KR20150062443A - Ionone derivatives compounds - Google Patents

Abstract

An aspect of the present invention relates to an ionone derivative compound, an isomer of the same, a pharmaceutically allowable salt of the same, a prodrug of the same, a hydrate of the same, or a solvate of the same. Another aspect of the present invention relates to a composition for preventing skin-aging, wherein an ionone derivative compound, an isomer of the same, a pharmaceutically allowable salt of the same, a prodrug of the same, a hydrate of the same, or a solvate of the same is included.

Description

IONONE DERIVATIVES COMPOUNDS < RTI ID = 0.0 >

The present invention relates to ionone derivative compounds.

All organisms age with aging, and so are the skin. Efforts to delay such aging have been constantly being carried out, and thus the question of what is the nature of aging and why aging is constantly being raised. Skin aging can be roughly classified into two types according to the factors. One of them, intrinsic aging, is that the structure and physiological functions of the skin are constantly declining with aging, and the other, extrinsic aging, is caused by accumulated external stresses such as the sun's rays . Especially, sunlight is one of the well known cause of aging. Skin exposed to ultraviolet rays for a long time becomes thickened and collagen is denatured and skin elasticity is lost. This aging of the skin is accompanied by various functional and structural changes.

First of all, structural changes of the skin due to aging will reduce the thickness of the epidermis, dermis and subcutaneous tissue components of the skin. In addition, the extracellular matrix (ECM) component of the dermal tissue responsible for elasticity and tensile of the skin changes. ECM consists of two major components. One is elastic fiber, which is about 2 to 4% of total ECM, and the other is collagen, which accounts for about 70 to 80% of total ECM. The production of collagen is aggravated by the aging process, and the production of collagen is regulated by various factors during the biosynthesis process. The expression of matrix metalloprotease such as collagenase Resulting in collagen degradation resulting in reduced collagen content in the skin. When collagen is reduced in the dermis, the epidermis of the skin becomes rough and wrinkles appear, which is the aging phenomenon.

U.S. Patent Application No. 4,900,478 Korean Patent Application No. 2000-0046873

Dermatologoy therapy, 1998, 16, 357-364 FASEB J, 1996, 10, 1014-1024

A number of materials have been developed and used to suppress the reduction of collagen that causes wrinkles, especially retinol and retinoic acid wrinkles (Dermatologoy therapy, 1998, 16, 357-364). However, retinol and retinoic acid have a disadvantage in that they have a positive effect of improving wrinkles and stimulation even when only a small amount is applied to the skin. In addition, there is a restriction on the use due to low absorption capacity and instability due to fat-soluble.

Therefore, a new anti-aging derivative that retains the efficacy of retinol and retinoic acid while reducing skin irritation of retinol and retinoic acid is required. Various derivatives have been synthesized for this purpose. However, retinoic acid derivatives are not utilized because of unsatisfactory anti-aging effect, low stability, and skin irritation. Therefore, it is necessary to develop antioxidant substances with improved safety and stability, which are disadvantages of retinoic acid derivatives while maintaining the efficacy of existing retinoic acid derivatives.

Accordingly, the present invention provides a novel type of anti-aging agent, Ionone derivative, in order to develop a compound having safety and stability that does not exhibit skin irritation, discoloration, and detachment, which are problems of retinol and retinoic acid. Still another object of the present invention is to provide a composition for external application for skin for preventing skin aging which comprises the above-mentioned ionone derivative as an active ingredient.

The ionone derivative compound of the present invention comprises, in one aspect, a structure represented by the following formula (1)

[Chemical Formula 1]

In Formula 1,

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkyl, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy, a C ₁ to C ₃ alkyl ester and - COOH, wherein two or more of the R ¹ , R ² , R ³ , R ⁴ and R ⁵ groups are selected from the group consisting of carbon or oxygen An additional ring may be formed,

X is NH or O,

and n is an integer selected from 0 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

In another aspect, the present invention provides:

N- (4-hydroxyphenyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (4-hydroxybenzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (2- (4-hydroxyphenyl) -ethyl) -3- (2,6,6, -trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (3-hydroxy-phenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (3-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- [2- (3-hydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (2-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (3,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- [2- (3,4-dihydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (2,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (4-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (4-hydroxy-3-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo- 1- hexenyl)

N- (3,4-dimethoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N-benzo [1,3] dioxol-5-ylmethyl-3- (2,6,6-trimethyl-cyclo- 1- hexenyl)

N- (4-hydroxy-3-methylphenyl) -3- (2,6,6-trimethyl-cyclohexenyl) -acrylamide,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloyl] -benzoic acid ethyl ester,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid- methyl ester,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid, and

An iso derivative compound selected from the group consisting of 3-methyl-4- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid methyl ester, A pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

In another aspect, the present invention provides a composition comprising the above-mentioned ionone derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof, and a composition for preventing skin aging.

