Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-24
1996-07-16
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 548200, 548518, C07D40306, C07D41706, A61K 3140, A61K 31425
Patent
active
055367372
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP93/01687 filed Nov. 17, 1993.
TECHNICAL FIELD
The present invention relates to a novel compound having a prolyl endopeptidase inhibitory activity, which is used in the medical field.
BACKGROUND ART
With the advent of an aging society, the problem of the medical care of senile citizens has been drawing attention. Above all, senile dementia has become a serious social problem, and many developments have been made in an attempt to provide new pharmaceuticals to cope with the situation. The conventional therapeutic agents for amnesia and dementia have been named obscurely as cerebral circulation-improving agents, cerebral metabolism activator or cerebral function-improving agents according to their action mechanisms. While they are effective for the improvement of peripheral symptoms such as depression, emotional disturbances, abnormal behavior, etc., they do not show definite effects on the central symptoms of dementia, such as memory disorder, disorientation and the like. Thus, the development of pharmaceutical agents which can provide dependable action and effects on these symptoms is desired.
Prolyl endopeptidase; EC, 3.4.21.26 is known to act on peptides containing proline and to specifically cleave the carboxyl side of the proline. Further, this enzyme vasopressin which is presumably concerned with learning and memory process, to decompose and inactivate same.
In view of the foregoing findings, a compound possessing specific inhibitory activity on this enzyme is expected to suppress decomposition and inactivation of vasopressin, etc., thus suggesting a potential application thereof to the treatment and prevention of amnesia and dementia, as a pharmaceutical agent which directly acts on the central symptoms of dementia [see Seikagaku, 55, 831 (1983); FOLIA PHARMACOL. JAPON, 89, 243 (1987); and J. Pharmacobio-Dyn., 10, 730 (1987)]. It is also expected that such a compound suppresses decomposition and inactivation of hormones and neurotransmitters such as TRH, substance P, neurotensin etc., thereby improving various symptoms caused by the decomposition and inactivation of these substances. Recent studies have revealed that beta amyloid protein plays a substantial and important role in the onset of Alzheimer's disease by the neorotoxic action thereof in in vitro and in vivo tests. Based on the hypothesis that prolyl endopeptidase is an enzyme for cleaving out a beta amyloid from an amyloid precursor protein (FEBS Lett., 260, 131-134 (1990)] and the experimental fact that the neurotoxic action of beta amyloid protein is suppressed by substance P [Proc. Natl. Acad. Sci. USA, 88, 7247-7251 (1991)], a prolyl endopeptidase inhibitor is considered to become an effective medicine for Alzheimer's disease.
There have been conventionally attempted to develop prolyl endopeptidase inhibitors and various proline derivatives are described and disclosed in, for example, Japanese Patent Unexamined Publication Nos. 148467/1987, 42475/1989, 6263/1989, 230578/1989 and 28149/1990.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel compound having a specific and strong prolyl endopeptidase inhibitory activity.
Another object of the present invention is to provide a pharmaceutical composition useful as a prolyl endopeptidase inhibitor, specifically a pharmaceutical agent which directly acts on the central symptoms of dementia, i.e., a medicament effective for the prophylaxis and treatment of amnesia and dementia. The compound of the present invention is also expected to be useful as a therapeutic agent for Alzheimer's disease.
Based on the aforementioned findings, the present inventors have conducted intensive studies in an attempt to find a compound having, as a fragment, a dipeptide residue formed by amino acids, particularly by proline residue and thioproline residue in combination, and which specifically and strongly inhibits the action of prolyl endopeptidase, and found that the novel compound of the formula [I] to be mentioned later has a specific
REFERENCES:
Database WPI, Derwent Publications Ltd., Week 9337, Abstract of JP-A-5 201 970.
Abe Hiroyuki
Akamatsu Minoru
Kobayashi Koji
Kogayu Motohiro
Toide Katsuo
Gerstl Robert
Japan Tobacco Inc.
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