FR2656306A1 - Heterocyclic derivatives, their preparation and the medicaments containing them - Google Patents

Abstract

Compounds of formula R1-(CH2)n-Het in which - R1 represents a residue of formula - n is equal to 2 or 3, - Het represents a piperidino radical substituted in the 4-position by a -(CH2)m-R2- or =CH-R2 chain, a 1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by a -(CH2)m-R2 chain or a 1-piperazinyl radical substituted in the 4-position by a -(CH2)m-R2 chain, - m is equal to 1 or 2, - R2 represents a 2- or 3-indolyl (optionally substituted by a halogen atom and/or on the nitrogen atom by a straight- or branched-chain alkyl radical containing 1 to 4 carbon atoms), 1- or 2- indolyl or 1- or 2-indenyl radical, it being understood that when R1 represents a residue of formula (A) or (B), n is equal to 2, Het represents a piperidino radical substituted in the 4-position by a -(CH2)m-R2 chain, R2 represents a 2- or 3-indolyl radical optionally substituted by a halogen atom and m is other than 1, their preparation and the medicaments containing them.

Description

The present invention relates to compounds of formula:
R1 - (CH2) n - Het (I) their preparation and the drugs containing them.

- n est égal à 2 ou 3, - Het représente un radical pipéridino substitué en position -4 par une chaîne -(CH2)m-R2 ou =CH-R21 tétrahydro-1,2,3,6 pyridyl-1 substitué en position -4 par une chaîne -(CH2)n-R2 ou pipérazinyl-1 substitué en position -4 par une chaîne -(CH2)n-R2, - m est égal à 1 ou 2, - R2 représente un radical indolyl-2 ou -3 (éventuellement substitué par un atome d'halogène et/ou sur l'atome d'azote par un radical alkyle contenant 1 à 4 atomes de carbone en chaîne droite ou ramifiée), indanyl-1 ou -2 ou indényl-1 ou -2, étant entendu que lorsque Ri représente un reste de formule (A) ou (B), n est égal à 2, Het représente un radical pipéridino substitué en position -4 par une chaîne -(CH2)m-R2, R2 représente un radical indolyl-2 ou -3 éventuellement substitué par un atome d'halogène, m est différent de 1.In formula (I), - R1 represents a residue of formula

- n is equal to 2 or 3, - Het represents a piperidino radical substituted in position -4 by a chain - (CH2) m-R2 ou = CH-R21 tétrahydro-1,2,3,6 pyridyl-1 substituted in position -4 by a chain - (CH2) n-R2 or piperazinyl-1 substituted in position -4 by a chain - (CH2) n-R2, - m is equal to 1 or 2, - R2 represents an indolyl-2 radical or -3 (optionally substituted by a halogen atom and / or on the nitrogen atom by an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain), indanyl-1 or -2 or indenyl-1 or -2, it being understood that when Ri represents a residue of formula (A) or (B), n is equal to 2, Het represents a piperidino radical substituted in position -4 by a chain - (CH2) m-R2, R2 represents an indolyl-2 or -3 radical optionally substituted by a halogen atom, m is different from 1.

 The invention also relates to the salts of the compounds of formula (I) with mineral or organic acids.

 In formula (I) the halogen atoms are preferably fluorine atoms.

The compounds of formula (I) can be prepared by the action of a halogenated derivative of formula
R1 - (CH2) n - Hal (II) in which RI and n have the same meanings as in formula (I) and Hal represents a halogen atom, on a derivative of formula
H - Het (III) in which Het has the same meanings as in formula (I).

 This reaction is generally carried out in an inert solvent such as tetrahydrofuran, dimethylformamide or a mixture of these solvents, in the presence of a base such as an alkali metal bicarbonate or a tertiary amine such as a trialkylamine. , at the boiling point of the solvent.

The halogenated derivatives of formula (II) can be obtained by the action of a derivative of formula
R1 - H (IV) in which R1 has the same meanings as in formula (I), on a dihalogenated derivative of formula
Hal - (CH2) n - X (v) in which Hal and X represent a halogen atom and has the same meanings as in formula (I).

 This reaction is generally carried out in an inert solvent such as dimethylformamide in the presence of sodium hydride, at a temperature between 200C and the boiling point of the solvent.

 The derivative of formula (IV) for which R1 represents a residue of formula (B) can be obtained by the action of 8-amino-1,2,5,6-tetrahydroquinoline on the sulfonamide.

 This reaction is generally carried out in an inert solvent such as diglyme, at a temperature between 100 and 1700C.

 The derivative of formula (IV) for which R1 represents a residue of formula (C) can be obtained by cyclization of 4-bromo-5-isoquinolyl-sulfonamide.

 This cyclization is carried out, preferably by means of a base such as an alkali metal hydride, in an inert organic solvent such as dimethylformamide or tetrahydrofuran, at a temperature between 200C and the boiling point of the solvent.

 Bromo-4 isoquinolyl-5 sulfonamide can be prepared by the action of ammonia on bromo-4 isoquinolyl-5 sulfonyl chloride, preferably within tetrahydrofuran, at a temperature ranging from -50 to + 200C.

 4-bromo-5-isoquinolyl sulfonyl chloride can be prepared by the action of sodium nitrite on 5-amino-4-bromo isoquinoline in the presence of hydrochloric acid at a temperature in the region of 0 ° C. and then sulfur dioxide in the acetic acid in the presence of cuprous chloride at a temperature in the region of 2O0C.

