2-alkyliminobenzothiazoline derivatives, processes for preparing them and medicinal products containing them

Compounds of formula: ##STR1## R.sub.1 represents a polyfluoroalkoxy radical, R.sub.2 represents an alkylthioalkyl, alkylsulphinylalkyl or alkylsulphonylalkyl radical, and PA0 R.sub.3 represents an alkyl radical, as well as the salts of these compounds with an inorganic or organic acid, processes for preparing them and medicinal products containing them.

FIELD OF THE INVENTION 
The present invention relates to 2-alkyliminobenzothiazoline derivatives of 
formula: 
##STR2## 
to their salts, to processes for preparing them and to medicinal products 
containing them. 
In the formula (I), 
R.sub.1 represents a polyfluoroalkoxy radical, 
R.sub.2 represents an alkylthioalkyl, alkylsulphinylalkyl or 
alkylsulphonylalkyl radical, and 
R.sub.3 represents an alkyl radical. 
In the definitions above and those to be mentioned below, the alkyl 
radicals and alkyl and alkoxy portions contain 1 to 4 carbon atoms in a 
straight or branched chain. 
The polyfluoroalkoxy radicals are preferably trifluoromethoxy, 
pentafluoroethoxy, 2,2,2-trifluoro-ethoxy or 1,1,2,2-tetrafluoroethoxy 
radicals. 
The invention also relates to the addition salts of the compounds of 
formula (I) with inorganic or organic acids. 
DETAILED DESCRIPTION OF THE INVENTION 
According to the invention, the compounds of formula (I) may be prepared by 
the action of a derivative of formula: 
##STR3## 
in which R.sub.1 and R.sub.3 have the same meanings as in the formula (I), 
on a derivative of formula: 
EQU R.sub.2 --X (III) 
in which R.sub.2 has the same meanings as in the formula (I) and X 
represents a reactive group such as a tosyloxy radical or a halogen atom 
(preferably chlorine, bromine or iodine), or an addition salt of such a 
derivative with an inorganic or organic acid. 
This reaction is generally performed in an inert organic solvent such as an 
alcohol (ethanol, propanol, etc.), a ketone (acetone, methyl ethyl ketone, 
etc.) or dimethylformamide, at a temperature between 20.degree. C. and the 
boiling point of the solvent, optionally in the presence of sodium iodide. 
The derivatives of formula (II) may be obtained by the action of an 
alkylamine on a 2-chloro-6-polyfluoroalkoxybenzothiazole. 
This reaction is preferably performed in an aqueous medium. 
2-Chloro-6-polyfluoroalkoxybenzothiazoles may be obtained by the 
chlorination of a 2-hydrazino-6-polyfluoroalkoxybenzothiazole. 
The chlorination is performed by means of a chlorinating agent, preferably 
by means of thionyl chloride, at a temperature of between 20.degree. C. 
and 70.degree. C. 
2-Hydrazino-6-polyfluoroalkoxybenzothiazoles may be prepared by the action 
of hydrazine on a 2-amino-6-polyfluoroalkoxybenzothiazole. 
This reaction is generally performed in an organic solvent such as ethylene 
glycol, at a temperature in the region of 140.degree. C. 
2-Amino-6-polyfluoroalkoxybenzothiazoles may be obtained by application or 
adaptation of the method described by L. M. YAGUPOL'SKII et al., Zh. 
Obshch. Khim. 33 (7), 2301 (1963). 
The compounds of formula (I) for which R.sub.2 represents an 
alkylsulphinylalkyl or alkyl-sulphonyl-alkyl radical may also be obtained 
by oxidation of the corresponding derivatives of formula (I) for which 
R.sub.2 represents an alkylthioalkyl radical. 
The oxidation to alkylsulphinylalkyl is generally performed by means of 
m-chloroperbenzoic acid, in an alcohol, at a temperature of between 
-15.degree. C. and -40.degree. C. 
The oxidation to alkylsulphonylalkyl may be performed by means of hydrogen 
peroxide, in acetic acid, at a temperature in the region of 100.degree. 
C., or by means of m-chloroperbenzoic acid in an inert solvent such as 
dichloromethane or chloroform, at a temperature in the region of 
20.degree. C. 
The reaction mixtures obtained by the various processes described above are 
treated according to conventional physical methods (evaporation, 
extraction, distillation, crystallization, chromatography, etc.) or 
chemical methods (salt formation, etc.). 
The compounds of formula (I), in free base form, can be optionally 
converted to addition salts with an inorganic or organic acid, by the 
action of such an acid in an organic solvent such as an alcohol, ketone, 
ether or chlorinated solvent. 
