Benzoic acid amide compound

Abstract

Disclosed are a novel benzoic acid amide derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof. The novel compound and the like inhibit melanin production, prevent tyrosinase activity, and have an excellent skin whitening effect.

Claims

1. A compound of the following chemical formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof: ##STR00016## wherein R.sub.1 of Chemical Formula 1 is selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl, and C.sub.6-C.sub.18 aryl group, wherein the aryl group is unsubstituted or substituted with one or more selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, methylenedioxy, and nitro groups.

2. The compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof according to claim 1, wherein the compound is selected from the group consisting of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-methyl-benzoic acid amide, 5-bromo-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, 5-tert-butyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-phenyl-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-fluoro-phenyl)-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-methoxy-phenyl)-benzoic acid amide, 5-benzo[1,3]dioxol-5-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, 5-cyclohexene-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,5-dimethyl-phenyl)-benzoic acid amide, 5-cyclohexyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,4-difluoro-phenyl)-benzoic acid amide, and N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3-nitro-phenyl)-benzoic acid amide.

3. The compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof according to claim 1, wherein the compound is N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,5-dimethyl-phenyl)-benzoic acid amide.

4. A method of preparing the compound of chemical formula 1, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof according to claim 1, wherein the method comprises a first step of reacting a benzoic acid derivative of the following chemical formula 2 and a hydroxyl group substituted alkyl-phenyl amine as reactants: ##STR00017## wherein R.sub.1 of chemical formula 1 is selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl and C.sub.6-C.sub.18 aryl group, wherein the aryl group is unsubstituted or substituted with one or more selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, methylenedioxy, and nitro groups; and ##STR00018## wherein R of chemical formula 2 is selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkenyl; wherein the first step is performed in presence of N-hydroxysuccinimide and N,N-dicyclohexylcarbodiimide (DCC).

5. The method of preparing the compound of chemical formula 1 according to claim 4, wherein the R of chemical formula 2 is halogen.

6. The method of preparing the compound of chemical formula 1 according to claim 5, wherein the method further comprises a second step of reacting the resulting bromo benzoic acid amide derivative and arylboronic acid, in a case where the R of chemical formula 2 is bromine group to form a bromo benzoic acid derivative.

7. The method of preparing the compound of chemical formula 1 according to claim 6, wherein the second step is performed in presence of a palladium catalyst under base condition.

8. The method of preparing the compound of chemical formula 1 according to claim 6, wherein the aryl bromic acid is unsubstituted or substituted with one or more selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, methylenedioxy, and nitro groups.

9. A method for skin whitening comprising administering the compound according to claim 1, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof to a subject in need thereof.

10. The method for skin whitening according to claim 9, wherein the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof is contained in a composition in a concentration of 0.01 wt % to 20 wt % based on total weight of the composition.

11. The method for skin whitening according to claim 9, wherein the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof inhibits melanin production.

12. The method for skin whitening according to claim 9, wherein the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof inhibits tyrosinase activity.

13. The method according to claim 9, wherein the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof is one for external application to skin.

14. The method according to claim 9, wherein the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the hydrate thereof, or the solvate thereof is one for a cosmetic composition, a pharmaceutical composition, or health food composition.

Description

DETAILED DESCRIPTION

(1) In an aspect, the present invention provides a compound comprising a structure of the following Chemical Formula 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof:

(2) ##STR00002##
R.sub.1 of Chemical Formula 1 is independently selected from the group consisting of halogen, C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl, and aryl group, wherein the aryl group is unsubstituted or substituted with one or more selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, methylenedioxy, and nitro groups.

(3) In another aspect, the present invention provides the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof, comprising one selected from the group consisting of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-methyl-benzoic acid amide, 5-bromo-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, 5-tert-butyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-phenyl-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-fluoro-phenyl)-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-methoxy-phenyl)-benzoic acid amide, 5-benzo[1,3]dioxol-5-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, 5-cyclohexene-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,5-dimethyl-phenyl)-benzoic acid amide, 5-cyclohexyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide, N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,4-difluoro-phenyl)-benzoic acid amide, and N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3-nitro-phenyl)-benzoic acid amide.

