Diaryl alkane compounds and compositions for skin aging and methods of production thereof

Abstract

Disclosed are diaryl alkane compounds for resisting aging, reducing wrinkles, and promoting topical skin care of extracellular matrix. Also disclosed are data and information from clinical trials that demonstrate a reduction in the number of fine and wrinkles, a reduction in wrinkle depth, and a reduction in skin roughness after treatment with the compounds.

Description

[0001] This U.S. patent application claims priority to U.S. Provisional Patent Application Serial No. 63,330,002 filed on April 12, 2022, which is commonly owned and incorporated herein in its entirety. Technical Field

[0002] The contemplated compounds and compositions involve topical application of at least one diarylalkane compound including dimethoxycresylpropylresorcinol (as found in the International Nomenclature of Cosmetic Ingredients or INCI) for reversing or preventing 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 Art

[0003] Skin care ingredients that reverse or prevent signs of skin aging, such as fine lines and wrinkles on facial skin and especially periorbital skin, are needed. With aging due to a natural decline in skin cell replication, skin elasticity and water content, wrinkles form in the skin, which can be accelerated by UV light exposure, smoking and pollutant exposure (Farage MA, 2007)(Fore, 2006)(Haydont V, 2019). The skin is composed of an epidermis, which includes several layers of squamous cells that form an external skin barrier, and below the epidermis is a basement membrane (Michalak M, 2021). Like all basement membranes in epithelial tissue, it is an interface between a cell layer and an extracellular matrix. The basement membrane in the skin is called the dermal-epidermal junction, and as the skin ages, the signaling between these compartments is impaired, and the vascular support and structural support of the epidermis are also impaired (Langton AK, 2016). The extracellular matrix below the basement membrane includes the dermis of the skin. This layer contains fibroblasts, nerves, blood vesicles, hair follicles, sweat glands and sebaceous glands, as well as forming a matrix through which immune cells travel. The extracellular matrix is ​​composed of fibrous proteins and water-binding glycosaminoglycans, and its composition determines the cushioning and elasticity of the skin. Hyaluronic acid (HA) is a glycosaminoglycan that is naturally present in connective tissue throughout the body. Hyaluronic acid binds to cellular HA receptors, causing cell signaling cascades that affect cell survival, proliferation, adhesion and migration activity. In the skin, its main function is to bind water molecules to retain water within the tissue and maintain the integrity of the dermis (Bukhari SNA, 2018). Fibrous proteins in the dermis include collagen, fibronectin, laminin and elastin. These proteins are secreted by fibroblasts present in the ECM and form the structural components of the dermis of the skin. Downregulation of ECM proteins leads to thinning of the dermis and decreased water content, compromising the structural support of the skin, resulting in sagging skin and visible wrinkles (Farage MA, 2007; Fore, 2006; Haydont V, 2019). Current topical treatments for reducing wrinkles include retinoids, vitamins, hydroxy acids, peptides, extracts, and others. Their mechanisms of action include moisturizing 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] Diaryl alkane compounds for anti-aging, wrinkle reduction and extracellular matrix promotion are contemplated and their use is disclosed. The diaryl alkane compounds contemplated include dimethoxytolylpropyl resorcinol.

[0005] The contemplated compositions include the compound in an amount of 0.001 weight percent to 2 weight percent. In some embodiments, the contemplated compositions include the compound in an amount of about 0.2 weight percent. BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 Shown is a contemplated diarylalkane compound for anti-aging, wrinkle reduction, which is dimethoxycresylpropylresorcinol. DETAILED DESCRIPTION

[0007] The diarylalkane compounds contemplated include those having the INCI name dimethoxycresylpropylresorcinol, such as Figure 1 The compounds shown in the table and the 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 have been previously isolated from Dianella ensifolia and used for other skin care applications unrelated to anti-aging or wrinkle treatment (Nesterov A, 2008). Methods for extracting and purifying the compounds from Dianella ensifolia and organic synthesis methods for producing the compounds and skin whitening uses based on tyrosinase inhibition are patented in US Patent Nos. 7,767,661; 8,592,488; 8,729,136; 9,126,913; and 10,857,082B2.

[0008] The contemplated embodiments relate to reversing and preventing fine lines and wrinkles associated with aging on the skin. Specifically, the contemplated compounds and compositions comprise at least one topical ingredient that was used in clinical trials to reduce the number and appearance of fine lines and wrinkles, increase brightness in Asian populations, and reduce spots and age spots in Caucasian populations. The mechanism of action of the contemplated embodiments was explored by in vitro gene expression and protein expression experiments, and it was found that the present invention increased proteins involved in the extracellular matrix. Additional gene expression changes observed included increases in genes associated with cytoskeleton, immune signaling, cell signaling, DNA repair, transcription, anti-oxidation, cell growth, skin barrier, wound healing, and keratinocyte differentiation.

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

[0010] As shown herein, these results were confirmed by an in vitro increase in extracellular matrix genes and genes that increase hyaluronic acid synthesis. Additional genes that were found to be upregulated have such skin-related functions as wound healing, cytoskeleton regulation, anti-oxidation, immune signaling, cell growth, cell signaling, DNA repair, transcriptional regulation, and skin barrier function.

[0011] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer in the listed range, and include their fractions (such as one tenth and one hundredth of integers) when appropriate. In addition, unless otherwise indicated, any numerical ranges related to any physical characteristics such as polymer subunits, sizes or thicknesses listed herein should be understood to include any integer in the listed range. Unless otherwise indicated, the terms "about" and "consisting essentially of..." as used herein mean ±20% of the indicated range, value or structure. It should be understood that the terms "one / kind (a)" and "an" as used herein refer to "one / kind or more / kind" or "at least one / kind" in the enumerated components / components. The use of alternatives (e.g., "and / or") should be understood to mean one, both or any combination thereof in the alternatives. Unless the context requires otherwise, throughout the specification and claims, the word "comprise" and variations such as "comprises" and "comprising," and synonymous terms such as "include" and "having" and variations thereof, should be interpreted in an open, inclusive sense; that is, "including but not limited to."

[0012] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" at various locations 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 the 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 in a manner that cleaves the parent compound of the present disclosure during routine manipulation or in vivo. Prodrugs include compounds of the present disclosure in which a hydroxyl, amino or sulfhydryl group is bonded to any group that cleaves to form a free hydroxyl, free amino or free sulfhydryl group, respectively, when the prodrug of the compounds of the present disclosure is administered to a mammalian subject. Examples of prodrugs include acetate, formate and benzoate derivatives of alcohol functional groups or amide derivatives of amine functional groups in the compounds of the present disclosure, etc.

[0014] "Stable compound" and "stable structure" are meant 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" components or compounds are intended to indicate one or more inherent chemical components or compounds in the disclosed plants, plant extracts, or compositions having a combination of 2-3 plant extracts, which are used to control the quality, consistency, integrity, stability and / or biological function of the compositions of the present invention.

[0016] "Mammal" includes humans and domestic animals, such as experimental animals or household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domestic animals, such as wild animals, etc.

[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 where the element, component, event or circumstance occurs and instances where the element, component, event or circumstance does not occur. For example, "optionally substituted aryl" means that aryl may or may not be substituted, and that the description includes both substituted aryl and unsubstituted aryl.

[0018] "Pharmaceutically or nutraceutically acceptable carriers, diluents or excipients" include any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0019] "Pharmaceutically or nutraceutically acceptable salts" include both acid addition salts and base addition salts. "Pharmaceutically or nutraceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such 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-hydroxyethyl Sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic 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, undecylenic acid, etc.

