KR100708613B1 - Phenyl imidazol sulfonamide derivatives and preparation method thereof and whitening cosmetic composition containing it - Google Patents

Abstract

The present invention relates to a phenyl imidazole sulfonamide derivative represented by the following formula (1), a preparation method thereof, and a cosmetic composition for skin whitening containing the same. More specifically, the phenyl imidazole sulfonamide derivative of the formula 1 according to the present invention improves pigmentation of the skin by inhibiting the activity of c-kit protein and inhibiting melanin production, thereby exhibiting an excellent whitening effect.

(Wherein

이다.) R =

to be.)

Phenyl imidazole sulfonamide, c-kit, melanin, whitening, cosmetics

Description

Phenyl imidazol sulfonamide derivatives and preparation method thereof and cosmetic preparation for skin whitening containing the same

1 is a graph of c-kit activity showing concentration-dependent inhibition by SU11248.

Figure 2 is a graph measuring the c-kit activity inhibition effect by the phenyl imidazole sulfonamide derivatives.

The present invention relates to a phenyl imidazole sulfonamide derivative represented by the following formula (1), a preparation method thereof, and a cosmetic composition for skin whitening containing the same. More specifically, the phenyl imidazole sulfonamide derivative of the formula 1 according to the present invention improves pigmentation of the skin by inhibiting the activity of c-kit protein and inhibiting melanin production, thereby exhibiting an excellent whitening effect.

Human skin color is complexly determined by red blood cells, carotene, and melanin in blood, but hyperpigmentation such as race skin color, blemishes, and freckles is influenced by melanin. Melanin in the epidermal layer, the outer skin of the skin, protects the skin organs under the dermis by acting as a sunscreen, and catches free radicals generated in the skin. . However, melanin produced by stress stimulation inside and outside the human body is a stable substance that does not disappear until it is released to the outside through skin keratinization even if the stress disappears. In addition, the production of free radicals in the skin is increased or inflammatory reactions are caused by polymerization of the enzymes such as tyrosinase and tyrosine or dopa in vivo. In the presence of ultraviolet rays or melanin production increases. In particular, ultraviolet rays may increase the production of melanin, which may partially cause melanin to develop into blemishes, resulting in undesired results, or even worse, may cause skin cancer and the like, and may pose a risk to life. Thus, many melanin production inhibitors such as ointments, creams, and lotions containing kojic acid, arbutin, glutathione, vitamin A, vitamin C, and the like have been developed and used. There is no situation. In addition, the hydroquinone-containing whitening agent has a certain whitening effect, but has a disadvantage in that its use is limited due to severe skin irritation.

c-kit is a cell surface protein belonging to the receptor type tyrosine kinase type III family and is known as a receptor for stem cell factor (SCF). Studies in white spotting and steel mice show that SCF / c-kit function is important for cell maintenance, hematopoiesis, pigmentation and reproduction. It is to play a role. As a result of the interaction between SCF / c-kit, c-kit protein has dimerization and diphosphates itself. Intracellular signal transduction then undergoes a Ras-Raf-MAP kinase cascade and finally activates Mitf (MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION FACTOR) to promote tyrosinase synthesis and melanin at melanocytes. Will induce production.

SCF / c-kit signal transduction is also involved in pigmentation induced by ultraviolet B, a mechanism that probably increases SCF expression in keratinocytes and c-kit expression in melanocytes, respectively. It seems to be related to Indeed, stimulation with ultraviolet B during cell culture of keratinocytes and melanocytes increases the expression of genes and proteins in SCF and c-kit. This phenomenon was also confirmed that when treated with ultraviolet B on the epidermis of human, the expression of SCF gene and protein was significantly increased in the exposed part compared to the part not exposed to ultraviolet B. The same is true for Brown's Guinea pigs, an excellent model for studying melanosite function. That is, when the inhibitory antibody against c-kit protein was injected subcutaneously (subepidermal), it was confirmed that the pigmentation induced by ultraviolet B is completely inhibited. Therefore, it can be seen that signaling of SCF / c-kit interactions is ultimately closely related to pigmentation (Hachiya et al., J. Invest Dermatol., 116: 578-586, 2001).

