Adhesive photoprotective compounds and uses thereof

Abstract

To provide photoprotective compounds comprising a photoprotective moiety and a functional group, both being linked to each other through a linker.SOLUTION: The present invention relates to a compound represented by the following formula (I): A[B-(C)v]w (I), where A is a photoprotective moiety, B is a linker, C is a functional group, v is an integer from 1 to 2000, and w is an integer from 1 to 6. The present invention also relates to a composition comprising the same and, more specifically, to a cosmetic or a sunscreen composition. The present invention also relates to the use of such compounds in cosmetic and therapeutic applications. The invention also relates to the use of such compounds for reducing photodegradation and / or photoinstability of pharmaceuticals and cosmetics. The invention further relates to a material comprising a support and such a compound adhered to the support.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to photoprotective compounds having adhesive properties. The present invention also relates to compositions containing same, more particularly 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 the photodegradation and / or photoinstability of pharmaceuticals and cosmetics. The present invention further relates to a material comprising a support and such a compound attached to the support. [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- and 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 radiation spectrum has become a major concern and challenge. Many sunscreens are currently available on the market. Despite their apparent efficacy, the active agents in these sunscreens have been demonstrated to be able to penetrate epidermal cells via the skin and have even been detected in urine and breast milk. Small, non-adhesive nanoparticles have been developed for sunscreen compositions and are now commercially available. However, such materials have also been demonstrated to be skin-penetrating. Bioadhesive particles are also designed to adhere to the skin and encapsulate the active agent, so that neither the particle nor the active agent penetrates the skin. However, such bioadhesive particles are prepared by complex and expensive manufacturing processes. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] US8,106,108 [Patent Document 2] ES2730924 Summary of the Invention [Problem to be solved by the invention]

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

[0005] In this context, the inventors have developed photoprotective compounds comprising a photoprotective moiety and a functional group, both of which are linked to each other via a linker. The functional group allows the photoprotective compound to be adhesive, more particularly bioadhesive. The photoprotective compound can interact with any substrate, such as biological, organic, and / or inorganic substrates, via its functional group, making it particularly effective in the field of photoprotection. In particular, the compounds according to the present invention can be used in cosmetic or therapeutic applications, such as treating or preventing diseases or conditions of the skin and mucous membranes, or reducing the photodegradation and / or photoinstability of active pharmaceutical ingredients or cosmetics.

[0006] Thus, the present invention provides a compound represented by the following formula (I): A[B-(C) v ] w (I) [In the formula, A is a photoprotective moiety; 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. Regarding.

[0007] In certain embodiments, photoprotective moiety A is derived from a UV filter and / or SPF booster. Preferably, photoprotective moiety A is selected from the group consisting of bemotrizinol, diethylaminohydroxybenzoylhexyl benzoate, bisdisulizole disodium, melazimate, terephthalylidene dicamphorsulfonic acid, bisoctrizol, oxybenzone, sulisobenzone, iscotrizinol, octinoxate, octisalate, octyltriazone, padimate O, homosalate, amiloxate, octocrylene, PEG-25 PABA, ensulizole, trolamine salicylate, cinoxate, benzofurafine, benzotriazol, benzotriazol-1, benzotriazol-2, benzotriazol-3, benzotriazol-4, benzotriazol-5, benzotriazol-6, benzotriazol-7, benzotriazol-8, benzotriazol-9, benzotriazol-10, benzotriazol-11, benzotriazol-12, benzotriazol-13, benzotriazol-14, benzotriazol-15, benzotriazol-16, benzotriazol-17, benzotriazol-18, benzotriazol-19, benzotriazol-20, benzotriazol-21, benzotriazol-22, benzotriazol-23, benzotriazol-24, benzotriazol-25, benzotriazol-26, benzotriazol-27, benzotriazol-28, benzotriazol-29, benzotriazol-30, benzotriazol-31, benzotriazol-32, benzotriazol-33, benzotriazol-34, benzotriazol-35, benzotriazol-36, Derived from benzophenone-9, dioxybenzone, avobenzone, enzacamene, diethylhexyl naphthalate, diethylhexyl syringylidene, tetramethylhydroxypiperidinol, sodium benzotriazolyl butylphenol sulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylate copolymer, butyloctyl salicylate, bis(butylcyanoacetate)anthracenediylidene, dimethylcapramide or ethylhexylmethoxycrylene. More preferably, photoprotective moiety A is derived from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid, sulisobenzone, octisalate, octocrylene, ensulizole, avobenzone, polyester-8, bisdisulizole disodium, melazimate, oxybenzone-3, iscotridinol, octanoate, octyl triazone, padimate O, cinoxate, benzophenone-9, or dioxybenzone. Even more preferably, photoprotective moiety A is derived from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid, or octocrylene.

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

[0009] In another particular embodiment, the linker B has the following formula (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, when Y is -O-, 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 may form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl; p is 0, Z is selected from a single bond, -NH-, -O-, -NH-C(O)-, -S- and -S(O)2-; ⇒s is an integer between 0 and 6, ⇒k is an integer from 1 to 4, preferably from 1 to 2. is expressed by

[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, the functional group C is selected from aldehyde, acetal, thiocetal, thiol, maleimide, Michael acceptor, vinyl sulfone, disulfanyl pyridine, sulfonyl aziridine, epoxide, haloacetyl, isocyanate, isothiocyanate, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, hydroxy, amino, ammonium, guanidinium, imidocarbonate, carboxylic acid, carboxylic acid ester, anhydride, sulfonic acid, folic acid, biotin, streptavidin, avidin, antibody and single chain antibody or fragment thereof, and derivative thereof. Preferably, the functional group C is selected from thiol, acetal, maleimide, vinyl sulfone, disulfanyl pyridine, guanidinium, folic acid, biotin, and derivative thereof, and more preferably, C is maleimide or a derivative thereof.

[0012] In certain embodiments, moiety B-(C) v is the following formula:

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

[0014] [wherein, in each formula, n is independently an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12; t is independently an integer from 0 to 30, preferably from 0 to 12. is represented by one of the following:

[0015] In certain embodiments, the compounds according to the invention are - 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-maleimido-1-hexanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyldisulfanyl)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)butan]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-maleimido-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)-piperidin-4-ylsulfonyl]acetic acid; - N-[(2-hydroxybenzoyl)-piperidin-4-ylsulfonyl]acetic acid; - (3-(2H-benzo[d][1,2,3]triazol-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidin-4-ylsulfonyl)acetic acid]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester; - 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester; - 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide; - 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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-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]propenamide; and - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide is selected from the group consisting of:

[0016] The present invention also relates to a composition 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 certain embodiments, the composition is a pharmaceutical or veterinary composition.

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

[0018] Another object of the present invention is a cosmetic process for combating and / or reducing the signs of skin ageing such as the formation of wrinkles and / or fine lines, sagging skin, loss of skin elasticity, loss of radiance and / or evenness of complexion, and / or for reinforcing the skin barrier, comprising the step of topically applying to the skin a composition as defined herein.

[0019] Another object of the present invention is to provide a composition as defined herein, a cleaning composition, preferably a powder, shampoo, soap, lotion, solution, solid, scrub, scraper, mousse, foam, synthetic detergent, gel, shower gel, spray, mist, wax, strips, enzyme composition, detergent composition or textile or nonwoven fabric, - possibly instruction guides, The kit includes:

[0020] The present invention also relates to a composition as defined herein for use in treating and / or preventing a disease or condition of the skin, mucous membranes, the cornea of ​​the eye or a skin appendage. Preferably, the disease or condition of the skin, mucous membranes, cornea of ​​the eye or skin appendages is selected from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, Merker cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, leprosy, pimples, cellulitis, bacterial skin infections such as impetigo, fungal infections such as athlete's foot (intertrigo) and sporotrichosis, fungal nail infections, viral infections such as herpes, sunburn, lice, scabies, pressure sore disinfection and pressure sore healing.

[0021] In particular embodiments, the composition as defined herein or the composition for use as defined herein is a topical composition. In more particular embodiments, the composition as defined herein or the composition for use as defined herein is in the form of a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilisate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam.

[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 an active pharmaceutical ingredient or a cosmetic product, wherein in this particular application, said at least one compound is in the form of a micelle or liposome.

[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 attached to said support, preferably said support being a natural or synthetic polymeric support, a natural or synthetic fiber support, a stone, metal, plastic, rubber or glass support. DETAILED DESCRIPTION OF THE INVENTION

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

[0025] The compounds of the present invention typically have the following formula (I): A[B-(C) v ] w (I) [In the formula, A is a photoprotective moiety; 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. is expressed by

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

[0027] As used herein, w is linked to a photoprotective moiety A [B-(C) v

[0023] groups. In accordance with the present invention, w is an integer from 1 to 6. In other words, photoprotective moiety A is linked to 1 to 6 linkers B. For example, if w is 3, photoprotective moiety A is linked 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, when v is 2, linker B contains two 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] Photoprotective moiety A and linker B may be covalently and / or non-covalently, e.g., ionically, linked (or "bound") to one another. Preferably, photoprotective moiety A and linker B are covalently linked to one another.

[0031] Linker B and functional group C may be covalently and / or non-covalently, e.g., ionically, linked (or "bonded") to one another. Preferably, linker B and functional group C are covalently linked to one another.

[0032] Light protection part A According to the present invention, the compound of formula (I) comprises a photoprotective moiety A. As used herein, "photoprotective moiety" refers to a photoprotector that has been deprived of one or more atoms or atomic groups, where the photoprotective activity of the photoprotective moiety is substantially similar to that of the photoprotector from which it is derived. Photoprotective agents are typically organic substances that can block or absorb all or part of light, particularly light that can damage the object or material to be protected, such as ultraviolet ("UV") light. Photoprotective agents are typically UV filters and / or SPF boosters.

[0033] In certain embodiments, photoprotective moiety A is derived from a UV filter and / or an SPF booster.

[0034] In particular, 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, bemotrizinol, diethylaminohydroxybenzoylhexylbenzoate (DHHB), bisdisulizole disodium, melazimate, or ecamsule.