[0020] "Pharmaceutically or nutraceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by the addition of inorganic or organic bases to the free acids. Salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. In certain embodiments, the inorganic salt is an ammonium salt, sodium salt, potassium salt, calcium salt, 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, denanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, phenethylamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Particularly useful organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0021] Typically, crystallization produces a solvate of the compounds of the present disclosure. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the present disclosure and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist in the form of a hydrate, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., and corresponding solvated forms. The compounds of the present disclosure may be true solvates, while in other cases, the compounds of the present disclosure may retain only exogenous water or a mixture of water plus some exogenous solvents.

[0022] "Pharmaceutical composition" or "nutraceutical composition" refers to a formulation of a compound of the present disclosure and a medium generally accepted in the art for delivering biologically active compounds to a mammal (e.g., a human). For example, the pharmaceutical composition of the present disclosure can be formulated or used as an independent composition, or as a component in a prescription drug, an over-the-counter (OTC) drug, a botanical, an herbal medicine, a natural medicine, a homeopathic remedy, or any other form of health care product reviewed and approved by a government agency. Exemplary nutraceutical compositions of the present disclosure can be formulated or used as an independent composition, or as a nutrient or biologically active component in a food, a functional food, a beverage, a bar, a food flavor, a medical food, a dietary supplement, or a herbal product. Medium generally accepted in the art includes all pharmaceutically or nutraceutically acceptable carriers, diluents, or excipients thereof.

[0023] As used herein, "enriched" means that the amount of one or more active compounds of a plant extract or other preparation is increased by at least two times to about 1000 times compared to the amount of one or more active compounds found in the weight of the plant material or other source before extraction or other preparation. In certain embodiments, the weight of the plant material or other source before extraction or other preparation can be dry weight, wet weight, or a combination thereof.

[0024] As used herein, "major active ingredient" or "major active component" refers to one or more active compounds found in plant extracts or other preparations or enriched in plant extracts or other preparations, which have at least one biological activity. In certain embodiments, the major active ingredient of the enriched extract will be one or more active compounds enriched in the extract. Typically, compared with other extract components, one or more major active components will directly or indirectly confer most of one or more measurable biological activities or effects (i.e., greater than 50%, or 20% or 10%). In certain embodiments, the major active ingredient can be a minor component of the extract weight percentage (e.g., less than 50%, 25%, or 10% or 5% or 1% of the components contained in the extract), but still provides most of the required biological activity. Any composition containing the major active ingredient of the present disclosure may also contain minor active ingredients, which may or may not contribute to the drug or nutraceutical activity of the enriched composition, but do not contribute to the level of the major active ingredient, and in the absence of the major active ingredient, the minor active component alone may not be effective.

[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, liver spots (solar lentigo), 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 biologically active compound or biomarker of the condition being treated and the severity of the condition, the mode of administration, the duration of treatment, or the age of the subject being treated, but can be routinely determined by one of ordinary skill in the art based on their own knowledge and this disclosure.

[0027] As used herein, "treating" or "treatment" refers to the treatment of a target disease or condition in a mammal, such as a human, that has the target disease or condition, and includes: (i) preventing the occurrence of the disease or condition in the mammal, particularly when such mammal is susceptible to the condition but has not yet been diagnosed as having the condition; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) alleviating or modifying the disease or condition, i.e., causing regression of the disease or condition; or (iv) alleviating the symptoms caused by the disease or condition (e.g., reducing the appearance of fine lines, wrinkles and liver spots (pigmentation spots) without addressing the underlying disease or condition); or (v) altering the phenotype of the disease or condition.

[0028] As used herein, the terms "disease" and "disorder" may be used interchangeably, or may be different in that a particular disease or disorder may not have a known etiology (so that the cause has not yet been figured out) and therefore has not been recognized as a disease, but only as an undesirable condition or syndrome in which clinicians have identified a group of more or less specific symptoms.

[0029] As used herein, "statistically significant" refers to a p-value of 0.050 or less when calculated using Student's t-test, and indicates that the particular event or result measured is unlikely to have occurred by chance.

[0030] For administration purposes, the compounds under consideration (such as diaryl alkane compounds including dimethoxytolylpropyl resorcinol) can be applied as raw chemicals or can be formulated as pharmaceutical or nutraceutical compositions. The pharmaceutical or nutraceutical compositions under consideration comprise compounds of the structures described herein and pharmaceutically or nutraceutically acceptable carriers, diluents or excipients. The compounds of the structures described herein are present in the composition in an amount effective to treat a specific target disease or condition, i.e., in an amount generally sufficient to reduce the appearance of fine lines, wrinkles and liver spots (solar pigmentation spots) or any other related indications described herein, and are generally present in an amount acceptable to the patient.

[0031] Can be via any acceptable mode of administration of reagent for providing similar effect, carry out in pure form or with suitable medicine or nutraceutical composition to apply the diaryl alkane compound (including dimethoxytolyl propyl resorcinol or other related compositions disclosed herein) or its pharmaceutically or nutraceutical acceptable salt considered.Medicine or nutraceutical composition of the present disclosure can be prepared by combining compound of the present disclosure with suitable pharmaceutically or nutraceutical acceptable carrier, diluent or excipient, and can be formulated into solid, semisolid, liquid or gaseous preparations, such as powder, granule, ointment, solution, injection, inhalant, gel, cream, lotion, tincture, facial mask and microsphere.The typical approach of using such medicine or nutraceutical composition includes oral, topical, transdermal, suction, parenteral, sublingual, oral, rectal, vaginal or intranasal.Term parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion technology.

[0032] Prepare medicine, dermatology or nutraceutical compositions disclosed herein so that after the composition is applied to the patient, the active ingredients contained therein are bioavailable. The composition to be applied to a subject or patient or mammal is in the form of one or more dosage units, wherein for example tablets can be single dosage units, and the container of the compound of the present disclosure or extract or 2-3 plant extracts in the form of aerosol can accommodate multiple dosage units. The actual method of preparing such dosage forms is known to those skilled in the art, or will be obvious; for example, referring to Remington: The Science and Practice of Pharmacy, the 20th edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be applied will contain a therapeutically effective amount of the compound of the present disclosure or its pharmaceutically or nutraceutical acceptable salt in any case, for treating target diseases or disorders according to the teaching disclosed herein.

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

[0034] When intended for oral administration, the dermatological, pharmaceutical or nutraceutical composition is in solid or liquid form, with semi-solid, semi-liquid, suspension and gel forms included within the forms considered herein as solid or liquid.

[0035] As solid compositions for oral administration, dermatological, pharmaceutical or nutraceutical compositions can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gums, sashays, wafers, sticks, etc. Such solid compositions will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following items 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] Liquid dermatological, pharmaceutical or nutraceutical compositions of the present disclosure, whether they are solutions, suspensions or other similar forms, may contain one or more of the following adjuvants: sterile diluents, such as water for injection, saline solutions, such as physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils, such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, propylene glycol or other solvents that can be used as solvents or suspension media; antibacterial agents, such as benzyl alcohol or methyl parabens; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates; and agents for adjusting tonicity, such as sodium chloride or glucose. Parenteral preparations can be packaged in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a commonly available adjuvant. Injectable pharmaceutical or nutraceutical compositions are sterile.

