Compounds and methods for preparation of bakuchiol derivatives and its application to skin care

Abstract

Methods of preparing bakuchiyl esters are disclosed wherein bakuchiol is reacted with an acid ligand in the presence of a chlorinating reagent, acid scavenging base and a solvent to form a bakuchiyl ester. Compositions including the bakuchiyl esters and methods of treatment or use of the compounds are also disclosed.

Description

COMPOUNDS AND METHODS FOR PREPARATION OF BAKUCHIOL DERIVATIVES AND ITS APPLICATION TO SKIN CARETECHNICAL FIELD

[0001] The present invention is directed to an improved process for the preparation of bakuchiol derivatives from bakuchiol. In particular, the invention includes the preparation of Bakuchiol derivatives prepared via a one-pot esterification method from the corresponding bakuchiol and various acids, which enables ease of operations and ensures better quality and yield of the product. The present invention also includes novel bakuchiol esters and their uses as cosmetics or pharmaceuticals.BACKGROUND OF THE INVENTION

[0002] Skin aging is a complicated multifactorial biological process that is impacted by both intrinsic and extrinsic factors. Intrinsic aging is an inevitable physiological process, while extrinsic aging is caused by external environmental factors such as air pollution, smoking, malnutrition, and sunlight exposure. At the molecular level, skin aging is caused by an imbalanced redox status, mitochondrial dysfunction, DNA mutation, telomere shortening, cell senescence, and the deposition of advanced glycation end products (AGEs) within the dermis, among other things. The effects of aging are observed due to the loss of skin elasticity, rough texture, and appearance of age spot caused by collagen degradation, trans epidermal water loss, and melanin synthesis and its transport to the keratinocytes. Thus, a variety of products and techniques have been launched for a decade to ease the signs of skin aging, such as the introduction of new actives, transdermal delivery (TDD) of the actives and cosmetic surgeries.

[0003] Several active ingredients such as retinoic acid and its derivatives, Vitamin C, bakuchiol and peptides are used in this realm. All these ingredients are widely used in skin care, but they have limitations, too. For example, retinoic acid is one of most effective cosmeceutical ingredients, but its poor tolerability with the sensitive skin patient limits its uses. It also requires a prescription to manage side effects or toxicity.On the other hand, bakuchiol which is marketed as "natural alternative of retinol" showed cytotoxicity at higher doses or concentrations and has a narrow therapeutic window. Therefore, there is always a demand for novel bioactives with superior efficacy and favorable safety profiles.

[0004] Bakuchiol is a meroterpene phenol, isolated from Psoralea corylifolia seeds. It has been used in Indian Ayurvedic and Traditional Chinese Medicine for centuries. But the uses in cosmetics were limited until the natural derived bakuchiol was free from two phototoxic compounds, psoralen and iso-psoralen. Studies have shown that bakuchiol acts as a "functional analog of retinol" as it shows similar gene expression patterns of retinol. The present invention succeeds in addressing these issues and provides other related advantages.

[0005] Another skin disorder that affects about 85% of people to some degree in their adolescent lives is Acne Vulgaris, also known as "Cutibacterium acnes" (C. acne). In severe cases, it can cause facial and emotional scarring. It will continue into adulthood for 18% of the population, with 6% more females suffering chronic outbreaks then males.

[0006] Acne is thought to be the result of several environmental and pathophysiological factors like diet, pollution, stress level, androgen (hormone) level and age. External factors contribute to acne, such as friction (acne mechanica) or contact with irritant oils or cosmetics (acne cosmetica). The acne lesion or comedone, is an enlarged hair follicle plugged with oil and bacteria. Blackheads (open comedones) and whiteheads (closed comedones) result from such blockage.

[0007] Pilosebaceous units are comprised of a sebaceous (oil producing) gland connected to a hair follicle. Blockage of the pilosebaceous unit is a contributing factor in acne. This can occur from hyperkeratinization from abnormal desquamation of follicular epithelium. In normal skin, sebum is produced which flows unimpeded onto the skin surface through the open follicle. Increased sebum production is also implicated in the development of acne. Sebum is a lipid-rich secretion from sebaceous glands and theirsize and production volume is under the control of androgenic hormones. The onset of acne is typically associated with hormonal surges before and during puberty.

[0008] Another prime factor in acne development is the proliferation of bacterium like Cutibacterium acnes (C. acne), formerly called Propionbacterium acnes (P. acnes), which generate inflammation and infection. C. acnes is an organism that can multiply in a clogged pilosebaceous unit once an anaerobic environment is created. This leads to pustule formation and an inflammatory response (due to bacterial release of enzymatic and chemical agents that promote inflammation), resulting in the need of a topical or oral anti-inflammatory agent. Other micro-organisms besides C. acnes have been identified and associated with acne, thus requiring an antimicrobial treatment to have broad spectrum activity.

[0009] Oral antibiotics are used for treating moderate to severe acne lesions. Long-term use requires routine laboratory monitoring. C. Acne and other bacteria have, in varying degrees, become resistant to many antibiotics and such use is on the decline. Attempts to decrease sebum production using oral vitamin or hormonal regulation can be highly effective. Oral Vitamin A acid derivatives are only approved for severe nodular acne but commonly exhibit serious side effects or adverse reactions, including birth defects, which requires careful screening, registration and monitoring for treatment candidates and users.

[0010] Numerous topical treatments for acne are available as OTC drugs as a serum (ex. aqueous or hydroalcoholic solution), gels, and emulsion (cream or lotion). These preparations can be effective to varying degrees, but none have been proven to be uniformly effective and without side effects. Treatments have included benzoyl peroxide, salicylic acid, retinoic acids or retinoid derivatives, antibiotic combinations including clindamycin, tetracycline, doxycycline, or erythromycin with or without benzoyl peroxide, Resorcinol, sulfur, azelaic acid, pantothenic acid, retinoic acids, and their derivatives have been used in acne treatments as a cocktail of combined antibiotics, vitamins, and hormonal regulators.

[0011] Benzoyl peroxide can leave the skin with a dry, spotty, mottled appearance and can cause bleach damage to clothing or linens in contact with the face during sleeping or other activities. Topical antibiotics decrease the number of mild to moderate inflammatory lesions by inhibiting the growth of C. acnes but they are also associated with skin irritation, dryness, and potential antibiotic resistance. There is still a high demand for effective topical remedies, without side effects.

[0012] Comedolytic agents like salicylic acid, glycolic acid and the salts of both acids are popular for exfoliating dead skin cells and opening and draining the pores, but significant irritation can occur owing in part to the relatively high use levels employed in many instances. There still exists the need to effectively use these agents near their lower use limits as opposed to their upper limits in terms of concentrations to avoid dryness or irritation issues. For example, salicylic acid is used at a minimum concentration of 0.5% in the FDA monograph for OTC acne treatments.

[0013] Bakuchiyl salicylate (Comp-1) (CAS# 3024002-49-8) is a unique bioactive which possesses several advantages over bakuchiol (SM-1) in terms of tolerability and efficacy. See US Patent No. 10,471,035, Krzysztof Bojanowski, the disclosure of which is incorporated herein by reference.B«kuchioi (SM-1)

[0014] Bakuchiyl salicylate is more lipophilic compared to bakuchiol and has superior skin permeation over the parent compound bakuchiol. As an ionic acid, salicylic acid typically stays on the surface of the skin epidermis and does not penetrate well into thedermis. It is a monographed anti-acne active ingredient in the US and other regions OTC applications. Besides acting on skin as its own active ingredient, the INCI name ba kuchiyl salicylate also has the potential to deliver salicylic acid via enzymatic hydrolysis into the skin dermis, thereby acting as a controlled release agent for salicylate, offering a more effective route for flawless skin.

[0015] In recent years, vitamin B3 compounds such as nicotinic acid and niacinamide have garnered attention for their multifaceted anti-aging effects on the skin. These substances demonstrate remarkable activity in promoting skin rejuvenation, enhancing collagen synthesis, and supporting hydration, making them valuable components in skincare formulations.

[0016] Nicotinic acid and its derivatives contribute to skin revitalization primarily through their influence on collagen activity. Collagen is a key structural protein in the skin, responsible for maintaining its elasticity and firmness. By stimulating collagen production, these compounds help restore skin structure, reducing the appearance of fine lines and wrinkles.

[0017] One of the fundamental processes involved in skin aging is cellular turnover. Vitamin B3 compounds have been shown to promote cell turnover, encouraging the renewal of the skin's outer layers and maintaining a youthful, healthy complexion. These compounds also serve as potent protectors against oxidative stress, a key contributor to skin aging. By reducing oxidative damage, they help minimize the formation of free radicals that break down cellular structures and accelerate the aging process.

[0018] While research does not distinguish between the nutrient and drug-like effects of nicotinic acid and quinolinic acid, existing studies suggest that both mechanisms are likely involved in their skin benefits. A crucial factor in skin aging is DNA damage, especially from UV radiation, which leads to cellular mutations and skin degradation. Recent advancements have highlighted the role of niacin-dependent poly(ADP-ribose) polymerases (PARPs) in DNA repair. These enzymes require high cellular concentrations of nicotinamide adenine dinucleotide (NAD+) for optimal activity, suggesting that niacin or its precursors may serve as protective micronutrients for the skin.

[0019] Nicotinic acid, through its conversion to NAD+, may help repair DNA damage caused by UV exposure and prevent further cellular mutations that could lead to skin cancer. Niacin deficiencies have been shown to mimic the effects of radiation-induced DNA damage, including single- and double-strand breaks and oxidative lesions. By increasing NAD+ levels in the skin, nicotinic acid may enhance DNA repair mechanisms, preventing further photodamage and the onset of age-related skin changes.

[0020] Niacin-derived NAD+ plays a critical role in cellular energy production and the constant renewal of the epidermis, making it a key component in maintaining skin health. As skin ages, its cellular NAD+ pool declines, contributing to a weakened epidermal barrier and diminished skin function. The epidermis, being constantly renewed, is particularly susceptible to nutrient deficiencies, and UV exposure exacerbates the depletion of key micronutrients like niacin.

[0021] NAD+ is also essential in the formation of lipid components in the stratum corneum, the outermost layer of the skin. These lipids are vital for maintaining the skin's barrier function, which protects against environmental stressors. By improving niacin status and boosting NAD+ and NADP levels, these compounds can enhance epidermal differentiation and bolster the skin's barrier, thereby supporting overall skin health and resilience.

