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  • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
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  • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
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  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/06—Peri-condensed systems

Definitions

• the present invention relates to compounds of formula:
• - 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
• 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
• 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
• - alk represents an alkyl or alkylene radical.
• 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.
• 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-
• -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,
• R-12 is a phenyl radical, R13 and R14,
• 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
• 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.
• 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.
• a base such as sodium hydroxide or potassium hydroxide
• 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. .
• an inert solvent such as tetrahydrofuran, dioxane
• a tertiary amine such as a trialkylamine (triethylamine, for example
• This reaction is carried out at a temperature close to 100 ° C.
• 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.
• 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.
• 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:
• R-j ⁇ represents a 2H-3-naphtho [1,8-cd] isothiazol-2-yl -1 ⁇ 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-
• 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.
• a base such as an alkali metal hydride, an alkali metal carbonate or an alkali metal hydroxide
• an inert organic solvent such as tetrahydrofuran or dimethylformamide
• 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.
• a base such as an alkali metal hydroxide (soda, potash, lithium hydroxide for example)
• an inert solvent such as an alcohol or a water-alcohol mixture
• water-tetrahydrofuran water-dioxane
• 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.
• an inert solvent such as dimethylformamide, dimethoxyethane, dioxane
• the derivatives of formula (X) can be obtained by the action of phosphorus pentachloride or phosphoryl chloride with an amide of formula:
• 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.
• 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-
• 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.
• the acid 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
• an ester 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
• an acid acceptor such as butyllithium, the lithian of diisopropylamine or an organic nitrogenous base
• R11 represents a radical -0-alk-R-
• This reaction is generally carried out at a temperature between 20 and 160 ° C.
• 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.
• a base such as an alkali metal hydride (sodium hydride for example), a metal alcoholate.
• alkaline sodium ethylate, sodium tert-butoxide, for example
• R5 represents a hydroxy radical and or R represents a phenylalkyl radical substituted by at least one carboxy radical
• R5 represents a hydroxy radical and or R represents a phenylalkyl radical substituted by at least one carboxy radical
• R5 represents a hydroxy radical and or R represents a phenylalkyl radical substituted by at least one carboxy radical
• 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.
• a base such as an alkali metal hydroxide (sodium hydroxide or potassium hydroxide, for example lithium hydroxide)
• 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.
• a hydrogenation catalyst such as palladium on carbon
• an inert solvent such as an alcohol
• tin (II) chloride in an inert solvent such as an alcohol
• 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.
• a catalyst such as palladium on carbon
• an inert solvent such as an alcohol (ethanol for example)
• 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.
• a base such as a trialkylamine (triethylamine for example)
• the compounds of formula (l) for which R represents a radical -a ⁇ k-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. .
• an oxidizing agent such as m-chloroperbenzoic acid
• an inert solvent such as a chlorinated solvent (dichloromethane)
• represents a radical -CO-NHOH can also be prepared by debenzylation of a compound of formula (I) corresponding to which R-
• 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.
• an inert solvent such as an alcohol (methanol-ethanol for example)
• a catalyst such as palladium on carbon
• 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.
• salts with alkali metals sodium, potassium, lithium
• alkaline earth metals calcium, magnesium
• the ammonium salt the tetraalkylammonium salts (tetrabutylammonium for example)
• salts of nitrogenous bases ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl- ⁇ -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.
• NMDA N-methyl-D-aspartate receptor
• certain compounds of formula (I) are antagonists of the ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA), also known as the quisqualate receptor.
• AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid 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.
• 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.
• 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 ⁇ M.
• 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. ,
• 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 ⁇ M.
• the compounds of formula (I) have a low toxicity.
• Their LD50 is generally greater than 40 mg / kg by the IP route.
• 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.
• 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-benzo
• 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).
• 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.
• 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).
• 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.
• 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
• 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 7 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.
• 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.
• 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.
• the 2-amino-5-chtorobenzenesulfonamide can be prepared according to the method described in US Patent 2,986,573.
• 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.
• 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.
• Example 13 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Example 18 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.
• Example 18 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.
• 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.
• Example 18 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.
• 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.
• the aqueous phase is acidified using 1N hydrochloric acid and the organic phase extracted with dichloromethane.
• 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 H ⁇ 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
• 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.
• 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.
• 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.
• 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.
• 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.
