ACAT inhibitors

This invention relates to novel compounds which are ACAT inhibitors rendering them useful in lowering blood cholesterol levels. The compounds contain two urea or thiourea, amide, or amine moieties or combinations of said moieties and have the following general formula: ##STR1## wherein m and n are zero or one, W and YNH and ##STR2## form the urea, thiourea, amide or amine moieties; and R.sub.1 and R .sub.2 are hydrogen or a hydrocarbon radical.

BACKGROUND OF THE INVENTION 
This invention relates to chemical compound having pharmacological 
activity, to pharmaceutical compositions which include these compounds, 
and to a pharmaceutical method of treatment. More particularly, this 
invention concerns certain novel compounds which inhibit the enzyme 
acylcoenzyme A: cholesterol acyltransferase (ACAT), pharmaceutical 
compositions containing these compounds, and a method of treating 
hypercholesterolemia and atherosclerosis. 
In recent years the role which elevated blood plasma levels of cholesterol 
plays in pathological conditions in man has received much attention. 
Deposits of cholesterol in the vascular system have been indicated as 
causative of a variety of pathological conditions including coronary heart 
disease. 
Initially, studies of this problem were directed toward finding therapeutic 
agents which could be effective in lowering total serum cholesterol 
levels. It is now known that cholesterol is transported in the blood in 
the form of complex particles consisting of a core of cholesteryl esters 
plus triglycerides and an exterior consisting primarily of phospholipids 
and a variety of types of protein which are recognized by specific 
receptors. For example, cholesterol is carried to the sites of deposit in 
blood vessels in the form of low density lipoprotein cholesterol (LDL 
cholesterol) and away from such sites of deposit by high density 
lipoprotein cholesterol (HDL cholesterol). 
Following these discoveries, the search for therapeutic agents which 
control serum cholesterol turned to finding compounds which are more 
selective in their action; that is, agents which are effective in 
elevating the blood serum levels of HDL cholesterol and/or lowering the 
levels of LDL cholesterol. While such agents are effective in moderating 
the levels of serum cholesterol, they have little or no effect on 
controlling the initial absorption of dietary cholesterol in the body 
through the intestinal wall. 
In intestinal mucosal cells, dietary cholesterol is absorbed as free 
cholesterol which must be esterified by the action of the enzyme acyl-CoA: 
cholesterol acyltransferase (ACAT) before it can be packaged into the 
chylomicrons which are then released into the blood stream. Thus, 
therapeutic agents which effectively inhibit the action of ACAT prevent 
the intestinal absorption of dietary cholesterol into the blood stream or 
the reabsorption of cholesterol which has been previously released into 
the intestine through the body's own regulatory action. 
SUMMARY OF THE INVENTION 
The present invention provides a class of compounds which have acyl-CoA: 
cholesterol acyltransferase (ACAT) inhibitory activity and intermediates 
useful in preparing said compounds having the following structure: 
##STR3## 
wherein each of m and n is zero or one with the proviso that the sum of m 
and n is one; wherein 
(a) each of R.sub.1 and R.sub.2 is selected from hydrogen, a straight or 
branched alkyl group having from one to six carbon atoms, or an alkyl 
group having from one to six carbon atoms wherein the terminal carbon atom 
is substituted with a hydroxy group with the proviso that one of R.sub.1 
and R.sub.2 is other than hydrogen; or 
b) R.sub.1 is hydrogen and R.sub.2 is a cycloalkyl group having from three 
to six carbon atoms; or 
(c) R.sub.1 is a straight or branched alkyl group having from one to six 
carbon atoms or an alkyl group having from one to six carbon atoms wherein 
the terminal carbon atom is substituted with a hydroxy group, and R.sub.2 
is 
(i) phenyl (CH.sub.2).sub.p - wherein p is zero or one and wherein the 
phenyl moiety is unsubstituted or is substituted with from 1 to 3 
substituents selected from alkyl having from 1 to 6 carbon atoms and which 
is straight or branched, alkoxy having from 1 to 6 carbon atoms and which 
is straight or branched; phenoxy, hydroxy, fluorine, chlorine, bromine, 
nitro, trifluoromethyl, -COOH, -COOalkyl wherein alkyl has from 1 to 4 
carbon atoms -NR.sub.3 R.sub.4 wherein R.sub.3 and R.sub.4 are 
independently hydrogen or alkyl of from 1 to 4 carbon atoms; 
(ii) 1- or 2-naphthyl which is unsubstituted or substituted with from one 
to three substituents selected from: alkyl having from 1 to 6 carbon atoms 
and which is straight or branched; alkoxy having from 1 to 6 carbon atoms 
and which is straight or branched; hydroxy, fluorine, chlorine, bromine, 
nitro, trifluoromethyl, --COOH, --COOalkyl wherein alkyl has from 1 to 4 
carbon atoms -NR.sub.3 R.sub.4 wherein R.sub.3 and R.sub.4 are as defined 
above; 
(iii) a 5- or 6- membered monocyclic or fused bicyclic heterocycle 
containing at least one to four nitrogen, oxygen, or sulfur atoms in at 
least one ring member; or 
(d) R.sub.1 is hydrogen, a straight or branched alkyl group having from one 
to six carbon atoms, or an alkyl group having from 1 to 6 carbon atoms 
wherein the terminal carbon atom is substituted with a hydroxy group, and 
R.sub.2 is an amino acid residue selected from 
##STR4## 
(e) R.sub.1 and R.sub.2 taken together with the carbon atom to which they 
are attached form a carbocyclic ring having from three to six carbon 
atoms; wherein y and Z are independently selected from: 
##STR5## 
wherein X is oxygen or sulfur; wherein Ar is selected from: (a) phenyl 
which is unsubstituted or is substituted with from 1 to 3 substituents 
