The present invention provides novel 4-phenyl-triazol-3-yl- and 3-phenyl-triazol-4-yl-piperidines which are useful as analgesics.

DESCRIPTION 
Background 
The present invention provides novel compositions of matter. More 
particularly, the present invention provides novel 4-phenyl-triazol-3-yl- 
and 3-phenyl-triazol-4-yl- piperidines which are useful as analgesics. 
Some of these compounds are also useful as anti-psychotic agents. 
Relief of pain is of course one of the primary objectives in medicine. 
Drugs which have a predominant pain relieving action are called analgesics 
and commonly classified as narcotic and non-narcotic. This classification 
scheme is based on legal considerations, since there is greater federal 
regulation of narcotic analgesics over non-narcotic analgesics. A more 
useful classification scheme is to classify the analgesics as strong, 
moderate and mild analgesics. Most narcotic analgesics are strong 
analgesics and most non-narcotic analgesics are mild to moderate 
analgesics. 
The narcotic analgesics include the alkaloids of opium and numerous related 
synthetic drugs. These include, for example, naturally occuring alkaloids 
and semi-synthetic opiates, meperidine and related phenyl-piperidines, 
methadone and related drugs, benzomorphans, morphinan derivatives, and 
narcotic antagonists. The non-narcotic, or mild to moderate analgesics 
include the salicylates, pyrazolones, para-aminophenol derivatives, and a 
class of non-steroidal anti-inflammatory compounds including indomethacin, 
mefenamic acid, ibuprofen, fenoprofen, naproxen, and tolmetin. 
What is needed in the art is an analgesic which relieves pain similar to 
narcotic analgesics without the side effects associated with these 
analgesics. 
PRIOR ART 
Bohm, et al., Die Pharmazie 36:246 (1981) discloses certain phenyl 
substituted 1,3,4-triazoles which are stated to be useful as analgetics 
and/or anti-phlogistics. Behringer, et al., Liebigs Ann. Chem. 1264 (1975) 
describes the metallation of a triazole ring with butyllithium and 
condensation of the anion thus formed with ketones. Derwent Farmdoc No. 
17865E, corresponding to Belgian Pat. No. 890,035 (Roussel UCLAF) 
discloses certain phenyl substituted 1,3,4-triazoles which are stated to 
be useful as analgesics to treat nerve, muscle or joint pain or toothache. 
SUMMARY OF THE INVENTION 
The present invention particularly provides: 
a compound of the Formula I wherein either 
(1) R.sub.10 is a substituent of the Formula II and R.sub.20 is a 
substituent of the Formula III or 
(2) R.sub.10 is a substituent of the Formula IV and R.sub.20 is a 
substituent of the Formula II; 
wherein the wavy lines represent the cis or trans configuration; 
wherein R.sub.31 is 
(a) hydrogen, 
(b) C.sub.1 to C.sub.2 -alkyl, 
(c) --SCH.sub.3, 
(d) --S(O)CH.sub.3, 
(e) --S--phenyl, 
(f) --S(O)--phenyl, 
(g) --CH(OH)CH.sub.3, 
(h) --CH.sub.2 OC(O)R.sub.11, or 
(i) phenyl, 
with the provisos that 
(1) when R.sub.20 is the Formula III substituent, R.sub.31 is --SCH.sub.3, 
--S(O)CH.sub.3, --S--phenyl, --S(O)--phenyl, --CH(OH)CH.sub.3 or 
--CH.sub.2 OC(O)R.sub.11 only when R.sub.3 is hydrogen and 
(2) R.sub.31 is phenyl only when R.sub.20 is the Formula III substituent 
and R.sub.3 is --OC(O)R.sub.21 ; 
wherein X.sub.1 is 
(a) o-, m-, or p-fluoro; 
(b) hydrogen, 
(c) methoxy, 
(d) m-acetoxy, or 
(e) (C.sub.1 -C.sub.2)alkyl; 
wherein Y.sub.1 is 
(a) hydrogen, 
(b) m-methoxy, or 
(c) (C.sub.1 -C.sub.2)alkyl; 
with the provisos that Y.sub.1 is m-methoxy only when X.sub.1 is p-methoxy; 
and Y.sub.1 is (C.sub.1 -C.sub.2)alkyl only when X.sub.1 is (C.sub.1 
-C.sub.2)alkyl; 
wherein R.sub.1 is 
(a) hydrogen, 
(b) --CH.sub.3, 
(c) --C.sub.2 H.sub.5, or 
(d) CH.sub.2 .dbd.CH--CH.sub.2 --, 
with the proviso that R.sub.1 is CH.sub.2 .dbd.CH--CH.sub.2 -- only when 
R.sub.20 is a Formula III substituent; 
wherein R.sub.2 is 
(a) hydrogen, or 
(b) methyl; 
wherein R.sub.3 is 
(a) hydrogen, or 
(b) --OC(O)R.sub.21 ; 
wherein R.sub.11 and R.sub.21 are the same or different and are hydrogen, 
methyl and ethyl; and the pharmacologically acceptable salts thereof. 
Thus, the compounds of the present invention are of the Formulas Ia and Ib. 
Compounds of the present invention have been evaluated in at least one of 
the following standard laboratory tests which demonstrate analgesic 
activity. Thus, the compounds of the present invention have been evaluated 
in the in vivo tests conducted on mice known as the "tail flick"; the 
"tail pinch"; and the "HCl writhing" tests which may be briefly described 
as follows: 
Procedure--Groups of 6 Carworth Farms (CF-1)-derived mice, weighing 18 to 
22 grams, are used. A solution or suspension of the test compound is 
administered subcutaneously at a dose of 100 mg/kg. Fifteen minutes 
following the dosing, a series of procedures are carried out as follows: 
Tail Flick: A high intensity light is directed at the middle third of the 
test animal's tail, simultaneous with the start of a photoelectric timer. 
The number of seconds required for the animal to "flick" its tail out of 
the light path is recorded. 
Tail Pinch: A bulldog arterial clamp is applied to the base of a test 
animal's tail, and the number of animals that do not turn within 30 
seconds are recorded. 
HCl Writhing: The test animals receive an intraperitoneal dose of 0.15 
percent hydrochloric acid solution, one ml, per 100 g body weight. The 
number of animals failing to writhe within 15 minutes is recorded. 
Evaluation: Analgesia is measured by the Tail Flick, Tail Pinch, and 
Writhing responses. In the latter two cases, where the animals fail to 
respond within the measuring time interval the compound is scored as 
analgesic. Where the tail flick time is more than 2 standard derivations 
greater than mean for the control group, the compound is scored as 
analgesic. 
Test compounds scored as analgesic in at least 5 of 6 animals are retested 
at multiple dose levels for estimation of ED.sub.50 values calculated by 
the methods of Spearman and Karber (in D. J. Finney, "Statistical Methods 
in Biological Assay," Hafner Publ. (1952)). 
These comounds have also been evaluated in an in vitro opiate receptor 
binding assay, which demonstrates narcotic analgesic-like activity. For a 
discussion of opiate receptor binding assays, see, e.g., Pert, et al., 
Proc. Nat. Acad. Sci. USA, 70:2243 (1973). 
All of the compounds of the present invention have been found active in one 
or more of these tests. Some of the compounds of this invention are more 
preferred as they are active in the in vivo mouse analgesia tests, but 
show little or no activity in the opiate receptor binding assay, meaning 
that the compound is an effective analgesic agent, without the detrimental 
side effects of narcotic analgesics. A compound of this type is 
1-(2-phenylethyl)-4-(4-phenyl-4H-1,2,4-triazol-3-yl)-piperidine (Example 
12). 
(3.alpha.,4.beta.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1- 
(2-phenylethyl)-4-piperidinol, acetate (ester) and its monohydrochloride 
isomer B (Example 4, Part C) are preferred for subcutaneous 
administration, having an ED.sub.50 in the Tail Flick, Tail Pinch and HCl 
Writing tests of approximately 0.004 mg/kg. 
By virtue of their analgesic activity the compounds of Formula I are useful 
in treating pain in humans and animals. A physician or veterinarian of 
ordinary skill readily determines a subject who is in need of analgetic 
treatment. Regardless of the route of administration selected, the 
compounds of the present invention are formulated into pharmaceutically 
acceptable dosage forms by conventional methods known to the 
pharmaceutical art. 
The compounds can be administered in such oral unit dosage forms as 
tablets, capsules, pills, powders, or granules. They also may be 
administered rectally or vaginally in such forms as suppositories or 
bougies. They may also be introduced parenterally, (e.g., subcutaneously, 
intravenously, or intramuscularly), using forms known to the 
pharmaceutical art. In general, the preferred route of administration is 
oral. 
An effective but non-toxic quantity of the compound is employed in 
treatment. The dosage regimen for treating pain by the compounds of this 
invention is selected in accordance with a variety of factors including 
the type, age, weight, sex, and medical condition of the mammal, the 
severity of the pain, the route of administration and the particular 
compound employed. An ordinarily skilled physician or veterinarian will 
readily determine and prescribe the effective amount of the compound of 
the present invention to prevent, arrest, lessen or eliminate the 
sensation of pain. In so proceeding, the physician or veterinarian could 
employ relatively low dosages at first, subsequently increasing the dose 
until a maximum response is obtained. 
Initial dosages of the compounds of the invention are ordinarily in the 
area of 0.01 mg/kg up to at least 10 mg/kg per dose orally, preferably 0.1 
to 5 mg/kg orally and are given from one to four times daily or as needed. 
When other forms of administration are employed equivalent doses are 
administered. When dosages beyond 10 mg/kg are employed, care should be 
taken with each subsequent dose to monitor possible toxic effects. 
The compounds of this invention can also be administered as 
pharmacologically acceptable acid addition salts such as the 
hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, 
propionate, lactate, maleate, malate, succinate, tartrate, 
cyclohexanesulfamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 
toluenesulfonate and the like. Such acid addition salts are prepared by 
known methods. Additionally, the compounds of this invention may be 
administered in a suitable hydrated form. 
The compounds of the present invention are prepared by the methods depicted 
in Charts A, B and C. In these charts R.sub.5 is phenyl, R.sub.6 is 
hydrogen or methyl, R.sub.30 is hydrogen, methyl, ethyl, or phenyl, 
R.sub.32 is methyl, ethyl, methylthio, phenylthio, --CH(OH)CH.sub.3, or 
--CH.sub.2 OC(O)R.sub.11, and X.sub.1, Y.sub.1, R.sub.1, R.sub.2, R.sub.3, 
R.sub.11, and R.sub.21 are as defined above (unless otherwise noted). 
Compounds produced as in these charts can be isolated and purified by 
known methods, for example, extraction, crystallization, column 
chromatography, and the like. The required starting materials for the 
procedures of these charts are known or can be prepared by known methods. 
As used herein ambient temperature refers to the prevailing room 
temperature usually about 20.degree. to 23.degree. C. 
The procedures of Chart A are used to prepare compounds of the Formula Ia 
wherein R.sub.3 is --OC(O)R.sub.21. In Chart A, a heterocycle of the 
Formula A-1 (prepared by methods similar to those described in U.S. Pat 
No. 4,338,453) containing a reactive C--H or C--Br bond is dissolved in 
tetrahydrofuran (THF), cooled to -78.degree. to -30.degree. C., is treated 
with a solution of n- or sec-butyllithium in hexane or pentane, and 
stirred one tenth to one half hour until anion formation is substantially 
complete. 