Accordingly, the present inventors have studied to develop a substance that effectively inhibits the c-kit protein on the surface of the melanosite in the skin while solving the disadvantages of the existing whitening agent, the phenyl imidazole sulfonamide derivative represented by the following formula (1) While inhibiting the activity of c-kit protein and at the same time confirmed that the effect of inhibiting melanin production is very excellent and completed the present invention.

Accordingly, an object of the present invention is to provide a novel phenyl imidazole sulfonamide derivative represented by the following general formula (1) as a substance showing a new whitening effect.

Another object of the present invention is to provide a method for preparing the compound.

In addition, another object of the present invention to provide a cosmetic composition for skin whitening containing the compound.

In order to achieve the above object, the present invention is characterized by providing a phenyl imidazole sulfonamide derivative represented by the following formula (1).

[Formula 1]

(Wherein

이다.) R =

to be.)

The phenyl imidazole sulfonamide derivative represented by Chemical Formula 1 may include (1) preparing sulfonyl chloride by refluxing sulfonic acid and thionyl chloride under an organic solvent; And (2) reacting the sulfonyl chloride produced in step (1) with aminophenyl imidazole under an organic solvent to prepare a phenylimidazole sulfonamide derivative.

Hereinafter, the present invention will be described in more detail.

Method for producing a phenyl imidazole sulfonamide derivative represented by the formula (1) according to the present invention is as shown in Scheme 1, (1) by the reflux reaction of sulfonic acid and thionyl chloride in an organic solvent (II) Preparing a sulfonyl chloride compound; And (2) reacting the sulfonyl chloride produced in step (1) with an organic base group and aminophenyl imidazole in an organic solvent to prepare a phenylimidazole sulfonamide derivative as compound (I) of Scheme 1 below; Characterized in that it comprises a.

(Wherein

이다.)R =

to be.)

Hereinafter, a method for preparing the phenyl imidazole sulfonamide derivative compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

(1) preparing a sulfonyl chloride as a compound (II) of Scheme 1 by refluxing sulfonic acid with thionyl chloride under an organic solvent.

Dichloromethane, tetrahydrofuran, methylformamide, toluene, benzene, etc. may be used as the organic solvent used in the step (1), and preferably, dichloromethane and tetrahydrofuran are mixed. At this time, the mixing ratio of dichloromethane and tetrahydrofuran is 1: 1 ~ 1: 5.

In addition, the reaction temperature in step (1) is 10 ~ 60 ℃, preferably 30 ℃, the reaction time is about 4 hours.

(2) preparing a phenylimidazole sulfonamide derivative as the compound (I) of Scheme 1 by reacting the sulfonyl chloride produced in step (1) with an organic base group and aminophenyl imidazole in an organic solvent.

The equivalent ratio of aminophenyl amidazole reacted with the sulfonyl chloride is 1: 1 to 1: 3. This is because if the equivalent ratio is less than 1: 1, the desired product cannot be obtained, and if it exceeds 1: 3, an excess of by-products are generated in addition to the desired product.

In addition, as the organic base used in the step (2) may be used an organic base such as triethylamine, morpholine, pyridine.

In addition, as the organic solvent used in step (2), methanol, ethanol, propanol, tetrahydrofuran, dichloromethane, and the like may be used, and a mixture of tetrahydrofuran and ethanol may be used to complete the reaction in the fastest time. It is preferable because it can be made. At this time, the mixing ratio of ethanol and tetrahydrofuran is preferably 1: 1 to 5: 1, more preferably 5: 1.

In addition, in step (2), the reaction temperature is about 10 to 60 ° C, preferably about 30 ° C.

The novel phenylimidazole sulfonamide derivatives according to the present invention may be contained in cosmetic compositions for skin whitening. At this time, the content is preferably contained in 0.01 to 20% by weight based on the total weight of the composition. This is difficult to obtain the effect at a concentration of less than 0.01% by weight, and may result in safety or formulation difficulties at concentrations above 20.0% by weight.

The cosmetic composition for skin whitening according to the present invention, in addition to the novel phenylimidazole sulfonamide derivative, does not impair the main effect aimed at by the present invention, and other whitening which may give a synergistic effect to the main effect. It may also contain a component or the like. Examples of such components include kojic acid, arbutin, ascorbic acid derivatives, and the like.

