murray, Gee-Hong Kuo
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, PO Box 776, Spring House, PA 19477-0776, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester
transfer protein inhibitors. The most potent compound 6a (IC50 = 26 nM) possessed a favorable pharma-
cokinetic profile with good oral bioavailability in rat (F = 53%) and long human liver microsome stability
(t1/2 = 62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The struc-
ture and activity relationship of this series will be described in this Letter.
Received 2 December 2009
Revised 20 December 2009
Accepted 22 December 2009
Available online 4 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cholesteryl ester transfer protein
CETP
CETP inhibitors
HDL-C
Atherosclerosis
Low levels of high density lipoprotein-cholesterol (HDL-C) and
high levels of small-dense low density lipoprotein-cholesterol
(LDL-C) are independent risk factors for the development of ath-
erosclerosis and eventually coronary heart disease (CHD), which
remain the leading cause of death in the developed countries.1–3
HDL-C plays important role in removal of excess cholesterol from
peripheral cells to the liver for metabolic degradation in a reverse
cholesterol transport (RCT) process.4–6 Therefore, the increase in
HDL-C level offers a new and promising therapeutical principle
for treatment of CHD.7
itors include irreversible inhibitor JTT-705 (Fig. 1, Roche and Japan
Tobacco, phase III),14,15 which has moderate potency, Torcetrapib
(Pfizer, phase III, discontinued),16–18 which was withdrawn from
phase III studies in December 2006 due to hypertension observed,
and Anacetrapib (Merck, phase III).19 3,4-Dihydro-2,5-diphenyl-
a-
trifluoromethyl-1-quinolineethanol derivatives were discovered in
our laboratories as potent CETP inhibitors.20,21 In order to improve
aqueous solubility, 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines 6
were designed and synthesized as a new series of potent CETP
inhibitors.22,23
Cholesteryl ester transfer protein (CETP) is a plasma glycopro-
tein that mediates the transfer of cholesteryl ester (CE) from HDL
to very low density lipoprotein (VLDL) and LDL in exchange for tri-
glyceride.8,9 The general net effect of this process is a reduction in
atheroprotective HDL-C level and with increase in proatherogenic
VLDL-C and LDL-C levels. However, the potential antiatherogenic
role of CETP in participation of reverse cholesterol transport has
also been suggested.4,10–12 In spite of controversies regarding the
roles of CETP in the progression of atherosclerosis,13 the growing
body of evidence showing the profound beneficial effects of low
levels of LDL or high levels of HDL suggests that specific and effec-
tive inhibition of CETP to raise HDL-C level13 may outweigh the risk
and provide a potential therapeutic benefit for patients with CHD.
Considerable efforts have been made toward the development
of potent and selective CETP inhibitors. The most advanced inhib-
The synthesis of 2,3-dihydro-3,8-diphenylbenzo[1,4]oxazines 6
is shown in Scheme 1. Reduction of 2-bromo-6-nitrophenol with
Na2S2O4 provided 2-amino-6-bromophenol 1.
a-Bromoketone 2
was prepared in two steps by methylation of 3-(1,1,2,2-tetrafluoro-
ethoxy)benzoic acid with MeLi at low temperature to give methyl
ketone, and bromination of this intermediate with bromine in ace-
tic acid to yield 2. Alkylation of 2-amino-6-bromophenol 1 with a-
bromoketone 2 by using base Cs2CO3 in CH3CN produced phenoxy
ketone 3 in 88% yield. Intramolecular reductive cyclization of 3 to
racemic 8-bromo benzoxazine 4 was accomplished in quantitive
yield by using NaBH(OAc)3 in the presence of 1 equiv of TFA. Suzu-
ki coupling of aryl bromide 4 with 3-trifluoromethoxybenzene
boronic acid gave compound 5 in high yield. In the presence of cat-
alytic amount of Lewis acid ytterbium trifluoromethanesulfonate,
N-alkylation of 5 with commercially available ꢀ90% enriched
(S)-1,1,1-trifluoro-2,3-epoxypropane occurred to produce a mix-
ture of four diastereomers 6a (3S,
aS), 6b (3R, aR), 6c (3R, aS),
* Corresponding author. Tel.: +1 215 628 5020; fax: +1 215 540 4612.
E-mail address: awang1@its.jnj.com (A. Wang).
and 6d (3S,
a
R).24 The mixture was separated by silica gel column
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.12.096

A. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1432–1435
1433
F C
3
CF
O
3
F
CF
3
N
N
O
O
O
F C
3
N
S
H
N
CF
3
O
O
O
CF
O
O
3
JTT-705
Anacetrapib
Merck
Torcetrapib
Roche & Japan Tobacco
Pfizer
Figure 1. Structures of CETP inhibitors.
