AU754778B2 - Treatment of prostate cancer - Google Patents

Description

WO 02/11743 PCT/AU01/00966 -1- TREATMENT OF PROSTATE CANCER FIELD OF THE INVENTION The present invention relates generally to chemical agents useful in treatment and prophylaxis of prostate cancer or a related cancer or condition or in the amelioration of symptoms resulting from or facilitated by prostate cancer or a related cancer or condition in a mammalian animal including human or primate. More particularly, the present invention provides a chemical agent of the diterpene family obtained from a member of the Euphorbiaceae family of plants or botanical or horticultural relatives thereof or derivatives or chemical analogs or chemically synthetic forms of the agents for use in the treatment or prophylaxis of prostate cancer or a related cancer or condition or in the amelioration of symptoms resulting from or facilitated by prostate cancer or a related cancer or condition in a mammal and in particular a human. The present invention further contemplates a method for the prophylaxis or treatment of a mammalian subject presenting with prostate cancer or a related cancer or condition or with symptoms of prostate cancer or a related cancer or condition by topical or systemic administration of a diterpene obtainable from a member of the Euphorbiaceae family or botanical or horticultural relatives thereof or a derivative, chemical analog or chemically synthetic form of the agent. The chemical agent of the present invention may be in the form of a purified compound, mixture of compounds, a precursor form of one or more of the compounds capable of chemical transformation into a therapeutically active agent or be in the form of a chemical fraction, sub-fraction or preparation or extract of the plant. The present invention particularly relates to the treatment of either hormone-resistant or hormone-sensitive prostate cancer or metastatic prostate cancer using a chemical agent or fraction from the sap of Euphorbia peplus. The chemical agents or chemical fractions of the present invention may be given alone or in combination with other cancer symptom-ameliorating chemical or physical agents and/or other therapeutic interventions including interventionist procedures.

WO 02/11743 PCT/AU01/00966 -2- BACKGROUND OF THE INVENTION Bibliographic details of the publications referred to by author in this specification are collected at the end of the description.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.

As the most common internal cancer in older men and the seventh most common cause of death in men of all ages in developed countries, cancer of the prostate is a serious health problem in terms of drawn-out personal suffering and premature death not to.mention the cost to the health care system. The incidence of prostate cancer appears to be increasing, over and above improved detection rates in recent years (Post et al., 1999). Although many men with cancer of the prostate die from other causes, the high incidence results in significant morbidity and death directly from the prostatic tumor. Currently-available therapy carries a significant risk of major side effects, including incontinence and impotence, and consequently many men are reluctant to accept treatment at an early stage of the disease. The need to improve the treatment of prostate cancer is underlined by the existence of over 150 clinical trials world wide (Future Oncology, vol. 4, number 3, 1998), including 34 new or modified products (http://www.phrma.org/pdf/charts/cancer99.pdf).

Hormone-resistant bony secondaries (hrbs) are universally found in the natural history of advanced prostate cancer and are resistant to all current chemotherapy. They cause severe pain, prolonged hospitalization, pathological fractures, spinal-cord compression and paraplegia, and may be fatal. External beam radiotherapy is the mainstay of palliative treatment. However, it can only be used once for a given bony secondary. A range of boneseeking compounds can image prostate cancer metastases (Bushnell et. al., 1999; Norris et al., 1999). Parenteral strontium isotopes have had limited success for treatment but their use is limited by their toxicity to the bone narrow, especially platelets. Bisphosphonates (osteoclast inhibitors) may decrease the bone pain in a few cases, but again are generally WO 02/11743 PCT/AU01/00966 -3disappointing and do not increase life expectancy.

There is a need, therefore, to develop more effective therapeutic protocols and more efficacious therapeutic agents to assist in the treatment of this disease.

Natural product screening is a term applied to the screening of natural environments for bioactive molecules. Particularly sought after bioactive molecules are those having potential as useful therapeutic agents. Natural environments include plants, microorganisms, coral and marine animals. The search for potential therapeutic agents for the treatment of cancer and infection by pathogenic organisms remains an important focus.

The Euphorbiaceae family of plants covers a wide variety of plants including weeds and other types of plants of Euphorbia species. There has been a variety of inconclusive reports on the potential effects of the sap of these plants on a range of conditions as well as promoting tumorigenesis and causing skin and ocular irritation.

The most intensively studied species of this group is Euphorbia pilulifera L (synonyms E.

hirta E. capitata Lam.), whose common names include pill-bearing spurge, snakeweed, cat's hair, Queensland asthma weed and flowery-headed spurge. The plant is widely distributed in tropical countries, including India, and in Northern Australia, including Queensland.

A recent report describes selective cytotoxicity of a number of tigliane diterpene esters from the latex of Euphorbia poisonii, a highly toxic plant found in Northern Nigeria, which is used as a garden pesticide. One of these compounds has a selective cytotoxicity for the human kidney carcinoma cell line A-498 more than 10,000 times greater than that of adriamycin (Fatope et al., 1996).

Euphorbia hirta plants and extracts thereof have been considered for a variety of purposes, including tumor therapy (European Patent Application No. 0 330 094), AIDS-related complex and AIDS (Hungarian Patent Application No. 208790) and increasing immunity WO 02/11743 PCT/AU01/00966 -4and as an anti-fungoid agent for treatment of open wounds (German Patent Application No. 4102054).

Thus, while there are isolated reports of anti-cancer activity of various Euphorbia preparations (see Fatope et al., 1996; Oksuz et al, 1996), not only are the compounds present in at least one Euphorbia species reported to be carcinogenic (Evans and Osman, 1974; Stavric and Stolz, 1976; Hecker, 1970), but at least one species has a skin-irritant and tumor-promoting effect (Gundidza and Kufa, 1993) and another species reduces EBVspecific cellular immunity in Burkitt's lymphoma (Imai, 1994).

In accordance with the present invention, the inventors have identified chemical agents and fractions comprising these agents from a plant of the Euphorbiaceae family which are useful in the treatment and prophylaxis of prostate cancer in mammalian and in particular human subjects.

WO 02/11743 PCT/AU01/00966 SUMMARY OF THE.INVENTION Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

The present invention is predicated in part on the identification of chemical agents and fractions comprising same from plants of the Euphorbiaceae family and in particular Euphorbia peplus which are useful in the treatment and prophylaxis of prostate cancer or a related cancer or condition. The chemical agents or fractions comprising same are particularly useful for the treatment or prophylaxis of, or in the amelioration of symptoms associated with, prostate cancer including metastatic prostate cancer.

Accordingly, one aspect of the present invention contemplates a method for the treatment or prophylaxis of prostate cancer or a related cancer or condition in a subject, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from a plant of the Euphorbiaceae family or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is represented by any one of the general formulae as defined herein and wherein said chemical agent or its derivatives or chemical analogs is administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer.

More particularly, the present invention is directed to a method for the treatment or prophylaxis of prostate cancer or a related cancer or condition in an subject, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from E. peplus or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is WO 02/11743 PCT/AU01/00966 -6represented by any one of the general formulae as defined herein and wherein said chemical agent or its derivatives or chemical analogs is administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer.

Another aspect of the present invention contemplates a method for the immunopotentiation of a subject in the treatment and prophylaxis of said subject for prostate cancer or a related cancer or condition, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a diterpene, or a chemical fraction comprising same from a plant of the family Euphorbiaceae or a derivative or chemical analog of said diterpene having the structures as defined herein against prostate cancer cells.

Yet another aspect of the present invention contemplates a method for the treatment or prophylaxis of a subject with prostate cancer or a related cancer or condition or with the symptoms of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of an angeloyl-substituted ingenane or a chemical fraction or plant extract comprising same.

Still another aspect of the present invention provides a method for the treatment or prophylaxis of a subject with prostate cancer or a related cancer or condition or with the symptoms of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of one or more of ingenol-3-angelate, ingenol-3-angelate and/or 20-O-acetyl-ingenol-3-angelate or a derivative thereof or a pharmaceutically acceptable salt of these or a chemical fraction or plant extract comprising same.

Even yet another aspect of the present invention contemplates a method for the treatment or prophylaxis of prostate cancer or a related cancer or condition in a subject, said method comprising the simultaneous or sequential administration to said subject of a symptomameliorating effective amount of a chemical agent derived from a plant of the Euphorbiaceae family as hereinbefore described together with a therapeutic protocol or a WO 02/11743 PCT/AU01/00966 -7symptom-ameliorating effective amount of another chemical agent or a physical agent.

A further aspect of the present invention also provides a composition for treatment and/or prophylaxis of prostate cancer or a related cancer or condition in a subject, comprising one or more chemical agents of the present invention, together with a pharmaceutically acceptable carrier and/or diluent, and optionally one or more other active compounds.

Yet another aspect of the present invention encompasses the use of one or more chemical agents of the present invention and optionally one or more other active compounds in the preparation of a medicament for the treatment and/or prophylaxis of prostate cancer or a related cancer or condition.

WO 02/11743 PCT/AU01/00966 -8- BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a diagrammatic representation illustrating the selective toxicity of E. peplus sap against prostate cancer cell lines, as compared to normal fibroblasts (NFF). PC-3 and DU145 are hormone resistant prostate cancer cell lines. LNcap is a hormone-sensitive prostate cancer cell line.

Figure 2 is a graphical representation of the effects of topical administration of PEP003 from E. peplus on DU145 tumors in nude mice.

Figure 3 is a graphical representation of the effects of topical administration of PEP003 from E. peplus on PC-3 tumors in nude mice.

Figure 4 is a graphical representation of the effects of intralesional treatment by PEP003 on PC-3 tumors in nude mice.

Figure 5 is a graphical representation of the effects of intralesional treatment by PEP003 on DU145 tumors in nude mice.

Figures 6A to 6E are graphical representations showing the synergistic behaviour of angeloyl-substituted ingenanes in combination with chemotherapeutic agents on killing DU145 cells.

WO 02/11743 WO 0211743PCT/AU01/00966 -9- Compounds may be referred to in the subject specification by a compound code. These are defined in Table 1 below:- TABILE 1 .COMPOUND CODE DESCRIPTION PEP001 Crude sap PEP002 Methanol and ether extract of E. peplus sap prepared according to Example 7 of PCT/AU98100656 PEP003 Ingenane enriched fraction prepared according to Examples 2 and 4 PEP004 Jatrophane/Pepluane enriched fraction prepared according to Example 7 of PCT/AU98/00656 PEP005 20-deoxy-ingenol-3-angelate PEP006 Ingenol-3-angelate PEP008 20-O-acetyl-ingenol-3-angelate PEP009 Acetone Extract of XAD (water extract) prepared according to Example 2 PEPO 10 Ingenane enriched fraction prepared according to Examples 3 and 4 WO 02/11743 PCT/AU01/00966 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is predicated in part on the identification of biologically useful properties of chemical agents and chemical fractions comprising these agents obtainable from a member of the Euphorbiaceae family of plants or their botanical or horticultural relatives. These biologically useful properties include their use in the prophylaxis and/or treatment of prostate cancer including facilitating potentiation of the immune system or of cells or other components of the immune system in the treatment or amelioration of symptoms associated with prostate cancer.

Reference to "prostate cancer" includes cancers related thereto such as at the biochemical, physiological, pharmacological and immunological levels. Examples of related cancers include prostatic carcinogenesis, benign prostatic hyperplasia, prostatic intraepithelial carcinoma, carcinoma of the bladder, adenocarcinoma of the prostate and renal cell carcinoma. The term "prostate cancer" includes a condition having the characteristics of prostate cancer and includes conditions associated with cancers related to prostate cancer.

The term "treatment" is used in its broadest sense and includes the prevention of a disease condition as well as facilitating the amelioration of the effects of symptoms of prostate cancer or a related condition.

The term "prophylaxis" is also used herein in its broadest sense to encompass a reduction in the risk of development of prostate cancer. In certain conditions, an agent may act to treat a subject prophylactically. Furthermore, the prophylactic administration of an agent may result in the agent becoming involved in the treatment of a disease condition. Use of the terms "treatment" or "prophylaxis" is not to be taken as limiting the intended result which is to reduce the adverse effects of prostate cancer or to potentiate the immune system or components therein to ameliorate the symptoms or risk of development of symptoms caused or facilitated by prostate cancer.

The present invention is particularly directed to the use of one or more diterpenes from a WO 02/11743 WO 0211743PCT/AUOI/00966 11member of the Euphorbiaceae family of plants or botanical or horticultural relatives of such plants. Reference herein to a member of the Euphorbiaceae family includes reference to species from the genera Acalypha, Acidoton, Actinostenon, Adelia, Adenocline, Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea, Aichorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Antanoa, Andrachne, Angostyles, Anisophyllurn, Antidesma, Aphora, Aporosa, Aporosella, Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia, Beyeriopsis, Bisehofta, Blachia, Blumeodondron, Bonania, Bradleta, Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron, Celianella, Cephalocroton, Chaenotheca, Chaetocarp us, Chamaesyce, Cheilosa, Chiropetalum, Choriophylwnt, Cicca, Chaoxylon, leidon, Cleistanthus, Cluytia, Cnesrnone, Cnidoscolus, Coccoceras, Codiaeum, Coelodiscus, Conaini, Conceveiba, Conceveibastrumn, Conceve~bum, Corythea, Croizatia, Croton, Crotonopsis, Crozophora, Cuba nthus, Cunuria, Dactyl ostemon, Dalechampia, Dendrocousinsia, Diaspers us, Didyrnocistus, Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingna, Drypetes, Dysopsis, Elateriospermum, Endadenium, Endospermurn, Erisrnanthus, Erythrocarpus, Erythrochilus, Eumecanthus, Euphorbia, Euphorbiodendron, Excoecaria, Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia, Glochidion, Clochidionops is, Glycydendron, Gymnanthes, Gymnosparia, Ha eratospermurn, Hen decandra, Hevea, Hieronirna, Hieronyma, Hippocrepandra, Hornalanthus, Hyinenocardia, Janip ha, Jatropha, Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus, Leucocroton, Mabea, Macaranga, Mallowu, Manihot, Mappa, Map rounea, Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesm is, Microelus, Microstachy, Maocroton, Monadeniun, Mozinna, Neoscortechinia, Ornalanthus, Omphalea, Ophellant ha, Orb icularia, Ostodes, Oxydectes, Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilanthus, Pera, Peridiurn, Petalostigma, Phyllanthus, Picrodendro, Pierardia, Pilinophytuin, Pirneleodendron, Piranhea, Platygyna, Plukenetia, Podocalyx, Poinsettia, Poraresia, Prosartena, Pseudanthus, Pycnoconia, Quadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarp us, Rottlera, Sagotia, Sanwithia, Sapiun, Savia, Scierocroton, Sebastiana, Securinega, Sen efeldera, Senefilderopsis, Serophyton, Siphonia, Spathiosternon, Spixia, Stillingia, Strop hioblachia, Synadeniurn, Tetracoccus, Tetraplandra, Tetrorchidiun, Thyrsanthera, Tithyrnalus, Trageia, Trewia, Trigonosternon, Tyria and Xylophylla.

WO 02/11743 WO 0211743PCT/AUOI/00966 -12- The most preferred genus and most suitable for the practice of the present invention is the genus Euphorbia. Particularly useful species of this genus include Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algomarginata, Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbia andrornedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeri, Euphorbia berniudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbia bifurcata, Euphorbia bilobata, Euphorbia biramensis, Euphorbia biuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbia boerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbia britton ii, Euphorbia caesia, Euphorbia calcicola, Euphorbia camp est ris, Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carinenensis, Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbia commutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrinia, Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbia cymnbiformnis, Euphorbia darlington ii, Euphorbia defobliata, Euphorbia degeneri, Euphorbia deltoidea, Euphorbia dentata, Euphorbia depressa Euphorbia dictyospenna, Euphorbia dictyosperma, Euphorbia dioeca, Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumiondii, Euhorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbia eglandulosa, Euphorbia elata, Euphorbia enalla, Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeforrnis, Euphorbia espirituensis, Euphorbia esula, Euphorbia exccisa, Euphorbia exciusa, Euphorbia exstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbia filicaulis, Euphorbia filiformis, Euphorbia florida, Euphorbia fruticulosa, Euphorbia garber, Euphorbia gaunterii, Euphorbia gerardiana, Euphorbia geyeri, Euphorbia glyptospermna, Euphorbia gorgonis, Euphorbia gracilior, WO 02/11743 WO 0211743PCT/AUOI/00966 13 Euphorbia gracillima, Euphorbia gradyi, Euphorbia graminea, Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbia guanarensis, Euphorbia gynadenia, Pup horbia haematantha, Euphorbia hedyotoides, Eup ho rbia heidrich ii, Euphorbia helenae, Euphorbia helleri, Pup horbia helwigii, Euphorbia hen rickson ii, Eup horbia heterophylla, Pup horbia hexagona, Pup horbia hexagonoides, Euphorbia hinkleyorurn, Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbia hooveri, Euphorbia humistrata, Euphorbia hypericifolia, Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna, Pup horbia johnston, Eup horbia juttae, Euphorbia knuthii, Puphorbia lasiocarpa, Euphorbia Jata, Euphorbia latazi, Euphorbia lateri color, Euphorbia laxiflora Euphorbia lecheoides, Pup horbia ledienii, Euphorbia leucophylla, Euphorbia lineata, Pup horbia linguiforrnis, Pup horbia longecornuta, Puphorbia longepetiolata, Euphorbia longeramosa, Euphorbia longinsulicola, Euphorbia longipila, Euphorbia lupulina, Euphorbia lwida, Euphorbia lycicides, Euphorbia macropodoides, macvaughiana, Euphorbia manca, Euphorbia mandoniana, Euphorbia mangleti, Pup horbia mango, Pup horbia marylandica, Euphorbia inayana, Euphorbia melanadenia, Pup horbia melanocarpa, Euphorbia mneridensis, Pup horbia merton ii, Euphorbia mexiae, Puphorbia microcephala, Euphorbia microclada, Euphorbia micromera, Euphorbia misella, Euphorbia missuica, Euphorbia montana, Puphorbia Inontereyana, Euphorbia niulticaulis, Euphorbia ,nultiform is, Pup horbia multinodis, Euphorbia mult is eta, Euphorbia muscicola, Euphorbia neoinexicana, Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana, Euphorbia occidentalis, Euphorbia odontodenia, Euphorbia olivacea, Euphorbia olowaluana, Euphorbia opthialmica, Euphorbia ovata, Puphorbia pachypoda, Euphorbia pachyrhiza, Euphorbia padifolia, Euphorbia palmeri, Euphorbia paludicola, Euphorbia paralias, Euphorbia parciflora, Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Pup horbia pedicuifera, Puphorbia peplidion, Euphorbia peploides, Euphorbia peplus, Pup horbia pergamena, Euphorbia perlignzea, Etqphorbia petaloidea, Pup horbia petaloidea, Pup horbia petrina, Euphorbia picachensis, Euiphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbia pinetorum, Euphorbia pionospenna, Pup horbia platysperma, Euphorbia plicata, Euphorbia poeppigli, Euphorbia poliosperma, Euphorbia polycarpa, Puphorbia polycnemoides, Euphorbia poivphylla, Euphorbia portoricensis, WO 02/11743 WO 0211743PCT/AUOI/00966 14- Euphorbia portulacoides Euphorbia portulana, Euphorbia presii, Euphorbia pros trata, Euphorbia pteroneura, Euphorbia pycnanthema, Euphorbia ramosa, Euphorbia rapulum, Euphorbia reniyi, Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis, Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbia rubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbia saxatilis MA Bieb, Euphorbia schizoloba, Euphorbia scierocyathium, Euphorbia scopulorum, Euphorbia senilis, Euphorbia serpyllifolia, Euphorbia serndla, Euphorbia setiloba Engeim, Euphorbia sonorae, Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperina, Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea, Euphorbia stellata, Euphorbia submammilaris, Euphorbia subpeltata, Euphorbia subpubens, Euphorbia subreniformne, Euphorbia subtrifoliata, Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides, Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli, Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii, Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor, Euphorbia troyana, Euphorbia tuerckheimii, Euphorbia turczaninowii, Euphorbia umnbellulata, Euphorbia undulata, Euphorbia vermiformis, Euphorbia versicolor, Euphorbia vilifera, Euphorbia violacea, Euphorbia whitei, Euphorbia xanti Engeim, Euphorbia xylopoda Greenm., Euphorbia yayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica and Euphorbia zinniiflora.

Particularly preferred species of the genus Synadenium include Synadenium grantii and Synadeniurn compactum.

Particularly preferred species of the genus Monadentiumn include Monadeniwnz lugardae and Monadenjuyn guentheri.

A preferred species of the genus Endadenium is Endadenium gossweileni.

Euphorbia peplus is particularly useful and is preferred in the practice of the present invention. Reference herein to "Euphorbia peplus or its abbreviation peplus includes various varieties, strains, lines, hybrids or derivatives of this plant as well as its botanical or horticultural relatives. Furthermore, the present invention may be practiced WO 02/11743 PCT/AU01/00966 using a whole Euphorbiaceae plant or parts thereof including sap or seeds or other reproductive material may be used. Generally, for seeds or reproductive material to be used, a plant or plantlet is first required to be propagated.

Reference herein to a Euphorbiaceae plant, a Euphorbia species or E. peplus further encompasses genetically modified plants. Genetically modified plants include transgenic plants or plants in which a trait has been removed or where an endogenous gene sequence has been down-regulated, up-regulated, mutated or otherwise altered including the alteration or introduction of genetic material which exhibits a regulatory effect on a particular gene. Consequently, a plant which exhibits a character not naturally present in a Euphorbiaceae plant or a species of Euphorbia or in E. peplus is nevertheless encompassed by the present invention and is included within the scope of the above-mentioned terms.

Furthermore, the present invention contemplates hybrid plant cells or plants comprising hybrid plant cells formed by the fusion of two or more plant cells from different strains, species or genera and optionally regenerating a plant therefrom. Such hybrid plant cells are proposed to generate novel secondary metabolites having useful therapeutic properties.

