HK1066797B - Dimeric isoflavones - Google Patents

Description

Dimeric isoflavones

Technical Field

The present invention relates generally to novel dimeric molecules based on a1, 2-diphenylpropane (isoflavone-like) ring structure. The invention further relates to the synthesis of the dimeric isoflavonoid molecules, compositions containing the molecules and their use as therapeutic agents.

Background

Naturally occurring plant isoflavones are known to have a wide range of fundamental biological effects on human cells, including antioxidant and up-and down-regulation of a wide variety of enzymes and signal transduction mechanisms. Mitotic arrest and cytotoxicity of human cancer cells, increased capillary permeability, increased cellular adhesion, increased vascular smooth muscle cell response to vasodilators, and estrogen receptor stimulation, to name a few examples of the response of animal cells to the biological effects of naturally occurring isoflavones.

As a result of these biological effects, a range of therapeutic benefits have been identified, including the treatment and prevention of premenopausal symptoms such as premenstrual syndrome, endometriosis, uterine fibroids, hyperlipidemia, cardiovascular disease, menopausal symptoms such as osteoporosis and senile dementia, alcoholism, benign prostatic hypertrophy, and cancers such as prostate cancer, breast cancer and colorectal cancer [ see WO 93/23069; WO 96/10341; US 5424331; JP 62-106017; JP 62-106016; US 5516528; JP 62-106016A 2; JP 62-106017A 2; JP 61-246124; WO 98/50026; WO 99/43335; WO 00/49009; WO 00/644438; WO 99/48496 ].

Although over 700 different naturally occurring isoflavones are described, only a few have been identified as having potential therapeutic benefit in animals, including humans. These include daidzein, genistein, 7-hydroxy-4' -methoxyisoflavone, biochanin and glycitein. These and all naturally occurring isoflavones are found in nature as monomeric forms either in the free state or more likely bound to carbohydrate fragments (glycosides). The isoflavones must be separated from such fragments in order to be biologically active.

Many compounds having structures related to naturally occurring plant isoflavones are also described as having biological properties that are potentially therapeutically beneficial to animals, including humans. These include compounds belonging to the naturally occurring metabolites of plant isoflavones produced by fermentation of bacteria of the intestinal flora, and embrace compounds such as equol and O-desmethyl angolol pterocarpan [ WO 93/23069; WO 98/08503; WO 01/17986; WO 00/66576 ]. This class also includes the synthetic isoflavonoid eplerenone developed for the treatment of postmenopausal osteoporosis [ WO 91/14429 ] and a wide range of synthetic isoflavonoid analogs [ WO 98/08503 ].

Recently, some interest has been expressed in the biological properties of the dimeric form of the isoflavonoid. Four forms of the isoflavonoids having the following structures have been claimed to have 5- α -reductase inhibitory activity useful for the treatment of prostatic hypertrophy [ JP 9067362-A ].

A C-C bridged bisisoflavone dimer has also been described as shown below, but no biological activity or therapeutic benefit has been ascribed to it [ A1-Maharik et al ].

Thus, there is a need for a new generation of compounds that exhibit important pharmacological effects that can be used as prophylactic and for therapy.

Disclosure of Invention

Surprisingly, the present inventors have discovered a novel class of molecules based on dimeric isoflavone compounds and derivatives. The dimeric molecules of the present invention generally exhibit strong binding affinity for both estrogen receptors, and thus exhibit extraordinary physiological activity.

Thus, according to a first aspect of the present invention, there is provided a compound of formula (I) or (II):

in the formula

R₁、R₂、R₃、R₄、R₅、R₆、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)H、OC(O)R₉、OS(O)R₉、OSi(R₁₀)₃、C(O)R₁₁、CO₂R₁₂Alkyl, haloalkyl, aryl, aralkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halogen,

R₉is an alkyl, haloalkyl, aryl, aralkyl or alkaryl radical,

R₁₀independently hydrogen, alkyl or aryl,

R₁₁is hydrogen, alkyl, aryl, aralkyl or an amino acid, and

R₁₂is hydrogen, alkyl, haloalkyl, arylA group selected from the group consisting of an aryl group and an aralkyl group,

x is O, NR₄Or S, and

symbol'"represents either a single or double bond,

the compounds include pharmaceutically acceptable salts thereof,

with the proviso that in formula (I), R₅、R₆、R₇And R₈At least one of which is hydrogen.

According to a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) or (II) by reacting a compound of formula (III) with a coupling agent

In the formula

R₁、R₂、R₃、R₄、R₅、R₆、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)H、OC(O)R₉、OS(O)R₉、OSi(R₁₀)₃、C(O)R₁₁、CO₂R₁₂Alkyl, haloalkyl, aryl, aralkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halogen,

R₉is an alkyl, haloalkyl, aryl, aralkyl or alkaryl radical,

R₁₀independently hydrogen, alkyl or aryl,

R₁₁is hydrogen, alkyl, aryl, aralkyl or an amino acid, and

R₁₂is hydrogen, alkyl, haloalkyl, aryl or aralkyl,

OR₁₃is a hydroxyl group, another leaving group or an electron withdrawing group,

x is O, NR₄Or S, and

symbol'"represents either a single or double bond,

the compounds include pharmaceutically acceptable salts thereof,

with the proviso that in formula (I), R₅、R₆、R₇And R₈At least one of which is hydrogen.

