Anti-atherosclerotic agents of the formula: ##STR1## wherein R.sup.1 is (a) alkyl having from 1 to 22 carbon atoms; or PA1 (b) of the formula ##STR2## in which m is 0, 1 or 2, and each of R' and R" is, independently, hydrogen, halo or lower alkyl or alkoxy; R.sup.2 and R.sup.3 are joined to form with the silicon atom a heterocyclic ring having from 3 to 20 ring members; and R is an aralkyl-, phenyl- tryptophanyl- or benzocycloalkyl-type radical, eg 1-butyl-N-[(2-(4'-methyl-phenyl)-1-phenylethyl]-1-silacyclohexane propanamide, are obtained by reducing corresponding .alpha.,.beta.-unsaturated analogs.

This invention relates to silicon-bearing amides, and more particularly to 
a class of novel amides which bear a silacycloalkane moiety, novel 
intermediates in preparation of said class of amides, and the 
pharmaceutical use of said novel compounds and certain intermediates, as 
well as pharmaceutical compositions comprising said pharmaceutically 
useful novel compounds and intermediates. 
The final compounds (I) which are obtainable by the process of this 
invention may conveniently be represented by the formula I: 
##STR3## 
wherein R.sup.1 is either (a) alkyl having from 1 to 22 carbon atoms; or 
(b) of the formula 
##STR4## 
in which m is 0, 1 or 2, and each of R' and R" is independently a hydrogen 
atom, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 
carbon atoms, or halo having an atomic weight of from about 19 to 127; 
R.sup.2 and R.sup.3 are joined to form with the silicon, a cyclic 
structure of from 3 to 20 ring members; and R is of type (a) an 
aralkyl-type radical of the structure 
##STR5## 
wherein g is 0, 1 or 2; R.sup.a is a hydrogen atom, halo having an atomic 
weight of from about 19 to 127, alkoxy having from 1 to 4 carbon atoms, or 
alkyl having from 1 to 4 carbon atoms, or trifluoromethyl; 
R.sup.b is a hydrogen atom, alkyl having from 1 to 3 carbon atoms, alkoxy 
having from 1 to 3 carbon atoms, or halo having an atomic weight of from 
about 19 to 36; and 
R.sup.c is subtype (i) a hydrogen atom; 
subtype (ii) a radical of the structure 
##STR6## 
in which p is 0, 1 or 2, and y is a hydrogen atom, halo having an atomic 
weight of from about 19 to 127, alkoxy having from 1 to 4 carbon atoms, or 
alkyl having from 1 to 4 carbon atoms; and 
y' is a hydrogen atom, alkoxy having from 1 to 3 carbon atoms, alkyl having 
from 1 to 3 carbon atoms, or halo having an atomic weight of from about 19 
to 36; or 
subtype (iii) alkyl having from 1 to 8 carbon atoms; or 
R is of type (b) a phenyl-type radical of the structure 
##STR7## 
in which R.sup.b is as defined above, and R.sup.o is a hydrogen atom, halo 
having an atomic weight of from about 19 to 127, ie. alkoxy having from 1 
to 4 carbon atoms, or alkyl having from 1 to 4 carbon atoms; or 
R.sup.o is a radical of the structure R.sup.f : 
##STR8## 
in which D is --CH.sub.2 -- or --O--; f is 0 or 1; and 
W is a hydrogen atom, halo having an atomic weight of from about 19 to 80, 
alkoxy having from 1 to 3 carbon atoms, or alkyl having from 1 to 3 carbon 
atoms; or 
R is of type (c) an indolyl radical of the structure: 
##STR9## 
wherein R.sup.b is as defined above; R.sup.4 is alkyl having from 1 to 8 
carbon atoms or benzyl; and 
R.sup.5 is a hydrogen atom, alkyl having from 1 to 8 carbon atoms or 
benzyl; or 
R is (d) a benzocycloalkyl nucleus of the structure: 
##STR10## 
wherein y and y' are as defined above; and j is a whole integer of from 1 
to 4. 
In the above-presented definition of Compounds I, halo having an atomic 
weight of from about 19 to 36, includes fluoro and chloro; halo having an 
atomic weight of from about 19 to 80 includes fluoro, chloro and bromo; 
while halo having an atomic weight of from about 19 to 127 includes 
fluoro, chloro, bromo and iodo. Exemplary of alkyl or alkoxy having from 1 
to 3 or 1 to 4 carbon atoms is methyl, or methoxy and ethoxy. Unless 
otherwise indicated, alkyl and alkoxy may be branched or unbranched. 
Particular embodiments of this invention are compounds I described above, 
and II, (hereinafter described), and intermediates thereof. The compounds 
and their intermediates may be viewed as falling into two-classes 
depending on whether R.sup.1 is of type (a) or type (b). Additional 
subclasses are those in which R.sup.1 is (of type a) alkyl having from 1 
to 14 carbon atoms, such as n-butyl and n-decyl. Those compounds in which 
R.sup.1 is of type (b) may be for example, phenyl or benzyl. It is also 
preferred that R is of type (a), particularly 
2-(p-methylphenyl)-1-phenylethyl. 
