5-(1,1-Diphenyl-3-(5- or 6-hydroxy-2-azabicyclo(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles and related compounds

This invention encompasses novel 5-[1,1-diphenyl-3-(5-or 6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-alkyl-1,3,4-oxadiazoles and their lower O-alkanoyl derivatives. These compounds are useful anti-diarrheal agents and also possess little or no analgesic activity.

The present invention is concerned with 5-[1,1-diphenyl-3-(5-or 
6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl) propyl]-2-alkyl-1,3,4-oxadiazoles 
and their lower O-alkanoyl derivatives. More particularly, this invention 
is concerned with compounds of the formula 
##STR1## 
wherein R is lower alkyl containing from 1 to 6 carbon atoms; R' is 
hydrogen or lower alkanoyl containing from 2 to 7 carbon atoms; and OR' 
is attached at the 5- or 6-position in either the endo or exo 
configuration. 
Particularly preferred compounds of this invention are those of the formula 
##STR2## 
wherein R' is hydrogen or acetyl and OR' at the 5- or 6-position is in 
either the endo or exo configuration. 
The lower alkyl radicals referred to above contain 1 to 6 carbon atoms and 
are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the 
corresponding branched chain isomers thereof. The lower alkanoyl radicals 
contain 2 to 7 carbon atoms and are typified by acetyl, propionyl, butyryl 
and the like. 
Equivalent to the compounds of formulas (I) and (II) for the purposes of 
the invention are the pharmaceutically acceptable acid addition salts 
thereof. Such acid addition salts can be derived from a variety of 
inorganic and organic acids such as sulfuric, phosphoric, hydrochloric, 
hydrobromic, hydroiodic, sulfamic, citric, lactic, pyruvic, oxalic, 
maleic, succinic, tartaric, cinnamic, acetic, benzoic, salicylic, 
gluconic, ascorbic and related acids. 
The compounds of the present invention are useful in consequence of their 
valuable pharmacological properties. They are, for example, potent 
anti-diarrheal agents as evidenced by their ability to inhibit 
gastrointestinal motility as set out in the following tests. 
CHARCOAL MEAL TEST 
The method used for this assay is a modification of the techniques 
previously described by Macht and Barba-Gose, J. Amer. Pharm. Ass., 20, 
558 (1931), and Janssen and Jageneau, J. Pharm. Pharmacol., 9, 381 (1957). 
Details are as follows: 
A group of six, male Charles River mice weighing 20-25 g. which have been 
previously fasted for 24 hours are pretreated with the test compounds 
administered orally as a solution in water or suspended in 0.5% methyl 
cellulose. A constant volume of 10 ml./kg. is employed. Thirty minutes 
following administration of the test compounds, the animals are given a 
single oral dose of charcoal which consists of 0.2 ml. per mouse of 10% 
charcoal suspended in 1.0% methyl cellulose. Three and a half hours after 
charcoal administration the animals are sacrificed and the cecum examined 
for the absence or presence of charcoal on an all-or-none basis. 
The median effective dose (ED.sub.50) is then calculated for each compound 
using the logistic method of Berkson (1953). 
CASTOR OIL-INDUCED DIARRHEA IN THE RAT 
Adult Charles River male rats are fasted in community cages for 24 hours 
prior to the test with free access to water. The test compound is then 
administered intragastrically (suspended in 0.5% methyl cellulose) one 
hour prior to the intragastric administration of a dose of 1.0 ml. castor 
oil per rat. The rats are then observed for the presence or absence of 
diarrhea at hourly intervals for up to 8 hours past the castor oil 
administration. Using the method of Berkson (1953), the median effective 
dose (ED.sub.50) values are calculated at each hourly interval for the 
test compound. 
In addition to their anti-diarrheal activity, the compounds of this 
invention demonstrate little or no analgesic activity at the test doses. 