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

[0038] The dermatological, pharmaceutical or nutraceutical compositions of the present disclosure in solid or liquid form may contain agents that bind to the compounds of the present disclosure and thereby facilitate the delivery of the compounds. Suitable agents that may perform this function 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 reducing the size of the particles, for example to improve bioavailability. The size of the powders, granules, particles, microspheres, etc. in the composition may be macroscopic (e.g., visible to the naked eye or at least 100 μm in size), microscopic (e.g., the size may be in the range of about 100 μm to about 100 nm), nano (e.g., the size may not exceed 100 nm), and any size therebetween or any combination thereof, with or without excipients, to improve size and packing density.

[0040] The dermatology, medicine or nutraceutical compositions of the present disclosure can be prepared by methods well known in the field of medicine or nutraceuticals. For example, medicine 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 promote the formation of uniform solutions or suspensions. Surfactants are compounds that non-covalently interact with the compounds of the present disclosure to promote dissolution or uniform suspension of the compounds in an aqueous delivery system.

[0041] The compounds of the present disclosure, or dermatologically, pharmaceutically or nutraceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on a variety of factors, including the activity of the specific compound employed; the metabolic stability and duration of action of the compound; the age, weight, general health, sex and diet of the patient; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the subject undergoing treatment.

[0042] It is understood that throughout the specification, combinations of substituents or variables of the depicted formulas are permissible only if such combinations result in stable compounds.

[0043] Those skilled in the art will also appreciate that in the methods described herein, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, sulfhydryl and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for sulfhydryl include C (O) R "(wherein R " is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, etc. Suitable protecting groups for carboxylic acid include alkyl esters, aryl esters or aralkyl esters. Protecting groups can be added or removed according to standard techniques, which are known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd edition, Wiley. As will be appreciated by those skilled in the art, the protecting group may also be a polymeric resin such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

[0044] Those skilled in the art will also appreciate that, although such protected derivatives of the contemplated compounds disclosed herein may not themselves have dermatological and pharmacological activity, they can be administered to mammals and then metabolized in vivo to form pharmacologically active compounds of the present disclosure. Therefore, such derivatives can be described as "prodrugs". All prodrugs of the compounds of the present invention are included within the scope of the present disclosure.

[0045] In addition, all compounds or extracts of the present disclosure that exist in free base or acid form can be converted into their pharmaceutically or nutraceutical acceptable salts by methods known to those skilled in the art with appropriate inorganic or organic bases or acids. Salts of compounds of the present disclosure can be converted into their free base or acid forms by standard techniques.

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

[0047] Also contemplated herein are reagents of the disclosed and contemplated diarylalkane compounds, including dimethoxytolylpropylresorcinol. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Thus, the contemplated compounds are those produced by methods including administering the contemplated compound or composition to a mammal for a period of time sufficient to produce its metabolites.

[0048] The compound, pharmaceutical composition and composition considered may include or additionally include at least one pharmaceutically or nutraceutical or cosmetically acceptable carrier, diluent or excipient or consist of it. As used herein, the phrase "pharmaceutically or 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, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration as acceptable for human or livestock. The compound, pharmaceutical composition and composition considered may include or additionally include at least one pharmaceutically or nutraceutical or cosmetically acceptable salt or consist of it. As used herein, the phrase "pharmaceutically or nutraceutical or cosmetically acceptable salt" includes both acid addition salts and base addition salts.

[0049] In some embodiments, the diarylalkane compound under consideration (including those comprising dimethoxytolylpropylresorcinol) can be separated from plant and / or marine sources. Suitable plant parts for separating the compound include leaves, bark, trunk, trunk bark, stem, stem bark, branches, tubers, roots, rhizomes, root bark, bark surface, twigs, seeds, fruits, stamen groups, pistils groups, calyx, stamens, petals, sepals, carpels (pistil), flowers or any combination thereof. In some related embodiments, the compound or extract is separated from plant sources and synthetically modified to contain any substituents listed. In this regard, the synthetic modification of the compound separated from the plant can be completed using a variety of techniques known in the art and fully within the knowledge of those of ordinary skill in the art. In some related embodiments, the diarylalkane compound under consideration (including those comprising dimethoxytolylpropylresorcinol) is biosynthesized by plant tissue or fungal tissue, stem cell and transgenic microorganism, and is synthetically modified to contain any substituents listed by separating or expressing enzymes. In this regard, biosynthetic modifications of the contemplated compounds can be accomplished using a variety of synthetic biology techniques known in the art and well within the knowledge of one of ordinary skill in the art.

[0050] Herein, the anti-aging effects of the contemplated diarylalkane compounds (including those containing dimethoxytolylpropylresorcinol) on human keratinocytes in vitro and in human clinical trials are disclosed. In keratinocytes treated with the contemplated diarylalkane compounds (including those containing dimethoxytolylpropylresorcinol), we found profound similarities in differentially expressed genes compared to retinol-treated keratinocytes. Additional changes specific to the contemplated diarylalkane compounds (including those containing dimethoxytolylpropylresorcinol) include increased extracellular matrix protein and proteoglycan synthesis, and contribute to the reorganization of the extracellular matrix. These and other activities (such as growth factor signaling, keratinocyte differentiation, cell-cell communication, and cell-ECM communication) enriched in keratinocytes treated with the contemplated diarylalkane compounds (including those containing dimethoxytolylpropylresorcinol) are related to anti-aging. In human clinical trials, we found that contemplated diarylalkane compounds, including those containing dimethoxycresylpropylresorcinol, in a 0.2% cream applied twice daily on the face improved the appearance of fine lines and wrinkles, as well as increased skin lightness / brightness in human subjects of the Asian population and reduced skin spots / age spots in Caucasian populations.

[0051] Example

[0052] The examples herein focus on the use of dimethoxytolylpropylresorcinol, but it is understood that similar diarylalkane compounds may be used, and one of ordinary skill in the art will understand how those similar diarylalkane compounds may be used in the compositions contemplated herein.

[0053] Example 1. Global gene expression changes in keratinocytes treated with dimethoxycresylpropylresorcinol

[0054] To determine the specific expression changes of dimethoxytolylpropyl resorcinol on human keratinocyte senescence genes, keratinocytes (Hacat cell line) were treated with 40 μM dimethoxytolylpropyl resorcinol and gene expression was analyzed by RNA-seq. The differential gene expression of untreated keratinocytes and cells treated with 40 μM retinol A was compared to find genes involved in aging. Statistically significantly differentially regulated genes (p < 0.05) were included in the analysis. Retinol was selected 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 effects of retinol on keratinocytes compared with the same concentration of dimethoxytolylpropyl resorcinol.

[0055] Localization and biological processes of proteins enriched in both retinol-treated and DMRP-treated keratinocytes

[0056] First, we compared the enriched biological processes common to both retinol-treated keratinocytes and DMRP-treated keratinocytes (Table 1). Protein localization and biological processes associated with skin aging were enriched in both retinol-treated keratinocytes and DMRP-treated keratinocytes, including the extracellular space, protein extracellular matrix, extracellular area, epidermal development, and epithelial cell differentiation.

[0057] Table 1. Protein localization and biological processes upregulated in both retinol-treated keratinocytes and DMRP-treated keratinocytes (listed according to the number of genes affected in retinol-treated keratinocytes)

[0058]

[0059]

[0060]

[0061] Localization and biological processes of proteins enriched only in dimethoxycresylpropylresorcinol-treated keratinocytes

[0062] In our study, we found several aging-related biological processes that were enriched in keratinocytes treated with dimethoxytolylpropylresorcinol, but not in keratinocytes treated with retinol. Importantly, the wound healing process enrichment indicates increased dynamics in the tissue, which may affect the appearance of aging phenotypes in the skin. Increased keratinocyte differentiation enrichment indicates an enhancement of the skin barrier, which makes the skin less sensitive to external damage (Gutowska-Owsiak D, 2020). Hyaluronic acid is important for the hydration of the skin because it is a proteoglycan that binds water molecules in the extracellular matrix of the skin. The processes that were enriched in keratinocytes treated with dimethoxytolylpropylresorcinol but not in keratinocytes treated with retinol are listed in Table 2.

