Adhesive photoprotective compounds and their use

Abstract

The present invention relates to a compound, 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenyl acrylate. The present invention also relates to compositions comprising the compound, more particularly to cosmetic or sunscreen compositions. The present invention also relates to the use of such compounds in cosmetic and therapeutic applications. The present invention also relates to the use of such compounds to reduce photodegradation and / or photoinstability of pharmaceuticals and cosmetics. The present invention further relates to supports and materials comprising such compounds adhered to said supports.

Description

[Technical Field]

[0001] The present invention relates to adhesive photoprotective compounds. The present invention also relates to compositions comprising such compounds, and more particularly to cosmetic or sunscreen compositions. The present invention also relates to the use of such compounds in cosmetic and therapeutic applications. The present invention also relates to the use of such compounds to reduce photodegradation and / or photoinstability of pharmaceuticals and cosmetics. The present invention further relates to supports and materials comprising such compounds adhered to said supports. [Background technology]

[0002] Approximately 5% of the sun's electromagnetic energy 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, more specifically UV-B light, can have harmful short-term or long-term effects on the body. Serious skin damage, such as accelerated skin aging or skin cancer, can occur from exposure to UV light. As a result, the development of new sunscreens that provide effective protection across the entire UV irradiation spectrum has become a matter of paramount importance and a major concern. Many sunscreens are available on the market today. Despite their apparent efficacy, the active ingredients in these sunscreens have been shown to penetrate epidermal cells through the skin and have been detected in urine or breast milk. Small, non-adhesive nanoparticles have been developed for sunscreen compositions and are currently available on the market. However, such materials have also been shown to be skin-penetrating. Bioadhesive particles are designed to adhere to the skin and encapsulate activators, so that neither the particles nor the activators penetrate the skin. However, such bioadhesive particles are prepared using complex and costly manufacturing methods. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] US8,106,108 [Patent Document 2] ES 2 730 924 [Overview of the project] [Problems that the invention aims to solve]

[0004] Therefore, there remains a need to produce efficient adhesive photoprotective compounds that can be easily manufactured. [Means for solving the problem]

[0005] In this context, the inventors have developed a photoprotective compound comprising a photoprotective portion and functional groups, both linked to each other via linkers. The functional groups make the photoprotective compound adhesive, more specifically bioadhesive. The photoprotective compound can interact with any support, such as a biological organic and / or inorganic support, through its functional groups, thereby becoming particularly efficient in the field of photoprotection. In particular, the compounds according to the present invention can be used in cosmetic or therapeutic applications, such as the treatment or prevention of skin and mucous membrane diseases or conditions, or to reduce the photodegradation and / or photoinstability of pharmaceutically active ingredients or cosmetics.

[0006] Therefore, the present invention relates to the following formula (I): A[B-(C)] v ] w (I) (In the formula, A is the light-protective part, B is a linker, C is a functional group, v is an integer between 1 and 2000. w is an integer between 1 and 6. This relates to compounds represented by [the given formula / method].

[0007] In certain embodiments, the light-protective portion A is derived from a UV filter and / or an SPF booster. Preferably, the light-protective portion A is bemotridinol, diethylaminohydroxybenzoyl hexyl benzoate, bisdisurisol disodium, meladimate, terephtalylidene dicamphor sulfonic acid, bisoctrisol, oxybenzone, surisobenzone, iscotridinol, octinoxate, octisalate, octiltriazone, padimate O, homosalate, amyloxate, octocrylene, PEG-25 PABA, ensurisol, trolamine salicylate. It is derived from salicylate, cinoxate, benzophenone-9, dioxybenzone, avobenzone, enzacamene, diethylhexylnaphthalate, diethylhexylsyringylidene, tetramethylhydroxypiperidinol, sodium benzotriazolylbutylphenol sulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylate copolymer, butyloctyl salicylate, bis(cyanobutylacetate)anthracenediylidene, dimethylcaplamide, or ethylhexylmethoxycrylene. More preferably, the light-protective portion A is derived from bemotoridinol, diethylamino hydroxybenzoyl hexyl benzoate, terephthalylidene dicamphor sulfonic acid, thrizobenzone, octisalate, octocrylene, ensulizole, avobenzone, polyester-8, bisdisulizole disodium, meladimate, oxybenzone-3, iscotridinol, octanoate, octyltriazone, padimate O, cinoxate, benzophenone-9, or dioxybenzone. Even more preferably, the light-protective portion A is derived from bemotoridinol, diethylamino hydroxybenzoyl hexyl benzoate, terephthalylidene dicamphor sulfonic acid, or octocrylene.

[0008] In certain embodiments, linker B is a linear polymer, a branched polymer, a highly branched polymer, a dendrimer, or a residue thereof. In more detailed embodiments, linker B further comprises at least one -S(O)2- group.

[0009] In another specific embodiment, linker B is given by the following equation (II): -[Y-(CH2) q -(O-CH2-CH2) p -Z-(CH2) s ] k - (II) (In the formula, → Y is selected from -O-, -NH-, and -C(O)-, q is an integer from 0 to 35, preferably from 0 to 12, more preferably from 0 to 6. However, if Y is -O-, then q is different from 0. p is an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. p+q is different from 0, or → Y-(CH2) q It can form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, p is 0, → Z is selected from single bonds, -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-. → s is an integer from 0 to 6, (→ k is an integer from 1 to 4, preferably from 1 to 2.) It is represented by [this].

[0010] In a preferred embodiment, Z is selected from -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-. In a more preferred embodiment, Z is -S(O)2-.

[0011] In certain embodiments, functional group C is selected from aldehydes, acetals, thiocetals, thiols, maleimides, Mickael acceptors, vinyl sulfones, disulfanylpyridines, sulfonylaziridines, epoxides, haloacetyls, isocyanates, isothiocyanates, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, hydroxy, amino, ammonium, guanidine, imidocarbonate, carboxylic acids, carboxylic acid esters, anhydrides, sulfonic acids, folic acid, biotin, streptavidin, avidin, antibodies and single-chain antibodies or fragments thereof, and derivatives thereof. Preferably, functional group C is selected from thiols, acetals, maleimides, vinyl sulfones, disulfanylpyridines, guanidine, folic acid, biotin and derivatives thereof, and more preferably, C is maleimide or a derivative thereof.

[0012] In certain embodiments, part B-(C) v The formula is as follows:

[0013] [ka] [ka] [ka] [ka] [ka]

[0014] (In each equation, n is an independent integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. (t is an integer independently ranging from 0 to 30, preferably from 0 to 12.) It is represented by one of the following.

[0015] In a particular embodiment, the compound according to the present invention is - 2,2'-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-[(3-propyl-1H-pyrrole-2,5-dione)oxy]phenol]; - 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 6-maleimide-1-hexanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyl disulfanyl)ethanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[5-(-2,5-dihydro-1H-pyrrole-2,5-dione)pentyl]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[4-(1,3-dioxolan-2-yl)butane]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, biotin-PEG2 amide; - N-[4-(-2,5-dihydro-1H-pyrrole-2,5-dione)butyl]salicylamide; - 2-Cyano-3,3-diphenylpropenoic acid, 6-maleimide-1-hexanol ester; - 2-Cyano-3,3-diphenylpropenoic acid, folate-PEG-1k ester; - 2-Cyano-3,3-diphenylpropenoic acid, 1,3-bis(vinylsulfonyl)-1-propanol ester; - 2-phenyl-1H-benzimidazole-5-(biotin-PEG8-N-ethyl)sulfonamide; - 2-Hydroxy-4-methoxybenzophenone-5-(biotin-PEG8-N-ethyl)sulfonamide; - [N-(2-cyano-3,3-diphenylpropenoyl)-piperidine-4-ylsulfonyl]acetic acid; - N-[(2-hydroxybenzoyl)-piperidine-4-ylsulfonyl]acetic acid; - (3-(2H-benzo[d][1,2,3]triazole-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidine-4-ylsulfonyl)acetic acid]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester; - 2-Cyano-N-[2-[3-(2,5-Dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-Diphenyl-propa-2-enamide; - 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; - 3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]propenamide; - 3-(2,5-dioxopyrrole-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]propoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]propyl]propenamide; - 3-(2,5-dioxopyrrole-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide; and 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate It is selected from the group consisting of the following.

[0016] This also relates to compositions comprising at least one compound of formula (I) as defined herein, and at least one excipient. In certain embodiments, the composition is a sunscreen composition or a cosmetic composition. In other specific embodiments, the composition is a pharmaceutical or veterinary composition.

[0017] A further object of the present invention is the cosmetic use of the compositions as defined herein for combating and / or reducing signs of skin aging, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or unevenness of complexion, and / or for reinforcing the skin barrier.

[0018] Another object of the present invention is a cosmetic method for counteracting and / or reducing signs of skin aging, such as the formation of wrinkles and / or fine lines, sagging of the skin, loss of skin firmness, loss of radiance and / or uniformity of complexion, and / or for reinforcing the skin barrier, the method comprising the step of topically applying a composition as defined in the specification to the skin.

[0019] Another objective of the present invention is, - Compositions as defined herein, - Cleaning compositions, preferably powders, shampoos, soaps, lotions, solutions, solids, scrubbing products, scrapers, mousses, foams, synthetic detergents (syndet), gels, shower gels, sprays, mists, waxes, strips, enzyme compositions, detergent compositions, or woven or nonwoven fabrics, and - This is a kit that includes an optional instruction guide.

[0020] The present invention also relates to compositions as defined herein for use in the treatment and / or prevention of diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages. Preferably, the diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages are selected from lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, rashes, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, pustules; bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; sunburn, lice, scabies, pressure ulcer disinfection, and pressure ulcer healing.

[0021] In certain embodiments, the compositions defined herein, or the compositions for use defined herein, are topical compositions. In more detailed embodiments, the compositions defined herein, or the compositions for use defined herein, are in the form of suspensions, creams, sprays, aerosols, butters, sticks, gels, ointments, lotions, solutions, solids, emulsions, microemulsions, oils, lyophilized products, emulsions, powders, pastes, waxes, mousses, patches, films, micelles, liposomes, or foams.

[0022] The present invention also relates to the use of at least one compound of formula (I) as defined herein for reducing the photodegradation and / or photoinstability of pharmaceutical active ingredients or cosmetics. In this particular use, at least one said compound is in the form of micelles or liposomes.

[0023] Another object of the present 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 fibrous support, a stone, a metal, a plastic, a rubber or a glass support.

Embodiments for Carrying Out the Invention

[0024] Photoprotective compounds The present invention relates to compounds comprising a photoprotective moiety functionalized with at least one functional group and linked to the photoprotective moiety via at least one linker. The linker can be linear, branched, highly branched or dendritic and may or may not be polymeric. The functional group can make the compounds of the present invention adhesive, preferably bioadhesive.

[0025] The compounds of the present invention typically have the following formula (I): A[B-(C) v w (I) (wherein A is a photoprotective moiety, B is a linker, C is a functional group, v is an integer from 1 to 2000, w is an integer from 1 to 6) is represented by.

[0026] Thus, the compounds of formula (I) according to the present invention comprise a photoprotective moiety A linked to at least one linker B(w) having at least one functional group C(v).

[0027] ​As used herein, w is connected to the light-shielding portion A [B-(C) v This represents the number of links. According to the present invention, w is an integer from 1 to 6. In other words, the light-shielding portion A is connected to 1 to 6 linkers B. For example, if w is 3, the light-shielding portion A is connected to 3 linkers B.

[0028] In certain embodiments, w is an integer from 1 to 4, preferably from 1 to 3, and more preferably, w is 1 or 2.

[0029] As used herein, v represents the number of functional groups C linked to each linker B. According to the present invention, v is an integer from 1 to 2000. In other words, each linker B is independently linked to 1 to 2000 functional groups C. For example, if v is 2, linker B contains 2 functional groups C. In certain embodiments, v is an integer from 100 to 1000, preferably from 150 to 500, more preferably from 150 to 250. In another particular embodiment, v is 1 or 2, preferably 1.

[0030] The light-shielding portion A and the linker B may be linked (or "bonded") to each other by covalent and / or non-covalent bonds, for example, ionically. Preferably, the light-shielding portion A and the linker B are covalently bonded to each other.

[0031] Linker B and functional group C can be linked (or "bonded") to each other by covalent and / or non-covalent bonds, for example, ionically. Preferably, linker B and functional group C are covalently bonded to each other.

[0032] Light protection part A According to the present invention, the compound of formula (I) comprises a photoprotective portion A. As used herein, “photoprotective portion” refers to a photoprotective agent from which one or more atoms or groups of atoms have been removed, and the photoprotective activity of the photoprotective portion is substantially the same as that of the photoprotective agent from which it is derived. A photoprotective agent is typically an organic substance that can block or absorb all or part of light, more particularly light that can cause damage to the object or material being protected, such as ultraviolet ("UV") light. A photoprotective agent is typically a UV filter and / or SPF booster.

[0033] In certain embodiments, the light-protective portion A is derived from a UV filter and / or an SPF booster.

[0034] In detail, the UV filter may be a UVA filter, such as a UVA I or UVA II filter, a UVB filter, or a combination thereof.

[0035] Examples of UVA I filters include, but are not limited to, bemotoridinol, diethylaminohydroxybenzoyl hexyl benzoate (DHHB), bisdisurisole disodium, meladimate, or ecamsul.

[0036] Examples of UVA II / UVB filters include, but are not limited to, oxybenzone, surisobenzone, iscotridinol, octinoxate, octisalate, octyltriazone, padimate O, homosalate, amyloxate, octocrylene, PEG-25 PABA, ensulizole, trolamine salicylate, cinoxate, benzophenone-9, dioxybenzone, or avobenzone.

