Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis

Disclosed are imidazoles linked to bicyclic heterocyclic groups, as inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT), processes for their preparation, pharmaceutical compositions, and their use as antihypercholesterolemics and/or antiatherosclerotics.

FIELD OF THE INVENTION 
This invention relates to imidazoles linked to bicyclic heterocyclic 
groups, as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT), 
pharmaceutical compositions containing them, processes for their 
preparation, and their use as antihypercholesterolemic and/or 
antiatherosclerotic agents. 
BACKGROUND OF THE INVENTION 
Hypercholesterolemia is an established risk factor in the development of 
atherosclerosis. Therapeutic agents which control the level of serum 
cholesterol have proven to be effective in the treatment of coronary 
artery disease. While agents exist that can modulate circulating levels of 
cholesterol-carrying lipoproteins, these agents have little or no effect 
on the intestinal absorption of cholesterol. Dietary cholesterol can 
increase the level of serum cholesterol to levels which place an 
individual at increased risk for the development or exacerbation of 
atherosclerosis. Since much of the free or unesterified cholesterol that 
is absorbed by intestinal mucosal cells must first be esterified by ACAT 
prior to its incorporation and secretion into the bloodstream in large 
lipoprotein particles called chylomicrons, inhibition of ACAT can reduce 
the absorption of dietary cholesterol. In addition, the accumulation and 
storage of cholesteryl esters in the arterial wall is associated with 
increased activity of ACAT. Inhibition of the enzyme is expected to 
inhibit the formation or progression of atherosclerotic lesions in 
mammals. 
There are an increasing number of patents in the literature disclosing 
compounds which are useful as ACAT inhibitors in particular and 
antiatherosclerotic agents in general. For example, U.S. Pat. No. 
4,623,662, issued to DeVries on Nov. 18, 1986, discloses ureas and 
thioureas as ACAT inhibitors useful for reducing the cholesterol ester 
content of an arterial wall, inhibiting atherosclerotic lesion 
development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 
4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted 
pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for 
inhibiting intestinal absorption of cholesterol. U.S. Pat. No. 4,824,843, 
issued to Hoefle et al. on Apr. 25, 1989, and the related U.S. Pat. No. 
4,882,357, issued to Creger et al. on Nov. 21, 1989, disclose a series of 
substituted N-phenyl-2,2-dimethyl-5-aryloxypentanamides, which prevent the 
intestinal absorption of cholesterol in mammals by inhibiting ACAT. 
European Patent Application 325,397, filed by Ito on Jul. 26, 1989, 
discloses a series of compounds consisting of two N-cycloalkyl-N'-arylurea 
units linked at nitrogen by a dialkylphenyl unit, which are inhibitors of 
the ACAT enzyme. U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 
1989, and the related European Patent Applications 335,374 filed by 
Trivedi on Mar. 30, 1988, and 386,487, filed by Trivedi on Feb. 9, 1989, 
disclose certain N-2,6-dialkyl- or N-2,6-dialkoxlphenyl-N'-arylalkyl ureas 
as potent inhibitors of ACAT. European Patent Application 354,994, filed 
by Meguro and Ikeda on Feb. 21, 1990, discloses certain 
N-aryl-N'-quinolin-4-yl ureas as ACAT inhibitors. European Patent 
Application 370,740, filed by Jackson et al. on Nov. 21, 1988, discloses 
ACAT inhibitors similar in composition to those of DeVries (supra). 
U.S. Pat. No. 4,900,744, issued to Billheimer, et al. on Feb. 13, 1990, 
discloses antihypercholesterolemic thioimidazoles of the formula 
##STR1## 
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 
independently are H, F, Cl, CF.sub.3, alkyl of 1 to 4 carbon atoms, or 
alkoxy of 1 to 4 carbon atoms; 
A is alkylene of 7-20 carbon atoms or an alkenyl residue thereof with no 
more than 2 double bonds; R.sup.3 is H, CH.sub.3 OR C.sub.2 H.sub.5 ; and 
n is 0, 1 or 2, such as 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid 
ethyl ester. 