1. MeLi, Et2O
-78oC to RT
Br
O
Br
HO2C
OCF2CF2H
Na2S2O4
OH
Br
OCF2CF2H
OH
2. Br2, AcOH
EtOH, H2O
NH2
NO2
2, 56%
OCF3
B(OH)2
1, 90%
Br
Br
O
Cs2CO3
CH3CN
O
NaBH(OAc)3
O(CF2)2H
O
1 + 2
O(CF2)2H
TFA, CH2Cl2
N
H
NH2
Pd(PPh3)2Cl2
K2CO3
3, 88%
4, 100%
OCF3
OCF3
O
O
CF3, CH3CN
Yb(SO3CF3)3
O
3s
O(CF2)2H
+ 6b (3R, αR) + 6c (3R, αS) + 6d (3S, αR)
N
O(CF2)2H
N
H
F3C
αs
higher Rf lower Rf
5, 89%
6a
OH
Scheme 1.
chromatography into two diastereomeric pairs. The higher Rf pair
consisted of 6a (3S, S) as a major component and 6b (3R, R) as
a minor one, while the lower Rf pair made up of 6c (3R, S) as a ma-
jor component and 6d (3S, R) as a minor one.
potency of lower Rf diastereomeric pairs of (3R,
isomers was consistently much poorer than that of its counterpart,
higher Rf diastereomeric pairs of (3S, S) and (3R, R), therefore, the
data of lower Rf diastereomers are not listed in Table 1.
As exemplified in diastereomers 6a–d, the (3S, S) stereochem-
ical configuration (6a) possessed the highest potency among the
four diastereomers. R1 replacement of 3-OCF3 in 6e with 3-F in 7
decreased the potency dramatically. However, when the number
of F-atom increased to 3,5-difluoro 8 or 3,4,5-trifluoro 9, the po-
tency increased.
aS)- and (3S, aR)-
a
a
a
a
a
a
The optically pure compounds were prepared either by chiral
HPLC resolution of the advanced intermediate, racemic compound
5, or by enantioselective synthesis. Eq. 1 shows the example of
asymmetric reductive cyclization of 3 to (S)-4 in 96% yield and
>96% ee by employing chiral sodium triacyloxyborohydride 7 at
ꢁ78 °C.25 Following the reaction sequence in Scheme 1, the enan-
tiomer (S)-4 was carried through Suzuki coupling and N-alkylation
with ꢀ90% enriched (S)-1,1,1-trifluoro-2,3-epoxypropane to obtain
a
The SAR of substituent R2 on the right-side phenyl ring was also
investigated. Moving the OCF2CF2H group from meta- in 6e to
ortho- in 13 or para-position in 14 dramatically reduced the po-
tency. The OCF3 group also exhibited preference for meta- (15b)
to para-orientation (16). The 3-OCF2CF2H group on the right-side
aryl ring was 2–5-fold more potent than the short 3-OCF3 by com-
parison of 6a with 15a, 8 with 11, and 9 with 12. None of other
compounds (17–23) carrying different R2 was as potent as 6e
(R2 = 3-OCF2CF2H).
Scheme 2 is the chemical approach developed to quickly ex-
plore the heteroaryl and aliphatic replacements of the right-side
phenyl group. Cyclization of 2-amino-6-bromophenol 1 with chlo-
roacetyl chloride provided lactam 25 in quantitive yield. Suzuki
reaction of 25 with 3-trifluoromethoxybenzene boronic acid and
protection of the resulting intermediate as N-Boc afforded com-
pound 26. Aminoether 27 was obtained by DIBAL-H reduction of
lactam 26 to hemiaminal followed by reaction with EtOH in the
presence of p-toluene sulfonic acid. Treatment of aminoether 27
with Lewis acid such as BF3ꢂOEt2 generated in situ an N-acyliminium
two separable 6a (3S,
aS) and its diastereomer 6d (3S, aR) in 75%
and 18% yield, respectively.
