WO2008018683A1

WO2008018683A1 - Hydroxycinnamic acid derivatives and preparation method thereof and cosmetic composition containing it

Info

Publication number: WO2008018683A1
Application number: PCT/KR2007/002847
Authority: WO
Inventors: Heung Soo Baek; Jae Won You; Gae Won Nam; Soo Mi Ahn; Boo Min Kim; Ho Sik Rho; Duck Hee Kim
Original assignee: Amorepacific Corp
Current assignee: Amorepacific Corp
Priority date: 2006-08-10
Filing date: 2007-06-13
Publication date: 2008-02-14
Anticipated expiration: 2009-02-10
Also published as: KR20080014279A; KR100957465B1

Abstract

The present invention relates to hydroxycinnamic acid derivatives conjugated with adamantylamide, a preparation method thereof and cosmetic compositions containing the same. The hydroxycinnamic acid derivatives of the present invention have activities of inhibiting melanin generation by anti-oxidation and promoting collagen synthesis. Therefore, compositions containing the derivatives of the invention can be effectively used as cosmetic compositions with anti-oxidation effect, skin pigmentation improving effect and anti-wrinkle effect by promoting collagen synthesis.

Description

[DESCRIPTION]

[invention Title]

HYDROXYCINNAMIC ACID DERIVATIVES AND PREPARATION METHOD THEREOF AND COSMETIC COMPOSITION CONTAINING IT

[Technical Field]

The present invention relates to hydroxycinnamic acid derivatives conjugated with adamantylamide represented by the following formula 1 and a preparation method thereof and a cosmetic composition containing the same as an active ingredient .

[Formula I]

[Wherein, R₁ is H or C1-C7 alkyl; A is -CH=CH- or -CH₂- CH₂-.]

[Background Art]

UV irradiation causes skin troubles such as pigmentation or wrinkles. Recent studies report that the active oxygen acts as a key factor to cause such skin troubles .

Human skin color is determined by many factors such as erythrocytes in blood, carotene and melanin. But, it is melanin that makes difference in skin tone among races and brings hyperchromasia represented by skin stain and freckle. Melanin existing in the outer skin layer plays a role in blocking UV to protect skin organ under the coriutn and at the same time in scavenging free radical generated in skin system to protect proteins and genes therein.

However, melanin is a very stable substance that is not easily gotten rid of until keratinization once it is generated by internal or outer stress stimulus. Endogenous melanin is produced by polymerizing oxidation using tyrosine or DOPA as a substrate and tyrosinase as a catalyst and this melanin is increased with the increase of free radical, inflammation or UV. UV increases the generation of endogenous active oxygen and this active oxygen increases melanin generation. And then, the increased local melanin becomes skin stain which might spoil the beauty and further cause serious problems such as wrinkles and skin cancer with threatening our lives.

To overcome those problems, active oxygen inhibitors such as ascorbic acid and its derivatives, Mori Cotex Radicis extract, green tea extract, aloe extract, Scutellariae Radix extract, which are so called natural polyphenol extracts, have been tried. But, these natural polyphenol extracts are so unstable that their effects cannot be constant during mixing procedure and percutaneous absorption is difficult, resulting in doubt in whitening and anti-wrinkle effects. [Disclosure]

[Technical Problem]

The present inventors studied to overcome the disadvantages of the natural polyphenol and aftermath the inventors succeeded in increasing anti-oxidation activity by using hydroxycinnamic acid of natural polyphenol and prepared hydroxycinnamic acid derivatives conjugated with adamantylamide by reacting thereof with adamantaneamine having hydrophobic group to improve percutaneous absorption. Most of hydroxycinnamic acid derivatives conjugated with adamantylamide exhibit active oxygen inhibitory effect and melanin generation inhibitory effect as well as procollagen synthesis inducing effect. The present inventors completed this invention by confirming that hydroxycinnamic acid derivatives conjugated with adamantylamide had melanin generation inhibitory activity or procollagen synthesis inducing effect, and therefore it can be an excellent cosmetic composition to bring whitening effect or anti-wrinkle effect. It is an object of the present invention to provide hydroxycinnamic acid derivatives conjugated with adamantylamide having a novel chemical structure and a preparation method thereof.

