FR2737723A1 - New 1-(2-(1H-inden-3-yl) ethyl) 4-(naphthalen-1-yl) piperazine derivs - have affinity for serotoninergic receptors and are used to treat anxiety, depression, phobia(s), migraine, hypertension, and to regulate appetite - Google Patents

Abstract

1-(2-(1H-inden-3-yl)-ethyl)-4-(naphthalen-1-yl) piperazine derivs. of formula (I) and their acid addn. salts are new. One of R1 and R2 = OH and the other is H, OH or methoxy.

Description

The subject of the present invention is derivatives of 1- [2- (1H- inden-3-yl) ethyl] -4- (naphthalen-1-yl) piperazine, their preparation and their therapeutic application.

dans laquelle l'un des symboles Rl et R2 représente un groupe hydroxy, et l'autre représente un atome d'hydrogène ou un groupe hydroxy ou méthoxy.The compounds of the invention correspond to the general formula

wherein one of the symbols R1 and R2 represents a hydroxy group, and the other represents a hydrogen atom or a hydroxy or methoxy group.

The compounds according to the invention can exist in the form of bases or of addition salts with acids.

Compounds of chemical structure analogous to that of the compounds of general formula (I), and which can be used as antidepressant and anxiolytic agents, are described in patent application EP-0490772.

According to the invention, the compounds of general formula (I) can be prepared by methods illustrated by schemes 1 and 2 which follow.

According to scheme 1, a compound of general formula (II) is treated, in which Y represents a methoxy group and X represents a hydrogen atom or a methoxy group, with boron tribromide, in an inert aprotic solvent, for example dichloromethane, at a temperature of -700C to -5 C, to obtain a compound of general formula (Ia), which corresponds to the general formula (I) when Rí represents a hydroxy group and R2 represents a hydrogen atom or a methoxy group.

Diagram 1

When X represents a methoxy group, and if desired, the compound of general formula (II) is treated with a large excess of boron tribromide, to finally lead to the compound of formula (Ib) which corresponds to the general formula (I ) when Rl and R2 each represent a hydroxy group.

puis on traite ce dernier avec le dérivé de pipérazine de formule (IV), dans un solvant inerte, tel qu'un solvant éthéré, par exemple le tétrahydrofurane ou le dioxane, à une température de 20 à 500C, pour obtenir l'amide de formule générale (V).According to scheme 2, the 1Hindene-3-acetic acid derivative of general formula (III) is reacted, in which Y represents a hydrogen atom or a methoxy group, first with N, N'-carbonyldiimidazole, in an inert solvent, such as tetrahydrofuran, at a temperature of 20 to 500C, to obtain the corresponding imidazolide in situ,
Diagram 2

then the latter is treated with the piperazine derivative of formula (IV), in an inert solvent, such as an ethereal solvent, for example tetrahydrofuran or dioxane, at a temperature of 20 to 500C, to obtain the amide of general formula (V).

Finally, the latter is reduced by means of a simple or complex reducing agent, such as an alkali or metal hydride, for example lithium aluminum hydride, boron hydride, boron hydride-tetrahydrofuran complex. or boron hydride-dimethyl sulfide, aluminum hydride, in an inert, aromatic or ethereal solvent, for example toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, at a temperature of 30 to 1400C, depending on the solvent, to obtain a compound of general formula (Ic), which corresponds to the general formula (I) when R1 represents a hydrogen atom or a methoxy group and R2 represents a hydroxy group.

The starting compounds of general formula (II) can be prepared by a process illustrated by scheme 3 which follows.

A 1H-indene-3-acetic acid derivative of general formula (III), in which Y is as defined above, is treated with a simple or complex reducing agent, such as an alkali metal hydride, for example lithium aluminum hydride, boron hydride, boron hydride-tetrahydrofuran or boron hydride-dimethyl sulfide complex or aluminum hydride, in an inert, aromatic or ethereal solvent, for example toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, at a temperature of 30 to 1400C, depending on the solvent, to form the alcohol of general formula (III).

