WO2005016895A1 - Novel compound of 6-methyl-3-phenethyl-3,4-dihydro-1h-quinazoline-2-thinone, its preparation and a depigmentation compositon containing the same as an effective component - Google Patents

Novel compound of 6-methyl-3-phenethyl-3,4-dihydro-1h-quinazoline-2-thinone, its preparation and a depigmentation compositon containing the same as an effective component Download PDF

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WO2005016895A1
WO2005016895A1 PCT/KR2003/002545 KR0302545W WO2005016895A1 WO 2005016895 A1 WO2005016895 A1 WO 2005016895A1 KR 0302545 W KR0302545 W KR 0302545W WO 2005016895 A1 WO2005016895 A1 WO 2005016895A1
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methyl
phenethyl
dihydro
quinazoline
thione
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PCT/KR2003/002545
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French (fr)
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Youngsoo Kim
Sang-Hun Jung
Kyung Rak Min
Jun Kyu Park
Jee-Hyun Lee
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Youngsoo Kim
Sang-Hun Jung
Kyung Rak Min
Jun Kyu Park
Jee-Hyun Lee
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Priority to AU2003282429A priority Critical patent/AU2003282429A1/en
Publication of WO2005016895A1 publication Critical patent/WO2005016895A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/93—Sulfur atoms

Definitions

  • the present invention relates to a novel compound of 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione represented by the following formula 1, a preparation method thereof, a medicinal composition for prevention and treatment of hyperpigmentation comprising the same as an effective component, and a skin- whitening cosmetic composition comprising the same as an effective component:
  • a technology to control the melanin biosynthesis comes under the core technology in development of skin- whitening products for preventing excessive melanin pigmentation in the skin or lightening the color of the melanin pigment which has been already 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).
  • tyrosine as a starting material is converted into DOPA and DOPAquinone by tyrosinase.
  • the DOPA undergoes intermediates of 5,6-dihydroxyindole 2-carboxylic acid and 5,6- dihydroxyindole to produce two types of eumelanins.
  • the DOPAquinone reacts with cysteine to produce pheomelanin.
  • the eumelanin derived from 5,6-dihydroindole 2- carboxylic acid is a brown pigment
  • the eumelanin derived from 5,6-dihydroindole is a black pigment
  • the pheomelanin is a yellow-red color pigment (Hearing, N J., FASEB , 5:2902-9, 1991; Hearing, V. J., J. Invest. Dermatol, 4:24-8, 1999).
  • TRP-1 tyrosinase-related protein 1
  • the tyrosinase-related protein 1 does not show any enzymatic activity in the human, though it shows an enzymatic activity of 5,6- dihydroindole 2-carboxylic acid oxidase in the mouse, and is known to participate in the stabilization of tyrosinase (Kobayashi, T, et al, J. Biol. Chem., 272:31801-5, 1998).
  • the UV rays paly an important role in the synthesis of melanin in the skin. When the melanocyte is exposed to the UV rays, it activates protein kinase C by diacylglycerol and then, promotes the synthesis of melanin (Gilchrest, B.
  • Keratinocyte when being exposed to solar rays, releases nitrogen monoxide, alpha-melanocyte stimulating hormone, prostaglandin E 2 and endothelin-1. These released factors are transferred to the melanocyte, in which nitrogen monoxide increases the synthesis of melanin via signal transduction of cGMP and protein kinase G and the rest of the factors increase the synthesis of melanin via signal transduction of cAMP and protein kinase A (Romero-Graillet, C, et al., J. Biol.
  • melanin biosynthesis inhibitors which are developed so far include kojic acid, arbutin, hydroquinone, vitamin C, mulberry root extract, licorice extract and the like.
  • the kojic acid chelates a copper ion needed for activation of tyrosinase to inhibit the melanin biosynthesis. It has excellent skin- whitening effect. However, recently, it is recognized as a calcinogenic agent and thus, its use is limited. Vitamin C and derivatives thereof show relatively low whitening effect. Hydroquinone is limited in its application in terms of safety due to high skin irritation. In addition, it is known that most of plant extracts show the depigmentation effect only at high concentration but little effect at low concentration.
  • the present inventors have conducted screenings by introducing a multi-polarized activity analysis to find a novel compound of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2- thione. Also, we have confirmed that medicinal compositions and cosmetic compositions comprising the compound as an effective component have excellent skin- whitening effect and completed the present invention based on these discoveries.
  • a novel compound of 6- methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione a preparation method thereof, and a medicinal composition for prevention and treatment of hype ⁇ igmentation and a skin-whitening cosmetic composition comprising the same as an effective component.
  • the present invention is directed to a novel compound of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione represented by the following formula 1, a preparation method thereof, a medicinal composition for prevention and treatment of hype ⁇ igmentation comprising the same as an effective component, and a skin- whitening cosmetic composition comprising the same as an effective component
  • 6-methyl-3-phenethyl-3,4-dihydro-lH- quinazoline-2-thione of the formula 1 may be prepared by reacting 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-one of the formula 4 with Lawesson's reagent as shown in the reaction scheme 1.
