Potent inhibitors of Acyl-CoA:cholesterol acyltransferase. 2. Structure- activity relationships of novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7- yl)amides

Article abstract of DOI:10.1021/jm950828+

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6- tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3- dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3- dihydrobenzofuran-7-yl)-2,2-dimethyldodecanamide (10) and 6-(4- chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5- (dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl]-2,2- dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC₅₀ = 0.020 μM, rabbit liver IC₅₀ = 0.009 μM), foam cell formation inhibitory activity (rat peritoneal macrophage IC₅₀ = 0.030 μM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (C(max) = 2.68 μg/mL at 1 h, 10 mg/kg po).

Full text of DOI:10.1021/jm950828+

1262
J . Med. Chem. 1996, 39, 1262-1270
P oten t In h ibitor s of Acyl-CoA:Ch olester ol Acyltr a n sfer a se. 2.
Str u ctu r e-Activity Rela tion sh ip s of Novel
N-(2,2-Dim eth yl-2,3-d ih yd r oben zofu r a n -7-yl)a m id es
Ken-ichiro Kataoka,* Tatsuki Shiota, Takumi Takeyasu, Toru Minoshima,† Kenzo Watanabe,† Hiroko Tanaka,
Tsutomu Mochizuki, Keiko Taneda, Mikio Ota, Hirofumi Tanabe, and Hisao Yamaguchi
Teijin Institute for Bio-Medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191, J apan, and Pharmaceuticals Production
Technology Development Laboratories, Teijin Limited, 2-1 Hinode-cho Iwakuni-shi, Yamaguchi-ken 740, J apan
Received November 9, 1995X
Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and
tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltrans-
ferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized
compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent
ACAT inhibitory activity. The synthesis and structure-activity relationships of these
compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety
was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-
2,3-dihydrobenzofuran-7-yl)amides, lipophilicity of the acyl moiety was necessary for the potent
ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-
dihydrobenzofuran-7-yl)-2,2-dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyloctanamide (50) showed potent activity.
Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety
resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran-7-yl]-2,2-dimethyldodecanamide (13, TEI-6620), showed
highly potent ACAT inhibitory activity (rabbit small intestine IC50 ) 0.020 µM, rabbit liver
IC50 ) 0.009 µM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50
)
0.030 µM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71%
at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax ) 2.68 µg/mL at 1 h,
10 mg/kg po).
In tr od u ction
Acyl-CoA:cholesterol acyltransferase (ACAT)1 is the
intracellular enzyme responsible for catalyzing the
esterification of free cholesterol in various tissues. In
a developing atherosclerotic lesion, ACAT-mediated
cholesterol esterification is believed to play an important
role in the accumulation of cholesteryl esters by mac-
rophages. Therefore, the inhibition of ACAT in the
arterial wall is expected to prevent the formation of
cholesteryl ester-loaded macrophages (foam cell).2,3 This
enzyme also plays a key role in intestinal dietary
cholesterol absorption4,5 and in the secretion of very low
density lipoproteins (VLDL) from the liver.6,7 For these
reasons, a systematically available ACAT inhibitor is
an attractive target for new treatments of atheroscle-
rosis and hyperlipidemia.
In recent years, a number of ACAT inhibitors have
been reported.8 As amide class ACAT inhibitors, amide
derivatives consist of an aromatic ring moiety and a
lipophilic long-chain moiety: CI-976 (4)9 and CP-113818
(5)10 were reported (Figure 1). We have reported that
a series of N-(7-alkoxy-4-oxochroman-8-yl)amides [e.g.,
2 (TEI-6522), 3 (TEI-6657)] had highly potent ACAT
inhibitory activities.11 Structure-activity relationship
studies have shown that this N-(7-alkoxy-4-oxochroman-
8-yl)amide moiety is one of the optimum arylamide
moieties for potent ACAT inhibitory activities. The
most potent compound, TEI-6522, showed ca. 10-fold
F igu r e 1. General structures for N-(2,2-dimethyl-2,3-dihy-
drobenzofuran-7-yl)amide derivatives 1 and N-(4-oxochroman-
8-yl)amide derivatives TEI-6522 (2) and TEI-6657 (3). ACAT
inhibitors: CI-976 (4) and CP-113818 (5).
more potent ACAT inhibitory activities than CI-976 both
in vitro and in vivo. The finding that modification of
the aryl moiety furnished potent ACAT inhibitors
encouraged us to evaluate other novel aryl moieties to
find more potent systematically available inhibitors
† Pharmaceuticals Production Technology Development Laborato-
ries, Teijin Ltd.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
0022-2623/96/1839-1262$12.00/0 © 1996 American Chemical Society

Potent Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1263
Sch em e 1. Preparation of Target Molecules by Method
Sch em e 3. Preparation of
Ba
7-Amino-2,2-dimethyl-2,3-dihydrobenzofuransa
a
Reagents: (a) 3-chloro-2-methylpropene, NaOH/H2O; (b) MgCl2,
180 °C; (c) H2 (1 atm), Pd/C (5%), EtOH.
Sch em e 4. Preparation of
7-Amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofurana
a
Reagents: (a) HNO3, Ac2O, 10 °C; (b) H2 (1 atm), Pd/C (10%),
EtOH, 50 °C; (c) H2 (18 atm), Pd/C (10%), HCHO, H2O/EtOH, 90
°C.
Sch em e 2. Preparation of Target Molecules by Method
Ca
a
Reagents: (a) 3-chloro-2-methylpropene, NaOCH3/CH3OH; (b)
MgCl2, 210 °C; (c) (1) HNO3, Ac2O, room temperature, (2) H2 (1
atm), Pd/C (5%), room temperature; (d) H2 (18 atm), Pd/C (10%),
EtOH, 115 °C.
2,3-dihydrobenzofuran (21b ) and 7-amino-2,2,6-tri-
methyl-2,3-dihydrobenzofuran (21a ) were prepared as
shown in Scheme 312 from the corresponding 2-nitro-
phenols 19a ,b by (a) O-methallylation using NaOH, (b)
cyclization at 180 °C in the presence of MgCl2, and (c)
catalytic hydrogenation in the presence of Pd/C.
7-Amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (14)
was synthesized as shown in Scheme 4, that is, meth-
allylation of 4-chloro-3,5-xylenol (22) with 3-chloro-2-
methylpropene gave O-methallylphenol 23. Cyclization
of 23 at 210 °C using MgCl2 afforded 5-chloro-2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran (24). Nitration of
the 2,3-dihydrobenzofuran followed by reduction of the
nitro group by catalytic hydrogenation in the presence
of Pd/C under a mild condition gave 7-amino-5-chloro-
2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (25). It was
necessary to carry out the reduction under stronger
conditions (H2, 18 atm, 120 °C) in order to complete
hydrogenolysis of the C-Cl bond at position 5 to give
the 7-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran
(14). To develop a useful process for the reduction under
mild conditions, electrochemical reduction was exam-
ined. Electroreduction of the 5-chloro-7-nitro-2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran in DMF-tBuOH/
Bu4NBF4/Zn-Zn system effected conversion of the nitro
group into amino group and ensuing removal of the
chlorine atom in one pot to give 14 (Scheme 5).13
a
Reagents: (a) 4-hydroxybenzoic acid, DCC, CH2Cl2, room
temperature; (b) RBr, K2CO3, CH3CN, reflux.
than TEI-6522. We now report on the synthesis and
ACAT inhibitory activity of a series of N-(2,2-dimethyl-
2,3-dihydrobenzofuran-7-yl)amides 1. The structure-
activity relationships of these amides are discussed on
the basis of in vitro ACAT inhibitory activity and
percent change of serum total cholesterol in cholesterol-
fed rats.
