This invention provides trans-3,4 1-substituted-3-substituted-4-methyl-4-(3-substituted phenyl)piperidines as opioid antagonists capable of blocking the mu or kappa receptors in the brain.

SUMMARY OF THE INVENTION 
The present invention relates to a trans-3,4 isomer of a compound of the 
formula 
##STR1## 
wherein: R.sup.1 is hydrogen or C.sub.1 -C.sub.4 alkanoyl; 
R.sup.2 is hydrogen, C.sub.1 -C.sub.4 alkyl or C.sub.2 -C.sub.6 alkenyl; 
R.sup.3 is C.sub.4 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.8 cycloalkenyl, 
C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.1 -C.sub.4 alkyl 
substituted C.sub.4 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.4 alkyl 
substituted C.sub.4 -C.sub.8 cycloalkenyl or thiophene; 
Z is 
##STR2## 
or a bond; R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl, 
##STR3## 
R.sup.5 is C.sub.1 -C.sub.4 alkyl or 
##STR4## 
n is 1, 2 or 3; and the pharmaceutically acceptable salts thereof. 
The present invention also provides methods of employing, and 
pharmaceutical formulations containing, a compound of the invention. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "C.sub.1 -C.sub.4 alkanoyl", as used herein, represents an 
alkanonyl group having from one to four carbon atoms. Typical C.sub.1 
-C.sub.4 alkanoyl groups include acyl, propanoyl, butanoyl and the like. 
C.sub.4 -C.sub.8 Cycloalkyl represents cyclobutyl, cyclopentyl, cyclohexyl, 
cycloheptyl and cyclooctyl. 
C.sub.4 -C.sub.8 Cycloalkenyl includes cyclobutenyl, cyclopentyl, 
cyclohexenyl, cycloheptenyl, cyclooctenyl and the like. 
C.sub.1 -C.sub.6 Alkyl includes methyl, ethyl, n-propyl, isopropyl, 
n-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, and the like. 
C.sub.2 -C.sub.6 Alkenyl includes vinyl, allyl, 3-butenyl, 
3-methyl-2-butenyl,2,3-dimethyl-2-butenyl, and the like. 
C.sub.1 -C.sub.4 Alkyl substituted C.sub.4 -C.sub.8 cycloalkyl represents a 
C.sub.4 -C.sub.8 cycloalkyl group having one or more C.sub.1 -C.sub.4 
alkyl substituents. Typical C.sub.1 -C.sub.4 alkyl substituted C.sub.4 
-C.sub.8 cycloalkyl groups include cyclobutylmethyl, 2-cyclobutylpropyl, 
(2-methylcyclobutyl)methyl,2-cyclohexylethyl, and the like. 
C.sub.1 -C.sub.4 Alkyl substituted C.sub.4 -C.sub.8 cycloalkenyl represents 
a C.sub.4 -C.sub.8 cycloalkenyl group having one or more C.sub.1 -C.sub.4 
alkyl groups. Typical C.sub.1 -C.sub.4 alkyl substituted C.sub.4 -C.sub.8 
cycloalkenyl groups include cyclobutenylmethyl, cyclopropenylethyl, 
(2-ethylcyclohexenyl)methyl, and the like. 
C.sub.1 -C.sub.6 Alkoxy represents a straight or branched alkoxy chain 
having from one to six carbon atoms. Typical C.sub.1 -C.sub.6 alkoxy 
groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n-propoxy and 
the like. 
"Halo" or "halogen" represents fluoro, chloro, bromo or iodo. 
Thiophene means 2-thiophene or 3-thiophene. 
While all of the compounds of the present invention are useful opioid 
antagonists, certain of the present compounds are preferred for that use. 
Preferably, Z is 
##STR5## 
R.sup.1 R.sup.2 and R.sup.4 are hydrogen, and R.sup.3 is C.sub.4 -C.sub.8 
cycloalkyl, and especially cyclohexyl. Also, the compounds preferably 
exist as pharmaceutically acceptable salts. Other preferred aspects of the 
present invention will be noted hereinafter. 
The piperidines of the invention as illustrated in formula I occur as the 
trans stereochemical isomers by virtue of the substituents at the 3- and 
4-positions. More specifically, the alkyl or alkenyl group at the 
3-position is situated in a trans position relative to the methyl group at 
the 4-position. As such, the compounds can exist as the trans (+) isomer 
of the formula 
##STR6## 
or the trans (-) isomer of the formula 
##STR7## 
The present invention comtemplates both the individual trans (+) and (-) 
stereoisomers, as well as the racemic mixture of the trans stereoisomers. 
Also, when Z is 
##STR8## 
the carbon atom attached to the OR.sup.4 group is asymmetric. As such, 
this class of compounds can further exist as the individual R or S 
stereoisomers, or the racemic mixture of the isomers, and all are 
contemplated within the scope of the compounds of the present invention. 
The piperidines of this invention form pharmaceutically acceptable acid 
addition salts with a wide variety of inorganic and organic acids. The 
particular acid used in salt formation is not critical; however, the 
corresponding salt that is formed must be substantially non-toxic to 
animals. Typical acids generally used include sulfuric, hydrochloric, 
hydrobromic, phosphoric, hydroiodic, sulfamic, citric, acetic, maleic, 
malic, succinic, tartaric, cinnamic, benzoic, ascorbic, and related acids. 
The piperidines additionally form quaternary ammonium salts with a variety 
of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids, and 
the like. Among such esters are methyl chloride, ethyl bromide, propyl 
iodide, butyl bromide, allyl iodide, isobutyl chloride, benzyl bromide, 
dimethyl sulfate, diethyl sulfate, methyl benzensulfonate, ethyl 
toluenesulfonate, crotyl iodide, and the like. 
The compounds of the present invention may be prepared by a variety of 
procedures well known to those of ordinary skill in the art. The preferred 
procedure involves the reaction of a 
3-substituted-4-methyl-4-(3-substituted phenyl)piperidine with an 
appropriate acylating agent to provide the corresponding intermediate, 
which is reduced to the compound of the present invention under standard 
conditions. This reaction may be represented by the following scheme: 
##STR9## 
wherein R.sup.1, R.sup.2, R.sup.3 and Z are as defined above and X is 
--OH, or a good leaving group such as 
##STR10## 
C.sub.1 -C.sub.6 alkoxy or halogen. 
The first step of the above-described process wherein X is hydroxy 
necessitates the use coupling reagents commonly employed in the synthesis 
of peptides. Examples of such coupling reagents include the carbodiimides 
such as N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, or 
N,N'-diethylcarbodiimide; the imidazoles such as carbonyldiimidazole; as 
well as reagents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline 
(EEDQ). The direct coupling of a substituted carboxylic acid and a 
3-substituted-4-methyl-4-(3-substitutedphenyl)piperidine is carried out by 
adding about an equimolar quantity of the piperidine starting material to 
a solution of the carboxylic acid in the presence of an equimolar quantity 
or slight excess of coupling reagent. The reaction generally is carried 
out in an unreactive organic solvent such as dichloromethane or 
N,N-dimethylformamide, and usually is complete within about twenty-four 
hours when conducted at a temperature of about 0.degree. C. to about 
30.degree. C. The product is then typically isolated by filtration. The 
acylated product thus formed can be further purified, if needed, by any of 
several routine methods, including crystallization from common solvents, 
chromatography over solid supports such as silica or alumina, and related 
purification techniques. 
The reaction wherein X isother than hydroxy is conducted as follows. The 
preferred leaving group in this reaction is where X is halogen, especially 
chloro. The reaction can be carried out by combining the substituted 
carboxylic acid derivative with about an equimolar quantity of the 
3-substituted-4-methyl-4-(3-substituted phenyl)piperidine in a mutual 
solvent such tetrahydrofuran, diethyl ether, dichloromethane, dioxane, 
dimethylsulfoxide, N,N-dimethylformamide, benzene, toluene, and the like. 
If desired, a base can be utilized in the acylation reaction when X is 
halogen to act as an acid scavenger. Commonly used bases include sodium 
carbonate, potassium carbonate, pyridine, triethylamine and related bases. 
Bases such as pyridine act as their own solvent and need no additional 
solvent. The reaction generally is substantially complete after about two 
to about 200 hours when carried out at a temperature of about 20.degree. 
C. to about 200.degree. C., preferably from about 30.degree. C. to about 
100.degree. C. The product of the reaction may be isolated by simply 
removing the reaction solvent, for instance by evaporation under reduced 
pressure. Also, the reaction mixture may be added to water, and the 
product collected by filtration or extracted into a water immiscible 
solvent. The product thus isolated can be further purified, if desired, by 
any of several well known techniques. 
The acylated intermediates thus prepared are finally reduced according to 
standard procedures to provide the present compounds. Typical reducing 
agents suitable for use include the hydride reducing agents such as 
lithium aluminum hydride and sodium bis(2-methoxyethoxy)aluminum hydride, 
which is preferred. Typically, an excess of reducing agent is combined 
with the acylated intermediate in a mutual solvent. The reaction is 
substantially complete after about one to about 12 hours when conducted at 
a temperature in the range of about 20.degree. C. to about 100.degree. C. 
The desired product may then be isolated by procedures well known to those 
of ordinary skill in the art. 
The compounds of the present invention may also be prepared by the direct 
substitution of a halogen substituted compound with the 
3-substituted-4-methyl-4-(3-substituted phenyl)piperidine intermediate. 
This reaction is represented by the following scheme: 
##STR11## 
wherein R.sup.1, R.sup.2, R.sup.3 and Z are as defined above and Y is 
halogen. 
This reaction is conducted by combining approximately equimolar amounts of 
the two starting materials in a mutual solvent. A slight excess of the 
halogen substituted compound may be employed to ensure complete reaction. 
