FR2690160A1 - Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives to the preparation of medicaments, new products, their preparation and the medicaments containing them. - 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

un sel d'un tel composé ou un précurseur d'un tel composé à la préparation de médicaments antagonistes du récepteur NMDA et/ou du récepteur AMPA, les nouveaux composés de formule (I), leur préparation et les médicaments les contenant.APPLICATION OF 2H-1,2,4-BENZOTHIADIAZINE-1,1- ACID DERIVATIVES
DIOXIDE-3- CARBOXYLIC IN THE PREPARATION OF MEDICINES,
NEW PRODUCTS, THEIR PREPARATION AND THE
DRUGS CONTAINING THEM
The present invention relates to the application of 2H1, 2,4-benzothiadiazine-1, 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.

 Certain derivatives of formula (I) have already been described as diuretics (Russian Pharmacol. And Toxicol., 40, 19-23 (1977); Chem.

Abst., 99, 384399 (1983)).

In formula (I), - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -ORs radical or a group convertible into carboxy radical in vivo, - R2, R3 and R4, identical or different, represent a hydrogen atom
or halogen 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
find in their tautomeric form:

 As groups convertible into a carboxy radical in vivo, mention may be made of the radicals -CO-R8 in which R6 represents an amino, alkylamino, dialkylam ino radical, -O-alk-O-CO-alk, -O-alk-O-COOalk , -O-alk-O-CO-R7, -O-aI k-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O- alk-S-R7 -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NR8R9, -NH-alk-O-CO-alk, -N H-alk- O-COOalk, -N H-alk-O-CO-R7, -N H-alk-OH, -NH-alk-O-alk, -NH-alk-O-R7, -NH-alk-S-R7 , -NH-alk-COOH, -N H-alk-COOalk, -WH-alk-NR8R9.

 In these definitions, alk represents an alkylene or alkyl radical, R7 is a phenyl radical, R8 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 atoms of carbon.

 Certain compounds of formula (I), the salts of these compounds or the prodrugs of these compounds are new and as such are part of the invention. These are the compounds of formula (I) for which: - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N radical (alk) -ORs or -CO-R6 in which R6 represents a radical, amino, alkylamino, dialkylamino, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O- CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O- alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-N RgRg, -N H-alk-O-CO-alk, -N H-alk-O-COOalk, -NH -alk-O-CO-R7, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S- R7, -N H-alk-COOH, -N H-alk-COOalk, -N H-alk-N RgRg, - 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, - R8 and Rg, identical or different, each represents a hydrogen atom or a phenyl or phenylalkyl alkyl radical or else form with 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 R1 represents a carboxy, alkoxycarbonyl or -CO- radical R6 in which R6 represents an amino or alkylamino radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-R6 radical in which R6 represents an amino or alkylamino radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-R6 radical in which R6 represents an amino or alkylamino radical.

 New drugs 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 novel compounds of formula (I) for which R1 represents a carboxy radical can be prepared by hydrolysis of the corresponding compounds of formula (I) for which R1 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), within a nene solvent such as an alcohol or a water-alcohol mixture, other 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.

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R10 représente un radical alkyle.The new compounds of formula (I) for which R1 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 R10 represents an alkyl radical.

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

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I).The derivatives of formula (II) can be prepared by the action of a derivative of formula:
Cl-CO-COOR1 o (111) in which R10 has the same meaning as in formula (II) on a derivative of formula:

in which R2, 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 compounds of formula (I) for which R1 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 in an inert solvent such as an alcohol, at a temperature in the region of 20 C.

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I)
Cette réaction s'effectue généralement à une température voisine de 20 C.The derivatives of formula (IV) 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 in the region of 20 C.

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I). The compounds of formula (V) can be prepared by the action of ClSO3H on an aniline of formula:

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

 This reaction is carried out at a temperature in the region of 1 00 C.

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R11 représente un atome d'hydrogène ou un radical alkyle.The compounds of formula (I) for which RI 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 (I) and R11 represents a hydrogen atom or an alkyl radical.

