FR2481278A1 - Antidepressant 4:benzyloxy piperidine(s) - are prepd. from 4:hydroxy piperidine and benzyl halide - Google Patents

Abstract

Benzyl piperidine derivs of formula (I) and their acid addn salts, are new. (where R is H, alkyl, hydroxyalkyl, cycloalkyl, alkyl-aryl, alkyl-cycloalkyl, aryl, arylalkylidene, alkoxycarbonyl, alkanoyl, or arylcarbonyl; R1, R2 and R3 may be the same or different and are H, halogen, alkoxy, alkyl, nitro, cyano, amino, mono- or di-alkylamino, trihaloalkyl, or a group -CONR4R5; R4 and R5 is H or alkyl; or R1 is as defined and R2 and R3 together form a methylene- or ethylene-dioxy group in which the two 0 atoms are on adjacent C atoms of the phenyl ring; all the alkyl, alkoxy, and alkylidene groups have 1-6C and cycloalkyl groups have 3-6C; with the proviso that R, R1, R2 and R3 are not all H). Used as antidepressants at dialy dosage of 2-20 mg/kg given orally.

Description

 The present invention relates to peridine derivatives, to a process for their preparation and to their therapeutic application, particularly as antidepressants.

dans laquelle
- R représente un atome d'hydrocgène, un groupe alkyle en C1-C6, un groupe hydroxyalkyle en C1-C6, un groupe cycloalkyle en C3-C6 un groupe alkyl (C1-C6) aryle, notamment alkyl (C1-C6), phényle, un groupe alkyl (C1-C6) cycloalkyle (C3-C6) , un groupe aryle, notamment un groupe phényle, un groupe arylalkylidène (C1-C6), notamment un groupe phénylalkylidène (C1-C6), un groupe alkoxy (C1-C6) carbonyle, un groupe alcanoyle en C1-C6, un groupe arylcarbonyle, notamment benzoyle,
- R1, R2 et R3 représentent indépendamment ltun de l'autre un atome d'hydrogène, un atome d'halogène, un groupe alkoxy en C1 -C6, un groupe allyle en C1 -C6, un groupe nitro, cyano, amino, mono- ou dialkyl (C1-C6) arnino, un groupe trie haloalkyle en C1-C6 ou un groupe -CONR R dans lequel R4 et
R5 représentent un atome d'hydrogène ou un groupe alkyle en
C1-C6'
ou bien R1 a la signification donnée précédemment et R2 et R3 représentent ensemble un radical méthylène- ou éthylène-dioxy dont les 2 atomes d'oxygène sont fixés sur des atomes adjacents du noyau phényle,
R, R1, R2 et R ne représentant pas simultanément un atome d'hydrogène,
ainsi que leurs sels d'addition avec des acides pharmaceutiquement acceptables,
Une classe avantageuse de composés de formule I est celle dans laquelle
R est un atome d'hydrogène, un groupe alkyle en C1 - C6 ,
un groupe hydroxy alkyle en C1 - C6 ou un groupe alko
xy (C1 - C6) carbonyle,
R1 représente un atome d'hydrogène, un atome d'halogène,
un groupe alkoxy en C1 - C6, un groupe alkyle en Cl
C6 ou un groupe trifluorométhyle et R2 et R3 représen
tent des atomes d'hydrogène, des groupes alkoxy en C1 -
C6 ou forment ensemble un groupe méthylène dioxy dont
les atomes d'oxygène sont fixés sur des atomes de Car-
bone adjacents du noyau phényle.The present invention relates to compounds of formula

