Adhesive photoprotective compounds and uses thereof

Abstract

The present invention relates to adhesive photoprotective compounds of formula (I). It also relates to a composition comprising the same and, more particularly, to a cosmetic or a sunscreen composition. It also relates to the use of such compounds in cosmetic and therapeutic applications.

Description

[0001] ADHESIVE PHOTOPROTECTIVE COMPOUNDS AND USES THEREOF

[0002] TECHNICAL FIELD

[0003] The present invention relates to photoprotective compounds having adhesive properties. It also relates to a composition comprising the same and, more particularly, to a cosmetic or a sunscreen composition. It also relates to the use of such compounds in cosmetic and therapeutic applications. The invention also relates to the use of such compounds for reducing photodegradation and / or photoinstability of pharmaceuticals and cosmetics. The invention further relates to a material comprising a support and such a compound adhered to said support.

[0004] TECHNICAL BACKGROUND

[0005] Almost 5 % of the electromagnetic energy of the sun is emitted in the form of UV light. This UV light can be divided into three groups: UV-A (400-315 nm), UV-B (315-280 nm) and UV-C (280-100 nm). UV light, and more particularly UV-B light, can have damaging short-term or long-term effects on the body. Serious skin damages may occur due to an exposure to UV light, such as an accelerated skin ageing or a skin cancer. As a result, the development of new sunscreens providing effective protection throughout the whole UV radiation spectrum has become a prime concern and a major issue.

[0006] Many sunscreens are nowadays available on the market. Despite an undeniable efficacy, it has been demonstrated that active agents of these sunscreens can penetrate through the skin into epidermal cells, and have also been detected in urine or breast milk. Small and non-adhesive nanoparticles have been developed for sunscreen compositions and are currently available on the market. However, such materials have also proven to be skin-penetrating.

[0007] Bioadhesive particles have also been designed to adhere to the skin and to encapsulate active agents, such that neither the particles nor the active agents penetrate the skin. However, such bioadhesive particles are prepared by complex and costly manufacturing processes.

[0008] Also, to prevent the active ingredient from penetrating the skin, bioadhesive photoprotective compounds have been developed and were reported in the international patent application WO2021 / 123116. However, this approach needs to be more investigated to develop further efficient bioadhesive photoprotective compounds easy to produce and having solubility properties suitable for the formulation of cosmetics and therapeutic products.

[0009] Therefore, there remains a need to prepare further efficient adhesive photoprotective compounds.

[0010] SUMMARY OF THE INVENTION

[0011] In this context, the inventors have developed photoprotective compounds comprising a photoprotective moiety derived from the UV filter ethylhexyl triazone (CAS number: 88122-99-0; also referenced herein as “EHT”), which is commercialized by several companies, such as BASF under the name Uvinul® T 150. Said photoprotective moiety is linked to a functional maleimide group via an aliphatic linear hydrocarbonated linker. As demonstrated by the following examples, the compounds of formula (I) according to the invention exhibit efficient adhesive properties and solubility properties in a large number of solvent currently used in the formulation field. Also, the compounds of formula (I) according to the invention are photostable and exhibit a Sun Protection Factor SPF similar to the corresponding free commercial filters.

[0012] The present invention thus relates to a compound represented by the following formula (I):

[0013]

[0014] wherein:

[0015] X is O or NH, and

[0016] n is an integer from 0 to 23.

[0017] In a particular embodiment, n is an integer from 1 to 11, preferably from 1 to 7.

[0018] In an embodiment X is O. In an embodiment X is NH.In a preferred embodiment, the compound according to the invention is selected from the group consisting of:

[0019] bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EEM);

[0020] bis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EBM);

[0021] bi s(2-ethylhexyl) 4,4'-((6-((4-((6-(2, 5 -dioxo-2, 5 -dihy dro- 1 H-pyrrol- 1 -yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EHM); and

[0022] bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EOM).

[0023] It also relates to a composition comprising at least one compound of formula (I) as defined herein and at least one excipient. In an embodiment, said composition is a topical composition. In a particular embodiment, said composition is in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a microemulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam.

[0024] In a further particular embodiment, said composition is a sunscreen composition or a cosmetic composition.

[0025] A further object of the present invention is a cosmetic use of a composition as defined herein, for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier. Another object of the present invention is a cosmetic process for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of skin firmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier, comprising applying topically to the skin, a composition as defined herein.

[0026] Another object of the present invention is a cosmetic use of a composition as defined herein for protecting and / or caring the hair or the nail.Another object of the present invention is a kit comprising:

[0027] - a composition as defined herein,

[0028] - a washing composition, and

[0029] - optionally an instruction guide.

[0030] In another particular embodiment, said composition is a pharmaceutical or a veterinary composition.

[0031] The present invention also relates to a composition as defined herein, for use for treating and / or preventing a skin, mucosa, eye cornea, or skin appendage disease or condition. Preferably, said skin, mucosa, eye cornea, or skin appendage disease or condition is chosen from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) and sporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection, and pressure ulcer healing.

[0032] The present invention also relates to a use of at least one compound of formula (I) as defined herein for reducing photodegradation and / or photoinstability of a pharmaceutical active ingredient or a cosmetic. In this particular application, said at least one compound is in a form of a micelle or a liposome.

[0033] Another object of the invention is a material comprising a support and at least one compound of formula (I) as defined herein, said compound being adhered to said support. Preferably, said support is a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, a metal, a plastic, a rubber or a glass support.

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] A compound of the invention is typically by the following formula (I):

[0036]

[0037] wherein:

[0038] X is O or NH, and

[0039] n is an integer from 0 to 23.

[0040] According to the invention, n is an integer from 0 to 23. Particularly, n is an integer from 1 to 19, from 1 to 15, from 1 to 11, from 1 to 9, from 1 to 7. Preferably, n is an integer from 1 to 11, more preferably from 1 to 7. In a more preferred embodiment, n is 1, 3, 5, or 7.

[0041] According to the invention X is O or NH.

[0042] In an embodiment X is O. According to this embodiment, n is an integer from 1 to 19, from 1 to 15, from 1 to 11, from 1 to 9, from 1 to 7. Preferably, n is an integer from 1 to 11, more preferably from 1 to 7. In a more preferred embodiment, n is 1, 3, 5, or 7.

[0043] In a further embodiment X is NH. According to this embodiment, n is an integer from 1 to 19, from 1 to 15, from 1 to 11, from 1 to 9, from 1 to 7. Preferably, n is an integer from 1 to 11, more preferably from 1 to 7. In a more preferred embodiment, n is 1, 3, 5, or 7.