It is another object of the present invention to provide an anti-oxidative cosmetic composition, a whitening cosmetic composition or an anti-wrinkle cosmetic composition containing the hydroxycinnamic acid derivatives conjugated with adamantylamide as an active ingredient in an amount of 0.01 - 20 weight%.

[Technical Solution]

The present invention relates to hydroxycinnamic acid derivatives conjugated with adamantylamide represented by formula 1 and a preparation method thereof as well as an antioxidant, a whitening or an anti-wrinkle cosmetic composition containing the same as an active ingredient. [Formula I]

[Wherein, Ri is H or C1-C7 alkyl; A is -CH=CH- or -CH₂- CH₂-.]

Hereinafter, the present invention is described in detail. The hydroxycinnamic acid derivatives conjugated with adamantylamide of the present invention represented by formula 1 are generated by the following reaction formula, in which the following steps are included, 1) preparing the acetylated compound of formula III by converting H of hydroxy1 group to acetyl group by using hydroxycinnamic acid of formula II, acetic anhydride, base and a catalyst; 2) preparing the amide compound of formula IV by reacting the acetylated compound of formula III prepared in the above step 1) with adamantaneamine having hydrophobic group and ethylchloroformate; and

3) obtaining hydroxycinnamic acid derivatives conjugated with adamantylamide of formula I by hydrolyzing the acetyl group of the amide compound of formula IV prepared in the above step 2) .

[Reaction Formula 1]

[Wherein, Ri is H or C1-C7 alkyl ; A is - CH=CH- or - CH₂ -

CH₂ - ; and When Ri is C1-C7 alkyl , Ri is the same as R₂ but when Ri is H , R₂ is acetyl . ]

The method of preparing hydroxycinnamic acid derivatives conj ugated with adamantylamide , as explained in the above reaction formula 1, is described in more detail hereinafter.

In step 1) , hydrogen atom of hydroxyl group is converted to acetyl group by the reaction of hydroxycinnamic acid, acetic anhydride and base in the presence of a catalyst. In this reaction, base is pyridine or triethylamine, and a reaction solvent is selected from the group consisting of dichloromethane, chloroform and tetrahydrofuran. For smooth reaction, dimethylaminopyridine is used as a catalyst, and if not, the reaction is not smoothly carried out and yield is not high. The reaction temperature is preferably 10 - 80^°C and more preferably 40°C .

In step 2) , the reaction of the acetylated compound (III) with adamantylamine having hydrophobic group and ethylchloroformate is induced to give an adamantylamide compound (IV) . This reaction can be induced by acid halogenation, active ester method, or acid anhydride method, but it is preferred to convert the compound to adamantylamine having hydrophobic group under anhydrous condition to produce adamantylamide compound (IV) . The equivalence ratio of adamantylamine having hydrophobic group to be reacted with the acetylated compound (III) is preferably 1.1 - 1.3. If the equivalence ratio is under 1:1, the level of adamantylamide compound (IV) is reduced.

The base herein is pyridine or triethylamine but preferably triethylamine . A reaction solvent is selected from the group consisting of dichloromethane, acetone, N, N- dimethylformatnide, acetonitrile and tetrahydrofuran, but N, N- dimethylformaraide and tetrahydrofuran are preferred. The preferable reaction temperature is 10 - 60°C and 30^°C is more preferred.

In step 3) , hydroxycinnamic acid derivatives conjugated with adamantylamide represented by formula I is obtained. The hydrolysis of acetyl group of adamantylamide compound (IV) is induced in the presence of a base selected among alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. In this reaction, a reaction solvent is selected from the group consisting of water, methanol, ethanol, propanol, tetrahydrofuran and dichloromrthane . It is preferred to mix tetrahydrofuran and methanol at the volume ratio of 1 : 1 - 1 : 5, and more preferably 1 : 1 for desirable reaction in a short period of time.

The preferable embodiments of hydroxycinnamic acid derivatives conjugated with adamantylamide represented by formula I which can be generated by the above preparation method are as follows .

