TWI308148B - Novel compound of 6-methyl-3-phenethyl-3,4-dihydro-1h-quinazoline-2-thione, its preparation and a depigmentation composition containing the same as an effective component - Google Patents

Description

1308148 发明, DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a novel 6-methyl-3-phenethyl-3,4-dihydrolin-2-thione compound represented by Structural Formula 1. A method for producing the same, comprising: a pharmaceutical composition for preventing and treating hyperpigmentation comprising the compound as an active ingredient; and a skin whitening cosmetic composition comprising the compound as an active ingredient.

[Prior Art] The reason why the skin becomes dark and dull is because melanocytes synthesize too much melanin (a natural pigment) under ultraviolet irradiation, hormone imbalance or psychological stress (Nordlund, JJ et al. , The Pigmentation System: Physiology and Pathophysiology. New York, Oxford Univ. Press, pp. 1-1025, 1998). Therefore, the technology for controlling melanin synthesis has become the core technology for producing whitening products. The whitening products are used to prevent excessive production of melanin in the skin or to dilute melanin which has accumulated in the skin to inhibit hyperpigmentation such as discoloration or freckles. (Hori, W., Drug Discovery Approaches for Developing Cosmeceuticals. Advanced Skin Care and Cosmetic Products. Southborough, IBC Library Series, pp. 3.1.1-3.1.21, 1997) ° According to the melanin biosynthesis procedure, the starting material tyramine Acid (tyrosine) is converted from tyrosinase to dopa (DOPA) and dopaquinone (DOPAquinone); dopa is in 5,6-1308148 dihydroxyindole 2-carboxylic acid and 5,6-dihydroxyindole Participate in the production of two eumelanins; dopa and cysteine (cysteine) react to produce phenyl melanin. The true melanin derived from 5,6-dihydroxyindole-2-carboxylic acid is a brown pigment. The true melanin derived from 5,6-dihydroxy"5 is a black pigment and chromophoid melanin is a yellow pigment. - Red pigment. (Hearing, V. J., FASEB J., 5: 2902-9, 1991; Hearing, V. J., J. Invest Dermatol., 4:24-8, 1999). According to the gene knockout study, the lack of tyrosinase causes white (white mice), while the lack of tyrosinase-related protein 2 (TRP-2) causes ash. Furthermore, tyrosinase-related protein l (TRP-1) is currently known to play an important role in the development of brown (Rieder, S., et al., Mamm Genome, 12:450-5, 2001; Tanita, M ., et al., J. Hum. Genet., 47:1-6, 2002; Kameyama, K., et al., Pigment Cell Res., 8:97-104, 1995). The tyrosinase-related protein 1 does not exhibit any enzyme activity in the human body, but it exhibits the enzyme activity of 5,6-dihydro 61# 2-carboxylic acid oxidase in mice, and is known to be stable and stable. Amino acid enzyme related (Kobayashi, T., et al., J. Biol. Chem., 272: 31801-5, 1998). Ultraviolet rays play an important role in the melanin synthesis of the skin. When melanocytes are exposed to ultraviolet light, they activate proteinase C by dimercaptoglycerol, which promotes melanin synthesis (Gilchrest, BA, et al., Photochem. Photobiol., 93:1-10, 1996; Park , Η. Y., et al., J. Biol. Chem., 274: 16470-8, 1999). When exposed to sunlight, keratinocytes release nitric oxide, and alpha-melanocytes stimulate hormone prostaglandin E2 and endothelin-1. These release factors are transferred to melanocytes, where nitric oxide increases melanin synthesis via cGMP signaling and proteinase G, and the release of these factors increases melanin synthesis via cAMP signaling and proteinase A (Romero-Graillet) , C., et al., J. Biol. Chem., 271:28052-6, 1996; Rasmussen, N., et al., Neuroendocrinol. Lett., 20:265-282, 1999;

