IE922342A1 - Imidazo[2,1-b]benzothiazole-3-acetamide derivatives, their¹preparation and their use in therapeutics - Google Patents

Abstract

Compounds corresponding to the general formula (I) in which X represents a hydrogen or halogen atom or a methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylsulphonyl, cyano or aminocarbonyl group, R1 represents a hydrogen atom or a C1-C4 alkyl group, R2 represents either a hydrogen atom; or a linear, branched or cyclic C1-C5 alkyl group, optionally substituted by one or more fluorine atoms, by a methoxy group, by a dimethylamino group or by a phenyl group; or a prop-2-enyl group; or a prop-2-ynyl group; or a phenyl group; or else R1 and R2 together form, and with the nitrogen atom which carries them, a 1-pyrrolidinyl, 1-piperidinyl, 1-hexahydroazepinyl, 4-(phenylmethyl)piperidin-1-yl, 4-methylpiperazin-1-yl, 4-(phenylmethyl)piperazin-1-yl, 1-morpholinyl or 1-thiomorpholinyl group. Application in therapeutics.

Description

The present invention relates to imidazo[2,lb]benzothiazole-3-acetamide derivatives, their preparation and their use in therapeutics.

The invention provides a compound which is an imidazo[2,l-b]benzothiazole-3-acetamide derivative represented by formula (I) R (I) in which X represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylsulphonyl, cyano or aminocarbonyl; R1 represents hydrogen or 0,-C^ alkyl; and 20 Rj represents hydrogen, prop-2-enyl, prop-2-ynyl, phenyl, or C^-Cj alkyl optionally substituted by at least one fluorine atom, a methoxy group, a dimethylamino group or a phenyl group; or R1 and R2 form, together with the nitrogen atom to which they 25 are attached, pyrrolidin-l-yl, piperidin-l-yl, hexahydroazepin1-yl, 4-(phenylmethyl)piperidin-l-yl, 4-methylpiperazin-l-yl, 4-(phenylmethyl)piperazin-l-yl, morpholin-l-yl or thiomorpholin-l-yl; provided that when X represents hydrogen or bromine in position - 3 4, R1 and R2 do not both represent hydrogen; or a pharmaceutically acceptable acid addition salt thereof.

Compounds of formula (I) in which X is hydrogen or bromine in position 4, and R1 and R2 are both hydrogen are 5 described as synthesis intermediates in Chem. Pharm. Bull., 36(12), 4760-4768 (1988).

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

The group R2 may be a linear, branched or cyclic alkyl group of up to 5 carbon atoms. A linear alkyl group may, for example, be methyl, ethyl, n-propyl or n-butyl. A branched alkyl group may be isopropyl, sec- or tert-butyl. A cyclic alkyl group may be cyclopentyl.

In preferred compounds of the invention, R1 and R2, which may be the same or different, each represents hydrogen or methyl. When R, and R2 form a substituent containing a ring, X preferably represents hydrogen, chlorine, methyl or methoxy.

A compound of the invnetion is useful as a type 1 and 2 benzodiazepine receptor antagonist or agonist, and hence is useful as an anticonvulsant or an anxiolytic agent.

The invention also provides a process for producing a compound of the invention, which process comprises dehalogenation of an α-halogenoacetamide derivative represented by formula (V) (V) in which X, R1 and R2 are as hereinbefore defined and Hal represents a halogen atom, and optionally converting the compound of formula (I) thereby obtained into a physiologically acceptable acid addition salt thereof. process illustrated by scheme 1 above.

An imidazo[2,1-b]benzothiazole derivative of general formula (II) (in which X is as defined above) is reacted with glyoxylic acid in a protic solvent such as acetic acid, at a temperature of 20 to 120’C, in order to form an a-hydroxyacetic acid derivative of general formula (III). The latter is reacted with acetic anhydride in the presence of an organic base such as pyridine, at a temperature of 20 to 60°C, in order to form the corresponding α-acetyloxyacetic acid derivative, which itself is treated with Ν,Ν'-carbonyldiimidazole in an inert solvent, such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 to 50°C, and the intermediate imidazolide thus obtained is then treated in situ with an amine of general formula HNR,^ (in which R1 and R2 are as defined above) at a temperature of 0 to ’C.

An α-hydroxyacetamide derivative of general formula (IV) is obtained, which is then treated with a sulphuric or phosphoric acid polyhalide, such as thionyl chloride or phosphorus oxychloride or any other equivalent agent, in an inert solvent such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 to 80°C, in order to form an α-halogenoacetamide derivative of general formula (V) (in which X, R, and R2 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 borohydride or potassium borohydride, in a protic solvent, such as an aliphatic alcohol, for example methanol or ethanol, or in a water-miscible inert solvent, for example dioxane or tetrahydrofuran, at a temperature of -40 to 40*0, or with a reducing agent such as an alkali metal hyposulphite or dithionite, for example sodium hyposulphite or sodium dithionite, or with sodium hydroxymethylsulphoxylate (Rongalite·), in an inert solvent such as a chlorinated solvent, for example dichloromethane, optionally in the presence of a water-miscible inert cosolvent, for example Ν,Νdimethylformamide or N-methylpyrrolidone, at a temperature of to 40°C.

When one of the symbols R1 and R2 represents a methyl group, a variant of the process consists in preparing the ahydroxyacetamide derivative of general formula (IV) by treating the compound of general formula (II) with the glyoxamide of general formula HC (0) C (0) NR1R2 (in which R, and R2 each represent a methyl group and which is prepared in situ using 2,2-diethyoxy-N,N-dimethylacetamide as described in European Patent Application 251859), in a protic solvent such as acetic acid, at a temperature of 20 to 80'C.

The compounds of general formulae (IV) and (V) are novel and form part of the invention as intermediates in the preparation process illustrated by scheme 1.

Another preparation process is illustrated by scheme below.

It consists in reacting an imidazo[2,lb]benzothiazole-3-acetic acid derivative of general formula (VI) (in which X is as defined above) with a reagent such as Ν,Ν'-carbonyldiimidaazole or thionyl chloride, or any other equivalent reagent, in an inert solvent such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 to 50°C, in order to obtain a compound of general formula (VII) (in which X is as defined above and Z represents a halogen atom or an imidazolyl group), and finally the said compound is treated with an amine of general formula HNR,R2, in which R, and R2 are as defined above, at a temperature of 0 to 25’C.

The imidazo[2,l-b]benzothiazole derivatives of general formula (II) may be prepared by all of the methods described in the literature, for example in Yakugaku Zasshi, 60, 132 (1940); Bull. Soc. Chim. Fr., 1277 (1966); J. Indian Chem., Soc. 51, 1031 (1974); J. Med. Chem., 29, 386 (1986).

Scheme 2 IE 92^3^2 The imidazo[2,l-b]benzothiazole-3-acetic acid derivatives of general formula (VI) may be prepared by a method analogous to that described in Chem. Pharm. Bull., 36, 4760 (1988) .

