2-Alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides having the formula ##STR1## wherein X is oxygen or sulfur; R.sub.1 is loweralkyl; and R.sub.2 is selected from the group consisting of hydrogen, halo, 4,5-benzo, alkoxy or Am and n is 1 or 2, and the pharmaceutically acceptable acid addition salts thereof having gastrokinetic and anti-emetic activity are disclosed.

BACKGROUND OF THE INVENTION 
1. Field of Invention. 
The present invention relates to certain novel 
N-(3-quinuclidinyl)benzamides and thiobenzamides; namely, the 
2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides 
which exhibit gastrokinetic and anti-emetic properties in warm blooded 
animals with minimal neuropharmacological side effects. The invention is 
also concerned with methods of and compositions for increasing gastric 
emptying and alleviating emesis, particularly emesis due to administration 
of platinum anticancer drugs such as cisplatin. 
2. Information Disclosure Statement. 
Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. 
E. et al as reported in Khim-Farmatsevt, Zh. 10. No. 11, 56-60 (1976); 
C.A. 86 : 155489r exemplified by the compound: 
5-aminosulfonyl-N-[1-azabicyclo [2.2.2]oct-3-yl)-2-methoxybenzamide. This 
compound and others in the series were reported by the authors not to have 
antiemetic activity. The above named compound was reported in USSR Pat. 
No. SU-414-261 to have neuroleptic activity. In comparison, the compounds 
of the present invention show strong gastrokinetic and antiemetic activity 
without neuroleptic activity {blockade of d-amphetamine lethality in 
mice). 
Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamide and 
N-[1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. 
et al in Khim-Farmatsevt. Zh. 7, 20-24 (1974); C.A. 79, 146358a and the 
latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); 
C.A. 65: 2220b. These compounds were reported to exhibit hypotensive, 
narcotic and ganglionic stimulation and blocking activities, properties 
not seen in the compounds of the present invention. 
Synthesis of 
4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid 
e was reported in Ger. Offen. No. 2,548,968; C.A. 87, 68001c and in 
equivalently related U.S. Pat. No. 4,093,734 from 
4-amino-3-chloro-5-trifluoromethyl benzoic acid chloride and 
3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and 
piperidinyl benzamides which are said to be useful as anxiolytics, 
anticonvulsives, antiemetics and antiulcerogenics. None of the compounds 
have orthoalkoxy substitution on benzamide as do the compounds of the 
present invention. 
It is widely recognized that substituted benzamides are a class of drugs 
known to be effective in psychiatry and gastroenterology (Sulpiride and 
other Benzamides; International Workshop on Sulpiride and other 
benzamides, Florence, Feb. 17-18 (1978), Raven Press]. However, the 
2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides of this invention 
exhibit effects only on gastrointestinal motility and do not show 
neuropharmacological activity. This is in marked contrast to the compounds 
described in the prior art which show a range of pharmacological 
activities that include both neuropharmacological and gastrointestinal 
effects. 
SUMMARY OF THE INVENTION 
The novel 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamides and 
thiobenzamides of this invention have the formula: 
##STR2## 
wherein X is oxygen or sulfur, R.sub.1 is loweralkyl and R.sub.2 is 
selected from the group consisting of hydrogen, halo, 4,5-benzo, alkoxy or 
Am wherein Am is selected from amino, methylamino or dimethylamino, and n 
is 1 or 2, and the pharmaceutically acceptable acid addition salts 
thereof. 
In the further definition of symbols in the formulas hereof and where they 
appear elsewhere throughout this specification and the claims, the terms 
have the following significance. 
The term "loweralkyl" as used herein includes straight and branched chain 
radicals of up to eight carbons inclusive and is exemplified by such 
groups as methyl, ethyl, propyl, isopropyl, butyl, amyl, hexyl, heptyl, 
and octyl radicals and the like. The term "loweralkyl" has the 
formula--0--loweralkyl. 
