4-[Cycloalkyl- or cycloalkenyl-amino(cycloalkyl- or cycloalkenyl-alkenyl)amino]phenyl compounds, useful as hypolipidemic and antiatherosclerotic agents

This disclosure describes novel 4-[(cycloalkyl or cycloalkenyl substituted)amino, alkylamino or alkenylamino]phenyl compounds, salts and derivatives of these such as cycloalkylamino, cycloalkenylamino, cycloalkyl-alkylamino, cycloalkyl-alkenylamino, cycloalkenyl-alkylamino, and cycloalkyl-cycloalkylamino phenyl compounds and derivatives and suitable salts of these; these compounds are useful as hypolipidemic and antiatherosclerotic agents.

BRIEF SUMMARY OF THE INVENTION 
This invention deals with 4-[(cycloalkyl or cycloalkenyl substituted) 
amino, alkylamino or alkenylamino] phenyl compounds, salts and derivatives 
of the formula: 
##STR1## 
wherein Z is: (a) 
##STR2## 
wherein J is selected from the group consisting of hydrogen, loweralkyl, 
and loweralkyl bearing one or more carboxy, carboloweralkoxy, carbamoyl, 
acyl, sulfinyl or sulfonyl groups, or 
(b) 
##STR3## 
wherein B is a saturated or unsaturated loweralkylene group and K is 
selected from the group consisting of hydrogen, loweralkyl, 
loweralkoxyethyl, diloweralkylaminoethyl, (mono- or polyhydroxy)-lower 
alkyl, (mono or polycarboxy)loweralkyl, (mono- or 
polycarboxy)hydroxyloweralkyl, allyl, 2,3-epoxypropyl, substituted or 
unsubstituted(phenyl, benzyl or 3-pyridyl), pyridylmethyl, and 
tetrahydropyranyl; 
R is selected from the group consisting of hydrogen, or a group convertible 
in vivo thereinto, such as methyl, carboxymethyl, acetyl, succinyl 
1-(sodium sulfo)loweralkyl, 1-(sodium sulfo)polyhydroxyalkyl and 
1,3-bis-(sodium sulfo)aralkyl; 
n is either zero or one; 
Y is a divalent radical selected from the group consisting of unbranched or 
branched C.sub.1 -C.sub.13 alkylene or alkenylene and is either 
unsubstituted or substituted with at least one C.sub.1 -C.sub.4 alkyl 
group; 
and D is selected from the group consisting of C.sub.3 -C.sub.16 cycloalkyl 
or C.sub.4 -C.sub.17 cycloalkenyl and is either unsubstituted or 
substituted with at least one C.sub.1 -C.sub.13 alkyl, C.sub.4 -C.sub.8 
cycloalkyl, decahydronaphthyl, methylene, ethylidene, or isopropylidene 
group; 
with the proviso that the total number of 
carbon atoms in D and Y shall not exceed twenty; and with the further 
proviso that when n is 1, D is not an unsubstituted cyclopropyl nor a 
cyclopropyl substituted with at least one C.sub.1 -C.sub.13 alkyl; 
and the pharmaceutically acceptable non-toxic acid addition and cationic 
salts thereof. 
Preferred compounds of the invention are as follows: 
when n is 1, 
(Formula IA) Y is a divalent radical selected from the group consisting of 
branched or unbranched C.sub.1 -C.sub.13 alkylene or alkenylene and is 
either unsubstituted or substituted with at least one C.sub.1 -C.sub.4 
alkyl; D is a moiety selected from the group consisting of C.sub.3 
-C.sub.8 cycloalkyl which is either unsubstituted or substituted with at 
least one C.sub.1 -C.sub.13 alkyl, a C.sub.5 -C.sub.7 cycloalkyl, or a 
decahydronaphthyl group; with the proviso that D is not an unsubstituted 
cyclopropyl nor a cyclopropyl substituted with at least one C.sub.1 to 
C.sub.13 alkyl, or 
(Formula IB) Y is a divalent radical selected from the group consisting of 
branched or unbranched C.sub.1 -C.sub.13 alkylene or alkenylene; and is 
either unsubstituted or substituted with at least one C.sub.1 -C.sub.2 
alkyl; and D is a moiety selected from the group consisting of C.sub.4 
-C.sub.9 cycloalkenyl and is either unsubstituted or substituted with at 
least one C.sub.1 -C.sub.13 alkyl group; and C.sub.5 -C.sub.8 cycloalkyl 
unsubstituted or substituted with at least one methylene moiety, and/or at 
least one C.sub.1 -C.sub.13 alkyl. 
