DK169383B1 - Drugs containing 2-aminobenzothiazole compounds, 2-amino-benzothiazole compounds, methods for their preparation and use of 2-aminobenzothiazole compounds for the manufacture of drugs. - Google Patents

Description

in DK 169383 B1

The present invention relates to novel drugs containing 2-aminobenzothiazole compounds, novel 2-aminobenzothiazole compounds, methods of preparing the novel 2-aminobenzothiazole compounds and the use of 2-aminobenzothiazole compounds for the manufacture of drugs.

The 2-aminobenzothiazole compounds encompassed by the present invention exhibit anticonvulsant activity as they are effective against seizures induced by glutamate.

EP 50551 A1 discloses the compound 2-amino-6-trifluoromethoxybenzothiazole, which i.a. exhibits anticonvulsant effect.

However, the 2-aminobenzothiazole compounds encompassed by the present invention surprisingly exhibit a better therapeutic index (LD50 / ED50) than the known compound.

More particularly, the present invention relates to novel drugs containing as active ingredient at least one 2-aminobenzothiazole compound of formula I

R 3 wherein R 1 is a polyfluoroalkoxy group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, tert-butyl group, trimethylsilyl group or trifluoromethylthio group, and R 2 and R 3 are a hydrogen atom, or

R 2 represents a polyfluoroalkoxy group, R 2 represents a hydrogen atom, and R 3 represents an alkyl group, amino group or phenyl-alkyl group, or R 1 represents a polyfluoroalkoxy group, R 2 represents an amino group, and R 3 means a hydrogen atom, except for 6-tri-169173 B1 is 2 fluoromethoxy-2-benzothiazolamine, and it should be understood that the alkyl and alkoxy groups or moieties are straight or branched and contain from 1 to 4 carbon atoms or a salt of such a compound with an inorganic or organic acid.

The preferred polyfluoroalkoxy groups are the pentafluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy and 2,2,3,3,3-pentafluoro-propoxy groups.

The compounds of formula (I), with the exception of βίο trifluoromethylthio- and 6-trifluoromethoxy-2-benzothiazolamine, are novel.

Thus, the invention also relates to novel 2-amino-benzothiazole compounds of formula (Ia) -ζΧ, Χ ”1 * 3 wherein

R 1a is a polyfluoroalkoxy group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, tert-butyl group or trimethylsilyl group, and R 2 and R 3 are a hydrogen atom, or R 1a is a polyfluoroalkoxy group, R 2 is a hydrogen atom, and R3 represents an alkyl group, amino group, or phenylalkyl group, or

R 1a is a polyfluoroalkoxy group, R 2 is an amino group, and R 3 is a hydrogen atom with the exception of 6-trifluoromethoxy-2-benzothiazolamine, and it is to be understood that the alkyl and alkoxy groups and moieties are straight or branched and contain 1- 4 carbon atoms, or a salt of such a compound with an inorganic or organic acid.

6-Trifluoromethylthio-2-benzothiazolamine is described in Zh. Obshch. Khim., 22, 2216 (1952) (Chem. Abst. 47, 4771 35 c) and 33 (7), 2301 (1963), but no pharmacological property is disclosed for this compound.

3 DK 169383 B1

The invention further relates to a process for the preparation of the 2-aminobenzothiazole compounds of formula (Ia) according to the invention, wherein

R 1a is a polyfluoroalkoxy group, tert-butyl group, 2,2,2-trifluoroethyl group or pentafluoroethyl group, and R 2 and R 3 are a hydrogen atom, or

R 1a is a polyfluoroalkoxy group, R 2 is a hydrogen atom and R 3 is an alkyl group or phenylalkyl group, the process being characterized in that bromine and an alkali metal thiocyanate are reacted with an amine of formula II

'24J-B2 (II) R 3 wherein R 1a, R 2 and R 3 have the same meanings as above and that the product is isolated and optionally converted into a salt with an inorganic or organic acid.

This reaction is usually carried out in an organic solvent, such as acetic acid, at a temperature near 20 ° C. As the alkali metal thiocyanate, potassium thiocyanate is preferably used.

The amines of formula (II) can be prepared using or adapting the methods described in J. Org. Chem., 29, 1 (1964)? Beilstein 12, 1166, in U.S. Patent Nos. 3,920,444, U.S. 2,436,100, DE No. 3,195,926, DE No. 2,606,982, EP No. 205,821, and in the Examples.

