KR101851928B1 - Composition for skin whitening comprising S-Methylmethionine sulfonium derivatives - Google Patents
Composition for skin whitening comprising S-Methylmethionine sulfonium derivatives Download PDFInfo
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- KR101851928B1 KR101851928B1 KR1020170118805A KR20170118805A KR101851928B1 KR 101851928 B1 KR101851928 B1 KR 101851928B1 KR 1020170118805 A KR1020170118805 A KR 1020170118805A KR 20170118805 A KR20170118805 A KR 20170118805A KR 101851928 B1 KR101851928 B1 KR 101851928B1
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- present
- skin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
Description
본 발명은 S-메틸메티오닌 설포늄(S-Methylmethionine sulfonium, SMMS)의 유도체를 유효성분으로 포함하는 피부 미백용 조성물에 관한 것으로서, 보다 상세하게는 S-메틸메티오닌 설포늄의 유도체 또는 이의 염을 유효성분으로 함유하는 피부 미백용 화장료 조성물, 건강기능식품 조성물, 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물 및 의약외품 조성물을 제공한다.The present invention relates to a skin whitening composition comprising a derivative of S-methylmethionine sulfonium (SMMS) as an active ingredient. More particularly, the present invention relates to a composition for skin whitening comprising a derivative of S-methylmethionine sulfonium or a salt thereof A cosmetic composition for skin whitening, a health functional food composition, a pharmaceutical composition for preventing or treating melanin pigment hyperpigmentation diseases, and a quasi-drug composition.
멜라닌은 피부와 머리카락의 색상을 결정하는 주요한 인자이며 검은 색소와 단백질의 복합체 형태를 갖는 페놀계 고분자 물질로서 자외선 차단 역할을 한다. 단파장의 자외선 및 발암물질은 피부에서 유해한 자유 라디칼을 형성하는데 멜라닌은 이러한 자유 라디칼 등을 제거하여 단백질과 유전자들을 보호해 주는 유용한 역할을 한다. 따라서 멜라닌의 양이 많다는 것은 물리적 또는 화학적 독성 물질로부터 피부를 보호할 수 있는 효과적인 대응 체계를 가지고 있다는 것을 의미한다.Melanin is a major factor in determining the color of skin and hair. It is a phenolic polymer with a complex of black pigment and protein. Ultraviolet rays and carcinogens of short wavelength form harmful free radicals in skin, but melanin plays a useful role to protect proteins and genes by removing such free radicals. Thus, a high amount of melanin means that it has an effective countermeasure to protect the skin from physical or chemical toxicants.
멜라닌은 색소 세포 내에 존재하는 티로시나아제(tyrosinase)의 작용에 의해 티로신(tyrosine)으로부터 복잡한 과정을 거쳐 생성된다. 이때 생성된 멜라닌은 피부 세포에 전달되고 표피 박리와 함께 멜라닌이 상실되어 소멸되는 순환 작용을 보인다. 이러한 멜라닌 생성 과정은 자연적으로 일어나는 현상으로서, 정상 상태의 피부에서는 멜라닌의 과다 생성이 일어나지 않는다. 그러나 피부가 자외선, 환경오염 또는 스트레스와 같은 외부의 자극에 반응하면 멜라닌이 과다 생성되어 피부 밖으로 배출되지 못하고 각질형성세포(keratinocyte)로 전달되고 피부 표피층에 축적되어 기미, 주근깨 및 노인성 흑자 등 심각한 미용상의 문제를 일으킬 뿐만 아니라, 피부노화를 촉진하며 피부암을 유발하기도 한다.Melanin is produced by a complex process from tyrosine by the action of tyrosinase present in the pigment cells. At this time, melanin produced is transferred to skin cells, and melanin is lost with epidermal detachment and disappearing circulation. This process of melanin production is a naturally occurring phenomenon and does not result in excessive production of melanin in normal skin. However, when the skin responds to external stimuli such as ultraviolet rays, environmental pollution, or stress, melanin is overproduced and is not discharged out of the skin. It is transferred to keratinocyte and accumulates in the skin surface layer, Not only cause problems, but also promote skin aging and cause skin cancer.
피부 미백제의 개발에 있어서, 생성된 멜라닌 색소를 환원시켜 탈색하는 방법과 멜라닌 색소를 형성하는 효소인 티로시나아제의 활성을 억제하는 방법이 널리 알려져 있다. 그러나 멜라닌 색소를 환원시키기 위해 사용되는 토코페롤이나 비타민류 등을 사용한 미백제는 멜라닌 색소의 탈색효과가 아주 작은 것으로 알려져 있다. 따라서 티로시나아제의 활성을 저해시킴으로써 멜라닌 색소의 생성을 억제하는 저해제가 주목받고 있다.In the development of a skin lightening agent, a method of decolorizing the resulting melanin pigment and a method of inhibiting the activity of tyrosinase, an enzyme that forms a melanin pigment, are widely known. However, it is known that the whitening agent using tocopherol or vitamins used for reducing the melanin pigment has a very small discoloring effect of the melanin pigment. Accordingly, inhibitors that inhibit the activity of tyrosinase and inhibit the production of melanin pigment have been attracting attention.
종래의 화장품 분야에서는 미백 성분으로서, 코지산(Kojic acid), 알부틴(Arbutin) 등과 같은 티로시나아제 효소 활성을 억제하는 물질, 하이드로퀴논(Hydroquinone), 비타민 C(L-Ascorbic acid) 및 이들의 유도체와 각종 식물 추출물이 사용되었다. 그러나 코지산은 티로시나제의 활성 부위에 존재하는 구리 이온을 흡착시켜 효소활성을 저해하지만, 화장품에 배합 시 불안정성, 피부 부작용의 문제 및 최근 동물실험 결과 간암을 유발한다고 밝혀져 화장품 원료로 사용이 중지되었다. 또한, 비타민 C 및 그 유도체는 산화가 잘 되는 불안정성 때문에 화장품 원료로서 사용이 어려우며, 하이드로퀴논은 피부에 대한 미백효과는 탁월하지만 알레르기를 유발하는 성질, 멜라닌 생성 세포에 대한 독성, 피부의 영구 탈색화 등 피부에 대한 자극성이 높으며, 최근 발암성 물질로 규정되어 사용이 금지되어 각 나라별로 제한적인 농도만 허가하고 있다. 뿐만 아니라, 알부틴은 하이드로퀴논에 글루코피라노사이드(Glucopyranoside)가 결합된 유도체로 하이드로퀴논 사용 시 나타나는 부작용이 적으면서 인체에 대한 독성은 없이 멜라닌 색소의 합성을 억제하는 작용이 있어, 멜라닌 색소 침착이 증가되는 피부 질환의 치료제로서의 이용 가능성이 제시되었으나, 피부 효소에 의해 일부 분해되는 단점이 있다. 따라서, 소량으로도 효능이 우수하고 부작용이 적은 안전한 대체 미백제의 개발이 시급한 실정이다.In the conventional cosmetics field, as a whitening ingredient, substances inhibiting tyrosinase enzyme activity such as kojic acid and arbutin, hydroquinone, L-ascorbic acid and derivatives thereof And various plant extracts were used. However, Kojisan inhibits enzyme activity by adsorbing copper ions present in the active site of tyrosinase. However, it has been proved that it causes instability, skin side effects and recent liver cancer in cosmetics. In addition, vitamin C and its derivatives are difficult to use as a raw material for cosmetics due to the instability of oxidation, and hydroquinone has excellent whitening effect on the skin, but it has allergenic properties, toxicity to melanocytes, And is currently prohibited from being prescribed as a carcinogenic substance. Therefore, only limited concentration is allowed in each country. In addition, arbutin is a derivative in which glucopyranoside is bound to hydroquinone. As a result, hydroquinone is less toxic to the human body while suppressing the synthesis of melanin pigment, and melanin pigmentation The possibility of its use as a therapeutic agent for increased skin diseases has been suggested, but it has a disadvantage that it is partially decomposed by skin enzymes. Therefore, it is urgent to develop a safe alternative whitening agent which has excellent efficacy and few side effects even in small amounts.
S-메틸메티오닌 설포늄(S-Methylmethionine sulfonium, SMMS)은 메티오닌 유도체로서, 양배추, 콜라비, 순무, 토마토, 샐러리 등에 풍부하게 포함되어 있는 활성 물질이다. SMMS는 위장 궤양(gastrointestinal ulceration)을 보호할 수 있는 치료 효과가 있어, 비타민 U로서 널리 알려져 사용되고 있다. 예를 들면, 소화성 궤양(peptic ulcer)에 대하여 SMMS가 빠른 치료 효과를 가질 수 있음이 보고되었다. S-Methylmethionine sulfonium (SMMS) is a methionine derivative and is an active substance abundantly contained in cabbage, cola, turnip, tomato, celery and the like. SMMS has a therapeutic effect to protect gastrointestinal ulceration and is widely known as vitamin U. For example, it has been reported that SMMS can have a rapid therapeutic effect on peptic ulcer.
