EP1472219A1

EP1472219A1 - Novel benzothiazine and benzothiadiazine derivatives, method for preparing same and pharmaceutical compositions containing same

Info

Publication number: EP1472219A1
Application number: EP02805406A
Authority: EP
Inventors: Alex Cordi; Patrice Desos; Pierre Lestage
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2001-12-21
Filing date: 2002-12-20
Publication date: 2004-11-03
Also published as: JP2005518385A; BR0214926A; MA27088A1; HK1071746A1; NZ533329A; FR2833955B1; GEP20063757B; EA007492B1; US7262189B2; EA200400757A1; UA78742C2; US20050065146A1; PL370166A1; CN1606559A; AU2002364673B2; KR20040073479A; HUP0402583A3; FR2833955A1; HUP0402583A2; NO20042708L

Abstract

The invention concerns a compound of formula (I), wherein: R1 represents an aryl or heteroaryl; R2 represents hydrogen, halogen or a hydroxy; X represents oxygen or sulphur; Y represents oxygen, sulphur or NR wherein R represents hydrogen or an alkyl; A represents CR4R5 or NR4; R3 represents hydrogen, alkyl or cycloalkyl; R4 represents hydrogen or alkyl; or A represents nitrogen and forms with adjacent -CHR3-the cycle (a) wherein m represents 1, 2, or 3, R3 represents hydrogen or halogen; their isomers and their addition salts. Said compounds are useful as medicines, as AMPA modulators.

Description

NOVEL DERIVATIVES OF BENZOTHIAZINE AND BENZOTHIADIAZINE,

THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new benzothiazine and benzothiadiazine derivatives, their preparation process and the pharmaceutical compositions containing them.

It is now recognized that the excitatory amino acids and especially 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, countless studies have demonstrated in recent years the existence of receptor subtypes for excitatory amino acids and their functional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).

Among these receptors, the AMPA receptor ("-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 memorization processes. 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 for mnemocognitive processes. Likewise, nootropic agents such as aniracetam have been described very recently as positively modulating the AMPA receptors of neuronal cells (Journal of 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 BA 74 compound, in particular, is the most active among these new pharmacological agents.

Finally, patent EP 692 484 describes a benzothiadiazme derivative having a facilitating activity on the AMPA current and patent application WO 99/42456 describes inter alia certain benzothiadiazme derivatives as modulators of AMPA receptors.

The benzothiazine and benzothiadiazme derivatives, objects of the present invention, in addition to the fact that they are new, have, surprisingly, pharmacological activities on the AMPA current clearly superior to those of compounds of similar structures described in the Art. Prior. They are useful as AMPA modulators for the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depressive syndromes, progressive neurogenerative diseases, Alzheimer's disease, Pick's disease, chorea. Huntington's, schizophrenia, sequelae of acute neurodegenerative diseases, sequelae of ischemia and sequelae of epilepsy.

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

in which :

Ri represents an aryl or heteroaryl group,

R ₂ represents a hydrogen atom, a halogen atom or a hydroxy group,

X represents an oxygen or sulfur atom,

Y represents an oxygen or sulfur atom or a group NR in which R represents a hydrogen atom or an alkyl group (Cι-C ₆ ) linear or branched, A represents a group CR_jR ₅ or a group NR4, R ₃ represents a hydrogen atom, a linear or branched alkyl group (Cι-C ₆ ) or a cycloalkyl group (C ₃ -C), Rj represents a hydrogen atom or a linear or branched alkyl group (Cι-C ₆ ) , or A represents a nitrogen atom and forms with the group -CHR ₃ - adjacent the ring in which m represents 1, 2 or 3,