[0022] Recent studies have shown that niacin-derived NADPH is essential for the formation of key lipid components in the stratum corneum, which in turn are critical for maintaining epidermal barrier function. This suggests that increasing niacin availability in the skin could significantly benefit skin health by promoting differentiation and preserving the skin's natural defenses.

[0023] Additionally, the discovery of a nicotinic acid receptor in the skin, which stimulates leptin release, opens the possibility for nicotinic acid to exert drug-like effects. Leptin has been shown to promote epidermal differentiation, wound healing, and immune function— further supporting the potential of nicotinic acid as a key component in skincare.

[0024] The esterification reaction is one of the oldest, most widely used and most important chemical transformations in organic synthesis, with wide application in chemical industry, pharmaceuticals, food, perfume, and cosmetics.

[0025] None of the reported methods of preparing bakuchiyl salicylate on a large scale met the criteria required for cost-effective production. For example, bakuchiyl salicylate was prepared from bakuchiol and salicylic acid via modified Steglich esterification method using A / ,A / '-dicyclohexylcarbodiimide (DCC) as a condensing reagent and 4- dimethylaminopyridine (DMAP) as catalyst [Ma et al Clin. Exp. Dermatol., 2017, 3, 251- 260]. Although preparation of bakuchiyl salicylate was feasible via this method, the synthesis was of relatively low yield and produced significant amounts >5% of undesired side products SP-1 & SP-2, (hereby referred to as bakuchiyl disalate (SP-1) and bakuchiyl trisalate derivatives (SP-2), that cause poor yield and may be carried forward into the product, even after purification by column chromatography.

[0026] In addition, one of the byproducts, dicyclohexylurea (DCU) that was formed during the reaction, is difficult to separate and requires vigorous column chromatography for purification to get the desired purity of the target compound. Altogether, the formation of the SP-1 and SP-2 byproducts and the DCU byproduct makes this route prohibitively inefficient for large-scale production and green chemistry goals due in part to the waste involved in chromatography media and solvents.

[0027] To overcome these issues, an attempt was made for esterification by using 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as coupling reagent in different conditions and using different solvents. Although it could be easier to separate the EDC by-products, the two major side products (SP-1 & SP-2) remained challenging to avoid as they were >5% by wt. Also, EDC is costlier than DCC, making the process more expensive as a tradeoff.

[0028] Therefore, reactions using DCC or EDC coupling require column chromatography due to multiple impurities which were identified to be related to coupling agents and the formation of disalate and trisalate bakuchiol ester derivatives (SP-1 & SP-2). Such impurities are highly undesirable, particularly salsa late (disalate) as it is a listed FDA drug active in neat form. Any potential hydrolysis of the bakuchiyl disalate ester could result in the unintended release of the drug active as a byproduct, which is unacceptable for cosmetic applications. Column Chromatography requires excessive solvent use which not only increases cost but also removes it from being considered green chemistry. Steglich type esterification also employ carbodiimides which are potent skin irritants and so should be avoided for cosmetic applications that are not otherwise highly purified.

[0029] Another attempted route, transesterification, which is widely used in industry was attempted to get the desired product. To explore this reaction, extensive studies were designed using Wintergreen oil (a natural salicylate ester) and bakuchiol reacted in the presence of different catalysts (shown in comparative examples below). The poor conversion rate made this experimental process unfeasible. The present invention fulfills these needs and provides other related advantages.

[0030] Yet another attempted route was using acyl halide with a halogen leaving group and the intermediate reagent salicyloyl chloride (CAS 1441-87-8), however it was determined that use of this intermediate reagent was not viable due to its instability during transit and storage, leading to the conclusion that the reagent had to be made fresh on site and used immediately, thus forming the basis of a two-step reaction and potentially a one pot synthesis. The synthesis of salicyloyl chloride yields ~95% purity, with disalate and trisalate impurities dominating in the byproducts. Therefore, due to theformation of the drug active byproduct disalate, even if the coupling occurs with bakuchiol, this route was determined to require column chromatography.

[0031] There is an unmet need for a route to make bakuchiol esters with low SP-1 and SP-2 impurities, with about 5% by wt or less, preferably 1% by wt or less and preferably non-detectible levels, such that column chromatography with excessive solvent use is avoided such that a new method provides economic, environmental and safety advantages for materials ultimately in contact with human skin

[0032] Another area of interest is the use of Retinoic acid esters. Retinoic acid esters have been used to treat skin disorders to repair damaged skin and to counter skin aging processes. Retinoic acid esters, such as, hydroxypinacolone retinoate (HPR), a non- prescriptive topical retinoid have been used for the treatment of skin aging (extrinsic and intrinsic factors). Hydroxypinacolone retinoate (HPR) is sold as a crystalline powder or sold as a liquid mixture. The liquid mixture is known commercially as Granactive Retinoid, which is composed of HPR and dimethyl isosorbide. This clear yellow liquid mixture allows for ease of use in the addition to various formulatons (such as, oil-in-water; water-in-oil; anhydrous). The combination of both HPR and Bakuchiol Salicylate (Comp-1) would be beneficial for enhanced skin care activity.

[0033] Furthermore, stability in a delivery vehicle that promotes uniform dosing of an active by penetration into the skin is highly beneficial for treating sensitive skin, skin ageing and skin disorders. A time-release and uniform delivery can be achieved by enhancing lipophilic properties of the active to enhance formulation compatibility and enhancing molecular properties to allow skin penetration followed by hydrolysis of the active. Bakuchiyl Salicylate (Comp-1) in Vitamin F glyceryl ester solvents have been shown to demonstrate this behavior.SUMMARY OF THE INVENTION

[0034] The present disclosure provides a novel, robust and more efficient method of preparing bakuchiyl esters, including, but not limited to bakuchiyl salicylate (Comp-1)

[0035] The present invention also includes novel compounds / composition of matter including bakuchiyl esters and their uses as topical cosmetics and general pharmaceutical ingredients.

[0036] In accordance with a first aspect of the invention, the methods of preparing bakuchiyl esters include reacting bakuchiol (SM-l)Bakuchiol (SM-1) with an acid ligand in the presence of a chlorinating reagent, acid scavenging base and a solvent to form a bakuchiyl ester such as those corresponding to Formula-1 and Formula-2Formula-1 Formula-2 wherein R and R' are as defined below. More preferably, the bakuchiol ester resulting from the process isBakuchiyl salicylate (Comp-1)

[0037] Generally, the acid ligand can be selected from various natural as well as synthetic acids. Some suitable acid ligands used in the reaction correspond to Formula-Sa: R-C(O)-OH (Formula 3a) wherein R is the remainder of a carbonyl group in an acid such as itaconic acid, maleic acid, azelaic acid, succinic acid, ferulic acid, salicylic acid (SM2), nicotinic acid (SM3), isonicotinic acid (SM4), glycolic acid (SM5), mandelic acid (SM6) and biotin (SM7). In some preferred aspects, the acid ligand is salicylic acid. Alternatively, R can be alkyl, allyl, aryl or aralkyl group which completes the carboxylic acid of Formula-3a.

[0038] In a further aspect of this embodiment, the acid ligand is of the Formula-3b:R'-C(O)-OH (Formula-3b) wherein R' is the remainder in the carbonyl group of a naturally occurring saturated and unsaturated fatty acid, such as, butyric, hexanoic, octanoic, decanoic, lauric, lauroleic, myristic, myristoleic, pentadecanoic, palmitic, palmitoleic, margaric, stearic, oleic, linoleic, linolenic, retinoic acid and diacid.

[0039] The R and R' groups in the reaction product, i.e. the bakuchiyl ester, or compounds corresponding to Formula-1 and Formula-2, are described herein as "remainders" and correspond to the R or R' portion of the acid ligand of Formula-3a or Formula-3b after the reaction with the bakuchiol (SM-1).

[0040] If so desired, the method can be carried out with an alternative meroterpene phenol species in place of the preferred bakuchiol species as a starting material.

[0041] This invention also includes the uses of these compounds for the treatment of skin disorders and systemic skin diseases that may be caused due to extrinsic or intrinsic factors through topical application, i.e. methods of treatment of these conditions by applying formulations containing the compounds described herein to the skin of a person or animal in need of such treatment or desirous of preventing such conditions. More specifically, the uses of these compounds are for cosmetics applications and alleviating the signs of skin aging and potentially for the treatment of skin diseases or skin conditions in pharmaceutical applications.

[0042] As a result of the present invention, it is no longer necessary to carry out a highly inefficient purification step in order to obtain the bakuchiol esters of interest in higher yields and with significantly reduced amounts of undesired impurities.

[0043] Another aspect of the invention is to allow the extension of lipophilicity and compatibility compared to bakuchiol that enhances superior skin permeation over the parent compound bakuchiol. Compatibility allows better permeation of the active into the skin, as well as better stability in the formulation to prevent degradation and prevent separation from the composition of the formulation. A key goal of the invention is to improve and enhance the compatibility and stability to prevent separation from the formula which would lead to haze, precipitation, crystallization, destabilization, discoloration and appearance of the formula. The compositions of the invention are therefore unlike prior art compositions which have poor compatibility and stability and which lead to poor skin care performance because the active does not penetrate the skin effectively.

[0044] The slow delivery and more uniform delivery of an active by penetration into the skin is highly beneficial for treating sensitive skin, skin ageing and skin disorders. A timerelease and uniform delivery is achieved by enhancing lipophilic properties of the active to enhance formulation compatibility and by enhancing molecular properties to allow skin penetration followed by hydrolysis of the active. Bakuchiyl Salicylate (Comp-1) has been shown to demonstrate this behavior.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Fig. 1 is a graph illustrating formula stability and residual activity of HPR and bakuchiyl salicylate corresponding to Example 7.DETAILED DESCRIPTION OF THE INVENTION

[0046] In a first aspect of the invention, there is provided an efficient method of synthesis for compounds useful for the preparation of bakuchiol ester in one-pot, and without the requirement for tedious column chromatography and particularly whensalicylic acid is used as acid ligand source, not forming SP-1 and SP-2 or other side products that would otherwise require separation and work up to remove them.

[0047] Within this aspect of the invention, the methods of preparing bakuchiyl esters include reacting bakuchiol or a meroterpene phenol with an acid ligand, in the presence of a chlorinating reagent, acid scavenging base and a solvent in-situ to form the corresponding bakuchiyl or other monoterpene phenolic esters, depending on selection of starting monoterpene phenolic material.