[Formula I-a] 3- (3 , 4-dihydroxyphenyl) -N-adamantyl- propeneamide

[Formula I-b] 3 - (4 -hydroxy- 3 -methoxyphenyl ) -N-adamantyl - propeneamide

[Formula I-c] 3 - ( 3 -hydroxy-4 -methoxyphenyl ) -N-adamantyl- propeneamide

(3,4-dihydroxyphenyl) -N-adamantyl- propaneamide

The hydroxycinnamic acid derivatives conjugated with adamantylamide (I) prepared by the method of the present invention can be included in an anti-oxidant, a whitening or an anti-wrinkle cosmetic composition as an active ingredient, and at this time, the concentration can be determined considering the maximum effect of anti-oxidant, whitening or anti-wrinkle activity. For example, the compound can be contained in an amount of 0.01 - 20.0 weight%, based on the total cosmetic composition and formulation form can be cream, lotion, toner, massage cream or essence but not always limited

[Formula I-b] 3 - (4 -hydroxy- 3 -methoxyphenyl ) -N-adamantyl - propeneamide

[Formula I-c] 3 - ( 3 -hydroxy-4 -methoxyphenyl) -N-adamantyl- propeneamide

(3,4-dihydroxyphenyl) -N-adamantyl- propaneamide

The hydroxycinnamic acid derivatives conjugated with adamantylamide (I) prepared by the method of the present invention can be included in an anti-oxidant, a whitening or an anti-wrinkle cosmetic composition as an active ingredient, and at this time, the concentration can be determined considering the maximum effect of anti-oxidant, whitening or anti-wrinkle activity. For example, the compound can be contained in an amount of 0.01 - 20.0 weight%, based on the total cosmetic composition and formulation form can be cream, lotion, toner, massage cream or essence but not always limited thereto.

The composition of the present invention can include other general ingredients according to its formulation and the kinds, and contents of such ingredients can be generally- determined by those in the art. The composition of the present invention can include any other anti-oxidant, whitening or anti-wrinkle agent in addition to the hydroxycinnamic acid derivatives conjugated with adamantylamide (I) of the present invention in order to increase the anti-oxidative, whitening or anti-wrinkle effect. At this time, the kind and concentration of an acceptable conventional anti-oxidant, whitening or anti-wrinkle agents are well informed to those in the art.

[Best Mode]

Practical and presently preferred embodiments of the present invention are illustrative as shown in the following Examples . However, it will be appreciated that those skilled in the art, on consideration of this disclosure, may make modifications and improvements within the spirit and scope of the present invention. 10

[Example 1] 3- (3,4-dihydroxyphenyl) -N-adamantyl-propeneamide (Formula I-a)

3 , 4-dihydroxycinnamic acid (100 g, 0.56 mol) was dissolved in 1000 ml of dichloromethane, to which dimethylaminopyridine (4 g, 0.03 mol) was added as a catalyst, followed by reflux for 5 minutes. Triethylamine (199 ml, 1.43 mol) was added thereto. To the reaction solution, acetic anhydride (135 ml, 1.43 mol) was added slowly, followed by reflux for 2 hours at 40^°C. Upon completion of the reaction, dichloromethane (1000 ml) was added to the reaction solution for dilution, which was then washed with 1000 ml of water and 500 ml of 1 M HCl solution. The mixture was dried over manganese anhydride (100 g) , filtered and concentrated, and crystallized with hexane. The product was filtered again and hydrogen atom of 3, 4-dihydroxy group of 3 , 4-dihydroxycinnamic acid was converted to acetyl group to give 123 g of an acetyl compound (yield = 83%). The resulted compound (100 g, 0.38 mol) was dissolved in tetrahydrofuran (1500 ml) , to which triethylamine (76.1 ml, 0.55 mol) was slowly added. 1.3 equivalence ratio of ethylchloroformate (56.9 ml, 0.49 mol) was slowly added to the mixture, followed by stirring for 30 minutes. Upon completion of the stirring, adamantaneamine hydrochloric acid (78.8 g, 0.42 mol) and triethylamine (68.3 ml, 0.49 mol) dissolved in 1500 ml of N,N-dimethylformamide by heat 11

