WO2011083264A1 - Thiochroman derivatives, method for preparing same and pharmaceutical compositions containing same - Google Patents

Abstract

The invention relates to compounds of formula (I), where R₁, R₂, R₃ and R₄, identical or different, each represent a hydrogen atom, a halogen atom or a cyano, hydroxyl, thio, nitro, alkyl, aryl, alkoxy, aryloxy, alkylthio, arylthio, carboxyl, alkoxycarbonyl, aryloxycarbonyl, acyloxy, arylcarbonyloxy, acyl, arylcarbonyl, amino, arylamino, acylamino, arylcarbonylamino, aminocarbonyl, arylaminocarbonyl, alkylsulfonylamino, or arylsulfonylamino group. The invention can be used in the field of drugs.

Description

 THIOCHROMAN DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS THEREOF

CONTAIN

The present invention relates to novel thiochroman derivatives, process for their preparation, pharmaceutical compositions containing them and their use as positive allosteric modulators of AMP A receptors.

It is now recognized that excitatory amino acids, and particularly glutamate, play a crucial role in the physiological processes of neural 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, some 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 AMPA receptor ("α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic 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 AMPA to its receptor in the hippocampus, one of the brain areas essential to mnemocognitive 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.

Finally, EP 692 484 discloses a benzothiadiazine derivative having AMPA current facilitating activity and WO 99/42456 discloses, inter alia, certain benzothiadiazine derivatives as AMPA receptor modulators.

The thiochroman derivatives, which are the subject of the present invention, are novel and constitute powerful positive allosteric modulators of AMPA receptors.

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

dans laquelle

in which

R 1, R ₂ , R ₃ and (, which may be identical or different, each represent a hydrogen atom, a halogen atom or a linear or branched cyano; hydroxy; thio; nitro; alkyl (C! -C ₆ ) alkyl group; optionally substituted, aryl, (C 1 -C ₆ ) alkoxy, linear or branched unsubstituted or substituted by one or more halogen atoms, aryloxy, linear or branched alkylthio (Ci-C ₆ ), arylthio, carboxy, alkoxycarbonyl (QC _O) straight or branched; aryloxycarbonyl; acyl (C -C ₆₎ linear or branched;! acyloxy (CJ _O-C) straight or branched; arylcarbonyloxy, arylcarbonyl, amino unsubstituted or substituted with one or two alkyl groups (CrC ₆ ) linear or branched, identical or different, arylamino unsubstituted or substituted on the nitrogen atom by a linear or branched alkyl (CC ₆ ); acylamino (C 6 C 6) linear or branched unsubstituted or substituted on the nitrogen atom by a linear or branched (Ci-Ce) alkyl group; arylcarbonylamino substituted or substituted on the nitrogen atom by a linear or branched (C ₁ -C ₆ ) alkyl group; aminocarbonyl unsubstituted or substituted with one or two linear or branched (C ₁ -C ₆ ) alkyl groups, which are identical or different; arylaminocarbonyl unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; alkylsulfonylamino (Ci-C ₆₎ linear or branched unsubstituted or substituted on the nitrogen atom by an alkyl group (QC _O) straight or branched; or arylsulfonylamino which is unsubstituted or substituted on the nitrogen atom by a linear or branched (C ₁ -C ₆ ) alkyl 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 "aryl" and the term "aryl" contained in the aryloxy, arylthio, aryloxycarbonyl, arylcarbonyloxy, arylcarbonyl, arylamino, arylcarbonylamino, arylaminocarbonyl and arylsulfonylamino groups represent the phenyl group which is unsubstituted or substituted by one or more groups, identical or different, chosen from a halogen atom, or a cyano group; hydroxy; thio; nitro; alkyl (Ci-C ₆₎ linear or branched optionally substituted; linear or branched alkoxy (C ₁ -C ₆ ) unsubstituted or substituted by one or more halogen atoms; linear or branched alkylthio (C ₁ -C ₆ ); carboxy; linear or branched alkoxycarbonyl (CC); linear or branched acyloxy (Cj-C); amino unsubstituted or substituted with one or two linear or branched (C ₁ -C 6) alkyl groups, which are identical or different; linear or branched acylamino (C] -C ₆ ) which is unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; aminocarbonyl unsubstituted or substituted by one or two identical or different linear or branched alkyl groups (QC _δ ); aminosulfonyl unsubstituted or substituted with one or two linear or branched (C 1 -C) alkyl groups, which are identical or different; alkylsulfonylamino (QC _O) -straight or branched unsubstituted or substituted on the nitrogen atom by an alkyl group (CJ _O-C) straight or branched; or N-hydroxycarboximidamide; the expression "optionally substituted" assigned to the term alkyl means that this group may be substituted by one or more halogen atoms, or by a cyano group; hydroxy; thio; nitro; aryl; linear or branched alkoxy (C] -C ₆ ) unsubstituted or substituted by one or more halogen atoms; linear or branched alkylthio (Ci-C ₆ ); carboxy; alkoxycarbonyl (Ci-C ₆₎ linear or branched; linear or branched acyloxy (C] -C ₆ ); amino unsubstituted or substituted with one or two linear or branched (Cj-C) alkyl groups, identical or different; acylamino (CrC ₆ ) linear or branched unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C 6) alkyl group; aminocarbonyl unsubstituted or substituted with one or two linear or branched (C ₁ -C ₆ ) alkyl groups, which are identical or different; aminosulfonyl unsubstituted or substituted with one or two identical or different linear or branched alkyl groups (QC _δ ); alkylsulfonylamino (C ₆ -C?) straight or branched unsubstituted or substituted on the nitrogen atom by an alkyl (Ci-C ₆₎ linear or branched; or N-hydroxycarboximidamide. 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 and methanesulphonic acids. , benzenesulfonic, camphoric.

