Cyclic sugar amino acid derivatives

Abstract

The present invention relates to a compound of formula (I): JPEG2024504135000093.jpg31170 and processes for their preparation, their use in cosmetic or dermatological applications, in particular for the treatment and / or prevention of skin ageing, for skin protection or skin regeneration; for skin plumping and / or skin volumizing and / or skin densification and / or wrinkle filling and / or moisturizing the skin or hair and / or re-lipidizing the skin or hair and / or stimulating hair growth; for the treatment of dry skin and / or atopic dermatitis and / or eczema and / or psoriasis; for the treatment and / or prevention or healing of fibrosis (e.g. excessive scars, such as keloids or hypertrophic scars); or for the treatment of inflammation (e.g. chronic low-grade inflammation), and their use as adjuvants for the preservation and / or protection and / or regeneration of biological materials or microorganisms.

Description

[Technical field]

[0001] The present invention relates to cyclic sugar amino acid derivatives, and to processes for their preparation; their use in cosmetic or dermatological applications, in particular for the treatment and / or prevention of skin ageing, skin protection or skin regeneration; for plumping the skin, and / or skin volumizing, and / or skin densifying, and / or wrinkle filling, and / or moisturizing the skin or hair, and / or relipidizing the skin or hair, and / or stimulating hair growth; for the treatment of dry skin, and / or atopic dermatitis, and / or eczema, and / or psoriasis; for the treatment and / or prevention or healing of fibrosis (e.g. excessive scarring, e.g. keloids or hypertrophic scars); or for the treatment of inflammation, especially chronic low-grade inflammation, especially that which occurs in various aged tissues and which is referred to as "inflammaging", and their use as adjuvants for the preservation and / or protection and / or regeneration of biomaterials or microorganisms. [Background technology]

[0002] Skin aging is due to both internal and external factors. Intrinsic aging is an inevitable chronological process that results in thinning, dry skin, fine wrinkles and gradual skin atrophy. Aging reduces cell proliferation in the basal layer, thins the epidermis, reduces the contact surface area between the dermis and epidermis, provides a smaller exchange surface for nutritional supply to the epidermis and weakens the proliferation ability of basal cells. This process of reducing the proliferation ability of cells includes keratinocytes, fibroblasts and melanocytes. Extrinsic aging is due to constant exposure of the skin to stresses, including environmental (e.g. UV radiation), chemical (e.g. smoking) and nutritional stresses. These stresses affect the skin and cause changes such as loss of elasticity, appearance of wrinkles and fine lines, dryness, itching, hyperpigmented areas, hypopigmented lesions, failure of the skin's protective barrier function and predisposition to skin cancer. In particular, long-term exposure to ultraviolet (UV) radiation from the sun is the major contributor to extrinsic aging of the skin, referred to as photoaging.

[0003] Another characteristic of the aging process is the chronic progressive progression of proinflammatory conditions, which was originally called "inflammaging". Inflammaging refers to the ongoing low-grade inflammation associated with aging. Such chronic inflammatory responses can build up over time and gradually cause tissue damage. This is thought to be one of the driving forces behind many aging-related diseases and skin aging. This suggests the potential benefit of anti-inflammatory treatment in preventing aging-related changes in adipose tissue (reviewed in Metabolism. March 2013;62(3):337-340).

[0004] Ageing affects different types of cells, including adipocytes (mentioned in Journal of Dermatology Science 71 (2013), pp. 58-66), causing changes in the facial contour. This loss of adiposity is also due to UV exposure and is also related to increased fibrosis. This process is related to the inflammatory response that occurs in both ageing and photoaging, especially due to the production of inflammatory cytokines, such as IL6. Fat loss is due to sun exposure, as in ageing, and involves at least two mechanisms: stimulation of lipolysis in mature adipocytes, or inhibition of differentiation of preadipocytes into mature adipocytes, and lipid biosynthesis.

[0005] Differentiation of preadipocytes requires remodeling of the matrix necessary for the cells to differentiate and grow in size. Inflammation induces a decrease in remodeling capacity. Therefore, to combat aging, it is clearly useful to avoid inflammation and to avoid fibrosis of adipose tissue.

[0006] With age, the loss of skin elasticity and the breakdown of adipose tissue cause undesirable visible effects on the body (hands, feet, buttocks, breasts, face), especially on the face, the appearance of lines and wrinkles, loss of skin volume around the eyes, and sunken cheeks. To reshape the body, fill in expression lines and wrinkles, and plump the skin, surgical fat injection (fat grafting or lipofilling) was developed, which consists of restoring the volume of the skin, especially the face, by reinjecting fat removed from fat-rich areas of the body. However, this technique currently used is expensive, can cause inflammatory reactions, and must be repeated several times for a satisfactory result. To find new lipofilling methods, scientists have been interested in the physiology of the skin, more specifically the adipose tissue and its components. Adipose tissue is mainly composed of adipocytes and other cells, such as preadipocytes, fibroblasts or endothelial cells. Adipocytes are the site of lipid synthesis and storage and are derived from the process of adipogenesis, also called adipocyte differentiation, in which preadipocytes develop into mature adipocytes (Eur. J. Cell Biol. 2013, 92, 229-236). It has also been shown that fibroblasts and adipocytes are derived from a common multipotent mesenchymal precursor (Exp. Dermatol. 2014, 23(9), 629-631). Adipocytes can therefore be generated either by differentiation of fibroblasts or by stimulation of differentiation from preadipocytes.

[0007] Furthermore, stimulation of adipogenesis and lipid synthesis leads to an increase in the volume of fat cells, thus restoring volume to the skin.

[0008] Thus, compounds that have the effect of increasing the number and volume of adipocytes are described for their ability to act as skin plumping, and / or skin volumizing, and / or skin densifying, and / or wrinkle filling, and / or skin relipidizing agents.

[0009] Compounds capable of promoting the growth (proliferation) of skin cells, in particular under stress conditions, protecting them against different stresses, especially oxidative stress, reducing fibrosis and inflammation through inhibition of cytokine, e.g. IL6 release, promoting matrix remodeling, promoting adipogenesis of adipocytes, are therefore useful for treating and / or preventing skin ageing, for skin plumping and for reducing wrinkles.

[0010] Aged skin, which is less plump than youthful skin, is characterized by reduced levels of hyaluronic acid (HA). HA is the simplest of the glycosaminoglycans, which is highly hygroscopic; hydrated hyaluronic acid can contain up to 1000 times its own mass in water. Hyaluronic acid has been known for its regulatory activity on epidermal proliferation and its ability to retain water.

[0011] HA is used in cosmetic formulations to treat a wide range of skin problems including wrinkles, nasolabial folds, anti-aging, skin augmentation, skin hydration, and as a collagen stimulator. HA is used to help the skin retain and maintain elasticity, turgor, and moisture, and is claimed to have a plumping effect (Dermato-endocrinology 2012, 43, pp. 253-258).

[0012] Thus, compounds that have the effect of increasing hyaluronic acid synthesis are described for their ability to act as skin plumping, and / or skin volumizing, and / or skin densifying, and / or wrinkle filling, and / or skin moisturizing agents.

[0013] Changes occurring with aging in adipose tissue and preadipocytes, termed inflammaging, also show serious implications in obesity and various metabolic disorders, such as insulin resistance and type 2 diabetes, as well as cardiovascular disease.

[0014] Compounds capable of reducing fibrosis and inflammation through inhibition of cytokine, such as IL6 release in adipose tissue, would provide a good treatment for inflammaging changes in adipose tissue, especially in obesity, and in preventing the development of various metabolic syndromes, such as type 2 diabetes.

[0015] The lipids of the stratum corneum are required for the epidermal permeability barrier and prevention of water loss, to prevent dehydration of the skin and / or act as a barrier to maintain hydration.

[0016] Lipids, such as fatty acids and cholesterol, are known to prevent and / or reduce skin dryness and wrinkles.In fact, aging reduces the synthesis of cholesterol in epidermis, which has a negative effect on the homeostasis of permeability barrier (Journal of Lipid Research 48 (2007), pp. 20531-20546).The endogenous synthesis of lipids by skin cells, such as keratinocytes, can be a good alternative to treat skin dryness and aging effects.

[0017] Furthermore, reduced lipid synthesis and inflammatory conditions may lead to abnormalities in the skin barrier observed in dry skin (WO98 / 10739), atopic dermatitis, eczema or psoriasis (J. Invest. Dermatol. 1991, 96, 523-526; Contact Dermatitis 2008, 58, 255-262; Skin Pharmacol. Physiol. 2015, 28, 42-55).

[0018] Hyaluronic acid is a special moisturizing active ingredient used in cosmetics, especially formulated as emulsions or serums, with a hydrating claim. Due to the high number of polar groups present in the molecule, hyaluronic acid is a hydrophilic polymer with a hydrating claim. In aqueous solution, it can form a viscoelastic gel, which ensures moisturization when applied to the skin. The use of cosmetics, for example creams or lotions containing HA, helps to moisturize the skin (molecules 2021, 26, 4429), but the promotion of the fibroblasts' own hyaluronic acid production could be an even better approach by preventing the stability problems associated with the external addition of HA.

[0019] Compounds that can alleviate inflammatory conditions, improve moisturization, restore barrier function and restore lipid synthesis would provide good treatment for dry skin, atopic dermatitis, eczema and psoriasis.

[0020] Furthermore, it has been demonstrated that lipids, and more specifically cholesterol synthesis, play a major role in hair biology: thus, a decrease in lipid synthesis, and in particular cholesterol synthesis, disrupts the hair cycle (J. Invest. Dermatol. 2010, 130(5), pp. 1205-1207; J. Invest. Dermatol. 2010, 130, pp. 1237-1248).

[0021] Moreover, proliferation is the most widely tested marker of dermal papilla cell activity (International Journal of Cosmetic Science, 2018, 40, pp. 429-450). Proliferation of dermal papilla cells determines their growth rate and mitotic index. Thus, the effect obtained on cell proliferation is indicative of an effect promoting hair growth. Moreover, these cells need to be protected from inflammation and cytokine production to promote growth and prevent apoptosis.

[0022] Compounds that can promote cell growth, alleviate inflammatory conditions, and restore lipid synthesis may be useful in stimulating hair growth.

[0023] Biomaterials, like microorganisms, are often stored for a period of time before being used in vivo or in vitro.

[0024] Storage conditions, such as temperature and preservation medium, have a profound effect on the quality of biomaterials (or microorganisms) over time, without compromising their biological regenerative potential, maintaining optimal cell growth and productivity, and preserving their vitality and functionality.

[0025] Many media and conditions have been developed to preserve cells, tissues and organs from plants, animals and humans. There is a need for media that protect the cells from damage.

[0026] Compounds that can promote cell growth and protect cells from stress, especially oxidative stress, can be good adjuvants in media for preserving biological materials or microorganisms.

[0027] During the classical wound healing process, three main complex steps are involved: 1) hemostasis / inflammation, 2) proliferation and 3) remodeling (BioMed Research International 2014, article 1D747584). First, platelet aggregation and cytokine delivery stop bleeding and prevent infection (formation of fibrin clot). Then, fibroblast proliferation, angiogenesis and synthesis of extracellular matrix lead to regeneration of dermal and epidermal tissue. Finally, remodeling of granulation tissue occurs.

[0028] Keloids and hypertrophic scars are the result of a malfunction of the classical wound healing process after injury, such as surgical intervention, puncture, vaccination, acne, cuts or burns. They consist of disfiguring dense fibrous tissue that, in keloids, extends beyond the initial site of injury, or, in hypertrophic scars, remains within the initial borders of the injury. [Prior art documents] [Patent documents]

[0029] [Patent Document 1] WO98 / 10739 [Patent Document 2] WO2006 / 059227 [Patent Document 3] WO2007 / 125203 [Patent Document 4] WO2015 / 140178 [Patent Document 5] WO2018 / 138541 [Patent Document 6] WO2012 / 085221 [Non-Patent Document]

[0030] [Non-Patent Document 1] Metabolism. March 2013; 62(3): pp. 337 - 340 [Non-Patent Document 2] Journal of Dermatology Science 71 (2013), pp. 58 - 66 [Non-Patent Document 3] Eur. J. Cell Biol. 2013, 92, pp. 229 - 236 [Non-Patent Document 4] Exp. Dermatol. 2014, 23(9), pp. 629 - 631 [Non-Patent Document 5] Dermato - endocrinology 2012, 43, pp. 253 - 258 [Non-Patent Document 6] Journal of Lipid Research 48 (2007), pp. 20531 - 20546 [Non-Patent Document 7] J. Invest. Dermatol. 1991, 96, pp. 523 - 526 [Non-Patent Document 8] Contact Dermatitis 2008, 58, pp. 255 - 262 [Non-Patent Document 9] Skin Pharmacol. Physiol. 2015, 28, pp. 42 - 55 [Non-Patent Document 10] Molecules 2021, 26, 4429

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

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Non-Patent Document 21

Non-Patent Document 22

[0031] Numerous treatments have been developed to treat, reduce and / or prevent keloids and hypertrophic scars, including conventional surgery, compression therapy, topical silicone gels, radiation, lasers, cryosurgery, corticosteroid injections and chemical agents. Despite the large number of promising options to prevent and / or treat and / or attenuate keloids, none of them are truly effective.

[0032] Compounds that are involved in the extracellular matrix organization, reducing fibrosis, reducing the tensile strength of the skin, and reducing the inflammatory state may provide a good treatment for the wound healing process, especially for keloids and hypertrophic scars.

[0033] CF is useful for preserving biomaterials 2 -glycopeptide derivatives have been disclosed in WO2006 / 059227 and WO2007 / 125203. However, these compounds have stability problems and can be used to treat highly sensitive CF 2 Decomposes at the -C(=O)-NH functional group.

[0034] Other CFs 2-Glycopeptide derivatives have been disclosed in WO2015 / 140178 for their antiseptic / protective effect on human skin fibroblasts and human nasal epithelial cells in vitro under different stresses, such as starvation, UV stress, oxidative stress or bacterial stress, and in WO2018 / 138541 for their effect on reducing fibrosis through downregulation of genes involved in extracellular matrix synthesis and upregulation of genes involved in extracellular matrix degradation collagen expression in normal, aged but also keloid fibroblasts. [Means for solving the problem]

[0035] New circular CF 2 -Sugar amino acid derivatives have been found which bring together all the properties required for their use as adjuvants for the cosmetic or dermatological applications mentioned above, namely anti-ageing, skin protection or skin regeneration; for skin plumping and / or skin volumizing and / or skin densification and / or wrinkle filling and / or skin or hair moisturizing and / or skin or hair relipidization and / or hair growth stimulation; for the treatment of dry skin and / or atopic dermatitis and / or eczema and / or psoriasis; for the treatment and / or prevention or healing of fibrosis (e.g. excessive scarring, e.g. keloids or hypertrophic scars); or for the treatment of inflammation, especially chronic low-grade inflammation, especially occurring in various aged tissues and referred to as "inflammaging"; and for the preservation and / or protection and / or regeneration of biomaterials or microorganisms.

[0036] The cyclic sugar amino acid derivatives are capable of promoting the growth of skin cells, protecting them from different stresses, especially oxidative stress, reducing fibrosis and inflammation through inhibition of cytokine, e.g. IL6 release, promoting matrix remodeling, promoting adipogenesis, modifying the organization of the extracellular matrix in reducing the tensile strength of the skin, moisturizing the skin through the production of hyaluronic acid, and promoting plumping.

[0037] Prior art CF disclosed in WO2015 / 140178 and WO2018 / 138541 2 Compared to -glycopeptide derivatives, the cyclic sugar amino acid derivatives according to the present invention unexpectedly exhibit superior efficacy at low concentrations.

[0038] The present invention relates to a compound represented by the following formula (I):

[0039] [ka]

[0040] (In the formula, n represents 1 or 2, preferably 2, R is a hydrogen or fluorine atom, or CH 3 , C.H. 2 F, C.H. 2 OSiR a1 R b1 R c1 , C.H. 2 OR 8 , C.H. 2 O.C.(O)R 9 , C.H. 2 OCO 2 R 10 , C.H. 2 OC(O)NR 11 R 12 , C.H. 2 OP(O)(OR 13 ) 2 Or CH 2 OSO 3 R 14 represents a group, - R 1 and R 2 are each independently a fluorine atom or an OSiR a2 R b2 R c2 , OR 15 , O.C.(O)R 16 , O.C.O. 2 R 17 , O-C(O)NR 18 R 19 , OP(O)(OR 20 ) 2 Or OSO 3 R21 represents a group, - R 3 is a fluorine atom or OSiR a3 R b3 R c3 , OR 22 , O.C.(O)R 23 , O.C.O. 2 R 24 ,OCONR 25 R 26 , OP(O)(OR 27 ) 2 , O.S.O. 3 R 28 , N 3 , Phthalimidyl, NR 29 R 30 , N.R. 31 C(O)R 32 , N.R. 33 C(O)OR 34 , N(C(O)R 35 )C(O)R 36 , N(C(O)R 37 )C(O)OR 38 and N(C(O)OR 39 )C(O)OR 40 represents a group, - R 4 is a hydrogen or halogen atom, or OSiR a4 R b4 R c4 , OR 41 , O.C.(O)R 42 , O.C.O. 2 R 43 ,OCONR 44 R 45 , OP(O)(OR 46 ) 2 Or OSO 3 R 47 represents a group, Or R and R 1 together with the carbon atom which carries them form the following formula:

[0041] [ka]

[0042] forming a cyclic acetal having the formula And / or (R 1 and R 2 ), (R 2 and R 3 ) and / or (R 3 and R 4 ), together with the carbon atom which carries them, form the following formula:

[0043] [ka]

[0044] forming a cyclic acetal having the formula - R 5 and R 6 are the same or different and represent a hydrogen atom or an N-protecting group, - R 8 , R 15 , R 22 and R 41 are each independently a hydrogen atom, an O-protecting group or (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 3 ~C 7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl, (C 1 ~C 6 )-alkyl-heteroaryl, saccharide or polysaccharide radicals, which optionally contain halogen atoms, (C 1 ~C 6 ) alkoxy, OH, COOH and CHO; in particular hydrogen atoms, (C 1 ~C 6 ) Alkyl, aryl, aryl-(C1 ~C 6 ) alkyl, saccharide or polysaccharide radicals, which may optionally contain halogen atoms, (C 1 ~C 6 ) alkoxy, OH, COOH and CHO; more particularly, hydrogen atom, (C 1 ~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) alkyl group, which may optionally contain a halogen atom, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 9 , R 10 , R 16 , R 17 , R 23 , R 24 , R 32 , R 34 From R 40 , R 42 and R 43 are independent of each other, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 3 ~C 7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl or (C 1 ~C 6 )-alkyl-heteroaryl group, which optionally contains a halogen atom, (C 1 ~C 6 ) alkoxy, OH, COOH and CHO; in particular (C 1~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) alkyl group, which may optionally contain a halogen atom, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 11 , R 12 , R 18 , R 19 , R 25 , R 26 , R 29 From R 31 , R 33 , R 44 and R 45 are each independently a hydrogen atom or (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl or (C 1 ~C 6 )-alkyl-heteroaryl group, which optionally contains a halogen atom, (C 1 ~C 6 ) alkoxy, OH, COOH and CHO; advantageously, hydrogen or (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) Alkynyl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl group, which may optionally contain a halogen atom, (C 1~C 6 ) alkoxy, OH, COOH and CHO; in particular, hydrogen or (C 1 ~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) alkyl group, which may optionally contain a halogen atom, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 13 , R 14 , R 20 , R 21 , R 27 , R 28 , R 46 and R 47 are each independently a hydrogen atom or (C 1 ~C 6 ) an alkyl group; - R a1 From R a4 , R b1 From R b4 and R c1 From R c4 are independent of each other, (C 1 ~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) an alkyl group; - R d and R e are each independently a hydrogen atom or (C 1 ~C 6 ) an alkyl group) or a salt, solvate, tautomer, stereoisomer or mixture of stereoisomers in any ratio, particularly a mixture of enantiomers, especially a racemic mixture, thereof.

