FR2649705A2 - Medicaments based on 2-benzothiazolamine derivatives, new derivatives and their preparation - Google Patents

Abstract

Medicaments containing, as active principle, at least one compound of formula in which: - either R1 represents a 2,2,2-trifluoroethyl or pentafluoroethyl radical and R2 and R3 represent a hydrogen atom; - or R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents a dimethylamino or dialkylaminoalkylthio radical and the salts of these compounds with an inorganic or organic acid.

Description

dans laquelle - soit R1 représente un radical polyfluoroalcoxy (1-4C), tertbutyle, triméthylsilyle ou trifluorométhylthio, R2 et R3 représentent un atome d'hydrogène, - soit R1 représente un radical polyfluoralcoxy (1-4C), R2 représente un atome d'hydrogène et R3 représente un radical alkyle (1-4C) ou amino, soit R1 représente un radical polyfluoroalcoxy (1-4C), R2 représente un radical amino et R3 représente un atome d'hydrogène, les composés nouveaux de formule (I), leurs sels et leurs procédés de préparation.The invention described in the main patent relates to drugs containing as active principle at least one compound of formula

in which - either R1 represents a polyfluoroalkoxy (1-4C), tertbutyl, trimethylsilyl or trifluoromethylthio radical, R2 and R3 represent a hydrogen atom, - or R1 represents a polyfluoralcoxy (1-4C) radical, R2 represents an atom of hydrogen and R3 represents an alkyl (1-4C) or amino radical, or R1 represents a polyfluoroalkoxy radical (1-4C), R2 represents an amino radical and R3 represents a hydrogen atom, the new compounds of formula (I), their salts and their preparation processes.

 The present invention relates to new drugs containing as active principle at least one compound of formula (I) in which - either R1 represents a trifluoro -2,2,2 ethyl or pentafluoroethyl radical and R2 and R3 represent a hydrogen atom , - either R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents a dimethylamino or dialkylaminoalkylthio radical or a salt of such a compound.

 In the above definitions and those which will be cited below, the alkyl and alkoxy portions containFt 1 to 4 carbon atoms in a straight or branched chain.

 The present application also relates to the compounds of formula (I) and their addition salts with mineral or organic acids.

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

dans laquelle R1, R2 et R3 ont les mêmes significations que dans la formule (I).The compounds of formula (I) can be obtained by the action of bromine and an alkali metal thiocyanate on an amine of formula

in which R1, R2 and R3 have the same meanings as in formula (I).

 This reaction is generally carried out within acetic acid, at a temperature in the region of 200C.

 As the alkali metal thiocyanate, potassium thiocyanate is preferably used.

The amines of formula (II) can be obtained by application or adaptation of the methods described in the patent
DE 2 606 982 and in the examples described below.

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) methods.
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, ether or chlorinated solvent.

 The compounds of formula (I) and their salts have interesting pharmacological properties. These compounds are active vis-à-vis 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, related phenomena. cerebral ischemia as well as neurological conditions where glutamate may be involved such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and ol ivopontocerebellar 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 DE5O is less than 10 mg / kg.

 The compounds of formula (I) have a low toxicity. Their LD50 is greater than 15 mg / kg I.P. 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, theophylline acetate, salicylate, phenolphthalinate, methylene -bis
B-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 solution of 2.1 g of (2,2,2-trifluoroethyl) aniline in 25 cm 3 of acetic acid, 2.3 g of potassium thiocyanate are added and the mixture is stirred for 10 minutes at a temperature in the region of C. To the solution thus obtained, a solution of 0.6 cm3 of bromine in 30 cm3 of acetic acid is poured dropwise over 35 minutes at a temperature between 200C and 350C. Then stirred for 16 hours at a temperature in the region of 200C.

The reaction mixture is poured onto a mixture of water and ice (150 cm 3), basified with 35 cm 3 of ammonia at 28 t and extracted 3 times with 170 cm 3 of ethyl acetate in total. After decantation, the organic solution is washed with distilled water until pH8, dried over magnesium sulfate, filtered and evaporated at 50 C under reduced pressure (20mm of mercury; 2.7 kPa).

 After purification on a first silica column, eluting with the cyclohexane-ethyl acetate mixture (50-50 by volume), a beige solid (1.7 g) melting at 1750C is obtained, which is chromatographed on silica using this times a mixture of dichloromethane and ethyl acetate (50-50 by volume). 0.8 g of (trifluoro-2,2,2 ethyl) -6 benzothiazolamine -2 is thus recovered, melting at 1860C.

