WO2018053706A1

WO2018053706A1 - Composition comprising paeoniflorin or albiflorin analogue, method of preparation thereof

Info

Publication number: WO2018053706A1
Application number: PCT/CN2016/099572
Authority: WO
Inventors: Chunyu MA; Severine Jeulin; Xavier Marat; Maria DALKO-CSIBA; Biao Yu
Original assignee: L'oreal
Priority date: 2016-09-21
Filing date: 2016-09-21
Publication date: 2018-03-29

Abstract

A composition comprises a compound of formula (I) and at least one cosmetically acceptable carrier. It can be used for preventing or decreasing skin pigmentation and /or lightening skin tone.

Description

Composition comprising Paeoniflorin or albiflorin analogue, method of preparation thereof

Field of the invention

The present invention relates to the field of active cosmetic agents, more particularly paeoniflorin or albiflorin analogues, and their use for acting on pigmentation of the keratin materials, such as the skin and/or of the semi-mucous membranes.

Background of the invention

At different periods in their lives, people witness the appearance on the skin and more especially on the hands and face of darker and/or more highly coloured blemishes which give the skin a heterogeneous appearance. These blemishes are due in particular to a high concentration of melanin in the keratinocytes situated at the surface of the skin.

The use of inoffensive topical depigmenting substances which are highly effective is very particularly sought after with a view to treating pigment blemishes.

The mechanism of formation of the pigmentation of the skin, that is to say of the formation of melanin, is particularly complex and involves, schematically, the following main stages:

Tyrosine ---> Dopa ---> Dopaquinone ---> Dopachrome ---> Melanin

Tyrosinase (monophenol dihydroxyl phenylalanine: oxygen oxidoreductase EC 1.14.18.1) is the essential enzyme involved in this sequence of reactions. In particular, it catalyses the conversion reaction of tyrosine to give Dopa (dihydroxyphenylalanine) , by virtue of its hydroxylase activity, and the conversion reaction of Dopa to give dopaquinone, by virtue of its oxidase activity. This tyrosinase only acts when it is in the maturation state under the effect of certain biological factors.

Depigmenting agents usually acts, either by inhibiting one of the enzymes involved in melanogenesis or by being inserted as structural analogue of one of the chemical compounds in the sequence for the synthesis of melanin, which sequence can then be blocked and thus ensure depigmentation.

In prior art, in order to prevent or decrease skin pigmentation and/or lighten dark skin tone or spots on skin, active ingredients with melanogenesis inhibition activity were used in whitening cosmetic compositions. For instance, ascorbic acid and its derivatives, resorcinol derivatives, and botanical extracts have already been described.

CN105307729 disclosed in its figure 1 the measurement of the depigmentation activity (reduction of melanin) of Paeonia lactiflora root extract using normal human melanocytes in vitro assay.

It is known that Paeoniflorin and albiflorin are the main active ingredients in Paeonia lactiflora root extract. In order to have a better depigmenting and/or whitening effect, efforts have been made to increase the amount of active ingredients in the extract. However the inventors found that the depigmenting and/or whitening effect does not necessarily improve along with the increase of the active ingredients in the extracts.

None of the aforementioned prior arts had disclosed active ingredients with an improved depigmenting and/or whitening effect on the skin, in particular when used at same amount or preferably lower amount comparing to Paeonia lactiflora root extract.

Thus there is a need to develop active ingredients with better efficacy on depigmentation and/or whitening of the skin, i.e., active ingredients with an improved effect when used in the same or lower amount.

There is also a need to develop a novel compound with an improved depigmenting and/or whitening effect on the skin.

There is also a need for identifying new compounds with an improved skin depigmenting and/or whitening effect.

Preferably, such an improved effect is seen even when the compound is used in a low amount.

There is also a need to develop a novel process for preparing the compounds with the effect disclosed above.

Summary of the invention

According to one aspect of the present invention, there is provided a composition comprising a compound of formula (I) as described hereunder, which is different from paeoniflorin or albiflorin, and a physiologically acceptable medium.

Preferably, the composition is a cosmetic composition.

Another aspect of the present invention relates to a compound of formula (I) , as described hereunder.

According to another aspect, the present invention also relates to the use of a compound of formula (I) as described hereunder in depigmenting and/or whitening keratin materials, in particular the skin.

