HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND MEDICINES CONTAINING THEM.

Abstract

Composés de formule: (CF DESSIN DANS BOPI) dans laquelle - R1 représente un reste de formule (CF DESSIN DANS BOPI) (CF DESSIN DANS BOPI) - n est égal à 2 ou 3, - Het représente un radical pipéridino substitué, leurs sels, leur préparation et les médicaments les contenant.

Description

The invention described in the main patent relates to compounds of formula R1-(CH2)n-Het (I) in which - R1 represents a remainder of formula Image available on "Original document" - n is equal to 2 or 3, - Het represents a piperidino radical substituted at position -4 by a -(CH2)m-R2 or =CH-R2 chain, 1,2,3,6-1-tetrahydropyridyl substituted at position -4 by a -(CH2)m-R2 chain, or 1-piperazinyl substituted at position -4 by a -(CH2)m-R2 chain, - m is equal to 1 or 2, - R2 represents a 2- or 3-indolyl radical (possibly 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), 1- or 2-indanyl, or 1- or 2-indenyl, it being understood that when R1 represents a remainder of formula (A) or (B), n is equal to 2, Het represents a piperidino radical substituted at position -4 by a chain (CH2)m-R2, R2 represents an indolyl-2 or -3 radical possibly substituted by a halogen atom, m is different from 1, their salts, their preparation processes and the drugs containing them. This addition relates to new compounds of formula (I), their salts, their preparation processes and the drugs containing them. According to this addition, -R1 represents a formula remainder. Image available on "Original document" -n is equal to 2 or 3 - Het represents a piperidino radical substituted at position -4 by an indenylidene-1, indenyl-1, indanyl-3 radical or by a (CH2)m-R2 chain in which R2 represents a tetrahydro-1,2,3,4,5H-pyrido(4,3-b)-2-indolyl radical (possibly substituted by a halogen atom), quinolyl-3, chromanyl-3, (tetrahydro-1,2,3,4-quinolyl)-3, (tetrahydro-1,2,3,4-naphtyl)-2 (possibly substituted by a halogen atom) or indolyl-1 radical - m is equal to 1 or 2 In the preceding definitions and those that will be cited below, alkyl radicals contain 1 to 4 carbon atoms in a straight or branched chain. Halogen atoms are preferably fluorine or chlorine atoms. The invention also relates to the addition salts of compounds of formula (I) with mineral or organic acids. Compounds of formula (I) can be prepared by the action of a halogenated derivative of formula R1 - (CH2)n - Hal (Il) in which R1 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, 1,3-dimethylimidazolinone-2 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 a temperature between 50 and 1600C. Halogenated derivatives of formula (II) can be obtained by applying or adapting the method described in patent EP 350 403. Preferably, a derivative of formula is reacted 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 na have 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 remainder of formula (B) can be obtained by action of amino-8 tetrahydro-1,2,5,6 quinoline on the sulfamide. This reaction usually takes place in an inert solvent such as diglyme, at a temperature between 100 and 1700C. The derivative of formula (IV) for which R1 represents a remainder of formula (C) can be obtained by cyclization of bromo-4 isoquinolyl-5 sulfonamide. This cyclization is carried out, preferably using 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-bromo-4-isoquinoline in the presence of hydrochloric acid at a temperature close to 00°C and then of sulfur dioxide in acetic acid in the presence of cuprous chloride at a temperature close to 200°C. 5-Amino-4-bromo-4-isoquinoline can be obtained by the reduction of 4-bromo-5-nitro-isoquinoline. This reduction is preferably carried out using stannous chloride and hydrochloric acid at the boiling point of the reaction mixture. Bromo-4-nitro-5-isoquinoline can be prepared by applying the method described by MD NAIR et al., Indian J. Chem. Soc., 5, 224 (1967). The derivative of formula (IV) for which R1 represents a remainder of formula (D) can be prepared by hydrolysis of N-tert-butyl (α hydroxybenzyl)-2 benzenesulfonamide. This reaction is preferably carried out using sulfuric acid, at a temperature between 20 and 300°C. N-tert-butyl (cx-hydroxybenzyl)-2 benzenesulfonamide can be obtained by the action of butyllithium