The assessment of this activity is conducted by the following assay: 
TAIL CLIP TEST 
A special clip is applied to the base of the tail of an adult male mouse 
weighing 18-25 grams and the time for the animal to turn around to bite at 
the clip is measured. The sensitivity of each mouse is determined 1/2 hour 
prior to drug administration and only those mice attempting to bite the 
clip are included in the experiment. The test compound is then 
administered intraperitoneally and the response to placement of the clip 
is determined at 30, 60, 90 and 120 minutes after treatment. A response is 
considered positive if the animal takes more than 2 times the pre-drug 
time to bite at the clip at any of these time intervals. A test compound 
is considered active when 50 percent or more of the animals used show a 
positive response. 
A representative compound of this invention which is particularly active in 
the Charcoal Meal Test anti-diarrheal assay and which possesses no 
analgesic activity is 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)-propyl]-2-me 
thyl-1,3,4-oxadiazole. 
The compounds of formula (I) may be combined with various pharmaceutical 
carriers to provide compositions suitable for use in the treatment of 
diarrhea. The dosage of these compounds is dependent upon various factors 
such as the compound employed and the particular response obtained. 
Typical dosages for use as an anti-diarrheal agent vary from 0.1 to 25 
mg./kg. per day administered orally. 
The compounds of the present invention are conveniently prepared by the 
reaction sequence set out in Scheme A. 
##STR3## 
As illustrated in Scheme A, the secondary amine of formula (IV) is reacted 
with an alkyl halide of formula (III) wherein the X represents an iodo, 
bromo or chloro atom to form the nitrile of formula (V). This reaction is 
preferably, but not absolutely, carried out in an organic solvent. An 
alkylation promoter, such as sodium iodide or potassium iodide, and an 
acid acceptor, such as potassium carbonate, may optionally be added to 
facilitate the reaction. Suitable organic solvents are those such as 
benzene, toluene, and methylene chloride, with a particularly preferred 
solvent being methyl isobutyl ketone. 
The nitrile of formula (V) is then reacted with an azide ion by methods 
similar to those described by Moersch and Morrow, J. Med. Chem., 10, 149 
(1967) to obtain the tetrazole of formula (VI). 
The tetrazoles of formula (VI) are converted to the compounds of formula 
(I) wherein R' is a lower alkanoyl radical containing 2 to 7 carbon atoms, 
i.e., the compounds illustrated in the above scheme by formula (Ia) by 
reaction with an appropriate acylating agent of formula (VII) wherein R is 
defined as hereinbefore. This reaction is conveniently conducted in an 
organic solvent, with a particularly preferred solvent being pyridine. 
Alkaline hydrolysis of the compounds of formula (Ia) with a suitable 
reagent such as sodium hydroxide affords the compounds of formula (I) 
wherein R' is hydrogen, i.e., the compounds illustrated in the above 
Scheme A by formula (Ib). 
The following examples describe in detail the preparation of compounds of 
the present invention. It will be apparent to those skilled in the art 
that many modifications, both of materials and methods, may be practiced 
without departing from the purpose and intent of this disclosure. 
Throughout the examples hereinafter set forth, temperatures are given in 
degrees Centigrade (.degree.C.) and relative amounts in parts by weight, 
except as otherwise noted.

EXAMPLE 1 
15.5 Parts of methyl 2-hydroxy-4-aminobenzoate is dissolved in 
approximately 180 parts of ethanol. Then, 3.89 parts of a 5% 
rhodium-on-alumina catalyst is added and the mixture shaken at 60.degree. 
C. at a pressure of about 60 psi for approximately 53 hours. The catalyst 
is removed by filtration and the filtrate concentrated under reduced 
pressure. The residual oil which solidifies upon standing is triturated 
with 60 parts by volume of a 4:1 ether-ethanol mixture, filtered, washed 
with 100 parts by volume of a 4:1 ether-ethanol mixture, and dried in 
vacuo to give methyl 2-cis-hydroxy-4-cis-aminocyclohexanecarboxylate 
acetate. This compound melts at about 134.degree.-137.degree. C., and is 
represented by the following structural formula. 