R.sup.2 and R.sup.3 are especially joined to form a saturated acyclic 
hydrocarbon radical forming with the silicon atom a heterocyclic ring 
having at least 3 but not more than 20 ring members and no more than 25 
carbon atoms. Such hydrocarbon radical may be branched, typically by 
methyl or ethyl groups, particularly 1 or 2 methyl groups, but is 
conveniently unbranched and represented by a polymethylene chain, ie 
--(CH.sub.2)-- which together with the silicon atom forms a cyclic 
structure; n being from 2 to 19, preferably from 2 to 13, particularly 2 
to 7 and especially 4 or 5. It is also preferrd that the total number of 
carbon atoms in R.sup.1 +R.sup.2 +R.sup.3 is not more than 35. 
Further preferred forms of Compounds I when R is of type (a) or (b) and 
R.sup.o is not R.sup.f, are that it is preferred that when R.sup.a, 
R.sup.o or y is other than a hydrogen atom and R.sup.b (or y') is a 
hydrogen atom, that R.sup.o, or R.sup.a, or y be located at the 
4-position; and that when R.sup.b (or y') is also other than a hydrogen 
atom that R.sup.a or R.sup.o and R.sup.b (or y and y') are the same, and 
it is additionally preferred that they be located at the 2- and 
4-positions of the phenyl ring. When R is of type (a) where g=1, and 
R.sup.c is of type (ii) where p=0, then R can be an 
.alpha.-(phenyl)-.beta.-(p-methylphenyl) ethyl radical, and when R.sup.c 
is of type (ii) where p=1, then R can be an .alpha.-(benzyl)-phenylethyl 
radical. 
With particular respect to the substituent R.sup.o when it is a radical 
R.sup.f, it will be appreciated that when D=CH.sub.2 and f=1, then the 
radical R.sup.f is of the benzyl type. When D=oxygen and f=1, then the 
radical R.sup.f is of the phenoxy-type. When f=zero, then the radical 
R.sup.f is of the phenyl-type. Hence, when R is of type (b), and R.sup.o 
is of type R.sup.f where f=zero, then R can be a biphenylyl radical. The 
radical R.sup.f is preferably at the para-position. When W is other than a 
hydrogen atom, it is preferably at the para-position. 
With respect to R, when it is of type (c), it is preferred that when 
R.sup.b is other than a hydrogen atom, it be located at the 5-position of 
the indole nucleus. It is also preferred that when R.sup.4 is alkyl, it is 
unbranched, particularly ethyl. 
With respect to R when it is of type (d) it is preferred that when y is 
other than a hydrogen atom, that it be located at a carbon atom ortho to 
the ring junction; and that when y' is also other than a hydrogen, it is 
preferred that it be the same as y, and it is additionally preferred that 
it be in para-relationship to y'. It is additionally preferred that the 
amide group be linked to a carbon of the cycloalkyl moiety which is 
directly bonded to a ring junction carbon. It is also preferred that j be 
1, ie, that the benzocycloalkyl nucleus be indanyl, and particularly 
1-indanyl. 
In the above-presented definitions, when R.sup.o, R.sup.1 or y is halo, it 
is preferably fluoro or chloro, and particularly chloro; and when R.sup.2 
or y' is halo it is preferably chloro. 
The above-described compounds I are obtainable by reduction of 
corresponding ethylenically unsaturated silicon-bearing compounds of 
formula II: 
##STR11## 
in which R.sup.1, R.sup.2, R.sup.3, and R are as defined above (process 
a). Compounds I and II have pharmaceutical activity as is described 
hereinafter under the heading "Statement of Utility." 
The above described compounds II are obtainable by reduction of 
corresponding alkynyl Compounds (III): 
##STR12## 
in which R.sup.1, R.sup.2, R.sup.3 and R are as defined above (process b). 
Process (b) may be accomplished by means conventionally employed in 
converting an alkynyl-bearing compound to its corresponding 
alkenyl-analog. A convenient method of carrying out process (b) is by 
treating a compound III with hydrogen in the presence of an appropriate 
catalyst such as palladium on calcium carbonate (eg 5%), or rhodium, 
platinum or platinum oxide, on such "controlling" porous supports as 
calcium carbonate, barium sulfate and the like, in an inert medium e.g. a 
lower alkanol such as ethanol, lower fatty acids and esters, such as 
acetic acid and ethyl acetate, hydrocarbons, such as benzene or toluene or 
a cyclic ether such as tetrahydrofuran (THF), at moderate temperatures, 
for example from about 10.degree. to 80.degree. C. particularly at from 
about 20.degree. to 30.degree. C., at moderate pressures, e.g. from about 
15 to 100 psi (over atmospheric pressure), e.g. at 15 psi (over at.). 
