Intermediates of peripherally selective N-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists

Intermediates of N-carbonyl-3,4,4-substituted piperidines are provided which are useful in the preparation of peripheral opioid antagonists.

FIELD OF THE INVENTION 
This invention relates to certain N-substituted piperidines and their use 
as peripherally selective opioid antagonists. 
BACKGROUND OF THE INVENTION 
A substantial body of evidence indicates that peripheral opioid peptides 
and their receptors have a major physiological role in the regulation of 
gut motility. Consequently gastrointestinal disorders such as idiopathic 
constipation and irritable bowel syndrome may relate to a dysfunction of 
opioid receptor mediated control and agents which act as antagonists for 
these receptors may benefit a patient suffering from such a dysfunction. 
Natural and synthetic opiates such as morphine have been used extensively 
in the mediation of pain. However, these agents can produce undesirable 
side effects such as constipation, nausea, and vomiting which are 
peripheral to the desired action as analgesics. Thus, a peripheral opioid 
antagonist should not substantially affect the analgesic effects of the 
opiate while acting to control gastrointestinal function and to minimize 
the undesirable side effects of the narcotic drug. 
A number of opioid antagonists have been reported including naloxone and 
naltrexone (Blumberg et al., Toxicol. Appl. Pharmacol., 10, 406, 1967). 
Other derivatives of these compounds have been recently reported 
(Portoghese et al., J. Med. Chem., 31, 281-282, 1988). 4-Arylpiperidines 
have also been reported as having analgesic activity and in some instances 
acting as narcotic antagonists. Zimmerman, U.S. Pat. No. 4,191,771 (1980); 
Barnett, U.S. Pat. No. 4,581,456 (1986): Zimmerman, U.S. Pat. No. 
4,081,450 (1978). These compounds are disclosed as having useful analgesic 
activity and in some cases acting as potent narcotic antagonists. 
It would be advantageous to have compounds which would act as antagonists 
to the peripheral effects of opiate analgesics and endogenous opioid 
peptides. It would also be advantageous if these compounds had a minimal 
effect on the analgesic activity of the opiate drugs. It would be further 
advantageous to have compounds which can act to minimize the effects of 
idiopathic constipation and irritable bowel syndrome. 
It has now been found that the N-substituted piperidines of the instant 
invention are useful as peripherally selective opioid antagonists. The 
instant compounds are useful in preventing peripherally mediated, 
undersired opiate effects and in relieving the symptoms of idiopathic 
constipation and irritable bowel syndrome. Certain of the instant 
compounds are also useful as intermediates in preparing new piperidine 
compounds. 
SUMMARY OF THE INVENTION 
The present invention relates to a trans-3,4-isomer of a compound of 
Formula I 
##STR1## 
wherein: R.sup.1 is H or (C.sub.1 -C.sub.5)alkyl; 
R.sup.2 is H, C.sub.1 -C.sub.5)alkyl, or (C.sub.2 -C.sub.6)alkenyl; 
R.sup.3 is H, (C.sub.1 -C.sub.10)alkyl, (C.sub.3 -C.sub.10)alkenyl, 
(C.sub.3 -C.sub.8)-cycloalkyl, (C.sub.3 -C.sub.8) cycloalkyl-(C.sub.1 
-C.sub.3) alkyl, phenyl, (C.sub.5 -C.sub.8) cycloalkenyl, (C.sub.5 
-C.sub.8)cycloalkenyl-(C.sub.1 -C.sub.3)alkyl, or phenyl-(C.sub.1 
-C.sub.3) alkyl. 
R.sup.4 is H, (C.sub.3 -C.sub.8) cycloalkyl, (C.sub.1 -C.sub.10) alkyl, 
(C.sub.3 -C.sub.10)alkenyl, (C.sub.3 -C.sub.8)cycloalkyl-(C.sub.1 
-C.sub.3)alkyl, phenyl or phenyl-(C.sub.1 -C.sub.3) alkyl. 
R.sup.5 is H, (C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.10)alkanoyl, 
C(O)CH--[(CH.sub.2).sub.3 NHC(NH)NHNO.sub.2 ]NHC(O)W, C(O)NH(C.sub.1 
-C.sub.10)alkyl, [C(O)(C.sub.2).sub.m C(O)].sub.q R.sup.6, or 
[C(O)(CH.sub.2).sub.m NHC(O)].sub.q R.sup.6 ; 
W is (C.sub.1 -C.sub.10)alkyl, O(C.sub.1 -C.sub.10)alkyl, (C.sub.1 -C.sub.4 
alkyl)NHC(O)(C.sub.1 -C.sub.6)- alkyl, or (C.sub.1 -C.sub.4 alkyl)C(O)NHB, 
where B is (C.sub.1 -C.sub.10)- alkyl, phenyl or phenyl-(C.sub.1 
-C.sub.3)alkyl; 
R.sup.6 is OR.sup.7, NHR.sup.7, OCH.sub.2 C(O)NR.sup.8 R.sup.9, O(C.sub.1 
-C.sub.4 alkyl)OC(O)R.sup.10, (C.sub.1 -C.sub.10)alkyl, or NHCHR.sup.11 
C(O)R.sup.12 ; 
R.sup.7 is H, (C.sub.1 -C.sub.10)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, 
(C.sub.3 -C.sub.8)cycloalkyl-(C.sub.1 -C.sub.3) alkyl or (CH.sub.2).sub.m 
C(O)NR.sup.8 R.sup.9 ; 
R.sup.8 is H, or (C.sub.1 -C.sub.10)alkyl; 
R.sup.9 is H, or (C.sub.1 -C.sub.10)alkyl; 
R.sup.10 is (C.sub.1 -C.sub.10)alkyl, C.sub.3 -C.sub.8)cycloalkyl, or 
##STR2## 
R.sup.11 is H, (C.sub.1 -C.sub.10)alkyl, or phenyl-(C.sub.1 
-C.sub.3)alkyl; 
R.sup.12 is OR.sup.13 or NR.sup.13 R.sup.14 ; 
R.sup.13 is H or (C.sub.1 -C.sub.10)alkyl; 
R.sup.14 is H or (C.sub.1 -C.sub.10)alkyl; 
n=1-3; 
m=1-3; 
q=1-3; and 
the pharmaceutically acceptable salts thereof. 
The present invention also provides methods of employing, and 
pharmaceutical formulations containing, a compound of the invention. 
The present invention further provides trans-3,4-isomers of the 
intermediates of Formula II 
##STR3## 
wherein: R.sup.1 is hydrogen or (C.sub.1 -C.sub.5) alkyl; 
R.sup.2 is hydrogen, (C.sub.1 -C.sub.5) alkyl, or (C.sub.2 -C.sub.6) 
alkenyl; 
R.sup.3 is hydrogen, (C.sub.1 -C.sub.10) alkyl, (C.sub.3 
-C.sub.8)cycloalkyl, C.sub.3 -C.sub.10 alkenyl, (C.sub.3 
-C.sub.8)cycloalkyl-(C.sub.1 -C.sub.3)alkyl, phenyl, (C.sub.5 
-C.sub.8)cycloalkenyl, (C.sub.5 -C.sub.8)cycloalkenyl-(C.sub.1 
-C.sub.3)alkyl, or phenyl-(C.sub.1 -C.sub.3)alkyl; 
R.sup.4 is hydrogen, (C.sub.3 -C.sub.8) cycoalkyl, (C.sub.1 -C.sub.10) 
alkyl, C.sub.3 -C.sub.10 alkenyl, (C.sub.3 -C.sub.8)cycloalkyl-(C.sub.1 
-C.sub.3)alkyl, phenyl or phenyl-(C.sub.1 -C.sub.3)alkyl; and 
n=1-3. 
In another embodiment the instant invention provides compounds of Formula 
IIb which are intermediates in the preparation of Formula IIa compounds 
##STR4## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and n are as defined above and 
Z is hydrogen when R.sup.4 is phenyl or an amino blocking group when 
R.sup.4 is other than phenyl.

DETAILED DESCRIPTION OF THE INVENTION 
The term "(C.sub.1 -C.sub.10) alkyl," as used herein, represents a branched 
or linear alkyl group having from one to ten carbon atoms. Typical C.sub.1 
-C.sub.10 alkyl groups include methyl, ethyl, n-propyl, iso-propyl, butyl, 
iso-butyl, sec-butyl, tert-butyl, pentyl n-hexyl, iso-hexyl, and the like. 
The terms "(C.sub.1 -C.sub.3) alkyl" and "(C.sub.1 -C.sub.5)alkyl" 
similarly is a linear or branched alkyl group having one to three and one 
to five carbon atoms respectively. 
The term "(C.sub.3 -C.sub.8) cycloalkyl" represents cyclopropyl, 
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. 
The term "(C.sub.3 -C.sub.8) cycloalkyl-(C.sub.1 -C.sub.3) alkyl" 
represents a linear C.sub.1 -C.sub.3 alkyl chain substituted at a terminal 
carbon with a (C.sub.3 -C.sub.8) cycloalkyl group. Typical alkylcycloalkyl 
groups include cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl and 
the like. 
The term "C.sub.2 -C.sub.6 alkenyl" refers to a group containing 2 to 6 
carbon atoms and one double bond and the term "C.sub.3 -C.sub.10 " alkenyl 
refers to a group containing 3 to 10 carbon atoms and one double bond. The 
groups can be branched or straight chain. Examples of such groups include 
2-propenyl (--CH.sub.2 --CH.dbd.CH.sub.2), 1-butenyl (--CH.dbd.CHCH.sub.2 
CH.sub.3) and the like. 
The term "(C.sub.5 -C.sub.8)cycloalkenyl" represents an olefinically 
unsaturated ring having five to eight carbon atoms, eg., cyclohexenyl, 
cyclopentenyl, etc. 
The term "(C.sub.5 -C.sub.8)cycloalkenyl-(C.sub.1 -C.sub.3)alkyl" 
represents a linear C.sub.1 -C.sub.3 group substituted with a (C.sub.5 
-C.sub.8)alkenyl group. 
The term "phenyl" includes a benzene ring as well as a benzene ring 
substituted with one or two C.sub.1 -C.sub.2 alkyl groups. 
The term "phenyl (C.sub.1 -C.sub.3) alkyl" represents a linear C.sub.1 
-C.sub.3 alkyl chain substituted at a terminal carbon with a benzene ring. 
Typical phenylalkyl groups are phenmethyl, phenethyl and phenpropyl. 
The term "(C.sub.1 -C.sub.10) alkanoyl" represents group of formula 
C(O)(C.sub.1 -C.sub.9 alkyl). Typical C.sub.1 -C.sub.10 alkanoyl groups 
include acetyl, propanoyl, butanoyl and the like. 
The term "amino-blocking group" is used herein as it is frequently used in 
synthethic organic chemistry, to refer to a group which will prevent an 
amino group from reacting with the carbonyl group instead of the 
piperidine nitrogen as shown in Scheme 3 herein, but which can be removed 
from the amine when it is desired to do so. Such groups are discussed by 
T. W. Greene in chapter 7 of Protective Group in Organic Synthesis, John 
Wiley and Sons, New York, 1981, and J. W. Barton in chapter 2 of 
Protective Groups in Organic Chemistry, J. F. W. McOmie, ed., Plemun 
Press, New York, 1973, which are incorporated herein by reference in their 
entirety. Preferred amino blocking groups include 
tertiary-butyloxycarbonyl, benzyloxycarbonyl and carbamates such as 
benzylcarbamate, vinylcarbamate and cinnamylcarbamate. 
While all of the compounds of the present invention are useful peripheral 
opioid antagonists, certain of the present compounds are preferred for 
that use. Preferably, R.sup.1 is hydrogen; R.sup.2 is methyl; R.sup.3 is 
phenyl, phenyl-(C.sub.1 -C.sub.3 alkyl), (C.sub.3 -C.sub.8) cycloalkyl, 
(C.sub.3 -C.sub.8) cycloalkyl-(C.sub.1 -C.sub.3) alkyl especially 
cyclohexylmethyl, phenyl, benzyl, or isobutyl; R.sup.4 is hydrogen or 
(C.sub.3 -C.sub.8) cycloalkyl, especially cyclohexyl; R.sup.5 is 
--C(O)(CH.sub.2).sub.m C(O)R.sup.6, where R.sup.6 is NH.sub.2, --OCH.sub.2 
CH.sub.3 or especially --OH, and m is 3; and n is 1 or preferably 2. 
While all of the intermediates of the present invention are useful for the 
synthesis of peripherally selective opioid antagonists, certain of the 
intermediates are preferred for that use. Preferably, R.sup.1 is hydrogen; 
R.sup.2 is (C.sub.1 -C.sub.6)alkyl, most preferably methyl; R.sup.3 is 
(C.sub.3 -C.sub.8) cycloalkyl (C.sub.1 -C.sub.3)alkyl especially 
cyclohexylmethyl, or isobutyl, R.sup.4 is hydrogen or cycloalkyl, 
especially cyclohexyl; and n is 1 or especially 2. 
Other preferred aspects of the present invention are set forth hereinbelow. 
The piperidines of the invention as illustrated in Formula I can occur as 
the trans and cis stereochemical isomers by virtue of the substituents at 
the 3- and 4-positions. The present invention encompasses the individual 
trans stereoisomers including individual enantiomers as well as the 
racemic mixtures. The compounds of the present invention are those isomers 
in which the R.sup.2 group at the 3-position is situated on the opposite 
side of the ring, i.e. trans, to the methyl group in the 4-position and on 
the same side of the ring, i.e. Zusammen or Z, relative to the higher 
priority phenyl group at the 4-position. These trans or Z-isomers exist as 
the 3R,4R-isomers as shown in Formula III 
##STR5## 
or the 3S,4S-isomer as represented in Formula IV 
##STR6## 
The present invention contemplates both the individual 3R,4R- and 
3S,4S-stereoisomers, as well as mixtures of these stereoisomers. The most 
preferred compounds are those of Formula III in which the configuration is 
3R,4R. These compounds have been found to be peripheral opioid antagonists 
with little or no agonist activity. 
Also, when R.sup.3 is not hydrogen, the carbon atom attached to R.sup.3 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 present invention. The 
preferred stereoisomers are those in which the chiral center to which 
R.sup.3 is bound is S, i.e., those stereoisomers in which the 
configuration at the three chiral centers is 3R, 4R, S. 
Furthermore, when R.sup.5 is an arginine residue, ie. 
C(O)CH[(CH.sub.2).sub.3 NHC(NH)NHNO.sub.2 ]NHC(O)W, or R.sup.6 an 
alphaamino acid residue ie. NHCHC(O)R.sup.8 ]R.sup.9, another asymmetric 
carbon is introduced into the molecule. As such, these classes of 
compounds can exist as the individual R or S stereoisomers, or the racemic 
mixture of the isomers, and all are contemplated within the scope of the 
present invention. 
The terms "R" and "S" are used herein as commonly used in organic chemistry 
to denote specific configuration of a chiral center. The term "R" refers 
to "right" and refers that configuration of a chiral center with a 
clockwise relationship of group priorities (highest to second lowest) when 
viewed along the bond toward the lowest priority group. The term "S" or 
"left" refers to that configuration of a chiral center with a 
counterclockwise relationship of group priorities (highest to second 
lowest) when viewed along the bond toward the lowest priority group. The 
priority of groups is based upon their atomic number (heaviest isotope 
first). A partial list of priorities and a discussion of stereo chemistry 
is contained in the book: The Vocabulary of Organic Chemistry, Orchin, et 
al., John Wiley and Sons Inc., publishers, page 126, which is incorporated 
herein by reference. 
As set forth hereinabove racemic mixtures as well as the substantially pure 
stereoisomers of the compound of Formula I are contemplated as within the 
scope of the instant invention. By the term "substantially pure", it is 
meant that at least about 90 mole percent, more preferably at least about 
95 mole percent and most preferably at least 98 mole percent of the 
desired stereoisomer is present compared to other possible stereoisomers. 
Preferred compounds of the instant invention include: 
Q--(CH.sub.2).sub.2 CH(E)NHC(O)(CH.sub.2).sub.2 C(O)OH; Q--(CH.sub.2).sub.2 
CH[CH.sub.2 CH(CH.sub.3).sub.2 ]NHC(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 
CH.sub.3 ; Q--(CH.sub.2).sub.2 CH[CH.sub.2 CH(CH.sub.3).sub.2 
]NHC(O)(CH.sub.2).sub.3 C(O)OH; Q--(CH.sub.2).sub.2 
CH(U)NHC(O)(CH.sub.2).sub.3 C(O)OH; Q(CH.sub.2).sub.2 CH(D)NHC(O)CH.sub.3 
; QCH.sub.2 CH(K)NHC(O)CH.sub.2 C(O)OCH.sub.2 CH.sub.3 ; QCH.sub.2 
CH(K)NHC(O)CH.sub.2 C(O)OH; QCH.sub.2 CH(K)NHC(O)(CH.sub.2).sub.2 C(O)OH; 
QCH.sub.2 CH(E)NHC(O)(CH.sub.2).sub.3 C(O)OH; Q(CH.sub.2).sub.2 
N(U)C(O)(CH.sub.2).sub.2 C(O)O(CH.sub.2).sub.2 CH.sub.3 ; 
Q(CH.sub.2).sub.3 N(U)C(O)(CH.sub.2).sub.3 C(O)(CH.sub.2).sub.3 
C(O)OCH.sub.2 CH.sub.3 ; Q(CH.sub.2).sub.3 N(U)C(O)(CH.sub.2).sub.3 
C(O)NH.sub.2 ; Q(CH.sub.2).sub.2 N(U)C(O)CH.sub.2 C(O)NHCH.sub.2 
C(O)NHCH.sub.3 ; Q(CH.sub.2).sub.2 N(D)C(O)(CH.sub.2).sub.2 
C(O)NHCH[CH.sub.2 CH(CH.sub.3).sub.2 ]C(O)OH; Q(CH.sub.2).sub.2 
NHC(O)CH[NHC(O)CH.sub.3 ](CH.sub.2).sub.3 NHC(NH)NHNO.sub.2 ; 
Q(CH.sub.2).sub.2 N(U)C(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 
CH(CH.sub.3).sub.2 ; (3S,4S)--(S)--T--OH; (-)(3S,4S)--(R)--T--OH; 
(3R,4R)--(S)--T--OH; (3R,4R)--(S)--T--OCH.sub.3 ; 
(3R,4R)--(S)--T--OCH.sub.2 CH.sub.3 ; (3R,4R)--(S)--T--O(CH.sub.2).sub.2 
CH.sub.3 ; (3S,4S)--(S)--T--OCH.sub.2 CH(CH.sub.3).sub.2 ; 
(3R,4R)--(S)--T--OCH.sub.2 CH(CH.sub.3).sub.2 ; 
(3R,4R)--(S)--T--O(CH.sub.2).sub.6 CH.sub.3 ; (3S,4S)--(R)--T--OCH.sub.2 
CH(CH.sub.3).sub.2 ; (3R,4R)--(R)--T--OCH.sub.2 CH(CH.sub.3).sub.2 ; 
(3S,4S)--(S)--T--OCH.sub.2 C(O)NH.sub.2 ; (3R,4R)--(S)--T--OCH.sub.2 
C(O)NH.sub.2 ; (3S,4S)--(S)--T--OCH.sub.2 C(O)NHCH.sub.3 ; (3 
R,4R)--(S)--T--OCH.sub.2 C(O)NHCH.sub.3 ; (3S,4S)--(S)--T--OCH.sub.2 
C(O)NHCH.sub.2 CH.sub.3 ; (3R,4R)--(S)--T--OCH.sub.2 C(O)NHCH.sub.2 
CH.sub.3 ; (3S,4S)--(S)--T--O--G; and (3R,4R)--(S)--T--O--J. 
wherein: 
##STR7## 
The piperidines of this invention form pharmaceutically acceptable acid 
addition salts with a wide variety of inorganic and organic acids. Typical 
acids generally used include sulfuric, hydrochloric, hydrobromic, 
phosphoric, hypophosphoric, hydroiodic, sulfamic, citric, acetic, maleic, 
malic, succinic, tartaric, cinnamic, benzoic, ascorbic, mandelic, 
p-toluenesulfonic, benzenesulfonic, methanesulfonic, trifluoroacetic, 
hippuric and the like. Such pharmaceutically acceptable salts are within 
the scope of the present invention. 
The compounds of the present invention can be prepared by a variety of 
procedures well known to those skilled in the art. The 
3-substituted-4-methyl-4-(3-hydroxy- or alkanoyloxyphenyl)piperidine 
derivatives employed as starting materials in the synthesis of the instant 
compounds can be prepared by the general procedure taught by Zimmerman in 
U.S. Pat. No. 4,115,400 (1978), incorporated herein by reference. The 
starting material for the synthesis of the preferred compounds of the 
present invention, (3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine, can 
be prepared by the procedure of Barnett in U.S. Pat. 4,581,456, herein 
incorporated by reference, but adjusted as described in such patent so 
that the .beta.-stereochemistry is primarily obtained. This process is 
depicted in Scheme 1, wherein R.sup.20 is C.sub.1 -C.sub.3 alkoxy, 
R.sup.21 is C.sub.1 -C.sub.6 alkyl, R.sup.22 is C.sub.1 -C.sub.4 alkyl, 
R.sup.23 and R.sup.24 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 a leaving group such as halogen. 
##STR8## 
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-alkyl-4-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 in 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.23 R.sup.24 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 introduces 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 has been reported to be 
dependent upon the purity of the starting materials in regard to the 
presence or absence of various catalyst poisons. Typically 2.5 equivalents 
of catalyst are used. If hydrogen uptake is not complete, more catalyst is 
added. 
The hydrogen pressure in the reaction vessel is not critical but can 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 can 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 can 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 9.8. 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 can 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 lithiated intermediate with the halide CH.sub.3 
Y to provide the corresponding 
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)tetrahydropyridinemethanamine. This 
compound is then reduced and converted to the starting material as 
indicated above. 