and when n is 0, 
(Formula IC) D is a moiety selected from the group consisting of C.sub.4 
-C.sub.7 cycloalkyl and is either unsubstituted or substituted with at 
least one C.sub.4 -C.sub.7 cycloalkyl, and decahydronaphthalene 
unsubstituted or substituted with at least one C.sub.1 to C.sub.4 alkyl; 
or 
(Formula ID) D is selected from the group consisting of C.sub.4 -C.sub.16 
cycloalkyl substituted with at least one C.sub.1 -C.sub.5 alkyl; or 
(Formula IE) D is a moiety selected from the group consisting of C.sub.4 
-C.sub.17 cycloalkenyl which is either unsubstituted or substituted with 
at least one C.sub.1 -C.sub.4 alkyl, and C.sub.4 -C.sub.10 cycloalkyl 
substituted with a moiety selected from the group consisting of methylene, 
ethylidene, and isopropylidene and/or at least one C.sub.1 -C.sub.4 ; with 
the proviso that the sum of the number of carbon atoms contained in D and 
Y in Formula I shall not exceed twenty; and the pharmaceutically 
acceptable acid addition and cationic salts of the above. 
The loweralkyl, loweralkenyl, loweralkynyl, loweralkoxy, loweralkanoyl, and 
loweralkanesulfonyl groups herein contain 1 to 6 carbon atoms and may be 
branched or unbranched. The number of hydroxyl groups in the polyhydroxy 
compounds herein are from 2 to 4 hydroxy groups. The number of carboxy 
groups in the polycarboxy compounds herein are from 2 to 4 carboxyl 
groups. 
Suitable keto-acids and keto-esters contemplated by the present invention 
are those in which the group J is selected from the group consisting of 
carboxymethyl; carboxyethyl; 2-carboethoxy-2-propyl; dicarboethoxymethyl; 
carboethoxyvinyl and the like. Suitable alkanoic, alkenoic and alkynoic 
acids and esters are those in which the radical Z is selected from the 
group consisting of 4-carboxybutyl; 2-carboethoxyethyl; 2-carboxyvinyl; 
2-carboethoxyethynyl, and the like. 
Preferred compounds of the Formula IA are those wherein Y is a divalent 
radical selected from those consisting of straight-chain C.sub.1 -C.sub.13 
alkylene; and still more preferred are the compounds of Formula IA wherein 
D is a moiety selected from the group consisting of C.sub.5 to C.sub.8 
cycloalkyl. The most preferred compounds of Formula IA are those where Y 
is a divalent radical selected from the group consisting of a straight 
chain C.sub.6 to C.sub.8 alkylene. 
Preferred compounds of Formula IB are those where D is selected from the 
group consisting of C.sub.5 -C.sub.8 cycloalkenyl unsubstituted or 
substituted with at least one C.sub.1 -C.sub.2 alkyl and Y is a divalent 
radical selected from the group consisting of C.sub.1 -C.sub.13 alkylene; 
and those compounds wherein Y is a divalent radical selected from the 
group consisting of C.sub.4 -C.sub.13 alkylene and/or D is C.sub.5 or 
C.sub.6 cycloalkyl are even more preferred. Additionally preferred 
embodiments of compounds of Formula IB are those where D is selected from 
the group consisting of C.sub.5 to C.sub.8 cycloalkyl substituted with a 
methylene moiety and/or at least one C.sub.1 -C.sub.2 alkyl, and Y is 
--CH.sub.2 -- or --CH(CH.sub.3)--. 
Preferred embodiments of the compounds of Formula IC are those where D is 
selected from the group consisting of C.sub.5 -C.sub.6 cycloalkyl which is 
either unsubstituted or substituted with at least one C.sub.5 -C.sub.6 
cycloalkyl, and decahydronaphthyl unsubstituted or substituted with at 
least one C.sub.1 -C.sub.4 alkyl. 