[0037] Examples of UVA / UVB filters include, but are not limited to, enzacamene or bisoctrizole.

[0038] In detail, the SPF booster may be a TT quencher, an excited-state quencher, or a combination thereof.

[0039] Examples of TT quenchers include, but are not limited to, diethylhexyl naphthalate or diethylhexyl syringylidene.

[0040] Examples of excited-state quenchers include, but are not limited to, tetramethylhydroxypiperidinol, sodium benzotriazolylbutylphenol sulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylate copolymer, butyloctyl salicylate, bis(cyanobutylacetate)anthracenediylidene, dimethylcaplamide, or ethylhexylmethoxycrylene.

[0041] In certain embodiments, the light-protective portion A is bemotoridinol, diethylaminohydroxybenzoyl hexyl benzoate (Uvinul® A Plus), bisdisurisol disodium, meladimate, terephthalylidene dicamphor sulfonic acid (also known as ecamsul), bisoctrisol, oxybenzone, surisobenzone, iscotridinol, octinoxate, octisalate, octiltriazone, padimate O, homosalate, amyloxate, octocrylene, PEG-25 Derived from PABA, ensulizol, trolamine salicylic acid, cinoxate, benzophenone-9, dioxybenzone, avobenzone, enzacamen, diethylhexyl naphthalate, diethylhexyl syringylidene, tetramethylhydroxypiperidinol, sodium benzotriazolyl butylphenol sulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylate copolymer, butyloctyl salicylate, bis(cyanobutyl acetate)anthracene diylidene, dimethylcaplamide, or ethylhexyl methoxycrylene.

[0042] In preferred embodiments, the light-protective portion A is derived from bemotoridinol, diethylaminohydroxybenzoyl hexyl benzoate, terephthalylidene dicamphor sulfonic acid, surisobenzone, octisalate, octocrylene, ensurizole, avobenzone, polyester-8, bisdisurizole disodium, melazimate, oxybenzone-3, iscotridinol, octanoate, octyltriazone, padimate O, cinoxate, benzophenone-9, or dioxybenzone.

[0043] In a more preferred embodiment, the light-protective portion is derived from bemotoridinol, diethylaminohydroxybenzoyl hexyl benzoate, terephthalylidene dicamphor sulfonic acid, or octocrylene.

[0044] In a more preferred embodiment, the light-protective portion A is derived from terephthalylidene dicamphor sulfonic acid or diethylamino hydroxybenzoyl hexyl benzoate.

[0045] In certain embodiments, the photoprotective moiety A is derived from a tris-aryltriazine. Examples of tris-aryltriazines include, but are not limited to, the tris-aryltriazine compounds described in US8,106,108. In other specific embodiments, the photoprotective moiety A is derived from a hydroxyphenylbenzotriazole. Examples of hydroxyphenylbenzotriazoles include, but are not limited to, bisoctrizole, benzenepropanoic acid, and their 3-(2H-benzotriazol-2-yl)-5-(1,1-dimethylethyl)-4-hydroxy- and C7-C9-branched or linear alkyl esters.

[0046] Functional group C According to the present invention, C represents a functional group. As used herein, a “functional group” is a group that can react with or bind to any support, any material, any tissue, cell, intracellular or extracellular material, thereby making the compound of formula (I) adhesive or bioadhesive.

[0047] In certain embodiments, the functional group C is selected from aldehydes, acetals, thioacetals, thiols, maleimides, Michael acceptors, vinyl sulfones, disulfanylpyridines, sulfonylaziridines, epoxides, haloacetyls, isocyanates, isothiocyanates, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, hydroxy, amino, ammonium, guanidine, imide carbonates, carboxylic acids, carboxylic acid esters, anhydrides, sulfonic acids, folic acid, biotin, streptavidin, avidin, antibodies, and single-chain antibodies or fragments thereof. In more detailed embodiments, C further comprises derivatives of any of the functional groups described above.

[0048] For example, the term "maleimide" (Mal) refers to the maleimide group and any of its derivatives. More specifically, maleimide (Mal) is represented by the following formulas (Mal1) and (Mal2):

[0049] [ka]

[0050] It contains two groups.

[0051] The symbol "- - - - -" used in the formulas disclosed in this application represents a bond in which the part of the formula is attached to the rest of the molecule. For example, the symbol represented in (Mal1) or (Mal2) above represents a bond in which the part is attached to linker B.

[0052] In preferred embodiments, functional group C is selected from thiols, acetals, maleimides, vinyl sulfones, disulfanylpyridines, guanidines, folic acid, biotin, and derivatives thereof.

[0053] In preferred embodiments, C is a maleimide (also referred to as "Mal") or a derivative of a maleimide as disclosed herein. More preferably, C is Mal1 or Mal2.

[0054] In more detailed embodiments, C represents an unmodified (native) functional group.

[0055] As used herein, "unmodified functional groups" of polymers are functional groups that are inherently present in the polymer structure and have not been converted into other functional groups. For example, the hydroxyl group is an unmodified functional group of cellulose, and the carboxylic acid (or carboxylate) is an unmodified functional group of polymethacrylic acid.

[0056] In more detailed embodiments, C represents a modified functional group.

[0057] The "modified functional groups" of polymers used herein are functional groups resulting from the conversion of an unmodified functional group to another functional group, as defined herein, such as the hydroxyl group of cellulose, or the aldehyde group resulting from the oxidation of biotin linked to the hydroxyl group of cellulose.

[0058] Linker B According to the present invention, the compound of formula (I) comprises at least one linker B(w).

[0059] A "linker" refers to any organic chain having at least one carbon atom that connects the light-protective portion to at least one functional group. Linker B can be linear, branched, highly branched, or dendritic. B may or may not be polymeric.

[0060] In certain embodiments, linker B is biodegradable.

[0061] The term "biodegradable linker (or compound)" refers to a linker (or compound) that, under physical, chemical, and / or biological conditions, breaks down or erodes into smaller units or chemical species that can be metabolized, removed, or excreted by the target. Decomposition time and rate are functions of composition and / or form. Decomposition time can range from a few hours to several weeks.

[0062] In certain embodiments, linker B is a linear polymer, a branched polymer, a highly branched polymer, a dendrimer (or "dendritic polymer"), or a residue thereof.

[0063] As used herein, the term “linear polymer” refers to a polymer that does not have any branching.

[0064] The term "branched polymer" refers to a polymer having linear chains that are substituted by primary branching and optionally by secondary branching. The term "highly branched polymer" refers to a polymer having randomly arranged primary and secondary branching. The term "dendrimer" (also called "dendritic polymer" or "dendronized polymer") refers to a repeating branched polymer having a symmetrical and organized tree structure in which branching arises from a common branching point. The term "polymer residue" refers to a polymer from which one or more of its functional groups (e.g., -NH2, -COOH, -OH) or atoms (e.g., H or -OH) have been removed.

[0065] The linear, branched, highly branched polymer or dendritic polymer may be a homopolymer or copolymer. The linear, branched, highly branched polymer or dendritic polymer may be natural, semi-synthetic, hemi-synthetic, or synthetic.

[0066] The term "homopolymer" generally refers to a polymer composed of identical monomers.

[0067] The term "copolymer" generally refers to a polymer composed of two or more different monomers. A copolymer can be in any form, such as random, block, or graft. A copolymer may have any of the terminal groups.

[0068] Examples of semi-synthetic, semi-synthetic, or synthetic polymers include poly(hydroxy acids) such as poly(lactic acid), poly(glycolic acid), and poly(lactic acid-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyglycerols, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides such as poly(ethylene oxide), and polyalkylene terephthalates (polyalkylenePoly(ethylene terephthalates), e.g., poly(ethylene terephthalate), polyvinyl alcohol, polyvinyl ether, polyvinyl ester, polyhalogenated vinyl, e.g., poly(vinyl chloride), polyvinylpyrrolidone, polysiloxane, poly(vinyl alcohol), poly(vinyl acetate), polystyrene, polyurethane and their copolymers, derivatized cellulose, e.g., alkylcellulose, hydroxyalkylcellulose, cellulose ether, cellulose ester, nitrocellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, carboxyethylcellulose, cellulose triacetate This includes, but is not limited to, rose and sodium cellulose sulfate (collectively referred to herein as "synthetic cellulose"), polymers of acrylic acid and methacrylic acid, or derivatives comprising copolymers or esters thereof, copolymers of acrylate and ammonium methacrylate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate) (collectively referred to herein as "polyacrylic acid"), poly(butyric acid), poly(valeric acid) and poly(lactide-co-caprolactone), copolymers and blends thereof.

[0069] Examples of natural polymers include, but are not limited to, proteins such as albumin, collagen, gelatin, and prolamin (e.g., zein), as well as polysaccharides such as alginates, dextran, chitosan, cellulose derivatives, and polyhydroxyalkanoates (e.g., polyhydroxybutyrate), and microbial anatoxins.

[0070] In certain embodiments, linker B further comprises at least one -S(O)2- group. The -S(O)2- group can be located at any position of linker B. For example, the -S(O)2- group can be at one or both ends of linker B and / or interrupt linker B at either position. The -S(O)2- group advantageously improves the photoprotective properties of the compounds of the present invention. In particular, a higher refractive index and / or higher transparency can be obtained for the compounds of the present invention.

[0071] According to the present invention, linker B is linked to at least one functional group C(v). In one embodiment, linker B comprises at least one residue of the polymer. In such embodiment, functional group C is linked to at least one residue of the polymer of linker B. In such embodiment, C represents one or more functional groups of at least one residue of the polymer of linker(B).

[0072] Part [B-(C) v To illustrate various embodiments of ], a cellulose-based moiety [B-(C) as polymer linker B v Different expressions for ] are shown below. - [B-(C)] v ] can be cellulose. In this embodiment, B represents a residue of cellulose, C represents a hydroxyl group (which is an unmodified group of cellulose), and v is the number of hydroxyl groups; - [B-(C)] v ] may also be aldehyde-modified cellulose. In this embodiment, B represents a residue of cellulose, C represents an aldehyde group (which is a modifying group of cellulose), and v is the number of aldehyde groups; - [B-(C)] v ] may also be biotin-modified cellulose. In this embodiment, B represents a residue of cellulose, C represents a biotin group (a modifying group of cellulose), and v is the number of biotin groups.

[0073] In another specific embodiment, linker B is given by the following equation (II): -[Y-(CH2) q -(O-CH2-CH2) p -Z-(CH2) s ] k - (II) (In the formula, → Y is selected from -O-, -NH-, and -C(O)-, q is an integer from 0 to 35, preferably from 0 to 12, more preferably from 0 to 6. However, if Y is -O-, then q is different from 0. p is an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. p+q is different from 0, or → Y-(CH2) q It can form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, p is 0, → Z is selected from single bonds, -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-. → s is an integer from 0 to 6, (→ k is an integer from 1 to 4, preferably from 1 to 2.) It is represented by [this].

[0074] In a more detailed embodiment, linker B is given by the following equation (II): -[Y-(CH2) q -(O-CH2-CH2) p -Z-(CH2) s ] k - (II) (In the formula, → Y is selected from -O-, -NH- and -C(O)-, and is preferably -O-. q is an integer from 1 to 35, preferably from 1 to 12, more preferably from 1 to 6. p is an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. or → Y-(CH2) q It can form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, p is 0, → Z is selected from single bonds, -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-. → s is an integer from 0 to 6, (→ k is an integer from 1 to 4, preferably from 1 to 2.) It is represented by [this].

[0075] In certain embodiments, linker B is of formula (II), where, Y is selected from -O-, -NH- and -C(O)-, preferably -O- and -NH-. q is an integer from 0 to 12, preferably from 0 to 6. However, if Y is -O-, then q is different from 0. p is an integer from 0 to 50, preferably from 0 to 20, more preferably from 0 to 12. p+q is not equal to 0.

[0076] In a more detailed embodiment, p is 0.

[0077] In a further, more detailed embodiment, p is an integer from 1 to 50, more preferably from 1 to 12.

[0078] In another specific embodiment, linker B is of formula (II), where, Y-(CH2) q It forms a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, and p is 0.

[0079] In certain embodiments, Z is selected from a single bond, -NH-, -NH-C(O)-, and -S(O)2-. In preferred embodiments, Z is a single bond. In another preferred embodiment, Z is selected from -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-, and more preferably Z is -S(O)2-.

[0080] In certain embodiments, s is an integer from 0 to 2, preferably s is 0. In other specific embodiments, s is an integer from 1 to 6.

[0081] In a particular embodiment, k is 1.

[0082] In a particular embodiment, linker B is of formula (II), where, → Y is selected from -O-, -NH- and -C(O)-, preferably from -O- and -NH-, q is an integer from 0 to 35, preferably from 0 to 12, more preferably from 0 to 6. However, if Y is -O-, then q is different from 0. p is an integer from 0 to 50, preferably from 0 to 12, and more preferably p is 0. p+q is different from 0, or → Y-(CH2) q It can form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, p is 0, → Z is selected from single bonds, -NH-, -O-, and -S(O)2-, → s is 0 or 1, preferably 0. → k is 1.

[0083] In a more detailed embodiment, linker B is of formula (II), where, → Y is selected from -O- and -NH-, q is an integer from 1 to 12, preferably from 1 to 6. p is 0, → Z is a single bond, → s is 0, → k is 1.

[0084] In such embodiments, the functional group C is preferably disulfanylpyridine, maleimide, vinyl sulfone, acetal, or a derivative thereof, more preferably maleimide or a derivative thereof.

[0085] In a further, more detailed embodiment, linker B is of formula (II), where, → Y-(CH2) q It forms a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, p is 0, → Z is -S(O)2- → s is an integer from 1 to 6, preferably from 1 to 3. → k is 1.

[0086] In such embodiments, the functional group C is preferably a carboxylic acid.