  • 6-methyl-3-phenethyl-3,4-dihydro-lH- quinazoline-2-one of the formula 4 may be prepared by reducing (5-methyl-2- nitrobenzyl)phenethylamine of the formula 2 to obtain 4-methyl-2- (phenethylaminomethyl)phenylamine of the formula 3, as shown in the following reaction scheme 2, and reacting the product with 1 , l'-carbonyldiimidazole.
  • (5-methyl-2-nitrobenzyl)phenethylamine of the formula 2 may be prepared by reacting 5-methyl-2-nitrobenzyl chloride with phenethylamine, as shown in the following reaction scheme 3.
  • the present invention is directed to a medicinal composition for prevention and treatment of hype ⁇ igmentation comprising 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione.
  • the medicinal composition comprises 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione in an amount of 0.0001 to 1% by weight based on the total weight of the composition.
  • the medicinal composition is used for prevention or treatment of melanin hype ⁇ igmentation such as discoloration, freckles, senile pigmentary macule and the like and can be formulated into various formulations with a pharmaceutically acceptable carrier, excipient and/or additive.
  • transdermal formulations such as creams, ointments, gels, lotions, solutions or patches.
  • the present invention is directed to a skin-whitening cosmetic composition comprising 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione.
  • the skin-whitening cosmetic composition comprises 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione in an amount of 0.0001 to 1 % by weight based on the total weight of the composition.
  • the skin-whitening cosmetic composition is used for treatment or prevention of skin pigment anomaly such as discoloration, freckles, senile pigmentary macule and the like and its formulation is not particularly limited.
  • formulation include toners, astringents, nourishing creams, massage creams, essence, ' packs, gels, lotions, patches, sprays or liquid powders.
  • the 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione according to the present invention synthetically inhibits the melanin biosynthesis via protein kinase C, the melanin biosynthesis via cAMP/protein kinase A, the melanin biosynthesis via cGMP/protein kinase G without cytotoxicity and has skin-whitening effect several hundreds times stronger than kojic acid and arbutin which have been already known to the art.
  • Fig. la shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cAMP/protein kinase A according to the result of Experimental Example 1 ;
  • Fig. lb shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cAMP/protein kinase A, as compared to that of arbutin and kojic acid, according to the result of Experimental Example 1 (•: the material of the present invention O: Arbutin A: Kojic Acid); Fig.
  • FIG. 2a shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cGMP/protein kinase G according to the result of Experimental Example 2;
  • Fig. 2b shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cGMP/protein kinase G, as compared to that of arbutin and kojic acid, according to the result of Experimental Example 2 (•: the material of the present invention O: Arbutin ⁇ : Kojic Acid); Fig.
  • Fig. 3 b shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3 ,4-dihydro- 1 H-quinazoline-2-thione via 1 -oleoyl-2- acetylglycerol(OAG)/protein kinase C, as compared to that of arbutin, according to the result of Experimental Example 3 (•: the material of the present invention O:
  • Fig. 4 shows the content of tyrosinase produced by a melanoma B16 cell line treated with alpha-melanocyte stimulating hormone and 6-methyl-3-phenethyl-3,4- dihydro-lH-quinazoline-2-thiones at the same time in DMEM supplemented with 10% fetal bovine serum, relative to 100 of the content of tyrosinase produced by a melanom B16 cell line treated only with alpha-melanocyte stimulating hormone, according to the result of Experimental Example 4; Fig.
  • 5a shows the cell growth of a melanoma B16 cell line group (None) propagated in DMEM supplemented with 10% fetal bovine serum and the cell growth of a melanoma B16 cell line group ( ⁇ -MS ⁇ ) proliferated in the same medium with alpha-melanocyte stimulating hormone added, according to the result of Experimental
  • Example 5 (•: None O: ⁇ -MS ⁇ only); and Fig. 5b shows the number of surviving cells of melanoma B16 cell line group proliferated in DMEM supplemented with 10% fetal bovine serum with alpha- melanocyte stimulating hormone added and the number of surviving cells of melanoma B16 cell line group proliferated in the same medium with alpha-melanocyte stimulating hormone and 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione (concentration 0.5 to 4 ⁇ M) added, at the fourth day of cultivation, according to the result of Experimental Example 5.
  • Example 1-1 Synthesis of (5-methyl-2-nitrobenzyl phenethylamine Phenethylamine (2 eq. wt, 3.38 ml) and triethylamine (3 eq. wt, 5.6 ml) were dissolved in tetrahydrofuran and 5-methyl-2-nitrobenzyl chloride (2.5 g, 0.0135 mole) dissolved in tetrahydrofuran was added thereto. 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, followed by vacuum distillation. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column.
  • Example 1-2 Synthesis of 4-methyl-2-(phenethylaminomethyl)phenylamine (5-methyl-2-nitrobenzyl)phenethylamine (3 g) was dissolved in a mixture solution of dichloromethane and methanol (1 :1). Pd carbon (240 mg) was added thereto and the mixture was stirred under a hydrogen pressure of 30 psi for 4 hours. The reaction was filtered by suction through a celite cake and washed with dichloromethane. The filtrate was vacuum distilled to obtain 4-methyl-2- (phenethylaminomethyl)phenylamine. The characteristics of the product are as follows.
