WO1997025327A1

WO1997025327A1 - 5H,10H-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZINE-4-ONE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME

Info

Publication number: WO1997025327A1
Application number: PCT/FR1997/000018
Authority: WO
Inventors: Dominique Damour; Jean-Claude Hardy; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1996-01-10
Filing date: 1997-01-06
Publication date: 1997-07-17
Also published as: FR2743364A1; AU1382997A

Abstract

Compounds of formula (I), wherein R is a hydrogen atom or a -COOH or CH2OH radical, R1 is a -CH-R2 radical, R2 is a 3-dimethyl-1H-pyrazole-4-yl, 4-chloro-1-methylimidazole-5-yl or 3-hydroxy-isoxazole-5-yl radical, except for 10-(1,3-dimethyl-1H-pyrazole-4-methylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one, isomers thereof, salts thereof, the preparation thereof and drugs containing said compounds, are disclosed. The compounds of formula (I) have valuable pharmacological properties and are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor also known as the quisqualate receptor. Furthermore, the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate (NMDA) receptor, and specifically ligands for NMDA receptor glycine modulator sites.

Description

DERIVATIVES OF 5H.1QH-IMIDAZθri .2-a1.NDENθri .2-e1PYRAZINE-4-ONE. THEIR PREPARATION AND THE MEDICINES CONTAINING THEM

The present invention relates to compounds of formula:

their isomers, their salts, their preparation and the drugs containing them.

In formula (I), R represents a hydrogen atom or a -COOH or -CH ₂ OH radical, R _T represents a -CH-R ₂ radical and R ₂ represents a 1,3-dimethyl-1H-pyrazole radical -4-yl, 4-chloro-1-methylimidazole-5-yl or 3-hydroxy-isoxazole-5-yl, except for 10- (1,3-dimethyl-1H-pyrazole-4-methylene) - 5H, 10H- imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one.

Unless otherwise stated, in the definitions which follow, the alkyl and alkoxy radicals contain 1 to 6 carbon atoms in a straight or branched chain.

The E and Z isomeric forms of the compounds of formula (I) also form part of the invention.

The compounds of formula (I) can be prepared by the action of a derivative of formula:

(II)

in which Ra represents a hydrogen atom or an alkoxycarbonyl radical or -CH ₂ OH on an aldehyde R ₂ -CHO for which R ₂ has the same meanings as in formula (I), optionally followed by hydrolysis to release the carboxy function.

This reaction is generally carried out either in an inert solvent such as dimethylformamide, 1,2-dimethoxyethane, an alcohol (methanol, ethanol for example) or a mixture of these solvents, in the presence of a base such as soda, potash, a strong organic base such as 1, 8-diazabicyclo [5,4,0jUndec-7-ene, at a temperature between 20 and 100 ° C, or within dimethyl sulfoxide, in the presence of an alkali hydride such as sodium hydride, at a temperature in the region of 20 ° C, or in the presence of tetrabutylammonium bromide and a base such as an alkali metal hydroxide (soda, potash for example), within dimethyl sulfoxide, at a temperature between 20 and 100 ° C, either within acetic acid or acetic anhydride, in the presence of ammonium acetate, at a temperature between 20 ° C and the temperature d 'boiling of the reaction medium. The hydrolysis is preferably carried out by means of aqueous hydrochloric acid, within dioxane, at a temperature in the region of 100 ° C.

The aldehyde R ₂ -CHO for which R ₂ represents a 4-chloro-1-methylimidazole-5-yl radical can be obtained by the action of aqueous hydrochloric acid on the aldehyde Rb-CHO for which Rb represents a 4- radical bromo-1-methylimidazole-5-yl, at the boiling temperature of the reaction medium. The other aldehydes can be obtained by applying the methods described by MA ANDREEVA et al., Zh. Obshch. Khim., 50 (10), 2370 (1980) and in patent JP6815974.

The derivatives of formula (II) for which Ra represents a hydrogen atom or an alkoxycarbonyl radical can be obtained by cyclization in the presence of ammonium acetate of a derivative of formula: Ra

in which Ra represents a hydrogen atom or an alkoxycarbonyl radical and alk represents an alkyl radical.

This cyclization takes place in an organic acid such as acetic acid, at the boiling temperature of the reaction medium.

The derivatives of formula (III) can be obtained by the action of 2-bromoindanone on a derivative of formula:

Ra

HN _^ -N (IV)

COOalk

in which Ra and alk have the same meanings as in formula (III).

