WO1993021171A1 - Use of 2h-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives for preparing nmda/ampa receptor antagonist drugs, novel products, preparation thereof and drugs containing same - Google Patents

Abstract

The use of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives of formula (I), a salt thereof or a precursor thereof, for preparing NMDA and/or AMPA receptor antagonist drugs, the novel compounds of formula (I), preparation thereof, and drugs containing same, are disclosed.

Description

APPLICATION OF 2H-l, 2,4-BENZ0THIADIAZINE-l, l-DI0XYDE-3-CARB0XYLIC ACID DERIVATIVES TO THE PREPARATION OF ANTAGONIST DRUGS OF NMDA / AMPA RECEPTORS, AS WELL AS NEW PRODUCTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING

The present invention relates to the application of 2H-1,2,4-benzothiadiazine-1,.-Dioxide-3-carboxylic acid derivatives of formula:

a salt of such a compound or a precursor of such a compound for the preparation of medicaments antagonists of the NMDA receptor and / or of the AMPA receptor, the new compounds of formula (I), their preparation and the medicaments containing them.

In formula (I),

- Rj represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk) ₂ , -CO-NHOH, -CO-N.alk.OH, -CO-NH radical -O-R5,

15 -CO-N (alk) -OR5 or a group convertible into a carboxy radical in vivo,

- R2, R3 and R4, identical or different, represent a hydrogen or halogen atom or an alkyl radical,

- R5 represents an alkyl or phenylalkyl radical and

- alk represents an alkylene or alkyl radical.

It is understood that the compounds of formula (I) can also be in their tautomeric form:

As groups convertible into a carboxy radical in vivo, there may be mentioned the radicals -CO-Rg in which Rβ represents a radical -O-alk-Rγ, -O-alk-O-CO-alk, -O-alk-O-COOalk , -O-alk-O-CO-Ry, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-Rγ, -O-alk -SF.7 -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₈ Rg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH- alk-0-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-Ry, -NH-alk-SR ₇ , -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ Rg.

In these definitions, alk represents an alkylene or alkyl radical, R7 is a phenyl radical, Rβ and Rg, identical or different, represent a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or else form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino cycle.

The halogen atoms are the chlorine, bromine, fluorine and iodine atoms.

In the above definitions and those which will be cited below, unless otherwise stated, the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions contain 1 to 6 carbon atoms in a straight or branched chain and preferably 1 to 4 carbon atoms.

The compounds of formula (I) for which either R 1, R 3 and R 4 represent a hydrogen atom and R-j represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and Rj represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical, or R3 represents a chlorine or bromine, R2 and R4 represent a hydrogen atom and R- | represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical have already been described as diuretics (Russian

Pharmacol. and Toxicol., ^ 0, 19-23 (1977); Farm. Zh. (Kiev), 2,62 (1983); -Chern. Abst, 99, 38439g (1983)).

The other compounds of formula (I), the salts of these compounds or the precursors of these compounds are new and as such form part of the invention. These are the compounds of formula (I) for which: - R- | represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2 radical. -CO-NH-alk, -CO-N (alk) ₂ , -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-R5, -CO-N (alk) -OR5 or - CO-Rg in which Rβ represents a radical -0-alk-R7 -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-R7, -O-alk -OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-R7, -0-alk-S-R7, -O-alk-COOH, -O-alk -COOalk, -0-alk-NR ₈ Rg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-0-CO-R, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-R, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ Rg,

- R2, R3 and R4, identical or different, each represent a hydrogen or halogen atom or an alkyl radical,

- R5 represents an alkyl or phenylalkyl radical,

- R7 represents a phenyl radical,

- R ₈ and Rg, identical or different, each represent a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or else form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino ring,

- alk represents an alkylene or alkyl radical, with the exception of the compounds for which either R2, R3 and R4 represent a hydrogen atom and R-j represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and R-j represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R-j represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical.

Medicines containing at least one new compound of formula (I), a salt of such a compound or a precursor of such a compound also form part of the invention.

The new compounds of formula (I) for which Rj represents a carboxy radical can be prepared by hydrolysis of the compounds of formula (I) correspondents for which R- | represents an alkoxycarbonyl radical.

This hydrolysis is generally carried out by means of a base such as an alkali metal hydroxide (soda, potash, lithium hydroxide for example), in an inert solvent such as an alcohol or a water-alcohol mixture , water-tetrahydrofuran, water-dioxane, at a temperature between 20 and 100 ° C or by means of potassium trimethylsilanolate, in an inert solvent such as tetrahydrofuran, dioxane, dichloromethane, at a temperature close to 20 ° C. The new compounds of formula (I) for which R-j represents an alkoxycarbonyl radical can be prepared by cyclization of a derivative of formula:

in which R2, R3 and R4 have the same meanings as in formula (I) and R-JO represents an alkyl radical.

This cyclization is preferably carried out by means of a base such as an alkali metal alcoholate, within the corresponding alcohol, at a temperature between 15 and 70 ° C.

The derivatives of formula (II) can be prepared by the action of a derivative of formula:

CI-CO-COOR10 (III)

in which R-JO has the same meaning as in formula (II) on a derivative of formula:

in which R, R3 and R4 have the same meanings as in formula (I).