selected from alkyl having from 1 to 6 carbon atoms and which is straight 
or branched, alkoxy having from 1 to 6 carbon atoms and which is straight 
or branched, phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, 
trifluoromethyl, --COOH, --COOalkyl wherein alkyl has from 1 to 4 carbon 
atoms -NR.sub.3 R.sub.4 wherein R.sub.3 and R.sub.4 are independently 
hydrogen or alkyl of from 1 to 4 carbon atoms; and 
(b) 1- or 2-naphthyl which is unsubstituted or substituted with from one to 
three substituents selected from: alkyl having from 1 to 6 carbon atoms 
and which is straight or branched; alkoxy having from 1 to 6 carbon atoms 
and which is straight or branched, hydroxy, fluorine, chlorine, bromine, 
nitro, trifluoromethyl, --COOH, --COOalkyl wherein alkyl has from 1 to 4 
carbon atoms, -NR.sub.3 R.sub.4 wherein R.sub.3 and R.sub.4 are as defined 
above; 
wherein R is selected from: 
(a) a straight or branched hydrocarbon chain having from 1 to 20 carbon 
atoms and which is saturated or contains from 1 to 3 double bonds; 
(b) a straight or branched hydrocarbon chain having from 1 to 6 carbon 
atoms wherein the terminal carbon atom is substituted with chlorine; 
fluorine; bromine; straight or branched lower alkoxy having from 1 to 4 
carbon atoms; straight or branched thioalkoxy having from 1 to 4 carbon 
atoms; a --COOR.sub.5 group wherein R.sub.5 is hydrogen or a straight or 
branched alkyl having from 1 to 4 carbon atoms; an -NR.sub.6 R.sub.7 group 
wherein R.sub.6 and R.sub.7 are independently hydrogen or lower alkyl 
having from 1 to 4 carbon atoms wherein said alkyl is unsubstituted or is 
substituted with hydroxy, or wherein -NR.sub.6 R.sub.7 taken together form 
a monocyclic heterocyclic group selected from pyrrolidino, piperidino, 
piperazino or piperazino substituted in the 4-position with a lower alkyl 
having from 1 to 4 carbon atoms or -COOR.sub.5 wherein R.sub.5 has the 
meaning defined above; and 
(c) a 5- or 6-membered monocyclic or fused bicyclic heterocycle containing 
at least one to four nitrogen, oxygen or sulfur atoms in at least one ring 
member; 
(d) the group 
##STR6## 
wherein t is zero to 4; q is zero to 4 with the proviso that the sum of t 
and q is not greater than 5; R.sub.8 and R.sub.9 are independently 
selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when 
R.sub.8 is hydrogen, R.sub.9 can be the same as R.sub.10 ; and R.sub.10 is 
phenyl or phenyl substituted with from 1 to 3 substituents selected from 
straight or branched alkyl having from 1 to 6 carbon atoms, straight or 
branched alkoxy having from 1 to 4 carbon atoms, straight or branched 
thioalkoxy having from 1 to 4 carbon atoms, phenoxy, hydroxy, fluorine, 
chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl 
has from 1 to 4 carbon atoms, or NR.sub.6 R.sub.7 ; wherein R.sub.6 and 
R.sub.7 have the meanings defined above; and 
(e) phenyl or phenyl substituted with from 1 to 3 substituents selected 
from straight or branched alkyl having from 1 to 6 carbon atoms, straight 
or branched alkoxy having from 1 to 4 carbon atoms, straight or branched 
thioalkoxy having from 1 to 4 carbon atoms, phenoxy, hydroxy, fluorine, 
chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl 
has from 1 to 4 carbon atoms, or NR.sub.6 R.sub.7 having the meanings 
defined above; wherein W is selected from: 
(a) hydrogen 
(b) a straight or branched hydrocarbon chain having from 1 to 20 carbon 
atoms and which is saturated or contains from 1 to 3 double bonds; 
(c) a straight or branched hydrocarbon chain having from 1 to 6 carbon 
atoms wherein the terminal carbon atom is substituted with chlorine; 
fluorine, bromine, straight or branched lower alkoxy having from 1 to 4 
carbon atoms; straight or branched thioalkoxy having from 1 to 4 carbon 
atoms; a --COOR.sub.5 group wherein R.sub.5 is hydrogen or a straight or 
branched alkyl having from 1 to 4 carbon atoms; an -NR.sub.6 R.sub.7 group 
wherein R.sub.6 and R.sub.7 are independently hydrogen or lower alkyl 
having from 1 to 4 carbon atoms wherein said alkyl is unsubstituted or is 
substituted with hydroxy, or wherein -NR.sub.6 R.sub.7 taken together form 
a monocyclic heterocyclic group selected from pyrrolidino, piperidino, 
piperazino or piperazino substituted in the 4-position with a lower alkyl 
having from 1 to 4 carbon atoms or --COOR.sub.5 wherein R.sub.5 has the 
meaning defined above; 
(d) the group 
##STR7## 
wherein t is zero to 4; q is zero to 4 with the proviso that the sum of t 
and q is not greater than 5; R.sub.8 and R.sub.9 are independently 
selected from hydrogen or alkyl having from 1 to 6 carbon atoms, or when 
R.sub.8 is hydrogen, R.sub.9 can be the same as R.sub.10 ; and R.sub.10 is 
phenyl or phenyl substituted with from 1 to 3 substituents selected from 
straight or branched alkyl having from 1 to 6 carbon atoms, straight or 
branched alkoxy having from 1 to 4 carbon atoms, straight or branched 
thioalkoxy having from 1 to 4 carbon atoms, phenoxy, hydroxy, fluorine, 
chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl 
has from 1 to 4 carbon atoms, or NR.sub.6 R.sub.7 wherein R.sub.6 and 
R.sub.7 have the meanings defined above; and 
(e) phenyl or phenyl substituted with from 1 to 3 substituents selected 
from straight or branched alkyl having from 1 to 6 carbon atoms, straight 
or branched alkoxy having from 1 to 4 carbon atoms, straight or branched 
thioalkoxy having from 1 to 4 carbon atoms, phenoxy, hydroxy, fluorine, 
chlorine, bromine, nitro, trifluoromethyl, --COOH, COOalkyl wherein alkyl 
has from 1 to 4 carbon atoms, or NR.sub.6 R.sub.7 wherein R.sub.6 and 
R.sub.7 have the meanings defined above; or a pharmaceutically acceptable 
salt and N-oxides thereof; with the provisos: 
(a) when both Z and W are the group 
##STR8## 
R.sub.9 and R.sub.10 are not the same; and (b) each of Y, Z, and W are 
not hydrogen at the same time. 
