WO1995007899A1

WO1995007899A1 - 3,4-dihydro-2h-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylic acid derivatives, their preparation and drugs containing same

Info

Publication number: WO1995007899A1
Application number: PCT/FR1994/001069
Authority: WO
Inventors: Patrick Jimonet; Serge Mignani
Original assignee: Rhone-Poulenc Rorer S.A.
Priority date: 1993-09-17
Filing date: 1994-09-12
Publication date: 1995-03-23
Also published as: FR2710062B1; JPH09502711A; ZA946930B; FR2710062A1; EP0719262A1; IL110940A0; AU7660194A

Abstract

Compounds of formula (I) wherein R1 is a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-R10, -CO-N(alk)-OR10 radical or a group convertible in vivo into a carboxy radical, R2, R3 and R4, which are the same or different, are hydrogen or halogen atoms or alkyl or alkoxy radicals, R5 is a hydroxy, -NHOH, -NH-CO-NH2, -CH2-NH2, hydroxyalkyl, alkoxyalkyl or -alk=NOH radical, R6, R7, R8 and R9, which are the same or different, are hydrogen or halogen atoms or alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoylamino, phenylcarbonyl, hydroxy, -NHOH, -NH-CO-NH2, -CH2-NH2, hydroxyalkyl, alkoxyalkyl, -alk=NOH or phenoxy, with the phenyl ring being optionally substituted by one or several substituents selected from the halogen atoms and the alkyl, alkoxy or polyfluoroalkyl radicals, R10 is an alkyl or phenylalkyl radical and alk is an alkyl or alkylene radical. The invention also concerns the salts of thereof, the preparation thereof, and drugs containing same.

Description

ACID DERIVATIVES 3.4-DIHYDRO-2H-1.2.4-BENZOTHIAD1AZINE

1.1-DIOXIDE-3-CARBOXYLIC. THEIR PREPARATION AND THE

DRUGS CONTAINING THEM

The present invention relates to the compounds of formula:

their salts, their preparation and the drugs containing them.

In formula (I),

- R- | represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk) ₂ , -CO-NHOH, -CO-N (alk) OH, -CO-NH-O radical -R10. -CO-N (alk) -OR- | o or a group convertible into a carboxy radical in vivo,

R2, R3 and R4, identical or different, represent hydrogen or halogen atoms or alkyl or alkoxy radicals,

- R5 represents a hydroxy radical, -NHOH, -NH-CO-NH2, -CH2-NH2, hydroxyalkyl, alkoxyalkyl or -alk≈NOH,

- RQ, R7, Rs and Rg, identical or different, represent hydrogen or halogen atoms or alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoyiamino, phenylcarbonyl, hydroxy, -NHOH, -NH-CO-NH2, -CH2-NH2, hydroxyalkyl, alkoxyalkyl, -alk≈NOH or phenoxy in which the phenyl ring is optionally substituted by one or more substituents chosen from d atoms 'halogen and the alkyl, alkoxy or polyfluoroalkyl radicals,

- R10 represents an alkyl or phenylalkyl radical and

- alk represents an alkyl or alkylene radical. 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 10 carbon atoms in straight or branched chain and, preferably, 1 to 6 carbon atoms.

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

The polyfluoroalkyl radicals are preferably trifluoromethyl radicals.

The polyfluoroalkoxy radicals are preferably trifluoromethoxy radicals.

Convertible groups in vivo are those that cut easily in the human body to lead to acid.

As groups convertible into a carboxy radical in vivo, mention may be made of the radicals -CO-R11 in which Rj -j represents a radical -0-alk-R- | 2. -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-R-j2, -O-alk-OH, -O-alk-O-alk, - O-alk-S-alk, -0-alk-0-R- | 2, -0-alk-S-Ri2. -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₁₃ R ₁₄ , -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-0 -CO-Ri2, -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-Ri2. -NH-alk-S-Ri2, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR- | 3Ri4.

In these definitions, R- | 2 represents a phenyl radical, R13 and Rj which are identical or different, each represents 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 and alk represents an alkylene or alkyl radical.

A preferred class of compounds of formula (I) is that for which Rj represents a carboxy or alkoxycarbonyl radical, R2, R3 and R4, identical or different, represent hydrogen or halogen atoms and in particular chlorine atoms or bromine. A particularly interesting class is constituted by the compounds of formula (I) in which R3 represents a hydrogen atom and R2 and R4 each represent a halogen atom and more particularly a chlorine or bromine atom.

The compounds of formula (I) have isomeric forms. The racemates and the enantiomers of these compounds also form part of the invention.

The compounds of formula (I) for which R- | represents a carboxy radical can be prepared by condensation of a derivative of formula:

in which alk, R2, R3, R4, R5, R6> R7. ^ 8 ^{and R} 9 ^{have the} same meanings as in formula (I), with glyoxylic acid.

This reaction is generally carried out either in an aqueous medium, in the presence of a base such as sodium hydroxide or potassium hydroxide, at a temperature in the region of 100 ° C., or in an inert solvent such as dioxane, a dioxane mixture -water, at a temperature close to 100 ° C.

