FI93109B - Process for the preparation of 2-imino-3-heterocyclylalkylbenzothiazoline derivatives useful as medicaments - Google Patents

Abstract

Compounds of formula: <IMAGE> in which R1 denotes a substituted 1-piperazinyl, substituted 1,2,3,6-tetrahydro-1-pyridyl or substituted piperidino radical, R2 denotes a polyfluoroalkoxy radical and n is equal to 2 or 3, salts of these compounds with an acid, processes for their preparation and medications containing them.

Description

93109

The invention relates to the preparation of compounds of formula (I) and their salts. The invention relates to a process for the preparation of 2-imino-3-heterocyclylalkylbenzothiazoline derivatives useful as medicaments.

~ fY> io (i) (CH2) n - R1

In formula (I),

R 1 represents a piperazin-1-yl radical substituted in the 4-position by a) a phenyl radical, (b) a phenyl radical substituted by at least one substituent which is a halogen atom, an alkyl or alkoxy radical, (c) a phenylalkyl radical, (d) a pyridyl radical or (e) a pyrimidinyl radical, 1,2,3,6-tetrahydro-1-pyridyl substituted in the 4-position by a phenyl radical or a phenyl radical substituted by at least one substituent. 1a is a halogen atom, an alkyl or alkoxy radical, a piperidino radical substituted in the 4-position by a phenyl radical or a phenyl radical substituted by at least one substituent which is a halogen atom, an alkyl or alkoxy radical, R2 represents a polyfluoroalkoxy radical, .

In the above and in the following definitions, alkyl and alkoxy radicals and alkyl and alkoxy moieties contain 1 to 4 carbon atoms in a straight-chain or branched manner.

2 93109

The polyfluoroalkoxy radicals are preferably trifluoromethoxy, pentafluoromethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy radicals.

Halogen atoms are preferably fluorine, chlorine and bromine atoms.

The invention also relates to the preparation of acid addition salts of the compounds of formula (I) formed with inorganic or organic acids.

Compounds of formula (I) may be prepared by hydrolysis of a derivative of formula: V N - CO - CF 3 '(II) 15 \ (CH 2) n "R 1 wherein R 1, R 2 and n are the same as in formula (I).

This hydrolysis is generally carried out with a base such as alkali metal carbonate (preferably sodium, potassium carbonate) or concentrated ammonia in an aqueous-alcoholic mixture at a temperature of about 20 ° C.

Derivatives of formula (II) may be prepared by reacting a derivative of the formula: 25 * 2- \ H - CO - CF3 (in) \ (CH2) n - 0 - r3 ·; * 30 wherein R2 and n are as defined in formula ( I) and R 3 • ♦ '* represents a reactive group, such as a methanesulfonyl or p-toluenesulfonyl radical, to react with an amine of formula: HR, (IV) 35. where R, has the same meaning as in formula (I).

11 • · 3 93109 This reaction is generally carried out in an inert solvent such as an aromatic solvent (for example, benzene, toluene, xylene) or dimethylformamide at a temperature between 20 ° C and the boiling point of the solvent.

Derivatives of formula (III) may be prepared by reacting a derivative of formula: 10 R2 \ N - CO - CF3 (V) \

(CH2) n - OH

wherein R 2 and n are as defined in formula (I), react with methanesulfonic acid or p-toluenesulfonic acid chloride in either an inert solvent such as an aromatic solvent (e.g. benzene, toluene, xylene) or a chlorinated solvent (e.g. chloroform), methylene chloride, methylene chloride in the presence of an amine such as triethylamine at about 20 ° C or in pyridine at about 0 ° C.

Derivatives of formula (V) may be prepared by reacting ethyl trifluoroacetate with a derivative of formula:

25. S

* 2-r \

I II V NH

(VI)

(CH2) n - OH

·: 30 • · where R2 and n have the same meaning as in formula (I).

This reaction is generally carried out in an alcohol (e.g. methanol, ethanol) in the presence of a tertiary amine such as triethylamine at a temperature of about 20 ° C.

. · I

93109 4

Derivatives of formula (VI) may be prepared by reacting a halogenated derivative of formula:

Hal - (CH 2) n --OH (VII) wherein n is as defined in formula (I) and Hal represents 5 halogen atoms (preferably bromine or chlorine) to react with 2-amino-6-polyfluoroalkoxybenzothiazole.

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

2-Amino-6-polyfluoroalkoxybenzothiazoles can be prepared by applying or using the method described by Yagupol'sk et al., Zh. Obshch. Khim., 33 (7), 2301, (1963).

Compounds of formula (I) may also be prepared by reacting bromine and an alkaline earth metal thiocyanate with a derivative of the formula: I (Vili) - (CH 2) n - * 1 wherein R 1, R 2 and n are the same than in formula (I).

This reaction is preferably carried out in acetic acid at a temperature of about 20 ° C.

Potassium thiocyanate is preferably used as the alkali metal thiocyanate.

Derivatives of formula (VIII) may be prepared by reacting an amine of general formula (IV) with a derivative of formula: R 2 -

30 \ H

- (CH 2) n -O-R 5 (IX 1 R 4 wherein R 2 and n are as defined in formula (I) and R 4 and R 5 represent a p-toluenesulfonyl radical.

i.

This reaction is preferably carried out in the presence of sodium hydrogen carbonate in an inert solvent such as dimethylformamide at a temperature of 50 to 100 ° C.

Derivatives of formula (IX) can be prepared by reacting p-toluenesulfonyl chloride with a derivative of formula: * 2 ~ (\

10 "<CH2> n - 0H

wherein R 2 and n are the same as in formula (I).