The bromo compound of the Formula A-1 can be prepared from the anion of a 
Formula A-1 compound by reaction with bromine at low temperature (down to 
approximately -78.degree. C.) followed by allowing the mixture to warm to 
room temperature and conventional isolation procedures. 
The heterocyclic anion thus formed from a Formula A-1 compound is treated 
with a solution of the phenethylpiperidone of the Formula A-2 in THF at 
-30.degree. C. and warmed slowly to ambient temperature, to produce an 
amino alcohol of the Formula A-3. 
Following the procedures of H. Vorbruggen (Angew Chem Int Ed. Eng. 17, 569 
(1978)) a solution of 5.15 mmol of amino alcohol (Formula A-3) dissolved 
in 40 ml methylene chloride is treated with 2-10 equivalents of 
triethylamine, 2-5 equivalents of acid anhydride (or formic acid) and 
0.2-0.8 equivalents of 4-(dimethylamino)pyridine at a temperature of from 
-40.degree. C. to room temperature to yield the Formula A-4 product. 
Alternatively esterification is achieved by reaction of a Formula A-3 
alcohol with an appropriate mixed anhydride, for example that of acetic 
and formic acids, in the presence of pyridine at 0.degree. C. to ambient 
temperature for a time sufficient to form the desired ester (usually up to 
about 18 hours). 
When a Formula A-4 compound wherein X.sub.1 is m-acetoxy is desired, it is 
prepared from a Formula A-3 compound wherein X.sub.1 is m-methoxy, which 
is treated with 48% aqueous hydrogen bromide at reflux for a time 
sufficient to form the corresponding intermediate compound wherein X.sub.1 
is hydroxy (usually about 18 hours). Esterification with acetic anhydride 
as described above then forms a diester of the Formula A-4 wherein X.sub.1 
is m--OC(O)CH.sub.3 and R.sub.21 is methyl. Selective hydrolysis of the 
phenol ester with potassium bicarbonate in aqueous methanol then produces 
a compound of the Formula A-4 wherein X.sub.1 is hydroxy and R.sub.21 is 
methyl, which compound is used as an intermediate for preparing other 
desired A-4 esters wherein X.sub.1 is m-acetoxy. 
As an alternative to the conversion of A-1 to A-3 by reaction with A-2 as 
in Chart A, a piperidone similar to A-2 but bearing on the piperidone 
nitrogen a benzyl rather than a 2-phenylethyl group is reacted with the 
anion from the A-1 compound. Hydrogenolysis of the benzyl group then 
yields an alcohol similar to A-3 but bearing a hydrogen on the piperidine 
nitrogen. Reaction of this compound with 2-phenylethyl bromide then 
produces the 2-phenylethyl compound of the Formula A-3. 
The procedures of Chart B are used to prepare compounds of the Formula Ia 
wherein R.sub.3 is hydrogen. In Chart B, the isonicotinic acid hydrazide 
(Formula B-1) is treated with an appropriately substituted phenyl 
isothiocyanate (Formula B-2) in ethanol to give the Formula B-3 compound 
by a known method (see for example U.S. Pat. No. 4,338,453). 
This product is treated with an aqueous 10-40% solution of sodium hydroxide 
and refluxed for 1-3 hours to produce the crude product of Formula B-4 
which is filtered and cautiously added in small portions to a hot solution 
of 20% nitric acid heated on a steam bath to produce the Formula B-5 
compound. A vigorous frothing occurs on adding each portion of sulfide. 
The phenyl triazolo pyridine (Formula B-5) dissolved in acetic acid is 
treated with an amount preferably an equal weight of a platinum oxide 
catalyst and hydrogenated in a Parr Bomb at 50 psi initial pressure. The 
catalyst is filtered, the acetic acid is removed in vacuo and the product 
of the Formula B-6 is neutralized and crystallized from a suitable solvent 
if desired. 
The secondary piperidine (Formula B-6) is treated with 1.6 equivalents of 
phenethyl bromide, 1.4 equivalents of potassium carbonate in absolute 
ethanol (approximately 0.3M) and refluxed for 24 hr. After work-up from 
aqueous sodium hydroxide and chloroform extraction, the Formula B-7 
product is crystallized. 
The anion of the compound of the Formula B-7 is generated at -78.degree. to 
-30.degree. C. in THF as in Chart A and is treated with: 
(a) methyl or ethyl iodide, 
(b) dimethyl disulfide, 
(c) diphenyl disulfide, 
(d) acetaldehyde, or 
(e) formaldehyde followed by suitable esterification to produce a compound 
of the Formula B-8 wherein R.sub.32 is, respectively, 
(a) methyl or ethyl, 
(b) methylthio, 
(c) phenylthio, 
(d) --CH(OH)CH.sub.3, or 
(e) --CH.sub.2 OC(O)R.sub.11. 
When this reaction is undertaken using methyl iodide, both 5-methyl and 
5-ethyl-triazole products result. The methylthio and phenylthio compounds 
of the Formula B-8 are oxidized to the corresponding sulfoxide with a 
suitable oxidant under acidic conditions so as to avoid oxidation of 
nitrogen, for example with hydrogen peroxide in acetic acid. 
As an alternative a Formula B-7 compound is reacted directly with 
paraformaldehyde in a suitable hydrocarbon solvent such as xylene at 
elevated temperature for a time sufficient to form the hydroxymethyl 
compound (see U.S. Pat. No. 4,338,453) which is esterified to produce a 
compound of the Formula B-8 wherein R.sub.32 is --CH.sub.2 OC(O)R.sub.11. 
The procedures of Chart C are used to prepare compounds of the Formula Ib 
of this invention. In Chart C following the procedure of Lobbezoo, Journal 
of Medicinal Chemistry, Vol. 24, 777 (1981), a piperidone of the Formula 
C-1 (R.sub.1 is not CH.sub.2 .dbd.CH--CH.sub.2 --) is reacted with 
hydrogen gas and benzylamine in the presence of some thiophene and 10% 
palladium on carbon (Pd/C) in methanol to produce the compound of the 
Formula C-2, which upon further hydrogenolysis over fresh Pd/C is 
converted to the amine of the Formula C-3. Alternatively the Formula C-3 
amine is produced by reaction of the Formula C-1 piperidone with 
hydroxylamine to produce the Formula C-4 oxime which is reduced with 
sodium in ethanol to produce the Formula C-3 amine. This C-1 to C-4 to C-3 
route must be used if R.sub.1 is CH.sub.2 .dbd.CH--CH.sub.2 --. In the C-1 
to C-4 to C-7 route the sequence can be carried out with a benzyl rather 
than 2-phenylethyl group on the piperidone nitrogen. After triazole ring 
formation the benzyl group is removed by hydrogenolysis and the resulting 
piperidine nitrogen is alkylated with 2-phenylethyl bromide as described 
above. Reaction of the Formula C-3 amine with N,N-dimethylformamide 
dimethyl acetal at reflux for about 3 hours produces the amidine of the 
Formula C-5 which is heated with the appropriate benzoic acid hydrazide 
first at 55.degree. C. for about 14 hours to produce the Formula C-6 
compound and then at reflux for about 4 hours to produce the compound of 
the Formula C-7. As described above for the Formula B-7 compound, the 
formula C-7 triazole is converted to its anion and reacted to produce the 
various Formula C-8 compounds. The Formula C-8 sulfoxides are prepared as 
described above. 
Note that for compounds of the Formula I and more particularly for 
compounds of the Formulas Ia and Ib, up to three carbon atoms of the 
piperidine ring may be asymmetrically substituted and thus may 
independently possess the R or S configuration. The Formula I compounds 
may thus have as many as 8 stereoisomers which comprise four pairs of 
enantiomers; each enantiomeric pair is termed a racemate. See for example 
J. B. Hendrickson, et al., Organic Chemistry, Third Edition, McGraw-Hill 
Book Company, New York, N.Y. 1970, pages 198-230, particularly pages 207, 
208, 213, and 215 thereof. The four possible racemates of the Formula I 
compounds can each exist as a mixture of the two enantiomers or each 
enantiomer of each pair can be separated and obtained substantially free 
of other enantiomers. Varying mixtures of enantiomers are also possible. 
All such stereoisomers resulting from asymmetric substitution at up to 
three carbon atoms of the piperidine ring of Formula I compunds are within 
the scope of this invention. 
When it is desired to specify for a Formula I compound or intermediate 
therefor the configuration of the other asymmetric centers relative to 
that of the lowest numbered asymmetric carbon atom, this is done according 
to the Chemical Abstracts Service publication, "Naming and Indexing of 
Chemical Substances for CHEMICAL

EXAMPLE 1 
4-[4-(3-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
piperidinol, acetate (ester) (Formula Ia: X.sub.1 is m--OCH.sub.3, Y.sub.1 
is H, R.sub.3 is OC(O)CH.sub.3, R.sub.31 is --CH.sub.3, and R.sub.1 and 
R.sub.2 are hydrogen). 
T A 
4-[4-(3-Methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
piperidinol (Formula Ia: X.sub.1 is m--OCH.sub.3, Y.sub.1 is H, R.sub.3 is 
OH, R.sub.31 is --CH.sub.3, and R.sub.1 and R.sub.2 are hydrogen). 
Refer to Chart A (conversion of A-1 to A-3). 
To a stirred mixture of 3.8 g (0.02 mole) of 
4-(3-methoxyphenyl)-3-methyl-4H-1,2,4-triazole in 150 ml of 
tetrahydrofuran at -78.degree. C. (dry ice-isopropanol both) under an 
atmosphere of nitrogen is added dropwise 13.0 ml (0.02 mole) of 1.6N 
n-butyllithium in hexane (Aldrich Chemical Co.). The new mixture is 
stirred between -78.degree. and -40.degree. C. for 10 min before recooling 
to -78.degree. C. A solution of 4.1 g (0.02 mole) of 
1-(.beta.-phenethyl)-4-piperidone (Aldrich Chemical Co.) in 50 ml of 
tetrahydrofuran then is added within two min. The coolant is removed and 
the reaction flask allowed to warm to ambient temperature over 1 hr. The 
reaction is quenched with 50 ml of water and the solvents are removed in 
vacuo. The resultant mixture is partitioned between chloroform and 10% 
aqueous NaOH and the phases are separated. The chloroform layer is washed 
with 10% aqueous sodium hydroxide, water, and brine, and then dried over 
sodium sulfate and concentrated in vacuo at 40.degree. C. to yield 9.7 g 
of dark oil. 
Crystallization of 9.7 g of this oil from an ethyl acetate-hexane mixture 
affords a first crop of 4.7 g (60%) of the subtitled product, with a 
melting point of 169.degree.-170.degree. C.; IR (Nujol) peak at 3200 
cm.sup.-1 ; NMR (CDCl.sub.3 .delta.) peaks at 1.55-2.11, 2.16, 2.25-2.90, 
3.84 and 6.75-7.5. The mass spectrum reveals peaks at m/e 392 and 374. 
Anal. Calcd. for C.sub.23 H.sub.28 N.sub.4 O.sub.2 ; MW 392.51; C, 70.38; 
H, 7.19; N, Found: C, 70.29; H, 7.39; N, 14.31. 