The derivatives of formula (II) are marketed or can be obtained by application or adaptation of the methods described by JH SHORT et al., J. Am. Chem. Soc, 82, 1135-1137 (1960), GP TOPLISS et al., J. Med. Chem., 6, 122 (1963) and J. Med. Chem., 7, 269 (1964), V. DESMEDT and A. BRUYLANTS, Bull. Soc. Chim. Belg., 74, 344 (1965), GJ THOMAS, J. Agric. Food Chem., 32, 747 (1984), in US patents 2,986,573, US 3251837 and in the examples. In particular, these derivatives are obtained by the action of a derivative of formula:

in which R2, R3 and R4 have the same meanings as in formula (I), on an amine of formula:

in which alk, R5, Rβ, R7, Rs and Rg have the same meanings as in formula (I).

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

The derivatives of formula (III) can be obtained by application or adaptation of the method described by J. H. SHORT et al., J. Am. Chem. Soc, 82, 1135-1137 (1960) or by the action of CISO3H 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 close to 100 ° C.

The derivatives of formula (IV) are marketed or can be prepared by the reaction of GABRIEL from halogen derivatives correspondents (GIBSON and BRADSHAW, Angew. Chem. Int. Ed. Engl., 7, 919-930 (1968)) or by application or adaptation of the methods described in the examples.

The derivatives of formula (V) are marketed or can be obtained by application or adaptation of the methods described in the examples.

The compounds of formula (I) for which R-j represents a carboxy radical can also be prepared by hydrolysis of the corresponding compounds of formula (I) for which R-j 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 compounds of formula (I) for which Rj represents an alkoxycarbonyl radical can be prepared by condensation of a derivative of formula (II) with glyoxylic acid, in an acid medium and in the presence of an alcohol R15OH in which R-15 represents an alkyl radical.

This reaction is preferably carried out in the presence of sulfuric acid, at a temperature in the region of 80 ° C.

The compounds of formula (I) for which R- | represents a radical -CO-NH ₂ , -CO-NH-alk, -CO-N (alk) 2, -CO-NHOH, -CO-N (alk) OH,

-CO-NH-O-R10. -CO-N (alk) -OR- | o can be prepared by reaction of a corresponding compound of formula (I) for which R-j represents a carboxy or alkoxycarbonyl radical on a derivative of formula:

HN (R ₁₆ ) -R ₁₇ (VI) in which R16 represents a hydrogen atom or an alkyl radical and Rj 7 represents a hydrogen atom or an alkyl, hydroxy or -ORI Q- radical

When the acid is used, the operation 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 '' an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide for example) or a chlorinated solvent (methylene chloride, chloroform for example), optionally in the presence of a nitrogenous base such as dimethylaminopyridine, at a temperature between 0 ° C and the boiling 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 boiling point of the reaction medium, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline earth base (soda, potassium hydroxide for example) or of an alkali or alkaline earth metal carbonate or bicarbonate, at a temperature between 0 and 40 ° 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 alk, R2, R3, R4, R5, R6. R7. Rδ ^{and R} 9 ^{have the} same meanings as in formula (I). This reaction is preferably carried out in an inert solvent such as dimethylformamide, dimethoxyethane, dioxane, at a temperature between 20 ° C and the reflux 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 alk, R2, R3, R4, R5, Rβ. R7. R8 ^and ⁹ 'same ^ΘS significa ^¬ tions as in formula (I).

This reaction is generally carried out in an inert sovant such as dimethylformamide, 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 amide or secondary and in particular by adapting the methods described by QE KENT et al., Organic Synthesis, III, 490; W. S. BISHOP, Organic Synthesis, III, 613.

The compounds of formula (I) for which R * ι represents a radical -CO-R- * | - | in which R11 represents a radical -0-alk-R-j2, -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-Ri2, -O-alk -OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-Ri2 _> -0-alk-S-Ri2. -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₁₃ Rι ₄ , -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-0 -CO-Ri2 _> -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-Ri2, -NH-alk-SR- | 2- - NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NRi3R- | 4, can be prepared by reaction of a corresponding compound of formula (I) for which R- \ represents a carboxy or alkoxycarbonyl radical on a derivative of formula: R11-H (IX)

in which R-j - \ has the same meanings as above.

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

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

in which R-j, R2. R3 and R4 have the same meanings as in formula (I) on a derivative of formula:

in which alk, R5, Rβ, R7, Rg and Rg have the same meanings as in formula (I) and X represents a halogen atom.

This reaction is generally carried out in an inert solvent such as dimethylformamide, tetrahydrofuran, dioxane, in the presence of a base such as an alkali metal hydride (sodium hydride for example), a metal alcoholate. alkaline (sodium ethylate, sodium tert-butoxide, for example), at a temperature between 20 ° C and the boiling temperature of the reaction medium.

The derivatives of formula (X) can be obtained by analogy to the processes for preparing the compounds of formula (I) described above and in the examples. The derivatives of formula (XI) are marketed or can be obtained by application or adaptation of the methods described in patents EP 350403 and 429341 and in the examples.

The compounds of formula (I) for which R5 and / or Rβ, R7, Rg and Rg represent a radical -NHOH can also be prepared by reduction of a corresponding compound for which R5 and or Rβ, R7, Rs and Rg represent a nitro radical.

This reduction is generally carried out by means of a reducing agent such as zinc, in the presence of ammonium chloride, in an inert solvent such as tetrahydrofuran, water, at a temperature in the region of 20 ° C. .

The corresponding nitro derivatives can be obtained by applica¬ tion or adaptation of the processes described above for the preparation of the compounds of formula (I) and in the examples.