R ₅ represents a hydrogen or halogen atom,

their isomers and their addition salts with a pharmaceutically acceptable acid or base, it being understood that: by aryl group is understood a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, optionally substituted by a or more groups, identical or different, halogen, alkyl (Cι-C ₆ ) linear or branched, alkoxy (Cι ~ C ₆ ) linear or branched, perhaloalkyl (Cι-C ₆ ) linear or branched, perhaloalkoxy (Cι-C ₆ ) linear or branched, hydroxy, cyano, nitro, amino (optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched), aminosulfonyl (optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched ), alkyl (Cι-C ₆ ) sulfonylamino, or phenyl (optionally substituted by one or more groups, identical or different, halogen, alkyl (Cι-C ₆ ) linear or branched, perhalo genoalkyl (Cι-C ₆ ) linear or branched, hydroxy or alkoxy (Cι-C ₆ ) linear or branched), by heteroaryl group, one understands monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, containing a , two or three heteroatoms, identical or different, chosen from nitrogen, oxygen and sulfur, optionally substituted by one or more groups, identical or different, halogen, alkyl (Cι ~ C ₆ ) linear or branched, alkoxy (Cι-C ₆ ) linear or branched, perhaloalkyl (Cι-C ₆ ) linear or branched, perhaloalkoxy (Cι ~ C ₆ ) linear or branched, hydroxy, cyano, nitro, amino (optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched), aminosulfonyl

(optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched), or alkyl (Cι-C ₆ ) sulfonylamino.

Among the pharmaceutically acceptable acids, non-limiting mention may be made of: hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methane sulfonic, camphoric acids, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

The preferred aryl group is the phenyl group.

The preferred group R is the hydrogen atom.

A preferably represents an NR group or else a nitrogen atom and forms with the group -CHR ₃ - adjacent the —N - ring, m preferably representing

the number 1.

Y preferably represents an oxygen or sulfur atom.

The invention also extends to the process for the preparation of the compounds of formula (I).

The process for preparing the compounds of formula (I) in which A represents an NR ₄ group or A represents a nitrogen atom and forms with the CHR _{3 group}

adjacent the cycle N - in which m represents 1, 2 or 3, is characterized in that one

uses as starting material a compound of formula (II):

in which: R'i represents a linear or branched alkoxy group (Cι-C ₆ ),

R ′ ₂ represents a hydrogen or halogen atom or a linear or branched alkoxy group (Cι-C ₆ ), who is :

(a) either reacted with the acid chloride of formula (III) in the presence of a base, in a tetrahydrofuran or acetonitrile medium:

Cl - CH ₂ - (CH ₂ ) _m - CH ₂ - COC1 (III) in which _{m has} the same meaning as in formula (I), to lead to the compound of formula (IN):

in which R'i, R ' ₂ and m are as defined above,

which is then cyclized in basic medium, to lead to the compound of formula (V)

in which R'i, R ' ₂ and m are as defined above,

which undergoes a reduction, in alcoholic or dimethylformamide medium, in the presence of sodium borohydride, to lead to the compound of formula (NI):

in which R'i, R ' ₂ and m are as defined above, which undergoes the action of boron tribromide, to lead to the compound of formula (Nil): in which m is as defined above,

(b) either cyclized:

in the presence of an amidine of formula (VIII):

in which :

R ₃ is such a defined in formula (I),

to lead to the compound of formula (IX)

in which R'i, R ', and R' ₃ have the same meaning as above,

who is :

4 or else reduced by a metal hydride, to yield the compound of formula (X):

in which R'i, R ' ₂ , and R' ₃ have the same meaning as before,

or else alkyl by the action of a strong base in the presence of an alkylating agent R ' ₄ X in which R ' ₄ represents a linear or branched alkyl group (Cι-C ₆ ) and X a halogen atom, then reduced, to lead to the compound of formula (XI):

in which R'i, R ' ₂ , R ₃ and R' ₄ have the same meaning as above,

> in the presence of an aldehyde of formula (XII):

in which R ₃ is as defined in formula (I), to lead to the compound of formula (X) described above,

compound of formula (X) or (XI), which is transformed, the group R'i and the group R ' ₂ when the latter represents an alkoxy group (Cι ~ C ₆ ) linear or branched, into hydroxy groups, to lead to the compound of formula (XIII):

in which R ₂ , R ₃ and i have the same meaning as in formula (I),

compound of formula (VII) or (XIII) which is reacted

• with a compound of formula (XlVa):

R— Y'-C-Cl (XlVa) X in which Ri, X have the same meaning as in formula (I), and Y 'represents a oxygen, sulfur atom or a group NR 'in which R' represents a linear or branched alkyl group (Cι-C ₆ ),