The examples which follow illustrate the preparation of a few compounds of the invention. The elementary microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.

The numbers indicated in brackets in the titles of 10 the examples correspond to those in column one of Table 1 which follows.

Example 1 (Compound No. 1) N-Methy1-2-phenylimidazo[2,1-b]benzothiazole-3-acetamide. 1.1. a-Hydroxy-2-phenylimidazo[2,1- b]benzothiazole-3acetic acid.

A mixture of 36 g (0.14 mol) of 2-phenylimidazo[2,1b]benzothiazole and 26.5 g (0.28 mol) of glyoxylic acid in 1 1 of acetic acid is heated for 6 hours in a bath at 120°C. The solvent is evaporated under reduced pressure and the residue is crystallised from a mixture of water and dichloromethane. The solid is collected by filtering off and is washed with water and dried. 37.6 g of compound are obtained.

Melting point: 140-143°C. 1.2. α-Hydroxy-N-methyl-2-phenylimidazo[2,1b]benzothiazole-3-acetamide. 37.6 g of a-hydroxy-2-phenylimidazo[2,1bJbenzothiazole-3-acetic acid are dissolved in 750 ml of a - 9 50/50 (V/V) mixture of pyridine and acetic anhydride, the mixture is stirred overnight at ambient temperature and the solvent is evaporated under reduced pressure. The residue is crystallised from ethanol, washed with diethyl ether and dried 12.2 g (0.033 mol) of the α-acetyloxyacetic acid thus obtained are reacted with 8.1 g (0.05 mol) of N,N'-carbonyldiimidazole in 160 ml of dry tetrahydrofuran, stirring the mixture for 1.5 hours at ambient temperature, and the mixture is then treated with excess dry gaseous methylamine. Stirring is continued for 16 hours and the solvent is then evaporated under reduced pressure. The residue is taken up in dichloromethane and water the organic phase is separated off and dried and the solvent i evaporated under reduced pressure. 9.9 g of product are obtained, which is purified by chromatography on a silica gel column eluting with a 98/2 dichloromethane/methanol mixture. 9.3 g of compound are obtained.

Melting point: 230-232’C. 1.3. a-Chloro-N-methyl-2-phenylimidazo[2,120 b]benzothiazole-3-acetamide hydrochloride. 9.2 g (0.027 mol) of a-hydroxy-N-methyl-2phenylimidazo[2,l-b]benzothiazole-3-acetamide in 200 ml of dry dichloromethane are treated with 50 ml of thionyl chloride for 16 hours at ambient temperature. The solvent is evaporated under reduced pressure and the residue is crystallised from diethyl ether and dried. 10.2 g of hydrochloride are obtained, the latter being used as such in the following step. 1.4.

N-Methyl-2-phenylimidazo[2,1-b]benzothiazole-3IE 922342 - 10 acetamide. 9.8 g (0.025 mol) of a-chloro-N-roethyl-2phenylimidazo[2,l-b]benzothiazole-3-acetamide in 200 ml of dichloromethane are treated with 11.6 g (0.075 mol) of Rongalite· for 24 hours at ambient temperature. The suspension is filtered, the filtrate is washed with a bicarbonate solution, dried over sodium sulphate and filtered and the filtrate is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column eluting with a 99/1 dichloromethane/methanol mixture and is recrystallised from ethanol. 4.1 g of compound are finally obtained.

Melting point: 260-263 °C.

Example 2 (Compound No. 20) 2-(4-Methoxypheny1)-N,N-dimethylimidazo[2,1-b] benzothiazole-3acetamide. 2.1. a-Hydroxy-2-(4-methoxyphenyl)imidazo[2,1b]benzothiazole-3-acetic acid.

A mixture of 50 g (0.178 mol) of 2-(4methoxyphenyl)imidazo[2,1-b]benzothiazole, 32.8 g (0.356 mol) of glyoxylic acid and 1200 ml of acetic acid is heated for 5.5 hours in a bath at 80°C. The solvent is evaporated under reduced pressure and the residue is crystallised from a mixture of water and dichloromethane. The insoluble matter is separated off by filtering and is washed with water, then with ethanol and then with diethyl ether. 34.65 g of compound are obtained. Melting point: 160-163 °C. - 11 2.2. a-Hydroxy-2-(4-methoxyphenyl)-N,Ndimethylimidazo[2,1-b]benzothiazole-3-acetamide. 34.65 g of a-hydroxy-2-(4-methoxyphenyl)imidazo[2,1b]benzothiazole-3-acetic acid are dissolved in 480 ml of a 50/50 (V/V) mixture of pyridine and acetic anhydride and the mixture is stirred overnight at ambient temperature. The solvent is evaporated under reduced pressure, the residue is crystallised from ethanol and the crystals are washed with diethyl ether and dried.

A mixture of 7.5 g (0.019 mol) of the aacetyloxyacetic acid thus obtained, 4.32 g (0.027 mol) of Ν,Ν'carbonyldiimidazole and 90 ml of dry tetrahydrofuran is stirred for 1.5 hours at ambient temperature. The mixture is cooled in an ice bath and treated with excess dry gaseous dimethylamine.

Stirring is continued for 16 hours at ambient temperature and the solvent is evaporated under reduced pressure. The residue is taken up in water and the insoluble matter is separated off by filtration; it is washed with water, with ethanol and then with diethyl ether. After recrystallisation from ethanol, 3.08 g of compound are obtained.

Melting point: 225-227°C. 2.3. a-Chloro-2-(4-methoxyphenyl)-N,N-dimethylimidazo[2,l-b]benzothiazole-3-acetamide hydrochloride. 2.95 g of a-hydroxy-2-(4-methoxyphenyl)-N,Ndimethylimidazo-[2,l-b]benzothiazole-3-acetamide in 60 ml of dry dichloromethane are treated with 15 ml of thionyl chloride for 16 hours at ambient temperature. The solvent is evaporated under reduced pressure, the residue is crystallised from diethyl ether and 3.13 g of hydrochloride are obtained, the latter being used as such in the following step. 2.4. 2-(4-Methoxyphenyl)-N,N-dimethylimidazo-[2,15 b]benzothiazole-3-acetamide. 3.0 g (0.007 mol) of a-chloro-2-(4-methoxyphenyl)N,N-dimethylimidazo-[2,l-b]benzothiazole-3-acetamide hydrochloride are treated with 3.34 g (0.022 mol) of Rongalite* in 50 ml of dichloromethane and 40 ml of Ν,Ν-dimethylformamide for 24 hours at ambient temperature. The suspension is filtered, the filtrate is evaporated under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated off, washed with water containing bicarbonate and then with water and dried, and the solvent is evaporated under reduced pressure. The residue is recrystallised from ethanol and finally 1.62 g of compound are isolated.

Melting point: 210-213’C.

Example 3 (Compound No. 15) N-Methyl-2-(3-methylphenyl)imidazo[2,1-b]benzothiazole-3acetamide. 3.1. a-Hydroxy-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetic acid.