[0048] Suitable acid ligands can be selected from a wide range of natural or synthetic acids. For example, in some aspects, the acid ligand can include, but not limited to, a Ci-C22 aliphatic mono carboxylic acid, biotin, a C1-C12 aliphatic diacid, an aromatic acid, a hydroxycinnamic acid, an alpha-hydroxy acids or a mixture thereof.

[0049] In addition, the acid ligand may be a carboxylic acid of the Formula-3a:R-C(O)-OH (Formula-3a) wherein R is the remainder of a carbonyl group in an acid of, for example, itaconic acid, maleic acid, azelaic acid, succinic acid, ferulic acid, salicylic acid (SM2), nicotinic acid (SM3), isonicotinic acid (SM4), glycolic acid (SMS), mandelic acid(SM6), biotin (SM7) and quinolinic acid (SM8).See representative acids corresponding to Formula-3a below:Salicylic acid (SM-2) Nicotinic acid (SM-3) Isonicotinic acid (SM-4) Glycolic acid (SM-5)

[0050] Mandelic acid (SM-6) Biotin (SM-7) QuinoOnic add (SM-S)Within this aspect of the invention, a preferred acid ligand is salicylic acid. Alternatively, R can be alkyl, allyl, aryl or aralkyl group which completes the carboxylic acid of Formula-3a.

[0051] In yet a further aspect of this embodiment, the acid ligand is of the Formula-3b:R'-C(O)-OH (Formula-3b) wherein R' is the remainder in the carbonyl group of a naturally occurring saturated and unsaturated fatty acid, such as, butyric, hexanoic, octanoic, decanoic, lauric, lauroleic, myristic, myristoleic, pentadecanoic, palmitic, palmitoleic, margaric, stearic, oleic, linoleic, linolenic, retinoic acid and diacid. See representative acids as corresponding to Formula-3b below:Butyric acid Hexanoic acid Octanoic acid Decanoic acidLauric acid Lauroleic acidPentadecanoic acid Palmitic acidRetinoic acidFor clarity, the following table illustrates the relationship of acid ligand (starting material) to residual R or R' group after reaction on product.TABLE 1

[0052] Suitable solvents used in the methods of the invention include polar aprotic solvents and non-ionic solvents. A non-limiting list of such solvents include dichloromethane, tetra hydrofuran, toluene, xylene, and mixtures thereof. Other solvents known to those of ordinary skill may also be used if desired in alternative aspects of the invention.

[0053] A chlorinating reagent is also used in the methods of the invention. A nonlimiting list of suitable chlorinating reagents includes thionyl chloride (SOCb), oxalyl chloride (COCI)?, phosphorus chloride (PCI3), phosphorus oxychloride (POCI3), and mixtures thereof. Those of ordinary skill will realize that alternative recognized chlorinating reagents can be used if desired and such alternatives are included in alternative aspects of the invention. In some preferred aspects, however, the chlorinating reagent is phosphorus oxychloride or thionyl chloride, with phosphorus oxychloride being more preferred.

[0054] The method also includes the use of an acid scavenging base. Suitable bases include tertiary nitrogen bases such as but not limited to 1,8-Diazabicyclo[5.4.0]undec- 7-ene (DBU); l,5-Diazabicyclo[4.3.0]non-5-ene (DBN); l,4-diazabicyclo[2.2. 2]octane, also known as triethylenediamine DABCO or TEDA; 4-Dimethylaminopyridine (DMAP); pyridine; or triethylamine. In some aspects, a preferred acid scavenging base is pyridine and triethylamine with the most preferred amine being pyridine. Alternative bases known to those of ordinary skill can be used if desired in place of some or all of the bases identified herein.

[0055] The reaction is carried out via one-pot esterification method with near stochiometric amounts of bakuchiol and an acid ligand and is efficiently prepared using a chlorinating reagent such as POCI3 as a near quantitative in-situ coupling reagent with an excess of water-soluble tertiary amine acid scavenger. The methods of the present invention generally provide for bakuchiyl esters of Formula (1)Formula 1 wherein R is as set forth above, i.e. the remainder of a carbonyl group in an acid, or a group which completes the carboxylic acid such as alkyl, allyl, aryl or aralkyl, or a stereoisomer, tautomer or salt thereof. Alternatively, the method of the present invention yields the bakuchiyl ester is of Formula (2)wherein R' is as set forth above, i.e. the remainder in the carbonyl group of a saturated and unsaturated fatty acids, such as, butyric, hexanoic, octanoic, decanoic, lauric, lauroleic, myristic, myristoleic, pentadecanoic, palmitic, palmitoleic, margaric, stearic, oleic, linoleic, linolenic, retinoic acid and diacid or a stereoisomer, tautomer or salt thereof.

[0056] In some preferred aspects, the bakuchiyl ester resulting from the process described herein is Comp-1and preferred bakuchiyl esters resulting from the methods of the invention can be selected from TABLE 2:TABLE 2

[0057] In some further aspects of the invention, the methods include a separation or purification step of treating the bakuchiyl ester with water washing solvents. For example, the bakuchiyl ester is diluted with an organic solvent, such as ethyl acetate, and washed with a water-based wash containing aqueous sodium bicarbonate, ammonium chloride, aqueous hydrochloric acid and brine. The organic solvent is then removed by evaporation in vacuo to achieve at least >90% final purity, preferably at least > 95% or >98% purity. Stated alternatively, the amount of impurities after the reaction is also minimal. For example, in the case of bakuchiyl salicylate, the reaction product contains a total amount of unwanted salates is less than 5% and preferably less than 2%, total salates, identified hereinabove as (SP-1), (SP-2) disalate (SP-3) and trisalate (SP-4), and preferably the amount of SP-1 and SP-2 being less than 1% combined.

[0058] (SP-3) (SP-4)

[0059] The reactions described herein can be carried out at temperatures of from about 0° C to about 10° C, or from about 0° C to about 50C, for about 3 to 4 hours, followed by room temperature for from about 2 to about 16 hours. As will be appreciated by those of ordinary skill, the length of time and other reaction conditions will of course varysomewhat, depending upon expected circumstances, batch sizes, ambient or room temperature, etc.

[0060] While the methods described herein are generally applicable for producing bakuchiyl esters or other monoterpene phenolic esters, the method is particularly well- suited for preparing bakuchiyl salicylate

[0061] In this regard, the method includes reacting bakuchiol and salicylic acid in one step and in situ (one-pot) in the presence of POCL and a base selected from pyridine or triethyl amine. The reaction is preferably carried out at temperatures of from about 0° C to about 10° C or, preferably in some aspects at temperatures of from about 0° C to about 50C, as such unexpectedly yielded low to no by products, e.g. SP-1 or SP 2 and disalate and / or trisalate, (SP-3 or SP-4) by-products from forming and resulting in higher yields than that achievable with prior art methods with exceptionally high purity and low amounts of impurities. DCC coupling is also conducted at similar low temperatures but still yielded >5% unwanted byproducts, so there was no anticipation that similar low temperature reactions with the in situ chlorinating reagent would have solved this problem by yielding no to low byproducts SP-1 and SP2.

[0062] As used herein, the following terms have the meanings set forth below: alkyl means an optionally substituted, straight chain or branched, noncyclic or cyclic, unsaturated, or saturated aliphatic hydrocarbon containing from 1 to 18 carbon atoms having hydrophobic properties. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl. n-butyl, n-pentyl, n-hexyl, and the like; while saturated branched alkyls include isopropyl. Sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls are also referred to herein as "homocycles" or"homocyclic rings." Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl' or "alkynyl', respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1- butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-l-butenyl, 2-methyl-2- butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2- pentynyl, 3-methyl-l-butynyl, and the like. "Allyl means an alkyl group, as defined above, comprising a methylene connected to a terminal alkene, for example — CH-CH=CH.

[0063] "Alkoxy' means an alkyl moiety as defined above (i.e., an optionally Substituted, straight chain or branched, noncyclic or cyclic, unsaturated or saturated aliphatic hydrocarbon containing from 1 to 18 carbon atoms) attached through an oxygen bridge (i.e., — O-alkyl) such as methoxy, ethoxy, and the like.

[0064] Aryl means an optionally substituted aromatic carbocyclic moiety such as phenyl, naphthyl and the like. Aralkyl means one or more aryl moieties as defined above attached through an alkyl bridge (i.e., -a Ikyl-(aryl), wherein n is 1, 2 or 3). Non-limiting examples of aralkyl moieties include benzyl (-CH2-phenyl, i.e., Bn), diphenyl methyl (CH- (phenyl)) and trityl (— C-(phenyl)).

[0065] "Heterocycle' (also referred to herein as a "heterocycle ring) means an optionally substituted 5- to 7-membered monocyclic, or an optionally Substituted 7- to 14- membered polycyclic, heterocycle ring which is either saturated, unsaturated or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring as well as tricyclic (and higher) heterocyclic rings. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include "heteroaryl' which is an optionally substituted aromatic heterocycle ring of 5- to 10-members and having at least one heteroatom selected from nitrogen, oxygen, and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems. Representative heteroarylsinclude (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azain, dolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl pyridaZinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl.

[0066] Thus, in addition to the aromatic heteroaryls listed above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperizinyl, piperidinyl, hydantoinyl, Valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0067] In a still further embodiment, there are provided compounds of the general structure Formula-2Formula-2 wherein R' is, as described above, "the remainder" of carboxyl group of a naturally occurring saturated or unsaturated fatty acid, such as, butyric, hexanoic, octanoic, decanoic, lauric, lauroleic, myristic, myristoleic, pentadecanoic, palmitic, palmitoleic, margaric, stearic, oleic, linoleic, linolenic. Alternatively, and in another embodiment, the acid part of the ester is derived selected from retinoic acid and diacid. As was the case with reactions using acid ligands of Formula -3a, reactions in this embodiment using acid ligands of Formula 3-b and bakuchiol form of esters in which the remainder R' portion is provided by the acid ligand. See representative compounds below:Bakuchiyl retinoate

[0068] In yet another aspect, the present invention also provides the synthesis of novel ester derivatives further reacted on the free ortho-hydroxyl group present on bakuchiyl salicylate, thus yielding compounds corresponding to Formula-3c.