 The (trifluoro-2,2,2 ethyl) -4 aniline was prepared as follows: to a solution of 3.8 g of (trifluoro-2,2,2 ethyl) -4 nitrobenzene in 20 cm3 of ethanol , 0.17 g of palladium on carbon is added to 10 t of palladium and poured dropwise, over 20 minutes, with stirring, a solution of 1.8 cm 3 of hydrazine hydrate in 10 cm 3 of ethanol; the mixture is then heated to reflux for 15 minutes and the temperature is allowed to return to around 200C. The catalyst is filtered, the filtrate is concentrated to half the pressure under reduced pressure (20 mm of mercury; 2.7 kPa), 30 cm3 of water are added and extracted with 200 cm3 of ethyl acetate in total. The organic solution is dried over magnesium sulphate, filtered, evaporated under reduced pressure (20 mm of mercury; 2.7 kPa) and the evaporation residue (2.7 g) is purified by chromatography on a silica column using as eluent a mixture of cyclohexane and ethyl acetate (70-30 by volume). 2.3 g of (trifluoro-2,2,2 ethyl) -4 aniline are obtained in the form of a yellow oil used directly in the cyclization step.

 (Trifluoro-2,2,2 ethyl) -4 nitrobenzene can be prepared according to the methods described by S.A. FUQUA et al., J. Org.

Chem., 30, 1027 (1965), L.M. YAGUPOLSKII et al., Synthesis, (11), 932 (1980), I. KUMADAKI et al., J. Org. Chem., 53, 3637 (1988).

EXAMPLE 2
The procedure is as in Example 1, from 14.6 g of 4-pentafluoroethyl aniline, 14 g of potassium thiocyanate and 3.6 cm 3 of bromine in 150 cm 3 of acetic acid. After purification on a silica column with a mixture of cyclohexane and ethyl acetate (50-50 by volume) as eluent, a yellow solid is obtained (17 g) which is converted into the hydrochloride by the action of hydrochloric acid. in solution in ethyl ether. The precipitate obtained (16 g) is recrystallized from a mixture of 100 cm3 of acetone and 60 cm3 of ethanol. 3.8 g of pentafluoroethyl-6 benzothiazolamine-2 hydrochloride are obtained, melting at 1910C.

 Pentafluoroethyl-4 aniline can be prepared according to the method described in patent DE 2,606,982.

EXAMPLE 3
The procedure is as in Example 1, starting with 2 g of 2-dimethylamino-4-trifluoromethoxy-aniline, 3.5 g of potassium thiocyanate dissolved in 30 cm 3 of acetic acid and 1.45 g (0.47 cm 3) bromine. Stirring is maintained for 12 hours at this temperature. The mixture is evaporated to dryness at 80 ° C. under reduced pressure (20mu of mercury; 2.7 KPa). The residue obtained is taken up in 100 cm3 of water and the pH is brought to 9-10 with concentrated sodium hydroxide (ION). After extraction with twice 50 cm3 of ethyl acetate, washing of the combined phases with two times 20 cm3 of water, drying over anhydrous magnesium sulfate and evaporation to dryness at 400C under reduced pressure (20 n of mercury; 2 , 7 KPa) a brown oil is isolated which 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 in volumes). A solid is isolated which is dissolved in 30 cm3 of ethyl ether and hydrochloric ether (6.2N) is added thereto until complete precipitation.

0.7 g of 4-dimethylamino-6-trifluoromethoxy-2-benzothiazolamine are thus isolated in the form of dihydrochloride melting at 1840C.

 Dimethylamino-2 trifluoromethoxy-4 aniline can be prepared as follows: 2.9 g of dimethylamino-2 trifluoromethoxy-6 acetanilide and 40 cm3 of concentrated sulfuric acid (10N) dissolved in 40 cm3 of water are heated to 80 C for 2 hours.

After adding 80 cm3 of water, neutralization with concentrated sodium hydroxide (10N) until pH11 and extraction with twice 100 cm3 of ethyl acetate, 2 g of 2-dimethylamino-4-trifluoromethoxy-aniline are isolated. as a brown oil.

 Dimethylamino-2 trifluoromethoxy-6 acetanilide can be prepared as follows: to 4.68 g of amino-2 trifluoromethoxy-6 acetanilide and 6 g of paraformaldehyde dissolved in 120 dm3 of acetic acid is added, with stirring, to a temperature close to 2oOC, 6.1 g of sodium cyanoborohydride for 1 hour. The mixture is stirred for 12 hours at a temperature in the region of 200C. After cooling to this temperature and addition of 120 cm3 of water, neutralization with concentrated sodium hydroxide (10N) until pH 9 and extraction with twice 200 cm3 of ethyl acetate, an oil is isolated which is purified by flash- chromathography on a silica column, under nitrogen pressure, at medium pressure (0.5-1.5 bar) with dichloromethane as eluent. This isolates 2.2 g of 2-dimethylamino-6 trifluoromethoxy-6 acetanilide in the form of a yellow oil.

 The 2-amino-6-trifluoromethoxy-acetanilide can be prepared as follows: 13.2 g of 2-nitro-6-trifluoromethoxy-acetanilide and 34.8 g of sodium dithionite dissolved in a mixture of 200 cm3 of dioxane and 150 cm3 of water are heated, with stirring, to a temperature of 650C for 1 hour. After cooling to a temperature in the region of 200C, addition of 100 cm3 of water, extraction with 250 cm3 of ethyl acetate and drying over anhydrous magnesium sulfate, 5.7 g of 2-amino-6-trifluoromethoxy-acetanilide are isolated. melting at 800C.

