KR20200104476A - 7-benzyl-4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives and Composition for skin whitening and Pharmaceutical composition for use in preventing or treating disorders of Melanin Hyperpigmentation containing the same as an active ingredient - Google Patents
7-benzyl-4-(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives and Composition for skin whitening and Pharmaceutical composition for use in preventing or treating disorders of Melanin Hyperpigmentation containing the same as an active ingredient Download PDFInfo
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- KR20200104476A KR20200104476A KR1020190022646A KR20190022646A KR20200104476A KR 20200104476 A KR20200104476 A KR 20200104476A KR 1020190022646 A KR1020190022646 A KR 1020190022646A KR 20190022646 A KR20190022646 A KR 20190022646A KR 20200104476 A KR20200104476 A KR 20200104476A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound represented
- halogen
- hydrogen
- melanin
- Prior art date
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- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 239000000203 mixture Substances 0.000 title claims abstract description 81
- 230000002087 whitening effect Effects 0.000 title claims abstract description 44
- 239000004480 active ingredient Substances 0.000 title claims abstract description 23
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- OLKDDGYSUJVGTB-UHFFFAOYSA-N 7-benzyl-4-(4-phenylpiperazin-1-yl)pyrrolo[2,3-d]pyrimidine Chemical class C(C1=CC=CC=C1)N1C=CC2=C1N=CN=C2N1CCN(CC1)C1=CC=CC=C1 OLKDDGYSUJVGTB-UHFFFAOYSA-N 0.000 title abstract description 9
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- 150000001875 compounds Chemical class 0.000 claims description 114
- 150000003839 salts Chemical class 0.000 claims description 42
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- 238000000034 method Methods 0.000 claims description 20
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- GOSDNMBNNPLCMT-UHFFFAOYSA-N 4-[7-benzyl-4-[4-(2-fluorophenyl)piperazin-1-yl]pyrrolo[2,3-d]pyrimidin-5-yl]-2,6-dichlorophenol Chemical compound C(C1=CC=CC=C1)N1C=C(C2=C1N=CN=C2N2CCN(CC2)C2=C(C=CC=C2)F)C2=CC(=C(C(=C2)Cl)O)Cl GOSDNMBNNPLCMT-UHFFFAOYSA-N 0.000 claims description 2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/045—Organic compounds containing nitrogen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
Abstract
Description
7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체 및 이를 유효성분으로 함유하는 피부 미백용 조성물 및 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. 구체적으로, 상기 피부 미백용 조성물은 피부 미백용 화장료 조성물 및 피부 미백용 건강기능 건강기능 식품을 포함한다.7-Benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative and skin whitening composition containing the same as an active ingredient and prevention of melanin hyperpigmentation disease Or it relates to a pharmaceutical composition for treatment. Specifically, the composition for skin whitening includes a cosmetic composition for skin whitening and a health functional food for skin whitening.
사람의 피부색은 크게 멜라닌, 헤모글로빈, 카로틴등에 의해 결정되는데 이중에서 멜라닌이 가장 중요한 역할을 한다. 멜라닌(melanin)은 동물, 식물, 미생물 등에서 발견되는 검은 색소로 생육이나 발달에 필수적이진 않지만, 환경에 대한 생존력과 경쟁력을 높여주는 물질이다. 멜라닌은 생물체에서 발견되는 색소 중에서도 안정성이 있는 색소이고, 거의 모든 용매에 용해되지 않으며, 멜라닌 색소 합성(melanogenesis) 과정은 특별히 분화된 세포인 멜라노사이트(melanocytes)의 소기관인 멜라노좀(melanosome)에서 일어나는 것으로 밝혀졌다. 즉, 피부색은 멜라닌의 함량, 분포 등에 따라 결정되며 멜라노사이트(melanocyte) 내에서 생성된 후 세포 외부로 방출되는 멜라노좀의 수와 분포에 연관되어 있으며, 멜라닌은 자외선 광으로부터 피부를 보호하는 순기능을 가지고 있지만, 과다 생성되는 경우 기미, 주근깨 등 피부색 침착(hyperpigmentation) 및 흑색종(melanomas) 등을 유발의 중요 요인으로 알려져있다(J. Drugs Dermatol., 2004, 3, 668-678).Human skin color is largely determined by melanin, hemoglobin, and carotene, among which melanin plays the most important role. Melanin (melanin) is a black pigment found in animals, plants, microorganisms, etc., and is not essential for growth or development, but is a substance that enhances viability and competitiveness for the environment. Melanin is a pigment with stability among pigments found in living organisms, and is insoluble in almost all solvents, and the melanogenesis process occurs in melanosomes, organelles of melanocytes, which are specially differentiated cells. Turned out to be. In other words, skin color is determined according to the content and distribution of melanin, and is related to the number and distribution of melanosomes that are produced in melanocytes and then released to the outside of the cell, and melanin has a pure function of protecting the skin from ultraviolet light. However, when over-produced, it is known as an important factor in inducing hyperpigmentation and melanomas such as melasma and freckles (J. Drugs Dermatol., 2004, 3, 668-678).
멜라닌의 생체내 합성과정은 다음과 같다. 멜라닌을 합성하는 세포인 멜라노사이트(Melanocyte)내 멜라노좀(Melanosome)에서 티로시나제(Tyrosinase)라는 효소에 의해 티로신(Tyrosine)을 기질로 하여 도파(DOPA), 도파퀴논(DOPA quinone)을 거쳐 도파크롬 (DOPA chrome)을 생성시키는 자동산화 반응을 거쳐 공중합체인 멜라닌이 생성된다. 이렇게 생성된 멜라닌은 멜라노좀이라는 주머니를 통해 케라티노사이트로 옮겨지게 되고 케라티노사이트에서 28일간의 각화 과정을 거치면서 피부표면으로 올라오게 된다. 그러나 이 과정에서 멜라닌 생성을 촉진하는 요인에 의해서 멜라닌이 과량 생성되고 각질화 과정의 주기가 생리적으로 길어지면서 각질과 함께 멜라닌이 피부에서 소실되지 않고 색소침착(Pigmentation) 현상이 나타나게 된다. 따라서 이러한 색소 침착 현상을 막아주기 위해서는 멜라닌 생성과정에서의 일부 과정을 조절해 줌으로서 억제할 수가 있다.The synthesis process of melanin in vivo is as follows. In the melanocyte, the cell that synthesizes melanin, by an enzyme called tyrosinase, tyrosine is used as a substrate through dopa, dopaquinone, and dopacrom (Dopa quinone). Through an automatic oxidation reaction that generates DOPA chrome), melanin, a copolymer, is produced. The melanin produced in this way is transferred to keratinocytes through a pocket called melanosomes, and comes up to the skin surface through a 28-day keratinization process from keratinocytes. However, in this process, melanin is produced in excess due to the factors that promote melanin production, and the cycle of the keratinization process is physiologically lengthened, so that melanin along with keratin is not lost from the skin, and pigmentation occurs. Therefore, in order to prevent such pigmentation phenomenon, it can be suppressed by controlling some processes in the melanin production process.
구체적으로, 타이로시네이즈(tyrosinase, EC 1.14.18.1)는 식물, 미생물, 포유동물 세포에서 일어나는 멜라닌 생합성의 가장 중요한 효소로서 타이로신을 멜라닌 생합성의 핵심 전구체인 도파퀴논(DOPA Quinone)로 전환시킨다. 이 효소는 L-타이로신(L-tyrosine)을 L-도파(DOPA, 3,4-dihydroxyphenylalanin)로 전환시키는 모노페놀레이즈(monophenolase) 기능과 L-도파를 L-도파퀴논으로 전환시키는 디페놀레이즈 (diphenolase)기능을 수행한다(J. Appl. Microbiol., 2006, 100, 219-232; Int. J. Biochem. Cell Biol., 2004, 36, 235-246). 여기서 만들어진 도파퀴논은 효소작용의 도움없이 자동적으로 멜라닌으로 전환된다. 따라서, 타이로시네이즈의 활성을 억제함으로써, 멜라닌 생합성을 억제하게 되는 것이다.Specifically, tyrosinase (EC 1.14.18.1) converts tyrosine into dopaquinone, a key precursor of melanin biosynthesis, as the most important enzyme in melanin biosynthesis occurring in plants, microorganisms, and mammalian cells. This enzyme functions as a monophenolase that converts L-tyrosine to L-dopa (3,4-dihydroxyphenylalanin) and diphenolase (which converts L-dopa to L-dopaquinone). diphenolase) function (J. Appl. Microbiol., 2006, 100, 219-232; Int. J. Biochem. Cell Biol., 2004, 36, 235-246). Dopaquinone made here is automatically converted to melanin without the aid of enzymatic action. Therefore, by inhibiting the activity of tyrosinase, melanin biosynthesis is suppressed.
멜라닌 합성을 저해하는 기작은 여러가지 존재한다. 대표적인 멜라닌 합성 저해과정은 멜라닌 합성의 중요한 효소인 티로시나제의 활성을 저해하는 것이며, 상업화되어 있는 대표적인 성분으로는 구리이온을 활성 부위로 갖고 있는 티로시나제의 활성을 억제하는 코직산(Kojic acid)(대한민국 공개특허 제10-2015-0062272)과 같은 킬레이트(chelator)나, 알부틴(Arbutin)과 같이 티로시나제의 기질인 티로신과 유사한 구조를 갖고 있는 물질을 사용하여 티로시나제에 티로신과 더불어 경쟁적으로 반응하게 함으로서 멜라닌 생성을 억제시키는 물질들도 색소침착 억제제로 많이 사용되고 있다. 그러나 대부분의 미백 원료들은 안정성이 낮아 효과가 오래 지속되지 못하는 단점을 가지고 있어 제품에 적용하는데 있어 많은 한계점을 갖고 있다.There are several mechanisms that inhibit melanin synthesis. A typical melanin synthesis inhibition process is to inhibit the activity of tyrosinase, an important enzyme in melanin synthesis, and as a commercially available representative component, Kojic acid, which inhibits the activity of tyrosinase, which has copper ions as an active site (Korean Patent Publication) No. 10-2015-0062272) or a substance having a structure similar to tyrosine, which is a substrate of tyrosinase, such as arbutin, is used to competitively react with tyrosine to tyrosinase, thereby inhibiting melanin production. Substances that cause pigmentation are also widely used as pigmentation inhibitors. However, most of the whitening ingredients have a disadvantage in that the effect does not last long due to low stability, so there are many limitations in application to products.