[0045] The present invention relates to a process for preparing a compound of formula (I) as defined above, comprising the following steps: (a) Formula (II):

[0046] [ka]

[0047] (In the formula, - n is as defined above, - R', R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' and R 6 ' are each an optionally protected form of R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is equivalent to - R 7 is (C 1 ~C 6 ) alkyl (e.g., tert-butyl or methyl) or aryl-(C 1 ~C 6 ) alkyl (e.g. benzyl), preferably (C 1 ~C 6 ) alkyl (e.g. tert-butyl or methyl) to obtain a compound of formula (I), optionally in protected form, (b) R', R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' and / or R 6 'But, R, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 R, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 to obtain a compound of formula (I), and (c) optionally salifying or solvating the compound obtained in the previous step (a) or (b) to obtain a salt or solvate of the compound of formula (I).

[0048] The present invention also relates to a cosmetic or pharmaceutical (eg dermatological) composition comprising at least one compound of formula (I) as defined above, and at least one physiologically acceptable excipient.

[0049] The present invention also relates to a dressing comprising a pad, compress or sponge impregnated with a pharmaceutical composition according to the invention as defined above.

[0050] The present invention also relates to a culture, storage and / or preservation medium comprising at least one compound of formula (I) as defined above.

[0051] The present invention also relates to the use of a compound of formula (I) as defined above or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention as defined above, more particularly the use as a cosmetic, for the treatment and / or prevention of skin ageing, for protecting the skin or for regenerating the skin; or for plumping the skin, and / or for volumizing the skin, and / or for compacting the skin, and / or for filling wrinkles, and / or for moisturizing the skin or hair, and / or for re-lipidizing the skin or hair, and / or for stimulating hair growth.

[0052] The present invention also relates to a compound of formula (I) as defined above, or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention, for use in the treatment and / or prevention of skin ageing, in skin protection or in skin regeneration.

[0053] The present invention also relates to a compound of formula (I) as defined above, or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention, for use in the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis; for use in the treatment and / or prevention of fibrosis, in particular excessive scarring, such as keloids or hypertrophic scars, or in the healing; or for use in the treatment of inflammation, especially chronic low-grade inflammation, especially that which occurs in various aged tissues and is referred to as "inflammaging".

[0054] The present invention also relates to the use of the compounds of formula (I) as defined above for the preservation and / or protection and / or regeneration of biological materials or microorganisms.

[0055] The present invention also relates to the use of a compound of formula (I) as defined above as an adjuvant in culture, storage and / or preservation media.

[0056] definition For the purposes of the present invention, the term "physiologically acceptable" is intended to mean useful for preparing a cosmetic or pharmaceutical (e.g. dermatological) composition, i.e. generally safe and non-toxic for cosmetic or pharmaceutical (e.g. dermatological) use in animals, especially mammals, such as humans.

[0057] "Topical" administration means, in the framework of the present invention, administration onto the skin or mucous membranes (eg the conjunctiva).

[0058] "Parenteral" administration means, in the framework of the present invention, administration by injection, for example intradermal or subcutaneous injection.

[0059] The term "physiologically acceptable salts and / or solvates" is intended, within the framework of the present invention, to mean salts and / or solvates of compounds which are physiologically acceptable as defined above and which possess the cosmetic or pharmacological activity of the corresponding compounds.

[0060] In the context of the present invention, "salts" are more particularly "physiologically acceptable salts". A salt or a physiologically acceptable salt is (1) Acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids, such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and trifluoroacetic acid; or (2) Salts formed when an acid proton present in the compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion; or coordinated with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.

[0061] In the context of the present invention, "solvates" are more specifically "physiologically acceptable solvates". Solvates of the cyclic sugar amino acid derivatives of the present invention or physiologically acceptable solvates of the cyclic sugar amino acid derivatives of the present invention include conventional solvates, for example those formed by the presence of a solvent during the last step of preparing the compound of the present invention. As examples, solvates due to the presence of water (these solvates are also called hydrates) or ethanol may be mentioned.

[0062] For the purposes of the present invention, "tautomer" is intended to designate the various tautomeric forms that the sugar of compound (I) may take, namely, pyranose (6-membered ring), furanose (5-membered ring) or linear (open ring form). However, for practical reasons, the sugar of compound (I) is represented herein by its pyranose form.

[0063] However, the compounds of the present invention are 4 The R 1 must also exhibit an OH group so that the compounds of the invention can be in the furanose form.

[0064] Thus, for example, in the galactose series, the compounds of the invention may occur in the following various forms:

[0065] [ka]

[0066] [ka]

[0067] Represents.

[0068] base

[0069] [ka]

[0070] is R 4 =R 1 In the case of =OH, therefore, the following tautomeric forms: - Pyranose type:

[0071] [ka]

[0072] - Furanose type:

[0073] [ka]

[0074] and - Linear:

[0075] [ka]

[0076] It is possible to take.

[0077] By the same means,

[0078] [ka]

[0079] is R 4 =R 1 In the case of =OH, therefore, the following tautomeric forms: - Pyranose type:

[0080] [ka]

[0081] - Furanose type:

[0082] [ka]

[0083] and - Linear:

[0084] [ka]

[0085] It is possible to take.

[0086] The anomeric carbon can occur in two different configurations in the closed pyranose and furanose forms.

[0087] The compounds of the invention may have different tautomeric forms that may exist in solution at equilibrium, which may optionally be the predominant tautomeric form compared to other tautomeric forms, or the compounds of the invention may have only one tautomeric form, e.g., the pyranose form, depending on the nature of the medium, temperature, compound concentration, etc., among others.

[0088] In this last case, where the sugar has only one tautomeric form, the configuration of the sugar in this tautomeric form is R 4 The ═OH can be blocked, inter alia, when it is converted by substitution of the OH group or by a hydrogen or halogen atom.

[0089] In the sense of the present invention, "stereoisomers" is intended to designate diastereoisomers or enantiomers. These are therefore optical isomers. Stereoisomers that are not mirror images of one another are therefore designated as "diastereoisomers" and stereoisomers that are non-superimposable mirror images are designated as "enantiomers".

[0090] In particular, the sugar and amino acid moieties of the compounds of the invention may belong to the D or L series.

[0091] A carbon atom bonded to four nonidentical substituents is called a "chiral center."

[0092] An equimolar mixture of two enantiomers is called a racemic mixture.

[0093] The term "halogen" as used in the present invention refers to an atom of fluorine, bromine, chlorine or iodine. Advantageously, it is an atom of fluorine.

[0094] The "(C 1 ~C6 The term "alkyl" refers to a saturated straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms, in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl groups.

[0095] The "(C 2 ~C 6 The term "alkyl-alkenyl" refers to a straight or branched hydrocarbon chain containing at least one double bond and containing from 2 to 6 carbon atoms, such as, for example, ethenyl (vinyl) or propenyl (eg, allyl) groups.

[0096] The "(C 2 ~C 6 The term "alkynyl" refers to a straight or branched hydrocarbon chain containing at least one triple bond and containing from 2 to 6 carbon atoms, such as, for example, an ethynyl or propynyl group.

[0097] The "(C 1 ~C 6 The term "alkoxy" refers to an alkyl group, as defined above, attached to the molecule via an oxygen atom. 1 ~C 6 ) alkyl groups, including, but not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy and the like.

[0098] The "(C 3 ~C 7 The term "cycloalkyl" refers to a saturated hydrocarbon ring containing from 3 to 7, advantageously from 5 to 7, carbon atoms, in particular a cyclohexyl, cyclopentyl or cycloheptyl group.

[0099] The term "heterocycloalkyl" as used herein refers to a saturated hydrocarbon ring having 5 to 7 members in which one or more, preferably one or two, carbon atoms are replaced by a heteroatom, such as a sulfur, nitrogen or oxygen atom, respectively. This may be, inter alia, a tetrahydrofuranyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl or 1,3-dioxolanyl group.

[0100] The term "aryl" as used in the present invention refers to an aromatic hydrocarbon group, preferably containing from 6 to 10 carbon atoms and containing one or more fused rings, such as a phenyl or naphthyl group, etc. Advantageously, it is a phenyl group.

[0101] The term "heteroaryl" as used herein refers to an aromatic group containing one or more fused rings, preferably a 5- to 10-membered aromatic group, in which the ring atoms consist of one or more, advantageously one to four, more advantageously one or two heteroatoms, such as nitrogen, oxygen or sulfur atoms, and the remainder are carbon atoms. Heteroaryl groups can be thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, tetrazolyl or indyl groups, among others.

[0102] The "aryl-(C 1 ~C 6 The term "alkyl" is defined above. 1 ~C 6 )- refers to any aryl group as defined above attached to the molecule by an alkyl group. In particular, it may be a benzyl group.

[0103] The "heteroaryl-(C 1 ~C 6 The term "alkyl" is defined above. 1 ~C 6 )- refers to a heteroaryl group, as defined above, attached to the molecule by an alkyl group.

[0104] The "(C 1 ~C 6 The term "aryl" refers to a (C)-alkyl group, as defined above, attached to a molecule by an aryl group, as defined above. 1 ~C 6 In particular, it may be a methylphenyl group.

[0105] The "(C 1 ~C 6 The term "alkyl-heteroaryl" refers to a heteroaryl group, as defined above, attached to the molecule by a heteroaryl group, as defined above. 1 ~C 6 )-alkyl groups.

[0106] As used herein, the term "trialkylsilyl group" means -SiAlk 1 Alk 2 Alk 3 group, wherein Alk 1 , Alk 2 and Alk 3 are the same or different and are defined above (C 1 ~C 6 )-alkyl group. For example, it may be a trimethylsilyl or triethylsilyl group.

[0107] The term "protecting group" as used herein refers to chemical groups that selectively block reactive sites in a multifunctional compound, allowing chemical reactions to selectively take place on otherwise unprotected reactive sites.

[0108] The term "N-protecting group" as used in the present invention refers to a group intended to protect an amine function against undesired reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis", John Wiley & Sons, New York (1981). The amine function protected by the N-protecting group can be a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an aminoacetal derivative, an N-benzyl derivative, an imine derivative, an enamine derivative or an N-heteroatom derivative. In particular, N-protecting groups include formyl; aryl, for example phenyl, optionally substituted with one or several methoxy groups, e.g. p-methoxyphenyl (PMP); aryl-(C 1 ~C 6 ) alkyl, such as benzyl, e.g. benzyl (Bn), p-methoxybenzyl (PMB) or 3,4-dimethoxybenzyl (DMPM); GP1 , such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz) or p-methoxybenzylcarbonyl (Moz); 2 -R GP1 , for example t-butyloxycarbonyl (Boc), trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz or Z) or 9-fluorenylmethyloxycarbonyl (Fmoc); -SO 2 -R GP1 , for example, phenylsulfonyl, tosyl (Ts or Tos), or 2-nitrobenzenesulfonyl (also called nosyl-Nos or Ns); GP1 is optionally substituted with one or several halogen atoms, such as F or Cl (C 1 ~C 6 ) alkyl; (C 2 ~C 6 ) alkenyl, such as allyl; optionally, OMe (methoxy) and NO 2(nitro), for example phenyl; aryl-(C 1 ~C 6 ) alkyl, e.g. benzyl, optionally substituted with one or several methoxy groups, in which the aryl portion is substituted; or a 9-fluorenylmethyl group.

[0109] The N-protecting group is, in particular, -CO 2 -R GP1 , for example Cbz, Boc or Fmoc, especially Cbz or Boc.

[0110] The term "O-protecting group" as used in the present invention refers to a substituent that protects a hydroxyl group against undesired reactions during synthetic procedures, such as the O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis" (John Wiley & Sons, New York (1981)). The hydroxyl group protected by the O-protecting group can be, for example, an ether, an ester, a carbonate, an acetal, etc. In particular, the O-protecting group is optionally substituted with one or several (especially 1 to 3) halogen atoms, such as chlorine atoms (C 1 ~C 6 ) alkyl, for example methyl, ethyl, tert-butyl or 2,2,2-trichloroethyl; aryl-(C 1 ~C 6 ) alkyl, such as benzyl, e.g. benzyl (Bn) or p-methoxybenzyl (PMB); 1 Ar 2 Ar 3 trityl radicals of the formula -CH, such as triphenylmethyl (also called trityl-Tr), (4-methoxyphenyl)diphenylmethyl (also called methoxytrityl-NMT) or bis-(4-methoxyphenyl)phenylmethyl (also called dimethoxytrityl-DMT); 2 OR GP2 or -CH 2 S.R.GP2 (For details, see -CH 2 OR GP2 ) substituted methyl groups of the formula -CH, for example methoxymethyl (MOM), benzyloxymethyl, 2-methoxyethoxymethyl (MEM), 2-(trimethylsilyl)ethoxymethyl or methylthiomethyl; 2 CH 2 OR GP2 or -CH 2 CH 2 S.R. GP2 (For details, see -CH 2 CH 2 OR GP2 ) substituted ethyl groups, such as ethoxyethyl (EE); GP3 R GP4 R GP5 Silyl groups of the formula -CO-R, such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS or TBDMS) and t-butyldiphenylsilyl (TBDPS); GP6 a carbonylating group of the formula -CO, such as acetyl (Ac), pivaloyl (Piv or Pv) or benzoyl (Bz), 2 -R GP7 carbonylating groups such as allyloxycarbonyl (Alloc) or 9-fluorenylmethyloxycarbonyl (Fmoc); or tetrahydropyranyl (

[0111] [ka]

[0112] ) (THP) or tetrahydrofuranyl (

[0113] [ka]

[0114] ) group;

[0115] Ar 1 , Ar 2 and Ar 3R independently of one another represent aryl, for example phenyl, optionally substituted with one or several methoxy groups; GP2 is optionally substituted with aryl (e.g., phenyl) (C 1 ~C 6 ) alkyl (e.g. methyl or ethyl), (C 1 ~C 6 ) alkoxy (e.g., methoxy) or trialkylsilyl groups (e.g., SiMe 3 ) ; R GP3 , R GP4 and R GP5 are independent of each other, (C 1 ~C 6 ) represents an alkyl or aryl (e.g., phenyl) group; R GP6 and R GP7 are independent of each other, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) Alkenyl, aryl, aryl-(C 1 ~C 6 ) alkyl or 9-fluorenylmethyl group.

[0116] The O-protecting group is, in particular, 1 ~C 6 ) alkyl group or aryl-(C 1 ~C 6 ) alkyl group, preferably aryl-(C 1 ~C 6 ) alkyl group (eg, benzyl).

[0117] The term "saccharide" as used in the present invention refers to the D or L forms of erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, erythrulose, ribulose, xylulose, psicose, fructose, sorbose or tagatose.

[0118] The term "saccharide group" as used in this invention refers to a saccharide, as defined above, that is attached to the molecule by its oxygen atom located at the anomeric center.

[0119] The term "polysaccharide" as used in the present invention refers to a chain comprising at least two, preferably from two to ten, saccharides, as defined above, linked together by oxygen bridges formed between an OH functional group at the anomeric position of one saccharide and an OH functional group that is not at the anomeric position of another saccharide.

[0120] The term "polysaccharide group" as used in this invention refers to a polysaccharide, as defined above, which is linked to the molecule by an oxygen atom present in the anomeric center of the terminal saccharide.

[0121] The term "leaving group" as used in the present invention refers to a chemical group that can be easily displaced by a nucleophile during a nucleophile substitution reaction, the nucleophile being especially a primary amine. Such leaving groups may in particular be halogen atoms, sulfonates, N-succinimidyloxy, 4-nitro-phenyloxy, pentafluorophenoxy or N-benzotriazoloxy. Sulfonates in particular are represented by -OSO 2 -R LG is a group, R LG is (C 1 ~C 6 ) Alkyl, aryl, aryl-(C 1 ~C 6 ) alkyl or (C 1 ~C 6 ) alkyl-aryl groups, which are optionally substituted with one or several halogen atoms, such as fluorine atoms. Sulfonates are especially mesylates (CH 3 -S(O 2 )O-), triflate (CF 3 -S(O) 2 O-) or tosylate (p-Me-C 6 H 4 -S(O) 2 O-).

[0122] The term "preservation" of a biological material or a microorganism as used in the present invention refers to the fact of maintaining the state (in particular the structure and function) of the biological material or microorganism as already present, or of preventing or limiting the deterioration of this state.

[0123] The term "protection" of a biomaterial or a microorganism as used in the present invention refers to the fact that the biomaterial or the microorganism is protected against internal or external aggressions, such as stress, for example oxidative stress (e.g. UV), changes in temperature, changes in pH, chemical or bacterial contamination, starvation conditions, etc.

[0124] The term "regeneration" of a biomaterial or a microorganism as used in the present invention refers to the fact of restoring the state (particularly structure and function) of the biomaterial or microorganism as existed before after an internal or external attack, such as a stress, for example oxidative stress (e.g. UV), a change in temperature, a change in pH, chemical or bacterial contamination, starvation conditions, etc. This concerns more particularly biomaterials, such as cells.

[0125] The term "protection" of the skin as used in the present invention refers to the fact of maintaining the condition (especially structure and function) of the skin and of the cells of the skin as already present or preventing or limiting the deterioration of this condition by protecting them against internal or external aggressions, such as stresses, for example oxidative stress (e.g. UV), changes in temperature, changes in pH, chemical or bacterial contamination, malnutrition conditions, etc.

[0126] The term "renewal" of the skin as used in the present invention refers to the fact of restoring the condition (particularly structure and function) of the skin and cells as they existed before an internal or external aggression, e.g. stress, e.g. oxidative stress (e.g. UV), changes in temperature, changes in pH, chemical or bacterial contamination, malnutrition conditions, etc.

[0127] The term "treatment and / or prevention of skin aging" as used in the present invention means preventing, avoiding or delaying the onset of signs of skin aging and / or reducing or inhibiting the signs of skin aging, which may be, for example, wrinkles, fine lines, skin atrophy, loss of elasticity, dryness.

[0128] The terms "skin plumping", "skin volumizing" and "skin densification" as used in the present invention refer to the fact of increasing the volume of the skin by toning the skin and in particular by increasing the volume of fat.

[0129] The term "wrinkle filling" as used in the present invention refers to the fact of restoring volume, fullness and smoothness of the skin to reduce or eliminate wrinkles, including expression lines, particularly by increasing the volume of fat.

[0130] The term "moisturizing the skin or hair" as used in the present invention refers to the fact that the moisture content of the skin or hair is increased, particularly by increasing lipid (e.g. cholesterol) synthesis, and that the skin is kept soft, supple, and smooth, and the hair is kept soft, supple, and shiny.

[0131] The term "relipidation of the skin or hair" as used in the present invention refers to the fact of increasing the lipid content of the skin or hair in order to restore the sebum film of the skin or hair so as to keep the skin soft, supple and smooth and the hair soft, supple and shiny.

[0132] "Fibrosis" means in the present invention a disease accompanied by the formation of excess fibrous connective tissue. When this formation of excess fibrous connective tissue occurs in response to injury (e.g. surgical intervention, puncture, vaccination, acne, cut or burn), fibrosis is called "excessive scar". It can be keloid or hypertrophic scar. They consist of disfiguring dense fibrous tissue that in keloids extends beyond the initial site of injury, or in hypertrophic scars remains within the initial borders of injury.