The composition according to the present invention may take the form of a solution, an emulsion, a viscous mixture or the like. That is, the cosmetic composition for whitening according to the present invention is not particularly limited in the formulation, for example, latex, cream, lotion, essence, pack, gel, powder, foundation, lotion, ointment, patch, beauty liquid, cleansing foam, Formulations such as cleansing cream, cleansing water, soap, spray, and the like.

In the cosmetic composition of the formulation, other components than the compound represented by the formula (1) can be suitably selected by those skilled in the art according to the formulation or use of other cosmetics without difficulty. In addition, the composition according to the present invention may contain a skin absorption promoting substance to increase the whitening effect.

In addition, the cosmetic composition of the present invention may include a component selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymer peptides, polymer polysaccharides, sphingolipids and seaweed extract.

You may mix | blend the cosmetic composition of this invention with the said essential component other components normally mix | blended with cosmetics as needed. Other components that may be added include fats and oils, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, fungicides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, flavorings, Blood circulation accelerators, cooling agents, restriction agents, purified water and the like.

In addition, the compounding component which may be added other than this is not limited to this, Although any component can be mix | blended within the range which does not impair the objective and effect of this invention, Preferably it is 0.01-3 weight% with respect to the total weight of a composition. Compounded.

Hereinafter, the present invention will be described in more detail with reference to the following Examples and Test Examples, but the scope of the present invention is not limited only to these examples.

Example 1 [4-t-butylphenyl] -N- (4-imidazol-1-ylphenyl) sulfonamide

4-t-butylphenyl sulfonic acid (10 g, 0.05 mol) and thionyl chloride (6.7 g, 0.06 mol) were dissolved in dichloromethane (100 mL) and refluxed for 5 hours. After completion of the reaction, dichloromethane (200 mL) was added dropwise to the residue, followed by washing with 100 mL of water. Then, dried over anhydrous manganese (100 g), filtered and concentrated to give 9.7 g (yield = 90%) of 4-t- butylphenyl sulfonyl chloride.

Next, 4-t-butylphenyl sulfonyl chloride (9.7 g, 0.04 mol) was dissolved in ethanol and triethylamine (5.0 g, 0.05 mol) was added dropwise, followed by 1.3 equivalent of 4- (1H-imidazole- 1-day) aniline (8.0 g, 0.05 mol) was dissolved in 20 ml of ethanol and slowly added dropwise and further stirred at 40 ℃ for 3 hours. After the reaction was completed, the reaction mixture was filtered, the reaction solution was concentrated, dissolved in 250 ml of dichloromethane, and washed with distilled water (100 ml). Then, dried over anhydrous manganese (100 g), filtered, concentrated to crystallize with hexane and filtered to give 12.2 g of [4-t-butyl phenyl] -N- (4-imidazol-1-yl phenyl) sulfonamide (yield) = 82%).

TLC (ethyl acetate: hexane = 10: 1); R _f = 0.59

¹ H NMR (DMSO-d ₆ ): 10.44 (s, 1H), 8.24 (s, 1H), 7.62 (m, 7H), 7.18 (d, 2H), 7.08 (s, 1H), 1.21 (s, 9H ).

Example 2 Phenyl-N- (4-imidazol-1-yl phenyl) sulfone amide

Phenyl-N- (4-imidazol-1-yl phenyl) sulfonamide (11.3 g) in the same manner as in Example 1, except that benzene sulfonic acid was used instead of 4-t-butylphenyl sulfonic acid in Example 1 , 79%) was obtained as an off-white solid.

TLC (ethyl acetate: hexane = 10: 1); R _f = 0.51

¹ H NMR (DMSO-d ₆ ): 10.41 (s, 1H), 8.28 (s, 1H), 7.79 (d, 2H), 7.58 (m, 6H), 7.17 (d, 2H), 7.05 (s, 1H ).

Example 3 Naphthyl-N- (4-imidazol-1-ylphenyl) sulfone amide

Naphthyl-N- (4-imidazol-1-yl phenyl) sulfonamide in the same manner as in Example 1, except that naphthyl sulfonic acid is used instead of 4-t-butylphenyl sulfonic acid in Example 1. 16.9 g, 75%) was obtained as an off-white solid.