[0087] In a particular embodiment, linker B is of formula (II), where, → Y is selected from -O- and -NH-, q is an integer from 1 to 12, more preferably from 1 to 6. p is an integer from 1 to 50, preferably from 1 to 12. → Z is selected from single bonds, -NH-, -O-, and -S(O)2-, → s is 0, → k is 1.

[0088] In such embodiments, functional group C is preferably biotin or folic acid.

[0089] In another specific embodiment, linker B is of formula (II), where, → Y is selected from -O-, -NH-, and -C(O)-, q is an integer from 1 to 35, preferably from 2 to 12, more preferably from 2 to 4. p is an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12, or → Z is selected from -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-. → s is an integer from 1 to 6, → k is either 1 or 2.

[0090] In a preferred embodiment, linker B is of formula (II), where, → Y is selected from -O- and -NH-, q is an integer between 1 and 12, 1 and 6, preferably between 2 and 4. p is an integer from 0 to 12, preferably from 0 to 6. → Z is selected from -NH-C(O)- and -S(O)2-, preferably -NH-C(O)-, → s is an integer from 1 to 6, preferably s is 2. → k is 1.

[0091] In such embodiments, the functional group C is preferably a maleimide (also referred to as "Mal") or a derivative of a maleimide as disclosed herein.

[0092] In a further detailed embodiment, linker B is of formula (II) and further comprises a -S(O)2- group. In such an embodiment, the -S(O)2- group can be in any position of the group of formula (II). According to this detailed embodiment, linker B is of the following formula (II'): -[Y-(CH2) q' -S(O)2-(CH2) q'' -(O-CH2-CH2) p -Z-(CH2) s ] k - (II') (In the formula, → Y is selected from -O-, -NH- and -C(O)-, and is preferably -O-. q' and q'' are integers from 0 to 35, preferably from 1 to 12, and more preferably from 1 to 6. q'+q'' falls between 0 and 35, However, if Y is -O-, then q'+q'' is different from 0. p is an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. p+q is different from 0, or → Z is selected from a single bond, -NH-, -O-, -NH-C(O)-, -S-, and -S(O)2-, and is preferably -NH-C(O)-. → s is an integer from 0 to 6, preferably from 1 to 4. (→ k is an integer from 1 to 4, preferably from 1 to 2, and more preferably 1.) It can be represented by:

[0093] An example of linker B in equation (II') is:

[0094] [ka]

[0095] This includes, but is not limited to, the following:

[0096] In a preferred embodiment, linker B is given by the following formula:

[0097] [ka]

[0098] It is represented by one of the following.

[0099] In a preferred embodiment, part [B-(C) v ] is as follows: - v is 1, - B is given by the following formula:

[0100] [ka]

[0101] Selected from, - C is the functional group of formula (Mal1) shown above.

[0102] In another preferred embodiment, part [B-(C)] v] is as follows: - v is 1, - B is given by the following formula:

[0103] [ka]

[0104] It is represented by, - C is the functional group in formula (Mal2) shown above.

[0105] The compound of formula (I) according to the present invention is of the following formula (III): A-{[Y-(CH2) q -(O-CH2-CH2) p -Z-(CH2) s ] k -(C) v} w (III) (wherein A, C, v, w, Y, Z, q, p, s, and k are as defined above, including in all preferred and detailed embodiments.) It can be represented by:

[0106] In a particular embodiment, if the linker B is of formula (II), then v is an integer from 1 to 15, preferably from 1 to 6, more preferably v is 1 or 2, and even more preferably v is 1. According to this more preferred embodiment, i.e., when v is 1, the functional group C is preferably at the end of the linker B of formula (II).

[0107] In one embodiment, when v is greater than 1, one functional group C is preferably located at the end of linker B of formula (II), and additional functional groups C may be located at any position on linker B. Typically, each of the additional functional groups C can replace a hydrogen atom on linker B of formula (II).

[0108] In certain embodiments, part [B-(C) v ] is expressed by the following formula:

[0109] [ka] [ka] [ka] [ka] [ka]

[0110] (In each equation, n is an independent integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. (t is an integer independently ranging from 0 to 30, preferably from 0 to 12.) It is represented by one of the following.

[0111] Preferably, part B-(C) v The formula is as follows:

[0112] [ka] [ka]

[0113] (In each equation, n is an independent integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12. (t is an integer independently ranging from 0 to 30, preferably from 0 to 12.) It is represented by one of the following.

[0114] More preferably, part B-(C) v The formula is as follows:

[0115] [ka]

[0116] It is represented by one of the following.

[0117] In a particular embodiment, the compound according to the present invention is - 2,2'-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-[(3-propyl-1H-pyrrole-2,5-dione)oxy]phenol]; - 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 6-maleimide-1-hexanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyl disulfanyl)ethanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[5-(-2,5-dihydro-1H-pyrrole-2,5-dione)pentyl]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[4-(1,3-dioxolan-2-yl)butane]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, biotin-PEG2 amide; - N-[4-(-2,5-dihydro-1H-pyrrole-2,5-dione)butyl]salicylamide; - 2-Cyano-3,3-diphenylpropenoic acid, 6-maleimide-1-hexanol ester; - 2-Cyano-3,3-diphenylpropenoic acid, folic acid-PEG-1k ester; - 2-Cyano-3,3-diphenylpropenoic acid, 1,3-bis(vinylsulfonyl)-1-propanol ester; - 2-phenyl-1H-benzimidazole-5-(biotin-PEG8-N-ethyl)sulfonamide; - 2-Hydroxy-4-methoxybenzophenone-5-(biotin-PEG8-N-ethyl)sulfonamide; - [N-(2-cyano-3,3-diphenylpropenoyl)-piperidine-4-ylsulfonyl]acetic acid; - N-[(2-hydroxybenzoyl)-piperidine-4-ylsulfonyl]acetic acid; -(3-(2H-benzo[d][1,2,3]triazole-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidine-4-ylsulfonyl)acetic acid]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester; - 2-Cyano-N-[2-[3-(2,5-Dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-Diphenyl-propa-2-enamide; - 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; -3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]propenamide; -3-(2,5-dioxopyrrole-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]propoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxyphenoxy]propyl]propanamide; -3-(2,5-dioxopyrrole-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide; and - 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate It is selected from the group consisting of the following.

[0118] Preferably, the compound according to the present invention is - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester; - 2-Cyano-N-[2-[3-(2,5-Dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-Diphenyl-propa-2-enamide; - 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; -3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]propenamide; -3-(2,5-dioxopyrrole-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]propoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxyphenoxy]propyl]propanamide; and -3-(2,5-dioxopyrrole-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide; and - Selected from the group consisting of 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate.

[0119] In a more preferred embodiment of the present invention, the compound is of the following formula:

[0120] [ka]

[0121] It is 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid and 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester, which have the properties of 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid and 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester.

[0122] The 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid and 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester used herein are also known as "compound #17," "M10," or "DHHB-maleimide."

[0123] In a more preferred embodiment of the present invention, the compound is of the following formula:

[0124] [ka]

[0125] It is 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenyl acrylate having [a specific compound].

[0126] The term 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl2-cyano-3,3-diphenylacrylate as used herein is also known as "compound #23," "OOM," "octocrylene-octyl-maleimide," or "octocrylene-maleimide."

[0127] Properties of the compound of formula (I) According to the present invention, the compound of formula (I) is adhesive. More specifically, the compound of formula (I) may be bioadhesive.

[0128] The term "adhesive compound" refers to a compound capable of adhering to any support via one or more functional groups (e.g., functional group C as defined herein), wherein the support is biological, organic, and / or inorganic. More specifically, the compound adheres via one or more of its functional groups (e.g., functional group C as defined herein) that are capable of reacting with reactive groups or entities of the support.

[0129] "Bioadhesive compounds" are defined above and refer to adhesive compounds whose support is biological. Examples of biological supports include, but are not limited to, tissues (e.g., skin), cells (e.g., chondrocytes, osteoblasts, fibroblasts, blood cells, plasma cells), and intracellular or extracellular materials (e.g., proteins, glycoproteins, collagen, elastin, glycosaminoglycans, proteoglycans).

[0130] The reactive groups that may be found in the support, more particularly in the biological support, include, but are not limited to, amines, ammonium, guanidine, thiols, carboxylic acids, and carboxylates.

[0131] The functional group C can advantageously react selectively with specific reactive groups found in the support.

[0132] for example: - Maleimides, thiols, Michael receptors, sulfonylazeridines, vinyl sulfones, isocyanates, or thiocyanates can typically be selective for thiol groups. - Carboxylic acids, aldehydes, acetals, esters, NHS esters, sulfo-NHS esters, or anhydrides can typically be selective for amine groups. - Carboxylates can typically be selective for ammonium, - Amines can typically be selective for carboxylic acids, - Ammonium and guanidine may typically be selective for carboxylates.

[0133] The reaction between the functional group C of the compound of formula (I) and the reactive group results in the formation of an amide, disulfide, thioether, thiocarbamate, imine, or ion pair -NH3 + , -It creates a bond like OOC-. The bond (bound) created between the functional group of the compound of formula (I) and the reactive group of the support can be a covalent bond or an ionic bond. The bond is advantageously reversible. The bond can be cleaved by using a cleaving material selected from chemical and physical agents (e.g., proteins, peptides (e.g., glutathione), amino acids, enzymes (e.g., cathepsin B), thiols (e.g., 2-mercaptoethanol, N-acetylcysteine), dithiols (e.g., dithiothreitol), pH modifiers, acids, bases, solvents and / or woven or non-woven tissues). Those skilled in the art can select an appropriate cleaving material depending on the properties of the bond and / or the composition.

[0134] In certain embodiments, the compound of formula (I) is biocompatible.

[0135] The term "biocompatible compound" generally refers to a compound that is non-toxic to the recipient organism and does not cause any significant adverse effects in the recipient organism, along with any of its metabolites or degradation products. Generally speaking, a biocompatible material (or compound) is a compound that, when administered to a patient, does not induce a significant inflammatory or immune response.

[0136] In another specific embodiment, the compound of formula (I) is biodegradable.

[0137] composition Another object of the present invention is a composition comprising at least one compound of formula (I) as defined herein, and at least one excipient.

[0138] In certain embodiments, the composition contains 0.01 wt% to 99 wt%, preferably 0.01 wt% to 90 wt%, more preferably 1 wt% to 70 wt%, and even more preferably 5 wt% to 50 wt%, of the total mass of the composition, of the compound of formula (I).

[0139] The compositions according to the present invention may, in particular, be in the form of suspensions, creams, sprays, aerosols, butters, sticks, gels, ointments, lotions, solutions, solids, emulsions, microemulsions, oils, lyophilized products, emulsions, powders, pastes, waxes, mousses, patches, films, micelles, liposomes, or foams. The compositions may be prepared according to methods known to those skilled in the art.

[0140] The compositions of the present invention may include, for example, 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), and combinations thereof, as solvents or dispersion media.

[0141] Examples of excipients include, but are not limited to, surfactants, dispersants, emulsifiers, pH modifiers, pH buffers, viscosity modifiers, preservatives, polymerizers, pigments, colorants, stabilizers, flow enhancers, diluents, binders, water-soluble polymers, lubricants, disintegrants, leavening agents, fillers, stabilizers, antioxidants, emulsifiers, emollients, permeability enhancers, propellants, gases, decolorizers, film-forming agents, gelling agents, humectants, colorants, fragrance ingredients, exfoliants, solubilizers, solvents, binders, bulking agents, wetting agents, detergents, elastomers, astringents, masking agents, antistatic agents, protective substances, modifiers, absorbents, anti-solidification agents, matting agents, structuring agents, oxidizing agents, reducing agents, superfatting agents, activity boosters, and combinations thereof.

[0142] Examples of additional agents that may be included in the composition include, but are not limited to, desquaming agents, whitening agents, tensing effect agents, analgesics, anti-irritants, sebum-regulating agents, wound healing agents, anti-inflammatory agents, anti-acne agents, anti-glycation agents, slimming agents, self-tanning agents, anti-aging agents, and anti-wrinkle agents.

[0143] The 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, surfactants containing carboxylic acids, sulfonic acids, and sulfate ions, such as long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium, potassium, and ammonium sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2-ethylthioxyl)-sulfosuccinate; sulfated castor oil, propylene glycol, lecithin, capric acid / caprylic triglyceride, 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, stearyldimethylbenzylammonium chloride, polyoxyethylene, and coconutamines. 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, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, POLOXAMER® 401, stearoyl monoisopropanolamide, polyoxyethylene hydrogenated tallow amide, as well as emulsifying waxes, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrin, glyceryl monostearate, poloxamer, povidone, and cetyl palmitate.Examples of amphoteric surfactants include sodium N-dodecyl-beta-alanine, sodium N-lauryl-beta-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0144] Examples of preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, perillic acid, and thimerosal.

[0145] Examples of water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0146] Suitable stabilizers include, but are not limited to, butylhydroxytoluene (BHT), ascorbic acid, its salts and esters, vitamin E, tocopherol and its salts, sulfites such as sodium metabisulfite, cysteine ​​and its derivatives, citric acid, propyl gallate, and butylhydroxyanisole (BHA).

[0147] An example of a pH buffer that can be used in the composition is triethanolamine.

[0148] Examples of emollients include, but are not limited to, almond oil, castor oil, carob extract, cetostearoyl alcohol, cetyl alcohol, cetyl ester wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohol, petrolatum, petrolatum and lanolin alcohol, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol, and combinations thereof.