• or with a compound of formula (XlVb):

Rx - N = C = X (XlVb) in which Ri and X have the same meaning as in formula (I), to lead to the compound of formula (I / ai) or (I / a ₂ ), special cases of the compounds of formula (I):

in which X, Y, Ri, R ₂ , R ₃ and R have the same meaning as in formula (I),

in which X, Y, Ri, R ₂ and m have the same meaning as in formula (I),

compounds of formula (Lai) or (La ₂ ): which are purified where appropriate according to a conventional purification technique, the isomers of which are optionally separated according to a conventional separation technique and which are transformed, if desired , in their addition salts with a pharmaceutically acceptable acid or base.

The process for preparing the compounds of formula (I) in which A represents a group CR R. ₅ is characterized in that a compound of formula (XV) is used as starting material:

in which :

R'i represents a linear or branched alkoxy group (Cι-C ₆ ),

R ' ₂ represents a hydrogen, halogen atom or an alkoxy group (Cι-C ₆ ) linear or branched, which undergoes the action of chloroacetone in the presence of a mineral base in dimethylformamide medium, to lead to the compound of formula (XVI):

in which R'i and R ' ₂ have the same meaning as above, which undergoes a rearrangement in basic medium, to lead to the compound of formula

(XVII):

in which R'i and R ' ₂ have the same meaning as above, which is deacetylated by heating at reflux in benzene medium in the presence of an excess of ethylene glycol and of a catalytic amount of ^ -toluene sulfonic acid, for lead to the compound of formula (XVIII):

(XVIII)

in which R'i and R ' ₂ have the same meaning as above, which undergoes hydrolysis in an acid medium, to lead to the compound of formula (XIXa)

in which R'i and R ' ₂ have the same meaning as above, including, possibly, in the particular case where R ₃ is different from the hydrogen atom, we protects the nitrogen atom with a protective group, then, after treatment with a strong base, which is treated with a compound of formula R ' ₃ -P, in which R' represents an alkyl group (-C ₆ ) linear or branched or a cycloalkyl group (C ₃ -C) and P represents a leaving group, to lead after deprotection of the nitrogen atom, to the compound of formula (XlX'a):

in which R'i, R ' ₂ and R' have the same meaning as above, composed of formula (XIXa) and (XlX'a) represented by the formula (XIX):

in which R'i and R ' ₂ have the same meaning and R ₃ is as defined in formula (I), which:

- either undergoes a catalytic reduction, to lead to the compound of formula (XX):

in which R'i and R ' ₂ have the same meaning as before,

either is transformed into alcohol by the action of a hydride, the hydroxy group of which is transformed into a halogen atom by the action of an appropriate reagent, to yield the compound of formula (XXI):

in which R'i and R ' ₂ have the same meaning as above, R' ₅ represents a halogen atom,

- either undergoes the action of an organomagnesium R 'MgBr in which R' ₄ represents a linear or branched alkyl group (Cι-C ₆ ),

to lead to the compound of formula (XlXb):

in which R'i, R 'and R' have the same meaning as before,

compound of formula (XlXb):

- or else which undergoes a catalytic reduction, to lead to the compound of formula (XXII):

in which R'i, R ' ₂ and R' ₄ have the same meaning as above,

or of which the hydroxy group is transformed into a halogen atom by the action of an appropriate reagent, to yield the compound of formula (XXIII):

in which R'i, R ' ₂ and R' ₄ have the same meaning as above and R ' ₅ represents a halogen atom,

compound of formula (XX) to (XXIII) of which the group R'i and the group R ' ₂ when the latter represents a linear or branched alkoxy group (Cι-C ₆ ), in hydroxy groups, to lead to the compound of formula (XXIV):

in which R ₂ , i and R ₅ have the same meaning as in formula (I),

compound of formula (XXIN), which is reacted:

• with a compound of formula (XINa):

R-— Y'-C-Cl (XlVa)

¹ II

X in which Ri, X have the same meaning as in formula (I), and Y 'represents an oxygen or sulfur atom or a group Ν in which R represents a linear or branched (Cι-C ₆ ) alkyl group ,

• or with a compound of formula (XlVb): in which Ri and X have the same meaning as in formula (I), to lead to the compound of formula (I / b), special case of the compounds of formula (I):

in which X, Y, Ri, R ₂ , R, i, R ₅ have the same meaning as in formula (I),

which is purified where appropriate according to a conventional purification technique, the isomers of which are optionally separated according to a conventional separation technique and which, if desired, is converted into their addition salts with an acid or with a pharmaceutically acceptable base.

