SK278908B6 - 2-imino-3-heterocyclylalkyl benzothiazoline derivatives, a method for producing same and pharmaceutical composition containing said compounds - Google Patents

Abstract

This patent describes compounds with a general formula (I), where R1 means 1-piperazinyl group 1,2,3,6-tetrahydro-1-pyridyl group or piperidine group, while all of these groups can be substituted by substituents defined in the description part, R2 means polyfluoroalkoxy group and n means 2 or 3 and their addition salts with inorganic or organic acids. The description related to the procedure of the production closed to these compounds, together with an application of them playing role of the active compound closed to the pharmaceutical composition.

Description

Technical field

The present invention relates to 2-imino-3-heterocyclylalkylbenzothiazoline derivatives, a process for the preparation of these compounds and their use as active ingredients of medicaments.

BACKGROUND OF THE INVENTION

European patent specification EP 50551 describes compounds which may be referred to as related

2-amino-6-trifluoromethoxybenzothiazoles having anticonvulsant, anxiolytic and hypnotic effects.

SUMMARY OF THE INVENTION

The present invention provides 2-imino-3-heterocyclylalkylbenzothiazoline derivatives of formula (I),

I (CH) - R ¹ wherein

R ¹ is 1-piperazinyl substituted in the 4

a) a phenyl group,

b) a phenyl group substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups;

c) a phenylalkyl group

(d) a pyridyl group; or

e) a pyrimidinyl group, furthermore a 1,2,3,6-tetrahydro-1-pyridyl group substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups further represents a piperidino group which is substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups,

R ² represents a polyfluoroalkoxy, n is 2 or 3, and their salts, which have valuable pharmacological properties.

The alkyl groups and alkoxy groups as defined and hereinafter as well as the alkyl and alkoxy moieties contain 1 to 4 carbon atoms in the straight or branched chain.

Polyfluoroalkoxy is preferably trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy.

Halogen atoms are preferably fluorine, chlorine and bromine atoms. The invention also relates to addition salts of the compounds of formula (I) with mineral acids or organic acids.

Compounds of formula (I) may be prepared by hydrolysis of compounds of formula (II),

I (CH 2) —R ¹ wherein

R ¹ , R ² and n have the meanings given in formula (I).

Said hydrolysis is usually carried out by treatment with a base, such as an alkali metal carbonate, preferably sodium carbonate or potassium carbonate, or concentrated ammonia, in a mixture of water and alcohol, at a temperature of about 20 ° C.

Compounds of formula (II) may be obtained by reaction of a compound of formula (III),

in which

R ^{2 and} n are as defined in formula (I) and

R ³ is a reactive group such as methanesulfonyl or p-toluenesulfonyl, and the amine of formula (IV),

NHR ¹ (IV) wherein

R ¹ has the same meanings as under formula (I).

This reaction is usually carried out in an inert solvent such as an aromatic solvent, for example benzene, toluene, xylene or dimethylformamide, at temperatures between 20 ° C and the boiling point of the solvent.

Compounds of formula (III) may be prepared by reacting a compound of formula (V),

(V) (PHs) —OH in which

R ^{2 and} n are as defined in formula (I), methanesulfonyl chloride or p-toluenesulfonyl chloride, either in an inert solvent such as an aromatic hydrocarbon, e.g., benzene, toluene or xylene or in a chlorinated solvent such as chloroform, methylene chloride, in the presence of a tertiary amine such as triethylamine at a temperature of about 20 ° C, or in pyridine at a temperature of about 0 ° C.

Compounds of formula (V) may be obtained by reacting trifluoroacetic acid ethyl ester with a compound of formula (VI),

NH (VI) (CH 2 -OH in which

R ^{2 and} n are as defined in formula (I).

Said reaction is usually carried out in an alcohol such as methanol or ethanol in the presence of a tertiary base such as triethylamine at a temperature of about 20 ° C.

Compounds of formula (VI) may be prepared by reaction of a halogen derivative of formula (VII),

SK 278908-6

Hal - (CH ₂ ) n -OH (VII) wherein n is as defined in formula (I) a

Hal represents a halogen atom, preferably a bromine atom or a chlorine atom, with 2-amino-6-polyfluoroalkoxybenzothiazole.

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

2-Amino-6-polufluoroalkoxybenzothiazoles can be prepared using or adapting the method of L. M. Yaupolskii et al., J. Obsc. Chimii, 33 (7), 2301 (1963).

Compounds of formula (I) may also be prepared by reacting bromine and an alkali metal thiocyanate with a compound of formula (VIII),

(VIIII in which

R ¹ , R ² and n have the meanings given in formula (I).

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

The alkali metal thiocyanate is preferably potassium thiocyanate.

Compounds of formula (VIII) may be obtained by reacting an amine of formula (IV) with a compound of formula (IX),

The compounds of formula (I) in the free base form can optionally be converted into addition salts with inorganic or organic acids by treatment with an acid in an organic solvent such as an alcohol, acetone, ether or a chlorinated hydrocarbon.

The compounds of formula (I) and their salts possess interesting pharmacological properties. These compounds act against glutamate-induced seizures and can therefore be used for the treatment or prevention of convulsive conditions, schizophrenic conditions, and especially deficient forms of schizophrenia, sleep disorders, conditions associated with cerebral ischemia, as well as neurological disorders associated with the presence glutamate such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis such as olivopontocerebellam atrophy.