The ionone derivatives according to the present invention exhibit an effect of inhibiting the expression of matrix metalloprotease (MMP-1), a collagenase, and do not exhibit skin irritation. Therefore, medicines for improving wrinkles and elasticity, . ≪ / RTI >

In one aspect, the present invention relates to a substance having improved safety and stability while retaining the anti-aging effect of retinol and retinoic acid, and more specifically, it relates to a substance having beta-ionone as a basic skeleton and an unstable unsaturated carbon bond of retinoic acid as a benzene ring Or a polyphenol. The above aion derivatives can have an effect of inhibiting the expression of matrix metalloprotease, which is an excellent collagenase in one aspect, and can significantly reduce side effects of skin irritation of retinol and retinoic acid, which have been conventionally used .

Justice

In the present specification, the term " skin "refers to a tissue covering the body surface of an animal, and is a notion of the largest concept including a scalp and hair as well as a tissue covering a body surface such as a face or a body.

As used herein, "alkyl" means a monovalent saturated aliphatic hydrocarbon chain. The hydrocarbon chain can be linear or branched. In one aspect of the present invention "alkyl" are one to five carbon atoms ( "C ₁ to C ₅ alkyl") can have, and from 1 to 4 carbon atoms ( "C ₁ to C ₄ alkyl." In one aspect And in another aspect may have 1 to 3 carbon atoms ("C ₁ to C ₃ alkyl"). Specifically, "alkyl" includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl or t-amyl.

As used herein, "alkoxy" means an -OR group, wherein R is an alkyl group as defined above. Specific examples of " alkoxy " include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy or 1,2- But is not limited thereto.

As used herein, "cycloalkyl" means a cyclic saturated aliphatic hydrocarbon group. The C number is given in correspondence with the number of carbon atoms forming the ring and is mentioned together with the cycloalkyl group. For example, "C ₃ to C ₆ cycloalkyl" means a cycloalkyl having 3 to 6 ring-forming C atoms. In one aspect of the present invention, examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another aspect of the invention, a "cycloalkyl" group may be substituted with one or more alkyl groups, such as a C ₁ to C ₆ alkyl group, preferably a C ₁ to C ₃ alkyl group, particularly preferably a methyl group. If "cycloalkyl" has one or more substituents, these substituents may be the same or different.

As used herein, "cycloalkoxy" means an-OR group, wherein R is a "cycloalkyl" group as defined above.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo or iodo. In one aspect of the invention, the halo group may be fluoro or chloro.

As used herein, "aryl" means an aromatic hydrocarbon radical. Examples of "aryl" groups include phenyl, naphthyl, indenyl, azulenyl, or trasene, among which phenyl may be preferred.

As used herein, "hydroxy" means a radical -OH.

As used herein, the term "isomers" refers in particular to optical isomers (e.g., essentially pure enantiomers, essentially pure diastereomers or mixtures thereof, as well as conformation isomers (particularly tautomers) or geometric isomers (e. g., cis-trans isomers) (i. e., isomers where the angle of one or more chemical bonds is different, ).

As used herein, "essentially pure ", when used in connection with, for example, enantiomers or diastereomers, refers to an enantiomer or diastereomer of a specific compound that is about 90% or more, (W / w), more preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).

As used herein, "pharmaceutically acceptable" is intended to mean that the use of a medicinal dosage is not adversely affected by the administration, Have been received or are likely to be approved, or are identified in pharmacopoeia or in other general pharmacopoeias.

As used herein, "pharmaceutically acceptable salt" means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt may be (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (3-hydroxybenzoyl) benzoic acid, or an acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2,2,2] -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.

As used herein, the term " prodrug " refers to a drug that chemically changes a drug to control its physical and chemical properties. Although it does not exhibit physiological activity itself, The drug can be turned into a drug.

As used herein, " hydrate " means a compound to which water is bound, and is a broad concept that includes an inclusion compound having no chemical bonding force between water and the compound.

As used herein, " solvate " means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.

