WO2003051864A1 - Isoflavonoid conjugates, compositions thereof and therapeutic methods involving same - Google Patents

Isoflavonoid conjugates, compositions thereof and therapeutic methods involving same Download PDF

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WO2003051864A1
WO2003051864A1 PCT/AU2002/001722 AU0201722W WO03051864A1 WO 2003051864 A1 WO2003051864 A1 WO 2003051864A1 AU 0201722 W AU0201722 W AU 0201722W WO 03051864 A1 WO03051864 A1 WO 03051864A1
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compounds
alkyl
hydrogen
aryl
isoflavonoid
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PCT/AU2002/001722
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French (fr)
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Andrew Heaton
Graham Edmund Kelly
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Novogen Research Pty Ltd
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Priority to AU2002350275A priority Critical patent/AU2002350275A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C305/00—Esters of sulfuric acids
    • C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
    • C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/38—2,3-Dihydro derivatives, e.g. isoflavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • This invention relates to compounds, formulations, drinks, foodstuffs, methods and therapeutic uses involving, containing, comprising, including and/or for preparing certain isoflavone conjugate compounds and analogues thereof.
  • the invention relates to sulfoconjugates and glucoconjugates of isoflavonoids, medicaments involving same and therapeutic uses thereof.
  • Isoflavones and many derivatives thereof possess a very wide range of important biological properties including oestrogenic effects.
  • Isoflavones such as genistein and daidzein have been shown to be involved in the modulation or attenuation of levels of estrogenic steroids in the body.
  • isoflavonoids act as agonists of the estrogen receptor while others act as antagonists of the estrogen receptor. It is believed that there is a strong correlation between lowering levels of biologically active estrogenic steroids in the body with lower incidences of cancer such as breast cancer and many other diseases and conditions.
  • the present inventors have surprisingly found that sulfoconjugates and glucoconjugates of isoflavones and derivatives thereof exhibit beneficial biological properties.
  • the conjugates are thought to exhibit a wide range of therapeutic activities including the ability to address oestrogen levels in the body.
  • isoflavone conjugates and derivatives thereof may reduce the supply of estrogenic steroids, reducing the risk or severity of oestrogen- related diseases and conditions. It is also thought that the isoflavonoid conjugates of the invention regulate a range of molecular targets in mammalian cells, and that these molecular targets are intimately involved in signal transduction processes that are fundamental to critical cellular processes such as cell growth, differentiation, migration, and death. It can be seen therefore that these surprising biochemical effects have broad and important implications for the health of animals including humans.
  • Ri, R 2 and Z are independently -O-SO 2 OH, an O-sugar residue, hydrogen, hydroxy,
  • OR 9 OC(O)R ⁇ o, OS(O)R ⁇ o, CHO, C(O)R ⁇ 0 , COOH, CO 2 R ⁇ 0 , CONR 3 R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, a ino, alkylamino, dialkylamino, nitro or halo, or R 2 is as previously defined, and Ri and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
  • Ri is as previously defined, and R 2 and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
  • W is Ri
  • A is -O-SO 2 OH, an O-sugar residue, hydrogen, hydroxy, NR 3 R 4 or thio
  • B is selected from
  • W is Ri, and A and B taken together with the carbon atoms to which they are attached form a six-membered ring selected from
  • R 3 is hydrogen, alkyl, aryl, arylalkyl, an amino acid, C(O)R ⁇ where Rn is hydrogen alkyl, aryl, arylalkyl or an amino acid, or CO 2 R ⁇ 2 where R i2 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl or arylalkyl, R-i is hydrogen, alkyl or aryl, or R 3 and R 4 taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl, R 5 is -O-SO 2 OH, an O-sugar residue, hydrogen, C(O)R ⁇ where Rn is as previously defined, or CO 2 R ⁇ 2 where R ⁇ 2 is as previously defined,
  • R 6 is -O-SO 2 OH, an O-sugar residue, hydrogen, hydroxy, alkyl, aryl, amino, thio,
  • Rn is as previously defined, CO 2 R ⁇ 2 where R ⁇ 2 is as previously defined or CONR 3 I- , R is hydrogen, C(O)Rn where Rn is as previously defined, alkyl, haloalkyl, aryl, arylalkyl or Si(R ⁇ 3 ) 3 where each R ⁇ 3 is independently hydrogen, alkyl or aryl,
  • R 8 is -O-SO 2 OH, an O-sugar residue, hydrogen, hydroxy, alkoxy or alkyl
  • R 9 is alkyl, haloalkyl, aryl, arylalkyl, C(O)Rn where Rn is as previously defined, or
  • R ⁇ 4 , R15 and R ⁇ 6 are independently -O-SO 2 OH, an O-sugar residue, hydrogen, hydroxy, OR 9 , OC(O)R ⁇ o, OS(O)Ri 0 , CHO, C(O)R ⁇ 0 , COOH, CO 2 R ⁇ 0 , CONR 3 R 4 , alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, and wherein at least one of Ri, R 2 , R 5 , R-g, R 8 , R 14 , R 15 , R 16 .
  • Z, W or A where present is independently -O-SO 2 OH or an O-sugar residue, or a pharmaceutically acceptable salt or prodrug thereof.
  • the sulfoconjugate moiety is present as the corresponding salt of -O-SO 2 OM, where M is a pharmaceutically acceptable counter ion.
  • Ri, R 2 , W, A, B and Z are as defined above have particular utility and effectiveness in the treatment, prophylaxis, amelioration defence against, and/or prevention of the following diseases and disorders (for convenience hereinafter referred to as the "therapeutic indications"):
  • the compounds may be used as the sole form of anti-cancer therapy or in combination with other forms of anti-cancer therapy including but not limited to radiotherapy and chemotherapy;
  • papulosquamous skin lesions including but not limited to psoriasis, Bowen's Disease, and Reiter's Disease;
  • actinic damage characterized by degenerative changes in the skin including but not limited to solar keratosis, photosensitivity diseases, and wrinkling;
  • diseases and disorders associated with abnormal angiogenesis affecting any tissue within the body including but not limited to hemangiomas and telangiectasia;
  • proliferative disorders of bone marrow including but not limited to megaloblastic disease, myelodysplastic syndromes, polycythemia vera, thrombocytosis and myelofibrosis;
  • autoimmune disease characterized by abnormal immunological responses including but not limited to multiple sclerosis, Type 1 diabetes, systemic lupus erythematosis, and biliary cirrhosis;
  • neurodegenerative diseases and disorders characterized by degenerative changes in the structure of the neurological system including but not limited to Parkinson's Disease, Alzheimer's Disease, muscular dystrophy, Lou-Gehrig Disease, motorneurone disease;
  • diseases and disorders associated with degenerative changes within the walls of blood vessels including but not limited to atherosclerosis, atheroma, coronary artery disease, stroke, myocardial infarction, hypertensive vascular disease, malignant hypertension, thromboangiitis obliterans, fibromuscular dysplasia;
  • diseases and disorders associated with abnormal immunological esponses including but limited to dermatomyositis and scleroderma;
  • diseases and disorders associated with degenerative changes within the eye including but not limited to cataracts, macular degeneration, retinal atrophy.
  • isoflavone conjugates and various analogues thereof also surprisingly have been found to have a potent effect on the production and function of reproductive hormones such as estrogens and androgens.
  • reproductive hormones such as estrogens and androgens.
  • an agent for the treatment, prophylaxis, amelioration, defence against and/or treatment of the therapeutic indications which comprises one or more compounds of formula I either alone or in association with one or more carriers or excipients.
  • a therapeutic composition which comprises one or more compounds of formula I in association with one or more pharmaceutical carriers and/or excipients.
  • a drink or food-stuff which contains one or more compounds of formula I.
  • a microbial culture or a food-stuff containing one or more microbial strains which microorganisms produce one or more compounds of formula I According to another aspect of the present invention there is provided one or more microorganisms which produce one or more compounds of formula I.
  • the microorganism is a purified culture, which may be admixed and/or administered with one or more other cultures which product compounds of formula I.
  • isoflavonoid and “isoflavone” as used herein are to be taken broadly to include ring-fused benzopyran molecules having a pendent phenyl group from the pyran ring based on a 1,2-diphenylpropane system.