The present inventors have surprisingly found that isoflavone dimers of general formulae (I) and (II) have particular utility and effectiveness in the treatment, prevention, improved protection, and/or prevention of one or more of the following diseases and disorders (hereinafter referred to simply as "therapeutic indications" for convenience):

(a) all forms of cancer (premalignant, 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, and may also be used in combination with other forms of anti-cancer therapy including, but not limited to, radiation therapy and chemotherapy;

(b) diseases and disorders associated with abnormal or chronic inflammatory responses in any tissue of the body, including but not limited to rheumatoid arthritis, tenosynovitis, inflammatory bowel disease, ulcerative colitis, crohn's disease, sclerosing cholangitis;

(c) papular nodules of skin lesions, including but not limited to sarcoidosis, angiosarcoma, kaposi's sarcoma, diffuse angiokeratoma;

(d) papular squamous skin lesions including, but not limited to, psoriasis, bowen's disease (pre-cancerous dermatitis), and reiter's disease (syndrome);

(e) actinic damage characterized by degenerative changes in the skin, including but not limited to actinic keratosis, photosensitive diseases, and wrinkling;

(f) diseases and disorders associated with abnormal angiogenesis that has an effect on any tissue within the body, including but not limited to hemangiomas and telangiectasias;

(g) myeloproliferative disorders including, but not limited to, megaerythroblast disease, myelodysplastic syndrome, polycythemia vera, thrombocythemia, and myelofibrosis;

(h) autoimmune diseases characterized by aberrant immune responses, including but not limited to multiple sclerosis, type i diabetes, systemic lupus erythematosus, and biliary cirrhosis;

(i) neurodegenerative diseases and disorders characterized by degeneration of nervous system structures, including but not limited to parkinson's disease, alzheimer's disease, muscular dystrophy, Lou-Gehrig's disease, motor neuropathy;

(j) diseases and disorders associated with degenerative changes in the vessel wall, including, but not limited to, atherosclerosis, atheroma, coronary artery disease, stroke, myocardial infarction, hypertensive vascular disease, malignant hypertension, occlusive thromboangiitis, fibromyalgia;

(k) diseases and disorders associated with aberrant immune responses, including but not limited to dermatomyositis and dermatosclerosis;

(l) Diseases and disorders associated with changes in intraocular degeneration include, but are not limited to, cataracts, macular degeneration, and retinal atrophy.

In particular, it has also been surprisingly found that the isoflavone dimers have a strong influence on the production and function of reproductive hormones such as estrogens and androgens. Accordingly, these compounds may be useful in the treatment and prevention of one or more of the following disorders and diseases:

(a) conditions in women associated with abnormal estrogen/androgen balance including, but not limited to, periodic mastalgia, acne (acne), dysmenorrhea, uterine fibroids, endometriosis, ovarian cysts, premenstrual syndrome, acute menopausal symptoms, osteoporosis, senile dementia, infertility; and

(b) male disorders associated with abnormal estrogen/androgen balance include, but are not limited to, benign prostatic hypertrophy, infertility, gynecomastia, alopecia inheritance, and various other forms of alopecia.

Thus, according to a third aspect of the present invention, there is provided a method of treatment, prevention or amelioration of a disease or disorder, which method comprises the step of administering to a subject a therapeutically effective amount of one or more compounds of formulae (I) and (II).

According to a fourth aspect of the present invention there is provided the use of one or more compounds of formulae (I) and (II) for the manufacture of a medicament for the treatment of disease.

According to a fifth aspect of the present invention there is provided the use of one or more compounds of formulae (I) and (II) as antiestrogens or Selective Estrogen Receptor Modulators (SERMs).

According to a sixth aspect of the present invention, there is provided a therapeutic, prophylactic or ameliorating agent for a disease, which comprises one or more compounds of the formula (I) or (II).

According to a seventh aspect of the present invention there is provided a pharmaceutical composition comprising one or more compounds of formulae (I) and (II) in association with one or more pharmaceutical carriers and/or excipients.

According to an eighth aspect of the present invention there is provided a beverage or foodstuff comprising one or more compounds of formulae (I) and (II).

Throughout this specification and the claims which follow, unless the context 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 other integers or steps.

Detailed Description

The dimeric molecules of the present invention are structurally related to monomeric isoflavone compounds and derivatives thereof. The term "isoflavones" is used herein in a broad sense to include fused ring benzopyran molecules having a pendant phenyl group extending from the pyran ring on a1, 2-diphenylpropane system. Thus, the various classes of compounds, collectively referred to as isoflavones, isoflavenes, isoflavans, isoflavanones, isoflavonols, and the like, are collectively referred to herein as isoflavones, isoflavone derivatives, or isoflavone-like molecules.

The term "alkyl" refers to straight and branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like. The alkyl group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably methyl, ethyl, propyl or isopropyl. The alkyl group may be optionally substituted with one or more of the following groups: fluorine, chlorine, bromine, iodine, carboxyl, C₁-C₄Alkoxycarbonyl, C₁-C₄Alkylaminocarbonyl, di (C)₁-C₄Alkyl) aminocarbonyl, hydroxy, C₁-C₄Alkyl, formyloxy, C₁-C₄Alkyl carbonyl oxy, C₁-C₄Alkylthio radical, C₃-C₆Cycloalkyl or phenyl.

The term "aryl" is intended to include phenyl and naphthyl, and may be optionally substituted with one or more of the following groups: c₁-C₄Alkyl, hydroxy, C₁-C₄Alkoxy, carbonyl, C₁-C₄Alkoxycarbonyl, C₁-C₄Alkylcarbonyloxy or halogen.