in which
R represents a hydrocene atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group, a C 3 -C 6 cycloalkyl group or a (C 1 -C 6) alkyl aryl group, especially a (C 1 -C 6) alkyl group; phenyl, a (C 1 -C 6) alkyl (C 3 -C 6) alkyl group, an aryl group, in particular a phenyl group, a (C 1 -C 6) arylalkylidene group, in particular a phenylalkylidene (C 1 -C 6) group or an alkoxy group (C 1 -C 6) -C6) carbonyl, a C1-C6 alkanoyl group, an arylcarbonyl group, especially benzoyl,
- R1, R2 and R3 represent independently of each other a hydrogen atom, a halogen atom, a C1-C6 alkoxy group, a C1-C6 allyl group, a nitro, cyano, amino, mono group; or dialkyl (C1-C6) arnino, a C1-C6 haloalkyl group or a -CONR R group in which R4 and
R5 represent a hydrogen atom or an alkyl group
C1-C6 '
or else R 1 has the meaning given above and R2 and R3 together represent a methylene- or ethylene-dioxy radical whose 2 oxygen atoms are attached to adjacent atoms of the phenyl nucleus,
R, R1, R2 and R not simultaneously representing a hydrogen atom,
as well as their addition salts with pharmaceutically acceptable acids,
An advantageous class of compounds of formula I is that in which
R is a hydrogen atom, a C1-C6 alkyl group,
a C1-C6 hydroxyalkyl group or an alkoxy group
xy (C1 - C6) carbonyl,
R1 represents a hydrogen atom, a halogen atom,
a C1-C6 alkoxy group, a C1-C6 alkyl group
C6 or a trifluoromethyl group and R2 and R3 represent
hydrogen atoms, C1-alkoxy groups
C6 or together form a methylene dioxy group of which
the oxygen atoms are attached to carbon atoms
adjacent bones of the phenyl ring.

 The addition salts may be those formed for example with the hydrohalic, sulfuric, nitric, phosphoric, formic acids. citric, mandelic, acetic, maleic, fumaric, methane sulfonic, lactic, succinic, tartaric and acidic metal salts such as ortho-disodium phosphate or monopotassium sulfate.

dans laquelle R a la meme signification que dans la formule
I,
avec un composé de formule III

dans laquelle R1, 2 R3 ont la même signification que dans la formule I et Y est un radical réactif, de préférence un atome de chlore ou de brome.The compounds of formula I can be prepared by reaction of a compound of formula II

in which R has the same meaning as in the formula
I
with a compound of formula III

in which R 1, 2 R 3 have the same meaning as in formula I and Y is a reactive radical, preferably a chlorine or bromine atom.

 The condensation may be carried out in a water immiscible solvent, in the presence of aqueous sodium hydroxide and a phase transfer catalyst (quaternary ammonium salts with long carbon chains, for example, or ether-crowns), with temperatures between 200 and 110 OC.

To obtain the compounds of formula I in which R = H, it is preferable to react on the derivatives of formula III a compound of formula II in which
R = CO - R6, wherein R6 is a C1-C6 alkyl, C1-C6 alkoxy, aryloxy, aryl, or aryl radical substituted for example by a nitro group, The nitrogen acylating group (-CO-R6) is then removed by hydrolysis, preferably basic.

 To obtain the compounds of formula I in which R is other than H, direct or indirect alkylation or acylation of a compound of formula I in which R is a hydrogen atom can also be carried out.

The following examples illustrate the present invention: EXAMPLE 1 4-Fluoro-4-benzyloxy piperidine

1.1-benzoyl-1-fluoro-4-benzyloxy
-4 piperidine
A mixture of 1.6 g of 50% aqueous sodium hydroxide, 10 ml of dichloromethane, 2 g (0.008 mol) of (4-nitrobenzoyl) -1-hydroxy-4-piperidine, 2.32 g (0.012 mol) ) of 4-fluoro-benzyl bromide and 0.15 g (4 x 4-nitro-10-4 mol) of tetrabutylammonium iodide is stirred for 5 h at 50 OC. After dilution of the reaction medium with 20 ml of water and 30 ml of dichloromethane, the organic phase is decanted, washed with water until neutral, dried (MgSO 4) and evaporated under vacuum. The residual oil obtained is crystallized by stirring. in ether. 2.23 g (78%) of a product which is purified by dissolution in 11 ml of dimethylformamide (DMF) and reprecipitation by dropwise addition of 11 ml of water, with stirring, are obtained. After washing with water and drying under vacuum, 1.60 g (72%) of (4-nitrobenzoyl) -1 are obtained.
(4-fluoro-benzyloxy) -4 piperidine. Finst = 120 C.