on N-tert-butylbenzenesulfonamide and then benzaldehyde. This reaction takes place in an inert solvent such as tetrahydrofuran, at a temperature of OOC. N-tert-butylbenzenesulfonamide can be obtained by application of the method described by G. LOMBARDINO et al., J. Org. Chem., 36, 1843 (1971). The derivative of formula (IV) for which R1 represents a remainder of formula (F) can be prepared by the action of amino-8 tetrahydro-1,2,5,6 quinoline on urea. This reaction usually takes place in an inert solvent such as diglyme or toluene, at a temperature between 100 and 1700C. Derivatives of formula (III) can be obtained by applying or adapting the methods described in the examples. Compounds of formula (I) for which Het represents a piperidino radical substituted at position -4 by an indenylidene-1 radical can also be prepared by reaction of a derivative of formula Image available on "Original document" in which R1 and n have the same meanings as in formula (I) with a metallic derivative of indene. This reaction takes place in an inert solvent such as tetrahydrofuran or diethyl oxide for example at a temperature between -780C and 300C. As a metallic derivative, the lithium derivative is preferred. The derivatives of formula (VI) can be obtained by applying or adapting the method described in the examples. The reaction mixtures obtained by the various processes described above are treated according to classical physical methods (evaporation, extraction, distillation, crystallization, chromatography...) or chemical methods (formation of salts,...). Compounds of formula (I) in free base form can be transformed into addition salts with 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) exhibit interesting pharmacological properties. These compounds are 5-HT reuptake inhibitors and are therefore useful in the treatment of depression, obsessive-compulsive disorder, obesity and eating disorders, including alcohol abuse, as well as learning and memory disorders. The affinity of these products for the paroxetine binding site (reflecting the inhibition of 5-HT reuptake) was measured by the method of E. HABERT et al., Eur. J. Pharmacol., 118, 107 (1985). In this test, compounds of formula (I) exhibit an IC50 of less than 25 nM. The compounds of formula (I) exhibit low toxicity. They are generally non-toxic at 300 mg / kg orally in mice when administered orally in a single dose. The most interesting compounds are the following: - l[(indènylidene-1)-4 piperidino]-3 propyl)-2 naphtho [1,8-cd] iso thiazole dioxide-l,l - {[(indènyl-3)-4 piperidino]-3 propyl) -2 naphtho (I, 8-cdj isothiazo 1,1-dioxide-([(1-indanyl)-4-piperidino]-3-propyl)-2-naphtho[1,8-cd]isothiazole 1,1-dioxide-([(8-fluoro-1,2,3,4-tetrahydro-5H-pyridot4,3-b]-2-indolyl-methyl)-4 piperidino,-2 ethyl) -2 naphtho[1,8-cd] isothiazole dioxide-1,1 -(((3-quinolyl methyl)-4 piperidino]-2 ethyl}-2 naphtho [1,8-cd] isothiazole dioxide-1,1-([(3-chromanyl-methyl)-4-piperidino]-2-ethyl}-2-naphtho (I,8-cd) isothiazole dioxide-1,1-{[(1,2,3,4-tetrahydroquinolyl-3-methyl)-4-piperidino]-2-ethyl}-2 naphtho[1,8-cd]isothiazole dioxide-1,1-{[(fluoro-7-1,2,3,4-tetrahydro naphthyl)-2-methyl)-4-piperidino]-2 ethyl]-2 naphtho[1,8-cd] isothiazole dioxide-1,1 -{{[(indolyl-1) ethyl]-4 piperidino}-2 ethyl}-2 naphtho [1,8-cd] isothiazole dioxide-1,1 For medicinal use, compounds of formula (I) may be used as such or in the form of pharmaceutically acceptable salts, i.e. non-toxic at the doses of use. Examples of pharmaceutically acceptable salts include addition salts with mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophylline acetate, salicylate, phenolphthalinate, methylene-bis-ss-oxynaphthoate, hydrochloride, sulfate, nitrate, and phosphate. The following examples, given by way of non-limiting purpose, show how the invention can be put into practice. EXAMPLE i 3.6 g of an equimolar mixture of (indanyl-1)-4 piperidine and (indenyl-3)-4 piperidine, 5.1 g of (chloro-3 propyl-1)-2 naphtho[1,8-cd]isothiazole dioxide-1,1 and 1.5 g of sodium hydrogen carbonate in 50 cm3 of dimethylformamide are brought to reflux for 7 hours. After adding 50 cm³ of water and 200 cm³ of dichloromethane, drying the organic phase over anhydrous magnesium sulfate, and concentrating it to dryness at 80°C under reduced pressure (20 mmHg, 2.7 kPa), 8.5 g of a