The invention further relates to a process for preparing a compound of formula (Ia) according to the invention, wherein R 1a is a trimethylsilyl group and R 2 and R 3 are a hydrogen atom which is characterized by reacting chlorotrimethylsilane with a lithiated N, N-bistrimethylsilyl. -2-benzothiazolamine derivative 35 formed by reaction of butyllithium and chlorotrimethylsilane with 6-bromo-benzothiazolamine, then hydrolyzed and the product isolated and optionally converted into a salt with an inorganic or organic acid.

These reactions are carried out without separation of the lithiated derivative in an inert solvent such as hexane, tetrahydrofuran or a mixture of these solvents at a temperature of between -70 ° C and the boiling temperature of the mixture.

6-Bromo-2-benzothiazolamine can be prepared using the method described in Beilstein 27, 184.

The invention further relates to a process for the preparation of a compound of formula (Ia) according to the invention wherein R 1a is a polyfluoroalkoxy group and R 2 is an amino group and R 3 is a hydrogen atom or R 3 is a hydrogen atom.

15 which is characterized in that a compound of formula III

^ .S

. R1 \ B (III) Β2ϋγνκΑ r3 wherein R1a is a polyfluoroalkoxy group and R2 is a nitro group and R3 is a hydrogen atom and R2 is a hydrogen atom and R3 is a nitro group reduced and the product isolated and optionally converted to a salt with an inorganic or organic acid.

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

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

This nitration is usually carried out by means of a mixture of sulfuric and nitric acids at a temperature near 0 ° C.

5 DK 169383 B1 6-Polyfluoroalkoxy-2-benzothiazolamine can be obtained using or adapting the method described in Zh. Obshch. Khim. 33, 2301 (1963).

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

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

Finally, the present invention also relates to the use of compounds of formula (I) or a salt of such a compound with an inorganic or organic acid for the preparation of drugs.

The compounds of formula (I) and their salts have interesting pharmacological properties. These compounds 20 are active against seizures induced by glutamate and are therefore useful in treating and preventing seizure phenomena, schizophrenic disorders and especially schizophrenic deficiencies, sleep disorders, phenomena related to cerebral ischemia, and neurological diseases such as Alzheimer's disease, , Huntington's disease, amyotrophic lateral sclerosis, and olivopontocerebellar atrophy.

The effect of the compounds of Formula I on cramps induced by glutamate has been determined according to a method described by I.P. Lapin, J. Neural. Transmission, Vol. 54, 229-238 (1982). The injection of glutamate by intracerebroventricular administration is by a method of R. Chermat and P. Simon, J. Pharmacol. (Paris), Vol. 6, 489-492 (1975). Their ED5 value is less than or equal to 10 35 mg / kg.

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

DK 169383 B1 6

Their LD50 value is generally above 60 mg / kg upon intraperitoneal administration to mice.

The following compounds are of particular interest: 6-pentafluoroethoxy-2-benzothiazolamine, 6 6-tert.butyl-2-benzothiazolamine, 6-trifluoromethoxy-2,5-benzothiazole diamine, 6-trifluoromethoxy-2,4-benzothiazole diamine.

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

Examples of pharmaceutically acceptable salts include addition salts with inorganic or organic acids such as hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophylline acetate, salicylate , phenol phthaleinate and methylene bis-io-oxynaphthoate.

The medicaments of the invention comprise at least one compound of formula (I) or a salt of such compound in the pure state or in the form of a mixture in which it is attached to any other pharmaceutically compatible product which can be inert or physiologically active. These drugs can be used by oral, parenteral, rectal or topical administration.

As solid compositions for oral administration, tablets, pills, powders (hard gelatin capsules, cachets) or granules may be used. In these compositions, the active substance of the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica.

These compositions may also comprise materials other than diluents, e.g. one or more lubricants, such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish.

As liquid preparations for oral administration, solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs may be used containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise materials other than diluents, e.g. wetting agents, sweetening agents, thickening agents, flavoring agents or stabilizers.

The sterile preparations for parenteral administration may preferably be non-aqueous solutions, suspensions or emulsions. As the solvent or carrier, water, propylene glycol, a polyethylene glycol, 10 vegetable oils, especially olive oil, injectable organic esters, e.g. ethyl oleate or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting agents, isotonizing agents, emulsifiers, dispersing agents and stabilizers. Sterilization can be done in several ways, e.g. by aseptic filtration, by incorporation into the preparation of sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which, at the point of use, can be dissolved in sterile water or any other injectable sterile medium.

