OA16341A - New dihydrobenzoxathiazepine derivatives, their preparation process and the pharmaceutical compositions which contain them. - Google Patents

Abstract

Compounds of formula (I): <img file="OA16341A_A0001.tif"/> in which R1 represents a hydrogen atom, a heterocyclic, cyano, alkoxycarbonyl, alkylsulfonylaminoalkyl, or N-hydroxycarboximidamide group. Drugs.

Description

The present invention relates to novel dihydrobenzoxathiazepine derivatives, their preparation process, pharmaceutical compositions which contain them as well as their use as positive allosteric modulators of AMPA receptors.

It is now recognized that excitatory amino acids, and in particular glutamate, play a crucial role in the physiological processes of neuronal plasticity and in the mechanisms underlying learning and memory. Pathophysiological studies have clearly indicated that a deficit in glutamatergic neurotransmission is closely associated with the development of Alzheimer's disease (Neuroscience and Biobehavioral Reviews, 1992, 16, 13-24; Progress in Neurobiology, 1992, 39, 517- 545).

In addition, certain studies have demonstrated in recent years the existence of receptor subtypes to excitatory amino acids and their functional interactions (Molecular Neuropharmacology, 1992,2, 15-31).

Among these receptors, the ΓΑΜΡΑ receptor (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) appears to be the most involved in the phenomena of physiological neuronal excitability and in particular in those involved in the memorization process. For example, learning has been shown to be associated with increased binding of ΓΑΜΡΑ to its receptor in the hippocampus, one of the areas of the brain essential for memory processes. Likewise, nootropic agents such as aniracetam have been described as positively modulating the AMPA receptors of neuronal cells (J. Neurochemistry, 1992,58, 1199-1204).

In the literature, compounds of benzamide structure have been described to possess this same mechanism of action and to improve memory performance (Synapse, 1993, 15, 326-329). The compound BA 74, in particular, is the most active among these new pharmacological agents.

More recently, patent application WO 99/42456 describes benzothiadîazine and benzothiadiazepine derivatives as modulators of AMPA receptors and the application for

ORIGINAL

-2 Patent WO 02/100865 describes benzoxazepine derivatives having a facilitating activity on the AMPA current.

The dihydrobenzoxathiazepine derivatives, subjects of the present invention, are new and constitute potent positive allosteric modulators of AMPA receptors.

More specifically, the present invention relates to the compounds of formula (I):

in which Rj represents a hydrogen atom, a cyano group, a linear or branched alkoxycarbonyl (C] -C &) group, a linear or branched alkylfCi-Céjsulfonylaminoalkyl (Cj-Q) group, a .V-hydroxycarboximidamide group, or a heterocyclic group, their enantiomers and their diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base, it being understood that the term heterocyclic group denotes a monocyclic 5-membered aromatic group, containing one to four heteroatoms, identical or different , chosen from nitrogen, oxygen and sulfur, said heterocyclic group possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (Cj-C6) alkyl or linear or branched polyhaloalkyl (C | -Ce).

Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic acids , benzenesulfonic, camphoric.

ORIGINAL

Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine and tertbutylamine.

R 1 preferably represents a heterocyclic group.

More preferably, Rj represents a 5-membered aromatic monocyclic heterocyclic group containing at least one nitrogen atom, said group possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (Ci-C ₆ ) alkyl or linear or branched polyhaloalkyl (Ci-Cè).

R 1 advantageously represents the pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, thiadiazolyl, dithiazolyl, and oxadiazolyl groups, each of the groups possibly being substituted by one or more substituents, identical or different, chosen from among (Ci-Cg) linear or branched or polyhaloalkyl (Ci-C ^) linear or branched.

More particularly preferred are the compounds for which R 1 represents the oxadiazolyl and thiazolyl groups and, more particularly, the 1,2,4-oxadiazolyl and 1,3-thiazolyl groups, each of the preferred groups possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (C | -C6) alkyl or linear or branched polyhaloalkyl (C | -C &).

The preferred substituents of the heterocyclic group are the methyl group or the trifluoro methyl group.

The group R] is preferably in the meta or para position of the phenoxy nucleus which carries it. Advantageously, the Ri group is in the meta position.

The preferred compounds according to the invention are:

• 8- [3- (5-methyl-1,2,4-oxadiazol-3-yDphenoxy] -3,4-dihydro-2 / 7-5, l, 2ORIGINAL

-4benzoxathiazepine IJ -dioxide;

• 8- (3- (3-methyl -1,2,4-oxadiazol-5-yl) phenoxy] -3,4-dihydro-2H-5, l _t 2benzoxathiazepine l J-dioxide.

Pharmaceutically acceptable acid or base addition salts of preferred compounds of the invention form an integral part of the invention.

The invention also extends to the process for preparing compounds of formula (I) from the compound of formula (II):

(II) in which H1 represents a halogen atom, such as fluorine, chlorine or bromine, and

R ′ represents a linear or branched alkyl group (Ci-Ce), which is reacted with 2-chloroethylamine in a basic medium to yield the compound of formula (III):

in which Hal and R 'are as defined above, which then undergoes the action of a boric derivative to lead to the compound of formula (IV):

ORIGINAL

in which Hal is as defined above, which is then cyclized to lead to the compound of formula (V):

(V) in which Hal is as defined above, which undergoes a protective reaction on the atom of formula (VI):

nitrogen to lead to the compound

in which Hal is as defined above protective of the amine function, such as by butyloxycarbonyl,

R represents an example group the tertet group which is converted into boronic acid to lead to compounds of formula (VII):

ORIGINAL

(VII) in which R is as defined above, which is reacted with an alcohol of formula (VIII):

OH

(VIII) in which Ri has the same meaning as in formula (I), to lead to the compound of formula (IX),

in which R | and R are as defined above;

which is then subjected to a deprotection reaction of the amine function to lead to the compound of formula (I), a variant in the preparation of compounds of formula (I) consisting in the hydrolysis of the compound of formula (VII) to yield to the compound of formula (X):

ORIGINAL

(X) in which R is as defined above.

which is reacted with a boronic acid derivative of formula (XI):

OH

(XI) in which R | has the same meaning as in formula (I), to lead to the compound of formula (IX), which is then subjected to a deprotection reaction of the amine function to lead to the compound of formula (I), another alternative in the preparation of compounds of formula (I) consisting, after the preparation of compounds of formula (IX), in reuse of conventional chemical reactions in order to modify, in a second step, the substituent of the phenoxy ring, compound of formula (I) which can then be purified according to a conventional separation technique, which is converted, if desired into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated, if they exist , according to a conventional separation technique.