Typical mutual solvents suitable for use in this reaction include aprotic 
solvents such as N,N-dimethylformamide and the like. Further, the reaction 
is preferably conducted in the presence of a base, such as sodium 
bicarbonate, which acts as an acid scavenger for the hydrohalic acid which 
is formed as a by-product of the reaction. The reaction is generally 
complete after about 30 minutes to 24 hours when conducted at a 
temperature in the range of about 40.degree. C. to about 100.degree. C. 
The product is isolated and purified, if needed, by standard procedures. 
When R.sup.3 is an alkene group in the above reaction, the double bond can 
be subsequently reduced under standard conditions to provide an alkyl 
substituent. 
Compounds of the invention wherein Z is 
##STR12## 
may be prepared by the reaction of the 
3-substituted-4-methyl-4-(3-substituted phenyl)piperidine starting 
material with an appropriately substituted keto substituted alkene. This 
reaction is represented by the following scheme: 
##STR13## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above. 
This reaction is conducted by combining approximately equimolar quantities 
of the starting materials in a mutual solvent such as 
N,N-dimethylformamide. The reaction is substantially complete after about 
10 minutes to about 24 hours when conducted at a temperature in the range 
of about 20.degree. C. to about 150.degree. C. The product is isolated by 
standard procedures and purified, if desired, to provide a compound of the 
invention. 
Compounds of the invention wherein Z is 
##STR14## 
and R.sup.4 is hydrogen are preferably prepared by reducing the 
corresponding compound wherein Z is 
##STR15## 
with a standard reducing agent such as any of the hydride reducing agents, 
for example lithium aluminum hydride, sodium borohydride and the like. 
This reaction is conducted in a non-reactive solvent, with any residual 
water preferable removed, such as tetrahydrofuran, diethyl ether, and 
related solvents. The product is isolated by standard procedures. When 
R.sup.4 is C.sub.1 -C.sub.6 alkyl or benzyl, phenethyl, or phenpropyl, the 
alkali metal anion is formed with the R.sup.4 =hydrogen compound, and 
reacted with the corresponding halide derivative. When R.sup.4 is acyl, 
the R.sup.4 =hydrogen compound is acylated with an acyl halide, for 
example, according to standard acylation conditions. 
Salts of piperidines are prepared by methods commonly employed for the 
preparation of amine salts. In particular, acid addition salts of the 
piperidines are prepared by reaction of the piperidine with an appropriate 
acid of pKa less than about 4, generally in an unreactive organic solvent. 
Suitable acids include mineral acids such as hydrochloric, hydrobromic, 
hydroiodic, sulfuric, phosphoric, and like acids. Organic acids are also 
used, for example acetic acid, p-toluenesulfonic acid, chloroacetic acid, 
and the like. The usual solvents used in the reaction include acetone, 
tetrahydrofuran, diethyl ether, ethyl acetate, and the like. Quaternary 
salts can be prepared in generally the same way by reaction of the 
piperidne with an alkylsulfate or alkyl halide, for example, methyl 
sulfate, methyl iodide, ethyl bromide, propyl iodide, and the like. 
The 3-substituted-4-methyl-4-(3-hydroxy- or -alkanoyloxyphenyl)piperidine 
derivatives employed as starting materials in the synthesis of the 
compounds of the present invention are prepared by the general procedure 
taught by Zimmerman in U.S. Pat. No. 4,081,450, herein incorporated by 
reference. The compounds wherein R.sup.2 is hydrogen are preferably 
prepared by the procedure of Barnett in U.S. Pat. No. 4,581,456, herein 
incorporated by reference, but adjusted so that .beta.-stereochemistry is 
preferred, in contrast to the .alpha.-stereochemistry which is preferred 
by the process taught in the Barnett patent. According to the Barnett 
procedure, a 3-alkoxybromobenzene derivative is converted to the 
3-alkoxyphenyllithium analog by reaction with an alkyllithium reagent. The 
3-alkoxyphenyllithium derivative is reacted with a 1-alkyl-4-piperidone to 
provide the corresponding 1-alkyl-4-(3-alkoxyphenyl)piperidinol 
derivative. The piperidinol thus prepared is dehydrated with acid to 
provide the corresponding 1-alkyl-4-(3-alkoxyphenyl)tetrahydropyridine 
derivative, which readily undergoes a metalloenamine alkylation to provide 
the appropriate 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine 
derivative. The compound thus prepared is converted to a 
1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine upon 
reaction with formaldehyde, an appropriate amine and sulfuric acid. Next, 
the methanamine is catalytically hydrogenated to the 
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine, which is finally 
dealkylated at the 1-position, and the methoxy group is converted to a 
hydroxy group at the 3-position of the phenyl ring to provide the 
3,4-dimethyl-4-(3-hydroxyphenyl)piperidine starting material employed in 
the present invention. This reaction sequence will be readily understood 
by the following scheme: 
##STR16## 
wherein R.sup.6 is C.sub.1 -C.sub.3 alkoxy, R.sup.7 is C.sub.1 -C.sub.6 
alkyl, R.sup.8 is C.sub.1 -C.sub.4 alkyl, R.sup.9 and R.sup.10 
independently are C.sub.1 -C.sub.3 alkyl or, when taken together with the 
nitrogen atom to which they are attached, form piperidine, piperazine, 
N-methylpiperazine, morpholine or pyrrolidine, and Y is halogen. 
The first step of the above-described process involves the formation of the 
3-alkoxyphenyllithium reagent by reacting 3-alkoxybromobenzene with an 
alkyllithium reagent. This reaction is typically performed under inert 
conditions and in the presence of a suitable non-reactive solvent such as 
dry diethyl ether or preferably dry tetrahydrofuran. Preferred 
alkyllithium reagents used in this process are n-butyllithium, and 
especially sec.-butyllithium. Generally, approximately an equimolar to 
slight excess of alkyllithium reagent is added to the reaction mixture. 
The reaction is conducted at a temperature between about -20.degree. C. 
and about -100.degree. C., more preferably from about -50.degree. C. to 
about -55.degree. C. 
Once the 3-alkoxyphenyllithium reagent has formed, approximately an 
equimolar quantity of a 1-alkyl4-piperidone is added to the mixture while 
maintaining the temperature between -20.degree. C. and -100.degree. C. The 
reaction is typically complete after about 1 to 24 hours. At this point, 
the reaction mixture is allowed to gradually warm to room temperature. The 
product is isolated by the addition to the reaction mixture of a saturated 
sodium chloride solution in order to quench any residual lithium reagent. 
The organic layer is separated and further purified if desired to provide 
the appropriate 1-alkyl-4-(3-alkoxyphenyl)piperidinol derivative. 
The dehydration of the 4-phenylpiperidinol prepared above is accomplished 
with a strong acid according to well known procedures. While dehydration 
occurs in various amounts with any one of several strong acids such as 
hydrochloric acid, hydrobromic acid, and the like, dehydration is 
preferably conducted with phosphoric acid, or especially p-toluenesulfonic 
acid and toluene or benzene. This reaction is typically conducted under 
reflux conditions, more generally from about 50.degree. C. to about 
150.degree. C. The product thus formed is generally isolated by basifying 
an acidic aqueous solution of the salt form of the product and extracting 
the aqueous solution with any one of several water immiscible solvents. 
The resulting residue following evaporation may then be further purified 
if desired. 
The 1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine derivatives are 
prepared by a metalloenamine alkylation. This reaction is preferably 
conducted with n-butyllithium in tetrahydrofuran under an inert 
atmosphere, such as nitrogen or argon. Generally, a slight excess of 
n-butyllithium is added to a stirring solution of the 
1-alkyl-4-(3-alkoxyphenyl)tetrahydropyridine in THF cooled to a 
temperature in the range of from about -50.degree. C. to about 0.degree. 
C., more preferably from about -20.degree. C. to about -10.degree. C. This 
mixture is stirred for approximately 10 to 30 minutes followed by the 
addition of approximately from 1.0 to 1.5 equivalents of methyl halide to 
the solution while maintaining the temperature of the reaction mixture 
below 0.degree. C. After about 5 to 60 minutes, water is added to the 
reaction mixture and the organic phase is collected. The product may be 
purified according to standard procedures, but it is desirable to purify 
the crude product by either distilling it under vacuum or slurrying it in 
a mixture of hexane:ethyl acetate (65:35, v:v) and silica gel for about 
two hours. According to the latter procedure, the product is then isolated 
by filtration and evaporating the filtrate under reduced pressure. 
The next step in the process involves the application of the Mannich 
reaction of aminomethylation to non-conjugated, endocyclic enamines. This 
reaction is carried out by combining from about 1.2 to 2.0 equivalents of 
aqueous formaldehyde and about 1.3 to 2.0 equivalents of the secondary 
amine NHR.sup.9 R.sup.10 in a suitable solvent. While water is the 
preferred solvent, other non-nucleophilic solvents such as acetone and 
acetonitrile may also be employed in this reaction. The pH of this 
solution is adjusted to approximately 3.0-4.0 with an acid which provides 
a non-nucleophilic anion. Examples of such acids include sulfuric acid, 
the sulfonic acids such as methanesulfonic acid and p-toluenesulfonic 
acid, phosphoric acid, and tetrafluoroboric acid. The preferred acid is 
sulfuric acid. To this solution is added one equivalent of a 
1-alkyl-4-methyl-4-(3-alkoxyphenyl)tetrahydropyridine, typically dissolved 
in aqueous sulfuric acid, and the pH of the solution readjusted to from 
3.0-3.5 with the non-nucleophilic acid or a secondary amine as defined 
above. While maintenance of this pH during the reaction is preferred for 
optimum results, this reaction may be conducted at a pH in the range of 
from about 1.0 to 5.0. The reaction is substantially complete after about 
1 to 4 hours, more typically about 2 hours, when conducted at a 
temperature in the range of from about 50.degree. C. to about 80.degree. 
