FR2699920A1 - New 2-phenyl-imidazo-(2,1-b)benzothiazole-3-acetamide derivs - Google Patents

Abstract

Imidazo-(2,1-b)benzothiazole derivs. of formula (I) and their acid-addn. salts are new. X = H or Cl; Y = F, Cl, Br or Me; R1 and R2 = H or Me.

Description

The present invention relates to imida zo [2,1-b] benzothiazole-3-acetamide derivatives, their preparation and their therapeutic application.

dans laquelle
X représente un atome d'hydrogène ou de chlore,
Y représente un atome de fluor, de chlore ou de brome, ou un groupe méthyle, Rl représente un atome d'hydrogène ou un groupe méthyle, et
R2 représente un atome d'hydrogène ou un groupe méthyle.The compounds of the invention correspond to the general formula (I)

in which
X represents a hydrogen or chlorine atom,
Y represents a fluorine, chlorine or bromine atom, or a methyl group, R1 represents a hydrogen atom or a methyl group, and
R2 represents a hydrogen atom or a methyl group.

The compounds of the invention may be in the form of free bases or addition salts with acids.

According to the invention, these compounds can be prepared according to methods illustrated by the following diagrams 1 and 2.

une amine de formule générale HNRlR2 (dans laquelle RI et R2 sont tels que définis ci-dessus) à une température de 0 à 200C, pour obtenir un dérivé d'a-hydroxyacétamide de formule générale (IV). According to process (a) of Scheme 1, an imidazo (2,1b) benzothiazole derivative of general formula (II) (wherein X and Y are as defined above) is reacted with glyoxylic acid in a protic solvent such as acetic acid, at a temperature of 20 to 1200C, to form an α-hydroxyacetic acid derivative of general formula (III) .The latter is reacted with acetic anhydride in the presence of a organic base such as pyridine, at a temperature of 20 to 60 ° C, to form the corresponding α-acetyloxyacetic acid derivative, which is itself treated with N, N'-carbonyldiimidazole in an inert solvent , for example a chlorinated or ethereal solvent such as dichloromethane or tetrahydrofuran, at a temperature of 20 to 500C, then the intermediate imidazolide thus obtained is treated in situ with
Diagram 1

an amine of general formula HNR1R2 (wherein R1 and R2 are as defined above) at a temperature of 0 to 200C, to obtain an α-hydroxyacetamide derivative of general formula (IV).

When each of the symbols R1 and R2 represents a methyl group, a variant of the process consists in preparing an α-hydroxyacetamide derivative of general formula (IV) by treating a compound of general formula (II) with a glyoxamide of general formula HC ( O) C (O) NR1R2 (wherein R1 and R2 each represent a methyl group and are prepared in situ by means of 2,2-diethoxy-N, N-dimethylacetamide as described in patent application EP-251859 ), in a protic solvent, for example acetic acid, at a temperature of 20 to 800C.

The α-hydroxyacetamide derivative of general formula (IV) is then treated with a polyhalide of sulfuric or phosphoric acid, for example thionyl chloride or phosphorus oxychloride or any other equivalent agent, in an inert solvent, for example a chlorinated or ethereal solvent such as dichloromethane or tetrahydrofuran, at a temperature of 20 to 800 ° C., to form an α-haloacetamide derivative of general formula (V) (in which X,
Y, R 1 and R 2 are as defined above and Hal represents a halogen atom, for example chlorine).

Finally, the compound of general formula (V) is reacted either with a reducing agent such as a simple or complex alkali metal hydride, for example sodium or potassium borohydride, in a protic solvent, for example an aliphatic alcohol such as methanol or ethanol, or in an inert solvent miscible with water, for example dioxane or tetrahydrofuran, at a temperature of -40 to 400C, or with a reducing agent such as hyposulphite or an alkaline dithionite, by for example, sodium hyposulphite or dithionite, or with sodium hydroxymethylsulfoxylate (Rongalite), in an inert solvent, for example a chlorinated solvent such as dichloromethane, optionally in the presence of an inert water-miscible cosolvent; for example N, N-dimethylformamide or N-methylpyrrolidone at a temperature of 20 to 400C.

