Diarylalkane compounds and compositions for use in skin aging and methods for their preparation - Patents.com

Abstract

Diarylalkane compounds are disclosed for use in anti-aging, wrinkle reduction and extracellular matrix strengthening topical skin care. Also disclosed are data and information from clinical trials that demonstrate reduced number of fine lines and wrinkles, reduced wrinkle depth, and reduced skin roughness upon treatment with the compounds.

Description

[Technical field]

[0001] This U.S. patent application claims priority to U.S. Provisional Patent Application No. 63330002, filed April 12, 2022, which is commonly owned and is incorporated herein in its entirety.

[0002] The contemplated compounds and compositions relate to the topical application of at least one diarylalkane compound comprising dimethoxytrylpropyl resorcinol (as found in the International Nomenclature of Cosmetic Ingredients or INCI) to reverse or prevent the signs of skin aging, specifically fine lines, coarse lines, periorbital lines and wrinkles. Specifically, the contemplated compounds and compositions comprise active ingredients for the manufacture and use of anti-aging skin care formulations. [Background technology]

[0003] There is a need for skin care ingredients that reverse or prevent signs of skin aging, such as fine lines and wrinkles on facial skin, especially periorbital skin. Wrinkles form in the skin with age due to a natural decline in skin cell replication, skin elasticity and moisture content, and wrinkle formation can be accelerated by UV exposure, smoking and pollution exposure (Farage MA, 2007) (Fore, 2006) (Haydont V, 2019). Skin is composed of the epidermis, which contains several layers of squamous cells that form the outer skin barrier beneath which lies the basement membrane (Michalak M, 2021). Like all basement membranes in epithelial tissues, the basement membrane of skin is the interface between cell layers and the extracellular matrix. The basement membrane of skin is called the dermal-epidermal junction, and as skin ages, signaling between these compartments is compromised, as is vascular support and structural support to the epidermis (Langton AK, 2016). The extracellular matrix beneath the basement membrane constitutes the dermal layer of the skin. This layer contains fibroblasts, nerves, blood follicles, hair follicles, sweat glands and sebaceous glands as well as forming the matrix through which immune cells migrate. The extracellular matrix is ​​composed of fibrillar proteins and water-binding glycosaminoglycans, the composition of which determines the cushioning and elasticity of the skin. Hyaluronic acid (HA) is a glycosaminoglycan that occurs naturally in connective tissues throughout the body. Hyaluronic acid binds to cellular HA receptors, triggering cell signaling cascades that affect cell survival, proliferation, adhesion and migration activity. In the skin, the main function of hyaluronic acid is to bind water molecules to retain moisture in the tissue and maintain the integrity of the dermal skin layer (Bukhari SNA, 2018). Fibrous proteins in the dermis include collagen, fibronectin, laminin and elastin. These proteins are secreted by fibroblasts present in the ECM to form the structural components of the dermis of the skin. Downregulation of ECM proteins leads to thinning of the dermal layer and reduced water content, impairing structural support to the skin and resulting in sagging skin and visible wrinkles (Farage MA, 2007; Fore, 2006; Haydont V, 2019).Current topical treatments to reduce wrinkles include retinoids, vitamins, hydroxy acids, peptides, extracts, etc. Their mechanisms of action include hydrating the skin to increase water content, filling the skin to reduce the appearance of wrinkles, increasing skin cell turnover, increasing collagen production, and retaining collagen and other proteins in the dermis (Imhof L, 2021). Summary of the Invention

[0004] Diarylalkane compounds are contemplated and their uses disclosed for use in anti-aging, wrinkle reduction and extracellular matrix strengthening. Contemplated diarylalkane compounds include dimethoxytrylpropyl resorcinol.

[0005] Contemplated compositions include the compound in an amount of 0.001 to 2 percent by weight, hi some embodiments, contemplated compositions include the compound in an amount of about 0.2% by weight. [Brief description of the drawings]

[0006] [Figure 1] FIG. 1 shows a contemplated diarylalkane compound for use in anti-aging, wrinkle reduction, which is dimethoxytrylpropyl resorcinol. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] Contemplated diarylalkane compounds, including those with the INCI name dimethoxytrylpropyl resorcinol and chemical names 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',4'-dihydroxyphenyl)-propane or 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',5'-dihydroxyphenyl)-propane as shown in Figure 1, have previously been isolated from Dianella ensifolia and used in other skin care applications not related to anti-aging or wrinkle treatment (Nesterov A, 2008). Methods for extraction and purification of compounds from Dianella ensifolia, as well as organic synthesis methods for producing the compounds and their use for skin lightening based on tyrosinase inhibition, have been patented in U.S. Patent Nos. 7,767,661; 8,592,488; 8,729,136; 9,126,913; and 10,857,082.

[0008] Contemplated embodiments relate to reversing and preventing aging-related fine lines and wrinkles on the skin. Specifically, contemplated compounds and compositions include at least one topical ingredient to reduce the number of fine lines and wrinkles, reduce the appearance of fine lines and wrinkles, increase luminosity in Asian populations, and reduce blotchiness and age spots in Caucasian populations in clinical trials. The mechanism of action of contemplated embodiments was investigated through in vitro gene expression and protein expression experiments, and the present invention was found to increase proteins contained in the extracellular matrix. Additional gene expression changes observed included increases in genes related to cytoskeleton, immune signaling, cell signaling, DNA repair, transcription, antioxidant, cell proliferation, skin barrier, wound healing, and keratinocyte differentiation.

[0009] Contemplated diarylalkane compounds, including those with the INCI name dimethoxytrylpropylresorcinol, and compositions containing those compounds are highly effective for use as topical anti-wrinkle ingredients in topical formulations, as evidenced by a statistically significant reduction in the number of fine lines, skin roughness, and wrinkle depth in female subjects in clinical trials. There was also an increase in luminosity / brightness in Asian subject populations, and a reduction in the appearance of pigmented skin and age spots in Caucasian subject populations.

[0010] These results were demonstrated by the in vitro increase in extracellular matrix genes and genes that increase hyaluronic acid synthesis, as shown herein. Additional genes found to be upregulated had skin-related functions, such as wound healing, cytoskeleton regulation, antioxidant, immune signaling, cell proliferation, cell signaling, DNA repair, transcriptional regulation and skin barrier function.

[0011] Any concentration range, percentage range, ratio range, or integer range herein should be understood to include any integer value within the recited range, and fractions thereof (such as tenths and hundredths of integers), where appropriate, unless otherwise indicated. Also, any numerical range recited herein for any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "consist essentially of" mean ±20% of the indicated range, value, or structure, unless otherwise indicated. The terms "a" and "an" as used herein should be understood to refer to "one or more" or "at least one" of the recited components. The use of alternatives (e.g., "and / or") should be understood to mean either, both, or any combination thereof of the alternatives. Unless the context requires to the contrary, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," as well as cognate words such as "include" and "have" and variations thereof, are to be interpreted in an open-ended and inclusive sense, i.e., "including, but not limited to."

[0012] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0013] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound of the present disclosure in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the present disclosure can be prepared by modifying functional groups present in the compounds of the present disclosure such that the modifications are cleaved to the parent compounds of the present disclosure either by routine manipulation or in vivo. Prodrugs include compounds of the present disclosure in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that is cleaved to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the compound of the present disclosure is administered to a mammalian subject. Examples of prodrugs include acetate, formate, and benzoate derivatives of alcohols, or amide derivatives of amine functional groups in the compounds of the present disclosure, and the like.

[0014] "Stable compound" and "stable structure" are intended to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0015] "Biomarker" or "marker" moiety or compound is intended to refer to one or more unique chemical moieties or compounds in a disclosed plant, plant extract, or combined composition having two or three plant extracts that are utilized to modulate the quality, consistency, integrity, stability and / or biological function of the compositions of the present invention.

[0016] "Mammal" includes humans and both domestic animals, such as laboratory animals or household pets (eg, cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0017] "Optional" or "optionally" means that the subsequently described element, component, event, or circumstance may or may not occur, and that the description includes instances in which the element, component, event, or circumstance occurs as well as instances in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups that have no substitution.