This reaction is generally carried out in an inert solvent such as a chlorinated solvent (for example, chloro-15, methylene chloride) at a temperature of 0 to 30 ° C.

Derivatives of formula (X) may be prepared by reacting 4-polyfluoroalkoxyaniline with a derivative of formula (VII).

This reaction is generally carried out at a temperature of 100 to 170 ° C.

The reaction mixtures prepared by the various methods described above are treated using various classical physical (evaporation, extraction, distillation, crystallization, chromatography ...) or chemical (salt formation) methods.

The compounds of formula (I) which are free bases can be converted into acid addition salts using an inorganic or organic acid by reacting such an acid in an organic solvent such as an alcohol, ketone, ether or chlorinated solvent.

The compounds of formula (I) and their salts have considerable pharmacological properties. These compounds act on glutamate-induced seizures and are therefore useful in the treatment and prevention of seizures, schizophrenic disorders and in particular 6 93109 schizophrenia disorders, sleep disorders, cerebral ischemic events and neurological diseases such as Alzheimer's disease, which may include glutamate. disease, Huntington’s disease, lateral amyotro-5 disease, and Olivo-Ponto-cerebellum atrophy.

The effect of the compounds of formula (I) on glutamate-induced seizures is determined by a technique derived from I.P. On the technique of LAPIN, J. Neural. Transmission, vol. 54, 229-238 (1982); intracerebral ventriculation of glutamate rye-10 is performed by a technique similar to that described by R. CHERMAT and P. SIMON, J. Pharmacol. (Paris), vol. 6, 489-492 (1975). Their ED 50 is generally less than 10 mg / kg.

The compounds of formula (I) have low toxicity. They have an LD50 greater than 15 mg / kg i.p. with the mouse.

For medical use, the compounds of formula (I) may be used as such or as pharmaceutically acceptable salts, i.e. non-toxic dosages.

Examples of pharmaceutically acceptable salts include acid addition salts with inorganic or organic acids such as acetate, propionate, succinate, benzoate, fumarate, malate, oxalate, methanesulfonate, isethionate, theophylline acetate, phenolate, salicylate; 25 β-oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate.

The following examples show how the invention can be practiced without limiting it in any way.

Example 1 “1.3 g of 3- {2- [4- (2-pyridyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline dissolved in a mixture of 19 cm 3 7% aqueous potassium carbonate solution and 32 cm3 of methanol are stirred at a temperature in the region of 20 [deg.] C. for 4 hours. The solution

• I

II

7 93109 are concentrated under reduced pressure (20 mm of mercury; 2.7 kPa) and the residue is dissolved in 300 cm3 of distilled water. The aqueous phase is extracted 3 times with 200 cm3 of ethyl ether, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with acetone. Upon formation of trihydrochloride by the addition of 4.2 N hydrochloric acid ether in acetone, 0.73 g of 2-imino-3- {2- [4- (2-pyridyl) piperazin-1-yl] -10-ethyl-6-trifluoromethoxybenzothiazoline trihydrochloride is obtained. , which melts at about 230 ° C.

3- {2- [4- (2-pyridyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared by the following method: a mixture of 4.52 g of 2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 100 cm 3 of toluene and 6.9 g of 2-pyridylpiperazine, heated under reflux for 2 hours, cooled to + 4 ° C and centrifuged. The toluene filtrate is evaporated under reduced pressure and purified on a silica gel chromatography column eluting with dichloromethane. 1.3 g of 3- {2- [4- (2-pyridyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline are obtained, melting at 132 ° C.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate can be prepared as follows: 6.9 g of triethylamine are gradually added to a mixture of 120 cm 3 of methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2- (2-tri-fluoroacetylimino-6-trifluoromethoxybenzothiazolin-3-yl) ethanol. After stirring for 1 hour at a temperature in the region of 20 [deg.] C., the reaction mixture is cooled to 10 [deg.] C., centrifuged, washed with 20 cm <3> of cold methylene chloride, then dried at 40 [deg.] C. under reduced pressure. There are thus obtained 10 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy) · 8 93109 3-benzothiazolinyl) ethyl methanesulfonate, melting at 145 ° C. A second batch of 2.7 g is obtained by washing the filtrate with 100 cm3 of water, drying over magnesium sulphate, concentrating to a residual volume of about 50 cm @ 3, cooling to 5 ° C and then centrifuging.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol can be prepared as follows: 20.7 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol hydrobromide, 9.8 g of ethyl trifluoroacetate and 16.1 g 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 silica gel column chromatography eluting with ethyl acetate. 19.2 g of 2- (2-15 trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol are thus obtained, melting at 144 ° C.

2- (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol can be prepared as follows: 9.4 g of 2-amino-6-trifluoromethoxybenzothiazole and 10 g of 2-bromo-20 ethanol in 30 cm3 of absolute ethanol are heated 95 hours at boiling point. The mixture is then cooled to about 20 ° C. The precipitate formed is filtered off and washed with 100 cm3 of ethyl ether. This gives 6.4 g of hydrobromide of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol, melting at 219 ° C.

2-Amino-6-benzothiazole can be prepared by the method described by L.M. Yagupol'skii and colleagues, Zh. Obshch. Khim, 33 (7), 2301 (1963).

Example 2 Making as in Example 1, but starting from 0.9 g of 3- {2- [4- (4-methylphenyl) piperazin-1-yl] ethyl-2-trifluoroacetylimino-trifluoromethoxybenzothiazoline, 18 cm 3: methanol and 14 cm3 of a 7% aqueous alcohol solution of potassium carbonate, 0.7 g of 2-35 imino-3- {2- [4- (4-methylphenyl) piperazin-1-yl] ethyl

II

• 9 93109 Li} -6-trifluoromethoxybenzothiazoline, melting at 120 ° C.