Scott, M. C., et al., J. Cell. Sci. 115: 2349-55, 2002). 1308148 Understanding the melanin synthesis pathway is important in developing skin whitening products that inhibit hyperpigmentation (discloration, freckles, etc.). A representative example is the melanin biosynthesis inhibitor' development which has so far included kjjj add, arbutin, vitamin C, mulberry extract, licorice extract and other similar ingredients. The chelation of kojic acid with a copper ion requires activation of tyrosinase, which inhibits the synthesis of melanin and has superior whitening effect. However, kojic acid is recently considered to be a calcinogenic agent, thus limiting the use of kojic acid. Vitamin C and its derivatives exhibit relatively low whitening efficacy. Hydroquinone is also irritating to the skin and limits its application based on safety considerations. In addition, it is known that plant extracts exhibit decolorization only at high concentrations, and almost no plant extracts exhibit decolorization at low concentrations. Therefore, in order to solve the problem of the conventional melanin synthesis inhibitor and to seek a better whitening substance, the inventors of the present invention have found a novel 6-methyl-3-benzene by screening by multiple polarization activity analysis. Ethyl_3,4·dihydro-17^ quinazoline-2_thione compound. Further, we have determined that pharmaceutical compositions and cosmetic compositions containing the compound as an active ingredient have good skin whitening efficacy, and according to the findings, the present invention provides a novel 6-methyl-3-phenethyl group. _3,4_dihydrooxazoline 2 sulphonate compound, a process for producing the same, and a pharmaceutical composition and skin whitening cosmetic composition for preventing and treating hyperpigmentation comprising the above compound as an active ingredient. SUMMARY OF THE INVENTION The present invention relates to a novel t 6_methyl-3-phenylethyl-, 3,4-dihydro-1-soxazoline-2-thione compound of the formula i; A method for producing a skin care composition comprising a chemical composition for preventing and treating hyperpigmentation; and a skin whitening cosmetic composition comprising the most effective component of the foregoing compound. 9 1308148 h3c

In the present invention, the 6-methyl-3-phenylethyl 3 oxazoline-2-thione compound represented by Structural Formula 1 can be represented by the reaction formula 4: dihydro-1H-ethyl -3,4-Dihydro-1//+ sitting and Lawes_, s ^ methyl-3-stray shown in Figure 1. Table preparation, such as flow reaction flow chart h3c

(4)

In the foregoing Reaction Scheme 1, the preparation of 6-methyl-3-phenethyl- 3 4 dihydro-l/ί-oxazolin-2-one of the formula 4 is as shown in the following Reaction Scheme 2 It is shown that the (5-methyl-2-nitrophenyl)phenethylamine of the formula 2 is first reduced to obtain 4 methyl-2-(ethyloxymethyl)phenylamine of the formula 3 Then, the product was reacted with 1,1 ί carbon-based di-salt to prepare a compound of structure 4. 1308148 Reaction Flow Chart 2

In the foregoing reaction scheme, (5-methyl-2-nitrophenyl)phenethylamine of the formula 2 can be obtained by reacting 5-methyl-2-nitrobenzene with phenethylamine. The preparation is as shown in the following Reaction Scheme 3. Reaction flow chart 3

The process for preparing the 6-methyl-3-phenylethyl-3,4-dioxa-1 //oxazoline-2-thione compound of the formula 1 of the present invention is summarized in Reaction Scheme 4. 11 1308148 Reaction Flowchart 4