The term "halogen" is intended to include fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine, more preferably fluorine. References to "haloalkyl" include monohalogenated, dihalogenated, and up to perhalogenated alkyl groups. Preferred haloalkyl groups are trifluoromethyl and pentafluoroethyl.

The compounds of the invention include all salts, such as acid addition salts, anionic salts and zwitterionic salts, including especially pharmaceutically acceptable salts.

The term "pharmaceutically acceptable salt" refers to an organic or inorganic residue which carries a charge and which may be administered in conjunction with a pharmaceutical agent, such as a counter cation or counter anion in a salt. Pharmaceutically acceptable cations are known to those skilled in the art and include, but are not limited to, sodium, potassium, calcium, zinc, and quaternary ammonium. Pharmaceutically acceptable anions are known to those skilled in the art and include, but are not limited to, chloride, acetate, citrate, bicarbonate, and carbonate.

Dimeric isoflavone molecules and derivatives have only recently appeared in the literature. Japanese patent application No. JP 9067362-A (Sankyo corporation) describes bisisoflavones which are linked from either side chain phenyl groups of one monomer or a side chain phenyl group to the aromatic benzopyran ring of another isoflavone monomer. The isoflavonoids are believed to be useful as 5-alpha-reductase inhibitors.

The synthesis of C-C bridged bisisoflavones has also been described by nucleophilic substitution of 2-bromomethylisoflavone derivatives (Al-Maharik et Al). This double alkylation reaction produces a bridged isoflavone linked by a 2-methyl group. It has been confirmed that no activity is attributable to these newly synthesized bisisoflavones.

In sharp contrast, the dimeric molecules of the present invention are linked to either of the two aromatic rings through the 4-position of the isoflavone pyran ring. That is, the 4-position of the pyran ring is attached to an aromatic benzopyran ring (formula I), or to a side chain phenyl group (formula II).

Preferred dimeric molecules of the invention are described by the general formulae (Ia) and (IIa):

in the formula

R₁、R₂、R₃、R₄、R₅、R₆、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)H、OC(O)R₉、OS(O)R₉、OSi(R₁₀)₃、C(O)R₁₁、CO₂R₁₂Alkyl, haloalkyl, aryl, aralkyl, thio, alkylthio, amino, alkylamino, dialkylamino, nitro or halogen,

R₉is an alkyl, haloalkyl, aryl, aralkyl or alkaryl radical,

R₁₀independently hydrogen, alkyl or aryl,

R₁₁is hydrogen, alkyl, aryl, aralkyl or an amino acid, and

R₁₂is hydrogen, alkyl, haloalkyl, aryl or aralkyl,

x is O, NR₄Or S, and

symbol'"represents either a single or double bond,

the compounds include pharmaceutically acceptable salts thereof,

with the proviso that in formula (Ia), R₅、R₆、R₇And R₈At least one of which is hydrogen;

more preferably, they have the following substituents, among them

R₁、R₂、R₃、R₄、R₅、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉、OS(O)R₉Alkyl, aryl, aralkyl, sulfur, alkylthio, bromine, chlorine or fluorine,

R₆is a hydrogen atom, and is,

R₉is alkyl, fluoroalkyl or aralkyl, and

x is O;

it is further preferred that they have the following substituents, among them

R₁And R₆Is a hydrogen atom, and is,

R₂、R₃、R₅and R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉An alkyl, aryl or aralkyl group,

R₄and R₇Independently of one another is hydroxy, OR₉Or OC (O) R₉，

R₉Is methyl, ethyl, propyl, isopropyl or trifluoromethyl, and

x is O; and

most preferably, they have the following substituents, among them

R₁And R₆Is a hydrogen atom, and is,

R₂、R₃、R₅and R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉Or a methyl group, or a mixture of methyl and ethyl,

R₄and R₇Independently of one another is hydroxy, OR₉Or OC (O) R₉，

R₉Is methyl, and

x is O.

Preferably, the novel dimeric compounds of formula (I) and (II) are:

tetraacetoxy 6- (4- (isoflavan-4 ', 7-diol)) -isoflav-3-en-4', 7-diol (2)

6- (4- (isoflavan-4 ', 7-diol)) -isoflav-3-en-4', 7-diol (3)

Tetraacetoxy 6- (4- (isoflavan-4 ', 7-diol)) -isoflavan-4', 7-diol (4)

6- (4- (isoflavan-4 ', 7-diol)) -isoflavan-4', 7-diol (5)

6- (4- (4 ', 7-dimethoxyisoflavan)) -4', 7-dimethoxyisoflav-3-ene (6)

6- (4- (4 ', 7-dimethoxyisoflavan)) -4', 7-dimethoxyisoflavan (7)

Tetraacetoxy 3 ' - (4- (isoflavan-4 ', 7-diol)) -isoflav-3-en-4 ', 7-diol (8)

3 ' - (4- (isoflavan-4 ', 7-diol)) -isoflav-3-en-4 ', 7-diol (9)

Tetraacetoxy 3 ' - (4- (isoflavan-4 ', 7-diol)) -isoflavan-4 ', 7-diol (10)

3 ' - (4- (isoflavan-4 ', 7-diol)) -isoflavan-4 ', 7-diol (11)

The compounds 2-11 are represented by the following structural formulas:

without intending to be limited by theory, it is believed that the dimer molecules of the present invention are formed as a result of electrophilic aromatic substitution of one of the aromatic rings. Generally, plant-based isoflavone compounds have hydroxyl groups at least at the 4' -and 7-positions of the isoflavone backbone. It is believed that these electron donating groups facilitate electrophilic aromatic substitution and are substituted directly onto the ortho or para position of the electron donating substituent.

