TWI426926B - Skin whitening compounds and skin compositions - Google Patents

Description

Skin whitening compound and skin composition

The present invention relates to a cosmetically or medically useful compound, and more particularly to a skin whitening compound, and a skin composition containing the same.

In general, skin color is determined by several physiological factors, one of which is the amount of melanin present in the skin. If the melanin content is higher, the skin tone will be darker. Therefore, the research and development direction of the whitening field in the past few decades has focused on how to reduce the content of melanin in the skin, in order to achieve skin whitening effect.

Tyrase is an important enzyme in melanin biosynthesis, so if the activity of tyrosinase is inhibited or reduced, the amount of melanin synthesized can be reduced.

Many whitening ingredients on the market, such as ellagic acid, citric acid and arbutin, are all tyrosinase inhibitors. Among them, ellagic acid and citric acid can chelate the copper ions in the activated region, so that tyrosinase loses its activity, while arbutin can prevent melanin synthesis by reacting with tyrosinase and the substrate through a competitive inhibition mechanism.

Although the aforementioned ingredients have been widely used for many years, there is still a need for continuous improvement. For example, it is currently known that tannic acid can be made In addition to allergies, there is a risk of carcinogenicity, and the presence of hydroquinone in the molecular structure of arbutin may affect the human body by metabolizing cytotoxic hydroquinone after entering the human body.

Accordingly, although the existing whitening ingredients have achieved certain effects in use, there is still room for improvement in terms of effectiveness or safety.

One of the main objects of the present invention is to provide a skin whitening compound comprising the structure represented by the following formula (I) or (II) or a cosmetically acceptable salt thereof: Wherein, m and n are each independently an integer of 0 to 6, and when either of m and n is 0, X is directly bonded to a corresponding benzene ring; X is N, O or S; R ¹ and R ^{2 is} each independently hydrogen, hydroxy, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ hydroxyalkyl, halo, C ₁ - C ₁₂ haloalkyl, thiol, amine, C ₁ -C ₁₂ alkylamino, carboxyl, C ₆ -C ₂₀ aryl or C ₆ -C ₂₀ heteroaryl; and R ₃ is thiol, C _1- C ₁₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₂ alkoxy, halo, C ₁ -C ₁₂ haloalkyl, amine or C ₁ -C ₁₂ alkylamino.

The skin whitening compound of the present invention has superior or substantially equivalent activity and safety as compared with the existing whitening ingredients.

Further, the present invention provides a dermal composition comprising a pharmaceutically effective amount of the above-mentioned skin whitening compound and a pharmaceutically acceptable carrier, or substantially consisting of the above two components.

The following is a description of the definition of the terms of the present invention, the properties of the skin whitening compound and the composition, and the specific embodiments and examples of the present invention.

Term definition

First, some parts of the text describe the components and technical features of the present invention by using "a", "an", "an" or the like. The description is only for convenience of expression and provides a general description of the technical features of the present invention. The meaning of sex. Therefore, unless otherwise indicated, the description is to be understood to include one or at least one

In this article, the terms "including", "including" and "having" are non-exclusive and open tortuous. That is, a process, composition, or requirement that includes a series of plural constituent elements is not necessarily limited to those listed, but may include not explicitly listed However, it is a component of the process, composition or element. In addition, “substantially composed of” is mainly composed of certain features, components or elements, and there are no features, components or elements that will substantially change the distinctive features, but other Essentially altering the characteristics, components, or elements of distinctive features.

As used herein, unless otherwise specified, "or" means an inclusive "or" rather than an exclusive "or". For example, the following three cases satisfy the description of "A or B": A is true (or exists) and B is pseudo (or non-existent), A is false and B is true, and A and B are both true.

In the context of a specific number, the range is to be construed as including the value of the ends of the range, all sub-ranges in the range, and all values in the range. For example, the range C ₁ -C ₄ should include C ₁ , C ₂ , C ₃ , C ₄ and C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₂ -C ₃ , C ₂ -C ₄ , C ₃ -C ₄ .