[0133] "Treatment" of a disease means in the present invention the elimination or reduction of one or some, especially all, of the symptoms of the disease.

[0134] "Prevention" of a disease means in the present invention the fact of preventing or reducing the appearance of one or several (especially all) of the symptoms of the disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0135] Cyclic sugar amino acid derivatives The cyclic sugar amino acid derivative according to the present invention is a compound of formula (I) as defined above.

[0136] The compounds of formula (I) according to the present invention may be, for example, compounds of the following formula (Ia) or (Ib):

[0137] [ka]

[0138] (In the formula, n, R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above or below), or a salt, solvate, tautomer, stereoisomer or a mixture of stereoisomers in any ratio, particularly a mixture of enantiomers, in particular a racemic mixture, thereof.

[0139] The compounds of formula (I) according to the present invention may, for example, be represented by the following formula (Ic) or (Id):

[0140] [ka]

[0141] (In the formula, n, R, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is as defined above or below), or a salt, solvate, tautomer, stereoisomer or a mixture of stereoisomers in any ratio, particularly a mixture of enantiomers, in particular a racemic mixture, thereof.

[0142] R is CH 2 OSiR a1 R b1 R c1 , C.H. 2 OR 8 , C.H. 2 O.C.(O)R 9 , C.H. 2 OCO 2 R 10 , C.H. 2 OC(O)NR 11 R 12 , C.H. 2 OP(O)(OR 13 ) 2 or CH 2 OSO 3 R 14 group, preferably CH 2 OSiR a1 R b1 R c1 , C.H. 2 OR 8 or CH 2 O.C.(O)R 9 group, more preferably CH 2 OR 8 or CH 2 O.C.(O)R 9 group, more preferably CH 2 OR 8 It may represent a group.

[0143] R is, in particular, CH 2 OR 8 R may represent a group; 8 is a hydrogen atom, an O-protecting group or (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group; or CH 2 O.C.(O)R 9 R may represent a group; 9 is (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group.

[0144] R is more particularly CH 2 OR 8 R may represent a group; 8 represents a hydrogen atom or an O-protecting group. For example, R is CH 2 OH or CH 2 It may represent an OBn group.

[0145] R 1 and R 2 are independent of each other, a2 R b2 R c2 , OR 15 , O.C.(O)R 16 , O.C.O. 2 R 17 or OC(O)NR 18 R 19 Groups, advantageously OSiR a2 R b2 R c2 , OR 15 or O.C.(O)R 16 group, more preferably OR 15 or O.C.(O)R 16 More preferably, OR 15 It may represent a group.

[0146] R 1 and R 2 In detail, independently of each other, OR 15 R may represent a group;15 is a hydrogen atom, an O-protecting group or (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group, or OC(O)R 16 R may represent a group; 16 is (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group.

[0147] R 1 and R 2 More specifically, independently of each other, OR 15 R may represent a group; 15 represents a hydrogen atom or an O-protecting group. For example, R 1 and R 2 may represent an OH or OBn group.

[0148] Preferably, R 1 and R 2 are identical and represent in particular an OH or OBn group.

[0149] In particular, R is CH 2 OR 8 represents a group, R 1 and R 2 are independent of each other, OR 15 represents a group, R 8 and R 15 R advantageously represents a hydrogen atom or an O-protecting group (e.g. Bn). 8 and two R 15 The groups may be the same, for example H or an O-protecting group (eg Bn).

[0150] According to another particular embodiment, R=CH 2 OH and R 1 =R 2 =OH or R=CH 2 OBn and R 1 =R 2 =OBn.

[0151] According to a first embodiment, R 3 is OSiR a3 R b3 R c3 , OR 22 , O.C.(O)R 23 , O.C.O. 2 R 24 ,OCONR 25 R 26 , N.R. 29 R 30 , N.R. 31 C(O)R 32 , N.R. 33 C(O)OR 34 , N(C(O)R 35 )C(O)R 36 , N(C(O)R 37 )C(O)OR 38 ORN(C(O)OR 39 )C(O)OR 40 Groups, advantageously OSiR a3 R b3 R c3 , OR 22 , O.C.(O)R 23 , N.R. 29 R 30 , N.R. 31 C(O)R 32 or NR 33 C(O)OR 34 group, more preferably OR 22 , O.C.(O)R 23 or NR 31 C(O)R 32 More preferably, OR 22 or NR 31 C(O)R 32 Represents a group.

[0152] R 3 For more information, see OR 22 R may represent a group; 22 is a hydrogen atom, an O-protecting group or (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group;OC(O)R 23 R may represent a group; 23 is (C 1 ~C6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group; or NR 31 C(O)R 32 R may represent a group; 31 is a hydrogen atom or (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group, R 32 is (C 1 ~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) represents an alkyl group.

[0153] R 3 For more details, see OR 22 R may represent a group; 22 represents a hydrogen atom or an O-protecting group (e.g., Bn); or NR 31 C(O)R 32 R may represent a group; 31 represents a hydrogen atom, R 32 is (C 1 ~C 6 ) alkyl. For example, R 3 may represent an OH, OBn, OMOM or NHAc group, in particular OH or OBn.

[0154] According to a second embodiment, R 3 is OSiR a3 R b3 R c3 , OR 22 , O.C.(O)R 23 , O.C.O. 2 R 24 or OCONR 25 R 26 Groups, advantageously OSiR a3 R b3 R c3 , OR 22 or O.C.(O)R 23 group, more preferably OR 22 or O.C.(O)R 23 More preferably, OR 22 It may represent a group.

[0155] R 3 For more information, see OR 22 R may represent a group; 22 is a hydrogen atom, an O-protecting group or (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group; or OC(O)R 23 R may represent a group; 23 is (C 1 ~C 6 )-alkyl, aryl or aryl-(C 1 ~C 6 )-alkyl group.

[0156] R 3 For more details, see OR 22 R may represent a group; 22 represents a hydrogen atom or an O-protecting group (e.g., Bn). For example, R 3 may represent an OH or OBn group.

[0157] According to a particular embodiment, R 1 , R 2 and R 3 are identical.

[0158] According to another particular embodiment, R is CH 2 OR 8 R represents a group; 1 and R 2 are independent of each other, OR 15 R represents a group; 3 OR 22 represents a group, R 8 , R 15 and R 22 R advantageously represents a hydrogen atom or an O-protecting group (e.g. Bn). 8 and two R 15 The groups can be the same, for example H or an O-protecting group (e.g. Bn). 8 , 2 R 15 and R 22 The groups may also be the same, for example H or an O-protecting group (eg Bn).

[0159] According to another particular embodiment, R=CH 2 O.H., R. 1 =R 2 =OH or R 1 =R 2 =R 3 =OH.

[0160] R 4 is advantageously a hydrogen or halogen atom, or OR 41 group; in particular, a hydrogen atom or an OR 41 group; more specifically, OR 41 It may represent a group.

[0161] Even more advantageously, R 4 is a hydrogen or halogen atom, or OH, an O-protecting group, -O-(C 1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl group; in particular a hydrogen atom or an OH, O-protecting group, -O-(C 1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl groups; more particularly OH, O-protecting groups, -O-(C 1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl groups.

[0162] R 4 is a hydrogen or halogen atom, or OH, -O-(C 1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl group; in particular a hydrogen atom or OH, -O-(C 1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl groups; more particularly OH, -O-(C1 ~C 6 )-alkyl, -O-aryl and -O-(C 1 ~C 6 )-alkyl-aryl groups.

[0163] For more details, see R 4 may represent a hydrogen or halogen (e.g. Br, Cl, F) atom, or an OH or O-protecting group (e.g. OMe or OBn); advantageously a hydrogen atom, or an OH or O-protecting group (e.g. OMe or OBn); e.g. H or OH.

[0164] R 4 may in particular be an OH or O-protecting group, such as OH, OMe or OBn; preferably an OH group.

[0165] R 5 and R 6 are identical or different and are preferably a hydrogen atom or -CO 2 -R GP1 R GP1 may represent an N-protecting group as defined above, such as Cbz, Boc or Fmoc, especially Cbz or Boc. 5 and R 6 At least one of R is a hydrogen atom. 5 and R 6 Both represent hydrogen atoms.

[0166] According to a particular embodiment, R=CH 2 OH or CH 2 OBn and R 1 =R 2 =R 3 =OH or OBn.

[0167] According to another particular embodiment, R=CH 2 OH and R 1 =R 2 =R 3 =OH.

[0168] According to yet another particular embodiment, R=CH2 O.H., R. 1 =R 2 =R 3 =OH and R 4 =H or OH, particularly OH.

[0169] According to a particular embodiment, the compound of the present invention has formula (I): or a salt, solvate, tautomer, stereoisomer or mixture of stereoisomers in any ratio, particularly a mixture of enantiomers, in particular a racemic mixture, of the formula: During the ceremony, - n represents 1 or 2, and preferably 2, - R, CH 2 OR 8 represents - R 1 and R 2 are independent of each other, OR 15 represents - R 3 OR 22 represents - R 4 is H or OR 41 , for details see OR 41 represents or Or R and R 1 together with the carbon atom which carries them form the following formula:

[0170] [ka]

[0171] and / or forming a cyclic acetal having the formula (R 1 and R 2 ), (R 2 and R 3 ) and / or (R 3 and R 4 ), together with the carbon atom which carries them, form the following formula:

[0172] [ka]

[0173] forming a cyclic acetal having the formula - R 8 , R 15 and R 22 are each independently a hydrogen atom or an O-protecting group (e.g., a(C 1 ~C 6 ) alkyl or aryl-(C 1 ~C 6 ) an alkyl group; - R 41 represents a hydrogen atom, an O-protecting group (e.g., (C 1 ~C 6 ) alkyl or aryl-(C 1 ~C 6 ) alkyl group) or (C 1 ~C 6 ) Alkyl, aryl, aryl-(C 1 ~C 6 ) alkyl, or (C 1 ~C 6 )-alkyl-aryl groups, which are optionally unsubstituted or which contain halogen atoms and (C 1 ~C 6 ) alkoxy; - R d and R e are each independently a hydrogen atom or (C 1 ~C 6 ) represents an alkyl group.

[0174] In this embodiment, R 5 and R 6 are identical or different and are preferably a hydrogen atom or -CO 2 -R GP1 R GP1 may represent an N-protecting group as defined above, such as Cbz, Boc or Fmoc, especially Cbz or Boc. 5 and R 6 At least one of R is a hydrogen atom. 5 and R 6 Both represent hydrogen atoms.

[0175] The compound of formula (I) is the following compound:

[0176] [ka]

[0177] and the salts and solvates thereof, especially the acid addition salts with hydrochloric acid or acetic acid, more especially with hydrochloric acid.

[0178] The compound of formula (I) is the following compound:

[0179] [ka]

[0180] and the salts and solvates thereof, especially the acid addition salts with hydrochloric acid or acetic acid, more especially with hydrochloric acid.

[0181] In particular, the compound of formula (I) may be Compound 4, Compound 5, Compound 6, Compound 15, Compound 19, Compound 22, Compound 23, Compound 24, Compound 27, Compound 28, Compound 29, Compound 32, Compound 33 or Compound 34 as described in the Examples below.

[0182] Preferably, the compound of formula (I) is compound 6 or a salt and / or solvate thereof, for example an acid addition salt, in particular with hydrochloric acid or acetic acid, for example with hydrochloric acid. Most preferably, it is compound 6.

[0183] Preparation process The present invention also relates to a process for preparing a compound of formula (I) as defined above, comprising steps (a) to (c).

[0184] Process (a): The cyclization step may be carried out in an acidic medium for compounds of formula (II), especially in the presence of an acid, such as acetic acid.

[0185] The reaction may be carried out in a solvent such as toluene, especially at reflux.

[0186] In the case of this reaction, advantageously R 5 '≠ H and / or R 6 '≠H, R'≠CH 2 O.H., R. 1 '≠OH,R 2 '≠OH,R 3 ' ≠ OH and R 4 Therefore, to prepare compounds with such substituents, OH or NH 2 The functional groups should be protected, preferably by protecting groups as defined above, before cyclizing the compound of formula (II) to the compound of formula (I).

[0187] The compound of formula (II) has the following formula (III):

[0188] [ka]

[0189] (In the formula, n, R', R 1 ', R 2 ', R 3 ', R 4 ', R 5 ', R 6 ' and R 7 can be prepared by reducing the imine function of a compound of formula (I) which is as defined above.

[0190] The reduction reaction can be carried out with borohydrides, e.g. NaBH 3 CN or NaBH(OAc) 3 The method may be carried out in the presence of

[0191] The reaction may be carried out in a solvent such as dichloroethane.

[0192] The compound of formula (III) Formula (IV):

[0193] [ka]

[0194] (In the formula, R', R 1 ', R 2 ', R 3 ' and R 4 ' is as defined above, and A 1 is CHO or C(OA 2 )(OA 3 ), and A 2 and A 3 are independent of each other, H, (C 1 ~C 6 ) alkyl or aryl-(C 1 ~C 6 ) alkyl; in particular A 2 =H, and A 3 is (C 1 ~C 6 ) alkyl or aryl-(C 1 ~C 6 ) alkyl, especially (C 1 ~C 6 ) alkyl) The following formula (V):

[0195] [ka]

[0196] (In the formula, n, R 5 ', R 6 ' and R 7 can be prepared by reacting a compound of Formula (I) with a compound of Formula (I), which is as defined above, or a salt thereof, for example the hydrochloride salt.

[0197] This reaction may be carried out in toluene at reflux temperature in the presence of a Dean-Stark apparatus.

[0198] The reaction can be carried out in the presence of a base, such as triethylamine or NaHCO 3 and optionally a desiccant, e.g., MgSO 4In this case, dichloromethane or dichloroethane can be used as the solvent. The base facilitates purification of PsNEt 2 (diethylaminomethyl-polystyrene). In this case the solvent may be dichloroethane.

[0199] The reaction between the compound of formula (IV) and the compound of formula (V) and the reduction of the compound of formula (III) may be in one pot.

[0200] In the case of these reactions, advantageously, R 5 '≠ H and / or R 6 '≠H, R'≠CH 2 O.H., R. 1 '≠OH,R 2 '≠OH,R 3 ' ≠ OH and R 4 Therefore, to prepare compounds with such substituents, OH or NH 2 The functional groups should preferably be protected by protecting groups as defined above before carrying out the reaction between the compound of formula (IV) and the compound of formula (V). Of course, CH 2 -(CH 2 ) n -NH 2 Partial NH 2 The base is A 1 The compound is left unprotected (which may be in the form of a salt) so as to be capable of reacting with the

[0201] Compounds of formula (IV) may be prepared as disclosed in WO2015 / 140178. Compounds of formula (V) may be prepared according to the methods disclosed in the Examples below.

[0202] The compound of formula (II) has the following formula (VI):

[0203] [ka]

[0204] (In the formula, R', R 1 ', R 2 ', R 3 ' and R 4 may also be prepared by reacting a compound of formula (V) as defined above, or a salt thereof, wherein LG′ is as defined above and LG represents a leaving group, especially a sulfonate, for example a triflate.

[0205] The substitution reaction is advantageously carried out using a base, e.g. K 2 CO 3 The reaction may be carried out in a solvent such as DMF.

[0206] In the case of this reaction, advantageously R 5 '≠ H and / or R 6 '≠H, R'≠CH 2 O.H., R. 1 '≠OH,R 2 '≠OH,R 3 ' ≠ OH and R 4 Therefore, to prepare compounds with such substituents, OH or NH 2 The functional groups should preferably be protected by protecting groups as defined above before carrying out the reaction between the compound of formula (VI) and the compound of formula (V).

[0207] Compounds of formula (VI) may be prepared as disclosed in WO2015 / 140178.

[0208] The compound of formula (II) has the following formula (VII):

[0209] [ka]

[0210] (In the formula, R', R 1 ', R 2 ', R 3 ' and R 4 ' is as defined above), Formula (VIII):

[0211] [ka]

[0212] (where n, R 5 ', R 6 ' and R 7 can also be prepared by reacting a compound of formula (I) with a compound of formula (II) which is as defined above.

[0213] The reduction reaction can be carried out with borohydrides, e.g. NaBH 3 CN or NaBH(OAc) 3 The method may be carried out in the presence of

[0214] The reaction may be carried out in a solvent such as dichloroethane.

[0215] In the case of this reaction, advantageously R 5 '≠ H and / or R 6 '≠H, R'≠CH 2 O.H., R. 1 '≠OH,R 2 '≠OH,R 3 ' ≠ OH and R 4 Therefore, to prepare compounds with such substituents, OH or NH 2 The functional groups should preferably be protected by protecting groups as defined above before carrying out the reaction between the compounds of formula (VII) and (VIII).

[0216] Compounds of formula (VII) can be prepared according to the methods disclosed in the following examples. Compounds of formula (VIII) are commercially available or can be easily prepared by those skilled in the art (as described in Journal of Organic Chemistry 1998, 63, pp. 3741-3744).

[0217] Process (b): The protected forms are protected groups, in particular OH groups protected with any O-protecting group, e.g. as defined previously, in particular a benzyl group, and / or one or two NH groups protected with N-protecting groups, e.g. as defined previously, in particular a Cbz or Boc group. 2 Contains a group.

[0218] Deprotection conditions are well known to those skilled in the art (e.g., "Greene's Protective Groups In Organic Synthesis", 4th Edition, 2007, John Wiley & Sons, Hoboken, New Jersey). For example, OH groups protected with benzyl groups or NH groups protected with Cbz groups can be deprotected with 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,19,20,19,21,22,23,24,25,26,27,28,29,30,31,32,27,33,28,29,34,29,35,36,29,37,38,39,40,39,41,42,43,44,55,56,57,67,78,79,80,8 2 The deprotection of the group is carried out by H 2 and may be carried out in the presence of a catalyst, such as Pd / C.

[0219] A deprotection step may be carried out after and / or during step (a).

[0220] The deprotection step may be carried out after, before and / or during step (c).

[0221] Process (c): The salification or solvation step can be carried out by methods well known to those skilled in the art, in particular by reaction of the compound of formula (I) obtained in step (a) or (b) with an organic or inorganic acid, an organic or inorganic base or a solvent as previously defined.

[0222] The solvent may especially be the solvent used in the last step of preparing the compound according to the invention, in particular the solvent used in step (a) or (b).

[0223] Thus, steps (a) and / or (b), and (c) may be carried out in a single step without isolating intermediate compounds.

[0224] The compounds obtained by the process according to the invention may be separated from the reaction medium by methods well known to those skilled in the art, for example by extraction, evaporation of the solvent or by precipitation or crystallization followed by filtration.

[0225] The compounds may, if necessary, also be purified by methods well known to those skilled in the art, for example by recrystallization, by distillation, by ion exchange purification (DOWEX® 50Wx8), by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC).

[0226] Cosmetic or pharmaceutical composition The present invention also relates to a cosmetic or pharmaceutical (eg dermatological) composition comprising at least one compound of formula (I) as defined above, and at least one physiologically acceptable excipient.

[0227] Such compositions are more particularly intended for topical (e.g. transdermal) or parenteral (e.g. subcutaneous or intradermal) administration, preferably for topical administration on the skin, particularly the scalp, or for injection, particularly subcutaneous or intradermal injection.

[0228] Thus, such a composition may be a solution, dispersion, emulsion, oil, ointment, shampoo, paste, cream, lotion, milk, foam, gel, suspension, spray, serum, patch, stick or mask.

[0229] The compositions of the invention may contain one or several additives as excipients, such as suspending agents, wetting agents, antioxidants, emollients, other moisturizing agents, thickening agents, chelating agents, buffering agents, tonicity agents, fragrances, preservatives, pigments or colorants, opacifiers or mattifying agents. Such additives are conventional to those skilled in the art and are exemplified below.