The invention also extends to pharmaceutical compositions containing as a principle active a 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, simple or coated tablets, sublingual tablets, capsules, tablets, suppositories, creams, ointments, dermal gels, injections, oral suspensions, etc.

The useful dosage is adaptable according to the nature and severity of the disease, the route of administration as well as the age and weight of the patient. This dosage varies from 1 to 500 mg per day in one or more doses.

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

The starting materials used are known products or prepared according to known procedures.

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

EXAMPLE 1: 5,5-Dioxido-2,3 a, 4-tetrahvdro-1H-pyrrolor2, l-eU 2.4T benzothiadiazin-7-yl phenyl carbonate

Stage A; N-2- (AminosuIfonyl) -4 ~ ~ 4 ~ méthoxyphényll chIorobtttanamide

To a solution containing 96.4 mmol of 2-amino-5-methoxybenzenesulfonamide in 200 ml of tetrahydrofuran (THF), 144 mmol of triethylamine are added and then dropwise a solution containing 135 mmol of 4-chlorobutanoic acid chloride in 30 ml of THF. After stirring overnight at room temperature, the THF is evaporated and the residue is taken up in water. After extraction with ethyl acetate, the organic phase is washed, dried. After evaporation, the expected product is obtained in the form of an oil. Stage B: 5,5-Dioxido-7-methoxy-2,3-dihy dro-1H-pyrrolo [2,1 -cl n, 2,41benzothiadiazine

The product obtained in the preceding stage is stirred overnight, at room temperature, in 320 ml of an aqueous solution of IN sodium hydroxide. After adding 50 ml of ethyl acetate and vigorous stirring, the expected product which precipitates is filtered, rinsed and dried.

Stage C: 5.5 _" Dioxido-7-methoxy-2,3,3a, 4 ~ tetrahvdro-1H-pyrroIof2, l-cl 11,2,41 benzothiadiazme

To a suspension containing 35.5 mmol of the product obtained in the preceding stage in 40 ml of dimethylformamide (DMF) are added 106.5 mmol of sodium borohydride. After stirring overnight at room temperature, the reaction medium is cooled and then

150 ml of an ice-cold solution of IN hydrochloric acid are added to the preceding mixture. The expected product precipitates and is filtered. Fusion point ; 193 98 ° C

Stage D: 5,5-Dioxιdo-2,3,3a, 4-tetrahydro-1H-pyrrolo [2, l-m, 2,41benzothiadiazin-7-oI

To a suspension containing 26.7 mmol of the product obtained in the preceding stage in

350 ml of dichloromethane maintained at -60 ° C. under nitrogen are added dropwise to 79.3 mmol of boron tribromide. The temperature is maintained for one hour then the whole returns to ambient temperature and is stirred overnight. After the reaction medium has cooled in an ice bath, 100 ml of water are added and the biphasic system which forms is vigorously stirred. The suspension thus formed is filtered.

The white solid obtained is washed with water, with ether, dried and leads to the expected product. Fnsion point: 237-242 ° C

Stage E: 5,5-Dioxido-2,3.3a.4-tetrahvdro-1H-pyrrolol2, l-cl 11.2.41 benzothiadiazin-7-yl phenyl carbonate

To a suspension containing 0.83 mmol of the compound described in the preceding stage in 30 ml of dichloromethane (CH ₂ C1 ₂ ), 0.175 ml of trietylamine, 5 mg of 4-dimethylaminopyridine are added and dropwise 0.136 ml of phenyl chloroformate dissolved in 2 ml of CH ₂ C1. After stirring overnight at room temperature, the solution is washed with IN hydrochloric acid, then with a saturated solution of sodium chloride, dried and evaporated. After taking up the residue with ether, the expected product is obtained by filtration. Melting point: 197-198 ° C Elementary microanalysis:

C H N S% theoretical 56.66 4.47 7.77 8.90

% experimental 56.44 4.55 7.61 9.02

The following examples were obtained according to the method described in Example 1 using the corresponding starting materials.