(4) In an aspect, the present invention provides i) the first step of preparing a benzoic acid amide compound by reacting a benzoic acid derivative of the following Chemical formula 2 and a hydroxyl group substituted alkyl-phenyl amine;

(5) ##STR00003##
R is selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl, and C.sub.3-C.sub.6 cycloalkenyl.

(6) In a case where the R of Chemical formula 2 is a bromine group to form a bromo benzoic acid derivative, the resulting obtained from the first step may be subject to the following second step.

(7) In an aspect, the present invention provides the method of preparing a benzoic acid amide compound which is substituted with an alkyl or aryl group comprising the second step of reacting the resulting bromo benzoic acid amide derivative and suitable arylboronic acid under a palladium as a catalyst to form a benzoic acid amide compound with a form of bi-aryl.

(8) In an aspect of the present disclosure, the method of preparing a benzoic acid amide compound which is substituted with an alkyl or aryl group may be schematized by the following Reaction formula 1.

(9) ##STR00004##

(10) In Reaction formula 1, R is selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkenyl, and aryl group, wherein the aryl group is unsubstituted or substituted with one selected from the group consisting of halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, methylenedioxy, and nitro groups. The present disclosure is selected from the group consisting of the compound including the resulting from Reaction formula 1, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof.

(11) In an aspect of the present invention, a method of preparing a benzoic acid amide compound may comprise the step of preparing a benzoic acid amide compound which is substituted with alkyl or aryl group, comprising the steps of: i) preparing a benzoic acid amide compound by reacting an alkyl (or bromo) benzoic acid derivative and a hydroxyl group substituted alkyl-phenyl amine; and ii) reacting the resulting bromo benzoic acid amide derivative and suitable arylboronic acid under a palladium as a catalyst to form a benzoic acid amide compound with a form of bi-aryl.

(12) In an aspect of the present invention, a method of preparing a benzoic acid amide compound may comprise the steps of: i) preparing a benzoic acid amide compound by reacting an alkyl (or bromo) benzoic acid derivative and a hydroxyl group substituted alkyl-phenyl amine in a presence of N-hydroxysuccinimide (HOSu) and N, N-dicyclohexylcarbodiimide (DCC); and ii) reacting the resulting bromo benzoic acid amide derivative and suitable arylboronic acid under a palladium as a catalyst and base condition by Suzuki cross coupling to form a benzoic acid amide compound with a form of bi-aryl.

(13) In an aspect, the present invention provides a composition for skin whitening comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient.

(14) In an aspect, the present invention provides a method of improving skin whitening of a subject, wherein the method may comprise the step of administering an active dosage of the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof to a subject in needed thereof.

(15) In an aspect, the present invention provides a use of the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof for preparing a composition for improving skin whitening.

(16) In an aspect, the present invention provides the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate thereof for improving skin whitening.

(17) The compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate thereof may inhibit melanin production and prevent tyrosinase activity, thereby having excellent skin whitening effect.

(18) In an aspect, the composition of the present invention may comprise 0.01 wt % to 20 wt % of the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof based on total weight of the composition.

(19) In a view, a content of the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof may be 0.01 wt % or more, 0.02 wt % or more, 0.03 wt % or more, 0.04 wt % or more, 0.05 wt % or more, 0.1 wt % or more, 0.2 wt % or more, 0.3 wt % or more, 0.4 wt % or more, 0.5 wt % or more, 0.6 wt % or more, 0.7 wt % or more, 0.8 wt % or more, 0.9 wt % or more, 1.0 wt % or more, 2.0 wt % or more, 3.0 wt % or more, 4.0 wt % or more, 4.1 wt % or more, 4.2 wt % or more, 4.3 wt % or more, 4.4 wt % or more, 4.5 wt % or more, 4.6 wt % or more, 4.7 wt % or more, 4.8 wt % or more, 4.9 wt % or more or 5.0 wt % or more based on total weight of the composition.