  • isoflavones classes of compounds generally referred to as isoflavones, isoflavenes, isoflavans, isoflavanones, isoflavanols and the like are generically referred to herein as isoflavonoid compounds, isoflavones, isoflavone derivatives or isoflavone compounds and derivatives thereof.
  • sugar residue is taken to include residues of natural sugars or saccharides, modified sugars, and di- and poly-saccharides including those selected from the group consisting of glucose, altrose, mannose, galactose, fructose, talose, xylose, arabinose, ribose, sorbose including the related furanoside and pyranoside moieties, and sucrose, lactose, maltose and the like.
  • Particularly preferred sugar residues are selected from the group consisting of ,D-glucoside, malonyl glucoside, acetyl glucoside and ⁇ ,D- glucuronide.
  • alkyl is taken to include straight chain, branched chain and cyclic (in the case of 5 carbons or greater) saturated alkyl groups of 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertiary butyl, pentyl, cyclopentyl, and the like.
  • the alkyl group is more preferably methyl, ethyl, propyl or isopropyl.
  • the alkyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C 4 -alkylamino- carbonyl, di-(C ⁇ -C 4 -alkyl)-amino-carbonyl, hydroxyl, C ⁇ -C 4 -alkoxy, formyloxy, C1-C4- alkyl-carbonyloxy, C ⁇ -C 4 -alkylthio, C -C 6 -cycloalkyl or phenyl.
  • alkenyl is taken to include straight chain, branched chain and cyclic (in the case of 5 carbons or greater) hydrocarbons of 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, with at lease one double bond such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-methyl-l-peopenyl, 2-methyl-2-propenyl, and the like.
  • the alkenyl group is more preferably ethenyl, 1-propenyl or 2-propenyl.
  • the alkenyl groups may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, C ⁇ -C 4 - alkoxycarbonyl, C ⁇ -C 4 -alkylamino-carbonyl, di-(C ⁇ -C 4 -alkyl)-amino-carbonyl, hydroxyl, C ⁇ -C 4 -alkoxy, formyloxy, C ⁇ -C 4 -alkyl-carbonyloxy, C ⁇ -C 4 -alkylthio, C 3 -C 6 -cycloalkyl or phenyl.
  • alkynyl is taken to include both straight chain and branched chain hydrocarbons of 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, with at least one triple bond such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like.
  • the alkynyl group is more preferably ethynyl, 1-propynyl or 2-propynyl.
  • the alkynyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C 4 -alkylamino-carbonyl, di-(C ⁇ -C 4 -alkyl)-amino- carbonyl, hydroxyl, C ⁇ -C 4 -alkoxy, formyloxy, C ⁇ -C 4 -alkyl-carbonyloxy, C ⁇ -C 4 -alkylthio, C 3 -C 6 -cycloalkyl or phenyl.
  • aryl is taken to include phenyl, biphenyl and naphthyl and may be optionally substituted by one or more C ⁇ -C -alkyl, hydroxy, C ⁇ -C 4 -alkoxy, carbonyl, C ⁇ -C 4 - alkoxycarbonyl, C ⁇ -C 4 -alkylcarbonyloxy or halo.
  • heteroaryl is taken to include five-menibered and six-membered rings which include at least one oxygen, sulfur or nitrogen in the ring, which rings may be optionally fused to other aryl or heteroaryl rings including but not limited to furyl, pyridyl, pyrimidyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isopuinolyl, purinyl, morpholinyl, oxazolyl, thiazolyl, pyrrolyl, xanthinyl, purine, thymine, cytosine, uracil, and isoxazolyl.
  • the heteroaromatic group can be optionally substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, C ⁇ -C 4 -alkoxycarbonyl, C ⁇ -C 4 - alkylamino-carbonyl, di-(C ⁇ -C 4 -alkyl)-amino-carbonyl, hydroxyl, C ⁇ -C 4 -alkoxy, formyloxy, C ⁇ -C 4 -alkyl-carbonyloxy, C ⁇ -C 4 -alkylthio, C 3 -C 6 -cycloalkyl or phenyl.
  • the heteroaromatic can be partially or totally hydrogenated as desired.
  • halo is taken to include fluoro, chloro, bromo and iodo, preferably fluoro and chloro, more preferably fluoro.
  • Reference to for example "haloalkyl” will include monohalogenated, dihalogenated and up to perhalogenated alkyl groups. Preferred haloalkyl groups are trifluoromethyl and pentafluoroethyl.
  • pharmaceutically acceptable salt refers to an organic or inorganic moiety that carries a charge and that can be administered in association with a pharmaceutical agent, for example, as a counter-cation or counter-anion in a salt.
  • Pharmaceutically acceptable cations are known to those of skilled in the art, and include but are not limited to sodium, potassium, calcium, zinc and quaternary amine.
  • Pharmaceutically acceptable anions are known to those of skill in the art, and include but are not limited to chloride, acetate, citrate, bicarbonate and carbonate.
  • pharmaceutically acceptable derivative refers to a derivative of the active compound that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound or metabolite, or that exhibits activity itself.
  • treatment As used herein, the terms “treatment”, “prophylaxis” or “prevention”, “amelioration” and the like are to be considered in their broadest context. In particular, the term “treatment” does not necessarily imply that an animal is treated until total recovery. Accordingly, “treatment” includes amelioration of the symptoms or severity of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the invention in particular relates to the compounds of the general formulae II - VIII and uses thereof:
  • isoflavone compound or derivative is a mono-, di-, or per-conjugated glucuronide or sulfate derived from the following hydroxyl-containing isoflavone compounds and derivatives 1 - 30 as follows:
  • R 2 , R ⁇ 6 , W and Z are independently H, OH, Cl, Me or OMe, and R M is H, OMe, Me or Cl.
  • conjugated isoflavone or derivative is a novel mono-, di- or per-sulfoconjugate or glucoconjugate of daidzein, genestein, equol, formomonetin, dihydrodaidzein, dihydrogenestein, dehydro-O-desmethylangolensin, tetrahydrodaidzein, dehydroequol, O-desmethyl-angolensin (ODMA) or 6-hydroxy-O-desmethylangolensin.
  • ODMA O-desmethyl-angolensin
  • Compounds of the present invention have particular application in the treatment of diseases associated with or resulting from estrogenic effects, androgenic effects, vasodilatory and spasmodic effects, inflammatory effects and oxidative effects.
  • the amount of one or more compounds of formula I which is required in a therapeutic treatment according to the invention will depend upon a number of factors, which include the specific application, the nature of the particular compound used, the condition being treated, the mode of administration and the condition of the patient.
  • Compounds of formula I may be administered in a manner and amount as is conventionally practised. See, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 1299 (7th Edition, 1985).
  • the specific dosage utilised will depend upon the condition being treated, the state of the subject, the route of administration and other well known factors as indicated above.
  • a daily dose per patient may be in the range of 0.1 mg to 2 g; typically from 0.5 mg to 1 g; preferably from 50 mg to 200 mg.
  • the length of dosing may range from a single dose given once every day or two, to twice or thrice daily doses given over the course of from a week to many months to many years as required, depending on the severity of the condition to be treated or alleviated. It will be further understood that for any particular subject, specific dosage regimens should be adjust over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • compositions for the treatment of the therapeutic indications herein described are typically prepared by admixture of the compounds of the invention (for convenience hereafter referred to as the "active compounds") with one or more pharmaceutically or veterinarially acceptable carriers and/or excipients as are well known in the art.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the subject.
  • the carrier or excipient may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose, for example, a tablet, which may contain from 0.5% to 59% by weight of the active compound, or up to 100% by weight of the active compound.
  • One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
  • the formulations of the invention include those suitable for oral, rectal, optical, buccal (for example, sublingual), parenteral (for example, subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
  • Formulation suitable for oral administration may be presented in discrete units, such as capsules, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • a suitable carrier which may contain one or more accessory ingredients as noted above.
  • the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture such as to form a unit dosage.
