Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-01-21
2001-01-30
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S401000, C424S436000, C424S451000, C424S459000, C424S461000
Reexamination Certificate
active
06180661
ABSTRACT:
INTRODUCTION
The PCT/CH97/00168 application of Apr. 28, 1997 (EPA 97'917'205-3) describes ultramicroemulsions from spontaneously dispersible concentrates comprising esters with bioflavonoid compounds having antitumor, antiviral, virucidal and/or antiparasitic efficacy. Thanks to the demonstrated solubilization of the active principles, in the form of thermostable, oil-in-water emulsions possessing very small micelles in the lowest nanosize region, an excellent bioavailability can be achieved for them. In the course of an intensive elaboration of the properties of this class of compounds, it was found that surprisingly also the glycoside peresters of the studied bioflavonoids have comparative pharmacological properties, provided that they are also formulated correspondingly. In such manner they can be used for curative as well as preventive purposes. Because they are non-toxic and yet highly active, members of this group of natural agents, which up-to-now is only scarcely investigated, these findings can be instrumental in opening a broad therapeutic window. The application of the fatty-tail principle for the esterification and the incorporation of the newly obtained glycoside esters into inventive, spontaneously dispersible concentrates form a systematic two step-approach—the extension of a procedure which has already been described in principle in the Swiss patent CH 683'426 (U.S. Pat. No. 5,593,691) and in the CH patent application 2239-95 (PCT/CH96/00280; EPA 96'925'634-6). The subject of the present invention consequently are Flavonol-glycoside peresters as characterized hereafter, their incorporation into pharmaceutically practicable application forms, as well as their use as medicaments having efficacy against tumors, eczemae, psoriasis, viral and parasitic infections and metabolic disorders.
DESCRIPTION OF THE INVENTION
1.0 Definition of Scope
Flavonol-Glycoside-Peresters, as the term is used in this invention, comprise the following compounds:
1. QUERCETIN (R
1
-R
5
=H); Merck-Index 11.8044
2. SPIRAEOSIDE (R
1
, R
3
-R
5
=H; R=Glucose)
4
′-&bgr;-D-Glucopyranosidoquercetin
3. ISOQUERCETIN (R
2
-R
5
=H; R=hu
1
=l =Glucose) 3-&bgr;-D-Glucopyranosidoquercetin
4. QUERCITRIN (R
2
-R
5
=H; R=hu
1
=l =Rhamnose); Merck-index 11.8047 3-&agr;-L-Rhamnopyranosidoquercetin; Merck-index 11.8044
5. RUTIN (R
2
-R
5
=H; R=hu
1
=l =Rutinose); Merck-index 11.8276/77 3-[&agr;-L-Rhamnopyranosil (1→6)-&bgr;-glucopyranosil]-quercetin=3-&agr;-L-Rutinosylquercetin
6. ERIODICTYOL (R
1
-R
4
=H); Merck-index 11.3616
7. ERIODICTIN (R
1
, R
2
, R
4
=H; R=hu
3
=l =Rhamnose) 7-&agr;-L-Rhamnopyranosido-eriodictyol
8. HESPERIDIN (R
2
, R
4
=H; (R
1
=CH
3
; R
3
=Rutinose) 7-&bgr;-Rutinosyl-4′-methyl-eriodictyol; Merck-Index 11.4591
whereby all R=H stand for a saturated or unsaturated carbonic acid of the type C
6-22
alkyl, C
6-22
alkenyl or C
6-22
alkapolyene.
1.1 Foundations
A selected number of derivatives of QUERCETIN, produced according to formula (I),1 with the glycosides 2, 3, 4, 5, and of its biogenetic precursor ERIODICTYOL (II),6 produced with the glycosides 7 and 8, was made the subject of the present investigation. It can firstly be said that these compounds widely occur in dicotyledones (see the tables 8.15 and 11.1 in “The Flavonoids”, Ed. J. B. Harborne, T. J. Mabry, H. Mabry, Academic Press, New York 1975) and are, in part at least, easily accessible. A second reason is that many of them have quite thoroughly been studied also in medicine (cf. V. Cody, E. Middleton, J. B. Harborne: “Plant Flavonoids in Biology and Medicine”, A. R. Liss, New York, 1986). Note in particular, that the compounds 4, 7 and 8 are components of the once intensely investigated substance “Vitamin P” (the permeability vitamin); see H. Vogel: “Chemie und Technik der Vitamine”, Enke, Stuttgart, 1940. See also H. Wagner in “Recent Advances in Phytochemistry”, Vol. 12, p. 589; Ed. T. Swain, J. B. Harborne, C. F. VanSumere; Plenum Press, New York, 1979. Cf. further Jirina Spilkov{acute over (a)} and Josef Hubik: Biologische Wirkungen von Flavonoiden. Pharmazie in unserer Zeit, January 1988, pp.1-9; Apr. 1992, pp. 174-182.
