FR2640622A1 - 2-Iminobenzothiazoline derivatives, processes for their preparation and medicaments containing them - Google Patents

Abstract

Compounds of formula: in which - R1 represents a perfluoroalkoxy or trifluoromethyl radical and - R2 represents a chain -CH2-CH2-R3 in which R3 represents a dialkylamino, piperidino, 1-pyrrolidinyl, mercapto, alkylthio, alkylsulphinyl or alkylsulphonyl radical, it being understood that the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain, and the salts of these compounds with an inorganic or organic acid, processes for their preparation and medicaments containing them.

Description

leurs sels, leurs procédés de préparation et les médicaments les contenant.The present invention relates to 2-imino benzothiazoline derivatives of formula:

their salts, their preparation processes and the drugs containing them.

In formula (I),
.- R1 Presents a perfluoroalkoxy or trifluoromethyl radical and
- R2 represents a chain -CH2-CH2-R3 in which R3 represents a dialkylamino, piperidino, -pyrrolidinyl-i, nercapto, alkylthio, alkylsulfinyl or alkylsulfonyl radical.

 Unless otherwise stated in the above definitions and those which will be cited below, the alkyl and alkoxy portions contain 1 & 4 carbon atoms in a straight or branched chain.

 The invention also relates to the addition salts of the compounds of formula (1) with mineral or organic acids.

dans laquelle R1 a les mêmes significations que dans la formule (I) sur un dérivé de formule
R2 -X (III) dans laquelle R2 a les mêmes significations que dans la formule (I) et X représente un groupe réactif tel qu'un radical tosyloxy ou un atome d'halogène (chlore, brome, iode de préférence) ou un sel d'addition d'un tel composé avec un acide minéral ou organique. According to the invention, the compounds of formula (I) can be prepared by the action of an amino derivative of formula

in which R1 has the same meanings as in formula (I) on a derivative of formula
R2 -X (III) in which R2 has the same meanings as in formula (I) and X represents a reactive group such as a tosyloxy radical or a halogen atom (chlorine, bromine, iodine preferably) or a salt of addition of such a compound with a mineral or organic acid.

 This reaction is generally carried out in an inert organic solvent such as ethanol, propanol, methyl ethyl ketone or dimethylformamide, at a temperature between 600C and the boiling temperature of the solvent, optionally in the presence of sodium iodide and optionally after fusion at 130-1400C of the compounds of formulas (II) and (III).

 The compounds of formula (II) can be obtained by application or adaptation of the method described by L.M. YAGUPOL'SKII et al, Zh. Obshch. Khim., 33 (7), 2301-7, 1963 (Chem. Abst., Vol.60, 692 a-f, 1964) or of the method described in US Patent 2,822,359.

 The compounds of formula (III) are marketed or can be prepared by application or adaptation of the method described by T.P. DAWSON, J. Amer. Chem. Soc., 69, 1211 (1947).

 According to the invention, the compounds of formula (I) for which R2 represents a chain -CH2-CH2-R3 in which R3 represents an alkylsulfinyl or alkylsulfonyl radical and R1 is defined as above, can also be obtained by oxidation of the corresponding derivatives for which R3 represents an alkylthio radical.

 The oxidation to alkylsulfinyl is generally carried out by means of m-chloroperbenzoic acid, in an alcohol, at a temperature close to -200C.

 The oxidation to alkylsulfonyl is generally carried out by means of hydrogen peroxide, within acetic acid, at a temperature close to 1000C.

 According to the invention, the compounds of formula (I) for which R2 represents a chain -CH2-CH2-R3 in which R3 represents a mercapto radical and R1 is defined as above, can also be prepared by hydrolysis of a corresponding derivative for which R3 represents a tert-butylthio radical.

 This hydrolysis is generally carried out using hydrobromic acid, at a temperature in the region of 110 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), 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 against glutamate-induced convulsions and are therefore useful in the treatment and prevention of convulsive phenomena, schizophrenic disorders and in particular of 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 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 3 mg / kg.