European Patent Application EP-A-372,445, filed by Billheimer et al. on 
Dec. 3, 1989, discloses compounds of formulae 
##STR2## 
R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 
alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, 
C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3- or 
4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 
3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 
-C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, 
NO.sub.2, CF.sub.3, or NR.sup.7 R.sup.8 ; or 
R.sup.1 and R.sup.2 can also be taken together as 
##STR3## 
where L is O, O(CH.sub.2 ).sub.m+1 O, or (CH.sub.2).sub.m where m is 0-4; 
R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl optionally 
substituted with F, Cl, CH.sub.3, CH.sub.3 O, or CF.sub.3 ; 
R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted 
with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, 
C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the 
aryl group is optionally substituted with 1 to 3 groups selected from 
C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, 
CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8, or 
NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 
perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected 
from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 
-C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, 
NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; 
pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups 
selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, 
CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 
R.sup.8 or NCOR.sup.7 ; 2-, 3- or 4-pyridinyl, pyrimidinyl, or biphenyl; 
R.sup.5 is H, C.sub.1 -C.sub.6 alkyl, or benzyl; 
R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 
-C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl 
optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 
alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, 
NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; 
pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups 
selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, 
CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.8 
R.sup.9 or NCOR.sup.7 ; 
R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 
alkyl; 
X is S(O).sub.r, O, NR.sup.5, CH.sub.2 ; 
A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 
-C.sub.10 alkenyl, or C.sub.3 -C.sub.10 alkynyl; 
Y is O, S, H.sub.2, NH; 
Z is NHR.sup.4 , OR.sup.4 , or R.sup.4 ; 
r is 0-2, 
or a pharmaceutically acceptable salt thereof. 
These compounds are potent in vitro inhibitors of ACAT and are therefore 
potential antihypercholesterolemic agents. 
International Application WO 91/09021 of Bridge et al., discloses compounds 
of the formula: 
##STR4## 
wherein A represents methylene or a group --CH.sub.2 --A'--CH.sub.2 --, 
wherein 
A' represents a direct bond, linear alkanediyl, alkenediyl or alkynediyl, 
hydroxymethylene, or optionally substituted phenylene; 
R.sup.1 and R.sup.2 each represents hydrogen, halogen, alkyl, alkoxy, 
alkylthio, alkylamino, carboxy or alkoxycarbonyl; 
a and b are 0, 1, or 2; 
and Het represents a heterocyclic group containing from 5 to 7 ring atoms 
chosen from carbon, nitrogen, sulfur and oxygen atoms, and salts thereof. 
These compounds are disclosed to be inhibitors of ACAT useful for the 
treatment of conditions such as atherosclerosis, hyperlipidemia, 
cholesterol ester shortage disease and atheroma in vein grafts. 
International Application WO 91/10662 of Bridge et al., discloses compounds 
of the formula [DPIM]--S(O).sub.p --W--Y, wherein: 
##STR5## 
wherein R and R.sup.1 each represents hydrogen, halogen, alkyl or alkoxy; 
p is 0, 1, or 2; 
W represents alkylene; 
Y represents an optionally substituted 5- or 6-membered unsaturated ring 
containing 1 to 4 nitrogen atoms; 
and pharmaceutically acceptable acid addition salts thereof. 
Such compounds are disclosed to be inhibitors of ACAT. 
International Application WO 91/13876 of Bridge et al., discloses compounds 
of the formula: 
##STR6## 
wherein R.sup.1 is hydrogen or one or more substituents; 
k is 0, 1, or 2; 
Q is a straight or branched alkylene group; 
Z is a hydrogen or a substituent group; 
and pharmaceutically acceptable salts thereof. 
Such compounds are disclosed to be inhibitors of ACAT. 
U.S. Pat. No. 4,460,598, issued to Lautenschlager et al. on Jul. 17, 1984, 
discloses compounds of the formula: 
##STR7## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 
independently are H, F, Cl, Br, I, alkyl, alkoxy, or CF.sub.3, with the 
proviso that one or several of R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, 
or R.sup.5 and R.sup.6 taken together represent methylenedioxy; 
R.sup.7 is H, alkali metal ion, alkyl of 1 to 6 carbon atoms, or benzyl; 
and 
n is 0 to 10. 
The synthesis and the use of these compounds in the treatment of 
thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed. 
U.S. Pat. No. 4,654,358, issued to Lautenschlager et al. on Mar. 31, 1987, 
discloses compounds of the formula: 
##STR8## 
wherein k is 0, 1, or 2, 
R.sup.1, R.sup.2 and R.sup.3 independently are H, F, Cl, CH.sub.3, CH.sub.3 
O, or CF.sub.3 ; 
R.sup.4 is H, Na, K, CH.sub.3, CH.sub.3 CH.sub.2, (CH.sub.3).sub.2 CH, 
CH.sub.3 (CH.sub.2).sub.2, or butyl; 
A is C(CH.sub.3).sub.2, CH(CH.sub.2).sub.m CH.sub.3, (CH.sub.2).sub.n, or 
(CH.sub.2).sub.n-2 CH(CH.sub.3 ); 
m is 0 to 8; and 
n is 2 to 10. 
