FR2634208A1 - 2-[(4-Piperidyl)methyl]-2,3-dihydro-1H-isoindole derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds of general formula I: in which R represents either a hydrogen atom or a group of general formula -Z-R' in which Z represents a -CO- or -CH2- group and R' represents a phenyl group optionally substituted in position 3 by a chlorine atom, a linear or branched (C1-C3)alkyl group or a linear or branched (C1-C3)alkoxy group. Application in therapeutics.

Description

The subject of the present invention is [(4-piperidinyl) methyl] -2-dihydro-1H-isoindole derivatives, their preparation and their therapeutic application.

dans laquelle R représente soit un atome d'hydrogène, soit un groupe de formule générale -Z-R' dans laquelle Z représente un groupe -CO- ou -CH2- et R' représente un groupe phényle éventuellement substitué en position 3 par un atome de chlore, un groupe (C1-C3)alkyle linéaire ou ramifié ou un groupe (C1-C3)alcoxy linéaire ou ramifié.The compounds of the invention correspond to the general formula (I)

in which R represents either a hydrogen atom or a group of general formula -ZR 'in which Z represents a group -CO- or -CH2- and R' represents a phenyl group optionally substituted in the 3-position by a chlorine atom a linear or branched (C1-C3) alkyl group or a linear or branched (C1-C3) alkoxy group.

They can exist as free bases or addition salts with acids.

In accordance with the invention, the compounds of general formula (I) can be prepared by a process illustrated in Scheme 1 on the following page.

The dihydro-2,3H-isoindole of formula (II), prepared according to the method described in Organic Syntheses, is reacted.
Collective Vol. V, 406-408 and 1064-1066, with a tosylate of general formula (III) (wherein Tos represents a tosyl group and R 'is as defined above), either in the absence or in the presence of a solvent inert such as dimethylformamide or xylene, at a temperature of 20 to 1500C, and optionally in the presence of an organic base, such as a tertiary amine, or mineral, such as an alkali carbonate or hydrogencarbonate.

Diagram 1

There is thus obtained a compound of general formula (Ia) which corresponds to the general formula (I) when Z represents a group -CO-.

The compounds of general formula (I), where Z represents a group -CH 2 - can be obtained by reduction of the compounds of general formula (Ia) by means of a simple or complex alkali hydride such as lithium aluminum hydride, a boron hydride or aluminum such as diborane, diborane-dimethyl sulfide complex, aluminum hydride, etc., in an ethereal solvent such as diethyl ether, tetrahydrofuran, dioxane, at a temperature of 20 to 1000C.

There is thus obtained a compound of general formula (Ib) which corresponds to the general formula (I) when Z represents a -CH 2 - group.

Finally, the compound of general formula (I) in which R represents a hydrogen atom can be obtained by debenzylation of the compound of general formula (I) in which R represents a benzyl group, for example by means of a hydrogen hydrogenolysis. gaseous, under a pressure of 0.1 to 0.5 MPa, in the presence of a metal catalyst, optionally on an inert or basic support, for example palladium on carbon, barium sulfate or calcium carbonate, in an alcoholic solvent, for example methanol or ethanol, at a temperature of 20 to 800C.

The tosylate of general formula (III) can be prepared according to a method illustrated by scheme 2 below.

Piperidine-4-methanol of formula (IV) is reacted with an acid chloride of general formula R'COCl (in which
R 'is as defined above), in an inert solvent such as a chlorinated solvent, at a temperature of 20 to 80 ° C. An ester-amide of general formula (V), which is saponified, is thus obtained , for example by means of sodium or potassium hydroxide, in a lower aliphatic alcoholic solvent, preferably ethanol, to obtain the alcohol of general formula (VI), the tosylate of which is finally prepared by means of tosyl, in a basic medium such as pyridine.

Figure 2

Piperidine-4-methanol of formula (IV) can be obtained for example by reduction of piperidine-4-ethyl carboxylate with mcyen of lithium aluminum hydride, or by such a reduction of benzyl-1 piperidine-4 ethylcarboxylate followed by catalytic hydrogenolysis under pressure.

Finally, the compound of formula (I), where R is an unsubstituted benzyl group (i.e.
Z represents a group -CH2- and R 'represents an unsubstituted phenyl group), according to another process illustrated by Scheme 3 given below.