Preferred compounds of Formula ID are those where D is selected from the 
group consisting of C.sub.4 -C.sub.16 cycloalkyls which may be 
unsubstituted or substituted with at least one C.sub.1 -C.sub.5 alkyl and 
most preferred are those where D is selected from the group consisting of 
C.sub.5 to C.sub.12 cycloalkyl. 
Preferred compounds of Formula IE are those where D is C.sub.4 -C.sub.17 
cycloalkenyl or C.sub.4 -C.sub.8 cycloalkenyl substituted with at least 
one C.sub.1-4 alkyl group; and even more preferred of these is where D is 
C.sub.5 -C.sub.17 cycloalkenyl and even more preferred of these is where D 
is C.sub.6 to C.sub.15 cycloalkenyl. Other preferred compounds of Formula 
IE are those where D is C.sub.4 -C.sub.10 cycloalkyl substituted with 
methylene, ethylidene or isopropylidene. Of these the most preferred are 
those in which D is a C.sub.5 -C.sub.10 cycloalkyl substituted with a 
methylene. 
The invention also pertains to novel compositions of matter useful as 
antiatherosclerotic agents and to methods of ameliorating atherosclerosis 
by counteracting hyperlipemia and arterial plaque formation in mammals 
therewith; the active ingredients of said compositions of matter being the 
novel 4-[(cycloalkyl or cycloalkenyl substituted)amino, alkylamino or 
alkenylamino]phenyl compounds, salts and derivatives of these of the 
present invention. These compounds may be utilized either as the free 
bases or in the form of a pharmaceutically acceptable salt with an organic 
or inorganic acid or base. The invention also contemplates a method for 
lowering serum lipids and for amerliorating atherosclerosis in mammals by 
the administration of said acids and derivatives. 
BACKGROUND OF THE INVENTION 
Considerable effort has been directed in recent years to obtain substances 
useful in counteracting the consequences of hyperlipidemia, a condition 
involving elevated cholesterol, phospholipid and/or triglyceride levels in 
the blood, and of hyperlipoproteinemia, involving an imbalance of the 
lipo-proteins. The most serious condition associated with hyperlipidemia 
and hyperlipoproteinemia is atherosclerosis, a form of arteriosclerosis 
characterized by lipid accumulation and thickening of the walls of both 
medium-sized and large arteries such as the aorta. Their walls are thereby 
weakened and the elasticity and effective internal size of the arteries 
decreased. Atherosclerosis, the most common cause of coronary artery 
disease, is of great medical importance since it tends to occlude those 
arteries supplying blood to the heart muscles and brain, thereby producing 
permanent damage to these organs. Such damage may lead to ischemic heart 
disease, congestive heart failure, life-threatening arrhytmias, senility, 
or stroke. Involvement of leg arteries may lead to gangrene and loss of 
the limb. It has been known for more than 100 years that cholesterol is a 
major component of atherosclerotic lesions or plaques. Investigators have 
been trying to determine the role of cholesterol in lesion initiation and 
development and also, most importantly, whether lesion formation can be 
prevented or reversed and enlargement of lesions be slowed to stopped. The 
earliest lesions are now known to be fatty streaks, largely or 
cholesterol, which often progress in stages to plaques containing 
cellular, fibrous and calcified material in addition to the lipids. 
The evidence that hyperlipidemia is one of the factors involved in coronary 
heart disease is very impressive. A most important study carried out in 
Framingham, Mass. (Gordon and Verter, 1969) in over 5,000 persons for more 
than 12 years established a correlation between high concentrations of 
blood cholesterol and increased risk of heart attack. Although the causes 
of coronary artery disease are multiple, one of the most constant factors 
has been the elevated concentration of lipids in the blood plasma. A 
combined elevation of cholesterol and triglycerides had been shown 
(Carlson and Bottiger, 1972) to carry the highest risk of coronary heart 
disease. The majority of patients with ischemic heart disease or 
peripheral vascular disease were found to have hyperlipoproteinemia, 
involving very low-density and/or low-density lipoproteins (Lewis et. al. 
1974). 