3- {2- [4- (4-methylphenyl) piperazin-1-yl] ethyl -2-trifluoroacetylimino-trifluoromethoxybenzothiazoline-5 can be prepared as follows: as in Example 1 using 4.52 g of 2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 150 cm 3 of toluene and 5.29 g of 4- (4-methylphenyl) piperazine. After purification by silica gel column chromatography eluting with a mixture of dichloromethane and ethyl acetate (98-2 by volume), 0.9 g of 3- {2- [4- (4-methylphenyl) piperazin-1-yl] ethyl} -2- trifluoroacetylimino-6-trifluoromethoxybenzothiazoline.

15 Example 3

By making as in Example 1 starting from 5.88 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 200 cm3 of toluene and 6.87 g of 4- (2-methylphenyl) piperazine-20 and after heating for 2 hours under a vertical condenser, the toluene filtrate is evaporated off under reduced pressure, 100 cm3 of methanol and 20 cm3 of 7% aqueous alcoholic potassium carbonate solution are added to the residue thus obtained and the mixture is stirred for 2 hours at about 20 [deg.] C. The alcohol is evaporated off under reduced pressure and the residue is purified. eluting with dichloromethane-ethyl acetate (79-30 by volume) followed by ethyl acetate-cyclohexane (50-50 by volume) to give 1.8 g of 2-imino-3- {2- [4- (2-methylphenyl) piperazine. 1-γ-30β] ethyl} -6-trifluoromethoxybenzothiazoline, melting at 135 ° C.

Example 4

By proceeding as in Example 1, but starting from 3.8 g of 3- [2- (4-benzylpiperazin-1-yl) -35-ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzene • 10 93109 sothiazoline per 20 cm3: methanol and 10 cm 3 of a 7% aqueous alcohol solution of potassium carbonate and, after purification by column chromatography on silica gel, eluting with ethyl acetate-cyclohexane (50 to 50 by volume) and then adding 4.2 N hydrochloric acid, 2.5 g of 3- [2- (4 -benzylpiperazin-1-yl) ethyl] -2-imino-6-trifluoromethoxybenzothiazoline hydrochloride, melting at 230 ° C.

3- [2- (4-Benzylpiperazin-1-yl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows: as in Example 1, but using 4.52 g of 2- (2 trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 120 cm 3 of toluene and 7 g of 4-benzylpiperazine. After purification on a silica-15 gel chromatography column eluting with dichloromethane-ethyl acetate (50-50 by volume), 3.8 g of 3- [2- (4-benzyl) piperazin-1-yl] ethyl-2-trifluoroacetylimino are obtained. -6-trifluoromethoxybenzothiazoline.

Example 5 As in Example 1, 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 150 cm3 of toluene and 6.5 g of 4- (2-pyrimidinyl) piperazine and After heating under reflux for 4 hours, the toluene filtrate is evaporated under reduced pressure. To the toluene residue are added 100 cm3 of methanol and 20 cm3 of a 7% aqueous alcoholic solution of potassium carbonate. After stirring for 2 hours at about 20 [deg.] C., the methanol is evaporated off under reduced pressure and the residue is purified by column chromatography on silica gel, eluting with dichloromethane-methanol. with a mixture of li (in volumes of 9-10). After the formation of trihydrochloride with the addition of 4.2 N hydrochloric acid ether, 1.13 g of 2-imino-3- {4- [2- (2-pyrimidinyl) piperazin-1-yl] ethyl} -6- trifluoromethoxybenzothiazine 35 trihydrochloride, melting at about 270 ° C.

> · 11 93109

Example 6 3.6 g of 3- [3- (4-phenylpiperazin-1-yl) propyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride dissolved in a mixture of 45 cm 3 of a 7% aqueous alcohol solution of potassium carbonate and 150 cm3 of methanol, stirred for 4 hours at a temperature in the region of 20 ° C. After concentration to dryness, the reaction mixture is dissolved in 100 cm3 of distilled water and the organic phase is extracted twice with 100 cm3 of ethyl acetate, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). After formation of the dihydrochloride on addition of 4 cm3 of 4.2 N hydrochloric acid ether in ethyl acetate, the precipitate is recrystallized from a mixture of absolute ethanol and ethyl ether (50 to 50 by volume). 1.6 g of 2-imino-3 - [- 3- (4-phenyl-lipiperazin-1-yl) propyl] -6-trifluoromethoxybenzothiazoline dihydrochloride are obtained, melting at 260 ° C.

3- [3- (4-Phenylpiperazin-1-yl) propyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride 20 can be prepared by the following method: 4.4 g of 3- (2-trifluoroacetylimino-6- trifluoromethoxy-3-benzothiazolinyl) propyl p-toluenesulfonate, 1.44 g of N-phenylpiperazine and 0.68 g of sodium hydrogen carbonate in 50 cm 3 of dimethylformamide are heated at 80 ° C for 19:25 hours. The reaction mixture is concentrated to dryness under reduced pressure (7 mm of mercury; 0.95 kPa), the residue is dissolved in 100 cm3 of distilled water and the organic phase is extracted with 50 cm3 of dichloromethane. After drying over magnesium sulphate and concentration under reduced pressure, the oily residue obtained is dissolved in 15 °. to 1 cm3 of 1N hydrochloric acid solution and the hydrochloride formed are mixed with 15 cm3 of distilled water. 4 g of 3- [3- (4-phenyl) piperazin-1-ylpropyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline are thus obtained, melting at 238 ° C.