[0018] A "pharmaceutically or nutraceutical acceptable carrier, diluent or excipient" includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0019] "Pharmaceutically or nutraceutically acceptable salts" includes both acid addition salts and base addition salts. "Pharmaceutically or nutraceutically acceptable acid addition salts" are salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, glucoside, glyceric acid, glycerol ... It refers to salts formed with organic acids such as carboxylic acid, glycerol acid, sucrose acid, glycerol acid, glycyl acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid.

[0020] "Pharmaceutically or nutraceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salt is an ammonium, sodium, potassium, calcium, or magnesium salt. Salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2 dimethylaminoethanol, 2 diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly useful organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0021] Often, crystallization produces a solvate of the disclosed compound. As used herein, the term "solvate" refers to a strong aggregate that contains one or more molecules of the disclosed compound together with one or more molecules of a solvent. The solvent can be water, in which case the solvate can be a hydrate. Or the solvent can be an organic solvent. Thus, the disclosed compound can exist as a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a pentadecahydrate, a trihydrate, a tetrahydrate, and the like, and the corresponding solvated forms. The disclosed compound can be a true solvate, but in other cases, the disclosed compound can simply retain adventitious water or can be a mixture of water plus some adventitious solvent.

[0022] A "pharmaceutical composition" or "nutraceutical composition" refers to a combination of a compound of the present disclosure with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. For example, a pharmaceutical composition of the present disclosure may be formulated or used as a separate composition or as an ingredient in a prescription drug, an over-the-counter (OTC) drug, a botanical drug, a herbal medicine, a natural medicine, a homeopathic medicine, or any other form of health care product reviewed and approved by a government agency. An exemplary nutraceutical composition of the present disclosure may be formulated or used as a separate composition or as a nutritional or bioactive ingredient in a food, functional food, beverage, bar, food flavoring, medical food, dietary supplement, or herbal product. A vehicle generally accepted in the art includes any pharma- ceutical or nutraceutical acceptable carrier, diluent, or excipient therefor.

[0023] As used herein, "enriched with respect to" refers to a plant extract or other preparation having at least a 2-fold to about a 1000-fold increase in one or more active compounds compared to the amount of one or more active compounds found in the weight of the plant material or other source prior to extraction or other preparation. In certain embodiments, the weight of the plant material or other source prior to extraction or other preparation can be a dry weight, a wet weight, or a combination thereof.

[0024] As used herein, "major active ingredient" or "major active component" refers to one or more active compounds capable of at least one biological activity found in or concentrated in a plant extract or other preparation. In certain embodiments, the major active ingredients of a concentrated extract are one or more active compounds concentrated in the extract. In general, one or more major active ingredients directly or indirectly impart a greater amount (i.e., more than 50%, or more than 20%, or more than 10%) of one or more measurable biological activities or effects compared to other extract components. In certain embodiments, a major active ingredient may be a minor component by weight of the extract (e.g., less than 50%, less than 25%, or less than 10%, or less than 5% or less than 1% of the components contained in the extract) but still provide a greater amount of the desired biological activity. Any of the compositions of the present disclosure that contain a major active ingredient may or may not contribute to the pharmaceutical or nutraceutical activity of the concentrated composition, but may also contain minor amounts of active ingredients that do not contribute to the level of the major active ingredient, and the minor active ingredients alone may not be effective in the absence of the major active ingredient.

[0025] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound or composition of the present disclosure that, when administered, is sufficient to reduce the appearance of wrinkles and fine lines, melasma (solar lentigines), and other markers of skin aging.

[0026] The amount of a compound, extract, or composition of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the bioactive compound, or biomarker for the condition being treated and its severity, the mode of administration, the duration of the treatment, or the age of the subject to be treated, but can be routinely determined by one of ordinary skill in the art having regard to his or her own knowledge and this disclosure.

[0027] "Treating" or "treatment" as used herein refers to the treatment of a disease or condition of interest in a mammal, e.g., a human, having the disease or condition of interest, and includes (i) preventing the disease or condition from occurring in a mammal, particularly where such a mammal has a predisposition to the condition but has not yet been diagnosed as having the condition; (ii) inhibiting the disease or condition, i.e., halting its development; (iii) alleviating or altering the disease or condition, i.e., causing regression of the disease or condition; or (iv) reducing the symptoms resulting from the disease or condition without addressing the underlying disease or condition (e.g., reducing the appearance of fine lines, wrinkles, and melasma (lentigines)); or (v) altering the phenotype of the disease or condition.

[0028] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular illness or condition may not have a known causative agent (so that the etiology has not yet been elucidated) and therefore is not yet recognized as a disease, but only as an undesirable symptom or syndrome, and a more or less specific set of symptoms has been identified by clinicians.

[0029] As used herein, "statistical significance" refers to a p-value of less than or equal to 0.050 as calculated using Student's t-test, indicating that the particular event or outcome being measured is unlikely to have occurred by chance.

[0030] For administration, contemplated compounds such as diarylalkane compounds including dimethoxytrylpropyl resorcinol can be administered as raw chemicals or can be formulated as pharmaceutical or nutraceutical compositions. Contemplated pharmaceutical or nutraceutical compositions include compounds of the structure described herein and pharma- ceutical or nutraceutical acceptable carriers, diluents or excipients. Compounds of the structure described herein are present in the composition in an amount effective to treat the particular disease or condition of interest, i.e., in an amount sufficient to generally reduce the appearance of fine lines, wrinkles and melasma (solar lentigines) or any of the other relevant indications described herein, generally with acceptable toxicity to the patient / animal.

[0031] Administration of the contemplated diarylalkane compounds, including dimethoxytrylpropyl resorcinol or other related compositions disclosed herein, or their pharma- ceutically or nutraceutical acceptable salts, in pure form or in suitable pharmaceutical or nutraceutical compositions, can be carried out by any of the accepted modes of administration of drugs to perform similar functions. The pharmaceutical or nutraceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharma-ceutically or nutraceutical acceptable carriers, diluents or excipients, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as powders, granules, ointments, solutions, injections, inhalants, gels, creams, lotions, tinctures, masks and microspheres. Typical routes of administration of such pharmaceutical or nutraceutical compositions include oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal or intranasal. The term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0032] The pharmaceutical, dermatological or nutraceutical compositions disclosed herein are formulated so that the active ingredients contained therein are bioavailable when the composition is administered to a patient / animal. The composition administered to a subject or patient / animal or mammal may take the form of one or more dosage units, e.g., a tablet may be a single dosage unit, and a container of a composition of the disclosed compound or extract or two or three plant extracts in aerosol form may hold multiple dosage units. Actual methods of preparing such dosage forms are known or apparent to those skilled in the art, see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition administered will, in any event, contain a therapeutically effective amount of the disclosed compound or a pharma- ceutically or nutraceutically acceptable salt thereof for the treatment of the disease or condition of interest according to the teachings disclosed herein.

[0033] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure may be in solid or liquid form. In one aspect, the carrier is particulate, such that the composition is, for example, in tablet or powder form. The carrier may be liquid, such that the composition is, for example, an oral syrup, an injectable liquid or an aerosol that is useful, for example, in inhalation administration.

[0034] If intended for oral administration, the dermatological, pharmaceutical or nutraceutical composition may be in either solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms being included in the forms considered herein as either solid or liquid.

[0035] As a solid composition for oral administration, the dermatological, pharmaceutical or nutraceutical composition may be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gums, sashays, wafers, bars, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethylcellulose, cyclodextrin, microcrystalline cellulose, tragacanth or gelatin; excipients such as starch, lactose or dextrin, disintegrants such as alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and colorants.