T B 
4-[4-(3-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
piperidinol, acetate (ester) (Formula Ia: R.sub.31 is methyl, Y.sub.1 is H, 
X.sub.1 is m--OCH.sub.3, R.sub.3 is --OC(O)CH.sub.3, and R.sub.1 and 
R.sub.2 are hydrogen). 
Refer to Chart A (conversion of A-3 to A-4). 
To a solution of approximately 1.0 g (2.5 mmole) of starting piperidinol 
(the compound of Part A above), 1 ml of triethylamine and approximately 80 
mg of 4-(dimethylamino)pyridine in 10 ml of methylene chloride is added 2 
ml of acetic anhydride. The solution is stirred for 24 hr at ambient 
temperature under a nitrogen atmosphere. Aqueous 5% sodium hydroxide is 
added to the reaction and the phases are separated. The organic phase is 
washed with water, and brine, and dried over sodium sulfate and 
concentrated in vacuo to yield 1.4 g of a yellow-orange oil. 
The oil is crystallized from ethyl acetate-hexane to afford 0.68 g (63%) of 
powdered titled crystals with a melting point of 144.degree.-145.degree.: 
IR (Nujol) shows a peak at 1730 cm.sup.-1. NMR (CDCl.sub.3 .delta.) 
reveals peaks at 1.76, 2.13, 2.25-2.5 2.5-219, 3.84, and 6.6-7.5. The mass 
spectrum reveals an ion at m/e 435. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O.sub.3, MW 434.55; C, 69.10; H, 
6.96; N, 12.89. Found: C, 69.07; H, 7.08; N, 12.91. 
EXAMPLE 2 
4-[4-[3-(acetyloxy)phenyl]-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl 
)-4-piperidinol, acetate (ester), dihydrochloride (Formula Ia: X.sub.1 is 
m--OC(O)CH.sub.3, Y.sub.1 is H, R.sub.3 is OC(O)CH.sub.3, R.sub.31 is 
--CH.sub.3, and R.sub.1 and R.sub.2 are hydrogen). 
T A 
4-[4-(3-hydroxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
Piperidinol, (Formula Ia: X.sub.1 is m--OH, Y.sub.1 is H, R.sub.3 is OH, 
R.sub.31 is --CH.sub.3, and R.sub.1 and R.sub.2 are hydrogen). 
A mixture of 0.5 g (1.27 mmol) of the methyl ether of Example 1, Part A 
above and 15 ml of 48% aqueous hydrobromic acid is refluxed for 18 hrs. 
The excess hydrobromic acid is removed in vacuo at 80.degree. C. to yield 
an oily salt which then is dissolved in 10 ml of water and approximately 5 
ml of 50% aqueous sodium hydroxide. The mixture is heated on a steam bath 
for 30 min. The solution is chilled in an ice bath and acidified with 
concentrated hydrochloric acid to a pH of 2. The precipitated hydrochloric 
acid salt is basified with a saturated solution of aqueous sodium 
bicarbonate to a pH of 8. The precipitate is filtered, washed several 
times with water and dried in vacuo at 80.degree. C. to afford 0.4 g (83%) 
of the subtitled product having an R.sub.f of 0.2 (20% 
methanol-chloroform) with a melting point of 240.degree.-245.degree. C. 
(decomposes). The NMR spectrum is in aggreement with the desired product. 
T B 
4-[4-(3-acetoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
piperdinol, acetate (ester), dihydrochloride (Formula Ia: X.sub.1 is 
m--OC(O)CH.sub.3, Y.sub.1 is H, R.sub.3 is OC(O)CH.sub.3, R.sub.31 is 
--CH.sub.3, and R.sub.1 and R.sub.2 are hydrogen). 
Refer to Chart A (conversion of A-3 to A-4). 
A solution of 0.55 g (1.45 mmol) of the piperidinol of Example 2, Part A 
above, 1 ml of triethylamine, 10 mg of 4-(dimethylamino)pyridine and 2 ml 
of acetic anhydride in 10 ml of methylene chloride is stirred at ambient 
temperature for 48 hr. The solution is washed with a 5% aqueous sodium 
hydroxide solution, twice with water, once with brine, dried over sodium 
sulfate and concentrated in vacuo to yield 0.7 g of a yellow oil. 
The oil is chromatographed on 50 g of Silica Gel 60.RTM. and eluted with 4% 
methanol-chloroform mixture. The eluant from fractions 40 through 65 
contains 0.4 g of pure subtitled free base product. 
The 0.4 g of product is treated with ethereal hydrochloric acid and the 
precipitated salt is crystallized from an ethanol-diethyl ether mixture to 
afford 0.33 g (42%) of the subtitled salt product, a white powder with a 
melting point of 217.degree.-219.degree.. IR (Nujol) yields peaks at 1733 
and 1766 cm.sup.-1. NMR (DMSOd.sub.6, .delta.) yields peaks at 1.75, 2.1, 
2.6, 2.6-3.6, 7.2-7.75, and 11.2. The mass spectrum reveals an ion at m/e 
402. 
Anal. Calcd. for C.sub.26 H.sub.30 N.sub.4 O.sub.4.2HCl: MW 535.48: C, 
58.31; H, 6.02; N, 10.46. Found: C, 58.10; H, 6.05; N, 10.43. 
T C 
4-[4-(3-hydroxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4- 
piperidinol, acetate (ester), dihydrochloride (Formula Ia: X.sub.1 is 
m--OH, Y.sub.1 is H, R.sub.3 is OC(O)CH.sub.3, R.sub.31 is --CH.sub.3, 
and R.sub.1 and R.sub.2 are hydrogen). 
A mixture of 0.25 g (0.46 mmol) of the diacetate salt of Part B above and 1 
g of potassium carbonate in 5 ml of methanol and 5 ml of water is stirred 
at ambient temperature for 20 hr. The mixture is extracted three times 
with chloroform and the chloroform extracts are washed with water, brine, 
dried over sodium sulfate and concentrated in vacuo at 45.degree. C. to 
yield 0.17 g of oil. 
The oil is dissolved in ethanol and treated with hydrochloric acid in 
diethyl ether. The precipitate is recystallized from ethanol-diethyl ether 
mixture to afford 0.13 g of the titled product with a melting point of 
231.degree.-235.degree.. The IR (Nujol) spectrum reveals a peak at 1739 
cm.sup.-1. The mass spectrum reveals ions at m/e 360, 60, 58, 104, 228, 
271, 91, 105, 148, 269, and 65. 
Anal. Calcd. for C.sub.24 H.sub.28 N.sub.4 O.sub.3.2HCl, m.w. 493.43: C, 
58.42; H, 6.13; N, 11.36. Found: C, 58.64; H, 6.41; N, 11.36. 
EXAMPLE 3 
(3.alpha.,4.alpha.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1- 
(2-phenylethyl)-4-piperidinol, acetate (ester), dihydrochloride, isomer A 
(Formula Ia: R.sub.31 is methyl, R.sub.3 is OC(O)CH.sub.3, R.sub.1 is 
methyl cis to R.sub.3, R.sub.2 is H, and X.sub.1 and Y.sub.1 are H). 
T A 
(3.alpha., 
4.alpha.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(phenylme 
thyl)-4-piperidinol, isomer A and 
(3.alpha.,4.beta.)-3-methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1- 
(phenylmethyl)-4-piperidinol, isomer B (Formula Ia: R.sub.31 is methyl, 
R.sub.3 is OH, R.sub.1 is methyl, R.sub.2 is H, and X.sub.1 and Y.sub.1 
are H). 
The amino ester is prepared according to a similar procedure by Beckett, et 
al., (J. Med. and Pharm. Chem. 1, p. 37 (1959)). A solution of 161 ml (1.5 
mole) of methyl methacrylate in 50 ml of methanol and 100 g (0.93 mole) of 
benzylamine is stored at room temperature for 12 days. The methanol and 
excess reagents are removed in vacuo at 40.degree.. 
The remaining liquid is distilled under high vacuum; bp 
112.degree.-114.degree. (9 mm Hg), to afford 106 g (55%) of colorless 
liquid 2-methyl-3-[(phenylmethyl)amino]propanoic acid, methyl ester. An 
NMR spectrum supports the desired product structure and TLC analysis 
indicates one homogenous spot, R.sub.f 0.66 (15% MeOH/CHCl.sub.3). 
A solution of 78.2 g (0.38 mole) of starting amino-ester from above, 70 ml 
(0.77 mole) of methyl acrylate and 1 ml of Triton B solution 
(N-benzyltrimethylammonium hydroxide) is refluxed for 3 days. TLC 
indicates no starting material remaining. 
Distillation of the product under high vacuum affords 95.1% (85%) of 
colorless product, 
3-[N-[2-(methoxycarbonyl)ethyl]-N-(phenylmethyl)amino]-2-methylpropanoic 
acid, methyl ester, bp 140.degree.-144.degree. (0.8 mm Hg). An NMR 
spectrum supports the desired product structure. 
A mixture of 70 g (0.24 mole) of amino-diester from above in 500 ml touene 
and 11.7 g (0.24 mole) of sodium hydride is refluxed in a nitrogen 
atmosphere for 3 h. The yellow mixture is cooled in an ice bath and 
acidified with dilute acetic acid. The phases are separated. The organic 
phase is concentrated in vacuo to afford 65 g of a yellow, oily 
keto-ester. 
To the 65 g from above is added 300 ml of 20% aqueous hydrochloric acid and 
the mixture is slowly heated to reflux. After 1 hour carbon dioxide 
ebullition quelled. A ferric chloride test is positive. The yellow 
solution is refluxed for 2 hours; ferric chloride test is negative. The 
cooled solution is concentrated in vacuo at 70.degree. to an oily 
hydrochloride which is basified with 10% aqueous sodium hydroxide. The 
liberated amine is extracted with chloroform and washed with water, brine, 
dried over sodium sulfate and concentrated in vacuo to 37.6 g (84.5%) of 
1-(phenylmethyl)-3-methyl-4-piperidone as an amber oil. 
The oil is distilled under high vacuum, bp 100.degree. (0.1 mm Hg), to 
afford 30 g of colorless liquid. An NMR spectrum supports the desired 
product and TLC analysis indicates one homogenous spot, R.sub.f =0.73 (20% 
MeOH/CHCl.sub.3). 
Refer to Chart A (conversion of A-1 to A-3 except that A-2 contains an 
N-benzyl group). 
A solution of 7.96 g (0.05 mol) of 3-methyl-4-phenyl-4H-1,2,4-triazole 
(prepared as in Example 1, Part A of U.S. Pat. No. 4,338,453) in 350 ml of 
tetrahydrofuran at -78.degree. C. under a nitrogen atmosphere is treated 
dropwise, via a syringe, with 35 ml (0.055 mol) of a 1.6N solution of 
n-butyllithium in hexane. After completing the addition the mixture is 
stirred for 15 min. A solution of 10.5 g (0.05 mol) of 
1-(phenylmethyl)-3-methyl-4-piperidone in 50 ml of tetrahydrofuran is 
added via syringe rapidly into the mixture. The coolant is removed and the 
solution allowed to reach ambient temperature in 1.5 hr. The reaction is 
quenched with aqueous ammonium chloride and the solvents are evaporated in 
vacuo. The resulting mixture is partitioned between 5% aqueous sodium 
hydroxide and chloroform. The combined chloroform extracts are washed with 
water and brine, dried over sodium sulfate and concentrated in vacuo at 
50.degree. C. to yield 17.5 g of white solid. An NMR spectrum of a 
homogeneous deutrochloroform solution of the white mixture indicated a 1:1 
ratio of isomeric products and trace amounts of starting materials 
present. 