(1) (4) In another aspect, the present invention relates to a method for preventing and treating a pigment comprising a 6-methyl-3-phenylethyl-3,4-dihydroquinazoline-2-thione compound. A pharmaceutical composition that is overly sedative. Preferably, the pharmaceutical composition comprises a 6-methyl-3-phenylethyl-34 dihydro-1 oxazoline-2-thione compound in an amount of from 0.0001 to 1% by weight based on the total weight of the pharmaceutical composition. The pharmaceutical composition is used for the prevention and treatment of melanin hyperswelling such as discoloration, freckles, ageing pigmentation and other similar problems, and can be formulated with different pharmaceutically acceptable carriers, excipients and/or additives. Different formulations. Representative examples include skin formulas such as creams, ointments, gels, lotions or patches. In another aspect, the present invention relates to a whitening cosmetic composition comprising a 6-methyl-3-phenylethyl-3,4-dihydroquinolin-2-thione compound. The whitening cosmetic composition preferably comprises 0001.0001 to 1% of 6-methyl-3-phenylethyl-3,4-dihydro-1//-oxazoline in an amount of 10,000 to 1% by weight of the total whitening cosmetic composition. 2-thione compound. 12 1308148 Skin whitening cosmetic composition is used to treat or prevent skin pigment abnormalities such as discoloration, freckles, ageing pigmentation and other similar problems, and the formulation thereof is not particularly limited. Representative examples of formulations include toners, astringents, nourishing creams, massage creams, serums, masks, gels, lotions, patches, sprays or liquid powders. The 6-methyl-3-phenylethyl-3,4-dinitro-1//-quine sigma-infraline-thione compound synthesized by the invention can inhibit melanin via proteinase C, cAMP/protein enzyme A Or synthesized via cGMP/proteinase G, is non-cytotoxic, and has a whitening effect several hundred times better than kojic acid and arbutin known in the art. EXAMPLES The present invention is further illustrated by the following examples, formulation examples, and experimental examples, which are not intended to limit the invention. Example 1 Preparation of 6-Methyl-3-phenylethyl-3,4-dinitro-1-side 11 sits sigmaline-2-thioindole Example 1-1. Synthesis (5-methyl-2 Benzylamine phenethylamine (2 eq. wt·, 3.38 ml) and triethylamine (3 eq. wt., 5.6 ml) were dissolved in tetrahydrofuran and dissolved in tetrahydrofuran. 5-Methyl-2-nitrobenzene (2.5 g, 0.0135 mol) was added to the above solution. The mixture was stirred at room temperature for 10 minutes and refluxed at 60 to 70 ° C for 12 hours. The reaction was cooled to ambient temperature and distilled in vacuo. The organic layer was dehydrated with anhydrous sodium sulfate, distilled in vacuo and separated by a column. The characteristics of (5-mercapto-2-nitrophenyl)phenethylamine are as follows. Orange oil

Rf = 0_26 (hexane: ethyl acetate = 2: 1); yield 84.8%; IR (KBr) 3350, 3050, 3020, 2930, 2850, 1610, 1585, 1520, 1455, 1340, 1265, 1120cm'1 ; lR NMR (CDC13, 89.45MHz) δ 2.40 (s, 3H), 2.88 (m, 4H), 4.03 (s, 2H), 7.13-7.93 (m, 8H) 13 1308148 Example 1-2: Synthesis 4- Methyl-2-(p-ethylaminomethyl)phenylamine (5-methyl-2-nitrophenyl)phenethylamine (3 g) dissolved in a mixture of dichloromethane and methanol (1:1) in. Palladium carbide (240 mg) was added to the above solution, and the mixture was stirred at a hydrogen pressure of 30 psi for 4 hours. The reaction was filtered through a celite caket and washed with di-methane. The filtrate was vacuum distilled to obtain 4-methyl-2-(phenethylaminomethyl)phenylamine. The characteristics of the product are as follows. Brown oil

Rf = 0.045 (hexane: ethyl acetate = 2: 1); yield 89.7%; IR (KBr) 3550-3200, 3025, 2930, 2895, 2750, 1620, 1500, 1455, 1265 cm'1; *H NMR (CDC13, 89.45MHz) δ 2.20(s, 3H), 2.83(m, 2H), 2.91(s, 2H), 3.91(m, 2H), 4.27(br, NH2), 6.41-7.21(m, 8H) Implementation Force 1-3: Synthesis of 6-Methyl-3-Phenylethyl-3,4-dihydrooxazolin-2-one 4-methyl-2-(phenethylaminomethyl)phenylamine ( 2 g, 0.00832 mol) was dissolved in anhydrous tetrahydro alpha fumon. 1,1'-monomethomidol (1.1 eq. wt·, 1.48 g) was added. The mixture was refluxed at 50 to 60 ° C for 12 hours. The tetrahydrofuran was removed and extracted with chloroformic acid. The organic layer was dehydrated with anhydrous sodium sulfate, distilled in vacuo and separated by column. The characteristics of 6-methyl-3-phenylethyl-3,4-dihydro-1 //-oxazolin-2-one are as follows. Yellow solid