  • Example 1-3 Synthesis of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-one 4-methyl-2-(phenethylaminomethyl)phenylamine (2 g, 0.00832 mole) was dissolved in anhydrous tetrahydrofuran. 1,1 ' -carbonylimidazole (1.1 eq. wt., 1.48 g) was added thereto. The mixture was refluxed at 50 to 60 ° C for 12 hours. Tetrahydrofuran was removed, followed by extraction with hydrated dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column.
  • Example 1-4 Synthesis of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-one (880 mg, 0.0033 mole) was dissolved in toluene and heated. The Lawesson's reagent (0.6 eq. wt., 802 mg) was added thereto. The mixture was refluxed at 100 ° C for 8 hours. Toluene was removed by vacuum distillation, followed by extraction with hydrated dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column.
  • Formulation 1 Medicinal composition for prevention and treatment of hyperpigmentation comprising 6-methy_-3-phenethyl-3,4-dihydro-lH-quinazoline- 2-thione - Ointment
  • the melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 2,500/well of a 96-well plate, under conditions of 37 ° C and 5% CO 2 . After Incubation of 24 hours, the cells were divided into a non-treatment group, a group treated with alpha-melanocyte stimulating hormone and a group treated with alpha-melanocyte stimulating hormone (final concentration 1 nM) and 6-methyl-3 -phenethyl-3, 4-dihydro-lH-quinazoline-2-thi one as an effective agent at the same time.
  • each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the abso ⁇ tion at wavelength 405 run.
  • the melanoma B16 cells cultured for 3 days in the non-treatment group released 33.2+ 1.4 ⁇ glml of melanin and the cells cultured in the group treated with alpha-melanocyte stimulating hormone released 143.9+ 1.6 ⁇ glml of melanin.
  • the cells were divided into a non-treatment group, a group treated with protopo ⁇ hyrin IX and a group treated with protopo ⁇ hyrin IX (final concentration 30 ⁇ M) and 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione as an effective agent at the same time.
  • Each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the abso ⁇ tion at wavelength 405 nm.
  • the melanoma B16 cells cultured for 3 days in the non-treatment group released 43.4+ 0.8 ⁇ glml of melanin and the cells of the group treated with protopo ⁇ hyrin IX released 135.2+ 1.9 ⁇ glml of melanin.
  • the melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 2,500/well of a 96-well plate, under conditions of 37 "C and 5% CO 2 . After Incubation of 24 hours, the cells were divided into a non-treatment group, a group treated with l-oleoyl-2-acetylglycerol and a group treated with l-oleoyl-2- acetylglycerol (final concentration 200 ⁇ M) and 6-methyl-3-phenethyl-3,4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time.
  • each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the abso ⁇ tion at wavelength 405 nm.
  • the melanoma B16 cells cultured for 3 days in the non-treatment group released 49.8+ 1.0 //g/ml of melanin and the group treated with l-oleoyl-2- acetylglycerol released 109.4+ 0.2 ⁇ glml of melanin.
  • the tyrosinase content produced by the melanoma B 16 cell line cultured in DMEM supplemented with 10% fetal bovine serum for 3 days was increased 6 to 7 times.
  • the tyrosinase content produced by the melanoma B16 cell line treated only by alpha-melanocyte stimulating hormone was assigned to 100%
  • the tyrosinase content of the group treated with alpha-melanocyte stimulating hormone and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time was 17% at an agent concentration of 4 ⁇ M, 35% at 2 ⁇ M, 83% at 1 ⁇ M, 92% at 0.5 ⁇ M, which showed dose-denpendent inhibiting effect (Fig. 4). Therefore, it was noted that 6-methyl-3 -phenethyl-3, 4-dihydro- 1H- quinazoline-2-thione shows the depigmentation effect by a mechanism reducing tyrosinase content.
  • the cells cultured in the same medium treated with alpha- melanocyte stimulating hormone showed growth delay but did not show cell killing toxicity (Fig. 5a).
  • the group treated with both alpha-melanocyte stimulating hormone and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione (concentration 0.5 to 4 ⁇ M) showed a substantially equal number of living cells, as compared to the group treated only with alpha-melanocyte stimulating hormone and did not show cell killing toxicity (Fig. 5b).
  • the present invention provides a novel compound of 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione with excellent skin- whitening effect which prevent melanin hype ⁇ igmentation of the skin, or light the color of melanin pigment which has been already accumulated to improve hype ⁇ igmentation such " as discoloration and freckles, preparation method thereof, and a medicinal composition and a cosmetic composition comprising the same.