The activity of the compounds of formula (I) on glutamate-induced seizures was determined by the modified method of IP Lapin, J. Neural. Transmission, Vol. 54, 229-238 (1982), the injection of glutamate is administered by the intracerebroventricular route by a modified technique described by R. Chermat and P. Simon, J. Pharmacol (Paris), Vol. 6, 489-492 (1975). Their DE ₅₀ is usually less than 10 mg / kg, as shown in the table below.

Table Compound of Example ED ₅₀ (mg / kg)

in which

R ² and n have the same meanings as in formula (I) and R ⁴ and R ⁵ represent a p-toluenesulfonyl group.

This reaction is preferably carried out in the presence of sodium bicarbonate, in an inert solvent such as dimethylformamide, at a temperature ranging between 50 ° C and 100 ° C.

Compounds of formula (IX) may be obtained by treating p-toluenesulfonic acid chloride with a compound of formula (X),

NH- (CH 2) -OH (X)

1 3 2 10 3 4.6 4 10 5 8.3 6 10 7 10 8 2.2 9 3.5 10 2.5 11 3.8 12 2.3 13 5 14 3 15 6.3 16 10 17 8.5 18 3.2

in which

R ² and n have the same meanings as under formula I.

This reaction is usually carried out in an inert solvent such as a chlorinated solvent, for example chloroform, methylene chloride, at a temperature between 0 ° C and 30 ° C.

Compounds of formula (X) may be obtained by reacting 4-polyfluoroalkoxyaniline with a compound of formula (VII). This reaction is usually performed at temperatures between 100 ° C and 170 ° C.

The reaction mixtures obtained by the various processes described are then worked up by classical physical methods (evaporation, extraction, distillation, crystallization, chromatography, etc.) or by chemical methods (salt formation, etc.).

The compounds of formula (I) exhibit low toxicity. Their DL _{5 ()} is greater than 15 mg / kg in the mouse when ip is applied.

For medical use, the compound of formula (I) may be ingested alone or in the form of pharmaceutically acceptable salts, i. j. salts which are not toxic at the doses administered.

Examples of pharmaceutically acceptable salts include addition salts with inorganic or organic acids such as acetates, propionates, succinates, benzoates, fumarates, maleates, oxalates, methanesulfonates, isothionates, theophylacetates, salicillates, phenolphthalinates; methylenebis-beta-oxynaphioates, hydrochlorides, sulfates, nitrates and phosphates.

The following examples illustrate the invention but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1.3 g of 3- / 2- [4- (2-pyridyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzotazoline dissolved in a mixture of 19 ml of 7% aqueous potassium carbonate solution and 32 ml of methanol are stirred at at about 20 ° C for 4 hours. The reaction mixture is then concentrated under reduced pressure (2.7 kPa) and the residue is taken up in 300 ml of distilled water. The aqueous phase is extracted three times with 200 ml of diethyl ether each time, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using acetone as eluent. After conversion to trihydrochloride by addition of 4.2 N ethereal hydrogen chloride in acetone, 0.73 g of 2-imino-3- / 2- (4- (2-pyridyl) -1-piperazinyl) ethyl) -6-trifluoromethoxybenzotazoline trihydrochloride is obtained with 230 ° C.

3- / 2- [4- (2-pyridyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzotazole can be prepared by the following procedure:

A mixture of 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 100 ml of toluene and 6.9 g of (2-pyridyl) piperazine is heated under reflux for 2 hours, then The reaction mixture was cooled to 4 ° C and centrifuged. The toluene filtrate was evaporated under reduced pressure and the residue thus obtained was purified by silica gel column chromatography using dichloromethane as eluent. 1.3 g of 3- [2- [4- (2-pyridyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzotazoline, m.p. 132 DEG C., are obtained.

Methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester can be prepared as follows:

6.9 g of triethylamine are added sequentially to a mixture of 120 ml of methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinylethanol), after stirring for 1 hour at about 20 ° C. The reaction mixture is cooled to 10 ° C, filtered, washed with 20 ml of cooled methylene chloride and dried at 40 ° C under reduced pressure to give 10 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester with m.p. 145 DEG C. A second crop of 2.7 g of product is obtained by washing with 100 ml of water, drying over magnesium sulphate, concentrating to a volume of 50 ml, cooling to 5 DEG C. and centrifuging.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinylethanol may be prepared as follows:

20.7 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyljetanol hydrobromide), 9.8 g of trifluoroacetic acid ethyl ester and 16.1 ml of triethylamine are stirred in 100 ml of ethanol for 22 hours at a temperature of about 20 ° C. evaporation to dryness under reduced pressure, the residue thus obtained is purified by silica gel column chromatography eluting with ethyl acetate to give 19.2 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol, m.p. 144 ° C. .

2- (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol can be prepared by the following procedure:

9.4 g of 2-amino-6-trifluoromethoxybenzothiazole and 10 g of bromoethanol in 30 ml of absolute ethanol are heated at reflux for 95 hours. The reaction mixture is then cooled to about 20 ° C. The precipitate formed is filtered off and washed with 100 ml of diethyl ether. 6.4 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinylethanol hydrobromide, m.p. 219 DEG C.) are obtained.

2-Amino-6-trifluoromethoxybenzothiazole can be prepared by the method of L. M. Yagupolskii et al., J. Chimii 33 (7), 2301 (1963).

