Inhibitors of acyl-CoA:Cholesterol O-acyltransferase. 17. Structure-activity relationships of several series of compounds derived from N-chlorosulfonyl isocyanate

Article abstract of DOI:10.1021/jm9509455

Several series of acyl-CoA:cholesterol O-acyltransferase inhibitors were prepared by the stepwise addition of nitrogen, oxygen, and sulfur nucleophiles to N-chlorosulfonyl isocyanate. The (aminosulfonyl)ureas 3-44 were the most potent inhibitors in vitro,

Full text of DOI:10.1021/jm9509455

J . Med. Chem. 1996, 39, 1243-1252
1243
In h ibitor s of Acyl-CoA:Ch olester ol O-Acyltr a n sfer a se. 17. Str u ctu r e-Activity
Rela tion sh ip s of Sever a l Ser ies of Com p ou n d s Der ived fr om N-Ch lor osu lfon yl
Isocya n a te1
J oseph A. Picard,* Patrick M. O’Brien, Drago R. Sliskovic, Maureen K. Anderson,† Richard F. Bousley,†
Katherine L. Hamelehle,† Brian R. Krause,† and Richard L. Stanfield†
Departments of Medicinal Chemistry and Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research,
Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105
Received December 27, 1995X
Several series of acyl-CoA:cholesterol O-acyltransferase inhibitors were prepared by the stepwise
addition of nitrogen, oxygen, and sulfur nucleophiles to N-chlorosulfonyl isocyanate. The
(aminosulfonyl)ureas 3-44 were the most potent inhibitors in vitro, with several compounds
having IC50 values < 1 µM. Although the other series of compounds were not as potent in
vitro, many compounds did display good in vivo activity in cholesterol-fed rats. Several of the
oxysulfonyl carbamates (including CI-999, 115) showed excellent lipid-lowering activity in the
chronic in vivo screen, demonstrating significant cholesterol lowering in a pre-established
hypercholesterolemic state.
In tr od u ction
The possibility that an acyl-CoA:cholesterol O-acyl-
transferase (ACAT) inhibitor may significantly regulate
lipid levels in hypercholesterolemic animals has resulted
in extensive drug discovery efforts to identify a clinically
CI-999
effective ACAT inhibitor.2 Early work in this area
In this paper we present the full structure-activity
concentrated on identifying inhibitors of the intestinal
relationship (SAR) leading up to the identification of the
enzyme. Such inhibitors were designed to mimic fatty
novel lipid regulator CI-999 (115) and several related
acyl-CoA, the natural substrate of ACAT, and prevent
series in which we continue to elaborate the structural
the absorption of dietary cholesterol.
motif (nitrogen substituted with carbonyl and sulfonyl)
However, with the recent failure of a number of
previously identified.7,8
lipophilic inhibitors in the clinic3 (designed to inhibit
Ch em istr y
cholesterol absorption), the focus has switched from
inhibition of intestinal ACAT to inhibition of ACAT in
the liver and at the arterial wall. It has been proposed
that inhibition of ACAT in the liver would decrease
apoB secretion from the liver and also decrease the
cholesteryl ester content (and therefore the atheroge-
nicity) of plasma low-density lipoproteins (LDL).4 Ad-
ditionally, ACAT inhibition in the macrophages of the
artery wall is predicted to be beneficial by preventing
foam cell and fatty streak formation in the developing
atheroma.4a Inhibition at these peripheral sites re-
quires compounds that are well absorbed, as opposed
to the intestinal ACAT inhibitors which in general were
lipophilic and poorly absorbed. Lipophilicity and ioniza-
tion potential are two important factors that contribute
to the disposition of a drug after oral dosing.5 Our most
recent approach has been to functionalize some of our
lipophilic inhibitors to alter these physical properties,
thereby altering their ability to reach the peripheral
sites of interest.
N-Chlorosulfonyl isocyanate (2, CSI) is a very reactive
and versatile reagent whose applications have been
extensively reviewed.9 For our purposes, it provided a
convenient route to a variety of (oxy- or aminosulfonyl)-
ureas and -carbamates (Scheme 1). Reaction of an
oxygen or nitrogen nucleophile (I) at the isocyanate
moiety of CSI in an inert solvent (e.g., diethyl ether) at
0 °C gave a stable (chlorosulfonyl)carbamate or -urea
intermediate (II) in >90% yields. Reaction of II with a
second oxygen or nitrogen nucleophile in the presence
of an acid-scavenging base (e.g., triethylamine) afforded
four distinct series of compounds: (aminosulfonyl)ureas
(Table 1), (oxysulfonyl)ureas (Table 2), (aminosulfonyl)-
carbamates (Table 3), and (oxysulfonyl)carbamates
(Tables 4 and 5).
Some of the compounds in the oxysulfonyl series
(Tables 2, 4, and 5) could be synthesized by an alternate
route (Scheme 2) via an oxysulfonyl isocyanate. It has
been reported that the intermediate (chlorosulfonyl)-
carbamate IIb, formed when some phenols react with
CSI at room temperature, will rearrange at elevated
temperatures (>100 °C) to give an oxysulfonyl isocyan-
ate (III).10 This highly reactive intermediate may then
be combined with nitrogen nucleophiles to give the
(oxysulfonyl)ureas, oxygen nucleophiles to give the
(oxysulfonyl)carbamates, or sulfur nucleophiles to give
the (oxysulfonyl)carbamothioates. Additionally, com-
pounds in which the same nucleophile is added to both
sides of CSI can easily be synthesized in one step, using
2 equiv of the requisite nucleophile.
In a recent report on a series of N-carbonyl-function-
alized ureas, carbamates, and thiocarbamates (1), we
indicated the possibility that the acidic proton on the
central nitrogen atom is important for in vivo activity.6
We have also recently reported a communication de-
scribing the design and synthesis of the first water
soluble ACAT inhibitor, CI-999, in which a base addition
salt is formed at a central acidic site.7
† Department of Atherosclerosis Therapeutics.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
0022-2623/96/1839-1243$12.00/0 © 1996 American Chemical Society

1244 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Sch em e 1. Stepwise Addition of Nucleophiles to CSI
Picard et al.
2
Sch em e 2. Alternate Route to Oxysulfonyl Compounds
2
Sch em e 3. Functionalization of the Central Nitrogen Atom
Members of these series possess an acidic proton on
the nitrogen atom situated between the carbonyl and
sulfonyl groups. The acidic nature of this proton allows
the formation of base addition salts (IV) or treatment
of the anion with alkylating agents to give N-alkylated
products (V; Scheme 3).
diisopropylphenyl group imparts good ACAT inhibitory
activity to a variety of amides, ureas, and carbamates.2b
In order to identify potent ACAT inhibitors in the
compounds of the present work, we incorporated the 2,6-
diisopropylphenyl group into each of the series of
compounds examined.
Table 1 shows a series of (aminosulfonyl)ureas (X )
N, Y ) N) with in vitro potencies between 0.1 and 69
µM. The most potent compounds (IC50 < 1.0 µM) were
those which contained the (2,6-diisopropylphenyl)urea
in combination with an (N,N-dialkylamino)sulfonyl
group (e.g., 14-16, 18-20, and 22-26). Compounds
in which the N,N-dialkylamino group contains six
carbon atoms or less (3-13) are less potent than the
longer chain analogues. In addition, in vitro potency
decreased when the number of carbons in the N,N-
dialkylamino group exceeded 15 (30-33). The excep-
tions to these trends are compound 21 (with an N-me-
thyl, N-octyl substitution pattern), which falls within
the optimal rnage of carbon atoms but is about 10-fold
less potent than other compounds within the range, and
compound 32 (with a N,N-didecylamino group), which
displayed an unexpected potency of 0.72 µM despite
having a total of 20 carbon atoms in its N,N-dialkyl-
amino group. Branching of the alkyl groups (especially
R to the nitrogen atom) resulted in increased in vitro
potency, as seen by comparing 14 and 20 to their n-alkyl
isomers 10 and 16.
Aminosulfonyl compounds with aryl or aryl-substi-
tuted alkyl substituents (34-42) were not very potent
in vitro. Compound 41 however, which possessed a
benzyl moiety as one of the groups on the aminosulfonyl
and an isopropyl as the other group, did display good
potency in vitro (0.40 µM), presumably due to the
branched alkyl group. Compounds 43 and 44 (where
the 2,6-diisopropylphenyl group is incorporated into the
aminosulfonyl side of the molecule) are 7-fold less potent
in vitro, compared to the corresponding (2,6-diisopro-
pylphenyl)urea isomers 39 and 35. The importance of
the ionizable proton on the central nitrogen of these
molecules is indicated by compounds 17 and 18. The
central nitrogen of compound 16 was methylated to give
compound 17, which abolished the in vitro and in vivo
Biology
The in vitro ACAT inhibitory activity was determined
by measuring the incorporation of [1-14C]oleoyl-CoA into
cholesterol esters in microsomes isolated from rat liver.
