KR101488583B1 - New compounds having skin whitening activity and medical use thereof - Google Patents
New compounds having skin whitening activity and medical use thereof Download PDFInfo
- Publication number
- KR101488583B1 KR101488583B1 KR20130013594A KR20130013594A KR101488583B1 KR 101488583 B1 KR101488583 B1 KR 101488583B1 KR 20130013594 A KR20130013594 A KR 20130013594A KR 20130013594 A KR20130013594 A KR 20130013594A KR 101488583 B1 KR101488583 B1 KR 101488583B1
- Authority
- KR
- South Korea
- Prior art keywords
- thiazolo
- benzo
- imidazole
- benzylidene
- hydroxy
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 34
- 230000002087 whitening effect Effects 0.000 title claims abstract description 18
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- -1 4- hydroxy-benzylidene Chemical group 0.000 claims description 106
- CQFXAHSRHLYIDT-UHFFFAOYSA-N imidazo[2,1-b][1,3]thiazol-3-one Chemical compound C1=CN2C(=O)CSC2=N1 CQFXAHSRHLYIDT-UHFFFAOYSA-N 0.000 claims description 63
- 125000005605 benzo group Chemical group 0.000 claims description 34
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
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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
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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
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- 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
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- 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
본 발명은 피부미백 활성을 갖는 신규 화합물 및 이의 의학적 용도에 관한 것으로, 본 발명에 따른 화합물들은 티로시나아제를 억제하는 피부미백 활성을 지니므로 피부미백용 약학조성물, 화장료조성물 또는 건강기능식품으로 사용될 수 있다.The present invention relates to novel compounds having skin whitening activity and medicinal uses thereof, and the compounds according to the present invention have a skin whitening activity inhibiting tyrosinase, and therefore, they can be used as skin whitening pharmaceutical compositions, cosmetic compositions or health functional foods .
Description
본 발명은 피부미백 활성을 갖는 신규 화합물 및 이의 의학적 용도에 관한 것이다.The present invention relates to novel compounds having skin whitening activity and their medical uses.
사람의 피부색은 멜라닌, 카로틴, 헤모글로빈의 양에 따라 결정되며, 그 중 멜라닌이 가장 결정적인 요소로 작용한다. 멜라닌 색소는 검은 색소와 단백질의 복합체 형태를 갖는 페놀계 고분자 물질로서 자외선 차단 역할을 하여, 멜라닌 색소가 부족한 사람은 햇빛에 매우 민감하여 화상을 입기 쉬우며 어린 나이에도 피부암의 발생 확률이 높다. 반면, 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.The color of human skin is determined by the amount of melanin, carotene and hemoglobin, among which melanin is the most crucial factor. The melanin pigment is a phenolic polymer substance having a complex form of black pigment and protein. It plays a role of blocking ultraviolet rays, and a person who lacks the melanin pigment is very sensitive to sunlight and is likely to burn, and skin cancer is likely to occur at a young age. On the other hand, ultraviolet rays and carcinogens of short wavelength form harmful free radicals in the 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 티로시나아제의 작용에 의해 티로신으로부터 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 외부의 자극, 예를 들면 자외선, 환경오염 또는 스트레스 등에 반응하면 멜라닌이 과다 생성되어 피부 밖으로 배출되지 못하고 각질형성세포(keratinocyte)로 전달되어 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 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, stress, or the like, melanin is excessively produced and is not discharged out of the skin. It is transferred to keratinocyte and accumulates in the skin surface layer to become stain, freckles, Not only does it cause serious cosmetic problems, it also promotes skin aging and skin cancer.
한편, 피부에서의 멜라닌 색소침착 방지는 주로 다음의 네 가지 관점에서 연구되어 왔다. 첫째로, 멜라닌 합성의 주효소인 티로시나아제 활성을 조절하기 위하여 티로시나아제 합성 저해 물질이나, 티로시나아제의 기질에 대한 길항물질을 개발한다. 둘째로, 동물의 멜라닌 생합성 장소인 멜라노사이트의 기능을 저하시키기 위해 멜라노사이트에 독성을 나타내는 물질을 개발한다. 셋째로, 멜라닌 합성 경로의 중간 대사물질인 도파(dopa)의 산화방지를 위해 도파 환원물질을 개발한다. 마지막으로, 멜라닌 생성 기구인 제1 효소 티로시나아제와 도파크롬(DOPA chrome)에서 DHICA(5,6-dihydroxyindole-2-carboxyic acid)로의 변환을 촉매하는 제2 효소인 도파크롬 타우토머라아제(DOPA chrome tautomerase), 및 DHICA에서 인돌-5,6-퀴논-2-카르복실산(indole-5,6-quinone-2-carboxylic acid)으로의 변환을 촉매하는 제3 효소의 활성을 동시에 감소시킨다.On the other hand, the prevention of melanin pigmentation in the skin has been mainly studied in the following four perspectives. First, to regulate tyrosinase activity, the main enzyme of melanin synthesis, antagonists against tyrosinase synthesis inhibitors or tyrosinase substrates are developed. Secondly, a substance exhibiting toxicity to melanocytes is developed in order to lower the function of melanocyte, which is the place of melanin biosynthesis in animals. Third, a dopa reducing material is developed to prevent the oxidation of dopa, an intermediate metabolite of the melanin synthesis pathway. Finally, a first enzyme tyrosinase, a melanin producing mechanism, and dopachrome tautomerase (DOPA chrome), a second enzyme that catalyzes the conversion of 5,6-dihydroxyindole-2-carboxyic acid into DHICA DOPA chrome tautomerase) and the activity of a third enzyme that catalyzes the conversion of DHICA to indole-5,6-quinone-2-carboxylic acid .
최근, 동양권의 여성들은 백옥같이 하얗고 깨끗한 피부를 선호하며 이를 미의 중요한 기준으로 삼고 있기 때문에 피부 색소 이상 침착의 치료 및 미용 욕구 충족을 위한 미백제에 대한 개발이 활발히 이루어지고 있다.In recent years, oriental women prefer white, clean skin like white whiting, and since they use it as an important criterion of beauty, they are actively developing a whitening agent to treat skin pigmentation abnormalities and meet beauty needs.
미백제의 개발에 있어서, 생성된 멜라닌 색소를 환원시켜 탈색하는 방법과 멜라닌 색소를 형성하는 효소인 티로시나아제의 활성을 억제하는 방법이 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 whitening agent, there is known a method of decolorizing by reducing the produced melanin pigment and a method of inhibiting the activity of tyrosinase, an enzyme that forms a melanin pigment. 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, 예를 들면, 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 사용되어 왔다. 그러나, 처방계 중에서의 안정성이 나빠 분해되어 착색되거나, 이취의 발생, 생체 레벨에서의 효능, 효과의 불분명 및 안전성 문제 등으로 그 사용이 제한되고 있는 실정이다. 또한, 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. 비타민 C 및 그 유도체는 산화가 잘되는 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. 또한, 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.As a whitening ingredient in the conventional cosmetics field, for example, substances inhibiting tyrosinase enzyme activity such as kojic acid and arbutin, hydroquinone, L-ascorbic acid, And derivatives thereof and various plant extracts have been used. However, the use thereof is limited due to poor stability in the prescription system and coloration, generation of odor, efficacy at a living body level, unclear effects, and safety problems. In addition, 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 liver cancer as a result of recent animal tests. Vitamin C and its derivatives are difficult to use as raw materials for cosmetics because of their good oxidative instability. Hydroquinone has excellent whitening effect on the skin, but it does not cause skin irritation such as allergenicity, toxicity to melanocytes, It is highly irritating to the public and is recently prohibited to use as a carcinogen. In addition, arbutin is a derivative in which hydroquinone is conjugated with glucopyranoside. As a result, hydroquinone is less toxic to human body, and inhibits the synthesis of melanin pigment, resulting in an increase in melanin pigmentation However, it has a disadvantage in 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.
한편, 한국공개특허 제2006-0031007호에서 천마 추출물 및 이로부터 분리된 화합물을 이용한 피부 노화방지 및 미백용 화장료 조성물을 개시하고 있지만, 본 발명의 화합물과는 화학 구조가 전혀 상이한 화합물을 개시하고 있다.Korean Patent Laid-Open Publication No. 2006-0031007 discloses a cosmetic composition for preventing skin aging and whitening using a chondroma extract and a compound isolated therefrom, but discloses a compound having completely different chemical structure from the compound of the present invention .
본 발명의 목적은 피부미백 활성을 갖는 신규 화합물 및 이의 의학적 용도를 제공하는 데에 있다.It is an object of the present invention to provide novel compounds having skin whitening activity and medicinal uses thereof.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물,이의 이성질체 및 이들의 혼합물을 제공한다:In order to achieve the above object, the present invention provides a compound represented by the following general formula (1), an isomer thereof and a mixture thereof:
[화학식 1][Chemical Formula 1]
상기 식에서, R1 내지 R4는 각각 같거나 다를 수 있으며, H, OH, 할로겐, C1 내지 C4의 알킬 또는 C1 내지 C4의 알콕시 중 어느 하나이고, X 및 Y는 H 또는 CH3일 수 있다.Wherein each of R 1 to R 4 may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y may be H or CH 3 .
보다 상세하게는, 상기 화합물은 (2Z)-2-(4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(4-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(4-하이드록시-3-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3-하이드록시-4-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3-에톡시-4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3,4-디하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3-브로모-4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(2,4-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3,4-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(4-하이드록시-3,5-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (2Z)-2-(3,4,5-트리메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(2-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(4-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(4-하이드록시-3-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3-하이드록시-4-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3-에톡시-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(2,4-디하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3,4-디하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3-브로모-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(2,4-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3,4-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3,4-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온, (Z)-2-(3,5-디브로모-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 및 (Z)-2-(3,4,5-트리메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온으로 이루어진 군에서 선택될 수 있다.More specifically, the compound (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy-ben Vinylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy-3,5- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5- trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- hydroxy-benzylidene ) Benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (2- hydroxybenzylidene) benzo [ d ] thiazolo [ a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy -4 -hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [d ] Thiazolo [ 3,2- a] -3 (2 H) imidazol-on, (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole- 3 (2 H) - one, (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3, 4-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,4- dimethoxy-benzylidene) benzo [d ] Thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (3,5- dibromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [ 3,2- a] imidazole -3 (2 H) - one and (Z) -2- (3,4,5- trimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] already (2 H ) -one. ≪ / RTI >
본 발명에 따른 화합물은 약제학적으로 허용가능한 이들의 염의 형태로 제공될 수 있으며, 상기 약제학적으로 허용가능한 이들의 염으로는 염산염, 브롬산염, 황산염, 인산염, 질산염, 구연산염, 초산염, 젖산염, 주석산염, 말레산염, 글루콘산염, 숙신산염, 포름산염, 트리플루오로아세트산염, 옥살산염, 푸마르산염, 메탄술폰산염, 벤젠술폰산염, 파라톨루엔술폰산염 및 캠퍼술폰산염으로 이루어진 군에서 선택된 어느 하나일 수 있다.The compounds according to the present invention may be provided in the form of their pharmaceutically acceptable salts, wherein the pharmaceutically acceptable salts thereof include hydrochloride, bromate, sulfate, phosphate, nitrate, citrate, acetate, lactate, A salt of any one selected from the group consisting of maleic acid salts, maleic acid salts, gluconic acid salts, succinic acid salts, formic acid salts, trifluoroacetic acid salts, oxalic acid salts, fumaric acid salts, methanesulfonic acid salts, benzenesulfonic acid salts, para toluenesulfonic acid salts and camphorsulfonic acid salts .
또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 피부미백용 조성물을 제공한다. 상기 조성물은 화장료조성물, 약학조성물 또는 건강기능식품의 형태로 제공될 수 있다.The present invention also provides a skin whitening composition comprising the above-mentioned compound as an active ingredient. The composition may be provided in the form of a cosmetic composition, a pharmaceutical composition or a health functional food.