Rf = 〇_34 (hexane: ethyl acetate = 5: 1); yield 81.9%; melting point 174.8-175.8 ° C; IR (KBr) 3200, 3100-3000, 2920, 1650, 1610, 1500, 1455, </ RTI> <RTIgt; 4.31(s, 2H), 6.57-7.01(m, 3H), 7.26(m, 5H), 7.88(br, NH) Example 1-4: Synthesis of 6-methyl-3-ethylidene-3,4 -Dihydro-1//-quinazoline-2-thione 6-methyl-3-phenylethyl-3,4-dihydro-1//-oxazolin-2-one (880 mg, 0.0033 Mohr) was dissolved in toluene and heated. Lawesson's reagent (0.6 eq. wt., 802 mg) was added. The mixture was refluxed at 100 ° C for 8 hours. The toluene was removed by vacuum distillation and then extracted with hydrated dioxane. The organic layer was dehydrated with anhydrous sodium sulfate, distilled in vacuo and separated by a column. The characteristics of 6-methyl-3-phenylethyl-3,4-dihydro-1//-carbazole φ porphyrin-2-thione are as follows. Light yellow solid; Rf = 〇. 63 (hexane: ethyl acetate = 2: 1); yield 47.2%; melting point 177.2-177.7 ° C; IR (KBr) 3200, 3020, 2920, 1620, 1550-1480, 1450, 1325, 1265, 1240, 1 175, 1150cm·1 ; !H NMR (CDC13, 89.45MHz) δ 2.27(s, 3H), 3.10(t, J=7.7, 2H), 4.12(t, J=7.7 , 2H), 4.36(s, 2H), 6.60-7.02(m, 3H), 7.28(m, 5H), 8.48(br, NH);