(20) In a view, a content of the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof may be 20 wt % or less, 19.5 wt % or less, 19 wt % or less, 18 wt % or less, 17 wt % or less, 16 wt % or less, 15 wt % or less, 14 wt % or less, 13 wt % or less, 12 wt % or less, 11 wt % or less, 10 wt % or less, 9 wt % or less, 8 wt % or less, 7 wt % or less, 6 wt % or less, 5.9 wt % or less, 5.8 wt % or less, 5.7 wt % or less, 5.6 wt % or less, 5.5 wt % or less, 5.4 wt % or less, 5.3 wt % or less, 5.2 wt % or less or 5.1 wt % or less based on total weight of the composition.

(21) Within the above-described range, the effect desired by the present disclosure can be achieved adequately while satisfying both stability and safety of the composition, and the range is suitable in terms of cost effectiveness. Specifically, in the case where the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof is included in an amount less than 0.01 wt %, skin whitening effect may be insufficient. Further, when it is included in an amount exceeding 20 wt %, cost effectiveness may wear off.

(22) In an aspect, the present invention provides a composition for external application to skin, comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient. In another aspect, the present invention provides a cosmetic composition comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient. The cosmetic composition may exhibit superior skin whitening effect and, specifically, may improve or prevent stains, freckles, dark spots, or pigmentation.

(23) The cosmetic composition according to the present invention may be provided as any formulation suitable for topical application. For example, it may be provided in the formulation of solution, oil-in-water emulsion, water-in-oil emulsion, suspension, solid, gel, powder, paste, foam, or aerosol. The composition of formulations may be prepared by a method commonly used in the art.

(24) The cosmetic composition according to the present invention may further comprise other ingredients in a range that does not affect its primary effect negatively and preferably may provide synergic effect. Specifically, the composition according to the present invention may further comprise arbutin or ascorbic acid derivatives that can enhance skin whitening effect. Further, the cosmetic composition according to the present invention may further comprise moisturizer, emollient, surfactant, UV absorbent, antiseptic, fungicide, antioxidant, pH adjuster, organic or inorganic pigment, flavor, cooling agent, or antiperspirant. The amount of these ingredients may be determined within ranges not negatively affecting the purpose and effect of the present invention by those skilled in the art. The amount of these ingredients may be 0.01 wt % to 5 wt %, specifically 0.01 wt % to 3 wt %, based on the total weight of the composition.

(25) In another aspect, the present invention provides a pharmaceutical composition comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient. The pharmaceutical composition may exhibit excellent skin whitening effect, specifically, may improve or treat stains, freckles, dark spots, or pigmentation.

(26) The pharmaceutical composition according to the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, or the like. Formulations for oral administration may be in the form of tablet, pill, soft or hard capsule, granule, powder, fine granule, liquid, emulsion, or pellet, but are not limited thereto. Formulations for parenteral administration may be in the form of solution, suspension, emulsion, gel, injection, medicinal drip, suppository, patch, or spray, but are not limited thereto. These formulations may be prepared easily by a method commonly used in the art and surfactant, vehicle, hydrating agent, emulsification accelerator, suspension, salt or buffer for osmotic pressure control, colorant, flavor, stabilizer, antiseptic, preservative, or other commonly used adjuvants may be used adequately.

(27) The active ingredient of the pharmaceutical composition according to the present invention will vary depending on the age, gender, body weight, pathological condition, and severity of a subject, administration route or discretion of a diagnoser. Determination of the administration dosage considering these factors is in the level of those skilled in the art. A daily dosage may be, for example, 0.1 mg/kg/day to 100 mg/kg/day, more specifically 5 mg/kg/day to 50 mg/kg/day, but is not limited thereto.

(28) In an aspect, the present invention provides a composition for external application to skin comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient. In another aspect, the present invention provides a food composition comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof as an active ingredient. In an aspect of the present invention, the food composition may be a health functional food composition.

(29) Formulations of the food composition according to the present invention are not particularly limited. For example, it may be formulated into a tablet, a granule, a powder, a liquid such as a drink, a caramel, a gel, a bar, and the like. The food composition of each formulation may comprise, in addition to the active ingredient, ingredients, according to the desired object, commonly used in the art that can be selected by those skilled in the art without difficulty. When applying other ingredients together, a synergic effect may be achieved.