Results are reported as the micromolar concentration
of drug required to inhibit the enzymatic activity by 50%
(IC50).11 The in vivo hypocholesterolemic activity was
measured in an acute, cholesterol-fed rat model. This
acute screen measures the ability of a single dose of drug
to prevent the rise in plasma cholesterol induced by a
single cholesterol-rich meal (5.5% peanut oil, 1.5%
cholesterol, and 0.5% cholic acid). The drugs were
administered by gavage at a dose of 30 or 3 mg/kg, and
the animals (n ) 5/group/cage) were then fed the test
diet overnight. Plasma cholesterol levels were mea-
sured by standard enzymatic methods, and the results
are expressed as the percent change from the levels
observed in control animals given vehicle (CMC/Tween
in water) and diet only.11
Compounds which showed good potency in the acute
in vivo screen were tested in a chronic screen which
measured the drugs ability to affect a pre-established
hypercholesterolemic state (Table 6). In the chronic
screen, rats were fed the cholesterol-rich diet, described
above, for 1 week to elevate plasma cholesterol levels.
The 30 mg/kg dose of drug was then given daily by
gavage for a second week while continuing the choles-
terol-rich diet. Total plasma cholesterol (TC) levels were
measured, and the concentration of plasma high-density
lipoproteins (HDL) was calculated. The results were
compared to control animals given only vehicle and the
cholesterol-rich diet for 2 weeks.11
Resu lts a n d Discu ssion
In several previous series of ACAT inhibitors devel-
oped in our laboratories, we demonstrated that the 2,6-

ACAT Inhibitors From N-Chlorosulfonyl Isocyanate
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1245
Ta ble 1. (Aminosulfonyl)ureas
acute in vivo (% ∆TC)
compd
R
R1
R2
R3
R4
in vitro IC50 (µM)b 30 mg/kg
3 mg/kg
formulad
mp (°C)
3
4
5
6
7
H
2,6-(i-Pr)2Rh
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
Et
Me
i-Pr
Et
3.9
18
2.5
15
2.3
2.1
2.7
1.1
1.2
8.1
NT
-17
-19*
NT
NT
NT
NT
-37**
NT
C15H25N3O3S
C16H27N3O3S
C17H29N3O3S
C17H27N3O3S
C18H31N3O3S
C18H29N3O3Se
C19H29N3O3S
C19H33N3O3S
C19H33N3O3Sf
C19H33N3O3S
C18H29N3O3S
C19H33N3O3S
144-147
177-179
139-142
153-155
109-110
124-128
142-145
119-121
101-104
161-162.5
159-161
151-153
146-147
98-101
H
H
H
H
H
H
H
H
H
H
H
H
H
-(CH2)4-
-49***
-56****
-48***
-67****
-60****
-70****
-19*
Me
Et
allyl
n-Pr
Et
n-Bu
allyl
allyl
n-Pr
n-Bu
n-hexyl
8
9
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
-51***
-29*
NT
NT
NT
H
-(CH2)5-
17
-13
i-Pr
i-Pr
i-Pr
t-Bu
n-Bu
n-Bu
n-Bu
i-Bu
s-Bu
n-octyl
cyclohexyl
n-pentyl
i-pentyl
n-hexyl
cyclohexyl
0.24
0.14
0.36
-59c ****
-17****
-55**** C20H35N3O3S
n-Bu
n-Bu
n-Bu
i-Bu
s-Bu
Me
-66c **** -52***
C21H37N3O3S
Me 2,6-(i-Pr)2Ph
>5.0
-8
NT
C22H39N3O3Sg
oil
Na+ 2,6-(i-Pr)2Ph
0.53
0.42
0.10
3.8
-68****
-75****
-71****
-59***
-68****
-76****
-60****
-77****
-64****
-53***
-30**
-64**** C21H36NaN3O3Sh 217-219
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
CH2Ph
-61**** C21H37N3O3S
-65**** C21H37N3O3S
-57**** C22H39N3O3S
-60**** C22H37N3O3S
-68**** C23H41N3O3S
-66**** C23H41N3O3S
-63**** C25H45N3O3S
-60**** C25H41N3O3S
-45***
NT
-65**** C28H51N3O3S
-38**
-18
-17
NT
NT
NT
NT
NT
-27***
-18*
-38*
NT
-17
NT
-5
122-125
144-146
oil
162-164
93-95
106-110
70-73
163-165
oil
i-Pr
0.36
0.42
0.42
0.51
0.23
1.7
55
0.33
1.9
n-pentyl
i-pentyl
n-hexyl
cyclohexyl
CH2-2-THFa CH2-2-THFa
(CH2)3N(Me)2 (CH2)3N(Me)2
C23H37N3O3S
C23H43N5O3S
oil
Me
n-octyl
Me
n-decyl
n-dodecyl
H
H
H
H
Ph
n-tetradecyl
n-octyl
n-octadecyl
n-decyl
n-dodecyl
2,6-(i-Pr)2Ph
benzhydryl
9-fluorene
CH2CH(Ph)2
Ph
-65****
-53****
-60***
-57****
5
49-52
C29H53N3O3S
C32H59N3O3S
C33H61Ni3O3Sii
C37H69N3O3S
C25H37N3O3S
C26H30N3O3S
C26H28N3O3S
C27H32N3O3S
C25H29N3O3S
C27H33N3O3S
C22H31N3O3S
C23H33N3O3S
C24H34N3O3S
C27H33N3O3S
C26H30N3O3S
70-72
1.9
0.72
59-59
35-37
69
11
4.1
25
5.9
16
2.2
1.7
0.40
10.4
16
30
oil
-54c ****
-14c
169-172
182-185
224-227
190-191
169-170
123-126
128-133
142-144
154-159
140-142
92-95
-4c
-20c *
-37**
CH2Ph
Me
i-Pr
CH2Ph
(CH2)2Ph
CH2Ph
-36**
-71****
-60c ****
-67****
-44**
4-Ph-piperidine
CH2Ph
benzhydryl
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
H
NT
a
b
d
THF ) tetrahydrofuryl. In vitro ACAT Inhibition determined in rat liver microsomes. c Dosed at 50 mg/kg. C,H,N analysis within
0.4% unless otherwise noted. e C: calcd, 58.83; found, 59.50. f C: calcd, 62.08; found, 62.75. C: calcd, 59.50; found, 59.95. N: calcd,
9.69; found, 8.74. C: calcd, 59.50; found, 59.95. *Significantly different from control using the unpaired, two-tailed t-test: p < 0.1, **p
< 0.01, ***p < 0.001, and ****p < 0.0001. NT ) not tested.
g
h
i
activity. Conversely, ionization of the proton of this
central nitrogen, as in the sodium salt 18, retained in
vitro potency and in vivo efficacy.
potent in vitro than the (aminosulfonyl)ureas discussed
above. Surprisingly, some of the compounds in this
series possessed good in vivo efficacy despite having IC50
values in the micromolar range. The (2,6-diisopropyl-
phenyl)urea, in combination with a long chain alkoxy-
sulfonyl group, gave maximum in vitro and in vivo
potency with a chain length of 12 carbon atoms (49).
Compound 50 demonstrated that the generation of the
base addition salt at the acidic central nitrogen had no
adverse effect on the biological profile in this series.
Incorporating an (aryloxy)sulfonyl group with the (2,6-
diisopropylphenyl)urea moiety also gave efficacious
compounds (52 and 53). Incorporation of the 2,6-
diisopropylphenyl group into the oxysulfonyl portion of
the molecule and the alkyl group into the urea half (54)
resulted in a much less efficacious compound in vivo.