 This reaction is preferably carried out in an inert solvent such as dimethylformamide, at a temperature between 20 and 300C.

dans laquelle R2, R3 et R4 ont les mêmes significations que dans la formule (I) et R11 représente un atome d'hydrogène ou un radical alkyle.The derivatives of formula (VII) can be obtained by the action of phosphorus pentachloride on an amide of formula:

in which R2, R3 and R4 have the same meanings as in formula (I) and R11 represents a hydrogen atom or an alkyl radical.

 This reaction is generally carried out at a temperature between 110 and 1 60 C.

The amides of formula (vi) can be prepared from the compounds of formula (I) for which R1 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; WS BISHOP, Organic Synthesis, III, 613.

The compounds of formula (I) for which R1 represents a radical -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -ORs can be prepared by reaction of a compound of formula (I) for which R1 represents a carboxy or alkoxycarbonyl radical on a derivative of formula:
HN (R12) -R13 (IX) in which R12 represents a hydrogen atom or an alkyl radical and
R13 represents a hydroxy radical, -O-alk or -ORs 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 (tetrahydrnfuran, dioxane for example), an amide (dimethylformamide for example) or a chlorinated solvent (methyl chloride ne, chloroform for example), at a temperature between 00C 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 butylithlum. diisopropylamine lithium 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 such as mentioned above or a mixture of these solvents, at a temperature between 00C 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 d '' an alkali or alkaline earth metal carbonate or bicarbonate, at a temperature between 0 and 40 C.

The compounds of formula (I) for which R1 represents a radical 6 in which R6 represents an amino, alkylamino, dialkylam ino, -O-alk-O-CO-alk, -O-alk-0-COOalk, -O- radical alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R1 2, -O-alk-S- R7, -O-alk-COOH, -O-alk-COOalk, -O-alk-NH2, -O-alk-NRgRg, -NH-alk-O-CO-alk, -N H-alk-0-COOalk , -N H-alk-O-CO-R7, -N H-alk-OH, -N H-alk-O-alk, -N H-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8RS, can be prepared by reaction of a compound of formula (I) for which R1 represents a radical carboxy or alkoxycarbonyl on a derivative of formula:
R6-H (X) in which R6 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.

 Examples of pharmaceutically acceptable salts which may be mentioned are the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), the ammonium salt, the tetraalkylammonium salts (tetrabutylammonium for example), salts of nitrogenous bases (ethanolamine, trimethylamine, methgylarnine, benzylamine, N-benzyl- (3-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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropion acid receptor as (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, arterial hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of effects due to anoxia, whether perinatal or following drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and
PARKINSON. These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of anxiety (KEHNE et al., Eur. J. Pharmacol., 193, 283 (1991), of depression ( TRULLAS et al., Eur. J. Pharmacol., 185, 1 (1990), of 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) and to treat poisonings by neurotoxins or other NMDA receptor agonist substances, 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).

 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 a method derived from that described by BARON et al., Eur. J. Pharm., 206, 149 (1991). The [3H] -DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 "C for 10 minutes in 50 mM HEPES buffer, pH 7.5. The non-specific binding is determined in the presence of glycine 1 mM The bound radioactivity is separated by filtration on Whatman GF / B filters.

The inhibitory activity of these products is generally less than 100 FM.

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

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

Are particularly interesting as receptor antagonists
NMDA the compounds of formula (I) for which R1 represents a carboxy or alkoxycarbonyl radical and R2, R3 and R4 are hydrogen atoms or else R2 and R4 are hydrogen atoms and R3 represents a halogen atom or else R2 and R3 represent hydrogen atoms and R4 represents a halogen atom or R3 represents a hydrogen atom and R2 and R4 represent halogen atoms
Are particularly interesting as receptor antagonists
AMPA the compounds of formula (I) for which R1 represents a carboxy radical, R2 and R4 represent a halogen atom and R3 represents a hydrogen atom or else R2 and R4 represent a hydrogen atom and
R3 represents a halogen atom.