1.2 - (4-fluoro-benzyloxy) -4 piperidine (mandelate)
A mixture of 11.48 g (0.032 mol) of the product obtained in 1-1, 192 ml of ethanol at 960 and 48 ml of 10 M aqueous potassium hydroxide is stirred under nitrogen and heated for 4 h to 50 OC.

The alcohol is removed under vacuum, the residue taken up in 200 ml of water, 72 g of sodium chloride and 200 ml of ether. After filtration, the aqueous phase is extracted twice with 200 ml of ether, the total organic phase is dried (MgSO4) and evaporated under vacuum.

 6.29 g (94%) of an oil is obtained which is converted to d, 1-mandelate by dissolving in 100 ml of ether and adding 4.57 g (0.03 mol) of dichloromethane. -mandelic.

The salt obtained is filtered and recrystallized from isopropanol.

Yield: 6.94 g (64%). F. t = 1460C
EXAMPLE 2 Piperonyloxy-4-piperidine

2.1-. (4-nitro benzoyl) -1 piper
piperidine
A mixture of 8 g of 50% aqueous sodium hydroxide, 50 ml of dichloromethane, 10 g (0.04 mol) of (4-nitrobenzoyl) -1-hydroxy-4-piperidine, of 10.23 g (0.06 mol) ) of piperonyl chloride and 0.8 g (0.002 mole) of tetrabutylammonium iodide, is stirred for 5 h at 50 OC. After dilution with 100 ml of water and 150 ml of dichloromethane, the organic phase is decanted, washed with water to neutrality, dried (MgSO4) and evaporated under vacuum. The residual oil crystallized by stirring in ether. 11.17 g (73%) of a product which was purified by dissolution in 55 ml of DMF and slow reprecipitation by addition of 55 ml of water. After filtration, washing with water and drying under vacuum, 8.67 g (56%) of (4-nitro-benzoyl) -1-piperonyloxy-4-piperidine, Finst = 98 ° C. are obtained.

2.2 - Piperonyloxy-4 piperidine (mandelate)
A mixture of 8.37 g (0.022 mol) of the product obtained in 2.1, 134 ml of 96 ethanol and 33 ml of 10 M aqueous potassium hydroxide is stirred under nitrogen and heated for 4 hours at 50 ° C.

The alcohol is removed under vacuum, the residue taken up in 60 ml of water, 21 g of sodium chloride and 60 ml of dichloromethane. After filtration, the aqueous phase is extracted with twice 60 ml of dichloromethane, the total organic phase is dried (MgSO4) and evaporated under vacuum.

 4.7 g (91%) of an oil is obtained which is formed into d, 1-mandelate by dissolving in 80 ml of meth.

thanol and addition of 3.04 g (0.02 mol) of d, 1-mandelic acid. The solvent is evaporated under vacuum, and the residue is recrystallized from isopropanol.

Yield e 3.95 g (51%) Finit = 1370C
EXAMPLE 3 (3,4,5-trimethoxybenzyloxy) piperidine

3.1 - (4-nitrobenzyl) -1 (3,4,5-trimethoxy)
benzyloxy) -4 piperidine
A mixture of 0.8 g of 50% aqueous sodium hydroxide of 5 ml of dichloromethane, 1 g (0.004 mol) of (4-nitrobenzoyl) -1-hydroxy-4-piperidine, 1.30 g (0.006 mol) of 3,4,5-trimethoxy benzyl chloride and 0.08 g (2 x mole) of tetrabutylammonium iodide is stirred for 5 h at 50 OC. After dilution with 10 ml of water and 15 ml of dichloromethane, the organic phase is decanted, washed with water to neutrality, dried (MgSO 4) and evaporated in vacuo. The residual oil obtained crystallized by stirring in 11 ether.