Ch em istr y
A coupling of the corresponding aromatic amine with
the appropriate acid chloride in the presence of triethyl-
amine (method A) was used to synthesize the majority
of compounds (general structure 1) described in this
paper. Preparation of compounds 11-13, which have
a nitro or an amino group at position 5 of the 2,3-
dihydrobenzofuran, was achieved by method B as
outlined in Scheme 1. Nitration of N-(2,2,4,6-tetra-
methyl-2,3-dihydrobenzofuran-7-yl)amide 10 afforded
N-(2,2,4,6-tetramethyl-5-nitro-2,3-dihydrobenzofuran-7-
yl)amide 11, which was reduced by catalytic hydrogena-
tion to the corresponding N-(5-amino-2,2,4,6-tetramethyl-
2,3-dihydrobenzofuran-7-yl)amide 12. Reductive meth-
ylation of the 5-nitro derivative 11 using formaldehyde
to 5-dimethylamino derivative 13 was achieved by
catalytic hydrogenation in the presence of Pd/C.
Some benzamide analogs were prepared as shown in
Scheme 2 (method C). 7-Amino-2,2,4,6-tetramethyl-2,3-
dihydrobenzofuran (14) was acylated with 4-hydroxy-
benzoic acid using DCC as a coupling agent. Alkylation
of the resulting 4-hydroxybenzamide with alkyl bromide/
K2CO3 gave 18.
The acid chlorides used in the general method A were
prepared as follows. R,R-Dimethyl carboxylic acids were
prepared by alkylation of the dianion14 of isobutyric acid
by treatment with 2 equiv of LDA. Alternatively,
alkylation of the anion of methyl isobutyrate by treat-
ment with 1 equiv of LDA followed by hydrolysis gave
the carboxylic acids. The acid chlorides were prepared
from the corresponding carboxylic acids by treatment
with thionyl chloride. 4-Alkoxybenzoyl chlorides were
prepared from methyl 4-hydroxybenzoate.
Preparations of 2,3-dihydrobenzofuranylamine inter-
mediates which were used in methods A and C are
outlined in Schemes 3 and 4. 7-Amino-2,2-dimethyl-

1264 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Kataoka et al.
Sch em e 5. Preparation of
of having potent activity in vitro. On the other hand,
we reported in our previous paper11 that 2,2-dimethyl-
dodecanamides have potent in vitro and in vivo activity
in the series of N-(7-alkoxy-4-oxochroman-8-yl)amides.
For these reasons, these acyl structures A-C were
selected to examine the potential of novel aryl moieties.
Using these acyl structures A-C, N-(2,2-dimethyl-2,3-
dihydrobenzofuran-7-yl)amides were synthesized.
7-Amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofurana
a
Reagents: (a) electroreduction, DMF-tBuOH/Bu4NBF4/Zn-
A methyl group at the 6-position of the 2,3-dihy-
drobenzofuran moiety was important for potent ACAT
inhibitory activity in the series of N-(2,2-dimethyl-2,3-
dihydrobenzofuran-7-yl)amide derivatives. Introduction
of a methyl group at the 6-position of the N-(2,2-
dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives
30 and 31 increased in vitro activity (32 and 33).
Introduction of an additional methyl group at the
4-position of the 2,3-dihydrobenzofuran moiety (34 and
35) retained potent activity in vitro. N-(2,2,4,6-Tetra-
methyl-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldode-
canamide (10) showed potent in vitro activity and
lowered serum cholesterol 61% at a dose of 1.0 mg/kg/
day. Thus, it became obvious that the N-(2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran-7-yl)amide is an op-
timal structure for potent ACAT inhibitory activity.
Zn.
Resu lts a n d Discu ssion
The structures and biological activities of the synthe-
sized compounds are shown in Tables 1-4. The ACAT
inhibitory activities were determined using [1-14C]-
oleoyl-CoA as an enzyme substrate and small intestinal
microsomes from cholesterol-fed rabbits as an enzyme
source. The IC50, which is the concentration that
inhibited 50% of the enzyme activity, was determined
for all compounds. Serum total cholesterol-lowering
activity was assessed in the cholesterol-fed animal
model in which male Wistar rats were administered an
oral dose of a tested compound once a day and then
allowed to consume overnight a diet supplemented with
cholesterol (2%), cholic acid (1%), casein (20%), sucrose
(45%), coconut oil (12%), KC flock (4%), vitamin mixture
(1%), mineral mixture (7%), and dried fish powder (8%).
After 3 days of oral administration and cholesterol
feeding, the serum total cholesterol was measured, and
the percent change vs the difference between the control
and normal levels was determined. These assays were
carried out by the method reported.11
Next, effects of substituents at the 5-position of the
2,3-dihydrobenzofuran (R2) were examined. A chloro
(36), nitro (11), and amino (12) group introduced at this
position retained potent activity, while a dimethylamino
group introduced at this position (13) resulted in highly
potent activity. 13 also showed more potent in vivo
cholesterol-lowering activity (81% at a dose of 1.0 mg/
kg/day) than the nonsubstituted (R2 ) H) analog 10.
On the basis of our study of the N-(7-alkoxy-4-
oxochroman-8-yl)amides,11 we anticipated that molec-
ular lipophilicity of the N-(2,2,4,6-tetramethyl-2,3-
dihydrobenzofuran-7-yl)amide derivatives might be a
important factor for potent ACAT inhibitory activity. To
examine the effect of the acyl moiety (-CO-Y group in
general structure 1), the analogs having a lipophilic
group in the acyl moiety were synthesized; the results
are shown in Tables 2-4. The 2,2,4,6-tetramethyl-2,3-
The compounds listed in Table 1 were synthesized to
study the effects of substituents on the 2,3-dihydroben-
zofuran ring of the N-(2,2-dimethyl-2,3-dihydrobenzo-
furan-7-yl)amides. We used the acyl moieties A-C
listed in this table. Roth et al. reported9b that the
anilides of saturated fatty acids possessing group A, B,
or C were found to have ACAT inhibitory activities in
the series of N-(2,4,6-trimethoxyphenyl)amides. Group
B was reported to have reduced activity in vivo in spite
Ta ble 1. Chemical Properties and Biological Data for N-(2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)amides
yield,
ACAT inhibition
change TC,d,e
% (mg/kg)f
compd
R1
R2
R3
Y
%a (method)
mp, °C
formulab
IC50, µMc
30
31
32
33
34
35
10
36
11
12
13
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
B
C
B
C
B
C
A
C
A
A
A
90 (A)
91 (A)
82 (A)
96 (A)
89 (A)
73 (A)
92 (A)
98 (A)
58 (B-a)
72 (B-b)
70 (B-c)
90-92
oil
C26H43NO2
0.89
0.50
0.024
0.24
0.026
0.17
0.042
0.29
0.036
0.059
0.020
C
26H41NO2
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
76-77
97-107
84-86
65-66
57-59
69-70
87-90
C27H45NO2
C27H43NO2
C28H47NO2
C28H45NO2
C26H43NO2
C28H44NO2Cl
C26H42N2O4
C26H44N2O2
C28H48N2O2
-52 (10)
-61 (1)
NO2
NH2
N(CH3)2
125
87-88
-88 (1)
a
b
Yield (%) of final step. Satisfactory elemental analyses were obtained for C, H, and N unless otherwise indicated. c IC50 (µM) for the
d
enzyme obtained from rabbit intestine microsomes. Serum cholesterol-lowering activity in the cholesterol-fed rat expressed as the ratio
of the observed reduction to the difference between the control and base-line levels × 100. e Compounds with no change indicated were
not tested. f Dose: compounds were administered orally to rats at the indicated dose once a day for 3 days.

Potent Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1265
Ta ble 2. Chemical Properties and Biological Data for N-(2,2,4,6-Tetramethyl-2,3-dihydrobenzofuran-7-yl)amides
yield,
ACAT inhibition
change TC,d,e
% (mg/kg)f
compd
R
%a (method)
mp, °C
formulab
IC50, µMc
37
10
38
39
40
(CH2)7CH3
(CH2)9CH3
(CH2)11CH3
(CH2)6OCH2CH(CH3)2
(CH2)6-piperidin-1-yl
93 (A)
92 (A)
68 (A)
66 (A)
26 (A)
81-82
57-59
C24H39NO2
C26H43NO2
C28H47NO2
C26H43NO3
0.14
0.042
0.033
0.059
>0.5
-61 (1)
36-38
45-47
177-180
-62 (10)
C27H44N2O2‚HCl
a-f See corresponding footnotes of Table 1.