brown oil is isolated. This oil is purified by flash chromaography on a silica column under nitrogen pressure at medium pressure (0.5–1.5 bar) with a dichloromethane-methanol mixture (97% by volume) as the eluent. On the one hand, 1.3 g of a colorless oil is obtained. Dissolving this oil in 35 cm³ of acetone and adding 4N hydrochloric ether yields 1.5 g of ([(3-indenyl-4-piperidino]-3-propyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1 as a hydrochloride that melts at 2200C and, on the other hand, 1.6 g of a colorless oil which dissolves in 30 cm3 of acetone and addition of hydrochloric ether (4N) leads to 1.3 g of (t(indanyl-1)-4 piperidino]-3 propyl)-2 naphtho[1,8-cd]isothiazole dioxide-1,1 in the form of hydrochloride melting at 2370C. The equimolar mixture of (indanyl-1)-4 piperidine and (indenyl-3)-4 piperidine can be prepared as follows: a mixture of 5.7 g of hydroxy-1 (pyridyl-4)-1 indane, 2.5 cm³ of concentrated hydrochloric acid (12N), 75 cm³ of methanol and 0.5 g of platinum oxide is hydrogenated under a pressure of 5 bar at a temperature close to 250°C for 5 hours. After filtering the catalyst, adding 20 cm³ of water, extraction with 100 cm³ of dichloromethane, drying the organic phase over anhydrous magnesium sulfate, and concentrating to dryness at 500°C under reduced pressure (20 mmHg: 2.7 kPa), 5 g of a brown oil is isolated and purified by flash chromatography on silica gel under nitrogen pressure at medium pressure (0.5-1.5 bar). with a dichloromethane-methanol mixture (90-10 by volume) as the eluent.This yields 4 g of a colorless oil which is a mixture of (indanyl-1)-4 piperidine and (indenyl-3)-4 piperidine in an equimolar ratio determined by proton NMR (250 MHz) in deuterated chloroform. This oil is used as is in subsequent syntheses. 1-Hydroxy(4-pyridyl)-1-indane can be prepared as follows: To a solution of 7.8 g of 4-bromopyridine in 35 cm³ of diethyl ether, at -78°C, 40.6 cm³ of n-butyllithium (1.6 M in hexane) is added. The reaction mixture is left for 1 hour at -40°C. Then, 6.6 g of indanone-1 dissolved in 25 cm³ of diethyl ether are added, and the mixture is stirred for 12 hours at a temperature close to 25°C. After adding 50 cm3 of water, three extractions of 75 cm3 of dichloromethane were carried out, the combined organic phases were dried on anhydrous magnesium sulfate, and the dry concentration was achieved at 500°C under reduced pressure (20 mm of mercury: 2.7 kPa). 11.8 g of a yellow oil was isolated, which, when purified by flash chromatography on silica, under a stream of nitrogen, at medium pressure (0.5-1.5 bar), with a dichloromethane-methanol mixture (98-2 by volume) as the eluent, gave 5.7 g of hydroxy-1 (pyridyl-4)-1 indane melting at 1510°C. (3-chloropropyl-1)-2 naphtho[1,8-cd]isothiazole dioxide-1,1 can be obtained according to the method described in patent EP 350 403. EXAMPLE 2 A mixture of 1 g of (8-fluoro-1,2,3,4-5H-pyrido(4,3-b]indolyl-4-methyl)-piperidine, 0.94 g of (2-chloro-2-ethyl)-2-naphthothiazole-1,1-dioxide, and 0.59 g of sodium bicarbonate in 25 mL of 1,3-dimethyl-2-imidazolidinone is heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution is poured into 75 mL of water, and 75 mL of ethyl acetate is extracted three times. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography on a silica column under nitrogen pressure at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (90-10 by volume) as eluent. 0.35 g of E (fluoro-8 tetrahydro-1,2,3,4 5H-pyrido(4,3-b]indolyl-2 methyl)-4 piperidino]-2 ethyl}-2 naphtho[1,8-cd]isothiazole dioxide-1,1 is obtained melting at 2280C. (8-Fluoro-1,2,3,4-5H-pyrido[4,3-b]in-2-dolyl methyl)-4-piperidine can be prepared as follows: 47.3 g of trityl-1 (8-Fluoro-1,2,3,4-5H-pyrido[4,3-b]in-2-dolyl methyl)-4-piperidine, 225 cm³ of 5N hydrochloric acid, and 450 cm³ of ethanol are stirred for 12 hours at a temperature close to 250°C. The mixture is then concentrated to dryness at 400°C under reduced pressure (20 mmHg: 2.7 kPa). 