Yet another subject-matter of the invention is a non-therapeutic method for depigmenting, lightening, and/or whitening keratin materials, in particular the skin, comprising the application of a composition comprising the compound of formula (I) as described hereunder.

Yet another object of the present invention is a process for synthesizing a compound of formula (I) as described hereunder.

By “keratin materials” we intend to cover the skin, mucous membranes such as the lips, the nails. The skin is most particularly considered according to the invention.

For the purpose of the present invention, the term “compound of paeoniflorin or albiflorin analogue” excludes the compounds of paeoniflorin or albiflorin.

Detailed description of the invention

Compound of formula (I)

The present invention relates to a composition comprising a compound of formula (I) ,

wherein:

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group； R2 and R3, identical or different, represent –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

optionally, R2 and R3 form with the carbon of the cycle a C＝O group, R1 and any one of R2 and R3 form together a –C–O–C–group；

R4 represents a H, or a

group；

R5 represents a H, a monosaccharide comprising 5 or 6 carbon atoms, optionally substituted by a

group, a

group, or a

group.

According to one embodiment, the compound of the present invention is selected from the group consisting of compounds corresponding to formula (A) :

wherein R1 and R4 are as defined as above.

Preferably, in formula (A) :

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a

group.

More preferably, in formula (A) :

R1 represents a –OR1’ group, wherein R1’ represents a –CH₃ group, a –CH₂CH₃ group, or a

group； and

R4 represents a

group.

Examples of the compound of formula (A) that can be used in the present invention are:

According to another embodiment, the compound of formula (I) of the present invention is selected from the compound corresponding to formula (B) :

wherein:

R2 and R4 are as defined above；

R6 and R7, identical or different, represent a H group, a

group, a

group, or a group.

Preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a

group；

R6 represents a H group, a

group, a

group, or a

group；

R7 represents a H group, a

group, or a

group.

More preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a H group, or a

group；

R6 represents a H group, a

group, or a

group；

R7 represents a H group, a

group, or a

group.

Examples of the compound of formula (B) which can be mentioned are:

Yet according to another embodiment, the compound of formula (I) of the present invention is selected from the group consisting of compounds corresponding to formula (C) :

wherein R2, R4 and R5 are as defined above.

Preferably, in the formula (C) :

R4 represents a

group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms, optionally substituted by a group, a

group, or a

group.

More preferably, in the formula (C) :

R2 represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a

group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms.

Examples of the compounds of formula (I) of this type can be mentioned, such as:

According to a preferred embodiment, the compound of formula (I) is present in an amount ranging from 0.01％to 10％by weight, preferably from 0.1％to 5％by weight, relative to the total weight of the composition.

Physiologically acceptable medium

The term “physiologically acceptable medium” is understood to mean a medium compatible with human keratin materials, such as the skin of the body or of the face, the lips, the mucous membranes, the eyelashes, the nails, the scalp and/or the hair.

The composition according to the invention is advantageously a cosmetic composition: it can comprise adjuvants normally employed in the cosmetics field.

The composition according to the invention may further comprise additional adjuvants commonly used in the envisaged application field.

Mention may be made, to the adjuvants, especially of water； organic solvents, especially C₁-C₆ alcohols and C₂-C₁₀ carboxylic acid esters； carbon-based and/or silicone oils, of mineral, animal and/or plant origin； waxes, pigments, fillers, colorants, surfactants, emulsifiers, co-emulsifiers； cosmetic or dermatological active agents, UV-screening agents, polymers, hydrophilic or lipophilic gelling agents, thickeners, preserving agents, fragrances, bactericides, ceramides, odour absorbers, antioxidants.

These additional adjuvants may be present in the composition in a proportion of from 0.001％to 80％by weight and especially from 0.1％to 40％by weight relative to the total weight of the composition. Depending on their nature, these adjuvants may be introduced into the fatty phase or into the aqueous phase of the composition, or into lipid vesicles. In any case, these adjuvants, and the proportions thereof, will be chosen by a person skilled in the art such that the advantageous properties of the compounds according to the invention are not, or are not substantially, adversely affected by the envisaged addition.