A mixture of 19 g (0.072 mol) of 2-(3methylphenyl)imidazo[2,l-b]benzothiazole and 13.2 g (0.143 mol) of glyoxylic acid in 450 ml of acetic acid is stirred for 2 days at ambient temperature. The solvent is evaporated under reduced pressure and the residue is crystallised from a mixture - 13 of water and dichloromethane. The suspension obtained is filtered and the solid is washed with water, with ethanol and then with diethyl ether. After drying under vacuum, 23.7 g of compound are obtained.

Melting point: 173-176°C. 3.2. a-Hydroxy-N-methyl-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetamide. g (0.068 mol) of a-hydroxy-2-(310 methylphenyl)imidazo[2,l-b]benzothiazole-3-acetic acid are dissolved in 440 ml of a 50/50 (V/V) mixture of pyridine and acetic acid, the mixture is stirred at ambient temperature for 16 hours and the solvents are then evaporated under reduced pressure.

A mixture of 9.33 g (0.024 mol) of the oily aacetyloxyacetic acid thus obtained and 5.37 g (0.033 mol) of Ν,Ν-carbonyldiimidaazole in 175 ml of dry tetrahydrofuran is stirred for 1.5 hours at ambient temperature. The mixture is cooled using a bath of water and ice and is treated with excess dry gaseous methylamine. Stirring is continued at ambient temperature for 16 hours and the solvent is then evaporated under reduced pressure. The residue is taken up in water and dichloromethane, the organic phase is separated off and dried and the solvent is evaporated under reduced pressure. 7.3 g of product are obtained, the latter being purified by chromatography on a silica gel column eluting with a 99/1 dichloromethane/methanol mixture. 5.3 g of compound are obtained.

Melting point: 179-182 °C. 3.3. a-Chloro-N-methyl-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetamide hydrochloride. 4.6 g (0.013 mol) of a-hydroxy-N-methyl-2-(3methylphenyl)imidazo[2,l-b]benzothiazole-3-acetamide are treated with 24 ml of thionyl chloride in 100 ml of dichloromethane for 16 hours at ambient temperature. The solvent is evaporated under reduced pressure and the residue is crystallised from diethyl ether. 5.17 g of hydrochloride are obtained, the latter being used as such in the following steps. 3.4. N-Methyl-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetamide. .17 g (0.013 mol) of a-chloro-N-methyl-2-(3methylphenyl)imidazo[2,l-b]benzothiazole-3-acetamide hydrochloride are treated with 5.9 g (0.038 mol) of Rongalite* in 90 ml of dichloromethane and 70 ml of Ν,Ν-dimethylformamide at ambient temperature for 24 hours.

The suspension obtained is filtered, the filtrate is evaporated under reduced pressure, the residue is taken up in water and dichloromethane, the organic phase is separated off, washed with water containing bicarbonate and then with water and dried, and the solvent is evaporated under reduced pressure. After purification of the residue by recrystallisation from ethanol, 2.37 g of compound are finally isolated.

Melting point: 201-203'C.

Example 4 (Compound No. 6) 2-(2-Chlorophenyl)-N,N-dimethylimidazo[2,l-b]benzothiazole-315 acetamide. 4.1. 2-(2-Chlorophenyl)-a-hydroxyimidazo[2,1b]benzothiazole-3-acetic acid.

A mixture of 27.7 g (0.097 mol) of 2-(25 chlorophenyl)imidazo[2,1-b]benzothiazole and 14.4 g (0.194 mol) of glyoxylic acid in 500 ml of acetic acid is heated for 3.5 hours in a bath at 80‘C.

The solution is evaporated under reduced pressure, the residue is taken up in water, the solid is collected by filtering off, washed with water and dissolved in ethanol and the solution is concentrated under reduced pressure. The residue is washed with diethyl ether and dried under vacuum. 32.6 g of compound are obtained. Melting point: 180-184 °C. 4.2. 2-(2-Chlorophenyl)-a-hydroxy-N,N-dimethylimidazo[2,1b]benzothiazole-3-acetamide.

A mixture of 32.6 g (0.091 mol) of 2-(2chlorophenyl)-a-hydroxyimidazo[2,l-bjbenzothiazole-3-acetic acid, 400 ml of pyridine and 400 ml of acetic acid is stirred for 16 hours at ambient temperature. It is concentrated under reduced pressure, the residue is taken up in diethyl ether and the solid is collected by filtering off and dried under vacuum. g (0.027 mol) of the α-acetyloxyacetic acid thus obtained are reacted with 4.9 g (0.030 mol) of N,N'25 carbonyldiimidazole in 140 ml of dry tetrahydrofuran and the mixture is stirred for 1 hour at ambient temperature, then cooled using an ice bath and treated with excess dry gaseous dimethylamine.

Stirring is continued for 16 hours at ambient temperature and the solvent is then evaporated under reduced pressure. The residue is taken up in dichloromethane and water, the organic phase is separated off, washed with water to neutral pH and dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is washed with diethyl ether and dried. 6.7 g of compound are obtained. Melting point: 203°C. 4.3. a-Chloro-2-(2-chlorophenyl)-N,N-dimethylimidazo[2,1b]benzothiazole-3-acetamide hydrochloride. 6.4 g (0.016 mol) of 2-(2-chlorophenyl) -a-hydroxyN,N-dimethylimidazo[2,l-b]benzothiazole-3-acetamide in 340 ml of dry dichloromethane are treated with 34 ml of thionyl chloride for 16 hours at ambient temperature and the solvent and the excess thionyl chloride are then evaporated under reduced pressure. The solid residue is washed with dry diethyl ether and dried under vacuum. 7.0 g of compound are obtained. 4.4. 2-(2-Chlorophenyl)-N,N-dimethylimidazo[2,1b]benzothiazole-3-acetamide. 7.0 g (0.016 mol) of a-chloro-2-(2-chlorophenyl)-N,Ndimethylimidazo[2,l-b]benzothiazole-3-acetamide are treated with 7.3 g (0.047 mol) of Rongalite® in 320 ml of a 50/50 (V/V) mixture of dichloromethane and Ν,Ν-dimethylformamide for 40 hours at ambient temperature. The suspension is filtered, the filtrate is concentrated under reduced pressure, the residue is taken up in water, the solid is collected by filtering off, washed with water containing bicarbonate and then with water to neutral pH and dissolved in ethanol, the ethanol is evaporated - 17 under reduced pressure and the residue is crystallised from diethyl ether, dried under vacuum and purified by chromatography on a silica gel column eluting with a 98/2 dichloromethane/methanol mixture and recrystallised from ethyl acetate. 1.5 g of compound are obtained.

Melting point: 159-162°C.