The solid mixture is dissolved in methanol-ethyl acetate mixture and 
allowed to crystallize. The first crop of 2.2 g contains an approximate 
75:25 ratio of isomers. Recrystallization of the 2.2 g from 
methanol-acetone-hexane mixture affords 0.55 g of colorless needles of the 
titled isomer A (R.sub.f =0.48), with a melting point of 
228.degree.-229.degree.; and IR (Nujol) peak at 3201 cm.sup.-1 ; NMR 
(CDCl.sub.3, .delta.) peaks at 0.72, 1.7-2.7, 2.13, 3.35, 3.4, 7.2, and 
7.6. The mass spectrum yields ions at m/e 362, 344, and 271. 
Anal. Calcd. for C.sub.22 H.sub.26 N.sub.4 O, MW 362.48: C, 72.90; H, 7.23; 
N, 15.46. Found: C, 72.70; H, 7.33; N, 15.58. 
A fourth crop of 1.5 g of crystals is obtained from the initial 17.5 g of 
crude reaction product. Recrystallization of this 90:10 isomer mixture 
from a methanol-hexane mixture affords 0.62 g of colorless prisms, the 
titled isomer B (R.sub.f =0.61), with a melting point of 
185.degree.-187.degree.; IR (Nujol) peak at 3243 cm.sup.-1 ; NMR 
(CDCl.sub.3 .delta.) peaks at 0.88, 1.3-2.9, 2.11, 2.95, 3.4, 7.24, and 
7.45. The mass spectrum yields ions at m/e 362, 344, 271, and 202. 
Anal. Calcd. for C.sub.22 H.sub.26 N.sub.4 O, MW 362.48: C, 72,90; H, 7.23; 
N, 15.46. Found: C, 72.82; H, 7.25; N, 15.43. 
Additional quantities of each isomer are obtained from 3.6 g of 1:1 mixture 
of isomers separated by HPLC. Eluant from a 7:3 ratio of acetone-methanol 
mixture affords 1.25 g of isomer B and 0.6 g of isomer A. 
Part B 
(3.alpha.,4.alpha.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4- 
piperidinol, Isomer A. 
To a solution of 1.0 g (2.76 mmole) of the (3.alpha.,4.alpha.)-amino 
alcohol, isomer A of Part A above, in 100 ml absolute ethanol containing 2 
ml of approximately 4.5N methanolic hydrochloric acid solution is added 1 
g of 10% palladium on carbon. The Parr bottle is charged with 50 psi of 
hydrogen. After 72 hours the mixture is filtered through a Celite pad and 
the clear filtrate is evaporated in vacuo to an oily hydrochloride salt. 
The amine free base is liberated with a 10% aqueous solution of sodium 
hydroxide and extracted twice into chloroform. The extracts are dried over 
sodium sulfate and concentrated in vacuo to afford 0.64 g (85%) of white 
solid. A thin-layer chromatography analysis indicated a new polar spot, 
R.sub.f =0.04 (50% acetone-chloroform), and no starting n-benzyl compound. 
This product is used without further purification in the alkylation 
reaction to provide the corresponding 1-(2-phenylethyl) piperidinol 
compound. 
T C 
(3.alpha.,4.alpha.)-3-methyl-4-(5-methyl-4-phenyl-4h-1,2,4-triazol-3-yl)-1- 
(2-phenylethyl)-4-piperidinol, isomer a (formula ia: r.sub.31 is methyl, 
x.sub.1 and y.sub.1 are hydrogen, r.sub.1 is methyl cis to r.sub.3, 
r.sub.2 is hydrogen, and r.sub.3 is hydroxy) (This is an alternative 
method to produce a Formula A-3 compound). 
A mixture of 0.64 g (2.36 mmole) of the crude amino alcohol of Part B 
above, 0.48 g (2.6 mmole) of (2-bromoethyl)benzene, and 0.69 g (5 mmole) 
of potassium carbonate in 25 ml of ethanol is refluxed under a nitrogen 
atmosphere for 22 hours. The solvent is removed in vacuo. The residue is 
diluted with water and extracted thrice with chloroform. The extracts are 
washed with brine, dried over sodium sulfate and concentrated in vacuo to 
afford 0.84 g (94%) of the titled white solid. TLC yields an R.sub.f of 
0.5 (50% acetone-chloroform). The NMR spectrum supports the desired 
product structure. This material is used without further purification to 
prepare the corresponding acetate (ester). 
T D 
(3.alpha.,4.alpha.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1- 
(2-phenylethyl)-4-piperidinol, acetate (ester), dihydrochloride, isomer A 
(Formula Ia: R.sub.31 is methyl, R.sub.3 is OC(O)CH.sub.3, R.sub.1 is 
methyl cis to R.sub.3 , R.sub.2 is H, and X.sub.1 and Y.sub.1 are H). 
Refer to Chart A (conversion of A-3 to A-4). 
A solution of 0.84 g of amino alcohol isomer A, from Part C above, 2 ml of 
acetic anhydride, 1 ml of triethylamine, and a micro spatula tipful 
(approximately 10 to 80 mg) of 4-(dimethylamino)pyridine in 20 ml of 
methylene chloride was stirred at ambient temperature, under a nitrogen 
atmosphere for 5 days. A comparison of TLC after 5 days indicates 
virtually all the starting material remains. After removing solvents in 
vacuo, treating with 3 ml pyridine and 3 ml acetic anhydride and purifying 
as in Example 4, Part C below, 0.4 g of oil is obtained. The oil is 
converted to its hydrochloric acid salt and recrystallization from 
methanol-diethyl ether mixtures affords 0.25 g of the titled white powder 
salt, melting point of 233.degree.-235.degree. C. (bubble, amber), IR 
(Nujol) peaks at 1741 cm.sup.-1, NMR (free base, .delta.) reveals peaks at 
0.97, 1.70, 2.08, 2.0-2.9, 7.0-7.3, 7.3-7.7, NMR (DMSOd.sub.6, HCl salt, 
.delta.) 0.90, 1.60, 2.05, 2.6-3.4, 7.1-7.4, and 7.4-7.65. The mass 
spectrum yields ions at m/e 418, 327, 358, 267, and 226. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O.sub.2.2 HCl, MW 491.49; C, 
61.10; H, 6.56; N, 11.40, Cl, 14.43. Found: C, 61.47; H, 6.71; N, 11.38; 
Cl, 13.14. 
EXAMPLE 4 
(3.alpha.,4.beta.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-( 
2-phenylethyl)-4-piperidinol, acetate (ester), monohydrochloride, 
sesquihydrate, isomer B (Formula Ia: R.sub.31 is methyl, R.sub.3 is 
OC(O)CH.sub.3, R.sub.1 is methyl trans to R.sub.3, R.sub.2 is H, and 
X.sub.1 and Y.sub.1 are H). 
T A 
(3.alpha.,4.beta.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-4-p 
iperidinol, Isomer B. 
Following the procedure of Example 3, Part B above, the 
(3.alpha.,4.beta.)amino alcohol, Isomer B, from Example 3, Part A, above 
is debenzylated to the corresponding secondary amino alcohol, which is 
used without purification in the alkylation reaction (Part B). 
T B 
(3.alpha.,4.beta.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-( 
2-phenylethyl)-4-piperidinol, Isomer B. (Formula Ia: R.sub.31 is methyl, 
X.sub.1 and Y.sub.1 are hydrogen, R.sub.1 is methyl trans to R.sub.3, 
R.sub.2 is hydrogen, and R.sub.3 is hydroxy). 
Following the procedure for the alkylation of isomer A set forth in Example 
3, Part C, above, 0.60 g (2.21 mmole) of the (3.alpha.,4.beta.) secondary 
amino-alcohol (Isomer B) from Part A above, 0.48 g (2.6 mmole) of 
(2-bromoethyl)benzene 0.7 g (5 mmole) of potassium carbonate in 25 ml of 
absolute ethanol affords after work-up, 0.80 g (96%) of titled yellow 
product having an R.sub.F OF 0.6 (50% acetone/chloroform). The NMR 
spectrum supports the desired product structure. This product is used 
directly to prepare the corresponding acetate. 
T C 
(3.alpha.,4.beta.)-3-Methyl-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-( 
2-phenylethyl)-4-piperidinol, acetate (ester), monohydrochloride, 
sesquihydrate, isomer B (Formula Ia: R.sub.31 is methyl, R.sub.3 is 
OC(O)CH.sub.3, R.sub.1 is methyl trans to R.sub.3, R.sub.2 is H, and 
X.sub.1 and Y.sub.1 are H). 
Refer to Chart A (conversion of A-3 to A-4). 
A solution of 0.83 g (2.2 mmol) of the 
(3.alpha.,4.beta.)-(2-phenylethyl)amino-alcohol, Isomer B, of Part B 
above, 2 ml of acetic anhydride, 1 ml of triethylamine, and a micro 
spatula tip full of 4-(dimethylamino)pyridine in 20 ml of methylene 
chloride is stirred for 5 days at ambient temperature, under a nitrogen 
atmosphere. TLC analysis (15% methanol in chloroform) indicates 
approximately a 60% conversion of starting material. The solvents are 
removed in vacuo and the residue is treated with 3 ml pyridine and 3 ml 
acetic anhydride and heated to 110.degree. C. for 2 hr. The reaction is 
cooled and is concentrated in vacuo to yield a gummy, brown oil. The oil 
is dissolved in chloroform and is washed with cold 10% aqueous sodium 
hydroxide, water, and brine, and dried over sodium sulfate and 
concentrated in vacuo to yield 1 g of crude product. The 1 g of crude 
product is chromatographed over 30 g of Silica Gel 60. The eluant from 5% 
methanol-chloroform in fractions 21 through 40 are combined and 
concentrated in vacuo to afford 0.35 g of a light yellow oil. 
The 0.35 g of oil in diethyl ether is treated with ethereal hydrochloric 
acid, and the precipitated salt is recrystallized from a 
methanol-diethylether mixture to afford 0.22 g of the titled powdered salt 
with a melting point of 183.degree.-185.degree. C. (bubbles, amber). The 
IR (Nujol) spectrum reveals a peak at 1743 cm.sup.-1. The NMR (CDCl.sub.3, 
free base, .delta.) reveals peaks at 0.94, 1.79, 2.11, 1.8-2.9, 6.9-7.3 
and 7.3-7.6. The NMR (DMSOd.sub.6 -HCl-salt, .delta.) reveals peaks at 
1.06, 1.85, 2.15, 2.7-3.6, 7.1-7.3, 7.3-7.7 and 10.75. The mass spectrum 
reveals a molecular ion at m/e 418, with fragment ions at m/e 358, 327, 
267, and 226. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O.sub.2.HCl.1.25 H.sub.2 O, MW 
477.54; C, 62.88; H, 7.02; N, 11.73; Cl, 7.42. Found: C, 62.54; H, 6.58; 
N, 11.39; Cl, 8.93. 