In addition to being pharmaceutically useful compounds, the compounds of 
Formula I wherein Y, Z, or W is hydrogen also can be intermediates to 
prepare other compounds of Formula I which will be apparent from the 
general description of the preparation of the compounds and the specific 
examples.

DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides a novel class of compounds which contain 
moieties selected from amine, amide, urea, and thiourea groups which are 
ACAT inhibitors rendering them useful in treating hypercholesterolemia and 
atherosclerosis. 
Illustrative examples of straight or branched saturated hydrocarbon chains 
having from 1 to 20 carbon atoms include methyl, ethyl, n-propyl, 
isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 
n-heptyl, n-octyl, n-undecyl, n-dodecyl, n-hexadecyl, 2,2-dimethyldodecyl, 
2-ethyltetradecyl, and n-octadecyl groups. 
Illustrative examples of straight or branched hydrocarbon chains having 
from 1 to 20 carbon atoms and having from 1 to 3 double bonds include 
ethenyl, 2-propenyl, 2-butenyl, 3-pentenyl, 2-octenyl, 5-nonenyl, 
4-undecenyl, 5-heptadecenyl, 3-octadecenyl, 9-octadecenyl, 
2,2-dimethyl-11-eicosenyl, 9,12-octadecadienyl, and hexadecenyl. 
Straight or branched alkoxy groups having from 1 to 6 carbon atoms include, 
for example, methoxy, ethoxy, n-propoxy, t-butoxy, and pentyloxy. 
Illustrative of straight or branched thioalkoxy groups having from 1 to 4 
carbon atoms are methylthio, ethylthio, n-propylthio, isopropylthio, and 
butylthio. The thioalkoxy group may also be referred to as alkylthio. 
A 5- or 6- membered monocyclic or fused bicyclic heterocycle is a 
monocyclic or fused bicyclic aromatic ring containing at least one to four 
hetero atoms in at least one ring, such as nitrogen, oxygen, sulfur, or a 
combination thereof. Such a heterocyclic group includes, for example, 
thienyl, benzothienyl, furanyl, benzofuranyl, pyridyl, pyrimidinyl, 
pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, isothiazolyl, oxazolyl, 
isoxazolyl, triazolyl, tetrazolyl, imidazolyl, benzothiazolyl, indolyl, 
quinolinyl, isoquinolinyl, or N-oxides of heterocycle containing a 
nitrogen atom. 
More specifically, such a heterocycle may be a 2-or 3-thienyl; 2- or 
3-furanyl; 2-, 3-, or 4-pyridyl or -pyridyl-N-oxide; 2-, 4-, or 
5-pyrimidinyl; 3- or 4-pyridazinyl; 2-pyrazinyl; 2- or 3-pyrrolyl; 3-, 4-, 
or 5-pyrazolyl, 3-, 4-, or 5-isoxazolyl; 3-, 4-, or 5-isoxazolyl; 3-, 4-, 
or 5-oxazolyl; 3-, 4-, or 5-isothiazolyl; 5-tetrazolyl; 2-, 4-, or 
5-imidazolyl; 2-, 3-, 4-, 5-, 6-, or 7-indolyl; 2-, 3-, 4-, 5-, 6-, 7-, or 
8-quinolinyl; 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl; 2-, 4-, 5-, 6-, 
or 7-benzothiazolyl; or 2-, 3-, 4-, 5-, 6-, or 7-benzothienyl. 
Illustrative examples of straight or branched alkyl groups having from 1 to 
6 carbon atoms include methyl, ethyl, n-propyl, n-butyl, isopropyl, and 
tert-butyl. 
The group phenyl(CH.sub.2).sub.p - wherein p is zero or one represents 
phenyl or benzyl wherein the phenyl ring or the aromatic ring of the 
benzyl group is unsubstituted or is substituted with from one to three 
substituents selected from straight or branched alkyl having from 1 to 6 
carbon atoms, straight or branched alkoxy having from 1 to 6 carbon atoms, 
phenoxy, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl, 
--COOH, --COOalkyl wherein the alkyl moiety has from 1 to 4 carbon atoms 
or -NR.sub.3 R.sub.4 wherein each of R.sub.3 and R.sub.4 is selected from 
hydrogen or an alkyl group having from 1 to 4 carbon atoms. 
Cycloalkyl groups having from 3 to 6 carbon atoms include cyclopropyl, 
cyclobutyl, cyclopentyl, and cyclohexyl. 
It is apparent from Formula I that compounds of the present invention 
wherein both Y and Z are 
##STR9## 
are bis-urea or bis-thiourea derivatives, or wherein both Y and Z are 
##STR10## 
are bis-amide derivatives, or wherein both Y and Z are R-CH.sub.2 - are 
bis-amine derivatives. It is also apparent form Formula I that the 
substituent groups Y and Z may be different in which case the compounds of 
the present invention are urea-amide or thiourea-amide compounds, or are 
urea-amine or thiourea-amine compounds or are amide-amine compounds. 
In one preferred embodiment of the present invention at least one of the 
groups Y or Z represents a urea or thiourea moiety, i.e., Y or Z is the 
group 
##STR11## 
In another preferred embodiment of the present invention at least one of Y 
or Z is a urea moiety, i.e., the group 
##STR12## 
wherein X is oxygen. Compounds of the following general Formula II wherein 
each of Y and Z represents the group 
##STR13## 
represent preferred compounds of the present invention: 
##STR14## 
Compounds of Formula II wherein X is oxygen are more preferred. Another 
preferred embodiment of the present invention are compounds wherein one of 
Y or Z represents 
##STR15## 
and the other of Y or Z represents 
##STR16## 
which compounds are depicted by the following Formulas III and IV: 
##STR17## 
Compounds of Formula II and IV wherein X is oxygen are more preferred. 