[0036] Examples of UVA II / UVB filters include, but are not limited to, oxybenzone, sulisobenzone, iscotridinol, octinoxate, octisalate, octyltriazone, padimate O, homosalate, amiloxate, 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 particular, 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 benzotriazolylbutylphenolsulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylate copolymer, butyloctyl salicylate, bis(cyano butylacetate)anthracenediylidene, dimethylcapramide, or ethylhexylmethoxycrylene.

[0041] In certain embodiments, photoprotective moiety A is bemotrizinol, diethylaminohydroxybenzoyl hexyl benzoate (Uvinul® A Plus), bisdisulizole disodium, melazimate, terephthalylidene dicamphorsulfonic acid (also known as ecamsule), bisoctrizole, oxybenzone, sulisobenzone, iscotridinol, octinoxate, octisalate, octyltriazone, padimate O, homosalate, amiloxate, octocrylene, PEG-25 PABA, ensulizole, trolamine salicylate, cinoxate, benzophenone-9, dioxybenzone, avobenzone, enzacamene, diethylhexyl naphthalate, diethylhexyl syringylidene, tetramethylhydroxypiperidinol, sodium benzotriazolyl butylphenolsulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylates copolymer, butyloctyl salicylate, bis(butylcyanoacetate)anthracenediylidene, dimethylcapramide, or ethylhexylmethoxycrylene.

[0042] In preferred embodiments, the photoprotective moiety A is derived from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid, sulisobenzone, octisalate, octocrylene, ensulizole, avobenzone, polyester-8, bisdisulizole disodium, melazimate, oxybenzone-3, iscotridinol, octanoate, octyltriazone, padimate O, cinoxate, benzophenone-9, or dioxybenzone.

[0043] In more preferred embodiments, the photoprotective moiety is derived from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid, or octocrylene.

[0044] In an even more preferred embodiment, the photoprotective moiety A is derived from terephthalylidene dicamphorsulfonic acid or diethylaminohydroxybenzoylhexylbenzoate.

[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 U.S. Pat. No. 8,106,108. In another specific embodiment, 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 capable of reacting with or binding to any material, any tissue, cell, any substrate of intracellular or extracellular matter, making the compound of formula (I) adhesive or bioadhesive.

[0047] In certain embodiments, the functional group C is selected from aldehyde, acetal, thioacetal, thiol, maleimide, Michael acceptor, vinyl sulfone, disulfanylpyridine, sulfonylaziridine, epoxide, haloacetyl, isocyanate, isothiocyanate, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, hydroxy, amino, ammonium, guanidinium, imidocarbonate, carboxylic acid, carboxylic acid ester, anhydride, sulfonic acid, folic acid, biotin, streptavidin, avidin, antibody, and single chain antibody or fragment thereof. In more particular embodiments, C further comprises any derivative of such functional groups as detailed above.

[0048] For example, the term "maleimide" (Mal) refers to the maleimide group and any derivatives thereof. In particular, maleimide (Mal) comprises two groups of the formulae (Mal 1) and (Mal 2):

[0049] [ka]

[0050] As used in the formulas disclosed in this application, the symbol "- - - - -" in the formula represents the bond by which a moiety of said formula is attached to the rest of the molecule. For example, the symbol shown above in (Mal 1) or (Mal 2) represents the bond by which said moiety is attached to linker B.

[0051] In a preferred embodiment, the functional group C is selected from thiol, acetal, maleimide, vinyl sulfone, disulfanylpyridine, guanidinium, folic acid, biotin and derivatives thereof.

[0052] In a preferred embodiment, C is maleimide (also referred to as "Mal") or a derivative of maleimide as disclosed above. More preferably, C is Mal 1 or Mal 2.

[0053] In further particular embodiments, C represents a unique functional group.

[0054] As used herein, an "inherent functional group" of a polymer is a functional group that is inherently present in the structure of the polymer and therefore has not been converted to another functional group. For example, a hydroxyl group is an inherent functional group of cellulose, and a carboxylic acid (or carboxylate) is an inherent functional group of polymethacrylic acid.

[0055] In a further particular embodiment, C represents a modifying functional group.

[0056] As used herein, a "modified functional group" of a polymer is a functional group resulting from the conversion of an inherent functional group, as defined herein, to another functional group, for example, an aldehyde group resulting from the oxidation of a hydroxy group of cellulose or biotin linked to a hydroxy group of cellulose.

[0057] Linker B According to the present invention, the compounds of formula (I) comprise at least one linker B(w).

[0058] "Linker" refers to any organic chain having at least one carbon that connects a photoprotective moiety with at least one functional group. Linker B can be linear, branched, hyperbranched, or dendritic. B may or may not be polymeric.

[0059] In certain embodiments, linker B is biodegradable.

[0060] The term "biodegradable linker (or compound)" refers to a linker (or compound) that will degrade or erode under physical, chemical, and / or biological conditions into smaller units or chemical species that can be metabolized, excreted, or excreted by a subject. The degradation time and rate is a function of composition and / or morphology. Degradation times can range from a few hours to a few weeks.

[0061] In certain embodiments, linker B is a linear polymer, a branched polymer, a hyperbranched polymer, a dendrimer (or "dendritic polymer"), or a residue thereof.

[0062] As used herein, the term "linear polymer" refers to a polymer that does not have any branches. The term "branched polymer" refers to a polymer having linear chains substituted with primary branches and optionally secondary branches. The term "hyperbranched polymer" refers to a polymer having randomly arranged primary and secondary branches. The term "dendrimer" (also called "dendritic polymer" or "dendronized polymer") refers to a repeatedly branched polymer having a symmetrical, organized tree structure, in which the branches originate from a common branch point. The term "residue of a polymer" refers to a polymer that has been deprived of one or more of its functional groups (such as -NH, -COOH, -OH, etc.) or atoms (such as H or -OH).

[0063] The linear, branched, hyperbranched or dendritic polymers may be homopolymers or copolymers. The linear, branched, hyperbranched or dendritic polymers may be natural, semi-synthetic, semi-synthetic or synthetic.

[0064] The term "homopolymer" generally refers to a polymer made up of identical monomers.

[0065] The term "copolymer" generally refers to a polymer composed of two or more different monomers. Copolymers can be of any configuration, such as random, block, or graft. Copolymers can have any end groups.

[0066] Examples of semi-synthetic, semi-synthetic or synthetic polymers include poly(hydroxy acids), such as poly(lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, polyamides, polycarbonates, polyglycerol, polyalkylenes, such as polyethylene and polypropylene, polyalkylene glycols, such as poly(ethylene glycol), polyalkylene oxides, such as poly(ethylene oxide), ), polyalkylene terephthalates, such as poly(ethylene terephthalate), polyvinyl alcohol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, such as poly(vinyl chloride), polyvinylpyrrolidone, polysiloxane, poly(vinyl alcohol), poly(vinyl acetate), polystyrene, polyurethanes and copolymers thereof, derivatized celluloses, such as alkyl cellulose, hydroxyalkyl cellulose, cellulose ethers, cellulose esters, nitrocellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, carboxyethyl cellulose, cellulose triacetate, and sodium cellulose sulfate (collectively referred to herein as "synthetic celluloses"), polymers of acrylic acid, methacrylic acid, or derivatives thereof, including copolymers or esters thereof, acrylates and ammonium methacrylates. copolymers of acrylic acid, 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);Including, but not limited to, copolymers and blends thereof.

[0067] Examples of natural polymers include, but are not limited to, proteins such as albumin, collagen, gelatin, and prolamines (e.g., zein), and polysaccharides such as alginate, dextran, chitosan, cellulose derivatives, and polyhydroxyalkanoates (e.g., polyhydroxybutyrate), and microbial anatoxins.

[0068] In certain embodiments, linker B further comprises at least one -S(O)2- group. The -S(O)2- group may be located at any position of linker B. For example, the -S(O)2- group may be located at one or two ends of linker B and / or may interrupt linker B at any 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 of the compounds of the present invention may be obtained.

[0069] According to the present invention, linker B is linked to at least one functional group C(v). In certain embodiments, linker B comprises at least one residue of a polymer. In such embodiments, functional group C is linked to at least one residue of the polymer of linker B. In such embodiments, C represents one or more functional groups of at least one residue of the polymer of linker (B).

[0070] Part [B-(C) v To illustrate various embodiments of the polymer linker B, a cellulose-based moiety [B-(C) v Different representations of ] are provided below. - [B-(C) v ] can be cellulose. In this embodiment, B represents a residue of cellulose, C represents a hydroxy group (which is an inherent group of cellulose), and v is the number of hydroxy groups. - [B-(C) v] may be an 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 be biotin-modified cellulose. In this embodiment, B represents a residue of cellulose, C represents a biotin group (which is a modifying group of cellulose), and v is the number of biotin groups.

[0071] In another particular embodiment, the linker B has the following formula (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, when Y is -O-, 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 may form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl; p is 0, Z is selected from a single bond, -NH-, -O-, -NH-C(O)-, -S- and -S(O)2-; ⇒s is an integer between 0 and 6, ⇒k is an integer from 1 to 4, preferably from 1 to 2. is expressed by

[0072] In a further particular embodiment, the linker B has the following formula (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)-, 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 may form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl; p is 0, Z is selected from a single bond, -NH-, -O-, -NH-C(O)-, -S- and -S(O)2-; ⇒s is an integer between 0 and 6, ⇒k is an integer from 1 to 4, preferably from 1 to 2. is expressed by

[0073] In certain embodiments, the linker B is 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, when Y is -O-, 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 different from 0, It is of formula (II).

[0074] In a more particular embodiment, p is 0.

[0075] In a further more particular embodiment, p is an integer from 1 to 50, more preferably from 1 to 12.

[0076] In another particular embodiment, the linker B is Y-(CH2)q form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl, and p is 0; It is of formula (II).

[0077] In certain embodiments, Z is selected from a single bond, -NH-, -NH-C(O)-, and -S(O)-. 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)-, more preferably Z is -S(O)-.