[0070] In this Formula, R" represents the location on the ortho-hydroxyl group wherein R" is as set forth above, i.e. the acid ligand generally defined above as R and R' residuals plus the inclusion of the carboxylic acid group esterified on the hydroxy group. Nicotinic acid is the preferred acid ligand in this case yielding R" as the ester residual of Nicotinic acid as shown in Comp-8:

[0071] This ester may be prepared by using any esterification technique that provides the highest purity and yield and is exemplified below in Example 4.

[0072] A significant aspect of the present invention resides in the chemical modification of bakuchiol to augment its lipophilic character and compatibility within cosmetic and pharmaceutical formulations. This modification yields a compound with demonstrably superior skin permeation properties relative to the parent bakuchiol molecule. Enhancing compatibility facilitates optimal incorporation of the modified bakuchiol into diverse formulation matrices, thereby mitigating issues associated with instability and phase separation.

[0073] Specifically, the enhanced compatibility and solubility of the modified bakuchiol serves to substantially reduce or eliminate the occurrence of undesirable phenomena such as: haze formation; precipitation; crystallization; destabilization; discoloration; malodor; and alteration of the macroscopic appearance of the formulation.

[0074] Such improvements in stability are critical for maintaining the aesthetic and functional integrity of the formulation throughout its shelf life. Furthermore, the enhanced compatibility directly translates to improved skin permeation of the active compound. In contrast, inadequate compatibility and stability of unmodified bakuchiol result in diminished skin penetration, thereby compromising the therapeutic or cosmetic efficacy of the formulation.

[0075] The modification of bakuchiol to bakuchiyl salicylate (Comp-1) of the present invention, by virtue of its augmented lipophilicity and compatibility, provides a significant advancement over the prior art, enabling the development of more effective and stable topical formulations.

[0076] Another significant objective of the present invention is to achieve a sustained and homogeneous delivery of bakuchiol to the dermal layers, particularly advantageous for the treatment of sensitive skin, skin aging, and various dermatological disorders. Traditional topical delivery of active ingredients often results in rapid release and uneven distribution, potentially leading to irritation and reduced therapeutic efficacy.

[0077] The present invention addresses this limitation by modifying bakuchiol to enhance its lipophilic properties, thereby improving formulation compatibility. Furthermore, the molecular structure of the modified bakuchiol, specifically Bakuchiyl Salicylate (Comp-1), is engineered to facilitate skin penetration followed by a controlled hydrolysis reaction. This hydrolysis mechanism enables a time-release delivery of bakuchiol within the skin.

[0078] Specifically, the increased lipophilicity of Comp-1 enhances its compatibility with lipid-rich skin layers, promoting efficient penetration and distribution. The subsequent hydrolysis of the salicylate moiety releases bakuchiol in a gradual and sustained manner, providing a more uniform and prolonged therapeutic effect. This controlled release mechanism minimizes peak concentrations of bakuchiol and salicylic acid, reducing the potential for irritation, particularly in sensitive skin.

[0079] The controlled release and uniform delivery of bakuchiol and salicylic acid, as achieved by Comp-1, offers significant advantages over conventional delivery methods. This approach optimizes the therapeutic efficacy of bakuchiol and salicylic acid while minimizing adverse effects, making it particularly suitable for the treatment of skin aging, sensitive skin, and a range of dermatological conditions.

[0080] Therefore, Bakuchiyl Salicylate (Comp-1) and the rest of the preferred range of bakuchiol esters (Comp-2 to Comp-7) , by virtue of ester modified molecular structure and enhanced lipophilic properties, provides a novel and effective means for achievingcontrolled and uniform delivery of bakuchiol and active form of the acid to the skin, resulting in improved therapeutic outcomes.Detailed Preparations

[0081] Preparation of bakuchiol derivatives1. A: Comparative Preparations of bakuchiyl ester (Scheme 1)

[0082] As mentioned earlier, various reports have described the preparaton of esters in general, however, none of the reported methods were suitable for optimized large-scale production. One of the prior art methods was an EDC coupling method (Scheme 1) where the yield could be achieved up to 50% but required extensive purification by silica gel column chromatography using copious amounts of organic solvents, resulting in a more costly and non-green chemistry principles process. Of note, the desired pure bakuchiol salicylate ester product never formed a crystal at any stage, including at low temperature, thus preventing a desired recrystallization process from being employed as a desired separation technique. As a result, this method did not meet the criteria required for cost-effective large-scale preparation of this compound.Scheme 1. EDC coupling with salicylic acid and bakuchiol to synthesis of bakuchiyl salicylate(Comp-1)Improved preparation of bakuchiyl salicylate (Comp-1)

[0083] As noted above, known methods were economically unsuitable for preparation of bakuchiol salicylate, particularly at large scales and maintained more than 5% byproducts of SP1 and SP2, as much as 6-7% by-products, which required extensive column chromatography as mentioned above. The compounds and methods provided bythe present invention address the problems previously associated with preparation of bakuchiyl salicylate (Comp-1).

[0084] It was unexpectedly discovered that Bakuchiol ester can be prepared according to general synthetic scheme (Scheme 2) by using an appropriate coupling agent in-situ.

[0085] Scheme 2. General One-step & one-pot esterification reaction using chlorinating agent and basic acid scavenger from starting materials SM-3 to SM-6 to yield Comp-2 to Comp-6.Acid (SM-3 to SM-7 Bakuchiol (SM-1) Bakuchiyl ester

[0086] Examples also include coupling agents include chlorinating agents such as, but not limited to, Phosphorus oxychloride (POCI3), thionyl chloride (SOCI2), oxalyl chloride ((COCI)?), and phosphorus chloride (PCI3). Phosphorus oxychloride (POCI3) is a preferred chlorinating reagent.

[0087] Basic compounds can act as acid scavengers to remove free acids. Mineral acid HCL is liberated in this reaction and is byproduct that needs to be removed. Tertiary amine (Basic) compounds are preferred to render the acid inactive to form an amine chloride salt. This practice prevents the acid from building up and otherwise, de- esterifying the desired ester product. The net result is increased yield and promotes less by-products. Basic compounds can be organic bases or inorganic bases, preferably tertiary nitrogen bases, more preferably, but not limited to, pyridine (Py) or triethylamine (Et3N).

[0088] The solvents may be selected from aprotic polar or non-polar solvent or mixtures thereof, preferably dichloromethane (DCM) or tetra hydrofuran aprotic polar and xylene and / or toluene for non-polar solvent examples. Toluene is a preferred solvent.

[0089] In accordance with the present invention, bakuchiyl salicylate is preferably efficiently prepared via novel one-pot esterification method using POCI3 as a near quantitative in-situ coupling reagent in the presence of near stochiometric amounts ofbakuchiol and an acid ligand such as salicylic acid, with an excess of water-soluble tertiary amine acid scavenger, like triethyl amine or pyridine and toluene as a solvent to enable ease of operations and ensures better quality and yield of the product. Pyridine is a preferred acid scavenger.

[0090] Surprisingly, this direct in-situ method yielded less than 0.01% bakuchiol disalate or trisalate by-products in comparison to prior methods which rely upon salicyloyl chloride (SM-9) or DCC coupling, for example.

[0091] The process of the present invention allows for only a simple water rinse to remove all unwanted reaction by-products and is a second inventive step. Hence, the unexpected lack of forming these closely related by-products, (whereby by-products are structurally analogous derivatives to the desired product and have similar polarity and solubility profiles to the product) fully avoids the need for column chromatography separations and improves the efficiency of the overall process in terms of yielding a highly pure product at industrial scale.

[0092] Accordingly, this innovative approach is amenable to the most efficient production of bakuchiyl salicylate (Comp-1) ester at scales previously not obtainable to multi-kilogram and greater than the multi-ton scale. As mentioned, the workup is instead water-based green chemistry separation of unreacted acid components, amine-salts, and any trace water-soluble by-products (SP-1 & SP-2, i.e. disalate or trisalate derivatives of bakuchiol) without the requirement for column chromatography or other tedious separation methods. Likewise, the avoidance of column chromatography removes the disposal of the solvent poisoned silica gels and further allows for the clean recycling of the process solvents used, via simple re-distillation in a virtuous cycle. The water can also be distilled to concentrate the salts to recycle the water and remove the salt bottom for proper disposal.

[0093] The methods of the present invention include the preparation of Comp-1 in a one-step and one-pot method. In certain embodiments, the methods result in at least a 25% increased yield of bakuchiol esters relative to other known methods. In addition to increased yield, the method of the invention also provides a bakuchiyl salicylate productof highest purity after workup, as compared to other prior referenced methods. This high yield and higher intermediate purity make Comp-1, according to the present inventon, easier to increase final purity after water-based work up. Accordingly, in some embodiments, Comp-1 prepared according to the disclosed method have a purity of at least 95% to greater than 99%, with up to 99.99% purity as determined by HPLC.

[0094] As mentioned, the present invention also includes a one-step method for the efficient preparation of new bakuchiol esters, preferably using a chlorinating agent as a coupling reagent. The ester compounds of the present invention may be prepared by other known organic synthesis techniques, including the methods described in more detail in the examples, but those methods result in lower yields, more byproducts and therefore require the use of column chromatography or other tedious work up methods.

[0095] In general, the compounds of structure, Comp-2 to Comp-7 may be prepared by the following general reaction scheme (Scheme 3), wherein acid was selected from various acids either natural or synthetic sources and alcohol was bakuchiol.Scheme-3 Preferred One-step & one-pot synthesis of bakuchiyl ester (Comp-1 to Comp-6)and Scheme 3a Preferred One-step & one-pot synthesis of bakuchiyl salicylate (Comp-1)Table 3

[0096] Methods of the present invention include preparation of compounds of structure, Comp-2 - Comp-7 via a one-step and one-pot. In certain embodiments, the methods result in at least a 25% increased yield of bakuchiol esters relative to other known methods without need for separation of closely related by-products via column chromatography.

[0097] The present invention also includes cosmetic or pharmaceutical compositions comprising at least one skin anti-aging of bakuchiol ester described herein. The compositions of the present invention can be formulated to include other components such as a cosmetically and / or pharmaceutically acceptable excipient, an adjuvant, and / or a carrier. The modes of administration include, but are not limited to, topical applications for skin and hair care.

