FR2700546A1 - Imidazo benzoxazole acetamide derivs. having anxiolytic and anticonvulsant activity - Google Patents

Abstract

Imidazo 2,1-b benzoxazole- 3-acetamide derivs. of formula (I) and their acid addition salts are new. X = H, halogen, 1-3C alkyl, or 1-3C alkoxy; Y = H, halogen, or 1-3C alkyl; R1 = H or methyl; R2 = H or methyl. The compounds may be given enterally or parenterally at a daily dosage of 1-1000 mg. EXAMPLE 22.6 g 2,2-diethoxy- N,N-dimethyl acetamide and 3.5 ml 37% HCl in 140 ml acetic acid were stirred at 50 deg.C for 1 hour then 13 g sodium acetate and 12.3 g (II; X = Y = H) was added and the mixture stirred at the same temperature for 2.5 hours. The mixture was evaporated and the residue dissolved in water and dichloromethane, filtered, and the organic phase separated, dried and purified to give 10.2 g (IV; X = Y = H; R1 = R2 = methyl), m.pt. 153-155 deg C. 2.73 g (IV) was treated with 10 ml thionyl chloride in 60 ml dichloromethane at ambient temperature for 15 hours. Excess thionyl chloride was removed, to give 2.5 g (V.HCl; Hal = Cl; X = Y = H; R1 = R2 = methyl). This was reduced with 2.92 g Rongalite (RTM) in 80 ml dichloromethane for 16 hours at ambient temperature, and purified to give 0.9g (I; X = H; R1 = R2 = methyl) m.pt. 190-192 deg C.

Description

The present invention relates to imida zo (2,1-b) benzoxazole-3-acetamide derivatives, their preparation and their therapeutic application.

dans laquelle
X représente un atome d'hydrogène ou d'halogène ou un groupe (C1-C3)alkyle ou (C1-C3)alcoxy,
Y représente un atome d'hydrogène ou d'halogène ou un groupe (C1-C3) alkyle 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 halogen atom or a (C1-C3) alkyl or (C1-C3) alkoxy group,
Y represents a hydrogen or halogen atom or a (C 1 -C 3) alkyl group R 1 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.

solvant chloré ou éthéré tel que le dichlorométhane ou le tétrahydrofurane, à une température de 20 à 500C, puis on traite in situ l'imidazolide intermédiaire ainsi obtenu avec une amine de formule générale HNRlR2 (dans laquelle R1 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 imidazoC2,1-bbenzoxazole 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 an 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
Diagram 1

a chlorinated or ethereal solvent such as dichloromethane or tetrahydrofuran, at a temperature of 20 to 500 ° C., and then the intermediate imidazolide thus obtained is treated in situ with an amine of general formula HNR 1 R 2 (in which R 1 and R 2 are as defined above; 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 ( O) C (O) NRtR2 (wherein R1 and R2 each represent a methyl group and are prepared in situ using 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 800C, to form an α-haloacetamide derivative of general formula (V) (in which X, Y, Rt and R2 are 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 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 (Rongalites), 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.

Figure 2

Another process (b) of preparation is illustrated by scheme 2 above
It is suitable for the preparation of primary amides of general formula (I, R1 = R2 = H), and comprises reacting an imidazot2,1-b] benzoxazole derivative of general formula (II) (in which X and Y are as defined above) with formaldehyde and dimethylamine in the presence of an excess of acid, for example 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 a 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 sodium or potassium cyanide, in the presence of water and in an alcoholic solvent, for example ethanol or 2 -methoxyethanol, at the reflux temperature, to obtain a derivative of aces tamide of general formula (Ia), which corresponds to the general formula (I) when R1 and R2 each represent a hydrogen atom.

The imidazo [2,1-b] benzoxazole derivatives of the general formula (II) can be prepared according to any method described in the literature, for example in J. Het. Chem., 2, 287 (1965) and Chem. Pharm. Bull., 18, 2204 (1970).

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 Table 1 given below.

Example 1 (Compound No. 3)
N, N-dimethyl-2-phenylimidazo [2,1-b] benzoxazol-3-acetamide.

1.1α-Hydroxy-N, N-dimethyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide.