Another preferred embodiment of the present invention are compounds 
wherein one of Y and Z represents 
##STR18## 
and the other of Y and Z represents R-CH.sub.2 - which compounds are 
depicted by the following Formulas V and VI: 
##STR19## 
Of the compounds represented by Formulas II through VI the compounds for 
Formulas II, III, and V are more preferred and within these compounds 
those wherein X is oxygen are more preferred. Other preferred compounds of 
this invention are those wherein Ar is phenyl or substituted phenyl and 
more preferably wherein Ar is phenyl substituted on the 2,6-positions. 
Other preferred compounds of this invention are those wherein W is 
hydrogen. 
Pharmaceutically acceptable salts of the compounds of Formula I are also 
included as a part of the present invention. 
The acid salts may be generated from the free base by reaction of the 
latter with one equivalent of a suitable nontoxic, pharmaceutically 
acceptable acid, followed by evaporation of the solvent employed for the 
reaction and recrystallization of the salt if required. The free base may 
be recovered from the acid salt by reaction of the salt with an aqueous 
solution of a suitable base such as sodium carbonate, sodium bicarbonate, 
potassium carbonate, sodium hydroxide, and the like. 
Suitable acids for forming acid salts of the compounds of this invention 
include, but are not necessarily limited to acetic, benzoic, 
benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, 
gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, 
pamoic, salicylic, stearic, succinic, sulfuric, and tartaric acids. The 
class of acids suitable for the formation of nontoxic, pharmaceutically 
acceptable salts is well known to practitioners of the pharmaceutical 
formulation arts (see, for example, Stephen N. Berge, et al, J Pharm 
Sciences, 66:1-19 (1977)). 
The compounds of the present invention may also exist in different 
stereoisomeric forms by virtue of the presence of asymmetric centers in 
the compound. The present invention contemplates all stereoisomeric forms 
of the compounds as well as mixtures thereof, including racemic mixtures. 
Further, the compounds of this invention may exist in unsolvated as well as 
solvated forms with pharmaceutically acceptable solvents such as water, 
ethanol and the like. In general, the solvated forms are considered 
equivalent to the unsolvated forms for the purposes of this invention. 
As shown by the data presented below in Table 1, the compounds of the 
present invention are potent inhibitors of the enzyme acyl-CoA: 
cholesterol acyltransferase (ACAT), and are thus effective in inhibiting 
the esterification and transport of cholesterol across the intestinal cell 
wall. The compounds of the present invention are thus useful in 
pharmaceutical formulations for the treatment of hypercholesterolemia or 
atherosclerosis. 
The ability of representative compounds of the present invention to inhibit 
ACAT was measured using an in vitro test more fully described in Field, F. 
J. and Salone, R. G., Biochemica et Biophysica, 712:557-570 (1982). The 
test assesses the ability of a test compound to inhibit the acylation of 
cholesterol by oleic acid by measuring the amount of radiolabeled 
cholesterol cleate formed from radiolabeled oleic acid in a tissue 
preparation containing rabbit intestinal microsomes. 
The data appear in Table 1 where they are expressed in IC.sub.50 values; 
i.e., the concentration of test compound required to inhibit 50% 
expression of the enzyme. 
TABLE 1 
______________________________________ 
Compound 
IC.sub.50 
of Example 
(.mu.M) 
______________________________________ 
1 0.61 
2 2.50 
3 0.25 
4 0.096 
5 0.51 
6 0.057 
7 0.49 
8 0.085 
9 0.27 
10 0.41 
______________________________________ 
In one in vivo screen designated APCC, male Sprague-Dawley rats (200 to 225 
g) were randomly divided into treatment groups and dosed at 4 PM with 
either vehicle (CMC/Tween) or suspensions of compounds in vehicle. The 
normal, chow diet was then replaced with the PCC diet with either 1% or 
0.5% cholic acid, as indicated. The rats consumed this diet ad libitum 
during the night and were sacrificed at 8 AM to obtain blood samples for 
cholesterol analysis using standard procedures. Statistical differences 
between mean cholesterol values for the same vehicle were determined using 
analysis of variance followed by Fisher's least significant test. The 
results of this trial for representative compounds of the present 
invention appear in Table 2. 
TABLE 2 
______________________________________ 
Compound % Change 
of Example (mg/dl) 
______________________________________ 
6 -25 
7 -31 
8 -17 
9 -33 
10 -46 
______________________________________ 
In therapeutic use as agents for treating hypercholesterolemia or 
atherosclerosis, the compounds of Formula I or pharmaceutically acceptable 
salts thereof are administered to the patient at dosage levels of from 250 
to 3000 mg per day. For a normal human adult of approximately 70 kg of 
body weight, this translates into a dosage of from 5 to 40 mg/kg of body 
weight per day. The specific dosages employed, however, may be varied 
depending upon the requirements of the patient, the severity of the 
condition being treated, and the activity of the compound being employed. 
The determination of optimum dosages for a particular situation is within 
the skill of the art. 
For preparing the pharmaceutical compositions from the compounds of this 
invention, inert, pharmaceutically acceptable carriers can be either solid 
or liquid. Solid form preparations include powders, tablets, dispersible 
granules, capsules, and cachets. 
A solid carrier can be one or more substances which may also act as 
diluents, flavoring agents, solubilizers, lubricants, suspending agents, 
binders, or tablet disintegrating agents; it can also be an encapsulating 
material. 
In powders, the carrier is a finely divided solid which is in a mixture 
with the finely divided active component. In tablets, the active compound 
is mixed with the carrier having the necessary binding properties in 
suitable proportions and compacted in the shape and size desired. 
Powders and tablets preferably contain between about 5% to about 70% by 
weight of the active ingredient. Suitable carriers are magnesium 
dicarbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, 
starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a 
low-melting wax, cocoa butter, and the like. 
The term "preparation" is intended to include the formulation of the active 
compound with encapsulating material as a carrier providing a capsule in 
which the active component (with or without other carriers) is surrounded 
by a carrier, which is thus in association with it. In a similar manner 
cachets are also included. 
Tablets, powders, cachets, and capsules can be used as solid dosage forms 
suitable for oral administration. 