The terms "halo" or "halogen" when referred to herein include fluorine, 
chlorine, bromine and iodine unless otherwise stated. 
"Pharmaceutically acceptable acid addition salts" include the acid addition 
salts, hydrates, alcoholates and salts of the compounds of Formula which 
are physiologically compatible in warm blooded animals. The acid addition 
salts may be formed by either strong or weak acids. Representative of 
strong acids are hydrochloric, sulfuric and phosphoric acids. 
Representative of weak acids are fumaric, maleic, succinic, oxalic, 
citric, tartaric, cyclohexamic and the like. 
Protected amino groups used in synthesis are acetylamino or benzoylamino 
radicals and the like on the benzamide moiety mentioned hereinbelow in 
synthetic methods. 
The gastric emptying activity was determined by the method of Droppleman, 
D., Gregory, R., and Alphin, R., J. Pharmacological Methods 4(3) 227-30 
(1980) wherein the rate of emptying of a test meal in rats compared to 
controls was observed. Indicative of the activity of two preferred 
compounds of Examples 1 and 3 are the results obtained by intraperitoneal 
administration of 1.0 mg/kg which significantly increased gastric emptying 
(as determined by the Student t-test) 60 minutes after feeding the test 
meal by 49% and 61% respectively. 
Anti-emetic properties are exhibited in the compounds when tested by the 
procedure of Chen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 (1950) and 
Leonard, A. et al., J. Pharmac. Exp. Ther. 154, 339-345 (1966). 
Anti-emetic properties in the control of emesis due to administration of 
platinum anti-cancer drugs were determined by a modification of the method 
described by Gylys, J. A., in Res. Commun. Chem. Pathol. Pharmacol. 23, 
No. 1, January 1979, pp 61-68 as follows: cisplatin 
(cis-diamminedichloro-platinum) is administered at a dose of 3 mg/kg 
intravenously to non-fasted dogs (both sexes). Ninety minutes after 
cis-platinum administration, the test drug in saline at a dose volume of 2 
ml/kg is administered intravenously. A control group of dogs are given the 
cisplatin followed by saline at 90 min without test drug. The dogs are 
observed continuously for a period of 5 hr counting the number of emetic 
episodes compared to emetic episodes observed for the controls. Utilizing 
this procedure, the two compounds of Examples 1 and 3, preferred for 
control of emesis due to cisplatin administered in a single dose of 1 
mg/kg gave 68% and 94% reduction in the number of emetic episodes 
respectively. 
It is therefore a primary object to provide novel 
2-alkoxy-N-[1-azabicyclo[2.2.2]oct-3-yl-benzamides and thiobenzamides. 
A further object is to provide 2-alkoxy-N-(1-azabicyclo 
[2.2.2]oct-3-yl-benzamides and thiobenzamides having antiemetic and 
gastric-emptying enhancement properties. 
A still further object is to provide means for controlling violent emetic 
episodes due to administration of platinum anticancer drugs. 
An additional object is to provide novel compositions useful as 
anti-emetics generally and specifically in combination with platinum 
anticancer drugs and compositions for controlling gastric emptying. 
DETAILED DESCRIPTION OF THE INVENTION 
Preparation of Benzamides 
The benzamido compounds of Formula I are prepared by reacting a suitably 
activated benzoic acid derivative with 3-aminoquinuclidine to form the 
corresponding benzamide under a variety of conditions. Two general 
methods, A and B, are illustrated in the following equations: 
Method A, using an Acid Chloride 
##STR3## 
R.sub.1, R.sub.2 and n are as defined under Formula I except R.sub.2 
cannot be unprotected amino. 
(a) Suitable solvents are chloroform and diethyl ether. 
Method A is illustrated by Examples 5, 6, 7 and 9. 
Method B, using 1,1'-Carbonyldiimidazole 
##STR4## 
R.sub.1, R.sub.2 and n are as defined under Formula I. (a) e.g., 
tetrahydrofuran. 
Method B is illustrated in Examples 1, 3 and 8. 