If desired Compounds III may be converted to their corresponding Compounds 
I (without recovery of any Compounds II formed during the process, i.e. 
process a') by means conventionally employed in reducing an alkynyl 
compound to its corresponding alkyl analog. 
Processes (a) and (a') may be accomplished, for example, by hydrogenating 
under pressures of e.g., from about 15 psi to about 100 psi (all over 
atmospheric pressure), e.g. 50 psi in the presence of a catalyst such as 
platinum oxide or other hydrogenation catalysts mentioned in connection 
with process (b) above, or on active supports, such as charcoal, in an 
inert medium, such as ethyl acetate, or such media as mentioned in 
connection with the discussion of process (b) above, and at moderate 
temperatures, e.g. 10.degree. to 100.degree. C., particularly at from 
about 20.degree. to 30.degree. C. 
It will be appreciated that by selection of such factors as catalyst, 
pressure of hydrogen, temperature, and reaction time, optimum yields of 
the desired compounds I or II may be obtained from corresponding Compounds 
III, since "total" hydrogenation of the starting alkynyl compound (III) 
will result in the formation of a corresponding Compound I, while 
controlled hydrogenation will give predominantly Compound II. 
Compounds III are obtainable by reaction of a corresponding organo-metallo 
Compound of the formula IV: 
##STR13## 
in which R is as defined above and M is an equivalent of an active metal 
eg an alkali metal or a magnesium halide with a halo-silane of the formula 
V: 
##STR14## 
in which R.sup.1, R.sup.2 and R.sup.3 are as defined, and Z is halo having 
an atomic weight of from about 19 to 127, i.e. fluoro, chloro, bromo or 
iodo, preferably chloro, (process c), to form an adduct which is then 
hydrolyzed (process c'). 
Process (c) is carried out under essentially anhydrous conditions, eg under 
an atmosphere of inert gas such as dry nitrogen, as are conventionally 
observed in carrying out Grignard-type reactions, at moderate 
temperatures, e.g. -40.degree. to 0.degree. C., in an aprotic medium, e.g. 
an ether such as tetrahydrofuran, dimethoxyethane, or a hydrocarbon such 
as benzene or toluene, which yields an adduct which corresponds to a 
compound III but in which the "amido" nitrogen atom bears an M-unit (M 
being as defined above) or a hydrolyzable silyl group corresponding to V, 
where an excess thereof is used. 
The hydrolysis step (process c') may be accomplished in the conventional 
manner for hydrolyzing a Grignard-type adduct, by treatment with water or 
a dilute aqueous solution of a salt or acid, e.g., saturated aqueous 
ammonium chloride, at moderate temperatures e.g. from about 5.degree. to 
90.degree. C., preferably at from about 20.degree. to 30.degree. C. 
The above-described Compounds IV are obtainable by treatment of a 
corresponding propiolamide of the formula VI: 
##STR15## 
in which R is as defined above, with a M-contributing agent (process d). 
Process (d) may be accomplished in the conventional manner for forming 
organo-metallic reagents by replacing acidic hydrogen atoms of an organic 
compound with active metal atoms. For example Compounds IV may be obtained 
by treating the free form of a Compound VI with at least 2 equivalents of 
M-contributing agent (VII) at reduced temperatures, for example Compounds 
VI and VII may be combined at about -78.degree. to -20.degree. C., e.g. 
-60.degree. C., and held at low temperatures with agitation while they are 
reacting, e.g. at about -40.degree. C. to 0.degree. C., e.g. -20.degree. 
C., in an aprotic medium, e.g. an ether, such as THF, dimethoxyethane, or 
a hydrocarbon, such as hexane, benzene or toluene. Since Compounds IV are 
decomposed by moisture, it is convenient to employ them directly in 
Process (c) without recovery, which could involve exposure to moist air, 
or to maintain them in a conventional stabilizing medium, such as the 
moisture-free inert aprotic media suitable for use in process (d). 
In the M-contributing agents, (Compounds VII), M is an equivalent of an 
active metal, or a magnesium halide. Active metals include the alkali 
metals, i.e. lithium, sodium and potassium, lithium being preferred, while 
the halo portions of the magnesium halide may be chloro or bromo. A 
convenient lithium-contributing agent is lithium diisopropylamide (LDA) 
which may be prepared by reacting n-butyl lithium dissolved in an inert 
hydrocarbon, such as hexane, with an equivalent of diisopropylamine 
dissolved in an aprotic solvent, e.g. THF, at reduced temperatures such as 
at about -78.degree. to +25.degree. C., e.g. at -30.degree. C., under 
essentially anhydrous conditions. It is convenient to prepare the reagent 
(VII) and use it in situ in process (d). 