The reason for most treatment of hyperlipidemia or hyperlipoproteinemia is 
for arresting, reversing or preventing atherosclerosis. In the past, 
attempts have lower the levels of cholesterol, phospholipids, and 
triglycerides in the blood by the oral feeding of various substances which 
have been generally referred to in the art as hypolipidemic agents or 
hypocholesteremic adjuvants. Typical of such substances are lecithin, 
pectin, cottonseed oil, and the mucilaginous substances listed in U.S. 
Pat. No. 3,148,114. In addition, several synthetic hypolipidemic agents 
are now available, namely, clofibrate, D-thyroxine, cholestyramine, and 
nicotinic acid [Levy and Frederckson, Postgraduate Medicine 47, 130 
(1970)]. Clofibrate has the undesirable side-effect of causing hypertrophy 
of the liver in some patients. 
The development of agents capable of reducing elevated blood lipids and of 
favorably altering blood-lipoprotein patterns is considered by medical 
authorities to be extremely important for the treatment and prevention of 
atherosclerosis. Related compounds are the subject of our copending U.S. 
Patent Applicaion, Ser. No. 881,457. 
DETAILED DESCRIPTION OF THE INVENTION 
The compounds of this invention are new and novel 4-[(cycloalkyl or 
cycloalkenyl substituted) amino, alkylamino or alkenylamino]phenyl 
compounds, salts and derivatives of these, and have useful biological and 
pharmacological properties. No hypolipidemic activity has been reported in 
the literature for these compounds and they are different in structure 
from other hypolipidemic agents. The compounds of this invention lower 
serum-lipid concentrations and also minimize atheroma formation in the 
aorta. These compounds provide the oral administration required of 
hypolipidemic agents, which patients usually take for many years. The 
novel compounds of this invention are adequately and reliably absorbed 
from the gastrointestinal tract with little, if any, gastrointestinal 
irritation. 
I have now found that certain members of this class of compound can safely 
and effectively lower both serum-sterols and triglycerides in warm-blooded 
animals. Such actions on serum lipid components are considered to be very 
useful in the treatment of atherosclerosis, especially in contrast to 
available drugs whose action is much more limited. For some time it has 
been considered desirable to lower serum-lipid levels and to correct 
lipoprotein imbalance in mammals as a preventive measure against 
atherosclerosis. The compounds of the present invention do not act by 
blocking late states of cholesterol biosynthesis and thus do not produce 
accumulation of intermediates such as desmosterol, as equally undesirable 
as cholesterol itself. Compounds with the combination of therapeutically 
favorable characteristics possessed by those of the present invention can 
be safely administered to warm-blooded mammals for the treatment of 
hyperlipidemic and atherosclerotic states found in patients with or prone 
to heart attacks, to peripheral or cerebral vascular disease, and to 
stroke. 
The 4-[(cycloalkyl or cycloalkenyl substituted) amino, alkylamino or 
alkenylamino]phenyl compounds salts and derivatives of the present 
invention are, in general, white crystalline solids having characteristic 
melting points and absorption spectra. They are soluble in organic 
solvents such as lower alkanols, chloroform, toluene, dimethylformamide, 
and the like but are generally not very soluble in water. 
The novel compounds of the present invention which are organic bases may be 
converted to their non-toxic acid-addition or cationic salts with a 
variety of pharmaceutically acceptable organic and inorganic salt-forming 
reagents. Thus, acid-addition salts may be formed by admixture of the 
organic free base in a neutral solvent with one or two equivalents of an 
acid such as sulfuric, phosphoric, hydrochloric, hydrobromic, 
trifluoroacetic, citric, tartaric, ascorbic, and the like. Many of the 
novel compounds of the present invention which contain one or more acidic 
substituents may be converted to their organic or inorganic cationic salts 
for therapeutic use. The sodium of potassium salts which are formed in 
solution in the course of the above described hydrolysis reactions may be 
isolated as solids by cooling. When it is desirable to purify a compound 
in the form of the acid, the salt is conveniently formed by treating its 
solution with exactly one equivalent of base and evaporation or 
lyophylization. Alkaline earth salts are prepared similarly, often using 
their acetate salts as a conveniently soluble form. Organic base salts 
such as those of N-methylglucamine are prepared by dissolving equimolar 
amounts of the acid and the base in hot ethanol or aqueous alcohols and 
cooling to crystallization. 