In a particularly preferred embodiment of the invention, when the monomer is dehydrated with phosphorus pentoxide, the isoflavone diethoxytetrahydroiodic glycoside (1), R ═ Ac, couples to form a dimeric molecule.

(1) Electrophilic substitution of the ring-fused benzene ring of (a) occurs preferentially in the alpha position of the 7-oxo substituent and in the beta position of the ring attachment point. It is believed that the beta position is more available because its steric hindrance is less than the steric hindrance of the alpha position of the loop attachment point. It is believed that the pyran oxygen contributes to the activation of the electrophilic aromatic substitution by the ring-fused benzene in preference to the substitution selectivity of the pendant phenyl group.

Other synthetic methods well known to those skilled in the art may also be used in the synthesis of the dimeric molecules of the present invention. Such other suitable synthetic methods include friedel-crafts alkylated coupling of two flavones or derivatives thereof. Typical Friedel-crafts reaction conditions are used with reagents such as aluminum chloride, boron trifluoride or similar Lewis acid catalysts. The coupling reaction is not limited to Friedel-crafts type conditions but may also include other reaction conditions that produce "carbenium" species, such as the conversion of a secondary alcohol to a phosphonate or similar easily leaving group. Oxidative coupling reaction conditions such as hydrogen peroxide, dilute permanganate, phosphorus pentoxide, or other oxidizing compounds may also be used in the synthesis of the dimeric molecules of the present invention.

Linking two monomeric isoflavone compounds or derivatives with a bridging group also results in the dimeric isoflavone molecule of the present invention. Suitable divalent bridging groups include, for example, -O-, -S-, -CH₂-、-(C(R)H)_n-, -NR-, or-C ═ O.

Where applicable, chemical functional group protection, deprotection, synthons and other techniques known to those skilled in the art may be used to facilitate the synthesis of the compounds of the invention and other starting materials.

The preferred starting flavonoid monomer, diacetoxytetrahydroiodic glycoside (1) R ═ Ac-can be obtained using standard procedures known in the art. For (1) and the useful synthetic methods for the production of related isoflavones, reference is made in particular to published international patent applications WO 98/08503 and WO00/49009 and the references cited therein (Novogen Research Pty Ltd).

However, the isoflavone monomers used in the present invention may be derived from any number of sources that can be readily identified by those skilled in the art. For example, the isoflavones are commercially available or may be extracted from plant sources. Those skilled in the art will readily be able to identify suitable plant species from which suitable isoflavone derivatives for use in the present invention may be derived, however, plants specifically used in the present invention include plants of the genus Cicer, Glycine, Trifolium (Trifolium), and the like. More preferably, the isoflavone extract is obtained from Medicago sativa or Medicago sativa.

The isoflavone extract may be prepared by any number of techniques known in the art. For example, suitable isoflavone extracts may be prepared from natural plant sources by aqueous/organic solvent extraction. It is to be understood that the isoflavone extract may be prepared from any single tissue of a single plant species or a combination of two or more different tissues thereof. Similarly, the extract may be prepared from a starting material comprising a heterogeneous mixture of tissues from two or more different plant species.

Generally, in the case of preparing an isoflavone extract from plant material, the material may be comminuted or cut into smaller pieces, partially comminuted or cut into smaller pieces, and contacted with water and an organic solvent, such as a water-miscible organic solvent. Alternatively, the plant material is contacted with water and an organic solvent without any pretreatment. The ratio of water to organic solvent may be in the range of 1: 10 to 10: 1, and may contain, for example, water and solvent in an equal ratio or 1% to 30% (v/v) organic solvent. Any organic solvent or mixture of such solvents may be used. The organic solvent may preferably be a C2-10, more preferably C1-4 organic solvent (e.g., methanol, chloroform, ethanol, propanol, propylene glycol, erythritol, butanol, butylene glycol, acetonitrile, ethylene glycol, ethyl acetate, glycidol, glycerol, dihydroxyacetone, or acetone). Optionally, the water/organic solvent mixture may include an enzyme that cleaves the isoflavone glycoside to the aglycone form. The mixture may be vigorously stirred to form an emulsion. The temperature of the mixture may range, for example, from ambient to boiling temperature. The exposure time may be between 1 hour and several weeks. A convenient extraction period is 24 hours at 90 ℃. The extract can be separated from undissolved plant material and the organic solvent removed, such as by distillation, rotary evaporation or other standard solvent removal procedures. The resulting extract containing water-soluble and water-insoluble components may be dried to give an isoflavone-containing extract which may be formulated with one or more pharmaceutically acceptable carriers, excipients and/or adjuvants according to the invention.

Extracts made as described in the preceding paragraphs may contain small amounts of oil that includes isoflavones in their aglycone form (referred to herein simply as isoflavones). The isoflavone rich oil may be subjected to HPLC to adjust the isoflavone ratio or, when it has the desired isoflavone ratio, may be dried, such as in the presence of silica, and formulated with one or more carriers, excipients and/or adjuvants to give an isoflavone containing extract. Alternatively, the isoflavones contained in the small amount of oil may be further concentrated by adding to the oil a water-insoluble organic solvent such as hexane, heptane, octane, acetone or mixtures of one or more of such solvents. An example is 80% hexane/20% acetone (w/w) which has a high solubility for oils but a low solubility for isoflavones. The oil readily partitions into the organic solvent, while the isoflavone rich extract settles out of solution. The recovered extract may be dried, such as in an oven, at 50 ℃ to about 120 ℃, and then formulated with one or more pharmaceutically acceptable carriers, excipients, and/or adjuvants.

