KR101209253B1 - Ｎ'-retinoylpolyethyleneglycol hydrazide derivatives and method for preparing the same - Google Patents

Abstract

The present invention relates to a N'-retinoyl polyethyleneglycolated hydrazide derivative of Formula 1, a method for preparing the same, and a cosmetic raw material or pharmaceutical composition containing the same as an active ingredient:

In Formula 1, R represents hydrogen or lower alkyl of C1-C6, n is an integer of 2 to 100.

Description

N'-retinoyl polyethyleneglycolated hydrazide derivatives and a method for preparing the same {N'-retinoylpolyethyleneglycol hydrazide derivatives and method for preparing the same}

The present invention relates to a N'-retinoyl polyethyleneglycolated hydrazide derivative of the formula (1) and a method for producing the same. As shown in Chemical Formula 1, the hydrazide derivative including an all-trans retinol moiety is highly soluble in water, non-irritating, and has excellent enzymatic resolution, thereby promoting collagen synthesis with excellent skin absorption. It can be used as a raw material for anti-aging functional cosmetics or, if necessary, pharmaceuticals.

(In Formula 1, R represents hydrogen or lower alkyl of C1 ~ C6, n is an integer of 2 to 100)

Retinoic acid and retinyl esters belong to derivatives of vitamin A (retinol), collectively known as retinoids, and derivatives of vitamin A are, for example, beta carotene, retinal, all-trans retinoic acid, 9-cis. (cis) is present in various forms, including retinoic acid and 13-cis retinoic acid.

Vitamin A is known as an essential nutrient, and vitamin A deficiency is known medically to cause keratinization (hyperkeratosis) in the mucous membranes, especially the respiratory tract. In addition, hypersensitivity symptoms or deficiencies caused by bronchial infections are essential to the human body that can lead to blindness (see Cell Pathol., 45, 197-219, 1984, McDowell, E.M., et al.).

Long-term exposure to ultraviolet rays by sunlight is a major cause of skin diseases such as skin aging, skin wrinkles, roughness, and spots. All-trans retinoic acid is effective in alleviating skin roughness and wrinkles caused by skin photoaging, such as JAMA, 259 (1988), 527-532, Weiss C. N, etc. It has been reported that applying cosmetics containing it to the skin can improve aging. On the other hand, cis isomers of vitamin A are known to be used for the treatment of acne and cancer. As such, vitamin A, particularly retinoic acid, has been used as an active ingredient in cosmetic raw materials or medicine for preventing aging.

However, because all-trans retinoic acid is very unstable in light, heat, oxygen, water, etc., it needs to be stabilized for practical use, and the problem of low absorption due to physical properties such as stability and fat soluble in vivo should be solved. In some cases, adverse events have been reported. Therefore, there is a need for development of derivatives of retinoic acid that are stable and non-irritating and maintain the efficacy of photoaging inhibition.

On the other hand, with respect to ester or amide derivatives of retinoic acid, U.S. Patent No. 4,677,120 discloses that 2- (all-trans-retinoyloxy) -4-methoxyacetophenone compound is relatively hypoallergenic and suppresses skin cancer and photoaging. It has been disclosed that the effect of the present invention, US Patent Publication No. 4,900,478 discloses that the esterified compound of tetraethylene glycol and retinoic acid has an effect of enhancing penetration into the skin. In addition, N- (4-hydroxyphenyl) retinamide and retinoyl β-gluronide via amide bonds have been reported to have low toxicity while having anti-aging activity of retinoic acid (FASEB J., 10, 1014). -1024, 1996).

Since such esterified or amidated retinoic acid is fat-soluble, it is insoluble in water and has not solved the problem of stability. Therefore, it is easily decomposed by enzymatic degradation and it is difficult to expect the effect of inhibiting photoaging in vivo. Therefore, the solution of problems such as solubility and stability for the practical use of the anti-aging retinoid compound is urgent.

Recently, there has been a patent document (PCT / US2002 / 036421, Bentley, M.D., et al.), In which a retinoid formulation stabilized by esterifying and cyclizing a lipid-soluble retinoid family compound with polyethylene glycol to improve solubility in water. These formulations are relatively easy to process and absorb in the body, and are particularly well suited for inhalation administration, which can produce small doses of therapeutic effects in the treatment of chronic obstructive pulmonary disease, maximizing bioavailability and reducing systemic toxicity. It is said to be possible.

