WO2007089069A1

WO2007089069A1 - Phenyl imidazol sulfonamide derivatives, the preparation method thereof and the whitening cosmetic composition containing the same

Info

Publication number: WO2007089069A1
Application number: PCT/KR2006/004763
Authority: WO
Inventors: Heung Soo Baek; Ho Sik Rho; Soo Mi Ahn; Yong Joo Na; Duck Hee Kim; Ih Seop Chang
Original assignee: Amorepacific Corporation
Priority date: 2006-01-31
Filing date: 2006-11-14
Publication date: 2007-08-09
Also published as: KR100708613B1

Abstract

The present invention relates to phenyl imidazol sulfonamide derivatives expressed by the above formula I and a method for producing the same, and a whitening cosmetic composition comprising the same. More particularly, the phenyl imidazol sulfonamide derivatives of Formula I according to the present invention inhibit activity of c-kit protein and synthesis of melanin, thereby preventing pigmentation and showing excellent whitening effect.

Description

[DESCRIPTION]

[Invention Title]

Phenyl imidazol sulfonamide derivatives, the preparation method thereof and the whitening cosmetic composition containing the same [Technical Field]

The present invention relates to phenyl imidazol sulfonamide derivatives expressed by the following formula I and a method for preparing the same, and a whitening cosmetic composition comprising the same. More particularly, the present invention relates to phenyl imidazol sulfonamide derivatives of the following formula I for inhibiting activity of c-kit protein and production of melanin to improve pigmentation on skin, thereby providing whitening effect. [Formula 1 ]

In which,

[Background Art]

The skin color of an individual is determined compositively by hematocyte in blood, carotene and melanin but the difference in the skin color between races or hyperpigmentation such as discoloration on the face and freckles is affected by melanin. The melanin which exists in the epidermis, the outer shell of the skin, intercepts the transmittance of UV rays to protect the skin organs under the dermis while capturing free radicals produced in the skin to protect proteins and genes in the skin. However, the melanin is a stable substance produced by stressful stimulation from the inside/outside of the body and remains in the skin until it is discharged by keratinization of the skin. Also, the production of the melanin is increased when free radical is generated in a large amount through polymerization oxidization using tyrosine or DOPA as a substrate in the presence of an enzyme such as tyrosinase as a catalyst, inflammatory response occurs or the body is exposed to UV rays. Particularly, the UV rays increase production of melanin and cause discoloration on the face due to partial increase of melanin, thereby injure the appearance. When it is severe, skin cancer can be induced to threaten the life. Therefore, a number of products for inhibiting melanin formation such as ointments, creams lotions containing kojic acid, albutin, glutathione, vitamin A, vitamin C and the like have been development and widely used but there is few whitening products consumers are satisfied with. Also, the whitening products containing hydroquinone show whitening effect to some degree but has limitative defect since they may cause irritation.

C-kit is a cell surface protein belonging to receptor tyrosine kinase type III and is known as a receptor of SCF (stem cell factor). According to the study in the White spotting and steel mouse, SCF/c-kit plays important roles in hematopoiesis, pigmentation, reproduction and the like, as well as cell maintenance. By the interaction between SCF/c-kit, the c-kit protein undergoes dimerization and phosphated spontaneously. Subsequently, it undergoes Ras-Raf-MAP kinase cascade in the signal transmission in the cell and finally activates Mitf (microphthalmia-associated transcription factor) to promote tyrosinase synthesis, inducing melanin formation in melanocyte.