[0063] Table 2. Gene clusters enriched in DMRP-treated keratinocytes (listed according to the number of genes affected in DMRP-treated keratinocytes)

[0064]

[0065] Differentially regulated genes in retinol-treated keratinocytes and DMRP-treated keratinocytes

[0066] Specific senescence genes that are commonly regulated between retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-treated keratinocytes are listed in Tables 3-8.

[0067] Extracellular matrix (ECM) genes that were upregulated in both retinol-treated keratinocytes and dimethoxytolylpropylresorcinol-treated keratinocytes included TFP12, which encodes a serine protease inhibitor that inhibits trypsin and a matrix metalloproteinase that decomposes the extracellular matrix, and CRISPLD2, which is believed to be involved in glycosaminoglycan binding and directly affects 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. Increases in the expression of these genes can indicate an increase in cell-ECM communication and adhesion.

[0068] Among the ECM genes that were down-regulated in both the keratinocytes treated with retinol and the keratinocytes treated with dimethoxytolylpropylresorcinol, all were related to cell adhesion and were proteins and proteoglycans present in the extracellular matrix. The down-regulation of these genes may be related to changes in matrix composition or changes in cell adhesion dynamics. The differential expression of these genes is listed in Table 3.

[0069] Table 3. ECM genes differentially expressed in both retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-treated keratinocytes (listed according to fold change in retinol-treated keratinocytes)

[0070]

[0071]

[0072] Among the upregulated genes involved in plasma membrane fusion, cytoskeletal remodeling and lipid metabolism, RAPGEF3 activated small GTPases involved in cytoskeletal remodeling and plasma membrane dynamics, indicating that retinol and dimethoxytolylpropyl resorcinol 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.

[0073] KIF13A (microtubule motor protein) was downregulated in both retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-treated keratinocytes. KIF13A is involved in the transport of endosomes along microtubules, and its downregulation may indicate changes in transport dynamics. The differential expression of these genes is listed in Table 4.

[0074] Table 4. Cytoskeletal and transport genes differentially regulated in both retinol-treated and DMRP-treated keratinocytes

[0075]

[0076] ANOS1, TNC and SEMA3D are extracellular matrix proteins that are primarily involved in neuronal cell adhesion and axon extension, so downregulation of these genes could indicate a shift away from skin innervation. Tenascin C (TNC) has previously been shown to be downregulated in retinoic acid treated rat glioma cells (Alvarez-Dolado M, 1999). These proteins may have other functions in the extracellular matrix that affect skin aging and explain their downregulation in retinol treated keratinocytes and dimethoxytolylpropylresorcinol treated keratinocytes. The differential expression of these genes is listed in Table 5.

[0077] Table 5. Extracellular matrix proteins involved in neural cell adhesion and axon extension differentially expressed in both retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-treated keratinocytes

[0078]

[0079] Both retinol and dimethoxytolylpropyl resorcinol induce changes in the expression of growth-related genes. In general, the net effect of these changes is a decrease in cell proliferation, as three genes involved in negative regulation of growth are upregulated: PTPRR, C3orf33 and ANGPTL4, and four genes involved in growth are downregulated: BMP4, FGF1, FGF11 and TP73. The differential expression of these genes is listed in Table 6.

[0080] Table 6. Growth genes differentially regulated in retinol-treated keratinocytes and DMRP-treated keratinocytes

[0081]

[0082]

[0083] Immune signaling is increased in keratinocytes treated with retinol and keratinocytes treated with dimethoxytolylpropylresorcinol because CYP1A1 (a cytochrome p450 family member oxygenase) is involved in drug metabolism. These genes can be upregulated in direct response to drug treatment, especially CYP1A1. The changes seen in immune signaling genes can demonstrate the effect of increasing immune signaling in keratinocytes treated with retinol and keratinocytes treated with dimethoxytolylpropylresorcinol. The differential expression of these genes is listed in Table 7.

[0084] Table 7. Immune genes differentially expressed in retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-treated keratinocytes

[0085]

[0086] TXNRD1 (antioxidant enzyme) was upregulated in both retinol-treated keratinocytes and dimethoxycresylpropylresorcinol-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.

[0087] Table 8. Differentially expressed antioxidant genes in retinol-treated keratinocytes and dimethoxyphenylpropylresorcinol-treated keratinocytes

[0088]

[0089] Genes differentially expressed only in DMRP-treated keratinocytes

[0090] There is a large subset of skin aging genes that are differentially expressed in DMRP-treated keratinocytes but not in retinol-treated keratinocytes and are listed in Tables 9-14.

[0091] Among the extracellular matrix and cell adhesion genes, hyaluronan synthases HAS2 and HAS3 are upregulated the most in keratinocytes treated with dimethoxytolylpropylresorcinol. These genes are responsible for the production of hyaluronic acid, which is a proteoglycan abundant in the extracellular matrix and is essential for skin hydration. LAMC2 and LAMA3 laminins (proteins in the extracellular matrix) are upregulated, and COL1A1 (the most abundant collagen in the connective tissue of the skin) is also upregulated. ECM1 (extracellular matrix protein) and NID2 (extracellular glycoprotein) are also upregulated. PI3 (inhibitor of elastase) is upregulated, and the result will be the stability of elastin in the extracellular matrix. Elastin is an extracellular matrix protein that is essential for the elasticity of the connective tissue of the skin. Cell surface adhesion molecules SELE and ITGA6 are also upregulated in keratinocytes treated with dimethoxytolylpropylresorcinol, while ITGBL1 (integrin-associated protein) is downregulated.

[0092] Together, these changes demonstrate that dimethoxycresylpropylresorcinol conferred increased production of extracellular matrix proteins, which was paired with increased cell adhesion to the extracellular matrix. The differential expression of these genes is listed in Table 9.

[0093] Table 9. Extracellular matrix genes differentially expressed in DMRP-treated keratinocytes

[0094]

[0095] Compared with retinol-treated keratinocytes, growth factor and motility signaling are differentially regulated in dimethoxytolylpropylresorcinol-treated keratinocytes. TGF-β signaling increases the expression of extracellular matrix proteins and proteoglycans, and reduces matrix metalloproteinase (MMP) gene expression in the skin (Imfeld D, 2015). We found that dimethoxytolylpropylresorcinol increased the expression of TGFB1, a ligand for TGF-β signaling, causing increased signaling of the pathway. IL1A (cytokine) is also upregulated in dimethoxytolylpropylresorcinol-treated keratinocytes, but not in retinol-treated keratinocytes. IL-1α is important for inducing wound healing in the skin by causing migration to keratinocytes via autocrine signaling and migration to fibroblasts via paracrine signaling (Chen JD, 1995)(Zheng R, 2019). The differential expression of these genes is listed in Table 10.