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

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

Of particular interest are the following compounds
- N, N-dimethylaminoethyl-3 imino-2 trifluoromethoxy-6 ben
zothiazoline,
- imino-2 (2-piperidino ethyl) -3 trifluoromethoxy-6 benzo
thiazoline,
- [(pyrrolidinyl-1) -2 ethyl] -3 imino-2 trifluoromethoxy-6
benzothiazoline,
- imino-2 (2-methylthio ethyl) -3 trifluoromethoxy-6 benzo
thiazoline,
- (4thylthio-2 ethyl) -3 imino-2 trifluoromethoxy-6 benzo
thiazoline,
- (2-ethylsulfinylethyl) -3-2-imino trifluoromethoxy-6
benzothiazoline,
- (2-ethylsulfonylethyl) -3 imino-2 trifluoromethoxy-6
benzothiazoline,
- (2-imino-6-trifluoromethoxy-3-benzothiazoline) -2 ethane
thiol,
- imino-2 (methylsulfinyl-2 ethyl) -3 trifluoromethoxy-6
benzothiazoline- (RS),
- (2-ethylthio-ethyl) -3 imino-2 trifluoromethyl-6 benzo
thiazoline.

 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 -P-oxynaphtoate, hydrochloride, sulfate, nitrate and phosphate.

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

EXAMPLE i
7 g of 2-amino-6-trifluoromethoxy-benzothiazole and 4.8 g of 2-chloro-N, N-dimethyl ethylamine are heated for 1 hour at 1300C. 10 cm3 of propanol-2 are added and the heating is continued for 20 hours at boiling point. After cooling to a temperature in the region of 200C, the reaction medium is concentrated to 400C under reduced pressure (20 mm of mercury; 2.7 kPa) and the residue treated with 40 cm3 of 1N sodium hydroxide. After extraction with 100 cm3 of dichloromethane, drying over magnesium sulfate and concentration at 400C under reduced pressure, the residue is purified by chromatography on a silica column with a mixture of ethyl acetate and methanol (90-10 by volume) as eluent. 2.1 g of 3-dimethylaminoethyl-2-imino-trifluoromethoxy-6 benzothiazoline are obtained in the form of a yellowish oil which is converted into subliming dihydrochloride around 2000C.

 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).

EXAMPLE 2
9.4 g of 2-amino-6-trifluoromethoxy-benzothiazole and 8.1 g of N- (2-chloro-ethyl) piperidine hydrochloride in 20 cm 3 of absolute ethanol are heated for 1 hour at 1300C. 20 cm3 of dimethylformamide are then added and the reaction is continued for 24 hours at 1300C. After cooling to a temperature in the region of 200C, the precipitate is filtered, then treated with 50 cm3 of sodium hydroxide in 100 cm3 of distilled water. The residue obtained by extraction with dichloromethane, drying over magnesium sulfate and concentration to dryness under reduced pressure (20 mm of mercury; 2.7 kPa), is purified by chromatography on a silica column with ethyl acetate and then a mixture of ethyl acetate and methanol (95-5 by volume) as eluents. 2.9 g of 2-imino (2-piperidino-ethyl) -3 trifluoromethoxy-6 benzothiazoline are obtained in the form of a yellow oil which is transformed into subliming dihydrochloride around 2000C after recrystallization from 20 cm3 of boiling absolute ethanol.

EXAMPLE 3
9.4 g of 2-amino-6-trifluoromethoxy-benzothiazole and 7.5 g of N- (2-chloro-ethyl) pyrrolidine chlorbydrste in 20 cm3 of absolute ethanol are heated for 2 hours at 1300C. 30 cm3 of propanol-2 are then added and the reaction is continued for 40 hours & boiling.

After cooling to a temperature in the region of 200C, the precipitate is filtered, then treated with 20 cm3 of IN sodium hydroxide solution in 100 cm3 of distilled water. The residue obtained by extraction with dichloroiethane, drying over magnesium sulfate and concentration to dryness under reduced pressure (20 ma of mercury; 2.7 kPa), is taken up in 50 cm3 of ethyl ether and treated with 3.1 cm3 d hydrochloric ether 4.2N. After recrystallization from 50 cm3 of boiling 2-propanol, 1.9 g of l (Pyrrolidinyl-1) -2 ethyl] -3 imino-2-trifluoromethoxy-6 benzo thiezoline are obtained, melting at a temperature above 2600C.