Anal. Calcd. for C17H18N2S C,72.3; H,6.42; N;9.92; S,11.3 _

Found: C,71.9; H,6.89; N,8.64; S,13.1 15 1308148 Composition Formulation 1. Contains 6-methyl-3-phenylethyl-3,4-dihydro-1 ugly-quinazoline Pharmaceutical composition for the prevention and treatment of hyperpigmentation of 2-thione compounds - ointment component content 6-methyl-3-phenylethyl-3,4-dihydro-1 η 奎奎琳-2 Thiol oxime. 5g white can 4.0 g cholesterol 1.6 g white petrolatum remaining cetyl alcohol 1.6 g total 100 g formula 2. contains 6-methyl-3-phenylethyl-3,4-diaza-1_ΒΓ-β Pharmaceutical composition for preventing and treating hyperpigmentation of kujunlin-2-thiophene compound_gel component content 6-mercapto-3-phenylethyl-3,4-dihydroquawine-2 -thione oxime. 5g ethanol 18 g kaolin 5 g 1,3-butanediol 5 g glycerol 8 g CMC-sodium 9 g gelatin 3 g methylparabene 0.1 g propyl vinegar (propylparabene) 0.2 g 16 1308148 pure Other parts of water total 100 g Formulation 3. Whitening cosmetic composition containing 6-methyl-3-phenylethyl-3,4·dihydro-1 ugly-oxazoline-2-thione compound - nourishing cream ingredient content Triethanolamine 0.1 g glycerol 3.0 g Ding B Glycol 3.0 g liquid stone can be 7.0 g yS-glucan 7.0 g Carbomer 0.1 g 6-methyl-3-phenylethyl-3,4-dihydroindole.5g -1 open-σ奎σ全u林-2 · thiopurine with octanoic acid/capric triglyceride 3.0 g squalene 5.0 g hexadecanoic acid glucosinolate 1.5 g sorbitan stearate 0.4 g polysorbate fatty acid ester 60 1.2 g Methylparabene 0.1 g propyl S (Propylparabene) 0.1 g perfume 0.1 g pure water other parts total 100 g 17 1308148 Formula 4. Contains 6-methyl-3-phenylethyl-3,4-di Hydrogen-1 ugly-oxazoline-2-thione compound whitening cosmetic composition - mask component content ethanol 6.0 g glycerin 4.0 g polyvinyl alcohol 15.0 g hyaluronic acid extract 5.0 g lu-glucan 7.0 g allantoin 0.1 g 6-methyl-3-phenylethyl-3,4-dihydrogen 0.5g -1 σ sitin-2-thioindole with decylphenyl ether 0.4 g polysorbate fatty acid ester 60 1.2 g A Methylparabene 0.2 g propyl vinegar (Propylparabene) 0.1 g Fragrance 0.1 g Pure water Other parts Total 100 g Experimental Example 1: Inhibition of melanin via cAMP/proteinase A Efficacy produced in the melanoma B16 cell line by α-melanocyte stimulation of hormones, which is transmitted by cAMP/protein enzyme Α signal to produce melanin (Rasmussen, N., et al., Neuroendocrinol. Lett., 20 :265-282, 1999; Scott, MC, Heart/·, 乂Ce//H 115:2349-55, 2002). Melanoma B16 cells were suspended in 18 1308148 DMEM supplemented with 10% bovine embryo serum in a 96-well plate, and seeded at 37t, 5% c〇, JV, at a density of 2,5〇〇/well. (4) Adding (4) After 24 hours of culture, the experimental group of Heermon and the same #Λ) added melanocyte thorn concentration and 6-methyl·3·= base ^melanocyte stimulation hormone (final agent) The experimental group. Each group was cultured for 3 days, and the heart was determined by the action of 1 thiopurine. The melanin released into the culture solution contained the wavelength of the milk. (10) Absorption value Experimental results The melanoma m6 33.2 soil l々g /ml of melanin. Mu Λ "" hip ^ days after release, ', σ α • melanocytes stimulate the hormone release of the experimental group of cells (4) see "heart / such as" to Mencibel Bell 冢 ^. , .. 