This reaction is carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as a tertiary amine (triethylamine for example), at a temperature in the region of 20 ° C.

The derivatives of formula (IV) are marketed or can be obtained by application or adaptation of the methods described by J. H. SHORT et al., J. Amer. Chem. Soc, 82, 1135 (1960), Y. GIRARD et al., J. Chem. Soc. Perkin Trans I, 1, 1043 (1979), J. G. TOPLISS et al., J. Med. Chem., 6, 122 (1963), in US patent 3251837 and in the examples. In particular, these derivatives can be prepared by the action of ammonia on a derivative of formula:

in which R2, R3 and R4 have the same meanings as in formula (I).

This reaction is generally carried out at a temperature close to

20 ° C.

The derivatives of formula (V) can be prepared by the action of CISO3H on an aniline of formula:

(VI)

in which R2, R3 and R4 have the same meanings as in formula (I).

This reaction is carried out at a temperature close to 100 ° C.

The new compounds of formula (I) for which R-j represents an alkoxycarbonyl radical can also be prepared by the action of a derivative of formula (IV) on a dialkyl oxalate.

This reaction is preferably carried out by means of a base such as an alkali metal alcoofate, in an inert solvent such as an alcohol, at a temperature in the region of 20 ° C. The compounds of formula (I) for which R-j represents a tetrazolyl radical can be prepared by reaction of sodium azide on a derivative of formula:

in which R2, R3 and R4 have the same meanings as in formula (1).

This reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethoxyethane, at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The derivatives of formula (VII) can be obtained by the action of phosphorus pentachloride or phosphoryl chloride on an amide of formula:

in which R2, R3 and R4 have the same meanings as in formula (I).

This reaction is generally carried out at a temperature between 20 and 160 ° C.

The amides of formula (VIII) can be prepared from the compounds of formula (I) for which Rj represents a carboxy or alkoxycarbonyl radical by any known method making it possible to pass from an acid or an ester to a primary or secondary amide and in particular by adapting the methods described by QE KENT et al., Organic Syntheses, III, 490; W. S. BISHOP, Organic Synthesis, III, 613.

The compounds of formula (I) for which R-j represents a radical -CO-NH, -CO-NH-alk, -CO-N (alk) 2. -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-R5, -CO-N (alk) -OR5 can be prepared by reaction of a corresponding compound of formula (I) for which R * ι represents a carboxy or alkoxycarbonyl radical on a derivative of formula:

in which Rjj represents a hydrogen atom or an alkyl radical and R-J2 represents a hydrogen atom or an alkyl, hydroxy, -O-alk or -OR5 radical in which R5 represents an alkyl or phenylalkyl radical.

When the acid is used, it is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or N, N'-diimidazolecarbonyl, in an inert solvent such as ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide for example) or a chlorinated solvent (methylene chloride, chloroform for example), at a temperature between 0 ° C and the reflux temperature of the reaction medium.

When an ester is used, the operation is carried out either in an organic medium, optionally in the presence of an acid acceptor such as butyllithium, the lithian of diisopropylamine or an organic nitrogenous base (trialkylamine, pyridine, diaza-1, 8 bicyclo [5.4.0] undecene-7 or diaza-1, 5 bicyclo [4.3.0] nonene for example), in a solvent as mentioned above or a mixture of these solvents, at a temperature between 0 ° C. and the reflux temperature of the reaction medium, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline earth base (soda, potash for example) or of a carbonate or bicarbonate of an alkali or alkaline earth metal, at a temperature between 0 and 40 ° C.

The new compounds of formula (I) for which Rj represents a radical -CO-Rβ in which R ₈ represents a radical -0-alk-R7, -O-alk-O-CO-alk, -O-alk-O- COOalk, -0-alk-0-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-R7, -0- alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₈ Rg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, - NH-alk-0-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-R7, -NH-alk-S -R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ Rg, can be prepared by reaction of a corresponding compound of formula (I) for which Rj represents a carboxy or alkoxycarbonyl radical on a derivative of formula:

R6-H (X)

in which R ₈ has the same meanings as above.

This reaction is carried out under the conditions described above for the reaction of acids or esters with the derivatives of formula (IX).

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

The compounds of formula (I) can optionally be converted 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, a tetraalkylammonium, an amine or a salt of an organic acid 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 the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, tetraalkylammonium salts (tetrabutylammonium for example) , the salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-β-phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine).

The compounds of formula (I) have interesting pharmacological properties. These compounds are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the NMDA receptor.

Furthermore, certain compounds of formula (I) are antagonists of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), also known as the quisqualate receptor.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, motor neuron diseases, amyotrophic lateral sclerosis, olivopontocerebellar atrophy, PARKINSON's disease. These compounds can also be used with regard to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, of 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), as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991), antianorexics (SORRELS et al., Brain Res., 572, 265 (1992), antimetics, antimigraine and to treat poisoning by neurotoxins or other agonist substances of the NMDA receptor, as well as neurological disorders associated with viral diseases such as 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 of symptoms of drug and alcohol abstinence and inhibition of addiction and opioid dependence.