Example 5 (Compound No. 4) 2-(4-Fluorophenyl)-N,N-dimethylimidazo[2,l-b]benzothiazole-310 acetamide. .1. 2-(4-Fluorophenyl)-a-hydroxy-N,N-dimethylimidazo[2,1b]benzothiazole-3-acetamide. 39.2 g (0.22 mol) of 2,2-diethoxy-N,Ndimethylacetamide and 55 ml of 37% hydrochloric acid diluted in 370 ml of acetic acid are mixed in a 1000 ml round-bottomed flask and the mixture is heated, with stirring, in a bath at °C for 1.5 hours. 18.3 g (0.22 mol) of sodium acetate are then added, followed, in small portions, by 20 g (0.074 mol) of 2-(420 fluorophenyl)imidazo[2,l-b]benzothiazole, and heating and stirring are continued for 2 hours.

The mixture is evaporated under reduced pressure, the residue is taken up in water and dichloromethane, the insoluble matter is removed by filtering off and the organic phase is separated off, washed with water containing bicarbonate and dried over sodium sulphate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a 97/3 dichloromethane/methanol mixture and then by crystallisation from diethyl ether. 7.7 g of compound are obtained.

Melting point: 212-215’C. .2. a-Chloro-2-(4-fluorophenyl)-N,N-dimethylimidazo[2,15 b]benzothiazole-3-acetamide hydrochloride. 7.6 g (0.02 mol) of 2-(4-fluorophenyl)-α-hydroxy-N,Ndimethylimidazo[2,l-bJbenzothiazole-3-acetamide are treated with 40 ml of thionyl chloride in 400 ml of dichloromethane at ambient temperature for 16 hours and the solvent and the excess thionyl chloride are evaporated under reduced pressure. The residue is taken up in dry diethyl ether, filtered off and dried. 7.9 g of compound are obtained. .3. 2-(4-Fluorophenyl)-N,N-dimethylimidazo[2,1b]benzothiazole-3-acetamide. 7.9 g (0.019 mol) of a-chloro-2-(4-fluorophenyl)-N,Ndimethylimidazo[2,l-b]benzothiazole-3-acetamide hydrochloride in 360 ml of a 50/50 (V/V) mixture of dichloromethane and N,Ndimethylformamide are treated with 8.6 g (0.056 mol) of Rongalite® for 18 hours at ambient temperature.

The suspension is filtered, the filtrate is evaporated under reduced pressure and the evaporation residue is treated with an aqueous sodium bicarbonate solution. The solid is collected by filtering off, washed with water to neutral pH and then with ethanol and diethyl ether and dried under vacuum. Finally, the product is purified by chromatography on a silica gel column eluting with a 98/2 dichloromethane/methanol mixture and recrystallised from ethanol. 3.0 g of compound are obtained.

Melting point: 230-231’C.

Example 6 (Compound No. 9) 2-(4-Chlorophenyl)-N-methylimidazo[2,l-bJbenzothiazole-3acetamide. g (0.003 mol) of 2-(4-chlorophenyl)imidazo[2,15 b]benzothiazole-3-acetic acid is treated with 0.54 g (0.0033 mol) of Ν,Ν'-carbonyldiimidazole in 15 ml of dry tetrahydrofuran for 1 hour at ambient temperature.

The mixture is cooled using an ice bath and treated with excess dry gaseous methylamine. The mixture is stirred for hours at ambient temperature and concentrated under vacuum and the solid is collected by filtering off, washed with water to neutral pH and then with ethanol and with diethyl ether, dried and purified by recrystallisation from ethanol. 0.57 g of compound is obtained.

Melting point: 277-278 °C (decomposition).

Example 7 (Compound No. 21) 2-Phenylimidazo[2,1-b]benzothiazole-3-acetamide. 7.1. a-Hydroxy-2-phenylimidazo[2,l-b]benzothiazole-320 acetic acid.

A mixture of 36 g (0.144 mol) of 2-phenylimidazo[2,1bjbenzothiazole, 1000 ml of acetic acid and 26.5 g (0.288 mol) of glyoxylic acid is heated for 6 hours in a bath at 120’C.

The solvent is evaporated, the residue is taken up in 25 diethyl ether and the crystals are collected by filtering off and dried. 37.63 g of compound are obtained. 7.2. a-Hydroxy-2-phenylimidazo[2,l-b]benzothiazole-3acetamide.

A mixture of 37.6 g (0.116 mol) of a-hydroxy-2phenylimidazo[2,l-bJbenzothiazole-3-acetic acid, 380 ml of pyridine and 380 ml of acetic anhydride is stirred for 16 hours at ambient temperature.

The solvents are evaporated under reduced pressure, the residue is twice taken up in toluene, which is evaporated, the residue is taken up in ethanol and the solid is collected by filtering off, washed with diethyl ether and dried. 31.17 g of the intermediate α-acetyloxyacetic derivative are obtained and 12.2 g (0.033 mol) of this derivative are dissolved in 160 ml of tetrahydrofuran, 8.1 g (0.050 mol) of N,N'carbonyldiimidazole are added, in fractions, and stirring is continued for 1.5 hours and the mixture is then treated with a stream of dry ammonia for 1.5 hours. Stirring is continued for 16 hours, water is added and the tetrahydrofuran is evaporated under reduced pressure, the residue is taken up in dichloromethane, the solid is collected by filtering off, dried and treated with a mixture of 100 ml of methanol, 100 ml of water and 20 g of potassium carbonate, and the solid is collected by filtering off and washed with water and then with diethyl ether. After drying, 6.59 g of compound are obtained. Melting point: 239-241°C. 7.3. a-Chloro-2-phenylimidazo[2,1-b]benzothiazole-325 acetamide hydrochloride. ml (0.5 mol) of thionyl chloride are added dropwise to a solution of 6.45 g (0.020 mol) of a-hydroxy-2phenylimidazo[2,l-b]benzothiazole-3-acetamide in 150 ml of dichloromethane and the mixture is stirred for 16 hours. The dichloromethane is evaporated under reduced pressure, the excess thionyl chloride is driven off with toluene and the solid obtained is washed with diethyl ether. 6.84 g of hydrochloride are obtained.

Yield: 90%. 7.4. 2-Phenylimidazo[2,l-b]benzothiazole-3-acetamide.

A mixture of 6.5 g (0.0159 mol) of a-chloro-2phenylimidazo[2,l-b]benzothiazole-3-acetamide hydrochloride, 150 ml of dichlorometane and 7.94 g (0.048 mol) of Rongalite® is stirred at ambient temperature for 16 hours.

An aqueous sodium bicarbonate solution is added and the solid is collected by filtering off, washed with water, then with ethanol and then with diethyl ether and recrystallised from ethanol and then twice from methanol. 0.81 g of compound is finally obtained.

Melting point: 246-248°C.

Example 8 (Compound No. 22) 2-(4-Bromophenyl)imidazo[2,1-b]benzothiazole-3-acetamide. 8.1. 2-(4-Bromophenyl)-a-hydroxyimidazo[2,1b]benzothiazole-3-acetic acid.