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

The group K preferably represents a hydrogen atom or a halogen atom, and more particularly the fluorine atom.

The group R ₂ preferably represents a hydrogen atom; a halogen atom, and more particularly the fluorine, chlorine or bromine atom; the cyano group; the carboxy group; or alkyl (QC _O) -straight or branched, more particularly a methyl group.

The group R ₃ preferably represents a hydrogen atom; an atom halogen, and more particularly the fluorine, chlorine or bromine atom; the cyano group; the hydroxy group; the alkoxy (Ci-C ₆₎ linear or branched, more particularly methoxy; the acylamino group (CJ _O-C) -straight or branched, more particularly the acetylamino group; the unsubstituted or substituted aminocarbonyl group, and more particularly the N, N-dimethylaminocarbonyl group; the linear or branched alkyl (CrC ₆ ) group, and more particularly the methyl group; or the aryloxy group.

The group R ₄ preferably represents a hydrogen atom or a halogen atom, more particularly the fluorine, chlorine or bromine atom and, advantageously, the fluorine atom.

Compounds in which two of the groups R _1, R ₂ , R 3 or R 4 represent a hydrogen atom are more particularly preferred, while the two other substituents, which are identical or different, represent a group that is distinct from a hydrogen atom, preferably chosen from halogen atoms, such as the fluorine, chlorine or bromine atom, the hydroxyl group and the cyano group.

According to a preferred embodiment, R 1, R ₂ and R 4 represent a hydrogen atom while R ₃ represents the phenoxy group which is unsubstituted or substituted with a halogen atom; a cyano group; an optionally substituted linear or branched (C ₁ -C ₆ ) alkyl group; a linear or branched alkoxy (Ct-C6) group; a linear or branched (C ₁ -C ₆ ) acylamino group which is unsubstituted or substituted on the nitrogen atom by a linear or branched (C ₁ -C ₆ ) alkyl group; an unsubstituted aminocarbonyl group or substituted by one or two alkyl groups (QC _O) straight or branched; a linear or branched alkylsulfonylamino (QQ) group which is unsubstituted or substituted on the nitrogen atom by a linear or branched (C ₁ -C ₆ ) alkyl group; or an N-hydroxycarboximidamide group.

When R ₃ represents a phenoxy group substituted with an optionally substituted linear or branched alkyl (Ci-Ce) group, said alkyl group preferably represents a methyl or ethyl group substituted with one or more atoms of halogen, or a linear or branched (C ₁ -C 8) alkoxy group which is unsubstituted or substituted with one or more halogen atoms; alkoxycarbonyl (Ci-C ₆₎ linear or branched; acylamino (dC ₆ ) linear or branched unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; unsubstituted or substituted aminocarbonyl with one or two identical or different linear or branched (C ₁ -C ₆ ) alkyl groups; aminosulfonyl unsubstituted or substituted with one or two linear or branched (C ₁ -C ₆ ) alkyl groups, which are identical or different; or alkylsulfonylamino (CrC ₆ ) linear or branched unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group. More particularly preferred compounds for which R ₃ represents the phenoxy group unsubstituted or substituted by a fluorine, chlorine or bromine atom, and more particularly, a fluorine atom; a methyl group; a methoxy group; an acetylamino group; a group -CONH ₂ ; an N-methylaminocarbonyl group; an N, N-dimethylaminocarbonyl group; a methylsulfonamide group; an acetylaminomethyl group; or a methylsulfonylaminomethyl group.

Advantageously, R ₃ represents the phenoxy group substituted in the meta or para position, and more preferably in the meta position.

The preferred compounds according to the invention are:

• 4-cyclopropyl-thiochroman 1,1-dioxide;

 4-cyclopropyl-5-fluoro-thiochroman 1,1-dioxide;

 6-chloro-4-cyclopropylthiochroman 1,1-dioxide;

 4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;

 6-bromo-4-cyclopropyl-thiochroman 1,1-dioxide;

 7-chloro-4-cyclopropylthiochroman 1,1-dioxide;

 7-bromo-4-cyclopropyl-thiochroman 1,1-dioxide;

 4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;

4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide; • 8-chloro-4-cyclopropyl-thiochroman 1,1-dioxide;

 8-bromo-4-cyclopropyl-thiochroman 1,1-dioxide;

 4-cyclopropyl-5,6-difluoro-thiochroman 1,1-dioxide;

 4-cyclopropyl-5,7-difluoro-thiochroman 1,1-dioxide;

 • 6,7-dichloro-4-cyclopropyl-thiochroman 1,1-dioxide;

 6-bromo-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;

 4-cyclopropyl-6,8-difluoro-thiochroman 1,1-dioxide;

 4-cyclopropyl-6,7-difluoro-thiochroman 1,1-dioxide;

 8-chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;

 8-bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;

 8-bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide;