1.2 Significance of the Appropriate Solubilization of the Active Principles
In CASE CH-2088/95; PCT/CH97/00168 of Apr. 28, 1997 it was demonstrated for selected bioflavonoid esters that the application of the fatty-tail principle to the formation of derivatives leads to important physicochemical changes in their properties, and particularly to a strongly enhanced lipophilic character, coupled with a noteable depression of the melting point (if compared with the starting material). These properties facilitate emulsification and render aqueous ultramicroemulsions of very good stability. As a consequence, the targeted delivery (i.e. the bioavailability) and hence also the bioreactivity of the inventive agents are also decisively potentiated.
1.3 Production of the Peresters
The new procedure is being applied with naturally occurring Flavonolglycosides, which can be found in many plants. The glycoside perester compounds corresponding to the formulae (III) and (IV):
can be prepared in accordance with the following procedures:
1.31 Fatty Acid Esters of Spiraeoside, Conforming to Formula (I), 2
Spiraeoside is a flavonolglycoside, which occurs with ca. 1.2% in the dried leaves of the flowers of
Spiraea ulmaria
L., sive
Filipendula ulmaria
(L.) Maxim. It was discovered by E. Steinegger and P. Casparis [Pharm. Acta Helv. 1945, 20, 154, 174]; later investigations revealed its existence in many plants, particularly in species, which since ancient times were known and used in popular medicine, such as, e.g., in a proportion of 1% in onion peels (
Allium cepa
L.) [K. Hermann, Naturwiss. 1956, 43, 158; Arch. Pharm. 1958, 291, 238]; of 3% in dried flowers of
Hamamelis japonica
S. & Z. [L. Hörhammer and R. Griesinger, Naturwiss. 1959, 46, 427], in the seeds of horse-chestnuts
Aesculus hippocastanum
L. [J. Wagner, Naturwiss. 1960, 47, 158], in the leaves of diverse kinds of hamamelidaceae [K. Egger and H. Reznik, Planta, 1961, 57, 239] and in the flowers of gorse (
Ulex europaeus
L. [J. B. Harborne, Phytochem. 1962, 1, 203].
Newer publications mention the presence in flowers of gardening hybrids of Fuchsia [Y. Yasaki, Botanical Magazine (Tokyo) 1976, 89, 45], as well as in numerous hybrids of gardening roses [K. Nayeshiro and C. H. Eugster, Helv. Chim.Acta 1989, 72, 985]. In the last named cases, spiraeoside contributes decisively to the stabilization of the anthocyanine complexes, which are responsible for colouring.
Despite the general presence of spiraeoside in medicinal plants, the compound has rarely been studied scientifically for its role in traditional popular healing, and no effort was made so far to investigate the pharmaceutical properties of the pure substance.
The chemical structure of spiraeoside as 4′-&bgr;-D-Glucopyranosylquercetin was determined by E. Steinegger et al. (loc.c.) and by L. Hörhammer and R. H{umlaut over (a)}nsel, Arch.Pharm. 1954, 287, 36, with the help of classical methods. The analytical control, employing modern equipment and methods, was carried out in connection with the purity assay for the freshly isolated starting material which was then esterified as described in the present invention. It confirmed the chemical structure as given in formula (V):
Sufficient quantities of (V) can be obtained from the indicated sources by relatively simple extraction and enrichment steps. In the present case, the commercially available drug ‘Flos Spiraeae ulmariae’ was processed. Following processes of mild extraction, separation, column chromatography and cristallisation, compound (V) was isolated and subsequently esterified using a fatty acid chloride, in order to obtain compound (VI). Of importance is the enhanced stability
Eugster Carl
Eugster Conrad Hans
Foley & Lardner
Marigen S.A.
Wilson James O.
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