This reaction is generally carried out in an inert solvent such as an alcohol (methanol, ethanol for example), a ketone (acetone for example), an aromatic hydrocarbon (toluene for example), dimethylformamide or in the absence of solvent , optionally in the presence of a base such as sodium hydride or potassium carbonate with optionally a crown ether such as 18C6, at a temperature between 20 ° C. and the boiling point of the reaction medium or the fusion of the reaction medium.

The derivatives of formula (IV) can be obtained by application or adaptation of the methods described by PS BRANCO et al., Tetrahedron, 48 (30), 6335 (1992), JE OLIVIER et al., J. Org. Chem., 38 (7), 1437 (1973) and in U.S. Patent 3,600,399. The derivative of formula (II) for which Ra represents a -CH ₂ OH radical can be obtained by the action of lithium hydroboride and lithium triethylborohydride on a derivative of formula (II) for which Ra represents an alkoxycarbonyl radical. This reaction is generally carried out within tetrahydrofuran, at the boiling temperature of the reaction medium.

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The isomers of the compounds of formula (I) can be separated by the usual known methods, for example by crystallization or chromatography.

The compounds of formula (I) comprising a basic residue can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.

The compounds of formula (I) comprising an acid residue can optionally be transformed into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline-earth for example), ammonia, an amine or a salt of an amine on a compound of formula (I) , in a solvent. The salt formed is separated by the usual methods.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentioned addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophyllinacetate, salicylate, methylene- bis-β- oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate), salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, salts of nitrogen bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine). / 25327 PC17FR97 / 00018

The compounds of formula (I) have interesting pharmacological properties. These compounds are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, also known as the quisqualate receptor.

Furthermore, the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulating sites of the NMDA receptor.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents such as thromboembolic and hemorrhagic stroke, cardiac arrest, hypotension, cardiac, vascular or surgical intervention. pulmonary or severe hypoglycemia. They are also useful in the treatment of the effects due to anoxia, whether it is perinatal or following drowning, high pressure or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease and other dementias, amyotrophic lateral sclerosis or other motor neuron diseases, olivo-pontocerebellar atrophy and PARKINSON's disease. These compounds can also be used vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to the degeneration of the inner ear (R. PUJOL et al., Neuroreport, 3 , 299-302 (1992) or retina (JL MONSINGER et al., Exp. Neurol., 113, 10-17 (1991), tinnitus, anxiety (KEHNE et al., Eur. J. Pharmacol ., 193, 283 (1991)), depression (TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990)), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), TOURETTE syndrome, hepatic encephalopathies, sleep disturbances, attention deficit disorders, disorders of hormonal conditions (excess HG or HL secretion, corticosterone secretion), as analgesics (DICKENSON et al. , Neurosc. Letters, 121, 263 (1991)), anti-inflammatory drugs (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) anti-inflammatory drugs (SORRELS et al. , Brain Res., 572, 265 (1992)), 25327 PC17FR97 / 00018

antimigraine, antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA or AMPA receptor, as well as neurological disorders associated with viral diseases such as meningitis and viral encephalitis, AIDS (LIPTON et al., Neuron, 7, 111 (1991)), rabies, measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention, tolerance and dependence of symptoms of abstinence from drugs, alcohol and the inhibition of addiction and dependence on opiates, barbiturates, amphetamine and benzodiazepines. They can also be used in the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric-aminoaciduria , saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The affinity of the compounds of formula (I) vis-à-vis the AMPA receptor was determined by studying the antagonism of the specific binding of [3iH] -AMPA on membranes of rat cerebral cortex (HONORE et al., Neuroscience letters, 54, 27 (1985)). The [Hl-AMPA is incubated in the presence of 0.2 mg of protein at 4 ° C for 30 minutes in 10mM KH2PO4 buffer, 100mM KSCN, pH7.5. The non-specific binding is determined in the presence of 1 mM L-glutamate. The bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A). The inhibitory activity of these products is less than or equal to 100 μM.

The affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described. by T. CANTON et al., J. Pharm. Pharmacol., 44, 812 (1992). The [3H] -DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5. The non-specific fixation is determined in the presence of 1 mM glycine. The bound radioactivity is separated by filtration on Whatman GF / B filters. The inhibitory activity of these products is less than or equal to 100 μM. The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.

