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WO2025015023A2 - Composés de diphényléthylène et compositions associées - Google Patents

Composés de diphényléthylène et compositions associées Download PDF

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Publication number
WO2025015023A2
WO2025015023A2 PCT/US2024/037345 US2024037345W WO2025015023A2 WO 2025015023 A2 WO2025015023 A2 WO 2025015023A2 US 2024037345 W US2024037345 W US 2024037345W WO 2025015023 A2 WO2025015023 A2 WO 2025015023A2
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WIPO (PCT)
Prior art keywords
hpv
solvate
prodrug
pharmaceutically acceptable
acceptable salt
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PCT/US2024/037345
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WO2025015023A3 (fr
Inventor
Mario CASTELLANOS
Daniel Banov
Guiyun W SONG
August S BASSANI
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Innovene Inc
Professional Compounding Centers of America Ltd
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Innovene Inc
Professional Compounding Centers of America Ltd
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Publication of WO2025015023A2 publication Critical patent/WO2025015023A2/fr
Publication of WO2025015023A3 publication Critical patent/WO2025015023A3/fr
Pending legal-status Critical Current
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages

Definitions

  • the present application relates to uses of diphenylethylene compounds and compositions thereof in therapy.
  • the present application relates to uses of diphenylethylene compounds and compositions thereof in the treatment of papillomavirus infections, and diseases, disorders or conditions arising from a papillomavirus infections such as cancer.
  • Diphenylethylene compounds have aromatic groups bonded to each end of a carbon-carbon double bond, are versatile in scope, and participate in various biochemical, photochemical, and photochromatic reactions. Plants produce incredibly diverse and bioactive forms, characterized by the presence of a 1,2-diphenylethylene nucleus, with (E)-stilbenes being the most biologically relevant stereoisomer.
  • HPV Human papillomavirus
  • benign growths e.g., warts
  • HPV Human papillomavirus
  • Papillomaviridae is a family of small non-enveloped DNA viruses. They infect various species, such as birds, reptiles, and mammals, such as dogs, cats, rabbits, mice, and humans. Collectively, these viruses are known as papillomaviruses. They are host-specific and do not cross species. Thus, human papillomavirus (HPV) is only transmitted between people and infects cutaneous or mucous membranes. HPV can cause papillomas (warts) on the skin, larynx, or urogenital area, while some genotypes induce malignant transformation to cause overt cancer. There are more than 400 types of HPV, and many are classified as either low or high-risk HPVs depending on their cancer-causing potential.
  • HPV HPV is the main cause of cervical cancer.
  • 1.8 million women have chronic cervical HPV, leading to 200,000 cervical precancer cases each year.
  • Globally, over 28 million women with persistent cervical HPV infection and are at risk of developing cervical carcinoma These patients have no specific treatment options.
  • HPV vaccines can prevent HPV and cervical cancer. However, they are ineffective in treating those with established infections.
  • HPV infection one of the most problematic viral infections in women, with cervical cancer remaining the 4 th most common malignancy in females worldwide.
  • HPV infection also causes a spectrum of diseases in men and women, leading to additional morbidity and mortality. Twenty-five percent of men in the US carry genital oncogenic HPV infections that, at present, cannot be treated and are a major source of continued viral spread. HPV infection also induces other malignancies such as oral, anal, vaginal, and penile carcinoma. Low-risk HPV genotypes cause a variety of difficult-to-treat and painful papillary growths (warts) on the skin and external genitals, as well as laryngeal papillomas and lesions on body surfaces. The CDC estimates that each year there are 14 million new cases of HPV infection.
  • Resveratrol trans-3,5,4' trihydroxystilbene
  • Resveratrol is a polyphenolic phytoalexin that was first isolated and identified from the roots of Veratrum grandiflorum O.Loes and possesses anticancer and antiviral properties.
  • resveratrol modulates a large number of cell-signaling and regulatory proteins, including Wnt, nuclear factor -KB (NF-KB), cytokines, caspases, Notch, matrix metalloproteinases (MMPs), 5 ’ -AMP-activated protein kinase (AMPK), sirtuin type 1 (SIRT1), and tumor necrosis factor a (TNF-a).
  • Wnt nuclear factor -KB
  • cytokines nuclear factor -KB
  • MMPs matrix metalloproteinases
  • AMPK 5 -AMP-activated protein kinase
  • SIRT1 sirtuin type 1
  • TNF-a tumor necrosis factor a
  • the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein
  • X 1 and X 2 are independently selected from OH and OR 1 ;
  • X 3 and X 4 are independently selected from OH and OCH3;
  • the present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I as defined in claim 1, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to a subject in need thereof
  • the method comprises administering an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin.
  • the present application includes a method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the method comprises administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin.
  • the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein
  • X 1 and X 2 are independently selected from OH and OR 1 ;
  • X 3 and X 4 are independently selected from OH and OCHs;and in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to a subject in need thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the method comprises administering to the subject, an effective amount of one or more compounds of Formula I in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in further combination with a curcuminoid and a catechin.
  • the present application also includes a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, wherein
  • X 1 to X 4 are as defined above.
  • the pharmaceutical composition comprises one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin,
  • the composition comprises two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin.
  • the present application includes a pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • composition of the application refers to a composition comprising one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, a curcuminoid and a catechin; pterostilbene, or a salt, prodrug and/or solvate thereof, a curcuminoid and a catechin; or a combination of one or more compounds Formula I, or a salt, prodrug and/or solvate thereof, pterostilbene, or a salt, prodrug and/or solvate thereof, and optionally a curcuminoid and a catechin.
  • suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and/or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so
  • cell refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.
  • subject as used herein includes all members of the animal kingdom including mammals. Thus, the methods and uses of the present application are applicable to both human therapy and veterinary applications.
  • pharmaceutically acceptable means compatible with the treatment of subjects.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with an active ingredient (for example, one or more compounds of the application) to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.
  • pharmaceutically acceptable salt means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic acid addition salt of any basic compound.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic base addition salt of any acidic compound.
  • solvate as used herein means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered.
  • prodrug means a compound, or salt of a compound, that, after administration, is converted into an active drug.
  • viral infection refers to an invasion of cells or bodily tissues by one or more foreign, undesirable viruses.
  • administered means administration of a therapeutically effective amount of a compound or a pharmaceutically acceptable salt, prodrug and/or solvate thereof or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to a cell either in cell culture or in a subject
  • the term “effective amount”, “therapeutically effective amount” or “antiviral-effective amount” means an amount of a compound or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, or compositions comprising a compound or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, that is effective, at dosages and for periods of time necessary to achieve the desired result, including therapeutic and prophylactic results.
  • subject as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans. Thus the methods and uses of the present application are applicable to both human therapy and veterinary applications.
  • composition refers to a composition of matter for pharmaceutical use.
  • parenteral means taken into the body or administered in a manner other than through the gastrointestinal tract.
  • treating means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of a disease, disorder or condition, stabilized (i.e.
  • Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “Treating” and “treatment” as used herein also include prophylactic treatment.
  • “Palliating” an infection and/or disease means that the extent and/or undesirable clinical manifestations of an infection and/or disease are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the infection and/or disease.
  • prevention or “prophylaxis” or “prophylactic” and the like as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a viral infection and/or a disease caused by a viral infection or manifesting a symptom associated with a viral infection or a disease caused by a viral infection.
  • the term “effective amount” or “therapeutically effective amount” means an amount of a compound, or one or more compounds, that is effective, at dosages and for periods of time necessary to achieve a desired result.
  • disease, disorder or condition caused by a papillomavirus infection means that the disease, disorder or condition to be treated is affected by and/or modulated by either direct or indirect, a papillomavirus infection.
  • a subject for example a subject “in need thereof’ is a subject who has been diagnosed with, is suspected of having, may come in to contact with, and/or was previously treated for a papillomavirus infection or a disease caused by a papillomavirus infection.
  • papillomavirus refers a virus of the papillomaviridae family
  • human papillomavirus infection or “HPV infection” is an infection of a human papillomavirus.