[0078] In certain embodiments, s is an integer from 0 to 2, and preferably, s is 0. In another particular embodiment, s is an integer from 1 to 6.

[0079] In certain embodiments, k is 1.

[0080] In certain embodiments, the linker B is 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, when Y is -O-, q is different from 0; p is an integer from 0 to 50, preferably from 0 to 12, more preferably p is 0; p+q is different from 0, or ⇒Y-(CH2) q may form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl; p is 0, Z is selected from a single bond, -NH-, -O- and -S(O)2-; ⇒ s is 0 or 1, preferably 0; ⇒k is 1, It is of formula (II).

[0081] In a more particular embodiment, the linker B is ⇒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, It is of formula (II).

[0082] In such embodiments, functional group C is preferably a disulfanylpyridine, maleimide, vinyl sulfone, acetal, or derivative thereof, more preferably a maleimide or derivative thereof.

[0083] In a further more particular embodiment, the linker B is ⇒Y-(CH2) q form 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, It is of formula (II).

[0084] In such embodiments, the functional group C is preferably a carboxylic acid.

[0085] In certain embodiments, the linker B is ⇒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 a single bond, -NH-, -O- and -S(O)2-; ⇒s is 0, ⇒k is 1, It is of formula (II).

[0086] In such embodiments, functional group C is preferably biotin or folic acid.

[0087] In another particular embodiment, the linker B is ⇒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 or Z is selected from -NH-, -O-, -NH-C(O)-, -S- and -S(O)2-; ⇒s is an integer between 1 and 6, ⇒k is 1 or 2, It is of formula (II).

[0088] In a preferred embodiment, the linker B is ⇒Y is selected from -O- and -NH-; q is an integer from 1 to 6, preferably q is an integer from 2 to 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, It is of formula (II).

[0089] In such embodiments, functional group C is preferably maleimide (also referred to as "Mal") or a derivative of maleimide as disclosed above.

[0090] In a further particular embodiment, the linker B is of formula (II) and further comprises a -S(O)2- group. In such an embodiment, the -S(O)2- group may be located at any position of the group of formula (II). According to this particular embodiment, the 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)-, preferably -O-; q' and q" are each an integer from 0 to 35, preferably from 1 to 12, more preferably from 1 to 6; q'+q" is between 0 and 35 inclusive, However, when Y is -O-, 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-, 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 expressed by:

[0091] Examples of linkers B of formula (II') are:

[0092] [ka]

[0093] Including but not limited to:

[0094] In a preferred embodiment, the linker B has the following formula:

[0095] [ka]

[0096] is represented by one of the following:

[0097] In a preferred embodiment, the moiety [B-(C) v ]teeth, - v is 1, B has the formula:

[0098] [ka]

[0099] is selected from C is a functional group (Mal 1) of the formula as depicted above It's like this.

[0100] In another preferred embodiment, the moiety [B-(C) v ]teeth, - v is 1, B has the formula:

[0101] [ka]

[0102] is represented by C is a functional group (Mal 2) of the formula as shown above It's like this.

[0103] The compound of formula (I) according to the present invention has 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 all preferred and specific embodiments. It can be expressed by:

[0104] In certain embodiments where linker B is of formula (II), 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, functional group C is preferably at the terminus of linker B of formula (II).

[0105] In embodiments where v is greater than 1, one functional group C is preferably at the end of linker B of formula (II), and additional functional groups C may be at any position of linker B. Typically, each of said additional functional groups C may replace a respective hydrogen atom of linker B of formula (II).

[0106] In certain embodiments, the moiety [B-(C) v ] is the formula:

[0107] [ka] [ka] [ka] [ka]

[0108] [wherein, in each formula, n is independently an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12; t is independently an integer from 0 to 30, preferably from 0 to 12. is represented by one of the following:

[0109] Preferably, moiety B-(C) v is the following formula:

[0110] [ka] [ka]

[0111] [wherein, in each formula, n is independently an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12; t is independently an integer from 0 to 30, preferably from 0 to 12. is represented by one of the following:

[0112] More preferably, moiety B-(C) v is the following formula:

[0113] [ka]

[0114] is represented by one of the following:

[0115] In certain embodiments, the compounds according to the invention are - 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-maleimido-1-hexanol ester; - 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyldisulfanyl)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)butan]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-maleimido-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)-piperidin-4-ylsulfonyl]acetic acid; - N-[(2-hydroxybenzoyl)-piperidin-4-ylsulfonyl]acetic acid; - (3-(2H-benzo[d][1,2,3]triazol-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidin-4-ylsulfonyl)acetic acid]amide; - 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester; - 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester; - 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide; - 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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-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; and - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide is selected from the group consisting of:

[0116] Preferably, the compound according to the invention is 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester, 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester, 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide, 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester, - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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-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; and - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide is selected from the group consisting of:

[0117] Properties of the compounds of formula (I) According to the present invention, the compounds of formula (I) are adhesive. More particularly, the compounds of formula (I) can be bioadhesive.

[0118] The expression "adhesive compound" denotes a compound that can be attached to any substrate via one or more functional groups (e.g., functional group C as defined herein), said substrate being biological, organic, and / or inorganic. More specifically, said compound is attached via one or more of its functional groups (e.g., functional group C as defined herein) that can react with reactive groups or entities of said substrate.

[0119] "Bioadhesive compound" refers to an adhesive compound as defined above, where the substrate is biological. Examples of biological substrates include, but are not limited to, tissues (e.g., skin), cells (e.g., chondrocytes, osteoblasts, fibroblasts, blood cells, plasma cells), intracellular or extracellular substances (e.g., proteins, glycoproteins, collagen, elastin, glycosaminoglycans, proteoglycans).

[0120] Reactive groups found on the support, and more particularly on the biological support, include, but are not limited to, amine, ammonium, guanidinium, thiol, carboxylic acid, and carboxylate.

[0121] The functional group C can advantageously react selectively with specific reactive groups found on the support. for example, maleimides, thiols, Michael acceptors, sulfonylazeridines, vinyl sulfones, isocyanates or thiocyanates can typically be selective towards 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, - the amine can typically be selective for the carboxylic acid; and - Ammonium and guanidinium can typically be selective for carboxylates.

[0122] The reaction of functional group C of the compound of formula (I) with a reactive group can form an amide, disulfide, thioether, thiocarbamate, imine, or ion pair -NH + , - A bond such as OOC- is formed. The bond formed between the functional group of the compound of formula (I) and the reactive group of the support may be covalent or ionic. The bond is advantageously reversible. The bond can be cleaved by using a cleavage material selected from chemical and physical agents, such as proteins, peptides (e.g., glutathione), amino acids, enzymes (e.g., cathepsin B), thiols (e.g., 2-mercaptoethanol, N-acetylcysteine), dithiols (e.g., dithiothreitol), pH adjusters, acids, bases, solvents, and / or woven or nonwoven fabrics. Those skilled in the art will be able to select an appropriate cleavage material depending on the nature of the bond and / or composition.

[0123] In certain embodiments, the compounds of formula (I) are biocompatible.

[0124] The term "biocompatible compound" refers to a compound that, together with any metabolic or decomposition products thereof, is generally non-toxic to a recipient and does not cause any significant adverse effects in the recipient. Generally speaking, a biocompatible material (or compound) is one that does not provoke a significant inflammatory or immune response when administered to a patient.

[0125] In another particular embodiment, the compound of formula (I) is biodegradable.

[0126] 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.

[0127] In certain embodiments, the composition comprises from 0.01 wt% to 99 wt%, preferably from 0.01 wt% to 90 wt%, more preferably from 1 wt% to 70 wt%, and even more preferably from 5 wt% to 50 wt% of a compound of formula (I), relative to the total weight of the composition.

[0128] The compositions according to the invention may be in the form of, inter alia, a suspension, a cream, a spray, an aerosol, a butter, a stick, a gel, an ointment, a lotion, a solution, a solid, an emulsion, a microemulsion, an oil, a lyophilisate, a milk, a powder, a paste, a wax, a mousse, a patch, a film, a micelle, a liposome or a foam. The compositions may be prepared according to processes known to those skilled in the art.

[0129] The compositions of the present invention may contain a solvent or dispersion medium comprising, 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, etc.), and combinations thereof.

[0130] Examples of excipients include, but are not limited to, surfactants, dispersants, emulsifiers, pH modifiers, pH buffers, viscosity modifiers, preservatives, polymerizers, pigments, colorants, stabilizers, glidants, fillers, binders, water soluble polymers, lubricants, disintegrants, swelling agents, fillers, stabilizers, antioxidants, emulsifiers, emollients, penetration enhancers, propellants, gases, decolorizing agents, film-forming agents, gelling agents, humectants, colorants, fragrance ingredients, exfoliating agents, solubilizing agents, solvents, binders, bulking agents, moisturizing agents, cleansing agents, elastomers, astringents, masking agents, antistatic agents, protective agents, denaturing agents, absorbents, anticaking agents, matting agents, structuring agents, oxidizing agents, reducing agents, superfatting agents, activity boosters, and combinations thereof.

[0131] Examples of additional agents that may be included in the composition include, but are not limited to, exfoliants, whitening agents, tensioning effect agents, soothing agents, 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.

[0132] 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, carboxylic acid, sulfonic acid, and sulfate ion-containing surfactants, such as long-chain alkyl sulfonates and alkylaryl sulfonates such as sodium dodecylbenzenesulfonate, sodium, potassium, and ammonium; dialkyl sodium sulfosuccinates such as sodium dodecylbenzenesulfonate; dialkyl sodium sulfosuccinates such as sodium bis-(2-ethylthiol)-sulfosuccinate; sulfated castor oil, propylene glycol, lecithin, capric / 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 coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4 oleate, acylated sorbitan, acylated sucrose, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, 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 wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbates, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrin, glyceryl monostearate, poloxamer, povidone, cetyl palmitate.Examples of amphoteric surfactants include sodium N-dodecyl-.beta.-alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

[0133] 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, phenethyl alcohol, perillic acid, and thimerosal.