 8-chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;

 7-chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;

 6-chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;

 7-bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;

 7-bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide;

 6,8-dibromo-4-cyclopropyl-thiochroman 1,1-dioxide;

 6-bromo-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide;

 5-chloro-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide;

 4-cyclopropyl-7,8-difluoro-thiochroman 1,1-dioxide;

 4-cyclopropyl-6-methyl-thiochroman 1,1-dioxide;

 4-cyclopropyl-7-methyl-thiochroman 1,1-dioxide;

 • 4-cyclopropyl-7-methoxy-thiochroman 1,1-dioxide;

 4-cyclopropyl-7-thiochromanol 1,1-dioxide;

 6-chloro-4-cyclopropyl-7-thiochromanol 1,1-dioxide;

 4-cyclopropyl-N, N-dimethyl-7-thiochromanecarboxamide 1,1-dioxide;

N- (4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) acetamide;

4-cyclopropyl-5-thiochromanecarbonitrile 1,1-dioxide;

 4-cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide;

 4-cyclopropyl-7-thiochromanecarbonitrile 1,1-dioxide;

8-bromo-4-cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide; 4-cyclopropyl-6-thiochromanecarboxylic acid 1,1-dioxide;

4-cyclopropyl-7-phenoxy-thiochroman 1,1-dioxide;

7- (3-bromophenoxy) -4-cyclopropylthiochroman 1,1-dioxide;

7- (4-bromophenoxy) -4-cyclopropylthiochroman 1,1-dioxide;

3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile;

4- [4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile;

4-cyclopropyl-7- (3-methylphenoxy) -thiochroman 1,1-dioxide;

4-cyclopropyl-7- (4-methylphenoxy) -thiochroman 1,1-dioxide;

4-cyclopropyl-7- (3-methoxyphenoxy) -thiochroman 1,1-dioxide;

4-cyclopropyl-7- (4-methoxyphenoxy) -thiochroman 1,1-dioxide;

N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} acetamide;

N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} acetamide;

N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} acetamide;

N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} acetamide;

3 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -ΛΡ-hydroxybenzenecarboximidamide;

4- [4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-hydroxybenzenecarboximidamide;

3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide;

4- [4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide;

3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-methyl-benzamide;

4 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N- methyl benzamide;

 3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N, N-dimethylbenzamide;

 • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-dimethyl-benzamide;

 N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} methanesulfonamide;

 N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} methanesulfonamide;

 N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} methanesulfonamide;

 And N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} methanesulfonamide.

The enantiomers, diastereoisomers as well as the addition salts with an acid or a pharmaceutically acceptable base of the preferred compounds of the invention form an integral part of the invention.

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

dans laquelle Ri, R₂, R₃ et R4 sont tels que définis dans la formule (I), que l'on met en réaction avec le bromure de cyclopropylmagnésium pour conduire au composé de formule (III) :

in which R 1, R ₂ , R ₃ and R 4 are as defined in formula (I), which is reacted with cyclopropylmagnesium bromide to yield the compound of formula (III):

wherein R ₁₅ R ₂ , R ₃ and R ₄ are as previously defined,

that is put in an acid medium, to yield the compound of formula (IV),

wherein R ₁₅ R ₂ , R ₃ and R ₄ are as previously defined,

which undergoes an oxidation reaction to yield the compound of formula (V):

in which R 1, R ₂ , R ₃ and R 4 are as defined above, reacting with a reducing agent, to give the compounds of formula (I), a variant in the preparation of compounds of formula (I) consisting of the reduction of the compound of formula (IV) to yield the compound of formula (VI):

dans laquelle R_l5 R₂, R₃ et R4 sont tels que définis précédemment, qui subit une réaction d'oxydation pour conduire aux composés de formule (I), une autre alternative dans la préparation des composés de formule (I) consistant, après réalisation de l'étape de réduction du composé de formule (V) ou de l'oxydation du composé de formule (VI), en l'utilisation des réactions classiques de chimie afin de modifier, dans un deuxième temps, les substituants du noyau benzénique, composé de formule (I) qui peut être ensuite purifié selon une technique classique de séparation, que l'on transforme, si on le souhaite en ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable et dont on sépare éventuellement les isomères selon une technique classique de séparation.

in which R ₁₅ R ₂ , R ₃ and R 4 are as defined above, which undergoes an oxidation reaction to give the compounds of formula (I), another alternative in the preparation of the compounds of formula (I) consisting, after performing the step of reducing the compound of formula (V) or of the oxidation of the compound of formula (VI), by using conventional chemistry reactions in order to modify, in a second step, the substituents of the benzene ring; compound of formula (I) which can then be purified according to a conventional separation technique, which, if desired, is converted into its addition salts with a pharmaceutically acceptable acid or base and the isomers according to a conventional separation technique.

The compounds of formula (II) are commercially available or readily accessible to those skilled in the art by conventional chemistry reactions or described in the literature.

The compounds of formula (I) according to the invention have activating properties of AMPA receptors that make them useful in 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 disease, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementia, sequelae of ischemia and sequelae of epilepsy.

The invention also extends to pharmaceutical compositions containing as active ingredient 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, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, single or coated tablets, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, dermal gels, injectables, and oral suspensions.

