Substituted piperidines therapeutic process and compositions

The compounds are of the heterocyclic class of 2-phenethylpiperidines having an amido substituent in the ortho position of the phenethyl moiety. Substituents in the ortho position include formamido, benzamido, cinnamamido, 2-thiophenecarboxamido, alkanesulfonamido and alkanoylamido. They are useful as antiarrhythmic and/or antiserotonin agents. The novel compounds are prepared by reaction of appropriately substituted o-aminophenethylpiperidines and the carbonyl or sulfonyl halides or anhydrides. Typical embodiments of this invention are 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide and 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide.

BACKGROUND OF THE INVENTION 
The present invention is concerned with certain heterocyclic organic 
compounds which can be referred to as substituted piperidines and acid 
addition salts thereof. In particular, this invention relates to 
physiologically active novel piperidine compounds which are particularly 
effective as antiarrhythmic and antiserotonin agents. It is also concerned 
with chemical intermediates useful in the preparation of the piperidine 
compounds. Other features of the invention are pharmaceutical compositions 
containing the piperidines as active ingredients and a therapeutic process 
for producing antiserotonin and antiarrhythmic effects in mammals by 
administration of them. 
Agents which antagonize serotonin are of interest in experimental biology 
and in treatment of various physiological disorders such as migraine 
headache, serotonin producing tumors, toxemia in pregnancy, habitual 
abortion and management of various inflammatory and allergic reactions. 
Methysergide and lysergide are well known antiserotonin agents. Other 
serotonin antagonists which have been reported in the prior art literature 
on the subject are 2'-(3-dimethylaminopropylthio)cinnamanilide and related 
compounds disclosed by Krapcho, et al., J. Med. Chem., 6, 219 (1963); 7, 
376 (1964); 9, 809, (1966); and 12, 164 (1969); and U.S. Patent 3,192,213. 
A number of structurally unrelated chemical substances have been employed 
in the treatment of cardiac arrhythmia; refer to A. Burger, Medicinal 
Chemistry, 3rd Edition, pages 1082-1085 (Wiley). One of the most important 
drugs in clinical treatment of disorders of cardiac rhythm is quinidine. 
Another chemical agent which has been used as an antiarrhythmic is the 
local anesthetic procaine amide. Still other antiarrhythmic agents are 
lidocaine, and diphenylhydantoin. None of these compounds are structurally 
related to the piperidines of the present invention. 
SUMMARY OF THE INVENTION 
This invention relates to a series of substituted piperidines characterized 
by Formula I and Formula XII and non-toxic pharmaceutically acceptable 
acid addition salts thereof. 
##STR1## 
The substances of Formula I and Formula XII are new compositions of matter 
possessing valuable pharmacological properties which render them useful as 
synthetic medicinals. In particular, the substituted piperidines of 
Formula I and Formula XII exhibit utility as antiserotonin and/or 
antiarrhythmic agents in standard pharmacological tests in mammals. This 
invention also is concerned with the production of the compounds of 
Formulas I and XII from novel chemical intermediates, pharmaceutical 
compositions containing them and a therapeutic process for producing an 
antiserotonin effect in mammals comprising the administration of such 
compounds thereto. Another feature of this invention is a therapeutic 
process for producing an antiarrhythmic effect in mammals by 
administration of compounds of Formula I wherein R.sup.5 is R.sup.6 
substituted cinnamoyl as depicted by Formula Ia or R.sup.7 substituted 
benzoyl as depicted by Formula Ib. 
Still another feature of this invention provides novel 
o-aminophenethylpiperidines of Formula II which are useful as chemical 
intermediates in the production of compounds of Formula I. 
##STR2## 
In the compounds characterized by the above general Formulas I and II, the 
R.sup.1 substituent stands for hydrogen or lower alkyl. The substituent 
R.sup.2 represents hydrogen, lower alkoxy or methylenedioxy attached in 
the benzenoid 4,5-position. R.sup.3 stands for hydrogen or a lower alkyl 
substituent. Substituent R.sup.4 represents hydrogen, lower alkyl, or a 
dialkylcarboxamido substituent wherein the dialkyl groups are lower alkyl. 