The above-described propiolamides (VI) are obtainable by amidation of 
propiolic acid, or an active derivative thereof, with an R-bearing primary 
amine of the formula IX: 
EQU H.sub.2 N--R IX 
in which R is as defined above. A convenient method of carrying out such an 
amidation reaction is by reacting a mixed anhydride of propiolic acid of 
the formula VIII: 
##STR16## 
in which R.sup.6 is lower alkyl having from 1 to 6 carbon atoms, e.g. 
ethyl, with a compound IX (process e). The desired compound VIII may be 
prepared and used in situ, by treating propiolic acid with an equivalent 
amount (or slight excess) of a non-nucleophilic base, e.g. an alkali 
hydride, such as lithium hydride or sodium hydride, or triethylamine, 
under essentially anhydrous conditions, in an aprotic medium, e.g. an 
ether, such as THF, or dimethoxyethane, a hydrocarbon such as benzene or 
toluene, or a halogenated hydrocarbon such as methylene chloride or 
chloroform, at moderate temperatures e.g. from about 0.degree. to 
30.degree. C., preferably from about 20.degree. to 25.degree. C., then 
slowly introducing into the reaction mixture a chloroformate of the 
formula X: 
##STR17## 
in which R.sup.6 is as defined above, (process e'), at reduced 
temperatures, e.g. from about -20.degree. to -5.degree. C., preferably 
below 10.degree. C., in an aprotic medium such as was used in preparing 
the reaction mixture, under essentially anhydrous conditions. 
The desired amido compound (VI) may be conveniently obtained by slowly 
adding an amine (IX) to a mixed anhydride, in such aprotic media as 
described in connection with the preparation of the mixed anhydride (e.g. 
in situ) at reduced temperatures, e.g. from about -25.degree. C. to 
0.degree. C., preferably at from about -15.degree. to 0.degree. C. 
The above-described series of reactions may conveniently be represented by 
Reaction Scheme A, below in which R, R.sup.1, R.sup.2, R.sup.3, R.sup.6, Z 
and M are as defined above. 
##STR18## 
Various modifications of the above-described procedure for obtaining 
Compounds I and II are possible, and may be conveniently practiced, 
depending upon such factors as relative availability of starting materials 
and reagents, scale of production, ease of handling etc. For example, to 
obtain Compounds III, one may prepare silicon-bearing esters of the 
formula XI 
##STR19## 
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are as defined above, and 
react such ester (or free acid form thereof), with an amino compound (IX), 
under conditions conventionally employed in preparing amides. 
Alternatively, the acetylenically unsaturated position of an ester 
compound (XI) as defined above, may be hydrogenated fully to obtain an 
ester of the formula XII 
##STR20## 
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are as defined above, and 
then reacted with an amine (IX) to obtain the corresponding final compound 
I; or partially hydrogenated to obtain a ethylenically unsaturated ester 
XIII: 
##STR21## 
in which R.sup.1, R.sup.2, R.sup.3 and R.sup.6 are as defined above, which 
upon rection with an amine IX will yield the corresponding compound II. 
An alternative method of preparing Compounds III is by reacting under 
essentially anhydrous conditions an active metal salt form of propiolic 
acid of the formula XIV: 
##STR22## 
in which M.sup.a is an equivalent of active metal or magnesium halide, 
with a suitable tri-substituted halo silane (V, as described above) in 
connection with process (c), in an aprotic medium, at moderate 
temperatures, eg. 0.degree. to 40.degree., preferably at 20.degree. to 
30.degree. C. The same media may be used as mentioned in connection with 
process (c) to obtain a trisubstituted alkynoic acid compound of the 
formula XV 
##STR23## 
in which R.sup.1, R.sup.2 and R.sup.3 are as defined above, which is then 
reacted with a suitable amine (IX) to obtain the corresponding compound 
III. 
If desired, an ester form of propiolic acid may be employed in place of 
compound XIV, ie of the formula XIV' 
##STR24## 
in which M.sup.a and R.sup.6 are as defined above. 
The above-described alternative procedures may be conveniently represented 
by Reaction Scheme B, below, in which R.sup.1, R.sup.2, R.sup.3, R.sup.6, 
R, Z, and M.sup.a are as defined above. 
##STR25## 
Recovery of the intermediates and products obtained by the above-described 
procedures may be effected by conventional techniques, such as 
crystallization, precipitation, vacuum distillation, and chromatographic 
techniques such as column or thin layer chromatography and the like. 
It will be understood that many compounds of this invention, eg I, II and 
III, may exist in the form of stereoisomers, eg optically active isomers, 
ie enantiomers, which can be prepared from respective stereoisomers, eg 
optically active compounds IX or separated and recovered by conventional 
techniques, eg resolution and such isomeric forms are also included within 
the scope of this invention. 
Many of the reagents and compounds involved in the above-described 
procedures are known, eg propiolic acid and compounds v and IX, and may be 
obtained commercially or may be prepared by methods described in the 
literature, while those compounds not specifically described in the 
literature may be prepared by analogous methods from known starting 
materials. 