As noted above, the compounds of the present invention can 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 racemic mixture of a 
1-alkyl-3,4-dimethyl-4-(3-alkoxyphenyl)piperidine with either (+)- or 
(-)-di-benzoyl 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 2 wherein R.sup.20 and 
R.sup.22 are as defined above: 
##STR9## 
The 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine prepared as shown in Scheme 
2 can then be reacted with an appropriate acylating agent to provide the 
intermediate amide of the instant invention, Formula IIb, which is then 
reduced under standard conditions to give the intermediate of Formula IIa 
of the present invention. This reaction can be represented by the 
following Scheme 3 wherein R.sup.3, R.sup.4, and n are as defined above 
and Z is hydrogen when R.sup.4 is phenyl or an amino blocking group when 
R.sup.4 is other than phenyl: 
##STR10## 
When R.sup.4 is not phenyl, it is necessary to protect the nitrogen of the 
amino acid prior to reaction with the starting 
3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. Standard nitrogen protecting 
groups, (amino blocking group) are acceptable but preferred amino blocking 
groups include the tertiary-butyloxycarbonyl (t--BOC) group, 
benzyloxycarbonyl (C.sub.6 H.sub.5 CH.sub.2 O(O)--), benzylcarbamate, 
vinylcarbamate and cinnanylcarbamate. 
This protection step with for example the t-BOC group is conveniently 
performed by dissolving the unprotected amino acid in a mixture of water 
and an unreactive, water miscible solvent, such as tetrahydrofuran or 
preferably dioxane, in a ratio of approximately 1:2 respectively. To this 
solution is then added between 1.5 and 2.0 equivalents of an aqueous base, 
typically sodium hydroxide, at ice bath temperatures, typically from 
0.degree. to 10.degree. C. To this solution is then added approximately 
2.0 equivalents of di-tert-butyl dicarbonate. The reaction is complete in 
about 1 to 2 hours at a temperature ranging from 0.degree. C. to ambient. 
The next step is careful acidification of the reaction mixture to a pH of 
approximately 2. Acidification is accomplished by the addition of a 
minerial acid, typically hydrochloric, hydrobromic, sulfuric or especially 
sodium hydrogen sulfate. The desired product is then extracted from the 
reaction mixture in an inert, water immiscible solvent and isolated by 
crystallization. The product thus formed can be further purified, if 
needed, by any of several routine methods, including recrystallization, 
chromatography and related techniques. 
In the next step in the process of Scheme 3, coupling reagent commonly used 
in the synthesis of peptides can be employed. Examples of such coupling 
reagents include the carbodimides such as N,N'-di-cyclohexylcarbodiimide, 
N,N'-diisopropylcarbodiimide, or N,N'-diethylcarbodimide; 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 
3,4-dimethyl-4-(3-hydroxyphenyl)piperidine is conveniently carried out by 
adding about an equimolar quantity or slight excess of the coupling 
reagent to a solution of the substituted carboxylic acid, with equimolar 
quantitites of 3,4-dimethyl-4-(3-hydroxyphenyl)-piperdine and 
1-hydroxybenzotriazole. The reaction is carried out in an inert organic 
solvent such as dichloromethane or N,N-dimethylformamide, and the reaction 
is complete within about twenty four to seventy two hours at a temperature 
of about 0.degree. C. to about 30.degree. C. The product is then typically 
isolated by crystallization and filtration. The product thus formed can be 
further purified, if needed, by any of several routine methods, including 
recrystallization from common solvents, chromatography and related 
purification techniques. 
These coupled compounds can now be reduced to provide the intermediates of 
the present invention. Typical reducing agents suitable for use include 
the hydride reducing agents such as lithium aluminum hydride and sodium 
bis(2-methoxyethoxy) aluminum hydride (Red A1), which is preferred. An 
excess of reducing agent is combined with the coupled intermediate in a 
mutual solvent, typically toluene. The reaction is substantially complete 
after about one to about eighteen hours when conducted at a temperature in 
the range of about .degree. C. to about 100.degree. C. 
Some of the intermediates (Formula IIa) of the present invention can 
alternately be prepared by direct alkylation of 
3,4-dimethyl-4-(3-hydroxyphenyl) piperidine with a haloalkylnitrile 
followed by reduction of the nitrile to give a primary amine. The amine 
can optionally be reductively alkylated to give other intermediates 
contemplated by this invention. This reaction is represented by the 
following Scheme 4 wherein R.sup.4 and n are defined above and X is 
chloro, bromo or iodo: 
##STR11## 
The reaction is conducted by combining approximately equimolar amounts of 
the two starting materials in a mutual solvent. A slight excess of the 
haloalkylnitrile can be used to assure complete reaction. Typical inert 
solvents for use in this reaction include aprotic solvents such as 
N,N-dimethylformamide and the like. The reaction is conducted in the 
presence of a base, such as sodium bicarbonate or potassium carbonate, 
which acts to neutralize the hydrohalic acid formed as a side product of 
the reaction. The reaction is generally complete after about 30 minutes to 
24 hours at a temperature from about 40.degree. C. to about 100.degree. C. 
The nitrile is isolated under standard conditions. This product is then 
subjected to the hydride reducing conditions previously discussed. 
Alternatively, the nitrile can be subjected to standard catalytic 
hydrogenation over Raney nickel or a noble metal catalyst, such as 
palladium or platinum, preferably in an acidic solvent such as acetic 
acid. The product is isolated under standard conditions. 
The amine thus formed can now be functionalized under standard reductive 
alkylation procedures. The reaction proceeds by adding a slight excess of 
an appropriate aldehyde or ketone, especially a cycloalkanone such as 
cyclohexanone or cyclopentanone, to a solution of the above-synthesized 
amine and a base such as potassium hydroxide in a lower alkanol such as 
ethanol or especially methanol. This solution is stirred at room 
temperature for from 30 minutes to 18 hours. At this time an equimolar to 
slight excess of a solution of a boronhydride reducing agent, especially 
sodium cyanoborohydride, in the same lower alkanol is added and the 
reaction mixture is stirred at room temperature for an additional 30 
minutes to 18 hours. The reaction is now treated with a strong base such 
as potassium hydroxide, to decompose any boron-nitrogen complexes present 
and the product is isolated under standard conditions. The product can be 
purified as desired by chromatography, crystallization or related 
techniques. 
The compounds of the present invention can be conveniently prepared by 
contacting the particular amine intermediate prepared as described 
hereinabove in a typical amide forming reaction. For example, the amine 
can be reacted with the desired carboxylic acid compound using a coupling 
agent as described hereinabove. Alternatively, an acid anhydride can be 
used if available. Examples of these procedures are described hereinbelow. 
The following examples and preparations are provided for the purpose of 
illustration and are not to be construed as limiting the instant 
invention. 
As used in the instant examples the following terms have the meanings 
indicated. "Hobt" refers to 1-hydroxybenzotriazole hydrate. "THF" refers 
to tetrahydrofuran. "DMF" refers to dimethylformamide. "TEA" refers to 
triethylamine. "DCC" refers to dicyclohexylcarbodiimide. "di-t-BOC" refers 
to di-tert-butyl dicarbonate (O[CO.sub.2 C)CH.sub.3).sub.3 ]) and "tBOC" 
refers to --CO.sub.2 C(CH.sub.3).sub.3. "Red Al" refers to sodium 
bis(2-methoxyethoxy) aluminum hydride. "Q-H" refers to 
trans-dimethyl-4-(3-hydroxyphenyl)piperidine, i.e., where Q is 
##STR12## 
The column chromatography procedure used involved gravitational flow with 
Allied Fischer silica gel (70-150 mesh). Gradient solvent procedures were 
employed using the solvent systems specified in the particular example. 
The gradient procedure involved starting the indicated solvent system and 
incrementally changing the solvent mixture until the indicated final 
solvent system was obtained. Fractions containing product were evaporated 
generally under reduced vacuum to provide product. 
Preparative liquid chromatography was performed with the Waters Prep LC/500 
apparatus using dual silica prep pack cartridges. Gradient solvent systems 
were employed as listed in the particular example. 
For those examples indicated, purification of the specified compound was 
accomplished by preparative, centrifugal, thin layer chromatography on a 
Harrison Model 7924A Chromatron using Analtech silica gel GF rotors. The 
plate thickness and solvent system employed are indicated in the 
particular example 
Optical rotations were obtained using methanol as the solvent. 
The hydrochloride salt of the particular compound was prepared by placing 
the free base into ethyl ether. While stirring this ether solution, a 
solution of HCl in ethyl ether was added dropwise until the solution 
became acidic. A precipitate formed which was filtered and dried to 
provide the corresponding hydrochloride salt of the free base. 
Preparation I 
Synthesis of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)-piperidine 
(hereinafter "(3R,4R)-QH"). 
3-Bromophenol was combined with an equal molar amount of 2-bromopropane in 
ethanol and in the presence of potassium carbonate to provide 
3-bromoisopropoxybenzene. 
The 3-bromo-i-propoxybenzene (200 g, 0.08703 mol) was combined with THF 
(540 ml) under nitrogen and cooled to about -75.degree. C. n-Butyl lithium 
(565 ml, 0.8306 mol) was added dropwise while maintaining the mixture at 
less than -70.degree. C. After 2 hours 1,3-Dimethyl-4-piperidone (106.7 g, 
0.8389 mol) was added while maintaining the temperature of the mixture 
between -80.degree. C. and -70.degree. C. After stirring 2 hours at 
-70.degree. C., the reaction mixture was then added to 6N HCl (280 ml) 
while maintaining the temperature at 20.degree.-25.degree. C. The pH was 
adjusted to 1 with 12 N HCl. The aqueous layer containing product was 
separated and heptane (320 ml) was added along with 50% NaOH (48 ml, 
pH=13-14) and the resulting mixture allowed to stand overnight. The 
mixture was heated to 45.degree. -50.degree. C. and the upper layer was 
separated. The remaining aqueous layer was extracted with heptane (320 ml) 
at 45.degree.-50.degree. C. The combined organic fractions were washed 
with de-ionized water (120 ml) at 45.degree.-50.degree. C. The resulting 
organic layer was vacuum distilled at a pot temperature of about 
55.degree. C. at 100 mmHg. Crystallization from heptane and drying 
provided 151.8 g of 
3-(3-i-propoxyphenyl)-1,3-dimethyl-4-hydroxypiperidine. Melting point 
75.0.degree.-76.0.degree. C. 
This 4-hydroxypiperidine (463 g, 1.758 mol) was combined with ethyl acetate 
(2275 ml) under nitrogen. The solution was cooled to 0.degree.-5.degree. 
C. and ethyl chloroformate (205 ml, 2.144 mol) was added while maintaining 
the temperature below 15.degree. C. The reaction mixture was stirred for 
an additional 3 hours at room temperature. The mixture was then added to 
5N NaOH (750 ml) with stirring (pH=12-13) the organic layer was separated 
and washed with de-ionized water. Solvate was removed by evaporation at 
50.degree. C. to provide 591 g of a viscous oil. 
This viscous oil (284.8 g) was dissolved in ethanol (2.6 L) and warmed to 
55.degree. C. under nitrogen. (+)-Di-p-toluoyl-D-tartaric acid, 
monohydrate was added and the solution heated to reflux. After stirring 
overnight at room temperature, the mixture was cooled to 
0.degree.-5.degree. C. before filtering. The filter cake was washed with 
cold ethanol, air dried for 30 minutes and then vacuum dried at 
45.degree.-50.degree. C. Recrystallization from ethanol provided 201.7 g 
of product with a melting point of 153.5.degree.-155.degree. C. (dec). 
This material had a ratio of isomers by proton NMR of 97:3. 
Product prepared in this manner (411.7 g) was added to heptane (1200 ml) 
and 2N NaOH (550 ml) over a 15 minute period. pH of the mixture was 
adjusted to about 13 with 50% NaOH and stirred until all solid had 
dissolved. The layers were separated and the organic layer washed with 1N 
NaOH (275 ml), de-ionized water (275 ml) and then saturated aqueous sodium 
chloride (210 ml). The organic fraction was dried over 175 g of sodium 
sulfate, filtered and washed with heptane (125 ml). The solvate was 
removed by evaporation to provide 189.4 g of a colorless viscous oil. 
[.alpha.].sub.589 of -6.92.degree. (c=1.01 methanol). 
This product (50.0 g) and decalin (250 ml) were heated at 
190.degree.-195.degree. C. for 19 hr. under nitrogen while removing the 
ethanol formed by distillation. The solution was cooled to 
15.degree.-20.degree. C. under nitrogen and 1N HCl (155 ml) was added with 
stirring. The aqueous fraction was separated and extracted with heptane 
(2.times.30 ml). The pH of the aqueous layer was adjusted to about 13 by 
adding 50% NaOH and extracted with heptane 36.5 g of a yellow-orange 
liquid were removed from the organic layer. [.alpha.].sub.589 
=-67.24.degree.. 
This product (19.6 g) was combined with THF (175 ml) and cooled to 
-15.degree. C. to -20.degree. C. under nitrogen. n-Butyl lithium (70.0 ml) 
was added with stirring over about 0.5 hour while maintaining the internal 
temperature at about -10.degree. C. to about -20.degree. C. The mixture 
was stirred for another 0.5 hour at -10.degree. C. to -15.degree. C. and 
then cooled to -45 to -50.degree. C. Dimethyl sulfate (7.7 ml) was added 
slowly over 20-30 minutes while maintaining the temperature between 
-45.degree. C. and -50.degree. C. The mixture was then stirred for an 
additional 30 minutes at about -50.degree. C. This reaction mixture was 
then added slowly to a dilute solution of aqueous ammonium hydroxide (15.5 
ml aqueous ammonium hydroxide solution plus 55 ml de-ionized water) at 
0.degree.-5.degree. C. The mixture was warmed to 20.degree.-25.degree. C. 
over 30-45 minutes and stirred an additional 2 hours at 
20.degree.-25.degree. C. The organic layer was recovered and washed with 
de-ionized water followed by removal of solvate by evaporation to provide 
21.44 g of 4-(3-i-propoxyphenyl)-1,4,5-trimethyl-2,3-dehydropiperidine as 
an orange liquid. 
The dehydropiperidine (21.2 g) and methanol (195 ml) were combined under 
nitrogen and cooled to 0.degree.-5.degree. C. Sodium borohydride (4.2 g) 
was added slowly while maintaining the temperature below 15.degree. C. The 
reaction mixture was stirred at room temperature Acetone (21 ml) was added 
to the reaction mixture and stirred for 5 minutes. A saturated solution of 
sodium bicarbonate (25 ml) was added and the mixture stirred for 5 
minutes. The alcohols were removed by evaporation at 50.degree. C. 
De-ionized water (95 ml) and ethyl acetate (95 ml) were added and the 
resulting mixture stirred to form a solution. Phases were separated and 
the organic phase extracted with ethyl acetate (20 ml). Combined organic 
fractions were washed with de-ionized water (95 ml) and the solvate 
removed by evaporation at 50.degree. C. to provide 
(+)-4-(3-i-propoxyphenyl)-1,3,4-trimethylpiperidine as a yellow liquid 
(20.5 g). 
Dried ethanol (75 ml) and (+)-di-p-toluoyl-D-tartaric acid, monohydrate 
(12.48 g) were combined and heated to 55.degree.-60.degree. C. under 
nitrogen. An ethanol solution of the trimethyl piperidine (8.07 g and 20 
ml) was added while heating to reflux (about 75.degree. C.). De-ionized 
water (6 ml) was added to obtain a clear homogeneous solution which was 
stirred at reflux for 0.5 hour. Cooling, filtering, washing with cold 
dried ethanol, and drying provided 6.6 g of 
(+)-4-(3-i-pripoxyphenyl)-1,3,4-trimethylpiperidine/(+)-di-p-toluoyl-D-tar 
taric acid salt with a melting point 150.degree.-151.5.degree. C. (dec). 
Toluene (1400 ml) and 2N NaOH (700 ml) were combined and cooled to 
15.degree.-20.degree. C. The piperidine-tartaric salt (395.0 grams) was 
added with stirring at 15.degree.-25.degree. C. and stirred until all 
solids had dissolved. The layers were separated and the organic fraction 
washed with 1N NaOH (385 ml) and di-ionized water (385 ml). The organic 
fraction was filtered and the solvate removed by evaporation (50.degree. 
C.) to provide 164.8 g of the free base as an oil. [.alpha.].sub.589 
=+74.18.degree.. 
To a mixture of the free base 
(+)-4-(3-i-propoxyphenyl)-1,3,4-trimethyl-piperidine (25 g) and toluene 
(160 ml) at 80.degree.-90.degree. C. was added phenylchloroformate (17.2 
g). The mixture was heated at reflux (110.degree. C.) for 2 hours and then 
cooled to 45.degree.-50.degree. C. NaOH (5 ml, 50%, in 40 ml water) was 
added and the mixture stirred with cooling to room temperature. After 30 
minutes the layers were separated and the organic layer extracted with a 
1:1 mixture of methanol and 1N HCl, a 1:1 mixture of methanol and 1N NaOH, 
and then extraction by water. Evaporation of the solvate provided 33.9 g 
of the phenyl piperidineformate as an oil. 
The phenyl piperidineformate (13.95 g), 48% HBr (17.4 ml) and glacial 
acetic acid (4.7 ml) were combined and refluxed for 18 hours. The solution 
was cooled to room temperature; water (50 ml) was added; and the solution 
was extracted 3 times with t-butyl methyl ether (30 ml aliquots). The pH 
of the aqueous phase was adjusted to 8.5-8.8 with 50% NaOH solution. 
Methanol (15 ml) was added and the pH adjusted to 10.5 with the 50% NaOH 
solution. The mixture was stirred for 1.5 hours, cooled to 5.degree. C. 
and filtered to provide the white solid 
(+)-trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine (7.24 g). 
[.alpha.].sub.365 =+380.37 (methanol). 
Preparation II 
Synthesis of 
trans-3-[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-1-phenylpropylani 
ne [Q-(CH.sub.2).sub.2 -CH(C.sub.6 H.sub.5)-NH.sub.2 ]. 
To a solution of 5.0 gm (30.3 mMol) of DL-3-amino-3-phenylpropionic acid in 
a mixture of dioxane (100 ml) and water (50 ml) were added 1N aqueous 
sodium hydroxide (51.7 ml) with stirring and cooling in an ice bath 
followed by the addition of 12.67 gm (56.9 mMol) of di-tBOC. The reaction 
mixture was stirred for 1 hour at 0.degree. C. and then for an additional 
hour at room temperature. The volatiles were partially evaporated at 
reduced pressure. The remaining aqueous residue was extracted once with 
ethyl acetate, acidified to pH 2 with saturated aqueous potassium hydrogen 
sulfate and extracted three times with ethyl acetate. The combined organic 
extracts were washed with saturated aqueous sodium chloride, dried over 
magnesium sulfate and concentrated under reduced pressure. The crude 
product recovered was recrystallized from ethyl acetate/petroleum ether to 
give 6.3 gm (78.5%) of N-tBOC-3-phenyl-3-aminopropanoic acid as a 
crystalline solid. 
Calculated for C.sub.14 H.sub.19 NO.sub.4 : Theory: C, 63.38; H, 7.22; N, 
5.28 Found: C, 63.43; H, 7.42; N, 5.06 
To a solution of 1.0 gm (4.9 mMol) of 
trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine in dimethylformamide (50 
ml) were added sequentially 1.3 gm (4.9 mMol) 
N-tBOC-3-phenyl-3-aminopropionic acid, 0.662 gm (4.9 mMol) 
1-hydroxybenzotriazole and 1.011 gm (4.9 mMol) dicyclohexylcarbodiimide. 
The reaction mixture was allowed to stir for 24 hours at room temperature. 
The reaction mixture was then cooled to 0.degree. C., filtered and the 
filter cake washed with cold dimethylformamide. The filtrate was 
concentrated under reduced pressure and the residue dissolved in diethyl 
ether. The organic solution was washed with cold 1N hydrochloric acid, 
dried over potassium carbonate and concentrated under reduced pressure to 
give 1.9 gm (85.8%) 
trans-1-(N-tBOC-3-phenyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethy 
lpiperidine. 
ms (fd)=452 M.sup.+ 
Calculated for C.sub.27 H.sub.36 N.sub.2 O.sub.4 : Theory: C, 71.65 H, 
B.02; N, 6.19 Found: C, 71.90 H, 7.98N, 6.31 
To a solution of 1.9 qm (4 mMol) 
trans-1-(N-tBOC-3-phenyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethy 
lpiperidine in dichloromethane (20 ml) and anisole (5 ml) at 0.degree. C. 
was added trifluoroacetic acid (10 ml) and the solution stirred at 
0.degree. C. for 30 minutes and then at ambient temperature for an 
additional 30 minutes. The reaction mixture was then concentrated under 
reduced pressure and the residue triturated with ether and filtered. The 
resulting solid was dissolved in water and the solution was treated with 
1N sodium hydroxide to adjust pH to 9.8. This mixture was then extracted 
with ethyl acetate. The organic extracts were combined, dried over 
potassium carbonate and concentrated under reduced pressure to give 0.722 
gm (51%) crude 
trans-1-(3-phenyl-3-aminopropionyl)-4.TM.(3-hydroxyphenyl)-3,4-dimethylpip 
eridine. 
A solution of 0.700 gm (2 mMol) crude 
trans-1-(3-phenyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethylpiperi 
dine in toluene (20 ml) was added to a solution RedAl (7 ml) in toluene (40 
ml) and the solution was stirred at 60.degree. C. for 1 hour. The reaction 
mixture was then poured into ice water buffered at pH 10 and the pH 
adjusted to 9.8 with 1N hydrochloric acid. The aqueous mixture was then 
extracted two times with 3:1 n-butanol:toluene. The organic extracts were 
then combined, dried over potassium carbonate and concentrated under 
reduced pressure. The crude material was purified by flash silica gel 
chromatography, eluting with methanol. The fractions containing product 
were combined, concentrated under reduced pressure and the residue was 
triturated with hexane to give 0.33 gm (50%) of the title compound as a 
white solid. 
m.p.=50.degree.-70.degree. C. 
Calculated for C.sub.22 H.sub.31 N.sub.2 O: Theory: C, 77.83; H, 9.20; N, 
8.25; Found: C, 77.73, H, 8.97; N, 7.96. 
