Note: Descriptions are shown in the official language in which they were submitted.
7~Q~
The present invention concerns novel substituted
N--(2-pyrrolidinylalkyl)benzamides of general formula I, their
pharmaceutically acceptable acid addition salts, their
quaternary ammonium salts, their dextrorotatory and levo-
rotatory isomers, and the process for the preparation thereof.
The benzamides of the present invention have the
following formula:
(CH2)m
CO - NH - W ~ N J
~ H (I)
in which:
A represents a hydrogen atom, a Cl 5 alkyl group or
a C2 5 alkenyl group;
X represents a hydrogen atom, a Cl 5 alkoxy group,
a Cl 5 alkyl group, a C2 5 alkenyloxy group or a
C2 5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a Cl 5
alkyl, Cl 5 alkoxy, amino, or amino substituted
group, such as alkylamino, acylamino, benzylamino,
or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a Cl 5
alkoxy group, a Cl 5 alkylsulfonyl group, or a
S02NRlR2 group in which Rl and R2 which can be
identical or different are hydrogen or a Cl 5
lower alkyl group, or together with the nitrogen
atom to which they are attached form a heterocycle,
possibly containing another heteroatom;
l.n~s~
W represents an alkylene group having from 1 to 4
carbon atoms which can form a straight or branched
chain, and
m represents an integer of 1, 2 or 3.
The benzamides of the present invention can be
prepared by the reaction of a compound having the formula:
COB
~ OA
ZJ~LX ( I I )
in which:
B represents a halogen group, a hydroxy group or an
organic residue;
A, X, Y, Z are as def;ned above,
on a dextrorotatory, levorotatory or racemic amine having the
formula:
I_(CH2 )m ( I I I )
H2N-W--~ J
R3
in which:
W, m are as defined above;
R3 represents a benzyl group or a hydrogen atom,
or by reaction of their reactive derivatives.
Of the amino substituted groups represented by Y,
alkyl amino can be selected from the mono or dialkylamino Cl 5
groups, and acylamino can be selected from the acetamido,
formamido, propionamido, butyramido, benzamido, phthalimido~
etc groups.
In the case where R3 is a benzyl group, this is
converted into hydrogen atom by catalytic reduction by means
~ ~47504
of hydrogen in the presence of catalysts such as Raney nickel,
palladium-bearing carbon, platinum black, etc. The hydrogen-
ation pressure used varies from atmospheric pressure to 200
atmospheres.
In the starting compound (II), the organic residue
includes groups capable of forming acid reactive derivatives.
These can be carboxylic esters such as methyl, ethyl, propyl,
butyric, isobutyric, pentanoic, etc. esters, reactive acid
esters such as cyanomethyl or methoxymethyl esters, or N-
hydroxyimide esters, or substituted or unsubstituted aromaticesters; acid hydrazides; acid azides; symmetrical anhydrides;
mixed anhydrides, for example formed with lower alkyl halo-
formiates; azolides such as triazolides, tetrazolides or
imidazolides; or acid isocyanates. The invention however is
not limited to the derivatives listed above.
According to the process of the invention, the
following compounds can be used as reactive derivatives of the
amine (III): the products of reaction of the amine with
phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl
or orthophenylenechlorophosphites, alkyl or aryl dichloro-
phosphites, or the isothiocyanate of the amine. The reactive
derivatives listed above can react with the acid in situ or
after having first been isolated.
It is also possible to carry out the reaction of the
free acid and the free amine in the presence of a condensing
agent such as silicon tetrachloride, phosphoric anhydride or a
carbodiimide such as dicyclohexyl carbodiimide.
The amidification reaction of the invention can be
carried out in the presence or in the absence of solvent. The
systems used as a solvent, which are inert with respect to the
amidification reaction, are for example alcohols, polyols,
benzene, toluene, dioxan, chloroform, diethyleneglycol
-- 3
~ U~7~Q4
dimethylether. It is also possible to use as a solvent an
excess of the amine used as the starting material. It may be
preferable to heat the reaction mixture during amidification,
for example to the boiling point of the solvents listed above.
The compound produced according to the process of
the invention can react if necessary with pharmaceutically
acceptable mineral or organic acids such as hydrochloric acid,
hydrobromic acid, sulfuric ac;d, phosphoric acid, acetic acid,
tartric acid, citric acid or methane sulfonic acid, to give
acid addition salts. It can also react if necessary with
alkyl sulfates or halides, to give quaternary ammonium salts.