Liquid form preparations include solutions, suspensions, or emulsions 
suitable for oral administration. Aqueous solutions for oral 
administration can be prepared by dissolving the active compound in water 
and adding suitable flavorants, coloring agents, stabilizers, and 
thickening agents as desired. Aqueous suspensions for oral use can be made 
by dispersing the finely divided active component in water together with a 
viscous material such as natural or synthetic gums, resins, methyl 
cellulose, sodium carboxymethylcellulose, and other suspending agents 
known to the pharmaceutical formulation art. 
Preferably, the pharmaceutical preparation is in unit dosage form. In such 
form, the preparation is divided into unit doses containing appropriate 
quantities of the active component. The unit dosage form can be a packaged 
preparation containing discrete quantities of the preparation, for 
example, packeted tablets, capsules, and powders in vials or ampoules. The 
unit dosage form can also be a capsule, cachet, or tablet itself, or it 
can be the appropriate number of these packaged forms. 
The compounds of this invention are prepared by procedures generally well 
known in the art. Two general methods for preparing compounds of Formula I 
are set forth in Chart I and Chart II hereof. In Chart I the various 
symbols R, Ar, and X have the meanings defined in Formula I. R.sub.11 and 
R.sub.12 are the same as definitions (a), (b), (c), and (e) for R.sub.1 
and R.sub.2 in Formula I. In Chart II the various symbols Ar, R, R.sub.1, 
R.sub.2, and X have the same meanings as defined in Formula I, and BOC is 
tertiary butoxycarbonyl. Chart III hereof sets forth the general scheme 
for the preparation of compounds (9) in Chart II. It is apparent from 
general Formula I and Charts I and II that the compounds of the present 
invention contain various combinations of urea, thiourea, amide, and amine 
groups. It is also apparent from Charts I and II that the order in which 
the various amide, amine, urea, and thiourea groups are incorporated into 
the final products may vary and can be manipulated easily by one skilled 
in the art. 
Referring to Chart I the amino nitrile (2) is prepared via a Strecker 
synthesis by treating an appropriate aldehyde or ketone (1) with sodium 
cyanide, ammonium chloride, and ammonium hydroxide in a lower aqueous 
alcohol, such as, aqueous methanol at a temperature range from 50.degree. 
C. to 75.degree. C. for 1 to 24 hours. The amino nitrile (2) may be 
treated with an acylating agent, an alkylating agent, or with an 
appropriate isocyanate or thioisocyanate as depicted in Chart I to give 
the nitriles represented by formulas (3), (4), and (5). The nitriles are 
then reduced using Raney nickel in methanolic ammonia at 50 psi or by 
using palladium on charcoal in methanol/sulfuric acid to give the amines 
depicted by formulas (6), (7), and (8). In referring to Chart II the 
diamine (9) wherein one of the amine groups is protected with an easily 
removed protecting group such as tertiary butoxycarbonyl is treated with 
an appropriate isocyanate, thioisocyanate, alkylating agent, or acylating 
agent to give the amine protected isocyanate or thioisocyanate (10), amide 
(11) or amine (12). Compounds (10), (11), and (12) are then deprotected 
using HCl gas in dichloromethane at room temperature to give the free 
amine compounds (13), (14), and (15). In referring again to Chart I the 
amino nitrile (2) may be resolved by treatment with D or L tartaric acid 
as generally described in J. Med. Chem. 28(9):1280 (1985) by adding a 
methanolic solution of tartaric acid to a solution of the amino nitrile in 
benzene-methanol (4:1), filtering the precipitate, washing with 
benzene-methanol (2:1), and recrystallizing from methanol. When the 
resolved amino nitrile is treated as depicted in Chart I and as described 
herein the corresponding resolved final products of Formula I are 
obtained. 
It is readily apparent from Charts I and II that compounds (6), (7), (8), 
(13), (14), and (15) can be further alkylated, acylated, or treated with 
an appropriate isocyanate or thioisocyanate to give the compounds of 
Formula I. To form compounds containing a urea or thiourea moiety the 
appropriate amine is treated with an aryl isocyanate or an aryl 
thioisocyanate of the formula ArNCX wherein Ar and X have the meanings 
defined in Formula I at room temperature in methylene chloride, ethyl 
acetate, tetrahydrofuran, or acetonitrile. To form compounds containing an 
amide moiety the appropriate amine is treated with an acid anhydride of 
the formula (RCO).sub.2 O wherein R has the meaning defined in Formula I. 
Additionally, an appropriate acid, RCO.sub.2 H or acid halide RCOhalo 
wherein halo is, e.g., chlorine, may also be used. The reaction is carried 
out at room temperature in tetrahydrofuran, methylene chloride, or 
chloroform and in the presence of triethylamine. In preparing compounds 
wherein R is heteroaryl an appropriate heteroarylcarboxylic acid is used 
with a coupling agent such as carbonyldiimidazole in tetrahydrofuran or 
dicyclohexylcarbodiimide in methylene chloride. 
The amine containing compounds are formed by reducing the corresponding 
amide via a metal (aluminum) hydride reduction at reflux in toluene or by 
alkylating a primary or secondary amine-containing compound. Alkylation is 
achieved by reacting a primary or secondary amine compound with an 
aldehyde of the formula WCHO wherein W has the meaning defined in Formula 
I in a lower alcohol such as methanol in the presence of sodium sulfate or 
calcium sulfate to give the corresponding imine. This reaction may require 
heating if hindered amines are used. The imine is reduced to the amine 
using a metal hydride reducing agent such as sodium borohydride in 
tetrahydrofuran at room temperature. This alkylation may also be achieved 
using a suitable halide alkylating agent in methylene chloride or 
tetrahydrofuran using triethylamine as base. When alkylating a primary or 
secondary amine as depicted in Charts I and II to form compounds of 
Formula I wherein W is phenyl or a substituted phenyl group the most 
suitable alkylating agent is the aldehyde WCHO wherein W is phenyl or 
substituted phenyl. 