STATEMENT OF UTILITY 
The compounds of formulas I and II of this invention are useful as 
pharmaceutical agents in animals. In particular, the compounds I and II 
are useful in controlling the cholesterol ester content of mammalian 
arterial walls and are therefore particularly indicated for use as 
antiatherosclerotic agents, ie. agents useful in the prophylactic 
treatment of atherosclerosis and in the controlling of atherosclerotic 
conditions due to cholesterol ester accumulation in the arterial walls. 
Such ability of the compounds I and II are indicated by known test 
procedures in which the total cholesterol ester content of cultured cells 
is shown to be reduced by a test compound, as compared to untreated cells, 
and carried out, for example, by the following procedures: 
(A) Cell culture 
Rhesus monkey smooth muscle cells (from the arterial, eg. aorta, wall) 
obtained by the method of K. Fisher-Dzoga et al (Experimental and 
Molecular Pathology 18, 162-176 (1973)) are routinely grown in 75 cm.sup.2 
tissue culture flasks using Minimum Essential Medium (Eagle) supplemented 
with 10% fetal bovine serum. For testing a 75 cm.sup.2 flask with a near 
confluent cell growth is selected. The cells are removed from the flask 
surface by mild enzymatic treatment with pronase. After centrifugation and 
decanting the enzyme solution, the cell pellet is resuspended in an 
appropriate volume of media for seeding the desired number of 60 mm tissue 
culture dishes. Five (5) ml of the diluted cell suspension are pipetted 
into each dish. After seeding, the dishes are labelled with the cell type, 
date and flask number of origin and incubated at 37.degree. C. in 
approximately 5% CO.sub.2 atmosphere in a high humidity incubator. When 
the cultures are confluent, the actual drug testing is begun. Test 
compounds are routinely solubilized in 100% ethanol. An equivalent amount 
of ethanol is added to control groups as well. The tissue culture dishes 
are randomly divided into groups. To one group, hyperlipemic rabbit serum 
(HRS) is added at 5% by volume (control). To the remaining groups, 5% HRS 
and 1 mg per 100 ml of media of the test compound are added. The dishes 
are returned to the incubator for an additional 24 hours. All operations 
through to the final incubation are performed using sterile technique in a 
laminar flow hood. After the incubation period, the dishes are 
microscopically observed with the Zeiss Axiomat with phase contrast optics 
and the conditions of the cultures are recorded; especially in regard to 
the size, number and configuration of cytoplasmic inclusions and to 
cellular morphology. The media is removed from the cultures and 0.9% 
sodium chloride solution is added. The cells are removed from the flasks 
with the aid of a rubber policeman and transferred to a conical graduated 
centrifuge tube. The cells are washed three times by suspending in an 
isotonic salt solution, centrifuging at 800.times.g for 10 minutes and 
aspirating the supernatant fluid. 
(B) Cell extraction procedure 
An appropriate volume of isopropyl alcohol (about 1 ml/mg protein) is then 
added to the cell pellet and the sample sonicated with a micro probe 
(140.times.3 mm) for 10 seconds with a "LO" setting of 50 on a Bronwell 
Biosonik IV. After centrifugation for 15 minutes at 800.times.g, the clear 
supernatant is decanted and an aliquot taken for cholesterol analysis. 
The residue is dissolved in 0.1 N sodium hydroxide and an aliquot taken for 
protein determination by the method of Lowry, et al. (J. Biol. Chem. 193, 
265; 1951). 
(C) Assay 
Free cholesterol: The isopropyl alcoholic solutions of standards, samples 
and blank (isopropyl alcohol alone) are treated in a similar manner. An 
aliquot of 0.4 ml of free reagent (Reagent A, Table 1 below) is added to a 
10.times.75 mm disposable glass test tube to which 20 .mu.l of the 
isopropyl alcoholic solution is added and mixed. After standing at room 
temperature for approximately 5 minutes, 0.8 ml of 0.5 N sodium hydroxide 
(Reagent C, Table 1) is added and mixed. The fluorescence is measured with 
an Aminco-Bowman spectrophotofluorometer with an excitation wavelength of 
325 nm and emission wavelength of 415 nm. A 1 cm light path cuvette is 
used with a xenon lamp, an IP28 photomultiplier tube and 2 mm slits. 
Total cholesterol: The same procedure described above for free cholesterol 
is followed for total cholesterol except that the total reagent (Reagent 
B, Table 1) is used instead of the free reagent and the samples are 
incubated for 20 minutes at 37.degree. C. before the addition of the 0.5 N 
sodium hydroxide solution (Reagent C, Table 1). 
Alternatively, the assay for cholesterol, ie Step C (above) obtained from 
Steps A and B, may be carried out by the meethod of Ishikawa et al (J. 
Lipid Res. 15, 286; 1974). 
The amount of cholesterol ester is found by subtracting the amount of free 
cholesterol from the total cholesterol content of the cells determined by 
the assay. A finding of a lower amount of cholesterol ester in the group 
of cells to which test compound was added, as compared to the control 
group (untreated) shows that the test compound is active in reducing the 
cholesterol ester in the cells. 
