Trifarotene ester

Abstract

Described herein are certain trifarotene fatty acid esters and topical, topical skin care compositions containing one or more such compounds. In some embodiments, after hydrolysis in the skin, the shorter chain trifarotene fatty acid esters release short chain fatty acids such as octanoic acid and lauric acid, known to contribute to penetration enhancement in topical skin delivery. Also described are methods of topically applying the topical compositions to the skin of a subject to inhibit or reduce light aging or acne signs.

Description

Technical Field

[0001] This invention relates to trafarotine fatty acid esters and various topical compositions containing one or more trafarotine fatty acid esters, methods of using these compositions, and processes for preparing these compositions. When a topical composition is applied to the skin, it subsequently undergoes a hydrolysis reaction within the skin, releasing short-chain fatty acids such as caprylic acid and lauric acid from the shorter-chain esters. These are known to contribute to enhanced penetration during local skin delivery. Background Technology

[0002] Visible skin lesions, particularly on the face, are among the most common targets of dermatological and cosmetic treatments. Untreated facial skin lesions can lead to anxiety and psychological trauma. Facial skin lesions are often caused by photoaging and may manifest as actinic keratosis, solar freckles, loss of collagen and elastin in the underlying skin, wrinkles, and sagging skin. In its early stages, photoaging may present as inflamed erythema and enlarged freckles. Other facial skin lesions may be caused by acne, resulting in inflamed pores and post-acne scarring.

[0003] Topical retinoids are first-line treatments in cosmetic and prescription drug products for skin damage caused by photoaging and acne. These include first-generation retinoids associated with vitamin A, such as retinol (retinyl alcohol) and retinoic acid. In addition, there are second-generation retinoids, which are further variants of vitamin A. These materials are lipophilic and relatively easy to formulate in topical products, although they have two main drawbacks: they cause significant erythema, scaling, and peeling of the skin, and they are teratogenic.

[0004] Trafarotine (4-[3-(3-tert-butyl-4-pyrrolidone-1-ylphenyl)-4-(2-hydroxyethoxy)phenyl]benzoic acid) is a fourth-generation retinoid used topically as a selective retinoic acid receptor γ (RAR-γ) agonist for the treatment of acne. However, derivatives with different chemical properties are needed to provide enhanced efficacy.

[0005] This disclosure relates to trafarotin fatty acid esters. In some embodiments, upon hydrolysis in the skin, the shorter-chain esters release short-chain fatty acids such as caprylic acid and lauric acid, which can provide antimicrobial benefits on the skin. Furthermore, it is known that the release of shorter-chain fatty acids such as lauric acid and longer-chain fatty acids such as oleic acid upon ester hydrolysis contributes to enhanced penetration in topical dermal delivery. Summary of the Invention

[0006] In all respects, the present invention relates to compounds of formula I:

[0007] Formula I

[0008] R1 is an unsubstituted hydrocarbon group having seven to seventeen carbon atoms.

[0009] A further aspect relates to topical skin care compositions comprising one or more Formula I compounds in a cosmetically acceptable carrier.

[0010] On the other hand, a method for inhibiting or reducing signs of photoaging or acne includes applying the composition described herein topically to the skin of a subject in need. Detailed Implementation

[0011] Generally, the present invention relates to trafarotine fatty acid esters, various topical compositions containing one or more trafarotine fatty acid esters, methods of using these compositions, and processes for preparing these compositions. When the topical composition is applied to the skin, upon hydrolysis in the skin, the shorter-chain esters release short-chain fatty acids such as caprylic acid and lauric acid, which can provide antimicrobial benefits on the skin. Furthermore, it is known that the release of shorter-chain fatty acids such as lauric acid and longer-chain fatty acids such as oleic acid after ester hydrolysis contributes to enhanced penetration in local skin delivery.