1.36 g (79%) of a product which is purified by dissolution in 7 ml of DMF and slow reprecipitation with 7 ml of water are obtained. After washing with water and drying under vacuum, there are obtained 1.14 g (66%) of (4-nitrobenzoyl) -1 (4-trimethoxy-3-benzyloxy) piperidines Finit = 1240 ° C.
3.2 - (3,4,5-trimethoxy-4-benzyloxy) piperidine
(Mandelate)
A mixture of 12 g (0.028 mol) of the product obtained in 3.1, 168 ml of 96 ethanol and 48 ml of 10 M aqueous potassium hydroxide is stirred under nitrogen and heated for 4 h to 50 OC. The alcohol is removed under vacuum, the residue 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 with twice 70 ml of chloroform, the total organic phase is dried (MgSO4) and evaporated under vacuum.

 7.85 g (100%) of a pasty solid which is converted to d, 1-mandelate by dissolving in 120 ml of methanol, adding 4.26 g (0.028 mol) of mandelic acid and filtration are obtained. after stirring the medium overnight at room temperature. The precipitate obtained is recrystallized from methanol. The product crystallizes with half a molecule of water.

Yield: 6.87 g (57%)
Finst: 114 C
In a similar manner to Examples 1, 2 and 3, the initial acylated compounds indicated in Table I are obtained by hydrolysing the corresponding final products. Example Initial acylated compound Finst Product findi Finst
Example 4 (4-nitrobenzyl) -1 (2-methyl-2-methyl-2-methyl-2-mandelate oil
benzyloxy) -4 piperidine benzyloxy) -4 piperidine
Example 5 (5-nitrobenzyl) -1 (methyl-4117C) methyl (4-methyl-4-aml) -1-mandelate
benzyloxy) -4 piperidine benzyloxy) -4 piperidine
Example 6 (4-nitro-benzyl) -1 (trifluoromethyltrifluorocarbon)
3-methyl-benzyloxy) -4-methyl-3-benzyloxy) piperidine
piperidine
Example 7 (4-nitrobenzyl) -1 (methox-2H 170 C hydrochloric acid
xy-2 benzyloxy) -4 piperidine benzyloxy) -4 piperidine
EXAMPLE 8 (4-nitrobenzyl) -1 (methoxy-3-methylene-1,1-mandelate methylene ether)
xy-3 benzyloxy) -4 piperidine benzyloxy) -4 pipxeridine TABLE I
EXAMPLE 12 Methyl-1-benzyloxy-4-piperidine (mandelate)

 A solution of 2.27 g (0.01 mol) of benzyloxy-4-piperidine hydrochloride, prepared as in Example 1 through p-nitrobenzoyl-1-benzyloxy-4-piperidine (F = 119 C), of 33 1 ml of methanol, 0.84 g (0.01 mol) of sodium bicarbonate and 9.3 ml of 38% solution of formaldehyde in water are stirred for 30 minutes under reflux. The medium is immersed in an ice bath and after cooling, 1.5 g of sodium borohydride are gradually incorporated. After stirring overnight at room temperature, the solvent is evaporated in vacuo, the residue is stirred with 100 ml of dichloromethane, the filtered solution is dried (MgSO4).

 The product obtained by evaporation (1.65 g, 80%) is converted into d, 1-mandelate by dissolving it in 30 ml of ether, adding 1.22 g of d, 1-mandelic acid and filtration after stirring. night at room temperature.