[0134] Examples of water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0135] Suitable stabilizers include, but are not limited to, butylated hydroxytoluene (BHT), ascorbic acid, its salts and esters, vitamin E, tocopherol and its salts, sulfites such as sodium metabisulfite, cysteine ​​and its derivatives, citric acid, propyl gallate, and butylated hydroxyanisole (BHA).

[0136] An example of a pH buffering agent that may be used in the composition is triethanolamine.

[0137] Examples of emollients include, but are not limited to, almond oil, castor oil, carob extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters 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 alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol, and combinations thereof.

[0138] Examples of emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomer, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glyceryl monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohol, lecithin, medium chain triglycerides, methylcellulose, mineral oil and lanolin alcohol, sodium dihydrogen phosphate, monoethanolamine, non-isopropyl cellulose, methyl ... Examples of suitable emulsifying agents include, but are not limited to, ionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum, PEG-100 stearate / glyceryl stearate (Arlacel 165®), decyl glucoside (Plantaren 2000®), lauryl glucoside (Plantaren 1200®), cetearyl glucoside, cetearyl alcohol (Emulgade PL68 / 50®), and combinations thereof.

[0139] Examples of penetration enhancers include, but are not limited to, fatty alcohols, fatty acid esters, fatty acids, fatty alcohol ethers, amino acids, phospholipids, lecithin, cholate, enzymes, amines and amides, complexing agents (liposomes, cyclodextrins, modified cellulose and diimides), macrocycles, including macrocyclic lactones, ketones and anhydrides and cyclic ureas, surfactants, N-methylpyrrolidone and its derivatives, DMSO and related compounds, ionic compounds, azone and related compounds, and solvents, including, but not limited to, alcohols, ketones, amides, polyols (e.g., glycols).

[0140] Examples of propellants include, but are not limited to, dichlorofluoromethane, difluoroethane, isobutane, n-butane, propane, dichlorofluoromethane, nitrogen, and carbon dioxide.

[0141] Examples of exfoliants include, but are not limited to, beta hydroxy acids, alpha hydroxy acids, urea, cinnamic acid, Sophora japonica extract, and proteases such as trypsin.

[0142] Examples of depigmenting agents include, but are not limited to, vitamin C and its derivatives, ferulic acid, resorcinol, alpha and beta arbutin.

[0143] Examples of anti-glycation agents include, but are not limited to, black tea extract and Vaccinium myrtillus extract.

[0144] Examples of slimming agents include, but are not limited to, caffeine, tea extract, Hedera helix extract, and theobromine.

[0145] Examples of sedatives and anti-irritants include, but are not limited to, caffeine, vitamins E, C, B5, B3, glycyrrhetinic acid, salts or derivatives thereof.

[0146] Examples of sebum regulating agents include, but are not limited to, zinc salts such as zinc gluconate or zinc pidolate, vitamin B6, selenium chloride, and benzoyl peroxide.

[0147] Examples of wound healing agents include, but are not limited to, arginine, hydroxyproline, chitosan and derivatives, propolis extract, folic acid and chitosan.

[0148] Examples of self-tanning agents include, but are not limited to, erythrulose.

[0149] Examples of anti-aging agents include, but are not limited to, placenta extract, beta-glucan, fucoidan, sodium hyaluronate, and collagen.

[0150] Examples of antistatic agents include, but are not limited to, methylsulfonylmethane.

[0151] Examples of bulking agents include, but are not limited to, Polypropylene A.

[0152] Examples of film-forming agents include, but are not limited to, copolymers of 1-vinyl-2-pyrrolidone and vinyl acetate, and polyquaternium-6.

[0153] Purpose The compositions of the present invention can be administered orally, topically, parenterally, subcutaneously, epicutaneously, intradermally, transdermally, intramuscularly, enterally, intranasally, intrarespiratoryly, intravascularly, via ophthalmic preparations, intravaginally, intraurethrally, or via nasal inhalation. In a specific embodiment, the compositions of the present invention are administered subcutaneously, epicutaneously, intradermally, transdermally, or topically, preferably topically. The compositions of the present invention may be administered via microneedle or patch.

[0154] The composition may be applied in particular to mucous membranes, stratum corneum, epidermis, dermis, epithelium, endothelium, skin, skin appendages, connective tissue or bone tissue, preferably to skin, skin appendages or mucous membranes.

[0155] In some embodiments, the compositions of the present invention are selected from sunscreen compositions, cosmetic compositions, dermatological compositions, and therapeutic compositions. In preferred embodiments, the composition is a sunscreen or cosmetic composition.

[0156] Topical Compositions In certain embodiments, the compositions of the present invention are topical compositions comprising at least one compound of formula (I) as defined herein and at least one topically acceptable excipient.

[0157] "Topically acceptable excipient" as used herein denotes an excipient suitable for topical application. Such excipients may be judiciously selected by one skilled in the art, for example, from among the excipients mentioned above.

[0158] Such topical compositions may be dermatological, therapeutic and / or cosmetic compositions.

[0159] The topical composition may be in the form of, inter alia, a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilisate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam. The composition may be prepared according to processes known to those skilled in the art.

[0160] Preferably, the topical composition is selected from a cream, a spray, a gel, an ointment, a lotion, an emulsion, a foam, a suspension and a milk.

[0161] The topical composition may be applied to mucous membranes, stratum corneum, epidermis, dermis, epidermis, endodermis, skin or skin appendages (eg, hair and nails), preferably mucous membranes, skin or skin appendages.

[0162] Cosmetic Composition In another particular embodiment, the composition of the present invention is a cosmetic composition.

[0163] Said cosmetic composition comprises at least one compound of formula (I) according to the invention and at least one cosmetically acceptable excipient.

[0164] "Cosmetically acceptable excipients" as used herein refers to excipients suitable for cosmetic use. Such excipients can be judiciously selected by those skilled in the art, for example, from among the excipients mentioned above.

[0165] The cosmetic composition may be administered orally, topically, parenterally, subcutaneously, epicutaneously, intradermally, transdermally, intramuscularly, enterally, intranasally, intrarespiratory, or by nasal inhalation. In a preferred embodiment, the cosmetic composition is administered topically.

[0166] Preferably, the cosmetic composition is a topical or dermatological composition, more preferably a topical composition.

[0167] The cosmetic composition may be applied in particular to mucous membranes, stratum corneum, epidermis, dermis, epidermis, endothelium, skin or skin appendages (eg hair and nails), preferably to mucous membranes, skin or skin appendages.

[0168] The cosmetic composition may be in the form of, inter alia, a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilisate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam. The composition may be prepared according to processes known to those skilled in the art.

[0169] The compositions of the present invention may be particularly well suited for combating and / or reducing signs of skin aging such as the formation of wrinkles and / or fine lines, sagging skin, loss of elasticity, loss of radiance and / or evenness of complexion, and / or for reinforcing the skin barrier.

[0170] Signs of skin aging can be related not only to intrinsic factors associated with aging, but also to extrinsic factors, particularly UV light exposure.

[0171] The object of the present invention relates to the cosmetic use of a composition according to the invention for combating and / or reducing the signs of skin ageing, such as the formation of wrinkles and / or fine lines, sagging skin, loss of elasticity, loss of radiance and / or evenness of complexion, and / or for reinforcing the skin barrier.

[0172] Another object of the present invention is a cosmetic process for combating and / or reducing the signs of skin ageing, such as the formation of wrinkles and / or fine lines, sagging skin, loss of skin elasticity, loss of radiance and / or evenness of complexion, and / or for reinforcing the skin barrier, comprising the step of topically applying to the skin or its appendages a composition of the present invention.

[0173] sunscreen In another particular embodiment, the composition of the present invention is a sunscreen composition.

[0174] The sunscreen composition is advantageously applied topically (i.e., a topical composition). The sunscreen composition may be in the form of, inter alia, a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilisate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam. In a particular embodiment, the sunscreen composition is a formulated sunscreen butter.

[0175] therapeutic composition In a particular embodiment, the composition of the invention is a therapeutic composition, more particularly said composition is a pharmaceutical or veterinary composition.

[0176] Therapeutic compositions comprise at least one compound of formula (I) according to the present invention and at least one pharmaceutically acceptable excipient.

[0177] The term "pharmaceutically acceptable," as used herein, refers to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, in accordance with guidelines from agencies such as the U.S. Food and Drug Administration, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable excipient," as used herein, refers to all components of a pharmaceutical or therapeutic composition that facilitate manufacture, storage, and / or in vivo delivery of the composition. Pharmaceutically acceptable excipients include, but are not limited to, fillers, preservatives, binders, lubricants, disintegrants, swelling agents, fillers, stabilizers, and combinations thereof.

[0178] The therapeutic composition may be administered orally, topically, parenterally, subcutaneously, epicutaneously, intradermally, transdermally, intramuscularly, enterally, intranasally, intrarespiratory, or by nasal inhalation. In a preferred embodiment, the therapeutic composition is administered topically.

[0179] In certain embodiments, the therapeutic composition is applied to a tissue selected from skin, skin appendages, mucous membranes, stratum corneum, epidermis, dermis, epithelium, endothelium, connective tissue, bone tissue, and combinations thereof, preferably skin, skin appendages, mucous membranes, stratum corneum, epidermis, dermis, epithelium, and endothelium, more preferably skin, skin appendages, and mucous membranes. In another embodiment, the therapeutic composition is applied to a circulating medium such as blood or plasma.

[0180] In certain embodiments, the therapeutic composition is a dermatological composition.