Galenic form

This composition may be in any galenical form normally used in the cosmetic or pharmaceutical field, and especially in the form of an optionally gelled aqueous or aqueous-alcoholic solution, a dispersion, optionally a two-phase dispersion, of the lotion type, an oil-in-water or water-in-oil or multiple emulsion (for example W/O/W or O/W/O) , an aqueous gel, a dispersion of oil in an aqueous phase with the aid of spherules, these spherules possibly being polymer nanoparticles such as nanospheres and nanocapsules or, better still, lipid vesicles of ionic and/or nonionic type； aqueous or oily gels. These compositions are prepared according to the usual methods. According to this invention, a composition in the form of an emulsion, especially an oil-in-water emulsion, is preferably used.

The composition may be more or less fluid and may have the appearance of a white or coloured cream, an ointment, a milk, a lotion, a serum, a paste, a gel or a mousse. It may optionally be applied in aerosol form. It may also be in solid form, in particular in the form of a stick.

When the composition is an emulsion, the proportion of the fatty phase may range from 5％to 80％by weight and preferably from 8％to 50％by weight relative to the total weight of the composition. The emulsifier and the co-emulsifier may be present in a proportion ranging from 0.3％to 30％by weight and preferably from 0.5％to 20％by weight relative to the total weight of the composition.

The composition used according to the invention may constitute a skincare composition, and especially a cleansing, protecting, medicated or care cream for the face, the hands, the feet, the major anatomical folds or the body (for example day creams, night creams, makeup-removing creams, foundation creams or antisun creams) ； a fluid foundation, a makeup-removing milk, a protective or care body milk or an antisun milk； a skincare lotion, gel or mousse, such as a cleansing lotion.

Method and use

According to one aspect of the present invention, there is provided a process for preparing a compound of formula (I) :

wherein:

R4 represents a H, or a

group；

group, a

group, or a

group, comprising the steps of:

I) reaction of a compound of formula (a)

wherein:

R8 represents a

group, a

group, or a

group；

R9 represents a a –OH group, or a –OMe group；

with a compound selected from the group consisting of benzoyl chloride (b) , compound (c) with a formula R-OH, wherein R is a C₁-C₆ alkyl group, a phenyl group, a C₁-C₆ alkylphenyl group, BnOH (d) , or CH₃I (e) ；

II) optionally reaction of the compound obtained in the step I) with benzoyl chloride (b) , TBDMSCl (f) ；

III) optionally reaction of the compound obtained in the step II) with LiOH (g) ；

IV) optionally reaction of the compound obtained in the step III) with a group selected from

group；

V) optionally reaction of the compound obtained in step IV) with TBAF, and/or H₂.

Optionally, there is provided a process for preparing the compound of formula (a) as described above, comprising the steps of:

reaction of L-ribose, or 2-deoxyribose with MeOH, BnBr, and AcOH；

reaction of the compound obtained in the previous step with the compound selected from the groups consisting of NPTAC, EDCl, DMAP, TBSOTf, DCM, and/or PPh₃AuNTf.

According to one aspect of the present invention, there is provided a non-therapeutical cosmetic process for preventing or decreasing skin pigmentation and/or lightening skin tone comprising application of the composition according to the present invention to the skin.

According to another aspect of the present invention, there is provided the use of the compound of formula (I) as described above, in preventing or decreasing pigmentation of keratin materials, and/or lightening keratin materials, in particular the skin.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about. "

Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible.

Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective measurements. The following examples are intended to illustrate the invention without limiting the scope as a result. The percentages are given on a weight basis.

Examples

Example 1: Preparation examples

Compounds 1 to 10 according to the formula (I) of the present invention were prepared.

Synthesis of Compound 1

Compound 1 corresponds to the formula (1) as described above,

AcCl (0.1 ml, 1％volume of MeOH) was added to a solution of Paeoniflorin (1 g, 2.08 mmol) in methanol (10 ml) . The mixture was stirred at 25℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Dichloromethane /Methanol ＝ 15: 1) in order to result in Compound 1 with a yield of 50％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 2 and Compound 4

Compound 2 corresponds to the formula (2) as described above,

Compound 4 corresponds to the formula (4) as described above,

AcCl (0.1 ml, 1％volume of EtOH) was added to a solution of Paeoniflorin (100 mg, 0.21 mmol) in ethanol (10 ml) . The mixture was stirred at 25℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Dichloromethane /Methanol ＝ 15: 1) in order to result in Compound 4 with a yield of 25％, and Compound 2 with a yield of 45％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 3