The synthesis and the use of these compounds in the treatment of 
inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic 
diseases is disclosed. 
German Laid Open Application No. DE 3504679, Lautenschlager et al., 
published Aug. 14, 1986, discloses compounds of the formula: 
##STR9## 
wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 
carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or 
##STR10## 
R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl of 1 to 
9 carbon atoms; 
R.sup.6 and R.sup.7 independently are H, OH, saturated or unsaturated 
alkyl, cycloalkyl, or hydroxyalkyl of 1 to 10 carbon atoms, 
##STR11## 
R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently 
are H, F, Cl, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon 
atoms, CF.sub.3, and alkoxy of 1 to 3 carbon atoms, with the proviso that 
R.sup.8 and R.sup.9, R.sup.10 and R.sup.11, or R.sup.12 and R.sup.13 taken 
together represent methylenedioxy; 
R.sup.14 is alkyl of 1 to 2 carbon atoms; 
m and n taken together represent a whole number from 0 to 9; 
p is 0 to 2; 
s is 0 to 2; and 
t is 0 or 2. 
The synthesis and the use of these compounds in the treatment of 
thromboembolic, inflammatory, atherosclerotic, and lipid metabolism 
diseases in general is disclosed. 
German Laid Open Application No. DE 3504680, Lautenschlager et al., 
published Aug. 14, 1986, discloses compounds of the formula: 
##STR12## 
wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 
carbon atoms, cycloalkyl of 1 to 6 carbon atoms, or 
##STR13## 
R.sup.1 and R.sup.2 can be taken together with the carbon atoms in the 4 
and 5 position of the imidazole ring to represent a carbocyclic five- or 
six-membered aromatic or partially hydrogenated ring which may be 
substituted by R.sup.8 or R.sup.9 ; 
R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5, or alkyl of 1 to 
9 carbon atoms; 
R.sup.6 is alkyl, cycloalkyl, or hydroxyalkyl of 1 to 20 carbon atoms, H, 
alkali metal if X is --COO--, 1-phenethyl, or 
##STR14## 
R.sup.7 is H, OH if X is --CONR.sup.7 --, or alkyl of 1 to 4 carbon atoms; 
R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are independently H, Cl, F, Br, 
NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, or 
alkoxy of 1 to 3 carbons, or R.sup.8 and R.sup.9 or R.sup.10 and R.sup.11 
taken together represent methylene-dioxy; 
X is a bond, O, OC(.dbd.O)O, C(.dbd.O)O, CONR.sup.7, OC(.dbd.O), or 
OC(.dbd.O)NR.sup.7 ; 
m and n taken together represent a whole number from 0 to 9; 
p is 0 to 2; 
s is 0 to 2; and 
t is 0 or 2. 
The synthesis and the use of these compounds in the treatment of 
thromboembolic, inflammatory, atherosclerotic, and lipid metabolism 
diseases in general is disclosed. 
Durant et al., U.S. Pat. 4,228,291, issued Oct. 14, 1980, teaches compounds 
of the formula: 
##STR15## 
wherein: A together with the carbon atom form an unsaturated heterocyclic 
nucleus which may be an imidazole, pyrazole, pyrimidine, pyrazine, 
pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, 
thiadiazole, benzimidazole, or 5,6,7,8-tetrahydro-imidazol[1,5-a]pyridine 
ring; 
X.sub.1 is H, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, 
amino, or 
##STR16## 
X.sub.2 is H, or when X.sub.1 is lower alkyl, lower alkyl or halogen; k is 
0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; 
Y is O, S, or NH; 
E is NR.sup.2 ; 
R.sup.1 is H, lower alkyl or di-lower alkyl amino-lower alkyl; 
and R.sup.2 is H, nitro, or cyano. 
The compounds are said to be antihistamines of the H.sub.2 receptor 
blocking type, as well as having anti-inflammatory activity. 
White, U.S. Pat. 4,413,130, Nov. 1, 1983, discloses histamine H.sub.2 
receptor antagonists of the formula: 
##STR17## 
wherein 
A together with the carbon atom form an unsaturated heterocyclic nucleus 
which may be an imidazole, pyridine, thiazole, isothiazole, oxazole, 
isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or 
pyridazine; 
X.sub.1 and X.sub.2 may be H, lower alkyl, trifluoromethyl, hydroxyl, 
halogen, amino, or X.sub.1 and X.sub.2 and at least two of the atoms 
comprising A may form a further ring; 
k is 0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; 
E is O, S, or NR.sup.2 ; 
R.sup.1 is H, lower alkyl, acyl, or dialkylamino-alkyl; 
and R.sup.2 is H, NO.sub.2, CN, alkansulphonyl or arenesulphonyl. 