Ta ble 3. Chemical Properties and Biological Data for N-(2,2,4,6-Tetramethyl-2,3-dihydrobenzofuran-7-yl)amides
yield,
ACAT inhibition
change TC,d,e
% (mg/kg)f
compd
n
X
R
%a (method)
mp, °C
formulab
IC50, µMc
41
42
43
44
45
46
47
48
49
50
51
4
5
6
3
3
4
5
5
4
6
6
bond
bond
bond
bond
O
O
O
O
OCH2
O
H
H
H
29 (A)
78 (A)
85 (A)
82 (A)
75 (A)
87 (A)
83 (A)
71 (A)
54 (A)
75 (A)
38 (A)
73-74
69-71
51-52
98-100
C26H35NO2
0.21
0.12
0.081
0.040
0.26
0.33
0.15
0.086
0.40
0.076
0.050
C
C
27H37NO2
28H39NO2
-66 (10)
-57 (3)
CH2CH(CH3)2
C29H41NO2
Cl
Cl
Cl
H
H
Cl
CH3
117
C
C
C
C
25H32NO3Cl
26H34NO3Cl
27H36NO3Cl
27H37NO3
91-92
-61 (10)
-64 (1)
90-91
108
78-79
72-73
79-80
C27H37NO3
28H38NO3Cl
C29H41NO3
-50 (10)
-75 (1)
C
O
a-f See corresponding footnotes of Table 1.
dihydrobenzofuran-7-yl group was selected as the com-
mon aryl moiety.
analog 49 (X ) OCH2) showed reduced activity com-
pared with the phenoxyalkyl analog 48. In the series
of phenoxyalkyl analogs, 47 and 50 showed similar
potent in vivo cholesterol-lowering activity to the cor-
responding 2,2-dimethyldodecanamides 10. Thus, it
became obvious that the 8-(4-chlorophenoxy)-2,2-di-
methyloctanamide (n ) 6) is an optimal structure for
potent in vivo activity.
The results of R,R-dimethylalkanoic acid amides are
shown in Table 2. As the R group shown in this table,
alkyl groups in the C10-C12 range functioned well for
ACAT inhibitory activity. A branched alkoxyl group
introduced into the R group to increase metabolic
stability (39) retained activity in vitro but resulted in
less in vivo activity. Introduction of the 1-piperidinyl
group into the R group to increase water solubility (40)
resulted in a dramatic loss of activity.
The compounds listed in Table 3 were synthesized to
examine the effect of introduction of a benzene ring into
the acyl moiety. In the series of phenylalkyl analogs
(X ) bond), when the acyl moiety had a lipophilic group
with a range of more than C6 in addition to the benzene
ring (43), potent in vitro activities were obtained. A
benzene ring introduced in the middle of the alkyl
moiety (44) retained potent in vitro activity as compared
with the corresponding 2,2-dimethyldodecanamide 10;
however, it showed reduced in vivo activity.
The effects of substituents on the benzene ring of
N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)benz-
amides were examined; the results are shown in Table
4. The benzamide derivatives were found to have potent
ACAT inhibitory activity in vitro, when they had a
highly lipophilic substituent like decyloxy (53) at the
para position. However, 53 was inactive in vivo in spite
of potent activity in vitro. Interestingly, the 4-[[6-(4-
chlorophenoxy)hexyl]oxy] group, which showed potent
activity in the case of N-(7-methoxy-4-oxochroman-8-
yl)benzamide,11 showed rather reduced activity. These
results suggest that the benzamide structure was not
beneficial for N-(2,2,4,6-tetramethyl-2,3-dihydrobenzo-
furan-7-yl) derivatives.
In the series of phenoxyalkyl analogs (X ) O), the in
vitro activity was increased depending on the length of
the alkyl chain, in the order of caron number of 3 (45)
) 4 (46) < 5 (47) < 6 (50). Substituents on the benzene
ring of the phenoxyalkyl group, such as p-chloro and
p-methyl, did not affect the activity. (Benzyloxy)alkyl
Selected compounds, with 2 and CI-976, were further
evaluated for the ability to inhibit rabbit liver ACAT
and acetyl-LDL-induced cholesteryl ester accumulation
in rat peritoneal macrophages (foam cell formation).
Assays of these activities were carried out by using the

1266 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Kataoka et al.
Ta ble 4. Chemical Properties and Biological Data for N-(2,2,4,6-Tetramethyl-2,3-dihydrobenzofuran-7-yl)benzamides
yield,
ACAT inhibition
change TC,d,e
% (mg/kg)f
compd
R
%a (method)
mp, °C
formulab
IC50, µMc
52
53
54
55
56
O(CH2)7CH3
O(CH2)9CH3
O(CH2)11CH3
O(CH2)6O(CH2)2CH3
O(CH2)6OC6H4(4-Cl)
79 (C)
99 (A)
99 (C)
98 (C)
86 (A)
85-88
97-98
C27H37NO3
C29H41NO3
C31 H45NO3
C28H39NO4
C31H36NO4Cl
>0.2
0.030
0.090
>0.2
>0.2
0 (3)
g
57-60
69-71
135-136
g
a-f See corresponding footnotes of Table 1. Calcd, 77.62; found, 78.14.
Ta ble 5. Biological Activities of Selected Compounds
ACAT inhibition
IC50, µM
rabbit
rabbit
hypocholesterolemic activity (rat)
change TC,d % (mg/kg)e
foam cell formation
compd
intestinea
liverb,c
inhibition (rat) IC50, µMf
50
10
0.076
0.042
0.020
0.013
0.14
-64 (0.3)
-44 (0.3)
-71 (0.3)
-66 (0.3)
-50 (3.0)
1.5
0.65
0.030
0.16
3.8
13 (TEI-6620)
2 (TEI-6522)
CI-976
0.009
0.016
0.149
a
b
IC50 (µM) for the enzyme obtained from rabbit intestine microsomes. IC50 (µM) for the enzyme obtained from rabbit liver microsomes.
c Compounds with no IC50 indicated were not tested. Serum total cholesterol-lowering activity in the cholesterol-fed rat expressed as
the ratio of the observed reduction to the difference between the control and normal levels × 100. e Dose: compounds were administered
orally to rats at the indicated dose once a day for 3 days. f IC50 (µM) for acetyl-LDL-induced cholesteryl ester accumulation in rat peritoneal
macrophages.
d
suspended in 0.5% methyl cellulose solution at a dose
of 10 mg/kg. As shown in Figure 2, the bioavailability
of 13 was found to increase dramatically in the fed state
as compared with the fasted state. The peak serum
concentration in fed dogs was 2.68 µg/mL at 1 h after
oral administration. Even at the 24 h point, the serum
concentration of 13 (260 ng/mL) exceeded its in vitro
rat foam cell formation IC50 concentration. These
results suggest that 13 has potential to inhibit foam cell
formation in the developing atherosclerotic lesion.
Con clu sion
This study has identified a novel series of N-(2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran-7-yl)amides with po-
tent ACAT inhibitory activities. Examination of struc-
ture-activity relationships in this series revealed the
following features. (1) The methyl group at position 6
of the 2,3-dihydrobenzofuran was essential for potent
activity. (2) Introduction of a dimethylamino group at
position 5 of the 2,3-dihydrobenzofuran moiety resulted
in highly potent activity. (3) The necessary factor to
elicit the potent ACAT inhibitory activity was high
lipophilicity of the molecules.