[0098] The invention also includes methods of topical treatment of skin. The methods comprise administering or applying an effective amount of at least one of the novel bakuchiol esters of the instant invention to skin, preferably an area of the skin in need of such treatment. The treatments contemplate administering of a bakuchiol ester in a suitable composition containing one or more vehicles such as but not limited to anhydrous serums, oil in water emulsions, water in oil emulsions in creams, lotions, and other liquid physical forms.EXAMPLES

[0099] Certain compounds of the present invention are prepared according to the following schemes. Comparative examples were made with reference to cited prior art. All temperatures are in degrees Celsius (°C.) unless otherwise indicated. At a minimum,all of the synthesized compounds were characterized by proton1H-NMR,13C-NMR and LC / MS.

[0100] During the work up of reactions, the organic extract was dried over sodium sulfate (NazSCU), unless mentioned otherwise. The following abbreviations are used for the commonly employed reagents: NazSCU (sodium sulfate), HCI (hydrochloric acid), NaOH (sodium hydroxide), KOH (potassium hydroxide), NaCI (sodium chloride), NaHCOs (sodium bicarbonate), DMF is dimethyl formamide) and RT is room temperature. DCC is N,A / '-dicyclohexylcarbodiimide, EDC is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide. DMAP is 4-methylaminopyridine, DCM is dichloromethane, SOCIz is thionyl chloride, (COCI)z is oxalyl chloride, POCI3 is phosphorus oxy chloride, PCI3 is phosphorus trichloride, Py is pyridine, EtsN is triethyl amine. TLC is thin layer chromatography.

[0101] Following synthesis of the present invention, formula compatibility and stability were studied.Example 1: Synthesis of Bakuchiyl Salicylate (Comp-1) (Scheme 3a above)

[0102] The synthesis of bakuchiol salicylate was executed by the reaction protocol invented herein. The synthetic scheme involved one-pot direct esterification by POCI3 using naturally and commercially available starting materials bakuchiol and salicylic acid (naturally derived from oil of Wintergreen) in the presence of the tertiary amine pyridine as acid scavenger.

[0103] To a 2L dry, jacketed kettle fitted with stirrer, distillation column, additional funnel and inert gas (Nz) feed, bakuchiol (121.8g, 0.48 mol), salicylic acid (69.1 g, 0.5 mol) and anhydrous pyridine (120mL) were combined with anhydrous toluene (800 ml) under nitrogen atmosphere and cooled to 0-5°C while stirring to form a homogenous solution. From the additional funnel, POCI3 (76g, 0.5 mol in toluene (80ml)) was slowly added to the bakuchiol solution while maintaining 0-5°C. A white precipitate appears during the addition which was dispersed by vigorous stirring to ensure reaction homogeneity.

[0104] After addition is complete, the reaction mixture is slowly increased to room temperature and further held there and allowed to stir until the consumption ofbakuchiol was completed by TLC analysis. The white precipitate was filtered off on a sinter funnel and solids washed with ethyl acetate. The organic layer was subsequently washed with water, brine and then dried over Na2SO4. The filtered solution was concentrated and dried under vacuum until achieved constant weight to produce (Comp- 1) (144g, 80% yield, >99% purity).:XH-NMR (CDCI3, 400 MHz): d 10.85 (1H, s), 8.40 (1H, dd, 4 & 8 Hz), 7.85(1H, t, J=4Hz), 7.77 (2H, d, J=8Hz), 7.48 (1H, d, J=8Hz), 7.37 (1H, d, J=8Hz), 7.30 (1H, t, J=8Hz), 6.78 (1H, d, J=16Hz), 6.54 (1H, d, J=16Hz), 6.23 (1H, dd, 7=12 & 16Hz), 5.45-5.47 (1H, dd, 7=12 & 16Hz), 5.35-5.45 (2H, m), 2.28-2.32 (2H, m), 2.02 (3H, s), 1.93 (3H, s), 1.84-1.89 (2H, m), 1.22 (3H, s). TLC analysis of this product demonstrated that SP-1 and SP-2 were absent.

[0105] Example 2: Synthesis of Bakuchiyl nicotinate using POCI3

[0106] Using the general protocol as illustrated in Example 1, the solution of Bakuchiol (25.6 g, 0.1 mol) and nicotinic acid (12.3 g, 0.1 mol) in anhydrous toluene (100 ml) and anhydrous pyridine (60 mL) was treated slowly with POCI3 (15.3 g / 0.1 mol) in anhydrous toluene (20 mL) under nitrogen atmosphere at 0-5°C. The reaction mixture was allowed to rise to room temperature (RT) slowly and then stirred overnight at RT unbl complete consumption of bakuchiol by TLC. A white precipitate was formed and filtered. The filtrate (toluene layer) was concentrated in rotary evaporator under reduced pressure and was diluted with ethyl acetate (500mL). Then the combined ethyl acetate was washed and separated with brine water. The ethyl acetate layer was then dried over dry sodium sulfate and concentrated under vacuum at 40-45°C.

[0107] This procedure produced (Comp-2) (28.2g, 80% yield) as a yellowish viscous liquid. The product, Comp-2, was obtained in yield of 80%. Purity >99%.

[0108] 1H-NMR (CDCI3, 400 MHz): d 9.40 (1H, s), 8.86(1H, d, 7=4Hz), 8.45 (1H, d, 7=4Hz), 7.48 (1H, d, 7=4Hz), 7.44 (1H, d, 7=8Hz), 7.16 (1H, d, 7=8Hz), 6.34 (1H, d, 7=16Hz), 6.20(1H, d, 7=16Hz), 5.89 (1H, dd, 7=12 & 16Hz), 5.12 (1H, t, 7=8Hz), 5.05-5.10 (2H, m), 1.94- 2.04 (2H, m), 1.68 (3H, s), 1.54 (3H, s), 1.50-1.53 (2H, m), 1.22 (3H, s).

[0109] Example 3: Synthesis of bakuchiyl quinolinate (Comp-7)

[0110] Using the general protocol as illustrated in Example 1 , the solution of Bakuchiol (25.6 g, 0.1 mol) and quinolinic acid (8.4 g, 0.05 mol) in anhydrous toluene (100 ml) and anhydrous pyridine (60 mL) was treated slowly with POCl3(15.3 g / 0.1 mol) in anhydrous toluene (20 mL) under nitrogen atmosphere at 0-5°C. The reaction mixture was allowed to rise to room temperature (RT) slowly and then stirred overnight at RT until complete consumption of bakuchiol byTLC. A white precipitate was formed and filtered. The filtrate (toluene layer) was concentrated in rotary evaporator under reduced pressure and diluted with ethyl acetate (500mL). Then the combined ethyl acetate was washed and separated with brine water. The ethyl acetate layer was then dried over dry sodium sulfate and concentrated under vacuum at 40-45°C. This procedure produced (Comp-7) (25.1 g, 78% yield) as a yellowish viscous liquid. The product, Comp-7, was obtained in yield of 78%. Purity >99%.1H-NMR (DMSO-d6, 400 MHz): 58.96 (1 H, d, 7=4Hz), 8.58 (1 H, d, 7=4Hz), 7.82 (1 H, dd, 7=4 & 8Hz), 7.48 (2H, d, 7=8Hz), 7.44 (2H, d, 7=8Hz), 7.23 (2H, d, 7=8Hz), 7.15 (2H, d, 7=8Hz), 6.23-6.34 (4H, m), 5.84-5.91 (2H, m), 5.08-5.10 (2H, m), 4.97-5.04 (4H, m), 1 .88-1 .93 (4H, m), 1 .65 (3H, s), 1 .63 (3H, s), 1 .53 (3H, s), 1 .51 (3H, s), 1 .39- 1.1.47 (4H, m), 1.16(3H, s), 1.15 (3H, s).

[0111] Example 4: Synthesis of bakuchiyl salicyl nicotinate (Comp-8):Baktrch ty! salicyl nicotinate (Co«ip-8>

[0112] Using the general protocol as illustrated in Example 1 , the solution of Bakuchiyl salicylate (Comp 1) (37.6 g, 0.1 mol) and nicotinic acid (12.3 g, 0.1 mol) in anhydrous toluene (100 ml) and anhydrous pyridine (60 mL) was treated slowly with POCl3(15.3 g / 0.1 mol) in anhydrous toluene (20 mL) under nitrogen atmosphere at 0-5°C. The reaction mixture was allowed to rise to room temperature (RT) slowly and then stirred overnight at RT until complete consumption of bakuchiol by TLC. A white precipitate was formed and filtered. The filtrate (toluene layer) was concentrated in rotary evaporator under reduced pressure and diluted with ethyl acetate (500mL). Then the combined ethyl acetate was washed and separated with brine water. The ethyl acetate layer was then dried over dry sodium sulfate and concentrated under vacuum at 40-45°C. This procedure produced (Comp-8) (39.5g, 82% yield) as a solid. The product, Comp-8, was obtained in high yield of 82%. Purity >99%.1H-NMR (CDCI3, 400 MHz): 5 9.39 (1 H, s), 8.80 (1 H, d, 7=4Hz), 8.44 (1 H, d, 7=8Hz), 8.29 (1 H, d, 7=8Hz), 7.71 (1 H, d, 7=4Hz), 7.46 (1 H, d, 7=4Hz), 7.42 (1 H, d, 7=4Hz), 7.40 (1 H.J=4Hz), 7.38 (2H, d, J- 8Hz), 7.32 (2h, d, J=8Hz), 6.27 (1 H, d, 7=16Hz), 6.13 (1 H, d, 7=16Hz), 5.87 (1 H, dd, 7=12 & 16Hz), 5.05 (1 H, t, 7=8Hz), 4.97-5.05 (2H, m), 1 .92-1 .94 (2H, m), 1.67 (3H, s), 1.57 (3H, s), 1 .46-1 .5 (2H, m), 1.18 (3H, s)

[0113] Example 5: Composition stability of Bakuchiyl Salicylate in Vitamin F Glyceryl esters 75 grams of Glyceryl Linoleate and Glyceryl Linolenate (Vitamin F Glyceryl Esters) was added to a 250 mL beaker with a magnetic str bar. 25 grams of Bakuchiyl Salicylate was added to this mixture while continuously mixing for 30 minutes. The mixture was then evaluated based on its appearance upon completion of mixing. Fluid was a lightyellow oil with minimal odor. This mixture was then split evenly into four separatecontainers and underwent accelerated stability. Please refer to Table 'Summary of compatibility studies' for results. The Vitamin F Glyceryl Esters managed to both have an acceptable odor as well as high compatibility with Bakuchiyl salicylate. Stability studies determined this specific composition to be highly stable and favorable.