  • resveratrol refers to a compound having the chemical name: (E)- 5-(4-hydroxystyryl)benzene- 1,3 -diol or trans-3,5,4'-trihydroxystilbene and having the following chemical structure and numbering
  • resveratrol resistant cancer refers a cancer showing very low sensitivity to treatment with resveratrol so that the symptoms thereof are not improved, relieved, alleviated, or treated by the resveratrol.
  • the resveratrol resistant cancer can be a cancer originally resistant to treatment with a resveratrol, or the resveratrol resistant cancer can be a cancer not originally resistant to resveratrol.
  • the Applicant has identified certain plant species, for example medicinal rhubarb plant species, which contain trans-resveratrol and further investigated other diphenylethylene compounds present in the plant species for anti-papillomavirus activity such as anti-human papillomavirus (HPV) activity.
  • anti-papillomavirus activity such as anti-human papillomavirus (HPV) activity.
  • HPV anti-human papillomavirus
  • a drug screen of the other identified natural diphenylethylene compounds present in the medicinal rhubarb plant species including Rheum rhaponticum and Rheum rhabarbarum) that were known to contain resveratrol was performed.
  • candidate diphenyl ethylene phytochemicals were selected which possessed the 1,2-diphenyl ethylene scaffold in the trans configuration.
  • the selected diphenylethylene compounds were tested to establish a dose-response curve based on their ability to eliminate HPV-18 (+) HeLa cells. This HPV-18 (+) HeLa cervical cancer line was also used to develop subclonal populations of HeLa cells, demonstrating strong resistance to resveratrol, designated HeLa-GSl.
  • the most active of the identified compounds (IC50 ⁇ 30 pM) were then tested against a newly developed resveratrol-resistant cell line, HeLa-GSl.
  • the Applicants identified diphenyl ethylenes compounds having unexpectedly good cytotoxicity against HPV (+) cells.
  • the Applicant investigated the activity of combinations of the identified diphenylethylene compounds and in further combination with a curcuminoid, such as curcumin, and a catechin, such (-)-epigallocatechin gallate (EGCg), and found compound combinations demonstrating high and synergistic anti-papillomavirus activity.
  • a curcuminoid such as curcumin
  • a catechin such as (-)-epigallocatechin gallate (EGCg)
  • X 1 and X 2 are independently selected from OH and OR 1 ;
  • X 3 and X 4 are independently selected from OH and OCH3;
  • the present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for treating or preventing a papillomavirus infection in a subject; a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for preparation of a medicament for treating or preventing a papillomavirus infection in a subject; and one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for use to treat or prevent a papillomavirus infection in a subject.
  • the papillomavirus infection is an infection of at least one papillomavirus.
  • the papillomavirus infection is a human papillomavirus (HPV) infection.
  • the HPV infection is an infection of one or more HPV genotypes selected from 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV-16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV- 31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).
  • the HPV infection is an infection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, the HPV infection is an infection of HPV genotype 16. In some embodiments, the HPV infection is an infection of HPV genotype 18. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1, 3, 27, 29, and 57.
  • the HPV genotypes are selected from 1, 3, 27, 29, or 57 cause common warts.
  • the HPV infection is an infection of one or more HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57.
  • the HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57 cause plantar warts such as deep palmoplantar warts.
  • the compounds of Formula I have been shown active against the HPV-16 (+) and HPV- 18 (+) cervical cancer cell lines and resveratrol resistant cancer cell lines, the compounds of Formula I have are useful for treating diseases, disorders or conditions caused by a papillomavirus infection
  • the present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to a subject in need thereof
  • the present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection, as well as a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for the preparation of a medicament for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection.
  • the application further includes one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for use in treating or preventing a disease, disorder or condition caused by a papillomavirus infection.
  • the disease, disorder or condition caused by a papillomavirus infection is a papillomavirus-related cancer or precancer (dysplasia).
  • the disease, disorder or condition caused by a papillomavirus infection is papillomavirus-related cancer.
  • the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof.
  • the papillomavirus-related cancer is cervical cancer.
  • the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).
  • the papillomavirus-related cancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18).
  • the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).
  • the papillomavirus-related cancer is a papillomavirus-related cancer as defined above that is resveratrol resistant. Therefore, in some embodiments, the papillomavirus-related cancer is a resveratrol resistant cancer. Accordingly, in some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a resveratrol resistant cancer.
  • the disease, disorder or condition caused by a papillomavirus infection is selected from warts and laryngeal papilloma and combinations thereof.
  • the disease, disorder or condition caused by a papillomavirus infection is warts.
  • the warts are caused by one or more of HPV-1, HPV-2, HPV-3, HPV-4, HPV-6, HPV-8, HPV-11, HPV-27, HPV-29, and HPV-57.
  • the warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, periungual warts, anal warts and genital warts and combinations thereof.
  • the genital warts are selected from vaginal and anal warts and combinations thereof.
  • the warts are plantar warts.
  • the compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof treats or prevents a papillomavirus infection or treats or prevents a disease, disorder or condition caused by a papillomavirus infection by inhibiting papillomavirus replication.
  • one of X 1 and X 2 is OR 1 and the other of X 1 and X 2 is OH.
  • X 1 is OR x and and X 2 is OH.
  • R 1 has the following configuration: [0078] In some embodiments, X 1 and X 2 are both OH.
  • X 3 and X 4 are both OH. In some embodiments, X 3 and X 4 are both OCHj. In some embodiments, one of X 3 and X 4 is OH and the other of X 3 and X 4 is OCH3. In some embodiments, X 3 is OH and X 4 is OCH3.
  • the one or more compounds of Formula I are selected from one or more compounds listed below or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the methods and uses comprise administering to the subject, an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 0.5:1 to about 1:10, about 05:1 to about 1:8, about 05:1 to about 1:5, about 05:1 to about 1:4, about 05:1 to about 1:375, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1:1.
  • the methods and uses comprise administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin.
  • the Applicants have shown that the combinations of two or more compounds of Formula (I) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in further combination with a curcumin and a catechin have further improved activity and work synergistically against various cancer cell line. Accordingly, in some embodiments, the methods and uses comprise administering to the subject, an effective amount of two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12: 1-3: 15-35, or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the of the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1:20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 0.5: 1 to about 1 : 10, about 0.5: 1 to about 1 :8, about 0.5: 1 to about 1 :5, about 0.5: 1 to about 1 :4, about 0.5: 1 to about 1 :3.75, about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 :1 to about 1 :3.75, about 1: 1 to about 1:3, or about 1 : 1 to about 1 :2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 0.5: 1 to about 1 :3.75, about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 : 1 to about 1:3.75, about 1 : 1 to about 1 :3, about 1 :1 to about 1 :2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1 :8, about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1:2 or about 1 : 1.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 :1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 : 1.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the curcuminoid is tetrahydrocurcumin.
  • the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate, ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epi gallocatechin gallate.
  • the compound of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is selected from 1-1 (isorhaponti genin) and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the compound of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to 1-3 or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are further administered or used in molar ratio of about 1 :3.75 of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to I- 1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin, wherein the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are T-l (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-1 (
  • the Applicants have shown that pterostilbene has activity against resveratrol resistant cell lines. Accordingly, the present application includes method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application also includes a use of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for treating a resveratrol resistant cancer in a subject; a use of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for preparation of a medicament for treating or preventing a resveratrol resistant cancer in a subject; and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, for use to treat or prevent a resveratrol resistant cancer in a subject.
  • the resveratrol resistant cancer is a papillomavirus-related cancer or precancer (dysplasia). Therefore, in some embodiments, the methods and uses of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are for treating or preventing resveratrol resistant papillomavirus-related cancers or precancers. [0096] In some embodiments, the resveratrol resistant cancer is papillomavirus-related cancer.
  • the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof. In some embodiments, the papillomavirus-related cancer is cervical cancer.
  • the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).
  • the papillomavirus-related cancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18).
  • the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).
  • pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof treats or prevents resveratrol resistant papillomavirus-related cancer or precancer by inhibiting papillomavirus replication.
  • the methods and uses comprise administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with a curcuminoid and a catechin.
