Heterocyclic ureas: Inhibitors of acyl-CoA:cholesterol O- acyltransferase as hypocholesterolemic agents

Article abstract of DOI:10.1021/jm960404v

A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA:cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopr

Full text of DOI:10.1021/jm960404v

4382
J . Med. Chem. 1996, 39, 4382-4395
Heter ocyclic Ur ea s: In h ibitor s of Acyl-CoA:Ch olester ol O-Acyltr a n sfer a se a s
Hyp och olester olem ic Agen ts1
Andrew D. White,* Mark W. Creswell, Alexander W. Chucholowski, C. J ohn Blankley, Michael W. Wilson,
Richard F. Bousley,† Arnold D. Essenburg,† Katherine L. Hamelehle,† Brian R. Krause,† Richard L. Stanfield,†
Mark A. Dominick,§ and Martin Neub‡
Departments of Medicinal Chemistry, Atherosclerosis Therapeutics, Pathology and Experimental Toxicology, Pharmacokinetics
and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road,
Ann Arbor, Michigan 48105
Received J une 6, 1996X
A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-
CoA:cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in
cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N′-tetrazole-
or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons
substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the
alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma
total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia
and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL
cholesterol 113% in rats with pre-established hypercholesterolemia.
In tr od u ction
Previous work in our laboratories11-16 identified
several series of potent ACAT inhibitors which lowered
plasma total cholesterol in cholesterol-fed animal mod-
els. The early work focused on primarily amide inhibi-
tors.11 This culminated in the discovery of CI-976,
which exerted its antiatherosclerotic effects by inhibi-
tion of arterial ACAT independent of cholesterol lower-
ing.3,17 The urea moiety was later found to be an
excellent isosteric replacement for amide.12 Among
these ureas, the secondary urea moiety containing a
sterically hindered N-2,6-disubstituted aryl moiety pro-
vided optimal activity.13 A surprising variety of sub-
stitutions is then tolerated on the other nitrogen.3
Initially we chose the tetrazole moiety to furnish a more
polar linker as compared with our previous com-
pounds.12,18 We reasoned this would yield a compound
with improved pharmacokinetic properties that would
inhibit arterial ACAT. We discovered a series of potent
compounds upon alkylation of the tetrazole ring and
sought to optimize the tetrazole ring substitution with
respect to biological activity. In an effort to investigate
the importance of the tetrazole moiety as a linker, we
synthesized a series of heterocyclic replacements for
tetrazole. A comparison of the tetrazoles and 2- and
3-heteroatom-containing heterocyclic replacements is
presented here together with synthetic and biological
data.
Coronary heart disease is the leading cause of death
among nations of the Western hemisphere. Elevated
levels of plasma low-density lipoprotein cholesterol
represent an independent risk factor definitively linked
to coronary heart disease (CHD).2 The body obtains
cholesterol from only two sources: one-third via absorp-
tion from the diet and the balance from endogenous
biosynthesis.3 Inhibition of either process represents an
approach to lowering plasma cholesterol. Notably HMG-
CoA reductase inhibitors, which inhibit the rate-limiting
enzyme in cholesterol biosynthesis, have proven clini-
cally effective at lowering total cholesterol and, most
recently, have been shown to reduce CHD and total
mortality in men with4 or without5 previously diagnosed
CHD.
Evidence suggests that inhibition of the enzyme acyl-
CoA:cholesterol O-acyltransferase (ACAT, EC 2.3.1.26),
which catalyzes the intracellular formation of choles-
teryl esters, may have beneficial effects on plasma total
cholesterol by preventing the absorption of dietary
cholesterol.6 Additional studies show hepatic choles-
teryl ester content is directly proportional to very-low-
density lipoprotein (VLDL) secretion rate.7 Recently
ACAT inhibition has been shown to decrease both the
secretion rate of cholesteryl esters and apolipoprotein
B from perfused monkey livers.8 Inhibition of ACAT
in the arterial wall may reduce accumulation of choles-
teryl ester (CE) in monocyte macrophages. These CE
rich cells are the precursors of the foam cells of the early
atherosclerotic lesion.9 The additional data suggesting
a role for ACAT in the liver and at the artery wall have
maintained this enzyme as a very attractive target for
pharmacological intervention even though ACAT inhibi-
tion has yet to be proven clinically relevant for the
treatment of hypercholesterolemia.10
Ch em istr y
The heterocyclic ureas were generally synthesized via
coupling of an isocyanate with an amino heterocycle.
The substitution on the amino heterocyclic ring could
be put in place before or after reaction with isocyanate,
depending on the heterocycle. Tetrazole ureas were
synthesized by the routes illustrated in Schemes 1 and
2. Reaction of 5-aminotetrazole with an aryl isocyanate
in the presence of base gave a good yield of tetrazole
urea 1. Alkylation of the tetrazole urea with an alkyl
halide and triethylamine gave the 2-substituted tetra-
zole urea 2 as the major product (Scheme 1). A small
amount of 1-alkyltetrazole urea 3 was sometimes ob-
† Department of Atherosclerosis Therapeutics.
‡ Department of Pharmacokinetics and Drug Metabolism.
§ Department of Pathology and Experimental Toxicology.
X Abstract published in Advance ACS Abstracts, October 1, 1996.
S0022-2623(96)00404-9 CCC: $12.00 © 1996 American Chemical Society

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4383
Sch em e 1a
a
(a) ArNCO, Et3N, MeCN; (b) RBr, Et3N, MeCN; (c) p-TSA, MeOH.
Sch em e 2a
1- (8b) and 2- (8a ) isomers. Saponification of 8a
afforded the acid 9, which was subjected to a Curtius
rearrangement with diphenyl phosphorazidate. Trap-
ping the isocyanate with the requisite aniline yielded
the ureas 10 and 11 (Scheme 3).
The 1,3,4-thiadiazole ureas 14a -c were obtained from
an alkyl carboxylic acid, which was converted to the acyl
thiosemicarbazide 12 and then cyclized under acidic
conditions20 to give the alkyl amino 1,3,4-thiadiazole 13
which was coupled with an isocyanate to give the ureas
(Scheme 4).
a
(a) RBr, NaOH, EtOH/H2O; (b) ArNCO, Et3N, MeCN.
served. The 1-substituted tetrazole was obtained in a
synthetically useful quantity via alkylation of 5-ami-
notetrazole with an alkyl halide in basic aqueous
ethanol to give a mixture of the 1- and 2-alkylated
aminotetrazoles 4 and 5, respectively. The ratio of
isomers varied. For R ) C12H25, a 2:1 ratio was
observed favoring the 2-isomer. For R ) benzyl, only
the 1-isomer was observed under the reaction condi-
tions. The isomers were easily separable by crystal-
lization or column chromatography.
The 1,3,4-oxadiazole urea 16 was assembled via
conversion of a carboxylic acid to an acyl hydrazide via
reaction of the methyl ester with hydrazine. Subse-
quent base-induced cyclization of the acyl hydrazide
with cyanogen bromide21 yielded the 5-alkyl-2-amino-
1,3,4 oxadiazole 15 which was coupled with an isocy-
anate by the same method used for the tetrazole ureas
to give urea 16 (Scheme 5).
The C-alkylated triazole derivative 19 was obtained
via cyclization of aminoguanidine and tridecanoic acid
to afford the triazole 17. Reaction with an aryl isocy-
anate afforded the undesired ring-acylated product 17a .
Prior ring acylation with acetyl chloride to give 18 and
subsequent reaction with isocyanate followed by depro-
tection was necessary to obtain the urea 19 in good
overall yield (Scheme 6).
The 1-alkyl-5-aminotetrazole was coupled with an
aryl isocyanate in the presence of triethylamine to give
the 1-substituted urea 3 (Scheme 2). The 2-substituted
isomers could also be synthesized by this route. The
regioisomers were assigned based on their NMR chemi-
cal shifts. The 2-isomer N-methylene protons are
always downfield (∼0.3 ppm) from the 1-isomer. The
terminally substituted 2-alkyl tetrazoles 2m and 6 were
synthesized via alkylation of the intermediate 1 with
an appropriately substituted bromo alcohol. Deprotec-
tion of 6 gave the terminal alcohol 7 (Scheme 1).
The N-alkylated 1,2,4-triazole derivatives 21a -c were
obtained via functionalization of a preformed triazole
ring. The N-alkyl derivatives were obtained via alky-
lation of 3-amino-1,2,4-triazole with an alkyl bromide
to give a mixture of the three ring-alkylated regioiso-
mers 20a -c). After separation by column chromatog-
raphy, the assignment of regiochemistry was based on
analogy with the known methyl-substituted regioiso-
The methylene-spaced tetrazole ureas 10 and 11 were
synthesized from tetrazoleacetic acid ethyl ester (7a ),19
via alkylation and chromatography to separate the
Sch em e 3a
a
(a) Me(CH2)11Br, Et3N, MeCN; (b) chromatography; (c) KOH, EtOH; (d) diphenyl phosphorazidate, ArNH2.
Sch em e 4a
a
(a) THF, 18 h; (b) MeSO3H, toluene; (c) 2,6-(i-Pr)2PhNCO, MeCN.

4384 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
Sch em e 5a
under normal conditions yielded the urea 37, which was
isolated as the HCl salt (Scheme 11).
The thiazole ureas 39a ,b were prepared by heating
thiourea with an iodo ketone, which was generated in
situ from the appropriately substituted methyl ketone
and iodine.27 The regioisomeric mixture of thiazole
amines 38a ,b obtained was separable by column chro-
matography. Coupling with an aryl isocyanate gave the
desired ureas 39a ,b (Scheme 12).
a
(a) MeOH, HCl; (b) NH2NH2, MeOH; (c) BrCN, KHCO3,
dioxane; (d) 2,6-(i-Pr)2PhNCO, MeCN.
Biologica l Meth od s
ACAT inhibition in vitro (designated as IAI) was
determined via incubation of 14C-labeled oleoyl-CoA
with intestinal microsomes from cholesterol-fed rab-
bits.11 The degree of activity was expressed as the
micromolar concentration required to inhibit enzyme
activity 50% (IC50).
mers (Scheme 7).22 The aminotriazoles 20a -c were
coupled in good yield with 2,6-diisopropylphenyl isocy-
anate to afford the ureas 21a -c.
The thioalkyl derivatives 24-27 were synthesized via
alkylation of 3-amino-5-mercapto-1,2,4-triazole, which
occurred selectively on sulfur. Subsequent reaction with
an aryl isocyanate yielded only acylation on the triazole
ring. This was overcome by prior ring N-acylation with
acetyl chloride to give 23 and reaction of the exocyclic
nitrogen with an aryl isocyanate to yield 24 and
subsequent deprotection to give 25. Oxidation of 25
with 1 or 2 equiv of m-CPBA afforded the sulfoxide (26)
and sulfone (27) derivatives, respectively, in good yield
(Scheme 8).
The 3,5-disubstituted isoxazole ureas 30a -d and 32
were synthesized from the appropriate isoxazole amines
and 2,6-diisopropylphenyl isocyanate. The isoxazole
amines were assembled from an alkylacetylene via
conversion to a cyanoacetylene (28) with phenyl cyan-
ate.23 Cyclization of the cyanoacetylene 28 with hy-
droxylamine24 gave the 3-alkyl-5-aminoisoxazole 29;
conversely, the 5-alkyl-3-amino regioisomer 31 was
obtained via cyclization with hydroxylamine and base.
The regiospecific cyclizations occur because, in the
absence of base, hydroxylamine adds to the acetylene;
however, with base present addition to nitrile occurs
faster to afford cyclization via the amidoxime (Scheme
9).
The oxazole urea 35 was sythesized from an ap-
propriately substituted methyl ketone. Conversion to
the silyl enol ether under standard conditions and
oxidation with acidic workup yielded an R-hydroxy
ketone (33). Base-induced cyclization of 33 with cyana-
mide25 gave the oxazole amine 34 which was converted
to the urea 35 in the manner previously described
(Scheme 10).
The imidazole urea 37 was synthesized from 4-ni-
troimidazole. Alkylation under basic conditions of the
tetrabutylammonium salt of 4-nitroimidazole26 followed
by reduction of the nitro group yielded the 1-alkyl-4-
aminoimidazole. Coupling with an aryl isocyanate
In vivo efficacy was examined in an acute assay
(APCC).14 The compounds were administered in car-
boxymethylcellulose (1.5%) and Tween-20 (0.2%) in
water at either 3 or 30 mg/kg. The animals were then
allowed to consume a diet supplemented with choles-
terol. The data are expressed as percent decrease of
total cholesterol (TC) relative to controls. This model
measures the ability of the compound to prevent the
overnight rise in plasma TC induced by a high-fat high-
cholesterol meal. In a 2 week chronic model (CPCC),28
hypercholesterolemia was first established with 1 week
on a high-fat high-cholesterol diet followed by admin-
istration of the compounds for 1 week. In this model
changes in TC, HDL cholesterol (HDL-C), and non-HDL
cholesterol (non-HDL-C) were monitored.
Bioactivity was assessed in male New Zealand white
rabbits. The animals were conditioned to meal feeding
for 1 week and then given a meal containing the drug
at 25 mg/kg in an oil vehicle (3% peanut oil/3% coconut
oil). Blood samples were obtained at time zero (before
drug) and 1, 2, and 4 h postdrug meal. The plasma
samples (0.2 mL) were extracted into hexane, dried,
dissolved in chloroform/methanol (2:1, v/v), and assayed
for microsomal liver ACAT inhibition.28 Standards were
prepared for each drug by adding compound directly to
rabbit plasma in DMSO.
In vivo efficacy in cholesterol-fed female Beagle dogs
was examined according to the method described by
Krause et al.28 The dogs were dosed as bulk drug in
capsules daily before meals for 1 week. Efficacy is
expressed as the percent change in plasma TC before
and after treatment. Plasma blood drug levels were
determined in the dog with an HPLC assay. Animals
were dosed orally once daily for 1 week. Single blood
samples were taken 6 h post dose on the last day. The
Sch em e 6a
a
(a) C12H25CO2H, PhNMe2, toluene; (b) AcCl, THF, Et3N; (c) 2,6-(i-Pr)2PhNCO, MeCN; (d) MeOH.

