Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-16
2003-02-04
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S233500, C514S233800, C514S254110, C514S252130, C514S321000, C514S324000, C514S432000, C514S437000, C514S443000, C544S146000, C544S376000, C544S377000, C544S378000, C546S197000, C546S202000, C549S023000, C549S043000, C549S052000, C549S054000, C549S055000
Reexamination Certificate
active
06514967
ABSTRACT:
The present invention relates to compounds with anti-radical activity, as well as pharmaceutical compositions containing them, methods of obtaining them, and their use in the treatment of pathologies involving abnormally high concentrations of extracellular glutamate.
Neurotoxic concentrations of extracellular glutamate cause neuron death in various acute pathologies: traumatisms, ischaemias, exogenous intoxication. The same type of neuron death process also occurs during chronic neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis.
Molecules that are able to antagonize the neurotoxic action of glutamate in the acute pathologies mentioned above were the subject of European patent application 0 396 734 dated Nov. 20, 1989. This relates to arylcyclohexylamines acting as noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor. This receptor, on which the glutamate acts, is responsible for massive entry of Ca
2+
ions into the neurons, in the presence of abnormally high concentrations of extracellular glutamate, which causes neuron death. These noncompetitive antagonists of NMDA attach themselves to the receptor of phencyclidine (PCP) and thus block entry of the Ca
2+
ions
However, these molecules do not affect the extracellular concentration of glutamate, and are especially suitable for use in emergencies in the treatment of the aforementioned acute pathologies.
Recent Italian works tend to show that the release of free radicals derived from oxygen, which accompanies the release of glutamate, might amplify the deleterious action of the latter (Volterra A et al. Reactive oxygen species inhibit high-affinity glutamate uptake: molecular mechanism and neuropathological implications. Ann. N. Y. Acad. Sci. 738, 153-162 (1994). Volterra A et al. Glutamate uptake is inhibited by arachidonic acid and oxygen radicals via two distinct and additive mechanisms. Mol. Pharmacol. 46, 986-992 (1994). Volterra A et al. Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J. Neurosci. 14, 2924-2932 (1994). Volterra A et al. Inhibition of high-affinity glutamate transport in neuronal and glial cells by arachidonic acid and oxygen-free radicals. Molecular mechanisms and neuropathological relevance. Ren Physiol Biochem 17, 165-167 (1994)).
In fact, the astrocytic transporter of glutamate, which is the principal mechanism of removal of extracellular glutamate by recapture, is inhibited by the action of the radicals. This leads to accumulation of glutamate, not only as a result of considerable release, but also, and perhaps predominantly, as a result of non-capture.
Radicals in the central nervous system (CNS) are now under investigation in numerous studies. Many molecules, often of natural origin, such as vitamin E, vitamin C, melatonin, derivatives of ginkgo biloba, and glutathion have been proposed as radical scavengers, as well as molecules obtained synthetically. The main problem to be solved is the tropism of these structures for the CNS. Since the sequence of formation of the radicals generally begins with the production of the superoxide anion, and a quite widely occurring enzyme (superoxide dismutase, SOD) has the task of destroying them during normal metabolism, this is under investigation in numerous studies. Direct use of this enzyme, suitably vectorized, is being tried. In particular, this is one of the routes envisaged for the treatment of amyotrophic lateral sclerosis of familial origin (Ikeda K. et al., 1995, 5(5), 383-390). It should be noted, however, that these enzyme vectorization techniques apply more especially to intracellular action, and so are likely to be accompanied by significant side effects.
The aim of the present invention is to provide compounds possessing the following main properties:
easy and fast penetration of the CNS (lipophilic compounds that cross the blood-brain barrier),
preferably little or no affinity for the receptor of PCP,
no penetration into the cells (and therefore possessing extracellular action), which limits their field of action in any side effects,
and ability to protect the glutamate transporter(s) of the astrocytes, by acting as scavengers of free radicals derived from oxygen in the extracellular space of the CNS. In this way, by protecting the still uninhibited transporters, recapture of astrocytic glutamate remains active, and thus able to limit the concentrations of glutamate and, in consequence, the neurotoxic effects.
It should be emphasized that the expression CNS used in the foregoing and hereinafter, comprises the brain, the cerebellum and the spinal cord.
Another aim of the invention is to provide pharmaceutical compositions that can be used in the treatment of pathologies affecting the CNS and involving abnormally high concentrations of extracellular glutamate.
Another aim of the invention is to provide methods of preparation of the said compounds and pharmaceutical compositions.
The invention relates to compounds that possess the aforementioned properties, with the following general formula (I):
in which:
R
1
and R
2
, independently of one another, represent a hydrogen atom, an alkyl group with 1 to 5 carbon atoms, especially a methyl group, a hydroxyl group, a halogen atom, in particular an atom of chlorine, bromine, iodine or fluorine, or: R
1
and R
2
form, in conjunction with the carbon atoms carrying them, a substituted or unsubstituted, aromatic or non-aromatic ring, with 4 to 8 carbon atoms in the ring, especially a benzene ring,
R
3
represents a hydrogen atom or an alkyl group with 1 to 5. carbon atoms, especially a methyl group,
X and Y, independently of one another, represent CH
2
, or a heteroatom such as a sulphur atom S, or a group with the formula
in which R
4
and R
5
represent, independently of one another, a hydrogen atom or an alkyl group with 1 to 5 carbon atom, especially a methyl group, or R
4
and R
5
form, in conjunction with the nitrogen atom carrying them, a substituted or un substituted, aromatic or non-aromatic heterocycle, with 4 to 8 carbon atoms in the ring, including if necessary an additional heteroatom in the ring, especially a ring with the formula
in which A represents:
a group
in which Z represents CH or N, R
6
represents a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, especially a methyl group, or a hydroxyl group,
or a heteroatom such as O or S.
The invention relates more particularly to compounds of formula (I) mentioned above, in which at least either X or Y represents a group with the formula
in which R
4
and R
5
are as defined above.
The invention relates more particularly to the compounds of formula (I) mentioned above, in which:
R
1
and R
2
represent a hydrogen atom, or R
1
and R
2
form, in conjunction with the carbon atoms that they carry, a benzene ring,
R
3
represents a hydrogen atom or an alkyl group with 1 to 5 carbon atoms, especially a methyl group,
either X or Y represents a group with the formula
in which R
4
and R
5
represent a hydrogen atom, or R
4
and R
5
form, in conjunction with the nitrogen atom carrying them, a heterocycle with the formula:
in which A represents:
a group
in which Z represents CH or N, R
6
represents a hydrogen atom, a methyl group, or a hydroxyl group,
or a heteroatom such as O or S.
The invention relates even more especially to compounds as defined above, with the following formula (II):
in which R
3
, R
4
, and R
5
have the meanings indicated above, and Y represents CH
2
or a sulphur atom S.
Particularly preferred compounds of formula (II) are those represented by the following formulae:
A particularly preferred compound of formula (II) is the compound IC023 represented by the following formula:
Another particularly preferred compound of formula (II) is the compound IC180 represented by the following formula:
The invention relates even more particularly to the compounds as defined above, with the following formula (III):
in which R
3
, R
4
and R
5
have the meanings stated above.
Particularly preferred com
Barbanel Gerard
Caubere Isoline
Kamenka Jean-Marc
Bierman, Muserlian and Lucas
Centre National de la Recherche Scientifique
Rao Deepak
LandOfFree
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