Preparation III 
Synthesis of 
trans-3-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-cyclohexylpropy 
lamine. [Q-(CH.sub.2).sub.2 CH-(C.sub.6 H.sub.11)NH.sub.2 ]. 
To a solution of 25 gm (152 mMol) DL-3-amino-3-phenylpropionic acid in 
acetic acid (270 ml) were added platinum oxide (5 gm) and the mixture was 
pressurized to 60 p.s.i. with hydrogen and then stirred at 40.degree. C. 
for 1 hour. The reaction mixture was cooled to room temperature and 
filtered. The filtrate was then concentrated under reduced pressure and 
the resulting residue diluted with sufficient 6N hydrochloric acid to 
effect solvation. After stirring for 1 hour at room temperature a 
precipitate began to form and the mixture was cooled to 0.degree. C. for 
18 hours. DL-3-amino-3-cyclohexylpropionic acid hydrochloride was 
recovered by filtration. A yield of 21.0 gm (64%) was realized after 
drying filtered solid in an oven under vacuum. 
m.p.=230.degree.-232.degree. C. 
ms (fd)=172 (M.sup.+ +1), 127 (M-43(CO.sub.2)) 
Calculated for C.sub.9 H.sub.18 NO.sub.2 Cl: Theory: C, 52.05; H, 8.74; N, 
6.74 Found: C, 52.00; H, 8.52; N, 6.56 
The title compound was prepared by subjecting 
DL-3-amino-3-cyclohexylpropionic acid hydrochloride (21.48 gm) to the 
sequence of reactions performed on DL-3-amino-3-phenylpropionic acid as 
described in Preparation II and 0.740 gm of product was recovered as a 
colorless solid. 
ms (fd)=345 (M.sup.+) 
Preparation IV 
Synthesis of 
trans-1-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-amino-5-methylh 
exane. [Q--(CH.sub.2).sub.2 CH(NH.sub.2)-CH.sub.2 CH(CH.sub.3).sub.2 ]. 
To a solution of 43.06 gm (500 mMol) isovaleraldehyde in ethanol (150 ml) 
were added 52 gm (500 mMol) malonic acid followed by 57.75 gm (750 mMol) 
ammonium acetate. The suspension was stirred at reflux for 5 hours and the 
resulting solution was then cooled to 0.degree. C. The resulting solid was 
filtered, washed with 1:1 ethyl acetate:ethanol (200 ml) and dried under 
vacuum for 18 hours to give 40 gm of crude 3-amino-5-methylhexanoic acid. 
ms (fd)=145 (M.sup.+) 
The title compound was prepared by subjecting DL-3-amino-5-methylhexanoic 
acid (16.1 gm, 111 mMol) to the sequence of reactions performed on 
DL-3-amino-3-phenylpropionic acid as described in Preparation II to 
provide 2.41 gm of product. 
m.p.=50.degree.-55.degree. C. 
ms (fd)=318 (M.sup.+) 
Calculated for C.sub.20 H.sub.34 N.sub.2 O: Theory: C, 75.42; H, 10.76; N, 
8.80 Found: C, 75.64; H, 10.97; N, 8.65 
Preparation V 
Synthesis of 
(-)-1,5-dioxo-5-[(phenylmethyl)amino]-pentylamino-5-[[imino(nitroamino)met 
hyl]amino]-pentanoic acid. [(C.sub.6 H.sub.5)CH.sub.2 
NHC(O)(CH.sub.2).sub.3 C(O)NHCH(CO.sub.2 H)-(CH.sub.2).sub.3 
NHC(N)NHNO.sub.2 ]. 
To a solution of 25 gm (220 mMol) glutaric anhydride in dichloromethane 
(250 ml) was added a solution of 26.4 ml (242 mMol) benzylamine in 
dichloromethane (50 ml) dropwise. The reaction mixture was stirred for 3 
hours at room temperature. The reaction mixture was then poured into 
diethyl ether (500 ml) and the resulting solid was filtered. The filter 
cake was washed with diethyl ether, dried under vacuum and then 
recrystallized from ethyl acetate to give 24.8 gm (51%) 
5-oxo-5-(phenylmethylamino)pentanoic acid as a crystalline solid. 
m.p.=83.degree.-84.degree. C. 
Calculated for C.sub.12 H.sub.13 NO.sub.2 : Theory: C, 65.14; H, 6.83; N, 
6.33 Found: C, 65.38; H, 7.09; N, 6.27 
To a solution of 2.0 gm (8.44 mMol) N-w-methyl ester-nitro-L-arginine 
hydrochloride and 1.64 gm (7.42 mMol) 5-oxo-5-(phenylmethylamino)pentanoic 
acid in dimethylformamide (75 ml) at 5.degree. C. were added 1.0 gm (7.41 
mMol) 1-hydroxybenzotriazole, 1.42 ml (13.7 mMol) diethylamine and finally 
1.53 gm (7.41 mMol) dicyclohexylcarbodiimide and the reaction mixture 
stirred at room temperature for 48 hours. The volatiles were removed under 
reduced pressure and the residue was purified by flash silica 
chromatography, eluting with 10% methanol in ethyl acetate. Fractions 
containing product were combined, concentrated under reduced pressure and 
the residue triturated with ethyl acetate to give 1.13 gm (34.9%) 
(-)-methyl 
2-(1,5-dioxo-5-((phenylmethyl)amino)pentyl)amino-5-((imino(nitroamino)-met 
hyl)amino)pentanoate. 
m.p.=97.degree.-99.degree. C. 
[.alpha.].sub.589 (CH.sub.3 OH).dbd.-8.89.degree. 
Calculated for C.sub.19 H.sub.28 N.sub.6 O.sub.6 : Theory: C, 52.41; H, 
6.25; N,19.30 Found: C, 52.13; H, 6.46; N,19.41 
To a solution of 1.1 gm (2.58 mMol) (-)-methyl 
2-(1,5-dioxo-5-((phenylmethyl)amino)pentyl)amino-5-((imino(nitroamino)meth 
yl)amino)pentanoate in methanol (30 ml) and water (60 ml) was added 0.5 N 
sodium hydroxide (5.61 ml) and the solution was stirred at room 
temperature for one hour. The volatiles were removed under reduced 
pressure and the residue redissolved in water. The aqueous phase was 
washed once with ethyl acetate and the remaining aqueous phase was made 
acidic with 1N hydrochloric acid. This phase was then extracted with 3:1 
n-butanol:toluene two times. The organic extracts were combined, dried 
over magnesium sulfate and concentrated under reduce pressure to give 700 
mg (64.4%) of the title compound as a hygroscopic solid. 
m.p.=60.degree.-80.degree. C. 
ms (fd)=421(M.sup.30) 
[.alpha.].sub.D (CH.sub.3 OH)=-6.17.degree. 
Preparation VI 
Synthesis of 
(-)-2-(1-oxo-4-((2-methyl-1-oxopropyl)-amino)butyl)amino-5-((imino(nitroam 
ino)methyl)amino)-pentanoic acid. [(CH.sub.3).sub.2 
CHC(O)NH(CH.sub.2).sub.3 C(O)NHCH(CO.sub.2 H)-(CH.sub.2).sub.3 
NHC(N)NHNO.sub.2 ]. 
To a solution of 20 gm (194 mMol) 4-aminobutanoic acid in dichloromethane 
(700 ml) were added 54 ml (407 mMol) triethylamine and the reaction 
mixture was stirred at room temperature for 10 minutes. To this mixture 
was then added a solution of 40.6 ml (407 mMol) isobutyryl chloride in 
dichloromethane (300 ml) dropwise and the resulting mixture was stirred at 
room temperature for 2 hours. The reaction mixture was filtered and the 
filtrate concentrated under reduced pressure. The residue was dissolved in 
1N sodium hydroxide and stirred for 30 minutes. This solution was then 
poured into diethyl ether, diluted with water and the phases separated. 
The aqueous phase was acidified with hydrochloric acid and then extracted 
with ethyl acetate. The organic extracts were combined, dried over 
magnesium sulfate and concentrated under reduced pressure to give an oil. 
Bulb to bulb distillation (0.05 mm Hg, pot temperature=235.degree. C.) 
gave 13.98 gm (43.1%) N-(2-methyl)propionyl-4-aminobutanoic acid. 
Calculated for C.sub.8 H.sub.15 NO.sub.3 : Theory: C, 55.47; H, 8.73; N, 
8.09 Found: C, 55.77; H, 8.98; N, 8.00 
The N-(2-methyl)propionyl-4-aminobutanoic acid (1.28 gm) was converted to 
the title compound *(0.551 gm) by the procedure described in Preparation 
V. The title compound was recovered as a hygroscopic solid. 
[.alpha.].sub.589 (CH.sub.3 OH)=+0.79.degree. 
ms (fd)=374 (M.sup.+ +1) 
Preparation VII 
Synthesis of 
4-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(cyclohexyl)-2- 
aminobutane. [Q(CH.sub.2).sub.2 -CH(NH.sub.2)CH.sub.2 (C.sub.6 H.sub.11). 
To a solution of 60 gm (349 mMol) cyclohexylacetaldehyde dimethyl acetal in 
tetrahydrofuran (50 ml) and diethyl ether (100 ml) was added 1N 
hydrochloric acid (200 ml) and the resulting mixture was stirred for 2.5 
hours at room temperature. The reaction mixture was then partitioned 
between diethyl ether and water. The ether layer was then separated, dried 
over magnesium sulfate and concentrated under reduced pressure to give 58 
gm of crude cyclohexylacetaldehyde. 
To a solution of this aldehyde in ethanol (200 ml) were added 39.9 gm (384 
mMol) malonic acid and 53.8 gm (698 mMol) ammonium acetate. The mixture 
was then stirred at reflux for 20 hours. The reaction mixture was then 
evaporated to dryness under reduced pressure and the residue dissolved in 
1N hydrochloric acid. The mixture was extracted once with ethyl acetate 
and the remaining aqueous phase was diluted with ammonium hydroxide to pH 
9.8. This aqueous phase was then extracted with 3:1 butanol:toluene. The 
organic extract was dried over magnesium sulfate and the solvent removed 
under reduced pressure. The residue was purified by flash chromatography, 
eluting with a gradient system of ethyl acetate containing from 0-20% 
methanol. Fractions containing the desired 2-amino-4-cyclohexylbutanoic 
acid were concentrated under reduced pressure to give 5.67 gm of a 
colorless solid. 
ms (fd)=186 (M.sup.+ +1) 
The title compound was prepared by subjecting 2-amino-4-cyclohexylbutanoic 
acid (5.67 gm) to the sequence of reactions performed on 
3-amino-3-phenyl-propionic acid as described in Preparation II to provide 
1.6 gm of product. 
ms (fd)=359 (M.sup.+ +1) 
Preparation VIII 
Synthesis of 
1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2-aminop 
ropane. [Q--CH.sub.2 CH(NH.sub.2)-CH.sub.2 (C.sub.6 H.sub.5)]. 
The title compound was prepared by subjecting DL-phenylalanine to the 
sequence of reactions performed on 3-amino-3-phenylpropionic acid as 
described in Preparation II to give a colorless foam. 
ms (fd)=338 (M.sup.+)339 (M.sup.+ +1) 
Preparation IX 
Synthesis of D-(+)- and 
D-(-)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2- 
aminopropane. [Q--(CH.sub.2)CH(NH.sub.2)CH.sub.2 (C.sub.6 H.sub.5)]. 
The title compound was prepared by subjecting D-phenylalanine to the 
sequence of reactions performed on 3-amino-3-phenylpropionic acid as 
described in Preparation II. Prior to the RedAl reduction of the 
corresponding 1-oxo derivatives of the title compound, the (+)- and 
(-)-diastereomers were isolatable by flash silica chromatography. The 
separation was accomplished by eluting with ethyl acetate (0-50% 
methanol). The (+)-diastereomer was the least polar of the two. Each 
diastereomer was reduced separately to give the corresponding amine. 
D-(+)-(3R,4R,R)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3- 
phenyl-2-aminopropane (DIASTEREOMER A): 
The title compound was recovered as a colorless foam. 
ms (fd)=338(M.sup.+), 340(M.sup.+ +2). 
[.alpha.].sub.365 (CH.sub.3 OH)=+202.18.degree. 
D-(-)-(3S,4S,R)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3- 
phenyl-2-aminopropane (DIASTEREOMER B): 
The title compound was recovered as a yellow foam. 
ms (fd)=338(M.sup.+), 340(M.sup.+ +2). 
[.alpha.].sub.365 (CH.sub.3 OH)=-225.22.degree. 
Preparation X 
Synthesis of 
L-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2-amin 
opropane dihydrochloride. [Q-CH.sub.2 -CH(NH.sub.2)CH.sub.2 (C.sub.6 
H.sub.5)]. 
The title compound was prepared by subjecting L-phenylalanine to the 
sequence of reactions performed on 3-amino-3-phenylpropionic acid as 
described in Preparation II. The title compound was recovered as a 
colorless foam. 
m.p.=&gt;196.degree. C.(decomposition) 
ms (fd)=338(M.sup.+), 339(M.sup.+ +1) 
Calculated for C.sub.22 H.sub.30 N.sub.2 O.2HCl Theory: C, 64.23; H, 7.84; 
N, 6.81 Found: C, 63.95; H, 7.59; N, 6.70 
Preparation XI 
Synthesis of 
L-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-cyclohexyl-2- 
aminopropane. [Q-CH.sub.2 CH(NH.sub.2)CH.sub.2 (C.sub.6 H.sub.11)]. 
To a solution of 2.65 gm (10 mMol) L-N-tBOC-phenylalanine in ethanol (96 
ml) was added 1.3 gm platinum oxide. The reaction vessel was then 
pressurized to 60 p.s.i. with hydrogen and the reaction mixture was 
stirred at room temperature for 3 hours. The reaction mixture was then 
filtered and the filtrate concentrated under reduced pressure. The 
L-N-tBOC-2-amino-3-cyclohexylpropionic acid (2.6 gm, 96%) was recovered as 
a colorless foam. 
[.alpha.].sub.589 (CH.sub.3 OH)=-8.24 
[.alpha.].sub.365 (CH.sub.3 OH)=-21.77 
Calculated for C.sub.14 H.sub.25 NO.sub.4 : Theory: C, 61.97; H, 9.29; 
N,5.16 Found: C, 61.70: H, 9.03: N, 5.04 
The title compound was prepared by subjecting 
L-N-tBOC-2-amino-3-cyclohexylpropionic acid to the sequence of reactions 
performed on 3-amino-3-phenylpropionic acid as described in Preparation 
II. The title compound was recovered as a colorless foam. 
[.alpha.].sub.D (CH.sub.3 OH)=+73.12.degree. 
ms (fd)=356 (M+) 
Preparation XII 
Synthesis of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl 
amine. [Q-(CH.sub.2).sub.2 NH-(C.sub.6 H.sub.11)]. 
To a solution of 5.0 gm (24.3 mMol) 
trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine in dimethylformamide (250 
ml) were added 2.05 gm (26.7 mMol) sodium bicarbonate and 3.22 gm (26.7 
mMol) bromoacetonitrile. The reaction mixture was stirred at reflux for 
1.5 hours and the solvent then removed under reduced pressure. The residue 
was partitioned between ethyl acetate and water and the aqueous phase was 
then adjusted to pH=9.8 with 1N aqueous sodium hydroxide. The phases were 
separated and the aqueous phase was extracted with ethyl acetate. All of 
the ethyl acetate extracts were combined, dried over potassium carbonate 
and the volatiles removed under reduced pressure to give 6.0 gm of 
trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylacetonitrile as a 
yellow viscous oil. A portion of this oil was converted to the 
corresponding hydrochloride salt which was recovered as a colorless solid. 
m.p.=210.degree.-211.degree. C. 
Calculated for C.sub.145 H.sub.20 N.sub.2 O.HCl: Theory: C, 64.16; H, 7.54; 
N, 9.98 Found: C, 64.11; H, 7.53; N, 9.79 
To a solution of 35 ml (100 mMol) RedAl (3.5 M in toluene) was added 
dropwise a solution of 6.0 gm (24.3 mMol) 
trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylacetonitrile in 
toluene (100 ml). The resulting solution was stirred for 1 hour at 
60.degree. C. The reaction mixture was then cooled to room temperature and 
then poured into a slurry of ice/water buffered to pH 10.00. The aqueous 
phase was adjusted to pH of 9.8 with 1N hydrochloric acid and the mixture 
then extracted with 3:1 butanol:toluene. The organic phases were combined, 
dried over potassium carbonate and the volatiles removed under reduced 
pressure. The solid residue was crystallized from ethyl acetate/hexane 
(1:1) to give 3.5 gm (57.6%) 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine as a 
colorless solid. 
m.p.=114.degree.-115.degree. C. 
The mother liquors from the crystallization were purified by silica gel 
chromatography. Fractions shown to contain product were combined and 
concentrated under reduced pressure to give colorless crystals which were 
slurried in hexane and filtered to give an additional 1.1 gm (18.1%) the 
desired 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine. 
m.p.=129.degree.-130.degree. C. 
Calculated for C.sub.15 H.sub.24 N.sub.2 O: Theory: C, 72.54; H, 9.74; N, 
11.28 Found: C, 72.34; H, 9.69; N, 11.48 
A solution of 1.0 gm (4 mMol) 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine in a 
minimal volume of methanol was saturated with hydrogen chloride. The 
volatiles were removed under reduced pressure to give 1.38 gm of the 
corresponding dihydrochloride salt. To a solution of this salt in methanol 
(12 ml) was added 71 mg (1.26 mMol) potassium hydroxide and the solution 
was stirred until the hydroxide dissolved. To this solution was then added 
423 mg (4.3 mMol) cyclohexanone and the mixture stirred for 30 minutes at 
room temperature. To this mixture was added a solution of 105 mg (1.67 
mMol) sodium cyanoborohydride in methanol (10 ml) and the reaction mixture 
was stirred for an additional 30 minutes. An additional 70 mg (1.26 mMol) 
potassium hydroxide were added and the reaction mixture stirred for 15 
minutes. The reaction mixture was then poured into a slurry of ice/water 
and the pH adjusted to 9.8 with 1N NaOH. The mixture was then extracted 
with 3:1 butanol:toluene. The organic extracts were combined, dried over 
potassium carbonate and concentrated under reduced pressure. The residue 
was purified by silica gel chromatography, eluting with methanol. 
Fractions containing product were combined and concentrated under reduced 
pressure. The residue was triturated with ethyl acetate and the resulting 
solid crystallized from ethyl acetate/hexane (1:1) to give the title 
compound as a colorless crystalline solid (830 mg, 62.9%). 
m.p.=143.degree.-145.degree. C. 
Calculated for C.sub.21 H.sub.34 N.sub.2 O: Theory: C, 76.31; H, 10.37; 
N,8.48 Found: C, 76.11; H, 10.51; N, 8.52 
Preparation XIII 
Synthesis of 
N-cyclopentyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
lamine. [Q-(CH.sub.2).sub.2 gNH(C.sub.5 H.sub.9)]. 
A solution of 2.00 gm (8 mMol) 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine in a 
minimal volume of methanol was contacted with 656 mg (8 mMol) 
cyclopentanone according to the procedure described in Preparation XII. 
The title compound was recovered as a colorless crystalline solid (1.21 
gm, 47.9%). 
m.p.=150.degree.-152.degree. C. 
ms (fd)=316(M.sup.+) 
Calculated for C.sub.20 H.sub.32 N.sub.2 O: Theory: C, 75.90; H, 10.19; N, 
8.85 Found: C, 75.73; H, 10.14; N, 8.67 
Preparation XIV 
Synthesis of 
N-cyclohexyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propy 
lamine. [Q-(CH.sub.2).sub.3 NH-(C.sub.6 H.sub.11)]. 
The procedure of Preparation II was followed. 
A. Preparation of N-tBOC-N-cyclohexyl-3-aminopropionic acid 
The following materials were used: 
N-cyclohexyl-3-aminopropionic acid (19 gm) 
Dioxane (382 ml) 
Water (191 ml) 
Aqueous 1N sodium hydroxide (191 ml) 
Di-tert-butyl dicarbonate (47 gm) to give 10.26 gm of product 
recrystallized from hexane. 
m.p.=104.degree. -105.degree. C. 
Calculated for C.sub.14 H.sub.25 NO.sub.4 : Theory: C, 61.97; H, 9.29; N, 
5.16 Found : C, 61.68; H, 9.02; N, 5.27 
B. Preparation of 
trans-1-(N-tBOC-N-cyclohexyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dim 
ethylpiperidine 
The following materials were used: 
trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine (2.0 gm) 
N-tBOC-N-cyclohexyl-3-aminopropionic acid (2.64 gm) 
DCC (2.013 gm) 
HOBT (1.318 gm) 
DMF (100 ml) 
4.5 gm of product were obtained. 
ms (fd)=441 (M.sup.+ +1) 
C. Preparation of 
trans-1-(N-cyclohexyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethylpi 
peridine 
The following materials were used: 
Product from B above (4.54 gm) 
6N HCl (200 ml) 
2.8 gm of product were recovered. 
ms (fd)=359 (M.sup.+ +1) 
D. Preparation of 
1-(N-cyclohexyl-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidi 
ne 
The following materials were used: 
RedAl (9 ml, 3.4 molar in toluene) 
Toluene (100 ml) 
Product from C above (2.8 gm) in toluene (70 ml) 
2.62 gm of product were recovered. 
ms (fd)=262 (M.sup.+), 263 (M.sup.+ +1) 
Preparation XV 
Synthesis of 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propylamine. 
[Q-(CH.sub.2).sub.3 NH.sub.2 ]. 
The sequence of reactions described in Preparation II were followed. 
A. Preparation of 
trans-1-(N-tBOC-3-aminopropionyl)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidi 
ne 
The following materials were used: 
N-tBOC-3-aminopropionic acid (2.76 gm) 
Trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine 
(3 gm) 
HOBT (2.38 gm) 
DCC (3 gm) 
Dimethylformamide (150 ml) 
6.36 gm of product were obtained 
B. Hydrolysis of t-BOC 6N HCl (200 ml) 
C. Formation of title compound 
The following materials were used: 
Product from B above (5.25 gm) 
Toluene (300 ml) 
RedAl (30 ml) 
Inverse addition was required due to solubility. 3.1 gm of product were 
recovered. 
ms (fd)=263 (M.sup.+ +1) 
Preparation XVI 
Synthesis of 
N-phenyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamin 
e. [Q-(CH.sub.2).sub.2 NH(C.sub.6 H.sub.5)]. 
