Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-06-09
2004-11-02
Owens, Amelia A. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S025000, C549S275000, C536S004100
Reexamination Certificate
active
06812245
ABSTRACT:
BACKGROUND OF THE INVENTION
Cervinomycins (EP00246091; EP0054801; J.Antibiot. 1982, 35, 645-652; J.Am.Chem.Soc. 1986, 108, 6088-6089, J.Antibiot. 1987, 40, 301-308; J.Antibiot. 1994, 47, 342-348; synthetic derivatives J.Antibiot. 1986, 39, 1636-1639 and EP0259496) and citreamicins (J.Antibiot. 1989, 42, 846-851; J.Antibiot. 1990, 43, 504-512; EP0405151) are members of a family of naturally occurring antibiotics, all of which posses a xanthone based unit embedded within a larger polycyclic framework.
These compounds have demonstrated potent activity against aerobic and anaerobic bacteria and mycoplasma, but only cervinomycins have been described to display antitumour activity (EP0246091).
We have recently described also the antitumour activity of citreamicins in PCT/GB01/02148.
New anticancer drugs are still needed for treatment against many human tumours. Accordingly, a goal of the present invention is to provide new antitumour agents with a polycyclic xanthone structure.
Another objective of this invention is to provide pharmaceutical compositions for administering to a patient in need of treatment an active compound.
Yet another object is directed to the production of the polycyclic xanthone by controlled aerobic fermentation using a biologically pure culture of an organism in appropriate nutrient media, also to provide with methods for its recovery and concentration from the fermentation broth, and to the final purification of the active compound.
SUMMARY OF THE INVENTION
This invention provides a new class of active xanthone compounds founded on the discovery of a new compound IB-00208 isolated from a bacteria, useful as antitumour medicaments with the formula:
Thus, the present invention provides compounds with the general formula:
where each R
1
is the same or different and can be hydrogen, acyl, alkyl, alkenyl, aryl, benzyl, alkali metal, and/or sugar, and R
2
and R
3
can be hydrogen, alky, or together form an unsaturated bond.
This invention also provides processes for preparing such compounds including a process of obtaining IB-00208.
DETAILED DESCRIPTION OF THE INVENTION
IB-00208 and related compounds exhibits antitumour activity against mammalian tumours, such as human lung carcinoma, human colon carcinoma, human melanoma, etc. Thus, the invention includes a method of treating any mammal affected by a malignant tumour sensitive to them, which comprises administering to the affected individual a therapeutically effective amount of the compound or a pharmaceutical composition thereof.
The present invention also relates to pharmaceutical preparations which contain as active ingredient compound IB-00208 or any of its derivatives, or a pharmaceutical acceptable salt thereof, as well as the processes for its preparation. A pharmaceutically acceptable carrier is employed.
Pharmaceutical compositions are typically formulated from the active compound and include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) in combination with any carrier or other pharmacologically active compounds.
The correct dosage of a pharmaceutical composition of IB-00208 or its derivatives will vary according to the particular compound, formulation, mode of application, and sites of host and tumour being treated.
Others factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
The acyl groups can be aliphatic acyl, aromatic acyl, or mixed aliphatic/aromatic acyl. Thus, for example, they can be of the formula RCO—, where R is an alkyl group, an alkenyl group, an aryl group, an arylalkyl group, or an alkylaryl group. Examples include benzoyl.
The alkyl groups typically have from 1 to 18 carbon atoms. Alkyl groups preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members. The alkyl groups may be straight chain or branched chain.
The alkenyl groups typically have from 1 to 18 carbon atoms. Preferred alkenyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more preferably 2, 3 or 4 carbon atoms. The term alkenyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
The aryl groups can be carbocyclic or heterocyclic, and may have one or more fused rings. The carbocyclic aryl groups typically have 6 or 10 carbon atoms, as in phenyl or naphthyl. Heterocyclic aryl groups typically have 5 to 12 atoms, more usually 4, 5, 6, 10, 11 or 12 atoms, of which there is 1, 2, 3 or more heteroatoms usually chosen from oxygen, sulphur or nitrogen. Suitable heterocyclic aryl groups in the compounds of the present invention include coumarinyl including 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazol.
Notable alkali metals include sodium or potassium.
Sugars employed as substituents are typically mono-, di- or tri-saccharides or saccharide derivatives, prepferably mono- or di-saccharides. Pentose or hexose compounds are preferred. Derivatives include sugar glycosides, N-glycosylamines, O-acyl derivatives, O-methyl derivatives, sugar alcohols, sugar acids, deoxy sugars, and related compounds. Examples include the trimethyldeoxypyranose hexose of IB-00208.
This invention describes a new polycyclic xanthone IB-00208, isolated from the fermentation broth of a microorganism, preferably
Actinomadura
sp. PO13-046, a culture of which has been deposited in the Colección Española de Cultivos Tipo at the University of Valencia, Spain under the accession number CECT 5318. This deposit has been made under the provisions of the Budapest Treaty and all restrictions on the availability thereof to the public will be made upon the granting of a patent on this application.
The microbial strain was isolated from an unidentified marine polychaete collected at the Bay of Biscay.
While the deposited organism is clearly preferred, the present invention is not restricted or limited to any particular strain or organisms. It is the intention of the present invention to include other IB-00208 producing organisms, strains or mutants within the scope of this invention.
Actinomadura
sp. PO13-046 cultured under controlled conditions in a suitable medium produces the antibiotic IB-00208. This strain is preferably grown in an aqueous nutrient medium, under aerobic and mesophilic conditions.
The antibiotic IB-00208 can be isolated from the mycelial cake by extraction with a suitable mixture of solvent such as CHCl
3
:CH
3
OH:H
2
O. The activity is concentrated in the lower layer. The extracts from two repeated extractions can be combined and evaporated to dryness in vacuo.
Separation and purification of IB-00208 from the crude active extract can be performed by the use of the proper combination of conventional chromatographic techniques.
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Cañedo Librada Maria
Espliego Fernando
Garcia Gravalos Dolores
Perez-Baz Julia
Romero Francisco
Fish & Richardson P.C.
Instituto Biomar S.A.
Owens Amelia A.
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