The compounds of formula (II), (VIII) and (XI) are commercially available or easily accessible to those skilled in the art by conventional chemical reactions or those described in the literature.

ORIGINAL

-8The compounds of formula (V) are new and also form part of the invention as intermediates for the synthesis of compounds of formula (I),

The compounds of formula (I) according to the invention exhibit activating properties of AMPA receptors which make them useful in the treatment or prevention of mnemocognitive disorders associated with age, with anxiety or depressive syndromes, with progressive neurodegenerative diseases, with Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's chorea, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementias, sequelae of ischemia and sequelae of epilepsy.

The invention also extends to pharmaceutical compositions containing as active principle at least one compound of formula (I) with one or more inert, non-toxic and suitable excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more particularly those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, simple or sugar-coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injectables, and drinkable suspensions.

The useful dosage is adaptable according to the nature and severity of the affection, the route of administration and the age and weight of the patient. This dosage varies from 0.01 to 1000 mg per day in one or more doses.

The following examples illustrate the invention but do not limit it in any way.

The starting products used are known products or are prepared according to known preparatory methods.

The structures of the compounds described in the examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry).

ORIGINAL

-9The preparations described below lead to starting products used during the synthesis of the compounds of the invention.

Preparation 1: 3- (5-methyl-1,2,4-oxadiazol-3-yl) phenol

Stage A: N ', J-dihydroxybenzenecarboximidamide

To a suspension of 15.84 g (0.228 mol) of hydroxylamine hydrochloride in 75 ml of DMSO, are added 32 ml (0.228 ntol) of triethylamine. The solution is stirred vigorously for 30 minutes and then diluted with a little THF. After 10 minutes of stirring, the triethylamine hydrochloride is filtered off and the residue is rinsed with THF. Once the filtrate is concentrated (evaporation of the THF), 10 g (83.9 mmol) of 3-hydroxybenzonitrile are added to the solution obtained. The solution is stirred at room temperature for 16 hours. After dilution with cold water, the mixture is extracted 3 times with ethyl acetate and the organic phase is washed with brine. The expected product is obtained after drying over MgSO ₄ and evaporation.

Stage B: 3-fti '- (acetyloxy) carbamimidoyl] phenyl acetate

To a suspension of 10.2 g (67 mmol) of the product obtained in the preceding Stage A in 150 ml of CH2Cl2, 28 ml (0.201 mol) of triethylamine are added. 13.9 ml (0.147 mol) of acetic anhydride are added dropwise and the solution is stirred overnight at room temperature. After washing 3 times with water and then with brine, the organic phase is dried over MgSO ₄ and evaporated. The solid obtained is taken up in isopropyl ether then filtered and dried to yield the title product.

Melting point: 128 ° C

Elementary Mjçrqanqlyse:

VS H NOT % theoretical 55.93 5.12 11.86 % experimental 55.94 5.13 11.71

ORIGINAL

- ΙΟ Stage C: 3- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl acetate

To a solution of 9.40 g (39.8 mmol) of the product obtained in the preceding Stage B in 300 ml of toluene, are added 150 mg of para-toluene sulfonic acid and the reaction medium is heated to reflux with a dean system. -stark for 12 hours. The title product is obtained after evaporation of the toluene on a rotavapor.

Point_d_ejïi_s ion: 94 ° C

Stage D: 3- (5-melhyl-1,2,4-oxadiazol-3-yl) phenol

A solution of 8.55 g (39.18 mmol) of the product obtained in the preceding Stage C in 120 ml of a 1N HCl solution is heated for 90 minutes at reflux, then left at room temperature with stirring overnight. The precipitate is filtered off to yield the title product. Melting point: 118 ° C

Elementary MlÇ.TJianq / yse:

VS H NOT % theoretical 61.36 4.58 15.90 % experimental 61.44 4.55 15.82

Preparation 2: 3- (1,3-oxazol-2-yl) phenol

Stage A: 2- (3-methoxyphenyl) -1,3-oxazole

A suspension containing 1.16 ml of 1-bromo-3-methoxybenzene (9.2 mmol), 2.12 ml of 2- (tributylstannanyl) -1, 3-oxazole (5.9 mmol), and 276 mg (0 , 2 mmol) of Palladium tetrakis [triphenylphosphine] in 50 ml of toluene is stirred overnight at reflux under argon. The toluene is evaporated off on a rotary evaporator, the residue is then taken up in suspension in ethyl acetate. After filtration of the suspension, the filtrate is evaporated to dryness and the crude is purified by chromatography on silica gel, eluting with CH2Cl2 then ClhC4 / acetone 98/2 to yield the title product in the form of an oil.

ORIGINAL

- II Stage B: 3- (l, 3-oxazol-2-yl) phenol

The product obtained in the preceding Stage A (250 mg, 1.13 mmol) is suspended in 10 ml of an aqueous solution of 48% HBr and the reaction medium is stirred overnight at 115 ° C. After cooling to room temperature, the mixture is poured into 10 ml of a 10% NaHCO ₃ solution. The pH is adjusted to 7 and the aqueous phase is extracted with ethyl acetate. The organic phase is washed (saturated NaCl), dried (MgSCU) to yield, after filtration and evaporation, the title product in the form of a white solid.

Preparation 3: [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] boronic acid

Stage A: N‘-hydroxy-4-iodobenzenecarboximidamide

In 80 ml of DMSO, are added 17.3 g (249 mmol) of hydroxylamine hydrochloride then 35 ml (251 mmol) of triethylamine. A large white precipitate forms and the reaction medium is diluted in a little THF. After stirring for 1 hour, the precipitate is filtered. The filtrate is recovered and then transferred to a flask to which are added 9.55 g (41.7 mmol) of 4-iodobenzonitrile. The reaction is stirred overnight at room temperature and then cooled in an ice bath and 200 mL of water are added. The precipitate is filtered off to yield the expected product.