[0012] Therefore, the present invention provides active agents of trafarotine derivatives that can be used to treat acne. These fourth-generation retinoids include C8-C 18 Fatty acids and trefaridine. For example, trefaridine esters of fatty acids include those compounds of formula I:

[0013] Formula I

[0014] R1 is an unsubstituted hydrocarbon group having seven to seventeen carbon atoms. The hydrocarbon group can be branched or straight-chain, saturated or unsaturated. In various embodiments, R1 is a saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon group. Preferably, R1 is an unsubstituted branched or straight-chain alkyl or alkenyl group having seven or more carbon atoms, for example, C7-C. 17 Carbon chain. When R1 is an alkenyl group, the substituent has at least one double bond, but may optionally have two or more double bonds. Examples of acceptable hydrocarbon groups (R1) include C7-C... 17 Alkyl or alkenyl groups. Where C7 and C8 are present. 11 and C 15 Alkyl and C 17 Alkenyl groups are preferred. The alkyl or alkenyl ester chain in the compound of formula I is preferably a chain that is soluble in the oil phase and miscible with lipophilic emollients commonly used in topical skin products. The compound may be in the form of an amorphous solid (i.e., an amorphous solid).

[0015] In some embodiments, the compound is selected from the group consisting of:

[0016] Formula II (3″-(tert-butyl)-4′-(2-(octanoyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid),

[0017] Formula III (3″-(tert-butyl)-4′-(2-(dodecyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid),

[0018] Formula IV (3″-(tert-butyl)-4′-(2-(palmitoyloxy)ethoxy)-4″-(pyrrolidone-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid), and

[0019] Formula V (3″-(tert-butyl)-4′-(2-(oleoyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid).

[0020] The esterification of fatty acids with trefaridine can be accomplished by the following methods and other methods known in the art. Trefaridine alcohol and fatty acids can be added in stoichiometric amounts, and esterification catalysts such as sulfonic acids and organotin catalysts can be used to increase the reaction rate, while reaction water can be removed by a reflux condenser. Alternatively, acyl chlorides (also known as alkyl acyl chlorides) can be used instead of fatty acids, and the reaction can proceed rapidly without a catalyst. For example, trefaridine can be reacted with octanoyl chloride in a suitable solvent to produce trefaridine octanoyl ester (trefaridine octanoate).

[0021] This invention also includes mixtures of active agents in cosmetically acceptable carriers such as oils and emollients (i.e., lipophilic carriers). These include, but are not limited to, emollient esters, triglycerides, plant oils, polyesters, polyol esters, wax esters such as jojoba oil, guerbet esters, fatty alcohols, fatty acid ethers, plant waxes, hydrocarbon fluids such as mineral oil, petrolatum, alkanes and isoalkanes, silicones, squalane, and other topical lipophilic emollients known in the art. Cosmetically acceptable lipophilic carriers may contain esters. The lipophilic solution contains the amount of active agent necessary to achieve an anti-acne effect. Typically, trefaridine fatty acid esters are dissolved in the lipophilic carrier in a minimum amount of about 1% to 10% by weight or higher. Trefaridine fatty acid esters may be dissolved in the lipophilic carrier in a minimum amount of 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight or higher.

[0022] Trafarotine fatty acid esters can be formulated into premixed compositions with a lipophilic carrier at even higher concentrations. Typically, the concentration of trafarotine fatty acid esters in the premixed composition will be at least about 1% by weight, and the weight ratio of trafarotine fatty acid esters to the lipophilic carrier will be from about 1:999 to about 2:8. The weight ratio of the compound to the cosmetically acceptable lipophilic carrier can be at least 1:99. The weight ratio of the compound to the cosmetically acceptable lipophilic carrier can be from about 1:9 to about 3:7. The premixed composition can be in the form of a homogeneous liquid solution or a single-phase amorphous solid.

