Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-11-29
2002-08-13
Davis, Brian J. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S503000
Reexamination Certificate
active
06433014
ABSTRACT:
BACKGROUND OF THE INVENTION
A subjet of the invention is compounds in particular constituting effectors of central nervous system effectors sensitive to neuroexcitatory amino acids (NEAA's), in particular glutamate (Glu), their preparation and their biological uses.
It relates more particularly to agonist, antagonist or reverse agonist compounds of these receptors.
It is known that glutamate is involved in numerous cerebral functions.
Important roles are therefore attributed to glutamatergic receptors, in particular in the conduction of nerve impulse, synaptic plasticity, the development of the central nervous system, learning and memory.
Glutamate is also the main endogenous neurotoxin, being responsible for the neuronal death observed after ischemia, hypoxia, epileptic fits or traumatisms of the brain. It is not therefore surprising that glutamate receptors are considered to be involved in various disorders of the central nervous system and neurodegenerative diseases.
The usefulness can therefore be measured of having means of modulating the effects of the glutamate in the central nervous system by using glutamatergic receptors as targets.
Two main types of glutamatergic receptors have been characterized: ionotropic receptors and metabotropic receptors. The ionotropic receptors are cationic channels activated by the glutamate and directly responsible for the rapid depolarization of post-synaptic cells. They are compounds of different sub-units and classified into three groups according to their pharmacological and functional properties. A distinction is thus made between the NMDA receptors (N-methyl-D-aspartic acid), AMPA (&agr;-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid) and kainate. Metabotropic receptors (mGluRs) have been revealed more recently (1985), and have been studied in less depth owing to their lack of specific effectors, until the discovery of 1-amino cyclopentane 1,3 dicarboxylic acid or ACPD. They regulate the activity of the ionic channels or enzymes producing second messengers via G proteins binding the GTP. Although they are generally not directly involved in rapid synaptic transmission, these receptors modulate the efficacy of these synapses by regulating either the ionic post-synaptic channels and their receptors, or the release or recapture of the glutamate. The mGluRs therefore play an important role in particular in the induction of the long-term potentialization (LTP) and the long-term depression (LDP) of synaptic transmission, in the regulation of baroceptive reflexes, spatial learning, motor learning, postural and kinetic integration. They are probably also involved in acute or chronic degenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease or Huntington's chorea.
To date, eight mGluRs have been cloned and can be classified into 3 groups according to their sequence homologies, their pharmacological properties and their signal transduction mechanisms.
The metabotropic receptors are very useful as targets for the modulation of the effects of glutamate, but their role in various physiological responses involving glutamate remains poorly characterized to date owing to the absence of totally specific tools. Different ligands, analogues of glutamic acid, have been recently described and are used for the pharmacological and physiological characterization of the metabotropic receptors, but turn out to be insufficiently selective and do not allow a perfect differentiation between groups or, within a group, of the sub-group to which the receptor belongs.
There is a requirement for new molecules allowing the differentiation between the ionotropic and metabotropic receptors. It is also important to have more selective molecules available which, within the metabotropic receptor family, allow these receptors to be sought and studied, the bioactive structures specific to each receptor to be defined and new pharmacologically active molecules to be produced.
In this context, the inventors have studied cyclic analogues of glutamic acid with a restricted conformation and have observed that the presence of certain groups in specified positions, with the resulting stereochemical possibilities, led to compounds endowed with strengthened and/or new activities vis-à-vis the glutamatergic receptors.
BRIEF SUMMARY OF THE INVENTION
A purpose of the invention is therefore to provide new compounds endowed with advantageous effects vis-à-vis the receptors of the central nervous system.
It also aims to provide a process for synthesizing these compounds which is easy to implement and can be exploited on an industrial scale.
It also aims to make use of the properties of these new compounds for producing agonist or antagonist agents of these receptors, which can be used as research and study tools, or as medicaments.
The compounds of the invention are characterized in that they correspond to formula (I)
in which
R
1
to R
4
, identical to or different from each other, represent a hydrogen atom, an alkyl radical or an aryl radical, these radicals themselves being substituted where appropriate, R
1
and R
2
together being able to further represent a —(CH
2
)
m
31
bridge, where m is an integer from 1 to 5, or a bridge X representing a linear combination of m hydrocarbon groups, m being as defined above, and where appropriate comprising at least one heteroatom such as O, N or S, or a bridge X representing a linear combination of p heteroatoms O, N and/or S, where p is an integer from 1 to 3,
A
1
and A
2
represent —COOH, —SO
3
H or —PO
3
H
2
radicals or their derivatives such as esters or amides or, when R
1
and R
2
represent a single bond between the carbons in positions 3 and 4, A
1
or A
2
has the above meanings, the other of these groups being a hydrogen atom,
Y represents a hydrocarbon chain —(CH
2
)
n
—, n being nil or an integer from 1 to 5, or represents a linear combination of n hydrocarbon groups and at least one heteroatom O, N or S, or a linear combination of q heteroatoms O, N and/or S, where q is an integer from 1 to 3.
A preferred family is formed by monocyclic compounds. These are compounds of formula I in which Y and the carbons carrying R
1
and R
2
are not linked together in forming one of the aforementioned bridges.
In another family of the invention, the compounds are also monocyclic and correspond to formula I above, in which the carbons carrying R
1
and R
2
are not linked together in forming one of the aforementioned bridges, and Y represents a group or a combination as defined above.
In yet another family of the invention, the compounds are bicyclic and correspond to formula I above in which X or both X and Y are present and are defined as indicated above.
In a preferred group of compounds of these different families, A
1
and A
2
are identical. In preferred compounds of this group, A
1
and A
2
both represent a carboxyl group, or the corresponding esters or amides.
In another group, A
1
and A
2
are as defined above, but are different from each other.
Advantageous compounds of these families and groups include R
1
, R
2
, and/or R
3
and R
4
substituents representing an alkyl or aryl radical, these radicals being substituted where appropriate.
By “alkyl” radical is understood according to the invention a radical of 1 to 10 carbon atoms, in particular 1 to 5 carbon atoms. By “aryl” radical is understood a mono- or polycyclic aromatic radical. A preferred aryl radical is constituted by the phenyl radical.
The alkyl or aryl radicals can be substituted, for example, by a halogen atom or a hydroxyl group.
In other advantageous compounds, R
1
and R
2
and/or R
3
and R
4
represent a hydrogen atom.
The compounds defined above can exist as achiral or chiral molecules, in the form of different diastereoisomers, optionally as racemic, where appropriate in the form of one of the enantiomers.
REFERENCES:
patent: 5500420 (1996-03-01), Maiese
patent: WO94/27602 (1994-12-01), None
Database CAPLUS on STN, Acc. No. 1976:477972, Madakyan et al., ‘Synthesis of stereoisomeric 2,5-dimethyl-4-aminotetrahydroth
Acher Francine
Azerad Robert
Pin Jean Philippe
Burns, Doane, Swecker & Mathis, LLP.
Centre National de la Recherche Scientifique (C.N.R.S.)
Davis Brian J.
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