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 binding

Specific for [3H] -DCKA (6,8-dichloro kynurenic acid) on membranes of rat cerebral cortex according to a method derived from that described by BARON et al., Eur. J. Pharm., 206, 149 (1991). [3HJ-DCKA (20nM) is incubated in the presence of 0.1 mg of protein at 4 ° C for 10 minutes in HEPES buffer ((N- [2-hydroxyethyl] piperazine-N'- acid)

15 [2-ethanesulfonic]) 50 mM, pH 7.5. The non-specific binding 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 generally less than 100 μM.

The affinity of the compounds of formula (I) for the AMPA receptor has

20 determined by studying the antagonism of the specific binding of

[^ Hl-AMPA on membranes of rat cerebral cortex (HONORE et al.,

Neuroscience letters, 54, 27 (1985)). The [3H] -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. Non-specific fixation is

25 determined in the presence of 1mM L-glutamate. The bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A). The inhibitory activity of these products is generally less than 100 μM.

The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route.

- 30 Are particularly interesting as receptor antagonists

NMDA the compounds of formula (I) for which Rj represents a carboxy or alkoxycarbonyl radical and R2, R3 and R4 are hydrogen atoms or else R2 and R3 represent hydrogen atoms and R4 represents a halogen atom or else R3 represents a hydrogen atom and R2 and R4 represent halogen atoms or alkyl radicals.

Of particular interest as antagonists of the AMPA receptor are the compounds of formula (I) for which R-j represents a carboxy radical, R2 and R4 represent a halogen atom or an alkyl radical and

R3 represents a hydrogen atom.

Of particular interest are the following compounds:

- 2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylate of ethyl,

- 2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylic acid, - 6,8-dichloro-2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylate— de methyl,

- 6,8-dichloro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid,

- methyl 6-iodo-2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylate,

- 6-iodc ~ 2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, - 6,8-difluoro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3 -methylcarboxylate,

- 6,8-difluoro-2H-1, 2,4-benzothidiazine-1, 1-dioxide-3-carboxylic acid,

6,8-dimethyl-2H-1, 2,4-benzothiadiazine-1, 1-methyl dioxide-3-carboxylate, - acid 6,8-dimethyl-2H-1, 2,4-benzothiadiazine-1, 1- 3-carboxylic dioxide,

- 8-iodo-2H-1, 2,4-benzothidiazine-1, 1-dioxide-3-carboxylic acid,

- 6,8-dibromo-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid,

- 6-chloro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid.

The following examples illustrate the invention without limiting it.

Example 1

At 100 cm3 of a 1 N solution of sodium methylate in methanol stirred under nitrogen at a temperature in the region of 20 ° C., the mixture is poured slowly a solution of 17.2 g of 2-aminobenzenesulfonamide and 14.6 g of diethyl oxalate in 40 cm3 of methanol. After 24 hours of stirring at this temperature, the reaction medium is poured into 2 liters of distilled water and acidified using 1N hydrochloric acid. The precipitate formed is filtered and washed with water until neutral pH, then dissolved in 50 cm3 of dimethylformamide heated to 100 ° C. The solution obtained is cooled and diluted with 150 cm3 of methanol. The crystals formed are filtered and washed with methanol. 5.3 g of product thus obtained are dissolved in 70 cm3 of dimethylformamide and then added to 40 cm3 of a solution of 1.4 g of potassium hydroxide in absolute ethanol. The reaction medium is stirred at a temperature in the region of 20 ° C for 15 hours and then concentrated to dryness under reduced pressure. After addition of ethyl ether and filtration of the insoluble material, 6.4 g of potassium salt of 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid are obtained in powder form. melting at 235 ° C.

Example 2

5.4 g of potassium salt of 2H-1, 2,4-benzothiadiazine 1,1-dioxide-3-ethyl carboxylate are dissolved in a mixture of 200 cm3 of ethanol and 50 cm3 of heated distilled water at 50 ° C. 1.1 g of potassium hydroxide are then added and the reaction is allowed to continue for 1 hour. The precipitate formed is filtered, washed with ethanol and then dried to yield 4.7 g of potassium disel of 1, 2,4-benzothiadiazine 1 _r 1-3-dioxide-carboxylic acid in the form of a powder with a melting point above 270 ° C (Analysis% calculated C: 31.78; H: 1.33; N: 9.26; S: 10.60;% found C: 32.4; H: 1.2; N: 9.3; S: 10.8).

Example 3

To a methanolic solution of sodium methoxide, prepared by adding 0.75 g of sodium in -50 cm3 of methanol, 11 g of _ ^ 4,6-dichloro-2-ethyloxalylamino-benzenesulfonamide in solution in nitrogen are added under nitrogen. methanol at 40 ° C. The reaction is continued for 2 hours at this temperature, then the reaction medium is concentrated to dryness under reduced pressure. The solid thus obtained is taken up in 1 liter of distilled water and then acidified using 1N hydrochloric acid to yield a white precipitate. After filtration, washing and drying, 8.6 g of 6,8-dichloro-2H-1,2,4-benzothiadiazine are obtained. Methyl 1, 1-dioxide-3-carboxylate melting at around 270 ° C. (Analysis% calculated C: 34.97; H: 1.96; Cl: 22.94; N: 9.06; S: 10.37; % found C: 34.8; H: 1.8; Cl: 22.8; N: 9.2; S: 10.4).