The ionone derivative compound of the present invention comprises, in one aspect, a structure represented by the following formula (1)

[Chemical Formula 1]

In Formula 1,

R ¹ , R ² , R ³ _, R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkyl, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkyl, aryloxy and C ₁ to C ₅ haloalkoxy, C ₁ to C ₃ alkyl ester (e.g., -COOCH _3, COOCH ₂ CH _3, etc.), and is independently selected from the group consisting of -COOH, where the ^{R 1, R 2, R 3} , R 4 , and Two or more of R < ⁵ > may form an additional ring mediated by carbon or oxygen,

X is NH or O (oxygen)

and n is an integer selected from 0 to 5, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₃ alkyl, C C ₃ -C ₆ cycloalkoxy, -COOCH ₃ , -COOCH ₂ CH _3, and -COOH, wherein R ¹ , R ² , R ³ , and R ⁴ are independently selected from the group consisting of C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkoxy, And R < ⁵ > may form an additional ring mediated by carbon or oxygen, X is NH, and n may be an integer selected from 0 to 2.

In another aspect, the present invention is a compound selected from the group consisting of the following compounds, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof:

N- (4-hydroxyphenyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (4-hydroxybenzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (2- (4-hydroxyphenyl) -ethyl) -3- (2,6,6, -trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (3-hydroxy-phenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (3-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- [2- (3-hydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (2-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (3,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- [2- (3,4-dihydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,

N- (2,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,

N- (4-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N- (4-hydroxy-3-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo- 1- hexenyl)

N- (3,4-dimethoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)

N-benzo [1,3] dioxol-5-ylmethyl-3- (2,6,6-trimethyl-cyclo- 1- hexenyl)

N- (4-hydroxy-3-methylphenyl) -3- (2,6,6-trimethyl-cyclohexenyl) -acrylamide,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloyl] -benzoic acid ethyl ester,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid- methyl ester,

3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid, and

3-Methyl-4- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid methyl ester.

The present invention also relates to a process for preparing the ionone derivative of formula (1).

In one aspect, the present invention provides a method for preparing an iodine derivative, comprising the steps of: i) synthesizing beta-ionone acid by reacting bromine and sodium hydroxide with beta-ionone; ii) reacting the above-mentioned beta-ionone acid with an alkylphenylamine substituted with a hydroxy, an aniline substituted with a hydroxy or an amino-benzoate-alkyl ester to prepare an ionone derivative.

The preparation method can be schematized by the following reaction formula (1).

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkyl, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are independently selected from the group consisting of C ₁ -C ₅ haloalkoxy, C ₁ -C ₃ alkyl ester (eg, -COOCH ₃ , COOCH ₂ CH _3, etc.) Two or more of R < ⁵ > may form an additional ring mediated by carbon or oxygen,

X is NH or O,

n is an integer selected from 0 to 5;

In another aspect, the present invention provides a method for producing an iodine derivative, comprising the steps of: i) reacting a water solvent in which sodium hydroxide is dissolved with bromine, adding beta-ionone dissolved in 1,4- synthesizing an acid ii) (O - (7- azabenzotriazol-(azabenzotriazol) -1- yl) - N, N, N, N - tetramethyluronium (tetramethyluronium) hexafluorophosphate) (HATU), or (I) in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), said beta-ionone acid and an alkylphenylamine substituted with hydroxy, aniline substituted with hydroxy, - < / RTI > alkyl ester to produce an ionone derivative.

One aspect of the present invention provides an effect of improving skin wrinkles comprising an ionone derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient. The compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof is effective for inhibiting the expression of a matrix metalloprotease, which is an enzyme that degrades collagen, The wrinkle improving effect can be exhibited.

The composition according to one aspect of the present invention comprises from 0.01% to 20% by weight, specifically from 0.1% to 10% by weight, more specifically from 0.5% to 5% by weight, based on the total weight of the composition, of an ionone derivative compound, An isomer, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. When it is included in the above range, it is not only suitable for exhibiting the intended effect of the present invention but also can satisfy both the stability and safety of the composition and may be suitably included in the above range in terms of cost effectiveness. Specifically, when the ionone derivative compound, its isomer, its pharmaceutically acceptable salt, its prodrug, its hydrate or its solvate is less than 0.01% by weight based on the total weight of the composition, %, It may be undesirable because it is not cost effective.

One aspect of the present invention provides a composition comprising an ionone derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient and a composition for external application for skin in another aspect do. Another aspect of the present invention relates to a cosmetic composition containing an iodine derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient and exhibiting excellent skin wrinkle- .

The cosmetic composition according to the present invention may be provided in all formulations suitable for topical application. For example, it may be provided as a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an oil phase in water, a suspension, a solid, a gel, a powder, a paste, a foam or an aerosol composition. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may contain, in addition to the above-mentioned materials, other ingredients capable of synergistic effect on the main effect within a range not impairing the main effect. Specifically, the cosmetic composition according to the present invention may further include other conventional wrinkle-improving ingredients capable of improving the skin wrinkle-reducing effect of the cosmetic composition according to the present invention. The cosmetic composition according to the present invention may further comprise a moisturizing agent, an emollient agent, a surfactant, an ultraviolet absorber, an antiseptic, a bactericide, an antioxidant, a pH adjuster, an organic or inorganic pigment, a fragrance, have. The compounding amount of the above components can be easily selected by those skilled in the art within a range not to impair the objects and effects of the present invention. The amount thereof may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight, have.

