DERIVES DE LA PIPERIDINE

PIPERIDINE DERIVATIVES

Abrégé anglais

Abstract of the Disclosure
Compounds and process for their preparation, of formula
<IMG> I
[wherein R represents a lower alkoxy or allyloxy goup; R1 represents ahydrogen atom R' and R2, which may be the same or different, each represent
a halogen atom, or a sulphamoyl, amino, lower alkylamino di(lower)alkylamino,
lower alkylsulphonyl or lower alkylsulphamoyl group, or a lower acylamino
group in which the acyl moiety is derived from a carboxylic acid, the halogen
atom or group represented by the symbol R1 being in the 3- or 4-position of
the phenyl ring; R3 represents a hydrogen atom or a lower alkyl group, R4
represents a cyclohexenyl or cyclohexadienyl group optionally substituted by an
alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable
acid addition salts and quaternary ammonium derivatives and N-oxides thereof.
These compounds find pharmaceutical use as agents to antagonize tho effects
of dopamino and dopaminoergic agents.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of a N-(piperid-4-yl)benzamide
derivative or a pharmaceutically-acceptable acid addition salt thereof, of
the general formula:
<IMG>
(I)
[wherein R represents a lower alkoxy or allyloxy group; R1 represents a
hydrogen atom or R1 and R2, which may be the same or different, each represent
a halogen atom, or a sulphamoyl, amino, lower alkylamino, di(lower)alkylamino,
lower alkylsulphonyl or lower alkylsulphamoyl group, or a lower acylamino
group in which the acyl moiety is derived from a carboxylic acid, the halogen
atom or group represented by the symbol R1 being in the 3- or 4-position of
the phenyl ring; R3 represents a hydrogen atom or a lower alkyl group; R4
represents a cyclohexenyl or cyclohexadienyl group optionally substituted by
an alkyl group containing 1 to 3 carbon atoms] and pharmaceutically-acceptable
acid addition salts and quaternary ammonium derivatives and N-oxides thereof,
which process comprises reacting a reactive derivative of a benzoic acid of
the general formula:
<IMG> III
(wherein R, R1 and R2 are as defined above) with a piperidine derivative of
the general formula:
<IMG> IV
14

wherein the various symbols are as defined above, and if desired, converting
the thus obtained compound into a pharmaceutically acceptable acid addition
salt.
2. N-(piperid-4-yl)benzamide derivatives of general formula I, as
defined in claim 1, whenever prepared by the process of claim 1 or by an
obvious chemical equivalent thereof.
3. A process according to claim 1 in which the reactive derivative of
the benzoic acid is a halide, an alkyl ester, anhydride, a mixed anhydride,
the N-imidazolamide or acid azide.
4. A process according to claim 1 or 3 in which the reaction is carried
out in an inert organic solvent at a temperature between -5° and 120°C.
5. A modification of the process claimed in claim 1 in which the
benzoic acid of general formula III is reacted with the piperidine derivative
of general formula IV in the presence of a dehydrating agent.
6. A process according to claim 5 in which the dehydrating agent is
silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride, titanium tetra-
chloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride, sulphur trioxide
in dimethyl sulphoxide, toluene-p-sulphonyl chloride, acetone dimethyl acetal
or a polymeric dehydrating agent.
7. A process according to claim 5 or 6 in which the reaction is carried
out in an inert organic solvent at a temperature between 20° and 110°C.
8. Process according to claim 1 for the preparation of piperidine deri-
vatives of the general formula II:
<IMG> II