The useful dosage is adaptable according to the nature and severity of the condition, 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 starting materials used are known products or 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).

By way of information, the compounds below correspond to racemic mixtures. These can be separated to obtain the pure enantiomers by chiral separation techniques on an HPLC column, for example of the CHIRALCEL OF, CHIRALPACK AS-H or CHIRALPACK AD-H type. EXAMPLE 1 4-cyclopropyl-thiochroman 1,1-dioxide

Step A: 4-Cyclopropyl-4-hydroxy-thiochroman

Magnesium chips (590 mg, 24.3 mmol) are added to a flask containing dry ether (25 mL). To this medium is added 1 mL of a solution of cyclopropyl bromide (2.94 g, 24.3 mmol) in dry ether (10 mL) via an addition funnel. The reaction between magnesium and cyclopropyl bromide is initiated by stirring and heating of medium. The rest of the ethereal solution of cyclopropyl bromide is then added. After 10 minutes the medium is cooled on an ice bath and a solution of thiochromane-4-one (2 g; 12.2 mmol) in dry ether (10 mL) is added dropwise. After stirring for 20 minutes, a solution of 10% NtLCI (5 mL) is slowly added. Then, ether (20 mL) and water (20 mL) are added. The ether phase is decanted and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated to dryness and the residue is purified by chromatography on silica gel (CH ₂ Cl ₂ / hexane 1: 1) to give a clear oil which is engaged in the next step. Stage B: 4-cyclopropyl-2H-thiochromene

The mixture of 4-cyclopropyl-4-hydroxythiochroman (1.3 g, 6 mmol) in 2.5 M sulfuric acid (25 mL) was heated at 60 ° C for 90 minutes. After cooling to room temperature, the reaction product is extracted three times with dichloromethane (3 x 20 mL). The organic phases are combined and dried over anhydrous MgSO ₄ . The filtrate is treated with absorbent charcoal and filtered. The filtrate obtained is concentrated to dryness under vacuum. The title product is obtained as an orange oil which is used without further purification in the next step.

Stage C: 4-cyclopropyl-2Y [-thiochromene 1,1-dioxide

The solution of 4-cyclopropyl-2H-thiochromene from the previous step in dichloromethane (25 mL) is treated with 7-chloroperbenzoic acid (2 g, 11.5 mmol) and the medium is stirred on an ice-bath for 20 minutes. minutes. Then the middle The reaction mixture is added with water (50 ml) and is brought to basic pH by the addition of 10% w / v NaOH. The organic phase is decanted and the aqueous medium is extracted twice with dichloromethane (2 × 20 mL). The organic phases are combined and dried over anhydrous MgSO ₄ . The filtrate is treated with absorbent charcoal and filtered. The filtrate obtained is concentrated to dryness and the residue is taken up in hexane. The suspension is refluxed for 5 minutes and then cooled. The precipitate of the title product is collected by filtration and washed with hexane to give a white solid.

Potodejusion: 109-111 ° C

Step D: ^■ 4-cyclopropyl-thiochroman 1,1-dioxide The solution of 4-cyclopropyl-2H-thiochromène 1,1-dioxide (400 mg; l, 8 mmole) in ethanol (30 mL) was added coal palladium 10% (100 mg) and the suspension obtained is placed in the hydrogenator under 10 atm of hydrogen for 1 hour. Then, the suspension is filtered and the filtrate is concentrated to dryness. The residue is taken up in hexane (20 mL) and stirred until a fine precipitate is obtained. This is collected by filtration and washed with hexane. This solid is redissolved hot in dichloromethane (3 mL) and the addition of hexane provides a precipitate which is collected by heat by filtration and washed with hexane. This precipitate is purified by chromatography on a silica column using the ethyl acetate / hexane 3/17 mixture as eluent phase to form a white solid.

Melting point: 149-150 ° C

EXAMPLE 2 4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide

Step A: 4-cyclopropyl-7-fluoro-2H-thiochromene 1,1-dioxide

The expected product is obtained from 7-fluorothiochroman-4-one (synthesized according to FR 2 367 754, m.p .: 60-63 ° C.) according to the process described in Steps A to C of Example 1.

Withstand: 138-140 ° C Stage B: 4-cyclopropyl-7-fluorothiochromane 1,1-dioxide

The title product is obtained according to the process described in Step D of Example 1 using the product obtained in the preceding Step in place of 4-cyclopropyl-2H-thiochromen 1,1-dioxide.

Uptake point: 159-161 ° C

EXAMPLE 3 4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide

Step A: 4-cyclopropyl-8-fluoro-2H-thiochromene 1,1-dioxide

The expected product is obtained from 8-fluorothiochroman-4-one (synthesized according to FR 2 367 754, melting point: 77-79 ° C.) according to the process described in Steps A to C of Example 1.

 Wearing pin: 111-113 ° C

Stage B: 4-cyclopropyl-8-fluorothiochromane 1,1-dioxide

The title product is obtained according to the process described in Step D of Example 1 using the product obtained in the preceding Step in place of 4-cyclopropyl-2H-thiochromen 1,1-dioxide.

 MS of use: 182-183.5 ° C

EXAMPLE 4 4-cyclopropyl-7-methoxy-thiochroman 1,1-dioxide

Step A: 4-cyclopropyl-7-methoxy-2H-thiochromene 1,1-dioxide

The expected product is obtained from 7-methoxythiochroman-4-one (synthesized according to FR 2 367 754, melting point: 39-42 ° C.) according to the process described in Steps A to C of Example 1.