Like the (aminosulfonyl)urea compounds (Table 1),
the (N,N-dialkylamino)sulfonyl substitution pattern also
gave the most potent compounds in the (aminosulfonyl)-
carbamate series (Table 3). However, the (aminosulfo-
nyl)carbamates were typically 1 order of magnitude less
potent than the corresponding urea compounds. The
in vitro potency of the (N,N-dialkylamino)sulfonyl com-
Several compounds in this series were very efficacious
in the acute in vivo screen, with changes in total plasma
cholesterol up to -77% when dosed at 30 mg/kg. An
examination of these compounds at lower doses estab-
lished the superiority of several examples. The (N,N-
dialkylamino)sulfonyl compounds (i.e., 15 and 18-26),
which were the most potent compounds in vitro, also
demonstrated the best potency in vivo, with changes in
total cholesterol ranging from -55% to -68% when
dosed at 3 mg/kg in the acute screen. Several of these
potent (N,N-dialkylamino)sulfonyl compounds (19, 20,
and 22-25) were also effective in the chronic in vivo
screen, with 62-69% decreases in total cholesterol,
coupled with 86-207% increases in HDL cholesterol
(Table 6).
Replacing the aminosulfonyl group with an oxysul-
fonyl gave the series of (oxysulfonyl)ureas 45-54 shown
in Table 2. Although the (2,6-diisopropylphenyl)urea
functionality was maintained, the most potent com-
pounds in this series were 1 order of magnitude less

1246 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ta ble 2. (Oxysulfonyl)ureas
Picard et al.
acute in vivo (% ∆ TC)
compd
R
R1
R2
R3
in vitro IC50 (µM)a
30 mg/kg
3 mg/kg
formulab
mp (°C)
45
46
47
48
49
50
51
52
53
54
H
H
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,5-(i-Pr)2Ph
2,4,6-(i-Pr)3Ph
s-Bu
H
H
H
H
H
H
H
H
n-hexyl
2-octyl
n-decyl
2-dodecyl
n-dodecyl
n-dodecyl
n-octadecyl
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
27
35
>10
16
6.8
5
14
8.7
23
12
-56***
-51**
-31*
-8
C19H32N2O4S
C21H36N2O4S
C23H40N2O4S
C25H44N2O4S
C25H44N2O4S
C25H43N2O4SNa
C31H56N2O4S
C25H36N2O4S
C28H42N2O4S
C21H36N2O4Sc
148-151
109-113
133-135
110-112
112-115
foam
+10
NT
-68***
-75****
-60****
-42**
-43*
-48***
-53****
-34****
-5
-1
-51***
NT
H
Na+
H
95-98
H
H
H
186-189
202-203
oil
H
s-Bu
-68****
-20
a
b
In vitro ACAT inhibition determined in rat liver microsomes. C, H, N analysis within 0.4% unless otherwise noted. c C: calcd, 61.13;
found, 60.57. *Significantly different from control using the unpaired, two-tailed, t-test: p < 0.1, **p < 0.01, *** p < 0.001, and ****p
< 0.001. NT ) not tested.
Ta ble 3. (Aminosulfonyl)carbamates
acute in vivo (% ∆ TC)
in vitro
compd
R
R1
R2
R3
IC50 (µM)b 30 mg/kg
3 mg/kg
formulad
mp (°C)
55
56
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
-(CH2)4-
-(CH2)5-
53
>100
-53***
-11
-4
NT
C17H26N2O4S
C18H28N2O4S‚
0.5H2Oe
89-91
86-88
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
H
H
H
H
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr02Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
-(CH2)2O(CH2)2-
>100
>100
43
15
21
1.9
1.9
5.1
22
1.3
4.2
58
12
58
20
38.1
25.8
52
10.6
49
11
19
16.8
11.4
4.6
21.8
3.2
19.4
3.2
18
2.2
4.3
2.7
89
164
21
31
31
23.4
13.5
11.5
24.4
15
-14
NT
NT
-31**
C17H26N2O5S
185-187
N-Me-piperazine‚HCl
indoline
i-Pr
-21*
C18H29N3O4S‚HClf 179 dec
-77****
-76****
-58****
-57****
-66****
-60****
-60****
-74****
-62****
-70****
-70****
-67****
-43****
-55c ****
-65c ****
8c
C21H26N2O4S
127-128
126-131
105-106.5
94-97
i-Pr
H
n-Bu
n-Bu
i-Pr
Me
-65**** C19H32N2O4S
n-hexyl
n-Bu
n-Bu
cyclohexyl
n-octyl
n-pentyl
n-hexyl
n-octyl
CH2Ph
Ph
CH2Ph
Ph
2,6-(i-Pr)2Ph
2-benzimidazole
benzhydryl
CH2CH(Ph)2
CH2Ph
-12
C19H32N2O4S
-47**** C21H36N2O4S
-64**** C21H35N2O4SNa
-49**** C22H36N2O4Sg
-57**** C22H38N2O4S
-66**** C23H40N2O4S
-74**** C25H44N2O4S
-67**** C29H52N2O4S
-59**** C23H32N2O4S
-46**** C25H28N2O4S
Na+ 2,6-(i-Pr)2Ph
162-166
133-135
32-35
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(t-Bu)2Ph
2,6-(t-Bu)2Ph
2,6-(t-Bu)2Ph
2,6-(t-Bu)2Ph
n-pentyl
n-hexyl
n-octyl
i-Pr
69-70
57-61
64-67
156-159
149-151
143-146
165-168
154-159
159-162
185-187
103-105
182-183
169-172
180-181
162-166
175-178
147-150
198-199
123-128
134-135
65-68
Ph
CH2Ph
H
H
H
H
H
CH2Ph
H
H
H
H
H
i-Pr
H
n-Bu
Me
-17**
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
-10
NT
1
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
NT
-29*
-15
NT
NT
NT
NT
C27H32N2O4S
C19H24N2O4S
C25H36N2O4S
C20H24N4O4S
C26H30N2O4S
C27H32N2O4S
C29H36N2O4Sh
C21H28N2O4S
C27H40N2O4Si
C28H34N2O4S
C29H36N2O4S
C29H36N2O4Sj
C22H38N2O4S
C22H38N2O4S
C24N42N2O4S
C25H44N2O4S
C26H46N2O4S
C28H50N2O4S
C32H58N2O4S
C36H66N2O4S
C26H48N4O4S
C26H42N2O6S
C24H36N3ClO4Sk
C24H34N3O4SNa
C22H30N2O4S
C28H42N2O4S
C29H36N2O4S
C30H38N2O4S
C28H42N2O5S
C30H38N2O5S
C31H32N2O4S
C14H22N2O4S
C25H44N2O4S
C22H38N2O7S
46c ***
-29c **
-3c
Ph
-26c ***
-57c ****
-35c **
4
2,6-(i-Pr)2Ph
benzhydryl
banzhydryl
CH2CH(Ph)2
i-Pr
n-hexyl
n-Bu
Me 2,6-(t-Bu)2Ph
H
H
H
H
H
H
H
H
H
H
H
H
2,6-(t-Bu)2Ph
-32c *
-19*
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
-52***
-4
n-octyl
-55**
-42**
-40**
0
n-pentyl
n-hexyl
n-octyl
n-decyl
n-pentyl
n-hexyl
n-octyl
107-108
66-68
53-55
n-decyl
-4
63-65
(CH2)3N(Me)2 (CH2)3N(Me)2
-13
oil
CH2-2-THFa
CH2-2-THFa
(CH2)2-2-pyridyl‚HCl
(CH2)2-2-pyridyl
Ph
2
108-111
178-181
133-136
186-188
176-178
150-152
142-144
155-158
132-138
166-168
152-155
82-84
Me
Me
H
H
H
H
H
H
H
-10
-22*
Na+ 2,6-(t-Bu)2-4-Me-Ph
H
H
H
H
H
H
H
H
H
H
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-Me-Ph
2,6-(t-Bu)2-4-MeO-Ph
2,6-(t-Bu)2-4-MeO-Ph
2,6-(Ph)2Ph
Me
n-dodecyl
n-dodecyl
-33c ****
-56c ****
-42c ****
-54c ****
-77****
-55****
-39**
NT
2,6-(i-Pr)2Ph
benzhydryl
CH2CH(Ph)2
2,6-(i-Pr)2Ph
CH2CH(Ph)2
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,4,6-(MeO)3Ph
82
>25
H
H
H
>100
33
0
-8
30
133-136
a
b
d
THF ) tetrahydrofuran. In vitro ACAT inhibition determined in rat liver microsomes. c Dosed at 50 mg/kg. C,H,N analysis within
0.4% unless otherwise noted. e N: calcd, 10.00; found 8.68. f N: calcd, 7.42; found 6.98. C: calcd, 62.23; found, 62.65. C: calcd, 68.47;
found, 68.05. C: calcd, 66.36; found, 65.75. C: calcd, 68.47; found, 67.98. C: calcd, 57.87; found, 57.32. *Significantly different from
g
h
i
j
k
control using the unpaired, two-tailed, t-test: p < 0.1, **p < 0.01, ***p < 0.001, and ****p < 0.0001. NT ) not tested.

