Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-08-11
2002-09-03
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S212010, C514S218000, C514S227500, C514S231200, C514S252100, C514S252110, C514S256000, C514S277000, C514S315000, C514S365000, C514S374000, C514S406000, C514S408000, C514S691000, C540S544000, C540S575000, C540S579000, C540S612000, C544S059000, C544S107000, C544S242000, C544S358000, C544S410000, C548S146000, C548S235000, C548S335100, C548S373100, C548S565000, C548S579000, C548S950000, C548S366700, C548S374100, C536S063000, C536S063000
Reexamination Certificate
active
06444662
ABSTRACT:
SUBJECT OF THE INVENTION
The subject of the invention is the provision of stable salts of hyperforin and adhyperforin which are capable of pharmacological activity as they are or by release of the hyperforin or adhyperforin. A fundamental aspect of the invention relates to the provision of a method of enriching or purifying hyperforin and adhyperforin from extracts of St. John's wort by means of precipitation in the form of these stable salts. Another especially important subject of the invention comprises the provision of new active substances for controlling Alzheimer's disease (hereinafter abbreviated to “AD”) by treating the cause of the disease.
A further important aspect of the present invention relates to the provision of active-substance combinations which can be used to treat the cause of AD, and at the same time eliminate, considerably improve, or at least halt the progression of psychopathological concomitant phenomena which frequently arise in association with AD, such as anxiety, depressive illnesses, and cognitive disturbances.
BACKGROUND OF THE INVENTION
The amyloid peptide A&bgr;1-42, a processed product of Alzheimer Precursor Protein APP, plays a central role in the occurrence of AD [Lamb, B. T.: Presenilins, amyloid-&bgr; and Alzheimer's Disease. Nature Med. 3 (1997) 28-29. Selkoe, D. J.: Alzheimer's Disease: Genotypes, Pheno-type, and Treatments. Science 275 (1997) 630-631]. This hypothesis is supported by the following experimental findings:
APP Missense mutations (patients with familial AD) lead to an increased release of A&bgr;1-42 [Scheuner, D. et al.: Secreted amyloid &bgr;-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nature Med. 2 (1996) 864-870].
Mutations in presenilin 1 and presenilin 2 (patients with familial AD) similarly lead to an increase in released A&bgr;1-42 [Scheuner, D. et al]. Transgenic mice, which overexpress mutated APP, develop age-dependent deposits of A&bgr; and show cognitive disturbances [Games, D. et al.: Alzheimer-type neuropathology in transgenic mice overexpressing V717F &bgr;-amyloid precursor protein. Nature 373 (1995) 523-527. Hsiao, K. et al.: Correlative memory deficits, A&bgr; Elevation, and Amyloid Plaques in Transgenic Mice. Science 274 (1996) 99-102].
The proteolytic cleavage of the pathogenic A&bgr; from the Alzheimer Precursor Protein APP is mediated by &bgr;- and &ggr;-secretase, the molecular identity of which is unknown. &agr;-Secretase processes APP to a soluble form (sAPP) and a cytoplasmatic residue. The cleavage of &agr;-secretase lies within A&bgr;, with the result that in this case no pathogenic A&bgr; arises. The molecular identity of &agr;-secretase is similarly unknown.
&agr;-Secretase is stimulated by acetylcholine, mediated by the muscarinic receptors m1 and m3 [Nitsch, R. M. et al.: Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science 258 (1992) 304-307]. The cellular mediator is protein kinase C (“PKC”). This is also confirmed by experiments which, following direct stimulation of PKC by phorbol ester, reach the same result [Buxbaum, J. D. et al.: Processing of Alzheimer beta/A4 amyloid precursor protein: Modulation by agents that regulate protein phosphorylation. Proc. Natl. Acad. Sci. USA 87 (1990) 6003-6006].
Tacrine, the most successful therapeutic agent to date against AD is an acetylcholine inhibitor [Giacobini, E.: Cholinomimetic therapy of Alzheimer disease: Does it slow down deterioration? In Recent Advances in the Treatment of Neurodegenerative Disorders and Cognitive Dysfunction, Int. Acad. Biomed. Drug Res. 7 (1994) 51-57. Racagni, G. et al., eds. Basel: Karger].