An aspect of the present invention provides a pharmaceutical composition comprising an ionone derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient. The pharmaceutical composition may exhibit an excellent skin wrinkle-reducing effect.

The pharmaceutical composition according to one aspect of the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like. Formulations for oral administration may be in the form of tablets, pills, soft and hard capsules, granules, powders, granules, solutions, emulsions or pellets, It is not. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or spray formers. The formulations may be readily prepared according to conventional methods in the art and may be prepared by conventional means including, but not limited to, surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, Other commonly used adjuvants may be used.

The effective ingredients of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathological condition and severity of the subject to be administered, route of administration, or judgment of the prescriber. Determination of the amount of application based on these factors is within the level of ordinary skill in the art and its daily dose is, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / kg / day. < / RTI >

Hereinafter, the constitution and effects of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these examples and experimental examples are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited thereto.

Example 1 Preparation of N- (4-hydroxyphenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

(1) Preparation of 3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylic acid

Sodium hydroxide (51 g) was dissolved in water (200 ml), and bromine (51 g) was added dropwise while stirring at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. To this was added ß-ionone (13.5 g) dissolved in dioxane (30 ml) dropwise, and the mixture was stirred at room temperature for 4 hours. 10% sodium bisulfite solution (300 ml) is added to the stirred mixture, and the mixture is extracted three times with ethyl ether to remove impurities. The basic aqueous layer was acidified with a concentrated hydrochloric acid solution to obtain a white solid precipitate. The precipitate was washed with water several times while being washed with water, crystallized with ethanol and water, and then filtered again to obtain 11 g of the target product. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.54 (d, J = 15.9Hz, 1H), 5.83 (d, J = 15.9Hz, 1H), 2.04 (m, 2H), 1.75 (s, 3H), 1.57 (m, 2H), 1.45 (m, 2H), 1.04 (s, 6H)

(2) Preparation of N- (4-hydroxyphenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

(1 g) obtained in (1) above was dissolved in dichloromethane / N, N-dimethylformamide (10 ml) HATU (2.35 g) was added and stirred. Then, 4-aminophenol (0.5 ml) and diisopropylethylamine (1.1 ml) were added dropwise and the mixture was stirred for 12 hours. After the reaction is completed, 1 N hydrochloric acid (HCl) solution is added to the mixed solution, extracted with dichloromethane, and the organic solution layer is washed twice with 1N hydrochloric acid solution. The dichloromethane layer was concentrated and recrystallized from dichloromethane / hexane to obtain 0.9 g of the title compound as a white solid. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.42 (d, J = 8.1Hz, 1H), 7.38 (d, J = 15.9Hz, 1H), 6.78 (d, J = 8.7Hz, 2H), 5.98 ( 2H, d, J = 15.9 Hz, 1H), 2.05 (m, 2H), 1.78 (s, 3H), 1.62 (m, 2H)

Example 2 Preparation of N- (4-hydroxybenzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

By using substantially the same method as (2) of Example 1 except that 4-aminomethylphenol was used instead of 4-aminophenol, 1.1 g of the title compound as a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.34 (d, J = 15.6Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 6.78 (d, J = 8.1Hz, 2H), 5.74 ( d, J = 15.6Hz, 1H) , 4.42 (s, 2H), 2.02 (m, 2H), 1.72 (s, 3H), 1.62 (m, 2H), 1.47 (m, 2H), 1.04 (s, 6H )

Example 3 Preparation of N- (2- (4-hydroxyphenyl) -ethyl) -3- (2,6,6, -trimethyl-cyclo-1- hexenyl) -acrylamide

1.05 g of the title compound as a white solid is obtained using substantially the same method as in (2) of Example 1, except for using 4- (2-amino-ethyl) -phenol instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ8.01 (s, OH), 7.28 (d, J = 15.6Hz, 1H), 7.05 (d, J = 8.4Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 5.66 (d , J = 15.6Hz, 1H), 3.57 (q, J = 6.6Hz, 2H), 2.79 (t, J = 6.6Hz, 2H), 2.01 (m, 2H), 1.71 ( (s, 3H), 1.59 (m, 2H), 1.46 (m, 2H), 1.03

Example 4 Preparation of N- (3-hydroxy-phenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