Substituent R.sup.5 represents radicals selected from the group comprised 
of lower alkanoyl of from 1 to 4 carbon atoms inclusive, lower 
alkanesulfonyl of from 1 to 4 carbon atoms inclusive, 
##STR3## 
The symbol R.sup.6 represents hydrogen or lower alkyl and R.sup.7 is 
selected from the group consisting of hydrogen, halogen, trifluoromethyl, 
amino, dimethylamino, hydroxy, acetoxy, carboxy, alkylthio of from 1 to 4 
carbon atoms inclusive, alkyl of from 1 to 4 carbon atoms inclusive, lower 
alkoxy of from 1 to 4 carbon atoms inclusive, and wherein when R.sup.7 is 
hydrogen or alkoxy the phenyl ring can have up to 2 additional alkoxy 
substituents of from 1 to 4 carbon atoms inclusive. 
In the compounds characterized by Formula XII, the symbol R.sup.8 
represents hydrogen or lower alkyl. The symbol R.sup.9 represents a 
radical selected from the group consisting of cinnamoyl or 
##STR4## 
wherein R.sup.10 is lower alkoxy. The symbol "A" represents a divalent 
radical selected from the group consisting of 
It is to be understood that the term "lower alkyl" and "lower alkoxy" as 
used herein refers to carbon chains which include both straight and 
branched chain carbon radicals of from 1 to 4 carbon atoms inclusive. 
Illustrative of these radicals are carbon chains which can be methyl, 
ethyl, propyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl and 
tert.-butyl. 
Compounds which are particularly preferred for their strong antiserotonin 
activity are compounds of Formula Ia. 
##STR5## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.6 have the meanings 
hereinabove given for Formula I. Representative of these compounds is the 
individually preferred compound 
2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide. 
Compounds of the present invention which are particularly preferred for 
their strong antiarrhythmic activity are those of Formula Ib. 
##STR6## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.7 have the meanings 
hereinabove given for Formula I. Representative of these compounds are the 
individually preferred compounds 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, and 
2'-[2-(1-methyl-2-piperidyl)ethyl]-3,4,5-trimethoxybenzanilide. 
A still further group of preferred compounds are those characterized by 
Formula Ib wherein R.sup.1, R.sup.2, and R.sup.4 are hydrogen, R.sup.3 is 
methyl and R.sup.7 is hydrogen or alkoxy. 
A particularly preferred antiarrhythmic compound of Formula XII is 
2'-[3-(1-methyl-2-piperidyl)propyl]-p-anisanilide. 
The o-aminophenethylpiperidines of Formula II are considered to be another 
aspect of the present invention. They are particularly useful as chemical 
intermediates in the preparation of compounds of Formula I. Apart from 
being particularly suitable as key intermediates in the preparation of 
compounds of Formula I, some of the members such as 
2-(o-aminophenethyl)-1-methylpiperidine have antiarrhythmic properties. 
A compound of Formula XII particularly preferred as an antiarrhytmic agent 
is 2-[2-[(p-methoxybenzyl)amino]phenethyl]-1-methylpiperidine and 
non-toxic pharmaceutically acceptable salts thereof. 
It will be apparent to those skilled in the art that the compounds of 
Formula I, Formula II and Formula XII exists in at least one racemic 
stereoisomeric form since they contain one asymmetric carbon atom (the 2 
position of the piperidine ring). Whenever the R.sup.4 substituent is not 
hydrogen, an additional asymmetric carbon atom (the 5 position of the 
piperidine ring) is present and two racemic modifications exist. Such 
mixture of racemates can be separated into the individual racemic 
compounds on the basis of physico-chemical differences such as solubility; 
for example, by fractional crystallization of the basis or as acid 
addition salts thereof or by chromatography. Optically active 
stereoisomers are obtained by resolution methods well known to the art 
such as the use of optically active acids. 
It is to be understood that as used herein, the term "non-toxic 
pharmaceutically acceptable acid addition salts" refers to a combination 
of compounds of the present invention with relatively non-toxic inorganic 
or organic acids. Illustrative of suitable acids which may be used are 
sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, 
methanesulfonic, benzenesulfonic, para-toluenesulfonic, acetic, lactic, 
succinic, maleic, mucic, tartaric, citric, gluconic, benzoic, cinnamic, 
isethionic and related acids. 
The compounds characterized by Formula I and Formula XII exhibit valuable 
antiarrhythmic activity in mammals. These antiarrhytmic effects are 
illustratively demonstrated in standard in vitro and in vivo 
pharmacological tests. 
In the dog, for example, electrically or aconitine induced arrhythmia is 
prevented by oral or parenteral administration of the piperidines of 
Formula I according to the following in vivo test. 