The signal transmissions of SCF and c-kit are associated with the pigmentation induced by UV ray B and their mechanisms are believed to be probably connected with increase of SCF expression in keratinocyte and increase of C-kit expression in melanocyte, respectively. In deed, when the keratinocyte and melanocyte are stimulated by UV ray B during culture, it is found that expression of genes and proteins of SCF and c-kit is increased. Such phenomenon is also observed when the epidermis of human beings is treated with UV ray B, in which the part which has been exposed to UV ray B shows a significant increase in expression of genes and proteins of SCF, as compared to the part which has not been exposed to UV ray B. The result of the guinea pig test, which is an exemplary model in the study of functions of melanocyte showed the same result. That is, it is proven that when an antibody to inhibit expression of c-kit protein is injected subepidermally, the pigmentation induced by UV ray B is completely prevented. Therefore, ultimately, it is noted that the signal transmission of the SCF/c-kit interaction is closely associated with pigmentation (Hachiya et al, J. Invest Dermatol., 116:578-586, 2001). [Disclosure] [Technical problem]

Therefore, the present inventors have conducted research to develop a substance effectively inhibiting c-kit protein on the melanocyte surface of skin while addressing defects of the conventional whitening products and finally, found that the phenyl imidazol sulfonamide derivatives expressed by the following formula I is excellently effective in inhibiting c-kit protein activity and melanin production. Based on the above finding, the present invention has been completed.

Accordingly, it is an object of the present invention to provide a novel phenyl imidazol sulfonamide derivative expressed by the following formula I for showing whitening effect. [Formula 1]

In which,

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

It is a further object of the present invention to provide a whitening cosmetic composition comprising the above described compound.

[Technical solution] Accordingly, In order to accomplish the above objects, according to the present invention, there is provided a phenyl imidazol sulfonamide derivative expressed by the following formula I. [Formula I]

In which,

The phenyl imidazol sulfonamide derivative expressed by the above Formula I is prepared by the steps of (1) reacting sulfonic acid with Thionyl chloride at reflux in an organic solvent to prepare sulfonyl chloride; and (2) reacting the sulfonyl chloride prepared in the step (1) with aminophenyl imidazol in an organic solvent to prepare a phenyl imidazol sulfonamide derivative.

Now, the present invention is described in detail. The method for preparing the phenyl imidazol sulfonamide derivative expressed by the above formula I according to the present invention comprises the steps of (1) reacting sulfonic acid with Thionyl chloride at reflux in an organic solvent to prepare sulfonyl chloride (II); and (2) reacting the sulfonyl chloride prepared in the step (1) with aminophenyl imidazol and an organic base in an organic solvent to prepare a phenyl imidazol sulfonamide derivative (I), as shown in Scheme I. [Scheme 1 ]

In which,

Now, the method for preparing the phenyl imidazol sulfonamide derivative expressed by the above formula I according to the present invention is described in detail step by step.

(1) The step for reacting sulfonic acid with Thionyl chloride at reflux in an organic solvent to prepare sulfonyl chloride (II) The organic solvent which can be used in the step (1) includes dichloromethane, tetrahydrofuran, methyl, toluene, benzene and the like, with preference being a mixture of dichloromethane and tetrahydrofuran. Here, the mixing ratio of dichloromethane and tetrahydrofuran is 1 :1 to 1 :5 °1¹^.

Also, the reaction temperature in the step (1) is 10 to 60 ^°C, preferably 30^°C and the reaction time is about 4 hours.

(2) The step for reacting the sulfonyl chloride prepared in the step (1) with aminophenyl imidazol and an organic base in an organic solvent to prepare a phenyl imidazol sulfonamide derivative (I)

The equivalence ratio of sulfonyl chloride and aminophenyl imidazol is 1 :1 to 1 :3. If the equivalence ratio is less than 1 :1, the target compound cannot be produced. If the ratio exceeds 1:3, a large quantity of by-products in addition to the target compound can be produced.

Also, the organic base which can be used in the step (2) includes triethyl amine, morpholine, pyridine and the like. Also, the organic solvent which can be used in the step (2) includes methanol, ethanol, propanol, tetrahydrofuran, dichloromethane and the like. A mixture of tetrahydrofuran and ethanol is the most preferable, since the reaction can be completed in the fastest reaction time. Here, the mixing ratio of ethanol and tetrahydrofuran is preferably 1 :1 to 5:1, more preferably 5:1. Also, the reaction temperature in the step (2) is 10 to 60 ^°C, preferably

30^°C . The novel phenyl imidazol sulfonamide derivative according to the present invention can be contained in a whitening cosmetic composition. Here, the derivative is preferably contained in an amount of 0.01 to 20 wt% based on the total weight of the composition. This is because if the content is less than 0.01 wt%, the effect is deteriorated while if the content exceeds 20.0 wt%, there may be difficult in stability and formulation.