4,6-dichloro-2-ethyloxalylamino-benzenesulfonamide can be prepared as follows: to a solution of 12 g of 2-amino-4,6-dichloro benzenesulfonamide and 7.1 cm3 of triethylamine in 40 cm3 of tetrahydrofuran anhydrous cooled to 5 ° C., a solution of 5.8 cm3 of ethyloxalyl chloride in 5 cm3 of tetrahydrofuran is added dropwise over approximately 30 minutes. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure. The solid residue is washed with water and then dissolved hot in 120 cm3 of aqueous ethanol at 10% water. After cooling, filtering and drying the crystals formed, 11 g of 4,6-dichloro-2-ethyl oxalylamino-benzenesulfonamide are obtained, melting at 200 ° C. -

2-amino-4,6-dichlorobenzenesulfonamide can be prepared according to the method described by J.H. SHORT and U. BIERMACHER, J. Am. Chem. Soc, 82, 1135-1137 (1960).

Example 4

3.1 g of 6,8-dichloro-2H-1, 2,4-benzothiadiazine-1, 1-methyl dioxide-3-carboxylate in solution in 400 cm3 of absolute ethanol are treated at 50 ° C with 120 cm3 of a 1% aqueous potash solution. After 1 hour of reaction at this temperature, the precipitate formed is filtered, washed with ethanol then with water and dried to yield 3.2 g of potassium disel hydrate of 6,8-dichloro acid. -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic powder form melting at a temperature above 300 ° C

(Analysis% calculated C: 24.68; H: 1.04; Cl: 18.21; N: 7.20; S: 8.24;% found C: 25.5; H: 1.1, Cl: 17.9; N: 6.9; S: 7.9). Example 5

To a solution of sodium methylate, prepared from 10 cm 3 of methanol and 0.06 g of sodium, a suspension of 1.03 g of 2-ethyloxalylamino-4-iodobenzenesulfonamide in 125 cm 3 of methanol is added. The reaction mixture is heated at 40 ° C for 4 hours, then concentrated in vacuo (16 mm of mercury). The white solid obtained is taken up in 150 cm3 of water, filtered and the filtrate is brought to pH 1 with normal hydrochloric acid. The precipitate formed is filtered, dried in air, then at 50 ° C under vacuum (2 mm of mercury) to give 0.68 g of 6-iodo-2H-1, 2,4-benzothiadiazine-1, 1- methyl dioxide-3-carboxylate melting above 260 ° C. (Analysis% calculated C: 29.53; H: 1.93; N: 7.65; 0: 17.48; S: 8.76, % found C: 29.9; H: 2 _r 0; N: 8.0; 0: 17.4; S: 8.6).

2-Ethyloxalylamino-4-iodobenzenesulfonamide can be prepared as follows: to a solution of 1.35 g of 2-amino-4-iodo benzenesulfonamide in 10 cm3 of tetrahydrofuran and 0.65 cm3 of triethylamine is added at 5 ° C a solution of 0.62 g of ethyloxalyl chloride in 5 cm3 of tetrahydrofuran. The reaction mixture is stirred for 2 hours at room temperature, then concentrated in vacuo (16 mm of mercury). The solid obtained is triturated with 15 cm 3 of aqueous ethanol (50% by volume), filtered and air dried to provide 1.03 g of 2-ethyloxalylamino-4-iodobenzenesulfonamide used as it is in the subsequent syntheses.

The 2-amino-4-iodobenzenesu! Fonamide can be prepared in the following manner: to a solution cooled to -5 ° C. of 17.7 g of chlorosulfonyl isocyanate in 110 cm 3 of nitromethane is slowly added a solution of 21, 9 g of 3-iodoaniline in 35 cm3 of nitromethane, then around 0 ° C, 16.67 g of aluminum chloride. It is then heated to reflux and the reaction is stopped when the reflux temperature reaches 101-102 ° C. by cooling in an ice bath. The reaction mixture is poured onto crushed ice and the precipitate formed is filtered, washed with water and air dried. The crude product is purified by chromatography as follows: 9 g of mixture are dissolved in 200 cm3 of methanol and 50 cm3 of triethylamine, fixed on 20 g of silica by concentration on a rotary evaporator, deposited on a column of 500 g of silica and eluted with a mixture of ethyl acetate, methanol and triethylamine (80/20/1 by volume). A fraction is thus isolated which, after evaporation, is recrystallized twice from isopropanol, treated with 20 cm3 of decinormal hydrochloric acid, filtered and dried at 50 ° C. to give 0.95 g of 6-iodo-1, 2,4-Benzothiadiazine-3 (4H) -one-1, 1- dioxide melting above 260 ° C. This product is then hydrolyzed by heating at 140 ° C for 3 hours with 50 cm3 of 50% sulfuric acid (by volume). The reaction mixture is cooled and made alkaline with ammonia, the precipitate formed is extracted with 100 cm 3 of tert-butyl methyl oxide and the organic solution is evaporated under vacuum (16 mm of mercury) to give 0.8 g of 2 -amino-4-iodobenzenesulfonamide melting at 160 ° C.