[0036] The liquid dermatological, pharmaceutical or nutraceutical compositions of the present disclosure, whether in solution, suspension or other similar form, may contain one or more of the following adjuvants: water for injection, physiological saline solution such as saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono- or diglycerides that can act as solvents or suspension media, sterile diluents such as polyethylene glycol, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol, methylparaben; antioxidants such as ascorbic acid, sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for adjusting isotonicity such as sodium chloride or dextrose. Parenteral preparations may be enclosed in glass or plastic ampoules, disposable syringes or multiple dose vials. Saline is a commonly useful adjuvant. The injectable pharmaceutical or nutraceutical compositions are sterile.

[0037] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, cream, lotion, ointment or gel base. The base may comprise, for example, one or more of the following: petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, water, diluents such as alcohol, emulsifiers and stabilizers. A thickening agent may be present in the pharmaceutical or nutraceutical composition for topical administration. If intended for transdermal administration, the composition may comprise a transdermal patch or iontophoresis device.

[0038] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure, in solid or liquid form, may include an agent that binds to the compounds of the present disclosure and thereby aids in the delivery of the compounds. Suitable agents that may serve in this capacity include monoclonal or polyclonal antibodies, proteins or liposomes.

[0039] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure in solid or liquid form may include particle size reduction, for example to improve bioavailability. The size of the powders, granules, particles, microspheres, etc. in the composition, with or without excipients, may be macro (e.g., visible or at least 100 μm in size), micro (e.g., may range in size from about 100 μm to about 100 nm), nano (e.g., may be 100 nm or smaller in size), and any size in between or any combination thereof to improve size and bulk density.

[0040] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure can be prepared by methodology well known in the pharmaceutical or nutraceutical fields.For example, the pharmaceutical or nutraceutical compositions intended to be administered by injection can be prepared by combining the compounds of the present disclosure with sterile distilled deionized water to form a solution.Surfactants can be added to facilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that interact non-covalently with the compounds of the present disclosure to facilitate the dissolution or homogeneous suspension of the compounds in aqueous delivery systems.

[0041] The compounds of the present disclosure, or their dermatologically, pharma- ceutical or nutraceutical acceptable salts, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the particular compound used; the metabolic stability and length of action of the compound; the age, weight, general health, sex and diet of the patient; the mode and time of administration; rate of excretion; drug combination; the severity of the particular disorder or condition; and the subject being treated.

[0042] It is understood that in this description, combinations of substituents or variables of the depicted formulae are permissible only if such contributions result in stable compounds.

[0043] It will also be appreciated by those skilled in the art that in the processes described herein, functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include C(O)R″ (wherein R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups can be added or removed according to standard techniques known to those skilled in the art and described herein. The use of protecting groups is described in detail in Green, T W and P G M Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art will appreciate, the protecting group can also be a polymeric resin, such as a Wang resin, a Rink resin, or a 2-chlorotrityl chloride resin.

[0044] It will also be understood by those skilled in the art that such protected derivatives of the contemplated compounds disclosed herein may not have dermatological or pharmacological activity themselves, but may be administered to a mammal and then metabolized in the body to form a pharmacologically active compound of the present disclosure. Thus, such derivatives may be described as "prodrugs." All prodrugs of the compounds of the present invention are included within the scope of the present disclosure.

[0045] Furthermore, all compounds or extracts of the present disclosure that exist in free base or acid form can be converted to their pharma- ceutically or nutraceutical acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of the compounds of the present disclosure can be converted to their free base or acid form by standard techniques.

[0046] The contemplated compounds, pharmaceutical compositions and compositions may include, or may further include, or may consist of at least one active ingredient. In some embodiments, the at least one bioactive ingredient may include, or consist of, a plant powder, plant extract, or the like.

[0047] Agents of the disclosed and contemplated diarylalkane compounds, including dimethoxytrylpropyl resorcinol, are also contemplated herein. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Thus, contemplated compounds are those produced by a method comprising administering a contemplated compound or composition to a mammal for a period of time sufficient to provide a metabolic product thereof.

[0048] The contemplated compounds, medicinal compositions and compositions may comprise, further comprise, or consist of at least one pharma- ceutically, nutraceutical, or cosmetically acceptable carrier, diluent, or excipient. As used herein, the phrase "pharma-ceutically, nutraceutical, or cosmetically acceptable carrier, diluent, or excipient" includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or veterinary medicine. The contemplated compounds, medicinal compositions and compositions may comprise, further comprise, or consist of at least one pharma-ceutically, nutraceutical, or cosmetically acceptable salt. As used herein, the phrase "pharma-ceutically, nutraceutical, or cosmetically acceptable salt" includes both acid and base addition salts.

[0049] In some embodiments, contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, can be isolated from plants and / or marine sources. Plant parts suitable for isolating compounds include leaves, bark, trunks, trunk bark, stems, stem bark, twigs, tubers, roots, rhizomes, root bark, bark surface, shoots, seeds, fruits, stamens, pistils, sepals, stamens, petals, sepals, carpels (pistils), flowers, or any combination thereof. In some related embodiments, compounds or extracts are isolated from plant sources and synthetically modified to contain any of the listed substituents. In this regard, synthetic modification of compounds isolated from plants can be accomplished using any number of techniques known in the art and well within the knowledge of one of ordinary skill in the art. In some related embodiments, contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, are biosynthesized from plant or fungal tissues, stem cells, and transgenic microorganisms, and are synthetically modified by isolated or expressed enzymes to contain any of the enumerated substituents. In this regard, biosynthetic modification of contemplated compounds can be accomplished using any number of synthetic biology techniques known in the art and well within the knowledge of one of ordinary skill in the art.

[0050] Disclosed herein are the anti-aging effects of contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, on human keratinocytes in vitro and in human clinical trials. In keratinocytes treated with contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, the inventors found greater similarity in differentially expressed genes compared to keratinocytes treated with retinol. Further changes specific to contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, included increased extracellular matrix protein and proteoglycan synthesis, contributing to extracellular matrix reorganization. These and other activities, such as growth factor signaling, keratinocyte differentiation, cell-cell communication, and cell-ECM communication, are believed to enrich contemplated diarylalkane compounds, including those containing keratinocytes treated with dimethoxytrylpropyl resorcinol, and contribute to anti-aging. In human clinical trials, the inventors have found that contemplated diarylalkane compounds, including those containing dimethoxytrylpropyl resorcinol, in a 0.2% cream applied twice daily to the face improve the appearance of fine lines and wrinkles, as well as increasing skin lightening / luminosity in an Asian population and skin blemishes / age spots in a Caucasian population of human subjects. EXAMPLES

[0051] It should be understood that while the examples herein focus on the use of dimethoxytrylpropyl resorcinol, similar diarylalkane compounds can be utilized and one of ordinary skill in the art would understand how they can be utilized in the compositions contemplated herein.

[0052] [Example 1] Global gene expression changes in keratinocytes treated with dimethoxytrylpropylresorcinol To determine the specific expression changes of dimethoxytrylpropyl resorcinol on human keratinocyte aging genes, keratinocytes (Hacat cell line) were treated with 40 μM dimethoxytrylpropyl resorcinol and gene expression was analyzed by RNA-seq. To find genes involved in aging, we compared the variable gene expression with untreated keratinocytes and cells treated with 40 μM retinol A. Genes that were statistically significantly variable regulated were included in the analysis (p<0.05). Retinol was chosen as a positive control because retinoids have been described to have effective anti-aging and anti-wrinkle effects (Zasada M, 2019). We directly compared the effect of retinol on keratinocytes using the same concentration of dimethoxytrylpropyl resorcinol.

[0053] Protein localization and biological processes enriched in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes First, we compared the enriched biological processes common to both retinol-treated and dimethoxytrylpropyl resorcinol-treated keratinocytes (Table 1). Both retinol-treated and dimethoxytrylpropyl resorcinol-treated keratinocytes were enriched for protein localization and biological processes related to skin aging, including extracellular space, proteinaceous extracellular matrix, extracellular domain, epidermal development, and epithelial cell differentiation.

[0054] Table 1. Protein localization and biological processes upregulated in both retinol-treated and dimethoxytrylpropylresorcinol-treated keratinocytes (listed according to the number of genes affected in retinol-treated keratinocytes).