Yield: 2.49 g (87%) F. t = 118 ° C
EXAMPLE 13 Ethoxycarbonyl-1-benzyloxy-4-piperidine

To a stirred mixture of benzyloxy-4-piperidine hydrochloride (6.83 g, 0.03 mol), 7.74 g (0.056 mol) of dry K 2 CO 3, 26 ml of water and 26 ml of chloroform were added. 3.4 g (0.033 mole) of ethyl chloroformate are added dropwise. After stirring for 1 h, the organic phase is decanted after dilution with 54 ml of chloroform, and washed with 3 times 20 ml of water, dried. (MgS04). Evaporation of the solvent under vacuum makes it possible to obtain a liquid which
21 is distilled under vacuum: Eb 0.4: 149-151 C: n D = 1.5178,
Yield: 4.98 g (63%)
EXAMPLE 14: (2-hydroxyethyl) -1 (trifluoromethyl-2)
benzyloxy) -4 piperidine (hydrochloride)

 A stirred mixture of 5.19 g (0.02 mol) of 4- (trifluoromethyl-3-banzyloxy) piperidine (compound of Example 6), 80 ml of n-butanol and 3.75 g 3 mol of 2-bromoethanol is heated for 7 hours to reflux the solvent is evaporated under vacuum, the residue is taken up in 100 ml of saturated aqueous sodium bicarbonate solution, 36 g of sodium chloride are added and the mixture is extracted with 200 g of sodium bicarbonate. After filtration, the aqueous phase is extracted twice with 200 ml of ether, the total organic phase is dried (MgSO 4) and evaporated.

 5.44 g (82%) of a yellow oil is obtained, to which a hydrochloric acid solution of ethanol is added. After evaporation of the solution, the hydrochloride residue is washed with ether, separated and dried.

Recrystallization from ethyl acetate gives 3.13 g (41%) of product. Finst = 1020C
EXAMPLE 15 Isopropyl-1 (3,4,5-trimethoxybenzylosyl) -4
piperidine (citrate)

 A stirred mixture of 6.6 g (0.015 mole) of (4,4-trimethoxy-4-benzyloxy) piperidine dl-mandelate (compound of Example 3), 10.36 g (5 × 0.015 mole) of potassium carbonate, 5.54 g (3 x 0.015 mole) of isopropyl bromide and 66 ml of n-butanol is brought to reflux for 16 hours. The solvent is removed under vacuum, the residue is dissolved in 100 ml of dichloromethane, the filtered solution is brought to dryness under vacuum. 4.32 g (89%) of an oil are obtained to which are added 10 ml of ethanol and 2.81 g of citric acid monohydrate. The citrate is filtered after stirring the solution overnight at room temperature.

5.52 g (95%) of product crystallizing with 0.7 molecule of water are obtained. Finst = 94-950C.

EXAMPLE 16 Ethoxycarbonyl-l (3,4,4-trimethoxy-benzyl)
loxy) -4 piperidine

It is prepared from the dl-mandelate of
(3-trimethoxy-4-benzyloxy) -4 piperidine (compound of Example 3) according to the technique described in Example 13. Finst = 64 C.

EXAMPLE 17 Isopropyl-1 (trifluoromethyl-3) benzyloxy) -4
piperidine (fumarate)

 It is prepared from (4-trifluoromethyl-3-benzyloxy) piperidine dl-mandelate (compound of Example 6) according to the technique described in Example 15. Finst 1170C.

 The compounds of formula I and their addition salts with pharmaceutically acceptable acids have valuable pharmacological properties, including antidepressant properties. They also exhibit a toxicity which appears only at doses much higher than the pharmacologically active doses, which allows their use in therapy. The results of the toxicological and pharmacological studies which highlight these properties will be given below.

I - Toxicities, aided in mice
The compounds of formula I are administered in increasing doses (in arithmetic or geometric progression) to batches of 5 female mice, SWISS, EOPS, NMRI / Han originating from EVIC CEEA breeding and having an average weight of 25 g.

 Where possible, the compounds are dissolved in distilled water for intravenous, intraperitoneal and oral administration.

 When the compounds are insoluble or poorly soluble in distilled water, they are suspended in the 10% pseudo solution of gum arabic for oral administration and in the pseudo solution of 0.5% carboxymethylcellulose. for intraperitoneal administration.

