FR2679233A1 - Imidazo[2,1-b]benzothiazole-3-acetamide derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

Compounds corresponding to the general formula (I) in which X represents a fluorine, chlorine or bromine atom or a methyl or methoxy group. Application in therapeutics.

Description

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

dans laquelle
X représente un atome de fluor, de chlore ou de brome, ou un groupe méthyle ou méthoxy, étant exclu le composé dans la formule duquel X représente un atome de brome en position 4, composé décrit dans Chem.The compounds of the invention correspond to the general formula (I)

in which
X represents a fluorine, chlorine or bromine atom, or a methyl or methoxy group, being excluded the compound in the formula of which X represents a bromine atom in the 4-position, compound described in Chem.

Pharm. Bulb., 36 (12), 4760-4768 (1988).

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 a process illustrated in scheme 1 below.

d'une base forte minérale telle qu'un hydroxyde ou carbonate alcalin, par exemple la soude ou le carbonate de potassium, à une température de 20 à 800C.An imidazo [2,1-b] benzothiazole derivative of general formula (II) (wherein X is 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 an organic base such as pyridine, at a temperature of 20 ° C. at 600 ° C., to form the corresponding α-acetyloxyacetic acid derivative, which is itself treated with N, N'-carbonyldiimidazole in an inert solvent such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 to 500C, then the intermediate imidazolide thus obtained is treated in situ with ammonia to form the corresponding acetyloxyacetamide derivative, the latter being deacetylated by means of
Diagram 1

a strong mineral base such as a hydroxide or alkali carbonate, for example sodium hydroxide or potassium carbonate, at a temperature of 20 to 800C.

An α-hydroxyacetamide derivative of general formula (IV) is obtained which is then treated with a polyhalide of sulfuric or phosphoric acid, such as thionyl chloride or phosphorus oxychloride or any other equivalent agent, in a an inert solvent such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 to 800 ° C, to form an α-haloacetamide derivative of general formula (V) (wherein X is as defined herein 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 alkaline hydride, for example sodium or potassium borohydride, in a protic solvent such as an aliphatic alcohol, for example methanol or ethanol, or in an inert solvent miscible with water, for example dioxane or tetrahydrofuran, at a temperature of -40 to 400 ° C., or with a reducing agent such as a hyposulphite or an alkaline dithionite, for example, sodium hyposulphite or dithionite, or with sodium hydroxymethylsulfoxylate (Rongalites), in an inert solvent such as a chlorinated solvent, for example dichloromethane, optionally in the presence of an inert miscible cosolvent; water, for example the
N, N-dimethylformamide or N-methylpyrrolidone at a temperature of 20 to 400C.

Another method of preparation is illustrated in Scheme 2 below.

un solvant inerte tel qu'un solvant chloré ou éthéré, par exemple le dichlorométhane ou le tétrahydrofurane, à une température de 20 à 500C, puis on traite in situ 1' imidazo- lide intermédiaire avec de l'ammoniac gazeux sec à une température de 0 à 200C.A first variant of this process consists of reacting an imidazo [2,1-b] benzothiazole-3-acetonitrile derivative of general formula (VI) (in which X is as defined above) with a mixture of hydrochloric acid. and acetic acid, at a temperature of 50 to 1500C, to form an acetic acid derivative of general formula (VII), then the latter is treated with N, N '-carbonyldiimidazole in
Figure 2

an inert solvent such as a chlorinated or ethereal solvent, for example dichloromethane or tetrahydrofuran, at a temperature of 20 ° C. to 500 ° C., and then the intermediate imidazolide is treated in situ with dry ammonia gas at a temperature of 0 to 200C.

A second variant of this process consists of reacting the imidazo derivative (2,1-bibenzothiazole-3-acetonitrile of general formula (VI) with dry gaseous hydrochloric acid in a solvent such as formic acid, at a temperature of 0 to 500C.

The imidazo derivatives (2,1-b) benzothiazole of the general formula (II) can be prepared according to any method described in the literature, for example in Yakugaku Zasshi, 60, 132 (1940), Bull, Soc., Chim. 1277 (1966) J. Indian
Chem. Soc., 51, 1031 (1974); J. Med. Chem., 29, 386 (1986).

The imidazo [2,1-b] benzothiazole-3-acetonitrile derivatives of general formula (VI) and of imidazo (2,1-b) benzothiazole-3-acetic acid of general formula (VII) can be prepared according to a method analogous to that described in Chem Pharm.

Bull., 36 (12), 4760-4768 (1988), already mentioned.

The examples which follow illustrate the preparation of some compounds of the invention. The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained.

The numbers given in parentheses in the titles of the examples correspond to those in the first column of the following table.

Example 1 (Compound NO6) 2- (3-methylphenyl) imidazo (2,1-b) benzothiazole-3-acetamide.

1.1. Α-hydroxy-2- (3-methylphenyl) imidazo [2,1-b] benzoacetic acid
thiazole-3-acetic acid.