Introduction of a lipophilic group at the acyl moiety,
except for the benzamide analogs, resulted in potent
activity. Among the synthesized derivatives, N-[5-
(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzo-
furan-7-yl]-2,2-dimethyldodecanamide (13) showed highly
potent ACAT inhibitory activity (rabbit small intestine
F igu r e 2. Serum concentrations of 13 in dogs.
method described.11 The results of these in vitro assays
and the in vivo effect on total plasma cholesterol
concentrations are summarized in Table 5. In vitro, 13
displayed high ACAT inhibitory potency (rabbit intes-
tine IC50 ) 0.020 µM, rabbit liver IC50 ) 0.009 µM) and
foam cell formation inhibitory activity (rat peritoneal
macrophage IC50 ) 0.030 µM). Under the same condi-
tions, the IC50 value of CI-976 was 0.14 µM (rabbit
intestine), 0.149 µM (rabbit liver), and 3.8 µM (rat
peritoneal macrophage), respectively. Furthermore, 13
was ca. 10-fold more potent with respect to hypocho-
lesterolemic activity in vivo than CI-976, that is, 13
lowered serum cholesterol 71% at a dose of 0.3 mg/kg/
day in cholesterol-fed rats. Under the same conditions,
CI-976 lowered serum cholesterol 25% at a dose of 1.0
mg/kg/day and 50% at a dose of 3.0 mg/kg/day.
IC50
) 0.020 µM, rabbit liver IC50 ) 0.009 µM) and
extremely potent serum cholsterol-lowering activity in
cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po,
ca. 10-fold more potent than CI-976). This compound
was the most potent inhibitor of foam cell formation (rat
Serum concentrations of 13 were measured in dogs
(n ) 2) following a single oral administration of the drug

Potent Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1267
to give crude 5-chloro-2,2,4,6-tetramethyl-2,3-dihydrobenzo-
furan (24): 225.2 g, pale red oil; 1H NMR (CDCl3, 270 MHz) δ
1.46 (s, 6 H), 2.23 (s, 3 H), 2.31 (s, 3 H), 2.93 (s, 2 H), 6.48 (s,
1 H).
peritoneal macrophage IC50 ) 0.030 µM, 127-fold more
potent than CI-976) among the synthesized compounds
including our earlier studies [N-(4-oxochroman-8-yl)-
amides].
The crude 24 (63.21 g) was dissolved in 160 mL of acetic
anhydride, and 28.35 g of nitric acid (70%, 1.05 equiv) was
slowly added with stirring at 0-15 °C (ice-water bath). The
reaction mixture was stirred for 0.5 h at room temperature
and then poured into ice-water (600 mL). The precipitated
product was filtered, washed with water (3 × 300 mL), and
dried. Recrystallization from EtOH (500 mL) afforded
5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran:
48.57 g, 63% yield from crude 24, pale yellow solid; mp 114.7-
The preliminary pharmacokinetics data showed that
13 had improved bioavailability (fed dogs, Cmax ) 2.68
µg/mL at 1 h, 10 mg/kg po) in comparison with our
earlier oxochroman compound 2. On the basis of these
findings, we conclude that 13 has an excellent profile
for development as therapeutic agent for the treatment
of hyperlipidemia and atherosclerosis. 13 was selected
for further pharmacological and toxicological studies. A
detailed study of 13 in WHHL rabbits, as well as studies
of 13 in several cholesterol-fed animals, will be the
subjects of future papers from this laboratory.
1
115.3 °C; H NMR (CDCl3, 270 MHz) δ 1.52 (s, 6 H), 2.28 (s,
3 H), 2.38 (s, 3 H), 3.01 (s, 2 H).
7-Am in o-5-ch lor o-2,2,4,6-tetr a m eth yl-2,3-d ih yd r oben -
zofu r a n (25). A solution of 5-chloro-2,2,4,6-tetramethyl-7-
nitro-2,3-dihydrobenzofuran (800 mg, 3.13 mmol) in EtOH (10
mL) was hydrogenated at 1 atm for 3 h in the presence of 5%
palladium on charcoal (300 mg) at room temperature. The
catalyst was removed by filtration through Celite and washed
with EtOH (30 mL). The combined filtrate was evaporated to
give a crude solid which was purified by silica gel column
chromatography (hexane-AcOEt) to give 7-amino-5-chloro-
2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (25): 494 mg, 70.0%
Exp er im en ta l Section
Melting points were determined on a Yanagimoto mi-
cromelting point apparatus and are uncorrected. Infrared
spectra were recorded on a J ASCO FT/IR-5300 spectrometer.
NMR spectra were acquired in the indicated solvent on a
J EOL-EX270, J EOL-GX400 FTNMR, or Hitachi R-90H spec-
trometer with Me4Si as an internal standard. Elemental
analyses were performed by Toray Research Center Inc. or the
Analytical Research Department of Teijin Ltd. Where analy-
ses are indicated only by symbols of the elements, analytical
results are within (0.4% of the theoretical values. Thin layer
chromatography (TLC) was performed on E. Merck Kieselgel
60 F-254 plates. Column chromatography was performed with
E. Merck silica gel 60 (40-63 µm, 230-400 mesh) under low
pressure. Unless otherwise noted, materials were obtained
from a commercial source and used without further purifica-
tion. CI-976 was synthesized in our laboratory following the
published procedure9b and characterized by NMR and elemen-
tal analysis (C, H, N).
Assa y of in Vitr o ACAT In h ibitor y Activity of Ra bbit
In testin a l Micr osom es. ACAT inhibitory activity of rabbit
intestine in vitro was evaluated with rabbit intestinal mucosa
microsome as reported.11
Assa y of in Vitr o ACAT In h ibitor y Activity of Ra bbit
Liver . ACAT inhibitory activity of rabbit liver in vitro was
evaluated with rabbit liver microsome as reported.11
Assa y of P er cen t Ch a n ge of Ser u m Tota l Ch olester ol
Level. Serum total cholesterol-lowering activity was deter-
mined in cholesterol-fed rats. The experimental details of the
in vivo assay have been described.11
Assa y of In h ibitor y Activity of Ma cr op h a ge F oa m Cell
F or m a tion . Peritoneal macrophages were prepared from rats
and used for IC50 determinations of acetyl-human-LDL-
induced cellular cholesteryl ester accumulation as described.11
5-Ch lor o-2,2,4,6-tetr a m eth yl-7-n itr o-2,3-d ih yd r oben zo-
fu r a n . Sodium methoxide (296 g, 28% solution in methanol,
1.2 equiv) and 3-chloro-2-methyl-1-propene (200 g, 1.73 equiv)
were added to a solution of 4-chloro-3,5-xylenol (200 g, 1.28
mol) in methanol (200 mL). The mixture was heated to 70 °C
with stirring for 24 h. After the reaction mixture was cooled,
the solvent was removed under reduced pressure. H2O (500
mL) was added to the residue, and the mixture was extracted
with ethyl acetate (500 mL). The organic layer was washed
with 5 N NaOH (500 mL), H2O (500 mL), and brine (100 mL)
and dried over MgSO4. The solvent was removed under
reduced pressure to give crude O-methallyl-4-chloro-3,5-xylenol
(23): 263.66 g, pale yellow oil; 1H NMR (CDCl3, 90 MHz) δ
1.81 (s, 3 H), 2.33 (s, 6 H), 4.37 (s, 2 H), 4.98 (br, 1 H), 5.06
(br, 1 H), 6.65 (s, 2 H).
1
yield, colorless needles; mp 90-91 °C; H NMR (CDCl3, 270
MHz) δ 1.47 (s, 6 H), 2.17 (s, 3 H), 2.22 (s, 3 H), 2.95 (s, 2 H),
3.45 (br, 2 H).
7-Am in o-2,2,4,6-tetr am eth yl-2,3-dih ydr oben zofu r an Hy-
d r och lor id e (14). In
a 500 mL autoclave were placed
5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran (20.00
g, 78.2 mmol), 10% palladium on charcoal (6.0 g), and EtOH
(160 mL). The mixture was hydrogenated at 18 atm for 12 h
at 115 °C. The catalyst was removed by filtration through
Celite and washed with EtOH (100 mL). To the combined
filtrate was added 6 N HCl solution in EtOH (20 mL), and
the solvent was removed under reduced pressure to give crude
hydrchloride. The crude product was recrystallized (from CH2-
Cl2-AcOEt, 1:2) to give 7-amino-2,2,4,6-tetramethyl-2,3-dihy-
drobenzofuran hydrochloride (14): 14.02 g, 78.8% yield, pale
yellow needles; mp 202.2-204.8 °C; 1H NMR (CDCl3 90 MHz)
δ 1.49 (s, 6 H), 2.13 (s, 3 H), 2.57 (s, 3 H), 2.91 (s, 2 H), 3.47
(s, 3 H), 6.45 (s, 1 H). Anal. (C12H18NOCl) C, H, N.