EXAMPLE 5 
(3.alpha.,4.beta.)-4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenyle 
thyl)-3-(2-propenyl)-4-piperidinol, acetate (ester), sesquihydrochloride, 
faster moving isomer B (Formula Ia: R.sub.31 is methyl, X.sub.1 and 
Y.sub.1 are H, R.sub.1 is CH.sub.2 .dbd.CH--CH.sub.2 -- trans to R.sub.3, 
R.sub.3 is --OC(O)CH.sub.3, R.sub.2 is H) 
T A 
(3.alpha.,4.beta.)-4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenyle 
thyl)-3-(2-propenyl)-4-piperidinol, faster moving (isomer B) and 
(3.alpha.,4.alpha.)-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-pheny 
lethyl)-3-(2-propenyl)-4-piperidinol, slower moving (isomer A) (Formula Ia: 
R.sub.31 is methyl, X.sub.1 and Y.sub.1 are H, R.sub.1 is CH.sub.2 
.dbd.CH--CH.sub.2 -- trans to R.sub.3, R.sub.3 is --OH, R.sub.2 is H). 
Following a similar procedure according to Bell, et al., (J. Med. Chem. 16, 
203 (1973)) an anhydrous solution of p-toluenesulfonic acid in toluene is 
prepared by refluxing 48.3 g (0.25 mole) of paratoluene-sulfonic acid 
monohydrate (TsOH.H.sub.2 O) in 400 ml of toluene with a Dean-Stark trap 
until 4.6 ml of water is collected. To the above cooled solution is added 
50 g (0.25 mole) of 1-(.beta.-phenethyl)-4-piperidone, 26.1 g (0.25 mole) 
of 2,2-dimethoxypropane and 32 g (0.55 mole) of allyl alcohol. The mixture 
is heated and refluxed under a jacketed Vigreux, 12 cm column fitted with 
a distillation head. The head temperature is maintained between 50.degree. 
and 60.degree. C. until about 20 ml of acetone is collected, then an 
additional 20 ml of distillate is collected up to 70.degree. C. The 
reaction vessel is allowed to cool overnight at room temperature. The 
resulting brown residue is diluted with ether, filtered and washed with 
ether. The brown salt is vacuum dried at 50.degree. C. to afford 103 g of 
crude product, 
4,4-bis(2-propenyloxy)-1-(2-phenylethyl)-piperidinium-p-toluenesulfonate. 
This material is used directly in the following rearrangement reaction. 
A suspension of the 103 g of crude salt from above in 300 ml of toluene 
containing about 0.5 g of TsOH.H.sub.2 O is heated under a 12.5 cm Vigreux 
column maintaining a head temperature between 90.degree. and 98.degree. C. 
until about 50 ml of allyl alcohol and toluene are collected. Then 
distillate is collected up to 110.degree. C. The reaction is cooled to 
room temperature and water is added. The toluene is removed; the aqueous 
layer is chilled in an ice bath and basified with 20% aqueous sodium 
hydroxide. The liberated amine is extracted twice with ether. The ether 
extracts are washed with water, brine, dried over sodium sulfate and 
concentrated in vacuo at 50.degree. C. to afford 65 g of dark brown oil. 
The oil is distilled twice under reduced pressure, bp 117.degree. (0.1 mm 
Hg) to afford 35 g (58%) of colorless product, 
1-(2-phenylethyl)-3-(2-propenyl)-4-piperidinone. An NMR spectrum supports 
the desired product structure and also shows a trace of the starting 
4-piperidone present. A TLC analysis gives one major homogenous spot, 
R.sub.f 0.4 (50% EtOAc/hexane) and a very faint spot of R.sub.f 0.2. 
Refer to Chart A (conversion of A-1 to A-3). 
To a stirred mixture of 5.0 g (0.031 mol) of 
3-methyl-4-phenyl-4H-1,2,4-triazole in 350 ml of tetrahydrofuran at 
-78.degree. C. (dry ice-isopropanol bath) under an atmosphere of nitrogen 
is added via syringe dropwise 22 ml (0.034 mol) of 1.55N n-butyllithium in 
hexane. The resulting slurry is stirred for 5 min between -78.degree. and 
-60.degree. C. A solution of 8.6 g (0.035 mol) of 
1-(2-phenylethyl)-3-(2-propenyl)-4-piperidinone in 50 ml of 
tetrahydrofuran is then added dropwise into the reaction mixture at 
-78.degree. C. within 3 min. The coolant is removed and the reaction flask 
is allowed to warm to approximately 20.degree. C. The reaction is quenched 
with water and the solvents are removed in vacuo. The aqueous mixture is 
extracted with chloroform and the phases separated. The chloroform phase 
is washed with water (twice) and brine, dried over sodium sulfate and 
concentrated in vacuo at 50.degree. C. to yield a white solid. 
The solid is dissolved with a mixture of ethyl acetate-methanol-hexane and 
allowed to crystallize overnight. The first (5.5 g) and the second (4.5 g) 
crops are combined and recrystallized from a methanol-acetone mixture to 
afford a combined first and second crop of 6.8 g of colorless crystals of 
the titled (3.alpha.,4.alpha.)-isomer A with a melting point of 
199.degree.-201.degree. C. TLC yields R.sub.f of 0.54 (50% methanol-50% 
acetone) (Isomer A, more polar, allyl cis to OH); and IR (Nujol) peak at 
3207 cm.sup.-1 ; NMR (CDCl.sub.3 .delta.) peaks at 1.6-2.1, 2.13, 2.2-2.8, 
3.72, 4.7-4.95, 5.2-5.8, 7.1-7.4 and 7.45-7.65. The mass spectrum yields 
ions at m/e 402, 384, 311, 152, 160, 312, 110 and 202. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O, MW 402.55: C, 74.59; H, 7.51; 
N, 13.92. Found: C, 74.30; H, 7.36; N, 13.93. 
The mother liquors from the ethyl acetate-methanol-hexane crystallizations 
are concentrated in vacuo, and the residue is crystallized from an ethyl 
acetate-hexane mixture to afford 2.0 g of colorless crystals of the titled 
(3.alpha.,4.beta.)-isomer B, with a melting point of 
193.degree.-194.degree. C.; and R.sub.f of 0.61 (50% methanol-50% acetone) 
(Isomer B, less polar, allyl trans to OH); IR (Nujol) peaks at 3238 
cm.sup.-1. The NMR (CDCl.sub.3 .delta.) shows peaks at 1.2-2.25, 2.15, 
2.28, 2.3-2.9, 4.65-4.95, 5.15-5.75, 7.1-7.35 and 7.4-7.6; and mass 
spectrum yields ions at m/e 402, 384, 311, 152, 312, 160, 110, and 202. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O, MW 402.55: C, 74.59; H, 7.51; 
N, 13.92. Found: C, 74.38; H, 7.98; N, 13.99. 
The total chemical yield is 11.7 g (93%). The pure less polar 
(3.alpha.,4.beta.)-isomer B accounts for 2.35 g, the pure more polar 
(3.alpha.,4.beta.)-isomer A accounts for 6.8 g, and a 1:1 mixture of 
isomers A and B accounts for 2.4 g. The ratio of the more polar to less 
polar isomer is approximately 7:3. 
T B 
(3.alpha.,4.beta.)-4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenyle 
thyl)-3-(2-propenyl)-4-piperidinol, acetate (ester), sesquihydrochloride, 
faster moving isomer B (Formula Ia: R.sub.31 is methyl, X.sub.1 and 
Y.sub.1 are H, R.sub.1 is CH.sub.2 .dbd.CH--CH.sub.2 -- trans to R.sub.3, 
R.sub.3 is --OC(O)CH.sub.3, R.sub.2 is H) 
Refer to Chart A (conversion of A-3 to A-4). 
A solution of 1.0 g (2.5 mmol) of (3.alpha.,4.beta.)-amino-alcohol, isomer 
B from Part A above, 2 ml of acetic anhydride and 2 ml of dry pyridine in 
6 ml of toluene is refluxed in an atmosphere of nitrogen for 18 hr. The 
cooled solution is concentrated in vacuo to yield a dark oil. The oil is 
dissolved in chloroform and washed with a 5% solution of aqueous sodium 
hydroxide, washed twice with water, once with brine, dried over sodium 
sulfate and concentrated in vacuo to yield 1.8 g of a dark oil. 
The 1.8 g of oil is chromatographed on 100 g of Silica Gel 60, eluting with 
a 3% methanol-chloroform mixture. Eluant from fractions 28-60 are combined 
and concentrated in vacuo to afford 0.93 g of a yellow, oily product. 
The 0.93 g of free base is treated with hydrochloric acid in diethyl ether 
and the resultant hydrochloride salt is recrystallized from a 
methanol-diethyl ether mixture to afford a first crop of 0.63 g (52%) of 
the titled white powder salt, which shrinks at 164.degree. C. and melts 
178.degree.-182.degree. C. (viscous, water clear). The IR (Nujol) spectrum 
shows a peak at 1750 cm.sup.-1. NMR (CDCl.sub.3, free base, .delta.) 
reveals peaks at 1.80, 2.11, 1.5-3.0, 4.75-5.10, 5.20-5.80, 7.0-7.4, and 
7.4-7.7. NMR (DMSOd.sub.6), HCl-salt, .delta., peaks observed are 1.90, 
2.21, 2.1-3.4, 5.1-5.35, 5.3-5.5, 7.1-7.4, 7.4-7.6 and 11.3. The mass 
spectrum yields ions at m/e 444, 401, 353, 343, 384, 293, and 252. High 
resolution mass spect.; Calcd. for C.sub.27 H.sub.32 N.sub.4 O.sub.2 
=444.2525; Found: 444.2518. 
Anal. Calcd. for C.sub.27 H.sub.32 N.sub.4 O.sub.2.HCl.CH.sub.3 
OH.0.5H.sub.2 O; MW 518.10: C, 64.91; H, 7.39; N, 10.81; Cl, 6.84. Found: 
C, 64.46; H, 7.05; N, 10.95; Cl, 9.28. 
A 40 mg sample of this product was converted to the free base with 10% 
aqueous sodium hydroxide and treated with one equivalent of 
p-toluenesulfonic acid to provide a colorless prism for x-ray analysis 
which unambiguously established the structure of this titled product with 
the (3.alpha.,4.beta.) stereochemistry. 
EXAMPLE 6 
(3.alpha.,4.beta.)-4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenyle 
thyl)-3-(2-propenyl)-4-piperidinol, acetate (ester), sesquihydrochloride, 
hemihydrate, slower moving isomer A (Formula Ia: R.sub.31 is methyl, 
X.sub.1 and Y.sub.1 are H, R.sub.1 is CH.sub.2 .dbd.CH--CH.sub.2 -- cis to 
R.sub.3, R.sub.3 is --OCOCH.sub.3, R.sub.2 is H). 
Refer to Chart A (conversion of A-3 to A-4). 
Following the procedure of Example 5, Part B, the titled compound is 
prepared from 1.7 g (4.2 mmol) of the (3.alpha.,4.alpha.)-amino-alcohol, 
isomer A of Example 5, Part A, 5 ml of acetic anhydride, and 5 ml of 
pyridine to afford 1.2 g of oily acetate. 
Conversion of the free base to the hydrochloride salt affords two crops of 
0.78 g of the titled white powder salt with a melting point of 
180.degree.-181.degree.. IR (Nujol) reveals a peak at 1738 cm.sup.-1. The 
NMR (CDCl.sub.3, free base, .delta.) reveals peaks at 1.76, 2.09, 2.0-3.0, 
4.80-5.10, 5.3-5.9, 7.0-7.4 and 7.4-7.65. The NMR (DMSOd.sub.6, HCl salt, 
.delta.) reveals peaks at 1.73, 2.11, 2.7-3.8, 5.35-5.9, 7.2-7.5, 7.5-7.75 
and 11.4. The mass spectrum yields ions at m/e 444, 401, 353, 343, 344, 
384, 354, 293, 160, 110, and 252. 
