Method of increasing gastrointestinal motility with substituted benzamides

The present invention relates to the use of substituted benzamides of formula (1): ##STR1## in which: A is linear or branched C.sub.1 -C.sub.3 alkyl; allyl or diethylaminoethyl; PA0 R.sub.1 is hydrogen or methyl, and PA0 Z-- is --NH--, --O-- or --S--, and of their pharmacologically acceptable salts for modifying gastric motility.

BACKGROUND OF THE INVENTION 
Gastrointestinal motility, or the ability of the gastrointestinal tract to 
move matter spontaneously, may be of beneficial therapeutic value for a 
variety of obvious reasons. For example, the gastrointestinal disruptions 
characteristic of conditions such as symptomatic gastroesophageal reflux 
and diabetic gastroparesis (diabetic gastric stasis) may result in 
symptoms which may be detrimental to the patient, such as nausea, 
vomiting, heartburn, persistent fullness after meals and anorexia. Such 
symptoms may be alleviated by increasing gastrointestinal motility, with 
consequent benefit to the patient. In addition, increased gastrointestinal 
motility may prevent the nausea and vomiting associated with emetogenic 
cancer therapy, may be used to facilitate small bowel intubulation and to 
stimulate gastric emptying and intestinal transit to facilitate 
radiological examination. Accordingly, chemical compounds that can 
increase gastrointestinal motility have been sought for use as 
pharmaceutical agents in the treatment of the associated symptoms. For 
example, the compound 
N-(2-diethylaminoethyl)-2-methoxy-4-amino-5-chlorobenzamide, known 
generically as metoclopramide, is disclosed in U.S. Pat. No. 3,177,252. 
This compound is commercially available and has been employed by 
physicians to increase gastrointestinal motility. Nevertheless, new agents 
that possess similar utility, or agents that are more potent that 
metoclopramide in increasing gastrointestinal motility, are desirable. 
SUMMARY OF THE INVENTION 
The present invention concerns the pharmaceutical uses of the compounds 
represented by the following chemical formula I: 
##STR2## 
in which: A is linear or branched C.sub.1 -C.sub.3 alkyl; allyl or 
diethylaminoethyl; 
R.sub.1 is hydrogen or methyl and 
Z is --NH--, --O--or --S-- 
and their pharmacologically acceptable salts. 
The methods for preparation of the compounds of the invention are described 
in French Patent No. 2,592,042 and U.S. Pat. No. 4,835,172, issued May 30, 
1989 to Acher, et al., the disclosures of which are incorporated herein by 
reference. In such citations the compounds are said to be useful as 
activators of the central nervous system and as antidepressants. New and 
extensive studies, however, have demonstrated that, in addition to their 
action on the central nervous system, the compounds of the invention 
increase gastrointestinal motility, which was not foreseeable from the 
properties previously mentioned. 
In addition, such activity offers the advantage of leading to methods of 
improving gastrointestinal motility with compounds of greater potency than 
the conventionally used metoclopramide. The compounds may be administered 
in therapeutically effective amounts to patients, including lower animals 
and humans.

DETAILED DESCRIPTION OF THE INVENTION 
Typical compounds useful in the present invention include: 
Compound I, 
N-[2-(diethylamino)ethyl]-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)-amino 
]-5-chlorobenzamide. 
Compound II 
N-[2-(diethylamino)ethyl]-2-methoxy-4-[(4,5-dihydro-2-thiazolyl)amino]-5-ch 
lorobenzamide. 
Compound III 
N-[2-(diethylamino)ethyl]-2-methoxy-4-[(4,5-dihydro-2-oxazolyl)amino]-5-chl 
orobenzamide. 
Compound IV 
N-methyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino] 
-5-chlorobenzamide. 
Compound V 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-[(4,5-dihydro-1H-imidazol-2-yl)-amino 
]-5-chlorobenzamide. 
Compound VI 
N-ethyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chloro 
benzamide. 
Compound VII 
N-isopropyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl) 
amino]-5-chlorobenzamide. 
Compound VIII 
N-allyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chlorobenzamide 
. 