##STR4## 
EXAMPLE 2 
44.5 Parts of methyl 2-cis-hydroxy-4-cis-aminocyclohexanecarboxylate 
acetate is heated at about 160.degree.-165.degree. C. for about 3.5 hours 
under a nitrogen atmosphere. The gas which evolves during heating is 
condensed by cooling and collected. The residual solid is, after cooling, 
triturated with 20 parts methanol, cooled to 0.degree. C., filtered, 
washed with methanol and ether, and air-dried. The resultant off-white 
solid is recrystallized from methanol to give 
exo-5-hydroxy-2-azabicyclo-[2.2.2]octan-3-one, melting at about 
263.degree.-266.degree. C., and represented by the following structural 
formula. 
##STR5## 
EXAMPLE 3 
To a suspension of 27.9 parts lithium aluminum hydride in 2500 parts dry 
ethyl ether under nitrogen is added 34.3 parts of 
exo-5-hydroxy-2-azabicyclo[2.2.2]octan-3-one. The resulting mixture is 
refluxed for 23 hours with stirring. The reaction is then decomposed by 
the successive addition of 29.4 parts water, 22 parts by volume of a 20% 
sodium hydroxide solution, and 108 parts water. The solution is then 
filtered, the inorganic salts washed with ethyl ether and the filtrates 
combined. These combined filtrates are then treated with a slight excess 
of a solution of hydrochloric acid in isopropanol. Removal of the solvents 
in vacuo affords a solid residue which is triturated with 32 parts 
acetone, filtered, washed, and air-dried to afford an off-white solid. 
Recrystallization of this solid from a mixture of acetone and methanol 
affords exo-2-azabicyclo[2.2.2]octan-5-ol hydrochloride. This compound 
melts at about 308.degree.-310.degree. C. with decomposition and is 
represented by the following structural formula. 
##STR6## 
EXAMPLE 4 
16.3 Parts of exo-2-azabicyclo[2.2.2]oct-5-ol hydrochloride is dissolved in 
67 parts of hot ethanol. After cooling the solution to room temperature a 
solution of 4.0 parts sodium hydroxide in 67 parts ethanol is added. The 
resulting precipitate is filtered off and washed with 32 parts ethanol. 
The filtrates are combined, mixed with 13.8 parts of potassium carbonate 
and 12.7 parts benzyl chloride, and heated to reflux for about 4 hours 
under a nitrogen atmosphere. After cooling, the solvents are removed in 
vacuo and the residue suspended in 140 parts by volume of a potassium 
carbonate solution which was saturated with sodium chloride. This 
suspension is extracted twice with ethyl ether. The ether extracts are 
then combined and twice extracted with dilute hydrochloric acid. These 
extracts are combined and basified with aqueous sodium hydroxide. The 
resulting liberated oil is separated by twice extracting with ether and 
combining the ether extracts which are then dried over anhydrous sodium 
sulfate and stripped of solvent in vacuo. The residual oil is dissolved in 
39 parts acetone, treated with 15 parts by volume of a 7.3 N solution of 
hydrochloric acid in isopropanol and cooled in a cold-water bath. The 
resulting precipitate is filtered, washed with acetone and air-dried to 
give exo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol hydrochloride. This 
compound melts at about 157.degree.-160.degree. C. and is represented by 
the following structural formula. 
##STR7## 
EXAMPLE 5 
7.83 Parts of exo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol hydrochloride is 
dissolved in 1200 parts boiling acetone. The hot solution is filtered and 
the volume reduced to about 450 ml. After cooling to about 15.degree. C., 
11.6 parts by volume of an 8 N Jones reagent is added and the solution 
stirred for about 2.5 hours. An additional 51.4 parts by volume Jones 
reagent is then added with the temperature being kept at 33.degree. C. by 
means of a cold-water bath. After stirring for an additional 16 hours at 
room temperature, the solution is quenched with 75 parts by volume 
isopropanol, treated with 21 parts of potassium carbonate in 150 parts 
water and reduced in volume in vacuo to about 200 ml. The resulting green 
slurry is then treated with a solution of 21 parts potassium carbonate in 
350 parts water and extracted with ethyl ether. The ether extracts are 
combined, dried over anhydrous sodium sulfate and stripped in vacuo to 
yield a yellow oil. This oil is dissolved in 24 parts acetone and treated 
with 3.5 parts by volume of a 7.25 N solution of hydrogen chloride in 
isopropanol, with cooling. The resulting white crystals are filtered, 
washed with acetone and dried under vacuum to afford 
2-benzyl-2-azabicyclo[2.2.2]-octan-5-one hydrochloride. This compound 
melts at about 153.degree.-154.degree. C. and is represented by the 
following structural formula. 