The diterpenes are generally in extracts of the Euphorbiaceae plants. An extract may comprise, therefore, sap or liquid or semi-liquid material exuded from, or present in, leaves, stem, flowers, seeds and bark or between the bark and the stem. Most preferably, the extract is from sap. Furthermore, the extract may comprise liquid or semi-liquid material located in fractions extracted from sap, leaves, stems, flowers, bark or other plant material of the Euphorbiaceae plant. For example, plant material may be subject to physical manipulation to disrupt plant fibres and extracellular matrix material and interand intra-tissue extracted into a solvent including an aqueous environment. The fractions may include aqueous or alcohol extracts. Other extraction media are also contemplated including fractions prepared by HPLC or other fractionation systems. All such sources of the diterpenes are encompassed by the present invention including diterpenes obtained by synthetic routes.

The preferred diterpenes are selected from compounds of the ingenane, pepluane and WO 02/11743 PCT/AU01/00966 -16jatrophane families. A dompound is stated to be a member of the ingenane, pepluane or jatrophane families on the basis of chemical structure and/or chemical or physical properties. A compound which is a derivative of an ingenane, pepluane or jatrophane is nevertheless encompassed by the present invention through use of the terms "ingenane", "pepluane" or "jatrophane" since these terms include derivatives, chemical analogs and chemically synthetic forms of these families of compounds. One particularly preferred derivative is an angeloyl-substituted derivative of ingenane.

The chemical agents of the present invention may be in purified or isolated form meaning that the preparation is substantially devoid of other compounds or contaminating agents other than diluent, solvent or carrier or isoforms of the agents. Furthermore, the term "chemical agent" includes preparations of two or more compounds either admixed together or co-purified from a particular source. The chemical agent may also be a chemical fraction, extract or other preparation including sap from the Euphorbiaceae plant. The chemical agents or extracts or fractions of the present invention may also be referred to as "drugs" or "actives" or "active ingredients". The term "agent" is not to imply a synthetic compound and may include a fraction obtainable from the sap of the Euphorbiaceae plant.

The term "obtainable" also includes "obtained".

Consequently, reference herein to a "chemical agent" includes a purified form of one or more compounds or a chemical fraction or extract such as from the sap of a Euphorbiaceae plant, and in particular a species of Euphorbia, and most preferably from E. peplus or botanical or horticultural relatives or variants thereof.

Accordingly, one aspect of the present invention contemplates a method for the treatment or prophylaxis of prostate cancer or a related cancer or condition, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from a plant of the Euphorbiaceae family or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is represented by any one of the general formulae (V) WO 02/11743 WO 0211743PCT/AUOI/00966 -17-

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B- Aj *n

N

wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; A-T are independently selected from hydrogen, RI, R 2 R(3, F, Cl, Br, I, CN, ORi, SRI, NR 1

R

2 N(=0) 2

NRIOR

2

ONR

1

R

2 SORI, S0 2 RI, S0 3 RI, SONR 1

R

2

SO

2

NR

1

R

2

SO

3

NR

1

R

2

P(R

1 3

P(=O)(R

1 3 Si(RIh3, B(Rl) 2

(C=X)R

3 or X(C=X)R 3 where X is selected from sulfur, oxygen and nitrogen; RI and R 2 are each'independently selected from CI-C 2 o alkyl (branched and/or straight chained), C 1

-C

2 o arylalkyl, C 3

-C

8 cycloallcyl, C6-Cw4 arYl, CI-C 14 heteroaryl, CI-CI 4 heterocycle, C 2

-C

10 ailkenyl. (branched and/or straight chained), C 2

-CI

0 alkynyl (branched and/or straight chained), C 1

-C

10 heteroarylalkyl, CI-Clo alkoxyalcyl,

CI-C

10 haloallcyl, dihaloallcyl, trihaloalkyl, haloalkoxy, C 1 -Clo [CN, OR,, SRI, NR 1

R

2 N(=0) 2

NRIOR

2 0NR 1

R

2 SORI, S0 2 RI, S0 3 Ri, SONR 1

R

2

SO

2 NRiR 2 S0 3 Nk 1

R

2 WO 02/11743 WO 0211743PCT/AU01/00966 18

R

3 is selected from R 1

R.

2 GPN, CORI, C0 2 RI, ORI, SRI, NR 1

R

2 N(=0) 2

NRIOR

2

ONR

1

R

2 SORI, S0 2 1 6 S0 3 RI, SONR 1

R.

2

SO

2

NR

1

R

2

SO

3

NR

1

R

2

P(R.)

3 1 3 Si(RI) 3

B(RI)

2 A connected to B(or g,D(or R(or 1!(or Q)or S(or D is a selection of CI-Cs disubstituted (fused) saturated or unsaturated carbocycic or heterocyclic rings further substituted by R 3

(C--X)R

3 and X(C=X)R 3 including epoxides and tbioepoxides; J connected to I (or ID, Q (or LF, K (or M (or N) or S (or D~ is a selection Of C 1

-C

8 disubstituted (fused) saturated and unsaturated carbocyclic or heterocyclic rings further substituted by R 3

(C=X)R.

3 and X (C=X)R 3 including epoxides and thioepoxides; D (or E) connected to B (or C) or G (or I (or Hi) connected to G (or P! (or 0) connected to R (or or M (or K (or L) connected to N (or M) is a selection of

C

1

-C

8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic rings substituted by R 3

(C=X)R

3 and X(C=X)R 3 including epoxides and thioepoxides; B and C Dand E.R and Q 1!and 0 1andH. G andF, K and L M and N or S and T are =X where X is selected from sulfur, oxygen, nitrogen, NR 1

R

2 and =CR 1

R

2 C1, F G wherein: WO 02/11743 PCT/AU01/00966 -19n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; are independently selected from hydrogen, R 4

R

5 R, F, Cl, Br, I, CN, COR 4 C0 2

R

4

OR

4

SR

4

NR

4

R

5

CONR

4 Rs, N(=0) 2 NR40R 5

ONR

4

R

5

SOR

4 S0 2 R4, S0 3

R

4

SONR

4

R

5

SO

2 NR4Rs, SO 3

NR

4

R

5

P(R

4 3 P(=0)(R4) 3 Si(R4)3, B(R 4 2 (C=X)R or X(C=X)R where X is selected from sulfur, oxygen and nitrogen;

R

4 and R 5 are each independently selected from CI-C 20 alkyl (branched and/or straight chained), CI-C 20 arylalcyl, C 3

-C

8 cycloalkyl, C 6

-C

14 aryl, C 1

-CI

4 heteroaryl,

C

1

-C

14 heterocycle, C 2 -Co 0 alkenyl (branched and/or straight chained), C 2 -Clo alkynyl (branched and/or straight chained), CI-Clo heteroarylalkyl, C 1 -Clo alkoxyalkyl, CI-Clo haloalkcyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C 1 -Clo [CN, OR4, SR 4 NR4Rs, N(=0) 2

NR

4 0R 5

ONR

4

R

5

SOR

4 S0 2 R4, S0 3 R4, SONR4R5, SO 2

NR

4

R

5

SO

3 NR4R 5

P(R

4 3 Si(R4)3, B(R4)2alkl;

R

6 is selected from R4, Rs, CN, COR4, C0 2 R4, OR4, SR4, NR 4

R

5 N(=0) 2

NR

4 0R 5

ONR

4

R

5

SOR

4 SO2R4, S0 3 R4, SONR 4

R

5

SO

2 NR4R 5

SO

3

NR

4

R

5 P(R4) 3

P(=O)(R

4 3 Si(R 4 3

B(R

4 2 E' and R' or H' and 0' is a C 2

-C

8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 6 including epoxides and thioepoxides; 0' connected to M' (or or Q' (or R' connected to Q2 (or or S' (or (or connected to A' (or A' (or connected to C' (or E' connected to C' (or or F' (or H' connected to I' connected to F J' connected to K' connected to L' connected to M' (or are CI-Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 6

(C=X)R

6 and X(C=X)R 6 including epoxides and thioepoxides; WO 02/11743 WO 0211743PCT/AU01/00966 A' BandCj, DandF'(iandM'_N'andP' Q and S',T'are=X where X is selected from sulfur, oxygen, nitrogen, NR 4

R

5

(C=X)R

5

X(C=X)R

6 and =CR 7

R

8 s;

R

7 and Rg are each independently selected from R,(C=X)R 6 and X(C=X)R 6 s' P

N

1 wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; are independently selected from hydrogen, R 9 Rio, R 11 F, Cl, Br, L, CN, OR 9

SR

9

NR

9

R

10 N(=0) 2

NR

9 0R 0 0NRR 10

SOR

9 S0 2

R

9 S0 3

R

9

SONR

9 Rio,

SO

2

NR

9 RIO, S0 3 NRRjo, P(R, 9 3

P(=O)(R

9 3 Si(R 9 3 B(R9) 2

(C=X)R

1 or X(C=XR 1 where X is selected from sulfur, oxygen and nitrogen;

R

9 and RIO are each independently selected from C 1

-C

20 alkyl (branched and straight chained), C 1

-C

20 arylalkyl, C 3

-C

8 cycloalkyl, C 6

-C

14 aryl, CI-CI 4 heteroaryl, CI-CI4 heterocycle, C 2 -Clo alkenyl (branched and straight chained), C 2

-CI

0 alkynyl (branched and straight chained), CI-C 10 heteroarylalkyl, CI-Clo alkoxyalkyl, C 1 -Clo haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, Cl-Clo [CN, OR 9

SR

9

NR

9 Rjo, N(0() 2

NR

9

ORIO,

0NRRjo, SOR 9 S0 2

R

9 S0 3

R

9

SONR

9

RI

0 S0 2

NR

9

R

1 0

SO

3

NR

9 RIO, P(R 9 3

P(=O)(R

9 3 Si(R 9 3

B(R

9 2 ]alkYl; WO 02/11743 PCT/AU01/00966 -21- RI is selected from R 9 R1o, CN, COR 9 C0 2 R, OR 9

SR

9

NR

9 Rjo, N(=0) 2

NR

9 ORjo, ONR 9 Rjo, SOR 9 S0 2

R

9 S0 3

R

9

SONR

9 RIO, SO 2

NR

9 Ro, S0 3

NR

9 Ro 0 P(R9) 3 P(0)(R 9 3 Si(R 9 3

B(R

9 2 B' and E' and 0' and B' and M' are selected from a C 2

-C

8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by RI, including epoxides and thioepoxides; A' (or A2) connected to A' (or A) or T' (or B' connected to A' (or A!) or C' (or Di). E' connected to i' or C' (or connected to 0 G (or HI) connected to (or or I' (or K' (or connected to I' (or t) or M connected to O' (or 01 connected O' (or or P' (or R' connected P' (or Q) or S' (or T) are C 1 -Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R11, (C=X)R 1 and X(C=X)R 11 including epoxides and thioepoxides; A and A, A and C' D' and and H and J'and K' L' and 0' and Q and S1, T' are =X where X is selected from sulfur, oxygen, nitrogen, NRRjo, including (C=X)RI 1 and X(C=X)Ri1, and =CR1 2

R

13 'R1 2 and R, 3 are independently selected from R11, (C=X)RI, and X(C=X)Ri, J2 K2 L2 D 2 1= F, 2 p G 2 2 M2 aN' A n N 2 p2 b2 IV wherein: WO 02/11743 PCT/AUO1/00966 -22n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; A2_ are independently selected from hydrogen, R 14

R

15

R

16 F, Cl, Br, I, CN, OR 14

SR

1 4

NR

14

R

1 5 2

NR

14 0R 5 ONR14R15, S0R 1 4 S0 2

R

1 4 S0 3

R

1 4

SONR

1 4

R

5 S0 2

NR

1 4

R

1 5 S0 3

NR

14

RI

5

P(R

1 4 3

P(=O)(R

1 4 3 Si(R 1 4 3

B(R

1 4

(C=Y)R

1 6 or Y(C=Y)R 16 where Y is selected from sulfur, oxygen and nitrogen;

R

1 4 and R 1 5 are each independently selected from C 1

-C

20 alkyl (branched and/or straight chained), C 1

-C

2 o arylalkyl, C 3

-C

8 cycloalkyl, C 6

-C

14 aryl, CI-C 1 4 heteroaryl,

C

1

-C

14 heterocycle, C 2 -Clo alkenyl (branched and/or straight chained), C 2

-C

10 alkynyl (branched and/or straight chained), Cj-Cj 0 heteroarylalkyl, C 1 -CIo alkoxyalkyl, CI-Clo haloalkyl, dihaloalkyl, trihaloalyl, haloalkoxy, C 1 -Co [CN, OR 14

SR

14

NR

1 4

R

10 N(=0) 2

NR

1 4 0R 1 5 0NR 1 4

RI

5 S0R 1 4 S0 2

R

1 4 S0 3

R

1 4 S0NR 1 4

R

5 S0 2

NR

1 4

R

5 S0 3

NR

1 4R 1 5

P(R

1 4 3

P(=O)(R

4 3 Si(R 1 4 3

B(R

14 2 1alkl;

R

1 6 is selected from R 14

R

15 CN, C0R 1 4 C0 2

R

1 5

OR

14

SR

14

NR

1 4

R

1 5 2

NR

1 4 0R 1 5 0NR 14

R

1 5 S0R 1 4 S0 2

R

1 4 S0 3

R

1 4 SONR14R1 5 S0 2

NR

1 4

R

1 5 S0 3

NR

1 4

R

1 5

P(R

1 4 3

P(=O)(R

1 4 3 Si(R 1 4 3

B(R

1 4 2 E2 and V 2

H

2 and S 2 and 12 and P 2 are C 2 -CR saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 16 including epoxides and thioepoxides;

A

2 (or B) connected to C 2 (or D 2 or W 2 (or Xb; E connected to C 2 (or D or F 2 (or g; H 2 connected to F2 (or or 12. f connected to J 2 (or K 2

L

2 (or M) connected to J 2 (or or N 2 (or 02); R 2 (or q) connected to P 2 or Y! connected to U2 (or V) or W 2 (or X) are CI-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 16

(C=Y)R

1 6 and Y(C=Y)R 1 6 including epoxides and tbioepoxides; WO 02/11743 WO 0211743PCT/AUOI/00966 -23

A

2

B

2

;D

2

;F~G~;J

2

K!;

2 2 W; te if, f and 2 War =Y where Y is selected from sulfur, oxygen, nitrogen, NR 14

R

15 and IMC 17

R

18

R

17 and R 18 are independently selected from R 16

(C=Y)R

1 6 and Y(C=Y)R 16 3 3 3 3 T 3 3 3 b heein n s0-0atm slctdfrmcabnoygn ntogn slur hopors silicon booVasncadslnuweentern eie ysi tm sstrtdo o0wrein:R 1 whr sslfr xgnan irgn R nd is0- 0 areeahomepnenl selected from caboxyeitogn auluyl (hoprache sconC, hborocy, arsenic andslenum (brnherdfied by stagtcaind) toms 0 isatukynylo (baraed, ancd/rsigh chxieand C 1

-C

10 hieteorlly, 1

C

0 akxyly, A hlaZyl dhoare tindepoadetyl h lkoxd from hydCn, Rg, SR2 9

NR

1

I

N, R 1 9 0NR 19 R, OR19, NS0 2 N0R 19 R2, SONR 1

R

20

S

2

R

1 9

RS

2 RIg, 3

NR

9

P(R

19

P=O)

1 S (R 19 3 B(3R 19 2 ]alkyl; P(O(I93 i(I)31(I92 C=)2 WO 02/11743 PCT/AU01/00966 -24-

R

21 is selected from R 1 9

R

20 CN, COR19, C0 2

R

1 9

OR

1 9

SR

1 9

NR

9

R

20 N(=0) 2

NR

19 0R 20

ONR

19

R

20

SOR

19 S0 2

R

1 9 S0 3

R

1 9

SONR

9

R

2 0 S0 2

NR

19

R

20

SO

3

NR

1 9

R

20

P(R

1 9 3 P(=0)(R 1 9 3 Si(R 1 9 3

B(R

1 9 2

D

3 connected to X 3 is a C 2

-C

8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 21 including epoxides and thioepoxides;

A

3 (or A) connected to B 3 (or C 3 or Z 3 (or Y3); D 3 connected to B 3 (or or E 3 (or F 3 G3 (or H 3 connected to E3 (or F 3 or J 3 (or J (or K) connected to 3 (or 2) or M3 (or 03 (or O 3 connected to N 3 (or 3 or P 3 (or Q3). S 3 (or R 3 connected to 3 (or P 3 or

U

3 (or T3). W 3 (or V 3 connected to U 3 (or 3 or X 3

X

3 connected to Y 3 (or Z 3 are Ci-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 2 1 0)R 21 and 0 0)R 2 1 including epoxides and thioepoxides; A, A3; B3, C; E, F3; G 3 H3; 3; K 3 M3 N3; 3, 3; 3, 3

R

3

U

3

T

3

W

3 V3, and Z 3

Y

3 are =0 where 0 is selected from sulfur, oxygen, nitrogen,

NR

1 9

R

20 and =CR 22

R

23 and

R

2 2 and R 23 are selected from R 2 1 0)R 21 and 0(C= 0)R 21 wherein said chemical agent or its derivatives or chemical analogs is administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer or a related condition.

More particularly, the present invention is directed to a method for the treatment or prophylaxis of prostate cancer or a related condition in an subject, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from E. peplus or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is WO 02/11743 PCT/AU01/00966 represented by any one of the general formulae as defined herein and wherein said chemical agent or its derivatives or chemical analogs is administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer.

In a related embodiment, the subject chemical agents may be used to increase the sensitivity of prostate cancer cells to the activity of the immune system or to chemical agents or otherwise be used to potentiate the immune system against prostate cancer cells.

This method involves the administration to a subject of the chemical agents of the invention. In an alternative embodiment, the prostate cancer cells may be removed such as by biopsy, treated with the subject chemical agents and returned to the subject in order to induce a more potent immune response against the prostate cancer cells.

Accordingly, the present invention provides a method for immunopotentiation of a subject in the treatment and prophylaxis of said subject for prostate cancer or a related cancer or condition, said method comprising administration to said subject of a symptomameliorating effective amount of a diterpene, or a chemical fraction comprising same from a plant of the Euphorbiaceae or a derivative or chemical analog of said diterpene having the structures as defined herein, said administration being for a time and under conditions sufficient to potentiate components of the immune system against prostate cancer cells.

Especially preferred chemical agents or derivatives or chemical analogs thereof in the practice of the present invention are represented by the general formula WO 02/11743 WO 0211743PCT/AU01/00966 -26

H

H

S R 2 6

R

24 vi

R

2 6 wherein:-

R

24

R

25 and R 26 are independently selected from hydrogen, R 27

R

28 F, Cl, Br, I, CN, OR 27

SR

2 7

NR

27

R

28 N(r=0) 2

NR

27 0R 28 0NR 27

R

28 S0R 27 S0 2

R

27 S0 3

R

27 S0NR 27

R

28

SO

2

NR

27 R28, 50 3

NR

27

R

28

P(R

27 3

P(=O)(R

27 3 Si(R 27 3

B(R

27 2

(C=X)R

29 or X(C=X)R 29 where X is selected from sulfur, oxygen and nitrogen;

R

27 and R 28 are each independently selected from C 1

-C

20 alkyl (branched and/or straight chained), CI-C 20 arylalkyl, C 3

-C

8 cycloalkyl, C 6

-C

14 aryl, Q 1

-C

14 heteroaryl,

CI-C

1 4 heterocycle, C 2

-CI

0 alkenyl (branched and/or straight chained), C 2

-G

10 alkynyl (branched and/or straight chained), CI-C 10 heteroarylalkyl, C 1 -CIa alkoxyalcyl, CI-C 10 haloallcyl, dihaloalkyl, trihaloalkyl, haloalkoxy, CI-CI 0 [CN, OR 2 7

SR

27

NR

27

R

2 8

N(O)

2

NR

27 0R 28 0NR 27

R

28 S0R 27 S0 2

R

27 S0 3

R

27 S0NR 27

R

28 S0 2

NR

27

R

28 S0 3

NR

27

R

28

P(R

27 3

P(=O)(R

27 3 Si(R 27 3

B(R

27 2 ]allcYl;

R

29 is selected from R 2 7

R

2 g, CN, G0R 27

CO

2 R27 OR 27

SR

27

NR

27

R

28 2

NR

27 0R 28 0NR 27

R

28 S0R 27 S0 2

R

27

SO

3

R

27 S0NR 27

R

28 S0 2

NR

27

R

28 S0 3

NR

27

R

28

P(R

2 7) 3

PQ=OR

27 3 Si(R 27 3 B(R2) 2 In a preferred embodiment, R 24 is hydrogen, OAcetyl or OH.

WO 02/11743 PCT/AU01/00966 -27- In another preferred embodiment, R 25 is OH.

In another preferred embodiment, R 26 is OH.

As used herein, the term "alkyl" refers to linear or branched chains. The term "haloalkyl" refers to an alkyl group substituted by at least one halogen. Similarly, the term "haloalkoxy" refers to an alkoxy group substituted by at least one halogen. As used herein the term "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein the term "aryl" refers to aromatic carbocyclic ring systems such as phenyl or naphthyl, anthracenyl, especially phenyl. Suitably, aryl is C 6

-C

14 with mono, di- and trisubstitution containing F, Cl, Br, I, NO 2

CF

3 CN, OR 1 CORI, C0 2

R

1 NHRI, NR 1

R

2

NR

1

OR

2

ONR

1

R

2

SOR

1 S0 2 RI, SO 3 RI, SONRIR 2

SO

2

NRIR

2

SO

3

NRIR

2

P(R

1 3

P(=Q)(RI)

3 Si(R 1 3

B(RI)

2 wherein Ri and R 2 are defined above As used herein the terms "heterocycle", "heterocyclic", "heterocyclic systems" and the like refer to a saturated, unsaturated, or aromatic carbocyclic group having a single ring, multiple fused rings (for example, bicyclic, tricyclic, or other similar bridged ring systems or substituents), or multiple condensed rings, and having at least one heteroatom such as nitrogen, oxygen, or sulfur within at least one of the rings. This term also includes "heteroaryl" which refers to a heterocycle in which at least one ring is aromatic. Any heterocyclic or heteroaryl group can be unsubstituted or optionally substituted with one or more groups, as defined above. Further, bi- or tricyclic heteroaryl moieties may comprise at least one ring, which is either completely, or partially, saturated. Suitable heteroaryl moieties include, but are not limited to oxazolyl, thiazaoyl, thienyl, furyl, 1isobenzofuranyl, 3H-pyrrolyl, 2H-pyrrolyl, N-pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyradazinyl, indolizinyl, isoindolyl, indoyl, indolyl, purinyl, phthalazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazoyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5oxatriazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, azepinyl, oxepinyl, thiepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, isothionaphthenyl, indoleninyl, 2- WO 02/11743 WO 0211743PCT/AU01/00966 28 isobenzazolyl, 1 ,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, isomndazolyl, indoxazinyl, benzoxazolyl, anthranilyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naplithyridinyl, pyrido[3,4-b]pyridinyl, and pyrido[3,2-b]pyridinyl, pyridoll4,3-b]pyridinyl.

