FR2654729A1 - Piperidine derivatives, their preparation and the medicaments containing them - Google Patents

Abstract

The present invention relates to derivatives of formula: in which R1 represents a 2-indolyl or 3-indolyl radical optionally substituted by a halogen atom and R2 represents a ring chosen from the formulae: to their process of preparation and to the medicaments containing them.

Description

leur procédé de préparation et les médicaments les contenant.The present invention relates to derivatives of formula

their preparation process and the drugs containing them.

In formula (I)
R1 represents an indolyl-2 or -3 radical optionally substituted by a halogen atom and
R2 represents a cycle chosen from the formulas

 The halogen atoms are preferably fluorine or chlorine atoms.

dans laquelle R1 a les mêmes significations que dans la formule (I).The compounds of formula (I) can be prepared by the action of a halogenated derivative of formula
R2 - CH2 - CH2 - Hal (II) in which Hal represents a halogen atom and R2 has the same meanings as in formula (I), on an amine of formula

in which R1 has the same meanings as in formula (I).

 This reaction is generally carried out in an inert solvent such as tetrahydrofuran or dimethylformamide, in the presence of a base such as an alkali metal bicarbonate or a tertiary amine such as triethylamine, at the boiling temperature. of the reaction medium.

The derivatives of formula (II) can be obtained by the action of a derivative of formula
R2 - H (IV) in which R2 has the same meanings as in formula (I), on a dihalogenated derivative of formula
X - CH2 - CH2 - Hal (V) in which X and Hal represent a halogen atom.

 This reaction is preferably carried out in the presence of a base such as an alkali metal hydride, an alkali metal hydroxide, in an inert solvent such as dimethylformamide or tetrahydrofuran, at a temperature between 20 "C and the boiling temperature of the reaction medium.

 Tetrahydro-1,2,5,6 4H-1,2,5-thiadiazolo [3,4,5-ij] quinoline dioxide-2,2 can be obtained by the action of 8-amino-1,2-tetrahydro, 5.6 quinoline on the sulfonamide.

 This reaction is generally carried out in an inert solvent such as diglyme, at a temperature between 100 and 170 "C.

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

 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 and eating disorders, in particular excessive alcohol, as well as in disorders of the body. learning and memory.

 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 a
IC50 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: - ((((f luoro-5 indolyl-3) methyl) -4 piperidino] -2 ethyl-2 naphtho [1,8-cd] isothiazole dioxide-1,1 - {[ ((5-fluoro-indolyl-2) methyl) -4 piperidino] -2 ethyl] -2 naphtho [1,8-cd] isothiazole dioxide-1,1 - ((((indolyl-3 methyl) -4 piperidino] -2 ethyl} -2 naphtho [1,8-cd] isothiazole dioxide-1,1 - (((((f luoro-5 indolyl-3) methyl) -4 piperidino] -2 ethyl} -1 tetrahydro-1,2,5 , 6 4H-1,2,5-thiadiazolo [3,4,5-1j] quinoline dioxide-2, 2.

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

EXAMPLE 1
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 20 C.

The precipitate formed is separated by filtration and the filtrate is evaporated to dryness at 400C under reduced pressure (20 mm of mercury; 2.7KPa). The residue obtained is purified by flash chromatography on a silica column, under a stream of argon, at medium pressure (0.5 - 1.5 bar) with ethyl acetate as eluent. 4.4 g of a brown oil are obtained. 2g 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 161 ° C. are thus obtained.

(2-Chloro-ethyl) -2 napto [1,8-cd] isothiazole dioxide-1,1 can be prepared as follows:
A 19.2 g of sodium hydride in dispersion at 50% in vaseline oil, crossed by a current of argon. A solution of 82 g of naphthosultam-1.8 in 1000 cm 3 of dimethylformamide is added over 2 hours, keeping the temperature close to 35 C. The reaction medium is stirred for 1 hour at a temperature close to 20 C. Then 35 is added, 2 cm3 of bromo-1 chloro-2 ethane. Stirring is continued for 15 hours at a temperature in the region of 20 C. The reaction mixture is concentrated to dryness at 70 C under reduced pressure (0.5 mm of 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 then 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 [1.8 - cd] isothiazole-dioxide-1.1 are obtained, melting at 96 C.

[(Fluoro-5 indolyl-3) methyl] -4 piperidine can be prepared according to the method described by C. GUEREMY, J. Med. Chem., 23, 1306 (1980).

EXAMPLE 2
A mixture of 2.9 g of (<f luoro-5 indolyl-2) methyl] -4 piperidine, 3.5 g of (2-chloroethyl) -1 naphtho (i, 8-cd) is brought to reflux for 12 hours. ] isothiazole dioxide-1,1 and 1,1 g of sodium hydrogen carbonate in 30 cm3 of tetrahydrofuran and 30 cm3 of dimethylformamide. After evaporation to dryness at 80 "C under reduced pressure (20 mm of mercury; 2.7 kPa) residue is taken up in 150 cm3 of water and extracted with twice 75 cm3 of ethyl acetate The combined organic phases are dried over magnesium sulphate and brought to dryness at 800C under reduced pressure (20 mmm of mercury; 2, 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 cyclohexane-ethyl acetate mixture (50 - 50 by volume ) as eluent. 2.3 g of {[((5-fluoro-indolyl-2) methyl) -4 piperidino-2] ethyl) -2 naphtho [1.8 - cd] isothiazole dioxide-1.1 are obtained. 154 C.