[wherein R' represents a lower alkoxy or allyloxy group, R1' represents a
hydrogen atom, or an amino, lower alkylamino, di(lower)alkylamino or a lower
acylamino group, R2' represents a halogen atom, or an amino, sulphamoyl or
lower alkylsulphonyl group, R3' represents a hydrogen atom or a lower alkyl
group and R4' represents a cyclohexenyl or cyclohexadienyl group optionally
substituted by an alkyl group containing 1 to 3 carbon atoms] and
pharmaceutically-acceptable acid addition salts thereof, which process
comprises reacting a reactive derivative of a benzoic acid of formula (III')
<IMG> (III')
with a piperidine derivative of general formula (IV')
<IMG>
(IV')
wherein the various symbols R are as defined above, and if desired, convert-
ing the thus obtained compound into a pharmaceutically acceptable salt there-
of.
9. N-(piperid-4-yl)benzamide derivatives of general formula II, as
defined in claim 8, and pharmaceutically acceptable salts thereof, whenever
prepared by the process of claim 8, or by an obvious chemical equivalent
thereof.
10. A process for the preparation of N-(1-cyclohexa-1',4'-dienylmethyl-
piperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide which process comprises
reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1',4'-
dienylmethyl-4-aminopiperidine.
16

11. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide whenever prepared by the process of claim 10 or by an obvious
chemical equivalent thereof.
12. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-
methylpiperid-4-yl)-2-methoxy-5-methylsulphonylbenzamide which process comprises
reacting 2-methoxy-5-methylsulphonylbenzoic acid with 1-cyclohexa-1',4'-
dienylmethyl-4-aminopiperidine.
13. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-
methylsulphonylbenzamide whenever prepared by the process of claim 12 or by
an obvious chemical equivalent thereof.
14. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-
methylpiperid-4-yl)-2-methoxy-4-amino-5-bromobenzamide which process comprises
reacting 2-methoxy-4-amino-5-bromobenzoic acid with 1-cyclohexa-1',4'-dienyl-
methyl-4-aminopiperidine.
15. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
bromobenzamide whenever prepared by the process of claim 14 or by an obvious
chemical equivalent thereof.
16. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-
methylpiperid-4-yl)-2-methoxy-5-sulphamoylbenzamide which process comprises
reacting 2-methoxy-5-sulphamoylbenzoic acid with 1-cyclohexa-1',4'-
dienylmethyl-4-aminopiperidine.
17. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-
sulphamoylbenzamide whenever prepared by the process of claim 16 or by an
obvious chemical equivalent thereof.
18. A process for the preparation of N-[1-(4-methylcyclohexa-1,4-dienyl)
methylpiperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which process comprises
reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(4-methylcyclohexa-1,
4-dienyl)methyl-4-aminopiperidine.
17

19. N-[1-(4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-4-
amino-5-chlorobenzamide whenever prepared by the process of claim 18 or by an
obvious chemical equivalent thereof.
A process for the preparation of N-[1-(1-cyclohexa-1',4'-dienylethyl)
piperid-4-yl]-2-methoxy-4-amino-5-chlorobenzamide which process comprises
reacting 2-methoxy-4-amino-5-chlorobenzoic acid with 1-(1-cyclohexa-1',4'-
dienyl-ethyl)4-aminopiperidine.
21. N-[1-(1-cyclohexa-1',4'dienylethyl)piperid-4-yl]-2-methoxy-4-amino-
5-chlorobenzamide whenever prepared by the process of claim 20 or by an
obvious chemical equivalent thereof.
22. A process for the preparation of N-[1-(1-cyclohexa-1',4'-dienylethyl)
piperid-4-yl]-2-ethoxy-4-amino-5-chlorobenzamide which process comprises
reacting 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-(1-cyclohexa-1',4'-
dienyl-ethyl)-4-aminopiperidine.
23. N-[1-(1-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-
5-chlorobenzamide whenever prepared by the process of claim 22 or by an
obvious chemical equivalent thereof.
24. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-
methylpiperid-4-yl)-2-methoxy-4-methylamino-5-chlorobenzamide which process
comprises reacting 2-methoxy-4-methylamino-5-chlorobenzoic acid with 1-cyclo-
hexa-1',4'-dienylmethyl-4-aminopiperidine.
25. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methyl-
amino-5-chlorobenzamide whenever prepared by the process of claim 24 or by
an obvious chemical equivalent thereof.
26. A process for the preparation of N-(1-cyclohexa-1'.4'-dienyl-
methylpiperid-4-yl)-2-allyloxy-4-amino-5-chlorobenzamide which process
comprises reacting 2-allyloxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1',
4'-dienylmethyl-4-aminopiperidine.
18

27. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-allyloxy-4-amino-
5-chlorobenzamide whenever prepared by the process of claim 26 or by an
obvious chemical equivalent thereof.
28. A process for the preparation of N-(1-cyclohexa-1',4'-dienyl-
methylpiperid-4-yl)-2-ethoxy-4-amino-5-chlorobenzamide which process comprises
reacting 2-ethoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexa-1',4'-
dienylmethyl-4-aminopiperidine.
29. N-(1-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-
chlorobenzamide whenever prepared by the process of claim 28 or by an
obvious chemical equivalent thereof.
30. A process for the preparation of N-(cyclohexen-3'-ylmethyl-piperid-
4-yl)-2-methoxy-4-amino-5-chlorobenzamide which process comprises reacting
2-methoxy-4-amino-5-chlorobenzoic acid with 1-cyclohexen-3'-ylmethyl-4-
aminopiperidine.
31. N-(cyclhexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide whenever prepared by the process of claim 30 or by an
obvious chemical equivalent thereof.
19

Description

10!~075
This invention relates to new therapeuticslly useful N-(piperid-4-
yl)benzamide derivatives, to processes for their preparation and pharm-
aceutical compositions containing them.
The new N-tpiperid-4-yl)benzanide derivatives of the present
invention are those compounds of the general for~ula:
R2
~ CONH- (C~2) X --~ N~ R
R R
twherein R represents a lower alkoxy or allyloxy group; Rl represents a
hydrogen atom or Rl and R2, which may be the same or different, each
represent a halogen atom, or a sulphamoyl, amino, lower alkylamino, di~lower)
alkylamino, lower alkylsulphonyl or lower alkylsulphamoyl group, or a lower
acylamino group in which the acyl moiety is derived from a càrboxylic acid,
including halogen substituted carboxylic acids such as trifluoroacetic acid
(preferably a lower alkanoylamino group), the halogen atom or group
represented by the symbol Rl being in the 3- or 4-position of the phenyl ring
(preferably in the 4-position); R3 represents a hydrogen atom or a lower alkyl
group; R4 represents a cyclohexenyl or cyclohexadienyl group optioDally
substituted by an alkyl group containing 1 to 3 carbon atoLs3and pharmaceuti-
cally-acceptable acid addition salts and quaternary anmonium derivatives and
N-oxides thereof.
The qualification "lower" as applied in this specification to alkoxy,
alkyl, acyl and alkanoyl groups means that the group in question contains at
most 4 carbon atoms.

iO94075
Preferred compounds of general formula I are those of the more
specific formula:
Rl' ~ CONH ~ 3' II
\=~.
[wherein R' represents a lower alkoxy (preferably methoxy or ethoxy) or
allyloxy group, R represents a hydrogen atom, or an amino, lower alkylamino
(preferably methylamino), di(lower)alkylamino ~preferably dimethylamino), or
a lower acylamino (preferably lower alkanoylamino, e.g. acetamido or trifluoro-
acetamido) group, R represents a halogen (preferably chlorine or bromine)
atom, or an amino, sulphamoyl or lower alkylsulphonyl (preferably methyl-
sulphonyl group, R3 represents a hydrogen atom or a lower alkyl (preferably
methyl) group and R represents a cyclohexenyl or cyclohexadienyl group
optionally substituted by an alkyl group containing 1 to 3 carbon atoms
(preferably methyl)] and pharmaceutically-acceptable acid addition salts
thereof.
Of outstanding importance are those compounds of general formula II
wherein R represents the cyclohexa 1,4-dienyl group optionally substituted
by a methyl group and, in particular, N [l-cyclohexa-1',4'-dienylmethylpiperid-
4-yl]-2-methoxy-4-amino-5-chlorobenzamide, N-[l cyclohexa-1',4'-dienylmethyl-
piperid-4-yl]-2-methoxy-4-methylamino-5-chlorobenzamide, N-~l-cyclohexa-1',4'-
dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-5-chlorobenzamide and N-[1-(4-
methylcyclohexa-1,4-dienyl)methylpiperid-4-yl~-2-methoxy-4-amino-5-chlorobenz-
amide, and their pharmaceutically-acceptable acid addition salts.