To a solution of 2.0 gm (9.72 mMol) 
trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine and 1.48 gm (9.72 mMol) 
N-phenylglycine in dimethylformamide (200 ml) at 5.degree. C. were added 
sequentially 1.32 gm (9.72 mMol) 1-hydroxybenzotriazole and 2.02 gm (9.72 
mMol) dicyclohexylcarbodiimide and the reaction mixture stirred at room 
temperature for 72 hours. The reaction mixture was cooled to 0.degree. C., 
filtered and the filtrate was concentrated under reduced pressure. The 
residue was purified by silica gel chromatography, eluting with ethyl 
acetate. Fractions containing 
N-phenyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-2-oxo-et 
hylamine were combined and concentrated under reduced pressure to give 3.11 
gm (94.7%) of a colorless foam. 
ms (fd)=338(M.sup.+) 
To a solution of 10 ml (35 mMol) RedAl (3.5 M in toluene) was added a 
solution of 3.0 gm (8.87 mMol) 
N-phenyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-2-oxo-et 
hylamine in toluene (100 ml) dropwise. The reaction mixture was then 
stirred for 1 hour at 60.degree. C. The solution was cooled to room 
temperature and poured into an ice/water buffered to pH 10.00. The pH of 
the aqueous phase was adjusted to 9.8 with 1N HCl and the mixture was 
extracted well with 3:1 butanol:toluene. The organic phases were combined, 
dried over potassium carbonate and concentrated under reduced pressure. 
The residue is purified by silica gel chromatography, eluting with ethyl 
acetate. Fractions containing the title compound are combined and 
concentrated under reduced pressure. Crystalline residue is slurried in 
hexane and filtered to give the title compound as a white crystalline 
solid (2.2 gm, 76.6%). 
m.p.=112.degree.-113.degree. C. 
ms (fd)=324(M.sup.+) 
Calculated for C.sub.21 H.sub.27 N.sub.2 O: Theory: C, 77.74; H, 8.70; N, 
8.63 Found: C, 77.84; H, 8.92; N, 8.34 
Preparation XVII 
Synthesis of 
N-phenyl-3-[trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]propylami 
ne. [Q-(CH.sub.2).sub.3 NH(C.sub.6 H.sub.5)]. 
The procedure of Preparation XVI was followed with the following materials: 
N-phenyl-3-aminopropionic acid (1.65 gm, 10 mMol), 
trans-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine 
(1.65 gm) 
HOBT (1.35 gm) 
DCC (2.06 gm) 
DMF (100 ml) 
2.0 gm of 
N-phenyl-3-[trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-2-oxo-pr 
opylamine were recovered. 
ms (fd)=351 (M.sup.+) 
This product was reduced (1.66 gm) in toluene (100 ml) with RedAl (10 ml) 
to provide 500 mg of title product. 
ms (fd)=338 (M+) 
Preparation XVIII 
Synthesis of 
N-cyclohexylmethyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)ethylamine. [Q-(CH.sub.2).sub.2 -NHCH.sub.2 (C.sub.6 H.sub.11)]. 
The sequence of reactions described in Preparation XVI were used with the 
following materials to provide the title compound. 
2-trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine (1.0 gm) 
cyclohexylcarboxylic acid (512 mg) 
HOBT (540 mg) 
DCC (824 mg) 
DMF (60 ml) 
1.38 gm of 
N-(cyclohexylcarbonyl)-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperid 
inyl)ethylamine were recovered. 
ms (fd)=358 (M+), 359 (M.sup.+ +1) 
IR: 1671.3 cm.sup.-1 (C=O) 
This product (1.3 gm) in toluene (100 ml) was reduced with RedAl (12 ml) 
using inverse addition to provide 280 mg of product. 
ms (fd)=344 (M.sup.+), 345 (M.sup.+ +1) 
Preparation XIX 
Synthesis of 
N-cyclohexylmethyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)propylamine. [Q-(CH.sub.2).sub.3 NHCH.sub.2 (C.sub.6 H.sub.11)]. 
A 1.42 gm (5.4 mMol) portion of 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propylamine 
[Preparation XV] and 692 mg (5.4 mMol) cyclohexanecarboxylic acid were 
subjected to the sequence of reactions described in Preparation XVI to 
give the title compound as a colorless foam. 
ms (fd)=358(M.sup.+) 
Preparation XX 
Synthesis of 
N-(3-methyl)butyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl) 
ethylamine. [Q-(CH.sub.2).sub.2 NH(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 ]. 
An 800 mg (3.2 mMol) portion of 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylamine 
[Preparation XII] and 337 mg (3.2 mMol) 3-methylbutanoic acid were 
subjected to the sequence of reactions described in Preparation XVI to 
give the title compound as a colorless foam. 
ms (fd)=318(M.sup.+), 319(M.sup.+ +1) 
Preparation XXI 
Synthesis of 
N-(2-methyl)propyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)propylamine. [Q-(CH.sub.2).sub.3 -NHCH.sub.2 CH(CH.sub.3).sub.2 ]. 
A 1.42 gm (5.4 mMol) portion of 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propylamine 
[Preparation XV] and 475 mg (5.4 mMol) 2-methylpropanoic acid were 
subjected to the sequence of reactions described in Preparation XVI to 
give the title compound as a colorless foam. 
ms (fd)=318(M.sup.+) 
EXAMPLE 1 
4-[(3-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(cyclohexylmethyl) 
propyl)amino]-4-oxobutanoic acid monohydrate [Q-(CH.sub.2).sub.2 
CH[CH.sub.2 (C.sub.6 H.sub.11)]NHC(O)(CH.sub.2).sub.2 C(O)-OH]. 
To a solution of 500 mg (1.33 mMol) 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(cyclohexylmeth 
yl)propylamine (Prep VII) in dimethylformamide (50 ml) were added 199 mg 
(1.99 mMol) of succinic anhydride and the reaction mixture was stirred at 
room temperature for 3 days. Volatiles were removed under reduced pressure 
and the residue was purified by flash silica chromatography, eluting with 
1:1 ethyl acetate methanol. Fractions containing product were concentrated 
under reduced pressure and the solid residue was crystallized from ethyl 
acetate. The title compound was isolated as a crystalline solid (270 mg, 
42.6%). 
m.p.=117.degree.-120.degree. C. 
Calculated for C.sub.27 H.sub.42 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
68.04; H, 9.30; N, 5.87 Found: C, 68.08; H, 9.02; N, 5.91 
EXAMPLE 2 
4-[[1-[2-[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]-ethyl]-3-methylbu 
tyl)amino]-4-oxobutanoic acid ethyl ester. [Q-(CH.sub.2).sub.2 CH[CH.sub.2 
CH(CH.sub.3).sub.2 ]NHC(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 CH.sub.3 ]. 
To a solution of 1.0 gm (3.13 mMol) of 
trans-1-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-amino-5-methylh 
exane (Prep IV) in dimethylformamide (50 ml) were added sequentially 450 mg 
(3.13 mMol) monoethyl succinate, 420 mg (3.13 mMol) 1-hydroxybenzotriazole 
and 640 mg (3.13 mMol) dicyclohexylcarbodiimide. The reaction mixture was 
allowed to stir for 72 hours at room temperature. The reaction mixture was 
concentrated under reduced pressure and the residue was partitioned 
between ethyl acetate and water. The solution was adjusted to pH=9.8 with 
1N sodium hydroxide and the layers separated. The organic phase was washed 
with water, dried over potassium carbonate and concentrated under reduced 
pressure to give a solid residue which was purified by high pressure 
liquid chromatography, eluting with 20% methanol in ethyl acetate. Two 
pairs of diastereomers were separated by the chromatography. The least 
polar pair of diastereomers (A) recovered was isolated as the 
hydrochloride salt (520 mg, 34%). 
m.p.=65.degree.-75.degree. C. 
Calculated for C.sub.26 H.sub.42 N.sub.2 O.sub.4.HCl: Theory: C, 64.64; H, 
8.97; N, 5.80 Found: C, 64.44; H, 8.94; N, 5.94 
The second pair of diastereomers (B) recovered was isolated as a hydrate of 
the free base (260 mg, 17.8%). 
m.p.=70.degree.-85.degree. C. 
Calculated for C.sub.26 H.sub.42 N.sub.4 O.sub.4.H.sub.2 O: Theory: C, 
62.32; H, 9.05; N, 5.59 Found: C, 62.60; H, 8.88; N, 5.58 
EXAMPLE 3 
5-((1-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)-3-met 
hylbutyl)amino)-5-oxopentanoic acid ethyl ester monohydrochloride (232959). 
[Q-(CH.sub.2).sub.2 -CH[CH.sub.2 CH(CH.sub.3).sub.2 NHC(O)(CH.sub.2).sub.3 
C(O)OCH.sub.2 CH.sub.3.HCl]. 
A solution of 1.0 gm (3.13 mMol) of 
trans-1-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-amino-5-methylh 
exane (Prep IV) in dimethylformamide (50 ml) was reacted with 500 mg (3.13 
mMol) mono-ethyl glutarate under the conditions described in Example 2. 
The least polar pair of diastereomers was isolated as the hydrochloride 
salt (390 mg, 25%). 
m.p.=65.degree.-68.degree. C. 
Calculated for C.sub.27 H.sub.44 N.sub.2 O.sub.4.HCl: Theory: C, 65.24; H, 
9.12; N, 5.64 Found: C, 65.45; H, 8.82; N, 5.68 
The second pair of diastereomers (B) recovered was also isolated as the 
hydrochloride salt (255 mg, 16.3%). 
m.p.=50.degree.-70.degree. C. 
Calculated for C.sub.27 H.sub.46 ClN.sub.2 O.sub.4 : Theory: C, 65.24; H, 
9.12; N, 5.64 Found: C, 64.91; H, 8.97; N, 5.34 
EXAMPLE 4 
5-[[1-(2-methylpropyl)-3-[4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]pr 
opyl]amino]-5-oxopentanoic acid. [Q-(CH.sub.2).sub.2 CH[CH.sub.2 
CH(CH.sub.3).sub.2 ]NHC(O)(CH.sub.2).sub.3 C(O)OH]. 
Trans-1-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-amino-5-methylhe 
xane (400 mg, 1.25 mMol) (Prep IV) was contacted with glutaric anhydride 
(158 mg, 1.38 mMol) and the mixture stirred for 18 hours. The solvent was 
removed and the residue was purified by silica column chromatography 
eluting with ethanol/methanol 1:1. After removal of solvent from fractions 
containing product, the product was dissolved in hot acetonitrile and 
filtered. The acetonitrile was removed by vacuum and the solid 
recrystallized from ethyl acetate to give the title compound as a 
crystalline solid (300 mg, 55.5%). 
m.p=65.degree.-71.degree. C. 
Calculated for C.sub.25 H.sub.40 N.sub.2 O.sub.4 : Theory: C. 69.41; H, 
9.32; N, 6.48 Found: C, 69.18; H, 9.07; N, 6.38 
EXAMPLE 5 
5-((3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-cyclohexylpr 
opyl)amino)-5-oxo-pentanoic acid monohydrochloride monohydrate. 
(Q-(CH.sub.2).sub.2 CH(C.sub.6 H.sub.11)NHC(O)(CH.sub.2).sub.3 
C(O)OH.HCl.H.sub.2 O]. 
Trans-3-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-cyclohexylpropyl 
amine (800 mg, 2.32 mMol) (Prep III) was treated with glutaric anhydride 
and stirred overnight. The solvent was removed and the residue was passed 
through a silica column eluting with ethyl acetate and methanol (1:1). The 
recovered residue was heated in a mixture of acetonitrile and methanol 
(1:1), filtered and the solvent removed. The residue was taken into 
acetonitrile, filtered and the acetonitrile removed to provide a white 
solid. 
m.p.=120.degree.-130.degree. C. 
ms (fd)=460 (M.sup.+) 
The residue was converted to the HCl salt and triturated with ethyl ether 
to provide the hydrochloride salt as a monohydrate (410 mg, 38.5%). 
m.p.=80.degree.-90.degree. C. 
ms (fd)=460 (M.sup.+ +1) 
Calculated for C.sub.27 H.sub.42 N.sub.2 O.sub.4.HCl.H.sub.2 O: Theory: 
C,63.20; H, 8.77; N, 5.45 Found: C,63.06; H, 8.37; N, 5.46 
EXAMPLE 6 
N-(3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropyl) 
acetamide. [Q-(CH.sub.2).sub.2 -CH(C.sub.6 H.sub.5)NHC(O)CH.sub.3 ]. 
To a solution of 870 mg (2.57 mMol) 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropylami 
ne (Prep II) in dichloromethane (30 ml) were added 0.71 ml (5.13 mMol) 
triethylamine followed by 0.36 ml (5.13 mMol) acetyl chloride and the 
solution was stirred at room temperature for 1 hour. The volatiles were 
removed under reduced pressure and the residue partitioned between water 
and ethyl acetate. The pH of the mixture was adjusted to 9.8 with 1N 
sodium hydroxide and the phases separated. The organic phase was dried 
over potassium carbonate and concentrated under reduced pressure to give 
1.2 gm (100+%) crude 
N-(3-(trans-4-(3-acetoxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropyl 
)acetamide. 
To a solution of 1.2 gm 
N-(3-(trans-4-(3-acetoxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropyl 
)-acetamide in methanol (50 ml) was added 25% aqueous sodium hydroxide (50 
ml) and the solution was stirred at room temperature for 2 hours. The 
volatiles were removed under reduced pressure and an aqueous solution of 
the residue adjusted to pH 9.8 with 10% hydrochloric acid. The mixture was 
then extracted with 3:1 butanol:toluene. The organic phases were combined, 
dried over magnesium sulfate and concentrated under reduced pressure to 
give 1.1 gm of a solid residue. The residue was triturated with hexane and 
the filtered solid purified by flash silica chromatography eluting with 
ethyl acetate/methanol (1:1) to give the title compound as a solid (320 
mg, 16.4%). 
m.p.=78.degree.-85.degree. C. 
Calculated for Cz&lt;H.sub.32 N.sub.2 Oz: Theory: C, 75.75; H, 8.48; N, 7.36 
Found: C, 75.45; H, 8.37; N, 7.08 
EXAMPLE 7 
5-((1-(cyclohexylmethyl)-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperi 
dinyl)propyl)amino)-5-oxopentanoic acid monohydrochloride monohydrate. 
[Q-(CH.sub.2).sub.2 CH-[CH.sub.2 (C.sub.6 H.sub.11)]NHC(O)(CH.sub.2).sub.3 
C(O)OH.HCl.H.sub.2 O]. 
4-(Trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(cyclohexyl)-2-a 
minobutane (500 mg, 1.39 mMol) [Preparation VII] was treated with glutaric 
anhydride and the title compound isolated under the conditions described 
in Example 1. The title compound was isolated as a hydrochloride salt 
monohydrate (500 mg, 68.4%). 
m.p.=95.degree.-100.degree. C. 
Calculated for C.sub.28 H.sub.44 N.sub.2 O.sub.4.HCl.H.sub.2 O: Theory: C, 
63.80; H, 8.99; N, 5.31 Found: C, 63.54; H, 8.93; N, 4.94 
EXAMPLE 8 
(-)-N-(1-phenyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)pro 
pyl)-2-((1,5-dioxo-5-(phenylmethyl)amino)pentyl)amino-5-((imino(nitroamino) 
methyl)-amino)pentanamide. [Q-(CH.sub.2).sub.2 CH(C.sub.6 
H.sub.5)NHC(O)CH[(CH.sub.2).sub.3 -NHC(NH)NHNO.sub.2 
]NHC(O)(CH.sub.2).sub.3 C(O)NHCH.sub.2 (C.sub.6 H.sub.5)]. 
3-(Trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropylamin 
e (500 mg, 1.47 mMol) (Prep II) and 
(-)-2-(1,5-dioxo-5-((phenylmethyl)amino)-pentane)-5-((imino(nitroamino)met 
hyl)amino)pentanoic acid [Preparation V] (622 mg, 1.47 mMol) were coupled 
following the procedure of Example 2 to give the title compound (386 mg, 
35.3%). 
m.p.=100.degree.-105.degree. C. (foam) 
[.alpha.].sub.589 (CH.sub.3 OH)=-3.546.degree. 
[.alpha.].sub.365 (CH.sub.2 OH)=-7.092 
Calculated for C.sub.40 H.sub.54 N.sub.8 O.sub.6 : Theory: C, 64.76; H, 
7.20; N, 15.10 Found: C, 65.05; H, 7.50; N, 14.93 
EXAMPLE 9 
(-)-N-(1-phenyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)pro 
pyl)-2-((1-oxo-4-(2-methyl-1-oxopropyl)amino) 
butyl)amino-5-((imino(nitroamino)-methyl)amino)pentanamide. 
[Q-(CH.sub.2).sub.2 CH(C.sub.6 H.sub.5)NHC(O)CH-[(CH.sub.2).sub.3 
NHC(NH)NHNO.sub.2 ]NHC(O)(CH.sub.2).sub.3 NHC(O)CH(CH.sub.3).sub.2 ]. 
3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-phenylpropylamin 
e (500 mg, 1.47 mMol) (Prep II) and 
(-)-2-(1-oxo-4-((2-methyl-1-oxopropyl)-amino)butyl)amino-5-((imino(nitroam 
ino)methyl)amino)-pentanoic acid [Preparation VI] (550 mg, 1.47 mMol) were 
coupled as described in Example 2 except the mixture was stirred for 48 
hours and the residue was dissolved in 3:1 butanol/toluene prior to 
purification by chromatography. The title compound (170 mg, 15.8%) was 
recovered as the hydrochloride salt. 
m.p.=130.degree.-150.degree. C. (decomposition) 
[.alpha.].sub.D (CH.sub.5 OH)=-6.69.degree. 
Calculated for C.sub.36 H.sub.54 N.sub.8 O.sub.6.HCl: Theory: C, 59.21; H, 
7.45; N, 15.34 Found: C, 58.94; H, 7.67; N, 15.10 
EXAMPLE 10 
Ethyl 
trans-(3R,4R,R)-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-( 
D-(phenylmethyl)ethyl)amino))-3-oxopropionate hydrochloride (DIASTEREOMER 
A) [Q-CH.sub.2 CH[CH.sub.2 -(C.sub.6 H.sub.5)NHC(O)CH.sub.2 C(O)OCH.sub.2 
CH.sub.3.HCl]. 
To a solution of 500 mg (1.S mMol) 
D-(+)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2- 
aminopropane (Diastereomer A from [Preparation IX]) and 152 mg (1.5 mMol) 
triethylamine in dichloromethane (40 ml) was added a solution of 226 mg 
(1.5 mMol) ethyl malonyl chloride in dichloromethane (10 ml) dropwise at 
0.degree. C. The reaction mixture was allowed to stir for 1 hour at 
0.degree. C. and then for an additional 2 hours at room temperature. The 
reaction mixture was then concentrated to dryness under reduced pressure. 
The residue was dissolved in 3:1 butanol toluene and washed with saturated 
aqueous sodium chloride. The remaining organic phase was dried over 
potassium carbonate and concentrated under reduced pressure. The residue 
was purified by silica gel chromatography, eluting with a gradient system 
of hexane containing 10-100% ethyl acetate. Fractions containing the 
desired product were combined, concentrated under reduced pressure and the 
residue converted to the hydrochloride salt to give the title compound ( 
400 mg, 54.5%) as a colorless solid. 
m.p.=89.degree.-93.degree. C. 
ms (fd)=452(M.sup.+) 
[.alpha.].sub.365 (CH.sub.3 OH)=+22.46.degree. 
Calculated for C.sub.27 H.sub.36 N.sub.2 O.sub.4.HCl: Theory: C, 66.31; H, 
7.63; N, 5.73 Found: C, 66.09; H, 7.78; N, 5.61 
EXAMPLE 11 
Trans-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylme 
thyl)ethyl)amino))-3-oxopropionic acid (DIASTEREOMER A) (QCH.sub.2 
CH[CH.sub.2 (C.sub.6 H.sub.5)]NHC(O)CH.sub.2 C(O)OH]. 
To a solution of 700 mq (1.57 mMol) ethyl 
trans-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylm 
ethyl)ethyl)amino)-3-oxopropionate (prepared as in Example 10) in methanol 
(50 ml) were added 430 mg (3.14 mMol) potassium carbonate and the mixture 
was stirred at room temperature for 3 hours. The reaction mixture was 
filtered and the volatiles removed at room temperature. The residue was 
purified by silica gel chromatography, eluting with a gradient system of 
ethyl acetate containing 10-50% methanol to give the title compound as a 
colorless solid (500 mg, 75.1%). 
m.p.=119.degree.-123.degree. C. 
ms (fd)=424(M.sup.+), 425(M.sup.+ +1) 
[.alpha.].sub.365 (CH.sub.3 OH)=(+)48.71.degree. 
Calculated for C.sub.25 H.sub.32 N.sub.2 O.sub.4 Theory: C, 70.73; H, 7.60; 
N, 6.60 Found: C, 70.42; H, 7.40; N, 6.47 
EXAMPLE 12 
Ethyl 
trans-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylm 
ethyl)ethyl)amino))-3-oxopropionate hydrochloride (DIASTEREOMER B) 
[Q-CH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.5)]NHC(O)CH.sub.2 C(O)OCH.sub.2 
CH.sub.3.HCl]. 
1.0 gm (3.0 mMol) 
D-(-)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2- 
aminopropane (Diastereomer B from Preparation IX) was subjected to the 
reaction conditions described in Example 10 to give the title compound as 
a colorless solid (200 mg, 13.6%). 
m.p.=95.degree.-98.degree. C. 
ms (fd)=452(M.sup.+), 453(M.sup.+ +1). 