As used herein, "skin whitening" refers to making the skin tone whiter, and the degree of change is preferably greater than 5%, more preferably greater than 10%, and more preferably greater than 20%, measured by the skin color analyzer. Further, "skin" refers to the surface covering tissue of a human or animal, including but not limited to the skin on the face, neck, chest, arms, back, legs, and scalp.

As used herein, "cosmetically acceptable salts" include dermatologically acceptable salts which do not cause high levels of skin to the user. Toxic salts. The skin whitening is determined by the chemical nature of the compound, and these salts can be prepared by an organic base, an inorganic base, an organic acid or an inorganic acid, and can be a single salt or a mixture of a plurality of salts.

"Hydroxy" means an -OH group.

"Alkyl" includes straight-chain or branched hydrocarbon groups and may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, and the like. Etc., and not limited to this.

The "cycloalkyl group" includes a cyclic alkyl group which may have a monocyclic or fused ring structure, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and the like, and are not limited thereto.

"Alkoxy" means a structure (-O-alkyl) bonded to an alkyl group through an oxygen atom, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Base, second butoxy, third butoxy, and the like.

"Hydroxyalkyl" means a straight-chain, branched or cyclic alkyl group in which at least one carbon atom is replaced by a hydroxy group, examples of which include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl Base, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and the like.

"Halo" means fluorine, chlorine, bromine or iodine.

"Haloalkyl" means a straight-chain, branched or cyclic alkyl group in which at least one carbon atom is replaced by a halogen group. If the number of halo substitutions Above 1, the respective halogen groups may be the same or different from each other. In the present invention, "haloalkyl" includes, but is not limited to, chloromethyl, bromomethyl, trifluoromethyl, 1-bromoethyl, 2,2 difluoroethyl, 2-chloro-2-fluoroethyl 2,2,2-trifluoroethyl.

"Thiol group" means a group containing a mercapto group (-SH).

"Amine" refers to a -NH ₂ group.

The term "alkylamino" refers to -NR ₂ wherein at least one R is alkyl and the other R can be alkyl or hydrogen.

"Carboxyl" means -COOH.

"Aryl" means an aromatic carbocyclic group which may be a single ring or a polycyclic ring formed by condensing or covalently bonding to each other, and may be substituted or unsubstituted. As used herein, "aryl" includes phenyl, naphthyl, biphenyl, and the like, and is not limited thereto.

"Heteroaryl" means a group in which at least one carbon atom of an aromatic carbocyclic ring is replaced by a hetero atom (eg, oxygen, nitrogen, sulfur), which may be monocyclic or fused or covalently bonded to each other. The polycyclic ring is formed and may be substituted or unsubstituted. As used herein, "heteroaryl" includes pyridine, pyrazine, pyrimidine, pyridazine, indole, oxazole, oxazole, thiazole, thiophene, furan, and the like, and is not limited thereto.

"Tyreninase inhibitor" refers to a molecule whose mechanism of action is mainly to inhibit the reaction catalyzed by tyrosinase.

"Pharmaceutically effective amount" means a therapeutic or medical cosmetic foot To achieve a beneficial or desired result, the pharmaceutically effective amount of the compound or composition for a particular mode of administration can be determined by one of ordinary skill in the art without undue experimentation, according to an in vitro or animal experiment. The result is calculated or estimated.

"Pharmaceutically acceptable salt" means an ionic compound wherein the main active compound is modified to form a salt of an acid or a base. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic groups such as amine groups, or inorganic or organic base salts of acidic groups such as carboxyl groups. For the preparation of pharmaceutically acceptable salts, see "Pharmaceutical Salts: Properties, Selection, and Use", P. Heinrich Stahl and Camille G. Wermuth, published by John Wiley & Sons Inc, March 2011, All of them are incorporated herein by reference.