A mixture of 19 g (0.072 mol) of 2- (3-methylphenyl) imidazo (2,1-b) benzothiazole and 13.2 g (0.143 mol) of glyoxylic acid in 450 ml is stirred at room temperature for 2 days. The solvent is evaporated under reduced pressure and the residue is crystallized from a mixture of water and dichloromethane.The resulting suspension is filtered, the solid is washed with water, with ethanol and then with water. After drying in vacuo, 23.7 g of compound are obtained.

Yield: 97%. Melting point: 173-1760C.

1.2. -hydroxy-2- (3-methylphenyl) imidazo [2,1-b] benzothia-
zole-3-acetamide.

23 g (0.068 mol) of α-hydroxy-2- (3-methylphenyl) imidazo (2,1-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 room temperature for 16 hours, then the solvents are evaporated under reduced pressure.

A mixture of 9.33 g (0.024 mole) of the oily-acyloxyacetic acid thus obtained and 5.37 g (0.033 mole) of
N, N'-carbonyldiimidazole in 175 ml of dry tetrahydrofuran for 1.5 hours at room temperature. The mixture is cooled with a water-ice bath and treated with an excess of dry gaseous ammonia. Stirring is maintained at ambient temperature for 16 hours, then the solvent is evaporated off under reduced pressure. The residue is taken up with water and dichloromethane, the suspension obtained is filtered and the solid is washed with water, with ethanol then with diethyl ether. 6.1 g of α-acetyloxy are obtained. 2- (3-methylphenyl) imidazo [2,1-b] benzothiazole-3-acetamide 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 room temperature.

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

Yield: 65%. Melting point: 253-255C.

1.3. a-Chloro-2- (3-methylphenyl) imidazo (2,1-b) benzothiazole
3-acetamide, hydrochloride.

5.2 g (0.015 mol) of α-hydroxy-2- (3-methylphenyl) imidazo [2,1-b] benzothiazole-3-acetamide are treated with 28 ml of thionyl chloride in 110 ml of dichloromethane for 16 hours. at room temperature. The solvent is evaporated under reduced pressure and the residue is crystallized from diethyl ether. 5.7 g of hydrochloride are obtained, which is used as it is in the next step.

1.4. 2- (3-methylphenyl) imidazo (2,1-b) benzothiazole-3-acetone
acetamide.

5.7 g (0.014 mol) of α-chloro-2- (3-methylphenyl) imidazo [2,1-b] benzothiazole-3-acetamide hydrochloride are treated with 6.7 g (0.044 mol) of Rongalites in 100 ml. dichloromethane and 80 ml of N, N-dimethylformamide at room temperature for 24 hours.

The resulting suspension is filtered, the filtrate is evaporated under reduced pressure, the residue is taken up with water, the solid obtained is filtered, washed with saturated sodium bicarbonate solution, with water, with water, ethanol and then with diethyl ether. 2.1 g of compound is obtained which is recrystallized in ethanol and then in methanol. 1.03 g of pure compound is finally isolated.

Yield: 22%. Melting point: 243-246C.

Example 2 (Compound NO4) 2- (4-chlorophenyl) imidazo (2,1-b) benzothiazole-3-acetamide.

First variant 2.1. 2- (4-Chlorophenyl) imidazo [2,1-b] benzothiazole
3-acetic acid.

2.46 g (0.0076 mole) of 2- (4-chlorophenyl) imidazo [1,2,1-b] benzothiazole-3-acetonitrile are treated with 30 ml of a 50/50 (v / v) mixture of acid. Acetic acid and 37% hydrochloric acid in water, the mixture was refluxed for 2.5 hours and then evaporated to dryness.

The residue is taken up with water, the pH of the suspension is adjusted to 6 with aqueous sodium hydroxide, the solid is filtered off and washed with water, with ethanol, and then with water. diethyl ether. 2.4 g of compound are obtained.

Yield: 92%. Melting point: 242-2450C (decomp.).

2.2. 2- (4-Chlorophenyl) imidazo [2,1-b] benzothiazole-3-acetone
acetamide.

1 g (0.003 mol) of 2- (4-chlorophenyl) imidazo [2,1-benzothiazole-3-acetic acid is treated with 0.54 g (0.0033 mol) of N, N-carbonyldiimidazole in 15 ml. of dry tetrahydrofuran for 1 hour at room temperature.

The mixture is cooled by an ice bath and treated with an excess of dry gaseous ammonia. The mixture is stirred for 15 hours at room temperature, concentrated in vacuo, the solid is collected by filtration, washed with water until neutral pH, then with ethanol and with diethyl ether. dried and purified by recrystallization from ethanol. 0.63 g of compound is obtained.

Yield: 63%. Melting point: 288-2900C (decomp.)

Second variant
1.6 g (0.005 moles) of 2- (4-chlorophenyl) imidazo (2,1-b) benzothiazole-3-acetonitrile and 15 ml of formic acid are mixed, and the mixture is treated with an acid stream. gaseous hydrochloric acid for 1 hour, stirring is maintained for 4 hours at room temperature, the solution is then heated to degass it, evaporated to dryness, the residue is taken up with water and the residue is added. ammonia to adjust the pH to 10. The solid obtained is filtered off, washed with water until neutral pH, then with ethanol and then with diethyl ether. ethanol gives 1.12 g of compound.