However, this formulation has a problem of uncontrolled rate of enzymatic degradation of the polyethylene glycol skeleton (PEG backbone) and retinoic acid in the blood, and even if the solubility is improved, it shows actual efficacy after being absorbed into the blood of the human body. The problem is that the selectivity of the binding to the Retinoic Acid Receptor (RAR) is relatively low. In some respects, the problem of enzymatic degradation rate and selectivity means that the metabolic and excretory effects are insufficient.

Therefore, there is an urgent need for the development of new water-soluble retinoic acid derivatives which are stable at the blood pH of the human body, are selectively released after the selective binding to the receptor of retinoic acid, and also maintain the activity of vitamin A as it is (see US Patent Published Publication No. 6,180,670).

The present inventors have conducted intensive studies to solve the problems of the selectivity, biocompatibility and the rate of enzymatic degradation. In particular, the present invention is a bio-friendly biopolymer that can increase the solubility and water absorption of water and minimize residual toxicity. N'-retinoylpolyethylene glycol of Formula 1 of the present invention, which is a retinoic acid derivative in which a polyethylene glycol precursor is introduced, and a hydrazide moiety is introduced to selectively undergo binding to a retinoic acid receptor (RAR) and then undergo enzymatic metabolism by a hydrolase. A hydrazide derivative was developed. The compound of Formula 1 has improved chemical stability and superior water absorption due to improved solubility in water compared to conventional retinoic acid derivatives, and selectively binds to and is easily released with the retinoic acid receptor, thus preventing blood from aging and regenerating the skin. Properly enzymatically digested in the cells, hypoallergenic and non-toxic.

The present invention relates to a N'-retinoyl polyethyleneglycolated hydrazide derivative of the formula (1) and a method for producing the same.

In Formula 1, R is hydrogen or C1 ~ C6 Lower alkyl and n is an integer from 2 to 100. Preferably, the hydrazide derivative of Formula 1 is R is hydrogen or methyl and n is an integer from 4 to 40.

Hereinafter, a method of preparing the compound of Formula 1 according to the present invention will be described in detail.

As Preparation Method 1, a compound wherein X is hydroxy in a compound of Formula 2 is reacted with a compound of Formula 3 in a solvent in the presence of a condensing agent and an organic amine catalyst, or as Preparation Method 2, wherein X is A hydrazide compound of formula 1 may be prepared by reacting a compound that is a halogen with a compound of formula 3 in the presence of an organic amine base in a solvent.

In formulas (2) and (3), R and n are as defined above and X represents hydroxy or halogen. Hereinafter, the manufacturing method will be described in detail.

In the production method 1, N, N, N ', N'-tetramethyltyl- (benzotriazol-1-yl) -uronium tetrafluoroborate (TBTU), N- (3-dimethylamino as a condensing agent Propyl) -N'-ethyl-carbodiimide (EDC), N, N'-diisopropylcarbodiimide (DIC) or N, N-dicyclohexylcarbodiimide (DCC) Preference is given to using diisopropylethylamine (DIPEA) or N, N-dimethylaminopyridine (DMAP) as the organic amine catalyst to be promoted. The solvent may be optionally used among anhydrous organic solvents such as dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether. The reaction is usually carried out under a nitrogen atmosphere with light and water shielded and is cooled or warmed.

In preparation method 2, pyridine or triethylamine is preferably used as the organic amine serving as a base, and the solvent is selected from anhydrous organic solvents such as dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether. One or more kinds are used. At this time, the organic amine is preferably used in 1.0 to 2.0 molar amount based on the compound of the formula (3). The reaction is usually carried out under a nitrogen atmosphere with light and water shielded and is cooled or warmed.

Bases, condensing agents, catalysts, and solvents that may be used in the process according to the invention are listed above, but are not limited to those listed above, and are commonly used in the art within the scope of not adversely affecting the reaction. Known alternative compounds can be used.

The compound in which X in Formula 2 is a halide, which is used as a starting material in the preparation method of the present invention, may be prepared by reacting retinoic acid with a halogenating agent such as phosphorus trichloride, thionyl chloride, and the like. For example, it is possible to manufacture and use according to the well-known method described in literature (synthetic comm., Vol., 77 NO, 16, 1992, Timothy P. Kogan etc.). In addition, the compound of the formula (1) prepared by the above-described method can be purified using conventional separation and purification methods such as recrystallization or column chromatography.