Many of the novel compounds of the present invention may be prepared by 
reaction of a 4-aminophenyl compound with a suitable alkylating agent such 
as a cycloalkyl halide, sulfate, tosylate, or trifluoromethanesulfonate 
with or without a solvent at 30.degree. C. to 150.degree. C. Appropriate 
4-aminophenyl compounds are, for example, 4-aminophenylacetic acid; ethyl 
4-(aminophenyl)acetate; ethyl 3-(4-aminophenyl)-propionate; 
4-aminoacetophenone; 4-aminobenzaldehyde; 4-aminocinnamic acid; and methyl 
3-(4-aminophenyl)propenoate. Suitable solvents are lower alkanols, 
N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dimethoxyethane, 
acetonitrile, toluene, benzene, hexamethylphosphoramide and the like. The 
reaction may be carried out with two equivalents of the 4-aminophenyl 
compound or with one equivalent of the compound plus one equivalent of a 
base such as an alkali carbonate or bicarbonate or an unreactive organic 
base such as diisopropylethylamine or alternatively with a catalytic 
amount of copper powder when a cycloalkyl halide is used as the alkylating 
agent. Similarly, alkylation of the sodium salt (formed with sodium 
hydride) of either the amino group of a 4-aminophenyl compound or the 
anilide moiety of a 4-(acetylamino)phenyl compound yields the novel 
compounds of the invention or an N-acetyl derivative thereof. Removal of 
the N-acetyl group by conventional hydrolytic methods affords the desired 
amino compounds. 
Alternative methods of preparation of these compounds are by reductive 
alkylation of a 4-aminophenyl compound, which may be generated in situ by 
reduction of a 4-aminophenyl precursor such as a 4-nitrophenyl compound 
and the like or by a metal hydride reduction of a 4-(acylamino)-phenyl 
compound. For example, 10-cyclopentyldecanal, 7-cyclohexylheptyl ethyl 
ketone, or another carbonylalkane and ethyl 4-aminophenylacetate are 
reduced under 1-10 atmospheres of hydrogen using an activated metal 
catalyst or with a metal hydride such as sodium borohydride forming 
4-(10-cyclopentyldecylamino)phenylacetic acid and the like. Diborane 
reduction of 4-(cycloalkylalkanoylamino)phenyl compounds such as ethyl 
4-(11-cyclohexylundecanoylamino)-phenylacetate at room temperature or 
above for 1-6 hours yields the corresponding 
4-(cycloalkylalkylamino)phenyl compounds such as ethyl 
4-(11-cyclohexylundecylamino)phenylacetate. The 
4-(cycloalkylalkanoylamino)phenyl compounds used in these reductions are 
prepared by acylation of the appropriate 4-aminophenyl compounds with 
suitable acylating agents, such as cycloalkylalkanoyl halides. To prepare 
the 4-(substituted-amino)phenyl alkenoic and alkynoic acids it is 
advantageous to form the corresponding alkylchloroimide from the 
4-(acylamino)phenyl compounds using phosphorus oxychloride and base, and 
then reduce the alkylchloroimide moiety to an alkylamino group with sodium 
borohydride. 
The 4-(substituted-amino)phenyl compounds of this invention are often 
prepared from the corresponding p-aminophenyl compounds by the sequence 
involving esterification of any carboxyl groups present with ethanol or 
methanol in the presence of boron trifluoride etherate, followed by 
alkylation of the amino function as described above. The free acids are 
then liberated by hydrolysis of the ester with aqueous alcoholic sodiium 
hydroxide at 80.degree. for 2-10 hours followed by acidification. The 
acids obtained by this procedure may be converted to the corresponding 
cationic salts. For example, the sodium salt may be prepared by reaction 
of the benzoic acid with sodium hydroxide in a mixture of ethanol and 
water. Alternatively, the free acids may be prepared by hydrolysis of the 
corresponding nitriles of various amides, imidates or oxazolines. 