10~3 ~07S
According ~o a feature of the present invention, the N-(piperid-4-yl)
benzamide derivatives of general formula I are prepared by the process which
comprises reacting a reactive derivative of a benzoic acid of the general
formula:
~2
,~
~ r COOH III
/~
~: Rl R
. 10
(wherein R, Rl and R2 are as hereinbefore defined) with a piperidine derivative
of the general formula:
~ ,R
2N ~ N - ~ R IV
wherein the various symbols are as hereinbefore defined. The reactive deriva-
tive of the said benzoic acid may be a halide (preferably chloride), an alkyl
ester (preferably methyl ester), anhydride or a mixed anhydride, the N-imida-
zolamide or acid azide.
The reaction is preferably carried out in the presence of an inertorganic solvent, for example benzene, toluene, chloroform, tetrahydrofuran or
dioxan, at a temperature between -5 and 120~C.
The piperidine derivatives of general formula IV can be prepared by
reduction of corresponding piperid-4-one oximes with lithium aluminium hydride
in the presence of diethyl ether or tetrahydrofuran, or by reductive amination
of corresponding piperid-4-ones dissolved in an organic solvent, e.g. an alcohol
containing up to 6 carbon atoms, in the presence of Raney nickel or platinum
as catalyst. The piperidine derivatives of general formula IV whereill R4
represents a cyclohexadienyl group can be prepared from a corresponding phenyl
derivative of the fol~ula R4 represents a phenyl group by reduction with lithium
in the presence of liquid ammonia or a lower alkylamine.

~094~75
Halides of the benzoic acids of general formula III can be prepared
by reaction of the acid with thionyl chloride or a phosphorus halide in the
presence of an inert organic solvent such as benzene, toluene or a halogenated
hydrocarbon. Mixed anhydrides of the benzoic acids of general formula III can
be prepared by the reaction of the acid with, for example, an alkyl chloro-
formate in the presence of an organic nitrogen-containing base, e.g. triethyl-
amine, in an inert organic solvent, e.g. tetrahydrofuran or methylene chloride,
and at a temperature between -20C and +25C. Esters and anhydrides of the
benzoic acids of formula III, which may be employed as starting materials in
the aforementioned process, can be prepared from the benzoic acids by methods
known per se, as can also the N-imidazolamides or acid azides of the acids.
The N-(piperid-4-yl)benzamide derivatives of general formula I are
also prepared, according to a further feature of the invention, by the direct
reaction of a benzoic acid of general formula III with a piperidine derivative
of general formula IV in the presence of an appropriate dehydrating agent.
Such agents are silicon tetrachloride, a mono-, di- or trialkyl-silyl chloride,
titanium tetrachloride, N,N'-dicyclohexyl-carbodiimide, thionyl chloride,
sulphur trioxide in dimethyl sulphoxide, toluene-~-sulphonyl chloride, acetone
dimethyl acetal or a polymeric dehydrating agent. The reaction is carried
out in an inert organic solvent, e.g. methylene chloride, acetone, pyridine,
ethyl acetate or dioxan, at a temperature between 20 and 110C.
In the preparation of those compounds of general formula I wherein
the sym'ool(s) Rl and/or R2 represent(s) an amino group by the aforementioned
processes, it is sometimes advisable to protect the amino group(s) of the acid
of general formula III or derivative thereof before reacting the compound with
the piperidine derivative of general formula IV. In this case an N-acyl deri-
vative of the amino-substituted benzoic acid of general formula III is initially
prepared, the acyl protecting group preferably being acetyl, chloroacetyl,
trifluoroacetyl or phthalimido. After the reaction between the N-acylated
compound of general formula III, or reactive derivative thereof, with the
~ 4 _
. ~

