Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-27
2003-10-21
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S009000
Reexamination Certificate
active
06635635
ABSTRACT:
BACKGROUND OF THE INVENTION
It is now recognised that excitatory amino acids and more especially glutamate play a key 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).
Moreover, countless studies over recent years have shown the existence of excitatory amino acid receptor sub-types and of their functional interactions (Molecular Neuropharmacology, 1992, 2, 15-31).
Among those receptors, the AMPA receptor (“&agr;-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid”) seems to be the most implicated in the phenomena of physiological neuronal excitability and especially in those phenomena implicated in the processes of memorisation. For example, learning has been shown to be associated with an increase in AMPA binding to its receptor in the hippocampus, one of the cerebral regions essential to mnemocognitive processes. Similarly, nootropic agents, such as aniracetam, have very recently been described as modulating positively the AMPA receptors of neuronal cells (Journal of Neurochemistry, 1992, 58, 1199-1204).
DESCRIPTION OF THE PRIOR ART
In the literature, compounds of benzamide structure have been described as having that same mechanism of action and as improving mnesic 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 facilitatory action on the AMPA flux and Patent Application WO 99/42456 describes, inter alia, a number of benzothiadiazine compounds as AMPA receptor modulators.
In addition to being new, the benzothiadiazine compounds that are the subject-matter of the present invention, surprisingly, have pharmacological activity on the AMPA flux that is clearly superior to that of the compounds of similar structure described in the prior art. They are useful as AMPA modulators in the treatment or prevention of mnemocognitive disorders associated with age, anxiety or depression syndromes, progressive neurogenerative disorders, Alzheimer's disease, Pick's disease, Huntington's chorea, schizophrenia, sequelae of acute neurodegenerative disorders, sequelae of ischaemia and with sequelae of epilepsy.
DETAILED DESCRIPTION OF THE INVENTION
More specifically, the present invention relates to compounds of formula (I):
wherein:
R
1
represents a hydroxy, RCO—O— or RCO—NR
a
— group,
R
2
represents a hydrogen atom, a halogen atom, or a hydroxy, R′CO—O or R′CO—NR′
a
— group,
R and R′, which may be identical or different, represent a linear or branched (C
1
-C
6
)alkyl group optionally substituted by an aryl group, a linear or branched (C
2
-C
6
)alkenyl group optionally substituted by an aryl group, a linear or branched (C
1
-C
6
)perhaloalkyl group, a (C
3
-C
7
)cycloalkyl group, an adamantyl group, an aryl group or a heteroaryl group,
R
a
and R′
a
, which may be identical or different, represent a hydrogen atom or a linear or branched (C
1
-C
6
)alkyl group, a linear or branched (C
1
-C
6
)perhaloalkyl group, a linear or branched (C
1
-C
6
)acyl group, an aryl group or a heteroaryl group,
their isomers and addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that:
“aryl group” is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups are 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
)perhaloalkyl, linear or branched (C
1
-C
6
)perhaloalkoxy, 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 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),
“heteroaryl group” is understood to mean a monocyclic aromatic group or a bicyclic group in which at least one of the rings is aromatic, which groups contain one, two or three identical or different hetero atoms selected from nitrogen, oxygen and sulphur, and are 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
)perhaloalkyl, linear or branched (C
1
-C
6
)perhaloalkoxy, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C
1
-C
6
)-alkyl groups) and aminosulphonyl (optionally substituted by one or more linear or branched (C
1
-C
6
)alkyl groups).
Among the pharmaceutically acceptable acids, there may be mentioned by way of non-limiting example 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, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases, there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred aryl groups are the optionally substituted phenyl, naphthyl and tetrahydronaphthyl groups.
The preferred heteroaryl groups are the optionally substituted pyridyl, pyrrolyl, thienyl, furyl, imidazolyl and indolyl groups and more especially the groups pyridyl, thienyl and furyl.
Some preferred compounds of the invention are the compounds of formula (I) wherein R
1
represents a hydroxy group and R
2
represents a hydrogen or halogen atom.
Other preferred compounds of the invention are the compounds of formula (I) wherein R
1
represents an RCO—O group and R
2
represents a hydrogen atom. Among the compounds of the invention, when R
1
represents an RCO—O group and R
2
represents a hydrogen atom, the R group is preferably a (C
3
-C
7
)cycloalkyl group, an aryl group or a heteroaryl group.
The substituent R
1
of the compounds of formula (I) is preferably in the 7-position.
The preferred compounds of the invention are:
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl benzoate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl cyclohexane-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl cyclobutane-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 4-methyl-benzoate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 3-thiophene-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 2-thiophene-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 3-furan-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl 2-furan-carboxylate
5,5-dioxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-yl nicotinate.
The invention relates also to a process for the preparation of compounds of formula (I), 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, or a nitro group,
R′
2
represents a hydrogen at
Cordi Alex
Desos Patrice
Lefoulon François
Lestage Pierre
Ford John M.
Les Laboratoires Servier
The Firm of Hueschen and Sage
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