The carboxaldehydes of this invention may be prepared by several methods 
among which is alkylation of the corresponding acetals as described above 
followed by hydrolysis of the resulting 4-(cycloalkylalkylamino)phenyl 
compound to the desired aldehyde. Aldehydes may also be prepared by 
reduction of the appropriate nitriles. For example, treatment of 
4-(6-cyclopentylhexylamino)hydrocinnamonitrile with stannic chloride and 
anhydrous hydrogen chloride gas, followed by hydrolysis in hot water 
provides 4-(6-cyclopentylhexylamino)hydrocinnamaldehyde. These reductions 
are also conveniently carried out with hydrides such as diisobutylaluminum 
hydride. 
A method useful for the introduction of the 4-[(cycloalkyl or cycloalkenyl 
substituted)amino, alkylamino or alkenylamio] group into phenyl compounds 
is nucleophilic aromatic substitution. An example of this method is the 
reaction of (cyclohexylmethyl)amine (or the anion derived therefrom by 
treatment with a strong base) with ethyl 4-fluorobenzoate to yield ethyl 
4-[(cyclohexylmethyl)amino]-benzoate. In certain instances an amine such 
as (cyclohexyl)-amine may be reacted with a benzyne such as that derived 
from ethyl 4-bromobenzoate by treatment with sodium amide to yield the 
4-(substituted-amino) phenyl compound, in this case ethyl 
4-[(cyclohexylmethyl)amino]benzoate. 
The .alpha.-substituted 4-(substituted-amino)acetophenones of the invention 
are prepared by reaction of a derivative or the appropriate benzoic acid, 
such as 4-(11-cyclohexylundeylamino)benzoyl chloride hydrochloride, with 
two or more equivalents of the reactive salt of an acidic methylene 
compound, for example the sodium salt of diethylmalonate. Other benzoic 
acid derivatives are also suitable for this reaction, such as an 
N-trifluoroacetyl or N-tert-butyloxycarbonyl acid chloride, or a methyl 
ester of the acid. In some cases the final step in the preparation of the 
substituted 4-(substituted amino)acetophenones is the removal of the 
nitrogen-protecting group. In other cases, hydrolysis of one or more of 
the ester groups in the acylation product affords an unstable 
polycarboxylic acid which undergoes decarboxylation to allow the 
preparation of another acetophenone derivative. For example, the reaction 
of tert-butyl ethyl [4-(11-cyclopentylundecylamino)benzoyl]malonate with 
trifluoroacetic acid affords ethyl 
[4-(11-cyclopentylundecylamino)benzoyl]acetate. In other cases, hydrolysis 
of one or more of the ester groups allows the preparation of the 
corresponding acid derivative. For example, the hydrolysis of ethyl 
[4-(6-cyclobutylhexylamino)benzoyl]acetate yields 
[4-(6-cyclobutylhexylamino)benzoyl]acetic acid. 
An alternative procedure for preparing certain 
.alpha.-substituted-4-(substituted-amino)acetophenones is alkylation of 
the corresponding 4-aminoacetophenone by the methods above. For example, 
alkylation of methyl 3-(4-aminobenzoyl)propionate with 
11-cyclopentyludec-10-enyl bromide yields methyl 
3-[4-(11-cyclopentylundec-10-enylamino)benzoyl]propionate. The related 
carboxylic acids are then obtained by hydrolysis. Certain acids are 
particularly useful for the preparation of 
4-(substituted-amino)phenyl]alkanoic acids by reduction. For example, the 
Clemmensen or Wolff-Kishner reduction of 
3-[4-(6-cyclohexylhexylamino)benzoyl]propionic acid yields 
4-[4-(6-cyclohexylhexylamino)phenyl]butyric acid. 
The 4-(substituted-amino)phenylalkenoic acids may be prepared by 
condensation of the appropriate aldehydes or by dehydration of the 
corresponding substituted-phenylhydroxyalkanoic acids. For example, ethyl 
5-[4-(cyclopentylmethylamino)phenyl]-2,4-pentadienoate is obtained by the 
Wittig reaction of 4-(cyclopentylmethylamino)benzaldehyde with the Wittig 
reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkanoic 
acids are obtained by heating 
4-[N-(10-cyclopentyldecyl-N-methylamino]benzaldehyde and the like with the 
sodium salt of the carbonion of ethyl acetate or with a mixture of ethyl 
acetate, acetic anhydride and potassium acetate. The second method is 
illustrated by dehydration of ethyl 
3-[(4-cyclohexylmethylamino)phenyl]-3-hydroxypropionate to yield ethyl 
4-cyclohexylmethylaminocinnamate. 