뿐만 아니라, SMMS는 피부에 대하여 유의적인 상처 회복 효과 및 광보호 효과가 있어서, 화장료 조성물의 원료로서 사용될 수 있음이 공지된 바 있다. 예를 들어, 동물실험을 통해, 외상 또는 화학적인 상처 모두에 대하여 SMMS를 국소적으로 투여하는 것은 상처를 봉합하고 상처가 재-상피화(re-epithelialization)하는 것을 촉진할 수 있음을 확인하였다. 또한, SMMS을 처리하는 것은 인간 피부 섬유아세포(hDF)의 생장 및 이주능(migration)을 촉진할 수 있으며, SMMS이 ERK1/2 경로를 활성화시키기 때문에 이러한 hDF 증식 촉진 및 이주능 촉진 효과가 나타난다. 아울러, SMMS은 활성산소종(ROS)의 소거를 통해 UVB 조사 환경에서 피부 세포를 보호할 수 있다. SMMS을 처리하는 것은 UVB로 유도되는 홍반 지수(erythema index) 및 랑게르한스 세포(Langerhans cell)의 결핍을 감소시킬 수 있다. In addition, it has been known that SMMS can be used as a raw material for a cosmetic composition because of its significant wound restoration effect and light protecting effect on skin. For example, animal studies have shown that topical administration of SMMS for both trauma and chemical wounds can facilitate suturing of the wound and re-epithelialization of the wound. In addition, treatment with SMMS can promote the growth and migration of human dermal fibroblast (hDF), and SMMS activates the ERK1 / 2 pathway, thus promoting this hDF proliferation and promoting effect. In addition, SMMS can protect skin cells in the UVB irradiation environment by eliminating reactive oxygen species (ROS). Treatment of SMMS can reduce UVB-induced erythema index and Langerhans cell deficiency.
그러나, 이와 같이 SMMS의 피부 재생 효과에도 불구하고 안정성이 유지되지 않는다는 단점을 가져, 약물 또는 화장료 조성물로서 사용에 제한을 갖는다. 저장을 위한 온도 조절이 이루어지지 않은 양배추에서 SMMS의 함유량이 62% 수준으로 감소하는 것이 보고되었다. 또한, SMMS의 설포늄 기능기로부터 악취가 발생한다는 단점이 있으며, SMMS를 제형화하기 위한 용융 공정 중 가열 단계에서, SMMS 구조가 깨어져 디메틸 설파이드(dimethyl sulfide)를 형성하기 때문에 악취가 발생할 수 있음이 알려져 있다. 이에 따라, SMMS를 화장료 조성물에 사용하였을 때, 냄새가 좋지 않고 안정하지 않아 산업적으로 이용할 수 없다는 문제점을 가진다.However, such a disadvantage is that the stability is not maintained despite the skin regeneration effect of SMMS, and thus it has a limitation in use as a drug or cosmetic composition. It has been reported that the content of SMMS is reduced to 62% in cabbage without temperature control for storage. In addition, there is a disadvantage that a malodor occurs from the sulfonium functional group of SMMS. In the heating step during the melting process for forming SMMS, the SMMS structure is broken and dimethylsulfide is formed, so odor may be generated It is known. Accordingly, when SMMS is used in a cosmetic composition, there is a problem that the smell is not good, and it is not stable and can not be used industrially.
결과적으로, SMMS는 상처 회복 효과 및 UVB에 대한 피부 보호 효과가 뛰어남에도 불구하고 화장료 조성물로 사용될 수 없는 단점이 있다. 따라서, 종래 사용되는 SMMS과 유사한 구조를 가지는 유도체 중에서 보다 안정성이 증가되고 악취를 발생하지 않는 신규한 화합물을 대안으로서 제시하는 필요가 대두되었다.As a result, SMMS has a disadvantage that it can not be used as a cosmetic composition even though it has excellent wound restorative effect and skin protection against UVB. Therefore, a need has arisen to present, as an alternative, a novel compound which is more stable among the derivatives having a structure similar to that of SMMS conventionally used and does not generate malodor.
이에, 본 발명자들은 피부 미백 효과를 나타낼 수 있는 신규 화합물을 선별하고자 노력한 결과, SMMS 유도체인 (2S,4S), (2R,4S)-2-페닐티아졸리딘-4-카르복실산((2S,4S), (2R,4S)-2-phenylthiazolidine-4-carboxylic acid, 화합물 15) 및 (2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산((2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-phenyl-1,3-thiazinane-4-carboxylic acid, 화합물 16)이 피부 섬유아세포(Human dermal fibroblast, hDF) 및 피부 각질형성세포(dermal keratinocyte)에 대하여 세포 증식을 촉진할 뿐 아니라, 피부 미백 효과를 나타낼 수 있음을 확인함으로써, 본 발명을 완성하였다.Thus, the present inventors have made efforts to select a novel compound capable of exhibiting a skin whitening effect. As a result, the present inventors have found that (2S, 4S) -2,2-phenylthiazolidine-4-carboxylic acid (2S, 4S), (2R, 4S) -2-phenylthiazolidine-4-carboxylic acid, Compound 15) and (2S, 4R) Thiazinane-4-carboxylic acid ((2S, 4R), (2S, 4S) carboxylic acid, Compound 16) not only promotes cell proliferation but also has a skin whitening effect on human dermal fibroblast (hDF) and dermal keratinocyte, Completed.
이에, 본 발명자들은 다양한 S-메틸메티오닌 설포늄(SMMS)의 유도체 화합물 중에서 (2S,4S), (2R,4S)-2-페닐티아졸리딘-4-카르복실산(화합물 15) 및 (2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산(화합물 16)이 피부 미백 효과를 나타낼 수 있음을 확인하여 본 발명을 완성하였다.(2S, 4S) -2-Phenylthiazolidine-4-carboxylic acid (Compound 15) and (2S, 4S) -2-phenylthiazolidine- , 4R), (2S, 4S), (2R, 4R), (2R, 4S) -2-phenyl-1,3-thiazin-4-carboxylic acid (Compound 16) To complete the present invention.
따라서, 본 발명의 목적은 S-메틸메티오닌 설포늄의 유도체 화합물을 포함하는 피부 미백용 화장료 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a cosmetic composition for skin whitening comprising a derivative compound of S-methylmethionine sulfonium.
또한, 본 발명의 목적은 S-메틸메티오닌 설포늄의 유도체 화합물을 포함하는 피부 미백용 건강기능식품 조성물을 제공하는 것이다.It is also an object of the present invention to provide a health functional food composition for skin whitening comprising a derivative compound of S-methylmethionine sulfonium.
또한, 본 발명의 목적은 S-메틸메티오닌 설포늄의 유도체 화합물을 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is also an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of a melanin pigment hyperproliferative disorder comprising a derivative compound of S-methylmethionine sulfonium.
또한, 본 발명의 목적은 S-메틸메티오닌 설포늄의 유도체 화합물을 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 의약외품 조성물을 제공하는 것이다.It is also an object of the present invention to provide a quasi-drug composition for preventing or treating melanin pigment hyperproliferative disease, which comprises a derivative of S-methylmethionine sulfonium.
상기 목적을 달성하기 위해, 본 발명은 S-메틸메티오닌 설포늄(S-Methylmethionine sulfonium, SMMS)의 유도체 또는 이의 화장품학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다.In order to accomplish the above object, the present invention provides a cosmetic composition for skin whitening comprising a derivative of S-methylmethionine sulfonium (SMMS) or a cosmetically acceptable salt thereof as an active ingredient.
또한, 본 발명은 S-메틸메티오닌 설포늄의 유도체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for skin whitening comprising a derivative of S-methylmethionine sulfonium or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은S-메틸메티오닌 설포늄의 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating melanin pigment hyperproliferative disease, comprising a derivative compound of S-methylmethionine sulfonium or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 S-메틸메티오닌 설포늄의 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 의약외품 조성물을 제공한다.In addition, the present invention provides a quasi-drug composition for preventing or treating Melanin pigment hyperproliferative disorder, which comprises a derivative of S-methylmethionine sulfonium or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 바람직한 일실시예에서, 상기 S-메틸메티오닌 설포늄의 유도체는 하기 [화학식 1]의 구조를 가지는 화합물일 수 있다:In a preferred embodiment of the present invention, the derivative of S-methylmethionine sulfonium can be a compound having the structure of the following formula (1)
[화학식 1][Chemical Formula 1]
. .
(상기 화학식에서, R1은 S 또는 N 중 어느 하나 또는 둘 다를 포함하는, 5 또는 6 원자의 헤테로사이클(heterocycle)이다.)(In the above formula, R 1 is a heterocycle of 5 or 6 atoms, including either or both of S and N.)