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4385
Sch em e 7a
effective in lowering total cholesterol. Activity was
maximal with the C13 side chain analog 2i and declined
with a further increase in chain length. This probably
resulted from the compounds being extremely lipophilic
and consequently not being absorbed. The in vitro
activity of the 2-decyl to the 2-tetradecyl compounds
2f-j was IC50 e 0.014 µM. The effect of substitution
on the alkyl chain was examined. Terminal tetrahy-
dropyranyl ether (6) and hydroxyl (7) substituents
resulted in compounds less active in vivo though still
retaining good potency in vitro. The 2-geranyl deriva-
tive 2n was equipotent in vitro with the unsubstituted
analog of similar length (2b). However efficacy fell off
in vivo with the more substituted geranyl side chain. A
terminal ester functionality (2m ) imparted a significant
loss of in vitro and in vivo activity. However, possible
hydrolysis under the assay conditions would yield a
carboxylic acid function, which has been shown in other
series to have a detrimental effect on activity both in
vitro and in vivo.16
a
(a) (i) C11H21Br, NaOMe, MeOH, (ii) chromatography; (b) 2,6-
(i-Pr)2PhNCO, MeCN.
HPLC method comprised a Grom Spherisorb C8 column
with acetonitrile/water (4:1 v/v) as eluent and detection
at 190 nm. Retention times were 6.3 min for 2h and
7.6 min for 2i. Both compounds served as internal
standards alternately. The minimum quantitation limit
was 40 ng/mL.
Resu lts a n d Discu ssion
To examine which regioisomeric substitution on the
tetrazole was optimal, we compared the 1-substituted
isomers 3b,c with the corresponding 2-substituted
isomers 2h ,p and discovered the 2-substituted isomers
were optimal. Although in one case the 2,4,6-tri-
methoxyphenyl analog (2p vs 2h ) was more efficacious
in vivo than the 2,6-diisopropyl, we decided to expand
the tetrazole series using 2-substitution on the tetrazole
ring of the parent N-(2,6-diisopropylphenyl)-N′-tetrazoyl
urea moiety (1).
On the basis of the inactivity of compound 1 (Table
1), alkylation of the tetrazole NH is essential for activity.
However alkylation with the benzyl group produced a
compound (2a ) of modest potency (IAI IC50 ) 0.37 µM).
A 3-fold increase in potency in vitro was obtained with
the 2-butyl group (2b) (IAI IC50 ) 0.092 µM). This
compound however possessed little in vivo activity. We
had observed in other series14,16 a threshold lipophilicity
(CLOGP ) calculated lipophilicity)29 of greater than 6
was required for good in vivo efficacy. Further exten-
sion of the alkyl side chain increased the lipophilicity
and revealed a series of extremely potent compounds
in vitro and in vivo (2f-k ). The in vivo activity of
compounds 2c-k at a dose of 30 mg/kg was essentially
equivalent. At a dose of 3 mg/kg in the APCC rat model,
the undecyl to tetradecyl side chains (2g-j) were still
In order to determine which aryl moiety was optimal
in the heterocyclic ureas, we compared several 2,4,6-
trimethoxyphenyl (2p , 3c) and 2,6-diisopropylphenyl
(2h , 3b) analogs in the aminotetrazole series (Table 1)
and tetrazole methyleneamino series (10, 11) (Table 2)
and compared their abilities to inhibit ACAT in vitro
Sch em e 8a
a
(a) C13H27Br, Et3N, MeCN; (b) AcCl, Et3N, THF; (c) ArNCO, MeCN; (d) MeOH; (e) mCPBA (1 equiv), CH2Cl2; (f) m-CPBA (2 equiv),
CH2Cl2.
Sch em e 9a
a
(a) n-BuLi, Et2O, -78 °C, PhOCN; (b) NH2OH‚HCl, NaOH (2 equiv), EtOH; (c) NH2OH‚HCl, NaOH (1 equiv), EtOH; (d) 2,6-(i-
Pr)2PhNCO, MeCN.

4386 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
Ta ble 1. Tetrazole Ureas: ACAT Inhibition in Vitro and Hypocholesterolemic Activity in Vivo
APCCc % ∆TC
compd
Ara
R
IAIb IC50 (µM)
30 mg/kg
3 mg/kg
CLOGPd
1
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
DIP
TMP
DIP
DIP
TMP
DIP
DIP
H
>10
-19
ND
ND
ND
2.02
3.63
3.65
4.71
5.77
6.30
6.83
7.36
7.88
8.41
8.94
10.00
5.79
5.60
6.23
7.17
8.23
6.40
6.67
5.37
2a
2b
2c
2d
2e
2f
2g
2h
2i
2- CH2Ph
0.37
-27*
-26
2-(CH2)3Me
2-(CH2)5Me
2-(CH2)7Me
2-(CH2)8Me
2-(CH2)9Me
2-(CH2)10Me
2-(CH2)11Me
2-(CH2)12Me
2-(CH2)13Me
2-(CH2)15Me
2-(CH2)10CO2Me
2-geranyl
2-(CH2)11Me
1-(CH2)9Me
1-(CH2)11Me
1-(CH2)11Me
2-(CH2)11OTHP
2-(CH2)11OH
0.092
0.073
0.059
0.031
0.014
0.009
0.014
0.009
0.012
0.057
4.7
-59*
-67*
-65*
-62*
-70*
-67*
-67*
-65*
-67*
-23
-21
-24
+1
-35*
-63*
-61*
-67*
-56*
-43*
ND
2j
2k
2m
2n
2p
3a
3b
3c
6
0.063
0.066
0.18
-27
ND
-75*
-65*
-57*
ND
-69*
-22
-45*
ND
-28*
ND
0.21
28% @ 1 µM
0.037
0.032
-53*
-28*
7
a
b
DIP ) 2,6-diisopropylphenyl, TMP ) 2,4,6-trimethoxyphenyl. ACAT inhibition in vitro measured in rabbit intestinal microsomes.
c Denotes percent change in plasma TC in an acute C-fed rat model of hypercholesterolemia, with p < 0.05* and ND ) not determined.
Reference 29, CLOGP refers to calculated lipophilicity.
d
Sch em e 10a
Sch em e 12a
a
(a) LDA, THF; (b) TMSCl; (c) m-CPBA; (d) HCl, Et2O; (e)
H2NCN, THF/H2O, NaOH, Bu4NOH; (f) 2,6-(i-Pr)2PhNCO, MeCN,
Et3N.
a
(a) Thiourea, I2, 100 °C; (b) 2,6-(i-Pr)2PhNCO, Et3N, MeCN.
Sch em e 11a
Ta ble 2. Tetrazole Ureas: ACAT Inhibition in Vitro and
Hypocholesterolemic Activity in Vivo
APCCc % ∆TC
IAIb IC50
(µM)
30
3
compd Ara
R
mg/kg mg/kg CLOGPd
10
11
DIP 2-(CH2)11Me
TMP 2-(CH2)11Me
0.012
0.15
-58* -31*
-40* ND
7.86
6.21
a
(a) C12H25Br, NaOH, MeOH; (b) 5% Pd/C, H2, MeOH; (c) 2,6-
(i-Pr)2PhNCO, EtOAc; (d) HCl, Et2O.
a-d
See corresponding footnotes in Table 1.
and lower plasma TC in the acute C-fed rat assay. The
2,4,6-trimethoxyphenyl analogs 2p , 3c, and 11 were all
less potent in vitro than the corresponding 2,6-diiso-
propylphenyl analogs 2h , 3b, and 10. The 2,6-diisopro-
pylphenyl analog 2h and the corresponding 2,4,6-
trimethoxyphenyl 2p were equivalent in vivo. However
the 2,4,6-trimethoxyphenyl analog 11 was less effica-
cious than 2,6-diisopropyl analog 10. There was a
general trend toward better overall activity with the 2,6-
diisopropyl substitution; thus, this was chosen.
tetrazole ring was replaced by various other heterocycles
bearing 2- and 3-heteroatom replacements. From the
tetrazole urea studies, the 2,6-diisopropylphenyl and the
C11-14 alkyl chain were the substituents of choice
when assessing the viability of the heterocyclic replace-
ments for tetrazole. The 3-heteroatom replacements
were examined, and the results are depicted in Table
3. The 1,3,4-thiadiazole 14a was 3-fold less active in
vitro and also less active in vivo than the corresponding
tetrazole 2i. The 1,3,4-oxadiazole 16 proved an excel-
lent bioisosteric replacement for tetrazole in vitro and
in the APCC rat at a dose of 30 mg/kg. However lower
The potency of the tetrazole ureas necessitated an
examination of the role of the heterocyclic linker. The

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4387
Ta ble 3. 3-Heteroatom Heterocyclic Ureas: ACAT Inhibition in Vitro and Hypocholesterolemic Activity in Vivo
a-d
See corresponding footnotes in Table 1.
efficacy was observed at 3 mg/kg in vivo. The triazole
ureas 19-27 were considerably less active in vitro than
the tetrazoles. A comparison of the long chain regioi-
somers showed N-alkylation (21a -c) to be superior to
C-alkylation (19). C-Alkylation presents a free NH, the
presence of which may lower activities in vitro and in
vivo.16 The N-alkylated 1,3-substituted regioisomer 21b
imparted more activity than 1,2-substitution (21c) in
vitro, in agreement with the structure-activity relation-
ship (SAR) observed with 1- and 2-alkylated tetrazoles,
with relative 1,3-substitution being optimal. However,
in contrast 21b was essentially equipotent with the
other 1,2-regioisomer 21a .
Insertion of a sulfur in the alkyl chain on the triazoles
(25) improved the in vitro activity over the C-alkylated
series (19). Further oxidation of sulfur decreased in
vitro activity (26, 27). The presence of the free ring NH
in these derivatives is also detrimental to in vivo
activity. Only when the ring nitrogen was acylated (24)
was some in vivo activity observed, although this was
not statistically significant.
When the 2-heteroatom replacements for tetrazole
were examined (Table 4), the isoxazole (30a -d , 32)
moiety proved optimal in vitro and in vivo. The 3-alkyl
(30b) regioisomer when compared with the 5-alkyl (32)
showed no difference between the two regioisomers. The