The chest of an anesthetized dog is opened in the midline and the right and 
left atrial appendages exposed through small slits in the pericardium. 
Bypolar recording electrodes are affixed to the atrial surfaces and a 4 
.times. 4 mm. piece of clean cloth is fixed to the surface of the right 
auricular appendage. Control recordings are made of various heart 
functions including femoral arterial blood pressure and right and left 
atrial electrograms. Atrial arrhythmia is then induced by placing 3-5 
drops of a solution of aconitine on the cloth which is fixed to the right 
atrium. An irregular, rapid atrial rate is produced within one minute. 
Throughout the experiment, fresh aconitine is (2-3 drops) placed on the 
cloth at 10 minute intervals. The test compound is administered 
intravenously five minutes after the initial establishment of the 
arrhythmia and infusion continued at a slow rate until an effective does 
which re-establishes normal rhythm of the heart is obtained. 
Intravenous administration of as little as 0.8 mg./kg. of 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, a preferred 
compound of the present invention, effectively restores normal cardiac 
rhythm to aconitine induced arrhythmia in the dog. A well known 
antiarrhythmia agent such as quinidine administered in the same manner has 
an effective dose of 6.0 mg./kg. When arrhythmia is induced electrically, 
the effective dose of 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)-ethyl]benzanilide is 1.9 mg./kg. 
Under like conditions, the effective dose for quinidine is 14 mg./kg. 
Intraduodenal administration, which is a measure of oral effectiveness, of 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide prevents aconitine 
induced arrhythmia in the dog at a dose of less than 10 mg./kg. while the 
effective dose in the prevention of aconitine induced arrhythmia of 
quinidine is greater than 14 mg./kg. 
Another in vivo test involves the inhibition of chloroform induced 
arrhythmia in the mouse according to the method of J. W. Lawson, J. 
Pharmacol. Exp. Therap., 160, 22 (1968). Intraperitoneal administration of 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide to the mouse 
prevents chloroform induced arrhythmia at an ED.sub.50 of 7.1 mg./kg. 
compared to an Ed.sub.50 of 83 for quinidine. 
An in vitro test which demonstrates the antiarrhythmic effects of the 
compounds of the present invention employs the rabbit atrium. In this 
test, the left atrium is placed in Chenoweth's solution warmed to 
30.degree. C. and irrigated with 95% oxygen: 5% carbon dioxide. The lower 
end of the atrium is attached to a small hook fixed in the bath and the 
upper end is connected to a transducer to record contractile activity. The 
atrium is electrically stimulated at a basic rate of 30 per minute 
employing square wave pulses of 10 millisecond duraction at 1.2-1.5 
.times. threshold voltage. A test compound is introduced into the bath and 
the test repeated after a 5 minute interval. A dose-response relationship 
is obtained by additional doses of the test compound. The potency of a 
test agent can be expressed as the effective concentration which produces 
50% of the maximal increase in the measured refractory period of the 
steady state atrium. This value is designated the EC.sub.50. 
In the in vitro rabbit atrium test, the EC.sub.50 of 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide is 2.4 microgram 
per milliliter while the value for quinidine is 18.0 microgram per 
milliliter. 
Exemplary of compounds of the present invention which have particularly 
good antiarrhythmic properties are: 
2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, 
4-hydroxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, 
4-chloro-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, 
4-amino-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, 
4-acetoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]-3,4,5-trimethoxybenzanilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]-2-thiophenecarboxanilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]methanesulfonanilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide, 
2-(o-aminophenethyl)-1-methylpiperidine, 
2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, 
2'-[3-(1-methyl-2-piperidyl)propyl]-p-anisanilide. 
The compounds of Formula Ia and Formula Ib are characterized as 
particularly useful antiserotonin agents as can be demonstrated in the rat 
uterus. According to this test one of the uterine horns of a rat uterus is 
suspended in oxygenated salt solution at 30.degree. C. The contractions of 
this tissue are then recorded and varying concentrations of the test 
compound introduced into the bath in order to determine the concentration 
that would decrease the spasmogenic effect of 0.4 microgram per milliliter 
of serotonin by 50%. This value is designated the IC.sub.50. 
A preferred antiserotonin compound of the present invention is 
2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide, which has an IC.sub.50 of 
0.00185 microgram per milliliter. Another preferred substance, 
4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, has an IC.sub.50 
of 0.0046 microgram per milliliter. The antiserotonin agents lysergide 
(LSD) and methysergide have an IC.sub.50 of 0.012 and 0.0025 microgram per 
milliliter respectively. 