A mixture of 33 g (0.1 mol) of 2-(4bromophenyl)imidazo[2,l-b]benzothiazole, 650 ml of acetic acid and 18.45 g (0.2 mol) of glyoxylic acid is heated for 3.5 hours in a bath at 80'C.

The solvent is evaporated, the residue is taken up in dichloromethane and water and the solid is collected by filtering off and washed with water, then with ethanol and then with diethyl ether. After drying, 36.41 g of compound are obtained.

Yield: 90%. 8.2. 2-(4-Bromophenyl)-a-hydroxyimidazo[2,lb]benzothiazole-3-acetamide.

A mixture of 47 g (0.116 mol) of 2-(4-bromophenyl)-ahydroxyimidazo[2,l-b]benzothiazole-3-acetic acid, 380 ml of pyridine and 380 ml of acetic anhydride is stirred for 16 hours at ambient temperature.

The solvents are evaporated under reduced pressure, the residue is twice taken up in toluene, which is evaporated, the residue is taken up in ethanol and the solid is collected by filtering off, washed with diethyl ether and dried. 46.69 g of the intermediate α-acetyloxyacetic derivative are obtained and 15.3 g (0.034 mol) of this derivative are dissolved in 160 ml of tetrahydrofuran, 8.36 g (0.051 mol) of Ν,Νcarbonyldiimidazole are added, in fractions, and stirring is continued for 1.5 hours and the mixture is then treated with a stream of dry ammonia for 1.5 hours. Stirring is continued for 16 hours, water is added and the tetrahydrofuran is evaporated under reduced pressure, the residue is taken up in water, the solid is collected by filtering off, washed with water, then with ethanol and then with diethyl ether, dried and treated with a mixture of 120 ml of methanol, 120 ml of water and 25 g of potassium carbonate and the solid is collected by filtering off and washed with water and then with diethyl ether. After drying, 9.41 g of compound are obtained.

Melting point: 254-257'C. - 23 8.3. 2-(4-Bromophenyl)-α-chloroimidazo[2,1b]benzothiazole-3-acetamide hydrochloride. ml (0.56 mol) of thionyl chloride are added dropwise to a solution of 9 g (0.022 mol) of 2-(4-bromophenyl)5 a-hydroxyimidazo[2,l-b]benzothiazole-3-acetamide in 180 ml of dichloromethane and the mixture is stirred for 16 hours. The dichloromethane is evaporated under reduced pressure, the excess thionyl chloride is driven off with toluene and the solid obtained is washed with diethyl ether. 9.39 g of hydrochloride are obtained. 8.4. 2-(4-Bromophenyl)imidazo[2,l-b]benzothiazole-3acetamide.

A mixture of 9 g (0.0197 mol) of 2-(4-bromophenyl)-a15 chloroimidazo[2,1-b]benzothiazole-3-acetamide hydrochloride, 160 ml of dichloromethane, 160 ml of Ν,Ν-dimethylformamide and 9.1 g (0.059 mol) of Rongalite* is stirred at ambient temperature for 16 hours.

The mixture is filtered and the solid is washed with 20 a saturated aqueous sodium bicarbonate solution, then with water, then with ethanol and then with diethyl ether. 4.15 g of product are obtained. In addition, the filtrate is evaporated, the residue is taken up in water and the solid is collected by filtering off and washed successively with water, a saturated sodium bicarbonate solution, again with water, with ethanol and then with diethyl ether. After drying, a further 1.92 g of product are obtained, the latter being added to the above product, giving a total of 6.07 g. After recrystallisation from methanol, 2.02 g of compound are finally isolated. - 24 Melting point: 287-290°C.

Example 9 (Compound No. 29) N-(Prop-2-enyl)-2-phenylimidazo[2,l-b)benzothiazole-35 acetamide.

Under a nitrogen atmosphere, 1.77 g (0.011 mol) of Ν,Ν'-carbonyldiimidazole are added to a suspension of 2.5 g (0.008 mol) of 2-phenylimidazo[2,l-b]benzothiazole-3-acetic acid in 40 ml of dry tetrahydrofuran. The mixture is stirred for 2.5 hours at ambient temperature and 0.69 ml (0.0089 mol) of prop-2-enylamine is then added and stirring is continued for 4 hours. The solvent is evaporated under reduced pressure and the residue is taken up in water and dichloromethane. The organic phase is washed with water and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 2.33 g of residue are obtained, which is purified by chromatography on a silica gel column eluting with a 99/1 dichloromethane/methanol mixture and then by recrystallisation from ethanol. 1.65 g of compound are obtained.

Melting point: 210-212 °C.

Example 10 (Compound No. 42) N-Ethyl-2-(4-methoxyphenyl)imidazo[2,l-b]benzothiazole-3acetamide.

Under a nitrogen atmosphere, 1.44 g (0.0088 mol) of Ν,Ν'-carbonyldiimidazole are added to a suspension of 2 g (0.0059 mol) of 2-(4-methoxyphenyl)imidazo[2,l-b]benzothiazole3-acetic acid in 45 ml of dry tetrahydrofuran. The reaction mixture is stirred for 1.5 hours at ambient temperature and then cooled in an ice bath, 5 ml of anhydrous liquid ethylamine are introduced and the mixture is stirred for 18 hours at ambient temperature.

The solvent is evaporated under reduced pressure and the residue is taken up in water. The insoluble matter is separated off by filtration and washed with water, with ethanol and then with diethyl ether. The compound thus obtained is purified by recrystallisation from ethanol and then by chromatography on a silica gel column eluting with a 99/1 dichloromethane/methanol mixture. After crystallisation from diethyl ether, 1.16 g of compound are obtained.

Melting point: 224-225°C.

Example 11 (Compound No. 55) l-[(2-Phenylimidazo[2,l-b]benzothiazol-3-yl)acetyl]-4methylpiperazine. 2.35 g (0.0146 mol) of N,N'-carbonyldiimidazole are added to a suspension of 3 g (0.0097 mol) of 2phenylimidazo[2,1-b]benzothiazole-3-acetic acid in 100 ml of dry dichloromethane and the mixture is stirred for 10 minutes at ambient temperature. 0.97 g (0.0097 mol) of Nmethylpiperazine in solution in 10 ml of dichloromethane is added to the solution obtained. The reaction mixture is stirred for 6 hours at ambient temperature and then poured into 100 ml of water. The organic phase is decanted off, washed with water and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, 2.73 g of an oil are obtained, which crystallises in ethyl acetate. It is purified by preparing the hydrochloride with the aid of an ethereal - 26 solution of hydrochloric acid and is recrystallised from propanol. The hydrochloride is decomposed using a dilute ammonia solution and the base thus obtained is extracted with dichloromethane. The organic phase is washed with water and dried, the solvent is evaporated and the residue is recrystallised from ethyl acetate. 2.2 g of compound are obtained.

Melting point: 195-196’C.

