EP0636124A1 - 3,4-dihydro-2h-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid derivatives, preparation thereof and drugs containing same - Google Patents

Abstract

Compounds of formula (I), wherein R is (a) a hydrogen atom, (b) an alkyl radical, (c) an allyl radical, (d) a phenyl radical, (e) a 2-or-3-pyridyl alkyl radical, (f) a 2-quinolylalkyl radical, (g) a naphthylalkyl radical, (h) a cycloalkylalkyl radical, (i) a 2H-3-naphtho[1,8-cd]isothiazol-2-yl-1,1-dioxide)alkyl radical, (j) a (5,6-dihydro 1H,4H-1,2,5-thiadiazolo[4,3,2-ij]quinolyl-2,2-dioxide)alkyl, (k) an -alk-CO-R5 radical, (l) an -alk-R6-R7 radical, (m) a 4-phenylpirerazinyl-alkyl radical wherein the phenyl nucleus is optionally substituted by one or more substituents selected from halogen atoms and alkyl or alkoxy radicals, (n) a 10-phenothiazinylalkyl radical (o) a (10-alkyl-2-phenothiazinyl)alkyl radical, (p) a 3-indolylalkyl radical, (q) a phenylalkyloxy radical, (r) a 1-phenylalkyl-4-piperidyl radical, (s) a 2-thienylalkyl radical, or (t) a phenylalkyl radical wherein the phenyl is unsubstituted or substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoylamino, phenylcarbonyl and phenoxy radicals in which the phenyl nucleus is optionally substituted by one or more substituents selected from halogen atoms and alkyl, alkoxy or polyfluoroalkyl radicals; R1 is a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N(alk)2, -CO-NHOH, -CO-N(alk)OH, -CO-NH-O-R8, -CO-N(alk)-OR8 or a group which is convertible in vivo into a carboxy radical; each of R2, R3 and R4, which are the same or different, is a hydrogen or halogen atom or an alkyl or alkoxy radical; R5 is a hydroxy, alkoxy, phenyl or -NR9R10 radical; R6 is an oxygen, sulphur or nitrogen atom or a SO, SO2 or -N-alk radical, R7 is an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more hydrogen atoms; R8 is an alkyl or phenylalkyl radical; each of R9 and R10, which are the same or different, is a hydrogen atom or an alkyl or phenyl radical; and alk is an alkyl or alkylene radical, salts thereof; preparation thereof; and drugs containing same.

Description

 3,4-DIHYDRO-2H-1, 2,4-BENZOTHIADIAZINE ACID DERIVATIVES

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

DRUGS CONTAINING THEM

Λ \

The present invention relates to compounds of formula:

their salts, their preparation and the drugs containing them.

In formula (I),

- R represents (a) a hydrogen atom, (b) an alkyl radical, (c) an allyl radical, (d) a phenyl radical, (e) a 2 or 3-pyridylalkyl radical, (f) a radical

2-quinolylalkyl, (g) a naphthylalkyl radical, (h) a cycloalkylalkyyl radical, (i) a 2H-3-naphtho [1, 8-cd] isothiazol-2-yl-1, 1-dioxide dioxide) alkyl radical, (j) a radical

(5,6-dihydro 1 H.4H-1, 2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide) alkyl, (k) a radical -alk-CO-R5 _j ( I) an -alk-Rg-Ry radical, (m) a radical

4-phenylpiperazinylalkyl in which the phenyl ring is optionally substituted

By one or more substituents chosen from halogen atoms and alkyl or alkoxy radicals, (n) a 10-phenothiazinylalkyl radical, (o) a (10-alkyl-2-phenothiazinyl) alkyl radical, (p) a radical 3-indolylalkyl, (q) a phenylalkyloxy radical, (r) a ^" l-phenylalkyl-4-piperidyl radical, (s) a radical

2-thienylalkyl or (t) a phenylalkyl radical in which the phenyl is non

Substituted or substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy,

* phenylalkyloxy, phenylalkyl, benzoylamino, phenylcarbonyl and phenoxy

J whose phenyl ring is optionally substituted by one or more

»25 substituents chosen from halogen atoms and alkyl, alkoxy or polyfluoroalkyl radicals, - R- (represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk) ₂ , -CO-NHOH, -CO-N (alk) OH, -CO radical -NH-0-R ₈ , -CO-N (alk) -OR8 or a group convertible into carboxy radical in vivo,

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

- R5 represents a hydroxy, alkoxy, phenyl or -NRgR-jQ radical.

- RQ represents an oxygen, sulfur or nitrogen atom or an SO, SO2 or -N-alk radical,

- R7 represents an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more halogen atoms,

- R8 represents an alkyl or phenylalkyl radical,

- Rg and RJ O _", identical or different, represent a hydrogen atom or an alkyl or phenyl 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 a 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 triffuoromethyl 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 -O-alk-R- | 2.

* -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-Ri2, -O-alk-OH,

4 -O-alk-O-alk, -O-alk-S-alk, -0-alk-O-Ri2, -O-alk-S-F-12. -O-alk-COOH,

* »'5 -O-alk-COOalk, -0-alk-NRι ₃ R- | 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-OR-12, -NH-alk- S-Ri2, -NH-alk-COOH, -NH-alk-COOalk,

In these definitions, R-12 is a phenyl radical, R13 and R14,

10 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, which are identical or different, represent hydrogen or halogen atoms and in particular atoms of chlorine or bromine.

A particularly interesting class is constituted by the compounds of formula (I) in which R3 represents a hydrogen atom

20 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 1 represents a carboxy radical can be prepared by condensation of a derivative of formula:

in which R, R2, R3 and R4 have the same meanings as in formula (I), with glyoxyiic 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 close to 100 ° C - either in an inert solvent such as dioxane, a dioxane-water mixture, 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. _r 7, 269 (1964), V. DESMEDT and A. BRUYLANTS, Bull. Soc. Chim. Belg., 74, 344 (1965), GJ THOMAS. J. Agr ^' rc. 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 G), on an amine of formula:

NH ₂ -R (IV)

in which R has 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 (IfI) can be obtained 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.

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

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

The compounds of formula (II) for which R represents a hydrogen atom can also be obtained by hydrolysis of a derivative of formula:

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

This hydrolysis is generally carried out in an acid medium (sulfuric, hydrochloric, phosphoric acid for example), at a temperature in the region of 100 to 150 ° C. The derivatives of formula (VI) can be obtained by the action of an aniline of formula (V) in which R2, R3 and R4 have the same meanings as in formula (1) with sulfonylisocyanate chloride.

This reaction is carried out in an inert solvent such as nitromethane, in the presence of aluminum chloride, at a temperature of 100 to 105 ° C.

The compounds of formula (I) for which R- | represents an alkoxycarbonyl radical can be prepared by condensation of a derivative of formula (II) with glyoxyiic acid. in an acid medium and in the presence of an alcohol R-15OH 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 an alkoxycarbonyl radical and R represents a 2H-3-naphtho [1, 8-cd] isothiazoI-2-yl -1,1-dioxide) alkyl or (5,6 -dihydro 1 H, 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinoly [-2,2-dioxide) alkyl can be prepared by action of a derivative of formula:

in which R- | represents an alkoxycarbonyl radical, R, R3 and R4 have the same meanings as in formula (I) and R-jg represents a haloalkyl radical, and preferably bromoalkyl or chloroalkyl, on a derivative of formula:

H-R17 (VIII)

in which R-jγ represents a 2H-3-naphtho [1,8-cd] isothiazol-2-yl -1 _τ 1-dioxide) radical or (5,6-dihydro-1H, 4H-1.2,5-thiadiazolo [ 4,3,2-ij] quinolyl-2,2-dioxide) or an alkali metal salt of these derivatives. This reaction is optionally carried out in the presence of a base such as an alkali metal hydride, an alkali metal carbonate or an alkali metal hydroxide, in an inert organic solvent such as tetrahydrofuran or dimethylformamide, to a temperature between 10 ° C and the boiling point of the solvent.

The derivatives of formula (VII) can be obtained by the action of a derivative of formula (I) in which R represents a hydrogen atom and R- | represents an alkoxycarbonyl radical with a derivative of formula:

Hal-Ri6 (IX)

wherein RJ ^{6a 'are} same meanings as in formula (VII) and Hal represents a halogen atom.

This reaction is generally carried out in the presence of a base such as an alkali metal hydride, an alkali metal carbonate or an alkali metal hydroxide, in an inert organic solvent such as tetrahydrofuran or dimethylformamide, to a temperature between 10 ° C and the boiling point of the solvent.

The compounds of formula (I) for which R- | represents a carboxy radical can be prepared by hydrolysis of a corresponding ester of formula (I) 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 trimethylsiianolate, in an inert solvent such as tetrahydrofuran, dioxane, dichloromethane, at a temperature close to 20 ° C.

The compounds of formula (I) for which R- | represents a tetrazolyl radical can be prepared by reaction of sodium azide on a derivative of formula: in which R, R2, R3 and R4 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 (X) can be obtained by the action of phosphorus pentachloride or phosphoryl chloride with an amide of formula:

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

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 (XI) 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 WS BISHOP, Organic Synthesis, UI, 613.

The compounds of formula (I) for which R- | represents a radical -CO-NH2, -CO-NH-alk, -CO-N (aIk) 2 _" -CO-NHOH, -CO-N (alk) OH, -CO-NH-O-Rs, -CO-N (alk) -ORs can be prepared by reaction of a corresponding compound of formula (I) for which R- | represents a radical

^* carboxy or alkoxycarbonyl on a derivative of formula:

_ _ft HN (R ₁₇ ) -R ₁₈ (XII)

5 in which R17 represents a hydrogen atom or an alkyl radical and R-18 represents a hydrogen atom or an alkyl, hydroxy, -O-alk or -OR ₈ radical.

When the acid is used, it is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example the

Dicyclohexylcarbodiimide) or N, N'-diimidazolecarbonyl, in an inert solvent such as an ether (for example tetrahydrofuran, dioxane), an amide (for example dimethylformamide) or a chlorinated solvent (for example methylene chloride, chloroform), optionally in the presence of a nitrogenous base such as dimethylaminopyridine, at a temperature comprised

15 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

20 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, ie in a two-phase hydroorganic medium in the presence of an alkaline or alkaline earth base (soda, potash for example) or a carbonate or bicarbonate of an alkali metal or

25 alkaline earth at a temperature between 0 and 40 ° C.

The compounds of formula (I) for which R- | represents a radical

^• * -CO-R11 in which R11 represents a radical -0-alk-R- | 2.

-O-alk-O-CO-alk, -O-alk-O-COOalk, -0-aIk-0-C0-Ri2 _> -O-alk-OH,

* -O-alk-O-alk, -O-alk-S-alk, -O-alk-O-R-12. -O-alk-S-R- | 2. -O-alk-COOH,

30 -O-alk-COOalk, -0-alk-NR ₁₃ Rι ₄ , -NH-alk-O-CO-alk, -NH-alk-O-COOalk,

-NH-alk-0-CO-R- | 2. -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-NR-i3R- | 4, can be prepared by reaction of a compound of formula (I) corresponding for which Rj represents a carboxy or alkoxycarbonyl radical on a derivative of formufe:

R-I 1-H (XIII)

in which Ru 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) for which R is other than hydrogen can also be obtained by reaction of a corresponding compound of formula (I) for which R represents a hydrogen atom with a halide of formula:

R-X (XIV)

in which R has the same meanings as in formula (I) except hydrogen and X represents a halogen atom and preferably a chlorine or bromine 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 (XIV) 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 R represents a radical

-alk-CO-R5 in which R5 represents a hydroxy radical and or R represents a phenylalkyl radical substituted by at least one carboxy radical can also be prepared by hydrolysis of an ester of formula (I) corresponding for which R5 represents an alkoxy radical and / or R represents a phenylalkyl radical substituted by at least one alkoxycarbonyl radical.

This hydrolysis is generally carried out by means of a base such as an alkali metal hydroxide (sodium hydroxide or potassium hydroxide, for example lithium hydroxide), within an inert solvent such as an alcohol or an alcohol-water mixture , tetrahydrofuran-water, dioxane-water, at a temperature between 20 and 100 ° C.

The compounds of formula (I) for which R represents a phenylalkyl radical substituted by at least one amino radical can be prepared by reduction of the corresponding compounds of formula (I) for which R represents a phenylalkyl radical substituted by at least one nitro radical.

This reduction is preferably carried out either by means of hydrogen, in the presence of a hydrogenation catalyst such as palladium on carbon, in an inert solvent such as an alcohol, at a temperature in the region of 20 °. C, or by means of tin (II) chloride, in an inert solvent such as an alcohol, at a temperature between 20 ° C. and the boiling point of the reaction medium.

The compounds of formula (I) not containing benzyl radicals and for which R represents a phenylalkyl radical in which the phenyl nucleus is substituted by at least one ethyl radical can also be prepared by hydrogenation of a compound of formula (I) corresponding to which R represents a phenylalkyl radical in which the phenyl nucleus is substituted by at least one vinyl radical.

This hydrogenation is preferably carried out by means of hydrogen, in the presence of a catalyst such as palladium on carbon, in an inert solvent such as an alcohol (ethanol for example), at a temperature in the region of 20 °. vs.

The compounds of formula (I) for which R represents a phenylalkyl radical in which the phenyl nucleus is substituted by at least one benzoylamino radical can also be prepared by the action of a corresponding compound of formula (I) for which R represents a phenylalkyl radical the phenyl ring of which is substituted by at least one amino radical with benzoyl chloride.

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

The compounds of formula (l) for which R represents a radical -aïk-Rg-Ry and Rg represents a radical SO or SO2 can also be prepared by oxidation of a compound of formula (I) corresponding for which R represents a radical - alk-Rg-R7 and Rg represents a sulfur atom.

This oxidation is generally carried out by means of an oxidizing agent such as m-chloroperbenzoic acid, in an inert solvent such as a chlorinated solvent (dichloromethane), at ^" a temperature in the region of 20 ° C. .

The compounds of formula (I) not containing benzyl radicals and for which R- | represents a radical -CO-NHOH can also be prepared by debenzylation of a compound of formula (I) corresponding to which R- | represents a radical -CO-NH-O-Rg and R ₈ represents a benzyl radical.

This reaction is carried out by means of hydrogen, in an inert solvent such as an alcohol (methanol-ethanol for example), in the presence of a catalyst such as palladium on carbon, at a temperature in the region of 20 °. vs.

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 resolution of the racemates, 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 earth for example), ammonia, a tetraalkylammonium, 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.

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, 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, diseases of the motor neuron, amyotrophic lateral sclerosis, olivo- pontocerebellar atrophy, PARKINSON 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), anti-anorexics (SORRELS et al., Brain Res., 572, 265 (1992), antiemetic, anti-migraine and to treat poisonings by neurotoxins or other agonist substances of the NMDA receptor , as well as neurological disorders associated with viral diseases such as AIDS (L1PTON et al., Neuron, 1, 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 inhibition of opiate addiction and 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 specific binding of [ ³ H] -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). [ ³ H] -DCKA (20 nM) 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 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) vis-à-vis the AMPA receptor was determined by studying the antagonism of the specific binding of [ ³ H] -AMPA on membranes of rat cerebral cortex (HONORE et al. ,

Neuroscience letters, 54, 27 (1985)). The [ ³ H] -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 binding is determined in the presence of 1mM L-glutamate. Linked 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 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 an alkyl radical and R3 represents a hydrogen atom, ie 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 compounds of formula (I) for which R represents a radical —alk-COOH and R- are particularly advantageous as AMPA receptor antagonists. represents a carboxy radical.

The preferred compounds are: 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, 6,8-dichloro-3,4 -dihydro-2- (3-phenylpropyl) 2H-1, 2,4-benzothia-diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (2- phenethyl) -2H-1, 2,4-benzothia-diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (4-phenylbutyl) -2H-1, 2,4-benzothia-diazine-1, 1-3-dioxide-carboxylic, - 2-benzyl-6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-3-carboxylic dioxide,

- 6,8-dichloro-3,4-dihydro-2- (4-trifluoromethylbenzyl) -2H-1, 2,4-benzo thiadiazine-1, 1-dioxide-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethylbenzyl) -2H-1, 2,4-benzo thiadiazine-1, 1-dioxide-3-carboxylic acid, - 6,8-dichloro-3,4-dihydro-2- (2-trifluoromethylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- (3-nitrobenzyl) -2H-1, 2,4-benzothiadiazine- 1, 1-3-dioxide-carboxylic acid, - 2- (3-cyanobenzyl acid) ) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothia-dinazin-1, 1-3-carboxy-dioxide, 6,8-dichloro-3,4-dihydro-2 - (4-phenylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (2-quinolylmethyl) -2H -1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (1-naphthylmethyl) -2H-1, 2,4-benzothia diazine-1,1-dioxide-3-carboxylic acid 6,8-dichloro-3,4-dihydro-2- [3- (naphtho [1, 8-cd] isothiazol-1, 1 - dioxide-2-yl ) pro-pyl] -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carboxylic, - 6,8-dichloro-3,4-dihydro-2- [3- (5,6- dihydro-1H, 4H-1,2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide) propyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide- 3 -carboxyIique,

- 6,8-dichloro-3,4-dihydro-2- (3-phenoxybenzyl) -2H-1, 2,4-benzothia diazine-1, l-dioxide-3-carboxylic acid, - 6,8-dichloro acid -3,4-dihydro-2- (3-vinyIbenzyl) -2H-1, 2,4-benzothiadiazine- 1, 1-dio-xyde-3-carboxylic, 6,8-dichloro-3 _r 4-dihydro- acid 2- (3-aminobenzyl) -2H-1, 2,4-benzothia dazine-1, 1-dioxide-3-carboxylic acid 6,8-dichloro-3,4-dihydro-2- (2-phenoxyethyl) - 2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic, 6,8-dichloro-3,4-dihydro-2- (4-fluorobenzyl) -2H-1,2,4- benzothia diazine-1, 1-3-dioxide-3-carboxylic acid 6,8-dichoro-3,4-dihydro-2- (4-methylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide -3-carboxyIïque, - 6,8-dichloro-3,4-dihydro-2- (3-methylbenzyl) -2H-1, 2,4-benzothïa diazîne-1, 1-dioxide-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- (2-phenylthioethyl) -2H-1, 2,4-benzothiadia zine-1, 1-dioxide-3-carboxylic acid, 6,8-dichloro-3,4-dihydro-2- (4-chlorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid, 6,8-dichloro-3 , 4-dihydro-2- (2-methylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, - 6,8-dichloro-3,4-dihydro-2- acid (2-phenylsulfonylethyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic,

- 6,8-dichloro-3,4-dihydro-2-benzoylmethyl-2H-1, 2,4-benzothiadiazine- 1, 1-3-dioxide-3-carboxylic acid, 6,8-dichloro-3,4-dihydro -2- (3-fluorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic,

- 6,8-dichloro-3,4-dihydro-2- (2-methoxybenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- [2- (phenethylthio) ethyl] -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic acid, - acid 6, 8-dichloro-3,4-dihydro-2- (3-methoxybenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid 6,8-dichloro-3,4- dihydro-2- (4-methoxybenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (3-chlorobenzyl ) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic,

- 6,8-dichloro-3,4-dihydro-2- (3,4-dimethoxybenzyl) -2H-1, 2,4-benzothia diazine-1, 1-3-carboxyiic acid,

- 6,8-dichloro-3,4-dihydro-2- (3,4-dichlorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic acid, - acid 6,8 -dichloro-3,4-dihydro-2- (3-phenoxypropyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro -2- (2-chlorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (3-bromobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (2-fluorobenzyl) -2H-1, 2,4 -benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (3-pyridylmethyl) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-3-carboxylic acid,

- 6,8-dichloro-3 _r 4-dihydro-2- (3-iodobenzyl) -2H-1, 2,4-benzothiadiazine- 1, 1-doxide-3-carboxylic acid, - 6,8-dichloro- acid 3,4-dihydro-2- (3-ethylbenzyl) -2H-1, 2,4-benzothiadiazine- 1, 1-dioxide-3-carboxylic acid _t 6,8-dichloro-3,4-dihydro-2- ( 2-thienylmethyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethoxybenzyl) -2H-1 , 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic,

- 6,8-dichforo-3,4-dihydro-2- (3-phenylthiopropyl) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-3-carboxylic acid, 6,8-dichloro- acid 3,4-dihydro-2- (3-methoxycarbonylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxyIique, - 6,8-dichloro-3,4-dihydro-2- acid (5-phenylpentyI) -2H-1, 2,4-benzothia diazine-1,1-3-carboxylic oxide,

- 6,8-dichloro-3,4-dihydro-2- (3,5-dimethoxybenzyl) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic acid, acid 2- (3 -carboxybenzyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxyIique, acid 6 _J 8-dichloro-3,4-dihydro- 2- [4- (2-methylphenyl) butyl] -2H-1, 2,4-benzothiadia zine-1, 1-dioxide-3-carboxyIic, 6,8-dichloro-3,4-dihydro-2- [ 4- (4-methylphenyl) butyl] -2H-1, 2,4-benzothiadia zine-1, 1-dioxide-3-carboxyIic, - 6,8-dichloro-3,4-dihydro-2- [4- (3-methylphenyl) butyl] -2H-1,2,4- benzothiadiazine-1, 1-3-dioxide-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- (3,5-dichlorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic acid, 6.8- dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic, 6,8-dichloro-3,4-dihydro-2 - (3-phenyibenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic, - 6,8-dichloro-3,4-dihydro-2- (2-phenethylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- [3- (4-methylphenoxy) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1-3-carboxylic acid, - acid 6 , 8-dichloro-3,4-dihydro-2- (3,5-dimethylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic,

- 6,8-dichloro-3,4-dihydro-2- [3- (4-methoxyphenoxy) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid,

- 6,8-dichloro-3,4-dihydro-2- [2- (3-indolyl) ethyl] -2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-carboxylic acid, acid 6 , 8-dichioro-3,4-dihydro-2- (3,5-difluorobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid 6,8-dichloro-3, 4-dihydro-2- [3- (benzoylamino) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic, - 6,8-dichloro-3,4-dihydro-2 acid - (4-phenoxybenzyl) -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic,

- 2- (3 _: benzoylbenzyl) -6,8-dichloro-3,4-dihydro acid - 2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-3-carboxylic acid,

- 2- (3,5-diaminobenzyl) -6,8-dichloro-3,4-dihydro acid - 2H-1, 2,4-benzothia diazine-1, 1-3-dioxide-3-carboxylic acid,

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

The following examples illustrate the invention without limiting it.

EXAMPLE 1

To a reflux suspension of 3.6 g of 2-aminobenzenesulfonamide in 60 cm3 of distilled water, a solution of 2.8 g of giyoxylic acid and 1.2 g of sodium hydroxide pellets in 20 cm3 of distilled water. The. reaction medium is maintained at reflux for 1 hour and 30 minutes. After cooling to a temperature in the region of 0 ° C., the solution is acidified to pH 1 by addition of hydrochloric acid N. The crystals formed are filtered and washed with water. 4.3 g of 3,4-dihydro acid hydrate are obtained 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid in the form of a crystalline powder melting at 220 ° C.

EXAMPLE 2

To a reflux suspension of 4.8 g of 2-amino-4,6-dichloro benzenesulfonamide in 60 cm 3 of distilled water, the following are added dropwise:

20 cm3 of an aqueous solution of 2.8 g of giyoxylic acid and 1.2 g of soda. After 1 hour and 30 minutes of reflux, the reaction medium is cooled to a temperature in the region of 0 ° C. and then acidified using a 1N hydrochloric acid solution. The precipitate is filtered and washed with water. 5.9 g of 6,8-dichioro-3,4-dihydro-2H-1, 2,4-benzothiadiazoin-1, 1-dioxide are obtained.

3-carboxylic acid in the form of a crystalline powder melting around 270 ° C (Analysis (C ₈ HgC.2N ₂ θ4S)% calculated C.32.34; H: 2.04; Cl: 23.86; N: 9, 43;

0: 21.54; S.10.79,% found C.32.1; H: 1.9; Cl. 23.9; N: 9.2; 0: 21.6; S.10,6).

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

EXAMPLE 3

To a solution of 2.5 g of 2-amino-4,6-dichloro-N- (3-phenylpropyl) benzenesulfonamide in 60 cm3 of dioxane heated to reflux, a solution of 0.92 g is added dropwise giyoxylic acid in 15 cm3 of distilled water. Stirring is continued for 3 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is then taken up in an aqueous sodium hydroxide solution and the organic phase extracted with ethyl acetate. After drying over magnesium sulfate, the organic phase is concentrated to dryness under reduced pressure and leads to 2.6 g of sodium salt of the acid

6,8-dichloro-3,4-dihydro-2- (3-phenylpropyl) 2hM, 2.4-benzothîadiazine-1, 1 -dio xyde-3-carboxyϋque in the form of a powder melting at around 290 ° C (Analysis (Ci7H ₁₅ Cl2N2Na0 ₄ S)% calculated C: 46.70; H: 3.46; Cl: 16.22; N: 6.41; S: 7.33;% found C: 47.1; H: 3.9 ; Cl. 16.0; N: 6.3; S: 7.0). 2-amino-4,6-dichloro-N- (3-phenylpropyl) benzenesulfonamide can be prepared as follows: to a suspension of 5.2 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride in 80 cm3 of anhydrous tetrahydrofuran at a temperature in the region of 20 ° C., 2.8 cm 3 of triethylamine are added, then a solution of 2.8 g of 3-phenylpropylamine in 20 cm 3 of tetrahydrofuran. After 15 hours of stirring at this same temperature, the reaction medium is poured into water and the organic phase extracted with ethyl acetate, dried over magnesium sulfate and then concentrated to dryness under reduced pressure to yield 7 , 2 g of 2-amino-4,6-dichloro-N- (3-phenylpropyl) benzenesulfonamide in the form of an oil used as it is in subsequent syntheses.