[0181] Another object of the present invention is a compound of formula (I) according to the invention or a composition of the invention (in particular a therapeutic composition) for use in the treatment and / or prevention of diseases or conditions of the skin, mucous membranes, the cornea of ​​the eye or skin appendages. Preferably, said diseases or conditions of the skin, mucous membranes, the cornea of ​​the eye or skin appendages are lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, Hansen's disease, psoriasis ... The present invention relates to a method for treating a range of skin conditions, including: bacterial skin infections such as psoriasis, acne, cellulitis, 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, pressure ulcer healing, vaginitis, bladder cancer, endometriosis, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, skin and mucous membrane allergies. More preferably, the disease or condition of the skin, mucous membranes, cornea of ​​the eye or skin appendages is selected from lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, leprosy, pimples, cellulitis, bacterial skin infections such as impetigo, fungal infections such as athlete's foot (intertrigo) and sporotrichosis, fungal nail infections, viral infections such as herpes, sunburn, lice, scabies, pressure sore disinfection and pressure sore healing.

[0182] As used herein, the terms "prevent," "preventing," or "prevention" refer to any reduction, however small, in a subject's predisposition or risk of developing a condition, disease, disorder, or symptom thereof. For purposes of prevention, the subject is any subject, preferably a subject at risk of or predisposed to developing a condition, disease, or disorder. The term "prevention" includes either completely preventing the onset of a clinically evident condition, disease, or disorder, or preventing the onset of a preclinically evident condition, disease, or disorder in an at-risk individual. This includes prophylactic treatment of subjects at risk of developing a condition, disease, or disorder.

[0183] As used herein, the terms "treating" a disease, disorder, or condition, "treatment," or "treating" encompasses alleviating at least one symptom thereof, reducing its severity, or slowing or inhibiting its progression. Treatment does not necessarily mean that the disease, disorder, or condition is cured. The compositions useful herein need only reduce the severity of the disease, disorder, or condition, reduce the severity of symptoms associated therewith, provide an improvement in the quality of life of the patient or subject, or delay or inhibit the onset of the disease, disorder, or condition.

[0184] Another object of the present invention is a method for delivering at least one compound of formula (I) to a tissue of a subject in need thereof, comprising administering an effective amount of a composition of the present invention. The present invention also provides a method for delivering at least one compound of formula (I) to a tissue of a subject, comprising locally administering to a subject in need thereof a therapeutically effective amount of any of the presently described compositions useful in treating a disease, disorder, or condition of said tissue.

[0185] In particular, the tissue is selected from skin, skin appendages, stratum corneum, epidermis, dermis, epithelium, endothelium, connective tissue, bone tissue and combinations thereof. Preferably, the tissue is skin, skin appendages or mucous membranes.

[0186] "Effective amount" or "therapeutically effective amount," as used herein, refers to an amount of a drug or composition of the invention as disclosed herein effective to alleviate one or more symptoms of, delay the onset of, or prevent a disease or disorder.

[0187] Another object of the present invention is a method for treating or preventing a disease or condition of the skin, mucous membranes, the cornea of ​​the eye or the skin appendages, comprising the step of administering to a subject in need thereof a composition of the present invention (in particular a therapeutic composition), said composition comprising at least one compound of formula (I) as defined herein.

[0188] A further object of the present invention is a method of treating or preventing a disease, disorder or condition of the skin, mucous membranes, cornea of ​​the eye or skin appendages in a subject, comprising topically administering to a subject in need thereof a therapeutically effective amount of any of the presently described compositions useful in treating a disease, disorder or condition of the skin, mucous membranes or cornea of ​​the eye. In certain embodiments, the disease, disorder or condition of the skin, mucous membranes or cornea of ​​the eye is selected from the group consisting of lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, melasma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, Selected from bacterial skin infections such as pustules, leprosy, pimples, cellulitis, impetigo, fungal infections such as athlete's foot (intertrigo) and sporotrichosis, fungal nail infections, viral infections such as herpes, sunburn, lice, scabies, pressure sore disinfection and healing, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, skin and mucous membrane allergies.

[0189] For clarity, any element or feature of any method or composition or process described herein can be combined with any other element or feature of any other method or composition or process described herein.

[0190] Another object of the present invention is the use of the compounds of formula (I) of the present invention for preparing a composition for treating and / or preventing diseases or conditions of the skin, mucous membranes, the cornea of ​​the eye, and skin appendages.

[0191] Another object of the present invention is to provide a method for treating skin conditions such as lipodystrophy, keloid scars, acne, psoriasis, atopic dermatitis, actinic keratosis, rosacea, melasma, Merkel cell carcinoma, basal cell carcinoma, squamous cell carcinoma, scar treatment, wound healing, alopecia, vitiligo, urticaria (hives), herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, leprosy, pimples, cellulitis, bacterial skin infections such as athlete's foot (intertrigo) and sporotrichosis. The compound of formula (I) of the present invention or the composition of the present invention (particularly, a therapeutic composition) for use in the treatment and / or prevention of a disease or condition selected from the group consisting of fungal infections, fungal nail infections, viral infections such as herpes, sunburn, lice, scabies, bedsore disinfection and healing, vaginitis, cancer such as bladder cancer, endometriosis, uveitis, corneal diseases, keratitis, corneal herpes, keratoconus, corneal dystrophy, pharyngitis, and skin and mucous membrane allergies.

[0192] kit The present invention provides a composition according to the invention, a cleaning composition; - Possibly with instruction guide The present invention also relates to a kit comprising:

[0193] In a preferred embodiment, the composition according to the invention in the kit is a topical composition. In a more preferred embodiment, the composition according to the invention in the kit is a cosmetic or sunscreen composition, preferably a sunscreen composition.

[0194] "Cleansing composition" refers to a composition that allows for the removal of some or all of a composition according to the present invention that has previously been applied to tissue, such as the skin, skin appendages, or mucous membranes of a subject. More specifically, the cleaning composition allows for the removal of adhesive compounds.

[0195] The cleaning composition may contain at least one "detergent" and optionally one or more excipients. A "detergent" refers to a chemical or biological agent capable of disrupting the bond between an adhesive compound attached to tissue and said tissue. The detergent may be a protein, a peptide (e.g., glutathione), an amino acid, an enzyme (e.g., cathepsin B), a thiol (e.g., 2-mercaptoethanol, N-acetylcysteine), a dithiol (e.g., dithiothreitol), a pH adjuster, an acid, a base, a solvent, a saline solution (e.g., sodium chloride solution), or a combination thereof. The detergent may be judiciously selected by those skilled in the art depending on the nature of the bond between the adhesive compound attached to tissue and said tissue.

[0196] In certain embodiments, the cleaning composition is a powder, shampoo, soap, lotion, solution, solid, scrub, scraper, mousse, foam, syndet, gel, shower gel, spray, mist, wax, strips, enzyme composition, detergent composition, or a woven or nonwoven fabric.

[0197] Other uses - photoprotection and photoinstability Another object of the present invention is the use of at least one compound as defined herein for reducing the photodegradation and / or photoinstability of an active pharmaceutical ingredient or a cosmetic product.

[0198] The term "photodegradation" refers to partial or total degradation induced by light, especially UV light.

[0199] The term "photoinstability" refers to instability induced by light, especially UV light.

[0200] An "active pharmaceutical ingredient" includes, but is not limited to, a physically, physiologically, or pharmacologically active substance. An active pharmaceutical ingredient is a substance that can be used to treat (e.g., therapeutic agents, vaccine antigens or antigenic substances), prevent (e.g., protective agents, vaccines), diagnose (e.g., diagnostic agents), cure, or mitigate a disease or disorder. An active agent may be a substance that affects the structure or function of the body, or a prodrug that becomes biologically active or more active after being placed in a defined physiological environment.

[0201] "Cosmetics" are substances used in cosmetic uses, methods and processes, such as sunscreens, dyes, fragrances, deodorants, microbiota modulators, skin conditioners and skin lipid modulators.

[0202] In a particular embodiment, at least one compound used to reduce the photodegradation and / or photoinstability of the active pharmaceutical ingredient or cosmetic product is in the form of a micelle or liposome. The active pharmaceutical ingredient or cosmetic product may be encapsulated in at least one compound of the present invention, in particular in the form of a micelle or liposome.

[0203] A further object of the present invention is a material comprising a support and at least one compound as defined herein, said compound being attached to said support.

[0204] The substrate may be made of any organic and / or inorganic material, hi certain embodiments, the substrate is a natural or synthetic polymeric substrate, a natural or synthetic fiber substrate, a stone, metal, plastic, rubber, or glass substrate.

[0205] The present invention is further described in the following examples, which are not intended to limit the scope of the invention as defined by the appended claims. [Example]

[0206] Example 1 Preparation of Compounds of Formula (I) Compound No. 1. 2,2'-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-[(3-propyl-1H-pyrrole-2,5-dione)oxy]phenol]

[0207] [ka]

[0208] 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) was added 1-(3-bromopropyl)-1H-pyrrole-2,5-dione (128 mg, 0.58 mmol). The reaction mixture was refluxed overnight, filtered, and concentrated to dryness. The residue was dissolved in ethyl acetate, and the organic phase was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The crude residue was triturated with DIPE to give 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).

[0209] Compound No. 2. 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 6-maleimido-1-hexanol ester

[0210] [ka]

[0211] 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-maleimido-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, 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: EtOAc), and 75 mg of the desired product was obtained 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).

[0212] Compound No. 3. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyldisulfanyl)ethanol ester

[0213] [ka]

[0214] Compound No. 3 was prepared using the same protocol as Compound No. 2, replacing 6-maleimido-1-hexanol 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).

[0215] Compound No. 4. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[5-(-2,5-dihydro-1H-pyrrole-2,5-dione)pentyl]amide

[0216] [ka]

[0217] Compound No. 4 was prepared using the same protocol as Compound No. 2, replacing 6-maleimido-1-hexanol 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).

[0218] Compound No. 5. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, N-[4-(1,3-dioxolan-2-yl)butan]amide

[0219] [ka]

[0220] Compound No. 5 was prepared using the same protocol as Compound No. 2, replacing 6-maleimido-1-hexanol 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).

[0221] Compound No. 6. 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, biotin-PEG2-amide

[0222] [ka]

[0223] Compound No. 6 was prepared using the same protocol as Compound No. 2, replacing 6-maleimido-1-hexanol 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).