"Pharmaceutically acceptable carrier" means a non-toxic and generally inert carrier which is used to carry the main active ingredient without adversely affecting the active ingredient. "Pharmaceutically acceptable carrier" is generally beneficial to the user for absorption without causing serious toxicity, allergies or the like. In addition, it may include various carriers, excipients, dispersing agents, thickening agents, diluents, etc. In order to facilitate the preparation of the active compound of the present invention into a topical skin application such as a cream, an ointment, a lotion, an emulsion, a cosmetic liquid, a mask, a gel, a solid foundation, an emulsified foundation or the like.

Skin whitening compound and skin composition

The present invention relates generally to a skin whitening compound comprising the structure of the following formula (I) or (II) or a cosmetically acceptable salt thereof:

Wherein m, n may be the same or different, and each is an integer from 0 to 6, ie 0, 1, 2, 3, 4, 5 or 6, for example m=1 and n=1; m=0 and n=0; m=0 and n=1; m=1 and n=0. When either of m and n is 0, the corresponding benzene ring in the structure of formula (I) is directly bonded to X.

When both m and n are 0, a compound of the formula:

When both m and n are 1, the following compound can be obtained:

In the structure of formula (I), X may be N, O or S.

Further, R ¹ and R ² are each a substituent on two benzene rings, which may be the same or different, and each may be hydrogen, a hydroxyl group, a C ₁ -C ₁₂ alkyl group, a C ₁ -C ₁₂ cycloalkyl group. , C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ hydroxyalkyl, halo, C ₁ -C ₁₂ haloalkyl, thiol, amine, C ₁ -C ₁₂ alkylamino, carboxyl, C _6- C ₂₀ aryl or C ₆ -C ₂₀ heteroaryl.

In one embodiment, R ¹ and R ² are each independently hydrogen, hydroxy, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₆ alkoxy.

In the present invention, the substitution positions of each of R ¹ and R ² on the two benzene rings are not particularly limited, and they may be the same (symmetric) or different (asymmetric), and may be located adjacent to the X on the benzene ring. The bit, meta or para position, for example, R ¹ and R ² are respectively located at the para position of the benzene ring.

In the structure of formula (II), R ₃ is thiol, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₂ alkoxy, halo, C ₁ -C ₁₂ halo Alkyl, amine or C ₁ -C ₁₂ alkylamino. Further, the position of R ₃ relative to the hydroxyl group may be an ortho, meta or para position.

In one embodiment, R ³ is C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl or thiol.

If R ¹ , R ² or R ^{3 is a} non-aromatic substituent, the number of carbon atoms may be 1-12, 1-10, 1-8, 1-6 or 1-3. If R ¹ or R ² is an aromatic substituent, the number of carbon atoms may be 6-20, 6-15 or 6-10.

In the present invention, if the compound of formula (I) or formula (II) includes the center of the palm, there may be different optical isomers. Interpreting the invention In the scope of the invention, it is considered that the invention encompasses all optical isomers, stereoisomers and tautomers of the compounds of formula (I) or formula (II).

In the present invention, the application method of the skin whitening compound is not particularly limited as long as the skin whitening effect can be achieved. In one embodiment, the skin whitening compound is administered orally. In one embodiment, it is applied directly to the skin.

In a preferred embodiment, the skin whitening compound of the present invention comprises the compounds listed below or a mixture thereof:

In the previously disclosed structure, Compound A and Compound B can be obtained by extraction from Gastrodia elata or chemically synthesized, and the relevant extraction method can be obtained. The method and the synthesis method can be found in the Republic of China Patent No. I369213, the entire contents of which are incorporated herein by reference. ACROS ORGANICS. Further, other compounds encompassed by the structure represented by the formula (I) or (II) can also be obtained by a person having ordinary knowledge in the art without reference to the preparation method of the above compound without undue experiment, and thus will not be described herein.

Further, the present invention provides a composition for skin comprising the aforementioned skin whitening compound and a pharmaceutically acceptable carrier.

In one embodiment, the pharmaceutically acceptable carrier comprises water, physiological saline, oil, fat, wax, alcohol, fatty acid, fatty acid alcohol, fatty acid ester, surfactant, coloring agent, moisturizing agent, Any one or combination of a thickener, an antioxidant, a viscosity stabilizer, a chelating agent, a buffer, a bactericide, a nutrient.