Example 6

A suspension of 0.4 g of 6-iodo-2H-1,2,4-benzothiadiazine-1,1-dioxide-3 .5 methyl carboxylate in 150 cm3 of ethanol containing 0.18 g of potassium hydroxide pellets is heated for 2 hours at 50 ° C, then cooled in an ice bath. The solid formed is filtered, rinsed with ethanol and air dried. 0.44 g of potassium disel of 6-iodo-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, melting above 260 ° C., is obtained (melting% calculated). C: 22.44; H: 0.71; N: 6.54; S: 7.49,% found C: 22.0; H: 0.9; N: 6.5; S: 7.4) .

Example 7

The procedure is as in Example 5, but using 1.89 g of 2-ethyloxalylamino-4,6-difiuorobenzenesulfonamide. 1.4 g of 6,8-difluoro-2H-1, 2,4-benzothiadiazine-1, 1-methyl dioxide-3-carboxylate melting above 260 ° C. are obtained, melting above 260 ° C. (% analysis calculated C: 39 , 14; H: 2.19; F: 13.76; N: 10.14; S: 11.61,% found C: 39.2; H: 2.2; F: 13.5; N: 10 , 1; S: 11, 5).

2-ethyloxalylamino-4,6-difluorobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-

30- iodobenzenesulfonamide but from 3 g of 2-amino-4,6-difluorobenzenesulfonamide and 1.97 g of ethyloxalyl chloride. We obtains 1.89 g of 2-ethyloxalylamino-4,6-difluorobenzenesulfonamide used as it is in the subsequent syntheses.

The 2-amino-4,6-difluorobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4-iodobenzenesulfonamide but from 10 g of 3,5-difluoroaniline. The crude product resulting from the cyclization is extracted with 600 cm3 of ethyl acetate in total and the organic solution is evaporated in vacuo (16 mm of mercury). The evaporation residue is purified by beating in tert-butyl methyl oxide, filtered and dried. 11.72 g of 6,8-difluoro-1,2,4-benzothiadiazine-3 (4H) - one-1,1-dioxide are obtained, which is then hydrolyzed with 220 cm3 of 50% sulfuric acid (by volume ) for 5 hours at 130 ° C. The reaction mixture is cooled, basified to pH 8 and extracted with 900 cm3 of ethyl acetate in total. The organic solution is evaporated under vacuum (16 mm of mercury) and the evaporation residue is purified by chromatography on a silica column (500 g) with a mixture of cyclohexane and ethyl acetate (70-30 by volume) to give 4.86 g of 2-amino-4,6-difluorobenzenesulfonamide in the form ^"a pale pink solid used as is in the subsequent syntheses.

Example 8

The procedure is as in Example 6, but using 1 g of methyl 6,8-difluoro-2H-1,2,4-benzothiadiazine-1,1-oxide-3-carboxylate. 1.13 g of potassium disel of 6,8-difluoro-2H-1,2,4-benzothidiazine-1,1-dioxide-3-carboxylic acid, melting above 260 ° C., are obtained. calculated C: 28.40 H: 0.60; 11.23; N: 8.28; S: 9.48,% found C: 29.3; H: 0.4; F: 11.0; N: 8, 5; S: 9.7).

Example 9

The procedure is as in Example 5 but from 5.24 g of

2-ethyloxalylamino-4,6-dimethylbenzenesulfonamide. 3.88 g of

6,8-dimethyl-2H-1, 2,4-benzothiadiazine-1, 1-methyl dioxide-3-carboxylate melting at 260 ° C. 2-ethyloxalylamino-4,6-dimethylbenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide but starting from 4.15 g of 2-amino-4,6-dimethylbenzenesulfonamide and 2.73 g of ethyloxalyl chloride. 5.24 g of 2-ethyloxalylamino-4,6-dimethylbenzenesulfonamide are used, which is used as it is in the subsequent syntheses.

The 2-amino-4,6-dimethylbenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4,6-difluorobenzenesulfonamide but starting from 12.12 g of 3,5-dimethylaniline. 11.31 g of 6.8-dimethyl-1,2,4-benzothidiazine-3 (4H) -one-1,1-dioxide are obtained, which is subjected to acid hydrolysis under the same conditions, which leads, after chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (70-30 by volume), to 6.15 g of 2-amino-4,6-dimethylbenzenesulfonamide in the form of a pale pink solid used as is in subsequent syntheses.

Example 10

The procedure is as in Example 6, but using 2.88 g of methyl 6,8-dimethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. 3.6 g of potassium disel of 6,8-dimethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid, melting above 260 ° C., are obtained. calculated C: 36.35; H: 2.44; N: 8.48,% found C: 36.5; H: 2.0; N: 8.4).

Example 11

The procedure is as in Example 6, but using 2.9 g of methyl 7-methyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. 3.41 g of potassium disel of 7-methyl-2H-1,2,4-benzothidiazine-1, 1-dioxide-3-carboxylic acid melting above 260 ° C. are obtained (melting% calculated C : 34.16; H: 1.91; N: 8.85, S: 10.13,% found C: 34.2; H: 1.6; N: 8.7; S: 10.4).

