FR2663030A1 - Selenium-containing derivatives of benzothiazoline, their preparation and the medicaments containing them - Google Patents

Abstract

Compounds of formula: in which R represents a polyfluoroalkoxy radical, R1 represents a sulphur atom and R2 represents an alkylselenoalkyl radical, their salts, processes for their preparation and the medicaments containing them.

Description

leurs sels, leur préparation et les médicaments les contenant.The present invention relates to compounds of formula

their salts, their preparation and the drugs containing them.

 In formula (I), R represents a polyfluoroalkoxy radical, R1 represents a sulfur atom and R2 represents an alkylselenoalkyl radical.

 The polyfluoroalkoxy radicals are preferably the trifluoromethoxy, pentafluoroethoxy, trifluoro-2,2,2,2 ethoxy or tetrafluoro-1,1,2,2 ethoxy radicals.

 In the preceding definitions and those which follow, the alkyl radicals and the alkyl portions contain 1 to 4 carbon atoms in straight or branched chain.

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

dans laquelle R a les mêmes significations que dans la formule (I) et R3 représente un radical alkyle.The compounds of formula (I) can be prepared by the action of sodium alkylselenate on a derivative of formula

in which R has the same meanings as in formula (I) and R3 represents an alkyl radical.

 This reaction is generally carried out in an inert solvent such as an alcohol (methanol, ethanol for example), at a temperature in the region of 20 ° C.

dans laquelle R et R3 ont les mêmes significations que dans la formule (II), sur le chlorure d'acide méthanesulfonique, soit au sein d'un solvant inerte tel qu'un solvant aromatique (benzène, toluène, xylène par exemple) ou un solvant chloré (chloroforme, chlorure de méthylène par exemple), en présence d'une amine tertiaire telle que la triéthylamine, à une température voisine de 2O0C, soit au sein de la pyridine, à une température voisine de OOC. The derivatives of formula (II) can be prepared by the action of a derivative of formula

in which R and R3 have the same meanings as in formula (II), on methanesulfonic acid chloride, either in an inert solvent such as an aromatic solvent (benzene, toluene, xylene for example) or a chlorinated solvent (chloroform, methylene chloride for example), in the presence of a tertiary amine such as triethylamine, at a temperature in the region of 20 ° C., or in pyridine, at a temperature in the region of OOC.

dans laquelle R et R3 ont les mêmes significations que dans la formule (II). The derivatives of formula (III) can be obtained by the action of ethyl trifluoroacetate on a derivative of formula

in which R and R3 have the same meanings as in formula (II).

 This reaction is generally carried out in an alcohol (methanol, ethanol for example), in the presence of a tertiary base such as triethylamine, at a temperature in the region of 20 ° C.

The derivatives of formula (IV) can be prepared by the action of a halogenated derivative of formula
Hal - R3 - OH (V) in which R3 has the same meanings as in formula (I) and Hal represents a halogen atom (preferably bromine or chlorine) on a 2-amino-6-polyfluoroalkoxy-benzothiazole.

 This reaction is carried out in an alcohol (ethanol, preferably methanol) at the boiling point of the solvent.

 The 2-amino-6-polyfluoroalkoxy-benzothiazoles can be prepared by application or adaptation of the method described by L M. YAGUPOL'SKII and colt,, Zh. Obshch. Khi., 33 (7), 2301 (1963).

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

 The compounds of formula (I) and their salts have interesting pharmacological properties. These compounds are active vis-à-vis the glutamate-induced convulsions and are therefore useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders and in particular deficient forms of schizophrenia, sleep disorders, phenomena related to cerebral ischemia as well as neurological conditions where glutamate may be involved such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar atrophy.

 The activity of the compounds of formula (I) vis-à-vis the glutamate-induced convulsions was determined according to a technique inspired by that of I.P. LAPIN, J. Neural. Transmission, vol 54, 229-238 (1982); the injection of glutamate intracerebroventricularly being carried out according to a technique inspired by that of R. CHERMAT and P. SIMON, J. Pharmacol. (Paris), vol. 6, 489-492 (1975). Their ED50 is less than or equal to 10 mg / kg by I.P.

 The compounds of formula (I) have a low toxicity.

Their LD50 is greater than 15 mg / kg by I.P. route in mice.

 For medicinal use, use may be made of the compounds of formula (I) as such or in the form of pharmaceutically acceptable salts, that is to say nontoxic at the doses of use.

 As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with mineral or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isothionate, theophyllineacetate, salicylate, phenolphthalinate, methylene bis -ss- oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.

