COMPOSES A BASE DE 4-BENZYLOXYPIPERIDINE

4-BENZYLOXYPIPERIDINE COMPOUNDS

Abrégé anglais

A B S T R A C T
Piperidine derivatives of the general formula:
<IMG>
wherein R represents a hydrogen atom, or a (C1-4)alkyl
hydroxy(C1-4)alkyl, or (C1-4)alkoxycarbonyl radical
or a benzyl radical optionally carrying a substituent
selected from halogen atoms and (C1-4)alkoxy radicals
or the phenethyl radical, or the 3-phenylpropyl
radical, and X represents one or more hydrogen
or halogen atoms or (C1-4)alkyl, (C1-4)alkoxy,
trifluoromethyl or methylenedioxy radicals, or
alternatively X forms with the phenyl nucleus a naphthyl
radical, with the proviso that when R represents a
hydrogen atom X is other than a hydrogen atom, are
new compounds useful as medicaments and, more
particularly, as antidepressants. They may be
prepared by reaction of a 4-hydroxypiperidine with a
benzyl halide.

Revendications

- 22 -
The embodiments of the invention, in which an
exclusive privilege or property is claimed, are defined as
follows:
1. A process for the preparation of a
piperidine derivative of the general formula:
<IMG> (I)
wherein R represents a hydrogen atom, or a (C1-4)alkyl,
hydroxy(C1-4)alkyl, or (C1-4)alkoxycarbonyl radical,
or a benzyl radical or such radical carrying a substituent
selected from halogen atoms and (C1-4)alkoxy radicals,
or the phenethyl radical, or the 3-phenylpropyl
radical, and X represents one or more hydrogen or
halogen atoms or (C1-4)alkyl, (C1-4)alkoxy, trifluoromethyl
or methylenedioxy radicals, or alternatively X forms
with the phenyl nucleus a naphthyl radical, with the
proviso that when R represents a hydrogen atom
X is other than a hydrogen atom, which comprises
(A) the reaction of a compound of the general
formula:
<IMG> (II)

- 23 -
(wherein R1 represents a radical within symbol R as
hereinbefore defined, or a nitrogen-protecting radical
selected from substituted and unsubstituted benzoyl,
benzyl and alkyl radicals) with a compound of the general
formula:
<IMG> (III)
(wherein Y represents a reactive radical selected from
a chlorine or bromine atom, and X is as hereinbefore
defined) and, when R1 in the product obtained of the
general formula:
<IMG> (IV)
is other than a radical R as hereinbefore defined,
removing the nitrogen-protecting radical to yield a
piperidine derivative of general formula (I) wherein R
represents a hydrogen atom, or reducing a substituted
or unsubstituted benzoyl radical R1 in the compound
of general formula (IV) to a corresponding benzyl
radical, as is within the definition of symbol R, or

- 24 -
(B) in the case of a compound of general formula (I)
wherein R is other than a hydrogen atom, the reaction
of a piperidine derivative of the general formula:
(V)
<IMG>
(wherein X is as hereinbefore defined) with a compound
of the general formula:
Z-R2 (VI)
wherein Z represents a reactive atom or group such as
a halogen atom, and R2 represents a (C1-4)alkyl.
hydroxy(C1-4)alkyl or (C1-4)alkoxycarbonyl radical, or
a benzyl radical or such radical carrying a substituent selected
from halogen atoms and (C1-4)alkoxy radicals, or the
phenethyl radical or the 3-phenylpropyl radical,
and when an acid addition salt is required, reacting the
free base obtained with a corresponding acid.
2. Piperidine derivatives of the general
formula:
(I)
<IMG>