Methyl 7-methyl-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide but starting from 5.65 g of

2-ethyloxalylamino-5-methylbenzenesulfonamide. 3.94 g of 7-methyl-2H-1,2,4-benzothiadazine-1, 1-methyl dioxide-3-carboxylate melting above 260 ° C (Analysis% calculated C: 47.24; H: 3.96; N : 11.02; S: 12.61,% found C: 47.2; H: 4.0; N: 11.1; S: 12.5).

2-Ethyloxalylamino-5-methylbenzenesuifonamide can be prepared as in Example 5 for the preparation of 2-amino-4,6-difluorobenzenesulfonamide but starting from 4.85 g of 2-amino-5-methylbenzenesulfonamide and 3, 55 g of ethyloxalyl chloride. 5.65 g of 2-ethyloxaIylamino-5-methylbenzenesulfonamide are obtained, melting at 208 ° C.

2-amino-5-methylbenzenesulfonamide can be prepared according to the method described by Y. GIRARD et al., J. Chem. Soc, Perkin Trans.l, 1, 1043 (1979).

Example 12

The procedure is as in Example 6 from 2.35 g of methyl 7-methoxy-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. 2.52 g of potassium hydroxide are obtained from 7-methoxy-2H-1,2,4-benzothidiazine-1,1-dioxide-3-carboxylic acid, melting above 260 ° C. (% analysis calculated C : 32.52; H: 1.87; N: 8.43; S: 9.65,% found C33.2; H: 1.7; N: 8.5; S: 9.5).

Methyl 7-methoxy-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as in Example 5 for the preparation of 6-iodo-2H-1,2,4 -benzothiadîazîne-1, 1-methyl-3-hydroxide-carboxylate but from 5.15 g of 2-ethyloxalylamino-5-methoxybenzenesulfonamide. 2 g of methyl 7-methoxy-2H-1,2,4-benzothidiazine-1,1-dioxide-3-carboxylate, melting at 257 ° C., are obtained.

2-ethyloxalylamino-5-methoxybenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide but starting from 4.13 g of 2-amino-5-methoxybenzenesulfonamide and 2.8 g of chloride ethyloxalyl. 5.15 g of 2-ethyloxalylamino-5-methoxybenzenesu.fonamide are obtained, melting at 178 ° C.

The 2-amino-5-methoxybenzenesulfonamide can be prepared according to US patent 3251837. Example 13

The procedure is as in Example 6 but starting with 0.39 g of methyl 8-iodo-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate. 0.36 g of potassium disel of 8-iodo-2H-1,2,4-benzothidiazine-1,1-dioxide-3-carboxylic acid, melting above 260 ° C., is obtained (analysis% calculated C : 21.53; H: 1.13; 1: 28.43; N: 6.28; S: 7.18,% found C: 21.5; H: 1.1; 1: 28.6; N : 6.1; S: 6.8).

Methyl 8-iodo-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as in Example 5 for the preparation of 6-iodo-2H-1,2,4 -benzothiadiazine-1, 1-methyl-3-dioxide-carboxylate but from 0.54 g of 2-ethyloxalylamino-6-methylbenzenesulfonamide. 0.39 g of 8-iodo-2H-1, 2,4-iodobenzothiadiazine-1,1-dioxide-3-carboxylate methyl is thus used, used as it is in subsequent syntheses.

The 2-ethyloxalylamino-6-iodobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide but from 0.65 g of 2-amino-6-iodobenzenesulfonamide and 0.30 g ethyloxalyl chloride. 0.54 g of 2-ethyloxalylamino-6-iodobenzenesulfonamide is obtained, which is used as it is in the subsequent syntheses.

The 2-amino-6-iodobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4-iodobenzenesulfonamide but starting from 3-iodoaniline and continuing the elution of the chromatographic column with a mixture of ethyl acetate, methanol and triethylamine (70/30/1 by volume). After acid treatment, 0.6 g of 8-iodo-1,2,4-benzothiadiazine-3 (4H) -one-1, 1-dioxide is obtained. This product is then hydrolyzed under the same conditions to give 2-amino-6-iodobenzenesulfonamide in the form of a pale yellow solid used as it is in subsequent syntheses.

Example 14

The procedure is as in Example 6 but starting with 1.68 g of methyl 6,8-dibromo-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate. We obtain 1.72 g of potassium disel- 6,8-dibromo-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxyic acid melting above 260 ° C (1H NMR: 7.52 ppm (d, J = 1 Hz, 1 H Ar), 7.70 (d, J = 1 Hz, 1H Ar); IR: 1400 cm-1 (COO-), 1325 cm-1 (S02) , 1150 cm-1 (S02)).

The methyl 6,8-dibromo-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as in Example 5 for the preparation of 6-iodo-2H-1, Methyl 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate but from 2.6 g of 2-ethyloxalyamino-4,6-dibromobenzenesul.onamide. 1.68 g of 6,8-dibromo-2H-1,2,4-benzothiadazine-1,1-dioxide-3-10-carboxylate methyl are obtained, which is used as it is in the subsequent syntheses.

2-Ethyloxalylamino-4,6-dibromobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-ethyioxalylamino-4-iodobenzenesulfonamide but from 2.86 g of 2-amino-4,6-dibromobenzenesulfonamide and 1.18 g of ethyloxalyl chloride. 2.6 g of 2-ethyloxalylamino-4,6-dibromobenzenesulfonamide used as such in the subsequent syntheses are obtained.