  • the curcuminoid, the catechin and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3 :15-35, or about 6-8:2- 3:20-30 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1-16: 1-4: 10-40, about 1-10: 1-3: 1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 6:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8:1 :25, about 4:1 :6, or about 8:2:25 of the curcuminoid to the catechin to the pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epigallocatechin gallate.
  • the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes method of treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering to the subject, an effective amount of pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, in combination with a curcuminoid and a catechin, wherein the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25 iii) Methods and uses of combinations of compounds of Formula I and pterostilbene
  • the present application also includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein
  • X 1 to X 4 are as defined above for Formula I. in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for treating or preventing a papillomavirus infection in a subject; a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for preparation of a medicament for treating or preventing a papillomavirus infection in a subject; and one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for use to treat or prevent a papillomavirus infection in a subject.
  • the papillomavirus infection is an infection of at least one papillomavirus.
  • the papillomavirus infection is a human papillomavirus (HPV) infection.
  • the HPV infection is an infection of one or more HPV genotypes selected from 1 (HPV-1), 2 (HPV-2), 3 (HPV-3), 4 (HPV-4), 5 (HPV-5), 6 (HPV-6), 8 (HPV-8), 11 (HPV-11), 16 (HPV- 16), 18 (HPV-18), 21 (HPV-21), 22 (HPV-22), 23 (HPV-23), 27 (HPV-27), 29 (HPV-29), 31 (HPV- 31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 57 (HPV-57) 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).
  • the HPV infection is an infection of one or more HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) In some embodiments, HPV genotypes selected from 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 cause cancer. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from HPV genotypes 16 and 18. In some embodiments, the HPV infection is an infection of HPV genotype 16. In some embodiments, the HPV infection is an infection of HPV genotype 18. In some embodiments, the HPV infection is an infection of one or more HPV genotypes selected from 1, 3, 27, 29, and 57.
  • HPV genotypes selected from 1, 3, 27, 29, or 57 cause common warts.
  • the HPV infection is an infection of one or more HPV genotypes selected from 1 , 2, 3, 4, 27, 29, and 57.
  • HPV genotypes selected from 1, 2, 3, 4, 27, 29, and 57 cause plantar warts such as deep palmoplantar warts.
  • the present application also includes a method of treating or preventing a disease, disorder or condition caused by a papillomavirus infection, comprising administering a therapeutically effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to a subject in need thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the present application also includes a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection, as well as a use of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for the preparation of a medicament for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection.
  • the application further includes one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof for use in treating or preventing a disease, disorder or condition caused by a papillomavirus infection.
  • the disease, disorder or condition caused by a papillomavirus infection is a papillomavirus-related cancer or precancer (dysplasia).
  • the disease, disorder or condition caused by a papillomavirus infection is papillomavirus-related cancer.
  • the papillomavirus-related cancer is selected from cervical cancer, anal cancer, oropharyngeal cancer, penile cancer, vaginal cancer, vulvar cancer, oral cancer and skin cancer, and combinations thereof.
  • the papillomavirus-related cancer is cervical cancer.
  • the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16), 18 (HPV-18), 31 (HPV-31), 33 (HPV-33), 35 (HPV-35), 39 (HPV-39), 45 (HPV-45), 51 (HPV-51), 52 (HPV-52), 56 (HPV-56), 58 (HPV-58), 59 (HPV-59) and 68 (HPV-68).
  • the papillomavirus-related cancer is a cancer caused by one or more HPV genotypes selected from 16 (HPV-16) and 18 (HPV-18).
  • the papillomavirus-related cancer is a cancer caused by one or both HPV genotypes 16 (HPV-16) and 18 (HPV-18). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 16 (HPV-16). In some embodiments, the papillomavirus-related cancer is a cancer caused by HPV genotype 18 (HPV-18).
  • the papillomavirus-related cancer is a papillomavirus-related cancer as defined above that is resveratrol resistant. Therefore, in some embodiments, the papillomavirus-related cancer is a resveratrol resistant cancer. Accordingly, in some embodiments, the disease, disorder or condition caused by a papillomavirus infection is a resveratrol resistant cancer.
  • the disease, disorder or condition caused by a papillomavirus infection is selected from warts and laryngeal papilloma and combinations thereof.
  • the disease, disorder or condition caused by a papillomavirus infection is warts.
  • the warts are caused by one or more of HPV-2, HPV-3, HPV-4, HPV-27, HPV-29, and HPV-57.
  • the warts are selected from common warts, flat warts, filiform warts, mosaic warts, plantar warts, periungual warts and genital warts and combinations thereof.
  • the genital warts are selected from vaginal and anal warts and combinations thereof.
  • the warts are plantar warts.
  • the compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof treats or prevents a papillomavirus infection or treats or prevents a disease, disorder or condition caused by a papillomavirus infection by inhibiting papillomavirus replication.
  • one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 8:1 to about 1 : 10, about 4: 1 to about 1 :10, about 2: 1 to about 1 : 10, about 8: 1 to about 1 :5, about 4: 1 to about 1 :5, about 2: 1 to about 1 :5, about 0.5:1 to about 1 : 10, about 0.5: 1 to about 1 :8, about 0.5: 1 to about 1 :5, about 0.5: 1 to about 1 :4, about 0.5: 1 to about 1:3.75, about 0.5:1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 :1 to about 1 :3.75, about 1 : 1 to about 1 :3, about 1 : 1 to about 1 :2.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 0 5: 1 to about 1 :3.75, about 0.5: 1 to about 1 :4, about 1 : 1 to about 1 :4, about 1 : 1 to about 1 :3.75, about 1 : 1 to about 1 :3, about 1 : 1 to about 1:2.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1 :8, about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 :5, about 1 :4, about 1 :3.75, about 1 :3, about 1 :2 or about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 :5 to about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 :5.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in molar ratio of about 1 :3 75 In some embodiments, the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and are administered or used in molar ratio of about 1 : 1.
  • the methods and uses comprise administering to the subject, an effective amount of one or more compounds of Formula I or a pharmaceutically acceptable salt, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in further combination with a curcuminoid and a catechin.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 1-16:0.25-4: 1-40, about 1-16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3 : 15-35, or about 6-8:2- 3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12: 1-3 : 15-35 or about 6-8:2-3:20- 30of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are administered or used in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemethoxy curcumin, tetrahydrobi sdem ethoxy curcumin, a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC) (-)- epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epigallocatechin gallate.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate
  • the molar ratio of 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 3.75: 1.
  • the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 :5 to about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 :5.
  • the molar ratio 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate
  • the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes a method of treating or preventing a papillomavirus infection in a subject in need thereof comprising administering to the subject, an effective amount of one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and further in combination with a in further combination with a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or
  • an effective amount, of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is an amount that, for example, reduces the papillomavirus infection compared to the papillomavirus infection without administration of the compound(s), or a salt, prodrug and/or solvate thereof.
  • telomere shortening By “reduces the papillomavirus infection”, it is meant, for example, a reduction in the amount of the viral load in the subject and/or a reduction in the symptoms of the infection.
  • reduced it is meant, for example, any detectable decrease or reduction in the amount of the papillomavirus in the presence of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof, compared to otherwise the same conditions except in the absence of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof.
  • Effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of the one or more given compound that will correspond to such an amount will vary depending upon various factors, such as the given drug or compound, the pharmaceutical formulation, the route of administration, the type of papillomavirus infection of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • the effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered or used as soon as possible after exposure or possible exposure to the papillomavirus.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered or used until treatment of the papillomavirus infection is achieved. For example, until complete elimination of the papillomavirus is achieved, or until the number of papillomavirus has been reduced to the point where the subject’s defenses are no longer overwhelmed and can kill any remaining viruses.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered or used as soon as possible before an expected exposure to the papillomavirus.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered at least once a week.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered to the subject from about one time per two weeks, three weeks or one month
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered about one time per week to about once daily.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered 2, 3, 4, 5 or 6 times daily.
  • the length of the treatment period depends on a variety of factors, such as the severity of the papillomavirus infection or the disease, disorder or conditions caused by the papillomavirus infection genotype, the age of the subject, the concentration and/or the activity of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof.