2-amino-4,6-dichlorobenzenesulfonyl chloride 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

To a solution of 6.8 g of 2-amino-4,6-dichloro-N- (2-phenethyl) benzenesulfonamide in 160 cm3 of dioxane heated to reflux, a solution of 2.6 g is added dropwise giyoxylic acid in 40 cm3 of water. After 4 hours of reflux, the reaction medium is concentrated to dryness under reduced pressure and then the organic phase is added with water and extracted with ethyl acetate. The crude product is purified by flash chromatography on a silica column with a mixture of ethyl acetate and methanol (80/20 by volume) as eluent. 2.3 g of 6,8-dichloro-3,4-dihydro -2- (2-phenethyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid are thus obtained under powder form decomposing at 83 ° C (Analysis (C-I6H14CI2N2O4S)% calculated C: 47.89; H: 3.52; Cl: 17.67; N: 6.98; 0: 15.95;

S: 7.99; % found C: 48.2; H: 3.8; Cl: 16.8; N: 6.8; 0: 16.2; S: 7.6).

2-amino-4,6-dichloro-N- (2-phenethyl) benzenesulfonamide can be prepared in the following manner: 5.2 g of a stirred solution, at a temperature in the region of 20 ° C., under nitrogen 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.8 cm3 of triethylamine in 100 cm3 of anhydrous tetrahydrofuran, a solution of 2.4 g of 2-phenethylamine in 20 cm3 of the same solvent is added dropwise. The the reaction is continued for 2 hours at approximately 20 ° C. then the reaction medium is poured into distilled water. The organic phase is extracted with ethyl acetate, washed with water and then dried over magnesium sulfate to give, after dry concentration, 6.8 g of 2-amino-4,6-dichloro N- (2 -phenethyl) benzenesulfonamide in the form of an oil used as it is in subsequent syntheses.

EXAMPLE 5

The procedure is the same as in Example 3, starting with 6.5 g of 2-amino-4,6-dichloro-N- (4-phenylbutyl) benzenesulfonamide, 2.2 g of giyoxylic acid, 140 cm3 of dioxane and 35 cm3 of distilled water. After 3 hours of reaction at reflux, the reaction medium is concentrated to dryness under reduced pressure and the oil obtained taken up in ethyl acetate. After usual treatment, the crude residue is purified by flash chromatography on a ^" silica ^" column with a mixture of ethyl acetate and methanol (90/10 by volume) as eluent. The meringue obtained is redissolved in dichloromethane, l insoluble material removed and the filtrate diluted with diisopropyl ether After filtration and drying of the precipitate, 2 g of acid are obtained

6,8-dichloro-3,4-dihydro-2- (4-phenylbutyl) -2H-1, 2,4-benzothiadiazine-1, 1 -dio xyde-3-carboxylic in the form of a powder which decomposes towards 67 ° C (Analysis (C- | ₈ Hι ₈ Cl2N2θ4S)% calculated C: 50.36; H: 4.23; Cl: 16.52; N: 6.53;

0: 14.91; S: 7.47; % found (0.28H ₂ O; 0.37E-2θ) C: 50.6; H: 4.2; Cl: 17.2; N: 6.9; 0: 14.9; S: 7.2).

2-amino-4,6-d.chloro-N- (4-phenylbutyl) benzenesulfonamide can be prepared as described in Example 3 for the preparation of 2-amino-4,6-dichloro-N- (3- phenylpropyl) benzenesulfonamide, from 3.9 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride, 2.11 cm 3 of triethylamine, 2.28 g of 4-phenyl butyamine and 70 cm 3 of anhydrous tetrahydrofuran. 6.5 g of 2-am.no-4,6-dichloro-N- (4-phenylbutyl) benzenesulfonamide are thus obtained in the form of an oil used without further purification in the following steps. EXAMPLE 6

To a solution at a temperature in the region of 20 ° C. of 2.4 g of 2-benzyl-6,8-dichloro-3,4-dihydro 2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- ethyl carboxylate dissolved in 25 cm3 of dichloromethane, 0.82 g of potassium trimethylsilanolate is gradually added. After stirring overnight at this temperature, the reaction medium is concentrated to dryness under reduced pressure and the residue obtained recrystallized from 20 cm3 of 2-propanol. The salt thus prepared is taken up in 30 cm3 of distilled water and treated with a 1N aqueous solution of hydrochloric acid. The precipitate formed is filtered and dried to yield 0.45 g of 2-benzyl-6,8-dichloro-3,4-dihydro -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 acid -carboxylic in the form of crystalline powder melting at 219 ° C.

EXAMPLE 7

To a reflux solution of 4.45 g of 2-amino-4,6-dichloro-N-benzylbenzene sulfonamide in 100 cm3 of absolute ethanol, a solution of 2.5 g of acid is added dropwise giyoxylic in a mixture of 80 cm3 of absolute ethanol and 5.8 cm3 of concentrated sulfuric acid. After 1 hour and 30 minutes of reflux, the reaction medium is partially concentrated under reduced pressure. The precipitate formed is filtered and then recrystallized from 30 cm3 of absolute ethanol to yield 2.6 g of 2-benzyl-6,8-dichloro 3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1 -ethyl dioxide-3-carboxyiate in the form of crystalline powder melting at 159 ° C.

The 2-amino-4,6-dichloro-N-benzylbenzenesulfonamide can be prepared according to the method described in Example 3 for the preparation of 2-amino-4,6-dichloro-N- (3-phenylpropyl) benzenesulfonamide, from 4 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride, 2.16 cm3 of triethylamine, 1.68 cm3 of benzylamine and 45 cm3 of anhydrous tetrahydrofuran. After 1 hour of stirring at a temperature in the region of 20 ° C, the precipitate is filtered, then taken up in dichloromethane and washed with distilled water. 4.45 g of 2-arnino-4,6-dichloro-N-benzylbenzenesulfonamide are thus obtained after the usual treatment, in the form of a solid used as such in the subsequent syntheses. EXAMPLE 8

The procedure is as in Example 6 starting from 1.5 g of 6,8-dichloro-

3,4-dihydro-2-methyl 2H-1, 2,4-benzothiadiazine-1, 1-ethyl oxide-3-carboxylate and 0.57 g of potassium trimethylsilanolate in 13 cm3 of dichloromethane. After 1 hour at a temperature in the region of 20 ° C., the precipitate formed is filtered and then recrystallized from 10 cm 3 of ethanol. We obtain

0.95 g potassium salt of 6,8-dichloro-3,4-dihydro-2-methyl- acid

2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxyIique in the form of crystalline powder melting at a temperature above 260 ° C (Analysis (C H7Cl KN2θ S)% calculated C: 30.95; H : 2.02; Cl.20.30; N: 8.02; S: 9.18;% found (0.14H2O) C: 30.4; H: 2.1; CI-19.6; N: 7 , 8; S: 8.8).

EXAMPLE 9

Under nitrogen, 50 cm3 of a solution of 4. g of 6,8-dichloro-3,4-dihydro 2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d are added dropwise. ethyl in anhydrous tetrahydrofuran, 0.59 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 1.5 cm 3 of methyl iodide in 5 cm 3 of anhydrous tetrahydrofuran is poured dropwise. The reaction medium is then brought to 50 ° C for 1 hour, then concentrated to dryness under reduced pressure. The residue obtained is taken up in water, treated with a 1N aqueous hydrochloric acid solution and the organic phase extracted with ethyl acetate. After usual treatment, the recovered solid is recrystallized from 30 cm3 of ethanol, washed and dried to yield 2.5 g of 6,8-dichloro-3,4-dihydro-2-methyl-2H-1,2,4- benzo thiadiazine-1,1-dioxide-3-carboxylate ethyl in the form of crystalline powder melting at 145 ° C.

EXAMPLE 10

The procedure is as in Example 7, starting with 4 g of 2-amino-4,6-dichlorobenzenesuIfonamide, 3 g of giyoxylic acid, 5.2 cm3 of sulfuric acid and 40 cm3 of absolute ethanol . 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 absolute ethanol to yield 2.8 g of ethyl 6,8-dichloro-3,4-dihydro 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in the form of crystalline powder melting at 204 ° C.

EXAMPLE 11

A 0.63 g of 6,8-dichloro-3,4-dihydro-2-ethoxycarbonylmethyl 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic in solution in 20 cm3 of tetrahydrofuran to at a temperature in the region of 20 ° C., 0.16 g of lithium hydroxide hydrate dissolved in 6 cm 3 of distilled water is added dropwise. The reaction is continued for 7 hours at the same temperature, then the reaction medium concentrated to dryness under reduced pressure and the residue treated with 1N hydrochloric acid. After extraction with ethyl acetate, the solid obtained is recrystallized in acetonitrile to give 0.3 g of 2-carboxymethyl-6,8-dichloro-3,4-dihydro 2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid under as a solid, melting at 257 ° C.

The 6,8-dichloro-3,4-dihydro-2-ethoxycarbonylmethyl-2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid can be prepared as follows: to a solution at reflux of 0.9 g of 2-amino-4,6-dichloro-N-ethoxycarbonyl methylbenzenesulfonamide in 30 cm3 of dioxane, a solution of 0.35 g of giyoxylic acid in 6 cm3 of water is added dropwise distilled. The reaction is continued for 3 hours at reflux, then the reaction medium concentrated to dryness under reduced pressure. After purification by acid-base extraction, 0.63 g of 6,8-dichloro-3,4-dihydro 2-ethoxycarbo nylmethyl-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 is obtained. -carboxyli-that in the form of an oil used as it is in subsequent syntheses.

The 2-amino-4,6-dichloro-N-ethoxycarbonylmethylbenzenesulfonamide is prepared in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 0.7 g of ethyl giycinate is added dropwise to a solution 1.3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 0.7 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is diluted with 20 cm 3 of distilled water and the organic phase extracted with ethyl acetate. 1.5 g of 2-amino-4,6-dichioro-N-ethoxycarbonyl methylbenzene are obtained. sulfonamide in the form of an oil used as it is in subsequent syntheses.

EXAMPLE 12

To a reflux suspension of 1 g of 2-amino-5-chlorobenzenesulfonamide in 20 cm3 of water, a solution of 0.67 g of giyoxylic acid, 0.29 g of sodium hydroxide in 10 cm3 is added over 10 minutes of water. After 1 hour and 30 minutes of reflux, the reaction mixture is cooled to 10 ° C. and acidified with 7 cm 3 of hydrochloric acid N. The precipitate is filtered then redissolved in 4.2 cm 3 of sodium hydroxide N and 10 cm 3 of water. The solution is washed with 2 times 25 cm3 of ethyl acetate and acidified with 5 cm3 of hydrochloric acid N. After filtration and drying at 50 ° C under reduced pressure, 0.87 g of 7-chloro acid is obtained -2H-3,4-dihydro-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic melting at 234 ° C.

The 2-amino-5-chtorobenzenesulfonamide can be prepared according to the method described in US Patent 2,986,573.

EXAMPLE 13

A 2.6 g of 6,8-dichloro-3,4-dihydro-2- (4-trifluoromethylbenzyI) -2H-1,2,4- benzothiadiazine-1, 1-dioxide-3-carboxylic acid in solution in 60 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 0.45 g of lithium hydroxide dissolved in 15 cm3 of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium concentrated to dryness under reduced pressure and the residue treated with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over magnesium sulfate and then concentrated to dryness under reduced pressure to yield 1.2 g of 6,8-dichloro-3,4-dihydro-2- (4 - trifluoromethylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carboxylic in the form of a solid melting at around 110 ° C while decomposing, (Analysis (C ₁ gHιιC.2F ₃ N θ4S) % calculated C: 42.21; H: 2.44; 01: 15.58; F: 12.52; N: 6.15;

S: 7.04; % found (0.50H ₂ O; 0.42 iPr O) C: 41.9; H: 2.4; Cl: 15.7; F: 11.8; N: 6.3; S: 7.2). Ethyl 6,8-dichloro-3,4-dihydro-2- (4-trifluoromethylbenzyl) -2H-1,2,4-benzothia-diazine-1, 1-dioxide-3-carboxylate can be prepared from as follows: to 2.9 g of 2-amino-4,6-dichloro-N- (4-trifluoromethylbenzyl) - benzenesulfonamide in 50 cm3 of absolute ethanol brought to reflux, 1.33 g of giyoxylic acid in solution in 30 cm3 of absolute ethanol in the presence of 2.75 cm3 of concentrated sulfuric acid. The reaction is continued for 2 hours and 30 minutes at reflux, then the reaction medium cooled to a temperature in the region of 0 ° C. The precipitate formed is filtered, washed with ethanol and dried to yield 2.6 g of 6,8-dichloro 3,4-dihydro-2- (4-trifluoromethylbenzyl) -2H-1,2,4 -benzothiadiazine-1, 1 -dioxy-3-ethyl carboxylate in the form of a solid melting at 216 ° C.

2-amino-4,6-dichloro-N- (4-trifluoromethylbenzyl) -benzenesulfonamide can be prepared as follows: under nitrogen and at a temperature in the region of 20 ° C, 2.0 g of (4-trifluoromethyl) Benzylamine dissolved in 10 cm3 of tetrahydrofuran are added dropwise to a solution of 3.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.6 cm3 of triethylamine in 40 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is diluted with 30 cm 3 of distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column with a mixture of dichloromethane and cyclohexane (75/25 by volume) as eluent, 2.9 g of 2-amino-4,6-dichloro-N- (4 -trifluoromethylbenzyl) - benzenesulfonamide in the form of an oil used as it is in the following syntheses.

EXAMPLE 14

The procedure is as in Example 13, starting with 1.5 g of 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1- ethyl dioxide-3-carboxylate, 0.26 g of lithium hydroxide, 40 cm3 of tetrahydrofuran and 10 cm3 of distilled water. After washing the crude product obtained with hexane, 1.0 g of 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethylbenzyl) -2H-1,2,4-benzothiadiazine- is isolated. 1, 1-3-dioxide-carboxylic in the form of a powder melting at 98 ° C. Ethyl 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethyibenzyl) -2H-1,2,4-benzothia-diazfen-1, 1-dioxide-3-carboxylate can be prepared from as follows: under nitrogen and at a temperature in the region of 20 ° C., 3 g of 6,8-dichforo-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 3.57 g of m-trifluoromethylbenzyfe chloride in 25 cm3 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 crystallization from 20 cm 3 of isopropyl ether, 1.5 g of 6,8-dichloro-3,4-dihydro-2- (3-trifluoromethylbenzyl) -2H-1, 2,4-benzothiadiazine -1,1-ethyl dioxide-3-carboxylate are obtained in the form of a solid melting at 178 ° C.

EXAMPLE 15

To a solution of 1.8 g of 2-amino-4,6-dichloro-N- (2-trifluoromethibenzyD-benzenesulfonamide in 35 cm3 of dioxane heated to reflux, a solution of 0.58 g of is added dropwise giyoxylic acid in 10 cm 3 of distilled water, the reaction is continued for 6 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure, the residue is then taken up in an aqueous solution of sodium hydroxide and the organic phase extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with ethyl acetate. recrystallization of the crude product in isopropyl ether, 0.4 g of 6,8-dichloro-3,4-dihydro-2- (2-trifluoromethylbenzyl) -2H-1,2,4-benzo- is obtained. thiadiazine-1, 1-dioxide-3-carboxylic acid in the form of a crystalline powder which melts at 128 ° C while decomposing, (Analysis (C- | gHι ιCl 2F3N2θ4S)% calculated C: 42.21; H: 2.44; CI.15.58; N: 6.15; S: 7.04; % found (0.03H ₂ O;

1, 0îPr2θ) C: 42.1; H: 2.5; Cl: 16.0; N: 6.2; S: 7.4).

2-amino-4,6-dichloro-N- (2-trifluoromethylbenzyl) -benzenes or ifonamide can be prepared in the following manner: to a suspension of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride in 30 cm3 of anhydrous tetrahydrofuran at a temperature in the region of 20 ° C, 1.6 cm3 of triethylamine are added, then a solution of 2 g of o-trifluoromethylbenzylamine in 10 cm3 of tetrahydrofuran. After stirring overnight at this same temperature, the reaction medium is poured into water and the organic phase extracted with ethyl acetate. After recrystallization from acetonitrile, 1.8 g of 2-amino-4,6-dichloro-N- (2-trifluoromethylbenzyl) -benzenesulfonamide are obtained in the form of a melting solid which decomposes at around 200 ° C.

EXAMPLE 16

To 0.9 g of 6,8-dichloro-3,4-dihydro-2- (3-nitrobenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 3.9 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium concentrated to dryness under reduced pressure and the residue treated with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over sodium sulfate. magnesium then concentrated to dryness under reduced pressure. The residue obtained is taken up in petroleum ether and the insoluble material filtered and washed to yield 0.5 g of 6,8-dichloro-3,4-dihydro- 2- (3-nitrobenzyl) -2H acid. -1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic in the form of a solid melting towards 100 ° C while decomposing, (Analysis (C15H11CI2N3O6S)% calculated C.41, 68; H: 2, 57; Cl: 16.40; N: 9.72; S: 7.42;

% found (0.58EtOH; 0.16THF) C: 42.1; H: 2.6; Cl: 16.8; N: 9.8; S: 7.7).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-nitrobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1- 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 in solution in 40 cm3 of anhydrous tetrahydrofuran in a suspension of 0.44 g of 50% sodium hydride in 10 cm3 of the same siant. 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 to reflux for 4 hours, then cooled to a temperature in the region of 20 ° C., poured into 50 cm 3 of distilled water and the organic phase extracted with ethyl acetate. After the usual treatment and purification of the crude product by flash chromatography on a silica column with a mixture of cyclohexane and dichloromethane (60/40 by volume) as eluent, 0.9 g of 6,8-dichloro-3,4- dihydro-2- (3-nitrobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 - ethyl dioxide-3-carboxylate are obtained in the form of a solid melting at 237 ° C.

EXAMPLE 17

The procedure is as in Example 16, starting with 2.4 g of 2- (3-cyanobenzyl) - 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1 -ethyl dioxide-3-carboxylate, 10.8 cm3 of 0.5N sodium hydroxide and 30 cm3 of tetrahydrofuran. After recrystallization of the crude product from acetonitrile, 0.5 g of 2- (3-cyanobenzyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothia-diazine-1 acid , 1-dioxide-3-carboxylic acid are isolated in the form of a powder melting at 238 ° C.

Ethyl 2- (3-cyanobenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be obtained 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-benzothiadazine-1,1-dioxide are added dropwise -3- ethyl carboxylate in solution 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, poured , drop by drop, a solution of 3.7 g of m-cyanobenzyl bromide in 25 cm3 of anhydrous dimethylformamide. The reaction medium is heated at reflux for 4 hours and 30 minutes, 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 by flash chromatography on a silica column with dichloromethane as eluent, 2.4 g of 2- (3-cyanobenzyl) -6,8-dichloro-3,4-dihydro-2H- Ethyl 1,2,4-benzothiadazine-1,1-dioxide-3-carboxylate are obtained in the form of a solid melting at 156 ° C. EXAMPLE 18

A 1.2 g of 6,8-dichloro-3,4-dihydro-2- (4-phenylbenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5 cm3 of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature then the reaction medium concentrated to dryness under reduced pressure. After treatment of the residue obtained with 1N hydrochloric acid, the organic phase is extracted with dichloromethane, to lead, after recrystallization of the crude product in a mixture of cyclohexane and ethyl acetate (75/25 by volume) , to 0.5 g of 6.8-dichloro-3,4-dihydro-2- (4-phenylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxy-3-carboxylic acid under crystalline powder form melting around 130 ° C while decomposing, (Analysis (C2i H- | gCl2N2θ4S)% calculated C: 54.44; H: 3.48;

Cl: 15.30; N: 6.05; 0: 13.81; S: 6.92; % found C: 54.5; H: 3.9; Cl. 14.9; N: 5.7; 0: 13.7; S: 6.6).

Ethyl 6,8-dichloro-3,4-dihydro-2- (4-phenylbenzyl) -2H-1,2,4-benzothiadiazine-1,1-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 30 minutes of stirring at the same temperature, a solution of 2.8 g of p-phenylbenzyl 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 dichloromethane. After the usual treatment and washing of the crude product with acetonitrile, 1.2 g of 6,8-dichloro-3,4-dihydro-2- (4-phenylbenzyl) -2H- 1,2,4-benzothiadiazine- Ethyl 1, 1-dioxide-3-carboxylate are obtained in the form of a white solid, melting at 177 ° C. EXAMPLE 19

The procedure is as in Example 18, starting with 1.5 g of 6,8-dichloro-3,4-dihydro-2- (2-pyridylmethyl) -2H-1,2,4-benzothiadazine-1,1 -ethyl dioxide-3-carboxy late, 7.2 cm3 of 0.5N sodium hydroxide and 15 cm3 of tetrahydrofuran. 1.0 g of 6,8-dichloro-3,4-dihydro-2- (2-pyridyimethyl) -2H-1,2,4-benzothiadiazoin-1,1-3-carboxylic-3-carboxylic acid is obtained. crystalline powder melting at 264 ° C.

Ethyl 6,8-dichioro-3,4-dihydro-2- (2-pyridylmethyl) -2H-1,2,4-benzothîadiazine-1, 1-dioxide-3-carboxylate can be obtained as follows : under nitrogen and at a temperature in the region of 20 ° C., 3 g of 6,8-dichoro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3- ethyl carboxylate in solution in 40 cm3 of anhydrous tetrahydrofuran in a suspension of 0.44 g of sodium hydride at 50% in 10 cm3 of the same solvent After 30 minutes of stirring at the same temperature, poured , drop by drop, a solution of 2.36 g of 2-chioromethylpyridine in 25 cm3 of anhydrous dimethylformamide. 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 dichloromethane. After the usual treatment and purification of the crude product by flash chromatography on a silica column using dichloromethane as eluent, 1.5 g of 6,8-dichloro-3,4-dihydro-2- (2-pyridylmethyl) -2H -1,4,4-Benzothiadiazine-1, 1-dioxide-3-ethyl carboxylate are obtained in the form of a white solid melting at 136 ° C.

EXAMPLE 20

The procedure is as in Example 18, starting with 1.16 g of 6,8-dichloro-3,4-dihydro-2- (2-qu.notylmethyl) -2H-1, 2,4-benzothiadiazine-1 , Ethyl 1-dioxide-3-carboxylate, 4.97 cm3 of 0.5N sodium hydroxide and 10 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the precipitate formed filtered, washed with water and then with ether. isopropyl. After washing with methanol, 0.68 g of 6,8-dichloro-3,4-dihydro-2- (2-quinolylmethyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- acid carbonyl are thus obtained in the form of crystalline powder infusible up to 260 ° C on the Kόfler bench, (Analysis (C- | ₈ H- | 3Cl2N3θ4S)% calculated C: 49.33; H: 2.99; Cl : 16.18; N: 9.59; 0: 14.60; S: 7.32;% found (0.10H ₂ O; 0.05CH ₂ Cl2) C: 49.2; H: 3.0; Cl: 16.0; N: 9.7; 0: 14.6; S: 7.3).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-quinolylmethyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared according to the following process : 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 30 minutes of stirring at the same temperature, a solution of 2.45 g of 2-chloromethylquinoline in 25 cm 3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 5 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 dichloromethane. After the usual treatment and purification of the crude product by flash chromatography on a silica column using dichloromethane as eluent, 1.16 g of 6,8-dichloro-3,4-dihydro-2- (2-quinolylmethyl) -2H -1, 2,4-Benzothiadiazine-1, 1-dioxide-3-carbo xylate of ethyl are obtained in the form of a pale solid used as it is in the following syntheses.

EXAMPLE 21

The procedure is as in Example 18, starting with 2.1 g of 6,8-dichloro-3,4-dihydro-2- (1-naphthylmethyl) -2H-1, 2,4-benzothiadiazine-1, 1 -dioxide-3-carbo xylate, 9 cm3 of 0.5N sodium hydroxide and 25 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the precipitate formed filtered, washed with water and then with dichloromethane. 1.52 g of 6,8-dichloro-3,4-dihydro-2- (1- naphthylmethyl) -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carboxylic are thus obtained in the form of crystalline powder melting while decomposing around 140 ° C, (Analysis (C-fgH- | 4Cl N2θ4S) % calculated C: 52.19; H: 3.23;

CI: 16.21; N: 6.41; S: 7.33; % found (0.65H ₂ O) C: 51.8; H: 3.3; Cf: 15.8; N: 6.1; S: 7.1).