The compounds of formula (I) for which R5 and or Rβ, R7, Rs and

Rg represent a radical -NH-CO-NH2 can also be prepared by the action of a corresponding compound for which R5 and / or Rβ, R7, Rg and Rg represent an amino radical on the chlorosulfonyl isocyanate.

This reaction is preferably carried out in an inert solvent such as nitromethane, at a temperature between 0 and 25 ° C.

The amino derivatives can be obtained by reduction of the corresponding nitro derivatives, preferably by means of hydrogen, in the presence of a hydrogenation catalyst such as palladium on carbon, in an alcohol and at a temperature in the region of 20 ° C.

The compounds of formula (I) for which R5 and / or Rβ, R7, Rg and

Rg represent a hydroxy radical can also be prepared by debenzylation of a corresponding compound for which R5 and / or Rβ, R7, Rg and Rg represent a benzyloxy radical.

This reaction is preferably carried out by means of iodotrimethylsilane in an inert solvent such as a chlorinated solvent (chloroform, dichloromethane for example), at a temperature close to 20 ° C.

The corresponding derivatives for which R5 and / or Rβ, R7, Rs and Rg represent a benzyloxy radical can be obtained by application or adaptation of the methods described above for the preparation of the compounds of formula (I) and in the examples.

The compounds of formula (I) for which R5 and / or Rβ, R7, Rs and Rg represent a radical -alk≈NOH can also be prepared by the action of a corresponding derivative for which R5 and / or Rβ, R7, Rs and Rg represent a radical -CHO, -Ris-CHO, -CO-R-jg, -R20-CO-R21, R18 represents an alkylene radical containing 1 to 9 carbon atoms in straight or branched chain, R- | g represents a alkyl radical containing 1 to 9 carbon atoms in a straight or branched chain, R20 represents an alkylene radical containing 1 to 8 carbon atoms in a straight or branched chain and R21 represents an alkyl radical containing 1 to 8 carbon atoms, it being understood that the sum of the carbon atoms of R20 and R21 is at most equal to 9, on the hydroxylamine.

This reaction is preferably carried out in an inert solvent such as an alcohol (ethanol, methanol for example), water or a mixture of these solvents, at a temperature in the region of 20 ° C.

The corresponding derivatives for which R5 and / or Rβ, R7, Rs and Rg represent a radical -CHO, -Ris-CHO, -CO-Rj, -R20-CO-R21 can be obtained by application or adaptation of the methods described above for the preparation of the compounds of formula (I) and in the examples.

The corresponding derivatives for which R5 and / or Rβ, R7, Rs and Rg represent a radical -CO-R- | g, -R20-CO-R21 can also be obtained by oxidation of a compound of formula (I) corresponding to which R5 and / or Rβ, R7, Rs and Rg represent a hydroxyalkyl radical. This oxidation is preferably carried out in an inert solvent such as acetone, using chromium oxide and in the presence of an acid, at a temperature in the region of 20 ° C.

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

The enantiomers of the compounds of formula (I) can be obtained by synthesis from chiral precursors or by splitting of the archaemics, for example by chromatography on a chiral column according to WH PIRCKLE et al., Asymmetry synthesis, vol 1, Académie Press (1983 ).

The compounds of formula (I) comprising a carboxy radical 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 alkaline for example), ammonia, a tetraikylammonium, an amine or a salt of an organic acid on a compound of formula (I), in an inert 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), the ammonium salt, the tetraikylammonium salts (tetrabutylammonium for example), 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 α-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, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSON 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), 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)), syndrome TOURETTE, hepatic encephalopathies, as analgesics (DICKENSON et al., Neurosc. Letters, 121, 263 (1991)), anti-inflammatory drugs (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) (SORRELS et al., Brain Res., 572, 265 (1992)), antimigraine, antiemetics and to treat poisoning with neurotoxins or other NMDA receptor agonist substances, as well as tr neurological cells 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 abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates. They can also be used in the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT, homocysteinemia, hyperprolinemia, hydroxybutiric-amino acid, LEAD encephalopathy and sulfite oxidase deficiency.

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 (5,7-dichloro kynurenic acid) on membranes of rat cerebral cortex according to a method derived from that described by T. CANTON et al., J. Pharm. Pharmacol., 44, 812-816 (1992). [3H] - DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C for 10 minutes in HEPES buffer (acid (N- [2-hydroxyethyl] piperazine-N '- [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 through Whatman GF / B filters. The inhibitory activity of these products is generally less than 100 μM.

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 [3H] -AMPA on membranes of rat cerebral cortex (HONORE et al., J. Neurochem., 51, 457-461 (1988) [3H] -AMPA (10nM) is incubated in the presence of 0.2 mg of protein at 4 ° C for 30 minutes in 10mM KH2PO4 buffer, KSCN 100 mM, pH 7.5 The non-specific binding is determined in the presence of 1 m L-glutamate, the bound radioactivity is separated by filtration through 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 generally greater than 40 mg / kg by the IP route.

Particularly interesting as NMDA receptor antagonists are the compounds of formula (I) for which Rj represents a carboxy or alkoxycarbonyl radical and either R2 and R4 each represent a halogen atom and in particular a chlorine or bromine atom or a alkyl radical and R3 represents a hydrogen atom or R2 and R3 each represents a hydrogen atom and R4 represents a halogen atom and in particular a chlorine or bromine atom or an alkyl radical. The following examples illustrate the invention without limiting it.