본 발명의 바람직한 일실시예에서, 상기 화합물은 하기 [화학식 2]로 표시되는 (2S,4S), (2R,4S)-2-페닐티아졸리딘-4-카르복실산일 수 있다:In a preferred embodiment of the present invention, the compound may be (2S, 4S), (2R, 4S) -2-phenylthiazolidine-4-carboxylic acid represented by the following formula 2:
[화학식 2] (2)
본 발명의 또 다른 바람직한 일실시예에서, 상기 화합물은 하기 [화학식 3]으로 표시되는 (2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산일 수 있다:In another preferred embodiment of the present invention, the compound is (2S, 4R), (2S, 4S), (2R, 4R) 1,3-thiazin-4-carboxylic acid:
[화학식 3](3)
. .
본 발명의 S-메틸메니오닌 설포늄(SMMS) 유도체는 피부 미백 효과를 나타낼 뿐만 아니라 주근깨, 노인성 반점 등 멜라닌 색소 과다 침착 질환의 예방 또는 치료에 효과가 있으며, 종래 피부 손상 억제 및 피부 보호용 조성물에서 사용되고 있는 S-메틸메티오닌 설포늄(SMMS)이 가지는 불안정성 및 악취 발생의 한계를 극복할 수 있어, 화장료 조성물, 의약외품 조성물, 건강기능식품 조성물 및 약학적 조성물의 유효성분으로 유용하다.The S-methylmethionine sulfonium (SMMS) derivative of the present invention not only exhibits skin whitening effect but also is effective for preventing or treating melanin pigment hyperpigmentation diseases such as freckles and senile spots, It is possible to overcome the instability and odor generation limit of S-methylmethionine sulfonium (SMMS) which is used and is useful as an active ingredient of cosmetic composition, quasi-drug composition, health functional food composition and pharmaceutical composition.
도 1은 본 발명의 화합물 15 및 화합물 16의 피부 섬유아세포 증식 촉진 효과 및 UVB에 대한 세포 보호 효과 확인을 나타낸다: 도 1a는 다양한 SMMS 유도체의 피부 섬유아세포 증식 촉진 효과를 확인한 도이고, 도 1b는 다양한 SMMS 유도체의 UVB에 대한 세포 보호 효과를 확인한 도이다.
도 2는 본 발명의 화합물 15 및 화합물 16의 합성 단계를 나타낸다: 도 2a 및 도 2b는 각각 본 발명의 화합물 15 및 화합물 16의 구조를 나타내는 도이고, 도 2c는 본 발명의 화합물 15 및 화합물 16의 합성 과정을 나타내는 도이다.
도 3은 B16 세포주에서 화합물 15 및 16의 미백 효과를 확인한 사진이다.
도 4는 B16 세포주에서 화합물 15 및 16의 멜라닌 생합성 관련 유전자 발현 억제를 확인한 전기영동 결과이다.
도 5는 B16 세포주에서 화합물 15에 의해 TRP1 발현이 감소하는 것을 확인하기 위해 실시간 PCR(Real time PCR)을 수행한 결과이다.FIG. 1 shows the effect of
2A and 2B are diagrams showing the structures of
3 is a photograph showing the whitening effect of the
FIG. 4 shows electrophoresis results of confirming inhibition of melanin biosynthesis-related gene expression of
FIG. 5 shows the result of real-time PCR to confirm that TRP1 expression is decreased by
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
상술한 바와 같이, 자외선에 의한 피부 손상을 억제할 수 있는 화합물로서 종래 S-메틸메티오닌 설포늄(SMMS)이 많이 사용되고 있으나, 화합물의 구조가 안정적이지 않아 약제로의 생산이 용이하지 않으며 악취가 발생하여 화장료 조성물 등으로 사용하는 것에 제한을 가지고 있었다.As described above, conventional S-methylmethionine sulfonium (SMMS) has been widely used as a compound capable of inhibiting skin damage due to ultraviolet rays, but since the structure of the compound is not stable, production of a drug is not easy, So that it is limited to use as a cosmetic composition or the like.
본 발명의 구체적인 일실시예에서, 본 발명자들은 먼저 SMMS 유도체로서 피부 세포의 증식을 촉진하고 자외선에 대하여 보호 효과를 나타낼 수 있는 화합물을 선별하여, 다양한 화합물 중에서 화합물 15 및 화합물 16을 선별하였다(도 1 및 도 2). 또한, 본 발명자들은 선별한 화합물인 화합물 15 및 화합물 16이 B16 세포주에 미치는 영향을 확인한 결과, 화합물 15 및 화합물 16은 모두 B16 세포의 미백 효과를 나타내고(도 3), 멜라닌 생합성에 관여하는 유전자의 발현을 억제(도 4)하여 피부 미백 효과를 나타냄을 확인하였다.In one embodiment of the present invention, the present inventors firstly selected compounds capable of promoting the proliferation of skin cells and exhibiting a protective effect against ultraviolet rays as the SMMS derivatives, thereby selecting
따라서, 본 발명의 SMMS 유도체인 (2S,4S) 및 (2R,4S)-2-페닐티아졸리딘-4-카르복실산(화합물 15) 및 (2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산(화합물 16)은 피부 미백을 위한 화장료 조성물, 의약외품 조성물, 건강기능식품 조성물 및 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물의 유효성분으로 효과적이다.(2S, 4S), (2S, 4S) -2-phenylthiazolidine-4-carboxylic acid (Compound 15) and (2S, 4R) 2R, 4R), (2R, 4S) -2-phenyl-1,3-thiazin-4-carboxylic acid (Compound 16) is a cosmetic composition, quasi-drug composition, health functional food composition and melanin pigment- And is effective as an active ingredient of a pharmaceutical composition for preventing or treating a deposition disorder.
뿐만 아니라, 본 발명의 화합물 15 및 화합물 16은 종래 자외선에 의한 피부 손상 억제 및 피부 보호용 조성물, 피부 상처 회복 조성물 등 사용되고 있는 S-메틸메티오닌 설포늄(SMMS)이 가지는 불안정성 및 악취 발생의 한계를 극복할 수 있으며, SMMS보다 뛰어난 피부 미백 효과를 나타내기 때문에 효과적이다.In addition, the
따라서, 본 발명은 S-메틸메티오닌 설포늄(SMMS)의 유도체 또는 이의 화장품학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다.Accordingly, the present invention provides a cosmetic composition for skin whitening comprising as an active ingredient a derivative of S-methylmethionine sulfonium (SMMS) or a cosmetically acceptable salt thereof.
본 발명의 “S-메틸메티오닌 설포늄의 유도체”는 하기 [화학식 1]의 구조를 가지는 화합물인 것이 바람직하며, 하기 [화학식 1]에서, R1은 S 또는 N 중 어느 하나 또는 둘 다를 포함하는, 5 또는 6 원자의 헤테로사이클(heterocycle)인 것이 바람직하나, 이에 한정되지 않는다.The "S-methylmethionine sulfonium derivative" of the present invention is preferably a compound having a structure represented by the following formula (1), wherein R 1 represents any one or both of S and N , 5 or 6 atoms of a heterocycle, but is not limited thereto.
[화학식 1][Chemical Formula 1]
. .
보다 구체적으로, 본 발명의 “S-메틸메티오닌 설포늄의 유도체”는 하기 [화학식 2]로 표시되는 (2S,4S) 또는 (2R,4S)-2-페닐티아졸리딘-4-카르복실산((2S,4S) or (2R,4S)-2-phenylthiazolidine-4-carboxylic acid)일 수 있다.More specifically, the "derivative of S-methylmethionine sulfonium" of the present invention is a derivative of (2S, 4S) or (2R, 4S) -2-phenylthiazolidine-4-carboxylic acid ((2S, 4S) or (2R, 4S) -2-phenylthiazolidine-4-carboxylic acid.
[화학식 2](2)
또한, 본 발명의 “S-메틸메티오닌 설포늄의 유도체”는 하기 [화학식 3]으로 표시되는 (2S,4R), (2S,4S), (2R,4R) 또는 (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산((2S,4R), (2S,4S), (2R,4R) or (2R,4S)-2-phenyl-1,3-thiazinane-4-carboxylic acid) 중 어느 하나인 것이 바람직하다:(2S, 4R), (2S, 4S), (2R, 4R) or (2R, 4S) -2- (2R, 4S) -2-phenyl-1,3-thiazinane-4 (2S, 4R) -carboxylic acid) is preferable:
[화학식 3] (3)
본 발명의 용어 “피부 미백”은 멜라닌의 과다 생성으로 인하여 감소된 피부 밝기의 증가로 이해될 수 있으며, 구체적으로는 멜라닌의 과다 생성에 의한 기미, 주근깨, 검버섯 등의 개선(증상 경감), 치료, 예방, 발현 억제 또는 지연을 의미한다.The term " skin whitening " of the present invention can be understood as an increase in skin brightness reduced due to overproduction of melanin. Specifically, the skin whitening can be improved by improving melanin overexpression, freckles, , Prevention, suppression of expression or delay.