(30) In the food composition according to the present invention, determination of the administration dose of the active ingredient is within the level of those skilled in the art. For example, a daily dosage may be 0.1 mg/kg/day to 5000 mg/kg/day, more specifically, 1 mg/kg/day to 500 mg/kg/day. However, without being limited thereto, the administration dose may vary depending on various factors such as the age and health conditions of the subject, presence of complication(s), and the like.

(31) For example, the food composition according to the present invention may be various foods such as a chewing gum, a caramel, a candy, a popsicle, confectionery, and the like, drinks such as a soft drink, a mineral water, an alcohol beverage, and the like, or health functional foods comprising vitamin, mineral, and the like.

(32) In addition, the food composition according to the present invention may comprise various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and extenders (cheese, chocolate, and the like), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH control agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. Further, the functional food composition of the present invention may comprise pulps used to prepare natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients may be used independently or in combination. The content of these additives is of no great importance. Usually, they are comprised within a range of about 0 parts by weight to 20 parts by weight based on 100 parts by weight of the composition of the present invention.

EXAMPLES

(33) Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are for illustrative purposes only and the scope of the present invention is not limited by the examples and experimental examples.

[Example 1] Preparation of 5-tert-butyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic Acid Amide

(34) ##STR00005##

(35) 5-tert-butyl-2,4-dimethoxy-benzoic acid (0.5 g, 2.1 mmol) was dissolved in dichloromethane (20 mL). 2,4-dihydroxy-benzyl-amine acetate (0.46 g, 1.1 equivalent weight), HATU (=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate, 0.95 g, 1.2 equivalent weight) and DIPEA (=N,N-Diisopropylethylamine, 0.73 ml, 2 equivalent weight) were added and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was diluted with water (20 ml). After the organic layer was washed with the diluted hydrochloric acid solution, sodium bicarbonate solution and saturated aqueous sodium chloride solution, the mixture was dried by anhydrous magnesium sulfate. Then, the mixture was filtered and concentrated under reduced pressure. The residue was separated using column chromatography to obtain the desired product (0.49 g) as a white solid.

(36) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as 5-tert-butyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy benzoic acid amide.

(37) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.52 (brs, NH), 8.11 (s, 1H), 7.28 (s, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.40 (d, J=8.4 Hz, 1H), 6.32 (dd, J=8.1 Hz, J=2.4 Hz, 1H), 4.43 (d, J=6.6 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 1.34 (s, 9H).

[Example 2] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-methyl-benzoic Acid Amide

(38) ##STR00006##

(39) A method which was substantially same method used in example 1 was used except for using 5-methyl-2,4-dimethoxy-benzoic acid (0.4 g, 2.04 mmol) instead of 5-tert-butyl-2,4-dimethoxy-benzoic acid (2.1 mmol) and using 2,4-dihydroxy-benzylamine hydrochloride (0.39 g, 1.1 eq.) instead of 2,4-hydroxy benzylamine acetate (0.46 g, 1.1 eq.) so that the desired product was obtained as a white solid (0.48 g).

(40) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-methyl-benzoic acid amide.

(41) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.51 (s, OH), 8.57 (bs, NH), 7.69 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 6.65 (s, 1H), 6.27 (s, 1H), 6.12 (d, J=8.4 Hz, 1H), 4.29 (d, J=5.4 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H) and 2.08 (s, 3H).

[Example 3] Preparation of 5-bromo-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic Acid Amide

(42) ##STR00007##

(43) A method which was substantially same method used in Example 1 was used except for using 5-bromo-2,4-dimethoxy-benzoic acid (4 g, 15.3 mmol) instead of 5-tert-butyl-2,4-dimethoxy-benzoic acid (2.1 mmol) and using 2,4-dihydroxy-benzylamine hydrochloride (3.36 g, 1.1 eq.) instead of 2,4-hydroxy benzylamine acetate (0.46 g, 1.1 eq.) so that the desired product was obtained as a white solid (4.68 g).

(44) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as 5-bromo-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide.