  • the effective dosage of a compound or compounds used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered to the subject in an amount and for duration sufficient to treat the subject.
  • the subject is a mammal. In another embodiment, the subject is human. In an embodiment, the subject is a non-human animal. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary papillomavirus infections or diseases, disorders or conditions caused by a papillomavirus infection.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are either used or administered alone or in combination with other known agents useful for treating a papillomavirus infection or one or more diseases, disorders or conditions caused by a papillomavirus infection as described herein.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are used or administered contemporaneously with those agents or therapies.
  • “contemporaneous administration” or “contemporaneous use” of compounds, agents or therapies to a subject means providing at least two of the compounds, agents and therapies so that they are biologically active in the individual at the same time.
  • the exact details of the administration or use will depend on the pharmacokinetics of the compounds, agents or therapies in the presence of each other, and can include administering or using the compounds, agents or therapies within a few hours of each other, or even administering or using one compound, agent or therapy within 24 hours of administration or use of other(s), if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art.
  • the compounds, agents or therapies will be administered or used substantially simultaneously, i.e., within minutes of each other, or in a single composition in the case of administration or use of two or more compounds or agents. It is a further embodiment of the present application that a combination of compounds, agents or therapies is administered to a subject or used in a non-contemporaneous fashion.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered or used orally
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof is/are administered or used parenterally.
  • the parenteral administration is topical administration.
  • the dosage of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof can vary depending on many factors such as the pharmacodynamic properties of the compound(s), the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound(s) in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage(s) based on the above factors.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of compound(s) from about 0.01 pg/cc to about 1000 pg/cc, or about 0.1 pg/cc to about 100 pg/cc.
  • oral dosages of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg per day.
  • a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg will be administered or used.
  • a representative amount is from about 0 001 mg/kg to about 10 mg/kg or about 0 1 mg/kg to about 10 mg/kg
  • a representative amount is from about 0.1 mg/kg to about 10 mg/kg.
  • compositions are formulated for oral administration or use and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof may be administered or used in a single daily, weekly or monthly dose or the total daily dose may be divided into two, three, four, five or six daily doses.
  • the pharmaceutically acceptable salt is an acid addition salt or a base addition salt.
  • a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et ai., "Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19).
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic acid addition salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids.
  • organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non- pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any nontoxic organic or inorganic base addition salt of any acidic compound.
  • Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropyl amine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • organic amines such as isopropyl amine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2- diethylaminoethanol,
  • Exemplary organic bases are isopropylamine, diethyl amine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Solvates of the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof or the pterostilbene, or a salt, prodrug and/or solvate thereof include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, or the pterostilbene, or a salt, prodrug and/or solvate thereof may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, or the pterostilbene, or a salt, prodrug and/or solvate thereof may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application.
  • the compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, and/or the pterostilbene, or a salt, prodrug and/or solvate thereof are in the form of a pharmaceutically acceptable solvate.
  • the compound of one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, and/or the pterostilbene, or a salt, prodrug and/or solvate thereof are a neutral form (i .e. not a salt).
  • compositions of the Application i Compositions comprising compounds of Formula I
  • the compounds of Formula I are suitably formulated in a conventional manner into compositions using optionally one or more carriers.
  • the present application also includes a composition comprising one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, wherein
  • X 1 to X 4 are as defined above for Formula I in the “Methods and Use of the Application”.
  • the composition further comprises a carrier.
  • the compound of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, wherein
  • X 1 to X 4 are as defined above for Formula I in the “Methods and Use of the Application”.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the composition comprises two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the composition comprises two compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the composition when the composition comprises two compounds, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 05:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, or about 1:1 to about 1:2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1. In some embodiments, the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in molar ratio of about 1 : 1.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10:1- 3: 1-30, about 4-12: 1-3: 15-35, or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 16: 1-4: 10-40, about 1-10: 1-3:1-30, about 4-12: 1-3: 15- 35 or about 6-8:2-3 :20-30 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 16:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more, suitably two or more, compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemeth oxy curcumin, tetrahydrobisdemethoxycurcumin, or a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC), epigallocatechin (EGC), (-)-epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)-gallogallate ((+)- GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epigallocatechin gallate.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is selected from 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin
  • the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes a pharmaceutical composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, the curcuminoid is curcumin the catechin is (-)-epigallocatechin gallate and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the two compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof,
  • the two or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more, suitably two or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier.
  • the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and optionally a curcuminoid and a catechin and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition ii) Compositions of compounds of Pterostilbene
  • Pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is suitably formulated in a conventional manner into compositions using optionally one or more carriers.
  • Pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.
  • the present application also includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, [00156]
  • the pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is present in an amount that is effective to treat or prevent a resveratrol resistant cancer in a subject.
  • the present application includes a method for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising administering one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, to the subject.
  • the present application also includes a use of one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin for treating or preventing a resveratrol resistant cancer in a subject in need thereof.
  • the present application also includes a use of one or more compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin for preparing a medicament for treating or preventing a resveratrol resistant cancer in a subject in need thereof.
  • compositions comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin for use to treat or prevent a resveratrol resistant cancer in a subject in need thereof.
  • the resveratrol resistant cancer is as defined in the “Methods and Uses of compounds of Pterostilbene”.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3 : 15-35, or about 6-8:2-3:20-3 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1-16:1-4: 10-40, about 1-10: 1-3: 1-30, about 4-12: 1-3: 15-35 or about 6-8:2-3:20-30 of the curcuminoid to the
  • the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 16:2:25, about 8:4:25, about 4:1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bisdem ethoxy curcumin, tetrahydrobisdemethoxycurcumin or a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the catechin is selected from epicatechin gallate (ECG), epigallocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC), (-)- epi gall ocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epigallocatechin gallate.
  • the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes a pharmaceutical composition for treating or preventing a resveratrol resistant cancer in a subject in need thereof comprising an effective amount of pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and a catechin, wherein the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate, and the molar ratio of curcumin to (-)-epigallocatechin gallate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25
  • the pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier.
  • the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and optionally a catechin and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition.
  • the present application also includes a composition comprising one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof wherein
  • X 1 to X 4 are as defined above for Formula I in the “Methods and Use of the Application”, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof,
  • the composition further comprises a carrier.
  • the present application also includes a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compound of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, wherein
  • X 1 to X 4 are as defined above for Formula I in the “Methods and Use of the Application”, in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof,
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 8:1 to about 1:10, about 4:1 to about 1:10, about 2:1 to about 1:10, about 8:1 to about 1:5, about 4:1 to about 1:5, about 2:1 to about 1:5, about 0.5:1 to about 1:10, about 0.5:1 to about 1:8, about 0.5:1 to about 1:5, about 0.5:1 to about 1:4, about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 0.5:1 to about 1:3.75, about 0.5:1 to about 1:4, about 1:1 to about 1:4, about 1:1 to about 1:3.75, about 1:1 to about 1:3, about 1:1 to about 1:2.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1:8, about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1:5, about 1:4, about 1:3.75, about 1:3, about 1:2 or about 1:1.
  • the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in molar ratio of about 1:5 to about 1 : 1.
  • the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in molar ratio of about 1 :5.
  • one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1 :3.75.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1 : 1.
  • the composition further comprises a curcuminoid and a catechin.
  • Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1-16:0.25-4:1-40, about 1-16: 1-4:10-40, about 1-10: 1-3 :1-30, about 4-12: 1-3 : 15-35, or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 1-16: 1-4: 10-40, about 1-10: 1-3 : 1-30, about 4-12:1-3:15-35 or about 6-8:2-3:20-30 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 6:2:25, about 8:4:25, about 4: 1 :20, about 4:2:25, about 8: 1 :25, about 4: 1 :6, or about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid, the catechin and the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are present in the composition in a molar ratio of about 8:2:25 of the curcuminoid to the catechin to the one or more compounds of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is selected from curcumin (diferuloylmethane), tetrahydrocurcumin, demethoxycurcumin, tetrahydrodemethoxycurcumin, bi sdemethoxy curcumin, tetrahydrobisdemethoxycurcumin or a curcumin ester and combinations thereof.