본 발명의 용어 “화장품학적으로 허용 가능한 염”, “식품학적으로 허용 가능한 염”, “약학적으로 허용 가능한 염” 또는 “이의 염”은 유리산(free acid)에 의해 형성된 산 부가염일 수 있다. 산 부가염은 통상의 방법, 예를 들어 상기 SMMS 유도체 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한, 동 몰량의 화합물 및 물 중의 산 또는 알코올 (예를 들어, 글리콜 모노메틸 에테르)을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.The term "cosmetically acceptable salt", "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "salt thereof" of the present invention may be an acid addition salt formed by a free acid . The acid addition salt may be prepared by a conventional method, for example, by dissolving the SMMS derivative compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile . It is also possible to heat an equimolar amount of the compound and an acid or alcohol (e.g., glycol monomethyl ether) in water, and then evaporate the mixture to dryness, or the precipitated salt may be subjected to suction filtration.
상기 유리산으로는 무기산 또는 유기산을 사용할 수 있다. 상기 무기산의 비제한적인 예로는 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산 등을 사용할 수 있으며, 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다. 상기 유기산의 비제한적인 예로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산(galacturonic acid), 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로아이오딕산 등을 사용할 수 있다. 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다.As the free acid, an inorganic acid or an organic acid can be used. Non-limiting examples of the inorganic acid include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid and phosphorous acid, and they may be used alone or in combination of two or more. Non-limiting examples of the organic acid include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, The present invention also relates to the use of a compound of formula (I) as an acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillyric acid, hydroiodic acid and the like. These may be used alone or in combination of two or more.
또한, 염기를 사용하여 약학적으로 허용 가능한 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 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
상기 SMMS 유도체 화합물의 염은, 달리 지시되지 않는 한, 상기 SMMS 유도체의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 모두 포함할 수 있다. 예를 들어 상기 SMMS 유도체의 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 화장품학적으로 허용 가능한 염으로는 하드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄술포네이트 (메실레이트) 및 p-톨루엔술포네이트 (토실레이트)염 등을 들 수 있으며 당업계에서 알려진 염의 제조 방법을 통하여 제조될 수 있다.Salts of the SMMS derivative compounds may include all salts of an acidic or basic group that may be present in the compound of the SMMS derivative, unless otherwise indicated. For example, salts of SMMS derivatives may include sodium, calcium and potassium salts of hydroxy groups, and other cosmetically acceptable salts of amino groups include hardro-bromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate (Salicylate) salts such as hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p- toluenesulfonate Can be produced through a production method.
또한, 본 발명의 상기 SMMS 유도체 화합물은 화장품학적, 식품학적, 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, the SMMS derivative compound of the present invention includes all salts, hydrates and solvates which can be prepared by conventional methods, as well as cosmetically, pharmaceutically or pharmaceutically acceptable salts.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 상기 SMMS 유도체 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the SMMS derivative compound in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding an excess of organic acid, And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.
본 발명의 화장료 조성물은, 예를 들면 용액, 겔, 고체 또는 반죽 무수생성물, 수상에 유상을 분산시켜 얻은 에멀젼, 현탁액, 마이크로에멀젼, 마이크로캡슐, 미세과립구 또는 이온형(리포좀), 비이온형의 소낭 분산제의 형태, 영양크림, 아이크림, 마사지크림, 클렌징 크림과 같은 크림류, 팩류, 영양로션과 같은 로션류, 에센스류, 유연화장수, 영양화장수와 같은 화장수류, 파우더류, 파운데이션류 및 메이크업 베이스류, 스프레이 또는 콘실 스틱, 폼(foam)의 형태 또는 압축된 추진제를 더 함유한 에어로졸 조성물 등 본 발명의 목적을 달성하기 위하여 이러한 제형 중 어떠한 형태로도 제조되어 상용화될 수 있으며, 상기 예들에 한정되지 않는다. 또한, 본 발명에 따른 화장료 조성물에는 통상의 화장료 제조 방법으로 제형화할 수 있다.The cosmetic composition of the present invention may be in the form of a solution, a gel, a solid or a paste anhydrous product, an emulsion obtained by dispersing an oil phase in water, a suspension, a microemulsion, a microcapsule, a microgranule or an ionic (liposome) Such as lotions, such as creams, packs, nutrition lotions, essences, softening lotions, nutrition lotions, powders, foundations and makeup bases, such as follicular dispersing agent forms, nutritional creams, eye creams, massage creams, Aerosol compositions that further contain a propellant, a spray or a cone stick, a foam or a compressed propellant may be manufactured and commercialized in any of these formulations to achieve the object of the present invention, It does not. Further, the cosmetic composition according to the present invention can be formulated into a usual cosmetic preparation method.
구체적으로 본 발명의 화장료는 스킨로션, 스킨 소프너, 스킨토너, 아스트린젠트, 로션, 밀크로션, 모이스처 로션, 영양로션, 맛사지 크림, 영양크림, 모이스처 크림, 핸드크림, 에센스, 팩, 마스크팩, 마스크시트, 비누, 샴푸, 클렌징폼, 클렌징로션, 클렌징크림, 바디로션, 바디클렌저, 유액, 프레스파우더, 루스파우더 및 아이섀도로 구성된 그룹에서 선택된 어느 하나의 제형을 가지는 것일 수 있다.Specifically, the cosmetic composition of the present invention can be used as a skin lotion, a skin softener, a skin toner, an astringent, a lotion, a milk lotion, a moisturizing lotion, a nutrition lotion, a massage cream, a nutrition cream, a moisturizing cream, a hand cream, And may be any one selected from the group consisting of soap, shampoo, cleansing foam, cleansing lotion, cleansing cream, body lotion, body cleanser, milky lotion, press powder, loose powder and eye shadow.
본 발명의 화장료 조성물은 SMMS 유도체 또는 이의 염에 더하여 부형제, 담체 등 기타 첨가제를 포함할 수 있으며, 일반 피부 화장료에 배합되는 보통의 성분을 필요한 만큼 적용 배합하는 것이 가능하다.The cosmetic composition of the present invention may contain, in addition to the SMMS derivative or a salt thereof, an excipient such as an excipient, a carrier and the like, and it is possible to apply an ordinary ingredient to be blended with a general skin cosmetic composition as needed.
구체적으로, 본 발명의 화장료 조성물은 경피 침투 강화제를 추가로 포함할 수 있다. 본 발명에서 사용되는 용어, 경피 침투 강화제란 피부의 혈관세포 내로 원하는 성분이 높은 흡수율로 침투할 수 있게 해주는 조성물이다. 바람직하게는 레시틴 화장품에 사용되는 다른 인지질 성분, 리포좀 성분 등이 포함되지만 이에 국한되지는 않는다.Specifically, the cosmetic composition of the present invention may further comprise a transdermal penetration enhancer. As used herein, the term transdermal penetration enhancer is a composition that allows a desired component to penetrate into vascular cells of the skin at a high absorption rate. But are not limited to, other phospholipid components, liposomal components, and the like, preferably used in lecithin cosmetics.
또한, 유상 성분으로서 주로 사용될 수 있는 오일로는 식물성 오일, 광물성 오일, 실리콘유 및 합성유 중에서 선택된 하나 이상을 사용할 수 있다. 보다 구체적으로, 미네랄오일, 사이크로메치콘, 스쿠알란, 옥틸도데실 미리스테이트, 올리브오일, 비티스 비니페라 씨드 오일, 마카다미아너트오일, 글리세릴옥타노에이트, 캐스터오일, 에칠헥실 이소노나노에이트, 디메치콘, 사이크로펜타실록산 및 선플라워씨드 오일 등을 사용할 수 있다.As the oil which can be mainly used as an oil component, at least one selected from vegetable oil, mineral oil, silicone oil and synthetic oil can be used. More specifically, there may be mentioned mineral oil, cyclomethicone, squalane, octyldodecyl myristate, olive oil, Vitisviniferase seed oil, macadamia nut oil, glyceryl octanoate, castor oil, ethylhexyl isononanoate, Chicone, cyclopentasiloxane, sunflower seed oil and the like can be used.
또한, 유화 능력을 보강하기 위하여 계면활성제, 고급 알콜 등을 0.1 내지 5 중량% 첨가할 수 있다. 이러한 계면 활성제로는 비이온 계면활성제, 음이온성 계면 활성제, 양이온성 계면 활성제, 양성 계면 활성제, 인지질 등과 같은 통상적인 계면활성제를 사용할 수 있으며, 구체적으로, 소르비탄세스퀴놀리에이트, 폴리솔베이트 60, 글리세릴 스테아레이트, 친유형 글리세릴스테아레이트, 소르비탄올리에이트, 소르비탄 스테아레이트, 디이에이-세틸포스페이트, 소르비탄스테아레이트/ 슈크로스코코에이트, 글리세릴스테아레이트/폴리에틸렌글라이콜-100 스테아레이트, 세테아레스-6 올리베이트, 아라키딜알코올/ 베헤닐알코올/아라키딜 글루코사이드, 폴리프로필렌글라이콜-26-부테스-26/ 폴리에틸렌글라이콜-40 하이드로제네이티드 캐스터오일 등을 사용할 수 있다. 고급 알콜로는 탄소수가 12 내지 20인 알코올, 예컨대 세틸알코올, 스테아릴 알코올, 옥틸도데칸올, 이소스테아릴 알코올 등을 단독으로 또는 1종 이상 혼합하여 사용할 수 있다.Further, 0.1 to 5% by weight of a surfactant, a higher alcohol and the like may be added to reinforce the emulsifying ability. As such surfactants, conventional surfactants such as nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, phospholipids and the like can be used. Specific examples thereof include sorbitan sesquiunorate,
수상 성분은 수상의 점도 또는 경도를 조절하기 위하여 카보머, 잔탄검, 벤토나이트, 마그네슘알루미늄실리케이트, 셀룰로오스검, 덱스트린 팔미테이트 등과 같은 1종 이상의 점증제를 0.001 내지 5 중량% 더 첨가할 수 있다.In order to control the viscosity or hardness of the water phase, 0.001 to 5% by weight of at least one thickening agent such as carbomer, xanthan gum, bentonite, magnesium aluminum silicate, cellulose gum, dextrin palmitate and the like may be further added.