(45) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.59 (s, OH), 9.14 (s, OH), 8.53 (bs, NH), 8.00 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.28 (s, 1H), 6.15 (d, J=8.1 Hz, 1H), 4.31 (d, J=5.4 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H).

[Example 4] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-phenyl-benzoic Acid Amide

(46) A method which was substantially same method used in Example 1 was used except for using 4,6-dimethoxy-biphenyl-3-carboxylic acid (0.05 g, 0.19 mmol) instead of 5-tert-butyl-2,4-dimethoxy-benzoic acid (2.1 mmol) so that the desired product was obtained as a white solid (0.053 g).

(47) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-phenyl-benzoic acid amide.

(48) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.66 (s, OH), 9.15 (s, OH), 8.59 (bs, NH), 7.84 (s, 1H), 7.40 (m, 4H), 7.32 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 6.30 (s, 1H), 6.17 (dd, J=8.1 Hz, J=1.8 Hz, 1H), 4.33 (d, J=5.4 Hz, 2H), 4.01 (s, 3H), 3.87 (s, 3H).

[Example 5] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-methoxy-phenyl) Benzoic Acid Amide

(49) ##STR00008##

(50) 5-bromo-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide (0.42 g, 1.1 mmol) obtained in Example 3 and 4-methoxy benzene boronic acid (0.2 g, 1.3 mmol) were dissolved in toluene (20 ml) and ethanol (20 ml). 2 M sodium carbonate solution (2 ml) was added to the solution. Then tetrakis (triphenylphosphine)-palladium (0) (0.04 g, 3 mol %) was added as a catalyst. The mixture was refluxed at 100 C. for 6 hours. After completion of the reaction, the mixture was diluted with water and then was extracted with dichloromethane. Then the organic layer was dried under anhydrous magnesium sulfate to be concentrated under reduced pressure. The residue was separated using column chromatography to obtain the desired product (0.1 g) as a white solid.

(51) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-methoxy-phenyl) benzoic acid amide.

(52) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.68 (s, OH), 9.17 (s, OH), 8.59 (brs, NH), 7.81 (s, 1H), 7.36-7.34 (m, 2H), 6.90-6.93 (m, 3H), 6.79 (s, 1H), 6.28 (s, 1H), 6.18-6.15 (m, 1H), 4.33-4.31 (m, 2H), 3.99 (s, 3H), 3.86 (s, 3H), 3.77 (s, 3H).

[Example 6] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-fluoro-phenyl)-benzoic Acid Amide

(53) ##STR00009##

(54) A method which was substantially same method used in Example 5 was used except for using 4-fluorobenzene boronic acid (0.18 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a white solid (0.1 g).

(55) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(4-fluoro-phenyl)-benzoic acid amide.

(56) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.14 (s, 1H), 8.58 (brs, 1H), 7.82 (m, 1H), 7.46-7.44 (m, 2H), 7.23-7.19 (m, 2H), 6.95-6.93 (m, 1H), 6.82 (s, 1H), 6.28 (s, 1H), 6.18-6.15 (m, 1H), 4.31 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H).

[Example 7] Preparation of 5-benzo[1,3]dioxol-5-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic Acid Amide

(57) ##STR00010##

(58) A method which was substantially same method used in Example 5 was used except for using 3,4(-methylenedioxy)phenyl boronic acid (0.22 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a white solid (0.11 g).

(59) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as 5-benzo[1,3]dioxol-5-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide.

(60) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.64 (s, 1H), 9.14 (s, 1H), 8.58-8.54 (m, 1H), 7.79 (s, 1H), 7.65-7.54 (m, 2H), 6.97-6.78 (m, 3H), 6.29 (s, 1H), 6.18-6.15 (m, 1H), 6.03 (s, 2H), 4.32 (m, 2H), 3.99 (s, 3H), 3.87 (s, 3H).

[Example 8] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,5-dimethyl-phenyl) Benzoic Acid Amide

(61) ##STR00011##

(62) A method which was substantially same method used in Example 5 was used except for using 3,5-dimethylphenyl boronic acid (0.20 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a white solid (0.1 g).

(63) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,5-dimethyl-phenyl) benzoic acid amide.