Hydrazide derivatives of Formula 1 may be used for skin diseases and beauty, such as cancer or acne, skin wrinkles, freckles treatment. In particular, the compound of Formula 1 has no irritation upon skin application, has excellent skin absorption ability, promotes collagen biosynthesis and prevents degradation of elastin, and has a skin regeneration effect. In particular, the enzyme is easy to decompose and has high selectivity to the retinoic acid receptor. It is characterized by having

The compound of Formula 1 according to the present invention has excellent chemical stability and skin absorption, and has excellent solubility in water, compared to conventional retinoic acid derivatives. In addition, the compound of the formula (1) according to the present invention can effectively bind and release with RAR, because it is properly enzymatically degraded in the blood, there is no irritation and toxicity and can exhibit an excellent effect on skin regeneration.

FIG. 1 compares the increase rate of collagen synthesis of a compound of Formula 1 of the present invention [Manufacturing Method 1] and a compound having a retinoic acid, a retinol palmitate, and a pyriretinamide ring.
FIG. 2 compares the cytotoxic effect of the compound [I] of the present invention and a compound having a retinoic acid, retinol palmitate and a pyrethretinamide ring.
Figure 3 compares the hydrolysis rate of the hydrazide in the linkage form of formula 1 of the present invention with the fiji retinamide and monomethoxy fiji retin ester.

Experiments for confirming the physiological activity of the compound of formula 1 according to the present invention was performed as follows.

In the transdermal absorption test, the skin (dorsal region) of 7-week-old female rats was excised, and the skin and filtrate were analyzed using a 50 mM compound of the present invention using a transdermal absorption instrument (Franz cell) and HPLC. The cell regeneration effect was confirmed by measuring the collagen synthesis effect, which means to promote skin metabolism in phosphate fibroblasts. Allergy testing was conducted in rats using ethanol as a carrier medium. Skin irritation test was confirmed by the patch test and O / W emulsification mediated experiments with the Draize technology in Guinea Pigs in a concentration range of 0.05% to 1% of the compound of the present invention. Cytotoxicity test, MTT test for cell proliferation using hamster lung fibroblasts (V79-4). The hydrolysis test was dissolved in rat serum and treated through HPLC at 37 ° C. constant temperature.

As a result, the hydrazido derivative compounds according to the present invention showed a 2 to 10-fold increase in the transdermal absorption ability compared to the retinoic acid or retinol palmitate, which is a commercially available anti-aging drug and cosmetic ingredient. In the toxicity experiment, it was confirmed that the nontoxic property was less than 10 ^-4 w% / ml, and in particular, the enzymatic degradation and metabolic process after the selective binding to RAR were optimized, thereby greatly increasing the efficacy. Therefore, the hydrazide derivative according to the present invention is non-toxic, non-irritating, and has excellent skin absorption and collagen synthesis function, and thus can be widely used as an active ingredient of cosmetics (creams, lotions, gels, etc.) or pharmaceuticals. .

Hereinafter, the present invention will be described in more detail based on the following Examples and Experimental Examples. The following Examples and Experimental Examples are only for better understanding of the present invention, and the scope of the present invention is not limited to these Examples in any sense.

Example 1 Preparation of Monomethoxy Polyethylene Glycol Hydrazide (R: Me, n = 11)

Monomethoxypolyethylene glycol hydrazide (Formula 3) was prepared according to Reaction Scheme 1 below via a two step reaction from monomethoxypolyethylene glycol.

Reaction Scheme 1. Monomethoxypolyethyleneglycol hydrazide synthesis

V) 10 g (20 mmol) of monomethoxypolyethylene glycol and 1 g (3.1 mol) of tetrabutylammonium bromide (TBAB) were added to 125 ml of toluene, followed by distillation with 105 ml of toluene, followed by 0.8 g (14.2 mmol) of potassium hydroxide. Add and mix, and warm the mixture to 60 ° C. under a nitrogen atmosphere. 16 g (0.1 mmol) of ethylacrylate were then added over two hours and stirred at 60 ° C. overnight under a nitrogen atmosphere. The solvent was then distilled off under reduced pressure and the residue dissolved in dichloromethane solution. The solution was washed twice with distilled water, dried over anhydrous magnesium sulfate and separated by column chromatography (SiO ₂ , 270-400 mesh, dichloromethane / methanol = 10: 1, v / v) to monomethoxypolyethylene 7.8 g (yield: 65%) of glycol propionylethyl ester were obtained. NMR (d ₅ -DMSO): 1.20 (t, CH ₂ CH ₃ , 3H), 2.41 (t, -CH ₂ -COO-, 2H), 3.24 (s, O-CH ₃ , 3H), 3.51 (PEG) , 4.05 (q, CH ₂ CH ₃ , 2H)