There are no known literature references disclosing the imidazoles of this 
invention, their use as ACAT inhibitors, or their use to lower cholesterol 
or in the treatment of atherosclerosis. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides novel compounds of Formula (I), processes 
for their preparation, pharmaceutical compositions containing such 
heterocyclic compounds, and therapeutic methods for their use as 
antihypercholesterolemic and/or antiatherosclerotic agents. 
This invention provides compounds of Formula (I): 
##STR18## 
and stereoisomers and pharmaceutically acceptable salts thereof wherein: X 
and Y are selected independently from the groups S(O).sub.p, CH.sub.2, or 
NR.sup.4 ; 
Q is selected from either CH.sub.2, or an aromatic ring selected from the 
group consisting of benzene, pyridine, pyrrole, furan, or thiophene, said 
aromatic ring being connected through two ring substitution sites and said 
aromatic ring being optionally substituted with 1-3 groups independently 
selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 
alkyl, C.sub.3 -C.sub.8 branched alkyl, S(O).sub.t (C.sub.1 -C.sub.6 
alkyl), NO.sub.2, CF.sub.3, or NR.sup.15 R.sup.16 ; 
G is a bi- or tri-cyclic aromatic heterocyclic group, composed of five- and 
six-membered rings, containing at least one nitrogen atom, and being 
optionally substituted at valence-allowed sites with 1-3 groups 
independently selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, 
C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, S(O).sub.t 
(C.sub.1 -C.sub.6 alkyl), NO.sub.2, CF.sub.3, or NR.sup.15 R.sup.16 ; 
R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 
alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, 
C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 aralkyl, pyridyl, 
thienyl, furanyl, or phenyl; each being optionally substituted with 1-3 
groups independently selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, 
C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, S(O).sub.t 
(C.sub.1 -C.sub.6 alkyl), NO.sub.2, CF.sub.3, or NR.sup.15 R.sup.16 ; 
R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl, or phenyl; each being 
optionally substituted with F, Cl, CH.sub.3, OCH.sub.3, or CF.sub.3 ; 
R.sup.4 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 alkoxyalkyl, 
C.sub.5 -C.sub.12 (alkoxy)alkoxy-alkyl, C.sub.3 -C.sub.8 branched alkyl, 
C.sub.7 -C.sub.14 phenylalkyl, or phenyl, each being optionally 
substituted with 1-3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 
-C.sub.4 alkoxy, C.sub.2 -C.sub.8 dialkylamino, C.sub.1 -C.sub.4 
alkylthio, halogen, or NO.sub.2 ; 
R.sup.15 and R.sup.16 are selected independently from H, C.sub.1 -C.sub.8 
alkyl, benzyl, or phenyl; 
m and n are independently 0-6, and selected so that the total number of 
CH.sub.2 groups in the chain between X and G is at least 2; and 
p and t are independently 0-2. 
Preferred are compounds of Formula (I), wherein 
X and Y are independently S(O).sub.p or NR.sup.4 ; 
Q is selected from either CH.sub.2, or an aromatic ring selected from the 
group consisting of benzene, pyridine, pyrrole, furan or thiophene, said 
aromatic ring being connected through two ring substitution sites and said 
aromatic ring being optionally substituted with a 1-3 groups independently 
selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.2 
-C.sub.8 dialkylamino, C.sub.1 -C.sub.4 alkylthio, halogen or NO.sub.2 ; 
G is selected from the groups 
##STR19## 
each being optionally substituted at valence-allowed sites with 1-3 groups 
independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 
alkoxy, C.sub.2 -C.sub.8 dialkylamino, C.sub.1 -C.sub.4 alkylthio, 
halogen, or NO.sub.2 ; 
wherein A is O S or NH, and B, D and E are independently CH or N; 
R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.4 
alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, or 
phenyl, each being optionally substituted with 1-3 groups selected from 
Cl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.2 -C.sub.8 
dialkylamino, or C.sub.1 -C.sub.4 alkylthio; 
R.sup.3 is H; 
R.sup.4 is H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 alkoxyalkyl, 
C.sub.5 -C.sub.12 (alkoxy)alkoxy-alkyl, C.sub.3 -C.sub.8 branched alkyl, 
C.sub.7 -C.sub.14 phenylalkyl, or phenyl, each being optionally 
substituted with 1-3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 
-C.sub.4 alkoxy, C.sub.2 -C.sub.8 dialkylamino, C.sub.1 -C.sub.4 
alkylthio, halogen, or NO.sub.2 ; 
m and n are independently 0-6, and selected so that the total number of 
CH.sub.2 groups in the chain between X and G is at least 2; and 
p is 0-2; 
R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 branched alkyl, 
C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, or NR.sup.6 R.sup.7 ; 
R.sup.6 and R.sup.7 are independently selected from the groups H, C.sub.1 
-C.sub.4 alkyl, or phenyl. 
