Benzothiazine and benzothiadiazine compounds

The present invention relates to new benzothiazine and benzothiadiazine compounds, to a process for their preparation and to pharmaceutical compositions containing them. The compounds of the present invention are new and have very valuable pharmacological properties in respect of AMPA receptors.

It has now been recognised that the excitatory amino acids, 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 shown that a deficit in glutamatergic neurotransmission is closely linked to the development of Alzheimer's disease (Neuroscience and Biobehavioral reviews, 1992, 16, 13-24; Progress in Neurobiology, 1992, 39, 517-545).

In addition, innumerable works have in recent years demonstrated the existence of sub-types of excitatory amino acid receptors and their functional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).

Among those receptors, the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor appears to be involved to the greatest extent in the phenomena of physiological neuronal excitability and, especially, in those phenomena involved in memorisation processes. For example, it has been shown that learning is associated with an increase in the binding of AMPA to its receptor in the hippocampus, one of the areas of the brain essential to processes of memory and cognition. Likewise, nootropic agents such as aniracetam have very recently been described as modulating the AMPA receptors of neuronal cells in a positive manner (Journal of Neurochemistry, 1992, 58, 1199-1204).

In the literature, compounds having a benzamide structure have been described as possessing this same mechanism of action and improving memory performance (Synapse, 1993, 15, 326-329). Compound BA 74, in particular, is the most active of those new pharmacological agents.

Finally, patent specification EP 692 484 describes a benzothiadiazine compound having a facilitating action on the AMPA current, and patent application WO 99/42456 describes inter alia particular benzothiadiazine compounds as modulators of AMPA receptors.

The benzothiazine and benzothiadiazine compounds to which the present invention relates, besides being new, surprisingly exhibit pharmacological activity on the AMPA current that is markedly superior to the activity of the compounds having similar structures described in the prior art. They are useful as AMPA modulators for the treatment or prevention of disorders of memory and cognition that are associated with age, with syndromes of anxiety or depression, with progressive neurodegenerative diseases, with Alzheimer's disease, with Pick's disease, with Huntington's chorea, with schizophrenia, with the sequelae of acute neurodegenerative diseases, with the sequelae of ischaemia and with the sequelae of epilepsy.

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

wherein:

R 1 represents a hydrogen atom, a halogen atom or a linear or branched (C 1 -C 6 )alkyl group, R 1a represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group, R 2 represents a hydrogen atom, a halogen atom or a hydroxy group, A represents a CR 4 R 5 group or an NR 4 group, R 3 represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group or a (C 3 -C 7 )cycloalkyl group, R 4 represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group,

or

A represents a nitrogen atom and, together with the adjacent —CHR 3 — group, forms the ring

wherein m represents 1, 2 or 3,

R 5 represents a hydrogen or halogen atom, X represents an NR 6 R 7 , S(O) n R 8 or OR′ 8 group or a heterocyclic group, wherein:

R 6 represents a hydrogen atom, a linear or branched (C 1 -C 6 )alkyl group, S(O) p R 9 , COR 9 or P(O)OR 9 OR 10 , R 7 represents a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group, or R 6 and R 7 , together with the nitrogen atom carrying them, form a heterocyclic group, R 8 , R 9 and R 10 , which may be the same or different, represent a hydrogen atom; a linear or branched (C 1 -C 6 )alkyl group optionally substituted by one or more halogen atoms; an aryl-(C 1 -C 6 )alkyl group in which the alkyl moiety is linear or branched; or an aryl group, R′ 8 represents a linear or branched (C 1 -C 6 )alkyl group or a linear or branched (C 1 -C 6 )acyl group, n and p, which may be the same or different, represent 1 or 2,

to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,

it being understood that:

a heterocyclic group means a monocyclic or bicyclic, aromatic or non-aromatic group containing from one to four identical or different hetero atoms selected from nitrogen, oxygen and sulphur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )alkoxy, linear or branched (C 1 -C 6 )polyhaloalkyl, linear or branched (C 1 -C 6 )alkoxy-carbonyl, oxo, thioxo, carboxy, linear or branched (C 1 -C 6 )acyl, linear or branched (C 1 -C 6 )polyhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C 1 -C 6 )alkyl groups), aminosulphonyl (optionally substituted by one or more linear or branched (C 1 -C 6 )alkyl groups) and (C 1 -C 6 )alkylsulphonylamino, an aryl group is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl (optionally substituted by one or more hydroxy groups), linear or branched (C 1 -C 6 )alkoxy, linear or branched (C 1 -C 6 )polyhaloalkyl, linear or branched (C 1 -C 6 )alkoxy-carbonyl, oxo, thioxo, linear or branched (C 1 -C 6 )alkylthio, carboxy, linear or branched (C 1 -C 6 )acyl, linear or branched (C 1 -C 6 )polyhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C 1 -C 6 )alkyl or linear or branched (C 1 -C 6 )acyl groups), aminocarbonyl (optionally substituted by one or more linear or branched (C 1 -C 6 )alkyl groups), aminosulphonyl (optionally substituted by one or more linear or branched (C 1 -C 6 )alkyl groups), mono- or di-((C 1 -C 6 )alkylsulphonyl)amino, mono- or di-(trifluoromethylsulphonyl)amino, PO(OR a )(OR b ) (wherein R a and R b , which may be the same or different, represent a hydrogen atom or a linear or branched (C 1 -C 6 )alkyl group), benzyloxy and phenyl (optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )perhaloalkyl, hydroxy and linear or branched (C 1 -C 6 )alkoxy).

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methane-sulphonic acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.

The grouping

is preferably in position b of the phenyl carrying it.

Preference is given to the R 1a and R 2 groups being hydrogen atoms.

The grouping

is preferably in the meta- or para-position of the phenoxy ring structure carrying it.

X preferably represents an NR 6 R 7 or S(O) n R 8 group or a heterocyclic group.

More especially, the group X is preferably the NR 6 R 7 group wherein R 6 represents a hydrogen atom or an S(O) p R 9 group and R 7 represents a hydrogen atom, such as, for example, the groups NHSO 2 Me, NHSO 2 iPr, NHSO 2 CF 3 , NH 2 .

Preferred compounds of the invention are compounds wherein; A represents a nitrogen atom and, together with the adjacent —CHR 3 — group, forms the ring

wherein

m represents 1, 2 or 3, preferably 1.

Preferred compounds of the invention are:

{3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7yl)-oxy]phenyl}methanamine, N-{3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)-oxy]benzyl}methanesulphonamide, N-{4-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7yl)-oxy]benzyl}methanesulphonamide.

The invention relates also to the processes for the preparation of compounds of formula (I).

The process for the preparation of compounds of formula (I) wherein A represents an NR 4 group or A represents a nitrogen atom and, together with the adjacent CHR 3 group, forms the ring

wherein m represents 1, 2 or 3, is characterised in that there is used as starting material a compound of formula (II):

wherein:

R′ 1 represents a linear or branched (C 1 -C 6 )alkoxy group, R′ 2 represents a hydrogen atom, a halogen atom or a linear or, branched (C 1 -C 6 )alkoxy group,

which 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 —COCl  (III),

wherein m is as defined for formula (I),

to yield the compound of formula (IV):

wherein R′ 1 and R′ 2 are as defined hereinbefore,

which is then cyclised in a basic medium to yield the compound of formula (V):

wherein R′ 1 , R′ 2 and mn are as defined hereinbefore,

which is optionally subjected to reduction, in an alcoholic or dimethylformamide medium, in the presence of sodium borohydride, to yield the compound of formula (VI):

wherein R′ 1 , R′ 2 and mn are as defined hereinbefore,

which compound of formula (V) or (VI) is subjected to the action of boron tribromide

to yield the compound of formula (VII):

wherein R 2 is as defined for formula (I) and mn is as defined hereinbefore,

(b) or cyclised:

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

wherein R 3 is as defined for formula (I),

to yield the compound of formula (IX):

wherein R′ 1 , R′ 2 and R 3 are as defined hereinbefore,

which is:

either reduced, using a metallic hydride, to yield the compound of formula (X):

wherein R′ 1 , R′ 2 and R 3 are as defined hereinbefore,

or alkylated by the action of a strong base in the presence of an alkylating agent R′ 4 X, wherein R′ 4 represents a linear or branched (C 1 -C 6 )alkyl group and X represents a halogen atom, and then reduced to yield the compound of formula (XI):

wherein R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore,

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

wherein R 3 is as defined for formula (I),

to yield the compound of formula (X) described hereinbefore,

in which compound of formula (X) or (XI)

the group R′ 1 and, when the group R′ 2 represents a linear or branched (C 1 -C 6 )alkoxy group, the group R′ 2 are converted into hydroxy groups

to yield the compound of formula (XIII):

wherein R 2 , R 3 and R 4 are as defined for formula (I),

which compound of formula (VII) or (XIII) is reacted with a boronic acid compound of formula (XIV):

wherein R″ 1 represents a cyano group or an R 1 R 1a XC— group as defined for formula (I),

to yield (after optional conversion of the group R″ 1 , when the latter represents a cyano group, into an NR 6 R 7 group as defined for formula (I)) the compound of formula (I/a 1 ) or (I/a 2 ), particular cases of the compounds of formula (I):

wherein R 1 , R 1a , R 2 , R 3 , R 4 and X are as defined for formula (I),

wherein R 1 , R 1a , R 2 , m and X are as defined for formula (I),

which compounds of formulae (I/a 1 ) and (I/a 2 ):

are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their isomers according to a conventional separation technique and are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base.

The process for the preparation of compounds of formula (I) wherein A represents a CR 4 R 5 group is characterised in that there is used as starting material a compound of formula (XV):

wherein:

R′ 1 represents a linear or branched (C 1 -C 6 )alkoxy group, R′ 2 represents a hydrogen atom, a halogen atom or a linear or branched (C 1 -C 6 )alkoxy group,

which is subjected to the action of chloroacetone in the presence of dimethylformamide to yield the compound of formula (XVI)

wherein R′ 1 and R′ 2 are as defined hereinbefore,

which is subjected to a rearrangement in a basic medium tol yield the compound of formula (XVII):

wherein R′ 1 and R′ 2 are as defined hereinbefore,

is deacetylated by heating at reflux in a benzene medium in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulphonic acid to yield the compound of formula (XVIII):

wherein R′ 1 and R′ 2 are as defined hereinbefore,

which is subjected to hydrolysis in an acid medium to yield the compound of formula (XIXa):

wherein R′ 1 and R′ 2 are as defined hereinbefore,

the nitrogen atom of which is optionally, depending on the nature of the group R 3 that is desired, protected by a protecting group and which is then, after treatment with a strong base, treated with a compound of formula R′ 3 —P,

wherein R′ 13 represents a linear or branched (C 1 -C 6 )alkyl group or a (C 3 -C 7 )cycloalkyl group and P represents a leaving group,

to yield, after deprotection of the nitrogen atom, the compound of formula (XIX′a):

wherein R′ 1 , R′ 2 and R′ 3 are as defined hereinbefore,

which compound of formula (XIXa) or (XIX′a), represented by formula (XIX):

wherein R′ 1 and R′ 2 are as defined hereinbefore and R 3 is as defined for formula (I), is:

either subjected to catalytic reduction to yield the compound of formula (XX):

wherein R′ 1 and R′ 2 are as defined hereinbefore,

or converted by the action of a hydride into an alcohol, the hydroxy group of which is converted into a halogen atom by the action of an appropriate reagent

to yield the compound of formula (XXI):

wherein R′ 1 , R′ 2 and R 3 are as defined hereinbefore and R′ 5 represents a halogen atom,