Compounds wherein R.sub.2 is primary amino may also be prepared from a 
compound prepared by Methods A or B, wherein R.sub.2 is nitro by catalytic 
reduction of the nitro compound. 
Alternatively, compounds wherein R.sub.2 is amino may be prepared by 
procedures of Method A utilizing a starting benzoyl halide wherein the 
amino group has been protected, or they may be prepared from compounds 
prepared in Methods A or B wherein R.sub.2 is nitro and reducing the nitro 
radical to an amino radical. 
Preferably, the compounds wherein R.sub.2 is amino or methylamino are 
prepared by Method B. 
The free base of any compound of Formula I from its acid addition salt may 
be regenerated by usual procedures of partitioning between dilute aqueous 
base and a suitable solvent, separating the solvent layer, drying and 
evaporating. 
Preparation of Thiobenzamides 
The preparation of the thiobenzamido compounds of Formula II may be 
accomplished by mixing and reacting a benzamido compound of Formula I with 
a mixture of phosphorus pentasulfide (P.sub.2 S.sub.5) and potassium 
sulfide (K.sub.2 S) or by mixing and reacting 3-aminoquinuclidine with an 
appropriately substituted benzaldehyde and sulfur. The reaction sequences 
are illustrated by the following: 
##STR5## 
In these methods, compounds wherein R.sub.2 is nitro may be reduced to 
compounds wherein R.sub.2 is amino. 
A preferred group of compounds encompassed by Formula I have the formula: 
##STR6## 
wherein Am is amino (i.e., --NH.sub.2) or methylamino. The compounds are 
highly potent as gastric emptiers and as anti-emetics in conjunction with 
cisplatin cancer treatment, being more potent than metoclopramide and 
devoid of undesirable neuroleptic side effects even at much higher doses 
than required for their gastric emptying and anti-emetic effects. As will 
be recognized from the above description, these compounds (Ic) are 
preferably prepared by Method B.

The following examples are provided merely by way of illustrating the 
methods of preparation and compounds and are not to be construed as being 
limiting in nature. 
EXAMPLE 1 
4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, 
fumarate 1:1]. 
In a closed system equipped with an oil bubbler, 30 ml of tetrahydrofuran 
was added to a mixture of 4-amino-5-chloro-2-methoxybenzoic acid, 2.02 g, 
(0.010 mole, and 1,1'carbonyldiimidazole, 1.62 g (0.010 mole) with 
stirring. When evolution of carbon dioxide ceased, nitrogen was bubbled 
through the reaction mixture for 1 hr. A solution of 3-aminoquinuclidine, 
1.26 g, (0.010 mole) in 10 ml tetrahydrofuran was added dropwise to the 
stirred reaction mixture and stirring at room temperature continued for 3 
hrs. TLC analysis (3% conc. ammonium hydroxide solution in methanol) 
showed some product formation. The mixture was heated at reflux 
temperature for 18 hours and then concentraded to an oil. TLC analysis 
showed the presence of the product, imidazole, and 3-aminocuinuclidine. 
The oil was dissolved in methylene chloride (75 ml) and washed twice with 
50 ml portions of aqueous sodium bicarbonate solution. The methylene 
chloride layer was dried over anhydrous magnesium sulfate and concentrated 
to yield 2.0 g (67%) of a glassy amorphous solid, the free base of the 
title compound. 
In another reaction on a 0.020 mole scale, 5.18 g (83.8%) of the product as 
the free base was obtained. 
The products were combined, dissolved in methanol (20 ml) and the solution 
and treated with a solution of fumaric acid (2.73 g) in methanol (50 ml). 
Absolute ether was added to precipitate the salt which was collected by 
filtration and recrystallized from methanol-water (200:20) with isopropyl 
ether added to the point of incipient cloudiness. The recrystallized salt 
(5.38 g) melted at 223.degree.-225.degree. C. 