The following examples illustrate the invention.

EXAMPLE 1

Under an inert atmosphere, 2.16 g of 5H, 10H-imidazo [1,2-a.indeno [1,2- e] pyrazine-4-one, to a stirred suspension cooled to a temperature in the region of 18 ° C, 22 ml of dimethylsulfoxide and 1.4 g of 4-chloro-1-methylimidazole-5-carboxaldehyde 0.97 g of 60% sodium hydride are added in portions and stirring is continued for 3 hours at a similar temperature 20 ° C. The reaction mixture is hydrolyzed with 30 ml of water, then 3.2 ml of acetic acid. The precipitate obtained is filtered, washed with 2x20 ml of distilled water, then 2x20 ml of methanol and crystallized from a mixture of 75 ml of dimethylformamide and 25 ml of distilled water. The crystals are filtered, washed with 2x20 ml of distilled water, then 2x20 ml of acetone and dried under vacuum (1 mmHg; 0.13 kPa) near 50 ° C. 1.45 g of 10 - [(4-chloro-1-methylimidazole-5-yl) methylene] -5H, 10H-imidazo [1, 2-a] indeno [1,2- e] pyrazine-4- are obtained. one as an orange solid melting above 270 ° C [Analysis C18H12CIN5O% calculated C: 61, 81, H: 3.46, Cl: 10.14, N: 20.02, O: 4.57,% found C: 62.2, H: 3.2, Cl: 10.1].

5H, 10H-imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one can be prepared according to the method described in patent WO94 / 7893.

EXAMPLE 2

To a suspension of 3.29 g of 2-hydroxymethyl-5H, 10H-imidazo [1, 2- a] indeno [1, 2-e] pyrazine-4-one, of 1.8 g of 1,3-dimethyl -1 H-pyrazole-4-carboxaldehyde and 52 ml of dimethylsulfoxide, are added under a nitrogen atmosphere, at a temperature close to 22 ° C., 1.36 g of sodium hydride (80%) in small portions in 10 minutes. After one hour of stirring, 26 ml of dimethyl sulfoxide are added to the reaction medium and stirring is continued at a temperature in the region of 20 ° C for one hour and 15 minutes. The reaction medium is taken up in 2x150 ml of diethyl ether and the supernatant phase is eliminated. The resulting solid is filtered on sintered glass and rinsed with 2x150 ml of petroleum ether. 20 ml of hydrochloric ether (4.5N) are then added to the resulting gum, then 50 ml of ethanol and 65 ml of ethyl ether. The powder thus obtained is filtered on sintered glass, washed with 20 ml of acetone and with 20 ml of water and then dried at 60 ° C under reduced pressure. 4 g of a greenish solid are thus obtained. 1 g of this solid is recrystallized from 37 ml of a water-dimethylformamide mixture (15/22 by volume), which gives 0.3 g of 10- (1 , 3-dimethyl-1 H-pyrazole-4-yl methylene) -2-hydroxymethyl-5H, 10H-imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4- one in the form of yellow powder melting above 260 ° C [Analysis C- ₂ oH ₁₇ N ₅ θ2, 1.85 H ₂ O:% calculated C: 66.84, H: 4.77.N: 19.49, O: 8.90% found C: 66.6, H: 4.2.N: 19.3].

1,3-Dimethyl-1 H-pyrazole-4-carboxaldehyde can be prepared according to the method described by M.A. Andreeva et al., Zh. Obshch. Khim., 50 (10), 2370 (1980).

2-hydroxymethyl-5H, 10H-imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one can be prepared as follows: to a solution of 2.23 g of lithium borohydride in 100 ml of tetrahydrofuran, 3.4 ml of lithium triethylborohydride (1M solution in tetrahydrofuran) are added at a temperature in the region of 10 ° C. After 30 minutes of stirring at 15 ° C, 10 g of 4-oxo-5H, 10H-imidazo [1, 2-a] indeno [1, 2 e] ethyl pyrazine-2-carboxylate are added in portions . The reaction medium is then brought to reflux for 2 hours and 30 minutes. After the medium has cooled to a temperature in the region of 10 ° C., 50 ml of water are added dropwise and stirring is continued for 10 minutes. 100 ml of 1N hydrochloric acid are then added and the mixture is kept stirring for 30 minutes at a temperature in the region of 20 ° C. The above-mentioned above is filtered on sintered glass, rinsed with 2x150 ml of water and then dried at 60 ° C under reduced pressure .; 6.87 g of 2-hydroxymethyl-5H, 10H- imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one are thus obtained in the form of a beige powder melting above 260 ° C. . [Rf = 0.07; thin layer chromatography on silica gel, eluent: dichloromethane-methanol (95/5 by volume)].