ACAT Inhibitors From N-Chlorosulfonyl Isocyanate
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1247
Ta ble 4. Oxysulfonyl O-Aryl Carbamates and S-Aryl Thiocarbamates
acute in vivo (% ∆ TC)
compd
X
R
Ar
R1
in vitro IC50 (µM)a 30 mg/kg
3 mg/kg
formulab
mp (°C)
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
n-hexyl
n-dodecyl
n-hexadecyl
Ph
2,4-F2Ph
40
13
10.3
-52**
-18*
C19H31NO5S
C25H43NO5Sc
C29H51NO5S
C19H23NO5Sd
C19H21F2NO5S
110-111
69-72
H
H
H
H
H
H
H
H
H
-68****
-60****
-26**
-63****
-42****
NT
69-72
>50
100-104
78-81
>50
-11
NT
NT
2,6-F2Ph
38
9
C19H21F2NO5Se 137-142
2,6-(Me)2Ph
2,6-(MeO)2Ph
2,4,6-(MeO)3Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(t-Bu)2Ph
2,4,6-(i-Pr)3Ph
2,6-(i-Pr)2-4-OH-Ph
>50
>50
>50
9.4
5.3
50
50
29
>50
95
52
90
7.7
14
22
12
30
48
-58**
-37**
-63****
-37**
-54****
-59****
-18
-46***
-63****
NT
-14
-41***
-15
-52****
-57****
-32****
-50***
NT
C21H27NO5S
C21H27NO7S
C22H29NO8S
C25H35NO5S
134-137
132-133
130-132
132-133.5
-70****
-61***
-70****
-74****
-64****
-55****
-67****
-15*
Na+ 2,6-(i-Pr)2Ph
C25H34NO5SNa 252-255
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(t-Bu)2-4-Me-Ph n-hexyl
2,6-(t-Bu)2-4-Me-Ph n-dodecyl
2,6-(t-Bu)2-4-Me-Ph Ph
C26H37NO5S
C27H39NO5S
C28H41NO5S
C25H35NO6Sf
C22H37NO5S
C28H49NO5S
C22H29NO5S
C28H41NO5S
C28H41NO5S
C31H47NO5S
C27H39NO5Sg
C29H43NO5S
C25H43NO4S2
C25H35NO4S2
95-101
173-176
126-128
oil
118-121
85-87
-56****
-65****
-65****
-72****
-79****
-65****
-70****
-18*
122-125
140-142
122-123
144-146
109-114
195-197
83-84
2,6-(t-Bu)2-4-Me-Ph 2,6-(i-Pr)2Ph
2,4,6-(i-Pr)3Ph
2,4,6-(i-Pr)3Ph
2,6-(t-Bu)2Ph
2,6-(t-Bu)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,6-(i-Pr)2Ph
2,4,6-(i-Pr)3Ph
2,6-(i-Pr)2Ph
2,6-(t-Bu)2Ph
n-dodecyl
-9
-17*
NT
NT
h
S
2,6-(i-Pr)2Ph
8.7
92-94
a
b
In vitro ACAT inhibition determined in rat liver microsomes. C,H,N analysis within 0.4% unless otherwise noted. c C: calcd, 63.93;
found, 62.61. C: calcd, 60.46; found, 59.78. e C: calcd, 55.20; found, 54.77. f C: calcd, 62.87; found, 62.26. N: calcd, 2.86; found, 2.38.
N: calcd, 2.93; found, 2.42. *Significantly different from control using the unpaired, two-tailed, t-test: p < 0.1, **p < 0.01, ***p <
0.001, and ****p < 0.0001. NT ) not tested.
d
g
h
pounds was examined in the 2,6-diisopropylphenyl
carbamates 55-76 as well as for a series of 2,6-di-tert-
butyl-4-methylphenyl carbamates (83-98). As in the
(aminosulfonyl)ureas, the most potent compounds were
those in which the number of carbons in the alkyl chains
of the (N,N-dialkylamino)sulfonyl group totaled more
than six but less than 16 (62-68 and 85-88). The in
vitro activities of the 2,6-di-tert-butyl-4-methylphenyl
carbamates 83-98 parallelled the activity observed with
the 2,6-diisopropylphenyl carbamates except that the
(N,N-diisopropylamino)sulfonyl group gave in vitro
potency when coupled with a 2,6-di-tert-butyl-4-meth-
ylphenyl carbamate (83) but not when coupled with a
2,6-diisopropylphenyl carbamate (60). Interestingly, the
(N-methyl-N-octylamino)sulfonyl group, which was un-
expectedly inactive in the (aminosulfonyl)urea series,
was also inactive in this series (65 and 86). As in the
(aminosulfonyl)ureas, incorporation of an aryl or aryl-
substituted alkyl substituent into the aminosulfonyl
group (69-82 and 92-101) resulted in a decrease in
the in vitro activity. Replacement of the aryl carbamate
with an alkyl carbamate (102-104) also resulted in no
significant in vitro or in vivo activity.
The in vivo activity of this series reveals some
interesting results. Despite being roughly 1 order of
magnitude less potent in vitro, the 2,6-diisopropylphenyl
carbamates 55-76 show a similar in vivo activity profile
as observed in the corresponding (2,6-diisopropylphen-
yl)ureas (Table 1). Indeed, several of the 2,6-diisopro-
pylphenyl carbamates possessing the (N,N-dialkylami-
no)sulfonyl group (60 and 62-68) were very potent in
the acute in vivo screen and also demonstrated excellent
efficacy in the chronic in vivo screen. Inexplicably,
within this series, the corresponding 2,6-di-tert-butyl-
4-methylphenyl carbamates 83-98 possessed no in vivo
potency, although they were just as potent in vitro as
the corresponding 2,6-diisopropylphenyl carbamates
55-76.
The 2,6-diisopropylphenyl carbamate group that gave
excellent in vivo activity in the (aminosulfonyl)carbam-
ates (Table 3) was included in several examples of
(oxysulfonyl)carbamates (105-119; Table 4). Several
compounds in this series possessed in vitro IC50 values
in the micromolar range yet possessed excellent efficacy
in the acute and chronic in vivo screens (e.g., 106, 112,
114, 118, 121, 123, 124, and 126). For the alkoxysul-
fonyl examples 105-107, the long chain (i.e., dodecyl
and hexadecyl) compounds were two of the more potent
examples in vitro, in this series. In addition, they
possessed good efficacy in vivo. Compounds in which
the oxysulfonyl group was an unsubstituted phenyl
(108) or a phenyl substituted with fluorine atoms (109
and 110) possessed no significant activity in vitro or in
vivo. As larger substituents were incorporated onto the
phenoxysulfonyl group (i.e., CH3, CH3O, i-Pr, and t-Bu),
modest in vitro potency was observed in combination
with good in vivo efficacy. The (2,6-diisopropylphenoxy)-
sulfonyl compound 114 gave exceptional in vivo potency.
In this series, as in those previously discussed, methyl-
ation of the nitrogen atom in the center of the molecule
(116) had a detrimental effect on the activity profile,
while formation of the base addition salt at the nitrogen
atom (115) had little effect on the activity profile. Four
2,6-di-tert-butyl-4-methylphenyl carbamate examples
(120-123) were examined and displayed similar activity
patterns to the corresponding 2,6-diisopropylphenyl
carbamates 105, 106, 108, and 114. The (2,6-diisopro-
pylphenoxy)sulfonyl compound 123 displayed good in

1248 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ta ble 5. [(2,6-Diisopropylphenoxy)sulfonyl]carbamates
Picard et al.