Analysis: Calculated for C.sub.19 H.sub.24 N.sub.3 O.sub.5 Cl: C,53.59; 
H,5.68; N,9.89. Found: C,53.35; H,5.72; N,9.95. 
EXAMPLE 2 
4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide, 
hydrochloride, hydrate (1:1:1) 
To an isopropyl alcohol solution of the free base of the title compound 
such as was obtained by the procedure of Example 1 is added an equal molar 
amount of 37% (conc.) hydrochloric acid. The crude salt is separated by 
filtration and recrystallized from acetone-water to give the title 
compound, m.p. 158.degree.-160.degree. C. 
EXAMPLE 3 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide, 
fumarate [1:1]. 
To a mixture of 1,'-carbonyldiimidazole, 1.23 g (0.00756 mole) and 
5-chloro-2-methoxy-4-methylaminobenzoic acid, 1.63 g (0.00756 mole) was 
added 50 ml of tetrahydrofuran. Nitrogen was bubbled into the solution for 
30 minutes to remove any carbon dioxide that was present. To the solution 
was added 3-aminoquinuclidine, 0.95 g, (0.00756 mole) in one portion, and 
the reaction mixture was stirred at ambient temperature for 16 hours. The 
reaction mixture was concentrated to an oil which was shown to be 1:1 
mixture of the free base of the product and imidazole. The mixture was 
dissolved in 20 ml methanol and treated with a solution containing 0.47 g 
fumaric acid in 20 ml of hot methanol. Upon cooling, 1.52 g of white solid 
formed. Recrystallization from water-methanol gave 0.84 g of the product 
as a white solid; m.p. 237.degree.-238.degree. C. 
Analysis: Calculated for C.sub.20 H.sub.26 N.sub.3 O.sub.6 Cl: C,54.61; 
H,5.96; N,9.55. Found: C,54.61; H,5.98; N,9.51. 
EXAMPLE 4 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxy-4-(methylamino)-benzamid 
e, hydrochloride (1:1) 
To an isopropyl alcohol solution of the free base of the title compound, 
such as was obtained by the procedure of Example 3, is added an equal 
molar amount of 37% (conc.) hydrochloric acid. The crude salt is separated 
by filtration and recrystallized from ethanol-water to give the title 
compound, m.p. 225.degree.-258.degree. C. 
EXAMPLE 5 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide, fumarate 
[1:]hemihydrate 
In a closed system equipped with an oil bubbler, a solution of 
2-methoxybenzoyl chloride, 2.76 g (0.0016 mole) in 50 ml absolute ether 
was added dropwise over 10 min to a stirred solution of 
3-aminoquinuclidine, 1.81 g (0.0144 mole) in 100 ml absolute ether. After 
the addition was completed, the mixture was stirred at room temperature 
for an additional 2 hrs. The solid hydrochloride salt was collected by 
filtration under nitrogen. The salt (3.83 g) was dissolved in sodium 
bicarbonate solution and extracted twice with 25 ml portions of methylene 
chloride. The extract was dried over magnesium sulfate and concentrated to 
yield 1.25 g clear oil (33.3%). TLC analysis (3% conc. ammonium hydroxide 
in methanol) showed the free base to be pure. A solution of 1.17 g of the 
free base in 5 ml methanol was treated with a solution of 0.52 g fumaric 
acid in 10 ml methanol. Isopropyl ether was added to give approximately 
100 ml of solution from which the fumarate salt precipitated. The salt was 
collected under nitrogen and dried in a vacuum oven at 60.degree. C. 
overnight. NMR and elemental analyses showed that the product was a 
hemihydrate. Analysis: Calculated for C.sub.19 H.sub.25 N.sub.2 O.sub.6.5 
: C,59.21; H,6.54; N,7.27. Found: C,59.18; H,6.30. n,7.25. 