Ii) A solution of 5 g (8.3 mmol) of monomethoxypolyethylene glycol propionylethyl ester obtained in step iv) and 80 ml of anhydrous hydrazine was heated and stirred at 100 ° C. for 18 hours. Then, the reaction solution was slowly added to hot ethanol and then refrigerated for 24 hours to obtain a precipitate. The precipitate was collected by filtration and washed three times with ether to give 4.38 g of monomethoxyethylene glycol hydrazide (yield: 90%). NMR (CDCl ₃ ): 3.38 (s, O-CH ₃ , 3H), 3.5-3.8 (PEG), 4.08 (s, CH ₂ CO, 2H), 8.46 (bs, NH, 1H) (see literature 'synthetic comm. 'Vol. 77, No. 16, 1992)

Example 2 Preparation of Compound [I] (Retinoyl Polyethyleneglycolated Hydrazide Derivative, In Formula 1, R = Me, n = 11)

Monomethoxypolyethyleneglycol hydrazide obtained in Example 1 (wherein R is a methyl group, n = 1, average molecular weight 580) 1 g (1.72 mmol) and retinoic acid (X = OH in Formula 2) 0.52 g (1.72) mmol) was dissolved in 10 ml of anhydrous dichloromethane solution, and then 0.06 g of N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) -uronium tetrafluoroborate (TBTU) (0.172 mmol) and 6.7 mg (0.052 mmol) of diisopropylethylamine (DIPEA) were added thereto, followed by stirring at room temperature for 12 hours while blocking light and water under nitrogen. After filtering the reaction solution, the solvent was distilled off under reduced pressure and the residue was separated by column chromatography (SiO ₂ , 270-400mesh, dichloromethane / methanol = 10: 1, v / v) to obtain the title compound [1] 1.2g ( Yield: 65%).

Example 3 Preparation of Compound [II] (Retinoyl Polyethyleneglycolated Hydrazide Derivative, In Formula 1, R = Me, n = 11)

After dissolving 4.0 g (0.013 mol) of retinoic acid in 20 ml of toluene anhydride, 1.83 g (0.013 mol) of phosphorus trichloride (PCl ₃ ) was added dropwise thereto, and stirred under nitrogen for 15 hours while blocking light and water at room temperature. . The obtained retinoic acid chloride solution was added dropwise with 7.78 g (0.013 mol) of monomethoxypolyethylene glycol hydrazide and 1.57 g (0.016 mol) of triethylamine to 40 ml of anhydrous dichloromethane for 20 minutes under ice cooling. After this, the mixture was stirred for 5 hours at room temperature. The reaction solution was added to 50 ml of saturated aqueous sodium chloride solution, and the organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (SiO ₂ , 200-400 mesh, dichloromethane / methanol = 10: 1, v / v) to give 6.8 g (yield: 60%) of the title compound [II].

Experimental Example 1 Percutaneous Absorption Test

For the transdermal absorption test of the compound [I] of Formula 1 (using the one synthesized in Example 2) according to the present invention, as an anti-aging pharmaceutical and cosmetic raw material, retinol, retinol palmitate, retinoic acid and pyrazinamide, respectively Percutaneous absorption test was performed as a control. A 1: 1 mixed solvent of oil (caprylic capric-tri-administration ceres) and ethanol was used as a vehicle (J. Invest Dermatol., 1998, 91; 56-61).

First, the skin of a 7-week-old female hairless mouse was excised and 150 μl of a 50 mM sample solution of Compound [I] was applied to 1.7 cm ² of skin. After 24 hours, the receptor solution, 50 mM PBS buffer (pH 7.4) containing 2% Volpo 20 ^™ (Oleth-20), and the skin were extracted using a percutaneous absorption analyzer (Frnaz cell), followed by high performance liquid chromatography (HPLC). The results are shown in Table 1 below by quantitative analysis (in Table 1, the compound of Formula 1 refers to compound [I] prepared above).

