WO2012008767A2

WO2012008767A2 - Retinoid derivatives and cosmetic composition comprising the same

Info

Publication number: WO2012008767A2
Application number: PCT/KR2011/005174
Authority: WO
Inventors: Bong Youl Chung; Jin Hun Cho; Sung Sik Bang; Byoung Young Jeon; Ick Je Woo
Original assignee: Paraon, Inc.; Woongjin Coway Co., Ltd.
Priority date: 2010-07-14
Filing date: 2011-07-14
Publication date: 2012-01-19
Also published as: KR101194337B1; WO2012008767A3; KR20120007199A

Abstract

The present invention relates to retinoid derivatives and a cosmetic composition comprising the same. The retinoid derivatives according to the present invention have an excellent collagen synthesis increasing effect, is non-irritating, is non-toxic, have good chemical stability, is easily absorbed to the skin, and is long-wearing to show superior skin regeneration and anti-aging effects. Therefore, the retinoid derivatives according to the present invention can be effectively used for preparing an anti-aging cosmetic composition.

Description

RETINOID DERIVATIVES AND COSMETIC COMPOSITION COMPRISING THE SAME

The present invention relates to retinoid derivatives and a cosmetic composition comprising the same. More particularly, the present invention relates to retinoid derivatives having an excellent collagen synthesis increasing effect, being non-irritating, being non-toxic, having good stability, being easily absorbed to the skin and being long-wearing, and a cosmetic composition comprising the same.

Retinoids are derivatives of vitamin A, and include retinol, retinal, retinoic acid, retinyl esters such as retinyl acetate, retinyl propionate, retinyl linoleate and retinyl palmitate, etc.

Meanwhile, skin-aging such as wrinkles, roughness and flecks or dermatologic diseases such as skin cancer are mainly caused by long-term exposure to the UV radiation of the sun. It is reported that since all-trans retinoic acid can alleviate the skin wrinkles, roughness, etc. by the UV radiation, a cosmetic composition comprising it can improve the skin-aging [see: Weiss C. N et al., JAMA, 259(1988), 527-532, which is incorporated in its entirety here by reference].

However, since the retinoids are very unstable to light, heat, oxygen, water, etc., they need to be stabilized for practical use. Also, the retinoids have the problems of in vivo stability and cytotoxicity as a side effect due to retinoic acid receptor (RAR). Therefore, many researchers have been studied to develop retinoid derivatives having good stability, being non-toxic, and being non-irritating, as well as having the anti-photoaging effect.

Particularly, US Patent No. 4,677,120, which is incorporated in its entirety here by reference, discloses 2-(all-trans-retinoyloxy)-4-methoxyacetophenone, which is relatively low irritating and has the effects of inhibiting skin cancer and photoaging. Also, US Patent No. 4,900,478, which is incorporated in its entirety here by reference, teaches an ester compound of retinoic acid with tetraethyleneglycol, which has an improved skin penetration capability. Further, N-(4-hydroxyphenyl) retinamide and retinyl β-glucuronide are known to have the anti-aging effect, but have not solved the problem of the toxicity [see: FASEB J., 10, 1014-1024, 1996, which is incorporated in its entirety here by reference].

WO 03/037385, which is incorporated in its entirety here by reference, discloses retinoid derivatives wherein fat-soluble retinoids are esterified or cyclized with polyethylene glycol to improve water-solubility. The retinoid derivatives are easy to process and formulate, and well suited for administration by inhalation to allow administration of smaller doses of the retinoid derivatives to achieve therapeutically useful levels in treating chronic obstructive pulmonary diseases such as emphysema, thereby increasing their bioavailability and reducing their systemic toxicity. However, the retinoid derivatives have the problem that polyethylene glycol (PEG) backbone and retinoic acid are rapidly decomposed by an enzyme in the blood. Also, although their water-solubility is improved, they have low selectivity in binding to retinoic acid receptor to show actual efficacy after being absorbed to the blood of a human body [see: US Patent No. 6,180,670, which is incorporated in its entirety here by reference].

Therefore, there has been a need to develop a new retinoid derivative, which is stable at the blood pH value, maintains the activities of vitamin A, is non-irritating, is non-toxic, and is long-wearing.