[0055] [Table 1] TIFF2025513858000003.tif87168

[0056] Protein localization and biological processes enriched exclusively in keratinocytes treated with dimethoxytrylpropylresorcinol In our study, we found several aging-related biological processes enriched in keratinocytes treated with dimethoxytrylpropyl resorcinol but not in keratinocytes treated with retinol. Importantly, the enrichment of wound healing processes indicates increased dynamics in tissues, which may affect the appearance of aging phenotypes in skin. Increased keratinocyte differentiation enrichment indicates a strengthened skin barrier, which makes the skin less susceptible to exogenous damage (Gutowska-Owsiak, D, 2020). Hyaluronan is a proteoglycan that binds water molecules in the extracellular matrix of the skin, and is therefore important for skin moisturization. Processes enriched in keratinocytes treated with dimethoxytrylpropyl resorcinol but not in keratinocytes treated with retinol are listed in Table 2.

[0057] Table 2. Gene clusters enriched in dimethoxytrylpropylresorcinol-treated keratinocytes (listed according to the number of genes affected in dimethoxytrylpropylresorcinol-treated keratinocytes).

[0058] [Table 2]

[0059] Differentially regulated genes in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes Specific senescence genes that are commonly regulated between retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes are listed in Tables 3-8.

[0060] Extracellular matrix (ECM) genes that were upregulated in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes included TFP12, which encodes a serine protease inhibitor that inhibits trypsin and matrix metalloproteases that degrade the extracellular matrix, and CRISPLD2, which is involved in glycosaminoglycan binding and is thought to directly affect the integrity of the extracellular matrix. CEACAM1 is an immunoglobulin involved in cell adhesion and tissue structure, and ABCA12 is a transporter and integral membrane protein. Increased expression of these genes may indicate increased cell-ECM communication and adhesion.

[0061] Of the ECM genes that are downregulated in both retinol-treated and dimethoxytrylpropylresorcinol-treated keratinocytes, all are proteins and proteoglycans involved in cell adhesion and present in the extracellular matrix. These downregulations may be related to changes in matrix composition or altered cell adhesion kinetics. The differential expression of these genes is listed in Table 3.

[0062] Table 3. ECM genes differentially expressed in both retinol-treated and dimethoxytrylpropylresorcinol-treated keratinocytes (listed according to fold change in retinol-treated keratinocytes).

[0063] [Table 3]

[0064] Among the upregulated genes involved in cell membrane fusion, cytoskeleton reorganization and lipid metabolism, RAPGEF3 activates small GTPases involved in cytoskeleton reorganization and cell membrane dynamics, suggesting that retinol and dimethoxytrylpropylresorcinol treatment affected cell-ECM interactions in keratinocytes. UGCG is involved in the biosynthesis of membrane lipids. Upregulation may indicate increased cell-ECM communication and / or lipid turnover rate.

[0065] KIF13A, a microtubule motor protein, was downregulated in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes. KIF13A is involved in endosomal transport along microtubules, and its downregulation may indicate altered transport kinetics. The differential expression of these genes is listed in Table 4.

[0066] Table 4. Differentially regulated cytoskeletal and transport genes in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes.

[0067] [Table 4]

[0068] ANOS1, TNC and SEMA3D are extracellular matrix proteins mainly involved in neural cell adhesion and axonal extension, therefore downregulation of these genes may indicate changes from innervation of the skin. Tenascin-C (TNC) has previously been shown to be downregulated in rat glioma cells treated with retinoic acid (Alvarez-Dolado M, 1999). There may be other functions of these proteins in the extracellular matrix that affect skin aging and explain the downregulation of these proteins in keratinocytes treated with retinol and dimethoxytrylpropylresorcinol. The differential expression of these genes is listed in Table 5.

[0069] Table 5. Extracellular matrix proteins involved in neural cell adhesion and axonal outgrowth that are differentially expressed in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes.

[0070] [Table 5]

[0071] Both retinol and dimethoxytrylpropylresorcinol induced changes in the expression of growth-related genes. In general, the net effect of these changes was a decrease in cell proliferation, as three genes involved in the negative control of growth were upregulated: PTPRR, C3orf33, and ANGPTL4, and four genes involved in growth were downregulated: BMP4, FGF1, FGF11, and TP73. The differential expression of these genes is listed in Table 6.

[0072] Table 6. Growth genes differentially expressed in retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes

[0073] [Table 6]

[0074] Immune signaling was increased in retinol-treated and dimethoxytrylpropylresorcinol-treated keratinocytes, as was CYP1A1, a cytochrome p450 family member oxygenase involved in drug metabolism. These genes, especially CYP1A1, may be upregulated in direct response to drug treatment. The changes observed in immune signaling genes may demonstrate the role of increased immune signaling in retinol-treated and dimethoxytrylpropylresorcinol-treated keratinocytes. The differential expression of these genes is listed in Table 7.

[0075] Table 7. Differentially expressed immune genes in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes.

[0076] [Table 7]

[0077] TXNRD1, an antioxidant enzyme, was upregulated in retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes, increasing the antioxidant capacity in the cells. Antioxidants are important for reducing light-induced skin damage (Masaki, 2010). The differential expression of this gene is listed in Table 8.

[0078] Table 8. Antioxidant genes differentially expressed in both retinol- and dimethoxytrylpropylresorcinol-treated keratinocytes.

[0079] [Table 8]

[0080] Genes differentially expressed only in keratinocytes treated with dimethoxytrylpropylresorcinol There was a large subset of skin aging genes listed in Tables 9-14 that were variably expressed in dimethoxytrylpropylresorcinol-treated keratinocytes but not in retinol-treated keratinocytes.

[0081] Among the extracellular matrix and cell adhesion genes, the hyaluronan synthases HAS2 and HAS3 were among the most highly upregulated in dimethoxytrylpropyl resorcinol-treated keratinocytes. These genes are responsible for the production of hyaluronan, a proteoglycan that is abundant in the extracellular matrix and essential for skin moisturization. LAMC2 and LAMA3 laminins, proteins in the extracellular matrix, were upregulated, as was COL1A1, the most abundant collagen in skin connective tissue. ECM1, an extracellular matrix protein, and NID2, an extracellular glycoprotein, were also upregulated. PI3, an inhibitor of elastase, was upregulated, the result of which may be the stability of elastin in the extracellular matrix. Elastin is an extracellular matrix protein that is essential for the resilience of skin connective tissue. SELE and ITGA6, cell surface adhesion molecules, were also upregulated in dimethoxytrylpropyl resorcinol-treated keratinocytes, and ITGBL1, an integrin-associated protein, was downregulated.

[0082] Taken together, these changes demonstrate an increase in the production of extracellular matrix proteins conferred by dimethoxytrylpropylresorcinol, which was coupled with an increase in cell adhesion to the extracellular matrix. The differential expression of these genes is listed in Table 9.

[0083] Table 9. Extracellular matrix genes differentially expressed in keratinocytes treated with dimethoxytrylpropylresorcinol

[0084] [Table 9]

[0085] Growth factor and motility signaling were differentially regulated in dimethoxytrylpropyl resorcinol-treated keratinocytes compared to retinol-treated keratinocytes. TGF-β signaling increases the expression of extracellular matrix proteins and proteoglycans and decreases matrix metalloproteinase (MMP) gene expression in the skin (Imfeld D, 2015). We found that dimethoxytrylpropyl resorcinol increased the expression of TGFB1, a ligand for TGF-β signaling, causing increased signaling of this pathway. The cytokine IL1A was also upregulated in dimethoxytrylpropyl resorcinol-treated keratinocytes, but not in retinol-treated keratinocytes. IL-1α is important for inducing wound healing in the skin by inducing migration through autocrine signaling to keratinocytes and paracrine signaling to fibroblasts (Chen JD, 1995) (Zheng R, 2019). The differential expression of these genes is listed in Table 10.