C., more preferably at about 70.degree. C. The reaction is next cooled to 
approximately 30.degree. C. and added to a sodium hydroxide solution. This 
solution is extracted with a water immiscible organic solvent, such as 
hexane or ethyl acetate, and the organic phase, following thorough washing 
with water to remove any residual formaldehyde, is evaporated to dryness 
under reduced pressure. 
The next step of the process involves the catalytic hydrogenation of the 
1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine 
prepared above to the corresponding trans 
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine. This reaction actually 
occurs in two steps. The first step is the hydrogenolysis reaction wherein 
the exo C--N bond is reductively cleaved thereby generating the 
3-methyltetrahydropyridine. In the second step, the 2,3-double bond in the 
tetrahydropyridine ring is reduced thereby affording the desired 
piperidine ring. 
Reduction of the enamine double bond introduced the crucial relative 
stereochemistry at the 3 and 4 carbon atoms of the piperidine ring. The 
reduction does not occur with complete stereoselectivity. The catalysts 
employed in the process are chosen from among the various palladium and 
preferably platinum catalysts. 
The catalytic hydrogenation step of the process is preferably conducted in 
an acidic reaction medium. Suitable solvents for use in the process 
include the alcohols, such as methanol or ethanol, as well as ethyl 
acetate, tetrahydrofuran, toluene, hexane, and the like. 
Proper stereochemical outcome has been shown to be dependent on the 
quantity of catalyst employed. The quantity of catalyst required to 
produce the desired stereochemical result is dependent upon the purity of 
the starting materials in regard to the presence or absence of various 
catalyst poisons. 
The hydrogen pressure in the reaction vessel is not critical but may be in 
the range of from about 5 to 200 psi. Concentration of the starting 
material by volume should preferably be around 20 ml. of liquid per gram 
of starting material, although an increased or decreased concentration of 
the starting material could also be employed. Under the conditions 
specified herein, the length of time for the catalytic hydrogenation is 
not critical because of the inability for over-reduction of the molecule. 
While the reaction may continue for up to 24 hours or longer, it is not 
necessary to continue the reduction conditions after the uptake of the 
theoretical two moles of hydrogen. The product is isolated by filtering 
the reaction mixture through infusorial earth and evaporating the filtrate 
to dryness under reduced pressure. Further purification of the product 
thus isolated is not necessary and preferably the diastereomeric mixture 
is carried directly on to the following reaction. 
The alkyl substituent is next removed from the 1-position of the piperidine 
ring by standard dealkylation procedures. Preferably, a chloroformate 
derivative, especially the vinyl or phenyl derivatives, are employed and 
removed with acid. Next, the alkoxy compound prepared above is 
demethylated to the corresponding phenol. This reaction is generally 
carried out by reacting the compound in a 48% aqueous hydrobromic acid 
solution. This reaction is substantially complete after about 30 minutes 
to 24 hours when conducted at a temperature between 50.degree. C. to about 
150.degree. C., more preferably at the reflux temperature of the reaction 
mixture. The mixture is then worked up by cooling the solution, followed 
by neutralization with base to an approximate pH of 8. This aqueous 
solution is extracted with a water immiscible organic solvent. The residue 
following evaporation of the organic phase is then preferably used 
directly in the following step. 
The compounds employed as starting materials to the compounds of the 
invention may also be prepared by brominating the 
1-alkyl-4-methyl-4-(3-alkoxyphenyl)-3-tetrahydropyridinemethanamine 
prepared above at the 3-position, lithiating the bromo intermediate thus 
prepared, and reacting the bromo intermediate with the halide R.sup.2 
CH.sub.2 Y to provide the corresponding 
1-alkyl-3-substituted-4-methyl-4-(4-alkoxyphenyl)tetrahydropyridinemethana 
mine. This compound is then reduced and converted to the starting material 
as indicated above. 
As noted above, the compounds of the present invention may exist as the 
resolved stereoisomers. The preferred procedure employed to prepare the 
resolved starting materials used in the synthesis of these compounds 
includes treating a 1,3-dialkyl-4-methyl-4-(3-alkoxyphenyl)piperidine with 
either (+)- or (-)-dibenzoyl tartaric acid to provide the resolved 
intermediate. This compound is dealkylated at the 1-position with vinyl 
chloroformate and finally converted to the desired 
4-(3-hydroxyphenyl)piperidine isomer. This reaction is set forth in the 
following scheme: 
##STR17## 
wherein R.sup.2, R.sup.6 and R.sup.8 are as defined above. 
As will be understood by those skilled in the art, the individual trans 
stereoisomers of the invention may also be isolated with either (+)- or 
(-)-dibenzoyl tartaric, as desired, from the corresponding racemic mixture 
of the trans isomer compounds of the invention. 
The following Examples further illustrate certain of the compounds of the 
present invention, and methods for their preparation. The Examples are not 
intended to be limiting to the scope of the invention in any respect, and 
should not be so construed.

EXAMPLE 1 
trans-(+)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
A. trans-(+)-1-(n-Hexanoyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
A 250 ml round bottom flask was charged with 2.0 g (9.76 mmol) of 
trans-(+)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine, 100 ml of 
N,N-dimethylformamide and 2.90 g (4 ml, 28.8 mmol) of triethylamine. To 
the mixture was added 3.94 g (29.63 mmol) of hexanoyl chloride. The 
reaction mixture was refluxed for approximately two hours and cooled to 
room temperature. The mixture was poured into 400 ml of water and 
extracted with diethyl ether three times. The ether extracts were combined 
and washed with 1N hydrochloric acid and a saturated sodium chloride 
solution. The organic phase was dried over anhydrous sodium sulfate and 
filtered. The filtrate was concentrated under vacuum and the resulting 
residue containing 
trans-(+)-1-(n-hexanoyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine was 
used directly in the following reaction. 
B. 
A 250 ml round bottom flask was charged with 10 ml of Red-Al (sodium 
bis(2-methoxyethoxy)aluminum hydride from Aldrich Chemical Company, 
Milwaukee, Wis.) and 20 ml of toluene. To the mixture was added dropwise a 
solution of the residue isolated above dissolved in approximately 50 ml of 
toluene. The reaction was stirred for approximately 60 minutes at room 
temperature and quenched by the addition of 400 ml of a pH 10 buffer. The 
pH of the mixture was adjusted to approximately 9.8 with 1N hydrochloric 
acid and the mixture was extracted with toluene. The organic extracts were 
combined and dried over anhydrous sodium sulfate. The filtrate was 
concentrated under vacuum and the resulting residue was chromatographed 
over silica gel while eluding with hexane:ethyl acetate (1.5:1, v:v). 
Fractions containing the major component were combined and the solvent was 
evaporated therefrom to provide the desired compound as the free base. The 
base was dissolved in diethyl ether and combined with hydrochloric acid to 
provide trans-(+)-1-(n-hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride. 
Analysis calculated for C.sub.19 H.sub.31 ClNO: Theory: C, 70.02; H, 9.90; 
N, 4.30; Found: C, 70.27; H, 9.99; N, 4.48. 
H-NMR (CDCl.sub.3): .delta. 7.30-6.62 (m, 4H); 2.91-1.40 (m, 11H); 1.32 (s, 
6H); 1.29 (s, 3H); 0.88 (m, 3H); 0.76 (d, 3H, J=7 Hz). 
Examples 2-7 were prepared by the general procedure set forth in Example 1. 
EXAMPLE 2 
trans-(-)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.19 H.sub.31 ClNO: Theory: C, 70.02; H, 9.90; 
N, 4.30; Found: C, 70.09; H, 9.81; N, 4.42. 
H-NMR (CDCl.sub.3): .delta. 7.30-6.62 (m, 4H); 2.91-1.40 (m, 11H); 1.32 (s, 
6H); 1.29 (s, 3H); 0.88 (m, 3H); 0.76 (d, 3H, J=7 Hz). 
EXAMPLE 3 
trans-(.+-.)-1-(4-Methyl-4-pentenyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperi 
dine hydrochloride, mp=95.degree.-105.degree. C. 
Analysis calculated for C.sub.19 H.sub.30 ClNO: Theory: C, 70.45; H, 9.34; 
N, 4.32; Found: C, 70.52; H, 9.34; N, 4.23. 
H-NMR (CDCl.sub.3): .delta. 0.76 (3H, d, J=7 Hz); 1.3 (3H, s); 1.72 (3H, 
s); 4.7 (2H, d, J=5 Hz); 6.64 (1H, dd); 6.77 (1H, s); 6.86 (1H, d, J=7 
Hz); 7.18 (1H, t, J=6 Hz). 
EXAMPLE 4 
trans-(.+-.)-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride, mp=175.degree.-177.degree. C. 
Analysis calculated for C.sub.20 H.sub.36 ClNO: Theory: C, 70.66; H, 10.08; 
N, 4.12; Found: C, 71.00; H, 9.84; N, 4.44. 
H-NMR (CDCl.sub.3): .delta. 7.30-6.60, (m, 4H); 3.66-1.12 (m, 20H); [1.10 
(d, J=7H2), 0.97 (d, J=7H2), 3H]; 0.90-0.76 (m, 5H). 
EXAMPLE 5 
trans-(.+-.)-1-(Cyclopentylmethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidi 
ne hydrochloride 
Analysis calculated for C.sub.19 H.sub.31 ClNO: Theory: C, 70.45; H, 9.34; 
N, 4.32; Found: C, 70.68; H, 9.14; N, 4.58. 