[0230] Suspending agents may be, for example, alginates, sodium carboxymethylcellulose, methylcellulose, hydroxylmethylcellulose, hydroxylethylcellulose, hydroxylpropylmethylcellulose, microcrystalline cellulose, gums such as acacia, tragacanth or xanthan gum, gelatin, carrageenan, polyvinylpyrrolidone.

[0231] The humectant can be glycerin, propylene glycol, or a non-ionic surfactant such as lecithin, polysorbate, or poloxamer.

[0232] Antioxidants can be used to protect the components of the composition from oxidizing agents contained within or in contact with the composition. Examples of antioxidants include ascorbic acid, ascorbyl palmitate, citric acid, acetylcysteine, sulfites (bisulfites, metabisulfites), sodium formaldehyde sulfoxylate, monothioglycerol, thiourea, butylated hydroxyanisole, butylated hydroxytoluene, potassium propyl gallate, octyl gallate, dodecyl gallate, phenyl-α-naphthyl-amine, and tocopherols, such as α-tocopherol.

[0233] Emollients are agents that soften and smooth the skin.Examples of emollients include oils and waxes, such as siloxanes, such as dimethicone and its derivatives, microcrystalline wax, polyethylene, triglyceride esters, such as those of castor oil, cocoa butter, safflower oil, corn oil, olive oil, cod liver oil, almond oil, palm oil, squalene and soybean oil, acetylated monoglycerides, ethoxylated glycerides, fatty acids, alkyl esters of fatty acids, alkenyl esters of fatty acids, fatty alcohols, fatty alcohol ethers, ether-esters, lanolin and derivatives of lanolin, polyhydric alcohol esters, wax esters, such as beeswax, vegetable waxes, phospholipids, sterols, isopropyl palmitate or glyceryl stearate.

[0234] Moisturizers increase the water content of the skin and keep it soft and smooth, and can be, for example, urea, amino acids, lactic acid and its salts (e.g., sodium lactate), glycerol (also called glycerin), propylene glycol, butylene glycol, PEG (polyethylene glycols - e.g., PEG-4 to PEG-32), sorbitol, xylitol, maltitol, mannitol, polydextrose, collagen, elastin, hyaluronic acid and its salts (e.g., sodium or potassium salts), pectin, gelatin, chitosan, aloe vera, honey, etc.

[0235] Thickeners are used to increase the viscosity and concentration of compositions.Examples of thickeners include lipid thickeners, such as cetyl alcohol, stearyl alcohol, myristyl alcohol, carnauba wax or stearic acid; natural thickeners, such as cellulose derivatives, such as hydroxyethylcellulose, guar gum, locust bean gum, xanthan gum or gelatin; inorganic thickeners, such as silica, bentonite or magnesium aluminum silicate; synthetic thickeners, such as carbomer; ionic thickeners, such as NaCl.

[0236] The chelating agent can be an ethylenediaminetetraacetic acid (EDTA) salt.

[0237] The buffering agent can be acetate, citrate, tartrate, phosphate, triethanolamine (Tris).

[0238] Examples of fragrances or flavorings include peppermint, rose oil, rose water, aloe vera, clove oil, menthol, camphor, eucalyptus oil, and other plant extracts. Masking agents may be used to remove certain odors from the composition.

[0239] Preservatives can be used to protect the composition from decomposition.Examples of preservatives include phenol, cresol, chlorobutanol, phenoxyethanol, butylparaben, propylparaben, ethylparaben, methylparaben, propylparaben, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, and mixtures thereof, such as liquipar oil.However, the composition of the present invention may not contain preservatives.

[0240] Pigments or colorants are used to modify the color of the composition, for example to obtain a white composition.

[0241] Opacifying agents, such as titanium oxide, are used in transparent or clear compositions to make them opaque. Thus, the present invention can be transparent or opaque depending on the presence or absence of an opacifying agent.

[0242] A mattifying agent is an ingredient that mattifies the skin and thus prevents the skin from becoming shiny. It can be, for example, talc, silica, rice flour or mixtures thereof, among others, in micronized form.

[0243] Those skilled in the art will be able to vary the amount of the compounds of formula (I) according to the invention in a cosmetic or pharmaceutical (eg dermatological) composition in order to obtain the desired effect.

[0244] For parenteral, particularly subcutaneous or intradermal administration, the cosmetic or pharmaceutical composition according to the invention may more particularly be in the form of an aqueous suspension or solution, which is advantageously sterile. Such parenteral (e.g. subcutaneous) compositions advantageously contain a physiologically acceptable medium, generally based on isotonic saline solution, i.e. 0.9% aqueous NaCl solution (normal saline). Non-aqueous water-miscible cosolvents, such as ethanol, glycerin, propylene glycol or n-lactamides, may also be used. The parenteral composition of the invention may also contain one or more additives, such as suspending agents, wetting agents, preservatives, antioxidants, chelating agents, buffering agents, isotonicity agents, etc. Such additives are conventional to those skilled in the art, and examples have been mentioned above.

[0245] For topical administration, the cosmetic or pharmaceutical composition according to the invention may be in a conventional form for topical administration, including creams, lotions, serums, gels, foams, dispersions, suspensions, emulsions, sprays, shampoos, masks, milks, etc. The active ingredient may be administered to animals, preferably mammals, including humans, in a unit form for administration mixed with a conventional pharmaceutical carrier. Such topical compositions generally contain a physiologically acceptable medium, inter alia, based on water or a solvent, such as an alcohol (e.g. ethanol), ether or glycol. The topical composition of the invention may also contain one or more additives, such as antioxidants, emollients, other moisturizing agents, thickeners, fragrances, preservatives, pigments or colorants, or opacifiers. Such additives are conventional to those skilled in the art, and examples have been mentioned above.

[0246] For more details: For the treatment and / or prevention of skin ageing, for skin protection or skin regeneration, For skin plumping and / or skin volumizing and / or skin densification and / or wrinkle filling and / or moisturizing and / or re-lipidizing the skin or hair and / or stimulating hair growth, for the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis; or For the treatment and / or prevention of fibrosis (e.g. excessive scarring, e.g. keloids or hypertrophic scars) or for the healing; Cosmetic or pharmaceutical (e.g. dermatological) compositions for the treatment of inflammation (e.g. chronic low-grade inflammation, which occurs in particular in various aging tissues and is referred to as "inflammaging") are contemplated.

[0247] Cosmetic or pharmaceutical use According to a first aspect, the present invention relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use in the treatment and / or prevention of skin ageing, in skin protection or in skin regeneration.

[0248] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, such as a cosmetic, for the treatment and / or prevention of skin ageing, skin protection or skin regeneration.

[0249] The present invention also relates to a method, such as a cosmetic method, for the treatment and / or prevention of skin ageing, skin protection or skin regeneration, by applying to the skin a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0250] The present invention also relates to a method for the treatment and / or prevention of skin ageing, skin protection or skin regeneration by applying to the skin of a person in need thereof an effective amount of a compound of formula (I) according to the present invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0251] Indeed, it has been demonstrated that the compounds of formula (I) according to the invention in particular have the properties of promoting the growth (proliferation) of skin cells under stress conditions, protecting them against different stresses, in particular oxidative stress, reducing inflammation through the inhibition of cytokine, for example IL6, release, promoting the remodeling of the extracellular matrix, inducing the synthesis of hyaluronic acid and promoting adipogenesis.

[0252] In such uses or methods, the compounds of formula (I) according to the invention, or the cosmetic or pharmaceutical (eg dermatological) compositions, may be applied topically on the skin.

[0253] According to a second aspect, the present invention relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for plumping the skin, and / or volumizing the skin, and / or compacting the skin, and / or filling in wrinkles, and / or moisturizing the skin or hair, and / or re-lipidizing the skin or hair, and / or stimulating hair growth.

[0254] The present invention also relates to a method for plumping the skin, and / or volumizing the skin, and / or compacting the skin, and / or filling in wrinkles, and / or moisturizing the skin or hair, and / or re-lipidizing the skin or hair, and / or stimulating hair growth, which method comprises the topical administration, in particular on the skin (including the scalp for stimulating hair growth) or subcutaneously or intracutaneously, of an effective amount of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0255] The present invention also relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use for plumping the skin, and / or volumizing the skin, and / or compacting the skin, and / or filling in wrinkles, and / or moisturizing the skin or hair, and / or re-lipidizing the skin or hair, and / or stimulating hair growth.

[0256] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for preparing a cosmetic or dermatological composition intended for plumping the skin, and / or volumizing the skin, and / or compacting the skin, and / or filling in wrinkles, and / or moisturizing the skin or hair, and / or re-lipidizing the skin or hair, and / or stimulating hair growth.

[0257] In fact, the compounds of formula (I) according to the invention have been demonstrated to have an activity of increasing the volume of adipose tissue, in particular through the proliferation of preadipocytes, through the synthesis of lipids, for example cholesterol, through the reduction of inflammation, by inhibition of cytokine, for example IL6 release, through the synthesis of hyaluronic acid, as well as an activity of hair growth, in particular through the synthesis of lipids and also through the proliferation of fibroblasts.

[0258] In such uses or methods, a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, may be applied topically, subcutaneously or intradermally on the skin, including the scalp, preferably subcutaneously or intradermally.

[0259] According to a third aspect, the present invention relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use in the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis.

[0260] The present invention also relates to the use of a compound of formula (I) according to the invention or a cosmetic or pharmaceutical (e.g. dermatological) composition for the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis.

[0261] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, intended for the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis.

[0262] The present invention also relates to a method for the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis, comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) according to the present invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0263] Indeed, as reported in the literature (J. Invest. Dermatol. 1991, 96, 523-526; Contact Dermatitis 2008, 58, 255-262; Skin Pharmacol. Physiol. 2015, 28, 42-55), such pathologies are associated with a decrease in lipid synthesis causing damage to the skin barrier. Compounds of formula (I) according to the invention have been demonstrated to be useful in lipid synthesis, such that such compounds can be used for the treatment of these pathologies, in particular by stimulating lipid synthesis by keratinocytes.

[0264] The administration of the compounds of formula (I) according to the invention, or of the cosmetic or pharmaceutical (e.g. dermatological) compositions, in the case of the treatment of dry skin, and / or atopic dermatitis, and / or atopic eczema, and / or psoriasis, is advantageously topical or parenteral (e.g. subcutaneous or intradermal), preferably topical.

[0265] According to a fourth aspect, the present invention also relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use in the treatment and / or prevention of fibrosis, in particular excessive scarring, such as keloids or hypertrophic scarring, or for use in the healing.

[0266] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for the manufacture of a cosmetic or pharmaceutical (e.g. dermatological) composition intended for the treatment and / or prevention, or healing, of fibrosis, in particular excessive scarring, such as keloids or hypertrophic scarring.

[0267] The present invention also relates to the use of a compound of formula (I) or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention in the treatment and / or prevention of, or for the healing of, fibrosis, in particular excessive scarring, such as keloids or hypertrophic scarring.

[0268] The present invention also relates to a method for treating and / or preventing or healing fibrosis, in particular excessive scarring, such as keloids or hypertrophic scarring, comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0269] Indeed, it has been demonstrated that the compounds of formula (I) according to the invention have a role in the regulation of several genes involved in the mechanisms of healing and treating / preventing fibrosis, e.g. keloids (e.g. genes involved in extracellular matrix organization or in inhibiting fibrogenesis).

[0270] The compound of formula (I) according to the present invention, or the cosmetic or pharmaceutical (e.g. dermatological) composition, can be used in combination with, and more particularly after, laser or surgical treatment.Indeed, a patient suffering from fibrosis, particularly excessive scarring, such as keloid or hypertrophic scarring, can first be treated with a laser or by surgery to remove the excess fibrous connective tissue, and then the compound of formula (I) according to the present invention, or the cosmetic or pharmaceutical (e.g. dermatological) composition, can be applied topically on the wound during healing to prevent the reappearance of the excess fibrous connective tissue.

[0271] The administration of the compounds of formula (I) according to the invention, or of the cosmetic or pharmaceutical (e.g. dermatological) compositions, in the case of the treatment and / or prevention or healing of fibrosis, is advantageously topical or parenteral (e.g. subcutaneous or intradermal), preferably topical.

[0272] According to a fifth aspect, the present invention also relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use in the treatment of inflammation, especially chronic low-grade inflammation, which occurs in various aging tissues and is referred to as "inflammaging".

[0273] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, intended for the preparation of a cosmetic or pharmaceutical (e.g. dermatological) composition intended for the treatment of inflammation, in particular chronic low-grade inflammation, which occurs in various aging tissues and is referred to as "inflammaging".

[0274] The present invention also relates to the use of a compound of formula (I) or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention in the treatment of inflammation, in particular chronic low-grade inflammation, which occurs in various aging tissues and is referred to as "inflammaging".

[0275] The present invention also relates to a method for treating inflammation, in particular chronic low-grade inflammation, which occurs in a variety of aging tissues and is referred to as "inflammaging", comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition.

[0276] Indeed, it has been demonstrated that the compounds of formula (I) according to the invention have a role in regulating some genes involved in the mechanisms of inflammation (e.g. genes involved in the inhibition of inflammatory responses and chronic inflammatory disorders) and in reducing inflammation through the inhibition of IL6 release in tissues (e.g. adipocytes).

[0277] Thus, the compounds according to the invention may be useful for treating obesity or promoting weight loss or, more particularly, fat loss in patients suffering from obesity, and also for preventing the onset of metabolic syndrome, e.g. type 2 diabetes.

[0278] The present invention therefore also relates to a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, for use in a method for promoting weight loss, or more particularly fat loss, in the treatment of obesity or in patients suffering from obesity, or in preventing the onset of metabolic syndrome, e.g. type 2 diabetes.

[0279] The present invention also relates to the use of a compound of formula (I) according to the invention, or a cosmetic or pharmaceutical (e.g. dermatological) composition, intended for the treatment of obese or obese patients, for promoting weight loss or more particularly fat loss, or for preventing the onset of metabolic syndrome, such as type 2 diabetes.

[0280] The present invention also relates to the use of a compound of formula (I) or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention for promoting weight loss, or more particularly fat loss, in the treatment of obese or obese patients, or for preventing the onset of metabolic syndrome, e.g. type 2 diabetes.

[0281] The present invention also relates to a method for treating obesity or in a patient suffering from obesity, for promoting weight loss, or more particularly fat loss, or for preventing the onset of metabolic syndrome, such as type 2 diabetes, comprising the administration to a person in need thereof of an effective amount of a compound of formula (I), or a cosmetic or pharmaceutical (e.g. dermatological) composition according to the invention.

[0282] bandage The present invention also relates to a dressing comprising a pad, compress or sponge impregnated with a cosmetic composition or a pharmaceutical (eg dermatological) composition according to the invention as defined above.

[0283] Such dressings may be applied to injuries / wounds during the healing process to prevent or reduce the appearance of keloids or hypertrophic scars and may thus be for use in the treatment and / or prevention, especially in the prevention, or in the healing of fibrosis, particularly excessive scarring, such as keloids or hypertrophic scars.

[0284] It is therefore preferably sterile.

[0285] Such a dressing may more particularly be a compression dressing.

[0286] The pads, packs or sponges may be made of a variety of materials, preferably absorbent materials such as cotton, gauze, porous polymeric materials, or combinations thereof, especially cotton and / or gauze.

[0287] This may also include a bandage or adhesive means to maintain the pad or compress in intimate contact with the injury or wound.

[0288] This dressing may be used in combination with, and more particularly after, laser or surgical treatment. Indeed, a patient suffering from fibrosis, and particularly from excess scarring, such as keloids or hypertrophic scarring, may first be treated with a laser or by surgery to remove the excess fibrous connective tissue, and then a dressing according to the invention may be applied onto the wound to prevent the reappearance of the excess fibrous connective tissue during healing.

[0289] Preservation, protection and regeneration of biological materials or microorganisms The present invention also relates to the use of the compounds of formula (I) as defined above for the preservation and / or protection and / or regeneration of biological materials or microorganisms.

[0290] The present invention also relates to a method for preserving and / or protecting biological material or microorganisms by placing said biological material or microorganisms in a medium containing a compound of formula (I) as defined above.

[0291] Indeed, it has been demonstrated that the compounds of formula (I) according to the invention have cell growth promoting properties and cell protecting properties against stress, especially oxidative stress.

[0292] In particular, biological materials or microorganisms, in particular biological materials such as human organs, tissues (e.g. for transplantation), body fluids or cells, can be protected / preserved when placed at temperatures below 37°C, such as below 0°C, especially in cryopreservation conditions.

[0293] Cryopreservation of biological materials or microorganisms implies cooling the biological materials or microorganisms to subzero temperatures, in particular at temperatures of about -196°C, by using liquid nitrogen.

[0294] The biomaterial may in particular be a cell, a tissue, a body fluid or an organ, for example the biomaterial may be the organ or tissue intended to be transplanted (e.g. the skin or, in the case of a hair graft, a follicular unit, i.e. a part of the scalp containing one to four hair follicles).

[0295] Microorganisms may in particular be prokaryotic or eukaryotic microorganisms, especially unicellular or pluricellular.

[0296] The microorganisms may be selected from among bacteria, fungi including yeasts, algae, viruses including phages, microparasites (also called parasitic microorganisms) and protozoa, among others.

[0297] Culture, storage and / or preservation media The present invention also relates to a culture, storage and / or preservation medium comprising at least one compound of formula (I) as defined above.

[0298] The culture, storage and / or preservation medium may be in the form of a liquid or gel. It therefore contains water. However, the medium may also be in a dehydrated form that can be reconstituted by the addition of water.

[0299] This includes co-solvents (e.g., dimethyl sulfoxide (DMSO)), salts (e.g., NaCl, MgCl 2 , ZnCl 2 , MnCl 2 , CuCl 2 , K 2 PO 4 , K.H. 2 PO 4 , K 2 HPO 4 , Na 2 S 2 O 3 , K 2 SO 4 , MgSO 4 , KNO 3 , Ca(NO 3 ) 2 , Na 2 CO 3 , NaHCO 3 ), carbon sources, such as carbohydrates (e.g. glucose, lactose or sucrose) or polyols (e.g. mannitol or glycerol), vitamins (e.g. vitamins B1, B2, B6, B12, B3, B5, B9, B7, C, A, D, E and K), nitrogen and amino acid sources (e.g. peptones, beef or yeast extracts, serum, etc.), growth factors (e.g. insulin, transferrin, fibronectin, albumin), differentiation factors, antibiotics and antimycotics (also called antibacterial and antifungal agents - e.g. actinomycin D, amphotericin B, ampicillin, carbenicillin, cefotaxime, fosmidomycin, gentamicin, kanamycin, neomycin, streptomycin, penicillin, polymyxin B), hormones, cytokines and trace elements.

[0300] Other additives such as (eg pH) indicators, inhibitors may be present.

[0301] If it is in the form of a gel, the culture medium may further comprise a gelling agent, such as agar, gelatin, silica gel, and the like.

[0302] The present invention also relates to the use of the compounds of formula (I) as defined above as adjuvants in culture, storage and / or preservation media.

[0303] The culture, storage and / or preservation medium is intended for the culture, storage and / or preservation of biological material or microorganisms, which in the case of the culture medium are more particularly cells or tissues.

[0304] The invention is illustrated by the following non-limiting examples. EXAMPLES

[0305] The following abbreviations are used:

[0306] [Table 1A]

[0307] [Table 1B]

[0308] 1. Synthesis of the Compounds According to the Invention R 4 =R 1 It should be noted that the compounds according to the invention having =OH are obtained in the form of a mixture of the tautomeric forms illustrated in the above description. For practical reasons, these compounds are represented by the pyranose form.

