Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-10-13
2002-04-23
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C424S195110, C514S278000, C514S221000, C514S090000, C514S303000, C514S326000
Reexamination Certificate
active
06376657
ABSTRACT:
This application is the U.S. national phase of PCT International Application No. PCT/GB98/01100, filed Apr. 15, 1998, which claims priority to South African application No. 97/3201, filed Apr. 15, 1997.
THIS INVENTION relates to steroidal glycosides, to compositions containing such steroidal glycosides and to a new use for these steroidal glycosides and the compositions containing them. The invention further relates to a method of extracting and isolating these steroidal glycosides from plant material, to a method of synthetically producing these steroidal glycosides, and to the products of such an extraction and such a synthesis process.
In a particular application, the invention relates to an appetite suppressant agent, to a process for synthetically producing the appetite suppressant agent, to a process for extracting the appetite suppressant agent from plant material, to an appetite suppressant composition containing the appetite suppressant agent, and to a method of suppressing an appetite.
According to the invention, there is provided a process for preparing an extract of a plant of the genus Trichocaulon or of the genus Hoodia, the extract comprising an appetite suppressant agent, the process including the steps of treating collected plant material with a solvent to extract a fraction having appetite suppressant activity, separating the extraction solution from the rest of the plant material, removing the solvent from the extraction solution and recovering the extract. The extract so recovered may be further purified, eg by way of suitable solvent extraction procedures.
The invention also provides a plant extract made of plants of the group comprising the genus Trichocaulon and the genus Hoodia and having appetite suppressant activity.
The extract may be prepared from plant material such as the stems and roots of said plants of the genus Trichocaulon or of the genus. Hoodia. The genus Trichocaulon and the genus Hoodia include succulent plants growing in arid regions such as are found in Southern Africa. In one application of the invention, the active appetite suppressant extract is obtained from the species
Trichocaulon piliferum
. The species
Trichocaulon officinale
may also be used to provide an active appetite suppressant extract. In another application of the invention, the active appetite suppressant extract may be obtained from the species
Hoodia currorii, Hoodia gordonii
or
Hoodia lugardii
. Bioassays conducted by the Applicant on rats have indicated that certain of the extracts possess appetite suppressant activity.
The plant material may be homogenised in the presence of a suitable solvent, for example, a methanol/methylene chloride solvent, by means of a device such as a Waring blender. The extraction solution may then be separated from the residual plant material by an appropriate separation procedure such as, for example, filtration or centrifugation. The solvent may be removed by means of the rotary evaporator, preferably in a water bath at a temperature of 60° C. The separated crude extract may then be further extracted with methylene chloride and water before being separated into a methylene chloride extract and a water extract. The methylene chloride extract may have the solvent removed preferably by means of evaporation on a rotary evaporator and the resultant extract may be further purified by way of a methanol/hexane extraction. The methanol/hexane extraction product may then be separated to yield a methanol extract and a hexane extract. The methanol extract may be evaporated to remove the solvent in order to yield a partially purified active extract.
The partially purified active extract may be dissolved in methanol, and may be further fractionated by column chromatography, employing silica gel as an adsorption medium and a chloroform/30% methanol mixture as an eluent. A plurality of different fractions may be obtained, and each may be evaluated, by suitable bioassaying procedures, to determine the appetite suppressant activity thereof.
A fraction having appetite suppressant activity may preferably be further fractionated such as by column chromatography using silica gel as an adsorption medium and a 9:1 chloroform:methanol solvent, and the resultant sub-fractions bioassayed for their appetite suppressant activity. A sub-fraction displaying appetite suppressant activity may, if desired, be further fractionated and purified, conveniently using a column chromatographic procedure with silica gel as the adsorption medium and a 9:1 ethylacetate:hexane solvent. The resultant purified fractions may again be evaluated by suitable bioassay procedures for their appetite suppressant activity.
The Applicant has found that at least one such purified fraction has good appetite suppressant activity, and the active principle in the fraction was identified by conventional chemical techniques including nuclear magnetic resonance, and was found to be a compound of the structural formula
In accordance with S.I. nomenclature, the active principle (1) is the compound 3-0-[-&bgr;-D-thevetopyranosyl-(1→4)-&bgr;-D-cymaropyranosyl-(1→4)-&bgr;-D-cymaropyranosyl]-12&bgr;-0-tigloyloxy-14-hydroxy-14&bgr;-pregn-50-en-20-one (C
47
H
74
O
15
M
+
878).
According to another aspect of the invention, there is provided a process for preparing an extract of a plant of the genus Trichocaulon or of the genus Hoodia, the extract comprising an appetite suppressant agent, the process including the steps of pressing collected plant material to separate sap from solid plant material and recovering the sap free of the solid plant material to form the extract.
The extract may be dried to remove moisture, e.g. by spray-drying, freeze-drying or vacuum drying, to form a free-flowing powder.
The invention extends to a composition having appetite suppressant activity comprising an extract as described above.
The composition may be admixed with a pharmaceutical excipient, diluent or carrier and optionally it is prepared in unit dosage form.
The invention also extends to the use of an extract as described above in the manufacture of a medicament having appetite suppressant activity, to an extract as described above for use as a medicament having appetite suppressant activity, and to a method of suppressing an appetite by administering to a human or animal an effective dosage of a composition as described above.
Compound (1) is a novel compound and the invention extends to compound (1) and certain analogues or derivatives of this steroidal trisaccharide having appetite suppressant properties. The molecules chosen as the analogues or derivatives are intended to affect the properties of the steroidal trisaccharide with the aim of increasing the activity of the active ingredient. The following effects were taken into consideration when the analogues were chosen:
(i) Hydrophobic interactions and lipophilicity
Functional group modifications of the active molecule is intended to change the hydrophobicity and lipophilicity of the molecule. Increased lipophilicity has been shown to correlate with increased biological activity, poorer aqueous solubility, increased detergency/cell lysis, increased storage in tissues, more rapid metabolism and elimination, increased plasma protein binding and faster rate of onset of action.
(ii) Electronic properties and ionization constants
Functional group modification of the molecule is also intended to change the acidity and basicity which would have a major role in controlling the transport of the compound to its site of action and the binding at this target site.
(iii) Hydrogen bonding
Functional group modifications of carboxyl and carbonyl groups in the active molecule are intended to change the interactions between the proteins in biological systems and the chemically modified functional groups.
(iv) Steric parameters
The purpose of changing the steric features of the molecule is to increase binding to its receptor and thus increase its biological activity.
The following chemical modifications to the molecule are intended to affect the hydro
Horak Roelof Marthinus
Learmonth Robin Alec
Maharaj Vinesh
Van Heerden Fanie Retief
Vleggaar Robert
CSIR
Gitomer Ralph
Khare Devesh
Morgan & Lewis & Bockius, LLP
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