acute in vivo (% ∆ TC)
compd
R
R1
in vitro IC50 (µM)a
30 mg/kg
3 mg/kg
formulab
C14H21NO5Sc
15H23NO5S
C15N22NO5SNa‚0.5H2O
mp (°C)
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
H
H
Me
Et
Et
2-octyl
n-dodecyl
cyclohexyl
1-adamantyl
2-adamantyl
(()-menthyl
>100
>50
>50
26
NT
-14*
17
-32*
-62****
-38***
-10
NT
NT
NT
NT
1
NT
NT
NT
NT
NT
-29**
NT
NT
NT
NT
NT
92-95
72-74
C
Na+
H
230-239
74-76
C
C
C
C
C
C
21H35NO5S
25H43NO5Sd
19H29NO5S
23H33NO5S
23H33NO5S
23H37NO5S
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
13
38
13
23
32-35
119-121
foam
-36*
-40**
-35**
-70****
-2
185-187
115-117
115-118
122-126
150-155
137-139
121-125
143-146
113-115
93-97
21
trans-2,6-(i-Pr)2-cyclohexyl
cis-2,6-(i-Pr)2-cyclohexyl
3-pyridyl
5.7
3.6
>50
>50
97
>50
65
66
>50
20
>50
>50
49
C25H41NO5S
C25H41NO5S
C
C
C
18H22N2O5S
19H22FNO5S
19H22ClNO5S
4-FPh
4-ClPh
2,4-F2Ph
2,6-F2Ph
F5Ph
2,6-Me2Ph
-21**
-8
-5
C19H21F2NO5S
C19H21F2NO5S
C19H18F5NO5S
C21H27NO5S
C24H33NO5S
C23H31NO5S
-27
-5
NT
NT
NT
NT
NT
NT
-37**
-2
97-100
57-61
2,6-Et2PhCH2
2,3,5,6-Me4Ph
-17*
-37*
-15
120-128
143-145
114-116
151-153
200-204
87-92
H
H
H
2-(i-Pr)Ph
C
C
23H29NO5S
24H33NO5S
2-(t-Bu)-6-Me-Ph
2,6-(MeO)2Ph
2,6-(MeO)2Ph
2,4,6-(MeO)3Ph
2,4-(i-Pr)2Ph
>50
48
-61***
-49***
-5
-4
C21H27NO7S
C21H26NO7SNa
C22H29NO8S
Na+
H
-12
>25
>50
8.8
>25
>50
31
NT
H
H
H
H
H
H
H
H
6
NT
C25H35NO5S
95-98
146-148
81-83
2,6-(i-Pr)2-4-(t-Bu)Ph
2,6-(i-Pr)2-4-(MeO)Ph
2,6-(i-Pr)2-4-(NO2)Ph
2,6-(i-Pr)2-4-Br-Ph
2,6-(i-Pr)2-4-Cl-Ph
2,6-(i-Pr)2-4-F-Ph
2,6-(i-Pr)2-4-(OH)Ph
2,6-(i-Pr)2-4-(MeCO)Ph
2,3,5,6-(i-Pr)4-4-F-Ph
2,6-(t-Bu)2-4-(MeO)Ph
2,6-(t-Bu)2-4-(MeO)Ph
2,4,6-(t-Bu)3Ph
2,6-(t-Bu)2-4-(CH2N(Me)2)Ph
2,6-(Ph)2Ph
-58***
-56****
18
-55***
1
NT
NT
NT
NT
C29H43NO5Se
C26H37NO6Sf
C25H34N2O7S
C25H34BrNO5S
C25H34ClNO5S
C25H34FNO5S
C25H35NO6S
124-127
117-120
108-111
161-163
oil
164-167
155-158
137-139
276-279
149-150
125-130
140-142
-29*
42
2
>50
>50
41.8
13
4.8
10
26
22
12
-72****
-55****
-16
-71****
-72****
-60****
-76****
2
-5
NT
H
H
H
C27H37NO6S
C31H46FNO5S
C28H41NO6S
C28H40NO6SNa
C31H47NO5S
C30H46N2O5S
C31H31NO5S‚C4H10O
-47****
-58****
-42***
-69****
NT
Na+
H
H
H
-46***
NT
a
b
In vitro ACAT inhibition determined in rat liver microscomes. C,H,N analysis within 0.4% unless otherwise noted. c N: calcd, 4.44;
found, 3.80. N: calcd, 2.98; found, 2.45. e N: calcd, 2.71; found, 2.29. f C: calcd, 63.52; found, 64.06. *Significantly different from control
d
using the unpaired, two-tailed t-test: p < 0.1, **p < 0.01, ***p < 0.001, and ****p < 0.0001. NT ) not tested.
vitro activity coupled with exceptional in vivo efficacy.
The (2,6-diisopropylphenoxy)sulfonyl group gave similar
results when coupled to two other aryl carbamates (124
and 126). With these aryl carbamates, deviating from
the (2,6-diisopropylphenoxy)sulfonyl group (125 and
127) resulted in a decrease in in vivo potency.
A comparison of the S-aryl thiocarbamates 128 and
129 with the corresponding O-aryl carbamates 106 and
114 demonstrated that the replacement of an oxygen
atom by a sulfur atom led to a significant loss of in vivo
activity.
The excellent efficacy observed with the (2,6-diiso-
propylphenoxy)sulfonyl carbamates 114-116, 123, 124,
and 126 prompted us to examine a variety of carbamate
groups while keeping the (2,6-diisopropylphenoxy)-
sulfonyl group constant (Table 5). Several alkyl and
cycloalkyl carbamates (130-140) were synthesized. The
n-dodecyl carbamate 134 and some of the cycloalkyl
carbamates (136, 139, and 140) possessed modest in
vitro potency, but none of these compounds displayed
the excellent in vivo efficacy shown above in the aryl
carbamates (Table 4). The 3-pyridyl carbamate 141 and
several halogenated phenyl carbamates (142-146) were
completely inactive both in vitro and in vivo. Surpris-
ingly, several alkyl- and alkoxyphenyl carbamates
(147-155) were also inactive in vitro and in vivo. The
striking difference between these phenyl carbamates
and the extremely efficacious examples (114, 123, 124,
and 126; Table 4) is the absence of large (isopropyl or
tert-butyl) substituents in the 2- and 6-positions. It is
interesting to note that the 2,6-diethyl compound 148
and the large 2,6-diphenyl compound 169 gave some
activity in vitro but not in vivo, indicating a lower and
upper limit to the size of the 2,6-disubstituents. It was
also shown that neither the 2-isopropyl (150) or the
2-tert-butyl, 6-methyl (151) substitution patterns gave
good activity. A pair of ‘flanking’ isopropyl or tert-butyl
groups apparently are required for good efficacy and
potency. The 2,6-diisopropyl substitution pattern in
combination with an electron-withdrawing group in the
4-position (158-161) produced inactive compounds,
with the exception of the 4-fluoro compound 161 which
was very efficacious in vivo. Interestingly, the addition
of two more isopropyl groups to the 3- and 5-positions

ACAT Inhibitors From N-Chlorosulfonyl Isocyanate
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1249
Ta ble 6. Chronic Hypocholesterolemic Effect of Selected
Compounds in Cholesterol-Fed Rats
with an electron-withdrawing fluorine atom in the
4-position (164) retained the in vivo efficacy while also
improving the in vitro potency. Alkyl groups are
tolerated in the 4-position (156 and 167), while polar
groups such as hydroxy (162) or (dimethylamino)-
methylene (168) are not. Inexplicably, a 4-methoxy
substituent completely abolished the in vitro and in vivo
activity of the 2,6-diisopropylphenyl series (157) but
gives a very potent and efficacious compound in the 2,6-
di-tert-butylphenyl series (165).
compd
% ∆ TC
% ∆ HDL
10
14
15
16
18
19
20
21
22
23
24
25
26
27
29
30
34
38
39
40
41
49
50
51
52
53
60
62
63
64
65
66
67
-53***
-38***
-48*
78
83
43
167
82
122
86
123
94
193
133
207
92
123
19
150
80
-40****
-52***
-62***
-62**
-64***
-63**
-67****
-68****
-69****
-35**
-56**
-51*
-56****
-37***
-36*
-28**
-45***
-41****
-52**
-55***
-38*
Con clu sion
Some general trends are observed in the five series
of compounds presented here. In the two series of
aminosulfonyl compounds (Tables 1 and 3), the (N,N-
dialkylamino)sulfonyl group gave the most potent and
efficacious compounds in vitro and in vivo. Optimal
potency was observed when the total number of carbon
atoms in the (N,N-dialkylamino)sulfonyl group was
between 6 and 16 and especially if the alkyl chains were
branched. A comparison of the (2,6-diisopropylphenyl)-
urea compounds in Table 1 to the corresponding 2,6-
diisopropylphenyl carbamate analogues in Table 3
reveals a distinct difference in in vitro activity. Each
(aminosulfonyl)carbamate was roughly 1 order of mag-
nitude less potent in vitro than the corresponding
(aminosulfonyl)urea, although the in vivo efficacy of the
compounds in the two series was similar (cf. 14 and 60,
16 and 63, 25 and 67, etc.). Inexplicably, the N-
methyloctylamine group had a significantly negative
effect on the in vitro activity in both the ureas (21) and
carbamates (65 and 86).