More preferred because of their biological activity are compounds of 
Formula (I), wherein: 
X and Y are independently S(O).sub.p or NR.sup.4 ; 
Q is selected from either CH.sub.2, benzene, furan or thiophene, wherein 
the benzene, furan, or thiophene are unsubstituted except for the 
connection through two ring substitution sites; 
G is selected from the groups 
##STR20## 
each being optionally substituted at valence-allowed sites with 1-3 groups 
independently selected from C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 
alkoxy, C.sub.2 -C.sub.8 dialkylamino, C.sub.1 -C.sub.4 alkylthio, halogen 
or NO.sub.2 ; 
wherein A is O, S or NH, and B, D and E are independently CH or N; 
R.sup.1 and R.sup.2 are selected independently from C.sub.3 -C.sub.8 
branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, or phenyl, phenyl being 
optionally substituted with one of CH.sub.3 O, (CH.sub.3).sub.2 N, or 
CH.sub.3 S; 
R.sup.3 is H; 
R.sup.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.10 alkoxyalkyl, C.sub.5 
-C.sub.12 (alkoxy)alkoxyalkyl, C.sub.3 -C.sub.8 branched alkyl, or phenyl; 
m is 1-3; 
n is 0-3; 
p is 0; 
R.sup.5 is H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 branched alkyl, 
C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, or NR.sup.6 R.sup.7 ; 
R.sup.6 and R.sup.7 are independently selected from the groups H, C.sub.1 
-C.sub.4 alkyl, or phenyl. 
Representative compounds of the invention include: 
2-[5-(N-(1H-benzoxazol-2-yl)-N-heptylamino)pentyl]thio-4,5-diphenyl-1H-imid 
azole; 
4,5-bis(4-methoxyphenyl)-2-[5-(N-(1H-benzoxazol-2-yl)-N-heptylamino)-pentyl 
]thio-1H-imidazole; 
4,5-bis(4-methoxyphenyl)-2-[5-(N-(1H-benzimidazol-2-yl)-N-heptylamino)-pent 
yl]thio-1H-imidazole; 
4,5-bis(4-dimethylaminophenyl)-2-[5-(2-(1-methylethyl)-1H-benzimidazol-1-yl 
)pentyl]thio-1H-imidazole. 
The compounds described above are useful as antiatherosclerotic and 
antihypercholesterolemic agents in a mammal when administered as 
pharmaceutical compositions to a mammal in need of treatment with such 
antiatherosclerotic and antihypercholesterolemic agents. The present 
invention includes pharmaceutical compositions containing an effective 
ACAT-inhibiting or antiatherosclerotic amount of the above described 
compounds of Formula I. The present invention also includes methods of 
treating hypercholesterolemia or atherosclerosis in a mammal comprising 
administering to the mammal a therapeutically effective amount of a 
compound of Formula I described above. 
The compounds herein described may have asymmetric centers. All chiral, 
diastereomeric, and racemic forms are included in the present invention. 
Many geometric isomers of olefins, C.dbd.N double bonds, and the like can 
also be present in the compounds described herein, and all such stable 
isomers are contemplated in the present invention. 
When any variable (for example, R.sup.1 through R.sup.21) occurs more than 
one time in any constituent or structure herein, its definition on each 
occurrence is independent of its definition at every other occurrence. 
Also, combinations of substituents and/or variables are permissible only 
if such combinations result in stable compounds. 
As used herein, "alkyl" is intended to include both branched and 
straight-chain saturated aliphatic hydrocarbon groups having the specified 
number of carbon atoms; "alkoxy" represents an alkyl group of indicated 
number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is 
intended to include saturated ring groups, such as cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and 
"biycloalkyl" is intended to include saturated bicyclic ring groups such 
as [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane 
(decalin), [2.2.2] bicyclooctane, and so forth. "Alkenyl" is intended to 
include hydrocarbon chains of either a straight or branched configuration 
and one or more unsaturated carbon-carbon bonds which may occur in any 
stable point along the chain, such as ethenyl, propenyl, and the like; and 
"alkynyl" is intended to include hydrocarbon chains of either a straight 
or branched configuration and one or more triple carbon-carbon bonds which 
may occur in any stable point along the chain, such as ethynyl, propynyl 
and the like. "Halo" as used herein refers to fluoro, chloro, bromo, and 
iodo; and "counterion" is used to represent a small, negatively charged 
species such as chloride, bromide, hydroxide, acetate, sulfate, and the 
like. 