By using substantially the same method as in the step (2) of Example 1, except that 3-aminophenol was used instead of 4-aminophenol, 0.89 g of a white solid substance was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.47 (s, 1H), 7.41 (d, 1H), 7.13 (t, J = 8.1Hz, 1H), 6.83 (d, J = 7.8Hz, 1H), 6.60 (d, J = 7.8Hz, 1H), 5.97 (d, J = 15.9Hz, 1H), 2.07 (m, 2H), 1.79 (s, 3H), 1.63 (m, 2H), 1.49 (m, 2H ), 1.08 (s, 6 H)

Example 5 Preparation of N- (3-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide

Using essentially the same procedure as (2) of Example 1, but using 3-aminomethyl-phenol instead of 4-aminophenol, 1.2 g of the title compound as a white solid are obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.35 (d, J = 15.6Hz, 1H), 7.28 (s, 1H), 7.17 (t, J = 7.8Hz, 1H), 6.78 (d, J = 7.2 2H), 1.46 (m, 2H), 1.46 (m, 2H), 5.75 (d, J = 15.6 Hz, ), 1.04 (s, 6H)

Example 6 Preparation of N- [2- (3-hydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide

1.15 g of the title compound as a white solid was obtained using substantially the same method as (2) of Example 1, except that 3- (2-aminoethyl) -phenol was used instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.31 (s, 1H), 7.28 (d, 1H), 7.13 (t, J = 7.5Hz, 1H), 6.69 (d, J = 7.5Hz, 2H), (D, J = 15.9 Hz, 1H), 3.57 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.00 (M, 2H), 1.44 (m, 2H), 1.03 (s, 6H)

Example 7 Preparation of N- (2-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide

1.1 g of the title compound as a white solid is obtained using substantially the same method as (2) of Example 1, except that 2-aminomethyl-phenol is used instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

^{1 H NMR (DMSO-d6,} 300MHz): δ9.65 (s, OH), 8.42 (bs, NH), 7.16 (d, J = 15.6Hz, 1H), 7.10 (m, 2H), 6.78 (m, 2H), 6.07 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 5.7 Hz, 2H), 2.03 (m, 2H), 1.71 m, 2 H), 1.03 (s, 6 H)

Example 8 Preparation of N- (3,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

Using substantially the same procedure as in (2) of Example 1, except that 4-aminomethyl-benzene-1,2-diol was used instead of 4-aminophenol, 1.2 g of the title compound as a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.35 (d, J = 15.6Hz, 1H), 6.88 (d, J = 8.1Hz, 1H), 6.67 (d, J = 8.1Hz, 1H), 5.86 ( b, NH), 5.74 (d, J = 15.6 Hz, 1H), 4.41 (s, 2H), 2.01 (m, 2H), 1.70 (s, ), 1.01 (s, 6H)

Example 9 Preparation of N- [2- (3,4-dihydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide

Using essentially the same procedure as (2) of Example 1, except substituting 4- (2-amino-ethyl) -benzene-1,2-diol for 4-aminophenol, 1.3 g of the title compound as a white solid . The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.28 (d, J = 15.9Hz, 1H), 6.82 (s, 1H), 6.78 (d, J = 8.1Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.86 (bs , NH), 5.68 (d, J = 15.9Hz, 1H), 3.58 (q, J = 6.9Hz, 2H), 2.74 (t, J = 6.9Hz, 2H), 2.02 ( (m, 2H), 1.71 (s, 3H), 1.46 (m, 2H)

  Example 10 Preparation of N- (2,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

By using substantially the same method as in (2) of Example 1, except that 4-aminomethyl-benzene-1,3-diol was used instead of 4-aminophenol, 1.14 g of the title compound as a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.40 (d, J = 15.9Hz, 1H), 6.95 (d, J = 8.1Hz, 1H), 6.41 (s, 1H), 6.31 (dd, J = 8.1 Hz, 2.1Hz, 1H), 5.77 (d, J = 15.9Hz, 1H), 4.33 (d, J = 6Hz, 2H), 2.05 (m, 2H), 1.71 (s, 3H), 1.58 (m, 2H ), 1.45 (m, 2H), 1.02 (s, 6H)

Example 11 Preparation of N- (4-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

Using essentially the same procedure as (2) of Example 1 but using 4-methoxy-benzylamine instead of 4-aminophenol, 1.5 g of the title compound as a white solid are obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.35 (d, J = 15.9Hz, 1H), 7.25 (d, J = 5.4Hz, 2H), 6.87 (d, J = 8.4Hz, 2H), 5.75 ( (d, J = 15.9 Hz, 1H), 5.63 (bs, NH), 4.47 (d, J = 5.7 Hz, 2H), 3.80 1.58 (m, 2H), 1.45 (m, 2H), 1.04 (s, 6H)

