Quinolone derivatives

Details Quinolone derivatives Quinolone derivatives

1994-05-25

1997-03-25

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

546157, A61K 3147, C07D215227

Patent

active

056145322

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB92/02183, filed Nov. 25, 1992, and published as WO93/11115 Jun. 10, 1993.
This invention relates to a class of 2(1H)-quinolone derivatives which are substituted in the 3-position by an optionally substituted aryl substituent. These compounds are selective non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors. More particularly, the class of compounds provided by the present invention are ligands for the strychnine-insensitive glycine modulatory site of the NMDA receptor and are therefore useful in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by exogenous and endogenous NMDA receptor agonists and neurotoxins, including environmental neurotoxins.
By virtue of their NMDA receptor antagonist properties, the compounds according to the present invention are also useful as anticonvulsant and antiemetic agents, as well as being of value in the prevention or reduction of dependence on dependence-inducing agents such as narcotics.
NMDA receptor antagonists have recently been shown to possess analgesic (see, for example, Dickenson and Aydar, Neuroscience Lett., 1991, 121, 263; Murray et al., Pain, 1991, 44, 179; and Woolf and Thompson, Pain, 1991, 44, 293) and anxiolytic (see, for example, U.S. Pat. No. 5,145,866; and Kehne et al., Eur. J. Pharmacol., 1991, 193, 283) effects, and the compounds of the present invention may accordingly be useful in the management of pain and anxiety.
Compounds possessing functional antagonist properties for the NMDA receptor complex are stated in WO-A-91/19493 to be effective in the treatment of mood disorders, including major depression, bipolar disorder, dysthymia and seasonal affective disorder (cf. also Trullas and Skolnick, Eur. J. Pharmacol., 1990, 185, 1). The compounds of the present invention may consequently be of benefit in the treatment and/or prevention of such disorders.
The association of NMDA receptor antagonists with regulation of the dopaminergic system has recently been reported (see, for example, Werling et al., J. Pharmacol. Exp. Ther., 1990, 255, 40; Graham et al., Life Sciences, 1990, 47, PL-41; Hutson et al., Br. J. Pharmacol., 1991, 103, 2037; and Turski et al., Nature (London), 1991, 349, 414). This suggests that the compounds of the present invention may thus be of assistance in the prevention and/or treatment of disorders of the dopaminergic system such as schizophrenia and Parkinson's disease.
It has also been reported recently (see Lauritzen et al., Journal of Cerebral Blood Flow and Metabolism, 1991, vol. 11, suppl. 2, Abstract XV-4) that NMDA receptor antagonists block cortical spreading depression (CSD), which may thus be of clinical importance since CSD is a possible mechanism of migraine. The class of substituted 2-amino-4-phosphonomethylalk-3-ene carboxylic acids and esters described in EP-A-0420806, which are stated to be selective NMDA antagonists, are alleged thereby to be of potential utility in the treatment of inter alia migraine.
Excitatory amino acid receptor antagonists, including inter alia antagonists of NMDA receptors, are alleged in EP-A-0432994 to be of use in suppressing emesis.
Recent reports in the literature have also suggested a link between the neurotoxicity of certain viruses and the deleterious effects of these viruses on an organism caused by the potentiation of neurotransmission via excitatory amino acid receptors. By virtue of their activity as antagonists of NMDA receptors, therefore, the compounds of the present invention may be effective in controlling the manifestations of neuroviral diseases such as measles, rabies, tetanus (c

REFERENCES:
patent: 4006148 (1977-02-01), Wehrmeister
patent: 5348962 (1994-09-01), Kulagowski et al.
Stadlbauer, W., Montshefte fur Chemie, vol. 113, pp. 751-760, 1982.
Stadlbauer, W., Vestn. Slov. Kem. Drus., vol 33(3), pp. 271-281, 1986.
Chemical Abstracts 71:124273, 1969, abstract of JP 44016373, published Jul. 1969.
Chemical Abstracts 95:115244, 1981, abstract of an article by Stadlbauer, published vol 36B(6), pp. 739-744, 1981.
Chemical Abstracts 111:39201, 1988, abstract of JP 63295561, published Dec. 1988.
J. Chem. Soc. 1929, p. 2911, "Compounds of the Thioparaldehyde Type Derived from Chloral" by F. D. Chattaway and E. G. Kellett.
Monatsh. Chem., 1982, vol. 113, p. 751, "Isoquinolino[4,3-c]quinolines from Phenylmalonylheterocycles" by W. Stadlbauer and T. Kappe.
Vestn. Slov. Kem. Drus. vol. 33, No. 3, (1986), pp. 271-281, "Syntheses of Benzo-alpha and Benzo-gamma-carbolines via Azidoquinolines", by W. Stadlbauer and T. Kappa.
J. Heterocyclic Chem., vol. 26, pp. 281-284, (1989) "The Synthesis of Benzofuroquinolinws. IV." by S. Yamaguchi et al.
S. Yamaguchi, et al. Journal of Heterocyclic Chemistry, vol. 26, pp. 281-284, Mar.-Apr. 1989.

Affiliated with

Also associated with

Rating

Quinolone derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Quinolone derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Quinolone derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2203675