The preparation of Compounds I, II, III, VII and VIII is disclosed in the 
above-incorporated U.S. Pat. No. 4,835,172 issued May 30, 1989 in Examples 
I, XXXVII, XXXIX, XXXVI and XXXV, thereof, respectively. The synthesis of 
Compounds IV, V and VI is illustrated as follows: 
Synthesis of 
N-methyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chloro 
benzamide (Compound IV) 
150 ml of methanol and 2.3 g of sodium are introduced into a 500-ml 
three-necked flask. When all the sodium has been consumed, 26.95 g of 
2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chlorobenzoic acid 
were added. Discussion takes place, followed by crystallization. The 
solvent was driven off to dryness under vacuum and the crystals were then 
ground and introduced into a 500-ml three-necked flask with 100 ml of 
chloroform. 22 ml of thionyl chloride were poured slowly into the 
suspension. Gaseous evolution took place and the temperature rose to 
30.degree. C. The mixture was heated for 2 hours to 50.degree. C. and then 
cooled and the solvent was dried off. The residue was poured into 150 ml 
of 30% strength aqueous methylamine solution. After one hour's stirring, 
the product was drained, washed with water and dried at 70.degree. C. 
20.81 g of product (yield=73.7%) were obtained. 18.89 g of product were 
dissolved in 180 ml of water and 10 ml of acetic acid, treated with 
charcoal, filtered, precipitated with 25 ml of ammonia solution, drained, 
washed and dried at 70.degree. C. 17.5 g of product were obtained. An 
impurity estimated at 3% and traces of ester were detected by NMR. 16.5 g 
of product were dissolved under reflux in 215 ml of dimethylformamide, 
treated with charcoal, filtered while hot, crystallized when cold, 
drained, washed with dimethylformamide and then with water and dried. 13 g 
of product still containing an impurity were obtained. 
These 13 g were redissolved in 130 ml of water and 8 ml of acetic acid. The 
solution was filtered, and the precipitate obtained by adding 20 ml of 
ammonia solution was then drained, washed and dried at 70.degree. C. 
12.5 g of product (total yield=51.7%) were obtained. 
M.p. above 260.degree. C. 
Analysis: H.sub.2 O : 0.5%; Assay (corrected) : 98.8%; C1 (corrected) : 
12.63% (calculated: 12.54%); N (corrected) : 19.57% (calculated: 19.82%). 
The NMR and IR spectra were compatible with the expected structure. 
Synthesis of 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-[(4,5-dihydro-1H-imidazol-2-yl) 
amino]-5-chloro-benzamide (Compound V) 
Stage 1 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-isothio-cyano-5-chlorobenzamide 
hydrochloride 
57 g of N-[2-(diethylamino)ethyl]-2-hydroxy-4-amino-5-chlorobenzamide and 
300 ml of carbon tetrachloride were introduced into a 1-liter three-necked 
flask equipped with a stirrer, a thermometer, a condenser and a dropping 
funnel, and a solution of 20 ml of thiophosgene in 100 ml of carbon 
tetrachloride was then added. 
The mixture was brought to reflux for 3 hours with stirring and a solution 
of 8 ml of thiophosgene in 50 ml of carbon tetrachloride was then added. 
The mixture was left for a further 4 hours under reflux and then cooled to 
15.degree. C., and the product was drained washed twice with 50 ml of 
carbon tetrachloride and then three times with 50 ml of acetone and dried. 
68.63 g of product (yield=94%) were obtained. M.p. 153.degree. C. 
Stage 2 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-[N'-(2-aminoethyl)thioureido]-5-chlor 
obenzamide 
36.4 g of 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-isothiocyanato-5-chlorobenzamide 
hydrochloride, 200 ml of methylene chloride and 10 g of triethylamine were 
introduced into a beaker with stirring. The mixture was stirred for 15 
minutes and the salts formed were then filtered off. 
The filtrate was poured with stirring, in the course of 40 minutes, into a 
three-necked flask containing 15 g of ethylenediamine and 200 ml of 
isopropyl ether, the temperature being maintained below -10.degree. C. The 
mixture was stirred for 3 hours while the temperature was allowed to rise, 
and the precipitate was then filtered off. This precipitate was 
reintroduced into the flask. 200 ml of water were added, the mixture was 
stirred for 1 hour and the product was drained, washed with water and 
dried at 40.degree. C. 34.52 g of product (yield=89%) were obtained. 
M.p.=instantaneous decomposition at about 160.degree.-170.degree. C., the 
melting point then decreasing. 