  • the curcuminoid is curcumin.
  • the catechin is selected from epicatechin gallate (ECG), epi gall ocatechin gallate (EGCG or EGCg), epicatechin (EC) and epigallocatechin (EGC), (-)- epigallocatechin gallate ((-)-EGCG), (-)-epicatechin gallate ((-)-ECG), (-)-epigallocatechin ((-)-EGC), (+)- gallogallate ((+)-GCG), (-)-epicatechin ((-)-EC), (+) gallocatechin ((+)-GC) and (+)-catechin ((+)-C).
  • the catechin is (-)-epigallocatechin gallate
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are selected from 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate and 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate
  • the curcuminoid is curcumin
  • the catechin is (- )-epigallocatechin gallate
  • the molar ratio 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 3.75:1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin
  • the catechin is (-)-epigallocatechin gallate.
  • the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-1 (isorhapontigenin) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate.
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1:5 to about 1 : 1.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof.
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate.
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 :5.
  • the molar ratio of 1-3 (piceatannol) to pterostilbene or a pharmaceutically acceptable salt, prodmg and/or solvate thereof is about 1 : 1 In some embodiments, the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)- epigallocatechin gallate
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 :5 to about 1 :1 and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 :5 and the molar ratio of curcumin to (-)- epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof
  • the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate
  • the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 : 1 and the molar ratio of curcumin to (-)-epigallocatechin gallate to 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 8:2:25.
  • the present application includes a pharmaceutical composition comprising one or more compound of Formula I or a pharmaceutically acceptable salt, prodrug and/or solvate thereof in combination with pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and in further combination with a curcuminoid and a catechin, wherein the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, the curcuminoid is curcumin and the catechin is (-)-epigallocatechin gallate; and the molar ratio of 1-3 (piceatannol) or a pharmaceutically acceptable salt, prodrug and/or solvate thereof to pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof is about 1 : 1 or about 1 :5 and the molar ratio of curcum
  • the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and/or pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof are suitably used on its own but will generally be administered in the form of a composition in association with an acceptable carrier.
  • the composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and/or pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally a curcuminoid and a catechin and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of an acceptable carrier, all percentages by weight being based on the total composition.
  • the pharmaceutical compositions of the application are used in the treatment of any of the diseases, disorders or conditions described herein. [00180] Therefore, the present application further includes a method or use for treating or preventing a papillomavirus infection or for treatment or prevention of a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer by administering or using a composition of the application.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof, optionally the curcuminoid and the catechin are administered to a subject or used in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • administration may be by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • administration is by means of a pump for periodic or continuous delivery.
  • Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • a composition is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet.
  • an excipient is incorporated and a composition is in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, oral rinse, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like.
  • carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid.
  • Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • the tablets are coated by methods well known in the art.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations
  • modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • SR sustained-release
  • ER extended-release
  • CR controlled-release
  • Contin continuous-release
  • Timed-release compositions are formulated, for example as liposomes or those wherein active compound(s) is/are protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers or diluents include lactose and dried com starch
  • liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use.
  • aqueous suspensions and/or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents are added.
  • Such liquid preparations for oral administration are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); nonaqueous vehicles (e.g , almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p- hydroxybenzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • nonaqueous vehicles e.g , almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p- hydroxybenzoates or sorbic acid.
  • Useful diluents include lactose and high mo
  • administration is parenterally.
  • solutions are prepared in water suitably mixed with a surfactant such as pegylated oils, polysorbates and sorbitan esters.
  • dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • suitable formulations For parenteral administration, sterile solutions are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.
  • ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers.
  • such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers.
  • diluents or earners will be selected to be appropriate to allow the formation of an aerosol.
  • compositions are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with or without an added preservative
  • the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the compositions are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • Methods of sterilization are well known in the art, and include, for example, terminal sterilization via autoclave or irradiation, or sterilization via filtration such as aseptic filtration.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • the compositions are conveniently delivered by irrigation such as with a nasal irrigation device.
  • the compositions are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device.
  • the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer contains a solution or suspension of the active compound(s).
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of active compound(s) and a suitable powder base such as lactose or starch.
  • the aerosol dosage forms can also take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine is used.
  • Compositions suitable for buccal or sublingual administration include sublingual solutions or sublingual suspensions, wherein a carrier, for example, water is used.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter
  • Suppository forms are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature.
  • the substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter); glycerinated gelatin; other glycerides including stearoyl polyoxyl-32 glycerides and glyceryl dibehenate; hydrogenated vegetable oils; mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol including PEG-8 distearate; and phosphatidylcholine.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof, or combinations thereof, optionally the curcuminoid and the catechin, are coupled with soluble polymers as targetable drug carriers.
  • Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the polymers belong to a class of biodegradable polymers useful in achieving controlled release of a compound, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycy anoacryl tes and crosslinked or amphipathic block copolymers of hydrogels.
  • Administration may also be accomplished using nano-carrier systems, such as liposomes, micelles, nanoparticles, nano-emulsions, lipidic nano-systems and the like (see for example, Bhat, M. et al. Chem. and Phys, of Lipids, 2021, 236, 105053).
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof optionally the curcuminoid and the catechin may be coupled with viral, non-viral or other vectors.
  • Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses
  • Non- viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres.
  • Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers
  • compositions of the application are formulated as a suppository, a cream, gel, foam, spray, film, sponge, tablet, capsule, emulsion, solution, lotion, nanofiber, suspension, particles, nanoparticles, a bio-adhesive, or an oral rinse
  • compositions of the application are formulated as a cream.
  • the cream comprises about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% or of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and a curcuminoid and a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% acceptable carrier, all percentages by weight being based on the total composition.
  • the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, and the curcuminoid and the catechin.
  • the cream will comprise from about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof, a curcuminoid and optionally a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% of an acceptable carrier, all percentages by weight being based on the total composition.
  • the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of the pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally the curcuminoid and the catechin.
  • the cream will comprise from about 10 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt% or about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and/or pterostilbene or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally a curcuminoid and a catechin and from about 90 wt% to about 70 wt%, about 85 wt% to about 75 wt%, about 85 wt% to about 80 wt% or about 80 wt% acceptable carrier, all percentages by weight being based on the total composition.
  • the cream comprises about 15 wt% to about 20 wt% of the one or more compounds of Formula I, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and/or pterostilbene, or a pharmaceutically acceptable salt, prodrug and/or solvate thereof and optionally the curcuminoid and the catechin,
  • the acceptable carrier is selected from PluronicTM, lecithin, organogel, Lipoderm®, Vanpen®, Aladerm®, Perme8, Ellage®, VersaBas®e Cream, VersaBase® Lotion, VersaBase® Gel, VersaBase® Anhydrous HRT, XemaTop®, Mucolo and anhydrous gels
  • the acceptable carrier is Ellage®
  • a device comprising a composition of the application is placed into the oral cavity or anal cavity as a pellet, tablet, capsule, foam, or fdm.
  • compositions of the application are formulated to be attached to, incorporated into, or covering a vaginal device or a device that is inserted into oral or anal cavity, or placed in contact with the skin.
  • the vaginal device is a tampon, tampon-like device, ring, pessary, tablet, capsule or pellet, sponge, foam, or female condom.
  • compositions of the application are formulated to be attached to, incorporated into, coated onto, or imbedded into a condom.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, and/or pterostilbene, or a salt, prodrug and/or solvate thereof, and optionally the curcuminoid and the catechin are administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present application provides a single unit dosage form comprising the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, and/or pterostilbene, or a salt, prodrug and/or solvate thereof, and optionally the curcuminoid and the catechin, along with an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the one or more compounds of Formula I, or a salt, prodrug and/or solvate thereof, the pterostilbene, or a salt, prodrug and/or solvate thereof optionally the curcuminoid and the catechin may be used alone to treat or prevent a papillomavirus infections or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer in combination with another known agent useful for treating or preventing a papillomavirus infection or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer.