[0149] Examples of emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glyceryl monostearate, glyceryl monooleate, hydroxypropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohol, lecithin, medium-chain triglycerides, methylcellulose, mineral oil and lanolin alcohol, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, self-emulsifying glyceryl monostearate, and sodium citrate dihydrate. This includes, but is not limited to, dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum, PEG-100 stearate / glyceryl stearate (Arlacel 165®), decyl glucoside (Plantaren 2000®), lauryl glucoside (Plantaren 1200®), cetearyl glucoside, cetearyl alcohol (Emulgade PL68 / 50®), and combinations thereof.

[0150] Examples of permeability enhancers include, but are not limited to, aliphatic alcohols, fatty acid esters, fatty acids, aliphatic alcohol ethers, amino acids, phospholipids, lecithin, cholate salts, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified cellulose and diimides), macrocyclic compounds such as macrocyclic lactones, ketones and anhydrides and cyclic ureas, surfactants, N-methylpyrrolidone and its derivatives, DMSO and related compounds, ionic compounds, azones and related compounds, and solvents such as alcohols, ketones, amides, and polyols (e.g., glycols).

[0151] Examples of propellants include, but are not limited to, dichlorofluoromethane, difluoroethane, isobutane, n-butane, propane, nitrogen, and carbon dioxide.

[0152] Examples of desquamating agents include, but are not limited to, beta-hydroxy acids, alpha-hydroxy acids, urea, cinnamic acid, Sophora japonica (Saphora japonica) extract, and proteases such as trypsin.

[0153] Examples of decolorizing agents include, but are not limited to, vitamin C and its derivatives, ferulic acid, resorcinol, and alpha and beta arbutin.

[0154] Examples of anti-glycation agents include, but are not limited to, black tea extract and Vaccinium myrtillus extract.

[0155] Examples of weight-loss agents include, but are not limited to, caffeine, tea extract, Hedera helix extract, and theobromine.

[0156] Examples of analgesics and antistimulants include, but are not limited to, caffeine, vitamins E, C, B5, B3, glycylretinic acid, their salts, or derivatives.

[0157] Examples of sebum regulators include, but are not limited to, zinc salts such as zinc gluconate or zinc pidolate, vitamin B6, selenium chloride, and benzoyl peroxide.

[0158] Examples of wound healing agents include, but are not limited to, arginine, hydroxyproline, chitosan and derivatives, propolis extract, folic acid, and chitosan.

[0159] Examples of self-tanning agents include, but are not limited to, erythrulose.

[0160] Examples of anti-aging agents include, but are not limited to, placenta extract, beta-glucan, fucoidan, sodium hyaluronate, and collagen.

[0161] Examples of antistatic agents include, but are not limited to, methylsulfonylmethane.

[0162] Examples of thickeners include, but are not limited to, polypropylene A.

[0163] Examples of film-forming agents include, but are not limited to, copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate, and polyquaternium-6.

[0164] Uses The compositions of the present invention can be administered orally, topically, parenterally, subcutaneously, on the skin, intradermally, transdermally, intramuscularly, enterally, intranasally, into the respiratory tract, intravascularly, as an ophthalmic preparation, intravaginally, intraurethrally or by nasal inhalation. In certain embodiments, the compositions of the present invention are administered subcutaneously, on the skin, intradermally, transdermally or topically, preferably topically. The compositions of the present invention can be administered by micro needles or patches.

[0165] The composition can be applied, in particular, to mucosa, cutin, epidermis, dermis, epithelium, endothelium, skin, skin appendages, connective tissue or bone tissue, preferably to the skin, skin appendages or mucosa.

[0166] In one embodiment, the composition of the present invention is selected from sunscreen compositions, cosmetic compositions, skin compositions and therapeutic compositions. In a preferred embodiment, the composition is a sunscreen or cosmetic composition.

[0167] Topical composition In certain embodiments, the composition of the present 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.

[0168] As used herein, "topically acceptable excipient" refers to an excipient suitable for topical application. Such excipients can be carefully selected by those skilled in the art, for example, from among the above-mentioned excipients.

[0169] The topical composition can be a skin composition, a therapeutic composition and / or a cosmetic composition.

[0170] The topical composition can be in the form of, in particular, a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilizate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam. The composition can be prepared according to methods known to those skilled in the art.

[0171] Preferably, the topical composition is selected from creams, sprays, gels, ointments, lotions, emulsions, foams, suspensions and milks.

[0172] The topical composition can be applied to mucosa, cutin, epidermis, dermis, epithelium, endothelium, skin or skin appendages (such as hair and nails), preferably to mucosa, skin or skin appendages.

[0173] Cosmetic composition In another specific embodiment, the composition of the present invention is a cosmetic composition.

[0174] The cosmetic composition comprises at least one compound of formula (I) according to the present invention, and at least one excipient that is acceptable as a cosmetic.

[0175] As used herein, “excipients acceptable for cosmetic use” refers to excipients suitable for cosmetic applications. Such excipients may be thoughtfully selected by those skilled in the art from, for example, the excipients listed above.

[0176] The cosmetic composition may be administered orally, topically, parenterally, subcutaneously, topically, intradermally, transcutaneously, intramuscularly, enterally, intranasally, intrarespiratoryly, or by nasal inhalation. In a preferred embodiment, the cosmetic composition is administered topically.

[0177] Preferably, the cosmetic composition is a topical composition or a skin composition, and more preferably a topical composition.

[0178] The cosmetic composition may be applied in more detail to mucous membranes, keratin, epidermis, dermis, epithelium, endothelium, skin or skin appendages (e.g., hair and nails), preferably to mucous membranes, skin or skin appendages.

[0179] Cosmetic compositions may, in particular, be in the form of suspensions, creams, sprays, aerosols, butters, sticks, gels, ointments, lotions, solutions, solids, emulsions, microemulsions, oils, lyophilized products, lotions, powders, pastes, waxes, mousses, patches, films, micelles, liposomes, or foams. Compositions may be prepared according to methods known to those skilled in the art.

[0180] The compositions of the present invention may be particularly well suited to counteracting and / or reducing signs of skin aging, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or unevenness of complexion, and / or to reinforcing the skin barrier.

[0181] Signs of skin aging may be related to endogenous factors associated with aging and also to exogenous factors, in particular UV-light exposure.

[0182] The object of the present invention relates to the cosmetic use of the composition according to the invention for combating and / or reducing signs of skin aging, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, radiance and / or loss of color uniformity, and / or for strengthening the skin barrier.

[0183] Another object of the present invention is a cosmetic method for combating and / or reducing signs of skin aging, such as the formation of wrinkles and / or fine lines, skin sagging, loss of firmness of the skin, radiance and / or loss of color uniformity, and / or for strengthening the skin barrier, the method comprising the step of topically applying the composition according to the invention to the skin or its appendages.

[0184] Sun protection In another particular embodiment, the composition according to the invention is a sun protection composition.

[0185] Sun protection compositions are preferably applied topically (i.e. topical compositions). Sun protection compositions may in particular be in the form of a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilizate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam. In a particular embodiment, the sun protection composition is a formulation sunscreen type butter.

[0186] Therapeutic composition In a particular embodiment, the composition according to the invention is a therapeutic composition, and more particularly, said composition is a pharmaceutical composition or a veterinary composition.

[0187] The therapeutic composition comprises at least one compound of formula (I) according to the present invention, and at least one pharmaceutically acceptable excipient.

[0188] As used herein, “medically acceptable” means a compound, material, composition and / or dosage form that is within the bounds of medical common sense and suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic response, or other problems or complications, in proportion to a reasonable benefit / risk ratio, in accordance with the guidelines of an agency such as the Food and Drug Administration. As used herein, the term “medically acceptable excipient” means all components of a pharmaceutical or therapeutic composition that facilitate the manufacture, preservation and / or in vivo delivery of the composition. Medicinally acceptable excipients include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrants, leavening agents, fillers, stabilizers and combinations thereof.

[0189] The therapeutic composition may be administered orally, topically, parenterally, subcutaneously, topically, intradermally, transcutaneously, intramuscularly, enterally, intranasally, intrarespiratoryly, or by nasal inhalation. In a preferred embodiment, the therapeutic composition is administered topically.

[0190] In certain embodiments, the therapeutic composition is applied to skin, skin appendages, mucous membranes, keratin, epidermis, dermis, epithelium, endothelium, connective tissue, bone tissue, and combinations thereof, preferably skin, skin appendages, mucous membranes, keratin, epidermis, dermis, epithelium and endothelium, more preferably selected from skin, skin appendages and mucous membranes. In other embodiments, the therapeutic composition is applied to a circulating medium, such as blood or plasma.

[0191] In certain embodiments, the therapeutic composition is a skin composition.

[0192] Another object of the present invention is a compound of formula (I) according to the present invention, or a composition of the present invention (more specifically, a therapeutic composition), for use in the treatment and / or prevention of diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages.

[0193] Preferably, the diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages include lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria, herpes simplex, impetigo, eczema, rash, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, and pustules; This includes bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; and selected conditions such as sunburn, lice, scabies, pressure ulcer disinfection, pressure ulcer healing, vaginitis, bladder cancer, endometriosis, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, and skin and mucous membrane allergies. More preferably, the diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages are selected from lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria, herpes simplex, impetigo, eczema, rash, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, pustules; bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; sunburn, lice, scabies, pressure ulcer disinfection, and pressure ulcer healing.

[0194] As used herein, the terms “prevent,” “prevent,” or “prevent” refer to any reduction, however slight, of the predisposition or risk of an object developing a condition, disease, disorder, or symptoms thereof. For the purpose of prevention, the object is any object, preferably one that is at risk of or predisposed to developing a condition, disease, disorder. The term “prevent” includes completely preventing the development of a clinically apparent condition, disease, or disorder in an individual at risk, or preventing the development of a preclinically apparent condition, disease, or disorder. This includes preventive measures taken by an object at risk of developing a condition, disease, or disorder.

[0195] As used herein, the terms “to treat,” “treatment,” or “to treat” a disease, disorder, or condition include alleviation of at least one symptom, reduction in their severity, or delay or inhibition of their progression. Treatment does not necessarily mean totally cured. Useful compositions herein are only required to reduce the severity of a disease, disorder, or condition, reduce the severity of associated symptoms, improve the quality of life of a patient or subject, or delay or inhibit the onset of a disease, disorder, or condition.

[0196] Another object of the present invention is a method for delivering at least one compound of formula (I) to a target tissue in need thereof, comprising the step of administering an effective amount of the composition of the present invention. The present invention also provides a method for delivering at least one compound of formula (I) to a target tissue, comprising the step of topically administering to a target in need thereof a therapeutically effective amount of any of the compositions described herein that are useful for treating a disease, disorder or condition of the tissue.

[0197] In particular, the tissue is selected from skin, skin appendages, keratin, epidermis, dermis, epithelium, endothelium, connective tissue, bone tissue, and combinations thereof. Preferably, the tissue is skin, skin appendages, or mucous membrane.

[0198] As used herein, “effective dose” or “therapeutic dose” refers to the amount of the drug or composition of the present invention disclosed herein that is effective in alleviating, delaying the onset of, or preventing one or more symptoms of a disease or disorder.

[0199] Another object of the present invention is a method for treating or preventing a disease or condition of the skin, mucous membrane, cornea of ​​the eye, or skin appendages, comprising the step of administering a composition of the present invention (more specifically a therapeutic composition) to a subject in need thereof, wherein the composition comprises at least one compound of formula (I) as defined herein.

[0200] A further object of the present invention is a method for treating or preventing a disease, disorder, or condition of the skin, mucous membrane, cornea of ​​the eye, or skin appendages in a subject, comprising the step of topically administering to a subject in need of such treatment any of the compositions described herein that are useful for treating a disease, disorder, or condition of the skin, mucous membrane, or cornea. In particular embodiments, the diseases, disorders, or conditions of the skin, mucous membrane, or cornea include lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria, herpes simplex, impetigo, eczema, rash, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, and pustules; The following are selected from bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; sunburn, lice, scabies, pressure ulcer disinfection and healing, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, and skin and mucous membrane allergies.

[0201] For the purpose of clarity, any element or feature of any method, composition, or process described herein may be combined with any other element or feature of any other method, composition, or process described herein.

[0202] Another object of the present invention is the use of the compounds of formula (I) of the present invention to prepare compositions for treating and / or preventing diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, and skin appendages.

[0203] Another object of the present invention is lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria, herpes simplex, impetigo, eczema, rash, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, pustules; The present invention provides for use in the treatment and / or prevention of diseases or conditions selected from the group consisting of bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; sunburn, lice, scabies, pressure ulcer disinfection and healing, vaginitis, cancer such as bladder cancer, endometriosis, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, and allergies to the skin and mucous membranes, using compounds of formula (I) of the present invention or compositions of the present invention (more specifically, therapeutic compositions).

[0204] kit The present invention - Composition according to the present invention, - Cleaning composition and - Optionally, this also applies to kits that include instruction guides.

[0205] In a preferred embodiment, the composition according to the present invention in the kit is a topical composition. In a more preferred embodiment, the composition according to the present invention in the kit is a cosmetic or sunscreen composition, preferably a sunscreen composition.

[0206] "Cleansing composition" refers to a composition that enables the removal of some or all of the compositions according to the present invention previously applied to a target tissue, such as skin, skin appendages, or mucous membranes. More specifically, the cleansing composition enables the removal of adhesive compounds.

[0207] The cleaning composition may comprise at least one "cleansing agent" and optionally one or more excipients. The "cleansing agent" refers to a chemical or biological agent capable of disrupting the bonds between adhesive compounds adhering to the tissue and the tissue itself. The cleaning agent may be a protein, peptide (e.g., glutathione), amino acid, enzyme (e.g., cathepsin B), thiol (e.g., 2-mercaptoethanol, N-acetylcysteine), dithiol (e.g., dithiothreitol), pH modifier, acid, base, solvent, saline solution (e.g., sodium chloride solution), or a combination thereof. The cleaning agent may be thoughtfully selected by those skilled in the art depending on the nature of the bonds between adhesive compounds adhering to the tissue and the tissue itself.