The 2-amino-4,6-dibromobenzenesulfonamide can be prepared as in Example 5 for the preparation of 2-amino-4,6-difluorobenzenesulfonamide but from 21.9 g of 3,5-dibromoaniline. After 20 chromatography on silica, 15.5 g of 6,8-dibromo-1,2,4-benzothiadiazine-3 (4H) -one-1,1-dioxide are obtained, which is subjected to acid hydrolysis. under the same conditions, which provides, after purification on a silica column, 5.1 g of 2-amino-4,6-dibromobenzene suffonamide in the form of a light beige solid used as it is in subsequent syntheses.

3,5-Dibromoaniline can be prepared according to the method described by R. G. SHEPHERD, J. Org. Chem. 12, 275 (1947).

Example 15

The procedure is as in Example 6 but starting from 0.9 g of 6-chloro-2H-

^~ . Methyl 1,2,4-benzothiadazine-1, 1-dioxide-3-carboxyIate. We obtain

30 0.74 g of potassium disel of 6-chloro-2H-1, 2,4-benzothiadiazine- acid

1,1-dioxide-3-carboxylic melting at a temperature above 260 ° C (Analysis% calculated C: 28.52; H: 0.90; Cl: 10.53; N: 8.32; S: 9.52,% found C: 28.5; H: 0.78; Cl : 10.6; N: 8.1; S: 9.1).

Methyl 6-chloro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as in Example 5 for the preparation of 6-iodo-2H-1, 2,4 -benzothiadiazine-1, 1-methyl dioxide-3-carboxylate but from 5.8 g of 2-ethyloxalylamino-4-chlorobenzenesulfonamide. 2.3 g of methyl 6-chloro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate are obtained, which is used as it is in the subsequent syntheses.

The 2-ethyloxalylamino-4-chlorobenzenesulfonamide can be prepared as in Example ^' 5 for the preparation of 2-ethyloxalylamino-4-iodobenzenesulfonamide but from 4.6 g of 2-amino-4-chlorobenzene sulfonamide and from 3 g ethyloxalyl chloride. Is obtained 3.8 g of 2- éthyloxalylamino-4-chlorobenzenesulfonamide _^ used as such in the subsequent syntheses.

2-amino-4-chlorobenzenesulfonamide can be prepared according to the method described by J.G. TOPLISS et al., J. Med. Chem., 6, 122 (1963).

The medicaments according to the invention consist of a compound of formula (I) in free form or in the form of a salt, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product. , 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, sucrose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish. As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. 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 other organic solvents can be used. suitable. 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.

^* Compositions for topical administration may be for example creams, lotions, eyedrops, 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 NMDA receptor antagonist or an AMPA receptor antagonist. These compounds are particularly useful for

• treat or prevent all ischemia and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, motor neuron diseases, amyotrophic lateral sclerosis, olivo- pontocerebellar atrophy and PARKINSON's disease, with regard to epileptogenic and / or convulsive manifestations , for the treatment of cerebral or spinal trauma, anxiety, depression, schizophrenia, as analgesics, antiemetic anti-anorexics, antimigraine and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor , as well as neurological disorders associated with viral diseases such as AIDS, rabies, measles and tetanus. These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates.

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:

- 6,8-dichloro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid 50 mg

- Cellulose 18 mg

- Lactose 55 mg

- Colloidal silica "-. 1 mg

- Carboxymethyl starch sodium 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:

- 6,8-dichloro-2H-1, 2,4-benzothiadiazine-1, 1-methyl dioxide-3-carboxylate 50 mg

- Lactose 104 mg

- Cellulose 40 mg

- Polyvidone 10 mg

- Carboxymethyl starch sodium 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:

- 2H-1,2,4-Benzothiadiazine-1, 1-dioxide-3-carboxylic acid .... 10 mg - Benzoic acid 80 mg

- Benzyl alcohol 0.06 cm ³

- Sodium benzoate 80 mg

- 95% Ethanof 0.4 cm ³

- Sodium hydroxide 24 mg - Propylene glycol 1.6 cm ³

- Water q.s.p. 4 cm3

Claims

1 - Application of 2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid derivatives of formula:

in which

- Rj represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk), -CO-NHOH, -CO-N (alk) OH, -CO-NH- radical O-R5, -CO-N (alk) -OR5 or a group convertible into carboxy radical in vivo,

- R2, R3 and R4, identical or different, represent a hydrogen or halogen atom or an alkyl radical,

- R5 represents an alkyl or phenylalkyl radical and

alk represents an alkylene or alkyl radical,

it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions comprise 1 to 6 carbon atoms in a straight or branched chain, their tautomer, their salts, in the preparation of drugs which are antagonists of the NMDA receptor and / or of the AMPA receiver.