12 93109 3- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propyl p-toluenesulfonate can be prepared as follows: 11 g of 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) 5 li) Propanol is gradually added to 10.8 g of p-toluenesulfonyl chloride dissolved in 200 cm3 of pyridine cooled to 0 ° C. The reaction is continued for 1 hour at 5 [deg.] C., then the reaction mixture is kept cold (6-7 [deg.] C. for 15 hours. After adding the mixture to 2 liters of 10 ml of distilled water, extracted with 200 cm <3> of ethyl acetate, washed twice with 50 cm <3> 1N hydrochloric acid, dried over magnesium sulphate and concentrated to dryness under reduced pressure, gives 6.7 g of 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propyl p-15 toluenesulphonate, melting at 139 ° C. :in.

3- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propanol can be prepared as follows: 24.8 g of 3- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) propanol, 14.2 g of ethyl trifluoroacetate. 20 tates and 8.6 g of triethylamine are stirred in 250 cm3 of absolute ethanol for 24 hours at a temperature in the region of 20 ° C. The reaction mixture is then cooled to 0-5 ° C and the precipitate formed is filtered off and dried. 28.2 g of 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-25 benzothiazolinyl) propanol are thus obtained, melting at 144 ° C.

3- (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl) propanol can be prepared as follows: 82 g of 2-amino-6-trifluoromethoxybenzothiazole and 65 cm3 of 3-bromipropanol in 25 cm3 of absolute ethanol are heated for 30 72 hours. at the boiling point of time. The mixture is then cooled to a temperature of about 20 ° C. The oil obtained is dissolved in 1 liter of distilled water and the organic phase is extracted 3 times with 200 cm3 of dichloromethane. After drying over magnesium sulfate and concentration to dryness under reduced pressure, the crude product is purified by silica gel column chromatography eluting with ethyl acetate. 25 g of 3- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) propanol are thus obtained, melting at 106 ° C.

Example 7 By making as in Example 1 using Ig3- {2- [4- (m-tolyl) piperazin-1-yl] ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline in 30 cm3 of methanol and 15 cm3 of 7% an aqueous-alcoholic solution of potassium carbonate and, after column chromatography on silica gel, eluting with ethyl acetate-cyclohexane (50-50 ti in volumes), then adding 4.2 N hydrochloric acid ether gives 0.6 g of 2-imino- [4- (m-tolyl) piperazine-1]. -yl] ethyl-6-trifluoromethoxybenzothiazoline, melting at about 250 ° C.

3- {2- [4- (m-tolyl) piperazin-1-yl] ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows: as in Example 1 using 4.52 g of 2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl-20-yl) ethyl methanesulfonate in 150 cm 3 of toluene and 5.29 g of 4- (3-methylphenyl) piperazine. 70-30 volumes), 1 g of 3- {2- [4- (m-tolyl) piperazin-1-yl] ethyl-2-25 trifluoroacetylimino-6-trifluoromethoxybenzothiazoline is obtained.

Example 8

To a mixture of 2.62 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] -1,2,3,6-tetrahydropyridine 30 and 2.8 g of potassium thiocyanate in 50 cm3 of ethyl acetate: 1.15 g of bromine dissolved in 15 cm3 of acetic acid are added dropwise at a temperature in the region of 20 ° C. After the usual work-up, 0.67 g of 2-imino-3- [2- (4-phenyl-1,2,3,6-tetrahydro-1-pyridyl) ethyl] -6-trifluoromethoxy-35-benzothiazoline is obtained, melting 256 g. ° C.

14 93109 4-Phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] -1,2,3,6-tetrahydropyridine can be prepared as follows: a mixture of 5.56 g of Np-toluenesulfonyl-2- (4- trifluoromethoxyanilino) ethyl p-toluenesulfonate, 1.84 g of 4-phenyl-1,2,3,6-tetrahydropyridine and 0.97 g of sodium hydrogen carbonate in 95 cm 3 of dimethylformamide are heated at 80 ° C for 18 hours. After the usual work-up, 2.62 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] -1,2,3,6-tetrahydropyridine are obtained in the form of an oil, which is used as such for the following syntheses.

Np-Toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl p-toluenesulfonate can be prepared by the following method: to 5.0 g of 2- (4-trifluoromethoxyanilino) ethanol and to 6.35 cm 3 of triethylamine in 50 cm 3 8.6 g of p-toluenesulfonyl chloride are gradually added to dichloromethane cooled to 0 ° C. The reaction is continued for 2 hours at a temperature in the region of 20 ° C, then the reaction mixture is washed 3 times with 50 cm3 of distilled water and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). After the addition of 50 cm3 of absolute ethanol, the precipitate formed is filtered off. 7.3 g of N-p-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl p-toluenesulfonate are obtained, melting at 88 ° C.