270 cm³ of water is added to the resulting oil, and then the mixture is extracted with 50 cm³ of diethyl ether. The aqueous phase is neutralized with concentrated sodium hydroxide (10N) and extracted by two 300 mL aliquots of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate and concentrated to dryness at 500°C under reduced pressure (20 mmHg, 2.7 kPa). This yields 13.7 g of a yellow solid, which is purified by flash chromatography on a silica column under nitrogen pressure at medium pressure (0.5–1.5 bar) with a mixture of ethyl acetate, methanol, and triethylamine (70-29-1 by volume). Six g of (8-fluoro-1,2,3,4-5H-pyrido[4,3-b]indolyl-2-methyl)-4-piperidine is obtained, appearing as a yellow meringue which is used as is in subsequent syntheses. Trityl-1-(8-fluoro-1,2,3,4-5H-pyrido[4,3-b]indolyl-2-methyl)-4-piperidine can be prepared as follows: a mixture of 17 g of 8-fluoro-1,2,3,4-5H-pyrido(4,3-b]indole, 45.7 g of trityl-1-para-toluenesulfonyloxymethyl-4-piperidine, 24.7 g of potassium carbonate, and 225 cm³ of dimethylformamide is heated at 1000°C for 5 hours. After cooling to approximately 250°C, 90 cm³ of water is added, and the mixture is extracted with 450 cm³ of ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate. After concentration to dryness at 500°C under reduced pressure (20 mmHg: 2.7 kPa), the 77.6 g of trityl-1 (fluoro-8 tetrahydro-1,2,3,4 5H-pyrido[4,3-b]indolyl-2 methyl)-4 piperidine in the form of a yellow meringue which is used directly without further purification. Trityl-l para-toluenesulfonyloxymethyl-4 piperidine can be prepared according to the method described by C. GUEREMY, patent EP 42322. 8-Fluoro-1,2,3,4-5H-pyrido[4,3-b]indole can be prepared according to the method described by JJ PLATTNER, patent US 4 001 263. (2-chloroethyl)-2-naphtho[l,8-cd]isothiazole dioxide-l,l can be obtained according to the method described in patent EP 350 403. EXAMPLE 3 A mixture of 0.9 g of (3-quinolyl-4-methyl)-piperidine, 0.8 g of (2-chloroethyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1, 0.67 g of sodium bicarbonate, and 0.6 g of sodium iodide in 25 cm³ of 1,3-dimethyl-2-imidazolidinone is heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution is dissolved in 75 cm³ of water, and 75 cm³ of ethyl acetate is extracted three times. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography on silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar), with a dichloromethane-methanol mixture (98-2 by volume) as eluent.We obtain 0.52 g of a yellow oil which dissolves in 10 cm3 of acetone and the addition of 0.2 g of oxalic acid gives 0.55 g of ([(quinolyl-3 methyl)-4 piperidino]-2 ethyl)-2 naphtho[1,8-cd]isothiazole dioxide1,1 in the form of oxalate melting at 1500C. 3-(quinolyl-3-methyl)-4-piperidine can be prepared as follows: a mixture of 5.5 g of benzoyl-1 [3-(quinolyl-3)carbonyl]-4-piperidine, 75 cm³ of diethylene glycol, and 6 g of hydrazine monohydrate is heated to 1000°C for 3 hours. At this temperature, 5 g of potassium hydroxide is then added, and the temperature is raised to 1600°C for 2 hours. After cooling to approximately 250°C, the reaction mass is introduced into 200 cm³ of water. After extraction with 100 cm³ of dichloromethane, drying of the organic phase over anhydrous magnesium sulfate and concentration, an oil is obtained which is purified by chromatography on silica, under a pressure of 10 bar, with a toluene-diethylamine-ethanol mixture (80-10-10 by volume). The colorless oil (3 g) in the presence of hydrochloric ethanol gives 1.9 g of (3-quinolyl-4-methyl)piperidine as hydrochloride melting at 2650°C. Benzoyl-1 [(3-quinolyl)carbonyl]-4 piperidine can be prepared as follows: To a solution of 33.28 g of 3-bromoquinoline in 320 cm³ of diethyl ether, add 100 cm³ of n-butyllithium (1.6 M in hexane) and then 41.7 g of ethyl benzoyl-1-isonipecotate dissolved in 320 cm³ of tetrahydrofuran at -78°C for 30 minutes. After cooling to approximately 25°C, leave the mixture at this temperature for 1 hour, and then add 30 cm³ of water. After extraction with 100 cm3 of ethyl acetate, drying of the organic phase on anhydrous magnesium sulfate and concentration, an oil is obtained which is purified by chromatography on silica, under a pressure of 10 bar, with ethyl acetate as the eluent. 10.3 g of benzoyl-1 E(quinolyl-3) carbonyl 1-4 piperidine, melting at 1700C, is thus isolated. Ethyl benzoyl-1 isonipecotate was obtained by benzoylation of ethyl isonipecotate with benzoyl chloride. EXAMPLE 4A mixture of 1.8 g of (3-chromanyl-4-methyl)piperidine, 1.8 g of (2-chloroethyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1 g, 1.68 g of sodium bicarbonate, and 1 g of sodium iodide in 25 mL of 1,3-dimethyl-2-imidazolidinone is heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution is dissolved in 75 mL of water, and 75 mL of ethyl acetate is extracted three times. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography on silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol mixture (99-1 by volume) as eluent.1.9 g of a yellow oil is obtained which, when dissolved in 30 cm3 of acetone, and the addition of 0.37 g of oxalic acid gives 1.6 g of a yellow solid which is recrystallized in 20 cm3 of boiling dimethylformamide leading to 1.4 g of ([(chromanyl-3 methyl)-4 piperidino]-2 ethyl}-2 naphtho[l,8-cd] isothiazoladioxide-l,1 in the form of oxalate melting at 2300C. 4-Chromanyl-3-methyl (4-Piperidyl-4-methylene) can be prepared as follows: a solution of 14 g of 4-(pyridyl-4-)methylene-4-chromanone in 140 cm³ of acetic acid is hydrogenated in the presence of palladium on carbon (10%), at a temperature close to 250°C and under atmospheric pressure, for 5 hours. This yields 13 g of 4-Chromanyl-3-methyl (4-Piperidyl-3-methyl) in the form of a yellow oil, which is used without further purification. (Pyridyl-4)methylene-4-chromanone can be prepared as follows: a mixture of 30 g of chromanone-4, 42.8 g of (pyridyl-4)carboxaldehyde, 30 cm³ of concentrated sodium hydroxide (1 ON), 100 cm³ of methanol, and 60 cm³ of water is stirred for 2 hours at a temperature close to 100°C. This directly isolates 9.2 g of (pyridyl-4)methylene-4-chromanone, which melts at 132°C. EXAMPLE 5 A mixture of 1.4 g of (1,2,3,4-tetrahydroquinolyl-3-methyl)-4-piperidine, 1.4 g of (2-chloroethyl)-2-naphthoL1,8-cd]isothiazole dioxide-1,1 g, 1.3 g of sodium bicarbonate, and 0.78 g of sodium iodide in 25 mL of 1,3-dimethylimidazolidinone-2 is heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution is dissolved in 75 mL of water, and 75 mL of ethyl acetate is extracted three times. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography 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 the eluent. 2.3 g of a yellow oil is obtained which, after dissolution in 30 cm3 of acetone and addition of 0.47 g of oxalic acid, gives 0.85 g of a yellow solid. This solid is recrystallized in 15 cm3 of boiling dimethylformamide and leads to 0.53 g of (E(tetrahydro-1,2,3,4 quinolyl-3 methyl)-4 piperidino]-2 ethyl}-2 naphtho(1,8-cd) isothiazole dioxide1,1 as oxalate melting at 1340C. 4-(1,2,3,4-tetrahydro-3-quinolyl)-4-piperidine can be prepared as follows: To 8.25 g of acetyl-1-(4-piperidyl)-3-tetrahydro-1,2,3,4-quinolone and 25 mL of diethylene glycol, 5.1 mL of hydrazine monohydrate are added, and the mixture is heated to 150°C for 20 minutes. The temperature is then allowed to return to 110°C, 4.9 g of potassium hydroxide pellets are added, and the mixture is heated to 195°C for 1 hour. After cooling to approximately 50°C, 200 mL of water is added, and 100 mL of diethyl ether is extracted three times. The combined organic phases are dried over anhydrous magnesium sulfate and concentrated to dry at 400°C under reduced pressure (20 mm of mercury 2.7 kPa). 3.6 g of a yellow lake is isolated which dissolves in 18 cm3 of ethanol and the addition of 2.2 cm3 of 7N hydrochloric ether gives 2.5 g of (tetrahydro-1,2,3,4 quinolyl-3 methyl)-4 piperidine as hydrochloride melting at 2200°C. Acetyl-1 (piperidyl-4-methyl)-3-tetrahydro-1,2,3,4-quinolone-4 can be prepared as follows: 9.3 g of (pyridyl-4-methylene)-3-acetyl-1-tetrahydro-1,2,3,4-quinolone-4 dissolved in 95 cm³ of acetic acid are hydrogenated in the presence of 0.93 g of platinum oxide, under atmospheric pressure, for 1 hour. 8.25 g of the desired compound is obtained, in the form of a yellow lake used as is in subsequent syntheses. (4-Pyridyl-4-methylene)-3-acetyl-1,2,3,4-tetrahydro-4-quinolone can be prepared as follows: 15.4 g of acetyl-1,2,3,4-tetrahydro-4-quinolone are introduced into a solution of 25 mL of water, 40 mL of methanol, and 12.5 mL of 2N sodium hydroxide. At 0°C, 17.5 g of (4-Pyridyl)-4-carboxaldehyde are added. After 12 hours at 0°C, the resulting precipitate is filtered, yielding 6.8 g of (4-Pyridyl-4-methylene)-3-acetyl-1,2,3,4-tetrahydro-4-quinolone, which melts at 170°C. Four g of 1,2,3,4-4-acetyl-1,2,3,4-tetrahydroquinolone can be prepared as follows: a mixture of 4 g of 