Example 12 (Compound No. 59) 1- [(2-(4-Chlorophenyl)imidazo[2,l-b]benzothiazol-3yl)acetyljpyrrolidine. 1.4 g (0.0087 mol) of Ν,Ν-carbonyldiimidazole are added to a suspension of 2 g (0.0059 mol) of 2-(415 chlorophenyl)imidazo[2,l-b]benzothiazole-3-acetic acid in 50 ml of dry dichloromethane and the reaction mixture is stirred for 10 minutes at ambient temperature. 0.42 g (0.0058 mol) of pyrrolidine in solution in 5 ml of dichloromethane is added to the solution thus obtained. The reaction mixture is stirred for 6 hours at ambient temperature and then poured into 50 ml of water. The organic phase is decanted off, washed with water and dried over sodium sulphate. After evaporation of the solvent under reduced pressure, the residue is crystallised from propan-2-ol. 1.9 g of compound are obtained.

Melting point: 248-249°C.

Example 13 (Compound No. 72) 2- (3-Methylphenyl)imidazo[2,1-b]benzothiazole-3-acetamide. 13.1. a-Hydroxy-2-(3-methylphenyl)imidazo[2,1IE 922342 b]benzothiazole-3-acetic acid.

A mixture of 19 g (0.072 mol) of 2-(3methylphenyl)imidazo[2,l-b]benzothiazole and 13.2 g (0.143 mol) of glyoxylic acid in 450 ml of acetic acid is stirred for 2 days at ambient temperature. The solvent is evaporated under reduced pressure and the residue is crystallised from a mixture of water and dichloromethane. The suspension obtained is filtered and the solid is washed with water, with ethanol and then with diethyl ether. After drying under vacuum, 23.7 g of compound are obtained.

Melting point: 173-176°C. 13.2. a-Hydroxy-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetamide. 23 g (0.068 mol) of a-hydroxy-2-(3methylphenyl)imidazo[2,l-b]benzothiazole-3-acetic acid are dissolved in 440 ml of a 50/50 (V/V) mixture of pyridine and acetic acid, the mixture is stirred at ambient temperature for 16 hours and these solvents are then evaporated under reduced pressure.

A mixture of 9.33 g (0.024 mol) of the oily aacetyloxyacetic acid thus obtained and 5.37 g (0.033 mol) of N,NZ-carbonyldiimidazole in 175 ml of dry tetrahydrofuran is stirred for 1.5 hours at ambient temperature. The mixture is cooled using a bath of water and ice and is treated with excess dry gaseous ammonia. Stirring is continued at ambient temperature for 16 hours and the solvent is then evaporated under reduced pressure. The residue is taken up in water and dichloromethane, the suspension obtained is filtered and the - 28 solid is washed with water, with ethanol and then with diethyl ether. 6.1 g of a-acetyloxy-2-(3-methylphenyl)imidazo[2,1b]benzothiazole-3-acetamide are obtained, which is treated with 12 g of potassium carbonate in 300 ml of a 50/50 (V/V) mixture of water and methanol, stirring the mixture for 100 hours at ambient temperature.

The solid is separated off by filtration and washed several times with water, with ethanol and then with diethyl ether. 5.4 g of compound are obtained.

Melting point: 253-255°C. 13.3. a-Chloro-2-(3-methylphenyl)imidazo[2,1-b]benzothiazole-3acetamide hydrochloride. .2 g (0.015 mol) of a-hydroxy-2-(315 methylphenyl)imidazo[2,l-b]benzothiazole-3-acetamide are treated with 28 ml of thionyl chloride in 110 ml of dichloromethane for 16 hours at ambient temperature. The solvent is evaporated under reduced pressure and the residue is crystallised from diethyl ether. 5.7 g of hydrochloride are obtained, the latter being used as such in the following step. 13.4. 2-(3-Methylphenyl)imidazo[2,1-b]benzothiazole-3acetamide. .7 g (0.014 mol) of a-chloro-2-(325 methylphenyl)imidazo[2,l-b]benzothiazole-3-acetamide hydrochloride are treated with 6.7 g (0.044 mol) of Rongalite* in 100 ml of dichloromethane and 80 ml of Ν,Ν-dimethylformamide at ambient temperature for 24 hours. The suspension obtained is filtered, the filtrate is evaporated, the residue is taken up - 29 in water and the solid obtained is filtered off and washed with a saturated sodium bicarbonate solution, with water, with ethanol and then with diethyl ether. 2.1 g of compound are obtained, the latter being recrystallised from ethanol and then from methanol. 1.03 g of pure compound are finally isolated. Melting point: 243-246’C.

Example 14 (Compound No. 70) 2-(4-Chlorophenyl)imidazo[2,l-b]benzothiazole-3-acetamide. 1 g (0.003 mol) of 2-(4-chlorophenyl)imidazo[2,1b]benzothiazole-3-acetic acid is treated with 0.54 g (0.0033 mol) of Ν,Ν'-carbonyldiimidazole in 15 ml of dry tetrahydrofuran for 1 hour at ambient temperature.

The mixture is cooled using an ice bath and is 15 treated with excess dry gaseous ammonia. The mixture is stirred for 15 hours at ambient temperature and concentrated under vacuum and the solid is collected by filtering off, washed with water to neutral pH and then with ethanol and with diethyl ether, dried and purified by recrystallisation from ethanol. 0.63 g of compound is obtained.

Melting point: 288-290’C (decomposition).

Table 1 which follows illustrates the chemical structures and the physical properties of a few compounds of general formula (I). All of the compounds are in the form of the base, with the exception of No. 32, which is a hydrochloride, and No. 90, which is a hydrate.

In the m.p. (°C) column, (d) denotes a melting point with decomposition.