[0086] Table 10. Differentially expressed signaling and cytokine genes in keratinocytes treated with dimethoxytrylpropylresorcinol

[0087] [Table 10]

[0088] PARP15 is a protein-modifying enzyme that affects protein activity. Along with other PARP family members, PARP15 is involved in transcriptional regulation through histone modification and may affect DNA damage repair. SIRT genes have been implicated in aging through transcriptional repression by deacetylating histones and transcription factors, but can also deacetylate other protein targets. SIRT gene activity regulates proliferation and differentiation and maintains genomic stability (Simon M, 2020) (Dai Y, 2008). SIRT1 gene expression declines with age, and SIRT1 activators are being explored as topical treatments for skin aging due to their protection against UVR-induced aging effects (Bielach-Bazyluk A, 2021). The upregulation of these genes suggests that inhibition of skin aging by dimethoxytrylpropylresorcinol may be in part due to transcriptional repression. The variable expression of these genes is listed in Table 11.

[0089] Table 11. Differentially expressed DNA repair and transcriptional regulatory genes in keratinocytes treated with dimethoxytrylpropylresorcinol

[0090] [Table 11]

[0091] SERPINs are a family of serine protease inhibitors and are important for maintaining skin structure (Cork MJ, 2009). SERPINB2 has been shown to have a protective effect on the skin barrier, as knockout mice had reduced barrier function (Schroder WA, 2016). SERPINB2 and SERPINB4 have also been shown to be important for protection from UV radiation, a major cause of skin aging (Katagiri C, 2006) (Majoros H, 2019). FABP5 is involved in maintaining skin barrier function by regulating fatty acid synthesis and cell membrane homeostasis. Mice lacking fatty acid binding protein have been shown to have altered water barrier function in their skin (Owada Y, 2002). CDK5R1 activates cyclin-dependent kinase 5 (CDK5), a CDK that is primarily expressed in neurons but has function in other tissues. CDK5 knockdown mice had impaired epidermal structure, which was found to be due to a reduction in keratin 10 (K10), an intermediate filament in the epidermis (Dong C, 2017). As an endogenous tight junction protein, OCLN is involved in maintaining the barrier function of skin cells. These genes affect skin integrity, skin barrier function and response to injury, processes that are impaired in aged skin (Choi, 2019), and are upregulated in keratinocytes treated with dimethoxytrylpropylresorcinol. The differential expression of these genes is listed in Table 12.

[0092] Table 12. Differentially expressed skin barrier genes in keratinocytes treated with dimethoxytrylpropylresorcinol

[0093] [Table 12]

[0094] Oxidative stress caused by endogenous and exogenous factors plays a major role in the process of skin aging. UV radiation, pollution and other environmental factors are some of the exogenous causes of oxidative stress. Neutralizing reactive oxygen species in the skin is important to combat skin aging (Rinnerthaler M, 2015). HMOX1 is an enzyme upregulated by NRF2, a transcription factor that responds to oxidative stress by upregulating antioxidant genes. AHR is a transcription factor that is activated in response to xenobiotics. AHR activates genes involved in metabolism, but can also activate antioxidant programs through the upregulation of NRF2, SOD1 and other genes (Dietrich, 2016). SOD2 is a reactive oxygen species neutralizing enzyme, as it directly converts superoxide to hydrogen peroxide and dioxygen. HIF1A is a transcription factor involved in oxygen homeostasis. HIF1A is normally upregulated in oxygen-deficient environments, but it is also activated in response to hydrogen peroxide-rich environments and upregulates antioxidant genes (Li HS, 2019). Through neutralization of reactive oxygen species, these genes effectively reduce the signs of skin aging. The differential expression of these genes is listed in Table 13.

[0095] Table 13. Differentially expressed oxidative stress genes in keratinocytes treated with dimethoxytrylpropylresorcinol

[0096] [Table 13]

[0097] NGF is a potent neuronal growth factor, but in skin, it has a role in keratinocyte migration and wound healing (Matsuda H, 1998) (Gostynska N, 2020). Evidence that NGF is downregulated in aged skin suggests that NGF function is important for maintaining skin function and integrity (Adly MA, 2006). Both EREG and HBEGF are ligands for the epidermal growth factor receptor EGFR, which regulates many functions of keratinocytes, including proliferation, adhesion and migration, survival, and differentiation. In humans, inhibition of EGFR signaling has been shown to result in a skin aging phenotype, including downregulation of hyaluronan synthase genes and upregulation of aging genes in keratinocytes (Gerber PA, 2016). These growth signaling pathways are crucial for skin function and integrity, as evidenced by their decline in aged skin. The differential expression of these genes is listed in Table 14.

[0098] Table 14. Growth genes differentially expressed in keratinocytes treated with dimethoxytrylpropylresorcinol

[0099] [Table 14]

[0100] Taken together, the changes observed in dimethoxytrylpropyl resorcinol-treated keratinocytes showed similarities to retinol-treated keratinocytes in differentially regulated skin aging processes: extracellular matrix protein deposition, lipid dynamics, cell adhesion, cell migration, cytoskeletal reorganization and trafficking, neuronal maturation, immune signaling, and antioxidants. There were many skin aging processes that were differentially regulated in dimethoxytrylpropyl resorcinol-treated keratinocytes but not in retinol-treated keratinocytes, including extracellular matrix proteins, TGF-β signaling, transcriptional regulation, skin barrier function, oxidative stress, and growth. The net effect of these genetic changes represents an anti-aging phenotype in keratinocytes.

[0101] [Example 2] Identification of differential gene expression changes in dimethoxytrylpropylresorcinol-treated keratinocytes through protein quantification From the above Example 1, several genes that showed differential regulation that are particularly important for skin aging were confirmed through quantification of protein expression. Hacat immortalized human keratinocyte cells were treated with 40 μM dimethoxytrylpropyl resorcinol for 48 hours, then lysed and subjected to Western blot, and cell culture medium was subjected to Western blot to quantify protein levels. Keratinocyte samples treated with dimethoxytrylpropyl resorcinol were compared with untreated keratinocyte samples (control). Intracellular proteins of interest are listed in Table 15, and extracellular proteins of interest are listed in Table 16.

[0102] Table 15. Intracellular genes upregulated in RNA-seq with protein levels quantified by Western blot

[0103] [Table 15]

[0104] Table 16. Extracellular genes upregulated in RNA-seq with protein levels quantified by Western blot

[0105] [Table 16]

[0106] LAMC2, ECM1, COL1A1, HAS2 and HAS3 were found to have higher protein levels in dimethoxytrylpropyl resorcinol-treated conditions than in controls. These are all proteins involved in extracellular matrix composition. These changes suggest that the anti-wrinkle or anti-aging activity of dimethoxytrylpropyl resorcinol is based on an increase in extracellular matrix components.

[0107] [Table 17]

[0108] [Example 3] Dimethoxytrylpropylresorcinol has shown efficacy against fine lines and wrinkles in human clinical trials To evaluate the antioxidant properties of dimethoxytryl propyl resorcinol, a preliminary clinical efficacy evaluation study of a skin treatment product was conducted using dimethoxytryl propyl resorcinol cream at a concentration of 0.2%. The purpose of the study was to evaluate whether 8 weeks of use of the product would reduce the appearance of crow's feet, fine lines, and wrinkles. For this study, a panel of 12 subjects ranging from 35 to 65 years of age were recruited and assessed at baseline (BL), week 2 (W2), week 4 (W4), and week 8 (W8) as outlined in Table 17. The study was a single-blind, full-face, home study with four clinic visits after enrollment.

[0109] Table 17. Procedures for each clinic visit

[0110] [Table 18]

[0111] The following subjects were included: 1. Women aged 35 to 66 (inclusive) who are in good overall health 2. Individuals who have a fine line / wrinkle score of "5" (noticeable) or greater in the crow's feet area as assessed by a trained technician, with the wrinkles rated according to the following scale: 0-none, 1-3-slight, 4-6-noticeable, 7-9-very noticeable. 3. Individuals able to read, understand, and sign the informed consent form. 4. Individual is expected to be able to follow and participate in the study instructions, attend all clinical visits, and apply the products as directed.