  • Another known agent useful for treating or preventing to treat or prevent a papillomavirus infection or a disease, disorder or condition caused by a papillomavirus infection including a resveratrol resistant cancer are administered or used according to treatment protocol that is known the other known agents.
  • compounds of Formula I and pterostilbene are available from commercial sources, for example isorhaponti genin, rhapontigenin, piceatannol, pterostilbene, rhaponticin, and astringin are available from available from Millipore Sigma Aldrich (Burlington, Massachusetts, United States, USA).
  • a pharmaceutical composition selected from the group consisting of:
  • a pharmaceutical composition selected from the group consisting of: tetrahydrocurcumin, (-)-epigallocatechin gallate and pinostilbene at a molar ratio of 4: 1 : 12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate and pterostilbene at a molar ratio of 4:1:12.5; tetrahydrocurcumin, (-)-epigallocatechin gallate, piceatannol and pterostilbene at a molar ratio of
  • Hela cells were cultured in DMEM medium containing 10% FBS, lOO U/ml penicillin and 100 pg/ml streptomycin at a 37°C humidified incubator and an atmosphere of 5% CO2 (vol/vol) in a T75 flask.
  • the semi-confluent cells were trypsinized, pelled down, resuspended in the DMEM medium. After cell counting were done, about 4000 cells were seeded in each well of the 96 well plates and cultured overnight in the above condition.
  • Each well received 1% of ITS in DMEM.
  • the medium was replaced in each well with 200 pL of the corresponding drug solution. Each dilution was tested in 6 wells.
  • the cells were treated with the drugs for 72 h in a cell culture incubator.
  • Table 2 shows the dose-response effects of from the MTT assay for each of the identified natural diphenyl ethylene compounds in authenticated HPV-18 (+) HeLa cells.
  • the next most potent natural diphenylethylene compound identified in the drug screen of Rheum rhaponticum L. and Rheum rhabarbarum species was desoxyrhapontigenin (also called 4'-O-Methylresveratrol). This compound was found to have an IC50 of about 38.32 pM.
  • resveratrol The polyphenol, trans-3, 5, 4'-trihydroxy stilbene (resveratrol), is known to have anti-human papillomavirus (HPV) effects.
  • HPV anti-human papillomavirus
  • cancer cells become resistant to resveratrol, and this is one main reason for the limited clinical efficacy with resveratrol-based drugs (Colin D.J. et al., Cell Death Dis. 2014 Nov 20;5(l l):el533).
  • a resveratrol -resistant cell line was developed from the HPV- 18 (+) cervical cancer cell line HeLa. This mutated cell line was named HeLa-GSl and was found to demonstrate considerable resistance to resveratrol.
  • Authenticated original HeLa cells were obtained from American Type Culture Collection (Manassas, Virginia, USA) and used to generate Table 1 results.
  • HeLa-GSl cells were developed by having the parent cell line passage over long periods of time in cells incubated in the presence of resveratrol.
  • the IC50 of resveratrol in original HeLa cells on repeat experiments ranged from 7-1 1 pM, with an average IC50 value of 7.9189 pM.
  • the IC50 of resveratrol in HeLa-GSl cells ranged from > 80 pM to complete resistance, with the average IC50 of 11 1 .251 pM.
  • the four most active identified compounds from Example 1 and resveratrol were evaluated in the resveratrol -resistant cell line, HeLa-GSl .
  • Table 3 shows the dose-response results of the identified diphenylethylene compounds using an MTT assay in the resveratrol-resistant cells line, HeLa-GSl .
  • pterostilbene was found to be five times more potent than isorhapontigenin and about three times more potent than piceatannol
  • resveratrol-treated cells demonstrated overt resistance, with > 90% of HeLa-GSl cells viable at the highest dose tested (50 pM), confirming the unique properties of identified compounds that have not been reported in any prior art in HPV-infected cells.
  • resveratrol Like many plant polyphenols, resveratrol modulates a diverse number of cellular pathways. It was previously shown (Einbond et al. 2021, Br J Cancer. 2021 Mar;124(5):901-913) that resveratrol eliminates several HPV (+) cell lines, in cancerous and precancerous tissue. Prior to cell death, resveratrol upregulated pro-apoptotic gene, and affected cell cycle regulators like p53. Moreover, the compound suppressed the HPV viral transcripts E6 & E7, which induces malignant transformation and maintains cancer cell growth. Meanwhile, trans-stilbene, which is identical to resveratrol except lacking any functional groups, was not cytotoxic to HPV (+) cancer cells even at very high doses.
  • Table 4 Effects of isorhapontigenin, rhapontigenin & trans-resveratrol in HPV 16 positive CaSki cells
  • Table 5 Effects of piceatannol & pterostilbene in HPV 16 positive CaSki cells
  • the cytotoxicity results for the identified compounds in the HPV-16 (+) cancer cell line, SiHa parallel the values observed with CaSki cells.
  • the IC50 for rhapontigenin was 130.39pM, again this compound was not effective in another HPV-16 positive cell line, it was about ten times less potent than resveratrol. Examples 1-4 above show that different diphenylethylene compounds can cause differing anti-papillomavirus (e.g anti -HP V) effects.
  • Table 7 provides a summary of the testing results of examples 1 to 3.
  • resveratrol and some of the natural diphenylethylene compounds are phytoalexin compounds, used by plants to fend off microbial disease in a polyclonal manner (with multiple compounds). Accordingly, drug combinations were examined.
  • IC50 values of the compounds were as follows: pterostilbene (8pM), isorhapontigenin (30 pM), piceatannol (8pM). Table 9 shows the IC50 of these initial pair mixtures in Hela cells. Table 8: Exemplary concentrations of 1: 1 molar mixtures of isorhapontigenin and piceatannol
  • Table 9 shows that piceatannol plus pterostilbene at a molar ratio of 1 : 1 ratio was the most potent pair combination demonstrating an ICso of 4.308.
  • Table 10 shows the IC>o values for piceatannol, and pterostilbene as individual drugs against Hele cells, while Table 1 1 shows the IC50 values for the combination of piceatannol to pterostilbene at various ratios in Hela cells.
  • **Total drug is the pM amount of pice+ptero used to achieve the IC50 effect at a specific drug pair ratio.
  • Combination compositions comprising exemplary compounds of Formula I and/or pterostilbene, a curcumin and a catechin
  • Plant polyphenols such as resveratrol, modulate a diverse number of cellular pathways.
  • the polyphenol, trans-3,5,4'-trihydroxystilbene (resveratrol) is known to have anti-human papillomavirus (HPV) effects
  • HPV anti-human papillomavirus
  • a pharmaceutical mixture of curcumin (32 pM), epicatechin gallate (8 pM) & resveratrol (100 pM) was found to be synergistic in eliminating HPV (+) cancer cell lines (Mukherjee et al., 2017 Oncotarget. 2017 Mar 29;8(37); WO 2015/081319; US 2016/0287533, Einbond et al. 2021, Br J Cancer.
  • exemplary compound piceatannol in combination with pterostilbene at a molar ratio of 1: 1 had an IC50 of 1.0373 uM, which was 7-9 times more potent than piceatannol or pterostilbene individually.
  • Table 12 shows the IC50 values of exemplary compound piceatannol, or pterostilbene in combination with curcumin and (-)-EGCG, named T-Pice & T-Ptero respectively. Also shown are the IC50 values of exemplary compound piceatannol in combination with exemplary compound pterostilbene in a molar ratio of 1 : 1 and a molar ratio 1 :5 and in further combination with curcumin and (-)-EGCG, T- Pice:Ptero (1 : 1) and T-Pice:Ptero (1 :5) respectively. The combination of piceatannol and pterostilbene was found to act synergically in Example 4.
  • Table 12 shows all 4 tested combinations and the doses at which they were tested. All the combinations had equal amounts of curcumin, EGCG, and an equal amount of the diphenyl ethylene component in the combinations. These 4 combinations were tested in HPV-positive cell lines, CasKi, HeLa, and in the resveratrol-resistant cell line, HeLa-GSl . The data in Table 12 shows all 4 mixtures had strong efficacy against these HPV cell lines.