Ethyl 6,8-dichloro-3,4-dihydro-2- (1-naphthylmethyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be obtained 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 30 minutes of stirring at the same temperature, a solution of 3 g of 1- (bromornethyl) naphthalene in 25 cm3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 3 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 dichloromethane. After the usual treatment and washing of the crude product with methanol, 2.1 g of 6,8-dichloro-3,4-dihydro-2- (1-naphthylmethyl) -2H-1, 2,4-benzothiadiazine-1, Ethyl 1-dioxide-3-carboxylate are obtained in the form of a crystalline powder melting at 191 ° C.

EXAMPLE 22

The procedure is as in Example 18, starting with 0.84 g of 6,8-dichloro-3,4-dihydro-2- [3- (naphtho [1, 8-cd] isothiazol-1, 1-dioxide -2-yl) propyl] -2H-1, 2,4-ben-zothiadiazine-1,1-dioxide-3-ethyl carboxylate, 2.9 cm3 of 0.5N sodium hydroxide and 10 cm3 of tetrahydrofuran . After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with dichloromethane. After purification of the crude product by flash chromatography on a silica column with a mixture of dichloromethane and methanol (98/2 by volume) as eluent, 0.5 g of 6,8-dichloro-3,4- acid is isolated dihydro-2- [3- (naphtho [1,8-cd] isothiazol-1,1-dioxide-2-yl) pro- pyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic in the form of powder melting while decomposing around 100 ° C (Analysis (C2i Hι Cl2N ₃ 0gS2)% calculated C: 46.50 ; H: 3.16; Cl: 13.07; N: 7.75; S: 11.82;% found (0.48H ₂ O; 0.37acetone) C: 46.9; H: 3.1; Cl: 13.4; N: 7.5; S: 12.1).

6,8-dichloro-3,4-dihydro-2- [3- (naphtho [1, 8-cd] isothiazol-1, 1-dioxide-2- yl) propyl] -2H-1, 2,4- ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.14 g of naphtho [1,8-cd] isothiazol-1 , 1-dioxide dissolved in 16 cm3 of anhydrous tetrahydrofuran are added dropwise to 0.12 g of 50% sodium hydride suspended in 16 cm3 of the same solvent. After 30 minutes of stirring at the same temperature, a solution of 2 g of 2- (3-chloropropyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1 -dio xyde-3-carboxylate in 16 cm3 of anhydrous dimethylformamide is gradually poured into the reaction medium. After 20 hours of stirring at reflux, the suspension is concentrated to dryness under reduced pressure and the residue taken up in a mixture of water and dichloromethane. The organic phase is separated, dried, filtered and concentrated to yield, after purification of the crude product by flash chromatography on a silica column with a mixture of dichloromethane and cyclohexane (90/10 by volume) as eluent, to 0.84 g of 6,8-dichloro-3,4-dihydro-2- [3- (naphtho [1, 8- cd] isothiazol-1,1-dioxide-2-yl) propyl] -2H-1,2,4-benzothiadiazine -1,1-Dioxide-3-ethyl carboxylate in the form of a solid melting, decomposing around 80 ° C.

Ethyl 2- (3-chioropropyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be obtained as follows : under nitrogen and at a temperature in the region of 20 ° C., 10 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3- ethyl carboxylate dissolved in 50 cm3 of anhydrous tetrahydrofuran in a suspension of 1.44 g of 50% sodium hydride in 50 cm3 of the same solvent. After 30 minutes of stirring at the same temperature, a solution of 4.5 cm3 of 1-bromo-3-chloropropane in 50 cm3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 6 hours, then cooled to a temperature in the region of 20 ° C and concentrated to dryness under reduced pressure. The organic phase is extracted with dichloromethane and washed with water. After usual treatment and filtration of the crude product with silica with dichloromethane as eluent, 6.0 g of 2- (3-chloropropyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4- benzothiadiazine -1,1-ethyl dioxide-3-carboxylate are obtained in the form of a crystalline powder melting at 170 ° C.

EXAMPLE 23

The procedure is as in Example 18, starting with 1.64 g of 6,8-dichloro-3,4-dihydro-2- [3- (5,6-dihydro-1H, 4H-1,2,5 -thiadîazolo [4,3,2-ij] quinolyl-2,2-dio xyde) propyl] -2H-1,2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate, 5.7 cm3 0.5N sodium hydroxide and 10 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with dichloromethane. After purification of the crude product by flash chromatography on a silica column with a mixture of dichloromethane and methanol (95/5 by volume) as eluent and recrystallization from a mixture of isopropyl ether and ethyl acetate, 0 is isolated. , 3 g of 6,8-dichloro-3,4-dihydro-2- [3- (5,6-dihydro-1H, 4H-1, 2,5-thiadiazolo [4,3,2-ijlquinolyl- 2,2-dioxide) propyl] -2H-1, 2,4-benzothiadiazine-1, 1-3-carboxy-dioxide in the form of crystalline powder melting while decomposing around 130 ° C (Analysis (C2θH20 ^cl 2 ^N 4 ° 6 ^s 2) ^% calculated C: 43.88; H: 3.68; Cl: 12.95; N: 10.23; S: 11.71;% found (0.77H ₂ O; 0.94iPr ₂ O ) C: 44.2;

H: 3.6; CI: 12.6; N: 10.1; S: 12.0).

6,8-Dichloro-3,4-dihydro-2- [3- (5,6-dihydro-1 H, 4H-1,2,5-thîadiazo (o [4,3,2- ij] quinolyI- 2,2-dioxide) propyQ-2H-1, 2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate can be obtained in the following way: under nitrogen and at a temperature close to 20 ° C, 1.5 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1,1-3-dioxide-3-carboxylate are added dropwise dissolved in 12 cm3 of anhydrous tetrahydrofuran in a suspension of 0.22 g of 50% sodium hydride in 12 cm3 of the same solvent. After 30 minutes of stirring at the same temperature, a drop is poured in. 2.65 g solution of 1- (3-chloropropyl) -5,6-dihydro- 1 H, 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide in 12 cm3 of anhydrous dimethylformamide. The reaction medium is heated at reflux for 4 hours, then cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The organic phase is extracted with dichloromethane and washed with water. After usual treatment and purification of the crude product by flash chromatography on a silica column with a mixture of dichloromethane and cyclohexane (90/10 by volume) as eluent, 1.31 g of 6,8-dichloro-3,4-dihydro -2- [3- (5,6-dihydro-1H, 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide) propyl] -2H-1, 2, Ethyl 4-benzothiadiazine-1, 1-dioxide-3-carboxylate are obtained in the form of a white foam exfoliating at around 80 ° C.

1- (3-chloropropyl) -5,6-dihydro-1 H, 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide can be obtained according to the following method : under nitrogen and at a temperature in the region of 0 ° C., 12.5 g of potassium salt of 5,6-dihydro-1 H. 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinoline -2,2-dioxide are suspended in 230 cm3 of anhydrous dimethylformamide. 8.65 g of 1-bromo-3-chloro-propane dissolved in 70 cm 3 of the same solvent are gradually added. The reaction is continued for 72 hours at a temperature in the region of 20 ° C., the reaction medium concentrated to dryness under reduced pressure and then the organic phase extracted with dichloromethane. After the usual treatment, the crude product is purified by filtration on a silica column with dichloromethane as eluent. 9.6 g of 1- (3-chloropropyl) - 5,6-dihydro-1 H. 4H-1 are thus obtained, 2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide in the form of an oil which crystallizes used as it is in the subsequent syntheses.

EXAMPLE 24

The procedure is as in Example 13, starting with 1.37 g of 6,8-dichloro 3,4-dihydro-2-phenyl-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 ethyl carboxylate, 0.14 g of lithium hydroxide, 15 cm 3 of tetrahydrofuran and 7.5 cm 3 of distilled water. The insoluble material, obtained after acidification of the aqueous phase, is fliterated, washed with water, then purified by flash chromatography on a silica column with a mixture of dichloromethane and methanol (95/5 by volume) as eluent. Is isolated, after recrystallization from absolute ethanol, 0.22 g of 6,8-dichloro-3,4-dihydro-2-phenyl-2H-1, 2,4- acid hydrate benzothiadiazine-1, 1-dioxide-3-carboxylic acid in the form of a powder whose melting point is higher than 260 ° C on the Kofler bench (Analysis (C14H10CI2N2O4S)% calculated C: 45.06; H: 2.70 ; Cl: 19.00; N: 7.51; S: 8.59;

% found (1.0H2θ; 0.46EtOH) C: 44.7; H: 2.4; Cl: 18.6; N: 7.4; S: 8.5).

EXAMPLE 25

To a reflux solution of 4 g of 2-amino-4,6-dichloro-N-phenyl-benzenesulfonamide in 100 cm 3 of absolute ethanol, a solution of 1.16 g of giyoxylic acid in a solution is added dropwise. mixture of 60 cm3 of absolute ethanol and 5.3 cm3 of concentrated sulfuric acid. After 2 hours of stirring at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C., concentrated to dryness under reduced pressure and the organic phase extracted with dichloromethane. 1.37 g of 6,8-dichloro-3,4-dihydro-2-phenyl-2H-1, 2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in powder form are obtained. crystalline melting at 159 ° C.

The 2-amino-4,6-dichloro-N-phenyl-benzenesulfonamide can be prepared as follows: under nitrogen and at a temperature in the region of 20 ° C, a solution of 2.1 cm3 of aniline and 25 cm3 of tetrahydrofuran is added dropwise to a solution of 6.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 3.24 cm3 of triethylamine in 50 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated under reduced pressure and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column with dichloromethane as eluent, 5.6 g of 2-amino-4,6-dichloro-N-phenyl-benzenesulfonamide are obtained in the form of a powder melting at 112 ° C.

EXAMPLE 26

The procedure is as in Example 1 &, starting from 0.43 g of 2-cyclopropylmethyl-6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1 _. , Ethyl 1-dioxide-3-carboxylate, 2.26 cm3 of 0.5N sodium hydroxide and 5 cm & of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the precipitate formed filtered and washed with water. 0.24 g of 2-cyclopropylmethyl-6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothia-diazine-1, 1-dioxide-3-carboxylic acid are thus obtained in the form of crystalline powder melting as it decomposes around 110 ° C, (Analysis (C12H12CI2N2O4S)% calculated C: 41, 04; H: 3.44; Cl.20.19; N: 7.98; S.9.13;

O%;> found (1.20H ₂ O) C: 40.7; H: 3.1; Cl: 20.1; N: 7.9; S: 9.6).

Ethyl 2-cyclopropylmethyl-6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be obtained in the following manner: 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-3-carboxylate are added dropwise ethyl in solution in 25 cm3 of anhydrous tetrahydrofuran in a suspension of 0.44 g of 50% sodium hydride in 25 cm3 of the same solvent. After 30 minutes of stirring at the same temperature, a solution of 1.34 cm3 of bromomethylcyclopropane in 25 cm3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 3 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 dichloromethane. After the usual treatment and purification of the crude product by flash chromatography on a silica column with a mixture of dichloromethane and cyclohexane (60/40 by volume) as eluent, 0.43 g of 2-cyclopropylmethyl-6,8-dichloro-3 , 4-dihydro-2H- 1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate ethyl are obtained in the form of a crystalline powder melting at 193 ° C. EXAMPLE 27

The procedure is as in Example 18, starting with 0.88 g of 6,8-dichloro-3,4-dihydro-3- (3-phenoxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 - ethyl dioxide-3-carbo xylate, 3.5 cm3 of 0.5N sodium hydroxide and 8 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane. The aqueous phase is acidified using 1N hydrochloric acid and then made clear by adding acetone. After dry concentration under reduced pressure and washing of the solid thus obtained using pentane, 0.46 g of 6,8-dichloro-3,4-dihydro-2- (3-phenoxybenzyl) -2H-1 acid, 2,4-Benzothiadiazine-1, 1-3-oxide-3-carboxylic acid are isolated in the form of crystalline powder melting by erasing around 80 ° C. (Analysis (C21H18CI2N2O5S)% calculated C: 52.62; H: 3.36; CI: 14.79; N: 5.84;

0: 16.69; S: 6.69; % found C: 52.6; H: 3.6; Cl: 14.5; N: 5.6; 0: 16.5; S: 6.3).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-phenoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen and at a temperature in the region of 20 ° C., 2.22 g of 6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1 are added dropwise -dioxide-3-ethyl carboxylate dissolved in 15 cm3 of anhydrous tetrahydrofuran, to a suspension of 0.33 g of 50% sodium hydride in 15 cm3 of tetrahydrofuran. After 30 minutes of stirring, a solution of 3 g of 3-phenoxybenzyl chloride in 15 cm3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 4 hours, cooled to a temperature in the region of 20 ° C and poured into 50 cm3 of distilled water. The organic phase is extracted with dichloromethane. After usual treatment and purification of the crude product by recrystallization from absolute ethanol, 0.88 g of 6,8-dichloro-3,4-dihydro-2- (3-phenoxybenzyl) -2H-1, 2,4-benzothiadiazine -1, 1 - ethyl dioxide-3-carboxylate are obtained in the form of a crystalline powder melting at 149 ° C.

EXAMPLE 28

The procedure is as in Example 18, starting from 0.78 g of 6,8-dichloro-3,4-dihydro-2- (3-vinylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 -ethyl dioxide-3-carboxyla te, 3.5 cm3 of 0.5N sodium hydroxide and 5 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane. The aqueous phase is acidified using 1N hydrochloric acid and the precipitate formed is filtered and washed with water. 0.71 g of 6,8-dichloro-3,4-dihydro-2- (3-vinylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dio-xyde-3-carboxylic acid are isolated in the form of a crystalline powder melting in decomposing around 130 ° C (Analysis (C-i7H- | 4Cl2N2θ4S)% calculated

0: 49.41; H: 3.41; 01: 17.16; N: 6.78; S: 7.76; % found 0: 49.1; H: 3.3; 01: 16.8; N: 6.7; S: 7.9).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-vinylbenzyl) -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., 6 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3- ethyl carboxylate dissolved in 30 cm3 of anhydrous tetrahydrofuran, in a suspension of 0.89 g of 50% sodium hydride in 30 cm3 of tetrahydrofuran. After 30 minutes of stirring, a solution of 5.25 cm3 of 3-vinylbenzyl chloride in 30 cm3 of anhydrous dimethylformamide is poured in dropwise. The reaction medium is heated at reflux for 6 hours, cooled to a temperature in the region of 20 ° C, poured into 50 cm3 of distilled water and the organic phase extracted with dichloromethane. After usual treatment and purification of the crude product by flash chromatography on a silica column using a dichloromethane-cyclohexane mixture (50/50 by volume) as eluent, 2.77 g of 6,8-dichloro-3,4-dihydro- 2- (3-vinylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dio xyde-3-carboxylate ethyl are obtained in the form of a crystalline powder melting at 189 ° C.

EXAMPLE 29

The procedure is as in Example 18, starting with 0.65 g of 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 -ethyl dioxide-3-carboxyate, 3 cm3 of 0.5N sodium hydroxide and 5 cm3 of tetrahydrofuran. After stirring overnight at a temperature in the region of 20 ° C., the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with dichloromethane. The aqueous phase is acidified using 1N hydrochloric acid and the precipitate formed is filtered and washed with acetonitrile. 0.40 g of 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H- 1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid dihydrate are isolated in the form of a crystalline powder which melts as it decomposes around 200 ° C (Analysis Cl5H 3Cl2N ₃ 0 S)% calculated 0: 41.11; H: 3.91; 01: 16.18; N: 9.59; S: 7.32; % found C: 40.9; H: 3.2; Cl: 16.0; N: 9.6; S: 7.4).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxyfate can be prepared as follows : 1.2 g of 6,8-dichloro-3,4-dihydro-3- (3-nitrobenzyl) -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxyfate in solution in 140 cm3 of absolute ethanol are stirred 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 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate are thus isolated in the form of a crystalline powder melting at 174 ° C.

EXAMPLE 30

To a reflux suspension of 1 g of 2-amino-4-chloro-beπzènesulfonamide in 20 cm3 of distilled water, a solution of 0.67 g of giyoxylic acid and 0.29 g of sodium hydroxide is added dropwise in tablets in 10 cm3 of distilled water. After 1 hour and 30 minutes of reflux, the reaction medium is cooled to a temperature in the region of 0 ° C. and then acidified using a 1N hydrochloric acid solution. The precipitate formed is filtered and washed with water. 0.6 g of 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid hydrate is obtained in the form of a beige powder melting at 216 ° C.

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

EXAMPLE 31

A 1.9 g of 6,8-dichloro-3,4-dihydro-2- (2-phenoxyethyl) -2H-1,2,4- benzothiadiazirie-1,1-d.oxyde-3-carboxy.ate d ethyl in solution in 15 cm3 of dichloromethane at a temperature in the region of 20 ° C., 0.547 g of potassium trimethylsilanolate is gradually added. The reaction is continued for 15 hours at the same temperature, then the reaction medium is added to 50 cm3 of distilled water and acidified with 1N hydrochloric acid. The organic phase is extracted with dichloromethane, dried over magnesium sulfate and then concentrated. dry under reduced pressure to lead, after recrystallization from acetonitrile, to 0.47 g of 6,8-dichloro-3,4-dihydro-2- (2-phenoxyethyl) -2H-1, 2,4-benzothiadiazine acid -1, 1-3-dioxide-carboxylic acid in the form of a white solid, melting at 211 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-phenoxyethyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3.7 g of 1-bromo-2-phenoxyethane in 25 cm3 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 water. The organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using dichloromethane as eluent. 1.9 g of 6,8-dichloro-3,4-dihydro- 2- (2-phenoxyethyl) -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid are obtained under form of an oil used as it is in the subsequent steps.

EXAMPLE 32

Under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d are added dropwise. ethyl in anhydrous tetrahydrofuran, at 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.68 g of 4-fluorobenzyl chloride in 25 cm 3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for

5 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 40 cm3 of distilled water and the organic phase extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by recrystallization from acetonitrile. 1.5 g of 6,8-dichloro-3,4-dihydro-2- (4-fluorobenzyi) -2H-1, 2,4-benzothia diazine-1,1-dioxide-3-carboxylate are thus obtained. ethyl in the form of a white solid, melting at 201 ° C.

EXAMPLE 33

To 1.1 g of 6,8-dichloro-3,4-dihydro-2- (4-fluorobenzyl) -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylic acid in solution 0.21 g of lithium hydroxide dissolved in 5 cm3 of distilled water is added dropwise to 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over sulphate of magnesium then concentrated to dryness under reduced pressure to yield 0.5 g of 6,8-dichloro-3,4-dihydro-2- (4- f IuorobenzyI) -2H-1, 2,4-benzothiadiazine- acid 1, 1-3-dioxide-carboxylic in the form of a white solid decomposing at 94 ° C (Analysis (C15H11CI2F 2O4S)% calculated 0: 44.46; H: 2.74; Cl: 17.50; F: 4.69; N: 6.91; 0: 15.79; S: 7.91;% found (0.22 Et ₂ O) C: 44.5; H: 2.8; CI: 17.4; F : 4.7; N: 6.9; 0: 15.7; S: 8, 1).

EXAMPLE 34

A 1.3 g of 6,8-dichloro-3,4-dihydro-2- (4-methylbenzyl) -2H-1,2,4-benzothiadazine-1, 1-l-dioxide-3-carboxylate in solution 0.25 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise to 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C. The reaction is continued for 15 hours at the same temperature, then the reaction medium concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over magnesium sulphate then concentrated to dryness under reduced pressure to yield 1.0 g of 6,8-dichoro-3,4-dihydro-2- (4 - methylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carboxy liquefied as a white solid decomposing at 103 ° C (Analyzed (C-I6H14CI2N2O4S)% calculated C: 47.89; H: 3.52; 01: 17.67; N: 6.98; 0: 15.95; S: 7.99; % found C: 47.9; H: 3.8; 01: 17.5; N: 6.5; 0: 15.7; S: 8.1).

Ethyl 6,8-dichloro-3,4-dihydro-2- (4-methylbenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, with 0.44 g of 50% sodium hydride. suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3.4 g of α-bromo-p-xylene in 25 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness The crude product is purified by flash chromatography on a column of silica using a mixture of dichloromethane and cyclohexane (50/50 by volume) as eluent. 1.5 g of 6,8-dichloro-3,4-dihydro-2- (4-methylbenzyl) -2H-1,2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylate are thus obtained. in the form of a white solid, melting at 184 ° C.

EXAMPLE 35

Under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy late are added dropwise. ethyl in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3.4 g of α-bromo-m-xylene is poured in dropwise into 25 cm3 of dimethylformamide. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (50/50 by volume) as eluent. 1.7 g of 6.8-dichloro-3,4-dihydro are thus obtained. -2- (3-methylbenzyI) -2H-1, 2,4-benzothiadrazine-1, 1-ethyl dioxide-3-carboxylate in the form of a white solid, melting at 129 ° C.

EXAMPLE 36

A 1.2 g of 6,8-dichloro-3,4-dihydro-2- (3-methylbenzyl) -2H-1,2,4- benzothiadiazine-1, 1-dioxide-3-carboxylic acid in solution 0.23 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise to 25 cm ³ of tetrahydrofuran at a temperature in the region of 20 ° C.

The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with hydrochloric acid 1. The organic phase is extracted with ethyl ether, dried over magnesium sulfate and then concentrated to dryness under reduced pressure to yield 1.0 g of 6,8-dichloro-3,4-dihydro-2- (3 - methylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carboxylic in the form of a white solid decomposing around 100 ° C (Analysis (Cι Hι Cl2 2θ4S)% calculated C: 47, 89; H: 3.52; 01: 17.67; N: 6.98; 0: 15.95;

S: 7.99; % found (0.28 Et ₂ O) C: 48.0; H: 3.5; 01: 17.7; N: 6.7; 0: 15.6; S: 8.4).

EXAMPLE 37

A 2 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylthioethyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 25 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 0.18 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The precipitate obtained is filtered, washed with water and then with dichloromethane and recrystallized from acetonitrile to yield 0.91 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylthioethyl) -2H-1, 2,4-benzothiadîa zine-1, 1- acid dioxide-3-carboxyl.que in the form of a white powder melting at 224 ° C.

Ethyl 6,8-dichloro-3 _J 4-dihydro-2- (2-phenylthioethyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : to 3.6 g of 2-amino-4,6-dichloro-N- (2 phenylthioethyl) -benzenesulfonamide in 100 cm3 of absolute ethanol heated to reflux, dropwise added 1.92 g of giyoxylic acid in solution in 45 cm3 of absolute ethanol in the presence of 4.7 cm3 of concentrated sulfuric acid. The reaction is continued for 2 hours at reflux, then the reaction medium cooled to a temperature in the region of 20 ° C. The organic phase is extracted with dichloromethane, washed with water and then dried and concentrated to dryness under reduced pressure. The crude product is purified by flash chromatography on a silica column using dichloromethane as eluent. After recrystallization from isopropanol, 3.2 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylthioethyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide- are obtained. Ethyl 3-carboxylate in the form of a white solid, melting at 120 ° C.

The 2-amino-4,6-dichloro-N- (2-phenylthioethyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.76 g of 2-phenylthioethylamine in solution in 10 cm3 of tetrahydrofuran are added dropwise to a solution of 3.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.6 cm3 of triethylamine in 25 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is filtered and the filtrate concentrated to dryness under reduced pressure. The residue obtained is taken up in 30 cm3 of distilled water and the organic phase extracted with dichloromethane. 3.6 g of 2-amino-4,6-dichloro-N- (2-phenylthioethyl) -benzenesulfonamide are obtained in the form of a brown oil used without further purification in the following step.

EXAMPLE 38

Under nitrogen, 40 cm 3 of a solution of 2.5 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- are added dropwise. ethyl carboxy late in anhydrous tetrahydrofuran, 0.37 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.53 g of 4-chlorobenzyl chloride in 20 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 2 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 40 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The raw process is purified by recrystallization from acetonitrile. 1.4 g of 6,8-dichloro-3,4-hydro-2- (4-chlorobenzyl) -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate are thus obtained. ethyl in the form of a white solid, melting at 213 ° C.

EXAMPLE 39

To 1 g of 6,8-dichloro-3,4-dihydro-2- (4-chlorobenzyl) -2H-1,2,4-benzothiadiazite-1,1-dioxide-3-carboxylate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 0.19 g of lithium hydroxide dissolved in 7 cm3 of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in 10 cm3 of distilled water and then acidified with 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried to yield 0.46 g of 6,8-dichloro-3,4-dhydro-2- (4-chlorobenzyl) -2H-1, 2.4 acid -benzothiadiazine-1, 1 - dioxide-3-carboxylic acid in the form of a white solid melting at 125 ° C.