Unlike the aminosulfonyl compounds, in the two
series of oxysulfonyl compounds, the activity of the
ureas (Table 2) was very similar to the activities
observed in the carbamates (Table 4). Compounds
containing the (n-dodecyloxy)sulfonyl (i.e., 49, 106, and
121) or the (2,6-diisopropylphenoxy)sulfonyl (i.e., 52, 53,
114, 123, 124, and 126) groups gave the best potency
in vitro and in vivo. Replacement of an oxygen in the
(oxysulfonyl)carbamate series by a sulfur atom was not
tolerated (cf. 128 and 106, 129 and 114).
Overall, alkylation of the central nitrogen atom
resulted in a significant loss of activity. This same
result has also been observed in a structurally similar
series of acylurea and -carbamate6 and sulfonylurea8
ACAT inhibitors. Conversely, generation of the sodium
salt had very little effect on the biological activity, while
it did increase the aqueous solubility of the compounds.
The (aminosulfonyl)ureas (Table 1) are the only series
of compounds presented here which possessed signifi-
cant in vitro potency, coupled with good in vivo efficacy
in cholesterol-fed rats. Three other series of compounds
(Tables 2-5) only gave modest potency in vitro (>1.0
µM), although excellent in vivo effects were obtainable
in each of the series. One possible explanation for the
lack of correlation between ACAT inhibition in vitro and
hypocholesterolemic activity in vivo is that ACAT
inhibition may not be the primary mechanism by which
these drugs are acting. To search for other possible
mechanisms of action, compound 115 was tested and
found to be inactive against several acyltransferases and
other enzymes involved in lipid metabolism (i.e., acyl-
CoA:monoglyceride acyltransferase, lecithin:cholesterol
acyltransferase, acyl-CoA:retinol acyltransferase, car-
nitine acyltransferase, pancreatic cholesterolester hy-
170
183
43
150
67
11
-30
-43**
-59****
-59**
-72****
-69****
-71**
-64**
-73****
-75**
-80**
-69****
-37*
5
18
82
113
109
188
88
166
144
156
114
320
240
388
200
50
156
100
144
86
31
208
62
345
233
295
23
205
153
129
25
177
-8
143
95
208
380
108
108
21
68
69
70
72
73
79
80
96
-33
-9
-28*
-46*
-38***
-25*
97
98
99
-51**
-47***
-56*
106
112
113
114
115
118
121
123
124
125
126
156
157
161
162
164
165
166
167
169
-62**
-37*
-68***
-64*
-61****
-33*
-66**
-74****
-62****
-64**
-72**
-12
-52**
-25
-74**
-76***
-62***
-78****
-38*
a
Significantly different from control using the unpaired, two-
tailed t-test: p < 0.1, **p < 0.01, ***p < 0.001, and ****p < 0.0001.
drolase, hepatic lipase, and HMG-CoA reductase).12
However, the involvement of ACAT inhibition is further
supported by the fact that 115 inhibits cholesterol
absorption in a rat lymph-fistula model.4c In this model,
the lymphatic transport of ACAT-derived cholesterol
esters was inhibited 50-60% after a single 10 mg/kg
dose of 115.
To date, ACAT inhibition remains our best explana-
tion for the dramatic in vivo lipid-regulating effects

1250 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Picard et al.
mL of diethyl ether at -15 °C under an atmosphere of
nitrogen. The resulting off-white suspension was stirred at
-15 °C for 1 h. The solid was collected by vacuum filtration,
washed with hexanes, and air-dried to give 53.79 g (99%) of
the title compound as a white solid: mp 130-134 °C; 1H-NMR
(CDCl3) δ 7.23 (m, 3H), 3.01 (hept, 2H), 1.19 (d, 12H). Anal.
(C13H19ClN2O3S) C,H,N.
Gen er a l Meth od for th e Syn th esis of th e (Ch lor osu l-
fon yl)ca r ba m a te In ter m ed ia tes IIb: P r ep a r a tion of 2,6-
Bis(1-m eth yleth yl)p h en yl (Ch lor osu lfon yl)ca r ba m a te. A
solution of 2,6-diisopropylphenol (37.1 mL, 0.2 mol) in 200 mL
of diethyl ether was added dropwise to a solution of N-
chlorosulfonyl isocyanate (17.4 mL, 0.2 mol) in 200 mL of
diethyl ether at -15 °C under an atmosphere of nitrogen. The
reaction mixture was maintained at -15 °C for 16 h and then
concentrated in vacuo to give an orange oil. This was
triturated with hexanes, and the solid was collected by vacuum
filtration to give 55.64 g (87%) of the title compound as a white
solid: mp 78-81 °C; 1H-NMR (CDCl3) δ 7.21 (m, 3H), 2.99
(hept, 2H), 1.23 (d, 12H). Anal. (C13H18ClNO4S) N; C: calcd,
48.82; found, 49.59. H: calcd, 5.67; found, 6.08.
observed with these drugs. Since the structural design
of these compounds was based on a series of sulfonyl-
urea hypoglycemics, it is possible that these compounds
possess similar physical characteristics (i.e., protein
binding, log P, pKa, etc.). It is conceivable that en-
hanced absorption of these compounds (the structurally
related hypoglycemics are typically >90% bioavailable
after oral dosing13) could explain the excellent in vivo
lipid-lowering effects observed despite the modest in
vitro activity. Several mechanistic studies are ongoing
in a variety of animal models to further elucidate a
possible alternate mechanism and elaborate upon the
enhanced in vivo effect observed with these compounds.
Results of these studies will be reported in due course.
Exp er im en ta l Section
Unless otherwise noted, reagents and solvents obtained from
commercial sources were used without further purification. All
amines and alcohols were commercially available except the
following, which could be readily synthesized according to
literature methods: 2,4,6-triisopropylaniline, 2,6-diisopropyl-
hydroquinone, 2,6-diisopropyl-4-methoxyphenol, 4-chloro-2,6-
diisopropylphenol, 4-bromo-2,6-diisopropylphenol, 2,6-diiso-
propyl-4-nitrophenyl, 3′,5′-diisopropyl-4′-hydroxyacetophenone,
and 2,6-diisopropylcyclohexanol. Additionally, 4-fluoro-2,3,5,6-
tetraisopropylphenol and 2,6-diisopropyl-4-fluorophenol were
previously unknown in the literature, and their syntheses are
provided below.
Column chromatography was performed on Merck silica gel
60 (230-400 mesh). Proton NMR spectra were recorded with
a Gemini 300 spectrometer, and chemical shifts are expressed
in parts per million (ppm) relative to internal tetramethylsi-
lane. Melting points were measured with a Thomas-Hoover
capillary melting point apparatus and are uncorrected. El-
emental analyses were performed on a Perkin-Elmer model
240C elemental analyzer and are (0.4% of the theoretical
values unless otherwise noted.
In a similar manner, the following (chlorosulfonyl)carbam-
ates were also obtained.
2,6-Bis(1,1-d im eth yleth yl)p h en yl (ch lor osu lfon yl)ca r -
ba m a te: mp 135-137 °C; 1H-NMR (CDCl3) δ 7.26 (m, 3H),
1.36 (s, 18H). Anal. (C15H22ClNO4S) C,H,N.
2,6-Bis(1,1-d im eth yleth yl)-4-m eth ylp h en yl (ch lor osu l-
1
fon yl)ca r ba m a te: mp 138-140 °C; H-NMR (CDCl3) δ 7.13
(s, 2H), 2.33 (s, 3H), 1.35 (s, 18H). Anal. (C16H24ClNO4S)
C,H,N.
1,1′:3,1′′-Ter ph en yl-2′-yl (ch lor osu lfon yl)car bam ate: mp
159-162 °C; 1H-NMR (DMSO-d6) δ 7.43 (m, 13H), 6.90 (bs,
1H). Anal. (C19H14ClNO4S) H,N; C: calcd, 58.84; found, 57.27.
2,6-Bis(1,1-d im eth yleth yl)-4-m eth oxyp h en yl (ch lor o-
su lfon yl)ca r ba m a te: oil; 1H-NMR (CDCl3) δ 6.86 (s, 2H), 3.81
(s, 3H), 1.35 (s, 18H). Anal. (C16H24ClNO5S).
Gen er a l Meth od for th e Rea ction of a n Am in e w ith
(Ch lor osu lfon yl)u r ea In ter m ed ia te IIa To Give a n (Am i-
n osu lfon yl)u r ea (Ta ble 1): P r ep a r a tion of N-[2,6-Bis(1-
m eth yleth yl)ph en yl]-N′-[(dibu tylam in o)su lfon yl]u r ea (16).