[0208] In certain embodiments, the cleaning composition is a powder, shampoo, soap, lotion, solution, solid, scrubbing, scraper, mousse, foam, synthetic detergent, gel, shower gel, spray, mist, wax, strip, enzyme composition, detergent composition, or woven or nonwoven fabric.

[0209] Other uses - light protection and light instability Another object of the present invention is the use of at least one compound as defined herein to reduce the photodegradation and / or photoinstability of pharmaceutically active ingredients or cosmetics.

[0210] The term "photodegradation" refers to partial or total degradation induced by light, specifically UV light.

[0211] The term "photoinstability" refers to instability induced by light, specifically UV light.

[0212] "Medicinal active ingredients" include, but are not limited to, physically, physiologically, or pharmacologically active substances. Medicinal active ingredients are substances that can be used to treat (e.g., therapeutic agents, vaccine antigens, or antigenic materials), prevent (e.g., prophylactic agents, vaccines), diagnose (e.g., diagnostic agents), cure, or alleviate a disease or illness. Activators may also be substances that affect the structure or function of the body, or prodrugs that are biologically active or become more active after being placed in a given physiological environment.

[0213] "Cosmetics" refers to substances used in cosmetic purposes, methods, and processes, such as sunscreens, dyes, fragrances, deodorants, microbiome regulators, skin modifiers, and skin lipid regulators.

[0214] In certain embodiments, at least one compound used for photodegradation and / or photoinstability of a pharmaceutically active ingredient or cosmetic is in the form of a micelle or liposome. The pharmaceutically active ingredient or cosmetic may, more specifically, be encapsulated in the form of a micelle or liposome within at least one compound of the present invention.

[0215] A further object of the present invention is a material comprising a support and at least one compound as defined herein, wherein the compound is adhered to the support.

[0216] The support may be made of any organic and / or inorganic material. In certain embodiments, the support may be a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, metal, plastic, rubber, or glass support.

[0217] The present invention is described in further detail in the following embodiments, which are not intended to limit the scope of the invention as defined by the appended claims. [Examples]

[0218] (Example 1) Preparation of the compound of formula (I) Compound #1. 2,2'-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-[(3-propyl-1H-pyrrole-2,5-dione)oxy]phenol]

[0219] [ka]

[0220] 1-(3-bromopropyl)-1H-pyrrole-2,5-dione (128 mg, 0.58 mmol) was added to a suspension of 2,4-bis[2,4-dihydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine (200 mg, 0.49 mmol) and cesium carbonate (163 mg, 0.5 mmol) in acetonitrile (10 mL). The reaction mixture was refluxed overnight, filtered, and concentrated to dryness. The residue was placed in ethyl acetate, the organic phase was washed with water, dehydrated with magnesium sulfate, and concentrated under vacuum. The residue was ground with DIPE to obtain the desired product as a white solid (250 mg). 1 H NMR (400 Mhz, CDCl3), δ (ppm): 2.02 (4H, t), 3.80 (4H, t, J = 2.7 Hz), 3.89 (3H, s), 4.36 (4H, t, J = 7.0 Hz), 6.58 (2H, dd, J = 1.6 Hz), 7.03 (2H, dd, J = 8.2, 1.6 Hz), 7.15 (2H, ddd, J = 8.8, 1.4, 0.4 Hz), 7.45 (4H, d, J = 10.2 Hz), 7.83 -7.88 (4H).

[0221] Compound #2: 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 6-maleimide-1-hexanol ester

[0222] [ka]

[0223] A solution of 156 mg (0.5 mmol) of 2-(4-diethylamino-2-hydroxybenzoyl)benzoic acid, 78 mg (0.5 mmol) of EDCI, 100 mg (0.5 mmol) of 6-maleimide-1-hexanol, and 10 mg of DMAP in 30 mL of dichloromethane was stirred at room temperature for 2 hours. The reaction mixture was washed with water, 1N HCl, and aqueous NaHCO3, and again with water, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was filtered through a short silica column (solvent Â) to obtain 75 mg of the desired product as a pale yellow solid. 1 HNMR (CDCl3), δ (ppm): 1.10 (6H, t, J = 7.0 Hz), 1.29-1.44 (4H), 1.64 (2H, tt, J = 7.6, 7.1 Hz), 1.73 (2H, tt, J = 7.4, 7.1 Hz), 3.39 (4H, q, J = 7.0 Hz), 3.77 (2H, t, J = 7.6 Hz), 4.19 (2H, t, J = 7.1 Hz), 6.39 (1H, dd), 7.18 (1H, dd, J = 7.9, 1.3 Hz), 7.45 (2H, d, J = 10.2 Hz), 7.63 (1H, ddd, J = 7.8, 7.7, 1.3 Hz), 7.58-7.71 (3H), 7.82 (1H, dd, J = 7.9, 0.4 Hz).

[0224] Compound #3: 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyl disulfanyl)ethanol ester

[0225] [ka]

[0226] Compound #3 was prepared using the same protocol as for compound #2, in which 6-maleimide-1-hexanol was replaced with 2-(2-pyridinyldisulfanyl)ethanol. 54 mg of the desired product was obtained as a pale yellow solid. 1 HNMR (CDCl3) d (ppm): 1.10 (6H, t, J = 7.0 Hz), 3.39 (4H, q, J = 7.0 Hz), 3.50 (2H, t, J = 5.5 Hz), 4.45 (2H, t, J = 5.5 Hz), 6.39 (1H, dd, J = 1.3, 0.4 Hz), 7.16-7.25 (2H, dl), 7.36 (1H, ddd, J = 7.8, 1.7, 0.5 Hz), 7.58-7.71 (4H), 7.79-7.88 (2H), 8.43 (1H, ddd, J = 5.4, 1.9, 0.5 Hz).

[0227] Compound #4. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[5-(-2,5-dihydro-1H-pyrrole-2,5-dione)pentyl]amide

[0228] [ka]

[0229] Compound #4 was prepared using the same protocol as for compound #2, in which 6-maleimide-1-hexanol was replaced with 1-(5-aminopentyl)-2,5-dihydro-1H-pyrrole-2,5-dione. 210 mg of the desired product was obtained as a white solid. 1HNMR (CDCl3) d (ppm): 1.10 (6H, t, J = 7.0 Hz), 1.44 (2H, tt, J = 7.4, 7.1 Hz), 1.61-1.77 (4H), 3.39 (4H, q, J = 7.0 Hz), 3.77 (2H, t, J = 7.5 Hz), 4.20 (2H, t, J = 7.1 Hz), 6.39 (1H, dd, J = 1.3, 0.4 Hz), 7.18 (1H, dd, J = 7.9, 1.3 Hz), 7.45 (2H, d, J = 10.2 Hz), 7.58-7.71 (4H), 7.82 (1H, dd, J = 7.9, 0.4 Hz).

[0230] Compound #5: 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[4-(1,3-dioxolan-2-yl)butane]amide

[0231] [ka]

[0232] Compound #5 was prepared using the same protocol as for compound #2, in which 6-maleimido-1-hexanol was replaced with 4-(1,3-dioxolan-2-yl)butan-1-amine. 165 mg of the desired product was obtained as a beige solid. 1HNMR (CDCl3) d (ppm): 1.10 (6H, t, J = 7.0 Hz), 1.47-1.62 (6H, dt, J = 7.4, 7.3 Hz), 3.18 (2H, t, J = 7.1 Hz), 3.39 (4H, q, J = 7.0 Hz), 3.77-3.92 (4H, 3.84 (ddd, J = 10.4, 9.2, 5.7 Hz), 4.92 (1H, t, J = 5.8 Hz), 6.39 (1H, dd, J = 1.3, 0.4 Hz), 7.18 (1H, dd, J = 7.9, 1.3 Hz), 7.55-7.67 (4H), 7.82 (1H, dl, J = 7.9 Hz).

[0233] Compound #6. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, biotin-PEG2 amide

[0234] [ka]

[0235] Compound #6 was prepared using the same protocol as for compound #2, in which 6-maleimide-1-hexanol was replaced with biotin-PEG2-amine. 257 mg of the desired product was obtained as a white solid. 1HNMR (DMSO d6) d (ppm): 1.05-1.24 (8H), 1.41-1.62 (3H), 1.54 (1H, tt, J = 7.7, 7.4 Hz), 2.13-2.21 (2H, t, J = 7.4 Hz), 3.05-3.19 (2H, dd), 3.37-3.42 (4H, q), 3.43-3.51 (6H), 3.53-3.60 (2H, t, J = 6.1 Hz), 3.62-3.67 (4H, t, J = 4.2 Hz), 3.74 (1H, dt, J = 5.8, 4.5 Hz), 3.94-4.06 (2H, dl, J = 8.1, 5.8 Hz), 6.39 (1H, dd, J = 1.3 Hz), 7.18 (1H, dd, J = 7.9, 1.3 Hz), 7.55-7.67 (4H, dl, J = 7.8), 7.82 (1H, dl, J = 7.9 Hz).

[0236] Compound #7. N-[4-(-2,5-ジヒドロ-1H-ピロール-2,5-ジオン)ブチル]サリチルアミド

[0237]

change

[0238] Salicyloyl chloride (156 mg, 1 mmol) was dissolved in THF (10 mL), and 1-(4-aminobutyl)-2,5-dihydro-1H-pyrrole-2,5-dione (168 mg, 1 mmol) was added to the resulting solution. The solution was stirred for 10 minutes, and then triethylamine (279 μL, 2 mmol) was slowly added to the mixture. The reaction was stirred for 3 hours. TLC analysis of the reaction mixture showed complete disappearance of the starting materials. The reaction was then quenched with 40 mL of 10% hydrochloric acid solution. The solution was extracted with dichloromethane (2 × 30 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (2 × 20 mL), dried, and evaporated under vacuum. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane / MeOH to MeOH step gradient) to obtain 236 mg of product. 1 HNMR (CDCl3) d (ppm): 1.58 (2H, tt, J = 7.9, 7.2 Hz), 1.70 (2H, tt, J = 7.9, 7.6 Hz), 3.16 (2H, t, J = 7.2 Hz), 3.77 (2H, t, J = 7.6 Hz), 7.02 (1H, dd, J = 8.3, 1.3 Hz), 7.28 (1H, ddd, J = 8.1, 7.4, 1.3 Hz), 7.40-7.49 (4H).

[0239] Compound #8. 2-Cyano-3,3-diphenylpropenoic acid, 6-maleimide-1-hexanol ester

[0240] [ka]

[0241] A solution of 125 mg (0.5 mmol) of 2-cyano-3,3-diphenylpropenoic acid, 78 mg (0.5 mmol) of EDCI, 100 mg (0.5 mmol) of 6-maleimide-1-hexanol, and 10 mg of DMAP in 30 mL of dichloromethane was stirred at room temperature for 6 hours. The reaction mixture was washed with water, dilute HCl, and aqueous NaHCO3 solution, and again with water, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was filtered through a short silica column (solvent Â) to obtain 175 mg of the desired product as a pale yellow solid. 1 HNMR (CDCl3) d (ppm): 1.29-1.44 (4H, tt, J = 7.1, 7.0 Hz), 1.64 (2H, tt, J = 7.6, 7.1 Hz), 1.73 (2H, tt, J = 7.4, 7.1 Hz), 3.77 (2H, t, J = 7.6 Hz), 4.17 (2H, t, J = 7.1 Hz), 7.45 (2H, d, J = 10.2 Hz), 7.51-7.60 (4H), 7.70-7.79 (6H).

[0242] Compound #9. 2-Cyano-3,3-diphenylpropenoic acid, folic acid-PEG-1k ester

[0243] [ka]

[0244] Compound #9 was prepared using the same protocol as for compound #8, with 6-maleimide-1-hexanol replaced by folic acid-PEG-OH 1kDA (nanosoft polymer) and DMF used as the solvent. At the end of the reaction, the DMF was evaporated, and the precipitated residue in a methanol / acetone mixture was washed several times with acetone and dried under vacuum.

[0245] Compound #10. 2-Cyano-3,3-diphenylpropenoic acid, 1,3-bis(vinylsulfonyl)-1-propanol ester

[0246] [ka]

[0247] Compound #10 was prepared using the same protocol as for compound #8, in which 6-maleimide-1-hexanol was replaced with 1,3-bis(vinylsulfonyl)-1-propanol. 71 mg of the desired product was obtained as a white solid. 1 HNMR (CDCl3) d (ppm): 2.17-2.29 (2H, dt, J = 7.5, 7.0 Hz), 3.61-3.69 (2H, t, J = 7.0 Hz), 6.11 (1H, t, J = 7.5 Hz), 6.92-7.01 (2H, dd, J = 10.7, 1.8 Hz), 7.14-7.37 (3H, dd, J = 16.9, 1.8 Hz), 7.51-7.80 (11H).