Anal. Calcd. for C.sub.27 H.sub.32 N.sub.4 O.sub.2.1.5HCl.0.5H.sub.2 O; MW 
508.29; C, 63.83; H, 6.84; N, 11.02; Cl, 10.46. Found: C, 63.69; H, 6.70; 
N, 10.96; Cl, 10.39. 
EXAMPLE 7 
4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidinol 
, formate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 and Y.sub.1 are 
hydrogen, R.sub.3 is --OCOH, and R.sub.1 and R.sub.2 are hydrogen) 
Refer to Chart A (conversion of A-3 to A-4). The mixed anhydride is 
prepared according to Mehlenbacher, Org. Analysis, 1, 37 (1953) by slow 
addition of 5 ml of 97% formic acid to 10 ml of acetic anhydride at 
0.degree., and then warming to 50.degree. C. for 15 minutes. 
A solution of 0.7 g of the starting piperidinol of Example 15, Part A below 
in 2 ml of dry pyridine at 0.degree. C. was treated with 2 ml of the mixed 
anhydride reagent from above. The coolant is removed and the solution 
allowed to warm to ambient temperature for 18 hours. The reaction solution 
is poured into a cold saturated sodium bicarbonate solution and extracted 
twice with chloroform. The combined chloroform extracts are washed twice 
with water, dried over sodium sulfate and concentrated in vacuo to 0.65 g 
of oil. 
The 0.65 g of oil is chromatographed on 50 g of Silica Gel 60 which is 
eluted with 10% methanol-chloroform mixture to afford 0.3 g of desired 
titled product. Crystallization from diethyl ether affords a first crop of 
0.1 g as colorless clusters with a melting point of 
140.degree.-141.degree. C. (water-clear melt). The IR, mass spectrometry, 
and NMR spectra support the desired product structure. 
Anal. Calcd. for C.sub.23 H.sub.26 N.sub.4 O.sub.2, mw 390.49: C, 70.74; H, 
6.71; N, 14.35. Found: C, 70.23; H, 6.65; N, 14.40. 
EXAMPLE 8 
4-[4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4-p 
iperidinol, acetate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 is 
2-fluoro, Y.sub.1 is hydrogen, R.sub.1 and R.sub.2 are hydrogen, and 
R.sub.3 is OCOCH.sub.3) 
T A 
4-[4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4-p 
iperidinol. 
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 
2-fluorophenyl isothiocyanate and acethydrazide are reacted to produce 
4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole-3-thiol (mp 
236.degree.-237.degree. C., C:H:N:S:F ratio 51.69:3.86:20.10:15.84:9.10) 
which is converted to 4-(2-fluorophenyl)-3-methyl-4H-1,2,4-triazole (mp 
119.degree.-120.degree. C., C:H:N:F ratio 61.28:4.83:23.58:10.42). 
Refer to Chart A (conversion of A-1 to A-3) 
Using the method of Example 1, Part A above 
4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazole is converted to its anion 
and reacted with 1-(.beta.-phenethyl)-4-piperidinone to produce the 
subtitled compound, mp 172.degree.-174.degree. C. and C:H:N:F ratio 
69.05:6.55:14.51:5.22. 
T B 
4-[4-(2-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)-4-p 
iperidinol, acetate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 is 
2-fluoro, Y.sub.1 is hydrogen, R.sub.1 and R.sub.2 are hydrogen, and 
R.sub.3 is OCOCH.sub.3). 
Refer to Chart A (conversion of A-3 to A-4). 
A solution of 1.0 g (2.6 mmole) of the amino-alcohol from Part A above, 2 
ml of acetic anhydride, 2 ml of triethylamine and approximately 20 mg of 
4-dimethylamino pyridine in 5 ml of methylene chloride is stirred at 
ambient temperature under a nitrogen atmosphere for 72 hours. The 
resultant red colored solution is poured onto a 5% aqueous sodium 
hydroxide solution. The phases are separated. The organic phase is washed 
with water, brine, dried over sodium sulfate and concentrated in vacuo to 
1.2 g of crude product. 
The crude product is chromatographed on 50 g Silica Gel 60.RTM. and eluted 
with a 5% methanol-chloroform mixture to afford 0.82 g of crude solid 
product. Crystallization from an ethyl acetate-hexane mixture affords a 
first crop of 0.58 g (53%) of slightly yellow crystals of the titled 
product, melting point of 157.degree.-159.degree. C. 
Anal. Calcd. for C.sub.24 H.sub.27 FN.sub.4 O.sub.2 ; mw 422.51: C, 68.22; 
H, 6.44; N, 13.26; F, 4.50. Found: C, 68.05; H, 6.77; N, 12.93; F, 4.67. 
EXAMPLE 9 
4-[4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl) 
-4-piperidinol, acetate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 is 
2-methyl, Y.sub.1 is 6-methyl, R.sub.1 and R.sub.2 are hydrogen, and 
R.sub.3 is OCOCH.sub.3). 
T A 
4-[4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl) 
-4-piperidinol. 
Using the method of Example 1, Part A of U.S. Pat. No. 4,338,453, 
2,6-dimethylphenyl isothiocyanate and acethydrazide are reacted to produce 
4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol which is 
converted to 4-(2,6-dimethylphenyl)-3-methyl-4H-1,2,4-triazole. This 
triazole (1.87 g 0.01 mole) in 100 ml of tetrahydrofuran at -60.degree. C. 
bath temperature is reacted with 6.9 ml of 1.6N n-butyllithium in hexane. 
The resulting mixture is stirred for fifteen minutes. Then using the 
procedure of Example 1, Part A above, this anion is reacted with 
1-(.beta.-phenethyl)-4-piperidinone to produce the product, which is 
recrystallized from ethyl acetate-hexane to give the subtitled product, mp 
189.degree.-192.degree. C., with a C:H:N ratio of 73.30:7.77:14.27. 
T B 
4-[4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl) 
-4-piperidinol, acetate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 is 
2-methyl, Y.sub.1 is 6-methyl, R.sub.1 and R.sub.2 are hydrogen, and 
R.sub.3 is OCOCH.sub.3). 
Refer to Chart A (conversion of A-3 to A-4). Using an esterification 
procedure described herein the alcohol from Part A above is converted to 
the subtitled acetate ester (which is recrystallized from acetone-hexane), 
mp 138.degree.-140.degree. C., C:H:N ratio 72.20:7.44:12.95 (MW 432.58). 
EXAMPLE 10 
4-[4-(2,6-dimethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl) 
-4-piperidinol, propanoate (ester), and its monohydrobromide (Formula Ia: 
R.sub.31 is methyl, X.sub.1 is 2-methyl, Y.sub.1 is 6-methyl, R.sub.1 and 
R.sub.2 are hydrogen, and R.sub.3 is OCOCH.sub.2 CH.sub.3). 
Refer to Chart A (conversion of A-3 to A-4). Using an esterification 
procedure described herein the alcohol from Example 9, Part A above is 
converted to the titled propanoate ester (which is recrystallized from 
ethanol-water), mp 207.degree.-209.degree. C., with a C:H:N:Br ratio of 
61.05:6.79:10.20:15.00 (MW 527.53). 
EXAMPLE 11 
4-[4-(2,6-diethylphenyl)-5-methyl-4H-1,2,4-triazole-3-yl]-1-(2-phenylethyl) 
-4-piperidinol, acetate (ester) and its monohydrochloride, and its 
monohydrate (Formula Ia: R.sub.31 is methyl, X.sub.1 is 2-ethyl, Y.sub.1 
is 6-ethyl, R.sub.1 and R.sub.2 are hydrogen, and R.sub.3 is OCOCH.sub.3). 
Refer to Chart A for conversion of A-1 to A-4. Proceeding according to 
Example 9 above and starting with 2,6-diethylphenyl isothiocyanate and 
acethydrazide the following compounds are prepared in turn: 
4-(2,6-diethylphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol, mp 
182.degree.-183.5.degree. C. (from ethyl acetate-hexane), C:H:N:S ratio 
63.36:6.93:16.95:13.13; 
4-(2,6-diethylphenyl)-3-methyl-4H-1,2,4-triazole, mp 58.degree.-60.degree. 
C. (from pentane), C:H:N ratio 72.52:7.95:19.66; 
4-[4-(2,6-diethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)- 
4-piperidinol, mp 188.degree.-189.degree. C. (from ethyl acetate), C:H:N 
ratio 74.62:8.11:13.43 (MW 418.59); 
4-[4-(2,6-diethylphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]-1-(2-phenylethyl)- 
4-piperidinol, acetate (ester) as the monohydrochloride hydrate, mp 
121.degree.-123.degree. C. (from ethanol-diethyl ether) with a C:H:N:Cl 
ratio 65.72:7.28:10.86:7.33. 
EXAMPLE 12 
1-(2-Phenylethyl)-4-(4-phenyl-4H-1,2,4-triazol-3-yl)-piperidine (Formula 
Ia: R.sub.31 is hydrogen, X.sub.1 and Y.sub.1 are hydrogen, R.sub.1, 
R.sub.2 and R.sub.3 are hydrogen). Refer to Chart B. (Conversion of B-1 to 
B-7). 
T A 
4-Phenyl-5-(4-pyridinyl)-4H-1,2,4-triazole-3-thiol 
A one liter round bottomed flask, fitted with a reflux condenser, nitrogen 
inlet and magnetic stirrer bar, is charged with 40.5 g (0.30 mol) of 
phenyl isothiocyanate and 41.845 g (0.30 mol) of isonicotinic acid 
hydrazide in 300 ml of absolute ethanol. The mixture is heated to reflux 
for 3 hours. The resulting solid is filtered and washed with ethanol and 
then added to an aqueous solution of sodium hydroxide (prepared by 
dissolving 16.8 g, 0.42 mol, of sodium hydroxide in 240 ml of water). The 
mixture is heated to reflux for 5 hours and then stirred at ambient 
temperature for 18 hours. The solution is treated with 100 ml of distilled 
water to dissolve the gel which has formed. The solution is made acidic 
(to pH 2) with concentrated HCl and cooled with ice. The solid is 
filtered, taken up in 600 ml of warm absolute ethanol and filtered again 
to afford approximately 70 g (92%) of slightly wet titled product with a 
melting point of 288.degree.-290.degree. C. IR (nujol shows a peak at 1900 
cm.sup.-1 ; UV (95% ethanol) shows peaks at 257 nm and 317 nm; NMR 
(DMSO-d6 .delta.) 8.5 and 7.2-7.6; the mass spectra shows a strong 
molecular ion peak at m/e 254, with fragment ions at 253, 195 and 149. 
Anal. Calcd. for C.sub.13 H.sub.10 N.sub.4 S, mw 254.26: C, 61.41; H, 3.96; 
N, 22.04; S, 12.59. Found: C, 61.23; H, 4.05; N, 22.20; S, 12.59. 
T B 
4-(4-Phenyl-4H-1,2,4-triazol-3-yl)-pyridine 
The triazolethiol of Part A (17.0 g, 66.9 mmol) is cautiously added, in 
portions, to 48 ml of a 20% nitric acid solution heated on a steam bath. 