The acetylenic analogs are prepared by dehydrobromination of the side-chain 
vic-dibrominated alkanoic acid. For example, dehydrobromination of ethyl 
3-[(4-cyclobutylmethylamino)phenyl]-2,3-dibromopropionate, its isomers or 
N-acylanalogs or of ethyl 
3-[(4-cyclobutylmethylamino)phenyl]-3-bromoacrylate yields ethyl 
4-(cyclobutylmethylamino)phenylpropiolate. The acetylenic acids are also 
formed from (4-substituted-amino)phenylacetylene metal salts by 
carboxylation with carbon dioxide. The 
4-(substituted-amino)phenylacetylenes are also used by N-acylating with 
t-butyl azidoformate followed by conversion to the lithium acetylide salt 
and the subsequent reaction of the lithium salt with boron trifluoride 
etherate in tetrahydrofuran at -20.degree. C. to form 
tris-[(4-substituted-alkylamino)phenylethynyl]boranes. The tetrahydrofuran 
solution of the borane is in turn reacted with ethyl diazoacetate, 
followed by water to yield ethyl 4-[(4-monoalkylamino)phenyl]butynoate. 
The 4-(substituted-amino)phenylalkanoic acids, or esters are also prepared 
by catalytic reduction at 1 to 10 atmospheres of hydrogen of the 
corresponding alkenoic or alkynoic acid derivatives. 
The 4-(substituted-amino)phenylakenoic acids and derivatives are prepared 
by Friedel-Crafts acylation of the N-acyl-N-alkylanilines with the 
appropriate dicarboxylic acid anhydride or half acid chloride. The 
substituted-aminobenzoylalkanoic acids or esters, produced by this and 
other syntheses, may be converted to the corresponding 
4-(substituted-amino)phenylalkanoic acids by reduction with (a) hydrazine 
and alkali in diethylene glycol at 140.degree. for 3 hours, (b) zinc 
amalgam and ethanolic hydrochloric acid at 60.degree. for 5 hours, (c) red 
phosphorus and hydriodic acid, or (d) ketalization with 1,2-ethanedithiol 
followed by Raney nickel desulfurization. The amides of these 
4-(substitutedamino)-phenylalkanoic acids are prepared by heating the 
corresponding 4-(substituted-amino)phenylalkyl ketones with aqueous 
alcoholic ammonium polysulfide followed by hydrolysis to yield the acids 
with the same number of carbon atoms as the ketone. These acids are also 
prepared by reacting 
4-(N-t-butyloxycarbonyl-N-substituted-amino)phenylmagnesium halides with 
2-(3-halopropyl)-2-oxazolines, followed by mild acid removal of 
2-oxazolinyl and t-butoxycarbonyl protecting groups. Similarly, the above 
Grignard reagent can be reacted with 3-bromotriethylorthopropionate in the 
presence of dilithiumtetrachlorocuprate to yield the desired acids after 
removal of the protecting groups from the amino and carboxyl groups. 
In certain cases, the unsaturation is introduced at a late stage of the 
preparation of the 4-(cycloalkyl unsaturated-alkylamino)benzoic acid 
derivatives. For example, an alkyl 4-(cycloalkylhaloalkylamino)benzoate is 
dehydrohalogenated to the corresponding olefinic compound. 
Certain derivatives 
##STR4## 
of the aminobenzoyl nitrogen atom are useful for providing greater 
solubility, more uniform and reliable intestinal absorption, and for a 
certain degree of modification of the pharmacology of the compounds of the 
present invention. Some of these derivatives can be converted to the 
corresponding N-H forms by the acidity of the stomach or the alkalinity of 
the small intestine. Others are converted by metabolic processes. The 
methyl and carboxymethyl derivatives and the like are prepared by the 
alkylation, reductive alkylation, and acylamino reduction methods above. 