[0309] 1.1. Synthesis of compound 6 via the first synthetic route Compound 6 can be prepared according to the following synthetic route.

[0310] [ka]

[0311] Synthesis of intermediate compound 1: The preparation of compound 1 is disclosed in WO2015 / 140178 (see compound 2).

[0312] Synthesis of intermediate compound 2: Compound 2 is prepared according to the following two steps.

[0313] [ka]

[0314] Compound 8 is prepared from commercially available compound 7 according to the method disclosed in Organic Letters 2006, 8, 17, 3865-3868.

[0315] Compound 2 is then obtained from compound 8 according to the protocol disclosed in J. Org. Chem. 1994, Vol. 59, No. 11, pp. 3216-3218, as follows:

[0316] Compound 8 (1 eq., 1.0 g, 2.37 mmol) was dissolved in a solution of HCl (1 M in AcOEt, 2.0 eq., 4.73 mL, 4.73 mmol). The reaction mixture was stirred at room temperature for 18 h. HCl (1 M in AcOEt, 1 eq., 2.37 mL, 2.37 mmol) was added again to complete the reaction. The reaction mixture was stirred for another 5 h. The mixture was then concentrated and diluted with Et 2 Co-evaporation with O gave 2.37 g of compound 2 (67% purity). The material was used in the next step without purification. 1 H NMR (MeOD, 300MHz): 1.44 (s, 9H); 1.54-2.10 (m, 4H); 2.93 (m, 2H); 4.10 (m, 1H); 5.10 (s, 2H); 7.29-7.38 (m, 5H). Mass (ESI+): 323.2 [M+H] + (NH 2 form)

[0317] Synthesis of intermediate compound 3: A solution of compound 1 (1 eq., 1.20 g, 1.59 mmol) in DCE (12.6 mL) was treated with PsNEt 2 (Diethylaminomethyl-polystyrene 3.2 mmol / g, 2.0 eq., 1.10 g, 3.18 mmol), compound 2 (67% purity, 1.0 eq., 0.85 g, 1.59 mmol) and MgSO 4 (5 eq., 0.96 g, 7.95 mmol) were added sequentially. The reaction was then refluxed for 16 h. The mixture was cooled to room temperature and then quickly filtered, rinsing with 10 mL of DCE. The resulting yellow solution was transferred to a round bottom flask and cooled to 0° C. under an inert atmosphere. To this solution was added sodium triacetoxyborohydride (2.0 eq., 0.67 g, 3.17 mmol) and acetic acid (1.0 eq., 0.09 mL, 1.59 mmol) in portions. The reaction was stirred at 0° C. for 30 min, then allowed to warm to room temperature and stir for 3 h.

[0318] NaHCO 3 A saturated aqueous solution of was added and the mixture was stirred vigorously for 5 min. The mixture was then extracted with DCM (3x). The combined organic layers were washed with Na 2 SO 4 It was dried over 400 rpm, filtered and concentrated.

[0319] The resulting crude oil was purified by chromatography (SiO 2 Purification by cartridge, cyclohexane / AcOEt: 90 / 10 to 80 / 20) gave compound 3 (1.05 g, 95% purity). 19 Fdec NMR (CDCl 3 , 282.5MHz): -109.5 (d, 258Hz, 1F, CF 2 ); -110.4 (d, 258Hz, 1F, CF 2 ). Mass (ESI+): 1015.5 [M+H] + ; 1037.5 [M+Na] +

[0320] Synthesis of intermediate compound 4: A solution of compound 3 (1 eq., 95% purity, 1.05 g, 0.98 mmol) and acetic acid (10.5 eq., 0.59 mL, 10.34 mmol) in toluene (11.4 mL) was heated to reflux for 18 h in a sealed tube. The reaction mixture was concentrated. The residue was purified by flash chromatography (80 g SiO 2 Purification by cartridge, cyclohexane / EtOAc 90 / 10 to 55 / 45) afforded compound 4 (0.83 g, 85% purity, 55% over 3 steps) as a colourless gum. 19 F NMR (CDCl 3 , 282.5MHz): -108.0 (br dd, 256Hz, 33Hz, 1F); -112.3 (br dd, 256Hz, 26Hz, 1F). 19 F dec NMR (CDCl 3 , 282.5MHz): -108.0 (d, 256Hz, 1F); -112.3 (d, 256Hz, 1F). Mass (ESI+): 958.5 [M+NH4]+; 963.5 [M+Na]+; 979.5 [M+K]+

[0321] Synthesis of intermediate compound 5: Palladium (10 wt% loading, 0.10 eq., 0.11 g, 0.10 mmol) was added to a solution of compound 4 (1 eq., 0.93 g, 0.99 mmol) in THF (38 mL) previously degassed with nitrogen. A solution of HCl (2 M in water, 4.0 eq., 2.0 mL, 3.95 mmol) was then added. The mixture was placed under a hydrogen atmosphere and stirred for 18 h. The reaction was degassed with nitrogen and then filtered (0.45 μm, H-PTFE) to remove palladium residues. The filter was washed with a mixture of THF and water and the combined solution was concentrated to remove THF. The residue was then diluted with water and the solution was filtered (0.2 μm, H-PTFE) and freeze-dried to give compound 5 (0.45 g) as a white powder. The material was used in the next step without purification.

[0322] Compound 5 is obtained as a mixture of the two following tautomeric forms, designated Form 1 and Form 2.

[0323] [ka]

[0324] 19 F dec NMR (D 2 O, 282.5MHz): Form 1 (55%): -115,7 (ddd, 255Hz, 25Hz, 8Hz, 1F, CF 2 ; -118,5 (ddd, 251Hz, 24Hz, 9Hz, 1F, CF 2 ) Form 2 (45%): -115.0 (ddd, 251Hz, 27Hz, 8Hz, 1F, CF 2 ); -116,5 (ddd, 255Hz, 26Hz, 7Hz, 1F, CF 2 ) Mass (ESI - ): 391.0 (MH) -

[0325] Synthesis of compound 6: Amberlite® IRA-67 (previously washed with water, 1.73 g) was added to a solution of compound 5 (0.45 g, 1.15 mmol) in water (30 mL). The solution was stirred at room temperature for 1 h30. The pH of the solution was measured (pH=6.8-7.0) and the mixture was filtered (0.2 μm, H-PTFE). The filtrate was then freeze-dried to give compound 6 (0.28 g, 69% yield) as an off-white powder.

[0326] Compound 6 is obtained as a mixture of the two following tautomeric forms, designated Form 1 and Form 2:

[0327] [ka]

[0328] 19 F NMR (D 2 O, 282.5MHz): Form 1 (57%): -118.2 (ddd, 252Hz, 23Hz, 11Hz); -115.5 (ddd, 252Hz, 24Hz, 10Hz). Form 2 (43%): -116.4 (ddd, 253Hz, 27Hz, 15Hz, 1F, CF 2 ); -115.2 (ddd, 253Hz, 27Hz, 15Hz, 1F, CF 2 ) Mass (ESI+): 357.1 [M+H] +

[0329] 1.2. Synthesis of compound 6 via the second synthetic route Compound 6 can be prepared according to the following synthetic route.

[0330] [ka]

[0331] Synthesis of intermediate compound 10: LiOH (4.5 eq., 1.29 g, 0.90 mmol) was added to a solution of compound 9 (1 eq., 10.0 g, 12 mmol - compound prepared according to the process disclosed in WO2012 / 085221 (see synthesis of compound 15)) in a mixture of THF (98 mL) and water (21.5 mL). The reaction mixture was stirred at room temperature for 18 h. Brine and 1M HCl were added until an acidic pH was achieved. The aqueous layer was then extracted with AcOEt and the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give crude compound 10 (10.9 g, 126% yield, 80% purity) as a yellow oil. The material was used in the next step without purification. 19 F NMR (CDCl 3 , 282.5MHz): -109.3 (d, 269Hz, 1F, CF2 ); -111.56 (d, 269Hz, 1F, CF 2 ). Mass (ESI - ):723.3 [MH] -

[0332] Synthesis of intermediate compound 11: Compound 10 (1 eq., 10.83 g, 11.95 mmol), HATU (1.5 eq., 6.95 g, 17.93 mmol), NH 4 A mixture of Cl (3 eq., 1.92 g, 35.85 mmol) and DIPEA (5.0 eq., 7.72 g, 59.75 mmol) was stirred at room temperature for 5 h. Brine was added and the mixture was extracted with AcOEt (2×). The combined organic layers were washed with brine (4×) and MgSO 4 The crude residue was purified by flash chromatography (Biotage® 80 g, cyclohexane / AcOEt 90:10 to 70:30) to give compound 11 (5.7 g, 66% yield, 93% purity) as a colorless oil. 19 F NMR (CDCl 3 , 282.5MHz): -110.5 (d, 270Hz, 1F, CF 2 ); -112.5 (d, 270Hz, 1F, CF 2 ). Mass (ESI + ): 724.3[M+H] + , 746.3[M+Na] + , 762.3[M+K] +

[0333] Synthesis of intermediate compound 16: NaBH 4 (7 eq., 1.76 g, 46.5 mmol) was added to a solution of compound 9 (1 eq., 5.00 g, 6.64 mmol) in dry THF (11 mL) and MeOH (33 mL) cooled to 0 °C under an inert atmosphere. The mixture was then stirred at 25 °C for 2.5 h. If the reaction was not complete, additional NaBH 4(7 eq., 1.76 g, 46.5 mmol) was added to the reaction pre-cooled to 0° C. The reaction mixture was stirred at 25° C. for an additional 2.5 h. After completion of the reaction, NH 4 A saturated aqueous solution of Cl and brine was added. The aqueous layer was extracted with AcOEt, and the organic layer was separated and washed with brine and then with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give crude compound 16 (4.41 g, 93%) as an off-white solid. The material was used in the next step without purification. 19 F NMR (CDCl 3 , 282.5MHz): -113.3 (ddd, 264Hz, 14Hz, 14Hz, 1F, CF 2 ); -114.3 (ddd, 264Hz, 15Hz, 1F, CF 2 ) Mass (ESI + ): 728.3 [M+H 2 O] + ; 733.3 [M+Na] + ;749.2 [M+K] +

[0334] Synthesis of intermediate compound 17: A solution of compound 16 (1 eq., 8.00 g, 11.3 mol) in dry DCM (163 mL) was added to a solution of triflic anhydride (2.3 eq., 4.34 mL, 15.9 mmol) and pyridine (2.3 eq., 2.11 mL, 25.9 mmol) in dry DCM (163 mL) cooled to 0° C. under an inert atmosphere. The mixture was stirred at 0° C. for 1 h and at room temperature for an additional 2 h. Water was then added to the reaction mixture and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give crude compound 17 (9.44 g, 100%) as an off-white solid. The material was used in the next step without purification. 19 F NMR (CDCl 3 , 282.5MHz): -74.5 (s, 3F, CF 3); -113.8 (ddd, 258Hz, 23Hz, 5Hz, 1F, CF 2 ); -116.2 (brdd, 258Hz, 23Hz, <5Hz,1F, CF 2 ). Mass (ESI + ): 860.2 [M+H 2 O] + ; 865.2 [M+Na] + ; 881.2 [M+K] +

[0335] Synthesis of intermediate compound 18: Sodium azide (0.96 g, 14.8 mmol, 5 eq) was added to a solution of compound 17 (1 eq., 2.5 g, 2.97 mmol) in dry DMF at room temperature under an inert atmosphere. The reaction mixture was stirred at 50° C. for 7 h and then cooled to room temperature. AcOEt was added and the organic mixture was washed with brine (2×) and Na 2 SO 4 The crude material was purified by flash chromatography (AIT® 80 g SiO 2 Purification by cartridge, cyclohexane / ethyl acetate 100:0 to 80:20) afforded compound 18 (0.42 g, 19%) as a white solid. 19 F NMR (CDCl 3 , 282.5MHz): -111.4 (ddd, 257Hz, 21Hz, 10Hz, 1F, CF 2 ); -112.52 (ddd, 257Hz, 22Hz, 11Hz, 1F, CF 2 ). Mass (ESI + ): 753.3 [M+H 2 O] + 758.3 [M+Na]+; 774.3 [M+K] +

[0336] Synthesis of intermediate compound 12: Step A: From compound 11 In an inert atmosphere, BH 3.THF complex (6 eq., 1.0 M in THF, 43.9 mL, 43.9 mmol) was added to a solution of compound 11 (1 eq., 5.70 g, 7.32 mmol) in dry THF (26.5 mL) at room temperature. The reaction mixture was then refluxed for 18 h. After completion of the reaction, methanol (10 mL) was carefully added under stirring at room temperature and the mixture was refluxed for another 30 min before being cooled and concentrated. HCl (6 M in water, 10 mL) was added and the mixture was heated to reflux for a short period and then cooled. The mixture was purified by distillation with NaHCO 3 The pH was adjusted to 10 using a saturated aqueous solution of Na 2 SO 4 The crude residue was purified by flash chromatography (Biotage® ZIP KP-Sil 45 g cartridge, DCM / DCM:MeOH:NH 4 OH 80:18:2 v / v / v, 100:0 to 70:30) to give compound 12 (4.0 g, 77%) as a white solid.

[0337] Step B: From compound 18 Under an inert atmosphere, lithium aluminum hydride (1M in THF, 2 eq., 1.09 mL, 1.09 mmol) was added to a solution of compound 18 (1 eq., 0.40 g, 0.54 mmol) in dry THF (5.39 mL) precooled to 0° C. The reaction mixture was stirred at 0° C. for 2 h. Then, Na 2 SO 4 A saturated aqueous solution of was added, the mixture was allowed to reach room temperature gradually and stirred for an additional 2 h before being filtered through Celite®. The solid was washed with AcOEt and the organic layer of the filtrate was washed with Na 2 SO 4 The crude material was purified by flash chromatography (Biotage® KP-Sil 10 g cartridge, cyclohexane / ethyl acetate 100:0 to 60:40) to give compound 12 (0.13 g, 33%) in the form of a white solid. 19 Fdec NMR (CDCl 3, 282.5MHz): -114.5 (d, 254Hz, 1F, CF 2 ); -115.4 (d, 254Hz, 1F, CF 2 ). Mass (ESI + ): 710.3 [M+H] + ; 732.2 [M+Na] + ; 748.3 [M+K] +

[0338] Synthesis of intermediate compound 14: A solution of compound 12 (1 eq., 300 mg, 0.423 mmol) in DCE (1.7 mL) was added to a solution of compound 13 (obtained from Journal of Organic Chemistry 1998, 63, pp. 3741-3744) (1.1 eq., 160 mg, 0.465 mmol) in DCE (1.7 mL) under an inert atmosphere. MgSO 4 (10 eq., 508 mg, 4.23 mmol) was added and the reaction was stirred at reflux for 2 h. The mixture was cooled to 0° C., then sodium triacetoxyborohydride (2 eq., 184 mg, 0.845 mmol) and acetic acid (1 eq., 28.2 mg, 0.0269 mL, 0.423 mmol) were added and the resulting mixture was stirred at room temperature for 12 h. Water and NaHCO 3 (10% aq) was added to the mixture, which was then extracted with AcOEt. The combined organic layers were washed with water and 2 SO 4 The crude residue was purified by flash chromatography (Biotage® SNAP 10 g, cyclohexane / AcOEt 95 / 5 to 80 / 20) to give a mixture containing compound 14 (221 mg) in the form of a white solid. Mass (ESI + ):1039.5 [M+H] + ; 1061.5 [M+Na] + ; 1077.5 [M+K] + .

[0339] Synthesis of intermediate compound 15: A solution of a mixture containing compound 14 (1 eq., 20 mg, 0.98 mmol) and acetic acid (10 eq., 0.01 mL, 0.19 mmol) in toluene (0.5 mL) was heated to reflux for 7 h. The reaction mixture was concentrated to give crude compound 15 in the form of a beige solid. Mass (ESI + ):1029.4 [M+Na] + ; 1045.4 [M+K] +

[0340] Synthesis of intermediate compound 19: Trifluoroacetic acid (5.9 eq., 21.8 μL, 0.29 mmol) was added to a solution of crude compound 15 (1.0 eq., 50.0 mg, 0.05 mmol) in water (2.7 μL) and dichloromethane (109 μL). The reaction was stirred overnight at room temperature. Water was then added and the pH of the solution was adjusted to pH=8-9 with a solution of NaOH (2M in water). The aqueous layer was then extracted 3 times with AcOEt and the combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give crude compound 19 (38.7 mg) as a yellowish solid. Mass (ESI + ):807.4 [M+H] + .

[0341] Synthesis of intermediate compound 5: Palladium (10 wt% loading, 0.10 eq., 5.1 mg, 0.005 mmol) was added to a solution of crude compound 19 (1 eq., 38.7 mg, 0.05 mmol) in THF (1.9 mL) previously degassed with nitrogen. A solution of HCl (2 M in water, 4.0 eq., 0.09 mL, 0.19 mmol) was then added. The mixture was placed under a hydrogen atmosphere and stirred for 16 h. The reaction was degassed with nitrogen and then filtered (0.45 μm, H-PTFE) to remove palladium residues. The filter was washed with water and the filtrate was concentrated to give crude compound 5 (12 mg). Mass (ESI - ):391.0 [MH] -

[0342] 1.3. Synthesis of compound 24 Compound 24 can be prepared according to the following synthetic route.

[0343] [ka]

[0344] Synthesis of intermediate compound 20: Compound 20 is prepared according to the same protocol for preparing compound 1 and also disclosed in WO2015 / 140178 (see compound 2), applying a glucose moiety instead of the galactose moiety. Mass (ESI + ):772.3[M+NH 4 ] + ;777.3[M+Na] + ;793.3[M+K] +

[0345] Synthesis of intermediate compound 21: A solution of compound 20 (1.2 eq., 3.20 g, 4.24 mmol) in DCE (27 mL) was treated with PsNEt 2 (3.2mmol / g, diethylamine supported, 3.7eq., 4.13g, 13.2mmol) and MgSO 4 (3 eq., 1.30 g, 10.8 mmol) were added sequentially. A solution of compound 2 (1 eq., 2.15 g, 3.53 mmol) in DCE (9.75 mL) was then added and the reaction was refluxed for 18 h. The mixture was cooled to room temperature and then quickly filtered. The resulting solution was transferred to a round-bottom flask and cooled to 0° C. under an inert atmosphere. To this solution was added sodium triacetoxyborohydride (95%, 2.9 eq., 2.25 g, 10.1 mmol) and acetic acid (1 eq., 0.20 mL, 3.53 mmol) in portions. The reaction was stirred at room temperature for 18 h.

[0346] water, NaHCO 3 (10% in water) and DCM were added and the mixture was then extracted 3 times with DCM. Methanol was added and the combined organic layers were washed with Na2 SO 4 It was dried over 400 rpm, filtered and concentrated.