The antiarrhythmic and antiserotonin therapeutic process of the present 
invention is carried out in mammals by systemic administration of a 
non-toxic effective dose of the piperidines of Formulas I and XII ranging 
from about 0.01 to 20 milligram per kilogram of body weight of the mammal 
or more preferably from 0.1 to 10 mg./kg. Acceptable forms of systemic 
administration are oral and parenteral. Examples of parenteral 
administration are intramuscular, intravenous, intraperitoneal, and 
subcutaneous administration. The dosage of the present therapeutic agents 
of Formulas I and XII will vary with the form of administration and 
particular compound chosen. Generally, the compound is administered at a 
dosage substantially less than the optimum dose of the compound. 
Thereafter, the dosage is increased by small increments until the optimum 
effect under the circumstances is reached. It will generally be found that 
when the composition is administered orally, larger quantities of the 
active agent will be required to produce the same effect as a smaller 
quantity given parenterally. In general, the compounds of this invention 
are most desirably administered at a concentration level that will 
generally afford effective results without causing any harmful or 
deleterious side effects. 
The antiserotonin activity of 
2'-[2-(1-methyl-2-piperidyl)ethyl]-cinnamanilide can also be demonstrated 
in mice according to the method of S. J. Corne, et al., Brit. J. 
Pharmacol., 20, 106 (1963). This test is dependent on the metabolism of 
5-hydroxytryptophan to serotonin in the brain in mice which are pretreated 
with a monamine oxidase inhibitor. Depending on the route of 
administration and the pretreatment time, the following ED.sub.50 values 
are obtained; subcutaneous, 4.3 mg./kg. (30 minute pretreatment), 10 
mg./kg. (60 minute pretreatment); intraperitoneal, 21 mg./kg. (60 minute 
pretreatment). These values compare favorably with that obtained with 
methyldopa, a known serotonin inhibitor, which has an intraperitoneal 
ED.sub.50 of 37 mg./kg. (60 minute pretreatment). 
When the compounds of this invention characterized by Formulas I and XII 
are employed as antiserotonin or antiarrhythmic agents they may be 
administered to mammals alone or in combination with a pharmaceutically 
acceptable carrier. The proportion of the pharmaceutical carrier is 
determined by the solubility and chemical nature of the compound and 
chosen route of administration in standard pharmaceutical practice. For 
example, they may be administered orally in form of tablets, coated 
tablets or capsules containing such excipients as starch, milk, sugar, 
certain types of clay, gelatin, stearic acid or salts thereof, magnesium 
or calcium stearate, talc, vegetable fats or oils, gums, glycols, and 
other known excipients. They may be administered orally in the form of 
solutions which may contain coloring and flavoring agents or they may be 
injected parenterally, that is intramuscularly, intravenously, or 
subcutaneously. For parenteral administration they may be used in the form 
of sterile solution. Said pharmaceutical compositions are prepared by 
conventional methods. 
A recommended dosage unit form comprises a pharmaceutical carrier and the 
therapeutically active compound in an amount sufficient to provide a 
non-toxic effective antiserotonin or antiarrhythmic dose ranging from 
about 0.01 to 20 milligram per kilogram of body weight of the mammal 
treated. 
Advantageously, the compositions can be adapted to supply a fixed dose 
containing from 1 to 500 mg. and preferably 5 to 100 mg. of the active 
ingredient. 
Preparation of compounds of Formula I according to the process of the 
present invention is carried out according to Equation 1. 
##STR7## 
wherein R.sup.1, R.sup.2, R.sup.4, and R.sup.5 have the meaning stated 
above and R.sup.3 is limited to lower alkyl provided that when R.sup.5 is 
"R.sup.7 -benzoyl", R.sup.7 additionally represents "NO.sub.2 " but cannot 
stand for NH.sub.2 or OH. Compounds wherein R.sup.7 is "NO.sub.2 " are 
converted to compounds of Formula I wherein R.sup.7 is "NH.sub.2 " by 
hydrogenation. Compounds wherein R.sup.7 is "acetoxy" are converted to 
compounds of Formula I wherein R.sup.7 is "OH" by hydrolysis. The symbol 
"X" represents a halogenide of a R.sup.5 carbonyl or sulfonyl radical or 
R.sup.5 X taken together represents an anhydride. 