The piperidine-4-carboxamide of formula (VIII) is reacted with a benzyl halide, preferably benzyl bromide, in an inert solvent, for example toluene, at a temperature of 20 to 110 ° C. and in the presence of a base, for example potassium carbonate.

Benzyl-1-piperidine-4-carboxamide of formula (IX) is obtained which is reacted with di (bromomethyl) -1,2-benzene ("DBX") in the presence of a strong base, for example 1 sodium hydride, and in an aprotic solvent, for example dimethylformamide, at a temperature of 20 to 600C.

[(1-benzyl-4-piperidinyl) carbonyl] -2,3-dihydro-1H-isoindole of formula (X) thus obtained is then reduced by means of lithium aluminum hydride, in an ethereal solvent, by for example, diethyl ether or tetrahydrofuran, at a temperature of 20 to 600 ° C, to obtain [(1-benzyl-4-piperidinyl) methyl] -2,3-dihydro-1H-isoindole (formula (I), R = CH 2 C 6 H 5 ).

The order of the two preceding steps can be reversed, that is to say that the benzyl-1-piperidine-4-carboxamide of formula (IX) can be reduced with hydride, lithium and aluminum, under the conditions given above, to obtain the benzyl-1 piperidine-4-methanamine of formula (XI), and react it with the di (bromomethyl) -1,2 benzene in the presence of a base, for example the carbonate of potassium, and in an aprotic solvent, for example dimethylformamide, at a temperature of 0 to 20 OC.

minium, par exemple le triméthylaluminium, avec un benzyl-4 pipéridine-4-carboxylate d'alkyle, par exemple le benzyl-1 pipéridine-4-carboxylate d'éthyle de formule (XII), dans un solvant inerte, par exemple le toluène, et à une température de 20 à 1l00C. On obtient ainsi le [(benzyl-l pipéridinyl-4)carbonyl]-2 dihydro-2,3 1H-isoindole de formule (X) qu'on réduit comme déjà indiqué ci-dessus.It is still possible to start by reacting 2,3-dihydro-1H-isoindole in the form of a complex with a trialkylalu
Figure 3

minium, for example trimethylaluminum, with an alkyl benzyl-4-piperidine-4-carboxylate, for example ethyl-1-benzylpiperidine-4-carboxylate of formula (XII), in an inert solvent, for example toluene , and at a temperature of 20 to 1100C. There is thus obtained [(1-benzyl-4-piperidinyl) carbonyl] -2,3-dihydro-1H-isoindole of formula (X) which is reduced as already indicated above.

the following examples illustrate in detail the preparation of some compounds according to the invention. The microanalyses and the IR and NMR spectra confirm the structures of the products obtained.

The numbers given in parentheses in the titles of the examples correspond to those in the table given below.

Example 1 (Compound N06) [3-Methylbenzoyl) -1-piperidinyl-4] methyl-2] dihydro-2,3H-isoindole, hydrochloride.

1.1 Piperidine-4-methanol.

In a four-necked flask equipped with a mechanical stirring system and a condenser 28.5 g (0.75 mol) of lithium aluminum hydride and 1.2 l of tetrahydrofuran are introduced. 117.9 g (0.75 mole) of ethyl piperidine-4-carboxylate dissolved in 1.2 l of tetrahydrofuran are added to the suspension obtained, and the mixture is stirred at 200 ° C. It is cooled to 0 ° C. and then hydrolyzed by successively adding 22 ml of water, 22 ml of 1N sodium hydroxide and 46 ml of water. The mixture is stirred at 200 ° C. for 30 minutes, filtered and the precipitate is washed with tetrahydrofuran and then with ether. The solvents are evaporated under reduced pressure, and 84.4 g of an oil are obtained which is used as it is in the next step.

1.2. 3-Methyl-3-benzoyl benzoate [4-piperidinyl] methyl benzoate.

In a 3-liter three-neck flask, 42.25 g (0.367 mol) of piperidine-4-methanol and 430 ml of 1,2-dichloroethane are introduced under an argon atmosphere, and 82 g (0.degree. 81 moles) of triethylamine and then 125.2 g (0.81 moles) of 3-methylbenzoyl chloride. The mixture is refluxed for 4 h, 8.2 g (0.08 mol) of triethylamine and 12.5 g (0.08 mol) of 3-methyl-benzoyl chloride are added and the mixture is heated for a further 3h.

