FR2640624A1 - Medicaments based on 2-benzothiazolamine derivatives, new derivatives and their preparation - Google Patents

Abstract

Medicaments containing, as active principle, at least one compound of the formula: in which - either R1 represents a polyfluoroalkoxy, tert-butyl, trimethylsilyl or trifluoromethylthio radical and R2 and R3 represent a hydrogen atom, - or R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents a 1-4 C alkyl or amino radical, - or R1 represents a polyfluoroalkoxy radical, R2 represents an amino radical and R3 represents a hydrogen atom, or a salt of such a compound with an inorganic or organic acid, the new compounds of formula I and their preparation.

Description

ou un sel d'un tel composé avec un acide minéral ou organique, les nouveaux composés de formule (I) et leurs procédés de préparation.The present invention relates to medicaments containing as active principle at least one compound of formula

or a salt of such a compound with a mineral or organic acid, the new compounds of formula (I) and their methods of preparation.

The compounds of formula (I) or their salts incorporated as active principle in the medicaments according to the invention are those for which
either R1 represents a polyfluoroalkoxy (1-4 C), tertbutyl, trimethylsilyl or trifluoromethylthio radical and R2 and R3 represent a hydrogen atom,
either R1 represents a polyfluoroalkoxy radical (1-4 C),
R2 represents a hydrogen atom and R3 represents an alkyl (1-4 C) or amino radical,
either R1 represents a polyfluoroalkoxy radical (1-4 C),
R2 represents an amino radical and R3 represents a hydrogen atom.

 The preferred polyfluoroalkoxy radicals are the pentafluoroethoxy, 2,2,2,2-trifluoroethoxy and tétrafluoro-1, 1,2,2 ethoxy and trifluoromethoxy radicals.

 The compounds of formula (I), with the exception of trifluoro-6-methylthio-benzothiazolamine-2, are new and form part of the invention as such.

 Trifluoromethylthio-6 benzothiazolamine-2 is described in Zh. Obshch. Khis., 22, 2216 (1952) (Chem. Abst. 47, 4771 c) and 33 (7), 2301 (1963) but no pharmacological property is mentioned for this compound.

dans laquelle R1 et R3 ont les mêmes significations que précédemment.The compounds of formula (I) for which
either R1 represents a polyfluoroalkoxy, tert-butyl radical and R2 and R3 represent a hydrogen atom,
either R1 represents a polyfluoroalkoxy radical (1-4 C),
R2 represents a hydrogen atom and R3 represents an alkyl radical, can be obtained by the action of bromine and an alkali metal thiocyanate on an amine of formula

in which R1 and R3 have the same meanings as before.

 This reaction is generally carried out in an organic solvent such as acetic acid, at a temperature close to 200C. As the alkali metal thiocyanate, potassium thiocyanate is preferably used.

The amines of formula (II) can be prepared by application or adaptation of the methods described in J. Org. Chem., 29, 1 (1964); Beilstein 12, 1166 and in US patents 3,920,444,
US 2,436,100 and DE 3,195,926.

 The compound of formula (I) for which R1 represents a trimethylsilyl radical and R2 and R3 represent a hydrogen atom, can be obtained by the action of chlorotrimethylsilane on the 6-lithiated derivative of N, N-bistrimethylsilyl benzothiazolamine-2 obtained by action of butyllithium and chlorotrimethylsilane on 6-bromo-benzothiazolamine-2.

 These reactions are carried out without separation of the lithiated derivative in an inert solvent such as hexane, tetrahydrofuran or a mixture of these solvents, at a temperature between -700C and the boiling temperature of the medium.

 6-bromo benzothiazolamine-2 can be prepared by applying the method described in Beilstein 27, 184.

dans laquelle R1 représente un radical polyfluoroalcoxy et soit R2 représente un radical nitro et R3 représente un atome d'hydrogène, soit R2 représente un atome d'hydrogène et R3 représente un radical nitro.The compounds of formula (I) for which R1 represents a polyfluoroalkoxy radical and either R2 represents an amino radical and R3 represents a hydrogen atom, or R2 represents a hydrogen atom and R3 represents an amino radical, can be obtained by reduction a derivative of formula

wherein R1 represents a polyfluoroalkoxy radical and either R2 represents a nitro radical and R3 represents a hydrogen atom, or R2 represents a hydrogen atom and R3 represents a nitro radical.

 This reduction is carried out, generally, by means of iron and hydrochloric acid, in an alcohol such as ethanol or methanol, at the boiling point of the solvent.

 The compounds of formula (III) can be obtained by nitration of the corresponding polyfluoroalkoxy-6-benzothiazolamine-2 and separation of the two products.

 This nitration is generally carried out by means of a sulfonitric mixture, at a temperature close to OOC.