 The 5-amino-4-bromo isoquinoline can be obtained by reduction of the 4-bromo-5-nitro isoquinoline. This reduction is preferably carried out using stannous chloride and hydrochloric acid at the boiling temperature of the reaction mixture.

 4-bromo-5 nitro-isoquinoline can be prepared by applying the method described by M. D. NAIR et al., Indian J.

Chem. Soc., 5, 224 (1967).

 The derivative of formula (IV) for which R1 represents a residue of formula (D) can be prepared by hydrolysis of N-tert-butyl (a hydroxybenzyl) -2 benzenesulfonamide.

 This reaction is preferably carried out using sulfuric acid, at a temperature between 20 and 300 C.

 N-tert-butyl (a-hydroxybenzyl) -2 benzenesulfonamide can be obtained by the action of butyllithium on N-tertbutylbenzenesulfonamide and then benzaldehyde.

 This reaction is carried out in an inert solvent such as tetrahydrofuran, at a temperature of OOC.

 N-tert-butylbenzenesulfonamide can be obtained by applying the method described by G. LOMBARDINO et al., J.

Org. Chem., 36, 1843 (1971).

 The derivative of formula (IV) for which R1 represents a residue of formula (F) can be prepared by the action of 8-amino-1,2,5,6-tetrahydroquinoline on urea.

 This reaction is generally carried out in an inert solvent such as diglyme or toluene, at a temperature between 100 and 1700C.

 The derivatives of formula (III) can be obtained by application or adaptation of the methods described by C. GUEREMY et al., J. Med. Chem., 23, 1306 (1980); C.S. RUNTY et al., Gazz.

Chem. Ital., 81, 613 (1951); AOM STOPPANI, Revista Argentina
Microbiologica, 19, 121 (1987); C. GUEREMY et al. Patent EP 42322 and V. SNIECKUS, Can. J. Chem., 51, 792 (1973) and in the examples.

 The compounds of formula (I) for which R2 represents an indolyl-2 or -3 radical substituted on the nitrogen atom by an alkyl radical and optionally substituted by a halogen atom can also be obtained by alkylation of a compound of formula (I) corresponding for which R2 represents an indolyl-2 or 3 radical optionally substituted by a halogen atom.

 This alkylation is generally carried out by means of an alkyl halide in the presence of a base such as an alkali metal hydride, in an inert solvent such as dimethylformamide, tetrahydrofuran or dioxane, at a temperature close to 2O0C.

 The reaction mixtures obtained by the various processes previously are treated according to conventional physical (evaporation, extraction, distillation, crystallization, chromatography, etc.) or chemical (salt formation, etc.) methods.

 The compounds of formula (I), in the form of the free base can be converted into an addition salt with the acids by the action of a mineral or organic acid in an organic solvent such as an alcohol, a ketone, a chlorinated solvent or an ether.

 The compounds of formula (I) have interesting pharmacological properties. These compounds are inhibitors of 5HT reuptake and are therefore useful in the treatment of depression, obsessive-compulsive disorders, obesity, eating disorders, in particular excessive alcohol, as well as learning and memory, panic attacks and pain.

 The affinity of these products with respect to the paroxetine binding site (reflection of the inhibition of 5HT reuptake) was measured by the method of E. HABERT et al., Eur. J. Pharmacol., 118, 107 (1985).

 In this test, the compounds of formula (I) have an IC50 of less than 25nM.

 The compounds of formula (I) have a low toxicity. They are generally non-toxic at 300 mg / kg orally in mice given once.

The most interesting compounds are the following - {(((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl} -1 benzo [cd] indolone-2 - ([((fluoro-5 indolyl-3 ) methyl) -4 piperidino) -3 propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 - <((1-indenyl methyl) -4 piperidinoj-3 propyl) -2 naphtho (1,8 -cd] isothiazole dioxide-1,1 - {[(5-fluoro-indolyl-3) methyl) -4 tetrahydro-1,2,3,6 pyridyl-1] -2 ethyl) -2 naphtho [1,8-cd ] isothiazole dioxide-1,1 - <[((f luoro-5 indolyl-3) methyl) -4 piperidinol-2 ethyl} -2 2H-isothiazolo [3,4,5-de] isoquinoline dioxide dioxide-i, i
For therapeutic use, use may be made of the compounds of formula (I) as such or in the form of pharmaceutically acceptable salts.

 As pharmaceutically acceptable salts, there may be mentioned in particular the addition salts with mineral acids such as hydrochlorides, sulfates, nitrates, phosphates or organic compounds such as acetates, propionates, succinates, oxalates, benzoates, fumarates, maleates, methanesulfonates, isothionates, theophillineacetate , salicylates, phenolphthalinates, methylene-bis-B-oxynaphtoates or substitution derivatives of these derivatives.

 The following examples, given without limitation, show how the invention can be put into practice.

Example 1
A mixture of 5.4 g of (2-chloroethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, 4,6 g of [(indolyl-3) -2 ethyl] -4 piperidine , 1.7 g of sodium bicarbonate in 120 cm 3 of tetrahydrofuran and 120 cm 3 of dimethylformamide is heated for 8 hours to boiling and then cooled to a temperature in the region of 2O0C. The precipitate formed is separated by filtration, the filtrate is evaporated to dryness at 40 ° C. under reduced pressure (20 mm of mercury; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column, under a stream of nitrogen at medium pressure (0.5-1.5 bar) with ethyl acetate as eluent. After recrystallization from boiling acetonitrile , 2.6 g of <[((indolyl-3) -2 ethyl) -4 piperidino] -2 ethyl-2} naphtho [1,8-cd] isothiazole dioxide-1 are obtained, melting at i690C.