[0044] In a particular embodiment, n is i and X is NH. According to this embodiment, a compound of formula (I) of the invention is bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (also referenced herein as “EEM”) and has the following formula:

[0045]

[0046] In a further particular embodiment, n is 3 and X is NH. According to this embodiment, a compound of formula (I) of the invention is bis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (also referenced herein as “EBM”) and has the following formula:

[0047]

[0048] In a further particular embodiment, n is 5 and X is NH. According to this embodiment, a compound of formula (I) of the invention is bis(2-ethylhexyl) 4,4'-((6-((4-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (also referenced herein as “EHM”) and has the following formula:

[0049]

[0050] In a further particular embodiment, n is 7 and X is O. According to this embodiment, a compound of formula (I) of the invention is bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (also referenced herein as “EOM”) and has the following formula:

[0051]

[0052] A preferred embodiment of the invention is a compound of formula (I) selected from the group consisting of:

[0053] bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EEM);

[0054] bis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EBM);

[0055] bi s(2-ethylhexyl) 4,4'-((6-((4-((6-(2, 5 -dioxo-2, 5 -dihy dro- 1 H-pyrrol- 1 -yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EHM); and

[0056] bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EOM).

[0057] According to the present invention, a compound of formula (I) is adhesive. More particularly, a compound of formula (I) is bioadhesive.

[0058] The expression “adhesive compound” denotes a compound that is able to adhere, through its maleimide functional group to any support, said support being biological, organic, and / or inorganic. More specifically, said compound adheres through one or more of its maleimide functional group, which is able to react with reactive groups or entities of said support.

[0059] A “bioadhesive compound” refers to an adhesive compound as defined above, wherein the support is biological. Examples of biological supports include but are not limited to tissues (e.g. a skin), cells (e.g. chondrocytes, osteoblasts, fibroblasts, blood cells, plasmocytes), intracellular or extracellular materials (e.g. proteins, glycoproteins, collagen, elastin, glycosaminoglycans, proteoglycans).

[0060] Reactive groups that can be found on said supports, and more particularly on said biological supports, include, but are not limited to amine and thiol. The functional maleimide group may advantageously reacts selectively with a particular reactive group found on said support. For instance, maleimide can typically be selective to thiol groups.

[0061] Reaction of the maleimide functional group of a compound of formula (I) with a reactive group creates a bond such as an ether, a thioether, or an urea bound. The bound created between amaleimide functional group of a compound of formula (I) and a reactive group of a support is covalent. Said bound is advantageously reversible. Said bound may be cleaved by use of a cleaving material selected from chemical and physical agents (e.g. protein, peptide (e.g. glutathione), amino acid, enzyme (e.g. cathepsin B), thiol (e.g. 2-mercaptoethanol, N-acetyl cysteine), dithiol (e.g. dithiothreitol), pH-modifier, base, solvent, and / or woven or non-woven tissue. The skilled artisan is able to select an appropriate cleaving material depending on the nature of the bound and / or the composition.

[0062] Another object of the invention is a composition comprising at least one compound of formula (I) as defined herein and at least one excipient.

[0063] In a particular embodiment, the composition comprises from 0.01 wt% to 99 wt% of compound of formula (I), preferably from 0.01 wt% to 90 wt%, more preferably from 1 wt% to 70 wt%, even more preferably from 5 wt% to 50 wt%, relative to the total weight of the composition.

[0064] The composition according to the invention may in particular be in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a micro-emulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam. The composition can be prepared according to processes known to the skilled artisan.

[0065] An excipient in the compositions of the invention may include a solvent or a dispersion medium comprising, for instance, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils, such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. Examples of suitable solvents are, without limitation, dibutyl Adipate (Cetiol® B - BASF), dimethyl isosorbide (Dottisol® - Dottikon), propylene glycol gibenzoate (LexFeel® Shine - Inolex), tri ethyl citrate (CITROFOL® Al EXTRA -Jungbunzlauer), diisopropyl sebacate (DUB DIS - Stearinerie Dubois), C12-15 alkyl benzoate (Cetiol® AB - BASF), dipropylene glycol dibenzoate (Finsolv® PG-22 - Ingretech), diethylhexyl adipate (Crodamol™ DOA - Croda), cocoglycerides (Myritol 331 - BASF), isopropyl lauroyl sarcosinate (Eldew SL 205 - Ajinomoto), lauryl lactate (Schercemol LL ester - Lubrizol) and phenethyl benzoate (Xtend 226 - Ashland).Examples of further excipients include, but are not limited to, surfactants, dispersants, emulsifiers, pH modifying agents, pH-buffers, viscosity modifying agents, preservatives, polymerizers, pigments, colorants, stabilizing agents, glidants, diluents, binders, water-soluble polymers, lubricants, disintegrators, swelling agents, fillers, stabilizers, antioxidants, emulsifiers, emollients, penetration enhancers, propellants, gas, depigmenting agents, film forming agents, gelling agents, moisturizing agents, colorants, fragrance ingredients, exfoliants, solubilizers, solvents, binding agents, bulking agents, humectants, cleansing agents, elastomers, astringents, masking agents, anti-static agents, protectants, denaturants, absorbents, anti-caking agents, matting agents, structuring agents, oxidative agents, reducing agents, superfatting agents, active boosters, and combinations thereof.

[0066] Examples of additional agents which may be comprised in the composition include, but are not limited to, desquaming agents, whitening agents, tensing effect agents soothing agents, antiirritant agents, sebo-regulating agents, wound healing agents, anti-inflammatory agents, antiacne agents, anti-glycation agents, slimming agents, self-tanning agents, anti-aging agents, antiwrinkle agents,

[0067] Surfactants that can be used in the composition may be anionic, cationic, amphoteric or nonionic. Examples of anionic surfactants include, but are not limited to, carboxylate, sulfonate and sulfate ions-containing surfactants, such as sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; sulfated castor oil, propylene glycol, lecithin, capri c / capry lie triglycerides, PEG-12 oleate (FANCOL® HS3 US®), and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG- 150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenyl ether, PEG- 1000 cetyl ether, polyoxyethylene tri decyl ether, polypropylene glycol butyl ether, POLOXAMER® 401, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallow amide, but also emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castoroil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone, cetyl palmitate. Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

[0068] Examples of preservatives, include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, perillic acid and thimerosal.

[0069] Examples of water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0070] Suitable stabilizers include, but are not limited to, butylated hydroxytoluene (BHT), ascorbic acid, its salts and esters, Vitamin E, tocopherol and its salts, sulfites such as sodium metabisulphite, cysteine and its derivatives, citric acid, propyl gallate, and butylated hydroxyanisole (BHA).

[0071] An example of pH-buffer that can be used in the composition is triethanolamine.

[0072] Examples of emollients include, but are not limited to, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof.