7-Amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (free base)
was prepared from hydrochloride 14. Saturated NaHCO3
aqueous solution (50 mL) was added to a solution of 14 (1.0 g,
4.39 mmol) in CH2Cl2 (50 mL). Extraction with CH2Cl2, drying
over MgSO4, evaporation of the solvent, and column chroma-
tography (hexane-AcOEt, 10:1) gave 7-amino-2,2,4,6-tetra-
methyl-2,3-dihydrobenzofuran: 798 mg, 95% yield, colorless
1
needles; mp 37.5 °C; H NMR (CDCl3, 270 MHz) δ 1.47 (s, 6
H), 2.10 (s, 3 H), 2.13 (s, 3 H), 2.91 (s, 2 H), 3.33 (br s, 2 H),
6.40 (s, 1 H).
7-Am in o-2,2,6-tr im eth yl-2,3-d ih yd r oben zofu r a n (21a ).
3-Chloro-2-methyl-1-propene (7.69 g, 1.3 equiv) was added to
a solution of 3-methyl-2-nitrophenol (10 g, 65.3 mmol) and
NaOH (2.16 g, 1.0 equiv) in H2O (20 mL). The mixture was
heated to 90 °C with stirring for 6 h. After the reaction
mixture was cooled, H2O (50 mL) was added and the mixture
was extracted with ethyl acetate (100 mL). The organic layer
was washed with H2O (10 mL) and brine (10 mL) and dried
over MgSO4. The solvent was removed under reduced pressure
to give an oil which was purified by distillation under reduced
pressure to give O-methallyl-3-methyl-2-nitrophenol (20a ):
8.05 g, 60% yield, yellow oil; bp 78-82 °C/0.1 mmHg; 1H NMR
(CDCl3, 90 MHz) δ 1.78 (s, 3 H), 2.30 (s, 3 H), 4.50 (s, 2 H),
4.9-5.1 (m, 2 H), 6.83 (d-like, 2 H, J ) 7.9 Hz), 7.15-7.4 (m,
1 H).
To the crude 23 (262 g) was added 100 g of anhydrous
MgCl2, and the mixture was heated at 210 °C with stirring
for 18 h. Ethyl acetate (500 mL) was added to the cooled
reaction mixture, and MgCl2 was removed by filtration through
Celite and washed with ethyl acetate (200 mL). The combined
filtrate was washed successively with 2 N HCl (300 mL), 2 N
NaOH (500 mL), H2O (100 mL), and brine (100 mL) and dried
over MgSO4. The solvent was removed under reduced pressure
To 20a (7.0 g, 33.78 mmol) was added 322 mg of anhydrous
MgCl2, and the mixture was heated at 180 °C with stirring
for 5 h. Ethyl acetate (50 mL) was added to the cooled reaction
mixture, and MgCl2 was removed by filtration through Celite
and washed with ethyl acetate (20 mL). The combined filtrate
was washed with H2O (20 mL) and brine (20 mL) and dried
over MgSO4. The solvent was removed under reduced pressure
to give an oil which was purified by column chromatography

1268 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Kataoka et al.
(hexane-AcOEt, 12:1) to give 2,2,6-trimethyl-7-nitro-2,3-
dihydrobenzofuran: 2.26 g, 32% yield, pale yellow oil; 1H NMR
(CDCl3, 90 MHz) δ 1.52 (s, 6 H), 2.39 (s, 3 H), 3.03 (s, 2 H),
6.68 (d, 1 H, J ) 7.5 Hz), 7.12 (d, 1 H, J ) 7.5 Hz).
The crude product was recrystallized (from EtOH) to give N-(5-
amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-
dimethyldodecanamide (12): 37.73 g, 72.0% yield, colorless
needles; mp 125 °C; 1H NMR (CDCl3, 270 MHz) δ 0.88 (t, 3 H,
J ) 6.6 Hz), 1.2-1.5 (m, 22 H), 1.40 (s, 6 H), 1.55-1.65 (m, 2
H), 1.99 (s, 3 H), 2.04 (s, 3 H), 2.92 (s, 2 H), 2.7-3.7 (br, 2 H),
6.87 (s, 1 H). Anal. (C26H44N2O2) C, H, N.
A solution of 2,2,6-trimethyl-7-nitro-2,3-dihydrobenzofuran
(2.10 g, 10.1 mmol) in EtOH (30 mL) was hydrogenated at 1
atm for 15 h in the presence of 5% palladium on charcoal (600
mg) at room temperature. The catalyst was removed by
filtration through Celite and washed with EtOH (30 mL). The
combined filtrate was evaporated to give an oil which was
purified by silica gel column chromatography (hexane-AcOEt,
10:1) to give 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran
(21a ): 1.40 g, 78% yield, pale red oil; 1H NMR (CDCl3 270
MHz) δ 1.47 (s, 6 H), 2.15 (s, 3 H), 2.98 (s, 2 H), 3.46 (br, 2 H),
6.51 (d, 1 H, J ) 7.6 Hz), 6.57 (d, 1 H, J ) 7.6 Hz).
N -[5-(Dim e t h yla m in o)-2,2,4,6-t e t r a m e t h yl-2,3-d ih y-
d r ob en zofu r a n -7-yl]-2,2-d im et h yld od eca n a m id e (13).
Meth od B. In a 500 mL autoclave were placed N-(2,2,4,6-
tetramethyl-5-nitro-2,3-dihydrobenzofuran-7-yl)-2,2-dimethyl-
dodecanamide (11; 26.30 g, 58.9 mmol), formaldehyde (37%
solution in H2O, 20 g), 10% palladium on charcoal (7.9 g), and
EtOH (160 mL). The mixture was hydrogenated at 18 atm
for 5 h at 90 °C. The catalyst was removed by filtration
through Celite and washed with EtOH (100 mL). The com-
bined filtrate was evaporated to afford a crude solid, which
was dissolved in AcOEt (200 mL). The solution was washed
successively with saturated NaHCO3 aqueous solution (2 ×
60 mL), H2O (2 × 60 mL), and brine (50 mL) and dried over
MgSO4. The solvent was removed under reduced pressure to
afford a crude solid (26.25 g) which was purified by short silica
gel column chromatography (hexane-AcOEt, 19:1) and re-
crystallization (CH3CN-H2O, 25:2) to give N-[5-(dimethyl-
amino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl]-2,2-
dimethyldodecanamide (13, TEI-6620): 18.38 g, 70.2% yield,
colorless needles; mp 86.7-87.5 °C; 1H NMR (CDCl3, 270 MHz)
δ 0.88 (t, 3 H, J ) 6.8 Hz), 1.2-1.5 (m, 22 H), 1.42 (s, 6 H),
1.50-1.65 (m, 2 H), 2.09 (s, 3 H), 2.10 (s, 3 H), 2.79 (s, 6 H),
2.89 (s, 2 H), 6.82 (s, 1 H). Anal. (C28H48N2O2) C, H, N.
N-(2,2,4,6-Tetr a m eth yl-2,3-d ih yd r oben zofu r a n -7-yl)-4-
(octyloxy)ben za m id e (52). Meth od C. 4-Hydroxybenzoic
acid (361 mg, 2.61 mmol) was added to a solution of 7-amino-
2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (500 mg, 2.61 mmol)
and dicyclohexylcarbodiimide (539 mg, 2.61 mmol) in CH2Cl2
(20 mL). The reaction mixture was stirred at room temper-
ature for 3 days. Filtration through Celite, evaporation of the
solvent, and column chromatography (hexane-AcOEt, 2:1)
gave 4-hydroxy-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-
7-yl)benzamide (17): 600 mg, 73.8% yield, white solid; 1H NMR
(DMSO-d6, 270 MHz) δ 1.41 (s, 6 H), 2.08 (s, 3 H), 2.15 (s, 3
H), 2.91 (s, 3 H), 6.50 (s, 1 H), 6.81 (br d, 2 H, J ) 7.4 Hz),
7.85 (br d, 2 H, J ) 7.4 Hz), 9.18 (br, 1 H), 9.85 (br, 1 H).