  • a tablet may be prepared by compressing or moulding a powder or granules containing the active compound, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound of the free-flowing, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • Formulations suitable for buccal (sublingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • compositions of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compounds, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1% to 60% w/v of active compound and are administered at a rate of 0.1 ml/minute/kg. Formulations suitable for rectal or vaginal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations or compositions suitable for topical administration to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combination of two or more thereof.
  • the active compound is generally present at a concentration of from 0.1 % to 0.5% w/w, for example, from 0.5% to 2% w/w.
  • Examples of such compositions include cosmetic skin creams.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches suitably contain the active compound as an optionally buffered aqueous solution of, for example, 0.1 M to 0.2 M concentration with respect to the said active compound.
  • Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
  • Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 M to 0.2 M active ingredient.
  • Formulations suitable for inhalation may be delivered as a spray composition in the form of a solution, suspension or emulsion.
  • the inhalation spray composition may further comprise a pharmaceutically acceptable propellant such as carbon dioxide or nitrous oxide.
  • the active compounds may be provided in the form of food stuffs, such as being added to, admixed into, coated, combined or otherwise added to a food stuff.
  • food stuff is used in its widest possible sense and includes liquid formulations such as drinks including dairy products and other foods, such as health bars, desserts, etc.
  • Food formulations containing compounds of the invention can be readily prepared according to standard practices.
  • Compounds of the present invention have potent antioxidant activity and thus find wide application in pharmaceutical and veterinary uses, in cosmetics such as skin creams to prevent skin ageing, in sun screens, in foods, health drinks, shampoos, and the like.
  • composition comprising one or more compounds of formula I, vitamin E, and optionally a pharmaceutically, veterinarily or cosmetically acceptable carriers and/or excipients.
  • Therapeutic methods, uses and compositions may be for administration to humans or animals, such as companion and domestic animals (such as dogs and cats), birds (such as chickens, turkeys, ducks), livestock animals (such as cattle, sheep, pigs and goats), for use in aquaculture applications and the like.
  • companion and domestic animals such as dogs and cats
  • birds such as chickens, turkeys, ducks
  • livestock animals such as cattle, sheep, pigs and goats
  • the conjugates can also be co-administered with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antiftmgals, antiinflammatories, or antiviral compounds.
  • the active agent can comprise two or more isoflavones or derivatives thereof in combination or synergistic mixture.
  • the active compounds can also be administered with lipid lowering agents such as probucol and nicotinic acid; platelet aggregation inhibitors such as aspirin; antithrombotic agents such as coumadin; calcium channel blockers such as verapamil, diltiazem, and nifedipine; angiotensin converting enzyme (ACE) inhibitors such as captopril and enalapril, and ⁇ - blockers such as propanolol, terbutalol, and labetalol.
  • lipid lowering agents such as probucol and nicotinic acid
  • platelet aggregation inhibitors such as aspirin
  • antithrombotic agents such as coumadin
  • calcium channel blockers such as verapamil, diltiazem, and nifedipine
  • angiotensin converting enzyme (ACE) inhibitors such as captopril and enalapril
  • ⁇ - blockers such as propano
  • the compounds can also be administered in combination with nonsteriodal antiinflammatories such as ibuprofen, indomethacin, aspirin, fenoprofen, mefenamic acid, flufenamic acid and sulindac.
  • nonsteriodal antiinflammatories such as ibuprofen, indomethacin, aspirin, fenoprofen, mefenamic acid, flufenamic acid and sulindac.
  • the compounds can also be administered with corticosteroids.
  • the co-administration may be simultaneous or sequential. Simultaneous administration may be effected by the compounds being in the same unit dose, or in individual and discrete unit doses administered at the same or similar time. Sequential administration may be in any order as required and typically will require an ongoing physiological effect of the first or initial active agent to be current when the second or later active agent is administered, especially where a cumulative or synergistic effect is desired.
  • Isoflavonoid compounds are suitable starting materials for the synthesis of the isoflavonoid conjugates of formula I and these isoflavonoid starting materials may be prepared by standard methods known to those skilled in the art. Suitable methods may be found in, for example, International Patent Applications WO 98/08503 and WO 00/49009 which are incorporated herein in their entirety by reference. Chemical functional group protection, deprotection, synthons and other techniques known to those skilled in the art may be used where appropriate in the synthesis of the compounds of the present invention. Derivatisation of the hydroxy substituted isoflavones to form the conjugates of the present invention may be performed by any suitable method as known to one skilled in the art.
  • the isoflavonoid starting materials may also be obtained in the form of concentrates or extracts from plant sources. Again, those skilled in the art will readily be able to identify suitable plant species, however, for example, plants of particular utility include leguminous plants. More preferably, the isoflavone extract may be obtained from obtained from chickpea, lentils, beans, red clover or subterranean clover species and the like.
  • the phenolic groups of isoflavones are suitable nucleophiles for the Mitsunobu reaction. Furthermore, the electronic differentiation of the phenolic moieties in an isoflavone facilitates selective protection. Those skilled in the art would appreciate that selective protection and deprotection could mask either phenolic group from acting as a nucleophile for the Mitsunobu reaction. It is also possible to have a completely deprotected isoflavone thus effecting bis-Mitsunobu coupling.
  • dihydroxy substituted isoflavone dehydroequol is treated with sulfur trioxide to afford dehydroequol-di-O-sulfate as set out below:
  • the sulfate so formed may be either protonated as shown, or more preferably is present as a pharmaceutically acceptable salt.
  • conjugate syntheses by enzymatic formation employing a glucuronosyl transferase or sulfotransferase as appropriate, or by glucuronidation with microsomes.
  • substituted isoflavonoid conjugates of the invention can be synthesised by the use of different sugars, protecting groups, synthons and different starting isoflavonoid compounds as would be known to one skilled in the art.
  • Therapeutic formulations are prepared by admixing one or more isoflavonoid conjugates from compounds 1 to 30 with a soy flour base (defatted soy flour available from Edible Enhanced Protein St Marys, Australia).
  • a range of pharmaceutical formulations are prepared comprising between 40 mg and 200 mg of active compound to a dosage formed.
  • Gelatin capsules and tablets containing 200 mg of each of the active compounds 1 to 30 are prepared in the soy flour base referred to above, or in a cholesterol free yoghurt base.
  • EXAMPLE 5 A. Treatment of vascular conditions - menopausal syndrome, hot flushes, hypertension, atherosclerosis and male impotency
  • Vascular reactivity studies using rat aortic rings are generally regarded as directly predictive of biological effects of candidate compounds in the treatment of the above conditions (Karapapanis, S. et al (1994) Heptology, 20, 6, 1516-1521).
  • the inhibitory effect on restrictor responses in the aortic ring is measured in the presence of the vasoconstrictor noradrenaline according to the procedure of Karapapanis (supra).
  • Isoflavanoid conjugates from compounds 1 to 30 exhibit potent inhibitory effects on responses to noradrenaline, that is, they inhibit vaso-constrictor responses.
  • Hormone responsive cancer treatment - treatment of hormone related cancers including breast, ovarian, testicular, uterine, endometrial andprostatic cancer
  • the activity of compounds of the present invention in inhibiting the growth of hormone responsive cancer cells is tested using the well characterised human responsive cancer cell lines K562 and HL60.
  • the anti-cancer screening assay measures inhibition of cell proliferation which results in terminal differential cell death. Cell death is due to either apoptosis or necrosis. Isoflavonoid conjugates from compounds 1 to 30 are found to be potent inhibitors of growth of cell lines K563 and HL60, this result being therefore directly predictive that these compounds will inhibit the growth of hormone related cancers such as those mentioned above.
  • An elderly male subject suffering from prostate cancer receives a daily dosage of 16 mg of an isoflavonoid conjugate from compounds 1 to 30. After subsequent surgery for his prostate cancer condition the pathology report on the extracted prostate tissue shows an increased incidence of apoptosis (Stephens, F. O. (1997) J. Aus. Med. Assoc. 167, 3, 138-
  • a patient group was studied comprising women who had a past history of breast cancer (who had been treated either by surgery or radiation, or both) and women who had a strong familial connection to breast cancer, that is, where their mothers or siblings had suffered from breast cancer.
  • This study investigated whether isoflavonoid conjugates from compounds 1 to 30 administered transdermally each day through a skin patch could be used to prevent breast cancer or metastatic cancers following cancer therapy.