 (2-Chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-l, l can be prepared as follows: 19.2 g of sodium hydride in 50% dispersion in petroleum jelly oil, crossed by a stream of argon, a solution of 82 g of naphthosultam-1,8 in 1000 cm3 of dimethylformamide is added over 2 hours, maintaining at a temperature in the region of 350C. The reaction medium is stirred for 1 hour at a temperature in the region of 200C and then 35.2 cm3 of 1-bromo-2-chloroethane is added. Stirring is continued for 15 hours at a temperature in the region of 200C. The reaction mixture is concentrated to dryness at 7O0C under reduced pressure (0.5 mm mercury; 0.07 kPa) and the residue is taken up in 1000 cm3 of dichloromethane and filtered. The filtrate is washed with 4 times 1000 cm3 of water and the organic phase is decanted, dried over anhydrous magnesium sulfate and evaporated to dryness at 400C under reduced pressure (20 mm of mercury; 2.7 kPa). The oil obtained is purified by flash chromatography on a silica column, under a stream of argon at medium pressure (0.1-1.5 bar) with dichloromethane as eluent.

70.2 g of (2-chloroethyl) -2 naphtho (I, 8-cd] isothiazole dioxide-1,1 melting at 960C are obtained.

 [(Indolyl-3) -2 ethyl] -4 piperidine can be prepared according to the method described by C. GUEREMY et al., J. Med. Chem., 23, 1306 (1980).

Example 2
To 0.27 g of sodium hydride in dispersion at 50% in petrolatum oil, under a stream of argon, a mixture of 2.3 g of <(((fluoro-5 indolyl-3) methyl) -4 piperidino] -2 ethyl) -2 naphtho [i, 8-cdj isothiazole dioxide-l, l in 40 cm3 of dimethylformamide, maintaining the temperature close to 200C. The reaction medium is stirred for 1 hour at a temperature close to 200C and then a solution of 0.4 cm3 of methyl iodide in 20 cm3 of dioxane is added over 15 minutes. Stirring is continued for 15 hours at a close temperature. of 200C. The reaction mixture is taken up in 25 cm3 of distilled water and the organic phase is extracted with 4 times 50 cm3 of dichloromethane then washed with 25 cm3 of distilled water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness at 400C under reduced pressure (20 mm of mercury 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column, under an argon stream, at medium pressure (0.5-1.5 bar) with dichloromethane then a mixture of ethyl acetate and methanol (97 -3 by volume) as eluent. 0.8 g of <[((5-fluoro-1-methyl-3-indolyl) methyl) -4 piperidino] -2 ethyl) -2 naphtho [1,8-cd] isothiazole is obtained 1,1-dioxide in the form of a yellow oil which is transformed into acid oxalate melting at 150-152 C.

 <[((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl} -2 naphtho [1,8-cd] isothiazole dioxide-1,1 can be prepared as follows: a mixture of 5 , 3 g of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, 4,6 g of [(5-fluoro-indolyl-3) methyl] -4 piperidine and 1,68 g of sodium bicarbonate in 120 cm3 of tetrahydrofuran and 120 cm3 of dimethylformamide is heated 48 hours to boiling and then cooled to a temperature in the region of 200C. The precipitate formed is separated by filtration and the filtrate is evaporated to dryness at 400C under reduced pressure (20 mm of mercury; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column, under a stream of nitrogen at medium pressure (0.5-1.5 bar) with ethyl acetate as eluent. 4.4 g of a brown oil are obtained. 2 g of this oil are recrystallized from 15 cm3 of boiling acetonitrile. 1.6 g of ([(fluoro-5 indolyl-3) methyl) -4 piperidino] -2 ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 melting at 1610C are thus obtained.

 [(Fluoro-5 indolyl-3) methyl] -4 piperidine can be prepared according to the method described by C. GUEREMY et al., J. Med.

Chem., 23, 1306 (1980).

Example 3
The procedure is as in Example 1 starting from 2.7 g of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, of 2,5 g of [(fluoro-5 indolyl-3) -2 ethyl] -4 piperidine and 0.8 g of sodium bicarbonate in a mixture of 80 cm3 of dimethylformamide and 40 cm3 of tetrahydrofuran. The mixture is boiled for 9 hours then cooled to a temperature in the region of 200 C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with l acetate as eluent and recrystallization from 15 cm3 of boiling acetonitrile, 1.7 g of <[((fluoro-5 indolyl-3) -2 ethyl) -4 piperidino] -2 ethyl) -2 naphto are obtained [1,8-cd] isothiazole 1,1-dioxide melting at 1640C.

 [(Fluoro-5 indolyl-3) -2 ethyl] -4 piperidine can be prepared according to the method described by C. GUEREMY et al., J. Med.

Chem., 23, 1306 (1980).

Example 4
The procedure is as in Example 1, starting with 2 g of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, of 2 g of hydrochloride of [(5-fluoro indolyl- 3) methyl] -4 tetrahydro-1,2,3,6 pyridine and 1.3 g of sodium bicarbonate in a mixture of 70 cm3 of dimethylformamide and 45 cm3 of tetrahydrofuran. The mixture is heated for 20 hours at boiling point and then cooled to a temperature in the region of 200 C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with dichloromethane then ethyl acetate as eluents, 0.4 g of (I ((fluoro-5 indolyl-3) methyl) -4 tetrahydro-1,2,3,6 pyridyl-1 j -2 ethyl) is obtained -2 naphtho (1,8-cdj isothiazole dioxide-1,1 in the form of a yellow oil which is transformed into acid oxalate melting at 1280C.