또한, 본 발명의 화장료 조성물에는 필요에 따라 고급 지방산, 비타민 등의 약효 성분과 자외선 차단제, 산화 방지제(부틸히드록시아니솔, 갈릭산프로필, 엘리소르빈산, 토코페릴아세테이드, 부틸레이티드하이드록시톨루엔 등), 방부제(메칠파라벤, 부틸파라벤, 프로필파라벤, 페녹시에탄올, 이미다졸리디닐우레아, 클로르페네신 등), 착색제, pH 조절제(트리에탄올아민, 씨트릭애씨드, 시트르산, 시트르산나트륨, 말산, 말산나트륨, 프말산, 프말산나트륨, 숙신산, 숙신산나트륨, 수산화나트륨, 인산일수소나트륨 등), 보습제(글리세린, 솔비톨, 프로필렌 글라이콜, 부틸렌 글라이콜, 헥실렌 글라이콜, 디글리세린, 베타인, 글리세레스-26, 메칠글루세스-20 등), 윤활제 등의 성분을 더 첨가할 수 있다.In addition, the cosmetic composition of the present invention may contain, if necessary, a medicinal ingredient such as higher fatty acids and vitamins, an ultraviolet screening agent, an antioxidant (butylhydroxyanisole, gallic acid propylate, eicosorbic acid, tocopheryl acetatide, (Triethanolamine, citric acid, citric acid, sodium citrate, malic acid, citric acid, etc.), preservatives (methylparaben, butylparaben, propylparaben, phenoxyethanol, imidazolidinyl urea, chlorphenesin and the like) And the like), a humectant (glycerin, sorbitol, propylene glycol, butylene glycol, hexylene glycol, diglycerin, etc.), sodium hydrogen carbonate , Betaine, glycereth-26, methylglucose-20, etc.), lubricant, and the like.
또한, 본 발명의 화장료 조성물은 피부에 필수 영양소를 보조적으로 제공할 수 있는 물질을 추가로 포함하는데, 바람직하게는 천연향, 화장품향, 또는 한약재가 포함되지만 이들에 국한되지 않는 보조제를 함유할 수 있다. In addition, the cosmetic composition of the present invention further comprises a substance capable of supplementally providing an essential nutrient to the skin, and preferably it may contain an auxiliary agent including, but not limited to, a natural flavor, a cosmetic flavor, have.
또한, 본 발명은 S-메틸메티오닌 설포늄(SMMS)의 유도체 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for skin whitening comprising a derivative of S-methylmethionine sulfonium (SMMS) or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 ”S-메틸메티오닌 설포늄(SMMS)의 유도체”와 “이의 식품학적으로 허용가능한 염”에 대한 설명은 전술한 바와 같다.The description of the above " derivative of S-methylmethionine sulfonium (SMMS) " and " a pharmaceutically acceptable salt thereof "
본 발명에서 용어 “건강기능식품”은 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 건강기능식품 조성물은 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 피부 미백 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term " health functional food " in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, 'functional' refers to the structure and function of the human body to obtain nutritional effects and obtain useful effects for health use such as physiological action. The health functional food of the present invention can be prepared by a method commonly used in the art and can be prepared by adding raw materials and ingredients that are conventionally added in the art. In addition, the formulations of the above health functional foods may also be manufactured without limitations as long as they are acceptable as health functional foods. The health functional food composition of the present invention is advantageous in that it is free from side effects that may occur when a medicine is taken for a long time by using a food as a raw material, unlike a general medicine, and is excellent in portability and is an adjuvant for enhancing skin whitening effect It is possible.
본 발명의 건강기능식품 조성물은 정제, 과립, 분말, 캅셀, 액상의 용액 및 환으로 이루어진 군으로부터 선택된 어느 하나의 제형으로 제조된 것일 수 있다.The health functional food composition of the present invention may be prepared in any one form selected from the group consisting of tablets, granules, powders, capsules, liquid solutions and rings.
본 발명에 따른 건강기능식품 조성물은 SMMS 유도체를 유효성분으로 포함시켜 분말제, 액제, 정제, 연질캅셀제, 과립제, 티백차, 인스턴트 차 또는 드링크제 등의 형태로 제형화될 수 있다. 유효 성분으로서의 SMMS 유도체의 함량은 그 사 용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 조성물 중에 포함되는 SMMS 유도체의 양은 전체 식품 중량의 0.1 내지 90 중량%로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다. 또한, 본 발명에 따른 건강기능식품 조성물은 SMMS 유도체 이외에 본 발명이 목적으로 하는 주효과를 손상시키지 않는 범위 내에서 바람직하게는 주효과에 상승효과를 줄 수 있는 다른 성분 예를 들면, 비타민 C와 같은 주름 개선용 화합물 또는 녹차 추출물, 닥나무 추출물, 감초추출물, 상백피 추출물, 빈랑자 추출물, 황금 추출물, 산삼 추출물 등의 천연물을 함유하는 것도 무방하다.The health functional food composition according to the present invention may be formulated in the form of powders, liquids, tablets, soft capsules, granules, tea bags, instant tea or drinks containing SMMS derivatives as an active ingredient. The content of the SMMS derivative as an active ingredient can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the SMMS derivative contained in the health functional food composition may be 0.1 to 90% by weight of the total food weight. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range. In addition, the health functional food composition according to the present invention may contain, in addition to the SMMS derivative, other components that can give a synergistic effect to the main effect, for example, vitamin C Such as wrinkle-improving compound or green tea extract, mulberry extract, licorice extract, mulberry bark extract, bingo extract, golden extract, and wild ginseng extract.
상기와 같은 형태로 제형화된 건강기능식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품은 모두 포함한다.The health functional food composition formulated in the above-described form can be added directly to the food or can be used together with other food or food ingredients, and can be suitably used according to a conventional method. Examples of food products include dairy products including drinks, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, soups, , Dairy products and dairy products, and all health functional foods in the ordinary sense are included.
본 발명의 건강기능식품 조성물이 드링크제인 경우는 지시된 비율로 필수성분으로서 SMMS 유도체를 함유하며, 그 밖의 드링크제 제조를 목적으로 사용되는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상기 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등), 디사카라이드(예컨대, 말토스, 수크로오스 등), 올리고당, 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등), 또는 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)인 것이 바람직하다. 상기 향미제는 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등)와 합성 향미제(예컨대, 사카린, 아스파르탐 등)를 이용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.When the health functional food composition of the present invention is a drink, the SMMS derivative is contained as an essential ingredient at the indicated ratio. There are no particular restrictions on other ingredients used for the purpose of producing other drink products, and various flavors Or natural carbohydrate as an additional ingredient. The natural carbohydrate may be selected from the group consisting of monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g., dextrin, cyclodextrin, For example, xylitol, sorbitol, erythritol, etc.). The flavoring agent may be a natural flavoring agent (e.g., tau Martin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.). The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
또한 본 발명의 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 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 밖에도 본 발명의 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 SMMS 유도체 100 중량부 당 0.01 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition, the health functional food composition of the present invention can be used as a nutritional supplement, a vitamin, a mineral (electrolyte), a flavor such as a synthetic flavor and a natural flavor, a coloring agent and a thickening agent (cheese, chocolate etc.), a pectic acid and its salt, And salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the inventive food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the SMMS derivative of the present invention.
또한, 본 발명은 S-메틸메티오닌 설포늄(SMMS)의 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료를 위한 약학적 조성물 또는 의약외품 조성물을 제공한다.The present invention also provides a pharmaceutical composition or a quasi-drug composition for preventing or treating a melanin pigment hyperproliferative disorder, which comprises a derivative of S-methylmethionine sulfonium (SMMS) or a pharmaceutically acceptable salt thereof as an active ingredient .