상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The pharmaceutical compositions may further comprise suitable carriers, excipients or diluents conventionally used in the manufacture of pharmaceutical compositions.
본 발명에서 사용가능한 담체, 부형제 또는 희석제로는, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등을 들 수 있다.Examples of the carrier, excipient or diluent which can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil.
본 발명에 따른 약학조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to a conventional method .
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물은 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제할 수 있다. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose sucrose), lactose, gelatin, and the like.
또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.
본 발명에 따른 약학조성물의 유효성분인 화합물의 사용량은 환자의 나이, 성별, 체중, 질환에 따라 달라질 수 있으나, 0.001 내지 100 mg/kg으로, 바람직하게는 0.01 내지 10 mg/kg을 일일 1회 내지 수회 투여할 수 있다. The amount of the compound which is an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, body weight and disease of the patient, but is preferably 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / Or several times.
또한, 본 발명에 따른 화합물의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이 등에 따라서 증감될 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Further, the dose of the compound according to the present invention may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Thus, the dosage amounts are not intended to limit the scope of the invention in any manner.
상기 약학조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 기관지내 흡입, 자궁내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition may be administered to mammals such as rats, mice, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intratracheal, intrauterine or intracerebroventricular injections.
본 발명에 따른 화합물은 50% 치사량(LC50)이 2 g/kg 이상으로 안정성이 확보된 것으로서, 본 발명의 약학조성물에 사용할 수 있다. The compound according to the present invention has a stability of not less than 2 g / kg of 50% lethal dose (LC 50 ) and can be used in the pharmaceutical composition of the present invention.
또한, 상기 화장료 조성물은 유효성분인 본 발명에 따른 화합물 외에 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함할 수 있다.In addition, the cosmetic composition may contain, in addition to the compound according to the present invention as an active ingredient, conventional additives such as stabilizers, solubilizers, vitamins, pigments and flavors, and carriers.
상기 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 썬 크림, 유연 화장수, 수렴 화장수, 영양 화장수, 영양 크림, 마사지 크림, 에센스, 아이 크림, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.The cosmetic composition may be prepared in any form conventionally produced in the art and may be in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, oil, powder foundation, emulsion foundation, Wax foundation, spray, and the like. However, the present invention is not limited thereto. More specifically, it can be manufactured in the form of a sun cream, a flexible lotion, a convergent lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a pack, a spray or a powder.
상기 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation is a paste, cream or gel, an animal oil, a vegetable oil, a wax, a paraffin, a starch, a tracer, a cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component .
상기 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, chlorofluorohydrocarbons, propane / Or propellants such as dimethyl ether.
상기 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해 화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다. When the formulation is a solution or an emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, - butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid esters of sorbitan.
상기 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspension such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, a microcrystalline cellulose , Aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.
또한, 상기 건강기능식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강기능식품은 유효성분인 본 발명에 따른 화합물 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. The health functional food may be provided in the form of a powder, a granule, a tablet, a capsule, a syrup or a drink. The health functional food may be used together with food or food additives other than the compound according to the present invention, Can be suitably used according to the method of The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강기능식품에 함유된 화합물의 유효용량은 상기 약학조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose of the compound contained in the health functional food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for the purpose of health and hygiene or long-term intake for health control purposes , It is clear that the active ingredient can be used in an amount exceeding the above range since there is no problem in terms of safety.
상기 건강기능식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the kind of the above health functional food and examples thereof include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, , Drinks, alcoholic beverages and vitamin complexes.
본 발명에 따른 화합물들은 티로시나아제를 억제하는 피부미백 활성을 지니므로 피부미백용 약학조성물, 화장료조성물 또는 건강기능식품으로 유용하게 사용될 수 있다.Since the compounds according to the present invention have skin whitening activity inhibiting tyrosinase, they can be usefully used as a skin whitening pharmaceutical composition, a cosmetic composition or a health functional food.
도 1은 본 발명에 따른 화합물의 티로시네이즈 억제 활성을 나타낸 것이다. ND는 저해 활성이 검출되지 않았음을 의미한다.Figure 1 shows the tyrosinase inhibitory activity of the compounds according to the invention. ND means that no inhibitory activity was detected.
이하, 하기 실시예를 통해 본 발명을 보다 상세하게 설명한다. 다만, 이러한 실시예에 의해 본 발명이 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.
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실시예Example
1> 6(7)-메틸-[1,3]티아졸로[3,2- 1> 6 (7) -Methyl- [1,3] thiazolo [3,2-
aa
]벤즈이미다졸-3(2] Benzimidazole-3 (2
HH
)-온 [6(7)-methyl-[1,3]thiazolo[3,2-) -One [6 (7) -methyl- [1,3] thiazolo [3,2-
aa
]benzimidazol-3(2] benzimidazole-3 (2
HH
)-one](9)의 합성 ) -one] Synthesis of (9)
[반응식 1][Reaction Scheme 1]
(a) CS2, NaOH, H2O, EtOH, 환류, 5 시간; (b) NaOAc, Ac2O, 환류, 5분; (c) NaOAc, AcOH, 80℃, 1 - 3일.
(a) CS 2 , NaOH, H 2 O, EtOH, reflux, 5 h; (b) NaOAc, Ac 2 O, reflux, 5 min; (c) NaOAc, AcOH, 80 < 0 > C, 1-3 days.
1.One. 5-5- 메틸methyl -1-One HH -- 벤조[Benzo [ dd ]이미다졸] Imidazole -2--2- 티올Thiol [5- [5- methylmethyl -1H--1H- benzobenzo [d]imidazole-2-thiol](8)의 합성[d] imidazole-2-thiol] (8)
3,4-디아미노톨루엔(3,4-Diaminotoluene) (65.48 mmol, 8.0 g)을 물 (12 mL), 에탄올(ethanol) (80 mL), 소듐 하이드록사이드(NaOH) (1.16 당량, 3.03 g) 혼합용액에 조금씩 나누어 넣는다. 상기 반응 혼합물에 카본 디설파이드(carbon disulfide, CS2) (1.16 당량, 4.58 mL)를 0℃ 에서 천천히 떨어뜨려 첨가한 후, 5시간 동안 환류시킨다. 반응혼합물을 상온까지 냉각시킨 후, 차콜(charcoal)을 조금씩 나누어 넣은 뒤, 10분간 환류시킨다. 반응 혼합물에 뜨거운 물을 붓고, 불용성 고체를 여과하여 걸러낸다. 여과된 액(filtrate)에는 50 % 아세트산(acetic acid)을 처리 한 후, 냉장고 보관한다. 생성된 고체를 여과한 후, 과량의 물로 세정하여 화합물 8을 얻었다.3,4-Diaminotoluene (65.48 mmol, 8.0 g) was dissolved in water (12 mL), ethanol (80 mL) and sodium hydroxide (NaOH) (1.16 equivalents, 3.03 g ) Mixed solution. Carbon disulfide (CS 2 ) (1.16 eq., 4.58 mL) is slowly added dropwise to the reaction mixture at 0 ° C and refluxed for 5 hours. After cooling the reaction mixture to room temperature, the charcoal is gradually added in portions and refluxed for 10 minutes. The reaction mixture is poured into hot water and the insoluble solid is filtered off. The filtrate is treated with 50% acetic acid and stored in the refrigerator. The resulting solid was filtered and washed with excess water to obtain Compound 8.
갈색 고체; 반응시간 5 시간; 수율 55.8%;Brown solid; Reaction time 5 hours; Yield 55.8%;
1H NMR (500MHz, DMSO-d 6 ) δ 12.38 (brs, 1 H), 7.00 (d, 1 H, J = 8.0 Hz), 6.93 (s, 1 H), 6.92 (d, 1 H, J = 8.0 Hz), 2.32 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 168.4, 133.1, 132.3, 130.9, 123.9, 110.3, 109.8, 21.6.
1 H NMR (500MHz, DMSO- d 6) δ 12.38 (brs, 1 H), 7.00 (d, 1 H, J = 8.0 Hz), 6.93 (s, 1 H), 6.92 (d, 1 H, J = 8.0 Hz), 2.32 (s, 3 H); 13 C NMR (100 MHz, DMSO- d 6 ) ? 168.4, 133.1, 132.3, 130.9, 123.9, 110.3, 109.8, 21.6.
2.2. 6(7)-6 (7) - 메틸methyl -[1,3]티아졸로[3,2-- [l, 3] thiazolo [3,2- aa ]] 벤즈이미다졸Benzimidazole -3(2-3 (2 HH )-온 [6(7)-) -One [6 (7) - methylmethyl -[1,3]thiazolo[3,2-- [1,3] thiazolo [3,2- aa ]benzimidazol-3(2] benzimidazole-3 (2 HH )-one] (9) 의 합성) -one] Synthesis of (9)
5-메틸-1H-벤조[d]이미다졸-2-온(8)(5-methyl-1H-benzo[d]imidazole-2-thiol) (18.27 mmol, 3 g), 브로모아세트산(bromoacetic acid) (1.0 당량, 2.53 g) 및 소듐 아세테이트(sodium acetate) (1.0 당량, 1.5 g)의 혼합물을 무수 아세트산(acetic anhydride) (30 mL) 용매에서 5분간 환류시켰다. 반응 혼합물에 1 M 소듐 하이드록사이드 수용액(1 M NaOH aqueous solution)을 부가한 후 메틸렌 클로라이드(methylene chloride) 로 추출했다. 유기층은 MgSO4로 건조시키고 여과한 후 증발시켰다. 결과물인 잔여물을 전개용매로 에틸 아세테이트(ethyl acetate)와 메틸렌 클로라이드(methylene chloride)를 이용한 실리카 겔 컬럼 크로마토그래피를 통해 정제하여, 티아졸로벤즈이미다졸 화합물 9를 위치이성질체 혼합물로 얻었다.5-methyl -1 H - benzo [d] imidazol-2-one (8) (5-methyl- 1 H -benzo [d] imidazole-2-thiol) (18.27 mmol, 3 g), bromoacetic acid ( bromoacetic acid (1.0 eq, 2.53 g) and sodium acetate (1.0 eq, 1.5 g) in acetic anhydride (30 mL) was refluxed for 5 minutes. To the reaction mixture was added 1 M sodium hydroxide aqueous solution (1 M NaOH aqueous solution) and then extracted with methylene chloride. The organic layer was evaporated after drying with MgSO 4 and filtered. The resulting residue was purified by silica gel column chromatography using ethyl acetate and methylene chloride as developing solvent to obtain thiazolobenzimidazole compound 9 as a regioisomer mixture.
밝은 노란색 고체; 반응시간 5 분; 수율 34.8%;Light yellow solid; Reaction time 5 minutes; Yield 34.8%;
1H NMR (400MHz, CDCl3) δ 7.70 (d, 1 H, J = 8.4 Hz), 7.65 (d, 1 H, J = 0.8 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.32 (d, 1 H, J = 0.8 Hz), 7.11 (dd, 1 H, J = 0.8, 8.4 Hz), 7.04 (dd, 1 H, J = 0.8, 8.4 Hz), 4.27, 4.26 (each s, 4 H), 2.40 (s, 6 H); 13C NMR (100MHz, CDCl3) δ 164.9, 164.7, 158.6, 157.2, 150.3, 147.9, 136.3, 134.4, 130.3, 128.1, 127.3, 125.1, 119.4, 118.7, 112.9, 112.1, 39.1, 39.1, 22.0, 21.8.