 [(Fluoro-5 indolyl-3) methyl] -4 tetrahydro-1,2,3,6 pyridine can be prepared in the following way: 11 g of [(fluoro-5 indolyl-3) methyl] -4 vinyloxycarbonyl- 1 1,2,3,6-tetrahydro pyridine and 100 cm3 of a 6.3N hydrochloric dioxane solution are stirred for 1 hour at a temperature close to 200C. The mixture is then concentrated to dryness at 400C under reduced pressure (20 mm of mercury; 2.7kPa). The residual oil is taken up in 40 cm3 of ethanol and the solution obtained is heated for 90 minutes to a temperature close to 500C and then concentrated to dryness at 400C under reduced pressure (20 mm of mercury; 2.7 kPa). taken up in 50 cm3 of isopropyl ether; the precipitate formed is separated by filtration and purified by flash chromatography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (90-10 then 80 -20 by volume) as eluent. 3.3 g of [(5-fluoro-indolyl-3) methyl] -4-tetrahydro-1,2,3,6 pyridine are obtained in the form of a brown oil, used as it is in subsequent syntheses.

 [(Fluoro-5 indolyl-3) methyl] -4 vinyloxycarbonyl-1 tetrahydro-1,2,3,6 pyridine can be prepared as follows: 3.8 cm3 of vinyl chloroformate are added dropwise to a solution of 9 g of benzyl-1 [(f luoro-5 indolyl-3 methyl] -4 tétrahydro-1,2,3,6 pyridine in 150 cm3 of dichloromethane while maintaining the temperature close to 100C. The mixture is heated for 8 hours at boiling point, cooled to a temperature close to 200C and then concentrated to dryness at 200C under reduced pressure (20 mm of mercury; 2.7 kPa). 11 g of ((fluoro-5 indolyl-3) methyli-4 vinyloxyearbonyl- are obtained. 1 tetrahydro-1, 2,3,6 pyridine used in the crude state in the subsequent syntheses.

 Benzyl-1 [(fluoro-5 indolyl-3) methyl] -4 tetrahydro-1,2,3,6 pyridine can be prepared in the following way 1.4 g of sodium borohydride are added, under a stream of argon to a solution of 12 g of benzyl-1 [(fluoro-5 indolyl-3) methyl] -4 pyridinium bromide in 200 cm3 of ethanol, keeping the temperature close to 250C. Stirring is continued for 36 hours at this temperature and then 100 cm 3 of distilled water are added to the mixture. The organic phase is extracted with 4 times 50 cm3 of dichloromethane, washed with 50 cm3 of distilled water, dried over anhydrous magnesium sulfate and concentrated to dryness at 200C, under reduced pressure (20 mm of mercury; 2.7 kPa) . 9 g of benzyl-1 [(5-fluoro-indolyl-3) methyl] -4-tetrahydro-1,2,3,6 pyridine are obtained in the form of a yellow oil, used in the crude state in the subsequent syntheses.

 Benzyl-1 [(5-fluoro-indolyl-3) methyl] -4-tetrahydro-1,2,3,6 pyridine bromide can be prepared according to the method described by E. FRIEDERICHS et al, Arch. Pharm., 308, 209 (1975).

Example 5
The procedure is as in Example 1 starting from 2.4 g of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, of 2,2 g of [(fluoro-5 indolyl-3) methyl] -4 piperazine and 0.8 g of sodium bicarbonate in a mixture of 80 cm3 of dimethylformamide and 40 cm3 of tetrahydrofuran. The mixture is heated for 48 hours to boiling and then cooled to a temperature in the region of 200C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of ethyl acetate and methanol (90-10 by volume) as eluent and recrystallization from 7 cm3 of boiling acetonitrile, 1 g of ([((fluoro-5 indolyl-3) methyl) -4 piperazinyl-1] -2 ethyl} -2 naphtho [1,8-cd] isothiazole is obtained Dioxide-1,1 melting at 850C.

 [(3-fluoro-indolyl-3) methyl] -4 piperazine can be prepared according to the method described by C.S. RUNTY et al., Gazz.

Chem. Ital., 81, 613 (1951) and AOMSTOPPANI, Revista Argentina
Microbiologia, 19, 121 (1987).

Example 6
The procedure is as in Example 1 from 2.8 g of (3-chloro-propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1, from 2,3 g of ((f luoro- 5 indolyl-3) methyl] -4 piperidine and 0.8 g of sodium bicarbonate in a mixture of 90 cm3 of dimethylformamide and 60 cm3 of tetrahydrofuran The mixture is heated for 24 hours at boiling point and then cooled to a temperature in the region of 200 C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with ethyl acetate as eluent and recrystallization for the first time in 15 cm3 of acetonitrile then a second time in 5 cm3 of boiling acetonitrile, 2.1 g of <[((5-fluoro-indolyl-3) methyl) -4 piperidino] -3 propyl) -2 naphtho [1.8 -cd] isothiazole dioxide-1,1 melting at 1000C.