[0248] Compound #11. 2-Phenyl-1H-benzimidazole-5-(biotin-PEG8-N-ethyl)sulfonamide

[0249] [ka]

[0250] To a solution of O-(2-aminoethyl)-O'-[2-(biothinylamino)ethyl]octaethylene glycol (285 mg, 0.41 mmol) and triethylamine (279 μL, 2 mmol) in THF (15 mL), 2-phenyl-1H-benzimidazole-5-sulfonyl chloride hydrochloride (164 mg, 0.5 mmol) was added. The reaction was stirred for 4 hours and then quenched with 40 mL of 10% hydrochloric acid solution. The solution was extracted with dichloromethane (2 × 30 mL). The combined organic phase was washed with saturated sodium bicarbonate solution (2 × 20 mL), dried, and evaporated under vacuum. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane / MeOH to MeOH step gradient) to obtain 326 mg of product. HRMS(M+H) + =939

[0251] Compound #12. 2-Hydroxy-4-methoxybenzophenone-5-(biotin-PEG8-N-ethyl)sulfonamide

[0252] [ka]

[0253] Compound #12 was prepared using the same protocol as for compound #11, in which 2-phenyl-1H-benzimidazole-5-sulfonyl chloride hydrochloride was replaced with 2-hydroxy-4-methoxybenzophenone-5-sulfonyl chloride. 76 mg of the desired product was obtained as a beige solid. MRMS(M+H) + =973

[0254] Compound #13: [N-(2-cyano-3,3-diphenylpropenoyl)-piperidine-4-ylsulfonyl]acetic acid

[0255] [ka]

[0256] A solution of 125 mg (0.5 mmol) of 2-cyano-3,3-diphenylpropenoic acid, 78 mg (0.5 mmol) of EDCI, 110 mg (0.5 mmol) of methyl-(piperidine-4-ylsulfonyl)acetate, and 10 mg of DMAP in 30 mL of dichloromethane was stirred overnight at room temperature. The reaction mixture was washed with water, dilute HCl, and aqueous NaHCO3 solutions, and again with water, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was filtered through a short silica column (solvent DCM / MeOH) to obtain 203 mg of the desired ester as an off-white solid. This was then suspended in 5 mL of THF, and 1 mL of NaOH 1N was added. The reaction mixture was stirred at room temperature for 2 hours, acidified with HCl 0.5N, and the precipitate was filtered to obtain 180 mg of the desired product. 1 HNMR (DMSO d6) d (ppm): 2.14 (2H, dl), 2.60 (2H, dl), 3.23-3.40 (4H, 3.31), 3.50 (1H, tt, J = 10.3, 2.7 Hz), 4.36 (2H, s), 7.50-7.59 (4H), 7.68-7.76 (6H).

[0257] Compound #14. N-[(2-hydroxybenzoyl)-piperidine-4-ylsulfonyl]acetic acid

[0258] [ka]

[0259] A solution of 70 mg (0.5 mmol) of 2-hydroxybenzoic acid, 78 mg (0.5 mmol) of EDCI, 110 mg (0.5 mmol) of methyl-(piperidine-4-ylsulfonyl) acetate and 3 mg of DMAP in 10 mL of dichloromethane was stirred overnight at room temperature. The reaction mixture was washed with water, dilute HCl, and aqueous NaHCO3, and again with water, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was filtered through a short silica column (solvent DCM / MeOH) to obtain 147 mg of the desired ester as an off-white solid. This was then suspended in 5 mL of THF and 1 mL of NaOH 1N was added. The reaction mixture was stirred at room temperature for 2 hours, acidified with HCl 0.5N, and the precipitate was filtered to obtain 89 mg of the desired product. 1 HNMR (DMSO d6) d (ppm): 2.15 (2H, dl), 2.59 (2H, dl), 3.27-3.42 (4H), 3.49 (1H, tt, J = 10.3, 2.7 Hz), 4.36 (2H, s), 7.02 (1H, dd, J = 8.3, 1.3Hz), 7.29 (1H, ddd, J = 8.1, 7.4, 1.3 Hz), 7.45 (1H, ddd, J = 8.3, 7.4, 1.4 Hz), 7.74 (1H, dd, J = 8.1, 1.4 Hz).

[0260] Compound #15: (3-(2H-benzo[d][1,2,3]triazole-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidine-4-ylsulfonyl)acetic acid]amide

[0261] [ka]

[0262] A solution of 170 mg (0.5 mmol) of 3-(3-(2H-benzo[d][1,2,3]triazole-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, 78 mg (0.5 mmol) of EDCI, 110 mg (0.5 mmol) of methyl-(piperidine-4-ylsulfonyl) acetate, and 5 mg of DMAP in 15 mL of dichloromethane was stirred overnight at room temperature. The reaction mixture was washed with water, dilute HCl, and aqueous NaHCO3 solutions, and again with water, dried over Na2SO4, and the solvent was evaporated under vacuum. The crude product was filtered through a short silica column (solvent DCM / MeOH) to obtain 98 mg of the desired ester as an off-white solid. This was then suspended in 5 mL of THF and 1 mL of NaOH 1N was added. The reaction mixture was stirred at room temperature for 2 hours, acidified with 0.5N HCl, and the precipitate was filtered to obtain 75 mg of the desired product. 1 HNMR (DMSO d6) d (ppm): 1.26 (9H, s), 2.16 (2H, dl), 2.54-2.65 (4H), 2.95 (2H, t, J = 7.0 Hz), 3.27-3.42 (4H), 3.49 (1H, tt, J = 10.3, 2.7 Hz), 4.36 (2H, s), 6.96 (1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 1.6 Hz), 7.72 (2H, ddd, J = 8.0, 7.3, 1.9 Hz), 8.25 (2H, ddd, J = 8.0, 1.9, 0.5 Hz).

[0263] Compound #16. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester

[0264] [ka]

[0265] a) 3-(diethylamino)benzo[c][1]benzooxepin-6,11-dione In a 50 mL pear-shaped flask equipped with magnetic stirring, a suspension of 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid (4.90 g, 15.64 mmol) in 20 ml of ethyl acetate was mixed with a solution of DCC (3.48 g, 16.89 mmol) in 10 ml of ethyl acetate. The mixture was stirred at RT for 18 hours. Then 30 ml of petroleum ether was added. After stirring for 0.5 hours, the solid was filtered and washed with AcOEt / petroleum ether to obtain 3.97 g of 3-(diethylamino)benzo[c][1]benzooxepin-6,11-dione as a yellow solid (yield = 86%). LCMS-ESI:[M+H] + =296

[0266] b) 2-[3-(2,5-dioxopyrrole-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide In a 100 mL round-bottom flask equipped with magnetic stirring, 1.185 g of 2-(2-aminoethoxy)ethanol (11.27 mmol) was added to 100 mL of DCM. 3.00 g of N-hydroxysuccinimide 3-(maleimido)propionic acid (11.27 mmol) was slowly added at +5°C. The reaction was stirred at room temperature ("RT") for 4 hours. The DCM was evaporated under reduced pressure to obtain 4.25 g of 2-[3-(2,5-dioxopyrrole-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide as a colorless oil (yield = quantitative). The product was used directly in the next step without purification. LCMS-ESI:[M+H] + =257

[0267] c) 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 3-(diethylamino)benzo[c][1]benzooxepin-6,11-dione (3.10 g, 10.50 mmol) and 2-[3-(2,5-dioxopyrrole-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide (3.90 g, 10.50 mmol) were placed in a 50 mL diglyme. DBU (1,8-diazabicyclo[5.4.0]undeca-7-ene) (0.16 g, 1.05 mmol) was added, and the reaction was stirred at RT for 4 days. Diglycerin was evaporated under reduced pressure, and the crude oil was directly purified on a 40 g SiO2 column eluted with a cyclohexane-acetone gradient from 95 / 5 to 50 / 50 to obtain 1.40 g of 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid and 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethyl ester as a yellow oil (yield = 24%). LCMS-ESI: [M+H] + =552 1 H NMR 400 MHz, DMSOd6, δ (ppm): 1.10 (6H, t, J = 7.0 Hz), 2.31 (2H, t, J = 7 Hz), 3.10 (2H, t), 3.29-3.31 (2H, m), 3.37 (4H, q, J = 7.0 Hz), 3.41 (2H, sl), 3.58 (2H, t, J = 7 Hz), 4.21 (2H, t, J = 7.4 Hz), 6.10 (1H, sl), 6.20 (1H, dd, J = 8 Hz), 6.82 (1H, d, J = 8 Hz), 7.0 (2H, s), 7.45 (1H, d, J = 8 Hz), 7.66 (2H, td), 8.0 (2H, d, J = 8 Hz), 12.54 (1H, sl).

[0268] λ of diethylaminohydroxybenzoyl hexyl benzoate in ethanol / DMSO 9 / 1 max The UV absorbance of compound #16 was measured at 357 nm, and the λ max UV absorbance was measured at 357 nm.

[0269] Compound #17. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester (M10)

[0270] [ka]

[0271] a) 3-(2,5-dioxopyrrole-1-yl)-N-(2-hydroxyethyl)propanamide In a 250 mL round-bottom flask equipped with magnetic stirring, 0.838 g (13.72 mmol) of 2-aminoethanol was added to 100 mL of dihydrogenated chlorine (DCM). 3.32 g (12.47 mmol) of 3-(maleimido)propionic acid N-hydroxysuccinimide ester was slowly added at +5°C. The reaction was stirred at RT for 2 hours. The DCM was evaporated under reduced pressure to obtain 4.15 g of 3-(2,5-dioxopyrrole-1-yl)-N-(2-hydroxyethyl)propanamide as a white solid. The product was used directly in the next step without purification. LCMS-ESI:[M+H] + =213

[0272] b) 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 3-(diethylamino)benzo[c][1]benzooxepin-6,11-dione (3.68 g, 12.47 mmol) and 3-(2,5-dioxopyrrole-1-yl)-N-(2-hydroxyethyl)propanamide (4.08 g, 12.47 mmol) were added to a 50 mL diglyme. DBU (1,8-diazabicyclo[5.4.0]undeca-7-ene) (0.16 g, 1.05 mmol) was added, and the reaction was stirred at RT for 4 days. Diglycerin was evaporated under reduced pressure, and the crude oil was directly purified on a 40 g SiO2 column using a cyclohexane-acetone gradient from 95 / 5 to 50 / 50 to obtain 1.40 g of 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid and 2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl ester as a yellow solid (yield = 22%). LCMS-ESI: [M+H] + =508 1 H NMR 400 MHz, DMSOd6, δ (ppm): 1.10 (6H, t, J = 7.0 Hz), 2.32 (2H, t, J = 6.4 Hz), 3.24 (2H, dl), 3.37 (4H, q, J = 7.0 Hz), 3.59 (2H, t, J = 6.4 Hz), 4.06 (2H, t, J = 7.4 Hz), 6.09 (1H, s), 6.18 (1H, dd, J = 8 Hz), 6.80 (1H, d, J = 8 Hz), 6.97 (2H, s), 7.43 (1H, d, J = 8 Hz), 7.69 (2H, td), 8.04 (2H, d, J = 8 Hz), 12.51 (1H, sl).

[0273] λ of diethylaminohydroxybenzoyl hexyl benzoate in ethanol / DMSO 9 / 1 max The UV absorbance of compound #17 was measured at 357 nm, and the λ max UV absorbance was measured at 357 nm.

[0274] Compound #18. 2-Cyano-N-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-diphenyl-propa-2-enamide

[0275] [ka]

[0276] a) 2-Cyano-3,3-diphenyl-propa-2-enoic acid In a 250 mL round-bottom flask equipped with magnetic stirring, octocrylene (10.48 g, 28.99 mmol) was solubilized in THF (75 mL). Then, a solution of 1 N sodium hydroxide (31.89 mL, 31.89 mmol) was added at 5°C. The reaction mixture was stirred at RT for 18 hours, and then acidified with 1 N HCl (31.89 mL, 31.89 mmol). The THF was evaporated under reduced pressure, and the crude product was stirred with a mixture of water (400 mL) and heptane (150 mL) and filtered. The solid was washed again with water and heptane to obtain 6.26 g of 2-cyano-3,3-diphenyl-propa-2-enoic acid as a white solid (yield = 87%). LCMS-ESI:[M+H] + =250

[0277] b) tert-butyl N-[2-[(2-cyano-3,3-diphenyl-propa-2-enoyl)aminoethyl]carbamate In a 250 mL round-bottom flask equipped with magnetic stirring, 2-cyano-3,3-diphenyl-propa-2-enoic acid (2 g, 8.02 mmol) was added to DCM (50 mL) and DMF (catalytic amount). Oxalyl chloride (1.36 mL, 16.05 mmol) was slowly added at 5°C. The reaction was stirred at RT for 1 hour. The solvent and excess oxalyl chloride were evaporated under reduced pressure to obtain the acid chloride as a yellow solid.

[0278] In a 250 mL round-bottom flask equipped with magnetic stirring, N-Boc-ethylenediamine (2.7 g, 16.85 mmol) was added to DCM (50 mL). Then, the solution of the previous acid chloride in DCM (20 mL) was slowly added. The reaction was stirred at RT for 1 hour. The reaction mixture was washed with water (3 × 50 mL), dehydrated with MgSO4, and concentrated to dryness to obtain 3.19 g of tert-butyl N-[2-[(2-cyano-3,3-diphenyl-propa-2-enoyl)amino]ethyl]carbamate as an off-white solid (yield = quantitative). LCMS-ESI:[M+H] + =292

[0279] c) N-(2-aminoethyl)-2-cyano-3,3-diphenyl-propa-2-enamide In a 250 mL round-bottom flask equipped with magnetic stirring, tert-butyl N-[2-[(2-cyano-3,3-diphenyl-propa-2-enoyl)amino]ethyl]carbamate (3.14 g, 8.02 mmol) was added to DCM (50 mL). At 5°C, TFA (40.5 mL, 529 mmol) was slowly added. The reaction was stirred at RT for 1 hour (until gas generation ceased). The reaction mixture was concentrated under vacuum, 25 mL of DCM was added, and the resulting solution was washed with 0.5 N NaOH (8 mL), dehydrated with Na2SO4, concentrated to dryness, and 2.4 g of N-(2-aminoethyl)-2-cyano-3,3-diphenyl-propa-2-enamide was obtained as a colorless oil (yield = 91%). LCMS-ESI:[M+H] + =292

[0280] d) 2-Cyano-N-[2-[3-(2,5-Dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-Diphenyl-propa-2-enamide In a 250 mL round-bottom flask equipped with magnetic stirring, N-(2-aminoethyl)-2-cyano-3,3-diphenyl-propa-2-enamide (2.33 g, 8.01 mmol) was added to 60 mL of DCM. 3-(maleimide)propionic acid N-hydroxysuccinimide (2.774 g, 10.42 mmol) was slowly added. The reaction was stirred at RT for 18 hours, the solution was washed with water (50 mL), and dried over Na2SO4. The crude product was filtered on a silica pad that successively eluted with DCM, AcOEt, and acetone. The acetone layer was concentrated under vacuum to obtain an off-white solid, which was crystallized from an acetonitrile / iPrOH:1 / 4 mixture to obtain 660 mg of the desired compound. After concentration of the filtrate, a second crystallization from acetonitrile / iPrOH:1 / 4 yielded a second batch of 322 mg. The two batches were combined, stirred in 20 mL of diisopropyl ether for 1 hour, filtered, and dried to obtain 945 mg of 2-cyano-N-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethyl]-3,3-diphenyl-propa-2-enamide as a white solid (yield = 26%). LCMS-ESI: [M+H]+=443 1 H NMR 400 MHz, DMSOd6, δ (ppm): 2.27 (2H, tl), 2.79 (2H, dl), 2.97 (2H, dl), 3.58 (2H, tl), 7.01 (2H, s), 7.16-7.5 (10H, m), 7.84 (1H, sl, NH), 8.54 (1H, sl, NH).