Microajiajyseéléjpentaire:

VS H NOT 1 % theoretical 32.08 2.69 10.69 48.43 % experimental 32.05 2.77 10.55 47.46

Stage B: Î \ '- (acetylox) ’) - 4-iodobenzenecarboximidamide

To a suspension of the product obtained in the previous Stage A (8.43 g, 32.17 mmol) in 200 ml of CH2Cl2, are added 6.72 ml (48.2 mmol) of triethylamine, 3.34 ml (35.4 mmol) of acetic anhydride are added dropwise and the solution is stirred overnight at room temperature. After 3 washes with water and then with brine, the phase

ORIGINAL

- 12organique is dried over MgSO ₄ and evaporated. The solid obtained is taken up in isopropyl ether and then filtered to yield the title product

Melting point: 139 ° C

Stage C: 3- (4-iodophenyl) -5-methyl-1,2,4-oxadiazole

150 mg of para-toluene sulfonic acid are added to a solution of the product obtained in the preceding Stage B (9.7 g, 31.9 mmol) in 300 ml of toluene and the reaction medium is heated to reflux with a dean assembly. stark for 24 hours. The mixture is evaporated to dryness and dried with a vacuum pump.

Melting point: 91 ° C

Stage D: 3-methyl-3- [4- (4,4,5,5-teilamethyl-1,2,3-dioxaborolan-2-yl) phenylJ-

1,2,4-oxadiazole

To a solution of the product obtained in the preceding Stage C (500 mg, 1.74 mmol) in 5 ml of DMF, are added 510 mg (5.2 mmol) of potassium acetate and 577 mg (2.28 mmol) of bis-pinacoîatoborane. The reaction medium is degassed for 30 minutes with nitrogen and then 20 mg (0.09 mmol) of Pd (OAc) ₂ are added. The reaction is heated for 3 hours at 85 ° C. After cooling to room temperature then addition of water, the reaction medium is extracted with ethyl acetate. The organic phases are combined, washed (saturated NaCl) and dried (MgSO ₄ ). The crude is purified by chromatography on silica gel, eluting with a 7/3 heptane / ethyl acetate mixture to yield the expected product.

Melting point: 128 ° C

Stage E: [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenyl] boronic acid

A suspension of the product obtained in the preceding Stage D (6.5 g, 22.7 mmol) in 230 ml of acetone is stirred for 24 hours in the presence of 18.4 g (86.0 mmol) of sodium meta-periodate and 70 ml of a 1 M aqueous solution of ammonium acetate. The acetone is evaporated off in a rotary evaporator and, after addition of water, the reaction medium is extracted with acetate

4?

ORIGINAL

- 13 ethyl. The organic phases are combined, washed (saturated NaCl) and dried (MgSCU) to yield the expected product after evaporation.

Preparation 4: [3- (5-methyl-1,3,4-oxadiazol-2-yI) phenyl | boronic acid

Stage A: N'-acetyl-3-iodobenzohydrazide

To a suspension of 3-iodobenzoic acid (2.0 g, 8.06 mmol) in 60 ml of THF, are successively added DIPEA (1.83 ml, 10.48 mmol) and ΤΒΤΌ (2.59 g , 8.06 mmol).

The reaction is stirred overnight at room temperature. 1.19 g (16.12 mmol) of acetylhydrazide are added and the reaction medium is heated for 30 hours at reflux. After evaporation to dryness, the residue is taken up in water with a little CH2Cl2, a thick precipitate forms which is filtered off to yield the expected product.

Poinjdejusion: 178 ° C

Stage B: 2- (3-iodophenyl) -5-methyl-l, 3,4-oxadiazole

The product obtained in the preceding Stage A (2.9 g, 9.54 mmol) is heated at 120 ° C. for hours in 35 ml of POC13. After evaporation of the POCI3, the residue is taken up in toluene and the mixture is again evaporated to dryness. The evaporation residue is dissolved in ethyl acetate, the organic phase is washed successively with 10% NaHCCh solution, with water and then with brine. The organic phase is dried over MgSO ₄ to yield, after evaporation, the expected product in the form of a creamy white solid. Deflection point: 115 ° C

Stage C: 2-methyl-5- [3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -

1,3,4-oxadiazole

The title product is obtained according to the process described in Stage D of Preparation 3, taking as starting product the compound described in the preceding Stage B in place of 3- (4-iodophenyl) -5-methyl-1 , 2,4-oxadiazole.

ffflnJ.d.eAusjon: 153 ° C

ORIGINAL

- 14 Stage D: [3- (5-methyl-l, 3,4-oxadiazol-2-yl) phenyl] boromic acid

The title product is obtained according to the process described in Stage E of Preparation 3, taking as starting product the compound described in the preceding Stage C in place of 5-methyl-3- [4- (4,4 , 5,5-Tetramethyl-1,2,3-dioxaborolan-2-yl) phenyl] -l, 2,4-oxadiazole. Decision point: 254 ° C

EXAMPLE 1: 8- [3- (5-m ethyl- 1,2,4-o. \ Adiazol-3-yl) phenoxy | -3.4-dihvdro-2 // - 5, l, 2- benzoxathiazepine 1,1-dioxide Stage A: 5-Bromo-2-methoxybenzenesulfonyl chloride

To chlorosulfonic acid (140mL, 2 mol), cooled to 0-5 ° C, are added dropwise 35 ml (0.279 mol) of 4-bromoanisole. The solution is stirred for 30 minutes at 0 ° C. then about 16 hours at room temperature. The contents are slowly poured over ice, then stirred for a few more minutes. The white precipitate formed is filtered and then washed with plenty of water.

PoiMjeJusion: 107 ° C

Stage B: 5 ~ bromoDD (2-chloroethylj-2-methoxyberizenesulfonamide

To a suspension of 13.4 g (0.115 mol) of 2-chloroethylamine hydrochloride in 150 ml of CH2Cl2, are added 34 ml (0.241 mol) of triethylamine then dropwise 30 g (0.105 mol) of the product obtained in the preceding Stage A dissolved in 200 ml of CH2Cl2. The solution is stirred for 2 hours at room temperature and is then washed with a 1N HCl solution, water and brine. The organic phase is dried over MgSO ₄ and evaporated. The solid is taken up in suspension in ethyl ether and filtered to yield the title product.