`` 1094075
piperidine derivative of general formula IV, the corresponding N-acyl
derivative of the compound of general formula I is obtained and that compound
is then subjected to acid or alkaline hydrolysis to give the corresponding
compound of general formula I in which Rl and/or R2 represent(s) an amino
group. Acid hydrolysis of the N-acylated compound may be carried out by
heating with dilute hydrochloric acid, preferably at the boiling point of
the reaction mixture, while alkaline hydrolysis is preferably carried out at
room temperature with sodium or potassium hydroxide in an aqueous-alcoholic
solution.
The N-(piperid-4-yl)benzamide derivatives of general formula I
have as one of their principal ~harmacological properties the ability to
antogonize the effects of dopamine or dopaminergic agents of endogenous or
exogenous origin. They have exhibited activities which may be considered
beneficial in the treatment of gastrointestinal and cerebral malfunction in
mammals, including man. They have also been shown to be capable of exerting
anorectic properties. Their characteristic properties are an antagonism of
the effects of the dopaminergic agent, apomorphine, in animals, local
anaesthetic activity and the ability to induce catatonia in rats and mice.
~onsequently, they may be useful in the treatment of nausea and vomiting of
diverse origin and as neuroleptic or tranquillizing agents. They may be
useful for the treatment of nausea and vomiting resulting from gastrointestinal
disorders, congestive heart failure, post-operative conditions, etc., other
gastrointestinal disorders such as dyspepsia, flatulance, bile regurgitations,
hiatus hernia, peptic ulcer, reflux aerophagitis, gastritis, duodenitis and
cholethiasis, and a variety of conditions affecting the central nervous system
such as acute and chronic psychosis, manical psychosis, schizophrenias, serious
disturbances of behaviour and non-melancholic depressive states and migraine.
They may also be useful in the treatment of obesity and allied conditions
where the administration of an appetite supressant is warranted.
For therapeutic purposes the N-~piperid-4-yl)benzamide derivatives
of general formula I may be employed in the form of non-toxic pharmaceutically-
~ ~ - 5 -
... ...

10~407S
acceptable inorganic or organic acid addition salts such as sulphates,
hydrohalides, phosphates, lower alkanesulphonates, arylsulphonates, salts of
aliphatic mono-, di or tri- basic acids of from 1 to 20 carbon atoms which
may contain one or more double bonds, an aryl nucleus or other functional
group such as hydroxy, amino or keto; salts or aromatic acids in which the
aromatic nucleus may optionally be substituted by groups such as hydroxy,
lower alkoxy, amino, mono- or di-(lower)alkylamino and sulphonamido groups.
They may also be employed in the form of pharmaceutically-acceptable
quaternary ammonium salts such as those salts formed by reaction of the
N-(piperid-4-yl)benzamide derivatives of general formula I with lower alkyl
halides or sulphates, or in the form of oxygenated derivatives in which oxygen
is attached to the nitrogen atom of the piperidine nucleus, viz. the N-oxides.
The pharmaceutically-acceptable acid addition salts and quaternary
ammonium derivatives and N-oxides of the N-(piperid-4-yl)benzamide derivatives
of general formula I may be prepared by methods known per se.
Also included within the scope of the present invention are pharma-
ceutical compositions which comprise, as active ingredient, at least one
N-~piperid-4-yl)benzamide derivative of general formula I, or a non-toxic
pharmaceutically-acceptable acid addition salt or quaternary ammonium deriva-
tive or N-oxide thereof, in association with a pharmaceutically-acceptable
carrier or diluent. Preferably the compositions are made up in a form suitable
for oral, topical, percutaneous or parenteral administration.
The pharmaceutically-acceptable carriers or diluents which are
admixed with the active compound, or compounds, to form the compositions of
this invention are well known per se and the actual excipients used depend
inter alia on the method of administering the compositions. Compositions of
this invention are preferably adapted for administration per os. In this case,
the compositions for oral administration may take the form of tablets, capsules,
lozenges or effervescent granules or liquid preparations, such as mixtures,
- 6 -