1,2,3,4-tetrahydroquinolone and 12 mL of acetic anhydride is heated under reflux for 1 hour. After neutralization with concentrated sodium hydroxide (1 ON), extraction with diethyl ether, drying over anhydrous magnesium sulfate, and concentration, 4.2 g of a yellow solid melting at 890°C is isolated. Tetrahydro-1,2,3,4 quinolone-4 can be prepared according to the method described by RC ELDERFIELD, J. Am. Chem. Soc., 71, 1901 (1949). EXAMPLE 6 A mixture of 1.3 g of [(7-fluoro-1,2,3,4-naphthyl)-2-methyl]-4-piperidine, 1.22 g of (2-chloro-2-ethyl)-1,8-naphthothyl]isothiazole dioxide-1,1 g, 1.15 g of sodium bicarbonate, and 0.69 g of sodium iodide in 25 mL of 1,3-dimethyl-2-imidazolidinone is heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution is dissolved in 75 mL of water, and 75 mL of ethyl acetate is extracted three times. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography 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. 1.7 g of a brown oil is obtained which dissolves in 10 cm3 of acetone and the addition of 0.41 g of oxalic acid gives 1.3 g of a yellow solid.This solid is recrystallized in 13 cm3 of boiling dimethylformamide and leads to 1.05 g of {[(fluoro-7 tetrahydro-1,2,3,4 naphtyl)-2 methyl)-4 piperidino]-2 ethyl}-2 naphtho1,8-cd] isothiazole dioxide-l,l as oxalate melting at 2650C. [(7-fluoro-1,2,3,4-tetrahydro-naphthyl)-2-methyl]-4-piperidine is obtained by heating a mixture of 13.1 g of [(7-fluoro-1,2,3,4-oxo-l-naphthyl)-2-methyl]-4-piperidine and 9.4 g of hydrazine monohydrate in 75 mL of diethylene glycol to 160°C for 15 minutes. The temperature is then lowered to 120°C, 8.4 g of potassium hydroxide is added, and the mixture is heated to 160°C for 5 hours. After cooling to approximately 250°C, 650 mL of water is added, and the mixture is extracted with 350 mL of chloroform. The combined organic phases are dried over anhydrous magnesium sulfate and concentrated to dryness at 500°C under reduced pressure (20 mmHg: 2.7 kPa). 14.5 g of a yellow oil is thus isolated and purified by silica chromatography with a toluene-diethylamine mixture (4:1 by volume) as the eluent. 3.78 g of a colorless oil is isolated which, dissolved in 20 cm³ of diethyl ether, crystallizes with 2 cm³ of a 10.3 N ethanolic hydrochloric acid solution, leading to the formation of 3.1 g of [fluoro-7-1,2,3,4-tetrahydro-2-naphthyl)-2-methyl]-4-piperidine as a hydrochloride that melts at 2080°C. [(7-fluoro-1-tetralone)-2-methyl]-4-piperidine can be prepared as follows: 15.9 g of 7-fluoro-1-(4-pyridyl-2-methylene)-1-tetralone in 230 cm³ of acetic acid in the presence of 1.59 g of platinum oxide are hydrogenated under atmospheric pressure at a temperature of 350°C for 6 hours. This yields 12.6 g of the expected compound, which melts at 2240°C as the hydrochloride. Fluoro-7(pyridyl-4-methylene)-2-tetralone-1 can be prepared as follows: a mixture of 75 g of fluoro-7(pyridyl-4)hydroxymethyl-2-tetralone-1, 830 cm³ of concentrated hydrochloric acid (10N), and 270 cm³ of 98% formic acid is heated under reflux for 3 hours. After neutralization with concentrated sodium hydroxide (ion), extraction with dichloromethane, and concentration, 67.8 g of a yellow solid are isolated. Recrystallized from a mixture of 600 cm³ of ethanol and 230 cm³ of methanol, 47.5 g of the desired compound are obtained, melting at 1440°C. Fluoro-7 (4-pyridyl)-2-hydroxymethyl-1-tetralone naphthalene can be prepared as follows: To a mixture of 45.4 g of fluoro-7-tetralone-1, 140 cm³ of methanol, and 41.5 cm³ of 2N sodium hydroxide, at a temperature of 50°C, 59.2 g of (4-pyridyl)carboxaldehyde are added. The mixture is stirred at a temperature close to 250°C for 3 hours. 68.8 g of the expected compound, which melts at 1330°C, is directly isolated. Fluoro-7 tetralone-l can be prepared according to the method described by GA THIAULT, Bull. Soc. Chim. France, 1308 (1965). EXAMPLE 7 A mixture of 2 g of ([(1)-2-indolyl]-1)-4 piperidine, 2 g of (2-chloroethyl)-2 naphtho[1,8-cd]isothiazole dioxide-1,1,1, 1.26 g of sodium bicarbonate, and 1 g of sodium iodide in 25 mL of 1,3-dimethylimidazolidinone was heated for 16 hours at 150°C. After cooling to approximately 250°C, this solution was dissolved in 75 mL of water, and 75 mL of ethyl acetate was extracted three times. The combined organic phases were dried over magnesium sulfate and brought to dryness at 800°C under reduced pressure (20 mmHg: 2.7 kPa). The residue is purified by flash chromatography on a silica column under nitrogen pressure at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol mixture (99-1 by volume) as the eluent. 