[0112] Subjects excluded were: 1. Women who are pregnant, planning to become pregnant, lactating, and / or breastfeeding a child. 2. Individuals with any visible skin disease that may interfere with the evaluation. 3. Individuals with facial sunburn, non-irritated sunburn, or planning a vacation involving sun exposure or using a tanning booth during the study. 4. Individuals participating in a concurrent facial product research project. 5. Individuals taking medications that may interfere with study results, including the use of steroidal / nonsteroidal anti-inflammatory drugs or antihistamines. 6. Individuals who have undergone laser resurfacing or dermabrasion on the face or chemical facial dermabrasion in the past 2 years (deep peel in the past year; superficial peel in the past 2 months). 7. Individuals with acne, active atopic dermatitis / eczema or psoriasis. 8. Individuals who have had any surgical "cosmetic" treatment on the face within the past 10 years. 9. Treatment or history of cancer of any type. 10. Individuals receiving treatment for asthma or diabetes. 11. Individuals with known sensitivities to cosmetics or personal care products.

[0113] At all visits, a trained technician assessed the appearance of crow's feet, fine lines, and wrinkles based on the following scale: 0-none, 1-3-slight, 4-6-noticeable, 7-9-very noticeable. A technician also assessed each subject's face for irritation. None of the subjects had any irritation at any time point. Skin replicas were taken for each subject to assess fine lines / wrinkles and skin texture as follows: On a glass Petri dish, 3 inches of resin (approximately 3 mL) and 3 drops of catalyst were mixed thoroughly for approximately 15-20 seconds. Immediately after, the mixture was placed into a CuDerm replica placement ring that had been previously placed on the crow's feet of each subject. After 4-5 minutes, the ring was removed. The resulting skin replicas were shipped to BioNet, Inc. for analysis. At the final visit, subjects were required to complete a questionnaire.

[0114] result: After 2, 4, and 8 weeks of use of dimethoxytrylpropyl resorcinol 0.2% cream, crow's feet, fine lines, and wrinkles improved, with a clinically significant (≧10%) improvement at week 8 (Table 18).

[0115] Table 18. Mean crow's feet, fine lines and wrinkles scores and % change from baseline

[0116] [Table 19] *Demonstrated clinical significance (improvement of 10% or more)

[0117] Over the course of the study, a greater percentage of subjects experienced improvement in the appearance of crow's feet, fine lines, and wrinkles (Table 19).

[0118] Table 19. Incidence of Responses for Improvement of Crow's Feet, Fine Lines, and Wrinkles (% of Subjects with Improvement from Baseline)

[0119] [Table 20]

[0120] Skin replicas were analyzed using replica analysis methods A and B. Method A measured luminance along a set of 10 equal length parallel lines running across the replica parallel to the illumination direction. The luminance variation was treated as an indication of roughness and analyzed by traditional surface roughness statistics. Using Method A, the following parameters were analyzed: 1. Rz: The average maximum difference in brightness values ​​for five equal length segments in each of ten lines across the sample. Maximum optical roughness. 2. Ra: The average deviation of the luminance curve with respect to the average luminance for the same 10 lines. Average optical roughness. 3. FNum: The number of fine line markers per mm. As lines and creases disappear, F Num decreases. 4. IDL: The integrated developed length of the 10 scanline luminance trace. This is the total length of the luminance line as a fraction of the linear distance. (i.e. a flat, textured sample has an IDL of 1.000.)

[0121] After 4 weeks of initiating use of dimethoxytrylpropyl resorcinol 0.2% cream, coarse wrinkles showed a statistically significant 28% decrease in maximum luminance difference (Rz) and a 32.7% decrease in the integrated developed length of the luminance trace, indicating a decrease in surface roughness. A trend toward a decrease was still present at 8 weeks, but the changes were not statistically significant (Table 20).

[0122] Fine lines were statistically significantly reduced: maximum difference in luminance (Rz), mean deviation of luminance curve (Ra), number of fine lines per mm (FNum) and integrated developed length of luminance trace (IDL) at 2, 4 and 8 weeks of treatment with dimethoxytrylpropyl resorcinol 0.2% cream. These consistent and significant reductions in surface roughness measurements and in the number of fine lines (FNum) indicate a clear reduction in wrinkles and improvement in skin smoothness even after only 2 weeks of dimethoxytrylpropyl resorcinol use (Table 20), which persisted over the course of treatment.

[0123] Table 20. Changes (and % changes) in Method A parameters for skin replicas compared to baseline

[0124] [Table 21] *Indicates statistical significance (p<0.05).

[0125] The following parameters were analyzed using method B: This method divided the replica image area into 10 equal width bands or sub-areas. Shadow-like features were detected in each of these bands according to their brightness values ​​being below the detection threshold.

[0126] 1. Spacing: The average distance in millimeters between adjacent detected features (i.e., the spacing between the midpoints of adjacent shaded features). Decreases as deep wrinkles transform into fine wrinkles (hydration). Increases as wrinkles disappear. 2. Width: The average width in millimeters of the detected features expressed in millimeters. This parameter is proportional to the depth of the wrinkles that generate the shadow. It decreases as the wrinkles become shallower. 3. Shadows: The percentage of sampled replica area that has intensity values ​​below the detection threshold. This is the relative area of ​​shadows cast by wrinkles and fine lines in the replica. Decreases with skin smoothing. 4. Number of wrinkles: The total number of features detected in the 10 bands or sub-regions used to calculate spacing and width. In general, NumWr decreases with smoothing of the skin (fewer visible features).

[0127] For coarse wrinkles, there was no significant change in the parameters of Method B over the 8-week use of dimethoxytrylpropyl resorcinol 0.2% cream. For fine lines, there was a significant 42.3% and 37.5% reduction in wrinkles and shadows cast by fine lines at 2 and 4 weeks, respectively, after the start of the treatment course. At 8 weeks, there was a 30.9% reduction in shadows, which was not statistically significant. There was a statistically significant reduction in the number of wrinkles (NumWr) at 2, 4, and 8 weeks after the start of dimethoxytrylpropyl resorcinol use. The number of fine lines was reduced by 37.6% at 2 weeks, 32.8% at 4 weeks, and 29.0% at 8 weeks, demonstrating the immediate and sustained reduction in fine lines provided by dimethoxytrylpropyl resorcinol (Table 21).

[0128] Table 21. Changes (and % changes) in Method B parameters for skin replicas compared to baseline

[0129] [Table 22] *Indicates statistical significance (p<0.05).

[0130] Responses to the subjective questionnaire showed a high rate of subject acceptance of the product. Subjects' perceptions of their skin were analyzed from the questionnaire and are summarized in Table 22. The majority of subjects noticed that crow's feet, fine lines and wrinkles looked less noticeable, felt that their skin had a healthier appearance and noticed an improvement in the quality of their skin.

[0131] Table 22. Summary of responses to questionnaires by subjects at final visit

[0132] [Table 23]

[0133] [Example 4] Dimethoxytrylpropyl resorcinol has demonstrated efficacy in improving skin brightness and luminosity in an Asian human subject population and in reducing the appearance of skin pigmentation and age spots in a Caucasian human subject population. To evaluate the antioxidant properties of dimethoxytrylpropyl resorcinol, a preliminary clinical efficacy evaluation study of a skin treatment product was conducted using dimethoxytrylpropyl resorcinol cream at a concentration of 0.2%.

[0134] The aim of this study was to evaluate whether 8 weeks of product use would result in improved skin brightness / luminescence in an Asian population and reduce the appearance of skin pigmentation / age spots in a Caucasian population. For this study, a panel of 12 subjects (66 Asian and 6 Caucasian) ranging in age from 35 to 66 years were recruited and assessed at baseline (BL), week 2 (W2), week 4 (W4) and week 8 (W8) as outlined in 3. The study was a single-blind, full-face, home study with 4 clinic visits after enrolment.