Juice Point: 150 ° C a

ORIGINAL

- 15 Stage C: 5-bromo-'S- (2-cMoroethyl) -2-hydroxybenzenesulfonamide

To a suspension of 29.9 g (91 mmol) of the product obtained in the preceding Stage B in 450 ml of CH ₂ Cl ₂ , are added dropwise, at room temperature, 200 ml (200 mmol) of a solution of BBr ₃ l M in CH ₂ Cl ₂ . After 30 minutes of stirring, the solution is poured onto an ice / water mixture while maintaining stirring. After decantation and a single extraction with CI I ₂ Cl ₂ , the organic phase is washed with brine, dried over MgSO ₄ and evaporated. The oily residue is triturated in heptane until crystallization. The title product is recovered by filtration.

Jusion PQ: 109 ° C

Stage D: tert-butyl [(5-bromo-2-hydroxyphenyl) sulfonyl] (2-chloroethyl) carbamate

To a solution containing 25.55 g (81.2 mmol) of the product obtained in the preceding Stage C, 17.72 g (81.2 mmol) of di- / erz-butyl dicarbonate and 496 mg (4.06 mmol) of dimethylaminopyridine in 500 mL of CH2Cl2, 11.32 g (81.2 mmol) of triethylamine dissolved in 200 ml of CH2Cl2 are added dropwise. The mixture is stirred overnight at room temperature. The organic phase is washed (saturated NaCl), dried (MgSO ₄ ) and evaporated in a rotary evaporator to yield the title product.

Stage E: 8-bromo-3,4-dihydro-2U-5,1,2-benzoxathiazepine î, 1 -dioxide g (81 mmol) of the product obtained in the preceding Stage D are heated to reflux in the presence of 2.69 g (16 mmol) of K1 and 33.6 g (240 mmol) of K ₂ CO ₃ in 1.2 L of ethanol for about 18 hours. After cooling, the salts are filtered off and rinsed with acetone. After evaporation, the filtrate is taken up in water. The mixture is acidified with a 1N HCl solution then extracted 3 times with CH2Cl2. The organic phase is washed twice with brine, dried over MgSO ₄ and evaporated. The residue obtained (~ 22 g) is then triturated in heptane and the mixture is then allowed to settle in order to remove the supernatant heptane. The residue is once again triturated in a heptane / isopropyl ether mixture to obtain a solid. After filtration, the product is quickly dried and then ground in a mortar.

ORIGINAL

- 16The solid obtained is dissolved in heptane, stirred for about 1 hour and filtered to yield the expected product.

Melting point: 129 ° C

Stage F: 8-bromo-3,4-dihydro-2Y \ -5,1,2-benzoxathiuzepin-2-carboxylate 1,1 tert-butyl dioxide

To a solution of 19.65 g (70.6 mmol) of the product obtained in the preceding Stage E and 259 mg (2 mmol) of DM AP in 200 ml of CH2Cl2, 23.1 g (106 mmol) are added dropwise. of di-rert-butyl dicarbonate dissolved in 125 ml of CH2Cl2. The reaction mixture is stirred at room temperature and then, after 3 hours, 100 mg of DMAP are added. The solution is stirred for 45 minutes. After 2 washes with water and with brine, the organic phase is dried over MgSO ₄ and evaporated. The evaporation residue is triturated in heptane. The solid obtained is dissolved in heptane, stirred for 48 hours, giving a precipitate which will be filtered off to yield the title product. Melting point: 119 ° C

Stage G: [2- (tert-butoxycarbonyl) -1, 1 -dioxydo-3,4-dihydro-2 \ A-5,1,2benzoxathiazepin-8-yl] boronic acid

To a solution of the product obtained in the preceding Stage F (21.6 g, 57.3 mmol) and of 40 ml of trî-isopropylborate in 210 ml of THF, cooled to -65 ° C and under N ₂ , are added dropwise. 90 ml (143 mmol) drop of a 1.6 M “BuLi solution. The reaction mixture is stirred for 1 hour at -65 ° C. and allowed to return to ambient temperature. After stirring for 1 hour, the solution is cooled in an ice bath and hydrolyzed by adding 320 ml of a 0.5 M HCl solution. After 3 extractions with CH2Cl2, the organic phase is washed with brine and dried. on MgSO ₄ and evaporated. The residue is taken up in heptane which, after evaporation, is triturated in heptane and filtered to yield the title product.

Melting point: 197 ° C

ORIGINAL

- 17H stage: 8- [3- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] -3,4-dihydro-2W-5,1,2benzoxathiazepine-2-carboxylate 1,1- tevt-butyl dioxide

A suspension containing 2.5 g (7.28 mmol) of the product obtained in the preceding Stage G, 1.17 g (6.62 mmol) of the compound of Preparation 1, 1.61 ml (19.9 mmol) of pyridine , 1.8 g (9.9 mmol) of copper acetate and 8 g of a 4 Å sieve in 125 ml of CH ₂ C1 ₂ is stirred at room temperature and in air for 20 hours. The sieve is filtered and the filtrate is rinsed with 125 ml of a CFhCh / MeOH mixture. Then, 6 g of SiO ₂ are added to the filtrate before evaporation to dryness. The crude product is purified by chromatography on silica gel, eluting with a CFLCh / acetone 97/3 mixture to yield the expected product in the form of a meringue.