TLC (ethyl acetate: hexane = 10: 1); R _f = 0.54

¹ H NMR (DMSO-d ₆ ): 10.58 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 8.06 (m, 3H), 7.69 (m, 4H), 7.46 (d, 2H ), 7.17 (d, 2H), 7.02 (s, 1H).

Example 4 [3,4-dimethoxy phenyl] -N- (4-imidazol-1-yl phenyl) sulfonamide

[3,4-dimethoxy phenyl] -N- (4 in the same manner as in Example 1, except that 3,4-dimethoxybenzene sulfonic acid was used instead of 4-t-butylphenyl sulfonic acid in Example 1 -Imidazol-1-yl phenyl) sulfonamide (17.1 g, 86%) was obtained as an off-white solid.

TLC (ethyl acetate: hexane = 10: 1); R _f = 0.53

¹ H NMR (DMSO-d ₆ ): 10.44 (s, 1H), 8.28 (s, 1H), 7.79 (d, 2H), 7.58 (m, 5H), 7.17 (s, 1H), 7.05 (s, 1H ), 3.76 (s, 6 H).

Example 5 [3-acetyl phenyl] -N- (4-imidazol-1-yl phenyl) sulfonamide

[3-acetyl phenyl] -N- (4-imidazole-1- in the same manner as in Example 1, except that 3-acetylbenzene sulfonic acid was used instead of 4-t-butylphenyl sulfonic acid in Example 1. One phenyl) sulfone amide (15.7 g, 81%) was obtained as an off-white solid.

TLC (ethyl acetate: hexane = 10: 1); R _f = 0.53

¹ H NMR (DMSO-d ₆ ): 10.40 (s, 1H), 8.27 (s, 1H), 7.73 (m, 7H), 7.13 (d, 2H), 7.01 (s, 1H), 2.12 (s, 3H ).

[Test Example 1] Effects of Phenylimidazole Sulfonamide Derivatives on Melanin Production in Melanocytes

In order to determine the melanin production inhibitory effect of the compounds obtained in Examples 1 to 5, the following experiment was performed.

At this time, the degree of melanin production in the cell was measured by Dooley's method, using hydroquinone and kojic acid as a positive control, and melanin production inhibition was measured in comparison with the compounds of Examples 1-5. The cell line was a Mel-Ab cell line (supplied from Dr Thomas P. Dooley) derived from skin pigment cells of C57BL / 6. The culture was performed in DMEM medium containing 10% fetal placental serum, 100 nM 12-O-tetradecanoyl Phobol-13-acetate, 1 nM Cholera Toxin, 37 ° C., 5% CO ₂ Under the conditions of. Cultured Mel-Ab cells were detached with 0.25% Trypsin-EDTA, plated on a 24-well vessel again with the same number (1 × 10 ⁵ cells / well), and then continued for three days from the second day. The test material was treated in a manner of replacing with a medium containing 10ppm samples (each compound of Examples 1 to 5, the positive control koji acid and hydroquinone). After 5 days of treatment with 1N NaOH to melt the melanin contained in the cells to measure the amount of melanin by measuring the absorbance at 400nm, the results are shown in Table 1 below.

Test substance Melanin production amount (%) Hydroquinone (HQ) 11.46 Kojisan 88.0 Compound of Example 1 12.00 Compound of Example 2 15.71 Compound of Example 3 26.67 Compound of Example 4 29.03 Compound of Example 5 23.20

As shown in Table 1, it was found that each of the compounds of Examples 1 to 5 exhibited the effect of inhibiting melanin production, and in particular, the compounds of Examples 1 and 2 had an excellent effect similar to that of hydroquinone. It could be seen that.

[Test Example 2] c-kit inhibitory effect of the phenyl imidazole sulfonamide derivative

2-1. Evaluation of c-kit activity and inhibitory effect by SU11248

In this Test Example 2-1, c-kit activity inhibitory effect using SU11248 (Sugen), which binds to c-kit specifically and inhibits its activity, together with the c-kit protein alone activity, to verify the system used for activity evaluation Was observed.