Another process (b) of preparation is illustrated in Scheme 2 below.

l'acide acétique, éventuellement dans un co-solvant éthéré, par exemple le dioxane, à une température de 20 à 1000C, pour former une base de Mannich de formule générale (VI), que l'on quaternise au moyen d'un agent méthylant, par exemple l'iodométhane ou le sulfate de diméthyle, dans un solvant éthéré ou chloré, par exemple l'éther diéthylique ou le dichlorométhane.On traite ensuite le sel d'ammonium ainsi obtenu par un cyanure alcalin, par exemple le cyanure de sodium ou de potassium, en présence d'eau et dans un solvant alcoolique, par exemple l'éthanol ou le 2-méthoxyéthanol, à la température de reflux, pour obtenir un dérivé d'acétamide de formule générale (Ia), laquelle correspond à la formule générale (I) lorsque Rl et R2 représentent chacun un atome d'hydrogène.It consists in reacting an imidazo [2,1b) benzothiazole derivative of the general formula (II) (in which X and Y are as defined above) with formaldehyde and dimethylamine in the presence of an excess acid, for example
Figure 2

acetic acid, optionally in an ethereal co-solvent, for example dioxane, at a temperature of 20 to 1000C, to form a Mannich base of general formula (VI), which is quaternized by means of an agent methylating agent, for example iodomethane or dimethyl sulfate, in an ether or chlorinated solvent, for example diethyl ether or dichloromethane. The ammonium salt thus obtained is then treated with an alkaline cyanide, for example cyanide of sodium or potassium, in the presence of water and in an alcoholic solvent, for example ethanol or 2-methoxyethanol, at the reflux temperature, to obtain an acetamide derivative of general formula (Ia), which corresponds to the general formula (I) when R1 and R2 each represent a hydrogen atom.

If it is desired to prepare a compound of general formula (I) in which R 1 and / or R 2 represents a methyl group, the compound of general formula (Ia) is subjected to hydrolysis to obtain an acetic acid derivative of general formula (VIII ), then the latter is reacted with N, N'-carbonyl diimidazole or thionyl chloride, or any other equivalent reagent, in an inert solvent, for example a chlorinated or ethereal solvent such as dichloromethane or tetrahydrofuran, to a temperature of 20 to 500C, to obtain a compound of general formula (IX) (wherein X and Y are as defined above and Z represents an imidazolyl group or a chlorine atom), and finally said compound is treated with an amine of the general formula HNR1R2 (wherein R1 and / or R2 is methyl) at a temperature of 0 to 250C.

The imidazo [2,1-b] benzothiazole derivatives of the general formula (II) are commercially available or, failing this, may be prepared by any method described in the literature, for example in Khim. Geterosikl. Soedin. 72, 1271 (1972) or Bull. Soc. Chim. Fr. 1277 (1966), by the action of a 2-aminobenzothiazole, substituted with Y, on a-bromoacetophenone. The 2-amino-5-chloro and 2-amino-5-fluorobenzothiazoles can be prepared according to J. Med. Chem. 34, 914 (1991). 2-Amino-5-bromobenzothiazole can be prepared according to a variant of the process described in J. Chem. Soc. 268 (1969), illustrated by Scheme 3 below.

Figure 3

The following examples illustrate in detail the preparation of some compounds according to the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.

The numbers of the compounds indicated in parentheses in the titles correspond to those of the table given below.

Example 1 (Compound No. 15) 6-Bromo-N, N-dimethyl-2-phenylimidazo [2,1-b] benzothiazole-3-acetamide.

1.1 4-Bromo-2-nitrophenyl thiocyanate.

A mixture of 58 g (206 mmol) of 1,4-dibromo-2-nitrobenzene, 20 g (206 mmol) of potassium thiocyanate and 300 ml of N, N-dimethylformamide is heated for 4h30 to 1200C.

It is allowed to cool, the inorganic salts are removed by filtration, and the solvent is evaporated off under reduced pressure.

The residue is taken up with 300 ml of absolute ethanol, the suspension is stirred for 2 h, the solid is filtered off, washed with ethanol and dried.

19.5 g of compound are obtained.

Melting point: 126-127 ° C.

1.2 2-Amino-5-bromobenzothiazole.

A suspension of 19.5 g (75 mmol) of 4-bromo-2-nitrophenyl thiocyanate in 240 ml of 35% hydrochloric acid is prepared, and 80 g of shot tin are slowly added for 2.5 hours.

Stirring is maintained for 24 hours at room temperature, and the suspension is heated under reflux for 3 hours.

The mixture is poured into 500 ml of water, ammonia is added to pH 11, and allowed to stand overnight.