 The nitro-2 trifluoromethoxy-6 acetanilide can be prepared in the following way: to 219 g of trifluoromethoxy-4 acetanilide is added at an OOC temperature, with vigorous stirring, 755 cm 3 of concentrated sulfuric acid (10N). After stirring for 2 hours at a temperature close to 200C, a mixture of 245 cm3 of concentrated sulfuric acid (1 ON) and 64 d of concentrated nitric acid (11N) is added at a temperature of 100C for 1 hour. The reaction mixture is stirred for 12 hours at a temperature in the region of 200C. 2.5 liters of water are added to this solution at a temperature of 50C. The brown solid thus formed is purified by flash chromathography on a silica column, under a stream of nitrogen at medium pressure (0.5-1 , 5 bar) with dichloromethane as eluent. 11.8 g of 2-nitro-trifluoro-4-methoxy-acetanilide are thus isolated, melting at 63 ° C.

 Trifluoromethoxy-4-acetanilide can be prepared according to the method described by W.A.SHEPPARD, J. Org. Chem., 29 (1), 1, 1964.

EXAMPLE 4
The procedure is as in Example 1, starting with 4 g of (3-dimethylaminoethylthio) -2 trifluoromethoxy-4 aniline, 5.5 g of potassium thiocyanate dissolved in 50 cm3 of acetic acid and 2.28 g (0.73 cm3) of bromine. Stirring is maintained for 12 hours at this temperature. The mixture is evaporated to dryness at 800C under reduced pressure (20 mm of mercury; 2.7 KPa). The residue obtained is taken up in 10 cm3 of water and the pH is brought to 9-10 with concentrated sodium hydroxide (ION). After extraction with twice 50 cm3 of ethyl acetate, washing of the combined phases with twice 50 cm3 of water, drying with anhydrous magnesium sulfate and evaporation to dryness at 400C under reduced pressure (20 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) and recris taltized in 40 cm3 of isopropyl ether. 3.2 g of (3-dimethylaminoethylthio) -4-trifluoromethoxy-6-benzothiazolamine-2 are thus obtained, melting at 1230C
(3-Dimethylaminoethylthio) -2 trifluoromethoxy-4 aniline can be prepared as follows: 4.7 g of 2-amino-6-trifluoromethoxy-benzothiazole and 14 g of potassium hydroxide dissolved in 25 cm3 of water are brought to reflux for 12 hours, with stirring. The solution is then cooled to a temperature close to 200C and 2.9 g of 2-chloroethyl dimethylamine hydrochloride is added. The solution is brought to a temperature of 500C for 3 hours and then cooled to a temperature close to 20C 50 cm3 of water are added and the mixture is extracted twice with 50 cm3 of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate 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 a stream of nitrogen, at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane-methanol (95-5 by volume) as eluent. 4 g of (3-dimethylaminoethylthio) -2 trifluoromethoxy-4 aniline are obtained.

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

Obshch.Khim. 33, 2301 (1963).

 The medicaments according to the invention are constituted by 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 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 in 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 effect sought, the duration of the treatment and 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 the age1 of the weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention
EXAMPLE A
Prepared, according to the usual technique, capsules containing 50 mg of active product having the following composition - (2,2,2-trifluoroethyl) -6 benzothiazolamine-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 - (3-dimethylamino) -4-trifluoromethoxy-6 are prepared according to the usual technique.
benzothiazolamine-2 ............................... 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
titanium (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 - 4-dimethylamino-6-trifluoromethoxy is prepared.
benzothiazolinamine-2 ............................. 10 mg - benzoic acid ............. ..................... 80 mg - benzyl alcohol ........................ ....... 0.06 cm3 - sodium benzoate .............................. 80 mg - ethanol 95% .................................. 0.4 cm3 - sodium hydroxide ...... ...................... 24 mg - propylene glycol ....................... ......... 1.6 cm3 - water: gsp 4 cm3

Claims (4)

 in which, - either R1 represents a trifluoro -2,2,2 ethyl or pentafluoroethyl radical and R2 and R3 represent a hydrogen atom, - either R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents a dimethylamino or dialkylaminoalkylthio radical, it being understood that the alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain, or a salt of such a compound with a mineral or organic acid.

 CLAIMS 1 - Medicines characterized in that they contain as active ingredient at least one compound of formula 2 - Medicines according to claim 1 for which the polyfluoroalkoxy radical is a pentafluoroethoxy, trifluoro -2,2,2 ethoxy, tetrafluoro -1,1,2,2 ethoxy or trifluoromethoxy radical.  in which, - either R1 represents a trifluoro -2,2,2 ethyl or penta fluoroethyl radical and R2 and R3 represent a hydrogen atom, - or either R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents a dimethylamino or dialkylaminoalkylthio radical as well as the salts of these compounds with a mineral or organic acid.

3 - Compounds of formula 4 - Process for preparing the compounds of formula (I) according to claim 3 characterized in that bromine and an alkali metal thiocyanate are reacted on an amine of formula

 in which R1, R2 and R3 have the same meanings as in claim 3, isolates the product and optionally transforms it into an addition salt with a mineral or organic acid.