EXAMPLE 40

To 1.1 g of 6,8-dichloro-3,4-dihydro-2- (2-methylbenzyl) -2H-1,2,4- benzothiadiazine-1, 1-l-dioxide-3-carboxyiate in solution 0.22 g of lithium hydroxide dissolved in 8 cm ³ of distilled water is added dropwise to 25 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in 20 cm3 of distilled water and then acidified with IN hydrochloric acid. The organic phase is extracted with ethyl ether, washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure to lead, after beating in isopropyl ether, to 0.57 g of acid

6,8-dichloro-3,4-dihydro-2- (2-methylbenzyl) -2H-1, 2,4-benzothiadïazine-1, 1 - 3-carboxylic dioxide in the form of white meringue decomposing at around 95 ° C (Analysis (C16H1 CI2N2O S)% calculated C: 47.89; H: 3.52; 01: 17.67; N: 6.98; S: 7.99;% found (0.19H ₂ 0; 0, 41 iPr ₂ 0) C: 48.4; H: 3.5; Cl: 18.1; N: 6.7; S: 8.2). Ethyl 6,8-dichloro-3,4-dihydro-2- (2-methylbenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 30 cm3 of a solution of 2.5 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 are added dropwise -carboxy late of ethyl in anhydrous tetrahydrofuran, with 0.37 g of sodium hydride at 50% in suspension in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.84 g of α-bromo-o-xylene in 20 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 5 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (50/50 by volume) as eluent. 1.1 g of 6,8-dichloro-3,4-dihydro -2- (2-methylbenzyl) -2H-1,2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylate are thus obtained. in the form of a white solid, melting at 162 ° C.

EXAMPLE 41

A 1.36 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylsulfonylethyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5.5 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 is concentrated to dryness under reduced pressure. The residue is taken up in water and then acidified with 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure to lead to

0.34 g 6,8-dichloro-3,4-dihydro-2- (2-phenylsulfonylethyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in powder form white melting at 221 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-phenylsulfonylethyl) -2H-i, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylate can be obtained in this way following: to 2 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylthioethyl) -2H-1, 2,4- ethyl benzothiadiazine-1,1-dioxide-3-carboxyiate dissolved in 20 cm3 of dichloromethane at a temperature in the region of 20 ° C, 2.7 g of 55% m-chloroperbenzoic acid are added in approximately 15 minutes . After 15 hours of stirring at the same temperature, the insoluble material is filtered and the filtrate concentrated to dryness under reduced pressure. The residue is taken up in 25 cm3 of absolute ethanol and the insoluble material is filtered and dried to yield 1.36 g of 6,8-dichloro-3,4-dihydro-2- (2-phenylsulfonylethyl) -2H-1 , 2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in the form of an orange powder melting at 204 ° C.

EXAMPLE 42

To 1.58 g of 6,8-dichloro-3,4-dihydro-2-benzoylmethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 7.1 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 1 hour at the same temperature. The precipitate formed is filtered, washed with water and then with isopropyl ether. The solid obtained is taken up in a mixture of acetone (15 cm3) and water (15 cm3) and then treated with 1N hydrochloric acid. The insoluble material is filtered and washed to yield 0.37 g of 6,8-dichloro-3,4-dihydro-2-benzoylmethyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-3 acid -carboxyIique in the form of white powder melting at 130 ° C as it decomposes.

Ethyl 6,8-dichloro-3,4-dihydro-2-benzoylmethyl-2H-1, 2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 40 cm3 of a solution of 2.86 g of 6.8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate are added dropwise ethyl in anhydrous tetrahydrofuran, with 0.42 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.72 g of chloroacetophenone in 20 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 40 cm3 of distilled water and the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column in using dichloromethane as eluent and recrystallization of the product obtained in isopropanol. 1.58 g of 6,8-dichloro-3,4-dihydro-2-benzoylmethyl-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid are thus obtained in powder form cream melting at 166 ° C.

EXAMPLE 43

To a solution of 1.8 g of 2-amino-4,6-dichloro-N- (3-fluorobenzyl) benzenesulfonamide dissolved in 40 cm3 of dioxane heated to reflux, a solution of 0 is added in approximately 20 minutes. 71 g of giyoxylic acid in 10 cm3 of distilled water. The reaction is continued for 4 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is then taken up in an aqueous sodium hydroxide solution and the organic phase extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with ethyl ether. After usual treatment and washing with isopropanol, 0.45 g of 6,8-dichioro-3,4-dihydro-2- (3-fluorobenzyl) -2H-1, 2,4-benzothiadiazine-1 is obtained. , 1 - 3-carboxylic dioxide in the form of a white powder melting at 190 ° C.

2-amino-4,6-dichloro-N- (3-fluorobenzyl) -benzenesulfonamide can be obtained in the following way: under nitrogen and at a temperature in the region of 20 ° C, 2.09 cm3 of 3-fluorobenzylamine in solution in 20 cm3 of tetrahydrofuran are added dropwise to a solution of 4.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.15 cm3 of triethylamine in 20 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is filtered and the filtrate concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane as eluent (80/20 by volume), 1.82 g of 2-amino-4,6-dichloro-N- (3 -fluorobenzyl) -benzene sulfonamide in the form of a white powder melting at 88 ° C. EXAMPLE 44

At 1.4 g of 6,8-dichloro-3,4-dihydro-2- (2-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxy! Ate dissolved in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 6.3 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 4 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The precipitate formed is filtered, beaten in isopropanol then in pentane, then in again filtered and dried, to give 0.95 g of 6,8-dichloro-3,4-dihydro-2- (2-methoxybenzyI) -2H-1, 2,4-benzothiadiazine-1, l-dioxide acid -3-carboxylic in the form of white powder decomposing at around 80 ° C (Analysis (Cι ₆ H ₁₄ Cl2N2θ5S)% calculated C: 46.07; H: 3.38; 01: 16.99; N: 6.71; S: 7.68;

% found (0.22H ₂ O; 0.96îPrOH; C: 46.4; H: 2.9; Cl: 17.2; N: 6.9; S: 8.1).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : 2.76 g of 2-amino-4,6-dichloro-N- (2-methoxybenzyl) -benzenesuIfonamide in 45 cm3 of absolute ethanol brought to reflux, 1.4 g of giyoxylic acid are added dropwise dissolved in 45 cm3 of absolute ethanol in the presence of 3 cm3 of concentrated sulfuric acid. The reaction is continued for 2 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. After evaporation of approximately 50 cm3 of ethanol under reduced pressure, the precipitate formed is filtered and dried. The crude product is purified by recrystallization from 20 cm3 of absolute ethanol; 2.41 g of 6,8-dichloro-3,4-dihydro-2- (2-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1, 1 - ethyl dioxide-3-carboxyIate are obtained under form a white solid, melting at 133 ° C.

The 2-amino-4,6-dichloro-N- (2-methoxybenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 3.6 cm3. of 2-methoxybenzylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 6.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 3.23 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After a night of commotion in at the same temperature, the reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After washing the crude product with acetonitrile, 2.76 g of 2-amino-4,6-dichloro-N- (2-methoxybenzyD-benzenesulfonamide) are obtained in the form of a white solid, melting at 127 ° C.

EXAMPLE 45

At 1.87 g of 6,8-dichloro-3,4-dihydro-2- [2- (phenethylthio) ethyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate ethyl in solution in 15 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 7.6 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The precipitate formed is filtered and purified by flash chromatography on a silica column using a mixture of dichloromethane and methanol (95/5 by volume) as eluent. 0.3 g of 6,8-dichloro-3,4-dihydro-2- [2- (phenethylthio) ethyl] -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3- is obtained. carboxylic in the form of white powder melting at 181 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- [2- (phenethylthio) ethyl] -2H-1,2,4-benzothiadia zine-1, 1-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 60 cm3 of a solution of 6 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3-ethyl carbo xylate in anhydrous tetrahydrofuran, at 0.89 g of 50% sodium hydride suspended in 40 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 9.2 g of 1-chloro-2- (phenethylthio) -ethane in 50 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 16 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (85/15 in volumes) as eluent. 5.07 g of 6.8-dichloro-3,4-dihydro- 2- [2- (phenethylthio) ethyl] -2H-1,2,4-benzothiadazine-1, 1-3-carboxy-3-carboxy are thus obtained. ethyl late in the form of a brown oil used as it is in subsequent syntheses.

EXAMPLE 46

To 1.05 g of 6,8-dichloro-3,4-dihydro-2- [2- (phenethylsulfonyl) ethyl] -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylate ethyl in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 4 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over sulfate. magnesium and concentrated to dryness under reduced pressure. The residue thus obtained is taken up in ethyl ether, filtered and dried to yield 0.45 g of 6,8-dichloro-3,4-dihydro-2- [2- (phenethylsulfonyl) ethyl] -2H- acid. 1, 2,4-benzothiadia zine-1,1-dioxide-3-carboxylic in the form of white powder erasing around 100 ° C (Analysis (C- | ₈ Hι ₈ Cl2N2θgS2)% calculated C: 43.82; H: 3 , 68; 01: 14.37; N: 5.68; S: 13.00;% found (0.16H ₂ O; 1.0Et ₂ O) C: 44.2; H: 3.5; Cl: 14.9; N: 5.9; S: 13.4).

Ethyl 6,8-dichoro-3,4-dihydro-2- [2- (phenethylsulfonyl) ethyl] -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate can be obtained as follows: 3.2 g of 6,8-dichloro-3,4-dihydro-2- [2- (phenethylthio) ethyl] -2H- 1,2,4-benzoth.adiazine-1,1- ethyl dioxide-3-carboxylate dissolved in 30 cm3 of dichloromethane at a temperature in the region of 20 ° C, 4.1 g of 55% m-chloroperbenzoic acid are added in approximately 30 minutes. After 30 minutes of stirring at the same temperature, the insoluble material is filtered and the filtrate washed with water. After drying over magnesium sulfate and concentration to dryness under reduced pressure, the crude product is purified by flash chromatography on a column of silica using dichloromethane as eluent. 2.05 g of 6,8-dichioro-3,4-dihydro-2- [2- (phenethylsulfonyl) ethyl] -2H- 1,2,4-benzothidiazine-1,1-dioxide-3-carboxyate are obtained. ethyl in the form of lightly colored meringue used as it is in subsequent syntheses. EXAMPLE 47

A 1.1 g of 6,8-dichloro-3,4-dihydro-2- (3-methoxybenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution 0.21 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise to 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C.

The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over sulphate magnesium then concentrated to dryness under reduced pressure to yield 0.6 g of 6,8-dichloro-3,4-dihydro-2- (3-methoxybenzyl) -2H-1, 2,4-benzothiadiazine-1 acid , 1-dioxide-3-carboxylic acid in the form of a white solid decomposing around 109 ° C (Analysis (C16H14CI2N2O5S)% calculated C: 46.07; H: 3.38; 01: 16.99; N: 6, 71; 0: 19.17;

S: 7.68; % found C: 45.8; H: 3.8; 01: 16.8; N: 6.4; 0: 19.1; S: 7.5).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate are added dropwise ethyl in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.88 g of 3-methoxybenzyl chloride in 25 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 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using dichloromethane as eluent. 2.4 g of 6.8-dichloro-3,4-dihydro-2- (3-methoxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 are thus obtained, after recrystallization from acetonitrile, ethyl dioxide-3-carboxylate in the form of a white solid used as it is in subsequent syntheses. EXAMPLE 48

To 1.7 g of 6,8-dichloro-3,4-dihydro-2- (4-methoxybenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 40 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 0.32 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over sulphate. magnesium then concentrated to dryness under reduced pressure to yield 1 g of 6,8-dichloro-3,4-dihydro-2- (4-methoxybenzyI) -2H-1, 2,4-benzothiadiazine-1, 1- acid 3-carboxy-dioxide in the form of a white solid, melting at 110 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (4-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichforo-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.88 g of 4-methoxybenzyl chloride in 25 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 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by recrystallization from acetonitrile. 1.7 g of 6,8-dichloro-3,4-dihydro-2- (4-methoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate are thus obtained. in the form of a white solid melting at 180 ° C.

EXAMPLE 49

A 1 g of 6,8-dichloro-3,4-dihydro-2- (3-chlorobenzyl) -2H-1, 2,4-benzothia diazine-1,1-dioxide-3-carboxyIate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., dropwise added drop 0.19 g of lithium hydroxide in solution in 7 cm3 of distilled water. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The crude product is purified by beating in pentane to yield 0.4 g of 6,8-dichloro-3,4-dihydro-2- (3-chlorobenzyl) -2H- 1,2,4-benzothiadiazine- acid. 1, 1-dioxide-3-carboxylic acid in the form of a white solid decomposing around 105 ° C (Analysis (C15H11CI3N2O4S)% calculated C: 42.73; H: 2.63; Cl: 25.22; N: 6 , 64; S: 7.60;% found (0.67H ₂ O; 0.18C ₅ Hi2) C: 42.7; H: 2.3; 01: 25.1; N: 6.5; S: 7.9).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-chlorobenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3.69 g of 3-chlorobenzyl bromide in 25 cm 3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by recrystallization from acetonitrile. This gives 2 g of 6,8-dichloro-3,4-dihydro-2- (3-chlorobenzyl) -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3-carboxylate under form of white solid melting at 155 ° C.

EXAMPLE 50

To a solution of 1.7 g of 2-amino-4,6-dichloro-N- (3,4-dimethoxybenzyl) - benzenesulfonamide dissolved in 35 cm3 of dioxane heated to reflux, a solution of 0 is added dropwise , 56 g of giyoxylic acid in 10 cm3 of distilled water. The reaction is continued for 5 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is then taken up in a 1N aqueous sodium hydroxide solution and the organic phase is extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with ethyl acetate. After the usual treatment and washing with isopropyl ether, 0.70 g of 6,8-dichloro-3,4-dihydro-2- (3,4-dimethoxybenzyl) -2H-1,2,4- is obtained. benzothia diazine-1 ₅ 1-3-carboxy-dioxide in the form of white powder decomposing around 100 ° C (Analysis (C- | 7HιgCl2N2θ S)% calculated C: 45.65;

H.3.61; Cl: 15.85; N: 6.26; S: 7.17; % found (0.47H ₂ O; 0.41 iP ^ O) 0: 45.9; H: 3.7; Cl: 16.0; N: 6.1; S: 7.4).

The 2-amino-4,6-dichloro-N- (3,4-dimethoxybenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.9 g of 3.4 -dimethoxybenzylamine dissolved in 10 cm3 of tetrahydrofuran are added dropwise to a solution of 3.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.62 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is added to 30 cm3 of distilled water and the organic phase extracted with ethyl acetate. After purification by recrystallization from acetonitrile of the crude product thus obtained, 1.7 g of 2-amino-4,6-dichloro-N- (3,4-dimethoxybenzyl) -benzenesulfonamide are isolated in the form of a white powder melting at 143 ° C. .

EXAMPLE 51

A 2.21 g of 6,8-dichloro-3,4-dihydro-2- (3,4-dichlorobenzyl) -2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylate dissolved in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 9.1 cm3 of an aqueous solution of 0.5N sodium hydroxide are added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane and washed with water. A white product crystallizes; it is filtered and dried to yield 1 g of 6,8-dichloro-3,4-dihydro-2- (3,4-dichlorobenzyl) -2H-1, 2,4-benzothîadîazine-1, 1-dioxide acid -3- carboxy melting at 218 ° C. Ethyl 6,8-dichloro-3,4-dihydro-2- (3,4-dichlorobenzyl) -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxyiate can be prepared from as follows: under nitrogen, 25 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide- are added dropwise Ethyl 3-carbo xylate in anhydrous tetrahydrofuran, at 0.44 g of 50% sodium hydride suspended in 25 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 1.92 cm 3 of 3,4-dichlorobenzyl chloride in 25 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 a mixture of dichloromethane and methanol and the insoluble material filtered and dried to yield 2.21 g of 6,8-dichloro-3,4-dihydro- 2- (3,4-dichlorobenzyl) - 2H-1, 2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in the form of a pale yellow powder melting at 235 ° C.

EXAMPLE 52

A 2.38 g of 6,8-dichloro-3,4-dihydro-2- (3-phenoxypropyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 10.4 cm3 of a 0.5N aqueous sodium hydroxide solution is added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane and washed with water. A white product crystallizes; it is filtered and dried to yield 1.28 g of 6,8-dichloro-3,4-dihydro-2- (3-phenoxypropyl) -2H-1,2,4-benzothiadiazine-1 acid hydrate , 1 - 3-carboxylic dioxide decomposing around 110 ° C (Analysis (Cι ₇ Hι gCl2N2θ ₅ S; H ₂ 0)% calculated C: 45.44; H: 4.04; 01: 15.78; N: 6.23;

S: 7.14; % found (0.25H ₂ O) C: 45.0; H: 3.9; 01: 16.1; N: 6.2; S: 7.4).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-phenoxypropyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 25 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, at 0.44 g of hydride 50% sodium suspended in 25 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.18 cm 3 of 1-bromo-3-phenoxypropane is poured in dropwise

25 cm3 of dimethylformamide. 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 dichloromethane. After purification by flash chromatography on a silica column using dichloromethane as eluent, 2.38 g of 6,8-dichioro-3,4-dihydro-2- (3-phenoxypropyl) -2H-1.2 are obtained, Ethyl 4-benzothiadiazine-1, 1-dioxide-3-carboxylate in the form of a pale yellow powder melting at 134 ° C.

EXAMPLE 53

To 1.1 g of 6,8-dichloro-3,4-dihydro-2- (2-chlorobenzyl) -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylic acid in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 0.21 g of lithium hydroxide dissolved in 10 cm ³ of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The meringue thus obtained is taken up in isopropyl ether to yield 0.7 g of 6,8-dichloro-3,4-dihydro-2- (2-chlorobenzyl) -2H-1, 2,4-benzothiadiazine acid -1, 1-3-dioxide-carboxylic in the form of a beige solid decomposing at 90 ° C (Analysis (C15H11CI3N2O4S)% calculated C: 42.73; H: 2.63; Cf: 25.22; N: 6.64; S: 7.60;% found (0.38H ₂ O; 0.30iPr2θ) C: 42.5; H: 2.3; Cl: 25.3; N: 6.3; S: 7 , 7).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-chlorobenzyl) -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichforo-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, 0.44 g ^'of sodium hydride 50% were suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., it is poured dropwise drop a solution of 2.9 g of 2-chlorobenzyl chloride in 25 cm3 of dimethylformamide. 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 50 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by flash chromatography on a silica column using dichloromethane as eluent. 1.1 g of 6.8-dichloro-3,4-dihydro-2- (2-chlorobenzyl) -2H-1,2,4-benzothiadiazine-1, 1 - ethyl dioxide-3-carboxylate are thus obtained. in the form of white meringue used as it is in the subsequent syntheses.

EXAMPLE 54

A 1.6 g of 6,8-dichloro-3,4-dihydro-2- (3-bromobenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 6.4 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried. 1 g of 6,8-dichloro-3,4-dihydro-2- (3-bromobenzyl) -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, melting at 217 °, is obtained. vs.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-bromobenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 25 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate are added dropwise ethyl in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 25 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 4.73 g of 3-bromobenzyl bromide in 25 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 3 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 sulfate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is taken up in ethyl ether, filtered and dried. 1.6 g of 6,8-dichloro-3,4-dihydro-2- (3-bromobenzyl) -2H-1,2,4-benzothiadiazazine-1, 1-dioxide-3-carboxylic acid are isolated under white powder form melting at 160 ° C.

EXAMPLE 55

To 1.7 g of 6,8-dichloro-3,4-dihydro-2- (2-fluorobenzyl) -2H-1,2,4- benzothiadiaz.ne-1,1-dioxide-3-carboxylate dissolved in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 0.33 g of lithium hydroxide dissolved in 10 cm3 of distilled water is added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium is concentrated to dryness under reduced pressure and the residue taken up in a mixture of water and dichloromethane then acidified with 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried. The crude product thus obtained is taken up in isopropyl ether and again filtered and dried to yield 0.4 g of 6,8-dichloro-3,4-dihydro-2- (2-fluorobenzyl) -2H- acid. 1, 2,4-benzothiadîazine-1, 1-dioxide-3-carboxylic in the form of a white solid decomposing at 110 ° C (Analysis Ct ₅ HιιCl2FN2θ S)% calculated C: 44.46; H: 2.74; Cl: 17.50; F: 4.69; N: 6.91;

S: 7.91; % found (0.77H ₂ O; 0.05iPr ₂ O; 0.13CH ₂ Cl2) C: 44.5; H: 2.7; Cl: 17.4; F: 4.3; N: 6.9; S: 8.1).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-fluorobenzyl) -2H-1,2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be prepared in this way below: under nitrogen, 50 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadazine-1,1-dioxide-3- is added dropwise ethyl carboxy late in anhydrous tetrahydrofuran, with 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After

30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3.6 g of 2-fluorobenzyl bromide in 25 cm 3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in 40 cm3 of distilled water and the organic phase is extracted with ethyl acetate, dried over magnesium sulfate and concentrated to dryness. The crude product is purified by recrystallization from 15 cm3 of acetonitrile boiling. 1.7 g of 6,8-dichloro-3,4-dihydro-2- (2-fluorobenzyl) -2H-1,2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate are thus obtained. in the form of a white solid, melting at 157 ° C.

EXAMPLE 56

0.56 g of 6,8-dichloro-3,4-dihydro-2- (3-pyridylmethyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5.4 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 3 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried. 0.46 g of 6,8-dichloro-3,4-dihydro-2- (3-pyridylmethyl) -2H-1,2,4-benzothiadiazine-1, 1-3-carboxy-iic acid is obtained, of which the melting point is greater than 360 ° C on the Kofler bench (Analysis (C14H11CI2N3O4S)% calculated 0: 43.31; H: 2.86; 01: 18.26; N: 10.82;

S: 8.26; % found (0.48H ₂ O) C: 43.0; H: 2.6; Cl: 18.3; N: 10.9; S: 8.3).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-pyridylmethyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 25 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, with 0.44 g of 50% sodium hydride suspended in 25 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.36 g of 3- (chloromethyl) pyridine in 25 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 is extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 (99/1 by volume) as eluent. 0.56 g of 6,8-dichloro-3,4-dihydro-2- (3-pyridylmethyl) -2H- are isolated. Ethyl 1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in the form of a white powder melting at 157 ° C.

EXAMPLE 57

A 2.34 g of 6,8-dichloro-3,4-dihydro-2- (3-iodobenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 8.6 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 3 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in a mixture of water and dichloromethane and then acidified with hydrochloric acid 1. The precipitate formed is filtered, washed with water and dried to yield 1.75 g of 6,8-dichloro-3,4-dihydro-2- (3-iodobenzyl) acid hydrate.

2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic in the form of white powder decomposing around 130 ° C (Analysis (C15H11CI2IN2O4S; H2O) 0: 33.92; H.2.47; Cl: 13 , 35; N: 5.27; S: 6.04;% found (0.06CH Cl2) C: 33.8; H: 2.3; CI: 13.2; N: 5.3; S: 6 , 0).

Ethyl 6.8-dichloro-3,4-dihydro-2- (3-iodobenzyl) -2H-1,2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be prepared as follows: 3.28 g of 2-amino-4,6-dichloro-N- (3-iodobenzyl) -benzenesulfonamide in 55 cm3 of absolute ethanol brought to reflux, 1.3 g of giyoxylic acid in solution are added dropwise in 50 cm ³ of absolute ethanol in the presence of 3.56 cm3 of concentrated sulfuric acid. The reaction is continued for 4 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. The precipitate formed is filtered, washed with 50 cm3 of absolute ethanol and dried. This gives 2.34 g of 6,8-dichloro-3,4-dihydro-2- (3-iodobenzyl) - 2H-1,2,4-benzothiadazine-1,1-dioxide-3-carboxylic acid in the form of a white solid, melting at 184 ° C.

The 2-amino-4,6-dichloro-N- (3-iodobenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 5 g of 3-iodobenzylamine are gradually added to a solution of 4.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and of 4.33 cm3 of triethylamine in 50 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using dichloromethane as eluent, 3.28 g of 2-amino-4,6-dichloro-N- (3-iodobenzyD-benzenesulfonamide) are obtained in the form of a yellow solid melting at 110 ° C.

EXAMPLE 58

A 1, 1 g of 6,8-dichloro-3,4-dihydro-2- [3- (4-phenyl-1-piperazinyl) propyl] -2H- 1, 2,4-benzothiadiazine-1, 1-dioxide -3-ethyl carboxylate dissolved in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 4.2 cm3 of an aqueous solution of 0.5N sodium hydroxide are added dropwise. The reaction is continued for 4 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in a mixture of dichloromethane and distilled water. The insoluble material is filtered, washed with dichloromethane and dried. 0.77 g of sodium salt of 6,8-dichloro-3,4-dihydro-2- [3- (4-phenyl-1-piperazinyl) propyl] -2H-1,2,4 is obtained. -benzo thiadiazine-1, 1-dioxide-3-carboxylic acid in the form of white powder which decomposes at around 200 ° C on the Kofler bench (Analysis (C21 H23Cl2N4Naθ4S)

% calculated C: 48.38; H: 4.45; Cl: 13.60; N: 10.75; Na: 4.41; S: 6.15; % found (0.81 H 0) C: 48.7; H: 4.4; Cl: 14.0; N: 10.8; Na: 4.1; S: 5.5).

6,8-dichloro-3,4-dihydro-2- [3- (4-phenyl-1-piperazinyl) propyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d ethyl can be prepared as follows: under nitrogen, 15 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine- are added dropwise 1, 1- ethyl dioxide-3-carboxylate in anhydrous tetrahydrofuran, with 0.44 g of 50% sodium hydride suspended in 15 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.43 g of 1- (3-chloropropyl) -4-phenylpiperazine in 15 cm3 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 dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 (99/1 by volume) as eluent. After recrystallization from 12 cm3 of isopropanol, 1.1 g of 6,8-dichloro-3,4-dihydro-2- [3- (4-phenyl-1-piperazinyl) propyl] -2H-1.2 are isolated. , 4-benzo thiadiazine-1,1-dioxide-3-carboxylate of ethyl in the form of white powder melting at 148 ° C.