- 25 -
wherein R represents a hydrogen atom, or a (C1-4)alkyl,
hydroxy (C1-4)alkyl, or (C1-4)alkoxycarbonyl radical,
or a benzyl radical or such radical carrying a substituent
selected from halogen atoms and (C1-4)alkoxy radicals,
or the phenethyl radical, or the 3-phenylpropyl
radical, and X represents one or more hydrogen or
halogen atoms or (C1-4)alkyl, (C1-4)alkoxy,
trifluoromethyl or methylenedioxy radicals, or
alternatively X forms with the phenyl nucleus a
naphthyl radical, with the proviso that when R represents
a hydrogen atom X is other than a hydrogen atom, and
acid addition salts thereof, when prepared by the
process claimed in claim 1 or an obvious chemical
equivalent.
3. A process according to claim 1 wherein X
represents at least one chlorine atom, or forms with the
phenyl nucleus a naphthyl radical, or represents three
methoxy radicals.
4. Piperidine derivatives as defined in formula
(I) in claim 2 wherrein X represents one or more chlorine
atoms, or forms with the phenyl nucleus a naphthyl
radical, or represents three methoxy radicals, and acid
addition salts thereof, when prepared by the process
claimed in claim 3 or an obvious chemical equivalent.

- 26 -
5. A process according to claim 1 wherein X
represents at least one chlorine atom, or forms with the
phenyl nucleus a naphthyl radical, or represents three
methoxy radicals and R is a hydrogen atom or a (C1-4)
alkoxycarbonyl radical.
6. Piperidine derivatives as defined in formula
(I) in claim 2 wherein X represents at least one chlorine
atom, or forms with the phenyl nucleus a naphthyl radical,
or represents three methoxy radicals and R is a hydrogen
atom or a (C1-4) alkoxycarbonyl radical, when prepared
by the process claimed in claim 5 or an obvious chemical
equivalent.

Description

~ I 73039
-- 1 ~
DESCRIPTION
" P IPER ID INE DER IVAT IVE S, THE IR PREPARAT ION
AND PH~RM~CEUTICAL COMPOSITIONS CONTAINING T~EM"
The present invention relates to new
therapeutically useful piperidine derivatives, to a
process for their preparation, pharmaceutical
compositions containing them and their use in therapy.
5The piperidine derivatives of the present
invention are those compounds of the general formula: -
X CH2 - { ~N -- R ( I )
wherein R represents a hydrogen atom, or a (Cl 4)alkyl,
hydroxy(Cl 4)alkyl, or (Cl 4)alkoxycarbonyl radical,
or a benzyl radical optionally carrying a substituent
selected from halogen atoms and (Cl 4)alkoxy radicals, or
the phenethyl radical, or the 3-phenylpropyl radical, and
X represents one or more hydrogen or halogen atoms or
(Cl 4)alkyl, (Cl 4)alkoxy, trifluoromethyl or methylene-
dioxy radicals, or alternatively X forms with the phenylnucleus a naphthyl radical. with the proviso that when R
represents a hydrogen atom X is other than
a hydrogen atom, and pharmaceutically acceptable acid

~ 173039
addition salts thereof.
The piperidine derivatives of general formula (I)
are therapeutically useful in that they possess
antidepressive activity.
Preferred compounds of the invention are those
of general formula (I) wherein X represents one or more
chlorine atoms. or forms with the phenyl nucleus a
naphthyl radical, or represents three metho~y
radicals.
Of that class, those piperidine derivatives
wherein R represents a hydrogen atom are particularly
preferred.
According to a feature of the present invention,
the piperidine derivatives of general formula (I)
are prepared by the process which comprises the reaction
of a compound of the general formula:
r~ 1
HO ~ N-R (II)
(wherein Rl represents a radical within the definition
of symbol R, or a nitrogen-protecting radical such as
an optionally substituted benzoyl radical, e.g.
4-nitrobenzoyl, or an optionally substituted benzyl or
alkyl radical) with a compound of the general formula:

! 1 73 0 3 9
~ CH2-Y (III)
(wherein Y represents a .reactive radical such as a
chlorine or bromine atom, and X is as hereinbefore
defined) and, when Rl in the product obtained of the
general formula:
X ~ CH2 ~ N-Rl (IV)
is other than a radical R as hereinbefore defined, removing
the nitrogen-protecting radical to yield a compound of
general formula (I) wherein R represents a hydrogen
atom, or reducing by methods known E~ se an optionally
substituted benzoyl radical Rl in the compound of general
formula (IV) to a corresponding benzyl radical, as is within
~he definition of symbol R.
According to a further feature of the invention,
a piperidine derivative of the general formula:
~ CH2-0-~ ~ N-H (V)
X