  • Patches are prepared that contained a lipophylic carrier cream which is readily absorbed through the skin.
  • the cream comprises a glycerol cold cream which contains glycerin and peanut oil.
  • a selected active compound from any one of compounds 1 to 30 is mixed with the lipophylic cream such that each patch comprises 10 mg to 100 mg of active compound.
  • the patch is applied to the skin each day and rapid absorption occurs. After two hours the patch is removed. Alternatively, the patch may be left on for a greater part of each day.
  • a study of a group of patients suffering from benign prostatic hypertrophy (BPH) and prostatic cancer of various grades is carried out to determine the effect of admimstration of compounds 1 to 30.
  • the administration protocol is the same as for Example 4 involving daily administration of a gelatin capsule containing 200 mg of active compound.
  • a significant decrease in the rate of production of relevant cancer markers (PSA, prostate specific antigen) is observed. Tumours are again shown to have regressed, or show no further growth.
  • a patient suffering from advanced bowel cancer is treated daily for three weeks with an intravenous infusion of 2 g of an isoflavonoid conjugate from compounds 1 to 30 dissolved in sterile saline.
  • the patient's pain and discomfort is significantly reduced, and reduction in cancer markers is observed. Progression of the tumour is also arrested over the treatment period.
  • fri a further series of experiments a group of patients suffering from terminal bowel cancer are treated by bolus daily injections (intravenous or intramuscular) of 2 g of an isoflavonoid conjugate from compounds 1 to 30. Over the test period there is shown to be a marked reduction in pain and discomfort.
  • Tumour markers (carcino-embryonic antigen (CEA)) are reduced as evidenced by blood analysis and tumour spread decreased.

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Abstract

The invention relates to compounds, formulations, drinks, foodstuffs, methods and therapeutic uses involving, containing, comprising, including and/or for preparing isoflavone conjugate compounds and analogues thereof. More preferably the invention relates to sulfoconjugates and glucoconjugates of isoflavonoids, medicaments involving same and therapeutic uses thereof.

Description

ISOFLAVONOID CONJUGATES, COMPOSITIONS THEREOF AND THERAPEUTIC METHODS INVOLVING SAME
Field of the Invention
This invention relates to compounds, formulations, drinks, foodstuffs, methods and therapeutic uses involving, containing, comprising, including and/or for preparing certain isoflavone conjugate compounds and analogues thereof. In particular, the invention relates to sulfoconjugates and glucoconjugates of isoflavonoids, medicaments involving same and therapeutic uses thereof.
Background
Isoflavones and many derivatives thereof possess a very wide range of important biological properties including oestrogenic effects. Isoflavones such as genistein and daidzein have been shown to be involved in the modulation or attenuation of levels of estrogenic steroids in the body. In some areas of biological activity, there are even some contradictions, for example, some isoflavonoids act as agonists of the estrogen receptor while others act as antagonists of the estrogen receptor. It is believed that there is a strong correlation between lowering levels of biologically active estrogenic steroids in the body with lower incidences of cancer such as breast cancer and many other diseases and conditions.
However, the biological activity of isoflavonoids in animals is not conserved across the spectrum of the isoflavonoid family and therefore cannot be predicted. Thus each specific structural variation of the basic isoflavonoid molecule can yield a highly individual biological profile in animals ranging from nil effect through to potent effect. Furthermore, it is thought that some conjugates of biologically active molecules, such as sulfoconjugates of the biologically active estrogenic steroid, oestrogen, are largely inactive.
There is a strong need to identify new, improved, better and/or alternative pharmaceutical compositions and agents for the treatment, amelioration and prevention of diseases, conditions and disorders. There is also a need for new and different therapies to be available to both physicians and the general public to combat the numerous and various types of diseases and disorders which affect members of the population.
A requirement accordingly exists for the provision of new isoflavone compounds and derivatives thereof which are therapeutically beneficial and which show improved, alternative or at least comparable bioactive properties to that of known isoflavonoids.
Summary of the Invention The present inventors have surprisingly found that sulfoconjugates and glucoconjugates of isoflavones and derivatives thereof exhibit beneficial biological properties. In particular the conjugates are thought to exhibit a wide range of therapeutic activities including the ability to address oestrogen levels in the body.
Whilst not wishing to be limited to theory, it is believed that isoflavone conjugates and derivatives thereof, and in particular the isoflavonoid sulfoconjugates and glucoconjugates, may reduce the supply of estrogenic steroids, reducing the risk or severity of oestrogen- related diseases and conditions. It is also thought that the isoflavonoid conjugates of the invention regulate a range of molecular targets in mammalian cells, and that these molecular targets are intimately involved in signal transduction processes that are fundamental to critical cellular processes such as cell growth, differentiation, migration, and death. It can be seen therefore that these surprising biochemical effects have broad and important implications for the health of animals including humans. These and other preferred objects of the invention are described herein.
Thus, according to an aspect of the invention there is provided an isoflavonoid conjugate of the general formula I:
Figure imgf000004_0001
in which
Ri, R2 and Z are independently -O-SO2OH, an O-sugar residue, hydrogen, hydroxy,
OR9, OC(O)Rιo, OS(O)Rιo, CHO, C(O)Rι0, COOH, CO2Rι0, CONR3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, a ino, alkylamino, dialkylamino, nitro or halo, or R2 is as previously defined, and Ri and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
Figure imgf000004_0002
Ri is as previously defined, and R2 and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
Figure imgf000004_0003
and
W is Ri , A is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, NR3R4 or thio, and B is selected from
Figure imgf000004_0004
W is Ri, and A and B taken together with the carbon atoms to which they are attached form a six-membered ring selected from
Figure imgf000005_0001
W, A and B taken together with the groups to which they are associated comprise
Figure imgf000005_0002
W and A taken together with the groups to which they are associated comprise
Figure imgf000005_0003
and B is
Figure imgf000005_0004
wherein
R3 is hydrogen, alkyl, aryl, arylalkyl, an amino acid, C(O)Rπ where Rn is hydrogen alkyl, aryl, arylalkyl or an amino acid, or CO2Rι2 where Ri2 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl or arylalkyl, R-i is hydrogen, alkyl or aryl, or R3 and R4 taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl, R5 is -O-SO2OH, an O-sugar residue, hydrogen, C(O)Rπ where Rn is as previously defined, or CO2Rι2 where Rι2 is as previously defined,
R6 is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, alkyl, aryl, amino, thio,
NR3R4, COR11 where Rn is as previously defined, CO2Rι2 where Rι2 is as previously defined or CONR3I- , R is hydrogen, C(O)Rn where Rn is as previously defined, alkyl, haloalkyl, aryl, arylalkyl or Si(Rι3)3 where each Rι3 is independently hydrogen, alkyl or aryl,
R8 is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, alkoxy or alkyl, R9 is alkyl, haloalkyl, aryl, arylalkyl, C(O)Rn where Rn is as previously defined, or
Si(Rι3)3 where Rι3 is as previously defined, Rio is hydrogen, alkyl, haloalkyl, amino, aryl, arylalkyl, an amino acid, alkylamino or dialkylamino, the drawing "™" represents either a single bond or a double bond, T is independently hydrogen, alkyl or aryl, X is O, NR or S, preferably O, and Y is
Figure imgf000006_0001
wherein
Rι4, R15 and Rι6 are independently -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, OR9, OC(O)Rιo, OS(O)Ri0, CHO, C(O)Rι0, COOH, CO2Rι0, CONR3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, and wherein at least one of Ri, R2, R5, R-g, R8, R14, R15, R16. Z, W or A where present is independently -O-SO2OH or an O-sugar residue, or a pharmaceutically acceptable salt or prodrug thereof. In a preferred embodiment, the sulfoconjugate moiety is present as the corresponding salt of -O-SO2OM, where M is a pharmaceutically acceptable counter ion.