After the addition is complete (15 minutes) the brown solution is heated 
an additional 1/2 hour, cooled, and quenched in cold, aqueous ammonium 
hydroxide. The resulting tan solid is filtered to give 19.2 g of crude 
powder which is dissolved in hot methanol, treated with charcoal and dried 
over sodium sulfate and crystallized from methanol/ethyl acetate mixtures 
to afford beautiful prisms, (12.16 g, 81.8%, in two crops), melting point 
224.degree.-227.degree. C.: spectral data is as follows: IR (nujol) peaks 
at 3122 and 3052 cm.sup.-1 ; UV (95% ethanol) peaks at 244 nm; NMR 
(CDCl.sub.3 .delta.) peaks at 8.59, 8.37, and 7.2-7.6; mass spectrum shows 
a strong molecular ion peak at m/e 222, with a fragment ion at 221. 
Anal. Calcd. for C.sub.13 H.sub.10 N.sub.4, mw 222.25: C, 70.25; H, 4.54; 
N, 25.21. Found: C, 70.22; H, 4.54; N, 25.21. 
T C 
4-(4-Phenyl-4H-1,2,4-triazol-3-yl)-piperidine 
The starting material from Part B (8.92 g, 40.1 mmol) dissolved in 80 ml 
acetic acid is treated with 1.6 g of platinum oxide and hydrogenated in a 
Parr Bomb at 51.5 psi initial pressure. The pressure drops to 39.5 psi 
after 64 hours, but the reaction is continued for an additional 4 days 
(final pressure, 39.0 psi). The crude reaction mixture, including 
catalyst, is quenched in cold aqueous sodium hydroxide, treated with 
chloroform, and both layers are filtered through celite to remove 
platinum. The organic layer is separated, dried over sodium sulfate, and 
concentrated in vacuo to 10.79 g of solid which is crystallized from 
methanol/ethyl acetate mixtures (after Darco decolorizing carbon 
treatment) to afford 8.67 g (94.7%) of needles, in two crops, metling 
point 165.degree.-169.degree. C.: IR (nujol) 3291 cm.sup.-1 ; UV (95% 
ethanol) 256 nm, 257 nm with sh at 261, 264, 280, and 310 nm; NMR 
(CDCl.sup.3) 8.15, 7.2- 7.6, 1.7-3.2; mass spectrum shows a weak molecular 
ion peak at m/e 228 with a strong fragment ion at m/e 172. 
Anal. Calcd. for C.sub.13 H.sub.16 N.sub.4, mw 228.30: C, 68.39; H, 7.07; 
N, 24.55. Found: C, 68.08; H, 7.02; N, 24.10. An undried sample analyzed 
correctly for a 1/2 methanol solvate. 
T D 
1-(2-Phenylethyl)-4-(4-phenyl-4H-1,2,4-triazol-3-yl)-piperidine 
The starting triazolyl piperidine from Part C above (2.28 g, 10.0 mmol) and 
beta-phenylethyl bromide (2.04 g, 10.0 mmol) are dissolved in 30 ml of 
absolute ethanol and treated with potassium carbonate (1.93 g, 14.0 mmol). 
The mixture is refluxed for 24 hours, cooled, quenched in cold aqueous 10% 
sodium hydroxide, and the product is extracted with chloroform. The 
chloroform layer was dried over sodium sulfate and concentrated in vacuo 
to a solid (3.42 g, crude) which crystallized from methanol/ethyl acetate 
mixtures to afford 0.97 g (29.2%) of colorless prisms, melting point 
180.degree.-182.degree. C. A second crop weighed 1.04 g (31.3%): IR 
(nujol) 1596 cm.sup.-1 ; UV (95% ethanol) 258 nm, with shoulders at 259 
nm, 263 nm and 266 nm; NMR (CDCl.sub.3, .delta.) 8.15, 7.0-7.6, and 
1.7-3.2; mass spectrum: strong ion peak at m/e 333, with fragment ions at 
241 and 57. 
Anal. Calcd. for C.sub.21 H.sub.24 N.sub.4, mw 332.44: C, 75.87; H, 7.28; 
N, 16.86. Found: C, 76.00; H, 7.25; N, 16.92. 
EXAMPLE 13 
4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)piperidine 
(Formula Ia: R.sub.31 is methyl, X.sub.1 and Y.sub.1 are hydrogen, and 
R.sub.1, R.sub.2 and R.sub.3 are hydrogen). and 
4-(5-ethyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-piperidine 
(Formula Ia: R.sub.31 is ethyl, X.sub.1 and Y.sub.1 are hydrogen, and 
R.sub.1, R.sub.2 and R.sub.3 are hydrogen). 
Refer to Chart B (conversion of B-7 to B-8). The starting piperidine from 
Example 12, Part D above (1.328 g, 4.00 mmol), suspended in 24 ml of 
tetrahydrofuran in a 100 ml round bottomed flask with side-arm and rubber 
stopper, magnetic stirrer bar and nitrogen inlet, is treated rapidly, at 
0.degree. C., with two equivalents of a 1.6M solution of n-butyllithium, 
followed 30 seconds later by a tetrahydrofuran solution of methyl iodide 
(1.17 g, 8.24 mmol) in 2.0 ml of tetrahydrofuran. The solution is stirred 
for 1/2 hour at 0.degree. C., then quenched in a cold aqueous 10% sodium 
hydroxide solution. The organic products are extracted with CHCl.sub.3, 
which is dried (Na.sub.2 SO.sub.4), and concentrated in vacuo to 1.44 g of 
oil, which solidifies on standing. Thin layer chromatography using Silica 
Gel, 10% methanol/90% CHCl.sub.3, containing one drop of a concentrated 
NH.sub.4 OH solution) reveals the formation of at least three new 
products. These are separated by chromatography over Silica gel 60 (150 g) 
by eluting with 1 liter of 2% methanol/98% CHCl.sub.3, and 1 liter of 4% 
methanol/96% CHCl.sub.3, each containing 5 ml of a concentrated aqueous 
NH.sub.4 OH solution per liter. Following a 20 ml forerun. 20 ml fractions 
are collected. 
Fractions 65-80 contain 0.579 g of oil which crystallizes when triturated 
with diethyl ether. This material is crystallized slowly from ethyl 
acetate/diethyl ether mixtures to afford 0.169 g of the 5-ethyl adduct. 
The analytical sample has a melting point of 110.degree.-112.degree. C.: 
IR (Nujol) 1597 and 1500 cm.sup.-1 ; UV (95% ethanol) 258 nm, 262, and 
267.5 nm; NMR (CDCl.sub.3 .delta.) 7.2-7.6, 1.8-3.2, and 1.20; mass 
spectrum, very weak M+1 ion at m/e 361 with a base peak at m/e 269.1721. 
Anal. Calcd. for C.sub.23 H.sub.28 N.sub.4, mw 360.49: C, 76.63; H, 7.83; 
N, 15.55. Found: C, 75.91; H, 7.82; N, 15.39. 
Fractions 81-105 contain a solid which is crystallized twice from ethyl 
acetate/diethyl ether mixtures to afford 102 mg of the titled 5-methyl 
compound as a white powder with a melting point of 141-143: IR (Nujol) 
1596, 1528, and 1505 cm.sup.-1 ; NMR (CDCl.sub.3, .delta.) 7.4-7.6, 
7.0-7.2, 2.22, and 1.5-3.0; mass spectrum shows a weak molecular ion at 
m/e 346.2136. 
Anal. Calcd. for C.sub.22 H.sub.26 N.sub.4, mw 346.47: C, 76.26; H, 7.56; 
N, 16.17. Found: C, 76.17; H, 7.68; N, 15.94. 
EXAMPLE 14 
1-(2-Phenylethyl)-4-(3-phenyl-4H-1,2,4-triazol-4-yl)piperidine (Formula Ib: 
R.sub.31 is hydrogen, X.sub.1 and Y.sub.1 are hydrogen, and R.sub.1 and 
R.sub.2 are hydrogen). Refer to Chart C (conversion of C-1 to C-7). 
T A 
N-(.beta.-phenylethyl)-4-amino-piperidine 
Following the procedure of Lobbezoo, J. Med. Chem. 24:777 (1981). 
N-(.beta.-phenylethyl)-4-piperidinone (15.0 g, 74.0 mmol) dissolved in 200 
ml of methanol containing 1 ml of a 4% thiophene in methanol solution is 
treated with benzyl amine (10.0 g, 93.0 mmol) and 2 g of 10% 
palladium-on-carbon in a Parr flask and hydrogenated for 18 hours (initial 
pressure, 26.5 psi, final pressure 22.0 psi). The catalyst is filtered and 
replaced with 2.0 g of fresh 10% palladium-on-carbon. The catalyst is 
filtered and replaced again with 4.8 g of fresh 10% palladium-on-carbon. 
The hydrogenation is followed over 3 days, at which point, hydrogen uptake 
ceases (initial pressure, 35 psi, final pressure, 29 psi). The catalyst is 
filtered through Celite and is washed with methanol. GLC analysis (2 ft 
SE-30, 100 C, 1 minute, programmed 20 C/minute rise to 250 C) indicated 
that 7% unreacted benzyl amine remained). This material nevertheless was 
used for subsequent experiments. 
T B 
1-(2-Phenylethyl)-4-(3-phenyl-4H-1,2,4-triazol-4-yl)piperidine 
4-Amino-1-(2-phenylethyl)piperidine (13.95 g, 68.3 mmol) is treated with 
dimethylformamide dimethylacetal (16.28 g, 136.6 mmol) and heated to 
reflux for 3 hours. The reaction solution is concentrated in vacuo to an 
oil which solidifies on standing, but is not recrystallized. A portion of 
this crude formamidine (7.77 g, 30.0 mmol) is dissolved in 36 ml of 
benzoic acid hydrazide (4.08 g, 30.0 mmol) and heated first for 14 hour at 
55.degree. C., then 4 hours at reflux. The solution is quenched in cold 
aqueous 10% NaOH, which is extracted with CHCl.sub.3 and dried over 
Na.sub.2 SO.sub.4. The organic layer is concentrated in vacuo to a dark 
oil which is chromatographed over 300 g of silica gel by eluting with 2 
liters of 4% methanol/96% CHCl.sub.3, containing 5 ml of aqueous 
concentrated NH.sub.4 OH/liter. Following a 300 ml forerun, 20 ml 
fractions are collected. The product is collected in fractions 61-84 and 
crystallized from ethyl acetate/Et.sub.2 O to afford 3.936 g (39.5% yield) 
of tan prisms. The analytical sample has a melting point of 
124.degree.-125.degree. C.: IR (Nujol) 3031, and 2960 cm.sup.-1 ; UV (95% 
ethanol) 227 nm; NMR (CDCl.sub.3, .delta.) 8.35, 7.54, 7.23, 4.0, 3.07, 
2.70, and 2.04; mass spectra weak molecular ion at m/e 332 with a base 
peak at 241. 
Anal. Calcd. for C.sub.21 H.sub.24 N.sub.4, mw 332.44: C, 75.87; H, 7.28; 
N, 16.86. Found: C, 75.83; H, 7.40; N, 16.77. 