Example 2

Using the procedure described in Example I, but using 0.9 g

3- [2- [4- (4-methylphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline in 18 ml of methanol and 14 ml of a 7% solution of potassium carbonate in aqueous alcohol gives 0.7 g of 2 -imino-3- / 2- [4- (4-methylphenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline, m.p. 120 ° C.

- [2- [4- (4-Methylphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows:

The procedure is as in Example 1, but using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 150 ml of toluene and 5.29 g of 4- (4-methylphenyl) piperazine. Purification on a silica gel column using dichloromethane / ethyl acetate 98: 2 (v / v) as eluent gave 0.9 g of 3- / 2- [4- (4-methylphenyl) -1-piperazinyl] -1,2-trifluoroacetylimino-6-yl. -trifluórmetoxybenzotiazolínu.

Example 3

The procedure is as in Example 1, but using 5.88 g

Methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 200 ml of toluene and 6.87 g of 4- (2-methylphenyl) piperazine After 2 hours under reflux, the mixture is filtered and the toluene filtrate is filtered. To the residue thus obtained, 100 ml of methanol and 20 ml of a 7% solution of potassium carbonate in aqueous alcohol are added and the mixture is stirred for 2 hours at a temperature of about 20 DEG C. The alcohol is evaporated under reduced pressure and the residue is chromatographed Silica gel column, eluting with dichloromethane: ethyl acetate (30: 30) and then with ethyl acetate / cyclohexane (50:50) to give 1.8 g of 2-imino-3- / 2- [4- (2-methylphenyl) -1-piperazinyl] ethyl) -6-trifluoromethoxybenzothiazoline, m.p. 135 ° C.

Example 4

The procedure is as in Example 1, but using 3.8 g of 3- [2- (4-benzyl-1-piperazinyl) ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline] in 20 ml of methanol and 10 ml of a 7% solution. potassium carbonate in aqueous alcohol. After chromatographic purification on a silica gel column using a 50:50 mixture of ethyl acetate and cyclohexane as eluent, a 4.2 N ethereal hydrogen chloride solution is added. 2.5 g of 3- [2- (4-benzyl-1-piperazinyl) ethyl] -2-imino-6-trifluoromethoxybenzothiazoline hydrochloride, m.p. 230 DEG C., are obtained.

3- [2- (4-Benzyl-1-piperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows:

Proceed as in Example 1, using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 120 ml of toluene and 7 g of 4-benzylpiperazine, after chromatography on a silica gel column using dichloromethane / ethyl acetate.

The amount of lacetate in the ratio 50:50 as eluent is obtained

3.8 g of 3- [2- (4-benzyl-1-piperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline.

Example 5

Proceed as in Example 1 using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 150 ml of toluene and

6.5 g of 4- (2-pyrimidinyl) piperazine. The reaction mixture is heated at reflux for 4 hours and after filtration the toluene filtrate is evaporated under reduced pressure. 100 ml of methanol and 20 ml of a 7% solution of potassium carbonate in aqueous alcohol are added to the toluene residue. After stirring at about 20 ° C for 2 hours, the methanol was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using a 90/10 mixture of dichloromethane and methanol as eluent. The obtained compound is converted to the trihydrochloride by addition of a 4.2 N ethereal hydrogen chloride solution. 1.13 g of 2-imino-3- [2- [4- (2-pyrimidinyl) -1-piperazinyl-ethyl] - 6-trifluoromethoxybenzothiazoline trihydrochloride, m.p. 270 ^DEG C., are obtained.

Example 6

3.6 g of a solution of 3- [3- (4-phenyl-1-piperazinyl) propyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in a mixture of 45 ml of 7% aqueous potassium carbonate solution and 150 ml of methanol are stirred for 4 hours at at about 20 ° C. After concentrating the reaction mixture to dryness, the residue is taken up in 100 ml of distilled water and the organic phase is extracted twice with 100 ml of ethyl acetate each time, the ethyl acetate extract is dried over magnesium sulphate and then concentrated under reduced pressure (2.7 kPa). After formation of the dihydrochloride by addition of 4 ml of a 4.2 N solution of ethereal hydrogen chloride in ethyl acetate, the precipitate formed is recrystallized from a 50:50 (v / v) mixture of absolute ethanol and diethyl ether. 1.6 g of 2-imino-3- [3- (4-phenyl-1-piperazinyl) propyl] -6-trifluoromethoxybenzothiazoline dihydrochloride, m.p. 260 DEG C., are obtained.

3- [3- (4-Phenyl-1-piperazinyl) propyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared by the following procedure:

4.4 g of p-toluenesulfonic acid 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propyl ester, 1.44 g of N-phenylpiperazine and 0.68 g of sodium bicarbonate in 50 ml of dimethylformamide are heated at 80 ° C for 19 hours. The reaction mixture is then concentrated to dryness under reduced pressure (0.95 kPa), the evaporation residue is taken up, 100 ml of water (distilled) and the organic phase is extracted with 50 ml of dichloromethane, dried over magnesium sulphate and concentrated to a residue. Dry under reduced pressure, 15 ml of a 1N aqueous hydrochloric acid solution are added to the oily residue obtained, and the hydrochloride formed is eliminated by adding 15 ml of distilled water to give 4.0 g of 3- [3- (4-phenyl-piperazinyl) - hydrochloride. propyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, mp 238 ° C.

3- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propyl p-toluenesulfonic acid ester can be prepared by the following procedure:

g of 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propanol is gradually added to the solution

10.8 g of p-toluenesulfonyl chloride in 200 ml of pyridine, cooled to 0 ° C. The reaction is continued for 1 hour at 5 ° C, then the reaction mixture is kept at 6 to 7 ° C by cooling for 15 hours. After addition of 2 liters of distilled water, the mixture is extracted with 200 ml of ethyl acetate, the ethyl acetate extract is washed twice with 50 ml of 1 N hydrochloric acid each, dried over magnesium sulfate and concentrated under reduced pressure. 6.7 g of p-toluenesulfonic acid 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propyl ester are obtained, m.p. 139 ° C.

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 trifluoroacetic acid ethyl ester and 8.6 g of triethylamine are stirred in 250 ml of absolute ethanol for 24 hours at a temperature of about 20 ° C. The mixture is then cooled to 0-5 [deg.] C. and the precipitate formed is filtered off and dried. There was obtained 28.2 g of 3- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) propanol, m.p. 144 ° C.

3- (2-Imino-6-trifluoromethoxy-3-benzothiazolinyl) propanol can be prepared as follows:

g of 2-amino-6-trifluoromethoxybenzothiazole and 65 ml of 3-bromopropanol in 25 ml of absolute ethanol are heated at reflux for 72 hours. The reaction mixture is then cooled to about 20 ° C. The oil obtained is then taken up with 1 liter of distilled water and the organic phase is extracted three times with 200 ml of dichloromethane each time. After drying over magnesium sulfate and concentrating the filtrate to dryness under reduced pressure, the crude product is purified by silica gel column chromatography using ethyl acetate as eluent. 25 g of 3- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) propanol, m.p. 106 DEG C., are obtained.

Example 7

Proceed as in Example 1 but using 1 g of 3- [2- [4- (m-tolyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline in 30 ml of methanol and 15 ml of 7% solution potassium carbonate in aqueous alcohol. After chromatography on a silica gel column using a 50:50 mixture of ethyl acetate and cyclohexane as eluent, a 4.2 N ethereal hydrogen chloride solution is added to the eluate. 0.6 g of 2-imino-3- [2- [4- (m-tolyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline hydrochloride is obtained, m.p.

3- / 2- [4- (N-tolyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows:

proceed as in Example 1 using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 150 ml of toluene and 5.29 g of 4- (3-methylphenyl) piperazine. Purification by chromatography on a silica gel column using a 70/30 mixture of dichloromethane and ethyl acetate as eluent gave 1 g of 3- [2- [4- (m-tolyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino- 6-trifIuórmetoxybenzotiazolínu.

Example 8

To a mixture of 2.62 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] 1,2,3,6-tetrahydropyridine and 2.8 g of potassium thiocyanate in 50 ml of acetic acid is added dropwise a solution of 1. 15 g of bromine in 15 ml of acetic acid at a temperature of about 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-trifluoromethoxybenzothiazoline dihydrochloride, m.p. 256 DEG C., is obtained. .

4-Phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] -1,2,3,6-tetrahydropyridine can be prepared as follows:

A mixture of 5.56 g of p-tolulenesulfonic acid Np-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl ester, 1.84 g of 4-phenyl-1,2,3,6-tetrahydropyridine and 0.97 g of sodium bicarbonate in 95 ml of dimethylformamide is heated. After 18 hours at 80 [deg.] C. 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 oily product which is is used alone for further reactions.

6-Toluenesulfonic acid N-p-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl ester can be prepared as follows:

5.0 g of 2- (4-trifluoromethoxyanilino) ethanol and 6.35 ml of triethylamine in 50 ml of dichloromethane cooled to 0 DEG C. are added sequentially to 8.6 g of p-tolulenesulfonyl chloride. The reaction is allowed to proceed for 2 hours at approximately 20 ° C, after which the reaction mixture is washed three times with 50 ml of distilled water each time, the organic phase is dried over magnesium sulphate and the filtrate is concentrated under reduced pressure (2.7 kPa). After addition of 50 ml of absolute ethanol, the precipitate formed is filtered off. 7.3 g of p-toluenesulfonic acid N-p-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl ester of melting point 88 DEG C. are obtained.

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 the reaction mixture to about 20 ° C, the reaction mixture is taken up in 200 ml of dichloromethane, the insolubles are filtered off and the filtrate is concentrated under reduced pressure. Purification by chromatography on a silica gel column using a 40/60 mixture of ethyl acetate and cyclohexane as eluent gave 26.8 g of 2- (4-trifluoromethoxyanilino) ethanol as an orange oil.

Example 9

1.1 g of 3- [2- (4-phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride dissolved in a mixture of 5 ml of 7% aqueous potassium carbonate solution and 100 ml of methanol are stirred at about 20 ° C for 5 hours. hours. The reaction mixture is then added to 200 ml of distilled water and the organic phase is extracted three times with 150 ml of diethyl ether each time, the ether extract is dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). Addition of 0.45 ml of a 4.2 N ethereal hydrogen chloride solution in 30 ml of ethyl acetate forms the hydrochloride. 0.8 g of 2-imino-3- [2- (4-phenylpiperazinyl) ethyl] -6-trifluoromethoxybenzothiazoline hydrochloride, m.p. 230 DEG C., is obtained.