Illustrative of R.sup.5 X reactants which can be reacted with 
o-aminophenethylpiperidines of Formula II are: 
acetic-formic anhydride, 
acetic anhydride, 
n-propionic anhydride, 
n-butyric anhydride, 
isobutyric anhydride, 
benzoic anhydride, 
acetyl chloride, 
propionyl chloride, 
butyryl chloride, 
methanesulfonyl chloride, 
methanesulfonic anhydride, 
ethanesulfonic anhydride, 
isopropylsulfonyl chloride, 
n-butanesulfonyl chloride, 
4-methoxybenzoyl chloride, 
3,4,5-trimethoxybenzoyl chloride, 
3,5-dimethoxybenzoyl chloride, 
2-methoxybenzoyl chloride, 
2-chlorobenzoyl chloride, 
3-acetoxybenzoyl chloride. 
In addition R.sup.5 X taken together can represent a reactive ester such 
as, for example, methyl 4-(t-butoxy)benzoate, ethyl picolinate, ethyl 
propiolate, ethyl 4-dimethylaminobenzoate, ethyl furan-3-carboxylate and 
the like. 
The reaction proceeds when the reactants are contacted and mixed in an 
inert organic solvent as a reaction medium. Representative inert organic 
solvents which can be employed as reaction media include ether, benzene, 
toluene, acetonitrile halogenated hydrocarbons such as chloroform, and the 
like. Whenever halogenide reactants such as acetyl chloride, etc., are 
employed, it is desirable to add a hydrogen halide acceptor such as 
triethylamine to the reaction mixture. Pyridine is preferred particularly 
as a reaction medium because of its suitability both as a solvent and as 
an acid acceptor. The temperature at which the reaction is carried out is 
not critical, although from a convenience and ease of operability 
viewpoint, room temperature is preferred. The exact proportions of the 
reactants to be employed is not critical. However, since the 
o-aminophenethylpiperidines of Formula II and the R.sup.5 X reactants are 
consumed in equimolar proportions, the reactants are preferably employed 
in such proportions. The reaction is generally complete in about 1 to 24 
hr. depending upon the reaction temperature employed. The product can be 
conveniently separated from the reaction mixture by concentrating the 
reaction mixture under reduced pressure, dissolving the resulting residue 
in water and adding thereto a base such as aqueous sodium hydroxide, 
aqueous sodium carbonate, or aqueous potassium carbonate to make the 
mixture strongly basic. The product can then be separated by extraction 
with a halogenated hydrocarbon solvent, ether, benzene, ethyl acetate, 
etc. Generally, the product can be purified by recrystallization from 
organic solvents such as isopropyl ether, heptane, methanol, ethanol, 
isopropyl alcohol, ethyl acetate, water, acetone, and the like, or it can 
be converted to an acid addition salt. Other means of purification include 
chromatography, e.g. thin-layer or column. 
Conversion of the substances characterized by Formula I and Formula XII to 
pharmaceutically acceptable acid addition salts is accomplished by 
admixture of the Formula I and Formula XII bases with substantially one 
chemical equivalent of any of the various acids hereinbefore defined. 
Generally the reactions are carried out in an inert solvent. Suitable 
solvents by way of example, are ethanol, benzene, ethyl acetate, ether, 
and halogenated hydrocarbons. 
Synthesis of the novel o-aminophenethylpiperidine intermediates of Formula 
II begins with preparation of 2-styrylpyridines of Formula III which are 
obtained according to the method of L. Horwitz, J. Org. Chem., 21, 1039 
(1956) from the reaction of a R.sup.2 -o-nitrobenzaldehyde and a R.sup.4 
-2-methylpyridine. As shown in Equation 2, the nitro-2-styrylpyridines of 
Formula III are reduced to an o-aminophenethylpyridine of Formula IV. It 
is preferred that reduction be carried out catalytically in a solvent 
employing palladium on carbon catalyst. Suitable solvents by way of 
example are the lower alkanoyls such as methanol, ethanol, isopropanol, 
etc. 
##STR8## 
The o-aminophenethylpyridines of Formula IV are then formylated in order to 
block alkylation of the aromatic amine when the R.sup.3 substituent is 
introduced by quaternization of the pyridine nitrogen with an R.sup.3 
-halide. This conversion of the o-aminophenethylpyridines of Formula IV to 
the Formula V formyl derivative is illustrated by Equation 3 and is 
preferably carried out with acetic-formic anhydride. 