EXAMPLE 15 
4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidinol 
, acetate (ester) (Formula Ia: R.sub.31 is methyl, X.sub.1 and Y.sub.1 are 
hydrogen, R.sub.1 and R.sub.2 are hydrogen, and R.sub.3 is --OCOCH.sub.3); 
4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidino 
l, propanoate ester (Formula Ia: R.sub.31 is methyl, X.sub.1 and Y.sub.1 
are hydrogen, R.sub.1 and R.sub.2 are hydrogen, and R.sub.3 is 
--OCOCH.sub.2 CH.sub.3). 
T A 
4-(5-Methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidinol 
To a solution of 1.6 g of 3-methyl-4-phenyl-4H-1,2,4-triazole (10 mmol) in 
15 ml of THF at -78.degree. C. is added 7.0 ml of n-butyllithium (1.6N in 
hexane). The mixture is stirred for 50 minutes before a solution of 2.44 g 
of N-(2-phenylethyl)-4-piperidinone in 12 ml of THF is charged into the 
flask. After stirring for 30 minutes at -78.degree. C. and then 1 hour at 
-20.degree. C. the mixture is poured into cold water and is extracted 
three times with chloroform. The combined chloroform extracts are washed 
twice with water, brine, dried over sodium sulfate and concentrated in 
vacuo to yield an amber oil. 
The oil is dissolved in ethyl acetate-hexane mixture and is allowed to 
crystallize. Recrystallization from a methanol-ethyl acetate-hexane 
mixture affords 1.9 g of prisms of the subtitled product with a melting 
point of 183.degree.-184.degree. C. (clear): IR (Nujol) 3180, 2780, 1600, 
1580, 1540, 1515 and 1500 cm.sup.-1 ; NMR (CDCl.sub.3) .delta. 1.7-2.05, 
2.14, 2.20-2.85 and 2.95; mass spectrum molecular ion peak at m/e 363 
(very weak), with fragment ion peaks at m/e 271, 112, 160, 272 and 202. 
Anal. Calcd. for C.sub.22 H.sub.26 N.sub.4 O mw 362.46: C, 72.90; H, 7.23; 
N, 15.46. Found: C, 73.08; H, 7.18; N, 15.40. 
T B 
4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidinol 
, acetate (ester) 
To a solution of 0.5 g of the product of Part A in 20 ml of methylene 
chloride and 3 ml acetic anhydride is added 50 mg of 
4-(dimethylamino)pyridine (DMAP) and the mixture is refluxed for 18 hours. 
The solution is diluted with water, and the phases are separated. The 
organic phase is washed with water, dried over sodium sulfate and 
concentrated in vacuo to give 0.46 g of crude product. 
Crystallization from ethyl acetate-hexane gives 0.3 g of the desired 
subtitled ester with a melting point of 163.degree.-164.degree. C. 
NMR (CDCl.sub.3) .delta. 1.70, 2.15, 2.25-2.50, 2.55-2.95, and 7.0-7.65; 
mass spectral fragment ion peaks at 361, 344, 313, 253, 212 and 345. 
Anal. Calcd. for C.sub.24 H.sub.28 N.sub.4 O.sub.2, mw 404.52: C, 71.26; H, 
6.98; N, 13.85. Found: C, 70.93; H, 6.94; N, 13.98. 
T C 
4-(5-methyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1-(2-phenylethyl)-4-piperidinol 
, propanoate (ester). 
Using the procedure of Part B above, 0.62 g of the titled product ester are 
prepared from 1.0 g of the starting alcohol from Part A above, 2 ml of 
propionic anhydride and 0.45 g of DMAP. Spectral data support the proposed 
structure. 
Anal. Calcd. for C.sub.25 H.sub.30 N.sub.4 O.sub.2 : mw 418.55: C, 71.74; 
H, 7.22; N, 13.39. Found: C, 71.42; H, 7.32; N, 13.56. 
EXAMPLE 16 
4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-piperidine and its dihydrochloride. 
T A 
1-Benzyl-4-piperidinone-oxime 
Following a procedure of P. Brookes, et al., J. Chem. Soc., 3165 (1957), 
1-benzyl-4-piperidinone (44.6 g, 0.234 mol) and hydroxylamine 
hydrochloride (14.0 g, 0.201 mol) are added to 140 ml of dry pyridine and 
the resulting mixture is heated to 100.degree. C. in an oil bath for 3 
hours. The resulting solid is cooled overnight, filtered and crystallized 
from 1 liter of ethanol. The product is collected as colorless needles, 
38.17 g, in two groups with melting point of 225.degree.-237.degree. C., 
decomposed depending upon the rate of heating. 
T B 
1-Benzyl-4-amino-piperidine 
Following the procedure of Brookes, et al., the oxime hydrochloride salt 
from Part A above is suspended in hot absolute ethanol and treated with a 
solution of NaOEt prepared from Na (2.3 g, 0.10 mol) in 50 ml of absolute 
ethanol. The amorphous solid which forms is filtered. The mother liquor, 
containing the oxime free base is boiled on a steam bath while small 
pieces of Na (23.0 g, 1.0 g-atom) are added at a rate to prevent foaming. 
The addition takes 15 minutes. The mixture is heated an additional period 
until all the Na has reacted. Distilled water is then added to the 
reaction vessel (an Erlenmeyer flask) while the ethanol is removed by 
blowing a stream of nitrogen over the surface of the reaction solution. 
The flask is removed from the steam bath and permitted to cool. The 
product is isolated by extracting the aqueous layer with diethyl ether. 
The organic layer is dried (Na.sub.2 SO.sub.4) and concentrated in vacuo 
to an oil, 16.8 g (88.4% yield). By GLC, this oil is 83% pure. The 
impurity is not characterized. This material is used for subsequent 
experiments. 
T C 
N,N-Dimethyl-N'-(1-benzyl-piperidin-4-yl)-formamidine 
The starting 4-amino-1-benzylpiperidine from Part B above (15.0 g, 78.8 
mmol) is treated with dimethylformamide dimethylacetal (18.78 g, 157.6 
mmol) and refluxed for 2 hours. The solution is permitted to cool 
overnight, then concentrated in vacuo to the product (15.5 g of oil, 83.2% 
yield), which solidifies on standing. A small portion crystallizes from 
hexane to afford colorless needles with a melting point of 
61.degree.-65.degree. C.: NMR (CDCl.sub.3 .delta.) 7.28, 3.49, 2.80, and 
1.75-3.0; mass spectral molecular ion peak at m/e 245, with abundant 
fragment ions at m/e 200, 173, 172, 154, and 91. 
Anal. Calcd. for C.sub.15 H.sub.23 N.sub.3, mw 245.36: C, 73.42; H, 9.45; 
N, 17.13. Found: C, 73.02; H, 9.27; N, 16.96. 
T D 
Benzoic acid, 2-[[[1-(phenylmethyl)-4-piperidinyl]-imino]methyl]-hydrazide 
The starting formamidine from Part C above (11.61 g, 47.3 mmol) dissolved 
in 28 ml of warm diglyme, is treated with a solution of benzoic acid 
hydrazide (6.44 g, 47.3 mmol) dissolved in 28 ml of warm diglyme. The 
solution is heated for 14 hours at 55.degree. C. The resulting solid is 
filtered to afford 18.64 g of crude, "wet" amidrazone. Three grams of this 
material is saved and recrystallized from methanol/ethyl acetate mixtures 
to afford 0.91 g of powder (subtitled intermediate) with a melting point 
of 176-179: IR (Nujol) 3206 and 1673 cm.sup.-1 ; UV (95% ethanol) 278 nm; 
NMR (CDCl.sub.3 .delta.) 7.79-7.91, 7.26-7.37, and 1.45-3.5 the NH and 
N.dbd.CH signals are not visible; mass spectra weak molecular ion at m/e 
336 with fragment ions at m/e 216, 201, 172 (base peak) and 91. 
Anal. Calcd. for C.sub.20 H.sub.24 N.sub.4 O, mw 336.43: C, 71.40; H, 7.19; 
N, 16.66. Found: C, 71.06; H, 7.28; N, 16.56. 
The mother liquors deposit an additional 2.09 g of crude, wet amidrazone. 
All of the crude amidrazone is used for the reaction described below. 
T E 
1-(Phenylmethyl)-4-(3-phenyl-4H-1,2,4-triazol-4-yl)piperidine. 
The crude amidrazone (approximately 12 g, 35.7 mmol) described in Part D of 
this example is suspended in 80 ml of dry diglyme, then refluxed for 7 
hours, cooled overnight, and concentrated in vacuo. The crude material is 
taken up in CHCl.sub.3, extracted with an aqueous 10% NaOH solution, dried 
over Na.sub.2 SO.sub.4, and concentrated in vacuo to 9.84 g of tan oil, 
which is chromatographed over 520 g of silica gel by eluting with 2 liters 
of 4% methanol/96%CHCl.sub.3 and 4 liters of 5% methanol/95% CHCl.sub.3, 
each liter containing 5 ml of concentrated aqueous NH.sub.4 OH solution. 
After a 20 ml forerun, 20 ml fractions are collected. The subtitled 
product is collected in fractions 51-100 and crystallized as beautiful 
needles from ethyl acetate/hexane mixtures to afford 4.07 g (35.8% yield 
from the Formamidine) in two crops with a melting point of 
111.degree.-114.degree. C.: IR (Nujol) 1507 cm.sup.-1 ; UV (95% ethanol) 
228 nm; NMR (CDCl.sub.3 .delta.) 8.34, 4.0, 3.51, 1.99, and 1.82; mass 
spectra molecular ion at m/e 318 with fragment ions at m/e 317, 289, 241, 
227, 173, and 91. 
Anal. Calcd. for C.sub.20 H.sub.22 N.sub.4, nw 318.42: C, 75.43; H, 6.97; 
N, 17.60. Found: C, 75.14; H, 7.03; N, 17.57. 
T F 
4-(3-Phenyl-4H-1,2,4-triazol-4-yl)-piperidine and its dihydrochloride. 
The starting benzylamine from Part E above (2.85 g, 8.95 mmol) is dissolved 
in methanol, treated with ethereal HCl and concentrated in vacuo to a gum, 
which is taken up in 100 ml of absolute ethanol, treated with 2.8 g of 10% 
palladium-on-carbon and hydrogenated in a Parr Bomb for 11 days, until no 
starting material is observed by thin layer chromatography using Silica 
Gel G, eluting with 10% methanol/90% CHCl.sub.3). The catalyst is 
filtered, and the solvent is removed in vacuo. The product crystallized 
from methanol/ethyl acetate mixtures to afford 1.19 g (42.2% yield) of 
prisms with a melting point of 254-260 C: IR (Nujol) 2955 cm.sup.-1 ; UV 
(95% ethanol) 229 nm; NMR (CDCl.sub.3, .delta.) 9.73, 7.77, 3.0-3.7, and 
2.5; mass spectra molecular ion peak at m/e 228, with fragment ions at m/e 
200, 172, 157, 145, 82, 55, and 36. 
Anal. Calcd. for C.sub.13 H.sub.16 N.sub.4 --2HCl--0.5CH.sub.3 OH, mw 
315.22: C, 51.43; H, 6.40; N, 17.78; Cl, 22.49. Found: C, 51.18; H, 6.29; 
N, 17.53; Cl, 21.19. 
Alkylation of this subtitled compound with 2-phenylethyl bromide as 
described herein produces 
1-(2-phenylethyl)-4-(3-phenyl-4H-1,2,4-triazol-4-yl)piperidine, the same 
compound produced in Example 14, Part B above. 
##STR1##