This may be interpreted as indirect stimulation of &agr;-secretase by the following signal chain: Tacrine inhibits acetylcholinesterase. The concentration of acetylcholine is thereby increased. Acetylcholine activates the PKC via the muscarinic receptors m1 and m3. By this means the activity of &agr;-secretase is increased. In consequence the quantity of pathogenic A&bgr; is lowered.
From these findings it can be concluded that selective activation of PKC can be an effective therapeutic starting point to inhibiting the production of amyloidogenic A&bgr; and thus to the treatment of AD. Since, of all 11 PKC isoenzymes, the &ggr;-form is the only sub-type to be expressed exclusively in neuronal cells, substances which stimulate PKC-&ggr; represent a new starting point to the therapy of AD. Moreover, all substances or processes which stimulate &agr;-secretase or inhibit &bgr;- and &ggr;-secretase are suitable for preventing the release of pathogenic A&bgr; and thus for treating the cause of AD.
STATE OF THE ART
The phloroglucin derivative hyperforin is one of the principal ingredients in fresh St. John's wort. It is associated with its homologue adhyperforin in a lower concentration. As both substances are highly unstable to light and the influence of air, their content declines even when the fresh plant is dried. By fast and careful drying followed by suitable extraction methods, extracts with a content of about 3-60% hyperforin/adhyperforin can be obtained [DE 19619512 C1].
However, without addition of appropriate stabilisers, hyperforin is not stable, and can therefore be obtained and stored in an enriched or pure form only by use of expensive techniques.
Reference has already been made to the importance of hyperforin for achieving the antidepressant efficacy of St. John's wort extracts in EP-A-0599307. Since then it has been scientifically proven that, on the basis of its pharmacological profile, hyperforin exerts a considerable influence in the medical treatment of depression and other serotonin-dependent diseases [S. S. Chatterjee et al., hyperforin and hypericum extract, Interactions with some Neurotransmitter Systems (SL-82), 2nd Intern. Congress on Phytomedicine, Sep. 11-14, 1996, Munich. See also: Pharmacopsychiatry 1998, 31 Suppl. I, 1-60].
Alzheimer's dementia (AD) is a serious disease of gradual onset which affects a considerable proportion of the population especially the elderly. It is characterised by initial forgetfulness, then increasing memory disturbances and losses of other cognitive abilities. It concludes with complete mental degeneration and loss of personality, and takes an ultimately fatal course. To date, no satisfactory, cause-orientated therapy for AD is available [K. Mendla, Die Alzheimer-Krankheit: Neue Ansätze in der Pharmakotherapie (1996). Pharm.Ztg. 141, 351-356].
TECHNICAL PROBLEM
The technical problem underlying the invention thus consists in the fact that, firstly, there is no known technically satisfactory method for obtaining and stabilising pure or greatly enriched hyperforin and adhyperforin, severely impeding the isolation, storage and use of these substances; secondly, there is a deficiency of active substances for the cause-orientated therapy of Alzheimer's disease, resulting in massive financial outlays within the social services. The problem of the invention is to help eliminate these defects.
SOLVING THE TECHNICAL PROBLEM
This problem is resolved according to the invention by
the new salts of hyperforin and adhyperforin according to patent claims
1
to
5
;
the method of manufacturing these salts according to Claim
6
;
the method of enriching or purifying hyperforin and adhyperforin in the form of these salts according to Claims
7
and
8
;
the use of these salts for maintaining stable stocks of hyperforin, adhyperforin and their mixtures according to Claim
9
;
the pharmaceutical preparation according to Claim
10
, and
the new use of hyperforin, adhyperforin and their mixtures as medicinal products for the treatment of AD (2
nd
medical indication).
It was surprisingly found that the instability of hyperforin or of adhyperforin can
Chatterjee Shyam Sunder
Erdelmeier Clemens
Klessing Klaus
Marme Dieter
Schächtele Christoph
Frost Brown Todd LLC
McKenzie Thomas
Willmar Schwabe GmbH & Co.
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