 (3-Chloro-propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 can be prepared as follows: 40.2 g of sodium hydride in 50% dispersion in petroleum jelly oil, under a stream of argon, a solution of 175 g of naphthosultam-1,8 in 2,100 cm 3 of dimethylformamide is poured in 3 hours and 30 minutes, maintaining the temperature between 200C and 300C. The reaction medium is stirred for one hour at a temperature in the region of 200 ° C., then 83 cm 3 of bromo-1 chloro-3 propane are added over 10 minutes. Stirring is maintained for 15 hours at a temperature close to 200C. The reaction mixture is concentrated to dryness at 500C under reduced pressure (0.5 mm of mercury; 0.07 kPa). The residue is purified by flash chromatography on a silica column, under a stream of nitrogen, at medium pressure (0 , 5-1.5 bar) with a mixture of dichloromethane and cyclohexane (60-40 by volume) as eluent. 165.7 g of (3-chloro-propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 melting at 780C are obtained.

Example 7
The procedure is as in Example 1, starting with 2.13 g of (1-indenyl-methyl) -4 piperidine, 2.94 g of (2-chloroethyl) -2 naphtho [1,8-cd] isothiazole 1,1-dioxide and 0.92 g of sodium hydrogencarbonate in 50 cm3 of dimethylformamide and 50 cm3 of tetrahydrofuran. The mixture is heated for 12 hours at boiling point and then cooled to a temperature in the region of 200C. After evaporation to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 50 cm3 of water and extracted twice with 75 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flashchromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane methanol (99-1 by volume) as eluent. 2.7 g of a yellow oil are obtained. To this oil is added 0.54 g of oxalic acid in 20 cm3 of acetone. 2.5 g of <[(1-indenyl methyl) -4 piperidino] -2 ethyl) -2 naphtho [1,8-cd] isothiazole 1,1-dioxide is thus isolated in the form of an oxalate melting at 1660C.

 (1-Indenyl methyl) -4 piperidine can be prepared according to the method described by C.GUERiY et al., Patent EP 42322.

Example 8
The procedure is as in Example 1, starting with 2.13 g of (1-indenyl-methyl) -4 piperidine, 3.37 g of (3-chloro-propyl) -2 naphtho [1,8-cd] isothiazole 1,1 dioxide and 1 g of sodium hydrogen carbonate in 50 cm3 of dimethylformamide and 50 cm3 of tetrahydrofuran. The mixture is heated for 12 hours at boiling point and then cooled to a temperature in the region of 200C. After evaporation to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 50 cm3 of water and extracted twice with 75 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99-1 by volume) as eluent. 3.3 g of a yellow oil are obtained.

0.67 g of oxalic acid in 50 cm3 of acetone are added to this oil. Is thus isolated 3.5 g of {t (1-indenyl-methyl) -4 piperidino] -3 propyl} -2 naphtho [1,8-cd] isothiazole dioxide-1,1 in the form of oxalate melting at 1400C.

Example 9
The procedure is as in Example 1, starting with 2.7 g of (indanyl-1 methyl) -4 piperidine, 3.2 g of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-l, l and 2 g of sodium hydrogencarbonate in 50 cm3 of dimethylformamide and 50 cm3 of tetrahydrofuran. The mixture is heated for 12 hours at boiling point and then cooled to a temperature in the region of 200C. After evaporation to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 25 cm3 of water and extracted three times with 50 cm3 of dichloromethane. The combined organic phases are dried over sulphate of magnesium and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (98-2 by volume) as eluent. 4.4 g of a yellow oil are obtained which is recrystallized from 50 cm3 of boiling ethanol. Is thus isolated 2 g of <[(indanyl-1 methyl) -4 piperidino] -2 ethyl} -2 naphtho [1, 8-cd] isothiazole dioxide-1,1 melting at 1270C.

 (Indanyl-1 methyl) -4 piperidine can be prepared according to the method described by C. GUEREMY et al., Patent EP 42322.

Example 10
The procedure is as in Example 1, starting with 2.7 g of (indanyl-1 methyl) -4 piperidine, 3.37 g of (.chloro-3 propyl) -2 naphtho [1,8-cd ] isothiazole dioxide-1,1 and 1 g of sodium hydrogen carbonate in 50 cm3 of dimethylformamide and 50 cm3 of tetrahydrofuran. The mixture is heated for 24 hours at boiling point and then cooled to a temperature in the region of 200C. After evaporation to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 25 cm3 of water and extracted twice with 75 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol mixture (98-2 by volume) as eluent. 4.5 g of a yellow oil are obtained. 0.88 g of oxalic acid in 30 cm 3 of acetone is added to this oil. 3.3 g of {[(indanyl-1 methyl) -4 piperidino] -3 propyl) -2 naphtho [1,8-cd] isothiazole dioxide-1,1 are thus isolated in the form of oxalate melting at 1830C.

EXAMPLE 11
The procedure is as in Example 1, starting with 1 g of (indanyl-2 methyl) -4 piperidine, 1.2 g of (2-chloro ethyl) -2 naphtho (1,8-cd] isothiazole dioxide -1.1 and 0.72 g of sodium hydrogen carbonate in 25 cm3 of dimethylformamide The mixture is heated for 24 hours at boiling point and then cooled to a temperature in the region of 200 C. After evaporation to dryness at 800 C. under reduced pressure (20 mm mercury; 2.7 KPa), the residue is taken up in 25 cm3 of water and extracted twice with 50 cm3 of dichloromethane The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa) The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99 -1 by volume) as eluent. 1 g of a yellow solid is obtained which is recistallized in 40 cm3 of boiling ethanol. 0.95 g of ([(indanyl -2 methyl) -4 piperidino] -2 ethyl} -2 naphtho (1, 8-cd] isothiazole dioxide-i, 1 melting at 1260C.