3- [2- (4-Phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

6.5 g of p-toluenesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester, 2.2 g of N-phenylpiperazine and 1.0 g of sodium bicarbonate in 80 ml of dimethylformamide are heated at 60 ° C for 19 hours. Thereafter, 300 ml of distilled water are added to the reaction mixture, and the organic phase is extracted three times with 50 ml of dichloromethane each time, dried over magnesium sulphate and concentrated under reduced pressure, to the oily residue is added 20 ml of 1N hydrochloric acid solution. 20 ml of ethanol are obtained, yielding 1.1 g of 3- [2- (4-phenylpiperazinyl) ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride, m.p. 204 ° C.

P-Toluenesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester can be prepared as follows:

19.3 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinylethanol) are gradually added to a solution of 19.7 g of p-toluenesulfonyl chloride in 120 ml of pyridine cooled to 0 DEG C. The reaction is allowed to proceed for 1 hour at The reaction mixture is added to 500 ml of distilled water, the organic phase is extracted three times with 100 ml of dichloromethane each time, washed twice with 50 ml of 1 N hydrochloric acid solution, then twice with 50 ml of distilled water, dried over magnesium sulfate and dried. concentration under reduced pressure (2.7 kPa) gave 14.1 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol, m.p. 143 ° C.

2- (2-Trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinylethanol can be prepared as follows:

20.7 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyljetanol hydrobromide), 9.8 g of trifluoroacetic acid ethyl ester and 16.1 ml of triethylamine are stirred in 100 ml of ethanol for 22 hours at a temperature of about 20 ° C. Concentration in vacuo afforded the residue was purified by silica gel column chromatography using ethyl acetate as eluent to give 19.2 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol, m.p. 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-bromoethanol in 30 ml of absolute ethanol are heated to boiling for 95 hours. The reaction mixture is then cooled to about 20 ° C. The precipitate formed is filtered off and washed with 100 ml of diethyl ether. 6.4 g of 2- (2-imino-6-trifluoromethoxy-3-benzothiazolinyl) ethanol hydrobromide, m.p. 219 DEG C., are obtained. 2-Amino-6-trifluoromethoxybenzothiazole can be prepared by the method described by L. M. Yagupolskii et al., J. Shimshii, 33 (7), 2301 (1963).

Example 10

1.53 g of 3- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride, 33 ml of methanol and 21 ml of 7% potassium carbonate solution in 2 vol. parts of methanol and 5 vol. parts of water are stirred for 4 hours at about 20 ° C. The reaction mixture was then concentrated under reduced pressure and then extracted with ether. The organic phase is dried over magnesium sulphate and then treated with an excess of an alcoholic hydrogen chloride solution. The precipitate formed is filtered off, washed with ether and dried at 50 DEG C. under reduced pressure (2.7 kPa). 1.05 g of 2-imino-3- [2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline trihydrochloride, m.p. 240 DEG C., is obtained.

3- / 2- [4- (4-Methoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

A mixture of 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester, 120 ml of toluene and the free base liberated from 10.56 g of 4-p-methoxyphenylpiperazine dihydrochloride is heated under reflux for 1 hour. condenser, then cooled to 4 ° C and filtered. The toluene filtrate was evaporated under reduced pressure and then 45 ml of a 1.2 N aqueous hydrochloric acid solution was added. The hydrochloride precipitates as an amorphous product, which is then crystallized by trituration with 50 ml of ethanol. Filtration, washing with 15 ml of ethanol and drying at 50 ° C under reduced pressure (2.7 kPa) gave 1.7 g of 3- / 2- [4- (4-methoxyphenyl) -1-piperazinyl] ethyl hydrochloride / 2-trifluóracctylimino-6-trifluoromethoxybenzothiazoline.

Methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester can be prepared by the following procedure:

6.9 g of triethylamine are added successively to a mixture of 120 ml of methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazalinylethanol). The reaction mixture is cooled to 10 ° C, filtered, the product is washed with 20 ml of cooled methylene chloride and dried under reduced pressure at 40 ° C to give 10 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester. 145 DEG C. Another 2.7 g product is obtained by washing the filtrate with 100 ml of water, drying over magnesium sulphate, concentrating to a volume of 50 ml, cooling to 5 DEG C. and then filtering off.

Example 11

The procedure is as in Example 9 but using 1.4 g of 3- [2- [4- (3,4-dimethoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in 30 ml of methanol and 19 ml of a 7% solution of potassium carbonate in aqueous alcohol. 0.97 g of 2-imino-3- [2- [4- (3,4-dimethoxyphenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline trihydrochloride, m.p. 250 DEG C., is obtained.

3- [2- [4- (3,4-Dimethoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

The procedure is as in Example 9, but using 4.3 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester, 70 ml of toluene and a base released from 14 g of 4- (3,4-dimethoxyphenyl) piperazine dihydrochloride. 1.45 g of the desired hydrochloride of melting point 260 DEG C. is obtained.

Example 12

The procedure is as in Example 9 but using 1.7 g of 3- [2- [4- (4-fluorophenyl) -1-piperazinyl-ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride, 36 ml of methanol and 21 ml of 7 % solution of potassium carbonate in aqueous methanol. 3- [2- [4- (4-Fluorophenyl) -1-piperazinyl] ethyl] -2-imino-6-trifluoromethoxybenzothiazoline dihydrochloride, m.p. 260 [deg.] C.