 The LD 50 values are calculated by the method of BEHRENS (B.) and KARBER (C.) (Arch Exp Path Pharmakol 1935, 177, 379-388).

 The number of surviving animals in the different batches is definitely checked 15 days after administration of the compounds.

The results are given in Table II - TABLE II: Acute Toxicities in Mice

<tb><SEP> Compound <SEP> DL <SEP> 50 <SEP> in <SEP> mg / kg <SEP> DL <SEP> 50 <SEP> in <SEP> mg / kg <SEP> DL <SEP> 50 <SEP> in
<tb><SEP> Example <SEP> Route <SEP> Route <SEP> uintra- <SEP> mg / kg
<tb><SEP> n <SEP> intravenous <SEP> peritoneal <SEP> Oral <SEP> oral
<tb> 1 <SEP> 72 <SEP> 65 <SEP> 197
<tb><SEP> 2 <SEP> 42 <SEP> 50 <SEP> 215
<tb><SEP> 3 <SEP> 215 <SEP> 625 <SEP> 1 <SEP> 750
<tb><SEP> 4 <SEP> 48 <SEP> 87 <SEP> 270
<tb><SEP> 5 <SEP> 45 <SEP> 71 <SEP> 525
<tb><SEP> 6 <SEP> 66 <SEP> 79 <SEP> 300
<tb><SEP> 7 <SEP> 41 <SEP> 71 <SEP> 260
<tb><SEP> 8 <SEP> 47 <SEP> 58 <SEP> 165
<tb> 9 <SEP> 49 <SEP> 62 <SEP> 187
<tb> 10 <SEP> 44 <SEP> 79 <SEP> 250
<tb><SEP> 12 <SEP> 44 <SEP> 92 <SEP> 360
<tb> 13 <SEP> - <SEP> 475 <SEP> 2 <SEP> 500
<tb> 14 <SEP> 64 <SEP> 175 <SEP> 775
<tb><SEP> 15 <SEP> 64 <SEP> 142 <SEP> 525
<tb><SEP> 16 <SEP> - <SEP>> 500 <SEP>> 2 <SEP> 500
<tb><SEP> 17 <SEP> 30 <SEP> 80 <SEP> 250
<Tb>
II - Psychotropic antidepressant effects
These effects were highlighted in the following tests
- Potentiation of the 5-hydroxytryptophan (5 HTP) head-trigger syndrome caused by 5-hydroxytryptophan in mice by inhibition of synaptically synthesized serotonin reuptake.

 - potentiation of the syndrome of hyperexcitation, salivation and piloerection caused by L-dihydroxyphenylalanine (L-DOPA) in mice, by inhibition of the reuptake of Noradrenaline formed.

a) Potentiation of the effects of 5 HTP in the
Spuris
The compounds are administered intraperitoneally to batches of 5 to 10 mice at doses corresponding to approximately 1/10 of their respective LD 50's intraperitoneally (a batch of control animals receive only the administration vehicle). distilled water with carboxy methylcellulose (0.5%).

30 minutes later 5 HTP is injected at the dose of 200 mg / kg intraperitoneally. For each mouse, the number of shakes of the whole y13 Y2 and y3 respectively 10, 20 and 30 minutes after injection of 5 HTP is then counted for 2 minutes and the area under the curve theoretically determined by graphical representation is calculated. measurements in abscissae and number of jerks on the ordinate) as follows
S = 2 y1 + 2 y2 + y3
For each lot of animals, we determine an area under the average curve (#S) / n assigned its standard deviation of the mean.

 Statistical comparisons with experimenters at the same time are then performed by the STUDENT t-test.

 For each compound the results are expressed as percentages of variations with respect to the controls. They are collated in Table III. It is clear from this table that the compounds of formula I have a significant effect in this test, and more particularly the compound of example 3.