The present inventors have researched to overcome the above problems of the known retinoid derivatives, and found that the retinoid derivatives according to the present invention have an excellent collagen synthesis increasing effect, is non-irritating, is non-toxic, have good chemical stability, is easily absorbed to the skin, and is long-wearing.

An object of the present invention is, therefore, to provide a retinoid derivative of the following formula (I), which can be used as an ingredient of functional cosmetics.

Another object of the present invention is to provide a cosmetic composition comprising the retinoid derivative of the following formula (I).

The present invention relates to a retinoid derivative of the following formula (I), which can be used as an ingredient of functional cosmetics.

(I)

wherein,

X is NH, O, or S, particularly NH or O; and

R₁ and R₂ are identical or different, and hydrogen or C₁-C₆ alkyl, particularly different, and hydrogen or methyl.

The retinoid derivative according to one embodiment of the present invention is particularly a compound of the above formula (I) wherein X is NH, R₁ is methyl, and R₂ is hydrogen, that is, 2-methyl-1,5-diretinylpentanediamide (MDRPDA).

The term “C₁-C₆ alkyl” as used herein means a straight or branched hydrocarbon having 1 to 6 carbon atoms, which includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc. but is not limited thereto.

The retinoid derivative according to the present invention can be prepared as follows.

In one embodiment, the retinoid derivative according to the present invention can be prepared by reacting a compound of the following formula (II) wherein Y is hydroxy with a compound of the following formula (III) in a solvent in the presence of a coupling agent and an organic amine catalyst (hereinafter "Process I").

In another embodiment, the retinoid derivative according to the present invention can be prepared by reacting a compound of the following formula (II) wherein Y is halogen with a compound of the following formula (III) in a solvent in the presence of an organic amine (hereinafter "Process II").

(II)

(III)

wherein,

Y is hydroxy or halogen;

X is NH, O, or S; and

R₁ and R₂ are identical or different, and hydrogen or C₁-C₆ alkyl.

In the above Process I, the coupling agent can include N,N,N',N'-tetramethyl-(benzotriazol-1-yl)-uronium tetrafluoroborate (TBTU), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), or N,N‘-dicyclohexylcarbodiimide (DCC), but is not limited thereto. The organic amine catalyst to accelerate the coupling reaction can include diisopropylethylamine (DIPEA) and 4-dimethylaminopyridine (DMAP), but is not limited thereto. The solvent can include anhydrous organic solvents such as dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether, but is not limited thereto. The coupling reaction can be carried out under nitrogen atmosphere with blocking out light and moisture at cooled or warmed temperature.

In the above Process II, the organic amine functions as a base, which can include pyridine and triethylamine, but is not limited thereto. The organic amine can be used in an amount of 1.0 to 2.0 equivalents based on the compound of the above formula (III). The solvent can include anhydrous organic solvents such as dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether, but is not limited thereto. The coupling reaction can be carried out under nitrogen atmosphere with blocking out light and moisture at cooled or warmed temperature.

In one embodiment, the compound of the above formula (II) wherein Y is halogen, which is used as a starting material in the above Process II, can be prepared by reacting retinoic acid with a halogenating agent such as phosphorous trichloride, thionyl chloride and oxalyl chloride.

In one embodiment, the compound of the above formula (I), which is prepared as above, can be purified using common purification methods such as recrystallization and column chromatography.

The retinoid derivative of the above formula (I) according to the present invention can be used for skin care and skin disorders, for example for treating skin cancer, acne, skin wrinkles, freckles, etc. In particular, the retinoid derivative according to the present invention is characterized by being non-irritating, being easily absorbed to the skin, stimulating collagen synthesis, and inhibiting the decomposition of elastin to have a skin regeneration effect, and having high selectivity to the retinoic acid receptor.

The present invention further relates to a cosmetic composition, particularly an anti-aging cosmetic composition, comprising the retinoid derivative of the above formula (I).

In one embodiment, the cosmetic composition of the present invention can contain 0.01 to 20.0 wt%, particularly 0.1 to 10.0 wt% of the retinoid derivative of the above formula (I) as an active ingredient. The particular amount of the active ingredient can be determined depending on the purpose of use.