Other suitable methods can be found in Chang et al, which discloses methods suitable for the synthesis of various isoflavones and derivatives thereof.

The dimeric isoflavone structures shown in formulas (Ia) and (IIa) have the inherent ability to constrain the conformation between these two monomeric structures to a rectangular relationship. Suppose that: the apparent large conformational rigidity of the rectangular relationship and the inherent ability to confine the displacement of the H-bond donor within the monomer segment of the coordination binding domain of the dimer results in modulation of the normal excitatory effect of the monomer on the cellular receptor. In most cases this modulation leads to an up-regulation of the biological activity, while in some cases it leads to a down-regulation of this activity. That is, the biological image of the monomer, which can be predicted to a large extent from known structure-function relationships established empirically from large knowledge bases screening such compounds, is not predictable with the dimeric form. The functions regulated by the conversion from the monomeric to the dimeric form are as follows: absolute levels of agonism and antagonism of hER-alpha and hER-beta and relative levels of agonism/antagonism of the two receptor types; inhibition of 5-alpha-reductase and 17-beta-steroid dehydrogenase; antioxidation; mitotic arrest and apoptosis induction of cancer cells; prostaglandin and inflammatory cytokinin release; vascular activity; high density lipoprotein and low density lipoprotein levels.

The present inventors have therefore surprisingly found that the dimeric molecules of the present invention contribute to a new family of compounds that are indicative for the treatment and prevention of a range of important human diseases and disorders as listed above. Such diseases and disorders include cancer, inflammatory disorders, autoimmune disorders, cardiovascular disorders, and disorders associated with estrogen receptor activation.

In particular, the dimeric compounds of the present invention, by their potent ability to inhibit cancer cell proliferation and induce apoptosis, show utility in cancer prevention and treatment, a term that one of skill in the art would understand encompasses benign and malignant abnormal growth of any or all tissues of the body, including epithelial, mesenchymal and neural types. This includes, but is not limited to, carcinoma, adenocarcinoma, sarcoma, blastoma, adenoma, lymphoma, leukemia, glioma, and melanoma.

In particular, the dimeric compounds of the present invention, through their potent ability to act as h-ER β agonists, are particularly capable of providing estrogen support to perimenopausal and menopausal age women, and preventing and treating problems generally believed to represent acute withdrawal of steroidal estrogens such as vasomotor symptoms (hot flashes and night sweats) and mood symptoms (anxiety, depression, mood swings), problems generally believed to represent subacute withdrawal of steroidal estrogens such as urinary incontinence and bladder sagging, and problems generally believed to represent chronic withdrawal of steroidal estrogens such as osteoporosis and osteoporosis, and senile dementia.

In particular, the dimeric compounds of the present invention, by virtue of their potent ability to act as h-ER α antagonists, are capable of preventing or treating conditions in premenopausal women which are generally considered to be associated with hyperstimulation of the h-ER α receptor and which lead to the following symptoms: periodic mastalgia, endometriosis, endometrial hyperplasia, uterine fibroids, polycystic ovarian disease, and premenstrual syndrome.

In particular, the dimeric compounds of the present invention, through their potent ability to induce vasodilation and reduce vasospasm, show utility in the treatment and prevention of disorders generally recognized as either accidentally or indirectly associated with vasoconstriction and encompassing but not limited to hypertension and migraine.

In particular, the dimeric compounds of the present invention, through their powerful ability to antagonize inflammatory processes and modulate immune processes, show utility in the prevention and treatment of disorders generally thought to be associated with excessive inflammatory and obstructive immune function and encompassing, but not limited to, inflammatory disorders of the gastrointestinal tract, including inflammatory bowel disease, ulcerative colitis, crohn's disease, and sclerosing cholangitis, and inflammatory disorders of the synovial membrane, including rheumatoid arthritis.

In particular, the dimeric compounds of the present invention, by virtue of their potent ability to act as antioxidants, show utility in the prevention and treatment of conditions generally believed to be associated with oxidative effects leading to degenerative changes, including conditions such as cataracts, actinic damage, and atherosclerosis.

In particular, the dimeric compounds of the present invention, through their powerful ability to inhibit the development of androgens, show utility in the prevention and treatment of disorders generally thought to be linked, either accidentally or indirectly, to abnormal function of androgens and including, but not limited to, male pattern baldness (inheritance of hair loss) and prostate adenoma.

The amount of compound or compounds of formulae I and II required in the therapeutic treatment according to the present invention will depend on a number of factors including the particular administration, the nature of the particular compound used, the condition being treated, the mode of administration, and the patient's condition. The compounds of formula I or II may be administered in a manner and amount as is conventional practice. See, for example, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 1299(7th Edition, 1985). The specific dose utilized will depend upon the condition being treated, the condition of the subject being treated, the route of administration, and other well-known factors noted above. In general, the daily dose per patient may be in the range 0.1mg to 2g, typically 0.5mg to 1g, preferably 20mg to 200 mg.