The solid is filtered off with suction, washed with water, dried and extracted in a Soxhlet apparatus for 8 hours with toluene. After filtration, washing with toluene, washing with pentane and drying under vacuum, 13.2 g of compound are obtained.

Melting point: 186-1870C.

1.3 6-Bromo-2-phenylimidazo [2,1-b] benzothiazole.

9.8 g (43 mmol) of 2-amino-5-bromobenzothiazole and 9.4 g (47 mmol) of 1-bromo-2-phenylethan-2-one are dissolved in 85 ml of absolute ethanol and heated. the solution for 9h at reflux.

The mixture is allowed to cool, the precipitate is filtered off and, after drying, 8.3 g of crude hydrobromide is obtained.

It is taken up with a mixture of water and dichloromethane, ammonia is added until pH 11, the organic phase is separated, it is dried over sodium sulphate, the solvent is evaporated off under reduced pressure, and it is recrystallized. the residue in 100 ml of boiling ethanol.

2.7 g of compound are obtained.

Melting point: 167-1680C.

1.4 6-Bromo-α-hydroxy-N, N-dimethyl-2-phenylimidate
zo [2,1-b] benzothiazole-3-acetamide.

11.5 g (65 mmol) of 2,2-diethoxy-N, N-dimethylacetamide and 1.45 ml of hydrochloric acid (d = 1.17, ie 16.4 mmol) are dissolved in 110 ml of acid. acetic acid, and the solution is heated for 1 hour at 450C.

5.4 g (65 mmol) of sodium acetate are added, and the heating and stirring are maintained for 15 minutes.

7.2 g (22 mmol) of 6-bromo-2-phenylimidazo (2,1-b) benzothiazole are added to the suspension, and the mixture is heated for 14 hours at 450 ° C.

The acetic acid is removed by evaporation under reduced pressure, the residue is taken up in a 50/50 mixture of water and dichloromethane, ammonia is added until pH 11, the solid is filtered off, and the mixture is separated. the organic phase, dried over sodium sulfate, the solvent is evaporated under reduced pressure, the residue is crystallized from diethyl ether and dried under vacuum.

3.5 g of compound are obtained which are purified by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloromethane / methanol.

2.3 g of compound are obtained.

Melting point: 173-1750 ° C.

1.5 6-Bromo-N, N-dimethyl-2-phenylimidazot2,1-b] benzoate
thiazole-3-acetamide.

2.3 g (5.3 mmol) of 6-bromo-α-hydroxy-N, N-dimethyl-2-phenylimidazot-2,1-b] benzothiazole-3-acetamide are treated with 11 ml of thionyl chloride in 110 ml of dichloromethane at room temperature for 48 hours.

The solvent and the excess of thionyl chloride are evaporated under reduced pressure, the residue is taken up in diethyl ether, the solid is filtered off, washed with ether and dried. 2.3 g of 6-bromo-α-chloro-N, N-dimethyl-2-phenylimidazo [2,1b] benzothiazole-3-acetamide hydrochloride are obtained, which are reduced by means of 2.2 g ( 14 mmol) of Rongalites in 110 ml of dichloromethane at room temperature for 24 hours.

The solution is washed with a 4% aqueous solution of sodium hydrogencarbonate, then with water, dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is taken up with diethyl ether. and dried under vacuum. 1.6 g of compound are obtained which is purified by recrystallization from 320 ml of absolute ethanol and then by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane / methanol.

Finally, 0.7 g of compound is obtained.

Melting point: 212-213.5 ° C.

Example 2 (Compound NO7) 6-Chloro-2-phenylimidazo [2,1-b] benzothiazole-3-acetamide.

2.1 6-Chloro-2-phenylimidazo [2,1-b] benzothiazole.

9 g (49 mmol) of 2-amino-5-chlorobenzothiazole dissolved in 100 ml of ethanol are treated with 10.6 g (54 mmol) of 1-bromo-2-phenylethan-2-one for 2 h at room temperature. then for 8h at reflux temperature, then for 16h at room temperature.

The solid is filtered off and washed in 200 ml of boiling ethanol. 7.3 g of hydrobromide are obtained, the base is freed with ammonia, the mixture is extracted with dichloromethane, the organic phase is separated off, washed with water and dried over sodium sulphate. evaporates the solvent under reduced pressure.

4.75 g of compound are obtained.