Deflection: 140-142 ° C Stage B: 4-cyclopropyl-7-methoxy-thiochroman 1,1-dioxide

The title product is obtained according to the process described in Step D of Example 1 using the product obtained in the preceding Step in place of 4-cyclopropyl-2H-thiochromen 1,1-dioxide.

Melting point: 134.5-136.5 ° C

EXAMPLE 5 4-cyclopropyl-7-thiochromanol 1,1-dioxide

The expected product is obtained from 7-hydroxy-2,3-dihydro-4H-thiochromen-4-one according to the process described in Steps A to D of Example 1.

EXAMPLE 6: 4-Cyclopropyl-7- (4-fluoro-phenoxy) -thiochroman 1,1-dioxide

A solution of the compound of Example 5 (400 mg, 1.7 mmol) in dichloromethane (60 mL) is added with pyridine (10 drops), 4 A molecular sieve (5 g), 4-fluorophenylboronic acid (345 mg, 2.5 mmol) and cupric acetate (450 mg, 2.5 mmol). The suspension is stirred for 5 hours at 40 ° C. Then, a supplement of dichloromethane is added (40 mL) and the suspension is filtered. The filtrate is evaporated to dryness under vacuum and the residue obtained is taken up in water (50 mL) slightly acidified with HCl. The suspension is extracted with three portions of ethyl acetate (3 x 50 mL). The organic phases are combined and dried over anhydrous MgSO ₄ . After filtration, the filtrate is concentrated to dryness and the residue is purified by chromatography on silica gel (dichloromethane). After recrystallization from dichloromethane / petroleum ether (5/15), the title product is obtained as a white solid.

Point of use: 98-100 ° C

The compounds of Examples 7 to 67, mentioned below, are obtained according to the protocol described in Example 1, using the corresponding thiochroman instead of thiochromane-4-one. EXAMPLE 7 4-cyclopropyl-5-fluoro-thiochroman 1,1-dioxide

EXAMPLE 8 6-Chloro-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 9 4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide

EXAMPLE 10 6-Bromo-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 11 7-Chloro-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 12 7-Bromo-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 13 8-Chloro-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 14 8-bromo-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 15 4-cyclopropyl-5,6-difluoro-thiochroman 1,1-dioxide

EXAMPLE 16 4-cyclopropyl-5,7-difluoro-thiochroman 1,1-dioxide

EXAMPLE 17: 6,7-Dichloro-4-cyclopropyl-thiochroman 1,1-dioxide Example 18 6-bromo-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide Example 19 4-cyclopropyl-6,8 -difluoro-thiochromane 1,1-dioxide

EXAMPLE 20 4-cyclopropyl-6,7-difluoro-thiochroman 1,1-dioxide

EXAMPLE 21 8-Chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide Example 22 8-bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide EXAMPLE 23 8-Bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 24: 8-Chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide

EXAMPLE 25 7-Chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide

EXAMPLE 26 6-Chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide EXAMPLE 27 7-Bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide

EXAMPLE 28 7-Bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 29: 6,8-Dibromo-4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 30 6-bromo-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide

EXAMPLE 31 5-Chloro-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide Example 32 4-Cyclopropyl-7,8-difluoro-thiochroman 1,1-dioxide

EXAMPLE 33 4-cyclopropyl-6-methyl-thiochroman 1,1-dioxide

EXAMPLE 34 4-cyclopropyl-7-methyl-thiochroman 1,1-dioxide

EXAMPLE 35 6-Chloro-4-cyclopropyl-7-thiochromanol 1,1-dioxide

EXAMPLE 36 4-cyclopropyl-N, N-dimethyl-7-thiochromanecarboxamide 1,1-dioxide

EXAMPLE 37 N- (4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) acetamide EXAMPLE 38 4-Cyclopropyl-5-thiochromanecarbonitrile 1,1-dioxide

EXAMPLE 39 4-Cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide

EXAMPLE 40 4-Cyclopropyl-7-thiochromanecarbonitrile 1,1-dioxide

EXAMPLE 41 8-bromo-4-cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide Example 42 4-cyclopropyl-6-thiochromanecarboxylic acid 1,1-dioxide

EXAMPLE 43 4-Cyclopropyl-7-phenoxy-thiochroman 1,1-dioxide

EXAMPLE 44: 7- (3-bromophenoxy) -4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 45: 7- (4-bromophenoxy) -4-cyclopropyl-thiochroman 1,1-dioxide

EXAMPLE 46 3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile

EXAMPLE 47 4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile

EXAMPLE 48 4-Cyclopropyl-7- (3-methylphenoxy) -thiochroman 1,1-dioxide

EXAMPLE 49 4-Cyclopropyl-7- (4-methylphenoxy) -thiochroman 1,1-dioxide Example 50: 4-Cyclopropyl-7- (3-methoxyphenoxy) -thiochroman 1,1-dioxide

EXAMPLE 51 4-Cyclopropyl-7- (4-methoxyphenoxy) -thiochroman 1,1-dioxide

EXAMPLE 52: N- (3- (4-cyclopropyl-1,1-dioxido-3,4-dihydro-2-thiochromen-7-yl) oxy] phenyl} acetamide EXAMPLE 53: N- {4 - [(4-cyclopropyl-11-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl] -metamide