4388 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
Ta ble 4. 2-Heteroatom Heterocyclic Ureas: ACAT Inhibition in Vitro and Hypocholesterolemic Activity in Vivo
a-d
See corresponding footnotes in Table 1.
optimal isoxazoles 30c,d and 32 were essentially equi-
potent and efficacious with the optimal tetrazoles 2g-j
in vitro and in the APCC rat model when dosed at 3
mg/kg. The imidazole replacement 37 (IC50 ) 0.035 µM)
displayed good in vitro activity but was not as potent
as the tetrazole 2h in vivo in the APCC rat model dosed
TC and non-HDL-C at all doses tested as shown in Table
5. A dose dependent rise in HDL-C was also observed,
being significant at the 10 and 30 mg/kg doses. The
oxadiazole ureas were all evaluated at a single dose of
30 mg/kg. The isoxazole ureas 30b,c were essentially
equivalent to the tetrazoles. However, for the C10 and
C14 analogs 30d,a, efficacy fell off sharply. The 3-amino-
5-alkyl regioisomer 30b was superior to the 5-alkyl-3-
aminooxadiazole 32, especially for HDL-C elevation.
Effica cy in Ch olester ol-F ed Dogs a n d Ad r en a l
Toxicity. The compounds 2h -j were evaluated in
cholesterol-fed dogs at a dose of 3 mg/kg po (Table 6).
All compounds lowered plasma TC in a statistically
significant manner. Compound 2i containing the C13
side chain was the most effective at lowering TC.
Plasma drug blood levels were determined by HPLC in
the dog for 2i,h (Table 6); both compounds are present
in plasma although there is significant variability
consistent with the compounds being very lipophilic. The
assay could not determine levels below 40 ng/mL, and
the results (Table 6) represent a mean of 6 animals. As
a result of the excellent in vivo activity displayed by
these compounds, several were tested in a model to
assess adrenal toxicity in guinea pigs in vivo.30 This
problem has been observed previously with potent
lipophilic urea ACAT inhibitors but was thought to be
unrelated to ACAT inhibition.30 Unfortunately, 2i,h
at 30 mg/kg. The oxazole ring replacement 35 (IC50
)
0.063 µM) was weaker in vitro and in the APCC rat
model when dosed at 30 mg/kg than both tetrazole 2i
(IC50 ) 0.009 µM)] and the closely related isoxazole 30c
(IC50 ) 0.020 µM). The latter observation is suprising,
as lipophilicity is similar and the three compounds all
present 1,3-substitution on the heterocycle. The thia-
zole ring (39a ,b) was the least active of the 2-heteroatom
replacements, significantly less active both in vitro and
in vivo in the APCC rat dosed at 30 mg/kg. This
correlates with the 3-heteroatom replacement SAR, at
least in vivo, where lower activity was observed with
the sulfur-containing 1,3,4-thiadiazoles 14a -c in the
APCC rat model dosed at 30 mg/kg.
E ffica cy in t h e Ch r on ic R a t Mod el of P r e-
establish ed Hyper ch olester olem ia. The acute APCC
rat model was not sufficient to distinguish between the
more potent tetrazole ureas 2h -j and isoxazole ureas
30a -d and 32. The compounds were evaluated in the
chronic rat model. The tetrazole ureas 2h -j were all
efficacious and essentially equivalent at lowering both

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4389
Ta ble 5. Efficacy in the Rat Model of Pre-established Hypercholesterolemia
CPCC
compd
heterocycle
R
dosea (mg/kg)
% ∆TCb
% ∆HDL-Cc
% ∆non-HDL-Cd
2h
2h
2h
2i
2i
2i
2j
2j
2j
30a
30b
30c
30d
32
X
X
X
X
X
X
X
X
X
Y
Y
Y
Y
Z
(CH2)11Me
(CH2)11Me
(CH2)11Me
(CH2)12Me
(CH2)12Me
(CH2)12Me
(CH2)13Me
(CH2)13Me
(CH2)13Me
(CH2)13Me
(CH2)12Me
(CH2)11Me
(CH2)9Me
(CH2)12Me
30
10
3
30
10
3
30
10
3
30
30
30
30
30
-69*
-64*
-43*
-66*
-64*
-52*
-61*
-53*
-43*
-16
+93*
+87*
+20
-78*
-72*
-47*
-76*
-73*
-47*
-68*
-61*
-48*
-18
+113*
+113*
+21*
+93*
+87*
+47
+16
-53
+111*
+100*
-6
-65*
-68*
-14
-56*
-13
-40
+33
-45
a
b
Dose of compound administered daily for 1 week, after 1 week on high-C diet. Denotes percent change in plasma TC in the chronic
C-fed rat model of pre-established hypercholesterolemia. c Denotes percent change in HDL-C. Denotes percent change in non-HDL-C.
d
The percent change in TC, HDL-C, and non-HDL-C was statistically significant from control with p < 0.05*.
Ta ble 6. Tetrazole Ureas: Efficacy in Cholesterol-Fed Dogs at
fed dogs. Tetrazole 2i also lowered TC 52% and raised
3 mg/kg
HDL-C 113% in rats with pre-established hypercholes-
terolemia dosed at 10 mg/kg, but was adrenotoxic in
guinea pigs. The isoxazole urea 30c was not overtly
toxic. Our efforts to exploit the inherent activity of the
heterocycle and overcome the toxicities observed with
this series will be the subject of future publications.
%∆ plasma
plasma levelsb
(ng/mL)
compd
R
cholesterola
Exp er im en ta l Section
2h
2i
2j
(CH2)11Me
(CH2)12Me
(CH2)13Me
-39*
-47*
-22
29.3 ( 45.8
76.7 ( 65.6
ND
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without further purification.
Column chromatography was performed on Merck silica gel
60 (230-400 mesh). Melting points were determined on a
Thomas-Hoover melting point apparatus and are uncorrected.
a
Represents mean percent change in plasma TC relative to
controls dosed at 3 mg/kg, statistically significant, p < 0.05* using
b
NMR spectra were determined on
a Brucker 250 MHz,
paired, two-tailed t-test (n ) 6). Mean blood drug concentration
in the dog, compound dosed at 3 mg/kg. ND ) not determined.
VarianXL 300 MHz, or Varian Unity 400 MHz instrument.
Chemical shifts (δ) are expressed in ppm, relative to internal
tetramethylsilane. Mass spectra were obtained on a VG
Masslab Trio-2A, or VG Analytical 7070E/HF, or Finnigan
4500 mass spectrometer. Elemental analyses were determined
on a Perkin-Elmer 240C elemental analyzer and were within
(0.4%.
caused adrenal cortical atrophy of the zona fasciculata
and necrosis of adrenal cortical cells in the adrenal
cortex. The isoxazole urea 30c was also examined and
found not to be overtly toxic. However it did increase
cytoplasmic coarse vacuolation in the zona fasciculata.
The significance of this finding has yet to be established.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(1H-tetr a zol-5-yl)-
u r ea (1). 5-Aminotetrazole hydrate (45 g, 0.44 mol) was
refluxed in toluene (300 mL) in the presence of a Dean-Stark
trap. After removal of the theoretical amount of water (7.9
mL), the mixture was allowed to cool and concentrated in
vacuo and the resulting solid stirred with acetonitrile (500 mL).
Triethylamine (61 mL, 0.44 mol) and 2,6-diisopropylphenyl
isocyanate (89.3 mL, 0.44 mol) were added sequentially, and
the mixture was refluxed for 4 h. The mixture was then
allowed to cool and concentrated in vacuo to about 200 mL,
and acidified with l M citric acid. The solid was filtered,
washed with water (l L) and ethyl acetate (1 L), and pumped
in vacuo for 12 h to give the title compound, 87.6 g (69%
Con clu sion
This study has identified a series of ACAT inhibitors
which are extremely potent in vitro and effective at
lowering plasma cholesterol in cholesterol-fed rats and
dogs. The activity is optimized by having the substitu-
ent on the heterocycle 1,3-oriented. In vivo, certain
examples from the isoxazoles were shown to be equiva-
lent to the tetrazole at 30 mg/kg in cholesterol-fed rats.
The triazoles and thiazoles were significantly less active.
A heterocycle containing nitrogen and/or oxygen seems
to be desirable as a linker, except when this heterocycle
is triazole or even less optimal when it furnishes a free
ring NH. A sulfur atom in the heterocycle leads to
compounds of lower activity.
1
yield): mp >240 °C; 250 MHz H NMR (DMSO-d6) δ 1.14 (d,
J ) 7.5 Hz, 12Η), 3.11 (m, 2H), 7.18 (d, J ) 7 Hz, 2H), 7.27-
7.32 (m, 1H), 8.12 (s, 1H), 10.63 (s, 1H), 15.45 (s br, 1H); EIMS
m/ z 288 (M+). Anal. (C14H20N6O) C, H, N.
N-[2,6-bis(1-m eth yleth yl)p h en yl]-N′-(2-tetr a d ecyl-2H-
tetr a zol-5-yl)u r ea (2j). 1-Bromotetradecane (26.1 g, 0.094
mol) was added to a refluxing solution of 1 (24.8 g, 0.086 mol),
triethylamine (9.51 g, 0.094 mol), and acetonitrile (300 mL).
The mixture was allowed to reflux for 18 h, cooled, and filtered,
and the solid obtained recrystallized from hot acetonitrile to
give a white solid (25.0 g, 60%): mp 112-114 °C; 1H NMR
(CDCl3) δ 0.88 (t, J ) 7 Hz, 3H), 1.20 (s, 22H), 2.00 (m, 2H),
In general the tetrazole-substituted ureas were the
most potent in vitro and the most effective at lowering
plasma TC in vivo. The optimal tetrazole urea 2i when
dosed at 3 mg/kg lowered total cholesterol 49% in an
acute cholesterol-fed rat model and 47% in cholesterol-