EXAMPLE 4
A mixture of 40 g of 2-amino-6-trifluoromethoxy-benzothiazole and 22.2 g of chloro-1-methylthio-2 ethane in 250 cm3 of methyl ethyl ketone is heated for 18 hours to boiling and then cooled to a temperature in the region of 200C. The precipitate formed is made up and the filtrate concentrated at 400C under reduced pressure (20 mm of mercury; 2.7 kPa) to a volume of approximately 100 cm3. The reaction is then continued for 72 hours at boiling point, then, after cooling to a temperature in the region of 200C, the new precipitate formed is filtered and combined with the previous one. After washing with 200 cm3 of ethyl ether, 31.9 g of 2-imino-hydrochloride (2-methylthioethyl) -3 trifluoromethoxy-6 benzothiazoline, melting at 2180C, are obtained.

EXAMPLE 5
A mixture of 9.4 g of 2-amino-6-trifluoromethoxy-benzothiazole and 5.5 g of 1-chloro-2-ethylthio ethane in 20 cm3 of methyl ethyl ketone is heated for 15 hours to boiling. The precipitate formed is filtered hot, washed with 2 times 20 cm 3 of boiling methyl ethyl ketone. 11.5 g of (2-ethylthio-ethyl) -3-2-imino-6-trifluoromethoxy-6-benzothiazoline hydrochloride are obtained, sublimating at around 16 ° C.

EXAMPLE 6
1.5 g of (tert-butylthio-2-ethyl) -3-2-imino-trifluoromethoxy-6-benzothiazoline hydrochloride and 15 cm3 of hydrobromic acid at 47% are heated for 4 hours at 1000C. After cooling to OOC, the precipitate formed is filtered, washed with 2 times 25 cm3 of distilled water and then with 2 times 30 cm3 of ethyl ether. 0.9 g of (imino-2-trifluoromethoxy-6-benzothiazoline-3) -2 ethanethiol hydrobromide, melting at 1800C, is obtained.

 (Tert-butylthio-2-ethyl) -3-imino-2-trifluoromethoxy-6 benzothiazoline hydrochloride can be prepared according to the following process: 9.4 g of 2-amino-6-trifluoromethoxy-6 benzothiazole and 6.7 g of chloro-2 tert-butylthio-1 ethane in 30 cm3 of methyl ethyl ketone are heated for 42 hours at boiling point. After the reaction medium has cooled to 0 ° C., the precipitate formed is filtered and washed with twice 20 cm 3 of methyl ethyl ketone. 3.7 g of (tert-butylthio-2 ethyl) -3 imino-2-trifluoromethoxy-6 benzothiazoline hydrochloride are obtained, melting while erasing around 180-1900C.

 2-chloro tert-butylthio-1 ethane can be prepared according to the method described by T.P. DAWSON, J.Am.Chem.Soc., 69, 1211 (1947).

EXAMPLE 7
5 g of (2-ethylthioethyl) -3 imino-2 trifluoromethoxy-6 benzothiezoline, 10.3 cm3 of hydrogen peroxide at 30 t and 70 cm3 of acetic acid are heated for 24 hours at 1000C. After cooling to a temperature in the region of 200C, the reaction medium is added to 200 cm3 of distilled water cooled with OOC, treated with 120 cm3 of 30 t sodium hydroxide solution and then extracted with 300 cm3 of ethyl acetate. The organic phase is washed with 150 cm3 of distilled water and then twice with 150 cm3 of an aqueous solution of sodium bisulfite, dried over magnesium sulfate and concentrated to dryness under reduced pressure (20 mm sea cure; 2.7 kPa) .After formation of the hydrochloride by addition of 16 cm3 of 1N hydrochloric acid in 25 cm3 of chloroform, 1.9 g of (2-ethylsulfonylethyl) -3 imino-2 trifluoronétnoxy-6 benzothiazoline hydrochloride are obtained. 2120C.

EXAMPLE 8
To 1.7 g of (2-ethylthio-ethyl) -3 imino-2-trifluoromethoxy-6 benzothiazoline in 25 cm3 of absolute ethanol cooled to -200C, 0.9 g of m-chloroperbenzoSque acid is added in about 10 minutes . The reaction is continued for 30 minutes at the same temperature. The precipitate formed is filtered, then taken up in 50 cm3 of ethyl ether and treated with 2 cm3 of 4N hydrochloric ether. After filtration, 1.1 g of (2-ethylsulfinyl-ethyl) -3 inino-2-trifluorometboxy-6 benzothiazoline- (RS) hydrochloride is obtained, melting at 1740C.