 The polyfluoroalkoxy-6 benzothiazolamine-2 can be obtained by application or adaptation of the method described in Zh.

Obshch. Khim. 33, 2301 (1963).

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

 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 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 sclerosis and olivopontocerebellar atrophy.

 The activity of the compounds of formula (I) vis-à-vis glutamate-induced convulsions was determined according to a technique inspired by that described by 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 10 mg / kg.

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

Their LD50 is generally greater than 60 mg / kg I.P. in mice.

Of particular interest are the following compounds
- pentafluoroethoxy-6 benzothiazolamine-2,
- tert-butyl-6 benzothiazolamine-2;
- 6-trifluoromethoxy-benzothiazolediamine-2.5,
- 6-trifluoromethoxy-benzothiazolediamine-2,4.

 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, mention may be made of addition salts with mineral or organic acids such as hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllineacetate, salicylate, phenolphthalinate and methylene-bis-ss-oxynaphtoate.

 The following examples show how the invention can be put into practice.

BEWL1 !: 1
To a solution of 4.8 g of 4-pentafluoroethoxy-aniline in 35 cm 3 of acetic acid, 8.15 g of potassium thiocyanate is added, under argon sweep, and the mixture is stirred for 10 minutes at a temperature in the region of 200C. To the solution thus obtained, a solution of 1.1 cm3 of bromine in 10 cm3 of acetic acid is poured dropwise over 35 minutes at a temperature between 22 and 420C; then stirred for 20 hours at a temperature in the region of 200C. The reaction mixture is poured onto a mixture of water and ice (250 cl 3), basified with 50 cm 3 of ammonia at 28 t and extracted twice with 250 cm 3 of ethyl acetate in total. After decantation, the solution organic is washed with distilled water to pH 8, dried over magnesium sulfate, filtered and evaporated at 500C under reduced pressure (20 mm of mercury; 2.7 kPa). The product obtained (6.3 g) is purified by chromatography on a silica column (650 g, particle size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate (50-50 by volume) as eluent and recrystallized from 400 cm3 of boiling cyclohexane. 3.25 g of penta fluoroethoxy-6-benzothiazolamine-2, melting at 1560C, are obtained.

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

EXAMPLE 2
The procedure is as in Example 1, starting with 14.9 g of 4-tert-butyl aniline, 38.8 g of potassium thiocyanate and 5.1 cm 3 of bromine in 150 cm 3 of acetic acid. After purification on a silica column (700 g, particle size: 0.063-0.200 mm) with a cyclohexane-ethyl acetate mixture (40-60 by volume) as eluent and recrystallization in 450 cm3 of boiling cyclohexane, 12.2 is obtained. g of tert-butyl-6 benzothiazolamine-2-fondant at 1460C.

 Tert-4-butyl aniline can be prepared according to the method described in BEILSTEIN 12, 1166.

EXAMPLE 3
The procedure is as in Example 1, starting from (trifluoro-2,2,2 ethoxy) -4 aniline, potassium thiocyanate and bromine in acetic acid to obtain the (trifluoro-2,2,2 ethoxy ) -6 benzothiazolamine-2 which melts at 1340C.

 The (trifluoro-2,2,2 ethoxy) -4 aniline can be prepared according to the method described in US Patent 3,920,444.

EXAMPLE 4
To a solution cooled to -700C of 6.8 g of 6-bromo-benzothiazolamine-2 in 100 cm3 of anhydrous tetrahydrofuran, 46 cm3 of a 1.6 M solution of n are added, with argon sweeping and with stirring. -butyllithium in hexane. The temperature is then allowed to rise to OCC and a solution of 9.3 cm3 of chlorotrimethylsilane in 10 cm3 of anhydrous tetrahydrofuran is added. After returning to a temperature close to 200C, the mixture is brought to reflux for 1 hour and 30 minutes. Then cooled to -100C before adding 19 cm3 of the same n-butyllithium solution and the temperature is allowed to rise to OOC. To the light red solution obtained, a solution of 4.7 cm3 of chlorotrimethylsilane in 10-cm3 of anhydrous tetrahydrofuran is added and the temperature is allowed to rise to around 200 C. It is then heated at reflux for 4 hours and 30 minutes. After returning to a temperature in the region of 200 ° C., the reaction mixture is poured into 100 cm 3 of water while maintaining the temperature below 250 ° C. and it is made alkaline with ammonia. The lower aqueous phase is extracted 4 times with 200 cm3 of dichloromethane in total, the organic phases are combined, dried over magnesium sulfate, filtered and evaporated at 400C under reduced pressure (20 mm of mercury; 2.7 kPa). The orange oil obtained (10.1 g) is chromatographed twice on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (40-60 by volume). 0.55 g of is thus recovered. a white solid which is triturated with 10 cm3 of petroleum ether (40-650C) to obtain after wringing and drying under reduced pressure (2 hours at 500C under 1 mm of mercury; 0.13 kPa) 0.45 g of trimethylsilyl-6 benzothiazolamine-2 melting at 1400C.