This alcohol is then treated with 4-methylbenzenesulfonic acid chloride, in the presence of an organic base such as triethylamine or pyridine, and optionally in the presence of an inert solvent, at a temperature of 0 to 400C, to obtain the derivative of general formula (IV).

de préférence à 1300C, éventuellement dans un solvant à point d'ébullition élevé, tel que le toluène, le xylène, le
N,N-diméthylformamide ou la l-méthylpyrrolidin-2-one.Finally, the latter is reacted with a piperazine derivative of general formula (V), in which X is as defined above, at a temperature of 100 to 1500C,
Diagram 3

preferably at 1300C, optionally in a solvent with a high boiling point, such as toluene, xylene,
N, N-dimethylformamide or 1-methylpyrrolidin-2-one.

The starting compounds of general formula (III) are described in CA 76 (23) 140279s, CA 104 (1) 5652q and
J. Chem. Soc. Perkin Trans. (1972) 1 (7) 941: treating 2,3-dihydro-1H-inden-1-one (Y = H, commercially available) or 6-methoxy-2,3-dihydro-1H-inden -l-one (Y = OCH3, described in J. Org. Chem. (1970) 35 (3) 647 and J. Org. Chem (1977) 42 (12) 2155) with ethyl bromoacetate in the presence of zinc powder under the reaction conditions of
Reformatsky, to obtain a mixture of ethyl (6-Y-2,3-dihydro-1Hindén-1-ylidene) acetate and ethyl 5-Y-1H-indene-3-acetate. mixture in basic alcoholic medium then provides the acid of general formula (II)
The piperazine derivatives of general formula (VIII) are known and can be obtained by methods described in the literature, for example in patent applications EP-0343050, EP-0354093 and EP-0434561, in J. Med.

Chem. (1986) 29 (11) 2379, J. Med. Chem. (1988) 31 (10) 1968 and in J. Med. Chem. (1991) 34 (8) 2623.

The examples which follow illustrate in detail the preparation of the compounds according to the invention.

Elementary microanalyses and IR and NMR spectra confirm the structures of the products obtained.

Example 1 3- [2- [4- (7-Methoxynaphthalen-1-yl) piperazin-1-yl] ethyl] - 1H-inden-5-ol.

1.1. 5-Methoxy-1H-indene-3-ethanol.

Preparing a suspension of 0.76 g (0.02 mole) of lithium aluminum hydride in 50 ml of diethyl ether, adding a solution of 2.04 g (0.01 mole) of acid 5-methoxy 1H-indene-3-acetic, the mixture is stirred and heated to reflux for 32 hours.

The mixture is allowed to cool, it is hydrolyzed with 1.6 ml of 10 k aqueous solution of potassium and sodium double tartrate, it is heated to boiling for 1 hour, filtered, rinsing the residue with tetrahydrofuran, and the filtrate is evaporated under reduced pressure.

1.8 g of oily residue are obtained, which is purified by distillation.

1.55 g of yellow liquid are obtained, which is used as it is in the next step.

1.2. 2- (5-methoxy-1H-inden-3-) methylbenzenesulfonate
yl) ethyl.

1.27 g (0.0067 mol) of 5-methoxy-1H-indene-3-ethanol are dissolved in 11 ml of dry pyridine, the mixture is stirred, cooled by an ice bath, and added little by little 1.4 g (0.0073 mole) of 4-methylbenzenesulfonic acid chloride, and stirring is continued cold overnight, then at room temperature for 4 h.

The solution is poured onto a mixture of 16 ml of 10N hydrochloric acid and 48 g of ice, the mixture obtained is treated with diethyl ether, the organic phase is separated, it is washed with water, it is dried over magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure.

1.94 g of a colorless oily product are obtained, which is used as it is in the next step.

1.3. 4- [2- (5-Methoxy-1H-inden-3-yl) ethyl] -1- (7-methoxy-naphthalen-1-yl) piperazine.

