KR20140117842A - Novel phenylacetic acid amide derivative compound - Google Patents

Abstract

The present invention relates to a novel phenylacetic acid amide derivative compound, isomers thereof, pharmaceutically acceptable salt thereof, prodrug thereof, a hydrate or a solvate thereof, and a composition for skin whitening comprising the same. The novel compound or the like has excellent skin whitening effect.

Description

Novel phenylacetic acid amide derivative compound < RTI ID = 0.0 >

The present invention relates to novel phenyl acetic acid amide derivative compounds and skin whitening compositions containing them.

Melanin protects the skin by blocking the ultraviolet rays from the epidermis layer, protecting the dermis organs below the skin, and absorbing free radicals. In addition, melanin is a major factor in determining the color of skin, and when it is present in excess, melanin is a cause of skin pigmentation such as spots, freckles, and spots.

Melanin is produced in melanocytes in the basal layer of the skin, which is known to be stimulated by stimulation of ultraviolet light or inflammation. Therefore, it is possible to reduce the external stimulus, block the signal transmission, or inhibit the synthesis of melanin producing enzyme tyrosinase or inhibit the activity of melanin.

At present, it is known that accelerating the degradation of tyrosinase or regulating glycosylation, such as kojic acid, hydroquinone, arbutin, azelaic acid, aloesin, 4-butyl resorcinol, resveratrol, ceramide, sphingosine- It is known that melanin production can be regulated. However, they are not used because of unsatisfactory whitening effect, low stability, and skin irritation. Therefore, it is necessary to develop a substance having a good whitening effect and a low side effect.

Korean Patent No. 10-0899335

The present invention provides novel phenyl acetic acid amide derivative compounds. The present invention also provides a composition comprising a phenyl acetic acid amide derivative compound exhibiting a skin whitening effect.

An aspect of the present invention provides a compound represented by the following general formula (1), an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

[Chemical Formula 1]

R ₁ , R ₂ and R ₃ 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, C ₃ to C ₆ cycloalkoxy, C ₁ to C ₅ haloalkoxy, aryl and C ₁ to C ₅ haloalkyl, Ad is adamantane, m is an integer selected from 1 to 3, and n is 0 or an integer selected from 1 to 3 All.

Another aspect of the present invention provides a composition for skin whitening comprising the compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof.

A novel compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof according to an aspect of the present invention inhibits melanin production and inhibits tyrosinase activity and has an excellent skin whitening effect.

The inventors of the present invention synthesized polyhydroxyamide derivative compounds with phenyl acetic acid as a basic skeleton and developed adamantane group as a substituent in order to develop a material having improved skin whitening effect and less side effects Exhibit excellent melanin formation inhibitory effect and tyrosinase activity inhibitory effect, and thus the present invention has been completed.

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, the term 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. Particularly preferred examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy or 1,2-dimethylbutoxy 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, "haloalkyl" includes an "alkyl" group as defined above substituted with one or more halogen which is the same or different (eg, trifluoromethyl or pentafluoroethyl). In one aspect of the invention, it may be C ₁ to C ₅ haloalkyl.

As used herein, "haloalkoxy" includes "alkoxy" groups as defined above substituted with one or more halogen which are the same or different (e.g., trifluoromethyl or pentafluoroethyl). In one aspect of the invention, it may be C ₁ to C ₅ haloalkoxy.

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, "aryloxy" means a group Ar, wherein Ar means an "aryl" group as defined above.

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

As used herein, the term "isomers" refers in particular to optical isomers (for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof) as well as morphological isomers (i. e., isomers differing only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g., cis-trans isomers) do.

As used herein, "essentially pure ", when used in reference to an enantiomer or partial isomer, means that at least about 90%, preferably at least about 95%, of a specific compound, such as an enantiomer or partial isomer, , 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, the term " pharmaceutically acceptable "refers to the approval of a government or equivalent regulatory agency that can be used on animals, and more specifically on humans, by avoiding significant toxic effects when used in conventional medicinal dosage Received, approved, or listed in pharmacopoeia or other general pharmacopoeia.

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, "prodrug" means a drug that chemically changes a drug to regulate the physical and chemical properties thereof. Although the drug itself does not exhibit physiological activity, 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.

DETAILED DESCRIPTION OF THE INVENTION

R ₁ , R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, hydroxy, C ₁ to C ₅ alkyl, C ₁ to C ₅ alkoxy, C C ₃ to C ₆ cycloalkyl, C ₃ to C ₆ cycloalkoxy, aryloxy, C ₁ to C ₅ haloalkoxy, aryl and C ₁ to C ₅ haloalkyl, and Ad is selected from the group consisting of adamantane, , M is an integer selected from 1 to 3, and n is 0 or an integer selected from 1 to 3, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof do.