[.alpha.].sub.365 (CH.sub.3 OH)=-150.degree. 
Calculated for C.sub.27 H.sub.36 N.sub.2 O.sub.4.HCl: Theory: C, 66.31; H, 
7.63; N, 5.73 Found: C, 66.12; H, 7.41; N, 5.51 
EXAMPLE 13 
Trans-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylme 
thyl)ethyl)amino))-3-oxopropionic acid monohydrate (DIASTEREOMER B). 
[Q-CH.sub.2 CH[CH.sub.2 (C.sub.6 H.sub.5)]-NHC(O)CH.sub.2 C(O)OH]. 
To a solution of 630 mg (1.4 mMol) ethyl 
trans-3-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylm 
ethyl)ethyl)amino))-3-oxopropionate (prepared as in Example 12) in a 
solvent mixture of tetrahydrofuran (18 ml), methanol (6 ml) and water (6 
ml) were added 176 mg (4.2 mMol) lithium hydroxide and the reaction 
mixture was allowed to stir at room temperature for 3 hours. The reaction 
mixture was then poured into 10% hydrochloric acid, diluted with water and 
extracted with 3:1 butanol:toluene. The organic extracts were combined, 
washed with water, dried over magnesium sulfate and concentrated under 
reduced pressure. The residue was purified by silica gel chromatography, 
eluting with a gradient system of ethyl acetate containing 0-50% methanol. 
Fractions containing product were combined and concentrated under reduced 
pressure to give 430 mg (69.4%) of the title compound as a colorless 
solid. 
m.p.=137.degree.-140.degree. C. 
ms (fd)=424(M.sup.+), 425(M.sup.+ +1) 
[.alpha.].sub.365 (CH.sub.3 OH)=-248.degree. 
Calculated for C.sub.25 H.sub.34 N.sub.2 O.sub.5 : Theory: C, 67.85; H, 
7.60; N, 6.60 Found: C, 67.55; H, 7.76; N, 6.48 
EXAMPLE 14 
[2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl) 
-1-phenylmethyl-ethylamino]-4-oxobutanoic acid. [QCH.sub.2 CH[CH.sub.2 
(C.sub.6 H.sub.5)]NHC(O)(CH.sub.2).sub.2 C(O)OH. 
A solution of 700 mg (2.1 mMol) 
DL-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2-ami 
nopropane [Preparation VIII] and 220 mg (2.2 mMol) succinic anhydride in 
dichloromethane (50 ml) were combined and stirred at room temperature for 
3 hours. The mixture was filtered and the solid was recrystallized from an 
ethyl acetate, acetone, water (5:4:1) mixture to provide the title 
compound as a colorless solid (170 mg, 18.4%). 
m.p.=162.5.degree.-164.degree. C. 
ms (fd)=438(M.sup.+), 439(M.sup.+ +1) 
Calculated for C.sub.26 H.sub.34 N.sub.2 O.sub.4 : Theory: C, 71.21; H, 
7.81; N, 6.39 Found: C, 70.97; H, 7.70; N, 6.09 
EXAMPLE 15 
Trans-5-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-1-(D-(phenylme 
thyl)ethyl)amino))-5-oxopentanoic acid monohydrate. [Q-CH.sub.2 CH[CH.sub.2 
(C.sub.6 H.sub.5)]-NHC(O)(CH.sub.2).sub.3 C(O)OH]. 
A solution of 500 mg (1.5 mMol) 
(+)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2-am 
inopropane Preparation VIII and 188 mg (1.5 mMol) glutaric anhydride in 
dimethylformamide (50 ml) were stirred overnight at room temperature. The 
mixture was evaporated to dryness and the solid passed through a silica 
column eluting with an ethyl acetate to methanol gradient solvent. The 
title compound was isolated after recrystallization from acetonitrile 
water (9:1) as a colorless solid (370 mg, 52.4%). 
m.p.=98.5.degree.-101.degree. C. 
ms (fd)=452(M.sup.+), 453(M.sup.+ +1) 
Calculated for C.sub.27 H.sub.36 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
68.84; H, 8.09; N, 5.95 Found: C, 68.98; H, 7.92; N, 6.17 
EXAMPLE 16 
(+)-5-[[2-cyclohexyl-1-[[trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidin 
ylmethyl]ethyl]amino]-5-oxopentanoic acid. [Q-CH.sub.2 CH[CH.sub.2 (C.sub.6 
H.sub.11)]NHC(O)(CH.sub.2).sub.3 C(O)OH]. 
A solution of 600 mg (1.7 mMol) 
(+)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-cyclohexyl- 
2-amino-propane [Preparation XI] and 225 mg (1.9 mMol) glutaric anhydride 
in dimethylformamide (50 ml) were stirred at room temperature for 24 
hours. The solvent was evaporated and the residue was purified by silica 
gel chromatography, eluting with ethyl acetate containing 30% methanol, to 
give the title compound (410 mg) (52.6%). 
m.p=100.degree.-115.degree. C. (foam) 
[.alpha.[.sub.589 (CH.sub.3 OH)=+23.54.degree. 
[.alpha.[.sub.365 (CH.sub.3 OH)=+78.34.degree. 
Calculated for C.sub.27 H.sub.42 N.sub.2 O.sub.4 : Theory: C, 70.71; H, 
9.23; N, 6.11 Found: C, 70.47; H, 9.43; N, 6.07 
The material prepared above was converted to the corresponding 
hydrochloride monohydrate by adding methanolic hydrogen chloride to a 
methanol solution of the above described free base until the solution was 
acidic to pH paper. The volatiles were then removed under reduced pressure 
and the residue triturated with diethyl ether. The title compound was 
recovered as a colorless solid. 
m.p.=95.degree.-100.degree. C. 
Calculated for C.sub.27 H.sub.42 N.sub.2 O.sub.4.HCl.H.sub.2 O Theory: C, 
63.79; H, 8.98; N, 5.31 Found: C, 63.54; H, 8.93; N, 4.94 
EXAMPLE 17 
N-Ethyl-N'-2-(D-(1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3 
-phenyl)propyl)urea hydrochloride monohydrate (DIASTEREOMER B). [Q-CH.sub.2 
-CH[CH.sub.2 (C.sub.6 H.sub.5)]-NHC(O)NHCH.sub.2 CH.sub.3.HCl.H.sub.2 O]. 
To a solution of 300 mg (0.9 mMol) 
D-(-)-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2- 
aminopropane [Diastereomer B from Preparation IX] in dichloromethane (20 
ml) at 0.degree. C. was added a solution of 128 mg (1.8 mMol) ethyl 
isocyanate in dichloromethane (10 ml) dropwise. The reaction mixture was 
then stirred for 1 hour at room temperature. The volatiles were then 
concentrated under reduced pressure and the residue dissolved in 1:1 
methanol:25% aqueous sodium hydroxide. The resulting solution was stirred 
for 1 hour at room temperature and the solution concentrated to half 
volume under reduced pressure. The remaining solution was adjusted to 
pH=9.8 with hydrochloric acid and the resulting mixture extracted with 
ethyl acetate. The organic extracts were combined, washed with water, 
dried over potassium carbonate and concentrated under reduced pressure. 
The resulting residue was purified by silica gel chromatography, eluting 
with ethyl acetate. Fractions containing product were combined, 
concentrated under reduced pressure and the residue converted to the 
hydrochloride salt. The title compound was recovered as a colorless solid 
(300 mg, 71.8%). 
m.p=120.degree.-124.degree. C. 
ms (fd)=409(M.sup.+ -1), 410(M.sup.+) 
[.alpha.].sub.365 (CH.sub.3 OH)=-134.56.degree. 
Calculated for C.sub.25 H.sub.35 N.sub.3 O.sub.2.HCl.H.sub.2 O: Theory: C, 
64.70; H, 8.24; N, 9.05 Found: C. 65.03 H, 8.27: N, 8.91 
EXAMPLE 18 
Trans-(4-((1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-phe 
nylethyl)amino)-4-oxobutyl) carbamic acid, 1,1 dimethylethyl ester 
monohydrochloride. [Q-CH.sub.2 CH[CH.sub.2 (C.sub.6 
H.sub.5)]NHC(O)(CH.sub.2).sub.3 NHC(O)OC(CH.sub.3).sub.3.HCl]. 
A solution of 507 mg (1.5 mMol) 
DL-1-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-3-phenyl-2-ami 
nopropane [Preparation VIII] and 305 mg (1.5 mMol) N-tBOC-4-aminobutanoic 
acid in dimethylformamide (50 ml) were contacted as described in Example 
2. The title compound was recovered as a mixture of diastereomeric pairs 
(400 mg, 47.6%). 
m.p.=107.degree.-110.degree. C. (with decomposition) 
ms (fd)=523(M.sup.+ -1), 524(M.sup.+) 
Calculated for C.sub.31 H.sub.45 N.sub.3 O.sub.4.HCl: Theory: C, 66.47; H, 
8.28; N, 7.50 Found: C, 66.27; H, 8.31; N, 7.66 
EXAMPLE 19 
4-((2-(Trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)phenylami 
no-4-oxobutanoic acid monohydrate. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.5)C(O)(CH.sub.2).sub.2 C(O)OH.H.sub.2 O]. 
A 1.5 gm (4.63 mMol) portion of 
N-phenyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethylami 
ne [Preparation XVI] was contacted with succinic anhydride (465 mg) and 
triethylamine (935 mg) in 100 ml dry THF and stirred for 48 hours. The 
solvent was removed and the residue passed over a silica column eluting 
with methanol ethyl acetate (1:9). After solvent was removed from the 
fraction containing product, the resulting solid was slurried in hexane 
and filtered to provide 814 mg of solid product. 
m.p.=90.degree.-100.degree. C. 
Calculated for C.sub.25 H.sub.32 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
67.85; H, 7.74; N, 6.33 Found: C, 67.61; H, 7.60; N, 6.06 
EXAMPLE 20 
Trans-5-(phenyl-(2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)am 
ino)-5-oxopentanoic acid monohydrate. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.5)C(O)(CH.sub.2).sub.3 C(O)OH.H.sub.2 O]. 
A 500 mg (I.54 mMol) portion of 
N-phenyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethylami 
ne [Preparation XVI] was contacted with glutaric anhydride (176 mg) under 
the conditions described in Example 19. The title compound was recovered 
as a colorless solid (260 mg, 37.9%). 
m.p.=60.degree.-75.degree. C. 
Calculated for C.sub.26 H.sub.34 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
68.40; H, 7.95; N, 6.14 Found: C, 68.55; H, 7.97; N, 5.92 
EXAMPLE 21 
3-(cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-3-oxopropanoic acid monohydrate. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)CH.sub.2 C(O)OH.H.sub.2 O]. 
A 1 mMol portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl 
amine [Preparation XII] was treated with ethyl malonoyl chloride according 
to the procedure of Example 10. The resulting ester was hydrolyzed 
according to the procedure of Example 13 to give the title compound as a 
colorless solid (185 mg, 42.6%). 
m.p.=131.degree.-135.degree. C. 
ms (fd)=417(M.sup.+), 418(M.sup.+ +1) 
Calculated for C.sub.24 H.sub.38 N.sub.2 O.sub.5 : Theory: C, 66.33; H, 
8.81; N, 6.45 Found: C, 66.53; H, 8.68; N, 6.21 
EXAMPLE 22 
4-(Cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-4-oxobutanoic acid monohydrate. Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)(CH.sub.2).sub.2 C(O)OH.H.sub.2 O]. 
A 500 mg (1.5 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethy 
lamine [Preparation XII] was treated with succinic anhydride according to 
the procedure described in Example 1. The title compound was recovered by 
recrystallization from ethyl acetate as a colorless, crystalline solid 
(200 mg, 29.7%) 
m.p=111.5.degree.-113.degree. C. 
ms (fd)=430(M.sup.-) 
Calculated for C.sub.25 H.sub.38 N.sub.2 O.sub.4 H.sub.2 O: Theory: C, 
66.87; H, 8.90; N, 6.24 Found: C, 66.71; H, 8.71; N, 6.10 
EXAMPLE 23 
5-(Cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-5-oxopentanoic acid monohydrate. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)(CH.sub.2).sub.3 C(O)OH.H.sub.2 O]. 
A 400 mg (1.2 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethy 
lamine [Preparation XII] was contacted with glutaric anhydride (150 mg) in 
DMF (50 ml) with stirring at room temperature for 24 hours. The mixture 
was stripped to dryness and the solid triturated in ethyl ether. The solid 
was passed through a silica column using ethyl acetate methanol (4:1). The 
recovered solid was slurried in hot ethyl acetate three times, filtered, 
the filtrate stripped to dryness and triturated with ethyl ether to 
provide the title compound as a colorless solid (173 mg, 31.2%) 
m.p.=110.degree. C. (foam) 
Calculated for C.sub.26 H.sub.40 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
67.50; H, 9.08; N, 6.06 Found: C, 67.76; H, 8.95; N, 6.00 
EXAMPLE 24 
4-(cyclopentyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-4-oxobutanoic acid hemihydrate. [Q-(CH.sub.2).sub.2 N(C.sub.5 
H.sub.9)C(O)(CH.sub.2).sub.2 C(O)OH.1/2H.sub.2 O]. 
A 600 mg (1.9 mMOl) portion of 
N-cyclopentyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-eth 
ylamine [Preparation XIII] was treated with succinic anhydride according to 
the procedure described in Example 1. The title compound was 
recrystallized from ml acetonitrile/0.5 ml H.sub.2 O to provide 320 mg of 
colorless solid. 
m.p.=128.degree. C. 
ms (fd)=417 (M.sup.+ +1) 
Analysis for C.sub.24 H.sub.36 N.sub.2 O.sub.4.1/2H.sub.2 O Theory: C, 
67.72; H, 8.78; N, 6.58 Found: C, 67.75; H, 8.90; N, 6.57 
EXAMPLE 25 
5-(cyclohexyl-(3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)prop 
yl)amino)-5-oxopentanoic acid. [Q-(CH.sub.2).sub.3 N(C.sub.6 
H.sub.11)C(O)(CH.sub.2).sub.3 C(O)OH]. 
A 500 mg (1.45 mMol) portion of 
N-cyclohexyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-prop 
ylamine [Preparation XIV] was contacted with glutaric anhydride (165 mg) in 
dimethylformamide (50 ml) and refluxed for 1 hour. The solvent removed and 
the residue passed through a silica column eluting with methanol. The 
solvent was removed, the residue was dissolved in hot ethyl acetate, the 
solution filtered, and the solvent removed. The solid was recrystallized 
from ethyl acetate hexane to provide the title compound as a colorless, 
crystalline solid (380 mg, 57.1%) 
m.p.=100.degree.-108.degree. C. 
Calculated for C.sub.27 H.sub.42 N.sub.2 O.sub.4 : Theory: C, 70.71; H, 
9.23; N, 6.11 Found: C, 70.42; H, 9.03; N, 6.41 
EXAMPLE 26 
4-(cyclohexylmethyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidiny 
l)ethyl)amino)-4-oxobutanoic acid monohydrate. [Q-(CH.sub.2).sub.2 
N[CH.sub.2 (C.sub.6 H.sub.11)]C(O)(CH.sub.2).sub.2 C(O)OH.H.sub.2 O]. 
A 280 mg (0.82 mMol) portion of 
N-cyclohexylmethyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)ethylamine [Preparation XVIII] was treated with succinic anhydride (82 mg) 
according to the procedure described in Example 5. The product was 
purified by passing through a silica column eluting with a solvent 
gradient of ethyl acetate to ethyl acetate methanol (1:1). The title 
compound was recovered as a colorless solid (240 mg, 63.2%) 
m.p.=70.degree.-73.degree. C. 
ms (fd)=444(M.sup.+), 445(M.sup.+ +1) 
Calculated for C.sub.26 H.sub.40 N.sub.2 O.sub.4 : Theory: C, 67.44; H, 
9.15; N, 6.06 Found: C, 67.16; H, 8.88; N, 5.89 
EXAMPLE 27 
Trans-5-(cyclohexylmethyl(3-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)propyl)amino)-5-oxopentanoic acid monohydrate. [Q-(CH.sub.2).sub.3 
N[CH.sub.2 (C.sub.6 H.sub.11)]C(O)(CH.sub.2).sub.3 -C(O)OH.H.sub.2 O]. 
A 520 mg (1.45 mMol) portion of 
N-cyclohexylmethyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl 
)propylamine [Preparation XIX] was treated with glutaric anhydride (166 mg) 
in dimethylformamide (50 ml) according to the procedure described in 
Example 5 with the final mixture heated for 5 minutes with a heat gun. The 
product was purified by passing through a silica column eluting with a 
solvent gradient of ethyl acetate-methanol (9:1) to methanol. The title 
compound was recovered as a colorless solid (510 mg, 71.7%) 
m.p.=102.degree.-105.degree. C. 
ms (fd)=472(M.sup.+), 473(M.sup.+ +1) 
Calculated for C.sub.28 H.sub.44 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
68.57; H, 9.38; N, 5.71 Found: C, 68.47; H, 9.04; N, 5.98 
EXAMPLE 28 
4-(3-methylbutyl-(2-(trans-4-(3-hydroxyphenyl)-3,4- 
dimethyl-1-piperidinyl)ethyl)amino)-4-oxobutanoic acid monohydrate. 
[Q-(CH.sub.2).sub.2 N[(CH.sub.2).sub.2 CH(CH.sub.3).sub.2 
]C(O)-(CH.sub.2).sub.2 C(O)OH.H.sub.2 O]. 
A 400 mg (1.26 mMol) portion of 
3-methylbutyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-et 
hylamine [Preparation XX] was treated with succinic anhydride (126 mg) in 
dimethylformamide (40 ml) according to the procedure described in Example 
27. Purification was with column chromatography eluting with ethyl acetate 
to methanol solvent gradient. The title compound was recovered as a 
colorless solid (490 mg, 89.1%). 
m.p.=83.degree.-86.degree. C. 
ms (fd)=418(M.sup.+), 419(M.sup.+ +1) 
Calculated for C.sub.24 H.sub.38 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
65.96; H, 9.16; N, 6.41 Found: C, 66.20; H, 9.09; N, 6.36 
EXAMPLE 29 
5-(2-Methylpropyl-(3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl) 
propyl)amino)-5-oxopentanoic acid monohydrate. [Q-(CH.sub.2).sub.3 
-N[CH.sub.2 CH(CH.sub.3).sub.2 ]C(O)(CH.sub.2).sub.3 -C(O)OH.H.sub.2 O]. 
A 340 mq (1.07 mMol) portion of 
2-methylpropyl(3-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propylami 
ne [Preparation XXI] was treated with glutaric anhydride (122 mg) in 
dimethylformamide (50 ml) according to the procedure described in Example 
27. The title compound was recovered as a colorless solid (360 mg, 74.6%). 
m.p.=66.degree.-70.degree. C. 
Calculated for C.sub.25 H.sub.40 N.sub.2 O.sub.4.H.sub.2 O: Theory: C, 
66.30; H, 9.32; N, 6.22 Found: C, 66.38; H, 9.10; N, 6.10 
Example 30 
4-(Cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-4-oxobutanoic acid 1-methyl-ethyl ester. [Q-(CH.sub.2).sub.2 
-N(C.sub.6 H.sub.11)C(O)(CH.sub.2).sub.2 C(O)OCH(CH.sub.3).sub.2 ]. 
To a solution of 500 mg (1.51 mMol) of 
4-(cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
ylamine [Preparation XII] in DMF (45 ml) were added sequentially 242 mg 
(1.51 mMol) monoisopropyl succinate, 204 mg (1.51 mMol) 
1-hydroxybenzotriazole and 311 mg (1.51 mMol) dicyclohexylcarbodiimide. 
The reaction mixture was allowed to stir for 48 hours at room temperature 
under nitrogen. The reaction mixture was then cooled to 0.degree. C., 
filtered and the filter cake washed with cold dimethylformamide. The 
filtrate was concentrated under reduced pressure and the residue diluted 
with water. The pH of this solution was adjusted to 9.8 with 1N NaOH and 
the mixture was extracted well with butanol toluene (3:1). The organic 
extracts were combined, washed with water, dried over potassium carbonate 
and concentrated under reduced pressure. The residue was purified by 
silica gel chromatography, eluting with ethyl acetate. The title compound 
was isolated as a colorless foam (450 mg, 63%). 
m.p.=55.degree.-60.degree. C. 
Calculated for C.sub.28 H.sub.45 N.sub.2 O.sub.4 : Theory: C, 71.00; H, 
9.58; N, 5.91 Found: C, 71.08; H, 9.36; N, 5.89 
EXAMPLE 31 
4-(Cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-4-oxobutanoic acid propyl ester. Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)(CH.sub.2).sub.2 C(O)O(CH.sub.2).sub.2 CH.sub.3 ]. 
A 500 mg (1.51 mMol) portion of 
cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethylam 
ine [Preparation XII] was contacted with monopropyl succinate (242 mg), 
HOBT (204 mg), DCC (311 mg) and DMF (45 ml) under the conditions described 
in Example 30. The title compound (317 mg) was isolated as a white foam. 
m.p.=50.degree.-60.degree. C. 
ms (fd)=473 M.sup.+ 
Calculated for C.sub.28 H.sub.44 N.sub.2 O.sub.4 : Theory: C, 71.15; H, 
9.38; N, 5.93 Found: C, 70.87; H, 9.22; N, 5.98 
EXAMPLE 32 
5-(Cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-5-oxopentanoic acid ethyl ester monohydrochloride. 
[Q-(CH.sub.2).sub.2 N(C.sub.6 H.sub.11)C(O)-(CH.sub.2).sub.3 C(O)OCH.sub.2 
CH.sub.3.HCl]. 
A 575 mg (1.74 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl 
amine [Preparation XII] was contacted with monoethyl glutarate (278 mg), 
HOBT (235 mg) and DCC (360 mg) in DMF (50 ml) under the conditions 
described in Example 30. The title compound was isolated as its 
hydrochloride salt to give 400 mg (45.1%) of a colorless solid. 
m.p.=90.degree.-110.degree. C. 