Example 12 Preparation of N- (4-hydroxy-3-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylimide

By using substantially the same method as in the step (2) of Example 1, except that 4-aminomethyl-2-methoxyphenol was used instead of 4-aminophenol, 0.9 g of a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.35 (d, J = 15.6Hz, 1H), 6.88 (d, J = 8.1Hz, 1H), 6.85 (s, 1H), 6.81 (d, J = 8.1 Hz, 1H), 5.76 (d , J = 15.6Hz, 1H), 4.46 (d, J = 5.1Hz, 2H), 3.88 (s, 3H), 2.02 (m, 2H), 1.72 (s, 3H), 1.58 (m, 2H), 1.45 (m, 2H), 1.04 (s, 6H)

Example 13 Preparation of N- (3,4-dimethoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

Using substantially the same procedure as in (2) of Example 1, except that 3,4-dimethoxy-benzylamine was used instead of 4-aminophenol, 1.4 g of the title compound as a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

^{1 H NMR (DMSO-d6,} 300MHz): δ8.37 (bs, NH), 7.14 (d, J = 15.9Hz, 1H), 6.91 (s, 1H), 6.88 (d, J = 8.1Hz, 1H) , 6.78 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 15.9 Hz, 1H), 4.28 (d, J = 5.7 Hz, 2H) , 2.03 (m, 2H), 1.70 (s, 3H), 1.57

Example 14 Preparation of N-benzo [1,3] dioxol-5-ylmethyl-3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acrylamide

1.6 g of the title compound as a white solid were obtained using substantially the same procedure as in (2) of Example 1, except that C-benzo [1,3] dioxol-5-ylmethylamine was used in place of 4-aminophenol. . The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.35 (d, J = 15.9Hz, 1H), 7.27 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 5.94 (s, 2H ), 5.72 (d, J = 15.9Hz, 1H), 5.65 (bs, NH), 4.44 (d, J = 5.4Hz, 2H), 2.03 (m, 2H), 1.73 (s, 3H), 1.59 (m , 2H), 1.45 (m, 2H), 1.04 (s, 6H)

Example 15 Production of N- (4-hydroxy-3-methylphenyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide

By using substantially the same method as (2) of Example 1, except that 4-amino-2-methylphenol was used instead of 4-aminophenol, 0.8 g of the title compound as a white solid was obtained. The ¹ H NMR measurement results of the resulting compound were as follows.

^{1 H NMR (DMSO, 300MHz)} : δ9.68 (s, 1H), 7.35 (s, 1H), 7.28 (d, J = 15.6Hz, 1H), 7.25 (d, J = 8.4Hz, 1H), 6.70 (d, J = 8.4 Hz, 2H), 6.15 (d, J = 15.6 Hz, 1H), 3.32 (s, 3H), 2.06 (m, 2H), 1.74 , 1.45 (m, 2 H), 1.06 (s, 6 H)

Example 16 Preparation of 3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloyl] -benzoic acid-ethyl ester

1.3 g of the title compound as a white solid are obtained using substantially the same method as (2) of Example 1, except that 3-amino-benzoic acid ethyl ester is used instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ8.06 (s, 1H), 8.03 (d, J = 7.8Hz, 1H), 7.79 (d, J = 7.8Hz, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.39 (t , J = 7.8Hz, 1H), 5.09 (d, J = 15.6Hz, 1H), 4.38 (q, J = 7.2Hz, 2H), 2.07 (m, 2H), 1.78 ( 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.08 (s, 6H)

Example 17 Preparation of 3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid-methyl ester

1.2 g of the title compound as a white solid are obtained using substantially the same method as (2) of Example 1, except that 3-amino-benzoic acid methyl ester is used instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ8.11 (s, 1H), 7.98 (d, J = 7.8Hz, 1H), 7.68 (d, J = 7.8Hz, 1H), 7.50 (d, J = 15.6 1H), 7.41 (t, J = 7.8 Hz, 1H), 5.92 (d, J = 15.6 Hz, 1H), 3.90 (s, 3H), 2.06 1.61 (m, 2H), 1.48 (m, 2H), 1.08 (s, 6H)

[Example 18] Preparation of 3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid

(1 g) was treated with tetrahydrofuran in water (2: 1) to give the title compound as a colorless oil. 1) dissolve in a solvent (10 ml), add lithium hydroxide (500 mg) and stir for 6 hours. After the reaction is completed, the reaction mixture is neutralized by addition of acid. The reaction mixture is concentrated, and the residue is dissolved in ethyl acetate. After washing with water, the ethyl acetate layer is concentrated. Crystallization with ethyl acetate and hexane followed by filtration afforded 900 mg of the title compound as a pale yellow solid. The ¹ H NMR measurement results of the resulting compound were as follows.