Another aspect of the present invention provides a composition for skin whitening comprising the compound of Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof.

In another aspect of the present invention, there is provided the above compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof,

2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) acetamide (PAC-16924)

3- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) propanamide (PAC-16925)

2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxyphenethyl) acetamide (PAC-16929)

2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-methoxyphenethyl) acetamide (PAC-16942)

2- (3-adamantanyl-4-hydroxyphenyl) -N-phenylacetamide (PAC-16941),

2- (3-adamantanyl-4-hydroxyphenyl) -N- (2,4-dihydroxybenzyl) acetamide (PAC-16930)

2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxybenzyl) acetamide (PAC-16949)

2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxybenzyl) acetamide (PAC-16950), and

N-benzyl-2- (3-adamantanyl-4-hydroxyphenyl) acetamide (PAC-16948)

≪ / RTI > The names in parentheses are assigned by the present inventors for the naming of the compounds.

In one aspect of the present invention, there is provided a process for preparing adamantanyl-hydroxyphenyl acetic acid, comprising: i) synthesizing adamantanyl-hydroxyphenyl acetic acid by reacting hydroxyphenyl acetic acid and adamantane compound under acid catalyst; And ii) reacting the adamantanyl-hydroxyphenyl acetic acid and the alkylphenylamine to synthesize a phenyl acetic acid amide derivative compound having an adamantane group, an isomer thereof, a pharmaceutically acceptable salt thereof, , A prodrug thereof, a hydrate thereof or a solvate thereof.

In the present invention, the adamantane compound is not particularly limited as long as it is a compound having an adamantane group, and may be adamantanol, for example.

In the present invention, the alkylphenylamine may be selected from the group consisting of unsubstituted or hydroxy-substituted benzylamine, unsubstituted or hydroxy-substituted phenethylamine and dopamine, but is not limited thereto.

The method for preparing phenylalanine amide compounds substituted with adamantane groups according to one aspect of the present invention can be illustrated by the following reaction scheme 1. That is, hydroxyphenyl acetic acid, which is a starting material, is reacted with an adamantane compound in step i) to synthesize adamantanyl-hydroxyphenyl acetic acid, and in step ii), an alkylphenylamine is reacted to synthesize a phenyl acetic acid amide derivative compound do.

[Reaction Scheme 1]

In the above Reaction Scheme 1,

R ₁ , R ₂ and R ₃ 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, C ₃ to C ₆ cycloalkoxy, C ₁ to C ₅ haloalkoxy, aryl and C ₁ to C ₅ haloalkyl, Ad is adamantane, m is an integer selected from 1 to 3, and n is 0 or an integer selected from 1 to 3 All.

In the production process of the present invention, it is most preferred that the hydroxyphenyl acetic acid and the adamantane compound in step i) are reacted at a molar ratio of 1.5: 1 to 1: 1.5, preferably 1: 1. When the reaction ratio is within the above range, the starting material may be completely removed through recrystallization to facilitate purification of the final compound.

The adamantanyl-hydroxyphenyl acetic acid and the alkylphenylamine in the step ii) are most preferably reacted in a molar ratio of 1.5: 1 to 1: 1.5, preferably 1: 1. When the reaction ratio is within the above range, the starting material may be completely removed through recrystallization to facilitate purification of the final compound.

The production method of the present invention can be carried out by, for example, i) reacting 4-hydroxyphenyl acetic acid with 1-adamantanol in the presence of acetic acid and sulfuric acid catalyst in a dichloromethane solvent at room temperature to obtain 5-adamantanyl-4-hydroxyphenyl Synthesizing acetic acid; And ii) (O - (7- aza-benzotriazol-1-yl) - N, N, N, N - tetramethyl-right Ronnie to help hexafluorophosphate) (O - (7-azabenzotriazol -1-yl) - In the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), N , N , N , N'- tetramethyluronium hexafluorophosphate -Adamantanyl-4-hydroxyphenylacetic acid or 5-adamantanyl-4-hydroxyphenylpropionic acid and benzylamine or phenethylamine substituted with a hydroxy group to give an adamantane-substituted phenyl acetic acid amide compound . ≪ / RTI >

One aspect of the present invention provides a composition for skin whitening comprising the above 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 may inhibit melanin production and inhibit the activity of tyrosinase, thereby exhibiting an excellent skin whitening effect. It is considered that the excellent melanin formation inhibitory effect and the tyrosinase activity inhibiting effect are attributable to the improvement of the absorption ability due to the lipophilic property of the adamantane group.