In one embodiment, the cosmetic composition of the present invention can include cosmetic ingredients usually used in the art, for example, common adjuvants such as anti-oxidant, stabilizer, solubilizer, vitamin, colorant and perfumery, and carriers, in addition to the retinoid derivative according to the present invention.

In one embodiment, the cosmetic composition of the present invention can be formulated as any form usually used in the art, for example, solution, suspension, emulsion, paste, gel, cream, powder, spray, etc.

In the case where the cosmetic composition is formulated as paste, cream or gel, the examples of the carriers include animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talc, zinc oxide, etc.

In the case where the cosmetic composition is formulated as powder or spray, the examples of the carriers include lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, etc. In particular, in the case where the form is spray, the cosmetic composition can further include propellant such as chlorofluorohydrocarbon, propane/butane and dimethyl ether.

In the case where the cosmetic composition is formulated as solution or emulsion, the examples of the carriers include solvent, solubilizer and emulsifier such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol fatty acid ester, polyethylene glycol, sorbitan fatty acid ester, etc.

In the case where the cosmetic composition is formulated as suspension, the examples of the carriers include liquid diluent such as water, ethanol and propylene glycol, suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum methahydroxide, bentonite, agar, tragacanth, etc.

In one embodiment, the cosmetic composition of the present invention can be applied to cosmetics such as skin, lotion, cream, essence, pack, foundation, coloring cosmetics, sun block cream, two-way cake, face powder, compact, makeup base, skin cover, eye shadow, lip stick, lip gloss, lip fix and eyebrow pencil.

The retinoid derivatives according to the present invention have an excellent collagen synthesis increasing effect, is non-irritating, is non-toxic, have good chemical stability, is easily absorbed to the skin, and is long-wearing to show superior skin regeneration and anti-aging effects.

Therefore, the retinoid derivative according to the present invention can be effectively used as an active ingredient of cosmetics or medicine.

Fig. 1 is a graph illustrating the collagen synthesis effects of the compound (MDRPDA) according to the present invention, and retinyl palmitate, retinoic acid, ethyl retinoate and PEG-retinamide as comparative compounds.

Figs. 2 to 6 are graphs illustrating the cytotoxicities of retinyl palmitate, retinoic acid, ethyl retinoate and PEG-retinamide as comparative compounds, and the compound (MDRPDA) according to the present invention, repectively.

Fig. 7 is a graph illustrating the hydrolysis rates of the compound (MDRPDA) according to the present invention, and retinyl palmitate, ethyl retinoate and PEG-retinamide as comparative compounds.

The present invention is further illustrated by the following examples, which are not to be construed to limit the scope of the invention.

Example 1: Preparation of 2-methyl-1,5-diretinylpentanediamide (MDRPDA) (compound of formula (I) wherein X is NH, R ₁ is methyl, and R ₂ is hydrogen)

35.0 g (0.116 mol) of retinoic acid was dissolved in 150 ㎖ of anhydrous toluene, and 16.3 g (0.116 mol) of phosphorous trichloride (PCl₃) was added dropwise thereto, followed by stirring at room temperature with blocking out light and moisture under nitrogen atmosphere for 15 hours. The resulting solution was added dropwise in an ice bath for 30 minutes to a solution to dissolve 6.77 g (0.058 mol) of 2-methyl-1,5-diaminopentane and 11.8 g (0.117 mol) of triethylamine in 100 ㎖ of anhydrous dichloromethane, and stirred at room temperature for 5 hours.

The reaction solution was added to 250 ㎖ of saturated sodium chloride aqueous solution. Then, the organic phase was separated, washed with water, dried with anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was subjected to column chromatography (SiO₂, 200-400 mesh, ethyl acetate:hexane = 1:3, v/v) to give 56.1 g of the target compound (Yield: 71%).

Example 2: Preparation of 3-methyl-1,5-diretinylpentanediester (MDRPDE) (compound of formula (I) wherein X is O, R ₁ is hydrogen, and R ₂ is methyl)

25.0 g (0.083 mol) of retinoic acid was dissolved in 200 ㎖ of anhydrous toluene, and 4.92 g (0.042 mol) of 3-methyl-1,5-pentanediol, 20.6 g (0.100 mol) of dicyclohexylcarbodiimide (DCC) and 11.2 g (0.092 mol) of 4-dimethylaminopyridine (DMAP) were added threreto, followed by stirring at room temperature with blocking out light and moisture under nitrogen atmosphere for 15 hours.