EXAMPLE 2; O- (5,5-Dioxido-2,3,3a, 4-tetrahydro-1H-pyrrolor2.1-clfl, 2,41 benzothiadiazin-7-yI. Q-phenyl thiocarbonate

The expected product is obtained by replacing, in Stage E, phenyl chloroformate with phenyl thionochloroformate. Melting point: 252-254 ° C Elemental microanalysis: C H N S

% theoretical 54.24 4.28 7.44 17.03

% experimental 53.55 5.02 7.39 17.47

EXAMPLE 3 Q- (5,5-Dioxido-2,3.3a, 4-tetrahvdro-1H-pyrrolof2.1-cin.2.41 benzothiadiazin-7-yl) S-phenyl dithiocarbonate

The expected product is obtained by replacing, in stage E, phenyl chloroformate with phenyl dithiochloroformate. Melting point: 210-214 ° C Elementary microanalysis:

C H N S

% theoretical 52.02 4.11 7.14 24.51

% experimental 51.85 4.10 7.36 24.69

EXAMPLE 4: O- (5,5-DiQxido-2,3,3a, 4-tetrahvdro-1H-pyrrolol2α-cπi, 2,41 benzothiadiazin - ^ - vD O- (4-chlQrophenyl) thiocarbonate

The expected product is obtained by replacing, in stage E, phenyl chloroformate with 4-chlorophenyl thionochloroformate, Melting point: 189-194 ° C. Elemental microanalysis:

C H N S Cl

theoretical% 49.69 3.68 6.82 15.61 8.63

% experimental 49.39 3.64 7.02 16.20 9.70

EXAMPLE 5 Q- (4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl) -O- phenyl thiocarbonate

Stage A: 7-Metho-4-H-1,2,4-Benzothiadiazine 1,1-dioxide

A suspension of 3.0 g of 2-amino-5-methoxybenzenesulfonamide is stirred for 1 night at 80 ° C. in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene. The toluene is evaporated under vacuum, the residue is taken up in water and the precipitate is filtered.

Stage B: 7-Metho-4-ethyl-4H-1,2,4-Benzothiadiazine 1,1-dioxide

2.88 g of the product obtained in the preceding stage are added to a suspension of 9 ml of DMF containing 570 mg of NaH 60% in mineral oil. We shake

30 min until a black solution is obtained. To this is then added dropwise 929 μl of iodoethane. Stirring is continued for 1 hour and the reaction medium is precipitated by addition of water. The precipitate is filtered, rinsed with water and then with ether to give the expected product.

Stage C: 7-Methoxy-4-ethyl-3,4-dihydro-2H-1,2,4-Benzothiadiazine 1,1-dioxide

To a suspension of 2.37 g of the product of the preceding stage in 40 ml of ethanol. 1.19 g of sodium borohydride are added. The medium gradually becomes homogeneous. After 1 hour of reaction at room temperature, the mixture is cooled in an ice bath and neutralized by the addition of IN HCl. The white precipitate is stirred for 15 min and the title product is filtered.

Stage D; 4-Ethyl-3,4-dihydro-2-H-1,2,4-benzothiadiazin-7-ol 1,1-dioxide

To a suspension containing 2 g of the product obtained in the preceding stage in 200 ml of dichloromethane maintained at -60 ° C. under nitrogen are added dropwise 79.3 mmol of boron tribromide. The temperature is maintained for one hour then the whole returns to ambient temperature and is stirred overnight. After the reaction medium has cooled in an ice bath, 100 ml of water are added and the two-phase system is stirred vigorously. The suspension thus formed is filtered. The solid obtained is washed with water, with ether, dried and leads to the expected product. Melting point: 214-218 ° C

Stage E: O- (4-Ethyl-l, l-dioxido-3,4-dihydro-2-H-l, 2,4-benzothiadiazin-7-ylVO- phenyl thiocarbonate

The expected product is obtained according to the process described in Stage E of Example 1, replacing the phenyl chloroformate with the phenyl thionochloroformate.