Particularly useful compounds in accordance with the present invention include 5,8,9,10,1 4-pentaacetoxy-3 -benzoyloxy-1I5-hydroxypepluane (pepluane), derivatives of said pepluane, jatrophanes of Conformation HI including 2,3,5,7,1 5-pentaacetoxy-9niicotinoyloxy-14-oxojatropha-6(17),1 LE-diene (jatrophane derivatives of said jatrophane 1, 2,5,7,8,9,1 4-hexaacetoxy-3-benzoyloxy- 15-hydroxy-jatropha-6( 17),I1 Ediene (jatrophane derivatives of said jatrophane 2, 2,5,14-triactoxy-3-benzoyloxy- 8,1 5-cihydroxy-7-isobutyroyloxy-9-nicotinoyloxy-j atropha-6(17),1 lE-diene (jatrophane derivatives of said j atrophane 3, 2,5,9,14-tetraactoxy-3-benzoyloxy-g,l 5-dihydroxy-7isobutyroyloxyjatropha-6(17),l lE-diene) (jatrophane derivatives of said jatrophane 4, 2,5,7,1 4-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(1 1EBdiene (jatrophane derivatives of said jatrophane 5, 2,5,7,9,14-pentaacetoxy-3benzoyloxy-8, 15-dihydroxyjatropha-6(17),l IE-diene OIatrophane derivatives of said jatrophane 6, or pharmaceutically acceptable salts of these.

Even more particularly preferred compounds are angeloyl substituted ingenanes or derivatives thereof such as ingenol-3-angelate, 20-deoxy-ingenol-3-angelate, 20-0-acetylingenol-3-angelate, or derivatives of said angelates, or pharmaceutically acceptable salts of these.

The present invention extends to all functional jatrophane or pepluane derivatives. For example, such derivatives include acetyl derivatives jatrophane 4 with an acetylation of the 8-hydroxyl group), deacytlated derivatives jatrophane 1 with a deacetylation of the 2-hydroxy group). Pepluane derivatives as described by Hohmann et al. (1999) or with a hydroxylation of the 1 0-hydroxy group and all of the compounds described in International Patent Application No. PCT/AU98/00656, International Patent Application No. PCT/AUOI/00678, International Patent Application No. PCT/AUO1/00679 and International Patent Application No. PCT/AU01/00680 are also within the scope of the WO 02/11743 PCT/AU01/00966 -29present invention. Other exemplary derivatives contemplated by the present invention include angeloyl derivatives of jatrophanes and pepluanes, tiglic acid derivatives and derivatives comprising the trans-isomer of angelic acid. Derivatives or analogs of the compounds also include alterations which change the hydrophilicity or hydrophobicity of the molecule so as to improve its transport in a biological system are also encompassed within this scope. Suitable modifications can readily be effected and tested using methods known in the art. Whilst not intending to limit the invention to any proposed mechanism or action, it is proposed that activation can lead to down-regulation of protein kinase C (PKC) via the rapid destruction of activated enzyme and thus the beneficial effect may be due to the ultimate down-regulation of PKC activity or of PKC-mediated signalling in addition to direct killing of prostate cancer cells. Furthermore, again not wishing to limit the present invention to any one theory or mode of action, it is possible that a sum or all of the chemical agents of the invention mediate effects against cancer cells via activation of inflammatory cells and/or by the induction of cytokines and/or chemokines.

Accordingly, a particularly preferred embodiment of the present invention contemplates a method for the treatment or prophylaxis of a subject with prostate cancer or a related cancer or condition or with the symptoms of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of an angeloylsubstituted ingenane or a chemical fraction or plant extract comprising same.

Even more preferably, the present invention provides a method for the treatment or prophylaxis of a subject with prostate cancer or a related cancer or condition or with the symptoms of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of one or more of ingenol-3-angelate, ingenol-3-angelate and/or 20-O-acetyl-ingenol-3-angelate or a derivative thereof or a pharmaceutically acceptable salt of these or a chemical fraction or plant extract comprising same. Preferably, the derivative is selected from an ester derivative or an acetylated derivative.

The chemical agents of the present invention may be also optionally coupled to a targeting WO 02/11743 PCT/AU01/00966 agent. This may suitably be a bone-seeking agent such as a bisphosphonate, in order to target the chemical agents to bone metastases or an antibody directed to a prostate-specific tumor marker such as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), PSA receptor or other prostate cancer antigen, in order to target the active compound to prostate cancer cells. A preferred bisphosphonate is methylene disphosphonate. Where an antibody is used, the antibody is preferably monoclonal and more preferably is a humanized or human monoclonal antibody. Antibodies may be specific not only to prostate-specific tumor markers but also to components of the immune system such as dendritic cells, B- or T-cells. Methods for making such monoclonal antibodies and suitable methods for coupling the active agent to the targeting agent are well known in the art.

Representative coupling methods for linking the chemical agents of the invention through covalent or non-covalent bonds to the targeting agent include chemical cross-linkers and heterobifunctional cross-linking compounds "linkers") that react to form a bond between reactive groups (such as hydroxyl, amino, amido, or sulfhydryl groups) in a chemical agent and other reactive groups (of a similar nature) in the targeting agent. This bond may be, for example, a peptide bond, disulfide bond, thioester bond, amide bond, thioether bond and the like. In one illustrative example, conjugates of monoclonal antibodies with drugs have been summarized by Morgan and Foon (Monoclonal Antibody Therapy to Cancer: Preclinical Models and Investigations, Basic and Clinical Tumor Immunology, Vol. 2, Kluwer Academic Publishers, Hingham, Mass.) and by Uhr J. of Immunol. 133:i-vii, 1984). In another illustrative example where the conjugate contains a radionuclide cytostatic agent, U.S. Patent No. 4,897,255 (Fritzberg et al.) is instructive of coupling methods that may be useful. In a preferred embodiment, the therapeutic conjugate contains a metastasis- or prostate cancer specific antigen-binding protein monoclonal antibody) coupled covalently to a chemical agent of the invention. In this case, the covalent bond of the linkage may be formed between one or more amino, sulfhydryl, or carboxyl groups of the binding protein and the chemical agent itself; a carboxylic acid of the chemical agent; an ester of the chemical agent; or complexes of the chemical agent with poly-L-lysine or any polymeric carrier.

WO 02/11743 PCT/AU01/00966 -31- The choice of coupling method will be influenced by the choice of targeting agent and the chemical agent and also by such physical properties as, e.g. shelf life stability and/or by such biological properties as, e.g. half-life in cells and blood, intracellular compartmentalisation route and the like.

Reference herein to a subject includes a human, primate, livestock animal sheep, cow, horse, pig, goat, donkey), laboratory test animal mouse, rat, guinea pig, hamster) or companion animal dog, cat). The above-mentioned animals may also be useful in animal models for prostate cancer and the use of the subject chemical agents in an animal model is considered useful in accordance with the present invention.

The preferred subject is a human or primate or laboratory test animal.

The most preferred subject is a human.

The present invention further contemplates the use of the subject chemical agents in combination with other therapeutic procedures used in the treatment of prostate cancer and/or in the amelioration of symptoms associated with prostate cancer.

Accordingly, another aspect of the present invention contemplates a method for the treatment or prophylaxis of prostate cancer or a related cancer or condition in a subject, said method comprising the simultaneous or sequential administration to said subject of a symptom-ameliorating effective amount of'a chemical agent derived from a plant of the Euphorbiaceae family as hereinbefore described together with a therapeutic protocol or a symptom-ameliorating effective amount of another chemical agent or a physical agent.

For example, the subject chemical agents from Euphorbiaceae maybe used simultaneously with or sequentially to or otherwise in combination with chemotherapeutic agents. Such agents include the compounds gemicitabine, herceptin, irinotecan, leustatin navelbine, rituxan, ST1 571, taxotere, topotecan, xeloda, zometa vinblastine, vinorelbine, vinaesine, WO 02/11743 WO 0211743PCT/AU01/00966 -32treosulfan, tomudex, thiotepa, thioquaunine, streptozocin, procabazine, mitomycin, methotrexate mercaptopurine, melphaan, lomustine, irinotecan, ipospamide, idarubicin, gemacitabine fludarabine, etoposide, epirubicin, doxorubicin, paunorubicin, dacarbazine, cytarabine, cyclophosphamide, cisplatin, chiorambucil, carinustine, carboplatin, busuiphan, bleomycin, asparaginase, adriamycin, actinomycin P, mitoxanthrone, prednisone, taxol VP- 16 and ketokonazole.

The present invention also provides for use of cheinopreventive agents in combination with the chemical agents of the invention. Such chemopreventive agents include toremifene analogs or metabolites thereof which are well known to those skilled in the art.

Other examples of cancer chemopreventive agents include 4-chloro-l1,2-diphenyl-1-[4- [2- (N-methylanaino)ethoxy]phenyl]-1-butene; 4-cbloro-l ,2-diphenyl-4-[4-[2-(NN-1-diethylamino)ethoxy~phenyl]- 1-butene; 4-chloro-1 ,2-diphenyl-1 -14-(aniinoethoxy)phenyl]-1butene; 4-chloro-1 -(4-hydroxyphenyl)-1-[4-[2-(NN-dimethylamino)ethoxy]phenyl] -2phenyl- I-butene; 4-cbloro-l-(4-hydroxyphenyl)-1 [2-(N-methylamino)ethoxy]phenyl]- 2-phenyl-l1 -butene; and '4-chioro-1I,2-bis(4-hydroxyphenyl)-1-[4-[2-(NN-dimethylamino)ethoxy]phenyl]- 1-butene.

"Sequential" treatment includes the administration of Euphorbiaceae compounds and the chemotherapeutic compounds in either order and within seconds, minutes, hours, days, weeks or months. "Simultaneous" treatment means the agents are administred substantially at the same time such as in the same preparation or the concurrent administration of each agent by separate routes.

Prostate cancer therapy may in addition or as an alternative involve hormone therapy. Such hormone therapy includes the administration of gonadotrophic-releasing hormones (GuRH) (also known as luteinizing hormone-releasing hormones (LHiRH), lupron, zolodex, casodox, flutaniide and estrogen or analogs thereof.

Another prostate cancer therapy contemplated for use in combination with the Euphorbiaceac compounds is immunotherapy. For example, monoclonal antibodies WO 02/11743 PCT/AU01/00966 -33including human antibodies and humanized non-human antibodies directed to prostate cancer antigens may be administered. Alternatively, vaccine compositions directed to prostate cancer agents may be used. Examples of prostate cancer antigens include but are not limited to seminoprotein f-micro seminoprotein and isoforms and differentially acylated versions of isoforms and epitopes on fragments, carcinoembryonic antigen, chymotrypsin-like serine protease, members of the kallikrein family of proteins, prostate stem cell antigen and PSMA.

Still other therapies include exposure of the subjects or affected areas on subjects to physical agents. An example of a physical agent is radiation such as UV radiation, ionizing radiation or radioactive particles.

Furthermore, the administration of the above therapeutic agents or treatments may also accompany interventionist procedures such as surgery or biopsy.

In addition, prostate cancer therapy may also involve the reduction in expression of certain genes associated with prostate cancer such as metastatic sequences. Examples include the caveolin gene. Such genes or sequences may be down-regulated using, for example, antisense technology, sense suppression, co-suppression, ribozymes or molecules which induce RNAi specific for the genes or their transcripts. Alternatively, or in addition, an anti-caveolin antibody or antigen-binding fragment thereof may be administered.

The present invention further extends to pharmaceutical compositions useful in treating a subject presenting with prostate cancer or the symptoms of prostate cancer. In this regard, the chemical agents of the present invention can be used as actives for the treatment or prophylaxis of prostate cancer or a related condition in a subject. The chemical agents can be administered to a patient either by themselves, or in pharmaceutical compositions where they are mixed with a suitable pharmaceutically acceptable carrier alone or in combination with other compounds such as anti-cancer compounds.

WO 02/11743 PCT/AU01/00966 -34- Accordingly, the present invention also provides a composition for treatment and/or prophylaxis of prostate cancer or a related cancer or condition in a subject, comprising one or more chemical agents of the present invention, together with a pharmaceutically acceptable carrier and/or diluent, and optionally one or more other active compounds.

The term "composition" includes an agent or other formulation.

Depending on the specific conditions being treated, chemical agents may be formulated and administered systemically or locally. Topical and/or intralesional administration are particularly useful in the practice of the present invention. Techniques for formulation and administration may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest edition. Suitable routes may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The agents may also be delivered at or near the site of the tumor by catheter delivery into blood vessels supplying the prostate. For injection, the chemical agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Intra-muscular and subcutaneous injection is appropriate, for example, for administration of immunomodulatory compositions and vaccines.

The chemical agents can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the invention to be formulated in dosage forms such as tablets, beads, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. These carriers may be selected from sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, WO 02/11743 PCT/AU01/00966 alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, and pyrogen-free water. Slow release formulations are also contemplated by the present invention.

Formulations of active compounds in beads or other microparticles are particularly useful for topical or intralesional administration and are specifically encompassed by the present invention.

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. The dose of agent administered to a patient should be sufficient to effect a beneficial response in the patient over time such as a reduction in the symptoms associated with prostate cancer or related condition in a subject. The quantity of the agent(s) to be administered may depend on the subject to be treated inclusive of the age, sex, weight and general health condition thereof. In this regard, precise amounts of the agent(s) for administration will depend on the judgement of the practitioner. In determining the effective amount of the chemical agent to be administered in the treatment or prophylaxis of a condition associated with prostate cancer or related condition, the physician may evaluate progression of the disorder. In any event, those of skill in the art may readily determine suitable dosages of the chemical agents of the present invention.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

WO 02/11743 PCT/AU01/00966 -36- Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as., for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association one or more chemical agents as described above with the carrier which constitutes one or more necessary ingredients. In general, the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or lyophilising processes.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

WO 02/11743 PCT/AU01/00966 -37- Dosage forms of the chemical agents of the present invention may also include injecting or implanting controlled releasing devices designed specifically for this purpose or other forms of implants modified to act additionally in this fashion. Controlled release of an agent of the present invention may be effected by coating the same, for example, with hydrophobic polymers including acrylic resins, waxes, higher aliphatic alcohols, polylactic and polyglycolic acids and certain cellulose derivatives such as hydroxypropylmethyl cellulose. In addition, controlled release may be effected by using other polymer matrices, liposomes and/or microspheres, for example CaptisolR or hyaluronic acid. Encapsulation is preferred for permitting controlled release of the subject chemical agents. Preferred vehicles for encapsulation include but are not limited to the microspheres described, for example, by Kanellakopoulou et al. (2000), Jain et al. (1998) and Thomasin et al. (1998) and the liposomal deliver systems described, for example, by Gabizon (2001), Kunisawa et al. (2001), Muggia (2001) and Nishioka et al. (2001).

Chemical agents of the present invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulphuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.

For any chemical agent used in the method of the present invention, the therapeutically effective dose can be estimated initially from cell culture assays such as to reduce the growth of prostate cancer cells in vitro. For example, a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC50 as determined in cell culture the concentration of a test agent, which achieves a half-maximal inhibition of cancer cells). Such information can be used to more accurately determine useful doses in humans.

Toxicity and therapeutic efficacy of such chemical agents can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically WO 02/11743 PCT/AU01/00966 -38effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. Compounds that exhibit large therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosages for use in humans.

The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (see for example Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pl).

Dosage amount and interval may be adjusted individually to provide plasma levels of the active agent which are sufficient to maintain symptom-ameliorating effects. Usual patient dosages for systemic administration range from 1-2000 mg/day, commonly from 1-250 mg/day, and typically from 10-150 mg/day. Stated in terms of patient body weight, usual dosages range from 0.02-25 mg/kg/day, commonly from 0.02-3 mg/kg/day, typically from 0.2-1.5 mg/kg/day. Stated in terms of patient body surface areas, usual dosages range from 0.5-1200 mg/m 2 /day, commonly from 0.5-150 mg/m 2 /day, typically from 5-100 mg/m 2 /day.

Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into a tissue, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the tissue. In cases of local administration or selective uptake, the effective local concentration of the agent may not be related to plasma concentration.

The chemical agents of the present invention can also be delivered topically. For topical administration, a composition containing between 0.001-5% or more chemical agent is generally suitable. Regions for topical administration include the skin surface and also WO 02/11743 PCT/AU01/00966 -39mucous membrane tissues of the vagina, rectum, nose, mouth, and throat. Compositions for topical administration via the skin and mucous membranes should not give rise to signs of irritation, such as swelling or redness.

The topical composition may include a pharmaceutically acceptable carrier adapted for topical administration. Thus, the composition may take the form of a suspension, solution, ointment, lotion, sexual lubricant, cream, foam, aerosol, spray, suppository, implant, inhalant, tablet, capsule, dry powder, syrup, balm or lozenge, for example. Methods for preparing such compositions are well known in the pharmaceutical industry.

In one embodiment, the topical composition is administered topically to a subject, e.g. by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a "patch". Such compositions include, for example, lotions, creams, solutions, gels and solids. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein a chemical agent of the present invention. The carrier may include pharmaceutically-acceptable emollients, emulsifiers, thickening agents, solvents and the like.

The present invention also features a process for separating diterpenes from a biomass containing same, said process comprising contacting the biomass with an aqueous solvent for a time and under conditions sufficient to extract the diterpenes into said solvent.

The aqueous solvent is preferably water.

Suitably, the biomass is derived from a plant, which is preferably a member of the Euphorbiaceae family of plants or botanical or horticultural relatives of such plants. Matter from the plant foliage, stems, roots, seeds, bark, etc.) is preferably cut, macerated or mulched to increase the surface area of the plant matter for aqueous extraction of the diterpenes.

WO 02/11743 PCT/AU01/00966 The process preferably further comprises adsorbing the diterpenes to a non-ionic adsorbent, which is suitably a non-ionic porous synthetic adsorbent. Among the non-ionic porous synthetic adsorbents that can be used for the purposes of the present invention include, but are not restricted to, aromatic copolymers mainly composed of styrene and divinylbenzene, and methacrylic copolymers mainly composed of monomethacrylate and dimethacrylate. Such non-ionic porous synthetic adsorbents which comprise, as the basic structure, aromatic copolymers mainly composed of styrene and divinylbenzene include, for example, Diaion HP10, HP20, HP21, HP30, HP40, HP50, SP850, and SP205 (trade names: Mitsubishi Chemical Corp.), and Amberlite XAD-2, XAD4, (trade names: Rohm and Haas Examples of non-ionic porous synthetic adsorbent which comprise, as the basic structure, methacrylic copolymer mainly composed of monomethacrylate and dimethacrylate are Diaion HP2MG, Amberlite XAD-7, XAD-8 and XAD-16 and others.

Preferably, the process further comprises eluting diterpenes from the non-ionic adsorbent with water and water-soluble organic solvent(s).

The treatment may be conducted by a batch method using water and water-soluble organic solvent(s) which dissolve diterpenes, or may also be conducted continuously or in batch using a column chromatography method.

Examples of a water-soluble organic solvent which may be used in the present invention are alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, and tertbutanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone, amides such as dimethylformamide, sulfur-containing compounds such as dimethylsulfoxide. Two or more of such organic solvents may be mixed for use. In addition, solvents less soluble in water, for example, alcohols such as n-butanol, esters such as methyl formate and methyl acetate, and ketones such as methyl ethyl ketone may also be used to the extent that it does not separate during development. Particularly preferred water-soluble organic solvents are alcohols, in particular, methanol, ethanol, propyl alcohol, and the like. Furthermore, different kinds of solvent may also be used sequentially for development.

WO 02/11743 PCT/AU01/00966 -41- Diterpenes can be further purified using media and techniques which separate compounds on the basis of molecular size and/or polarity. In a preferred embodiment of this type, the diterpenes are separated using Sephadex LH-20 resin and preferably using water and water-soluble organic solvent(s) for development.

The testing of the chemical agents of the present invention is conveniently conducted using in vivo animal models for prostate cancer or related cancer. Any number of animal models are available. For example, surgical orthotopic implantation of histologically intact fragments of human prostate cancer may be transplanted to immunodeficient animals such as rodents. See, for example, Hoffnan (1999); Segawa et al. (2000).

There are also a range of in vitro models such as those described in the Examples herein or by Anidjar et al (2001).

The present invention is further described by the following non-limiting Examples.

WO 02/11743 PCT/AU01/00966 -42- EXAMPLE 1 Materials and methods Cells were cultured in RPMI1640 medium-10% w/v FCS in 5% v/v CO 2 and 5% v/v oxygen. The latter reproduces physiological conditions and is considered useful in assessing the molecular responses of normal and tumor cells to drugs. Inhibition of cell growth was determined 5-7 days after drug treatment by assay of cell numbers with sulforhodamine B (SRB) in microtitre plates.

General cell signalling activity of the E. peplus compounds is quantitated by a sensitive assay which the present inventors have developed, in which cells are simultaneously treated with the drug and infected with a non-relicating adenovirus containing the CMV promoter, which drives expression of /-galactosidase (in place of Ela). Approximately 24 hours later, the 3f-galactosidase activity is measured in an ELISA reader. The sensitivity of this assay ng/ml TPA) is sufficient to measure bioactivity in blood and organs and serves as the basis for comparison of structures and for translating doses determined in the mouse to humans.

Primary, short-term cultures of adherent tumor cells are established from aspirates for drug treatments.

DNA flow cytometry (FACSCAN) is used for determining effects on the cell cycle.

Microarrays of 4000 human cDNA sequences spotted on microscope slides are hybridized with fluorescent-labelled cDNA from reverse-transcribed cellular mRNA and quantitated as described by Bowtell (1999).

WO 02/11743 PCT/AU01/00966 -43- EXAMPLE 2 Pre-treatment of human tumor cells in culture with diterpene esters potentiates Sselective killing by untreated leukocytes The question of whether drug treatment of the target tumor cells causes them to become susceptible to effector cells of the immune system was addressed as follows.