4390 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
3.17 (heptet, J ) 7 Hz 2H), 4.54 (t, J ) 7 Hz, 2H), 7.19-7.35
(m, 3H), 8.70 (s, 1H), 9.03 (s, 1H); EIMS m/ z 485 (MH+). Anal.
(C28H48N6O) C, H, N.
lized from acetonitrile (48% yield): mp 154-156 °C; 300 MHz
1H NMR (CDCl3) δ 0.90 (t, J ) 7 Hz, 3H), 1.24 (s br, 14H),
1.35 (s, 4H), 2.02 (m, 2H), 3.19 (m, 2H), 4.55 (t, J ) 7 Hz, 2H),
7.21-7.33 (m, 3H), 7.53 (s, 1H), 8.99 (s, 1H); EIMS 372 (M+).
Anal. (C20H32N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-u n d ecyl-2H-tet-
r a zol-5-yl)u r ea (2g). The compound was prepared as in the
above procedure for 2i using 1-bromoundecane and chromato-
graphed on silica gel eluting with 15% ethyl acetate in hexane
(25% yield): mp 119-121 °C; 250 MHz 1H NMR (DMSO-d6) δ
0.85 (t, J ) 7 Hz, 3H), 1.14 (d, J ) 7.5 Hz, 12Η), 1.22 (s, 16H),
1.89 (m, 2H), 3.09 (m, 2H), 4.58 (t, J ) 7 Hz, 2H), 7.16-7.31
(m, 3H), 8.42 (s, 1H), 10.12 (s, 1H). EIMS m/ z 443 (MH+).
Anal. (C25H42N6O) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-[2-[10-(m et h oxy-
ca r bon yl)d ecyl]-2H-t et r a zol-5-yl]u r ea (2m ). The com-
pound was prepared as in the above procedure for 2i using
11-bromoundecanoic acid methyl ester and chromatographed
on silica gel eluting with 20% ethyl acetate in hexane (19%
yield): mp 80-85 °C; 250 MHz 1H NMR (CDCl3) δ 1.25 (m,
24Η), 1.61 (m, 2H), 1.99 (m, 2H), 2.30 (t, J ) 8 Hz, 2H), 3.19
(m, 2H), 3.66 (s, 3H), 4.54 (t, J ) 7 Hz, 2H), 7.19-7.34 (m,
3H), 8.58 (s, 1H), 9.02 (s, 1H); CIMS m/ z 487 (MH+). Anal.
(C26H42N6O3) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-[2-(3,7-d im eth yl-
2,6-octa d ien yl)-2H-tetr a zol-5-yl]u r ea (2n ). The compound
was prepared as in the above procedure for 2i using geranyl
bromide and chromatographed on silica gel eluting with 20%
ethyl acetate in hexane (33% yield): mp 98-107 °C; 250 MHz
1H NMR (CDCl3) δ 1.21 (m, 15H), 1.58 (s, 3H), 1.66 (s, 3H),
1.81 (s, 2H), 1.97 (m, 1H), 2.08 (s, 3H), 3.19 (m, 2H), 4.70 (m,
1H), 5.05 (m, 1H), 5.14 (d, J ) 7 Hz, 2H), 5.49 (t, J ) 7 Hz,
1H), 7.21-7.34 (m, 3H), 8.84 (s, 1H), 9.07 (s, 1H); EIMS m/ z
424 (M+). Anal. (C24H36N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-octyl-2H-tetr a -
zol-5-yl)u r ea (2d ). A mixture of 1 (2.0 g, 6.94 mmol),
l-bromooctane (1.8 mL, 10.4 mmol), and triethylamine (1.0 mL,
7 mmol) in a 1:1 mixture of dimethylformamide/toluene (100
mL) was heated to reflux for 18 h and then cooled and
partitioned between l N HCl and ethyl acetate. The organic
layer was washed three times with water, dried over MgSO4,
and filtered and the filtrate evaporated to dryness. The
remaining solid was chromatographed on silica gel in ethyl
acetate/hexane to give the title compound (0.94 g, 34%): mp
139-140 °C; 250 MHz 1H NMR (CDCl3) δ 0.88 (t, J ) 7 Hz,
3H), 1.24 (m, 22H), 2.00 (m, 2H), 3.19 (m, 2H), 4.54 (t, J ) 7
Hz, 2H), 7.19-7.35 (m, 3H), 8.44 (s, 1H), 9.02 (s, 1H); EIMS
m/ z 401 (MH+). Anal. (C22H36N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-d ecyl-2H-tetr a -
zol-5-yl)u r ea (2f). Solid NaHCO3 (2 g, 0.02 mol ) and
1-bromodecane (2 mL, 0.01 mol) were added to a solution of 1
in DMF (30 mL). The mixture was stirred at 80 °C for 6 h,
allowed to cool, diluted with DMF (100 mL), and extracted with
Et2O. The organic layer was washed three times with water,
dried with MgSO4, concentrated, and chromatographed on
silica gel in ethyl acetate/hexane to yield a greasy solid which
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-n on yl-2H-tetr a -
zol-5-yl)u r ea (2e). The compound was prepared as in the
above procedure for 2j using l-bromononane (17% yield): mp
128-130 °C; 250 MHz 1H NMR (DMSO-d6) δ 0.84 (t, J ) 7
Hz, 3H), 1.14 (d, J ) 7.5 Hz, 12Η), 1.22 (s, 12H), 1.89 (m, 2H),
3.13 (m, 2H), 4.58 (t, J ) 7 Hz, 2H), 7.16-7.31 (m, 3H), 8.44
(s, 1H), 10.18 (s, 1H); CIMS m/ z 414 (MH+). Anal. (C23H38N6O)
C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-d od ecyl-2H-tet-
r a zol-5-yl)u r ea (2h ). The compound was prepared as in the
above procedure for 2j using l-bromododecane (30% yield): mp
117-119 °C; 250 MHz 1H NMR (CDCl3) δ 0.88 (t, J ) 7 Hz,
3H), 1.25 (s sh, 30H), 2.00 (m, 2H), 3.19 (m, 2H), 4.54 (t, J )
7 Hz, 2H), 7.19-7.35 (m, 3H), 8.43 (s, 1H), 9.01 (s, 1H); CIMS
m/ z 457 (MH+). Anal. (C26H44N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-h exa d ecyl-2H-
tetr a zol-5-yl)u r ea (2k ). The compound was prepared as in
the above procedure for 2j using l-bromohexadecane (43%
1
yield): mp 108-111 °C; 250 MHz H NMR (DMSO-d6) δ 0.85
(t, J ) 7 Hz, 3H), 1.14 (d, J ) 7.5 Hz, 12Η), 1.23 (s, 26H), 1.89
(m, 2H), 3.12 (m, 2H), 4.57 (t, J ) 7 Hz, 2H), 7.16-7.31 (m,
3H), 8.43 (s, 1H), 10.15 (s, 1H); EIMS m/ z 513 (MH+). Anal.
(C30H52N6O) C, H, N.
N-(2,4,6-Tr im eth oxyp h en yl)-N′-(2-d od ecyl-2H-tetr a zol-
5-yl)u r ea (2p ). The compound was prepared as in the above
procedure for 2j and 1 using N-(2,4,6-trimethoxyphenyl)-
isocyanate.12 The crude reaction mixture was allowed to cool;
the precipitate obtained was filtered and chromatographed on
silica gel eluting with 50% ethyl acetate in hexanes to give an
off-white solid as the title compound (25% yield): mp 161-
166 °C; 250 MHz 1H NMR (DMSO-d6) δ 0.85 (t, J ) 7 Hz, 3H),
1.23 (s, 18H), 1.87 (m, 2H), 3.74 (s, 6H), 3.79 (s, 3H), 4.56 (t,
J ) 7 Hz, 2H), 6.27 (s, 2H), 7.79 (s, 1H), 9.88 (s, 1H); EIMS
m/ z 462 (M+). Anal. (C23H38N6O4) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-tr id ecyl-2H-tet-
r a zol-5-yl)u r ea (2i). 1-Bromotridecane (5.48 g, 0.022 mol)
was added to a refluxing solution of 1 (6.0 g, 0.021 mol),
triethylamine (2.1 g, 0.021 mol), and acetonitrile (175 mL).
The solution was refluxed for 6 days, cooled, concentrated, and
partitioned between l M citric acid and ethyl acetate. The
organics were washed with water, dried over Na2SO4, concen-
trated in vacuo, and chromatographed on silica gel eluting with
15% ethyl acetate in hexane to give a white solid (1.2 g, 12%):
1
mp 110-114 °C; 250 MHz H NMR (DMSO-d6) δ 0.85 (t, J )
7 Hz, 3H), 1.14 (d, J ) 7.5 Hz, 12Η), 1.23 (s, 20H), 1.89 (m,
2H), 3.13 (m, 2H), 4.58 (t, J ) 7 Hz, 2H), 7.16-7.31 (m, 3H),
8.43 (s, 1H), 10.18 (s, 1H); CIMS m/ z 471 (MH+). Anal.
(C27H46N6O4) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-[2-(ph en ylm eth yl)-
2H-tetr a zol-5-yl]u r ea (2a ). The compound was prepared as
in the above procedure for 2i using benzyl bromide. The crude
reaction mixture was cooled, concentrated in vacuo, and
partitioned between ethyl acetate/1 M HCl. The organics were
dried over MgSO4 and concentrated and the solid obtained
recrystallized from hot acetonitrile (29% yield): mp 180-181
°C; 300 MHz 1H NMR (CDCl3) δ 1.19 (s br, 12H), 3.15 (m, 2H),
5.70 (s, 2H), 7.16-7.43 (m, 8H), 7.94 (s, 1H), 8.92 (s, 1H); CIMS
m/ z 379 (MH+). Anal. (C21H26N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-bu tyl-2H-tetr a -
zol-5-yl)u r ea (2b). The compound was prepared as in the
above procedure for 2i using 1-bromobutane and chromato-
graphed on silica gel eluting with 50% ethyl acetate in hexane
(23% yield): mp 174-179 °C; 250 MHz 1H NMR (DMSO-d6) δ
0.90 (t, J ) 7 Hz, 3H), 1.14 (d, J ) 7.5 Hz, 12Η), 1.29 (m, 2H),
1.88 (m, 2H), 3.11 (m, 2H), 4.59 (t, J ) 7 Hz, 2H), 7.16-7.31
(m, 3H), 8.41 (s, 1H), 10.12 (s, 1H); EIMS m/ z 345 (MH+).
Anal. (C18H28N6O) C, H, N.
was recrystallized from Et2
O/hexane to give the title compound
1
(0.76 g, 34%): mp 123-124 °C; 250 MHz H NMR (CDCl3) δ
0.88 (t, J ) 7 Hz, 3H), 1.26 (m, 26H), 2.00 (m, 2H), 3.18 (m,
2H), 4.54 (t, J ) 7 Hz, 2H), 7.18-7.32 (m, 3H), 7.96 (s, 1H),
9.00 (s, 1H); EIMS m/ z 429 (MH+). Anal. (C24H40N6O) C, H,
N.
5-Am in o-1-d od ecyltetr a zole (4) a n d 5-Am in o-2-d od e-
cyltetr a zole (5). 1-Bromododecane (46.8 g, 0.188 mol) was
added in one portion to a refluxing solution of hydrated
5-aminotetrazole (20.0 g, 0.19 mol) and sodium hydroxide
(8 g, 0.2 mol) in 550 mL of ethanol/water (4:1.5, v/v). The
resulting mixture was refluxed for 18 h, allowed to cool,
filtered, and washed with ethanol (2 × 50 mL), and the
resulting solid was dried in vacuo to give 17.85 g of a mix-
ture of isomers. The mixture was recrystallized from aceto-
nitrile (250 mL) to give 6.85 g (14%) of 5-amino-1-dodecyl-
tetrazole: mp 159-160 °C; 250 MHz 1H NMR (DMSO-d6) δ
0.86 (t, J ) 7 Hz, 3H), 1.24 (s, 18H), 1.69 (m, 2H), 4.06 (t, J )
7 Hz, 2H), 6.66 (s, 2H); EIMS m/ z 254 (MH+). Anal.
(C13H27N5) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-h exyl-2H-tetr a -
zol-5-yl)u r ea (2c). The compound was prepared as in the
above procedure for 2i using 1-bromohexane, refluxed for 3
days, allowed to cool, and concentrated in vacuo. The mixture
was partitioned between ethyl acetate and 1 M HCl and the
organic layer dried over MgSO4, concentrated, and recrystal-