[0347] The resulting crude oil was purified by chromatography (irregular SiO 2 Purification by elution with 40-63 μm, cyclohexane / ethyl acetate 95:5 to 75:25) afforded compound 21 (2.8 g, 85% purity, 78% yield) as a colorless oil. 19 Fdec NMR (CDCl 3 , 282.5 MHz): -109.3 (d, 258 Hz, 1F, CF 2 ), -110.3 (d, 258 Hz, 1F, CF 2 ). Mass (ESI + ): 1015.5 [M+H] + , 1037.5 [M+Na] + , 1053.5 [M+K] +

[0348] Synthesis of intermediate compound 22: A solution of compound 21 (1 eq., 85% purity, 2.80 g, 2.34 mmol) and acetic acid (10 eq., 1.34 mL, 23.4 mmol) in toluene (26 mL) was heated to reflux for 18 h in a sealed tube. The reaction mixture was concentrated. The residue was purified by flash chromatography (80 g irregular SiO 2 Purification by 40-63 μm, cyclohexane / ethyl acetate 95:5 to 75:25) gave compound 22 (2.43 g, 80% purity, 100%). 19 F NMR (CDCl 3 , 282.5 MHz): -107.7 (brdd, 257 Hz, 30 Hz, 1F, CF 2 ), -110.8 (brdd, 258 Hz, 26 Hz, 1F, CF 2 ). Mass (ESI + ): 963.3 [M+Na] + , 979.3 [M+K] +

[0349] Synthesis of intermediate compound 23: Palladium (10 wt.% loading, on activated carbon, 0.22 g, 0.21 mmol, 0.1 eq) was added to a solution of 22 (80% purity, 2.43 g, 2.07 mmol, 1 eq) in THF (42 mL) previously degassed with nitrogen. A solution of HCl (2M in water, 4.1 mL, 8.2 6 mmol, 4 eq) was then added. The mixture was placed under a hydrogen atmosphere and stirred for 18 h. The reaction was degassed with nitrogen and then filtered (0.20 μm, polyamide) to remove palladium residues. The filter was washed with a mixture of THF and water and the filtrate was concentrated to remove THF. The residue was then diluted with water and the solution was filtered (0.2 μm, H-PTFE) and freeze-dried to give 23 (0.90 g, 90% purity, 100% yield) as a white foam. 19 FNMR (D 2 O, 282.5 MHz): -115.3 (ddd, 251 Hz, 26 Hz, 8 Hz, 1F, CF 2 ), -116.8 (ddd, 251 Hz, 26 Hz, 8 Hz, 1F, CF 2 ). Mass (ESI + ): 357.1 [M+H] + (NH 2 form)

[0350] Synthesis of compound 24: Compound 23 (90% purity, 0.90 g, 2.06 mmol) was dissolved in a minimum volume of water. The solution was loaded onto the top of a small column filled with resin (DOWEX® 50Wx8 pre-washed with water). Water was first used as the eluent to remove impurities, then aqueous ammonia (0.1 M NH 4 The desired compound was eluted from the resin using hexanes (OH). The solution of compound 24 was then freeze-dried to give pure compound 24 (630 mg, 86% yield). 19 FNMR (D 2O, 282.5 MHz): -115.2 (ddd, 251 Hz, 21 Hz, 13 Hz, 1F, CF 2 ), -116.4 (ddd, 251 Hz, 21 Hz, 13 Hz, 1F, CF 2 ). Mass (ESI + ): 357.1 [M+H] + , 379.1 [M+Na] + , 395.1 [M+K] +

[0351] 1.4. Synthesis of compound 29 Compound 29 was prepared according to the following synthetic route:

[0352] [ka]

[0353] Synthesis of compound 25 The synthesis of compound 25 is disclosed in WO2012085221 (see compound 2β).

[0354] Synthesis of intermediate compound 26: A solution of compound 25 (1.2 eq., 2.75 g, 4.24 mmol) in DCE (27 mL) was treated with PsNEt 2 (3.2mmol / g, diethylamine supported, 3.7eq., 4.13g, 13.2mmol) and MgSO 4 (3 eq., 1.30 g, 10.8 mmol) were added sequentially. A solution of compound 2 (1 eq., 2.15 g, 3.53 mmol) in DCE (9.75 mL) was then added and the reaction was refluxed for 18 h. The mixture was cooled to room temperature and then quickly filtered. The resulting solution was transferred to a round-bottom flask and cooled to 0° C. under an inert atmosphere. To this solution was added sodium triacetoxyborohydride (2.9 eq., 2.25 g, 10.6 mmol) and acetic acid (1 eq., 0.20 mL, 3.53 mmol) in portions. The reaction was stirred at room temperature for 2 h.

[0355] water, NaHCO 3 (10% in water) and DCM were added and the mixture was then extracted 3 times with DCM. Methanol was added and the combined organic layers were washed with Na 2 SO 4 It was dried over 400 rpm, filtered and concentrated.

[0356] The resulting crude oil was purified by chromatography (irregular SiO 2 Purification by elution with 40-63 μm, cyclohexane / ethyl acetate 95:5 to 75:25) afforded compound 26 (2.3 g, 72% yield) as a colorless oil. 19 Fdec NMR (CDCl 3 , 282.5 MHz): -108.6 (dddd, 255 Hz, 35 Hz, 18 Hz, 7 Hz, 1F, CF 2 ), -112.8 (dm, 255 Hz, 1F, CF 2 ). Mass (ESI + ): 909.4[M+H] + , 931 [M+Na] + , 947 [M+K] +

[0357] Synthesis of intermediate compound 27: A solution of compound 26 (1 eq., 2.51 g, 2.76 mmol) and acetic acid (10 eq., 1.58 mL, 27.6 mmol) in toluene (30 mL) was heated to reflux for 18 h in a sealed tube. The reaction mixture was concentrated. The residue was purified by flash chromatography (120 g irregular SiO 2 , cyclohexane / EtOAc 95:5 to 50:50). At this stage, a mixture of compounds 26 and 27 (1.84 g) was obtained. A portion of this mixture (140 mg) was redissolved in toluene (3 mL) and acetic acid (0.1 mL). The mixture was heated to reflux for 16 h. The reaction was concentrated to give only the desired compound 27 (130 mg). 19 F NMR (CDCl 3, 282.5 MHz): -107.2 (dm, 255 Hz, 1F, CF 2 ), -111.5 (dm, 255 Hz, 1F, CF 2 ). 19 F dec NMR (CDCl 3 , 282.5 MHz): 107.2 (d, 255 Hz, 1F, CF 2 ), -111.5 (d, 255 Hz, 1F, CF 2 ). Mass (ESI + ): 835.3 [M+H] + , 857.3 [M+Na] + , 873.3 [M+K] +

[0358] Synthesis of intermediate compound 28: Palladium (10 wt.% loading, charcoal supported, 17.8 mg, 17 μmol, 0.10 eq) was added to a solution of 27 (140 mg, 0.17 mmol, 1 eq) in THF (3.43 mL) previously degassed with nitrogen. A solution of HCl (2 M in water, 0.34 mL, 0.67 mmol, 4 eq) was then added. The mixture was placed under a hydrogen atmosphere and stirred for 18 h. The reaction was degassed with nitrogen and then filtered (0.45 μm, polyamide) to remove palladium residues. The filter was washed with a mixture of THF and water and the filtrate was concentrated to remove THF. The residue was then diluted with water and the solution was filtered (0.2 μm, H-PTFE) and freeze-dried to give 28 (40 mg, 63%) as a white powder. 19 FNMR (MeOD, 282.5 MHz): -103.1 (dm, 258 Hz, 1F, CF 2 ), -109.0 (dm, 258 Hz, 1F, CF 2 ). 19 Fdec NMR (MeOD, 282.5 MHz): -103.1 (d, 258 Hz, 1F, CF 2 ), -109.0 (d, 258 Hz, 1F, CF2 ). Mass (ESI + ): 341.1 [M+H] + , 363.1 [M+Na] + , 379.1 [M+K] + (NH 2 form).

[0359] Synthesis of compound 29: Compound 28 (40 mg, 0.11 mmol) was dissolved in a minimum volume of water. The solution was loaded onto the top of a small column filled with resin (DOWEX® 50Wx8 pre-washed with water). Water was first used as the eluent to remove impurities, then aqueous ammonia (0.1 M NH 4 The desired compound was eluted from the resin using hexanes (OH). The solution of compound 29 was then freeze-dried to give pure compound 29 (21 mg, 58% yield). 19 FNMR (D 2 O, 282.5 MHz): -107.8 (ddd, 255 Hz, 11 Hz, 7 Hz, 1F, CF 2 ), -113.6 (dm, 255 Hz, 1F, CF 2 ). 19 Fdec NMR (D 2 O, 282.5MHz): -107.8 (d, 255Hz, 1F, CF 2 ), -113.6 (d, 25 5Hz, 1F, CF 2 ). Mass (ESI - ): 339.2 [MH] - , 361.1 [M+Na-2H] - , 375.1 [M+Cl] -

[0360] 1.5. Synthesis of compound 34 Compound 34 can be prepared according to the following synthetic route.

[0361] [ka]

[0362] Synthesis of intermediate compound 30: Compound 30 is prepared according to the following two steps.

[0363] [ka]

[0364] Compound 36 is prepared from commercially available compound 35 according to the method disclosed in Organic Letters 2006, 8, 17, pp. 3865-3868 (supporting information, p. 17).

[0365] Compound 30 is then obtained from compound 36 according to the protocol disclosed in J. Org. Chem. 1994, Vol. 59, No. 11, pp. 3216-3218, as follows:

[0366] Compound 36 (1.0 eq., 1.8 g, 3.61 mmol) was dissolved in a solution of HCl (1M in AcOEt, 2.5 eq., 9.03 mL, 9.03 mmol). The reaction mixture was stirred at room temperature for 3 h. HCl (1M in AcOEt, 2.5 eq., 9.03 mL, 9.03 mmol) was added again to complete the reaction. The reaction was stirred at room temperature for another 18 h, then concentrated and coevaporated with diethyl ether to give 1.2 g of compound 30 (60% purity, 58% yield). The material was used in the next step without purification. 1 H NMR (MeOD, 300MHz): 1.44 (s, 9H), 2.04 (m, 1H), 2.20 (m, 1H), 3.02 (t, 7.2 Hz, 2H), 4.17 (dd, 9.3 Hz, 5.1 Hz, 1H), 5.12 (s, 3H,), 7.33-7.36 (m, 5H). Mass (ESI+): 309.2 [M+H] + (NH 2 form)

[0367] Synthesis of intermediate compound 31: A solution of compound 1 (2.0 eq., 3.15 g, 4.18 mmol) in DCE (16 mL) was treated with PsNEt 2 (3.2mmol / g, diethylamine supported, 3.1eq., 2g, 6.4mmol) and MgSO 4 (3 eq., 1.30 g, 10.8 mmol) were added sequentially. A solution of compound 30 (1.0 eq., 60% purity, 1.2 g, 2.09 mmol) in DCE (6 mL) was then added and the reaction was refluxed for 18 h. The mixture was cooled to room temperature and then rapidly filtered. The resulting solution was transferred to a round-bottom flask and cooled to 0° C. under an inert atmosphere. To this solution was added sodium triacetoxyborohydride (5.0 eq., 2.21 g, 10.4 mmol) and acetic acid (1.0 eq., 0.12 mL, 2.09 mmol) in portions. The reaction was stirred at room temperature for 2 h.

[0368] Water, sodium bicarbonate (10% aq. solution) and DCM were added and the mixture was then extracted with DCM (3x). Methanol was added and the combined organic layers were dried over sodium sulfate, filtered and concentrated.

[0369] The resulting crude was purified by chromatography (80 g irregular SiO2 40-63 μm, cyclohexane / ethyl acetate 95:5 to 70:30) to give compound 31 (1.35 g, 66% yield) as a colorless oil. 19 Fdec NMR (CDCl 3 , 282.5 MHz): -109.7 (d, 258 Hz, 1F, CF 2 ), -110.7 (d, 258 Hz, 1F, CF 2 ). Mass (ESI+): 1001.5 [M+H] + , 1039.5 [M+K] +

[0370] Synthesis of intermediate compound 32: A solution of compound 31 (1 eq., 86% purity, 1.35 g, 1.16 mmol) and acetic acid (10 eq., 0.66 mL, 11.6 mmol) in toluene (13 mL) was heated to reflux under inert atmosphere for 18 h. A solution of water, sodium bicarbonate (10% in water) and ethyl acetate was added. The aqueous layer was extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (40 g irregular SiO 2 , cyclohexane / EtOAc 90:10 to 80:20) to give compound 32 (960 mg, 91% purity, 72% yield). 19 F dec NMR (CDCl 3 , 282.5MHz): - 107.7(d, 259Hz, 1F, CF 2 ), -108.6 (d, 259 Hz, 1F, CF 2 ). Mass (ESI+): 927.4 [M+H] + , 944.5 [M+NH 4 ] + , 949.4 [M+Na] + , 965.4 [M+K] +

[0371] Synthesis of intermediate compound 33: Palladium (10 wt.% loading, on activated carbon, 0.13 g, 0.12 mmol, 0.10 eq) was added to a solution of compound 32 (1.25 g, 91% purity, 1.23 mmol, 1.0 eq) in THF (25 mL) previously degassed with nitrogen. A solution of HCl (2 M in water, 2.45 mL, 4.9 mmol, 4.0 eq) was then added. The mixture was placed under a hydrogen atmosphere and stirred for 2 days. The reaction was degassed with nitrogen and then filtered (0.45 μm, polyamide) to remove palladium residues. The filter was washed with a mixture of THF and water and the combined solution was concentrated to remove THF. The residue was then diluted with water and the solution was filtered (0.2 μm, H-PTFE) and freeze-dried to give compound 33 (0.55 g, 85% purity, 100% yield). Compound 33 is in the form of two tautomers as follows:

[0372] [ka]

[0373] 19 Fdec NMR (MeOD, 282.5 MHz): Two tautomeric forms with a ratio of 80:20 Main form: -117.5 (d, 257 Hz, 1F, CF 2 ), -118.4 (d, 257 Hz, 1F, CF 2 ). Subform: -115.2 (d, 253 Hz, 1F, CF 2 ), -116.9 (d, 253 Hz, 1F, CF 2 ). Mass (ESI + ): 343.1 [M+H] + , 365.1 [M+Na] + , 381.1 [M+K] +

[0374] Synthesis of compound 34: Compound 33 (550 mg, 1.23 mmol) was dissolved in a minimum volume of water. The solution was loaded onto the top of a small column filled with resin (1.5 g, DOWEX® 50Wx8, pre-washed with water). Water was first used as the eluent to remove impurities, then aqueous ammonia (0.1 M NH 4 The desired compound was eluted from the resin using 1,2-dichlorophenyl 2,4-tetrahydrofuran (OH). The solution of compound 34 was filtered (0.2 μm, H-PTFE) and then freeze-dried to give pure compound 34 (240 mg, 67% yield). Compound 34 is in the form of two tautomers as follows:

[0375] [ka]

[0376] 19 Fdec NMR (D 2 O, 282.5MHz): two tautomeric forms with a ratio of 56:44 Main form: -116.6 (d, 253 Hz, 1F, CF 2 ), -117.5 (d, 253 Hz, 1F, CF 2 ). Subform: -114.9 (d, 251 Hz, 1F, CF 2 ), -116.6 (d, 251 Hz, 1F, CF 2 ). Mass (ESI + ): 343.1 [M+H] + , 365.1 [M+Na] + , 381.1 [M+K] +

[0377] 2. Biological activity: 2.1. Effect of compound 6 on gene expression in human dermal fibroblasts. Human <<full transcriptome>> analysis using Affymetrix microarrays In this study, the transcriptional effects (modulation of gene expression) of compound 6 were evaluated in normal human dermal fibroblasts (NHDFs) under basal conditions.

[0378] More specifically, a comparative analysis of the different transcriptome profiles was performed using the Affymetrix GeneAtlas platform and the human "full transcriptome" U219 chip, which contains 36,000 transcripts and variants.

[0379] Materials and Methods Normal human dermal fibroblasts (NHDF) were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS), antibiotics (penicillin 50 U / ml - streptomycin 50 μg / ml) and L-glutamine 2 mM final. Cells were incubated at 37°C and 5% CO 2 Grown in an incubator.

[0380] Genetic Screening Assays Fibroblasts were seeded in 48-well plates, cultured in culture medium for 24 h and cultured in assay medium for another 24 h. The medium was then replaced with assay medium containing different concentrations of test compounds or not (control) for 48 h. All experimental conditions were performed in triplicate. At the end of the incubation, the culture supernatant was removed and the cells were washed in phosphate-buffered saline (PBS) solution and immediately frozen at -80°C.

[0381] Differential expression analysis Duplicates were pooled prior to RNA extraction. Total RNA was extracted from each sample using TriPure Isolation Reagent® according to the supplier's instructions. The quantity and quality of total RNA was assessed for all samples using capillary electrophoresis (Bioanalyzer 2100, Agilent technologies). From each RNA, labeled and amplified antisense RNA (aRNA) was obtained using the GeneChip 3'IVT PLUS Kit (Affymetrix). For each labeled and amplified aRNA sample, the pre- and post-fragmentation profiles were assessed using capillary electrophoresis (Bioanalyzer 2100, Agilent technologies). Hybridization of fragmented aRNA on the Affymetrix® U219 chip (36,000 transcripts and variants) was performed for 20 hours at 45°C in a GeneAtlas™ Fluidics Affymetrix® Hybridization Station. The U219 chips were analyzed using a GeneAtlas™ Imaging Station (Affymetrix® - 2 μm resolution) to generate fluorescence intensity data.

[0382] Data management and results presentation - Expression Console and quality control: Data were normalized using the RMA algorithm in Expression Console (Affymetrix®) software. Quality control of labeling and hybridization was then performed. Hybridization and labeling steps successfully passed quality control for these experiments. - Data reduction, Excel file instructions: Once normalized in Expression Console, data was transferred to a Microsoft Excel file for further data reduction. Calculations and tools were added to rank and sort the data and finally aid in data interpretation. A detection threshold for fold change was defined and applied to the normalized data.

[0383] [Table 2]

[0384] Results are considered and presented per gene (not probe). A probe set is a collection of probes designed to interrogate a given sequence of a gene. In interpreting the data, the most significant relative expression value obtained with one probe is considered to be representative of the corresponding gene.

[0385] The file contains the following data: ○ Relative expression (RE) for each sample, ○ Magnification change calculation, Genetic information. - Identification of involved biological processes: The list of significantly regulated genes was transferred to the online database DAVID (Database for Annotation, Visualization and Integrative Discovery: http: / / david.abcc.ncifcrf.gov / ) for functional analysis (Genome Biology 2007, 8:R183, Nucleic Acids Research, 2009, Vol. 37, No. 1, pp. 1-13). The Gene Ontology database was used more specifically for data interpretation. The DAVID functional annotation part was used to cluster the regulated genes into significant biological processes. This analysis did not consider trends (UR or DR) or signal intensity, but only identifies biological functions linked to the target comparison. The DAVID database describes gene products in terms of associated biological processes using the vocabulary (GO terms) of the Gene Ontology Consortium (http: / / www.geneontology.org). Of those, only biological processes with p-value ≦ 0.05 were considered. - Signaling pathway analysis: Results were then processed with IPA (Ingenuity Pathway Analysis, Qiagen®) software to identify signaling pathways modulated by each treatment. This software takes into account the fold change value of each gene and, if sufficient information exists, is able to identify the direction of modulation of a signaling pathway. The relevance of the effect of each treatment on a given pathway was quantified by a z-score, which predicts the change in the direction of its effect.

[0386] [Table 3]

[0387] result Identifying the biological processes involved Gene regulation in NHDF treated with compound 6 (2 mg / ml) versus control was analyzed and regulated genes were clustered into significant biological processes (p-value ≦0.05).

[0388] According to Table 1 below, test compound 6 inhibits the main biological processes. · lipid metabolism processes, as well as cholesterol biosynthesis and metabolism processes; ·Extracellular matrix organization; Wound healing and wound response; - Shown to be involved in redox processes.