##STR9## 
Equation 4 illustrates the alkylation of a Formula V pyridine with an alkyl 
iodide to provide a pyridinium salt of Formula VI. Depending on the 
R.sup.3 substituent desired, alkyl halides such as ethyl iodide, ethyl 
bromide, n-propyl iodide, 2-iodopropane, 1-iodobutane, 
1-iodo-2-methylpropane, 1-chloro-2-methylpropane, 2-iodo-2-methylpropane 
and the like are employed. The alkylation is carried out in an inert 
solvent such as acetone, acetonitrile, etc. 
##STR10## 
Compounds of Formula VI are converted to the phenethylpiperidines of 
Formula VII by reduction according to Equation 5. The reduction is carried 
out catalytically employing platinum as the catalyst in a suitable solvent 
such as the lower alkanols. The phenethylpiperidines of Formula VII can 
also be obtained by reduction first with metal borohydrides such as sodium 
borohydride, or potassium borohydride to provide a tetrahydropyridine 
which is then further reduced by well known catalytic methods to the 
piperidines of Formula VII. For example, reduction of 
5-diethylcarbamyl-2-(o-formamidophenethyl)-1-methylpyridinium iodide with 
sodium borohydride in methanol solution provides 
N,N-diethyl-6-(o-formamidophenethyl)-1-methyltetrahydropyridin-3-carboxami 
de which is then hydrogenated in ethanol with a 10% palladium on carbon 
catalyst. It will be recognized that compounds of formula VII represent 
the products of Formula I of the present invention wherein R.sup.1 is 
hydrogen and R.sup.5 is formyl. 
##STR11## 
Representative of the formanilides of Formula VII are: 
2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide, 
2'-[2-(5-methyl-1-methyl-2-piperidyl)ethyl]formanilide, 
2'-[2-(5-n-butyl-1-methyl-2-piperidyl)ethyl]-formanilide, 
2'-[2-(1-isopropyl-2-piperidyl)ethyl]formanilide, 
2'-[2-(1-n-butyl-2-piperidyl)ethyl]formanilide, 
4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formanilide, 
4'-n-butoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-formanilide, 
4'-isopropoxy-2'-[2-(5-isopropyl-1-methyl-2-piperidyl)-ethyl]formanilide, 
N,n-dimethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide, 
N,n-diethyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide, 
N,n-di-n-butyl-6-(o-formamidophenethyl)-1-methylpiperidine-3-carboxamide, 
N,n-diethyl-6-[(2-formamido-5-methoxyphenethyl)-1-methylpiperidine-3-carbox 
amide. 
If the o-aminophenethylpyridines of Formula IV are acylated with alkanoyl 
halides such as acetyl chloride, propionyl chloride, isobutyryl chloride, 
butyryl chloride and the like, and the sequence of reactions illustrated 
by Equations 3-5 repeated, products of Formula I are obtained wherein 
R.sup.1 is hydrogen and R.sup.5 is alkanoyl. Representative of the 
alkanoylanilides of Formula I thus formed are: 
2'-[2-(1-methyl-2-piperidyl)ethyl]acetanilide, 
4'-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-acetanilide, 
2'-[2-(1-n-butyl-2-piperidyl)ethyl]acetanilide, 
2'-[2-(5-ethyl-1-methyl-2-piperidyl)ethyl]acetanilide, 
N,n-diethyl-6-(o-acetamidophenethyl)-1-methylpiperidine-3-carboxamide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]butyranilide, 
2'-[2-(1-methyl-2-piperidyl)ethyl]-2-methylpropionanilide, 
4'-n-butoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]-proprionanilide. 
Acid hydrolysis of the formanilides of Formula VII or the analogous 
alkanoylanilides provide o-aminophenethylpiperidine intermediates of 
Formula II wherein R.sup.1 is hydrogen. Representative of 
o-aminophenethylpiperidines which can be obtained in this manner are: 
2-(o-aminophenethyl)-1-methylpiperidine, 
2-(o-aminophenethyl)-1,5-dimethylpiperidine, 
2-(o-aminophenethyl)-5-ethyl-1-methylpiperidine, 
2-(o-aminophenethyl)-5-n-butyl-1-methylpiperidine, 
2-(o-aminophenethyl)-1-isopropylpiperidine, 
2-(o-aminophenethyl)-1-n-butylpiperidine, 
2-(2-amino-5-methoxyphenethyl)-1-methylpiperidine, 
2-(2-amino-5-n-butoxyphenethyl)-1-methylpiperidine, 
2-(2-amino-5-isopropoxyphenethyl)-1-methylpiperidine, 
6-(o-aminophenethyl)-N,N-dimethyl-1-methylpiperidine-3-carboxamide, 
6-(o-aminophenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide, 
6-(o-aminophenethyl)-N,N-di-n-butyl-1-methylpiperidine-3-carboxamide, 
6-(2-amino-5-methoxyphenethyl)-N,N-diethyl-1-methylpiperidine-3-carboxamide 
. 