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4391
The crude reaction filtrate from above was concentrated to
two-thirds volume in vacuo and allowed to crystallize. The
mixture was filtered to yield a solid, which was dried in vacuo
to give 9.95 g (21%) of 5-amino-2-dodecyltetrazole: mp 62.5-
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-[2-(11-h yd r oxyu n -
d ecyl)-2H-tetr a zol-5-yl]u r ea (7). Compound 6 (24.6 g, 0.045
mol) was stirred at room temperature with p-toluenesulfonic
acid (0.5 g) in methanol (200 mL) for 1.5 h. The solution was
then concentrated in vacuo and redissolved in ethyl acetate
(20 mL). Hexane (200 mL) was added and the resultant
precipitate filtered. The residue was chromatographed on
silica gel, eluting with 35% ethyl acetate in hexanes to give
the title compound as a white solid (6.73 g, 33%): mp 84-87
1
63.5 °C; 400 MHz H NMR (DMSO-d6) δ 0.85 (t, J ) 6.8 Hz,
3H), 1.23 (s, 18H), 1.80 (m, 2H), 4.35 (t, J ) 6.8 Hz, 2H), 5.98
(s, 2H); CIMS m/ z 254 (MH+). Anal. (C13H27N5) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(1-d od ecyl-1H-tet-
r a zol-5-yl)u r ea (3b). Triethylamine (2.50 mL, 18.0 mmol)
was added to a slurry of 4 (4.56 g, 18.0 mmol) in acetonitrile
(150 mL). The mixture was heated to reflux, and upon
dissolution of the solid 2,6-diisopropylphenyl isocyanate (3.90
mL, 18.1 mmol) was added in one portion. The solution was
refluxed for 18 h and allowed to cool. The resultant precipitate
was filtered and the filtrate concentrated in vacuo and
partitioned between ethyl acetate and water. The organic
layer was washed with brine, dried over Na2SO4, filtered,
concentrated in vacuo, and chromatographed on silica gel,
eluting with 10% and then 15% ethyl acetate in hexanes to
give an oil which solidified on standing to give the title
compound as a white solid (1.95 g, 24%): mp 80-88 °C; 250
1
°C; 250 MHz H NMR (CDCl3) δ 1.15 (d, J ) 7 Hz, 12Η), 1.24
(m, 14H), 1.40 (m, 2H), 1.90 (m, 2H), 3.13 (heptet, J ) 7 Hz,
2H), 3.37 (m, 2H), 4.32 (br t, 1H), 4.58 (t, J ) 7 Hz, 2H), 7.31-
7.7.17 (m, 3H), 8.43 (s, 1H), 10.35 (s, 1H); EIMS m/ z 459
(MH+). Anal. (C25H42N6O2) C, H, N.
2-Dod ecyltetr a zolea cetic Acid Eth yl Ester (8a ) a n d
1-Dod ecyltetr a zolea cetic Acid Eth yl Ester (8b). 1-Bro-
mododecane (8.78 g, 0.035 mol) was added to a refluxing
solution of the tetrazoleacetic acid ethyl ester (5 g, 0.032 mol)19
and triethylamine (3.56 g, 0.035 mol) in acetonitrile (150 mL).
The mixture was refluxed for 18 h, allowed to cool, and filtered.
The filtrate was concentrated in vacuo and partitioned between
ethyl acetate (150 mL) and water (150 mL). The organic layer
was washed with brine (100 mL), dried over MgSO4, and then
filtered, concentrated, and chromatographed on silica gel,
eluting with 10% and then 20% ethyl acetate in hexanes to
give 8a as an oil (5.40 g, 52%): Rf 0.66, 50% ethyl acetate/
hexane; 250 MHz 1H NMR (DMSO-d6) δ 4.65(t, J ) 6.9 Hz,
2H), 4.12 (q, J ) 7.1 Hz, 2H), 4.04 (s, 2H), 1.90 (m, 2H), 1.23
(s, H), 0.85 (t, J ) 7.1 Hz, 3H); EIMS m/ z 325 (MH+). Anal.
(C17H32N4O2) C, H, N. 8b was obtained as a solid (3.39 g,
33%): mp 59-62 °C; Rf 0.50, 50% ethyl acetate/hexane; 250
1
MHz H NMR (DMSO-d6) δ 0.5 (t, J ) 6 Hz, 3H), 1.15 (d, J )
7.5 Hz, 12Η), 1.24 (s, 18H), 1.80 (m, 2H), 3.13 (m, 2H), 4.30 (t,
J ) 7 Hz, 2H), 7.17-7.32 (m, 3H), 8.93 (s, 1H), 10.24 (s, 1H);
EIMS m/ z 457 (MH+). Anal. (C26H44N6O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(1-d ecyl-1H-tetr a -
zol-5-yl)u r ea (3a ). 5-Amino-1-decyltetrazole (3.5 g, 0.0155
mol), made in a manner similar to 4, and 2,6-diisopropylphenyl
isocyanate (3.65 mL, 0.017 mol) were dissolved in 1,2-dichlo-
roethane (100 mL) to which triethylamine (2.4 mL) was added.
The reaction mixture was heated to reflux for 8 h, stirred
overnight, and then partitioned between saturated aqueous
ammonium chloride and methylene chloride. The organic
layer was washed twice with water and then dried over
MgSO4, filtered, and evaporated to give a solid which was
chromatographed on silica gel in ethyl acetate/hexane to give
a white solid which was recrystallized from hexane at -78 °C
to give the title compound (35% yield): mp 135-136 °C; 250
1
MHz H NMR (DMSO-d6) δ 4.34 (t, J ) 7.3 Hz, 2H), 4.27 (s,
2H), 4.14 (q, J ) 7.0 Hz, 2H), 1.81 (m, 2H), 1.24 (s, H), 0.86 (t,
J ) 7.0 Hz, 3H); EIMS m/ z 325 (MH+). Anal. (C17H32N4O2)
C, H, N.
2-Dod ecyltetr a zolea cetic Acid (9). A solution of KOH
(4.21 g, 0.075 mol) in water (10 mL) was added to a solution
of 8a (23.2 g, 0.0715 mol) in ethanol (250 mL). The mixture
was stirred at room temperature for 3 h, concentrated in vacuo
to 50 mL, diluted with water (200 mL), and washed with ethyl
acetate (100 mL). The aqueous layer was acidified with 1 M
HCl and extracted with ethyl acetate. The organic layer was
dried over MgSO4, filtered, and concentrated to give a white
solid (18.0 g, 85%): mp 70-71.5 °C; 250 MHz 1H NMR (CDCl3)
δ 4.60 (t, J ) 7.2 Hz, 2H), 4.04 (s, 2H), 2.01 (m, 2H), 1.32 (m,
2H), 1.25 (s, 16H), 0.88 (t, J ) 6.8 Hz, 3H); CIMS m/ z 297
(MH+). Anal. (C15H28N4O2) C, H, N.
1
MHz H NMR (CDCl3) δ 0.91 (t, J ) 7 Hz, 3H), 1.21 (m, 28H),
3.16 (m, 2H), 4.08 (t, J ) 7 Hz, 2H), 7.13-7.35 (m, 3H), 9.96
(s, 1H), 11.22 (s, 1H); EIMS m/ z 429 (MH+). Anal. (C24H40N6O)
C, H, N.
N-(2,4,6-Tr im eth oxyp h en yl)-N′-(2-d od ecyl-1H-tetr a zol-
5-yl)u r ea (3c). Triethylamine (0.85 mL, 6.1 mmol) and 2,4,6-
trimethoxyphenyl isocyanate12 (1.44 g, 6.1 mmol) were added
to a solution of 4 (1.55 g, 6.1 mmol) in acetonitrile (50 mL).
The mixture was refluxed for 18 h and allowed to cool; the
resulting precipitate was recrystallized from CH3CN to give
the title compound as needles (0.46 g, 17%): mp 139-140 °C;
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-[(2-d od ecyl-2H -
tetr a zol-5-yl)m eth yl]u r ea (10). Triethylamine (0.84 mL, 6.1
mmol) was added to a mixture of 9 (1.5 g, 5.0 mmol) and
diphenyl phosphorazidate (1.64 mL, 7.6 mmol) in dioxane (50
mL). The mixture was stirred for 15 min at room temperature
and then heated to reflux for 20 min and cooled, and 2,6-
diisopropylphenylamine (1.2 mL, 6.1 mmol) was added. The
mixture was stirred for 15 min at room temperature and then
heated to reflux for 30 min, allowed to cool, and poured into
ethyl acetate/water. The organic layer was washed with 1 M
HCl, water, saturated aqueous NaHCO3, and brine, dried over
Na2SO4, and chromatographed on silica gel eluting with 40%
ethyl acetate in hexanes to give the title compound (0.76 g,
1
250 MHz H NMR (DMSO-d6) δ 0.88 (t, J ) 7 Hz, 3H), 1.06-
1.25 (m, 18H), 1.68 (m, 2H), 3.79 (s, 6H), 3.83 (s, 3H), 4.24 (t,
J ) 7 Hz, 2H), 6.15 (s, 2H), 9.39 (s br, 1H), 11.15 (s br, 1H);
FABMS m/ z 463 (MH+). Anal. (C23H38N6O4) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-[2-[[(tetr a h yd r o-
2H-p yr a n -2-yl)oxy]u n d ecyl]-2H-tetr a zol-5-yl]u r ea (6). 11-
Bromoundecan-1-ol (11.2 g, 44.7 mmol) was added to a
vigorously stirred solution of dihydropyran (4.9 mL, 53.7 mmol)
and Amberlyst H15 (0.5 g; Aldrich D10, 620-8) in hexane (100
mL). After 3 h dihydropyran (4.9 mL) was added and the
solution stirred for a further 15 h. The mixture was then
filtered, and the filtrate was concentrated in vacuo and
chromatographed on silica gel, eluting with 2% ethyl acetate
in hexane to give 16.6 g of 2-[(11-bromoundecyl)oxy]tetrahy-
dropyran as an oil, which was added to a refluxing mixture of
1 (11.6 g, 40.2 mmol), triethylamine (6.2 mL, 44.2 mmol), and
acetonitrile (250 mL). The mixture was allowed to reflux for
18 h, allowed to cool, and concentrated to one-third volume.
The slurry obtained was filtered and the filtrate concentrated
in vacuo and recrystallized from acetonitrile to give the title
compound as a white solid (4.72 g, 19%): mp 105-111 °C; 250
MHz 1H NMR (CDCl3) δ 1.27 (m, 26H), 1.54 (m, 6H), 1.82-
1.71 (m, 2H), 2.00 (m, 2H), 3.18 (m, 2H), 3.39 (m, 1H), 3.52
(m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.54 (m, 3H), 7.35-7.19
(m, 3H), 8.19 (s, 1H), 9.00 (s, 1H); FABMS m/ z 543 (MH+).
Anal. (C30H50N6O3) C, H, N.
1
31%): mp 87-90 °C; 250 MHz H NMR (CDCl3) δ 0.88 (t, J )
7 Hz, 3H), 1.14-1.28 (m, 30H), 1.94 (m, 3H), 3.28 (m, 2H),
4.51 (t, J ) 7 Hz, 2H), 4.68 (s, 2H), 6.13 (s br, 1H), 7.13-7.37
(m, 3H); EIMS m/ z 471 (MH+). Anal. (C27H46N6O) C, H, N.
N-(2,4,6-Tr im eth oxyph en yl)-N′-[(2-dodecyl-2H-tetr azol-
5-yl)m eth yl]u r ea (11). The compound was prepared as in
the above procedure for compound 10 using 2,4,6-trimethox-
yphenylaniline12 and chromatographed on silica gel eluting
with 60% ethyl acetate in hexanes to give the title compound
(46%): mp 139-143.5 °C; 250 MHz 1H NMR (DMSO-d6) δ 0.85
(t, J ) 7 Hz, 3H), 1.23 (s, 18H), 1.88 (m, 2H), 3.70 (s, 6H),
3.76 (s, 3H), 4.47 (d, J ) 6 Hz, 2H), 4.62 (t, J ) 7 Hz, 2H),
6.22 (s, 2H), 6.49 (t, J ) 6 Hz, 1H), 6.96 (s, 1H); CIMS m/ z
477 (MH+). Anal. (C24H40N6O4) C, H, N.
Dod eca n oic Acid 2-(Am in ot h ioxom et h yl)h yd r a zid e
(12). Lauroyl chloride (12.9 g, 0.06 mol) in THF (70 mL) was