(64) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.14 (s, 1H), 8.57 (brs, 1H), 7.80 (s, 1H), 7.00 (s, 2H), 6.95-6.93 (m, 2H), 6.79 (s, 1H), 6.28 (s, 1H), 6.18-6.15 (m, 1H), 4.33-4.31 (m, 2H), 4.00 (s, 3H), 3.86 (s, 3H), 2.29 (s, 6H).

[Example 9] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,4-difluoro-phenyl) Benzoic Acid Amide

(65) ##STR00012##

(66) A method which was substantially same method used in Example 5 was used except for using 3,4-difluorophenyl boronic acid (0.20 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a white solid (0.05 g).

(67) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3,4-difluoro-phenyl) benzoic acid amide.

(68) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.15 (s, 1H), 8.57 (brs, 1H), 7.84 (m, 1H), 7.49-7.47 (m, 2H), 7.27 (brs, 1H), 6.95-6.91 (m, 1H), 6.82 (s, 1H), 6.28 (s, 1H), 6.16 (s, 1H), 4.31 (m, 2H), 4.01 (s, 3H), 3.88 (s, 3H).

[Example 10] Preparation of N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3-nitro-phenyl) Benzoic Acid Amide

(69) ##STR00013##

(70) A method which was substantially same method used in Example 5 was used except for using 3-nitrophenyl boronic acid (0.22 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a solid (0.12 g).

(71) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-5-(3-nitro-phenyl) benzoic acid amide.

(72) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.62 (s, 1H), 9.17 (s, 1H), 8.55 (brs, 1H), 8.26-7.57 (m, 5H), 6.93-6.88 (m, 1H), 6.81 (m, 1H), 6.29 (s, 1H), 6.15 (m, 1H), 4.30 (m, 2H), 4.02 (s, 3H), 3.95 (s, 3H).

[Example 11] Preparation of 5-cyclohexene-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic Acid Amide

(73) ##STR00014##

(74) A method which was substantially same method used in Example 5 was used except for using 1-cyclohexene-1-yl-boronic acid pinacol ester (0.27 g) instead of 4-methoxy-benzene boronic acid (0.2 g, 1.3 mmol) so that the desired product was obtained as a solid (0.2 g).

(75) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as 5-cyclohexene-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide.

(76) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.65 (s, 1H), 9.13 (s, 1H), 8.52 (brs, 1H), 7.64 (s, 1H), 6.94-6.90 (m, 1H), 6.66 (m, 1H), 6.27 (m, 1H), 6.17-6.15 (m, 1H), 5.63 (s, 1H), 4.29 (m, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 2.23 (m, 2H), 2.11 (m, 2H), 1.61 (m, 4H).

[Example 12] Preparation of 5-cyclohexyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic Acid Amide

(77) ##STR00015##

(78) 5-cyclohexene-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide (0.1 g) obtained in Example 11 was dissolved in ethanol (10 ml). Then 5% palladium-activated carbon catalyst was put in the solution. Then the reduction reaction was performed for 4 hours under hydrogen pressure. The reaction mixture was filtered using Celite, and then was concentrated under reduced pressure, thereby obtaining the desired product (0.09 g) as a white solid.

(79) NMR results were confirmed as below. From the confirmation results as below, the white solid was confirmed as 5-cyclohexyl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide.

(80) .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.69 (s, 1H), 9.15 (s, 1H), 8.55 (brs, 1H), 7.76 (s, 1H), 6.96-6.94 (m, 1H), 6.29 (m, 1H), 6.19-6.16 (m, 1H), 4.31 (m, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 2.79 (m, 1H), 1.80-1.65 (m, 5H), 1.40-1.10 (m, 5H).