Compound 3 corresponds to the formula (3) as described above,

AcCl (0.1 ml, 1％volume of EtOH) was added to a solution of Paeoniflorin (100 mg, 0.21 mmol) in benzyl alcohol (10 ml) . The mixture was stirred at 25℃ for 2 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Dichloromethane /Methanol ＝ 15: 1) in order to result in Compound 3 with a yield of 60％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 5

Compound 5 corresponds to the formula (5) as described above,

Ag2O (12.7 g, 55 mmol) and 50 ml of iodomethane was added to a solution of paeoniflorin (4.8 g, 10 mmol) in 300 ml of acetone. The mixture was stirred at 25℃ for 18 h. The mixture was filtered and washed with acetone three times. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane /methanol ＝ 10/1) to obtain a Compound 5’ in 55％yield.

TEA (303 mg, 3.0 mmol) was added to a solution of the compound 5’ (988 mg, 2.0 mmol) in 40 ml of dichloromethane. The solution of benzoyl chloride was slowly added into the mixture in 10 min at 0℃. Then the mixture was stirred at 25 ℃ for 18 h. The solvent was removed under reduced pressure. The resulting residue was purified by chromatography on silica gel (eluent: dichloromethane /methanol ＝ 20/1) in order to result in Compound 5 with a yield of 30％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 6

Compound 6 corresponds to the formula (6) as described above,

Synthesis of compound 2: Ag₂O (12.7 g, 55.0 mmol) and CH₃I (11.36 g, 80.0 mmol) was added to a solution of paeoniflorin (4.8 g, 10.0 mmol) in 200 ml of acetone. After stirring at 25 ℃ for 24 h, the mixture was filtered to remove insoluble matter. The filtrate was concentrated to dryness under vacuum. The residue was subjected to silica gel chromatography eluting with MeOH /CH₂Cl₂ from 1: 50 to 1: 40 to give 3.21 g of compound 2 as a white solid in 65％yield.

Synthesis of compound 3: TBDMSCl (4.9 g, 32.5 mmol) was added to a solution of compound 2 (11.38 g, 23.0 mmol) and imidazol (2.21 g, 32.5 mmol) in 200 ml of THF at 0℃. The reaction mixture was stirred at 25 ℃ for 18 h. Then, the mixture was poured into 500 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with CH₂Cl₂: MeOH ＝ 100: 1 in order to obtain compound 3 as a white solid in 80％yield.

Synthesis of compound 4: LiOH (1.2 g, 28.6 mmol) in 20 ml of water was added to a solution of compound 3 (12.9 g, 21.2 mmol) in 100 ml of THF at 0℃. The reaction mixture was stirred at 25 ℃ for 15 h. Then, the reaction mixture was acidified with 3.0 ml of conc. HCl and concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with EtOAc in order to obtain compound 4 as a white solid in 73％yield.

Synthesis of compound 6: DCC (620 mg, 3.0 mmol) and DMAP (240 mg, 2.0 mmol) was added to a solution of compound 4 (1.0 g, 2.0 mmol) and compound 5 (640 mg, 2.8 mmol) in 20 ml of CH₂Cl₂. The reaction mixture was stirred at 25 ℃ for 24 h. Then, the reaction mixture was filtered to remove the solid. The filtrate was concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with CH₂Cl₂: MeOH ＝ 100: 1 to obtain compound 6 as a white solid in 48％yield.

Synthesis of compound 7: 2.1 ml of 1 N of TBAF in THF was added to a solution of compound 6 (760 mg, 1.1 mmol) in 20 ml of THF. The reaction mixture was stirred at 25 ℃ for 24 h. Then, the reaction mixture was concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with EtOAc to obtain compound 7 as a white solid in 84％yield.