##STR8## 
EXAMPLE 6 
A solution of 3.77 parts 2-benzyl-2-azabicyclo[2.2.2]-octan-5-one in water 
is basified using aqueous sodium hydroxide. The liberated oil is separated 
by extracting with benzene, combining the extracts, drying the extracts 
over anhydrous sodium sulfate and anhydrous potassium carbonate and 
removing the solvent in vacuo. The residual oil is then redissolved in 
benzene and the solvent removed in vacuo. To the residual oil dissolved in 
45 parts dry tetrahydrofuran is added dropwise with stirring 39 parts by 
volume of a 1.17 M solution of diisobutyl aluminum hydride in toluene over 
a period of 70 minutes under nitrogen at -70.degree. C. Stirring at this 
temperature is continued for an additional 4 hours. The mixture is allowed 
to warm to room temperature and left to stir for a further 16 hours. After 
cooling to about 0.degree.-5.degree. C., the reaction mixture is 
decomposed with 16 parts methanol. The solvents are then removed in vacuo 
to leave a thick oil which is dissolved in methylene chloride, washed with 
sodium hydroxide, dried over anhydrous sodium sulfate and stripped in 
vacuo. Gas chromatography of the remaining oil shows a 6:4 mixture of 
endo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol and 
exo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol. 
This mixture is treated with a solution of hydrochloric acid in isopropanol 
to form the hydrochloride salt. Fractional crystallization of this salt 
from a 1:10 (v/v) mixture of methanol-acetone affords 98% pure 
endo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol hydrochloride, melting at 
about 189.degree.-192.degree. C. 
EXAMPLE 7 
0.52 Part of endo-2-benzyl-2-azabicyclo[2.2.2]octan-5-ol is dissolved in 
approximately 40 parts of ethanol. Then, 0.05 part of a 5% 
palladium-on-carbon catalyst is added and the mixture shaken at room 
temperature and at a pressure of about 60 psi for approximately 18.5 
hours. The catalyst is removed by filtration and the solvents removed in 
vacuo. The residual solid is triturated with 18 parts of dry ether, and 
filtered off and air-dried at 60.degree. C. Recrystallization of the solid 
from a mixture of methanol and tetrahydrofuran affords 
endo-2-azabicyclo[2.2.2]octan-5-ol hydrochloride, melting at about 
310.degree.-312.degree. C. with decomposition and gas evolution. This 
compound is represented by the following structural formula. 
##STR9## 
EXAMPLE 8 
141 Parts of m-chloroperbenzoic acid is added portionwise to a stirred 
solution of 90.0 parts methyl 3-cyclohexene-1-carboxylate in 2200 parts 
chloroform over a 20 minute period at -4 - 1.degree. C. The resultant 
solid suspension is stirred at room temperature for 70 minutes. The solid 
is separated by filtration and washed with chloroform. The filtrate and 
the washing are combined, washed successively with dilute sodium sulfate, 
dilute sodium bicarbonate and water, dried over anhydrous sodium sulfate, 
and stripped in vacuo. The residual oil is distilled to afford, as a 
colorless liquid boiling at 57.degree. C. at 0.6 mm. to 66.degree. C. at 
0.8 mm. pressure, a mixture of cis and trans methyl 
3,4-epoxycyclohexane-1-carboxylate. This mixture is represented by the 
following structural formulas. 