H-NMR (CDCl.sub.3): .delta. 7.31-6.64 (m, 4H); 3.70-1.42 (m, 18H); [1.40 
(s), 1.36 (s), 3H]; [1.10 (d, J=8 Hz), 1.00 (d, J=8 Hz), 3H] ppm 
EXAMPLE 6 
trans-(.+-.)-1-(2-Cyclopentylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperid 
ine hydrochloride 
H-NMR (CDCl.sub.3): .delta. 0.76 (3H, d, J=7 Hz) 1.32 (3H, s); 2.8-2.9 (1H, 
m); 6.65 (1H, m); 6.75 (1H, s); 6.85 (1H, d, J=8 Hz); 7.15 (1H, t, J=6 
Hz). 
EXAMPLE 7 
trans-(.+-.)-1-[2-(2-Cyclopenten-1-yl)ethyl]-3,4-dimethyl-4-(3-hydroxypheny 
l)piperidine hydrochloride, mp=100.degree.-130.degree. C. 
Analysis calculated for C.sub.20 H.sub.30 ClNO: Theory: C, 71.51; H, 9.00; 
N, 4.17; Found: C, 71.25; H, 8.92; N, 4.29. 
H-NMR (CDCl.sub.3): .delta. 0.75 (3H, d, J=6 Hz); 1.32 (3H, s); 5.72 (2H, 
m); 6.65 (1H, d, J=7 Hz); 6.75 (1H, s); 6.85 (1H, d, J=6 Hz); 7.16 (1H, t, 
J=7 Hz). 
EXAMPLE 8 
trans-(.+-.)-1-(n-Heptyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
To a solution of 1.0 g (0.0049 mol) of 
trans-(.+-.)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine and 1.25 g (0.012 
mol) of triethylamine in 20 ml of N,N-dimethylformamide was added 1.8 g 
(0.012 mol) of heptanoyl chloride. The reaction mixture was stirred at 
room temperature for approximately one hour and poured into 200 ml of 
water. The resulting mixture was extracted five times with 100 ml portions 
of ethyl acetate, and the organic phases were combined. The organic 
solution was washed with 200 ml of 1N hydrochloric acid, 200 ml of a 
saturated sodium bicarbonate solution, and 200 ml of brine, and dried over 
a mixture of sodium chloride and anhydrous sodium sulfate. The dried 
organic solution was concentrated under vacuum and the residue was 
dissolved in diethyl ether. This solution was cooled to approximately 
0.degree. C. and 600 mg (0.016 mol) of lithium aluminum hydride was added. 
The mixture was stirred at room temperature for one hour and 0.6 ml of 
water was added, followed by the addition of 1.8 ml of 15% sodium 
hydroxide and 0.6 ml of water. The solution was filtered and the filtrate 
was dried over sodium chloride and anhydrous sodium sulfate. The organic 
phase was evaporated under vacuum and the residue was chromatographed over 
silica gel employing hexane:ethyl acetate (3:1, v:v) containing 0.5% by 
volume of triethylamine as the eluent. Fractions containing the major 
component were combined and the solvent was evaporated therefrom. The 
hydrochloride salt was prepared to provide the title compound. 
mp=155.degree.-157.degree. C. 
Analysis calculated for C.sub.20 H.sub.34 ClNO: Theory: C, 70.66; H, 10.08; 
N, 4.12; Found: C, 70.83; H, 9.79; N, 3.89. 
H-NMR (CDCl.sub.3): .delta. 7.28-6.48 (m, 4H); 1.28 (s, 3H); 0.85 (m, 3H); 
0.75 (d, 3H, J=7 Hz). 
Examples 9-12 were prepared by the general procedure set forth in Example 
8. 
EXAMPLE 9 
trans-(.+-.)-1-(3-Cyclopentylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperi 
dine hydrochloride, mp=171.degree.-174.degree. C. 
Analysis calculated for C.sub.21 H.sub.24 ClNO: Theory: C, 71.66; H, 9.74; 
N, 3.98; Found: C, 71.53; H, 9.46; N, 4.06. 
H-NMR (CDCl.sub.3): .delta. 7.19-6.48 (m, 4H); 3.60 (t, 2H, J=7 Hz); 1.25 
(s, 3H); 0.78 (d, 3H, J=7 Hz). 
EXAMPLE 10 
trans-(.+-.)-1-(Cyclohexylmethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidin 
e hydrochloride, mp=80.degree. C. 
Analysis calculated for C.sub.20 H.sub.32 ClNO: Theory: C, 71.08; H, 9.55; 
N, 4.14; Found: C, 70.85; H, 9.48; N, 3.78. 
H-NMR (CDCl.sub.3): .delta. 7.20-6.49 (m, 4H); 3.44 (d, 2H, J=7 Hz); 1.28 
(s, 3H); 0.76 (d, 3H, J=7 Hz). 
EXAMPLE 11 
trans-(.+-.)-1-(3-Cyclohexylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperid 
ine hydrochloride, mp=195.degree.-197.degree. C. 
Analysis calculated for C.sub.22 H.sub.36 ClNO: Theory: C, 72.20; H, 9.92; 
N, 3.83; Found: C, 71.98; H, 9.79; N, 3.85. 
H-NMR (CDCl.sub.3): .delta. 7.19-6.48 (m, 4H); 3.60 (t, 2H, J=7 Hz); 1.28 
(s, 3H); 0.75 (d, 3H, J=7 Hz). 
EXAMPLE 12 
trans-(.+-.)-1-(3,3-Dimethylbutyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidi 
ne hydrochloride, mp=198.degree.-200.degree. C. 
Analysis calculated for C.sub.19 H.sub.32 ClNO: Theory: C, 70.02; H, 9.90; 
N, 4.30; Found: C, 70.19; H, 9.66; N, 4.38. 
H-NMR (CDCl.sub.3): .delta. 7.22-6.59 (m, 4H); 3.70-1.66 (m, 11H); 1.59 (s, 
3H); [1.42 (s), 1.37 (s) 3H]; [1.16 (d, J=7H2), 1.02 (d, J=7H2) 3H]; 0.99 
(s, 3H); 0.91 (s, 3H). 
EXAMPLE 13 
trans-(.+-.)-1-(2-Cyclohexylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)-piperid 
ine hydrochloride 
To a solution of 500 mg (2.4 mmol) of 
trans-(.+-.)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine dissolved in 50 ml 
of N,N-dimethylformamide was added 244 mg (2.9 mmol) of sodium bicarbonate 
and 554 mg (2.9 mmol) of 2-cyclohexylethylbromide. The reaction mixture 
was refluxed for one hour and cooled to room temperature. The mixture was 
poured into ice and the pH was adjusted to about 9.8. The mixture was 
extracted with diethyl ether and the organic phases were combined and 
dried over anhydrous potassium carbonate. The solvent was evaporated under 
vacuum to provide 690 ml of crude material. The hydrochloride salt was 
prepared to provide a total of 330 mg of 
cis-(.+-.)-1-(2-cyclohexylethyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidin 
e hydrochloride. mp=178.degree.-180.degree. C. 
Analysis calculated for C.sub.21 H.sub.34 ClNO: Theory: C, 71.66; H, 9.74; 
N, 3.98; Found: C, 71.36; H, 9.93; N, 4.23. 
H-NMR (CDCl.sub.3): .delta. 0.77 (3H, d, J=6 Hz); 1.32 (3H, s); 1.48-1.78 
(10H, m); 6.64 (1H, dd); 6.78 (1H, s); 6.87 (1H, d, J=6 Hz); 7.18 (1H, t, 
J=6 Hz). 
Examples 14-16 were prepared by the general procedure outlined in Example 
13. 
EXAMPLE 14 
trans-(.+-.)-1-(n-Pentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.18 H.sub.30 ClNO: Theory: C, 69.32; H, 9.70; 
N, 4.49; Found: C, 69.43; H, 9.85; N, 4.67. 
H-NMR (CDCl.sub.3): .delta.0.75 (3H, d, J=6 Hz); 0.88 (3H, t, J=6 Hz); 1.3 
(3H, s); 1.98 (1H, m); 6.64 (1H, dd); 6.75 (1H, s); 6.83 (1H, d, J=7 Hz); 
7.15 (1H, t, J=9 Hz). 
EXAMPLE 15 
trans-(.+-.)-1-(4-Methylpentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.19 H.sub.32 ClNO: Theory: C, 70.02; H, 9.90; 
N, 4.30; Found: C, 69.89; H, 9.77; N, 4.27. 
H-NMR (CHCl.sub.3): .delta.0.77 (3H, d, J=7 Hz); 0.88 (6H, d, J=7 Hz); 1.32 
(3H, s); 6.62 (1H, dd); 6.76 (1H, s); 6.83 (1H, d, J=6 Hz); 7.15 (1H, t, 
J=6 Hz). 
EXAMPLE 16 
trans-(.+-.)-1-(3-Methylbutyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride, mp=155.degree.-158.degree. C. 
Analysis calculated for C.sub.18 H.sub.30 ClNO: Theory: C, 69.32; H, 9.70; 
N, 4.49; Found: C, 69.50; H, 9.66; N, 4.45. 
H-NMR (CDCl.sub.3): .delta.0.77 (3H, d, J=6 Hz); 0.89 (6H, d, J=6 Hz); 6.62 
(1H, dd); 6.78 (1H, s); 6.87 (1H, d, J=6 Hz); 7.15 (1H, t, J=7 Hz). 
EXAMPLE 17 
trans-(.+-.)-1-(1-Cyclopentylpropanon-3-yl)-3,4-dimethyl-4-(3-hydroxyphenyl 
)piperidine hydrochloride, mp=80.degree.-100.degree. C. 
To a solution of 1.0 g of 
trans-(.+-.)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine in 60 ml of 
N,N-dimethylformamide was added to 5.0 g of 3-cyclopentylpropen-3-one. The 
mixture was stirred at room temperature for 3 hours and poured into a 
mixture of diethylether and water. The mixture was washed with a saturated 
sodium chloride solution and the organic phase was separated, dried over 
anhydrous potassium carbonate and concentrated under vacuum to provide 1.8 
g of the free base. This material was purified over a silicone dioxide 
resin and converted to the hydrochloride salt to provide the desired 
compound. The elemental analysis was calculated for the free base. 
