Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-01-24
2001-11-06
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S027000, C514S860000, C514S861000, C514S863000, C514S864000, C536S004100, C536S018100
Reexamination Certificate
active
06313099
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain glycoside containing compounds which are indicated as having an inhibiting effect on cell proliferation. More specifically the invention relates to sesquiterpene glycosides having a cytostatic effect on cells, and their use as cytostatic agents, in particular in the treatment of psoriasis.
BACKGROUND OF THE INVENTION
Crude Calendula plant extracts have been used in medicinal folklore for the treatment of several ailments for centuries. Such extracts have, for example, been used as or in anti-inflammatory medicaments and the like.
International patent application WO 91/15218 teaches a therapeutic composition against psoriasis comprising as active ingredient a solvent extract of at least six different herbs. This application teaches that marigold decoctions can be used against gastric and intestinal ulcers externally as well as for packing slowly healing wounds and ulcers. Nowhere is it stated that marigold extract is in fact used by itself as the active component in a therapeutical composition against psoriasis.
Pizza C., and de Tommasi N., Phytochemistry, Vol. 27, number 7, pp 2205-2208 (1988) teaches the isolation of and structure of a sesquiterpene glycoside from Calendula Arvensis. It is stated that Calendula Arvensis L. (Compositae) is an herbaceous plant used in Italian folk medicine as an anti-inflammatory and anti-pyretic remedy. There is no suggestion that the sesquiterpene glycosides obtained had cytostatic activity or could be used in the treatment of psoriasis.
Mascolo N. et al., Phytotherapy Research, Vo. 1, pp 28-31 (1987) teaches that marigold extract is known for anti-inflammatory activity. There is no mention of marigold extract being used as an anti-psoriatic agent.
Gracza L. Planta Medica 53, page 227 (1987) discloses various oxygen containing terpene derivatives from Calendula Officinalis. The uses of these are indicated for leukorrhoea and trichomonacide activity. There is no mention of using the terpene derivatives as anti-psoriatic agents.
Fazakas B. and Rácz, G. Farmacia Vol. XIII, number 2, page 91 (1965) also teaches that extracts from the flowers of Calendula Officianalis are employed in traditional herbal medicine for leukorrhoea (excessive fluor albus) and showed a good trichomonacide activity.
Gracza L. and Szász K. Acta Pharm. Hung. 38, pp 118-125 (1968) reports on a chemical analysis of the petals of marigold (Calendula Officianalis) with the aim of separating and identifying the solution or solutions which are responsible for the trichomonacide effect reported by Fazakas and Rácz (supra). The most active liquid compounds isolated were described as terpenic alcohols and terpenic lactons according to spectroscopic data.
Jakupovic et al. Planta Medica 54 (3) pp 254-256 (1988) teaches the extraction and isolation of five sesquiterpene glycosides from
Calendula persica
. There is no mention of potential or actual uses for the extracted and isolated molecules.
Ahmed A Ahmed et al., Journal of Natural Products Vol. 56, number 10, pp 1821-1824 (1993) relates to extraction products from
Calendula arvensis
. The products are described as four new sesquiterpene glycosides and three known ones. There is no reference to possible uses therefore.
EP 364442 B1 describes a therapeutic composition against psoriasis comprising an oil extract of at least three herbs selected from a range of herbs which range may include Calendula. However, it is stated that separate extractions of herbs did not provide a curative effect against psoriasis when used singly. Furthermore, it is stated that decoctions of Calendula per se are used for inter alia gastric and intestinal ulcer treatment. Calendula decoctions are not described as being beneficial for the treatment of skin diseases involving abnormal rates of proliferation of skin cells (e.g. hyperproliferation), in diseases such as psoriasis.
DE 3836519 C2 alleges that a pharmaceutical preparation containing freshly cut composite inflorescences of Calendula Officinalis with milking grease as a salve base is useful in treating psoriasis. However, the composition is described as being able to give rise to allergy which can lead to discontinuation of treatment, and there is no indication of, or the identification of, the active component of the composition. There is no indication of cytostatic activity and furthermore it is not apparent which component or mixture of components in the alleged pharmaceutical preparation based on Calendula Officianalis is/are the active component(s). In addition, there does not appear to be any actual evidence which demonstrates that the composition was employed in the treatment of psoriasis.
Co-pending application PCT/GB96/01792 lists a number of compounds useful in the treatment of psoriasis.
There exists a need for the development of new cytostatic drugs which are effective in combatting the onset, maintenance and/or development of disease involving hyperproliferation of dermis cells, in particular for psoriasis treatment.
SUMMARY OF INVENTION
Objects of the invention will become apparent from the following description and examples.
The present invention relates to certain sesquiterpene glycoside stereoisomers useful in the treatment of disease involving hyperproliferation of dermis cells, in particular, psoriasis.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention there is provided use of a compound of general Formula (I):
wherein R
1
and R
2
are independently selected from H, —OH
and related esters and ethers thereto;
R
3
is selected from —OH,
and related esters and ethers thereto;
R
4
is
R
5
is selected from the group CH
3
, —CHO, —COOH, —CH
2
OH and related esters and ethers thereto; and
R
6
is selected from OH,
in the preparation of a medicament for the treatment of disease involving hyperproliferation of dermis cells.
For the purposes of the present invention “related esters and ethers” refers to all defined esters of R groups mentioned herein and in general to saturated or unsaturated straight- or branched chain C
1
-C
20
carboxy alkyl esterifying acids. Suitable examples include esterifying acids comprising methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and all isomers of pentanyl, pentenyl, hexanyl and hexenyl alkyl groups. Also included within the term “related esters” are aromatic acids such as benzoic acid and cinnamic acid. C
1
-C
20
alkyl ethers comprising straight- or branched-chain alkyl groups as defined for “related esters” above are also encompassed herein.
In a preferred aspect there is provided use of a subset of compounds of Formula (I) as defined above, in the preparation of a medicament for the treatment of disease involving hyperproliferation of dermis cells for example, psoriasis wherein
R
1
and R
2
are independently selected from H and OH (&bgr;OH or &agr;OH);
R
3
is selected from OH,
R
4
is
R
5
is CH
3
; and
R
6
is selected from OH,
There is also provided use of a compound of Formula (I) extractable from a Calendula species in the preparation of a medicament for the treatment of disease involving hyperproliferation of dermis cells, for example, psoriasis wherein
R
1
and R
2
are independently selected from H and OH (&bgr;OH or &agr;OH);
R
3
is selected from OH and (E)-3-methylpent-2-enoate i.e.
R
4
is
R
5
is CH
3
; and
R
6
is OH.
The skilled addressee will also appreciate that groups R
1
, R
2
, R
6
and R
3
may be located in either the axial or equatorial position.
Naturally, the skilled addressee will appreciate that physiologically functional isomers of Formula (I) both those found in Calendula species and synthetically derived isomers therefrom including conformational and constitutional isomers as well as D and L forms of Formula (I) are encompassed by the present invention. Preferably, the fucose component of Formula (I) is D-fucose. Examples of conformational isomers of the invention are encompassed in Formulae (1a) and (1b) as follows:
wherein R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are as defined
Anand Chaman Lal
Gray Alexander Irvine
Habtemariam Solomon
Stimson William Howard
Waterman Peter George
Alston & Bird LLP
Gitomer Ralph
Khare D.
University of Strathclyde
LandOfFree
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