In one embodiment, the dermatological composition further comprises one or more advantageous ingredients including, but not limited to, a wrinkle remover, an anti-aging agent, a whitening agent, an anti-allergic agent, an antibiotic, an antibacterial agent, an antifungal agent, a vitamin , UV absorbers, perfumes, detoxification agents, sebum inhibitors, pigments, sunscreens, herbal extracts for whitening, or combinations thereof.

In one embodiment, the dermatological composition further comprises one or more of the following whitening ingredients to achieve synergistic or synergistic whitening effects: vitamin C magnesium phosphate, vitamin C glucoside, citric acid, arbutin, vitamin C sodium phosphate, Ellagic acid, chamomile extract, Chuanming Acid, potassium methoxysalicylate, 3-oxo-ethyl vitamin C, dipropyl biphenyl diol, cetyl tranexate, rhododendron and vitamin C tetraisopalmitate.

Example: Measurement of tyrosinase inhibition effect

The above compound AG and α-arbutin, β-arbutin, and citric acid (as a control example) were formulated into various concentrations of solutions such as 20 mM, 10 mM, 5 mM, 2.5 mM, 1.25 mM, 0.625 mM, and 0.3125 mM in DMSO. 30 μl of each was placed in a 96-well plate, then 100 μl of buffer (Na ₂ HPO ₄ -NaH ₂ PO ₄ , 67 mM, pH 6.8) was added and mixed for 5 minutes, followed by the addition of 20 μl of mushrooms. Tyrosinase (1250 U/mL) and 100 μl of L-tyrosine (1.25 mM) make the total volume 250 μl.

Thereafter, the ELx 808 ELISA analyzer was used to continuously detect at 475 nm for 30 minutes, and the absorbance of dopaquinone was recorded every 10 seconds. At least three replicates of each compound were measured, and the remaining tyrosinase was calculated by the following formula. Percentage of activity: tyrosinase residual activity (%) = (CB) / A × 100%

Among them, A is the absorbance at 475 nm of the control group; B is the absorbance at 475 nm before the reaction of the experimental group; C is the absorbance at 475 nm after the reaction of the experimental group.

In addition, the percentage of residual activity of tyrosinase was linearly regressed for different concentrations of the analyte in the 96-well plate to calculate the IC ₅₀ value (ie, the concentration at which 50% tyrosinase inhibition was achieved). The results are shown in Table 1. .

As can be seen from the data in Table 1, each of the examples of the present invention has an inhibitory effect on the enzyme level which is superior to or equivalent to the existing whitening component.

Example: Analysis of human melanocyte survival rate and melanin production inhibition ability

Cell culture: Human normal skin melanocytes (purchased from Cascade Biologics) were cultured in a 254 Medium (purchased from Cascade Biologics) containing human melanocyte growth additive (HMGS) in a 37 ° C, 5% CO ₂ incubator as the cells grew. Subculture is carried out at the end of eight minutes. When the test experiment was started, the cell culture medium was changed to melanocyte growth medium M2 (containing melanocyte growth medium M2 additive mixture).

Experimental method: 2×10 ⁵ cells/ml of cells were suspended in melanocyte growth medium M2, 0.1 ml was cultured in a 96-well plate to measure cell viability (MTT assay); 0.5 ml was cultured in a 24-well plate. Measure melanin.

Cell viability was measured: the plate was placed in a carbon dioxide incubator at 37 ° C overnight. Different concentrations of the sample (containing Compound A) were added, and the plate was placed in a carbon dioxide incubator at 37 ° C for 3 days. After the reaction was completed, the cell culture medium was removed, and 0.1 ml of a MTT (0.5 mg/ml) solution was added, and the mixture was further cultured in a carbon dioxide incubator at 37 ° C for 2 hours. The medium of the cell culture plate was then removed, and 200 μl of DMSO was added and allowed to stand for 10 minutes. The OD550 absorbance was measured with an optical analyzer (Molecular Devices Spectra Max M2). The measured MTT values were compared to the control group to define relative survival.