Derivatives such as the acetyl and succinyl compounds may be prepared 
using acetyl chloride, acetic anhydride, succinic anhydride, etc. in the 
presence of pyridine, triethylamine or the like at temperatures moderate 
enough to avoid acylation of the amide moiety. The 1-(sodium sulfo)alkyl 
derivatives are obtained by reaction of the 4-(substituted amino)phenyl 
compound with sodium bisulfite and an aliphatic aldehyde, a 
polyhydroxyaldehyde such as glyceraldehyde or glucose, or cinnamaldehyde 
in a mixed organic-aqueous medium. In the case of cinnamaldehyde, the 
di-sulfonate salts result from addition of the bisulfite to the 
carbon-nitrogen double bond of the anil intermediate as well as to the 
carbon-carbon double bond of cinnamaldehyde itself. 
The novel compounds of the present invention are not only potent 
hypolipidemic agents but also prevent or diminish the formation or 
enlargement of arterial plaques in mammals when administered in amounts 
ranging from about one milligram to about 250 mg. per kilogram of body 
weight per day. A preferred dosage regimen for optimum results would be 
from about 5 mg. to about 100 mg. per kilogram of body weight per day, and 
such dosage units are employed that a total of from about 0.35 gram to 
about 7.0 grams of the active compound, for a subject of about 70 kg. of 
body weight, are administered in a 24 hour period. This dosage regimen may 
be adjusted to provide the optimum theraputic response. For example, 
several divided doses may be administered daily or the dose may be 
proportionally reduced as indicated by the exigencies of the therapeutic 
situation. A decided practical advantage of this invention is that the 
active compound may be administered in a convenient manner by the oral 
route. The compounds of the present invention exert a more powerful 
hypocholestermic and antiatherosclerotic effect than the aforementioned 
adjuvants and synthetic medicaments. It is not known how these novel 
compounds operate in the blood serum and no theory of why these compounds 
so operate is advanced. It is not intended that the present invention 
should be limited to any particular mechanism of action of lowering serum 
lipids or of ameliorating atherosclerosis, or be limited to compounds 
acting by only one mechanism. 
The active compounds of the present invention may be orally administered, 
for example, with an inert diluent or with an assimilable edible carrier, 
or they may be enclosed in hard or soft shell gelatin capsules, or they 
may be compressed into tablets, or they may be incorporated directly with 
the food of the diet. For oral therapeutic administration, the active 
compounds may be incorporated with excipients and used in the form of 
ingestible tablets, buccal tablets, troches, capsules, elixirs, 
suspensions, syrups, wafers, and the like. Such compositions and 
preparations should contain at least 0.1% of active compound. The 
percentage of the compositions and preparations may, of course, be varied 
and may conveniently be between about 2 to about 60% of the weight of the 
unit. The amount of active ingredient in such therapeutically useful 
compositions is such that a suitable dosage will be obtained. Preferred 
compositions or preparations according to the present invention are 
prepared so that an oral dosage-unit form contains between about 50 and 
250 milligrams of active compound. 
The tablets, troches, pills, capsules and the like may also contain the 
following: a binder such as gum tragacanth, acacia, corn starch or 
gelatin; excipients such as dicalcium phosphate, a disintegrating agent 
such as corn starch, potato starch, alginic acid and the like; a lubricant 
such as magnesium stearate; and a sweetening agent such as sucrose, 
lactose or saccharin may be added or a flavoring agent such as peppermint, 
oil of wintergreen, or cherry flavoring. When the dosage-unit form is a 
capsule, it may contain, in addition to materials of the above type, a 
liquid carrier. Various other materials may be present as coatings or to 
otherwise modify the physical form of the dosage unit. For instance, 
tablets, pills or capsules may be coated with shellac, sugar or both. A 
syrup or elixir may contain the active compound, sucrose as a sweetening 
agent, methyl an propyl parabens as preservatives, a dye, and flavoring 
such as cherry or orange flavor. Of course, any material used in preparing 
any dosage-unit form should be pharmaceutically pure and substantially 
non-toxic in the amounts employed. In addition, the active ingredients may 
be incorporated into sustained-release preparations and formulations. 
The invention will be described in greater detail in conjunction with the 
following specific examples.