 Of particular interest are the following compounds: - 2H-1, 2,4-benzothiadiazine-1, 1-ethyl-3-dioxide-carboxylate, - acid 1, 2,4-benzothiadiazine 1,1-3-dioxide -carboxylic, - 6,8-dichloro-2H-1,2,4-benzothiadiazine 1,1-methyl dioxide-3-carboxylate, - 6,8-dichloro-2H-1 acid 52,4-benzothiadiazine-1 51 -dioxide-3-carboxylic.

 The following examples illustrate the invention without limiting it.

Example 1
At 100 cm 3 of a 1 N solution of sodium methylate in methanol stirred under nitrogen at a temperature in the region of 20 ° C., 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. g of product thus obtained are dissolved in 70 cm3 of dimethylformamide and then added to 40 sm3 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 then concentrated to dryness under reduced pressure next. After addition of ethyl ether and filtration of the insoluble material, 6.4 g of potassium salt of 2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylate in powder form are obtained. melting at 235 "C.

Example 2 5.4 g of potassium salt of 2H-1, 2,4-benzothiadiazine 1, 1-ethyl dioxide-3-carboxylate are dissolved in a mixture of 200 cm3 of ethanol and 50 cm3 of water distilled heated to 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 1,1-3-dioxide-3-carboxylic acid in the form of a powder with a melting point above 270 "C.

Example 3
To a methanolic solution of sodium methoxide, prepared by adding 0.75 g of sodium in 50 cm 3 of methanol, 1 1 g of 4,6-dichloro-2-ethyloxalylamino-benzenesulfonamide dissolved in methanol is added under nitrogen. 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 with 1N hydrochloric acid to yield a white precipitate. After filtration, washing and drying, 8.6 g of methyl 6,8-dichloro-2H-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylate, melting at around 270 ° C., are obtained.

4,6-dichloro-2-ethyloxalylamino-benzenesu Ifonamide can be prepared as follows: to a solution of 12 g of 2-amino-4,6-dichlorobenzenesulfonamide 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 (: 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-ethyloxalylamino-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 methyl 8,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 400 cm3 of absolute ethanol are treated at 50 ° C. with 120 cm 3 of a 1% aqueous potassium solution. After 1 hour of reaction at this temperature, the precipitate formed is filtered, washed with ethanol and then with water and dried to yield 3.2 g of potassium disel hydrate of 6,8-dichloro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid in the form of a powder melting at a temperature higher than 300 "C.

 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 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, use may be made of 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 carried out in several ways, for example by sanitizing 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 NMDA receptor antagonist or an AMPA receptor antagonist. These compounds are especially useful for treat or prevent all ischemia and in particular cerebral ischemia, the effects due to anoxia, the evolution of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSQGil disease, vis-à-vis epileptogenic and / or convective manifestations, for the treatment of anxiety, depression, schizophrenia5 as analgesics, antianorexics and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as e AIDS, rabies, measles and tetanus.

 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:
- Acid 6,8-dichioro-2H-l, 2,4-benzoth iadiazine-l, l
-dioxide-3-carboxylic 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
Prepared according to the usual technique of tablets dosed with 50 mg of active product having the following composition: - 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, oxide of
titanium (72-3.5-24.5) qs 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 acid
-dioxide-3-carboxylic 10 mg
- Benzoic acid ............................... 80 mg
- Benzyl alcohol 0.06 cm3
- Sodium benzoate ............................. 80 mg
- 95% ethanol ................................. 0.4 cm - Sodium hydroxide .... ....................... 24 mg - Propylene glycol 1.6 cm3 - Water ................ ...................... qs 4 cm

Claims (11)

 in which - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -OR radical; or a group convertible into carboxy radish 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, - alk represents an alkylene radical or alkyl, 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 medicaments antagonists of the NMDA receptor and / or the AMPA receiver.