(I) - 30 Table 1 ! No X Ri r2 m.p. (eC) i 1 I H H ch3 260-263 ί 2 j H CH3 ch3 206-2083 4-F H ch3 170-172 4 4-F CH3 ch3! 230-231 5 2-C1 H ch3 192-194 6 2-C1 CH3 ch3 159-162 7 3-C1 H ch3 234-234,5 8 3-C1 CH3 ch3 156 9 4-C1H ch3 277-278 (d) 10 4-Cl ch3 ch3 237-238 11 4-Br H ch3 288-291 12 4-Br ch3 ch3 237-240 13 2-CHj H ch3 162-165 14 2-CH3 ch3 ch3 182-184 15 3-CH3 H ch3 201-203 16 3-CHj ch3 ch3 168-171 17 4-CH3 H ch3 259,5-261 18 4-CHj ch3 ch3 238-239 19 4-OCHj H ch3 234-237 20 4-OCH3 ch3 ch3 210-213 21 H H η 246-248 No.X R. r2 m.p. (*C) 22 4-Br H H 287-290 23 H H CHjCHj 232-235 24 H H CHjCFj 293-295 25 H H (CH2)2CHj 200-202 26 H H CH(CHj)2 274-275 27 H H CH2CH(CHj)2 207-208 28 H H cycloCjH, 242-244 29 H H CH2-CH=CH2 210-212 30 H H CH2-CbCH 246-248 31 H H (CH2)2OCHj 174-176,5 32 H H (CHj) 2N (CHj) 2 132-135 33 H H c6h5 224-226 34 H H ch2c6h5 236-238 35 H H (CH2)2C6Hj 190-192 36 4-C1 H CH2CHj 261-263 37 4-Cl H (CH2)2CHj 249-251 38 2-CHj H CH2CHj 179-181 .39 4-CH3 H CH2CHj 246-248 40 4-CHj H (ch2)2ch3 220-222 41 4-CH2CH3 H CH2CHj 225-227 42 4-OCHj H CH2CHj 224-225 43 4-OCHj H (ch2)2ch3 210-212 44 H CHj (CH2)2CHj 110-111 45 H ch3 c6h5 156-157 46 H CHj CH2C6Hj 155-156 ! 47 H CHj (CH2)2C4Hs 147-148 No. ' 1 1 X R, ! R2 ί m.p. Cc) 67 4-F ( H H 268-270 (d) ‘ i 68 2-C1 H H 203-206 69 3-C1 H H 242-245 70 4-C1 H H 288-290 (d) 71 2-CH3 H H 203-206 72 3-CH3 H H 243-246 73 4-CH3 H H 253-254 74 4-OCHj H H 285-289 (d) 75 4-C2H5 H ch3 218-220 76 4-C2H5 ch3 ch3 170-172 77 4-C;Hj H H >250 78 4-SCHj H H >250 79 4-SCHj ch3 ch3 160-162 80 4-SCHj H ch3 250-252 81 4-OC2H5 ch3 ch3 174-176 82 4-OCjHj H H 265-2661 8 3 4-OC2H5 H ch3 238-240 84 4-C3H7 ch3 ch3 136-138 - 85 4-C3H7 H ch3 214-216 86 4-C3H7 H H 250-252 87 4-SO2CH3 H ch3 232-234 88 4-SO2CH3 H H 317-319 89 4-SO2CH3 ch3 CH3 202-204 90 4-CN H ch3 278-286 (d) 91 4-CN ch3 ch3 278-283 1 ; 92 4-CONH2 H CH3 281-292 1 93 4-CONH2 H H >290 ! 94 { 4-CONH2 ch3 ch3 215-217 Table 2 which follows illustrates the chemical structures and the physical properties of a few compounds of general formula (IV), which are intermediates in the process illustrated by Scheme 1. All of the compounds are in the form of the base.

In the m.p. (’C) column, (d) denotes a melting point with decomposition.

Table 2 rv \_7 N fi CH (IV) No. XR!R2 m.p. (’C) 1' H H H 239-241 2' H H CH3 230-232 3' H CHj ch3 191-193 4 · 4-F H H 267-269 5' 4-F H ch3 234-235 (d) 6' 4-F ch3 ch3 212-215 7' 2-C1 H H 244-246 8' 2-C1 H ch3 232-233 9' 2-C1C»3 ch3 203-204 10' 3-C1 H H 265-266 - 35 10 No. XriR2 m.p. (°C) 11' 3-C1 H ch3 228-229 12' 3-C1 ch3 ch3 169-170 13' 4-C1 H H 263-266 14' 4-C1 H ch3 246-249 (d) 15' 4-C1 ch3 ch3 227-229 16' 4-Br H H 254-257 17' 4-Br H ch3 261-264 18' 4-Br ch3 ch3 222-225 19' 2-CH3 H H 225-228 20' 2-CHj H ch3 221-224 21' 2-CH3 ch3 ch3 199-202 22 ' 3-CHj H H 253-255 23' 3-CH3 H ch3 179-182 24' 3-CH3 ch3 ch3 177-181 25' 4-CH3 H H 249-250 (d) 26' 4-CH3 H ch3 188-190 27' 4-CH3 ch3 ch3 205-206 28' 4-OCH3 H H 234-237 29' 4-OCH3 H CH3 229-231 30' 4-OCH3 ch3 ch3 225-227 The compounds of the invention were subjected to pharmacological tests which have demonstrated their value as substances having therapeutic activities. - 36 Study of the membrane bonding with respect to (x.^ (type 1 benzodiazepine) receptors and ω., (type 2 benzodiazepine) receptors.

The affinity of the compounds for the (*), receptors of 5 the cerebellum and the W2 receptors of the spinal cord was determined using a variant of the method described by S. Z. Langer and S. Arbilla in Fund. Clin. Pharmacol., 2, 159-170 (1988), using 3H-flumazenil in place of 3H-diazepam as radioligand. The cerebellum or spinal cord tissue is homogenised for 60 s in 120 or 30 volumes, respectively, of ice-cold buffer (50 mM Tris/HCl, pH 7.4, 120 mM NaCl, 5 mM KC1) and then, after dilution to 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 various concentrations, in a final volume of 525 μΐ. After incubating for 30 minutes at 0°C, the samples are filtered under vacuum on Whatman GF/B* filters and washed immediately with ice-cold buffer. The specific bonding of the 3H-flumazenil is determined in the presence of non-labelled 1 μΜ diazepam. The data are analysed using the customary methods and the IC50 concentration, the concentration which inhibits 50 % of the 3H—flumazenil bonding, is calculated.

The IC50 of the compounds of the invention are between 0.1 and 1000 nM in these tests.

Study of the anticonvulsant activity.

Activity with respect to maximum convulsions induced in mice bv electric shock or by injection of Pentetrazole.

The protocol for this experiment is described by E.

A. Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982). minutes after intraperitoneal administration of 5 the compound to be tested, the number of mice displaying convulsions (extensions of the rear paws) is noted, either immediately after application of an electric current (0.4 s, 60 mA, 50 Hz) using transcorneal electrodes or during the 30 minutes which follow the subcutaneous injection of Pentetrazole (125 mg/kg). The results are expressed by the AD5Q, the dosage which protects 50 % of the animals, calculated by the method of J. T. Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99113 (1949)) from 3 or 4 doses each administered to a group of 8 to 10 mice.

In this experiment, the AD50 of the compounds of the invention are between 1 and 100 mg/kg administered intraperitoneally.

Activity with respect to convulsions induced in mice bv isoniazid.

The intrinsic activity of the compounds is determined by the latency period before appearance of the convulsions induced by the subcutaneous administration of isoniazid (800 mg/kg) simultaneously with the compound to be tested, injected intraperitoneally, in accordance with the protocol described by G. Perrault, E. Morel, D. Sanger and B. Zivkovic in Eur. J. Pharmacol., 156, 189-196 (1988). The results are expressed by the AD50, the dose which produces 50 % of the maximum effect, with respect to control animals, determined from 3 or 4 doses ,E 922342 each administered to a group of 8 to 10 mice.

In this experiment, the AD50 of the compounds of the invention are between 1 and 50 mg/kg administered intraperitoneally and, depending on the compounds, the maximum effect may be up to 350 %.

Study of the anxiolytic activity.