3- / 2- [4- (4-Fluorophenyl) -1-piperazinyl-ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

The procedure is as in Example 9, but using 9 g of 4- (4-fluorophenyl) piperazine, 70 ml of toluene and 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester. 7 g of product, m.p. 240 ° C.

Example 13

Proceed as in Example 9, but using 1.4 g of 3- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, 30 ml of methanol and 19 ml of 7. % solution of potassium carbonate in aqueous methanol. 0.9 g of 3- [2- [4- (4-chlorophenyl) -1-piperazinyl] ethyl] -2-imino-6-trifluoromethoxybenzothiazoline dihydrochloride, m.p. 270 DEG C., is obtained. 3- / 2- [4- (4-Chlorophenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows:

A mixture of 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester, 70 ml of toluene and a base released from 13.45 g of 4- (4-chlorophenyl) piperazine dihydrochloride is heated for 1 hour and 15 minutes to reflux. After cooling the reaction mixture to 10 ° C, the precipitate formed is filtered off, the toluene filtrate is concentrated and then purified by chromatography on a silica gel column using a 50:50 mixture of cyclohexane and ethyl acetate as eluent. Recrystallization from 50 ml of ethanol yielded 1.4 g of the product, m.p. 165 ° C.

Example 14

To 3.0 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] -piperidine and 3.2 g of potassium thiocyanate in 25 ml of acetic acid are added dropwise 1.3 g of bromine dissolved in 15 ml of acetic acid. at about 20 ° C. The reaction mixture is then kept at this temperature for 18 hours. 100 ml of distilled water are then added, the reaction mixture is neutralized with 30% sodium carbonate solution and the organic phase is extracted three times with 50 ml of ethyl acetate each time, the ethyl acetate extract is dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue thus obtained is purified by silica gel column chromatography using ethyl acetate as eluent. The product obtained is converted to the dihydrochloride by adding 4 ml of 4.2 N ethereal hydrogen chloride in 30 ml of ethyl acetate. 2.4 g of 2-imino-3- [2- (4-phenylpiperidino) ethyl] -6-trifluoromethoxybenzothiazoline dihydrochloride sublime at about 220 ° C are obtained.

4-Phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] piperidine can be prepared as follows:

A mixture of 7.2 g of p-toluenesulfonic acid Np-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl ester, 4.9 g of 4-phenylpiperazine and 2.4 g of sodium bicarbonate in 50 ml of dimethylformamide is heated at 80 DEG C. for 18 hours. The reaction mixture is concentrated under reduced pressure (0.95 kPa), the residue is washed twice with 30 ml of water and then dissolved in 50 ml of ethanol, and the ethanol solution is concentrated again under reduced pressure. 30 ml of hydrochloric acid (37%) in a mixture of 30 ml of acetic acid and 20 ml of distilled water are added, and the mixture is heated to boiling for 3 hours, cooled to about 20 ° C and 100 ml of distilled water added. The organic phase was extracted with ethyl acetate to give 4.0 g of 4-phenyl-1- [2- (4-trifluoromethoxyanilino) ethyl] piperidine as an oily crude product which was used for the next reaction. .

P-Toluenesulfonic acid N-p-toluenesulfonyl-2- (4-trifluoromethoxyanilino) ethyl ester can be prepared by the following procedure:

To 5.0 g of 2- (4-trifluoromethoxyanilino) ethanol and 6.35 ml of triethylamine in 50 ml of dichloromethane at 0 ° C was gradually added 8.6 g of p-toluenesulfonyl chloride. The reaction is allowed to proceed for 2 hours at approximately 20 ° C, then the reaction mixture is washed three times with 50 ml of distilled water each time and the organic phase is dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). After addition of 50 ml of absolute ethanol, the precipitate formed is filtered off. 7.3 g of N-p-toluenesulfonyl-2- (4-trifluoromethoxyamino) ethyl ester of p-toluenesulfonic acid of melting point 88 DEG C. are obtained.

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 approximately 20 ° C, the reaction mixture is taken up with 200 ml of dichloromethane, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. Purification by chromatography on a silica gel column using a 40/60 mixture of ethyl acetate and cyclohexane gives 26.8 g of 2- (4-trifluoromethoxyanilino) ethanol as an orange oil.

Example 15

The procedure is as in Example 1, but using 0.6 g of 3- [2- [4- (2-Fluorophenyl) -1-piperazinyl] ethyl] -2-trifluoroacetyl imino-6-trifluoromethoxybenzothiazoline, 20 ml of methanol and 10 ml of a 7% solution of potassium carbonate in aqueous alcohol. Addition of 4.2 N ethereal hydrogen chloride affords 0.335 g of 2-imino-3- [2- [4- (2-fluorophenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline dihydrochloride, m.p. 260 ° C.

3- / 2- [4- (2-Fluorophenyl) -1-piperazinyl] ethyl / -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared as follows:

Proceed as in Example 1 to prepare 3- / 2- (4- (2-pyridyl) -1-piperazinyl] ethyl) -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline using 4.52 g of 2- (2-trifluoroacetylimino-6). methanesulfonic acid-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 70 ml of toluene and 9 g of 4- (2-fluorophenyl) piperazine After chromatography on a silica gel column using ethyl acetate as eluent, 0.6 g of 3- / 2- [ 4- (2-fluorophenyl) piperazinyl] ethyl / 2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline.