Compounds of Formula I wherein R represents an alkyl group having from one 
to six carbon atoms wherein the terminal carbon is substituted with 
halogen, methoxy, or NR.sub.6 R.sub.7 are prepared by acylating the 
appropriate amine using .omega.-bromoacyl chloride to afford a compound 
wherein R is --(CH.sub.2).sub.m Br wherein m is an integer of from one to 
six. The .omega.-bromoalkyl containing compound can be subjected to 
various nucleophilic substitutions to give the corresponding compounds 
wherein the terminal carbon is substituted with alkoxy, thioalkoxy, 
NR.sub.6 R.sub.7, or other halogen atoms. The alkoxy or 
thioalkoxy-containing compounds are obtained by treating the bromo 
compound with a suitable alkoxide or thioalkoxide in a lower alcoholic 
solvent. The NR.sub.6 R.sub.7 containing compounds are obtained, e.g., by 
treating the bromo compound with ammonia gas to give the corresponding 
.omega.-NH.sub.2 compound, or with dimethylamine gas to give the 
.omega.-N(CH.sub.3).sub.2 compound or with an excess of an appropriate 
amine in a lower alcohol solvent at elevated temperature, e.g., 80.degree. 
to 95.degree. C. to give the corresponding .omega.-NR.sub. 2 R.sub.3 
-containing compounds. To obtain compounds wherein the terminal carbon is 
substituted with a --COORs group the .omega.-bromo compound is treated 
with magnesium metal in ether at 0.degree. C. to form a Grignard reagent 
which is treated with solid CO.sub.2 to give the .omega.-COOH compound 
which is esterified at room temperature using a lower alcohol and a trace 
of mineral acid. 
In Chart III the general procedure for preparing the protected diamine 
compound (9) used in Chart II is depicted. The BOC-protected amino acid 
ester (16) is treated with lithium aluminum hydride in tetrahydrofuran or 
diethyl ether at a temperature ranging from 0.degree. C. to 25.degree. C. 
to give the corresponding alcohol (17). The alcohol (17) is converted to 
the mesylate (18) by treatment with methanesulfonyl chloride in 
dichloromethane, pyridine, or chloroform at a temperature of from 
-25.degree. C. to 0.degree. C. using triethylamine as base followed by a 
nucleophilic substitution reaction using sodium azide in dimethylformamide 
at 60.degree. C. to 80.degree. C. The azide (19) is reduced to the 
corresponding amine (9) using lithium aluminum hydride in tetrahydrofuran 
or diethyl ether at a temperature ranging from 0.degree. C. to 25.degree. 
C. 
The amino acid ester compounds (16) and the aldehyde or ketones compounds 
(1) are commercially available or are prepared by procedures generally 
well known in the art. 
The procedure outlined in Chart I gives the final products in the form of a 
racemic mixture. The procedure outlined in Chart II gives the final 
products as a racemic mixture or the individual enantiomers depending on 
the form of the starting material (16) used in Chart III. The enantiomers 
of compounds (16) are commercially available or may be prepared by well 
known procedures. 
EXAMPLE 1 
(.+-.)-N-[2-[[[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]amino]-1-methyl 
-1-(2-pyridinyl)ethyl]-4-methoxybenzamide monohydrochloride 
(a) N-[1-cyano-1-(2-pyridinyl)ethyl]-4-methoxygenzamide 
2-Acetylpyridine (10.0 g, 0.0825 mole) was added to 50.degree. C. solution 
of sodium cyanide (4.0 g, 0.0825 mole) ammonium chloride (4.9 g, 0.0908 
mole), and ammonium hydroxide (2.9 g, 0.0825 mole ) in water (22 mL) and 
methanol (15 mL). The resulting mixture was stirred at 50.degree. C. 
overnight. The mixture was cooled and concentrated under reduced pressure. 
The residue was dissolved in methylene chloride (40 mL) and washed with 
water (10 mL) and dried over MgSo.sub.4. Filtration and concentration gave 
a dark red oil which was dissolved in methanol and treated with saturated 
ethereal HCl. Concentration yielded a low melting solid which was 
dissolved in tetrahydrofurna (50 mL) and treated sequentially with 
triethylamine (13.7 g, 0.135 mole) and p-anisoyl chloride (8.4 g, 0.0495 
mole) dropwise. The solution was stirred 3 hours at room temperature then 
diluted with ether (100 mL) and washed with 2M HCl, 1M NaOH, saturated 
NaCl, and dried over MgSo.sub.4. Filtration and concentration of the 
solvent in vacuo provided a solid which was recrystalized from ethyl 
acetate/hexane to give 5.2 g of 
N-[-1-cyano-1-(2-pyridinyl)ethyl]-4-methoxybenzamide, mp 173.degree. C. 
(b) N-[2-amino-1-methyl-1-(2-pyridyl)ethyl]-4-methoxybenzamide 
N-[-1-cyano-1-(2-pyridinyl)ehtyl]-4-methoxy-benzamide (4.7 g, 0.0167 mole) 
was dissolved in 100 mL methanolic ammonia and treated with 1.5 g Raney 
nickel under 50 psi and warmed to 40.degree. C. for 10 hours. The mixture 
was filtered and the supernate concentrated in vacuo to yield a pale green 
oil. The crude product (2.3 g) was used in the next step without further 
purification. 
(c) The benzamide from (b) was dissolved in ethyl acetate (15 mL) and 
treated with 2,6-diisopropyl phenylisocyanate (1.7 g, 0.0083 mole). The 
resulting mixture was stirred 2 hours at room temperature then 
concentrated in vacuo. The residue was dissolved in methanol and treated 
with saturated ethereal HCl, concentrated in vacuo and crystalized from 
methanol/ether, and dried overnight in vacuo at 55.degree. C. to yield 2.8 
g of 
(.+-.)-N-[2-[[[[2,6-bis(1-methylethyl)phenyl]amino]carbonyl]amino]-1methyl 
-1 -(2-pyridinyl)ethyl]-4-methoxygenzamide, monohydrochloride, mp 
154.degree.-158.degree. C. 