[0224] Compound No. 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

[0225]

change

[0226] 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 material. 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 phases were 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, step gradient from 9:1 dichloromethane / MeOH to MeOH) 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).

[0227] Compound No. 8. 2-Cyano-3,3-diphenylpropenoic acid, 6-maleimido-1-hexanol ester

[0228] [ka]

[0229] 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-maleimido-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, 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: EtOAc), and 175 mg of the desired product was obtained 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).

[0230] Compound No. 9. 2-Cyano-3,3-diphenylpropenoic acid, folic acid-PEG-1k ester

[0231] [ka]

[0232] Compound No. 9 was prepared using the same protocol as Compound No. 8, replacing 6-maleimido-1-hexanol with folic acid-PEG-OH 1kDA (nanosoft polymer) and using DMF as the solvent. At the end of the reaction, DMF was evaporated and the residue was precipitated in a mixture of methanol / acetone, washed several times with acetone, and dried under vacuum.

[0233] Compound No. 10. 2-Cyano-3,3-diphenylpropenoic acid, 1,3-bis(vinylsulfonyl)-1-propanol ester

[0234] [ka]

[0235] Compound No. 10 was prepared using the same protocol as Compound No. 8, replacing 6-maleimido-1-hexanol 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).

[0236] Compound No. 11. 2-Phenyl-1H-benzimidazole-5-(biotin-PEG8-N-ethyl)sulfonamide

[0237] [ka]

[0238] To a solution of O-(2-aminoethyl)-O'-[2-(biotinylamino)ethyl]octaethylene glycol (285 mg, 0.41 mmol) and triethylamine (279 μL, 2 mmol) in THF (15 mL) was added 2-phenyl-1H-benzimidazole-5-sulfonyl chloride hydrochloride (164 mg, 0.5 mmol). 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 phases were washed with saturated sodium bicarbonate solution (2 × 20 mL), dried, and evaporated in vacuo. The resulting residue was purified by flash column chromatography (silica gel, 9:1 dichloromethane / MeOH to MeOH step gradient) to give 326 mg of product. HRMS (M+H) + = 939

[0239] Compound No. 12. 2-Hydroxy-4-methoxybenzophenone-5-(biotin-PEG8-N-ethyl)sulfonamide

[0240] [ka]

[0241] Compound No. 12 was prepared using the same protocol as Compound No. 11, replacing 2-phenyl-1H-benzimidazole-5-sulfonylchlorid hydrochloride with 2-hydroxy-4-methoxybenzophenone-5-sulfonylchloride. 76 mg of the desired product was obtained as a beige solid. MRMS (M+H) + = 973

[0242] Compound No. 13. [N-(2-cyano-3,3-diphenylpropenoyl)-piperidin-4-ylsulfonyl]acetic acid

[0243] [ka]

[0244] 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-(piperidin-4-ylsulfonyl)acetate, and 10 mg of DMAP in 30 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was washed with water, diluted HCl, 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), affording 203 mg of the desired ester as an off-white solid. This latter was suspended in 5 mL of THF, and 1 mL of 1N NaOH was added. The reaction mixture was stirred at room temperature for 2 hours, acidified with 0.5N HCl, and the precipitate was filtered to give 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).

[0245] Compound No. 14. N-[(2-hydroxybenzoyl)-piperidin-4-ylsulfonyl]acetic acid

[0246] [ka]

[0247] 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-(piperidin-4-ylsulfonyl)acetate, and 3 mg of DMAP in 10 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was washed with water, diluted HCl, 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), affording 147 mg of the desired ester as an off-white solid. This latter was 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 give 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).

[0248] Compound No. 15. (3-(2H-benzo[d][1,2,3]triazol-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidin-4-ylsulfonyl)acetic acid]amide

[0249] [ka]

[0250] A solution of 170 mg (0.5 mmol) of 3-(3-(2H-benzo[d][1,2,3]triazol-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, 78 mg (0.5 mmol) of EDCI, 110 mg (0.5 mmol) of methyl-(piperidin-4-ylsulfonyl)acetate, and 5 mg of DMAP in 15 mL of dichloromethane was stirred at room temperature overnight. The reaction mixture was washed with water, diluted HCl, 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), and 98 mg of the desired ester was obtained as an off-white solid. This latter was 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 give 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).

[0251] Compound No. 16. 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester

[0252] [ka]

[0253] a) 3-(diethylamino)benzo[c][1]benzoxepin-6,11-dione In a 50 mL pear-bottom flask equipped with magnetic stirring, a solution of DCC (3.48 g, 16.89 mmol) in 10 mL of ethyl acetate was added to a suspension of 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid (4.90 g, 15.64 mmol) in 20 mL of ethyl acetate. The mixture was stirred at room temperature 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 give 3.97 g of 3-(diethylamino)benzo[c][1]benzoxepin-6,11-dione as a yellow solid (yield=86%). LCMS-ESI: [M+H] + =296

[0254] b) 2-[3-(2,5-dioxopyrrol-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide In a 100 mL round-bottom flask equipped with magnetic stirring, 2-(2-aminoethoxy)ethanol (1.185 g, 11.27 mmol) was charged to DCM (100 mL). At +5° C., 3-(maleimido)propionic acid N-hydroxysuccinimide ester (3.00 g, 11.27 mmol) was slowly added. The reaction was stirred at room temperature ("RT") for 4 hours. The DCM was evaporated under reduced pressure to give 4.25 g of 2-[3-(2,5-dioxopyrrol-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide as a colorless oil (yield = quantitative). The product was used directly in the next step without further purification. LCMS-ESI: [M+H] + =257

[0255] c) 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 3-(diethylamino)benzo[c][1]benzoxepin-6,11-dione (3.10 g, 10.50 mmol) and 2-[3-(2,5-dioxopyrrol-1-yl)-N-[2-(2-hydroxyethoxy)ethyl]propanamide (3.90 g, 10.50 mmol) were added to 50 mL of diglyme. DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (0.16 g, 1.05 mmol) was added, and the reaction was stirred at room temperature for 4 days. Diglyme was evaporated under reduced pressure and the crude oil was directly purified on a 40 g SiO column eluted with a gradient of cyclohexane-acetone 95 / 5 to 50 / 50 to give 1.40 g of 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-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).

[0256] λ of diethylaminohydroxybenzoylhexyl benzoate in ethanol / DMSO 9 / 1 max The UV absorbance was measured at 357 nm, and the λ of compound No. 16 was maxUV absorbance was measured at 357 nm.

[0257] Compound No. 17. 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester

[0258] [ka]

[0259] a) 3-(2,5-dioxopyrrol-1-yl)-N-(2-hydroxyethyl)propanamide In a 250 mL round-bottom flask equipped with magnetic stirring, 2-aminoethanol (0.838 g, 13.72 mmol) was charged to DCM (100 mL). At +5° C., 3-(maleimido)propionic acid N-hydroxysuccinimide ester (3.32 g, 12.47 mmol) was added slowly. The reaction was stirred at room temperature for 2 hours. The DCM was evaporated under reduced pressure to give 4.15 g of 3-(2,5-dioxopyrrol-1-yl)-N-(2-hydroxyethyl)propanamide as a white solid. The product was used directly in the next step without further purification. LCMS-ESI: [M+H] + =213

[0260] b) 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 3-(diethylamino)benzo[c][1]benzoxepin-6,11-dione (3.68 g, 12.47 mmol) and 3-(2,5-dioxopyrrol-1-yl)-N-(2-hydroxyethyl)propanamide (4.08 g, 12.47 mmol) were added to 50 mL of diglyme. DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (0.16 g, 1.05 mmol) was added, and the reaction was stirred at room temperature for 4 days. Diglyme was evaporated under reduced pressure and the crude oil was directly purified on a 40 g SiO column with a gradient cyclohexane-acetone 95 / 5 to 50 / 50 to give 1.40 g of 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-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).

[0261] λ of diethylaminohydroxybenzoylhexyl benzoate in ethanol / DMSO 9 / 1 max The UV absorbance was measured at 357 nm, and the λ of compound No. 17 was max UV absorbance was measured at 357 nm.

[0262] Compound No. 18. 2-Cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide

[0263] [ka]

[0264] a) 2-cyano-3,3-diphenyl-prop-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 1N sodium hydroxide (31.89 mL, 31.89 mmol) was added at 5° C. The reaction mixture was stirred at room temperature for 18 hours and then acidified with 1N HCl (31.89 mL, 31.89 mmol). 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 give 6.26 g of 2-cyano-3,3-diphenyl-prop-2-enoic acid as a white solid (yield=87%). LCMS-ESI: [M+H] + =250

[0265] b) tert-butyl N-[2-[(2-cyano-3,3-diphenyl-prop-2-enoyl)amino]ethyl]carbamate In a 250 mL round-bottom flask equipped with magnetic stirring, 2-cyano-3,3-diphenyl-prop-2-enoic acid (2 g, 8.02 mmol) was placed in DCM (50 mL) and DMF (catalytic amount). At 5° C., oxalyl chloride (1.36 mL, 16.05 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. The solvent and excess oxalyl chloride were evaporated under reduced pressure to give the acid chloride as a yellow solid.