In a 1 liter flask, 22.6 g (0.157 mol) of 2,2-diethoxy-N, N-dimethylacetamide and 3.5 ml of 37% hydrochloric acid in 140 ml of acetic acid are mixed, and The mixture is heated by stirring at 500 ° C. for one hour.

13 g (0.157 mole) of sodium acetate are then added and then, in small portions, 12.3 g (0.052 mole) of 2-phenylimidazo (2,1-b) benzoxazole, and heating and heating are maintained. stirring for 2.5h.

The mixture is evaporated under reduced pressure, the residue is taken up with water and dichloromethane, an insoluble matter is removed by filtration, the organic phase is separated off, washed with water and dried over sodium sulphate. The solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloromethane / methanol and then crystallizing in diethyl ether.

10.2 g of compound are obtained.

Melting point: 153-1550 ° C 1.2 N, N-dimethyl-2-phenylimidazo [2,1-b] benzoxazole-3-acetone
acetamide.

2.73 g (0.0081 mmol) of α-hydroxy-N, N-dimethyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide are treated with 10 ml of thionyl chloride in 60 ml of dichloromethane at room temperature for 15h.

The solvent and the excess of thionyl chloride are evaporated under reduced pressure, the residue is taken up in dry diethyl ether, filtered off and dried.

2.5 g (6.3 mmol) of a-chloro hydrochloride are obtained.
N, N-dimethyl-2-phenylimidazo [2,1-b] benzoxazole-3-acetamide which is reduced by means of 2.9 g (19 mmol) of Rongalites in 80 ml of dichloromethane for 16 h at room temperature.

The suspension is filtered, water is added to the filtrate, the organic phase is separated off, washed with water, dried over sodium sulphate, the solvent is evaporated under reduced pressure and the residue is crystallized from water. diethyl ether.

The solid is purified by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloromethane / methanol and then by recrystallization from ethanol.

0.9 g of compound are obtained.

Melting point: 190-1920C.

Example 2 (Compound No. 5) 6-Chloro-N-methyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide.

2.1 6-Chloro-α-hydroxy-2-phenylimidazo (2,1-b) benzoxazole-3-acetic acid.

A mixture of 13 g (0.048 mol) of 6-chloro-2-phenylimidazo (2,1-b) benzoxazole and 9.2 g (0.097 mol) of glyoxylic acid in 400 ml is stirred at room temperature for 18 hours. of acetic acid.

The solvent is evaporated under reduced pressure and the residue is crystallized from a mixture of water and dichloromethane. The solid is collected by filtration, washed with water and then with diethyl ether and dried.

14.3 g of compound are obtained.

Melting point: 2000C (decomposition).

2.2. 6-Chloro-α-hydroxy-N-methyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide.

A mixture of 7 g (0.02 mol) of 6-chloro-α-hydroxy-2-phenylimidazo [2,1-b] benzoxazole-3-acetic acid and 55 ml of pyridine is stirred at room temperature for 48 hours. 55 ml of acetic anhydride.

The mixture is evaporated under reduced pressure and the residue is crystallized from ethanol, the suspension is filtered, the solid is washed with diethyl ether and dried in vacuo.

5.5 g (0.0143 mmol) of α-acetyloxy-6-chloro-2-phenylimidazo (2,1-b) benzoxazole-3-acetic acid are obtained which are reacted with 3.5 g (0.degree. , 0216 mmol) of N, N'-carbonyldiimidazole in 125 ml of dry tetrahydrofuran for 2.5 h at room temperature.

The mixture is cooled with an ice bath, treated with 5 ml of dry methylamine and stirring is continued for 12 hours at room temperature.
The solvent is evaporated off under reduced pressure, the residue is taken up with water, the suspension is filtered, the recovered solid is washed with water, ethanol and then with diethyl ether and dried under vacuum. .

3 g of compound are obtained.

Melting point: 272-2740C.

2.3 6-Choro-N-methyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide.

3 g (0.0084 mol) of 6-chloro-α-hydroxy-N-methyl-2-phenylimidazo-2,1-b] benzoxazole-3-acetamide are treated in 60 ml of dry dichloromethane with 16 ml of thionyl chloride. for 12 hours at room temperature.