##STR10## 
EXAMPLE 9 
A solution of 99.3 parts of the mixture of cis and trans methyl 
3,4-epoxycyclohexane-1-carboxylate and 71.5 parts benzylamine in 240 parts 
ethanol is refluxed for 18 hours, then cooled, and stripped of solvent in 
vacuo. The residue is then refluxed with 320 parts methanol and 405 parts 
by volume of a 10% potassium hydroxide solution for 1 hour. After cooling, 
the solution is neutralized to a pH of 7 with dilute hydrochloric acid and 
then stripped in vacuo to a volume of 550 ml. The resultant solid 
suspension is filtered and the solid washed with water and air-dried. This 
solid is heated for about 45 minutes at 215.degree.-225.degree. C. which 
results in the solid melting with water vapor evolution. After cooling, 
the residue is dissolved in methylene chloride, washed successively with 
dilute hydrochloric acid, water, dilute potassium carbonate and water, 
then dried over anhydrous sodium sulfate and stripped in vacuo. The 
residue is crystallized from ethyl acetate to afford 
endo-2-benzyl-6-hydroxy-2-azabicyclo[2.2.2] -octan-3-one, melting at 
96.5.degree.-99.degree. C., and represented by the following structural 
formula. 
##STR11## 
EXAMPLE 10 
To a suspension of 26.0 parts lithium aluminum hydride in 670 parts 
tetrahydrofuran under nitrogen at reflux is added with stirring a 
suspension of 43.0 parts 
endo-2-benzyl-6-hydroxy-2-azabicyclo[2.2.2]octan-3-one in 130 parts 
tetrahydrofuran over a 20 minute period. After refluxing the reaction 
mixture for about 64 hours, the mixture is decomposed by the successive 
addition of 27.4 parts water, 20.6 parts by volume of a 20% sodium 
hydroxide solution and 96 parts water. The solid is removed by filtration 
and washed with tetrahydrofuran. The filtrate is stripped in vacuo and the 
residue dissolved in ether. The ethereal solution is extracted with dilute 
hydrochloric acid and the hydrochloric acid extract basified with sodium 
hydroxide. The liberated oil is extracted into ethyl ether, dried over 
anhydrous sodium sulfate and stripped in vacuo. The residual solid is 
recrystallized from a mixture of ether and n-hexane to afford 
endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol, melting at about 
77.degree.-78.5.degree. C. This compound is represented by the following 
structural formula. 
##STR12## 
EXAMPLE 11 
18.0 Parts of endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol is dissolved in 
approximately 200 parts ethanol. Then, 1.8 parts of a 5% 
palladium-on-carbon catalyst is added and the mixture shaken at room 
temperature and at a pressure of 36- 60 psi for approximately 6 hours. The 
catalyst is removed by filtration and the filtrate concentrated under 
reduced pressure to afford a white solid. Recrystallization from a mixture 
of methylene chloride and n-hexane yields 
endo-2-azabicyclo[2.2.2]-octan-6-ol melting at about 
220.degree.-224.degree. C. This compound is represented by the following 
structural formula. 
##STR13## 
EXAMPLE 12 
A solution of 34.0 parts endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol in 106 
parts hot acetone is cooled in an icewater bath and treated with a slight 
excess of hydrochloric acid in isopropanol. Cooling to 0.degree. C. and 
seeding results in a precipitate which is filtered, washed with acetone 
and air-dried to afford endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol 
hydrochloride. This compound melts at about 174.degree.-175.degree. C. and 
is represented by the following structural formula. 
##STR14## 
EXAMPLE 13 
To a solution of 37.7 parts endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol 
hydrochloride in 790 parts acetone is added with stirring, 500 parts by 
volume of an 8 N solution of Jones reagent over a 20 minute period at 
20.degree.-30.degree. C. After stirring at about 15.degree.-20.degree. C. 
for 2 hours the temperature is reduced to 0.degree.-5.degree. C., and the 
solution stirred thereat for an additional 18 hours. Then, the reaction 
mixture is decomposed by the addition of 240 parts isopropanol and poured 
into 1000 parts by volume of an ice-cold 6 N sodium hydroxide solution. 
The solution is saturated with sodium chloride and extracted three times 
with 710 parts ethyl ether. The ether extracts are combined, dried over 
anhydrous sodium sulfate and stripped in vacuo. The residue is partitioned 
between water and ether. The ether layer is separated, dried over sodium 
sulfate and stripped in vacuo to afford a brown oil. Distillation of this 
oil affords the desired 2-benzyl-2-azabicyclo[2.2.2]octan-6-one, boiling 
at 126.degree.-141.degree. C. at 0.1 mm. pressure. 