It has surprisingly been found by the inventors that compounds of the general formula I:
Figure imgf000007_0001
in which
Ri, R2, W, A, B and Z are as defined above have particular utility and effectiveness in the treatment, prophylaxis, amelioration defence against, and/or prevention of the following diseases and disorders (for convenience hereinafter referred to as the "therapeutic indications"):
(a) all forms of cancer (pre-malignant, benign and malignant) in all tissues of the body. In this regard, the compounds may be used as the sole form of anti-cancer therapy or in combination with other forms of anti-cancer therapy including but not limited to radiotherapy and chemotherapy;
(b) diseases and disorders associated with inflammatory reactions of an abnormal or prolonged nature in any of the body's tissues including but not limited to rheumatoid arthritis, tendonitis, inflammatory bowel disease, ulcerative colitis, Crohn's Disease, sclerosing cholangitis; (c) papulonodular skin lesions including but not limited to sarcoidosis, angiosarcoma,
Kaposi's sarcome, Fabry's Disease
(d) papulosquamous skin lesions including but not limited to psoriasis, Bowen's Disease, and Reiter's Disease;
(e) actinic damage characterized by degenerative changes in the skin including but not limited to solar keratosis, photosensitivity diseases, and wrinkling;
(f) diseases and disorders associated with abnormal angiogenesis affecting any tissue within the body including but not limited to hemangiomas and telangiectasia; (g) proliferative disorders of bone marrow including but not limited to megaloblastic disease, myelodysplastic syndromes, polycythemia vera, thrombocytosis and myelofibrosis;
(h) autoimmune disease characterized by abnormal immunological responses including but not limited to multiple sclerosis, Type 1 diabetes, systemic lupus erythematosis, and biliary cirrhosis;
(i) neurodegenerative diseases and disorders characterized by degenerative changes in the structure of the neurological system including but not limited to Parkinson's Disease, Alzheimer's Disease, muscular dystrophy, Lou-Gehrig Disease, motorneurone disease;
(j) diseases and disorders associated with degenerative changes within the walls of blood vessels including but not limited to atherosclerosis, atheroma, coronary artery disease, stroke, myocardial infarction, hypertensive vascular disease, malignant hypertension, thromboangiitis obliterans, fibromuscular dysplasia; (k) diseases and disorders associated with abnormal immunological esponses including but limited to dermatomyositis and scleroderma;
(1) diseases and disorders associated with degenerative changes within the eye including but not limited to cataracts, macular degeneration, retinal atrophy.
In particular the isoflavone conjugates and various analogues thereof also surprisingly have been found to have a potent effect on the production and function of reproductive hormones such as estrogens and androgens. As a result of this, these compounds may be used in the treatment and prevention of the following disorders and diseases:
(a) conditions in women associated with abnormal estrogen/androgen balance including but not limited to cyclical mastalgia, acne, dysmenorrhoea, uterine fibroids, endometriosis, ovarian cysts, premenstrual syndrome, acute menopause symptoms, osteoporosis, senile dementia, infertility; and
(b) conditions in men associated with abnormal estrogen/androgen balance including but not limited to benign prostatic hypertrophy, infertility, gynecomastia, alopecia hereditaria and various other forms of baldness. Thus according to another aspect of the present invention there is provided a method for the treatment, prophylaxis, amelioration, defence against, and/or prevention of one or more of the therapeutic indications which comprises administering to a subject a therapeutically effective amount of one or more compounds of formula I as defined above.
According to another aspect of the present invention there is provided the use of compounds of formula I for the manufacture of a medicament for the treatment, amelioration, defence against, prophylaxis and or prevention of one or more of the therapeutic indications.
According to another aspect of the present invention there is provided the use of one or more compounds of formula I in the treatment, amelioration, defence against, prophylaxis and/or prevention of one or more of the therapeutic indications.
According to another aspect of the present invention there is provided an agent for the treatment, prophylaxis, amelioration, defence against and/or treatment of the therapeutic indications which comprises one or more compounds of formula I either alone or in association with one or more carriers or excipients.
According to another aspect of the present invention there is provided a therapeutic composition which comprises one or more compounds of formula I in association with one or more pharmaceutical carriers and/or excipients.
According to another aspect of the present invention there is provided a drink or food-stuff, which contains one or more compounds of formula I.
According to another aspect of the present invention there is provided a microbial culture or a food-stuff containing one or more microbial strains which microorganisms produce one or more compounds of formula I. According to another aspect of the present invention there is provided one or more microorganisms which produce one or more compounds of formula I. Preferably the microorganism is a purified culture, which may be admixed and/or administered with one or more other cultures which product compounds of formula I.
Throughout this specification and the claims which follow, unless the text requires otherwise, the word "comprise", and variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Detailed Description of the Invention
The terms "isoflavonoid" and "isoflavone" as used herein are to be taken broadly to include ring-fused benzopyran molecules having a pendent phenyl group from the pyran ring based on a 1,2-diphenylpropane system. Thus, the classes of compounds generally referred to as isoflavones, isoflavenes, isoflavans, isoflavanones, isoflavanols and the like are generically referred to herein as isoflavonoid compounds, isoflavones, isoflavone derivatives or isoflavone compounds and derivatives thereof.
The term "sugar residue" is taken to include residues of natural sugars or saccharides, modified sugars, and di- and poly-saccharides including those selected from the group consisting of glucose, altrose, mannose, galactose, fructose, talose, xylose, arabinose, ribose, sorbose including the related furanoside and pyranoside moieties, and sucrose, lactose, maltose and the like. Particularly preferred sugar residues are selected from the group consisting of ,D-glucoside, malonyl glucoside, acetyl glucoside and β,D- glucuronide.
The term "alkyl" is taken to include straight chain, branched chain and cyclic (in the case of 5 carbons or greater) saturated alkyl groups of 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertiary butyl, pentyl, cyclopentyl, and the like. The alkyl group is more preferably methyl, ethyl, propyl or isopropyl. The alkyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, Cι-C4-alkoxycarbonyl, Cι-C4-alkylamino- carbonyl, di-(Cι-C4-alkyl)-amino-carbonyl, hydroxyl, Cι-C4-alkoxy, formyloxy, C1-C4- alkyl-carbonyloxy, Cι-C4-alkylthio, C -C6-cycloalkyl or phenyl.
The term "alkenyl" is taken to include straight chain, branched chain and cyclic (in the case of 5 carbons or greater) hydrocarbons of 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, with at lease one double bond such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-methyl-l-peopenyl, 2-methyl-2-propenyl, and the like. The alkenyl group is more preferably ethenyl, 1-propenyl or 2-propenyl. The alkenyl groups may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, Cι-C4- alkoxycarbonyl, Cι-C4-alkylamino-carbonyl, di-(Cι-C4-alkyl)-amino-carbonyl, hydroxyl, Cι-C4-alkoxy, formyloxy, Cι-C4-alkyl-carbonyloxy, Cι-C4-alkylthio, C3-C6-cycloalkyl or phenyl.
The term "alkynyl" is taken to include both straight chain and branched chain hydrocarbons of 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, with at least one triple bond such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. The alkynyl group is more preferably ethynyl, 1-propynyl or 2-propynyl. The alkynyl group may optionally be substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, Cι-C4-alkoxycarbonyl, Cι-C4-alkylamino-carbonyl, di-(Cι-C4-alkyl)-amino- carbonyl, hydroxyl, Cι-C4-alkoxy, formyloxy, Cι-C4-alkyl-carbonyloxy, Cι-C4-alkylthio, C3-C6-cycloalkyl or phenyl.
The term "aryl" is taken to include phenyl, biphenyl and naphthyl and may be optionally substituted by one or more Cι-C -alkyl, hydroxy, Cι-C4-alkoxy, carbonyl, Cι-C4- alkoxycarbonyl, Cι-C4-alkylcarbonyloxy or halo.
The term "heteroaryl" is taken to include five-menibered and six-membered rings which include at least one oxygen, sulfur or nitrogen in the ring, which rings may be optionally fused to other aryl or heteroaryl rings including but not limited to furyl, pyridyl, pyrimidyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isopuinolyl, purinyl, morpholinyl, oxazolyl, thiazolyl, pyrrolyl, xanthinyl, purine, thymine, cytosine, uracil, and isoxazolyl. The heteroaromatic group can be optionally substituted by one or more of fluorine, chlorine, bromine, iodine, carboxyl, Cι-C4-alkoxycarbonyl, Cι-C4- alkylamino-carbonyl, di-(Cι-C4-alkyl)-amino-carbonyl, hydroxyl, Cι-C4-alkoxy, formyloxy, Cι-C4-alkyl-carbonyloxy, Cι-C4-alkylthio, C3-C6-cycloalkyl or phenyl. The heteroaromatic can be partially or totally hydrogenated as desired.