본 발명의 일 목적은 7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체를 제공하는 것이다.One object of the present invention is to provide a 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative.
본 발명의 다른 목적은 7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체를 유효성분으로 함유하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to prevent melanin hyperpigmentation disease containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient Or to provide a therapeutic pharmaceutical composition.
본 발명의 다른 목적은 7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체를 유효성분으로 함유하는 피부 미백용 화장료 조성물을 제공하는 것이다.Another object of the present invention is to provide a cosmetic composition for skin whitening containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient Is to do.
본 발명의 다른 목적은 7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체를 유효성분으로 함유하는 피부 미백용 건강기능 식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for skin whitening containing 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative as an active ingredient. To provide.
상기 목적을 달성하기 위하여,To achieve the above object,
본 발명의 일 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염이 제공된다:According to an aspect of the present invention, there is provided a compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
본 발명의 다른 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물이 제공된다.According to another aspect of the present invention, a pharmaceutical for the prevention or treatment of melanin hyperpigmentation disease comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
본 발명의 다른 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 화장료 조성물이 제공된다.According to another aspect of the present invention, there is provided a cosmetic composition for skin whitening comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
본 발명의 다른 측면에 따라, 상기 피부 미백용 화장료 조성물을 포함하는 피부 미백용 미용제품이 제공된다.According to another aspect of the present invention, there is provided a skin whitening cosmetic product comprising the cosmetic composition for skin whitening.
본 발명의 다른 측면에 따라, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 건강기능 식품이 제공된다.According to another aspect of the present invention, there is provided a functional food for skin whitening comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능 식품을 필요한 대상에게 투여하는 단계를 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, a pharmaceutical composition or health functional food containing the compound represented by Formula 1, its isomer, solvate, hydrate or pharmaceutically acceptable salt thereof as an active ingredient to a subject in need There is provided a method of preventing or treating melanin hyperpigmentation disease comprising administering.
본 발명의 다른 측면에 따라, 멜라닌 색소 과다 침착 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능 식품의 용도가 제공된다.According to another aspect of the present invention, a pharmaceutical containing a compound represented by Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof in the prevention or treatment of melanin hyperpigmentation disease The use of a suitable composition or dietary supplement is provided.
본 발명의 7-벤질-4(4-페닐피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 유도체는 적은 양을 사용하여도 멜라닌의 생성을 억제하는 효과를 나타내므로, 이를 멜라닌 색소 과다 침착 질환 치료용 조성물, 피부 미백용 화장료 조성물 및 피부 미백용 건강기능 식품으로 유용하게 사용할 수 있다.The 7-benzyl-4(4-phenylpiperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivative of the present invention exhibits an effect of inhibiting the production of melanin even when used in a small amount. Therefore, it can be usefully used as a composition for treatment of melanin hyperpigmentation diseases, a cosmetic composition for skin whitening, and a health functional food for skin whitening.
도 1은 실험예 1에서 수행한 본 발명에 따른 화합물의 멜라닌 생성 억제효과실험 결과를 나타낸 이미지이다.1 is an image showing the results of the melanin production inhibitory effect of the compound according to the present invention performed in Experimental Example 1.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
한편, 본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한, 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.On the other hand, embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided in order to more completely explain the present invention to those having average knowledge in the art. Furthermore, "including" a certain component throughout the specification means that other components may be further included, rather than excluding other components unless specifically stated to the contrary.
전술한 바와 같이, 지구 환경 변화와 오존층 파괴로 과다한 자외선 노출에 의한 질환들이 해결해야 할 숙제로 떠오르는 동시에, 하얗고 깨끗한 피부와 관련한 미용에 대한 현대인들의 관심이 높아지면서, 기미나 주근깨 등의 피부 색소 침착 치료 및 예방에 도움을 주기 위한 화장품 등이 개발되기 시작하였다. 그러나 대부분의 미백 원료들은 안정성이 낮아 효과가 오래 지속되지 못하는 단점을 가지고 있어, 제품에 적용하는데 있어 많은 한계점을 갖고 있다.As described above, diseases caused by excessive UV exposure due to changes in the global environment and the destruction of the ozone layer have emerged as a homework to be solved, and as modern people's interest in beauty related to white and clean skin has increased, skin pigmentation such as spots and freckles Cosmetics and the like have begun to be developed to help with treatment and prevention. However, most of the whitening ingredients have a disadvantage that the effect does not last a long time due to their low stability, so they have many limitations in applying to products.
본 발명의 일 측면은 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 제공한다.One aspect of the present invention provides a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
상기 화학식 1에서,In
상기 R1은 수소 또는 할로겐이고; 및R 1 is hydrogen or halogen; And
R2는 수소 또는 페닐이고, 상기 아릴은 -OH 및 할로겐으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다.R 2 is hydrogen or phenyl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH and halogen.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기 화합물 군을 들 수 있다: Examples of the compound represented by
(1) 7-벤질-4-(4-(4-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘;(1) 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine;
(2) 4-(7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘-5-일)-2,6-디클로로페놀.(2) 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 ,6-dichlorophenol.
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by
본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of
또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Further, the present invention includes not only the compound represented by
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecμLar force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1당량 이상, 바람직하게는, 1 당량 내지 5당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 이성질체 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecule force. Or its salt. The hydrate of the compound represented by
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term "solvate" refers to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor include volatile, non-toxic, and/or suitable solvents for administration to humans.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체, 광학 이성질체(enantiomer)가 모두 포함된다. 이들 모든 이성체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula, but structurally or sterically different. Such isomers include structural isomers such as tautomers, R or S isomers having an asymmetric carbon center, stereoisomers such as geometric isomers (trans, cis), and optical isomers. All these isomers and mixtures thereof are also included within the scope of the present invention.
상기 화학식 1로 표시되는 화합물에서, R2가 수소일경우, 하기 반응식 1에 나타난 바와 같이,In the compound represented by
화학식 2로 표시되는 화합물 및 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및Preparing a compound represented by
상기 단계 1에서 얻은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1a로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 제조방법으로 제조할 수 있다.It can be prepared by a manufacturing method including the step of preparing a compound represented by Formula 1a by reacting the compound represented by
[반응식 1][Scheme 1]
상기 반응식 1에서,In
R1 및 R2는 화학식 1에서 정의한 바와 같고;R 1 and R 2 are as defined in
X1 및 X2는 각각 독립적으로 할로겐이고; 및X 1 and X 2 are each independently halogen; And
화학식 1a로 표시되는 화합물은 R2가 수소인 본 발명의 화학식 1로 표시되는 화합물의 유도체이다.The compound represented by Formula 1a is a derivative of the compound represented by
상기 반응식 1의 제조방법에 있어서,In the preparation method of
단계 1은 화학식 2로 표시되는 화합물의 할로겐과 화학식 3으로 표시되는 화합물의 2차아민이 반응하여 아민 본드로 결합된 화학식 4로 표시되는 화합물을 제조하는 단계로서, 할로겐과 아민을 반응시켜 아민본드를 만드는 조건이라면 한정되지 않으며, 당업자에게 널리 알려진 방법을 사용할 수 있다. 본 발명에서는 실시예와 같은 조건으로 반응을 수행하였으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.
단계 2는 화학식 4로 표시되는 화합물의 2차 아민과 화학식 5로 표시되는 화합물의 할로겐이 반응하여 아민 본드로 결합된 화학식 1a로 표시되는 화합물을 제조하는 단계로서, 할로겐과 아민을 반응시켜 아민본드를 만드는 조건이라면 한정되지 않으며, 당업자에게 널리 알려진 방법을 사용할 수 있다. 본 발명에서는 실시예와 같은 조건으로 반응을 수행하였으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.
또한, 상기 화학식 1로 표시되는 화합물에서, R2가 C6-10의 아릴일경우, 하기 반응식 2에 나타난 바와 같이,In addition, in the compound represented by
화학식 1a로 표시되는 화합물을 할로겐화 시켜 화학식 7로 표시되는 화합물을 제조하는 단계(단계 1);Halogenating the compound represented by Formula 1a to prepare a compound represented by Formula 7 (Step 1);
상기 단계 1에서 얻은 화학식 7로 표시되는 화합물과 화학식 8로 표시되는 화합물을 반응시켜 화학식 1b로 표시되는 화합물을 제조하는 단계(단계 2);를 포함하는 제조방법으로 제조할 수 있다.It can be prepared by a manufacturing method including the step of preparing a compound represented by Formula 1b by reacting the compound represented by Formula 7 and the compound represented by Formula 8 obtained in Step 1 (Step 2).
[반응식 2][Scheme 2]
상기 반응식 1에서,In
R1 및 R2는 화학식 1에서 정의한 바와 같고;R 1 and R 2 are as defined in
X3은 할로겐이고;X 3 is halogen;
화학식 1a로 표시되는 화합물은 R2가 수소인 본 발명의 화학식 1로 표시되는 화합물의 유도체이고; 및The compound represented by Formula 1a is a derivative of the compound represented by
화학식 1b로 표시되는 화합물은 R2가 C6-10의 아릴인 본 발명의 화학식 1로 표시되는 화합물의 유도체이다.The compound represented by Formula 1b is a derivative of the compound represented by
상기 반응식 2의 제조방법에 있어서,In the preparation method of
화학식 1a로 표시되는 화합물은 상기 반응식 1의 제조방법으로 제조할 수 있다.The compound represented by Formula 1a can be prepared by the preparation method of
단계 1은 화학식 1a로 표시되는 화합물을 할로겐화 시켜 할로겐이 도입된 화학식 7로 표시되는 화합물을 제조하는 단계로서, 할로겐화를 수행할 수 있는 조건이라면 한정되지 않으며, 당업자에게 널리 알려진 방법을 사용할 수 있다. 본 발명에서는 실시예와 같은 조건으로 반응을 수행하였으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.