[0096] Table 10. Differentially expressed signal transduction and cytokine genes in DMRP-treated keratinocytes

[0097]

[0098] PARP15 is a protein modifying enzyme that affects protein activity. PARP15, together with other PARP family members, can be involved in transcriptional regulation through histone modification and affect DNA damage repair. SIRT genes are involved in aging by transcriptional repression via deacetylation of histones and transcription factors, although they can also deacetylate other protein targets. Their activity regulates proliferation and differentiation and maintains genomic stability (Simon M, 2020)(Dai Y, 2008). SIRT1 gene expression decreases with age, and SIRT1 activators are being used as topical treatments for skin aging due to their protective effects against UVR-induced aging effects (Bielach-Bazyluk A, 2021). The upregulation of these genes suggests that the inhibition of skin aging by dimethoxytolylpropylresorcinol may be partly due to transcriptional repression. The differential expression of these genes is listed in Table 11.

[0099] Table 11. Differentially expressed DNA repair and transcriptional regulatory genes in DMRP-treated keratinocytes

[0100]

[0101]

[0102] SERPIN is a family of serine protease inhibitors, which are important for maintaining skin structure (Cork MJ, 2009). SERPINB2 has been shown to have a protective effect on the skin barrier, because the barrier function of knockout mice is reduced (Schroder WA, 2016). SERPINB2 and SERPINB4 have also been shown to be important for protection from UV radiation, which is the main cause of skin aging (Katagiri C, 2006)(Majoros H, 2019). FABP5 is involved in the maintenance of skin barrier function by regulating fatty acid synthesis and cell membrane homeostasis. It has been shown that mice with fatty acid binding protein defects have changed the water barrier function in their skin (Owada Y, 2002). CDK5R1 activates cyclin-dependent kinase 5 (CDK5), i.e., CDK that is mainly expressed in neurons but functions in other tissues. CDK5 knocks down mice with impaired epidermal structure, and it is found that this is due to keratin 10 (K10), i.e., the reduction of epidermal intermediate filaments (Dong C, 2017). As an integral 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 aging skin (Choi, 2019), and are upregulated in keratinocytes treated with dimethoxytolylpropylresorcinol. The differential expression of these genes is listed in Table 12.

[0103] Table 12. Skin barrier genes differentially expressed in DMRP-treated keratinocytes

[0104]

[0105]

[0106] Oxidative stress caused by both intrinsic and extrinsic factors plays a major role in the skin aging process. UV irradiation, pollution, and other environmental factors are some of the extrinsic causes of oxidative stress. Neutralizing reactive oxygen species in the skin is important for combating 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 activated in response to xenobiotics. It activates genes involved in metabolism, but can also activate antioxidant programs by upregulating NRF2, SOD1, and other genes (Dietrich, 2016). SOD2 is an ROS-neutralizing enzyme because it directly converts superoxide into hydrogen peroxide and diatomic oxygen. HIF1A is a transcription factor involved in oxygen homeostasis. Although it is usually upregulated in hypoxic environments, it is also activated in response to hydrogen peroxide-rich environments and upregulates antioxidant genes (Li HS, 2019). By neutralizing reactive oxygen species, these genes effectively reduce the signs of skin aging. The differential expression of these genes is listed in Table 13.

[0107] Table 13. Oxidative stress genes differentially expressed in keratinocytes treated with dimethoxycresylpropylresorcinol

[0108]

[0109] Although NGF is an effective neuronal growth factor, in the skin, it plays a role in keratinocyte migration and wound healing (Matsuda H, 1998) (Gostynska N, 2020). Evidence that NGF is downregulated in aging skin shows that its function is important for maintaining skin function and integrity (Adly MA, 2006). Both EREG and HBEGF are ligands of epidermal growth factor receptor EGFR, which regulate many functions of keratinocytes, including proliferation, adhesion and migration, survival and differentiation. In humans, it has been shown that inhibition of EGFR signaling leads to skin aging phenotypes, including downregulation of hyaluronan synthase genes and upregulation of aging genes in keratinocytes (Gerber PA, 2016). These growth signaling pathways are critical for skin function and integrity, as demonstrated by their reduction in aging skin. The differential expression of these genes is listed in Table 14.

[0110] Table 14. Growth genes differentially expressed in DMRP-treated keratinocytes

[0111]

[0112] In summary, the changes observed in DMRP-treated keratinocytes indicate similarities with retinol-treated keratinocytes in differentially regulated skin aging processes: extracellular matrix protein deposition, lipid dynamics, cell adhesion, cell migration, cytoskeletal remodeling and trafficking, neuronal maturation, immune signaling, and antioxidation. There are many differentially regulated skin aging processes in DMRP-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 describes an anti-aging phenotype in keratinocytes.

[0113] Example 2: Confirmation of differential gene expression changes in DMRP-treated keratinocytes by protein quantification

[0114] From Example 1 above, several genes that demonstrated differential regulation were identified that were particularly important for skin aging by quantitative protein expression. Hacat immortalized human keratinocytes were treated with 40 μM dimethoxycresylpropyl resorcinol for 48 hours prior to lysis and subjected to Western blot, and the cell culture medium was subjected to Western blot to quantify protein levels. The dimethoxycresylpropyl resorcinol treated keratinocyte samples were compared to untreated keratinocyte samples (control). The target intracellular proteins are listed in Table 15, and the target extracellular proteins are listed in Table 16.

[0115] Table 15. Intracellular genes upregulated in RNA-seq with protein levels quantified by western blot

[0116] Function Gene protein ECM HAS2 Hyaluronan synthase 2 ECM HAS3 Hyaluronan synthase 3 Cell adhesion SELE Selectin E Transcriptional regulation SIRT7 Sirtuin 7 Transcriptional regulation SIRT1 Sirtuin 1 Skin Barrier SERPINB4 Serpin family B member 4 Skin Barrier SERPINB2 Serpin family B member 2 Oxidative stress SOD2 Superoxide dismutase 2 Oxidative stress HIF1A Hypoxia-inducible factor 1 subunit alpha

[0117] Table 16. Extracellular genes upregulated in RNA-seq with protein levels quantified by western blot

[0118]

[0119]

[0120] It was found that LAMC2, ECM1, COL1A1, HAS2, and HAS3 had higher protein levels in the DMRP-treated condition compared to the control. These are proteins involved in the composition of the extracellular matrix. These changes suggest that the anti-wrinkle or anti-aging activity of DMRP-treated is based on the increase of extracellular matrix components.

[0121]

[0122] Example 3: Dimethoxytolylpropylresorcinol shows efficacy on fine lines and wrinkles in human clinical trials

[0123] In order to evaluate the antioxidant properties of dimethoxycresylpropylresorcinol, a pilot clinical efficacy evaluation study of a skin treatment product was conducted using dimethoxycresylpropylresorcinol cream at a concentration of 0.2%. The purpose of the study was to evaluate whether the use of the product for 8 weeks would result in a reduction in the appearance of crow's feet fine lines and wrinkles. For this study, a group of 12 subjects ranging from 35 to 65 years old were recruited and evaluated at baseline (BL), week 2 (W2), week 4 (W4) and week 8 (W8) as summarized in Table 17. The study was a single-blind, full-face, home-based study with 4 clinical visits after enrollment.

[0124] Table 17. Procedures for each clinical visit

[0125]

[0126]

[0127] The included subjects are:

[0128] 1. Female subjects aged 35-66 (inclusive) in good general health

[0129] 2. Individuals with fine lines / wrinkles scored as "5" (noticeable) or higher in the crow's feet area as assessed by a trained technician, and whose wrinkles were rated according to the following scale: 0 - none, 1-3 - mild, 4-6 - noticable, 7-9 - very noticable.