Fusion point ; 173-175 ° C

Elementary microanalysis:

C Η N S% theoretical 52.73 4.43 7.69 17.60

% experimental 52.81 4.68 7.66 17.75 EXAMPLE 6 0-f4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl -S- pnenyl dithiocarbonate

The expected product is obtained according to the process described in Example 5 by replacing, in Stage E, phenyl thionochloroformate with phenyl dithiochloroformate. Melting point: 228-232 ° C Elementary microanalysis:

C H N S

theoretical% 50.50 4.24 7.36 25.28

% experimental 50.07 4.09 7.57 25.31

EXAMPLE 7 Q-f4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzQthiadiazin-7-yl) -O-

(4-chlorophenyl) thiocarbonate

The expected product is obtained according to the process described in Example 5 by replacing, in Stage E, phenyl thionochloroformate with 4-chlorophenyl thionochloroformate. Melting point: 155-156 ° C

Elementary microanalysis:

C H N S Cl

theoretical% 48.18 3.79 7.02 16.08 8.89

% experimental 48.64 3.93 6.91 16.08 8.98

PHARMACOLOGICAL STUDY OF THE PRODUCTS OF THE INVENTION

Study of excitation currents induced by AMPA in Xenopus oocvtes

a - Method:

MRNAs are prepared from the cerebral cortex of a male Wistar rat by the guanidium thiocyanate / phenol / chloroform method. Poly (A ⁺ ) mRNAs are isolated by chromatography on oligo-dT cellulose and injected at a rate of 50 ng per oocyte. The oocytes are left for 2 to 3 days in incubation at 18 ° C to allow the expression of receptors and then stored at 8-10 ° C.

The electrophysiological recording is carried out in a plexiglass® chamber at 20-24 ° C in OR2 medium (J. Exp. Zool., 1973, 184, 321-334) by the "voltage clamp" method with 2 electrodes, a third electrode placed in the bath serving as a reference.

All the compounds are applied via the incubation medium and the electric current is measured at the end of the application period. AMPA is used at a concentration of 10 μM. For each compound studied, we define the concentration doubling (EC2X) or quintupling (EC5X) the intensity of the current induced by AMPA alone (5 to 50 nA).

The compounds of the invention very strongly potentiate the excitatory effects of AMPA and their activity is very clearly superior to that of the reference compounds.

The compound of Example 2 has in particular an EC2X equal to 1.8 μM and an EC5X equal to 9.6 μM.

PHARMACEUTICAL COMPOSITION

Preparation formula for 1000 tablets dosed at 100 mg Compound of Example 1 100 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 :

Ri represents an aryl or heteroaryl group,

R ₂ represents a hydrogen atom, a halogen atom or a hydroxy group,

X represents an oxygen or sulfur atom,

Y represents an oxygen or sulfur atom or an NR group in which R represents a hydrogen atom or a linear or branched (Cι-C ₆ ) alkyl group,

A represents a CR-tR group or an NRi group,

R ₃ represents a hydrogen atom, a linear or branched alkyl group (Cι-C ₆ ) or a cycloalkyl group (C ₃ -C),

R represents a hydrogen atom or a linear or branched (Cι-C ₆ ) alkyl group, or else

A represents a nitrogen atom and forms with the group -CHR ₃ - adjacent the ring in which m represents 1, 2 or 3,

Rs represents a hydrogen or halogen atom,

their isomers and their addition salts with a pharmaceutically acceptable acid or base, it being understood that: by aryl group is understood a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, optionally substituted by a or several groups, identical or different, halogen, alkyl _(Cι-C6) straight or branched alkoxy _(Cι-C6) linear or branched, perhaloalkyl, (Cι ~ _C6) linear or branched perhalogénoalkoxy _(Cι-C6) linear or branched, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (Cι-C ₆ ) alkyl groups), aminosulfonyl (optionally substituted by one or more linear or branched (Cι-C ₆ ) alkyl groups), alkyl