Treatment of the above oil with a solution of hydrogen chloride and 
isopropanol affords the corresponding salt, 
2-benzyl-2-azabicyclo[2.2.2]octan-6 -one hydrochloride, as white crystals. 
This compound melts at about 215.degree.-216.degree. C., and is 
represented by the following structural formula. 
##STR15## 
EXAMPLE 14 
11.7 Parts 2-benzyl-2-azabicyclo[2.2.2]octan-6-one hydrochloride is 
suspended in 110 parts water and 13.8 parts potassium borohydride is added 
under nitrogen. After stirring overnight, the resulting two phases are 
extracted with ether. The ether extract is dried over anhydrous sodium 
sulfate and stripped in vacuo to give, as a light yellow oil, a 32:67 
mixture of endo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol and 
exo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol. 
This mixture is separated by low pressure chromatography using a neutral 
alumina column and increasing amounts of ethyl acetate in methylene 
chloride as eluant. The fractions eluded with 100% methylene chloride are 
combined, stripped in vacuo and the residue dissolved in ether. The 
ethereal solution is filtered and treated with a solution of hydrogen 
chloride in isopropanol. The white precipitate is filtered, and air-dried, 
to afford exo-2-benzyl-2-azabicyclo[2.2.2]octan-6 -ol hydrochloride, 
melting at 201.degree.-203.degree. C. This compound is represented by the 
following structural formula. 
##STR16## 
EXAMPLE 15 
Repetition of the procedure of Example 11 using 
exo-2-benzyl-2-azabicyclo[2.2.2]octan-6-ol affords 
exo-2-azabicyclo[2.2.2]octan-6-ol. This compound is represented by the 
following structural formula. 
##STR17## 
EXAMPLE 16 
To a solution of 2.46 parts exo-2-azabicyclo[2.2.2]-octan-5-ol 
hydrochloride in 10 parts water is added 3.32 parts potassium carbonate 
and 2.25 parts sodium iodide. Then, 4.80 parts 
2,2-diphenyl-4-bromobutyronitrile and 120 parts methyl isobutyl ketone is 
added and the mixture heated to reflux, with stirring. After refluxing for 
18 hours, the reaction mixture is cooled to room temperature and the 
solvents removed in vacuo. The residue is partitioned between ethyl ether 
and dilute sodium hydroxide. The ethereal layer is separated and extracted 
with dilute hydrochloric acid. This results in the formation of a solid 
precipitate. The ethereal layer and the solid precipitate are extracted 
with water and this water extract combined with the dilute hydrochloric 
acid extract. These combined extracts are basified with aqueous sodium 
hydroxide to liberate an oil. The oil is extracted into an ether layer 
which is then washed three times with water, dried successively over 
anhydrous sodium sulfate and anhydrous potassium carbonate and treated 
with excess hydrogen chloride in isopropanol solution. The precipitate 
which results is filtered, air-dried and recrystallized from a mixture of 
ethanol and ether to afford 
2,2-diphenyl-4-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)-butyronitrile 
hydrochloride. This compound melts at about 245.degree.-247.degree. C. 
Treatment of the above hydrochloride salt with aqueous sodium hydroxide, 
followed by extraction into ethyl ether and stripping of the solvents in 
vacuo affords the free base, 
2,2-diphenyl-4-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. 
This compound is represented by the following structural formula. 
##STR18## 
EXAMPLE 17 
A solution of 2.0 parts 
2,2-diphenyl-4-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 
0.51 parts sodium azide, 0.42 part ammonium chloride, 0.01 part lithium 
chloride and 9.5 parts dimethylformamide is heated with stirring at about 
163.degree. C. (oil bath temperature) for 18 hours under a nitrogen 
atmosphere. The reaction mixture is cooled to room temperature and the 
resulting solid precipitate is filtered, washed, and air-dried to afford 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-te 
trazole. This compound melts at about 285.degree.-286.degree. C. with gas 
evolution and is represented by the following structural formula. 