The reaction solution was added to 250 ㎖ of 1 M hydrochloride aqueous solution. Then, the organic phase was separated, washed with saturated sodium bicarbonate aqueous solution and water, dried with anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was subjected to column chromatography (SiO₂, 200-400 mesh, ethyl acetate:hexane = 1:3, v/v) to give 42.3 g of the target compound (Yield: 74.5%).

Experimental Example 1: Collagen synthesis effect test

The collagen synthesis effect test was performed to confirm the anti-aging effect of the compound (MDRPDA) obtained in Example 1 according to the present invention. As comparative compounds were used retinyl palmitate, retinoic acid, ethyl retinoate, and PEG-retinamide, which are being used as an ingredient of anti-aging medicine and cosmetics.

Human fibroblasts were cultured in a 24-well plate for 24 hours and treated with 1 and 10 μM of the samples. After 2 hours, the cultured cells were treated with procollagen type I C-peptide EIA kit reagent and cultured for 24 hours. The amount of collagen generated in the culture solution was measured with ELISA. The collagen synthesis effects were determined based on the measured amounts of collagen, and the results are shown in Fig. 1 [see: Am. J. Pathology, 2004, 165, 167-174; Analytical Biochemistry, 1979, 96, 220-224.; J. Invest Dermatol, 1991, 96, 473-477, which are incorporated in its entirety here by reference].

As shown in Fig. 1, when the concentration of the samples was 1 μM, the MDRPDA had better collagen synthesis increasing effect, as compared with the retinyl palmitate, retinoic acid, ethyl retinoate, and PEG-retinamide. Further, when the concentration of the samples was increased to 10 μM, the MDRPDA had much better collagen synthesis increasing effect, as compared with the above comparative compounds.

Experimental Example 2: Allergy test

The allergy test of the compound (MDRPDA) obtained in Example 1 according to the present invention was performed in accordance with a safety test using ethanol as a carrier vehicle [see: J. Appl. Toxicol., 1990, 10(3), 173~180, which is incorporated in its entirety here by reference].

Retinyl palmitate, retinoic acid, ethyl retinoate and PEG-retinamide as comparative compounds, and the MDRPDA were dissolved in acetone/olive oil (4/1, v/v) to prepare 0.3% and 1% solutions, respectively. 30 ㎕ of each solution was applied to both ears of a mouse (Balb/c) for 3 days, and the auricular lymph node of the mouse was separated. The lymph node was pulverized to single cell state, and a radioactive isotope (³H-thymidine) was added thereto, followed by culturing for 24 hours. The amplification degrees (cpm) of the cells were measured, and the results are shown in Table 1.

Table 1

Sample	Lymph node cells (10⁷ cells/ml)	Cpm (mean)	Amplification degree
Ethanol	1.13	1892	Carrier vehicle
Retinyl palmitate 0.3%	3.62	10119	5.35
Retinyl palmitate 1%	4.29	12332	6.52
Retinoic acid 0.3%	4.56	13224	6.99
Retinoic acid 1%	4.98	14612	7.72
Ethyl retinoate 0.3%	1.93	4535	2.40
Ethyl retinoate 1%	2.34	5890	3.11
PEG-retinamide 0.3%	1.64	3577	1.89
PEG-retinamide 1%	1.87	4337	2.29
MDRPDA 0.3%	1.24	2256	1.19
MDRPDA 1%	1.47	3015	1.59

As shown in Table 1, the MDRPDA showed very low allergy inducing effect, as compared with the retinyl palmitate, retinoic acid, ethyl retinoate, and PEG-retinamide.

Experimental Example 3: Skin irritability test

The skin irritability of the compound (MDRPDA) obtained in Example 1 according to the present invention was confirmed by a patch test using guinea pigs [see: Assoc. Food and Drug officials US., 1959, 46-59; Method of testing primary irritant substances, 1973, 38(187), 1500-1541, which are incorporated in its entirety here by reference].