Leukocytes obtained by lysis of human peripheral blood were added to 5000 MM96L human melanoma cells or 7000 neonatal foreskin fibroblasts per microtitre well at effector: target ratios of 1000, 100 and 10:1. The target cells had been treated with 60 ng/mL PEP008 for 20 hr beforehand, and washed and the medium replaced before the leukocytes were added. After 48 hr incubation with the leukocytes the cultures were washed and labelled with [3H]-thymidine for 2 hr. At 100:1 ratio of effector:target cells, the melanoma cells showed 12% survival with PEP008 whereas the normal fibroblasts had 100% survival. Untreated leukocytes had no effect on cell survival.

This result showed that the drugs also act by making tumor cells specifically sensitive to lysis by the immune system.

EXAMPLE 3 Effect of E. peplus sap on prostate cancer cells The ability of E. peplus sap to kill prostate cancer cells selectively was assessed by comparing the effect of the sap on prostate cancer cell lines and on normal fibroblasts.

Three prostate cancer cell lines were used; PC-3 and DU145 are hormone resistant prostate cancer cell lines and LNcap is a hormone-sensitive prostate cancer cell line.

The prostate cancer cell lines or normal fibroblasts were suspended to a concentration of X 103 cells/well in RPMI1640 tissue culture medium containing 10% w/v FCS, volume 0.1 ml in microtitre plates.

WO 02/11743 PCT/AU01/00966 -44- The cells were incubated for 6 hr at 37C, followed by the addition of E. peplus crude sap (approximately 110 mg dry solids per ml) to the final dilutions, as shown in Figure 1. After days, cells were scored visually for survival morphology changes and survival was also assessed by 3 H-thymidine incorporation into cell mass. The results are expressed as percentages of cell survival relative to the control (cells without drug treatment).

It can be seen that there was a concentration-dependent inhibition of all three prostate cancer cell lines, whereas normal fibroblasts remained unaffected or increased in number of concentrations of sap below 100 ig/ml.

EXAMPLE 4 The in vitro activity of the pure compounds E. peplus compounds already known to be active on other tumor types are tested for growth inhibition of the three prostatic cancer cell lines used in Example 1 and against primary cultures of tumor cells obtained by aspiration of bone marrow metastases from patients. Three patient samples are considered sufficient to confirm potency and selectivity in humans; approximately 20 suitable patients, who have accessible bone metastases in the spine, but are well enough to undergo the procedure, are available in Brisbane each year.

The E. peplus compounds are compared to TPA and Taxol as regards potency and selectivity against tumor cells.

The two best candidate compounds, which are shown to be potent and selective compared with activity against normal fibroblasts and bladder endothelial cells are then evaluated in xenografts of tumor cells in nude mice. This model is widely used in the art (see, for example, Agus et al., 1999; El Etreby et al., 2000; Navone et al., 1998) and is sufficient to evaluate drugs for treatment of metastatic disease. The diterpenes are lipophilic and are expected to be capable of reaching the bone marrow.

WO 02/11743 PCT/AU01/00966 Moreover, less polar derivations of the ingenane, pepluane and jatrophane structures are readily prepared, for example, by acylation of the C8 hydroxyl of the jatrophanes.

EXAMPLE Optimizing the use of the E. peplus compound It is expected that, as found by Han et al. (1998) for TPA and by others for Taxol, the drug dose can be increased in the presence of an anti-inflammatory agent such as prednisolone.

The optimum level of prednisolone is determined in the mouse model and then the dose of diterpene increased, in order to obtain maximum non-toxic daily dosing for at least three days.

On the basis of the anticipated cell cycle arrest by E. peplus diterpenes and from results with TPA, it is expected that a range of currently available drugs such as hydroxyurea, topoisomerase inhibitors and other PKC inhibitors will synergize the action of the E.

peplus diterpenes if administered at a suitable time. This is assessed in two ways. The candidate drugs are given to cultured prostatic cancer cells (cell lines and fresh tumor cells) at different temporal combinations with E. peplus diterpenes, to ascertain synergism.

Second, cDNA microarray profiling is carried out, preferably with fresh cultures and cDNA amplification used to determine the changes in gene expression induced by these drugs in prostate cancer cells. Changes that are exploited pharmacologically are followed up in vitro and then in vivo.

In a third approach, the most active diterpenes are chemically linked to methylene diphosphonate (MDP), a bone-seeking compound commonly used as an imaging agent (Norris et al., 1999) and the activity of the conjugate tested against prostate cancer cells.

The diterpenes are aliphatic esters which should be capable of an exchange reaction with a suitable derivative of MDP and would then be released by esterase activity in the bone marrow. The diterpenes have been found to be stable in human plasma and are not toxic to lymphoid cells. Combining physical and biological selectivity in this way may be highly advantageous.

WO 02/11743 PCT/AU01/00966 -46- EXAMPLE 6 Clinical trial It is estimated that 200-300 new cases of advanced prostate cancer present each year in Brisbane and the power of evaluation by the prostate specific antigen (PSA) test (Schroder et al., 2000) is such that only 20 patients will be required in the first instance if a 50% drop in PSA is taken as an indicator of response. Sterile diterpene and anti-inflammatory are administered essentially as described by Han et al. (1998) for TPA except that the first dose is 1/3 of the bioactivity of the amount of TPA used by Han et al. (1998) (based on the range of in vitro and in vivo data available). This dose is subsequently escalated. Vital signs are monitored closely during the first 48 hr. Blood profiles, including PSA, are measured weekly for four weeks, at which time a decision is made whether to repeat the treatment. A similar protocol is used for experiments involving intralesional injections and for the use of slow release formulations, beads or capsules.

The level of active diterpene in the blood is detected by bioassay on a tumor cell line as assessed by induction of fi-galactosidase due to transcriptional activation of the CMV promoter; the sensitivity of the assay is <1 ng/ml, which can be further enhanced by solvent extraction, concentration and HPTLC, if necessary. The changes in PSA (natural log PSA; Schroder et al., 2000; Vollmer et al., 1999) and other clinical indicators are correlated to determine the outcome of the trial. A reduction in PSA of >50% over three months is sought; however, pain relief, stabilization of disease and bone scans are also considered.

EXAMPLE 7 Topical treatment of DU145 prostate tumor in nude(nu"" mice with PEPO03 To assess whether the E. peplus compounds reduce tumors in mice, a DU145 prostate tumor was implanted into nude(nunu) mice and treated with PEP003 (see Table Ten mice were divided up into two groups of four mice and six mice, a control group and a WO 02/11743 PCT/AU01/00966 -47treatment group, respectively. In both groups, each mouse was injected with 1 x 106 ul) DU145 prostate tumor cells into each of two sites. After 20 days, the tumor was visible (4 mm 3 In the control group, all tumor sites were treated by a single topical application of 2 utl of 100% v/v acetone. In the treatment group, all tumor sites were treated by a single topical application of 2 tl of PEP003 in 100% v/v acetone, containing approximately 50 pg of PEP003. The mice were observed for nine weeks and the tumor size measured. Control mice were sacrificed before tumor burden became excessive.

The results (Figure 2) show a rapid increase of DU145 prostate tumor in the control group, to an average tumor size of 167 mm 3 46 days post inoculation. The results also show that treatment of DU145 prostate tumor by topical application of PEP003 cured the tumor, without re-growth after 62 days.

The data clearly show that topical application of PEP003 onto subcutaneous DU145 prostate tumors in nude(nu/nu) mice causes tumor cure.

EXAMPLE 8 Topical treatment of PC-3 prostate tumor in nude"" u- mice with PEP003 To assess whether the E. peplus compounds reduce tumors in mice, PC-3 prostate tumor was implanted into nude(n" mice and treated with PEP003 (see Table Thirteen mice were divided up into two groups of five mice and eight mice, a control group and a treatment group, respectively. In both groups, each mouse was injected with 1 x 106 pl) PC-3 prostate tumor cells into each of two sites. After three days, the tumor was visible (4 mm 3 In the control group, all tumor sites were treated by a single topical application of 2 pl of 100% v/v acetone. In the treatment group, all tumor sites were treated by a single topical application of 2 pl of PEP003 in 100% v/v acetone, containing approximately 50 ug of PEP003. The mice were observed for five weeks and the tumor size measured. Control mice were sacrificed before tumor burden became excessive.

WO 02/11743 PCT/AU01/00966 -48- The results (Figure 3) show a rapid increase of PC-3 prostate tumor in the control group, to an average tumor size of 136 mm 3 37 days post inoculation. The results also show that treatment of PC-3 prostate tumors by topical application of PEP003 cured the tumor, without re-growth after 37 days.

The data clearly show that topical application of PEP003 onto subcutaneous PC-3 prostate tumors in nude(nu nu) mice causes tumor cure.

EXAMPLE 9 Intralesional treatment of PC-3 prostate tumor in nude(nu-/nu-) mice with PEP003 To assess whether the E. peplus compounds reduce tumors in mice, PC-3 prostate tumor was implanted into nude("nu-) mice and treated with PEP003 (see Table Ten mice were divided up into two groups of six mice and four mice, a control group and a treatment group, respectively. In both groups, each mouse was injected with 1 x 106 (50 il) PC-3 prostate tumor cells into each of two sites. After six days, the tumor was visible (1 mm 3 In the control group, all tumor sites were treated by a single intralesional injection of 10% v/v acetone in saline. In the treatment group, all tumor sites were treated by a single intralesional injection of 10% v/v acetone in saline (50 pl), containing approximately 6.25 ug of PEP003. The mice were observed for 19 weeks and the tumor size measured. Control mice were sacrificed before tumor burden became excessive.

The results (Figure 4) show a rapid increase of PC-3 prostate tumor in the control group, to an average tumor size of 100 mm 3 34 days post inoculation. The results also show that treatment of PC-3 prostate tumors by intralesional injection of PEP003 cured the tumor, without re-growth after 131 days.

The data clearly show that intralesional injection of the PEP003 onto subcutaneous PC-3 prostate tumors in nude(nu 4nu mice causes tumor cure.

WO 02/11743 PCT/AU01/00966 -49- EXAMPLE Intralesional treatment of DU145 prostate tumor in nude(nu-/nu-) mice with PEP003 To assess whether the E. peplus compounds reduce tumors in mice, DU145 prostate tumor was implanted into nude u au mice and treated with PEP003 (see Table Six mice were divided up into two groups of four mice and two mice, a control group and a treatment group, respectively. In both groups, each mouse was injected with 1 x 106 (50 1Il) DU145 prostate tumor cells into each of two sites. After 20 days, the tumor was visible (2 mm 3 In the control group, all tumor sites were treated by a single intralesional injection of 10% v/v acetone in saline. In the treatment group, all tumor sites were treated by a single intralesional injection of 10% v/v acetone in saline (50 gl), containing approximately 2.5 gg of PEP003. The mice were observed for nine weeks and the tumor size measured. Control mice were sacrificed before tumor burden became excessive.

The results (Figure 5) show a rapid increase of DU145 prostate tumor in the control group, to an average tumor size of 167 mm 3 46 days post inoculation. The results also show that treatment of DU145 prostate tumors by intralesional injection of PEP003 cured the tumor, without re-growth after 62 days.

The data clearly show that intralesional injection of PEP003 onto subcutaneous DU145 prostate tumors in nude(nu" u mice causes tumor cure.

EXAMPLE 11 Synergisitic combination ofPEPOOS, PEPO06 or PEPO08 with cisplatin or suberic dihydroxamic amino acid on DU145 prostate cancer cell cytotoxicity DU145 prostate cancer cells were treated with a drug combination comprising a purified preparation of an angeloyl-substitued ingenane selected from PEP005, PEP006 or PEP008 and a chemotherapeutic agent selected from cisplatin or suberic dihydroxamic amino acid (SBHA) to assess whether such combination displays synergistic effects on prostate cancer cytotoxicity.

WO 02/11743 PCT/AU01/00966 The prostate cancer cells were treated with PEP006 and cisplatin, PEP008 and cisplatin, PEP005 and SBHA, PEP008 and SBHA and PEP005 and cisplatin for 24 hr after which the medium was changed and the cells permitted to grow in the presence of 3 H-thymidine for five days. The percentage cell survival was determined by measuring the incorporation of 3 H-thymidine in the cells.

The results presented in Figures 6A to 6E indicate that combinations of cisplatin or SBHA together with PEP005, PEP006 or PEP008 produce greater cytotoxicity compared to the additive cytotoxicity of the compounds when administered alone and are, therefore, synergistic combinations.

EXAMPLE 12 Methodsfor obtaining a low-chlorophyll, hydrophobic fraction from E. peplus and other plant species Standard methods for the isolation of hydrophobic compounds from plants involve alcoholic extraction of the whole plant. This produces an extract containing chlorophyll and other hydrophobic substances from the leaves that interfere with subsequent purification of compounds by solvent extractions and chromatography. This is a particular problem in isolating highly bioactive diterpenes from members of the Euphorbiaceae family, due to co-migration with chlorophyll on silica gel chromatography. Two methods, both of which can be scaled up for economical, commercial production, have been developed to overcome this problem, as described in the present Example and in Example 14.

Fresh E. peplus plants (17 kg) were chopped and soaked in 150 litres of water at 4 0 C for hr. The water was pumped through 50 and 100 mesh sieves, filtered through 5 and 2 micron filters and then recirculated through a 100 mm diameter column of Amberlite XAD-16 (1.5 kg, conditioned successively with ethyl acetate, methanol and water) at 4°C (approximately 1.2 L/min) for 72 hr. Adsorption of bioactivity to the resin was found to be virtually complete within 20 hr.

WO 02/11743 PCT/AU01/00966 -51- The resin was then washed successively with water and 50% v/v methanol, then eluted with 1L of methanol, followed by 2 x 1L acetone. The eluates were evaporated and combined to give approximately 7 g of a thick oil. This was shown by HPTLC to be substantially free of chlorophyll and to contain the desired ingenane esters which were then purified as described below.

The ability to extract diterpene esters from chopped plants in water was surprising given their relative hydrophobicity and water insolubility. A variety of manual (cutting with scissors) and mechanical (rotary cutters, motor-driven mulcher) plant maceration methods were successful, as was extraction at room temperature. Adsorption to the XAD-16 could be achieved by stirring the resin with the filtered or unfiltered water extract and then pouring off the latter. Filtration could also be carried out with minimal loss of bioactivity using diatomaceous earth, or membrane filters (220-650 microns). XAD-7 and XAD-4 were as effective as XAD-16.

The hydrophobic adsorbent polyamide (ICN Biomedical Research Products) was also used to trap the diterpenes from water; it had the advantage of allowing the diterpene esters to be selectively eluted with 50-80% v/v methanol, thus separating them from inactive, hydrophobic compounds, which remained on the column.

EXAMPLE 13 Method for separation of ingenane esters from other diterpenes The following method is based upon the surprising discovery that the stems of E. peplus contain approximately 90% of the bioactive diterpenes and significantly less chlorophyll compared with the leaves.

The plants are dried in air, shaken to remove the leaves and the stems compressed and covered with an equal weight of methanol for 24 hr. The solvent is then poured off, evaporated to dryness under reduced pressure and the residue dissolved in methanol for WO 02/11743 PCT/AU01/00966 -52chromatography on Sephadex LH-20 as described below. This method is also suitable for isolation of low-chlorophyll fractions from other plant species.

A solution of crude methanol extract from E. peplus in 4 mL 90% v/v ethanol was loaded onto a 25 mm x 1000 mm column and eluted with 90% v/v methanol. Fractions (4 mL) were analyzed by HPTLC (silica gel, developed with 4:1 toluene: acetone and heated with phosphoric acid at 110 0 C for 15 min). Typically, fractions 54-63 contained jatrophane and pepluane esters and fractions 64-77 the ingenane esters, thus achieving satisfactory separation. Bioactivity, as judged by induction of bipolar morphology in the human melanoma cell line MM96L, was retained as, for example, disclosed in International Patent Application No. PCT/AU98/00656.

This separation was surprising because the polarity of the ingenane esters as judged by HPTLC on silica completely overlapped the range shown by the jatrophane and pepluane esters.

EXAMPLE 14 Process for the purification of diterpene esters from E. peplus Crude extracts obtained by the methods according to Examples 17 or 18 above, or by ether extraction of latex, were fractionated by Sephadex HL-20 chromatography (as above).

Appropriate fractions from the latter were combined, the methanol evaporated under reduced pressure and the remaining water removed by freeze-drying or by ether extraction.

This sample (200 tL of 100 mg/mL in methanol per injection) was fractionated by HPLC on a Phenomenex Luna 250 x 10 mm C18 column with a Phenomenex guard column in 70-100% v/v methanol at 2 mL/min, with detection at 230 nm. Jatrophane and pepluane esters appeared at 25-42 min, PEP005 at 42-44 min, PEP008 at 46-50 min, and PEP006 at 50-54 min. Similar types of separation have been obtained by HPLC on C3 and C8 columns.

WO 02/11743 WO 0211743PCT/AIJQ1/00966 -53- Fractions pooled from repeated runs were evaporated to dryness (rotary evaporater or freeze dryer) and stored in acetone at. -20' C under argon or nitrogen.

Speculative procedures for synthesis of bisphosphonate substituted ingenanes.

EXAMPLE Synthesis of 2O-chloro-20-deoxyingenol 3,S-dibenzoate fromn ingenol Schemne I Ingenol can be converted to 20-chloro-20-deoxyingenol 3,5-dibenzoate by the procedure reported in Appendino et al. (1999). Thus, ingenol can be converted to ingenol ether by treatment with trityl chloride and 4-(N,N-dimethylamino)pyridine in dry pyridline.

ether can be converted to ingenol 3,5-benzoate by treatment with benzoic acid, 1 -(3-diniethylaminopropyl)-3-ethylcarbodiimide hydrochloride and dimethylaminopyridine in dichioromethane followed by reaction with metbanolic perchloric acid.

Ingenol 3,5-dibenzoate can be converted to 20-cbloro-20-deoxyingenol 3,5-dibenzoate by reaction with hexachloroacetone and triphenyiphosphine in dry dichioromethane.

EXAMPLE 16 Synthesis of 20-chloro-20-deoxyingenol 3, 5-dibenzoate froms ingenol 3 -angel ate Ingenot 3-angelate extracted from Euphorbia species could be converted to 20-chloro-20deoxyingenol 3-angelate 5-benzoate by the method of Example EXAMPLE 17 Synthesis of 2O-chloro-20-deoxyingenol 3,5-dibenzoate from ingenol Scheme 2 Ingenol is reacted with p-toluenesulphonic acid hydrate and acetone to give ingenol-5,20acetonide according to the procedure of Opferkuch et a. (198 Ingenol-5,20-acetonide is converted to the ingenol 3-acylate by treatment with the appropriate acyl chloride and 4- (N,N-dimnethylamino)pyridine or pyridine in toluene or benzene, or treatment with the appropriate acid, an alkylpyridinium salt and tributylanine in toluene then treatment with WO 02/11743 WO 0211743PCT/AUOI/00966 54methanolic perchioric acid according to the procedure of Sorg et al (1982). The ingenol 3acylate could be converted to the 20-chloro-20-deoxyingenol 3-acylate 5-benzoate by the method of Example EXAMPLE 18 Synthesis of 2O-chiloro-20-deoxyingenol 3,5-dibenzoate from ingenol Schemne 3 Ingenol can be converted to ingenol-3,4-acetonide by treatment with 4-toluenesuiphonic acid hydrate and acetone to give ingenol-3,4:5,20-diacetonide followed by treatment with perchloric acid in methanol or zinc bromide in dichioromethane and methanol according to the method of Opferkuch et al (1981). Ingenol-3,4-.acetonide could be converted to ingenol-3,4-acetonide-20-trityl ether by treatment with trityl chloride and 4-(N,Ndiinethylamino)pyridine in dry pyridine, acylated in an analogous manner to that described in Example 1 or Example 3 to give the ingenol-3,4-acetonide-20-trityl ether 5-acylate then treated with methanolic perchioric; acid according to the method of Example 15 or Example 18 to give the ingenol 5-acylate. The ingenol 5-acylate could then be converted to the ingenol-3,4-acetonide 5-acylate by treatment with 4-toluenesulphonic acid hydrate and acetone according to the method of Opferkuch et a. (1981). The ingenol-3,4-acetornide acylate could be converted to the 20-chloro-20-deoxy-3,4-acetonide 5-acylate by the method of Example EXAMPLE 19 Preparation of tetraalkylphthtalimido-1-htydroxyalkylbisphosphonates Tetraalkyl phthalimido-1-hydroxyalkylbisphosphonates can be prepared by the method of El Manouni et (1989). These could be converted to the corresponding tetraalkyl amnino- 1-hydroxyalkylbisphosphonates by standard treatment with hydrazine hydrate in ethanol.

WO 02/11743 WO 0211743PCT/AU01/00966 EXAMPLE Synthesis of bisphosphonic acid derivatives of acylingenols acylates from Examples 17-20 could be reacted with 1,1bis(dialkoxyphosphoryl)-1 -hydroxyallcylamines, triphenyiphosphine, diethylazodicarboxylate and tetrahydrofuran to give 20-deoxy-3-O-acylingenols and 20-[bis(dialkoxyphosphoryl)hydroxyalcylamino] according to the procedure of Appendino et al (1999). [Bis(dialkoxyphosphoryl)hydroxyalkylamino]-20-deoxy-3-Q-acylingenols and [bis(dialkoxyphosphoryl)hydroxyalkylamino]-20-deoxy-5-O-acylingenols could be converted to the corresponding 20-[bis(dihydroxyphosphoryl)hydroxyalkylamino] deoxy-3-O-acylingenols and 20-[bis(dihydroxyphosphoryl)hydroxyalklcamino]-20-deoxyby treatment with bromotrimethylsilane or iodotrimethylsilane and solvolysis with alcohol or water according to Lecouvey et al (2000) and references therein. The bisphosphonic acids could be converted to the appropriate salts by careful titration with an inorganic base, for example, sodium hydroxide.