2.2 6-Chloro-N, N-dimethyl-2-phenylimidazot-2,1-b] benzothiazole-3-methanamine.

0.85 ml of a 40% aqueous solution of dimethylamine and 0.68 ml of a 37% aqueous solution of formaldehyde in 14 ml of dioxane and 2 ml of acetic acid are mixed and then added in small portions. portions, 2 g (7 mmol) of 6-chloro-2-phenylimidazo [2,1-b] benzothiazole, and the mixture is stirred for 3h at room temperature and then for 1h30 at 800C.

The solvents are evaporated off under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated off, ammonia is added to pH 11, washed with water and dried. on sodium sulfate, the solvent is evaporated under reduced pressure, the residue is washed with pentane and dried.

1.9 g of compound are obtained which is used as such in the next step.

2.3 6-Chloro-N, N, N-trimethyl-2-phenylimidazo [2,1-b] benzothiazole-3-methanammonium iodide.

1.9 g (5.6 mmol) of 6-chloro-N, N-dimethyl-2-phenylimidazo [2,1-b] benzothiazole-3-methanamine are treated, dissolved in 10 ml of dichloromethane, with 0.41 g ml (6.7 mmol) of iodomethane for 24h at room temperature.

The precipitate is filtered off, washed with diethyl ether and dried in vacuo.

1.7 g of compound are obtained which is used as such in the next step.

2.4 6-Chloro-2-phenylimidazo [2,1-b] benzothiazole-3-acetal
mide.

1.7 g (3.5 mmol) of 6-chloro-N, N, N-trimethyl-2-phenylimidazo [2,1-b] benzothiazole-3-methanammonium iodide are treated, suspended in 11 ml of a 9/2 mixture of methoxyethanol / water, with 0.86 g (17.6 mmol) of sodium cyanide, while heating the mixture under reflux for 6 hours.

The methoxyethanol is evaporated under reduced pressure, the residue is taken up with water, filtered off, washed with water until cyanide ions disappear in the filtrate, dried under vacuum, and it is recrystallized from methanol.

Finally, 0.7 g of compound is obtained.

Melting point: 290-2920C (decomposition).

 Example 3 (Compound No. 19) 2- (4-Chlorophenyl) -6-fluoro-N-methylimidazo [2,1-b] benzothiazole-3-acetamide.

3.1 2- (4-Chlorophenyl) -6-fluoro-N-methylimidazo [2,1-b] ben-
zothiazole.

17 g (63.5 mmol) of 2-amino-5-fluorobenzothiazole, dissolved in 100 ml of ethanol, are treated with 15.1 g (63.5 mmol) of 1-bromo-2- (4-chlorophenyl) ) ethan-2-one, by heating the mixture under reflux for 7h and stirring at room temperature for 16h.

The solid hydrobromide is filtered off, suspended in dichloromethane, an excess of ammonia is added, the organic phase is separated, dried over sodium sulfate, the solvent is evaporated under reduced pressure and purified. the residue by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloromethane / methanol.

11.67 g of compound are obtained.

3.2 2- (4-Chlorophenyl) -6-fluoro-α-hydroxyimidazo [2,1-b] benzothiazole-3-acetic acid.

A mixture of 5.8 g (19 mmol) of 2- (4-chlorophenyl) -6-fluoro-N-methylimidazo [2,1b] benzothiazole and 2.9 g (38 mmol) is heated at 800 ° C. for 4 hours. of glyoxylic acid in 100 ml of acetic acid.

The solvent is evaporated off under reduced pressure, the residue is taken up with water, the solid is filtered off, washed with water, then with ethanol, then with diethyl ether and dried under vacuum.

5.2 g of compound are obtained.

3.3 2- (4-Chlorophenyl) -6-fluoro-α-hydroxy-N-methylimidazo [2,1-b] benzothiazole-3-acetamide.

5.16 g (13.7 mmol) of 2- (4-chlorophenyl) 6-fluoro-α-hydroxyimidazo [2,1-b] benzothiazole-3-acetic acid are dissolved in 66 ml of a 50/50 mixture. 50% pyridine / acetic acid, and the mixture is stirred at room temperature for 30h.

The solvents are evaporated under reduced pressure, the residue is taken up with diethyl ether, the solid is filtered off and dried in vacuo.

3.94 g (9.4 mmol) of the thus obtained α-acetyloxyacetic acid and 2.29 g (14.1 mmol) of N, N'-carbonyldiimidazole are reacted in 60 ml of dry tetrahydrofuran at room temperature for 30 minutes. lh.