Ethyl 4-oxo-5H, 10H-imidazo [1, 2-a] indeno [1, 2-e] pyrazine-2-carboxylate can be prepared as follows: to a solution of 2 g of 1- (1- oxoindane-2-yl) imidazole-2,4-dicarboxylate in 80 ml of acetic acid 51.2 g of ammonium acetate are gradually added and the mixture is heated at reflux for 2 hours. After cooling to a temperature in the region of 20 ° C., the precipitate formed is filtered and rinsed with distilled water, then with methyl ethyl ketone (2 × 10 ml) to give 0.65 g of 4-oxo-5H-10H-imidazo [1 , 2-a] indeno [1, 2-e] ethyl pyrazine-2-carboxylate in the form of a beige solid melting above 260 ° C. [Analysis% calculated C: 65.08, H: 4.44, N: 14.23,% found C: 65.2, H: 4.3, N: 13.8].

Diethyl 1 - (1-oxoindane-2-yl) imidazole-2,4-dicarboxylate can be prepared as follows: to a suspension of 3.5 g of 60% sodium hydride in 50 ml of dimethylformamide a solution of 17.2 g of diethyl imidazole-2,4-dicarboxylate in 200 ml of dimethylformamide is added dropwise with stirring at a temperature in the region of 15 ° C. and stirring is continued for 45 minutes. A solution of 17.1 g of 2-bromoindanone in 250 ml of dimethylformamide is then added over 40 minutes at a temperature in the region of 15 ° C and the stirring is continued, allowing the temperature of the reaction medium to rise to around 20 ° C; stirring is maintained in this state for 48 hours. The reaction mixture is concentrated on a rotary evaporator and treated with water, then extracted with dichloromethane (4x150 ml). The organic phase is washed with distilled water, dried over magnesium sulfate, filtered and evaporated on a rotary evaporator. A brown oil (29 g) is obtained which is chromatographed on a silica column, eluting with dichloromethane to give 11.6 g of diethyl 1- (1-oxoindan-2-yl) imidazole-2,4-dicarboxylate solid meringue used as is in subsequent syntheses.

Diethyl imidazole-2,4-dicarboxylate can be prepared as follows: to a suspension of 46 g of ethyl α-amino-oximinoacetate in 800 ml of xylene maintained at a temperature in the region of 0 ° C. 59 ml of triethylamine is added dropwise with stirring, then 41.6 g of ethyl propiolate. The temperature of the reaction medium is allowed to return to around 20 ° C. and the stirring is continued for 48 hours. The reaction mixture is treated with 220 ml of water and the organic phase is washed with 50 ml of distilled water, dried over magnesium sulphate, filtered and concentrated to half with a rotary evaporator: the insoluble product which has formed is eliminated by filtration and the filtrate is dried by azeotropy for 24 hours, then evaporated on a rotary evaporator. The evaporation residue is triturated in dichloromethane and the crystalline solid which forms is filtered to give 7 g of diethyl imidazole-2,4-dicarboxylate in the form of a beige solid melting at 170 ° C. By chromatography on a silica column, eluting with a mixture of cyclohexane and ethyl acetate (50-50 by volume), 7.2 g of imidazole are recovered from the crystallization filtrate. Diethyl 2,4-dicarboxylate, then eluting with ethyl acetate alone 3 g of diethyl imidazole-2,4-dicarboxylate.

Ethyl α-amino-oximinoacetate can be prepared as described by P. S. BRANCO et al., Tetrahedron, 48 (30), 6335 (1992).