TABLE 1 
______________________________________ 
Composition of Reagents for 
Cholesterol Determination 
______________________________________ 
A. Free Cholesterol Reagent 
Sodium phosphate buffer pH 7.0 
.05 M 
Cholesterol oxidase .08 U/ml 
Horseradish peroxidase 
30. U/ml 
p-Hydroxyphenylacetic acid 
.15 mg/ml 
B. Total Cholesterol Reagent 
Sodium phosphate buffer pH 7.0 
.05 M 
Cholesterol ester hydrolase 
.08 U/ml 
Cholesterol oxidase .08 U/ml 
Horseradish peroxidase 
30. U/ml 
Sodium taurocholate 5. mM 
Carbowax-6000 .17 mM 
p-Hydroxphenylacetic acid 
.15 mg/ml 
C. Sodium Hydroxide Solution 
.5N 
______________________________________ 
When the compounds are employed for the above utility, they may be combined 
with one or more pharmaceutically acceptable carriers, e.g., solvents, 
diluents and the like, and may be administered orally in such forms as 
tablets, capsules, dispersible powders, granules, suspensions containing, 
for example, from about 0.5 to 5% of suspending agent, syrups containing, 
for example, from about 10 to 50% of sugar, and elixirs containing, for 
example, from about 20 to 50% ethanol, and the like, or parenterally in 
the form of sterile injectable solutions or suspensions containing from 
about 0.5 to 5% suspending agent in an isotonic medium. These 
pharmaceutical preparations may contain, for example, from about 0.5% up 
to about 90% of the active ingredient in combination with the carrier, 
more usually between 5% and 60% by weight. 
The antiatherosclerotic effective dosage of active ingredient employed for 
the reduction of cholesterol ester content in the arterial walls of a 
mammal may vary depending on the particular compound employed, the mode of 
administration and the severity of the condition being treated. However, 
in general, satisfactory results are obtained when the compounds I and II 
are administered at a daily dosage of from about 0.2 milligrams to about 
500 milligrams per kilogram of animal body weight, preferably given in 
divided doses two to four times a day, or in sustained release form. For 
most large mammals, the total daily dosage is from about 10 milligrams to 
about 5,000 milligrams preferably from about 10 milligrams to 2,000 
milligrams. Dosage forms suitable for internal use comprise from about 2.5 
to 2,500 milligrams of the active compound in intimate admixture with a 
solid or liquid pharmaceutically acceptable carrier. Solid carriers 
include starch, lactose and kaolin, while liquid carriers include sterile 
water, polyethylene glycols and edible oils such as corn, peanut and 
sesame oils, as are appropriate to the nature of the active ingredient and 
the particular form of administration desired. Adjuvants customarily 
employed in the preparation of pharmaceutical compositions may be 
advantageously included, such as flavoring agents, coloring agents, 
preserving agents, and antioxidants eg vitamin E, ascorbic acid, BHT and 
BHA. 
The preferred pharmaceutical compositions from the stand-point of ease of 
preparation and administration are solid compositions, particularly 
tablets and hard-filled or liquid-filled capsules. 
A representative formulation for administration orally three times a day 
prior to feeding in the treatment of atherosclerosis is a gelatin capsule 
prepared by conventional techniques to contain the following 
______________________________________ 
Ingredient Weight (in mg.) 
______________________________________ 
1-butyl-N-[2-(p-methyl-phenyl)- 
1-phenylethyl]-1-silacyclohexane 
propanamide 250 
corn oil 500 
______________________________________ 
As is the present understanding in the art, controlling the total 
cholesterol content of an arterial wall by inhibiting the accumulation 
thereof by reducing the cholesterol ester content thereof, advantageously 
inhibits the formation of plaques in the arterial wall. 
Compounds I and II are also indicated as agents for the lowering of blood 
serum cholesterol and cholesterol ester levels, and hence also further 
indicated as antiatherosclerotic agents by feeding tests in rabbits eg at 
200 mg/kg of test compound per day for 9 weeks, in conjunction with a high 
cholesterol diet resulting in, compared to controls, a reduction in 
cholesterol and cholesterol ester blood serum levels, as well as a 
lessened formation or absence of arterial wall plaques.

The following examples of the preparation of intermediates and compounds I 
and II of the invention are illustrative of the invention. All 
temperatures are centigrade (.degree.C.) and room temperature is 
20.degree. to 30.degree. C. unless indicated otherwise. 