1 H NMR (400MHz, CDCl 3 ) δ 7.70 (d, 1 H, J = 8.4 Hz), 7.65 (d, 1 H, J = 0.8 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.32 (d, 1 H, J = 0.8 Hz), 7.11 (dd, 1 H, J = 0.8, 8.4 Hz), 7.04 (dd, 1 H, J = 0.8, 8.4 Hz), 4.27, 4.26 (each s, 4 H), 2.40 (s, 6 H); 13 C NMR (100MHz, CDCl 3 ) δ 164.9, 164.7, 158.6, 157.2, 150.3, 147.9, 136.3, 134.4, 130.3, 128.1, 127.3, 125.1, 119.4, 118.7, 112.9, 112.1, 39.1, 39.1, 22.0, 21.8.
3. 2-(치환된 3. 2- (substituted 벤질리덴Benzylidene )-6(7)-) -6 (7) - 메틸methyl -[1,3]티아졸로[3,2-- [l, 3] thiazolo [3,2- aa ]] 벤즈이미다졸Benzimidazole -3(2-3 (2 HH )-온 [2-() -One [2- ( substitutedsubstituted benzylidenebenzylidene )-6(7)-) -6 (7) - methylmethyl -[1,3]- [1,3] thiazolothiazolo [3,2-[3,2- aa ]benzimidazol-3(2] benzimidazole-3 (2 HH )-one] (9a - 9k) 의 합성) -one] (9a-9k) Synthesis of
티아졸로벤즈이미다졸론 이성질체 혼합물 9 (thiazolobenzimidazolone) (0.29 - 0.39 mmol), 치환된 벤즈알데히드(benzaldehydes) (1.0 - 1.1 당량) 그리고 소듐 아세테이트(sodium acetate) (3.0 당량) 혼합물을 아세트산 용매에서 1 - 3일 동안 80 ℃에서 교반시켰다. 반응 혼합물에 물을 넣은 뒤, 생성된 침전물을 여과하고 물로 세정하여 상기 목적 화합물 9a - 9k를 위치이성질체 혼합물로 얻었다.A mixture of thiazolobenzimidazolone (0.29 - 0.39 mmol), substituted benzaldehydes (1.0 - 1.1 eq) and sodium acetate (3.0 eq.) In acetic acid Lt; RTI ID = 0.0 > 80 C. < / RTI > After water was added to the reaction mixture, the resulting precipitate was filtered and washed with water to obtain the target compounds 9a-9k as a positional isomer mixture.
1) (2Z)-2-(4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(4-Hydroxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9a] 1) (2 Z) -2- ( 4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(2 Z ) -2- (4-Hydroxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9a]
노란색을 띄는 녹색 고체; 반응시간 20 시간; 수율 61.9%; 녹는점 >300℃;Green solid; Reaction time 20 hours; Yield 61.9%; Melting point> 300 ℃;
1H NMR (500 MHz, DMSO-d 6 ) δ 10.42 (brs, 2 H), 7.94 (s, 1 H), 7.93 (s, 1 H), 7.75 (d, 1 H, J = 8.0 Hz), 7.71 (d, 1 H, J = 1.0 Hz), 7.57 and 7.56 (each d, each 2 H, J = 8.0 Hz), 7.49 (d, 1 H, J = 8.0 Hz), 7.41 (s, 1 H), 7.17 (dd, 1 H, J = 1.0, 8.5 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 6.94 and 6.94 (each d, each 2 H, J = 8.0 Hz), 2.42 (s, 3 H), 2.38 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 161.3, 160.0, 159.9, 153.9, 153.1, 149.2, 146.9, 137.1, 137.0, 135.8, 134.3, 133.6, 130.9, 128.7, 127.2, 125.5, 124.2, 120.7, 119.8, 119.3, 117.2, 113.0, 112.4, 21.9, 21.8. 1 H NMR (500 MHz, DMSO- d 6) δ 10.42 (brs, 2 H), 7.94 (s, 1 H), 7.93 (s, 1 H), 7.75 (d, 1 H, J = 8.0 Hz), 7.71 (d, 1 H, J = 1.0 Hz), 7.57 and 7.56 (each d, each 2 H, J = 8.0 Hz), 7.49 (d, 1 H, J = 8.0 Hz), 7.41 (s, 1 H) , 7.17 (dd, 1 H, J = 1.0, 8.5 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 6.94 and 6.94 (each d, each 2 H, J = 8.0 Hz), 2.42 (s, 3 H), 2.38 (s, 3 H); 13 C NMR (100MHz, DMSO- d 6) δ 161.3, 160.0, 159.9, 153.9, 153.1, 149.2, 146.9, 137.1, 137.0, 135.8, 134.3, 133.6, 130.9, 128.7, 127.2, 125.5, 124.2, 120.7, 119.8, 119.3, 117.2, 113.0, 112.4, 21.9, 21.8.
2) (2Z)-2-(4-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(4-Methoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9b]2) (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(2 Z ) -2- (4-Methoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9b]
밝은 노란색 고체; 반응시간 3 일; 수율 70.2%; 녹는점 208.5 - 209.4℃;Light yellow solid; Reaction time 3 days; Yield 70.2%; Melting point 208.5 - 209.4 캜;
1H NMR (500MHz, CDCl3) δ 7.98 (s, 1 H), 7.97 (s, 1 H), 7.87 (d, 1 H, J = 8.5 Hz), 7.83 (s, 1 H), 7.55 and 7.55 (each d, each 2 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 9.0 Hz), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.0 Hz), 7.13 (d, 1 H, J = 8.0 Hz), 7.01 and 7.01 (each d, each 2 H, J = 9.0 Hz), 3.86 (s, 6 H), 2.49 (s, 3 H), 2.47 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 162.0, 160.1, 159.9, 153.7, 152.9, 149.2, 146.9, 136.8, 136.7, 136.1, 134.6, 132.7, 130.7, 128.5, 127.1, 125.7, 125.3, 122.0, 119.8, 119.1, 115.1, 113.2, 112.5, 55.7, 22.0, 21.8. 1 H NMR (500 MHz, CDCl 3 ) ? 7.98 (s, 1H), 7.97 (s, 1H), 7.87 (d, 1H, J = 8.5 Hz), 7.83 (each d, each 2 H, J = 8.0 Hz), 7.52 (d, 1 H, J = 9.0 Hz), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.0 Hz), 7.13 ( (d, 1H, J = 8.0 Hz), 7.01 and 7.01 (each d, each 2H, J = 9.0 Hz), 3.86 ); 13 C NMR (100MHz, CDCl 3 ) δ 162.0, 160.1, 159.9, 153.7, 152.9, 149.2, 146.9, 136.8, 136.7, 136.1, 134.6, 132.7, 130.7, 128.5, 127.1, 125.7, 125.3, 122.0, 119.8, 119.1, 115.1, 113.2, 112.5, 55.7, 22.0, 21.8.
3) (2Z)-2-(4-하이드록시-3-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(4-Hydroxy-3-methoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9c] 3) (2 Z) -2- ( 4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H imidazole) -one [(2 Z) -2- (4 -Hydroxy-3-methoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9c]
노란색을 띄는 녹색 고체; 반응시간 24 시간; 수율 58.2%; 녹는점 213.6 - 214.3℃;Green solid; Reaction time 24 hours; Yield 58.2%; Melting point 213.6 - 214.3 캜;
1H NMR (500MHz, DMSO-d 6 ) δ 10.10 (s, 2 H), 7.97 (s, 1 H), 7.96 (s, 1 H), 7.77 (d, 1 H, J = 8.5 Hz), 7.73 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.44 (s, 1 H), 7.28 (s, 2 H), 7.19 (d, 2 H, J = 8.0 Hz), 7.18 (d, 1 H, J = 8.0 Hz), 7.14 (d, 1 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.39 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 159.9, 150.8, 149.2, 148.8, 147.0, 137.4, 135.8, 134.4, 130.9, 128.7, 127.3, 125.5, 125.3, 124.7, 121.0, 119.9, 119.4, 117.0, 115.3, 113.0, 112.4, 56.4, 21.9, 21.8. 1 H NMR (500MHz, DMSO- d 6) δ 10.10 (s, 2 H), 7.97 (s, 1 H), 7.96 (s, 1 H), 7.77 (d, 1 H, J = 8.5 Hz), 7.73 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.44 (s, 1 H), 7.28 (s, 2 H), 7.19 (d, 2 H, J = 8.0 Hz), 7.18 (d, 1 H, J = 8.0 Hz), 7.14 (d, 1 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.39 (s, 3 H); 13 C NMR (100MHz, DMSO- d 6) δ 160.0, 159.9, 150.8, 149.2, 148.8, 147.0, 137.4, 135.8, 134.4, 130.9, 128.7, 127.3, 125.5, 125.3, 124.7, 121.0, 119.9, 119.4, 117.0, 115.3, 113.0, 112.4, 56.4, 21.9, 21.8.
4) (2Z)-2-(3-하이드록시-4-메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3-Hydroxy-4-methoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9d] 4) (2 Z) -2- ( 3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Hydroxy-4-methoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9d]
노란색을 띄는 녹색 고체; 반응시간 24시간; 수율 56.8%; 녹는점 229.8 - 230.9℃;Green solid; Reaction time 24 hours; Yield 56.8%; Melting point 229.8 - 230.9 캜;
1H NMR (500MHz, DMSO-d 6 ) δ 9.60 (brs, 2 H,7.91 (s, 1 H), 7.90 (s, 1 H), 7.77 (d, 1 H, J = 8.0 Hz), 7.73 (s, 1 H), 7.51 (d, 1 H, J = 8.0 Hz), 7.44 (s, 1 H), 7.20 (m, 3 H), 7.15 (d, 1 H, J = 8.0 Hz), 7.14 (s, 2 H), 7.09 (d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.40 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 159.9, 159.8, 153.9, 153.1, 151.3, 149.2, 147.8, 147.0, 137.2, 137.0, 135.8, 134.4, 130.9, 128.7, 127.3, 126.0, 125.5, 124.9, 121.9, 119.9, 119.4, 116.7, 113.2, 113.0, 112.4, 56.4, 21.9, 21.8. 1 H NMR (500MHz, DMSO- d 6) δ 9.60 (brs, 2 H, 7.91 (s, 1 H), 7.90 (s, 1 H), 7.77 (d, 1 H, J = 8.0 Hz), 7.73 ( s, 1 H), 7.51 ( d, 1 H, J = 8.0 Hz), 7.44 (s, 1 H), 7.20 (m, 3 H), 7.15 (d, 1 H, J = 8.0 Hz), 7.14 ( s, 2 H), 7.09 ( d, 2 H, J = 8.5 Hz), 3.84 (s, 6 H), 2.43 (s, 3 H), 2.40 (s, 3 H); 13 C NMR (100MHz, DMSO - d 6 ) ? 159.9, 159.8, 153.9, 153.1, 151.3, 149.2, 147.8, 147.0, 137.2, 137.0, 135.8, 134.4, 130.9, 128.7, 127.3, 126.0, 125.5, 124.9, 121.9, 119.9, 119.4, 116.7, 113.2 , 113.0, 112.4, 56.4, 21.9, 21.8.