 (2-Indanyl-methyl) -4 piperidine can be prepared according to the method described by C. GUEREMY, patent EP 42322.

Example 12
The procedure is as in Example 1, starting with 1 g of (2-indenyl methyl) -4 piperidine, 1.2 g of (2-chloroethyl) -2 naphtho [i, 8-cd] isothiazole dioxide -1.1 and 0.71 g of sodium hydrogencarbonate in 25 cm3 of dimethylformamide. The mixture is heated for 12 hours at boiling point and then cooled to a temperature in the region of 200C. After evaporation to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 25 cm3 of water and extracted twice with 75 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99-1 by volume) as eluent. 0.75 g of a yellow oil is obtained. To this oil is added 0.15 g of oxalic acid in 30 cm3 of acetone. 0.9 g of a yellow solid is thus isolated, which by recrystallization from 65 cm 3 of methanol provides 0.5 g of l (2-indenyl methyl) -4 piperidino] -2 ethyl) -2 naphtho [1.8 -cd] isothiazole dioxide-i, 1 in the form of an oxalate melting at 1760C.

 (2-Indenyl methyl) -4 piperidine can be prepared according to the method described by C. GUEREMY et al., Patent EP 42322.

Example 13
The procedure is as in Example 1, starting with 2.4 g of [(5-fluoro-2-indolyl) methylidene] -4 piperidine, 2.94 g of (2-chloro-ethyl) -2 naphtho (1, 8-cd] isothiazole dioxide-1,1 and 0.92 g of sodium hydrogencarbonate in 50 cm3 of tetrahydrofuran and 25 cm3 of dimethylformamide The mixture is heated for 12 hours to boiling and then cooled to a temperature in the region of 200C. dry evaporation at 800C under reduced pressure (20 mm of mercury; 2.7 KPa), the residue is taken up in 100 cm3 of water and extracted twice with 75 cm3 of dichloromethane The combined organic phases are dried over magnesium sulfate and brought to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 PKa). The residue is purified by flash chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1, 5 bar) with a dichloromethane-methanol mixture (98-2 by volume) as eluent, 1.4 g of a white meringue are obtained which is recrystallized in 25 cm3 of boiling dichloromethane to give 0.9 g of (I ((5-fluoro-2-indolyl) methylene) -4 piperidino] -2 ethyl) -2 2H-naphtho [1,8-cd] isothiazole dioxide-1,1 melting at 1600C.

 [(5-Indolyl-2-fluoro) methylene] -4 piperidine can be prepared according to the method described by V.SNIECKUS, Can. J. Chem., 51, 792, (1973).

Example 14
The procedure is as in Example 1, from 1.4 g of (2-chloro-ethyl) -l benzo [cd] indolone-2, from 1.6 g of [(5-fluoro-indolyl-3) methyl) - 4 piperidine and 1.5 g of sodium bicarbonate in a mixture of 20 cm3 of dimethylformamide and 15 cm3 of tetrahydrofuran. The mixture is heated for 48 hours to boiling and then cooled to a temperature in the region of 200C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-t, 5 bar) with ethyl acetate as eluent and recrystallization from a mixture of 70 cm3 of cyclohexane and 60 cm3 of boiling ethyl acetate, 1 g of <[((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl) -l benzo [cd] indolone-2 is obtained, melting at 1560C .

 (2-chloro-ethyl) -1 benzo [cd] indolone-2 can be prepared as follows: the procedure is as in Example 1 for the preparation of (2-chloro-ethyl) -2 naphtho (1,8- cd] isothiazole dioxide-1,1, from 1.1 g of sodium hydride at 50% in dispersion in petrolatum oil, from 1.9 cm3 of bromo-1 chloro-2 ethane and from 4, 1 g of benzo [cd] indolone-2 in 115 cm3 of dimethylformamide The mixture is stirred for 18 hours at a temperature close to 200C, under a stream of argon After purification by flash chromatography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of ethyl acetate and cyclohexane as eluent (70-30 by volume), 1.4 g of (2-chloroethyl) are obtained -1 benzo [cd] indolone-2 melting at 1360C.

Example 15
The procedure is as in Example 1, starting from 2.85 g of (2-chloro-ethyl) -2 phenyl-3 benzisothiazole-1,2 dioxide-l, l, 2.15 g of [(fluoro-5 indolyl-3) methyl) -4 piperidine and 2.3 g of sodium bicarbonate in a mixture of 30 cm3 of dimethylformamide and 20 cm3 of tetrahydrofuran. The mixture is heated for 48 hours to boiling and then cooled to a temperature in the region of 200C. . After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of ethyl acetate and cyclohexane (80/20 by volume) as eluent, 2.6 g of ([((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl} -2 phenyl-3-1,2-1,2-dioxide, which is converted into hydrochloride melting at 1750C.

 (2-Chloro-ethyl) -2 phenyl-3 benzisothiazole-1,2 dioxide-l, l can be prepared in the following way: the procedure is as in Example 1 for the preparation of (2-chloro-ethyl) -2 naphtho [1,8-cd] isothiazole dioxide-l, l, from 0.77 g of sodium hydride at 50% in dispersion in petrolatum oil, from 1.4 cm3 of bromo-1 chloro- 2 ethane and 4 g of 3-phenyl-benzisothiazole-1,2-1,1-dioxide in 80 cm3 of dimethylformamide. The mixture is stirred for 18 hours at a temperature close to 200C, under a stream of nitrogen.