K2CO3 (66 mg, 1.5 equiv) and octyl bromide (62 mg, 0.32
mmol) were added to a solution of 4-hydroxy-N-(2,2,4,6-
tetramethyl-2,3-dihydrobenzofuran-7-yl)benzamide (100 mg,
0.32 mmol) in CH3CN (2 mL). The mixture was refluxed for
6 h with stirring. H2O (30 mL) was added to the mixture, and
the mixture was extracted with AcOEt (50 mL). The organic
layer was washed with brine (10 mL) and dried over MgSO4.
The solvent was removed under reduced pressure to give a
solid which was purified by column chromatography (hexane-
AcOEt, 10:1) to give N-(2,2,4,6-tetramethyl-2,3-dihydrobenzo-
furan-7-yl)-4-(octyloxy)benzamide (52): 107 mg, 79% yield,
N-(2,2,4,6-Tet r a m et h yl-2,3-d ih yd r ob en zofu r a n -7-yl)-
2,2-d im eth yld od eca n a m id e (10). Meth od A. 2,2-Dimeth-
yldodecanoyl chloride (247 mg, 1.00 mmol) was slowly added
to a solution of 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 233 mg, 1.02 mmol) and triethyl-
amine (0.28 mL, 2.0 mmol) in CH2Cl2 (3.0 mL) with stirring.
The reaction mixture was stirred for 3 h at room temperature,
and then 2 N HCl (15 mL) was added. The organic layer was
separated, and the water layer was further extracted with
AcOEt (2 × 25 mL). The combined extracts were washed with
brine (25 mL) and dried over MgSO4. The solvent was
removed under reduced pressure to give a solid which was
purified by column chromatography (hexane-AcOEt, 9:1) to
give N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-
dimethyldodecanamide (10): 370 mg, 92% yield, white solid;
1
mp 57-58.5 °C; H NMR (CDCl3, 270 MHz) δ 0.88 (t, 3 H, J
) 6.6 Hz), 1.2-1.5 (m, 16 H), 1.26 (s, 6 H), 1.43 (s, 6 H), 1.57
(m, 2 H), 2.13 (s, 3 H), 2.14 (s, 3 H), 2.89 (s, 2 H), 6.50 (s, 1 H),
6.79 (br, 1 H). Anal. (C26H43NO2) C, H, N.
N-(2,2,4,6-Tetr a m eth yl-5-n itr o-2,3-d ih yd r oben zofu r a n -
7-yl)-2,2-d im eth yld od eca n a m id e (11). Meth od B. 2,2-
Dimethyldodecanoyl chloride (65.03 g, 264 mmol) was slowly
added to a solution of 7-amino-2,2,4,6-tetramethyl-2,3-dihy-
drobenzofuran hydrochloride (14; 60.00 g, 263 mmol) and
triethylamine (58.66 g, 2.2 equiv) in CH2Cl2 (600 mL) with
stirring at 10 °C (ice bath). The reaction mixture was stirred
for 3 h at room temperature and then cooled with an ice bath;
2 N HCl (200 mL) was added to the reaction mixture, the
organic layer was separated, and the water layer was further
extracted with CH2Cl2 (50 mL). The combined extracts were
washed with H2O (150 mL) and brine (50 mL) and dried over
MgSO4. The solvent was removed under reduced pressure to
give N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2-
dimethyldodecanamide (10): 104.80 g.
The crude 10 (104.80 g, 261 m mol) was dissolved in 500
mL of acetic anhydride, and 24.7 g of nitric acid (70%, 1.05
equiv) was slowly added with stirring at 0-15 °C (ice-water
bath). The reaction mixture was stirred for 3 h at 10 °C and
then poured into ice-water (1 L). The mixture was extracted
with AcOEt (1 L). The organic layer was washed with H2O (2
× 1 L), and 500 mL of H2O was added. The mixture was
basified (pH > 8) by adding K2CO3 with vigorous stirring, and
the organic layer was separated. The organic layer was
washed successively with saturated K2CO3 aqueous solution
(2 × 500 mL), H2O (300 mL), and brine (100 mL) and dried
over MgSO4. The solvent was removed under reduced pressure
to afford a crude solid (120.2 g) which was recrystallized from
hexane (200 mL) at 0 °C to give N-(2,2,4,6-tetramethyl-5-nitro-
2,3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecanamide (11):
1
white solid; mp 85-88 °C; H NMR (CDCl3, 400 MHz) δ 0.89
(t, 3 H, J ) 6.7 Hz), 1.2-1.6 (m, 16 H), 1.72-1.85 (m, 2 H),
2.16 (s, 3 H), 2.22 (s, 3 H), 2.91 (s, 2 H), 4.01 (t, 2 H, J ) 6.6
Hz), 6.56 (s, 1 H), 6.94 (br d, 2 H, J ) 8.3 Hz), 7.24 (br, 1 H),
7.86 (br d, 2 H, J ) 8.3 Hz). Anal. (C27H37NO3) C, H, N.
1-Decyl-N-(2,2-d im eth yl-2,3-d ih yd r oben zofu r a n -7-yl)-
1-cyclop en ta n eca r boxa m id e (31). This product was pre-
pared in a similar manner to that described in method A using
7-amino-2,2-dimethyl-2,3-dihydrobenzofuran (21b; 200 mg,
1.23 mmol) and 1-decyl-1-cyclopentanecarbonyl chloride (367
mg, 1.1 equiv) to give a solid which was purified by column
chromatography (hexane-AcOEt) to give 31: 322 mg, 91%
yield, pale yellow oil; 1H NMR (CDCl3, 90 MHz) δ 0.87 (br t, 3
H J ) 7.0 Hz), 1.0-1.9 (m, 30 H), 2.0-2.3 (m, 2 H), 3.04 (s, 2
H), 6.7-6.9 (m, 2 H), 7.4 (br 1 H), 8.0-8.15 (m, 1 H). Anal.
(C26H41NO2) C, H, N.
1
67.89 g, 57.7% yield, pale yellow solid; mp 87.2-90.0 °C; H
NMR (CDCl3, 270 MHz) δ 0.88 (t, 3 H, J ) 6.6 Hz), 1.2-1.7
(m, 18 H), 1.26 (s, 6 H), 1.47 (s, 6 H), 2.11 (s, 3 H), 2.15 (s, 3
H), 2.97 (s, 2 H), 6.80 (br, 1 H). Anal. (C26H42N2O4) C, H, N.
N-(5-Am in o-2,2,4,6-tetr am eth yl-2,3-dih ydr oben zofu r an -
7-yl)-2,2-d im eth yld od eca n a m id e (12). Meth od B. A solu-
tion of N-(2,2,4,6-tetramethyl-5-nitro-2,3-dihydrobenzofuran-
7-yl)-2,2-dimethyldodecanamide (11; 56.2 g, 126 mmol) in
EtOH (600 mL) was hydrogenated at 1 atm for 8 h in the
presence of 10% palladium on charcoal (20 g) at 50 °C. The
catalyst was removed by filtration through Celite and washed
with EtOH (150 mL). The combined filtrate was evaporated.
1-Decyl-N-(2,2,6-t r im et h yl-2,3-d ih yd r ob en zofu r a n -7-
yl)-1-cyclop en ta n eca r boxa m id e (33). This product was
prepared in a similar manner to that described in method A
using 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran (21a ; 100
mg, 0.56 mmol) and 1-decyl-1-cyclopentanecarbonyl chloride
(169 mg, 1.1 equiv) to give a solid which was purified by

Potent Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1269
column chromatography (hexane-AcOEt) to give 33: 224 mg,
96% yield, white solid; mp 97-107 °C; 1H NMR (CDCl3, 90
MHz) δ 0.87 (br t, 3 H, J ) 7.0 Hz), 1.05-1.80 (m, 30 H), 2.0-
2.35 (m, 2 H), 2.18 (s, 3 H), 2.97 (s, 2 H), 6.65 (d, 1 H, J ) 8.0
90 MHz) δ 0.89 (d, 6 H, J ) 6.5 Hz), 1.27 (s, 6 H), 1.38 (s, 6
H), 1.4-1.95 (m, 5 H), 2.13 (s, 6 H), 2.2-2.7 (m, 4 H), 2.87 (s,
2 H), 6.49 (s, 1 H), 6.75 (br s, 1 H), 6.9-7.2 (m, 4 H). Anal.
(C29H41NO2) C, H, N.