2.07 (0.006 mole) of 2- (5-methoxy-1H-inden-3-yl) ethyl 4-methylbenzenesulfonate is mixed and 2.90 g (0.012 mole) of 1- (7-methoxynaphthalen-1-yl) ) piperazine, the mixture is stirred, it is placed under an argon atmosphere and it is heated in an oil bath at 1300C for 2 hours.

The mixture is taken up in dichloromethane, the solution is washed with water, with dilute sodium hydroxide, then again with water, dried over magnesium sulphate, filtered, the filtrate is evaporated under reduced pressure.

4.08 g of oil are obtained, which is purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and acetone 92/8.

2.09 g of compound are obtained.

1.4. 3- [2- [4- (7-Methoxynaphthalen-1-yl) piperazin-1-yl] - ethyl] -1H-inden-5-ol.

1.85 g (4.45 mmol) of 4- [2- (5) are introduced into a three-necked flask placed under an argon atmosphere and cooled to -700C using an alcohol and dry ice bath. methoxy-1H-inden-3-yl) ethyl] -1- (7-methoxynaphthalen-1-yl) piperazine and 100 ml of dichloromethane, and 13.5 ml (3 equivalents) of boron tribromide in 1M solution in dichloromethane. Stirring is continued at -700C for 1h, then stirred at -200C for 1h, then at -50C for 30 min.

The reaction is stopped by adding ice and water, ammonia is added, the mixture is extracted three times with chloroform, the organic phase is washed with water, it is dried over sodium sulfate, it is filter and the solvent is evaporated off under reduced pressure.

1.6 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, first with a mixture of pentane and tetrahydrofuran 70/30, then with a mixture of diethyl ether and pentane 90 / 10.

After crystallization from diethyl ether, 0.245 g of compound is finally isolated.

Melting point: 162-1630C.

Example 2
8- [4- [2- (5-Hydroxy-1H-inden-3-yl) ethyl] dihydrochloride] piperazin-1-yl] naphthalen-2-ol.

1.5 g (3.1 mmol) of 4- [2- (5) are placed in a three-necked flask placed under an argon atmosphere and cooled to -700C using an alcohol and dry ice bath. -me thoxy-1H-inden-3-yl) ethyl] -1- (7-methoxynaphthalen-1-yl) piperazine and 100 ml of dichloromethane, and 19 ml (6 equivalents) of boron tribromide in 1M solution in dichloromethane. Stirring is continued at -700C for 1 h 30 min, the mixture is allowed to return to ambient temperature and the stirring is continued for 2 h, the mixture is cooled with an ice bath, ice and water are added and then ammonia, the precipitate is separated by filtration and dried under vacuum.

It is purified by chromatography on a column of silica gel, eluting first with a mixture of chloroform and methanol 96/4 then with a mixture of pentane and tetrahydrofuran 65/35.

The dihydrochloride is prepared by taking up the purified product in a mixture of chloroform and methanol, adding a little hydrochloric ether then diisopropyl ether, scraping the tube to cause crystallization, filtering the crystals and drying them immediately under vacuum.

Finally isolated 0.50 g of dihydrochloride.

Melting point: 178-1800C.

Example 3 8- [4- [2- (5-Methoxy-1H-inden-3-yl) ethyl] piperazin-1-yl] naphthalen-2-ol.

3.1. 8- (Piperazin-1-yl) naphthalen-2-ol.

12.5 g (7.85 mmol) of 8-aminonaphthalen-2-ol, 350 ml of butanol and 15.4 g (1.1 equivalent) of bis hydrochloride are introduced into a flask placed under an argon atmosphere. 2-chloroethyl) amine, the mixture is heated to reflux for 10 h, a further 7.7 g of bis (2-chloroethyl) amine hydrochloride are added and heating is continued for 18 h.

The mixture is concentrated by evaporating part of the butanol, and the precipitate is separated by filtration.