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

EXAMPLE 3
A mixture of 0.4 g of (indolyl-3 methyl) -4 piperidine, 0.53 g of (2-chloro-ethyl) -1 2H-naphtho [1,8-cd] isothiazole dioxide is brought to reflux for 12 hours. -1.1, 0.17 g of sodium hydrogen carbonate and 10 cm3 of dimethylformamide. After evaporation to dryness at 80 ° C. under reduced pressure (20 mm of mercury; 2.7 kPa), the residue is taken up in 30 cm3 of water and extracted with twice 50 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and brought to dryness at 800C under reduced pressure (200 mm of mercury; 2.7 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 dichloromethane-methanol mixture (99 -1 by volume) as eluent. 0.4 g of l [(3-indolyl-methyl) -4 piperidino] -2 ethyl) -2 naphtho [1,8-cd] isothiazole-1,1-dioxide melting at 184 ° C. is obtained.

 (3-Indolyl methyl) -4 piperidine can be prepared according to the method described by C. GUEREMY, J. Med. Chem., 23, 1306 (1980).

EXAMPLE 4
The procedure is as in Example 1 from 4.4 g of (2-chloro-ethyl) -1 tetrahydro-1,2,5,6 4H-1, 2,5-thiadiazolo [3,4,5-ij] quinoline dioxide-2,2, 3.8 g of [(f luoro-5 indolyl-3) methyl] -4 piperidine and 4 g of sodium bicarbonate in a mixture of 50 cm3 of dimethylformamide and 30 cm3 of tetrahydrofuran. The mixture is heated for 36 hours to boiling and then cooled to a temperature in the region of 20 C. After purification 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 and recrystallization from 50 cm3 of boiling acetonitrile, 1 g of ([((fluoro-5 indolyl-3) methyl) -4 piperidino] -2 ethyl) -l tetrahydro-1 is obtained, 2,5,6 4H-1,2,5 thiadiazolo [3,4,5-ij] quinoline 2,2-dioxide melting at 149 C.

(2-Chloro-ethyl) -1 1,2,5,6 tetrahydro 4H-1,2,5-thia diazolo [3,4,5-ij] quinoline 2,2-dioxide can be prepared in the following way
The procedure is as in Example 1 for the preparation of (2-chloroethyl) -2 naphthol1.8 -cd] isothiazole dioxide-l, l, from 0.82 g of sodium hydride at 50% in dispersion in petrolatum oil, 1.4 cm3 of bromo-1 chloro-2 ethane and 3.6 g of tetrahydro-1,2,5,6 4H-1,2,5-thiadiazolo [3,4, 5-ij] quinoline 2,2-dioxide in 70 cm3 of dimethylformamide. The mixture is stirred for 48 hours at a temperature close to 20 "C., under a stream of argon. 4.4 g of (2-ethyl chloro) -1, 1,2,5,6 tetrahydro are obtained after usual treatment. 4H-1,2,5-thiadiazolo [3,4,5-ij] quinoline dioxide-2,2 in the form of a brown oil used in the crude state in subsequent syntheses.

Tetrahydro-1,2,5,6 4H-1,2,5thiadiazolo [3,4,5-ij] quinoline dioxide-2,2 can be prepared in the following way
To a solution of 9 g of 8-amino-1,2,5,6-tetrahydro quinoline in 90 cm3 of diglyme, 6 g of sulfonamide are added. The mixture is heated at 160 ° C. for 90 minutes then cooled and diluted in a mixture of 300 cm3 of water and 300 cm3 of ethyl acetate. The organic phase is washed with 3 times 300 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 KPa). The residue is chromatographed on a column of silica gel (particle size 0.2-0.063 mm, diameter 6 cm, height 60 cm), eluting under a pressure of 0.7 bar of nitrogen, using a mixture of cyclohexane and ethyl acetate (80-20 by volume) and collecting 125 cm 3 fractions. Fractions 12 to 22 are combined and concentrated to dryness under reduced pressure (2.7 KPa). 9.4 g of tetrahydro-1,2,5,6 4H-1,2,5-thiadiazolo [3,4,5-ij] quinoline dioxide-2,2 is thus obtained melting at 96 "C.

 The amino-8 tetrahydro-1,2,5,6 quinoline can be prepared according to the method described by HAZLEWOOD et al., J. Pr. Soc., N. S.

WALES, 71, 462 (1937-1938).

 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, use may be made of pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil . 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 aseptic 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 and eating disorders, in particular excess alcohol, and also in learning disorders and memory.

 The doses depend on the effect sought, the duration of the 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 to be treated.

The following examples illustrate compositions according to the invention
Example A
Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared - f [((5-fluoro-indolyl-3) methyl) -4 piperidino] -2 ethyl) -2 naptho [1,8 -cd] isothiazole dioxide-1,1 ......... 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 - ([((f luoro-5 indolyl-2) methyl) -4 piperidino] -2 ethyl) -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, glycated
rine, titanium oxide (72-3,5-24,5) qs 1 tablet
film-coated finished at 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product having the following composition is prepared - ([(indolyl-3) methyl) -4 piperidino] -2 ethyl} -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 cm

Claims (4)

 in which R1 represents an indolyl-2 or indolyl-3 radical optionally substituted by a halogen atom and R2 represents a ring chosen from the formulas

 CLAIMS 1 - Compounds of formula  2 - Process for the preparation of a compound of formula (I) according to claim 1 characterized in that a halogenated derivative of formula is reacted  R2 - CH2 - CH2 - Hal (II) in which Hal represents a halogen atom and R2 has the same meanings as in claim 1, on an amine of formula

 wherein R1 has the same meanings as in claim 1 and then isolates the product.  3 - Medicines characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 1.  4 - Medicines according to claim 4, for the treatment of depression.