[0130] 3. Individuals who are able to read, understand and sign the informed consent form.

[0131] 4. Individuals who are expected to have the ability to follow study instructions, participate in the study, return for all visits, and administer the product according to the instructions.

[0132] Excluded subjects were:

[0133] 1. Women who are pregnant, planning to become pregnant, breastfeeding and / or nursing a child.

[0134] 2. Individuals with any visible skin disease that may interfere with the evaluation.

[0135] 3. Individuals who have a sunburn, facial tan, or plan to go on vacation for sun exposure or plan to use a tanning booth during the course of the study.

[0136] 4. Individuals involved in parallel research projects on facial products.

[0137] 5. Individuals using medications that may interfere with test results, including use of steroidal / nonsteroidal anti-inflammatory drugs or antihistamines.

[0138] 6. Individuals who have had a laser resurfacing or dermabrasion procedure or chemical facial skin peel on the face in the past 2 years (deep peel in the past year; superficial peel in the past 2 months).

[0139] 7. Individuals with acne, active atopic dermatitis / eczema, or psoriasis.

[0140] 8. Individuals who have had surgical "cosmetic" procedures on the face within the past 10 years.

[0141] 9. Treatment or history of any type of cancer.

[0142] 10. Individuals undergoing treatment for asthma or diabetes.

[0143] 11. Individuals with known sensitivity to cosmetics or personal care products.

[0144] At all visits, trained technicians evaluated the appearance of crow's feet, fine lines, and wrinkles based on the following scale: 0-none, 1-3-mild, 4-6-obvious, 7-9-very obvious. The technicians also evaluated each subject's face for irritation. No irritation was found in any part of any subject. A skin replica was obtained for each subject to evaluate 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 thoroughly mixed for about 15-20 seconds. Immediately thereafter, the mixture was placed on a CuDerm replica positioning ring pre-placed on the corner of each subject's eye. After 4-5 minutes, the ring was removed. The obtained skin replicas were shipped to BioNet, Inc for analysis. At the last visit, the subjects were asked to complete the questionnaire.

[0145] result:

[0146] Crow's feet, fine lines, and wrinkles improved after 2, 4, and 8 weeks of use of dimethoxycresol propyl resorcinol 0.2% cream, with clinically significant (≥10%) improvements at week 8.

[0147] Table 18. Mean scores for crow's feet, fine lines and wrinkles and % change from baseline

[0148] Average rating Change from Baseline Baseline 6.3 - Week 2 6.2 -1.6％ Week 4 6.1 -3.2％ Week 8 5.6 -11.1％*

[0149] *Indicates clinically significant (≥10% improvement)

[0150] Over the course of the study time, a higher proportion of subjects experienced an improvement in the appearance of their crow's feet, fine lines, and wrinkles (Table 19).

[0151] Table 19. Frequency of Responses for Improvement in Crow's Feet, Fine Lines, and Wrinkles (% of Subjects with Improvement from Baseline)

[0152]

[0153]

[0154] The skin replicas were analyzed using Replica Analysis Methods A and B. Method A measures brightness along a set of 10 parallel lines of equal length across the replica parallel to the direction of illumination. Changes in brightness are taken as an indication of roughness and analyzed by conventional surface roughness statistics. The following parameters were analyzed using Method A:

[0155] 1. Rz: The average maximum difference in the brightness values ​​of five equal length segments in each of the 10 lines passing through the sample. Maximum optical roughness.

[0156] 2. Ra: Average deviation of the brightness curve about the average brightness of the same 10 lines. Average optical roughness.

[0157] 3. FNum: The number of fine lines marks per mm. As fine lines and wrinkles disappear, FNum decreases.

[0158] 4. IDL: The integrated unfolded length of the luminance trace for 10 scan lines. This is the total length of the luminance line as a fraction of the straight-line distance. (ie, a flat, featureless sample has an IDL of 1.000).

[0159] Four weeks after starting to use dimethoxycresylpropylresorcinol 0.2% cream, the coarse lines had a statistically significant 28% reduction in the maximum difference in brightness (Rz) and a 32.7% reduction in the integrated spread length of the luminous trace, indicating a reduction in surface roughness. There was still a trend towards reduction at 8 weeks, but these changes were not statistically significant (Table 20).

[0160] After 2, 4 and 8 weeks of treatment with dimethoxycresylpropylresorcinol 0.2% cream, fine lines had statistically significant reductions in the maximum difference in brightness (Rz), the mean deviation of the luminescence curve (Ra), the number of fine lines per mm (FNum), and the integrated development length (IDL) of the luminescence trace. These consistent and significant reductions in surface roughness and the significant reduction in the number of fine lines (FNum) indicated significant wrinkle reduction and skin smoothness improvement (Table 20), even only two weeks after the start of dimethoxycresylpropylresorcinol use, and continued throughout the treatment course.

[0161] Table 20. Changes from Baseline in Method A Parameters for Skin Replicas (and % Change)

[0162]

[0163] * indicates statistical significance (p < 0.05)

[0164] 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 based on the brightness values ​​of these bands being less than a detection threshold.

[0165] 1. Spacing: The average distance between adjacent detected features (i.e., the spacing between the midpoints of adjacent shadow features) (in millimeters). Decreases with the transformation of deep wrinkles to fine wrinkles (moisturizing). Increases with the disappearance of wrinkles.

[0166] 2. Width: The average width (in millimeters) of the detected features (in millimeters). This parameter is proportional to the depth of the wrinkles that create the shadow. It decreases as the wrinkles become shallower.

[0167] 3. Shadows: The percentage of sampled replica area with brightness values ​​less than the detection threshold. This is the relative area of ​​shadows cast by wrinkles and fine lines in the replica. It decreases with smoother skin.

[0168] 4. NumWrinkles: The total number of features detected in the 10 bands or sub-regions used to calculate the spacing and width. In general, NumWr decreases with smoother skin (fewer visible features).

[0169] For coarse wrinkles, there were no significant changes in Method B parameters over the 8-week period of using dimethoxycresylpropylresorcinol 0.2% cream. For fine wrinkles, shadows cast by wrinkles and fine lines were significantly reduced by 42.3% and 37.5% at 2 and 4 weeks after the start of the treatment process, respectively. At 8 weeks, shadows were reduced by 30.9%, which was not statistically significant. The number of wrinkles (NumWr) was statistically significantly reduced at 2, 4, and 8 weeks after the start of dimethoxycresylpropylresorcinol. 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 that dimethoxycresylpropylresorcinol imparts an immediate and lasting reduction in fine lines (Table 21).

[0170] Table 21. Changes from Baseline in Method B Parameters for Skin Replicas (and % Change)

[0171]

[0172] * indicates statistical significance (p < 0.05)

[0173] The subjective questionnaire responses correlated with a high acceptance rate of the product by the subjects. The subjects' feelings about their own skin were analyzed based on the questionnaires and are summarized in Table 22. The vast majority of subjects noticed a reduction in the appearance of crow's feet, fine lines and wrinkles, felt that their skin had a healthier appearance, and noticed an improvement in the quality of their skin.

[0174] Table 22. Summary of Subject Questionnaire Responses at the Last Visit

[0175]

[0176]

[0177] Example 4: Dimethoxytolylpropyl resorcinol demonstrates efficacy in improving skin lightness and brightness in an Asian subject population and reducing the appearance of skin blotchiness and age spots in a Caucasian subject population

[0178] To evaluate the antioxidant properties of DMCR, a pilot clinical efficacy evaluation study of a skin treatment product was conducted using DMCR cream at a concentration of 0.2%.