[0114] Bakuchiyl Salicylate compatibility in ester fluids for use in the cosmetic field was studied in an effort to find a suitable delivery vehicle for the compound. The chosen ester fluid must readily solubilize Bakuchiyl Salicylate between 0.01-99.9% concentration only requiring minor agitation. Ester fluid must have minimal odor. Combined composition must withstand accelerated temperature stability where the composition does not phase separate after being exposed to different temperatures (0°C, 4°C, 25°C, 50°C) for prolonged periods of time.

[0115] Example 6: Compatibility of Hydroxypinacolone Retinoate and Bakuchiyl Salicylate in a cosmetic formula

[0116] The mixture of bakuchiyl salicylate (25%) in glyceryl linoleate and glyceryl linolenate was determined to be highly miscible and stable in a very broad range of 0.01- 99.99%. Hydroxypinacolone retinoate (10%) in dimethyl isosorbide was incorporated into a cosmetic formula to determine ease of compatibility and stability of the actives - bakuchiyl salicylate and hydroxypinacolone retinoate and stability of the formulation. Bakcuhiyl salicylate can be used in a range of 0.001% to 25% in a formula and hydroxypinacolone retinoate can be used in a range of 0.001% to 10%, although limits may be dependent on local and regional regulations. Preferably, the respective mixture of bakuchiyl salicylate and hydroxypinacolone retinoate in the invention consists of 0.01% to 0.5%. Other components of the formula known to the art may comprise of, but not limited to are water, emollients, oils, gels, surfactants, pH adjusters, preservatives, salts, chelating agents, film formers, silicones, etc.Phase INCI %A Water 64.950Butylene Glycol 5.000Sorbic Acid 0.200Sodium Citrate 0.300Citric Acid 0.100Glycerin 2.000Water & Propanediol & Polyglutamic Acid & 1,2-Hexanediol & Caprylyl Glycol 3.000Polyacrylate Crosspolymer-11 0.500Potassium Cetyl Phosphate 1.000Sodium Stearoyl Glutamate 0.750B Dimethicone & Polysi licone-ll & Butyrospermum Parkii (Shea) Butter 10.000Cetyl Alcohol 0.750Squalane & Amaranthus Caudatus Seed Oil & Hordeum Distichon (Barley) Extract& Triticum (Wheat) Germ Oil 0.200Polybutene 0.500Glyceryl Stearate 1.500Saccharomyces Ferment & Lauroyl Lysine 1.250Squalane 1.000Bis-Diglyceryl Polyacyladipate-2 0.500Dimethicone 3.000Cetearyl Alcohol 1.500C Glyceryl Linoleate & Glyceryl Linolenate & Bakuchiyl Salicylate (25%wt) 1.000Dimethyl Isosorbide & Hydroxypinacolone Retinoate (10%wt) 1.000FormulaTotal:100.0001. Weigh Phase A in the main kettle equipped with homogenizer. Heat to 70-75C.2. Weigh Phase B in the side kettle. Heat to 70-75C.3. When at proper temperature, add Phase B to Phase A. Mix well.4. Cool to 50C with side sweep agitation and add Phase C. Mix well to uniform.5. Continue cooling to room temperature.

[0117] Example 7: Granactive Retinoid (trademark, Grant Industries Inc.) and Bakuchiol Ester BCR cosmetic formula compatibility and stability. Granactive Retinoid and Bakuchiol Ester BCR were added in equal amounts to a cosmetic formula (Example 6) that was then tested for stability at elevated temperatures. Granactive Retinoid contains 10% Hydroxypinacolone Retinoate (HPR) in dimethyl isosorbide, and Bakuchiol Ester BCR contains 25% Bakuchiyl Salicylate in Vitamin F Glyceryl Ester. The formulas were placed at 40°C for 4-weeks and the concentration of both actives were evaluated by HPLC. The results are provided in Fig. 1 in which residual activity of HPR (Diamond) and Bakuchiyl Salicylate (Square) as a percent of the concentration at week zero are shown. The Bakuchiyl Salicylate concentration remains steady around 100% after 4-weeks, and the concentration of HPR decreases by about 30%.

[0118] No formulation issues were observed when combining these actives, and their initial activities were not negatively affected, suggesting that the active ingredients are compatible with each other. A sample of the formula was tested for activity after 7-weeks at room temperature and showed that the amount of HPR remained higher than 75% and the amount of Bakuchiyl Salicylate remained around 100%. Minor degradation of HPR is expected at elevated temperatures and when exposed to light. It is recommended to formulate with HPR by adding it during the cooling phase to avoid exposing it to oxygen during homogenization and elevated temperatures that could cause degradation. The pH of the formula after 12-weeks at room temperature was 4.6.Comparative Examples

[0119] Comparative Example 1: Synthesis of bakuchiol salicylate with EDC coupling:

[0120] Bakuchiol (0.36 mol; 92.16 grams), Salicylic Acid (0.378 mol; 52.16 grams), DMAP (0.036 mol; 5 grams) and excess portion of Dichloromethane (1200 mL) was added to a 2L kettle while stirring. The kettle was placed in an ice bath with salt to help reduce the temperature further. Reaction was also performed under a nitrogen blanket. The remaining portion of DCM (400 mL) was used to dissolve the EDC (0.45 mol; 70 grams), which was then added into the main reaction mixture slowly over the course of an hour. The reaction mixture turned cloudy about halfway through the addition. Once all the EDC was added, the reaction was left stirring under nitrogen for 24 hours. The reaction was monitored via TLC / HPLC. After 24 hours, a small dose of EDC / DMAP (10 gram / 1 gram, respectively) in DCM was added to the reaction to help push the reaction forward and mixed for another 3 hours. Once the HPLC showed no further conversion of the desired ester product, the reaction mixture was transferred to a separatory funnel and was washed with a saturated solution of ammonium chloride (2xlL), followed by brine (2xlL), and dried over sodium sulfate. The organic layer was filtered and concentrated using a rotary evaporator. The concentrate was an amber color. Notably, this example had significant SP-1 and SP-2 impurities (>6%) when tested by TLC, thus requiring additional column chromatography step for purification. Purification was performed by flash column chromatography. The starting eluent was 0.5% ethyl acetate / 99.5% Hexane and the finishing eluent was 1% ethyl acetate / 99% hexane. The final product was a light-yellow oil obtained after collecting the appropriate fractions and concentrated via rotary evaporator. After column chromatography the recovered yield was ~50% (>99%; HPLC, LCMS; Elemental Analysis), thus illustrating this method had much lower yield and value compared to the inventive example.Comparative Example 2: Bakuchiyl Salicylate: Transesterification reaction scheme (without any cofactors or catalysts)

[0121] This comparative example shows that transesterification methods using various catalysts and conditions are not viable for the large-scale production of bakuchiol salicylate when methyl salicylate is selected as the ester and bakuchiol is the alcohol.

[0122] Methyl Salicylate (0.117 moles) in excess was reacted with Bakuchiol (0.0235 moles) using several different catalysts (Table 4). Reaction conditions were to stir between 120-170°C for 12 hours. Thin Layer Chromatography (TLC) was used to track progress. Metal catalysts were observed to cause undesirable discoloration. Acid resin catalysts were sensitive to high temperatures. Both acid and basic catalysts saw minimal conversion. Overall product conversion to Bakuchiyl Salicylate was extremely poor and brought undesirable visual appearance therefore method was unviable.

[0123] This comparative example demonstrates that even though esterification methods, including transesterification are well known to one skilled in the art, the bakuchiol alcohol is highly unpredictable in terms of providing useful yield from proven esterification techniques and can be highly sensitive to thermal breakdown in the presence of traditional acid, base and resin catalysts. The practical distillation of methyl salicylate, which would theoretically assist in avoiding column chromatography for workup in the most ideal situation, was not herein viable because the yield was relatively non-existent using the methods above.Comparative Example 3 Enzyme Catalyzed Transesterification

[0124] Bakuchiol (0.0313 moles) and Methyl Salicylate (0.0302 moles) were added to a lOOmL round bottom flask and dissolved with Tetra hydrofuran (20 g). Novozyme 435 (0.35 g) was added to the reaction mixture. Two drops of water were added to activate the catalyst. Reaction was stirred at 45C for 48 hours and tracked by Thin Layer Chromatography. No reaction occurred due to Bakuchiol's incompatibility with the biocatalyst.Comparative Example 4 Mitsunobu Reaction

[0125] Bakuchiol (0.0195 moles), Salicylic Acid (0.0195 moles) and Triphenylphosphine (0.0293 moles) were dissolved in Dichloromethane (25 m L). Reaction mixture was chilled in an ice bath. Diisopropylazodicarboxylate (DIAD) (0.0293 moles) was dissolved in Dicholoromethane (20 mL) and added dropwise to the reaction mixture. Reaction conditions held and stirring continued for 14 hours. Afterwards, the temperature was raised to 40°C for 3 hours and then allowed to cool to room temperature. Reaction mix was added to a separatory funnel and worked up.

[0126] The resulting oil was dissolved in hexane to precipitate triphenyl oxide, filtered and concentrated by Rotovap. Product was purified via column chromatography.The yield was so poor that additional checks for byproducts were not conducted on the above comparative examples 2-4.Comparative Example 5:

[0127] One pot, two step synthesis using Salicyloyl chloride intermediate (SM-9)

[0128] Another aspect is a method of preparing the desired bakuchiyl esters via 2 step synthesis using the first step of making salicyloyl chloride intermediate (SM-9) followed by addition coupling with bakuchiol using different conditions.