EXAMPLE 3

Under a stream of nitrogen, to a stirred mixture of 3.86 g of 4-oxo-5H, 10H-imidazo [1, 2-a] indeno [1, 2-e] ethyl pyrazine-2-carboxylate, 150 ml of dimethyl sulfoxide and 1.9 g of 4-chloro-1-methylimidazole-5-carboxaldehyde are added in portions 1.9 g of 60% sodium hydride. Stirring is continued overnight at a temperature in the region of 20 ° C., then the reaction mixture is hydrolyzed with 150 ml of distilled water while maintaining the temperature around 25 ° C. After 15 minutes of stirring, the medium is acidified with 100 ml of acetic acid and the precipitate formed is filtered and washed with 2x20 ml of distilled water, then 2x20 ml of acetone. The solid obtained is stirred in 90 ml of a boiling mixture of distilled water and dimethylformamide (80-20 by volume), filtered, washed with 2x5 ml of distilled water, then 2x5 ml of acetone and dried under vacuum ( 1 mmHg; 0.13 kPa) near 50 ° C. 0.6 g of 10 - [(4-chloro-1-methylimidazole-5-yl) methylene] -4,5- dihydro-4-oxo-10H-imidazo [1, 2-a] indeno [ 1, 2-e] pyrazine-2-carboxylιque in the form of an ocher solid melting above 290 ° C. [NMR Specter ^" Η in DMSO-d6, T = 300K (δ in ppm, 300mhz): 3.70 (3H , s, CH3), 7.10 (1 H, d, J = 6Hz, CH arom.), 7.30 (1 H, t, J = 6Hz, CH arom.), 7.42 (1H, t, J = 6Hz, CH arom.), 7.70 (1 H, s, ethylenic CH), 7.90 (1 H, d, J = 6Hz, CH arom.), 7.95 (1 H, s, CH imidazole), 9.10 (1 H, s, CH imidazole), 12.8 (1 H, s, NH), 12.9 (1 H, s, COOH)]. 4-chloro-1-methylimidazole-5-carboxaldehyde can be prepared in the following manner: a mixture of 3.7 g of 4-bromo-1-methylimidazole-5-carboxaldehyde and 120 ml of liquid is heated at reflux for 24 hours concentrated hydrochloric acid. The reaction mixture is evaporated on a rotary evaporator and the evaporation residue is added with 45 ml of distilled water, neutralized to pH 7 with sodium hydrogen carbonate and extracted with 3 × 50 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, washed with distilled water and evaporated on a rotary evaporator. The evaporation residue is purified by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (75-25 by volume). 2.3 g of 4-chloro-1-methylimidazole-5-carboxaldehyde are obtained in the form of a white solid, melting at 62 ° C. [Mass spectrum (electronic impact) m / z 144 (M) ⁺ \ 143 (C ₅ H ₄ N ₂ OCI) ⁺ , 115 (C ₄ H ₄ N ₂ CI) ⁺ ; (desorption by chemical ionization with NH ₃ ) m / z 162 (MNH ₄ ) ⁺ , 145 (MH) ⁺ ].

4-Bromo-1-methylimidazole-5-carboxaldehyde can be prepared as described by M. OHBA et al., Heterocycles, 33 (1), 21 (1992).

EXAMPLE 4

To a suspension of 0.39 g of 4-oxo-5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazine-2-carboxylate, 0.15 g of 3-hydroxyisoxazole -5- carboxaldehyde and 8 ml of dimethyl sulphoxide, 0.19 g of sodium hydride (80%) are added under small nitrogen portions under a nitrogen atmosphere, at a temperature close to 20 ° C. The reaction medium is then kept under stirring for 20 hours at a temperature in the region of 20 ° C. It is cooled to a temperature in the region of 5 ° C., then 4 ml of acetic acid are added to the reaction medium and the medium is kept stirring at this temperature for 15 minutes. By adding 15 ml of water, at a temperature in the region of 5 ° C., followed by stirring, a precipitate is obtained which is filtered on sintered glass, washed with water and with diisopropyl ether and then dried to 60 ° C under reduced pressure. The black solid thus obtained is dissolved hot in 8 ml of dimethylformamide. After adding 3 ml of water and cooling to a temperature in the region of 5 ° C overnight, a precipitate is obtained which is filtered on sintered glass, washed with dimethylformamide and with diisopropyl ether and then dried at 60 ° C under pressure scaled down. We obtain thus 0.14 g of 10- (3-hydroxy-isoxazole-5-yl-methylene) -5H, 10H-imidazo [1,2- a] indeno [1, 2-e] pyrazine-4-one-2- ethyl carboxylate in the form of a green solid.