were slowly loaded to the reaction solution, followed by- further stirring for 3 hours. Upon completion of the reaction, the reaction mixture was filtered and concentrated. The concentrated reaction mixture was dissolved in 1500 m# of dichloromethane and then washed with distilled water (500 rd) and secondly washed with 500 mi of saturated sodium hydrogen carbonate. The mixture was dried over manganese anhydride (100 g) , filtered, concentrated and crystallized using hexane. The crystallized product was filtered again to give 133 g of an adamantylamide compound (yield = 88%) . The obtained compound (100 g, 0.25 mol) was dissolved in 1500 mi of solvent in which tetrahydrofuran and methanol were mixed at 1:1, followed by stirring in 100 mi of 15% potassium hydroxide for 30 minutes. Upon completion of the reaction, acid was added to neutralize the mixture. The reaction solution was then concentrated, to which 1500 mi of ethyl acetate was added to dissolve the mixture. The reaction mixture was then washed with 1000 mi of water, concentrated, crystallized using hexane and filtered to give 69 g of the target compound 3-(3,4- dihydroxyphenyl) -N-adamantyl-propeneamide (Formula I-a) as a light yellow solid (yield = 89%) . [Formula I-a]

12

TLC (ethyl acetate : hexane = 1 : 1) R_f = 0.78 1H NMR(DMSO-U₆, δ) : 9.05(m, 2H), 7.46(d, IH), 7.25(s, IH),

7.01(s, IH), 6.92(d, IH), 6.78 (d, IH), 6.16(d, IH), 1.96(m,

9H) , 1.52 (m, 6H) .

[Example 2] 3- (4-hydroxy-3-methoxyphenyl) -N-adamantyl- propeneamide (Formula I-b)

The target compound 3- (4-hydroxy-3-methoxyphenyl) -N- adamantyl-propeneamide (Formula I-b) was prepared as 72g of a light yellow solid (yield = 82%) by the same manner as described in Example 1 except that 4-hydroxy-3-methoxycinnamic acid was used instead of 3 , 4-dihydroxycinnamic acid.

[Formula I-b]

TLC (ethyl acetate : hexane = 1 : 1) R_f = 0.69

¹H NMR (DMSO-d₆, δ) : 9.02(s, IH), 7.52(d, IH), 7.31(s, IH), 7.28(s, IH), 7.12(d, IH), 6.82(d, IH), 6.46(d, IH), 3.82(s, 3H), 1.93 (m, 9H), 1.49(m, 6H).

[Example 3] 3- (3-hydroxy-4-methoxyphenyl) -N-adamantyl- propeneamide (Formula I-c)

The target compound 3- (3-hydroxy-4-methoxyphenyl) -N- adamantyl-propeneamide (Formula I-c) was prepared as 75g of a 13

light yellow solid (yield = 85%) by the same manner as described in Example 1 except that 3-hydroxy-4-methoxycinnamic acid was used instead of 3 , 4-dihydroxycinnamic acid. [Formula I-c]

TLC (ethyl acetate : hexane = 1 : 1) R_f = 0.70

¹H NMR (DMSO-d₆, δ) : 8.92(s, IH), 7.49(d, IH), 7.2β(s, IH), 7.12 (m, 2H), 6.92(d, IH), 6.26(d, IH), 3.81(s, 3H), 1.95(m, 9H) , 1.49(m, 6H) .

[Example 4] 3- (3 , 4-dihydroxyphenyl) -N-adamantyl-propaneamide (Formula I-d)

The target compound 3- (3 , 4-dihydroxyphenyl) -N-adamantyl- propaneamide (Formula I-d) was prepared as 72g of a light yellow solid (yield = 91%) by the same manner as described in Example 1 except that 3-4-dihydroxyhydrocinnamic acid was used instead of 3 , 4-dihydroxycinnamic acid.

[Formula I-d]

TLC (ethyl acetate : hexane = 1 : 1) R_f = 0.60

¹H NMR(DMSO-d₆, δ) : 8.65 (m, 2H), 7.1β(s, IH), 6.56 (m, 2H), 6.38(d, IH), 2.58(t, 2H), 2.15(t, 2H), 1.91(m, 9H), 1.45(m, 14

6H) .