: 2- (4-Trifluoromethoxyanilino) ethanol can be prepared as follows: 88.5 g of 4-trifluoromethoxyaniline and 31.2 g of 2-bromoethanol are heated at 160 ° C for 1.5 hours. After cooling to about 20 [deg.] C., the reaction mixture is dissolved in 200 cm <3> of dichloromethane, the Liu-30 non-lubricating substance is filtered off and the filtrate is concentrated to dryness under reduced pressure. Purification by silica gel chromatography using ethyl acetate-cyclohexane (40-60 by volume) as eluent gives 26.8 g of 2- (4-trifluoromethoxyanilino) -35 ethanol as an orange oil.

li 15 93109

Example 9 1.1 g of 3- [2- (4-phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride dissolved in 5 cm 3 of a 7% aqueous solution of potassium carbonate 5 and 100 cm 3 of methanol are stirred at about 20 ° C: n temperature for 5 hours. The reaction mixture is added to 200 cm3 of distilled water and the organic phase is extracted 3 times with 150 cm3 of ethyl ether, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). Upon formation of the hydrochloride by the addition of 0.45 cm 3 of 4.2 N hydrochloric acid ether to 30 cm 3 of ethyl acetate, 0.8 g of 2-imino-3- [2- (4-phenylpiperazinyl) ethyl] -6-trifluoromethoxybenzothiazoline is obtained, which melts at 230 ° C.

3- [2- (4-Phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: 6.5 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3 -benzothiazolinyl) ethyl p-toluenesulfonate, 2.2 g of N-phenyl-20-piperazine and 1.0 g of sodium bicarbonate in 80 cm 3 of dimethylformamide are heated at 60 ° C for 19 hours. The reaction mixture is added to 300 cm3 of distilled water and the organic phase is extracted 3 times with 50 cm3 of dichloromethane. After drying over magnesium sulphate and concentrating to dryness under reduced pressure, the oily residue obtained is dissolved in 20 cm3 of 1N hydrochloric acid and the hydrochloride formed is precipitated from 20 cm3 of ethanol. 1.1 g of hydrochloride of 3- [2- (4-phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazole-30 are obtained, melting at 204 ° C. j! (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl p-toluenesulfonate can be prepared by the following method: 19.3 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl-35 li) ethanol is gradually added to 19.7 g of p-toluene sulphonyl chloride dissolved in 120 cm3 of pyridine cooled to 0 ° C. The reaction is monitored for 1 hour at 10-15 ° C. The reaction mixture is added to 500 cm3 of distilled water and the organic phase is extracted 3 times with 100 cm3 of dichloromethane. After washing twice with 50 cm3 of 1N hydrochloric acid, then twice with 50 cm3 of distilled water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa), 14.1 g of 2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-10 benzothiazolinyl) ethanol, melting at 143 ° C.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol can be prepared as follows: 20.7 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol hydrobromide, 9.8 g of ethyl trifluoroacetate and 16.1 cm 3 of triethylamine are stirred in 100 cm 3 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 silica gel column chromatography eluting with ethyl acetate. 19.2 g of 2- (2-20 trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol are thus obtained, melting at 144 ° C.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol can be prepared by the following method: 9.4 g of 2-amino-6-trifluoromethoxybenzothiazole. 25 sol and 10 g of 2-bromoethanol in 30 cm3 of absolute ethanol are heated at reflux for 95 hours. The mixture is then cooled to about 20 ° C. The precipitate formed is filtered off and washed with 100 cm3 of ethyl ether. 6.4 g of hydrobromide of 2- (2-trifluoroacetylimino-6-30 trifluoromethoxy-3-benzothiazolinyl) ethanol are obtained, melting at 219 ° C.

9 2-Amino-6-trifluoromethoxybenzothiazole can be prepared by the method described by Yagupol'skii et al., Zh. Obshch. Khim., 33 (7), 2301 (1963).

Il 17 93109

Example 10 1.53 g of 3- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, 33 cm3 of methanol and 21 cm3 of The% potassium-5 carbonate solution in a mixture of 2 volumes of methanol and 5 volumes of water is stirred for 4 hours at a temperature in the region of 20 ° C. The reaction mixture is concentrated under reduced pressure, then extracted with sulfuric ether. The organic phase is dried over magnesium sulfate, then an excess of hydrochloric acid is added. The precipitate is centrifuged, washed with sulfuric acid ether, dried at 50 ° C under a pressure of 20 millimeters of mercury. 1.05 g of 2-imino-3- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl-6-tri-fluoromethoxybenzothiazoline are obtained, melting at 240 ° C.

3- {2- [4- (4-methoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: a mixture of 4.52 g of 2- (2-Trifluoroacetyl-20-imino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate, 120 cm 3 of toluene and 10.56 g of the base liberated from p-methoxy-4-phenylpiperazine hydrochloride are heated under reflux for 1 hour, cooled to + 4 ° C: and then centrifuged. The toluene filtrate is evaporated off under reduced pressure, then 45 cm3 of a 1.2 N aqueous hydrochloric acid solution are added. The hydrochloride is separated amorphously, then crystallized by trituration from 50 cm3 of ethanol. After centrifugation, washing with 15 cm3 of ethanol and drying at 50 ° C under a pressure of 20 millimeters of mercury, 1.7 g of 3- {2- [4- (4-methoxy - [* (ciphenyl) piperazine-1] are obtained. -yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate can be prepared as follows: 6.9 g of triethylamine are gradually added to a mixture of 120 cm 3 of methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2- (trifluoroacetylamino-6-trifluoromethoxybenzothiazolin-3-yl) ethanol. After stirring for 1 hour at a temperature in the region of 20 [deg.] C., the reaction mixture is cooled to 10 [deg.] C., centrifuged, washed with 20 cm <3> of cold methylene chloride, then dried at 40 [deg.] C. under reduced pressure. 10 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate are obtained, melting at 145 ° C. A second batch of 2.7 g is obtained by washing the filtrate with 100 cm3 of water, drying over magnesium sulphate, concentrating to a residual volume of about 50 cm3, cooling at 5 ° C and then centrifuging.