The rectal administration formulations are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The topical administration compositions can e.g. be it creams, pomades, lotions, eye water, mouthwash, nasal drops or aerosols.

The doses depend on the desired effect, duration of treatment and method of administration used. They generally range from 30 to 300 mg per day. per day by oral administration to an adult with unit doses of 10 to 100 mg of active substance.

The physician usually determines which dose is appropriate depending on the age, weight and all other factors that are peculiar to the individual to be treated.

The preparation of compounds of formula (I) il is illustrated in the following examples.

8 DK 169383 B1

Example 1

To a solution of 4.8 g of 4-pentafluoroethoxy-aniline in 35 ml of acetic acid is added 8.15 g of potassium thiocyanate under argon purification and stirred for 10 minutes at a temperature 5 near 20 ° C. To the solution thus formed, a solution of 1.1 ml of bromine in 10 ml of acetic acid is added dropwise over a period of 35 minutes at a temperature of between 22 and 42 ° C. It is then stirred for 20 hours at a temperature near 20 ° C. The reaction mixture is poured onto a mixture of water and ice (250 ml), basified with 50 ml of 28% ammonia and extracted twice with a total of 250 ml of ethyl acetate. After decantation, the organic solution is washed with distilled water until a pH of 8, dried over magnesium sulfate, filtered and evaporated at 50 ° C under reduced pressure (20 mm Hg, 2.7 15 kPa). The resulting product (6.3 g) is purified by chromatography on a silica column (650 g, grain size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate in 50:50 volume as eluent and recrystallized in 400 ml of boiling cyclohexane. There is obtained 3.25 g of 6-pentafluoroethoxy-2-benzothiazolamine melting at 156 ° C.

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

Example 2

Proceed as described in Example 1 but proceed from 14.9 g of 4-tert.butyl aniline, 38.8 g of potassium thiocyanate and 5.1 ml of bromine in 150 ml of acetic acid. After purification on a silica column (700 g, grain size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate at 40:60 volume as eluent and recrystallization in 450 ml of boiling cyclohexane, 12.2 g of 6-tert.butyl-2 is obtained. -benzothiazole-amine melting at 146 ° C.

4-Tert-butyl-aniline can be prepared according to the method 35 described in Beilstein 12, 1166.

9 DK 169383 B1

Example 3

Proceed as described in Example 1 but proceed from 4- (2,2,2-trifluoro-ethoxy) -aniline, potassium thiocyanate and bromine in acetic acid to give 6- (2,2,2-trifluoro-ethoxy) -5 2-benzothiazolamine, which melts at 134 ° C.

4- (2,2,2-Trifluoro-ethoxy) -aniline can be prepared according to the method described in U.S. Patent No. 3,920,444.

Example 4 To a solution cooled to -70 ° C of 6.8 g of 6-bromo-2-benzothiazolamine in 100 ml of anhydrous tetrahydrofuran is added under argon purification and with stirring 46 ml of a 1.6 M solution of n-butyllithium in hexane. . The temperature is then allowed to rise to approx. 0 ° C and a solution of 9.3 ral chlorotrimethylsilane in 10 ml of anhydrous tetrahydrofuran is added. After the temperature is again close to 20 ° C, reflux is heated for 1 hour and 30 minutes.

It is then cooled to ca. -10 ° C before adding 19 ml of the same solution of n-butyllithium and the temperature 20 being allowed to rise to approx. 0 ° C. To the resulting clear red solution is added a solution of 4.7 ml of chlorotrimethylsilane in 10 ml of anhydrous tetrahydrofuran and the temperature is allowed to rise to approx. 20 ° C. It is then heated to reflux for 4 hours and 30 minutes. After the temperature is again near 20 ° C, the reaction mixture is poured into 100 ml of water, keeping the temperature below 25 ° C and basified with ammonia. The lower aqueous phase is extracted four times with a total of 200 ml of dichloromethane and the organic phases are combined, dried over magnesium sulfate, filtered and evaporated at 40 ° C under reduced pressure (20 mm Hg, 2.7 kPa). The orange oil formed (10.1 g) is chromatographed twice on a silica column, eluting with a mixture of cyclohexane and ethyl acetate in the 40:60 volume ratio. There is thus obtained 0.55 g of a white solid, 35 which is triturated with 10 ml of petroleum ether (40-65 ° C) and after separation by suction and drying under reduced pressure 10 DK 169383 B1 (2 hours at 50 ° C under 0.45 g of 6-trimethylsilyl-2-benzothiazolamine melting at 140 ° C is obtained.