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

EXAMPLE 1
To a stirred solution of 0.265 g of sodium ethaneselenolate in 10 cm 3 of ethanol is added 0.420 g of <trifluoroacetylimino-2-trifluoromethoxy-3-benzothiazolinyl-3) -2 ethane methanesulfonate. The mixture is stirred for 22 hours at a temperature in the region of 200C, the solid formed is filtered and the filtrate is evaporated under reduced pressure (20 mm of mercury: 2.7 kPa). The residue is dissolved in 25 cm3 of dichloromethane. The solution is washed with 2 times 15 cm 3 of a 1N aqueous solution of sodium hydroxide. After drying the organic phase over sodium sulfate, evaporation under reduced pressure (20 mm of mercury: 2.7 kPa) formation of hydrochloride by adding 2 cm3 of a hydrochloric acid solution at 10% by weight in diethyl ether and recrystallization from isopropanol, 0.135 g of (2-ethylselenoethyl) -3 imino-2 trifluoromethoxy- hydrochloride is obtained 6 benzothiazole melting at 172-40C.

 Methane sulfonate (2-trifluoroacetylimino-6 trifluoromethoxy-3-benzothiazolinyl) -2 ethane can be prepared as follows: 6.9 g of triethylamine are gradually added to a mixture of 120 cm3 of methylene chloride, 7.34 g of methane sulfonic acid chloride and 12 g of (2-trifluoroacetylimino-6 trifluoromethoxy-benzothiazoline) -2 ethanol. After 1 hour of stirring at a temperature close to 200C, the reaction medium is cooled to iOOC, drained, washed with 20 cm3 of cold methylene chloride, then dried at 400C under reduced pressure. 10 g of methane sulfonate (2-trifluoroacetylimino-6 trifluoromethoxy-3-benzothiazolinyl-3) -2 ethyl are obtained, melting at 1450 C. A second 2.7 g jet is obtained by washing the filtrate with 100 cm3 of water, drying over sulfate of magnesium, concentration to a residual volume of approximately 50 cm3, cooling to 50C then spinning.

 Ethanol (2-trifluoroacetylimino-6 trifluoromethoxy-3-benzothiazolinyl) -2 can be prepared in the following manner 20.7 g of (2-imino-trifluoromethoxy-3-benzothiazolinyl) -2 ethanol, 9.8 g of ethyl trifluoroacetate and 16.1 cm3 of triethylamine are stirred in 100 cm3 of ethanol for 22 hours at a temperature in the region of 20 "C. After concentration to dryness under reduced pressure, the residue obtained is purified by chromatography on a column of silica with ethyl acetate as eluent, 19.2 g of (2-trifluoroacetylimino-6 trifluoromethoxy-3-benzothiazolinyl) -2 ethanol melting at 1440C are obtained.

 The (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) -2 ethanol can be prepared according to the following process: 9.4 g of 2-amino-6-trifluoromethoxy-benzothiazole and 10 g of 2-bromo ethanol in 30 cm3 of absolute ethanol are heated for 95 hours at boiling point. The mixture is then cooled to a temperature in the region of 200C. The precipitate formed is filtered and washed with 100 cm 3 of ethyl ether. 6.4 g of (imino-2-trifluoromethoxy-6-benzothiazolinyl-3) -2 ethanol hydrobromide melting at 2190C are obtained.

 The 2-amino-6-trifluoromethoxy-benzothiazole can be prepared according to the method described by L.M. YAGUPOL'SKII et al., Zh.

Obshch. Khim, 33 (7), 2301 (1963).

 The present invention also relates to medicaments consisting of at least one compound of formula (I) or a salt of such a compound in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, 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.

 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, ointments, lotions, eye drops, mouthwashes, nasal drops or aerosols.

 In human therapy, the compounds according to the invention are particularly useful for the treatment and prevention of convulsive phenomena, schizophrenic disorders and in particular deficient forms of schizophrenia, sleep disorders, phenomena related to cerebral ischemia and neurological conditions where glutamate may be involved such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar atrophy.

 The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 30 and 300 mg per day orally for an adult with unit doses ranging from 10 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.

Claims (5)

1. Family compounds:

 in which R represents a polyfluoroalkoxy radical, R1 represents a sulfur atom and R2 represents an alkylselenoalkyl radical, it being understood that the alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain, as well as their salts with mineral or organic acids . 2. Compounds of formula (I) according to claim I for which R represents a trifluoromethoxy, pentafluoroethoxy, trifluoro-2,2,2 ethoxy or tetrafluoro-1,2,2,2 ethoxy radical. 3. Process for preparing the compounds of formula (I) according to claim 1, characterized in that a sodium alkylselenolate is reacted with a derivative of formula

 in which R has the same meanings as in claim 1 and R3 represents an alkyl radical, isolates the product and optionally transforms it into an addition salt with a mineral or organic acid. 4. Medicines characterized in that they contain as active ingredient at least one compound of formula (I) according to claim 1 or 2. 5. Medicines according to claim 4 for the treatment of conditions in which glutamate is involved.