단계 2는 화학식 7로 표시되는 화합물의 할로겐과 화학식 8로 표시되는 화합물의 보론기가 반응하여 아릴화가 일어나 화학식 1b로 표시되는 화합물을 제조하는 단계로서, 당업자에게 널리 알려진 방법을 사용할 수 있다. 본 발명에서는 실시예와 같은 조건으로 반응을 수행하였으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.
본 발명의 다른 측면은, 하기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention is a pharmaceutical for the prevention or treatment of melanin hyperpigmentation disease comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
상기 멜라닌 색소 과다 침착 질환은 기미, 주근깨, 노인성 색소반 또는 일광흑색증(solar lentigines)일 수 있으나, 이는 일례일뿐, 이에 한정되는 것은 아니다.The melanin hyperpigmentation disease may be melasma, freckles, senile pigment spots, or solar lentigines, but this is only an example and is not limited thereto.
상기 화합물은 합물은 멜라닌(melanin) 생성을 억제할 수 있다.The compound can inhibit the production of melanin.
본 발명의 화합물의 멜라닌 색소 과다 침착 질환의 치료 효과를 확인하기 위하여, 멜라닌 생성 억제 효과를 평가한 결과, 본 발명에 따른 화학식 1로 표시되는 화합물은 멜라닌 생성을 우수하게 억제하고, 종래 멜라닌 생성 억제 화합물로 잘 알려진 코직산보다 현저하게 우수한 멜라닌 생성 억제 효과를 나타냄을 확인하였다.In order to confirm the therapeutic effect of the compound of the present invention in the treatment of melanin hyperpigmentation disease, as a result of evaluating the melanin production inhibitory effect, the compound represented by
따라서, 본 발명의 화학식 1로 표시되는 화합물은 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물로 유용하게 사용할 수 있다.Therefore, the compound represented by
본 발명에 따른 상기 약학적 조성물에 있어서, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 보다 바람직하게는 비경구 제형일 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.In the pharmaceutical composition according to the present invention, the compound represented by
본 발명은 또한 상기 화학식 1의 화합물을 유효성분으로 포함하는 피부 미백 효과를 위한 피부 외용제의 제형으로 제공할 수 있다.The present invention can also be provided as a formulation of a skin external preparation for skin whitening effect comprising the compound of
상기 화학식 1의 화합물을 피부외용제로 사용하는 경우, 추가로 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온봉쇄제 및 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 피부용 외용제에 통상적으로 사용되는 임의의 다른 성분과 같은 피부 과학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다. 또한 상기 성분들은 피부 과학분야에서 일반적으로 사용되는 양으로 도입될 수 있다.When the compound of
상기 화학식 1의 화합물이 피부 외용제 제형으로 제공될 경우, 이에 제한되는 것은 아니나, 연고, 패취, 겔, 크림 또는 분무제와 같은 제형을 가질 수 있다.When the compound of
본 발명의 약학적 조성물은 특히 바람직하게 비경구용 제제로 이용될 수 있으며, 예를 들어, 피부외용제는 바세린, 스테아릴알콜 등의 약학적으로 허용되는 적당한 기제; 폴리소르베이트, 솔르비탄 세스퀴올레이트 등의 약학적으로 허용되는 적당한 계면활성제; 글리세린 등의 약학적으로 허용되는 적당한 보습제; 약학적으로 허용되는 적당한 용제; 및 착향제, 착색제, 안정화제, 점성화제 등을 균질하게 혼합하는 통상의 피부외용제 제조방법에 의해서 제조될 수 있다.The pharmaceutical composition of the present invention may be particularly preferably used as a parenteral preparation. For example, the external preparation for skin may include a suitable pharmaceutically acceptable base such as petrolatum and stearyl alcohol; Suitable pharmaceutically acceptable surfactants such as polysorbate and sorbitan sesquioleate; Pharmaceutically acceptable suitable moisturizers such as glycerin; Suitable pharmaceutically acceptable solvents; And a flavoring agent, a colorant, a stabilizer, a viscous agent, and the like are homogeneously mixed.
또한, 본 발명의 상기 화학식 1의 화합물을 의약품으로 사용하는 경우, 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다. 예컨대, 공지의 피부 미백 성분을 포함할 수 있을 것이다. 추가적인 피부 미백 성분을 포함하게 되면 본 발명의 조성물의 피부 미백 효과는 더욱 증진될 수 있을 것이다.In addition, when the compound of
상기 성분추가 시에는 복합 사용에 따른 피부 안전성, 제형화의 용이성, 유효성분들의 안정성을 고려할 수 있다. 본 발명의 한 구체예에서, 상기 조성물은 당업계에 공지된 미백 성분으로서, 코즈산(Kojic acid), 알부틴(Arbutin) 등과 같은 타이로시네이즈 효소활성을 억제하는 물질, 하이드로퀴논(Hydroquinone), 비타민-C(L-Ascorbic acid); 및 이들의 유도체와 각종 식물 추출물로 구성되는 군으로부터 선택되는 1종 또는 2종 이상의 성분을 추가로 포함할 수 있다. 추가의 성분은 전체 조성물 중량에 대하여 0.0001 중량% 내지 10 중량%로 포함될 수 있을 것이며, 상기 함량 범위는 피부 안전성, 상기 화학식 1의 화합물의 제형화 시의 용이성 등의 요건에 따라 조절될 수 있을 것이다.When the above ingredients are added, skin safety, ease of formulation, and stability of active ingredients can be considered in combination with use. In one embodiment of the present invention, the composition is a whitening component known in the art, a substance that inhibits tyrosinase enzyme activity such as Kojic acid, arbutin, and hydroquinone, Vitamin-C (L-Ascorbic acid); And it may further include one or two or more components selected from the group consisting of derivatives thereof and various plant extracts. Additional ingredients may be included in an amount of 0.0001% to 10% by weight based on the total weight of the composition, and the content range may be adjusted according to requirements such as skin safety and ease of formulation of the compound of
본 발명의 약학적 조성물은 유효량의 상기 화학식 1의 화합물을 포함할 때 바람직한 피부 미백 효과를 제공할 수 있다. 본 발명에 있어서, '유효량'이라 함은 피부 미백 효과를 나타낼 수 있는 화합물의 양을 의미한다.When the pharmaceutical composition of the present invention contains an effective amount of the compound of
본 발명의 조성물에 포함되는 상기 화학식 1의 화합물의 유효량은 조성물이 제품화되는 형태, 상기 화합물이 피부에 적용되는 방법 및 피부에 머무르는 시간 등에 따라 달라질 것이다. 예컨대, 상기 조성물이 의약품으로 제품화되는 경우에는 일상적으로 피부에 적용하게 되는 화장품으로 제품화되는 경우에 비해 높은 농도로 상기 화학식 1의 화합물을 포함할 수 있을 것이다. 따라서, 일일 투여량은 상기 화학식 1의 화합물의 양을 기준으로 0.1 내지 100 ㎎/㎏이고, 바람직하게는 30 내지 80 ㎎/㎏이고, 더욱 바람직하게는 50 내지 60 mg/kg이며, 하루 1 ∼ 6 회 투여될 수 있다.The effective amount of the compound of
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches.These formulations include diluents (e.g., lactose) in addition to the active ingredients. , Dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (e.g. silica, talc, stearic acid and its magnesium or calcium salt and/or polyethylene glycol). Tablets may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and in some cases, boron such as starch, agar, alginic acid or sodium salt thereof. It may contain release or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
본 발명의 다른 측면은, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다.Another aspect of the present invention provides a cosmetic composition for skin whitening comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
상기 화합물은 합물은 멜라닌(melanin) 생성을 억제할 수 있다.The compound can inhibit the production of melanin.
본 발명의 화합물의 피부 미백 효과를 확인하기 위하여, 멜라닌 생성 억제 효과를 평가한 결과, 본 발명에 따른 화학식 1로 표시되는 화합물은 멜라닌 생성을 우수하게 억제하고, 종래 멜라닌 생성 억제 화합물로 잘 알려진 코직산보다 현저하게 우수한 멜라닌 생성 억제 효과를 나타냄을 확인하였다.In order to confirm the skin whitening effect of the compound of the present invention, as a result of evaluating the melanin production inhibitory effect, the compound represented by
따라서, 본 발명의 화학식 1로 표시되는 화합물은 피부 미백용 화장료 조성물로 유용하게 사용할 수 있다.Therefore, the compound represented by
본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 피부미용 개선용 조성물을 제조함에 있어서, 통상적으로 함유되는 피부미용 개선용 조성물에 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염이 3 내지 30 중량부, 바람직하게는 5 또는 20 중량부로 첨가할 수 있다.In preparing a composition for improving skin beauty containing a compound represented by
또한, 본 발명의 화장료 조성물에는 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염에 추가로 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온 봉쇄제 및 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 피부미용 개선용 조성물에 통상적으로 사용되는 임의의 다른 성분과 같은 피부 과학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다. In addition, the cosmetic composition of the present invention includes fatty substances, organic solvents, solubilizers, thickeners and gelling agents, emollients, antioxidants, suspending agents, in addition to the compound represented by
또한, 상기 성분들은 피부 과학 분야에서 일반적으로 사용되는 양으로 도입될 수 있다.In addition, the ingredients may be introduced in an amount generally used in the field of dermatology.
나아가, 본 발명에 따른 피부 미백용 화장료 조성물은 용액, 외용연고, 크림, 폼, 영양화장수, 유연화장수, 팩, 유연수, 유액, 메이크업베이스, 에센스, 비누, 액체 세정료, 입욕제, 선 스크린크림, 선오일, 현탁액, 유탁액, 페이스트, 겔, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션, 패취 및 스프레이로 구성된 군으로부터 선택되는 제형으로 제조할 수 있으나, 이에 제한되는 것은 아니다.Further, the cosmetic composition for skin whitening according to the present invention is a solution, external ointment, cream, foam, nutrient lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, Sun oil, suspension, emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray can be prepared in a formulation selected from the group consisting of However, it is not limited thereto.