1- (3-chloropropyl) -4-phenyl-piperazine can be obtained as follows: at a temperature in the region of 20 ° C, 5.3 cm3 of 1-chloro-3-bromo-propane are added dropwise to a mixture of 6.6 cm3 of N-phenylpiperazine in solution in 10 cm3 of acetone and of 6.3 cm3 of a 25% aqueous sodium hydroxide solution. The reaction is continued for 24 hours at the same temperature, then the organic phase is decanted and concentrated to dryness. The crude product is taken up in ethyl ether and treated with 14 cm3 of 4.2N hydrochloric ether. The precipitate formed is filtered, washed with ethyl ether and dried to yield 11.6 g of 1- (3-chloropropyl) -4-phenyl-piperazine in the form of dihydrochloride, melting at 170 ° C.

EXAMPLE 59

A 1.2 g of ^" 6,8-dichloro-3,4-dihydro-2- (1-benzyl-4-piperidinyl) -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylate ethyl in solution in 5 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 2.65 cm3 of a 1N aqueous sodium hydroxide solution is added dropwise. The reaction is continued for 24 hours at the same temperature The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried to conduct, after beating. in ethyl ether, 0.75 g of 6,8-dichloro-3,4-dihydro-2- (1-benzyl-4-piperidinyl) -2H-1,2,4-benzothiadiazine hydrate -1, 1-3-dioxide-carboxylic acid in the form of an off-white solid, melting at 205 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (1-benzyl-4-piperidinyl) -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate can be prepared as follows: to 4 g of 2-amino-4,6-dichloro-N- (1-benzyl-4-piperidinyl) - benzenesulfonamide in 20 cm3 of absolute ethanol brought to reflux, 1 is added dropwise , 78 g of giyoxylic acid in solution in 20 cm3 of absolute ethanol in the presence of 1.75 cm3 of concentrated sulfuric acid. The reaction is continued for 4 hours at reflux, then the reaction medium cooled to a temperature in the region of 20 ° C. The reaction medium is concentrated to dryness under reduced pressure, the residue is taken up in distilled water and the organic phase extracted with dichloromethane. After the usual treatment, the crude product is purified by flash chromatography on a silica column using a mixture of ethyl acetate and methanol (90/10 by volume) as eluent. 1.2 g of 6.8 is thus obtained -dichloro-3,4-dihydro-2- (1-benzyl-4-piperidinyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate in the form of lightly colored oil used as is in subsequent synthesis.

2-amino-4,6-dichloro-N- (1 -benzyl-4-piperidinyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 4 cm3 of 4-amino -1-benzylpiperidine are gradually added to a solution of 5.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 3 cm3 of triethylamine in 70 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up in 50 cm3 of distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent, 4.0 g of 2-amino-4,6-dichloro are obtained. N- (1-benzyl-4-piperidinyl) - benzenesulfonamide in the form of lightly colored oil used as it is in subsequent syntheses.

EXAMPLE 60

To 1.2 g of 6,8-dichloro-3,4-dihydro-2- (3-ethylbenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 12 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5.2 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water and dried over sulfate. magnesium. After concentration to dryness under reduced pressure, the residue is beaten in pentane to yield 0.87 g of acid hydrate

6,8-dichloro-3,4-dihydro-2- (3-ethylbenzyl) -2H-1, 2,4-benzothiadiazine-1,1 - 3-carboxylic oxide in the form of a white solid decomposing at around 100 ° C (Analysis (Ci7H ₁₆ Cl2N2θ4S; H ₂ 0)% calculated C: 47.12; H: 4.19; Cl: 16.36; N: 6.46; S: 7.40;% found (0.12C5H1 ₂ ) C: 47.0; H: 3.7; Cl: 16.0; N: 6.7; S: 7.7).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-ethylbenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : 1.3 g of 6,8-dichloro-3,4-dihydro-2- (3-vinylbenzyl) -2H-1,2,4-benzothia diazine-1,1-doxide-3-carboxylate in ethyl solution in 140 cm3 of absolute ethanol are stirred 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. 0.8 g of 6,8-dichloro-3,4-dihydro-2- (3-ethylbenzyi) -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxy late is thus obtained. ethyl in the form of a white powder melting at 115 ° C.

EXAMPLE 61

A 1 g of 6,8-dichloro-3,4-dihydro-2- (2-thieny.methyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 4.75 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using IN hydrochloric acid. The organic phase is extracted with ethyl ether, washed with water, dried over magnesium sulphate and concentrated to dryness under reduced pressure to give 0.6 g of 6,8-dichloro-3,4- acid dihydro-2- (2-thienylmethyl) -2H-1, 2,4-benzothiadia zine-1, 1-dioxide-3-carboxylic in the form of white powder decomposing around 80 ° C (Analysis (C13H10CI2N2O4S2)% calculated C: 39.70; H: 2.56; Cl: 18.03; N: 7.12; 0: 16.27; S: 16.31;% found (0.49H2θ; 0.29And ₂ O) C: 39 , 7; H: 2.5; Cl: 17.6; N: 7.1; 0: 16.5; S: 16.9).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-thienylmethyl) -2H-1,2,4-benzothiadiazine-1,1-3-dioxide-3-carboxylate can be prepared as follows : 2.33 g of 2-amino-4,6-dichloro-N- (2-thienylmethyl) -benzenesulfonamide in 50 cm3 of absolute ethanol brought to reflux, 1.27 g of giyoxylic acid are added dropwise solution in 25 cm3 of absolute ethanol in the presence of 2.5 cm3 of concentrated sulfuric acid. The reaction is continued for 4 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is taken up in water and the organic phase extracted with dichloromethane. After usual treatment and purification by flash chromatography on a silica column with dichloromethane as eluent, 1 g of 6,8-dichloro-3,4-dihydro-2- (2-thienylmethyl) -2H-1, 2 is obtained, Ethyl 4-benzothiadiazine-1, 1-dioxide-3-carboxylate in the form of a white meringue used as it is in the subsequent syntheses.

The 2-amino-4,6-dichloro-N- (2-thienylmethyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.33 cm 3 of 2-thiophenemethylamine are added gradually to a solution of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and of 1.61 cm 3 of triethylamine in 40 cm 3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using dichloromethane as eluent, 2.33 g of 2-amino-4,6-dichloro-N- (2-thienylmethyl) benzenesulfonamide are obtained in the form of a pale yellow solid melting at 103 ° C.

EXAMPLE 62

To a solution of 3.2 g of 2-amino-4,6-dichloro-N- (3-trifluoromethoxybenzyD-benzenesulfonamide in solution in 65 cm3 of dioxane heated to reflux, a solution of 1 g of d is added in approximately 20 minutes. giyoxylic acid in 15 cm 3 of distilled water, the reaction is continued for 8 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure, the residue is then taken up in a solution aqueous sodium hydroxide and the organic phase is extracted with ethyl acetate and discarded The aqueous phase is acidified with 1N hydrochloric acid and the organic phase is extracted with acetate ethyl, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The crude product thus obtained is purified by flash chromatography on a silica column using a mixture of ethyl acetate and methanol (90/10 by volume) as eluent. After recrystallization from boiling isopropanol, 1.3 g of 6.8-dichloro-3,4-dihydro-2- (3-trifluoromethoxybenzyl) -2H-1,2,4-benzothiadiazine- are obtained.

1,1-dioxide-3-carboxy in the form of white powder decomposing at 115 ° C (Analysis (Cf HιιCl2F ₃ N2θ5S)% calculated C: 40.79; H: 2.35; Cl: 15.05;

F: 12.09; N: 5.94; S: 6.80; % found (0.92iPrOH) C: 41.0; H: 2.4; Cl. 15.0; F: 12.1; N: 6.0; S: 7.2).

2-amino-4,6-dichloro-N- (3-trifluoromethoxybenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 2.94 g of 3-trifluoromethoxybenzylamine in solution in 20 cm3 of tetrahydrofuran are added dropwise to a solution of 4.0 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.15 cm3 of triethylamine in 20 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane as eluent (50/50 by volume), 3.2 g of 2-amino-4,6-dichloro-N- (3 -trifluoromethoxybenzyl) - benzenesulfonamide in the form of an orange oil used as it is in subsequent syntheses.

EXAMPLE 63

To 1.43 g of 6,8-dichloro-3,4-dihydro-2- (3-phenylthiopropyl) -2H-1,2,4- ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 6 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 3 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in a mixture of dichloromethane and distilled water. The organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dry under reduced pressure. After purification by flash chromatography on a silica column with dichloromethane as eluent, the product obtained is taken up in ethyl ether and treated with an aqueous solution of 1N sodium hydroxide. Extraction with ethyl acetate leads to 0.9 g of sodium salt of 6,8-dichloro-3,4-dihydro-2- (3-phenylthiopropyl) -2H-1, 2 acid , 4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in the form of a white powder melting at 240 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-phenylthiopropyl) -2H-1,2,4-benzothiadia zine-1,1-dioxide-3-carboxylate can be prepared in the following manner following: under nitrogen, 15 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- are added dropwise ethyl carboxy late in anhydrous tetrahydrofuran, with 0.44 g of 50% sodium hydride suspended in 15 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 2.59 g of 1-chloro-3-phenylthiopropane in 15 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 cyclohexane (70/30 by volume) as eluent. 2.23 g of 6,8-dichloro-3,4-dihydro-2- (3-phenylthiopropyl) -2H-1,2,4- ethyl benzothiadiazine-1,1-dioxide-3-carboxylate are isolated under white powder form melting at a temperature above 360 ° C on the Kofler bench.

EXAMPLE 64

A 1.1 g of 6,8-dichloro-3,4-dihydro-2- (3-methoxycarbonylbenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 4.6 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in distilled water, acidified with 1N hydrochloric acid. The organic phase is extracted with ethyl ether, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The product thus obtained is beaten in petroleum ether, filtered and then dried to yield 0.45 g of 6,8-dichloro-3,4-dihydro-2- (3-methoxycarbonylbenzyl) -2H- 1 acid, 2,4-Benzothiad.azine-1,1-dioxide-3-carboxylic acid in the form of a white powder melting at 257 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-methoxycarbonylbenzyl) -2H-1,2,4-benzothia dinazine-1,1-dioxide-3-carboxylate can be prepared in the following manner below: under nitrogen, 25 cm3 of a solution of 4 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, l-dioxide-3- are added dropwise ethyl carboxy late in anhydrous tetrahydrofuran, 0.59 g of 50% sodium hydride suspended in 25 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 5.5 g of methyl 3-bromomethylbenzoate in 15 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 6 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 taken up in isopropyl ether, and the precipitate formed recrystallized from boiling isopropanol 1.9 g of 6,8-dichloro- Ethyl 3,4-dihydro-2- (3-methoxycarbo nylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate are thus isolated in the form of a white powder melting at 173 ° C. .

EXAMPLE 65

To a solution of 4.3 g of 2-amino-4,6-dichloro-N- (5-phenylpentyl) benzenesulfonamide in solution in 90 cm3 of dioxane heated to reflux, a solution of 1 is added in approximately 20 minutes, 43 g of giyoxylic acid in 25 cm3 of distilled water. The reaction is continued for 5 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is then taken up in an aqueous sodium hydroxide solution and the organic phase extracted with ethyl acetate. The crude product thus obtained is purified by flash- chromatography on a silica column using a mixture of ethyl acetate and methanol (90/10 by volume) as eluent. 0.44 g of sodium salt of 6,8-dichloro-3,4-dihydro-2- (5-phenylpentyl) -2H- acid is obtained.

1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic in the form of white powder decomposing at around 130 ° C (Analysis (Ci 9H- | g.Cl2N2Naθ4S)

C: 49.04; H. 4.12; 01: 15.24; N: 6.02; S: 6.89; % found (0.85H ₂ O) C: 49.2; H: 4.3; CI: 15.0; N: 6.2; S: 6.7).

2-amino-4,6-dichloro-N- (5-phenylpentyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 4.3 g of 5-phenylpentylamine in solution in 25 cm3 of tetrahydrofuran are added dropwise to a solution of 6.7 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 3.6 cm3 of triethylamine in 25 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (60/40 by volume) as eluent, 4.3 g of 2-amino-4,6-dichloro-N- are obtained (5 -phenylpentyl) - benzenesulfonamide in the form of a yellow oil used as it is in subsequent syntheses.

5-phenylpentylamine can be obtained in the following way: 3.97 cm3 of hydrazine hydrate are added dropwise to 8 g of N- (5-phenylpentyOphthalimide in solution in 80 cm3 of absolute ethanol. The reaction medium is brought to reflux for 2 hours After cooling to 50 ° C., 24 cm 3 of concentrated hydrochloric acid are added dropwise, and the reaction medium again brought to reflux for 1 hour After cooling to a temperature in the region of 20 ° C, the white suspension is filtered, washed with water and the filtrate treated with concentrated sodium hydroxide to a pH close to 10. The organic phase is then extracted with dichloromethane, washed, dried over magnesium sulfate and concentrated dry under reduced pressure to give 4.3 g of 5-phenylpentylamine in the form of a yellow oil used as it is in subsequent syntheses. The N- (5-phenylpentyI) phthalimide can be obtained in the following manner: 5 g of 1-chloro-5-phenyl-pentane dissolved in 15 cm3 of dimethylformamide are added dropwise to 5.9 g of potassium phthalimide dissolved in 35 cm3 of the same solvent. The mixture is brought to reflux for 3 hours. After cooling to a temperature in the region of 20 ° C, the reaction medium is diluted with 100 cm3 of dichloromethane and 200 cm3 of distilled water. After decantation, the organic phase is extracted with 3 times 50 cm3 of dichloromethane, washed with a 1N sodium hydroxide solution then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 8 g of N- (5-phenylpentyl) phthalimide are thus obtained in the form of a yellow oil used as it is in the subsequent syntheses.

EXAMPLE 66

1.44 g of 6,8-dichioro-3,4-dihydro-2- [3- (10-phenothiazinyl) propyl] -2H- 1,2,4-benzothiadiazine-1, l-dioxide-3-carboxylate ethyl solution in 15 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 5.1 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in dichloromethane. The insoluble material thus obtained is filtered, washed with ethyl ether and dried to yield 1.19 g of sodium salt trihydrate of 6,8-dichloro-3,4-dihydro-2- acid [3 - (10-phenothiazinyl) propyl] -2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxylic in the form of white powder decomposing at 224 ° C (Analysis (C23H- | ₈ C.2N3Naθ4S2, 3H2Û) C45.10; H: 3.95; 01: 11.58; N: 6.86; Na: 3.75; S: 10.47;% found (0.38H2θ) C45.1; H: 3 , 5; Cl: 11.8; N: 6.9; Na: 3.8; S: 9.7).

Ethyl 6,8-dichloro-3,4-dihydro-2- [3- (10-phenothiazinyl) propyl] -2H-1,2,4-benzo thiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 20 cm3 of a solution of 3 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 0.44 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 2.87 g of 10- (3-chioropropyl) phenothiazine is poured in dropwise in 15 cm3 of dimethylformamide. The reaction medium is then brought to reflux for 5 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 cyclohexane (50/50 by volume) as eluent. 1.44 g of 6,8-dichloro-3,4-dihydro-2- [3- (10-phenothiazinyl) propyl] -2H- 1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d ethyl are isolated in the form of white powder melting at 191 ° C.

10- (3-chloropropyl) phenothiazine can be prepared according to the method described by H. Wunderlich et al., Pharmazie, 21, 57 (1966).

EXAMPLE 67

To a solution of 2.3 g of 2-amino-4,6-dichloro-N- (3,5-dimethoxybenzyl) benzenesulfonamide in 50 cm3 of dioxane heated to reflux, a solution of 0 is added in approximately 20 minutes. 77 g giyoxylic acid in

12 cm3 of distilled water. The reaction is continued for 8 hours at reflux, then the reaction medium is ^" cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is then taken up in an aqueous sodium hydroxide solution and the organic phase is extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase is extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness. under reduced pressure.

The product thus obtained is taken up in petroleum ether, filtered, washed and dried. 0.8 g 6,8-dichloro-3,4-dihydro-2- (3,5-dimethoxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in the form of white powder decomposing at 122 ° C (Analysis (Ci7H- | gCl2N2θ S)% calculated 0: 45.65;

H: 3.61; 01: 15.85; N: 6.26; 0:21, 46; S: 7.17; % found 0: 45.3; H: 3.7; 01: 15.6; N: 6.3; 0:21, 3; S: 7.6).

The 2-amino-4,6-dichloro-N- (3,5-dimethoxybenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.9 g of 3.5 -dimethoxybenzylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.62 cm 3 of triethylamine in 10 cm 3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (80/20 by volume) as eluent, 2.4 g of 2-amino-4,6-dichloro-N- are obtained (3 , 5-dimethoxybenzyl) - benzenesulfonamide in the form of a yellow oil used as it is in the subsequent syntheses.

EXAMPLE 68

To 1.9 g of 2-allyl-6,8-dichloro-3,4-dihydro-2H-1,2,4-.benzothiadiazine-1, 1- ethyl dioxide-3-carboxylate in solution in 25 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 10.4 cm 3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under pressure. reduced and the residue taken up in distilled water. The organic phase is extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase is extracted with ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure to lead, after beating in pentane, to 1 , 2 g of 2-allyl-6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzo thîadiazine-1, 1-dioxide-3-carboxylic acid in the form of white powder melting at 167 ° C.

Ethyl 2-allyl-6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothîadiazine-1, 1-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 20 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-ethyl oxide-3-carboxylate in anhydrous tetrahydrofuran, at 0.44 g of 50% sodium hydride suspended in 20 cm 3 of the same solvent After stirring for 30 minutes at a temperature in the region of 20 ° C., a solution of 2 is poured in dropwise, 17 g of allyl bromide in 15 cm3 of dimethylformamide. The reaction medium is then brought to reflux for 1 hour, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 cyclohexane (80/20 by volume) as eluent. 1.9 g of ethyl 2-allyl-6,8-dichloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate are isolated in the form of white powder melting at 137 ° C.

EXAMPLE 69

To 1 g of 6,8-dichloro-3,4-dihydro-2- (3-methoxycarbonyibenzyl) -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 8.44 cm3 of a 0.5N aqueous sodium hydroxide solution is added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The organic phase is extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase is extracted with ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure to yield, after beating in ether. petroleum, 0.6 g 2- (3-carboxybenzyl) -6,8- dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic under form of white powder decomposing around 130 ° C (Analysis (CιgH- | 2Cl2N ₂ 0gS)% calculated C: 44.56; H: 2.80; 01: 16.44; N: 6.50; S: 7, 44;% found (0.58 Et ₂ O; 0.23H ₂ O) C: 44.5; H: 2.6; Cl: 16.4; N: 6.4; S: 7.4).

EXAMPLE 70

To a solution of 4.3 g of 2-amino-4,6-dichloro-N- [4- (2-methylphenyl) butyl] - benzenesulfonamide in 50 cm3 of dioxane heated to reflux, a solution is added in approximately 20 minutes 2.04 g of giyoxylic acid in 20 cm3 of distilled water. The reaction is continued for 4 hours at reflux, then the reaction medium, cooled to a temperature in the region of 20 ° C, is added to 50 cm3 of distilled water. The organic phase is decanted, taken up in isopropyl ether and then concentrated to dryness under reduced pressure. 4 g 6,8-dichloro-3,4-dihydro-2- [4- (2-methylphenyl) butyl] -2H-1, 2,4-benzothiadia zine-1,1-dioxide-3-carboxylic acid in the form of orange viscous oil (Analysis (C-J9H20CI2N2O4S)% calculated 0: 51.47; H: 4.55; 01: 15.99; N: 6.32 ;

0: 14.44; S: 7.23; % found (0.9IPr ₂ O 0: 51.8; H: 4.4; 01: 16.4; N: 6.2; 0: 14.9; S: 7.2).

2-amino-4,6-dichloro-N- [4- (2-methylphenyl) butyl] -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 3 g of 4- (2-methylphenyl) butylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 4.8 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.6 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent, 4.5 g of 2-amino-4,6-dichloro- are obtained. N- [4- (2-methylphenyl) butyl] -benzenesulfo namide in the form of an orange oil used as it is in subsequent syntheses.

4- (2-methylphenyl) butylamine can be prepared as follows: 10 cm3 of hydrazine hydrate are added dropwise to 20 g of N- [4- (2-methylphenyl) butyl] phtafimide in solution in 300 cm3 of absolute ethanol. The reaction medium is brought to reflux for 2 hours. After cooling to 50 ° C, 60 cm3 of concentrated hydrochloric acid are added dropwise, and the reaction medium is again brought to reflux for 1 hour. After cooling to a temperature in the region of 20 ° C., the white suspension is filtered, washed with water and the filtrate treated with concentrated sodium hydroxide to a pH in the region of 10. The organic phase is then extracted with dichloromethane, washed, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 9 g of 4- (2-methylphenylbutylamine) are thus obtained in the form of an orange oil used as it is in the subsequent syntheses.

The N- [4- (2-methylphenyl) butyl] phthalimide can be obtained in the following manner: 13 g of 1-chloro-4- (2-methylphenyl) -butane in solution in 40 cm3 of dimethylformamide are added dropwise to 15.8 g of potassium phthalimide dissolved in 50 cm3 of the same solvent. The mixture is brought to reflux for 3 hours. After cooling to a temperature in the region of 20 ° C, the reaction medium is diluted with 200 cm3 of chloroform and 400 cm3 of distilled water. After decantation, the organic phase is extracted with 2 times 150 cm3 of chloroform, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 20 g of N- [4- (2-methylphenyl) butyl] phthalimide are thus obtained in the form of an orange oil which solidifies and which is used as it is in subsequent syntheses.

1-chloro-4- (2-methylphenyl) -butane can be prepared as follows: 11.5 cm3 of 4-bromo-1-chlorobutane and 1.9 g of copper iodide dissolved in 50 cm3 of anhydrous tetrahydrofuran at a temperature in the region of 20 ° C., the organomagnesium prepared from 13 cm 3 of 2-chlorotoluene and 2.6 g of magnesium in tetrahydrofuran is added in approximately 2 hours. The reaction is continued for 1 hour at a temperature in the region of 20 ° C. The reaction medium is then hydrolyzed by adding 50 cm3 of distilled water and the organic phase extracted with dichloromethane. The crude product thus obtained is purified by flash chromatography on a silica column using cyclohexane as eluent. 12 g of 1-chloro-4- (2-methylphenyD-butane are isolated in the form of a colorless liquid used as it is in subsequent syntheses.

EXAMPLE 71

A. a solution of 3.7 g of 2-amino-4,6-dichloro-N- [4- (4-methylphenyl) butyl] - benzenesulfonamide in 40 cm3 of dioxane heated under reflux, a solution of 1.76 g of giyoxylic acid in

15 cm3 of distilled water. The reaction is continued for 5 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and added to

50 cm3 of distilled water. The organic phase is decanted, taken up in isopropyl ether and then concentrated to dryness under reduced pressure. 2.5 g of acid

6,8-dichloro-3,4-dihydro-2- [4- (4-methylphenyl) butyl] -2H-1, 2,4-benzothiadia zine-1, 1-dioxide-3-carboxylic oil orange viscous (Analysis (C19H20CI2N2O4S)% calculated C: 51, 47; H: 4.55; Cl: 15.99; N: 6.32; 0: 14.44; S: 7.23; % found (0.20iPr2θ; 0.40dioxane) 0: 51.9; H: 4.7; 01: 16.4; N: 6.6; 0: 14.6; S: 7.6).

2-amino-4,6-dichloro-N- [4- (4-methylphenyl) butyl] -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 3 g of 4- (4-methylphenyl) butylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 4.8 g of 2-amino-4,6-dichforobenzenesulfonyl chloride and 2.6 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of ethyl acetate and cyclohexane (10/90 by volume) as eluent, 3.72 g of 2-amino-4,6-dichloro are obtained N- [4- (4-methylphenyl) butyl] -benzene sulfonamide in the form of an orange oil used as it is in subsequent syntheses.

4- (4-methylphenyl) butylamine can be prepared as follows: 10 cm3 of hydrazine hydrate are added dropwise to 20 g of N- [4- (4-methylphenyl) butyl] phthalimide in solution 300 cm3 of absolute ethanol. The reaction medium is brought to reflux for 2 hours. After cooling to 50 ° C, 60 cm3 of concentrated hydrochloric acid are added dropwise, and the reaction medium again brought to reflux for 1 hour. After cooling to a temperature in the region of 20 ° C., the white suspension is filtered, washed with water and the filtrate treated with concentrated sodium hydroxide to a pH in the region of 10. The organic phase is then extracted with dichloromethane, washed, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 8.6 g of 4- (4-methylphenylbutylamine) are thus obtained in the form of an orange oil used as it is in the subsequent syntheses.