 6-bromo benzothiazolamine-2 can be prepared according to the method described in BEILSTEIN 27, 184.

EXAMPLE 5
The procedure is as in Example 1, starting from 3.85 g of tri fluorouethylthio-4 aniline, 7 g of potassium thiocyanate and 1 cm 3 of bromine in 30 cm 3 of acetic acid. The light brown crude product is taken up in 250 cm3 of acetic acid & 800C and the solution obtained is treated with 0.4 g of bleaching black and filtered; the filtrate is cooled to iOOC, diluted with 150 cm3 of water and basified with 400 cm3 of ammonia at 28 t. The precipitate obtained is drained, air dried and recrystallized from a mixture of 250 cm3 of cyclohexane and 30 cm3 of isopropyl ether. 2.9 g of trifluoromethyl-6-benzothiazolamine-2 are obtained, melting at 1550C.

 Trifluoromethylthio-4 aniline can be prepared according to the method described in US Patent 2,436,100.

EXAMPLE 6
The procedure is as in Example 1, starting with 0.65 g of 4-trifluoromethoxy-2-methyl aniline, 1.3 g of potassium thiocyanate and 0.35 cm of bromine in 12 cm3 of acetic acid. After purification on a silica column (200 g, particle size: 0.0630,200 nm), eluting with the cyclohexane-ethyl acetate mixture (50-50 by volume), the white solid obtained (0.65 g) is triturated in 20 cm3 of cyclohexane, drained and dried at 60 ° C. under reduced pressure (1 mm of mercury; 0.13 kPa) to give 0.6 g of methyl-4-trifluoromethoxy-6-benzothiazolamine-2 melting at 1620C.

 Trifluoromethoxy-4-methyl-2 aniline can be prepared according to the method described in patent DE 3,195,926.

EXAMPLE 7
7.2 g of trifluoromethoxy-6-5-nitro-benzothiazolamine-2, 25 cm3 of ethanol, 25 cm3 of water, 8.7 g of iron powder and 1.1 cm3 of acid are heated at reflux for 2 hours. concentrated hydrochloric acid (d = 1.19). After returning to a temperature in the region of 200C, it is basified with 10 cm3 of 28% ammonia and extracted 4 times with 350 cm3 of ethyl acetate in total. The organic solution is evaporated at 500C under reduced pressure (20 mm of mercury; 2.7 kPa). The product obtained (6.4 g) is purified by chromatography on a silica column (800 g, particle size: 0.063-0.200 mm), eluting with an ethyl acetate-cyclohexane mixture (90-10 by volume) and recrystallized from 320 cm3 of toluene. Obtained 4 g of trifluoromethoxy-6 benzothiazolediamine-2,5 fondant & 1750C.

 The trifluoromethoxy-6 5-nitro benzothiazolamine-2 can be prepared as follows: to 11.7 g of trifluoromethoxy-6 benzothiazolamine-2 cooled to -10C, a cooled sulfonitric mixture is added dropwise, with mechanical stirring to 50C prepared from 20 cm3 of concentrated sulfuric acid (d = 1.83) and 10 cm3 of concentrated nitric acid (d = 1.42). During the addition (25 minutes) the temperature of the reaction mixture is kept below 50C and at the end of the addition the stirring is continued for 30 minutes between OOC and 20c. The reaction product is then poured onto a mixture of water and ice (150 cm3) and alkalized with 75 cm3 of ammonia at 25 & 28 t. The yellow precipitate obtained, which is a mixture of trifluoromethoxy-, is drained 6 nitro-5 benzothiazolamine-2 and trifluoromethoxy-6 nitro-4 benzothiazolamine-2.

After chromatography on a silica column (1 kg, particle size 0.063-0.200 mm), eluting with a cyclohexane-ethyl acetate mixture (60-40 by volume), 9.45 g of 6-trifluoromethoxy-5-nitro-benzothiazolamine are obtained. 2 melting at 2600C and 0.9 g of 6-trifluoromethoxy-4-nitro-benzothiazolamine-2 melting above 2600C [Rf = 0.28; thin layer chromatography on silica gel, solvent: cyclohexane-ethyl acetate (50-50 by volume)).

 Trifluoromethoxy-6 benzothiazolamine-2 can be prepared according to the method described by L.M. YAGUPOLSKII et al., Zh.

Obshch. Xhim. 33, 2301 (1963).