11 g of crude product are obtained, which is purified by chromatography on a column of silica gel using a mixture of chloroform and methanol 85/15 containing 1.5% of ammonia, then with a mixture of chloroform and methanol. 83/17 containing 1.7% ammonia.

6.8 g of compound are obtained.

3.2. 8- [4- [2- (5-Methoxy-1H-inden-3-yl) acetyl] piperazin-1-yl] naphthalen-2-ol.

6 g (29.3 mmol) of 5-methoxy-1H-indene-3-acetic acid, 200 ml of tetrahydrofuran and 7.15 g (1.5 equivalent) of N are introduced into a three-necked flask placed under argon. N1-car- bonyldiimidazole, the mixture is stirred at room temperature for 1.5 hours and a solution of 6.7 g (1.1 equivalents of 8- (piperazin-1-yl) naphthalen-2-ol is added dropwise) in 150 ml of a mixture of tetrahydrofuran and N, Ndimethylformamide 50/50.

Stirring is continued at room temperature for 2 hours, the mixture is warmed to 500C, and stirred at this temperature for a further 1.5 hours.

Ice water is added, the mixture is extracted three times with diethyl ether, the organic phase is washed twice with water, dried over magnesium sulphate, filtered and the solvent is evaporated off reduced pressure.

15 g of crude product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a mixture of diethyl ether and 99/1 methanol.

6.7 g of compound are obtained.

3.3. 8- [4- [2- (5-Methoxy-1H-inden-3-yl) ethyl] piperazin-1-yl] naphthalen-2-ol.

0.86 g (2 equivalents) of lithium aluminum hydride and 80 ml of tetrahydrofuran are introduced into a three-necked flask placed under an argon atmosphere and cooled by an ice bath. 4 , 7 g (11.3 mmol) of 8- [4- [2- (5-methoxy-1H-inden-3-yl) acetyl] piperazin-1-yl] naphthalen-2-ol dissolved in 400 ml of tetrahydrofuran, and the mixture is stirred for 2 h.

It is cooled with an ice bath, a saturated sodium sulphate solution is added, it is filtered through kieselguhr, rinsing the solid with diethyl ether and tetrahydrofuran, the aqueous phase is separated by decantation, it is extracted two times with diethyl ether, the organic phase is washed with water, dried over magnesium sulphate, filtered and the solvent is evaporated off under reduced pressure.

5 g of crude product are obtained which are purified by chromatography on a column of silica gel, eluting with a mixture of chloroform and ethanol 98.5 / 1.5.

Finally isolated 1.0 g of compound.

Melting point: 194-1950C.

The compounds of the invention have been the subject of tests which have demonstrated their interest as therapeutic substances.

Thus, they were tested in vitro as to their affinity for serotonergic receptors of the 5-HTIA type, present in the hippocampus of the rat, according to a protocol described by
Sanger and Schoemaker, Psychopharmacology (1992) 108 85-92.

The compounds displace the binding of a specific labeled ligand, [3H] -8-hydroxy-2- (di-n-propylamino) tetralin (hereinafter referred to as "[3H] -8-OH-DPAT" and described by Gozlan et al., Nature (1983) 305 140-142) on the 5HTlA receptors.

The animals used are male Sprague-Dawley rats weighing 160 to 200 g. After decapitation, the brain is removed and the hippocampus is excised. We grind the fabric in a device
Polytronn Ultra-Turrax for 30 s at half the maximum speed in 10 volumes of 50 mM Tris buffer, pH adjusted to 7.4 with hydrochloric acid (i.e. 100 mg of fresh tissue per ml). The homogenized tissues are washed three times at 40C, centrifuging them each time for 10 min at 48000xg and resuspending the pellet in fresh cooled buffer. Finally, the last pellet is suspended in the buffer to reach a concentration of 100 mg of starting tissue per ml of 50 mM buffer.

It is then left to incubate at 370C for 10 min.