또한, 본 발명의 화장료 조성물은 일반 피부 화장료에 배합되는 화장품학적으로 허용 가능한 담체를 1종 이상 추가로 포함할 수 있으며, 통상의 성분으로 예를 들면 유분, 물, 계면활성제, 보습제, 저급 알코올, 증점제, 킬레이트제, 색소, 방부제, 향료 등을 적절히 배합할 수 있으나, 이에 제한되는 것은 아니다.In addition, the cosmetic composition of the present invention may additionally include one or more cosmetically acceptable carriers blended in general skin cosmetics, and as common ingredients, for example, oil, water, surfactant, moisturizer, lower alcohol, A thickener, a chelating agent, a colorant, a preservative, a fragrance, and the like may be appropriately mixed, but are not limited thereto.
본 발명의 화장료 조성물에 포함되는 화장품학적으로 허용 가능한 담체는 제형에 따라 다양하다. 본 발명의 제형이 연고, 페이스트, 크림 또는 젤인 경우에는, 담체성분으로서 동물성 유, 식물성 유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 산화아연 또는 이들의 혼합물이 이용될 수 있다.The cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation. When the formulation of the present invention is an ointment, paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide or Mixtures of these can be used.
본 발명은 또한 상기 화학식 1로 표시되는 화합물을 개체의 피부에 도포하는 단계를 포함하는, 피부 미백 방법을 제공한다. 상기 개체는 쥐, 가축, 인간 등을 포함하는 포유동물을 제한 없이 포함한다. The present invention also provides a skin whitening method comprising the step of applying the compound represented by
본 발명의 다른 측면은, 상기 피부 미백용 화장료 조성물을 포함하는 피부 미백용 미용제품을 제공한다.Another aspect of the present invention provides a skin whitening cosmetic product comprising the skin whitening cosmetic composition.
상기 미백제품은은 용액, 외용연고, 크림, 폼, 영양화장수, 유연화장수, 팩, 유연수, 유액, 메이크업베이스, 에센스, 비누, 액체 세정료, 입욕제, 선 스크린크림, 선오일, 현탁액, 유탁액, 페이스트, 겔, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션, 패취 및 스프레이로 구성된 군으로부터 선택되는 제형으로 제조할 수 있으나, 이에 제한되는 것은 아니다.The whitening products are silver solution, external ointment, cream, foam, nutrient lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, sun oil, suspension, emulsion , Paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch, and spray can be prepared in a formulation selected from the group consisting of, but is not limited thereto. .
본 발명의 제형이 파우더 또는 스프레이인 경우에는, 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록사이드, 칼슘 실케이트, 폴리아미드 파우더 또는 이들의 혼합물이 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진제를 포함할 수 있다.When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, or mixtures thereof may be used as a carrier component, and in particular, in the case of a spray, additional chloro Propellants such as fluorohydrocarbon, propane/butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는, 담체 성분으로서 용매, 용해화제, 또는 유탁화제가 이용되고 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-브틸글리콜 오일이 있으며, 특히, 목화씨 오일, 땅콩 오일, 옥수수 배종 오일, 올리브 오일, 피마자 오일 및 참깨 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, a solvent, a solubilizing agent, or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl benzoate, propylene glycol, 1,3 -Butylglycol oil, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.
본 발명의 제형이 현탁액인 경우에는, 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리 옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, micro Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, and the like may be used.
본 발명의 제형이 비누인 경우에는 담체 성분으로서 지방산의 알칼리 금속 염, 지방산 헤미에스테르 염, 지방산 단백질 히드롤리제이트, 이세티오네이트, 라놀린 유도체, 지방족 알코올, 식물성 유, 글리세롤, 당 등이 이용될 수 있다.When the formulation of the present invention is a soap, an alkali metal salt of a fatty acid, a fatty acid hemiester salt, a fatty acid protein hydrolyzate, isethionate, a lanolin derivative, an aliphatic alcohol, vegetable oil, glycerol, sugar, etc. may be used as a carrier component. I can.
본 발명의 다른 측면은, 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 건강기능 식품을 제공한다.Another aspect of the present invention provides a functional food for skin whitening comprising a compound represented by the following
[화학식 1][Formula 1]
(상기 화학식 1에서,(In
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
본 명세서에서 '건강기능식품'이란, 상기 화학식 1의 화합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있다. 이와 같이 하여 얻어지는 본 발명의 건강기능식품은, 일상적으로 섭취하는 것이 가능하기 때문에 높은 피부 미백 효과를 기대할 수 있어 매우 유용하다.In the present specification, the term'health functional food' refers to a food prepared by adding the compound of
본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by
또한, 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 제조 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited to other ingredients other than containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates, etc. as additional ingredients, as in ordinary beverages. have. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and manufactured flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 g of the composition of the present invention.
나아가, 상기 외에 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 여러 가지 영양제, 비타민, 광물(전해질), 제조 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. Further, in addition to the above, the compound represented by
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능 식품을 필요한 대상에게 투여하는 단계를 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료 방법을 제공한다.Another aspect of the present invention is to administer a pharmaceutical composition or health functional food containing a compound represented by
본 발명의 다른 측면은, 멜라닌 색소 과다 침착 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능 식품의 용도를 제공한다.Another aspect of the present invention is a pharmaceutical containing a compound represented by
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.
<제조예 1> 1-(4-플루오로페닐) 피페라진의 제조<Production Example 1> Preparation of 1-(4-fluorophenyl) piperazine
단계 1: 터트-부틸 4-(4-플루오로페닐)피페라진-1-카르복실레이트의 제조Step 1: Preparation of tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate
터트-부틸 피페라진-1-카르복실레이트 (0.5 g, 2.69 mmol)과 1-브로모-4-플루오로벤젠 (0.47 g, 2.69 mmol)을 톨루엔 (10 mL)에 녹이고, 30분 동안 질소 기체로 정화하였다. BiNAP (0.17 g, 0.22 mmol), 팔라듐 아세테이트 (0.03 g, 0.043 mmol), 소듐 터트-부톡사이드 (0.90 g, 4.3 mmol)을 반응물에 넣고 20분 동안 질소 기체 정화를 실시하였다. 질소 환경 하에서 100 oC에서 8시간 동안 교반하였다. 반응이 완결되면, 반응물을 진공으로 농축하였다. 잔유물을 물에 녹이고, 에틸아세테이트 (3 x 50 mL)로 추출하였다. 실리카겔 칼럼으로 정제하여 터트-부틸 4-(4-플루오로페닐)피페라진-1-카르복실레이트 (0.59 g, 78%)을 얻었다.Tert-butyl piperazine-1-carboxylate (0.5 g, 2.69 mmol) and 1-bromo-4-fluorobenzene (0.47 g, 2.69 mmol) were dissolved in toluene (10 mL), and nitrogen gas was added for 30 minutes. Purified with. BiNAP (0.17 g, 0.22 mmol), palladium acetate (0.03 g, 0.043 mmol), and sodium tert-butoxide (0.90 g, 4.3 mmol) were added to the reaction and nitrogen gas purification was performed for 20 minutes. It was stirred for 8 hours at 100 o C under a nitrogen environment. When the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified by a silica gel column to obtain tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.59 g, 78%).
1H NMR (CDCl3, 300MHz) δ 1.47 (s, 9H), 3.04 (t, 4H, J = 4.2 Hz), 3.58 (t, 4H, J = 3.8 Hz), 6.89―6.90 (m, 2H), 6.97 (d, 2H, J = 7.8 Hz). 1 H NMR (CDCl 3 , 300MHz) δ 1.47 (s, 9H), 3.04 (t, 4H, J = 4.2 Hz), 3.58 (t, 4H, J = 3.8 Hz), 6.89-6.90 (m, 2H), 6.97 (d, 2H, J = 7.8 Hz).
단계 2: 1-(4-플루오로페닐) 피페라진의 제조Step 2: Preparation of 1-(4-fluorophenyl) piperazine
터트-부틸 4-(4-플루오로페닐)피페라진-1-카르복실레이트 (0.50 g, 1.78 mmol)을 디클로로메탄 (10 mL)에 녹이고 과량의 트리플루오로아세트산을 넣었다. 상온에서 2시간 교반하여 반응이 완결되면, 감압으로 용매를 제거하였다. 물을 넣고, 탄산수소나트륨 수용액을 첨가하고, 다이클로로메탄으로 추출하고, 황산나트륨으로 건조시키고, 필터하여 1-(2-플루오로페닐) 피페라진 (0.27 g, 83%)를 얻었다. Tert-butyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.50 g, 1.78 mmol) was dissolved in dichloromethane (10 mL) and an excess of trifluoroacetic acid was added. When the reaction was completed by stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. Water was added, an aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, dried over sodium sulfate, and filtered to obtain 1-(2-fluorophenyl) piperazine (0.27 g, 83%).