EXAMPLE 1

A 0.7 g of 2 - [(3-aminomethyl) benzyl] -6,8-dichloro-3,4-dihydro-2H-1,2,4-ben-zothiadiazine-1, 1-dioxide-3-carboxylate ethyl in solution in 40 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 3.15 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 15 hours at the same temperature then the reaction medium concentrated to dryness under reduced pressure; the residue is taken up in 3 cm3 of distilled water and acidified to pH 4 with 0.5N hydrochloric acid. The precipitate formed is filtered, washed with water and dried to yield 0.32 g of 2 - [(3-aminomethyl) benzyl] -6,8-dichloro-3,4-dihydro-2H- acid dihydrate. 1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in the form of a beige solid melting while decomposing at 236 ° C (Analysis (C16H15CI2N304S; 2H20) calculated C: 42.49; H: 4, 23; Cl: 15.68; N: 9.29; S: 7.09; found C: 42.6; H: 4.1; Cl: 15.7; N: 9.1; S: 7.0 ).

Ethyl 2- (3-aminomethyl) benzyl-6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate can be prepared from Next: 1.0 g of 2-amino-4,6-dichloro-N- (3-aminomethyl) benzyl-benzene-sulfonamide in 50 cm3 of absolute ethanol brought to reflux, 0 is added dropwise , 52 g of glyoxylic acid in solution in 30 cm3 of absolute ethanol in the presence of 1.1 cm3 of concentrated sulfuric acid. The reaction is followed for 4.5 hours at reflux, then the reaction medium cooled to a temperature close to 20 ° C. After concentrating to dryness under reduced pressure, the residue is taken up in dichloromethane, washed with water, dried over magnesium sulphate, filtered and the filtrate concentrated to dryness under reduced pressure. The crude product thus obtained is purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (95/5 by volume) as eluent. 1.3 g of expected product are obtained in the form of a yellow meringue (Rf = 0.18; thin layer chromatography on a Merck 60 F254 silica plate, eluent: dichloromethane / methanol (90/10 by volume)).

2-amino-4,6-dichloro-N- (3-aminomethyl) benzyl-benzenesulfonamide can be prepared as follows: 2.2 g of 2-amino-4,6-dichloro-N- (3- cya- nobenzyD-benzenesulfonamide dissolved in 60 cm3 of anhydrous tetrahydrofuran stirred at 65 ° C. under nitrogen, 18.6 cm3 of borane-dimethylsulfide complex in 2M solution in tetrahydrofuran are added dropwise over about 45 minutes. The reaction is continued for 1.5 hours at the same temperature, then the reaction medium cooled to a temperature of 0 ° C and treated dropwise with 35 cm3 of methanol. After 2 hours at 65 ° C and return to a temperature in the region of 20 ° C, 30 cm3 of distilled water are added to the reaction medium and the organic phase extracted with dichloromethane, washed with water and dried to yield 2.6 g of crude product in the form of a yellow oil. After purification by flash chromatography on a silica column using a mixture of dichloromethane and methanol (90/10 by volume) as eluent, 1 g of the expected product is obtained in the form of a pale yellow meringue.

2-amino-4,6-dichloro-N- (3-cyanobenzyl) -benzenesulfonamide can be obtained according to the following process: under nitrogen and at a temperature in the region of 20 ° C, 2.8 g of 3-cyanobenzylamine in solution in 20 cm3 of tetrahy¬ drofuran are added dropwise to a solution of 5.2 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.8 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is diluted with 30 cm3 of distilled water and the organic phase extracted with dichloromethane. 4.5 g of the expected product thus obtained in the form of a yellow meringue are used as such in the following steps.

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

3-cyanobenzylamine can be obtained according to the method described by W.R. MEINDL et al., J. Med. Chem., 27 (9), 1111 (1984).

EXAMPLE 2

The procedure is as in Example 1 from 0.7 g of 6,8-dichloro-3,4-dihyro-2 - [(3-hydroxyamino) benzyl] -2H-1, 2,4-benzothiadiazine -1, 1-ethyl dioxide-3-carboxylate, 3.1 cm3 of an aqueous solution of sodium hydroxide 0.5N and 7 cm3 of tetrahydrofuran. After purification by flash chromatography on a silica column (eluent: ethyl acetate / methanol (80/20 by volume)) of the crude product obtained, 0.25 g of 6,8-dichloro-3 acid is isolated. , 4-di- hydro-2 - [(3-hydroxyamino) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic in the form of a pale yellow powder decomposing around 200 ° C (Analysis (C16H13CI2N305S; H20) calculated C: 41.30; H: 3.47; Cl: 16.25; N: 9.63; S: 7.35; found (0.18 CH2Cl2) C: 41, 0; H: 3.0; Cl: 16.0; N: 9.6; S: 7.4).

