Note: Descriptions are shown in the official language in which they were submitted.
i8~S
This invention relates to N-substituted-benzamides
and to pharmaceutical compositions containing them.
Canadian application Serial No. 248,237 discloses
compounds of the general formula:-
R2\
~ 13
(~ ~ CON~I-(CH2)X7
R ~ \(CH ) Z
wherein R represents a Cl-C6 alkoxy or C2-C6 alkenyloxy group,
Rl and R2 are the same or different and each represents a hydro-
gen or halogen atom, or a sulphonamido, amino, Cl-C6 alkyl-, di-
(Cl-C6)-alkyl-amino, alkylsulphonyl, alkylsulphonamido or acyl- -
amino group, the symbol Rl being in the 3- or 4-position of the
phenyl ring, R3 represents a hydrogen atom or a Cl-C6 alkyl or
aryl group, Ar represents an optionally substituted aryl, aroyl
or a single ring aromatic heterocyclic group, x represents 0 or
l, _ represents 2 or 3, and z represents an integer from l to 6, `
and pharmaceutically acceptable acid addition salts thereof. The
compounds are stated to have useful pharmacological properties
and, more partieularly, the ability to antagonise the effeets of
dopamine or dopaminergie agents of endogenous or exogenous origin.
It has now been found that eertain compounds falling
within the scope of the above general formula but not speeifieally
disclosed in the prior application possess the aforesaid pharma-
eologieal properties and also properties not hitherto diselosed
in respeet of eompounds of general formula I.
Aeeordingly, the invention provides an N-piperid-4-
yl benzamide of the general formula:
:.,,~' l\
, -, , ~ ~
355
Rl ~ CON~ CI - Ar IA
[wherein R represents a methoxy, ethoxy or allyloxy group; R
represents an amino, acetamido, methylamino or dimethylamino
group; R2 represents a chloro or bromo atom, or an amino group;
R~ represents a hydrogen atom or a methyl group and Ar repre-
sents a ~naphthyl group or a phenyl group, optionally substit-
uted by a halogen atom, a trifluoromethyl, methyl or nitro
group, or by both a chlorine atom an~ a methoxy group], or a
pha.rmaceutically acceptable acid addition salt thereof.
10The new compounds of the present invention are thus
N-[l-(_-trifluoromethylbenzyl)piperid--4-yl]-2-methoxy-4-amino-
5-chlorobenzamide, N-[l-~l-phenylethyl)piperid-4-yl]-2-ethoxy-
4-amino-5-chlorobenzamide, N-[1-~2-methoxy-5-chlorobenzyl)-
piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l-~-
naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide,
N-[l-~p-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chloro- ~ -
benzamide, N-[l-~p-
r ~ la -
8~3S~ii
bromobenzyl)-piperid-4-yl~-2-methoxy-4-amino-5-c}llorobenzamide, N (1-(~-
fluorobenzyl)piperid-4-yl~-2-methoxy-4-amino-5-chlorobenzamide, N~ o-
methylbenzyl)piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide, N-(l-benzyl-
piperid-4-yl)-2-methoxy-4,5-diaminobenzamide, N-~l-(p-nitrobenzyl)-piperid-4-
yl~-2-methoxy-4-amino-5-chlorobenzamide, N-~l-(l-phenylethyl~piperid-4-yl~~2-
methoxy-4-amino-5-bromobenzamide, N-rl-(m-methylbenzyl)piperid-4-yl~-2-methoxy-
4-amino-5-chlorobenzamide, N-(l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chloro-
benzamide, N-ll-(l-phenylethyl)piperid-4-yl)-2-methoxy-4,5-diaminobenzamide,
N-(l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, N-[l-(l-
phenylethyl)piperid-4-yl~-2-methoxy-4-acetamido-5-aminobenzamide, N-(l-benzyl-
piperid)-2-methoxy-4-methylamino-5-chlorobenzamide, N~ benzylpiperid-4-yl)-
2-allyloxy-4-amino-5-chlorobenzamide, N~ -methylbenzylpiperid-4-yl)-2-
methoxy-4-acetamido-5-aminobenzamide, N-(l-benzylpiperid-4-yl~-2-methoxy-4-
acetamido-5-aminobenzamide, N-~1-(2-methoxy-5-chlorobenzyl)-piperid-4-yl~-2-
methoxy-4-acetamido-5-aminobenzamide and N-tl-benzylpiperid-4-yl)-2-ethoxy-4-
methylamino-5-chlorobenzamide and pharmaceutically acceptable acid addition
salts thereof. These compounds have been founcl to possess - in addition to
the pharmacological properties mentioned in the earlier patent application -
new activi~ies, the most interestin~ of which are anorexia ~mouse spaghetti -~
test) without amphetamine-like stimulation of the central nervous system,
vasodilatation ~mouse ear ~est) and inhibition of gastric acid secretion
~pyloric ligature model of Shay) and ulcer foTmation ~phenylbutazone or stress
models) in the rat.
These new compounds may be prepared by application of the methods
described in the speciication of Application Serial No. 248,237 for the
preparation of compounds of general formula I.