EXAMPLE 6 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide hydrochloride [1:1] 
A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.0349), 
2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole). anhydrous sodium 
carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was 
stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The 
chloroform layer was then separated, washed with water, dried over 
anhydrous magnesium sulfate, and concentrated to an impure oil. The oil 
was triturated twice with 20 ml portions of petroleum ether to remove some 
impurities. The oil was then dissolved in ether and filtered to remove a 
small amount of insoluble material. The filtrate was treated with ethereal 
hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% 
yield) white solid. The salt was recrystallized from ethanol-isopropyl 
ether. Further recrystallization from methanol-ethyl ether yielded a white 
solid, m.p. 211.degree.-212.degree. C. The NMR analysis was satisfactory. 
Analysis: Calculated for C.sub.16 H.sub.23 N.sub.2 O.sub.3 Cl: C,58.80; 
H,7.09; N,8.57. Found: C,58.38; H,7.13; N,8.44. 
EXAMPLE 7 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide, sulfate [1:1] 
In a closed system equipped with an oil bubbler, a solution of 
2,4-dimethoxybenzoyl chloride, 13.08 g, (0.0652 mole) in 200 ml absolute 
ether was added dropwise over 30 minutes to a stirred solution of 
3-aminoquinuclidine, 7.80 g, (0.0619 mole) in 200 ml absolute ether. The 
mixture was stirred overnight, and the solid hydrochloride salt of the 
product was filtered under nitrogen. The material was dried in a vacuum 
oven at 40.degree. C. to give 18.70 g (92%). A 2.94 g (0.009 mole) portion 
of the hydrochloride salt in 20 ml methanol was treated with a solution of 
sodium methoxide prepared from 0.23 g (0.010 mole) sodium metal and 10 ml 
methanol. After standing a few minutes, the mixture was filtered and the 
filtrate concentrated on a rotary evaporator, and the residue was 
triturated with 75 ml methylene chloride. After filtering to remove some 
insuluble solids, the filtrate was concentrated to yield 2.53 g of the 
free base of the title compound (97% recovery from the hydrochloride 
salt). The free base was dissolved in 100 ml acetone and concentrated 
sulfuric acid (0.483 ml) added dropwise with stirring. The solid that 
formed was collected under nitrogen to give 2.76 g of the salt which 
recrystallized from methanol-isopropyl ether and dried in a vacuum oven at 
60.degree. C. for 2 hrs and then overnight at 78.degree. C.; m.p. 
223.degree.-225.degree. C. 
Analysis: Calculated for C.sub.16 H.sub.24 N.sub.2 O.sub.7 S: C,49.47; 
N,7.23. Found: C,49.41; H,6.30; N,7.25. 
EXAMPLE 8 
N-(1-Azabicvclo[2.2.2]oct-3-yl)-2.4-dimethoxvbenzamide, fumarate [1:1.5] 
In a closed system equipped with an oil bubbler, tetrahydrofuran, 100 ml, 
was added to a mixture of 2,4-dimethoxybenzoic acid, 3.64 g (0.020 mole) 
and 1,1'carbonyldimidazole, 3.24 g (0.020 mole). No evolution of carbon 
dioxide was observed and after stirring for 3 hrs, TLC (ethyl acetate) and 
mass spectral analysis showed that the starting material had reacted to 
form (2,4-dimethoxybenzoyl) imidazole and imidazole. A solution of 
3-aminoquinuclidine, 2.52 g (0.020 mole) in 10 ml tetrahydrofuran was 
added to the mixture, and the solution was heated to reflux temperature 
for 1 hr and then allowed to stand overnight at room temperature. A 
solution of fumaric acid, 2.32 g (0.020 mole) in 50 ml methanol was added 
to the reaction mixture. Tetrahydrofuran was added until the solution 
became slightly turbid. The solution was chilled in a refrigerator. The 
solid which precipitated from solution was collected by filtration and 
found to be a fumarate salt of 3-aminoquinuclidine. The filtrate was 
concentrated to an oil and triturated with tetrahydrofuran. The solid 
precipitate which formed on standing was filtered and shown by TLC (3% 
concentrated ammonium hydroxide in methanol) to be the desired product 
plus traces of imidazole and 3-aminoquinuclidine. Recrystallization from 
methanol-iropropyl ether gave 5.41 g white crystalline solid (67% yield 
calculated as the monofumarate). NMR and elemental analysis showed the 
salt to contain less than one equivalent of fumaric acid. The salt was 
dissolved in boiling methanol (50 ml) and treated with an additional 0.77 
g (0.0066 mole) fumaric acid in 10 ml hot methanol. Isopropyl ether was 
added until the hot solution became turbid. The solid obtained on cooling 
was collected, recrystallized from methanol-isopropyl ether and dried in a 
vacuum oven at 78.degree. C. overnight. NMR and elemental analysis showed 
the salt to be a 1.5 fumarate, m.p. 192.degree.-192.5.degree. C. 