Analysis calculated for C.sub.21 H.sub.31 NO.sub.2 : Theory: C, 76.55; H, 
9.48; N, 4.25; Found: C, 76.28; H, 9.59; N, 4.12. 
H-NMR (CDCl.sub.3): .delta.0.74 (3H, d, J=7 Hz); 1.30 (3H, s); 6.63 (1H, d, 
J=8 Hz); 6.74 (1H, s); 6.84 (1H, d, J=6 Hz); 7.16 (1H, t, J=6 Hz). 
EXAMPLE 18 
trans-(.+-.)-1-[R,S-(1-Cyclopentylpropanol-3-yl)]-3,4-dimethyl-4-(3-hydroxy 
phenyl)piperidine hydrochloride 
To a solution of 
trans-(.+-.)-1-(1-cyclopentylpropanon-3-yl)-3,4-dimethyl-4-(3-hydroxypheny 
l)piperidine in 100 ml of dry diethyl ether was added 2.0 ml of 1M lithium 
aluminum hydride in THF. The mixture was refluxed for 90 minutes and 
cooled to about 0.degree. C. Five milliliters of ethyl acetate were added 
to the mixture followed by sufficient water to result in a 
crystallization. The solid was decanted and the resulting filtrate was 
dried over anhydrous potassium carbonate. The filtrate was concentrated 
under vacuum and converted to the hydrochloride salt to provide the 
desired compound. The elemental analysis was calculated for the free base. 
Analysis calculated for C.sub.21 H.sub.33 NO.sub.2 : Theory: C, 76.09; H, 
10.03; N, 4.23; Found: C, 76.07; H, 10.09; N, 4.01. 
H-NMR (CDCl.sub.3): .delta.0.54 (3H, d, J=6 Hz); 1.28 (3H, s); 3.62 (1H, q, 
J=10 Hz); 6.6 (1H, d, J=8 Hz); 6.71 (2H, t, J=9 Hz); 7.1 (1H, t, J=9 Hz); 
7.47 (1H, broad singlet). 
Examples 9-34 were prepared by the general procedures outlined above. 
EXAMPLE 19 
trans-(.+-.)-1-(3-Oxo-4-methylpentyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piper 
idine hydrochloride 
Analysis calculated for C.sub.19 H.sub.30 ClNO.sub.2 : Theory: C, 67.14; H, 
8.90; N, 4.12; Found: C, 67.43; H, 8.83; N, 3.82. 
EXAMPLE 20 
trans-(.+-.)-1-[R,S-(3-Hydroxy-4-methylpentyl)]-3,4-dimethyl-4-(3-hydroxyph 
enyl)piperidine hydrochloride 
Analysis calculated for C.sub.19 H.sub.32 ClNO.sub.2 : Theory: C, 66.74; H, 
9.43; N, 4.10; Found: C, 66.54; H, 9.45; N, 4.30. 
H-NMR (CDCl.sub.3): .delta.0.6 (3H, t, J=6 Hz); 0.92 (3H, t, J=4 Hz); 0.98 
(3H, t, J=5 Hz); 1.3 (3H, s); 6.62 (1H, d, J=8 Hz); 6.74 (2H, m); 7.12 
(1H, t, J=6 Hz); 7.4-7.2 (1H, broad singlet). 
EXAMPLE 21 
trans-(.+-.)-1-(5-n-Hexenyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.19 H.sub.30 ClNO: Theory: C, 70.45; H, 9.34; 
N, 4.32; Found: C, 70.68; H, 9.13; N, 4.16. 
H-NMR (CDCl.sub.3): .delta.0.77 (3H, d, J=6 Hz); 1.3 (3H, s); 4.92-5.06 
(2H, m); 5.74-5.9 (1H, m); 6.64 (1H, m); 6.76 (1H, s); 6.85 (1H, d, J=7 
Hz); 7.16 (1H, t, J=7 Hz). 
EXAMPLE 22 
trans-(.+-.)-1-(n-Hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.19 H.sub.32 ClNO: Theory: C, 70.02; H, 9.90; 
N, 4.30; Found: C, 69.79; H, 10.15; N, 4.17. 
H-NMR (CDCl.sub.3): .delta.0.76 (3H, d, J=6 Hz); 0.82-0.92 (3H, broad 
triplet); 1.3 (3H, s); 6.63 (1H, m); 6.75 (1H, s); 6.85 (1H, d, J=7 Hz); 
7.17 (1H, t, J=7 Hz). 
EXAMPLE 23 
trans-(+)-1-[S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphe 
nyl)piperidine, mp=142.degree.-143.degree. C. 
Analysis calculated for C.sub.22 H.sub.35 NO.sub.2 : Theory: C, 76.48; H, 
10.21; N, 4.05; Found: C, 76.64; H, 10.48; N, 4.17. 
EXAMPLE 24 
trans-(-)-1-[S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphe 
nyl)piperidine, mp=151.degree.-152.degree. C. 
[.alpha.].sub.589 =-64.9655, [.alpha.].sub.365 =-211.655. 
Analysis calculated for C.sub.22 H.sub.35 NO.sub.2 : Theory: C, 76.48; H, 
10.21; N, 4.05; Found: C, 76.71; H, 10.43; N, 4.05. 
EXAMPLE 25 
trans-(+)-1-[R-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphe 
nyl)piperidine, mp=150.degree.-151.degree. C. 
[.alpha.].sub.589 =+73.6069, [.alpha.].sub.365 =+238.963. 
Analysis calculated for C.sub.22 H.sub.35 NO.sub.2 : Theory: C, 76.48; H, 
10.21; N, 4.05; Found: C, 76.24; H, 9.92; N, 4.18. 
EXAMPLE 26 
trans-(-)-1-[R-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydroxyphe 
nyl)piperidine, mp=141.degree.-143.degree. C. 
[.alpha.].sub.589 =-68.81, [.alpha.].sub.365 =-223.88,. 
Analysis calculated for C.sub.22 H.sub.35 NO.sub.2 : Theory: C, 76.48; H, 
10.21; N, 4.05; Found: C, 76.40; H, 10.35; N, 4.01. 
EXAMPLE 27 
trans-(.+-.)-1-[R,S-(3-Hydroxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydro 
xyphenyl)piperidine hydrochloride 
Analysis calculated for C.sub.22 H.sub.36 ClNO.sub.2 : Theory: C, 69.18; H, 
9.50; N, 3.67; Found: C, 68.97; H, 9.37; N, 3.70. 
EXAMPLE 28 
trans-(+-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
[.alpha.].sub.365 =+195.429. 
Analysis calculated for C.sub.20 H.sub.34 ClNO: Theory: C, 70.66; H, 10.08; 
N, 4.12; Found: C, 70.42; H, 9.95; N, 4.09. 
EXAMPLE 29 
trans-(-)-1-(5-Methylhexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
[.alpha.].sub.365 =-207.669 
Analysis calculated for C.sub.20 H.sub.34 ClNO: Theory: C, 70.66; H, 10.08; 
N, 4.12; Found: C, 70.40; H, 10.31; N, 4.32. 
EXAMPLE 30 
trans-(.+-.)-1-[R,S-(3-Hydroxyhexyl)]-3,4-dimethyl-4-(3-hydroxyphenyl)piper 
idine hydrochloride 
Analysis calculated for C.sub.19 H.sub.32 ClNO.sub.2 : Theory: C, 66.74; H, 
9.43; N, 4.10; Found: C, 66.90; H, 9.20; N, 4.19. 
EXAMPLE 31 
trans-(.+-.)-1-[R,S-(3-Methoxy-3-cyclohexylpropyl)]-3,4-dimethyl-4-(3-hydro 
xyphenyl)piperidine hydrochloride mp=171.degree.-173.degree. C. 
Analysis calculated for C.sub.23 H.sub.38 ClNO.sub.2 : Theory: C, 69.76; H, 
9.67; N, 3.54; Found: C, 70.00; H, 9.93; N, 3.45. 
EXAMPLE 32 
trans-(.+-.)-1-(3-Oxo-n-octyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride, mp=122.degree.-123.degree. C. 
Analysis calculated for C.sub.21 H.sub.34 ClNO.sub.2 : Theory: C, 68.55; H, 
9.31; N, 3.81; Found: C, 68.82; H, 9.51; N, 3.71. 
EXAMPLE 33 
trans-(.+-.)-1-(3-Oxo-3-cyclohexylpropyl)-3,4-dimethyl-4-(3-hydroxyphenyl)p 
iperidine hydrochloride, mp=170.degree.-173.degree. C. 
Analysis calculated for C.sub.22 H.sub.35 ClNO.sub.2 : Theory: C, 69.54; H, 
9.02; N, 3.69; Found: C, 69.39; H, 8.84; N, 3.85. 
EXAMPLE 34 
trans-(.+-.)-1-(3-Oxo-n-hexyl)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine 
hydrochloride 
Analysis calculated for C.sub.19 H.sub.30 ClNO.sub.2 : Theory: C, 69.14; H, 
8.96; N, 4.12; Found: C, 69.36; H, 8.85; N, 4.34. 
EXAMPLE 35 
trans-(.+-.)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperi 
dine hydrochloride 
A. 3-(2-Thienyl)propionyl chloride 
To a solution of 5.0 g (0.032 mol) of 3-(2-thienyl)propionic acid in 2 ml 
of methylene chloride and 25 ml of oxalyl chloride was added three drops 
of N,N-dimethylformamide slowly. Following evolution of the gas the 
reaction mixture was concentrated under vacuum and 20 ml of hexane was 
added to the residue. The resulting mixture was filtered and the filtrate 
was concentrated under vacuum. The resulting compound, 
3-(2-thienyl)propionyl chloride, was used directly in the following 
reaction. 