5) (2Z)-2-(3-에톡시-4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3-Ethoxy-4-hydroxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9e]5) (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Ethoxy-4-hydroxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9e]
노란색을 띄는 녹색 고체; 반응시간 24시간; 수율 50.5%; 녹는점 200.2 - 200.8℃;Green solid; Reaction time 24 hours; Yield 50.5%; Melting point 200.2 - 200.8 캜;
1H NMR (500MHz, DMSO-d 6 ) δ 10.02 (s, 2 H), 7.95 (s, 1 H), 7.94 (s, 1 H), 7.76 (d, 1 H, J = 8.5 Hz), 7.72 (s, 1 H), 7.50 (d, 1 H, J = 8.0 Hz), 7.43 (s, 1 H), 7.24 (s, 2 H), 7.18 (m, 3 H), 7.13 (d, 1 H, J = 8.5 Hz), 6.96 (d, 2 H, J = 8.0 Hz), 4.09 (q, 4 H, J = 7.0 Hz), 2.42 (s, 3 H), 2.39 (s, 3 H), 1.37 (t, 6 H, J = 7.0 Hz); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 159.8, 153.8, 153.0, 151.1, 149.2, 147.9, 147.0, 137.4, 137.3, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.7, 120.9, 119.9, 119.4, 117.1, 116.2, 113.0, 112.4, 64.6, 21.9, 21.8, 15.3. 1 H NMR (500MHz, DMSO- d 6) δ 10.02 (s, 2 H), 7.95 (s, 1 H), 7.94 (s, 1 H), 7.76 (d, 1 H, J = 8.5 Hz), 7.72 (s, 1H), 7.50 (d, 1H, J = 8.0 Hz), 7.43 (s, 1H), 7.24 J = 8.5 Hz), 6.96 (d, 2H, J = 8.0 Hz), 4.09 (q, 4H, J = 7.0 Hz), 2.42 (t, 6H, J = 7.0 Hz); 13 C NMR (100MHz, DMSO- d 6) δ 160.0, 159.8, 153.8, 153.0, 151.1, 149.2, 147.9, 147.0, 137.4, 137.3, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.7, 120.9, 119.9, 119.4, 117.1, 116.2, 113.0, 112.4, 64.6, 21.9, 21.8, 15.3.
6) (2Z)-2-(3,4-디하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3,4-Dihydroxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9f] 6) (2 Z) -2- ( 3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(2 Z ) -2- (3,4-Dihydroxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 (2 H ) -one; 9f]
노란색을 띄는 녹색 고체; 반응시간 24시간; 수율 55.2%; 녹는점 284.0 - 285.2℃;Green solid; Reaction time 24 hours; Yield 55.2%; Melting point 284.0 - 285.2 DEG C;
1H NMR (500MHz, DMSO-d 6 ) δ 9.77 (brs, 4 H), 7.88 (s, 1 H), 7.87 (s, 1 H), 7.76 (d, 1 H, J = 8.0 Hz), 7.72 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.43 (s, 1 H), 7.17 (d, 1 H, J = 8.5 Hz), 7.14 (d, 1 H, J = 8.0 Hz), 7.13 (s, 2 H), 7.08 (d, 2 H, J = 7.5 Hz), 6.90 (d, 2 H, J = 7.5 Hz), 2.43 (s, 3 H), 2.39 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 159.9, 153.9, 153.2, 150.2, 149.2, 147.0, 146.7, 137.5, 137.4, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.6, 120.5, 119.8, 119.3, 117.3, 117.1, 113.0, 112.4, 21.9, 21.8. 1 H NMR (500MHz, DMSO- d 6) δ 9.77 (brs, 4 H), 7.88 (s, 1 H), 7.87 (s, 1 H), 7.76 (d, 1 H, J = 8.0 Hz), 7.72 (s, 1 H), 7.50 (d, 1 H, J = 8.5 Hz), 7.43 (s, 1 H), 7.17 (d, 1 H, J = 8.5 Hz), 7.14 (d, 1 H, J = 8.0 Hz), 7.13 (s, 2 H), 7.08 (d, 2 H, J = 7.5 Hz), 6.90 (d, 2 H, J = 7.5 Hz), 2.43 (s, 3 H), 2.39 (s, 3 H); 13 C NMR (100MHz, DMSO- d 6) δ 160.0, 159.9, 153.9, 153.2, 150.2, 149.2, 147.0, 146.7, 137.5, 137.4, 135.8, 134.3, 130.9, 128.7, 127.2, 125.5, 125.3, 124.6, 120.5, 119.8, 119.3, 117.3, 117.1, 113.0, 112.4, 21.9, 21.8.
7) (2Z)-2-(3-브로모-4-하이드록시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3-Bromo-4-hydroxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9g] 7) (2 Z) -2- ( 3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3 -Bromo-4-hydroxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9g]
밝은 노란색 고체; 반응시간 24 시간; 수율 61.2%; 녹는점 260.9 - 261.8℃;Light yellow solid; Reaction time 24 hours; Yield 61.2%; Melting point 260.9 - 261.8 캜;
1H NMR (500MHz, DMSO-d 6 ) δ 11.28 (s, 2 H), 7.93 (s, 1 H), 7.92 (s, 1 H), 7.87 (s, 2 H), 7.74 (d, 1 H, J = 8.0 Hz), 7.70 (s 1 H), 7.53 (d, 2 H, J = 8.5 Hz), 7.49 (d, 1 H, J = 8.5 Hz), 7.42 (s, 1 H), 7.16 (d, 1 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 7.11 (d, 2 H, J = 8.0 Hz), 2.41 (s, 3 H), 2.38 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 159.7, 159.6, 157.5, 153.6, 152.8, 149.2, 146.9, 136.7, 135.9, 135.5, 135.4, 134.5, 131.4, 130.9, 128.7, 127.3, 125.9, 125.6, 122.6, 119.9, 119.4, 117.7, 113.0, 112.4, 111.0, 21.9, 21.8. 1 H NMR (500 MHz, DMSO- d 6 ) ? 11.28 (s, 2H), 7.93 (s, 1H), 7.92 , J = 8.0 Hz), 7.70 (s 1 H), 7.53 (d, 2 H, J = 8.5 Hz), 7.49 (d, 1 H, J = 8.5 Hz), 7.42 (s, 1 H), 7.16 ( d, 1 H, J = 8.5 Hz), 7.12 (d, 1 H, J = 8.0 Hz), 7.11 (d, 2 H, J = 8.0 Hz), 2.41 (s, 3 H), 2.38 (s, 3 H); 13 C NMR (100MHz, DMSO- d 6) δ 159.7, 159.6, 157.5, 153.6, 152.8, 149.2, 146.9, 136.7, 135.9, 135.5, 135.4, 134.5, 131.4, 130.9, 128.7, 127.3, 125.9, 125.6, 122.6, 119.9, 119.4, 117.7, 113.0, 112.4, 111.0, 21.9, 21.8.
8) (2Z)-2-(2,4-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(2,4-Dimethoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9h] 8) (2 Z) -2- ( 2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [ (2 Z ) -2- (2,4-Dimethoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 (2 H ) -one; 9h]
밝은 노란색 고체; 반응시간 30시간; 수율 45.0%; 녹는점 217.8 - 218.3℃;Light yellow solid; Reaction time 30 hours; Yield 45.0%; Melting point 217.8 - 218.3 캜;
1H NMR (400MHz, CDCl3) δ 8.34 (s, 2 H), 7.86 (d, 1 H, J = 8.0 Hz), 7.82 (s, 1 H), 7.49 (d, 1 H, J = 8.8 Hz), 7.47 (d, 2 H, J = 8.8 Hz), 7.42 (s, 1 H), 7.14 (d, 1 H, J = 7.6 Hz), 7.10 (d, 1 H, J = 8.4 Hz), 6.59 (dd, 2 H, J = 2.0, 8.8 Hz), 6.44 (d, 2 H, J = 2.0 Hz), 3.89 (s, 6 H), 3.84 (s, 6 H), 2.47 (s, 3 H), 2.45 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 164.0, 160.6, 160.4, 160.2, 149.2, 146.9, 135.9, 134.4, 132.5, 132.4, 131.5, 130.8, 128.6, 127.0, 125.1, 121.7, 119.7, 119.0, 115.5, 113.2, 112.4, 105.9, 98.8, 55.8, 22.0, 21.8. 1 H NMR (400MHz, CDCl 3 ) δ 8.34 (s, 2 H), 7.86 (d, 1 H, J = 8.0 Hz), 7.82 (s, 1 H), 7.49 (d, 1 H, J = 8.8 Hz ), 7.47 (d, 2 H , J = 8.8 Hz), 7.42 (s, 1 H), 7.14 (d, 1 H, J = 7.6 Hz), 7.10 (d, 1 H, J = 8.4 Hz), 6.59 (d, 2H, J = 2.0, 8.8 Hz), 6.44 (d, 2H, J = 2.0 Hz), 3.89 , 2.45 (s, 3 H); 13 C NMR (100MHz, CDCl 3 ) δ 164.0, 160.6, 160.4, 160.2, 149.2, 146.9, 135.9, 134.4, 132.5, 132.4, 131.5, 130.8, 128.6, 127.0, 125.1, 121.7, 119.7, 119.0, 115.5, 113.2, 112.4, 105.9, 98.8, 55.8, 22.0, 21.8.
9) (2Z)-2-(3,4-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3,4-Dimethoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9i] 9) (2 Z) -2- ( 3,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [ (2 Z ) -2- (3,4-Dimethoxybenzylidene) -6 (7) -methylbenzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 9i]
노란색 고체; 반응시간 30시간; 수율 43.8%; 녹는점 199.2 - 199.7℃;Yellow solid; Reaction time 30 hours; Yield 43.8%; Melting point 199.2 - 199.7 캜;
1H NMR (400MHz, CDCl3) δ 7.94 (s, 1 H), 7.93 (s, 1 H), 7.85 (d, 1 H, J = 8.4 Hz), 7.81 (s, 1 H), 7.50 (d, 1 H, J = 8.0 Hz), 7.43 (s, 1 H), 7.20 (d, 2 H, J = 8.4 Hz), 7.15 (d, 1 H, J = 8.0 Hz), 7.11 (d, 1 H, J = 8.0 Hz), 7.06 (s, 2 H), 6.94 (d, 2 H, J = 8.4 Hz), 3.95 (s, 6 H), 3.92 (s, 6 H), 2.47 (s, 3 H), 2.45 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 160.0, 159.8, 153.5, 152.8, 151.8, 149.6, 149.3, 147.0, 136.9, 136.8, 136.1, 134.7, 130.7, 128.5, 127.2, 126.0, 125.4, 125.1, 122.4, 119.9, 119.2, 113.3, 112.8, 112.5, 111.7, 56.3, 56.2, 22.0, 21.8. 1 H NMR (400 MHz, CDCl 3 ) ? 7.94 (s, 1H), 7.93 (s, 1H), 7.85 (d, 1H, J = 8.4 Hz) , 1 H, J = 8.0 Hz ), 7.43 (s, 1 H), 7.20 (d, 2 H, J = 8.4 Hz), 7.15 (d, 1 H, J = 8.0 Hz), 7.11 (d, 1 H , J = 8.0 Hz), 7.06 (s, 2 H), 6.94 (d, 2 H, J = 8.4 Hz), 3.95 (s, 6 H), 3.92 (s, 6 H), 2.47 (s, 3 H ), 2.45 (s, 3 H); 13 C NMR (100MHz, CDCl 3 ) δ 160.0, 159.8, 153.5, 152.8, 151.8, 149.6, 149.3, 147.0, 136.9, 136.8, 136.1, 134.7, 130.7, 128.5, 127.2, 126.0, 125.4, 125.1, 122.4, 119.9, 119.2, 113.3, 112.8, 112.5, 111.7, 56.3, 56.2, 22.0, 21.8.