^{1 H NMR (DMSO-d6,} 300MHz): δ10.2 (s, 1H), 8.28 (s, 1H), 7.90 (d, J = 8.1Hz, 1H), 7.61 (d, J = 7.8Hz, 1H) , 7.43 (t, J = 8.1 Hz, 1H), 7.32 (d, J = 15.9 Hz, 1H), 6.21 (d, J = 15.9 Hz, 1H) , 1.57 (m, 2H), 1.48 (m, 2H), 1.08 (s, 6H)

Example 19 Preparation of 3-methyl-4- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid methyl ester

0.8 g of the title compound as a white solid was obtained by substantially the same method as in the step (2) of Example 1 except that 4-amino-3-methyl-benzoic acid methyl ester was used instead of 4-aminophenol. The ¹ H NMR measurement results of the resulting compound were as follows.

_{^{1 H NMR (CDCl 3, 300MHz}} ): δ7.91 (s, 1H), 7.88 (d, J = 7.8Hz, 1H), 7.55 (d, J = 15.9Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 5.97 (d , J = 15.9Hz, 1H), 3.90 (s, 3H), 2.34 (s, 3H), 2.06 (m, 2H), 1.79 (s, 3H), 1.63 (m, 2H ), 1.50 (m, 2H), 1.08 (s, 6H)

[Test Example 1] Measurement of inhibitory effect of type I collagenase (MMP-1) expression by ultraviolet light

Human fibroblasts (PromoCell, Germany) were cultured in a 96-well plate incubator at a concentration of 10 ⁴ , irradiated with ultraviolet ray A at 0.2 J / cm ² after 24 hours, The compound and retinoic acid were treated with 10 μM and 1 μM. On the third day of culture, the supernatant was harvested and the amount of type I collagenase (MMP-1) produced was quantified using the ELISA (AP biotech RPN2610) method. The results are shown in Table 1, in which the ultraviolet control group is set at 100 and the comparative values are shown in Table 1.

matter MMP-1 expression level (%) matter MMP-1 expression level (%) 10 μM 1 [mu] M 10 μM 1 [mu] M Untreated group 100 100 Example 10 67.1 61.6 Retinoic acid 37 57.4 Example 11 40 60.8 Example 1 82.8 92 Example 12 62.1 98 Example 2 69.3 62.7 Example 13 57.5 63.8 Example 3 61.4 73.5 Example 14 67.8 81.9 Example 4 29.3 95 Example 15 88 91 Example 5 50.2 65 Example 16 46.7 89.4 Example 6 57.5 74.9 Example 17 29.7 82.4 Example 7 38 72.5 Example 18 57.2 54.9 Example 8 3 75.5 Example 19 35 67 Example 9 40 79.1

The Ionone derivatives prepared in Examples 1 to 19 showed an inhibitory effect on type I collagenase (MMP-1) expression at 10 μM and showed similar effects to retinoic acid as a positive control.

[Test Example 2] Measurement of skin irritation degree by human skin patch test

A filter paper disk in a pin chamber (Epitest LtD Oy, Finland) on a scan por- ter tape having a diameter of 8 mm was placed on the human skin to measure the degree of direct influence of the ionon derivatives on the skin, The sample containing the solution was loaded in 15 mL increments. Specifically, 20 occlusive patches were applied to the upper forearm of the subjects for 48 hours, and after 30 minutes (after the disappearance of transient erythema), skin irritation was observed according to the ICDRG (International Contact Dermatitis Research Group) . After 48 hours from the removal of the patches, skin irritation at the patch area was judged again to confirm whether or not allergic reactions occurred. The results are shown in Table 2 below in comparison with retinol.

The criteria for the determination of irritation and the calculation method are as follows.

Average skin irritation range (%) = {Σ (average reference value x number of the corresponding evaluation value) / (total subject x maximum evaluation value value)} x 100

sample Evaluation result (population) Average skin irritation range (%) Irritability judgment +++ ++ + ± - Retinol 0 0 4 3 13 8.8 One Example 16 0 0 One One 18 3.8 One

<Evaluation Criteria Numbers>

+++: 2; ++: 1.5; +: 1; ±: 0. 5; -:0

&Lt; Determination of skin irritation according to a patch &

1: lowest stimulus (10 or less); 2: mild stimulation (10.1-20); 3: Normal stimulus (20.1 to 30); 4: Severe irritation (over 30.1)

As shown in the above results, the compound of Example 16 was found to be much less irritating than retinol. Therefore, it was confirmed that the Ionone derivative of the present invention is safe in terms of human stimulation.