Ethyl 6,8-dichloro-3,4-dihydro-2 - [(3-hydroxyamino) benzyl] -2H-1,2,4-benzothia-diazine-1,1-dioxide-3-carboxylate can be prepared as follows: at a temperature in the region of 20 ° C., 0.96 g of zinc powder is added to a mixture of 0.73 g of 6,8-dichloro-3,4-dihydro-2- (3 -nitrobenzyl) - 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate of ethyl and 0.13 g of ammonium chloride in solution in 20 cm3 of tetrahydrofuran and 7 cm3 of distilled water . The reaction is continued for 1 hour at the same temperature then the reaction medium is filtered through celite and the filtrate concentrated to dryness under reduced pressure. The residue is taken up in a dichloromethane-distilled water mixture and the organic phase separated, washed with water, dried and concentrated to dryness. The crude product thus obtained is purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (98/2 by volume) as eluent. 0.7 g of expected product is obtained in the form of a yellow powder, decomposing at around 90 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-nitrobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be prepared as follows : under nitrogen and at a temperature in the region of 20 ° C., 3 g of 6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3- ethyl carboxylate dissolved in 40 cm3 of anhydrous tetrahydrofuran in a suspension of 0.44 g of 50% sodium hydride in 10 cm3 of the same solvent. After one hour of stirring at the same temperature, a solution of 3 g of m-nitrobenzyl chloride in 25 cm 3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 4 hours, then cooled to a temperature in the region of 20 ° C, poured into 50 cm3 of distilled water and the organic phase extracted with ethyl acetate. After the usual treatment and purification of the crude product with flash chromatography on a silica column with a mixture of cyclohexane and dichloromethane (60/40 by volume) as eluent, 0.9 g of the expected product is obtained in the form of a white solid, melting at 237 ° C.

The 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy late ethyl can be prepared according to the following protocol: to a reflux solution of 4 g of 2-amino-4,6-dichlorobenzenesulfonamide in 40 cm3 of absolute ethanol, a solution of 3 g of glyoxylic acid in a mixture of 40 cm3 of absolute ethanol and 5.2 cm3 is added dropwise concentrated sulfuric acid. After 1 hour of stirring at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C. The precipitate formed is filtered, then recrystallized from 40 cm3 of absolute ethanol to yield 2.8 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide Ethyl carboxylate in the form of a crystalline powder melting at 204 ° C.

EXAMPLE 3

The procedure is as in Example 1 from 0.8 g of 6,8-dichloro-3,4-dihyro-2- (3-ureidobenzyl) -2H-1, 2,4 * -benzothiadiazine-1 , Ethyl 1-dioxide-3-carboxylate, 3.38 cm3 of an aqueous 0.5N sodium hydroxide solution and 10 cm3 of tetrahydrofuran. The solid obtained after dry concentration of the reaction medium is taken up in 15 cm3 of ethyl ether, filtered and dried to yield 0.70 g of sodium salt of 6,8-dichloro-3,4-dihydro- acid. 2- (3-ureidobenzyl) -2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylic in the form of a white powder decomposing around 230 ° C (Analysis (C16H13CI2N4Na05S) calculated C: 41, 13; H: 2.80; Cl: 15.17; N: 11.99; Na: 4.75; S: 6.51; found (0.69 H2O) C: 41.3; H: 3.1 ; Cl: 14.9; N: 11.6; Na: 4.9; S: 6.7).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-ureidobenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be obtained by the following procedure ¬ vante: to 0.87 g of 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1, 2,4-ben-zothiadiazine-1, 1-dioxide-3-carboxylate of ethyl in solution in 10 cm3 of nitromethane cooled to 5 ° C., a solution of 0.19 cm3 of chlorosulfonyl isocyanate in 5 cm3 of nitromethane is added in approximately 20 minutes. After returning to a temperature in the region of 20 ° C, a white precipitate appears. The reaction is continued for 1 hour at this temperature, then the medium reacts tional cooled to 0 ° C and treated with 1.75 cm3 of distilled water. After another hour of stirring at 20 ° C, the organic phase is extracted and treated according to the usual procedure. The crude product thus obtained is purified by flash chromatography on a silica column using ethyl acetate as eluent. 0.8 g of expected product is thus obtained in the form of a white powder, melting at 225 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be obtained as follows : 1.2 g of 6,8-dichloro-3,4-dihydro-2- (3-nitrobenzyl) -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate are stirred ethyl in solution in 140 cm3 of absolute ethanol, at a temperature in the region of 20 ° C, under a hydrogen atmosphere and in the presence of 5% palladium on carbon. After 2 hours of reaction, the catalyst is filtered and the solution concentrated to dryness under reduced pressure. The residue obtained is purified by flash chromatography on a silica column with dichloromethane as eluent. 1.05 g of expected product is thus obtained in the form of a white crystalline powder, melting at 174 ° C.

EXAMPLE 4

The procedure is as in Example 1 from 0.23 g of 6,8-dichloro-3,4-di-hydro-2- (3-hydroxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxyate, 1.07 cm3 of a 0.5N aqueous sodium hydroxide solution and 10 cm3 of tetrahydrofuran. The residue obtained after dry concentration of the reaction medium is taken up in dichloromethane and distilled water, the aqueous phase separated and then acidified with 1N hydrochloric acid. The white precipitate formed is filtered and washed with water to yield 0.03 g of 6,8-dichloro-3,4-dihydro-2- (3-hydroxybenzyl) -2H-1, 2,4- acid. benzothiadiazine-1, 1 - 3-dioxide-carboxylic in the form of a white powder decomposing at 126 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-hydroxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be obtained as follows : 3.2 g of 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate ethyl in solution in 50 cm3 of chloroform at a temperature in the region of 20 ° C. and under nitrogen, 1.72 cm3 of iodotrimethylsilane are added dropwise. After 7 hours of agitation at at the same temperature, the reaction medium is diluted drop by drop with 50 cm3 of distilled water, the organic phase decanted, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using dichloromethane as eluent, 0.25 g of expected product is obtained in the form of white meringue used as it is in subsequent syntheses.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared from Next way: under nitrogen, 20 cm3 of a solution of 1.46 g of 6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1 are added dropwise -ethyl dioxide-3-carboxylate in anhydrous tetrahydrofuran, at 0.22 g of 50% sodium hydride suspended in 5 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.1 g of 3-benzyloxybenzyl chloride in 10 cm 3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 4 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with ethyl acetate. After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is purified by flash chromatography on a column of silica using a mixture of dichloromé¬ thane and cyclohexane (60/40 by volume) as eluting. 1.1 g of the expected product are thus obtained in the form of a yellow oil which solidifies.