10) (2Z)-2-(4-하이드록시-3,5-디메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(4-Hydroxy-3,5-dimethoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9j] 10) (2 Z) -2- ( 4- hydroxy-3,5-dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazol-3 (2 H) - one [(2 Z) -2- (4 -Hydroxy-3,5-dimethoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one ; 9j]
어두운 노란색 고체; 반응시간 24시간; 수율 55.6%; 녹는점 247.2 - 247.8℃;Dark yellow solid; Reaction time 24 hours; Yield 55.6%; Melting point 247.2 - 247.8 캜;
1H NMR (400MHz, DMSO-d 6 ) δ 9.46 (brs, 2 H), 7.91 (s, 1 H), 7.90 (s, 1 H), 7.72 (d, 1 H, J = 8.4 Hz), 7.67 (s 1 H), 7.46 (d, 1 H, J = 8.4 Hz), 7.39 (s, 1 H), 7.13 (d, 1 H, J = 8.4 Hz), 7.09 (d, 1 H, J = 8.4 Hz), 6.94 (s, 4 H), 3.81 (s, 12 H), 2.38 (s, 3 H), 2.35 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 159.8, 159.7, 153.8, 153.0, 149.2, 148.9, 146.9, 140.0, 137.6, 137.5, 135.8, 134.4, 130.8, 128.6, 127.2, 125.5, 123.5, 121.2, 119.9, 119.4, 113.0, 112.4, 109.0, 56.8, 21.9, 21.8. 1 H NMR (400MHz, DMSO- d 6) δ 9.46 (brs, 2 H), 7.91 (s, 1 H), 7.90 (s, 1 H), 7.72 (d, 1 H, J = 8.4 Hz), 7.67 (s 1 H), 7.46 ( d, 1 H, J = 8.4 Hz), 7.39 (s, 1 H), 7.13 (d, 1 H, J = 8.4 Hz), 7.09 (d, 1 H, J = 8.4 Hz), 6.94 (s, 4H), 3.81 (s, 12H), 2.38 (s, 3H), 2.35 (s, 3H); 13 C NMR (100MHz, DMSO- d 6) δ 159.8, 159.7, 153.8, 153.0, 149.2, 148.9, 146.9, 140.0, 137.6, 137.5, 135.8, 134.4, 130.8, 128.6, 127.2, 125.5, 123.5, 121.2, 119.9, 119.4, 113.0, 112.4, 109.0, 56.8, 21.9, 21.8.
11) (2Z)-2-(3,4,5-트리메톡시벤질리덴)-6(7)-메틸벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(2Z)-2-(3,4,5-Trimethoxybenzylidene)-6(7)-methylbenzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 9k] 11) (2 Z) -2- ( 3,4,5- trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one [(2 Z) -2- (3,4,5 -Trimethoxybenzylidene) -6 (7) -methylbenzo [d] thiazolo [3,2- a] imidazol-3 (2 H) -one; 9k]
밝은 노란색 고체; 반응시간 23시간; 수율 65.4%; 녹는점 131.4 - 132.2℃;Light yellow solid; Reaction time 23 hours; Yield 65.4%; Melting point 131.4 - 132.2 DEG C;
1H NMR (400MHz, CDCl3) δ 7.94 (s, 1 H), 7.93 (s, 1 H), 7.86 (d, 1 H, J = 8.4 Hz), 7.82 (s, 1 H), 7.51 (d, 1 H, J = 8.4 Hz), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.4 Hz), 7.12 (d, 1 H, J = 8.4 Hz), 6.81 (s, 4 H), 3.93 (s, 12 H), 3.91 (s, 6 H), 2.48 (s, 3 H), 2.46 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 159.7, 159.6, 153.9, 153.4, 152.6, 149.3, 147.0, 140.9, 136.9, 136.8, 136.3, 134.9, 130.7, 128.5, 128.5, 127.3, 125.5, 124.2, 120.0, 119.3, 113.3, 112.5, 107.9, 61.3, 56.5, 22.0, 21.8.
1 H NMR (400 MHz, CDCl 3 ) ? 7.94 (s, 1H), 7.93 (s, 1H), 7.86 (d, 1H, J = 8.4 Hz) , 1 H, J = 8.4 Hz ), 7.44 (s, 1 H), 7.17 (d, 1 H, J = 8.4 Hz), 7.12 (d, 1 H, J = 8.4 Hz), 6.81 (s, 4 H ), 3.93 (s, 12 H), 3.91 (s, 6 H), 2.48 (s, 3 H), 2.46 (s, 3 H); 13 C NMR (100MHz, CDCl 3 ) δ 159.7, 159.6, 153.9, 153.4, 152.6, 149.3, 147.0, 140.9, 136.9, 136.8, 136.3, 134.9, 130.7, 128.5, 128.5, 127.3, 125.5, 124.2, 120.0, 119.3, 113.3, 112.5, 107.9, 61.3, 56.5, 22.0, 21.8.
<< 실시예Example 2> 2> 벤조[Benzo [ dd ]티]tea 아졸로[3,2-Azulo [3,2- aa ]] 이미다졸Imidazole -3(2-3 (2 HH )-온 [Benzo[) -One [Benzo [ dd ]thiazolo[3,2-] thiazolo [3,2- aa ]imidazol-3(2] imidazol-3 (2 HH )-one](10)의 합성 ) -one] Synthesis of (10)
[반응식 2][Reaction Scheme 2]
(a) NaOAc, AcOH, 85℃, 12 - 30 시간(a) NaOAc, AcOH, 85 ° C, 12-30 hours
1H-벤조[d]이미다졸-2-티올 (0.03 mol, 5.0 g), 브로모아세트산(bromoacetic acid) (1.5 당량, 6.90 g) 및 소듐 아세테이트(sodium acetate) (3.0 당량, 8.2 g)의 혼합물을 아세트산 (50 mL) 용매에서 하룻밤 동안 환류시켰다. 반응 혼합물에 물을 첨가한 후 여과하였고 물로 세정하였다. 여과 고체는 에탄올에서 재결정화시켜 상기 화합물 10을 68% 수율로 얻었다. (0.03 mol, 5.0 g), bromoacetic acid (1.5 eq., 6.90 g) and sodium acetate (3.0 eq., 8.2 g) were added to a solution of 1 H- benzo [ d ] imidazole- The mixture was refluxed in acetic acid (50 mL) solvent over night. Water was added to the reaction mixture, followed by filtration and washing with water. The filtrate solid was recrystallized from ethanol to give the above compound 10 in 68% yield.
1H NMR (400MHz, DMSO-d 6 ) δ 7.83 (d, 1 H, J = 7.6 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 7.29 (t, 1 H, J = 7.6 Hz), 4.58 (s, 2 H); 13C NMR (100MHz, DMSO-d 6 ) δ 166.7, 159.9, 150.0, 130.5, 126.2, 124.1, 119.2, 112.5, 40.4.
1 H NMR (400MHz, DMSO- d 6) δ 7.83 (d, 1 H, J = 7.6 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz) , 7.29 (t, 1H, J = 7.6 Hz), 4.58 (s, 2H); 13 C NMR (100 MHz, DMSO- d 6 ) ? 166.7, 159.9, 150.0, 130.5, 126.2, 124.1, 119.2, 112.5, 40.4.
1. 2-(치환된 1. 2- (substituted 벤질리덴Benzylidene )) 벤조Benzo [[ dd ]티아졸로[3,2-] Thiazolo [3,2- aa ]] 이미다졸Imidazole -3(2-3 (2 HH )-온 [2-(substituted ) -One [2- (& benzylidenebenzylidene )) benzobenzo [[ dd ]] thiazolothiazolo [3,2-[3,2- aa ]] imidazolimidazole -3(2-3 (2 HH )-) - oneone ] 유도체 (10a - 10n) 의 합성] Derivative (10a-10n) Synthesis of
티아졸로이미다졸론(thiazoloimidazolone) (5.2 mmol), 다양한 벤즈알데히드(benzaldehyde) (1.0 - 1.1 당량) 및 소듐 아세테이트(sodium acetate, NaOAc) (1.57mmol)의 혼합물을 아세트산(acetic acid) (1.0 mL) 용매에서 12 - 30시간 동안 85℃ 에서 교반시켰다. 반응 혼합물을 상온으로 식히고 난 뒤, 물을 넣었다. 상기 과정에서 생성된 침전물을 여과하고 물로 세정하여 상기 목적 화합물 (10a - 10n)을 얻었다.A mixture of thiazoloimidazolone (5.2 mmol), various benzaldehyde (1.0-1.1 equivalents) and sodium acetate (NaOAc) (1.57 mmol) was added to a solution of acetic acid (1.0 mL) Lt; RTI ID = 0.0 > 85 C < / RTI > for 12-30 hours. The reaction mixture was cooled to room temperature and then water was added. The resulting precipitate was filtered and washed with water to obtain the desired compound (10a-10n).
1) (Z)-2-(4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(4-hydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10a]1) (Z) -2- (4- hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4- hydroxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10a]
반응시간 하룻밤(overnight); 수율 55.3%;Reaction time overnight; Yield 55.3%;
1H NMR (500MHz, DMSO-d 6 ) δ 10.46 (s, 1 H), 7.99 (s, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.64 (d, 1 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.5 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 6.95 (d, 2 H, J = 8.5 Hz); 13C NMR (100MHz, DMSO-d 6 ) δ 161.3, 160.1, 154.0, 148.9, 137.2, 133.7, 130.8, 126.2, 124.6, 124.3, 120.8, 119.8, 117.2, 113.0. 1 H NMR (500MHz, DMSO- d 6) δ 10.46 (s, 1 H), 7.99 (s, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.64 (d, 1 H, J = 8.0 Hz), 7.60 (d, 2 H, J = 8.5 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 6.95 (d, 2 H, J = 8.5 Hz); 13 C NMR (100 MHz, DMSO- d 6 ) ? 161.3, 160.1, 154.0, 148.9, 137.2, 133.7, 130.8, 126.2, 124.6, 124.3, 120.8, 119.8, 117.2, 113.0.
2) (Z)-2-(2-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(2-hydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10b]2) (Z) -2- (2- hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (2- hydroxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10b]
반응시간 2 일; 수율 35.6%;
1H NMR (500MHz, DMSO-d 6 ) δ 12.92 (brs, 1 H), 8.39 (s, 1 H), 7.71 (d, 1 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 8.0 Hz), 7.49-7.45 (m, 3 H), 7.36 (t, 1 H, J = 8.0 Hz), 7.12 (m, 2 H). 1 H NMR (500MHz, DMSO- d 6) δ 12.92 (brs, 1 H), 8.39 (s, 1 H), 7.71 (d, 1 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 8.0 Hz), 7.49-7.45 (m, 3 H), 7.36 (t, 1H, J = 8.0 Hz), 7.12 (m, 2H).
3) (Z)-2-(4-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(4-methoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10c]3) (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4- methoxybenzylidene benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10c]
반응시간 하룻밤(overnight); 수율 82.2%; Reaction time overnight; Yield 82.2%;
1H NMR (500MHz, CDCl3) δ 8.04 (d, 1 H, J = 8.0 Hz), 8.01 (s, 1H), 7.67 (d, 1 H, J = 8.0 Hz), 7.57 (d, 2 H, J = 9.0 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.02 (d, 2 H, J = 9.0 Hz), 3.88 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 162.1, 160.1, 153.8, 149.1, 137.1, 132.8, 130.8, 126.0, 125.7, 124.3, 121.9, 119.7, 115.2, 113.1, 55.8. 1 H NMR (500MHz, CDCl 3 ) δ 8.04 (d, 1 H, J = 8.0 Hz), 8.01 (s, 1H), 7.67 (d, 1 H, J = 8.0 Hz), 7.57 (d, 2 H, J = 9.0 Hz), 7.38 ( t, 1 H, J = 8.0 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.02 (d, 2 H, J = 9.0 Hz), 3.88 (s, 3 H); 13 C NMR (100MHz, CDCl 3 ) δ 162.1, 160.1, 153.8, 149.1, 137.1, 132.8, 130.8, 126.0, 125.7, 124.3, 121.9, 119.7, 115.2, 113.1, 55.8.