~ 173039
-- 4 --
(wherein X is as hereinbefore defined) so obtained
by the aforedescribed process is converted to
another compound of general formula (I) by reaction
with a compound of the general ~ormula:
Z-R (VI)
wherein Z represents a reactive atom or group, e.g. a
halogen atom, and R represents a (Cl 4)alkyl, hydroxy-
(Cl 4)alkyl or (Cl 4)alkoxycarbonyl radical, or a benzyl
radical optionally carrying a substituent selected
from halogen atoms and (C1 4)alkoxy radicals, or the
phene-thyl radical or the 3-phenylpropyl radical.
Pharmaceutically acceptable acid addition
salts of the piperidine derivatives of general formula (I),
e.g. mandelates. fumarates, citrates and hydrochlorides,
may be obtained by methods known per se, for
example by treatment of the piperidine base with the
appropriate acid in a solvent medium. e.g. an ether
or an alkanol.
By the term 'methods known per se' as used
in this specification is meant methods heretofore used
or described in the literature.

! 1 7 3 0 3 9
The following Examples illustrate the
preparation of piperidine derivatives of the present
invention and acid addition salts thereof by the
hereinbefore described process. The analyses and the
IR and NMR spectra confirm the structure of the
compounds.
EXAMPLE 1
4-(4-Fluorobenzyloxy)-piperidine and its
mandelate
1(1) 1-(4-Nitrobenzoyl)-4 (0-r~lo~b_r~loxY)-Piperidine
A mixture of 1.6 g of a 50% aqueous sodium
hydroxide solution, 10 ml of methylene chloride, 2 y
(0.008 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine,
2.32 g (0.012 mol) of 4-fluorobenzyl bromide and 0.15 g
(4 x 10 4 mol) of tetrabutylammonium iodide is
stirred for 5 hours at 50C. After dilution of the
reaction medium with 20 ml of water and 30 ml of methylene
chloride, the organic phase is decanted, washed with
water until the washings are neutral. dried (MgSO4) and
evaporated in vacuo. The residual oil obtained
crystallises on stirring in diethyl ether. This yields
2.23 g of a product which is purified by dissolving it
in 11 ml of dimethylformamide (DMF) and reprecipitating
it by the dropwise addition of 11 ml of water, whilst
stirring. After washing with water and drying in
vacuo, l-(4-nitrobenzoyl)-4-(4-fluorobenzyloxy)-

! 1 730 39-- 6
piperidine, m.p. 120C. is obtained.
1(2) 4-(4-Fluorobenzyloxy)-piperidine (mandelate)
A mixture of 11.48 g (0.032 mol) of the
product obtained under 1(1), 192 ml of 96 ethanol and
48 ml of lOM aqueous potassium hydroxide solution is
stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is
taken up in 200 ml of water, 72 ~ of sodium chloride
and 200 ml of diethyl ether. After filtration. the
10 aqueous phase is extracted twice with 200 ml of diethyl
ether and the total organic phase is dried (MgS04)
and evaporated in vacuo.
This yields an oil which is converted to the
d,l-mandelate by dissolving it in 100 ml o-f diethyl ether
15 and adding 4.57 g (0.03 mol) of d,1-mandelic acid.
The salt obtained is filtered off and recrystallised
from isopropanol. Its melting point is 146C.
EXAMPLE 2
4-(3,4,5-Trimethoxybenzyloxy)-piperidine and
its mandelate
2(1) 1-(4-Nitrobenzoyl)-4-(3,4,5-trimethoxybenzYloxy)-
piperidine
A mixture of 0.8 g of 50% aqueous sodium
hydroxide solution, 5 ml of methylene chloride, 1 g
25 (0.004 mol) of 1-(4-nitrobenzoyl)-4-hydroxypiperidine,
1.30 g (0.006 mol) of 3,4,5-trimethoxybenzyl chloride