The composition according to one aspect of the present invention comprises 0.01 to 20% by weight, specifically 0.1 to 10% by weight, more particularly 0.5 to 5% by weight, based on the total weight of the composition, of the compound, its 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 compound, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or a solvate thereof is less than 0.01% by weight, sufficient skin whitening effect can not be obtained, and when it exceeds 20% by weight, The effect is low and may not be desirable.

An aspect of the present invention provides a composition for external application for skin comprising the above compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

Another aspect of the present invention provides a cosmetic composition comprising the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient. The cosmetic composition may exhibit an excellent skin whitening effect and specifically improve or prevent spots, freckles, dots and skin pigmentation.

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 can be formulated in the form of a softening agent, a convergent lotion, a nutritional lotion, an eye cream, a nutritional cream, a massage cream, a cleansing cream, a cleansing foam, a cleansing water, a powder, And the formulation is not particularly limited.

The cosmetic composition according to the present invention may contain, in addition to the above-mentioned substances, other ingredients which can give a synergistic effect to the main effect, so long as they do not impair the main effect. Specifically, the cosmetic composition according to the present invention may further comprise an arbutin or ascorbic acid derivative capable of enhancing the skin whitening effect. 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 the above 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 whitening effect and specifically improve or treat spots, freckles, dots and skin pigmentation.

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, ointments, injections, drops, suppositories, patches or spray formulations. 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 / / Day, but is not limited thereto.

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 2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) acetamide

(1) Preparation of 3-adamantanyl-4-hydroxyphenyl acetic acid

4-hydroxyphenyl acetic acid (5 g) and 1-adamantanol (5 g) were dissolved in dichloromethane (110 mL) and stirred. Acetic acid (9.3 mL) was mixed with concentrated sulfuric acid (1.8 mL), and the mixture was stirred at room temperature for 12 hours. Water (100 mL) was added to the stirred mixture, and sodium bicarbonate was added thereto so that the pH of the solution became 6. The resulting solid was filtered to give 8 g of 3-adamantanyl-4-hydroxyphenyl acetic acid as an off-white solid.

^{1 H NMR (300MHz, DMSO-} d 6) 9.12 (s, 1H), 6.93 (s, 1H), 6.85 (d, 1H), 6.67 (d, 1H) 3.38 (s, 2H), 2.048 (bs, 9H ), 1.71 (6H)

(2) Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) acetamide

(0.1 g), HATU (0.146 g) and triethylamine (39 mg) obtained in the above (1) were dissolved in dimethylformamide (2 mL) and stirred for 30 minutes. Tiramine (52.7 mg) was further added dropwise and stirred for 4 hours. Water was added to the mixture, and the crystallized solid was filtered, and further recrystallized with ethyl acetate to obtain 90 mg of the title compound as a white solid.

^{1 H NMR (300MHz, DMSO-} d 6) 9.16 (s, 1H), 9.08 (s, 1H), 7.92 (bs, 1H), 6.94 m, 3H), 6.82 (d, 1H), 6.65 (m, 3H ), 3.21 (s, 2H), 3.17 (dd, 2H), 2.55 (m, 2H), 2.05-2.02 (bs,

[Example 2]

Preparation of 3- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) propanamide

Using substantially the same method as in Example 1 (2) except that 3-adamantanyl-4-hydroxyphenylpropionic acid was used instead of 3-adamantanyl-4-hydroxyphenyl acetic acid, Of the target compound.

^{1 H NMR (300MHz, CDCl3-} d) 6.97 (s, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 6.76-6.73 (m, 3H), 6.57 (d, 1H), 6.09 (s 2H), 2.42 (t, 2H), 2.4 (t, 2H), 2.09-2.04 (s, bs, 9H), 1.81 (bs, 6H).

[Example 3]

Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxyphenethyl) acetamide

90 mg of the target substance as a white solid was obtained using substantially the same method as in (2) of Example 1, except that dopamine hydrochloride was used instead of tyramine.

^{1 H NMR (300MHz, DMSO-} d 6) 9.41 (s, 1H), 9.10 (s, 1H), 9.089 (s, 1H), 8.27 (t, 1H), 6.97 (s, 1H), 6.86-6.8 ( 2H), 6.64 (d, 1H), 6.23 (s, 1H), 6.12 (d, , 6H).

[Example 4]

 Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-methoxyphenethyl) acetamide

By using substantially the same method as in (2) of Example 1, except that 4-methoxyphenethylamine was used instead of thiamine, 80 mg of the title compound as a white solid was obtained.