The benzamides of the invention have attractive
therapeutic properties, in particular as anti-e~etics, anti-
ulcer agents and agents for modifying the central nervous
system. Their low level of toxicity is compatible with use in
human therapy, without the danger of causing side effects.
In order to illustrate the technical characteristics
of the present invention, some embodiments will now be
described, it being apparent that these are not limiting on
the invention as regards the manner in which they are per-
formed and the uses to which they can be put.
EXAMPLE 1
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide
hydrochloride
51.5 9 of methyl 2-methoxy-4-acetamido-5-chloro-
benzoate, 20 ml of water and 40 9 of 2-aminomethylpyrrolidine
were introduced into a balloon flask provided with a stirrer,
a thermometer and a condenser. The mixture was heated for 7
hours at reflux temperature, and then cooled. After the
addition of 50 ml of water and 50 ml of 40% sodium hydroxide
lye, the mixture was heated for 2 hours at reflux temperature.
The crystals formed by cooling were washed with water and
~ ~247S(.~
dr-ied in a drying oven at 50C. 32 9 of benzamide was
obtained, in the form of a base.
The hydrochloride was formed by dissolution of the
base in alcohol at boiling temperature, filtration in the hot
state and addition of hydrochloric acid (d 1.18). The
crystals formed by cooling were filtered, washed with ethanol
and dried in a drying oven at 50C. 24.2 9 of N-(2'-pyrroli-
dinylmethyl)-2-methoxy-4-amino-5-chlorobenzamidehydrochloride
was produced (melting point: 167C).
EXAMPLE 2
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-sulfamoyl-
benzamide
140 9 of methyl 2-methoxy-4-amino-5-sulfamoyl-
benzoate, 48.5 ml of water and 80 9 of 2-aminomethylpyrrolidine
were introduced into a 1 litre balloon flask provided with a
condenser. The suspension obtained was heated in a water bath.
After cooling the reaction mixture was diluted with 540 ml of
water. The solid formed was drained, washed with water and
dried at 45C.
The base produced was purified by conversion to the
hydrochloride and re-precipitation with 20% ammonia, then
drained, washed and dried at 50C. 97 9 of N-(2'-pyrrolidinyl-
methyl)-2-methoxy-4-amino-5-sulfamoylbenzamide was produced
(yield: 54.8%; melting point: 205-206C).
EXAMPLE 3
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide
130 9 of N-benzyl-2-aminomethylpyrrolidine, 620 ml
of methylethylketone, then with the temperature being main-
tained at from 5 to 10C, 162.6 9 of 2-methoxy-5-ethylsulfonyl-
benzoylchloride were introduced into a 2 litre balloon flask
provided with a stirrer, a condenser and a thermometer.
Stirring of the mixture was continued without heating for 1
1~475~4
hour. The solid formed was filtered, washed with a little
methylethylketone and then dissolved in hot ethanol. The
crystals obtained on cooling were f;ltered, washed, dried and
then introduced into a 1 litre autoclave with 500 ml of water,
150 g of Raney nickel and hydrogen, until a pressure of 170 kg
was obtained. The mixture was heated for 4 hours at 100C;
after cooling, the nickel was filtered and rinsed with water.
The solvents were evaporated under reduced pressure; the
residue was treated by means of a mixture of 25 ml of 36%
hydrochloric acid and water, until 500 ml of solution was
obtained. After heating at 80C, and filtration, the medium
was rendered alkaline by means of 40% sodium hydroxide. The
crystals obtained after cooling were filtered, washed with
water and dried. 111.5 g of N-(2'-pyrrolidinylmethyl)-2-
methoxy-5-ethylsulfonylbenzamide was obtained (yield: 70.3%;
melting point: 150C).
EXAMPLE 4
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-aminobenzamide
A solution of 1.4 9 of phosphorus trichloride in 8
ml of pyridine was poured dropwise, and with the temperature
being maintained at from 0 to 5C, with stirring, into a
solution of 2 9 of 2-aminomethylpyrrolidine in pyridine.
Stirring was continued at from 0 to 5C, and then at ambient
temperature. After the addition of 1.6 g of 2-methoxy-4-
aminobenzoid acid, the mixture was heated with stirring for
several hours.