Synthesis of Compound 6: A mixture of compound 7 (530 mg, 0.88 mmol) and 100 mg of 10％of Pd/C in 20 ml of methanol was stirred at 25 ℃ under hydrogen for 18 h. Then, the mixture was filtered to remove Pd/C. The filtrate was concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with CH₂Cl₂: MeOH ＝ 50: 1 in order to result in Compound 6 with a yield of 78％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 7

Compound 7 corresponds to the formula (7) as described above,

Synthesis of compound 2: Ag₂O (12.7 g, 55.0 mmol) and CH₃I (11.36 g, 80.0 mmol) was added to a solution of paeoniflorin (4.8 g, 10.0 mmol) in 200 ml of acetone. After stirring at 25 ℃ for 24 h, the mixture was filtered to remove insoluble matter. The filtrate was concentrated to dryness under vacuum. The residue was subjected to silica gel chromatography eluting with MeOH /CH₂Cl₂ from 1: 50 to 1: 40 to obtain compound 2 as a white solid in 65％yield.

Synthesis of compound 3: TBDMSCl (4.9 g, 32.5 mmol) was added to a solution of compound 2 (11.38 g, 23.0 mmol) and imidazol (2.21 g, 32.5 mmol) in 200 ml of THF at 0 ℃. The reaction mixture was stirred at 25 ℃ for 18 h. Then, the mixture was poured into 500 ml of water and extracted with EtOAc three times. The combined organic layers were washed with water three times and concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with CH₂Cl₂: MeOH ＝ 100: 1 to obtain compound 3 as a white solid in 80％yield.

Synthesis of compound 4: LiOH (1.2 g, 28.6 mmol) in 20 ml of water was added to a solution of compound 3 (12.9 g, 21.2 mmol) in 100 ml of THF at 0 ℃. The reaction mixture was stirred at 25 ℃ for 15 h. Then, the reaction mixture was acidified with 3.0 ml of conc. HCl and concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with EtOAc to obtain compound 4 as a white solid in 73％yield.

Synthesis of compound 6: DCC (358 mg, 1.74 mmol) and DMAP (122 mg, 1.0 mmol) was added to a solution of compound 4 (625 mg, 1.24 mmol) and compound 5 (358 mg, 1.74mmol) in 20 ml of CH₂Cl₂. The reaction mixture was stirred at 25 ℃ for 24 h. Then, the reaction mixture was filtered to remove the solid. The filtrate was concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with CH₂Cl₂: MeOH ＝ 100: 1 obtain compound 6 as a yellow solid in 62％yield.

Synthesis of Compound 7: 1.6 ml of 1 N of TBAF in THF was added to a solution of compound 6 (530 mg, 0.77 mmol) in 20 ml of THF. The reaction mixture was stirred at 25 ℃ for 24 h. Then, the reaction mixture was concentrated to dryness in vacuo. The crude product was further purified on silica gel column chromatography eluting with EtOAc to obtain Compound 7 as a yellow solid in 68％yield. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 8

Compound 8 corresponds to the formula (8) as described above,

Benzoyl chloride (78 mg, 0.55 mmol) was added to a solution of paeoniflorin (240 mg, 0.50 mmol) and TEA (56 mg, 0.55 mmol) in 5 ml of THF at 25 ℃. The reaction mixture was stirred at 25 ℃ for 16 h. The solvent was removed under reduced pressure. The resulted residue was purified by chromatography on silica gel (dichloromethane /methanol ＝ 10: 1) in order to result in Compound 8 with a yield of 38％. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 9

Compound 9 corresponds to the formula (9) as described above,

Synthesis of compound 1: Concentrated H₂SO₄ (0.2 ml) was added to a solution of L-ribose (10 g, 66.7 mmol) in methanol (150 ml) at 0 ℃. Then the reaction mixture was allowed to stir at 25 ℃ over night. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane/methanol ＝10: 1) to obtain compound 1 as a colorless syrup in 55％yield.

Synthesis of compound 2: Sodium hydride (0.75 g, 18.3 mmol) was added to a solution of compound 1 (1 g, 6.1 mmol) in dry tetrahydrofuran (15 ml) at 0 ℃. Then BnBr (2.2 ml, 18.3 mmol) was added dropwise over 10 minutes. Ice bath was removed after stirring for 0.5 h at 0 ℃. The reaction mixture was stirred at 25 ℃ over night. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝15: 1) to obtain compound 2 as a colorless syrup in 84％yield.

Synthesis of compound 3: 1 mol/l H₂SO₄ (3 ml) was added to a solution of compound 2 (7 g, 16.1 mmol) in AcOH (150 ml) . Then the reaction mixture was heated to 100 ℃ for 5 h. After cooling to 25 ℃, the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel ( (petroleum ether/ethyl acetate ＝8: 1) to obtain compound 3 as a colorless syrup in 45％yield.