^{1 H NMR (300MHz, DMSO-} d 6) 9.08 (s, 1H), 7.92 (t, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 6.939 (s, 1H), 6.81-6.79 ( (m, 3H), 6.64 (d, 1H), 3.70 (s, 3H), 3.28-3.18 (m, 3H), 2.61 (t, 2H), 2.05 (s, 9H), 1.71

[Example 5]

Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N-phenylacetamide

Using substantially the same procedure as in (2) of Example 1, except that phenethylamine was used instead of tyramine, 80 mg of the title compound as a white solid was obtained.

^{1 H NMR (300MHz, DMSO-} d 6) 9.10 (s, 1H), 7.98 (t, 1H), 7.28-7.14 (m, 5H), 6.94 (s, 1H), 6.82 (d, 1H), 6.64 ( d, 1 H), 3.29-3.22 (m, 3H), 2.68 (t, 2H), 2.04 (s, 9H), 1.718 (s, 6H).

[Example 6]

Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (2,4-dihydroxybenzyl) acetamide

 By using substantially the same method as (2) of Example 1, except that 2,4-dihydroxybenzylamine was used instead of tyramine, 100 mg of the title compound as a off-white solid was obtained.

^{1 H NMR (300MHz, DMSO-} d 6) 9.42 (s, 1H), 9.1 (bs, 2H), 8.28 (t, 1H), 6.975 (s, 1H), 6.86-6.80 (m, 2H), 6.65 ( 2H), 3.231 (s, 9H), 1.72 (s, 6H).

[Example 7]

 Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxybenzyl) acetamide

20 mg of the target substance as a white solid was obtained using substantially the same method as in the step (2) of Example 1, except that 4-hydroxybenzylamine was used instead of tyramine.

^{1 H NMR (300MHz, DMSO-} d 6) 9.24 (s, 1H), 9.06 (s, 1H), 8.29 (m, 1H), 7.01-6.98 (m, 3H), 6.85 (d, 1H), 6.67- 2H), 2.036 (bs, 9H), 1.72 (s, 6H), 6.63 (s,

[Example 8]

Preparation of 2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxybenzyl) acetamide

By using substantially the same method as (2) of Example 1, except that 3,4-dihydroxybenzylamine bromide salt was used in place of tyramine, 0.1 g of the title compound as a white solid was obtained.

^{1 H NMR (300MHz, DMSO-} d 6) 9.06 (s, 1H), 8.78 (s, 1H), 8.72 (s, 1H), 8.26 (m, 1H), 6.98 (s, 1H), 6.85 (d, 1H), 6.66-6.61 (m, 3H), 6.46 (d, 1H), 4.06 (d, 2H), 3.28 (s, 2H), 2.04 (s, 9H), 1.72

[Example 9] Preparation of N-benzyl-2- (3-adamantanyl-4-hydroxyphenyl) acetamide

0.11 g of the title compound as a off-white solid was obtained using substantially the same procedure as in (1) of Example 1, except that benzylamine was used instead of tyramine.

^{1 H NMR (300MHz, DMSO-} d 6) 9.09 (s, 1H), 8.44 (bs, 1H), 7.28-7.2 (m, 5H), 7 (s, 1H), 6.86 (d, 1H), 6.66 ( d, 1 H), 4.25 (d, 2H), 2.04 (bs, 9H), 1.72 (s, 6H).

[Test Example 1] Inhibitory effect on melanin formation in melanin pigment producing cells

The inhibitory effect of the phenyl acetic acid amide derivative compound prepared in the above Example on the melanin formation in the melanin pigment producing cells was measured by Dooley's method. The cell line used was mouse-derived B16F10 (melanoma cell) purchased from Korean Cell Line Bank. DMEM (Cat No. 11995), FBS (Cat No. 16000-044) and antibiotic-antifungal agent (Cat No. 15240-062) required for cell culture were purchased from Invitrogen (GIBCO). The cell lines were cultured under conditions of 37 ° C and 5% CO ₂ . The cultured B16F10 cells were removed with 0.05% trypsin-EDTA and inoculated again into the 48-well plate at the same number (1 x 10 ⁴ cells / well) Example I was replaced with media containing 10 ppm. Positive control kojic acid, rucinol and hydroquinone were used. After 5 days, the cells were treated with 1N NaOH and reacted at 60 ° C for 2 hours to dissolve the melanin contained in the cells. The amount of melanin was measured by measuring the absorbance at 405 nm. The concentration (IC ₅₀ ) of the example required to reduce the melanin production of the melanocyte from it by half was calculated and shown in the table below.