or subjected to the action of an organomagnesium compound R′ 4 MgBr, wherein R′ 4 represents a linear or branched (C 1 -C 6 )alkyl group,

to yield the compound of formula (XIXb):

wherein R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore,

which compound of formula (XIXb)

either is subjected to catalytic reduction to yield the compound of formula (XXII):

wherein R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore,

or the hydroxy group thereof is converted into a halogen atom by the action of an appropriate reagent

to yield the compound of formula (XXIII):

wherein R′ 1 , R′ 2 , R 3 and R′ 4 are as defined hereinbefore and R′ 5 represents a halogen atom,

in which compounds of formulae (XX) to (XXIII) the group R′ 1 and, when the group R′ 2 represents a linear or branched (C 1 -C 6 )alkoxy group, the group R′ 2 are converted into hydroxy groups

to yield the compound of formula (XXIV):

wherein R 2 , R 3 , R 4 and R 5 are as defined for formula (I),

which compound of formula (XXIV) is reacted with a boronic acid compound of formula (XIV):

wherein R″ 1 represents a cyano group or an R 1 R 1a XC— group as defined for formula (I),

to yield (after optional conversion of the group R″ 1 , when the latter represents a cyano group, into an NR 6 R 7 group as defined for formula (I)) the compound of formula (I/b), a particular case of the compounds of formula (I):

wherein R 1 , R 1a , R 2 , R 3 , R 4 , R 5 and X are as defined for formula (I),

which compound of formula (I/b) is purified, if necessary, according to a conventional purification technique, is separated, if desired, into its isomers according to a conventional separation technique and is converted, if desired, into its' addition salts with a pharmaceutically acceptable acid or base.

The invention relates also to pharmaceutical compositions comprising, as active ingredient, a compound of formula (I) with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient and ranges from 1 to 500 mg per day in one or more administrations.

The Examples that follow illustrate the invention but do not limit it in any way.

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

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

{3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}methanamine hydrochloride

A solution of BBr 3 (68.75 mmol) in 25 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 27.5 mmol of 7-methoxy-2,3-dihydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazine 5,5-dioxide in 350 ml of methylene chloride. Stirring is carried out at ambient temperature for 24 hours. The reaction mixture is poured into a mixture of ice and water, and the suspension is stirred for 30 minutes. The precipitate is filtered off, rinsed several times with water, filtered under suction and dried in vacuo to yield the expected product.

Melting point: >300° C. Elemental micro-analysis:

A suspension composed of 7.06 mmol of the product obtained in the Step above, 3-cyanophenylboronic acid (11.02 mmol), copper(II) acetate (11.02 mmol), pyridine (22.0 mmol) and about 500 mg of 4 Å molecular sieve in 200 ml of methylene chloride is stirred for 24 hours. The reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered. The filtrate is concentrated and then directly placed on a silica column which is eluted with a methylene chloride/methanol 95/5 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the expected product is recovered in the form of a white powder.

Melting point: 229-233° C. Elemental micro-analysis:

Step C: {3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl)}methanamine hydrochloride

112 mg (2.95 mmol) of LiAlH 4 are added, in small portions, to a solution of 0.58 mmol of the product of the Step above in 20 ml of anhydrous THF and the mixture is stirred at ambient temperature for 1 hour. The excess of hydride is hydrolysed by the successive dropwise addition of 1.5 ml of isopropanol and 1.5 ml of saturated aqueous NaCl solution. The aluminium salts are filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on a silica column, eluting with a mixture of CH 2 Cl 2 /EtOH/aq. NH 3 95/5/0.5. After evaporating the fractions containing the amine, the meringue is taken up in ethereal HCl. The solution is evaporated to dryness and the residue is redissolved in a minimum of isopropanol. The expected product crystallises out and is recovered by filtration.

Melting point: 145° C. Elemental micro-analysis

The procedure is as in Step B of Example 1, using the compound obtained in Step A of Example 1 and [3-(methoxycarbonyl)phenyl]boronic acid as starting materials.