[0023] The present invention further includes other topical compositions containing active agents dissolved or dispersed in oils and emollients, commonly referred to as an oil phase, wherein said oil phase is further dispersed in a physiologically acceptable topical formulation, such as a water-in-oil or oil-in-water emulsion, or a suspension of oil droplets in an aqueous matrix such as a gel. The aqueous phase of such compositions comprises water and may also contain emulsifiers, glycerin, and preservatives (e.g., octylglycerol ether, propylene glycol, and combinations thereof).

[0024] Furthermore, the present invention relates to topical compositions containing trafarotine fatty acid esters to inhibit or eliminate signs of photoaging and acne, such as reducing age spots, pigmentation, redness, blemishes, fine lines, and wrinkles. These topical compositions are particularly distinctive because the shorter-chain esters, upon hydrolysis in the skin, release short-chain fatty acids such as caprylic acid and lauric acid, which are known to have antimicrobial activity and are known to contribute to enhanced penetration in local skin delivery. Typically, trafarotine fatty acid ester active agents are present in such topical compositions at concentrations from about 10 ppm to about 1000 ppm and can be readily formulated from the aforementioned premixed compositions by mixing them with other cosmetically acceptable ingredients.

[0025] The trefarosine fatty acid esters described herein can be combined in topical compositions with other ingredients designed to inhibit photoaging and acne or reduce age spots, pigmentation, redness, blemishes, fine lines, and wrinkles. Examples of such ingredients include, but are not limited to, ascorbic acid and its derivatives, ferulic acid, azelaic acid, kojic acid, mandelic acid, α-hydroxy acids, β-hydroxy acids, lipohydroxy acids, fruit acids, polysaccharides, hyaluronic acid, humectants, gluconolactone, heparin sulfate, arbutin, nicotinamide, resveratrol, hydroquinone, psoralen, exfoliants, keratolytic agents, plant extracts, marine extracts, fermented extracts, isoflavones, bisabolol, anti-aging peptides, retinol, retinoic acid, retinyl esters, retinoic acid esters, adapalene, adapalene esters, and other retinoids.

[0026] Compositions of trafarotine fatty acid esters and one or more other ingredients described herein can be used as topical skin care compositions. This disclosure further relates to methods for inhibiting or reducing signs of photoaging or acne, comprising topically applying any composition described elsewhere herein to the skin of a subject in need.

[0027] definition

[0028] As used herein, the term "fatty acid" refers to a carboxylic acid consisting of an unsubstituted saturated or unsaturated hydrocarbon group and a terminal carboxyl group. Unless otherwise stated, fatty acids preferably contain 2 to about 30 carbon atoms or about 8 to about 18 carbon atoms, including branched or straight-chain types. Fatty acids may have an even or odd number of carbon atoms, but preferably an even number.

[0029] As used herein, the term "hydrocarbon group" refers to a hydrocarbon moiety that, unless otherwise stated, preferably contains 1 to about 50 carbon atoms, more preferably 1 to about 30 carbon atoms, and even more preferably 1 to about 18 carbon atoms, including branched or unbranched, and saturated or unsaturated types. The hydrocarbon group can be aromatic or aliphatic (i.e., non-aromatic). Unsubstituted hydrocarbon groups can be selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, etc. Unsubstituted hydrocarbon groups contain only carbon and hydrogen atoms and do not contain any further functional substituents. The hydrocarbon group can be optionally substituted. Thus, various substituted hydrocarbon groups can be further selected from substituted alkyl groups (e.g., cyano, alkoxy, alkylamino, thioalkyl, haloalkyl), substituted cycloalkyl groups (e.g., heterocyclic, N-heterocyclic, heterocyclic alkyl), substituted aryl groups (i.e., heteroaryl, N-heteroaryl, heteroarylalkyl), etc.

[0030] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon radical, preferably having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31, or 32 carbons and having one or more carbon-carbon double bonds. Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. The alkenyl group may be unsubstituted or substituted with one or more suitable substituents as defined above.

[0031] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon radical, preferably having 1 to 32 carbon atoms (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31, or 32 carbons). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Alkyl groups may be unsubstituted or substituted with one or more suitable substituents as defined above.