Stage 3 
N-[2-(diethylamino)ethyl]-2-hydroxy-4-[(4,5-dihydro-1H-imidazol-2-yl) 
amino]-5-chlorobenzamide 
62 g of N-[2-(diethylamino)ethyl]-2-hydroxy-4-[N'-(2-aminoethyl) 
thioureido]-5-chlorobenzamide and 500 ml of ethyl carbonate were 
introduced into a 1-liter three-necked flask equipped with a stirrer, a 
thermometer and a condenser. 
The mixture was brought to reflux for 2 hours in an oil bath at 
155.degree.-160.degree. C. Vegetable charcoal was added, the mixture was 
left under reflux for a further 10 minutes and filtered while hot and the 
filter was washed twice with 50 ml of hot ethyl carbonate. 
The product was collected in a breaker with stirring. As cooling began, a 
grey gum adhered to the walls. The mass was transferred while still hot to 
another beaker and cooled to -10.degree. C. with stirring. 
The precipitate was drained, washed and stirred to a paste with 4.times.50 
ml of petroleum ether, then dried. 25.25 g of product containing 
impurities were obtained. 
24.8 g of product and 225 ml of butyl acetate were brought to reflux for 10 
minutes. The mixture was cooled to 0.degree.-5.degree. C. and the product 
was drained, washed and stirred to a paste with 4.times.50 ml of isopropyl 
ether, then dried. 17.5 g of product still containing an impurity were 
obtained. 17 g of product were taken up under reflux in 85 ml of butyl 
acetate, cooled to 5.degree. C., drained, washed and stirred to a paste 
with 4.times.40 ml of isopropyl ether and then dried. 
15.32 g of product were obtained. 9.6 g of product were dissolved under 
reflux in 300 ml of ethyl carbonate. The solution was treated with 
charcoal and then filtered. The crystals formed in the cold were drained, 
washed with ethyl ether and dried at 60.degree. C. under vacuum, then for 
72 hours at 80.degree. C. under vacuum. 
6 g of product (total yield=17.7%) were obtained. M.p. 151.degree. C.; m.p. 
205.degree. C. when recrystallized. 
Analysis: Cl : 10.27% (calculated: 10.02); Assay : 96%. 
The NMR spectrum was compatible with the expected structure. 
Synthesis of 
N-ethyl-2-methoxy-4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chlorobenzamid 
e (compound VI) 
56.7 g of methyl 2-methoxy 
4-[(4,5-dihydro-1H-imidazol-2-yl)amino]-5-chlorobenzoate, 100 ml of 
ethylene glycol and 200 ml of a 60% aqueous ethylamine solution were 
introduced in a 500 ml three-necked flask equipped with a stirrer, a 
thermometer and a condenser. The mixture was heated for 120 hours at 
75.degree. C. with stirring and 10 ml of soda lye was then added. The 
mixture was stirred for a further hour, then cooled. 
42.5 g of product (yield : 72%) were obtained, which were recrystallized in 
512 ml of methanol. The precipitate was drained, washed with methanol and 
dried at 75.degree.-80.degree. C. 
38.2 g of product were obtained, which were dissolved in 400 ml of water 
and acetic acid. The solution was filtered and the precipitate obtained by 
addition of ammonia solution was left to crystallize overnight in a 
refrigerator. The crystals were drained, washed with water and dried under 
vacuum on phosphorus pentoxide at 70.degree. C. 
34.5 g of product (yield of purification=80.7%) were obtained 
M.p.=237.degree. C. 
The NMR and IR spectra were compatible with the expected structure. 
The increased gastrointestinal motility achieved by the methods of this 
invention has been demonstrated in standard laboratory animals. The 
following experimental protocol was observed in vivo in the guinea pig, in 
order to compare the action of the compounds of the invention with that of 
metaclopramide, a reference product in this field. 
Feeding of the animals were interrupted 14 hours before measurement of 
gastric emptying. The experimentation was conducted under weak 
illumination, with the least possible noise and disturbances, solely by 
experimentors having daily contact with the guinea pigs and having 
sufficient initial training in handling the animals. The animals were then 
subjected to minimal stress. 
The measurement of gastric emptying was carried out by x-ray localization 
(50 KV, 30 mA, 0.5-0.8 s.), on Kodak plates (NS-2T, 13.times.18 cm) of 
barium sulfate spheroids (approximately 30, 1 mm in diameter) coated with 
polystyrene, which the guinea pigs were made to swallow by placing them in 
the back of the throat, in a solution of 0.2 ml of 1% 
carboxymethylcellulose with 0.05 ml of glycerine, so as to initiate rapid 
and voluntary deglutition. 