The N- [4- (4-methylphenyl) butyl] phtaiimide can be obtained in the following manner: 13 g of 1-chloro-4- (4-methylphenyl) -butane dissolved in 40 cm3 of dimethylformamide are added dropwise 15.8 g of potassium phthalimide dissolved in 50 cm3 of the same solvent. The mixture is brought to reflux for 5 hours. After cooling to a temperature in the region of 20 ° C, the reaction medium is diluted with 200 cm3 of chloroform and 400 cm3 of distilled water. After decantation, the organic phase is extracted with 2 times 150 cm3 of chloroform, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 20 g of N- [4- (4-methylphenyl) butyl] phthalimide are thus obtained in the form of an orange oil which solidifies and which is used as it is in subsequent syntheses.

1-chloro-4- (4-methylphenyl) -butane can be prepared as follows: 11.5 cm3 of 4-bromo-1-chlorobutane and 1.9 g of copper iodide dissolved in 50 cm3 of anhydrous tetrahydrofuran at a temperature in the region of 20 ° C., the organomagnesium prepared from 13.5 cm 3 of 4-bromptoluene and 2.6 g of magnesium in anhydrous tetrahydrofuran is added in approximately 2 hours. The reaction is continued for 1 hour at a temperature in the region of 20 ° C. The reaction medium is then hydrolyzed by adding 50 cm3 of distilled water and the organic phase extracted with dichloromethane. The 1-chloro-4- (4-methylphenyl) -butane thus obtained (13 g) is isolated in the form of a colorless liquid and used without additional purification in the subsequent reactions.

EXAMPLE 72

To a solution of 2.8 g of 2-amino-4,6-dichloro-N- [4- (3-methylphenyl) butyl] - benzenesulfonamide dissolved in 35 cm3 of dioxane heated at reflux, added in about 20 minutes a solution of 1.33 g of giyoxylic acid in 15 cm3 of distilled water. The reaction is continued for 5 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C and is added to 50 cm3 of distilled water. The organic phase is decanted, taken up in isopropyl ether and then concentrated to dryness under reduced pressure. The product is beaten in ethyl ether and the insoluble material formed filtered, washed and dried. 0.6 g 6,8-dichloro-3,4-dihydro-2- [4- (3-methylphenyl) butyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- carboxylic acids are obtained in the form of a white powder melting at 251 ° C.

2-amino-4,6-dichloro-N- [4- (3-methylphenyl) butyl] -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature near 20 ° C, 3 g of 4- (3-methylphenyl) butylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 4.8 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and of 2.6 cm3 of triethylamine in 30 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in 40 cm3 of distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent, 5.6 g of 2-amino-4,6-dichloro- are obtained. N- [4- (3-methylphenyl) butyl] -benzene sulfona mide in the form of an orange oil used as it is in subsequent syntheses.

4- (3-methylphenyl) butylamine can be prepared as follows: 2.25 cm3 of hydrazine hydrate are added dropwise to 4.7 g of N- [4- (3-methylphenyl) butyl] phthalimide in solution in 100 cm3 of absolute ethanol. The reaction medium is brought to reflux for 2 hours. After cooling to 50 ° C, 15 cm3 of concentrated hydrochloric acid are added dropwise, and the reaction medium again brought to reflux for 1 hour. After cooling to a temperature in the region of 20 ° C., the white suspension is filtered, washed with water and the filtrate treated with concentrated sodium hydroxide to a pH in the region of 10. The organic phase is then extracted with dichloromethane, washed, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 3 g of 4- (3-methylphenylbutylamine) are thus obtained in the form of an orange oil used as it is in the subsequent syntheses.

The N- [4- (3-methylphenyl) butyl] phthalimide can be obtained as follows: 13 g of 1-iodo-4- (3-methylphenyl) -butane dissolved in 20 cm3 of dimethylformamide are added dropwise to 10.5 g of potassium phthalimide dissolved in 40 cm3 of the same solvent. The mixture is brought to reflux for 5 hours. After cooling to a temperature in the region of 20 ° C., the reaction medium is diluted with 100 cm 3 of chloroform and 300 cm 3 of distilled water. After decantation, the organic phase is extracted with 3 times 50 cm3 of chloroform, then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The raw product is purified by flash- chromatography on a silica column using a mixture of ethyl ether and cyclohexane (20/80 by volume) as eluent. 7 g of N- [4- (3-methylphenyl) butyl] phthalimide are thus obtained in the form of an orange oil which solidifies and which is used as it is in subsequent syntheses.

1-iodo-4- (3-methylphenyl) -butane can be prepared as follows: 9.85 g of 1-chloro-4- (3-methylphenyl) -butane and 20.3 g of sodium iodide dissolved in 200 cm3 of 2-butanone are stirred at reflux for 24 hours. The precipitate formed is removed and the filtrate concentrated to dryness under reduced pressure. The residue is taken up in distilled water and the organic phase extracted with ethyl ether, dried and concentrated to dryness 13.5 g of 1-iodo-4- (3-methylphenyl) -butane are thus obtained in the form of orange oil used as is in subsequent syntheses.

1-chloro-4- (3-methylphenyl) -butane can be prepared as follows: 11.5 cm3 of 4-bromo-1-chlorobutane and 1.9 g of copper iodide dissolved in 50 cm3 of anhydrous tetrahydrofuran at a temperature in the region of 20 ° C., the organomagnesium prepared from 13.5 cm 3 of 3-bromotoluene and 2.6 g of magnesium in anhydrous tetrahydrofuran is added in approximately 2 hours. The reaction is continued for 1 hour at a temperature in the region of 20 ° C. The reaction medium is then hydrolyzed by adding 50 cm3 of distilled water and the organic phase extracted with dichloromethane. The crude product thus obtained is purified by flash chromatography on a silica column using a mixture of ethyl ether and cyclohexane (10/90 by volume) as eluent. 9.85 g of 1-chloro-4- (3-methylphenyl) -butane are thus isolated in the form of a lightly colored oil used as it is in subsequent syntheses.

EXAMPLE 73

To a solution of 2.1 g of 2-amino-4,6-dichloro-N- (3,5-dichlorobenzyQ-benzenesulfonamide in solution in 40 cm3 of dioxane heated to reflux, a solution of 0 is added in approximately 20 minutes. , 69 g of giyoxylic acid in 10 cm 3 of distilled water The reaction is continued for 8 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. by one aqueous sodium hydroxide solution and the organic phase is extracted with ethyl acetate and discarded. The aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The product thus obtained is purified by flash chromatography on a silica column using dichloromethane as eluent. 0.35 g of 6,8-dichloro-3,4-dihydro-2- (3,5-dichlorobenzyl) - 2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid are isolated in the form of a white powder melting at 238 ° C.

2-amino-4,6-dichloro-N- (3,5-dichlorobenzyl) -benzenesuIfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 2.02 g of 3.5 -dichlorobenzylamine dissolved in 20 cm3 of tetrahydrofuran are added dropwise to a solution of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.62 cm3 of triethylamine in 20 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with ethyl acetate. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane as eluent (70/30 by volume), 2.1 g of 2-amino-4,6-dichloro-N- are obtained (3 , 5-dichlorobenzyl) -benzenesulfona mide in the form of a white powder melting at 130 ° C.

EXAMPLE 74

To 1.1 g of 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1,2,4- ethyl benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 4.22 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification using 1N hydrochloric acid, the organic phase is extracted with ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 0.3 g of 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 - acid 3-carboxy-dioxide are isolated in the form of a white powder decomposing at around 80 ° C. (Analysis (C22H- | ₈ Cl2N2θ5S)% calculated 0: 53.56;

H: 3.68; 01: 14.37; N: 5.68; 0: 16.21; S: 6.50; % found (0.92 Et 2θ) C: 54.0; H: 3.4; 01: 14.3; N: 5.8; 0: 16.3; S: 6.7).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1,2,4-benzothiadia zine-1,1-dioxide-3-carboxylate can be prepared in the following manner following: 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-dioxide- are added dropwise 3-ethyl carboxylate in anhydrous tetrahydrofuran, with 0.22 g of 50% sodium hydride in suspension in 5 cm 3 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 sulfate, filtration and concentration 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 cyclohexane (60/40 by volume) as eluent. 1.1 g of ethyl 6,8-dichloro-3,4-dihydro-2- (3-benzyloxybenzyl) -2H-1,2,4-benzothiadia zine-1, 1-dioxide-3-carboxylate are isolated in the form of a yellow oil which solidifies and which is used as it is in subsequent syntheses.

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 3-benzyloxybenzyl chloride are obtained in the form of a brown oil used as it is in the subsequent steps.

EXAMPLE 75

A 2.21 g of 6,8-dichloro-3,4-dihydro-2- (3-phenylbenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 15 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 9 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification using 1N hydrochloric acid, the precipitate formed is filtered, washed and then taken up in ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 1.6 g of acid

6,8-dichloro-3,4-dihydro-2- (3-phenylbenzyl) -2H-1, 2,4-benzothiadiazine-1, 1 - 3-carboxylic oxide are isolated as white powder decomposing around 100 ° C (Analysis (C2- | H-jgCl2N2θ4S)% calculated C: 54.44;

H: 3.48; 01: 15.30; N: 6.05; S: 6.92; % found C: 54.4; H: 4.0; Cl: 15.0; N: 5.6; S: 7.0).

Ethyl 6,8-dichloro-3,4-dihydro-2- (3-phenylbenzyI) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : under nitrogen, 20 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy are added dropwise ethyl late in anhydrous tetrahydrofuran, 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 4.57 g of 3-phenylbenzyl bromide in 15 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 5 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After drying over magnesium sulfate, filtration and concentration 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 cyclohexane (50/50 by volume) as eluent. 2.21 g of 6,8-dichloro-3,4-dihydro-2- (3-phenylbenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1,1-dioxide-3-carboxylate are isolated under white powder form melting at 186 ° C.

3-Phenylbenzyl bromide can be obtained according to the method described by C.W. SHOPPEE, J. Chem. Soc, 37 (1933).

EXAMPLE 76

2.67 g of 6,8-dichioro-3,4-dihydro-2- (2-phenethylbenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate in solution in 25 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 10.8 cm3 of a 0.5N aqueous sodium hydroxide solution are added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification with 1N hydrochloric acid, the organic phase is extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 2.19 g of 6,8-dichloro-3,4-dihydro-2- (2-phenethylbenzyl) -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylic acid are isolated under white powder form decomposing around 100 ° C (Analysis (C23H20CI2N2O4S)% calculated

0: 56.22; H: 4.10; 01: 14.43; N: 5.70; S: 6.53; % found C: 55.8; H: 4.5; 01: 14.1; N: 5.4; S: 6.6).

Ethyl 6,8-dichloro-3,4-dihydro-2- (2-phenethylbenzyl) -2H-1,2,4-benzothiadiazine -1, 1-dioxide-3-carboxyiate can be prepared as follows : under nitrogen, 20 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carbo are added dropwise ethyl xylate in anhydrous tetrahydrofuran, at 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3 g of 2-phenethylbenzyl chloride in 15 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 5 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is beaten in 20 cm 3 of methanol, then again filtered and dried. 2.67 g of 6,8-dichloro-3,4-dihydro-2- (2-phenethylbenzyl) -2H-1,2,4-benzothiadiazine- 1,1-dioxide-3-carboxylate are isolated under white powder form melting at 188 ° C.

2-Phenethylbenzyl chloride can be prepared according to the method described by JA MOORE et al., Org. Prep. Proced. Int., 16 (6), 411 (1984). EXAMPLE 77

To a solution of 1.2 g of 2-amino-4,6-dichloro-N- [3- (4-methyiphenoxy) benzyl] -benzenesulfonamide dissolved in 50 cm3 of dioxane heated to reflux, added in about 20 minutes a solution of 0.36 g of giyoxylic acid in 5 cm3 of distilled water. The reaction is continued for 4 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure.

The oil thus obtained is taken up in 1N sodium hydroxide and the organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid then the organic phase extracted with ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 0.6 g of 6,8-dichloro-3,4-dihydro-2- [3- (4-methylphenoxy) benzyl] -2H-1,2,4-benzothiadiazine-1, 1-oxide-3- carboxyli which are obtained in the form of a yellow solid decomposing at 86 ° C (Analysis (C22H18CI2N2O5S)% calculated C: 53.56; H: 3.68; 01: 14.37; N. 5.68;

S: 6.50; % found C: 53.4; H: 3.9; 01: 14.8; N: 5.5; S: 6.4).

The 2-amino 4,6-dichioro-N- [3- (4-methylphenoxy) benzyl] -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 2.2 g of 3- (4-methylphenoxy) benzyiamine dissolved in 40 cm3 of tetrahydrofuran are added dropwise to a solution of 2.68 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.45 cm3 of triethylamine in 40 cm3 of tetrahydrofuran. After 5 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in 50 cm3 of distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (80/20 by volume) as eluent, 1.2 g of 2-amino-4,6-dichloro-N- are obtained [3 - (4-methylphenoxy) benzyl] - benzenesulfonamide in the form of a pale yellow oil used as it is in subsequent syntheses.

3- (4-methylphenoxy) benzylamine can be prepared in the following manner: 6.5 g of 3- (4-methylphenoxy) benzaldehyde oxime dissolved in 50 cm3 of nitrogen are added dropwise anhydrous tetrahydrofuran containing 1.4 g of lithium aluminum hydride in 30 cm3 of the same solvent maintained at -10 ° C. After 2 hours of reaction at 50 ° C, the reaction medium is cooled to a temperature in the region of 20 ° C and then treated dropwise with 50 cm3 of distilled water. After adding 100 cm3 of dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (70/30 by volume) as eluent, 2 g of 3- (4-methylphenoxy) benzylamine are obtained in the form of a yellow oil used as which in subsequent syntheses.

3- (4-methylphenoxy) benzaldehyde-oxime can be prepared as follows: at a temperature in the region of 20 ° C, 3.19 g of hydroxylamine hydrochloride dissolved in 16 cm3 of water is added dropwise distilled in the presence of 4 cm3 of concentrated sodium hydroxide, to 8 g of 3- (4-methylphenoxy) benzaldehyde in solution in 8 cm3 of absolute ethanol. After 3 hours of reaction at the same temperature, the reaction medium is diluted with 30 cm3 of distilled water and 30 cm3 of dichloromethane, the organic phase is extracted and treated according to the usual process. 6.5 g of 3- (4-methylphenoxy) benzaldehyde-oxime are obtained in the form of a white solid, melting at 101 ° C.

EXAMPLE 78

A 1.9 g of 6,8-dichloro-3,4-dihydro-2- [2- (dimethylamino) ethyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate ethyl in solution in 40 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 9.58 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification using 1N hydrochloric acid, a gum separates which is taken up in dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The product thus obtained is recrystallized from boiling ethanol to yield 0.2 g of 6,8-dichloro-3,4-dihydro-2- [2- (dimethylamino) ethyl] -2H-1, 2, acid, 4- benzothiadiazine-1, 1-dioxide-3-carboxylic in the form of white powder decomposing at 224 ° C (Analysis (C12H15CI2N3O4S)% calculated 0: 39.13; H: 4.11; 01: 19.26; N: 11, 41; S: 8.71;% found (0.5EtOH) C: 39.1; H: 4.1; Cl: 19.3; N: 11.3; S: 9.0).

Ethyl 6,8-dichloro-3,4-dihydro-2- [2- (dimethylamino) ethyl] -2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 40 cm3 of a solution of 5 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide are added dropwise -3- ethyl carboxylate in anhydrous tetrahydrofuran, at 0.74 g of 50% sodium hydride suspended in 30 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 4.43 g of 1-chloro-2- (dimethylamino) -ethane in 20 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 5 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 washing with water, drying over magnesium sulfate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is purified by flash chromatography on a silica column using a mixture of ethyl acetate and methanol (95/5 by volume) as eluent. 1.9 g of 6,8-dich.oro-3,4-dihydro-2- [2- (dimethylamino) ethyl] -2H-1,2,4- benzothiadiazine-1, 1-dioxide-3-carboxylate d 'ethyl are isolated in the form of a yellow oil which solidifies and which is used as it is in subsequent syntheses.

EXAMPLE 79

To 1.98 g of ethyl 6,8-dichloro-3,4-dihydro-2- (3,5-dimethylbenzyl) -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylate dissolved in 15 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 8.9 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in water and acidified with 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried. 1.82 g of hydrate of 6,8-dichloro-3,4-dihydro-2- (3,5-dimethylbenzyl) -2H-1,2,4-benzothiadiazine-1, 1-dioxide are isolated. -3- carboxylic in the form of white powder decomposing at around 100 ° C (Analysis (C- | ₇ Hι Cl2N2θ4S.H2θ)% calculated C: 47.12; H: 4.19; 01: 16.36; N: 6.46; S: 7.40;% found (0.71 H ₂ 0; 0.15 CH ₂ Cl2) 0: 47.1; H: 3.8; 01: 16.1;

N: 6.6; S: 7.6.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3,5-dimethylbenzyl) -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylate can be prepared from as follows: to 3.5 g of 2-amino-4,6-dichloro-N- (3,5-dimethylbenzyl) -benzene sulfonamide in 50 cm3 of absolute ethanol brought to reflux, 1 is added dropwise, 64 g of giyoxylic acid in solution in 50 cm3 of absolute ethanol in the presence of 4.5 cm3 of concentrated sulfuric acid. The reaction is continued for 2 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is taken up in 20 cm3 of absolute ethanol and recrystallized. 1.98 g of 6.8-dichloro-3,4-dihydro-2- (3,5-dimethylbenzyl) -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylate are obtained. ethyl in the form of a white powder melting at 161 ° C.

The 2-amino-4,6-dichloro-N- (3,5-dimethylbenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.78 g of 3.5 -dimethylbenzylamine are gradually added to a solution of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and of 1.1 cm3 of triethylamine in 40 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 3.5 g of 2-amino-4,6-dichloro-N- (3,5-dimethylbenzyl) -benzenesulfonamide are obtained in the form of a beige solid used as it is in the subsequent syntheses.

EXAMPLE 80

0.5 g of 6,8-dichloro-3,4-dihydro-2- {3 - [(3-trifluoromethy) phenoxy] benzyl} - 2H-1, 2,4-benzothiadiazine-1, 1-dioxide- Ethyl 3-carboxylate in solution in 5 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 1.7 cm3 of an aqueous solution of 0.5N sodium hydroxide are added dropwise. The reaction is continued for 1 hour at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified with 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. We isolate

0.33 g 6,8-dichloro-3,4-dihydro-2- {3 - [(3-trifluoromethy) phenoxy] benzyl} -2H-1,2,4-benzothiadiazine-1,1-oxide -3-carboxylic in the form of white powder decomposing around 100 ° C (Analysis (C22H15CI2F3N2O5S)% calculated C: 48.28; H: 2.76; 01: 12.95; F: 10.41; N: 5, 12;

S: 5.86; % found 0: 48.2; H: 3.1; Cl: 13.0; R10.0; N: 5.5; S: 5.9).

6,8-dichloro-3,4-dihydro-2- {3 - [(3-trifluoromethy) phenoxy] benzyl} -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylate ethyl can be prepared as follows: to 3.04 g of 2-amino-4,6-dichloro-N- {3 - [(3-trifluoromethy) phenoxy] benzyl} -benzenesulfonamide in 40 cm3 of absolute ethanol carried at reflux, 1.14 g of giyoxylic acid dissolved in 40 cm3 of absolute ethanol in the presence of 3.9 cm3 of concentrated sulfuric acid are added dropwise. The reaction is continued for 3 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is taken up in distilled water and the organic phase extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flah-chromatography on a silica column using dichloromethane as eluent, 0.5 g of 6,8-dichloro-3,4-dihydro-2- {3 - [(3-trifluoromethy) phenoxy] benzyl is obtained. } -2H-1, 2,4-Benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in the form of a white powder melting at 125 ° C.

The 2-amino-4,6-dichloro-N- {3 - [(3-trifluoromethyl) phenoxy] benzyl} -benzene sulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 2 , 25 g of 3- [3- (trifluoromethyl) phenoxyjbenzylamine are gradually added to a solution of 1.93 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 2.08 cm3 of triethylamine in 25 cm3 of tetrahydrofuran. After 1 hour of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in 50 cm3 of distilled water and the organic phase extracted with dichloromethane. 3.04 g of 2-amino-4,6-dichloro-N- {3 - [(3-trifluoromethyl) phenoxy] benzyl} -benzenesulfonamide are obtained in the form of a brown oil used as it is in the subsequent stages. 3- [3- (trifluoromethyl) phenoxy] benzylamine can be prepared as follows: under nitrogen, 9.16 g of 3- (3-trifluoromethylphenoxy) benzaldehyde oxime dissolved in 60 cm3 of anhydrous tetrahydrofuran at 1.56 g of lithium aluminum hydride in 30 cm3 of the same solvent maintained at 0 ° C. After 8 hours of reaction at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C. then treated dropwise with 50 cm3 of distilled water. After adding 100 cm3 of dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by formation of the hydrochloride in ethyl ether and filtration, 2.25 g of 3- [3- (trifluoromethyl) phenoxy] benzylamine hydrochloride are obtained in the form of a white powder melting at 127 ° C.

3- (3-trifluoromethylphenoxy) benzaldehyde-oxime can be prepared according to the following method: at a temperature in the region of 20 ° C, 2.6 g of hydroxylamine hydrochloride dissolved in 20 cm3 of water are added dropwise distilled in the presence of 3.75 cm3 of concentrated sodium hydroxide, to 9.1 g of 3- (3-trifluoromethylphenoxy) benzaldehyde in solution in 10 cm3 of absolute ethanol. After 3 hours of reaction at the same temperature, the precipitate formed is filtered, washed with water and dried. 9.16 g of 3- (3-trifluoromethylphenoxy) benzaldehyde-oxime are obtained in the form of a pale yellow solid melting at 65 ° C.

EXAMPLE 81

At 1.8 g of 6,8-dichloro-3,4-dihydro-2- [3- (3,5-dichlorophenoxy) benzyl] -2H- 1,2,4-benzothiadiazine-1, 1-dioxide-3 - ethyl carboxylate in solution in 20 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 6.24 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 3 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over sulphate. magnesium and concentrated under reduced pressure until a product precipitates. After filtration and drying, 0.4 g of 6,8-dichloro-3,4- acid is isolated. dihydro-2- [3- (3,5-dichlorophenoxy) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1 - dioxide-3-carboxyIique in the form of white powder decomposing around 110 ° C (Analysis ( C2iH-f4θl4 2θ ₅ S)% calculated C.46.01; H: 2.57; Cl: 25.87;

N: 5.11; S: 5.85; % found C: 45.6; H: 2.5; Cl: 25.9; N: 5.3; S: 5.8).

Ethyl 6,8-dichloro-3,4-dihydro-2- [3- (3,5-dichlorophenoxy) benzyl] -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows: 2.9 g of 2-amino-4,6-dichloro-N- [3- (3,5- dichlorophenoxy) benzyl] -benzenesulfonamide in 40 cm3 of absolute ethanol brought to reflux 1.08 g of giyoxylic acid dissolved in 40 cm3 of absolute ethanol in the presence of 3.5 cm3 of concentrated sulfuric acid are added dropwise. The reaction is continued for 2 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. The precipitate formed is filtered, washed with ethanol and dried. 1.8 g of 6.8-dichloro-3,4-dihydro-2- [3- (3,5-dichlorophenoxy) benzyl] -2H-1,2,4-benzothiadia zine-1,1-dioxide are isolated. -3-ethyl carboxylate in the form of a white powder melting at 182 ° C.

The 2-amino-4,6-dichloro-N- [3- (3,5-dichiorophenoxy) benzyl] -benzene sulfona mide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 1 , 8 g of 3- (3,5-dichiorophenoxy) benzylamine are gradually added to a solution of 1.54 g of 2-amino-4,6-dichlorobenzenesulphonyl chloride and 1.66 cm3 of triethylamine in 20 cm3 of tetrahydrofuran . After 2 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue taken up in distilled water and the organic phase extracted with dichloromethane. 2.9 g of 2-amino-4,6-dichloro-N- [3- (3,5-dichlorophenoxy) benzyll-benzenesulfonamide are obtained in the form of a brown oil used as it is in the subsequent stages.

3- (3,5-dichlorophenoxy) benzylamine can be prepared in the following way: under nitrogen, 10.65 g of 3- (3,5-dichlorophenoxy) benzafdehyde oxime dissolved in 60 cm3 are added dropwise anhydrous tetrahydrofuran containing 1.86 g of lithium aluminum hydride in 30 cm3 of the same solvent maintained at 0 ° C. After 6 hours of reaction at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C. then treated dropwise with 50 cm3 of distilled water. After adding 100 cm3 of dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by formation of the hydrochloride in ethyl ether and filtration, 1.80 g of 3- (3,5-dichlorophenoxy) benzylamine hydrochloride are obtained in the form of a white powder melting at 163 ° C.

3- (3,5-dichlorophenoxy) benzaldehyde-oxime can be prepared according to the following method: at a temperature in the region of 20 ° C, 3.41 g of hydroxylamine hydrochloride dissolved in 20 cm3 are added dropwise distilled water in the presence of 4.9 cm3 of concentrated sodium hydroxide, to 11.94 g of 3- (3,5-dichlorophenoxy) benzaldehyde in solution in 10 cm3 of absolute ethanol. After 3 hours of reaction at the same temperature, the precipitate formed is filtered, washed with water and dried. 10.65 g of 3- (3,5-dichlorophenoxy) benzaldehyde-oxime are obtained in the form of a pale yellow solid melting at 94 ° C.