This experiment fan Verizon jet of a light ^TM kinase assay kit T Y Al 4 peptides one matching method proposed in (Panvera Z-lyte ^TM Kinase assay kit Tyr 4 peptide), the actual reaction temperature and time, the c-kit using Concentrations, ATP concentrations, etc. were conducted under optimized conditions.

First, 2 × ATP was dispensed in 5ul portions into a 384 well dish for fluorescence measurement. Subsequently, SU11248 made of 150 nM, 50 nM, 15 nM, 5 nM, 1.5 nM, and 0.5 nM, respectively, was treated using a 96-pin dish. To ensure the accuracy of the reaction, each sample was paired and the group without SU11248 / the group without c-kit / phospho-peptide 0% group / phospho-peptide Control experiments of the 100% group were also conducted at the same time. Thereafter, 5 μl of the solution containing the c-kit and the substrate peptide (peptide) mixed therein was dispensed for 5 minutes at 37 ° C. After the reaction was completed, the development solution was dispensed by 5ul each for 40 minutes at room temperature, and finally, 5ul of the stop solution was dispensed to complete the experiment. At this time, the final concentration of each material used in the reaction corresponds to ATP 500M, C-kit (Kinase) 1.5 ng, peptide 2M and SU11248 corresponds to the final concentration of 30nM, 10nM, 3nM, 1nM, 0.3nM, 0.1nM.

On the other hand, by measuring the fluorescence value of the reaction was completed samples to derive the inhibition rate of SU11248 to c-kit activity. The degree of enzyme activation can be measured by reading two fluorescence values using light activated through 405 nm and 535 nm filters, and calculating the ratio between them. The results are shown in Figure 1 below.

As can be seen in Figure 1, it was observed that the activity of c-kit was inhibited in a concentration-dependent manner of SU11248.

2-2. Inhibitory Effect of c-kit Activity by Phenylimidazole Sulfonamide Derivatives

Based on the c-kit activity evaluation system verification result of Test Example 2-1, the inhibition of c-kit activity by each compound of Examples 1 to 5 was compared. At this time, the reaction conditions were the same as in Test Example 2-1, the final concentration of each compound was 30uM, 10uM, 3uM, 1uM, 0.3uM, 0.1uM respectively. Inhibition rate derivation method was also as described above, the results are shown in FIG.

As can be seen in Figure 2, it was confirmed that each compound of Examples 1 to 5 inhibited the activity of c-kit in a concentration-dependent manner.

Test Example 3 Whitening Effect of Phenylimidazole Sulfonamide Derivatives on Human Skin

In order to investigate the whitening effect of the phenyl imidazole sulfonamide derivative of the present invention on the human skin, the following experiment was performed.

First of all, 12 healthy men were attached with an opaque tape with a hole of 1.5 cm in diameter in the upper part of the subject's upper arm and irradiated with 1.5 ~ 2 times of ultraviolet light (UVB) of the minimum erythema of each subject. Induced.

After the ultraviolet irradiation, 2% of each compound of Examples 1 to 5 (solvent is 1, 3-butylene glycol: ethanol = 7: 3), and hydroquinone and kojic acid were applied as a positive control for 10 weeks, and each week. The color of the skin was measured with a colorimeter (Colorimeter CR-300, Minolta, Japan) to evaluate the degree of increase of the "L" value ("ΔL"), and the results are shown in Table 2 below. The evaluation method judged that the higher the value of the improvement degree (pigment brightness) of pigmentation after use, the higher the relative whitening effect.

Test substance Skin color brightness degree (L) Solvent -6.0 Hydroquinone (HQ) -1.9 Kojisan -3.0 Example 1 -1.5 Example 2 -2.0 Example 3 -2.7 Example 4 -2.8 Example 5 -2.5

As shown in Table 2, it was found that each of the compounds of Examples 1 to 5 showed a whitening effect of brightening the skin color by improving pigmentation, and the effect was similar to hydroquinone and kojic acid used as positive controls. It could be seen that.

Hereinafter, an example of the formulation of a cosmetic composition for skin whitening according to the present invention will be described, but the present invention is not intended to limit the present invention, but is intended to be described in detail.

Formulation Example 1 Soap Preparation

Compound of Example 1 ..................... 1.00 (% by weight)

Maintenance .....................

Sodium hydroxide ...............