[Experimental Example 1] Investigation of anti-oxidative effect using HaCat model The anti-oxidative effect of hydroxycinnamic acid derivatives conjugated with adamantylamide prepared in Examples 1 - 4 was investigated. Human keratinocyte cell line HaCaT was distributed in 60 mm dish at the concentration of 1.OxIO⁶ cells per dish, which was cultured in DMEM (FBS 10%) supplemented with penicillin/streptomycin in a 37^°C, 5% CO₂ incubator for one day. The compounds of Examples 1 - 4, the most representative conventional anti-oxidant tocopherol (as a positive control) , EGCG (Epigallocatechin Gallate) and BHT (t- butyl hydroperoxide) were treated thereto at the concentration of 10^"4 mol, followed by culture in a 37^°C, 5% CO₂ incubator. Cells were obtained 4 hours later. The cells were lysed by freeze/thawing. The following experiments were performed according to the instructions of the assay kit.

To measure anti-oxidant effect, Calbiochem Lipid peroxidation assay kit (Cat. No.437634) was used. The level of lipid peroxidation was measured based on the principle that the reaction of long chain unsaturated fatty acid associated ester peroxide such as malondialdehyde (MDA) and 4- hydroxyalkenal (i.e. 4-hydroxy-2 (E) -nonenal, 4-HNE) with the 15

above reagent produces a very stable compound at 586nm. The low number indicated the higher inhibition of lipid peroxidation.

[Table 1] Anti-oxidative effect of hydroxycinnamic acid derivatives

MDA and HNE shown in Table 1 are the products from the peroxidation of saturated fatty acid associated ester. So, measuring such aldehydes leads to the understanding of the level of lipid peroxidation. And the lower the value, the greater the lipid peroxidation inhibitory effect will be. From the results of investigation of anti-oxidation shown in Table 1, it was confirmed that hydroxycinnamic acid derivatives prepared in Examples 1 - 4 had excellent anti-oxidative effect, compared with the representative conventional anti-oxidants such as t-BHP, tocopherol and EGEG.

[Experimental Example 2] Melanin synthesis inhibitory effect in melanocytes

The effect on melanin generation of the compounds prepared in Examples 1 - 4 was investigated by Dooley's method. 16

MeI-Ab cell line derived from cutaneous pigment cells of C57BL/6 was used. Cell culture was carried out in DEME supplemented with 10% FBS, 100 nM 12-OI-tetradecanoyl phobol- 13-acetate, 1 nM cholera toxin in a 37^°C, 5% CO₂ incubator. Cultured MeI-Ab cells were recovered using 0.25% trypsin- EDTA and then re-distributed in a 24 -well plate at the equal concentration (IxIO⁵ cells/well) . For the three consecutive days from the second day of distribution, media each containing 10 ppm of sample were replaced. 5 days later, IN NaOH was treated to take off melanin included in cells and the level of melanin was measured by measuring OD_40O- The level of melanin was compared with that in the non-treated control group and the ratio (%) was calculated, which was shown in Table 2. [Table 2] Inhibition of melanin generation by hydroxycinnamic acid derivatives

Inhibitory effects on melanin generation of hydroquinone

(HQ) and koj ic acid, positive controls, were investigated and compared with those of the hydroxycinnamic acid derivatives 17

conjugated with adamantylamide of Examples 1 - 4. As shown in Table 2, it was confirmed that the hydroxycinnamic acid derivatives conjugated with adamantylamide of Examples 1 - 4 had similar or greater inhibitory effect on melanin generation than the conventional whitening agents hydroquinone and kojic acid.

[Experimental Example 3] Whitening effect on human skin

12 healthy male volunteers were participated in this examination. An opaque tape with a hole of 1.5 cm in diameter was attached on the humeral region of the examinee . UVB was irradiated 1.5 - 2 times the minimal erythema dose to induce darkening of skin.