The compounds of formula (I) and their salts possess advantageous 
pharmacological properties. These compounds are active with respect to 
glutamate-induced convulsions, and are hence useful in the treatment and 
prevention of convulsive phenomena, schizophrenic disorders, and in 
particular the deficiency forms of schizophrenia, sleep disorders, 
phenomena linked to cerebral ischaemia and also neurological conditions in 
which glutamate may be implicated, such as Alzheimer's disease, 
Huntington's chorea, amyotrophic lateral sclerosis and 
olivopontocerebellar atrophy. 
The activity of the compounds of formula (I), with respect to 
glutamate-induced convulsions was determined according to a technique 
based on that of I.P. LAPIN, J. Neural. Transmission, vol. 54, 229-238 
(1982); intracerebroventricular injection of glutamate being performed 
according to a technique based on that of R. CHERMAT and P. SIMON, J. 
Pharmacol. (Paris), vol. 6, 489-492 (1975). Their ED.sub.5 0 is less than 
10 mg/kg. 
The compounds of formula (I) possess low toxicity. Their LD.sub.5 0 is more 
than 15 mg/kg when administered I.P. in mice. 
For medicinal use, the compounds of formula (I) may be employed as they 
are, or in the state of pharmaceutically acceptable salts, i.e. salts 
which are non-toxic at the doses at which they are used. 
As examples of pharmaceutically acceptable salts, the addition salts with 
inorganic or organic acids, such as acetate, propionate, succinate, 
benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate, 
theophyllineacetate, salicylate, phenolphthalinate, 
methylenebis(.beta.-hydroxynaphthoate), hydrochloride, sulphate, nitrate 
and phosphate, may be mentioned.

EXAMPLES 
The examples which follow, given without implied limitation, show how the 
invention may be put into practice. 
EXAMPLE 1 
A mixture of 2-methylamino-6-trifluoromethoxybenzothiazole (12.4 g) and 
1-chloro-2-methylthioethane (6.6 g) in methyl ethyl ketone (75 cc) is 
heated to boiling for 72 hours. After cooling to a temperature in the 
region of 20.degree. C., the precipitate formed is filtered off and washed 
with ethyl ether (3.times.50 cc). 
2-Methylimino-3-(2-methylthioethyl)-6-trifluoro-methoxybenzothiazoline 
hydrochloride (5.7 g), subliming at about 210.degree. C., is obtained. 
2-Methylamino-6-trifluoromethoxybenzothiazole may be prepared according to 
the following process: 2-chloro-6-trifluoromethoxybenzothiazole (22.0 g) 
and 40% strength aqueous methylamine (90 cc) are heated in an autoclave at 
110.degree. C. for 24 hours. After cooling to a temperature in the region 
of 20.degree. C., the reaction medium is added to distilled water (300 cc) 
and the precipitate formed filtered off and washed with distilled water 
(2.times.100 cc). After drying, 
2-methylamino-6-trifluoromethoxybenzothiazole (19.5 g), m.p. 162.degree. 
C., is obtained. 
2-Chloro-6-trifluoromethoxybenzothiazole may be prepared in the following 
manner: 2-hydrazino-6-trifluoromethoxybenzothiazole (133 g) is added in 
the course of 1 hour and a half to thionyl chloride (162 cc) heated to 
50.degree. C. Reaction is continued for 1 hour at this temperature. After 
cooling to a temperature in the region of 20.degree. C., the reaction 
medium is poured into ice-cold water (2.5 liters). The precipitate formed 
is filtered off, washed with distilled water (2 liters) and then taken up 
in dichloromethane (1 liter). The organic phase is washed with distilled 
water (3.times.200 cc), then dried over magnesium sulphate and 
concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). 
2-Chloro-6-trifluoromethoxybenzothiazole (122.4 g), m.p. below 50.degree. 
C., is obtained. 
2-Hydrazino-6-trifluoromethoxybenzothiazole may be prepared according to 
the following process: a mixture of 
2-amino-6-trifluoromethoxybenzothiazole (140.4 g), 85% strength hydrazine 
hydrate (69.6 cc) and hydrazine dihydrochloride (63 g) in ethylene glycol 
(600 cc) is heated to 140.degree. C. for 2 hours under a stream of 
nitrogen. After cooling to a temperature in the region of 20.degree. C., 
the precipitate formed is filtered off and washed with distilled water 
(4.times.250 cc) and then with ethyl ether (100 cc). 
2-Hydrazino-6-trifluoromethoxybenzothiazole (133.0 g), m.p. 208.degree. 
C., is obtained. 