Sodium Chloride ...............

Spices ..................................

The whole amount was 100 with purified water, and soap was prepared by the above blending ratio (%).

Formulation Example 2 Lotion Preparation

Compound of Example 2 ......... 3.00 (% by weight)

L-ascorbic acid-2-phosphate magnesium salt ......... 1.00

Water Soluble Collagen (1% Aqueous Solution) ................. 1.00

Sodium Citrate ............... 0.10

Citric Acid ........................... 0.05

Licorice Extract ......... 0.20

1,3-butylene glycol ............ 3.00

The whole amount was 100 with purified water, and a lotion was prepared by the above blending ratio (%).

Formulation Example 3 Cream Preparation

Compound of Example 3 ...................................... 1.00 (% by weight)

Polyethylene Glycol Monostearate ............ 2.00

Self-emulsifying glycerin monostearate ............ 5.00

Cetyl Alcohol ... 4.00

Squalene ............... 6.00

Glyceryl tri2-ethylhexanoate ......... 6.00

Sphingose Glucose Lipid ......... 1.00

1.3-Butylene Glycol ............ 7.00

The total amount was 100 with purified water, and a cream was prepared at the blending ratio (%).

Formulation Example 4 Pack Preparation

Compound of Example 4 .................. 5.00 (% by weight)

Polyvinyl Alcohol ........................ 13.00

L-ascorbic acid-2-phosphate magnesium salt .............. 1.00

Lauroylhydroxyproline ......... 1.00

Water Soluble Collagen (1% Aqueous Solution) ... 2.00

1,3-butylene glycol ...... 3.00

Ethanol ......................... 5.00

The total amount was 100 with purified water, and a pack was prepared at the blending ratio (%).

Formulation Example 5 Preparation of Cosmetic Solution

Compound of Example 5 ... 2.00 (% by weight)

Hydroxyethylene Cellulose (2% Aqueous Solution) ......... 12.00

Xanthan gum (2% aqueous solution) ........................ 2.00

1,3-butylene glycol ............... 6.00

Concentrated Glycerin ... 4.00

Sodium hyaluronate (1% aqueous solution) ........ 5.00

The whole amount was 100 with purified water, and a cosmetic liquid was prepared at the blending ratio (%).

Formulation Example 6 Preparation of Ointment

Compound of Example 1 ............ 2.00 (% by weight)

Lanolin Alcohol ........... 1.00

Stearyl Alcohol ................................. 2.00

Seta Aretsu-20 ..................... 2.00

Perlatum ... 84.5

Lecithin ............... 1.50

Caprylic / Capric Triglycerides ......... 2.00

PEG20 Corn Glyceride ......... 5.0

As described above in detail specific parts of the present invention, it is apparent to those skilled in the art that such specific descriptions are merely preferred embodiments, and thus the scope of the present invention is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

As described above, the phenyl imidazole sulfonamide derivative of the present invention has the effect of improving the pigmentation of the skin by inhibiting melanin production by c-kit inhibitory action, thereby showing a whitening effect. Therefore, the cosmetic composition for skin whitening containing the phenyl imidazole sulfonamide derivative according to the present invention can be used as a composition useful for improving pigmentation of hyperpigmentation, freckles, spots and the like.

Claims (4)

A phenyl imidazole sulfonamide derivative represented by the following formula (1). [Formula 1]

(Wherein R =

to be.) (1) reacting sulfonic acid with thionyl chloride under reflux in an organic solvent to prepare sulfonyl chloride, which is the compound of formula (II) below; And (2) reacting the sulfonyl chloride produced in step (1) with an organic base group and aminophenyl imidazole in an organic solvent to prepare a phenylimidazole sulfonamide derivative as compound (I) of Scheme 1 below; Method for producing a phenyl imidazole sulfonamide derivative of the formula (1) comprising a. Scheme 1

(Wherein R =

to be.) A cosmetic composition for skin whitening comprising a phenyl imidazole sulfonamide derivative represented by the following formula (1). [Formula 1]

(Wherein R =

to be.) The cosmetic composition for skin whitening according to claim 3, wherein the composition contains the phenyl imidazole sulfonamide derivative in an amount of 0.01-20% by weight based on the total weight of the composition.

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