After irradiation, 2% of each compounds of Examples 1 - 4 (solvent: 1, 3-butyleneglycol : ethanol=7 : 3) , 2% of hydroquinone (control) , 2% of lipoic acid and a vehicle were respectively applied for 10 weeks (one spot was just left without application) . Skin color change was investigated by Colorimeter CR-300 (Minolta, Japan) every week. The change of color tone (Δ L) was measured, which is represented by the difference of ^λL' value, and the results are shown in Table 3.

The improvement of pigmentation was investigated and used as basis for the evaluation of whitening effect and the results are shown in Table 3. 18

[Table 3] Whitening effect of hydroxycinnamic acid derivatives on human skin

As shown in Table 3, the hydroxycinnamic acid derivatives conjugated with adamantylamide of Examples 1 - 4 were confirmed to have excellent whitening effect, compared with lipoic acid that has been known as a whitening agent, which was also similar or even improved, compared with the whitening effect of hydroquinone (HQ) .

[Experimental Example 4] Promotion of collagen biosynthesis

Collagen biosynthesis promoting effects of hydroxycinnamic acid derivatives conjugated with adamantylamide of Examples 1 - 4 were compared with those of retinol and retinoic acid.

Fibroblasts were seeded in a 24 well plate at the concentration of 10⁵ cells per well and cultured until they grew 90%. After culturing in serum-free DMEM for 24 hours, the cells were treated with 10^"4 mol of hydroxycinnamic acid derivatives of Examples 1 - 4, retinol and retinoic acid, 19

followed by further culture for 24 hours in a CO₂ incubator. The supernatant was tested for procollagen level by using procollagen type (I) ELISA kit. The results are shown in Table 4. Synthetic capacity was presented as the ratio to non- treated group (100) .

[Table 4] Procollagen biosynthesis inducing effect of hydroxycinnamic acid derivatives

As shown in Table 4, hydroxycinnamic acid derivatives prepared in Examples 1 - 4 were confirmed to have similar or greater collagen biosynthesis inducing effect in skin, compared with retinol and retinoic acid.

[Experimental Example 5] Inhibitory effect on collagenase expression

The hydroxycinnamic acid derivatives prepared in Examples 1 - 4 were tested for the inhibitory effect on collagenase expression, by comparing those of retinol and retinoic acid.

Human fibroblasts were seeded in a 96 well microtiter plate containing DMEM (Dulbecco's Modified Eagle's Media) 20

supplemented with 2.5% FBS at the concentration of 5000 cells/well and cultured until they grew 90%. After culturing them in serum-free DMEM for 24 hours, the cells were treated with the hydroxycinnamic acid derivatives of Examples 1 - 4, retinol and retinoic acid by 10^"4 mol each for 24 hours and then the cell culture medium was obtained.

Collagenase generation in the cell culture medium was measured by collagenase measuring kit (Amersham Pharmacia, USA) . First, the cell culture medium was loaded in a 96 well plate supplemented evenly with the primary collagenase antibody to induce antigen-antibody reaction for 3 hours.

Three hours later, the chromophore-conjugated secondary collagen antibody was loaded in the 96 well plate again and reaction was induced for 15 minutes. A coloring material was added 15 minutes later to induce color development for 15 minutes and then 1 M sulfuric acid was added to terminate color development. The color of the reaction solution was yellow and the degree of yellow varied from the degree of reaction. OD₄₀₅ of the yellow 96 -well plate was measured and collagenase synthesis was calculated by the following mathematical formula 1. The optical density of the cell culture medium that had not been treated with any composition was considered as the control. 21

[Mathematical Formula 1]

Expression rate of collagenase (%) = OD of the composition-treated cell group / OD of the control group x 100

The results of the examination of the inhibitory effect on intracellular collagenase expression are shown in Table 5 and the expression inhibitory capacity was calculated by considering the synthesis ability of non-treated group as 100. [Table 5]

As shown in Table 5, the hydroxycinnamic acid derivatives of Examples 1 - 4 were confirmed to have similar or greater collagenase expression inhibitory effect in vitro, compared with retinol and retinoic acid.

Hereinafter, formulation examples of the hydroxycinnamic acid derivatives of the present invention are described, but it is well understood by those in the art that these cannot limit the spirit or scope of the present invention.