The anxiolytic activity is evaluated in rats in the drink-taking conflict test using the method described by J. R.

Vogel, B. Beer and D. E. Clody in Psychopharmacologia (Berl.), 21, 1-7 (1971).

Following a 48-hour water diet, the rat is placed in a chamber which is insulated from noise and equipped with a water pipette connected to an anxiometer delivering a slight electric shock every 20 licks with the tongue. The number of shocks received is automatically counted over a 3 minute period and enables the anxiolytic activity of the compounds tested to be evaluated. The results are expressed by the minimum effective dose (MED), the dose which produces a significant increase in the number of shocks received, compared with the number observed in the control animals.

In this experiment, the MED of the compounds of the invention are between 10 and 100 mg/kg administered intraperitoneally or orally.

The results of the tests carried out on the compounds of the invention show that, in vitro, they displace 3Hflumazenil from its specific bonding sites in the cerebellum and the spinal cord; consequently, they have an affinity for the 0), and ώ2 (type 1 and type 2 benzodiazepine) sites located within the GABAa-D sites-chloride channel macromolecular complex.

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

They possess anticonvulsant and anxiolytic properties and, consequently, may be used for the treatment of diseases associated with disorders of the GABAergic transmission, such as anxiety, sleeping disorders, epilepsy, spasticity, muscular contractions, cognitive disorders, withdrawal disorders in respect of alcoholism, and the like.

Thus, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable excipient and, as an active ingredient, a compound of the invention.

To this end, they may be supplied in any galenic 15 forms, in combination with suitable excipients, for enteral or parenteral administration, for example in the form of tablets, coated tablets, soft or hard capsules, drinkable or injectable solutions or suspensions, suppositories and the like, containing a dosage to permit daily administration of from 1 20 to 1000 mg of active substance.

Claims (16)

1. A compound which is an imidazo[2,1b]benzothiazole-3-acetamide derivative represented by formula (I) 10 in which X represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylsulphonyl, cyano or aminocarbonyl; R, represents hydrogen or C 1 -C 4 alkyl; and 15 R 2 represents hydrogen, prop-2-enyl, prop-2-ynyl, phenyl, or C^Cj alkyl optionally substituted by at least one fluorine atom, a methoxy group, a dimethylamino group or a phenyl group; or R, and R 2 form, together with the nitrogen atom to which they 20 are attached, pyrrolidin-l-yl, piperidin-l-yl, hexahydroazepinl-yl, 4-(phenylmethyl)piperidin-l-yl, 4-methylpiperazin-l-yl, 4-(phenylmethyl)piperazin-l-yl, morpholin-l-yl or thiomorpholin-l-yl; provided that when X represents hydrogen or bromine in position 25 4, R 1 and R 2 do not both represent hydrogen; or a pharmaceutically acceptable acid addition salt thereof.

2. A compound according to claim 1 wherein R 1 and R 2 may be the same or different and each represents hydrogen or methyl. - 41

3. A compound according to claim 1 wherein R 1 and R 2 form, together with the nitrogen atom to which they are attached, pyrrolidin-l-yl, piperidin-l-yl, hexahydroazepin-1yl, 4-(phenylmethyl)piperidin-l-yl, 4-methylpiperazin-l-yl, 5 4(phenylmethyl)piperazin-l-yl, morpholin-l-yl or thiomorpholin1-yl; and X represents hydrogen, chlorine, methyl or methoxy.

4. A compound according to claim 1 specifically identified herein.

5. A process for the production of a compound as 10 claimed in any one of the preceding claims, which process comprises dehalogenation of an α-halogenoacetamide derivative represented by formula (V) in which X, R 1 and R 2 are as defined in claim 1 and Hal represents a halogen atom, and optionally converting the 20 compound of formula (I) thereby obtained into a physiologically acceptable acid addition salt thereof.

6. A process according to claim 5 wherein the ahalogenoacetamide derivative is reacted with a reducing agent.

7. A process according to claim 6 wherein the a25 halogenoacetamide derivative is reacted with a simple or complex alkali metal hydride in a protic or water miscible inert solvent, or with an alkali metal hyposulphite or alkali metal dithionite.

8. A process according to claim 5 wherein the aIE 922342 - 42 halogenoacetamide derivative is reacted with sodium hydroxymethylsulphoxylate in a chlorinated inert solvent and optionally a water-miscible inert cosolvent.

9. A process according to any one of claims 5 to 5 8 wherein the α-halogenoacetamide derivative is obtained by reacting an imidazo[2,l-b]benzothiazole of formula (II) (II) in which X is as defined in claim 1, with glyoxylic acid in a protic solvent, to form an α-hydroxyacetic acid derivative of formula (III) in which X is as defined above, which α-hydroxyacetic acid derivative is then reacted with acetic anhydride in the presence of an organic base, to form the corresponding aacetyloxyacetic acid derivative, which is treated with N,N'25 carbonyldiimidazole in an inert solvent, the intermediate imidazolide thus obtained is then treated in situ with an amine of formula HNR,^ in which R, and R 2 are as defined in claim 1, to form an α-hydroxyacetamide derivative of formula (IV) (IV) in which X, R 1 and R 2 are as’defined above, which a5 hydroxyacetamide derivative is treated with a sulphuric or phosphoric acid polyhalide in an inert solvent.

10. A process for preparing a compound as claimed in claim 1 substantially as described in any one of Examples 1 to 14. 10

11. A compound according to any one of claims 1 to 4 whenever prepared by a process as claimed in any one of claim 5 to 10.

12. A compound represented by formula (IV) (IV) 20 in which X, R, and R 2 are as defined in claim 1.

13. A compound represented by formula (V) in which X, R 2 and R 2 are as defined in claim 1 and Hal represents a halogen atom.

14. A compound which is an imidazo[2,1(V) - 44 b]benzothiazole-3-acetamide derivative represented by formula (I) or a physiologically acceptable acid addition salt thereof, for use as a type 1 or 2 benzodiazepine receptor agonist or antagonist; 10 in which X represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylsulphonyl, cyano or aminocarbonyl; R 1 represents hydrogen or -C 4 alkyl; and 15 R 2 represents hydrogen, prop-2-enyl, prop-2-ynyl, phenyl, or C^-Cj alkyl optionally substituted by at least one fluorine atom, a methoxy group, a dimethylamino group or a phenyl group; or R 1 and R 2 form, together with the nitrogen atom to which they 20 are attached, pyrrolidin-l-yl, piperidin-l-yl, hexahydroazepinl-yl, 4-(phenylmethyl)piperidin-l-yl, 4-methylpiperazin-l-yl, 4-(phenylmethyl)piperazin-l-yl, morpholin-l-yl or thiomorpholin-l-yl.

15. A compound according to claim 14, for use as 25 an anticonvulsant or an anxiolytic agent.

16. A pharmaceutical composition comprising a physiologically acceptable excipient and, as an active ingredient, a compound as claimed in any one of claims 1 to 4 or as defined in claim 14.