It is filtered, the salts are washed with 1,2-dichloroethane, the filtrate is evaporated under reduced pressure, the residue is dissolved in ethyl acetate, and the solution is washed with saturated aqueous sodium chloride solution. the solvent is evaporated under reduced pressure and the residue is recrystallized from a 1/1 mixture of isopropyl alcohol / ethyl acetate. 80 g of a white solid are obtained. Melting point: 80-830C.

1.3. (3-Methylbenzoyl) -1-piperidine-4-methanol.

To a solution of 80 g (0.23 moles) of (methyl-3-benzoyl) -1-piperidinyl-4-methyl-3-benzoate in 400 ml of ethanol, a solution of 12.76 g (0, 23 moles) of potassium hydroxide in 75 ml of ethanol and 75 ml of water.

The mixture is stirred at 20 ° C. for 3 h, the ethanol is evaporated off under reduced pressure and the aqueous phase is extracted with ethyl acetate.The organic phase is washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate The solvent is evaporated under reduced pressure and 53 g of alcohol are obtained which is used as such in the next step.

1.4. (Methyl-3-benzoyl) -1-piperidinyl-4-methyl (4-methylphenyl) sulfonate.

To a solution of 52 g (0.22 mol) of (methyl-3-benzoyl) -1-piperidine-4-methanol in 100 ml of pyridine is added 53.3 g (0.28 mol) of methyl-4-phenylsulfonyl chloride. in 60 ml of pyridine. The mixture is stirred at 200 ° C. for 4 hours and then poured into ice. The phase is extracted with dichloromethane, the organic phase is washed with a 10N aqueous solution of hydrochloric acid and dried over magnesium sulphate. The solvents are evaporated under reduced pressure and 70 g of white solid are obtained. Melting point 68-700C.

1.5. [[3-methyl-benzoyl) -1-piperidinyl-4] methyl] -2-dihydro-1H-isoindole, hydrochloride.

Into a 250 ml flask placed under an argon atmosphere, 3.6 g (0.03 mole) of dihydro-2,3-H-isoindole and 12.8 g (0.033 mole) of (methyl-4-phenyl) are introduced. ) L (3-methylbenzoyl) -1-piperidinyl-4-methyl sulfonate and the mixture is heated at 1500C for 3h30. A thick brown oil is obtained which is diluted with dichloromethane, concentrated ammonia is added, the organic phase is separated, washed with water, dried over magnesium sulphate, evaporated. the solvents under reduced pressure and the residue is purified by chromatography on a silica column. 7.5 g of base are finally isolated; Melting point: 125-127 ° C.

The hydrochloride is prepared using 2-propanol and hydrocrine and is recrystallized from a mixture of ethyl acetate / propanol-2. Melting point: 217.5-2200C.

Example 2 (Compound N07) [[3-Methylbenzyl) -1-piperidinyl-4] methyl-2,-dihydro-2,3H-isoindole, difumarate.

0.54 g (14-, 4 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran are added to a 250 ml three-necked flask placed under an argon atmosphere. 3.15 g (9, 42 mmol) of [[3-methyl-benzoyl) -1-piperidinyl] -2-methyl] dihydro-2,3H-isoindole dissolved in 75 ml of tetrahydrofuran cooled to 0 ° C, the mixture is stirred cold for 5 minutes. The mixture is refluxed for one hour and a clear orange solution is obtained, to which is added 7 ml of 6.5% sodium hydroxide, while cooling it, containing a dark orange suspension, filtering and drying. filtrate over magnesium sulphate, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a silica column, eluting with a 96/4 mixture of dichloromethane / methanol. 2.35 g of a brown oil which crystallizes is isolated Melting point 93.5-95 ° C.

This base (7.33 mmol) is dissolved in 150 ml of ethanol, a solution of 1.7 g (14.7 mmol) of fumaric acid in 100 ml of ethanol is added, the mixture is concentrated until half of its initial volume, the white solid which crystallizes is filtered off and recrystallized from a 1/1 mixture of ethyl acetate / ethanol. 2.8 g of pure difumarate are finally obtained. Melting point: 198-200.50C.