Melting point: 211-214° C. Elemental micro-analysis:

A suspension of the product obtained in Step A (1.1 g, 2.55 mmol) in 18 ml of 1N NaOH is heated at 95° C. until a solution is obtained. The solution is allowed to return to ambient temperature, is acidified with 1N HCl and extracted (CH 2 Cl 2 ). The organic phases are combined, washed (saturated NaCl), dried (MgSO 4 ) and evaporated. The residue is triturated in Et 2 O; the title product precipitates out and is recovered by filtration.

A suspension of the product obtained in Step B (850 mg, 2.26 mmol) in 25 ml of THF in the presence of 675 μl (4.52 mmol) of DBU is refluxed for 1 hour. It is allowed to return to ambient temperature and is acidified with 1N HCl, and the white precipitate corresponding to the title product is filtered off. Elemental micro-analysis:

Step D: 3-[(5,5-Dioxido-2,3-dihydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)-oxy]-N,N-dimethylbenzamide:

To a suspension of the product obtained in Step C (1.40 g, 3.91 mmol) in 20 ml of CH 2 Cl 2 there are added 2 drops of DMF and then, dropwise, 684 μl (7.81 mmol) of oxalyl chloride diluted with 2 ml of CH 2 Cl 2 . Stirring is carried out at ambient temperature for 2 hours 30 minutes; evaporation to dryness is carried out; the residue is taken up in 15 ml of CH 2 Cl 2 ; 1.1 ml (7.81 mmol) of Et 3 N and then 2.94 ml (5.87 mmol) of a 2M solution of dimethylamine in THF are added. Stirring is carried out at ambient temperature for 1 hour. The reaction mixture is acidified with 0.5N HCl and extracted (CH 2 Cl 2 ). The organic phases are combined, washed (saturated NaCl), dried (MgSO 4 ) and evaporated. The residue is triturated in Et 2 O; the title product precipitates out and is recovered by filtration. Elemental micro-analysis:

Step E: {3-[(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl)oxy]benzyl}dimethylamine

3.72 ml (3.72 mmol) of a 1M solution of LiAlH 4 in THF are added dropwise to a suspension of 577 mg (1.49 mmol) of the product obtained in Step D in 20 ml of THF. The reaction mixture is observed passing into solution and stirring is carried out at ambient temperature for 3 hours. The excess of hydride is hydrolysed by the dropwise addition of water until the evolution of gas ceases. The suspension is stirred for 10 minutes, 20 ml of water are added, and extraction is carried out with AcOEt. The organic phases are combined, washed (saturated NaCl), dried (MgSO 4 ) and evaporated, and the residue is chromatographed on a silica column (CH 2 Cl 2 /MeOH 95/5) to yield the title product.

Melting point: 122° C. Elemental micro-analysis:

Pharmacological Study of Products of the Invention

a—Method:

mRNA's are prepared from cerebral cortex of male Wistar rats by the guanidinium thiocyanate/phenol/chloroform method. The poly (A + ) mRNA's are isolated by chromatography on oligo-dT cellulose and injected at a level of 50 ng per oocyte. The oocytes are incubated for 2 to 3 days at 18° C. to permit expression of the receptors and are then stored at 8-10° C.

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 using two electrodes, with a third electrode placed in the bath serving as 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 in a concentration of 10 μM. For each compound studied, the concentration that doubles (EC2×) or quintuples (EC5×) the intensity of the current induced by AMPA alone (5 to 50 nA) is determined.

b—Results:

The compounds of the invention potentiate the excitatory effects of AMPA to a very considerable degree and their activity is very clearly superior to that of compounds of reference. The compound of Example 1 especially has an EC2× of 3.5 μM and an EC5× of 9.2 μM, the compound of Example 2 an EC2× of 0.35 μM and an EC5× of 2.6 μM, and the compound of Example 21 an EC2× of 0.1 μM and an EC5× of 0.56 μM.