8 ..., pigment. Add α-melanocyte stimulation with hormone h to the hormone (final concentration 丨ηΜΗ〇6_methyl_3_phenylethyl _34 dihydro-m-jun seal_2_thione For the experimental group cells, 37.9±0.8#g/ml melanin was released in the sputum, 4: under the armpit, and 44.4 9.5/zg/ml black was released at the concentration of the agent 2 The pigment releases melanin of ι〇ι ι ± 1.0# g /ml at the concentration of the agent, and releases melanin of 126.5±$ $ /zg /ml at a concentration of 〇5 # μ. Therefore, the performance of the cells shows whitening effect. It is dose-dependent (Fig. la). When the 50% whitening effect (EC%) is reached, the effective dose concentration is 15wM. Under the same experimental model, the ec50 values of arbutin and kojic acid are shown as 151//. M and 261//M. Therefore, we noticed that 6-methyl-3-phenylethyl-3,4-dihydro-1 sets of -2-林-2-thione via melanoma B16 cell line via CAMP/protein The decolorization effect of melanin produced by the enzyme A signal is 100 times higher than that of arbutin and 170 times higher than that of kojic acid in EC5() (Example lb). Experimental Example 2: Inhibition of melanin production by cGMP/proteinase G The effect of melanoma B16 cell line was stimulated with 0-purine IX (ProtoP〇rphyrin IX) to produce melanin 1308148 via cGMP/proteinase G using nitric oxide (Romero-Graillet, C., et aL, J. Biol. Chem., 271:28052-6, 1996) 〇m pigmentoma Bl6 cells were suspended in dmem supplemented with 1% fetal bovine serum. The cells were cultured in a 96-well plate at a density of 2,500/well, and cultured in an environment of 37 〇, 5% c 〇 2. After 24 hours of culture, the cells were divided into a control group (no chemical added), and the original 1 was added. The experimental group of IX, and the simultaneous addition of pyridoxine (final concentration #Μ) and 6-mercaptophenethyl_3,4_dihydro_17/_oxazoline_2-thione acted ^ The experimental group of 丨. Each group was cultured for 3 days, and then the melanin content released into the culture solution was determined by measuring the absorption value at a wavelength of 405 mn. The results of the experiment showed that the melanoma B16 cells of the control group released 43.4 ± 0_8/zg/m of melanin after 3 days of culture. The cells of the experimental group cultured with the addition of pyridoxine were released with 135.2 ± 1.9 #g/ml of melanin. At the same time, add pyridoxine (final concentration 30//Μ) and 6-methyl-3-phenylethyl-3,4-dihydro-i/f·carbazole-2_thione as the agent Experimental group of cells, at the concentration of the agent! Release 52 5± 5 8# Lu's melanin under β M, release 94 4± 6 〇&quot;g /ml melanin at a concentration of 〇.5βΜ, release 1〇 at a concentration of 〇.25//M 5·2 melanin 9#g /ml melanin, release 118.7±32/zg/ml melanin at a concentration of 〇.13/zM. Therefore, the performance of the cells showed that the whitening effect was dose-dependent (Fig. 1). When the whitening effect (EC50) is reached at 5%, the effective dose concentration is 0.5 #M. Under the same experimental model, the whitening effect E of the fruit and the kojic acid was observed (the 5Q values were respectively 159#M &amp; 122, therefore, the experimental results showed that 6_methyl_3_phenethyl_3,4_ The decolorization effect of dihydro-ΐ7/_oxazoline-2·thione on the melanoma B16 cell line transmitted by cGMp/proteinase G signal is higher than that of arbutin 31% and higher than EC%. Kojic acid 240 times (Fig. 2b). Experimental Example 3: Inhibition of melanin production by 1-oleyl-2-ethinylglycerol/proteinase C. Melanoma B16 cell line was 1-oil 醯_2·B Stimulating with thiol glycerol, producing melanin via egg 20 1308148 white/enzyme c (Gilchrest, B. A·, from, household ^ (4)