Synthesis of compound 4: (E) -2, 2, 2-trifluoro-N-phenylacetimidoyl chloride (237 mg, 1.14 mmol) and Cs₂CO₃ (467 mg, 1.43 mmol) was added to a solution of compound 3 (200 mg, 0.48 mmol) in acetone (10 ml) at 25 ℃. Then the reaction mixture was stirred at 25 ℃ for 1 h. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝8: 1) to obtain compound 4 as a white solid in 99％yield.

Synthesis of compound 6: A solution of compound 4 (220 mg, 0.37 mmol) and compound 5 (50 mg, 0.15 mmol) in dry dichloromethane was added to a round bottle charged with activated 4A MS (1.1 g) . The mixture was stirred at 25 ℃ for 0.5 h. Then the mixture was cooled to 0 ℃. TBSOTf (7.9 mg, 0.03 mmol) was added. The reaction mixture was stirred at 0 ℃ for 2 h. Then 0.1 ml of triethylamine was added. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝5: 1) to obtain compound 6 (α/β＝5: 1) as a colorless syrup in 89％yield.

Synthesis of Compound 9: Raney Ni (200 mg) was added to a solution of compound 6 (98 mg, 0.13 mmol) in a mixed solvent of ethanol (2 ml) and ethyl acetate (2 ml) . The mixture was stirred under reflux at 70 ℃ for1 h. Then the mixture was cooled to 25 ℃. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane/methanol ＝20: 1) to obtain Compound 9 as a colorless syrup in 80％yield. The ¹H NMR and mass spectra are in accordance with the expected structure.

Synthesis of Compound 10

Compound 10 corresponds to the formula (10) as described above,

Synthesis of compound 1: Concentrated H₂SO₄ (0.1 ml) was added to a solution of 2-deoxyribose (1 g, 6.71 mmol) in a solution of 10 ml of methanol at 0 ℃. Then the reaction mixture was allowed to stir at 25℃ over night. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane/methanol ＝20: 1) to obtain compound 1 as a white solid in 82％yield.

Synthesis of compound 2: Sodium hydride (6.1 g, 155.40 mmol) was added to a solution of compound 1 (9.2 g, 62.21 mmol) in dry tetrahydrofuran (200 ml) at 0 ℃. Then BnBr (18.1 ml, 155.40 mmol) was added dropwise over 30 minutes. Ice bath was removed after stirring for 1 h at 0 ℃. The reaction mixture was stirred at 25 ℃ over night. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝15: 1) to obtain compound 2 as a colorless syrup in 86％yield.

Synthesis of compound 3: Compound 2 (15 g, 45.70 mmol) was added to a mixed solution of AcOH (320 ml) and H₂O (80 ml) . Then the reaction mixture was heated to 50 ℃ for 24 h. After cooling to 25 ℃, the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel ( (petroleum ether/ethyl acetate ＝8: 1) to obtain compound 3 as a colorless syrup in 50％yield.

Synthesis of compound 5: N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide (459 mg, 2.39 mmol) and DMAP (29 mg, 0.24 mmol) were added to a solution of compound 3 (500 mg, 1.60 mmol) and compound 4 in (511 mg, 2.52 mmol) dichloromethane (10 ml) at 25 ℃. Then the reaction mixture was stirred at 25 ℃ over night. The mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝ 15: 1) to obtain compound 5 as a white solid in 95％yield.

Synthesis of compound 7: A solution of compound 5 (750 mg, 1.50 mmol) and compound 6 (333 mg, 1.01 mmol) in dry dichloromethane (5 ml) was added to a round bottle charged with activated 4A MS (1.1 g) . The mixture was stirred at 25 ℃ for 0.5 h. Then a solution of PPh3AuNTf2 (149 mg, 0.20 mmol) in dry dichloromethane (2 ml) was added. Then the mixture was stirred at 25 ℃ for 3 h. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate ＝5: 1) to obtain compound 7 (α/β＝1: 5.6) as a colorless syrup in 70％yield.