The term "halo" is taken to include fluoro, chloro, bromo and iodo, preferably fluoro and chloro, more preferably fluoro. Reference to for example "haloalkyl" will include monohalogenated, dihalogenated and up to perhalogenated alkyl groups. Preferred haloalkyl groups are trifluoromethyl and pentafluoroethyl.
The term "pharmaceutically acceptable salt" refers to an organic or inorganic moiety that carries a charge and that can be administered in association with a pharmaceutical agent, for example, as a counter-cation or counter-anion in a salt. Pharmaceutically acceptable cations are known to those of skilled in the art, and include but are not limited to sodium, potassium, calcium, zinc and quaternary amine. Pharmaceutically acceptable anions are known to those of skill in the art, and include but are not limited to chloride, acetate, citrate, bicarbonate and carbonate.
The term "pharmaceutically acceptable derivative" or "prodrug" refers to a derivative of the active compound that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound or metabolite, or that exhibits activity itself.
As used herein, the terms "treatment", "prophylaxis" or "prevention", "amelioration" and the like are to be considered in their broadest context. In particular, the term "treatment" does not necessarily imply that an animal is treated until total recovery. Accordingly, "treatment" includes amelioration of the symptoms or severity of a particular condition or preventing or otherwise reducing the risk of developing a particular condition. The invention in particular relates to the compounds of the general formulae II - VIII and uses thereof:
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0003
Figure imgf000013_0004
in which Ri, R2, R5, R^, Rι4, R15, W and Z are as defined above. Particularly preferred compounds of the present invention are the conjugated isoflavonoids as follows:
Isoflavonoid-O-sugar residue and lsoflavonoid-0-S02OM
wherein M is hydrogen or a counter cation, and wherein the isoflavone compound or derivative is a mono-, di-, or per-conjugated glucuronide or sulfate derived from the following hydroxyl-containing isoflavone compounds and derivatives 1 - 30 as follows:
Figure imgf000014_0001
Figure imgf000014_0002
Figure imgf000014_0003
Figure imgf000015_0001
10
Figure imgf000015_0002
13 14
Figure imgf000015_0003
Figure imgf000016_0001
17 18
Figure imgf000016_0002
19 20
Figure imgf000016_0003
23 24
Figure imgf000016_0004
25 26
Figure imgf000017_0001
29 30 wherein
R2, Rι6, W and Z are independently H, OH, Cl, Me or OMe, and RM is H, OMe, Me or Cl.
In a most preferred embodiment conjugated isoflavone or derivative is a novel mono-, di- or per-sulfoconjugate or glucoconjugate of daidzein, genestein, equol, formomonetin, dihydrodaidzein, dihydrogenestein, dehydro-O-desmethylangolensin, tetrahydrodaidzein, dehydroequol, O-desmethyl-angolensin (ODMA) or 6-hydroxy-O-desmethylangolensin.
Compounds of the present invention have particular application in the treatment of diseases associated with or resulting from estrogenic effects, androgenic effects, vasodilatory and spasmodic effects, inflammatory effects and oxidative effects.
The amount of one or more compounds of formula I which is required in a therapeutic treatment according to the invention will depend upon a number of factors, which include the specific application, the nature of the particular compound used, the condition being treated, the mode of administration and the condition of the patient. Compounds of formula I may be administered in a manner and amount as is conventionally practised. See, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 1299 (7th Edition, 1985). The specific dosage utilised will depend upon the condition being treated, the state of the subject, the route of administration and other well known factors as indicated above. In general, a daily dose per patient may be in the range of 0.1 mg to 2 g; typically from 0.5 mg to 1 g; preferably from 50 mg to 200 mg. The length of dosing may range from a single dose given once every day or two, to twice or thrice daily doses given over the course of from a week to many months to many years as required, depending on the severity of the condition to be treated or alleviated. It will be further understood that for any particular subject, specific dosage regimens should be adjust over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
The production of pharmaceutical compositions for the treatment of the therapeutic indications herein described are typically prepared by admixture of the compounds of the invention (for convenience hereafter referred to as the "active compounds") with one or more pharmaceutically or veterinarially acceptable carriers and/or excipients as are well known in the art.
The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the subject. The carrier or excipient may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose, for example, a tablet, which may contain from 0.5% to 59% by weight of the active compound, or up to 100% by weight of the active compound. One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy consisting essentially of admixing the components, optionally including one or more accessory ingredients.
The formulations of the invention include those suitable for oral, rectal, optical, buccal (for example, sublingual), parenteral (for example, subcutaneous, intramuscular, intradermal, or intravenous) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used. Formulation suitable for oral administration may be presented in discrete units, such as capsules, sachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture such as to form a unit dosage. For example, a tablet may be prepared by compressing or moulding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound of the free-flowing, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Moulded tablets may be made by moulding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
Formulations suitable for buccal (sublingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Compositions of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of the active compounds, which preparations are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Such preparations may conveniently be prepared by admixing the compound with water or a glycine buffer and rendering the resulting solution sterile and isotonic with the blood. Injectable formulations according to the invention generally contain from 0.1% to 60% w/v of active compound and are administered at a rate of 0.1 ml/minute/kg. Formulations suitable for rectal or vaginal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Formulations or compositions suitable for topical administration to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include Vaseline, lanoline, polyethylene glycols, alcohols, and combination of two or more thereof. The active compound is generally present at a concentration of from 0.1 % to 0.5% w/w, for example, from 0.5% to 2% w/w. Examples of such compositions include cosmetic skin creams.
Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain the active compound as an optionally buffered aqueous solution of, for example, 0.1 M to 0.2 M concentration with respect to the said active compound.
Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6), 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 M to 0.2 M active ingredient.
Formulations suitable for inhalation may be delivered as a spray composition in the form of a solution, suspension or emulsion. The inhalation spray composition may further comprise a pharmaceutically acceptable propellant such as carbon dioxide or nitrous oxide.
The active compounds may be provided in the form of food stuffs, such as being added to, admixed into, coated, combined or otherwise added to a food stuff. The term food stuff is used in its widest possible sense and includes liquid formulations such as drinks including dairy products and other foods, such as health bars, desserts, etc. Food formulations containing compounds of the invention can be readily prepared according to standard practices.
Compounds of the present invention have potent antioxidant activity and thus find wide application in pharmaceutical and veterinary uses, in cosmetics such as skin creams to prevent skin ageing, in sun screens, in foods, health drinks, shampoos, and the like.
It has surprisingly been found that compounds of the formula I interact synergisticly with vitamin E to protect lipids, proteins and other biological molecules from oxidation.
Accordingly a further aspect of this invention provides a composition comprising one or more compounds of formula I, vitamin E, and optionally a pharmaceutically, veterinarily or cosmetically acceptable carriers and/or excipients.
Therapeutic methods, uses and compositions may be for administration to humans or animals, such as companion and domestic animals (such as dogs and cats), birds (such as chickens, turkeys, ducks), livestock animals (such as cattle, sheep, pigs and goats), for use in aquaculture applications and the like.
The conjugates can also be co-administered with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antiftmgals, antiinflammatories, or antiviral compounds. The active agent can comprise two or more isoflavones or derivatives thereof in combination or synergistic mixture. The active compounds can also be administered with lipid lowering agents such as probucol and nicotinic acid; platelet aggregation inhibitors such as aspirin; antithrombotic agents such as coumadin; calcium channel blockers such as verapamil, diltiazem, and nifedipine; angiotensin converting enzyme (ACE) inhibitors such as captopril and enalapril, and β- blockers such as propanolol, terbutalol, and labetalol. The compounds can also be administered in combination with nonsteriodal antiinflammatories such as ibuprofen, indomethacin, aspirin, fenoprofen, mefenamic acid, flufenamic acid and sulindac. The compounds can also be administered with corticosteroids.