EXAMPLE 21 Synthesis of ingenol-3-acylate-20-trityl ethers from ingenol-3-acylates Jngenol-3-acylates could be converted to the corresponding ingenol-3-acylate-20-trityl ethers by the method of Example 17. Ingenol-3-acylate-20-trityl ethers could be converted to 5-(chloromethylcarbonyloxy)ingenol-3-acylate-20-trity ethers or carbonyloxy)ingenol-3-acylate-20-trityl ethers by reaction with chioroacetyl chloride or bromoacetyl chloride and 4-(NN-dimethylamino)pyridine in pyridine and dry ether according to the procedure of Nangia et al (1996). 3-acylate-20-trityl ether or 5-(bromomethylcarbonyloxy)ingenol-3-acylate-20-trityl ethers could be converted to ingenol-3-acylate-20-trityl ethers by the method of Example 6 and then converted to '[bis(dialkoxyphosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol-3-acylates by the method of Example 15. These could then be converted to [bis(dihydroxy- WO 02/11743 WO 0211743PCT/AU01/00966 -56phosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol-3-acylates or salts thereof by the method of Example EXAMPLE 22 Synthesis of -fbs(dihtydroxyphosphoyl)hydroxyalkylaminomethylcarbonyloxyjingenols (9S)-9-Deoxo-9-hydroxyingenol-3,4:5,20-diacetonide can be prepared from ingenol- 3,4:5,20-diacetonide by reduction with lithium aluminium hydride in tetrahydrofuran and (9R)-9-deoxo-9-hydroxyingenol-3,4:5,20-diacetonide can be prepared from ingenol- 3,4:5,20-diacetonide by reduction with sodium in 2-propanol and ether according to the procedure of Bagavatbi et (1991). or (9R)-9-Deoxo-9-hydroxyingenol-3,4:5,20diacetonide could be converted to or (9R)-9-deoxo-9-(chloromethylcarbonyloxy)ingenol-3,4: 5,20-diacetonide or or (9R)-9-deoxo-9-(bromomethylcarbonyloxy)ingenol-3,4:5,20-diacetonide by reaction with chioroacetyichioride or bromoacetyichioride and 4-(N,N-dimethylamino)pyridine in pyridine and dry ether according to the procedure of Nangia et (1996). or (9R)-9-Deoxo-9- (chloromethylcarbonyloxy)ingenol-3,4:5,20-dihacetonide or or (9R)-9-deoxo-9- (bromomethylcarbonyloxy)ingenol-3,4:5,20-diacetonide could be converted to the corresponding or (9R)-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylaminomethylcarbonyloxy]ingenol-3,4:5,20-diacetonide by the method of Example 6. or (9R)-9-Deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylaniinomethylcarbonyloxy]ingenol- 3,4:5,20-diacetonide could be treated with methanolic perchioric acid followed by 4toluenesuiphonic acid hydrate to give or (9R)-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylaniinomethylcarbonyloxy]ingenol-5,20-acetonide according to the method of Example 17. This in turn could be converted to or (9R)-3-acyl-9-deoxo-9- [bis(dialkoxyphosphoryl)hydroxyallcylaminomethylcarbonyloxy]ingenol -5,20-acetonides then or (9R)-3-acyl-9-deoxo-9-[bis(dialkoxyphosphoryl)hydroxyalkylarminomethylcarbonyloxy]ingenols by the method of Example 19. These could then be converted into or (9R)-3 -acyl-9-deoxo-9-[bis(dihydroxyphosphoryl)hydroxyalkylamiinomethylcarbonyloxylingenols and salts thereof by the method of Example WO 02/11743 WO 0211743PCT/AU01/00966 -57- EXAMPLE 23 Acylated teiraalkyl bisphosphonate derivatives of ingenol Tetraalkyl bisphosphonate derivatives of ingenol can be ftuther acylated on any free hydroxyl. groups selected from the 3-OH, 5-OH 'and 20-OH by treatment with an appropriate acyl chloride and 4-(NN-dimethylaminopyridine) or pyridine in toluene or benzene according to the procedure of Sorg et aL (1982), then converted to the bisphosphonic, acid derivatives of ingenol or salts thereof by the method of Example EXAMPLE 24 Preparation of deoxyingenol 3,5-diacylatesfron 20-deoxj-1 7-hydroxyv-ingenol 20-Deoxy-17-hydroxy-ingenol obtained by hydrolysis of esters from Euphorbia species could be converted to 20-deoxy-17-hydroxy-ingenol 3,5-diacylate 17-trityl ethers then to 7-hydroxy-ingenol 3,5-diacylates and I 7-chloro-20-deoxyingenol diacylates by the method of Example 15. These could then be converted to 17- 3,5-diacylates and salts thereof by the method of Example EXAMPLE Preparation of bisphosphonate derivatives of acylingenols 17-Hydroxyingenol obtained by hydrolysis of esters from Euphorbia species could be converted to 17-hydroxyingenol-3,4:5,20-diacetonide by the method of Example 18 and thence to 17-chloroingenol-3,4:5,20-diacetomide by the method of Example 15. This could then be converted to 17-chioroingenol by treatment with methanolic perchioric acid and converted to 17-chloroingenol-5,20-acetonide then to 3-acyl-17-cbloroingenols by the method of Example 17. 3-Acyl-17-chloroingenols could be converted to 17- Ijbis(dihydroxyphosphoryl)hydroxyalkylamino]-20-deoxy-3-O-acylingelols and salts WO 02/11743 PCT/AU01/00966 -58thereof by the method of Example 20. Further acylation of these could be achieved by the method of Example 23.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

WO 02/11743 WO 0211743PCT/AUO1/00966 -59-

BIBLIOGRAPHY

Agus et al., Cancer Res. 59; 4761-4764, 1999.

Anidjar et al., Prostate 46: 2-10, 2001.

Antalis et J Exp. Med. 187: 1799-1811, 1998.

Appendino et al., Eur. J Org. Chem. 3413-3420, 1999.

Bagavatbi et al., Z Naturforsch 46b: 1425-1433, 1991.

Botwell, Nature Genet 21: 25-32, 1999.

Bushnell et Nuci. Med Commun. 20: 875-881, 1999.

Christenson et Endotheiumn 7: 75-82, 1999.

El Etreby et al., Prostate 42: 99-106, 2000.

Elliott et Vaccine 17: 2009-2019, 1999.

El Manouni et Phosphorus Sulfur and Silicon 42: 73-83, 1989.

Evans Osman, Nature 250: 348, 1974.

Fatope et al., J Med. Chem. 39: 1005-1008, 1996.

Gahizon, Cancer Invest. 19): 424-436, 2001.

Gonzalez et al., Melanoma Res. 9: 599-606, 1999.

WO 02/11743 WO 0211743PCT/AU01/00966 60 Greaves and Wall, Lancet 348): 938-940, 1996.

Gundidza and Kufa, Cent-. Aft. J Med 38: 444-447, 1992.

Han et Proc. Nat!. Acad Sci. USA 95: 5357-5361, 1998.

Hecker "Cocarcinogens from Euiphorbiaceae and Thymeleaceae" in "Symposiumn on Pharmacognosy and Phytochemistry", 147-165, (Wagner et al., eds., Springer Verlag, 1970).

Hoffmnann, Invest. New Drugs 17: 343-3 59, 1999.

Hohmann et J Nat. Products 6: 107-109, 1999.

Horsmanheimo et J Allergy Clin. Immunol. 98: 408-411, 1996.

Iniai et al., Anticancer Res. 14: 93 3-936, 1994.

Jain et al., Drug Dev. Ind. Pharm?. 24: 703-727, 1998.

Kanellakopoulou et al., Drugs 59 1223-1232, 2000.

Kunisawa et Gani To Kagaku Ryoho 28): 577-583, 2001.

La Linn et J Gen. T'irol. 77: 407-412, 1996.

Lecouvey and Leroux, Heteroatom Chemistry 11: 556-561, 2000.

Marks et Int. J. Cancer 53 585-590, 1993.

WO 02/11743 WO 0211743PCT/AU01/00966 -61- Matsushita et Int. J1 HenzatoL 72(1): 20-7, 2000.

Miller et J Am. Acad. DermatoL 30(5): 774-778, 1974.

Mollinedo, InununoL Today 20(12): 535 1999.

Muggia, Curr. OncoL Rep. 3:156-162, 2001.

Murali-Krishna et Immunity 8: 177-187, 1998.

Nangia eta!., J Chem. Res. Miniprint 7.:1716-1730, 1996.

Navone eta!., Cancer Metastasis Rev. 17: 361-371, 1999.

Nishioka et aL, Adv. Drug Deliv. Rev. 47): 55-64, 2001.

Norris et Cliz. Nuci. Med. 24(11). 905-907, 1999.

Oksuz; et Phytochemistry 42: 473-478, 1996.

Opferkuch et Z Naturforsch 36b: 878-887, 1981.

Post et Int. J Epidemiol 28: 403-408, 1999.

Schroder eta!., Prostate 42: 107-115, 2000.

Segawa eta!., Prostate 45: 33 5-340, 2000.

Sorg and Hecker, Z Naturforsch 37b: 748-756, 1982.

Starvic. and Stolz, Food Cosinet. Toxico!. 14: 141, 1976.

WO 02/1 1743 PCT/AUOI/00966 62 Steinkamnp et Science 215: 64-66, 1982.

Thomasin et A, J Pharm. Sci. 87:- 259-268, 1998.

Tobiume et aL, J Gen. ViroL 79: 1363-1371, 1998.

Volliner and Montana, Clin. Cancer Res 2476-2484, 1999.

Claims (26)

1. A method for the treatment or prophylaxis of prostate cancer in a subject, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from a plant of the Euphorbiaceae family or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is represented by any one of the general formulae F .H J I n J n L I N M O N wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; A-T are independently selected from hydrogen, RI, R 2 R 3 F, Cl, Br, I, CN, ORi, SRI, NRiR2, NRIOR2, ONRIR2, SORI, S02RI, SO3RI, SONRiR2, SO 2 NR 1 R 2 SO 3 NRIR 2 P(R) 3 P(=O)(R 1 3 Si(Ri) 3 B(R) 2 (C=X)R 3 or X(C=X)R 3 where X is selected from sulfur, oxygen and nitrogen; R and R 2 are each independently selected from C 1 -C 20 alkyl (branched Sand/or straight chained), Ci-C 20 arylalkyl, C 3 -C 8 cycloalkyl, C 6 -C 1 4 aryl, C 1 -C 1 4 WO 02/11743 WO 0211743PCT/AU01/00966 64 heteroaryl, C 1 -C 14 heterocycle, C 2 -C 10 alkenyl (branched and/or straight chained), C 2 -CI 0 alkcynyl (branched and/or straight chained), Cl-Cla heteroarylalkyl, CI-Cj 0 alkoxyalkyl, C 1 -C~o haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, Ct-CI 0 [CN, OR,, SRI, NRtR 2 N(=O) 2 NRIOR 2 ONR 1 R 2 SORI, S021(1, S0 3 R 1 SONRR 2 SO 2 NR 1 R 2 SO 3 NRiR 2 P(R 1 3 P(=O)(R 1 3 Si(R~I) 3 B(R 1 2 allcyl; R(3 is selected from RI, R 2 CN, CORI, C0 2 Ri, OR 1 SRI, NR 1 R 2 2 NR 1 OR 2 ONR 1 R 2 SORI, S0 2 R 1 S0 3 RI, SONRjR 2 SO 2 NR 1 R 2 SO 3 NR 1 R 2 P(R0 3 A connected to B (or D (or RZ (or 1P (or Q) or S (or is a selection of C 1 -Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic rings further substituted by R(3, (G=X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; J connected to I (or g (or K (or M (or N) or S (or j) is a selection of C 1 -C 8 disubstituted (fused) saturated and unsaturated carbocyclic or heterocyclic rings further substituted by R(3, (C--X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; D (or E) connected to B (or!C) or G (or I (or 1D connected to G (or 1! (or 0) connected to R (or or M (or K (or L) connected to N (or N) is a selection of CI-Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic rings substituted by R(3, (C=X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; B and C, Dand E, Rand Q Rand Q, Iand, G and FLCandL. M and N or S and T are =X where X is selected from sulfur, oxygen, nitrogen, NR 1 R 2 and ==CR 1 R 2 WO 02/11743 WO 0211743PCT/AUO1/00966 FFI wherein is01 tm Etdfo' abn xgn irgn ufr hshrs silco, ornarenc ndseEweenterndeiebysdaomisauaedr unsaturatedB:. inldn )eoi nd bopxds n0XR or -10R wheroXms selected from sulfr, oxygena nitrogen; fr hshrs R 4 and R are c independently selected from e,-0,R,6,F akl, Brche and/or straight chained), CI-C 2 0 arylalkyl, C 3 -Cg cycloalkyl, 06-014 aryl, 01-014 heteroaryl, 01-014 heterocycle, 02-010 alkenyl (branched and/or straight chained), 02-010 alkynyl (branched and/or straight chained), 01-010 heteroarylalkyl, 01-010 alkoxyalkyl, 01-010 haloalkyl, dihaloalcyl, trihaloalcyl, haloalkoxy, CI-CIO [ON, OR 4 SR4, NR 4 R 5 N(=0) 2 NRhOR 5 ONRS, SOR4, S0 2 R4, S0 3 R4, SONR4R 5 SO 2 NR4R 5 SO 3 NRhR 5 P(R 4 3 P'(0)(R 4 3 Si(R 4 3 B(R4) 2 ]alkyl; R 6 is selected from R4, R 5 ON, COR4, C02R4, OR4, SR4, NR 4 R 5 N(-0) 2 NR 4 OR 5 ONRhR 5 SOR4, S0 2 R4, S0 3 R4, SONRhR 5 SO 2 NR4R 5 SO 3 NR 4 R 5 P(R 4 3 P(=O)(R4) 3 Si(R 4 3 B(R4) 2 WO 02/11743 WO 0211743PCT/AU01/00966 66 E' and R' or H' and 0' is a C 2 -C8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 6 including epoxides and thioepoxides; 0' connected to M' (or j) or (or R' connected to Q(or f) or S' (or a' (or L) connected to A' (or Mj; AX (or P) connected to C' (or connected to C' (or M* or F (or 0J; H' connected to r' connected to F' F' connected to K' connected to L' connected to M' (or are CI-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 6 (C=X)R 6 and X(C=X)R 6 including epoxides and tiboepoxides; A' B' an _C D' and T' G, andMW N and and T' are =~Xwhere X is selected from sulfur, oxygen, nitrogen, NR 4 R 5 (C=x)R 6 X(C=X).r 6 and =CR 7 R8; R 7 and R8 are each independently selected from R 6 (C=X)R 6 and X(C=)R 6 s 1 R~ ~1 1 N wherein: n is0-1 atos slectd fom arbo, oygen nirogn, slfu, phsphrus siliconboron, rsenic nlnuweenterndeiebysdaomisauaedr where is seetdfo ufr oye n irgn WO 02/11743 WO 0211743PCT/AUOI/00966 -67- R 9 and RIO are each independently selected from Cl-C 20 alkyl (branched and straight chained), Cl-C 20 arylalkyl, C 3 -C 8 cycloalkyl, C 6 -CI 4 aryl, C1-C1 4 heteroaryl, C1-C 14 heterocycle, C 2 -CI 0 alkenyl (branched and straight chained), C 2 -Clo alkcymyl (branched and straight chained), C,-CIO heteroarylalcyl, CI-Clo alkoxyalcyl, CI-Clo haloalkyl, dihaloalkyl, trihaloalcyl, haloalkoxy, CI-Cio [GN, OR 9 SR 9 NR 9 Rjo, N(=0) 2 NR 9 OR,, ONR 9 Rjo, SOR 9 S0 2 R 9 S0 3 R 9 SONR 9 Rjo, SO 2 NR 9 RlO, SO 3 NR 9 RIO, P(R9) 3 P(0)(R 9 3 Si(R 9 3 ,1B(R 9 2 ]alkyl; Ri i is selected from R 9 Rio, CN, COR 9 C0 2 R 9 OR 9 SR 9 NR 9 Rjo, N(=0) 2 NR 9 OR,o, ONR 9 R, 0 SOR 9 S0 2 R 9 S0 3 R 9 SONR91R1o, SQ 2 NROR1 0 SO 3 NR 9 R, 0 P(R 9 3 P(=O)(R 9 3 Si(R 9 3 B(R9) 2 '1and R' E' and 01 and IR and M1 are selected from a C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by Ri I, including epoxides and tbioepoxides; Al (or Dl connected to A'(or A)or T' (or Si); B' connected to A' (or or C'I (or E' connected to E* or C' (or EL connected to f~ (or 6i; Gi (or Il connected to (or 6) or I' (or hj; K'i (or Lb) connected to 1' (or hj or M1; M' connected to 01 (or 0'connected 0' (or or?'1 (or Ri connected P' (or or S' (or T are CI-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by Ri I, and X(C=X)RI I, including epoxides and tbioepoxides; and A A and C 1 D' and andG H' and' VJP andK Land 0' and Q! and T' are =X where X is selected from sulfur, oxygen, nitrogen, NIR 9 R, 0 including (C=X)Ri i and and =CR1 2 RI 3 R1 2 and R1 3 are independently selected from RI i, (C-7X)R,,1 and X(C=X)R,,I WO 02/11743 WO 0211743PCT/AU01/00966 68 V Iv wherein is 0-0aosslce2rmcrooygn irgn ufr hshrs or is= 1 where atois selected from ul bor, oxygen nitrogen ufr hshrs R 4 and R are c independently selected from 1 ,R1, 16F ak l, Brche and/or straight chained), CI-C 2 o arylailkyl, C 3 -C 8 cycloalkyl, C 6 -C 1 4 aryl, CI-CI 4 heteroaryl, Cl-C 14 heterocycle, C 2 -Clo alkenyl (branched and/or straight chained), C 2 -G 10 ailcynyl (branched and/or straight chained), Cl-CI 0 heteroarylalkyl, C 1 -CIO alkoxyalkyl, CI-C 10 haloalkyl, dihaloalkyl, trihaloalcyl, haloalkoxy, C 1 -C 10 [CN, OR 14 SR 14 NR 14 Rw, N(-O) 2 NR 14 0R 15 0NR 14 R 15 S0R 14 S0 2 R 14 S0 3 R 1 4 S0NR 14 R 1 5 S0 2 NR 1 4 RI 5 S0 3 NR 14 R 15 R 16 is selected from R 1 4 R 15 CN, C0R 14 C0 2 R 15 OR 14 SR 14 NR 14 R 15 N(=O) 2 NR 14 0RtS, 0NR 4 R 15 S0R 14 S0 2 RI 4 S0 3 R 14 S0NR 14 R 5 S0 2 NR 14 RI 5 SO 3 NR 14 RIS, P(R 14 3 P(=O)(R 4 3 Si(R 14 3 B(R 4 2 WO 02/11743 WO 0211743PCT/AUOI/00966 69 E2 and V 2 H 2 and S2, and f2 and P 2 are C 2 -C 8 saturated or unsaturated carbocyclic. or heterocyclic ring system further substituted by R 16 including epoxides and tbioepoxides; A 2 (or 0) connected to C 2 (or 0) or W 2 (or X 2 )EB connected to C 2 (o 2~ orF2 H 2connected toF' (or gb or Iconnected toLJ or K5;1 2 (orM conectd t J (o K~ o N 2 (or02; R connected to P 2 or SV 2 connected to2 (or [4J or V 2 (or X 2 are CI-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems furthier substituted by R 16 (C=Y)R 16 and Y(C=Y)Rl 6 including epoxides and thioepoxides; A 1 Z f, k; N, 02!; _Q R 2 U 2 and X, W' are =Y where Y is selected f~rm sulfur, oxygen!, nitrogen, NR 14 R, 5 and =CR 1 7 R, 8 R 17 and R 1 8 are independently selected from R 16 (C=Y)R] 6 and Y(C=Y)R 16 3 3 vi TQ p3 wherein is 0-0aosslce3rmcrooygn irgn ufr hshrs nAs -10 arineenel selected from hydrooxgen, roge, RsulR 1 ,ful r, phshou, CN, OR 19 SR 1 9 NR 19 R 20 2 NR 19 0R 20 0NR 19 R 20 S0R 19 S0 2 R 19 S0 3 R 19 WO 02/11743 WO 0211743PCT/AI/00966 70 S0NR 19 R 20 S0 2 NR 19 R 20 SO 3 NR 19 R20, P(R 1 9 3 9 3 Si(R]9)3 B(R 1 9 2 (C=0)R 21 or 0(C=0)R 2 where 0 is sulfur, oxygen and nitrogen Rig and R 20 are each independently selected fr7om 01-020 alkyl (branched and/or straight chained), 01-020 arylalkyl, 03-08 cycloalkyl, 06-014 aryl, C 1 -C 1 4 heteroaryl, CI-C 1 4 heterocycle, 02-010 alkenyl (branched and/or straight chained), 02-010 alkynyl. (branched and/or straight chained), Ci-Cio heteroarylalkyl, 01-010 alkoxyalkyl, Ci-CIO haloalkyl, dihaloalkyl, trihaloalcyl, haloalkoxy, CI-C 10 [ON, OR 19 SR 19 1NR 19 R. 2 o, N(=0) 2 NR 19 0R 2 o, 0NRigR 2 o, S0R 19 S0 2 Rt 9 S0 3 R 19 SONRi 9 R 2 o, SO 2 NR 1 9R 2 o, S0 3 NRigR 2 o, P(R 19 3 P(=O)(R 9 3 Si(R19) 3 B(R 1 9 2 ]alkyl; R 2 is selected from Rig, R 2 o, ON, 00Th9, C0 2 Rjg, OR 19 SR 1 9 NR 19 R. 2 o, N(=0) 2 NR 19 0R 20 0NR 9 R 20 S0R 19 S0 2 R 19 S0 3 R 19 SONR 9 R 2 o, S0 2 NR 19 R. 2 o, SO 3 NR 1 9 R 20 P(R 19 3 P(=O)(R 9 3 Si(§R~I) 3 B(R 19 2 D 3 connected to X 3 is a 02-C8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R(21, including epoxides and thioepoxides; A 3 (or A)connected to BI3 (or 0) or Z 3 (or Y)D 3 connected to B (o 3 or3 (or F3). G' (or H)connected to EF3 (or 0) or j3(or ej); if(or connected to f~ (or j)or M3 (or N2 O 0 (or O) connected to N 3 (or M)or p 3 (or Q)S 3 (or g!3) connected to Q (or 6) or U(or j)W 3 (or connected to U 3 (or T)or X 3 X 3 connected to Y' (or j)are tC disubstituted. (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R(21, 0)1(21 and 0 0)R 21 including epoxides and thioepoxides; A 3 A 3 B 3 0 3 E 3 F 3 G 3 j! JK!, 3 le; 0,L& -QLP LR T3,2K, W 3 V 3 and Z, t 3 are =0 where 0 is selected from sulfur, oxygen, nitrogen, NRI 9 R 20 and =CR22R23; and 1(22 and R(23 are selected from R 21 0)R 21 and 0(0= 0)R 2 1 WO 02/11743 WO 0211743PCT/AUOI/00966 -71- and which chemical agent or derivative or chemical analog is administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer or related cancer or condition.