4) (Z)-2-(4-하이드록시-3-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(4-hydroxy-3-methoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10d]4) (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (4-hydroxy-3-methoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10d]
노란색 고체; 반응시간 하룻밤(overnight); 수율 61.3%; Yellow solid; Reaction time overnight; Yield 61.3%;
1H NMR (400MHz, DMSO-d 6 ) δ 10.13 (s, 1 H), 7.96 (s, 1 H), 7.88 (d, 1 H, J = 7.6 Hz), 7.61 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 7.30 (t, 1 H, J = 7.6 Hz), 7.25 (d, 1 H, J = 1.6 Hz), 7.17 (dd, 1 H, J = 1.6, 8.4 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 3.82 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 154.0, 150.9, 148.9, 148.7, 137.5, 130.7, 126.2, 125.3, 124.6, 124.5, 120.9, 119.8, 117.0, 115.2, 112.9, 56.3. 1 H NMR (400MHz, DMSO- d 6) δ 10.13 (s, 1 H), 7.96 (s, 1 H), 7.88 (d, 1 H, J = 7.6 Hz), 7.61 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 7.30 (t, 1 H, J = 7.6 Hz), 7.25 (d, 1 H, J = 1.6 Hz), 7.17 (dd, 1 H, J = 1.6, 8.4Hz), 6.95 (d, 1H, J = 8.4Hz), 3.82 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6 ) ? 160.0, 154.0, 150.9, 148.9, 148.7, 137.5, 130.7, 126.2, 125.3, 124.6, 124.5, 120.9, 119.8, 117.0, 115.2, 112.9, 56.3.
5) (Z)-2-(3-하이드록시-4-메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3-hydroxy-4-methoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10e]5) (Z) -2- (3- hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-hydroxy-4-methoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10e]
노란색 고체; 반응시간 하룻밤(overnight); 수율 60.8%; Yellow solid; Reaction time overnight; Yield 60.8%;
1H NMR (400MHz, DMSO-d 6 ) δ 9.60 (s, 1 H), 7.90 (s, 1 H), 7.89 (d, 1 H, J = 8.0 Hz), 7.62 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.31 (t, 1 H, J = 8.0 Hz), 7.18 (d, 1 H, J = 8.4 Hz), 7.12 (s, 1 H), 7.06 (d, 1 H, J = 8.4 Hz), 3.81 (s, 3 H); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 154.0, 151.3, 148.9, 147.7, 137.1, 130.8, 126.2, 125.9, 124.9, 124.6, 121.8, 119.8, 116.6, 113.1, 113.0, 56.4. 1 H NMR (400MHz, DMSO- d 6) δ 9.60 (s, 1 H), 7.90 (s, 1 H), 7.89 (d, 1 H, J = 8.0 Hz), 7.62 (d, 1 H, J = 8.0 Hz), 7.38 (t, 1H, J = 8.0 Hz), 7.31 (t, 1H, J = 8.0 Hz), 7.18 (d, 1H, J = 8.4 Hz), 7.12 , 7.06 (d, 1H, J = 8.4 Hz), 3.81 (s, 3 H); 13 C NMR (100 MHz, DMSO- d 6 ) ? 160.0, 154.0, 151.3, 148.9, 147.7, 137.1, 130.8, 126.2, 125.9, 124.9, 124.6, 121.8, 119.8, 116.6, 113.1, 113.0, 56.4.
6) (Z)-2-(3-에톡시-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3-ethoxy-4-hydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10f]6) (Z) -2- (3- ethoxy-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-ethoxy-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10f]
노란색 고체; 반응시간 하룻밤(overnight); 수율 45.1%; Yellow solid; Reaction time overnight; Yield 45.1%;
1H NMR (400MHz, DMSO-d 6 ) δ 10.05 (s, 1 H), 7.96 (s, 1 H), 7.90 (d, 1 H, J = 8.0 Hz), 7.63 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 7.25 (d, 1 H, J = 2.0 Hz), 7.18 (dd, 1 H, J = 2.0, 8.4 Hz), 6.95 (d, 1 H, J = 8.4 Hz), 4.07 (q, 2 H, J = 7.2 Hz), 1.34 (t, 3 H, J = 7.2 Hz); 13C NMR (100MHz, DMSO-d 6 ) δ 160.0, 154.0, 151.1, 148.9, 147.9, 137.5, 130.8, 126.2, 125.3, 124.7, 124.6, 120.9, 119.9, 117.1, 116.3, 113.0, 64.6, 15.3. 1 H NMR (400MHz, DMSO- d 6) δ 10.05 (s, 1 H), 7.96 (s, 1 H), 7.90 (d, 1 H, J = 8.0 Hz), 7.63 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1H, J = 8.0 Hz), 7.32 (t, 1H, J = 8.0 Hz), 7.25 (d, 1H, J = 2.0 Hz), 7.18 J = 2.0, 8.4 Hz), 6.95 (d, 1H, J = 8.4 Hz), 4.07 (q, 2H, J = 7.2 Hz), 1.34 (t, 3 H, J = 7.2 Hz); 13 C NMR (100 MHz, DMSO- d 6 ) ? 160.0, 154.0, 151.1, 148.9, 147.9, 137.5, 130.8, 126.2, 125.3, 124.7, 124.6, 120.9, 119.9, 117.1, 116.3, 113.0, 64.6, 15.3.
7) (Z)-2-(2,4-디하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(2,4-dihydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10g]7) (Z) -2- (2,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- ( 2,4-dihydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10g]
반응시간 하룻밤(overnight); 수율 42.1%; Reaction time overnight; Yield 42.1%;
1H NMR (500MHz, DMSO-d 6 ) δ 12.19 (brs, 1 H), 10.9 (s, 1 H), 8.41 (s, 1 H), 7.59 (d, 1 H, J = 8.5 Hz), 7.42 (m, 2 H), 7.14 (t, 1 H, J = 7.5 Hz), 7.12 (t, 1 H, J = 7.5 Hz), 6.82 (dd, 1 H, J = 2.5, 8.5 Hz), 6.77 (d, 1 H, J = 2.5 Hz); 13C NMR (125MHz, DMSO-d 6 ) δ 162.8, 159.3, 156.2, 149.9, 149.6, 147.6, 130.8, 130.6, 122.5, 122.1, 114.3, 114.0, 112.9, 112.3, 102.6, 102.3. 1 H NMR (500MHz, DMSO- d 6) δ 12.19 (brs, 1 H), 10.9 (s, 1 H), 8.41 (s, 1 H), 7.59 (d, 1 H, J = 8.5 Hz), 7.42 (m, 2 H), 7.14 (t, 1 H, J = 7.5 Hz), 7.12 (t, 1 H, J = 7.5 Hz), 6.82 (dd, 1 H, J = 2.5, 8.5 Hz), 6.77 ( d, 1H, J = 2.5 Hz); 13 C NMR (125MHz, DMSO- d 6) δ 162.8, 159.3, 156.2, 149.9, 149.6, 147.6, 130.8, 130.6, 122.5, 122.1, 114.3, 114.0, 112.9, 112.3, 102.6, 102.3.
8) (Z)-2-(3,4-디하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3,4-dihydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10h]8) (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- ( 3,4-dihydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10h]
반응시간 하룻밤(overnight); 수율 58.2%; Reaction time overnight; Yield 58.2%;
1H NMR (500MHz, DMSO-d 6 ) δ 9.99 (brs, 1 H), 9.57 (brs, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.90 (s, 1 H), 7.65 (d, 1 H, J = 8.0 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 7.34 (t, 1 H, J = 8.0 Hz), 7.14 (s, 1 H), 7.10 (d, 1 H, J = 8.5 Hz), 6.91 (d, 1 H, J = 8.5 Hz); 13C NMR (100MHz, DMSO-d 6 ) δ 160.1, 154.1, 150.1, 148.9, 146.7, 137.6, 130.8, 126.2, 125.4, 124.6, 124.5, 120.5, 119.8, 117.3, 117.1, 112.9. 1 H NMR (500MHz, DMSO- d 6) δ 9.99 (brs, 1 H), 9.57 (brs, 1 H), 7.92 (d, 1 H, J = 8.0 Hz), 7.90 (s, 1 H), 7.65 (d, 1H, J = 8.0 Hz), 7.38 (t, 1H, J = 8.0 Hz), 7.34 (t, 1H, J = 8.0 Hz), 7.14 1 H, J = 8.5 Hz), 6.91 (d, 1H, J = 8.5 Hz); 13 C NMR (100 MHz, DMSO- d 6 ) ? 160.1, 154.1, 150.1, 148.9, 146.7, 137.6, 130.8, 126.2, 125.4, 124.6, 124.5, 120.5, 119.8, 117.3, 117.1, 112.9.
9) (Z)-2-(3-브로모-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3-bromo-4-hydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10i]9) (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3-bromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10i]
반응시간 2 일; 수율 68.7%;
1H NMR (400MHz, DMSO-d 6 ) δ 11.31 (s, 1 H), 7.96 (s, 1 H), 7.90 (m, 2 H), 7.63 (d, 1 H, J = 8.0 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 7.10 (d, 1 H, J = 8.8 Hz); 13C NMR (100MHz, DMSO-d 6 ) δ 159.8, 157.6, 153.8, 148.9, 136.8, 135.6, 131.4, 130.8, 126.3, 125.9, 124.7, 122.6, 119.9, 117.7, 113.0, 111.0. 1 H NMR (400MHz, DMSO- d 6) δ 11.31 (s, 1 H), 7.96 (s, 1 H), 7.90 (m, 2 H), 7.63 (d, 1 H, J = 8.0 Hz), 7.56 (d, 1 H, J = 8.0 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.32 (t, 1 H, J = 8.0 Hz), 7.10 (d, 1 H, J = 8.8 Hz) ; 13 C NMR (100 MHz, DMSO- d 6 ) ? 159.8, 157.6, 153.8, 148.9, 136.8, 135.6, 131.4, 130.8, 126.3, 125.9, 124.7, 122.6, 119.9, 117.7, 113.0, 111.0.
10) (Z)-2-(2,4-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(2,4-dimethoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10j]10) (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (2 , 4-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10j]
반응시간 하룻밤(overnight); 수율 63.0%;Reaction time overnight; Yield: 63.0%;
1H NMR (500MHz, CDCl3) δ 8.39 (s, 1 H), 8.05 (d, 1 H, J = 7.5 Hz), 7.67 (d, 1 H, J = 7.5 Hz), 7.52 (d, 1 H, J = 8.5 Hz), 7.37 (t, 1 H, J = 7.5 Hz), 7.32 (t, 1 H, J = 7.5 Hz), 6.62 (d, 1 H, J = 8.5 Hz), 6.48 (s, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 164.1, 161.7, 160.7, 160.4, 154.3, 148.9, 132.9, 131.6, 125.9, 124.1, 121.5, 119.5, 115.4, 113.0, 105.9, 98.8, 55.9, 55.8. 1 H NMR (500MHz, CDCl 3 ) δ 8.39 (s, 1 H), 8.05 (d, 1 H, J = 7.5 Hz), 7.67 (d, 1 H, J = 7.5 Hz), 7.52 (d, 1 H , J = 8.5 Hz), 7.37 (t, 1 H, J = 7.5 Hz), 7.32 (t, 1 H, J = 7.5 Hz), 6.62 (d, 1 H, J = 8.5 Hz), 6.48 (s, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 164.1, 161.7, 160.7, 160.4, 154.3, 148.9, 132.9, 131.6, 125.9, 124.1, 121.5, 119.5, 115.4, 113.0, 105.9, 98.8, 55.9, 55.8.
11) (Z)-2-(3,4-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3,4-dimethoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10k]11) (Z) -2- (3,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - -2- ( 3 -on [(Z) , 4-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10k]
반응시간 하룻밤(overnight); 수율 50.2%; Reaction time overnight; Yield 50.2%;
1H NMR (400MHz, CDCl3) δ 8.01 (d, 1 H, J = 7.6 Hz), 7.98 (s, 1 H), 7.66 (d, 1 H, J = 7.6 Hz), 7.37 (t, 1 H, J = 7.6 Hz), 7.32 (t, 1 H, J = 7.6 Hz), 7.22 (dd, 1 H, J = 1.6, 8.8 Hz), 7.07 (d, 1 H, J = 1.6 Hz), 6.96 (d, 1 H, J = 8.8 Hz), 3.95 (s, 3 H), 3.93 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 160.0, 153.6, 151.9, 149.7, 148.9, 137.3, 130.7, 126.1, 126.0, 125.2, 124.4, 122.2, 119.7, 113.1, 112.8, 111.7, 56.3, 56.2. 1 H NMR (400MHz, CDCl 3 ) δ 8.01 (d, 1 H, J = 7.6 Hz), 7.98 (s, 1 H), 7.66 (d, 1 H, J = 7.6 Hz), 7.37 (t, 1 H , J = 7.6 Hz), 7.32 (t, 1 H, J = 7.6 Hz), 7.22 (dd, 1 H, J = 1.6, 8.8 Hz), 7.07 (d, 1 H, J = 1.6 Hz), 6.96 ( d, 1H, J = 8.8Hz), 3.95 (s, 3H), 3.93 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) ? 160.0, 153.6, 151.9, 149.7, 148.9, 137.3, 130.7, 126.1, 126.0, 125.2, 124.4, 122.2, 119.7, 113.1, 112.8, 111.7, 56.3, 56.2.