In Table 1, it was confirmed that the compound of Formula 1 according to the present invention is capable of transdermal absorption of 3.4 times of retinol, 6.1 times of retinol palmitate, and 2.7 times of retinoic acid. It was confirmed that the relatively higher transdermal absorption.

Experimental Example 2 Collagen Synthesis Effect Test

The collagen synthesis effect of the compound [I] of Formula 1 (In Formula 1, R = methyl, n = 11) of the present invention was confirmed to confirm the efficacy of anti-aging of the skin. Comparative tests were performed using retinoic acid, retinol palmitate and fiji retinamide, respectively, as controls.

The same number of human fibroblasts were incubated in a 24-well plate for 24 hours and then treated with samples 10 ⁻⁴ to 10 ⁻⁷ w / ml (%). After 2 hours, the cells were treated with triple water-substituted proline (L-2, ^3- H proline) and incubated for 24 hours, and the amount of collagen newly synthesized by fibroblasts was cultured using the culture medium. The amount of collagen sensitive protein (CSP) was calculated by measuring the number of minutes per minute (CPM). In addition, the results of comparing the collagen synthesis effect based on the calculated amount of CSP is shown in Figure 1 attached (see: Analytical Biochemistry, 1979; 96, 220-224 .; J. Invest Derma tol, 1991, 96, 473-477). However, in FIG. 1, the control group indicates that serum having an activity in collagen synthesis was added (not treated with an anti-aging agent). (Compound 1 in Figure 1 refers to compound [I] prepared above)

In Figure 1, retinol palmitate showed little collagen synthesis enhancing effect, while retinoic acid and pyrethretinamide showed an increase of up to 22% and 34% at 10 ⁻⁷ w% / ml, respectively. On the other hand, Compound [I] of Formula 1 gave better results than the activity of Fiji Retinamide, showing the highest (41%) enhancement effect at 10-7 w% / ml compared to retinoic acid.

Experimental Example 3 Allergy Test (LLNA)

The allergy test of the compound [I] of Formula 1 of Formula 1 (R = methyl, n = 11) of the present invention was confirmed through a safety test using ethanol as a carrier medium. (Note: J. Appl. Toxicol., 1990, 10 (3), 173-180). Retinol palmitate, retinoic acid, and the compound [I] of Formula 1 were prepared as a comparative solution of acetone / olive oil (4/1, v / v) at a concentration of 0.3% and 1%, respectively. 30 μl of both ears were applied to both ears of the mice (Balb / c) for 3 days, and auricular lymph nodes were isolated from the mice. Lymph nodes were pulverized into a single cell state and then cultured for 24 hours with the addition of radioisotope ( ³ H-thymidine), and then the results of measurement of amplification degree (CPM) of the cells are shown in Table 2 below. (Compound 1 in Table 2 refers to compound [I] prepared above)

In Table 2, Compound [I] showed 1-fold and 2.5-fold lower induction than 0.3-fold and 3-fold lower than ethanol, respectively, whereas the control groups Retinol Palmitate and Retinoic acid were more than 7-fold under the same conditions. It showed a high allergen.

Experimental Example 4 Skin Stimulation Test

In order to confirm the skin irritation degree of the compound [I] of Formula 1 (R = methyl, n = 11), a patch test was performed using Guinea Pig. (Reference: Assoc.Food and Drug officials US, 1959, 46-59; Method of testing primary irritant substances, 1973, 38 (187), 1500-1541).

A sample solution of 0.3% concentration was prepared using O / W emulsification of water and propylene glycol as a carrier medium. The hair at the site of application (back) was removed and allowed to acclimate to the environment for 24 hours for accurate measurement. The treated area was treated with a gauze soaked in the application area (1.5 cm x 1.5 cm) and then sealed with a solid foil to prevent evaporation and loss of the sample and fixed with an elastic bandage for 48 hours. After removing the closed patch, the degree of stimulation was determined at 2 hours and 24 hours (50 hours and 72 hours after the patch), and the results are shown in Table 3. (The compound of formula 1 in Table 3 refers to compound [I] prepared above) In Table 3, the compound of formula 1 showed a significantly lower level of stimulation compared to retinol palmitate or retinoic acid.