A solution of 0.14 g of 10- (3-hydroxy-isoxazole-5-yl-methylene) -5H, 10H- imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one- Ethyl 2-carboxylate, 10 ml of dioxane and 1.5 ml of hydrochloric acid (6N) is brought to reflux for 7 hours. After stirring overnight at a temperature in the region of 20 ° C., 2 ml of hydrochloric acid (6N) are added to the reaction medium, which is again brought to reflux for 24 hours. After the medium has cooled to a temperature in the region of 20 ° C., the suspension is filtered on sintered glass and washed with 3 × 5 ml of dioxane, 5 ml of water and diisopropyl ether. 60 mg of a yellow solid is thus obtained to which 1 ml of acetic acid and 1.5 ml of hydrochloric acid (6N) are added and the resulting suspension is brought to reflux for 60 hours. After cooling of the medium to a temperature in the region of 5 ° C, the suspension is filtered through sintered glass and washed with 2x1 ml of acetic acid and then dried at 60 ° C under reduced pressure. 20 mg of 10- (3-hydroxy-isoxazole-5-yl-methylene) -5H, 10H- imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one- are thus obtained. 2-carboxylic acid in the form of an orange-yellow solid, melting above 260 ° C.

3-hydroxyisoxazole-5-carboxaldehyde can be prepared according to the method described in patent JP6815974.

The medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other product. pharmaceutically compatible, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sac charose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

As liquid compositions for oral administration, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or 'paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or the like, can be used. suitable organic solvents. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and / or prevention of conditions which require the administration of an AMPA receptor antagonist or of an antagonist of the NMDA receptor. These compounds are particularly useful for treating or preventing all ischemia and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease and other dementias. , amyotrophic lateral sclerosis or other motor neuron diseases, olivo-pontocerebellar atrophy, PARKINSON disease, with regard to epileptogenic and / or convulsive manifestations, cerebral or spinal trauma, related trauma degeneration of the inner ear or retina, tinnitus, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathies, sleep disorders, attention deficit disorders, disorders of hormonal conditions (excess of HG or HL secretion, corticosterone secretion), as analgesics, anti-inflammatories, antianorexics, antimigraine antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA or AMPA receptor, as well as the neurological disorders associated with viral diseases such as meningitis and viral encephalitis, AIDS, rabies, measles and tetanus, for the prevention, tolerance and dependence of symptoms of abstinence from drugs, alcohol and the inhibition of addiction and dependence on opiates, barbiturates, amphetamine and benzodiazepines, in the treatment of deficits linked to mitochondrial abnormalities such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric- aminoaciduria, saturnine encephalopathy (chronic lead poisoning ) and sulfite oxidase deficiency.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to the invention:

EXAMPLE A

Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:

- Compound of formula (I) 50 mg

- Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica 1 mg

- Sodium carboxymethyl starch 10 mg - Talc 10 mg

- Magnesium stearate 1 mg

EXAMPLE B

Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique: - Compound of formula (I) 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg

- Sodium carboxymethyl starch 22 mg - Talc 10 mg

- Magnesium stearate 2 mg

- Colloidal silica 2 mg

- Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3,5-24,5) q.s. p. 1 film-coated tablet finished at 245 mg

EXAMPLE C

A solution for injection containing 10 mg of active product having the following composition is prepared:

- Compound of formula (I) 10 mg

- Benzoic acid 80 mg - Benzyl alcohol 0.06 ml

- Sodium benzoate 80 mg - 95% ethanol 0.4 ml

- Sodium hydroxide 24 mg

- Propylene glycol 1.6 ml

- Water q.s.p. 4 ml

Claims

1 - Compounds of formula:

in which, R represents a hydrogen atom or a -COOH or -CH ₂ OH radical,

Ri represents a radical -CH-R ₂ and

R ₂ represents a 1,3-dimethyl-1 H-pyrazole-4-yl radical,

4-chloro-1-methylimidazole-5-yl or 3-hydroxy-isoxazole-5-yl,

with the exception of 10- (1, 3-dimethyl-1 H-pyrazole-4-methylene) -5H, 10H- imidazo [1, 2-a] indeno [1, 2-e] pyrazine-4-one,

their E and Z isomers and their salts.

2 - Process for preparing the compounds of formula (I) according to claim 1 characterized in that a derivative of formula is reacted:

in which Ra represents a hydrogen atom or an alkoxycarbonyl radical or -CH ₂ OH on an aldehyde R ₂ -CHO for which R ₂ has the same meanings as in claim 1, then optionally hydrolyzed to release the carboxy function, isolates the product and optionally transforms it into salt.

3 - Medicines containing as active principle at least one compound of formula (I) according to claim 1 or a salt of such a compound.