[0281] λ of octocrylene in ethanol / DMSO 9 / 1 max The UV absorbance of compound #18 was measured at 305 nm, and the λ max UV absorbance was measured at 293 nm.

[0282] Compound #19. 2-Cyano-3,3-diphenyl-propa-2-enoate, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester

[0283] [ka]

[0284] a) tert-butyl-N-[2-(2-hydroxyethylsulfanyl)ethyl]carbamate In a 250 mL pear-shaped flask equipped with magnetic stirring, a solution of Boc2O (2.12 g, 9.69 mmol) in 20 mL of DCM was mixed with a solution of 2-((2-aminoethyl)-thio)ethanol (1.17 g, 9.69 mmol) in 10 mL of DCM. The mixture was stirred at RT for 30 minutes. The solvent was evaporated under reduced pressure to obtain 2.21 g of tert-butyl-N-[2-(2-hydroxyethylsulfanyl)ethyl]carbamate as a colorless oil (yield = quantitative). LCMS-ESI:[M+H] + =122(-Boc)

[0285] b) 2-Cyano-3,3-diphenyl-propa-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 2-cyano-3,3-diphenyl-propa-2-enoic acid (2 g, 8.02 mmol) was added to DCM (100 mL) and DMF (catalytic amount). Oxalyl chloride (1.36 mL, 16.05 mmol) was slowly added at +5°C. The reaction was stirred at RT for 1 hour. The solvent and excess oxalyl chloride were evaporated under reduced pressure to obtain the acid chloride as a yellow solid.

[0286] In a 250 mL round-bottom flask equipped with magnetic stirring, tert-butyl-N-[2-(2-hydroxyethylsulfanyl)ethyl]carbamate (2.13 g, 9.63 mmol) was added to DCM (50 mL), pyridine (973 μl), and a catalytic amount of DMAP. Then, the solution of the previous acid chloride in DCM (20 mL) was slowly added. The reaction was stirred at RT for 1 hour. The solution was washed with water (3 × 50 mL), dehydrated with MgSO4, and concentrated under reduced pressure to obtain 3.49 g of 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester as a colorless oil (yield = 96%). LCMS-ESI:[M+H] + =353(-Boc)

[0287] c) 2-Cyano-3,3-diphenyl-propa-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfonyl]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 3.49 g, 7.71 mmol of 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester (DCM) was added to 100 mL of DCM. 3.992 g, 23.13 mmol of m-CPBA was added, and the reaction was stirred at RT for 1 hour. The DCM solution was washed with NaHCO3, dehydrated with Na2SO4, and concentrated under reduced pressure to obtain 3.9 g of 2-cyano-3,3-diphenyl-propa-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester as a colorless oil (yield = quantitative). LCMS-ESI:[M+H]+=385(-Boc)

[0288] d) 2-[2-(2-cyano-3,3-diphenyl-propa-2-enoyl)oxyethylsulfonyl]ethylammonium,2,2,2-trifluoroacetate In a 250 mL round-bottom flask equipped with magnetic stirring, 3.55 g, 9.07 mmol of 2-cyano-3,3-diphenyl-propa-2-enoate and 2-[2-(tert-butoxycarbonylamino)ethylsulfonyl]ethyl ester were added to 100 mL of DCM. At +5°C, 6.94 mL, 90.69 mmol of TFA was slowly added. The reaction was stirred at RT for 1 hour (until gas generation ceased). The reaction mixture was concentrated under vacuum. 2 × 25 ml of toluene was added, and the mixture was concentrated to dryness to obtain 4.5 g of 2-[2-(2-cyano-3,3-diphenyl-propa-2-enoyl)oxyethylsulfonyl]ethylammonium, 2,2,2-trifluoroacetate as a pale yellow oil (yield = 99%). LCMS-ESI:[M+H] + =385

[0289] e) 2-Cyano-3,3-diphenyl-propa-2-enoate, 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 2-[2-(2-cyano-3,3-diphenyl-propa-2-enoyl)oxyethylsulfonyl]ethylammonium, 2,2,2-trifluoroacetate (4.5 g, 9.03 mmol) was added to 50 mL of DCM. 3-(maleimide)propionic acid N-hydroxysuccinimide (2.884 g, 10.83 mmol), followed by DIPEA (15.72 mL, 9.03 mmol), was slowly added. The reaction was stirred at RT for 2 hours. The solution was washed with water (50 mL), dehydrated with Na2SO4, and concentrated under reduced pressure to obtain a colorless oil (5.8 g). The crude oily substance was purified by solid loading on an 80g SiO2 column with an elution gradient from 100% DCM to 100% AcOEt to obtain 2g of 2-cyano-3,3-diphenyl-propa-2-enoate and 2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfonyl]ethyl ester as a white solid (yield = 41%). LCMS-ESI: [M+H] + =536 1 H NMR 400 MHz, DMSOd6, δ (ppm): 2.32 (2H, t), 3.21 (2H, t), 3.39 (4H, m), 3.59 (2H, t), 4.42 (2H, t), 6.99 (2H, s), 7.20 (2H, d), 7.38-7.52 (8H, m), 8.23 ​​(1H, sl, NH).

[0290] λ of octocrylene in ethanol / DMSO 9 / 1 max The UV absorbance of compound #19 was measured at 305 nm, and the λ max UV absorbance was measured at 308 nm.

[0291] Compound #20. 3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornane-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornane-1-yl]methylsulfonylamino]ethyl]propanamide

[0292] [ka]

[0293] a) Synthesis of tert-butyl N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-(tert-butoxycarbonylamino)ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]carbamate In a 250 mL round-bottom flask equipped with magnetic stirring, N-Boc-ethylenediamine (2.24 g, 14.01 mmol) and TEA (2.7 mL, 20.01 mmol) were added to THF (60 mL) as a coolant. The solution was cooled to +5°C, and then ecamsulsulfonyl chloride (4 g, 6.67 mmol) was slowly added. The reaction mixture was stirred at RT for 2 hours and then diluted with water (150 mL). The precipitate was filtered and washed with water to obtain 5.47 g of tert-butyl N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-(tert-butoxycarbonylamino)ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]carbamate as a pale yellow solid (yield = 97%). LCMS-ESI:[M+H] + =747(-Boc)

[0294] b) N-(2-aminoethyl)-1-[(3Z)-3-[[4-[(Z)-[4-(2-aminoethylsulfamoylmethyl)-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonamide, bistrifluoroacetate In a 250 mL round-bottom flask equipped with magnetic stirring, 5.46 g (6.45 mmol) of previously prepared tert-butyl carbamate in 20 mL of DCM was added. 19.7 mL (257.82 mmol) of TFA was then added. The reaction mixture was stirred at RT for 1 hour and concentrated under reduced pressure to obtain 9.5 g of a pale yellow solid. The solid was diluted with 30 mL of EtOH and 10 mL of water, and concentrated under reduced pressure to obtain 5.67 g of the desired compound as a yellow solid (yield = 100%). LCMS-ESI:[M+H] + =647

[0295] c)3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornan-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornan-1-yl]methylsulfonylamino]ethyl]propanamide In a 250 mL round-bottom flask equipped with magnetic stirring, the previous TFA salt (3.5 g, 4 mmol) and 3-(maleimide)propionic acid N-hydroxysuccinimide (2.13 g, 8 mmol) in THF (50 mL) were added. Then DIPEA (2.09 mL, 12 mmol) was added, and the reaction mixture was stirred at RT for 2 hours. The reaction mixture was poured into water (150 mL) and extracted with DCM. The organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow solid (4.2 g). The solid was purified by flash chromatography on a 40g SiO2 column eluted with a gradient from 100% DCM to DCM / MeOH 9 / 1 to obtain 1.26g of 3-(2,5-dioxopyrrole-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethylsulfamoylmethyl]-7,7-dimethyl-3-oxo-norbornane-2-ylidene]methyl]phenyl]methylene]-7,7-dimethyl-2-oxo-norbornane-1-yl]methylsulfonylamino]ethyl]propanamide as a white solid (yield = 33%). LCMS-ESI: [M+H] + = 949.8 11H NMR 400 MHz, DMSO-d6, δ (ppm): 0.76 (s, 6H), 1.08 (s, 6H), 1.59 (dd, 4H), 2.24 (sl, 2H), 2.34 (t, 4H), 3.03 - 3.13 (m, 12H), 3.41 (d, 2H), 3.61 (t, 4H), 7.01 (s, 4H), 7.14 (sl, 2H), 7.19 (s, 2H), 7.64 (s, 4H), 8.07 (s, 2H).

[0296] λ of ecamustine in ethanol / H2O / DMSO 5 / 3 / 2 max UV absorbance was measured at 341 nm and λ of Compound #20 max UV absorbance was measured at 344 nm.

[0297] Compound #21. 3-(2,5-Dioxopyrrol-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-Dioxopyrrol-1-yl)propanoylamino]propoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]propyl]propanamide

[0298] [Chemical Structure]

[0299] a) N-[3-[3-Hydroxy-4-[4-[2-hydroxy-4-[3-(tert-butoxycarbonylamino)propoxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]phenoxy]propyl]tert-butoxycarbamate In a 50 mL round-bottom flask equipped with magnetic stirring, 4-[4-(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]benzene-1,3-diol (300 mg, 0.74 mmol) and potassium carbonate (206 mg, 1.49 mmol), prepared according to ES 2 730 924, were added to N,N-dimethylformamide (3 mL). 3-(Boc-amino)propyl bromide (370 mg, 1.56 mmol) was added. The reaction mixture was stirred at 50°C for 6 hours. Another 3-(Boc-amino)propyl bromide (176 mg, 0.74 mmol) was added, and the reaction mixture was stirred at 80°C for 9 hours. After cooling, water (20 mL) was added under stirring, the resulting solid was filtered, washed with water, and dried under reduced pressure to obtain 454 mg of an off-white solid. The solid was dissolved in 3 ml of warm DMF, and 3 ml of ACN was added. After cooling and stirring for 30 minutes, the solid was filtered and washed with ACN to obtain 340 mg of the desired compound as an off-white solid (yield = 64%).

[0300] b) 5-(3-aminopropoxy)-2-[4-[4-(3-aminopropoxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]phenol, bishydrochloride In a 15 mL reactor equipped with magnetic stirring, N-[3-[3-hydroxy-4-[4-[2-hydroxy-4-[3-(tert-butoxycarbonylamino)propoxy]phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]phenoxy]propyl]carbamate (273 mg, 0.38 mmol) was added to dioxane (5 mL). HCl 6N (317 μL, 1.90 mmol) was added, and the reaction mixture was stirred at 50 °C for 1 hour, followed by RT for 18 hours. The reaction mixture was concentrated under reduced pressure to obtain 200 mg of 5-(3-aminopropoxy)-2-[4-[4-(3-aminopropoxy)-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]phenol as an off-white solid (quantitative yield). LCMS-ESI:[M+H] + = 518

[0301] c)3-(2,5-dioxopyrrole-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]propoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxyphenoxy]propyl]propanamide In a 15 mL reactor equipped with magnetic stirring, 5-(3-aminopropoxy)-2-[4-[4-(3-aminopropoxy)-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]phenol (197 mg, 0.38 mmol) and diisopropylethylamine (133 μL, 0.76 mmol) were added to dioxane (3 mL). (2,5-dioxopyrrolidine-1-yl)3-(2,5-dioxopyrrole-1-yl)propanoate (233 mg, 0.88 mmol) was added. The reaction was stirred at RT for 3 hours. The mixture was poured into water (20 mL), the solid was filtered, and washed with water to obtain 200 mg of an off-white solid. The solid was crystallized in AcOH (1 mL), filtered, and then successively washed with AcOH and ACN to obtain 100 mg of 3-(2,5-dioxopyrrole-1-yl)-N-[3-[4-[4-[4-[3-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]propoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxyphenoxy]propyl]propanamide as a brown solid (yield = 32%). LCMS-ESI: [M+H] + =820.3 1H NMR (400 Mhz, DMSOd6, δ (ppm): 1.91 (4H, sl), 2.34 (4H, sl), 3.18 (4H, sl), 3.62 (4H, sl), 3.90 (3H, s), 4.04 (4H, sl), 6.52 (2H, d), 6.65 (2H, sl), 7.01 (4H,s), 7.21 (2H, sl), 8.08 (2H, d), 8.34 (4H, sl), 13.19 (2H, sl)

[0302] Bemotoridinol λ in Ethanol / Benzyl Alcohol / DMSO / Phenoxyethanol 63 / 18 / 10 / 9 max The UV absorbance of compound #21 was measured at 342 nm, and the λ max UV absorbance was measured at 342 nm.