##STR19## 
EXAMPLE 18 
0.53 Part of 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]1H-tet 
razole is suspended in a solution of 2.3 parts by volume acetic anhydride 
in 5 parts dry pyridine and the suspension refluxed for approximately two 
hours under a nitrogen atmosphere. After cooling, the solvents are removed 
in vacuo. The residual gum is dissolved in water, strongly basified with 
aqueous potassium carbonate, saturated with sodium chloride and extracted 
four times with portions of ethyl ether. The ethereal extracts are 
combined, dried over anhydrous sodium sulfate and stripped in vacuo to 
afford, as brown gum, 
5-[1,1-diphenyl-3-(exo-5-acetoxy-2-azabicyclo[2.2.2]-oct-2-yl)propyl]-2-me 
thyl-1,3,4-oxadiazole. This compound is represented by the following 
structural formula. 
##STR20## 
EXMPLE 19 
0.57 Part of 
5-[1,1-diphenyl-3-(exo-5-acetoxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-met 
hyl-1,3,4-oxadiazole is dissolved in 15 parts methanol, diluted with 8 
parts by volume of a 20% sodium hydroxide solution and cooled for 48 
hours. The solvents are then stripped in vacuo and the resulting gum 
partitioned between water and ether five times. The ether extracts are 
combined, dried over anhydrous sodium sulfate, and reduced in volume in 
vacuo to about 30 ml. Cooling of this solution results in a white 
crystalline precipitate which is filtered, washed with ethyl ether, and 
dried to afford 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]-oct-2-yl)propyl]-2-me 
thyl-1,3,4-oxadiazole. This compound melts at about 123.degree.-125.degree. 
C. and is represented by the following structural formula. 
##STR21## 
EXAMPLE 20 
Repetition of the procedure detailed in the first paragraph of Example 16 
using an equivalent quantity of endo2-azabicyclo[2.2.2.]octan-5-ol 
hydrochloride in place of the exo-2-azabicyclo[2.2.2]octan-5-ol 
hydrochloride affords 
2,2-diphenyl-4-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile 
hydrochloride, as a tan solid melting at about 200.degree.-203.degree. C. 
The free base of this compound, i.e., 
2,2-diphenyl-4-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 
is obtained in the same manner as detailed in the second paragraph of 
Example 6. 
EXAMPLE 21 
Using an equivalent quantity of 
2,2-diphenyl-4-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 
the procedure of Example 17 is repeated to afford 
5-[1,1-diphenyl-3-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2yl)-propyl]-1H-t 
etrazole melting at about 294.degree.-295.degree. C. with gas evolution. 
EXAMPLE 22 
When an equivalent quantity of 
5-[1,1-diphenyl-3-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-t 
etrazole is substituted for the 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl) 
propyl]-1H-tetrazole of Example 18, and the procedure detailed therein 
substantially repeated, there is obtained 
5-[1,1-diphenyl-3-(endo-5acetoxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-met 
hyl-1,3,4-oxadiazole melting at about 147.degree.-149.degree. C. after 
recrystallization from ethyl ether. 
EXAMPLE 23 
0.18 Part of 
5-[1,1-diphenyl-3-(endo-5-acetoxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]2-met 
hyl-1,3,4-oxadiazole is dissolved in 5 parts of boiling methanol. After 
cooling in an ice-bath, 2.1 parts by volume of a 20% sodium hydroxide 
solution is added and the mixture allowed to stand for 15.5 hours at room 
temperature. The resultant crystals are then filtered, washed with 
methanol and dried in vacuo to afford white needles. Recrystallization 
from ethyl ether yields 
5-[1,1-diphenyl-3-(endo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)-propyl]-2-m 
ethyl-1,3,4-oxadiazole melting at about 105.5.degree.-108.degree. C. This 
compound is represented by the following structural formula. 
