Xanthine derivatives as adenosine A1 receptor antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514262, 544266, 544267, A61K 3152, C07D47301

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active

058407294

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a group of compounds which are xanthine derivatives and which act selectively at adenosine receptors. Adenosine antagonists acting at the A.sub.1 receptor can depolarize postsynaptic neurons and can pre-synaptically enhance the release of a number of neurotransmitters, including acetylcholine, glutamate, serotonin, and norepinephrine, and thus have potential for treatment of cognitive deficits and for cognition-enhancing effects.


BACKGROUND OF THE INVENTION

The profound hypotensive, sedative, antispasmodic, and vasodilatory actions of adenosine were first recognized over 50 years ago. Subsequently, the number of biological roles proposed for adenosine have increased considerably. The adenosine receptors appear linked in many cells to adenylate cyclase. A variety of adenosine analogues have been introduced in recent years for the study of these receptor functions. Alkylxanthines, such as caffeine and theophylline, are the best known nonselective antagonists of adenosine receptors.
Adenosine represents a general regulatory substance, since no particular cell type or tissue appears uniquely responsible for its formation. In this regard, adenosine is unlike various endocrine hormones. Nor is there any evidence for storage and release of adenosine from nerve or other cells. Thus, adenosine is unlike various neurotransmitter substances; it appears to be a neuromodulator rather than a neurotransmitter.
Although adenosine can affect a variety of physiological functions, particular attention has been directed over the years toward actions which might lead to clinical applications. It has now been recognized that there are not one but at least two classes of extracellular receptors involved in the action of adenosine. One of these has a high affinity for adenosine and at least in some cells couples to adenylate cyclase in an inhibitory manner. These have been termed the A.sub.1 receptors. The other class of receptors has a lower affinity for adenosine and in many cell types couples to adenylate cyclase in a stimulatory manner. These have been termed the A.sub.2 receptors.
The adenosine analogues exhibit differing rank orders of potencies at A.sub.1 and A.sub.2 adenosine receptors, providing a simple method of categorizing a physiological response with respect to the nature of the adenosine receptor. The blockade of adenosine receptors (antagonism) provides another method of categorizing a response with respect to the involvement of adenosine receptors.
Adenosine in the central nervous system (CNS) acts as a neuromodulator exerting its effects via the A.sub.1 and A.sub.2 receptors (G. L. Stiles, TIPS, 12, 486 (1986)). The majority of adenosine receptors is localized in the brain, where A.sub.2 receptors are found in the striatum, while A.sub.1 receptors predominate in the hippocampus and in the cortex (areas involved in learning and memory). In general terms, A.sub.1 receptors cause an inhibition of the release of excitatory as well as of inhibitory neurotransmitters and a postsynaptic decrease of excitability. These effects are G-protein dependent, and they are mediated by an inhibition of adenylate cyclase and of calcium influx and by an increase in potassium efflux (B. B. Fredholm, et al., TIPS, 9, 130 (1988)). In turn, A.sub.1 antagonists can be expected to depolarize postsynaptic neurons and to presynaptically enhance the release of various neurotransmitters (e.g. acetylcholine, glutamate, serotonin, and norepinephrine). This action could be of value in treating cognitive deficits such as those associated with Alzheimer's disease, as these transmitters have been implicated in learning and memory, and each of these transmitters is reduced in Alzheimer's disease.
In view of the above, the compounds disclosed herein would be useful as agents for the treatment of cognitive deficit disorders and conditions.


SUMMARY OF THE INVENTION

The present invention relates to compounds having the following general structures: ##STR1## including the (R) and (S) enanti

REFERENCES:
patent: 5047534 (1991-09-01), Peet et al.
patent: 5281607 (1994-01-01), Stone et al.
Schingnitz, G., Selective A.sub.1 -Antagonists For Treatment Of Cognitive Deficits, Nucleosides & Nucleotides, 10(5), 1067-76 (1991).
Kalaria, Biol. Abstr., 89(3):28690 (1989).
Arnsten et al., Psyshopharmacology, vol. 108, pp. 159-169 (1992).
Shimada, Junichi et al., J. Medicinal Chem., 1992, vol. 35, Mar. 1992, pp. 924-930.
Shimada, Junichi et al., J. Medicinal Chem., 1991, vol. 34, Jan. 1991, pp. 466-469.
Peet, Norton et al., J. Medicinal Chem., 1990, vol. 33, No. 12., pp. 3127-3130.

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