The binding with [3 H] -8-OH-DPAT (1 nM) is determined by incubation of 100 Zl of membrane suspension in a final volume of 1 ml of buffer containing 10 μM of pargyline and 3 μM of paroxetine.

After an incubation of 15 min at 370C, the membranes are recovered by filtration on Whatman GF / Bn filters which are washed three times with aliquots of 5 ml of ice-cold buffer. The filters are extracted into the scintillation liquid and the radioactivity is measured by liquid scintigraphy. The specific binding of [3H] -8-OH-DPAT is defined as the radioactive quantity retained on the filters and which can be inhibited by co-incubation in 5-hydroxy tryptamine at 10 μM. At a concentration of 1 nM of [3H] -8-OH-DPAT, the specific binding represents 90% of the total radioactivity recovered on the filter.

For each concentration of compounds studied, the percentage inhibition of the binding with [3H] -8-OH is determined.
DPAT, then the CI concentration, concentration which inhibits 50% of the binding.

The ICs are between 1 and 100 nM.

The compounds of the invention have also been the subject of an in vitro study as to their affinity for the serotoninergic receptors 5HT1D present in the caudate nucleus of bovine animals, demonstrated by the displacement of a specific labeled ligand, the [ 3H] -5-hydroxytryptamine, essentially as described by Heuring and Peroutka in J. Neurosci., (1987), 7, 804-903.

The caudate bovine nucleus (Collectorgane, Paris) is kept at -800C until use. The tissue is ground in an Ultra-Turrax Polytronn device for 30 s at half the maximum speed in 10 volumes of 50 mM Tris buffer, the pH of which is adjusted to 7.4 with hydrochloric acid (i.e. 100 mg of fresh tissue per ml). The homogenized tissues are washed twice at 40C and centrifuged for 10 min at 40000xg, the pellet being resuspended each time in ice-cold buffer. Finally the last pellet is suspended in the buffer to reach a concentration of 100 mg of starting tissue per ml of 50 mM buffer, and left to incubate at 370C for 15 min. The membrane suspension is then centrifuged for 10 min at 40000xg and the pellet is resuspended in 8 volumes of incubation medium containing Tris (50mM), ascorbic acid (0.1%), calcium chloride (4mM), pargylline (10M) , mesulergin (100nM) and 8-hydroxy-dipropylamino-tetralin (100nM), the pH of which is adjusted to 7.4 with hydrochloric acid.

The binding with [3H] -5-hydroxytryptamine (2nM) is determined by incubation of 100 μl of membrane suspension in a final volume of 1 ml of incubation medium.

After an incubation of 30 min at 370C followed by an incubation of 5 min between 0 and 40C, the membranes are recovered by filtration on Whatman GF / Bn filters which are washed twice with aliquots of 1 ml of ice-cold 50mM Tris buffer. , and whose pH is adjusted to 7.4 with hydrochloric acid.

The filters are extracted into the scintillation liquid and the radioactivity is measured by liquid scintigraphy.

The specific binding of [3H] -5-hydroxytryptamine is defined as the amount of radioactivity retained on the filters and which can be inhibited by co-incubation with 5-hydroxytryptamine at 0.1M. At a concentration of 2nM of [3H] -5-hydroxytryptamine the specific binding represents 70% of the total radioactivity recovered on the filter.

For each concentration of compound studied, the percentage of inhibition of the binding with [3H] -5-hydroxytryptamine is determined, then the concentration CI, a concentration which inhibits 50% of the binding.

The most active compounds of the invention, in this test, have an IC of 1 to 10 nM.

The compounds of the invention were also the subject of an in vitro test for displacement of the binding of spiperone to the serotoninergic receptors (5-HT2) of the cerebral cortex of the rat.