3-Benzyloxybenzyl chloride can be obtained according to the following method: 5 g of (3-benzyloxy) benzyl alcohol are heated to reflux in 10 cm3 of thionyl chloride. After 5 hours of reaction, the reaction medium is cooled and concentrated to dryness under reduced pressure. 5.2 g of expected product are obtained in the form of a brown oil used without additional purification in the subsequent steps.

EXAMPLE 5

The procedure is as in Example 1, starting with 1.5 g of 6,8-dichloro-3,4-dihyro-2- [3- (1-ethoxy) ethylbenzyl] -2H-1,2,4 -benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate, 6 cm3 of a 0.5N aqueous sodium hydroxide solution and 20 cm3 of tetrahydrofuran. The residue obtained after concentration at the reaction medium is taken up in distilled water and acidified using 1N hydrochloric acid. The white precipitate formed is filtered and washed with water and then with ethyl ether to give 1.3. g 6,8-dichloro-3,4-dihydro-2- [3- (1 -ethoxy) ethylbenzyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in the form of a white powder decomposing around 70 ° C (Analysis (C19H20CI2N2O5S) calculated C: 49.68; H: 4.39; Cl: 15.44; N: 6.10; S: 6.98; found (0 , 73 H2O; 0.20 Et 2 O) C: 49.8; H: 4.2; Cl: 15.7; N: 5.9; S: 7.1).

Ethyl 6,8-dichloro-3,4-dihydro-2- [3- (1-ethoxy) ethylbenzyl] -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylate can be obtained as follows: 2.5 g of 2-amino-4,6-dichloro-N- [3- (1-hydroxy) ethylbenzyl] -benzenesulfonamide in solution in 25 cm3 of ethanol, a solution of 1.22 g of glyoxylic acid and 2.9 cm3 of concentrated sulfuric acid in 25 cm3 of ethanol is added dropwise. The reaction medium is brought to reflux for 2 hours with stirring. After cooling to 20 ° C, the reaction medium is concentrated to dryness under reduced pressure, then the organic phase extracted with dichloromethane. The crude product is purified by flash chromatography on a silica column using dichloromethane as eluent. 1.5 g of expected product are obtained in the form of a white powder, melting at 150 ° C.

2-amino-4,6-dichloro-N- [3- (1-hydroxy) ethylbenzyl] -benzenesulfonamide can be prepared in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 14.2 g of 3- (1-hydroxy) ethylbenzylamine hydrochloride dissolved in 100 cm3 of tetrahydrofuran are added dropwise to a solution of 19.7 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 21 cm3 of triethylamine in 100 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is diluted with distilled water and the organic phase extracted with dichloromethane. After purification of the crude product by flash chromatography on a silica column using dichloromethane as eluent, 13.0 g of expected product is obtained in the form of a brown oil.

3- (1-hydroxy) ethylbenzylamine can be prepared according to the following method: to a solution heated to 65 ° C of 22.6 g of 3-acetylbenzonitrile in 110 cm3 of anhydrous tetrahydrofuran, it is poured dropwise in approximately 45 minutes, 220 cm3 of borane-dimethylsulfide complex in 2M solution in tetrahydrofuran. The reaction is continued for 1 hour at the same temperature. After cooling to a temperature in the region of 20 ° C., 440 cm 3 of methanol are added very slowly to the reaction medium. The organic solvents are then concentrated under reduced pressure, the residue taken up in 100 cm3 of ethyl ether and treated with 50 cm3 of 3N hydrochloric ether. The precipitate formed is filtered, washed with ethyl ether and then purified by flash chromatography on a silica column using dichloromethane then a mixture of dichloromethane and methanol (90/10 by volume) as eluents. This gives 6.6 g of the expected product in the form of a yellow oil (the least polar product) and 16 g of the hydrochloride of the expected product in the form of a white powder.

EXAMPLE 6

0.37 g of glyoxylic acid in solution in 4 cm3 of distilled water are added dropwise to a solution brought to reflux of 1 g of 2-amino-4,6-dichloro-N- [3- ( 1-hydroxy) ethylbenzyl] -benzenesulfonamide in 10 cm3 of dioxane. The reaction is continued for 3 hours at the same temperature then the reaction medium concentrated to dryness under reduced pressure. The extraction of the organic phase with dichloromethane and the purification of the crude product by flash chromatography on a silica column (eluent: dichloromethane / methanol (90/10 by volume)) lead to 0.17 g of acid 6 , 8-dichloro-3,4-dihydro-2- [3- (1-hydroxy) ethylbenzyl] -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid as a white powder decomposing around 140 ° C (Analysis (C17H16CI2N205S) calculated C: 47.34; H: 3.74; Cl: 16.44; N: 6.50; O: 18.55; S: 7, 43; found C: 46.9; H: 4.0; Cl: 16.0; N: 6.3; 0: 18.3; S: 7.5).