Example 16

The procedure is as in Example 1, but using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 120 ml of toluene and 7.8 g of 4- (3-chlorophenyl) piperazine. After refluxing, the toluene filtrate is evaporated under reduced pressure and, after evaporation of toluene, 100 ml of methanol and 10 ml of a 7% solution of potassium carbonate in aqueous alcohol are added and the mixture is stirred at a temperature of about 20 DEG C. Methanol is evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a 95: 5 mixture of dichloromethane and methanol and then ethyl acetate as the eluent to give 0.9 g of 2-imino-3 trihydrochloride after addition of a 4.2 N ethereal hydrogen chloride solution. 2- [4- (3-chlorophenyl) -1-piperazinyl] ethyl-6-trifluoromethoxybenzothiazoline, m.p. 260 ° C.

Example 17

The procedure is as in Example 1, but using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 120 ml of toluene and 6.7 g of 4- (3-fluorophenyl) piperazine. After refluxing the reaction mixture for one hour, the toluene filtrate is evaporated under reduced pressure and after evaporation of toluene 100 ml of methanol and 20 ml of a 7% solution of potassium carbonate in aqueous alcohol are added. The residue was purified by silica gel column chromatography using a 98: 2 mixture of dichloromethane and methanol and then ethyl acetate as eluent to give 1 g of 2-imino-3- dihydrochloride (4.2 g). 2- [4- (3-fluorophenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline, m.p. 270 ° C.

Example 18

The procedure is as in Example 1 but using 1.8 g of 3- [2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in 39 ml of methanol and 23 ml Of a 7% solution of potassium carbonate in aqueous alcohol. Chromatographic purification on a silica gel column using acetone as eluent followed by addition of 4.2 N ethereal hydrogen chloride gave 1.2 g of 2-imino-3- / 2- [4- (2-methoxyphenyl) -1-piperazinyl trihydrochloride]. 1-ethyl] -6-trifluoromethoxybenzothiazoline, m.p. 210 ° C.

3- [2- [4- (2-Methoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

Proceed as in Example 1 using 4.52 g of methanesulfonic acid 2- (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) ethyl ester in 120 ml of toluene and

7.7 g of 4- (2-methoxyphenyl) piperazine. Addition of 4.2 N ethereal hydrogen chloride gives 1.8 g of 3- [2- [4- (2-methoxyphenyl) -1-piperazinyl] ethyl] -2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride, m.p. 230 DEG. C.

The invention also relates to medicaments consisting of a compound of formula (I) or a salt of such a compound alone or in the form of a mixture, wherein the active ingredient is contained together with another pharmaceutically compatible substance which may be either inert or physiologically active. The medicaments of the invention may be administered orally, parenterally, rectally or topically.

As solid preparations for oral administration, tablets, pills, powders, gelatin capsules or granules may be used. In these preparations, the active ingredient of the invention is admixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica.

These preparations may also contain substances other than a diluent, such as one or more glidants, such as magnesium stearate or talc, colorants, dragee coatings or lacquers.

Liquid preparations for oral administration may be solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These preparations may still contain other substances such as diluents, such as plasticizers, sweeteners, thickeners, flavors or stabilizers.

The sterile compositions for parenteral administration may preferably be sterile solutions of an aqueous or non-aqueous nature, a suspension or an emulsion. The carrier medium may be water, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, injectable organic esters, for example ethyl oleic acid ester and other suitable organic solvents.

These compositions may also contain adjuvants such as plasticizers, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization is carried out in several ways, for example by filtration by adding a sterilizing agent, followed by irradiation or heating. It is also possible to prepare solid sterile compositions for dilution with sterile water or other sterile injectable solvent immediately prior to use.

Preparations for reactive administration are suppositories and rectal capsules which contain, in addition to the active ingredient, cocoa butter, semisynthetic glycerides or polyethylene glycols as the vehicle.

For topical administration, for example, creams, ointments, lotions, collyria, colutoria, nasal drops or areosols may be used.

In human medicine, the compositions can be used for the treatment and prevention of seizures, schizophrenic disorders, especially deficient forms of schizophrenia, sleep disorders, conditions associated with cerebral ischemia, i. j. neurological diseases in which glutamate such as Alzheimer's disease, Huntington's disease, lateral amyotrophic sclerosis and olivopontocerebellam atrophy can be administered.

The dose depends on the effect desired, the duration of treatment, the route of administration used, which is usually in the range of 30 to 300 mg / day when administered orally to an adult patient and may be divided into sub-doses. Unit doses contain 10 to 100 mg of active ingredient. The appropriate dose will be determined by the physician depending on the age, weight and other factors of the patient.

The following examples illustrate the composition of the medicaments of the invention in more detail. However, these examples do not limit the scope of the invention in any way.