EXAMPLE 8
The procedure is as in Example 8, starting with 6-trifluoromethoxy-4-nitro-2-benzothiazolamine, iron powder, concentrated hydrochloric acid and ethanol in 50 t of water (vol./vol.). After purification on a silica column with a mixture of cyclohexane and ethyl acetate (10-90 by volume) as eluent, a white solid (1.5 g) is recovered which is recrystallized from 130 cm3 of toluene to obtain 1 g of trifluoromethoxy-6 benzothiazolediamine-2,4 melting at 206 C.

EXAMPLE 9
The procedure is as in Example 1, starting with 10 g of (tetrafluoro-1,1,2,2 ethoxy) -4 aniline, 18.5 g of potassium thiocyanate, 2.4 cm3 of bromine and of 80 cm3 of acetic acid. After purification on a silica column (1 kg, particle size: 0.063-0.200 mm), eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume) and recrystallization from 22 cm3 of toluene, 2 g are obtained. of (tetrafluoro-1,1,2,2 ethoxy) -6 benzothiazolamine-2 melting at 1610C.

 Aniline (tetrafluoro-1,1,2,2 ethoxy) -4 can be prepared according to the method described by W.A. SHEPPARD, J. Org. Chem. 29, 1 (1964).

 The medicaments according to the invention consist 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. These drugs 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, 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 done in several ways, for example by aseptic filtration, incorporating the composition of the sterilizing agents, 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 a 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 as well as neurological conditions where glutamate may be involved such than 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 & 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 - 6-pentafluoroethoxy-2-benzothiazolamine .............. 50 mg - cellulose are prepared. ............................. 18 mg - lactose ................. ................... 55 mg - colloidal silica ........................ 1 mg - sodium carboxymethyl starch ......................... 10 mg - talc .................. ...................... 10 ng - magnesium stearate ...................... ......... 1 mg
Example B
Tablets containing 50 mg of active product having the following composition - 6-tert-butyl-2-benzothiazolamine ..................... 50 are prepared according to the usual technique. 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 is prepared - trimethylsilyl-6 benzothiazolamine-2 ................. 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 (7)

 1 - Medicines containing as active ingredient at least one compound of formula

 in which  - either R1 represents a polyfluoroalkoxy (1-4 C), tertbutyl, trimethylsilyl or trifluoromethylthio radical and R2 and R3 represent a hydrogen atom,  either R1 represents a polyfluoroalkoxy radical (1-4 C), R2 represents a hydrogen atom and R3 represents an alkyl radical (1-4 C) or amino,  - Either R1 represents a polyfluoroalkoxy radical, R2 represents an amino radical and R3 represents a hydrogen atom or a salt of such a compound with a mineral or organic acid.  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.  - Either R1 represents a polyfluoroalkoxy radical (1-4 C), R2 represents an amino radical and R3 represents a hydrogen atom or a salt of such a compound with a mineral or organic acid.  either Rt represents a polyfluoroalkoxy radical (1-4 C), R2 represents a hydrogen atom and R3 represents an alkyl radical (1-4 C) or amino,  either R1 represents a polyfluoroalkoxy (1-4 C), tertbutyl or trimethylsilyl radical and R2 and R3 represent a hydrogen atom,   in which

 -3 - Compounds of formula  4 - Compounds according to claim 3 for which the polyfluoroalkoxy radical is a pentafluoroethoxy, trifluoro-2,2,2 ethoxy, tetrafluoro-1,1,2,2 ethoxy or trifluoromethoxy radical.  5 - Process for preparing the compounds of formula (I) according to claim 3 for which  either R1 represents a polyfluoroalkoxy or tert-butyl radical and R2 and R3 represent a hydrogen atom,  - either R1 represents a polyfluoroalkoxy radical, R2 represents a hydrogen atom and R3 represents an alkyl radical characterized in that an alkali metal thiocyanate and bromine are reacted on an amine of formula

 in which R1 and R3 have the same meanings as previously, isolates the product and optionally transforms it into salt with a mineral or organic acid.  6 - Process for preparing the compound of formula (I) according to claim 3 for which R1 represents a trimethylsilyl radical and R2 and R3 represent a hydrogen atom characterized in that chlorotrimethylsilane is reacted on the lithiated derivative N, N-bistrimethylsilyl benzothiazolamine-2 obtained by the action of butyllithium and chlorotrimethylsilane on 6-bromo benzothiazolamine, isolates the product and optionally transforms it into a salt with a mineral or organic acid.  7 - Process for the preparation of the compound of formula (I) according to claim 3 for which R1 represents a polyfluoroalkoxy radical and  either R2 represents an amino radical and R3 represents a hydrogen atom,  - either R2 represents a hydrogen atom and R3 represents an amino radical, characterized in that a compound of formula is reduced

 in which R1 represents a polyfluoroalkoxy radical and either R2 represents a nitro radical and R3 represents a hydrogen atom, or R2 represents a hydrogen atom and R represents a radical  3 nitro, isolates the product and optionally transforms it into salt with a mineral or organic acid.