2-Amino-6-trifluoromethoxybenzothiazole may be prepared according to the 
method described by L. M. YAGUPOL'SKII et al., Zh. Obshch. Khim., 33 (7), 
2301 (1963). 
EXAMPLE 2 
The procedure is as in Example 1, starting with 
2-methylamino-6-trifluoromethoxybenzothiazole (7.1 g) and 
1-chloro-2-ethylthioethane (4.2 g) in methyl ethyl ketone (10 cc). After 
48 hours at the boil, the reaction medium is cooled to a temperature in 
the region of 20.degree. C. The precipitate formed is filtered off and 
washed with methyl ethyl ketone (3.times.10 cc). After recrystallization 
in 2-propanol (50 cc), 
2-methylimino-3-(2-ethylthioethyl)-6-trifluoromethoxybenzothiazoline 
hydrochloride (5.3 g), subliming at about 150.degree. C., is obtained. 
EXAMPLE 3 
m-Chloroperbenzoic acid (2.0 g) is added in the course of approximately 10 
minutes to 
2-methylimino-3-(2-methylthioethyl)-6-trifluoromethoxybenzothiazoline (2.6 
g) dissolved in absolute ethanol (40 cc) cooled to -30.degree. C. Reaction 
is continued for 15 minutes at the same temperature. The reaction medium 
is then diluted with ethyl ether (100 cc) and treated with 4.2N ethereal 
ether hydrogen chloride (2.2 cc). The precipitate formed is filtered off 
and then recrystallized in 2-propanol (30 cc). 
(RS)-2-Methylimino-3-(2-methylsulphinylethyl-)-6-trifluoromethoxybenzothia 
zoline hydrochloride (2.0 g), subliming at about 170.degree. C., is 
obtained. 
EXAMPLE 4 
m-Chloroperbenzoic acid (2.5 g) is added in the course of approximately 10 
minutes to 
2-methylimino-3-(2-ethylthioethyl)-6-trifluoromethoxy-benzothiazoline (3.7 
g) dissolved in absolute ethanol (50 cc) cooled to -20.degree. C. Reaction 
is continued for 15 minutes at the same temperature. The reaction medium 
is then diluted with ethyl ether (100 cc) and treated with 4.2N ethereal 
hydrogen chloride (2.5 cc). The precipitate formed is filtered off, then 
taken up in distilled water (50 cc) and neutralized with 1N sodium 
hydroxide. After extraction with ethyl acetate, drying over magnesium 
sulphate and concentration to dryness under reduced pressure (20 mm Hg; 
2.7 kPa), the crude product is purified by chromatography on a silica 
column, with ethyl acetate and then a mixture of ethyl acetate and 
methanol (80:20 by volume) as eluents. After conversion to hydrochlorides, 
2-methylimino-3-(2-ethylsulphonylethyl)-6-trifluoromethoxybenzothiazoline 
hydrochloride (0.5 g), subliming at about 180.degree. C., and 
(RS)-2-methylimino-3-(2-ethylsulphinylethyl)-6-trifluoromethoxybenzothiazo 
line (1.9 g), subliming at about 180.degree. C., are obtained. 
EXAMPLE 5 
A mixture of 2-ethylamino-6-trifluoromethoxybenzothiazole (7.45 g) and 
1-chloro-2-methylthioethane (3.76 g) in methyl ethyl ketone (20 cc) is 
heated to boiling for 94 hours. After cooling to a temperature in the 
region of 20.degree. C., the precipitate formed is filtered off and washed 
with methyl ethyl ketone (2.times.20 cc). After recrystallization in 
2-propanol, 
2-ethylimino-3-(2-methylthioethyl)-6-trifluoromethoxybenzothiazoline 
hydrochloride (0.75 g), m.p. 208.degree. C., is obtained. 
2-Ethylamino-6-trifluoromethoxybenzothiazole may be prepared according to 
the following process: 2-chloro-6-trifluoromethoxybenzothiazole (11 g) and 
33% strength aqueous ethylamine (80 cc) are heated in an autoclave at 
110.degree. C. for 24 hours. After cooling to a temperature in the region 
of 20.degree. C., the reaction medium is added to distilled water (200 cc) 
and the precipitate formed is filtered off and washed with distilled water 
(2.times.100 cc). 2-Ethylamino-6-trifluoromethoxybenzothiazole (10.32 g), 
m.p. 135.degree. C., is obtained. 
The present invention also relates to medicinal products consisting of at 
least one compound of formula (I), or a salt of such a compound, in the 
pure state or in the form of a composition in which it is combined with 
any other pharmaceutically compatible product, which can be inert or 
physiologically active. The medicinal products according to the invention 
may be employed orally, parenterally, rectally or topically. 