0.3% solutions of the samples were prepared using O/W emulsion of water and propylene glycol as a medium. The hair on the region to be tested (back) of the guinea pigs was removed, and the guinea pigs were adapted to the circumstances for 24 hours. The region to be tested (1.5 cm×1.5 cm) was treated with gauze wetted with the sample solution, sealed in a solid thin film to prevent evaporation and loss of the sample, and fixed with an elastic bandage for 48 hours. The skin irritability was measured 24 hours after removing the patch (72 hours after applying the patch). The results are shown in Table 2.

Table 2

Sample	Irritating index	Degree of irritation
O/W emulsion	1.0	Low irritation
O/W + Retinyl palmitate (0.3%)	1.0	Low irritation
O/W + Retinoic acid (0.3%)	1.5	Medium irritation
O/W + Ethyl retinoate (0.3%)	1.0	Low irritation
O/W + PEG-retinamide (0.3%)	0.7	Insignificant irritation
O/W + MDRPDA (0.3%)	0.6	Insignificant irritation

As shown in Table 2, the MDRPDA showed significantly low skin irritability, as compared with the retinyl palmitate, retinoic acid, and ethyl retinoate.

Experimental Example 4: Cytotoxicity test

The primary safety of the compound (MDRPDA) obtained in Example 1 according to the present invention as an ingredient of medicine or cosmetics was confirmed by its cytotoxicity using MTT test culturing Chinese hamster lung fibroblast cell line (V79-4) [see: Journal of Immunological Methods, 1983, 65, 55~63, which is incorporated in its entirety here by reference].

The results for retinyl palmitate, retinoic acid, ethyl retinoate, PEG-retinamide, and the compound (MDRPDA) according to the present invention are shown in Figs. 2 to 6, respectively.

As shown in Figs. 2 to 6, the MDRPDA showed no cytotoxicity as the ethyl retinoate as a comparative compound did not. However, the retinyl palmitate and retinoic acid had cytotoxicity at the concentration of 10 μM or more, and the PEG-retinamide showed significant cytotoxicity at the concentration of 25 μM or more.

Experimental Example 5: Light stability test

To confirm the light stability of the compound (MDRPDA) obtained in Example 1 according to the present invention, 10 mg of the sample was irradiated with UV-A light (wave length: 356 nm) (Spectroline Model CM-10; Fluorescence analysis cabinet; Spectronics Corporation, Westbury, New York, USA) depending on the time, and qualitatively analyzed with ¹H NMR (400 MHz). The results are shown in Table 3.

Table 3

Sample	0 hr	1 hr	4 hr	12 hr	24 hr	48 hr
Retinol	++++	+++	+++	++	+	+
Retinyl palmitate	++++	++++	+++	+++	++	++
Retinoic acid	++++	++++	+++	+++	++	+
Ethyl retinoate	++++	++++	+++	+++	++	++
PEG-retinamide	++++	++++	++++	+++	+++	+++
MDRPDA	++++	++++	++++	++++	++++	+++

++++ : No qualitative change

+++ : No qualitative change but small noise

++ : Qualitative change and large noise

+ : Qualitative analysis being difficult

As shown in Table 3, the MDRPDA had better light stability than the retinol, retinyl palmitate, retinoic acid and ethyl retinoate, and showed similar light stability as compared with the PEG-retinamide.

Experimental Example 6: Heat stability test

To confirm the heat stability of the compound (MDRPDA) obtained in Example 1 according to the present invention, the sample was stored in a constant temperature and humidity chamber (humidity: 56%) at room temperature, 0 ℃, 37 ℃ and 50 ℃ for 1 month, and the phase stability was analyzed with high performance liquid chromatography (HPLC) under the following conditions.

Column: Capcellpak UG 120 (5 μm, 4.6 mm X 150 mm, Shiseido, Japan);

Eluent: gradient elution of Solvent A: 0.1% acetic acid containing water, B: 0.1% acetic acid containing acetonitrile, C: 0.1% acetic acid containing methanol, and D: isopropyl alcohol;

Detector: UV (PDA 326 nm).

The results are shown in Table 4.