Test substance IC ₅₀ Kojic acid > 500 μM Lucinol 10 μM Hydroquinone 3 μM Example 1 2.4 μM Example 8 1.5 μM

As can be seen from the above results, the compounds of the Examples can inhibit melanin production even in a small amount compared with kojic acid and lucinol and hydroquinone. Therefore, the phenyl acetic acid amide derivative compounds according to the present invention inhibit melanin production and have an excellent skin whitening effect.

[Test Example 2] Inhibitory effect of tyrosinase activity on Mushroom

The mushroom tyrosinase inhibitory effect of the phenyl acetic acid amide derivative compounds prepared in the above examples was measured by the method of Vanni, et al. Specifically, 49.5 μl of 0.1 M potassium phosphate buffer (pH 6.8), 45 μl of distilled water (DW), 0.5 μl (10 units) of mushroom tyrosinase (SIGMAT-7755) and 5 μl of Example were mixed, Tyrosine aqueous solution was mixed in a 96-culture vessel (total of 150 占 퐇) and subjected to enzyme reaction at 37 占 폚 for 10 minutes. Lucinol was used as a positive control. The absorbance of the reaction solution was measured at 480 nm and the concentration (IC ₅₀ ) of the Example inhibiting 50% of the tyrosinase enzyme activity was calculated and shown in the table below

Test substance IC ₅₀ Lucinol 1.6 [mu] M Example 3 1.3 μM Example 6 1 μM

As can be seen from the above results, the phenyl acetic acid amide derivative compounds of the examples are excellent in inhibiting mushroom tyrosinase activity, and the effect is superior to lucinol. Therefore, the phenyl acetic acid amide derivative compounds according to the present invention inhibit the activity of tyrosinase and have excellent skin whitening effect.

Hereinafter, formulation examples 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, It is to be understood that the invention is not limited to the disclosed embodiments, but is only to be specifically described.

[Formulation Example 1] Lotion

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

ingredient Content (% by weight) Example 1 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) Example 2 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) Example 3 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) Example 4 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) Example 5 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) Example 6 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 (11)

Claims 1. A compound of 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 and R ₃ 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, C ₃ to C ₆ cycloalkoxy, C ₁ to C ₅ haloalkoxy, aryl and C ₁ to C ₅ haloalkyl, Ad is adamantane, m is an integer selected from 1 to 3, and n is 0 or an integer selected from 1 to 3 to be.
The method according to claim 1,
The compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) acetamide,
3- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxyphenethyl) propanamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxyphenethyl) acetamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-methoxyphenethyl) acetamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N-phenylacetamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (2,4-dihydroxybenzyl) acetamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (4-hydroxybenzyl) acetamide,
2- (3-adamantanyl-4-hydroxyphenyl) -N- (3,4-dihydroxybenzyl) acetamide, and
N-benzyl-2- (3-adamantanyl-4-hydroxyphenyl) acetamide
A pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.
A composition for skin whitening comprising a compound according to any one of claims 1 and 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.
The method of claim 3,
The composition comprises 0.01% by weight or more of a compound according to any one of claims 1 and 2, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof, By weight of the composition.
The method of claim 3,
Wherein said composition inhibits melanin formation and inhibits tyrosinase activity.
The method of claim 3,
Wherein the composition is an external preparation for skin.
The method of claim 3,
Wherein the composition is a cosmetic composition.
The method of claim 3,
Wherein the composition is a pharmaceutical composition.
i) reacting hydroxyphenyl acetic acid and adamantane compound under an acid catalyst to synthesize adamantanyl-hydroxyphenyl acetic acid; And
ii) reacting the adamantanyl-hydroxyphenyl acetic acid and the alkylphenylamine to synthesize a phenyl acetic acid amide derivative compound having an adamantane group according to any one of claims 1 and 2 , An isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.
10. The method of claim 9,
Wherein the production method is represented by the following reaction formula (1).
[Reaction Scheme 1]

In the above Reaction Scheme 1,
R ₁ , R ₂ and R ₃ 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, C ₃ to C ₆ cycloalkoxy, C ₁ to C ₅ haloalkoxy, aryl and C ₁ to C ₅ haloalkyl, Ad is adamantane, m is an integer selected from 1 to 3, and n is 0 or an integer selected from 1 to 3 to be.
10. The method of claim 9,
Wherein the alkylphenylamine is selected from the group consisting of an unsubstituted or hydroxy-substituted benzylamine, unsubstituted or hydroxy-substituted phenethylamine, and dopamine.