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

5

Example 5

Proceed as described in Example 1 but proceed from 3.85 g of 4-trifluoromethylthioaniline, 7 g of potassium thiocyanate and 1 ml of bromine in 30 ml of acetic acid. The pale chestnut brown crude product is taken up with 250 ml of acetic acid at 80 ° C and the resulting solution is treated with 0.4 g of decolorizing coal and filtered. The filtrate is cooled to ca. 10 ° C, diluted with 150 ml of water and made basic with 400 ml of 28% ammonia. The precipitate formed is separated by suction, dried in the air and recrystallized in a mixture of 250 ml of cyclohexane and 30 ml of isopropyl ether. 2.9 g of 6-trifluoromethylthio-2-benzothiazolamine are obtained which melt at 155 ° C.

4-Trifluoromethylthio-aniline can be prepared according to the method described in U.S. Patent No. 2,436,100.

20

Example 6

Proceed as in Example 1 but proceed from 0.65 g of 4-trifluoromethoxy-2-methyl-aniline, 1.3 g of potassium thiocyanate and 0.35 ml of bromine in 12 ml of acetic acid. After purification on a silica column (200 g, grain size: 0.063-0.200 mm), eluting with a 50:50 volume ratio of cyclohexane and ethyl acetate, the white solid (0.65 g) formed is triturated in 20 ml of cyclohexane , separated by suction and dried at 60 ° C under reduced pressure (1 mm Hg, 0.13 kPa) to give 0.6 g of 4-methyl-6-trifluoromethoxy-2-benzothiazole-amine, melting at 162 ° C.

4-Trifluoromethoxy-2-methyl-aniline can be prepared according to the method described in DE Patent No. 3,195,926.

35 11 DK 169383 B1

Example 7 7.2 g of 6-trifluoromethoxy-5-nitro-2-benzothiazolamine, 25 ml of ethanol, 25 ml of water, 8.7 g of powdered iron and 1.1 ml of concentrated hydrochloric acid (d = 1.19) are heated to reflux. -5 cooling for 2 hours. After bringing the temperature back to near 20 ° C, 10 ml of 28% ammonia is basified and extracted four times with a total of 350 ml of ethyl acetate. The organic solution is evaporated at 50 ° C under reduced pressure (20 mm Hg, 2.7 kPa). The resulting product (6.4 g) is purified by chromatography on a silica column (800 g, grain size: 0.063-0.200 mm), eluting with a mixture of ethyl acetate and cyclohexane in the 90:10 volume ratio, and recrystallized in 320 ml. toluene. 4 g of 6-trifluoro-methoxy-2,5-benzothiazole diamine are obtained, which melt at 175 ° C.

6-Trifluoromethoxy-5-nitro-2-benzothiazolamine can be prepared as follows. To 11.7 g of 6-trifluoro-methoxy-2-benzothiazolamine cooled to -1 ° C, a mixture of sulfuric acid and nitric acid cooled to ca. 5 ° C and prepared from 20 ml of concentrated sulfuric acid (d = 1.83) and 10 ml of concentrated nitric acid (d = 1.42). The temperature of the reaction mixture is kept below 5 ° C during the addition (25 minutes), and after the addition is complete, stirring is continued for 30 minutes at 0-2 ° C. The reaction product is then poured onto a mixture of water and ice (150 ml) and basified with 75 ml of 28% ammonia. The yellow precipitate formed, which is a mixture of 6-trifluoromethoxy-5-nitro-2-benzothiazolamine and 6-trifluoro-methoxy-4-nitro-2-benzothiazolamine, is separated by suction. After chromatography on a silica column (1 kg, grain size: 0.063-0.200 mm), eluting with a mixture of cyclohexane and ethyl acetate at 60:40 volume, 9.45 g of 6-trifluoromethoxy-5-nitro-2 is obtained. -benzothiazolamine melting at 260 ° C and 0.9 g of 6-trifluoromethoxy-4-nitro-2-benzothiazolamine melting above 260 ° C (Rf = 0.28, thin-layer chromatography on silica gel, solvent: cyclohexane and ethyl acetate in the 50:50 volume ratio).