Abstract

The present invention relates to a novel compound of 6-methyl-3-phenethyl-3,4-dihydro-1H-quinazoline-2-thione represented by following formula (1), a preparation method thereof, a medicinal composition for prevention and treatment of hyperpigmentation comprising the same as an effective component, and a skin-whitening cosmetic composition comprising the same as an effective component :

Description

NOVEL COMPOUND OF 6-METHYL-3-PHENETHYL-3,4-DIHYDRO-lH- QUINAZOLINE-2-THIONE, ITS PREPARATION AND A DEPIGMENTATION COMPOSITION CONTAINING THE SAME AS AN EFFECTIVE COMPONENT
Technical Field The present invention relates to a novel compound of 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione represented by the following formula 1, a preparation method thereof, a medicinal composition for prevention and treatment of hyperpigmentation comprising the same as an effective component, and a skin- whitening cosmetic composition comprising the same as an effective component:
Figure imgf000003_0001
(i)
Background Art ' The reason why the skin becomes black and darkened is the excessive biosynthesis of melanin, a natural pigment, in melanocyte due to ultraviolet rays, ill- balanced hormones, mental stress, etc. (Nordlund, J. J. et al., The Pigmentation System: Physiology and Pathophysiology. New York, Oxford Univ. Press, pp. 1-1025, 1998). Therefore, a technology to control the melanin biosynthesis comes under the core technology in development of skin- whitening products for preventing excessive melanin pigmentation in the skin or lightening the color of the melanin pigment which has been already 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, tyrosine as a starting material is converted into DOPA and DOPAquinone by tyrosinase. The DOPA undergoes intermediates of 5,6-dihydroxyindole 2-carboxylic acid and 5,6- dihydroxyindole to produce two types of eumelanins. The DOPAquinone reacts with cysteine to produce pheomelanin. The eumelanin derived from 5,6-dihydroindole 2- carboxylic acid is a brown pigment, the eumelanin derived from 5,6-dihydroindole is a black pigment and the pheomelanin is a yellow-red color pigment (Hearing, N J., FASEB , 5:2902-9, 1991; Hearing, V. J., J. Invest. Dermatol, 4:24-8, 1999). According to studies of gene knockout studies, the lack of tyrosinase causes the albino (white mouse) and the lack of tyrosinase-related protein 2 (TRP-2) causes the slaty. Also, it has been known that the tyrosinase-related protein 1 (TRP-1) plays an important role in development of brown color (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 show any enzymatic activity in the human, though it shows an enzymatic activity of 5,6- dihydroindole 2-carboxylic acid oxidase in the mouse, and is known to participate in the stabilization of tyrosinase (Kobayashi, T, et al, J. Biol. Chem., 272:31801-5, 1998). The UV rays paly an important role in the synthesis of melanin in the skin. When the melanocyte is exposed to the UV rays, it activates protein kinase C by diacylglycerol and then, promotes the synthesis of melanin (Gilchrest, B. A., et al, Photochem. Photobiol, 93:1-10, 1996; Park, H. Y., et al, J. Biol Chem., 274:16470-8, 1999). Keratinocyte, when being exposed to solar rays, releases nitrogen monoxide, alpha-melanocyte stimulating hormone, prostaglandin E2 and endothelin-1. These released factors are transferred to the melanocyte, in which nitrogen monoxide increases the synthesis of melanin via signal transduction of cGMP and protein kinase G and the rest of the factors increase the synthesis of melanin via signal transduction of cAMP and protein kinase 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). The understanding of the melanin synthesis route is very important in the development of skin-whitening products to inhibit hyperpigmentation (discloration, freckles, etc.). Representative examples of melanin biosynthesis inhibitors which are developed so far include kojic acid, arbutin, hydroquinone, vitamin C, mulberry root extract, licorice extract and the like. The kojic acid chelates a copper ion needed for activation of tyrosinase to inhibit the melanin biosynthesis. It has excellent skin- whitening effect. However, recently, it is recognized as a calcinogenic agent and thus, its use is limited. Vitamin C and derivatives thereof show relatively low whitening effect. Hydroquinone is limited in its application in terms of safety due to high skin irritation. In addition, it is known that most of plant extracts show the depigmentation effect only at high concentration but little effect at low concentration.
Therefore, in order to solve the problems involved in the conventional melanin synthesis inhibitors and to seek a more excellent whitening substance, the present inventors have conducted screenings by introducing a multi-polarized activity analysis to find a novel compound of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2- thione. Also, we have confirmed that medicinal compositions and cosmetic compositions comprising the compound as an effective component have excellent skin- whitening effect and completed the present invention based on these discoveries. According to the present invention, there are provided a novel compound of 6- methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione, a preparation method thereof, and a medicinal composition for prevention and treatment of hypeφigmentation and a skin-whitening cosmetic composition comprising the same as an effective component.
Disclosure of the Invention
The present invention is directed to a novel compound of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione represented by the following formula 1, a preparation method thereof, a medicinal composition for prevention and treatment of hypeφigmentation comprising the same as an effective component, and a skin- whitening cosmetic composition comprising the same as an effective component
Figure imgf000006_0001
(1)
According to the present invention, 6-methyl-3-phenethyl-3,4-dihydro-lH- quinazoline-2-thione of the formula 1 may be prepared by reacting 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-one of the formula 4 with Lawesson's reagent as shown in the reaction scheme 1.
Reaction Scheme 1.
Figure imgf000007_0001
(4) (1)
In the above reaction scheme 1, 6-methyl-3-phenethyl-3,4-dihydro-lH- quinazoline-2-one of the formula 4 may be prepared by reducing (5-methyl-2- nitrobenzyl)phenethylamine of the formula 2 to obtain 4-methyl-2- (phenethylaminomethyl)phenylamine of the formula 3, as shown in the following reaction scheme 2, and reacting the product with 1 , l'-carbonyldiimidazole.
Reaction Scheme 2.