Cosmetic compositions for whitening and anti-wrinkles were prepared with the hydroxycinnamic acid derivatives of 22

Examples 1 - 4 having excellent melanin generation inhibitory- effect and collagen biosynthesis promoting effect by the conventional cosmetic composition preparation method according to the following constitution and ratio.

[Formulation Example 1]

Anti-wrinkle cream formulation containing the compounds of Examples 1 - 4

Stearic acid 10% Palmitic acid 5%

Myristic acid 15%

Laurie acid 6%

Potassium hydroxide 6%

Glycerin 15% Compounds of Examples 1 - 4 0.5%

Proper amounts of antiseptic, non-ionic surfactant, pigment, flavor, etc were added thereto, and then distilled water was added until the total volume reached 100%.

[Formulation Example 2]

Whitening cream formulation containing the compounds of Examples 1 - 4

Stearic acid 2%

Glyceryl mono stearate 3% 23

Cetostearyl alcohol 3%

Squalene 20%

Macadamia nut 10%

Silicon oil 3% Polysorbate-60 2.5%

Glycerin 10%

Compounds of Examples 1 - 4 0.5% Proper amounts of flavor, pigment, antiseptic, antioxidant, etc were added thereto, and then distilled water was added until the total volume reached 100%.

[industrial Applicability]

As explained hereinbefore, hydroxycinnamic acid derivatives conjugated with adamantylamide of the present invention have the activities of inhibiting active oxygen and melanin generation, promoting procollagen biosynthesis and inhibiting collagenase expression. So, the compositions containing the hydroxycinnamic acid derivatives as an active ingredient can be effectively used as an anti-oxidative cosmetic composition with inhibiting effect of active oxygen, a cosmetic composition for whitening with improvement of skin pigmentation, or an anti-wrinkle cosmetic composition.

Claims

24

[CLAIMS]

[Claim l]

Hydroxycinnamic acid derivatives conjugated with adamantylamide having the following formula 1. [Formula I]

[Wherein, Ri is H or C1-C7 alkyl ; A is - CH=CH- or - CH₂ -

CH₂-.]

[Claim 2]

The hydroxycinnamic acid derivatives according to claim 1, wherein the derivatives have a structure selected from those represented by formulas I-a - I-d.

[Formula I-a]

[Formula I-b]

[Formula I-c]

[Formula I-d] 25

[Claim 3]

A method for producing hydroxycinnamic acid derivatives conjugated with adamantylamide comprising the following steps:

1) preparing an acetylated compound of formula III by converting H of hydroxyl group of hydroxycinnamic acid of formula II to acetyl group;

2) preparing an amide compound of formula IV by reacting the acetylated compound of formula III prepared in the above step 1) with ethylchloroformate and adamantaneamine having hydrophobic group; and

[Formula I]

[Formula II]

[Formula III] 26

[Formula IV]

[Wherein, R₁ is H or C1-C7 alkyl ; A is -CH=CH- or -CH₂- CH₂- ; and When R₁ is C1-C7 alkyl , Ri is the same as R₂ but when R₁ is H, R₂ is acetyl . ]

[Claim 4]

The preparation method for the hydroxycinnamic acid derivatives according to claim 3, wherein the reagent of step 1) is acetic anhydride, base and dimethylaminopyridine as a catalyst.

[Claim 5] The preparation method for the hydroxycinnamic acid derivatives according to claim 3, wherein the reaction solvent of step 3) is the mixture of methanol and tetrahydrofuran at the volume ratio of 1:1 - 1:5.

[Claim 6]

A cosmetic composition containing the hydroxycinnamic acid derivatives conjugated with adamantylamide of claim 1 or 27

claim 2.

[Claim 7]

The cosmetic composition according to claim 6, wherein the composition is for anti-oxidation.

[Claim 8]

The cosmetic composition according to claim 6, wherein the composition is for whitening.

[Claim 9]

The cosmetic composition according to claim 6, wherein the composition is for anti-wrinkle.

[Claim lθ]

The cosmetic composition according to claim 6, wherein the hydroxycinnamic acid derivative is contained in an amount of 0.01 -20 wt%, based on the total weight of the cosmetic composition.