12 DK 169383 B1 6-Trifluoromethoxy-2-benzothiazolamine can be prepared according to the method described by L.M. Yagupolskii et al., Zh. Obshch. Khim. 33, 2301 (1963).

Example 8

Proceed as described in Example 7 but proceed from 6-trifluoromethoxy-4-nitro-2-benzothiazolamine, iron in powder form, concentrated hydrochloric acid and 50% ethanol in water (v / v). After purification on a silica column with a mixture of cyclohexane and ethyl acetate in the volume ratio of 10:90 as an eluent, a white solid (1.5 g) is obtained which is recrystallized in 130 ml of toluene to give 1 g of 6-trifluoromethoxy-2.4 -benzothiazole diamine, which melts at 206 ° C.

15

Example 9

Proceed as described in Example 1, but assume 10 g of 4- (1,1,2,2-tetrafluoroethoxy) aniline, 18.5 g of potassium thiocyanate, 2.4 ml of bromine and 80 ml of acetic acid . After purification 20 on a column of silica (1 kg, grain size: 0.063-0.200 mm), eluting with a mixture of cyclohexane and ethyl acetate in 50:50 volume ratio, and recrystallization in 22 ml of toluene, 2 g of 6- (1, 1,2,2-Tetrafluoroethoxy) -2-benzothiazolamine melting at 161 ° C.

4- (1,1,2,2-Tetrafluoroethoxy) -aniline can be prepared according to the method described by W.A. Sheppard, J. Org. Chem.

29, 1 (1964).

Example 10 To a solution of 2.1 g of 4- (2,2,2-trifluoroethyl) aniline in 25 ml of acetic acid is added 2.3 g of potassium thiocyanate and stirred for 10 minutes at a temperature near 20 ° C. . To the solution thus formed, a solution of 0.6 ml of bromine in 30 ml of acetic acid is added dropwise over 35 minutes at a temperature of between 20 and 35 ° C. It is then stirred for 16 hours at a temperature near 20 ° C. The reaction mixture is poured onto a mixture of water and ice (150 ml), basified with 35 ml of 28% ammonia and extracted three times with a total of 170 ml of ethyl acetate. After decantation, the organic solution is washed with distilled water until a pH of 8.5 is dried over magnesium sulfate, filtered and evaporated at 50 ° C under reduced pressure (20 mm Hg, 2.7 kPa). After purification on a first column of silica eluting with a mixture of cyclohexane and ethyl acetate in the 50:50 volume ratio, a beige solid (1.7 'g) is obtained which melts 10 at 175 ° C and chromatographed on silica, using a mixture of dichloromethane and ethyl acetate at 50:50 by volume. There is thus obtained 0.8 g of 6- (2,2,2-trifluoroethyl) -2-benzothiazolamine which melts at 186 ° C.

4- (2,2,2-Trifluoro-ethyl) -aniline can be prepared as follows. To a solution of 3.8 g of 4- (2,2,2-trifluoroethyl) nitrobenzene in 20 ml of ethanol is added 0.17 g of 10% palladium on carbon and added dropwise over 20 ml. minutes, with stirring, a solution of 1.8 ml of hydrazine hydrate in 10 ml of ethanol. The mixture is then heated to reflux for 15 minutes and the temperature is allowed to drop to approx. 20 ° C. The catalyst is filtered off, the filtrate is concentrated to half under reduced pressure (20 mm Hg, 2.7 kPa), 30 ml of water is added and extracted with a total of 25 200 ml of ethyl acetate. The organic solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure (20 mm Hg, 2.7 kPa) and the evaporation residue (2.7 g) is purified by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate in volume ratio 70: As an eluent. 2.3 g of 4- (2,2,2-trifluoroethyl) aniline are obtained in the form of a yellow oil which is used directly in the cyclization step.

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

Chem., 30, 1027 (1965), L.M. Yagupolskii et al., Synthesis, (11), 932 (1980), I. Kumadaki et al., J. Org. Chem., 53, 14, 169383 B1 3637 (1988).