 EXAMPLE 54: N- (3-r (4-cyclopropyl) -1,4-dioxido-3,4-dihydro-2H-thiochromen-7-yl)

 oxy] benzyl-acetamide

EXAMPLE 55: _J / V- {4 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} acetamide

 EXAMPLE 56: 3 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -V-hydroxybenzeneecarboxinidamide

 EXAMPLE 57 4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-hydroxybenzeneecarboximidamide

 EXAMPLE 58: 3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide

 EXAMPLE 59: 4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide EXAMPLE 60: 3 - [(4-cyclopropyl) -1,1- 3,4-dioxido-dihydro-2-thiochromen-7-yl) oxy]

 -Λ ^ -methyl-benzamide

 EXAMPLE 61 4 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy]

 -N-methyl-benzamide

 EXAMPLE 62: 3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy]

-AyV-dimethyl-benzamide EXAMPLE 63 4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2- ^r- thiochromen-7-yl) oxy] -N-dimethyl-benzamide

EXAMPLE 64: N- (3- [4-cyclopropyl-11-dioxido-3,4-dihydro-2H-thiochromen-7-yl] oxy] phenyl} methanesulfonamide EXAMPLE 65: N- {4 - [(4-cyclopropyl) -1,1 3,4-Dihydro-2 "-thiochromen-7-yl) oxy] phenyl] methanesulfonamide

EXAMPLE 66: N- [3- [(4-cyclopropyl-1-dioxido-3,4-dihydro-2H-thiochromen-7-oxy] benzyl) methanesulfonamide

EXAMPLE 67 N- {4- (4-cyclopropyl-ia-dioxido-3,4-dihydro-2-ylthiochromen-7-yl) oxy] benzyl} methanesulfonamide

PHARMACOLOGICAL STUDY

EXAMPLE A Study of the effect of the products on AMPA-induced membrane depolarization on primary cultures of rat neurons.

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

The compounds of the invention strongly potentiate the excitatory effects of AMPA. By way of example, the compounds of Examples 1 and 3 have an EC ₂ x of 13 and 11 μΜ, respectively. EXAMPLE B Pharmaceutical Composition

Preparation formula for 1000 tablets dosed with 10 mg of 4-cyclopropyl-thiochroman 1,1-dioxide (Example 1) 10 g