Experimental Example 5 Cytotoxicity Test

Continuous cell line of Chinese hamster lung tissue fibroblasts to verify the primary safety of the compound [I] of Formula 1 according to the present invention (in Formula 1, R = methyl, n = 11) as an active material for medicine or cosmetics (V79-4) was cultured to confirm cytotoxicity by MTT experiment (Ref .: Journal of Immunological Methods, 1983, 65, 55-63), and the results are shown in FIG. 2. (In Figure 2, compound 1 refers to compound [I] prepared above.)

In FIG. 2, Compound [I] gradually showed toxicity at 10 ⁻³ w% / ml or more, but only weak toxicity at 10 ⁻⁴ w% / ml or less. These results show that the cell-promoting effect is lowered at the limit of 10 ^-4 w% / ml, which is not toxic, and shows the highest collagen synthesis promoting effect at 10 ^-7 w% / ml, and shows relatively high cytotoxicity. ^{At -3} w% / ㎖ or more it can be seen that the results are in good agreement with the experimental results of FIG. This confirmed that the compound [I] according to the present invention showed a significant decrease in cytotoxicity.

Experimental Example 6 Hydrolysis in Rat Serum [Conjugate PHLC]

Fijiretinamide in amide form in rat serum, compound [I] (I in formula 1 wherein R = Me, n = 11), which is a hydrazide derivative of the present invention, mPEG-ATRA in ester form The rate of hydrolysis was calculated under conditions (37 ° C.) modeling the rate of hydrolysis closer to the body.

80 mg of each of these compounds was dissolved in 5 ml of rat serum and the resulting solution was incubated at 37 ° C. At intervals of time, 0.7 ml of the serum mixture was taken and extracted twice with 2 ml of dichloromethane. The dichloromethane extracts were dried over Na ₂ SO ₄ , filtered, evaporated and dried under reduced pressure. Water was added to the dry residue and filtered. The filtrate was analyzed for PEG ATRA and PEG by reverse phase HPLC (Betasil C18, 100 × 2).

The experimental results are summarized in FIG. 3, from which the half-life (t ^1/2 ) of the hydrolysis was 2.5 hours for the ester form and 16 hours for the hydrazide derivative of the compound [I] of the present invention. On the other hand, the amide of PEG-retinamide was less than 5% even after 48 hours.

Claims (10)

delete N-retinoyl polyethyleneglycolated hydrazide derivative of Formula 1

(In Formula 1, R is hydrogen or methyl, n is an integer of 4 to 40) 3. The hydrazide derivative of formula 1 according to claim 2, wherein R is methyl and n is 11. A hydrazide derivative of Formula 1 as defined in claim 2 is prepared by reacting a compound in which X in Formula 2 is a hydroxy group with a polyethylene glycol hydrazide derivative of Formula 3 in the presence of a condensing agent and an organic amine catalyst. How to

(In Formula 3, R represents hydrogen or lower alkyl of C1 to C6, n is an integer of 2 to 100) A process for preparing a hydrazide derivative of formula 1 as defined in claim 2 characterized in that the compound of formula 2 is reacted with a compound of formula 3 in the presence of an organic amine in a solvent:

(In Formula 3, R represents hydrogen or lower alkyl of C1 to C6, n is an integer of 2 to 100) The condensation agent of claim 4, wherein the condensing agent is N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uroniumtetrafluoroborate (TBTU), N- (3-dimethyl Aminopropyl) -N'-ethylcarbodiimide (EDC), N, N'-diisopropylcarbodiimide (DIC), and N, N-dicyclohexylcarbodiimide (DCC) Method for producing a hydrazide derivative, characterized in that. The method of claim 4, wherein the organic amine catalyst is an organic salt of N, N-dimethylaminopyridine (DMAP) or diisopropylethylamine (DIPEA). The method for producing a hydrazide derivative according to claim 5, wherein the organic amine is pyridine or triethylamine, and the amount thereof is used in an amount of 1.0 to 2.0 molar amount based on the compound of the formula (3). The method for producing a hydrazide derivative according to any one of claims 4 to 8, wherein the solvent is at least one selected from the group consisting of dichloromethane, benzene, toluene, tetrahydrofuran and diethyl ether. Cosmetic raw material composition comprising a compound of formula (1) as defined in any one of claims 2 and 3.

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