A solution of [[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]-
sulfamoyl chloride (25.0 g, 0.078 mol) in 250 mL of tetrahy-
drofuran was added dropwise to a solution of di-n-butylamine
(10.13 g, 0.078 mol) and excess triethylamine (∼12 mL) in 250
mL of tetrahydrofuran at 25 °C under an atmosphere of
nitrogen. This was stirred at 25 °C for 16 h and then
concentrated in vacuo to give an oily residue which was
partitioned between 1 M HCl and ethyl acetate. The organic
layer was dried over MgSO4, filtered, and concentrated to give
a brown oil. Silica gel chromatography (10% ethyl acetate/
hexanes) gave a tan oil which was triturated with hexanes to
give 12.21 g (38%) of the title compound as a white solid: mp
98-101 °C; 1H-NMR (CDCl3) δ 8.68 (s, 1H), 7.74 (s, 1H), 7.26
(m, 3H), 3.26 (q, 4H), 3.10 (hept, 2H), 1.61 (m, 4H), 1.19 (m,
16H), 0.93 (t, 6H). Anal. (C21H37N3O3S) C,H,N.
Gen er a l Meth od for th e Alk yla tion of th e Cen tr a l
Nitr ogen Atom : P r ep a r a tion of N′-[2,6-Bis(1-m eth yleth -
yl)p h en yl]-N-m eth yl[(d ibu tyla m in o)su lfon yl]u r ea (17).
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.6 mL, 0.010 mol) was
added dropwise to a solution of N-[2,6-bis(1-methylethyl)-
phenyl]-N′-[(dibutylamino)sulfonyl]urea (16; 4.0 g, 0.0097 mol)
and methyl iodide (1.52 g, 0.010 mol) in 100 mL of acetonitrile
at -15 °C. The resulting mixture was warmed to room
temperature and stirred for 16 h. The reaction mixture was
concentrated in vacuo and partitioned between 1 M HCl and
ethyl acetate. The organic layer was dried over MgSO4,
filtered, and concentrated to give an orange oil. Silica gel
chromatography (10% ethyl acetate/hexanes) gave 3.34 g (81%)
of the title compound 17 as a clear oil: 1H-NMR (DMSO-d6) δ
8.57 (s, 1H), 7.18 (m, 3H), 3.21 (m, 7H), 3.05 (hept, 2H), 1.52
(m, 4H), 1.27 (m, 4H), 1.13 (d, 12H), 0.99 (t, 6H). Anal.
(C22H39N3O3S) H,N; C: calcd, 62.08; found, 62.75.
Representative experimental procedures are given below for
each of the four series of compounds described in this paper.
Analytical data and melting points for all of the final com-
pounds are given in Tables 1-5.
4-F lu or o-2,3,5,6-tetr a isop r op ylp h en ol. 4-Fluorophenol
(27.35 g, 0.244 mol) was dissolved in 55 mL of concentrated
sulfuric acid at 65 °C. 2-Propanol (112 mL, 1.46 mol) was
added dropwise, and the resulting mixture was heated at 70
°C for 1 h. An additional 30 mL of sulfuric acid was added,
and heating was continued for an additional 5 h. The reaction
mixture was cooled to room temperature and stirred for 3 days.
The reaction mixture was extracted with diethyl ether, and
the ether extracts were then washed with saturated sodium
bicarbonate solution followed by brine. The ether layer was
dried over MgSO4, filtered, and concentrated to give a black
oily solid. Silica gel chromatography (10% ethyl acetate/
hexanes) gave 4.53 g (7%) of the title compound as a yellow
solid: mp 180-182 °C; 1H-NMR (DMSO-d6) δ 3.56 (hept, 2H),
3.33 (hept, 2H), 1.27 (dd, 24H). Anal. (C18H29FO) C,H,N.
2,6-Diisop r op yl-4-flu or op h en ol. 4-Fluorophenol (10.9 g,
0.097 mol) and aluminum turnings (81 mg, 0.003 mol) were
combined in a sealed vessel and heated to 165 °C for 30 min.
This was then cooled to room temperature, and propylene (19.0
g, 0.451 mol) was added. The vessel was resealed, heated to
240 °C for 2 h, and then cooled to room temperature. The
vessel was washed with hexanes and the mixture concentrated
to give a black oil. The residue was chromatographed on silica
gel (1% ethyl acetate in hexanes) to give 6.92 g (36%) of 2,6-
diisopropyl-4-fluorophenol as a pale yellow oil: 1H-NMR
(CDCl3) δ 6.74 (d, 2H), 4.54 (s, 1H), 3.14 (hept, 2H), 1.24 (d,
6H). Anal. (C12H17FO) C,H,N.
Gen er a l Meth od for th e Syn th esis of th e (Ch lor osu l-
fon yl)u r ea In ter m ed ia tes IIa : P r ep a r a tion of [[[2,6-Bis-
(1-m eth yleth yl)ph en yl]a m in o]ca r bon yl]su lfa m oyl Ch lor -
id e. A solution of 2,6-diisopropylaniline (30.0 g, 0.169 mol)
in 150 mL of diethyl ether was added dropwise to a solution
of N-chlorosulfonyl isocyanate (14.73 mL, 0.169 mol) in 100
Gen er a l Meth od for th e F or m a tion of th e Sod iu m Sa lt:
P r epar ation of N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-[(dibu -
tyla m in o)su lfon yl]u r ea , Mon osod iu m Sa lt (18). A solu-
tion of N-[2,6-bis(1-methylethyl)phenyl]-N′-[(dibutylamino)-
sulfonyl]urea (16; 15.0 g, 0.036 mol) in 150 mL of tetra-

ACAT Inhibitors From N-Chlorosulfonyl Isocyanate
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1251
hydrofuran was added dropwise to a suspension of hexane-
washed sodium hydride (1.53 g, 60% dispersion in mineral oil,
0.038 mol) in 50 mL of tetrahydrofuran at 0 °C under an
atmosphere of nitrogen. The resulting solution was warmed
to room temperature and stirred for 16 h. The reaction
mixture was concentrated in vacuo, and the residue was
triturated with diethyl ether and filtered to remove inorganic
impurities. The filtrate was concentrated, and the resulting
solid was slurried in hexanes and filtered to give 9.16 g (58%)
for 16 h and concentrated in vacuo to remove the toluene. The
residue was distilled (109-114 °C at 0.9 mmHg) to give 42.62
g (89%) of the title compound as a clear, pale yellow oil:
1H-
NMR (CDCl3) δ 7.30 (m, 3H), 3.39 (hept, 2H), 1.78 (m, 2H),
1.26 (d, 12H). This compound is extremely moisture sensitive
and was stored under nitrogen to limit rapid decomposition.
Alter n ative Syn th esis of th e (Oxysu lfon yl)u r eas (Table
2). Rea ction of a n Am in e w ith Oxysu lfon yl Isocya n a te
In ter m ed ia te III: P r ep a r a tion of 2,6-Bis(1-m eth yleth yl)-
p h en yl [[Bis(1-m eth ylp r op yl)a m in o]ca r bon yl]su lfa m a te
(54). N,N-Di-sec-butylamine (1.81 mL, 0.011 mol) was added
dropwise to a solution of [2,6-bis(1-methylethyl)phenoxy]-
sulfonyl isocyanate (3.0 g, 0.011 mol) in 100 mL of diethyl ether
at ambient temperature under an atmosphere of nitrogen. The
reaction mixture was stirred for 16 h and then concentrated
in vacuo. Silica gel chromatography (20% ethyl acetate/
hexanes) gave 3.40 g (78%) of 54 as a white foam: 1H-NMR
(DMSO-d6) δ 7.15 (m, 3H), 3.72 (m, 2H), 3.12 (m, 2H), 1.71
(m, 2H), 1.44 (m, 2H), 1.12 (m, 18H), 0.88 (t, 3H), 0.82 (t, 3H).
Anal. (C21H36N2O4S1) H,N; C: calcd, 61.13; found, 60.57.