! 1 7 30 39
-- 7
and 0.08 g (2 x 10 4 mol) of tetrabutylammonium iodide
is stirred for 5 hours at 50C. After dilution with
10 ml of water and 15 ml of methylene chloride, the
organic phase is decanted, washed with water until the
washings are neutral, dried (MgS04) and evaporated ln
vacuo. The residual oil obtained crystallises on
stirring in diethyl ether. This yields 1.36 g (79%) of
a product which is purified by dissolving it in 7 ml
of DMF and slowly reprecipitating it with 7 ml of water.
After washing with water and drying in vacuo,
1-(4-nitrobenzoyl)-4-(3,4,5-trimethoxybenzyloxy)-
piperidine, m.p. 124C, is obtained.
2(2) 4-(3,4,5-Trimethoxybenzyloxy)-piperidine (mandelate)
A mixture of 12 g (0.028 mol) of the product
obtained under 2(1), 168 ml of 96 ethanol and
48 ml of lOM aqueous potassium hydroxide solution is
stirred under nitrogen and heated for 4 hours at 50C.
The alcohol is driven off in vacuo and the residue is
taken up in 70 ml of water, 25.2 g of sodium chloride
and 70 ml of chloroform. After filtration, the aqueous
phase is extracted twice with 70 ml of chloroform
and the total organic phase is dried (MgS04) and
evaporated in vacuo. This yields a pasty solid
which is converted to the dll-mandelate by dissolving
it in 120 ml of methanol, adding 4.26 g (0.028 mol) of
d,l-mandelic acid and filtering the medium after it has

~ 1 73039
-- 8 --
been stirred overnight at ambient temperature. The
precipitate obtained is recr~stallised from methanol.
The product crystallises with half a molecule o-E
water. Its melting point is 114C.
S EXAMPLE 3
l-Ethoxycarbonyl-4-benzyloxypiperidine
CH2 0~ - COOC2H5
3,4 g (0.033 mol) of ethyl chloroformate are
added dropwise to a stirred mixture of 6.83 g
(0.03 mol) of 4-benzyloxypiperidine hydrochloride,
7.74 g (0-056 mol) of dry K2C03, 26 ml of water
and 26 ml of chloroform. After stirring for 1 hourl
the organic phase is decanted after dilution with 54 ml
of chloroform, and wash~d 3 times with 20 ml of water
and dried (MgS04). Evaporation of the solvent in vacuo
gives a liquid. which is distilled ln vacuo.
Boiling point (0.4 mm Hg): 149-151C;
n21 - 1.5178.
EXAMPLE 4
1-Methyl-4-(4-chlorobenzyloxy)-piperidine and
its hydrochloride
In a 500 ml three-necked round-bottomed flask
placed under an argon atmosphere, 4.4 g (0.1 mol) of a

! 1 7 3 0 3 9
_ g _
55% suspension of sodium hydride in oil are washed
3 times with petroleum ether. 10.1 g (0.1 mol)
of l-methyl-4-hydroxypiperidine, dissolved in 100 ml of
DMF, are then added. The mixture is stirred for 1
hour at ambient temperature and then cooled with a
bath of iced water, and 19.3 g (0.~2 mol) of
~-chlorobenzyl chloride. dissolved in 50 ml of DMF,
are added. Once the introduction has ended, the
mixture is stirred for 4 hours at ambient temperature
and left to stand overnight. The reaction medium is
poured into iced water and extracted 3 times with
diethyl ether. The organic phase is washed once with
water and then extracted with dilute HCl (1-2 N).
The aqueous phase is then rendered alkaline with NaOH.
It is extracted with diethyl ether and the ether
extract is then washed 4 times with water. It is
dried over magnesium sulphate, riltered and concentrated.
The oil obtained is distilled twice and the
fraction passing over at 94-98C/0.04 mm Hg is collected.
This yields an oil. which is taken up in diethyl ether,
and the hydrochloride is precipitated by adding hydrogen
chloride. The hydrochloride is filtered off and rinsed
with diethyl ether. It is taken up in the minimum amount
of hot isopropanol. 5 times the volume of ethyl
acetate is then added and the compound is left to
recrystallise. The hydrochloride melts at 149-151~C.