Example 11 By proceeding as in Example 9, but starting from 1.4 g of 3- {2- [4- (3,4-dimethoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoro -methoxybenzothiazoline hydrochloride in 30 cm3 of methanol and 19 cm3 of a 7% aqueous alcohol solution of calimic carbonate, 0.97 g of 2-imino-3- {2- [4- (3,4-dimethoxyphenyl) piperazine -1-yl] ethyl-6-trifluoromethoxybenzothiazoline trihydrochloride, melting at 250 ° C.

3- {2- [4- (3,4-dimethoxyphenyl) piperazin-1-yl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzo; The thiazoline hydrochloride can be prepared as follows: as in Example 9, starting from 4.3 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate, 70 cm3 of toluene and 14 g of 4- ( 3,4-dimethoxyphenyl) piperazine-30 hydrochloride from the liberated base. This gives 1.45 g of the desired hydrochloride, melting at 260 [deg.] C.

a a li 19 93109

Example 12

By doing as in Example 9, but starting from 1.7 g of 3- {2- [4- (4-fluorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxy-5-benzothiazoline hydrochloride , 36 cm 3 of methanol and 21 cm 3 of a 7% aqueous methanol solution of potassium carbonate. There is thus obtained 3- {2- [4- (4-fluorophenyl) piperazin-1-yl] ethyl} -2-imino-6-trifluoromethoxybenzothiazoline dihydrochloride, melting at 260 ° C.

3- {2- [4- (4-fluorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows: as in Example 9 using 9 g of 4- (4-fluorophenyl) piperazine, 70 cm 3 of toluene and 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate. 1.7 g of the desired compound are obtained, melting at 240 ° C.

Example 13

By doing as in Example 9, but starting from 1.40 g of 3- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxy -benzothiazoline hydrochloride, 30 cm3 of methanol and 19 cm3 of a 7% aqueous methanolic solution of potassium carbonate, 0.9 g of 3- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethyl} -: 25 2-imino- 6-Trifluoromethoxybenzothiazoline hydrochloride, melting at 270 ° C.

3- {2- [4- (4-chlorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows: heat the mixture under reflux for 30 hours. where *, is 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate, 70 cm 3 of toluene and 13.45 g of 4- (4-chlorophenyl) piperazine dihydrochloride free base . After cooling to 35-10 ° C and centrifuging the precipitate, the toluene filtrate is concentrated and then purified by silica gel column chromatography eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume). After recrystallization from 50 cm3 of ethanol, 1.4 g of the desired compound are obtained, melting at 165 ° C.

Example 14 3.0 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] piperidine and 3.2 g of potassium thiocyanate in 25 cm3 of acetic acid are treated dropwise with 1.3 g of bromine dissolved in 15 cm3: acetic acid at a temperature of about 20 ° C. The reaction is continued for 18 hours at this temperature. After addition of 100 cm3 of distilled water, the reaction mixture is neutralized with 30% sodium hydroxide and the organic phase is extracted 3 times with 50 cm3 of ethyl acetate, dried over magnesium sulphate and concentrated under reduced pressure (20 mm of mercury; 2.7 kPa). The residue obtained is purified by silica gel column chromatography, eluting with ethyl acetate. After the formation of the dihydrochloride by the addition of 4 cm3 of 4.2 N hydrochloric acid ether in 30 cm3 of ethyl acetate, 2.4 g of 2-imino-3- [2- (4-phenylpiperidino) ethyl] -6-trifluoromethoxybenzothiazoline are obtained, which annoys at about 220 eC.

4-Phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] piperidine can be prepared as follows: A mixture of 7.2 g of Np-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl p-Toluenesulfonate, 4.9 g of 4-phenylpiperidine and 2.4 g of sodium bicarbonate in 50 cm 3 of dimethylformamide are heated at 80 ° C for 18 hours. After cooling to about 20 ° C, the reaction mixture is concentrated to dryness under reduced pressure *. (7 mm of mercury; 0.95 kPa). The residue is washed twice with 30 cm3 of water, then dissolved in 50 cm3 of ethanol and concentrated to dryness under reduced pressure. The crude product is treated with 30 cm3 of 37% hydrochloric acid in a mixture of acetic acid 35 (30 cm3) and water (20 cm3). The mixture is heated at reflux for 3 hours. After cooling to about 20 [deg.] C. and adding 100 cm <3> of distilled water, the aqueous solution is neutralized with 30% sodium hydroxide and the organic phase is extracted with ethyl acetate. 4.0 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethylpiperidine are thus obtained in the form of a brown oil, which is used as a crude product in the next reaction.

Np-Toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl p-toluenesulfonate can be prepared by the following method: to 5.0 g of 2- (4-trifluoromethoxyanilino) ethanol and to 6.35 cm 3 of triethylamine 8.6 g of p-toluenesulfonyl chloride are gradually added in 50 cm3 of dichloromethane cooled to 0 [deg.] C. The reaction is continued for 2 hours at a temperature in the region of 20 [deg.] C., then the reaction mixture is washed 3 times with 50 cm <3> of distilled water and the organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (20 mm of mercury; 2.7 kPa). After the addition of 50 cm3 of absolute ethanol, the precipitate formed is filtered off. There is thus obtained N-p-toluenesulfonyl-2-20 (4-trifluoromethoxyanilino) ethyl p-toluenesulfonate, melting at 88 ° C.