EXAMPLE 7

0.45 g of 6,8-dichloro-3,4-dihydro-2- (3-acetylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid solution in 5 cm3 of ethanol, a solution of 0.072 g of hydroxylamine hydrochloride and 0.13 cm3 of 30% sodium hydroxide in 3 cm3 of distilled water is added. The reaction is continued for 15 hours at a temperature in the region of 20 ° C., then the reaction mixture concentrated to dryness under reduced pressure and the residue taken up with ethyl acetate and water. The extraction of the organic phase leads to 0.25 g of 6,8-dichloro-3,4-dihydro-2- [3- (1-hydroxyimino) ethylbenzyl] -2H- 1,2,4-benzothiadiazine acid -1, 1-3-dioxide-carboxylic in the form of a pale yellow powder decomposing around 120 ° C (Analysis (C17H15CI2N305S) calculated C: 45.96; H: 3.40; Cl: 15.96; N: 9.46; S: 7.22; found (0.49AcOEt) C: 45.7; H: 3.6; Cl: 15.6; N: 9.2; S: 7.5).

6,8-dichloro-3,4-dihydro-2- (3-acetylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid can be obtained in this way next: a suspension of 2.66 g of chromium (VI) oxide and 2.3 cm3 of concentrated sulfuric acid in 4 cm3 of distilled water is added slowly to 2 g of 6.8 acid -dichloro-3,4-dihydro-2- [3- (1 -hydroxy) ethyl-benzyl] -2H-1, 2,4-ben-zothiadiazine-1,1-dioxide-3-carboxylic in solution in 10 cm3 acetone. The reaction is continued for 1 hour at a temperature in the region of 20 ° C., then the reaction medium is poured onto water and the organic phase extracted with ethyl acetate. The crude product obtained (1.9 g) is purified by flash chroma¬ tography on a silica column using a mixture of dichloromethane and methanol (85/15 by volume) as eluent. 1.0 g of the expected product is thus isolated in the form of a beige meringue.

The medicaments according to the invention consist of at least one 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 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, capsules) 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, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or l 'paraffin oil. These compositions may include substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.

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.

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 an NMDA receptor antagonist. These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSON's disease, for epileptogenic and / or convulsive manifestations, for the treatment of brain and spinal injuries, injuries related to degeneration of the inner ear or retina, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathy, as analgesics , anti-inflammatory, anti-anorexic, anti-migraine, antiemetic and to treat poisoning by neurotoxins or other substances agonists of the NMDA receptor, as well as the 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 as well as for the treatment of deficits associated with mitochondrial abnormalities such as mitochondrial myopathy, leber syndrome, WERNICKE encephalopathies, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutiric amino aciduria, LEAD encephalopathy 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 according to 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

Claims

- Lactose 55 mg

- Colloidal silica 1 mg

- Carboxymethyl starch sodium 10 mg

- Talc 10 mg - Magnesium stearate 1 mg

EXAMPLE P

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

- 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:

- Compound of formula (I) 10 mg

- Benzoic acid 80 mg

- Benzyl alcohol 0.06 cm ³ - Sodium benzoate 80 mg

- 95% ethanol 0.4 cm ³

- Sodium hydroxide 24 mg

- Propylene glycol 1.6 cm ³

- Water qs 4 cm3 CLAIMS

1 - 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-NH radical -OR ₁₀ , -CO-N (alk) -OR- | o or a group convertible into carboxy radical in vivo,

- R2, R3 and R4, identical or different, represent hydrogen or halogen atoms or alkyl or alkoxy radicals,

- R5 represents a hydroxy radical, -NHOH, -NH-CO-NH2, -CH2-NH2, hy¬ droxyalkyl, alkoxyalkyle or -alk≈NOH,

- Rβ, R7, Rs and Rg, identical or different, represent hydrogen or halogen atoms or alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoyiamino, phenylcarbonyl, hydroxy, -NHOH, -NH-CO-NH ₂ , -CH -NH ₂ , hydroxyalkyl, alkoxyalkyl, -alk≈NOH or phenoxy the phenyl ring of which is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy or polyfluoroalkyl radicals,

- R-jQ represents an alkyl or phenylalkyl radical and

alk represents an alkyl or alkylene radical,

it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions contain 1 to 10 carbon atoms in a straight or branched chain their racemates and their enantiomers and the salts of these compounds.

2 - Compounds of formula (I) according to claim 1 for which R- | represents a radical -CO-Rn in which R- | - | represents a radical -0-alk-R-j2, -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-Ri2 _> -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-Ri2. -0-alk-S-Ri2, -O-alk-COOH, -O-alk-COOalk, -0-alk-NR- | 3Ri4, -NH-alk-O-CO-alk, -NH-alk-O -COOalk, -NH-alk-0-CO-Ri2. -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-Ri2, -NH-alk-S-Ri2, -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR ^ R ^, R-J2 is a phenyl radical, R13 and R14, 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 and alk represents an alkylene or alkyl radical, their racemates and their enantiomers and the salts of these compounds.