~ 173039
-- 10 --
EXAMPLE 5
l-senzyl-4-(3~4~5-trimethox~benzyloxy)
piperidine and its Eumarate
In a 250 ml three-necked round-bottomed
flask placed under a nitrogen atmosphere, 2.2 g (0.05 mol)
of a 55% suspension of sodium hydride in oil are washed
3 times with petroleum ether. 9.6 g (0.05 mol) of
l-benzyl-4-hydroxypiperidine, dissolved in 30 ml
of DMF, are then introduced. Once the addition has
ended, the mixture is stirred for l hour at ambient
temperature. 13 g (0.06 mol) of 3,4,5-trimethoxy-
benzyl chloride in 30 ml of DMF are then added, whilst
cooling with a bath of iced water. The mixture is
stirred for 5 hours at ambient temperature and then left
to stand overnight. The reaction medium is poured
into iced water and then extracted with diethyl ether.
The product is then extracted with dilute HCl. The
aqueous phase is rendered alkaline with NaOH and then
extracted with diethyl ether, and the ether extract
is washed with water, dried over MgS04, filtered and
concentrated. The oil obtained is taken up in hot
pentane. The product crystallises. It is filtered
off and recrystallised from isopropanol. This yields
the base. which is dissolved in 70 ml of ethanol, and a
25 filtered solution of 2.9 g (0.025 mol) of fumaric acid
in 140 ml of ethanol is added. The fumarate salt

! 1 7303 9
-- 11 --
formed is filtered off and dried. Its melting point
is 160-161C.
EXAMPLE 6
1-(4-ChlorobenzYl)-4-~3,4.5-trimethoxybenzYloxv)-
piperidine and its fumarate
6(1) 1-(4-ChlorobenzoYl)-4-hydroxypiperidine
30 g (0.296 mol) of 4-hydroxypiperidine, 260 ml
of CHC13, 57.3 g (0.414 mol) of K2C03 and 260 ml of water
are placed in a one litre Erlenmeyer flask. 51.8 g
(0.2g6 mol) of ~-chlorobenzoyl chloride, dissolved in
50 ml of CHC13, are added in the course of 15 minutes.
whilst cooling with a bath of iced water. The mixture is
stirred overnight at ambient temperature. The organic phase
is decanted, the aqueous phase is extracted with CHC13 and
the CHC13 extract is washed with water until the pH is
6-7. It is dried over MgS04, filtered and concentrated.
The product is recrystallised from ethyl acetate.
6(2) 1-(4-ChlorobenzoYl)-4-(3,4.5-trimethox~benzyloxy)-
piperidine
In a three-necked round-bottomed flask under
a nitrogen atmosphere, 0.96 g (0.022 mol) of a 55%
suspension of sodium hydride in oil is washed 3 times
with petroleum ether. 4.8 g (0.02 mol) of 1-(4-chloro-
benzoyl)-4-hydroxypiperidine obtained as described in
6(1), dissolved in 50 ml of DMF, are then added. After
the addition has ended, the mixture is stirred for 1