2- (4-Trifluoromethoxyanilino) ethanol can be prepared as follows: 88.5 g of 4-trifluoromethoxyaniline and 31.2 g of 2-bromoethanol are heated at 160 ° C for 1.5 hours. After cooling to about 20 [deg.] C., the reaction mixture is extracted with 200 cm <3> of dichloromethane, the insoluble matter is filtered off and the filtrate is concentrated to dryness under reduced pressure. After purification by silica gel column chromatography using a mixture of ethyl acetate and cyclohexane (40-60 by volume) as the eluent, 26.8 g of 2- (4-trifluoromethoxyanilino) ethanol are obtained in the form of an orange oil.

Example 15

Proceed as in Example 1, but starting from 0.6 g of 3- {2- [4- (2-fluorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6 -trifluoromethoxy-benzothiazoline, 20 cm3 of methanol and 10 cm3 of 7% aqueous potassium carbonate solution. Addition of 4.2 N hydrochloric acid ether gives 0.335 g of 2-imino-3-5 {2- [4- (2-fluorophenyl) piperazin-1-yl] ethyl} -6-trifluoromethoxybenzothiazoline, m.p. about 260 ° C. :in.

3- {2- [4- (2-fluorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazole-10 can be prepared as follows: as in Example 1, 3- - [4- (2-Pyridyl) -piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline starting from 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3 -15 benzothiazolinyl) ethyl methanesulfonate in 70 cm 3 of toluene and 9 g of 4- (2-fluorophenyl) piperazine. After silica gel column chromatography using ethyl acetate as eluent, 0.6 g of 3- {2- [4- (2-fluorophenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-20 trifluoromethoxybenzothiazoline is obtained.

Example 16

Proceed as in Example 1, starting from 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulphonate in 120 cm3 of toluene and 7.8 g of 4- (3-chlorophenyl) piperazine. nia. After heating for 2 hours under a vertical condenser, the toluene filtrate is evaporated off under reduced pressure and 100 cm3 of methanol and 10 cm3 of 7% aqueous potassium carbonate solution are added to the residue of the toluene solution. The mixture 30 is stirred at about 20 ° C. The methanol is evaporated off under reduced pressure and the residue is purified by column chromatography on silica gel, eluting first with a mixture of dichloromethane and methanol (95-5 by volume) and then with ethyl acetate. Addition of 4.2 N hydrochloric acid ether-35 gives 0.9 g of 2-imino-3- {2- [4- (3-chlorophenyl) piperidine 23 93109 racin-1-yl] ethyl} -6 -trifluoromethoxybenzothiazoline trihydrochloride, melting at about 260 ° C.

Example 17

Make as in Example 1, starting from 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulphonate in 120 cm3 of toluene and 6.7 g of 4- (3-fluorophenyl) ) piperazine-ketone. After heating for 2 hours under a condenser, the toluene filtrate is evaporated off under reduced pressure and 100 cm3 of methanol and 20 cm3 of 7% aqueous potassium carbonate solution are added to the residue of the toluene-10 solution. After stirring for 2 hours at about 20 [deg.] C., the methanol is evaporated off under reduced pressure and the residue is purified by column chromatography on silica gel, eluting first with a mixture of dichloromethane and methanol (98-2 by volume) and then with ethyl acetate. Addition of 4.2 N hydrochloric acid ether gives 1 g of 2-imino-3- {2- [4- (3-fluorophenyl) piperazin-1-yl] ethyl} -6-trifluoromethoxybenzothiazoline trihydrochloride, melting at about 270 ° C.

20 Example 18

Proceed as in Example 1, but starting from 1.8 g of 3- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in 39 cm 3. methanol and 23 cm3 of a 7% aqueous-alcoholic solution of potassium carbonate. After silica gel column chromatography using acetone as eluent and after addition of 4.2 N hydrochloric acid ether, 1.2 g of 2-imino-3- {2- [4- (2-methoxyphenyl) piperazin-1-yl] are obtained. ethyl} -6-trifluoromethoxy-30-benzothiaziazoline trihydrochloride, melting at about 210 ° C.

3- C 2- [4- (2-Methoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxy-benzothiazoline hydrochloride can be prepared as follows: as in Example 1 using starting material 93109 24 g 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl methanesulfonate in 120 cm 3 of toluene and 7.7 g of 4- (3-methoxyphenyl) piperazine. After addition of 4.2 N hydrochloric acid ether, 1.8 g of 3- {2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl} -2-trifluoroacetylimino-6-trifluoromethoxy are obtained. -benzothiazoline hydrochloride, melting at 230 ° C.

The pharmaceutical preparations contain one compound of the general formula (I) or a salt of such a compound, neat or in admixture with a pharmaceutically acceptable compound, which may be physiologically active or inert. These preparations can be used orally parenteraalises-ti, rectally or topically.

Tablets, pills, powders (gelatin capsules, capsules) or granules can be used as solid preparations for oral administration. In these preparations, the active ingredient of the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica.

The preparations may contain substances other than diluents, for example one or more lubricants,. such as magnesium stearate or talc, colorant, coating (coated pills) or varnish.

Liquid preparations for oral administration include solutions, suspensions, emulsions, pharmaceutically acceptable syrups, or medicated syrups containing inert diluents, such as water, ethanol, glycerol, vegetable oil, or paraffin oil. These preparations may contain substances other than diluents, for example, foaming agents, sweetening, thickening, flavoring or preservative agents.

11 <25 93109

Sterile preparations for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, can be used as solvent or carrier. These preparations may also contain adjuvants, especially foaming agents, isotonizing agents, emulsifying agents, dispersing agents or preservatives. Sterilization can be accomplished in a number of ways, for example, by aseptic filtration, by the addition of sterilizing agents, irradiation, or heating. They may also be prepared as solid sterile preparations which are dissolved in sterile water or other sterile injectable solution at the time of use.

suitable for rectal administration are suppositories, preparations or rectal capsules, which contain in addition to the active substance, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycol-20.