Hz), 6.80 (br s, 1 H), 6.89 (d, 1 H, J ) 8.0 Hz). Anal. (C27H43
-
6-[(4-Ch lor op h en yl)oxy]-N-(2,2,4,6-tetr a m eth yl-2,3-d i-
h ydr oben zofu r an -7-yl)-2,2-dim eth ylh exan am ide (46). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 150 mg, 0.66 mmol) and 6-(4-
chlorophenoxy)-2,2-dimethylhexanoyl chloride (210 mg, 1.1
equiv) to give a solid which was purified by column chroma-
tography (hexane-AcOEt, 4:1) to give 46: 255 mg, 87% yield,
NO2) C, H, N.
N-(2,2,4,6-Tet r a m et h yl-2,3-d ih yd r ob en zofu r a n -7-yl)-
h exa d eca n a m id e (34). This product was prepared in a
similar manner to that described in method A using 7-amino-
2,2,4,6-tetramethyl-2,3-dihydrobenzofuran (14; 19.4 mg, 0.10
mmol) and palmitoyl chloride (30 mg, 1.1 equiv) to give a solid
which was purified by column chromatography (hexane-
AcOEt, 10:1) to give 34: 38.7 mg, 89% yield, white solid; mp
1
white solid; mp 91-91 °C; H NMR (CDCl3, 90 MHz) δ 1.31
1
84-85.5 °C; H NMR (CDCl3, 90 MHz) δ 0.88 (br t, 3 H, J )
(s, 6 H), 1.41 (s, 6 H), 1.1-1.9 (m, 6 H), 2.13 (s, 3 H), 2.16 (s,
3 H), 2.88 (s, 2 H), 3.93 (t, 2 H, J ) 6 Hz), 6.50 (s, 1 H), 6.79
(d, 2 H, J ) 9 Hz), 6.85 (br s, 1 H), 7.20 (d, 2 H, J ) 9 Hz).
Anal. (C26H34NO3Cl) C, H, N.
5.0 Hz), 1.05-1.55 (m, 24 H), 1.45 (s, 6 H), 2.15 (s, 6 H), 2.2-
2.5 (m, 2 H), 2.90 (s, 2 H), 6.51 (s, 1 H), 6.6 (br, 1 H). Anal.
(C28H47NO2) C, H, N.
N-(5-Ch lor o-2,2,4,6-tetr am eth yl-2,3-dih ydr oben zofu r an -
7-yl)-1-d ecyl-1-cyclop en ta n eca r boxa m id e (36). This prod-
uct was prepared in a similar manner to that described in
method A using 7-amino-5-chloro-2,2,4,6-tetramethyl-2,3-di-
hydrobenzofuran (25; 100 mg, 0.44 mmol) and 1-decyl-1-
cyclopentanecarbonyl chloride (133 mg, 1.1 equiv) to give a
solid which was purified by column chromatography (hexane-
AcOEt) to give 36: 201 mg, 98% yield, white solid; mp 69-70
7-[(4-Ch lor op h en yl)oxy]-N-(2,2,4,6-tetr a m eth yl-2,3-d i-
h ydr oben zofu r an -7-yl)-2,2-dim eth ylh eptan am ide (47). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 150 mg, 0.66 mmol) and 7-(4-
chlorophenoxy)-2,2-dimethylheptanoyl chloride (220 mg, 1.1
equiv) to give a solid which was purified by column chroma-
tography (hexane-AcOEt, 4:1) to give 47: 184 mg, 82.8% yield,
1
1
°C; H NMR (CDCl3, 90 MHz) δ 0.88 (br t, 3 H, J ) 7.0 Hz),
white solid; mp 90-91 °C; H NMR (CDCl3, 90 MHz) δ 1.29
1.1-1.8 (m, 30 H), 2.20 (s, 6 H), 2.0-2.35 (m, 2 H), 2.95 (s, 2
H), 6.78 (br, 1 H). Anal. (C28H44NO2Cl) C, H, N.
(s, 6 H), 1.42 (s, 6 H), 1.2-1.95 (m, 8 H), 2.13 (s, 6 H), 2.88 (s,
2 H), 3.91 (t, 2 H, J ) 6 Hz), 6.49 (s, 1 H), 6.7 (br s, 1 H), 6.7
(br s, 1 H), 6.79 (d, 2 H, J ) 9 Hz), 7.20 (d, 2 H, J ) 9 Hz).
Anal. (C27H36NO3Cl) C, H, N.
N-(2,2,4,6-Tet r a m et h yl-2,3-d ih yd r ob en zofu r a n -7-yl)-
2,2-dim eth yl-8-[(2-m eth ylpr opyl)oxy]octan am ide (39). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 160 mg, 0.70 mmol) and 2,2-
dimethyl-8-[(2-methylpropyl)oxy]octanoyl chloride (193 mg,
0.73 mmol) to give a solid that was purified by column
chromatography (hexane-AcOEt, 19:1) to give 39: 192 mg,
66% yield, white solid; mp 45-47 °C; 1H NMR (CDCl3, 90 MHz)
δ 0.89 (br t, 6 H, J ) 6.5 Hz), 1.1-1.9 (m, 23 H), 2.13 (s, 6 H),
2.88 (s, 2 H), 3.15 (d, 2 H, J ) 6.5 Hz), 3.38 (t, 2 H, J ) 6.5
Hz), 6.49 (s, 1 H), 6.8 (br s, 1 H). Anal. (C26H43NO3) C, H, N.
N-(2,2,4,6-Tet r a m et h yl-2,3-d ih yd r ob en zofu r a n -7-yl)-
2,2-d im eth yl-8-p ip er id in -1-ylocta n a m id e Hyd r och lor id e
(40). This product was prepared in a similar manner to that
described in method A using 7-amino-2,2,4,6-tetramethyl-2,3-
dihydrobenzofuran hydrochloride (14; 128 mg, 0.56 mmol) and
2,2-dimethyl-8-piperidin-1-yloctanoyl chloride (211 mg, 0.86
mmol) to give a solid that was purified by column chromatog-
raphy (CHCl3-CH3OH, 8:1) to give the free base of 40. To an
ether solution of this free base (5 mL) was added 3 N HCl
solution in ether (1 mL), and the solvent was removed under
reduced pressure to give hydrochloride 40: 68 mg, 26% yield,
N-(2,2,4,6-Tet r a m et h yl-2,3-d ih yd r ob en zofu r a n -7-yl)-
2,2-dim eth yl-6-[(ph en ylm eth yl)oxy]h exan am ide (49). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 150 mg, 0.66 mmol) and 2,2-
dimethyl-6-[(phenylmethyl)oxy]hexanoyl chloride (300 mg) to
give an oil which was purified by column chromatography
(hexane-AcOEt, 4:1) to give 49: 149 mg, 53.5% yield, white
solid; mp 78-79 °C (recrystallized from hexane); 1H NMR
(CDCl3, 90 MHz) δ 1.28 (s, 6 H), 1.41 (s, 6 H), 1.2-1.8 (m, 6
H), 2.13 (s, 6 H), 2.88 (s, 2 H), 3.47 (t, 2 H, J ) 6.5 Hz), 4.48
(s, 2 H), 6.49 (s, 1 H), 6.80 (br s, 1 H), 7.2-7.4 (m, 5 H). Anal.
(C27H37NO3) C, H, N.