[0389] [Table 4A]

[0390] [Table 4B]

[0391] Regulation of mRNA expression The following Tables 2, 3, 4, 5 (Tables 5, 6, 7, 8) respectively present different genes involved in lipid synthesis, cholesterol metabolism, cholesterol synthesis and adipocyte differentiation, which were regulated by the tested compound 6. The fold change represents whether they are upregulated (≧2) or downregulated (≦0.5).

[0392] The following Tables 6, 7, 8 (Tables 9, 10, 11) respectively present different genes involved in fibrosis, skin tensile strength, and reactive oxygen species (ROS) synthesis, which were regulated by the tested compound 6. The fold change represents whether they are upregulated (≧2) or downregulated (≦0.5).

[0393] The following Tables 9, 10 (Tables 12, 13) respectively present different genes involved in inflammatory responses and chronic inflammatory disorders, which were regulated by the tested compound 6. The fold change represents whether they are upregulated (≧2) or downregulated (≦0.5).

[0394] [Table 5A]

[0395] [Table 5B]

[0396] [Table 5C]

[0397] [Table 5D]

[0398] [Table 6]

[0399]

Table 7

[0400]

Table 8A

[0401]

Table 8B

[0402]

Table 9A

[0403]

Table 9B

[0404]

Table 10

[0405]

Table 11A

[0406]

Table 11B

[0407]

Table 12A

[0408]

Table 12B

[0409] [Table 12C]

[0410] [Table 13A]

[0411] [Table 13B]

[0412] [Table 13C]

[0413] Signaling pathway analysis A more advanced bioinformatics analysis was performed using the Ingenuity Pathway Analysis software (IPA from Qiagen®). This analysis allows the identification of affected signaling pathways and the prediction of their modulation. Modulation is stimulatory if the activation z-score is positive (Table 11) and inhibitory if the activation z-score is negative (Table 12).

[0414] [Table 14A]

[0415] [Table 14B]

[0416] Analysis of signaling pathways showed the predicted activation of lipogenic and cholesterol biosynthetic processes, as well as adipocyte differentiation, at the transcriptional level by compound 6.

[0417] Thus, treatment of NHDF with compound 6 upregulated lipid and cholesterol synthesis, as well as adipocyte differentiation.

[0418] [Table 15A]

[0419] [Table 15B]

[0420] Analysis of signaling pathways showed predictive inhibition of fibrosis, skin tensile strength, synthesis of ROS (reactive oxygen species), inflammatory response and chronic inflammatory disorders at the transcriptional level by compound 6.

[0421] Thus, treatment of NHDF with compound 6 downregulated fibrosis, skin tensile strength, synthesis of ROS, as well as inflammatory responses and chronic inflammatory disorders.

[0422] In another experiment, the inventors showed that treatment of aged human fibroblasts with compound 6 at 6 mg / ml increased SOD2 gene expression by 204% compared to the control, indicating that the compound is involved in oxidative and cellular stress responses in aged human fibroblasts.

[0423] 2.2. Effect of compound 6 on preservation / protection of neonatal dermal fibroblasts under starvation conditions, as assessed by neutral red uptake assay. Materials and Methods Subculture Neonatal skin fibroblasts (cell line: CCD-27SK, ATCC number CRL-1475) were grown in DMEM medium supplemented with fetal bovine serum 10% final, antibiotics (penicillin / streptomycin) 1% final and amphotericin B 0.1% final.

[0424] Fibroblasts were cultured at 37°C and 10% CO 2In the incubator, 75 cm 2 The cells were grown in culture flasks to 80% confluence, and the medium was replaced with fresh medium pre-warmed to 37°C every 2 days.

[0425] Starvation medium This medium consisted of 45% subculture medium without fetal bovine serum mixed with 55% phosphate-buffered saline IX containing EDTA (final concentration 0.45 mM) and was referred to as serum-free medium or starvation medium.

[0426] Product Preparation Compound 6 (MM=356.3 g / mol) was diluted to 17 mM final in the starvation medium by adding NaOH 1N and the pH was adjusted to 7.4.

[0427] General Experimental Procedure Assay in 96-well plates Fibroblasts, 2.10 5 The cells were concentrated to 10 cells / ml and 100 μl of the cell suspension was added to a well of a 96-well plate and incubated at 37° C. and 10% CO 2 The mixture was incubated in an incubator for 4 hours. After cell attachment, the medium was changed and the plates were incubated (37°C - 10% CO 2 ), the assay was performed as follows: ○ One plate for each sampling time: D0, D4, D7; ○ Three wells for each condition (triplicate counts) with the addition of 120 μl of culture medium (viability control), starvation medium (serum-free control) or 17 mM compound 6 solution.

[0428] Viability assay (neutral red uptake) Neutral red uptake assay was used to determine cell viability. This assay is based on the ability of viable cells to incorporate and bind the supravital dye neutral red in their lysosomes. Thus, only viable cells are colored. At D4 and D7, the plates were incubated with neutral red solution for 3.5 hours. The cells were then washed, the dye was extracted in each well, and the absorbance was read using a spectrometer.

[0429] For sampling, 1 mL of DMEM (without phenol red indicator) and neutral red (OD = 0.110) were added to the cells for 3.5 h (37 °C, 10% CO 2 After incubation, the medium was removed. Two washes with PBS were performed and 1 mL of extraction solution (49% absolute ethanol, 49% ultrapure water, 2% glacial acetic acid) was added. The plate was placed on a rotary shaker in the dark for 15 min before reading the OD at 540 nm.

[0430] The average OD540nm values ​​were compared and the variation in viability was calculated as follows: Variation of viability at Dx = (OD540nm of test solution-blank) at Dx / (OD540nm of stress control-blank) at Dx.

[0431] result The viability (OD540nm) of cells from stressed cultures to which the tested compounds were added was compared with stress-control cultures at different times and the variation in viability was calculated. The results are presented in Table 13 below.

[0432] [Table 16]

[0433] The viability of cells cultured in starvation medium but treated with 17 mM compound 6 was 2.3-fold higher than that of cells in serum-free controls after 4 days of culture and 3.4-fold higher after 7 days. Compound 6 therefore exhibited a significant antiseptic / protective effect on dermal fibroblasts as the cells were maintained in a healthy state under conditions unfavorable for growth.

[0434] 2.3. Evaluation of the protective, pro-adipogenic, anti-inflammatory and anti-aging properties of compound 6 To evaluate and characterize the protective effects, as well as the pro-adipogenic, anti-inflammatory and anti-aging properties, the effect of compound 6 on human dermal fibroblast and human preadipocyte proliferation in normal or fibro-inflammatory environments was examined.

[0435] method cell culture Human dermal fibroblasts were isolated from skin tissue by dermal explants and seeded in Petri dishes in DMEM-20% FBS for 3 weeks.The dermal fibroblasts were then seeded in 96-well plates and then incubated under different culture conditions as described below. Different culture conditions were performed in at least triplicate: - Positive control for cytotoxicity: cells in DMEM 1% FBS medium lysed with 0.2% triton at the end of the culture period - Control: Cells in DMEM 1% FBS medium - Test: cells in DMEM 1% FBS medium supplemented with test compound 6 and compound 44 of WO2015 / 140178.

[0436] Preadipocytes were isolated from subcutaneous tissue of human females (body mass index <30 kg / m2 and age <45 years). Preadipocytes were cultured in 100 μl of DMEM-10% fetal bovine serum (FBS) in 96-well plates for 24 h. Cells were then treated to induce differentiation in a classical or inflammatory environment for 13 days.

[0437] To induce preadipocytes, the differentiating cells were incubated in a preadipogenic cocktail (PAC) containing insulin, glucocorticoids, 3-isobutyl-1-methylxanthine (IBMX) and thiazolinedione in DMEM.

[0438] To induce a fibroinflammatory environment, cells were treated with activated human macrophage-conditioned medium (AcMC) prepared in RPMI medium. Treatment with 100 nM dexamethasone (DXM) was used as an anti-inflammatory response control.

[0439] At D0, preadipocytes were treated with the following conditions: ·“Undifferentiated”: DMEM+ 1 / 4 RPMI medium ·“Differentiation”: PAC+ 1 / 4 RPMI medium "AcMC" or inflammatory state: PAC+ 1 / 4 AcMC "AcMC+DXM": PAC+ 1 / 4 AcMC + 100nM of the anti-inflammatory drug DXM · “AcMc+ compound”: PAC+ 1 / 4 AcMC+Compound to be tested All conditions were performed in triplicate. Media was changed every 2 days for 13 days.

[0440] On D14, during the last 24 h of culture, the medium was replaced with DMEM / F12 medium in all conditions, and cell secretions were collected.

[0441] Compounds to be tested The effects of compound 6 and compound 44 of WO2015 / 140178 were evaluated at different concentrations in culture medium (DMEM).

[0442] cytotoxicity Cytotoxicity was estimated by measuring lactate dehydrogenase (LDH) released by damaged cells in the culture medium (using the kit CytoTox-One non-radioactive cytotoxicity assay, G1780, Promega). Cells were treated with 0.2% triton at the end of the culture to determine the maximum toxic response. LDH measurements were performed in 24 h medium secretions after 13 days of culture.

[0443] Results were normalized by cell number as determined by nuclear staining (with DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride) and expressed as a percentage of the cytolysis positive control. Compounds exhibiting a level of cytotoxicity below 20% relative to the control were considered non-toxic.

[0444] Lipid accumulation and lipid index After 14 days of culture, preadipocytes were fixed with 4% paraformaldehyde and then stained with AdipoRed™ at room temperature to reveal intracellular lipid droplets. Quantification of lipid accumulation was performed by measuring fluorescence intensity using a Spark spectrometer (TECAN).

[0445] A second analysis of lipid accumulation was performed by image acquisition and quantification. For more accurate data, the area and intensity of lipid droplets were evaluated and quantified. An index was calculated (area x intensity of AdipoRed staining) and normalized by cell number.

[0446] Quantification of extracellular secretions After 13 days, the 24h culture medium of different conditions was collected at the end of the treatment period. The concentrations of IL-6, procollagen I and MCP1 were evaluated by ELISA assay using specific kits (for IL-6: DY206, DuoSet ELISA, R&D Systems; for procollagen I: DY6220-05, DuoSet ELISA, R&D Systems; for MCP1: DY279-05 DuoSet ELISA, R&D Systems) according to the manufacturer's recommendations. Values ​​were normalized to cell number determined by DAPI staining.

[0447] Immunofluorescence (type I collagen network) One month after fixation of preadipocytes cultured in a proinflammatory environment, cells were incubated with 3% bovine serum albumin (BSA) for 30 min to block nonspecific sites, then with primary antibody anti-collagen type 1 (Novusbio, NB600-408) overnight. After washing with PBS, cells were incubated with 3% BSA for 30 min, then with secondary antibody (goat anti-rabbit alexa-fluor 488, ThermoFisher, A11008) and DAPI (for nuclear staining) for 1 h. After several washes, acquisition and quantification were performed with a videofluorescence microscope. Briefly, quantification was based on the detection and quantification of cell nuclei stained with DAPI and the detection of collagen type 1 staining. Collagen type 1 fibers were detected and measured for their length, thickness and intensity. The amount of collagen type 1 fibers was calculated (amount = length x thickness x fluorescence intensity) and normalized by cell number (DAPI staining).

[0448] result Effect of compound 6 on the viability of fibroblasts under classical conditions The amount of LDH released by the cells was normalized by the cell number in each culture condition. Data are expressed as a percentage of the positive control. Results are presented in Table 14.

[0449] [Table 17]

[0450] No toxicity was observed at 2 mg / ml, 0.5 mg / ml, and 0.1 mg / ml of compound 6. Rather, the results showed that in fibroblast cultures treated with compound 6, LDH release (cytotoxicity) was less (5.1% to 6.7%) compared to the control (22.4%).

[0451] In these experimental conditions, compound 6 has an antiseptic / protective effect on dermal fibroblasts, even under classical conditions in the absence of specific stress.

[0452] Compound 6 showed strong protective effects at all concentrations in such conditions, whereas compound 44 of WO2015 / 140178 does not exhibit any protective effect.

[0453] Effect of compound 6 on proliferation of preadipocytes under classical conditions The number of cells was determined for each condition by DAPI nuclear staining (nuclei) and expressed in arbitrary units. The results are presented in Table 15.

[0454] [Table 18]

[0455] The cell number is higher when cells are treated with compound 6 at 2 mg / ml (13197 AU) compared to the differentiated control condition (10118 AU).

[0456] Compound 6 at 2 mg / mL induced cell proliferation in preadipocytes cultured in a classical differentiation state.

[0457] Effect of compound 6 on human preadipocytes under differentiation conditions in a fibroinflammatory environment The effect of compound 6 was evaluated: ○Survival ability ○ Multiplication Lipid accumulation Extracellular secretion of IL-6, MCP1 and procollagen I  The amount of type 1 collagen fibres.

[0458] Preadipocyte viability under inflammatory conditions The amount of LDH measured in the medium was normalized by the number of cells in each culture condition. Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). The results are presented in Table 16.

[0459] [Table 19]

[0460] Instead, the results showed that in preadipocyte cultures treated with compound 6 (53.3% and 81.7% cytotoxicity at 2 and 1 mg / ml, respectively), LDH release was less compared to control AcMCs, i.e., inflammatory conditions with cytotoxicity fixed at 100%.

[0461] In these experimental conditions, compound 6 showed an antiseptic / protective effect on preadipocytes / adipocytes in inflammatory conditions.

[0462] Lower relative cytotoxicity was observed for compound 6 at 2 mg / ml (53.3%) and 1 mg / ml (81.7%) compared to compound 44 of WO2015 / 140178 at 5 mg / ml (103.3%) and compound 44 of WO2015 / 140178 at 1 mg / ml (91.5%). Compound 6 therefore showed better preservative efficacy than compound 44 of WO2015 / 140178.

[0463] Proliferation of preadipocytes under inflammatory conditions Cell numbers were determined by DAPI nuclear staining (nuclei) for each condition and expressed in arbitrary units. Results are presented in Table 17.

[0464] [Table 20]

[0465] The cell numbers are higher when cells are treated with compound 6 at 2 mg / ml and 1 mg / ml (20 147 AU and 18 154 AU, respectively) compared to AcMC control conditions, ie, inflamed conditions (12 819 AU).

[0466] Compound 6 induced cell proliferation in preadipocytes with dose-effects of 2 mg / ml and 1 mg / ml.

[0467] Compared to compound 44 of WO2015 / 140178 at 1 mg / ml, compound 6 at 1 mg / ml induced greater proliferation of preadipocytes in inflammatory conditions (15 026 vs. 18 154 cells, respectively).

[0468] Total lipid synthesis in preadipocytes / adipocytes under inflammatory conditions Lipid accumulation and lipid indices were assessed for each condition. Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). Results are presented in Tables 18A and 18B.

[0469] [Table 21]

[0470] Compound 6 induced an increase in lipid synthesis in inflammatory medium at both concentrations and acted better than compound 44 of WO2015 / 140178 at the lower concentration.

[0471] As shown in previous results, proliferation of preadipocytes leads to increased total lipid synthesis in inflammatory conditions, which clearly highlights the potential of compound 6 for plumping / wrinkle-filling effects.

[0472] [Table 22]

[0473] In order to obtain better accuracy, another method was used to quantify lipids.Compound 6 increases lipid index in inflammatory medium at both concentrations compared to AcMC control, and performs better than compound 44 of WO2015 / 140178.This confirms the ability of compound 6 to promote lipid synthesis in inflammatory conditions.

[0474] Extracellular secretion of IL-6 by preadipocytes under inflammatory conditions The amount of secreted IL-6 in the medium was measured and normalized by the number of cells in each culture condition. Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). Results are presented in Table 19.

[0475] [Table 23]

[0476] Compound 6 at 2 mg / ml and 1 mg / ml reduced IL-6 secretion in preadipocytes / adipocytes (28.1 and 84% secreted IL-6, respectively) compared to AcMC control conditions, i.e., 100% fixed inflammatory conditions.

[0477] Furthermore, the inhibitory effect on IL-6 synthesis induced by 2 mg / ml compound 6 (28.1%) is similar to that observed with 100 nM DXM (22.8%).

[0478] Compound 6 showed a strong anti-inflammatory effect on preadipocytes / adipocytes treated at dose-effects of 2 mg / ml and 1 mg / ml.

[0479] The reduction in IL-6 secretion is better with compound 6 at 2 mg / ml (28% of IL-6 production) than with compound 44 of WO2015 / 140178 at 5 mg / ml (66.5% of IL-6 production) in inflammatory conditions. Thus, compound 6 showed a better anti-inflammatory effect than compound 44 of WO2015 / 140178.

[0480] Extracellular secretion of MCP1 by preadipocytes under inflammatory conditions The amount of MCP1 secreted into the medium was measured and normalized by the number of cells in each culture condition. Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). Results are presented in Table 20.

[0481] [Table 24]

[0482] As expected, MCP1 secretion was increased in a proinflammatory environment (AcMC) compared to the differentiated state. Dexamethasone had no effect on MCP1 secretion.

[0483] Compound 6 at 2 mg / ml and 1 mg / ml reduced MCP1 secretion in differentiated preadipocytes (65% and 71%, respectively) compared to AcMC control conditions, i.e., inflammatory conditions fixed at 100%.

[0484] Compound 6 demonstrated anti-inflammatory effects on preadipocytes treated at 2 mg / ml and 1 mg / ml.

[0485] Extracellular secretion of procollagen I by preadipocytes under inflammatory conditions The amount of procollagen secreted into the medium was measured and normalized by the number of cells in each culture condition. Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). Results are presented in Table 21.

[0486] [Table 25]

[0487] Compound 6 at 2 and 1 mg / ml reduced procollagen I secretion (46.2% and 49.9%, respectively) compared to AcMC control conditions, i.e., inflammatory conditions fixed at 100%, which are known to increase procollagen secretion compared to normal differentiation conditions.

[0488] In inflammatory conditions, a more potent reduction in procollagen I secretion was observed with compound 6 at 1 mg / ml compared to compound 44 of WO2015 / 140178 at 1 mg / ml (49.9% vs. 69.4% secretion, respectively).

[0489] The amount of type 1 collagen fibrils produced by preadipocytes under inflammatory conditions The amount of type I collagen fibers (fibrillar type I collagen) was quantified and data was normalized by cell number (DAPI staining, quantification of nuclei number). Data are expressed as a percentage of the proinflammatory control condition (AcMC condition). Results are presented in Table 22.

[0490] [Table 26]

[0491] Compound 6 at 2 and 1 mg / ml increased the amount of type I collagen fibers (213% and 154%, respectively) compared to AcMC control conditions, ie, inflammatory conditions fixed at 100%.

[0492] Compound 6 at 2 and 1 mg / ml induced increased type I collagen deposition in the extracellular matrix of preadipocytes cultured in a proinflammatory environment.

[0493] Compound 6 has a matrix remodeling effect that appears to be close to that induced by the anti-inflammatory drug dexamethasone. The apparent decrease in procollagen I observed during previous studies can be explained by its conversion into type I collagen fibers.

[0494] 2.4. Evaluation of the effect of compound 6 on lipid synthesis in normal human epidermal keratinocytes (NHEK) Normal human epidermal keratinocytes (NHEK) were seeded in 12-well plates and incubated in culture medium for 24 hours. The medium was then diluted with radioactive tracer [ 14 C]-acetate, or a reference (CaCl 2 + Vitamin C, 1.5 mM + 200 μg / ml, respectively). Cells were incubated for 48 hours. All experimental conditions were performed in triplicate.

[0495] The culture medium was Keratinocyte-SFM supplemented with 0.25 ng / ml epidermal growth factor (EGF), 25 μg / ml pituitary extract (PE) and 25 μg / ml gentamicin. The assay medium was Keratinocyte-SFM supplemented with 25 μg / ml gentamicin.