EXAMPLE 1 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-1-silacyclohexane propanamide (a 
compound I) 
##STR26## 
Step A: N-[(1'-phenyl-2'-p-tolyl)-ethyl]-propiolamide 
##STR27## 
95 mg of lithium hydride are added to a solution of 850 mg propiolic acid 
in 15 ml of freshly distilled THF*, portion-wise, over a period of about 
45 min., with cooling to avoiding heating over room temperature (hydrogen 
evolves). The resulting mixture is then cooled to about -10.degree., and a 
solution of 1.3 g of ethyl chloroformate in 3 ml of dry THF is added 
drop-wise with stirring, while maintaining the temperature below 
-10.degree.. The resulting mixture is then stirred for 2 hrs. at about 
-15.degree.. A solution of 2.5 g of (1-phenyl 2-p-tolyl) ethylamine** in 5 
ml of dry THF is then added dropwise at from -15.degree. to 0.degree., 
with stirring. The mixture is then stirred at room temperature for 2 
hours. 
FNT *tetrahydrofuran 
FNT **also known as 2-(4'-methylphenyl)-1-phenylethylamine 
The reaction mixture is concentrated by evaporation in vacuo (solvent 
stripped) to obtain a residue, which is taken up in methylene chloride and 
is washed first with dilute aqueous sodium bicarbonate, then with dilute 
hydrochloric acid, then dried over anh. sodium sulfate, and concentrated 
in vacuo to obtain crude product. The crude product of this example is 
refined by crystallizing from diethyl ether m.p. 152.degree.-155.degree. 
C. 
Step B: n-butyl-cychopentamethylene-chlorosilane 
In a separate vessel, under nitrogen, to a solution of 800 mg of 
cyclopentamethylenedichlorosilane in 10 ml of dry THF, is added a solution 
of 290 mg of n-butyl lithium in 2.9 ml of dry hexane at a temperature of 
from about -10.degree. to -16.degree. with stirring. The mixture is 
continued stirring at room temperature for 30 min. and held for use in 
step C. 
Step C: 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-1-silacyclohexane-1-propynamide a 
Compound III) 
##STR28## 
In a vessel, under an atmosphere of dry nitrogen at -30.degree. a solution 
of 580 mg of n-butyl lithium in 5.8 ml of dry hexane is added to 900 mg of 
diisopropylamine in 10 ml of dry THF. The mixture stirred for 15 min., 
then cooled to -60.degree.. A solution of 1.29 g of 
[(1'-phenyl-2'-p-tolyl)-ethyl]propiolamide in 10 ml of dry THF is added 
dropwise thereto while the temperature of the mixture is maintained 
between about -40.degree. and -50.degree.. The mixture is then stirred for 
1 hr. at -25.degree.. The solution of n-butyl-pentamethylenechlorosilane 
prepared in step B is added dropwise, with stirring while maintaining the 
temperature at below about -10.degree. and the mixture stirred for 3 hr. 
(at -20.degree.). 
Aqueous saturated ammonium chloride is added to the reaction mixture, and 
the organic phase recovered, dried over anh. sodium sulfate, and 
concentrated by evaporation in vacuo to obtain the crude product as an 
oil, which is refined by eluting through a silica gel column using 
chloroform as eluate to yield the product of this step as an oil, which 
crystallizes on standing to a solid (m.p. 87.degree.-90.degree.). 
Step D: 1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-1-silacyclohexane 
propanamide (a Compound I) 
To a solution of 1 g 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]1-silacyclohexane-1-propynamide in 
1 liter of ethyl acetate in a hydrogenating apparatus, is added 300 mg of 
platinum oxide, and a pressure of 50 p.s.i. hydrogen is maintained for 24 
hours with shaking. The reaction mixture is then filtered, and the 
filtrate concentrated (by evaporation in vacuo) to obtain the title 
product as an oil. 
EXAMPLE 2 
1-Butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-1-silacyclohexane-1-propenamide (a 
Compound II) 
##STR29## 
To a solution of 300 mg of 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclohexane-2-propynamide in 
30 ml of ethanol in a hydrogenating apparatus, is added 50 mg of 5% 
palladium on calcium carbonate. The mixture is placed under 1 at. pressure 
of hydrogen and shaken until an equivalent of hydrogen gas had been taken 
up (about 45 min.). The reaction mixture is then filtered, and the 
filtrate concentrated (by evaporation in vacuo) to obtain the title 
product. 
EXAMPLE 3 
1-Butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclohexane-1-propanamide 
Treating 1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclohexane 
1-propenamide (obtained by Example 2) by the procedure of Step D of 
Example 1, the title product is obtained. 