After purification by flash chromatography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of ethyl acetate and cyclohexane as eluent (10-90 by volume ), 3 g of (2-chloro-ethyl) -2 phenyl-3 benzisothiazole-1,2 dioxide-1 are obtained, melting at 1210C.

 Phenyl-3 benzisothiazole-1,2 dioxide-1,1 can be prepared as follows: to a solution of 80 cm3 of concentrated sulfuric acid cooled to OOC, 10 g of N-tert-butyl (a- hydroxy benzyl) -2 benzenesulfonamide. The mixture is then stirred for 1 hour at 250C, then poured into 800 cm3 of ice water. After 1 hour of stirring, the precipitate is drained and then taken up in 100 cm3 of dichloromethane. The organic solution is washed with water (2 times 50 cm3), dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 7.1 g of 3-phenyl benzisothiazole-1,2 dioxide-1 are obtained, l melting at 1180 C.

N-tert-butyl (a-hydroxy benzyl) -2 benzenesulfonamide can be prepared as follows: to a solution of 8.5 g of
N-tert-butyl benzenesulfonamide in 100 cm3 of dry tetrahydrofuran cooled with OOC, 64 cm3 of a solution of
1.6 M N-butyllithium in hexane. After one hour of stirring, a solution of 6.5 cm3 of benzaldehyde in 30 cm3 of dry tetrahydrofuran is added, then stirring is continued for 2 hours at OOC.

The mixture is treated with 30 cm3 of 2N hydrochloric acid and extracted with 100 cm3 of ethyl acetate; the organic solution is washed with 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The solid residue is washed with 50 cm3 of isopropyl ether, drained and dried. 11.7 g of
N-tert-butyl (a-hydroxy benzyl) -2 benzenesulfonamide melting at 1600C.

 N-tert-butyl benzenesulfonamide can be prepared by the method described by J.G. LOMBARDINO, J. Org. Chem., 36, 1843, (1971).

Example 16
The procedure is as in Example 1 from 1.9 g of (2-chloroethyl) -2 2H-isothiazolo [3,4,5-de] isoquinoline dioxide-l, l, from 1.7 g of [ (f luoro-5 indolyl-3) methyl) -4 piperidine and 1.8 g of sodium bicarbonate in 40 cm3 of dimethylformamide. The mixture is heated for 18 hours at boiling point and then cooled to a temperature in the region of 200 C. After purification by flash chromathography on a silica column, under a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture ethyl acetate and methanol as eluent (80-20 by volume) and recrystallization from 160 cm3 of boiling acetonitrile, 0.52 g of <[((5-fluoro-indolyl-3) methyl) -4 is obtained piperidino] -2 ethyl} -2 2H-isothiazolo [3,4,5-de] isoquinoline dioxide-l, melting it at 2070C.

 (2-Chloro-ethyl) -2 2H-isothiazolo [3,4,5-de] isoquinoline dioxide-l, l can be prepared as follows: to a solution of the sodium salt of 2H-isothiazolo [3,4 , 5-de] isoquinoline dioxide-l, l (obtained by heating, after cessation of gassing, of a solution of 5.1 g of 4-bromo-isoquinolyl-5 sulfonamide in 30 cm3 of dimethylformamide and a suspension of 1.1 g of sodium hydride in 80% dispersion in petrolatum oil in 50 cm3 of dimethylformamide, for 3 hours at 110 ° C. cooled to 200C, 1.5 cm3 of 2-chloro-1 bromo is added ethane. The reaction medium is stirred for 2 hours and 30 minutes at 110 ° C. and then 18 hours at a temperature close to 200 ° C. The reaction mixture is concentrated to dryness at 500 ° C. under reduced pressure (0.5 mm of mercury; 0.07 kPa). The residue is taken up in 500 cm3 of dichloromethane; the organic phase is washed with 3 times 250 cm3 of distilled water, decanted, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness (20 mm of mercury; 2.7 kPa). The residue obtained is purified by flash chromatography on a silica column, under a stream of argon at medium pressure (0.1-1.5 bar) with a mixture of ethyl acetate and cyclohexane as eluent (80-20 in volumes) as eluent. 1.3 g of (2-chloroethyl) -2 2H-isothiazolo [3,4,5-de] isoquinoline dioxide-1,1 l are obtained in the form of an orange-brown solid used in the raw state in subsequent syntheses.

 The 4-bromo-5-isoquinolyl sulfonamide can be obtained in the following manner: the ammonia is bubbled until saturation in dry tetrahydrofuran at -500C. This solution is treated with a suspension of 8 g of 4-bromo-5-isoquinolyl sulfonyl chloride in 50 cm3 of tetrahydrofuran. The reaction mixture is allowed to return gradually to 200C. The precipitate formed is drained, washed 3 times with 10 cm 3 of tetrahydrofuran, 3 times with 30 cm 3 of water and 2 times with 10 cm 3 of ethyl acetate then drained and dried. 4.5 g of 4-isoquinolyl-5 sulfonamide are obtained in the form of a beige solid, the melting point of which is higher than 2700C.