Photobiol, 93: 1-10, 1996; Park, Η. Υ., ^ αί, J. Biol. Chem., 274: 16470-8, 1999). The melanoma Βΐ6 cells were cultured in DMEM supplemented with 1% fetal bovine serum, and seeded in a 96-well plate at a density of 2,500/well, and cultured in a 37 C, 5% C〇2 environment. After 24 hours of culture, the cells were divided into a control group (no chemical added), an experimental group supplemented with 丨_油醯_2_ acetyl glycerol, and a 1-oil 醯_2_ acetyl glycerin (final) The experimental group was treated with a concentration of 2 〇〇/zM) and 6-methyl-3-phenylethyl-3,4-dihydro-1/f_oxazoline-2-thione. Each group was cultured for 3 days' and then the amount of black pigment released into the culture solution was determined by measuring the absorption value at a wavelength of 405 nm. The results of the experiment showed that the melanoma B16 cells of the control group released 49.8 ± 1.0/mi of melanin after 3 days of culture. The cells of the experimental group which were cultured with the addition of the oil 醯_2_ acetyl glycerol released the melanin of 1〇9_4± 0_2&quot;§/〇11. At the same time, the experiment of adding buckwheat-2·acetamid glycerol (final concentration 20G//M) and 6-f phenylbutenyl·3,4-dihydro oxazoline-2-thione as an agent was added. In the group of cells, release 57.7± 2.9&quot;g/ml of melanin at a concentration of 〇·5#μ, and release 82.2± 6.1#g/ml of melanin at a concentration of 〇.25_ at the concentration of the agent. Release 1〇6 3 ± 〇.l#g /ml of melanin, and release the melanin of ι〇97 soil g/ml at the concentration of the agent 〇·〇6. Therefore, the performance of the cells shows the whitening effect and Dose-related (Fig. 3a). When the 50% whitening effect (EC5〇) is reached, the effective dose concentration is 〇3. Under the same experimental model, the whitening effect of bearberry fen is shown as 4. Therefore, the experimental results show that -methyl_3_phenethyl_3,4_dichloro-sucking, such as gulinium-2-sulfur (iv) melanoma B16 cell line, through the protein enzyme c signal transmission of melanin decolorization effect, higher than ec5〇 Bear fruit 157 times (Fig. 3b). Experimental Example 4: Whitening mechanism to reduce glutamate content Melanoma B16 cells were suspended in the addition of 1% fetal bovine serum to the coffee 2 1 1308148 Culture 'planted in a 96-well plate at a density of 2,500/well, and cultured for 24 hours at 37 (:, 5% C02). Adding α-melanocytes to the cells to stimulate hormones (final concentration) 1 ηΜ) and 6-methyl-3-phenylethyl-3,4-dihydro-1//-oxazoline_2_巯_ as the agent. After 3 days of culture, the cells were collected, dispersed and centrifuged. The suspension was used as the source of the enzyme. The 20#g enzyme source was separated by electrophoresis on a polyacrylamide gel containing SDS. The gel was then washed with 100 mM phosphate buffer (pH 6 8) to remove the SDS and then removed. To a phosphate buffer (pH 6 8) containing 5 mM D〇pA, and stored in the dark at 37 ° C. The black tyrosinase content was measured using a densitometer. Compared with the tyrosinase produced by the serum DMEM medium for 3 days in the melanoma Bi6 cell line, the tyrosinase produced by the melanoma Β16 cell strain cultured in the same culture medium but supplemented with α-melanocyte stimulation of hormones was compared. Increased by 6 to 7 times. Tyrosine produced by melanoma Β16 cell line stimulated only by α-melanocyte stimulation of hormones The content of the hormone is 1%%; melanoma stimulated by melanocytes and 6_methyl_3_phenethyl-3-, 'dihydroquinazoline-2-thione In the lysinase 3 produced by the B16 cell line, when the concentration of the agent is 4 &quot; Μ, the tyrosinase content is 丨7%; when the concentration of the agent is 2, the lysin content is 35%; When the concentration of the agent is i _, the content of the glutamic acid enzyme is 83%; when the concentration of the agent is 〇5_, the concentration of the tyrosinase is 92%, and the result shows that the inhibitory effect is dose-dependent (Fig. 4). . Accordingly, the present invention has been noted that 6-methylphenethyl _3,4-dichloro phthalocyanine-2_thione achieves the effect of discoloration by reducing the mechanism of tyrosinase content. Experimental Example S: The fine-flowing melanoma secret cells of melanoma B6 cell line were suspended in a 1%% bovine embryo Jinqingzhi ship, and planted in a 96-well flat plate at a density of 2,500/well. Shen, 5% called the clothing i brother to raise 24 small b. Simultaneous addition of melanocytes in the cells stimulates hormones (final concentrations of 1 _ and 6 rn phenethyl m+M-2-sulfo 22 1308148 ketones act as agents. Every 24 hours, the survival and death of cytokines is trypan blue) The dyeing method is calculated. Compared with the melanoma Β16 cell line cultured in the culture medium containing 1%) of bovine embryo serum, the cells cultured in the same culture medium but with the addition of sirolimus cells stimulated the hormone showed growth retardation, but It did not show the toxicity of killing cells (Fig. 5a). On the fourth day, cells cultured with the addition of Myocardial pigments to stimulate He-Mongo and 6-Methyl·3_phenethyl_3,4_h_b kuvirin-2-gamma (concentration 0.5 to 4#M) showed The number of viable cells was the same as that of the cultured cells in which only melanocytes were stimulated, and the toxicity of killing cells was not shown (Fig. 5b). INDUSTRIAL APPLICABILITY The present invention provides a novel 6-mercapto-3(4-ethylethyl-3,4-dihydro-1//-oxazoline-2-thione compound having superior whitening effect, which can be used for preventing skin Melanin over-sinking or diluting the melanin color that has accumulated in the skin, improving hyperpigmentation such as discoloration and freckles; a method of preparing the compound; and a pharmaceutical composition and a cosmetic composition comprising the compound.