The co-administration may be simultaneous or sequential. Simultaneous administration may be effected by the compounds being in the same unit dose, or in individual and discrete unit doses administered at the same or similar time. Sequential administration may be in any order as required and typically will require an ongoing physiological effect of the first or initial active agent to be current when the second or later active agent is administered, especially where a cumulative or synergistic effect is desired.
Isoflavonoid compounds are suitable starting materials for the synthesis of the isoflavonoid conjugates of formula I and these isoflavonoid starting materials may be prepared by standard methods known to those skilled in the art. Suitable methods may be found in, for example, International Patent Applications WO 98/08503 and WO 00/49009 which are incorporated herein in their entirety by reference. Chemical functional group protection, deprotection, synthons and other techniques known to those skilled in the art may be used where appropriate in the synthesis of the compounds of the present invention. Derivatisation of the hydroxy substituted isoflavones to form the conjugates of the present invention may be performed by any suitable method as known to one skilled in the art.
The isoflavonoid starting materials may also be obtained in the form of concentrates or extracts from plant sources. Again, those skilled in the art will readily be able to identify suitable plant species, however, for example, plants of particular utility include leguminous plants. More preferably, the isoflavone extract may be obtained from obtained from chickpea, lentils, beans, red clover or subterranean clover species and the like.
The examples that follow are not considered to limit the invention as described. EXAMPLE 1
General Syntheses of Sugar Conjugated Isoflavones
The phenolic groups of isoflavones are suitable nucleophiles for the Mitsunobu reaction. Furthermore, the electronic differentiation of the phenolic moieties in an isoflavone facilitates selective protection. Those skilled in the art would appreciate that selective protection and deprotection could mask either phenolic group from acting as a nucleophile for the Mitsunobu reaction. It is also possible to have a completely deprotected isoflavone thus effecting bis-Mitsunobu coupling.
The Scheme set out below shows the selective protection of daidzein at the 7-position followed by Mitsunobu coupling with an appropriately protected sugar moiety. Subsequent global deprotection yields the mono 4'-substituted daidzein conjugate.
Figure imgf000023_0001
Figure imgf000023_0002
Other substituted isoflavonoid conjugates of the invention can be synthesised by the use of different sugars, protecting groups, synthons and different starting isoflavonoid compounds as would be known to one skilled in the art. EXAMPLE 2
General Syntheses of Sulfate Conjugated Isoflavones
The dihydroxy substituted isoflavone dehydroequol is treated with sulfur trioxide to afford dehydroequol-di-O-sulfate as set out below:
Figure imgf000024_0001
Figure imgf000024_0002
The sulfate so formed may be either protonated as shown, or more preferably is present as a pharmaceutically acceptable salt.
It is also possible to effect the conjugate syntheses by enzymatic formation employing a glucuronosyl transferase or sulfotransferase as appropriate, or by glucuronidation with microsomes.
In a similar manner, the following compounds can be synthesised:
Figure imgf000024_0003
Figure imgf000025_0001
(cis) and/or (trans)
Figure imgf000025_0002
Figure imgf000025_0003
Other substituted isoflavonoid conjugates of the invention can be synthesised by the use of different sugars, protecting groups, synthons and different starting isoflavonoid compounds as would be known to one skilled in the art.
EXAMPLE 3
Various isoflavonoid conjugates of the invention were surprisingly found to exhibit good therapeutic activity, and in particular are found to address problems of oestrogen levels in the body. Thus the compounds of the present invention have particular application in the treatment, prophylaxis or amelioration of diseases associated with or resulting from estrogenic effects, androgenic effects, vasodilatory and spasmodic effects, inflammatory effects and oxidative effects. EXAMPLE 4
Therapeutic formulations are prepared by admixing one or more isoflavonoid conjugates from compounds 1 to 30 with a soy flour base (defatted soy flour available from Edible Enhanced Protein St Marys, Australia). A range of pharmaceutical formulations are prepared comprising between 40 mg and 200 mg of active compound to a dosage formed. Gelatin capsules and tablets containing 200 mg of each of the active compounds 1 to 30 are prepared in the soy flour base referred to above, or in a cholesterol free yoghurt base.
EXAMPLE 5 A. Treatment of vascular conditions - menopausal syndrome, hot flushes, hypertension, atherosclerosis and male impotency
Vascular reactivity studies using rat aortic rings are generally regarded as directly predictive of biological effects of candidate compounds in the treatment of the above conditions (Karapapanis, S. et al (1994) Heptology, 20, 6, 1516-1521). The inhibitory effect on restrictor responses in the aortic ring is measured in the presence of the vasoconstrictor noradrenaline according to the procedure of Karapapanis (supra). Isoflavanoid conjugates from compounds 1 to 30 exhibit potent inhibitory effects on responses to noradrenaline, that is, they inhibit vaso-constrictor responses.
Subsequent clinical studies are shown to demonstrate therapeutic benefits in the treatment of the above conditions using these compounds.
B. Hormone responsive cancer treatment - treatment of hormone related cancers including breast, ovarian, testicular, uterine, endometrial andprostatic cancer
The activity of compounds of the present invention in inhibiting the growth of hormone responsive cancer cells is tested using the well characterised human responsive cancer cell lines K562 and HL60. The anti-cancer screening assay measures inhibition of cell proliferation which results in terminal differential cell death. Cell death is due to either apoptosis or necrosis. Isoflavonoid conjugates from compounds 1 to 30 are found to be potent inhibitors of growth of cell lines K563 and HL60, this result being therefore directly predictive that these compounds will inhibit the growth of hormone related cancers such as those mentioned above.
Subsequent clinical studies are shown to demonstrate therapeutic benefits in the treatment of the above conditions using these compounds.
C. Antioxidant studies - relevant to the treatment of cancer; conditions associated with oxidation of cholesterol such as atherosclerotic vascular disease; myocardial infarction, stroke, heart disease; arthritis and cataracts
Many studies have shown that compounds having antioxidant activity are useful therapeutics in the treatment of the above conditions (see for example McLaughlan et al (1995) Biochem. Soc. Trans. 23 (2) 2575; and van't Veer et al (1996) Cander Epidemiol Biomarkers Prev. 5 (6) 441-7). Isoflavonoid conjugates from compounds 1 to 30 are found to have antioxidant activity when subjected to a standard LDL Antioxidation Test. Therefore, these compounds may be regarded as effective therapeutics in the treatment of cancer, myocardial infarction, stroke, arthritis, sunlight induced skin damage cataracts, and other conditions resulting from oxidative damage.
When these compounds are subjected to a Redox Test measuring the ability of a compound to prevent LDL lipid oxidation in the presence of vitamin E it is found that the active compounds give rise to a low redox index. This test shows that the isoflavonoid conjugates synergistically interact with vitamin E to prevent oxidation of lipids, proteins, and other biological species. Accordingly the isoflavonoid conjugates from compounds 1 to 30 in association with vitamin E may be used in the therapeutic treatment of cancer, myocardial infarction, stroke, arthritis, sunlight induced skin damage cataracts and other conditions responsive to treatment with antioxidants. EXAMPLE 6
Treatment of acne
A female subject with acne since puberty, with no response to the contraceptive pill or any topical cream, is administered an isoflavonoid conjugate from compounds 1 to 30.
Administration of 40 mg twice daily results in an improvement of acne condition, colour, and general appearance within two weeks.
A male subject with acne since puberty, and with no response to any topical cream, is administered an isoflavonoid conjugate from compounds 1 to 30 as described above. Unexpectedly, the subject reports an improvement in his acne within two weeks.
Subsequent clinical studies are shown to demonstrate therapeutic benefits in the treatment of the above conditions using these compounds.
EXAMPLE 7
An elderly male subject suffering from prostate cancer receives a daily dosage of 16 mg of an isoflavonoid conjugate from compounds 1 to 30. After subsequent surgery for his prostate cancer condition the pathology report on the extracted prostate tissue shows an increased incidence of apoptosis (Stephens, F. O. (1997) J. Aus. Med. Assoc. 167, 3, 138-
140). This study demonstrates the therapeutic benefits of the isoflavonoid conjugates.