<제조예 2> 1-(2-플루오로페닐) 피페라진의 제조<Production Example 2> Preparation of 1-(2-fluorophenyl) piperazine
단계 1: 터트-부틸 4-(2-플루오로페닐)피페라진-1-카르복실레이트의 제조Step 1: Preparation of tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate
터트-부틸 피페라진-1-카르복실레이트 (0.5 g, 2.69 mmol)과 1-브로모-2-플루오로벤젠 (0.47 g, 2.69 mmol)을 톨루엔 (10 mL)에 녹이고, 30분 동안 질소 기체로 정화하였다. BiNAP (0.17 g, 0.22 mmol), 팔라듐 아세테이트 (0.03 g, 0.043 mmol), 소듐 터트-부톡사이드 (0.90 g, 4.3 mmol)을 반응물에 넣고 20분 동안 질소 기체 정화를 실시하였다. 질소 환경 하에서 100 oC에서 8시간 동안 교반하였다. 반응이 완결되면, 반응물을 진공으로 농축하였다. 잔유물을 물에 녹이고, 에틸아세테이트 (3 x 50 mL)로 추출하였다. 실리카겔 칼럼으로 정제하여 터트-부틸 4-(2-플루오로페닐)피페라진-1-카르복실레이트 (0.59 g, 78%)을 얻었다.Tert-butyl piperazine-1-carboxylate (0.5 g, 2.69 mmol) and 1-bromo-2-fluorobenzene (0.47 g, 2.69 mmol) were dissolved in toluene (10 mL), and nitrogen gas was added for 30 minutes. Purified with. BiNAP (0.17 g, 0.22 mmol), palladium acetate (0.03 g, 0.043 mmol), and sodium tert-butoxide (0.90 g, 4.3 mmol) were added to the reaction and nitrogen gas purification was performed for 20 minutes. It was stirred for 8 hours at 100 o C under a nitrogen environment. When the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified with a silica gel column to obtain tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate (0.59 g, 78%).
1H NMR (CDCl3, 300MHz) δ 1.48 (s, 9H), 3.02 (t, 4H, J = 3.9 Hz), 3.59 (t, 4H, J = 3.9 Hz), 6.91―7.00 (m, 2H), 7.05 (d, 2H, J = 7.2 Hz). 1 H NMR (CDCl 3 , 300MHz) δ 1.48 (s, 9H), 3.02 (t, 4H, J = 3.9 Hz), 3.59 (t, 4H, J = 3.9 Hz), 6.91-7.00 (m, 2H), 7.05 (d, 2H, J = 7.2 Hz).
단계 2: 1-(2-플루오로페닐) 피페라진의 제조Step 2: Preparation of 1-(2-fluorophenyl) piperazine
터트-부틸 4-(2-플루오로페닐)피페라진-1-카르복실레이트 (0.50 g, 1.78 mmol)을 디클로로메탄 (10 mL)에 녹이고 과량의 트리플루오로아세트산을 넣었다. 상온에서 2시간 교반하여 반응이 완결되면, 감압으로 용매를 제거하였다. 물을 넣고, 탄산수소나트륨 수용액을 첨가하고, 다이클로로메탄으로 추출하고, 황산나트륨으로 건조시키고, 필터하여 1-(2-플루오로페닐) 피페라진 (0.23 g, 72%)를 얻었다.Tert-butyl 4-(2-fluorophenyl)piperazine-1-carboxylate (0.50 g, 1.78 mmol) was dissolved in dichloromethane (10 mL) and an excess of trifluoroacetic acid was added. When the reaction was completed by stirring at room temperature for 2 hours, the solvent was removed under reduced pressure. Water was added, an aqueous sodium hydrogen carbonate solution was added, extracted with dichloromethane, dried over sodium sulfate, and filtered to obtain 1-(2-fluorophenyl) piperazine (0.23 g, 72%).
<제조예 3> 2,6-디클로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)페놀의 제조<Preparation Example 3> Preparation of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
단계 1: 4-브로모-2,6-디클로로-페놀의 제조Step 1: Preparation of 4-bromo-2,6-dichloro-phenol
2,6-디클로로페놀 (8.1 g, 50 mmol)을 아세토니트릴 (40 mL)에 녹인 후, 0 oC로 식인 후, 아세토니트릴 (10 mL)에 녹여있는 브로민 (9.6 g)을 천천히 첨가하였다. 생성된 붉은 용액을 0 oC에서 2시간 동안 교반하고 포화 아황산나트륨 용액을 붉은색이 없어질 때까지 첨가하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 유기층을 농축하고 실리카겔 칼럼으로 정제하여 흰색 고체의 4-브로모-2,6-디클로로-페놀 (11.3 g, 94%)을 얻었다.2,6-dichlorophenol (8.1 g, 50 mmol) was dissolved in acetonitrile (40 mL), then cooled to 0 o C, and bromine (9.6 g) dissolved in acetonitrile (10 mL) was slowly added. . The resulting red solution was stirred at 0 ° C for 2 hours, and saturated sodium sulfite solution was added until the red color disappeared. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column to obtain 4-bromo-2,6-dichloro-phenol (11.3 g, 94%) as a white solid.
1H NMR (CDCl3, 300MHz) δ 5.82 (brs, 1H, OH), 7.24 (t, 2H, J = 7.2 Hz). 1 H NMR (CDCl 3 , 300 MHz) δ 5.82 (brs, 1H, OH), 7.24 (t, 2H, J = 7.2 Hz).
단계 2: 2,6-디클로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란- 2-일)페놀의 제조Step 2: Preparation of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol
4-브로모-2,6-디클로로-페놀 (1 g, 4.13 mmol), 비스(피나콜레이토)디보레인 (1.15 g, 4.54 mmol), 아세트산 칼륨 (0.81 g, 8.26 mmol), Pd(dppf)Cl2 (0.06 g, 0.08 mmol)을 1,4-다이옥산에 녹인후, 80 oC에서 24시간 동안 교반하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 잔유물을 물에 녹이고, 에틸아세테이트 (3 x 50 mL)로 추출하였다. 실리카겔 칼럼으로 정제하여 2,6-디클로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란- 2-일)페놀 (0.90 g, 75%)을 얻었다.4-bromo-2,6-dichloro-phenol (1 g, 4.13 mmol), bis(pinacollato)diborane (1.15 g, 4.54 mmol), potassium acetate (0.81 g, 8.26 mmol), Pd(dppf) After dissolving Cl 2 (0.06 g, 0.08 mmol) in 1,4-dioxane, the mixture was stirred at 80 o C for 24 hours. After the reaction was complete, the reaction was concentrated in vacuo. The residue was dissolved in water, and extracted with ethyl acetate (3 x 50 mL). Purified by silica gel column to obtain 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.90 g, 75%) Got it.
1H NMR (CDCl3, 300MHz) δ 1.32 (s, 12H), 6.03 (brs, 1H, OH), 7.68 (s, 2H). 1 H NMR (CDCl 3 , 300 MHz) δ 1.32 (s, 12H), 6.03 (brs, 1H, OH), 7.68 (s, 2H).
<실시예 1> 7-벤질-4-(4-(4-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘의 제조<Example 1> Preparation of 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine
단계 1: 4-(4-(4-플루오로페닐)피페라진-1-일)- 7H-피롤로[2,3-d]피리미딘의 제조Step 1: 4- (4- (4-phenyl) piperazin-1-yl-fluorophenyl) - Preparation of the pyrrolo [2,3- d] pyrimidin-7 H
4-클로로-7H-피롤로[2,3-d]피리미딘 (1 eq), 1-(4-플루오로페닐) 피페라진 (1 eq), DIPEA (2 eq)를 DMF (5 mL)에 녹이고, 120 oC에서 8시간 동안 가열하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 옅은 갈색 고체의 4-(4-(4-플루오로페닐)피페라진-1-일)- 7H-피롤로[2,3-d]피리미딘 (70% 수득율)를 얻었다. 4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 1-(4-fluorophenyl) piperazine (1 eq), DIPEA (2 eq) into DMF (5 mL) Dissolved in, and heated at 120 o C for 8 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4 a light brown solid was purified by a silica gel column (4- (4-fluorophenyl) piperazin-1-yl) - 7 H - pyrrolo [2,3- d] pyrimidine was obtained (70% yield) .
1H NMR (CDCl3, 300MHz) δ 3.22 (t, 4H, J = 4.5 Hz), 4.13 (t, 4H, J = 4.2 Hz), 6.70 (s, 1H), 7.02―7.11 (m, 5H), 7.23 (s, 1H), 8.21 (s, 1H), 10.67 (brs, 1H, NH). 1 H NMR (CDCl 3 , 300MHz) δ 3.22 (t, 4H, J = 4.5 Hz), 4.13 (t, 4H, J = 4.2 Hz), 6.70 (s, 1H), 7.02-7.11 (m, 5H), 7.23 (s, 1H), 8.21 (s, 1H), 10.67 (brs, 1H, NH).
단계 2: 7-벤질-4-(4-(4-플루오로페닐)-피페라진-1-일)-7H-피롤로[2,3-d]피리미딘의 제조Step 2: Preparation of 7-benzyl-4-(4-(4-fluorophenyl)-piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine
4-(4-(4-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (1 eq)를 DMF에 녹이고, 0 oC에서 수소화나트륨 (1.5 eq)를 넣고 상온에서 10분 교반한 후, 벤질브로마이드 (1.2 eq)를 넣고 상온에서 2시간 동안 교반하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 흰색 고체의 7-벤질-4-(4-(4-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (70% 수득율)를 얻었다. 4- (4- (4-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (1 eq) is dissolved in the DMF, sodium hydride at 0 o C ( 1.5 eq) was added and stirred at room temperature for 10 minutes, then benzyl bromide (1.2 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-benzyl-4 as a white solid and purified by silica gel column (4- (4-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (70% yield ).
1H NMR (Acetone-d6, 300MHz) δ 3.30 (t, 4H, J = 4.5 Hz), 3.81 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00―7.12 (m, 4H), 7.30―7.34 (d, 5H), 7.54 (s, 2H), 8.38 (s, 1H). 1 H NMR (Acetone-d6, 300MHz) δ 3.30 (t, 4H, J = 4.5 Hz), 3.81 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00-7.12 (m, 4H) , 7.30-7.34 (d, 5H), 7.54 (s, 2H), 8.38 (s, 1H).