TABLE III: Potentiation of the effects of 5 HTP
at the Mouse

<tb><SEP> Compounds <SEP> Doses <SEP>% <SEP> of <SEP> Overall <SEP> Variation <SEP> of <SEP> Number <SEP> of ani
<tb><SEP> example <SEP> mg / kg <SEP> severity <SEP> of <SEP> syndrome <SEP> sore <SEP> in
<tb><SEP> n <SEP> IP <SEP> of <SEP> jerks <SEP> of <SEP> the <SEP> head <SEP> experience
<tb><SEP> provoked <SEP> in <SEP> the <SEP> animals
<tb><SEP> processed <SEP> by <SEP> report
<tb><SEP> to <SEP> witnesses
<tb><SEP> 1 <SEP> 5 <SEP> + <SEP> 57 <SEP>% <SEP> 10
<tb><SEP> 3 <SEP> 30 <SEP> + <SEP> 197 <SEP>% <SEP> (p <SEP><<SEP> 0.001) <SEP> 15
<tb><SEP> 5 <SEP> 12.5 <SEP> + <SEP> 84 <SEP>% <SEP> 10
<tb> 6 <SEP> 7.5 <SEP> + <SEP> 68 <SEP>% <SEP> 10
<tb><SEP> 13 <SEP> 50 <SEP> + <SEP> 68 <SEP>% <SEP> 10
<tb><SEP> 17 <SEP> 12.5 <SEP> + <SEP> 182 <SEP>% <SEP> (p <SEP><SEP> 0.01) <SEP> 10
<Tb>
b) Potentiation of the effects of L-DOPA in
the mouse pretreated with an inhibitor of
monoaminoxidase (MAOI)
The day before the experiment, lots of 10 mice were treated with an IMAOI, Iiproniazide, at the dose of 60 mg / kg orally (administration in suspension in 10% gum arabic).

On the day of the experiment and at doses corresponding to 1/10 of their respective LD 50 orally, the compounds of formula I are administered orally (solutions in distilled water or suspensions in 10% gum arabic). 1 hour before the intraperitoneal injection of
L-DOPA at the dose of 100 mg / kg (suspension in 0.5% carboxymethylcellulose).

 A batch of control animals receive only the administration vehicle of the compounds and L-DOPA.

Every 10 min during the hour following the administration of L-DOPA, an overall assessment of the symptoms observed on 5 animals (a second series of 5 animals is also experimented thereafter) is carried out according to the following quotation
1 = slight piloerection, slight salivation
2 = piloerection, salivation, exophthalmia,
STRAUB phenomenon
3 = slight excitement, shuddering
4 = intense excitement, shuddering
5 = excitement, jumps, spontaneous cries
6 = excitement, jumps, intense spontaneous cries
7 = prostration.

 The more or less delayed mortality is also recorded in each batch of animals. For the control group and for the treated groups (10 animals), the scores obtained are added at each observation time. The percentages of variations are calculated with respect to the control group.

 The results are given in Table IV.

They demonstrate significant activity for a number of compounds and in particular for the compound of Example 13.

TABLE IV: Potentiation of the effects of L-DOPA
in the mouse pretreated by an MAOI

<tb> Compounds <SEP> Doses <SEP>% <SEP> of <SEP> global <SEP> variation <SEP> of <SEP><SEP> number of
<tb><SEP> example <SEP> mg / kg <SEP> severity <SEP> of <SEP> syndrome <SEP> deaths <SEP> to <SEP> la
<tb><SEP> n0 <SEP> PO <SEP> of hyperexcitation <SEP> caused <SEP> continued <SEP> of
<tb><SEP> in <SEP><SEP> animals <SEP> treated <SEP> experience
<tb><SEP> by <SEP> report <SEP> to <SEP> witnesses
<tb><SEP> 3 <SEP> 175 <SEP> + <SEP> 102 <SEP>% <SEP> 0/10
<tb><SEP> 9 <SEP> 20 <SEP> + <SEP> 70 <SEP>% <SEP> 0/10
<tb><SEP> 10 <SEP> 25 <SEP> + <SEP> 65 <SEP>% <SEP> I / 10
<tb><SEP> 12 <SEP> 35 <SEP> + <SEP> 50 <SEP>% <SEP> 0/10
<tb><SEP> 13 <SEP> 250 <SEP> + <SEP> 130 <SEP>% <SEP> 8/10
<tb><SEP> 14 <SEP> 80 <SEP> + <SEP> 68 <SEP>% <SEP> 1/10 <SEP> j
<tb><SEP> 16 <SEP> 250 <SEP> + <SEP> 100 <SEP>% <SEP> 0/10
<tb><SEP> 17 <SEP> 25 <SEP> + <SEP> 54 <SEP>% <SEP><SEP> 0/10
<Tb>
The compounds of formula I and their addition salts with pharmaceutically acceptable acids are manly or rectally administrable or injectable in depressions of any kind, endogenous, reactional or involutional.