B. 
To a solution of 1.0 g (4.9 mmol) of 
trans-(.+-.)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine and 2.6 g of 
1,8-bis(dimethylamino)naphthalene dissolved in 30 ml of 
N,N-dimethylformamide was added a solution of 2.2 g (0.0126 mol) of 
3-(2-thienyl)propionyl chloride dissolved in 20 ml of 
N,N-dimethylformamide dropwise. The reaction mixture was stirred at room 
temperature for approximately one hour and poured into 250 ml of water. 
The mixture was extracted with five 100 ml portions of ethyl acetate. The 
organic extracts were combined, washed with 1N hydrochloric acid, an 
aqueous saturated sodium bicarbonate solution, and a saturated sodium 
chloride solution and dried over a mixture of sodium chloride and 
anhydrous sodium sulfate. The organic phase was evaporated under vacuum 
and the residue was dissolved in 200 ml of toluene. This mixture was 
evaporated and the residue was dissolved in 50 ml of tetrahydrofuran. The 
mixture was cooled to about 0.degree. C., a solution of 5 ml of Red-Al 
(3.4M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene 
from Aldrich Chemical Company, Milwaukee, Wis.) in 50 ml of 
tetrahydrofuran was added. The resulting mixture was stirred at toom 
temperature for approximately one hour and 100 ml of pH 10 buffer was 
added. This solution was extracted with two 100 ml portions of ethyl 
acetate. The organic extracts were combined, washed with an aqueous 
saturated sodium chloride solution and dried over sodium chloride and 
anhydrous sodium sulfate. The organic solution was evaporated under vacuum 
and the residue was dissolved in 50 ml of ethyl acetate. The mixture was 
extracted with two 100 ml portions of 1N hydrochloric acid and the acidic 
extracts were combined and washed with diethyl ether. The pH of the 
aqueous mixture was adjusted to about 9.8 with sodium hydroxide, and the 
aqueous mixture was extracted twice with a total of 200 ml ethyl acetate. 
The extracts were combined and washed with an aqueous saturated sodium 
chloride solution, dried over sodium chloride and anhydrous sodium sulfate 
and concentrated under vacuum. The resulting residue was chromatographed 
employing hexane:ethyl acetate (3:1, v:v) containing 0.5% triethylamine by 
volume as the eluant. The hydrochloride salt was prepared to provide the 
title compound. mp=101.degree.-103.degree. C. 
Analysis calculated for C.sub.20 H.sub.28 ClNOS: Theory: C, 65.64; H, 7.71; 
N, 3.83; Found: C, 65.37; H, 7.98; N, 4.02. 
H-NMR (CDCl.sub.3): .delta.7.21-6.50 (m, 7H); 1.27 (s, 3H); 0.77 (d, 3H, 
J=7 Hz). 
Following the general procedures set forth above the remaining Examples 
were prepared. 
EXAMPLE 36 
trans-(+)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidin 
e, mp=110.degree.-112.degree. C. 
Analysis calculated for C.sub.20 H.sub.28 ClNOS: Theory: C, 65.64; H, 7.71; 
N, 3.83; Found: C, 65.40; H, 7.49; N, 3.77. 
H-NMR (CDCl.sub.3): .delta.7.4-6.54 (m, 7H); 3.46-1.7 (m, 13H); 1.34 (s, 
3H); 0.76 (d, 3H, J=7 Hz). 
EXAMPLE 37 
trans-(-)-1-[3-(2-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperidin 
e hydrochloride 
M.sup.+ =329. 
Analysis calculated for C.sub.20 H.sub.28 ClNOS: Theory: C, 65.64; H, 7.71; 
N, 3.83; Found: C, 65.94; H, 7.49; N, 3.95. 
H-NMR (CDCl.sub.3): .delta.7.4-6.54 (m, 7H); 3.46-1.7 (m, 13H); 1.34 (s, 
3H); 0.76 (d, 3H, J=7 Hz). 
EXAMPLE 38 
trans-(.+-.)-1-[2-(2-Thienyl)ethyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperid 
ine hydrochloride, mp=117.degree.-119.degree. C. 
Analysis calculated for C.sub.19 H.sub.26 ClNOS: Theory: C, 64.84; H, 7.45; 
N, 3.98; Found: C, 65.09; H, 7.62; N, 3.69. 
EXAMPLE 39 
trans-(.+-.)-1-[3-Oxo-3-(2-thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl) 
piperidine hydrochloride, mp=118.degree.-120.degree. C. 
Analysis calculated for C.sub.20 H.sub.26 ClNO.sub.2 S: Theory: C, 63.22; 
H, 6.70; N, 3.67; Found: C, 62.78; H, 6.31; N, 3.68. 
EXAMPLE 40 
trans-(.+-.)-1-[R,S-[3-Hydroxy-3-(2-thienyl)propyl]]-3,4-dimethyl-4-(3-hydr 
oxyphenyl)piperidine hydrochloride, mp=97.degree.-99.degree. C. 
Analysis calculated for C.sub.20 H.sub.28 ClNO.sub.2 S: Theory: C, 62.89; 
H, 7.39; N, 3.67; Found: C, 62.79; H, 7.36; N, 3.73. 
EXAMPLE 41 
trans-(.+-.)-1-[3-(3-Thienyl)propyl]-3,4-dimethyl-4-(3-hydroxyphenyl)piperi 
dine hydrochloride 
Analysis calculated for C.sub.20 H.sub.28 ClNOS: Theory: C, 65.64; H, 7.71; 
N, 3.83; Found: C, 65.42; H, 7.52; N, 3.92. 
As noted above, the compounds of the present invention are useful in 
blocking the effect of agonists at mu or kappa receptors. As such, the 
present invention also provides a method for blocking mu or kappa 
receptors in mammals comprising administering to a mammal requiring 
blocking of a mu or kappa receptor a receptor blocking dose of a compound 
of the invention. 
The term "receptor blocking dose", as defined herein, means an amount of 
compound necessary to block a mu or kappa receptor following 
administration to a mammal requiring blocking of a mu or kappa receptor. 
The active compounds are effective over a wide dosage range. For example, 
dosages per day will normally fall within the range of about 0.05 to about 
250 mg/kg of body weight. In the treatment of adult humans, the range of 
about 0.5 to about 100 mg/kg, in single or divided doses, is preferred. 
However, it will be understood that the amount of he compound actually 
administered will be determined by a physicial in light of the relevant 
circumstances, including the condition to be treated, the choice of 
compound to be administered, the age, weight, and response of the 
individual patient, the severity of the patient's symptoms, and the chosen 
route of administration, and therefore the above dosage ranges are not 
intended to limit the scope of the invention in any way. The compounds may 
be administered by a variety of routes such as the oral, transdermal, 
subcutaneous, intranasal, intramuscular and intravenous routes. 
A variety of physiologic functions have been shown to be subject to 
influence by mu and kappa receptors in the brain. As such, the compounds 
of the present invention are believed to have the ability to treat a 
variety of disorders in mammals associated with these receptors such as 
eating disorders, opiate overdose, depression, smoking, alcoholism sexual 
dysfunction, shock, stroke, spinal damage and head trauma. As such, the 
present invention also provides methods of treating the above disorders at 
rates set forth above for blocking the effect of agonists at mu or kappa 
receptors. The compounds of the present invention have been found to 
display excellent activity in an opioid receptor binding assay which 
meausres the ability of the compounds to block the mu or kappa receptors. 
This assay was conducted by the following procedure. 
Male Sprague Dawley rats for mu and delta site experiments and male Hartley 
guinea pigs for kappa site experiments were sacrificed via decapitation 
and the brains were removed. The brain tissue, rat whole brain minus 
cerebellum for mu and delta sites and guinea pig cortex for the kappa 
site, was homogenized in a Teflon and glass tissue homogenizer. A 
supernatant I, pellet IV, fraction was frozen in a nitrogen freezer at 
1.33 g/ml concentration and stored for not longer than five weeks prior to 
use. Pellets were rehydrated with physiological buffer prior to use. 
For mu and delta sites increasing concentrations of experimental compound, 
(0.1 to 1000 nanomolar (nM)), Kreb-Hepes buffer pH 7.4, and .sup.3 H 
ligand were combined in polystyrene tubes at room temperature. The 
reaction was initiated by the addition of the rehydrated tissue which has 
been preincubated at 37.degree. C. for 20 minutes. The reaction mixture 
was incubated in a 37.degree. C. water bath for 20 minutes. The reaction 
was terminated by rapid filtration, (Amicon vacuum manifolds), through 
Whatman GF/C glass filters that had been presoaked in Krebs-Hepes buffer 
pH 7.4. The filters were then washed 2x with 5 ml of ice cold Krebs-Hepes 
buffer pH 7.4. Washed filters were placed in scintillation vials and 10 ml 
PCS, (Amersham), was added and samples counted in a Searle D-300 beta 
counter. Means and standard error statistics were calculated for 
triplicate experimental determinations in certain cases. The procedure was 
slightly modified for the kappa site. The tissue was pretreated with 100 
nM concentrations of mu and delta receptor site blockers. The incubation 
time for the reaction mixture was 45 minutes at 37.degree. C. 
Ki values were calculated using a minitab statistical program according to 
the following formula: 
##EQU1## 
wherein IC.sub.50 is the concentration at which 50% of the .sup.3 H ligand 
is displaced by the test compound and K.sub.D is the dissociation constant 
for the .sup.3 H ligand at the receptor site. 