[Experimental Example 1] Effect of Reducing Melanin Production in Melanocytes

(81) The effect of inhibiting melanin production of the benzoic acid amide derivative compounds prepared in Examples in melanocytes was measured according to the Dooley's method. Mouse-derived B16F10 melanoma cells acquired from the Korean Cell Line Bank were used as cell lines. DMEM (Cat No. 11995), FBS (Cat No. 16000-044), and antibiotic-antifungal agents (Cat No. 15240-062) necessary for cell culturing were purchased from Invitrogen (GIBCO). The cell lines were cultured under the condition of 37 C. and 5% CO.sub.2. The cultured B16F10 cells were detached using 0.05% trypsin-EDTA and inoculated onto a 48-well plate with the same cell number (110.sup.4 cells/well). From the next day, the culture medium was replaced with one containing 10 ppm of each compound of Examples for three consecutive days. Rucinol (Tokyo Chemical Industry (Japan, Cat. No. B3773)) exhibiting excellent whitening ingredient was used as a positive control. After 5 days, melanin was melted and extracted from the cells by treating with 1 N NaOH at 60 C. for 2 hours, which was quantitated by measuring absorbance at 405 nm. The concentrations (IC.sub.50) of Examples required to inhibit melanin production in melanocytes to half were calculated and are given in the following Table 1.

(82) TABLE-US-00001 TABLE 1 Test material IC.sub.50 Rucinol IC.sub.50 = 0.8 M Example 1 IC.sub.50 = 2.3 M Example 5 IC.sub.50 = 0.7 M Example 6 IC.sub.50 = 0.7 M Example 7 IC.sub.50 = 0.7 M Example 8 IC.sub.50 = 1.5 M Example 9 IC.sub.50 = 0.6 M Example 10 IC.sub.50 = 1.3 M Example 11 IC.sub.50 = 0.9 M Example 12 IC.sub.50 = 2.1 M

(83) As seen from above, the compounds of Examples exhibit excellent inhibition ability of melanin production as rucinol. Accordingly, it can be seen that the benzoic acid amide derivative compounds according to the present invention have excellent skin whitening effect by reducing melanin production.

[Experimental Example 2] Effect of Inhibiting Mushroom Tyrosinase Activity

(84) The effect of inhibiting mushroom tyrosinase activity of the benzoic acid amide derivative compounds of Examples was measured according to the method of Vanni, et al. Specifically, 49.5 L of 0.1 M potassium phosphate buffer (pH 6.8), 45 L of distilled water (DW), 0.5 L (10 units) of mushroom tyrosinase (SIGMAT-7755), and 5 L of each benzoic acid amide derivative compound of Examples were mixed and reacted at 37 C. for 10 minutes by mixing with 50 L of 0.3 mg/mL tyrosine aqueous solution in a 96-well plate (total volume: 150 L). Rucinol and 5-adamantane-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxy-benzoic acid amide were used as a positive control. In particular, 5-adamantane-1-yl-N-(2,4-dihydroxy-benzyl)-2,4-dimethoxy-benzoic acid amide was a material synthesized by the present inventors, which was described in the US Patent Publication No.: US20140234241A1 which exhibits an excellent whitening effect thereof. Absorbance of the reaction solution was measured at 480 nm, and the concentrations of Examples required to inhibit tyrosinase activity to 50% (IC.sub.50) were calculated and are given in the following Table 2.

(85) TABLE-US-00002 TABLE 2 Test material IC.sub.50 Rucinol 0.06 M 5-adamantane-1-yl-N-(2,4-dihydroxybenzyl)-2,4- 0.31 M dimethoxy-benzoic acid amide Example 1 0.19 M Example 2 0.15 M Example 3 0.18 M Example 4 0.07 M Example 5 0.06 M Example 6 0.06 M Example 7 0.07 M Example 8 0.05 M Example 9 0.06 M Example 10 0.07 M Example 11 0.12 M Example 12 0.12 M

(86) As seen from above, the benzoic acid amide derivative compounds of Examples have excellent effect of inhibiting mushroom tyrosinase activity. Their effects as inhibiting activity were equal to or more than rucinol and were superior compared to benzoic acid amide derivatives in which 5-adamantyl group was substituted, as described in US20140234241A1. Accordingly, it can be seen that the benzoic acid amide derivative compounds according to the present invention have excellent skin whitening effect by inhibiting tyrosinase activity.

(87) Hereinafter, formulation examples of a composition comprising the compound, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, or the solvate thereof according to the present invention will be described in detail. However, the composition can be applied in various types of formulations. Thus, the following formulation examples are for illustrative purposes only, and the scope of the present invention is not limited thereby.