2 - Application according to claim 1 with compounds of formula (I) for which Rj represents a group convertible into carboxy radical in vivo chosen from the radicals -CO-Rβ in which Rβ represents a radical -0-alk-R7, -O -alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-R7, -O-alk-OH,

-O-alk-O-alk, -O-alk-S-alk, -0-alk-0-R, -0-alk-S-R7 -O-alk-COOH,

-O-alk-COOalk, -0-alk-NR ₈ Rg, -NH-alk-O-CO-alk, -NH-alk-O-COOalk,

-NH-alk-0-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-R,

-NH-alk-SR ₇ , -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ R _9> alk represents an alkylene or alkyl radical, R7 is a phenyl radical, R ₈ and Rg , identical or different, represent a hydrogen atom or a radical alkyl, phenyl or phenylalkyl, or together with the nitrogen atom ^r which they are attached a piperidino, morpholino or pyrrolidino group being understood that the alkyl, alkoxy and alkylene and the alkyl portions of alkoxy and alkylene groups have 1 to 6 carbon carbon in straight or branched chain, their tautomer, their salts, in the preparation of drugs which are antagonists of the NMDA receptor and / or of the AMPA receptor.

3 - Compounds of formula:

in which - Rj represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk) ₂ , -CO-NHOH, -CO-N (alk) OH, -CO radical -NH-O-R5, -CO-N (alk) -OR5 or -CO-R5 in which R ₈ represents a radical -0-alk-R7, -O-alk-O-CO-alk, -O-alk -O-COOalk, -0-alk-0-CO-R, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-R7, -0-alk-S-R7, -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₈ Rg, -NH-alk-O-CO-alk, -NH-alk-O- COOalk, -NH-alk-0-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-R7, -NH- alk-SR, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ R,

- R2 " ^R 3 ^and R4 _> identical or different, each represent a hydrogen or halogen atom or an alkyl radical, - R5 represents an alkyl or phenylalkyl radical.

- R7 represents a phenyl radical,

- R ₈ and Rg, identical or different, each represent a hydrogen atom or an alkyl, phenyl or phenylalkyl radical or else form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino ring,

alk represents an alkylene or alkyl radical, with the exception of the compounds for which either R2, R3 and R4 represent a hydrogen atom and Rj represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and Rj represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R- | represents a carboxy, alkoxycarbonyl, -CO-NH2 or -CO-NH-alk radical,

it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions comprise 1 to 6 carbon atoms in a straight or branched chain, their tautomer, their salts.

4 - Process for preparing the compounds of formula (I) according to claim 3 for which Rj represents a carboxy radical characterized in that one hydrolyzes a derivative of formula (I) corresponding for which Rj represents an alkoxycarbonyl radical, isolates the product and eventually transforms it into salt.

5 - Process for preparing the compounds of formula (I) according to claim 3 for which R-j represents an alkoxycarbonyl radical characterized in that a derivative of formula is cyclized:

in which R2, R3 and R4 have the same meanings as in claim 3 and R-J O represents an alkyl radical, isolates the product and optionally converts it to salt.

6 - Process for preparing the compounds of formula (I) according to claim 3 for which Rj represents an alkoxycarbonyl radical characterized in that a derivative of formula is reacted:

in which R, R3 and R4 have the same meanings as in claim 3, on a dialkyl oxalate, isolates the product and optionally transforms it into salt.

7 - Process for preparing the compounds of formula (1) according to claim 3 for which R-j represents a tetrazolyl radical characterized in that the sodium azide is reacted with a derivative of formula:

in which R2, R3 and R4 have the same meanings as in claim 3, isolates the product and optionally transforms it into salt.

8 - Process for preparing the compounds of formula (I) according to claim 3 for which Rj represents a radical -CO-NH2, -CO-NH-alk, -CO-N (alk) 2, -CO-NHOH, -CO -N (alk) OH, -CO-NH-O-R5, -CO-N (alk) -OR5 characterized in that a compound of formula (I) is reacted for which Rj represents a carboxy radical or alkoxycarbonyl on a derivative of formula:

in which Rj -j represents a hydrogen atom or an alkyl radical and R-J2 represents a hydrogen atom or an alkyl, hydroxy, -O-alk or -OR5 radical in which R5 represents an alkyl or phenylalkyl radical ₎ isolates the product and eventually transforms it into salt. _

9 - Process for preparing the compounds of formula (I) according to claim 3 for which Rj represents a radical -CO-Rg in which Rg represents a radical -0-alk-R7, -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-C0-R7, -0-alk-OH, -O-alk-0-alk, -O-alk-S-alk, -0-alk-0-R7, -0-alk- S-R7, -0-alk-COOH, -O-alk-COOalk, -0-alk-NR ₈ Rg,

-NH-alk-0-CO-alk, -NH-alk-O-COOalk, -NH-alk-0-C0-R7, -NH-alk-OH, -NH-alk-O-alk, -NH- alk-S-alk, -NH-alk-0-R, -NH-alk-SR ₇ , -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ₈ Rg, characterized in that a corresponding compound of formula (I) for which Rj represents a carboxy or alkoxycarbonyl radical is reacted with a derivative of formula:

R6-H (X)

in which Rβ has the same meanings as above, isolates the product and optionally transforms it into salt.

10 - Medicines comprising as active principle at least one compound of formula (I) according to claim 3 or their salts.

11 - Medicines according to claim 10 useful as antagonists of the NMDA receptor and / or of the AMPA receptor.