Formulations suitable for topical administration may include, for example, ointments, lotions, lotions, eye creams, mouthwashes, nasal drops or aerosols.

In human medicine, the medicaments of this invention are particularly useful in the treatment or prevention of seizures, schizophrenia disorders, and in particular in the treatment of schizophrenia insufficiency, sleep disorders, cerebral ischemic events, and in the treatment of neurological diseases such as Alzheimer's disease. Huntington's disease, lateral amyotrophic sclerosis or olivo-Ponto-cerebellum atrophy.

Doses depend on the subject, the duration of treatment and the route of administration; they are usually 30 to 300 mg 26 9 3 1 09 per day in an adult at single doses of 10 to 100 mg of active ingredient.

In general, the physician will determine the dosage he or she deems appropriate based on the age, weight, and other factors being treated.

The following examples illustrate the preparations of the invention:

Example A

Gelatin-10 capsules containing 50 mg of the active ingredient and having the following composition are prepared by conventional techniques: 2-imino-3- {2- [4- (2-pyridyl) piperazin-1-yl) ethyl] -6-trifluoromethoxybenzoic acid. thiazoline .................................. 50 mg 15 cellulose ............ ...................... 18 mg of lactose ......................... ........... 55 mg colloidal silica ...................... 1 mg sodium carboxymethyl starch .......... ..10 mg of talc ...................................... 10 mg of 20 magnesium stearate ... ....................... 1 mg

Example B

Tablets containing 50 mg of the active ingredient and having the following composition are prepared by conventional techniques: · 2-Imino-3- {2- [4- (4-methylphenyl) piperazin-1-yl) ethyl] -6-trifluoromethoxybenzoic acid. thiazoline ................................. 50 mg lactose ............. ...................... 104 mg of cellulose ......................... ......... 40 mg 30 Polyvidone .................................. 10 mg ' sodium carboxymethyl starch ............ 22 mg of talc .................................. .... 10 mg of magnesium stearate .......................... 2 mg of colloidal silica ............. ......... 2 mg

II

27 931 09 tablets weigh 245 mg.

Example c

Prepare an injectable solution containing 10 mg of the active substance and having the following composition: 3- [2- (4-benzylpiperazin-1-yl) ethyl] -2-imino-6-trifluoromethoxybenzothiazoline ....... ....... 10 mg benzoic acid .............................. 80 mg benzyl alcohol ....... ................... 0.06 cm3 10 sodium benzoate ........................ 80 mg of 95% ethanol ................................ 0.4 cm3 of sodium hydroxide ......... ................ 24 mg of propylene glycol .......................... 1.6 cm3 of water ad .................................... 4 cm3 15

The following tables show the results of comparative experiments comparing the compounds of the invention with 2-amino-6-trifluoromethoxybenzothiazole known from EP 50 551 and EP 282 971. The experiments examined the pharmacological activity (effect on glutamate-induced seizures) and toxicity of the compounds. The results show that all the compounds of the invention (except the compound of Example 14) are less,. toxic than the prior art compound and that the compound of Example 14 is significantly more active than the known compound.

m 93109 28

Pharmacological activity

Test compounds DEJ0 (mg / kg)

Compound 5 of the invention Example 14 3

Known compound (EP 50 551, EP 282971) 3.6

Toxicity 10 Test compounds DLS0 (mg / kg)

A compound of the invention

Example 1 57 2 non-toxic in 160 3 non-toxic in 160 15 4 73 5 73 6 55 7 over 80 8 non-toxic in 40 20 9 130. * 10 60 11 non-toxic in 40 12 65 13 non-toxic in 40 25 15 73 16 130: 17 120 18 60

Known compound 30 (EP 50 551, EP 282971) 36

Claims (2)

29 9 3 1 09 A process for the preparation of compounds of formula (I) which are useful as medicaments and their salts with inorganic or organic acids, R 2 - (Δ ^ = NH 10 (I) \ tCH 2) n - * i wherein R 1 represents 15 piperazine-1 a -yl radical substituted in the 4-position by a) a phenyl radical, (b) a phenyl radical substituted by at least one substituent which is a halogen atom or an alkyl or alkoxy radical, (c) a phenylalkyl radical, (d) a pyridyl radical or pyrimidinyl radical, 1,2,3,6-tetrahydro-1-pyridyl substituted in the 4-position by a phenyl radical or a phenyl radical substituted by at least one substituent. 1a, which is a halogen atom or an alkyl or alkoxy radical, a piperidino radical substituted in the 4-position by a phenyl radical or a phenyl radical substituted by at least one substituent which is a halogen atom or an alkyl or alkoxy radical, •: '30 r2 represents a polyfluoroalkoxy radical, n is 2 or 3, wherein the alkyl and alkoxy radicals and the alkyl and alkoxy moieties contain 1 to 4 carbon atoms in a straight-chain or branched manner, characterized in that: 92 929 A - hydrolyzing a derivative of the formula: * 2- > = N-COCl 3 (CH) -R 1 n where R 1, R 2 and n are as defined above, isolate the compound and optionally convert it into an acid addition salt with an inorganic or organic acid, B - react the bromine and alkali metal thiocyanate with a derivative which the formula is: 15 R - R2 I | (VII) wherein R 1, R 2 and n are as defined above, isolating the compound and optionally converting it to an acid addition salt with an inorganic or organic acid. Process according to Claim 1, characterized in that the compound of formula (I) is prepared. a compound in which R2 represents a trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy radical. ♦ li 93109