Example 11

Proceed as described in Example 1, but proceed from 5.6 g of 4-pentafluoroethyl aniline, 14 g of potassium thiocyanate and 3.6 ml of bromine in 150 ml of acetic acid. After purification on a silica column with a mixture of cyclohexane and ethyl acetate in the 50:50 volume eluent, a yellow solid (17 g) is obtained which is converted to hydrochloride by reaction with HCl in solution in ethyl ether. The resulting precipitate (16 g) is recrystallized in a mixture of 100 ml of acetone and 60 ml of ethanol. 3.8 g of 6-pentafluoroethyl-2-benzothiazolamine hydrochloride are obtained, which melts at 191 ° C.

4-Pentafluoroethyl aniline can be prepared according to the method described in DE Patent No. 2,606,982.

Example 12

To a solution of 2.65 g of 4- (2,2,3,3,3-pentafluoro-propoxy) -aniline in 25 ml of acetic acid is added 4.27 g of potassium 20 thiocyanate and stirred for 10 minutes at a temperature. near 20 ° C. To the solution thus formed, a solution of 0.56 ml of bromine in 5 ml of acetic acid is added dropwise over 35 minutes at a temperature of between 22 and 35 ° C and then stirred for 16 hours at a temperature close to 20 ° C. The reaction mixture is poured onto a mixture of 150 ml of water and ice, basified with 35 ml of 28% ammonia and extracted three times with a total of 170 ml of ethyl acetate. After decantation, the organic solution is washed with distilled water until a pH of 8, dried over magnesium sulfate, filtered and evaporated at 50 ° C under reduced pressure (20 mm Hg, 2.7 kPa).

The resulting product (3.2 g) is purified by chromatography on a silica column (250 g, grain size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate in 50:50 volume as eluent and recrystallized in 35 ml of toluene. 1.27 g of 6- (2,2,3,3,3-pentafluoro-propoxy) -2-benzothiazolamine are obtained, melting at 147 ° C.

DK-169383 B1 4- (2,2,3,3,3-Pentafluoro-propoxy) -aniline can be prepared according to the method described in EP Patent No. 205,821.

Example 13 5 Proceed as described in Example 1 but proceed from 1.5 g of 2-benzyl-4-trifluoromethoxy-aniline, 2.1 g of potassium thiocyanate dissolved in 15 ml of acetic acid and 0.88 g (0, 28 ml) of bromine. Stirring is continued for 12 hours at this temperature. The mixture is evaporated to dryness at 80 ° C under reduced pressure (20 mm Hg, 2.7 kPa). The residue formed is taken up with 10 ml of water and the pH is adjusted to 9-10 with 10N concentrated sodium hydroxide. After extraction with 2 x 100 ml of ethyl acetate, washing the combined organic phases with 2 x 50 ml of water, drying over anhydrous magnesium sulfate and evaporating to dryness at 40 ° C under reduced pressure (20 mm Hg, 2.7 kPa), 1 3 g of 4-benzyl-6-trifluoromethoxy-2-benzothiazolamine melting at 175 ° C.

2-Benzyl-4-trifluoromethoxy-aniline can be prepared as follows. 1.7 g of N- (2-benzyl-4-trifluoromethoxy-phe-new 1) tert-butyl carboxamide and 22 ml of 12N concentrated HCl dissolved in 35 ml of water are heated to reflux for 12 hours. After neutralization with 10 N concentrated sodium hydroxide to a pH of 11 and extraction with 2 x 50 ml of ethyl acetate and evaporation to dryness at 40 ° C under reduced pressure (20 mm Hg, 2.7 kPa), 1.5 g of 2- benzyl-4-trifluoro-methoxy-aniline in the form of an orange oil.