Table 4

Sample	Temperature (℃)	0 weeks	0.5 weeks	1 week	2 weeks	4 weeks
Retinol
		0	100	100	100	100	99.8
		R.T.	100	91.27	87.63	70.32	48.18
		37	100	86.08	68.56	44.26	28.96
50		100	82.73	57.14	27.82	10.02
PEG-retinamide	0	100	100	100	100	100
	R.T.	100	100	100	100	99.2
	37	100	94.00	82.54	63.28	58.82
	50	100	91.54	79.13	54.56	29.28
MDRPDA	0	100	100	100	100	100
	R.T.	100	100	100	99.27	98.66
	37	100	100	99.6	98.31	96.75
	50	100	99.32	99.02	97.36	92.79

As shown in Table 4, the MDRPDA had good heat stability at 37 ℃ and 50 ℃.

Experimental Example 7: Percutaneous absorption test

The percutaneous absorption test of the compound (MDRPDA) obtained in Example 1 according to the present invention was performed using retinol, retinyl palmitate, retinoic acid, ethyl retinoate and PEG-retinamide as comparative compounds, and 1:1 mixture of oil (capryliccapric triglyceride) and ethanol as a medium [see: J. Invest Dermatol., 1998, 91; 56-61, which is incorporated in its entirety here by reference].

The skin (on the back region) of a 7-week-old female nude mouse was severed, and 150 ㎕ of 50 mM sample solution was applied to 1.7 cm² of the skin. After 24 hours, the compound absorbed to the skin and receptor solution, which is 50 mM PBS buffer (pH 7.4) containing 2% Volpo 20(Oleth-20), were extracted with Franz cell and analyzed with HPLC. The results are shown in Table 5.

Table 5

Sample	Skin (nmol)	Receptor solution(nmol)	Percutaneous absorption amount(nmol)	Absorption rate (%)
Retinol	16.62	9.63	29.25	0.39
Retinyl palmitate	16.09	0.41	16.50	0.22
Retinoic acid	27.69	9.81	37.50	0.50
Ethyl retinoate	26.93	9.25	36.18	0.48
PEG-retinamide	36.97	53.03	90.00	1.20
MDRPDA	38.25	50.19	88.44	1.18

As shown in Table 5, the MDRPDA showed higher percutaneous absorption rate, as compared with the retinol, retinyl palmitate, retinoic acid, and ethyl retinoate. Also, the MDRPDA showed very similar percutaneous absorption rate, as compared with the PEG-retinamide, which is known to have improved solubility.

Experimental Example 8: Hydrolysis test

The hydrolysis rates of ethyl retinoate and retinyl palmitate, which are ester forms, and PEG-retinamide and the compound (MDRPDA) obtained in Example 1 according to the present invention, which are amide forms, were measured in rat serum under the condition which is very close to that in the body (37℃).

80 mg of each sample was dissolved in 5 ml of rat serum, and the resulting solution was incubated at 37 ℃. 0.7 ml of the serum mixture was taken at regular time intervals, and extracted twice with 2 ml of dichloromethane. The dichloromethane extract was dried with Na₂SO₄, filtered, and distilled under reduced pressure. To the residue was added water, followed by filtering. The filtrate was analyzed with reverse phase HPLC (Betasil C18, 100×2), and the results are shown in Fig. 7.

As shown in Fig. 7, the half-life (t^1/2) of the hydrolysis was 8.7 hours for the ester forms and 32 hours for the MDRPDA (amide form). Meanwhile, the PEG-retinamide (amide form) maintained about 60% even after 48 hours.

Claims

A retinoid derivative of the following formula (I):

(I)

wherein,

X is NH, O, or S; and

R₁ and R₂ are identical or different, and hydrogen or C₁-C₆ alkyl.
The retinoid derivative of Claim 1, wherein X is NH or O.
The retinoid derivative of Claim 1, wherein R₁ and R₂ are different, and hydrogen or methyl.
The retinoid derivative of Claim 1, wherein X is NH, R₁ is methyl, and R₂ is hydrogen.
A cosmetic composition comprising the retinoid derivative of any one of Claims 1 to 4.
The cosmetic composition of Claim 5, which the cosmetic composition is used for anti-aging.