Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1998-05-04
2000-04-11
Killos, Paul J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514538, 514570, 514618, 514619, 560 51, 560 11, 560 12, 562429, 562430, 562434, 562459, A01N 3710, C07C 6976
Patent
active
060488964
DESCRIPTION:
BRIEF SUMMARY
The present invention refers to the use in the prevention and/or treatment of neurodegenerative diseases, such as, for example, Huntington's chorea, Alzheimer's disease, dementia caused by acquired immunodeficiency syndrome (AIDS), infarctual dementia, cerebral ischemia, cerebral hypoxia, Parkinson's disease, epilepsy, head and spinal cord injury, amyotrophic lateral sclerosis, glaucoma/retinopathy, infections and inflammations of the brain, of 4-phenyl-4-oxo-2-butenoic acid derivatives which act as inhibitors of kynurenine 3-hydroxylase (KYN-3-OHase), an enzyme involved in the metabolism of kynurenine. This invention further comprises novel compounds, either as Z or E geometric isomers, which represent a selected class of the above mentioned 4-phenyl-4-oxo-2-butenoic acid derivatives, their pharmaceutically acceptable salts, a process for their preparation, and pharmaceutical compositions containing them.
It is well known in the art that through the kynurenine (KYN) pathway, tryptophan metabolism gives rise to the formation of quinolinic acid (QUIN) on the one side and kynurenic acid (KYNA) on the other, as shown in FIG. 1.
In the last decade, several lines of evidence have demonstrated that two intermediates of the kynurenine metabolism, (QUIN) and (KYNA), when injected in the CNS, act as a neurotoxin and as a neuroprotective agent, respectively. Consequently, the demonstration that these two metabolites of the kynurenine pathway (unable to cross the blood brain barrier), are normal constituents of the mammalian brain, reveals the existence of this pathway within the CNS and proposes the involvement of QUIN and KYNA in brain physiology and pathology (Stone T. W., Pharmacol. Rew., (1993), 310-379). Both QUIN and KYNA are able to interact with the ionotropic excitatory amino acid receptors. In particular, QUIN is a highly selective agonist at the N-methyl-D-aspartate (NMDA) receptor (Stone T. W., Eur. J. Pharmacol., 72, (1981) 411-412), whereas KYNA is a broad spectrum antagonist of the ionotropic excitatory aminoacid receptors, preferentially acting at the glycine co-agonist site of the NMDA receptor (J. Neurochem., 52, (1989) 1319-1328).
In vitro studies have demonstrated that the exposure of neuronal cell cultures to relatively low QUIN concentrations are neurotoxic either when applied over a prolonged period of time or in combination with glutamate (Schurr A., Brain Res., 568, (1991) 199-204). In vivo QUIN has been shown to produce convulsions and axon sparing lesions that mimic the nerve cell loss described in human neurodegenerative disorders (Schwarcz R., Science, 219, (1983) 316-318). Moreover an increase in QUIN production has been demonstrated in postischemic gerbil brain (Saito K., J. Neurochem., 60, (1993) 180-192), following spinal cord trauma in rats (Stokes B. T., Brain Res., 633, (1994) 348-352) and in guinea pig (Blight A. R., Brain Res., 632, (1993) 314-316), and, finally, in a model of experimental allergic encephalomyelitis (Flagan E. M., J.Neurochem., 64, (1995) 1192-1196).
On the other hand, KYNA has shown anticonvulsant and neuroprotective properties in several animal models (Stone T. W. Pharmacol.Rev.45,(1993) 309-379), and, additionally, the experimentally-evoked rise of KYNA concentrations is capable to elicit neuroprotection and seizures reduction (Nozaki K., J. Cereb. Blood Flow Metab., (1992), 12, 400-407; Russi P., J. Neurochem., 59, (1992) 2076).
Notably, KYNA when co-injected with QUIN is able to prevent the excitotoxic neuronal damage evoked by the neurotoxin (Foster A. C., Neurosci. Lett., 48, (1984) 273-278). These data taken together show that KYNA may act as the brain's own defence against detrimental events, such as excitotoxicity and seizures, leading to pathological situations (Schwarcz R., Neurotoxin and neurodegenerative disease, Ann. N.Y.Sci., 140, vol. 648, 1992).
It follows that, pharmacological interventions aimed at increasing KYNA formation and/or blocking QUIN synthesis, can be useful for the therapy of excitotoxic brain diseases. Since in the kynurenine pat
REFERENCES:
patent: 5519055 (1996-05-01), Schwarcz et al.
patent: 5708030 (1998-01-01), Schwarcz et al.
Giordani Antonio
Pevarello Paolo
Speciale Carmela
Varasi Mario
Killos Paul J.
Pharmacia & Upjohn S.p.A.
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