[0073] Examples of emulsifiers include, but are not limited to, acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum, PEG-100 Stearate / Gly ceryl stearate (Arlacel 165®), decyglucoside (Plantaren 2000®), laurylglucoside (Plantarenl200®), Cetearyl Glucoside, Cetearyl Alcohol (Emulgade PL68 / 50®), and combinations thereof.

[0074] Examples of penetration enhancers include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithins, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified celluloses, and diimides), macrocyclics, such as macrocylic lactones, ketones, and anhydrides and cyclic ureas, surfactants, N-methyl pyrrolidones and derivatives thereof, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, such as alcohols, ketones, amides, polyols (e.g., glycols).

[0075] Examples of propellant agents include, but are not limited to, dichlorofluoromethane, difluoroethane, isobutane, n-butane, propane, dichlorofluoromethane, nitrogen, carbon dioxide.

[0076] Examples of desquaming agents include, but are not limited to, beta hydroxyacids, alpha hydroxy acids, urea, cinnamic acid, Saphora japonica extract, proteases like trypsine.

[0077] Examples of depigmenting agents include, but are not limited to, vitamin C and its derivatives, ferulic acid, resorcinol, alpha and beta arbutin.

[0078] Examples of anti-glycation agents include, but are not limited to, black tea extract and Vaccinium myrtillus extract.

[0079] Examples of slimming agents include, but are not limited to, caffeine, tea extracts, Hedera helix extracts, and theobromine.

[0080] Examples of soothing agents and anti-irritation agents include, but are not limited to, caffeine, vitamins E, C, B5, B3, glycyrrhetic acid, a salt or a derivative thereof.Examples of sebo-regulating agents include, but are not limited to, zinc salts such as zinc gluconate or zinc pidolate, vitamin B6, selenium chloride, and benzoyl peroxide.

[0081] Examples of wound healing agents include, but are not limited to, arginine, hydroxyproline, chitosan and derivatives, propolis extracts, folic acid, and chitosan.

[0082] An example of self-tanning agent includes, but is not limited to, erythrulose.

[0083] Examples of anti-aging agents include, but are not limited to, placenta extracts, beta glucan, fucoidan, sodium hyaluronate, and collagen.

[0084] Examples of anti-static agents includes, but is not limited to, methyl sulfonyl methane.

[0085] An example of bulking agent includes, but is not limited to, polypropylene A.

[0086] Examples of film former include, but are not limited to, copolymer of l-vinyl-2-pyrrolidone and vinyl acetate, and Polyquatemium-6.

[0087] The composition of the invention can be administered orally, topically, parenterally, subcutaneously, epicutaneously, intra-dermically, transdermically, intramusculary, enterally, intranasally, intra-respiratory, intra-vascular, ophthalmic preparation, intra-vaginal, endo-urethral, or by nasal inhalation. In a particular embodiment, the composition of the invention is administered sub-cutaneously, epicutaneously, intra-dermically, transdermically, or topically, preferably topically. The composition of the invention may be administered by microneedles, or patches.

[0088] The composition may in particular be applied to mucosa, comeum, epidermis, dermis, epithelium, endothelium, skin, skin appendages, connective tissues, or bone tissues, preferably skin, skin appendages or mucosa.

[0089] In an embodiment, the composition of the invention is selected from a sunscreen composition, a cosmetic composition, a dermatological composition, and a therapeutic composition. In a preferred embodiment, the composition is a sunscreen or a cosmetic composition.In a particular embodiment, the composition of the invention is a topical composition. The topical composition comprises at least one compound of formula (I) as defined herein, and at least one topically acceptable excipient.

[0090] A “topically acceptable excipient”, as used herein, denotes an excipient suitable for a topical application. Such an excipient can be judiciously chosen by the skilled artisan, for instance among the excipients described above.

[0091] Said topical composition may be a dermatological composition, therapeutic composition and / or a cosmetic composition.

[0092] The topical composition may in particular be in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a microemulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam. The composition can be prepared according to processes known to the skilled artisan.

[0093] Preferably, the topical composition is selected from a cream, a spray, a gel, an ointment, a lotion, an emulsion, a foam, a suspension and a milk.

[0094] The topical composition may be applied to mucosa, corneum, epidermis, dermis, epithelium, endothelium, skin or skin appendages (e.g. hair and nails), preferably mucosa, skin or skin appendages.

[0095] In another particular embodiment, the composition of the invention is a cosmetic composition.

[0096] Said cosmetic composition comprises at least one compound of formula (I) according to the invention, and at least one cosmetically acceptable excipient.

[0097] A “cosmetically acceptable excipient”, as used herein, denotes an excipient suitable for a cosmetic application. Such an excipient can be judiciously chosen by the skilled artisan, for instance among the excipients described above.The cosmetic composition can be administered orally, topically, parenterally, sub-cutaneously, epicutaneously, intra-dermically, transdermically, intramusculary, enterally, intranasally, intra-respiratory, or by nasal inhalation. In a preferred embodiment, the cosmetic composition is administered topically.

[0098] Preferably, the cosmetic composition is a topical composition or a dermatological composition, more preferably a topical composition.

[0099] The cosmetic composition may in particular be applied to mucosa, corneum, epidermis, dermis, epithelium, endothelium, skin or skin appendages (e.g. hair and nails), preferably mucosa, skin or skin appendages.

[0100] The cosmetic composition may in particular be in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a microemulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam. The composition can be prepared according to processes known to the skilled artisan.

[0101] The composition of the invention may be particularly well-suited for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier.

[0102] The signs of cutaneous ageing may be related to intrinsic factors that are age-related, but also extrinsic factors, in particular UV-light exposure. Also, hair or nail damages may also appear with UV-light exposure.

[0103] An object of the invention relates to a cosmetic use of the composition of the invention for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier.

[0104] Another object of the invention is cosmetic process for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of skinfirmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier, comprising applying topically to the skin or its appendages, a composition of the invention.

[0105] An object of the invention relates to a cosmetic use of the composition of the invention for protecting and / or caring the hair. An object of the invention relates to a cosmetic use of the composition of the invention for protecting and / or caring the nail.

[0106] In another particular embodiment, the composition of the invention is a sunscreen composition.

[0107] The sunscreen composition is advantageously applied topically (i.e. a topical composition). The sunscreen composition may in particular be in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a microemulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam. In a particular embodiment, the sunscreen composition is a formulation sunscreen type butter.

[0108] In a particular embodiment, the composition of the invention is a therapeutic composition and, more particularly, said composition is a pharmaceutical composition or veterinary composition.

[0109] The therapeutic composition comprises at least one compound of formula (I) according to the invention and at least one pharmaceutically acceptable excipient.