Melanin measurement: The culture plate was placed in a carbon dioxide incubator at 37 ° C overnight. Different concentrations of sample (containing compound A) were added. After the reaction is completed, the culture medium of the cell culture plate is removed and 0.3 ml of 1 N NaOH (70 ° C) was added to each well and placed in an oven at 50 ° C for 10 minutes. After the dissolved melanin was mixed, 0.2 ml to 96-well plate was taken, and the OD405 absorbance was measured. The measured absorbance values were compared to the control group to define the relative melanin content.

The relevant measurement data is shown in Table 2.

As is apparent from the data of Table 2, each of the examples of the present invention has a melanin production inhibitory effect superior to or equivalent to the existing whitening component at the cell level.

Example: Analysis of zebrafish melanin inhibition ability

According to the method described by Wen Zhihong et al., "Identifying melanogenesis inhibitors from Cinnamomum subavenium with in vitro and in vivo screening systems by targeting the human tyrosinase", Experimental Dermatology, 20, 242-248, and the method of the Republic of China Patent Application Publication No. 201117111 Analysis of the melanin inhibition ability of Compound A in zebrafish, the aforementioned references are hereby incorporated by reference in its entirety.

Table 3 lists the results of pixel analysis of Compound A with different concentrations of β-arbutin, while Table 4 shows the results of pixel analysis of Compound A and citric acid at various concentrations.

As can be seen from the data in Table 3, the whitening compound of the present invention has a melanin production inhibitory effect superior to β-arbutin at a lower concentration, and it is known from the data of Table 4 that the whitening of the present invention is at the same concentration. The melanin production inhibition effect of the compound is much higher In tannic acid.

As apparent from the above examples, the whitening compound of the present invention has an effect superior to or equivalent to the existing whitening ingredients. In addition, in the case of Compound A, the toxicity analysis report of Compound A (Report No.: FR-AC00266E, Project Code: TA00498) was carried out at the Biotechnology Development Center of the Foundation, and the mice were administered 1500, 3000 and 6000 respectively. After four days of mg/kg of Compound A and clinical observation, all the mice survived without any clinical symptoms during the period, and all the mice did not find any lesions related to the treatment of Compound A, and the whitening of the present invention was known. The compound also has no safety concerns and can be used as an additive for whitening or medical use.

Accordingly, the inventors have fully described the concept of specific embodiments and examples in the foregoing description. It is to be understood that those skilled in the art can make various changes, changes and modifications in the scope of the invention as defined by the appended claims. Therefore, the present invention is to be construed as being limited by the scope of the invention.

In addition, some of the features of the various embodiments described herein may also be provided in combination in a separate embodiment, and the various embodiments may be provided separately or in any sub-combination. In addition, the relevant values described in the range should include those in the range Each value.

Claims (6)

A use of a compound of the formula (I) or a cosmetically acceptable salt thereof for whitening: Wherein m and n are each independently an integer of 0 to 6, and when m and n are 0, X is directly bonded to a benzene ring; X is N, O or S; and R ¹ and R ² are each independently hydrogen. , hydroxy, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₆ alkoxy. The use of claim 1, wherein R ¹ and R ² are each independently located at a para position of the benzene ring. The use of claim 1, wherein R ¹ and R ² are the same. The use of claim 1, wherein m and n are each independently an integer from 0 to 3. The use according to claim 1, wherein the compound of the structure represented by the formula (I) or a cosmetically acceptable salt thereof is a tyrosinase inhibitor. The use according to claim 1, wherein the compound of the structure represented by the formula (I) or a cosmetically acceptable salt thereof can be further used in combination with at least one of the following components: vitamin C magnesium phosphate, vitamin C glucoside , citric acid, arbutin, vitamin C sodium phosphate, ellagic acid, chamomile extract, tranexamic acid, potassium methoxysalicylate, 3-oxo-ethyl vitamin C, dipropyl biphenyl diol, cetyl tranexate, rhododendron or vitamin C tetraisopalmitate.