EXAMPLE 82

To a solution of 0.7 g of 2-amino-4,6-dichloro-N- [3- (4-chlorophenoxy) benzyl] -benzenesulfonamide in 40 cm3 of dioxane heated to reflux, a solution is added in approximately 20 minutes 0.20 g of giyoxylic acid in 5 cm3 of distilled water. The reaction is continued for 6 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The oil thus obtained is taken up in 1N sodium hydroxide and the organic phase is extracted with dichloromethane and discarded. The aqueous phase is acidified using 1N hydrochloric acid then the organic phase is extracted with ethyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using a mixture of dichloromethane and methanol (90/10 by volume) as eluent, 0.18 g of 6,8-dichloro-3,4-dihydro-2- acid [3- (4-chlorophenoxy) benzyl] -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy liquefied as a yellow solid decomposing at 79 ° C (Analysis (C21 H15CI3N2O5S) % calculated C: 49.10; H: 2.94; Cl: 20.70; N: 5.45; S: 6.24; % found (0.70iPr2θ.0.38CH2Cl2) C: 48.9; H: 2.8; Cl: 20.8; N: 5.7; S: 6.7).

The 2-amino-4,6-dichloro-N- [3- (4-chlorophenoxy) benzyl] -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.9 g of 3- (4-chlorophenoxy) benzylamine dissolved in 30 cm3 of tetrahydrofuran are added dropwise to a solution of 2.10 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.14 cm3 of triethylamine in 30 cm3 of the same solvent. After 3 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in 30 cm3 of distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (70/30 by volume) as eluent, 0.7 g of 2-amino-4,6-dichloro-N- is obtained [3 - (4-chlorophenoxy) benzyl] - benzenesulfonamide in the form of lightly colored oil used as it is in subsequent syntheses

3- (4-chlorophenoxy) benzylamine can be prepared in the following manner: 5.3 g of 3- (4-chlorophenoxy) benzaldehyde oxime dissolved in 30 cm3 of anhydrous tetrahydrofuran are added dropwise under nitrogen. 1.10 g of lithium aluminum hydride in 20 cm 3 of the same solvent maintained at 0 ° C. After 10 hours of reaction at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C. then treated dropwise with 50 cm3 of distilled water. After addition of dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using a mixture of dichloromethane and methanol (95/5 by volume) as eluent, 1.9 g of 3- (4-chlorophenoxy) benzylamine are obtained in the form of an oil yellow used as it is in subsequent syntheses.

3- (4-chlorophenoxy) benzaldehyde-oxime can be prepared according to the following method: at a temperature in the region of 20 ° C, 3.28 g of hydroxylamine hydrochloride dissolved in 20 cm3 of water is added dropwise distilled in the presence of 4.72 cm3 of concentrated sodium hydroxide, to 10 g of 3- (4-chlorophenoxy) benzaldehyde in solution in 10 cm3 of absolute ethanol. After 3 hours of reaction at the same temperature, the precipitate formed is filtered, washed with water and dried. 8.3 g of 3- (4-chlorophenoxy) benzaldehyde-oxime are obtained in the form of a white powder melting at 95 ° C.

EXAMPLE 83

To a solution of 1.2 g of 2-amino-4,6-dichloro-N- [3- (4-methoxyphenoxy) benzyi] -benzenesulfonamide dissolved in 40 cm3 of dioxane heated to reflux, added in about 20 minutes a solution of 0.48 g of giyoxylic acid in 10 cm3 of distilled water. The reaction is continued for 14 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The oil thus obtained is treated with 1 N sodium hydroxide solution to pH 8 and the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using a mixture of ethyl acetate and methanol (90/10 by volume) as eluent, the product obtained is taken up in ethyl acetate, washed with l hydrochloric acid 1 N, dried over magnesium sulphate and concentrated to dryness under reduced pressure. After beating in isopropyl ether, 0.30 g of 6,8-dichloro-3,4-dihydro-2- [3- (4-methoxyphenoxy) benzyl] -2H-1, 2,4-benzothiadiazine- 1, 1 - 3-carboxylic dioxide are obtained in the form of a white solid decomposing around 110 ° C (Analysis (C22H- | ₈ Cl2N2θgS)% calculated C: 51, 88;

H: 3.56; Cl: 13.92; N: 5.50; S: 6.29; % found (0.20 iPr O; 0.15H O) C: 52.2; H: 3.7; CI: 14.4; N: 5.6; S: 6.1).

The 2-amino-4,6-dichloro-N- [3- (4-methoxyphenoxy) benzyl] -benzenesulfona mide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 1.6 g of 3- (4-methoxyphenoxy) benzylamine dissolved in 50 cm3 of tetrahydrofuran are added dropwise to a solution of 1.56 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.69 cm3 of triethylamine in 50 cm3 of the same solvent. After 3 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in 50 cm3 of distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using ethyl acetate as eluent, 0.77 g of 2-amino-4,6-dichloro-N- [3- (4-methoxyphenoxy) benzyl] is obtained -benzenesulfonamide in the form of a yellow oil used as it is in subsequent syntheses.

3- (4-methoxyphenoxy) benzylamine can be prepared as follows: under nitrogen, 8.4 g of 3- (4-methoxy phenoxy) benzaldehyde-oxime dissolved in 50 cm3 of anhydrous tetrahydrofuran are added dropwise 1.86 g of lithium aluminum hydride in 30 cm3 of the same solvent maintained at 0 ° C. After 5 hours of reaction at reflux, the reaction medium is cooled to a temperature in the region of 20 ° C. then treated dropwise with 50 cm3 of distilled water. After addition of dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by formation of the hydrochloride of the product obtained in ethyl ether, 1.6 g of 3- (4-methoxyphenoxy) benzylamine are obtained in the form of a white solid used as such in the subsequent syntheses.

3- (4-methoxyphenoxy) benzaldehyde-oxime can be prepared according to the following method: at a temperature in the region of 20 ° C, 3.3 g of hydroxylamine hydrochloride dissolved in 20 cm3 of water are added dropwise distilled in the presence of 4.8 cm3 of concentrated sodium hydroxide, to 10 g of 3- (4-chlorophenoxy) benzaldehyde in solution in 10 cm3 of absolute ethanol. After 3 hours of reaction at the same temperature, the precipitate formed is filtered, washed with water and dried. 8.4 g of 3- (4-methoxyphenoxy) benzaldehyde-oxime are obtained in the form of a white powder melting at 119 ° C.

EXAMPLE 84

1.38 g of 6,8-dichloro-3,4-dihydro-2- {2 - [(10-methyl) phenothiazinyl] methyl} - 2H-1,2,4-benzothiadiazine-1, l-dioxide- Ethyl 3-carboxylate in solution in 15 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over sulfate. of magnesium and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using dichloromethane then a mixture of dichloromethane and methanol (90/10 by volume) as eluents and beating in a mixture of acetone and distilled water, 0.74 is isolated g of 6,8-dichloro-3,4-dihydro-2- {2 - [(10-methyl) pheno thiazinyl] methyl} -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 -carboxylic in the form of pink powder decomposing at around 110 ° C. (Analysis (C22H17CI2N3O4S2)% calculated C: 50.58; H: 3.28; Cl: 13.57; N: 8.04; 0: 12.25;

S: 12.27; % found (0.50 acetone) C: 50.4; H: 3.5; Cl: 13.8; N: 8.1; 0: 12.3; S: 11, 9).

6,8-dichloro-3,4-dihydro-2- {2 - [(10-methyl) phenothiazinyl] methyl} -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate ethyl can be prepared as follows: to 5 g of 2-amino-4,6-dichloro-N- {2 - [(10-methyl) phenothiazinyl] methyl} -benzenesulfonamide in 60 cm3 of absolute ethanol brought to reflux 1.97 g of giyoxylic acid dissolved in 70 cm3 of absolute ethanol in the presence of 5.8 cm3 of concentrated sulfuric acid are added dropwise. The reaction is continued for 3 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated to dryness under reduced pressure. The residue is taken up in distilled water and the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using dichloromethane as eluent, followed by washing with ethanol, 1.38 g of 6.8-dichloro-3,4-dihydro-2- {2 are obtained. - [(10-methyl) phenothiazinyl] methyl} -2H-1, 2,4-benzo thiadiazine-1, 1-dioxide-3-carboxylate as a white powder ^'melting at 224 ° C.

The 2-amino-4,6-dichloro-N- {2 - [(10-methyl) phenothiazinyl] methyl} -benzene sulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 3 , 19 g of 2 - [(10-methyl) phenothiazinyl] methylamine dissolved in 15 cm3 of tetrahydrofuran are added dropwise to a solution of 3 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.55 cm3 of triethylamine in 15 cm3 of the same solvent. After 15 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with dichloromethane. 5 g of 2-amino-4,6-dichloro-N- {2 - [(10-methyl) pheno thiazinyl] methyl} -benzenesulfonamide are obtained in the form of a brown meringue used as it is in the subsequent steps.

2 - [(10-methyl) phenothiazinyl] methylamine can be prepared as follows: 3.6 g of lithium aluminum hydride suspended in 60 cm3 of anhydrous tetrahydrofuran cooled to 0 ° C. drop by drop 11.4 g of 2-cyano-10-methyl-phenoth.azine in solution in 60 cm3 of the same solvent. The reaction is continued for 2 hours at a temperature in the region of 20 ° C. The reaction medium is added slowly to ice water then the mixture filtered through celite and the organic phase extracted with dichloromethane. 10 g of 2 - [(10-methyl) pheno thîazinyOmethylamine are obtained in the form of a yellow oil used as it is in subsequent syntheses.

2-cyano-10-methyl-phenothiazine can be prepared as follows: 20 g of 2-cyanophenothiazine, 8.5 cm3 of methyl iodide and 50 cm3 of methanol are heated at 120 ° C in an autoclave for 18 hours. The crude product is taken up in dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by flash chromatography on a silica column using dichloromethane as eluent and recrystallization from acetonitrile, 11.4 g of 2-cyano-10-methyl-phenothiazine are obtained in the form of a yellow powder melting at 136 ° C.

2-cyanophenothîazine can be prepared according to the method described in US Patent 2,877,224.

EXAMPLE 85

To 0.7 g of 6,8-dichloro-3,4-dihydro-2- [2- (3-indolyl) ethyl] -2H-1, 2,4-benzothiadiazine-1,1-dioxide-3-carboxyfate ethyl in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 3 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification with 1N hydrochloric acid, it separates one, precipitate which is filtered, washed with isopropyl ether and dried. 0.37 g 6,8-dichloro-3,4-dihydro-2- [2- (3-indolyl) ethyl] -2H-1, 2,4-benzothia diazine-1, 1-dioxide-3 acid -carboxylic are thus isolated in the form of a pale yellow powder melting at 118 ° C.

Ethyl 6,8-dichioro-3,4-dihydro-2- [2- (3-indolyl) ethyl] -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate may be prepared in the following manner: under nitrogen, 40 cm3 of a solution of 3 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 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 4 g of 1-bromo-2- (3-indolyl) ethane in 20 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 7 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After washing with water, drying over magnesium sulfate, filtration and concentration 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 cyclohexane (50/50 by volume) as eluent. 0.7 g of 6,8-dichloro-3,4-dihydro-2- [2- (3-indolyl) ethyl] -2H- 1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d 'ethyl are isolated in the form of white meringue used as it is in subsequent syntheses.

1-Bromo-2- (3-indolyl) ethane can be prepared according to the method described by T. HOSHINO et al., Justus Liebigs Ann. Chem., 520, 19 (1935).

EXAMPLE 86

A 1.5 g of 6,8-dichloro-3,4-dihydro-2- (3,5-difluorobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid dissolved in 40 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 6.6 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification using 1N hydrochloric acid, the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After recrystallization from boiling acetonitrile, 0.50 g of 6,8-dichloro-3,4-dihydro-2- (3,5-dif luorobenzyl) -2H-1, 2,4-benzothiadiazine-1 acid, 1-3-carboxy-dioxide are isolated in the form of a white powder melting at 112 ° C.

Ethyl 6,8-dichloro-3,4-dihydro-2- (3,5-difluorobenzyl) -2H-1,2,4-benzothiadiazine-1,1-doxide-3-carboxylate can be prepared from as follows: under nitrogen, 40 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3 are added dropwise ethyl carboxylate in anhydrous tetrahydrofuran, at 0.44 g of sodium hydride at 50% in suspension in 10 cm 3 of the same solvent After 30 minutes of stirring at a temperature close to 20 ° C., it is poured dropwise drop a solution of 3.8 g of (3,5-difluoro) benzyl bromide in 20 cm3 of dimethylformamide. The reaction medium is then brought to reflux for 3 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After washing with water, drying over magnesium sulfate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is purified by recrystallization from boiling acetonitrile. 1.5 g of 6,8-dichloro-3 are isolated. , 4-dihydro-2- (3,5-difluorobenzyl) -2H-1, 2,4-benzothia diazine-1,1-dioxide-3-carboxylate in the form of a white powder melting at 174 ° C.

EXAMPLE 87

To 1.5 g of 6,8-dichloro-3,4-dihydro-2- [3- (3,4-dichlorophenoxy) benzylJ-2H- 1,2,4-benzothiadiazine-l, 1-dioxide-3- ethyl carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C, 5.2 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue is taken up in water and acidified using 1N hydrochloric acid. The organic phase is extracted with ethyl ether, washed with water. , dried over magnesium sulfate and concentrated under reduced pressure. The product obtained is beaten in isopropyl ether, filtered and dried. 0.5 g of 6,8-dichloro- acid are isolated

3,4-dihydro-2- [3- (3,4-dichlorophenoxy) benzyl] -2H-1, 2,4-benzothiadiazine-

1, 1-3-dioxide-carboxylic in the form of white powder decomposing around 90 ° C (Analysis (C21 H14CI4N2O5S)% calculated C: 46.01; H: 2.57; 01: 25.87; N: 5, 11;% found (0.64H ₂ O; 0.50iPr2θ) C: 46.2; H: 2.4; Cl: 25.6; N: 5.4).

Ethyl 6,8-dichloro-3,4-dihydro-2- [3- (3,4-dichlorophenoxy) benzyl] -2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate can be prepared as follows: 3.5 g of 2-amino-4,6-dichloro-N- [3- (3,4- dichlorophenoxy) benzyl] -benzenesulfonamide in 50 cm3 of absolute ethanol brought to reflux 1.15 g of giyoxylic acid dissolved in 50 cm3 of absolute ethanol in the presence of 4.2 cm3 of concentrated sulfuric acid are added dropwise. The reaction is continued for 3 hours at reflux, then the reaction medium cooled to a temperature in the region of 20 ° C. The precipitate formed is filtered, washed with ethanol and dried. 1.5 g of 6,8-dichloro-3,4-dihydro-2- [3- (3,4-dichlorophenoxy) benzyl] -2H-1,2,4-benzo thiadiazine-1, 1-dioxide are isolated. -3-ethyl carboxylate in the form of a beige powder melting at 147 ° G.

The 2-amino-4,6-dichloro-N- [3- (3,4-dichlorophenoxy) benzyl] -benzenesuifo namide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C, 2, 05 g of 3- (3,4-dichlorophenoxy) benzylamine are gradually added to a solution of 1.75 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 1.9 cm3 of triethylamine in 40 cm3 of tetrahydrofuran. After 15 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with dichloromethane. 3.5 g of 2-amino-4,6-dichloro-N- [3- (3,4-dichloro phenoxy) benzyl] -benzenesulfonamide are obtained in the form of a brown oil used as it is in the subsequent stepsτ

3- (3,4-dichlorophenoxy) benzylamine can be prepared as follows: 1, 4 g of 3- (3,4-dichlorophenoxy) benzaldehyde oxime dissolved in 25 cm3 of acetic acid at 10 ° C , gradually adding 2.13 g of zinc powder. After 9 hours of reaction at 80 ° C., the reaction medium is cooled to a temperature close to 20 ° C then the insoluble matter filtered. The filtrate is concentrated to dryness, then taken up in water and acidified with 1N hydrochloric acid. The precipitate formed is filtered and dried. 0.72 g of 3- (3,4-dichlorophenoxy) benzylamine hydrochloride is obtained in the form of a white solid, decomposing at 71 ° C.

3- (3,4-dichlorophenoxy) benzaIdehyde-oxime can be prepared according to the following method: at a temperature in the region of 20 ° C, 2.8 g of hydroxylamine hydrochloride dissolved in 20 cm3 are added dropwise distilled water in the presence of 4 cm 3 of concentrated sodium hydroxide, to 10 g of 3- (4-chlorophenoxy) benzaldehyde in solution in 10 cm 3 of absolute ethanol. After 3 hours of reaction at the same temperature, the precipitate formed is filtered, washed with water and dried. 8.2 g of 3- (3,4-dichlorophenoxy) benzaldehyde-oxime are obtained in the form of a white powder melting at 97 ° C.

EXAMPLE 88

To 0.9 g of 6,8-dichloro-3,4-dihydro-2- [3- (benzoylamino) benzyl] -2H-1,2,4- benzothiadiazine-1,1-dioxide-3-carboxylate ethyl in solution in 10 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 3.4 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 2 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure, the residue is taken up in dichloromethane and the insoluble material is filtered, washed with ethyl acetate and dried.

0.65 g of sodium salt of the acid 6,8-dichloro-3,4-dihydro-2- [3-

(benzoylamino) benzyi] -2H-1, 2,4-benzothiadiazine-1, 1-3-dioxide-carbon dioxide in the form of a pale yellow powder decomposing around 220 ° C (Analysis (C2 Hι Cl2N3NaOsS)% calculated C: 50 , 01; H: 3.05; 01: 13.42;

N: 7.95; Na: 4.35; S: 6.07; % found (0.41 H2O; 0.42AcOEt) C: 50.0; H: 3.1; C !: 13.1; N: 8.0; Na: 4.4; S: 6.3).

Ethyl 6,8-dichloro-3,4-dihydro-2- [3- (benzoyfamino) benzyl] -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylate can be obtained as follows: 8.6 g of 6,8-dichloro-3,4-dihydro-2- (3-aminobenzyl) -2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate d ethyl and 2.2 cm3 of triethylamine are stirred in solution in 80 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C. 1.87 cm3 of benzoyl chloride are added drop by drop and the reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. The insoluble material is filtered, washed with water and then with methanol to yield 6.5 g of 6,8-dichloro-3,4-dihydro-2- [3- (benzoylamino) benzyl] -2H-1, 2 , 4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in the form of a white powder melting at 206 ° C.

EXAMPLE 89

A 1,4 g of 6,8-dichloro-3,4-dihydro-2- (4-phenoxybenzyl) -2H-1, 2,4-ethyl benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 5.52 cm3 of a 0.5N aqueous sodium hydroxide solution is added dropwise. The reaction is continued for 15 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure, the residue taken up in water and acidified with 1N hydrochloric acid. The organic phase is extracted with dichloromethane, washed with water, dried over sulphate. magnesium and concentrated under reduced pressure. The product obtained is beaten in isopropyl ether then in pentane, filtered and dried. 0.3 g of 6,8-dichloro-3,4-dihydro-2- (4-phenoxybenzyl) -2H-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid is isolated under white powder form decomposing at 88 ° C (Analysis (C2- | H- | gCl2N2θ5S)% calculated C: 52.63;

H: 3.36; Cl: 14.79; N: 5.84; S: 6.69; % found (0.42H O; 0.15 iPr ₂ O) C: 52.5; H: 3.4; CI: 15.1; N: 5.5; S: 6.9).

Ethyl 6,8-dichloro-3,4-dihydro-2- (4-phenoxybenzyl) -2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared as follows : 3.4 g of 2-amino-4,6-dichloro-N- (4-phenoxybenzyl) -benzenesulfonamide in 60 cm3 of absolute ethanol brought to reflux, 1.37 g of giyoxylic acid are added dropwise dissolved in 60 cm3 of absolute ethanol in the presence of 5 cm3 of concentrated sulfuric acid. The reaction is continued for 2 hours at reflux, then the reaction medium cooled to a temperature in the region of 20 ° C. The precipitate formed is filtered, washed with isopropyl ether and dried. 1.4 g of 6,8-dichloro-3,4-dihydro- 2- (4-phenoxybenzyl) -2H-1,2,4-benzothiadiazine-1, 1-3-dioxide-3-carboxylate are isolated under white powder form melting at 135 ° C. The 2-amino-4,6-dichloro-N- (4-phenoxybenzyl) -benzenesulfonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 2.98 g of 4-phenoxybenzylamine are added gradually to a solution of 3.9 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 4.2 cm3 of triethylamine in 50 cm3 of tetrahydrofuran. After 15 hours of stirring at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with dichloromethane. 3.4 g of 2-amino-4,6-dichloro-N- (4-phenoxybenzyl) -benzenesulfonamide are obtained in the form of a brown oil used as it is in the subsequent steps.

4-Phenoxybenzylamine can be prepared as described by ITO et al., Chem. Pharm. Bull., 5, 397 (1957).

EXAMPLE 90

To a solution of 0.6 g of 2-amino-4,6-dichloro-N-benzyloxy-benzenesulfonamide in solution in 10 cm 3 of dioxane heated to reflux, a solution of 0.24 g of giyoxylic acid in 3 cm3 of distilled water. The reaction is continued for 4 hours at reflux, then the reaction medium is cooled to a temperature in the region of 20 ° C. and concentrated until a precipitate appears. The insoluble material thus obtained is filtered, washed with water and then with dichloromethane and recrystallized from cyclohexane. 0.35 g of 2-benzyloxy-6,8-dichloro-3,4-dihydro-2H- 1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylic acid are obtained in the form of a white powder. decomposing around 90 ° C (Analysis (C15H1 CI2 2O5S)% calculated C: 44.68; H: 3.00; 01: 17.58; N: 6.95; S: 7.95;% found C: 44, 3; H: 3.4; CI: 17.3; N: 6.8; S: 8.0).

The 2-amino-4,6-dichloro-N-benzyloxy-benzenesuifonamide can be obtained in the following manner: under nitrogen and at a temperature in the region of 20 ° C., 2.4 g of O-benzylhydroxylamine hydrochloride are gradually added to a solution of 4 g of 2-amino-4,6-dichlorobenzenesulfonyl chloride and 4.2 cm3 of triethylamine in 50 cm3 of tetrahydrofuran. After stirring overnight at the same temperature, the reaction medium is concentrated to dryness under reduced pressure, then the residue is taken up in distilled water and the organic phase extracted with dichloromethane. After purification by flash chromatography on a silica column using a mixture of dichloromethane and cyclohexane (60/40 by volume) as eluent, 0.70 g of 2-amino-4,6-dichloro-N-benzyloxy- is obtained. benzenesulfonamide in the form of a white powder melting at 124 ° C.

EXAMPLE 91

A 0.9 g of ethyl 2- (3-benzoylbenzyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylate in solution in 30 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 3.5 cm3 of an aqueous solution of 0.5N sodium hydroxide is added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in distilled water. After acidification using 1N hydrochloric acid, the organic phase is extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness under reduced pressure. After threshing in petroleum ether of the product thus obtained, 0.60 g of 2- (3-benzoylbenzyl) - 6,8-dichloro-3,4-dihydro - 2H-1, 2,4-benzothiadiazine acid -1, 1-dioxide-3-carboxylic acid are isolated in the form of a white powder melting at 207 ° C.

Ethyl 2- (benzoylbenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1 - 3-dioxide-3-carboxylate can be prepared as follows: under nitrogen, 40 cm3 of a solution of 3 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy late d are added dropwise ethyl in anhydrous tetrahydrofuran, at 0.44 g of 50% sodium hydride suspended in 10 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 3 g of 3-bromomethylbenzophenone in 20 cm3 of dimethylformamide is poured in dropwise. The reaction medium is then brought to reflux for 7 hours, then concentrated to dryness under reduced pressure. The residue obtained is taken up in distilled water and the organic phase extracted with dichloromethane. After washing with water, drying over magnesium sulfate, filtration and concentration to dryness under reduced pressure, the crude product thus obtained is purified by flash chromatography on a silica column using dichloromethane as eluent. 0.9 g of 2- (benzoylbenzyl) -6,8- dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-ethyl dioxide-3-carboxylate in the form of d are isolated. little colored oil used as it is in subsequent syntheses.

3-Bromomethibenzophenone can be prepared according to the method described by D.C. SCHLEGEL et al., J. Med. Chem., 27 (12), 1682 (1984).

EXAMPLE 92

A 0.34 g of 2- (3,5-diaminobenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxy! Ate d ethyl dissolved in 5 cm3 of tetrahydrofuran at a temperature in the region of 20 ° C., 1.5 cm3 of an aqueous solution of 0.5N sodium hydroxide are added dropwise. The reaction is continued for 16 hours at the same temperature. The reaction medium is concentrated to dryness under reduced pressure and the residue taken up in ethyl acetate. The insoluble material is filtered and then recrystallized when cold from acetonitrile. 0.235 g sodium salt of 2- (3,5-diaminobenzyl) -6,8- dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3- acid carboxyiques are isolated in the form of a pale pink powder which decomposes around 220 ° C.

