Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1995-04-06
1998-07-28
MacMillan, Keith D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
560 39, 514564, 514563, 514535, 514538, A61K 31195, C07C23936
Patent
active
057865086
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new medical use for certain chemical compounds as well as to novel compounds, to a process for their preparation and to pharmaceutical compositions containing them.
In particular, the invention relates to the use in the treatment of cognitive disorders associated with the aging processes of the brain of compounds which act as inhibitors of the enzyme Kynurenine Aminotransferase (known in the art as KAT).
Compounds which act as KAT inhibitors may be identified using a standard test, for example, measuring their ability to inhibit KAT activity in rat brain homogenate as described, for example, in J. Neurochem., 57, 533-540 (1991) or their inhibitory effect on Kynurenic Acid (KYNA) production by rat brain slices as described, for example, in J. Neurochem., 52, 1629-1636 (1989).
KAT catalyzes the biosynthesis of KYNA from Kynurenine (KYN): ##STR2## and it is singularly responsible for the regulation of extracellular KYNA concentrations in the brain (J. Neurochem., 57, 533-540, 1991).
KYNA is an effective excitatory amino acid (EAA) receptor antagonist with a particularly high affinity to the glycine modulatory site of the N-methyl-D-aspartate (NMDA) receptor complex (J. Neurochem., 52, 1319-1328, 1989).
As a naturally occurring brain metabolite (J. Neurochem., 51, 177-180, 1988 and Brain Res., 454, 164-169, 1988), KYNA probably serves as a negative endogenous modulator of cerebral glutamatergic function (Ann. N.Y. Acad. Sci., vol. 648, p. 140-153, 1992).
EAA receptors and in particular NMDA receptors are known to play a central role in the function of the mammalian brain (J. C. Watkins and G. L. Collingridge--eds.--, The NMDA receptor, Oxford University Press, Oxford, 1989, pp. 242). For example, NMDA receptor activation is essential for cognitive processes, such as, for example, learning and memory (J. C. Watkins and G. L. Collingridge--eds.--, In: The NMDA receptor, Oxford University Press, Oxford, p. 137-151, 1989) and for brain development (Trends Pharmacol. Sci., 11, 290-296, 1990).
It follows that a reduction in NMDA receptor function will have detrimental consequences for brain physiology and, consequently, for the entire organism. For example, the decline in the number of NMDA receptors which occurs in the aged brain (Synapse, 6, 388-343, 1990) is likely associated with age-related disorders of cognitive functions.
In the brain, KYNA concentrations and the activity of KYNA's biosynthetic enzyme KAT show a remarkable increase with age (Brain Res. 558, 1-5, 1992 and Neurosci. Lett., 94, 145-150, 1988). KAT inhibitors, by providing an increase of the glutamatergic tone at the NMDA receptor, could therefore be particularly useful in situations where NMDA receptor function is insufficient and/or KAT activity and KYNA levels are abnormally enhanced. Hence they could be particularly useful in the treatment of the pathological consequences associated with the aging processes in the brain which are, for example, cognitive disorders including, e.g., attentional and memory deficits and vigilance impairments in the elderly.
KAT inhibitors may also be useful in the treatment of perinatal brain disorders which may be related to irregularities in the characteristic region specific pattern of postnatal KAT development (H. Baran and R. Schwarcz: Regional differences in the ontogenic pattern of KAT in the rat brain, Dev. Brain Res., in press).
Accordingly, the first object of the present invention includes the use of KAT inhibitors in the treatment of perinatal brain disorders.
In the present specification, the term "treatment" includes "prophylactic treatment" as well as "the acute alleviation of symptoms".
Particular compounds for use as KAT inhibitors according to the present invention are 5-substituted kynurenine derivatives of the following formula (I) ##STR3## wherein R is halogen, C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.7 cycloalkyl, phenyl-C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.6 alkoxy, C.sub.6 -C.sub.10 aryloxy, phenyl-C.sub.1 -C.sub.4 alkoxy or trifluoromethyl; and alkylamino
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Bianchetti Alberto
Della Torre Arturo
Schwarcz Robert
Speciale Carmela
Varasi Mario
MacMillan Keith D.
Pharmacia & Upjohn S.p.A.
University of Maryland at Baltimore
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