Figure imgf000008_0001
(2) (3)
Figure imgf000008_0002
(4)
In the above reaction scheme 2, (5-methyl-2-nitrobenzyl)phenethylamine of the formula 2 may be prepared by reacting 5-methyl-2-nitrobenzyl chloride with phenethylamine, as shown in the following reaction scheme 3.
Reaction Scheme 3.
Figure imgf000008_0003
The preparation of 6-methyl-3 -phenethyl-3 ,4-dihydro- 1 H-quinazoline-2-thione of the formula 1 according to the present invention is summarized as the following reaction scheme 4.
Reaction Scheme 4.
Figure imgf000009_0001
(1) (4)
In accordance with another aspect, the present invention is directed to a medicinal composition for prevention and treatment of hypeφigmentation comprising 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione. Preferably, the medicinal composition comprises 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione in an amount of 0.0001 to 1% by weight based on the total weight of the composition. The medicinal composition is used for prevention or treatment of melanin hypeφigmentation such as discoloration, freckles, senile pigmentary macule and the like and can be formulated into various formulations with a pharmaceutically acceptable carrier, excipient and/or additive. Representative examples include transdermal formulations such as creams, ointments, gels, lotions, solutions or patches. In another aspect, the present invention is directed to a skin-whitening cosmetic composition comprising 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione. Preferably, the skin-whitening cosmetic composition comprises 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione in an amount of 0.0001 to 1 % by weight based on the total weight of the composition. The skin-whitening cosmetic composition is used for treatment or prevention of skin pigment anomaly such as discoloration, freckles, senile pigmentary macule and the like and its formulation is not particularly limited. Representative examples of formulation include toners, astringents, nourishing creams, massage creams, essence,' packs, gels, lotions, patches, sprays or liquid powders. The 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione according to the present invention synthetically inhibits the melanin biosynthesis via protein kinase C, the melanin biosynthesis via cAMP/protein kinase A, the melanin biosynthesis via cGMP/protein kinase G without cytotoxicity and has skin-whitening effect several hundreds times stronger than kojic acid and arbutin which have been already known to the art.
Brief Explanation of Drawings Fig. la shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cAMP/protein kinase A according to the result of Experimental Example 1 ; Fig. lb shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cAMP/protein kinase A, as compared to that of arbutin and kojic acid, according to the result of Experimental Example 1 (•: the material of the present invention O: Arbutin A: Kojic Acid); Fig. 2a shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cGMP/protein kinase G according to the result of Experimental Example 2; Fig. 2b shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via cGMP/protein kinase G, as compared to that of arbutin and kojic acid, according to the result of Experimental Example 2 (•: the material of the present invention O: Arbutin ▲: Kojic Acid); Fig. 3a shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione via l-oleoyl-2- acetylglycerol(OAG)/protein kinase C according to the result of Experimental Example
3; Fig. 3 b shows the melanin biosynthesis inhibiting effect of 6-methyl-3- phenethyl-3 ,4-dihydro- 1 H-quinazoline-2-thione via 1 -oleoyl-2- acetylglycerol(OAG)/protein kinase C, as compared to that of arbutin, according to the result of Experimental Example 3 (•: the material of the present invention O:
Arbutin); Fig. 4 shows the content of tyrosinase produced by a melanoma B16 cell line treated with alpha-melanocyte stimulating hormone and 6-methyl-3-phenethyl-3,4- dihydro-lH-quinazoline-2-thiones at the same time in DMEM supplemented with 10% fetal bovine serum, relative to 100 of the content of tyrosinase produced by a melanom B16 cell line treated only with alpha-melanocyte stimulating hormone, according to the result of Experimental Example 4; Fig. 5a shows the cell growth of a melanoma B16 cell line group (None) propagated in DMEM supplemented with 10% fetal bovine serum and the cell growth of a melanoma B16 cell line group (α -MSΗ) proliferated in the same medium with alpha-melanocyte stimulating hormone added, according to the result of Experimental
Example 5 (•: None O: α -MSΗ only); and Fig. 5b shows the number of surviving cells of melanoma B16 cell line group proliferated in DMEM supplemented with 10% fetal bovine serum with alpha- melanocyte stimulating hormone added and the number of surviving cells of melanoma B16 cell line group proliferated in the same medium with alpha-melanocyte stimulating hormone and 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione (concentration 0.5 to 4 μ M) added, at the fourth day of cultivation, according to the result of Experimental Example 5.
Best mode for carrying out the invention
Now, the present invention will be illustrated in detail through the following
Examples, Formulation Examples and Experimental Examples. However, the present invention is not limited thereto.