Synthesis of Compound 10: Raney Ni (2.0 g) was added to a solution of compound 7 (530 mg, 0.84 mmol) in a mixed solvent of ethanol (10 ml) and ethyl acetate (10 ml) . The mixture was stirred under reflux for1 h. Then the mixture was cooled to room temperature. The mixture was filtered by using diatomite. The filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (dichloromethane/methanol ＝20: 1) to obtain Compound 10 as a white foam in 62％yield. The ¹H NMR and mass spectra are in accordance with the expected structure.

Example 2: Evaluation examples

Evaluations of the effects for preventing or decreasing skin pigmentation and/or lightening skin tone of the compounds according to the present invention were performed.

The measurement of the depigmentation activity (reduction of the production of melanin) of the compound examples using normal human melanocytes in vitro assay is as follows.

Firstly, normal human melanoyctes are grown and distributed in 384 plates. After 24 hours, the culture medium was replaced with medium containing the compounds of formula (I) prepared in the example 1. The cells were incubated 72 hours before final measurement of optical density which measures the amount of melanin produced by melanocytes.

The activities as well as the effect doses of the Compounds 1 to 10 were defined by EC₅₀ (effective dose) and IC₈₀ (cytotoxic dose, concentration for which 80％of the synthesis of the melanin is inhibited) . The test was also carried out with paeoniflorin and albiflorin, which are known depigmenting compounds.

The result is as follow:

Compound

Activity (1.0g/L)

Cytotoxicity on HTS (high

		through screening) (1.0g/L)
Paeoniflorin	Non-active	Cytotoxic
Albiflorin	Non-active	Cytotoxic
Compound 1	Active	Non-cytotoxic
Compound 2	Active	Non-cytotoxic
Compound 3	Active	Non-cytotoxic
Compound 4	Active	Non-cytotoxic
Compound 5	Active	Non-cytotoxic
Compound 6	Active	Non-cytotoxic
Compound 7	Active	Cytotoxic
Compound 8	Active	Non-cytotoxic
Compound 9	Active	Non-cytotoxic
Compound 10	Active	Non-cytotoxic

It is seen from the results listed above, that the Compounds 1 to 10 according to the present invention shows activity under the normal human melanocytes in vitro assay evaluation, using an amount of 1.0 g/L, whereas the comparative compounds paeoniflorin and albiflorin show no activity under the evaluation, under same amount.

Therefore, comparing to the known compounds for depigmenting and/or whitening of the skin, the Compounds of the invention present an improved efficacy.

Example 3: Formulation examples

The following cosmetic formulas were prepared, using the conventional preparation methods known in the cosmetic field.

Skincare gel formula I

Skincare cream formula II

Skincare lotion formula III

The formulas are stable over 2 months’ s torage, under different temperatures (4 ℃, 25 ℃, 40℃) , and show very good sensory after application.

Claims

A composition comprising:

a) a compound of paeoniflorin or albiflorin analogue of formula (I) :

wherein:

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R2 and R3, identical or different, represent –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

optionally, R2 and R3 form with the carbon of the cycle a C＝O group, R1 and any one of R2 and R3 form together a –C–O–C–group；

R4 represents a H, or a
group；

R5 represents a H, a monosaccharide comprising 5 or 6 carbon atoms, optionally substituted by a
group, a
group, or a
group； wherein the compound of formula (I) is different from paeoniflorin or albiflorin； and

b) at least one cosmetically acceptable carrier.
The composition of claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds corresponding to formula (A) ,

wherein R1 and R4 are defined according to claim 1；

preferably, in formula (A) :

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a
group；

more preferably, in formula (A) :

R1 represents a –OR1’ group, wherein R1’ represents a –CH₃ group, a –CH₂CH₃ group, or a
group； and

R4 represents a
group；

even more preferably, the compound of formula (I) is selected from the group consisting of compounds of formula (1) , formula (2) , and formula (3) ,
The composition of claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds corresponding to formula (B) ,

wherein:

R2 and R4 are defined according to claim 1；

R6 and R7, identical or different, represent a H group, a
group, a
group, or a
group；

preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a
group；

R6 represents a H group, a
group, a
group, or a
group；

R7 represents a H group, a
group, or a
group；

more preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a H group, or a
group；

R6 represents a H group, a
group, or a
group；

R7 represents a H group, a
group, or a
group；

even more preferably, the compound of formula (1) is selected from the group consisting of compounds of formula (4) to formula (8) ,
The composition of claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds corresponding to formula (C) ,

wherein R2, R4 and R5 are defined according to claim 1；

preferably, in the formula (C) :