[0496] At the end of the incubation, the cells were rinsed with PBS solution and then detached from the support by trypsinization. 14 Incorporation of [C]-acetate was measured by liquid scintillation (measurement of radioactivity). Incorporation correlates with total lipid neosynthesis. Results presented in Table 23 are expressed as cpm and % of control.

[0497] [Table 27]

[0498] Under these experimental conditions, the effect of compound 6 on lipid synthesis was significantly greater than that of the reference (CaCl 2 1.5 mM; vitamin C 200 μg / ml), as well as (at 3 mg / ml), where the stimulation was 21% and 23%, respectively, compared to the control.

[0499] Moreover, this effect of compound 6 was dose-dependent, since 1 mg / ml was less stimulating (10% vs. control).

[0500] Compound 6 showed an effect on stimulating lipid neosynthesis by normal human epidermal keratinocytes, which highlights its potential in restoring the barrier effect of the skin, especially in dry or atopic skin, and in atopic dermatitis, eczema and psoriasis. Moreover, this improved lipid synthesis reduced wrinkles associated with dry skin. 2.5. Evaluation of the effect of compound 6 on lipid peroxidation in normal human epidermal keratinocytes (NHEK)

[0501] Normal human epidermal keratinocytes were seeded in 48-well plates and cultured for 24 hours in culture medium and then for another 24 hours in assay medium. The medium was then removed and replaced with assay medium containing or not (irradiation control) test compound or reference (BHA - butyl hydroxyanisole, lipid peroxidation inhibitor - 100 μM) and the cells were pre-incubated for 24 hours. After pre-incubation, a specific fluorescent probe (C11-fluor) for measuring lipid peroxidation was added and the cells were incubated for 45 minutes. The medium was then removed and replaced with assay medium containing or not (irradiation control and test compound conditions) reference and the cells were exposed to UVB (+UVA) - 300 mJ / cm 2 (+2.1J / cm 2 ) was irradiated. The lamp used was a SOL500 Sun Simulator (Dr. Honle. AG) ​​equipped with an H2 filter. After illumination, the medium was removed and replaced by assay medium with or without test compound or reference (illumination controls) and the cells were incubated for 30 min before flow cytometry analysis. A non-illuminated control condition was performed in parallel. All experimental conditions were performed in triplicate.

[0502] At the end of the incubation, in each well, the cells were trypsinized and transferred to specific tubes for analysis of C11-fluor fluorescence intensity using a BD FACSVerse™ flow cytometer (acquisition of 2000 to 5000 events per tube).

[0503] The C11-fluor fluorescent probe is a lipid analogue that is integral to cell membranes. The fluorescence intensity of this probe decreases upon oxidation and is therefore inversely proportional to lipid peroxidation. To facilitate interpretation of the results, lipid peroxidation was expressed using a value of "1 / fluorescence intensity" to ensure a direct proportionality between the induction of lipid peroxidation and the value of "% of illuminated control".

[0504] The results, presented in Table 24, are expressed as fluorescence intensity and as % protection compared to the control.

[0505] [Table 28]

[0506] Under these experimental conditions, compound 6 showed a moderate protection against lipid peroxidation of 38% (compared to the control).

[0507] Compound 6 shows a protective effect against lipid peroxidation in normal human epidermal keratinocytes stimulated by UVB, highlighting its skin protection and anti-aging potential. In this detailed assay, compound 44 of WO2015 / 140178 does not have any effect on lipid peroxidation protection.

[0508] 2.6. Evaluation of the effect of compound 6 on the protection of normal human dermal fibroblasts under UVA irradiation, as assessed by MTT reduction assay. The protective effect of compound 6 was evaluated in normal human dermal fibroblasts (NHDFs). The viability of UVA-irradiated NHDFs was tested using a standard MTT reduction assay. Prior to these assays, preliminary cytotoxicity assays were performed on NHDFs using a standard WST-8 reduction assay and morphological observation under a microscope to determine the concentrations to be tested.

[0509] Materials and Methods Cell type: NHDF, Bioalternatives reference PF2 was used at passage 8 ·Culture conditions: 37℃, 5% CO 2 Culture medium: DMEM supplemented with L-glutamine 2mM, penicillin 50U / ml-streptomycin 50μg / ml, and 10% fetal calf serum (FCS). Irradiation medium: CaCl 2 0.2g / l, MgSO 4 EBSS supplemented with 0.2 g / l Test compound: Compound 6 (MM=356.3 g / mol) was diluted in culture medium at final concentrations of 1.25 and 2.5 mg / ml.

[0510] General Experimental Procedure Culture and treatment Fibroblasts were seeded in 96-well plates and cultured in culture medium for 24 hours. The medium was then replaced with culture medium containing or not containing the test compound (irradiation control) and the cells were pre-incubated for 24 hours. After pre-incubation, the medium was removed and replaced with irradiation medium and the cells were exposed to 35 J / cm2. 2 The cells were irradiated with 1000 x 1000 dl. The lamp used was a SOL500 Sun Simulator (Dr. Honle, AG) equipped with an H1 filter. After illumination, the medium was removed and replaced with assay medium containing or not containing test compound (illumination control) and the cells were incubated for 24 h. A non-illuminated control condition was performed in parallel.

[0511] All experimental conditions were performed with n=5, except for the control condition, which had n=12.

[0512] Assessment of cell viability – MTT assay At the end of the incubation, the cells were incubated with MTT (a tetrazolium salt), which was reduced to blue formazan crystals by succinate dehydrogenase (a mitochondrial enzyme). This conversion is proportional to the enzyme activity. After cell dissociation and solubilization of the formazan crystals using DMSO, the optical density (OD) of the extract at 540 nm, which is proportional to the number of viable cells and their metabolic activity, was recorded with a microplate reader (VERSAmax, Molecular Devices).

[0513] Data Management Raw data were analyzed using Microsoft Excel software. Comparisons between groups were performed by unpaired Student's t-test.

[0514] The standard error of the mean (sem) is a measure of how likely a sample mean is to deviate from the true population mean. The sem is calculated as the standard deviation (sd) divided by the square root of the number of subjects (n). Standard error of the mean: sem = sd / √n Percentage of viability: Viability (%) = (OD sample / OD control) x 100

[0515] result Cell viability (OD 540 nm) from irradiated cultures supplemented with the compounds to be tested was compared to irradiated control cultures and the percentage of viability was calculated. The results are presented in Table 25 below.

[0516] [Table 29]

[0517] When tested at 2.5 mg / ml in irradiated cells, compound 6 induced a significant increase in cell viability (130% of irradiated controls). Compound 6 exhibited a statistically significant protective effect against UVA irradiation.

[0518] 2.7. Evaluation of the effect of compound 6 on co-cultures of human senescent fibroblasts and mature adipocytes. To evaluate its effect on the fibroblast matrix and anti-inflammatory properties, the effect of compound 6 was tested in an adipocyte-senescent fibroblast co-culture model, which mimics the interaction between the dermis and subcutaneous tissue in the skin and allows the biological effects of the product on two cellular targets to be investigated in parallel.

[0519] Materials and Methods Experimental model: Co-culture of human mature adipocytes cultured in 3D and human dermal fibroblasts cultured in 2D (AM3D-FB2D co-culture). This experimental model of AM3D-FB2D co-culture mimics the interaction between the dermis and subcutaneous tissue in the skin and allows to investigate the biological effects of products on two cellular targets in parallel. Donor characteristics: The study was performed with mature adipocytes and fibroblasts from two different donors (one donor for mature adipocytes and the other donor for dermal fibroblasts). Fibroblast donor: 56-year-old woman, BMI = 28 kg / m 2 Fat cell donor: 27-year-old woman, BMI = 21.4 kg / m 2 Treatment procedure: Compound 6 was added to the co-culture medium daily for up to 6 days.

[0520] General Experimental Procedure Culture and treatment Dermal fibroblasts were seeded at 10000 cells / well in DMEM 10% FBS. The next day, 50 μl of adipocyte capsules were added on top of the fibroblasts in suspension, and the medium was changed and replaced by the specific culture medium for the co-culture AM3D-FB2D. An internal standardized protocol was followed for the formation of the adipocyte capsules. Briefly, fully matured adipocytes were isolated from the subcutaneous tissue after digestion with collagenase. The isolated adipocytes were then washed with a washing buffer and encapsulated in a peptide hydrogel to form 3D adipocyte capsules of size 50 μl. The cells were incubated at 37°C and 5% CO for stabilization. 2 The cells were incubated at RT overnight at -80°C. Treatment was initiated at D0 and medium was changed at D0, D2, D3 and D5. The whole culture medium of the 24 h incubation was collected at D3 and D6, centrifuged and stored at -80°C. Each culture condition was performed in triplicate.

[0521] biochemical analysis Biochemical analysis of the culture medium was performed by ELISA using specific kits according to the manufacturer's recommendations: IL-6 (Duoset DY206, R&D Systems), and hyaluronic acid (HA) (Duoset, DY3614-05, R&D Systems) and procollagen I (Duoset, DY6220-05, R&D Systems).

[0522] HA and procollagen I results were normalized by fibroblast cell number, which relates to the fact that these molecules are mainly secreted by fibroblasts. All biochemical results are expressed as a percentage of the control condition.

[0523] result Secretion of interleukin 6 To evaluate the effect of compound 6 on inflammation, the extracellular concentration of IL-6, secreted by fibroblasts but mainly by adipocytes, was measured at D3 and D6. The results are presented in Table 26 below.

[0524] [Table 30]

[0525] Dexamethasone, an anti-inflammatory reference item, reduced the secretion of this pro-inflammatory cytokine by 34% and 41% compared to the control condition (100%) after 3 and 6 days of treatment, respectively (Table 26). Compound 6 at 3 and 2 mg / ml also induced a reduction of IL-6 by 73% and 72% at D3 and 61% and 53% at D6, respectively.

[0526] These results indicate that compound 6 has an anti-inflammatory effect on co-cultures of senescent fibroblasts and mature adipocytes, highlighting its ability to treat inflammation.

[0527] Hyaluronic acid secretion To evaluate the effect of compound 6 on the fibroblast matrix, the extracellular concentration of hyaluronic acid (HA), which is secreted exclusively by fibroblasts, was measured at D3 and D6. The results are presented in Table 27 below.

[0528] [Table 31]

[0529] After 3 days of treatment, compound 6 induced an increase in HA secretion (140% of control) at the lowest concentration of 1 mg / ml. After 6 days of treatment, compound 6 induced a significant increase in HA secretion in the three tested conditions, i.e., 164%, 225% and 189% of control at concentrations of 3, 2 and 1 mg / ml, respectively.

[0530] These results indicated that compound 6 has an effect on the extracellular matrix of aged fibroblasts by increasing the production of HA, which plays a crucial role in skin moisturization and skin plumping.

[0531] Secretion of procollagen I To evaluate the effect of compound 6 on the fibroblast matrix, the extracellular concentration of procollagen I, which is secreted exclusively by fibroblasts, was measured at D3 and D6. The results are presented in Table 28 below.

[0532] [Table 32]

[0533] After 3 days of treatment, compound 6 at all concentrations induced a mild increase in procollagen I secretion, ie 173%, 159% and 163% of control at concentrations of 3, 2 and 1 mg / ml, respectively.

[0534] After 6 days of treatment, compound 6 increased procollagen I secretion to a greater extent at all concentrations, ie, 474%, 411% and 418% of control at concentrations of 3, 2 and 1 mg / ml, respectively.

[0535] This effect of D6 is close to or higher than that of the positive control (428%).

[0536] These results indicated that compound 6 has an effect on the extracellular matrix of aged fibroblasts by increasing the production of procollagen I, which plays a crucial role in preventing skin aging.

Claims

1. The following formula (I): 【Chemistry 1】 (In the formula, - n represents 1 or 2, - R, CH 2 OR 8 represents - R 1 and R 2 are ORed independently of each other. 15 represents - R 3 OR 22 represents - R 4 is a hydrogen or halogen atom, or OSiR a4 R b4 R c4 , OR 41 , O.C.(O)R 42 , O.C.O. 2 R 43 ,OCONR 44 R 45 , OP(O)(OR 46 ) 2 Or OSO 3 R 47 represents a group, Or R and R 1 together with the carbon atom which carries them form the following formula: 【Chemistry 2】 and / or forming a cyclic acetal having the formula (R 1 and R 2 ), (R 2 and R 3 ) and / or (R 3 and R 4 ), together with the carbon atom which carries them, form the following formula: 【Chemistry 3】 forming a cyclic acetal having the formula - R 5 and R 6 are the same or different and represent a hydrogen atom or an N-protecting group, - R 8 , R 15 , R 22 and R 41 are each independently a hydrogen atom, an O-protecting group or (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 3 ~C 7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl, (C 1 ~C 6 )-alkyl-heteroaryl, saccharide or polysaccharide radicals, which may optionally contain halogen atoms, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 42 and R 43 are independent of each other, (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, (C 3 ~C 7 ) cycloalkyl, 5- to 7-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl or (C 1 ~C 6 )-alkyl-heteroaryl groups, which may optionally contain halogen atoms, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 44 and R 45 are each independently a hydrogen atom or (C 1 ~C 6 ) alkyl, (C 2 ~C 6 ) alkenyl, (C 2 ~C 6 ) alkynyl, aryl, heteroaryl, aryl-(C 1 ~C 6 ) alkyl, heteroaryl-(C 1 ~C 6 ) alkyl, (C 1 ~C 6 )-alkyl-aryl or (C 1 ~C 6 )-alkyl-heteroaryl groups, which may optionally contain halogen atoms, (C 1 ~C 6 ) substituted with one or more groups selected from alkoxy, OH, COOH, and CHO; - R 46 and R 47 are each independently a hydrogen atom or (C 1 ~C 6 ) an alkyl group; - R a4 , R b4 and R c4 are independent of each other, (C 1 ~C 6 ) alkyl, aryl or aryl-(C 1 ~C 6 ) an alkyl group; - R d and R e are each independently a hydrogen atom or (C 1 ~C 6 ) represents an alkyl group or a salt, solvate, tautomer, stereoisomer or mixture of stereoisomers in any ratio thereof.

2. Formula (Ia), (Ib), (Ic) or (Id): 【Chemistry 4】 or a salt, solvate, tautomer, stereoisomer or mixture of stereoisomers in any ratio thereof.

3. R 4 is a hydrogen atom or OR 41 3. The compound according to claim 1 or 2,

4. R is CH 2 OH or CH 2 OBn and R 1 and R 2 are each independently OH or OBn, R 3 is OH or OBn, R 4 The compound according to any one of claims 1 to 3, wherein is H, OH or OBn.

5. R 1 , R 2 and R 3 The compound according to any one of claims 1 to 4, wherein are identical.

6. R 5 and R 6 are the same or different and are a hydrogen atom or -CO 2 -R GP1 R GP1 is optionally substituted with one or several halogen atoms (C 1 ~C 6 ) alkyl; (C 2 ~C 6 ) alkenyl; aryl optionally substituted with one or several groups selected from the group consisting of methoxy and nitro groups; aryl-(C 1 ~C 6 6. A compound according to claim 1, wherein R represents an alkyl group; R represents an aryl group; or R represents a 9-fluorenylmethyl group.

7. - R 8 , R 15 , R 22 and R 41 independently of one another represent a hydrogen atom or a (C 1 -C 6 ) alkyl, aryl or aryl-(C 1 -C 6 ) alkyl group, which is optionally substituted by one or more groups selected from halogen atoms, (C 1 -C 6 ) alkoxy, OH, COOH and CHO, R 42 and R 43 represent, independently of one another, a (C 1 -C 6 )alkyl, aryl or aryl-(C 1 -C 6 )alkyl group, optionally substituted by one or more groups selected from among halogen atoms, (C 1 -C 6 )alkoxy, OH, COOH and CHO, R 44 and R 45 independently of one another represent a hydrogen atom or a (C 1 -C 6 ) alkyl, aryl or aryl-(C 1 -C 6 ) alkyl group, said group being optionally substituted by one or more groups selected from among halogen atoms, (C 1 -C 6 ) alkoxy, OH, COOH and CHO, 7. A compound according to any one of claims 1 to 6.

8. A compound described in any one of claims 1 to 7, wherein n is 2; R is CH2OH or CH2OBn; ​​R1 and R2 are, independently of each other, OH or OBn; R3 is OH or OBn; R4 is H, OH or OBn; and R5 and R6 are the same or different and are H, benzyloxycarbonyl (Cbz) or t-butyloxycarbonyl (Boc).

9. The following compounds: 【Chemistry 5】 9. The compound according to any one of claims 1 to 8, selected from the group consisting of:

10. The compound according to claim 9, wherein the salt is an acid addition salt with hydrochloric acid or acetic acid.

11. A method for preparing a compound according to any one of claims 1 to 10, comprising the steps of: (a) Formula (II): 【Chemistry 6】 (In the formula, - n is as defined in claim 1, - R', R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' and R 6 ' are each R, R as defined in claim 1, optionally in protected form. 1 , R 2 , R 3 , R 4 , R 5 and R 6 is equivalent to - R 7 is (C 1 ~C 6 ) alkyl or aryl-(C 1 ~C 6 ) alkyl) to obtain a compound of formula (I), optionally in protected form, (b) R', R 1 ', R 2 ', R 3 ', R 4 ', R 5 ' and / or R 6 'But, R, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 R, R 1 , R 2 , R 3 , R 4 , R 5 and / or R 6 to obtain a compound of formula (I), and (c) optionally salifying or solvating the compound obtained in the previous step (a) or (b) to obtain a salt or solvate of the compound of formula (I).

12. A cosmetic or pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10 and at least one physiologically acceptable excipient.

13. Use of a compound according to any one of claims 1 to 10 or a cosmetic composition according to claim 12 for plumping the skin and / or volumizing the skin and / or firming the skin and / or filling wrinkles and / or moisturizing the skin or hair and / or re-lipidizing the skin or hair and / or stimulating hair growth or for the treatment and / or prevention of skin ageing.

14. - in the treatment and / or prevention of skin ageing, in the protection of the skin or in the regeneration of the skin, or in the treatment of dry skin and / or atopic dermatitis and / or atopic eczema and / or psoriasis, or in the treatment of inflammation, or in the treatment and / or prevention or in the healing of fibrosis 13. A cosmetic or pharmaceutical composition according to claim 12 for use.

15. 15. A cosmetic or pharmaceutical composition according to claim 14, for use in the treatment of inflammation, wherein the inflammation is chronic low-grade inflammation.

16. 15. A cosmetic or pharmaceutical composition according to claim 14, for use in the treatment and / or prevention of fibrosis, wherein said fibrosis is a keloid or hypertrophic scar.

17. A compound for topical use, or a cosmetic or pharmaceutical composition, in combination with a laser or surgical procedure, for the use as defined in claim 16.

18. - For the treatment and / or prevention of skin aging, for skin protection or for skin regeneration, or - for the treatment of dry skin and / or atopic dermatitis and / or atopic eczema and / or psoriasis, or - To treat inflammation, or - for the treatment and / or prevention or in the healing of fibrosis The use of a compound according to any one of claims 1 to 10 is intended for the manufacture of a cosmetic or pharmaceutical composition.

19. 13. A dressing comprising a pad, compress or sponge impregnated with the cosmetic or pharmaceutical composition of claim 12.

20. 11. Use of a compound according to any one of claims 1 to 10 for preserving and / or protecting and / or regenerating biological materials or microorganisms.

21. 11. A culture, storage and / or preservation medium comprising at least one compound according to any one of claims 1 to 10.

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