The mixture is cooled with a water-ice bath, treated with an excess of dry methylamine, and the stirring is maintained at room temperature for 16 hours.

The solvent is evaporated off under reduced pressure, the residue is taken up with water and dichloromethane, the organic phase is separated off, dried over sodium sulphate and the solvent is evaporated off under reduced pressure.

2.8 g of compound are obtained which is used as such in the next step.

3.4 a-Chloro-2- (4-chlorophenyl) -6-fluoro-N-methylimidazole
zo [2,1b] benzothiazole-3-acetamide hydrochloride.

2.8 g (7.2 mmol) of 2- (4-chlorophenyl) -6-fluoro-hydroxy-N-methylimidazo [2,1-b] benzothiazole-3-acetamide are treated in 65 ml of dry dichloromethane with 13 ml of thionyl chloride at room temperature for 24 hours.

The solvent and excess thionyl chloride are evaporated under reduced pressure, the solid residue is washed with diethyl ether and dried in vacuo.

3.04 g of compound are obtained.

3.5 2- (4-Chlorophenyl) -6-fluoro-N-methylimidazo [2,1-b] benzothiazole-3-acetamide.

3.04 g (6.8 mmol) of α-chloro-2- (4-chlorophenyl) -6-fluoro-N-methylimidazo [2,1-b] benzothiazole-3-acetamide hydrochloride are treated with 3 g. 16 g (20.5 mmol) of Rongalites in 80 ml of dichloromethane at room temperature for 16 hours.

The solid is removed by filtration, the filtrate is washed with water, dried over sodium sulfate, the solvent is evaporated off under reduced pressure, and the residue is purified by recrystallization from ethanol and then by gel column chromatography. of silica eluting with a 6/4 mixture of dichloromethane / ethyl acetate.

Finally, 0.14 g of compound is obtained.

Melting point: 292-294 ° C (decomposition).

The following table illustrates the chemical structures and the physical properties of some compounds according to the invention.

All compounds are in the form of bases.

In the last column, "(d)" indicates a melting point with decomposition.

Board

<tb> N <SEP> X <SEP> Y <SEP> R1 <SEP> R2 <SEP> F <SEP> (C) <SEP>
<tb><SEP> 1 <SEP> H <SEP> 6-F <SEP> H <SEP> H <SEP> 282-284
<tb><SEP> 2 <SEP> H <SEP> 6-F <SEP> CH3 <SEP> H <SEP> 296-298 <SEP> (d)
<tb><SEP> 3 <SEP> H <SEP> 6-F <SEP> CH3 <SEP> CH3 <SEQ> 166-168
<tb><SEP> 4 <SEP> H <SEP> 7-F <SEP> H <SEP> H <SEP> 277-279
<tb><SEP> 5 <SEP> H <SEP> 7-F <SEP> CH3 <SEP> H <SEP> 250-252
<tb><SEP> 6 <SEP> H <SEP> 7-F <SEP> CH3 <SEP> CH3 <SEQ> 102-104
<tb><SEP> 7 <SEP> H <SEP> 6-Cl <SEP> H <SEP> H <SEP> 290-292 <SEP> (d)
<tb><SEP> 8 <SEP> H <SEP> 6-Cl <SEP> CH3 <SEP> H <SEP> 294-296
<tb><SEP> 9 <SEP> H <SEP> 6-Cl <SEP> CH3 <SEP> CH3 <SEP> 201.5-202.5
<tb> 10 <SEP> H <SEP> 7-Cl <SEP> H <SEP> H <SEP> 281-282 <SEP> (d)
<tb> 11 <SEP> H <SEP> 7-Cl <SEP> CH3 <SEP> H <SEP> 277,5-279
<tb> 12 <SEP> H <SEP> 7-Cl <SEP> CH3 <SEP> CH3 <SEP> 192-194
<tb> 13 <SEP> H <SEP> 6-Br <SEP> H <SEP> H <SEP> 274-275
<tb> 14 <SEP> H <SEP> 6-Br <SEP> CH3 <SEP> H <SEP> 278-280
<tb> 15 <SEP> H <SEP> 6 -Br <SEP> CH3 <SEP> CH3 <SEP> 212-213.5
<tb> 16 <SEP> H <SEP> 7-CH3 <SEP> H <SEP> H <SEP> 302-304
<tb> 17 <SEP> H <SEP> 7-CH3 <SEP> CH3 <SEP> H <SEP> 263-264
<tb> 18 <SEP> H <SEP> 7-CH3 <SEP> CH3 <SEP> CH3 <SEP> 221,5-222 <SEP>
<tb> 19 <SEP> Cl <SEP> 6-F <SEP> CH3 <SEP> H <SEP> 292-294 <SEP> (d)
<tb> 20 <SEP> Cl <SEP> 6-F <SEP> CH3 <SEP> CH3 <SEP> 225-226
<Tb>
The compounds of the invention have been subjected to pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Study of membrane bonds with respect to ol (benzodiazepine type 1) and * (benzodiazepine type 2) receptors.