When in the procedure of Example 1 an appropriate amount of the starting 
material listed below is substituted for 2-acetylpyridine and the general 
procedure of Example 1 was followed the products listed below were 
obtained: 
______________________________________ 
Starting 
Example Material Product 
______________________________________ 
2 Dimethylketone 
N-[2-[[[[2,6-bis(1-methyl- 
ethyl)phenyl]amino]car- 
bonyl]amino]-1,1-dimethyl- 
ethyl]-4-methoxybenzamide, 
1.15 (12H, broad multiplet, 
##STR20## 
methyl groups); 3.20-3.25 
(4H, multiplet, --C .sub.-- H.sub.2 --, 
.sub.-- H-&gt;-); 3.84 (3H, singlet, 
##STR21## 
mult., N .sub.--H); 5.88 (1H, broad 
mult., N .sub.--H); 6.93-7.86 (7H, 
multiplet, aromatic); 8.12 
(1H, broad mult., N .sub.-- H) 
3 Cyclohexylal- 
(.+-.)-N-[2-[[[[2,6-bis(1- 
dehyde methylethyl)phenyl]amino]- 
carbonyl]amino]-1-cyclo- 
hexylethyl]-4-methoxybenz- 
amide, mp 231-232.degree. C. 
4 Di -n-propyl- 
N-[1-[[[[2,6-bis(1-methyl- 
ketone ethyl)phenyl]amino]car- 
bonyl]amino]methyl]-1- 
propylbutyl]-4-methoxy- 
benzamide, 0.848 (6H, 
##STR22## 
(16H, broad multiplet, 
##STR23## 
##STR24## 
3.17-3.28 (2H, heptet, 
.sub.-- H-&gt;-); 3.38-3.40 (2H, broad 
##STR25## 
##STR26## 
broad mult., N .sub.-- H); 5.88 (1H, 
broad mult., N .sub.--H); 6.88-7.75 
(8H, mult., aromatic, N .sub.-- H) 
5 Cyclopentyl- 
N-[1-[[[[[2,6-bis(1-methyl- 
ketone ethyl)phenyl]amino]car- 
bonyl]amino]methyl]cyclo- 
pentyl]-4-methoxybenzamide, 
mp 158-159.degree. C. 
______________________________________ 
EXAMPLE 6 
(S)-(-)-N-[2,6-bis(1-methylethyl)phenyl]-N'-[2-[[(4-methoxyphenyl)methyl]am 
ino]-4-methyl-pentyl]urea 
(a) (S)-(-)-1,1-Di-methylethyl-(1-hydroxymethyl-3-methylbutyl)carbamate 
Lithium aluminum hydride (0.65 g; 0.017 mole) was slurried in THF (60 mL) 
and cooled to 0.degree. C. under a N.sub.2 atmosphere. A solution of 
S-(-)-2[(1,1-dimethylethoxy)carbonylamino]-4-methylpentanoic acid, methyl 
ester (3.0 g; 0.012 mole) dissolved in THF (15 mL) was added dropwise and 
upon completion of the addition the suspension was gradually warmed to 
room temperature with stirring overnight. The mixture was further cooled 
to -40.degree. C. and treated with a solution of NaHSO.sub.4 (2.1 g; 0.015 
mole) in H.sub.2 O (10 mL), diluted with EtOAc (100 mL), and filtered 
through celtie. The filtrate was dried over MgSO.sub.4, filtered, and 
concentrated in vacuo leaving an orange syrup. The product was 
chromatographed using silica gel and Et.sub.2 O as the eluant. Yield: 2.2 
g (84%); oil. 
(b) (S)-)-)-1,1-Dimethylethyl 
[3-methyl-1-((methylsulfonyloxy)methyl)butyl]carbamate 
The product from (a) above (1.9 g; 8.7 mmole) was dissolved in CH.sub.2 
Cl.sub.2 (70 mL), cooled to 0.degree. C., and treated with NEt.sub.3 (1.7 
g; 17.4 mmole). Soon after, methanesulfonyl chloride (1.06 g; 9.5 mmole) 
was added at such a rate so as not to exceed a solution temperature of 
3.degree. C. The solution was stirred for 45 minutes, treated with aqueous 
saturated sodium chloride (40 mL), and the layers separated. The organic 
portion was dried over MgSo.sub.4, filtered, and concentrated to dryness. 
The residue was triturated with hexane and the resulting solid collected 
by filtration. Yield: 2.0 g (77%) [.alpha.].sub.D 23=-38.degree. (1% 
CHCl.sub.3). 
(c) (S)-(-)-1,1-Dimethylethyl(1-azidomethyl-3-methylbutyl)carbamate 
The product from (b) above (1.9 g; 6.4 mmole) was dissolved in DMF (20 mL) 
and treated with NaN.sub.3 (2.0 g; 32 mmole) in one portion. The mixture 
was heated to 80.degree. C. for over 4 hours, cooled, and diluted with 
H.sub.2 O (40 mL). The product was extracted with two portions of Et.sub.2 
O. The extracts were combined, dried over MgSO.sub.4, filtered, and 
concentrated n vacuo leaving a colorless liquid. The product was dissolved 
in hexane/ethyl acetate (4:1) and chromatographed using hexane/EtoAc as 
the eluant. Fractions containing the product were combined and 
concentrated in vacuo leaving a white solid. Yield: 1.2 g (76%) 
[.alpha.].sub.D 23=-50.degree. (1% CHCl.sub.3). 
(d) (S)-(-)-1,1-Dimethylethyl (1-aminomethyl-3-methylbutyl)carbamate 
Lithium aluminum hydride (0.24 g; 6.4 mmole) was slurried in THF (20 mL) 
and cooled to 0.degree. C. The suspension was treated with a solution of 
the carbamate from (c) above (1.1 g; 4.6 mmole) in THF (10 mL) and stirred 
for 2 hours at 0.degree. C. The mixture was further cooled to -30.degree. 
C. and a solution of NaHSO.sub.4 (0.6 g; 4.3 mmole) in H.sub.2 O (5 mL) 
was cautiously added and then diluted with EtOAc (50 mL), and filtered 
through celite. The filtrate was dried over MgSo.sub.4, filtered, and 
concentrated in vacuo leaving a colorless liquid. Yield: 1.0 g (100%) 
(e) 
(S)-(-)-1,1-Dimethylethyl[3-methyl-1-[[[[[2,6-bis(1-methylethyl)phenyl]ami 
no]carbonyl]-amino]methyl]butyl]carbamate. 