2. A method according to Claim 1 wherein the chemical agent is represented by the general formula H H 0 R26 R24 VI wherein:- 1(24,R125 and R(26 are independently selected from hydrogen, R 27 R(28, F, Cl, Br, I, CN, 01(27, SR 27 NR 27 R 28 N(=O) 2 NR 27 0R 28 ONR 2 7R 28 ,S50127, S0 2 R 27 SOR,7 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 28 P(R 27 3 P(=O)(R 27 3 Si(R 27 3 B(R 27 2 (C=X)R 29 or X(C=X)R 29 where X is selected from sulfur, oxygen and nitrogen;' R 27 and R285 are each independently selected from C 1 -C 20 alkyl (branched and/or straight chained), CI-C 2 o arylalkyl, C 3 -CS cycloalkyl, C 6 -C 14 arylCI-C 14 heteroaryl, CI-C 14 heterocycle, C 2 -C 10 ailkenyl (branched and/or straight chained), C 2 -C 10 alkynyl (branched and/or straight chained), C 1 -C 10 heteroarylalkcyl, C 1 -Cio alkoxyalkyl, CI-C 10 haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, Cl-CI 0 [CN, OR 2 7 SR 27 NR 27 R 28 N(=O) 2 WO 02/11743 WO 0211743PCT/AU01/00966 -72- NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 2 g, P(R 27 3 P(=O)(R 27 3 Si(R 27 3 B(R 2 7 2 ]allcYl; R 29 is selected from R 27 R 28 CN, GOR27, C0 2 R 27 OR 27 SR 2 NR 27 R 28 2 NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 2 8 P(R 27 3 P(=O)(R 27 3 Si(R 27 3 B(R2 7 2

3. A method according to Claim 2 wherein R 24 is H.

4. A method according to Claim 2 wherein R 24 is OAcetyl. A method according to Claim 2 wherein R 24 is ORl

6. A method according to Claim 2 wherein R. 2 5 is OH.

7. A method according to Claim 2 wherein R. 26 is OH.

8. A method according to Claim 1 wherein the plant is of the genus selected from Acalypha, Acidoton, Actinosternon, Adelia, Adenocline, Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea, Aichorneopsis, Alcinaeanthur, Alcoceria, Aleurites, Arnanca, Andrachne, Angostyles, Anisophyliwn, Antidesma, Aphora, Aporosa, Aporosella, Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia, Beyeriopsis, Bischofia, Blachia, Blumteodondron, Bonania, Bradleja, Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron, Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Chamnaesyce, Cheilosa, Chiropetalurn, Choriophyllum, Cicca, Chaoxvlon, Cleidon, Cleistanthus, Cluytia, Cnesmone, Cnidoscolus, Coccoceras, Codiaeum, Coelodiscus, Conami, Con ceveiba, Conceveibastrwni, Conceve~bum, Coiythea, Croizatia, Croton, Crotonopsis, C'rozophora, Cubanthus, Cunuria, Dactylostemon, Dalechampia, Dendr-ocousinsia, Diaspersus, Didyinocistus, Ditnorphocalyx, Discocarpus, Ditaxis, Dodecastingmna, Drypetes, Dysopsis, Elateriospermum, Endadenium, Endospermurn, Erisinanthus, Erythrocarpus, Erythrochilus, Eurnecanthus, Euphorbia, Euphorbiodendron, WO 02/11743 WO 0211743PCT/AUOI/00966 73 Excoecaria, Flueggea, Calearia, Garcia, Gavarretia, Gelonium, Giara, Givotia, Glochidion, Clochidionopsis, Glycydendron, Gymnanthes, Gyinnosparia, Haernatospermnurn, Hendecandra, Hevea, Hieronzina, ilieronyna, Hippocrepandra, ilornalanthus, Hyrnenocardia, Janipha, Jafropha, Julocroton, Lasiocroton, Leiccarpus, Leonardia, Lepidanthus, Leucocroton, Mabea, Macaranga, Mallotus, Manihot, Mappa, Maprounea, Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesmis, Microelus, Microstachy, Maocroton, Monadenium, Mozinna, Neoscortechinia, Omnalanthus, Omphalea, Ophellantha, Orbicularia, Ostodes, Oxydectes, Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilan thus, Pera, Peridium, Petalostigina, Phyllanthus, Picrodendro, Pierardia, Pilinophytum, Pimeleodendron, Piranhea, Platygyna, Plukenetia, Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudanthus, Pycnocoyna, 2uadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus, Rottlera, Sagotia, Sanwithia, Sapium, Savia, Scierocroton, Sebastiana, Securinega, Senefeldera, Senefilderopsis, Serophyton, Siphon ia, Spathiostemon, Spixia, Stillingia, Strop hioblachia, Synadeniurn, Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanth era, Tithymnalus, Trageia, Trewia, Trigonostemon, Tyria and Xylophylla.

9. A method according to Claim 7 wherein the plant is of the genus Euphorbia. A method according to Claim 8 wherein the species of Euphorbia is selected from Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algornarginata, Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbia andromedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeri, Euphorbia berniudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbia bifurcata, Euphom-bia bilobata, Euphorbia biramensis, Euphorbia biuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbia boerhlaavioides, Eupliorbia boliviana, Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbia brittonii, Euphorbia caesia, Euphorbia WO 02/11743 WO 0211743PCT/AUOI/00966 -74 calcicola, Euphorbia campestris, Euphorbia candelabrum, Euphorbia cap itellata, Euphorbia carmenensis, Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chamaerrhodos, Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colimae, Euphorbia colorata, Euphorbia coinmutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrimna, Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbia cymbiformis, Euphorbia darlingtonii, Euphorbia defoliata, Euphorbia degeneri, Euphorbia deltoidea, Euphorbia dent ata, Euphorbia depressa Euphorbia dictyosperma, Euphorbia dictyosperina, Euphorbia dioeca, Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumondii, Euphorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbia eglandulosa, Euphorbia elata, Euphorbia enalla, Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeformis, Euphorbia espirituensis, Euphorbia esula, Euphorbia excisa, Euphorbia exciusa, Euphorbia exstipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbia filicaulis, Euphorbia filifornis, Euphorbia florida, Euphorbia fruticulosa, Euphorbia garber, Euphorbia gaumerii, Euphorbia gerardiana, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbia gorgonis, Euphorbia gracilior, Euphorbia gracillinia, Euphorbia gradyi, Euphorbia graininea, Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbia haemnatantha, Euphorbia hedyotoides, Euphorbia heldrichii, Euphorbia helenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii, Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides, Euphorbia hinleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbia hooveri, Euphorbia huntistrata, Euphorbia hypericifolia, Euphorbia inundata, Euphiorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna, Euphorbia johnston, Euphorbia ]uttae, Euphorbia knzuthii4 Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbia latericolor, Euphorbia laxiflora Euphorbia lechecides, Euphorbia ledienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbia linguiformis, Euphorbia longecornuta, Euphorbia longepetiolata, Euphorbia longerainosa, Euphorbia longinsulicola, Euphorbia longipila, Euphorbia lupuina, Euphorbia lurida, Euphorbia lycioides, Euphorbia macropodoides, macvaughiana, Euphorbia inanca, Euphorbia WO 02/11743 WO 0211743PCT/AUO1/00966 inandoniana, Euphorbia mangleti, Euphorbia mango, Euphorbia marylandica, Euphorbia mayana, Euphorbia melanadenia, Euphorbia melanocarpa, Euphorbia meridensis, Euphorbia inertonii, Euphorbia mexiae, Euphorbia microcephala, Euphorbia microclada, Euphorbia micromera, Euphorbia misella, Euphorbia missurica, Euphorbia montana, Euphorbia ,nontereyana, Euphorbia multicaulis, Euphorbia multifonnis, Euphorbia multinodis, Euphorbia multiseta, Euphorbia muscicola, Euphorbia neomexicana, Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia oaxacana, Euphorbia occidentalis, Euphorbia odontodenia, Euphorbia olivacea, Euphorbia olowaluana, Euphorbia opthalmica, Euphorbia ovata, Euphorbia pachypoda, Euphorbia pachyrhiza, Euphorbia padifoblia, Euphorbia palmeri, Euphorbia paluicola, Euphorbia paralias, Euphorbia parciflora, Euphorbia parishii, Euphorbia panryi, Euphorbia paxiana, Euphorbia pediculifera, Euphorbia peplidion, Euphorbia peploides, Euphorbia peplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea, Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis, Euphorbia pilosuda, Euphorbia pilulifera, Euphorbia pinariona, Euphorbia pinetorum, Euphorbia pionosperma, Euphorbia platysperma, Euphorbia plicata, Euphorbia poeppigii, Euphorbia poliosperma, Euphorbia polycarpa, Eup/zorbia polyatnmoides, Euphorbia polyphylla, Euphorbia portoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbia preslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbia pycnanthema, Euphorbia ramzosa, Euphorbia rapulum, Euphorbia remyi, Euphorbia retroscabra, Euphorbia revoluta, Euphorbia rivularis, Euphorbia robusta, Euphorbia romtosa, Euphorbia rubida, Euphorbia rubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbia saxatilis M. Bieb, Euphorbia schizoloba, Euphorbia sclerocyathiuzn, Euphorbia scopulorwn, Euphorbia senilis, Euphorbia serpyllifolia, Euphorbia serrula, Euphorbia setiloba Engelin, Euphorbia sonorae, Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperzna, Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea, Euphorbia stellata, Euphorbia subnmammilaris, Euphorbia subpeltata, Euphorbia subpubenls, Euphorbia subrenifonne, Euphorbia subtrifoliata, Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephivides, Euphorbia tenuissima, Euphorbia tetrapora, Euphorbia tirucalli, Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii, Euphorbia tovariensis, Euphorbia trachysperzna, Euphorbia tricolor, Euphorbia troyana, Euphorbia' PA\OprXEjh.=mdd\79493-0 Lpcpfin.prstaau dd 1w-108102 -76- tuerckheimii, Euphorbia turczaninowii, Euphorbia umbellulata, Euphorbia undulata, Euphorbia vermiformis, Euphorbia versicolor, Euphorbia villifera, Euphorbia violacea, Euphorbia whitei, Euphorbia xanti Engelm, Euphorbia xylopoda Greenm., Euphorbia yayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica and Euphorbia zinniiflora.

11. A method according to Claim 9 wherein the species of Euphorbia is Euphorbia peplus.

12. A method according to Claim 1 wherein the cancer is prostate cancer.

13. A method according to any one of Claims 1 to 12 wherein the chemical agent is coupled to a targeting agent.

14. A method according to Claim 13 wherein the targeting agent is a bone- seeking agent. A method according to Claim 14 wherein the bone-seeking agent is bisphosphonate.

16. A method according to Claim 15 wherein the bisphosphonate is methylene disphosphonate.

17. A method according to Claim 13 wherein the targeting agent is an antibody to a prostate-specific tumor marker.

18. A method according to Claim 17 wherein the marker is prostate-specific antigen (PSA), prostate-specific membrane antigen (PMSA) or PSA receptor.

19. A method for the treatment or prophylaxis of prostate cancer in a subject, said method comprising the administration to said subject of a symptom-ameliorating -77 effective amount of a chemical agent obtainable from Euphorbia peplus or a derivative or chemical analog thereof which chemical agent is a diterpene selected from compounds of the mngenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is represented by any one of the general formulae D B- n H Q L~ ON4 Q wherein n: i0-0aosslcefrm rooyentoesupopos A s -T areineenen selected from hydrooxgen, niroge, su F lfBr, oshCNu, o~oo silicon, brn re and saeleachm. indeenentl dney selete froms isC 2 satu (ranced C 1 C0 halkl daro k idpnethloaslected hfroalkyog, 1 [R2, RF,SR 1 r,NL R 2 ORSI RRN=), RO2 N42 OI S2I 0RSNI2 -4NI2 0NI2 (I3,P=)R),S(I3 whr.Xislce rmsluoye n irgn RQ an72aeec"neenetyslce rmCIC0alY bace WO 02/11743 WO 0211743PCT/AU01/00966 *-78- 2 NR 1 0R 2 ONR 1 IR 2 SORI, S0 2 RI, S0 3 R 1 SONR 1 R 2 S0 2 NR 1 R 2 S0 3 NR 1 R 2 R 3 is selected from RI, R 2 CN, COR 1 C0 2 R 1 OR 1 SRI, NR 1 R 2 N(=0) 2 NR 1 OR 2 QNR 1 R 2 SORI, S0 2 R 1 S0 3 RI, SONRIR 2 SO 2 NRiR 2 SO 3 NRiR 2 P(R 1 3 Aconnected to B (or D (or RZ (or P! (or O) or S (or YDi selection Of C 1 -C 8 disubstituted. (fused) saturated or unsaturated carbocyclic or heterocyclic rings further substituted by R 3 (C=X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; J connected to I (or W~G(or K (or M (or N) or S (or D) is a selection of Cl-Cs disubstituted. (fused) saturated and unsaturated carbocyclic or heterocyclic rings fur-ther substituted by R 3 (C=X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; D(or B) connected to B (or C) or G (or 1 (or H) connected to G (or F;P (or 0) connected to R (or or M (or hD; KC (or L) connected to N (or W is a selection of CI-Cg disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic rings substituted by R 3 (C=X)R 3 and X(C=X)R 3 including epoxides and tbioepoxides; B and C D and E. RandQ, 1!and 01andH. G andF K and L~ M and N or S and T are =X where X is selected from sulfur, oxygen, nitrogen, NR 1 R 2 and =-CR 1 R 2 WO 02/11743 PCT/AUO1/00966 -79- wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; are independently selected from hydrogen, R4, Rs, R 6 F, CL, Br, I, CN, COR 4 C0 2 R 4 OR 4 SR4, NR4R 5 CQNRR 5 N(=0) 2 NR 4 0R 5 ONR4R, SOR4, S0 2 R4, S0 3 R4, SONR 4 R 5 SO 2 NR 4 R 5 SO 3 NR4R 5 P(R 4 3 P(=O)(R 4 3 Si(R 4 3 B(R 4 2 (C=X)R or X(C=X)R 6 where X is selected from sulfur, oxygen and nitrogen; R 4 and Rs are each independently selected from CI-C 2 o alkyl (branched and/or straight chained), C 1 -C 20 arylalkyl, C 3 -C 8 cycloalkyl, C 6 -Ct 4 aryl, CI-C14 heteroaryl, C1-C 1 4 heterocycle, C 2 -CI 0 alkenyl (branched and/or straight chained), C 2 -C 10 alkynyl (branched and/or straight chained), C 1 -C 1 0 heteroarylalkyl, CI-Clo alkoxyalkyl, C 1 -C 1 0 haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, CI-Clo [CN, OR4, SR4, NR 4 R, N(=0) 2 NR4OR 5 ONR4R5, SOR4, S0 2 R4, S0 3 R4, SONR 4 R 5 SO 2 NR4R 5 SO 3 NR4R5, P(R 4 3 P(=O)(R 4 3 Si(R 4 3 B(R 4 2 )alkyl; R 6 is selected from R 4 R 5 CN, COR4, C0 2 R 4 OR4, SR4, NRhR 5 N(0) 2 NR4OR, ONR 4 R 5 SOR 4 S0 2 R4, S0 3 R4, SONR4R 5 S02NRhR 5 S0 3 NR 4 R 5 P(R 4 3 4 3 Si(Kt) 3 B(R 4 2 E' and R' or H' and 0' is a C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 6 including epoxides and thioepoxides; 0' connected to M' (or or (or R' connected to 0' (or or S' (or S' (or connected to A' (or A' (or connected to C' (or 0D; E connected to C' (or or F' (or H' connected to I' connected to L. J connected to K' connected to L' L' connected to M' (or are C 1 -C 8 disubstituted (fused) WO 02/11743 WO 0211743PCT/AU01/00966 80 saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 6 (C=X)R 6 and X(C=X)R 6 including epoxides and tbioepoxides; a:and C' E and FG' and N' and P, Q and T' are =X where X is selected from sulfur, oxygen, nitrogen, NR 4 R 5 (C=X)R 6 X(C=X)R 6 and ':CR 7 Rg; R 7 and R~are each independently selected from R 6 6 and X(C=X)R 6 s 1 pP F1 N 1 wherein: n is~~ 0-0aosslceA mcro, oxgn niroen sufr phshrs whr i s10aos selected from. sulfur, oxygenan nitrogen ufr hshrs R 9 and 1 are c independently selected from rogen aRky (brache andFC, r straight chained), C 1 -C 20 arylalkyl, C 3 -C 8 cycloalkyl, C 6 -C 1 4 arYl, CI-CI 4 heteroaryl, CI-CI 4 heterocycle, C 2 -Clo alkenyl (branched and straight chained), C 2 -CI 0 ailcynyl (branched and straight chained), Ci-Cio heteroarylalkyl, C 1 -Cio alkoxyalkyl, C 1 -CI 0 haloalkyl, dihaloallkyl, trihaloalkyl, haloailkoxy, CI-Cl 0 [CN, OR 9 SR 9 NRgRio, N(=0) 2 NR 9 ORIO, WO 02/11743 WO 0211743PCT/AUO1/00966 81 0NRRjo, SOR 9 S0 2 R 9 S0 3 R 9 SONRgRjo, SO 2 NR 9 RIO, SO 3 NR 9 R, 0 P(R 9 3 P(=O)(R 9 3 Si(R9) 3 B(R 9 2 ]alkYl; R 11 I is selected from R 9 Rio, CN, COR 9 C0 2 R 9 OR 9 SIR 9 NR 9 R 1 o, N(=0) 2 NR 9 0R 10 ONR 9 Rjo, SOR 9 S0 2 R 9 S0 3 R 9 SONRRjo, SO 2 NR 9 Rjo, SO 3 NR 9 Rio, P(R 9 3 P(0)(R 9 3 Si(R 9 3 B(R 9 2 B' and IR. E' and 01 and R' and M1 are selected from a C 2 -C 8 saturated or unsaturated carbo cyclic or heterocyclic ring system further substituted by R 11 including epoxides and tbioepoxides; A' (or connected to A' (or ')or T' (or a1); B'1 connected to Ai (or A') or C' (or E' connected to ~'or C' (or 'connected to t' (or br; !aj (or Ii connected to t' (or 0~ or V~ (or I)K'(or 0~ connected to 11 (or or M; M' connected to 0'1 (or 0' connected 0' (or Nbor P 1 (or Q! R' connected P1 (or or S' (or 21) are CI-C 8 disubstituted. (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by IR11, (C=X)RI, and X(C=X)RII, including epoxides and thioepoxides; A and,& andC'L D'and F1 IdG Hand' ,JPand K' L' and 0' and P, 0' and S' T' are =X where X is selected from sulfur, oxygen, nitrogen, NR 9 Rto, including (C=X)RI 1 and X(C=X)RI 1, and =CR1 2 R, 3 R1 2 and R1 3 are independently selected from R1 1 and X(C=X)R,, WO 02/11743 WO 0211743PCT/AU01/00966 -82- wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thicepoxides; are independently selected from hydrogen, R 14 R 15 R 16 F, Cl, Br, I, CN, ORM 4 SR 14 NR14Ri, N(=0) 2 NR 14 0RI 5 ONR14RI 5 S0R 14 S0 2 R 14 SO3RI4, S0NR 14 R 1 5 S0 2 NR 14 R 15 S0 3 NR 14 RI 5 P(R 1 4 3 P(=O)(R 4 3 Si(R 1 4 3 B(R 14 (C=Y)R 16 or Y(C=Y)R 1 6 where Y is selected from sulfur, oxygen and nitrogen; R 14 and R 15 are each independently selected from CI-C 20 alkyl (branched and/or straight chained), Cl-C 2 o arylalcyl, C 3 -C 8 cycloallcyl, C 6 -G 14 arYl, C 1 -C 14 heteroaryl, CI-CI 4 heterocycle, C 2 -CI 0 alkenyl. (branched and/or straight chained), C 2 -C~o alkynyt (branched and/or straight chained), C I-CIO 'heteroarylalkcyl, C 1 -CI 0 alkoxyalkyl, C 1 -Clo haloalcyl, dihaloalkyl, trilialoalkyl, haloalkoxy, C 1 -C 10 [CN, OR 14 SR 14 NR 1 4 R 10 N(=0) 2 NR 14 0RI 5 0NR 14 R 15 S0R 14 S0 2 R 14 S0 3 RI 4 S0NR 14 RI 5 S0 2 NR 14 R 1 5 SO 3 NR 14 Pqs, P(R 14 3 P(=O)(R 4 3 Si(R 14 3 B(R 14 2 ]alkyl; R 16 is selected from R 14 R 15 CN, C0R 14 C0 2 RI 5 OR 14 SR 14 NR 1 4 R 15 N(-0) 2 NR 14 0R 15 0NR 1 4 R 1 5 S0RM 4 S0 2 R 1 4 S0 3 RI 4 S0NR 14 RI 5 S0 2 NR 14 R, 5 S0 3 NR 14 RIS, P(R 14 3 P(=O)(R 4 3 Si(R 14 3 B(R 1 4 2 E' and V 2 12and S 2 and 12 and p 2 are C 2 -CS saturated or unsaturated carbocyclic or heterocyclic ring system fuirther substituted by R 16 including epoxides and thioepoxides; A! (or E) connected to C 2 (or j) or W 2 (or B! connected to C 2 (or D or F 2 (or G 112 connected to F 2 (r 0 or f connected to (or K5; L 2 (or conecedto 2 orK~)orN~(or Q)R 2 (or Q) connected to P 2 or 2 V 2 connected to U 2 WO 02/11743 WO 0211743PCT/AUOI/00966 83 (or §4 or W 2 (or 2 are C 1 -C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 16 (C=Y)Rl 6 and Y(C=Y)R 16 including epoxides and thioepoxides; W; Q!;JZ W; QL R!;U,!andX W0 are =Y where Y is selected from sulfur, oxygen, nitrogen, NR 1 4 R 15 and =CR 1 7 R 1 8 R 17 and Rig are independently selected from Rt 6 (C-Y)Rl 6 and Y(C=Y)R 16 3 3 F 3 tj 3 3 3 bV wherein n i 010 tos sletedfr A rbn xgn irgn ufr hshrs ohrein:R 1 whr sslfr xgnan irgn R 9 and R are ec independently selected from nRg 1 C 2 oR1,F ak l, Branche and/or straight chained), C 1 -C 2 o arylalkyl, C 3 -C 8 cycloalcyl, C 6 -C 14 aryl C 1 -C 14 heteroaryl, C 1 -CI 4 heterocycle, C 2 -C 10 alkenyl (branched and/or straight chained), C 2 -Cio alkynyl. (branched and/or straight chained), C 1 -C 10 heteroarylalkyl, C 1 -G 10 alkoxyakl, Ci-C 10 WO 02/11743 WO 0211743PCT/AU01/00966

84- haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, C 1 -Clo [CN, OR 19 SR 1 9 N1Rt 9 R 2 o, N(=0) 2 NR 19 0R 2 o, 0NR 19 R 2 o, S0R 19 S0 2 R 19 S0 3 RI 9 SONRt 9 R 2 0, S0 2 NR 19 R 20 S0 3 NR 19 R 20 P(R 19 3 P(=O)(R 9 3 Si(R 1 9 3 B(RI9) 2 IallcYl; R 21 is selected from R 19 R 2 o, CN, C0R 19 C0 2 R 1 9 OR 19 SR 19 NRjqR 2 o, N(=O) 2 N 19 OR 20 0Nk 19 R 20 S0R 19 S0 2 R 1 9 S0 3 R 1 9 S0NR 19 R 20 S0 2 NR 19 R 20 SO 3 NR 19 R 20 P(R 19 3 P(=O)(R 1 9 3 Si(R19) 3 B(R 1 9 2 D 3 connected to X 3 is a C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 21 including epoxides, and thioepoxides; A3 (or ~)connected to B 3 (or 0) or Z 3 (or Y 3 D)3 connected to B 3 (or C3) or E (or 13): G 3 (or ll)connected to E 3 (or b) or j3(or hI; !2 (or nh connected to 13 (or or M3 (or Nb); 03 (or QO) connected to N 3 (or Mb or P' (or Qb 3(or BE) connected to Q! (or P 3 or L(or n 3 W 3 (or V 3 connected to U 3 (or ibor X X 3 connected to y 3 (or 6~ are Ct-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 21 0)R 21 and 0 0)R 21 including epoxides and thioepoxides; A A 3 C 3 2;B 3 F 3 ;G 3 le1; K?, 3 M;0, 2;Q~ 3 S 3 R U 3 T 3 WI, V 3 and Z 3 y 3 are =0 where 0 is selected from sulfur, oxygen, nitrogen, NR 19 R 2 o, and =CR 2 2 R 2 3 and R 22 and R 23 are selected from R 21 0)R 21 and 0(C= 0)R 2 1 and which chemical agent or derivative or chemical analogis administered for a time and under conditions sufficient to ameliorate one or more symptoms associated with said prostate cancer or related cancer or condition. A method according to Claim 19 wherein the chemidcal agent is represented by the general formula WO 02/11743 WO 0211743PCT/AUOI/00966 7 H 0 0 R 26 R2 R26 vi wherein:- 1(24, R2_5 and R26, are independently selected from hydrogen, R 27 R 2 g, F, Cl, B3r, 1, CN, OR 27 SR 27 NR 27 R 28 2 NR 27 0R 2 8, 0NR 27 R 28 S0R 27 S0 2 R 27 SO3R27, S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 28 P(R 27 3 P(=O)(R 27 3 Si(R 27 3 13(R 27 2 (C=X)R 29 or X(G=X)R 29 where X is selected from sulfur, oxygen and nitrogen; R 27 and R 28 are each independently selected firom C 1 -C 20 alkyl (branched and/or straight chained), CI-C 20 arylalkyl, C3-GS cycloalkyl, C 6 -C 14 aryl, C 1 -Cl 4 heteroaryl, C 1 -C 1 4 heterocycle, C 2 -CI 0 alkenyl (branched and/or straight chained), C 2 -C 10 alkynyl (branched and/or straight chained), CI-Cto heteroarylalcyl, C 1 -Clo alkoxyalkyl, CI-Clo haloalkyl, dihaloalkyl, trihaloalcyl, haloalkoxy, C 1 -CIO [CN, 01(27, SR 27 NR 27 R 28 2 7NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 2 8 P(R 27 3 PQ=O)(R 27 3 Si(R27) 3 B(R 27 h2]alcyl; R29 is selected from R 27 R 28 CN, C0R 27 CO 2 R 2 7, 01(27, SR 27 NR 2 7 R 28 N(=0O) 2 NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 28 P(R 27 3 P(=O)(R 27 3 Si(R 27 3 B(R 27 2 A method according to Claim 20 wherein R 2 4 is H. P:ftcrjh. mmddcd\79493 0 .peplin.prostte.nun dedd~doc-21/03102 -86- A method according to Claim 20 wherein R 24 is OAcetyl. A method according to Claim 20 wherein R 24 is OH. o°* o o ooo *o o.* *ooo 24. A method according to Claim 20 wherein R2 5 is OH. A method according to Claim 20 wherein R 26 is OH. 26. A method according to Claim 19 wherein the cancer is prostate cancer. 27. A method according to any one of Claims 19 to 26 wherein the chemical agent is coupled to a targeting agent. 28. A method according to Claim 27 wherein the targeting agent is a bone- seeking agent. 29. A method according to Claim 28 wherein the bone-seeking agent is bisphosphonate. 30. A method according to Claim 29 wherein the bisphosphonate is methylene disphosphonate. 31. A method according to Claim 27 wherein the targeting agent is an antibody to a prostate-specific tumor marker. 32. A method according to Claim 31 wherein the marker is prostate-specific antigen (PSA), prostate-specific membrane antigen (PMSA) or PSA receptor. 33. A method for the immunopotentiation of a subject in the treatment or prophylaxis of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of a chemical agent obtainable from a plant of S87- the Euphorbiaceae family or a derivative or chemical analog thereof which chemical agent is a diterpene selected from. compounds of the ingenane, pepluane and jatrophane families and which chemical agent or derivative or chemical analog is represented by any one of the general formulae V: D. L I NM wherein: n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides; and thioepoxides; A-T are independently selected from hydrogen, Ri, R 2 R 3 F, CL, Br, 1, CN, ORI, SRI, NR 1 R 2 N(=0) 2 NR 1 OR 2 ONR 1 R 2 SORI, S0 2 R 1 S0 3 R 1 SONR 1 R 2 SO 2 NRtR 2 SO 3 NR 1 R 2 P(Ri) 3 P(=O)(R 1 3 Si(R 1 3 B(R 1 2 (C=X)R 3 or X(C=X)R 3 where X is selected from sulfur, oxygen and nitrogen; RI and R2 are each independently selected from CI-C2, alkyl (branched and/Or Straight Chained), C 1 -C 20 arYlaikyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, C 1 -C 1 4 heteroaryl, C 1 -C 14 heterocycle, C 2 -C 10 alkenyl (branched and/or straight chained), C 2 -Cl 0 alkynyl (branched and/or straight chained), CI-C 10 heteroarylalkyl, C 1 -C 10 alkoxyalkyl, CI-C 10 haloalkyl, dihaloalkyl, trihaloalkyl, haloalkoxy, CI-Cio [CN, OR,, SRI, NR 1 R 2 N(=O) 2 NRiOR. 2 ONR 1 R 2 SORI, S0 2 R 1 S0 3 Rj, SONR 1 R 2 SO 2 NR 1 R 2 SO01NR 1 R 2 iiV P(R 1 3 P(=O)(R 1 3 Si(R 1 3 B(RI) 2 ]alkyl; WO 02/11743 WO 0211743PCT/AU01/00966 -88 R 3 is selected from RI, R 2 GN, CORI, C0 2 RI, OR,, SRI, NR 1 R 2 2 NR 1 OR 2 ONRjR 2 SORI, S0 2 RI, S0 3 RI, SONR 1 R 2 SO 2 NR 1 R 2 SO 3 NR 1 R 2 P(R 1 3 A connected to B (or D2 (or R, (or 1! (or Q) or S (or is a selection of Cl-C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic rings further substituted by R. 3 (C=X)R 3 and X(C=X)R 3 including epoxides and thicepoxides; J connected to I (or Gj (or K (or M (or n or S (or is a selection of C 1 -C 8 disubstituted (fused) saturated and unsaturated carbocyclic. or heterocyclic rings further substituted by R 3 (G=X)R 3 and X(C=X)R 3 including epoxides and thioepoxides; D2 (or B) connected to B (or ~)or G (or 1 (or H) connected to G (or 1! (or Q) connected to R (or or M (or K(or L) connected to N (or M) is a selection of C 1 -C 8 disubstituted (fused) saturated or unsaturated carbocyclic; or heterocyclic rings substituted by R 3 (C--X)R 3 and X(C=X)R 3 including epoxides and tbioepoxides; B andC, D and E, Rand Q EPandO 0,1andH, G andF, K and L, Mand N or S and T are =X where X is selected from sulfur, oxygen, nitrogen, NR 1 R 2 and =CR 1 R 2 D' G' wherein: WO 02/11743 PCT/AU01/00966 -89- n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and tbioepoxides; are independently selected from hydrogen, R 4 R 5 R 6 F, Cl, Br, I, CN, COR 4 C0 2 R 4 OR 4 SR 4 NRhR 5 CONR4R5, N(=O) 2 NR 4 OR 5 ONR4Rs, SOR4, S0 2 R4, S0 3 R4, SONR 4 R 5 SO 2 NR 4 R 5 SO 3 NR4R 5 P(R 4 3 Si(R 4 3 B(R 4 2 (C=X)R 6 or X(C=X)R6 where X is selected from sulfur, oxygen and nitrogen; R 4 and R 5 are each independently selected from C 1 -C 2 o alkyl (branched and/or straight chained), C 1 -C 2 0 arylalkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, C 1 -C 1 4 heteroaryl, C 1 -C 1 4 heterocycle, C 2 -C 10 alkenyl (branched and/or straight chained), C 2 -Clo alkynyl (branched and/or straight chained), C 1 -C 10 heteroarylalkyl, C 1 -Clo alkoxyalkyl, C 1 -Clo haloalkyl, dihaloalkyl, trihaloalkyl, haloallcoxy, Cl-Clo [CN, OR 4 SR 4 NR 4 R 5 2 NR 4 OR 5 ONMRR 5 SOR4, S0 2 R4, S0 3 R 4 SONR 4 R 5 SO 2 NR4R 5 S03NR 4 R 5 P(R 4 3 P(=O)(R 4 3 Si(R 4 3 B(R 4 2 ]alkl; R6 is selected from R 4 R 5 CN, COR4, C0 2 R4, OR4, SR 4 NR 4 R 5 2 NR 4 OR 5 ONR 4 R 5 SOR4, S0 2 R4, S0 3 R4, SONR 4 R 5 S02NR 4 R5, SO 3 NR 4 R 5 P(R4) 3 3 Si(R 4 3 B(R 4 2 E' and R' or H' and 0' is a C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 6 including epoxides and thioepoxides; 0' connected to M' (or or 2 (or R' connected to Q: (or D) or S' (or a' (or L) connected to A' (or 09; A' (or connected to C' (or P EI connected to C' (or PD or F (or W connected to I' connected to E connected to K' connected to L connected to M' (Or k) are C 1 -Cg disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 6 (C=X)R 6 and X(C=X)R 6 including epoxides and thioepoxides; WO OV11743 WO 0211743PCT/AUOI/00966 A' B3' andGC' D' andE' G' and M' N' and P, 0' andS KT' are =X where X is selected from sulfur, oxygen, nitrogen, NR 4 R 5 (C=X)R 6 X(C>X)R 6 and =CR 7 R8; R 7 and R 8 are each independently selected from R 6 (C=X)Th and X(C=X)R 6 wherein n i 0-0 tom seecedro cabn oxgn.n- oenHufuposhrs where iseetdfo:ufroye n irgn Rn and0 10 areeahonepnesl selected from caboxyeitogn alfur, (banhedphands hetirocyclero, arsenic andeenium banhen sterig chained by said atomsy isaraed and usturated chind), oxde andC 1 htolaklC-C 0 aloyaklC-C 0 haolk dihaloalcyl, ti arel indpeoa lky scted 1 from Oroge, NR 9 ,Rio 1,N F,) 2 r, 0 1 0NR 9 R 1 9, SR 9 SRgi, NS0R, SNR 9 R 10 ONRRo, SR9 0 3 NR 9 P(R 9 P(O)9R) 3 S2qjo 0N9IPR3,P-)R3,Si(R 9 3 B(R 9 2 Calkylr (C;)I WO 02/11743 WO 0211743PCT/AU01/00966 -91- R, I is selected from R 9 RIO, CN, COR 9 C0 2 R 9 OR 9 SR 9 NR 9 R, 0 o, N(=0) 2 NR 9 OR, 0 ONR 9 RI 0 SOR 9 S0 2 R 9 S0 3 R 9 SONR 9 R 10 SO 2 NIR 9 Rjo, SO 3 NR 9 Rjo, P(R 9 3 PQ=O))(R9) 3 Si(R 9 3 B(R 9 2 1B' and E' and 0' and P1' and M' are selected from a C 2 -CS saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 11 including epoxides and tliioepoxides; A' (or K) connected to A' (or ')or T' (or 5b; B' connected to A' (orA' or C' (or El connected to R' or C' connected to f (or b; (or ~i connected to Al' (or 6) or 11 (or bj; KW (or 0~ connected to 11 (or hi or M1. M1 connected to 0' (or j)0'connected 0' (or or P 1 (or Qb 'connected P1 (or Q)or S' (or are Cj-Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R11, (C=X)RII and X(C=X)Rll, including epoxides and thioepoxides; A' AandA and D' and F' tandG'31 H1 and I' J' and L'and 01 and P1!, Q' and T' are =X where X is selected from sulfur, oxygen, nitrogen, NR 9 R, 0 including (C=X)RI 1 and and =CR1 2 RI 3 RI 2 and R 13 are independently selected from R, 1 (C=X)R 1 and X(C=X)RI I Y K 2 L 2 D 2 F 2 G2 2 1 2 B 2 1. N 2 A -n 2 wherein: WO 02/11743 PCT/AUO1/00966 -92- n is 0-10 atoms selected from carbon, oxygen, nitrogen, sulfur, phosphorus, silicon, boron, arsenic and selenium, wherein the ring defined by said atoms is saturated or unsaturated, including epoxides and thioepoxides; A2_X2 are independently selected from hydrogen, R 14 R 1 5 R 16 F, Cl, Br, I, CN, OR 1 4 SR 1 4 NR 1 4 R 1 5 2 NR 1 4 0R 1 5 0NR 14 R 5 S0R 1 4 S0 2 R 1 4 S0 3 R 1 4 S0NR 14 R 1 5 S0 2 NR 1 4 R 1 5 SO 3 NR14RI 5 P(R 1 4 3 P(=O)(R 1 4 3 Si(R 1 4 3 B(R 14 (C=Y)R 1 6 or Y(C=Y)R 16 where Y is selected from sulfur, oxygen and nitrogen; R 1 4 and R 1 5 are each independently selected from C 1 -C 2 o alkyl (branched and/or straight chained), C 1 -C 2 0 arylalkyl, C 3 -CS cycloalkyl, C 6 -C 14 aryl, C 1 -C 14 heteroaryl, C 1 -C 1 4 heterocycle, C 2 -CI 0 alkenyl (branched and/or straight chained), C 2 -CI 0 alkynyl (branched and/or straight chained), C 1 -Clo heteroarylalkyl, C 1 -Clo alkoxyalkyl, CI-CIO haloallcyl, dihaloallyl, trihaloalkyl, haloalkoxy, CI-CIo [CN, OR 1 4 SR 14 NR 1 4 R 10 N(=0) 2 NR 14 0R 1 5 0NR 14 R 1 5 SOR 1 4 S0 2 R 1 4 S0 3 R 1 4 S0NR 1 4 R 5 S0 2 NR 1 4 R 1 5 S0 3 NR 1 4 R 1 5 P(R 1 4 3 P(=O)CR 1 4 3 Si(R 1 4 3 B(R 1 4 2 Ialkyl; R 1 6 is selected from R 14 R 15 CN, C0R 1 4 C0 2 R 1 5 OR 1 4 SR 1 4 NR 1 4 R 1 5 2 NR 1 4 0R 1 5 ONR14RI5, S0R 1 4 S0 2 R 14 S0 3 R 1 4 SONR1 4 RI5, S0 2 NR 1 4 R 1 5 S0 3 NR 1 4 R 1 5 P(R 1 4 3 P(=O)(R 1 4 3 Si(R 1 4 3 B(R 1 4 2 E 2 and V 2 H 2 and S 2 and 1 and P 2 are C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 16 including epoxides and thioepoxides; A 2 (or 0) connected to C 2 (or D 2 or W 2 (or E 2 connected to C 2 (or D92 or F 2 (or G 2 H 2 connected to F (or G2) or 2. 2 connected to J- (or K; L 2 (or M2) connected to J 2 (or K 2 or N 2 (or Q2); R 2 (or Q connected to P 2 or S 2 V 2 connected to U 2 (or T) or W 2 (or Xj) are C 1 -C 8 disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 1 6 (C=Y)R 1 6 and Y(C=Y)R 16 including epoxides and tbioepoxides; WO 02111743 WO 0211743PCT/AU01/00966 93 12F~ G~~KL 2 2 O;~R; 2 Tand 2 W are =Y where Y is selected from sulfur, oxygen, nitrogen, NR 14 RI 5 and =-CR 17 R, 8 R 17 and R 18 are independently selected from R 16 (C=Y)R 16 and Y(C=Y)R, 6 F3 3~j T 3 3 b wherein 3 is013tm eetdfo abn xgn irgn ufr hshrs silionboro, asenc an seeniu, wern tern eie ysi tm sstrtdo ohrein:R 1 whr sslfr xgnan irgn n isand-1 0 aeeahinepnenl selected from caboxyeCitogn suluy, (boprache scon, heorocl, ancad selenum whrnhe aindetaifhined tm isC saratedyo unaraed, ancd/rgstraight cand) tCiohieteorlly, 1 C 0 akxylyC- haoa3kZ3 dhoarel tihaloalkty halekoey fro [Cdon, Rg, SR 9 NR2 1 R, (CLB, I N, R 19 0NR 19 R, R 19 NS0 2 N0R 19 R2, SONRigR 2 o, S0 2 R 19 R9, SO 3 Rg, P(R 19 =OR 19 iR0, B(3R 1 9 2 0,PR1),Palkyl; i(t)3 (l92 C=)2 WO 02/11743 PCT/AU01/00966 -94- R 2 1 is selected from R 1 9 ig, R 20 CN, COR 19 C0 2 R 19 OR 19 SR 19 NR 1 9 R 20 N(=O) 2 NR 1 9 0R 20 ONR 1 9 R 20 SOR 19 S0 2 R 1 9 S0 3 R 1 9 SONR 1 9 R 2 o, SO 2 NRkR 2 0 S0 3 NR 19 R 20 P(R 19 3 P(=O)(R 9 3 Si(R 19 3 B(R 1 9 2 D 3 connected to X 3 is a C 2 -C 8 saturated or unsaturated carbocyclic or heterocyclic ring system further substituted by R 21 including epoxides and thioepoxides; A' (or 3 connected to B 3 (or C) or Z 3 (or Y3); D 3 connected to B 3 (or Or (oT 3; G3 (or H 3 connected to E3 (or F 3 or I 3 (or L 3 (or K) connected to I (or or M3 (or N 3 03 (or O) connected to N 3 (or M 3 or P 3 (or Q3). 3 (or R 3 connected to Q (or P) or U 3 (or n. W 3 (or Vy) connected to U 3 (or T or X 3 X 3 connected to Y (or are Cl-Cs disubstituted (fused) saturated or unsaturated carbocyclic or heterocyclic ring systems further substituted by R 21 0)R 21 and 0 0)R 2 1 including epoxides and thioepoxides; A 3 ,i B 3 C 3 (3 J 3 3 12; M3 NH; 6, P 3 S 3 R 3 U 3 T 3 W3 and Z 3 Y are =0 where 0 is selected from sulfur, oxygen, nitrogen, NR 1 9 R 2 0 and =CR 22 R 23 and R22 and R 2 3 are selected from R 21 0)R21 and 0(C= 0)R 21 and which chemical agent or derivative or chemical analogis administered for a time and under conditions sufficient to potentiate the immune system or components therein. 34. A method according to Claim 33 wherein the chemical agent is represented by the general formula WO 02/11743 WO 0211743PCT/AUOI/00966 95 H 0111 0 R 26 R2 R 2 5 vi wherein:- R 24 R 25 and R 26 are independently selected from hydrogen, R 27 R 28 F, Cl, Br, 1, CN, OR 27 SR 27 NR 27 R 28 N(=O) 2 NR 27 0R 2 8 0NR 27 R 2 8 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 SO 2 NR 27 R28, S0 3 NR 27 R 28 P(R 27 3 P(=O)(R27) 3 Si(R 27 3 B(R 27 2 (C=X)R 29 or X(C=X)R 29 where X is selected from sulfur, oxygen and nitrogen; R 27 and R 28 are each independently selected from 01-02 alkyl (branched and/or straight chained), C1-020 arylalkyl, C 3 -C 8 cycloalicyl, 06-014 aryl, CI-C 14 heteroaryl, CI-C14 heterocycle, 02-010 alkenyl (branched and/or straight chained), 02-010 alkynyl (branched and/or straight chained), CI-Clo heteroarylalkyl, 01-010 alkoxyalkyl, CI-Cia haloialkyl, dihaloallcyl, trihaloalcyl, haloalkoxy, Cl-CO [ON, OR 27 SR 27 NR 27 R 2 g, N(=0) 2 NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 S0 2 NR 27 R 28 S0 3 NR 27 R 28 P(R 27 3 P(=O)3R 27 3 Si(R 27 3 B(R 27 2 ]alkyl; R 29 is selected from R 27 R 2 g, ON, C0R 27 C0 2 R 27 OR 2 7 SR 27 NR 27 R 28 N(=0) 2 NR 27 0R 28 0NR 27 R 28 S0R 27 S0 2 R 27 S0 3 R 27 S0NR 27 R 28 SO 2 NR 27 R 28 S0 3 NR 27 R 28 P(R 27 3 27 3 Si(R 27 3 B(R 27 2 A method according to Claim 33 wherein R 24 is H. WO 02/11743 WO 0211743PCT/AU01/00966 96 36. A method according to Claim 33 wherein R 24 is OAcetyl. 37. A method according to Claim 33 wherein R 24 is OH. 38. A method according to Claim 3 3 wherein R 25 is OH. 39. A method according to Claim 33 wherein R 26 is OH. A method according to Claim 33 wherein the plant is of the genus selected fr-om Acalypha, Acidoton, Actinostemon, Adelia, Adenocline, Adenocrepis, Adenophaedra, Adisca, Agrostistachys, Alchornea, Aichorneopsis, Alcinaeanthus, Alcoceria, Aleurites, Ainanoa, Andrachne, Angostyles, Anisophyllum, Antidesma, Aphora, Aporosa, Aporosella, Argythamnia, Astrococcus, Astrogyne, Baccanrea, Baliospermum, Bernardia, Beyeriopsis, Bisychofia, Blachia, Blumeodondron, Bonania, Bradleia, Breynia, Breyniopsis, Briedelia, Buraeavia, Caperonia, Caryodendron, Celianella, Cephalocroton, Chaenotheca, Chaetocarpus, Charnaesyce, Cheilosa, Chiropetalun, Choriophylluin, Cicca, Chaoxylon, Cleidon, Cleistanthus, Cluytia, Cnesrnone, Cnidoscolus, Coccoceras, Codiaeum, Coelodiscus, Conami, Conceveiba. Conceveibastruni, Concevebuin, Corythea, Croizatia, Croton, Crotonopsis, Crozophora, Cubanthus, Cunuria, Dactyl ostemon, Dalechainpia, Dendrocousinsia, Diaspers us, Didymocistus, Dimorphocalyx, Discocarpus, Ditaxis, Dodecastingrna, Drypetes, Dysopsis, Elateriospermin, Endadenium, Endospemnum, Erismanthus, Erythrocarpus, Erythrochilus, Eurnecan thus, Euphorbia, Euphorbiodendron, Excoecaria, Flueggea, Calearia, Garcia, Gavarretia, Geloniwin, Giara, Givotia, Glochidion, Clochidionopsis, Glycydendron, Gymnnanthes, Gymnosparia, Haematosperinun, Hendecandra, Hevea, Hieronima, Hieronyma, Hippocrepandra, Homnalanthus, Hymenocardia, Janip ha, Jatrop ha, Julocroton, Lasiocroton, Leiocarpus, Leonardia, Lepidanthus, Leucocroton, Mabee, Macaranga, Mallotus, Manihot, Mappa, Map rounea, Melanthesa, Mercurialis, Mettenia, Micrandra, Microdesm is, Microelus, Microstachy, Maocroton, Monadeniurn, Mozinna, Neoscortechinia, Ornalanthus, Oinphalea, Ophellant ha, Orbicularia, Ostodes, Oxydectes, Palenga, Pantadenia, Paradrypeptes, Pausandra, Pedilanthus, Pera, Peridium, Petalostigma, Phyllan thus, WO 02/11743 WO 0211743PCT/AUOI/00966 97 Picrodendro, Pierardia, Pilinophytum, Pimeleodendron, Pirankea, Platygyna, Plukenetia, Podocalyx, Poinsettia, Poraresia, Prosartema, Pseudantius, Pycnocoma, Quadrasia, Reverchonia, Richeria, Richeriella, Ricinella, Ricinocarpus, Rottlera, Sagotia, Sanwithia, Sapium, Savia, Scierocroton, Sebastiana, Securinega, Sen efeldera, Senefilderopsis, Seroplhyton, Siphonia, Spathiostemon, Spixia, Stillingia, Strop hioblachia, Synadenium, Tetracoccus, Tetraplandra, Tetrorchidium, Thyrsanthera, Tithymalus, Trageia, Trewia, Trigonostemon, Tyria and Xylophylla. 41. A method according to Claim 40 wherein the plant is of the genus Euphorbia. 42. A method according to Claim 41 wherein the species of Euphorbia is selected from Euphorbia aaron-rossii, Euphorbia abbreviata, Euphorbia acuta, Euphorbia alatocaulis, Euphorbia albicaulis, Euphorbia algomarginata, Euphorbia aliceae, Euphorbia alta, Euphorbia anacampseros, Euphorbia andromedae, Euphorbia angusta, Euphorbia anthonyi, Euphorbia antiguensis, Euphorbia apocynifolia, Euphorbia arabica, Euphorbia ariensis, Euphorbia arizonica, Euphorbia arkansana, Euphorbia arteagae, Euphorbia arundelana, Euphorbia astroites, Euphorbia atrococca, Euphorbia baselicis, Euphorbia batabanensis, Euphorbia bergeri, Euphorbia bermnudiana, Euphorbia bicolor, Euphorbia biformis, Euphorbia bifurcata, Euphorbia bilobata, Euphorbia biramlensis, Euphorbia biuncialis, Euphorbia blepharostipula, Euphorbia blodgetti, Euphorbia boerhaavioides, Euphorbia boliviana, Euphorbia bracei, Euphorbia brachiata, Euphorbia brachycera, Euphorbia brandegee, Euphorbia brittonii, Euphorbia caesia, Euphorbia calcicola, Euphorbia camp estris, Euphorbia candelabrum, Euphorbia capitellata, Euphorbia carmenensis, Euphorbia carunculata, Euphorbia cayensis, Euphorbia celastroides, Euphorbia chalicophila, Euphorbia chaniaerrhodos, Euphorbia chamaesula, Euphorbia chiapensis, Euphorbia chiogenoides, Euphorbia cinerascens, Euphorbia clarionensis, Euphorbia colirnae, Euphorbia colorata, Euphorbia comimutata, Euphorbia consoquitlae, Euphorbia convolvuloides, Euphorbia corallifera, Euphorbia creberrima, Euphorbia crenulata, Euphorbia cubensis, Euphorbia cuspidata, Euphorbia cymnbiformnis, Euphorbia darlington ii, Euphorbia defoliata, -Euphorbia degeneri, Euphorbia deltoidea, WO 02/11743 WO 0211743PCT/AUO1/00966 98 Euphorbia dentata, Euphorbia depressa Euphorbia dictyosperma, Euphorbia dictyospennta, Euphorbia dioeca, Euphorbia discoidalis, Euphorbia dorsiventralis, Euphorbia drumnondii, Euphorbia duclouxii, Euphorbia dussii, Euphorbia eanophylla, Euphorbia eggersii, Euphorbia eglandulosa, Euphorbia_ elata, Euphorbia enalla, Euphorbia eriogonoides, Euphorbia eriophylla, Euphorbia esculaeform is, Euphorbia espirituensis, Euphorbia esula, Euphorbia excisa, Euphorbia exciusa, Euphorbia exstzipitata, Euphorbia exstipulata, Euphorbia fendleri, Euphorbia filicaulis, Euphorbia filiform is, Euphorbia florida, Euphorbia fruticulosa, Euphorbia garber, Euphorbia. gazinerii, Euphorbia gerardiana, Euphorbia geyeri, Euphorbia glyptosperma, Euphorbia gorgois, Euphorbia gracilior, Euphorbia gracillima, Euphorbia gradyi, Euphorbia gram inea, Euphorbia graminiea Euphorbia grisea, Euphorbia guadalajarana, Euphorbia guanarensis, Euphorbia gymnadenia, Euphorbia haernatantha, Euphorbia hedyotoides, Euphorbia heldrichii4 Euphorbia helenae, Euphorbia helleri, Euphorbia helwigii, Euphorbia henricksonii, Euphorbia heterophylla, Euphorbia hexagona, Euphorbia hexagonoides, Euphorbia hinleyorum, Euphorbia hintonii, Euphorbia hirtula, Euphorbia hirta, Euphorbia hooveri, Euphorbia humistrata, Euphorbia hypericifolia, Euphorbia inundata, Euphorbia involuta, Euphorbia jaliscensis, Euphorbia jejuna, Euphorbia johnston, Euphorbia juttae, Euphorbia knuthii, Euphorbia lasiocarpa, Euphorbia lata, Euphorbia latazi, Euphorbia latericolor, Euphorbia laxiflora Euphorbia lechecides, Euphorbia ledienii, Euphorbia leucophylla, Euphorbia lineata, Euphorbia linguiformis, Euphorbia longecornuta, Euphorbia longepetiolata, Euphorbia longeranmosa, Euphorbia longinsulicola, Euphorbia longipila, Euphorbia lupulina, Euphorbia lurida, Euphorbia lycicides, Euphorbia macropodoides, nwcvaughiana, Euphorbia manca, Euphorbia mandoniana, Euphorbia inangleti, Euphorbia mango, Euphorbia inarylandica, Euphorbia mayana, Euphorbia melanadenia, Euphorbia nielanocarpa, Euphorbia meridensis, Euphorbia mertonii, Euphorbia nexiae, Euphorbia microcephala, Euphorbia microclada, Euphorbia micronmera, Euphorbia misella, Euphorbia missurica, Euphorbia montana, Euphorbia montereyana, Euphorbia inulticaulis, Euphorbia multifonnis, Euphorbia multinodis, Euphorbia multiseta, Euphorbia muscicola, Euphorbia neornexicana, Euphorbia nephradenia, Euphorbia niqueroana, Euphorbia caxacanla, Euphorbia occidentalis, Euphorbia odontodenia, Euphorbia olivacea, Euphorbia olowaluana, WO 02/11743 WO 0211743PCT/AUOI/00966 99 Euphorbia opthalmica, Euphorbia ovata, Euphorbia pachypoda, Euphorbia pachyrhiza, Euphorbia pad~fblia, Euphorbia palmieri, Euphorbia paludicola, Euphorbia paralias, Euphorbia parcplora, Euphorbia parishii, Euphorbia parryi, Euphorbia paxiana, Euphorbia pediculi/'era, Euphorbia peplidion, Euphorbia peploides, Euphorbia peplus, Euphorbia pergamena, Euphorbia perlignea, Euphorbia petaloidea, Euphorbia petaloidea, Euphorbia petrina, Euphorbia picachensis, Euphorbia pilosula, Euphorbia pilulifera, Euphorbia pinariona, Euphorbia pinetorum, Euphorbia pionosperma, Euphorbia platysperma, Euphorbia plicata, Euphorbia poeppigii, Euphorbia poliospernia, Euphorbia polycarpa, Euphorbia polycnemoides, Euphorbia polyp hylla, Euphorbia portoricensis, Euphorbia portulacoides Euphorbia portulana, Euphorbia preslii, Euphorbia prostrata, Euphorbia pteroneura, Euphorbia pycnanthlema, Euphorbia ramosa, Euphorbia rapulum, Euphorbia rentyi, Euphorbia retrosca bra, Euphorbia revoluta, Euphorbia rivularis, Euphorbia robusta, Euphorbia romosa, Euphorbia rubida, Euphorbia rubrosperma, Euphorbia rupicola, Euphorbia sanmartensis, Euphorbia saxatilis M. Bieb, Euphorbia schizoloba, Euphorbia scierocyathium, Euphorbia scopuloruim, Euphorbia senilis, Euphorbia serpyllifolia, Euplzorbia serrsla, Euphorbia setiloba Engeim, Euphorbia sonorae, Euphorbia soobyi, Euphorbia sparsiflora, Euphorbia sphaerosperma, Euphorbia syphilitica, Euphorbia spruceana, Euphorbia subcoerulea, Euphorbia stellata, Euphorbia submamniilaris, Euphorbia subpeltata, Euphorbia subpubens, Euphorbia subrenifonne, Euphorbia subtrifoliata, Euphorbia succedanea, Euphorbia tamaulipasana, Euphorbia telephioides, Euphorbia ten uissima, Euphorbia tetrapora, Euphorbia tirucalli, Euphorbia tomentella, Euphorbia tomentosa, Euphorbia torralbasii, Euphorbia tovariensis, Euphorbia trachysperma, Euphorbia tricolor, Euphorbia troyana, Euphorbia tuerckheimnii, Euphorbia turczaninowii, Euphorbia umbellulata, Euphorbia undulata, Euphorbia venmiforrnis, Euphorbia versicolor, Euphorbia villifiera, Euphorbia violacea, Euphorbia whitei, Euphorbia xanti Engelin, Euphorbia x'ylopoda Greenm., Euphorbia yayalesia Urb., Euphorbia yungasensis, Euphorbia zeravschanica and Euphorbia zinniiflora. 43. A method according to Claim 41 wherein the species of Euphorbia is Euphorbiapeplus. WO 02/11743 PCT/AU01/00966 -100- A method according to Claim 33 wherein the cancer is prostate cancer. A method according to any one of Claims 33 to 44 wherein the chemical agent is coupled to a targeting agent. 46. A method according to Claim 45 wherein the targeting agent targets a component of the immune system. 47. A method according to Claim 46 wherein the targeting agent is an immunoglobulin. 48. A method according to Claim 47 wherein the immunoglobulin targets a dendritic cell. 49. A method according to Claim 48 wherein the immunoglobulin targets a B- or T-cell. A method according to Claim 1 or 33 wherein the chemical agent is a jatrophane or a derivative thereof or a pharmaceutically acceptable salt of these. 51. derivative. 52. derivative. A method according to Claim 50 wherein said derivative is an ester A method according to Claim 50 wherein said derivative is an acetylated 53. A method according to Claim 1 or 33 wherein said chemical agent is a pepluane or a derivative thereof or a pharmaceutically acceptable salt of these. WO 02/11743 PCT/AU01/00966 -101- 54. derivative. derivative. A method according to Claim 53 wherein said derivative is an ester A method according to Claim 53 wherein said derivative is an acetylated 56. A method according to Claim 1 or 33 wherein said chemical agent is a paraliane or a derivative thereof or a pharmaceutically acceptable salt of these. 57. derivative. 58. derivative. A method according to Claim 56 wherein said derivative is an ester A method according to Claim 56 wherein said derivative is an acetylated 59. A method according to Claim 1 or 33 wherein said compound is an angeloyl-substituted ingenane or a derivative thereof or a pharmaceutically acceptable salt of these. derivative. A method according to Claim 59 wherein said derivative is an acetylated 61. A method according to Claim 59 wherein said j atrophane is of conformation 2. 62. A method according to Claim 50 or 53 or 56 or 59 wherein the derivative comprises a substitution as represented in any one of general formulae (VI). 63. A method according to Claim 1 or 33 wherein said compound is 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane) or a derivative thereof or a pharmaceutically acceptable salt of these. WO 02/11743 PCT/AU01/00966 -102- 64. A method according to Claim 63 wherein said derivative is an ester derivative. A method according to Claim 1 or 33 wherein said compound is 2,3,5,7,15- pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),1 E-diene (jatrophane 1) or a derivative thereof or a pharmaceutically acceptable salt of these. 66. A method according to Claim 65 wherein said derivative is an ester derivative. 67. A method according to Claim 1 or 33 wherein said compound is 2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-jatropha-6(17),llE-diene (jatrophane 2) or a derivative thereof or a pharmaceutically acceptable salt of these. 68. A method according to Claim 67 wherein said derivative is an ester derivative. 69. A method according to Claim 1 or 33 wherein said compound is 2,5,14- triacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy-9-nicotinoyloxyjatropha-6(17), 11E-diene (jatrophane 3) or a derivative thereof or a pharmaceutically acceptable salt of these. A method according to Claim 69 wherein said derivative is an ester derivative. 71. A method according to Claim 1 or 33 wherein said compound is 2,5,9,14- tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxyjatropha-6(l7), 1 E-diene) (jatrophane 4) or a derivative thereof or a pharmaceutically acceptable salt of these. WO 02/11743 PCT/AU01/00966 -103- 72. derivative. A method according to Claim 71 wherein said derivative is an ester 73. A method according to Claim 1 or 33 wherein said compound is 2,5,7,14- tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxyjatropha-6(17),11E-diene (jatrophane 5) or a derivative thereof or a pharmaceutically acceptable salt of these. 74. derivative. A method according to Claim 73 wherein said derivative is an ester A method according to Claim 1 or 33 wherein said compound is 2,5,7,9,14- pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17),11E-diene (jatrophane 6) or a derivative thereof or a pharmaceutically acceptable salt of these. 76. derivative. A method according to Claim 75 wherein said derivative is an ester 77. A method according to Claim 1 or 33 wherein said compound is 20-0- acetyl-ingenol-3-angelate or a derivative thereof or a pharmaceutically acceptable salt of these. 78. derivative. A method according to Claim 77 wherein said derivative is an ester 79. A method according to Claim 1 or 33 or 63 or 65 or 67 or 69 or 71 or 73 or or 77 wherein said compound is provided in the form of a composition comprising a pharmaceutically- or cosmetically-acceptable carrier. A method for the treatment or prophylaxis of a subject with prostate cancer or a related condition or with the symptoms of prostate cancer, said method comprising the P:\Opa\Ejh-mded\79493 pp1 .ptumddw0/0