The manufacture of pharmaceutical compositions for the treatment of a therapeutic indication as described herein is typically carried out by mixing a compound of the invention (hereinafter referred to simply as "active compound" for convenience) with one or more pharmaceutically or veterinarily acceptable carriers and/or excipients which 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 harm the subject. The carrier or excipient may be solid or liquid or both and is preferably formulated with the compound as a unit dose such as a tablet which may contain 0.5 to 59% by weight of active compound, or up to 100% by weight of active compound. The formulations of the present invention, which may be prepared by any of the well-known pharmaceutical techniques, comprise one or more active compounds in admixture with one or more accessory ingredients.

The formulations of the present invention include those suitable for oral, rectal, ocular, buccal (e.g., sublingual), parenteral (e.g., 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 used.

Formulations suitable for oral administration may be presented as discrete units such as capsules, sachets, lozenges, or tablets, each unit containing a predetermined amount of the active compound; making into powder or granule; making into solution or suspension in water or non-water liquid; or making into oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable pharmaceutical method which includes the step of bringing into association the active compound with a suitable carrier, which may contain one or more accessory ingredients as described above. In general, the formulations of the invention are prepared by uniformly and intimately bringing into association the active compound with a liquid or finely divided solid carrier or both, and then, if necessary, shaping the resulting mixture to form a unit dose. For example, tablets may be prepared by compressing or molding a powder or granules containing the active compound and optionally one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound, e.g., powder or granules, which is free flowing, optionally mixed with a binder, lubricant, inert diluent, and/or surfactant/dispersant. Molded tablets may be made by molding the powdered compound moistened with an inert liquid binder on a suitable machine.

Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured, deodorising 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 invention suitable for parenteral administration conveniently comprise a sterile aqueous-based formulation of the active compound, which is preferably isotonic with the blood of the intended recipient. These formulations are preferably administered intravenously, although administration may also be by subcutaneous, intramuscular, or intradermal injection. Such formulations may be conveniently prepared by mixing the compound with water or glycine buffer and allowing the resulting solution to sterilize and become isotonic with blood. Injectable formulations according to the invention typically contain 0.1% to 60% (w/v) of the active compound and are administered at a rate of 0.1 ml/min/kg.

Formulations suitable for rectal administration are preferably formulated as unit dose suppositories. These may be prepared by mixing 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 take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Carriers that may be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The active compound is generally present in a concentration of 0.1 to 0.5 wt.%, for example 0.5 to 2 wt.%. Examples of such compositions include cosmetic skin creams.

Formulations suitable for transdermal administration may be formulated as discrete patches that are capable of being held in intimate contact with the epidermis of the recipient for a prolonged period of time. Such a patch suitably contains the active compound as an optionally buffered aqueous solution, e.g. at a concentration of 0.1 to 0.2M with respect to the active compound.

Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., panchagula et al) and are typically in 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 0.1M to 0.2M active ingredient.

The active compound can be provided in the form of a food product, e.g., added to, mixed into, coated onto, combined with, or otherwise added to a food product. The term food is used in its broadest possible sense and includes liquid formulations such as beverages, including dairy products, and other food products such as health bars, desserts, and the like. Food formulations containing the compounds of the present invention can be readily prepared in accordance with standard practice.

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 compositions of the present invention may also be administered to humans in the form of a dietary supplement. The nutrition enhancer incorporating the active ingredient can be prepared by adding the composition to a food during the preparation of the food. Any food product may be used, including but not limited to meats such as ground meats, emulsified meats, and salt-pickled meats; beverages such as nutritional beverages, sports beverages, protein-fortified beverages, fruit juices, dairy products, milk substitutes, and diet beverages; cheeses such as hard cheese, soft cheese, cream cheese, cottage cheese; frozen desserts such as ice cream, ice milk, low fat frozen desserts, and non-dairy frozen desserts; yogurt; soup; puddings; baking the food; a salad dressing; and dip-coated foods such as mayonnaise, margarine, butter substitutes, and other fat-containing coated foods. The composition is added to the food product in an amount selected to deliver a desired dose of the composition to a consumer of the food product.

The compounds of the present invention have strong antioxidant activity and are therefore widely used in medical and veterinary applications, in cosmetics such as skin creams for preventing skin aging, in sunscreens, in foods, health drinks, shampoos and the like.

It has been surprisingly found that the compounds of formula I or II interact synergistically with vitamin E to prevent oxidation of lipids, proteins and other biological molecules.

Thus, a further aspect of the invention provides a composition comprising one or more compounds of formulae I and II, vitamin E, and optionally a pharmaceutically, veterinarily or cosmetically acceptable carrier and/or excipient.

The methods of treatment, uses and compositions may be used for administration to humans or animals, such as companion and domestic animals (e.g., dogs and cats), birds (e.g., chickens, turkeys, ducks), livestock animals (e.g., cattle, sheep, pigs, goats), and the like.

The term "treatment" as used herein is to be considered in its broadest scope. This term does not necessarily mean that one animal is treated until complete recovery. Thus, "treating" includes ameliorating the symptoms or severity of a particular disorder, or preventing or otherwise reducing the risk of developing a particular disorder.

As used herein, "pharmaceutically acceptable carrier, excipient, adjuvant and/or diluent" shall be taken to include any carrier, excipient, adjuvant and/or diluent deemed useful in the preparation of a pharmaceutical composition. Such carriers, excipients, adjuvants or diluents will generally be safe, non-toxic, and neither biologically nor otherwise undesirable. The term also includes carriers, excipients, adjuvants or diluents which are acceptable for veterinary as well as human medical use. The term "pharmaceutically acceptable carrier, excipient, adjuvant and/or diluent" as used herein includes one or more than one of such substances.