[0179] The purpose of the study was to evaluate whether the use of the product for 8 weeks would result in an improvement in skin radiance / brightness in an Asian population, and a reduction in the appearance of skin spots / age spots in a Caucasian population. For this study, a group of 12 subjects ranging from 35 to 66 years old (6 Asian subjects and 6 Caucasian subjects) 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-based study with 4 clinical visits after enrollment.

[0180] Table 23. Procedures for each clinical visit

[0181]

[0182]

[0183] The included subjects are:

[0184] 1. Female subjects aged 35-66 (inclusive) in good general health

[0185] 2. Asian subjects whose facial (for assessment only) skin lightness / brightness scored "5" (moderate dull / sallow appearance) or higher as assessed by a trained technician, and whose lightness / brightness was rated according to the following scale: 0 - no visible dullness / sallowness, 1-3 - mild dull / sallow appearance, 4-6 - moderate dull / sallow appearance, 7-9 - severe dull / sallow appearance.

[0186] 3. Caucasian subjects with a facial (for assessment only) skin spot / age spot score of "5" (moderate skin spot / age spot area) or higher as assessed by a trained technician, and whose spots / age spots were rated according to the following scale: 0 - no visible skin spots or age spots, 1-3 - slight visible skin spots or age spot areas, 4-6 - moderate visible skin spots or age spot areas, 7-9 - severe visible skin spots or age spot areas.

[0187] 4. Individuals who are able to read, understand and sign the informed consent form.

[0188] 5. Individuals who are expected to have the ability to follow study instructions, participate in the study, return for all visits, and administer the product according to the instructions.

[0189] Excluded subjects were:

[0190] 1. Women who are pregnant, planning to become pregnant, breastfeeding and / or nursing a child.

[0191] 2. Individuals with any visible skin disease that may interfere with the evaluation.

[0192] 3. Individuals who have a sunburn, facial tan, or plan to go on vacation for sun exposure or plan to use a tanning booth during the course of the study.

[0193] 4. Individuals involved in parallel research projects on facial products.

[0194] 5. Individuals using medications that may interfere with test results, including use of steroidal / nonsteroidal anti-inflammatory drugs or antihistamines.

[0195] 6. Individuals who have had a laser resurfacing or dermabrasion procedure or chemical facial skin peel on the face in the past 2 years (deep peel in the past year; superficial peel in the past 2 months).

[0196] 7. Individuals with acne, active atopic dermatitis / eczema, or psoriasis.

[0197] 8. Individuals who have had surgical "cosmetic" procedures on the face within the past 10 years.

[0198] 9. Treatment or history of any type of cancer.

[0199] 10. Individuals undergoing treatment for asthma or diabetes.

[0200] 11. Individuals with known sensitivity to cosmetics or personal care products.

[0201] At all visits, trained technicians rated each subject's face for irritation. No irritation was found in any area of ​​any subject. The imaging system took digital images of each subject's face. Photos were taken from the front, right, and left sides. At the final visit, the subjects were asked to complete the questionnaire.

[0202] Results: Skin radiance / brightness (Asian subjects): To determine any changes in skin radiance / brightness, Visia Analysis of skin lightness (brightness). Facial lightness is a single numerical value calculated based on the uniformity of image lightening. An increase in facial lightness represents an improvement in overall skin lightness. A decrease indicates a deterioration. At each visit, Asian subjects rated their skin lightness / brightness according to the following scale: 0 - no visible dullness / sallowness, 1-3 - slightly dull / sallow appearance, 4-6 - moderate dull / sallow appearance, 7-9 - severe dull / sallow appearance. Additionally, at the last visit, subjects completed a questionnaire.

[0203] At any clinical visit, if Visia There were no significant changes in the lightness / brightness assessed by the analysis, although the mean scores for skin lightness / brightness trended toward an increase at 4 and 8 weeks after starting DMPR compared to baseline (Table 24), indicating an improvement in skin lightness / brightness.

[0204] Table 24. As measured by Visia Changes in light intensity / brightness measured for Asian subjects.

[0205]

[0206]

[0207] The following table shows the Visia Percentage of Asian subjects with improvement in skin lightness / brightness analysis (Table 25). Skin lightness / brightness improved in Asian subjects after 4 and 8 weeks of product use, with up to 67% of subjects showing improvement. Although there were no significant differences in the mean scores for skin lightness / brightness, these data demonstrate that there were individual improvements among responders and that the proportion of responders increased over the course of treatment.

[0208] Table 25. Skin Lightness / Brightness Analysis (Asian Subjects) Response Frequency (% of subjects with improvement from baseline).

[0209] improve% No change or deterioration% Week 2 33％ 67％ Week 4 67％ 33％ Week 8 67％ 33％

[0210] Self-assessment by Asian subjects at each visit showed improvements in skin lightness / brightness after 2, 4, and 8 weeks of product use. Notably, after 8 weeks of DMPR, self-assessed scores for skin lightness / brightness improved by 13%.

[0211] Table 26. Self-Assessment Ratings for Skin Lightness / Brightness – Asian Subjects

[0212] Baseline Week 2 Week 4 Week 8 Average rating 5.5 5.2 5.3 4.8 % Improvement from Baseline - 6％ 4％ 13％

[0213] Skin spots / age spots (Caucasian subjects): To determine any changes in skin spots / age spots, Visia Chroma was analyzed. The degree to which a color does not blend with other colors is a good indicator of its chroma. An increase in the chroma score indicates an improvement in skin spots / age spots. A decrease indicates a deterioration. At each visit, Caucasian subjects rated their skin spots / age spots according to the following scale: 0 - no visible skin spots or age spots, 1-3 - visible mild skin spots or age spots areas, 4-6 - visible moderate skin spots or age spots areas, 7-9 - visible severe skin spots or age spots areas. Additionally, at the last visit, the subjects completed a questionnaire.

[0214] At any clinical visit, if Visia There were no significant changes in the skin spots / age spots assessed in the analysis, although the mean skin spot / age spot scores trended toward an increase at 2, 4, and 8 weeks after starting DMRP compared to baseline, indicating an improvement in skin spots / age spots (Table 27).

[0215] Table 27. As shown by Visia Changes in skin mottling / age spots measured in Caucasian subjects.

[0216] Average score + / - SD p-value Change from Baseline Baseline 16.67+ / -2.89 - - Week 2 17.38+ / -2.13 0.156 4.3％ Week 4 17.90+ / -1.76 0.219 7.4％ Week 8 17.88+ / -0.98 0.219 7.3％

[0217] The following table shows the Visia Percentage of Caucasian subjects with improvement in the skin spot / age spot analysis (Table 28). There was improvement in skin spots / age spots in Caucasian subjects after 2, 4, and 8 weeks of product use, with up to 83% of subjects showing improvement. Although there were no significant differences in the mean scores for skin spots / age spots, these data demonstrate that there were individual improvements in responders and that a significant proportion of responders remained improved during treatment.

[0218] Table 28. Skin Spot / Age Spot Analysis (Caucasian) Response Frequency (% of subjects with improvement from baseline).

[0219] improve% No change or deterioration% Week 2 83％ 17％ Week 4 67％ 33％ Week 8 67％ 33％

[0220] Self-assessment by Caucasian subjects showed improvement in skin spots / age spots after 2, 4, and 8 weeks of product use. Notably, after 8 weeks of use of dimethoxytolylpropylresorcinol, the self-assessment score for skin spots / age spots improved by 37% (Table 29).