- 105~4075
elixirs, syrups or suspensions, all containing one or more compounds of the
invention; such preparations may be made by methods well known in the art.
The diluents which may be used in the preparation of the compositions
include those li~uid and solid diluents which are compatible with the active
ingredient, together with, if desired, colouring or flavouring agents. Tab-
lets or capsules may conveniently contain between 0.1 and 20 mg. of active
ingredient or the equivalent amount of an acid addition salt or quaternary
ammonium or N-oxide derivative thereof.
The liquid compositions adapted for oral use may be in the form of
solutions or suspensions. The solutions may be aqueous solutions of a soluble
salt or other derivative of the active compound in association with, for ex-
ample, sucrose to for~ a syrup. The suspension may comprise a water insoluble
active compound of the invention or an acid addition salt or quaternary ammoni-
um or N-oxide derivative thereof in association with water, together with 3
suspending agent and flavouring agent.
Compositions for parenteral injection may be prepared from water-
soluble salts, which may or may not be freeze-dried, and which may be dissolved
in water or an appropriate parenteral injection fluid.
In another aspect of the invention, the compounds may be mixed with
20 other active anti-acid and anti-ulcer agents (excluding anticholinergic agents)
for oral or, in appropriate cases, for parenteral use.
The following Reference Example and Examples illustrate the prepara-
tion of piperidine compounds of the present invention.
~ERENCE EXAMPLE
A solution of lithium (5 g.; 0.7 mol) in liquid ammonia (250 ml.) was
added little by little to another solution of l-benzyl-4-aminopiperidine (S0 g.;
0.264 moles) in anhydrous diethyl ether (100 ml.~. After stirring for half an
hour, absolute ethanol (180 ml.) was added little by little, the solvent re_
moved _ vacuo and the residue taken up with water. The aqueous solution was
extracted with diethyl ether and the organic layers dried and distilled in vacuo

`` 1094075
to give l-cyclohexa-l'J4'-dienylmethyl-4-aminopiperidine (48 g.), b.p. 117 -
118C,/0.5 mm.Hg.
Also prepared in similar manner were:
1-(4-methylcyclohexa_1,4-dienyl)methyl-4-aminopiperidine, b.p.
104 - 106C/0.07 mm.Hg.;
l-(l-cyclohexa-1',4'-dienyl-ethyl)-4-aminopiperidine, b.p. 103 -
105C./0.08 mm.Hg. and
l-cyclohexen_3'_ylmethyl_4_aminopiperidine, b.p. 101 - 103C./0.05
mm.Hg.
EXAMPLE 1
Triethylamine (7.0 ml.; 0.05 moles) and ethyl chloroformate (4.8 ml.;
0.05 moles) were added successively to a stirred suspension of 2-methoxr-4-
amino-5-chlorobenzoic acid (10.1 g.; 0.05 moles) in anhydrous tetrahydrofuran
(300 ml.) whilst maintaining the temperature between -5 and -10C. After
stirring at this temperature for 0.5 hours, a solution of 1-cyclohexa-1',4'-
dienylmethyl-4-aminopiperidine (9.6 g.; 0.05 moles) in anhydrous tetrahydro-
furan (50 ml.) was added; the temperature was maintained at -5 to -10C. for
1 hour and then the reaction mixture was allowed to stand overnight at room
temperature. The solvent was removed in vacuo, the residue poured into water,
extracted with chloroform and the organic layers washed with water. The chlo-
roform solution was dried (Na2S04) and the solvent removed in vacuo to give a
solid which was triturated with a mixture of methanol and diethyl ether. N-
(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenz-
amide (12.2 g.) was obtained.
The hydrochloride monohydrate was prepared by addition of a saturated
ethanolic solution of hydrogen chloride to a solution of the base in ethanol.
Recrystallization of the precipitate from ethanol gave a white solid, m.p.
226 - 227C. (dec.).
Also prepared in a similar manner were:
N-(l-cyclohexa-1',4'-dienrlmethylpiperid-4-yl)-2-methoxy-5-methyl-
sulphonylbenzamide hydrochloride, m.p. 209 - 211~C. (dec.);