 CLAIMS 1- Application of 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives i of formula: 2 - Application according to claim 1 with compounds of formula (I) for which R1 represents a group convertible into a carboxy radical in vivo chosen from the radicals -CO-R6 in which R6 represents an amino, alkylamino, dialkylamino, -O- radical alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O-alk-O-alk, -O-alk-S -alk, -O-alk-O-R7, -O-alk-S-R7 -O-alk-COOH, -0-alk-COOalk, -O-alk-N H2, -O-alk-NRgRg, - N H-alk-O-CO-alk, -N H-alk-O-COOalk, -N H-alk-O-CO-R7, -N H-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -N H-alk-COOH, -NH-alk-COOalk, -NH-alk-NR8R9, alk represents an alkylene or alkyl radical, R7 is a phenyl radical, R8 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, it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and t alkylene include 1 to 6 carbon atoms in a straight or branched chain, their tautomer, their salts, in the preparation of drugs antagonists of the NMDA receptor and / or of the AMPA receptor. 3 - Compounds of formula:

 in which - R1 represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N (alk) -ORs or -CO-R6 radical in which R6 represents a radical, amino, alkylamino, dialkylamino, -O-alk-O-CO-alk, -O-alk-0-COOalk, -O-aik-O-CO-R7, -O-aI k- OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R7, -O-alk-S-R7, -O-aIk-COOH5 -0-alk-COOalk , -O-alk-NH2, -O-alkNR8R9, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-O-CO-R7, -NH-alk-OH , -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -N H-alk-COOH, -N H-alk -COOalk, -N H-alk-N R8R9, - 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, - R8 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 ring or pyrrolidino, - 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 R1 represents a carboxy, alkoxycarbonyl or -CO-Rs radical in which R6 represents a amino or alkylamino radical; either R4 represents a chlorine or bromine atom, R2 and R3 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-Re radical in which R6 represents an amino or alkylamino radical; either R3 represents a chlorine or bromine atom, R2 and R4 represent a hydrogen atom and R1 represents a carboxy, alkoxycarbonyl or -CO-R6 radical in which R6 represents an amino or alkylamino radical, it being understood that the alkyl, alkoxy radicals and alkylene and the alkyl, alkoxy and afkylene 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 R1 represents a carboxy radical characterized in that one hydrolyzes a derivative of formula (I) corresponding for which R1 represents an alkoxycarbonyl radical, isolates the product and optionally transforms it into a salt. 5 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 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 formula (1) and R10 represents an alkyl radical, isolates the product and optionally transforms it into a salt. 6 - Process for preparing the compounds of formula (I) according to claim 3 for which R1 represents an alkoxycarbonyl radical characterized in that a derivative of formula is reacted:

 on a diaikyle oxalate, isolates the product and optionally transforms it into salt. 7 - Process for the preparation of the compounds of formula (I) according to claim 3 for which R1 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 formula (I) and R11 represents a hydrogen atom or an alkyl radical, isolates the product and optionally transforms it into a salt. 8 - Process for preparing the compounds of formula (I) according to claim 3 for which Ri represents a radical -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-alk, -CO-N ( alk) -ORs characterized in that a compound of formula (I) is reacted for which R1 represents a carboxy or alkoxycarbonyl radical on a derivative of formula:  HN (R1 2) -R13 (IX) in which R12 represents a hydrogen atom or an alkyl radical and R13 represents a hydroxy radical, -O-alk or -ORs 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 R1 represents a radical -CO-R6 in which R6 represents an amino, alkylamino, dialkylamino, -O-alk-O-CO-alk, -0-alk-O-COOalk, -O-alk-O-CO-R7, -O-alk-OH, -O radical -alk-O-alk, -O-alk-S-alk, -O-alk-O-R1 2 -O-alk-S-R7, -O-alk-COOH, -0-alk-COOalk, -O -alk-NH2, -O-alk-NR8R9, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-O-CO-R7, -N H-alk-OH , -NH-alk-O-alk, -N H-alk-S-alk, -NH-alk-O-R7, -NH-alk-S-R7, -NH-alk-COOH, -NH-alk- COOalk, -NH-alk-NR8R9, characterized in that a compound of formula (I) is reacted for which R1 represents a carboxy or alkoxycarbonyl radical on a derivative of formula:  R6-H (X) in which R6 has the same meanings as above, isolates the product and optionally transforms it into salt. 10 - Medicines comprising as active ingredient at least one compound of formula (I) according to claim 3 or optionally for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases. 11 - Medicines according to claim 10 useful as antagonists of the NMDA receptor and / or of the AMPA receptor.