The whitening cosmetic composition according to the present invention may further comprise other whitening components which give synergic effect to the main effect of the present invention in addition to the effective ingredient within the range that it did not damage the main effect of the present invention. Such components include kojic acid, albutin, derivatives of ascorbic acid and the like.

The composition according to the present invention may be in the form of solution, emulsion, viscous mixture and the like. That is, the whitening cosmetic composition is not particularly limited in its formulation and may be formulated into milky liquid, cream, skin lotion, essence, pack, gel, powder, foundation, lotion, ointment, patch, beauty solution, cleansing foam, cleansing cream, cleansing water, soap, spray and the like.

In the formulation of the cosmetic composition according to the present invention, the other components than the compound of Formula I may be selected and combined properly by the person in the art without difficulty according to the formulation type or the final use. Also, the composition according to the present invention may comprise a skin absorption enhancer to increase the whitening effect. Also, the cosmetic composition according to the present invention may comprise any one selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high molecular weight peptides, high molecular weight polysaccharides, sphingolipid and algae extracts.

The cosmetic composition according to the present invention may further comprise other components which are commonly added to cosmetic compositions in addition to the essential component, as needed. Examples of the other components include oily components, moisturizing agents, emollients, surfactants, organic and inorganic pigments, organic dispersing agents, UV absorbents, preservatives, anti-bacteria agents, anti-oxidants, plant extracts, pH controlling agents, alcohol, colorants, fragrance, blood circulation enhancers, cooling agents, anti-perspirants, purified water and the like.

The components which can be combined to the composition are not limited to the foregoing and are preferably added in an amount of 0.01 to 3 wt%, based on the total weight of the composition, though it can be combined in an amount within the range that it did not damage the purpose and effect of the present invention.

[Description of Drawings]

Further objects and advantages of the invention can be more fully understood from the following detailed description taken in conjunction with the accompanying drawings, in which: FIG. 1 is a c-kit activity graph showing the concentration dependent inhibition by SUl 1248; and

FIG. 2 is a graph showing the c-kit activity inhibiting effect of phenyl imidazol sulfonamide derivatives.

[Best Mode] Now, the present invention is explained in detail by the following examples and experiment examples. However, the present invention is not limited thereto.

[Example 1]

[4-t-butylphenyl]-N-(4-imidazol-l-yl phenyl) sulfonamide 4-t-butylphenyl sulfonic acid (1Og, 0.05 mol) and thionyl chloride (6.7g, 0.06 mol) were dissolved in dichloromethane (100 mi) and refluxed for 5 hours. After completion of the reaction, to the residue, dichloromethane (200 mi) was added dropwise and water (100 mi) was added for washing. Then, the residue was dried with anhydrous manganese (10Og), filtered and concentrated to obtain 9.7 g of 4-t-butylphenyl sulfonyl chloride (yield = 90%). Then, 4-t-butylphenyl sulfonyl chloride (9.7g, 0.04 mol) was dissolved in ethanol. To the solution, triethylamine (5.0g, 0.05 mol) was added dropwise and 1.3 equivalent weight of 4-(lH-imidazol-l-yl)aniline (8.0g, 0.05 mol) dissolved in ethanol (20 mi) was slowly added dropwise. The solution was stirred further for 3 hours at 40 °C . After completion of the reaction, the reaction was filtered, concentrated, dissolved in dichloromethane (250 mi) and washed with distilled water (100 mi). Next, the solution was dried with anhydrous manganese (10Og), filtered, concentrated, crystallized with hexane and filtered to obtain 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