109~075
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-chloro-
benzamide hydrochloride, m.p. 231 - 233C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
bromobenzamide hydrochloride, m.p. 215C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-5-sulpha~oyl-
benzamide hydrochloride, m.p. 230 - 231C. ~dec.);
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-acetamido-
5-chlorobenzamide hydrochloride monohydrate, m.p. 193 - 195C~
N-[1-~4-methylcyclohexa-1,4-dienyl)methylpiperid-4-yl]-2-methoxy-4-
amino-5-chlorobenzamide hydrochloride, m.p. 246 - 248C. ~dec.);
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-methoxy-4-
amino-5-chlorobenzamide hydrochloride, m.p. 241 - 242C. ~dec.);
N-~l~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-acet-
amido-5-chlorobenzamide, the fumarate of which melts at 171 - 173C.;
N-[l-~l-cyclohexa-1',4'-dienylethyl)piperid-4-yl]-2-ethoxy-4-amino-
5-chlorobenzamide hydrochloride, m.p. 264 - 266C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4,5-di-
aminobenzamide dihydrochloride monohydrate, m.p. 240 - 242C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-dimethyl-
amino-5-chlorobenzamide, the fumarate of which melts at 182 - 184C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-methyl-
amino-5-chlorobenzamide, the fumarate of which melts at 203 - 205~C.;
N-~l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-allyloxy-4-amino-
5-chlorobenzamide hydrochloride, m.p. 180 - 182C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-amino-5-
chlorobenzamide hydrochloride, m.p. 247 - 249C.;
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-ethoxy-4-acetamido-
5-chlorobenzamide, the fumarate of which melts at 173 - 175C., and
N-( cyclohexen-3'-ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chloro-
benzamide, m.p. 189 - 191C.
_ g
~,
~ ",, ,

1094075
The fumarates of th0 piperidine derivatives mentioned aboYe were
obtained by adding fumaric acid to a hot ethanolic solution of the piperidine
base, the amount of added acid being substantially equimolecular to that of
the piperidine base present, stirring the hot mixture until dissolution, and
then cooling the resulting solution to crystallize the fumarate.
EXAMPLE 2
To a warm solution of N-(l-cyclohexene-3'-ylmethylpiperid-4-yl)-2-
methoxy-4-amino_5-chlorobenzamide (3.5 g; 0.0093 moles) in acetone (75 ml.) a
solution of methyl iodide (2.63 g.; 0.0185 moles) in acetone (25 ml.) was slow-
ly added. The mixture was stirred at room temperature for 12 hours and thenheated under reflux for 4 more hours. The mixture was then concentrated in
vacuo to a small volume and the residue filtered off to give N-~l-cyclohexen-
3'_ylmethylpiperid-4-yl)-2-methoxy-4-amino-5-chlorobenzamide methyl iodide
(4 g.), m.p. 231 - 233C (dec.) after recrystallization from a mixture of
ethanol-water.
The following Examples illustrate pharmaceutical compositions accord-
ing to the present invention and procedures for their preparation.
EXAMPLE 3
100,~00 Tablets each containing 2 mg. of N-(l-cyclohexa-1',4'-
dienylmethylpiperid-4-yl)-2-methoxy-4-amino_5-chlorohenzamide hydrochloride
monohydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide hydrochloride
monohydr~te 200 g.
microcrystalline cellulose 1870 ~.
lactose spray dried 9880 g.
car~oxyme~hyl starch 430 g.
sodium stearyl fumarate 60 g.
colloidal silicon dioxide 60 g.