The passage of the spheroids was followed for 3 to 4 hours, the animals 
being placed in their customary cages for that time and taken out only 5 
minutes before x-ray exposure (at intervals of 30-60 minutes). During the 
x-ray procedure, the animals were placed in individual holding cages, 
keeping them comfortably in a stable position, the cage being sufficiently 
sized (33.times.15 cm and 13 cm high) so as to comfortably maintain a 450 
to 550 gram guinea pig between the padded walls, the animal being trained 
to enter the cage and remain there tranquilly and without stress. 
Gastric emptying was measured by the number of spheroids leaving the 
stomach. For each dose of product studied, 6 guinea pigs were used, and 
the responses were compared to those of guinea pigs receiving the 
appropriate vehicle. 
Compound (I) was studied at doses of 1 mg/kg and 0.01 mg/kg, Compounds (II) 
to (V) were studied at a dose of 1 mg/kg, the compounds (VI) to (VIII) at 
a dose of 5 mg/kg. Metoclopramide was evaluated at doses of 1 mg/kg and 5 
mg/kg. 
The results are recorded in graphic form in FIG. 1. The compounds according 
to the invention and metoclopromide were dissolved in distilled water and 
the doses are expressed as base. 
Administration intraperitoneally of metoclopramide and the compounds 
according to the invention caused an increase in gastric emptying as 
illustrated in FIG. 1 in immobilized guinea-pigs. 
This emptying is expressed, in FIG. 1 and Table 1, as a percentage of 
spheroids leaving the stomach. 
TABLE 1 
______________________________________ 
Gastric emptying as a function of time, in guinea-pigs, 
after i.p. administration of 1 mg/kg of compound 
Compound After 1 hour 
After 2 hours 
______________________________________ 
I 24 63 
II 12.5 60 
III 20 57 
IV 38 62 
V 32 55 
metoclopramide 16 39 
______________________________________ 
From the results obtained, it is clear that gastric emptying is 
significantly increased in comparison with control groups. Compounds (I) 
to (V) at a dose of 1 mg/kg induced a gastric emptying of 55 to 63% after 
2 hours, whereas that of the control group was only 28%. Compounds (VII) 
and (VIII), administered at a dose of 5 mg/kg, induced a gastric emptying 
of 46.2 and 47.4%, respectively, after 2 hours, whereas that of the 
control group was only 24.8%. 
Furthermore, from the tests conducted, it is apparent that the compounds 
according to the invention are more potent than metoclopramide. It was 
found, for example, that, at a dose of 1 mg/kg of the compounds (I) and 
(IV) under study, a result equivalent to the use of 5 mg/kg of 
metoclopramide was obtained. 
The acute toxicity of the compounds of the invention administered 
intravenously was studied in male mice. The following median lethal doses 
(LD.sub.50) were determined as shown in Table 2: 
TABLE 2 
______________________________________ 
Compound LD.sub.50 in mg/kg 
______________________________________ 
I 12.8-14.4 
II 40.6-48.7 
III 91-116 
IV 95.8-138 
V 65.7-76.7 
metoclopramide 25.4-37.9 
______________________________________ 
The compounds of the invention can be administered in any number of 
conventional pharmaceutical forms, including, but not limited to, tablets, 
capsules, pills, syrups, injectable solutions or other common dosage forms 
intended for oral, parenteral or any other conventional pharmaceutical 
administration, in combination with solid or liquid excipients. Substances 
which are inert relative to the compounds can be used in these 
preparations, such as lactose, magnesium stearate, starch, talc, 
cellulose, levillite, alkali metal lauryl-sulphates, saccharose and other 
vehicles commonly employed in pharmaceutical preparations. 
By way of illustration only, the compounds may be formulated in tablet 
dosage form as shown below. As the formulation is provided for 
illustrative purposes only, it is understood that the invention is not 
restricted or limited thereto, as the scope of the invention is defined 
and restricted or limited solely as set forth in the appended claims. 
______________________________________ 
N-[2-(diethylamino)-ethyl]-2- 
100 mg 
methoxy-4-[(1-H-4,5-dihydro-2- 
oxazolyl)-amino]-5-chlorobenzamide 
dried starch 20 mg 
lactose 100 mg 
methylcellulose 1500 cps 1.5 mg 
levilite 10 mg 
magnesium stearate 4 mg 
______________________________________