3.3 g of a yellow oil is obtained, which, after crystallization in 30 cm³ of boiling acetonitrile, yields 1.52 g of [(1-indolyl)ethyl]-4-piperidino)-2-ethyl}-2-naphthol,8-cd]isothiazole dioxide-1,1 melting at 1520°C. 4-piperidine can be prepared as follows: a solution of 37 g of 4-pyridyl-2-ethyl indole, 3.7 g of platinum oxide in 350 cm3 of acetic acid is hydrogenated, under atmospheric pressure, at a temperature close to 25 C for 10 hours and leads to 33 g of 4-piperidine whose hydrochloride melts at 2040C. The ((pyridyl-4)-2 ethyl]-1 indole can be prepared according to the method described by AP GRAY, J. Am. Chem. Soc. 79, 3554 (1957). EXAMPLE 8 To a solution of 4.6 g of indene in 100 cm3 of tetrahydrofuran, at a temperature close to -780C, 25 cm3 of n-butyl lithium (t,6 M) is introduced and the whole is left for 45 minutes at this temperature. Next, 13.7 g of [(oxo-4 piperidino)-3 propyl]-2 naphtho[1,8-cd] isothiazole dioxide-l,l dissolved in 80 cm3 of tetrahydrofuran is added drop by drop and left under stirring for 12 hours at a temperature close to 250C. After adding 160 cm³ of water, extraction with 500 cm³ of dichloromethane, drying of the organic phase over anhydrous magnesium sulfate, and concentration to dryness under reduced pressure at 50°C (20 mmHg: 2.7 kPa), 18 g of an oil is isolated and purified by flash chromatography on a silica column under a nitrogen stream at medium pressure (0.5–1.5 bar) with a dichloromethane-methanol mixture (98% by volume) as the eluent. This process yields 5 g of a yellow meringue, which, dissolved in 100 cm³ of diethyl ether and treated with 4N hydrochloric ether, provides 4.4 g of (((1-indenyllidene)-4-piperidino]-3-propyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1 as a hydrochloride that melts at 210 C. [(4-oxo-4-piperidino)-3-propyl]-2-naphtho[1,8-cd]isothiazole dioxide-1,1 can be prepared as follows: a mixture of 21.5 g of piperidone-4 monohydrate, 39.4 g of (3-chloropropyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1 and 23.5 g of sodium bicarbonate in 420 cm³ of dimethylformamide and 420 cm³ of tetrahydrofuran is refluxed for 16 hours. After cooling to approximately 250°C, the precipitate formed is filtered, 150 cm³ of water is added, the mixture is extracted with 250 cm³ of dichloromethane, the organic phase is dried over anhydrous magnesium sulfate, and the mixture is concentrated to dryness at 400°C under reduced pressure (20 mmHg: 2.7 kPa), 48.6 g of a yellow oil which is purified by flash chromatography on silica column, under nitrogen flow, at medium pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99-1 by volume) as eluent.This yields 36.2 g of [(oxo-4 piperidino)-3 propyl]-2 naphtho (I,8-cd] iso thiazole dioxide-1,1 melting at 1080C. (3-chloropropyl)-2-naphtho[1,8-cd]isothiazole dioxide-1,1 can be prepared according to the method described in patent EP 350 403. The medicinal products according to the invention consist of a compound of formula (I) in free form or as an addition salt with a pharmaceutically acceptable acid, either in its pure form or in a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicinal products according to the invention may be administered orally, parenterally, rectally, or topically. Tablets, pills, powders (gelatin capsules, caplets), or granules may be used as solid compositions for oral administration. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose, or silica, under an argon current. These compositions may 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. Liquid compositions for oral administration may include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils, or paraffin oil. These compositions may include substances other than diluents, such as wetting agents, sweeteners, thickeners, flavorings, or stabilizers. Sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions, or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, injectable organic esters such as ethyl oleate, or other suitable organic solvents may be used as solvents or vehicles. These compositions may also contain adjuvants, particularly wetting, isotonic, emulsifying, dispersing, and stabilizing agents. Sterilization may be achieved in various ways, such as aseptic filtration, the incorporation of sterilizing agents into the composition, irradiation, or heating. They may also be prepared as sterile solid compositions that can be dissolved at the time of use in sterile water or any other sterile injectable medium. 