Analysis: Calculated for C.sub.22 H.sub.28 N.sub.2 O.sub.9 : C,56.89; 
H,6.08; ,6.03. Found: C,56.81; H,6.13; N,6.04. 
EXAMPLE 9 
N-[1-Azabicyclo[2.2.2]oct-3-yl)-2-propoxybenzamide hydrochloride [1:1] 
To a solution of 3.82 g (0.0192 mole) of 3-amino quinuclidine 
dihydrochloride in about 25 ml of carbon dioxide-free water was added 8 g 
(0.025 mole) of barium hydroxide octahydrate. The mixture was warmed for 5 
minutes and then dried to a powder on a rotary evaporator. While 
protecting from contamination with carbon dioxide in the atmosphere, the 
powder was extracted in sequence with hot benzene and a 1:1 mixture of 
benzene-methylene chloride solution. The combined extracts were dried over 
magnesium sulfate and the mixture filtered. To the filtrate with agitation 
was added dropwise a solution of 3.4 g (0.0171 mole) of 2-propoxybenzoyl 
chloride in 50 ml of methylene chloride. The mixture was warmed on a steam 
bath to evaporate about 75% of the methylene chloride. Ligroin (60-110) 
was added and the mixture solidified. The solid was recrystallized from 
anhydrous ethyl alcohol to give 3.9 g (62.0%), m.p. 
210.degree.-211.degree. C. 
Analysis: Calculated for C.sub.17 H.sub.25 N.sub.2 O.sub.2 Cl: C,62.86; 
H,7.75; N,8.62. Found: C,62.62; H,7.59; N,8.54. 
EXAMPLE 10 
N-(1-Azabicyclo[2.2.2]oct-3-yl)-3-methoxy-2-naphthalenecarboxamide, 
hydrochloride [1:1] 
A solution of 1.69 g (0.00768 mole) of 3-methoxy-2-naphthoic acid chloride 
in 15 ml of methylene chloride was added dropwise to a stirred solution of 
0.97 g (0.00768 mole) of 3-aminoquinuclidine in 25 ml of methylene 
chloride in a closed system equipped with an oil bubbler. The reaction 
mixture was stirred overnight at ambient temperature, and then 
concentrated to give an off-white glassy solid. Two recrystallizations 
from methanol-isopropyl ether gave 1.95 g (73.4%) of the product as an 
off-white solid which was vacuum dried at ambient temperature, m.p. 
248.degree.-252.degree. C. Analysis: Calculated for C.sub.19 H.sub.23 
N.sub.2 O.sub.2 Cl: H,6.68; N,8.08. Found: C,65.40; H,6.72; N,8.01. 
EXAMPLE 11 
4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxythiobenzamide 
fumarate. 
One half mole of 
4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide 
fumarate is partitioned between dilute sodium hydroxide and 400 ml of 
benzene. The benzene solution is dried with sodium sulfate and distilled 
to a volume of 250 ml. To this is added a finely-ground mixture of 9 g of 
phosphorous pentasulfide and 9 g of potassium sulfide. The mixture is 
refluxed for 4 hr. and an additional 9 g of phosphorous pentasulfide is 
added and reflux continued for 2 hr. The benzene is decanted off. The 
solid is dissolved in a suitable solvent and reacted with fumaric acid to 
give the title compound. 
