Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-07
1999-12-14
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142325, 514 81, 5142285, 5142332, 5142248, 544346, 544354, 544356, 544115, 544 81, 544 57, 544 582, 544 586, C07D48704, A61K 31495
Patent
active
060018321
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to therapeutically active heterocyclic compounds, a method of preparing the same, pharmaceutical compositions comprising the compounds, and a method of treating therewith.
More specifically, the invention relates to [1,2,4]triazolo[4,3-a]quinoxalinone derivatives, which are useful in the treatment of any indication caused by hyperactivity of excitatory amino acids.
Various related compounds are known from the prior art.
Thus, EP-A-0040401 generically describes inter alia triazoloquinoxalin-4-ones substituted at the triazolo ring with e.g. an alkyl, acyl or carbalkoxy group. These compounds are claimed to possess useful anti-hypertensive activity.
In U.S. Pat. No. 5,153,196 some excitatory amino acid receptor antagonists and methods for the use thereof are disclosed. The compounds conform inter alia to triazoloquinoxalinones having one substituent being H, alkyl, aromatic or CF.sub.3 at the triazolo ring.
Further, international patent publication No. WO 93/20077 deals inter alia with fused quinoxalinone derivatives optionally substituted in the triazolo-ring with lower alkyl which may be substituted by mono- or di(lower alkyl)amino.
L-glutamic acid, L-aspartic acid and a number of other closely related amino acids have in common the ability to activate neurons in the central nervous system (CNS). Biochemical, electrophysiological and pharmacological studies have substantiated this and demonstrated that acidic amino acids are transmitters for the vast majority of excitatory neurons in the mammalian CNS.
Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases. Thus, known antagonists of excitatory amino acids have shown potent anxiolytic (Stephens et al., Psychopharmacology,90, 143-147, 1985), anticonvulsant (Croucher et al., Science 216, 899-901, 1982) and muscle relaxant properties (Turski et al., Neurosci. Lett. 53, 321-326, 1985).
It has been suggested that accumulation of extracellular excitatory amino acids, followed by overstimulation of neurons, may explain the neuronal degenerations seen in neurological disorders such as amyotrophic lateral sclerosis, Parkinsonism, Alzheimer's disease, Huntington's disease, epilepsy, and deficiencies of mental and motor performance seen after conditions of brain ischemia, anoxia and hypoglycemia or head and spinal cord trauma (McGeer et al., Nature 263, 517-519, 1976; Simon et al., Science 226, 850-852, 1984; Wieloch, Science 230, 681-683, 1985; Faden et al., Science 244, 798-800, 1989; Turski et al., Nature 349, 414-418, 1991). Other possible indications are psychosis, muscle rigidity, emesis and analgesia.
Excitatory amino acids exert their actions via specific receptors located postsynaptically or presynaptically. Such receptors are at present conveniently subdivided into three groups bases on electrophysiological and neurochemical evidence: 1 the NMDA (N-methyl-D-aspartate) receptors, 2 the AMPA receptors, and 3 the kainate receptors. L-glutamic acid and L-aspartic acid probably activate all the above types of excitatory amino acid receptors and possibly other types as well.
The above mentioned classification of excitatory amino acid receptors into NMDA, AMPA, and kainate receptors is based primarily on the following electrophysiological and neurochemical findings.
1) N-methyl-D-aspartate (NMDA) receptors exhibit high selectivity for the excitant NMDA. Ibotenic acid, L-homocysteic acid, D-glutamic acid and trans-2,3-piperidine dicarboxylic acid (trans-2,3-PDA) exert a strong to moderate agonist activity on these receptors. The most potent and selective antagonists are the D-isomers of the 2-amino-5-phosphonocarboxylic acids, e.g. 2-amino-5-phosphono-valeric acid (D-APV) and 3-[(.+-.)-2-carboxy-piperazin-4-yl]-propyl-1-phosphonic acid (CPP), while moderate antagonist activity is shown by the D-isomers of long chain 2-amino dicarboxylic acids (e.g. D-2-amino-adipic acid) and long chain diaminodicarboxylic acids (e.g. diaminopimelic acid). The NM
REFERENCES:
patent: 5153196 (1992-10-01), McQuaid et al.
patent: 5559106 (1996-09-01), Jacobsen et al.
P.L. Herrling, Synaptic Physiology of Excitatory Amino Acids, pp. 202-208 Arzeim-Forsch Drug Res. vol. 42, No. 2a (1992).
Ford John M.
Novo Nordiskals
Rozek Carol E.
Zelson Steve T.
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