Hydroxypropylcellulose 2 g Wheat starch 10 g

Lactose 100 g

Magnesium stearate 3 g

Talc 3 g

Claims

1. Compounds of formula (I):

in which R 1, R ₂ , R ₃ and R 4, which may be identical or different, each represent a hydrogen atom, a halogen atom or a cyano group; hydroxy; thio; nitro; linear or branched (C ₁ -C 6) alkyl optionally substituted; aryl; linear or branched alkoxy (CrC ₆ ) unsubstituted or substituted by one or more halogen atoms; aryloxy; linear or branched alkylthio (Ci-C ₆ ); arylthio; carboxy; linear or branched alkoxycarbonyl (C ₁ -C); aryloxycarbonyl; linear or branched acyloxy (CrC ₆ ); arylcarbonyloxy; linear or branched (C ₁ -C ₆ ) acyl; arylcarbonyl; amino unsubstituted or substituted with one or two linear or branched (C ₁ -C 6) alkyl groups, which are identical or different; arylamino unsubstituted or substituted on the nitrogen atom by a linear or branched (CpC ₆ ) alkyl group; acylamino (Ci-C ₆₎ linear or branched unsubstituted or substituted on the nitrogen atom by an alkyl group (QQ) linear or branched; arylcarbonylamino unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; aminocarbonyl unsubstituted or substituted with one or two linear or branched (C 1 -C ₆ ) alkyl groups, identical or different; arylaminocarbonyl unsubstituted or substituted on the nitrogen atom with a linear or branched alkyl (QC ₆ ) group; alkylsulfonylamino (C _\ -C) linear or branched unsubstituted or substituted on the nitrogen atom by an alkyl group (CJ _O-C) straight or branched; or arylsulfonylamino unsubstituted or substituted on the atom nitrogen with an alkyl group (QC _O) straight or branched; their enantiomers and their diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base, it being understood that: the term "aryl" and the term "aryl" contained in the aryloxy, arylthio, aryloxycarbonyl, arylcarbonyloxy, arylcarbonyl, arylamino, arylcarbonylamino, arylaminocarbonyl and arylsulfonylamino groups represent the phenyl group which is unsubstituted or substituted by one or more groups, identical or different, chosen from a halogen atom, or a cyano group; hydroxy; thio; nitro; optionally substituted linear or branched (CC ₆ ) alkyl; linear or branched alkoxy (C ₁ -C ₆ ) unsubstituted or substituted by one or more halogen atoms; linear or branched alkylthio (Ci-C ₆ ); carboxy; linear or branched (C 6 -C 8) alkoxycarbonyl; amino unsubstituted or substituted with one or two linear or branched (C 1 -C 6) alkyl groups, which are identical or different; acyloxy (Ci-C ₆₎ linear or branched; acylamino (CrC ₆ ) linear or branched unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; aminocarbonyl unsubstituted or substituted with one or two identical or different linear or branched (C 1 -C 6) alkyl groups; aminosulfonyl unsubstituted or substituted with one or two identical or different linear or branched alkyl (dC ₆ ) groups; alkylsulfonylamino (C ₆ -C?) straight or branched unsubstituted or substituted on the nitrogen atom by an alkyl (Ci-C ₆₎ linear or branched; or N-hydroxycarboximidamide; the expression "optionally substituted" assigned to the term alkyl means that this group may be substituted by one or more halogen atoms, or by a cyano group; hydroxy; thio; nitro; aryl; linear or branched (C ₁ -C ₆ ) alkoxy unsubstituted or substituted by one or more halogen atoms; linear or branched alkylthio (C ₁ -C e); carboxy; linear or branched alkoxycarbonyl (C ₁ -C e); linear or branched acyloxy (C ₁ -C e); amino unsubstituted or substituted with one or two linear or branched (C ₁ -C e) alkyl groups, which are identical or different; linear or branched (C ₁ -C ₆ ) acylamino unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C ₆ ) alkyl group; unsubstituted or substituted aminocarbonyl with one or two identical or different linear or branched (C 1 -C ₆ ) alkyl groups; aminosulphonyl which is unsubstituted or substituted with one or two identical or different linear or branched alkyl groups (CpC0); alkylsulfonylamino (C ₁ -C ₆ ) linear or branched unsubstituted or substituted on the nitrogen atom with a linear or branched (C ₁ -C e) alkyl group; or N-hydroxycarboximidamide. 2. Compounds of formula (I) according to claim 1, characterized in that R _\ represents a hydrogen atom or a halogen atom. 3. Compounds of formula (I) according to claim 1, characterized in that R ₂ represents a hydrogen atom; a halogen atom; a methyl group; a cyano group; or a carboxy group. 4. Compounds of formula (I) according to claim 1, characterized in that R ₃ represents a hydrogen atom; a halogen atom; a cyano group; a hydroxy group; a methyl group; a methoxy group; an acetylamino group; an N, N-dimethylaminocarbonyl group; or an aryloxy group. 5. Compounds of formula (I) according to claim 1, characterized in that R4 represents a hydrogen atom or a halogen atom. 6. Compounds of formula (I) according to Claim 1, characterized in that two of the groups R _ls R _2, R ₃ and R 4 are other than hydrogen. 7. Compounds of formula (I) according to claim 1, characterized in that R _1} R ₂ and R 4 represent a hydrogen atom while R ₃ represents the phenoxy group unsubstituted or substituted by a halogen atom; a cyano group; a (C ₁ -C ₆ ) linear or branched alkyl group optionally substituted; a linear or branched (C ₁ -C ₆ ) alkoxy group; an acylamino group (QC _O) -straight or branched unsubstituted or substituted on the nitrogen atom by an alkyl (Ci-C ₆₎ linear or branched; an aminocarbonyl group unsubstituted or substituted with one or two linear or branched (C 1 -C 6) alkyl groups; a linear or branched linear or branched alkylsulphonylamino (C ₁ -C 8) group which is unsubstituted or substituted on the nitrogen atom by a linear or branched alkyl (QQ) group; or an N-hydroxycarboximidamide group. 8. Compounds of formula (I) according to claim 7, characterized in that R ₃ represents the phenoxy group which is unsubstituted or substituted by a fluorine, chlorine or bromine atom; a methyl group; a methoxy group; an acetylamino group; a group -CONH ₂ ; an N-methylaminocarbonyl group; an N, N-dimethylaminocarbonyl group; a methylsulfonamide group; an acetylaminomethyl group; or a methylsulfonylaminomethyl group. 9. Compounds of formula (I) according to claim 7 or 8, characterized in that R ₃ represents the phenoxy group substituted in the meta position. 10. Compounds of formula (I) according to claim 1, which are: • 4-cyclopropyl-thiochroman 1,1-dioxide;  4-cyclopropyl-5-fluoro-thiochroman 1,1-dioxide;  • 6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide;  4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;  6-bromo-4-cyclopropyl-thiochroman 1,1-dioxide;  7-chloro-4-cyclopropyl-thiochroman 1,1-dioxide;  7-bromo-4-cyclopropyl-thiochroman 1,1-dioxide;  4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;  4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide;  8-chloro-4-cyclopropyl-thiochroman 1,1-dioxide; 8-bromo-4-cyclopropyl-thiochroman 1,1-dioxide; 4-cyclopropyl-5,6-difluoro-thiochroman 1,1-dioxide;  4-cyclopropyl-5,7-difluoro-thiochroman 1,1-dioxide;  • 6,7-dichloro-4-cyclopropyl-thiochroman 1,1-dioxide;  6-bromo-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide; 4-cyclopropyl-6,8-difluoro-thiochroman 1,1-dioxide;  4-cyclopropyl-6,7-difluoro-thiochroman 1,1-dioxide;  8-chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;  8-bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;  8-bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide; 8-chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;  7-chloro-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;  6-chloro-4-cyclopropyl-7-fluoro-thiochroman 1,1-dioxide;  7-bromo-4-cyclopropyl-6-fluoro-thiochroman 1,1-dioxide;  7-bromo-6-chloro-4-cyclopropyl-thiochroman 1,1-dioxide; · 6,8-dibromo-4-cyclopropyl-thiochroman 1,1-dioxide;  6-bromo-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide;  5-chloro-4-cyclopropyl-8-fluoro-thiochroman 1,1-dioxide; >  4-cyclopropyl-7,8-difluoro-thiochroman 1,1-dioxide;  4-cyclopropyl-6-methyl-thiochroman 1,1-dioxide; 4-cyclopropyl-7-methyl-thiochroman 1,1-dioxide;  • 4-cyclopropyl-7-methoxy-thiochroman 1,1-dioxide;  4-cyclopropyl-7-thiochromanol 1,1-dioxide;  6-chloro-4-cyclopropyl-7-thiochromanol 1,1-dioxide;  4-cyclopropyl-N, N-dimethyl-7-thiochromanecarboxamide 1,1-dioxide; N- (4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) acetamide; 4-cyclopropyl-5-thiochromanecarbonitrile 1,1-dioxide;  4-cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide;  4-cyclopropyl-7-thiochromanecarbonitrile 1,1-dioxide;  8-bromo-4-cyclopropyl-6-thiochromanecarbonitrile 1,1-dioxide; 4-cyclopropyl-6-thiochromanecarboxylic acid 1,1-dioxide; 4-cyclopropyl-7-phenoxy-thiochroman 1,1-dioxide; 7- (3-bromophenoxy) -4-cyclopropyl-thiochroman 1,1-dioxide;  7- (4-bromophenoxy) -4-cyclopropyl-thiochroman 1,1-dioxide;  3 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile;  • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzonitrile;  4-cyclopropyl-7- (3-methylphenoxy) -thiochroman 1,1-dioxide;  4-cyclopropyl-7- (4-methylphenoxy) -thiochroman 1,1-dioxide;  4-cyclopropyl-7- (3-methoxyphenoxy) -thiochroman 1,1-dioxide;  4-cyclopropyl-7- (4-methoxyphenoxy) -thiochroman 1,1-dioxide;  N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} acetamide;  N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} acetamide;  N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} acetamide;  N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} acetamide;  3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-hydroxybenzenecarboximidamide;  • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -Λ-hydroxybenzenecarboximidamide;  3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide;  • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzamide;  3 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-methyl-benzamide;  • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-methyl-benzamide; 3 - [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-V dimethyl benzamide;  • [(4-Cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] -N-dimethyl-benzamide;  N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} methanesulfonamide;  N- {4- [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] phenyl} methanesulfonamide;  N- {3 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} methanesulfonamide;  N- {4 - [(4-cyclopropyl-1,1-dioxido-3,4-dihydro-2H-thiochromen-7-yl) oxy] benzyl} methanesulfonamide; their enantiomers, their diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 11. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a compound of formula (II) is used as starting material:

in which R 1, R ₂ , R ₃ and are as defined in formula (I), that is reacted with cyclopropylmagnesium bromide to yield the compound of formula (III):

in which R 1, R ₂ , R ₃ and R ₄ are as defined above, which are put in an acidic medium, to yield the compound of formula (IV),

wherein R _ls R _2, R ₃ and R 4 are as defined above, which undergoes an oxidation reaction to yield the compound of formula (V)

wherein R _ls R _2, R ₃ and R ₄ are as defined above, reacting with a reducing agent, to give the compounds of formula (I), a variant in the preparation of compounds of formula (I) consisting of the reduction of the compound of formula (IV) to yield the compound of formula (VI):

wherein R ₁₅ R ₂ , R ₃ and R ₄ are as previously defined, which undergoes an oxidation reaction to yield compounds of formula (I), another alternative in the preparation of compounds of formula (I) consisting of after carrying out the step of reducing the compound of formula (V) or of the oxidation of the compound of formula (VI), by using conventional chemistry reactions in order to modify, in a second step, the substituents of the nucleus benzene compound of formula (I) which can then be purified according to a conventional separation technique, which is converted, if desired in its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated isomers according to a conventional separation technique. 12. Pharmaceutical composition containing as active ingredient a compound according to any one of claims 1 to 10, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 13. Pharmaceutical compositions according to claim 12 useful as AMPA receiver modulators. 14. Pharmaceutical compositions according to claim 12, useful for the treatment or the prevention of mnemocognitive disorders associated with age, with anxiety or depressive syndromes, with progressive neurodegenerative diseases, with Alzheimer's disease, with Parkinson's disease, with Parkinson's disease. Pick's disease, Huntington's disease, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementia, sequelae of ischemia and sequelae of epilepsy. 15. Use of the compounds of formula (I) according to any one of claims 1 to 10 for the manufacture of medicaments useful as modulators of the receptor AMPA. 16. Use of the compounds of formula (I) according to any one of claims 1 to 10 for the manufacture of medicaments useful for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, neurodegenerative diseases progressive diseases, Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementia, sequelae of ischemia, and sequelae of epilepsy. 17. Compounds of formula (I) according to any one of claims 1 to 10 useful as modulators of the AMPA receptor. 18. Compounds of formula (I) according to any one of claims 1 to 10 for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurodegenerative diseases, disease of Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, Korsakoff's disease, schizophrenia, sequelae of acute neurodegenerative diseases, frontal and subcortical dementia, sequelae of ischemia and sequelae of epilepsy.