Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1998-05-01
2001-11-27
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S563000, C514S535000, C514S538000, C514S676000, C514S678000, C462S080000, C560S039000
Reexamination Certificate
active
06323240
ABSTRACT:
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-butanoic acid derivatives which act as inhibitors of kynurerine-3-hydroxylase (KYN-3-OHase), an enzyme involved in the metabolic pathway of kynurenine.
This invention further comprises novel compounds which represent a selected class of the above mentioned 4-phenyl-4-oxo-butanoic acid derivatives, their pharmaceutically acceptable salts, a process for their preparation and pharmaceutical compositions containing them. 4-Phenyl-4-oxo-butanoic acid compounds are known in the art. For instance, British patent no. 1498903 discloses aromatic ketoacids acids useful in the prevention and treatment of inflammatory syndromes and atherosclerosis.
British patent no. 1565616 refers to 4-phenylbutyric acid derivatives having analgesic and anti-inflammatory properties. Published French patent application no. 2503140 claims diphenyl-4-oxo-4-methylene-3-butyric acid derivatives having valuable hypolipaemic properties and therefore useful as antiatherosclerotic agents. British patent no. 1068751 discloses phenolic diphenylbenzocycloalkenes having anti-inflammatory activity. U.S. Pat. No. 3,876,800 relatives to 4-(disubstituted phenyl)butyric acids and functional derivatives thereof having analgesic and anti-inflammatory properties.
FIG. 1
shows the Kynurenine pathway.
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 post-ischemic 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 pathway (
FIG. 1
) KYN-3-OHase is the first enzyme involved in the formation of QUIN from KYN, compounds which act as inhibitors of this enzyme are expected to block the metabolism toward QUIN and, at the same time, to increase KYNA formation.
Consequently, compounds able of inhibiting this enzyme are useful in the prevention and/or treatment of a variety of pathologies involving quinolinic acid or excessive activation of the neurotransmission mediated by excitatory amino acid receptors.
Accordingly, the present invention provides a 4-phenyl-4-oxo-butanoic acid derivative of formula (I) either as a single isomer or as mixture of isomers
wherein
X, Y and Z are, each independently, hydrogen, halogen, cyano, nitro, C
1
-C
6
alkyl, phenyl, benzyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
1
-C
6
alkoxy or C
1
-C
6
alkylthio;
R is hydroxy; —OR
5
in which R
5
is C
1
-C
6
alkyl, phenyl, benzyl, C
2
-C
4
alkenyl or C
2
-C
4
alkynyl; —N(R
6
)
2
or —N(R
6
)OR
6
in which each R
6
is, independently, hydrogen, C
1
-C
6
alkyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, phenyl or benzyl;
R
1
, R
2
, R
3
and R
4
are, each independently, hydrogen, halogen, hydroxy, thiol, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, C
1
-C
6
alkyl, C
2
-C
4
alkenyl, phenyl or benzyl, or
R
1
and R
3
or R
2
and R
4
together form a group ═CHR
8
in which R
8
is hydrogen, a straight C
1
-C
5
alkyl chain or phenyl;
or a pharmaceutically aceptable salts thereof, for use in a method of treatment of the human or animal body by therapy.
Typically, the 4-phenyl-4-oxo-butanoic acid derivative is provided for use as a kynurenine-3-hydroxylase inhibitor.
In particular, the present invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the prevention and/or treatment of a neurodegenerative disease wherein the inhibition of the enzyme kynurenine-3-hydroxylase is needed.
More in particular, this invention refers to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the prevention and/or treatment of a neurodegenerative disease which comprises 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.
A preferred class of compounds of formula (I) according to the invention are compounds of formula (I), if the case, either as single isomers or as a mixture of isomers, wherein
R is hydroxy or —OR
5
in which R
5
is C
1
-C
6
alkyl;
one of X, Y and Z is hydrogen and the other two are, each independently, hydrogen, halogen, cyano, nitro, C
1
-C
6
alkyl, phenyl, benzyl, C
2
-C
4
alkenyl, C
2
-C
4
alkynyl, C
1
-C
6
alkoxy or C
1
-C
6
alkylthio;
R
1
, R
2
, R
3
and R
4
are, each independently, hydrogen, halogen, hydroxy, thiol, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, C
1
-C
6
alkyl, phenyl, benzyl or C
2
-C
4
alkenyl, or
R
1
and R
3
or R
2
and R
4
together form a group ═CHR
8
in which R
8
is hydrogen, a straight C
1
-C
5
Giordani Antonio
Pevarello Paolo
Speciale Carmela
Varasi Mario
Criares Theodore J.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pharmacia & Upjohn S.p.A.
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