Calculated for C.sub.28 H.sub.44 N.sub.2 O.sub.4.HCl: Theory: C, 66.06; H, 
8.91; N, 5.50 Found: C, 65.85; H, 9.15; N, 5.61 
EXAMPLE 33 
5-(Cyclohexyl-(3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)prop 
yl)amino)-5-oxopentanoic acid ethyl ester monohydrochloride. 
[Q-(CH.sub.2).sub.3 N(C.sub.6 H.sub.11)C(O)-(CH.sub.2).sub.3 C(O)OCH.sub.2 
CH.sub.3.HCl]. 
A 600 mg (1.74 mMol) portion of 
N-cyclohexyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propy 
lamine [Preparation XIV] was contacted with monoethyl glutarate (278 mg), 
HOBT (235 mg) and DCC (360 mg) in DMF (50 ml) under the conditions 
described in Example 30. The title compound was isolated as its 
hydrochloride salt to give 160 mg (17.6%) of a colorless solid. 
m.p.=75.degree.-85.degree. C. (foam) 
Calculated for C.sub.29 H.sub.46 N.sub.2 O.sub.4.HCl: Theory: C, 66.58; H, 
9.06; N, 5.35 Found: C, 66.64; H, 8.82; N, 5.16 
EXAMPLE 34 
N-Cyclohexyl-N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
yl)propanediamidehydrochloride monohydrate. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)CH.sub.2 C(O)NH.sub.2 ]. 
A portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl 
amine [Preparation XII] was contacted with ethyl malonoyl chloride as 
described in Example 10 to give 500 mg (1.02 mMol) 
3-(cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
yl)amino)-3-oxopropionic acid ethyl ester hydrochloride. This material was 
stirred overnight at room temperature in 10 ml of ammonium hydroxide 
(28%). The mixture was evaporated to dryness. The residue was partitioned 
between butanoltoluene (3:1) and water with the pH of the water layer 
adjusted to 9.8 with 1N sodium hydroxide. The organic layer was separated, 
dried over potassium carbonate, and the solvent evaporated. The residue 
was passed through a silica column eluting with an ethyl acetate to ethyl 
acetate-methanol (1:1) gradient. The solvent was removed to provide 290 mg 
of the free base compound. 
ms (fd)=415 (M.sup.+), 416 (M.sup.+ +1) 
The free base was converted to the HCl salt and dried to provide the title 
compound as a colorless solid (213 mg, 44.4%). 
m.p.=113.degree.-118.degree. C. 
Calculated for C.sub.24 H.sub.37 N.sub.3 O.sub.3.HCl.H.sub.2 O: Theory: C, 
61.32; H, 8.58; N, 8.94 Found: C, 61.32; H, 8.37; N, 8.66 
EXAMPLE 35 
N-Cyclohexyl-N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
yl)butanediamide monohydrochloride. [Q-(CH.sub.2).sub.2 N(C.sub.6 
H.sub.11)C(O)(CH.sub.2).sub.2 C(O)NH.sub.2.HCl]. 
A 500 mg (1.51 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethy 
lamine [Preparation XII] was contacted with succinamic acid (177 mg), HOBT 
(204 mg) and DCC (312 mg) in DMF (50 ml) under the conditions described in 
Example 30 to give the free base of the title compound as a colorless, 
crystalline solid (200 mg, 30.8%). 
m.p.=85.degree.-100.degree. C. (foam) 
ms (fd)=430(M.sup.+) 
Calculated for C.sub.25 H.sub.39 N.sub.3 O.sub.3 : Theory: C, 69.90; H, 
9.15; N, 9.78 Found: C, 69.82; H, 9.01; N, 9.66 
The hydrochloride salt of the above free base was formed to give the title 
compound as a colorless solid. 
m.p.=160.degree.-162.degree. C. 
EXAMPLE 36 
N-Methyl-3-oxo-3-((2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl) 
ethyl)cyclohexylamino)propanamidemonohydrochloride monohydrate. 
[Q-(CH.sub.2).sub.2 N(C.sub.6 H.sub.11)C(O)-CH.sub.2 
C(O)NHCH.sub.3.HCl.H.sub.2 O]. 
A 500 mg (1.02 mMol) portion of Q-(CH.sub.2).sub.2 N(C.sub.6 
-H.sub.11)C(O)CH.sub.2 C(O)OCH.sub.2 CH.sub.3.HCl was contacted with 
methylamine (25 ml, 40%) under the reaction conditions described in 
Example 34 except the mixture was stirred for 2 hours. The product was 
purified through a silica column using ethyl acetate to ethyl 
acetate-methanol (1:1) solvent gradient. The free base was recovered (270 
mg). 
ms (fd)=429(M.sup.+ -1), 430(M.sup.+) 
The free base was converted to the HCl salt and dried to gain the title 
compound (277 mg). 
m.p.=82.degree.-85.degree. C. (foam) 
Calculated for C.sub.25 H.sub.39 N.sub.3 O.sub.3.HCl.H.sub.2 O: Theory: C, 
62.03; H, 8.75; N, 8.68 Found: C, 61.84; H, 8.54; N, 8.48 
EXAMPLE 37 
N-(3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)propyl)-N-cycloh 
exylpentanediamide monohydrochloride monohydrate. [Q-(CH.sub.2).sub.3 
N(C.sub.6 H.sub.11)C(O)(CH.sub.2).sub.3 -C(O)NH.sub.2.HCl.H.sub.2 O. 
A 688 mg (2.00 mMol) portion of 
N-cyclohexyl-3-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-prop 
ylamine [Preparation XIV] was contacted with glutaramic acid (262 mg), HOBT 
(270 mg) and DCC (412 mg) in DMF (50 ml) under the conditions described in 
Example 30. The solid product was converted to the HCl salt to give the 
title compound as a colorless solid (290 mg, 28.3%). 
m.p.=81.degree.-84.degree. C. 
Calculated for C.sub.27 H.sub.43 N.sub.3 O.sub.3.HCl.H.sub.2 O: Theory: C, 
63.25; H, 8.98; N, 8.20 Found: C, 62.94; H, 8.79; N, 7.99 
EXAMPLE 38 
N-cyclohexyl-N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
yl)-N'-(2-(methylamino)-2-oxoethyl)propanediamide monohydrochloride. 
[Q-(CH.sub.2).sub.2 N(C.sub.6 -H.sub.11)C(O)CH.sub.2 C(O)NHCH.sub.2 
C(O)NHCH.sub.3.HCl]. 
A 1.05 gm (2.5 mMol) portion of 
4-(cyclohexyl(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethy 
l)amino)-4-oxobutanoic acid was contacted with glycine ethyl ester 
hydrochloride under the conditions described in Example 30 to give 
N-cyclohexyl-N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)et 
hyl)-N'-(2-ethyl acetyl)propanediamide hydrochloride (950 mg). 
m.p.=110.degree.-114.degree. C. 
Calculated for C.sub.27 H.sub.42 N.sub.3 O.sub.5.HCl: Theory: C, 62.S0; H, 
8.24; N, 7.80 Found: C, 62.76; H, 8.32' N, 7.95 
A 350 mg (0.65 mMol) portion of this material was then subjected to the 
reaction conditions described in Example 36 with dioxane and under 
nitrogen to give the title compound as a colorless solid (145 mg, 42.6%). 
m.p.=124.degree.-128.degree. C. 
Calculated for C.sub.27 H.sub.42 N.sub.4 O.sub.4.HCl: Theory: C, 61.99; H, 
8.28; N, 10.71 Found: C, 62.10; H, 8.36; N, 10.65 
EXAMPLE 39 
N-(1,4-dioxo-4-((2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1piperidinyl)ethyl)phe 
nylamino)butyl)leucine monohydrochloride monohydrate. [Q-(CH.sub.2).sub.2 
N(C.sub.6 H.sub.5)C(O)(CH.sub.2).sub.2 C(O)NHCH-[CH.sub.2 
CH(CH.sub.5).sub.2 ]C(O)OH.HCl.H.sub.2 O]. 
A 1.06 gm (2.4 mMol) portion of 
4-((2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)-phenyla 
mino-4-oxobutanoic acid was reacted with L-leucine methyl ester 
hydrochloride under the conditions described in Example 30 to give 
N-(1,4-dioxo-4-((2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)- 
ethyl)phenylamino)butyl)leucine methyl ester as a crystalline solid (660 
mg, 49.9%). 
m.p.=60.degree.-65.degree. C. 
Calculated for C.sub.32 H.sub.45 N.sub.3 O.sub.5 : Theory: C, 69.66; H, 
8.22; N, 7.61 Found: C, 69.45; H, 8.45; N, 7.62 
A 340 mg (0.62 mMol) portion of this material was then dissolved in dioxane 
(30 ml) and 6N hydrochloric acid (20 ml) and the resulting solution 
stirred at reflux for 3 hours. The reaction mixture was then concentrated 
under reduced pressure and the residue triturated with diethyl ether to 
give the title compound as a colorless solid (280 mg). 
m.p.=100.degree.-115.degree. C. (foam) 
Calculated for C.sub.31 H.sub.43 N.sub.3 O.sub.5.HCl.H.sub.2 O: Theory: C, 
62.87; H, 7.83; N, 7.10 Found: C, 62.57; H, 7.74; N, 6.93 
EXAMPLE 40 
N-cyclohexyl-N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)eth 
yl)-N'-(2-methyl-4-oxobutyl)-1-oxo-1,4-butanediamine hydrochloride. 
[Q-(CH.sub.2).sub.2 N(C.sub.6 H.sub.11)-C(O)(CH.sub.2).sub.3 
NHC(O)CH.sub.2 CH(CH.sub.3).sub.2.HCl]. 
To a solution of 20 gm (194 mMol) 4-aminobutyric acid in dichloromethane 
(700 ml) was added 56.8 ml (407 mMol) triethylamine and the mixture was 
stirred for 10 minutes. To the reaction mixture was then added a solution 
of 47.4 ml (388 mMol) isovaleryl chloride in dichloromethane (200 ml) 
dropwise and the resulting mixture was then stirred at room temperature 
for 2 hours. The reaction mixture was then filtered and the volatiles 
removed under reduced pressure. The residue was dissolved in 1N aqueous 
sodium hydroxide (150 ml) and the solution was stirred for 1.5 hours at 
room temperature. The aqueous solution was extracted with diethyl ether 
and the combined ether extracts were washed with water. All aqueous phases 
were combined and then acidified with concentrated hydrochloric acid. This 
mixture was then extracted well with ethyl acetate. These organic extracts 
were combined, dried over magnesium sulfate and concentrated under reduced 
pressure. The residue was slurried in hexane and the hexane decanted from 
the residue. Remaining residue was distilled in a bulb to bulb apparatus 
at 220.degree. C. at 0.05 mmHg to give 8.0 g (22%) 
N-isovaleryl-4-aminobutyric acid. 
Calculated for C.sub.9 H.sub.17 NO.sub.3 : Theory: C, 57.73; H, 9.15; N, 
7.48 Found: C, 57.67; H, 9.21; N, 7.25 
A 500 mg (1.5 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethy 
lamine [Preparation XII] was contacted with N-isovaleryl-4-aminobutanoic 
acid (283 mg), HOBT (204 mg) and DCC (312 mg) in DMF (50 ml) under the 
conditions described in Example 32 to give the title compound as a 
colorless solid (262 mg, 32.6%). 
m.p.=100.degree.-115.degree. C. 
Calculated for C.sub.30 H.sub.49 N.sub.3 O.sub.3.HCl: Theory: C, 67.20; H, 
9.40; N, 7.84 Found: C, 67.03; H, 9.34; N, 7.90 
EXAMPLE 41 
2-((1,4-dioxo-4-(cyclohexyl-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-pi 
peridinyl)ethyl)amino)butyl)-amino)-3-phenylpropanoic acid, methyl ester. 
[Q(CH.sub.2).sub.2 N(C.sub.6 H.sub.11)C(O)(CH.sub.2).sub.2 
C(O)NHCH[CH.sub.2 (C.sub.6 H.sub.5)]C(O)OCH.sub.3 ]. 
A 1.08 gm (3.0 mMol) portion of 
N-cyclohexyl-2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethy 
lamine [Preparation XII] was contacted with L-phenylalanine methyl ester 
hydrochloride (541 mg), HOBT (340 mg), diethylamine (0.44 ml), and DCC 
(518 mg) in DMF (100 ml) under the conditions described in Example 32 to 
give the title compound as a colorless solid (800 mg). 
m.p.=60.degree.-90.degree. C. 
[.alpha.].sub.589 =+3.37 
[.alpha.].sub.365 =+21.39 
Calculated for C.sub.35 H.sub.49 N.sub.3 O.sub.5 : Theory: C, 71.05; H, 
8.35; N, 7.10 Found: C, 70.98; H, 8.46; N, 7.20 
EXAMPLE 42 
N-(2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)-2-(acetyl 
amino)-5-((imino(nitroamino)-methyl)amino)pentanamide monohydrate. 
[Q-(CH.sub.2).sub.2 -NHC(O)CH[NHC(O)CH.sub.3 ](CH.sub.2).sub.3 
NHC(NH)NHNO.sub.2.H.sub.2 O]. 
To a solution of 2.0 gm (8.9 mMol) arginine methyl ester hydrochloride and 
1.5 gm (14.8 mMol) triethylamine in dimethylformamide (150 ml) was added 
776 mg (7.4 mMol) acetic anhydride dropwise at 0.degree. C. The reaction 
mixture was stirred at room temperature for 1 hour and then the volatiles 
removed under reduced pressure. The residue was purified using silica gel 
chromatography, eluting with ethyl acetate containing 0-50% methanol, to 
give N-acetyl arginine methyl ester as a crystalline solid (2.53 g). 
m.p.=145.degree.-146.5.degree. C. 
Calculated for C.sub.9 H.sub.17 N.sub.5 O.sub.5 : Theory: C, 39.27; H, 
6.23; N, 25.44 Found: C, 38.98; H, 6.19; N, 25.69 
To a solution of 1.65 gm (6 mMol) of this methyl ester in methanol (48 ml) 
and water (98 ml) was added 0.5 N aqueous sodium hydroxide (12.45 ml) and 
the reaction mixture was then stirred at room temperature for 2 hours. The 
methanol was then removed under reduced pressure and the remaining 
solution diluted with water. The solution was then extracted once with 
ethyl acetate. The remaining aqueous phase was then made acidic with 1N 
hydrochloric acid and extracted with 3:1 butanol:toluene. These organic 
extracts were combined, washed with saturated aqueous sodium chloride, 
dried over magnesium sulfate and concentrated under reduced pressure to 
give N-acetyl arginine. 
The material thus prepared was reacted with a 400 mg (1.6 mMol) portion of 
2-(trans-4-(3-hydroxyphenyl)3,4-dimethyl-1-piperidinyl)ethylamine 
[Preparation XII] HOBT (216 mg) and DCC (330 mg) in DMF (50 ml) under the 
conditions described in Example 30 to give the title compound as a 
colorless solid (360 mg). 
m.p.=62.degree.-65.degree. C. [.alpha.].sub.365 =-32.28.degree. 
Calculated for C.sub.23 H.sub.39 N.sub.7 O.sub.6.H.sub.2 O: Theory: C, 
54.11; H, 7.64; N, 19.21 Found: C, 54.12; H, 7.34; N, 18.92 
EXAMPLE 43 
Trans-N-(2-(4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)ethyl)-2-((3-met 
hyl-1-oxobutyl)amino)-5-((imino(nitroamino)methyl)amino) pentanamide. 
[Q-(CH.sub.2).sub.2 NHC(O)-CH[NHC(O)CH.sub.2 CH(CH.sub.3).sub.2 
](CH.sub.2).sub.3 NHC(NH)NHNO.sub.2 ]. 
A 2.0 g (8.9 mMol) portion of arginine methyl ester hydrochloride was 
contacted with isovaleric acid (755 mg), HOBT (1 g), triethylamine (747 
mg) and DCC (1.52 g) in DMF (150 ml) under the conditions described in 
Example 30 to give N-isovaleryl-arginine methyl ester as a crystalline 
solid (1.71 g). 
m.p.=133.degree.-135.degree. C. 
Calculated for C.sub.12 H.sub.23 N.sub.5 O.sub.5 : Theory: C, 45.42; H, 
7.31; N, 22.07 Found: C, 45.71; H, 7.55; N, 22.31 
The N-isovaleryl arginine methyl ester thus prepared was converted to its 
corresponding acid and then coupled with a 317 mg (1.3 mMol) portion of 
2-(trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)-ethylamine 
[Preparation XII] under the conditions described in Example 30 using HOBT 
(173 mg) and DCC (264 mg) in DMF (30 ml) to give the title compound as a 
colorless solid (400 mg). 
m.p.=182.degree.-184.degree. C. (with decomposition) 
Calculated for C.sub.26 H.sub.43 N.sub.7 O.sub.5 : Theory: C, S8.52; H, 
8.12; N, 18.37 Found: C, 58.43; H, 8.21; N, 18.14 
EXAMPLE 44 
(1-(((2-(Trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl) 
ethyl)amino)carbonyl)-4-((imino(nitroamino)methyl)amino)butyl) carbamic 
acid, 1,1-dimethylethyl ester. [Q-(CH.sub.2).sub.2 
NHC(O)CH[NHC(O)OC(CH.sub.3).sub.3 ](CH.sub.2).sub.3 -NHC(NH)NHNO.sub.2 ]. 
N-tBOC-nitro-L-arginine (798 mg) 
2-[Trans-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]ethylamine (620 
mg), HOBT (338 mg), DCC (516 mg), and DMF (50 ml). The procedure of 
Example 43 was followed with these reagents to give the title compound as 
a colorless solid (870 mg). 
m.p.=107.degree.-115.degree. C. 
Calculated for C.sub.26 H.sub.43 N.sub.7 O.sub.6 : Theory: C, 56.81; H, 
7.89; N, 17.84 Found: C, 57.00; H, 7.93; N, 17.65 
EXAMPLE 45 
Preparation of (3R,4R)-(S)-Q-CH.sub.2 -C(E)H-NHC(O)-(CH.sub.2).sub.3 
CO.sub.2 H where E is cyclohexylmethyl. 
A. (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)-piperidine (Q-H) (5 g) prepared 
as in Preparation I, (L)-HOOC-C(R)H-NH.tBOC (6.55 g), HOBT (3.30 g), DCC 
(5.02 g) were dissolved in dry DMF (800 ml) and stirred three days at room 
temperature under nitrogen. The mixture was evaporated to dryness and the 
residue taken into ethyl acetate. The solution was washed one time with 
water, dried over K.sub.2 CO.sub.3 and the solvent evaporated to provide 
21.38 g of product. This material was passed over a silica column eluting 
with a solvent gradient of hexane-ethyl acetate (9:1) to ethyl acetate. 
Evaporation of solvent provided 11.01 g of the product. 
[.alpha.].sub.365 (CH.sub.3 OH)=+126.37.degree. 
ms (fd)=458 (M+) 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 Theory C, 70.71; H, 9.23; N, 
6.11 Found C, 70.52; H, 9.14; N, 5.97 
B. Preparation of (3R,4R)-(S)-Q-C(O)-C(E)H-NH.sub.2 
Product from 45 A above (11 g), 6N HCl (600 ml), and methanol (300 ml) were 
mixed together and stirred overnight at room temperature. The mixture was 
then evaporated to dryness and the residue partitioned between water (1 L) 
and a solution of butanol-toluene (3:1, 1 L). The pH was adjusted to 9.8 
using 1N NaOH and the layers were separated. The organic layer was washed 
one time with water, dried over K.sub.2 CO.sub.3 and evaporated to provide 
9.84 g of a viscous yellow oil. This material was passed over a silica 
column using a solvent gradient of ethyl acetate-methanol (9:1) to ethyl 
acetate-methanol (1:1) to provide 6.13 g of product. 
ms (fd)=359 (M.sup.+ +1) 
[.alpha.].sub.365 =+104.30.degree. 
C. Preparation of (3R,4R)-(S)Q-CH.sub.2 CH(E)-NH.sub.2 
Product from 45 B above (6.1 g) in toluene (160 ml) was added dropwise to 
RedAl (22 ml) at room temperature under nitrogen. The mixture was then 
heated at 75.degree. -80.degree. C. for 5 hours and then cooled to room 
temperature. The mixture was added to a pH 10 buffer (300 ml) and then the 
pH was adjusted to 9.8 with 1N HCl. This mixture was extracted with a 
butanol-toluene (3:1) solution. The organic layer was separated, washed 
one time with water and dried over K.sub.2 CO.sub.3. Evaporation of the 
solvent provided 5.87 g of a tan solid. This was passed over a silica 
column eluting with a solvent gradient of ethyl acetate-methanol (9:1) to 
ethyl acetate-methanol (1:1). The evaporation of solvent provided 4.91 g 
of a white crystalline product. 
mp=137.5.degree.-138.degree. C. 
ms (fd)=344 (M+), 345 (M.sup.+ +1) 
[.alpha.].sub.365 (CH.sub.3 OH)=+308.21.degree. 
Analysis for C.sub.22 H.sub.36 N.sub.2 O: Theory: C, 76.69; H, 10.53; N, 
8.13 Found: C, 76.51; H, 10.41; N, 8.10 
D. Preparation of title compound. 
Product from 45 C above (4.83 g), glutaric anhydride (1.60 g), and dry DMF 
(325 ml) were combined and stirred at room temperature under nitrogen. 
After 3 hours the mixture was evaporated to dryness to provide 6.44 g of 
viscous oil. This was passed over a silica column eluting with a solvent 
gradient of ethyl acetatemethanol (9:1) to ethyl acetate-methanol (1:1). 
Evaporation of solvent provided 6.30 g of a white foam. This was dissolved 
in hot ethyl acetate, filtered and evaporated to provide 5.93 g of a white 
solid. 
mp=107.degree.-110.degree. C. 
ms (fd)=459 (M.sup.+ +1) 
[.alpha.].sub.365 =+204.82.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 Theory: C, 70.71: H, 9.23: 
N, 6.11 Found: C, 70.47: H, 9.27: N, 6.19 
EXAMPLE 46 
Preparation of (3R,4R)-(R)-Q-CHz-C(E)H-NH-C(O)(CH.sub.2).sub.3 CO.sub.2 H 
where E is cyclohexylmethyl. 