12) (Z)-2-(4-하이드록시-3,5-디메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(4-hydroxy-3,5-dimethoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10l]12) (Z) -2- (4- hydroxy-3,5-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z) -2- (4-hydroxy-3,5-dimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10l]
반응시간 하룻밤(overnight); 수율 68.4%; Reaction time overnight; Yield 68.4%;
1H NMR (400MHz, DMSO-d 6 ) δ 9.50 (s, 1 H), 7.95 (s, 1 H), 7.89 (d, 1 H, J = 7.6 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1 H, J = 7.6 Hz), 7.30 (t, 1 H, J = 7.6 Hz), 6.97 (s, 2 H), 3.82 (s, 6 H); 13C NMR (100MHz, DMSO-d 6 ) δ 159.9, 153.9, 149.0, 149.0, 140.1, 137.7, 130.8, 126.2, 124.6, 123.5, 121.3, 119.9, 112.9, 109.0, 56.8. 1 H NMR (400MHz, DMSO- d 6) δ 9.50 (s, 1 H), 7.95 (s, 1 H), 7.89 (d, 1 H, J = 7.6 Hz), 7.62 (d, 1 H, J = 7.6 Hz), 7.34 (t, 1H, J = 7.6 Hz), 7.30 (t, 1H, J = 7.6 Hz), 6.97 (s, 2H), 3.82 (s, 6H); 13 C NMR (100 MHz, DMSO- d 6 ) ? 159.9, 153.9, 149.0, 149.0, 140.1, 137.7, 130.8, 126.2, 124.6, 123.5, 121.3, 119.9, 112.9, 109.0, 56.8.
13) (Z)-2-(3,5-디브로모-4-하이드록시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3,5-dibromo-4-hydroxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10m]13) (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one [(Z ) -2- (3,5-dibromo-4-hydroxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10m]
반응시간 24시간; 수율 79.9%; Reaction time 24 hours; Yield 79.9%;
1H NMR (400MHz, DMSO-d 6 ) δ 9.72 (brs, 1 H), 8.02 (s, 2 H), 7.93 7.87 (m, 2 H), 7.66 (d, 1 H, J = 8.0 Hz), 7.39 7.32 (m, 2 H). 1 H NMR (400MHz, DMSO- d 6) δ 9.72 (brs, 1 H), 8.02 (s, 2 H), 7.93 7.87 (m, 2 H), 7.66 (d, 1 H, J = 8.0 Hz), 7.39 7.32 (m, 2H).
14) (Z)-2-(3,4,5-트리메톡시벤질리덴)벤조[d]티아졸로[3,2-a]이미다졸-3(2H)-온 [(Z)-2-(3,4,5-trimethoxybenzylidene)benzo[d]thiazolo[3,2-a]imidazol-3(2H)-one; 10n]14) (Z) -2- (3,4,5- trimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one [(Z) -2 - (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one; 10n]
반응시간 3 일; 수율 78.4%; Reaction time 3 days; Yield 78.4%;
1H NMR (500MHz, CDCl3) δ 8.03 (d, 1 H, J = 7.5 Hz), 7.98 (s, 1 H), 7.68 (d, 1 H, J = 7.5 Hz), 7.39 (t, 1 H, J = 7.5 Hz), 7.34 (t, 1 H, J = 7.5 Hz), 6.84 (s, 2 H), 3.94 (s, 6 H), 3.93 (s, 3 H); 13C NMR (100MHz, CDCl3) δ 159.7, 153.9, 153.4, 149.0, 140.9, 137.2, 130.6, 128.5, 126.2, 124.5, 124.1, 119.9, 113.1, 107.9, 61.3, 56.5.
1 H NMR (500MHz, CDCl 3 ) δ 8.03 (d, 1 H, J = 7.5 Hz), 7.98 (s, 1 H), 7.68 (d, 1 H, J = 7.5 Hz), 7.39 (t, 1 H , J = 7.5 Hz), 7.34 (t, 1H, J = 7.5 Hz), 6.84 (s, 2H), 3.94 (s, 6H), 3.93 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) ? 159.7, 153.9, 153.4, 149.0, 140.9, 137.2, 130.6, 128.5, 126.2, 124.5, 124.1, 119.9, 113.1, 107.9, 61.3, 56.5.
<< 실험예Experimental Example 1> 티로시나아제 억제 효과 1> Tyrosinase inhibitory effect
버섯 유래 티로시나아제를 본 실험의 효소원으로 사용하였다. 티로시나아제 활성은 약간의 변형을 거쳐 종래 알려진 방법(Life Sci ., 1999, 65, 241-246)에 따라 분석하였다. 즉, 버섯 유래 티로시나아제 (1000 units) 수용액 20 μl를 96-well microplate (Nunc, Denmark)에 가하여 1mM L-티로신 용액과 50mM 인산 완충액 (pH 6.5)을 함유한 총 200 μl 부피의 분석 혼합물을 준비하였다. 상기 분석 혼합물을 25℃에서 30분 동안 배양하였다. 배양 후, 반응 혼합물에서 생성된 도파크롬의 양을 492nm (OD492)에서 마이크로플레이트리더 (Hewlett Packard)를 이용하여 측정하였다. Mushroom-derived tyrosinase was used as an enzyme source in this experiment. The tyrosinase activity was slightly modified and the activity was determined according to a known method ( Life Sci . , 1999, 65, 241-246). That is, 20 μl of a 1000-unit aqueous solution of mushroom-derived tyrosinase was added to a 96-well microplate (Nunc, Denmark), and a total of 200 μl of the assay mixture containing 1 mM L-tyrosine and 50 mM phosphate buffer Prepared. The assay mixture was incubated at 25 < 0 > C for 30 minutes. After incubation, the amount of dopachrome produced in the reaction mixture was measured at 492 nm (OD 492 ) using a microplate reader (Hewlett Packard).
코지산(Kojic acid)의 저해 활성 정도를 100으로 두었을 때, 합성한 화합물들의 저해 정도를 상대적인 값으로 나타내었다. 합성한 총25개의 화합물들의 티로시네이즈(Tyrosinase) 저해 활성을 측정한 결과, 화합물 9b, 9f, 10e, 10f 및 10h가 양성대조군인 코지산(Kojic acid)보다 더 좋은 저해활성을 보여 주었다. 화합물 10k와 10n은 코지산(Kojic acid)보다 약간 낮은 저해 활성을 보여 주었다(도 1).
When the degree of inhibition of kojic acid was set at 100, the degree of inhibition of the synthesized compounds was shown as a relative value.
<< 실험예Experimental Example 2> 독성실험 2> Toxicity experiment
웅성 Balb/c 마우스에 화합물 9f를 0.5% 메틸셀룰로즈 용액에 각각 현탁하여 0.5g/kg, 1g/kg 및 2g/kg의 용량으로 1회 단회 경구투여하고 7일간 마우스의 생존율 및 체중을 조사하였다.
이러한 투여 후 동물의 폐사여부, 임상증상, 체중변화를 관찰하고 혈액학적 검사와 혈액생화학적 검사를 실시하였으며, 부검하여 육안으로 복강장기와 흉강장기의 이상여부를 관찰하였다.After this administration, we observed the mortality of the animal, clinical symptoms, weight change, hematologic test and blood biochemical test, and autopsied the visceral organs and thoracic organs were observed.
그 결과, 모든 동물에서 특기할 만한 임상증상이나 폐사된 동물은 없었으며, 체중변화, 혈액검사, 혈액생화학 검사, 부검소견 등에서도 독성변화는 관찰되지 않았다. As a result, no clinical symptoms or dead animals were found in all animals, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings.
이상의 결과, 본 발명의 화합물들은 랫트에서 2g/㎏까지 독성변화를 나타내지 않으며, 따라서, 경구 투여 중간치사량(LD50)은 2g/kg 이상인 안전한 물질로 판단되었다. As a result, the compounds of the present invention did not show toxic changes to 2 g / kg in rats, and thus, the
하기에 본 발명에 따른 화합물 9f를 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Hereinafter, formulation examples of the composition containing the
<< 처방예Prescription example 1> 약학조성물의 1 > 처방예Prescription example
<처방예 1-1> 산제의 제조≪ Prescription Example 1-1 > Preparation of powder
화합물 9f 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.20 mg of
<처방예 1-2> 정제의 제조≪ Prescription Example 1-2 > Preparation of tablets
화합물 9f 20 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.20 mg of
<처방예 1-3> 캅셀제의 제조≪ Prescription Example 1-3 > Preparation of capsules
화합물 9f 10 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2mg을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.10 mg of
<처방예 1-4> 주사제의 제조≪ Prescription Example 1-4 > Preparation of injection
화합물 9f 10 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조하였다.
<처방예 1-5> 연고제의 제조≪ Prescription Example 1-5 > Preparation of ointment preparation
화합물 9f 10mg, PEG-4000 250mg, PEG-400 650mg, 백색바셀린 10mg, 파라옥시안식향산메칠 1.44mg, 파라옥시안식향산프로필 0.18mg 및 잔량의 정제수를 혼합한 후 통상의 연고제의 제조방법에 따라서 연고제를 제조하였다.
<< 처방예Prescription example 2> 2> 화장료Cosmetics 조성물의 Of the composition 처방예Prescription example
<처방예 2-1> 영양 로션의 제조≪ Prescription Example 2-1 > Production of nutrition lotion
프로필렌글리콜 3.0 중량부, 카르복시폴리머 0.1 중량부, 방부제 미량과 잔량의 정제수를 혼합교반하면서 80 내지 85℃로 가열하여 제조부에 투입한 후 유화기를 작용시키고, 폴리솔베이트60 1.0 중량부, 솔비탄 세스퀴올레이트 0.5 중량부, 유동 파라핀 10.0 중량부, 솔비탄 스테아레이트 1.0 중량부, 친유형 모노스테아린산 글리세린 0.5 중량부, 스테아린산 1.5 중량부, 글리세릴스테아레이트/PEG-400 스테아레이트 1.0 중량부, 트리에탄올아민 0.2 중량부를 80 내지 85℃로 가열하여 투입한 뒤 유화하였다. 유화가 끝나면 교반기를 이용하여 교반하면서 50℃까지 열 냉각한 뒤 향료 미량을 투입하고, 45℃까지 냉각한 뒤 색소 미량을 투입하고, 35℃에서 화합물 9f를 투입하여 25℃까지 냉각한 뒤 숙성시켰다.3.0 parts by weight of propylene glycol, 0.1 part by weight of carboxy polymer, purified water of a small amount of preservative and remaining amount were heated to 80 to 85 ° C while stirring and mixing, and then charged into a manufacturing part. Then, an emulsifying agent was allowed to act. 1.0 part by weight of Polysorbate 60, 0.5 parts by weight of sesquioleate, 10.0 parts by weight of liquid paraffin, 1.0 part by weight of sorbitan stearate, 0.5 part by weight of glycerin monostearate as a parent type, 1.5 parts by weight of stearic acid, 1.0 part by weight of glyceryl stearate / PEG-400 stearate, And 0.2 parts by weight of amine were heated to 80 to 85 DEG C and then emulsified. After the emulsification was completed, the mixture was thermally cooled to 50 DEG C with stirring using an agitator, and a trace amount of fragrance was added thereto. After cooling to 45 DEG C, a trace amount of pigment was added.