Ethyl 2- (3,5-daminobenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylate can be prepared from as follows: to 2.55 g of 2- (3,5-dinitrobenzyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1,1-dioxide-3- ethyl carboxylate dissolved in 30 cm3 of absolute ethanol at a temperature in the region of 20 ° C, 5.64 g of tin (II) chloride dihydrate is gradually added. The reaction medium is heated at reflux for 30 minutes, then cooled and concentrated to dryness under reduced pressure. The residue is taken up in water and the organic phase is extracted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated to dryness. After purification by flash chromatography on a silica column using a mixture of dichloromethane and methanol (95/5 by volume) as eluent, 0.81 g of 2- (3,5-dinaminobenzyl) is obtained. dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-ethyl oxide-3-carboxylate in the form of a white powder melting at 183 ° C. Ethyl 2- (3,5-dinitrobenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-3-carboxylate can be prepared from as follows: under nitrogen, 20 cm3 of a solution of 4 g of 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3 are added dropwise -carboxy late of ethyl in anhydrous tetrahydrofuran, with 0.59 g of sodium hydride at 50% in suspension in 20 cm3 of the same solvent. After 30 minutes of stirring at a temperature in the region of 20 ° C., a solution of 4 g of 3,5-dinitrobenzyl chloride in 20 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 a mixture of distilled water and dichloromethane. The insoluble material is filtered, washed with isopropanol and dried. 2.55 g of 2- (3,5-dinitrobenzyl) -6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid are isolated. ethyl in the form of a pink powder, melting at 258 ° C.

EXAMPLE 93

A stirred solution of 3.1 g of 6,8-dichloro-3,4-dihydro -2H-1, 2,4-benzothia diazine-1, 1-methyl dioxide-3-carboxylate in 60 cm3 of N, N -dimethylethylenediamine is heated at 95 ° C for 45 minutes. After dry concentration at 40 ° C under reduced pressure (15 mm Hg; 2 kPa), suspension in 6 cm3 of ice-cold methanol, filtration and drying at 20 ° C under reduced pressure (15 mmHg; 2 kPa), the product obtained (1.4 g) is dissolved in 30 cm3 of boiling methanol and the solution, supplemented with bleaching black, is filtered hot, cooled and then stored at 5 ° C for 18 hours. The crystals which appear are separated by filtration, washed twice with 2 cm 3 in total of ice-cold methanol and then dried at 65 ° C. under reduced pressure (1 mm Hg; 0.13 kPa). 0.58 g of N- (2-dimethylaminoethyl) -6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carbo xamide is thus obtained. 224 ° C.

EXAMPLE 94

A stirred solution of 1.55 g of 6,8-dichloro-3,4-dihydro -2H-1, 2,4-benzo thiadiazine-1, 1-methyl dioxide-3-carboxylate in 60 cm ³ of methanol is saturated with ammonia gas at 5 ° C. After 4 hours of stirring at 20 ° C, dry concentration at 40 ° C under reduced pressure (15 mm Hg; 2 kPa), the product obtained is dissolved in 40 cm3 of boiling acetonitrile and the solution, supplemented with bleaching black, is filtered hot, cooled and then stored at 5 ° C for 18 hours. The crystals which appear are separated by filtration, washed twice with 2 cm 3 in total of acetonitrile and dried at 65 ° C under reduced pressure (1 mm Hg; 0.13 kPa). 0.83 g of 6.8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxamide mide, melting at 280 ° C., is thus obtained.

Methyl 6,8-dichloro-3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-car boxylate can be prepared as follows: to a stirred solution of 12 g of 2-amino-4,6-dichlorobenzenesulfonamide in 150 cm3 of methanol, a solution of 9.2 g of giyoxylic acid monohydrate and 11 cm3 is added dropwise over 20 minutes at a temperature close to 20 ° C. 95% sulfuric acid in 50 cm3 of methanol. After 3 hours of stirring at boiling point and cooling to a temperature in the region of 5 ° C., the crystals which appear are separated by filtration, washed twice with 10 cm 3 in total of methanol and dried at 40 ° C. under reduced pressure (10 mm Hg; 1.3 kPa). 8.8 g of 6,8-dichloro-3,4-dihydro2H-1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxy late methyl, melting at 220 ° C., are thus obtained.

EXAMPLE 95

A suspension of 1 g of 2-amino-5-chlorobenzenesulfonamide in 20 cm 3 of water is brought to reflux and a solution of 0.67 g of giyoxylic acid, 0.29 g of sodium hydroxide and 10 cm3 of water. After 1 hour and 30 minutes of reflux, the reaction mixture is cooled to 10 ° C and acidified with 7 cm3 of hydrochloric acid N. A precipitate is obtained which is filtered, then redissolved in 4.2 cm3 of 1N sodium hydroxide and 10 cm3 water; the solution is washed with 2 times 25 cm3 of ethyl acetate and acidified with 5 cm3 of hydrochloric acid N. After filtration and drying at 50 ° C under reduced pressure (2 mm of mercury; 0.26 kPa), 0 is obtained , 87 g of 7-chloro-2H-3,4-dihydro-1,2,4-benzothiadiazine-3-carboxylic acid 1, 1-dioxide melting at 234 ° C (dec).

The 2-amino-5-chlorobenzenesulfonamide can be prepared according to US Patent 2,986,573. EXAMPLE 96

The procedure is as in Example 95, but using 0.8 g of 2-amino-4-iodobenzenesulfonamide and 0.37 g of giyoxylic acid. 0.65 g of 6-iodo-2H-3,4-dihydro-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, melting at 243 ° C. (dec), is obtained.

The 2-amino-4-iodobenzenesulfonamide can be prepared as follows: to a solution cooled to -5 ° C of 17.7 g of chlorosulfonyl isocyanate in 110 cm3 of nitromethane is slowly added a solution of 21.9 g of 3-iodoaniline in 35 cm3 of nitromethane, then at 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 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-benzothidiazine-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 97

The procedure is as in Example 95 but starting from 1.05 g of 2-amino-4-methylbenzenesulfonamide. and 0.77 g of giyoxylic acid. 0.87 g of 6-methyl-2H-3.4-dihydro-1,2,4-benzothia diazine-1, 1 - is obtained. 3-carboxylic dioxide (Analysis% calculated C: 44.62; H: 4.16; N: 11.56; 0: 26.42; S: 13.24, found C: 45.0; H: 3, 9; N: 11.7; 0: 26.4; S: 13.4).

2-amino-4-methylbenzenesulfonamide can be prepared according to the method described by V. DE SMEDT and A. BRUYLANTS, Bull. Soc. Chim. Belg., 74, 344 (1965).

EXAMPLE 98

The procedure is as in Example 95 but starting with 1.6 g of 2-amino-5-methoxybenzenesulfonamide and 1.12 g of giyoxylic acid. 1.65 g of 7-methoxy-2H-3,4-dihydro-1,2,4-benzothidiazine-3-carboxylic acid 1, 1-dioxide, melting at 182 ° C., are obtained.

The 2-amino-5-methoxybenzenesu IFonamide can be prepared according to US patent 3251837.

EXAMPLE 99

The procedure is as in Example 95 but starting with 0.6 g of 2-amino-6-iodobenzenesulfonamide and 0.28 g of giyoxylic acid. 0.50 g of 8-iodo-2H-3,4-dihydro-1,2,4-benzothia diazine-1,1-dioxide-3-carboxylic acid are thus obtained (Analysis% calculated 0: 27.4; H: 1.99; 1: 35.84; N: 7.91; 0: 18.07; S: 9.05,% found C: 27.1; H: 2.0; 1: 35.9; N: 7.9; 0: 18.3; S: 9.4).

The 2-amino-6-iodobenzenesulfonamide is prepared as described in Example 96 for the preparation of 2-amino-4-iodobenzenesulfonamide but 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-benzothidiazine-3 (4H) -one 1, 1-dioxide is obtained. The product is then hydrolyzed to give 2-amino-6-iodobenzenesuifonamide in the form of a pale yellow solid used as it is in subsequent syntheses. EXAMPLE 100

The procedure is as in Example 95 but starting with 0.66 g of 2-amino-6-methyl benzenesulfonamide and 0.49 g of giyoxylic acid. Obtained 0.38 g of 8-methyl-2H-3,4-dihydro-1,2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic acid, melting at 231 ° C.

2-amino-6-methylbenzenesulfonamide can be prepared according to the method described by G. J. THOMAS, J. Agric Food Chem., 32, 747 (1984).

EXAMPLE 101

The procedure is as in Example 95 but using 0.58 g of 2-amino-4,5-dichlorobenzenesulfonamide and 0.33 g of giyoxylic acid. 0.35 g of 6,7-dichloro-2H-3,4-dihydro-1,2,4-benzothia diazine-3-carboxylic acid 1, 1-dioxide melting at 226 ° C. is obtained (dec).

The 2-amino-4,5-dichlorobenzenesulfonamide can be prepared according to the method described by J. A. SHORT and U. BIERMACHER, J. Am. Chem. Soc, 82, 1135, (1960).

EXAMPLE 102

The procedure is as in Example 95 but using 0.38 g of 2-amino-5,6-dichlorobenzenesulfonamide and 0.22 g of giyoxylic acid. 0.19 g of 7,8-dichloro-2H-3,4-dihydro-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid, melting at 240 ° C., is obtained.

2-amino-5,6-dichlorobenzenesulfonamide can be prepared according to the method described by J. G. TOPLISS et al., J. Med. Chem., 7, 269 (1964).

EXAMPLE 103

The procedure is as in Example 95, but using 1.86 g of 2-amino-4,6-difluorobenzenesulfonamide and 1.23 g of giyoxylic acid. 1.44 g of 6,8-difluoro-2H-3,4-dihydro-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid, melting at 234 ° C., are obtained (dec.) The 2-amino-4,6-difluorobenzenesulfonamide can be prepared as described in Example 96 for the preparation of 2-amino-4-iodobenzenesulfonamide but starting from 10 g of 3,5-difluoroaniIine. The crude product resulting from the cyciisation is extracted with 600 cm3 of ethyl acetate in total, the organic solution is evaporated in vacuo (16 mm of mercury) and the evaporation residue is purified by beating in methyl tert-butyl oxide, filtered and dried to give 11.72 g of 6,8-difluoro-1,2,4-benzothiadiazine- 3 (4H) -one 1,1-dioxide which is then hydrolyzed with 220 cm3 of sulfuric acid at 50% (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 ^as' a pale pink solid used as is in the subsequent syntheses.

EXAMPLE 104

The procedure is as in Example 95 but starting with 3 g of 2-amino-4,6-dibromobenzenesulfonamide and 1.29 g of giyoxylic acid. 3.14 g of 6.8-dibromo-2H-3,4-dihydro-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid, melting at 266-8 ° C, are obtained. ).

The 2-amino-4,6-dibromobenzenesulfonamide can be prepared as described in Example 103 for the preparation of 2-amino-4,6-difluorobenzene sulfonamide but from 21.9 g of 3,5-dibromoaniline. After chromatography on silica, 15.5 g of 6,8-dibromo-1,2,4-benzothia diazine-3 (4H) -one 1, 1-dioxide are obtained, which is subjected to acid hydrolysis in the same conditions, which provides, after purification on a silica column, 5.1 g of 2-amino-4,6-dibromobenzenesulfonamide 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 RG SHEPHERD, J. Org. Chem., 12, 275 (1947). EXAMPLE 105

The procedure is as in Example 95 but starting with 2 g of 2-amino-4,6-dimethylbenzenesulfonamide and 1.38 g of giyoxylic acid. 1 g of 6,8-dimethyl-2H-3,4-dihydro-1,2,4-benzothia diazine-1, 1-dioxide-3-carboxylic acid, melting at 210 ° C. (dec), is obtained.

The 2-amino-4,6-dimethylbenzenesulfonamide can be prepared as described in Example 103 for the preparation of 2-amino-4,6-difluorobenzene sulfonamide but from 12.12 g of 3,5-dimethylaniline. 11.31 g of 6,8-dimethyl-1,2,4-benzothia diazine-3 (4H) -one 1, 1-dioxide are obtained, which are 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 106

A 2 g of 6,8-dichloro-3,4-dihydro-2- (3-methylbenzyl) -2H-1, 2,4-benzothia diazine-3-carboxylic acid in solution in 40 cm3 of tetrahydrofuran at a temperature near 20 ° C, 30 cm3 of a solution in dichloromethane of 0.12 g of 4-dimethylaminopyridine and O-benzylhy droxylamine are added in the form of the base obtained from 2.4 g of hydrochloride treated with carbonate potassium. To this solution, 1.24 g of dicyclohexylcarbodiimide dissolved in 30 cm 3 of dichloromethane are added dropwise. The reaction is continued for 15 hours at the same temperature, then the reaction medium concentrated to dryness under reduced pressure and the residue purified by flash chromatography on a silica column using dichloromethane as eluent. After beating in isopropyl ether, 0.8 g of 6,8-dichioro-3,4-dihydro-2- (3-methylbenzyl) -2H-1,2,4-benzothiadiazine-3-carbohydroxamate is obtained. in the form of a white powder melting at 155 ° C. EXAMPLE 107

0.8 g of 6,8-dichloro-3,4-dihydro-2- (3-methylbenzyl) -2H-1,2,4-benzothia diazine-3-carbohydroxamate in solution in 40 cm3 of methanol are stirred at a temperature in the region of 20 ° C. under a hydrogen atmosphere and in the presence of 0.1 g palladium on carbon at 5%. After 5 hours of reaction, the catalyst is filtered through celite and the filtrate concentrated to dryness under reduced pressure. After beating in ethyl ether, 0.6 g of 6,8-dichloro-3,4-dihydro-2- (3-methylbenzyl) -2H-1,2,4-benzothia diazine-3- is obtained. carbohydroxamic in the form of white powder decomposing around 230 ° C (Analysis (C- | gH-j5Cl2N3θ4S, 2H2θ)% calculated

0: 42.49; H: 4.23; CI: 15.68; N: 9.29; S: 7.09,% found (0.78H ₂ O) C: 42.5; H: 4.0;

01: 15.4; N: 9.2; S: 7.1).

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 can be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerof, vegetable oils or oil paraffin.

These compositions can include substances other than thinners, 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.

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 in particular useful for treating or preventing all ischemia and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, diseases motor neuron, amyotrophic lateral sclerosis, olivo- pontocerebellar atrophy and PARKINSON's disease, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal trauma, anxiety, depression, schizophrenia, as analgesics, antiemetic antiemetic, antimigraine and to treat poisoning by neurotoxins or other agonist substances 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.

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-dichloro-3,4-dihydro-2H-1, 2,4-benzothîa- dîazine-1,1-dioxide-3-carboxyIique 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-3,4-dihydro-2- (3-phenylpropyl) -2H- acid

1, 2,4-benzothiadiazine-1, 1-dioxide-3-carboxylic 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:

- Acid 3,4-dihydro-2H-1, 2,4-benzothiadiazine-1, 1-

1, 1-dioxide-3-carboxylic 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 q.s.p. 4 cm3

Claims

1 - Compounds of formula:

in which

- R represents (a) a hydrogen atom, (b) an alkyl radical, (c) an allyl radical, (d) a phenyl radical, (e) a 2 or 3-pyridylalkyl radical, (f) a radical

2-quinolylalkyl, (g) a naphthylalkyl radical, (h) a cycloalkylalkyl radical, (i) a 2H-3-naphtho [1,8-cdIisothiazol-2-yl-1,1-dioxide) alkyl radical, (j) a radical

(5,6-dihydro 1 H.4H-1, 2,5-thiadiazoio [4,3,2-ij] quinolyl-2,2-doxide) alkyl, (k) a radical -a! K-CO-R5 ₎ (I) a radical -alk-Rg-R7, (m) a radical

4-phenyIpiperazinylalkyl in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl or alkoxy radicals, (n) a 10-phenothiazinylalkyl radical, (o) a (10-alkyl-2- phenothiazinyl) alkyl, (p) a 3-indolylalkyl radical, (q) a phenylalkyloxy radical, (r) a 1-phenylalkyl-4-piperidyl radical, (s) a 2-thienylalkyl radical or (t) a phenylalkyl radical in which phenyl is unsubstituted or substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, polyfluoroalkyl, amino, nitro, cyano, phenyl, vinyl, polyfluoroalkoxy, alkoxycarbonyl, carboxy, phenylalkyloxy, phenylalkyl, benzoylamino, radicals phenylcarbonyl and phenoxy, the phenyl ring of which is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy or polyfluoroalkyl radicals,

- Ri represents a carboxy, alkoxycarbonyl, tetrazolyl, -CO-NH2, -CO-NH-alk, -CO-N (alk) 2, -CO-NHOH, -CO-N (alk) OH, -CO-NH radical -0-R ₈ , -CO-N (alk) -OR ₈ or a group convertible into carboxy radical in vivo, - R2, R3 and R4, identical or different, each represent a hydrogen or halogen atom or an alkyl or alkoxy radical,

- R5 represents a hydroxy, alkoxy, phenyl or -NR9R1O1 radical

Rg represents an oxygen, sulfur or nitrogen atom or an SO, SO2 or -N-alk radical,

- R7 represents an alkyl, phenylalkyl or phenyl radical optionally substituted by one or more halogen atoms,

- R ₈ represents an alkyl or phenylalkyl radical,

- Rg and R-jQ. identical or different, represent a hydrogen atom or an alkyl or phenyl 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, their enantiomers and for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases.

2 - Compounds of formula (I) according to claim 1 for which R- | represents a group convertible into a carboxy radical in vivo chosen from the radicals -CO-R11 in which RJ -J represents a radical -0-alk-R- | 2 _ι -O-alk-O-CO-alk, -O-alk -O-COOalk, -0-alk-0-CO-Rι ₂ , -O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-OR ^, -0-alk-S-Rι ₂ , -O-alk-COOH, -O-alk-COOalk, -0-alk-NRι ₃ 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-OR-12, -NH-alk-S-Ri2. -NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NR- | 3Ri4, R12 is a phenyl radical, R13 and R14, identical or different, each represent a hydrogen atom or an alkyl radical, phenyl or phenylalkyl or else form with the nitrogen atom to which they are attached a piperidino, morpholino or pyrrolidino ring and alk represents an alkyl or alkylene radical, it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene contain 1 to 10 atoms of carbon in a straight or branched chain, their racemates, their enantiomers and for the compounds comprising a carboxy radical, their ^"" metal salts and their addition salts with nitrogenous bases.

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, it being understood that the alkyl, alkoxy and alkylene radicals and the alkyl, alkoxy and alkylene portions contain 1 to 10 atoms of carbon in a straight or branched chain, their racemates, their enantiomers and for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases.

4 - Compounds according to claim 3 for which R2 and R4 each represent a halogen atom and R3 represents a hydrogen atom, their racemates, their enantiomers and for compounds comprising a carboxy radical, their metal salts and their salts addition with nitrogenous bases.

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

in which R, R2, R3 and R4 have the same meanings as in claim 1, with giyoxylic 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 an alkoxycarbonyl radical characterized in that a derivative of formula is condensed: in which R, R2, R3 and R4 have the same meanings as in claim 1, with giyoxylic acid, in an acid medium and in the presence of an alcohol R15OH in which R15 represents an alkyl radical, isolates the product and transforms it possibly in salt.

7 - Process for the preparation of the compounds of formula (I) for which Rj represents an alkoxycarbonyl radical and R represents a 2H-3-naphtho [1, 8-cd] isothiazol-2-yl -1, 1-dioxide) alkyl radical or (5,6-dihydro 1H, 4H- 1,2,5-thiadiazolo [4,3,2-ij] quinolyl-2,2-dioxide) alkyl characterized in that a derivative of formula is reacted:

in which R- | represents an alkoxycarbonyl radical, R2, R3 and R4 have the same meanings as in claim 1 and R-jg represents a haloalkyl radical on a derivative of formula: HR-17 (VIII)

in which R-J7 represents a 2H-3-naphtho [1, 8-cd] isothiazol-2-yl radical

-1, 1-dioxide) or (5,6-dihydro-1 H. 4H-1, 2,5-thiadiazolo [4,3,2-ij] quinolyl -2,2-dioxide) or an alkali metal salt of these derivatives, isolates the product and optionally transforms it into salt.

8 - Process for preparing the compounds of formula (I) according to claim 1 for which R- | represents a carboxy radical characterized in that a corresponding ester of formula (I) is hydrolyzed for which R- | represents an alkoxycarbonyl radical, isolates the product and optionally transforms it into a 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 reacting sodium azide with a derivative of formula:

in which R, R2, R3 and R4 have the same meanings as in claim 1, isolates the product and optionally converts it to salt.

10 - 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) ₂ , -CO-NHOH, -CO _: N (aIk) OH, -CO-NH-0-R ₈ or -CO -N (alk) -OR ₈ characterized in that a compound of formula (I) corresponding to which R- | represents a carboxy or alkoxycarbonyl radical on a derivative of formula:

HN (Rι ₇ ) -R ₁₈ (XII)

in which Rj 7 represents a hydrogen atom or an alkyl radical and R- [ ₈ represents a hydrogen atom or an alkyl, hydroxy, -O-alk or -OR ₈ radical, isolates the product and optionally transforms it into a salt .

11 - Process for preparing the compounds of formula (I) according to claim 1 for which R- | represents a radical -CO-R-j - | in which

R-11 represents a radical -0-alk-R-j2, -O-alk-O-CO-alk, -O-alk-O-COOalk, -0-alk-0-CO-R- | 2> - O-alk-OH, -O-alk-O-alk, -O-alk-S-alk, -O-alk-ORj 2,

-O-aIk-SR-12, -O-alk-COOH, -O-afk-COOalk, -0-alk-NRι ₃ Rι ₄ ,

-NH-alk-O-CO-alk, -NH-alk-O-COOalk, -NH-alk-0-CO-R ₁₂ , -NH-alk-OH,

-NH-alk-O-alk, -NH-alk-S-alk, -NH-alk-0-Ri2, -NH-alk-S-R- | 2>

-NH-alk-COOH, -NH-alk-COOalk, -NH-alk-NRi3R- | 4 characterized in that a compound of formula (I) is reacted for which Rf represents a carboxy radical or alkoxycarbonyl on a derivative of formula:

Rl -lH (XIII) in which Rj -ja has the same meanings as above, isolates the product and optionally transforms it into salt.

•

12 - Process for preparing the compounds of formula (I) according to claim 1 for which R is different from hydrogen characterized in that

5 which a derivative of formula (I) corresponding to which R represents a hydrogen atom is reacted on a halide of formula:

R-X (XIV)

wherein R has the same meanings as in claim 1 except hydrogen and X represents a halogen atom, isolates the product and optionally converts it to salt.

13 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents an -alk-CO-Rs radical in which R5 is a hydroxy radical and / or R represents a phenylalkyl radical substituted by at least one carboxy radical characterized in that a corresponding ester of formula (I) is hydrolyzed in which R5 represents an alkoxy radical and / or R represents a phenylalkyl radical substituted by at least one alkoxycarbonyl radical, isolates the product and optionally transforms it into a salt.

14 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a phenylalkyl radical substituted by at least one amino radical characterized in that a corresponding compound of formula (I) is reduced for which R represents a phenylalkyl radical substituted by at least one nitro radical, isolates the product and optionally transforms it into a salt.

25 15 - Process for preparing the compounds of formula (I) according to claim 1 not comprising benzyl radicals and for which R represents a phenylalkyl radical in which the phenyl ring is substituted by at least one ethyl radical characterized in that one hydrogen a compound of corresponding formula (I) for which R represents a phenylalkyl radical

30, the phenyl ring of which is substituted by at least one vinyl radical, isolates the product and optionally converts it to a salt. 16 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a phenylalkyl radical in which the ^" phenyl nucleus is substituted by at least one benzoylamino radical characterized in that a compound of formula ( I) correspondent for which R represents a phenylalkyl radical in which the phenyl nucleus is substituted by at least one amino radical with benzoyl chloride, isolates the product and optionally transforms it into a salt.

17 - Process for the preparation of compounds of formula (I) for which R represents an -alk-Rg-R7 radical and Rg represents an SO or SO2 radical characterized in that a corresponding compound of formula (I) is oxidized for which R represents an -alk-Rg-R7 radical and Rg represents a sulfur atom, isolates the product and optionally transforms it into salt.

18 - Process for preparing the compounds of formula (l) according to your claim 1 not containing benzyl radicals and for which Rj represents a radical -CO-NHOH characterized in that a compound of formula (I) corresponding to debenzyl is which Rj represents a radical

-CO-NH-0-R ₈ and R ₈ represents a benzyl radical, isolates the product and optionally transforms it into a salt.

19 - Medicines comprising as active principle at least one compound of formula (I) according to claim 1 or optionally for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases.

20 - Medicines comprising as active principle at least one compound of formula (I) according to claim 2 or optionally for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases.

21 - Medicines comprising as active principle 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. 22 - Medicines comprising as active principle at least one compound of formula (I) according to claim 4 or optionally for the compounds comprising a carboxy radical, their metal salts and their addition salts with nitrogenous bases.

23 - Medicines according to one of claims 19 to 22 useful as antagonists of the NMDA receptor and / or of the AMPA receptor.