[0110] The term “pharmaceutically acceptable”, as used herein, refers to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio, in accordance with the guidelines of agencies such as the Food and Drug Administration. A “pharmaceutically acceptable excipient”, as used herein, refers to all components of a pharmaceutical or therapeutic composition which facilitate the manufacture, the preservation and / or the delivery of the composition in vivo. Pharmaceutically acceptable excipients include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.The therapeutic composition can be administered orally, topically, parenterally, subcutaneously, epicutaneously, intra-dermically, transdermically, intramusculary, enterally, intranasally, intra-respiratory, or by nasal inhalation. In a preferred embodiment, the therapeutic composition is administered topically.

[0111] In a particular embodiment, the therapeutic composition is applied to a tissue chosen from the skin, skin appendages, mucosa, corneum, epidermis, dermis, epithelium, endothelium, connective tissues, bone tissues, and combinations thereof, preferably skin, skin appendages, mucosa, corneum, epidermis, dermis, epithelium, and endothelium, and more preferably skin, skin appendages, and mucosa. In another embodiment, the therapeutic composition is applied to a circulating medium, such as blood or plasma.

[0112] In a particular embodiment, the therapeutic composition is a dermatological composition.

[0113] Another object of the invention is a compound of formula (I) according to the invention or a composition of the invention (in particular, a therapeutic composition), for use in the treatment and / or prevention of a skin, a mucosa, an eye cornea, or skin appendage disease or condition. Preferably, said skin, mucosa, eye cornea or skin appendage disease or condition is chosen from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) and sporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection, pressure ulcer healing, vaginitis, bladder cancer, endometriosis, uveitis, cornea diseases, cornea keratitis, corneal herpes, keratoconus, corneal dystrophies, pharyngitis, cutaneous and mucosal allergies. More preferably, said skin, mucosa, eye cornea or skin appendage disease or condition is chosen from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) andsporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection and pressure ulcer healing.

[0114] As used herein, the terms "prevent," "preventing," or "prevention," refer to any reduction, no matter how slight, of a subject's predisposition or risk for developing a condition, disease, disorder or symptom thereof. For purposes of prevention, the subject is any subject, and preferably is a subject that is at risk for, or is predisposed to, developing a condition, disease, disorder. The term "prevention" includes either preventing the onset of a clinically evident condition, disease, disorder altogether or preventing the onset of a pre-clinically evident condition, disease, disorder in individuals at risk. This includes prophylactic treatment of subjects at risk of developing condition, disease, disorder.

[0115] As used herein, the terms “treat”, “treatment” or “treating” of a disease, disorder, or condition encompass alleviation of at least one symptom thereof, a reduction in the severity thereof, or the delay or inhibition of the progression thereof. Treatment need not mean that the disease, disorder, or condition is totally cured. A useful composition herein needs only to reduce the severity of a disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide improvement to a patient or subject’s quality of life, or delay or inhibit the onset of a disease, disorder, or condition.

[0116] Another object of the invention is a method for delivering at least one compound of formula (I) to a tissue of a subject in need thereof, comprising administering an effective amount of a composition of the invention. The present invention also provides a method of delivering at least one compound of formula (I) to a tissue of a subject, comprising: topically administering to a subject in need thereof a therapeutically effective amount of any presently described compositions useful in treating a disease, disorder, or condition of the tissue.

[0117] Particularly, said tissue is chosen from the skin, skin appendages, comeum, epidermis, dermis, epithelium, endothelium, connective tissues, bone tissues, and combinations thereof. Preferably, said tissue is the skin, a skin appendage, or a mucosa.

[0118] "Effective amount" or "therapeutically effective amount", as used herein, refers to an amount of drug or composition of the invention as disclosed herein effective to alleviate, delay onset of, or prevent one or more symptoms of a disease or disorder.Another object of the invention is a method for treating or preventing a skin, a mucosa, an eye cornea or skin appendage disease or condition, comprising administering to a subject in need thereof, a composition of the invention (in particular, a therapeutic composition), said composition comprising at least one compound of formula (I) as defined herein.

[0119] A further object of the invention is a method of treating or preventing a skin, a mucosa, an eye cornea or a skin appendage disease, disorder, or condition in a subject, comprising: topically administering to a subject in need thereof a therapeutically effective amount of any presently described compositions useful in treating a skin, a mucosa, or an eye cornea disease, disorder, or condition. In a particular embodiment, the skin, mucosa, or eye cornea disease, disorder, or condition is selected from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) and sporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection and pressure ulcer healing, uveitis, cornea diseases, cornea keratitis, corneal herpes, keratoconus, corneal dystrophies, pharyngitis, cutaneous and mucosal allergies.

[0120] For the purpose of clarity, any element or feature of any method or composition or process described herein, can be combined with any other element or feature of any other method or composition or process described herein.

[0121] Another object of the invention is a use of a compound of formula (I) of the invention for making a composition for treating and / or preventing a skin, mucosa, eye cornea, skin appendage disease or condition.

[0122] Another object of the invention is a compound of formula (I) of the invention or a composition of the invention (in particular, a therapeutic composition), for use in the treatment and / or prevention of a disease or condition selected in the group consisting of lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis,warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) and sporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection and pressure ulcer healing, vaginitis, cancer such as bladder cancer, endometriosis, uveitis, cornea diseases, cornea keratitis, corneal herpes, keratoconus, corneal dystrophies, pharyngitis, cutaneous and mucosal allergies.

[0123] The present invention also relates to a kit comprising:

[0124] - a composition according to the invention,

[0125] - a washing composition, and

[0126] - optionally an instruction guide.

[0127] In a preferred embodiment, the composition according to the invention in the kit is a topical composition. In a more preferred embodiment, the composition according to the invention in the kit is a cosmetic or a sunscreen composition, preferably a sunscreen composition.

[0128] A “washing composition” refers to a composition which enables the removal of part or all of a composition according to the invention, previously applied to a tissue such as the skin, skin appendages or a mucosa of a subject. More specifically, the washing composition enables the removal of adhesive compounds.

[0129] The washing composition may comprise at least one “washing agent” and, optionally one or more excipients. The “washing agent” refers to a chemical or biological agent which is able to break the bond between adhesive compounds adhered to a tissue and said tissue. The washing agent may be a protein, a peptide (e.g. glutathione), an amino acid, an enzyme (e.g. cathepsin B), a thiol (e.g. 2-mercaptoethanol, N-acetyl cysteine), a dithiol (e.g. dithiothreitol), a pH-modifier, an acid, a base, a solvent, a saline solution (e.g. sodium chloride solution) or a combination thereof. Said washing agent can be judiciously chosen by the skilled artisan, depending on the nature of the bond between adhesive compounds adhered to a tissue and said tissue.