The procedures of Example 45 were followed using the materials indicated 
below. 
A. Preparation of (3R,4R)-(R)Q-C(O)-C(E)H-NH.tBOC 
______________________________________ 
Q--H (2.0 g) 
(D)HOOC--C(E)H--NH.tBOC 
(2.62 g) 
HOBT (1.32 g) 
DCC (2.01 g) 
DMF (145 ml) 
Product (3.79 g) 
______________________________________ 
ms (fd)=458 (M+) 
[.alpha.].sub.365 =+142.29.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 : Theory: C, 70.71; H, 9.23; 
N, 6.11 Found: C, 70.85; H, 9.33; N, 6.25 
B. Preparation of (3R,4R)-(R)-Q-C(O)-C(E)H-NH.sub.2 
Product from 46 A (3.75 g) 
6N HCl (250 ml) 
Methanol (200 ml) 
Product (2.43 g) as white crystals 
mp=177.degree.-179.degree. C. 
ms (fd)=359 (M.sup.+ +1) 
[.alpha.].sub.365 =+168.24.degree. 
Analysis for C.sub.22 H.sub.34 N.sub.2 O.sub.2 : Theory: C, 73.70; H, 9.56; 
N, 7.81 Found: C, 73.47; H, 9.42; N, 7.62 
C. Preparation of (3R,4R)-(R)-Q-CH.sub.2 -C(E)H-NH.sub.2 
Product from B (2.43 g) in dry THF (100 ml) 
RedAl (10 ml) 
Product (1.92 g) as white crystals 
mp=175.degree.-176.5.degree. C. 
ms (fd)=345 (M.sup.+ +1) 
[.alpha.].sub.365 =+182.37.degree. 
Analysis for C.sub.22 H.sub.36 N.sub.2 O: Theory: C, 76.60; H, 10.53; N, 
8.13 Found: C, 76.42; H, 10.50; N, 8.04 
D. Preparation of (3R,4R)-(R)Q-CH.sub.2 -C(E)H-NH-C(O)-(CH.sub.2).sub.3 
CO.sub.2 H 
Compound from 46 C above (1.88 g) 
Glutaric anhydride (0.571 mg) 
Dry DMF (140 ml) 
Product (2.16 g) 
mp=92.degree.-95.degree. C. 
ms (fd)=459 (M.sup.+ +1) 
[.alpha.].sub.365 =+59.31.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 Theory: C, 70.71; H, 9.23; 
N, 6.11 Found: C, 70.36; H, 9.33; N, 5.75 
EXAMPLE 47 
Preparation of (3S,4S)-(S)-Q-CH.sub.2 C(E)H-NH-C(O)(CH.sub.2).sub.3 
CO.sub.2 H 
The procedure of Example 45 was followed using materials indicated. 
A. Preparation of (3S,4S)-(S)-QC(O)C(E)H-NH(tBOC) 
(3S,4S)-dimethyl-4-(3-hydroxyphenyl)-piperidine (Q-H) (2 g). 
______________________________________ 
(L)HOOC--CH(E)--NH(tBOC) 
(2.62 g) 
HOBT (1.32 g) 
DCC (2.01 g) 
Dry DMF (145 ml) 
Product (4.11 g) 
______________________________________ 
ms (fd)=258 (M+) 
[.alpha.].sub.365 (CH.sub.3 OH)=-144.55.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 : Theory: C, 70.71; H, 9.23; 
N, 6.11 Found: C, 70.54; H, 9.14; N, 6.09 
B. Preparation of (3S,4S)-(S)-QC(O)CH(E)NH.sub.2 Product from 47 A above 
(4.05 g) 
______________________________________ 
Product from 47 A above 
(4.05 g) 
6N HCl (250 ml) 
Methanol (200 ml) 
Product (2.58 g) 
______________________________________ 
ms (fd)=358 (M+), 359 (M.sup.+ +1) 
[.alpha.].sub.365 -165.78.degree. 
Analysis for C.sub.22 H.sub.34 N.sub.2 O.sub.2 : Theory: C, 73.70; H, 9.55; 
N, 7.81 Found: C, 73.49; H, 9.64; N, 7.65 
C. Preparation of (3S,4S)-(S)-Q-CH.sub.2 -CH(E)-NH.sub.2 Product from 47 B 
(2.34 g) in dry THF (100 ml). 
RedAl (10 ml) 
Product (1.70 g) 
mp=176.degree.-177.degree. C. 
ms (fd)=344 (M+), 345 (M.sup.+ +1) 
[.alpha.].sub.365 =-180.04.degree. 
Analysis for C.sub.22 H.sub.36 N.sub.2 O: Theory: C, 76.69; H, 10.53; N, 
8.13 Found: C, 76.48; H, 10.58; N, 8.03 
D. Formation of title compound 
Product from 47 C (1.62 g) 
______________________________________ 
Product from 47 C 
(1.62 g) 
Glutaric anhydride 
(537 mg) 
Dry DMF (125 ml) 
Product (1.90 g) as white solid 
______________________________________ 
m.p.=102.5.degree.-104.degree. C. 
ms (fd)=459 (M.sup.+ +1) 
[.alpha.].sub.365 =-54.46.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 Theory: C, 70.71; H, 9.23; 
N, 6.11 Found: C, 70.41; H, 9.49; N, 5.94 
EXAMPLE 48 
Preparation of (-)-(3S,4S)-(R)-Q-CH.sub.2 
-CH(E)-NH-C(O)-(CH.sub.2)aCO.sub.2 H where E is cyclohexylmethyl. 
The procedure of Example 45 was followed using the materials indicated 
below. 
A. Preparation of (-)-(3S,4S)-(R)-Q-C(O)CH(E)NH(BOC) 
______________________________________ 
(--)--(3S,4S)--dimethyl-4- 
(2.0 g) 
(3-hydroxyphenyl)piperidine- 
(Q--H) 
(D)HOOC--CH(E)--NH(tBOC) 
(2.62 g) 
HOBT (1.32 g) 
DCC (2.01 g) 
DMF (dry) (145 ml) 
______________________________________ 
Product (3.86 g) as white foam 
ms (fd)=458 (M+) 
[.alpha.].sub.365 (CH.sub.3 OH)=-128.13.degree. 
B. Preparation of (3S,4S)-(R)-Q-C(O)CH(E)NH.sub.2 
Product from 48 A (3.86 g) 
6N HCl (250 ml) 
Methanol (200 ml) 
Product (2.36 g) as pink foam 
ms (fd)=359 (M.sup.+ +1) 
[.alpha.].sub.365 =-180.58.degree. 
Analysis for C.sub.22 H.sub.34 N.sub.2 O.sub.2 : Theory: C, 73.70; H, 9.56; 
N, 7.81 Found: C, 73.41; H, 9.45; N, 7.41 
C. Preparation of (3S,4S)-(R)-Q-CH.sub.2 -CH(E)NH.sub.2 Product from 48 B 
(2.36 g) in dry toluene (100 ml) 
RedAl (10 ml) 
Product (1.94 g) 
ms (fd)=345 (M.sup.+ +1) 
[.alpha.].sub.365 =-291.71.degree. 
Analysis for C.sub.22 H.sub.36 N.sub.2 O: Theory: C, 76.69; H, 10.53; N, 
8.13 Found: C, 76.51; H, 10.62; N, 8.05 
D. Formation of title compound. Product from 48 C above (1.88 g) 
Glutaric anhydride (570 mg) 
DMF (dry) (140 ml) 
Product (2.03 g) 
mp=106.degree.-109.degree. C. 
ms (fd)=459 (M.sup.+ +1) 
[.alpha.].sub.365 =-194.96.degree. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4 Theory: C, 70.71; H, 9.23; 
N, 6.11 Found: C, 71.00; H, 9.33; N, 6.41 
In Examples 49-59 the following procedure was used. The reactants were 
mixed and refluxed under nitrogen with the reaction followed by thin layer 
chromatography. The reaction was normally complete after about 1 hour. The 
mixture was evaporated to dryness and the residue partitioned between 
ethyl acetate and water. The pH of the water layer was adjusted to 9.8 
with 1N NaOH. The layers were separated and the organic layer washed with 
water. After drying over K.sub.2 CO.sub.3, the ethyl acetate was 
evaporated. The resulting residue was either passed through a silica 
column eluting with ethyl acetate or passed over a chromatron using a 2 mm 
plate and eluting with ethyl acetate. Removal of the ethyl acetate 
provided the product. 
In Examples 49-70 "T" represents Q-CH.sub.2 -CH(E)-NH-C(O)(CH.sub.2).sub.3 
-C(O)- where E is cyclohexylmethyl The indicated configuration refers to 
the 3 and 4 positions of the piperidine and the other designation refers 
to the configuration of the asymmetric center in the moiety attached to 
the nitrogen of the piperidine. 
EXAMPLE 49 
Preparation of (3S,4S)-(S)-T-OCH.sub.3 (3S,4S)-(S)-T-OH (400 mg) 
Methanol (20 ml) 
Methanol saturated with HCl (20 ml) 
Product as the HCl salt (325 mg) 
m.p.=74.degree.-78.degree. C. 
[.alpha.].sub.365 (CH.sub.3 OH)=-62.23.degree. 
Analysis for C.sub.28 H.sub.44 N.sub.2 O.sub.4.HCl Theory: C, 66.06; H, 
8.91; N, 5.50 Found: C, 66.29; H, 9.11; N, 5.67 
EXAMPLE 50 
______________________________________ 
Preparation of (3R,4R)--(S)--T--OCH.sub.3 
______________________________________ 
(3R,4R)--(S)--T--OH (400 mg) 
Methanol (20 ml) 
Methanol saturated with HCl 
(20 ml) 
Product as the HCl salt 
(300 mg) 
______________________________________ 
mg=167.degree.-170` C. 
[.alpha.].sub.365 (CH.sub.3 OH)=+155.83.degree. 
Analysis for C.sub.28 H.sub.44 N.sub.2 O.sub.4.HCl Theory: C, 66.06; H, 
8.91; N, 5.50 Found: C, 65.81; H, 9.02; N, 5.53 
EXAMPLE 51 
Preparation of (3S, 4S)-(S)-(T)-OCH.sub.2 CH.sub.3 
(3S,4S)-(S)-T-OH (300 mg) 
Ethanol (20 ml) 
Ethanol saturated with HCl (20 ml) 
Product as the HCl salt (210 mg) 
m.p.=83.degree.-87.degree. C. 
Analysis for C.sub.29 H.sub.46 N.sub.2 O.sub.4.HCl Theory: C, 66.58; H, 
9.06; N, 5.35 Found: C, 66.84; H, 9.22; N, 5.60 
EXAMPLE 52 
Preparation of (3R,4R)-(S)-T-OCH.sub.2 CH.sub.3 
(3R,4R)-(S)-T-OH (400 mg) 
Ethanol (20 ml) 
Ethanol saturated with HCl (20 ml) 
Product as the HCl salt (200 mg) 
m.p.=163.degree.-168.degree. C. 
Analysis for C.sub.29 H.sub.46 N.sub.2 O.sub.4.HCl Theory: C, 66.58; H, 
9.06; N, 5.36 Found C, 66.85; H, 8.80; N, 5.18 
EXAMPLE 53 
______________________________________ 
Preparation of (3S,4S)--(S)--T--O(CH.sub.2).sub.2 CH.sub.3 
______________________________________ 
(3S,4S)--(S)--T--OH (300 mg) 
1-Propanol (20 ml) 
1-Propanol saturated with HCl 
(20 ml) 
Product as the HCl salt 
(215 mg) 
______________________________________ 
m.p.=75.5.degree.-79.degree. C. 
Analysis for C.sub.30 H.sub.48 N.sub.2 O.sub.4.HCl Theory: C, 67.08; H, 
9.19; N, 5.22 Found: C, 67.31; H, 9.40; N, 5.37 
EXAMPLE 54 
Preparation of (3R,4R)-(S)-T-O(CH.sub.2).sub.2 CH.sub.3 
(3R,4R)-(S)-T-OH (1 g) 
1-Propanol (60 ml) 
1-Propanol saturated with HCl (60 ml) 
Product as the HCl salt (900 mg) as white solid 
m.p.=173.degree.-175.degree. C. 
[.alpha.].sub.365 =+178.88.degree. 
Analysis for C.sub.30 H.sub.48 N.sub.2 O.sub.4.HCl Theory: C, 67.08; H, 
9.19; N, 5.21 Found: C, 66.80; H, 9.10; N, 5.05 
EXAMPLE 55 
Preparation of (3S,4S)-(S)-T-OCH.sub.2 CH(CH.sub.3).sub.2 
(3S,4S)-(S)-T-OH (250 mg) 
Isobutyl alcohol (20 ml) 
Isobutyl alcohol saturated with HCl (20 ml) 
Product as the HCl salt (200 mg) 
m.p.=79.degree.-82.degree. C. 
Analysis for C.sub.31 H.sub.50 N.sub.2 O.sub.4.HCl Theory: C, 67.55; H, 
9.33; N, 5.08 Found: C, 67.29; H, 9.55; N, 5.36 
EXAMPLE 56 
Preparation of (3R,4R)-(S)-T-OCH.sub.2 CH(CH.sub.3).sub.2 
(3R,4R)-(S)-T-OH (1 g) 
Isobutyl alcohol (60 ml) 
Isobutyl alcohol saturated with HCl (60 ml) 
Product as the HCl salt (845 mg) 
m.p=168.degree.-172.degree. C. 
[.alpha.].sub.365 =+176.48.degree. 
Analysis for C.sub.31 H.sub.50 N.sub.2 O.sub.4.HCl Theory: C, 67.55; H, 
9.33; N, 5.08 Found: C, 67.61; H, 9.40; N, 5.09 
EXAMPLE 57 
Preparation of (3R,4R)-(S)-T-O(CH.sub.2).sub.6 CH.sub.3 
(3R,4R)-(S)-T-OH (300 mg) 
Heptyl alcohol (20 ml) 
Heptyl alcohol saturated with HCl (20 ml) 
Product as the HCl salt (300 mg) 
m.p.=177.degree.-179.degree. C. 
[.alpha.].sub.365 =+143.48.degree. 
Analysis for C.sub.34 H.sub.56 N.sub.2 O.sub.4.HCl Theory: C, 68.83; H, 
9.68; N, 4.72 Found: C, 68.57; H, 9.53; N, 4.96 
EXAMPLE 58 
Preparation of (3S,4S)-(R)-T-OCH.sub.2 CH(CH.sub.3).sub.2 
(3S,4S)-(R)=T-OH (360 mg) 
Isobutyl alcohol (20 ml) 
Isobutyl alcohol saturated with HCl (20 ml) 
Product as the HCl salt (270 mg) 
m.p.=178.degree.-180.degree. C. 
[.alpha.].sub.365 =-170.80.degree. 
Analysis for C.sub.31 H.sub.50 N.sub.2 O.sub.4.HCl.1/2H.sub.2 O Theory: C, 
66.45; H, 9.36; N, 5.00 Found: C, 66.23; H, 9.14; N, 5.18 
EXAMPLE 59 
Preparation of (3R,4R)-(R)-T-OCH.sub.2 CH(CH.sub.3).sub.2 
(3R,4R)-(R)-T-OH (350 mg) 
Isobutyl alcohol (20 ml) 
Isobutyl saturated with HCl (20 ml) 
Product as the HCl salt (270 mg) 
m.p.=81.degree.-84.degree. C. 
[.alpha.].sub.365 =+46.24.degree. 
Analysis for C.sub.31 H.sub.50 N.sub.2 O.sub.4.HCl Theory: C, 67.55; H, 
9.33; N, 5.08 Found: C, 67.67; H, 9.23; N, 5.26 
The following procedure was used in Examples 60-66. The reactants were 
mixed together with the DCC added last and stirred at room temperature 
under nitrogen. After about 24 hours the reaction mixture was filtered and 
evaporated to dryness. The residue was dissolved in ethyl acetate which 
was then washed one time with water, dried over K.sub.2 CO.sub.3 and 
evaporated. The residue was then either passed over a silica column or 
over a chromatron using a 2 mm plate. Removal of the solvent provided the 
product which was then converted to the HCl salt. 
EXAMPLE 60 
______________________________________ 
Preparation of (3S,4S)--(S)--T--OCH.sub.2 C(O)NH.sub.2 
______________________________________ 
(3S,4S)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NH.sub.2 
(66 mg) 
HOBT (118 mg) 
DCC (180 mg) 
DMF dry (40 ml) 
______________________________________ 
Product was passed over a chromatron eluting with a gradient of ethyl 
acetate to ethyl acetate/ethanol (19:1) to provide the free amide product 
(194 mg). 
ms (fd)=515 (M+), 516 (M.sup.+ +1) 
Product as the HCl salt 
m.p.=110.degree.-116.degree. C. 
Analysis for C.sub.29 H.sub.45 N.sub.3 O.sub.5.HCl.1/2H.sub.2 O Theory: C, 
62.06; H, 8.44; N, 7.48 Found: C, 62.11; H, 8.52; N, 7.24 
EXAMPLE 61 
______________________________________ 
Preparation of (3R,4R)--(S)--T--OCH.sub.2 C(O)NH.sub.2 
______________________________________ 
(3R,4R)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NH.sub.2 
(66 mg) 
HOBT (118 mg) 
DCC (180 mg) 
______________________________________ 
Reaction product was passed over a silica column eluting with a gradient of 
ethyl acetate to ethyl acetate/methanol (9:1). The recovered material was 
then passed over a chromatron eluting with a gradient of ethyl acetate to 
ethyl acetate/ethanol (19:1) to provide the free amide product. 
ms (fd)=515 (M+), 516 (M +1) 
Conversion of the amide to the HCl salt provided 
130 mg of material. 
m.p.=103.degree.-106.degree. C. 
Analysis for C.sub.29 H.sub.45 N.sub.3 O.sub.5.HCl Theory: C, 63.08, H, 
8.40; N, 7.61 Found: C, 63.40; H, 8.64; N, 7.32 
EXAMPLE 62 
______________________________________ 
Preparation of (3S,4S)--(S)--T--OCH.sub.2 C(O)NHCH.sub.3 
______________________________________ 
(3S,4S)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NHCH.sub.3 
(78 mg) 
HOBT (118 mg) 
DCC (180 mg) 
DMF dry (40 ml) 
______________________________________ 
The reaction residue was passed over a silica column eluting with ethyl 
acetate to provide the free amide product (170 mg). 
ms (fd)=530 (M.sup.+ +1) 
The amide was converted to the HCl salt (156 mg) 
m.p.=67.degree.-71.degree. C. 
Analysis for C.sub.30 H.sub.47 N.sub.3 O.sub.5.HCl Theory: C, 63.64; H, 
8.54; N, 7.42 Found: C, 63.41; H, 8.56; N, 7.59 
EXAMPLE 63 
______________________________________ 
Preparation of (3R,4R)--(S)--T--OCH.sub.2 C(O)NHCH.sub.3 
______________________________________ 
(3R,4R)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NHCH.sub.3 
(78 mg) 
HOBT (118 mg) 
DCC (180 mg) 
DMF dry (40 ml) 
______________________________________ 
The reaction residue was passed over a silica column eluting with ethyl 
acetate. Removal of solvent provided the product amide. (160 mg). 
ms (fd)=530 (M.sup.+ +1) 
The amide was converted to the HCl salt (140 mg) 
m.p.=97.degree.-100.degree. C. 
Analysis for C.sub.30 H.sub.47 N.sub.3 O.sub.5.HCl Theory: C, 63.64; H, 
8.54; N, 7.42 Found: C, 63.92; H, 8.49; N, 7.19 
EXAMPLE 64 
______________________________________ 
Preparation of (3R,4R)--(S)--T--OCH.sub.2 C(O)N(CH.sub.3).sub.2 
______________________________________ 
(3R,4R)--(S)--T--OH 
(550 mg) 
HOCH.sub.2 C(O)N(CH.sub.3).sub.2 
(124 mg) 
HOBT (162 mg) 
DCC (247 mg) 
DMF dry (50 ml) 
______________________________________ 
The reaction residue was passed over a silica column eluting with a 
gradient of ethyl acetate to ethyl acetate/methanol (1:1) providing the 
free amide (206 mg) as a yellow foam. 
ms (fd)=544 (M+) 
The amide was converted to the HCl salt (178 mg) 
m.p.=80.degree.-83.degree. C. 
Analysis for C.sub.31 H.sub.49 N.sub.3 O.sub.5.HCl.H.sub.2 O Theory: C, 
62.23; H, 8.76; N, 7.03 Found: C, 61.93; H, 8.45; N, 7.30 
EXAMPLE 65 
______________________________________ 
Preparation of (3S,4S)--(S)--T--OCH.sub.2 C(O)NHCH.sub.2 CH.sub.3 
______________________________________ 
(3S,4S)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NHCH.sub.2 CH.sub.3 
(90 mg) 
HOBT (118 mg) 
DCC (180 mg) 
DMF dry (40 ml) 
______________________________________ 
The residue was passed over a silica column eluting with ethyl acetate and 
then passed over chromatron eluting with ethyl acetate-ethanol (19:1) to 
provide a viscous oil (145 mg). 
ms (fd)=544 (M.sup.+ +1) 
This material was converted to the HCl salt (140 mg). 
m.p.=89.degree.-93.degree. C. 
Analysis for C.sub.31 H.sub.49 N.sub.3 O.sub.5.HCl Theory: C, 64.17; H, 
8.69; N, 7.24 Found: C, 64.45; H, 8.73; N, 7.36 
EXAMPLE 66 
______________________________________ 
Preparation of (3R,4R)--(S)--T--OCH.sub.2 C(O)NHCH.sub.2 CH.sub.3 
______________________________________ 
(3R,4R)--(S)--T--OH 
(400 mg) 
HOCH.sub.2 C(O)NHCH.sub.2 CH.sub.3 
(90 mg) 
HOBT (118 mg) 
DCC (180 mg) 
DMF dry (40 ml) 
______________________________________ 
The residue was passed over a silica column eluting with a gradient of 
ethyl acetate to ethyl acetatemethanol (9:1). The recovered material was 
passed over a chromatron eluting with a gradient of ethyl acetate to ethyl 
acetate-ethanol (19:1) to provide a viscous oil (146 mg). 
ms (fd)=544 (M.sup.+ +1) 
This material was converted to the HCl salt (135 mg). 
m.p.=84.degree.-87.degree. C. 