23 l3〇8l48 [Simple description of the diagram] The first diagram is the result of Experimental Example 1, which shows the effect of 6_methyl stupid Emei 3 Kui Lin Lin_2_sulfur_ via cAMp/proteinase A. The thorn... has been primed, and the system is the result of the experimental example. It compares bearberry*, kojic acid with soil _3_ethylethyl 3,4_dihydro hydrazine ° sitin-2-thioindole Through cAMp, amateurs inhibit the production of melanin. (·: the compound of the present invention ^glyxate). See Fig. 2a for the results of Experimental Example 2, which shows that 6-methyl"·phenemene-3, oxazoline-2_sulfur_via _ protein yeast "inhibition into the effect. ..., οι king

6_甲ίΓ? is the result of Experimental Example 2, which compares bearberry #, kojic acid and soil--this ethyl-3,4-dihydro·1/7_ 口套嗤琳_2_sulfur Tune via cGM

: The effect of melanin production. (10): Compound of the present invention: J

Figure 3a is the result of Experimental Example 3 and shows 6-methyl + phenethyl &amp; W ^ (tetra) porphyrin. Marriage is brewed through Bu oil. _2_ Ethyl glycerol: White matter Enzyme C inhibits pigmentation. ^ f 3b—The figure is the experimental real _ 3 silk, which is the comparison of bear ^, kojic acid and - soil --3-ethyl 3,4-dihydro_1 private edge 嗤 _2 _ thione &amp;;1_油醯_2_Acetylglycerol (〇AG)/protein Enzyme ΟInhibition of melanin production Ο: 'Arbutin. ▲: kojic acid) (• This July 4th is an experimental example As a result of 4, it was shown that the melanoma B16 cell strain which was stimulated by the same _=stimulus (4) and 6-methyl-3 phenethyl _3m quinone rod and cultured in DMEM containing 10% bovine embryo serum was produced. The content of lysin was compared with that of the melatonin B16 cell line which was only stimulated by melanocytes and stimulated by melanoma to be (10). The results of the test were the experimental example 5 As a result, it was shown that melanoma (4) cells were raised in the same culture medium and added - melanin fine: cell proliferation of thorn H, growth result H 〇 · · only added α strain culture: === fruit, showing melanin TM dm earning, and Peining the same culture #素细胞刺刺_蒙蒙的赫蒙蒙和六•methyl_3_苯乙_34二^寺Add α • Melanocyte stimulation -.M)t 〇·3 25

Claims (1)

Pick and Shenjing patent scope: - 6-A ^ ^ ^ Bu Structural formula (" soil -, - stupid ethyl _3,4_ dihydro _1 / ^ quinazoline 2 - thione compound, such as h3c (1) A method for preparing 0-methyl-3-phenylethyl-3,4-dihydro-1//_quinazoline-2-thione compound, which comprises the structural formula (4) 6-Methyl-3-phenylethyl-3,4-dihydro- ι _ 嗤 嗤 -2- 酮 ketone is reacted with Lawesson's reagent. (4) The method according to the second aspect of the patent application, wherein the method for preparing 6_mercapto_3_ethylidene_3,4_dihydro-1//-quinazoline·2-ketone comprises a structural formula (2) Reduction of (5·methyl-2-nitrophenyl)phenethylamine shown to obtain 4 methyl-2-(phenethylaminomethyl)phenylamine represented by structural formula (3) Then, the product 4 methyl 2 - (p-ethylaminomethyl) phenylamine is reacted with 1, hydrazine-carbonyldiimidazole to prepare 6-methyl-3-phenylethyl-3,4-diazepine. - Kui. Sitting on the Lin-2. 26 (2)