Hereinafter, a formulation example of a compound according to one aspect of the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof will be described in more detail, And is intended to be illustrative only, rather than limiting, of the invention.

[Formulation Example 1] Lotion

Lotion is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 0.1 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 PEG 12 nonyl phenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 2] Nourishing cream

Nutritive creams are prepared according to the usual methods with the composition shown in the table below.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 hardened castor oil 2.0 Liquid paraffin 10.0 Squalane 5.0 Caprylic / caproic triglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 3] Massage cream

A massage cream is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 1.0 Wax 10.0 Polysorbate 60 1.5 PEG 60 hardened castor oil 2.0 Sorbitan sesquioleate 0.8 Liquid paraffin 40.0 Squalane 5.0 Caprylic / capric triglyceride 4.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 4] Pack

A pack is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 0.2 Polyvinyl alcohol 13.0 Sodium carboxymethylcellulose 0.2 glycerin 5.0 Allantoin 0.1 ethanol 6.0 PEG 12 nonyl phenyl ether 0.3 Polysorbate 60 0.3 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 5]

The gel is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 0.5 Ethylenediamine sodium acetate 0.05 glycerin 5.0 Carboxyvinyl polymer 0.3 ethanol 5.0 PEG 60 hardened castor oil 0.5 Triethanolamine 0.3 Preservative, coloring, fragrance Suitable amount Purified water Balance

[Formulation Example 6] ointment

Ointment was prepared by the conventional method with the composition shown in the following table.

ingredient Content (% by weight) The ionone derivative compounds of Examples 1 to 19 1.5 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / capric triglyceride 3.0 Squalane 1.0 Cetearyl glucoside 1.5 Sorbitan stearate 0.4 Cetearyl alcohol 1.0 Wax 4.0 Preservative, coloring, fragrance Suitable amount Purified water Balance

Claims (7)

An ionone derivative compound represented by the following formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof:
[Chemical Formula 1]

In Formula 1,
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkyl, C ₁ to C ₅ alkoxy, C ₃ to C ₆ cycloalkoxy, aryloxy and C ₁ to C ₅ haloalkoxy, a C ₁ to C ₃ alkyl ester and - COOH, wherein two or more of the R ¹ , R ² , R ³ , R ⁴ and R ⁵ groups are selected from the group consisting of carbon or oxygen An additional ring may be formed,
X is NH or O,
n is an integer selected from 0 to 5; The method according to claim 1,
Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently selected from hydrogen, hydroxy, C ₁ to C ₃ alkyl, C ₁ to C ₃ alkoxy, C ₃ to C ₆ cycloalkoxy, -COOCH ₃ , -COOCH ₂ CH ₃ and -COOH, wherein two or more of R ¹ , R ² , R ³ , R ⁴ and R ⁵ may be independently selected from the group consisting of carbon or oxygen- , X is NH, and n is an integer selected from 0 to 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. The method according to claim 1,
The ionone derivative compound is:
N- (4-hydroxyphenyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,
N- (4-hydroxybenzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,
N- (2- (4-hydroxyphenyl) -ethyl) -3- (2,6,6, -trimethyl-cyclo- 1- hexenyl) -acrylamide,
N- (3-hydroxy-phenyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N- (3-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N- [2- (3-hydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,
N- (2-hydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N- (3,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N- [2- (3,4-dihydroxy-phenyl) -ethyl] -3- (2,6,6-trimethyl-cyclo- 1- hexenyl) -acrylamide,
N- (2,4-dihydroxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1- hexenyl) -acrylamide,
N- (4-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N- (4-hydroxy-3-methoxy-benzyl) -3- (2,6,6-trimethyl-cyclo- 1- hexenyl)
N- (3,4-dimethoxy-benzyl) -3- (2,6,6-trimethyl-cyclo-1-hexenyl)
N-benzo [1,3] dioxol-5-ylmethyl-3- (2,6,6-trimethyl-cyclo- 1- hexenyl)
N- (4-hydroxy-3-methylphenyl) -3- (2,6,6-trimethyl-cyclohexenyl) -acrylamide,
3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloyl] -benzoic acid ethyl ester,
3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid- methyl ester,
3- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid, and
An iso derivative compound selected from the group consisting of 3-methyl-4- [3- (2,6,6-trimethyl-cyclo-1-hexenyl) -acryloylamino] -benzoic acid methyl ester, A pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. A composition comprising an ionone derivative compound according to any one of claims 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. 5. The method of claim 4,
The composition comprises 0.01% to 20% by weight, based on the total weight of the composition, of an ionone derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. 5. The method of claim 4,
Wherein the composition is for preventing skin aging. 5. The method of claim 4,
Wherein said composition inhibits collagenase enzyme matrix metalloprotease expression.