For this test, take the brains of rats, dissect the cortex and homogenize it with OOC in 10 volumes of a mixture containing, per liter, 50 millimoles of buffer.
Tris / HCl at pH = 7.4, 120 millimoles of sodium chloride and 5 millimoles of potassium chloride. The homogeneous mixture is centrifuged at 40,000 × g for 10 min then, twice, the pellet is recovered, it is washed by suspending it in the same buffer mixture, it is homogenized again and it is centrifuged. Finally, the final pellet is diluted in the same buffer mixture at the rate of 100 mg of wet tissue for 1 ml of buffer.

The tissue is then subjected to a 10 min preliminary incubation at 370C in the presence of 10 micromoles / l of pargyline, then to a 20 min incubation at 370C in the presence of 3H-spiperone (specific activity: 15 to 30 Ci per millimole) at the concentration of 0.3 nanomoles / l and of the compound to be studied.

The membranes are then recovered by filtration through filters
Whatman GF / B, which is washed twice with 5 ml of cold buffer. The radioactivity retained by the filter is measured by liquid scintigraphy.

To evaluate the activity of the compounds, the curve of the percentage inhibition of the specific binding of 3H-spiperone as a function of the concentration of displacing drug is established.

The CI concentration is determined graphically, a concentration which inhibits 50% of the specific binding.

The specific bond is defined as being the bond displaced by 100 micromoles / l of 5-HT.

The most active compounds in this test have an IC of 1 10 nM.

Finally, the compounds of the invention were the subject of an in vitro study as to their affinity for the 5HTlc serotoninergic receptors present in the pig choroid plexus, demonstrated by the displacement of the binding of a specific labeled ligand. , [3H] mesulergin, essentially as described by Pazos et al. in Eur. J. Pharmacol., (1984), 106, 539-546, and by Yagalof and Hartig in
Mol. Pharmacol., (1986), 26, 120-125.

The choroid plexus (Collectorgane, Paris) is stored at -800C until use. The tissue is homogenized in a Pattern homogenizer by 10 to 15 movements (800 rpm) in 10 volumes of sucrose (0.32M) at a temperature of 0 to 40C. The membrane suspension is centrifuged for 10 min at 1000xg (40C) and the supernatant is centrifuged for 20 min at 30000xg (40C). The pellet is suspended in 10 volumes of 50 mM Tris buffer, pH adjusted to 7.4 with hydrochloric acid, and is then incubated at 370C for 15 min. Finally the suspension is centrifuged for 20 min at 30,000 xg ( 40C), and the pellet is taken up in 28 volumes of incubation buffer containing Tris (50mM), ascorbic acid (0.1%), calcium chloride (4mM) and pargylline (10yM), and whose pH is adjusted to 7.4 with hydrochloric acid.

The binding with [3H] mesulergin (1nM) is determined by incubation of 100 μl of suspension of membranes in a final volume of 500 μl of incubation medium.

After an incubation of 30 min at 370C followed by an incubation of 5 min between 0 and 40C, the membranes are recovered by filtration on Whatman GF / Bn 'filters, previously treated for 30 min with 0.05% polyethyleneimine, and washed with twice 1 ml of ice-cold 50 mM Tris buffer, the pH of which is adjusted to 7.4 with hydrochloric acid.

The filters are extracted into the scintillation liquid and the radioactivity is measured by liquid scintigraphy.

The specific binding of [3H] mesulergin is defined as the amount of radioactivity retained on the filters and which can be inhibited by co-incubation with 5-hydroxytryptamine at 10yM. At a concentration of 1 nM of [3 H] mesulergin, the specific binding represents 90 W of the total radioactivity recovered on the filter.

For each concentration of compound studied, the percentage of inhibition of the binding with [3H] mesulergin is determined, then the concentration CI, a concentration which inhibits 50% of the binding.

The compounds of the invention have, in this test, CIw of 1 to 10 nM.

In vivo, the central activity (of the 5HTlA type) of the compounds of the invention was evaluated by their hypothermic effects induced in mice 30 min after intraperitoneal injection of each compound studied, at doses of 0.1 to 10 mg / kg.

The AMD is then determined, the minimum active dose that causes a statistically significant drop in temperature.