Analysis for C.sub.31 H.sub.49 N.sub.3 O.sub.5.HCl.H.sub.2 O Theory: C, 
62.23; H, 8.76; N, 7.02 Found C, 62.17; H, 8.74; N, 6.86 
EXAMPLE 67 
Preparation of (3R,4R)-(S)-T-OCH(CH.sub.3)OC(O)CH.sub.3 
(3R,4R)-(S)-T-OH (687 mg) 
BrCH(CH.sub.3)OC(O)CH.sub.3 (926 mg) in CH.sub.2 Cl.sub.2 (100 ml) 
K.sub.2 CO.sub.3 (1.89 g) 
The above reagents were mixed together at room temperature and stirred 
overnight. The mixture was filtered and then evaporated to dryness to 
provide a black oil (725 mg). This material was passed through a silica 
column eluting with a gradient of ethyl acetate to ethyl acetate-methanol 
(1:1). Removal of solvent provided a yellow foam (200 mg). 
ms (fd)=545 (M+) 
This material was converted to the HCl salt and dried at 60.degree. C. to 
provide a tan solid (170 mg). 
m.p.=142.degree.-146.degree. C. 
Analysis for C.sub.31 H.sub.48 N.sub.2 O.sub.6.HCl.1/2H.sub.2 O Theory: C, 
63.08; H, 8.54; N, 4.75 Found: C, 62.82; H, 8.33; N, 4.79 
EXAMPLE 68 
Preparation of (3R,4R)-(S)-T-O-G where is G is 4-methoxycyclohexyl 
(3R,4R)-(S)-T-OH (463 mg) and K.sub.2 CO.sub.3 (1.83 g) were combined with 
DMF (70 ml) and heated to 70.degree.-80.degree. C. At this temperature 
C.sub.6 H.sub.5 SO.sub.2 O-G (1.52 g) was added and the mixture stirred an 
additional 20 hours at 70.degree.-80.degree. C. The mixture was cooled to 
room temperature, filtered and evaporated to dryness. The residue was 
partitioned between ethyl acetate and water. The water layer was adjusted 
to a pH of 9.8 with 1N NaOH and the layers separated. The ethyl acetate 
layer was washed one time with water, dried over K.sub.2 CO.sub.3 and 
evaporated to dryness to provide a residue (900 mg). This material was 
passed over a silica column eluting with ethyl acetate. 
Removal of solvent provided 400 mg of material which was converted to the 
HCl salt (355 mg). 
m.p.=169.degree.-172.degree. C. 
Analysis for C.sub.34 H.sub.54 N.sub.2 O.sub.5.HCl Theory: C, 67.24; H, 
9.13; N, 4.61 Found: C, 67.01; H, 9.14; N, 4.84 
EXAMPLE 69 
Preparation of (3S,4S)-(S)-T-O-G where G is 4-methoxycyclohexyl 
The procedure of Example 68 was followed using the following materials: 
(3S,4S)-(S)-T-OH (463 mg) 
p-CH.sub.3 C.sub.6 H.sub.5 SO.sub.2 -O-G (1.52 g) 
K.sub.2 CO.sub.3 (1.83 g) 
DMF (70 m) 
The reaction residue was passed over a silica column eluting with ethyl 
acetate to provide a white foam (450 mg). 
ms (fd)=570 (M+), 571 (M.sup.+ +1) 
This material was converted to the HCl salt and dried at 60.degree. C. to 
provide 395 mg of product. 
m.p.=86.degree.-90.degree. C. 
Analysis for C.sub.34 H.sub.54 N.sub.2 O.sub.5.HCl Theory: C, 67.25; H, 
9.13; N, 4.61 Found: C, 67.08; H, 9.09; N, 4.85 
EXAMPLE 70 
Preparation of (3R,4R)-(S)-T-O-J where J is 
##STR13## 
Under a nitrogen atmosphere J-Br (720 mg) in dry CH.sub.2 Cl.sub.2 (100 ml) 
was added dropwise to (3R,4R)-(S)-T-OH (458 mg) and K.sub.2 CO.sub.3 (1.27 
g) at 0.degree. C. The mixture was allowed to warm to room temperature and 
stirred for one hour. The mixture was filtered and the liquid phase 
evaporated to dryness to provide a residue (600 mg). This material was 
passed over a silica column eluting with a gradient of ethyl acetate to 
ethyl acetatemethanol (9:1). Removal of solvent provided a white solid 
which was recrystallized from ethyl acetate (210 mg). 
m.p.=145.degree.-147.degree. C. 
ms (fd)=537 (M.sup.+ +1) 
This material was converted to the HCl salt and dried at 60.degree. C. to 
provide a white solid (185 mg). 
m.p.=137.degree.-141.degree. C. 
Analysis for C.sub.32 H.sub.46 N.sub.2 O.sub.7.HCl.H.sub.2 O Theory C, 
61.47; H, 7.90; N, 4.48 Found: C, 61.83; H, 7.98; N, 4.69. 
EXAMPLE 71 
Preparation of B-C(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 CH.sub.3 where B is 
(tran.sub.3)-Q-(CH.sub.2).sub.2 N(cyclohexyl)-(Prep XII) 
______________________________________ 
B--H (600 mg) 
HOC(O)CH.sub.2 CH.sub.2 C(O)OCH.sub.2 CH.sub.3 
(264 mg) 
HOBT (244 mg) 
DCC (373 mg) 
DMF dry (50 ml) 
______________________________________ 
The above reactants were mixed together (DCC added last) and stirred at 
room temperature under nitrogen. After 24 hours the reaction mixture was 
filtered and the filtrate was evaporated to dryness. The residue was 
dissolved in ethyl acetate which was washed once with water, dried over 
K.sub.2 CO.sub.3 and evaporated to provide a residue (1.09 g). The residue 
was passed over a silica column eluting with a gradient of hexane/ethyl 
acetate (9:1) to ethyl acetate. Removal of solvent provided 570 mg of 
material. This was passed over a 2 mm plate on a chromatron eluting with 
ethyl acetate. Removal of the solvent provided a viscous oil (470 mg). 
ms (fd)=459 (M.sup.+ +1) 
This material was converted to the HCl salt and dried to provide a solid 
(450 mg). 
m.p.=96.degree.-100.degree. C. 
Analysis for C.sub.27 H.sub.42 N.sub.2 O.sub.4.HCl.1/2H.sub.2 O Theory: C, 
64.32; H, 8.80; N, 5.56; Found: C, 64.22; H, 8.85; N, 5.56. 
EXAMPLE 72 
Preparation of B-C(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2 
where B is as defined in Example 71. The procedure of Example 71 was 
followed using B-H (600 mg) prepared as in Preparation XII. 
HOC(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 CH(CH.sub.3).sub.2 (315 mg) 
HOBT (244 mg) 
DCC (373 mg) 
DMF dry (40 ml) 
The residue was passed over a silica column eluting with a gradient of 
hexane/ethyl acetate (9:1) to ethyl acetate. The recovered material was 
put over a 2 mm plate on a chromatron eluting with ethyl acetate to 
provide a white foam (380 mg). 
ms (fd)=487 (M.sup.+ +1) 
This material was converted to the HCl salt and dried. 
m.p.=82.degree.-86.degree. C. 
Analysis for C.sub.29 H.sub.46 N.sub.2 O.sub.4.HCl Theory: C, 66.58; H, 
9.06; N, 5.36; Found: C, 66.18; H, 8.89; N, 5.12. 
EXAMPLE 73 
Preparation of B-C(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 (C.sub.6 H.sub.11) 
where B is defined in Example 71 and C.sub.6 H.sub.11 is cyclohexyl. 
______________________________________ 
B--H prepared as in Preparation XII 
(600 mg) 
HOC(O)(CH.sub.2).sub.2 C(O)OCH.sub.2 (C.sub.6 H.sub.11) 
(387 mg) 
HOBT (244 mg) 
DCC (373 mg) 
DMF dry (40 ml) 
______________________________________ 
The residue was passed over a silica column eluting with a gradient of 
hexane/ethyl acetate (9:1) to ethyl acetate. The recovered material was 
then passed over a 2 mm plate on a chromatron eluting with ethyl acetate 
to provide a viscous oil (370 mg). 
ms (fd)=526 (M+), 527 (M.sup.+ +1) 
This material was converted to the HCl salt and dried. 
m.p.=79.degree.-84.degree. C. 
Analysis for C.sub.32 H.sub.50 N.sub.2 O.sub.4.HCl Theory: C, 68.24; H, 
9.13; N, 4.97; Found: C, 67.85; H, 9.42; N, 4.93. 
The instant compounds are useful in blocking peripherial opioid receptors 
and preventing peripherally opiate induced side effects. These side 
effects induced by the administration of an opiate such as morphine to a 
mammal can include constipation, nausea, and vomiting. These compounds can 
also be useful in the treatment of irritable bowel syndrome and idiopathic 
constipation. While not wishing to be bound by the theory, it is believed 
that the instant compounds act as opioid antagonists and bind to 
peripherial opioid receptors outside of the brain. The compounds do not 
substantially pass through the blood-brain barrier and therefore do not 
mitigate the opioid's effect on central (brain and spinal cord) opioid 
receptors. 
In order to determine in vivo opioid receptor antagonism, the mouse 
writhing analgesis test was used. Test compounds were measured for their 
ability to block morphine-induced analgesis. 
Five CF-1 male mice (Charles River, Portage, MI), weighing approximately 20 
g after being fasted overnight, were observed simultaneously for the 
writhing response. The writhing response was defined as a contraction of 
the abdominal musculature, followed by the extension of the hind limbs, 
and was induced by the intraperitoneal administration of 0.6% acetic acid 
in a volume of 1 ml/100 g body weight. The observation period was 10 min. 
in duration, beginning 5 min. after injection of acetic acid. The percent 
inhibition of writhing was calculated from the average number of writhes 
in the control (non-drug) group. Each data point is the mean (.+-.standard 
error) for five mice. The ED.sub.50 was defined as the dose of agonist 
that inhibited mean writhing by 50%. The AD.sub.50 was defined as the dose 
of antagonist that reduced the inhibition of writhing produced by a 1.25 
mg/kg dose of morphine sulfate to 50%. Each mouse was only used once. All 
drugs were administered subcutaneously (1 ml/100 g bwt) 20 min. before the 
injection of acetic acid. 
Determinations of peripheral opioid activity were conducted. Mice 
maintained (6 mice/cage) on 0.01 M saccharin water with 1 g/1 morphine 
sulfate for a minimum of 10 days with mice averaging 3.0 +g 
water/mouse/day for at least three days are used as subjects. The morphine 
water was removed 45 min. prior to injection with the proposed opioid 
antagonist. Initial testing consisted of 5 mice/dose of compound. The 
antagonist was given by the subcutaneous or oral, route of administration, 
and the mice were placed in 11-14".times.4 7/12 I.D. clear plastic 
cylinders with white paper towels used for a floor. 
The mice were then monitored visually for 30 minutes post-injection for the 
presence of jumping and of diarrhea. Jumping was scored as positive if at 
least one jump occurred in 30 min. Diarrhea was scored as positive when 
feces were moist enough to stain the white paper at the base of the 
cylinder. After 30 minutes of testing, the mice were placed back in 
original cages, put back on morphine water, and not tested again for 48 
hrs. Lower doses of the antagonist compounds were tested until threshold 
doses for diarrhea were determined. Diarrhea is a peripherally mediated 
sign of precipitated opiate abstinence. 
The extent of the effect on peripheral activity compared to central 
activity of the present compounds can be determined by comparing the 
AD.sub.50 for the mouse writhing test with the ED.sub.50 for the mouse 
diarrhea test. The higher the ratio, the greater the relative antagonism 
of the peripheral opioid receptors by a particular compound. This ratio 
for each compound is provided in Table I. 
TABLE I 
______________________________________ 
Example 
No..sup.(1) 
AD.sub.50.sup.(2) 
ED.sub.50.sup.(3) 
Ratio.sup.(4) 
______________________________________ 
1 &gt;40 0.01 &gt;4000 
2A 8.4 0.29 29 
2B 10.2 0.19 54 
3A 14.2 0.16 89 
3B 15.5 0.14 111 
4 17.5 0.07 250 
5 &gt;20 0.012 &gt;1666 
6 30 0.07 428 
7 8.62 0.45 19 
8 &gt;1.25 0.64 &gt;2 
9 &gt;1.25 0.25 &gt;5 
10 9.3 0.12 78 
11 12.4 0.30 41 
12 20 0.20 100 
13 &gt;40 0.29 &gt;138 
14 21 0.32 656 
15 1.39 0.028 50 
16 &gt;20 0.12 &gt;166 
17 &gt;40 3.28 &gt;12 
18 1.31 0.30 4.5 
19 6.3 0.082 77 
20 2.1 0.06 35 
21 17.1 0.073 71 
22 1.25 0.016 63 
23 &gt;1.25 0.24 &gt;5 
24 19.2 0.62 31 
25 0.61 0.06 10 
26 3.6 0.05 72 
27 11 0.18 61 
28 &gt;1.25 0.10 &gt;12 
29 7.6 0.99 7.7 
30 12.4 &lt;0.30 &gt;40 
31 &gt;40 0.19 &gt;200 
32 9.4 0.16 59 
33 3.67 0.03 122 
34 8.2 0.39 21 
35 &gt;1.25 0.42 &gt;3 
36 2.9 0.39 8 
37 12.8 0.05 256 
38 28.9 0.018 1605 
39 5.1 0.05 102 
40 2.20 0.74 3 
41 32 0.43 74 
42 &gt;20 0.12 &gt;160 
43 &gt;10 &lt;1.0 &gt;10 
44 &gt;2 0.07 &gt;30 
45D &gt;40 0.029 &gt;1379 
46D 6.5 0.09 72 
47D &gt;40 0.01 &gt;4000 
48D &gt;40 0.05 &gt;800 
49 9.9 &gt;10 &gt;1 
50 20 0.056 357 
51 &gt;40 
52 28 0.02 1400 
53 &gt;40 1.06 &gt;38 
54 27 0.0015 18000 
55 &gt;40 0.05 &gt;800 
56 &gt;40 0.002 20000 
57 &gt;40 0.068 &gt;588 
58 &gt;40 0.17 &gt;235 
59 &gt;40 0.059 &gt;678 
60 &gt;10 0.035 &gt;285 
61 22 0.13 169 
62 &gt;40 0.03 &gt;1333 
63 12 0.003 4000 
64 13.5 
65 &gt;40 0.02 &gt;2000 
66 12.2 0.005 2440 
67 &gt;40 
68 18.8 0.29 65 
69 &gt;40 0.03 &gt;1333 
70 18.2 0.017 1070 
71 3.71 0.29 13 
72 5.5 0.017 324 
73 9.2 0.17 54 
______________________________________ 
.sup.(1) compounds tested correspond to example number 
.sup.(2) mg/kg in mouse writhing test 
.sup.(3) mg/kg in mouse diarrhea test 
.sup.(4) ratio of AD.sub.50 to ED.sub.50 
The compounds of the present invention have been found to display excellent 
activity in an opioid receptor binding assay which measures the affinity 
of the compounds to to bind to mu receptors. This assay was conducted by 
the following procedure. 
Male Sprague Dawley rats for mu site experiments were sacrificed via 
decapitation and the brains were removed. The brain tissue, rat whole 
brain minus cerebellum for mu 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 sites increasing concentrations of experimental compound, [0.1 to 
1000 nanomolar (nM)], Kreb-Hepes buffer pH 7.4, and tritiated naloxone 
(0.5 nM) (.sup.3 H ligand) were combined in polystyrene tubes at room 
temperature. The reaction was initiated by the addition of the resuspended 
tissue which had 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, (Brandel Cell 
Harvestor), through Whatman GF/B 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 RedySolv, (Brandel), 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 incubation time for the reaction mixture was 20 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 compounds and K.sub.D is the dissociation 
constant for the .sup.3 H ligand at the receptor site. K.sub.D can be 
determined as described by Bennett, "Methods in Binding Studies", 
Neurotransmitter Receptor Binding, Yamamura, et al., ed., p. 57-90, Raven 
Press, N.Y. (1978) incorporated herein by reference. 
The results of the evaluation of certain compounds of the present invention 
in the opioid receptor binding assay are set forth below in Table II. In 
the Table, column 1 sets forth the Example Number of the compound 
evaluated, column 2 and 3, the Ki value in nanomolar (nM) at the mu 
receptor and columns 3 and 4 the percent displacement by the test compound 
at the indicated concentration, ie., 10 nm or 100 nm. 
TABLE II 
______________________________________ 
Naloxone [.sup.3 H] Binding Assay 
(mu receptor) 
Example Ki.sup.(1) 10 nM.sup.(2) 
100 nM.sup.(2) 
______________________________________ 
1 6.88 72 94 
2A 0.64 98 100 
2B 1.20 93 99 
3A 0.30 100 100 
3B 0.86 93 99 
4 1.41 86 94 
5 0.30 100 100 
6 6.49 82 94 
7 0.63 99 100 
8 0.68 95 99 
9 1.33 92 100 
10 1.46 61 94 
11 -- 36 80 
12 -- 43 87 
13 -- 24 72 
14 32.40 20 64 
15 2.96 80 99 
16 0.96 97 100 
17 -- 38 82 
18 0.63 86 100 
19 -- 48 92 
20 0.74 95 99 
21 -- 53 80 
22 3.59 51 93 
23 4.38 77 100 
24 -- 48 89 
25 1.18 77 93 
26 1.91 73 100 
27 8.00 63 93 
28 -- 67 100 
29 -- 56 88 
30 11.00 79 96 
31 2.52 82 97 
32 -- 40 100 
33 0.26 83 99 
34 -- 77 91 
35 2.15 80 99 
36 3.01 85 99 
37 0.61 88 100 
38 2.98 79 98 
39 0.22 100 99 
40 1.16 87 100 
41 2.45 87 99 
42 -- 44 89 
43 -- 59 97 
44 2.34 63 85 
45D 0.56 82 94 
46D -- 48 84 
47D 1.55 85 95 
48D -- 30 78 
49 8.19 83 97 
50 3.24 87 99 
51 -- 73 97 
52 2.34 87 96 
53 -- 50 88 
54 5.07 81 96 
55 -- 40 86 
56 -- 61 92 
57 -- 0 9 
58 -- 0 38 
59 -- 6 53 
60 5.96 76 95 
61 2.86 88 97 
62 -- 70 96 
63 2.13 87 99 
64 1.51 81 94 
65 -- 67 93 
66 1.84 81 94 
67 -- 73 95 
68 -- 68 95 
69 -- 37 83 
70 1.78 89 99 
71 3.85 78 96 
72 -- 73 96 
73 -- 46 88 
______________________________________ 
.sup.(1) In nanomoles 
.sup.(2) % displacement 
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 
excipient and at least one compound of the invention. Such compositions 
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 excipient therefor. 
In making the compositions of the present invention, the active ingredient 
is usually mixed an excipient which can be a carrier, or a diluent or be 
diluted by a carrier, or enclosed within a carrier which can be in the 
form of a capsule, sachet, paper or other container. When the carrier 
serves as a diluent, it can 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 excipients, 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 formulations can also include wetting agents, emulsifying and 
suspending agents, preserving agents, sweetening agents or flavoring 
agents. The formulations of the invention can 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 is preferably admixed 
with one or more excipients, 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 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 excipient. 
In order to more fully illustrate the operation of this invention, the 
following formulation examples are provided. The samples 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) 
______________________________________ 
N-(1,4-dioxo-4-((2-(4- 
250 mg 55.0 
(3-hydroxyphenyl)-3,4- 
dimethyl-1-piperidinyl)- 
ethyl)-phenylamino)butyl)- 
leucine monohydrochloride 
monohydrate (Example 39) 
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) 
______________________________________ 
4-[(3-(4-(3-hydroxy- 
20 mg 10.0 
phenyl)-3,4-dimethyl-1- 
piperidinyl)-1-(cyclo- 
hexylmethyl)-propyl)- 
amino]-4-oxobutanoic 
acid monohydrate 
(Example 1) 
starch 89 mg 44.5 
microcrystalline 89 mg 44.5 
cellulose 
magnesium stearate 
2 mg 1.0 
200 mg 100.0 mg 
______________________________________ 
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) 
______________________________________ 
5-[[1-(2-methylpropyl)- 
100 mg 30.00 
3-[4-(3-hydroxyphenyl)- 
3,4-dimethyl-1-piperi- 
dinyl]-propyl]amino]-5- 
oxopentanoic acid 
(Example 4) 
polyoxyethylene sorbitan 
50 mg 0.02 
monooleate 
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 
Tablet (percent) 
______________________________________ 
N-(3-(trans-4-(3- 
10 mg 10.0 
hydroxyphenyl)-3,4- 
dimethyl-1-piperidinyl)- 
1-phenylpropyl)-acetamide 
(Example 6) 
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) 
______________________________________ 
[2-(trans-4-(3- 250 mg 38.0 
hydroxyphenyl)-3,4- 
dimethyl-1-piperidinyl)- 
1-phenylmethyl-ethyl- 
amino]-4-oxobutanoic 
acid (Example 14) 
cellulose 400 mg 60.0 
microcrystalline 
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 
______________________________________ 
4-(cyclohexyl-(2-(trans-4-(3- 
5 mg 
hydroxyphenyl)-3,4-dimethyl- 
1-piperidinyl)ethyl)amino)- 
4-oxobutanoic acid propyl 
ester (Example 31) 
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) 
______________________________________ 
5-(cyclohexyl-(3-trans-4-(3- 
0.25 
hydroxyphenyl)-3,4-dimethyl- 
1-piperidinyl)propyl)amino)- 
5-oxopentanoic acid ethyl 
ester monohydrochloride 
(Example 33) 
ethanol 29.75 
Propellant 22 70.00 
(chlorodifluoromethane) 
100.00 
______________________________________ 
The active compound is mixed with 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.