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or 
naphthyl; "carbocyclic" is intended to mean any stable 5- to 7- membered 
monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon 
ring, any of which may be saturated, partially unsaturated, or aromatic, 
for example, indanyl or tetrahydronaphthyl (tetralin). 
As used herein, the term "heterocycle" is intended to mean a stable 5- to 
7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic 
heterocyclic ring which is either saturated or unsaturated, and which 
consists of carbon atoms and from 1 to 3 heteroatoms selected from the 
group consisting of N, O and S and wherein the nitrogen and sulfur 
heteroatoms may optionally be oxidized, and the nitrogen may optionally be 
quaternized, and including any bicyclic group in which any of the 
above-defined heterocyclic rings is fused to a benzene ring. The 
heterocyclic ring may be attached to its pendant group at any heteroatom 
or carbon atom which results in a stable structure. The heterocyclic rings 
described herein may be substituted on carbon or on a nitrogen atom if the 
resulting compound is stable. Examples of such heterocycles include, but 
are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, 
pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, 
indolenyl, quinolinyl, isoquinolinyl or benzimidazolyl, piperidinyl, 
4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, 
tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 
decahydroquinolinyl or octahydroisoquinolinyl. The term "substituted", as 
used herein, means that an one or more hydrogen on the designated atom is 
replaced with a selection from the indicated group, provided that the 
designated atom's normal valency is not exceeded, and that the 
substitution results in a stable compound. 
By "stable compound" or "stable structure" is meant herein a compound that 
is sufficiently robust to survive isolation to a useful degree of purity 
from a reaction mixture, and formulation into an efficacious therapeutic 
agent. 
As used herein, "pharmaceutically acceptable salts and prodrugs" refer to 
derivatives of the disclosed compounds that are modified by making acid or 
base salts, or by modifying functional groups present in the compounds in 
such a way that the modifications are cleaved, either in routine 
manipulation or in vivo, to the parent compounds. Examples include, but 
are not limited to, mineral or organic acid salts of basic residues such 
as amines; alkali or organic salts of acidic residues such as carboxylic 
acids; acetate, formate and benzoate derivatives of alcohols and amines; 
and the like. 
Pharmaceutically acceptable salts of the compounds of the invention can be 
prepared by reacting the free acid or base forms of these compounds with a 
stoichiometric amount of the appropriate base or acid in water or in an 
organic solvent, or in a mixture of the two; generally, nonaqueous media 
like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are 
preferred. Lists of suitable salts are found in Remington's Pharmaceutical 
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, 
the disclosure of which is hereby incorporated by reference. 
SYNTHESIS 
The novel compounds of Formula (I) may be prepared using the reactions and 
techniques described in this section. The reactions are performed in 
solvents appropriate to the reagents and materials employed and are 
suitable for the transformations being effected. Also, in the description 
of the synthetic methods provided below, it is to be understood that all 
proposed reaction conditions, including choice of solvent, reaction 
atmosphere, reaction temperature, duration of the experiment and workup 
procedures, are chosen to be the conditions standard for that reaction, 
which should be readily recognized by one skilled in the art. It is 
understood by one skilled in the art of organic synthesis that the 
functionality present on various portions of the educt molecule must be 
compatible with the reagents and reactions proposed. Not all compounds of 
Formula (I) falling into a given class may be compatible with some of the 
reaction conditions required in some of the methods described. Such 
restrictions to the substituents which are compatible with the reaction 
conditions will be readily apparent to one skilled in the art and 
alternate methods must then be used. 
The strategy of synthesis of compounds of Formula I can be chosen based on 
the availability of starting materials. One must chose such a strategy 
from among two cases, which are shown in Scheme I. The first is to begin 
with a compound such as compound 1, wherein J represents a group 
susceptible to displacement by nucleophilic reagents, such as halide, 
alkanesulfonate, arylsulfonate, and the like, and M represents a different 
group which is not susceptible to nucleophilic attack but is suitable for 
manipulation (by oxidation, deprotection, functionalization, or other 
transformations familiar to the organic chemist)to give such a leaving 
group in a later step. The second case is to begin with a compound such as 
compound 7, a dielectrophile. 
In the former case, either the imidazole group or the G group is introduced 
first in the synthesis by nucleophilic coupling to give either compound 2 
or 5. This general type of alkylative coupling reaction will be referred 
to throughout this section, and will be discussed in greater detail below. 