The carbamate obtained in (d) above (1.0 g; 4.6 mmole) was dissolved in 
EtOAc (25 mL) and treated with 2,6-diisopropylphenylisocyanate (1.0 g; 5.0 
mmole) in one portion. Precipitation occurred after 5 minutes of stirring 
at room temperature. The mixture was stirred an additional hour and the 
solid was collected by filtration and washed with hexane. Yield: 1.2 g 
(63%). 
(f) 
(S)-(-)-N-[2-Amino-4-methylpentane]-N'-[2,6-bis(1-methylethyl)phenyl]urea 
The carbamate from (e) above (1.0 g; 2.3 mmole) was slurried in CH.sub.2 
Cl.sub.2 (125 mL) and treated with HCl (g) in a continuous stream with 
stirring for over 30 minutes. The solution was concentrated in vacuo 
leaving a white foam. The HCl salt was triturated with hexane and filtered 
leaving a white solid (0.85 g). The salt was dissolved in ethyl acetate 
(25 mL)/CH.sub.3 OH (2 mL) and treated with NEt.sub.3. After stirring for 
10 minutes, H.sub.2 O was added and the layers separated. The organic 
portion was dried over MgSo.sub.4, filtered, and concentrated in vacuo 
leaving a white solid. Yield: 0.7 g (100%). 
(g) 
(S)-(-)-N-[2,6-bis(1-methylethyl)phenyl]-N'-[2-[[(4-methoxyphenyl)methyl]a 
mino]-4-methyl-pentyl]urea 
The urea from (f) above (0.7 g; 2.1 mmole) was dissolved in CH.sub.3 OH (50 
mL) and stirred over Na.sub.2 SO.sub.4 (2.2 g; ANH) for 10 minutes. 
4-Anisaldehyde (0.24 g; 2.1 mmole) was added in one portion and stirred at 
room temperature overnight. The suspension was concentrated in vacuo and 
the residue was treated with THF (50 mL). The insoluble material was 
removed by filtration and to the filtrate was added NaBH.sub.4 (0.39 g) 
with stirring for 30 minutes. The mixture was treated with H.sub.2 O (50 
mL) and the product was extracted using two portions of CHCl.sub.3. The 
organic solution was dried over Na.sub.2 SO.sub.4, filtered, and 
concentrated in vacuo leaving a viscous liquid. The crude product was 
treated with warm EtOAc hexane and crystalized on standing. Yield: 0.54 g 
(56%). [.alpha.].sub.D 23=-20.degree. (1 6% CHCl.sub.3) of the title 
compound. 
NMR (CDCl.sub.3): .delta.8.0 (s, 1H), 7.4 (d, 2H), 7.2 (t, 1H), 7.1 (d, 
2H), 6.8 (d, 2H), 6.0 (bs, 1H), 4.4 (bs, 1H), 3.6 (s, 3H), 3.5 (m, 1H), 
3.2 (m, 4H), 1.4 (m, 2H), 1.3 (m, 2H), 1.2 (bs, 12H), 0.9 (dd, 6H) ppm. 
When in the procedure of Example 6, an appropriate amount of the starting 
material listed below is substituted for 
(S)-(-)-2[(1,1-dimethylethoxy)carbonylamino]-4-methylpentanoic acid, 
methyl ester and the general procedure of steps (a) through (g) of Example 
6 are followed the products listed below are obtained. 
______________________________________ 
Starting 
Example Material Product 
______________________________________ 
7 (S)-(-)-2-[(1,1-di- 
(S)-(-)-N-[2,6-Bis- 
methylethoxy)car- 
(1-methylethyl)- 
bonylamino]-4- phenyl]-N'-[2-[[(4- 
methylthiobutyric 
methoxyphenyl)- 
acid, methyl ester 
methyl]amino]-4- 
(methylthio)butyl] 
urea, mp 96-97.degree. C. 
8 (S)-(-)-2-[(1,1-di- 
(S)-(-)-N[2,6-Bis- 
methylethoxy)car- 
(1-methylethyl)- 
bonylamino]-3- phenyl]-N'-[2- 
methylbutyric acid, 
[[(4-methoxyphenyl]- 
methyl ester methyl]amino]-3- 
methylbutyl]urea 
mp 84-86.degree. C. 
9 (S)-(-)-2-[(1,1-di- 
(S)-(-)-N-[2,6-Bis- 
methylethoxy)car- 
(1-methylethyl)- 
bonylamino]-3- phenyl]-N'-[2-[[(4- 
phenylpropionic 
methoxyphenyl)- 
acid methyl]amino]-3- 
phenylpropyl]urea, 
mp 124-125.degree. C. 
______________________________________ 
EXAMPLE 10 
When in the procedure of Example 6 an appropriate amount of 
(S)-(-)-2-[(1,1-dimethylethoxy)carbonylamino]-3-phenylpropionic acid is 
substituted for 
(S)-(-)-2[(1,1-dimethylethoxy)carbonylamino]-4-methylpentanoic acid, 
methyl ester and an appropriate amount of 2-hydroxybenzaldehyde is 
substituted for 4-anisaldehyde and the general procedure of Example 6 was 
followed (S)-(-)-N-[2,6-bis 
(1-methylethyl)-phenyl]-N'-[2-[[(2-hydroxyphenyl)methyl]amino]-3-phenylpro 
pylurea was obtained. 
NMR (CDCl.sub.3): .delta.7.4 (T, 1H), 7.3 (M, 7H), 7.1 (T, 1H), 6.9 (D, 
2H), 6.8 (D, 1H), 6.7 (T, 2H), 6.0 (BS, 1H), 4.3 (BS, 1H , 3.9 (Q, 2H), 
3.3 (M, 4H), 2.9 (M, 1H), 2.6 (D, 2H , 1.2 (D, 12 H) ppm. [.alpha.].sub.D 
23=-10.degree. (1% CHCl.sub.3). 
##STR27##