[Formulation Example 1] Cosmetic Water

(88) A cosmetic water was prepared according to a commonly used method with the composition described in the following Table 3.

(89) TABLE-US-00003 TABLE 3 Ingredient Content (wt %) Example 0.1 Glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 PEG 12 nonylphenyl ether 0.2 Polysorbate 80 0.4 Ethanol 10.0 Triethanolamine 0.1 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 2] Nourishing Cream

(90) A nourishing cream was prepared according to a commonly used method with the composition described in the following Table 4.

(91) TABLE-US-00004 TABLE 4 Ingredient Content (wt %) Example 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 hydrogenated castor oil 2.0 Liquid paraffin 10.0 Squalane 5.0 Caprylic/capric triglyceride 5.0 Glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 3] Massage Cream

(92) A massage cream is prepared according to a commonly employed method with the composition described in the following Table 5.

(93) TABLE-US-00005 TABLE 5 Ingredient Content (wt %) Example 1.0 Beeswax 10.0 Polysorbate 60 1.5 PEG 60 hydrogenated 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 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 4] Pack

(94) A pack is prepared according to a commonly employed method with the composition described in the following Table 6.

(95) TABLE-US-00006 TABLE 6 Ingredient Content (wt %) Example 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 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 5] Gel

(96) A gel is prepared according to a commonly employed method with the composition described in the following Table 7.

(97) TABLE-US-00007 TABLE 7 Ingredient Content (wt %) Example 0.5 Sodium ethylenediaminetetraacetate 0.05 Glycerin 5.0 Carboxyvinyl polymer 0.3 Ethanol 5.0 PEG 60 hydrogenated castor oil 0.5 Triethanolamine 0.3 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 6] Ointment

(98) An ointment is prepared according to a commonly employed method with the composition described in the following Table 8.

(99) TABLE-US-00008 TABLE 8 Ingredient Content (wt %) Example 1.5 Glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 -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 Beeswax 4.0 Antiseptic, pigment and flavor Adequate Purified water Balance

[Formulation Example 7] Health Food

(100) TABLE-US-00009 Example 1000 mg Vitamin mixture Vitamin A acetate 70 g Vitamin E 1.0 mg Vitamin B1 0.13 mg Vitamin B2 0.15 mg Vitamin B6 0.5 mg Vitamin B12 0.2 g Vitamin C 10 mg Biotin 10 g Nicotinamide 1.7 mg Folic acid 50 g calcium pantothenate 0.5 mg Mineral mixture Ferrous sulfate 1.75 mg Zinc oxide 0.82 mg Magnesium carbonate 25.3 mg The first potassium phosphate 15 mg The second calcium phosphate 55 mg Potassium citrate 90 mg Calcium carbonate 100 mg Magnesium chloride 24.8 mg

(101) The composition ratio of the mixture of vitamins and minerals is relatively suitable for mixing the components in a healthy foods as preferred formulation examples, but the mixing ratio may be modified optionally.

[Formulation Example 8] Health Beverage

(102) TABLE-US-00010 Example 1000 mg Citric acid 1000 mg Oligosaccharides 100 g Taurine 1 g Purified water Balance

(103) The above ingredients were mixed according to a conventional method of preparing health beverage, and then heated and stirred at 85 C. for about 1 hour. Then the prepared solution was filtered and sterilized.

[Formulation Example 10] Tablet

(104) 100 mg of Example, 50 mg of soybean extract, 100 mg of glucose, 50 mg of red ginseng extract, 96 mg of starch, and 4 mg of magnesium stearate were mixed, and 40 mg of 30% ethanol was added to the mixture to form granules. Then granules were dried at 60 C. and pressed into tablets using a tablet press machine.

[Formulation Example 10] Granule

(105) 100 mg of Example, 50 mg of soybean extract, 100 mg of glucose, and 600 mg of starch were mixed, and 100 mg of 30% ethanol was added to the mixture to form granules. Then granules were dried at 60 C. to prepare granules and then were filled in bags.