8-[(4-Ch lor op h en yl)oxy]-N-(2,2,4,6-tetr a m eth yl-2,3-d i-
h ydr oben zofu r an -7-yl)-2,2-dim eth yloctan am ide (50). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 150 mg, 0.66 mmol) and 8-(4-
chlorophenoxy)-2,2-dimethyloctanoyl chloride (230 mg, 1.1
equiv) to give an oil which was purified by column chroma-
tography (hexane-AcOEt) to give 50: 234 mg, 75% yield, white
solid; mp 72-73 °C; 1H NMR (CDCl3, 90 MHz) δ 1.29 (s, 6 H),
1.42 (s, 6 H), 1.3-1.9 (m, 10 H), 2.13 (s, 6 H), 2.88 (s, 2 H),
3.90 (t, 2 H, J ) 6.5 Hz), 6.49 (s, 1 H), 6.79 (d, 2 H, J ) 6.9
1
white solid; mp 177-180 °C; H NMR (free base, CDCl3, 90
MHz) δ 1.27-1.65 (m, 16 H), 1.27 (s, 6 H), 1.43 (s, 6 H), 2.12
(s, 6 H), 2.32-2.56 (m, 6 H), 2.88 (s, 2 H), 6.48 (s, 1 H), 6.86
(br, 1 H). Anal. (C27H44N2O2HCl) C, H, N.
Hz), 6.8 (br s, 1 H), 7.19 (d, 2 H, J ) 6.9 Hz). Anal. (C28H38
NO3Cl) C, H, N.
-
2,2-Dim eth yl-N-(2,2,4,6-tetr a m eth yl-2,3-d ih yd r oben zo-
fu r a n -7-yl)-8-p h en ylocta n a m id e (43). This product was
prepared in a similar manner to that described in method A
using 7-amino-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran hy-
drochloride (14; 200 mg, 0.88 mmol) and 2,2-dimethyl-8-
phenyloctanoyl chloride (234 mg, 1.0 equiv) to give a solid
which was purified by column chromatography (hexane-
AcOEt) to give 43: 315 mg, 85% yield, white solid; mp 51-52
N-(2,2,4,6-Tetr a m eth yl-2,3-d ih yd r oben zofu r a n -7-yl)-4-
[6-(p r op yloxy)h exyl]ben za m id e (55). This product was
prepared in a similar manner to that described in method C
using 4-hydroxy-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofu-
ran-7-yl)benzamide (17; 94 mg, 0.30 mmol) and 6-(propyloxy)-
hexyl chloride (69.6 mg, 0.31 mmol) to give an oil which was
purified by column chromatography (hexane-AcOEt, 4:1) to
give 55: 133 mg, 98% yield, white solid; mp 69-71 °C; 1H NMR
(CDCl3, 90 MHz) δ 1.4-1.7 (m, 16 H), 1.82 (m, 2 H), 2.16 (s, 3
H), 2.22 (s, 3 H), 2.91 (s, 2 H), 3.37 (t, 2 H, J ) 6.8 Hz), 3.42
(t, 2 H, J ) 6.5 Hz), 4.01 (t, 2 H, J ) 7.4 Hz) 6.56 (s, 1 H), 6.93
(br d, 2 H, J ) 8.3 Hz), 7.26 (s, 1 H), 7.85 (br d, 2 H, J ) 8.3
Hz). Anal. (C28H39NO4) C, H, N.
4-[[6-[(4-Ch lor op h en yl)oxy]h exyl]oxy]-N-(2,2,4,6-t et -
r am eth yl-2,3-dih ydr oben zofu r an -7-yl)ben zam ide (56). This
product was prepared in a similar manner to that described
in method A using 7-amino-2,2,4,6-tetramethyl-2,3-dihydroben-
zofuran hydrochloride (14; 150 mg, 0.66 mmol) and 4-[[6-(4-
chlorophenoxy)hexyl]oxy]benzoyl chloride (166 mg, 2.5 equiv)
to give a solid which was purified by column chromatography
1
°C; H NMR (CDCl3, 90 MHz) δ 1.27 (s, 6 H), 1.40 (s, 6 H),
1.0-1.8 (m, 10 H), 2.13 (s, 6 H), 2.59 (t, 2 H, J ) 6.5 Hz), 2.87
(s, 2 H), 6.48 (s, 1 H), 6.75 (br s, 1 H), 7.1-7.4 (m, 5 H). Anal.
(C28H39NO2) C, H, N.
2,2-Dim eth yl-N-(2,2,4,6-tetr a m eth yl-2,3-d ih yd r oben zo-
fu r an -7-yl)-5-[4-(2-m eth ylpr opyl)ph en yl]pen tan am ide (44).
This product was prepared in a similar manner to that
described in method A using 7-amino-2,2,4,6-tetramethyl-2,3-
dihydrobenzofuran hydrochloride (14; 246 mg, 1.08 mmol) and
2,2-dimethyl-5-[4-(2-methylpropyl)phenyl]pentanoyl chloride
(296 mg, 1.06 mmol) to give a solid which was purified by
column chromatography (hexane-AcOEt, 19:1) to give 44: 379
1
mg, 82% yield, white solid; mp 98-100 °C; H NMR (CDCl3,

1270 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
(hexane-AcOEt; 3:1) to give 56: 295 mg, 85.7% yield, white
Kataoka et al.
(7) Burrier, R. E.; Deren, S.; McGregor, D. G.; Hoos, L. M.; Smith,
A. A.; Davis, H. R., J r. Demonstration of a Direct Effect on
Hepatic Acyl CoA:Cholesterol Acyl Transferase (ACAT) Activity
by Orally Administered Enzyme Inhibitor in the Hamster.
Biochem. Pharmacol. 1994, 47, 1545-1551.
1
solid; mp 135-136 °C; H NMR (CDCl3, 400 MHz) δ 1.4-1.7
(m, 14 H), 1.83 (m, 4 H), 2.16 (s, 3 H), 2.21 (s, 3 H), 2.92 (s, 2
H), 3.94 (t, 2 H, J ) 6.5 Hz), 4.03 (t, 2 H, J ) 6.5 Hz), 6.56 (s,
1 H), 6.81 (d, 2 H, J ) 9 Hz), 6.93 (br d, 2 H, J ) 8 Hz), 7.2 (br
s, 1 H), 7.22 (d, 2 H, J ) 9 Hz), 7.86 (br d, 2 H, J ) 8 Hz).
Anal. (C31H36NO4Cl) C, H, N.
(8) (a) Sliskovic, D. R.; Trivedi, B. K. ACAT Inhibitors: Potential
Anti-atherosclerotic Agents. Curr. Med. Chem. 1994, 1, 204-
225. (b) Higley, C. A.; Wilde, R. G.; Maduskuie, T. P.; J ohnson,
A. L.; Pennev, P.; Billheimer, J . T.; Robinson, C. S.; Gillies, P.
J .; Wexler, R. R. Acyl CoA:Cholesterol Acyltransferase (ACAT)
Inhibitors: Synthesis and Structure-Activity Relationship Stud-
ies of a New Series of Trisubstituted Imidazoles. J . Med. Chem.
1994, 37, 3511-3522. (c) Maduskuie, T. P., J r.; Wilde, R. G.;
Billheimer, J . T.; Cromley, D. A.; Germain, S.; Gillies, P. J .;
Higley, C. A.; J ohnson, A. L.; Pennev, P.; Shimshick, E. J .;
Wexler, R. R. Design, Synthesis, and Structure-Activity Rela-
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S.; Kogan, T. P.; Salisbury, B.; Vaccaro, W. Substituted (1,2-
Ack n ow led gm en t. We gratefully acknowledge Pro-
fessor S. Horiuchi of Kumamoto University Medical
School for technical instruction in the assay of inhibitory
activity of macrophage foam cell formation and helpful
discussion and Professor S. Torii and Dr. H. Okumoto
of Okayama University for development of the elec-
troreduction method in the synthesis of a key interme-
diate, 14. We thank Dr. N. Endo and Dr. S. Kurozumi
for helpful support and Mr. M. Kanoh for help in the
biological assays.
Diarylethyl)amide
Acyl-CoA:Cholesterol
Acyltransferase
Inhibitors: Effect of Polar Groups on in Vitro and in Vivo
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J M950828+