4392 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
added dropwise to a vigorously stirred suspension of thiosemi-
carbazide (10.9 g, 0.12 mol) in THF (300 mL) at 0 °C. After
the addition was complete, the mixture was allowed to warm
to room temperature and stirred for 24 h. The mixture was
concentrated in vacuo to one-fourth of the original volume and
filtered through silica gel, eluting with ethyl acetate (500 mL).
The filtrate was concentrated to 250 mL and filtered, and the
residue was washed with ethyl acetate and dried in vacuo to
mol) was then added, the mixture was refluxed for 18 h,
allowed to cool, concentrated, diluted with water (20 mL), and
filtered, and the solid was chromatographed on silica gel,
eluting with 20% ethyl acetate in hexanes to give the title
compound (0.54 g, 8% yield) as a white solid: mp 114-116.5
1
°C; 250 MHz H NMR (DMSO-d6) δ 11.02 (br s, 1H), 8.99 (br
s, 1H), 7.33-7.17 (m, 3H), 3.09 (m, 2H), 2.76 (t, J ) 7.3 Hz,
2H), 1.67 (m, 2H), 1.24 (s, 20H), 1.15 (s, 6H), 1.13 (s, 6H), 0.85
(t, J ) 6.7 Hz, 3H); EIMS m/ z 471 (MH+). Anal. (C28H46N4O2)
C, H, N.
1
give a white solid (12.0 g, 73%): 250 MHz H NMR (DMSO-
d6) δ 9.63 (s, 1H), 9.15 (s, 1H), 7.83 (s, 1H), 7.37 (s, 1H), 2.09
(t, J ) 7.3 Hz, 2H), 1.48 (br m, 2H), 1.24 (s, 16H), 0.86 (t, J )
6.5 Hz, 3H); EIMS m/ z 273 (M+). Anal. (C13H25N3O) C, H,
N.
3-Am in o-5-d od ecyl-1H-1,2,4-tr ia zole (17). A slurry of
aminoguanidine bicarbonate (15.24 g, 112 mmol), tridecanoic
acid (12.0 g, 56.0 mmol), and N,N-dimethylaniline (0.1 mL,
0.8 mmol) in toluene (100 mL) was heated under reflux with
the azeotropic removal of water (72 h). The resulting slurry
was cooled (25 °C) and concentrated in vacuo. The residue
was partitioned between ethyl acetate (300 mL) and saturated
sodium bicarbonate (300 mL). The aqueous layer was back-
extracted with ethyl acetate. After filtration, the combined
organic extracts were washed with brine (1 × 250 mL) and
5-Un decyl-1,3,4-th iadiazol-2-am in e (13). Methanesulfon-
ic acid (6.26 g, 0.065 mol) was added in one portion to a slurry
of 12 (11.9 g, 0.044 mol) in toluene (300 mL) at 0 °C. After 5
min, the mixture was heated to reflux for 18 h, allowed to cool
to 0 °C, and filtered, and the residue was washed with cold
toluene (50 mL at 5 °C). The solid was dried in vacuo,
suspended in water (200 mL), and made basic with 0.1 M
ammonium hydroxide while stirring vigorously. The resulting
solid was filtered, washed with water, and dried in vacuo to
give the title compound as a white solid (4.5 g, 41%): mp 176-
177.5 °C; 250 MHz 1H NMR (DMSO-d6) δ 7.02 (br s, 2H), 2.77
(t, J ) 7.4 Hz, 2H), 1.59 (m, 2H), 1.24 (s, 16H), 0.85 (t, J ) 6.8
Hz, 3H); EIMS m/ z 256 (MH+). Anal. (C13H25N3O) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(5-u n d ecyl-1,3,4-
th ia d ia zol-2-yl)u r ea (14b). 2,6-Diisopropylphenyl isocyan-
ate (3.85 g, 0.019 mol) was added to a solution of 13 (4.4 g,
0.017 mol) in acetonitrile (150 mL). The mixture was refluxed
for 1 h and then allowed to stand at room temperature
overnight, concentrated to three-fourths volume, and filtered.
The residue obtained was washed with acetonitrile (50 mL)
and hexanes (200 mL) to give 5.9 g of the title compound as a
white solid (75% yield): mp 111-113 °C; 250 MHz 1H NMR
(DMSO-d6) δ 11.93 (br s, 1H), 8.17 (s, 1H), 7.32-7.16 (m, 3H),
3.09 (m, 2H), 2.90 (t, J ) 7.4 Hz, 2H), 1.66 (m, 2H), 1.23 (s,
16H), 1.15 (s, 6H), 1.13 (s, 6H), 0.85 (t, J ) 6.9 Hz, 3H); EIMS
m/ z 459 (MH+). Anal. (C26H42N4OS‚0.1H2O) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(5-t r id ecyl-1,3,4-
th ia d ia zol-2-yl)u r ea (14a ). The compound (63% yield) was
prepared as in the above procedure for 14b: mp 85-91 °C;
250 MHz 1H NMR (DMSO-d6) δ 10.90 (br s, 1H), 8.08 (br s,
1H), 7.29-7.16 (m, 3H), 3.07 (m, 2H), 2.89 (t, J ) 7.3 Hz, 2H),
1.65 (m, 2H), 1.23 (s, 20H), 1.13 (d, J ) 7.5 Hz, 12Η), 0.85 (t,
J ) 6.8 Hz, 3H); EIMS m/ z 487 (MH+). Anal. (C28H46N4OS)
C, H, N, S.
then dried (MgSO4
) and concentrated in vacuo. The resulting
solid was dissolved in hot chloroform and chromatographed
on silica eluting with ethyl acetate and then 90:10 chloroform/
methanol to give an off-white powder (4.4 g, 31% yield): mp
118-127 °C; 250 MHz 1H NMR (DMSO-d6) δ 2.38 (br t, J )
7.2 Hz, 2H), 1.55 (m, 2H), 1.24 (br s, 18H), 0.85 (t, J ) 6.4 Hz,
3H); EIMS m/ z 253 (MH+). Anal. (C14H28N4) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(2-a cetyl-5-d od e-
cyl-2H-1,2,4-tr ia zol-3-yl) u r ea (18). Acetyl chloride (1.18
mL, 16.6 mmol) was added in one portion to a slurry of 17
(4.0 g, 15.8 mmol) in THF (100 mL). The resulting slurry was
stirred (1 h, 25 °C) and then concentrated in vacuo. The
residue was suspended in ethyl acetate (350 mL), washed with
ice cold water (2 × 100 mL) and ice cold brine (1 × 100 mL),
and then dried (MgSO4) and concentrated to yield a waxy solid,
2-acetyl-3-amino-5-dodecyl-2H-1,2,4-triazole (4.2 g, 90%
yield): 250 MHz 1H NMR (DMSO-d6) δ 7.40 (s, 2H), 2.48 (s,
3H), 2.40 (t, J ) 7.5 Hz, 2H), 1.59 (m, 2H), 1.24 (br s, 20H),
0.85 (t, J ) 6.4 Hz, 3H). Without further purification a slurry
of 2-acetyl-3-amino-5-dodecyl-2H-1,2,4-triazole (4.1 g, 13.9
mmol) in acetonitrile (300 mL) was warmed until homoge-
neous. 2,6-Diisopropylphenyl isocyanate (3.0 mL, 13.9 mmol)
was added, and the solution was heated under reflux for 15 h.
The resulting solution was cooled (25 °C) and concentrated in
vacuo. The residue was chromatographed on silica gel eluting
with hexane and then 85:15 hexane/ethyl acetate to yield a
clear oil (4.2 g, 61% yield): 250 MHz 1H NMR (DMSO-d6) δ
10.05 (s, 1H), 9.42 (s, 1H), 7.35-7.10 (m, 3H), 3.16 (heptet, J
) 6.9 Hz, 2H), 2.67 (s, 3H), 2.60 (t, J ) 7.6 Hz, 2H), 1.69 (m,
2H), 1.24 (br s, 30H), 0.88 (t, J ) 6.6 Hz, 3H); EIMS m/ z 498
(MH+). Anal. (C29H47N5O2) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-(5-dodecyl-1H-1,2,4-
tr ia zol-3-yl)u r ea (19). A solution of 18 (4.1 g, 8.2 mmol) in
methanol (100 mL) was stirred for 16 h at 25 °C. The slurry
was cooled (-20 °C); then the resulting precipitate was
collected by filtration, washed with cold methanol, and dried
in vacuo (16 h, 40 °C) to yield the title compound as a white
powder (3.35 g, 89% yield): mp 154-164 °C; 400 MHz 1H NMR
(DMSO-d6) δ 7.20 (t, J ) 7.7 Hz, 1H), 7.10 (d, J ) 7.7 Hz, 2H),
3.04 (heptet, J ) 6.8 Hz, 2H), 2.55 (br s, 2H), 1.57 (m, 2H),
1.14 (m, 30H), 0.79 (t, J ) 6.8 Hz, 3H); EIMS m/ z 455(M+).
Anal. (C27H45N5O) C, H, N.
3-Am in o-2-dodecyl-1,2,4-tr iazole (20a), 3-Am in o-1-dode-
cyl-1,2,4-tr ia zole (20b), a n d 3-Am in o-4-d od ecyl-1,2,4-tr ia -
zole (20c). A methanol solution of sodium methoxide was
generated by dissolving sodium (2.73 g, 0.119 mol) in methanol
(400 mL). 3-Amino-1,2,4-triazole (10.0 g, 0.119 mol) was added
and the resulting solution was stirred (10 min, 25 °C). Dodecyl
bromide (28.6 mL, 0.119 mol) was then added, and the
resulting solution was heated under reflux for 24 h. The
solution was cooled (25 °C) and concentrated in vacuo. The
residue was taken up in ethyl acetate (450 mL), washed with
brine (2 × 150 mL), and then dried (MgSO4) and concentrated
in vacuo. The resulting solid was dissolved in a minimal
amount of chloroform and chromatographed on silica gel
eluting with 2% chloroform in methanol to yield 20a (4.5 g,
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(5-n on yl-1,3,4-th i-
a d ia zol-2-yl)u r ea (14c). The compound (6.6 g, 76%) was
prepared as in the above procedure for 14b: mp 94-98 °C;
250 MHz 1H NMR (DMSO-d6) δ 10.91 (br s, 1H), 8.07 (br s,
1H), 7.32-7.16 (m, 3H), 3.07 (m, 2H), 2.89 (t, J ) 7.4 Hz, 2H),
1.66 (m, 2H), 1.23 (s, 12H), 1.13 (d, J ) 7.5 Hz, 12Η), 0.85 (t,
J ) 6.8 Hz, 3H); EIMS m/ z 431 (MH+). Anal. (C24H38N4OS)
C, H, N, S.
2-Am in o-5-tr id ecyl-1,3,4-oxa d ia zole (15). Hydrazine (1.9
mL, 0.058 mol) was added to a solution of methyl tetrade-
canoate (13.96 g, 0.058 mol) in methanol (300 mL) and the
solution refluxed for 3 days. The mixture was allowed to cool
and filtered to yield hydrazide (6.17 g, 44%), mp 107-111 °C.
Cyanogen bromide (2.9 g, 0.027 mol) was added to a mixture
of hydrazide (6.1 g, 0.025 mmol) and KHCO3 (2.8 g, 0.028 mol)
in dioxane/water (1:1, 50 mL) at room temperature. The
mixture was refluxed for 1 h, allowed to cool, filtered, washed
with dioxane/water (1:1, 20 mL) and then water (50 mL), and
dried in vacuo. The solid was recrystallized from chloroform
to yield the title compound (4.16 g, 27% yield) as a white
1
solid: mp 147-150 °C; 250 MHz H NMR (DMSO-d6) δ 6.82
(br s, 2H), 2.60 (t, J ) 6.9 Hz, 2H), 1.59 (m, 2H), 1.24 (s, 20H),
0.86 (t, J ) 6.8 Hz, 3H); EIMS m/ z 268 (MH+). Anal.
(C15H29N3O) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(5-t r id ecyl-1,3,4-
oxa d ia zol-2-yl)u r ea (16). Triethylamine (1.67 g, 0.017 mol)
was added to a solution of 15 (4.0 g, 0.015 mol) in acetonitrile
(200 mL) and the mixture refluxed until the solution became
homogeneous. 2,6-Diisopropylphenyl isocyanate (3.71 g, 0.018