Reduction of some of the compounds of Formula VII with lithium aluminum 
hydride provide o-aminophenethylpiperidine intermediates of Formula II 
wherein R.sup.1 is alkyl. Representative of 
o-(N-alkylaminophenethyl)piperidines which can be obtained in this manner 
are: 
2-(o-methylaminophenethyl)-1-methylpiperidine, 
2-(o-methylaminophenethyl)-1,5-dimethylpiperidine, 
2-(o-methylaminophenethyl)-5-ethyl-1-methylpiperidine, 
2-(o-methylaminophenethyl)-5-n-butyl-1-methylpiperidine, 
2-(o-methylaminophenethyl)-1-isopropylpiperidine, 
2-(o-methylaminophenethyl)-1-n-butylpiperidine, 
2-(2-methylamino-5-methoxyphenethyl)-1-methylpiperidine, 
2-(2-methylamino-5-n-butoxyphenethyl)-1-methylpiperidine, 
2-(2-methylamino-5-isopropoxyphenethyl)-1-methylpiperidine, 
2-(o-ethylaminophenethyl)-1-methylpiperidine, 
2-(2-ethylamino-5-methoxyphenethyl)-1-methylpiperidine, 
2-(2-ethylaminophenethyl)-1-n-butylpiperidine, 
2-(2-ethylaminophenethyl)-5-ethyl-1-methylpiperidine, 
2-(2-n-butylaminophenethyl)-1-methylpiperidine, 
2-(2-isobutylaminophenethyl)-1-methylpiperidine, 
2-(2-n-propylamino-5-n-butoxyphenethyl)-1-methylpiperidine. 
An alternate method for the preparation of compounds of Formula II wherein 
R.sup.1 is hydrogen is depicted in Equation 6. 
##STR12## 
Pyridinium iodides of Formula VIII prepared from the corresponding aromatic 
aldehyde and the 2-alkylpyridinium salt according to the method of L. 
Horwitz, J. Org. Chem., 21, 1039 (1956) are reduced according to the 
method of A. P. Phillips, J. Am. Chem. Soc., 72, 1850 (1950). Preferably 
the catalytic reduction is carried out employing a platinum catalyst in 
methanol solution. 
An alternate method for the preparation of compounds of Formula II wherein 
R.sup.1 is alkyl is depicted in Equation 7. 
##STR13## 
Reductive alkylation of o-aminophenethylpiperidines of Formula X with an 
aldehyde such as acetaldehyde, propionaldehyde, n-butyraldehyde, 
isobutyraldehyde, or a ketone such as acetone or butanone provide R.sup.1 
-aminophenethylpiperidines of Formula XI. This method is well known to 
those skilled in the art, refer to Synthetic Organic Chemistry, Wagner and 
Zook, Wiley, 1953, page 662. 
Compounds of Formula I and Formula XII wherein R.sup.3 and R.sup.8 are 
hydrogen, lower alkyl, or R.sup.5 or R.sup.9 are isonipecotoyl are 
obtained by catalytic reduction of the corresponding pyridyl compounds. 
For example, reduction of 2'-[2-(2-pyridyl)ethyl]-p-anisanilide employing 
a palladium on carbon catalyst provides 
2'[-2-(2-piperidyl)ethyl]-p-anisanilide. Similarly, reduction of 
2'-[2-(1-methyl-2-piperidyl)ethyl]isonicotanilide affords 
2'-[2-(1-methyl-2-piperidyl)ethyl]isonipecotoicanilide. 
Compounds of Formula XII (illustrated by Formula XV) wherein the divalent 
radical "A" is 
##STR14## 
and R.sup.8 is lower alkyl can also be obtained by reaction of an 
o-formylanilide of Formula XIII with a 2-(N-R.sup.8 -2-piperidyl)ethyl 
magnesium chloride of Formula XIV as depicted by Equation 8.