104- administration to said subject of a symptom-ameliorating effective amount of an angeloyl substituted ingenane or a chemical fraction or plant extract comprising same. 81. A method for the treatment or prophylaxis of a subject with prostate cancer or with the symptoms of prostate cancer, said method comprising the administration to said subject of a symptom-ameliorating effective amount of one or more of ingenol-3-angelate, 20-deoxy-ingenol-3-angelate and/or 20-O-acetyl-ingenol-3-angelate or derivative thereof or a pharmaceutically acceptable salt of these or a chemical fraction or plant extract comprising same. 82. A method for the treatment or prophylaxis of prostate cancer in a subject, said method comprising the simultaneous or sequential administration to said subject of a symptom-ameliorating effective amount of a chemical agent derived from a plant of the Euphorbiaceae family together with a therapeutic protocol or a symptom-ameliorating effective amount of another chemical agent or a physical agent. 83. Use of a chemical agent or derivative or chemical analog thereof as represented by any one of the present Formulae to or (VI) in the manufacture of a medicament for treatment and/or prophylaxis of prostate cancer in a subject. 84. A chemical agent derived from a plant of the Euphorbiaceae family coupled to a targeting agent. A chemical agent according to Claim 84 wherein said agent prior to coupling is a compound of any of formulae or (VI). 86. A chemical agent according to Claim 85 wherein said chemical agent is jatrophane. WO 02/11743 PCT/AU01/00966 -105- 87. A chemical agent according to Claim 86 wherein the chemical agent is j atrophane of conformation 2. 88. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 5,8,9,10,14-pentaacetoxy-3-benzoyloxy-15-hydroxypepluane (pepluane) or a derivative thereof or a pharmaceutically acceptable salt of these. 89. A chemical agent according to Claim 88 wherein said derivative is an ester derivative. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,3,5,7,15-pentaacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17), 1E-diene (jatrophane 1) or a derivative thereof or a pharmaceutically acceptable salt of these. 91. A chemical agent according to Claim 90 wherein said derivative is an ester derivative. 92. -A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,5,7,8,9,14-hexaacetoxy-3-benzoyloxy-15-hydroxy-jatropha-6(17), lE- diene (jatrophane 2) or a derivative thereof or a pharmaceutically acceptable salt of these. 93. A chemical agent according to Claim 92 wherein said derivative is an ester derivative. 94. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,5,14-triacetoxy-3-benzoyloxy-8, 5-dihydroxy-7-isobutyroyloxy-9- nicotinoyloxyjatropha-6(17), 11E-diene (jatrophane 3) or a derivative thereof or a pharmaceutically acceptable salt of these. A chemical agent according to Claim 94 wherein said derivative is an ester derivative. WO 02/11743 PCT/AU01/00966 -106- 96. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,5,9,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-7-isobutyroyloxy- jatropha-6(17),11E-diene) (jatrophane 4) or a derivative thereof or a pharmaceutically acceptable salt of these. 97. A chemical agent according to Claim 96 wherein said derivative is an ester derivative. 98. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,5,7,14-tetraacetoxy-3-benzoyloxy-8,15-dihydroxy-9-nicotinoyloxy- jatropha-6(17),1lE-diene (jatrophane 5) or a derivative thereof or a pharmaceutically acceptable salt of these. 99. A chemical agent according to Claim 98 wherein said derivative is an ester derivative. 100. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 2,5,7,9,14-pentaacetoxy-3-benzoyloxy-8,15-dihydroxyjatropha-6(17), 1E- diene (jatrophane 6) or a derivative thereof or a pharmaceutically acceptable salt of these. 101. A chemical agent according to Claim 100 wherein said derivative is an ester derivative. 102. A chemical agent according to Claim 85 wherein said chemical agent prior to coupling is 20-O-acetyl-ingenol-3-angelate or a derivative thereof or a pharmaceutically acceptable salt of these. 103. A chemcial agent according to Claim 102 wherein said derivative is an ester derivative. WO 02/11743 PCT/AU01/00966 -107- 104. A chemical agent according to any one of Claims 84 to 103 wherein said chemical agent is provided in the form of a composition comprising a pharmaceutically- or cosmetically-acceptable carrier.

105. A chemical agent according to any one of Claims 84 to 103 wherein the targeting agent is a bone-seeking agent.

106. A chemical agent according to Claim 105 wherein the bone-seeking agent is bisphosphonate.

107. A chemical agent according to Claim 106 wherein the bisphosphonate is methylene disphosphonate.

108. A chemical agent according to any one of Claims 84 to 103 wherein the targeting agent is an antibody.

109. A chemical agent according to Claim 108 wherein the targeting agent is an antibody to a prostate-specific tumor marker.

110. A chemical agent according to Claim 108 wherein the marker is prostate- specific antigen (PSA), prostate-specific membrane antigen (PMSA) or PSA receptor.

111. A chemical agent according to Claim 108 wherein the antibody is specific to a component of the immune system.

112. A chemical agent according to Claim 111 wherein the immune system component is a dendritic cell, B- or T-cell.