<실시예 2> 4-(7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘-5-일)-2,6-디클로로페놀의 제조<Example 2> 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl) Preparation of -2,6-dichlorophenol
단계 1: 4-(4-(2-플루오로페닐)피페라진-1-일)- 7H-피롤로[2,3-d]피리미딘의 제조Step 1: 4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) - Preparation of the pyrrolo [2,3- d] pyrimidin-7 H
4-클로로-7H-피롤로[2,3-d]피리미딘 (1 eq), 1-(2-플루오로페닐) 피페라진 (1 eq), DIPEA (2 eq)를 DMF (5 mL)에 녹이고, 120 oC에서 8시간 동안 가열하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 옅은 갈색 고체의 4-(4-(2-플루오로페닐)피페라진-1-일)- 7H-피롤로[2,3-d]피리미딘 (72% 수득율)를 얻었다. 4-chloro-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 1-(2-fluorophenyl) piperazine (1 eq), DIPEA (2 eq) into DMF (5 mL) Dissolved in, and heated at 120 o C for 8 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4 a light brown solid was purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) - 7 H - pyrrolo [2,3- d] pyrimidine was obtained (72% yield) .
1H NMR (CDCl3, 300MHz) δ 3.24 (t, 4H, J = 4.5 Hz), 4.17 (t, 4H, J = 4.8 Hz), 6.56 (s, 1H), 6.98―7.11 (m, 5H), 8.38 (s, 1H), 10.43 (brs, 1H, NH). 1 H NMR (CDCl 3 , 300MHz) δ 3.24 (t, 4H, J = 4.5 Hz), 4.17 (t, 4H, J = 4.8 Hz), 6.56 (s, 1H), 6.98-7.11 (m, 5H), 8.38 (s, 1H), 10.43 (brs, 1H, NH).
단계 2: 7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘의 제조Step 2: 7-Benzyl-4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) -7 H - Preparation of the pyrrolo [2,3- d] pyrimidine
4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (1 eq)를 DMF에 녹이고, 0 oC에서 수소화나트륨 (1.5 eq)를 넣고 상온에서 10분 교반한 후, 벤질브로마이드 (1.2 eq)를 넣고 상온에서 2시간 동안 교반하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 흰색 고체의 7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (71% 수득율)를 얻었다. 4- (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (1 eq) is dissolved in the DMF, sodium hydride at 0 o C ( 1.5 eq) was added and stirred at room temperature for 10 minutes, then benzyl bromide (1.2 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-benzyl-4 as a white solid and purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidine (71% yield ).
1H NMR (CDCl3, 300MHz) δ 3.23 (t, 4H, J = 4.5 Hz), 4.15 (t, 4H, J = 4.2 Hz), 5.41 (s, 2H), 6.94―7.08 (m, 6H), 7.25 (d, 2H, J = 6.0 Hz), 7.30 (d, 3H, J = 7.8 Hz), 8.41 (s, 1H). 1 H NMR (CDCl 3 , 300MHz) δ 3.23 (t, 4H, J = 4.5 Hz), 4.15 (t, 4H, J = 4.2 Hz), 5.41 (s, 2H), 6.94-7.08 (m, 6H), 7.25 (d, 2H, J = 6.0 Hz), 7.30 (d, 3H, J = 7.8 Hz), 8.41 (s, 1H).
단계 3: 7-벤질-5-브로모-4-(4-(2- 플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘의 제조Preparation of pyrrolo [2,3- d] pyrimidin-7-benzyl-5-bromo-4- (4- (2-phenyl) piperazin-1-yl-fluorophenyl) -7 H:
7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (1 eq)을 DMF에 녹인 후, N-브로모숙신이미드 (1.1 eq)를 넣고 상온에서 2시간 동안 교반하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 흰색 고체의 7-벤질-5-브로모-4-(4-(2- 플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (66% 수득율)를 얻었다. After dissolving 7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq) in DMF, N- Bromosuccinimide (1.1 eq) was added and stirred at room temperature for 2 hours. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 7-Benzyl-5-bromo-4 as a white solid and purified by silica gel column (4- (2-fluorophenyl) piperazin-1-yl) -7 H - pyrrolo [2,3- d] pyrimidin Obtained mydin (66% yield).
1H NMR (CDCl3, 300MHz) δ 3.32 (t, 4H, J = 4.5 Hz), 3.84 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00―7.12 (m, 3H), 7.30―7.34 (m, 5H), 7.54 (s, 5H), 8.38 (s, 1H). 1 H NMR (CDCl 3 , 300MHz) δ 3.32 (t, 4H, J = 4.5 Hz), 3.84 (t, 4H, J = 3.9 Hz), 5.47 (s, 2H), 7.00-7.12 (m, 3H), 7.30-7.34 (m, 5H), 7.54 (s, 5H), 8.38 (s, 1H).
단계 4: 4-(7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘- 5-일)-2,6-디클로로페놀의 제조Step 4: 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidin- 5-yl)- Preparation of 2,6-dichlorophenol
7-벤질-5-브로모-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘 (1 eq), 2,6-디클로-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란- 2-일)페놀 (1.2 eq), 탄산나트륨 (3 eq), PdCl2(PPh3)2 (0.02 eq)를 1,4-다이옥산:물 (2:1)에 녹이고, 100 oC에서 마이크로웨이브로 20분 동안 가열하였다. 반응이 완결된 후, 반응물을 진공으로 농축하였다. 층을 분리하였고, 수용액 층을 에틸아세테이트로 추출하였다. 실리카겔 칼럼으로 정제하여 흰색 고체의 4-(7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘- 5-일)-2,6-디클로로페놀 (45% 수득율)를 얻었다.7-benzyl-5-bromo-4-(4-(2-fluorophenyl)piperazin-1-yl)-7 H -pyrrolo[2,3- d ]pyrimidine (1 eq), 2, 6-Dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.2 eq), sodium carbonate (3 eq), PdCl 2 (PPh 3 ) 2 (0.02 eq) was dissolved in 1,4-dioxane:water (2:1), and heated at 100 ° C. in microwave for 20 minutes. After the reaction was complete, the reaction was concentrated in vacuo. The layers were separated, and the aqueous solution layer was extracted with ethyl acetate. 4- (7-benzyl-4- (4- (2-fluorophenyl as a white solid and purified by silica gel column) piperazin-1-yl) -7 H-pyrrolo [2,3- d] pyrimidine - 5-yl)-2,6-dichlorophenol (45% yield) was obtained.
1H NMR (CDCl3, 300MHz) δ 3.00 (t, 4H, J = 4.2 Hz), 3.52 9t, 4H, J = 3.9 Hz), 5.43 (s, 2H), 6.91―6.97 (m, 2H), 7.04 (s, 2H), 7.28―7.34 (m, 4H), 7.42 (s, 2H), 7.49 (s, 2H), 8.56 (s, 1H). 1 H NMR (CDCl 3 , 300MHz) δ 3.00 (t, 4H, J = 4.2 Hz), 3.52 9t, 4H, J = 3.9 Hz), 5.43 (s, 2H), 6.91-6.97 (m, 2H), 7.04 (s, 2H), 7.28-7.34 (m, 4H), 7.42 (s, 2H), 7.49 (s, 2H), 8.56 (s, 1H).
<실험예 1> 멜라닌 생성 저해 평가<Experimental Example 1> Melanin production inhibition evaluation
본 발명에 따른 실시예 화합물의 멜라닌 생성 저해를 평가하기 위하여 하기와 같은 실험을 수행하였으며, 그 결과를 표 1 및 도 1에 나타내었다.In order to evaluate the inhibition of melanin production of the example compounds according to the present invention, the following experiment was performed, and the results are shown in Table 1 and FIG. 1.
실험에 사용한 세포는 C57/BL6 생쥐 유래의 흑색종 세포주(melanoma cell line)로서, 미백물질 스크리닝에 일반적으로 사용하는 세포로, total melanin 및 신규 melanin 생성 저해능 및 melanin 생성에 관여하는 각 종 효소의 활성 저해능, 관련 유전자 및 cytokine 변화량 등의 측정이 가능한 것으로 보고되고 있는 생쥐유래 피부암 세포주인 B16F10 세포를 사용하였다.The cells used in the experiment are melanoma cell lines derived from C57/BL6 mice, which are generally used for screening whitening substances, and are capable of inhibiting total melanin and new melanin production, and the activity of various enzymes involved in melanin production. B16F10 cells, a mouse-derived skin cancer cell line, which are reported to be capable of measuring inhibitory activity, related genes and cytokine changes, were used.
구체적으로, B16F10 세포를 10 cm dish에 1*106 cell로 seeding하고 2시간 후, 화합물(실시예 화합물 및 비교예로써 kojic acid)을 처리한다. 다음 날 α-MSH(α-melanocyte stimulating hormome)를 1 uM 처리 하고 실험용 약물을 처리한 지 72 시간이 지났을 때, 1% Triton X-100이 포함된 10 mM phosphate buffer(pH 6.8)을 이용하여 pellet 모아서 1 N NaOH와 DW를 1:2로 넣고 60℃에서 1시간동안 세포를 완전히 녹인 뒤 흡광도 475 nm에서 멜라닌의 양을 측정하여 하기 표 1에 나타내었다. 이때, 수치가 낮을수록 멜라닌 생성이 저해됨을 의미한다. 아울러, 진하기를 육안으로 평가하기 위하여, 상기 실험예 1을 수행한 시료를 촬영하여 도 1에 나타내었다.Specifically, B16F10 cells were seeded with 1*10 6 cells in a 10 cm dish, and 2 hours later, a compound (an example compound and kojic acid as a comparative example) were treated. On the following day, 1 uM of α-MSH (α-melanocyte stimulating hormome) was treated, and 72 hours after the experimental drug was treated, pellets using 10 mM phosphate buffer (pH 6.8) containing 1% Triton X-100. Collected, 1 N NaOH and DW were added at a ratio of 1:2, and the cells were completely dissolved at 60° C. for 1 hour, and then the amount of melanin was measured at an absorbance of 475 nm. In this case, the lower the value, the more melanin production is inhibited. In addition, in order to visually evaluate the darkness, the sample performed in Experimental Example 1 was photographed and shown in FIG. 1.