<처방예 2-2> 영양 크림의 제조≪ Prescription Example 2-2 > Preparation of nutritional cream
카르복시폴리머 0.3 중량부, 부틸렌글리콜 5.0 중량부, 글리세린 3.0 중량부 및 잔량의 정제수를 혼합교반하면서 80 내지 85℃로 가열하여 제조부에 투입한 후 유화기를 작용시키고, 스테아린산 2.0 중량부, 세틸알콜 2.0 중량부, 글리세릴모노스테아레이트 2.0 중량부, 폴리옥시에틸렌솔비탄모노스테아레이트 0.5 중량부, 솔비탄세스퀴올레이트 0.5 중량부, 글리세릴모노스테아레이트/글리세릴스테아레이트/폴리옥시에틸렌스테아레이트 1.0 중량부, 왁스 1.0 중량부, 유동파라핀 4.0 중량부, 스쿠알란 4.0 중량부, 카프릴릭/카프릭트리글리세라이드 4.0 중량부를 80 내지 85℃로 가열하여 투입한 뒤 트리에탄올아민 0.5 중량부를 투입하여 유화하였다. 유화가 끝나면 교반기를 이용하여 교반하면서 35℃까지 냉각한 뒤 화합물 9f를 투입하여 25℃까지 냉각한 뒤 숙성시켰다.0.3 parts by weight of carboxy polymer, 5.0 parts by weight of butylene glycol, 3.0 parts by weight of glycerin and the remaining amount of purified water were heated to 80 to 85 캜 while stirring and mixing, 2.0 parts by weight, glyceryl monostearate 2.0 parts by weight, polyoxyethylene sorbitan monostearate 0.5 part by weight, sorbitan sesquioleate 0.5 part by weight, glyceryl monostearate / glyceryl stearate / polyoxyethylene stearate 1.0 part by weight of wax, 4.0 parts by weight of liquid paraffin, 4.0 parts by weight of squalane, and 4.0 parts by weight of caprylic / capric triglyceride were heated to 80 to 85 ° C. and 0.5 part by weight of triethanolamine was added thereto to emulsify . After the emulsification was completed, the mixture was cooled to 35 DEG C while stirring with an agitator, and then Compound 9f was added thereto, followed by cooling to 25 DEG C and aging.
<처방예 2-3> 워시폼의 제조<Prescription Example 2-3> Manufacture of Wash Foam
TEA-코코일 글루타메이트 30.0 중량부, 디소듐 라우레스 설포숙시네이트글리세린 10.0 중량부, 글리세린 10.0 중량부, 코카마이드 DEA 2.0 중량부, PEG-120 메칠글루코오스 디올리에이트 1.0 중량부, 메칠글루세스-20 0.5 중량부, PEG-150 펜타에리트리틸 테트라 스테아레이트 0.5 중량부, 테트라소듐 EDTA 0.05 중량부 및 방부제 미량을 순차적으로 제조부에 투입하고 60 내지 65℃로 가열한 후 15분 동안 교반하였다. 교반이 끝나면 정제수의 일부를 투입하여 30분 동안 교분한 후, 다시 정제수의 일부를 천천히 투입하고 30분 동안 교반한 후 35℃까지 냉각하고, 화합물 9f와 향료를 투입하여 25℃까지 냉각한 뒤 숙성시켰다.
30.0 parts by weight of TEA-cocoyl glutamate, 10.0 parts by weight of disodium laureth sulfosuccinate glycerin, 10.0 parts by weight of glycerin, 2.0 parts by weight of cocamide DEA, 1.0 part by weight of PEG-120 methyl glucoside diolate, 20, 0.5 part by weight of PEG-150 pentaerythrityl tetrastearate, 0.05 part by weight of tetrasodium EDTA and a trace amount of preservative were sequentially added to the preparation part, and the mixture was heated to 60 to 65 占 폚 and stirred for 15 minutes. After the stirring, a portion of the purified water was added, and the mixture was stirred for 30 minutes. Then, a portion of the purified water was slowly added thereto, stirred for 30 minutes, cooled to 35 ° C, cooled to 25 ° C by adding
<< 처방예Prescription example 3> 건강보조식품 3> Health supplement
<처방예 3-1> 건강기능식품의 제조<Prescription Example 3-1> Preparation of Health Functional Foods
화합물 9f 1 ㎎, 비타민 혼합물 적량(비타민 A 아세테이트 70 ㎍, 비타민 E 1.0 ㎎, 비타민 B 1 0.13 ㎎, 비타민 B 2 0.15 ㎎, 비타민 B 6 0.5 ㎎, 비타민 B 12 0.2 ㎍, 비타민 C 10 ㎎, 비오틴 10 ㎍, 니코틴산아미드 1.7 ㎎, 엽산 50 ㎍, 판토텐산 칼슘 0.5 ㎎) 및 무기질 혼합물 적량(황산제1철 1.75 ㎎, 산화아연 0.82 ㎎, 탄산마그네슘 25.3 ㎎, 제1인산칼륨 15 ㎎, 제2인산칼슘 55 ㎎, 구연산칼륨 90 ㎎, 탄산칼슘 100 ㎎, 염화마그네슘 24.8 ㎎)을 혼합한 다음 과립을 제조하고 통상의 방법에 따라 건강기능식품을 제조하였다.
<처방예 3-2> 건강음료의 제조≪ Prescription Example 3-2 > Preparation of health drink
화합물 9f 1 ㎎, 구연산 1000 ㎎, 올리고당 100 g, 매실농축액 2 g, 타우린 1 g 및 정제수를 가하여 전체 900 ㎖가 되도록 하며, 통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 L 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관하였다.
To the mixture was added 1 mg of
Claims (6)
[화학식 1]
상기 식에서,
X는 수소, Y는 CH3이며, R1 내지 R4는 각각 같거나 다를 수 있으며, H, OH, 할로겐, C1 내지 C4의 알킬 또는 C1 내지 C4의 알콕시 중 어느 하나;
X는 CH3, Y는 수소이며, R1 내지 R4는 각각 같거나 다를 수 있으며, H, OH, 할로겐, C1 내지 C4의 알킬 또는 C1 내지 C4의 알콕시 중 어느 하나;
X 및 Y는 수소이며, R1 내지 R4 중 R1을 포함한 3개의 치환기는 수소이고, 나머지 1개의 치환기는 OH 또는 C1 내지 C4의 알콕시 중 어느 하나;
X 및 Y는 수소이며, R3은 OH이고, R1, R2 및 R4 중 2개의 치환기는 수소이며, 나머지 1개의 치환기는 C2 내지 C4의 알콕시, OH 또는 Br 중 어느 하나;
X 및 Y는 수소이며, R3은 OH이고, R1, R2 및 R4 중 1개의 치환기는 수소이며, 나머지 2개의 치환기는 Br이거나;
X 및 Y는 수소이며, R3이 C1 내지 C4의 알콕시이고, R1, R2 또는 R4는 각각 같거나 다를 수 있으며, 수소 또는 C1 내지 C4의 알콕시 중 어느 하나로 이루어진 군에서 선택됨.A compound represented by the following formula (1):
[Chemical Formula 1]
In this formula,
X is hydrogen, Y is CH 3 , R 1 to R 4 may be the same or different and are any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy;
X is CH 3, Y is hydrogen, R 1 to R 4 may be the same or different, each, H, OH, halogen, alkoxy of any one of C1 to C4 alkyl or C1 to C4;
X and Y are hydrogen, and three substituents including R 1 of R 1 to R 4 are hydrogen and the remaining one substituent is either OH or C1 to C4 alkoxy;
X and Y are hydrogen, R 3 is OH, two substituents of R 1 , R 2 and R 4 are hydrogen, and the remaining one substituent is any of C 2 to C 4 alkoxy, OH or Br;
X and Y are hydrogen, R 3 is OH, one substituent of R 1 , R 2 and R 4 is hydrogen and the remaining two substituents are Br;
X and Y are hydrogen, R 3 is C 1 to C 4 alkoxy, and R 1 , R 2 or R 4 may be the same or different and is selected from the group consisting of hydrogen and C 1 to C 4 alkoxy.
[화학식 1]
상기 식에서, R1내지 R4는 각각 같거나 다를 수 있으며, H, OH, 할로겐, C1 내지 C4의 알킬 또는 C1 내지 C4의 알콕시 중 어느 하나이고, X 및 Y는 H 또는 CH3임.A pharmaceutical composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient:
[Chemical Formula 1]
Wherein each of R 1 to R 4 may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y are H or CH 3 .
[화학식 1]
상기 식에서, R1내지 R4는 각각 같거나 다를 수 있으며, H, OH, 할로겐, C1 내지 C4의 알킬 또는 C1 내지 C4의 알콕시 중 어느 하나이고, X 및 Y는 H 또는 CH3임.A cosmetic composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient:
[Chemical Formula 1]
Wherein each of R 1 to R 4 may be the same or different and is any one of H, OH, halogen, C 1 to C 4 alkyl or C 1 to C 4 alkoxy, and X and Y are H or CH 3 .
The method according to claim 5, wherein the compound is (2 Z) -2- (4- hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H ) -one, (2 Z) -2- (4- methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (4- hydroxy-3-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one , (2 Z) -2- (3- hydroxy-4-methoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3-ethoxy-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (3,4- dihydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - on, (2 Z) -2- (3- bromo-4-hydroxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one, (2 Z) -2- (2,4- dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) -one , (2 Z) -2- (3,4- dimethoxy- Tired den) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (2 Z) -2- (4- hydroxy -3,5 -dimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (2 Z) -2- (3,4,5 -trimethoxy-benzylidene) -6 (7) -methyl-benzo [d] thiazolo [3,2- a] -3 (2 H-imidazole) -one, (Z) -2- (4- hydroxy-benzyl vinylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2- hydroxy-benzylidene) benzo [d] thiazolo [3,2 - a] imidazole -3 (2 H) - one, (Z) -2- (4- methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4- hydroxy-3-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2 - (3-hydroxy-4-methoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3-ethoxy- 4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dihydroxy-benzylidene) benzo [ d] thiazole [3,2- a] -3 (2 H ) imidazol-on, (Z) -2- (3,4- dihydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3- bromo-4-hydroxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (2,4- dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3 , 4-dimethoxy-benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (4-hydroxy-3,5-dimethoxy benzylidene) benzo [d] thiazolo [3,2- a] imidazole -3 (2 H) - one, (Z) -2- (3,5- dibromo-4-hydroxy-benzylidene) benzo [ d ] thiazolo [3,2- a ] imidazol-3 ( 2H ) -one and ( Z ) -2- (3,4,5-trimethoxybenzylidene) benzo [ d ] thiazolo [3 , 2- a ] imidazol-3 (2 H ) -one.
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| US20040034075A1 (en) * | 2002-06-17 | 2004-02-19 | The Pennsylvania State University Research Foundation | Sphingosine kinase inhibitors |
| WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
| US20100190832A1 (en) * | 2008-10-17 | 2010-07-29 | National Institute Of Immunology. | Mechanism-based inhibitors of transthyretin amyloidosis: studies with biphenyl ethers and structural templates |
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| US20040034075A1 (en) * | 2002-06-17 | 2004-02-19 | The Pennsylvania State University Research Foundation | Sphingosine kinase inhibitors |
| WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
| US20100190832A1 (en) * | 2008-10-17 | 2010-07-29 | National Institute Of Immunology. | Mechanism-based inhibitors of transthyretin amyloidosis: studies with biphenyl ethers and structural templates |
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