The affinity of the compounds for the xI receptors of cerebellum and Co2 of the spinal cord was determined according to a variant of the method described by SZ Langer and S. Arbilla in
Fund. Clin. Pharmacol., 2, 159-170 (1988), using 3H-flumazenil instead of 3H-diazepam as radioligand.

The tissue of the cerebellum or spinal cord is homogenized for 60 seconds in 120 or 30 volumes, respectively, of ice-cold buffer (50 mM Tris / HCl, pH 7.4, 120 mM NaCl, 5 mM KCl) and then, after dilution with 1/3, the suspension is incubated with 3H-flumazenil (specific activity 78 Ci / mmol, New
England Nuclear) at a concentration of 1 nM and with the compounds of the invention at different concentrations, in a final volume of 525 μl. After 30 minutes of OOC incubation, the samples were vacuum filtered on Whatman GF / Bs filters and washed immediately with ice-cold buffer. The specific binding of 3H-flumazenil is determined in the presence of unlabeled 1M diazepam. The data are analyzed according to the usual methods and the IC 2 concentration is calculated which inhibits the binding of 3H-flumazenil by 50%.

The compounds of the compounds of the invention are in these tests between 1 and 1000 nM.

Study of anticonvulsant activity.

Activity against peak convulsions induced in mice by electroshock or by pentetrazol injection.

The protocol for this trial is described by EA Swinyard and
JH Woodhead in Antiepileptic Drugs, Raven Press, New
York, 111-126 (1982).

30 minutes after intraperitoneal administration of the test compound, we note the number of mice with convulsions (extensions of the hind legs), or immediately after application of an electric current (0.4 s, 60 mA, 50 Hz) to the using transcorneal electrodes, ie during the 30 minutes following the subcutaneous injection of pentetrazol (125 mg / kg). The results are expressed by DAS, a dose which protects 50% of the animals, calculated according to the method of JT Lichtfield and F. Wilcoxon (J. Pharm Exp Ther, 96, 99-113 (1949)) from 3 or 4 doses each administered to a group of 8 to 10 mice.

The DA50 of the compounds of the invention are, in this test, between 1 and 100 mg / kg by the intraperitoneal route.

Activity against convulsions induced in mice by isoniazid.

The intrinsic activity of the compounds is determined by the latent onset time of convulsions induced by the subcutaneous administration of isoniazid (800 mg / kg) simultaneously with the test compound, injected intraperitoneally, according to protocol described by G. Perrault,
E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988). The results are expressed as DA50, a dose which produces 50% of the maximal effect, relative to the control animals, determined from 3 or 4 doses administered each to a group of 8 to 10 mice.

The DAso of the compounds of the invention are, in this test, between 3 and 30 mg / kg by the intraperitoneal route.

Study of anxiolytic activity.

The anxiolytic activity is evaluated in the rat in the drink intake conflict test, according to the method described by
JR Vogel, B. Beer and DE Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971).

After a 48-hour water diet, the rat is placed in an enclosure isolated from noise and equipped with a water pipette connected to an anxiometer delivering a slight electric shock every 20 licks. The number of shocks received is automatically counted for 3 minutes, and makes it possible to evaluate the anxiolytic activity of the compounds tested. The results are expressed as the minimum effective dose (DEM), a dose that produces a significant increase in the number of shocks received, compared to the number observed in the control animals.

The DEMs of the compounds of the invention are, in this test, between 10 and 100 mg / kg by the intraperitoneal route.

The results of the tests carried out on the compounds of the invention show that, in vitro, they displace 3H-flumazenil from its specific binding sites in the cerebellum and the spinal cord; therefore they have an affinity for o, and 6d2 (benzodiazepine type 1 and type 2) sites located within the macromolecular complex GABAA-z-channel chloride sites.