[0130] In a particular embodiment, said washing composition is a powder, a shampoo, a soap, a lotion, a solution, a solid, a scrubbing, a scraper, a mousse, a foam, a syndet, a gel, a shower gel, aspray, a mist, a wax, a strip, an enzyme composition, a detergent composition or a woven or non-woven fabric.

[0131] Another object of the invention is a use of at least one compound as defined herein for reducing photodegradation and / or photoinstability of a pharmaceutical active ingredient or a cosmetic.

[0132] The term “photodegradation” refers to a partial or total degradation induced by the light, in particular UV-light.

[0133] The term “photoinstability” refers to an instability induced by the light, in particular UV-light.

[0134] A “pharmaceutical active ingredient” includes, without limitation, physically, physiologically or pharmacologically active substances. A pharmaceutical active ingredient is a substance that can be used for the treatment (e.g., therapeutic agent, vaccine antigen or antigenic material), prevention (e.g., prophylactic agent, vaccine), diagnosis (e.g., diagnostic agent), cure or mitigation of disease or illness. An active agent may also be a substance which affects the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0135] A “cosmetic” is a substance used in cosmetics uses, methods and processes, such as a sunscreen, a dye, a fragrance, a deodorant, a microbiote modulator, a skin modifier, and a skin lipid modulator.

[0136] In a particular embodiment, the at least one compound used for reducing photodegradation and / or photoinstability of a pharmaceutical active ingredient or a cosmetic, is in a form of a micelle or a liposome. Said pharmaceutical active ingredient or cosmetic may, in particular, be encapsulated within the at least one compound of the invention in a form of a micelle or a liposome.

[0137] A further object of the invention is a material comprising a support and at least one compound as defined herein, said compound being adhered to said support.The support may be made of any organic and / or inorganic matter. In a particular embodiment, the support is a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, a metal, a plastic, a rubber or a glass support.

[0138] The invention will also be described in further detail in the following examples, which are not intended to limit the scope of this invention, as defined by the attached claims.

[0139] EXAMPLES

[0140] Example 1: Preparation of compounds of formula (I)

[0141] 1. Synthesis of EEM, EBM, and EHM,

[0142] EEM, EBM, and EHM were synthesized according to the following general schemes 1-3.

[0143] Scheme 1 :

[0144]

[0145] 4-((4,6-dichloro-l,3,5-triazin-2-yl)amino)benzoic acid (compound 3)

[0146] In a 4 L reactor was introduced Cyanuric chloride (135.2 g, 0.733 mol, 1.02 eq) followed by 2-MeTHF (600 mL). The solution was cooled at -2.5 °C and then was added solid Na2COs (67.4 g, 0.636 mol, 0.88 eq). No exotherm was observed. Then a solution of 4-Aminobenzoic acid (98.6 g, 0.719 mol, 1.00 eq) in 2-MeTHF (1100 mL) was added slowly over lhl5 maintaining the internal temperature below 2 °C. At the end of the addition, addition funnel was washedwith 2-MeTHF (200 mL) and the reaction mixture was stirred at 0°C for 2h30. After the complete conversion, 2 L of a 0.5 N aqueous HC1 solution were added and the reaction mixture was warmed at 35°C. Phases were separated and the organic phase was washed with water (2 x 2 L). The organic phase was concentrated to dryness under reduced pressure and DIE (600 mL) was added and the suspension was stirred at 23 °C for 30 minutes. The solid was collected by filtration, washed with DIE (100 mL) and dried under vacuum at 40°C for 18 hours to afford 4-((4,6-dichloro-l,3,5-triazin-2-yl)amino)benzoic acid (213.7 g, 0.75 mol, quantitative yield) which was used as such for the next step.

[0147] LCMS-ESI: [M+H]+= 283.9

[0148] 4-((4,6-bis((4-(((2-ethylhexyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazin-2-yl)amino)benzoic acid (compound 5)

[0149] In 10 L reactor was introduced compound 3 (210.3 g, 0.74 mol, 1.0 eq) followed by toluene (3.5 L). This suspension was heated at 80°C and a solution of 2-ethylhexyl aminobenzoate (367.5 g, 1.48 mol, 2.0 eq) in toluene (1.25 L) was slowly added. The addition funnel was washed with toluene (750 mL) and the reaction mixture was warmed to 100°C and stirred at the same temperature for 18 hours. After the complete conversion the reaction mixture was cooled to 40 °C and 0.5 N aqueous HC1 (2 L) was added. The mixture was stirred for 20 minutes and layers were separated. The aqueous layer was extracted with 2-MeTHF (2 x 2 L) and the combined organic phases were washed with water (2x2.5 L) and concentrated under vacuum to dryness. The residue was then co-evaporated several time with EtOAc (2 L) and with toluene (1.5 L) to afford a white solid. The solid was then suspended in water (2.5 L) and stirred at 23 °C for Ih. After that the solid was collected by filtration (poor filtration, particle size small blocking the filter), washed with water (I L) and dried under vacuum at 45 °C for 24h to afford 4-((4,6-bis((4-(((2-ethylhexyl)oxy)carbonyl)phenyl)amino)-l, 3, 5-tri azin-2 -yl)amino)benzoic acid (520.8g, 0.73 mol, 99% yield) as a white solid.

[0150] LCMS-ESI: [M+H]+= 711

[0151] bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (EEM)

[0152]

[0153] In a 100 mL glass round bottom flask was introduced compound 5 (5.00 g, 0.007 mol, 1.0 eq) and DCM (50 mL). To this solution was added EtiN (3.4 mL, 0.025 mol, 3.4 eq) and N-(2-Aminoethyl) maleimide Hydrochloride (1.49 g, 0.008 mol, 1.2 eq). The reaction mixture was warmed to 40°C and then HATU (6.82 g, 0.018 mol, 2.5 eq) was added slowly. After the full conversion the reaction mixture was cooled to 23 °C, diluted with EtOAc (100 mL) and washed with a saturated solution of NaHCCh (100 mL). The organic layer was concentrated under reduced pressure to afford 10 g of crude product. The crude was purified by flash chromatography on SiCh, with a gradient heptane / ethyl acetate 1 / 0 to 7 / 3 to 1 / 1, to afford bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate compound EEM (2.30 g, 0.003 mol, 39.4%) as a pale yellow solid.

[0154] LCMS-ESI: [M+H]+= 833

[0155] ‘HNMR (400 MHz, DMSO) 59.86 (s, 2H), 9.71 (s, 1H), 8.45 (s, 1H), 8.03 (d, J = 8.5 Hz, 4H), 7.91 (dd, J = 9.1, 2.4 Hz, 6H), 7.85 - 7.61 (m, 2H), 7.03 (s, 2H), 4.41 - 3.99 (m, 4H), 3.60 (dd, J = 6.6, 4.9 Hz, 2H), 3.42 (q, J = 5.8 Hz, 2H), 1.69 (q, J = 6.0 Hz, 2H), 1.52 - 1.22 (m, 16H), 0.91 (m, 12H).