Example 1: Preparation of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoIine-2- thione
Example 1-1 : Synthesis of (5-methyl-2-nitrobenzyl phenethylamine Phenethylamine (2 eq. wt, 3.38 ml) and triethylamine (3 eq. wt, 5.6 ml) were dissolved in tetrahydrofuran and 5-methyl-2-nitrobenzyl chloride (2.5 g, 0.0135 mole) dissolved in tetrahydrofuran was added thereto. 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, followed by vacuum distillation. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column. The characteristics of (5-methyl-2-nitrobenzyl)phenethylamine are as follows. Orange oil; Rf=0.26(hexane: ethyl acetate=2:l); Yield 84.8%; IR(KBr) 3350, 3050, 3020, 2930, 2850, 1610, 1585, 1520, 1455, 1340, 1265, 1120cm"1; 1H NMR(CDC13, 89.45MHz) δ 2.40(s, 3H), 2.88(m, 4H), 4.03(s, 2H), 7.13-
7.93(m, 8H)
Example 1-2: Synthesis of 4-methyl-2-(phenethylaminomethyl)phenylamine (5-methyl-2-nitrobenzyl)phenethylamine (3 g) was dissolved in a mixture solution of dichloromethane and methanol (1 :1). Pd carbon (240 mg) was added thereto and the mixture was stirred under a hydrogen pressure of 30 psi for 4 hours. The reaction was filtered by suction through a celite cake and washed with dichloromethane. 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:l); Yield 89.7%; IR(KBr) 3550-3200, 3025, 2930, 2895, 2750, 1620, 1500, 1455, 1265cm-1; Η 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 -7.2 l(m, 8H)
Example 1-3: Synthesis of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-one 4-methyl-2-(phenethylaminomethyl)phenylamine (2 g, 0.00832 mole) was dissolved in anhydrous tetrahydrofuran. 1,1 ' -carbonylimidazole (1.1 eq. wt., 1.48 g) was added thereto. The mixture was refluxed at 50 to 60 °C for 12 hours. Tetrahydrofuran was removed, followed by extraction with hydrated dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column. The characteristics of 6-methyl-3-phenethyl-3,4-dihydro-lH- quinazoline-2-one are as follows. Yellow solid; Rr=0.34(hexane: ethyl acetate=5:l); Yield 81.9%; mp 174.8-175.8°C ; IR(KBr) 3200, 3100-3000, 2920, 1650, 1610, 1500, 1455, 1320, 1270, 1240, 1180cm-1; 1H NMR(CDC13, 89.45MHz) δ 2.25(s, 3H), 2.95(t, J=7.5 Hz, 2H), 3.67(t,
J=7.5 Hz, 2H), 4.3 l(s, 2H), 6.57-7.01(m, 3H), 7.26(m, 5H), 7.88(br, NH)
Example 1-4: Synthesis of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-one (880 mg, 0.0033 mole) was dissolved in toluene and heated. The Lawesson's reagent (0.6 eq. wt., 802 mg) was added thereto. The mixture was refluxed at 100°C for 8 hours. Toluene was removed by vacuum distillation, followed by extraction with hydrated dichloromethane. The organic layer was dehydrated with anhydrous sodium sulfate, vacuum distilled and separated on a column. The characteristics of 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione are as follows. Light yellow solid; Rt=0.63(hexane: ethyl acetate=2:l); Yield 47.2% ; mp 177.2-177J°C ; IR(KBr) 3200, 3020, 2920, 1620, 1550-1480, 1450, 1325, 1265, 1240, 1175, 1150cm'1; Η NMR(CDC13, 89.45MHz) δ 2.27(s, 3H), 3.10(t, J=7.7 Hz, 2H), 4.12(t, J=7.7 Hz, 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
Formulation of Composition
Formulation 1. Medicinal composition for prevention and treatment of hyperpigmentation comprising 6-methy_-3-phenethyl-3,4-dihydro-lH-quinazoline- 2-thione - Ointment
Figure imgf000015_0001
Formulation 2. Medicinal composition for prevention and treatment of hyperpigmentation comprising 6-methyI-3-phenethyl-3,4-dihydro-lΗ-quinazoline- 2-thione - Gel
Figure imgf000015_0002
Figure imgf000016_0001
Formulation 3. Skin-whitening cosmetic composition comprising 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione - Nourishing cream
Figure imgf000016_0002
Formulation 4. Skin-whitening cosmetic composition comprising 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione - Pack
Figure imgf000017_0001
Experimental Example 1: Inhibiting effect on melanin production via cAMP/protein kinase A A melanoma B16 cell line treated with alpha-melanocyte stimulating hormone produces melanin by signal transduction of cAMP/protein kinase A (Rasmussen, N., et al, Neuroendocrinol. Lett., 20:265-282, 1999; Scott, M. C, et al, J. Cell. Sci.
115:2349-55, 2002). The melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 2,500/well of a 96-well plate, under conditions of 37 °C and 5% CO2. After Incubation of 24 hours, the cells were divided into a non-treatment group, a group treated with alpha-melanocyte stimulating hormone and a group treated with alpha-melanocyte stimulating hormone (final concentration 1 nM) and 6-methyl-3 -phenethyl-3, 4-dihydro-lH-quinazoline-2-thi one as an effective agent at the same time. Each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the absoφtion at wavelength 405 run. As a result, the melanoma B16 cells cultured for 3 days in the non-treatment group released 33.2+ 1.4 μglml of melanin and the cells cultured in the group treated with alpha-melanocyte stimulating hormone released 143.9+ 1.6 μglml of melanin. The cells of the group treated with both alpha-melanocyte stimulating hormone and 6- methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione as an effective agent released 37.9+ 0.8 μglml of melanin at an agent concentration of 4 μ M, 44.4± 9.5 μglml of melanin at 2 μ M, 101.1+ 1.0 μglml of melanin at 1 μ M, 126.5+ 5.5 μglml of melanin at 0.5 μ M, that is, the cells showed dose-dependently the whitening effect (Fig. la). The concentration at which 50% whitening effect was observed (EC50) was 1.5 μ M. In the same experimental model, arbutin and kojic acid showed EC50 values of the whitening effect of 151 μ M and 261 μ M, respectively. Therefore, it was noted that the depigmentation effect of 6-methyl-3 -phenethyl-3, 4-dihydro-lH- quinazoline-2-thione on the melanin production of melanoma B16 cell line by signal transduction of cAMP/protein kinase A was 100 times higher than arbutin and 170 times higher than kojic acid in terms of the EC50 value (Fig. lb).