[0266] In a 250 mL round-bottom flask equipped with magnetic stirring, N-Boc-ethylenediamine (2.7 g, 16.85 mmol) was charged to DCM (50 mL). Then, a solution of the acid chloride in DCM (20 mL) was slowly added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was washed with water (3 × 50 mL), dried over MgSO4, and concentrated to dryness to give 3.19 g of tert-butyl N-[2-[(2-cyano-3,3-diphenyl-prop-2-enoyl)amino]ethyl]carbamate as an off-white solid (yield = quantitative). LCMS-ESI: [M+H] + =292

[0267] c) N-(2-aminoethyl)-2-cyano-3,3-diphenyl-prop-2-enamide In a 250 mL round-bottom flask equipped with magnetic stirring, tert-butyl N-[2-[(2-cyano-3,3-diphenyl-prop-2-enoyl)amino]ethyl]carbamate (3.14 g, 8.02 mmol) was charged in DCM (50 mL). At 5 °C, TFA (40.5 mL, 529 mmol) was slowly added. The reaction was stirred at room temperature for 1 hour (until gas evolution ceased). The reaction mixture was concentrated in vacuo, 25 mL of DCM was added, and the resulting solution was washed with NaOH 0.5N (8 mL), dried over Na2SO4, and concentrated to dryness to give 2.4 g of N-(2-aminoethyl)-2-cyano-3,3-diphenyl-prop-2-enamide as a colorless oil (yield = 91%). LCMS-ESI: [M+H] + =292

[0268] d) 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide In a 250 mL round-bottom flask equipped with magnetic stirring, N-(2-aminoethyl)-2-cyano-3,3-diphenyl-prop-2-enamide (2.33 g, 8.01 mmol) was placed in 60 mL of DCM. 3-(Maleimido)propionic acid N-hydroxysuccinimide ester (2.774 g, 10.42 mmol) was slowly added. The reaction was stirred at room temperature for 18 hours, and the solution was washed with water (50 mL) and dried over Na2SO4. The crude product was filtered on a silica pad and eluted successively with DCM, AcOEt, and acetone. The acetone layer was concentrated under vacuum to give an off-white solid, which was crystallized from a mixture of acetonitrile / iPrOH:1 / 4 to give 660 mg of the desired compound. After concentration of the filtrate, a second crystallization from acetonitrile / iPrOH:1 / 4 gave 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 give 945 mg of 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-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).

[0269] λ of octocrylene in ethanol / DMSO 9 / 1 max The UV absorbance was measured at 305 nm, and the λ of compound No. 18 was max UV absorbance was measured at 293 nm.

[0270] Compound No. 19. 2-Cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester

[0271] [ka]

[0272] a) tert-butyl-N-[2-(2-hydroxyethylsulfanyl)ethyl]carbamate In a 250 mL pear-bottom flask equipped with magnetic stirring, to a solution of BocO (2.12 g, 9.69 mmol) in 20 mL of DCM was added a solution of 2-((2-aminoethyl)-thio)ethanol (1.17 g, 9.69 mmol) in 10 mL of DCM. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give 2.21 g of tert-butyl-N-[2-(2-hydroxyethylsulfanyl)ethyl]carbamate as a colorless oil (yield = quantitative). LCMS-ESI: [M+H] + =122 (-Boc)

[0273] b) 2-cyano-3,3-diphenyl-prop-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-prop-2-enoic acid (2 g, 8.02 mmol) was placed in DCM (100 mL) and DMF (catalytic amount). At +5° C., oxalyl chloride (1.36 mL, 16.05 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour. The solvent and excess oxalyl chloride were evaporated under reduced pressure to give the acid chloride as a yellow solid.

[0274] 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. A solution of the acid chloride (20 mL) in DCM was then slowly added. The reaction was stirred at room temperature for 1 hour. The solution was washed with water (3 × 50 mL), dried over MgSO4, and concentrated under reduced pressure to give 3.49 g of 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester as a colorless oil (yield = 96%). LCMS-ESI: [M+H] + =353 (-Boc)

[0275] c) 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfonyl]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfanyl]ethyl ester (3.49 g, 7.71 mmol) was charged to 100 mL of DCM. m-CPBA (3.992 g, 23.13 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The DCM solution was washed with NaHCO, dried over NaSO, and concentrated under reduced pressure to give 3.9 g of 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfonyl]ethyl ester as a colorless oil (yield = quantitative). LCMS-ESI: [M+H]+=385 (-Boc)

[0276] d) 2-[2-(2-cyano-3,3-diphenyl-prop-2-enoyl)oxyethylsulfonyl]ethylammonium, 2,2,2-trifluoroacetate In a 250 mL round-bottom flask equipped with magnetic stirring, 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-(tert-butoxycarbonylamino)ethylsulfonyl]ethyl ester (3.55 g, 9.07 mmol) was added to DCM (100 mL). At +5° C., TFA (6.94 mL, 90.69 mmol) was added slowly. The reaction was stirred at room temperature for 1 hour (until gas evolution ceased). The reaction mixture was concentrated under vacuum. 2×25 mL of toluene was added and concentrated to dryness to give 4.5 g of 2-[2-(2-cyano-3,3-diphenyl-prop-2-enoyl)oxyethylsulfonyl]ethylammonium; 2,2,2-trifluoroacetate as a pale yellow oil (yield=99%). LCMS-ESI: [M+H] + =385

[0277] e) 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester In a 250 mL round-bottom flask equipped with magnetic stirring, 2-[2-(2-cyano-3,3-diphenyl-prop-2-enoyl)oxyethylsulfonyl]ethylammonium 2,2,2-trifluoroacetate (4.5 g, 9.03 mmol) was added to 50 mL of DCM. 3-(Maleimido)propionic acid N-hydroxysuccinimide ester (2.884 g, 10.83 mmol) was added slowly, followed by DIPEA (15.72 mL, 9.03 mmol). The reaction was stirred at room temperature for 2 hours. The solution was washed with water (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a colorless oil (5.8 g). The crude oil was purified on an 80 g SiO column with a solid load and eluted with a gradient of 100% DCM to 100% AcOEt to give 2 g of 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-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).

[0278] λ of octocrylene in ethanol / DMSO 9 / 1 max The UV absorbance was measured at 305 nm, and the λ of compound No. 19 was max UV absorbance was measured at 308 nm.

[0279] Compound No. 20. 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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

[0280] [ka]

[0281] 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, the refrigerant was added to N-Boc-ethylenediamine (2.24 g, 14.01 mmol) and TEA (2.7 mL, 20.01 mmol) in THF (60 mL). The solution was cooled to +5° C., and then ecamsulsulfonyl chloride (4 g, 6.67 mmol) was added slowly. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water (150 mL). The precipitate was filtered and washed with water to give 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)

[0282] 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 To a 250 mL round-bottom flask equipped with magnetic stirring was added the above tert-butyl carbamate (5.46 g, 6.45 mmol) in DCM (20 mL). TFA (19.7 mL, 257.82 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give 9.5 g of a pale yellow solid. The solid was diluted with EtOH (30 mL) and water (10 mL) and concentrated under reduced pressure to give 5.67 g of the desired compound as a yellow solid (yield=100%). LCMS-ESI: [M+H] + =647

[0283] c) 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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 To a 250 mL round-bottom flask equipped with magnetic stirring, the above TFA salt (3.5 g, 4 mmol) and 3-(maleimido)propionic acid N-hydroxysuccinimide ester (2.13 g, 8 mmol) in THF (50 mL) were added. DIPEA (2.09 mL, 12 mmol) was then added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (150 mL) and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (4.2 g). The solid was purified by flash chromatography on a 40 g SiO column eluting with a gradient of DCM 100% to DCM / MeOH 9 / 1 to give 1.26 g of 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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 as a white solid (yield=33%). LCMS-ESI: [M+H] + = 949.8 1H NMR 400 MHz, DMSOd6, 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).

[0284] λ of ecamsule in ethanol / H2O / DMSO 5 / 3 / 2 max The UV absorbance was measured at 341 nm, and the λ of compound No. 20 was max UV absorbance was measured at 344 nm.

[0285] Compound No. 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

[0286] [ka]

[0287] 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-triazin-2-yl]benzene-1,3-diol (300 mg, 0.74 mmol) prepared according to ES2730924 and potassium carbonate (206 mg, 1.49 mmol) 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 portion of 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 with stirring, and the resulting solid was filtered, washed with water, and dried under reduced pressure to give 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 min, the solid was filtered and washed with ACN to give 340 mg of the desired compound as an off-white solid (yield=64%).

[0288] b) 5-(3-aminopropoxy)-2-[4-[4-(3-aminopropoxy)-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-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-triazin-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 and then at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to give 200 mg of 5-(3-aminopropoxy)-2-[4-[4-(3-aminopropoxy)-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]phenol as an off-white solid (quantitative yield). LCMS-ESI: [M+H] + =518

[0289] c) 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 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-triazin-2-yl]phenol (197 mg, 0.38 mmol) and diisopropylethylamine (133 μL, 0.76 mmol) were added to dioxane (3 mL). (2,5-Dioxopyrrolidin-1-yl)3-(2,5-dioxopyrrol-1-yl)propanoate (233 mg, 0.88 mmol) was added. The reaction was stirred at room temperature for 3 hours. The mixture was poured into water (20 mL), and the solid was filtered and washed with water to give 200 mg of an off-white solid. The solid was crystallized in AcOH (1 mL), filtered, and washed successively with AcOH and ACN to give 100 mg of 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 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)

[0290] λ of bemotrizinol in ethanol / benzyl alcohol / DMSO / phenoxyethanol 63 / 18 / 10 / 9 max The UV absorbance was measured at 342 nm, and the λ of compound No. 21 was max UV absorbance was measured at 342 nm.

[0291] Compound No. 22. 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide

[0292] [ka]

[0293] a) tert-Butyl N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-ethoxyphenyl)-1,3,5-triazin-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-triazin-2-yl]benzene-1,3-diol (590 mg, 1.46 mmol) and K2CO3 (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 h. Water (20 mL) was added, and the organic layer was extracted with AcOEt, washed with water, brine, and dried over MgSO4. The mixture was filtered, and the solvent was concentrated under reduced pressure. The crude oil was purified by chromatography on a SiO2 column, eluting with DCM 100% to DCM / MeOH (93 / 7) to give 1.58 g of the desired product as a yellow oil (yield=quantitative).