3 - Compounds of formula (I) according to claim 1 for which R- | represents a carboxy or alkoxycarbonyl radical, R2, R3 and R4, identical or different, represent hydrogen or halogen atoms, their racemates and their enantiomers and the salts of these compounds.

4 - Compounds of formula (I) according to claim 1 for which R3 represents a hydrogen atom and R2 and R4 each represent a halogen atom, their racemates and their enantiomers and the salts of these compounds.

5 - Process for preparing the compounds of formula (I) according to claim 1 for which R-j represents a carboxy radical characterized in that a derivative of formula is condensed:

Rg R ₈

in which alk, R2, R3, R4, R5, Rβ, R7, Rs and Rg have the same meanings as in claim 1, with glyoxylic acid, isolates the product and optionally transforms it into salt.

6 - Process for preparing the compounds of formula (I) according to claim 1 for which Rj represents a carboxy radical characterized in that a corresponding compound of formula (I) is hydrolyzed for which Rj represents an alkoxycarbonyl radical, isolates the product and eventually transforms it into salt.

7 - Process for preparing the compounds of formula (I) according to claim 1 for which R-j represents an alkoxycarbonyl radical characterized in that a derivative of formula is condensed:

in which alk, R2, R3, R4, R5, Rβ, R7, Rs and Rg have the same meanings as in claim 1, with glyoxylic acid, in an acid medium and in the presence of an alcohol R15OH in which R15 represents 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 1 for which R- | represents a radical -CO-NH2, -CO-NH-alk, -CO-N (alk), -CO-NHOH, -CO-N (alk) OH, -CO-NH-0-Rκ), -CO- N (alk) -OR- | o, characterized in that a compound of formula (I) corresponding to which Rj represents a carboxy or alkoxycarbonyl radical is reacted with a derivative of formula:

HN (R ₁₆ ) -R ₁₇ (VI)

in which R- | β represents a hydrogen atom or an alkyl radical and Rj 7 represents a hydrogen atom or alkyl, hydroxy or -OR-J Q. radical isolates the product and optionally converts it to salt. 9 - Process for preparing the compounds of formula (I) according to claim 1 for which R- | represents a tetrazolyl radical characterized in that the sodium azide is reacted with a derivative of formula:

in which alk, R2, R3, R4, R5, RQ, R7, Rs and Rg have the same meanings as in claim 1, isolate the product and optionally transform it into salt.

10 - Process for preparing the compounds of formula (I) according to claim 1 for which Rj represents a radical -CO-R- | 1 in which R-11 represents a radical -0-alk-Ri2, -O-alk-O-CO-alk, -O-alk-O-COOalk, -O-alk-O-CO-R-12. -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -0-alk-0-Ri2, -0-alk-S-Rt2. -O-alk-COOH, -O-alk-COOalk, -0-alk-NR ₁₃ Ri4, -NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-0- CO-Ri2 _> -NH-alk-OH, -NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-R ₁₂ , -NH-alk-SR- | 2, - NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NRi3Ri4, characterized in that a corresponding compound of formula (I) is reacted for which R- | represents a carboxy or alkoxycarbonyl radical on a derivative of formula:

R11-H (IX)

in which R-J I has the same meanings as above, isolates the product and optionally transforms it into salt.

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

(X)

in which Rj, R2, R3 and R4 have the same meanings as in claim 1 on a derivative of formula:

in which alk, R5, Rβ, R7, Rs and Rg have the same meanings as in claim 1 and X represents a halogen atom, isolates the product and optionally transforms it into salt.

12 - Process for preparing the compounds of formula (I) according to claim 1 for which R5 and / or RQ, R7, Rs and Rg represent a radical -NHOH characterized in that a corresponding compound for which R5 and / is reduced or Rβ, R7, Rs and Rg represent a nitro radical, isolates the product and optionally transforms it into salt.

13 - Process for preparing the compounds of formula (I) according to claim 1 for which R5 and / or Rβ, R7, Rs and Rg represent a radical -NH-CO-NH2 characterized in that a corresponding compound is reacted for which R5 and / or Rβ, R7, Rs and Rg represent an amino radical on the chlorosulfonyl isocyanate, isolates the product and optionally transforms it into salt.

14 - Process for preparing the compounds of formula (I) according to claim 1 for which R5 and / or Rβ, R7, Rs and Rg represent a hydroxy radical characterized in that a corresponding compound is debenzyled for which R5 and / or Rβ, R7, Rs and Rg represent a benzyloxy radical, isolates the product and optionally transforms it into a salt.

15 - Process for preparing the compounds of formula (I) according to claim 1 for which R5 and / or Rβ, R7, Rs and Rg represent a radical -alk≈NOH characterized in that the hydroxylamine is reacted on a corresponding derivative for which R5 and / or Rβ, R7, Rs and Rg represent a radical -CHO, -R-jβ-CHO, -CO-R * ιg, -R20-CO-R21, R- | 8 represents an alkylene radical containing 1 to 9 carbon atoms in a straight chain or branched, R- | g represents an alkyl radical containing 1 to 9 carbon atoms in a straight or branched chain, R20 represents an alkylene radical containing 1 to 8 carbon atoms in a straight or branched chain and R21 represents an alkyl radical containing 1 to 8 carbon atoms, it being understood that the sum of the carbon atoms of R20 and R21 is at most equal to 9, isolates the product and optionally transforms it into salt.

16 - Medicines containing as active principle at least one compound of formula (I) according to claim 1.