The invention is further described below with reference to the following non-limiting examples.

Examples

Example 1 tetraacetoxy 6- (4- (isoflavan-4', 7-diol)) isoyellow Synthesis of (2) -3-ene-4', 7-diol

A mixture (300g) of approximately 1: 1 cis and trans diacetoxytetrahydroiodic glycoside (1) was dissolved in dry dichloromethane and stirred under a nitrogen bed at 15 ℃ until all material had dissolved. Phosphorus pentoxide (500g) was rapidly added under vigorous stirring, and the reaction was continued for 4 to 6 hours. The reaction mixture was then filtered through a silica gel bed, the dimer structure having a lower Rf than the monomer side product. The dimer compound was further purified by selective recrystallization from ethyl acetate.

¹H NMR(CDCl₃，400MHz)：7.40(2H，d，J＝8Hz)，7.15(2H，d，J＝8Hz)，7.13(2H，d，J＝8Hz)，7.05(2H，d，J＝8Hz)，6.90(1H，d J＝7.6Hz)，6.75(1H，d，＝1.5Hz)，6.65(1H，bs s)，6.63(1H，br s)，6.60(1H，dd，J＝7.6，1.5Hz)，6.58(1H，br s)，5.05(2H，brs)，4.38(1H，dd，J＝9，3Hz)，4.30(1H br d，J＝Hz)，4.25(1H，dd，J＝9，6Hz)，3.38(1H，m)，2.32(3H，s)，2.30(3H，s)2.28(3H，s)，2.08(3H，br s)

Example 26- (4- (isoflavan-4 ', 7-diol)) isoflav-3-en-4', 7 Synthesis of diol (3)

To a suspension of tetraacetoxy 6- (4- (isoflavan-4 ', 7-diol)) isoflav-3-en-4', 7-diol (0.2g) in absolute ethanol (2.0ml) was added imidazole (0.166 g). The mixture was refluxed under nitrogen for 12 hours. The solution was concentrated under vacuum and deionized water (10ml) was added to precipitate the product. The mixture was left in the refrigerator overnight. The off-white solid was filtered off and lyophilized to give (0.1g, 67%) free phenolic dimer compound.

¹H NMR(D6-DMSO，400MHz)：9.1(4H，br，OH)，7.26(2H，d，J＝7.6Hz)，7.04(2H，d，J＝7.6Hz)，6.72(2H，d，J＝7.6Hz)，6.61(1H，s)，6.60(2H，d，J＝7.6Hz)，6.56(1H，s)，6.46(1H，d，J＝8Hz)，6.25(1H，s)，6.22(1H，brd，J＝8Hz)，6.20(1H，brs)，4.95(2H，s)，4.44(1H，d，J＝8.4Hz)，4.13(1H，dd，J＝11，3.3Hz)，4.06(1H，dd，J＝11，7.7Hz)，3.28(1H，ddd，J＝8.4，7.7，3.3Hz).

Example 3 Estrogen receptor binding assays

The ability of tetraphenolic dimer (structure 3) and tetraethoxy dimer (structure 2) to interact with estrogen receptors alpha and beta was determined using a commercially available estrogen receptor binding kit. This kit employs a competitive binding assay to determine the relative binding affinity of test compounds to recombinant human estrogen receptors alpha (ER-alpha) and beta (ER-beta). Briefly, recombinant human estrogen receptor α or β is added to a fluorescently labeled estrogen ligand to produce an estrogen ligand/receptor complex that exhibits high fluorescence polarization. The complex is then added to a concentration of decreasing competitor test compound. The relative affinity of the test compound for the estrogen receptor is determined by the shift in polarization in the presence of the test compound. When tested using the manufacturer's instructions, we determined the concentration of estradiol required to displace 50% of the bound fluorescent estrogen ligand (EC)₅₀) This is consistent with published values for ER- α of 0.011 μ M and ER- β of 0.006 μ M (Bolger et al, 1998). Tetraphenol-type dimers (structure 3) show equivalent binding affinities for estrogen receptors α and β (ER- α 0.35 ± 0).05 mu M; ER- β 0.37 ± 0.05 μ M), whereas tetraacetoxy dimer (structure 2) did not bind to either receptor.

Example 4 Anticancer activity

The anticancer potential of tetraphenol dimer (structure 3) and tetraethoxy dimer (structure 2) was evaluated using a panel of human tumor cell lines, including glioma (C6), prostate cancer (PC3), breast cancer (MCF-7), soft tissue cancer (Kym-1), and lung cancer (NCI-H23 and NCI-H460). Cytotoxicity assays were performed according to Alley et al 1988. Each cell line was exposed to different concentrations of test compound for a fixed period of time. At the end of the assay, the viability of each of the cell populations was determined using the hydrogen acceptor reagent 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT). Concentration of compound required to inhibit cell growth by 50% (IC) compared to control₅₀) Is an indicator of the effectiveness of the compound. (i.e., the lower the concentration of compound required to inhibit 50% of normal cell proliferation, the more effective.) both dimers showed strong anti-cancer activity against the cancer types tested (table 1).