The M group is then transformed to a J leaving group, and the other 
heterocyclic group is coupled in a third step. In the latter case, the 
least reactive heterocycle (only 1 molar equivalent or less) is coupled to 
compound 7 to give either compound 3 or 6, which are used to prepare the 
final product. This second case is one step fewer than the first, although 
the possibility exists for the coupling of two units of the chosen 
heterocyclic reagent with compound 7. The laws of statistics give this 
result as being 25% probable. This by-product may be minimized by proper 
choice of the heterocycle, the J group, stoichiometry, and choice of the 
reaction conditions. For example, choosing J=Cl or a similarly-mild 
leaving group and using excess quantities of reagent 7 can give good 
yields of compounds 3 or 6. 
##STR21## 
The source of compounds such as 1, 4, or 7 will depend upon the choice of 
the Q group and the values for m and n. For example, for Q=CH.sub.2, two 
examples of differentiated functionalized compounds could be whalo esters 
(such as compound 8 in Scheme II) or bromochloroalkanes (compound 16, 
Scheme III). In the haloester scheme, the first step of the sequence 
involves displacement of a bromide ion by a suitably-nucleophilic form of 
either the imidazole or the G group (see below). The ester group in 
compounds such as 9 or 13 can be transformed to a hydroxymethylene group 
by the use of such reagents as lithium aluminum hydride or 
diisobutylaluminum hydride. The hydroxyl group in compounds 10 and 12 can 
be transformed to a halide or other leaving group by standard methods 
(bromide is arbitrarily shown for compounds 11 and 15). Alcohols can be 
converted to chlorides by many reagents, including triphenylphosphine in 
carbon tetrachloride or hexachloro-ethylene, thionyl chloride or 
phosphorus oxychloride. Conversion to bromides is achieved by such 
reagents as phosphorus tribromide, carbon tetrabromide/triphenylphosphine 
or thionyl bromide. Iodides are prepared from alcohols by such reagents as 
triphenylphosphine/iodine or iodotrimethylsilane. Alcohols can be 
converted to the toluenesolfonate leaving group by the action of 
toluenesulfonyl chloride and an amine base such as pyridine. Alcohols can 
be converted to alkanesulfonate leaving groups by the action of either the 
corresponding sulfonyl anhydride or chloride and an amine base such as 
triethylamine. The bromide of compounds 11 or 15 can be displaced in the 
standard way to give compound 12, the final product. 
Similarly, Scheme III shows how a bromochloroalkane (compound 16) may also 
be used as a differentiated dielectrophile. Alkylation of compound 16 
occurs selectively mono, with bromide displacement, to give either 
compound 17 or 18. The second displacement reaction may then be allowed to 
occur under more forceful conditions (see below) to afford the product, 
compound 12. 
##STR22## 
Much of the same technology presented in Schemes I, II, and III may be 
employed for compounds wherein Q is chosen to be an aromatic ring (either 
phenylene or a heterocycle). Synthesis of the starting materials for these 
routes would also largely depend upon the available starting material. One 
method, used for when either n or m=1, involves the free-radical 
bromination of a methyl group on the ring of an aralkanoate ester 
(compound 19, Scheme IV). Treatment with such reagents as 
N-bromosuccinimide, N-bromophthalimide, or 
1,3-dibromo-5,5-dimethylhydantoin with free-radical initiation provided by 
such reagents as benzoyl peroxide, azoisobutyonitrile or UV light effect 
the bromination of a benzyl group to give an a-bromomethylene group in 
compound 20. Displacement and introduction of the imidazole system gives 
compound 21. Reduction of the carboxylic ester group as discussed above 
gives the alcohol compound 22, and transformation to a leaving group as 
discussed above gives the compound 23. Displacement of the J group then 
yields the final product, compound 24. 
##STR23## 
For a general Q group, the technology required to extend a chain to prepare 
any length of m or n can begin with the Q group bearing a carboxylic ester 
group. This chain-extension methodology should be readily familiar to 
those skilled in the art, and only a few of the many possible routes to 
achieve this goal will be discussed here. Scheme V shows a plan for making 
alcohols with chains of 1, 2, 3, and n methylene units long, starting with 
carboxylic ester 25. Reagents such as lithium aluminum hydride will reduce 
the ester group to a hydroxy-methylene group (compound 26), which can be 
oxidized to the aldehyde 27 by such reagents as dimethylsulfoxide/oxalyl 
chloride/triethylamine. Alternatively, the carboxylic ester may be 
directly reduced to an aldehyde group with bulky reducing agents such as 
diisobutylaluminum hydride at low temperature. Aldehyde-bearing compound 
27 may be allowed to undergo reaction with such reagents as 
triphenylphosphonium methylide to give vinyl compound 28. Hydroxylation of 
the vinyl group may be achieved by using such reagents as 9-BBN followed 
by basic hydrogen peroxide, to afford the hydroxyethyl compound 29. The 
reaction of the aldehyde 27 with a reagent such as the anion of a diethyl 
alkoxycarbonylmethylphosphonate would produce the unsaturated ester group 
of compound 30. Both the carbon-carbon double bond and the alkoxycarbonyl 
group may be reduced using such reagents as lithium/ liquid ammonia, thus 
generating the hydroxypropyl compound 31. Finally, an extension to a chain 
of length n may be achieved by the reaction of aldehyde compound 27 with a 
(siloxy)alkylidene triphenyl-phosphorane reagent. The double bond in 
compound 32 may be reduced using hydrogen and palladium, platinum or other 
catalysts. Removal of the silicon group may be achieved by the use of such 
reagents as tetrabutylammonium fluoride. 