[0303] Compound #22. 3-(2,5-dioxopyrrole-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide

[0304] [ka]

[0305] a) tert-butyl N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-ethoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate In a 50 mL round-bottom flask equipped with magnetic stirring, 4-[4-(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]benzene-1,3-diol (590 mg, 1.46 mmol) and K2C03 (404 mg, 2.93 mmol) were added to N,N-dimethylformamide (3 ml). Tert-butyl(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethyl)carbamate (998 mg, 2.93 mmol) was added. The reaction mixture was stirred at 50°C for 18 hours. Water (20 mL) was added, and the organic layer was extracted with AcOEt, washed with water and brine, and dehydrated with MgSO4. The mixture was filtered, and the solvent was concentrated under reduced pressure. The crude oily substance was purified by chromatography on an SiO2 column, specifically by elution of DCM / MeOH(93 / 7) from 100% by DCM, yielding 1.58 g of the desired product as a yellow oily substance (yield = quantitative).

[0306] b) 5-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-2-[4-[4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]phenol, bishydrochloride In a 100 mL round-bottom flask equipped with magnetic stirring, tert-butyl N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-ethoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.40 g, 1.46 mmol) was placed in dioxane (5 mL). 6N HCl (1.22 mL, 7.31 mmol) was added and the reaction mixture was stirred at 60 °C for 1 hour and then at RT for 18 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was solubilized in MeOH and triturated with Na2SO4, bentonite and charcoal. After stirring for 30 minutes, the solution was filtered through a pad of celite and concentrated under reduced pressure to give 0.80 g of 5-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-2-[4-[4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]phenol, bis hydrochloride as a yellow solid (yield = 72%). LCMS-ESI: [M+H] + : 754

[0307] c) 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide In a 15 mL reactor equipped with magnetic stirring, the previous compound (0.80 g, 1.06 mmol) and DIPEA (0.37 mL, 2.12 mmol) were added to dioxane (6 mL). (2,5-Dioxopyrrolidine-1-yl)3-(2,5-Dioxopyrrole-1-yl)propanoate (0.65 g, 2.43 mmol) was added. The mixture was stirred at RT for 3 hours. The solution was poured into water (100 mL) and extracted with AcOEt. The organic layer was washed with water and brine, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude oil was purified by chromatography on an SiO2 column with elution gradient from 100% heptane to 100% acetone to obtain 0.28 g of 3-(2,5-dioxopyrrole-1-yl)-N-[2-[2-[2-[2-[4-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrole-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxyphenyl]-6-(4-methoxyphenyl)-1,3,5-triazine-2-yl]-3-hydroxyphenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide as a yellow oil (yield = 25%). LCMS-ESI:[M+H] + :1056.4

[0308] Compound #23. 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate (OOM)

[0309] [ka]

[0310] a) 2-Cyano-3,3-diphenyl-propa-2-enoic acid In a 250 mL round-bottom flask equipped with magnetic stirring, octocrylene (10.48 g, 28.99 mmol) was solubilized in THF (75 mL). Then, a solution of 1 N sodium hydroxide (31.89 mL, 31.89 mmol) was added at 5°C. The reaction mixture was stirred at RT for 18 hours, and then acidified with 1 N HCl (31.89 mL, 31.89 mmol). The THF was evaporated under reduced pressure, and the crude product was stirred with a mixture of water (400 mL) and heptane (150 mL) and filtered. The solid was washed again with water and heptane to obtain 6.26 g of 2-cyano-3,3-diphenyl-propa-2-enoic acid as a white solid (yield = 87%). LCMS-ESI:[M+H] + =250

[0311] b) 3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-N-(8-hydroxyoctyl)propanamide In a 16 L glass reactor, amino-octanol (476.430 g, 3.280 mol, 1.053 eq) was dissolved in 17.5 vol DCM (8000.0 mL) to obtain a troublesome solution. N-succimidyl 3-maleimide propionate (919.130 g, 3.453 mol, 1.053 eq) was added to this solution and rinsed with 2.5 vol DCM (1000 mL). The temperature was raised to 25°C at the end of the addition. After the temperature was reduced to RT, DIPEA (687.0 mL, 3.944 mol, 1.202 eq) was slowly added (over 10 minutes). At the end of the addition, T=27.8°C and the mixture was a suspension. The suspension was concentrated under vacuum to a residual volume of 3 L (6 vol), siRNA (5000.0 mL) was added, and the mixture was stirred overnight in RT. The mixture was filtered under vacuum through a 25 μm filter to obtain a white powder. The product was washed with siRNA (1000.0 mL) and then dried under nitrogen in RT for 2 hours and at 50°C for 18 hours. The solid was manually ground and stirred in a reactor in the presence of siRNA (9000.0 mL) at 24°C for 2 hours, then the solid was filtered and dried under nitrogen for 1 hour and at 45°C under vacuum for 18 hours to obtain the desired product (705.970 g, 2.382 mol, 73%) as a white powder.

[0312] c) 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate In a 16 L glass reactor, the previous product (650.637 g, 2.195 mol, 1.000 eq) was added, followed by DCM (8000.0 mL), and the suspension was stirred at RT. To this suspension, 2-cyano-3,3-diphenylacrylic acid (547.310 g, 2.196 mol, 1.000 eq) was added and rinsed with DCM (500.0 mL). Methylimidazole (0.525 L, 6.582 mol, 2.998 eq) was added and rinsed with DCM (500.0 mL) (T=24.2°C). After 10 minutes, DMC (445.180 g, 2.633 mol, 1.200 eq) was added and rinsed with DCM (1000.0 mL). The mixture became an orange-brown solution (T=37.5°C). HCl 0.5N (13.0 L, 6.500 mol, 2.961 eq) was added and the mixture was stirred for 20 minutes (T max = 26.8°C). DCM was evaporated under reduced pressure, then HCl (16000.0 mL) was added, and the mixture was stirred at 30°C for 30 minutes (solubilization occurred). Stirring was stopped, and the phase was allowed to settle for 45 minutes. Three layers were observed: the aqueous layer and the oily intermediate layer were discarded. The organic phase was washed with NaHCO3 (565.000 g, 6.726 mol, 3.067 eq) dissolved in 6.5 L of water (pH approximately 9-10), then washed with 7 × 6.5 L of water (pH approximately 6-7), and concentrated to dryness under reduced pressure to obtain 1053 g of oily substance. The crude product was dissolved in DCM (600.0 mL) and then filtered through a silica gel pad (eluent: heptane / siRNA, 50 / 50 to 20 / 80) to obtain an oily substance. This oily substance was diluted with 800 mL of acetone, concentrated to dryness (this process was repeated four times), and then dried under high vacuum for 6 hours to obtain the desired product (763.000 g, 1.446 mol, 66%) as a pale yellow oil. LCMS-ESI: [M+H] + : 528 1H NMR (400 MHz, DMSO) δ 7.89 (t, 1H), 7.50 (m, 4H), 7.41 (m, 4H), 7.17 (m, 2H), 7.00 (s, 2H), 4.01 (t, J = 6.4 Hz, 2H), 3.60 (t, J = 6.7 Hz, 2H), 2.98 (q, J = 5.5 Hz, 2H), 2.32 (t, J = 6.6 Hz, 2H), 1.34 (m, 4H), 1.17 (m, 6H), 1.04 (m, 2H).

[0313] λ of octocrylene in ethanol max The UV absorbance of compound #23 was measured at 304 nm, and the λ max UV absorbance was measured at 304 nm.

[0314] (Example 2) Bioadhesion test of the compound of formula (I) Adhesion in the liquid phase The bioadhesion of the compounds was performed in solution for protein binding and for the specific binding of the sulfhydryl-reactive chemical group of cysteine. The compounds were mixed with an equimolar solution of cysteine ​​(2 molar equivalents of cysteine ​​for a compound containing two maleimides) or an excess of cysteine ​​solution (5 or 10 times the molar concentration of the compound) and incubated for 1 to 2 minutes in ethanol-1 × PBS, pH 6.8 solution, and for compound #23, in ethanol-1 × PBS, pH 6.0 solution.

[0315] Compounds and compounds bound to cysteine ​​were identified by LC-MSD (Agilent 1260 Infinity II with Uptisphere strategy C18 or SunFire C18 column) and assayed by HPLC using an Agilent Infinity II Prime UHPLC UV detector system. Separation was achieved using a water-acetonitrile gradient phase on an Agilent Poroshell 120 EC-C18 column (3 × 100 mm, 2.7 μM).

[0316] The results of bioadhesion tests for compounds #16 to #20 and #23 obtained with an equimolar cysteine ​​solution (a 2-molar equivalent solution of cysteine ​​for a compound containing two maleimides) are shown in Table 1 below.

[0317] [Table 1]

[0318] The results in Table 1 show that 71% to 100% of the compounds of the present invention bind to cysteine ​​in the presence of an equimolar solution of cysteine ​​(2 molar equivalents of cysteine ​​per compound #20). These results demonstrate that efficient bioadhesion was achieved with the compounds of the present invention.

[0319] The results of bioadhesion tests for compounds #16, #18, #20, and #23 obtained using excess cysteine ​​in solution are shown in Table 2 below.

[0320] [Table 2]

[0321] The results in Table 2 show that, in the presence of excess cysteine, 92% to 100% of the compounds of the present invention bind to cysteine. These results also demonstrate that efficient bioadhesion was achieved with the compounds of the present invention.

[0322] Adhesion to thiolated polylysine matrix Polylysine and polylysine enriched with SH by thiolation of primary amines using Trout's reagent were used to coat 96-well microplates. Compound #23 (OOM) was incubated overnight under orbital agitation in ethanol / PBS (90% / 10%) solution in different matrices (n=3 for each condition) (uncoated wells were used as negative controls). After incubation, each microplate well was thoroughly washed 10 times with ethanol, and then UV absorbance was measured. The entire UV / Vis absorbance spectrum from 220 to 1000 nm was measured at the center of each microplate well. In addition, specific UV absorbance at 300 nm was measured as a 10×10 matrix by matrix scanning across the entire well.

[0323] At 300 nm, compound #23 (OOM) showed bioadhesion to a thiolated polylysine matrix, while octocrylene did not. Furthermore, bioadhesion of OOM to a non-thiolated polylysine matrix was not observed. These results indicate bioadhesion of compound #23 (OOM).

[0324] UV protection performance UVB protection was evaluated ex vivo in pig skin by measuring autofluorescence quenching. OOM (compound #23) and OCR (octocrylene) were solubilized in dotisol (isosorbide dimethyl ether) at the same molar concentration, and then incubated at 6.25 cm³. 2 Skin squares were covered and incubated at 37°C for 4 hours, then washed with 10 mL of ethanol for 5 minutes with stirring, or left unwashed. Next, 7 mm diameter skin punches were cut out and placed in a black 96-well plate. UVB protection was measured after excitation at 300 nm and fluorescence emission read at 460 nm, respectively. The results are shown in Table 3 below.

[0325] [Table 3]

[0326] The results show that the UVB protection obtained in pig skin with compound #23 (OOM) is more than twice as high as the UVB protection provided by octocrylene (OCR).

[0327] After ethanol washing, the UVB protection of porcine skin obtained with the OOM solution was reduced to 30% compared to the initial protection before washing. The same protocol was applied to octocrylene, a non-bioadhesive control of OOM, and after the ethanol washing step, the UVB protection was equivalent to that of the unprotected control. Such results indicate that OOM is bioadhesive, while octocrylene is not.

Claims

1. The compound is 8-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)propanamide)octyl 2-cyano-3,3-diphenylacrylate.

2. A composition comprising at least one compound according to claim 1 and at least one excipient.

3. The composition according to claim 2, which is a sunscreen composition or a cosmetic composition.

4. Aesthetic use of the composition according to claim 2 for counteracting and / or reducing signs of skin aging, the formation of wrinkles and / or fine lines, skin sagging, loss of firmness, loss of radiance and / or unevenness of complexion, and / or for reinforcing the skin barrier.

5. - The composition according to claim 2, - Cleaning compositions, and - Optional instruction guide A kit that includes this.

6. The composition according to claim 2, which is a pharmaceutical or veterinary composition.

7. The composition according to claim 6, for use in the treatment of diseases or conditions of the skin, mucous membranes, cornea of ​​the eye, or skin appendages.

8. The composition for use according to claim 7, wherein the disease or condition of the skin, mucous membrane, cornea of ​​the eye, or skin appendage is selected from lipodystrophy, keloid scarring, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melanoma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria, herpes simplex, impetigo, eczema, rash, dermatitis, ichthyosis, warts, blisters, itching, gangrene, contusions, pustules; bacterial skin infections such as leprosy, carbuncles, cellulitis, and impetigo; fungal infections such as athlete's foot (intertrigo) and sporotrichosis; fungal nail infections; viral infections such as herpes; sunburn, lice, scabies, pressure ulcer disinfection, and pressure ulcer healing.

9. A topical composition according to any one of claims 2, 3, and 6, preferably in the form of a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilized product, emulsion, powder, paste, wax, mousse, patch, film, micelle, liposome, or foam.

10. Use of at least one compound according to claim 1 for reducing photodegradation and / or photoinstability of pharmaceutically active ingredients or cosmetics.

11. A material comprising a support and at least one compound according to claim 1, wherein the compound is adhered to the support, and the support is preferably a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, metal, plastic, rubber, or glass support.

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