한편, α-MSH는 풋아편흑색소부신겉질자극호르몬 (pro-opiomelanocortin, POMC) 유래의 호르몬이며, POMC는 부신피질자극호르몬(adrenocorticotrophin, ACTH), 리포트로핀(lipotrophins, LPH), 엔돌핀 등의 전구물질이다. 케라티노사이트(keratinocyte)로부터 α-MSH, ACTH가 만들어지는 것으로 밝혀져 있으며, 이들은 멜라노코르틴 수용체(melanocortin receptor)를 통해 멜라노사이트(melanocyte)의 활성에 기여하는 작용을 갖는다. 또한, α-MSH는 아데닐산 시클라아제(adenylate cyclase)계를 활성화하여 멜라노사이트의 증식 및 티로시나아제(tyrosinase) 활성의 상승 작용을 유도한다.On the other hand, α-MSH is a hormone derived from pro-opiomelanocortin (POMC), and POMC is a hormone such as adrenocorticotrophin (ACTH), lipotrophins (LPH), and endorphins. It is a precursor. It has been found that α-MSH and ACTH are produced from keratinocytes, and these have an action that contributes to the activity of melanocytes through melanocortin receptors. In addition, α-MSH activates the adenylate cyclase system to induce the proliferation of melanocytes and a synergistic effect of tyrosinase activity.
상기 표 1에서, 475 nm에서의 흡광도 수치가 낮을수록 멜라닌 생성이 현저히 억제되어 미백 효과가 우수함을 의미한다.In Table 1, as the absorbance value at 475 nm is lower, melanin production is significantly suppressed, indicating that the whitening effect is excellent.
상기 표 1에 나타난 바와 같이, 멜라닌 생성을 촉진하는 것으로 알려진 인자인 IBMX(isobutylmethyl xanthine)를 처리하지 않은 세포(번호 1)과 비교하여 IBMX를 처리하였을 때(번호 2) 멜라닌의 양이 약 2배 상승되어, 멜라닌 생성이 유도되었음을 확인하였다.As shown in Table 1, when IBMX was treated (No. 2) compared to cells not treated with IBMX (isobutylmethyl xanthine), a factor known to promote melanin production (No. 1), the amount of melanin was about twice It was elevated, confirming that melanogenesis was induced.
IBMX로 멜라닌 생성을 유도하고, 멜라진 생성 억제 물질로 알려진 코직산을 20 μM 처리한 결과(번호 3), 멜라닌 생성이 오히려 증가한 것을 알 수 있다.As a result of inducing melanin production with IBMX and 20 μM treatment of kojic acid, which is known as a melanin production inhibitory substance (No. 3), it can be seen that melanin production was rather increased.
반면, 본 발명의 실시예 1 및 2를 처리한 세포(번호 4 및 5)는 코직산보다 1/2의 10 μM를 처리하였음에도 불구하고, 실시예 1의 경우, 50% 이상 멜라닌 양이 감소되었으며, 실시예 2의 경우, 75% 이상 멜라닌 양이 감소된 것을 확인하였다.On the other hand, the cells treated with Examples 1 and 2 of the present invention (
또한, 도 1에 나타난 바와 같이, 코직산을 처리할 경우, 시료의 색이 IBMX를 처리할 경우보다 색이 진해진 반면, 본 발명의 실시예 1 및 2를 처리할 경우, 시료의 색이 투명하여 멜라닌의 양이 현저하게 감소하였음을 육안으로도 확인할 수 있었다.In addition, as shown in Fig. 1, when the kojic acid is treated, the color of the sample is darker than that of the IBMX treatment, whereas when the examples 1 and 2 of the present invention are treated, the color of the sample is transparent. It could be confirmed with the naked eye that the amount of melanin was significantly reduced.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은 적은 양을 사용하여도 멜라닌의 생성을 억제하는 효과를 나타내므로, 이를 멜라닌 색소 과다 침착 질환 치료용 조성물, 피부 미백용 화장료 조성물 및 피부 미백용 건강기능 식품으로 유용하게 사용할 수 있다.Therefore, since the compound represented by
<제제예 1> 산제의 제조<Formulation Example 1> Preparation of powder
화학식 1로 표시되는 화합물
2gCompound represented by
유당 1gLactose 1g
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above ingredients were mixed and filled in an airtight cloth to prepare a powder.
<제제예 2> 정제의 제조<Formulation Example 2> Preparation of tablets
화학식 1로 표시되는 화합물
100 ㎎Compound represented by
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘
2 ㎎
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above ingredients, tablets were prepared by tableting according to a conventional tablet preparation method.
<제제예 3> 캡슐제의 제조<Formulation Example 3> Preparation of capsules
화학식 1로 표시되는 화합물
100 ㎎Compound represented by
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘
2 ㎎
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above ingredients, a gelatin capsule was filled according to a conventional capsule preparation method to prepare a capsule.
<제제예 4> 주사제의 제조<Formulation Example 4> Preparation of injection
화학식 1로 표시되는 화합물
100 ㎎Compound represented by
만니톨 180 ㎎Mannitol 180 mg
Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 ㆍ2H 2 O 26 mg
증류수 2974 ㎎Distilled water 2974 mg
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to a conventional method for preparing injections, injections were prepared by containing the above ingredients in the indicated amount.
<제제예 5> 연고제의 제조<Formulation Example 5> Preparation of ointment
화학식 1로 표시되는 화합물
5 gCompound represented by
세틸팔미테이트 20 gCetyl Palmitate 20 g
세탄올 40 gCetanol 40 g
스테아릴알콜 40 gStearyl alcohol 40 g
미리스탄이소프로필 80 gMyristic isopropyl 80 g
폴리솔베이트 60 gPolysorbate 60 g
파라옥시안식향산 프로필 1 gParaoxybenzoic acid profile 1 g
파라옥시안식향산 메틸 1 gMethyl paraoxybenzoate 1 g
인산 및 정제수 적당량Phosphoric acid and purified water Appropriate amount
통상적인 연고제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 연고제를 제조하였다.According to a conventional method for preparing an ointment, an ointment was prepared by containing the above ingredients in the indicated amount.
<제제예 6> 건강기능식품의 제조<Formulation Example 6> Preparation of health functional food
화학식 1로 표시되는 화합물
500ngCompound represented by
비타민 혼합물 적량Vitamin mixture Appropriate amount
비타민 A 아세테이트 70mg Vitamin A acetate 70mg
비타민 E 1.0mgVitamin E 1.0mg
비타민 0.13mgvitamin 0.13mg
비타민 B2 0.15mgVitamin B2 0.15mg
비타민 B6 0.5mgVitamin B6 0.5mg
비타민 B12 0.2mgVitamin B12 0.2mg
비타민 C 10mgVitamin C 10mg
비오틴 10mgBiotin 10mg
니코틴산아미드 1.7mgNicotinic acid amide 1.7mg
엽산 50mgFolic acid 50mg
판토텐산 칼슘 0.5mgCalcium pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture Appropriate amount
황산제1철 1.75mgFerrous sulfate 1.75mg
산화아연 0.82mgZinc oxide 0.82mg
탄산마그네슘 25.3mgMagnesium carbonate 25.3mg
제1인산칼륨 15mgPotassium Phosphate Monobasic 15mg
제2인산칼슘 55mgDicalcium phosphate 55mg
구연산칼륨 90mgPotassium citrate 90mg
탄산칼슘 100mgCalcium carbonate 100mg
염화마그네슘 24.8mgMagnesium chloride 24.8mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강기능식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강기능식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강기능식품 조성물 제조에 사용할 수 있다.The composition ratio of the vitamin and mineral mixture is relatively suitable for the health functional food, but it is possible to arbitrarily modify the composition, and the above ingredients are mixed according to the general health functional food manufacturing method. Then, granules are prepared, and can be used to prepare a health functional food composition according to a conventional method.
<제제예 7> 건강기능음료의 제조<Formulation Example 7> Preparation of health functional beverage
화학식 1로 표시되는 화합물
500ngCompound represented by
구연산 1000mgCitric acid 1000mg
올리고당 100goligosaccharide 100g
매실농축액 2gPlum Concentrate 2g
타우린 1gTaurine 1g
정제수를 가하여 전체 900mlWhole by adding purified water 900ml
통상의 건강 기능 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 기능 음료 조성물 제조에 사용하였다.After mixing the above ingredients according to the general health function beverage manufacturing method, stirring and heating at 85°C for about 1 hour, the resulting solution is filtered and obtained in a sterilized container, sealed and sterilized, and then stored in a refrigerator. It was used to prepare a beverage composition.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.The composition ratio is a mixture of ingredients suitable for a relatively preferred beverage in a preferred embodiment, but the mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.
