1995-02-07
1998-01-20
Bond, Robert T.
Tools
546 23, A61K 31695, C07F 960
Patent
active
057101396
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This is a 371 of international application PCT/SE94/01211 with an international filing date of Dec. 16, 1994, claiming priority to Swedish applications 93 04 269-5 (filed Dec. 22, 1993); 94 00 968-5 (filed Mar. 23, 1994) and 94 02 122-7 (filed Jun. 16, 1994).
FIELD OF THE INVENTION
The present invention relates to new quinoline compounds, to methods for their preparation, their use, and pharmaceutical compositions thereof. The compounds are antagonists of N-methyl-D-aspartate (NMDA) receptors and are useful in the treatment of disorders known to be responsive to blockade of the NMDA excitatory amino acid receptor. Accordingly they are especially useful in the treatment of disorders such as pain, anxiety, and cerebral ischemia and as an anaesthetic.
BACKGROUND OF THE INVENTION
The endogenous acidic amino acids, L-glutamate and L-aspartate, have been established as major excitatory neurotransmitters. The action of these excitatory amino acids is mediated by several distinct receptor subtypes of which one is the N-methyl-D-aspartate (NMDA) receptor. Excessive activation of the NMDA receptor complex is implicated in a number of neuropathological conditions and hence antagonists of this receptor complex have a potential for providing new therapeutic agents. In animal models of human disorders it has been shown that certain known NMDA antagonists have anticonvulsant activity cf. e.g. Lehmann et al. J. Pharmacol. Exp. Therap., 246, 65 (1988). This implicates the usefulness of NMDA antagonists as antiepileptic agents. Known NMDA antagonists also give protection against neuronal cell death caused by excessive stimulation cf. Boast et al. Brain Res., 442, 345 (1982). Hence, these agents may be used in the treatment of ischemic and hypoxic conditions and also of neurodegenerative disorders e.g. Alzheimer's disease. By intrathecal injection known NMDA antagonists have exhibited analgetic activity cf. Cahusac et al. Neuropharmacology, 23, 719 (1984). The antagonists may also be beneficial in the treatment of migraine, anxiety, hearing loss, motor neuron diseases, trauma from infections and illness linked to lutenizing hormone secretion. NMDA antagonists with an aryl-spaced phosphono .alpha.-amino acid structure have been described in e.g. J. Med. Chem., 32, 1580 (1989) and in J. Med. Chem., 36, 331 (1993).
OUTLINE OF THE INVENTION
The present invention is concerned with a group of novel NMDA antagonists, methods to prepare them, pharmaceutical compositions containing them and therapeutic use of the antagonists to prevent and/or relieve the physiological effects induced by overstimulation of excitatory amino acid receptors of the nervous system.
The novel compounds of the invention exhibit the following structural formula I ##STR2## in which m is 0,1 or 2; n is 1,2 or 3; and R.sup.1 and R.sup.2 are, independently and being the same or different, hydrogen, C.sub.1 -C.sub.7 alkyl, C.sub.2 -C.sub.7 alkenyl, C.sub.4 -C.sub.7 alkadienyl, C.sub.6 aryl, C.sub.6 aryl-C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.1 -C.sub.7 alkanoyl, C.sub.1 -C.sub.7 alkanoyloxy, C.sub.6 aroyl, C.sub.6 aroyloxy, C.sub.6 aryl-C.sub.1 -C.sub.7 alkanoyl, C.sub.1 -C.sub.7 alkoxycarbonyl, C.sub.6 aryl-C.sub.1 -C.sub.7 alkoxycarbonyl, C.sub.1 -C.sub.7 alkylthio, trifluoromethyl, trifluoromethoxy, C.sub.1 -C.sub.7 alkylsulfonyl-amino, C.sub.1 -C.sub.7 alkylamino, C.sub.1 -C.sub.7 alkanoylamino, nitro, halogen, or R.sub.1 and R.sub.2 are taken together, C.sub.1 -C.sub.7 alkylene, C.sub.2 -C.sub.7 alkenylene or C.sub.4 -C.sub.7 alkadienylene; and the pharmaceutically acceptable esters and salts, including hydrates, of compounds according to the formula (I).
Preferred compounds of the present invention are compounds according to the formula (II) ##STR3## wherein R.sup.1 and R.sup.2 are as defined above.
The compounds of the invention are .alpha.-amino acid derivatives and thus the compounds of the invention include not only the individual enantiomers, but mixtures of enantiomers, including racemic
REFERENCES:
patent: 5118675 (1992-06-01), Jirkovsky et al.
patent: 5124319 (1992-06-01), Baudy et al.
patent: 5217963 (1993-06-01), Hutchison et al.
Baudy, Reinhardt B. et al. "Potent Quinoxaline-Spaced Phosphono .alpha.-Amino Acids of the AP-6 Type as Competitive NMDA Antagonists: Synthesis and Biological Evaluation," J. Med. Chem. 36:331-342 (1993).
Bigge, Christopher F. et al., "Exploration of Phenyl-Spaced 2-Amino-(5-9)-phosphonoalkanoic Acids as Competitive N-Methyl-D-aspartic Acid Antagonists," J. Med. Chem. 32:1580-1590 (1989).
Boast, Carl A. et al., "The N-methyl-D-aspartate antagonists CGS 19755 and CPP reduce ischemic brain damage in gerbils," Brain Res. 442:345-348 (1988).
Cahusac, P.M.B. et al., "The Behavioural Effect of an N-Methylaspartate Receptor Antagonist Following Application to the Lumbar Spinal Cord of Conscious Rats," Neuropharmacology 23:719-724 (1984).
Lehmann, J. et al., "CGS 19755, a Selective and Competitive N-Methyl-D-Aspartate-Type Excitatory Amino Acid Receptor Antagonist," J. Pharmacol. Exp. Therap. 246:65-75 (1988).
Astra AB
Bond Robert T.
Sanzo Michael A.
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