[0032] As used herein, the term "substituted" refers to a chemically acceptable functional substituent group, preferably one that does not deactivate the compound. Such substituents include, but are not limited to, hydroxyl groups, oxo groups, alkoxy groups, and / or cycloalkyl groups.

[0033] As used herein, the term "alkoxy" refers to an alkyl group as defined herein that is attached to the parent molecule via an oxygen atom.

[0034] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic radical, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, etc., optionally substituted with one or more suitable substituents, preferably substituted with 1 to 5 suitable substituents as defined above.

[0035] As used herein, the term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic radical (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, and bicyclic [5.2.0]nonyl, etc.); optionally containing one or two double bonds. The cycloalkyl group may be unsubstituted or substituted with one or more suitable substituents, preferably substituted with one to five suitable substituents as defined above.

[0036] As used in this article, the term "hydroxyl group" refers to the -OH group.

[0037] As used herein, the term "oxo" refers to a double-bonded oxygen (=O) radical, where the bonding partner is a carbon atom. Such radicals can also be considered carbonyl groups.

[0038] After a detailed description of the invention, it will be apparent that modifications and variations are possible without departing from the scope of the invention as defined by the appended claims.

[0039] Example

[0040] The following non-limiting embodiments are provided to further illustrate the invention.

[0041] Example 1 — Synthesis of Trafarotine Fatty Acid Ester Surfactant

[0042] Trofarosine octanoate was prepared according to the following steps: 1. Attach a mechanical stirrer and a dropping funnel to a 250 ml flask.

[0043] 2. Add 10 g trefaridine, 5.2 g triethylamine and 100 ml dichloromethane to the flask.

[0044] 3. Place the flask in an ice / water bath. Turn on the stirrer and stir the mixture for 1 hour.

[0045] 4. At 0°C, add 4.3 g of octanoyl chloride dropwise to the flask.

[0046] 5. Slowly warm the reaction mixture to room temperature while stirring.

[0047] 6. Monitor the reaction by TLC. When the reaction is complete, add water to quench it.

[0048] 7. The reaction mixture was washed three times with water and dried over Na2SO4, and then purified by column chromatography to obtain 16 g of the final product.

[0049] Example 2 — Trafarotine solution

[0050] A 1% trofarotine caprylate premixed solution was prepared by mixing 1 gram of trofarotine caprylate with 99 grams of caprylic / capric triglyceride, heating to 75°C for 10 minutes, and then cooling to room temperature. A homogeneous, clear solution was formed.

[0051] Example 3 — Trifarotine Caprylate Lotion for External Use

[0052] Table 1.

[0053] The lotion was prepared by first combining phase A, mixing until homogeneous and free of lumps, and heating to 80°C-85°C. Then, phase B was combined and mixed at 80°C-85°C until homogeneous. Finally, phase B was added to phase A at the same temperature and mixed until homogeneous, cooled to room temperature, and the pH was adjusted using phase C. The final formulation contained 100 ppm of trefarosen octanoate.

[0054] Example 4 — Clinical Trial of Trafarotine Octanoate Composition

[0055] To evaluate the anti-aging and skin rejuvenation effects, the lotion trial of Example 3 was conducted on adult subjects.

[0056] Validated Claim Support LLC in Teaneck, New Jersey, recruited ten female participants aged 35–65 (mean age 57) for this study. They were provided with the lotion of Example 3 and instructed to apply it once daily to their facial skin before bedtime, as they would normally do in their daily beauty routine.

[0057] Skin firmness and elasticity were measured regularly using a CUTOMETER device (purchased from Courage & Khazaka Electronic GmbH). After twelve weeks, 50% of participants experienced an increase in skin firmness, and 70% experienced an increase in skin elasticity.

[0058] The facial skin of each participant was also regularly graded by trained clinical technicians. The grading system tracked changes in skin condition over the twelve-week study period, and the results are reported in Table 2.