(
)3NaBH
CO2
N
Br
O
O
O
ð1Þ
7
O(CF2)2H
3
N
H
TFA, CH2Cl2, -78oC
(S)-4, 96%, > 96% ee
By modification of the top and right-side phenyl substituents,
analogs were prepared and evaluated for their ability to inhibit hu-
man CETP, some of which are illustrated in Table 1. Except opti-
cally pure compounds indicated in the parenthesis, all of the
other compounds listed in Table 1 are high Rf diastereomeric pairs
of (3S,
aS) as major components and (3R, aR) as minor ones. It was
demonstrated in all of this class of compounds prepared, the

1434
A. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1432–1435
Table 1
Table 2
In vitro inhibition of human CETP by derivatives with substitution variations on 3,8-
diphenyl groups
In vitro inhibition of human CETP by derivatives with terminal chain variations on N-
atom
OCF3
O
R1
O
3S
3S
OCF2CF2H
N
R2
N
R3
F3C
αS
OH
Compda
R3
% Inhibition at 1
lM
IC50 (nM)
Compda
R1
R2
% Inhibition at 1
lM
IC50 (nM)
6a (3S,
a
S)
CH2CH(OH)CF3
CH2CH(OH)CH2F
CH2CH(OH)CH2F
CH2C(O)CF3
91
77
55
5
26
14
147
ND
ND
6a (3S,
6b (3R,
6c (3R,
6d (3S,
6e
a
a
a
a
S)
R)
S)
R)
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-F
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-O(CF2)2H
3-OCF3
91
26
14
23
96
79
100
101
59
100
94
6
33
69
65
38
43
62
37
29
56
68
48
26
30a (3S,
30b (3S,
31 (3S)
a
S)
ND
ND
ND
45
322
50
a
R)
32 (3S,
a
S)
CH2CH(OH)CH2OH
27
7
O
33
25
ND
8 (3S,
9 (3S,
a
a
S)
S)
a
a
a
3,5-F2
O
CH
2
3,4,5-F3
3,5-(CF3)2
3,5-F2
41
34a (3S,
34b (3S,
35 (3S)
36
a
R)
CH2CH(OH)CH3
CH2CH(OH)CH3
CH2C(O)CH3
CH2CH(OH)CH(CH3)2
CH2C(OH)(CH3)2
50
28
5
86
29
88
10 (3S,
11 (3S,
12 (3S,
13
S)
S)
S)
580
193
94
a
S)
ND
ND
129
560
3,4,5-F3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
3-OCF3
2-O(CF2)2H
4-O(CF2)2H
3-OCF3
3-OCF3
4-OCF3
ND
ND
133
107
ND
ND
214
ND
ND
490
360
271
37
14
15a (3S,
15b
16
17
18
19
20
21
22
aS)
38
0
ND
(CH ) N
2 2
O
39
40
41
42
43
44
45
46
(CH2)2OH
(CH2)3OH
(CH2)2OCH3
(CH2)2NH2
29
10
25
2
ND
ND
ND
ND
ND
190
ND
ND
3-H
3-Cl
3-CF3
3-OCH3
3-OEt
3-SCF3
(CH2)2N(CH3)2
9
Pr
Et
CO2CH3
39
24
16
23
3,4-OCF2O
ND, not determined.
ND, not determined.
a
a
Except optically pure compounds indicated in the parenthesis, all of the other
compounds were high Rf diastereomeric pairs of (3S, S) as major components and
(3R, R) as minor ones.
Except optically pure compounds indicated in the parenthesis, all of the other
compounds were high Rf diastereomeric pairs of (3S,
a
a
S) as major components and
a
(3R,
a
R) as minor ones.
OCF3
produced target 29. As in the case of preparation of 6, the two high-
er and lower Rf bands were separated by SiO2 flash chromatogra-
phy into two diastereomeric pairs.
Br
O
Br
O
Cl
1.
OH
B(OH)2
Cl
K2CO3
Pd(PPh3)2Cl2, K2CO3
2. Boc2O, DMAP, Et3N
O
N
H
By utilizing aminoether 27 as a late stage common intermedi-
ate, many analogs 29 were prepared bearing Nu as furan, thiophen,
2-methoxythiophen, 3-methoxythiophen, 2-ethylthiophen, 3-
methylthiophen, 3-ethylthiophen, allyl, 1-hydroxypropyl, 1-
methoxypropyl, and 3,3-dimethylbutan-2-one. Among them, the
2-ethylthiophen derivative was the most potent (IC50 = 502 nM).
Further exploration was limited due to commercial availability of
such class of nucleophiles carrying OCF2CF2H or OCF3 substituents,
which contributed good inhibitory potency to the right-side phenyl
analogs such as 6e and 15b.
NH2
25, 100%
1
OCF3
O
OCF3
Lewis acid
or Acid
1. DIBAL-H
O
2. PTSA, EtOH
Nucleophiles
N
Boc
OEt
N
Boc
O
26, 87%
27, 87%
OCF3
Focus was then placed on the studies of 1,1,1-trifluoro-2-propa-
nol moiety on the N-atom. The results are summarized in Table 2.
The stereocenter of the chain was very important for the inhibitory
potency as demonstrated in compounds, 6a and 6d (Table 1), 30a
and 30b (10-fold difference), as well as 34a and 34b. Surprisely,
changing trifluoromethyl in 6a to monofluoromethyl in 30a re-
sulted in a twofold more potent inhibitor 30a. However, human li-
ver microsome stability of 30a (t1/2 = 21 min) was much shorter
than that of 6a (t1/2 = 62 min). Replacement of trifluoromethyl in
6a with hydrophilic hydroxymethyl group in 32 was detrimental
to the inhibition of CETP. Modification of it with less lipophilic
methyl in 34a or elimination of trifluoromethyl in 39 resulted in
decreased inhibitory potency as well. When the hydroxyl group
in 6a and 34a was oxidized to ketone functionality in 31 and 35,
the CETP inhibitory potency abolished.