[0135] Table 23. Procedures for each clinic visit

[0136] [Table 24]

[0137] The following subjects were included: 1. Women aged 35 to 66 (inclusive) who are in good overall health 2. Asian subjects with a skin brightness / luminance score of "5" (slightly dull / pallor appearance) or greater on the face (for quantification purposes only) assessed by a trained technician, with brightness / luminance rated according to the following scale: 0 - no visible dullness / pallor, 1-3 - slight dullness / pallor, 4-6 - slight dullness / pallor, 7-9 - severe dullness / pallor. 3. Caucasian subjects with a facial blemish / age spot score of "5" (blemishes or moderate areas of age spots) or greater (for quantification purposes only) assessed by a trained technician, with blemish / age spots rated according to the following scale: 0 - no visible blemishes or age spots, 1-3 - blemishes or slight areas of age spots, 4-6 - blemishes or moderate areas of age spots, 7-9 - blemishes or significant areas of age spots. 4. Individuals able to read, understand, and sign the informed consent form. 5. Individual is expected to be able to follow and participate in the study, attend all study visits, and apply the products as directed.

[0138] Subjects excluded were: 1. Women who are pregnant, planning to become pregnant, lactating, and / or breastfeeding a child. 2. Individuals with any visible skin disease that may interfere with the evaluation. 3. Individuals with facial sunburn, non-irritated sunburn, or planning a vacation involving sun exposure or using a tanning booth during the study. 4. Individuals participating in a concurrent facial product research project. 5. Individuals taking medications that may interfere with study results, including the use of steroidal / nonsteroidal anti-inflammatory drugs or antihistamines. 6. Individuals who have undergone laser resurfacing or dermabrasion on the face or chemical facial dermabrasion in the past 2 years (deep peel in the past year; superficial peel in the past 2 months). 7. Individuals with acne, active atopic dermatitis / eczema or psoriasis. 8. Individuals who have had any surgical "cosmetic" treatment on the face within the past 10 years. 9. Treatment or history of cancer of any type. 10. Individuals receiving treatment for asthma or diabetes. 11. Individuals with known sensitivities to cosmetics or personal care products.

[0139] At all visits, a trained technician assessed each subject's face for irritation. None of the subjects had any irritation at any time point. Digital images of each subject's face were taken using a Visia CR® Imaging System. Photographs were taken from the front, left, and right sides. At the final visit, subjects were required to complete a questionnaire.

[0140] Results: Skin Lightness / Brightness (Asian Subjects): Skin lightness (brightness) was analyzed by Visia CR® to determine changes in skin lightness / brightness. Facial brightness was a single number calculated based on the uniformity of the lightening of the image. An increase in facial brightness represented an improvement in overall skin brightness. A decrease represented a deterioration. At each visit, Asian subjects were given a score for skin lightness / brightness according to the following scale: 0 - no visible dullness / bad appearance, 1-3 - slightly dull / bad appearance, 4-6 - moderate dull / bad appearance, 7-9 - markedly dull / bad appearance. Additionally, at the last visit, subjects completed a questionnaire.

[0141] Although there were no significant changes in lightness / luminance as assessed by the Visia CR® assay at any visit, the mean skin lightness / luminance scores tended to increase at 4 and 8 weeks after initiating dimethoxytrylpropyl resorcinol use compared to baseline (Table 24), indicating an improvement in skin lightness / luminance.

[0142] Table 24. Brightness / Luminance Change in Asian Subjects Measured by Visia CR(R).

[0143] [Table 25]

[0144] The following table presents the percentage of Asian subjects who showed improvement in Visia CR® skin lightness / luminance analysis at each visit (Table 25). Skin lightness / luminance improved in Asian subjects after 4 and 8 weeks of product use, with up to 67% of subjects showing improvement. Despite no significant differences in the mean scores for skin lightness / luminance, these data demonstrate that there was individual improvement in responders, and that the proportion of responders increased over the course of treatment.

[0145] Table 25. Skin Lightness / Luminance Analysis (Asian Subjects) Response Frequency (% of subjects with improvement from baseline).

[0146] [Table 26]

[0147] Self-assessment of Asian subjects at each visit showed improvement in skin lightness / luminosity after 2, 4, and 8 weeks of product use. Notably, there was a 13% improvement in self-assessed scores for skin lightness / luminosity after 8 weeks of dimethoxytrylpropyl resorcinol use (Table 26).

[0148] Table 26. Self-assessment scores for skin lightness / luminance - Asian subjects

[0149] [Table 27]

[0150] Skin blemishes / age spots (Caucasian subjects): To determine changes in skin blemishes / age spots, chroma was analyzed by Visia CR®. The degree to which a color does not blend with other colors is a good indicator of its chroma. An increase in chroma score represented an improvement in skin blemishes / age spots. A decrease represented a worsening. At each visit, the skin blemishes / age spots of the Caucasian subjects were scored according to the following scale: 0 - no visible skin blemishes or age spots, 1-3 - visible skin blemishes or slight areas of age spots, 4-6 - visible skin blemishes or moderate areas of age spots, 7-9 - visible skin blemishes or severe areas of age spots. Additionally, at the last visit, the subjects completed a questionnaire.

[0151] Although there were no significant changes in skin pigmentation / age spotting as assessed by the Visia CR® assay at any visit, the mean skin pigmentation / age spotting scores all tended to increase at 2, 4, and 8 weeks after initiating dimethoxytrylpropyl resorcinol use compared to baseline, indicating improvement in skin pigmentation / age spotting (Table 27).

[0152] Table 27. Skin blemishes / changes in age blemishes in Caucasian subjects as measured by Visia CR®.

[0153] [Table 28]

[0154] The following table presents the percentage of Caucasian subjects who showed improvement in the Visia CR® Skin Pore / Age Spot analysis at each visit (Table 28). Skin Pore / Age Spot improved in Caucasian subjects after 2, 4 and 8 weeks of product use, with up to 83% of subjects showing improvement. Despite no significant differences in the mean scores for Skin Pore / Age Spot, these data demonstrate that there was individual improvement in responders, and that a significant proportion of responders maintained improvement over the course of treatment.

[0155] Table 28. Skin Spot Condition / Age Spot Analysis (Caucasian Subjects) Frequency of Responses (% of subjects with improvement from baseline).

[0156] [Table 29]

[0157] Self-assessment of Caucasian subjects showed improvement in skin blemishes / age spots after 2, 4 and 8 weeks or product use. In particular, there was a 37% improvement in self-assessment score for skin blemishes / age spots after 8 weeks of dimethoxytrylpropyl resorcinol use (Table 29).

[0158] Table 29. Self-assessment scores for skin blemishes / age spots - Caucasian subjects

[0159] [Table 30]

[0160] At the last visit, subjects were asked to complete a questionnaire. Subjective questionnaire responses showed a high rate of subjective product acceptance. Subjects' perceptions of their skin were analyzed from the questionnaire and summarized in Tables 30 and 31. The vast majority of Asian subjects noticed an increase in skin brightness / luminosity and felt that their skin had a healthier appearance. The vast majority of Caucasian subjects felt that their skin was less blemished and that age spots were less noticeable and felt that their skin had a healthier appearance.

[0161] Table 30. Responses to the Subject Questionnaire for Asian Subjects

[0162] [Table 31]

[0163] Table 31. Responses to the Subject Questionnaire for White Subjects

[0164] [Table 32]

[0165] From the above examples, it was demonstrated that keratinocytes treated with dimethoxytrylpropyl resorcinol have many differentially expressed genes involved in aging pathways compared to untreated controls.Comparing the genes expressed in keratinocytes treated with dimethoxytrylpropyl resorcinol with the genes differentially expressed in keratinocytes treated with retinol, there were many common protein locations and biological processes between these treatments, including extracellular domain, proteinaceous extracellular matrix, extracellular matrix organization, epidermal development, epithelial cell differentiation, and cellular response to retinoic acid.Specific gene clusters that were similarly regulated in keratinocytes treated with dimethoxytrylpropyl resorcinol and keratinocytes treated with retinol included extracellular matrix genes, cytoskeleton genes, neural cell adhesion, negative regulators of cell proliferation, immune signaling, and antioxidants.This may suggest similar activities between dimethoxytrylpropyl resorcinol and retinol in keratinocytes.