N- (2-Benzyl-4-trifluoromethoxy-phenyl) tert-butylcarboxamide can be prepared as follows. To a mixture of 1.1 g of 50% 1 s sodium hydride in dispersion in petroleum oil 30 dissolved in 24 ml of carbon disulfide is added dropwise 11 g of N- (2-hydroxyphenylmethyl-4-trifluoromethoxy-phenyl) tert. butylcarboxamide dissolved in 96 ml of carbon disulfide at a temperature between 30 and 34 ° C. The solution is allowed to stand for 1 hour at 25 ° C and 42.6 g (19 ml) of methyl iodide are added dropwise. The whole mixture is left stirring at 25 ° C for one night. After adding 150 ml of a saturated ammonium chloride solution, extraction with 100 ml of dichloromethane, drying over anhydrous magnesium sulfate and concentration under reduced pressure (20 mm Hg, 2.7 kPa), isolate 3.4 g of a yellow oil. . This oil is dissolved directly in 25 ml of toluene with 0.07 g of azobis-5 isobutyronitrile and the whole mixture is heated to 80 ° C. 8 ml of tributyltin hydride are added dropwise and under nitrogen. The solution is allowed to stand for 45 minutes at 85 ° C. After evaporation to dryness at 30 ° C under reduced pressure (20 mm Hg, 2.7 kPa), the residue formed by flash chromatography is purified on a silica column under a nitrogen flow at medium pressure (0.5-1.5 bar ) with a mixture of cyclohexane and ethyl acetate in the 95: 5 volume ratio as eluant.

1.7 g of N- (2-benzyl-4-trifluoromethoxy-phenyl) tert-butyl carboxamide, which melts at 88 ° C, are isolated.

N- (2-Hydroxyphenylmethyl-4-trifluoromethoxy-phenyl) -tert.butylcarboxamide can be prepared as follows.

To 15.7 g of N- (4-trifluoromethoxy) tert-butyl carboxamide dissolved in 75 ml of tetrahydrofuran is added at 0 ° C with stirring over 30 minutes 75 ml of n-butyl lithium (1.6M in hexane).

The mixture is stirred at a temperature of 0 ° C for 3 hours. Then, 7 g (6.7 ml) of benzaldehyde is added and the whole mixture is allowed to stand for 12 hours at 25 ° C. After the addition of 200 ml of water, extraction with 2 x 100 ml of ethyl acetate, drying over magnesium sulfate and concentration under reduced pressure (20 mm Hg, 2.7 kPa), 14.1 g of N- (2-hydroxyphenyl-methyl-4) are isolated. trifluoromethoxy-phenyl) tert. butyl carboxamide, which melts at 140 ° C.

The following examples illustrate some compositions of the invention.

30 17 DK 169383 B1

Example Å

Generally, soft capsules containing 50 mg of active compound are prepared having the following composition: 5 6-Pentafluoroethoxy-2-benzothiazolamine .......... 50 mg

Cellulose ...................................... 18 mg

Lactose ........................................ 55 mg

Colloidal Silicon Dioxide ........................ 1 mg

Sodium Carboxymethyl Starch ................. 10 Mg 10 Talc ........................ ................. 10 mg

Magnesium stearate ............................... 1 mg

Example B

Generally, tablets containing 50 mg of active compound are prepared having the following composition: 6-Tert.butyl-2-benzothiazolamine.

Lactose ........................................ 104 mg

Cellulose ...................................... 40 mg

Polyvinylpyrrolidone ............................ 10 mg 20 Sodium carboxymethyl starch ............. .... 22 mg

Talc ......................................... 10 mg

Magnesium stearate ............................... 2 mg

Colloidal Silicon Dioxide ........................ 2 mg

Mixture of hydroxymethylcellulose, glycerol, titanium oxide (72: 3.5: 24.5) ................. up to 1 finished film-coated tablet on ....... 245 mg 18 DK 169383 B1

Example C

An injectable solution containing 10 mg of active compound is prepared having the following composition: 6-Trimethylsilyl-2-benzothiazolamine ............ 10 mg 5 Benzoic acid ......... ............................ 80 mg

Benzyl Alcohol .................................. 0.06 ml

Sodium Benzoate ................................. 80 mg 95% ethanol ......... ......................... 0.4 ml

Sodium Hydroxide ................................ 24 mg 10 Propylene Glycol ............ .................... 1.6 ml

Water .................................... up to 4 ml

Together 1 test attempt:

Determination of the therapeutic index (ratio of LD50 to ED50) determined by the method described on page 5 of the description) of compounds of the invention and compound 2-amino-6-trifluoromethoxybenzothiazole known from EP 50551 A1.

The results given in the following table are obtained.

20 DK 169383 B1 19

ED50 LD50 THERAPEUTIC

CONNECTION mg / kg mg / kg INDEX

(i.p., mouse) LD50 / ED50

According to the invention, example no.