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

[Example 2] Phenyl-N-(4-imidazol-l-yl phenyl) sulfonamide Except for using benzene sulfonic acid instead of 4-t-butylphenyl sulfonic acid, the same procedures of Example 1 were performed to obtain phenyl-N-(4-imidazol-l-yl phenyl) sulfonamide (11.3g, 79%) as yellowish white solid. TLC(ethyl acetate:hexane = 10:1); R_f = 0.51

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

[Example 3] Naphthyl-N-(4-imidazol-l-yl phenyl) sulfonamide

Except for using naphthyl sulfonic acid instead of 4-t-butylphenyl sulfonic acid, the same procedures of Example 1 were performed to obtain naphthyl-N-(4-imidazol-l-yl phenyl) sulfonamide (16.9g, 75%) as yellowish white solid. TLC (ethyl acetate:hexane = 10: 1 ); R_f = 0.54

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

[Example 4] [3,4-dimethoxyphenyl]-N-(4-imidazol-l-yl phenyl) sulfonamide

Except for using 3,4-dimethoxy benzene sulfonic acid instead of 4-t- butylphenyl sulfonic acid, the same procedures of Example 1 were performed to obtain [3,4-dimethoxyphenyl]-N-(4-imidazol-l-yl phenyl) sulfonamide (17. Ig, 86%) as yellowish white solid. TLC (ethyl acetate:hexane = 10: 1 ); R_f = 0.53

¹H NMR (DMSO^₆): 10.44(s, IH), 8.28(s, IH), 7.79(d, 2H), 7.58(m, 5H), 7.17(s₉ IH), 7.05(s, IH), 3.76(s, 6H).

[Example 5]

[3-acetylphenyl]-N-(4-imidazol-l-yl phenyl) sulfonamide Except for using 3-acetyl benzene sulfonic acid instead of 4-t- butylphenyl sulfonic acid, the same procedures of Example 1 were performed to obtain [3-acetylphenyl]-N-(4-imidazol-l-yl phenyl) sulfonamide (15.7g, 81%) as yellowish white solid.

TLC (ethyl acetate:hexane = 10:1); R_f = 0.53 ¹H NMR (DMSO-d₆): 10.40(s, IH), 8.27(s, IH), 7.73(m, 7H), 7.13(d,

2H), 7.01(s, IH), 2.12(s, 3H).

[Experimental Example 1]

Inhibition effect of phenyl imidazol sulfonamide derivative on synthesis of melanin in melanocyte

In order to examine the inhibition effect of the compounds prepared in Examples 1 to 5 on synthesis of melanin, the following experiment was performed.

The production of melanin in melanocytes was measured by the Dooley method and hydroquinone and kojic acid were used as positive controls. The inhibition effect on melanin production was measured by comparing the compounds of Examples 1 to 5 to each other. The cell line was MeI-Ab cell line (supplied by Dr Thomas P. Dooley) derived from skin pigment cell of C57BL/6. The cells were cultured in DMEM medium containing 10% fetal bovine serum, 10OnM 12-O-tetradecanoyl Phobol-13- acetate, InM cholera toxin, under conditions of 37 ^"C and 5% CO₂. The cultured MeI-Ab cells were separated using 0.25% Trypsin-EDTA, placed in a 24- well plate at 1 X 10⁵ cells/well and treated with 10 ppm of the samples (compounds of Examples of 1 to 5 and kojic acid and hydroquinone as positive controls) from the second day for continuous 3 days by exchanging the medium with a fresh medium containing the samples. On the 5^th day, the cells were treated with IN NaOH to dissolve the melanin contained in the cells and absorption was measured at 400 run to determine the produced amount of melanin. The result is shown in Table 1. [Table 1 ]

As shown in Table 1 , the compounds of Examples 1 to 5 showed the inhibition effect on the melanin production. Particularly, the compounds of Example 1 and 2 excellent effect similar to that of hydroquinone.