  • All formulations comprise curcumin and (-)-EGCg ((-)-epigallocatechin gallate) at a molar ratio of 8:2.
  • T-Pice curcumin (8 pM) + (-)-EGCg (2 pM) + pice (25 pM)
  • T-Ptero curcumin (8 pM) + (-)-EGCg (2 pM) + ptero (25 pM)
  • T-Pice:Ptero (1 :1) curcumin (8 pM) + (-)-EGCg (2 pM) + pice (12.5 pM) + ptero (12.5 pM)
  • T-Pice:Ptero (1:5) curcumin (8 pM) + (-)EGCg (2 pM) + pice (4.2 pM)+ptero (20.8 pM) [00239] All mixture ratios had equal amounts of diphenylethylene compounds used for comparisons. As a control, curcumin and (-)-EGCg were evaluated individually in HPV-18 positive HeLa cells (Table 13) and HeLa-GSl cell lines (Table 13)
  • Table 14 shows the combination index for each of the four mixtures at the drug IC50, IC75, IC90 and IC95.
  • T-l 1 : (Curc+Epi+Pice+Ptero [32:8:50:50])
  • the data in Table 14 shows that not all the mixtures are optimal over the entire dose-range tested. Some mixtures have a CI value > 1, indicating that that mixture is not effective as a drug combination at that ratio and dose effect. However, the data shows that the mixture T-l : 1 which is piceatannol and pterostilbene at a 1 : 1 molar ratio, plus curcumin and (-)-EGCg is a highly potent combination which is synergistic at the highest doses and additive at the IC50. Mixtures in Table 14 are derived through combinatorial testing, and effects are validated by experimentation.
  • Table 15 and Table 16 shows the full statistical output of the data in Table 14 which is a summary of the CI values for each mixture.
  • Curcumin (or diferuloylmethane) is a yellow crystalline compound isolated from turmeric (Curcuma longa L., Zingiberaceae) and is the main curcuminoid present in turmeric. Additionally, this medicinal root contains demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids are natural phenols that can exist in at least two tautomeric forms, keto and enol. Tetrahydrocurcumin, a metabolite of curcumin, is a reduced form of the compound Curcumin contains an a, f>- unsaturated carbonyl group, while tetrahydrocurcumin lacks a,P-dienes. Similarly, demethoxycurcumin and bisdemethoxycurcumin can be reduced to form tetrahydrodemethoxy curcumin and tetrahydrobisdemethoxycurcumin.
  • curcumin is 500% more potent than reduced curcumin (tetrahydrocurcumin) against these HPV (+) cancer cells.
  • curcumin was more effective than tetrahydrocurcumin by 200% (Table 18).
  • combinations with tetrahydrocurcumin were superior and more effective compared to mixtures with natural curcumin.
  • T-l :5 contains the following: curcumin (32 pM), EGCG (8 pM), piceatannol (16.67 pM), and pterostilbene (83.33 pM). This was compared to an equal amount of the mixture containing the reduced form of curcumin: tetrahydrocurcumin (32 pM), EGCG (8 pM), piceatannol (16.67 pM), and pterostilbene (83.33 pM). This combination was designated TW-1:5. In vitro testing was conducted in HeLa cells at various concentrations as described in Table 19.
  • TW-E5 The IC50 of TW-E5 was observed to be 1.2395 pM, while the mixture with curcumin, T-l :5, had an IC50 of 2.4196 pM.
  • the diphenylethylene mixture of the invention using tetrahydrocurcumin was 100% more potent.
  • TW-1:5 tetrahydrocurcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM)
  • T-l:5 curcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM)
  • MmuPVl The mus musculus papillomavirus 1 (MmuPVl) mouse model is known in the art to be a crucial tool in papillomavirus research. MmuPVl infects laboratory mice, making it the first rodent papillomavirus capable of such infection, thus offering the opportunity to study papillomavirus biology and pathogenesis. MmuPVl can infect both cutaneous and mucosal (oral and genital) tissues of mice, closely mimicking human papillomavirus (HPV) infections. This model is unique and allows for viral host examination, as well as preclinical assessment of drugs for antiviral efficacy.
  • HPV human papillomavirus
  • the MmPV/mouse model was used to evaluate diphenylethylene mixtures to see if they had in vivo activity against mouse vaginal papillomas.
  • the study aimed to assess the ability to deliver drug intravaginally and determine if antiviral effects could be seen against MmuPV-1 Parameters used to assess an anti-viral effect included: 1) MmuPVl viral DNA copy number in vaginal and anal swabs, 2) Histological assessment of papillomas for virological assessments upon the termination of the study. Experimental methods have been previously detailed. In brief, NU/J heterozygous mice with the Foxnl nu/+ genotype were used.
  • mice were subcutaneously injected with 3 mg of progesterone in the form of Depo-Provera, diluted in 100 microliters of PBS. Three days post-injection, the mice were sedated, and Doctors' Brush Picks were gently rotated 15 times in the vaginal canals to create minor abrasions. After twenty-four hours, the mice were anesthetized again, and 25 pl of a sterilized viral suspension was pipetted into their vaginal canals.
  • mice in Groups A-E were inoculated with MmuPV-1 at vaginal and anal sites.
  • All mice received 25 pl of a formulated compounds into the vaginal canal using a soft plastic pipette tip, with treatments administered five times per week for up to five weeks.
  • the study included five groups (A-E), with one placebo group as a control to assess local treatment effects. Vaginal lavages were performed every Monday to determine viral copy numbers (weeks 3 and 4), which were then analyzed to calculate viral DNA titers.
  • TW-Pinsotilbcnc tetrahydrocurcumin (32 pM ) + EGCG (8 M ) + Pinostilbcnc(100 pM)
  • T-Pinsotilbene curcumin (32 pM ) + EGCG (8 pM ) + Pinostilbene(100 pM)
  • T-Pterostilbene curcumin (32 pM ) + EGCG (8 pM ) + Pinostilbene(100 pM) Table 21 . Change in Q-PCR signal from week 3 to week 4
  • vaginal lavage viral loads were measured to assess the acute effects of drugs and the feasibility of intravaginal delivery.
  • a positive effect on viral load changes between weeks 3 and 4 was noted (Table 20).
  • Short-term drug exposure reduced the rate of viral replication in Groups A. C, and the positive control group compared to vehicle-treated mice.
  • the Cottontail Rabbit Papillomavirus (CRPV) model established in the 1930s, is considered a gold standard for studying human papillomavirus (HPV) pathogenesis and testing anti-HPV treatments.
  • HPV human papillomavirus
  • This model closely mimics human HPV infections and disease progression, including the development of papillomas and cancers. It has been pivotal in developing and testing both prophylactic and therapeutic HPV vaccines by providing insights into immune responses and vaccine efficacy.
  • CRPV infections in rabbits recapitulates human HPV infections, making it possible to studying viral pathogenesis and therapeutic in ten entions.
  • the experimental plan was based on previously published protocols. Twenty- five adult New Zealand White rabbits of both sexes were purchased from Inotiv and quarantined for 14 days. On Day 0, each rabbit was inoculated with 5 pg/site of wild type (wt-CRPV) DNA at two sites and 25 pl/site of a mutant virus (mE8-CRPV) at two other sites. From Day 10, rabbits in the LI and L2 groups received drug treatments, while R-sites (R1 and R2) were left untreated as internal controls for papilloma growth. Topical treatments began on Day 10, administered five times weekly (Monday through Friday, twice daily) to the left-side papillomas only.
  • wt-CRPV wild type
  • mE8-CRPV mutant virus
  • Papillomas were measured weekly in three axes (length x width x height) in mm. Data was entered into a spreadsheet, and calculations were conducted to determine the geometric mean diameter of each papilloma, mean ⁇ SEM for each group, and Student’s t-test between each paired group. Plots were made of papilloma size vs. time, and weight changes were also plotted. Skin/papilloma sites were monitored photographically, a summary of mixtures and treatment groups are in Tables 22 and 23. Compositions are as follows:
  • TW-SD1 tetrahydrocurcumin (32 pM) + EGCG (8 pM) + Pinostilbene (100 pM)
  • TW-L 1 tetrahydrocurcumin (32 pM ) + EGCG (8 pM ) + Piceatannol (50 pM) +Pterostilbene (50 pM)
  • TW-L5 tetrahydrocurcumin (32 pM) + EGCG (8 pM) + Piceatannol (16.67 pM) +Pterostilbene (83.33 pM)
  • This mixture contained a resveratrol derivative called trans inostilbene, (3,4'-dihydroxy-5-methoxystilbene), a mono methoxy derivative of resveratrol shown to have activity during standardizations.