(Cι-C ₆ ) sulfonylamino, or phenyl (optionally substituted by one or more groups, identical or different, halogen, alkyl (Cι-C ₆ ) linear or branched, perhaloalkyl (Cι-C ₆ ) linear or branched, hydroxy or alkoxy (Cι-C ₆ ) linear or branched), by heteroaryl group, we understand monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, containing one, two or three heteroatoms, identical or different, chosen from nitrogen, oxygen and sulfur, optionally substituted by one or more groups, identical or different, halogen, alkyl _(Cι-C6) straight or branched alkoxy _(Cι-C6) linear or branched, perhaloalkyl _(Cι-C6) linear or branched , linear or branched perhaloalkoxy (Cι-C ₆ ), hydroxy, cyano, nitro, amino (optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched), aminosulfonyl (optionally substituted by one or more alkyl groups (Cι-C ₆ ) linear or branched), or alkyl (Cι-C ₆ ) sulfonylamino.

2- Compounds of formula (I) according to claim 1 characterized in that Ri represents an aryl group.

3- Compounds of formula (I) according to any one of claims 1 or 2 characterized in that R ₂ represents a hydrogen atom.

4- Compounds of formula (I) according to any one of claims 1 to 3 characterized in that A represents an NR ₄ group.

5- Compounds of formula (I) according to any one of claims 1 to 3 characterized in what A forms with the group -CHR ₃ - adjacent the

6- Compounds of formula (I) according to claim 5 characterized in that m represents the number 1.

7- Process for preparing the compounds of formula (I) in which A represents an NR group or A represents a nitrogen atom and forms with the CHR _{3 group}

uses as starting material a compound of formula (II)

in which: R'i represents a linear or branched alkoxy group (Cι-C ₆ ),

R ' ₂ represents a hydrogen, halogen atom or a linear or branched alkoxy group (Cι-C ₆ ), which is:

Cl - CH ₂ - (CH ₂ ) _m - CH ₂ - COC1 (III) in which _{m has} the same meaning as in formula (I), to lead to the compound of formula (IV):

in which R'i and R ' ₂ are as defined above, which is then cyclized in basic medium, to lead to the compound of formula (V)

in which R'i, R ' ₂ and m are as defined above,

which undergoes a reduction, in alcoholic medium or dimethylformamide, in the presence of sodium borohydride, to lead to the compound of formula (VI):

which undergoes the action of boron tribromide, to lead to the compound of formula (VII):

in which m is as defined above,

(b) either cyclized:

in the presence of an amidine of formula (VIII):

in which :

R ₃ is such a defined in formula (I), to lead to the compound of formula (IX)

in which R'i, R ' ₂ , and R' ₃ have the same meaning as before,

which is: or reduced by a metallic hydrogen, to lead to the compound of formula (X):

in which R'i, R ' ₂ , and R' ₃ have the same meaning as before,

or alkyl by the action of a strong base in the presence of an alkylating agent R ' ₄ X in which R' represents a linear or branched alkyl group (Cι-C ₆ ) and X a halogen atom, then reduced , to lead to the compound of formula (XI):

in which R'i, R ' ₂ , R ₃ and R' have the same meaning as above,

> in the presence of an aldehyde of formula (XII)

in which R ₃ is as defined in formula (I), to lead to the compound of formula (X) described above, compound of formula (X) or (XI), which is transformed, the group R 'and the group R' ₂ when the latter represents a linear or branched alkoxy group (Cι-C ₆ ), into hydroxy groups, to lead to the compound of formula (XIII):

in which R, R ₃ and R ₄ have the same meaning as in formula (I),

compound of formula (VII) or (XIII) which is reacted:

• with a compound of formula (XlVa):

R— Y'-C-Cl (XlVa) X in which Ri, X have the same meaning as in formula (I), and Y 'represents an oxygen or sulfur atom or a group NR' in which R ' represents a linear or branched (Cι-C ₆ ) alkyl group,

• or with a compound of formula (XlVb):

Ri - N = C = X (XlVb) in which Ri, Y and X have the same meaning as in formula (I), to lead to the compound of formula (I / ai) or (I / a ₂ ), special cases compounds of formula (I):

in which X, Y, Ri, R ₂ , R ₃ and R ₄ have the same meaning as in formula (I), in which X, Y, Ri, R ₂ and m have the same meaning as in formula (I),

compounds of formula (I / ai) or (La ₂ ): which are purified where appropriate according to a conventional purification technique, the isomers of which are optionally separated according to a conventional separation technique and which are transformed, if one so desired, in their addition salts with a pharmaceutically acceptable acid or base.