Pharmaceutical Methods and Compositions 
Generally, the method of controlling emesis and gastric emptying in 
accordance with this invention comprises administering internally to warm 
blooded animals including human beings certain 2-alkoxy-N-[1-azabicyclo[2 
2.2]oct-3-yl)benzamides and thiobenzamides of Formula I, preferably 
Formula Ic, or a non-toxic organic or inorganic acid addition salt thereof 
in a wide variety of pharmaceutical forms well known in the art, 
preferably with a non-toxic pharmaceutical carrier such as is described 
below in an amount to control emesis and/or facilitate gastric emptying. 
The active agent is administered orally, subcutaneously, intravenously or 
intramuscularly or parenterally and, if necessary, in repeated doses until 
satisfactory response is obtained. The daily dosage is from about 5 to 
about 300 mg of active medication, advantageously from about 5 mg to 50 
mg. Co-administration of the compounds of Formula I and the platinum drug 
is within the purview of the method of this invention. 
In the particular method of controlling emesis due to administration of 
platinum drugs in cancer treatment, it may at times be desirable to 
administer a mixture comprised of compounds of Formula I. preferably Ic, 
and the platinum drug to the animal, including humans, the daily dosage 
being within the range cited above. 
The pharmaceutical compositions for general use as antiemetics and gastric 
emptyiers of this invention comprise at least one of the compounds of 
Formula I, preferably Formula Ic above, as active ingredients in an amount 
to provide effective antiemetic or gastric emptying action. The 
compositions contain 0.05 to 100 mg active medicament per unit dose. 
Preferably, the compositions contain from about 5 mg to 100 mg of 
medicament, advantageously from about 5 mg to about 50 mg per unit dose. 
The compounds are thus presented in a therapeutic composition suitable for 
oral, parenteral, subcutaneous, intramuscular, intraperitoneal or 
intravenous administration. Thus, for example, compositions for oral 
administration can take the form of elixirs, capsules, tablets or coated 
tablets containing carriers conveniently used in the pharmaceutical art. 
Exemplary of solid carriers including tableting and capsulating excipients 
are lactose, sucrose, potato and maize starches, talc, gelatin, agar, 
pectin or acacia, stearic and silicic acids, magnesium stearate, terra 
alba and polyvinyl pyrrolidone. 
For parenteral administration, the carrier or excipient can be comprised of 
a sterile parenterally acceptable liquid; e.g., water or arachis oil 
contained in ampoules. 
The pharmaceutical compositions for use in conjunction with administration 
of platinum drugs in cancer treatment will be formulated to contain from 
about 0.1 mg/kg to about 3.0 mg/kg body weight, preferably 1.0 mg/kg body 
weight or less. As stated above, co-formulation of platinum anti-cancer 
drug and compounds of Formula I are within the scope of this invention and 
it is only necessary that the active ingredient of Formula I constitute an 
effective amount. 
In all of the above, it is only necessary that a suitable effective dosage 
will be consistent with the dosage form employed. The exact individual 
dosages, as well as daily dosages, will of course be determined according 
to standard medical principles under the direction of a physician or 
veterinarian. Generally, the pharmacology tests on rats in comparison to 
metoclopramide suggests that much less of the active agent selected from a 
compound of Formula Ic would be required for a given antiemetic effect or 
gastric emptying effect than would be required for metaclopramide and 
dosages can thereby be estimated to some extent. 
The principles, preferred embodiments and modes of operation of the present 
invention have been described in the foregoing specification. The 
invention which is intended to be protected herein, however, is not to be 
construed as limited to the particular forms disclosed, since these are to 
be regarded as illustrative rather than restrictive. Variations and 
changes may be made by those skilled in the art without departing from the 
spirit of the invention, and it is therefore understood that the invention 
is to be limited only by the scope of the appended claims.