  • This compound did not completely suppress the papillomas during treatment like Groups B-E, confirming not all resveratrol derivatives have equal efficacy.
  • Group B which has one of the potent diphenylethylene compounds identified (TW-Pterostilbene), when used in equal amounts in our cream performed better than TW-Pinostilbene in suppressing the size of the wild-type and mutant CRPV papillomas at the end of 11 weeks following study.
  • Group D (TW-L5) demonstrated a significant reduction in papilloma size in treated groups, with a drug-induced reduction of 82% for wild-type CRPV and 81.9% for mutant CRPV at end of 10 weeks.
  • Lead #2 (TW-Ll) showed the most substantial reduction, with a drug-induced reduction of 92% for wild-type CRPV and 85.7% for mutant CRPV at 10 weeks.
  • Lead #2 (TW-L l) proved to be the most effective treatment in reducing papilloma size, followed by Lead #1 (TW-L5), with the positive control (T-SD1) being the least effective among the three.
  • the positive control group (Group E). which received T-SDl(Pinostilbene), showed no cures in both wild-type and mutant CRPV warts (Table 23) . with 0 out of 5 rabbits cured (0%) in each category.
  • Group D treated with TW-L5 (containing Piceatannol & Pterostilbene at a molar ratio of 1 :5) demonstrated a cure rate of 40% for wild-type CRPV warts, curing 2 out of 5 rabbits, and a 60% cure rate for mutant CRPV warts, curing 3 out of 5 rabbits.
  • the formulation comprises by percentage of weight:
  • the pharmaceutically acceptable carrier is:
  • PEG-32 Stearate 10.0000% from about 1% to about 20%
  • Soy Acid 0.0500% 0.05% to 0.5%
  • Poloxamer 407 2.0000% from about 1% to about 25%
  • the above the pharmaceutically acceptable carrier is an anhydrous, self-emulsifying ointment composition that enhances the delivery and stability of the active pharmaceutical ingredients.
  • the formulation improved contact time and adherence within the vaginal environment, formed micelles upon contact with vaginal moisture, and mitigated the risk of hydrolysis and oxidation of the active pharmaceutical ingredients, thereby enhancing drug stability- and efficacy.
  • Carrier A An aqueous penetration enhancing gel-cream composition that enhances the transdermal and transmucosal delivery of the active pharmaceutical ingredients the active pharmaceutical ingredients .
  • the composition comprises lecithin, poloxamer 407, isopropyl myristate and propylene glycol. This formulation has good adhesion to mucosal surfaces, has gel and cream like aesthetics and improves delivery' of a variety of APIs.
  • Carrier B A topical, cosmetically elegant, penetration enhancing oil in water (O/W) emulsion that improves the delivery of active pharmaceutical ingredients the active pharmaceutical ingredients through intact human and animal skin.
  • the composition comprises phosphatidylcholine, isopropyl myristate, cetearyl alcohol and ceteareth-20 as key ingredients to create the permeation enhancement as well as polyacry lamide and dimethicone to improve cosmetic elegance.
  • Carrier C A Topical or Vaginal Penetration Enhancing O/W Emulsion (Cream) that improves the delivery of active pharmaceutical ingredients the active pharmaceutical ingredients into and through human and animal skin or vaginal tissue.
  • the composition comprises lecithin, urea, isopropyl palmitate, isopropyl myristate, glyceryl stearate, PEG-40 stearate as key ingredients to improve permeation of APIs.
  • Carrier D A topical water in oil (W/O) Emulsion (Cream), with high moisturizing properties for superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients .
  • This heavier cream forms a moisturizing barrier over the skin and releases actives on the skin’s surface.
  • the composition comprises petrolatum, urea, stearyl alcohol, lanolin alcohol, PEG-40 stearate and mineral oil as key ingredients to form the thick emulsion with good barrier formation.
  • Carrier E An anhydrous (low water activity ) permeation enhancing topical ointment, with superior cosmetic elegance (silky feel) and excellent spreadability.
  • the composition comprises phosphatidylcholine, PEG- 16 macadamia glycerides, PEG-8 caprylic/capric glycerides as key ingredients for delivery, in a carrier of dimethicone and caprylyl methicone, with poly silicone- 11 and PEG-12 dimethicone/PPG-20 crosspolymer to provide viscosity and a cosmetically elegant feel.
  • Carrier F An anhydrous (low water activity) self-emulsifying vaginal cream with good mucoadhesion, designed to deposit active pharmaceutical ingredients the active pharmaceutical ingredients onto the surface of the vaginal mucosa.
  • the composition comprises PEG-32 stearate, glyceryl stearate, poloxamer 407 and glyceryl ricinoleate as key ingredients in a carrier of medium chain triglyceride oil.
  • the formulation has a gel-cream like aesthetic and an attribute of low-leakage from the vagina once instilled.
  • Carrier G A topical oil in water (O/W) non-ionic lamellar emulsion (Cream) for superficial delivery of active pharmaceutical ingredients, with a soft/smooth cosmetically elegant feel.
  • the composition comprises emulsifying wax, ethylhexyl stearate and cyclopentasiloxane as key ingredients, and a natural preservative system that is free from parabens and formaldehyde donors.
  • Carrier H A topical oil in water (O/W) emulsion, with a lotion consistency that is highly moisturizing, for superficial delivery of active pharmaceutical ingredients.
  • the composition comprises ethylhexyl stearate, cyclopentasiloxane, PEG- 100 Stearate, glycery l stearate, PEG/PPG-18/18 dimethicone and sorbitol as key ingredients for the physicochemical attributes of the lotion and API release.
  • Carrier I An aqueous topical gel for superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients , with a soft “velvety'’ feel once dry on surface of the skin.
  • the composition comprises ammonium acryloyldimethyltaurate/VP copolymerin a water based carrier as the key ingredient responsible for the physicochemical characteristics (drug release and cosmetic aesthetics) of the gel system.
  • Carrier J A topical oil in water (O/W) emulsion (Cream) for the superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients in patients with sensitive skin or atopic dermatitis (eczema) or psoriasis.
  • O/W oil in water
  • emulsion emulsion for the superficial delivery of active pharmaceutical ingredients the active pharmaceutical ingredients in patients with sensitive skin or atopic dermatitis (eczema) or psoriasis.
  • This composition comprises polyglyceryl-3 cetearyl ether olivate, carapa guaianesis seed oil, theanine, vitis vinifera (grape)seed extract, xylitylglucoside, boswelia serrata resin extract, phosphatidylcholine, phosphatidylglycerol and brassica campestris sterols as key ingredients API delivery and skin calming, with dimethicone and cyclopentasiloxane for film formation and cosmetic elegance.
  • exemplary combination compositions comprise Pterostilbene, and a curcuminoid and a catechin
  • T-Ptero (25:2:8): curcumin (10 pM) + EGCG (10 pM) + pterostilbene (10 pM)
  • IC50 2.433 pM
  • This ratio is the exemplified molar concentration in Examples 6-8.
  • the formulation comprises by percentage of weight an equimolar composition as follows:

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Abstract

La présente invention concerne des utilisations de composés de diphényléthylène ou de sels pharmaceutiquement acceptables, de promédicaments et/ou de solvates de ceux-ci et/ou de ptérostilbène ou de sels pharmaceutiquement acceptables, de promédicaments et/ou de solvates de ceux-ci, et des compositions les comprenant et en outre une combinaison avec un curcuminoïde et une catéchine dans le traitement d'infections par papillomavirus, et de maladies, de troubles ou d'états résultant d'infections par papillomavirus telles que le cancer.
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