" 1094075
Procedure-
All the powders were passed through a screen with an opening of 0.6
mm. They were then all mixed in a suitable mixer for 20 minutes and compressed
into 125 mg. tablets using 6 mm. discs and flat bevelled punches. The disin-
tegration time of the tablets was about 60 seconds.
EXAMPLE 4
100,000 Capsules each containing 1 mg. of N-(l-cyclohexa-1',4'-di-
enylmethylpiperid-4-yl)-2-methoxy-4_amino_5_chlorobenzamide hydrochloride mono-
hydrate were prepared from the following formulation:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide hydrochloride
nohydrate 100 g.
lactose 9000 g.
sodium lauryl sulphate 370 g.
corn starch 8000 g.
alpine talc 530 g.
Procedure:
The above ingredients were sieved through a 40 mesh sieYe, then
mixed in a suitable mixer and distributed into 100,000 gelatine capsules (180
mg.).
EXAMPLE 5
10,000 Suppositories each containing 5 mg. o~ N-(l-cyclohexa-1',4'-
dienylmethylpiperid_4_yl)_2_methoxy-4_amino_5-chlorobenzamide hydrochloride
monohydrate were prepared as follows:
N-(l-cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide hydrochloride
monohydrate 50 g.
~heobroma oil 19950 g.
Proc _ ure:
The theobroma oil was melted and the N~ cyclohexa-1',4'-dienyl-

109~075
methylpiperid-4-yl)_2_methoxy-4-amino-5-chlorobenzamide hydrochloride monohyd-
rate suspended in it. The mixture was then poured into appropriate suppository
moulds to make 2.0 g. suppositories.
EXAMPLE 6
50,000 Ampoules each containing 2 mg. of N-(l-cyclohexa-1',4'-dienyl-
methylpiperid-4_yl)_2_methoxy_4_amino-5_chlorobenzamide hydrochloride monohyd-
rate were prepared from the following formulation:
N-(l-cyclohexa-1'-4'-dienylmethylpiperid-4-yl)_2_methoxy_4_amino-5-
chlorobenzamide hydrochloride monohydrate
monohydrate 100 g.
sodium chloride 500 g.
water injectable grade q.s. 100 litres
Procedure:
The N-(l -~yclohexa .1',4'_dienylmethylpiperid-4_yl)-2-methoxy-4-
amino-5_chlorobenzamide hydrochloride monohydrate and the sodium chloride were
dissolved in approximately 80 litres of water with slight heating. The solu-
tion was diluted with water to 100 litres passed through a bacteria-retaining
filter and filled into 2 ml. glass ampoules in known msnner. The production
of the injectable solution can take place under sterile conditions. It is also
possible to work under normal conditions and then to heat-sterilize the filled
ampoules.
EXAMPLE 7
1,000 Bottles of 150 ml. each containing 75 mg. of N-(l-cyclohexa-
1',4'-dienylmethylpiperid-4_yl)-2_methoxy_4_amino-S_chlorobenzamide hydrochlo-
ride monohydrate were prepared as follows:
N~ cyclohexa-1',4'-dienylmethylpiperid-4-yl)-2-methoxy-4-amino-5-
chlorobenzamide hydrochloride
monohydrate 75 g,
sorbitol 70000 g.
sorbic acid 125 g.

-~ 10~407S
citric acid 125 g.
distilled water q.s. 150 litres
flavouring agent q.s.
Procedure:
-
The N-(l-cyclohexa-1',4'-dienylmethylpeperid-4-yl)-2-methoxy-4-amino-
5-chlorobenzamide hydrochloride monohydrate and the sorbic acid were dissolved
in 100 litres of water and then the sorbitol, citric acid and flavouring agent
were added with stirring until dissolution. The mixture was diluted *o 150
litres and divided amongst the bottles.
Similar compositions to those described in Examples 3 to 7 can be
prepared having as the active ingredient piperidine derivatives of general
formula I other than N-(l-cyclohexa-$',4'-dienylmethylpiperid-4-yl)-2-methoxy-
4-amino-5-chlorobenzamide, for example other products conforming to that for-
mula mentioned in Example 1.
The piperidine derivatives of general formula IV are new compounds
and as such constitute another feature of the present invention.