As solid compositions for oral administration, tablets, pills, powders 
(gelatin capsules, wafer capsules) or granules may be used. In these 
compositions, the active principle according to the invention is mixed 
with one or more inert diluents such as starch, cellulose, sucrose, 
lactose or silica. 
These compositions can also comprise substances other than diluents, e.g. 
one or more lubricants such as magnesium stearate or talc, a coloring, a 
coating (dragees) or a varnish. 
As liquid compositions for oral administration, solutions, suspensions, 
emulsions, syrups and elixirs of a pharmaceutically acceptable nature, 
containing inert diluents such as water, ethanol, glycerol, vegetable oils 
or liquid paraffin, may be used. These compositions can comprise 
substances other than diluents, e.g. wetting products, sweeteners, 
thickeners, flavorings or stabilizers. 
The sterile compositions for parenteral administration can preferably be 
suspensions, emulsions or non-aqueous solutions. As a solvent or vehicle, 
water, propylene glycol, a polyethylene glycol, vegetable oils, especially 
olive oil, injectable organic esters, e.g. ethyl oleate, or other suitable 
organic solvents may be employed. These compositions can also contain 
adjuvants, especially wetting agents, tonicity regulators, emulsifiers, 
dispersants and stabilizers. The sterilization may be carried out in 
several ways, e.g. by aseptic filtration, by incorporating sterilizing 
agents in the composition, by irradiation or by heating. They may also be 
prepared in the form of sterile solid compositions which can be dissolved 
at the time of use in sterile water or any other sterile injectable 
medium. 
The compounds for rectal administration are suppositories or rectal 
capsules which contain, apart from the active product, excipients such as 
cocoa butter, semi-synthetic glycerides or polyethylene glycols. 
The compounds for topical administration can be e.g. creams, ointments, 
lotions, eye washes, mouth washes, nasal drops or aerosols. 
In human therapy, the compounds according to the invention are especially 
useful in the treatment and prevention of convulsive phenomena, 
schizophrenic disorders, and in particular the deficiency forms of 
schizophrenia, sleep disorders, phenomena linked to cerebral ischaemia and 
neurological conditions in which glutamate may be implicated, such as 
Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis 
and olivopontocerebellar atrophy. 
The doses depend on the effect sought, the treatment period and the 
administration route used; they are generally between 30 and 300 mg per 
day in oral administration for an adult, with unit doses ranging from 10 
to 100 mg of active substance. 
Generally speaking, the doctor will determine the appropriate dosage in 
accordance with the age and weight and all other factors characteristic of 
the subject to be treated. 
EXAMPLES 
The examples which follow illustrate compositions according to the 
invention: 
EXAMPLE A 
Hard gelatin capsules containing 50 mg of active product and having the 
following composition are prepared according to the usual technique: 
______________________________________ 
2-methylimino-3-(2-methylthioethyl)-6- 
50 mg 
trifluoromethoxybenzothiazoline 
cellulose 18 mg 
lactose 55 mg 
colloidal silica 1 mg 
carboxymethylstarch sodium 
10 mg 
talc 10 mg 
magnesium stearate 1 mg 
______________________________________ 
EXAMPLE B 
Tablets containing 50 mg of active product and having the following 
composition are prepared according to the usual technique: 
______________________________________ 
2-methylimino-3-(2-ethylthioethyl)-6- 
50 mg 
trifluoromethoxybenzothiazoline 
lactose 104 mg 
cellulose 40 mg 
polyvidone 10 mg 
carboxymethylstarch sodium 
22 mg 
talc 10 mg 
magnesium stearate 2 mg 
colloidal silica 2 mg 
mixture of hydroxymethyl cellulose, 
1 finished 
glycerol and titanium oxide 
(72:3.5:24.5) q.s. 
tablet weighing 245 mg 
______________________________________ 
EXAMPLE C 
An injectable solution containing 10 mg of active product and having the 
following composition is prepared: 
______________________________________ 
2-methylimino-3-(2-ethylsulphonylethyl)-6- 
10 mg 
trifluoromethoxybenzothiazoline 
benzoic acid 80 mg 
benzyl alcohol 0.06 cc 
sodium benzoate 80 mg 
ethanol, 95% 0.4 cc 
sodium hydroxide 24 mg 
propylene glycol 1.6 cc 
water q.s. 4 cc 
______________________________________ 
Although the invention has been described in conjunction with specific 
embodiments, it is evident that many alternatives and variations will be 
apparent to those skilled in the art in light of the foregoing 
description. Accordingly, the invention is intended to embrace all of the 
alternatives and variations that fall within the spirit and scope of the 
appended claims. The above references are hereby incorporated by reference 
.