Example 3 (Compound NO 3) [(Benzyl-1-piperidinyl-4-methyl-2-dihydro-2,3H-isoindole, dihydrochloride.

A. First variant.

3.A.1. Benzyl-1 piperidine-4-carboxamide.

Under an argon atmosphere, 123.0 g (0.96 mol) of piperidine-4-carboxamide and 90.8 g (1.08 mol) of sodium bicarbonate in 2 l of dry toluene are introduced. 180.6 g, ie 125.6 ml (1.056 mole) of benzyl bromide peton were added to reflux the mixture for 5 hours.

The mixture is filtered while hot. During the cooling of the filtrate a white precipitate forms. It is isolated and dried, and 113.4 g of dry product are obtained. Melting point: 160-1620C.

3.A.2. Benzyl-1-piperidinyl-4-carbonyl-2-dihydro-2,3H-isoindole hydrochloride.

Under an argon atmosphere, 2.3 g of 50% sodium hydride in oil (48.1 mmol), previously washed with petroleum ether and then 100 ml of dimethylformamide, are introduced into a flask and then solution of 5 g (22.9 mmol) of benzyl-1 piperidine-4-carboxamide in 45 ml of dimethylformamide at room temperature and within 20 minutes. The suspension is stirred for 1 h at room temperature and then 1 h at 600C.

A solution of 6.05 g (22.9 mmol) of di (bromomethyl) -1,2 benzene in 40 ml of dimethylformamide is then added, so as to maintain the temperature between 60 and 700 ° C., and the mixture is stirred for 3 h. at room temperature.

It is poured onto a mixture of water and ice, treated with ethyl acetate, the organic phase is separated off, washed with water, dried and the solvent is evaporated off. An orange solid is obtained which is recrystallized from cyclohexane, washed with ether and recrystallized once more in cyclohexane. 1.1 g of white solid are obtained.

It is introduced into a mixture of 50 ml of isopropyl alcohol and 34.3 ml of 0.1N hydrochloric isopropyl alcohol, heated at reflux and the solution is allowed to cool. 1.2 g of hydrochloride are obtained. Melting point 243-2460C (decomposition).

3.A.3. 4-Benzyl-4 -piperidinyl-2-methyl-2,3-dihydro-1H-isoindole, dihydrochloride.

A solution of 10.0 g (31.2 mmol) of [4-benzyl-4-piperidinyl] carbonyl] -2,3-dihydro-1H-isoindole was slowly added in 20 ml of dry, cold, dry ether. 85 g (48.4 mmol) of lithium aluminum hydride in 300 ml of dry ether.

The mixture is stirred for 30 minutes at room temperature and then for 7 hours under reflux. Then it is hydrolyzed with 8 ml of water, filtered by rinsing the solid with ether, the filtrate is dried and concentrated. A yellow oil is obtained which crystallises rapidly. It is taken up with methanol and a stream of gaseous hydrochloric acid is passed into the solution. A cream-colored solid is obtained which is recrystallized twice in a 2/1 mixture of ethanol / methanol. 7.7 g of dihydrochloride are obtained. Melting point: 291-2930C.

B. Second variant.

 3.B.1. Benzyl-1 piperidine-4-methanamine hydrochloride.

Under argon atmosphere, 50.0 g (229 mmol) of benzyl-1-piperidine-4-carboxamide and 13.0 g (343 mmol) of lithium aluminum hydride in 2.5 l of ether are introduced. dry, and the mixture is refluxed for 8 hours.

50 ml of water are added, the mixture is filtered off by rinsing the solid with ether, the organic phase is separated off, dried and the solvent is evaporated off. 40.7 g of a yellow oil are obtained which are dissolved in 1.99 l of 0.1N hydrochloric isopropyl alcohol. The solution is concentrated to 3/4, allowed to cool, the precipitated white solid is filtered and recrystallized from isopropyl alcohol. 33.7 g of hydrochloride are obtained. Melting point: 188-1900C.

 3.B.2. [(1-Benzyl-4-piperidinyl) -2-methyl-2,3-dihydro-1H-isoindole, dihydrochloride.

Under an argon atmosphere 1.97 g (7.48 mmol) of di (bromomethyl) -1,2 benzene and 5.2 g (3.74 mmol) of potassium carbonate in 40 ml of dimethylformamide are introduced. The mixture is cooled by an ice bath and 1.8 g of benzyl-1-piperidine-4-methanamine hydrochloride are slowly added.