OCF3
O
O
O
CF3
Yb(SO3CF3)3
Nu
N
Nu
N
H
F3C
OH
28, 50-87%
29, ~40%
Scheme 2.
ion,26 which was trapped by nucleophiles such as 2-ethylthiophen
or allyltrimethylsilane leading to dihydrobenzo[1,4]oxazines 28.
Reaction of 28 with ꢀ90% enriched (S)-1,1,1-trifluoro-2,3-epoxy-
propane in the presence of catalytic quantity of Yb(OTf)3

A. Wang et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1432–1435
1435
S
creased 11%, 10%, and 28%, respectively. High-fat fed hamsters
were also treated with 6a orally for 5 days. At 10 and 30 mg/kg
doses of 6a, the hamsters plasma HDL-C was increased 9% and 16%.
Br
Br
Br
1. tetradecane, 207oC
2. NaOH, MeOH, H2O
O
NMe2
OH
Me2N
Cl
S
DABCO, DMF
NO2
NO2
47, 100%
As we expected, 6a displayed higher aqueous solubility (11
mL at pH 2.0, and 2.7 g/mL at pH 7.4) than its C-analog, (2R,
3,4-dihydro-2-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-5-[3-(triflu-
oromethoxy)-phenyl]- -(trifluoromethyl)-1(2H)-quinolineethanol
(<1 g/mL at pH 2.0, and <1
g/mL at pH 7.4).20,21
lg/
l
a
S)-
O
Br
O
Br
1.
OC2F4H
a
SH
S
NH2
OCF2CF2H
l
l
In conclusion, we have discovered 2,3-dihydro-3,8-diph-
enylbenzo[1,4]oxazines as a novel class of potent CETP inhibitors.
The most potent compound 6a exhibited favorable pharmacoki-
netic profile with good oral bioavailability in rat (F = 53%). It was
a weak inhibitor of P450 isozymes and had long human liver
microsome stability (t1/2 = 62 min). It increased HDL-C in human
CETP transgenic mice and high-fat fed hamsters. Its aqueous solu-
bility was also improved.
KOH, MeOH
2. Pd/C, H2, EtOAc
NO2
48, 84%
49, 72%
OCF3
Br
S
NaBH(OAc)3
TFA, CH2Cl2
B(OH)2
OCF2CF2H
N
Pd(PPh3)2Cl2
K2CO3
H
50, 76%
OCF3
OCF3
Acknowledgment
O
We thank Jef Proost for chiral HPLC resolution of compound 5.
References and notes
CF3
S
S
N
Yb(OTf)3
O(CF2)2H
O(CF2)2H
N
H
F3C
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52 (higher Rf), 8%
OH
Scheme 3.
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48 was prepared in three steps in 84% yield by first reaction of 2-
bromo-6-nitrophenol with N,N-dimethylcarbamoyl chloride to
thiocarbamate 47, then O- to S-rearrangement occurred over
200 °C followed by hydrolysis with NaOH. The rest of reaction se-
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Compound 6a was the most potent inhibitor prepared in this
series with IC50 = 26 nM in a CETP SPA assay and IC50 = 1.0 lM in
a human plasma 3H-CE HDL assay. In the studies of human liver
microsome cytochrome P450 inhibition assay 1A2, 2C9, 2C19,
2D6, 3A4-T, and 3A4-M, compound 6a showed no significant inhib-
itory effect on the P450 isozymes tested (IC50 >100 lM). It also dis-
played long human liver microsome stability (t1/2 = 62 min).
The pharmacokinetic (PK) profile of 6a was studied in rats orally
dosed at 10 mg/kg using sesame oil as the vehicle, and iv dosed at
2 mg/kg using 10% EtOH:10% solutol:80% D5W as the vehicle. The
oral bioavailability in rats was 53% with significant plasma expo-
sure (AUC = 19.8 lg h/mL) and slow oral absorption (Tmax = 11.5 h).
It also exhibited low systemic clearance (CL = 4.6 mL/min kg) and
low volume of distribution (Vss = 0.73 L/kg).
In vivo efficacy studies, treatment of female and male human
CETP transgenic mice on a normal chow diet with 6a orally for
5 days resulted in an increase in HDL-C. At 3, 10, and 30 mg/kg
doses of 6a, the female mice plasma HDL-C was increased 4%, 8%,
and 24%, respectively, and the male mice plasma HDL-C was in-
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