TABLE 1 IC of two dimeric isoflavones on tumor cell lines₅₀Measurement of

Dimer MCF-7 PC 3C 6 Kym-1 NCI-

Glioma H460H 23

Structure 318 + -213.517.53.214.413.5

Structure 210 + -56 NT NT NT NT 7.3

NT ═ untested

Reference to any prior art in this specification is not, and should not be taken as, a sink or any form of suggestion that prior art forms part of the common general knowledge in the field of endeavour.

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.

Reference to the literature

The patent:

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Claims (19)

1. A compound of the general formula (Ia):

in the formula

R₁、R₂、R₃、R₄、R₅、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)H、OC(O)R₉、C(O)R₁₁、CO₂R₁₂、C_1-6Alkyl radical, C_1-6Haloalkyl, amino, nitro or halogen,

R₆is a hydrogen atom, and is,

R₉is C_1-6Alkyl or C_1-6A haloalkyl group, a halogen-alkyl group,

R₁₁is hydrogen or C_1-6An alkyl group, a carboxyl group,

R₁₂is hydrogen or C_1-6An alkyl group, a carboxyl group,

x is O, and

symbolRepresents either a single bond or a double bond,

the compounds include pharmaceutically acceptable salts thereof,

with the proviso that compounds of the formula are excluded:

wherein

When in useWhen the carbon atom is a single bond or a double bond,

R_Gand R_HIs hydrogen or methyl, and

when in useIs a single bond, and R_GIn the case of a methyl group, the alkyl group,

R_His hydrogen or benzyl.

2. The compound of claim 1, wherein

R₁、R₂、R₃、R₄、R₅、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉、C_1-6Alkyl, bromo, chloro or fluoro.

3. The compound of claim 2, wherein

R₁Is a hydrogen atom, and is,

R₂、R₃、R₅and R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉Or C_1-6An alkyl group, a carboxyl group,

R₄and R₇Independently of one another is hydroxy, OR₉Or OC (O) R₉And is and

R₉is methyl, ethyl, propyl, isopropyl or trifluoromethyl.

4. The compound of claim 3, wherein

R₂、R₃、R₅And R₈Independently hydrogen, hydroxy, OR₉、OC(O)R₉Or a methyl group, and

R₉is methyl.

5. The compound of claim 4 selected from:

6- (4- (isoflavan-4 ', 7-diacetoxy)) -4', 7-diacetoxy-3-ene, and

6- (4- (isoflavan-4 ', 7-diol)) -isoflav-3-en-4', 7-diol.

6. A process for the preparation of a compound of formula (Ia) as defined in claim 1, which process comprises the reaction of a compound of formula (III) with a coupling agent

In the formula

R₁、R₂、R₃、R₄、R₅、R₇And R₈Independently hydrogen, hydroxy, OR₉、OC(O)H、OC(O)R₉、C(O)R₁₁、CO₂R₁₂、C_1-6Alkyl radical, C_1-6Alkyl halidesA group, an amino group, a nitro group or a halogen,

R₆is a hydrogen atom, and is,

R₉is C_1-6Alkyl or C_1-6A haloalkyl group, a halogen-alkyl group,

R₁₁is hydrogen or C_1-6An alkyl group, a carboxyl group,

R₁₂is hydrogen or C_1-6An alkyl group, a carboxyl group,

OR₁₃is a hydroxyl group, another leaving group or an electron withdrawing group,

x is O, and

symbolRepresents either a single bond or a double bond,

the compounds include pharmaceutically acceptable salts thereof.

7. A process according to claim 6, wherein the compound of formula (Ia) is as defined in any one of claims 2 to 5.

8. The process of claim 6 or 7, wherein the coupling agent is phosphorus pentoxide, hydrogen peroxide, permanganate or a Lewis acid.

9. Use of one or more compounds selected from formula (Ia) as defined in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer.

10. The use of claim 9, wherein the cancer is selected from the group consisting of pre-malignant, benign and malignant cancers.

11. The use of claim 9, wherein the cancer treatment is used in combination with other anti-cancer treatment modalities selected from radiation therapy and chemotherapy.

12. The use of claim 9, wherein the cancer is glioma, prostate cancer, breast cancer, soft tissue cancer and lung cancer.

13. Use of one or more compounds of formula (Ia) as defined in claim 1 for the manufacture of a medicament for the treatment of a disease or disorder selected from:

(i) conditions in women associated with abnormal estrogen/androgen balance, and

(ii) male conditions associated with abnormal estrogen/androgen balance.

14. The use of claim 13, wherein the condition in women associated with abnormal estrogen/androgen balance is selected from the group consisting of periodic mastalgia, acne, dysmenorrhea, uterine fibroids, endometriosis, ovarian cysts, premenstrual syndrome, acute menopausal symptoms, osteoporosis, senile dementia and infertility.

15. The use of claim 13, wherein the male condition associated with abnormal estrogen/androgen balance is selected from the group consisting of benign prostatic hypertrophy, infertility, gynecomastia, alopecia inheritance, and other forms of alopecia.

16. Use of one or more compounds of formula (Ia) as defined in claim 1 for the manufacture of a medicament as an antiestrogen or selective estrogen receptor modulator, SERM.

17. A pharmaceutical composition comprising one or more compounds of formula (Ia) as claimed in claim 1 in association with one or more pharmaceutical carriers and/or excipients.

18. A beverage or foodstuff containing one or more compounds of formula (Ia) as claimed in claim 1.

19. A composition comprising one or more compounds of formula (Ia) as defined in claim 1, vitamin E, and optionally a pharmaceutically, veterinarily or cosmetically acceptable carrier and/or excipient.