Yield: 66%. Melting point: 288-2900C (decomp.)

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

In the right column "(d)" denotes a melting point with decomposition.

<Tb>

NO <SEP> X <SEP> Salt <SEP> or <SEP> base <SEP> F <SEP> (OC)
<tb><SEP> 268-270 <SEP> (d)
<tb><SEP> 1 <SEP> 4-F <SEP> base
<tb><SEP> 3 <SEP> 3-Cl <SEP> base <SEP> 242-245
<tb><SEP> 4 <SEP> 4-Cl <SEP> base <SEP> 288-290 <SEP> (d)
<tb><SEP> 5 <SEP> 2-CH3 <SEP> basis <SEP> 203-206
<tb><SEP> 6 <SEP> 3-CH3 <SEP> basis <SEP> 243-246
<tb><SEP> 7 <SEP> 4-CH3 <SEP> base <SEP> 253-254
<tb><SEP> 8 <SEP> 4-OCH3 <SEP> base <SEP> 285-289 <SEP> (d)
<Tb>
The compounds of the invention have been subjected to pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Study of the membrane bonds vis-à-vis the receptors 1 (benzodiazepiniaues tsPe 1) and commat; 2 (benzodiazépiniaues tvPe 2).

The affinity of the compounds for receptors 1 of the cerebellum and 02 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 ° C. After 30 minutes of incubation at 0 ° C, the samples are filtered under vacuum on Whatman GF / Be filters. and washed immediately with ice-cold buffer. The specific binding of 3H-flumazenil is determined in the presence of unlabeled 1 μM diazepam. The data are analyzed according to the usual methods and the concentration CIw, a concentration which inhibits the binding of i-flumazenil by 50%, is calculated.

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

Study of anticonvulsant activity.

Activity with respect to maximum convulsions induced in the mouse by electroshock or by iniection of pentetrazol.

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 DAw, 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 DAw 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 the convulsions induced by the subcutaneous administration of isoniazid (800 mg / kg) simultaneously with the test compound, injected intraperitoneally, according to 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 DAw, a dose which produces 50% of the maximal effect, relative to the control animals, determined from 3 or 4 doses each administered to a group of 8 to 10 mice.

The DAw of the compounds of the invention are, in this test, between 1 and 30 mg / kg by the intraperitoneal route and, according to the compounds, the maximum effect can be up to 350%.

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 DEM of the compounds of the invention are, in this test, between 1 and 30 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 i-flumazenil from its specific binding sites in the cerebellum and spinal cord; therefore they have an affinity for o, and cL> 2 (benzodiazepine type 1 and type 2) sites located within the macromolecular complex GABA-sites o-channel chloride.

In vivo they behave as complete or partial agonists, or as antagonists and / or inverse agonists, vis-à-vis 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 (5)

claims 1. Compounds having the general formula - (I)

 in which X represents a hydrogen, fluorine, chlorine or bromine atom, or a methyl or methoxy group, being excluded the compound in the formula of which X represents a bromine atom in position 4, in the form of free bases or addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of compounds according to claim 1, characterized in that an imidazo derivative L2,1-bjbenzothiazole of general formula (II) is reacted.

 (wherein X is as defined in claim 1) 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 the general formula (III)

 and then the latter is reacted with acetic anhydride in the presence of an organic base such as pyridine, at a temperature of 20 to 600C, to form the corresponding α-acetyloxyacetic acid derivative, which is treated itself. by means of N, N'-carbonyldiimidazole in an inert solvent such as a chlorinated or ethereal solvent, at a temperature of 20 to 500C, and then treating in situ the intermediate imidazolide thus obtained with ammonia to form the derivative corresponding acetyloxyacetamide, said acetyloxyacetamide is acetylated using a strong inorganic base such as a hydroxide or alkali carbonate, at a temperature of 20 to 800C, to form an α-hydroxyacetamide derivative of the general formula ( iv)

 it is then treated with a polyhalide of sulfuric or phosphoric acid, such as thionyl chloride or phosphorus oxychloride or any other equivalent agent, in an inert solvent such as a chlorinated or ethereal solvent, at a temperature of 20 to 800C, to form an α-haloacetamide derivative of the general formula (V)

 (wherein X is as defined above and Hal represents a halogen atom), and finally the compound of general formula (V) is reacted either with a reducing agent such as a simple or complex alkaline hydride, in a protic solvent such as an aliphatic alcohol, 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 such as a chlorine solvent, optionally in the presence of an inert cosolvent miscible with water, at a temperature of 20 to 400C. 3. Compounds corresponding to the general formula (V)

 in which X represents a hydrogen, fluorine, chlorine or bromine atom, or a methyl or methoxy group, and Hal represents a halogen atom, as intermediates necessary in the process according to claim 2. 4. Medicinal product characterized in that it consists of a compound according to claim 1. 5. Pharmaceutical composition characterized in that it contains a compound according to claim 1, combined with a pharmaceutical excipient.