The results of the evaluation of certain compounds of the present invention 
in the opioid receptor binding assay are set forth below in Table I. In 
the Table, column 1 sets forth the Example Number of the compound 
evaluated; column 2, the Ki value in nanomolar (nM) at the mu receptor; 
and column 3, the Ki value in nM at the kappa receptor. Also in the Table, 
compounds identified as Compounds A-F in Tables I-IV which follow are 
known compounds which were evaluated to compare their activity to the 
compounds of the present invention. Compounds A-F have the following 
identities: 
Compound A: 
4.beta.-(3-Hydroxyphenyl)-3.beta.,4.alpha.-dimethyl-.alpha.-phenyl-1-piper 
idinepropanol hydrochloride 
Compound B: 3-(1,3.alpha.,4.alpha.-Trimethyl-4.alpha.-piperidyl)phenol 
hydrochloride 
Compound C: 
3-[4.beta.-(3-Hydroxyphenyl)-3.beta.,4.alpha.-dimethylpiperidino]propiophe 
none maleate 
Compound D: 
3-(3.alpha.,4.beta.-Dimethyl-1-phenethyl-4.alpha.-piperidyl)phenol 
hydrochloride 
Compound E: naloxone 
Compound F: naltrexone 
TABLE I 
______________________________________ 
Opioid Receptor Binding Displacement Assay 
Example No. 
of Compound Ki Ki 
Tested Mu (nM) Kappa (nM) 
______________________________________ 
1 1.10 5.20 
2 5.61 5.79 
3 2.95 .+-. 1.12 
13.89 .+-. 6.66 
4 0.46 .+-. 0.20 
6.04 .+-. 0.44 
6 0.94 7.18 
7 12.06 1.04 
8 0.62 -- 
9 0.37 .+-. 0.07 
3.41 .+-. 0.08 
10 17.10 28.2 
11 0.49 2.34 
13 0.65 .+-. 0.12 
2.32 .+-. 0.26 
14 4.33 -- 
15 1.25 .+-. 0.40 
9.43 .+-. 1.67 
16 31.75 70.10 
17 0.84 0.55 
18 0.41 5.47 
21 1.61 -- 
22 0.29 9.62 
23 0.41 .+-. 0.09 
2.02 .+-. 0.46 
24 1.40 .+-. 0.61 
11.45 .+-. 4.29 
25 2.40 .+-. 0.61 
11.45 .+-. 4.29 
26 2.24 .+-. 0.17 
14.29 .+-. 2.10 
27 0.22 .+-. 0.03 
5.04 .+-. 0.58 
28 0.89 1.91 
29 1.36 3.04 
31 0.77 3.82 
35 0.56 6.10 
36 0.20 .+-. 0.08 
3.29 .+-. 1.02 
37 1.78 .+-. 0.10 
12.47 .+-. 1.34 
38 5.28 -- 
40 0.50 11.70 
41 -- 10.30 
Compound A 1.0 22.7 
Compound B 80.0 833.0 
Compound C 5.4 208.0 
Compound D 1.2 51.0 
Compound E 6.3 66.4 
Compound F 0.8 3.8 
______________________________________ 
The compounds of the invention also demonstrate excellent activity in an in 
vivo mu and kappa opioid receptor antagonist test in mice. The procedure 
used to establish this activity follows. 
In order to determine in vivo opioid receptor antagonism, the writhing 
test, usually used for measuring analgesia, was used with mice. The mouse 
writhing response was defined as a contraction of the abdominal 
musculature, followed by the extension of the hind limbs. Writhing was 
induced by the intraperitoneal administration of 0.6% acetic acid in a 
volume of 1 ml/100 g of body weight. Five CF-1 male mice (Charles River, 
Portage, MI), weighing approximately 20-22 grams each after being fasted 
overnight, were observed simultaneously for 10 minutes for the writhing 
response, beginning five minutes after injection of acetic acid. The 
percent inhibition of writhing was calculated from the average number of 
writhes in the control group. Each dose combination was administered to 
five mice. 
Each potential opioid antagonist was administered in various doses with an 
analgesic dose of morphine, a prototypical mu opioid receptor agonist, and 
an analgesic dose of U-50,488H, a prototypical kappa opioid receptor 
agonist. The respective doses were 1.25 and 2.5 mg/kg s.c. These doses 
produce between 90 and 100% inhibition of writhing. Each potential 
antagonist was tested at 1.25 mg/kg s.c. with morphine and U-50,488. If 
there was a significant antagonism of the analgesia of either morphine or 
U-50,488, then enough subsequent doses of the antagonist would be tested 
so as to generate a complete dose-response curve and to calculate an 
antagonist dose-50 (AD.sub.50). The AD.sub.50 was calculated from a linear 
regression equation of probit-plotted data and defines the estimated dose 
which reduces the analgesic effect of the agonist to 50% inhibition of 
writhing. Injections of test drugs and the prototypical agonists occurred 
20 minutes before the injection of acetic acid. 
The results of the foregoing mouse writhing assay are set forth below in 
Table II. In the Table, column 1 provides the Example Number of the 
compound evaluated in the assay; column 2, the amount of the compound 
evaluated in mg/kg necessary to reduce the analgesic effect of the agonist 
at the mu receptor to 50% inhibition of writhing; and column 3, the amount 
of the compound evaluated in mg/kg necessary to reduce the analgesic 
effect of the agonist at the kappa receptor to 50% inhibition of writhing. 
TABLE II 
______________________________________ 
Mouse Writhing Assay 
Example No. 
of Compound Mu Kappa 
Tested AD.sub.50 (mg/kg) 
AD.sub.50 (mg/kg) 
______________________________________ 
1 0.26 0.22 
2 0.21 0.29 
3 0.08 0.095 
4 0.35 0.23 
5 1.01 0.54 
6 0.13 0.22 
7 0.11 0.12 
8 0.21 0.64 
9 0.12 0.13 
10 0.46 0.34 
11 0.19 0.35 
12 0.56 0.42 
13 0.10 0.12 
14 0.37 0.60 
15 0.11 0.09 
16 0.87 0.62 
17 0.21 0.19 
18 0.04 0.08 
20 0.14 0.35 
22 0.05 0.11 
23 0.01 0.07 
24 0.05 0.24 
25 0.03 0.36 
26 0.07 0.52 
27 0.07 0.14 
28 0.08 0.22 
29 0.35 0.89 
30 0.11 0.47 
31 1.42 0.44 
32 0.17 3.50 
33 0.12 0.26 
35 0.22 0.30 
36 0.05 0.11 
37 0.24 0.65 
38 0.25 0.25 
40 0.065 0.14 
41 0.12 0.24 
Compound A 0.05 0.92 
Compound B 0.74 2.50 
Compound C 0.14 4.5 
Compound D 0.16 1.38 
Compound E 0.08 1.12 
Compound F 0.05 0.06 
______________________________________ 
It is well documented that marked diuretic effects are derived from the 
interaction of opioid antagonists with the kappa-opioid receptor of 
mammals See, e.g., Leander The Journal of Pharmacology and Experimental 
Therapeutics Vol. 224, No. 1, 89-94 (1983). As such, the compounds of the 
invention were also evaluated in a rat diuresis assay conducted according 
to the following procedure described by Leander et al. in Drug Development 
Research 4: 41-427 (1984) in an effort to further establish the ability of 
the present compounds to block kappa receptors. 
According to this procedure, sixty male Long-Evans hooded rats (Charles 
River Breeding Laboratories, Portage, MI) weighing between about 300 and 
500 grams each were housed either individually or in pairs in a 
temperature-controlled (23.degree. C.) colony room which was illuminated 
between 6:00 A.M. and 6:00 P.M. Rodent chow and tap water were 
continuously available except during the measurement of urine output. The 
animals were used repeatedly, but no more frequently than twice a week. 
In determining the antagonist activity of the present compounds, each 
animal was injected with 0.08 mg/kg of bremazocine, a potent kappa 
agonist, to induce urination. The animals were then injected with various 
doses of the test compounds. To measure urine output, the animals were 
removed from the home cages, weighed, injected and placed in metabolism 
cages for 5 hr. Excreted urine was funneled into graduated cylinders. 
Cumulative urine volumes were determined at designated time intervals, 
usually at 2 and 5 hr after injection. 
The compounds which are salt forms were dissolved in distilled water. If 
necessary, the compounds were dissolved in distilled water with the aid of 
either a few drops of lactic acid or hydrochloric acid and gentle warming. 
All injections were s.c. in a volume of 1 ml/kg of body weight. During 
tests for antagonism, two injections were given, one on each side of the 
body. 
The results of the rat diuresis study are set forth below in Table III. In 
the Table, column 1 provides the Example Number of the compound tested; 
column 2, the amount of compound in mg/kg necessary to reduce the urinary 
output to 50% of the effect produced by 0.08 mg/kg of bremazocine alone 
two hours after injection of bremazocine and the test compound; and column 
3, the amount of compound in mg/kg necessary to reduce the urinary output 
to 50% of the effect produced by 0.08 mg/kg of bremazocine alone five 
hours after injection of bremazocine and the test compound. 
TABLE III 
______________________________________ 
Rat Diuresis Assay 
AD.sub.50 (mg/kg) 
Example No. of Two Five 
Compound Tested Hours Hours 
______________________________________ 
3 0.27 0.39 
4 0.17 0.46 
5 1.91 0.92 
6 -- 0.67 
7 1.30 1.38 
8 3.77 3.33 
9 2.40 0.79 
10 14.90 3.90 
11 1.90 1.02 
12 7.89 8.13 
14 0.78 0.69 
15 0.27 0.39 
16 7.70 4.45 
22 1.31 0.70 
23 0.40 0.38 
35 2.20 1.04 
36 4.65 1.65 
37 2.92 1.66 
38 -- 2.00 
40 3.78 1.44 
41 2.70 1.90 
Compound A 4.09 2.65 
Compound E 2.71 3.49 
Compound F 2.17 2.45 
______________________________________ 
The compounds of the present invention have also been found to have the 
ability to decrease the amount of food consumed in vivo. The following 
assay was employed to evaluate the ability of the compounds of the 
invention to effect food and water consumption of meal fed obese Zucker 
rats. 