##STR22## 
EXAMPLE 24 
A solution of 21.0 parts 2,2-diphenyl-4-bromobutyronitrile and 8.9 parts 
endo-2-azabicyclo[2.2.2]oct-6-ol in 55 parts dimethylsulfoxide is heated 
on a steam bath for about 16 hours. Then, the solution is cooled, poured 
over chipped ice and water, strongly basified with aqueous sodium 
hydroxide, and extracted with methylene chloride. The methylene chloride 
extract is dried over anhydrous sodium sulfate and stripped in vacuo to 
give a brown gum. The gum is dissolved in ether and the insoluble material 
removed by filtration. The filtrate is then treated with a solution of 
hydrogen chloride in isopropanol. The resultant precipitate is filtered, 
washed, and air dried to yield an off-white solid. Recrystallization of 
this solid from an ethanol-ether mixture affords 
2,2-diphenyl-4-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile 
hydrochloride hemihydrate. This compound melts at about 
181.degree.-184.degree. C. and is represented by the following structural 
formula. 
##STR23## 
Treatment of the above hydrochloride salt with aqueous sodium hydroxide, 
followed by extraction into ethyl ether and stripping of the solvents in 
vacuo affords the free base, 
2,2-diphenyl-4-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. 
EXAMPLE 25 
Substitution of an equivalent quantity of 
2,2-diphenyl-4-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile 
in the procedure of Example 17 affords 
5-[1,1-diphenyl-3-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-t 
etrazole. This compound melts at about 277.degree.-278.degree. C. with gas 
evolution. 
EXAMPLE 26 
When an equivalent quantity of 
5-[1,1-diphenyl-3-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-t 
etrazole is substituted for the 
5-[1,1-diphenyl-3-(exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-te 
trazole of Example 18, and the procedure detailed therein substantially 
repeated, there is obtained, as a gum, 
5-[1,1-diphenyl-3-(endo-6-acetoxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-me 
thyl-1,3,4-oxadiazole. 
EXAMPLE 27 
0.10 Part of 
5-[1,1-diphenyl-3-(endo-6-acetoxy-2-azabicyclo[2.2.2]oct-2yl)propyl]-2-met 
hyl-1,3,4-oxadiazole is dissolved in 5 parts methanol and treated with 1.5 
parts by volume of a 20% sodium hydroxide solution. After standing for 11 
days, the solution is neutralized with acetic acid and stripped in vacuo. 
The residue is then suspended in dilute sodium hydroxide and extracted 
into ethyl ether. The ethereal extract is dried over anhydrous sodium 
sulfate and stripped in vacuo to afford, as a gum, 
5-[1,1-diphenyl-3-(endo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-me 
thyl-1,3,4-oxadiazole. This compound is represented by the following 
structural formula. 
##STR24## 
EXAMPLE 28 
Repetition of the procedure detailed in the first paragraph of Example 24 
using an equivalent quantity of exo-2-azabicyclo[2.2.2]octan-6-ol in place 
of the endo-2-azabicyclo[2.2.2]oct-6-ol affords 
2,2-diphenyl-4-(exo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile 
hydrochloride. 
The free base of this compound is obtained in the same manner in the second 
paragraph of Example 24. 
EXAMPLE 29 
Using an equivalent quantity of 
2,2-diphenyl-4-(exo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 
the procedure of Example 17 is repeated to yield 5-[1,1 
-diphenyl-3-[exo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazol 
e. 
EXAMPLE 30 
When an equivalent quantity of 
5-[1,1-diphenyl-3-[exo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-te 
trazole is substituted for the 
5-[1,1-diphenyl-3-[exo-5-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-te 
trazole of Example 18, and the procedure detailed therein substantially 
repeated, there is obtained 
5-[1,1-diphenyl-3-(exo-6-acetoxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-met 
hyl-1,3,4-oxadiazole. 
EXAMPLE 31 
Repetition of the procedure of Example 27 using 
5-[1,1-diphenyl-3-(exo-6-acetoxy-2-azabicyclo[2.2.2]oct-2-yl)-propyl]-2-me 
thyl-1,3,4-oxadiazole affords 
5-[1,1-diphenyl-3-(exo-6-hydroxy-2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-met 
hyl-1,3,4-oxadiazole. This compound is represented by the following 
structural formula. 
##STR25##