[0156] km ax UV absorbance of EHT in dimethyl isosorbide was measured at 313 nm and km ax UV absorbance of compound EEM was measured at 310 nm.

[0157] Scheme 2 :

[0158]

[0159] EBMbis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (Compound EBM)

[0160]

[0161] In a 1 L double jacketed reactor was charged compound 5 (32.6 g, 0.043 mol, 1.0 eq) followed by DCM (320 mL) and Et3N (30.0 mL, 0.216 mol, 5.0 eq). Then HATU (47.2 g, 0.124 mol, 2.9 eq) was added and the suspension was stirred at 23 °C for 30 minutes. 1 -(4- Aminobutyl)- 1H-pyrrole-2, 5-dione hydrochloride (10.1 g, 0.049 mol, 1.16 eq) was then added portion wise as a solid over 5 minutes and the temperature was raised to 40 °C. The reaction mixture was stirred at this temperature for lh30. After the full conversion the reaction was cooled to 23°C and quenched by the addition of water (100 mL). Phases were separated and the organic phase was filtered and concentrated under reduced pressure. The brown oil obtained was dissolved in heptane (95 mL) and EtOAc (225 mL) and stirred for 10 min at 23°C. Phases were separated and the bottom layer (containing mostly impurities) was discarded. The upper layer was then washed with a 0.1 N aqueous citric acid solution (5x100 mL). The organic layer was washed again with a 0. IN aqueous citric acid solution (3x100 mL). The organic layer was concentrated to dryness under reduced pressure to afford a brown solid (38 g). The crude was purified by chromatography over SiCh eluting with HeptaneZEtOAc 90:10 to 40:60. Purest fractions were combined and concentrated to dryness to afford bis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate compound EBM (24 g, 65% yield) as a pale yellow solid. SFC-ESI: [M+H]+= 861

[0162] ‘HNMR (400 MHz, DMSO) 59.83 (s, 2H), 9.68 (s, 1H), 8.31 (t, J = 5.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 4H), 7.95 - 7.88 (m, 6H), 7.87 - 7.77 (m, 2H), 7.02 (s, 2H), 4.32 - 4.03 (m, 4H), 3.45 (t, J = 6.7 Hz, 2H), 3.27 (q, J = 6.3 Hz, 2H), 1.84 - 1.65 (m, 2H), 1.62 - 1.15 (m, 20H), 1.01 -0.74 (m, 12H).

[0163] km ax UV absorbance of EHT in dimethyl isosorbide was measured at 313 nm and km ax UV absorbance of compound EBM was measured at 311 nm.Scheme 3 :

[0164]

[0165] EHM

[0166] bis(2-ethylhexyl) 4,4'-((6-((4-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (Compound EHM)

[0167]

[0168] In a 4 L double jacketed reactor was charged compound 5 (65.2 g, 0.085 mol, 1.0 eq) followed by DCM (650 mL) and Et3N (59.3 mL, 0.426 mol, 5.0 eq). Then HATU (97.3 g, 0.256 mol, 3.0 eq) was added and the suspension was stirred at 23 °C for 30 minutes. 1 -(6- Aminohexyl)- 1H-pyrrole-2, 5-dione 2,2,2-trifluoroacetate (30.4 g, 0.098 mol, 1.15 eq) was then added portion wise as a solid over 5 minutes. The reaction mixture was stirred at 23 °C for 20 minutes. After the full conversion the reaction was quenched by the addition of water (200 mL). Phases were separated and the organic phase was filtered and concentrated under reduced pressure. The brown oil obtained was dissolved in heptane (180 mL) and EtOAc (450 mL) and stirred for 10 min at 23°C. Phases were separated and the bottom layer (containing mostly impurities) was discarded. The upper layer was then washed with a 0.1 N aqueous citric acid solution (6x100 mL). The organic layer was washed with water (100 mL) and concentrated to dryness under reduced pressure to afford a yellow solid (68.5 g). The crude was purified by chromatography over SiCh eluting with HeptaneZEtOAc 9:1 to 4:6 to afford bis(2-ethylhexyl) 4,4'-((6-((4-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate compound EHM (48.4 g, 64% yield) as an off white solid. SFC-ESI: [M+H]+= 889TI NMR (400 MHz, DMSO) 59.85 (s, 2H), 9.70 (s, 1H), 8.32 (t, J = 5.6 Hz, 1H), 8.03 (d, J = 8.5 Hz, 4H), 7.96 - 7.87 (m, 6H), 7.87 - 7.76 (m, 2H), 7.01 (s, 2H), 4.33 - 4.12 (m, 4H), 3.40 (t, J = 7.0 Hz, 2H), 3.24 (q, J = 6.7 Hz, 2H), 1.78 - 1.62 (m, 2H), 1.60 - 1.17 (m, 24H), 1.03 -0.75 (m, 12H).

[0169] km ax UV absorbance of EHT in dimethyl isosorbide was measured at 313 nm and km ax UV absorbance of compound EHM was measured at 310 nm.

[0170] 2. Synthesis of EOM,

[0171] EOM was synthesized according to the following scheme 4.

[0172] Scheme 4 :

[0173]

[0174] EOM

[0175] l-(8-Hydroxyoctyl)-lH-pyrrole-2, 5-dione (compound 11)

[0176] In a 500 mL round bottom flask was introduced 8-aminooctanol (30.000 g, 0.165 mol, 1.000 eq) followed by ACN (168 mL) and water (72 mL). The suspension was stirred for 5 min at 23°C until complete solubilization. To this solution was added methyl-2,5-dioxo-2,5-dihydro-IH-pyrrole-l-carboxylate (25.630 g, 0.165 mol, 1.000 eq) portionwise and the solution was stirred for 3h at 23°C. The solution was diluted with 2-MeTHF (600 mL) and water (500 mL) and phases were separated. The organic layer was washed with water (300 mL) and combinedaqueous layers was extracted with 2-MeTHF (2x400 mL). Organic layers were combined, dried over Na2SO4, filtered and concentrated under reduce pressure affording 46 g of an orange oil. This residue was taken up in ACN (150 mL) leading to an orange solution which started to crystallize. To this suspension was added DIE (300 mL) and the suspension was stirred at 23°C for 16h. The solid was collected by filtration over a P3 glass filter to give 31.2 g of methyl (Z)-4-((8-hydroxyoctyl)amino)-4-oxobut-2-enoate as a white solid.