상기 ”S-메틸메티오닌 설포늄(SMMS)의 유도체”와 “이의 약학적으로 허용가능한 염”에 대한 설명은 전술한 바와 같다.The description of the above " derivatives of S-methylmethionine sulfonium (SMMS) " and " pharmaceutically acceptable salts thereof "
본 발명에서 상기 멜라닌 색소 과다 침착 질환은 주근깨, 노인성 반점, 간반, 기미, 갈색 또는 흑점, 일광 색소반, 푸른흑피증(cyanic melasma), 약물 사용 후의 멜라닌 색소 과다 침착, 임신성 갈색반(gravidic chloasma), 또는 찰상 및 화상을 비롯한 상처 또는 피부염으로 인한 염증 후 과다 색소 침착일 수 있으나, 이에 한정되지 않는다.In the present invention, the melanin pigment hyperpigmentation disorder may be selected from the group consisting of freckles, senile spots, liver, spots, brown or black spots, daylight pigmentation, cyanic melasma, melanin pigmentation after drug use, gravidic chloasma, , Or post-inflammatory hyperpigmentation due to scratches or dermatitis, including scratches and burns.
본 발명의 멜라닌 색소 과다 침착 질환 예방 또는 치료를 위한 약학적 조성물은 SMMS 유도체를 단독으로 함유하거나 또는 SMMS 유도체와 그의 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다. 추가적인 성분을 포함하게 되면 본 발명의 조성물의 멜라닌 색소 과다 침착 질환 예방 또는 치료 효과가 더욱 증진될 수 있을 것이다. 상기 성분 추가 시에는 복합 사용에 따른 피부 안전성, 제형화의 용이성, 유효성분들의 안정성을 고려할 수 있다. The pharmaceutical composition for prevention or treatment of melanin pigment hyperpigmentation disease of the present invention may contain one or more active ingredients which contain SMMS derivatives alone or exhibit similar functions to SMMS derivatives. When the composition contains an additional component, the effect of preventing or treating the melanin pigment hyperpigmentation disease of the composition of the present invention may be further enhanced. When the above ingredients are added, skin safety, easiness of formulation, and stability of effective ingredients can be considered according to the combined use.
또한, 본 발명의 멜라닌 색소 과다 침착 질환 예방 또는 치료를 위한 약학적 조성물은 약학적으로 허용 가능한 담체를 더 포함할 수 있다. 약학적으로 허용되는 담체는 완충액, 주사용 멸균수, 일반 식염수 또는 인산염 완충 식염수, 슈크로스, 히스티딘, 염 및 폴리솔베이트 등과 같은 여러 성분을 함유할 수 있다.In addition, the pharmaceutical composition for preventing or treating melanin pigment hyperproliferative disorder of the present invention may further comprise a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may contain a variety of ingredients such as buffer, injectable sterile water, normal saline or phosphate buffered saline, sucrose, histidine, salts and polysorbates.
본 발명의 조성물을 의약품으로 사용하는 경우, 상기 SMMS 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a medicament, the pharmaceutical composition containing the SMMS derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated into various oral or parenteral dosage forms at the time of clinical administration, But is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 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 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (E.g., silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycols), such as, for example, water, rosin, sucrose, mannitol, sorbitol, cellulose and / or glycine. The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.
경피 투여제의 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태가 포함된다. 상기에서 '경피 투여'는 약학 조성물을 국소적으로 피부에 투여하여 약학 조성물에 함유된 유효한 양의 활성성분이 피부 내로 전달되는 것을 의미한다. Examples of transdermal dosage forms include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges. In the above, 'transdermal administration' means that the pharmaceutical composition is locally administered to the skin, whereby an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.
본 발명의 SMMS 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 SMMS 유도체 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.The pharmaceutical composition comprising the SMMS derivative compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be carried out by injecting subcutaneous injection, intravenous injection, intramuscular injection, It depends on the method. In this case, in order to formulate the formulation for parenteral administration, the SMMS derivative compound or a pharmaceutically acceptable salt thereof is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is prepared into an ampule or vial unit dosage form . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.
또한, 본 발명의 화합물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 60 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.001 ~ 1,000 ㎎/일이며, 바람직하게는 0.01 ~ 500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The dose of the compound of the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity. In general, when referring to an adult patient weighing 60 kg, And may be 0.01 to 500 mg / day, preferably 0.01 to 500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.
본 발명에서 사용되는 용어 "의약외품"은 사람이나 동물의 질병을 진단, 치료, 개선, 경감, 처치 또는 예방할 목적으로 사용되는 물품들 중 의약품보다 작용이 경미한 물품들을 의미하는 것으로, 예를 들어 약사법에 따르면 의약외품이란 의약품의 용도로 사용되는 물품을 제외한 것으로, 사람ㆍ동물의 질병 치료나 예방에 쓰이는 제품, 인체에 대한 작용이 경미하거나 직접 작용하지 않는 제품 등이 포함된다.The term "quasi-drug product" used in the present invention means products that are less active than drugs, among the products used for diagnosing, treating, improving, alleviating, treating or preventing diseases of human or animal. For example, Quasi-drugs are products that are used for the purpose of treating or preventing diseases of humans or animals, products that are mild or have no direct action on the human body.
본 발명의 의약외품 조성물은 색소 과다 침착 질환 예방 또는 치료를 목적으로 사용되는 것으로, 그 제형에 있어서 특별히 한정되는 바가 없으며, 상기 제형화된 제품은 자외선 차단제, 선크림, 선로션, 선스프레이, 헤어토닉, 헤어로션, 헤어크림, 헤어스프레이, 헤어무스, 헤어젤, 헤어컨디셔너, 헤어샴푸, 헤어 린스, 헤어팩, 헤어트리트먼트, 눈썹발모제, 속눈썹발모제, 속눈썹영양제, 애완동물용 샴푸, 애완동물용 린스, 손 세정제, 세제 비누, 비누, 소독청결제, 물티슈, 마스크, 연고제, 패치 또는 필터 충진제 등이 있으며, 통상적인 의미에서의 의약외품을 모두 포함한다.The quasi-drug composition of the present invention is used for the purpose of preventing or treating hyperpigmentation diseases, and is not particularly limited in its formulation. The formulated product may be selected from the group consisting of sunscreen, sunscreen, sun lotion, sun spray, hair tonic, Hair lotion, hair cream, hair spray, hair mousse, hair gel, hair conditioner, hair shampoo, hair rinse, hair pack, hair treatment, eyebrow hair extender, eyelash hair extender, eyelash nutritional agent, pet shampoo, pet rinse, hand A cleaning agent, a detergent soap, a soap, a disinfectant cleaner, a wet tissue, a mask, an ointment agent, a patch or a filter filler, and includes quasi-drugs in a conventional sense.
또한, 각 제형에 있어서 의약외품 조성물은 다른 성분들을 기타 의약외품의 제형 또는 사용목적 등에 따라 임의로 선정하여 배합할 수 있다. 유효 성분의 혼합양은 사용 목적(억제 또는 완화)에 따라 적합하게 결정될 수 있다. 예를 들어, 점증제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 및 담체 등을 포함할 수 있다.In addition, the quasi-drug composition in each formulation can be blended by arbitrarily selecting other components according to the formulation of the other quasi-drugs, the purpose of use, and the like. The mixing amount of the active ingredient can be appropriately determined according to the intended use (inhibition or relaxation). For example, conventional adjuvants such as thickeners, stabilizers, solubilizers, vitamins, pigments and flavors, and carriers and the like.
본 발명의 SMMS 유도체 또는 이의 염의 함량은 의약외품 조성물의 총중량을 기준으로 각각 0.0001 내지 20 중량% 인 것이 바람직하다. 20 중량%를 초과하는 경우에는 조성물 제조시 색상 및 안정성이 떨어지며, 0.0001% 미만의 경우에는 그 작용효과가 미미하다.The content of the SMMS derivative or its salt of the present invention is preferably 0.0001 to 20% by weight based on the total weight of the quasi-drug composition. When it is more than 20% by weight, the color and stability are poor when the composition is prepared, and when it is less than 0.0001%, the effect is insignificant.
또한, 각 제형의 의약외품 조성물에 있어서, 상기한 필수 성분 이외의 다른 성분들은 제형 또는 사용목적 등에 따라 당업자가 어려움 없이 적의 선정하여 배합할 수 있다.In addition, in the quasi-drug composition of each formulation, components other than the above-mentioned essential components may be mixed and selected without difficulty by those skilled in the art depending on the formulation or purpose of use.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지 않는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.
실시예Example 1. One. hDFhDF 세포 증식 촉진 효과를 가지는 신규 화합물의 제조 및 선별 Preparation and screening of novel compounds with cell proliferation promoting effect
<1-1> <1-1> hDFhDF 증식 효과를 가지는 화합물 선별 Selection of compound having proliferation effect
본 발명의 대상 화합물로서 사용하기 위해 신규한 화합물을 합성하여, 총 50 개의 합성 화합물을 제조하였다.Novel compounds were synthesized for use as the subject compounds of the present invention to produce a total of 50 synthetic compounds.