Example A

Coated pills containing 50 mg of active ingredient are prepared in the usual manner using the following ingredients:

2-Imino-3- / 2- [4- (2-pyridyl) -1-piperazinyl] -ethyl] -6-trifluoromethoxybenzothiazoline 50mg cellulose 18mg lactose 55mg colloidal silicic acid 1mg sodium carboxymethylated starch10 mg talcum10 mg magnesium stearate 1mg

Example B

Tablets containing 50 mg of active ingredient are prepared in the usual manner using the following ingredients: 2-imino-3- [2- [4- (4-methylphenyl) -1-piperazinyl] ethyl] -6-trifluoromethoxybenzothiazoline 50 mg lactose 104 mg cellulose 40mg

Povidone 10mg sodium carboxymethyl starch 22mg talc 10mg magnesium stearic acid2 mg colloidal silicic acid2 mg mixture of hydroxymethylcellulose, glycerol and titanium dioxide (71-3,5-24,5) total tablet weight 245 mg as needed

Example C

A solution for injection containing 10 mg of the active ingredient is prepared in the usual manner, using the following ingredients: 3- [2- (4-benzyl-1-piperazinyl'Jetyl) -2-imino-6-trifluoromethoxybenzothiazoline 10mg benzoic acid 80mg benzyl alcohol 0.06 ml sodium benzoate 80mg% ethanol 0.4ml sodium hydroxide 24mg propylene glycol 1.6 ml water to 4 ml

Claims (8)

PATENT CLAIMS CLAIMS 1. A compound of formula (I), wherein: 2-imino-3-hetrocyclylalkylbenzothiazoline: R ¹ is 1-piperazinyl substituted in the 4 a) a phenyl group, b) a phenyl group substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups; c) a phenylalkyl group d) a pyridyl group or e) a pyrimidinyl group, furthermore a 1,2,3,6-tetrahydro-1-pyridyl group substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups, also represents piperidino substituted in the 4 position with phenyl or phenyl substituted by at least one substituent selected from the group which consists of halogen atoms, alkyl groups and alkoxy groups, R ² represents a polyfluoroalkoxy, n is 2 or 3 . Wherein the alkyl and alkoxy groups as well as the alkyl and alkoxy portions of the other groups contain 1 to 4 straight or branched carbon atoms, as well as their acid addition salts. 2-Imino-3-heterocyclylalkylbenzothiazoline derivatives of general formula (I) according to claim 1, CH 1 -CH ³ -R ¹ in which ^R1 is 4-phenyl-l-piperazinyl group, wherein the phenyl moiety is optionally substituted by one or two alkoxy groups or halogen atoms, or is 4-phenylpiperidino, and R ² represents a polyfluoroalkoxy, wherein the alkoxy groups and the alkoxy portions of other radicals contain 1 to Straight and branched chain carbon atoms, as well as their acid addition salts. The 2-imino-3-heterocyclylalkylbenzothiazoline derivatives according to claim 1 or 2, wherein R ² is trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy or 1,1,2,2-tetrafluoroethoxy. Compounds according to claims 1 to 3, wherein R ¹ represents a 1-piperazinyl group which is substituted in the 4-position by a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group or a 4-methylphenyl group, 2-methoxyphenyl or 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl, 3-chlorophenyl or 4-chlorophenyl, benzyl, 2-pyridyl or 2- or R is 4-phenyl-1,2,3,6-tetrahydro-1-pyridyl or 4-phenylpiperidino. 5. Preparation of a 2-imino-3-heterocyklylalkylbenzotiazolinu of formula (I) according to claim 1, (CH) -R ¹ wherein R ¹ is 1-piperazinyl substituted in the 4 a) a phenyl group, (b) a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups; c) a phenylalkyl group (d) a pyridyl group; or e) a pyrimidinyl group, furthermore a 1,2,3,6-tetrahydro-1-pyridyl group substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups, a piperidino group which is substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups, R ² represents a polyfluoroalkoxy, n is 2 or 3, wherein the alkyl and alkoxy groups and alkyl and alkoxy portions of other radicals contain 1 to 4 carbon atoms in a straight or branched chain, and also addition salts thereof, characterized in characterized by hydrolyzing the compound of formula (II), I (CH) -R ¹ wherein R ^1, R ^{2 and} n are the same významy.ako in general formula (I), the product isolated and optionally converted to an addition salt with an organic or inorganic acid. A process for the preparation of a 2-imino-3-heterocyclylalkylbenzothiazoline derivative of the general formula (I) according to claim 1, in which: R ¹ is 1-piperazinyl substituted in the 4 a) a phenyl group, b) a phenyl group substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups; c) a phenylalkyl group (d) a pyridyl group; or e) a pyrimidinyl group, furthermore a 1,2,3,6-tetrahydro-1-pyridyl group substituted in the 4-position by a phenyl group or a phenyl group substituted by at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups, further represents a piperidino group which is substituted at the 4-position with a phenyl group or a phenyl group substituted with at least one substituent selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups, R 'represents polyfluoroalkoxy, n represents a number 2 or 3, wherein alkyl groups and the alkoxy groups as well as the alkyl and alkoxy moieties of the other groups contain 1 to 4 carbon atoms in the straight or branched chain, as well as the acid addition salts of these compounds, characterized in that the alkali metal bromine and thiocyanate are reacted with a compound of formula VIII ) ΫΊ1 L 1 <vii-> r 'in which SK 278908-6 R ^1, R ^{2 and} n have the same meanings as in formula (I), the product isolated and optionally converted to an addition salt with an inorganic or organic acid. A pharmaceutical composition suitable for the treatment and prevention of convulsions, schizophrenia, sleep disorders, conditions associated with cerebral ischemia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar atrophy, characterized in that it contains at least one derivative of 2- imino-3-heterocyclylalkylbenzothiazoline of formula (I) according to claims 1, 2, 3 or 4 in the form of a base or a pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutically acceptable carrier or coating composition. The 2-imino-3-heterocyclylalkylbenzothiazoline derivatives of formula (I) according to claims 1, 2, 3 or 4 for use in the treatment of conditions in which inhibition of glutamate is desired.