##STR24## 
The coupling of an intermediate bearing the Q group (compound 35 or 37 in 
Scheme VI) by displacement of a leaving group is accomplished by a 
nucleophilic reagent introducing either heterocycle (compound 34 or 38). 
The conditions of the reaction will depend upon the choice of X or Y; for 
X or Y=S or NH, the reaction is performed under basic conditions, in the 
presence of an inorganic reagent such as potassium carbonate, in polar 
aprotic solvents such as dimethylformamide or tetrahydrofuran at elevated 
temperatures. A catalyst may be used to facilitate the reaction, such as 
tetrabutylammonium iodide. Alternatively, the salts of compounds 34 or 38 
may be prepared by the treatment with such a reagent as sodium hydride. 
The salt, prepared in situ, is then allowed to react with the 
electrophiles 35 or 37 to give the coupled products (compounds 36 or 39). 
##STR25## 
In the case where X is CH.sub.2, a convenient coupling reaction is shown in 
Scheme VII. A 2-unsubstituted imidazole is protected at nitrogen with an 
ethoxyethyl group (compound 40), prepared by the action of ethyl vinyl 
ether and an acid catalyst. Compound 40 can be deprotonated selectively at 
the 2-position using a strong base such as n-butyllithium. The anion 
(intermediate 41) is then allowed to react with electrophile 35 to 
generate the coupled product, compound 42. The ethoxyethyl protecting 
group may be removed at a later point, and the R.sup.3 group may then be 
introduced. 
##STR26## 
When Y is NR.sup.4, a special synthesis may be used involving a 
nucleophilic aromatic displacement reaction (Scheme VIII). For this 
purpose, the compound containing the NR.sup.4 group is required (compound 
46). This can be prepared, starting with ester-bearing compound 43 
(prepared using technology discussed above). The ester may be cleaved to 
the carboxylic acid (compound 44), using such reagents as sodium hydroxide 
in aqueous ethanol or lithium iodide in warm dimethyl-sulfoxide. The acid 
may then be coupled to an amine to give the amide compound 45. This 
reaction may be performed with such reagents as dicyclohexylcarbodiimide 
and catalysts such as 1-hydroxy-1H-benzotriazole. The amide carbonyl group 
may then be reduced to a methylene, using such reagents as lithium 
aluminum hydride or boranetetrahydrofuran complex. The amine, compound 46, 
is then used to displace a leaving group (J) from a heterocyclic compound 
such as 47 or 49. Particularly successful choices for J include Cl and 
SO.sub.2 CH.sub.3. The reaction proceeds in the presence of a base such as 
diisopropylethyl-amine, in a polar aprotic solvent such as acetonitrile at 
reflux temperature. Application of high pressure to the reaction vessel 
(1000-5000 psi) may also be used to accelerate the process. 
##STR27## 
The synthesis of compounds with the G group attached to the rest of the 
molecule at a ring nitrogen atom is shown in Scheme IX. Such a bond may be 
formed by alkylation of the nitrogen atom with a J-bearing intermediate, 
either compound 51 (which already bears the imidazole group), or a simpler 
electrophile (compound 56), which requires two more steps (55 to 54 to 53) 
to generate the desired final product. 
All the heterocyclic starting materials employed in this section can be 
easily prepared by well-established protocols in heterocyclic chemistry. 
Such protocols are well-covered in the common literature, and are readily 
apparent to those skilled in the art. 
In the cases where X or Y is SO or SO.sub.2, the corresponding sulfides may 
be oxidized to their sulfoxide or sulfone counterparts by the use of such 
reagents as m-chloroperbenzoic acid, potassium peroxomonosulfate, 
potassium permanganate, and the like. Control of the extent of the 
oxidation may be achieved by control of stoichiometry, temperature and/or 
solvent.