 The bromo-4 isoquinolyl-5 sulfonyl chloride can be obtained in the following way: a solution of 4.46 g of 5-amino bromo-4 isoquinoline in 44 cm3 of hydrochloric acid (d = 1.19) is cooled to -50C and then treated with a solution of 1.93 g of sodium nitrite in 10 cm3 of water. The reaction mixture is stirred for 1 hour at OOC. The solution obtained is poured onto a saturated solution of sulfur dioxide in 48 cm3 of acetic acid to which has been added a solution of 0.65 g of cuprous chloride in 5.6 cm3 of water. The reaction mixture is stirred until the end of gas evolution and is then extracted twice with 100 cm 3 of dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulfate and concentrated. 5.6 g of bromo-4 isoquinolyl-5 sulfonyl chloride are obtained in the form of a yellow solid used as it is in the subsequent syntheses.

 The amino-5 bromo-4 isoquinoline can be prepared in the following way: to a solution of 90 g of stannous chloride in 100 cm3 of concentrated hydrochloric acid (d = 1.19), a suspension of 25 is gradually added, 3 g of 4-bromo-5 nitro-isoquinoline in 180 cm3 of 2N hydrochloric acid. The reaction mixture is heated at reflux for 90 minutes then is cooled and poured into 2 liters of 2N sodium hydroxide solution with stirring and cooling to 0 C. The precipitate is washed with water, drained and dried. 21.6 g of amino-5 bromo-4 isoquinoline are obtained in the form of yellow crystals melting at 1550C.

 The bromo-4 nitro-5 isoquinoline can be obtained by the method described by M.D. NAIR et al., Indian J. Chem. Soc., 5, 224 (1967).

 The medicaments according to the invention consist of a compound of formula (I) in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

 As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

 As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

 The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

 The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

 The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

 In human therapy, the compounds according to the invention are particularly useful for the treatment of depression, obsessive-compulsive disorders, obesity, eating disorders, in particular excess alcohol, learning and memory, panic attacks and pain.

 The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 50 and 300 mg per day orally for an adult with unit doses ranging from 25 to 100 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention
Example A
One prepares, according to the usual technique, capsules proportioned with 50 mg of active product having the following composition - {[((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl} -1 benzo [cd] indolone -2 ..................................... 50 mg - cellulose ....... ................................. 18 mg - lactose ............. ........................... 55 mg - colloidal silica .................. ................... 1 mg - sodium carboxymethyl starch .......................... .. 10 mg - talc ......................................... 10 mg - magnesium stearate .................................. 1 mg
Example B
Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique - ([((fluoro-5 indolyl-3) methyl) -4 piperidino) -3 propyl) -2 naptho [1,8 -cd] isothiazole dioxide-1,1 ................... 50 mg - lactose .................. ....................... 104 mg - cellulose ....................... ................. 40 mg - polyvidone ............................. ............ 10 mg - sodium carboxymethyl starch ............................ 22 mg - talc. ....................................... 10 mg - magnesium stearate ..... ............................. 2 mg - colloidal silica ................ ...................... 2 mg - mixture of hydroxymethylcellulose, glycerin, oxide of
titanium (72-3.5-24.5) qs 1 film-coated tablet finished at 245 mg
Example C
A solution for injection containing 10 mg of active product having the following composition is prepared - ([(indenyl-1) methyl) -4 piperidino] -3 propyl) -2 naptho [1,8-cd] isothiazole dioxide-1,1. ................................. 10 mg - benzoic acid ............ ............................ 80 mg - benzyl alcohol ................. ..................... 0.06 cm3 - sodium benzoate ..................... ................ 80 mg - 95% ethanol ........................... .............. 0.4 cm3 - sodium hydroxide ............................ ........ 24 mg - propylene glycol ..................................... .. 1.6 cm3 - water ........................................ qs 4 cm3

Claims (5)

 - n is equal to 2 or 3, - Het represents a piperidino radical substituted in position -4 by a chain - (CH2) m-R2 ou = CH-R2, tétrahydro-1,2,3,6 pyridyl-1 substituted in position -4 by a chain - (CH2) n-R2 or piperazinyl-1 substituted in position -4 by a chain - (CH2) m-R2, - m is equal to 1 or 2, - R2 represents an indolyl-2 radical or -3 (optionally substituted by a halogen atom and / or on the nitrogen atom by an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain), indanyl-1 or -2 or indenyl-1 or -2, it being understood that when R1 represents a residue of formula (A) or (B), n is equal to 2, Het represents a piperidino radical substituted in position -4 by a chain - (CH2) m-R2, R2 represents an indolyl-2 or -3 radical optionally substituted by a halogen atom, m is different from 1, as well as their salts with mineral or organic acids.

 R1 - (CH2) n - Het (I) in which R1 represents a residue of formula  CLAIMS 1 - Compounds of formula  2- Compounds of formula (I) according to claim 1 for which the halogen atoms are fluorine atoms.  3 - Process for preparing the compounds of formula (I) according to claim I characterized in that a halogenated derivative of formula is reacted  R1 - (CH2) n - Hal (II) in which R1 and n have the same meanings as in claim 1 and Hal represents a halogen atom, on a derivative of formula  H - Het (III) in which Het has the same meanings as in claim 1, isolates the product and optionally converts it to an addition salt with a mineral or organic acid.  4 - Process for preparing the compounds of formula (I) according to claim 1 for which R2 represents an indolyl-2 or -3 radical substituted on the nitrogen atom by an alkyl radical and optionally substituted by a halogen atom characterized in that an appropriate compound of formula (I) is alkylated, for which R2 represents an indolyl-2 or -3 radical optionally substituted by a halogen atom, isolates the product and optionally transforms it into an addition salt with a mineral or organic acid.  5 - Medicines characterized in that they contain as active material at least one compound of formula (I) according to claim 1.