[Experimental Example 2]

Inhibition effect of phenyl imidazol sulfonamide derivatives on c-kit 2-1. c-kit activity evaluation and inhibition effect by SUl 1248 In this Experimental Example 2-1, the activity of the c-kit protein alone and the c-kit activity inhibiting effect of SUl 1248 (Sugen) which is specifically bonded to c-kit to inhibit the activity were examined.

This experiment agreed the method presented by Panvera Z-lyte™ Kinase assay kit Tyr 4 peptide but the actual reaction temperature and time, and the used concentration of c-kit and ATP were optimized. 2X ATP was placed in 384 well plate for measurement of fluorescence in an amount of 5ul. Then, the contents of the plate was treated with SUl 1248 at a concentration of 15OnM, 5OnM, 15nM, 5nM, 1.5nM and 0.5nM using 96 pin plate. For accuracy of the reaction, each sample was duplicated and controls including the SUl 1248 free group/c-kit free group/phospho- peptide free group/100% phospho-peptide group were also examined. The solution of c-kit and its substrate peptide was distributed in an amount of 5ul and reacted at 37 °C for 45 minutes. After completion of the reaction, 5 ul of development solution was added and reacted at room temperature for 40 minutes. Finally, 5 ul of the stop solution was added to end the experiment. Here, the final concentrations of the materials used in the reaction were ATP 500 M, corresponding to 1.5 ng of c-kit (Kinase), 2M of peptide and the final concentration of SUl 1248 was 3OnM, 1OnM, 3nM, InM, 0.3nM and 0.InM.

Meanwhile, the inhibition of SUl 1248 on c-kit activity was calculated by measuring fluorescence of the samples which had finished the reaction. Two fluorescence data were readen using lights activated through 405nm and 535nm filters and the ratio between the two data was calculated to obtain the activation degree of the enzyme. The result is shown in FIG. 1.

As shown in FIG. 1 , it was noted that the activity of c-kit was inhibited depending on the concentration of SUl 1248.

2-2. Inhibitive effect of phenyl imidazol sulfonamide derivatives on c- kit activity

Based on the result of the c-kit activity evaluation system of Experimental Example 2-1, the inhibition of c-kit activity by the compounds of Examples 1 to 5 was examined. Here, the reaction conditions were the same to those of Experimental Example 2-1 but the final concentrations of the compounds were 3OuM, lOuM, 3uM, IuM, 0.3uM and O.luM, respectively. The inhibition rate was also calculated as described above and the result is shown in FIG. 2.

As shown in FIG. 2, it was noted that the compounds of Examples 1 to 5 inhibited the c-kit activity concentration-dependently.

[Experimental Example 3]

Whitening effect of phenyl imidazol sulfonamide derivative on the skin of human beings In order to examine the whitening effect of the phenyl imidazol sulfonamide derivatives according to the present invention, the following experiment was performed.

12 healthy males took opaque tape with a hole of 1.5 cm diameter attached on the upper arm and the taped skin part was exposed to 1.5 to 2 times of the minimal erythema dosage of UV ray B (UVB) to induce melanism.

After irradiation of UV rays, 2% solution of the compounds of

Examples 1 to 5 (solvent is 1,3-butylene glycol:ethanol = 7:3), and hydroquinone and kojic acid as positive controls were applied on the exposed skin and the color of the skin was measured using Colorimeter CR-300

(Minolta, Japan) to evaluate the increase of "L" value ( "ΔL" ). The result is shown in Table 2. The evaluation was based on that after use of the test samples, when the improvement of the pigmentation (skin whiteness) was high the whitening effect was excellent. [Table 2]

As shown in Table 2, the compounds of Examples 1 to 5 improved pigmentation, showing whitening effect. Particularly, the whitening effect of the compounds of Example 1 and 2 was similar to that of hydroquinone and kojic acid used as positive control

[Mode for Invention]

The formulations of the whitening cosmetic composition according to the present invention are described below. However, they are only for illustrative purpose and the present invention is not limited thereto.

Formulation 1.