<제제예 8> 피부미용 개선용 조성물의 제조<Formulation Example 8> Preparation of a composition for improving skin beauty
<8-1> 크림의 제조<8-1> Preparation of cream
화학식 1로 표시되는 화합물
4.6 중량부Compound represented by
세토스테아릴알코올 2.8 중량부Cetostearyl alcohol 2.8 parts by weight
밀납 2.6 중량부Beeswax 2.6 parts by weight
스테아린산 1.4 중량부Stearic acid 1.4 parts by weight
친유형모노스테아린산글리세린
2 중량부
피이지-100 스테아레이트
1 중량부PEG-100
세스퀴올레인산소르비탈 1.4 중량부Sorbital sesquioleate 1.4 parts by weight
호호바오일
4 중량부
스쿠알란 3.8 중량부Squalane 3.8 parts by weight
폴리소르베이트 60 1.1 중량부Polysorbate 60 1.1 parts by weight
마카다이아오일
2 중량부
초산토코페롤 0.2 중량부Tocopherol acetate 0.2 parts by weight
메칠폴리실록산 0.4 중량부Methylpolysiloxane 0.4 parts by weight
에칠파라벤 0.1 중량부Echil Paraben 0.1 parts by weight
프로필파라벤 0.1 중량부Profile Paraben 0.1 parts by weight
Euxyl K-400 0.1 중량부Euxyl K-400 0.1 parts by weight
1,3-부칠렌글리콜 7 중량부1,3-butylene glycol 7 parts by weight
메칠파라벤 0.05 중량부Methylparaben 0.05 parts by weight
글리세린 6 중량부glycerin 6 parts by weight
d-판데놀 0.2 중량부d-pandenol 0.2 parts by weight
트리에탄올아민 0.2 중량부Triethanolamine 0.2 parts by weight
pt 41891 0.2 중량부pt 41891 0.2 parts by weight
p-H2O 46.05 중량부pH 2 O 46.05 parts by weight
<8-2> 로션의 제조 <8-2> Preparation of lotion
화학식 1로 표시되는 화합물
3.5 중량부Compound represented by
세토스테아릴알코올 1.6 중량부Cetostearyl alcohol 1.6 parts by weight
스테아린산 1.4 중량부Stearic acid 1.4 parts by weight
친유형모노스테아린산글리세린 1.8 중량부Glycerin monostearate 1.8 parts by weight
피이지-100 스테아레이트 2.6 중량부PEG-100 Stearate 2.6 parts by weight
세스퀴올레인산소르비탈 0.6 중량부Sorbital sesquioleate 0.6 parts by weight
스쿠알렌 4.8 중량부Squalene 4.8 parts by weight
마카다이아오일
2 중량부
호호바오일
2 중량부
초산토코페롤 0.4 중량부Tocopherol acetate 0.4 parts by weight
메칠폴리실록산 0.2 중량부Methylpolysiloxane 0.2 parts by weight
에칠파라벤 0.1 중량부Echil Paraben 0.1 parts by weight
프로필파라벤 0.1 중량부Profile Paraben 0.1 parts by weight
1,3-부칠렌글리콜
4 중량부1,3-
메칠파라벤 0.1 중량부Methylparaben 0.1 parts by weight
산탄검 0.1 중량부Xanthan gum 0.1 parts by weight
글리세린
4 중량부
d-판데놀 0.15 중량부d-pandenol 0.15 parts by weight
알란토인 0.1 중량부Allantoin 0.1 parts by weight
카르보내(2% aq. Sol) 4 중량부Carbonae (2% aq. Sol) 4 parts by weight
트리에탄올아민 0.15 중량부 Triethanolamine 0.15 parts by weight
에탄올
3 중량부
pt 41891 0.1 중량부pt 41891 0.1 parts by weight
p-H20 48.3 중량부pH 2 0 48.3 parts by weight
<8-3> 유연 화장수의 제조 <8-3> Preparation of flexible lotion
화학식 1로 표시되는 화합물
0.2 중량%Compound represented by
에탄올 10.0 중량%ethanol 10.0% by weight
폴리라우린산폴리옥시에틸렌소르비탄 1.0 중량%Polylaurate polyoxyethylene sorbitan 1.0% by weight
파라옥시안식향산메틸 0.2 중량%Methyl paraoxybenzoate 0.2% by weight
글리세린 5.0 중량%glycerin 5.0% by weight
1,3-부틸글리콜 6.0 중량%1,3-butyl glycol 6.0% by weight
향 적량incense Appropriate amount
색소 적량Pigment Appropriate amount
정제수 적량 Purified water Appropriate amount
총 100gun 100
<8-4> 영양 화장수의 제조<8-4> Preparation of nutritional lotion
화학식 1로 표시되는 화합물
0.1 중량%Compound represented by
와셀린 2.0 중량%Washelin 2.0% by weight
세스퀴올레인산소르비탄 0.8 중량%Sorbitan sesquioleate 0.8% by weight
폴리옥시에틸렌올레일에틸 1.2 중량%Polyoxyethyleneoleylethyl 1.2% by weight
파라옥시안식향산메틸 적량Methyl paraoxybenzoate Appropriate amount
프로필렌글리콜 5.0 중량%Propylene glycol 5.0% by weight
에탄올 3.2 중량%ethanol 3.2% by weight
카르복시비닐폴리머 18.0 중량%Carboxyvinyl polymer 18.0% by weight
색소 적량Pigment Appropriate amount
향 적량incense Appropriate amount
정제수 적량 Purified water Appropriate amount
총 100gun 100
<8-5> 에센스의 제조<8-5> Preparation of essence
화학식 1로 표시되는 화합물
5.0 중량%Compound represented by
프로필렌글리콜 10.0 중량%Propylene glycol 10.0% by weight
글리세린 10.0 중량%glycerin 10.0% by weight
히알루론산나트륨수용액(1%) 5.0 중량%Sodium hyaluronate aqueous solution (1%) 5.0% by weight
에탄올 3.2 중량%ethanol 3.2% by weight
폴리옥시에틸렌경화피마자유 1.0 중량%Polyoxyethylene hardened castor oil 1.0% by weight
파라옥시안식향산메틸 0.1 중량%Methyl paraoxybenzoate 0.1% by weight
향 적량incense Appropriate amount
정제수 적량 Purified water Appropriate amount
총 100gun 100
<8-6> 팩의 제조<8-6> Preparation of the pack
화학식 1로 표시되는 화합물
0.5 중량%Compound represented by
글리세린 5.0 중량%glycerin 5.0% by weight
프로필렌글리콜 4.0 중량%Propylene glycol 4.0% by weight
폴리비닐알코올 15.0 중량%Polyvinyl alcohol 15.0% by weight
에탄올 8.0 중량%ethanol 8.0% by weight
폴리옥시에틸렌올레일에틸 1.0 중량%Polyoxyethyleneoleylethyl 1.0% by weight
파라옥시안식향산메틸 0.2 중량%Methyl paraoxybenzoate 0.2% by weight
향 적량incense Appropriate amount
색소 적량Pigment Appropriate amount
정제수 적량 Purified water Appropriate amount
총 100gun 100
상기 조성비는 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 성분 또는 배합비를 임의로 변형 실시하여도 무방하다.The composition ratio is mixed with suitable ingredients in a preferred embodiment, but the composition or mixing ratio may be arbitrarily modified according to regional and ethnic preferences such as the demand class, the country of demand, and the purpose of use.
Claims (10)
[화학식 1]
(상기 화학식 1에서,
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).
A compound represented by the following Formula 1, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In Formula 1,
R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
상기 R1은 수소 또는 할로겐이고; 및
R2는 수소 또는 페닐이고, 상기 아릴은 -OH 및 할로겐으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있는 것을 특징으로 하는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염.
The method of claim 1,
R 1 is hydrogen or halogen; And
R 2 is hydrogen or phenyl, and the aryl is a compound characterized in that one or more substituents selected from the group consisting of -OH and halogen may be substituted, isomers thereof, solvates thereof, hydrates thereof, or pharmaceutically acceptable Possible salts.
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 이성질체, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용가능한 염:
(1) 7-벤질-4-(4-(4-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘; 및
(2) 4-(7-벤질-4-(4-(2-플루오로페닐)피페라진-1-일)-7H-피롤로[2,3-d]피리미딘-5-일)-2,6-디클로로페놀.
The method of claim 1,
The compound represented by Formula 1 is a compound, an isomer thereof, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the following compound group:
(1) 7-benzyl-4-(4-(4-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine; And
(2) 4-(7-benzyl-4-(4-(2-fluorophenyl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2 ,6-dichlorophenol.
[화학식 1]
(상기 화학식 1에서,
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).
A pharmaceutical composition for preventing or treating melanin hyperpigmentation disease comprising a compound represented by the following Formula 1, its isomer, its solvate, its hydrate or its pharmaceutically acceptable salt as an active ingredient:
[Formula 1]
(In Formula 1,
R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of —OH, halogen and straight or branched C 1-6 alkyl).
상기 화학식 1로 표시되는 화합물은 멜라닌(melanin) 생성을 억제하는 것을 특징으로 하는 약학적 조성물.
The method of claim 4,
The compound represented by Formula 1 is a pharmaceutical composition, characterized in that it inhibits the production of melanin (melanin).
상기 멜라닌 색소 과다 침착 질환은 기미, 주근깨, 노인성 색소반 또는 일광흑색증(solar lentigines)인 것을 특징으로 하는 약학적 조성물.
The method of claim 4,
The melanin hyperpigmentation disease is a pharmaceutical composition, characterized in that melasma, freckles, senile pigment spots or solar melanosis (solar lentigines).
[화학식 1]
(상기 화학식 1에서,
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).
A cosmetic composition for skin whitening comprising a compound represented by the following Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]
(In Formula 1,
R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of —OH, halogen and straight or branched C 1-6 alkyl).
A cosmetic product for skin whitening comprising the cosmetic composition for skin whitening of claim 7.
상기 미용제품은 용액, 외용연고, 크림, 폼, 영양화장수, 유연화장수, 팩, 유연수, 유액, 메이크업베이스, 에센스, 비누, 액체 세정료, 입욕제, 선 스크린크림, 선오일, 현탁액, 유탁액, 페이스트, 겔, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션, 패취 및 스프레이로 구성된 군으로부터 선택되는 제형으로 제조할 수 있는 것을 특징으로 하는 피부 미백용 미용제품.
The method of claim 8,
The above beauty products are solutions, external ointments, creams, foams, nutritional lotion, softening lotion, pack, softening water, emulsion, makeup base, essence, soap, liquid detergent, bathing agent, sunscreen cream, sun oil, suspension, emulsion, For skin whitening, characterized in that it can be prepared in a formulation selected from the group consisting of paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray Beauty products.
[화학식 1]
(상기 화학식 1에서,
R1은 수소, 할로겐 또는 직쇄 또는 분지쇄의 C1-6알킬이고; 및
R2는 수소 또는 C6-10의 아릴이고, 상기 아릴은 -OH, 할로겐 및 직쇄 또는 분지쇄의 C1-6알킬으로 이루어지는 군으로부터 선택되는 치환기로 하나 이상 치환될 수 있다).A health functional food for skin whitening comprising a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]
(In Formula 1,
R 1 is hydrogen, halogen or straight or branched C 1-6 alkyl; And
R 2 is hydrogen or C 6-10 aryl, and the aryl may be substituted with one or more substituents selected from the group consisting of -OH, halogen and linear or branched C 1-6 alkyl).
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