그런 다음, 인간 유래의 피부 섬유아세포(Human dermal fibroblast, hDF)를 1% 우태아혈청(FBS; Gibco, Invitrogen, Carlsbad, CA, USA), 1% 페니실린(penicillin) 및 스트렙토마이신(streptomycin)을 포함하는 DMEM(Hyclone, Thermo Scientific, Logan, UT, USA) 배지에 접종하고, 37℃의 5% 이산화탄소 배양기에서 배양하여 세포를 준비하였다. 세포 배양 시, 배지는 2일에 1회씩 신선한 배지로 교체하였다. 준비한 hDF 세포를 3×104 /well 농도로 10% FBS를 포함하는 DMEM에 접종하였다. 하룻밤 동안 배양한 후, 배양 배지를 혈청을 포함하지 않는 DMEM 배지로 교환하여 기아 상태(starvation)을 유도하였다. 그런 다음, 각각의 합성 화합물을 10 μM 농도로 처리하여 48 시간 동안 추가 배양하였다. 배양 중에는, UVB(400 mJ)를 처리하거나 처리하지 않은 조건으로 나누어 배양하였다. 그런 다음, PBS 완충용액 내의 5 ㎎/㎖ MTT 용액을 각 웰에 첨가된 배지 부피의 5% 부피로 첨가하고, 2 시간 동안 37℃ 온도에서 배양한 후, 상층액을 제거하였다. 상층액이 제거된 웰의 침전된 불용성의 포르마잔(formazan crystal)은 디메틸 술폭사이드(Dimethyl sulfoxide)를 첨가하여 용해한 다음, ELISA 리더기를 사용하여 595 ㎚에서 흡광도를 측정하여, 생존 세포의 정도를 확인하였다. 측정한 흡광도 값을 사용하여, 합성 화합물을 처리하지 않은 대조군(control)에 대한 합성 화합물의 세포 생존 정도를 계산하였다. 계산된 상대적인 세포 생존 정도를 사용하여, UVB를 조사하지 않은 실험군에서의 상대적인 세포 생존 정도를 증식 효과(proliferation, %)으로서 확인하였으며, UVB를 조사한 실험군에서의 상대적인 세포 생존 정도를 세포 생존률(cell viability, %)로서 확인하였다.Human dermal fibroblast (hDF) was then incubated with 1% fetal bovine serum (FBS; Gibco, Invitrogen, Carlsbad, CA, USA), 1% penicillin and streptomycin (Hyclone, Thermo Scientific, Logan, UT, USA), and the cells were cultured in a 5% carbon dioxide incubator at 37 ° C. For cell culture, the medium was replaced with fresh medium once every two days. The prepared hDF cells were inoculated into DMEM containing 10% FBS at a concentration of 3 × 10 4 / well. After overnight incubation, starvation was induced by exchanging the culture medium with DMEM medium containing no serum. Each of the synthetic compounds was then treated with a concentration of 10 [mu] M and further incubated for 48 hours. During the cultivation, UVB (400 mJ) was treated or not treated and cultured separately. Then, 5 mg / ml MTT solution in PBS buffer was added at 5% volume of the medium added to each well, incubated at 37 캜 for 2 hours, and then the supernatant was removed. The precipitated insoluble formazan crystals of the wells from which the supernatant was removed were dissolved by adding dimethyl sulfoxide and the absorbance was measured at 595 nm using an ELISA reader to confirm the extent of the viable cells Respectively. Using the measured absorbance values, the degree of cell viability of the synthetic compound was calculated for a control without treatment of the synthetic compound. Using the calculated relative cell viability, the relative cell viability in the experimental group without UVB irradiation was confirmed as proliferation (%), and the relative cell viability in the UVB-irradiated experimental group was evaluated as cell viability ,%).
그 결과, 도 1a 및 도 1b에서 나타난 바와 같이, 10 μM 농도로 합성 화합물을 처리하였을 때, 화합물 15, 16 및 20에서 유의적으로 hDF 세포에서 증식 촉진 효과가 나타나는 것을 확인하였다(도 1a). 또한, UVB를 처리하였을 때 hDF의 생존이 감소하였으나, 화합물 5, 9, 15, 16, 17, 20 또는 22을 처리한 실험군에서 hDF의 생존률이 증가하는 것을 확인하였다(도 1b).As a result, when the synthetic compound was treated at a concentration of 10 μM as shown in FIG. 1A and FIG. 1B, it was confirmed that the proliferation-promoting effect was shown in the hDF cells significantly in the
그러나, 화합물 5 및 화합물 9에서는 UVB에 대하여 hDF 세포를 보호할 수 있는 효과를 나타냄에도 불구하고, 분해되지 않고 악취가 난다는 단점이 있음을 확인하였다. 또한, 화합물 17, 20 및 22의 경우는 화합물 15 및 화합물 16과 구조가 유사하나, UVB를 조사하지 않은 환경에서 세포 증식 촉진 효과를 유의적으로 나타내지 않아, 보다 효과적인 신규 합물로서 화합물 15 및 화합물 16을 선별하였다.However, although Compound 5 and Compound 9 showed an effect of protecting hDF cells against UVB, it was confirmed that they had a disadvantage that they did not decompose and stink.
<1-2> <1-2>
신규한New
화합물 15 및 화합물 16의 합성 및 특성 확인 Synthesis and Characterization of
다양한 합성 화합물 중에서, 피부 섬유상 세포의 증식 촉진 효과 및 UVB에 대한 세포 보호 효과가 가장 효과적인 것으로 확인한 화합물 15 및 화합물 16에 대하여 NMR 분석으로 화합물의 구조를 분석하였다.Among the various synthetic compounds, the structure of the compound was analyzed by NMR analysis for
본 발명의 화합물 15 및 화합물 16은 도 2C의 과정을 유도함으로써 합성을 수행하였다. 구체적으로, 0.74 mmol의 L-시스테인(L-cysteine) 또는 DL-호모시스테인(DL-homocysteine)을 4 mL의 에탄올 및 1 mL의 증류와 혼합한 다음, 0.74 mmol의 벤조알데하이드(benzaldehyde)를 첨가하였다. 혼합물을 3 일 동안 실온에서 혼합한 다음, 필터링하여 상층액을 제거하고 침전물을 수득하고, 에테르(ether)로 세척한 후 진공 상태에서 건조하여 백색 결정의 화합물을 수득하였다.
그 결과, 본 발명의 화합물 15의 NMR 분석 결과는 다음과 같음을 확인하였다:As a result, it was confirmed that the NMR analysis result of the
White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.52 (m, 5H), 5.67 (s, 0.6H), 5.50 (s, 0.4H), 4.23 (dd, J = 4.8, 4.8 Hz, 0.6H), 3.90 (dd, J = 7.6, 8.0 Hz, 0.4H), 3.28-3.40 (m, 1H), 3.06-3.16 (m, 1H). 즉, 화합물 15는 하기 [화학식 2]의 구조를 가지는 (2S,4S) 및 (2R,4S)-2-페닐티아졸리딘-4-카르복실산((2S,4S) and (2R,4S)-2-phenylthiazolidine-4-carboxylic acid)으로 나타났다.White solid; (D, J = 4.8, 4.8 Hz, 0.6H), 5.50 (s, 0.4H), 4.23 , 3.90 (dd, J = 7.6, 8.0Hz, 0.4H), 3.28-3.40 (m, 1H), 3.06-3.16 (m, 1H). That is, the
[화학식 2](2)
또한, 본 발명의 화합물 16의 NMR 분석 결과는 다음과 같음을 확인하였다: In addition, it was confirmed that the NMR analysis results of
White solid; 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.45 (m, 5H), 5.27 (s, 1H), 3.60 (dd, J = 3.2, 12 Hz, 1H), 3.19-3.26 (m, 1H), 2.88-2.93 (m, 1H), 2.04-2.08 (m, 1H), 1.50 (m, 1H). 따라서, 화합물 16은 하기 [화학식 3]의 구조를 가지는 (2S,4R), (2S,4S), (2R,4R) 및 (2R,4S)-2-페닐-1,3-티아지난-4-카르복실산((2S,4R), (2S,4S), (2R,4R), (2R,4S)-2-phenyl-1,3-thiazinane-4-carboxylic acid)으로 나타났다.White solid; 1H NMR (400 MHz, DMSO-d6)? 7.28-7.45 (m, 5H), 5.27 (s, IH), 3.60 (dd, J = 3.2,12 Hz, IH), 3.19-3.26 2.88-2.93 (m, 1 H), 2.04-2.08 (m, 1 H), 1.50 (m, 1 H). Accordingly, the
[화학식 3](3)
실시예Example
2. 화합물 15 및 화합물 16의 피부 미백 효과 확인 2. Identification of Skin Whitening Effect of
멜라닌 형성 세포주인 B16 세포주에서 본 발명의 화합물 15 및 화합물 16에 의한 미백 효과를 세포 침전물의 색 변화를 통하여 확인하였다.In the melanin-forming cell line B16 cell line, whitening effect of
구체적으로, B16 세포를 60 mm 플레이트에 1.5×105로 시딩(seeding)한 후 1일 뒤에 본 발명의 화합물 15 및 화합물 16을 각각 농도별로 처리하였다(10 μM, 50 μM, 100 μM). 3일 후에 트립신을 처리하여 플레이트에서 세포를 분리한 후, 분리한 세포를 EP Tube에 넣고 원심분리기로 모아 가라앉은 세포 침전물의 색 변화를 확인하였다.Specifically, B16 cells were seeded on a 60 mm plate at 1.5 × 10 5 , and after 1 day,
그 결과 도 3에 나타난 바와 같이, 화합물 15를 100 μM 처리한 세포 침전물에서 확연하게 미백 효과가 나타난 것을 알 수 있었고, 화합물 16을 처리한 세포 침전물의 경우 화합물 15보다는 미약하지만 농도의존적으로 미백 효과가 나타난다는 것을 확인할 수 있었다.As a result, as shown in FIG. 3, the whitening effect was remarkably observed in the cell suspension treated with 100 μM of
실시예Example
3. 화합물 15 및 화합물 16의 멜라닌 색소 관련 유전자 억제 효과 3. Inhibitory effect of