[0177] This intermediate was dissolved in THF (280 mL) and water (105 mL). To this solution was added K2CO3 (10.500 g, 0.076 mol, 1.304 eq) and the solution was stirred at 23°C for 16h. The solution was diluted with EtOAc (300 mL) and Water (400 mL). Phases were separated and the organic layer was washed once with a 0.5 M HC1 aqueous solution (400 mL) and once with water (300mL) with some brine. Organic layer recovered was dried over Na2SO4, filtered and concentrated under reduced pressure. Oily residue crystallized at 23 °C affording l-(8-Hy droxy octyl)- lH-pyrrole-2, 5-dione (12.200 g, 0.054 mol, 38% over 2 steps) as a white solid.

[0178] bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate (Compound

[0179]

[0180] In a 500 mL three necked round bottom flask was introduced compound 5 (20.000 g, 0.028 mol, 1.000 eq) followed by DCM (200 mL). To this suspension was added NMI (5.6 mL, 0.070 mol, 2.5 eq) and compound 11 (6.972 g, 0.031 mol, 1.100 eq). 5 min later was added DMC (8.561 g, 0.051 mol, 1.800 eq). The reaction was stirred at 40°C for 19h. The solution was allowed to come-back at 23 °C before EtOAc (600 mL) was added. Cloudy solution was diluted with water (200 mL) and a 0.5 M NaOH aqueous solution (400 mL) was added. After phase separation, the aqueous layer was extracted a second time with EtOAc (200 mL). Organic layers were combined and washed once with a 0.5 M HC1 aqueous solution (600 mL) and twice with water (600 mL) with some brine, dried over Na2SO4, filtered and concentrated under reduced pressure affording a yellowish oil. Oily residue was taken up into acetone and concentrated under reduce pressure affording bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate compound EOM (25.2 g, 0.025 mol, 88%) as an amorphous yellowish solid.

[0181] LCMS-ESI: [M+Na]+= 941

[0182] 'H NMR (400 MHz, DMSO) 5 10.29 - 9.72 (m, 3H), 8.44 - 8.05 (m, 2H), 8.02 (d, J = 8.2 Hz, 4H), 7.91 (dd, J = 8.8, 4.2 Hz, 6H), 6.99 (s, 2H), 4.34 - 4.04 (m, 6H), 3.38 (t, J = 7.0 Hz, 2H), 1.81 - 1.59 (m, 4H), 1.55 - 1.07 (m, 26H), 1.02 - 0.75 (m, 12H).

[0183] ^max UV absorbance of EHT in ethanol was measured at 314 nm and ^max UV absorbance of compound EOM was measured at 314 nm.

[0184] Example 2: Bioadhesion tests of compounds of formula (I)

[0185] 1) Adhesion in liquid phase

[0186] The compounds bio adhesion was carried out in solution, for the protein binding, and for the specific binding of sulfhydryl-reactive chemical groups of cysteine. The compounds were mixed either with an equimolar solution of cysteine or an excess of cysteine solution (5 eq.) and were incubated 1 to 2 minutes in an Ethanol- IX PBS, pH 6 solution.

[0187] The compound and the compound bound to the cysteine were identified by LC-MSD (Agilent 1260 Infinity II equipped with an Upti sphere strategy C18 or SunFire Cl 8 column) and assayed by HPLC using an Agilent Infinity II Prime UHPLC UV detector system. The separation was achieved by using a gradient phase of water and acetonitrile on an Agilent Poroshell 120 EC-C18 column (3 x 100 mm, 2.7 pM).

[0188] The bio adhesion results of compounds EEM, EBM, EHM, and EOM obtained with an equimolar cysteine solution are shown in Table 1 below.Table 1: Percentage of free and cysteine-bound compound assayed by HPLC in an equimolar cysteine:compound solution.

[0189]

[0190] Results of Table 1 show that, in the presence of an equimolar solution of cysteine, 82 % to 100% of the compound of the invention is bound to cysteine. These results demonstrate that an efficient bioadhesion was obtained with the compounds of the invention.

[0191] The bio adhesion results of compounds EEM, EBM, EHM, and EOM obtained with an excess of cysteine (5 eq.) in solution are shown in Table 2 below.

[0192] Table 2: Percentage of free and cysteine-bound compound assayed by HPLC with an excess of cysteine.

[0193]

[0194] Results of Table 2 show that, in the presence of an excess (5 eq.) of cysteine, 100 % of the compound of the invention is bound to cysteine. These results also demonstrate that an efficient bioadhesion was obtained with the compounds of the invention.

[0195] 2) Adhesion on thiolated polylysine matrix

[0196] Polylysine and Polylysine enriched in SH by thiolation of primary amines using Traut’ s reagent were used for coating 96-well microplates, compounds EOM, EHM, EBM incubated overnight under orbital agitation on the different matrices (n=3 for each condition) (uncoated wells wereused as negative controls), in an ethanol / PBS (90% / 10%) solution. After incubation, each microplate well was thoroughly washed 10 times with ethanol, before measuring UV absorbance. Whole UV / Visible absorbance spectrum from 220 to 1000 nm were measured in the center of each microplate well. In addition, specific UV absorbance at 310 nm was measured by matrix scan over the whole the well as a 10x10 matrix.

[0197] At 310 nm, compounds EOM, EHM, EBM showed a bio adhesion on thiolated polylysine matrix whereas EHT (Ethylhexyl triazone), did not show a bio adhesion. Also, no bioadhesion of compounds EOM, EHM, EBM on polylysine matrix (non thiolated) was observed. These results show the bio adhesion of compounds EOM, EHM, EBM.

[0198] Example 3: Solubility tests of compounds of formula (I)

[0199] A part of UV filter and a part of solvents commonly used in solar formulations were heated at 78°C for 15 min. If necessary another part of solvent was added until complete and sustainable solubilization (no recrystallization) of the filter at room temperature. Results are detailed in the following table 3.

[0200] Table 3:

[0201] > > > >

[0202]

[0203] >

[0204]

[0205] ND : Not determined

[0206] In general terms, the results show that compounds of the invention have a similar or higher solubility in solar formulation solvents than the commercial UV filter EHT.

[0207] Example 4: Photoprotective properties of compounds of formula (I)

[0208] 1) In Vitro SPF and Photostability study

[0209] Objective:

[0210] The aim of the present study was the assessment of the UVB (Ultraviolet-B) protection and Photostability after UV exposure of sunscreen products by means of a UV spectral absorbance curve from an in vitro procedure. Results of this measurement procedure can be used for the estimation of the Sun Protection Factor (SPF) and the calculation of photostability percentage.