Stage 1: 8- [3- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] -3,4-dihydro-2W-5,1,2benzoxathiazepine 1,1-dioxide

A solution of 1.92 g (4.05 mmol) of the product obtained in the preceding Stage H is heated at 80 ° C. for 2 hours in 15 ml of a solution of 4 N HCl in dioxane. The mixture is evaporated to dryness and dried under vacuum. The crude is purified by chromatography on silica gel, eluting with a CH ₂ Cl ₂ / AcOEt mixture. The solid taken up in isopropyl ether and filtered to yield the title product

Juice Point: 177 ° C

EXAMPLE 2: 8- | 3- (1,3-thiazol-2-vl) phenoxy | -3.4-dihvdro-2 // - 5, l, 2benzoxathiazepine 1,1-dioxide

Stage A: 8- [3- (1,3-ihiazol-2-yl) phenoxy] -3,4-dihydro-2W-5,1,2-benzoxathiazepine -2-carboxylate 1,1-lexUbutyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 using (3-thiazoL2-yl) phenol (the preparation of which is described in Bioor g. Med. Chem. 2003, U (7) , 1235-48) in place of the compound of Preparation 1.

ORIGINAL

- 18 Stage B: 8- [3- (1,3-thiazol-2-yl) phenoxy] -3,4-dihydro-2H.-5,1,2-benzoxathiazepine

1,1-dioxide

The title product is obtained according to the protocol described in Stage 1 of ΓExample 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3-yl) phenoxy] -3,4-dihydro-2 / 7-5, 1,2-benzoxathiazepine-2-carboxylate 1,1-rm-butyl dioxide.

Melting point: 148 ° C

Elementary micrognaly.se:

VS H NOT S % theoretical 54.53 3.71 7.48 17.13 % experimental 54.68 3.85 7.34 17.18

EXAMPLE 3: 8-j3- (1,3-thiazol-5-yl) plienoxy] -3.4-dihvdro-2 // - 5, l, 2benzoxathiazepine 1,1-dioxide

Stage A: 8- [3- (1,3-thiazol-5-yl) phenoxy] -3,4-dihydr 0-233-5,1,2-benzoxathiazepine

-2-carboxylate 1,1-tert-butyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 using (3-thiazol-5-yl) phenol (the preparation of which is described in Bioorg. Med. Chem. 2003,11 (7 )> 1235-48) in place of the compound of Preparation 1,

Stage B: 8- [3- (1,3-thiazol-5-yl) phenoxy] -3,4-dihydro-2 \ 3-5,1,2-benzoxathiazepine

1,1-dioxide

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2 // - 5,1,2-benzoxathiazepine-2-carboxy late 1,1-zm-butyl dioxide.

_D_efu_sion point: 60 ° C (meringue)

ORIGINAL

- 19MiÇKPJinalyseéléjnenlaire:

VS H NOT S % theoretical 54.53 3.77 7.48 17.13 % experimental 54.69 3.76 7.06 17.10

EXAMPLE 4:

8- [3- (1,3-oxazol-2-yl) phenoxy] -3,4-dihydro-2 // - 5, l, 2benzoxathiazepine 1,1-dioxide

Stage A: 8- [3- (1,3-oxazol-2-yl) phenoxy] -3,4-dîhydro-2H-5,1,2-benzoxathiazepine2-carboxylate 1,1-tert-butyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 using the compound of Preparation 2 in place of the compound of Preparation 1.

Stage B: 8- [3- (1,3-oxazol-2-yl) phenoxy] -3,4-dihydro-2H-5,1,2-benzoxathiazepine

1,1-dioxide

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2L / '- 5,1.2-benzoxathiazepine-2-carboxylate 1,1-rerZ-butyl dioxide.

Deflection point: 180 ° C

Mi <p-oanqlyseélé_ment_aire:

VS H NOT S % theoretical 56.98 3.94 7.82 8.95 % experimental 56.60 3.92 7.65 8.61

ORIGINAL

EXAMPLE 5: 8- | 4- (5-ηΐί4ΐινΙ-1.2,4-οχ; ΐ (1ί; ΐζοΙ-3-νΙ) [) 1ιέηοχν | -3,4-ύίΙιν (1ι · ο-2 / 7-5,1,2 - benzoxathiazepine 1,1-dioxide Stage A: 8-hydroxy-3,4-dihydro-2} 4-5 _> 1,2-benzoxathiazepine-2-carboxylate 1,1 tert-butyl dioxide

A suspension of 4.7 g (13.69 mmol) of the product of Stage G of Example 1 in a mixture of 90 ml of THF and 90 ml of water is stirred at room temperature in the presence of 5.27 g ( 34 mmol) sodium perborate tetrahydrate overnight. The reaction medium is diluted by adding a saturated aqueous solution of NH ₄ C1 and then extracted with CH2Cl2. The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated on a rotary evaporator. The evaporation residue is taken up and triturated in heptane in the presence of a few drops of isopropyl ether, a precipitate forms which is filtered to yield the expected product.

Melting point: 143 ° C

Stage B: 8- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] -3,4-dïhydro-2H-5,1,2benzoxathiazepine-2-carboxylate 1,1-dioxide tert-butyl

The title product is obtained according to the protocol described in Stage H of Example 1 using the compound of Preparation 3 in place of the compound of Preparation 1.

Stage C: 8- [4- (5-methyl-1,2,4-oxadiazol-3-yl) phenoxy] -3,4-dihydro-2} 4-5,1,2benzoxathiazepine 1,1-dioxide

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage B in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2f / -5, 1,2-benzoxathiazepine-2-carboxylate 1,1 rerr-butyl dioxide.

Temperature point: 171 ° C

ORIGINAL

-2l Elemental microanalysis:

VS H NOT S % theoretical 54.69 4.05 11.25 8.59 % experimental 54.81 4.07 10.96 8.54

EXAMPLE 6: 8- [3- (5-methyl-1,3,4-oxadiazol-2-yl) plienoxy] -3,4-dihydro-2f7-5, 1,2benzoxathiazepine 1,1-dioxide

Stage A: 8- [3- (5-methyl-1,3 _! 4-oxadiazol-2-yl) phenoxy] -3,4-dihydro-2Il-5 _! Xert-butyl 1,2benzoxathiazepine-2-carboxylate 1,1-dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 by reacting the product obtained in Stage A of Example 5 with the compound of Preparation 4 in place of the compound of Preparation 1.

Stage B: 8- [3- (5-methyl-1,3,4-oxadiazol-2-yl) phenoxy] -3,4-dihydro-2 \\ - 5, l, 2benzoxathiazepine 1,1-dioxide

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2j ^r / -5, 1,2-benzoxathiazepine-2-carboxylate 1,115 ter Abut y le.