Experimental Example 2: Inhibiting effect on melanin production via cGMP/protein kinase G A melanoma B 16 cell line stimulated with protopoφhyrin IX produces melanin via cGMP/protein kinase G using nitrogen monoxide (Romero-Graillet, C, et al, J. Biol. Chem., 271 :28052-6, 1996). The melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 2,500/well of a 96-well plate, under conditions of 37 °C and 5% CO2. After Incubation of 24 hours, the cells were divided into a non-treatment group, a group treated with protopoφhyrin IX and a group treated with protopoφhyrin IX (final concentration 30 μ M) and 6-methyl-3- phenethyl-3,4-dihydro-lH-quinazoline-2-thione as an effective agent at the same time. Each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the absoφtion at wavelength 405 nm. As a result, the melanoma B16 cells cultured for 3 days in the non-treatment group released 43.4+ 0.8 μglml of melanin and the cells of the group treated with protopoφhyrin IX released 135.2+ 1.9 μglml of melanin. The cells of the group treated with both protopoφhyrin IX and 6-methyl-3 -phenethyl-3, 4-dihydro-lH- quinazoline-2-thione as an effective agent released 52.5+ 5.8 μglml of melanin at an agent concentration of 1 μ M, 94.4+ 6.0 μglml of melanin at 0.5 μ M, 105.2+ 0.9 μglml of melanin at 0.25 μ M, 118.7+ 3.2 μglml of melanin at 0.13 μ M, that is, the cells showed dose-dependently the whitening effect (Fig. 2a). The concentration at which 50% whitening effect was observed (EC50) was 0.5 μ M. In the same experimental model, arbutin and kojic acid showed EC50 values of the whitening effect of 159 μ M and 122 μ M, respectively. Therefore, it was shown that the depigmentation effect of 6-methyl-3 -phenethyl-3, 4-dihydro-lH-quinazoline-2-thione on melanin production of melanoma B 16 cell line by signal transduction of cGMP/protein kinase G was 310 times higher than arbutin and 240 times higher than kojic acid in terms of the EC50 value (Fig. 2b). Experimental Example 3: Inhibiting effect on melanin production via l-oleoyl-2- acetylglycerol/protein kinase C A melanoma B16 cell line stimulated with l-oleoyl-2-acetylglycerol produces melanin via protein kinase C (Gilchrest, B. A., et al, Photochem. Photobiol, 93:1-10, 1996; Park, H. Y, et al, J. Biol. Chem., 274:16470-8, 1999). The melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 2,500/well of a 96-well plate, under conditions of 37 "C and 5% CO2. After Incubation of 24 hours, the cells were divided into a non-treatment group, a group treated with l-oleoyl-2-acetylglycerol and a group treated with l-oleoyl-2- acetylglycerol (final concentration 200 μ M) and 6-methyl-3-phenethyl-3,4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time. Each group was cultured for 3 days and the amount of melanin released into the medium was determined by measurement of the absoφtion at wavelength 405 nm. As a result, the melanoma B16 cells cultured for 3 days in the non-treatment group released 49.8+ 1.0 //g/ml of melanin and the group treated with l-oleoyl-2- acetylglycerol released 109.4+ 0.2 μglml of melanin. The group treated with both 1- oleoyl-2-acetylglycerol and 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione as an effective agent released 57J+ 2.9 g/ml of melanin at an agent concentration of 0.5 μ M, 82.2+ 6.1 μglml of melanin at 0.25 μ M, 106.3+ 0.1 μg/ml of melanin at 0.13 μ M, 109J± 0.4 μglml of melanin at 0.06 μ M, that is, the cells showed dose- dependently the whitening effect (Fig. 3a). The concentration at which 50% whitening effect was observed (EC50) was 0.3 μ M. In the same experimental model, arbutin showed EC50 values of the whitening effect of 473 μ M. Therefore, it was shown that the depigmentation effect of 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2- thione on melanin production of melanoma B16 cell line by signal transduction of protein kinase C was 1,570 times higher than arbutin in terms of the EC50 value (Fig. 3b).