~ 1 73039
- ~2 -
hour at ambient temperature. It is -then cooled with a
bath of iced water, and 5.4 g (0.025 mol) of
3,4,5-trimethoxybenzyl chloride, dissolved in 10 ml
of DMF, are added. The mixture is stirred for 3 hours
at ambient temperature and then left to stand
overnight. It is poured into iced water and extracted
with ethyl acetate. The ethyl acetate extract is
washed with water, dried over MgS04, filtered and
concentrated. The oil obtained is taken up in diethyl
ether and the solution is then filtered. The filtrate
is concentrated and passed through an alumina column
(eluant: CHC13). The product does not crystallise and
is used as such in the following step.
6(3) 1-(4-Chlorobenzyl)-4-(3,4,5-trimethoxybenzyloxy)-
piperidine and its fumarate
In a round-bottomed flask under a nitrogen
atmosphere, 7 g (0.0167 mol) of the product obtained
under 6(2), dissolved in 70 ml of dry diethyl ether,
are added at ambient temperature to a suspension of
0.38 g (0.01 mol) of AlLiH4 in 30 ml of dry diethyl
ether. The mixture is heated for 3 hours at the reflux
temperature. It is hydrolysed with 2.6 ml of isopropanol
and 3.3 ml of a saturated aqueous solution of NaCl.
The mixture is filtered and the material on the filter
is rinsed with diethyl ether. The product is extracted
into dilute hydrochloric acid and the reaction mixture

~ 173039
- 13 -
is then rendered alkaline with N~I~OH and extracted
with diethyl ether. The ether extract is washed
with water, dried over MgSO4, filtered and
concentrated. This yields an oil, which is dissolved
in 30 ml of e-thanol and the solution is added to a
filtered solution of 1.2 g (0.0105 mol) of fumaric
acid in 60 ml of ethanol. The fumarate precipitates
gradually. It is filtered off, rinsed with a small
amount of ethanol and then with diethyl ether, and
dried. Its melting point is 178-180C.
~ he compounds of the invention prepared by
procedures described in the foregoing Exarnples are
shown in the following Table.

' 173039
-- 14 --
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1 1 73039
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' 173039
-- 16
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" 73039
-- 17 --
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~ 1 73039
-- 18 --
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~ 173039
-- 19 --
The piperidine derivatives of general formula (I)
of the present invention were subjected to pharmacological
experiments which demonstrated their antidepressive
activity.
The toxicity of the compounds was determined on
mice by intraperitoneal administration. The LD50
varies from 30 to 1000 mg/kg animal body weight.
The antidepressive activity was determined
by the test for the antagonism towards the ptosis caused
by reserpine (C. Gouret et al., J. Pharmacol. (Paris) 8,
333-350 (1977)).
Mice (male, CDl Charles River, France, 18-22 g)
simultaneously receive the products to be studied or the
solvent (administered intraperitoneally) and reserpine
(4 mg/kg animal body weight, administered
subcutaneously).
Sixty minutes later. the degree of palpebral
ptosis is estimated by means of a rating scale (0 to 4)
for each mouse.
For each dose, the average rating and the
percentage variation, compared with the control batch, are
calculated.
For each product, the AD 50, or the dose
which reduces the average ptosis score, compared with the
controls. by 50%, is determined graphically.

0 73039
- 20 -
The AD 50 varies from 4 to lO mg~kg animal
body weight, administered lntraperitoneally.
The antidepressive activity was also determined
by the test for potentiation of the head twitches caused
by L-5-hydroxytryptophan tH. Van Riezen (1972) Arch.
Int. Pharmacology. 198, 256-269).
The procedure is as follows:
24 hours before the experiment, the animals
are placed in the laboratory in which the operation is to
be carried out. On the day of the experiment, the
mice are weighed and put to sleep.
The products to be tested are then injected
intraperitoneally before L5-HTP is injected subcutaneously
in an amount of 125 mg/kg animal body weight as a
suspension in Tween. 30 minutes after the injection of
L5-HTP, the number of head twitches is counted for 60
seconds.
For each dose, the average number of head
twitches and the percentage variation, relative to the
control animals, are calculated. The 50% active dose
is established from a curve.
The AD 50 varies from 0.1 to 5 mg~kg animal
body weight, administered intraperitoneally.
The pharmacological results show that the
piperidine derivatives of the present invention can be
useful for the treatment of depression.

t 1 73039
- 21 -
The compounds of the invention can be
presented in any form suitable for oral or parenteral
administration. for example in the form of tablets,
coated tablets, capsules, solutions to be -taken orally
or injected, and the like, in association with any
suitable excipient.
The daily posology can range from 5 to 200 mg.