- After the mixture had been cooled and the solvent
removed, the residue was dissolved in chloroform, then the
solution was washed with aqueous sodium carbonate and dried
over anhydrous magnesium sulfate. After concentration under
reduced pressure, 1.5 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-
lS.~4~ 4
4-aminobenzamide was produced (yield: 62.8%; melting point:
98C).
EXAMPLE 5
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide
750 ml of methylethyl ketone, 103 9 of N-benzyl-2-
aminomethylpyrrolidine and then, with the temperature being
maintained at 15 to 20, 133 9 of 2-methoxy-5-methylsulfonyl-
benzoylchloride were introduced into a balloon flask provided
with a mechanical stirrer and a thermometer. Stirring of the
reaction mixture was maintained for 2 hours at ambient temper-
ature. The solid formed was drained and treated with ice-cold
methylethyl ketone, then dissolved in hot ethanol. The
crystals obtained upon cooling were filtered, washed, dried
and then introduced into a 5 litre autoclave with 1 litre of
water and 20 9 of Raney nickel. After the usual purging
operations, hydrogen was introduced to a pressure of 130 kg
and the mixture was heated at 100C for 4 hours.
After cooling, the nickel was filtered and washed.
The solvents were then evaporated under vacuum. The residue
was treated with water and hydrochloric acid until a volume of
500 ml was obtained. The solution formed was heated at 80C,
filtered and rendered alkaline by means of sodium hydroxide.
After cooling, the crystals formed were filtered, washed with
water and dried. 98 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-
5-methylsulfonylbenzamide was produced (yield: 68.9%; melting
point: 152.5C).
EXAMPLE 6
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide
7.3 9 of 2-methoxy-5-ethylsulfonyl benzoic acid, 200
ml of tetrahydrofuran, and 7.3 9 of carbonyldiimidazole were
introduced into a balloon flask provided with a stirrer and a
condenser.
-- 7
75(~4
After the mixture had been stirred at ambient temper-
ature for 30 minutes, 4.8 9 of 2-aminomethylpyrrolid;ne was
added. Stirring of the mixture was continued at ambient
temperature, and then the solvent was evaporated under vacuum.
The residue was dissolved in hydrochloric acid and the solution
obtained was filtered and then treated with sodium hydroxide
until the pH-value was 12-13. The mixture was extracted with
chloroform. After drying and filtration, the solvent was
evaporated under vacuum. After purification in ethanol, 6.5 9
10 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide
was obtained (yield: 66.5%; melting point: 150C).
EXAMPLE 7
N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-
hvdrochloride
-
1 litre of acetone and 200 9 of N-benzyl-2-amino-
methylpyrrolidine were introduced into a 4 litre balloon flask
provided with a mechanical stirrer and a thermometer. The
mixture was cooled to 0C and 280 9 of 2,3-dimethoxy-5-
sulfamoylbenzoylchloride was added, the temperature of the
20 reaction medium being kept below 10C.
The mixture was then stirred for 4 hours. The
precipitate formed was drained, washed over a filter with
acetone and then introduced into an autoclave with 1200 ml of
water, 40 ml of hydrochloric acid (d = 1.18) and 5 spoonfuls
of Raney nickel.
After the usual purge operations, hydrogen was intro-
duced to give a pressure of 140 kg. The mixture was heated at
100C for 4 hours. After cooling the nickel was filtered and
the mixture was rendered alkaline with 150 ml of ammonia. The
30 precipitate obtained was filtered and dried, then dissolved at
boiling temperature in 150 ml of absolute ethanol and acidified
with 40 ml of hydrochloric ethanol. The crystals obtained by
~ ~47504
cooling were filtered, washed and dried at 5QC. 95 9 of
N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-
hydrochloride was produced (melting point: 195-198C).
EXAMPLE 8
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide
51.8 9 of ethyl 2-methoxy-5-sulfamoylbenzoate, 24 9
of 2-aminomethylpyrrolidine and 200 ml of butanol were intro-
duced into a 1 litre balloon flask.
The mixture was heated for 7 hours at reflux temper-
ature. After cooling, and evaporation under vacuum of thesolvent, the residue was recrystallized from dimethylformamide.
51 9 of benzamide was produced (yield: 73%).
A second recrystallization step provided 43 9 of
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide
(yield: 61.5%; melting point: 185C).