[0211] Materials:

[0212] • Tested products: 2 equivalent sunscreens O / W emulsions based on the same formulation chassis but with different UVB filters (bioadhesive and commercial at the same molar proportion):

[0213] Formula containing 5.0% of free commercial EHT

[0214] Formula containing 5.4% of the bioadhesive EHM

[0215] • UV spectrophotometer: Labsphere, Inc. - UV-2000S

[0216] • Substrate: Helioplate HD6 Molded PMMA plate & Helioplate SB6 Sandblasted PMMA plate

[0217] • Robotic spreading: WENEOS SAS - HD-SPREADMASTER UR3

[0218] • Solar simulator: Solar Light Company, LLC - LS1000-6S-009 UV Pre-Irradiation Solar Simulator

[0219] Methods:

[0220] 1.3 mg / cm2(±1.6%) of formula was applied on Molded HD6 plate and 1.2 mg / cm2(±1.5%) for Sandblasted SB6 plate.Transmittance was analyzed to determine an in vitro SPF value before and after irradiation with a solar simulator.

[0221] Calculation of the in vitro SPF :

[0222] During in vitro test, the SPFi (Individual Sun Protection Factor) was calculated from the irradiance spectrum of UVA + UVB source (1( )) which was multiplied with the erythema action spectrum (E(X)) at each wavelength and the integral of the resultant ("effective erythema illumination") calculated from 290 nm to 400 nm. The UV absorbance value (Ai(X)) of the product measured on a substrate at each wavelength was multiplied by the "effective erythema illumination" on each wavelength and the integral of the resultant calculated over the same wavelength range ("effective erythema protection"). The ratio of two integrals corresponds to in vitro SPFi calculated for the same pair of plates (both Molded and Sandblasted plates) and the in vitro SPF is equal to the arithmetic mean of all valid individual SPFi values obtained from all tests performed and expressed to one decimal (truncation).

[0223] Results:

[0224] Table 4:

[0225] >

[0226]

[0227] The results of Table 4 show the photostability of EHM in the UVB range and demonstrate SPF protection similarly to the free commercial filter EHT.

[0228] 2) Hybrid Diffuse Reflectance Spectroscopy (HDRS)

[0229] Objective:

[0230] The aim of the present study was the evaluation of the Sun Protection Factor (SPF) of a product by the Hybrid Diffuse Reflectance Spectroscopy (HDRS) following ISO 23698:2024.

[0231] This method implies a non-invasive DRS stage conducted on human volunteers and an in vitro step conducted on substrates.

[0232] Materials:• Tested products: 2 equivalent sunscreens O / W emulsions based on the same formulation chassis but with different UVB filters (bioadhesive and commercial at the same molar proportion):

[0233] Formula containing 5.0% of free commercial EHT

[0234] Formula containing 5.4% of the bioadhesive EHM

[0235] • Volunteers: n=5 from 24 to 63 y.o (4 females and 1 man) with ITA >28°

[0236] • In vivo DRS Polychromatic spectrometer: Poly602 from Solar Light Company, LLC • UV spectrophotometer: Labsphere, Inc. - UV-2000S

[0237] • Substrate: Helioplate HD6 Molded PMMA plate & Helioplate SB6 Sandblasted PMMA plate

[0238] • Robotic spreading: WENEOS SAS - HD-SPREADMASTER UR3

[0239] • Solar simulator: Solar Light Company, LLC - LS1000-6S-009 UV Pre-Irradiation Solar Simulator

[0240] Methods:

[0241] The test was based on the assessment of light diffuse reflectance by the skin, before and after spreading of a thin film (2.00 ± 0.05 mg / cm2) of the sun product sample. Due to the lack of UVB’s signal and information on photo-degradation, it was completed by the assessment of UV transmittance through a thin film of the sun product sample, spread on a roughened substrate (1.3 mg / cm2(±1.6%) on Molded HD6 plate and 1.2 mg / cm2(±1.5%) for Sandblasted SB6 plate ), before and after exposure to a controlled dose of UV radiation, from a defined UV source.

[0242] Calculation of the hybrid SPF:

[0243] The final HDRS SPF protection factor (SPF) was calculated from the hybridization of the reflectance data and the adjusted absorbance data of the UV exposed sample.

[0244] Table 5:

[0245]

[0246] The results of Table 5 show that EHM demonstrates SPF protection similarly to the free commercial filter EHT.

Claims

CLAIMS1. A compound represented by the following formula (I):wherein:X is O or NH, andn is an integer from 0 to 23.

2. The compound according to claim 1, wherein n is an integer from 1 to 11, preferably from 1 to 7.

3. The compound according to claim 1 or 2, wherein X is NH.

4. The compound according to claim 1 or 2, wherein X is O.

5. The compound according to any one of claims 1 to 4, wherein said compound is selected from the group consisting of:bis(2-ethylhexyl) 4,4'-((6-((4-((2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate;bis(2-ethylhexyl) 4,4'-((6-((4-((4-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate;bis(2-ethylhexyl) 4,4'-((6-((4-((6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexyl)carbamoyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate; and bis(2-ethylhexyl) 4,4'-((6-((4-(((8-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)octyl)oxy)carbonyl)phenyl)amino)-l,3,5-triazine-2,4-diyl)bis(azanediyl))dibenzoate.

6. A composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 5 and at least one excipient.

7. The composition according to claim 6, wherein said composition is a topical composition.

8. The composition according to claim 6 or 7, wherein said composition is in the form of a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a micro-emulsion, an oil, a lyophilizate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome, or a foam.

9. The composition according to any one of claims 6 to 8, wherein said composition is a sunscreen composition or a cosmetic composition.

10. A cosmetic use of a composition as defined in claim 9, for combatting and / or reducing the signs of cutaneous ageing, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or evenness of the complexion, and / or for reinforcing the skin barrier, or for protecting and / or caring the hair or the nail.

11. A kit comprising:- a composition as defined in any one of claim 6 to 9,- a washing composition, and- optionally an instruction guide.

12. The composition according to any one of claims 6 to 8, wherein said composition is a pharmaceutical or a veterinary composition.

13. A composition as defined in claim 12, for use for treating and / or preventing a skin, mucosa, eye cornea, or skin appendage disease or condition, preferably said skin, mucosa, eye cornea, or skin appendage disease or condition is chosen from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatments, wound healing, alopecia, vitiligo, urticaria (hives), cold sores, impetigo, eczema, rashes dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, bacterial skin infections like leprosy, carbuncles, cellulitis, impetigo, fungal infections like Athlete’s foot (intertrigo) and sporotrichosis, fungal nail infections, viral infection like herpes, sunburns, lice, scabies, pressure ulcer disinfection, and pressure ulcer healing.

14. A use of at least one compound as defined in any one of claims 1 to 5 for reducing photodegradation and / or photoinstability of a pharmaceutical active ingredient or a cosmetic.

15. A material comprising a support and at least one compound as defined in any one of claims 1 to 5, said compound being adhered to said support which is preferably a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, a metal, a plastic, a rubber or a glass support.

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