[0129] Salicyloyl chloride (SM-9) (CAS 1441-87-8) was prepared according to patent [EP964659 Bl] Thionyl chloride (0.65 L) is added slowly to salicyclic acid (1 Kg) in toluene (10 L) / DMF (100 mL) and heated to about 70-75 °C along with stirring. The stirring is continued for about 1 h and the volatile components are distilled off to obtain the syrup of salicyloyl chloride (1.1 Kg). This salicyloyl chloride intermediate (SM-9) was isolated and used in a second step route to make a bakuchiyl esters described herein. SM-9 product mass is condensed with bakuchiol using a base pyridine. The acid chloride of any of the acid ligand compounds can be similarly made and used to form the desired bakuchiyl ester. While it is possible to conduct a two-step reaction by making SM-9 and coupling with bakuchiol, we noted the final purity of the salicyloyl chloride intermediate was <95% and contained disalate and trisalate. Moreover, holding the acid chloride of salicylic acid as an intermediate for short periods of time leads to further dimerization (disalate) and trimerization (trisalate) as unwanted by-products that forced column chromatography purification and loss of production value after coupling with bakuchiol or other alcoholic reagents. After some initial reactions, further attempts to use SM-9 basedon commercially available feedstock or freshly prepared feedstock were abandoned due to the relative instability of this reagent and the byproducts formed in the reaction. It is noted that EP964659 Bl teaches that 70-75 °C is the required temperature range for forming SM-9, thus leading to a higher degree of unwanted byproduct. In contrast, the inventive examples above discovered it is possible to achieve a direct one step one pot conversion at below <10°C, preferable 0°C. In contrast, the novel one-pot synthesis of this invention unexpectedly formed less than 0.01% disalate or trisalate in-situ and avoided use of isolating and storing salicyloyl chloride as an intermediate.Comparative Example 6: Composition stability of Bakuchiyl Salicylate in Linoleic Acid

[0130] 75 grams of conjugated Linoleic acid was added to a 250 mL beaker with a magnetic stir bar. 25 grams of Bakuchiyl Salicylate was added to this mixture with continuous mixing for 30 minutes. Mixture was then evaluated based on its appearance upon completion of mixing. Fluid was a light yellow oil with minimal odor. This mixture was then split evenly into four separate containers and underwent accelerated stability. Please refer to Table 4 'Summary of compatibility studies' for results. Conjugated Linoleic Acids odor was minimal, however the composition phase separated after undergoing temperature stability.Comparative Example 7: Composition stability of Bakuchiyl Salicylate in Glyceryl Ricinoleate

[0131] 75 grams of Glyceryl Ricinoleate was added to a 250 mL beaker with a magnetic stir bar. 25 grams of Bakuchiyl Salicylate was added to this mixture with continuous mixing for 30 minutes. The mixture was then evaluated based on its appearance upon completion of mixing. Fluid was a light yellow oil with an unpleasant rancid odor. Fluid was also sensitive to mild temperature fluctuations resulting in a half oily, half waxy heterogenous mixture. This mixture was then split evenly into four separate containers and underwent accelerated stability. Table 5 below provides results. The GlycerylRicinoleate failed to meet the criteria due to unpleasant odor as well as precipitation of waxy ester material.

[0132] Table 5: Summary of compatibility studiesConditions for Stability Study in Table 5:

[0133] Accelerated stability of a sample is performed by placing the material in various temperature controlled environments for an extended period of time. The temperatures chosen for this study was freeze-thaw cycle, 4°C, 25°C and 50°C. By subjecting the sample to a wide range of temperatures we are able to deduce how stable the material is and how it would hold up to shipping / transport conditions.

[0134] Temperature study to conduct a total of six freeze thaw cycle study, was conducted by placing the sample in a refrigerator (0°C) for 24 hours. After 24 hours, the sample was placed in a 50°C oven for 24 hours, followed by placing it in a 25°C oven for 24 hours. That sequence constitutes one freeze-thaw cycle. The final step involves observing any physical changes compared to the initial time stamp. If there are no observable changes to the detriment of the material after six freeze-thaw cycles such as phase separation, precipitation, extreme color changes or odor change then the material is stable to freezing / thawing conditions. This accelerated study demonstrates the stability regarding potential conditions of shipping, warehouse storage and shelf-life.

[0135] Standard temperature stability studies (4°C, 25°C and 50°C) involve placing the sample in a temperature controlled environment for one week followed by observation of the sample for any changes such as phase separation, precipitation, extreme color changes or odor change. If there are no observable changes to the detriment of thematerial after four weeks of temperature stability, then the material is determined to be highly stable. This accelerated study demonstrates the stability regarding potential conditions of shipping, warehouse storage and shelf-life. Reference Table 5 for the accelerated stability results of 25% Bakuchiyl Salicylate in an ester fluid.Biological Assays

[0136] The present invention also provides a topical composition comprising bakuchiol ester derivatives for skin treatments. The preferred derivatives are represented by the following compounds: Comp-1, Comp-2, Comp-3, Comp-4, Comp-5, Comp-6, Comp-7, and Comp-8. These compounds have been synthesized and tested for their effects on key biomarkers and cellular pathways involved in the aging process with all compounds having a potential for a high level of activity.

[0137] Most of these derivatives have been evaluated using various biological assays, including but not limited to collagen synthesis, elastin synthesis, hyaluronic acid production, and modulation of key transcription factors such as NRF2 and NF-kB. Notably, Comp-1, Comp-7 and Comp-8 demonstrated top-tier activity in PCR type gene expression assays, making them particularly useful as active ingredients in anti-aging cosmetic formulations.

[0138] The anti-aging properties of these bakuchiol ester derivatives were evaluated through a series of biological assays, including: a) Collagen Synthesis: The ability of the derivatives to stimulate collagen production was assessed by measuring collagen content in cultured skin cells. b) Elastin Synthesis: The derivatives were tested for their ability to enhance elastin production, which is critical for maintaining skin elasticity. c) Hyaluronic Acid Production: The production of hyaluronic acid, a major component of the skin extracellular matrix, was measured to evaluate the potential of the derivatives in improving skin hydration. d) Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) Activation: NRF2 is a key transcription factor involved in the regulation of cellular stress responses. The activity ofthe derivatives in activating NRF2 was assessed to determine their potential as antioxidant agents. e) Nuclear Factor Kappa-B (NF-kB) Inhibition: NF-kB is a transcription factor involved in inflammation. The ability of the bakuchiol ester derivatives to inhibit NF-kB signaling was measured to evaluate their anti-inflammatory effects.

[0139] Among the tested compounds, Comp-1, Comp-7 and Comp-8 demonstrated particularly strong effects in one or more of all the aforementioned biological assays, indicating their superior anti-aging activity. These compounds were found to significantly enhance collagen and elastin production, stimulate hyaluronic acid synthesis, activate NRF2, and inhibit NF-kB, all of which are important for promoting skin health and reducing the signs of aging.Challenges in Skin Penetration and Transdermal Delivery:

[0140] One of the key challenges faced by nicotinic acid and niacinamide in topical formulations is their poor penetration across the skin's phospholipid bilayer, particularly the stratum corneum. This limits their effectiveness in traditional skincare products. However, advancements in transdermal delivery (TDD) technology have provided a solution to this challenge.

[0141] By enhancing the permeability of active ingredients through the stratum corneum, TDD technology enables the controlled and passive delivery of crucial actives such as nicotinic acid and quinolinic acid directly into the epidermis. This approach has gained significant traction in the anti-aging market, as it allows for more effective delivery of key nutrients and compounds to the skin.

[0142] One promising development in transdermal delivery is the formation of its ester using lipophilic alcohol, e.g. bakuchiol nicotinate (Comp-2), bakuchiol quinolinate (Comp-7) and bakuchiol salicyl nicotinate. As an ester of nicotinic acid / or quinolinic acid and bakuchiol, this compound is expected to exhibit superior skin permeability compared to its parent molecules. Upon topical application, these ester derivatives would pass through the stratum corneum and into the epidermis, where it would behydrolyzed by esterases, particularly abundant in the epidermis, to release both bakuchiol and corresponding acids.

[0143] This innovative pro-coupling of co-actives could deliver the dual benefits of bakuchiol and niacin and its precursors to the skin, enhancing the NAD+ pool, improving mitochondrial function, reducing oxidative stress, and supporting skin barrier integrity. Additionally, bakuchiol has been shown to have anti-aging effects similar to retinol, further complementing the benefits of niacin in promoting youthful, healthy skin.

[0144] In further aspects of the invention there are provided uses of the compounds (Comp-1 to Comp-8) more specifically, Comp-1, Comp-2, Comp-7 and Comp-8 in methods of treating various skin conditions or disorders or systemic skin diseases or photo-damaged skin. In a further aspect, the compounds can be used in treatments either when used alone or as part of a multi-faceted approach to anti-aging skincare. In each of these aspects, the methods include applying a composition such as a cosmetic composition or a topical pharmaceutical composition including one or more of the compounds described herein either alone or in combination with a compatible ingredient to an area of skin of a person or animal requiring such treatment or which would benefit from the application of such compositions. Suitable cosmetic or pharmaceutical compositions can be applied one or more times daily as needed or desired.

[0145] Through their roles in enhancing collagen synthesis, supporting hydration, promoting cellular turnover, and protecting against oxidative stress and DNA damage, these compounds show promise as powerful skincare ingredients. Advances in transdermal delivery technologies and the development of innovative formulations like bakuchiol nicotinate are poised to overcome the challenges of skin penetration, ensuring that these benefits reach deeper layers of the skin and additionally allow for targeted hydrolysis of the two species into a more effective skin active via targeted esterase and or lipase activity.

[0146] The present invention also relates to pharmaceutical compositions that contain at least one bakuchiol ester derivative as described herein. These compositions can beformulated for use as cosmetic or pharmaceutical preparations, which may include additional ingredients such as cosmetically or pharmaceutically acceptable excipients, adjuvants, and / or carriers. For instance, the compositions may be formulated in an excipient that is compatible with the host to be treated. Excipients are inert substances used to dilute or carry the therapeutic agent and can include, but are not limited to, water, buffers, saline, Ringer's solution, dextrose solution, mannitol, Hank's solution, preservatives, and other aqueous solutions that are physiologically balanced.Nonaqueous vehicles like fixed oils (e.g., sesame oil, ethyl oleate), triglycerides, and others may also be used. Additional formulations may involve suspensions with viscosity-enhancing agents like sodium carboxymethylcellulose, sorbitol, or dextran. Excipients can further include minor additives to enhance isotonicity and chemical stability, such as buffers (e.g., phosphate, bicarbonate, tris, histidine, citrate, and glycine) or preservatives (e.g., EDTA, disodium EDTA, BHA, BHT, vitamin C, vitamin E, sodium bisulfite, SnCI2, thimerosal, m- or o-cresol, formalin, and benzyl alcohol). These standard formulations can be either liquid or solid, where the solid formulation is intended to be suspended or dissolved in a suitable liquid before administration.