Experimental Example 4: Whitening mechanism reducing tyrosinase content Melanoma B16 cells were seeded in DMEM supplemented with 10% fetal bovine serum at a density of 20,000/well of a 6-well plate, under conditions of 37 °C and 5% CO2 and cultured for 24 hours. The cells were treated with alpha-melanocyte stimulating hormone (final concentration 1 nM) and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time. After incubation for 3 days, the cells were harvested, disrupted and centrifuged. The supernatant was used as an enzyme source. 20 μg of the enzyme source was electrophoresed on polyacrylamide gel containing SDS. Then, the gel was washed with 100 mM phosphate buffer solution (pΗ 6.8) to remove SDS, transferred to 100 mM phosphate buffer solution (pΗ 6.8) containing 5 mM DOPA and stored at 37 °C under light shielded condition. The content of black-dyed tyrosinase was measured using a densitometer. As compared to the tyrosinase content produced by the melanoma B 16 cell line cultured in DMEM supplemented with 10% fetal bovine serum for 3 days, the tyrosinase content produced in the same medium with alpha-melanocyte stimulating hormone added was increased 6 to 7 times. If the tyrosinase content produced by the melanoma B16 cell line treated only by alpha-melanocyte stimulating hormone was assigned to 100%), the tyrosinase content of the group treated with alpha-melanocyte stimulating hormone and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time was 17% at an agent concentration of 4 μ M, 35% at 2 μ M, 83% at 1 μ M, 92% at 0.5 μ M, which showed dose-denpendent inhibiting effect (Fig. 4). Therefore, it was noted that 6-methyl-3 -phenethyl-3, 4-dihydro- 1H- quinazoline-2-thione shows the depigmentation effect by a mechanism reducing tyrosinase content.
Experimental Example 5: cytotoxicity on Melanoma B16 cell line Melanoma B16 cell line suspended in DMEM supplemented with 10% fetal bovine serum were seeded at 2,500/well of a 96-well plate and cultured for 24 hours under conditions of 37°C and 5% CO . The cells were treated with alpha-melanocyte stimulating hormone (final concentration 1 nM) and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione as an effective agent at the same time. Every 24 hours, the numbers of living cells and dead cells were counted using the trypan blue dye method. As compared to a melanoma B 16 cell line cultured in DMEM supplemented with 10% fetal bovine serum, the cells cultured in the same medium treated with alpha- melanocyte stimulating hormone showed growth delay but did not show cell killing toxicity (Fig. 5a). At the fourth day, the group treated with both alpha-melanocyte stimulating hormone and 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-thione (concentration 0.5 to 4 μ M) showed a substantially equal number of living cells, as compared to the group treated only with alpha-melanocyte stimulating hormone and did not show cell killing toxicity (Fig. 5b).
Industrial applicability The present invention provides a novel compound of 6-methyl-3-phenethyl- 3,4-dihydro-lH-quinazoline-2-thione with excellent skin- whitening effect which prevent melanin hypeφigmentation of the skin, or light the color of melanin pigment which has been already accumulated to improve hypeφigmentation such" as discoloration and freckles, preparation method thereof, and a medicinal composition and a cosmetic composition comprising the same.

Claims

1. A compound of 6-methyl-3 -phenethyl-3 ,4-dihydro- lH-quinazoline-2-thione represented by the following formula 1 :
Figure imgf000024_0001
(1)
2. A method for preparing 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline- 2-thione comprising reacting 6-methyl-3 -phenethyl-3, 4-dihydro- lH-quinazoline-2-one represented by the following formula 4 with Lawesson's reagent.
Figure imgf000024_0002
(4)
3. The method according to claim 2, in which 6-methyl-3 -phenethyl-3, 4- dihydro-lH-quinazoline-2-one is prepared by reducing (5-methyl-2- nitrobenzyl)phenethylamine represented by the following formula 2 to obtain 4-methyl-
2-(phenethylaminomethyl)phenylamine represented by the following formula 3 and reacting the product with l,l'-carbonyldiimidazole.
Figure imgf000025_0001
(2) (3)
4. A medicinal composition for prevention and treatment of hypeφigmentation comprising 6-methyl-3-phenethyl-3,4-dihydro-lH-quinazoline-2-thione as an effective component in an amount of 0.0001 to 1 % by weight based on the total weight of the composition.
5. The medicinal composition according to claim 4, in which the composition is formulated in the form of cream, ointment, gel, lotion, liquid or patch.
6. A skin- whitening cosmetic composition comprising 6-methyl-3-phenethyl- 3, 4-dihydro- lH-quinazoline-2-thione as an effective component in an amount of 0.0001 to 1 % by weight based on the total weight of the composition.
7. The skin- whitening cosmetic composition according to claim 6, in which the composition is formulated in the form of toner, astringent, nourishing cream, massage cream, essence, pack, gel, lotion, patch, spray or liquid powder.
8. A method for preventing or treating hypeφigmentation comprising administering a therapeutically effective amount of the compound of claim 1.
9. Use of the compound of claim 1 as preventing or treating agent for hypeφigmentation.
10. Use of a compound of claim 1 in the preparation of a medicinal composition for prevent or treatment of hypeφigmentation.
1 1. Use of a compound of claim 1 in the preparation of a skin cosmetic composition for improving hypeφigmentation.
PCT/KR2003/002545 2003-08-19 2003-11-25 Novel compound of 6-methyl-3-phenethyl-3,4-dihydro-1h-quinazoline-2-thinone, its preparation and a depigmentation compositon containing the same as an effective component WO2005016895A1 (en)

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