Set point: 192 ° C pk

ORIGINAL

-22EXAMPLE 7: 3 - [(1,1-dioxydo-3,4-dihydro-2 / Z-5, 1,2-benzoxathiazepin-8-yl) oxy] benzoate

Stage A: 8- [3- (ethoxycarbonyl) phenoxy] -3,4-dihydro-2W-5,1,2benzoxathiazepine-2-carboxylate 1,1-tert-butyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 by reacting the product obtained in Stage A of Example 5 with [3- (ethoxycarbonyl) phenyl] boronic acid.

Stage B: ethyl 3 - [(1,1-dioxydo-3,4-dihydro-2H-5,1,2-benzoxathiazepin-8-yl) oxy] benzoate

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2 // - 5,1,2-benzoxathiazepine-2-carboxylate 1,1-reri-butyl dioxide.

No Juice ion; 120 ° C

Micropnqlyseéléjnenpiire:

VS H NOT S % theoretical 56.19 4.72 3.85 8.82 % experimental 55.71 4.70 4.07 9.02

EXAMPLE 8: 3 - [(1,1-dioxydo-3,4-dihydro-2 // - 5, 1,2-benzoxathiazepin-8yl) oxy] benzonitrile

Stage A: 8- (3-cyanophenoxy) -3,4-dihydro-2tA-5,1,2-benzoxathiazepine-2carboxylate 1,1-dioxide (ert-butyl

The title product is obtained according to the protocol described in Stage H of Example 1 by reacting the product obtained in Stage A of Example 5 with (3-cyanophenyl) boronic acid.

ORIGINAL

-23 Stage B: 3 - [(I, 1-dioxydo-3,4-dihydro-2 \ ï-5, L2-henzoxathiazepin-8-yl) oxy] benzonitrile

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2 // - 5, L2-benzoxathiazepine-2-carboxylate 1,1 / err-butyl dioxide.

Melting point: 131 ° C

Elementary miçroanalysis:

VS H NOT S % theoretical 56.95 3.82 8.86 10.14 % experimental 56.66 3.88 8.64 9.98

EXAMPLE 9: 7V- {3 - [(I, 1-dioxydo-3,4-dihydro-2J / -5, 1,2-benzoxathiazepin-8-yl) oxy] benzy IJmethanesulfonamide

Stage A: 8- (3 - {[(methylsulfonyl) amino] methyl} phenoxy) -3,4-dihydro-2Î [-5,1,2benzoxathiazepine-2-carboxylate 1,1-tert-butyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 by reacting the product obtained in Stage A of Example 5 with the acid (3 - {[(methylsulfonyl) amino] methyl} phenyl ) boronic.

Stage B: fi- {3 - [(1,1-dioxydo-3,4-dihydro-2 \ A-5,1,2-benzoxathiazepin-8-yl) oxy] benzyl} methanesulfonamide

The title product is obtained according to the protocol described in Stage 1 of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2LA5, 1,2-benzoxathiazepine-2-carboxylate 1,1 / t77-butyl dioxide.

.PoinjdeJusjon: 57-60 ° C <= ί—

ORIGINAL

-24EXAMPLE ΙΟ: 8-phenoxy-3,4-dihydro-2 // - 5, l, 2-benzoxatliiazepine 1,1-dioxide

Stage A: 8-phenoxy-3,4-dihydra-2Vi-5,1,2-benzoxathiazepine-2-carboxy! Aie 1,1 tert-butyl dioxide

The title product is obtained according to the protocol described in Stage H of Example 1 by reacting the product obtained in Stage A of Example 5 with phenylboronic acid.

Stage B: 8-phenoxy-3,4-dihydro-2 \\ - 5,1,2-benzoxathiazepine 1,1-dioxide

The title product is obtained according to the protocol described in Stage I of Example 1 using the compound obtained in the preceding Stage A in place of 8- [3- (5-methyl-1,2,4oxadiazol-3- yl) phenoxy] -3,4-dihydro-2 / 7-5,1,2-benzoxathiazepine-2-carboxylate 1,110 ZcvV-butyl dioxide.

Setpoint: 110 ° C

EXAMPLE 11: 3 - [(1,1-dioxydo-3,4-dihydro-2ff-5, 1,2-benzoxathiazepin-8-yl) oxy] -2V'hydroxybenzenecarboximidamide

The title product is obtained according to the protocol described in Stage A of Preparation 1, using the compound of Example 8 in place of 3-hydroxybenzonitrile.

Ion point: 163-166 ° C

Elementary microanalysis:

VS H NOT S % theoretical 51.57 4.33 12.03 9.18 % experimental 51.27 4.42 11.62 9.31

ORIGINAL

-25 EXAMPLE 12: 8- {3- [5- (triluoromethyl) -1, 2,4-oxadiazol-3-yl] phenoxy} -3,4-dihydro27 / -5,1,2-benzoxathiazepine 1,1- dioxide

To a suspension of the compound of Example 11 (800 mg, 2.29 mmol) in 15 ml of CH2Cl2, are added 958 μΐ (6.87 mmol) of triethylamine then 701 μΐ (5.04 mmol) of trifluoroacetic anhydride drip. After stirring for 1 hour at room temperature, the reaction medium is washed with water and then with saturated NaCl solution and dried over MgSO4. The crude is purified by chromatography on silica gel eluting with CH2Cl2 to yield the expected product in the form of a meringue.

Micr ^ jmelementary analysis:

VS H NOT S % theoretical 47.78 2.83 9.83 7.50 % experimental 47.66 3.18 9.59 7.69

EXAMPLE 13: 8- [3- (3-methyl-1,2,4-oxadiazol-5-yI) phenoxy] -3,4-dihydro-2 / 7-5, 1,2benzoxathiazepine 1,1-dioxide

Stage A: 3 - [(1,1 -dioxydo-3,4-dihydro-2H-5, l, 2-benzoxathiazepm-8yl) oxy] benzoic acid

A suspension of 1.0 g (2.23 mmol) of the product obtained in Stage A of Example 7 in 20 ml of a solution of 1N NaOH and 1 ml of THF is stirred for 3 hours at 100 ° C. After cooling to room temperature, the reaction medium is acidified by slowly adding a 1N HCl solution. The white precipitate is filtered off and dried to yield the expected product.