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. Compositions for topical administration may include, for example, creams, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols. In human therapeutics, the compounds according to the invention are particularly useful for the treatment of depression, obsessive-compulsive disorders, obesity and eating disorders, including alcohol abuse, as well as learning and memory disorders. Doses depend on the desired effect, the duration of treatment and 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 being treated. The following examples illustrate compositions according to the invention EXAMPLE A Capsules containing 50 mg of active ingredient are prepared using the usual technique, with the following composition: - {[(1-indenyllidene)-4-piperidino]-3-propyl}-2 naphtho[1,8-cd] isothiazole 1,1-dioxide ..... 50 mg - cellulose ............................. 18 mg - lactose ............... . . .... 55 mg - colloidal silica............... .... 1 mg - sodium carboxymethyl starch .... .... 10 mg - talc .............................. 10 mg - magnesium stearate .... i mg EXAMPLE B Tablets containing 50 mg of active ingredient with the usual composition are prepared according to the usual technique. - {[(3-quinolyl-4-methyl)-4-piperidino]-2-ethyl}-2 naphtho[1,8-cd] isothiazole 1,1-dioxide ...... 50 mg - lactose .............................. 104 mg - cellulose ..... .... 40 mg - povidone ... 10 10 mg - sodium carboxymethyl starch ..... .... 22 mg - talc ............................. ... 10 mg - Magnesium stearate ... 2 mg - colloidal silica ......................... 2 mg -mixture of hydroxymethylcellulose, glycerin, titanium dioxide (71-3, 5-24, 5) q.s. 1 tablet film-coated tablet containing 245 mg EXAMPLE C An injectable solution containing 10 mg of the active ingredient is prepared, having the following composition: - {[(chromanyl-3-methyl)-4-piperidino]-2-ethyl}-2 naphtho[1,8-cd] isothiazole 1,1-dioxide ....... 10 mg - Benzoic acid ..................... 80 mg - benzyl alcohol ...... .... 0.06 cm - sodium benzoate .... . .... 80 mg - 95% ethanol........... .... 0.4 cm - sodium hydroxide ....... . ... 24 mg - Propylene glycol........... .......... 1.6 cm - water ................. ....qsp 4 cm

Claims

CLAIMS 1 - Formula compounds: R1 - (CH2)n - Het (I) in which R1 represents a remainder of formula: Image available on "Original document" - n is equal to 2 or 3, - Het represents a piperidino radical substituted at position -4 by an -(CH2)m-E2 chain, an indenyl-1, indenyl-1 or indanyl-1 radical, -R2 represents a tetrahydro-1,2,3,4 5H-pyrido (4,3-bJ) radical, indolyl-2 (possibly substituted by a halogen atom), quinolyl-3, chromanyl-3, (tetrahydro-1,2,3,4 quinolyl)-3, (tetrahydro-1,2,3,4 naphthyl)-2 (possibly substituted by a halogen atom) or indolyl-1 - m is equal to 1 or 2, as well as their salts with mineral or organic acids. 2- Compounds of formula (I) according to claim 1 for which the halogen atones are fluorine atares. 3- Process for preparing compounds of formula (I) characterized in that a halogenated derivative of formula is reacted R1-(CH2)n-Hal(II) wherein 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 transforms it into an addition salt with a mineral or organic acid. 4- Process for preparing compounds of formula (I) for which R1 represents a piperidino radical substituted at position -4 by an indenylidene-1 radical characterized in that a derivative of formula is reacted Image available on "Original document" in which nna has the same meanings as in claim 1 with a metallic derivative of indene, isolates the product and optionally transforms it into a salt with a mineral or organic acid. 5- Medicinal products characterized in that they contain at least one active ingredient compound of formula (I) according to claim 1. 6- Drugs according to claim 5 for the treatment of depression.