• Example 13 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.
• 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.
• Example 1 & 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.
• 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.
• Example 18 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.
• 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.
• Example 18 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.
• 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.
• Example 18 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.
• 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.
• 2-amino-4-chlorobenzenesulfonamide can be prepared according to the method described by J.G. TOPLISS et al., J. Med. Chem., 6, 122 (1963).
• 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.
• 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.
• 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 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.
• 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.
• 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 .
• 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.
• 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.
• 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.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 (C ⁇ 7 H ⁇ gCl2N2 ⁇ 5 S; H 2 0)% calculated C: 45.44; H: 4.04; 01: 15.78; N: 6.23;
• 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
• 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.
• 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.
• 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
• 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.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the reaction medium 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.
• 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.
• 10- (3-chloropropyl) phenothiazine can be prepared according to the method described by H. Wunderlich et al., Pharmazie, 21, 57 (1966).
• 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.
• 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.
• 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 (C ⁇ gH-
• 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.
• 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 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.
• reaction medium 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
• 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.
• 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.
• 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.
• 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.
• 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 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 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.
• 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.
• 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.
• 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.
• 3-Phenylbenzyl bromide can be obtained according to the method described by C.W. SHOPPEE, J. Chem. Soc, 37 (1933).
• 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.
• 2-Phenethylbenzyl chloride can be prepared according to the method described by JA MOORE et al., Org. Prep. Proced. Int., 16 (6), 411 (1984).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 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.
• 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 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.
• 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.
• 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.
• 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 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 .
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• 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 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.
• 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.
• 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.
• 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 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).
• 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.
• 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.
• 3-Bromomethibenzophenone can be prepared according to the method described by D.C. SCHLEGEL et al., J. Med. Chem., 27 (12), 1682 (1984).
• 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.
• 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.
• 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.
• 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.
• 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.
• the 2-amino-5-chlorobenzenesulfonamide can be prepared according to US Patent 2,986,573.
• Example 95 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).
• 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.
• 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).
• the 2-amino-5-methoxybenzenesu IFonamide can be prepared according to US patent 3251837.
• 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 95 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).
• 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 95 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 95 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 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.
• 3,5-dibromoaniline can be prepared according to the method described by RG SHEPHERD, J. Org. Chem., 12, 275 (1947).
• 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.
• 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.
• compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
• 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.
• inert diluents such as starch, cellulose, sucrose, lactose or silica
• 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.
• 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.
• inert diluents such as water, ethanol, glycerof, vegetable oils or oil paraffin.
• 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.
• 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.
• compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
• compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.
• 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
• 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.
• the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
• capsules containing 50 mg of active product having the following composition are prepared:
• 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
• a solution for injection containing 10 mg of active product having the following composition is prepared:

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• 1993
  • 1993-04-09 EP EP93909013A patent/EP0636124A1/fr not_active Ceased
  • 1993-04-09 CA CA002130096A patent/CA2130096A1/fr not_active Abandoned
  • 1993-04-09 WO PCT/FR1993/000360 patent/WO1993021170A1/fr not_active Application Discontinuation
  • 1993-04-09 HU HU9402980A patent/HUT70955A/hu unknown
  • 1993-04-09 AU AU39570/93A patent/AU3957093A/en not_active Abandoned
  • 1993-04-09 JP JP5518047A patent/JPH07505411A/ja active Pending
  • 1993-04-14 IL IL105390A patent/IL105390A0/xx unknown
• 1994
  • 1994-10-14 NO NO943898A patent/NO943898L/no unknown
  • 1994-10-14 FI FI944854A patent/FI944854A0/fi not_active Application Discontinuation

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