[0147] In one embodiment, the composition may also contain an adjuvant or a carrier. Adjuvants are substances that enhance the biological response of the host to a bioactive agent and can include, but are not limited to, Freund's adjuvant, bacterial cell wall components, metals (e.g., aluminum, magnesium, zinc), silica, polynucleotides, toxoids, serum proteins, viral coat proteins, and other bacterial-derived materials. Examples include block copolymer adjuvants (e.g., Hunter's Titermax, Ribi adjuvants) and saponins such as Qui I A. Carriers are compounds that increase the half-life of the therapeutic composition in the host and can include polymeric controlled release formulations, biodegradable implants, liposomes, oils, esters, and glycols. The use of suitable carriers is well documented in "Remington: The Science and Practice, Twentieth Edition," the contents of which are incorporated herein by reference.

[0148] In one embodiment, the composition is formulated as a controlled release formulation, designed to release the composition slowly into the host. A controlledrelease formulation consists of the bakuchiol ester derivative incorporated into a controlled release vehicle, with biodegradable (bioerodible) vehicles being preferred.

[0149] The compositions of the present invention can be administered through any method known in the art. The treatment involves administering a therapeutically effective amount of at least one bakuchiol ester derivative of the invention, either internally or topically, to a patient in need.

[0150] In one embodiment, the therapeutic agents of the invention are applied topically by any suitable means, such as ointments, gels, lotions, creams, or coatings, or in the form of patches, dressings, masks, nonstick gauze, bandages, swabs, or wipes.

[0151] For example, a suitable ointment can contain an effective concentration of at least one bakuchiol ester, typically ranging from 0.001% to 100% by weight of the topical formulation. The ointment may include 65-100% white soft paraffin (preferably 75-96%), 0-15% liquid paraffin, and 0-7% lanolin or its derivatives. Another formulation may comprise a polyethylene-liquid paraffin matrix.

[0152] In another embodiment, a suitable cream may include an emulsifying system, with the desired bakuchiol ester concentration as mentioned above. The emulsifying system can consist of 2-10% polyoxyethylene alcohols (e.g., Cetomacrogol™ 1000), 10- 25% stearyl alcohol, 20-60% liquid paraffin, and 10-65% water, along with preservatives such as 0.1-1% N,N"-methylenebis[N'-[3-(hydroxymethyl)-2,5-dioxo-4- imidazolidinyl]urea] (Imidurea), 0.1-1% alkyl 4-hydroxy benzoates, 0.01-0.1% sodium butyl 4-hydroxybenzoate, and 0.1-2% phenoxyethanol.

[0153] A suitable gel may consist of a semi-solid system where a liquid phase is encapsulated within a cross-linked polymeric matrix. The liquid phase can include water along with the bakuchiol ester derivative and up to 20% water-miscible additives (e.g., glycerol, polyethylene glycol, propylene glycol). The gel can also contain thickening agents like tragacanth, pectin, carrageen, agar, alginic acid, methylcellulose, or Carbopol, and preservatives such as 0.1-2% methyl 4-hydroxybenzoate (methyl paraben) or phenoxyethanol.

[0154] Additionally, a polyethylene glycol-based base may comprise the bakuchiol ester derivative along with 70-90% polyethylene glycol, 5-20% water, 0.02-0.25% antioxidants (e.g., butylated hydroxytoluene), and 0.005-0.1% chelating agents (e.g., EDTA).

[0155] In these formulations, soft paraffin refers to white or yellow soft paraffin used as the base in creams or ointments, while lanolin refers to wool fat or its purified, modified, or synthetic equivalents used in the cosmetic and pharmaceutical industries.

Claims

WHAT IS CLAIMED IS:

1. A method of preparing an ester of bakuchiol, comprising reacting bakuchiol with a carboxylic acid ligand in the presence of a chlorinating reagents, an acid scavenging base and a solvents whereby a bakuchiyl ester is formed.

2. The method of claim 1, wherein the carboxylic acid ligand is a C1-C22 a li phatic saturated or unsaturated mono carboxylic acid, a C1-C12 saturated or unsaturated aliphatic diacid, an aromatic acid, a hydroxycinnamic acid, an alpha hydroxy acid or a mixture thereof.

3. The method of claim 2, wherein the carboxylic acid ligand is selected from the group consisting of itaconic acid, maleic acid, azelaic acid, succinic acid, ferulic acid, salicylic acid, nicotinic acid, isonicotinic acid, glycolic acid, mandelic acid, biotin, and quinolinic acid, caffeic acid, caftaric acid, chlorogenic acid, cinnamic acid, coumaric acid, butyric acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, lauroleic acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, retinoic acid.

4. The method of claim 3, wherein the carboxylic acid ligand is salicylic acid.

5. The method of claim 1, wherein the solvent is a polar aprotic solvent or a non-ionic solvent.

6. The method of claim 5, wherein the solvent is selected from the group consisting of dichloromethane, tetra hydrofuran, toluene, xylene and mixtures thereof.

7. The method of claim 1, wherein the chlorinating reagent is selected from the group consisting of thionyl chloride (SOCI2), oxalyl chloride (COCIh), phosphorus chloride (PCI3), phosphorus oxychloride (POCI3), and mixtures thereof.

8. The method of claim 7, wherein the chlorinating reagent is phosphorus oxychloride or thionyl chloride.

9. The method of claim 8, wherein the chlorinating reagent is phosphorus oxychloride.

10. The method of claim 1, wherein the acid scavenging base is tertiary nitrogen base.

11. The method of claim 10, wherein the acid scavenging base is pyridine or triethylamine.

12. The method of Claim 11, wherein the acid scavenging base is pyridine.

14. The method of claim 1, wherein the ester of bakuchiol is Formula (1)wherein R is the remainder of a carbonyl group in an acid, or a group which completes the carboxylic acid, preferably alkyl, allyl, aryl or aralkyl, or a stereoisomer, tautomer or salt thereof.

15. The method of claim 14, wherein the ester of bakuchiol is of Formula-1 wherein R is the remainder of a carbonyl group selected from a group of: naturally occurring saturated or unsaturated acid, selected from the group consisting of butyric acid, hexanoic acid, octanoic acid, decanoic acid, lauric acid, lauroleic acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, biotin, and retinoic acid; or diacids of the group itaconic acid, maleic acid, azelaic acid, and succinic acid; or aromatic acids of the group salicylic acid, nicotinic acid, and isonicotinic acid; or alpha hydroxy acids consisting of the group glycolic acid and mandelic acid; or hydroxycinnamic acids of the group ferulic acid, quinolinic acid, caffeic acid, caftaric acid, chlorogenic acid, cinnamic acid, and coumaric acid; or a stereoisomer, tautomer or salt thereof.

16. The method of claim 15, wherein the ester of bakuchiol is bakuchiyl salicylate:Bakuchiyl salicylate (C<«np 1)17. The method of claim 1, wherein the ester of bakuchiol is selected from the group consisting of:

18. The method of claim 1, further comprising a separation / purification step of treating the ester of bakuchiol with water washing solvents to achieve at least >95% final purity.

19. The method of claim 1, wherein said reacting is carried out at a temperature of from about 0° C to about 20° C, preferably about 0° C to about 10° C , more preferably from about 0° C to about 50C.

20. The method of claim 16, wherein the bakuchiyl salicylate contains less than 2% disalates or trisalates.

21. The method of claim 20, wherein the bakuchiyl salicylate contains less than 1% disalates or trisalates.

22. The method of claim 15, wherein the reaction is carried out in one pot, the chlorinating reagent is POCI3 and acid scavenging base is pyridine.

23. The process of claim 22, wherein said reacting is carried out at a temperature of from about 0° C to about 10° C or from about 0° C to about 5 ° C.

24. A compound of Formulawherein R' is the remainder of a carbonyl group selected from the group of: a naturally occurring saturated or unsaturated acid selected from the group consisting of butyric acid,hexanoic acid, octanoic acid, decanoic acid, lauric acid, lauroleic acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, biotin, and retinoic acid; or diacids of the group itaconic acid, maleic acid, azelaic acid, and succinic acid; or aromatic acids of the group nicotinic acid and isonicotinic acid; or alpha hydroxy acids consisting of the group glycolic acid and mandelic acid; or hydroxycinnamic acids of the group quinolinic acid, caffeic acid, caftaric acid, chlorogenic acid, cinnamic acid, and coumaric acid; or a stereoisomer, tautomer or salt thereof.

25. The compound of claim 24 selected from the group consisting of26. The compound of claim 25 being bakuchiyl nicotinate.

27. The compound of claim 25 being bakuchiyl isonicotinate28. The compound of claim 25 being bakuchiyl glycolate29. The compound of claim 25 being bakuchiyl mandeliateBakuchiyl maudaltete (C<>mp-5|30. The compound of claim 25 being bakuchiyl biotinateBakuchiyl biotinate (Comp-S)31. The compound of claim 25 being bakuchiol quinolinate32. The compound bakuchiyl salicyl nicotinateBakuchiyl salicyl nicotines33. A method for preparing bakuchiyl salicylate in two steps, comprising a) converting salicylic acid to salicyloyl chloride with chlorinating reagent and b) reacting the salicyloyl chloride of step a) with bakuchiol to form bakuchiyl salicylate.

34. A method for the treatment of skin of a person or animal, comprising topically applying a composition of claim 25 to an area of the skin-requiring such treatment.

35. A method for the treatment of photo damaged skin, comprising topically applying a composition of claim 25 to the area of the skin in need of such treatment.

36. A method for the treatment of skin disorders and systematic skin diseases comprising topically applying a composition of claim 25 to the area of skin in need of such treatment.

37. The method for treatment of aged skin, comprising topically applying a composition of claim 25 to the area of skin in need of such treatment.

38. A composition comprising a bakuchiol ester of claim 24 or made by the method of claim 14, the bakuchiol ester being soluble and compatible in one or more cosmetic fluids.

39. The composition of claim 38, wherein the cosmetic fluids are selected from the group consisting of cosmetic grade esters, alkanes, ethers, alcohols, silicones, fatty acids, and mixtures thereof.

40. The composition of claim 39, wherein the cosmetic fluid is a fatty ester mixture of Vitamin F, and a blend of the solvents glyceryl linoleate and glyceryl linolenate.

41. The composition of Claim 40 is a stable clear light-yellow oil with minimal odor.

42. A composition comprising hydroxypinacolone and bakuchiyl salicylate or a compound of claim 24 in a cosmetic formulation, said composition having enhanced stability and compatible with no phase separation or precipitation.

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