The mixture is stirred for 4 hours at room temperature and then poured onto a mixture of water and ice. The solid is extracted with ethyl acetate, the organic phase is separated off, washed with water, dried and the solvent evaporated. 1.8 g of a yellow oil which crystallizes and is dissolved in hot water in 59 ml of 0.1N hydrochloric isopropyl alcohol. The mixture is allowed to cool, the white solid which has precipitated is filtered off and 0.8 g of dihydrochloride are isolated.

Melting point: 291-291.5 ° C.

Example 4 (Compound N01) (4-piperidinyl) methyl 2-dihydro-2,3H-isoindole, dihydrochloride.

56.6 g (149 mmol) of [(1-benzyl-4-piperidinyl) methyl] -2,3-dihydro-1H-isoindole dihydrochloride, 300 ml of ethanol, 50 ml of water and 5 g of water are introduced. 10% palladium on charcoal in a Parr apparatus and hydrogenolysis is carried out at about 0.41 MPa for 9 hours.

The resulting mixture is filtered, the filtrate is evaporated and the residue is taken up in a 1/1 mixture of methanol / ethanol in the presence of activated charcoal. Filtered, the filtrate is evaporated and 39.6 g of slightly bluish white dihydrochloride are obtained. Melting point: 298-301 ° C.

The following table illustrates the chemical structures and the physical properties of some compounds according to the invention.

Board

<tb> N <SEP> R <SEP> Sel <SEP> or <SEP> base <SEP> F (OC) <SEP>
<tb><SEP> 1 <SEP> H <SEP> Dihydrochloride <SEP> 298-301
<tb><SEP> 2 <SEP> C6H5-CO- <SEP> Hydrochloride <SEP> 225-227
<tb><SEP> 3 <SEP> C6H5-CH2- <SEP> Dihydrochloride <SEP> 291-293
<tb><SEP> 4 <SEP> Cl-3-C6H4-CO- <SEP> fumarate <SEP> 141-143
<tb><SEP> 5 <SEP> Cl-3-C6H4-CH2- <SEP> difumarate <SEP> 198.5-200.5 <SEP>
<tb><SEP> 6 <SEP> CH3-3-C6H4-CO- <SEP> Hydrochloride <SEP> 217-220
<sep>SEP> 7 <SEP> CH3-3-C6H4-CH2- <SEP> difumarate <SEP> 198-200.5
<tb><SEP> 8 <SEP> C2H5O-3-C6H4-CO- <SEP> Hydrochloride <SEP> 168-170
<tb><SEP> 9 <SEP> C2H5O-3-C6H4-CH2- <SEP> difumarate <SEP> 206.5-208
<Tb>
The compounds of the invention have been subjected to a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Thus, they have been studied for their affinity for serotonergic receptors of the 5-HT1A type.

The compounds displace in the rat hippocampus the binding, on these receptors, of a labeled specific ligand, [3H] -8-hydroxy-2-dipropylamino-tetralin (hereinafter referred to as "[3H] -8-oH-DPAT ") described by Gozlan et al., Nature, (1983), 305, 140-142.

The animals used are male Sprague-Dawley rats of 160 to 200 g. After decapitation, the brain is removed and the hippocampus excised. The fabric is ground in a machine
Ultra-Turrax Polytron for 30 s at half the maximum speed in 10 volumes of 50 mM Tris buffer pH adjusted to 7.4 with hydrochloric acid (ie 100 mg of fresh tissue per ml). The homogenized tissues are washed three times at 40 ° C., centrifuging each time for 10 nm at 48,000 × g and resuspending the pellet in cooled fresh buffer. Finally, the last pellet is suspended in the buffer to give a concentration of 100 mg of starting tissue per ml of 50 mM buffer.

It is then allowed to incubate at 370 ° C. for 10 minutes.

Binding with [3H] -8-OH-DPAT (1 nM) is determined by incubating 100 μl of the membrane suspension in a final volume of 1 ml of buffer containing 10 mM pargylline and 3 mM paroxetine.