1 2.5 120 48 2 4 130 32.5 3 6.5 160 · 24.6 4 5 non-toxic at 80> 16 5 8 120 15 6 6.5 130 20 7 3.1 147 47.4 8 2 non-toxic at 80> 80 9 8.5 non-toxic wood 60> 18.8 10 8 non-toxic wood 60> 20 11 2.5 55 22 12 7.5 non-toxic wood 60> 21.3 13 10 non-toxic at 160> 16 EP 50551 Al 6-Tri-3.2 40 14.3 Fluoromethoxybenzothiazole DK 169383 B1

As can be seen from the table, the compounds of the invention exhibit an improved therapeutic index over the known compound.

5

Claims (11)

21 DK 169383 B1 Pharmaceuticals, characterized in that they contain, as an active substance, at least one 2-aminobenzothiazole compound of formula I wherein R3 represents a polyfluoroalkoxy group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, tert-butyl group , trimethylsilyl group or trifluoromethylthio group, and R 2 and R 3 are a hydrogen atom, or R 1 is a polyfluoroalkoxy group, R 2 is a hydrogen atom and R 3 is an alkyl group, amino group or phenylalkyl group, or R 1 is a polyfluoroalkoxy group, R 2 is an amino group, and R 3 is a hydrogen atom, with the exception of 6-trifluoromethoxy-2-benzothiazolamine, and it is to be understood that the alkyl and alkoxy groups or moieties are straight or branched chain and contain from 1 to 4 carbon atoms or a salt of such compound with an inorganic or organic acid. Drugs according to claim 1, characterized in that the polyfluoroalkoxy group is a pentafluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy group, trifluoromethoxy group or 2,2,3 , 3,3-pentafluoro-propoxy-group. A medicament according to claim 1 or 2 for the treatment of diseases in which glutamate is implicated. 2-Aminobenzothiazole compounds of formula Ia 3 wherein R 1a means a polyfluoroalkoxy group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, tert-butyl group or trimethylsilyl group, and R 2 and R 3 represent a hydrogen atom, or R 1a an alkyl group, amino group or phenylalkyl group, or R 1a is a polyfluoroalkoxy group, R 2 is an amino group, and R 3 is a hydrogen atom, with the exception of the 6-trifluoromethoxy-2-benzothiazolamine, and the moieties are straight-chain or branched and contain from 1 to 4 carbon atoms, or a salt of such a compound with an inorganic or organic acid. Compounds according to claim 4, characterized in that the polyfluoroalkoxy group is a pentafluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2-tetrafluoroethoxy group, trifluoromethoxy group or 2.2 , 3,3,3-pentafluoro-propoxy-group. A process for preparing the compounds of formula (Ia) according to claim 4, wherein R 1a is a polyfluoroalkoxy group, 2,2,2-trifluoroethyl group, pentafluoroethyl group or tert-butyl group, and R 2 and R 3 are a hydrogen atom, or R 1a is a polyfluoroalkoxy group, R 2 is a hydrogen atom, and R 3 is an alkyl group or phenyl alkyl group, characterized in that an alkali metal thiocyanate and bromine are reacted with an amine of formula II (ID 2). Wherein R 1a, R 2 and R 3 have the same meanings as above and that the product is isolated and optionally converted to salt with an inorganic or organic acid. A process for preparing a compound of formula (Ia) according to claim 4, wherein R 1a is a trimethylsilyl group and R 2 and R 3 are a hydrogen atom, characterized in that chlorotrimethylsilane is reacted with a lithiated N, N-bistrimethylsilyl 2-Benzothiazolamine derivative formed by reaction of butyllithium and chlorotrimethylsilane with 6-bromo-benzothiazolamine, then hydrolyzed and the product isolated and optionally converted to salt with an inorganic or organic acid. A process for preparing a compound of formula (Ia) according to claim 4, wherein R 1a is a polyfluoroalkoxy group and R 2 is an amino group and R 3 is a hydrogen atom, or R 2 is a hydrogen atom and R 3 is an amino group, characterized in that a compound of formula III is -QCX 0 0 3 wherein R 1a is a polyfluoroalkoxy group and R 2 is a nitro group and R 3 is a hydrogen atom, or R 2 represents a hydrogen atom and R 3 represents a nitro group, is reduced, and the product is isolated and optionally converted to salt with an inorganic or organic acid. 24 DK 169383 B1 Use of compounds of formula I as claimed in claim 1 or a salt of such a compound with an inorganic acid for the preparation of drugs.