 They may be presented in the form of tablets, capsules or any other form for the oral route, in the form of suppositories and preparation for the injectable route.

 The daily dosage may vary from 2 to 20 mg / kg for the oral route.

Claims (8)

R B V E N D I C AT IO N S 1 - Compounds of formula

 in which  R represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group or a C 3 -C 6 cycloalkyl group; an (C 1 -C 6) alkyl group, especially (C 1 -C 6) alkyl; phenyl, a C 1 -C 6 alkyl (C 1 -C 6) cycloalkyl group, an aryl group, in particular a phenyl group, a (C 1 -C 6) arylalkylidene group, in particular a phenyl-C 1 -C 6 alkylidene group, a group alkoxy (C1-C6) carbonyl, a C1-C6 alkanoyl group, an arylcaxbonyl group, in particular benzoyl,  R 1, R 2 and R 3 independently of one another represent a hydrogen atom, a halogen atom, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a nitro group, cyano, amino, mono- or diaikyl (C1-C6) amino, a C1-C6 haloalkyl group or a -CONR4R group in which R4 and R5 represent a hydrogen atom or an alkyl group;  C1-C6,  or else R 1 has the meaning given above and R2 and R3 together represent a methylene- or ethylene-dioxy radical whose 2 oxygen atoms are attached to adjacent atoms of the phenyl nucleus,  R, R1, R2 and R3 not simultaneously representing a hydrogen atom,  as well as their addition salts with pharmaceutically acceptable acids.  2 - Compounds according to claim 1, characterized in that R is a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 hydroxyalkyl group or a C 1 -C 6 alkoxycarbonyl group,  R 1 represents a hydrogen atom, a halogen atom, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group or a trifluoromethyl group and R 1 and R 2 represent hydrogen atoms, C 1 -C 6 alkoxy groups or together form a methylene dioxy group whose oxygen atoms are attached to adjacent carbon atoms of the phenyl ring.  3- (4-trimethoxy-4-benzyloxy) piperidine and its pharmaceutically acceptable addition salts.  4-ethoxycarbonyl-1-benzyloxy-4-piperidine and its pharmaceutically acceptable addition salts.  5 - Pharmaceutical composition characterized in that it contains as active ingredient a compound according to any one of claims 1 to 4.  6 - Process for preparing compounds of formula I as defined in claim 1, characterized in that a compound of formula II is reacted

 in which R has the same meaning as in the formula I  with a compound of formula III

 wherein R 1, R 2, R 3 have the same meaning as in formula I and Y is a reactive radical, preferably a chlorine or bromine atom.  7 - Process according to claim 6, for the preparation of compounds of formula I wherein R is a hydrogen atom, characterized in that a compound of formula II in which R is a group is reacted with a compound of formula III -CO-R6, R6 being a C1-C6 alkyl, C1-C6 alkoxy aryloxy, aryl or aryl substituted by a nitro group, then the -COR6 group is removed by hydrolysis.  8 - Process for the preparation of the compounds of formula I as defined in claim 1 in which R is other than hydrogen, characterized in that an alkylation or an acylation of a compound of formula I in which R is hydrogen is carried out.