Preparation of soap

Compound of Example 1 1.00 (wt%) Oils and fats q.s.

Sodium hydroxide q.s.

Sodium chloride q.s.

Fragrance q.s. Distilled water was added to make the total weight 100 and the soap was prepared following the above mixing ratio (%).

Formulation 2.

Preparation of lotion Compound of Example 2 3.00 (wt%)

Magnesium L-ascorbyl-2-phosphate 1.00

Water soluble collagene (1 % aqueous solution) 1.00

Sodium citrate 0.10

Citric acid 0.05 Licorice root extract 0.20

1,3-butylene glycol 3.00

Distilled water was added to make the total weight 100 and the lotion was prepared following the above mixing ratio (%).

Formulation 3.

Preparation of cream

Compound of Example 3 1.00(wt%)

Polyethylene glycol monostearate 2.00

Self-emulsifying glycerine monostearate 5.00 Cetyl alcohol 4.00

Squalene 6.00 Glyceryl tri-2-ethyl hexanoate 6.00

Sphingoglycolipid 1.00

1.3-butylene glycol 7.00

Distilled water was added to make the total weight 100 and the cream was prepared following the above mixing ratio (%).

Formulation 4.

Preparation of pack

Compound of Example 4 5.00(wt%) Polyvinyl alcohol 13.00

Magnesium L-ascorbyl-2-phosphate 1.00

Lauloylhydroxyproline 1.00

Water soluble collagene (1% aqueous solution) 2.00

1,3-butylene glycol 3.00 Ethanol 5.00

Distilled water was added to make the total weight 100 and the pack was prepared following the above mixing ratio (%).

Formulation 5. Preparation of beauty solution

Compound of Example 5 2.00(wt%)

Hydroxyethylene cellulose (2 % aqueous solution)...2.00

Xanthan gum (2 % aqueous solution) 2.00

1,3-butylene glycol 6.00 Cone, glycerine 4.00

Sodium hyaluronate (1 % aqueous solution) 5.00 Distilled water was added to make the total weight 100 and the beauty solution was prepared following the above mixing ratio (%). Formulation 6. Preparation of ointment Compound of Example 1 2.00(wt%)

Lanoline alcohol 1.00

Stearyl alcohol 2.00

Seteareth -20 2.00

Pearlatum 84.5 Lecithin 1.50

Caprilic /capric triglyceride 2.00

PEG20 corn glyceride 5.0

[Industrial Applicability] As described above, the phenyl imidazol sulfonamide derivatives according to the present invention inhibits synthesis of melanin by inhibition of c-kit, thereby improving pigmentation and showing whitening effect. Therefore, the whitening cosmetic composition comprising the phenyl imidazol sulfonamide derivatives according to the present invention can be used in improvement of pigmentation such as hyperpigmentation, freckles, various spots and the like.

While the present invention has been described with reference to the particular illustrative embodiments, it is not to be restricted by the embodiments but only by the appended claims. It is to be appreciated that those skilled in the art can change or modify the embodiments without departing from the scope and spirit of the present invention.

Claims

[CLAIMS] [Claim 1 ]

A phenyl imidazol sulfonamide derivative expressed by the following formula I. [Formula I]

In which,

[Claim 2] A method for preparing a phenyl imidazol sulfonamide derivative of formula I comprising the steps of:

(1) reacting sulfonic acid with thionyl chloride at reflux in an organic solvent to prepare sulfonyl chloride, the compound II in the following scheme I; and (2) reacting the sulfonyl chloride prepared in the step (1) with aminophenyl imidazol in an organic solvent to prepare a phenyl imidazol sulfonamide derivative, the compound I in the following scheme I. [Scheme I]

In which,

[Claim 3]

A whitening cosmetic composition comprising the phenyl imidazol sulfonamide derivative defined in claim 1. [Claim 4]

The composition according to claim 3, which comprises the phenyl imidazol sulfonamide derivative in an amount of 0.01 to 20wt%, based on the total weight of the composition.