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a
group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms, optionally substituted by a
group, a
group, or a
group；

more preferably, in the formula (C) :

R2 represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a
group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms；

even more preferably the compound of formula (C) is selected from the group consisting of compounds of formula (9) , and formula (10) ,
The composition of any one of the preceding claims 1 to 4, wherein the compound of formula (I) is present in an amount ranging from 0.01 to 10％by weight, preferably from 0.1 to 5％by weight, relative to the total weight of the composition.
Cosmetic process for preventing or decreasing skin pigmentation and/or lightening skin tone comprising application of the composition according to any one of the preceding claims 1 to 5 to the skin.
Use of the composition of any one of the preceding claims 1 to 5, in preventing or decreasing pigmentation of keratin materials, and/or lightening keratin materials, in particular the skin.
Compound of formula (I) ,

wherein:

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R2 and R3, identical or different, represent –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₆ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

optionally, R2 and R3 form with the carbon of the cycle a C＝O group, R1 and any one of R2 and R3 form together a –C–O–C–group；

R4 represents a H, or a
group；

R5 represents a H, a monosaccharide comprising 5 or 6 carbon atoms, optionally substituted by a
group, a
group, or a
group.
Compound of claim 8 is selected from the group consisting of compounds corresponding to formula (A) ,

wherein R1 and R4 are defined according to claim 8；

preferably, in formula (A) :

R1 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a
group；

more preferably, in formula (A) :

R1 represents a –OR1’ group, wherein R1’ represents a –CH₃ group, a –CH₂CH₃ group, or a
group； and

R4 represents a
group；

even more preferably, the compound of formula (I) is selected from the group consisting of compounds of formula (1) , formula (2) , and formula (3) ,
Compound of claim 8 selected from the group consisting of compounds corresponding to formula (B) ,

wherein:

R2 and R4 are defined according to claim 8；

R6 and R7, identical or different, represent a H group, a
group, a
group, or a
group；

preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a H, or a
group；

R6 represents a H group, a
group, a
group, or a
group；

R7 represents a H group, a
group, or a
group；

more preferably, in the formula (B) ,

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a H group, or a
group；

R6 represents a H group, a
group, or a
group；

R7 represents a H group, a
group, or a
group；

even more preferably, the compound of formula (B) is selected from the group consisting of compounds of formula (4) to formula (8) ,
Compound of claim 8 selected from the group consisting of compounds corresponding to formula (C) ,

wherein R2, R4 and R5 are defined according to claim 8；

preferably, in the formula (C) :

R2 represents a –OH group, a –OR1’ group, wherein R1’ represents a C₁–C₃ alkyl group, linear or branched, saturated or unsaturated, optionally substituted by at least one aryl group；

R4 represents a
group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms, optionally substituted by a
group, a
group, or a
group；

more preferably, in the formula (C) :

R2 represents a –CH₃ group, or a –CH₂CH₃ group；

R4 represents a
group；

R5 represents a H, a monosaccharide comprising 5 carbon atoms；

Even more preferably the compound of formula (C) is selected from the group consisting of compounds of formula (9) , and formula (10) ,
Process of preparing the compound of formula (I) according to any one of the preceding claims 1 to 11, comprising the steps of:

I) reaction of a compound of formula (a)

wherein:

R8 represents a
group, a
group, or a
group；

R9 represents a a –OH group, or a –OMe group；

with a compound selected from the group consisting of benzoyl chloride (b) , compound (c) with a formula R-OH, wherein R is a C₁-C₆ alkyl group, a phenyl group, a C₁-C₆ alkylphenyl group, BnOH (d) , or CH₃I (e) ；

II) optionally reaction of the compound obtained in the step I) with benzoyl chloride (b) , TBDMSCl (f) ；

III) optionally reaction of the compound obtained in the step II) with LiOH (g) ；

IV) optionally reaction of the compound obtained in the step III) with a group selected

from
or
group；

V) optionally reaction of the compound obtained in step IV) with TBAF, and/or H₂.
Use of the compound of formula (I) according to any one of the preceding claims 1 to 11, in preventing or decreasing pigmentation of keratin materials, and/or lightening keratin materials, in particular the skin.