Stage B: 3 - [(l, l-dioxydo-3,4-dihydro-2H-5, l, 2-benzoxathiazepin-8-yl) oxy] -H [(lZ) -N-hydroxyelhanimidoyl] benzamide

To a suspension of the product obtained in the preceding Stage A (540 mg, 1.61 mmol) in 10 ml of CH2Cl2, are successively added 516 mg (1.61 mmol) of TBTU then 364 μΐ (2.09 mmol) of DIEA. After 20 minutes of stirring, 120 mg (1.61 mmol) of

ORIGINAL

-26A-hydroxyacetamidine are added and the reaction medium is stirred for 1.5 hours at room temperature. The reaction medium is washed with water and then with saturated NaCl solution, dried (MgSO ₄ ) and evaporated to dryness. The residue is taken up in CH2Cl2, a white precipitate forms which is filtered to yield the expected product.

Stage C: 8- [3- (3-methyl-1,2,4-oxadiazol-5-yl) phenoxy] -3,4-dihydro-2 \ 3-5, l, 2benzoxathiazepine 1,1 -dioxide

To a solution of 390 mg (0.99 mmol) of the product obtained in the preceding Stage B in 50 ml of toluene, are added 35 mg of para-toluene sulfonic acid and the reaction medium is heated to reflux with a dean-stark system. for 12 hours. After evaporation, the reaction crude is purified on silica gel, eluting with a 9/1 hClLC / AcOEt mixture to yield the expected product.

PQinJdeJfision: 140 ° C

Elementary micrjoanglyse:

VS H NOT S % theoretical 54.69 4.05 11.25 8.59 % experimental 54.78 4.11 11.00 8.70

ZORIGINAL

-27 PHARMACOLOGICAL STUDY

EXAMPLE A Study of the Effect of the Products on Membrane Depolarization Induced by AMPA on Primary Cultures of Rat Neurons.

The test consists of the in vitro measurement, by fluorescence, of the membrane depolarization induced on embryonic rat neurons in culture, by the joint action of AMPA and the product tested, in comparison to the action of AMPA only. Brain cells are cultured and maintained in a cell culture incubator for 18 days. After incubation, the culture medium is removed and replaced with loading medium in fluorescence probe for measuring the membrane potential (20 μΐ; membrane potential kit from Molecular Devices) and left at room temperature for 1 hour. The baseline fluorescence of the wells is read (Hamamatsu FDSS apparatus), then AMPA is injected into the cells (20 μΐ; concentration range 3 to 100 μΜ) and the action of AMPA is measured kinetically. The tested product is then introduced into the wells (20 μΐ; in the concentration range, crossed with that of AMPA) and the action of the product is measured in kinetics. At the end of each of the 2 kinetic measurement periods, the value retained for each well is the average of the reading over the last 15 seconds of the period. AMPA effect curves are shown at different product concentrations. For each concentration of product, the value retained is calculated under the AMPA curve at this concentration and the ECîx, the concentration of product which doubles the membrane potential induced by AMPA, is calculated.

The compounds of the invention strongly potentiate the excitatory effects of AMPA. By way of example, the compounds of Example 1 and Example 13 exhibit an EC x of 5 and 18 μl, respectively.

AT

ORIGINAL

-28EXAMPLE B: Object recognition in CD1 mice

The object recognition test (Behav. Brain Res., 1988, 31, 47-59) is based on the spontaneous exploratory activity of the animal and has the characteristics of episodic memory in humans. Sensitive to aging (Eur. J. Pharm. 1997, 325, 173-180), as well as to cholinergic dysfunctions (Pharm. Biochem. Behav., 1996, 53 (2), 277-283), this memory test is based on the differential exploration of 2 objects, one familiar, the other new. The experimental procedure, adapted to the CD1 mouse, comprises 3 phases which take place in the same experimental enclosure. During the 1 ^st phase, which lasts 30 minutes, the mice are accustomed to the environment (habituation phase). During the 2 ^nd phase, which takes place the next day, two identical objects are placed in the enclosure and the mouse is free to explore them (familiarization phase). When this exploration reaches a total duration of 20 seconds, the mouse is removed from the enclosure. During the 3 ^rd phase (5 minutes, retention phase), 6 hours later, one of the two objects is presented again (it acquires the status of "familiar" object), as well as a new object. ("new" object). The exploration time, expressed in seconds, of each of the two objects is timed. The control animals, having previously received the vehicle orally 60 minutes before the familiarization phase, explore for an equivalent period of time the “familiar” object and the “new” object during the retention phase, which means forgetting. of the object already presented. Animals which have received a mnemocognitive facilitator compound preferentially explore the new object, which means maintaining the memory of the object already presented.

The results obtained with the compounds of the present invention show a significantly greater exploration of the new object compared to the familiar object at doses of 0.3, 1 and 3 mg / kg, PO, by doubling or even tripling the duration. exploration of the “new” object versus the “familiar” object, which indicates that the compounds of the invention improve memorization significantly.

ORIGINAL

EXAMPLE C: Pharmaceutical composition

Preparation formula for 1000 tablets containing 10 mg of 8- [3- (5-methyl-l, 2,4oxadiazol-3-yl) phenoxy] -3,4-dihydro-2 // - 5, l, 2- benzoxathiazepine l, l-dioxide (Example l) ........................................ .................................................. ............................. 10g

Hydroxypropylcellulose ................................................. .................................................. ... 2g

Wheat starch10 g

Lactose................................................. .................................................. ......................... 100g

Magnesium stearate ............................................... .................................................. ....... 3g

Talc................................................. .................................................. ................................... 3g