Thus, compounds of formula I may be prepared by ~a) reacting a
mixed anhydride of a substituted benzoic acid of the general formula: :
;
2-
35~
R2
R~ C2 II
with a piperidine derivative of the general formula:
13 :
H2N ~ N - CH - Ar III
wherein groups R, R1, R2, R3 and Ar are as defined for formula
IA above, and if necessary, converting a product of formula IA
to a pharmaceutically acceptable acid addition salt thereof, or
vice versa.
The acid addition salts may be prepared by reacting
the base in a solvent such as methanol, ethanol, acetone or
waterg or a suitable mixture of such solvents, at a temperature
between 10C and the boiling point of the
, ~
.
, . .-
~15 51~
reaction mixture.
The present invention also includes within its scope pharmaceuti-
cal compositions comprising one or more of the afore-named compounds, or a
pharmaceutically acceptable acid addition salt thereof, in association with
a pharmaceutical carrier. The pharmaceutical carrier may be a solid, a liquid
or a mixture of a solid and a liquid, and the compositions of this invention
may be adapted for oral, rectal or parenteral use, the preferred method of
administration being ~ os. In this case, the compositions may take the form
of tablets, capsules, lozenges, effervescent granules, syrups or suspensions.
Such compositions may be made by methods well known in the art.
The following Example illustrates the preparation in detail of one
of the compounds of the invention. Other compounds of the invention may be
prepared in a similar manner.
EXAMPLE
N-[l-~m-Trifluoromethylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide
To a suspension of 6.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid
in 400 ml of anhydrous tetrah~drofuran, a solution of 4.2 ml of triethylamine
in 28 ml of tetrahydrofuran was added. The resulting solution was cooled to
-10C and then a solution of 2.98 ml of ethyl chloroformate in 25 ml of tetra-
hydrofuran was slowly added. The mixture was stirred at the same temperature
for half an hour and a solution of 8.58 g of 1-(_-trifluoromethylbenzyl)-4-
aminopiperidine in 25 ml of tetrahydrofuran was added. After stirring for 1
hour at -10 to -5C, the temperature was allowed to rise to room temperature
and the reaction mixture was left to stand overnight. The mixture was eva-
porated to dryness and the residue dissolved in a mixture of chloroform and
water. The mixture was made strongly basic with sodium hydroxide solution,
the chloroform phase was separated and washed with water, dried ~sodium sul-
phate) and evaporated to dryness to yield 9.5 g of the title compound, m.p.
138 - 140C (after crystallisation from acetone/n-hexane). Its hydrochloride
melted at 219 - 221C.
S~ ,
By a similar procedure and using appropriate starting materials
and appropriate quantities thereof, the following compounds were prepared:-
N-[l-(l-phenylethyl)piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide, the
hydrochloride of which melts at 282 - 284C;
N-[1-~2-methoxy-S-chlorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenz-
amide, the hydrochloride of which melts at 200 - 203C;
N-[l-~-naphthylmethyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the
hydrochloride of which melts at 220 - 221C;
N-[l-(~-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the
hydrochloride of which melts at 234 - 235C
N-[l-~p-bromobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the
hydrochloride of which melts at 242 - 243C;
N-[l-~p-1uorobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the
hydrochloride monohydrate of which melts at 256 - 258C ~dec); .
N-[l-~o-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide the
hydrochloride of which melts at 186 - 188C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4~5-diaminobenzamide, the hydrochloride
monohydrate of which melts at 244 - 246C;
N~ p-nitrobenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamade, the
hydrochloride of which melts at 223 - 225C;
N-[l-~l-phenylethyl)piperid-4-yl]-2 methoxy-4-amino-5-bromobenzamide, the
hydrochloride o which melts at 239 - 241C;
N-Ll-~m-methylbenzyl)piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide, the
hydrochloride of which melts at 217 219C;
N-~l-benzylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide, the hydrochloride
o which melts at 271 - 273C;
N-[l-~l-phenylethyl)piperid-4-yl]-2-methoxy-4,5-diaminobenzamide, the dihydro-
chloride monohydrate of which melts at 246 - 248C;
N-~l-benzylpiperid-4-yl)-2-methoxy-4-dimethylamino-5-chlorobenzamide, the
fumarate of which melts at 185 - 187aC;
-- 5 --
., ~ , .. ..
5~55
Bis{N-[l-(l-phenylethyl)piperid-4-yl]-2-methoxy-4-acetamido-5-aminobenzamide}
fumarate, m.p. 165 - 166C;
N-(l-benzylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide, the
fumarate of which melts at 221 - 222C (dec.);
N-(l-benzylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide, the hydro-
chloride of which melts at 223 - 225C;
N-(l-~-methylbenzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the
fumarate of which melts at 172 - 174C (dec.);
N-(l-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-aminobenzamide, the fumarate
of which melts at 177 - 179C; -
N-[1-(2-methoxy-5-chlorobenzyl)piperid-4-yl]-2-methoxy-4-acetamido-5-amino-
benzamide, the fumarate of which melts at 182 - 184C (dec.); and
N-~l-benzylpiperid-4-yl)-2-ethoxy-4-methylamino-5-chlorobenzamide, the
fumarata of which melts at 229 - 231C (dec.).