The most active compounds in this test have a DAM of 1 to 10 mg / kg.

Finally, the antiserotonergic activity (of the 5HT2 type) of the compounds of the invention has been studied as to their effect on the inhibition of "head-twitches" (head snarls) caused by L-5-hydroxy-tryptophan (L-5-HTP) in mice, according to the method described by Corne et al., Br. J.

 Phannacol. (1962) 20 106-120.

The mice (CD1 males, Charles River France (18 to 22 g of body weight) receive the products to be studied, in increasing doses, or the solvent, intraperitoneally or orally, simultaneously (ip route) or sixty minutes before (oral route) ) an injection of L-5-HTP at a dose of 250 mg / kg subcutaneously Forty-five minutes after this injection of 5-HTP, the number of snatches is counted, for each mouse, for one minute .

For each treatment, the average of the swatches, as well as the percentage of variation compared to the control batch, are calculated.

From the dose-effect curve, the DA is determined (active dose 50% or dose which decreases the average number of groundings by 50k compared to the control animals) by the graphic method of Miller and Tainter (Proc. Soc. Exp. Biol.

Med. (1944) 57 261).

The AMDs of the compounds of the invention are less than 3 mg / kg intraperitoneally and are of the order of 1 to 3 mg / kg orally.

The results of the tests show that the compounds of the invention have a strong affinity for the serotoninergic receptors of the 5HTlA, 5HTlD and 5HTIC types, as well as a certain affinity for the 5HT2 receptors. In vivo they have 5HTlA agonist and 5HT2 antagonist properties.

These results suggest that the compounds can be used for the treatment of all conditions linked to dysfunctions of the serotonergic receptors of the 5HT1Â, 5HT1D, 5HTlC and / or 5HT2 type, in particular for the treatment of anxiety states, depression, disorders. sleep, phobias, obsessive-compulsive disorder, alcoholism-related disorder, sexual behavior disorder, for the regulation of food intake, and also for the treatment of vascular or cardiovascular disorders such as migraine and migraine 'hypertension.

For this purpose they can be presented in all pharmaceutical forms suitable for enteral or parenteral administration, in combination with appropriate excipients, for example in the form of tablets, dragees, capsules, capsules, suppositories, solutions or suspensions, drinkable or injectable, dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (5)

Claims. 1. Compound corresponding to the general formula (I)

 in which one of the symbols R1 and R2 represents a hydroxy group, and the other represents a hydrogen atom or a hydroxy or methoxy group, in the base state or of an addition salt with an acid. 2. Compound according to claim 1, characterized in that one of the symbols R1 and R2 represents a hydroxy group, and the other represents a hydroxy or methoxy group. 3. Method for preparing a compound according to claim 1, characterized in that a compound of general formula (II) is treated

 in which Y represents a methoxy group and X represents a hydrogen atom or a methoxy group, using boron tribromide, to obtain a compound of general formula (Ia)

  which corresponds to the general formula (I) when R 1 represents a hydroxy group and R 2 represents a hydrogen atom or a methoxy group, or else, when X represents a methoxy group, and if desired, the compound of formula is treated general (II) with a large excess of boron tribromide, to obtain a compound of formula (Ib)

 which corresponds to the general formula (I) when R1 and R2 each represent a hydroxy group, or else the 1H-indene-3acetic acid derivative of general formula (III) is reacted

 in which Y represents a hydrogen atom or a methoxy group first with N, Nt-carbonyldiimidazole, in order to obtain the corresponding imidazolide in situ, then the latter is treated with the piperazine derivative of formula (IV)

 to obtain the amide of general formula (V)

 which is finally reduced to obtain a compound of general formula (Ic)

 which corresponds to the general formula (I) when R1 represents a hydrogen atom or a methoxy group and R2 represents a hydroxy group. 4. Medicament, characterized in that it consists of a compound according to claim 1 or 2. 5. Pharmaceutical composition characterized in that it contains a compound according to claim 1 or 2, associated with an excipient.