EXAMPLE 9
The procedure is as in Example 8, from 3.7 g of 2-imino-2-methylthio-3-trifluoromethoxy-6 benzothiazoline and 2.3 g of m-chloroperbenzoic acid in 60 cm3 of ethanol absolute. After 30 minutes at -200C, the precipitate formed is filtered and the hydrochloride prepared in 60 cm3 of acetone. 1.5 g of imino-2 hydrochloride (2-methylsulfinyl-ethyl) -3 trifluoromethoxy-6 benzothiazoline- (RS), melting & 1860C, are obtained.

EXAMPLE 10
6.55 g of 2-amino-trifluoromethyl-6 benzothiazole and 7.48 g of 1-chloro-ethylthio-2 ethane in 20 cm3 of methyl ethyl ketone are heated for 18 hours to boiling and then the mixture is cooled to a temperature in the region of 200C. After dry concentration at 500C under reduced pressure (20 mm of mercury; 2.7 kPa), the residue is taken up in 50 cm3 of methyl ethyl ketone. The precipitate formed is filtered and recrystallized from 50 cm3 of propanol-2. 3.1 g of (2-ethylthio-ethyl) -3-2-imino-6-trifluoromethyl-6-benzothiazoline hydrochloride are obtained, sublimating around 1600C.

 2-amino-6-trifluoromethyl benzothiazole can be prepared according to the method described in US Pat. No. 2,822,359.

 The present invention also relates to medicaments consisting of at least one compound of formula (I) or a salt of such a compound in its pure state or in the form of a composition in which it is combined 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.

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 batten, 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 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 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 or glutamate may be involved such as Alzheimer's disease, Huntington's disease, anyotrophic 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.

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-ethylsulfinyl-ethyl) -3 imino-2-trifluoromethoxy-6
benzothiazoline ..................................., .. 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 Dg of active product having the following composition - imino-i (2-methylthio-ethyl) -3-trifluoromethoxy-6 are prepared according to the usual technique.
benzothiszoline ................................ 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 hydroxymethylcellulose, glycerin, oxide
titanium (72-3,5-24,5) .................... qs p 1 tablet
film-coated finished at 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product having the following composition - (2-ethylsulfonyl) -3-2-imino-trifluoromethoxy-6 is prepared.
benzothiazoline ............................. 10 mg - benzoic acid ............... .................. 80 mg - benzyl alcohol ........................... ...... 0.06 cm3 - sodium benzoate .................................. 80 mg - 95 t ethanol ............................... 0.4 cm3 - sodium hydroxide ...... ............................ 24 mg - propylene glycol ................. .................. 1.6 cD3 - water .......................... .............. qs 4 cm3

Claims (5)

 - R2 represents a chain -CH2- CH -R in which R3 represents a dialkylamino, piperidino, pyrrolidinyl-1, mercapto, alkylthio, alkylsulfinyl or alkylsulfonyl radical, it being understood that the alkyl and alkoxy portions contain 1 to 4 carbon atoms in chain straight or branched, as well as the salts of these compounds with a mineral or organic acid.  - R1 represents a perfluoroalkoxy or trifluoromethyl radical and  in which

 CLAIMS 1 - Compounds of formula  2 - Process for preparing the compounds of formula (I) according to claim 1 characterized in that one reacts an amino derivative of formula

 in which R1 has the same meanings as in formula (I) on a derivative of formula  R2 - X (III) in which R2 has the same meanings as in formula (I) and X represents a reactive group or an addition salt of such a compound with a mineral or organic acid, isolates the product and transforms it optionally as an addition salt with a mineral or organic acid.  3 - Process for preparing the compounds of formula (I) according to claim 1 for which R2 represents a chain -C82-CH2-R3 in which R3 represents an alkylsulfonyl or alkylsulfinyl radical, RI has the same meanings as in claim 1 characterized in the corresponding derivatives are oxidized for which R3 represents an alkylthio radical, isolates the product and optionally transforms it into an addition salt with a mineral or organic acid.  4 - Process for preparing the compounds of formula (I) according to claim 1 for which R2 represents a chain -CH2-CH2-R3 in which R3 represents a mercapto radical and R1 has the same meanings as in claim 1 characterized in that hydrolyzing a corresponding derivative for which R3 represents a tert-butylthio radical, isolates the product and optionally transforms it into an addition salt with a mineral or organic acid.  5 - Medicines characterized in that they contain as active ingredient at least one compound according to claim 1 or a salt of such a compound.