Heterocyclic Ureas as Inhibitors of ACAT
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22 4393
15% yield): mp 75-80 °C; 250 MHz 1H NMR (DMSO-d6) δ
7.29 (s, 1H), 6.12 (s, 2H), 3.81 (t, J ) 7.0 Hz, 2H), 1.63 (m,
2H), 1.24 (br s, 18H), 0.86 (t, J ) 6.4 Hz, 3H); EIMS m/ z 252
(M+). Anal. (C14H28N4 ) C, H, N; 20b (4.0 g, 13% yield): mp
101-107 °C; 250 MHz 1H NMR (DMSO-d6) δ 7.64 (s, 1H), 4.17
(br s, 2H), 3.93 (t, J ) 7.1 Hz, 2H), 1.81 (m, 2H), 1.25 (br s,
18H), 0.88 (t, J ) 6.4 Hz, 3H); EIMS m/ z 252 (M+). Anal.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-[5-(tr id ecylth io)-
1H-1,2,4-tr ia zol-3-yl]u r ea (25). The urea 24 (4.4 g, 0.0081
mol) was stirred in methanol (100 mL) at room temperature
for 2 h; the solution was then allowed to stand overnight. The
solid obtained was filtered and dried in vacuo to give a white
solid (2.57 g, 63%): mp 131-135 °C; 250 MHz 1H NMR
(DMSO-d6) δ 7.27-7.15 (m, 3H), 3.13-2.95 (m, 4H), 1.63 (m,
2H), 1.23 (s, 18H), 1.14 (d, J ) 7.5 Hz, 12Η), 0.85 (t, J ) 7 Hz,
3H); EIMS m/ z 502 (MH+). Anal. (C28H47N5OS) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-[5-(tr id ecylsu lfi-
n yl)-1H-1,2,4-tr ia zol-3-yl]u r ea (26). m-Chloroperbenzoic
acid (0.26 g, 1.49 mmol) was added to a cooled (0 °C) solution
of the compound 25 (0.5 g, 1.0 mmol) in dichloromethane (25
mL). The solution was allowed to warm to room temperature
and stirred for 4 h. The mixture was diluted with dichlo-
romethane (100 mL), washed with aqueous NaHSO3, water,
saturated aqueous NaHCO3, and brine, dried over Na2SO4,
concentrated, triturated with hexane, filtered, and dried in
vacuo to give a white solid as the title compound (0.42 g,
1
(C14H28N4) C, H, N. 20c (2.0 g, 7% yield): 250 MHz H NMR
(DMSO-d6) δ 7.89 (s, 1H), 5.75 (s, 2H), 3.71 (t, J ) 7.2 Hz,
2H), 1.60 (m, 2H), 1.24 (br s, 18H), 0.86 (t, J ) 6.2 Hz, 3H).
20c was used without further purification in the synthesis of
21c.
N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-(2-dodecyl-1H-1,2,4-
tr ia zol-3-yl) u r ea (21a ). A solution of 20a (4.43 g, 0.176 mol)
and 2,6-diisopropylphenyl isocyanate (3.75 mL, 0.176 mol) in
acetonitrile (100 mL) was heated under reflux (8 h). The
resulting solution was cooled (25 °C) and concentrated in
vacuo. The oil was chromatographed on silica gel eluting with
1% methanol in chloroform to give an oil, which was triturated
with acetonitrile to give a solid, which was dried in vacuo to
yield the title compound as a white solid (4.0 g, 50% yield):
mp 128-140 °C; 250 MHz 1H NMR (CDCl3) δ 10.74 (s, 1H),
10.44 (s, 1H), 7.57 (s, 1H), 7.28 (t, J ) 7.6 Hz, 1H), 7.18 (d, J
) 7.6 Hz, 2H), 3.90 (t, J ) 7.4 Hz, 2H), 3.19 (heptet, J ) 6.9
Hz, 2H), 1.49 (m, 2H), 1.21 (m, 30H), 0.89 (t, J ) 6.6 Hz, 3H);
EIMS m/ z 456 (MH+). Anal. (C27H45N5O ) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-(1-dodecyl-1H-1,2,4-
tr ia zol-3-yl)u r ea (21b). The compound was prepared as in
the above procedure for 21a using 20b (5.30g, 74% yield): mp
191-207 °C; 250 MHz 1H NMR (CDCl3) δ 9.38 (s, 1H), 8.80
(s, 1H), 7.87 (s, 1H), 7.25 (m, 3H), 4.10 (t, J ) 7.0 Hz, 2H),
3.23 (heptet, J ) 6.9 Hz, 2H), 1.85 (m, 2H), 1.25 (br s, 30H),
0.88 (t, J ) 6.6 Hz, 3H); EIMS m/ z 456 (MH+). Anal.
(C27H45N5O) C, H, N.
1
81%): mp 178-181 °C; 250 MHz H NMR (DMSO-d6) δ 13.67
(br s, 1Η), 10.45 (br s, 1Η), 8.16 (br s, 1H), 7.32-7.17 (m, 3H),
3.19-3.05 (m, 4H), 1.56 (m, 2H), 1.35 (m, 2H), 1.24 (s, 18H),
1.16 (s, 6H), 1.14 (s, 6H), 0.85 (t, J ) 8 Hz, 3H); CIMS m/ z
518 (MH+). Anal. (C28H47N5O2S‚0.5H2O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)ph en yl]-N′-(5-tr idecylsu lfon yl)-
1H-1,2,4-tr ia zol-3-yl]u r ea (27). m-Chloroperbenzoic acid
(0.52 g, 3.0 mmol) was added to a cooled (0 °C) suspension of
25 (0.5 g, 1 mmol) in dichloromethane (25 mL), and the
procedure for 26 was followed to give the title compound as a
1
white solid (0.36 g, 68%): mp 136-138 °C; 250 MHz H NMR
(DMSO-d6) δ 13.93 (br s, 1Η), 10.56 (br s, 1Η), 8.15 (br s, 1H),
7.29-7.16 (m, 3H), 3.35 (t, 2H), 3.11 (m, 2H), 1.63 (m, 2H),
1.23 (s, 20H), 1.14 (d, J ) 7.5 Hz, 12Η), 0.85 (t, J ) 6.8 Hz,
3H); FABMS m/ z 534 (MH+). Anal. (C28H47N5O3S) C, H, N.
2-P en ta d ecyn en itr ile (28). n-Butyllithium (2.2 M, 24.3
mL, 0.054 mol) was added dropwise to a cooled (-78 °C) slurry
of tetradecyne (10.3 g, 0.053 mol) in anhydrous ether (60 mL)
at such a rate that the temperature did not rise above -40
°C. The resulting slurry was stirred (5 min, -70 °C); then
phenyl cyanate23 (6.9 g, 0.058 mol) was added dropwise at such
a rate that the temperature did not rise above -60 °C. The
slurry was stirred (45 min, -78 °C) and then warmed to room
temperature, diluted with ether (140 mL), washed with 1.5 M
NaOH (2 × 100 mL) and brine, (100 mL), dried (MgSO4), and
concentrated in vacuo. The oil was chromatographed on silica
gel eluting with 5% ether in pentane to give a pale yellow
liquid (9.0 g, 78%): 1H NMR (CDCl3) δ 2.35 (t, J ) 7.0 Hz,
2H), 1.60 (m, 2H), 1.38 (m, 2H), 1.27 (br s, 16H), 0.88 (t, J )
6.5 Hz, 3H); EIMS m/ z 220 (MH+). Anal. (C15H25N) C, H, N.
5-Am in o-3-d od ecylisoxa zole (29). A solution of 28 (10.0
g, 0.046 mol) in ethanol (50 mL) was added to a stirred solution
of hydroxylamine hydrochloride (3.8 g, 0.055 mmol) in 2.5 M
NaOH (20.0 mL, 0.05 mol). The mixture was diluted with
ethanol (100 mL), stirred for 22 h at room temperature,
concentrated, and then partitioned between ethyl acetate (300
mL) and brine (100 mL). The organic layer was dried (MgSO4),
concentrated in vacuo, and chromatographed on silica gel
eluting with 5-30% ethyl acetate in hexane to yield the title
compound as a waxy solid (8.2 g, 71%): mp 48.5-49.5 °C; 1H
NMR (CDCl3) δ 4.98 (s, 1H), 4.41 (br s, 2H), 2.50 (t, J ) 7.6
Hz, 2H), 1.60 (m, 2H), 1.25 (br s, 18H), 0.88 (t, J ) 6.6 Hz,
3H); EIMS m/ z 253 (MH+). Anal. (C15H28N2O) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(3-d od ecyl-5-isox-
a zolyl)u r ea (30c). A slurry of 29 (1.44 g, 5.71 mmol) in
acetonitrile (50 mL) was warmed until homogeneous. 2,6-
Diisopropylphenyl isocyanate (1.22 mL, 5.71 mmol) was then
added in one portion, the resulting solution was heated under
reflux for 24 h and cooled to -20 °C, and the precipitate was
collected by filtration and chromatographed on silica gel
eluting with 30% ethyl acetate in hexane to give a solid which
was recrystallized from acetonitrile to yield the title compound
N-[2,6-bis(1-m eth yleth yl)ph en yl]-N′-(4-dodecyl-4H-1,2,4-
tr ia zol-3-yl)u r ea (21c). The compound was prepared as in
the above procedure for 21a using 20c (1.3 g, 38% yield): 250
MHz 1H NMR (CDCl3) δ 10.74 (br s, 1H), 10.42 (br s, 1H), 7.81
(s, 1H), 7.23 (m, 3H), 3.77 (t, J ) 7.2 Hz, 2H), 3.21 (heptet, J
) 6.8 Hz, 2H), 1.43 (m, 2H), 1.23 (m, 30H), 0.90 (t, J ) 6.6
Hz, 3H); EIMS m/ z 456 (MH+). Anal. (C27H45N5O) C, H, N.
2-(Tr id ecylth io)-5-a m in o-1,2,4-tr ia zole (22). 1-Bromot-
ridecane (45.2 mL, 0.18 mol) was added to a slurry of 3-amino-
5-mercapto-1,2,4-triazole (18.66 g, 0.16 mol) and triethylamine
(24.6 mL, 0.18 mol) in acetonitrile (250 mL). The mixture was
allowed to reflux for 2 h and cooled, and the precipitate was
filtered and recrystallized from acetonitrile to give the title
compound as a tan solid (47.7g, 95%): mp 101-103 °C; 300
1
MHz H NMR (DMSO-d6) δ 11.85 (br s, 1H), 6.00 (br s, 2H),
2.90 (t, J ) 7.2 Hz, 2H), 1.57 (m, 2H), 1.21 (s, 20H), 0.83 (t, J
) 6.9 Hz, 3H); CIMS m/ z 299 (MH+) Anal. (C15H30N4S) C, H,
N.
1-Acetyl-2-(tr id ecylth io)-5-a m in otr ia zole (23). Acetyl
chloride (13.8 mL, 0.19 mol) was added to a cooled (0 °C)
solution of 22 (46.7 g, 0.185 mol) and triethylamine (27 mL,
0.185 mol) in THF (600 mL). The mixture was stirred for 1 h
at 0 °C, poured into ethyl acetate, and filtered, and the residue
was washed with water and dried in vacuo to give the title
compound as a white solid (14.9 g, 23%): mp 99-102 °C; 250
MHz 1H NMR (CDCl3) δ 6.60 (br s, 2H), 3.06 (t, J ) 7.3 Hz,
2H), 2.58 (s, 3H), 1.73 (m, 2H), 1.42 (m, 2H), 1.26 (s, 18H), 0.8
(t, J ) 6.9 Hz, 3H); EIMS m/ z 340 (M+). Anal. (C17H32N4OS)
C, H, N.
N-[4-Acetyl-5-(tr idecylth io)-4z-1,2,4-tr iazol-3-yl]-N′-[2,6-
bis(1-m eth yleth yl)p h en yl]u r ea (24). 2,6-Diisopropylphenyl
isocyanate (8.35 mL, 0.039 mol) was added to a solution of 23
(9.27 g, 0.030 mol) in THF (250 mL), the mixture was refluxed
for 24 h, concentrated in vacuo to 50 mL, and filtered, and
the filtrate was concentrated in vacuo and chromatographed
on silica gel, eluting with 5-10 ethyl acetate in hexanes to
1
1
give the title compound as an oil (4.83 g, 30%): 250 MHz H
as white needles (0.53 g, 20%): mp 112.5-114 °C; H NMR
NMR (DMSO-d6) δ 10.20 (s, 1H), 8.93 (s, 1H), 7.36-7.14 (m,
3H), 3.15 (m, 2H), 2.54 (m, 3H), 1.69 (m, 2H), 1.24 (s, 18H),
1.16 (s, 6H), 1.13 (s, 6H), 0.86 (t, J ) 6.1 Hz, 3H); EIMS m/ z
544 (MH+). Anal. (C30H49N5O2S) C, H, N, S.
(CDCl3) δ 7.35 (m, 3H), 6.91 (br s, 1H), 6.85 (br s, 1H), 6.06
(br s, 1H), 3.24 (m, 2H), 2.54 (t, J ) 7.7 Hz, 2H), 1.61 (m, 2H),
1.25 (m, 30H), 0.88 (t, J ) 6.5 Hz, 3H); EIMS m/ z 456 (MH+).
Anal. (C28H45N3O2) C, H, N.