[0059] Table 2

[0060] When describing elements of the invention or preferred embodiments thereof, the articles “a,” “an,” “the,” and “described” are intended to indicate the presence of one or more elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that other elements besides those listed may be present.

[0061] In view of the above, it can be seen that several objectives of the present invention have been achieved and other advantageous results have been obtained.

[0062] Since various changes can be made to the above compositions, methods and processes without departing from the scope of the invention, all contents contained in the above description should be understood as illustrative and not restrictive.

Claims

1. Compounds of Formula I: Formula I R1 is an unsubstituted hydrocarbon group having seven to seventeen carbon atoms.

2. The compound of claim 1, wherein R1 is a saturated or unsaturated, straight-chain or branched aliphatic hydrocarbon group.

3. The compound of claim 1, wherein R1 is an unsubstituted straight-chain or branched alkyl or alkenyl group.

4. The compound of claim 1, wherein R1 is C7, C6, C7, C8, C9 ... 11 or C 15 alkyl.

5. The compound of claim 1, wherein R1 is C 17 Alkenyl group.

6. The compound of claim 1, wherein the compound is selected from the group consisting of: Formula II (3″-(tert-butyl)-4′-(2-(octanoyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid), Formula III (3″-(tert-butyl)-4′-(2-(dodecyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid), Formula IV (3″-(tert-butyl)-4′-(2-(palmitoyloxy)ethoxy)-4″-(pyrrolidone-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid), and Formula V (3″-(tert-butyl)-4′-(2-(oleoyloxy)ethoxy)-4″-(pyrrolidine-1-yl)-[1,1′:3′,1″-triphenyl]-4-carboxylic acid).

7. A topical skin care composition comprising a compound of any one of claims 1 to 6 in a cosmetically acceptable lipophilic carrier, wherein the compound is at least partially soluble in the cosmetically acceptable lipophilic carrier.

8. The composition of claim 7, wherein the cosmetically acceptable lipophilic carrier is selected from the group consisting of: emollient esters, triglycerides, vegetable oils, polyesters, polyol esters, wax esters, guerbert esters, fatty alcohols, fatty acid ethers, vegetable waxes, hydrocarbon fluids, petrolatum, alkanes, isoalkanes, silicones, squalane, and combinations thereof.

9. The composition of claim 7, wherein the cosmetically acceptable lipophilic carrier comprises an ester.

10. The composition of claim 7, wherein the compound is dissolved in the cosmetically acceptable lipophilic carrier in a minimum amount of about 1% by weight.

11. The composition of claim 7, wherein the weight ratio of the compound to the cosmetically acceptable lipophilic carrier is at least 1:

99.

12. The composition of claim 7, wherein the weight ratio of the compound to the cosmetically acceptable lipophilic carrier is from about 1:9 to about 3:

7.

13. The composition of claim 7, wherein the composition comprises an oil phase and an aqueous phase, the oil phase comprising the compound in the lipophilic carrier, and the aqueous phase comprising water.

14. The composition of claim 13, wherein it is in the form of a water-in-oil emulsion, an oil-in-water emulsion, or a suspension of oil droplets in an aqueous matrix such as a gel.

15. The composition of claim 7, wherein the composition further comprises at least one ingredient selected from the group consisting of: ascorbic acid and its derivatives, ferulic acid, azelaic acid, kojic acid, mandelic acid, α-hydroxy acid, β-hydroxy acid, lipohydroxy acid, psoralen, fruit acid, polysaccharide, hyaluronic acid, humectant, gluconolactone, heparin sulfate, arbutin, nicotinamide, resveratrol, hydroquinone, exfoliant, keratolytic agent, plant extract, marine extract, fermentation extract, isoflavone, bisabolol, anti-aging peptide, retinol, retinoic acid, retinyl ester, retinoic acid ester, adapalene, adapalene ester and other retinoids.

16. A method for inhibiting or reducing signs of photoaging or acne, the method comprising applying topically the composition of claim 7 to the skin of a subject in need.

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