8- Process for preparing the compounds of formula (I) in which A represents a group CI jRs is characterized in that a compound of formula (XV) is used as starting material:

in which :

R'i represents a linear or branched alkoxy group (Cι-C ₆ ),

R ' ₂ represents a hydrogen, halogen atom or a linear or branched alkoxy group (Cι-C ₆ ), which undergoes the action of chloroacetone in the presence of dimethylfoπnamide, to lead to the compound of formula (XVI):

(XVII): in which R'i and R 'have the same meaning as above, which is deacetylated by heating at reflux in a benzene medium in the presence of an excess of ethylene glycol and of a catalytic amount of -toluene sulfonic acid, to lead to the composed of formula (XVIII):

(XVIII)

in which R'i and R ' ₂ have the same meaning as above, which undergoes hydrolysis in an acid medium, to lead to the compound of formula (XIXa):

in which R'i and R 'have the same meaning as above, including, optionally, in the particular case where R ₃ is different from the hydrogen atom, the nitrogen atom is protected by a protective group, then , after treatment with a strong base, which is treated with a compound of formula R ' ₃ -P, in which R' ₃ represents a linear or branched alkyl group (Cι-C ₆ ) or a cycloalkyl group (C ₃ - C ₇ ) and P represents a leaving group, to lead after deprotection of the nitrogen atom, to the compound of formula (XlX'a):

in which R'i, R ' ₂ and R' ₃ have the same meaning as above, composed of formula (XIXa) and (XlX'a) represented by the formula (XIX) in which R'i and R ' ₂ have the same meaning and R ₃ is as defined in the formula

©. who :

in which R'i and R ' ₂ have the same meaning as before,

either undergoes the action of an organomagnesium R ' ₄ MgBr in which R' ₄ represents a linear or branched (Cι-C ₆ ) alkyl group,

to lead to the compound of formula (XlXb)

in which R'i, R ' ₂ and R' ₄ have the same meaning as above,

compound of formula (XlXb):

in which R'i, R ' ₂ and R' ₄ have the same meaning as above,

- or else whose hydroxy group is transformed into a halogen atom by the action of an appropriate reagent, to yield the compound of formula (XXIII):

in which R'i, R ' ₂ and R' ₄ have the same meaning as above and R 'represents a halogen atom,

compound of formula (XX) to (XXIII) of which the group R'i and the group R ' ₂ are transformed when the latter represents a linear or branched alkoxy group (Cι-C ₆ ), into hydroxy groups, to lead to the compound of formula (XXIV):

in which R, Ri and R have the same meaning as in formula (I),

compound of formula (XXIN) which is reacted: • with a compound of formula (XINa):

R— Y'-C-Cl (XINa)

X in which Ri, X have the same meaning as in formula (I), and Y 'represents an oxygen or sulfur atom or a group ΝR' in which R 'represents a linear (Cι-C ₆ ) alkyl group or branched,

• or with a compound of formula (XlVb):

Rι - Ν = C = X (XlVb) in which Ri and X have the same meaning as in formula (I), to lead to the compound of formula (I / b), special case of the compounds of formula (I):

in which X, Y, Ri, R ₂ , R, i, R ₅ have the same meaning as in formula (I),

9- Pharmaceutical compositions containing as active ingredient a compound according to any one of claims 1 to 6 in combination with one or more excipients or inert, non-toxic, pharmaceutically acceptable vehicles.

10- Pharmaceutical compositions according to claim 9 containing as active ingredient a compound according to any one of claims 1 to 6 useful as medicaments, as AMPA modulators.