[0221] Table 29. Self-Assessment Scores for Skin Spots / Age Spots – Caucasian Subjects

[0222] Baseline Week 2 Week 4 Week 8 Average rating 6.3 4.3 4.0 4.0 % Improvement from Baseline - 32％ 37％ 37％

[0223] At the last visit, the subjects were asked to respond to the questionnaire. The subjective questionnaire responses correlated with a high acceptance rate of the product by the subjects. The subjects' feelings about their own skin were analyzed based on the questionnaire and summarized in Tables 30 and 31. The vast majority of Asian subjects noticed an increase in skin radiance / brightness and felt that their skin had a healthier appearance. Most Caucasian subjects felt that their skin had less spots and a reduction in the appearance of age spots, and felt that their skin had a healthier appearance.

[0224] Table 30. Responses of Asian subjects to the subject questionnaire

[0225]

[0226] Table 31. Responses of Caucasian Subjects to Subject Questionnaire

[0227]

[0228]

[0229] From the above examples, it can be demonstrated that the keratinocytes treated with dimethoxytolylpropylresorcinol have many differentially expressed genes compared to untreated controls, and these genes are related to aging pathways. The genes expressed in the keratinocytes treated with dimethoxytolylpropylresorcinol are compared with the genes differentially expressed in the keratinocytes treated with retinol, and there are many common protein localizations and biological processes between the treatments, including extracellular regions, protein extracellular matrix, extracellular matrix organization, epidermal development, epithelial cell differentiation, and cellular responses to retinoic acid. The specific gene clusters similarly regulated in the keratinocytes treated with dimethoxytolylpropylresorcinol and the keratinocytes treated with retinol include extracellular matrix genes, cytoskeleton genes, neural cell adhesion, negative regulators of cell growth, immune signaling, and anti-oxidation. This may mean that the activities of dimethoxytolylpropylresorcinol and retinol in keratinocytes are similar.

[0230] The biological processes that are differentially expressed in keratinocytes treated with dimethoxytolylpropyl resorcinol compared with the control, but not differentially expressed in keratinocytes treated with retinol include wound healing, keratinocyte differentiation, and hyaluronic acid biosynthesis. The specific gene clusters that are differentially regulated in keratinocytes treated with dimethoxytolylpropyl resorcinol, but not differentially regulated in keratinocytes treated with retinol, are extracellular matrix genes, cell signaling genes, transcriptional regulatory genes, skin barrier genes, oxidative stress genes, and growth factors. The selection of genes that are differentially regulated in keratinocytes treated with dimethoxytolylpropyl resorcinol, but not differentially regulated in keratinocytes treated with retinol, is further explored by Western blotting for differential protein expression. The confirmed changes include upregulation of HAS2 and HAS3 (increased by 14% and 17%, respectively, compared with control keratinocytes), LAMC2 (increased by 16%), ECM1 (increased by 40%), and COL1A1 (procollagen increased by 34% and mature collagen increased by 27%). We could not definitively confirm or refute changes in expression of the other proteins tested, including SELE, SIRT7, SIRT1, SERPINB4, SERPINB2, SOD2, HIF1A, TGFB1, NGF, EREG, and HBEGF.

[0231] Increases in HAS2 and HAS3 indicate increased synthesis of hyaluronic acid and an increased ability to bind water molecules in the extracellular matrix, promoting skin hydration and moisturization. Increases in LAMC2, ECM1, and COL1A1 indicate increased deposition of ECM components. This implies the potential for anti-aging by promoting ECM reduction and preventing fine lines and wrinkles.

[0232] In a clinical trial, where 0.2% dimethoxycresylpropylresorcinol cream was used twice daily for eight weeks, scores for crow's feet, fine lines, and wrinkles as assessed by trained technicians were significantly reduced at the end of the study. As assessed using brightness measurements of skin replicas, dimethoxycresylpropylresorcinol cream reduced the brightness of coarse lines and the length of the glow trace after four weeks of use, indicating a reduction in surface roughness. Even at two weeks of use, the brightness, number, and length of the glow trace of fine lines were significantly reduced, and these changes continued to the end of the eight-week study, indicating an improvement in skin smoothness. When fine lines were evaluated using shadow assessments of skin replicas, dimethoxycresylpropylresorcinol cream significantly reduced the shadows cast by wrinkles when used for only two weeks and four weeks. The number of wrinkles and fine lines was also significantly reduced during the two weeks and duration of the study.

[0233] In clinical assessments of skin brightness, such as by Visia Mean ratings of brightness / brightness did not change in Asian subjects as measured, but visual assessment by trained technicians indicated improvement at two weeks and greater improvement at four weeks. Skin spots / age spots were measured in Caucasian subjects. The mean spot / age spot scores did not change, but again, visual assessment by trained technicians showed improvement at two weeks of use, with the majority of subjects continuing to improve throughout the duration of the study.

[0234] These data demonstrate that DMCR cream reduced the appearance of fine lines and wrinkles in a clinical study, with improvements in visual scores of brightness and skin spots / age spots over the duration of the study. The mechanism of action for these improvements may lie in changes in the expression of genes involved in extracellular matrix composition, promoting ECM components, moisturizing the skin, and filling fine lines and wrinkles.

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Claims

1. A diarylalkane compound for anti-aging, wrinkle reduction and extracellular matrix promotion.

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

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

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

5. The compound according to claim 1, for use in increasing skin smoothness.

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

7. A compound according to claim 1 for use in reducing the number of rough lines on the skin.

8. A compound according to claim 1 for use in reducing the appearance of rough lines on the skin.

9. The compound according to claim 1, for use in increasing hyaluronic acid synthesis and skin hydration.

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

11. The compound of claim 1, wherein the anti-aging benefit is achieved by modulating changes in the expression of genes in skin keratinocytes involved in extracellular matrix composition, promoting ECM components, moisturizing the skin, and filling fine lines and wrinkles.

12. The compound of claim 2, wherein the anti-aging benefit is achieved by modulating changes in the expression of genes in skin keratinocytes involved in extracellular matrix composition, promoting ECM components, moisturizing the skin, and filling fine lines and wrinkles.

13. The compound of claim 1, wherein at least one gene associated with functions such as wound healing, cytoskeletal regulation, anti-oxidation, immune signaling, cell growth, 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 functions such as wound healing, cytoskeletal regulation, anti-oxidation, immune signaling, cell growth, cell signaling, DNA repair, transcriptional regulation, and skin barrier function is upregulated.

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

16. The compound of claim 2, wherein at least one anti-aging benefit is achieved by modulating 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 according to 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 according to 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. The compound according to claim 1, wherein the compound is extracted, enriched and purified from Rhizoma Cibotii.

20. The compound according to claim 2, wherein the compound is extracted, enriched and purified from Rhizoma Cibotii.

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

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

25. The compound of claim 1, wherein the compound is formulated in a carrier and may include a solution, emulsion, cream, lotion, ointment or gel containing one or more of petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.

26. The compound of claim 2, wherein the compound is formulated in a carrier and may include a solution, emulsion, cream, lotion, ointment or gel containing one or more of petrolatum, lanolin, polyethylene glycol, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.

27. A composition comprising the compound according to claim 1, wherein the amount of the compound in the composition is 0.001% to 2%.

28. A composition comprising the compound according to claim 2, wherein the amount of the compound in the composition is 0.001% to 2%.

29. A composition comprising the compound according to claim 1, wherein the amount of the compound in the composition is 0.2%.

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

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