EXAMPLE 8
A patient group was studied comprising women who had a past history of breast cancer (who had been treated either by surgery or radiation, or both) and women who had a strong familial connection to breast cancer, that is, where their mothers or siblings had suffered from breast cancer. This study investigated whether isoflavonoid conjugates from compounds 1 to 30 administered transdermally each day through a skin patch could be used to prevent breast cancer or metastatic cancers following cancer therapy. Patches are prepared that contained a lipophylic carrier cream which is readily absorbed through the skin. The cream comprises a glycerol cold cream which contains glycerin and peanut oil. A selected active compound from any one of compounds 1 to 30 is mixed with the lipophylic cream such that each patch comprises 10 mg to 100 mg of active compound. The patch is applied to the skin each day and rapid absorption occurs. After two hours the patch is removed. Alternatively, the patch may be left on for a greater part of each day.
Over a one year study period it is found that this high risk group does not show any evidence, or at least shows a statistically lower incidence, of breast cancer or other metastatic cancer. This study demonstrates the therapeutic benefits of the isoflavonoid conjugates.
EXAMPLE 9
A study of a group of patients suffering from benign prostatic hypertrophy (BPH) and prostatic cancer of various grades is carried out to determine the effect of admimstration of compounds 1 to 30. The administration protocol is the same as for Example 4 involving daily administration of a gelatin capsule containing 200 mg of active compound. A significant decrease in the rate of production of relevant cancer markers (PSA, prostate specific antigen) is observed. Tumours are again shown to have regressed, or show no further growth.
In another study a middle aged male with BPH presented with urinary obstruction and frequency of urination. The subject takes 40 mg per day of an isoflavonoid conjugate from compounds 1 to 30 and finds that his symptoms decrease and in some cases disappeared.
A patient suffering from advanced bowel cancer is treated daily for three weeks with an intravenous infusion of 2 g of an isoflavonoid conjugate from compounds 1 to 30 dissolved in sterile saline. The patient's pain and discomfort is significantly reduced, and reduction in cancer markers is observed. Progression of the tumour is also arrested over the treatment period. fri a further series of experiments a group of patients suffering from terminal bowel cancer are treated by bolus daily injections (intravenous or intramuscular) of 2 g of an isoflavonoid conjugate from compounds 1 to 30. Over the test period there is shown to be a marked reduction in pain and discomfort. Tumour markers (carcino-embryonic antigen (CEA)) are reduced as evidenced by blood analysis and tumour spread decreased.
Subsequent clinical studies are shown to demonstrate therapeutic benefits in the treatment of the above conditions using these compounds.
COMPARATIVE EXAMPLES
The examples above are repeated with the corresponding non-conjugated isoflavonoid compounds, or are at least compared with similar studies on the non-conjugated compounds. The isoflavonoid conjugates of the invention quite unexpectedly show beneficial and/or marked activity in the subjects being treated. This comparison shows the particular utility and effectiveness of conjugated isoflavonoid compounds of the invention, and in particular those conjugates from compounds 1 to 30 described above.
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.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in the field of endeavour.

Claims

CLAIMS:
1. An isoflavonoid conjugate of the general formula I:
Figure imgf000031_0001
in which
Ri, R2 and Z are independently -O-SO2OH, an O-sugar residue, hydrogen, hydroxy,
OR9, OC(O)Rιo, OS(O)Rιo, CHO, C(O)Rιo, COOH, CO2Rι0, CON 3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, or R is as previously defined, and Ri and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
Figure imgf000031_0002
Ri is as previously defined, and R2 and Z taken together with the carbon atoms to which they are attached form a five-membered ring selected from
Figure imgf000031_0003
and
W is Ri, A is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, NR^ or thio, and B is selected from
Figure imgf000032_0001
W is Ri, and A and B taken together with the carbon atoms to which they are attached form a six-membered ring selected from
Figure imgf000032_0002
W, A and B taken together with the groups to which they are associated comprise
Figure imgf000032_0003
W and A taken together with the groups to which they are associated comprise
Figure imgf000032_0004
and B is
Figure imgf000033_0001
wherein
R3 is hydrogen, alkyl, aryl, arylalkyl, an amino acid, C(O)Rn where Rn is hydrogen alkyl, aryl, arylalkyl or an amino acid, or CO2Rι2 where Rι2 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl or arylalkyl, R is hydrogen, alkyl or aryl, or R and R4 taken together with the nitrogen to which they are attached comprise pyrrolidinyl or piperidinyl, R5 is -O-SO2OH, an O-sugar residue, hydrogen, C(O)Rn where Rn is as previously defined, or CO2Rι2 where Rι2 is as previously defined, R6 is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, alkyl, aryl, amino, thio,
N R4, CORn where Rn is as previously defined, CO2Rι2 where Rι2 is as previously defined or CONR3R4, R is hydrogen, C(O)Rn where Rn is as previously defined, alkyl, haloalkyl, aryl, arylalkyl or Si(Rι3)3 where each Rι is independently hydrogen, alkyl or aryl, R8 is -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, alkoxy or alkyl, R9 is alkyl, haloalkyl, aryl, arylalkyl, C(O)Rn where Rn is as previously defined, or
Si(Rι3)3 where Rι3 is as previously defined, Rio is hydrogen, alkyl, haloalkyl, amino, aryl, arylalkyl, an amino acid, alkylamino or dialkylamino, the drawing "™" represents either a single bond or a double bond, T is independently hydrogen, alkyl or aryl, X is O, R-t or S, preferably O, and Y is
Figure imgf000034_0001
wherein
R14, Rι5 and Rι6 are independently -O-SO2OH, an O-sugar residue, hydrogen, hydroxy, OR9, OC(O)Rιo, OS(O)Rιo, CHO, C(O)Rιo, COOH, CO2Rιo, CONR3R4, alkyl, haloalkyl, arylalkyl, alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, alkoxyaryl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halo, and wherein at least one of Ri, R2, R5, R6, R8, Rι4, R15, Ri6, Z, W or A where present is independently -O-SO2OH or an O-sugar residue, or a pharmaceutically acceptable salt or prodrug thereof.
2. An isoflavonoid conjugate of claim 1, wherein the sulfocoηjugate moiety is present as a corresponding salt -O-SO2OM, where M is a pharmaceutically acceptable cation.
3. An isoflavonoid conjugate of claim 1 , wherein the sugar residue is selected from the group consisting of natural sugars, modified sugars, and mono-, di- and poly- saccharides.
4. An isoflavonoid conjugate of claim 3, wherein the sugar residue is selected from the group consisting of glucose, altrose, mannose, galactose, fructose, talose, xylose, arabinose, ribose, sorbose, sucrose, lactose and maltose.
5. An isoflavonoid conjugate of claim 4, wherein the sugar residue is selected from the group consisting of /3,D-glucoside, malonyl glucoside, acetyl glucoside and /3,D- glucuronide.
6. A method for the treatment, prophylaxis, amelioration, defence against, and/or prevention of one or more of the therapeutic indications as hereinbefore defined, which comprises administering to a subject a therapeutically effective amount of one or more compounds of formula I as defined in claim 1.
7. Use of one or more compounds of formula I for the manufacture of a medicament for the treatment, amelioration, defence against, prophylaxis and/or prevention of one or more of the therapeutic indications as hereinbefore described.
8. An agent for the treatment, prophylaxis, amelioration, defence against and/or treatment of one or more of the therapeutic indications as hereinbefore defined which comprises one or more compounds of formula I either alone or in association with one or more carriers or excipients.
9. A method for the treatment, prophylaxis, amelioration, defence against and/or prevention of conditions in a subject associated with abnormal estrogen/androgen balance.
10. A method of claim 9, wherein the subject is a woman.
11. A method of claim 9, wherein the subject is a man.
12. Use of one or more compounds of formula I for the manufacture of a medicament for the treatment, amelioration, defence against, prophylaxis and/or prevention of conditions in a subject associated with abnormal estrogen/androgen balance.
13. A therapeutic composition which comprises one or more compounds of formula I in association with one or more pharmaceutical carriers and/or excipients.
14. A drink or food-stuff, which contains one or more compounds of formula I.
15. A composition comprising one or more compounds of formula I, vitamin E, and optionally pharmaceutically, veterinarily or cosmetically acceptable carriers and/or excipients.
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