[0294] b) 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; bishydrochloride In a 100 mL round flask equipped with magnetic stirring, tert-butyl N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-ethoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.40 g, 1.46 mmol) was placed in dioxane (5 mL). HCl 6N (1.22 mL, 7.31 mmol) was added, and the reaction mixture was stirred at 60° C. for 1 hour and then at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was solubilized in MeOH and triturated with NaSO, 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 salt as a yellow solid (yield=72%). LCMS-ESI: [M+H] + : 754

[0295] c) 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]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 above compound (0.80 g, 1.06 mmol) and DIPEA (0.37 mL, 2.12 mmol) were added to dioxane (6 mL). (2,5-Dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)propanoate (0.65 g, 2.43 mmol) was added. The mixture was stirred at room temperature for 3 hours. The solution was poured into water (100 mL) and extracted with AcOEt. The organic layer was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude oil was purified by chromatography on a SiO column eluting with a gradient of 100% heptane to 100% acetone to give 0.28 g of 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide as a yellow oil (yield=25%). LCMS-ESI: [M+H] + : 1056.4

[0296] Example 2 Bioadhesion Testing of Compounds of Formula (I) Bioadhesion of compounds was performed in solution for protein binding and specific binding of sulfhydryl-reactive chemical groups of cysteine: Compounds were mixed with either an equimolar solution of cysteine ​​(2 molar equivalents of cysteine ​​for compounds containing two maleimides) or an excess of cysteine ​​(5 or 10 times the molar compound concentration) and incubated for 1 to 2 minutes in ethanol-1×PBS, pH 6.8.

[0297] Compounds and cysteine-linked compounds were identified by LC-MSD (Agilent 1260 Infinity II equipped with an AptiSphere Strategy C18 or Sunfire C18 column) and assayed by HPLC using an Agilent Infinity II Prime UHPLC UV detector system. Separation was achieved on an Agilent Poroshell 120 EC-C18 column (3 × 100 mm, 2.7 μM) using a gradient phase of water and acetonitrile.

[0298] The bioadhesion results for compounds Nos. 16 to 20 obtained in equimolar cysteine ​​solution (2 molar equivalents of cysteine ​​solution for compounds containing two maleimides) are shown in Table 1 below.

[0299] [Table 1]

[0300] The results in Table 1 show that in the presence of an equimolar solution of cysteine ​​(2 molar equivalents of cysteine ​​for compound No. 20), 71% to 85% of the compounds of the invention are conjugated to cysteine. These results demonstrate that efficient bioadhesion was obtained with the compounds of the invention.

[0301] The bioadhesion results for Compounds Nos. 16, 18 and 20 obtained with excess cysteine ​​in solution are shown in Table 2 below.

[0302] [Table 2]

[0303] The results in Table 2 show that in the presence of excess cysteine, 92% to 100% of the compounds of the present invention are conjugated to cysteine. These results also demonstrate that efficient bioadhesion was obtained with the compounds of the present invention.

Claims

1. A compound represented by the following formula (I): A[B-(C) v ] w (I) [In the formula, A is a photoprotective moiety; 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].

2. Photoprotective moiety A is bemotrizinol, diethylaminohydroxybenzoylhexyl benzoate, bisdisulizole disodium, melazimate, terephthalylidene dicamphorsulfonic acid, bisoctrizol, oxybenzone, sulisobenzone, iscotrizinol, octinoxate, octisalate, octyltriazone, padimate O, homosalate, amiloxate, octocrylene, PEG-25 PABA, ensulizole, trolamine salicylate, cinoxate, benzophenone-9, dioxybenzone, avobenzone, enzacamene, diethylhexyl naphthalate, diethylhexyl syringylidene, tetramethylhydroxypiperidinol, sodium benzotriazolyl butylphenolsulfonate, benzotriazole dodecyl p-cresol sulfonate, polyester-8, acrylates 2. The compound according to claim 1, which is derived from methyl methyl acrylate copolymer, butyloctyl salicylate, bis(butylcyanoacetate)anthracenediylidene, dimethylcapramide or ethylhexylmethoxycrylene, preferably from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid, sulisobenzone, octisalate, octocrylene, ensulizole, avobenzone, polyester-8, bisdisulizole disodium, melazimate, oxybenzone-3, iscotridinol, octanoate, octyl triazone, padimate O, cinoxate, benzophenone-9 or dioxybenzone, more preferably from bemotridinol, diethylaminohydroxybenzoylhexylbenzoate, terephthalylidene dicamphorsulfonic acid or octocrylene.

3. 3. The compound of claim 1 or 2, wherein linker B is a linear polymer, a branched polymer, a hyperbranched polymer, a dendrimer, or a residue thereof.

4. Linker B has at least one -S(O) 2 4. The compound of claim 1, further comprising a - group.

5. The linker B is represented by the following formula (II): -[Y-(CH 2 ) q -(O-CH 2 -CH 2 ) p -Z-(CH 2 ) 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, when Y is -O-, 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-(CH 2 ) q may form a heterocycle selected from the group consisting of pyrrolidinyl and piperidinyl; p is 0, ⇒Z is a single bond, -NH-, -O-, -NH-C(O)-, -S-, and -S(O) 2 - selected from ⇒s is an integer between 0 and 6, ⇒k is an integer from 1 to 4, preferably from 1 to 2.

5. The compound according to any one of claims 1 to 4, represented by:

6. Z is -NH-, -O-, -NH-C(O)-, -S- and -S(O) 2 6. The compound of claim 5, selected from:

7. 7. The compound according to claim 1, wherein the functional group C is selected from aldehyde, acetal, thioacetal, thiol, maleimide, Michael acceptor, vinyl sulfone, disulfanyl pyridine, sulfonyl aziridine, epoxide, haloacetyl, isocyanate, isothiocyanate, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, hydroxy, amino, ammonium, guanidinium, imidocarbonate, carboxylic acid, carboxylic acid ester, anhydride, sulfonic acid, folic acid, biotin, streptavidin, avidin, antibodies and single-chain antibodies or fragments thereof, and derivatives thereof, preferably thiol, acetal, maleimide, vinyl sulfone, disulfanyl pyridine, guanidinium, folic acid, biotin, and derivatives thereof, more preferably C is maleimide or a derivative thereof.

8. Part B-(C) v But the following formula: 【Chemistry 1-1】 【Chemistry 1-2】 [Chemistry 1-3] [Chemistry 1-4] [wherein, in each formula, n is independently an integer from 0 to 250, preferably from 0 to 50, more preferably from 0 to 12; t is independently an integer from 0 to 30, preferably from 0 to 12.

8. The compound of any one of claims 1 to 5 and 7, represented by one of:

9. 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-maleimido-1-hexanol ester; 2-[4-(diethylamino)-2-hydroxybenzoyl]benzoic acid, 2-(2-pyridinyldisulfanyl)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)butan]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-maleimido-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)-piperidin-4-ylsulfonyl]acetic acid; N-[(2-hydroxybenzoyl)-piperidin-4-ylsulfonyl]acetic acid; - (3-(2H-benzo [d][1,2,3]triazol-2-yl)-5(tert-butyl)-4-hydroxyphenyl)propanoic acid, N-[(4-piperidin-4-ylsulfonyl)acetic acid]amide; 2-[4-(diethylamino)-2-hydroxybenzoyl]-benzoic acid, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethyl ester; 2-[4-(diethylamino)-2-hydroxy-benzoyl]benzoic acid, 2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl ester; 2-cyano-N-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethyl]-3,3-diphenyl-prop-2-enamide; 2-cyano-3,3-diphenyl-prop-2-enoate, 2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethylsulfonyl]ethyl ester; 3-(2,5-dioxopyrrol-1-yl)-N-[2-[[(3Z)-3-[[4-[(Z)-[4-[2-[3-(2,5-dioxopyrrol-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-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; and - 3-(2,5-dioxopyrrol-1-yl)-N-[2-[2-[2-[2-[4-[4-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-hydroxy-phenyl]-6-(4-methoxyphenyl)-1,3,5-triazin-2-yl]-3-hydroxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]propanamide 2. The compound of claim 1, selected from the group consisting of:

10. A composition comprising at least one compound of formula (I) according to any one of claims 1 to 9 and at least one excipient.

11. 11. The composition according to claim 10, which is a sunscreen composition or a cosmetic composition.

12. 11. Cosmetic use of a composition according to claim 10 for combating and / or reducing signs of skin ageing such as the formation of wrinkles and / or fine lines, sagging skin, loss of elasticity, loss of radiance and / or evenness of complexion, and / or for reinforcing the skin barrier.

13. - a composition according to claim 10; a cleaning composition, preferably a powder, shampoo, soap, lotion, solution, solid, scrub, mousse, foam, synthetic detergent, gel, shower gel, spray, mist, wax, strips or woven or nonwoven fabrics, - possibly instruction guides, Includes a kit.

14. 11. The composition of claim 10, which is a pharmaceutical or veterinary composition.

15. A composition for use in treating and / or preventing a disease or condition of the skin, mucous membranes, the cornea of ​​the eye or the skin appendages, preferably wherein said disease or condition of the skin, mucous membranes, the cornea of ​​the eye or the skin appendages is lipodystrophy, keloid scars, 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 15. The composition of claim 14, wherein the active ingredient is selected from bacterial skin infections such as hives, herpes simplex, impetigo, eczema, exanthematous dermatitis, ichthyosis, warts, blisters, pruritus, gangrene, bruises, pustules, leprosy, pimples, cellulitis, impetigo, fungal infections such as athlete's foot (intertrigo) and sporotrichosis, fungal nail infections, viral infections such as herpes, sunburn, lice, scabies, bedsore disinfection and bedsore healing.

16. 16. A composition according to claim 10, 11 or 12 or a composition for use according to claim 15, which is a topical composition, preferably in the form of a suspension, cream, spray, aerosol, butter, stick, gel, ointment, lotion, solution, solid, emulsion, microemulsion, oil, lyophilisate, milk, powder, paste, wax, mousse, patch, film, micelle, liposome or foam.

17. 10. Use of at least one compound according to any one of claims 1 to 9 for reducing the photodegradation and / or photoinstability of an active pharmaceutical ingredient or a cosmetic product.

18. 10. A material comprising a support and at least one compound according to any one of claims 1 to 9, wherein said compound is adhered to said support, preferably a natural or synthetic polymeric support, a natural or synthetic fibre support, a stone, metal, plastic, rubber or glass support.

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