In vivo they behave as complete or partial agonists, or as antagonists to these receptors.

They possess anticonvulsant and anxiolytic properties and, therefore, can be used for the treatment of disorders related to GABAergic transmission disorders, such as anxiety, sleep disorders, epilepsy, spasticity, muscle contractures , cognitive disorders, withdrawal problems with alcoholism, etc.

For this purpose they may be presented in all galenic forms, combined with appropriate excipients, for enteral or parenteral administration, for example in the form of tablets, dragees, capsules, capsules, oral or injectable solutions or suspensions, suppositories, etc. dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (4)

claims 1. Compound corresponding to general formula (I)

 in which X represents a hydrogen or chlorine atom, Y represents a fluorine, chlorine or bromine atom, or a methyl group, R1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group, in the form of a base or an addition salt with an acid. 2. Process for the preparation of compounds according to claim 1, characterized in that a) is reacted a derivative of imidazot2tl-b] benzothiazole of general formula (II)

 (wherein X and Y are as defined in claim 1) with glyoxylic acid in a protic solvent at a temperature of 20 to 1200C to form an α-hydroxyacetic acid derivative of the general formula (III)

 and reacting the latter with acetic anhydride in the presence of an organic base, at a temperature of 20 to 600 ° C, to form the corresponding α-acetyloxyacetic acid derivative, which is itself treated by means of N, N'-carbonyldiimidazole in an inert solvent at a temperature of 20 to 500C, then the intermediate imidazolide thus obtained is treated in situ with an amine of the general formula HNR1R2 (in which R1 and R2 are as defined in the claim 1) at a temperature of 0 to 200C, to obtain an α-hydroxyacetamide derivative of general formula (IV)

 or, when each of the symbols R1 and R2 represents a methyl group, an α-hydroxyacetamide derivative of general formula (IV) is prepared by treating a compound of general formula (II) with a glyoxamide of general formula HC (o) C (O) NR 1 R 2 (wherein R 1 and R 2 each represent a methyl group) in a protic solvent, at a temperature of 20 to 800 ° C., and then treating the α-hydroxyacetamide derivative of general formula (IV) with a polyhalogenide of sulfuric acid or phosphoric acid, in an inert solvent, at a temperature of 20 to 800C, to form an α-haloacetamide derivative of general formula (V)

 (wherein X, Y, R 1 and R 2 are as defined in claim 1 and Hal represents a halogen atom), and finally the compound of general formula (V) is reacted with either a reducing agent such as a single or complex alkali metal hydride in a protic solvent or in an inert solvent miscible with water at a temperature of -40 to 400C, either with a reducing agent such as hyposulphite or an alkaline dithionite, or with sodium hydroxymethylsulfoxylate, in an inert solvent, optionally in the presence of an inert water-miscible cosolvent, at a temperature of 20 to 400 ° C, or b) an imidazo [2,1-b derivative] is reacted ] benzothiazole of general formula (II) with formaldehyde and dimethylamine in the presence of an excess of acid, optionally in an ethereal co-solvent, at a temperature of 20 to 1000C, to form a Mannich base of general formula ( VI)

 quaternize by means of a methylating agent, and then the ammonium salt thus obtained is treated with an alkaline cyanide, in the presence of water and in an alcoholic solvent, at the reflux temperature, to obtain a derivative of acetamide of the general formula (Ia)

 which corresponds to the general formula (I) when R1 and R2 each represent a hydrogen atom, then, if it is desired to prepare a compound of general formula (I) in which R1 and / or R2 represents a methyl group, the compound of general formula (Ia) for hydrolysis to obtain an acetic acid derivative of general formula (VIII)

 then the latter is reacted with N, N'-carbonyldiimidazole or thionyl chloride, in an inert solvent, at a temperature of 20 to 500C, to obtain a compound of general formula (IX)

 (wherein X and Y are as defined in claim 1 and Z represents an imidazolyl group or a chlorine atom), and finally said compound is treated with an amine of the general formula HNR1R2 (wherein R1 and / or R2 represents a methyl group) at a temperature of 0 to 250C. 3. Medicinal product characterized in that it consists of a compound corresponding to the general formula (I). 4. Pharmaceutical composition characterized in that it contains a compound associated with a pharmaceutical excipient.