After incubation for 5 minutes at 370 ° C., the membranes are recovered by filtration on Whatman GF / B filters which are washed three times with 5 ml aliquots of ice-cold buffer. The filters are extracted into the scintillation fluid and the radioactivity is measured by liquid scintigraphy. The specific binding of [3H3-8-OH-DPAT is defined as the radioactive amount retained on the filters and capable of being inhibited by co-incubation in 5-hydroxy-5-tryptamine FILM. At a concentration of 1 nM [3H] -8-OH-DPAT the specific binding represents 70 to 80% of the total radioactivity recovered on the filter.

For each concentration of compounds studied, the percentage inhibition of binding with [3H1-8-OH-DAT, then the IC50 concentration, concentration which inhibits 50% of the binding is determined.

For the compounds of the invention, the IC50s are between 0.001 and 1 μM.

The central activity of the compounds of the invention was evaluated by their effects on the "PGO" (ponto-geniculo-occi vitales) induced by reserpine (PGO-R test) in the cat, according to the method described by H Depoortere, Sleep 1976, 3rd
Europ. Cong. Sleep Res., Montpellier 1976, 358-361 (Karger,
Basel 1977).

Cumulative doses of test compounds (from 0.001 to 3 mg / kg intravenously) are administered at intervals of 30 minutes, 4 hours after intraperitoneal injection of a dose of 0.75 mg / kg of reserpine, at curarized cats, under artificial ventilation. The electroencephalographic and phasic activities (PGO-R points) are collected using cortical and deep electrodes (lateral knee).

For each dose of compound studied, the percentage of decrease in the number of PGO spikes is determined, then the DA50 active dose which reduces by 50% this number of spikes.

For the compounds of the invention, the ED50 values are between 0.003 and 3 mg / kg intravenously.

The results of the tests show that the compounds of formula (I) possess, in vitro, a high affinity and a selectivity for serotoninergic receptors of 5-HT1A type. In vivo, they show a partial agonist or agonist activity at these receptors.

The compounds of the invention can therefore be used for the treatment of diseases and conditions involving serotoninergic receptors of the 5-HT1A type, directly or indirectly, in particular for the treatment of depressive states, states of anxiety, sleep disorders , and for the regulation of food intake, and also for the treatment of vascular, cardiovascular and cerebrovascular disorders such as hypertension or migraine.

For this purpose they may be presented in any form suitable for their oral or parenteral administration, combined with any suitable excipients, and dosed to allow a daily dosage of 1 to 1000 mg.

Claims (3)

claims 1. Compounds of general formula (I)

 in which R represents either a hydrogen atom or a group of general formula -ZR 'in which Z represents a group -CO- or -CH2- and R' represents a phenyl group optionally substituted in position 3 by a -atom of chlorine, a linear or branched (C1-C3) alkyl group or a linear or branched (C1-C3) alkoxy group, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that the dihydro-2,3H-isoindole is reacted with a tosylate of general formula (III)

 (wherein Tos represents a tosyl group and R 'represents a phenyl group as defined in claim 1), either in the absence or in the presence of an inert solvent such as dimethylformamide or xylene, at a temperature of 20 to 1500C, and optionally in the presence of an organic base, such as a tertiary amine, or mineral, such as an alkali metal carbonate or hydrogen carbonate, to obtain a compound of general formula (Ia)

 then, if it is desired to obtain a compound of general formula (I) in which Z represents a group -CH 2 -, the compound of general formula (Ia) is reduced by means of a simple or complex alkaline hydride such as lithium hydride and aluminum, a boron or aluminum hydride such as diborane, the diborane-dimethyl sulfide complex, aluminum hydride, in an ethereal solvent such as diethyl ether, tetrahydrofuran, dioxane, at a temperature of from 20 to 1000 ° C., and finally, if the compound of general formula (I) in which R represents a hydrogen atom is desired, the compound of general formula (I) (in which R represents a benzyl group) is subjected to a hydrogenolysis with gaseous hydrogen, at a pressure of 0.1 to 0.5 MPa, in the presence of a metal catalyst, optionally on an inert or basic support, for example palladium on carbon, barium sulfate or calcium carbonate in an alcoholic solvent, for example methanol ethanol at a temperature of 20 to 80 ° C. 3. Pharmaceutical composition characterized in that it contains a compound according to claim 1, associated with a suitable pharmaceutical excipient.