Claims (16)

l. Compounds of formula (I): in which Rj represents a hydrogen atom, a cyano group, a linear or branched (C1-C6) alkoxycarbonyl group, a linear or branched (C] -C6) alkyl (C | -C6) sulfonyiaminoalkyl group, a group A- hydroxycarboximidamide, or a heterocyclic group, their enantiomers and their diastereomers, as well as their addition salts with a pharmaceutically acceptable acid or base, it being understood that the term heterocyclic group denotes a 5-membered monocyclic aromatic group, containing one to four heteroatoms , identical or different, chosen from nitrogen, oxygen and sulfur, said heterocyclic group possibly being substituted by one or more substituents, identical or different, chosen from linear or branched (Ci-Cg) alkyl or linear or polyhaloalkyl (Ci-C &) or branched. 2. Compounds of formula (I) according to claim 1, characterized in that R] represents a heterocyclic group. 3. Compounds of formula (I) according to claim 1, characterized in that R] represents a 5-membered aromatic monocyclic heterocyclic group containing at least one nitrogen atom, said group possibly being optionally substituted by one or more substituents, identical. or different, chosen from linear or branched alkyl (Cj-Cé) or linear or branched polyhaloalkyl (CpCé). ORIGINAL 4. Compounds of formula (I) according to claim l, characterized in that Rj represents a pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, thiadiazolyl, dithiazolyl or oxadiazolyl group, each of the groups possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (C 1 -C 6) alkyl or linear or branched polyhaloalkyl (CpC 6). 5. Compounds of formula (I) according to claim l, characterized in that R | represents a thiazolyl or oxadiazolyl group, each of the groups possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (Cj-Cé) alkyl or linear or branched (Ci-Cé) polyhaloalkyl. 6. Compounds of formula (I) according to claim l, characterized in that R represents a l.3-thiazolyl or l, 2,4-oxadiazolyl group, each of the groups possibly being optionally substituted by one or more substituents, identical or different, chosen from linear or branched (Ci-C6) alkyl or linear or branched polyhaloalkyl (Ci-C6). 7. Compounds of formula (I) according to claim 1, characterized in that R [represents a 1,3-thiazolyl or 1,2,4-oxadiazolyl group substituted with a methyl or trifluoromethyl group. 8. Compounds of formula (I) according to claim 1, characterized in that R] is in the meta position of the phenoxy nucleus which carries it. 9. Compounds of formula (I) according to claim 1, which are: • 8- [3- (5-methyl -1,2,4-oxadiazol-3-yl) phenoxy] -3,4-dihydro-27 / -5, l, 2benzoxathiazepine 1,1-dioxide; • 8- [3- (3-methyl-1,2,4-oxadiazol-5-yl) phenoxy] -3,4-dihydro-2 / f-5, l, 2- ORIGINAL -32benzoxathiazepine 1,1-dioxide; their enantiomers, their diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 10, Process for the preparation of compounds of formula (I) according to claim l, 5 characterized in that a compound of formula (II) is used as starting material: (Π) in which Hal represents a halogen atom, such as fluorine, chlorine or bromine, and R 'represents a linear or branched (C | -C6) alkyl group, 10 which is reacted with 2-chloroethylamine in a basic medium to yield the compound of formula (III): in which Hal and R 'are as defined above, which then undergoes the action of a boric derivative to lead to the compound of Formula (IV): ORIGINAL in which Hal is as defined above, which is then cyclized to lead to the compound of formula (V): (V) 5 in which Hal is as defined above, which undergoes a protective reaction on the nitrogen atom to lead to the compound of formula (VI): in which Hal is as defined above and R represents a group 10 protector of the amine function, such as for example the tertbutyloxycarbonyl group, which is converted into boronic acid to lead to compounds of formula (Vil): ORIGINAL (VII) in which R is as defined above, which is reacted with an alcohol of formula (VIII): (HIV) 5 in which R 1 has the same meaning as in formula (I), to result in the compound of formula (IX), in which R 1 and R are as defined above; which is then subjected to a deprotection reaction of the amine function to yield the compound of formula (I), a variant in the preparation of the compounds of formula (1) consisting in the hydrolysis of the compound of formula (VII) to lead to the compound of formula (X): ORIGINAL in which R is as defined above, which is reacted with a boronic acid derivative of formula (XI): OH ^R, rr ^ ^0H (XI) 5 in which R 1 has the same meaning as in formula (I), to lead to the compound of formula (IX), which is then subjected to a deprotection reaction of the amine function to lead to the compound of formula (I), a another alternative in the preparation of the compounds of formula (I) consisting, after the preparation of the compounds of formula (IX), in the reuse of conventional chemical reactions in order to modify, in a second step, the substituent of the phenoxy ring, composed of formula (I) which can then be purified according to a conventional separation technique, which is converted, if desired into its addition salts with an acid or with a pharmaceutically acceptable base and from which the isomers are optionally separated according to a classic separation technique. ORIGINAL II. Compounds of formula (V): (V) in which Ha! represents a halogen atom such as fluorine, chlorine or bromine, characterized in that they are useful as intermediates in the synthesis of compounds of formula (I), 12. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 9, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 13. Pharmaceutical compositions according to claim 12 useful as modulators of the AMPA receptor. 14. Pharmaceutical compositions according to claim 12 useful for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's chorea, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementias, sequelae of ischemia and sequelae of epilepsy. 15. Use of the compounds of formula (I) according to any one of claims 1 to 9 for the manufacture of medicaments useful as modulators of the AMPA receptor. ORIGINAL 16. Use of the compounds of formula (I) according to any one of claims 1 to 9 for the manufacture of medicaments useful for the treatment or prevention of mnemocognitive disorders associated with age, with anxiety or depressive syndromes, with neurodegenerative diseases progressive, Alzheimer's disease, 5 Parkinson's, Pick's disease, Huntington's chorea, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementias, sequelae of ischemia and sequelae epilepsy. 17. Compounds of formula (I) according to any one of claims 1 to 9 useful as modulators of the AMPA receptor. 18. Compounds of formula (I) according to any one of claims 1 to 9 useful for the treatment or prevention of mnemocognitive disorders associated with age, with anxiety or depressive syndromes, with progressive neurodegenerative diseases, with disease. '' Alzheimer's, Parkinson's disease, Pick's disease, Huntington's chorea, Korsakoff's disease, schizophrenia, sequelae of 15 acute neurodegenerative diseases, frontal and subcortical dementias, sequelae of ischemia and sequelae of epilepsy.