EXAMPLE 4 
Repeating the procedure of steps (A), (B) and (C) of Example 1, but using 
in place of the (1-phenyl-2-p-tolyl)ethylamine used in Step (A), therein, 
an approximately equivalent amount of the following amines as compounds 
IX: 
(a) 1-amino-indane; 
(b) DL-tryptophan ethyl ester, hydrochloride; 
(c) (d,1) .alpha.-methylbenzylamine; (racemate); 
(d) 2-methylaniline; or 
(e) 1-benzyl-2-phenylethylamine: there is accordingly obtained, 
respectively (as compounds III): 
(a) 1-butyl-N-(1'-indanyl)-1-silacyclohexane-1-propynamide; 
(b) 1-(4'-sila-4',4'-pentamethylene-n-octoyl)-tryptophan, ethyl ester; 
(c) 1-butyl-N-(.alpha.-methylbenzyl)-1-silacyclohexane-1-propynamide; (as a 
racemic mixture); 
(d) 1-butyl-N-(o-methylphenyl)-1-silacyclohexane-1-propynamide; and 
(e) 1-butyl-N-(1'-benzyl-2'-phenylethyl)-1-silacyclohexane-1-propynamide; 
which upon treatment by the method of Step (D) of Example 1 yield the 
corresponding compounds I, or by treatment by the method of Example 2 
yield the corresponding compounds II which upon treatment by the method of 
Step (D) of Example 1, then, yield the corresponding compounds I. 
EXAMPLE 5 
Following the general procedure of steps (A), (B), and (C) of Example 1, 
but using in place of the n-butyl-silapentamethylenechlorosilane used in 
step (C) therein, an approximately equivalent amount of the following 
compounds V (which may be prepared in a manner analogous to that of step B 
of Example 1): 
(a) 1-butyl-tetramethylenechlorosilane 
(b) 1-butyl-hexamethylenechlorosilane; 
(c) 1-n-decyl-pentamethylenechlorosilane; 
(d) 1-n-decyl-tetramethylenechlorosilane; 
(e) 1-methyl-pentamethylenechlorosilane; 
(f) 1-butyl-undecamethylenechlorosilane; 
(g) 1-benzyl-pentamethylenechlorosilane; 
(h) 1-phenyl-pentamethylenechlorosilane; or 
(i) l-butyl 1-chloro-4-methyl-silacyclohexane; 
there is accordingly obtained, respectively (as Compounds III): 
(a) 1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclopentane-1-propynamide; 
(b) 1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacycloheptane-1-propyamide; 
(c) 
1-n-decyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclohexane-1-propynamide; 
(d) 
1-n-decyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclopentane-1-propynamide; 
(e) 1-methyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclohexane-1-propynamide; 
(f) 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclododecane-1-propynamide; 
(g) 1-benzyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silahexane-1-propynamide; 
(h) 1-phenyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silahexane-1-propynamide; and 
(i) 1-butyl-4-methyl-N-[(1'-phenyl-2'-tolyl)ethyl]-silahexane-1-propyamide. 
EXAMPLE 6 
Repeating the procedure of step (D) of Example 1, but using in place of the 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]silacyclohexane-1-propynamide used 
therein, an approximatly equivalent amount of each of the products (a) to 
(i) of Example 5, there is accordingly obtained, respectively, the 
corresponding compounds I: 
(a) 1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclopentane propanamide; 
(b) 1-butyl-N-[(1'-phenyl-2-p-tolyl)-ethyl]-silacycloheptane propanamide; 
(c) 1-n-decyl-N-[(1'-phenyl-2-p-tolyl)-ethyl]-silacyclohexane propanamide; 
(d) 
1-n-decyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclopentane-propanamide; 
(e) 1-methyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-silacyclohexane propanamide; 
(f) 1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclododecane-propanamide. 
(g) 1-benzyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclohexane propanamide; 
(h) 1-phenyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-silacyclohexane propanamide; 
and 
(i) 1-butyl-4-methyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-sila-cyclohexane 
propanamide. 
EXAMPLE 7 
Repeating the procedure of Example 2, but using in place of the 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]silacyclohexane-1-propynamide used 
therein, an approximately equivalent amount of each of the products (a) to 
(i) of Example 5, there is accordingly obtained, respectively, the 
corresponding compounds II: 
(a) 
1-butyl-N-[(1'-phenyl-2-p-tolyl)-ethyl]-sila-cyclopentane-1-propenamide; 
(b) 1-butyl-N-[(1'-phenyl-2-p-tolyl)-ethyl]-sila-cycloheptane-1propenamide; 
(c) 
1-n-decyl-N-[(1'-phenyl-2-p-tolyl)-ethyl]-sila-cyclohexane-1-propenamide; 
(d) 
1n-decyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-sila-cyclopentane-1-propenamide. 
(e) 
1-methyl-N-[(1'-phenyl-2'-p-tolyl)-ethyl]-sila-cyclohexane-1-propenamide; 
(f) 
1-butyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-sila-cyclododecane-1-propenamide; 
(g) 1-benzyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-sila-hexane-1-propenamide; and 
(h) 
1-phenyl-N-[(1'-phenyl-2'-p-tolyl)ethyl]-sila-cyclohexane-1-propenamide; 
(i) 1-butyl-4-methyl-N-[(1'-phenyl-2'-p-tolyl-)ethyl]-silacyclohexane 
propenamide; 
which upon treatment by the procedure of Step (D) of Example 1 yield the 
corresponding compounds I, ie compounds (a) to (i) of Example 6.