[0166] Biological processes that were variably expressed in keratinocytes treated with dimethoxytrylpropyl resorcinol compared to control but not in keratinocytes treated with retinol included wound healing, keratinocyte differentiation and hyaluronan biosynthesis processes.Specific gene clusters that were variably regulated in keratinocytes treated with dimethoxytrylpropyl resorcinol but not in keratinocytes treated with retinol were extracellular matrix genes, cell signaling genes, transcriptional regulator genes, skin barrier genes, oxidative stress genes and growth factors.Selected genes that were variably regulated in keratinocytes treated with dimethoxytrylpropyl resorcinol but not in keratinocytes treated with retinol were further investigated for variably protein expression by Western blot. Changes identified included upregulation of HAS2 and HAS3 (14% and 17% increase, respectively, compared to control keratinocytes), LAMC2 (16% increase), ECM1 (40% increase) and COL1A1 (34% increase in procollagen and 27% increase in mature collagen). We were unable to definitively confirm or refute expression changes for other proteins tested, including SELE, SIRT7, SIRT1, SERPINB4, SERPINB2, SOD2, HIF1A, TGFB1, NGF, EREG and HBEGF.

[0167] Increased HAS2 and HAS3 indicate increased hyaluronic acid synthesis and increased ability to bind water molecules in the extracellular matrix, enhancing skin moisturization and hydration. Increased LAMC2, ECM1 and COL1A1 indicate increased deposition of ECM components. This suggests anti-aging potential through reduction and prevention of fine lines and wrinkles by strengthening the ECM.

[0168] In a clinical trial using 0.2% dimethoxytryl propyl resorcinol cream twice daily for 8 weeks, scores for crow's feet, fine lines and wrinkles assessed by trained technicians were significantly reduced at the end of the study. When assessed using skin replica brightness measurements, dimethoxytryl propyl resorcinol cream reduced the brightness and brightness trace length of coarse wrinkles after 4 weeks of use, indicating reduced surface roughness. Fine line brightness, number and brightness trace length for fine lines were significantly reduced even after 2 weeks of use, and these changes continued through the end of the study at 8 weeks, indicating improved skin smoothness. When fine lines were assessed using skin replica shadow assessment, dimethoxytryl propyl resorcinol cream significantly reduced the shadow cast by wrinkles after only 2 and 4 weeks of use. The number of wrinkles and fine lines was also significantly reduced at the second week and throughout the study.

[0169] In clinical evaluation of skin luminance measured by Visia CR® in Asian subjects, the mean brightness / luminance score did not change, but visual assessment by trained technicians showed improved scores after 2 weeks of use, with greater improvement after 4 weeks of use. In parallel, skin blemishes / age spots were measured by Visia CR® in Caucasian subjects. The mean brightness / luminance score did not change, but visual assessment by trained technicians also showed improved scores after 2 weeks of use, with the majority of subjects maintaining the improvement throughout the study period.

[0170] These data demonstrate that dimethoxytryl propyl resorcinol cream reduced the appearance of fine lines and wrinkles in a clinical trial, and also improved visual scores for luminosity and skin blemishes / age spots over the study period. The mechanism of action for these improvements may lie in altered expression of genes involved in extracellular matrix composition, enhancing ECM components, moisturizing the skin, and filling in fine lines and wrinkles.

[0171]

Table 33

Claims

1. Diarylalkane compounds for use in anti-aging, wrinkle reduction and extracellular matrix strengthening.

2. The compound of claim 1 , wherein the diarylalkane compound comprises dimethoxytrylpropyl resorcinol.

3. 10. A compound according to claim 1 for use in reducing the number of fine lines and wrinkles on the skin.

4. 10. A compound according to claim 1 for use in reducing the appearance of fine lines and wrinkles on the skin.

5. 10. A compound according to claim 1 for use in increasing the smoothness of the skin.

6. 10. A compound according to claim 1 for use in increasing the radiant / bright appearance of the skin.

7. 10. A compound according to claim 1 for use in reducing the number of coarse wrinkles on the skin.

8. 10. A compound according to claim 1 for use in reducing the appearance of coarse wrinkles on the skin.

9. 10. A compound according to claim 1 for use in increasing hyaluronic acid synthesis and skin moisturisation.

10. 10. A compound according to claim 1 for use in increasing the production of a component of the extracellular matrix.

11. 2. The compound according to claim 1, wherein the anti-aging benefit is achieved by controlling the altered expression of genes in skin keratinocytes involved in the extracellular matrix composition, enhancing ECM components, moisturizing the skin, and filling in fine lines and wrinkles.

12. 3. The compound according to claim 2, wherein the anti-aging benefit is achieved by controlling the altered expression of genes in skin keratinocytes involved in the composition of the extracellular matrix, enhancing ECM components, moisturizing the skin and filling in fine lines and wrinkles.

13. The compound of claim 1, wherein at least one gene associated with wound healing, cytoskeleton regulation, antioxidant, immune signaling, cell proliferation, cell signaling, DNA repair, transcriptional regulation and skin barrier function is upregulated.

14. The compound of claim 2, wherein at least one gene associated with wound healing, cytoskeleton regulation, antioxidant, immune signaling, cell proliferation, cell signaling, DNA repair, transcriptional regulation and skin barrier function is upregulated.

15. 2. The compound of claim 1, wherein at least one anti-aging benefit is achieved by regulating protein expression of HAS2, HAS3, LAMC2, ECM1 (40% increase), COL1A1, SELE, SIRT7, SIRT1, SERPINB4, SERPINB2, SOD2, HIF1A, TGFB1, NGF, EREG and HBEGF.

16. 3. The compound of claim 2, wherein at least one anti-aging benefit is achieved by regulating protein expression of HAS2, HAS3, LAMC2, ECM1 (40% increase), COL1A1, SELE, SIRT7, SIRT1, SERPINB4, SERPINB2, SOD2, HIF1A, TGFB1, NGF, EREG and HBEGF.

17. The compound of claim 1, wherein the compound is 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',4'-dihydroxyphenyl)-propane or 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',5'-dihydroxyphenyl)-propane.

18. The compound of claim 2, wherein the compound is 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',4'-dihydroxyphenyl)-propane or 1-(3-methyl-2,4-dimethoxyphenyl)-3-(2',5'-dihydroxyphenyl)-propane.

19. 2. The compound of claim 1, wherein the compound is extracted, concentrated and purified from Dianella ensifolia.

20. 3. The compound of claim 2, wherein the compound is extracted, concentrated and purified from Dianella ensifolia.

21. The compound of claim 1 , wherein the compound is synthesized and purified.

22. The compound of claim 2, wherein the compound is synthesized and purified.

23. 10. The compound of claim 1, wherein the compound is biosynthesized from plant or fungal tissue, stem cells, and transgenic microorganisms and is synthetically modified by isolated or expressed enzymes.

24. 3. The compound of claim 2, wherein the compound is biosynthesized from plant or fungal tissue, stem cells and transgenic microorganisms and is synthetically modified by isolated or expressed enzymes.

25. 10. The compound of claim 1, wherein the compound is formulated in a carrier and may include solutions, emulsions, creams, lotions, ointments or gels containing one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, emulsifiers and stabilizers.

26. 3. The compound of claim 2, wherein the compound is formulated in a carrier and may include solutions, emulsions, creams, lotions, ointments or gels including one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, emulsifiers and stabilizers.

27. 10. A composition comprising the compound of claim 1, wherein the compound is present in the composition in an amount of 0.001-2%.

28. 3. A composition comprising the compound of claim 2, wherein the compound is present in the composition in an amount of 0.001-2%.

29. 10. A composition comprising the compound of claim 1, wherein the compound is present in the composition in an amount of 0.2%.

30. 3. A composition comprising the compound of claim 2, wherein the compound is present in the composition in an amount of 0.2%.

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