4394 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
White et al.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(3-t et r a d ecyl-5-
isoxa zolyl)u r ea (30a ). The compound was prepared as in
the above procedure for 30c (1.1 g, 19% yield): mp 104-106
resulting two-phase mixture was stirred for 48 h at room
temperature and then redissolved in ethyl acetate (200 mL),
washed with brine (2 × 65 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was chromatographed on silica
gel eluting with chloroform and then 5% methanol in chloro-
form to give the title compound as an off-white powder (0.70
g, 63%): mp 55-58 °C; 1H NMR (DMSO-d6) δ 7.01 (s, 1H),
6.40 (s, 2H), 2.22 (t, J ) 7.4 Hz, 2H), 1.48 (m, 2H), 1.24 (br s,
16H), 0.86 (t, J ) 6.3 Hz, 3H); EIMS m/ z 239 (MH+). Anal.
(C14H26N2O) C, H, N.
1
°C; H NMR (CDCl3) δ 7.32 (m, 3H), 7.06 (br s, 1H), 6.85 (br
s, 1H), 6.06 (br s, 1H), 3.24 (m, 2H), 2.53 (t, J ) 7.6 Hz, 2H),
1.61 (m, 2H), 1.25 (br s, 34H), 0.88 (t, J ) 6.5 Hz, 3H); EIMS
m/ z 484 (MH+). Anal. (C30H49N3O2) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(3-tr id ecyl-5-isox-
a zolyl)u r ea (30b). The compound was prepared as in the
above procedure for 30c (1.55 g, 18% yield): mp 101-104 °C;
1H NMR (CDCl3) δ 7.34 (m, 3H), 6.84 (br s, 1H), 6.56 (br s,
1H), 6.08 (br s, 1H), 3.23 (m, 2H), 2.55 (t, J ) 7.6 Hz, 2H),
1.64 (m, 2H), 1.19 (m, 32H), 0.88 (t, J ) 6.5 Hz, 3H); EIMS
m/ z 469 (MH+). Anal. (C29H47N3O2) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(3-d ecyl-5-isox-
a zolyl)u r ea (30d ). The compound was prepared as in the
above procedure for 30c (5.9 g, 32% yield): mp 112-114 °C;
1H NMR (CDCl3) δ 7.35 (m, 3H), 7.06 (br s, 1H), 6.86 (br s,
1H), 6.05 (br s, 1H), 3.24 (m, 2H), 2.53 (t, J ) 7.6 Hz, 2H),
1.60 (m, 2H), 1.21 (m, 26H), 0.88 (t, J ) 6.5 Hz, 3H); EIMS
m/ z 427 (MH+). Anal. (C26H41N3O2) C, H, N.
3-Am in o-5-tr id ecylisoxa zole (31). A solution of 2-hexa-
decynenitrile (7.35 g, 0.032 mmol), synthesized in a manner
similar to 28, in ethanol (115 mL) was added to a stirred
solution of hydroxylamine hydrochloride (2.26 g, 0.038 mol)
in 2.5 M NaOH (27.7 mL, 0.069 mol). The slurry was stirred
for 16 h at room temperature and filtered, and the crystals
were washed with cold water and dried in vacuo at 40 °C (24
h) to yield the title compound as a white solid (5.6 g, 67%):
mp 83-84.5 °C; 1H NMR (CDCl3) δ 5.53 (s, 1H), 3.95 (br s,
2H), 2.60 (t, J ) 7.6 Hz, 2H), 1.64 (m, 2H), 1.26 (br s, 20H),
0.88 (t, J ) 6.5 Hz, 3H); EIMS m/ z 267 (MH+). Anal.
(C16H30N2O) C, H, N.
N-[2,6-Bis(1-m et h ylet h yl)p h en yl]-N′-(4-u n d ecyl-2-ox-
a zolyl)u r ea (35). 2,6-Diisopropylphenyl isocyanate (0.57 g,
0.0028 mol) was added to a refluxing mixture of 34 (0.56 g,
0.0024 mol), triethylamine (0.26 g, 0.0026 mol), and acetoni-
trile (50 mL). The mixture was refluxed for 2.5 h under
nitrogen, allowed to cool, and concentrated in vacuo. The
residue was partitioned between ethyl acetate (100 mL) and
water (75 mL). The organic layer was washed with brine,
dried with Na2SO4, filtered, concentrated, and triturated with
acetonitrile to give a yellow solid which was dried in vacuo to
give the title compound (0.73 g, 70%): mp 104-108 °C; 1H
NMR (DMSO-d6) δ 10.82 (s, 1H), 9.85 (s, 1H), 7.27-7.16 (m,
3H), 3.06 (heptet, J ) 6.8 Hz, 2H), 2.37 (t, J ) 7.2 Hz, 2H),
1.52 (m, 2H), 1.18-1.12 (m, 28H), 0.83 (t, J ) 6.8 Hz, 3H);
EIMS m/ z 442 (MH+). Anal. (C27H43N3O2) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(d od ecyl-1H-im i-
d a zol-4-yl)u r ea Mon oh yd r och lor id e (37). To a solution of
4-nitro(tetrabutylammoniumyl)imidazole26 (36) (0.5 g, 1.4
mmol) in DMF (10 mL) was added the dodecyl bromide (0.35
g, 1.4 mmol). The mixture was stirred at room temperature
for 18 h, concentrated in vacuo, diluted with water (50 mL),
and extracted with 1:1 ethyl acetate/hexane (2 × 100 mL). The
combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo to yield 1-dodecyl-
4-nitroimidazole which was used without further purification.
The 1-dodecyl-4-nitroimidazole (1.5 g, 5.3 mmol) was treated
with 5% Pd/C in methanol at 50 psi of hydrogen for 6 h at
22-28 °C in a Parr apparatus. The crude reaction mixture
containing 1-dodecyl-4-aminoimidazole was concentrated and
used without further purification. To a solution of 1-dodecyl-
4-aminoimidazole in ethyl acetate (5 mL) was added the 2,6-
diispropylphenyl isocyanate (0.64 g, 3.2 mmol). The resulting
mixture was stirred for 3 h at room temperature, diluted with
water (10 mL), and stirred for 30 min. The organic layer was
separated, washed with saturated NaHCO3 and brine, and
dried (MgSO4). The mixture was filtered, concentrated, and
column chromatographed on silica gel eluting with 10%, 20%,
30%, 40%, and 60% ethyl acetate in hexane. The brown oil
obtained was treated with saturated ethereal HCl, concen-
trated, and dissolved in methanol, and water was added. The
mixture was concentrated in vacuo and then lyophilized
overnight to yield the title compound (0.25 g, 16%): foam; 250
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(5-tr id ecyl-3-isox-
a zolyl)u r ea (32). The compound was prepared as in the
above procedure for 30c using 31 (4.4 g, 47% yield): mp 85-
1
100 °C; H NMR (CDCl3) δ 7.21 (m, 3H), 5.75 (br s, 1H), 3.21
(m, 2H), 2.65 (t, J ) 7.4 Hz, 2H), 1.67 (m, 2H), 1.27 (m, 32H),
0.89 (t, J ) 6.5 Hz, 3H); EIMS m/ z 469 (M+). Anal.
(C29H47N3O2) C, H, N.
1-Hyd r oxy-2-tr id eca n on e (33). A solution of n-butyl-
lithium (12.6 mL, 0.028 mol, 2.2 M in hexane) was added
dropwise via syringe to a cooled (-78 °C) solution of diisopro-
pylamine (4.1 mL, 0.029 mol) in dry THF (200 mL). The
solution was stirred (15 min -78 °C); then a solution of
2-tridecanone (5.0 g, 0.025 mol) in dry THF (50 mL) was added
dropwise via a dropping funnel. The mixture was stirred (30
min, -78 °C); then a solution of chlorotrimethylsilane (3.5 mL,
0.028 mol) in dry THF (40 mL) was added in one portion. The
mixture was allowed to warm to 10 °C; then the reaction was
quenched with saturated NaHCO3 (100 mL). Dichloromethane
(400 mL) and water (80 mL) were added, and the organic layer
was washed with brine (200 mL), dried (MgSO4), and concen-
trated in vacuo to yield 2-[(trimethylsilyl)oxy]-1-tridecene (6.7
g, 98%) which was used without further purification. m-
Chloroperoxybenzoic acid (8.5 g, 0.025 mol) was added in one
portion to a cooled (0 °C) solution of 2-[(trimethylsilyl)oxy]-1-
tridecene in hexane (200 mL). The ice bath was removed, and
the slurry was stirred for 4 h at room temperature. Ether (200
mL) and 1.5 M HCl (130 mL) were added, and the resulting
two-phase mixture was stirred vigorously for 4.5 h. The
organic layer was washed with saturated NaHCO3 (2 × 130
mL) and brine (130 mL), dried (MgSO4), and concentrated in
vacuo. The residue was chromatographed on silica gel eluting
with 10% ethyl acetate in hexane and concentrated in vacuo.
The solid was washed with cold hexane and collected by
filtration to yield the title compound as a white solid (1.5 g,
29%): mp 52-54 °C; 1H NMR (CDCl3) δ 4.24 (s, 2H), 3.15 (br
s, 1H), 2.41 (t, J ) 7.5 Hz, 2H), 1.63 (m, 2H), 1.26 (br s, 16H),
0.88 (t, J ) 6.5 Hz, 3H); EIMS m/ z 215 (MH+). Anal.
(C13H26O2) C, H.
1
MHz H NMR (CDCl3) δ 0.85 (t, J ) 5.88 Hz, 3H), 1.12-1.34
(m, 30H), 1.73 (br t, 2H), 3.15 (hept, 2H), 4.04 (br t, 2H), 7.03-
7.51 (m, 4H), 8.47 (br s, 1H), 9.79 (br s, 1H); EIMS m/ z 454
(M+). Anal. (C28H46N4O‚HCl) C, H, N.
2-Am in o-4-m eth yl-5-d ecylth ia zole (38a ) a n d 2-Am in o-
4-u n d ecylth ia zole (38b). 2-Tridecanone (19.3 g, 0.1 mol) and
thiourea (15.24 g, 0.2 mol) were stirred at 40 °C until a slurry
was obtained. Iodine (25.4 g, 0.1 mol) was added in one
portion, and the mixture was heated at 100 °C for 18 h, allowed
to cool, and diluted with water (50 mL). The aqueous solution
was made basic with saturated aqueous NH4OH solution,
precipitating a white gum which was partitioned into ethyl
acetate (200 mL). The organic layer was washed with satu-
rated NaHSO3, dried with Na2SO4, and concentrated in vacuo
to give an oil which was chromatographed on silica gel, eluting
with 20%, 25%, and 50% ethyl acetate in hexanes to yield
2-amino-4-methyl-5-decylthiazole (38a ) (4.95 g, 19%): mp 39-
1
40 °C; 400 MHz H NMR (DMSO-d6) δ 6.52 (s, 2H), 2.47 (t, J
) 7.4 Hz, 2H), 1.95 (s, 3H), 1.42 (m, 2H), 1.24 (s, 14H), 0.85
(t, J ) 6.8 Hz, 3H); CIMS m/ z 255 (MH+). Anal. (C14H26N2S)
C, H, N. Also eluted was 2-amino-4-undecylthiazole (38b)
(13.5 g, 53%): mp 60-61.5 °C; 400 MHz H NMR (DMSO-d6)
δ 6.77 (s, 2H), 6.07 (s, H), 2.36 (t, J ) 7.0 Hz, 2H), 1.53 (m,
2-Am in o-4-u n d ecyloxa zole (34). To a solution of 33 (1.0
g, 4.7 mmol) and cyanamide (0.2 g, 4.7 mmol) in THF (3.0 mL)
were added aqueous sodium acetate (2.0 mL, 1.0 M), tetra-n-
butylammonium hydroxide (0.6 mL, 0.4 M, 0.2 mmol), and 1
M sodium hydroxide (0.2 mL, 0.2 mmol) sequentially. The
1

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2H), 1.24 (s, 16H), 0.85 (t, J ) 6.8 Hz, 3H); CIMS m/ z 255
(MH+). Anal. (C14H26N2S) C, H, N.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(5-d ecyl-4-m eth yl-
2-th ia zolyl)u r ea (39a ). 2,6-Diisopropylphenyl isocyanate
(11.2 g, 0.055 mol) was added to a solution of 38a (13.4 g, 0.053
mol) in ethyl acetate (200 mL). The mixture was stirred for 2
h at room temperature; then acetonitrile (50 mL) was added,
the mixture was refluxed for a further 2 h and concentrated,
and the resulting oil was crystallized from acetonitrile (10 mL),
filtered, and washed with hexane (200 mL) to give the title
compound as a white solid (8.38 g, 35%): mp 101-108 °C; 250
1
MHz H NMR (CDCl3) δ 0.88 (t, J ) 7 Hz, 3H), 1.22 (m, 26H),
1.57 (m, 2H), 2.12 (s, 3H), 2.60 (t, J ) 7 Hz, 2H), 3.20 (m, 2H),
7.10-7.43 (m, 3H); EIMS m/ z 458 (MH+). Anal. (C27H43N3-
OS) C, H, N, S.
N-[2,6-Bis(1-m eth yleth yl)p h en yl]-N′-(4-u n d ecyl-2-th ia -
zolyl)u r ea (39b). 2,6-Diisopropylphenyl isocyanate (4.0 g,
0.02 mol) was added to a solution of 38b (4.78 g, 0.019 mol) in
ethyl acetate (150 mL) and the mixture refluxed for 18 h. The
precipitate obtained was filtered and the filtrate concentrated
and chromatographed on silica gel, eluting with 5-10% ethyl
acetate in hexanes to give the title compound as an oil (4.57
1
g): 300 MHz H NMR (DMSO-d6) δ 0.83 (t, J ) 6.2 Hz, 3H),
1.11 (d, J ) 7.5 Hz, 12Η), 1.21 (s, 16H), 1.57 (br m, 2H), 2.51
(t, 2H), 3.07 (m, 2H), 6.57 (s, 1H), 7.15 (m, 2H), 7.26 (m, 1H),
8.15 (br s, 1H), 10.54 (br s, 1H); EIMS m/ z 458 (MH+). Anal.
(C27H43N3O) C, H, N.
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