본 발명의 화합물 15 및 화합물 16이 멜라닌 색소 생합성에 관여하는 티로시나제(tyrosinase), TRP1(Tyrosinase-related protein 1), TRP2(Tyrosinase-related protein 2) 발현을 저해하는지 여부를 확인하기 위하여, 하기와 같은 실험을 수행하였다.In order to confirm whether the
구체적으로, 상기 실시예 2와 동일하게 B16 세포를 60 mm 플레이트에 1.5×105로 시딩(seeding)한 후 1일 뒤에 본 발명의 화합물 15 및 화합물 16을 각각 농도별로 처리하였다(10 μM, 50 μM, 100 μM). 3일 후에 트리졸(Trizol) 시약을 사용하여 세포막을 융해하고, 이소프로판올과 에탄올로 정제하여 전체 RNA를 분리하였다. 분리된 RNA로부터 하기 [표 1]에 기재된 프라이머 및 역전사 효소를 사용하여 티로시나아제, TRP1 및 TRP2의 cDNA를 합성하였다. 그 다음, 상기 합성한 cDNA 30 ㎕를 주형으로 하여, Tag 중합효소와 각각의 표적 유전자의 상보적 프라이머를 이용하여 해당 DNA를 증폭하였다. Specifically, in the same manner as in Example 2, B16 cells were seeded on a 60 mm plate at 1.5 × 10 5 , and after one day,
PCR 수행 조건은 다음과 같다: 95℃에서 5분간 변성; 95 ℃에서 0s, 54℃에서 20s 및 72℃에서 30s간 증폭(총 35 사이클); 및 72℃에서 10분간 최종 연장. GAPDH mRNA 발현 수준은 시료의 표준화(strandarization)을 위해 사용하였다.PCR conditions were as follows: denaturation at 95 ° C for 5 min; 0 s at 95 째 C, 20 s at 54 째 C and 30 s at 72 째 C (35 total cycles); And final extension at 72 ° C for 10 minutes. GAPDH mRNA expression levels were used for strandarization of samples.
미처리 대조군(control)은 본 발명의 화합물을 처리하지 않은 세포주를 대상으로 하였다.An untreated control (control) was a cell line that was not treated with the compound of the present invention.
그 결과, 도 4 및 도 5에 나타난 바와 같이 화합물 15를 처리한 경우 TRP1 유전자의 발현이 농도의존적으로 감소하였고, 도 4에 나타난 바와 같이 화합물 16을 처리한 경우 농도 의존적으로 티로시나아제 유전자의 발현이 감소한 것을 확인할 수 있었다.As a result, as shown in FIG. 4 and FIG. 5, the expression of TRP1 gene decreased in a concentration-dependent manner when
<110> Industry-Academic Cooperation Foundation, Yonsei University <120> Composition for skin whitening comprising S-Methylmethionine sulfonium derivatives <130> 1062919 <160> 8 <170> KoPatentIn 3.0 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> TRP1_F <400> 1 cccctagcct atatctccct ttt 23 <210> 2 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> TRP1_R <400> 2 taccatcgtg gggataatgg c 21 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> TRP2_F <400> 3 attacaccgt cgctcatctt 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> TRP2_R <400> 4 ctttgaccgt ggtgaatgac 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Tyrosinase_F <400> 5 ggagggacat tgattttgcc 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Tyrosinase_R <400> 6 tcccaagtac tcatctgtgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_F <400> 7 ctggagaaac ctgccaagta 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_R <400> 8 aagagtggga gttgctgttg 20 <110> Industry-Academic Cooperation Foundation, Yonsei University <120> Composition for skin whitening comprising S-methylmethionine sulfonium derivatives <130> 1062919 <160> 8 <170> KoPatentin 3.0 <210> 1 <211> 23 <212> DNA <213> Artificial Sequence <220> <223> TRP1_F <400> 1 cccctagcct atatctccct ttt 23 <210> 2 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> TRP1_R <400> 2 taccatcgtg gggataatgg c 21 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> TRP2_F <400> 3 attacaccgt cgctcatctt 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> TRP2_R <400> 4 ctttgaccgt ggtgaatgac 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Tyrosinase_F <400> 5 ggagggacat tgattttgcc 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Tyrosinase_R <400> 6 tcccaagtac tcatctgtgc 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_F <400> 7 ctggagaaac ctgccaagta 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> GAPDH_R <400> 8 aagagtggga gttgctgttg 20
Claims (8)
상기 유효성분은 10 ~ 100 μM 농도로 포함되고, 멜라닌 형성 세포(B16) 미백 또는 TRP1(Tyrosinase related protein 1), TRP2(Tyrosinase related protein 2) 및 티로시나아제 유전자 발현 저하를 특징으로 하는 피부 미백용 화장료 조성물:
[화학식 3]
.
(2S, 4R), (2S, 4S), (2R, 4R) or (2R, 4S) -2-phenyl-1,3-thiazin- (2S, 4S) -2-phenyl-1,3-thiazinane-4-carboxylic acid or a cosmetically acceptable salt thereof as an active ingredient ≪ / RTI &
The active ingredient is contained at a concentration of 10 to 100 μM and is used for whitening melanocytes (B16) or skin whitening characterized by the expression of TRP1 (Tyrosinase related protein 1), TRP2 (Tyrosinase related protein 2) and tyrosinase gene Cosmetic composition:
(3)
.
상기 유효성분은 10 ~ 100 μM 농도로 포함되고, 멜라닌 형성 세포(B16) 미백 또는 TRP1(Tyrosinase related protein 1), TRP2(Tyrosinase related protein 2) 및 티로시나아제 유전자 발현 저하를 특징으로 하는 피부 미백용 건강기능식품 조성물:
[화학식 3]
.
(2S, 4R), (2S, 4S), (2R, 4R) or (2R, 4S) -2-phenyl-1,3-thiazin- (2S, 4S) -2-phenyl-1,3-thiazinane-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient ≪ / RTI &
The active ingredient is contained at a concentration of 10 to 100 μM and is used for whitening melanocytes (B16) or skin whitening characterized by the expression of TRP1 (Tyrosinase related protein 1), TRP2 (Tyrosinase related protein 2) and tyrosinase gene Health functional food composition:
(3)
.
상기 유효성분은 10 ~ 100 μM 농도로 포함되고, 멜라닌 형성 세포(B16) 미백 또는 TRP1(Tyrosinase related protein 1), TRP2(Tyrosinase related protein 2) 및 티로시나아제 유전자 발현 저하를 특징으로 하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 약학적 조성물:
[화학식 3]
.
(2S, 4R), (2S, 4S), (2R, 4R) or (2R, 4S) -2-phenyl-1,3-thiazin- (2S, 4S) -2-phenyl-1,3-thiazinane-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient ≪ / RTI &
The active ingredient is contained at a concentration of 10 to 100 μM and is melanin-pigmented, characterized by melanin-forming cell (B16) whitening or a decrease in expression of TRP1 (Tyrosinase related protein 1), TRP2 (Tyrosinase related protein 2) and tyrosinase gene A pharmaceutical composition for the prevention or treatment of a deposition disorder:
(3)
.
상기 유효성분은 10 ~ 100 μM 농도로 포함되고, 멜라닌 형성 세포(B16) 미백 또는 TRP1(Tyrosinase related protein 1), TRP2(Tyrosinase related protein 2) 및 티로시나아제 유전자 발현 저하를 특징으로 하는 멜라닌 색소 과다 침착 질환의 예방 또는 치료용 의약외품 조성물:
[화학식 3]
.(2S, 4R), (2S, 4S), (2R, 4R) or (2R, 4S) -2-phenyl-1,3-thiazin- (2S, 4S) -2-phenyl-1,3-thiazinane-4-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient ≪ / RTI &
The active ingredient is contained at a concentration of 10 to 100 μM and is melanin-pigmented, characterized by melanin-forming cell (B16) whitening or a decrease in expression of TRP1 (Tyrosinase related protein 1), TRP2 (Tyrosinase related protein 2) and tyrosinase gene Quasi-drug composition for prevention or treatment of deposition disorder:
(3)
.
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