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

3.15 g (0.0076 mmol) of α, 6-di-chloro-N-methyl-2-phenylimidazo (2,1-b) benzoxazole-3-acetamide hydrochloride are obtained, which is reduced by means of 3 , 6 g (0.023 mol) of Rongalites in 140 ml of dichloromethane for 12 hours at room temperature.

The suspension is filtered, the filtrate is washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue is taken up in a mixture of ethanol, dichloromethane and diethyl ether and the suspension is filtered. The recovered solid is purified by recrystallization from propan-2-ol.

0.7 g of compound are obtained.

Melting point: 259-2610C.

Table 1 which follows illustrates the chemical structures and the physical properties of some compounds according to the invention. All compounds are in the basic state.

Table 1

<tb> N <SEP> X <SEP> Y <SEP> R1 <SEP> R2 <SEP> F <SEP> (C) <SEP>
<tb><SEP> 1 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> 266-268
<tb><SEP> 2 <SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> 244-246
<tb><SEP> 3 <SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 190-192
<tb><SEP> 4 <SEP> H <SEP> 6-Cl <SEP> H <SEP> H <SEP> 288-290
<tb><SEP> 5 <SEP> H <SEP> 6-Cl <SEP> H <SEP> CH3 <SEP> 259-261
<tb><SEP> 6 <SEP> H <SEP> 6-Cl <SEP> CH3 <SEP> CH3 <SEP> 211-212
<Tb>
Table 2 which follows illustrates the chemical structures and the physical properties of some compounds of general formula (IV), intermediate in the process illustrated by Scheme 1. All compounds are in the basic state.

Table 2

<tb> N <SEP> X <SEP> Y <SEP> R1 <SEP> R2 <SEP> F <SEP> (C) <SEP>
<tb> 1 '<SEP> H <SEP> H <SEP> H <SEP> CH3 <SEP> 261-263 <SEP> (d)
<tb> 2 '<SEP> H <SEP> H <SEP> CH3 <SEP> CH3 <SEP> 153-155
<tb> 3 '<SEP> H <SEP> 6-Cl <SEP> H <SEP> CH3 <SEP> 272-274
<tb> 4 '<SEP> H <SEP> 6-Cl <SEP> CH3 <SEP> CH3 <SEP> 238-240
<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 with respect to the xl (benzodiazepine type 1) and * (benzodiazepine tyPe 2) receptors.

The affinity of the compounds for the cerebral cerebellar and W2 receptors 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 525 111. After 30 minutes of incubation at OOC, 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 IC concentration, concentration which inhibits the binding of 3H-flumazenil by 50%, is calculated.

The IC50 of the compounds of the invention are, in these tests, between 1 and 1000 nM.

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 48h water diet, the rat is placed in a chamber 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 or oral route.

Study of anticonvulsant activity.

Activity with respect to maximum convulsions induced in mice by electroshock or by injection of entetrazol.

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 DA50, a dose that protects 50% of 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 with respect to convulsions induced in the mouse 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 by the IN, dose which produces 50% of the maximum effect, relative to the control animals, determined from 3 or 4 doses each administered to a group of 8 to 10 mice.

The SARs of the compounds of the invention are in this test between 1 and 50 mg / kg by the intraperitoneal route.

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

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

They possess anxiolytic and anticonvulsant 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 halogen atom or a (C 1 -C 3) alkyl or (C 1 -C 3) alkoxy group, Y represents a hydrogen or halogen atom or a (C 1 -C 3) alkyl group, R 1 represents a hydrogen atom or a methyl group, and R2 represents a hydrogen atom or a methyl group, in the form of a free base or of an addition salt with an acid. 2. Process for the preparation of compounds according to claim 1, characterized in that a) is reacted an imidazo derivative (2,1-b) benzoxazole 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 with N, N'-car bonyldiimidazole 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 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 the α-hydroxyacetamide derivative of the general formula (IV) is treated with a polyhalogenide. sulfuric or phosphoric acid, in an inert solvent, at a temperature of 20 to 80 ° C, to form an α-haloacetamide derivative of the 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 cosolvent miscible with water, at a temperature of 20 to 400C, or, in the case of a primary amide of general formula (I), b) an imidazo (2,1-b) benzoxazole derivative of general formula (II) is reacted 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 e (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. 3. Medicinal product characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it contains a compound according to claim 1, combined with a pharmaceutical excipient.