Alter n a tive Syn th esis of th e (Oxysu lfon yl)ca r ba m a tes
(Ta bles 4 a n d 5). Rea ction of a n Alcoh ol w ith Oxysu l-
fon yl Isocya n a te In ter m ed ia te III: P r ep a r a tion of 2,4,6-
Tr im eth oxyp h en yl [[2,6-Bis(1-m eth yleth yl)p h en oxy]su l-
fon yl]ca r ba m a te (154). 2,4,6-Trimethoxyphenol (1.30 g,
0.007 mol) was added dropwise to a solution of [2,6-bis(1-
methylethyl)phenoxy]sulfonyl isocyanate (2.0 g, 0.007 mol) in
50 mL of diethyl ether at ambient temperature under an
atmosphere of nitrogen. The reaction mixture was stirred for
16 h and then concentrated in vacuo. Silica gel chromatog-
raphy (20% ethyl acetate/hexanes) gave 2.30 g (70%) of 154
as a white powder: mp 87-92 °C; 1H-NMR (CDCl3) δ 8.37 (bs,
1H), 7.20 (m, 3H), 6.17 (s, 2H), 3.80 (s, 9H), 3.51 (hept, 2H),
1.23 (d, 12H). Anal. (C22H29N1O8S1) C,H,N.
Syn th esis of th e (Oxysu lfon yl)ca r ba m oth ioa tes (Ta ble
4). Rea ction of a Th iol w ith Oxysu lfon yl Isocya n a te
In ter m ed ia te III: P r ep a r a tion of S-2,6-Bis(1-m eth yleth -
yl)p h en yl [[2,6-Bis(1-m eth yleth yl)p h en oxy]su lfon yl]ca r -
ba m oth ioa te (129). A solution of 2,6-diisopropylthiophenol
(2.26 g, 0.012 mol) in 50 mL of diethyl ether was added
dropwise to a solution of [2,6-bis(1-methylethyl)phenoxy]-
sulfonyl isocyanate (3.0 g, 0.011 mol) in 100 mL of diethyl ether
at room temperature under a nitrogen atmosphere. The
mixture was allowed to stir for 16 h and then concentrated in
vacuo. The residue was triturated with hexanes, and the solid
was collect to give 2.52 g (50%) of 129 as a white solid: mp
92-94 °C; 1H-NMR (CDCl3) δ 8.76 (bs, 1H), 7.48 (t, 1H), 7.26
(m, 4H), 7.17 (d, 1H), 3.59 (hept, 2H), 3.44 (hept, 2H), 1.23 (d,
24H). Anal. (C25H35N1O4S2) C,H; N: calcd, 2.93; found, 2.42.
Gen er a l Meth od for th e On e-P ot Syn th esis of Com -
p ou n d s P ossessin g th e Sa m e Nu cleop h ile on Both Sid es
of th e Molecu le: P r ep a r a tion of 2,6-Bis(1-m eth yleth yl)-
p h en yl [[2,6-Bis(1-m et h ylet h yl)p h en oxy]su lfon yl]ca r -
ba m a te (114). A solution of 2,6-diisopropylphenol (150.0 g,
0.841 mol) and triethylamine (64.5 mL, 0.463 mol) in 600 mL
of tetrahydrofuran was added dropwise to a solution of
N-chlorosulfonyl isocyanate (38.5 mL, 0.442 mol) in 500 mL
of tetrahydrofuran at -15 °C under an atmosphere of nitrogen.
The reaction mixture was warmed to ambient temperature,
stirred for 72 h, and then concentrated in vacuo. The residue
was partitioned between 1 M HCl and ethyl acetate. The
organic layer was dried over MgSO4, filtered, and concentrated
to give an oily solid. Silica gel chromatography (10% ethyl
acetate/hexanes) gave 139.9 g (72%) of 114 as a white solid:
mp 132-133.5 °C; 1H-NMR (CDCl3) δ 7.20 (m, 6H), 3.53 (hept,
2H), 3.06 (hept, 2H), 1.25 (d, 12H), 1.22 (d, 12H). Anal.
(C25H35N1O5S1) C,H,N.
1
of 18 as a white solid: mp 217-219 °C; H-NMR (DMSO-d6)
δ 7.37 (bs, 1H), 7.04 (m, 3H), 3.34 (hept, 2H), 2.97 (m, 4H),
1.47 (m, 4H), 1.24 (m, 4H), 1.10 (d, 12H), 0.88 (t, 6H). Anal.
(C21H36N3O3SNa) C,H; N: calcd, 9.69; found, 8.74.
Gen er a l Meth od for th e Rea ction of a n Alcoh ol w ith
(Ch lor osu lfon yl)u r ea In ter m ed ia te IIa To Give a n (Oxy-
su lfon yl)u r ea (Ta ble 2): P r ep a r a tion of Dod ecyl [[[2,6-
Bis(1-m eth yleth yl)ph en yl]am in o]car bon yl]su lfam ate (49).
A solution of [[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]-
sulfamoyl chloride (5.0 g, 0.016 mol) in 75 mL of tetrahydro-
furan was added dropwise to a solution of n-dodecanol (2.92
g, 0.016 mol) and excess triethylamine (∼3 mL) in 75 mL of
tetrahydrofuran at ambient temperature, under an atmo-
sphere of nitrogen. The resulting suspension was stirred for
16 h and concentrated in vacuo, and the residue was parti-
tioned between 1 M HCl and ethyl acetate. The organic layer
was dried over MgSO4, filtered, and concentrated to give a
yellow/green oil. Trituration with cold hexanes gave 2.35 g
(32%) of 49 as a white solid: mp 112-115 °C; 1H-NMR (DMSO-
d6) δ 8.01 (s, 1H), 7.18 (m, 3H), 4.24 (q, 2H), 3.06 (hept, 2H),
1.66 (m, 2H), 1.24 (m, 18H), 1.13 (d, 12H), 0.86 (t, 3H). Anal.
(C25H44N2O4S1) C,H,N.
Gen er a l Meth od for th e Rea ction of a n Am in e w ith
(Ch lor osu lfon yl)ca r ba m a te In ter m ed ia te IIb To Give a n
(Am in osu lfon yl)ca r ba m a te (Ta ble 3): P r ep a r a tion of 2,6-
Bis(1-m eth yleth yl)p h en yl [(Dip en tyla m in o)su lfon yl]ca r -
ba m a te (66). A solution of 2,6-bis(1-methylethyl)phenyl
(chlorosulfonyl)carbamate (5.0 g, 0.016 mol) in 50 mL of
tetrahydrofuran was added dropwise to a solution of di-n-
pentylamine (2.46 g, 0.016 mol) and triethylamine (1.74 g,
0.017 mol) in 100 mL of tetrahydrofuran at -15 °C under an
atmosphere of nitrogen. This was then warmed to ambient
temperature and stirred for 16 h. The reaction mixture was
concentrated in vacuo, and the residue was partitioned be-
tween 1 M HCl and ethyl acetate. The organic layer was dried
over MgSO4, filtered, and concentrated to give a yellow oil.
Silica gel chromatography (10% ethyl acetate/hexanes) gave
1
1.22 g (18%) of 66 as a white solid: mp 69-70 °C; H-NMR
(DMSO-d6) δ 11.98 (s, 1H), 7.22 (m, 3H), 3.24 (q, 4H), 2.93
(hept, 2H), 1.56 (m, 4H), 1.27 (m, 8H), 1.15 (d, 12H), 0.88 (t,
6H). Anal. (C23H40N2O4S1) C,H,N.
Gen er a l Meth od for th e Rea ction of a n Alcoh ol w ith
(Ch lor osu lfon yl)ca r ba m a te In ter m ed ia te IIb To Give a n
(Oxysu lfon yl)ca r ba m a te (Ta bles 4 a n d 5): P r ep a r a tion
of 2,6-Bis(1-m eth yleth yl)p h en yl [(Dod ecyloxy)su lfon yl]-
ca r ba m a te (106). A solution of 2,6-bis(1-methylethyl)phenyl
(chlorosulfonyl)carbamate (5.0 g, 0.016 mol) in 75 mL of
tetrahydrofuran was added dropwise to a solution of n-dodecyl
alcohol (2.91 g, 0.016 mol) and triethylamine (1.74 g, 0.017
mol) in 100 mL of tetrahydrofuran at -15 °C under an
atmosphere of nitrogen and then warmed to ambient temper-
ature and stirred for 16 h. The reaction mixture was concen-
trated in vacuo, and the residue was partitioned between 1 M
HCl and ethyl acetate. The organic layer was dried over
MgSO4, filtered, and concentrated to give a colorless oil.
Trituration with hexanes gave 5.02 g (69%) of 106 as a white
solid: mp 69-72 °C; 1H-NMR (CDCl3) δ 7.99 (s, 1H), 7.18 (m,
3H), 4.54 (q, 2H), 2.98 (hept, 2H), 1.78 (m, 2H), 1.23 (m, 30H),
0.88 (t, 3H). Anal. (C25H43N1O5S1) H,N; C: calcd, 63.93; found,
62.61.
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