According to this procedure, 3-4 month old obese Zucker rats were trained 
to eat food daily from 8:00 A.M. to 4:00 P.M. only, such that the body 
weight gain approximates that if the rats were fed ad libitum. These rats 
were allowed to consume water at all times. Four groups of rats with four 
rats in each group, two female and two male, were formed. One group served 
as control for the other three groups each day. Each of the other groups 
were given a subcutaneous dose of the compound to be evaluated. The test 
compound was formulated in physiological saline containing 10% 
dimethylsulfoxide by volume. 
Animals remained drug free for 4 days before the next test. Food and water 
consumption of each rat were measured for the first four hours. A test on 
one compound was run for three consecutive days. The drug effect was 
expressed as the percent of the control for that test day. 
The results of this test are set forth below in Table IV. In the Table, 
column 1 gives the Example Number of the compound evaluated; and column 2 
provides the ED.sub.20 in mg/kg, wherein ED.sub.20 represents the amount 
of compound evaluated in mg/kg necessary to decrease food consumption 20% 
during the first four hours of the experiment. 
TABLE IV 
______________________________________ 
Food Consumption Assay 
Example No. of ED.sub.20 
Compound Tested (mg/kg) 
______________________________________ 
1 0.08 
2 1.25 
3 0.29 
4 0.05 
6 0.33 
7 0.34 
8 0.44 
9 1.25 
10 1.25 
11 0.15 
13 4.56 
14 4.47 
15 3.65 
16 &gt;20.0 
17 0.31 
18 0.07 
20 0.91 
21 9.37 
22 0.78 
23 0.05 
24 0.12 
25 0.13 
26 0.35 
27 0.04 
28 0.12 
29 0.31 
35 0.08 
36 0.05 
37 0.19 
40 0.11 
Compound A 0.55 
Compound B 3.99 
Compound C 3.72 
Compound D 0.94 
Compound E 1.40 
Compound F 2.05 
______________________________________ 
While it is possible to administer a compound of the invention directly 
without any formulation, the compounds are preferably employed in the form 
of a pharmaceutical formulation comprising a pharmaceutically acceptable 
carrier, diluent or excipient and a compound of the invention. Such 
compositions will contain from about 0.1 percent by weight to about 90.0 
percent by weight of a present compound. As such, the present invention 
also provides pharmaceutical formulations comprising a compound of the 
invention and a pharmaceutically acceptable carrier, diluent or excipient 
therefor. 
In making the compositions of the present invention, the active ingredient 
will usually be mixed with a carrier, or diluted by a carrier, or enclosed 
within a carrier which may be in the form of a capsule, sachet, paper or 
other container. When the carrier serves as a diluent, it may be a solid, 
semi-solid or liquid material which acts as a vehicle, excipient or medium 
for the active ingredient. Thus, the composition can be in the form of 
tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, 
solutions, syrups, suspensions, aerosols (as a solid or in a liquid 
medium, and soft and hard gelatin capsules. 
Examples of suitable carriers, excipients, and diluents include lactose, 
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium 
phosphate, alginates, calcium silicate, microcrystalline cellulose, 
polyvinylpyrrolidone, cellulose, tragacanth, gelatin, syrup, methyl 
cellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, 
water, and mineral oil. The formultions may also include wetting agents, 
emulsifying and suspending agents, preserving agents, sweetening agents or 
flavoring agents. The formulations of the invention may be formulated so 
as to provide quick, sustained, or delayed release of the active 
ingredient after administration to the patient by employing procedures 
well known in the art. 
For oral administration, a compound of this invention ideally can be 
admixed with carriers and diluents and molded into tablets or enclosed in 
gelatin capsules. 
The compositions are preferably formulated in a unit dosage form, each 
dosage containing from about 1 to about 500 mg, more usually about 5 to 
about 300 mg, of the active ingredient. The term "unit dosage form" refers 
to physically discrete units suitable as unitary dosages for human 
subjects and other mammals, each unit containing a predetermined quantity 
of active material calculated to produce the desired therapeutic effect, 
in association with a suitable pharmaceutical carrier. 
In order to more fully illustrate the operation of this invention, the 
following formulation examples are provided. The examples are illustrative 
only, and are not intended to limit the scope of the invention. The 
formulations may employ as active compounds any of the compounds of the 
present invention. 
FORMULATION 1 
Hard gelatin capsules are prepared using the following ingredients: 
______________________________________ 
Concentration 
Amount Per 
by Weight 
Capsule (percent) 
______________________________________ 
trans-(+)-1-[S--(3-hydroxy-3- 
250 mg 55.0 
cyclohexylpropyl)]-3,4- 
dimethyl-4-(3-hydroxy- 
phenyl)piperidine 
hydrochloride 
starch dried 200 mg 43.0 
magnesium stearate 
10 mg 2.0 
460 mg 100.0 
______________________________________ 
The above ingredients are mixed and filled into hard gelatin capsules in 
460 mg quantities. 
FORMULATION 2 
Capsules each containing 20 mg of medicament are made as follows: 
______________________________________ 
Concentration 
Amount Per 
by Weight 
Capsule (percent) 
______________________________________ 
trans-(.+-.)-1-[R-(3-hydroxy-3- 
20 mg 10.0 
cyclohexylpropyl)]-3,4- 
dimethl-4-(3-hydroxy- 
phenyl)piperidine 
starch 89 mg 44.5 
microcrystalline 
cellulose 89 mg 44.5 
magnesium stearate 
2 mg 1.0 
200 mg 100.0 
______________________________________ 
The active ingredient, cellulose, starch and magnesium stearate are 
blended, passed through a No. 45 mesh U.S. sieve and filled into a hard 
gelatin capsule. 
FORMULATION 3 
Capsules each containing 100 mg of active ingredient are made as follows: 
______________________________________ 
Concentration 
Amount Per 
by Weight 
Capsule (percent) 
______________________________________ 
trans-(.+-.)-1-(3-oxo-n-octyl)- 
100 mg 30.0 
3,4-dimethyl-4-(3-hydroxy- 
phenyl)piperidine 
hydroiodide 
polyoxyethylene sorbitan 
monooleate 50 mcg 0.02 
starch powder 250 mg 69.98 
350.05 mg 100.00 
______________________________________ 
The above ingredients are thoroughly mixed and placed in an empty gelatin 
capsule. 
FORMULATION 4 
Tablets each containing 10 mg of active ingredient are prepared as follows: 
______________________________________ 
Concentration 
Amount Per 
by Weight 
Capsule (percent) 
______________________________________ 
trans-(.+-.)-1-(5-methylhexyl)- 
10 mg 10.0 
3,4-dimethyl-4-(3-hydroxy- 
phenyl)piperidine maleate 
starch 45 mg 45.0 
microcrystalline 35 mg 35.0 
cellulose 
polyvinylpyrrolidone 
4 mg 4.0 
(as 10% solution 
in water) 
sodium carboxymethyl 
4.5 mg 4.5 
starch 
magnesium stearate 
0.5 mg 0.5 
talc 1 mg 1.0 
100 mg 100.0 
______________________________________ 
The active ingredient, starch and cellulose are passed through a No. 45 
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone 
is mixed with the resultant powders which are then passed through a No. 14 
mesh U.S. sieve. The granule so produced is dried at 50.degree.-60.degree. 
C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl 
starch, magnesium stearate and talc, previously passed through a No. 60 
mesh U.S. sieve, are then added to the granule which, after mixing, is 
compressed on a tablet machine to yield a tablet weighing 100 mg. 
FORMULATION 5 
A tablet formula may be prepared using the ingredients below: 
______________________________________ 
Concentration 
Amount Per 
by Weight 
Capsule percent) 
______________________________________ 
trans(.+-.)-1-[S-(3-hydroxy-3- 
250 mg 38.0 
cyclohexylpropyl)]-3,4- 
dimethyl-4-(3-hydroxy- 
phenyl)piperidine 
hydrochloride 
cellulose 
microcrystalline 400 mg 60.0 
silicon dioxide fumed 
10 mg 1.5 
stearic acid 5 mg 0.5 
665 mg 100.0 
______________________________________ 
The components are blended and compressed to form tablets each weighing 665 
mg. 
FORMULATION 6 
Suspensions each containing 5 mg of medicament per 5 ml dose are made as 
follows: 
______________________________________ 
per 5 ml of 
suspension 
______________________________________ 
trans-(.+-.)-1-(3-hydroxy-n-hexyl)-3,4- 
5 mg 
dimethyl-4-(3-hydroxyphenyl)- 
piperidine hydrochloride 
sodium carboxymethyl cellulose 
50 mg 
syrup 1.25 ml 
benzoic acid solution 0.10 ml 
flavor q.v. 
color q.v. 
water q.s. to 5 
ml 
______________________________________ 
The medicament is passed through a No. 45 mesh U.S. sieve and mixed with 
the sodium carboxymethylcellulose and syrup to form a smooth paste. The 
benzoic acid solution, flavor and color is diluted with some of the water 
and added to the paste with stirring. Sufficient water is then added to 
produce the required volume. 
FORMULATION 7 
An aerosol solution is prepared containing the following components: 
______________________________________ 
Concentration by 
Weight (percent) 
______________________________________ 
trans-(.+-.)-1-[R-(3-methoxy-3-cyclo- 
0.25 
hexylpropyl)]-3,4-dimethl-4- 
(3-hydroxyphenyl)piperidien 
hydrochloride 
ethanol 29.75 
Propellant 22 
(chlorodifluoromethane) 
70.00 
100.00 
______________________________________ 
The active compound is mixed withe ethanol and the mixture added to a 
portion of the Propellant 22, cooled to -30.degree. C. and transferred to 
a filling device. The required amount is then fed to a stainless steel 
container and diluted further with the remaining amount of propellant. The 
valve units are then fitted to the container.