KR101366372B1

KR101366372B1 - New compounds having skin whitening, antioxidant and PPAR activity, and medical use thereof

Info

Publication number: KR101366372B1
Application number: KR1020120009109A
Authority: KR
Inventors: 정해영; 박민희; 정기웅; 박윤정; 이혜진; 박지영; 문형룡
Original assignee: 부산대학교 산학협력단
Priority date: 2012-01-30
Filing date: 2012-01-30
Publication date: 2014-02-25
Also published as: KR20130087877A

Abstract

본 발명은 피부미백, 항산화 및 PPAR 활성을 갖는 신규 화합물 및 이의 의학적 용도에 관한 것으로, 본 발명에 따른 화합물들은 티로시나아제를 억제하는 피부미백 활성을 지니므로 피부미백용 약학조성물 또는 화장품에 유용하게 사용될 수 있고, 항산화 활성을 지니므로 피부노화 등의 예방 또는 치료에 유용하게 사용될 수 있으며, 또한 PPAR 활성 특히, PPARα 및 PPARγ 활성을 지니므로 비만, 대사성 질환 또는 심혈관계 질환을 예방하고 치료하는 데에 유용한 약학조성물 또는 건강식품으로 사용될 수 있다.The present invention relates to a novel compound having skin whitening, antioxidant and PPAR activity, and a medicinal use thereof, and the compounds according to the present invention have a skin whitening activity that inhibits tyrosinase, and thus is useful for a skin whitening pharmaceutical composition or cosmetic And has antioxidative activity. Therefore, it can be usefully used for prevention or treatment of skin aging and the like, and also has PPAR activity, especially PPAR alpha and PPAR gamma activity, so that it can be used for prevention and treatment of obesity, metabolic disease or cardiovascular disease May be used as a useful pharmaceutical composition or as a health food.

Description

(New compounds having skin whitening, antioxidant and PPAR activity, and medical use thereof)

본 발명은 피부미백, 항산화 및 ＰＰＡＲ 활성을 갖는 신규 화합물 및 이의 의학적 용도에 관한 것이다.The present invention relates to novel compounds having skin whitening, antioxidant and PPAR 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.

그리고, 산소와 관련된 인체 내 독성물질을 활성산소종 (ROS: reactive oxygen species)이라고 하는데 이러한 ROS의 종류로는 수퍼옥사이드 (superoxide), 히드록실 (hydroxyl), 페록실 (peroxyl), 알콕실 (alkoxyl), 히드로페록실 (hydroperoxyl)과 같은 자유라디칼 (유리기, free radical)과 히드로젠페록사이드 (hydrogen peroxide), 히포클로로스산 (hypochlorous acid), 오존 (ozone), 일중항 산소 (singlet oxygen), 퍼옥시나이트라이트 (peroxynitrite) 등과 같은 비자유라디칼 (비유리기, non free radical)이 있다. The toxic substances related to oxygen are called reactive oxygen species (ROS). Examples of such ROS include superoxide, hydroxyl, peroxyl, alkoxyl, Free radicals such as hydrogen peroxide and hydroperoxyl and hydrogen peroxide, hypochlorous acid, ozone, singlet oxygen, phosphorus, And non-free radicals such as peroxynitrite.

이 중에서 산소 독성 중 가장 많이 연구되어 왔고 중요한 역할을 하는 것은 수퍼옥사이드 자유라디칼 (superoxide free radical, 활성산소 또는 유해산소)이다 (Fridorich L., Science, 201, pp175-180, 1978). 강한 산화제인 자유라디칼은 짝이 없는 전자이다. 자유라디칼은 다양한 생물체의 산화 환원 반응에서 생성되며, 식용유지의 변질 또는 여러 생체물질(지질, 단백질, 핵산, 탄수화물)에 산화적인 손상을 유발할 수 있으며 여러 단계를 거치게 되면서 결과적으로 돌연변이가 일어날 수 있다 (Yen GC et al., J. Agric. Food Chem., 43, pp27-32, 1995). 생체막 구성성분인 인지질의 불포화지방산은 활성산소종과 같은 자유라디칼에 의해 과산화 반응이 개시되며 또한 연쇄적으로 진행된다. 그러므로 자유라디칼에 의한 과산화반응은 세포막의 투과성을 항진시킬 뿐 아니라 전반적인 세포독성을 초래하여 노화현상이나 이에 따른 여러 가지 질환의 병리현상을 유도하여 발암과정에도 관여한다. 라디칼 작용은 산화적 스트레스와 관련된 질환인 아토피성 질환, 암, 고혈압, 심근경색, 동맥경화, 류머티스, 백내장, 파킨슨씨병 등 여러 가지 만성질환의 진행에 많은 영향을 주며 (DeSouza LC et al., Bioorg. Med. Cehm. Lett., 14, pp5859-5861, 2004), 면역계 기능을 약화시키는 요인으로 작용될 수 있다(Pike J et al., Int. J. Vitam. Nutr. Res., 65, pp117-120, 1995).Of these, oxygen toxicity has been the most studied and plays an important role in superoxide free radicals (free radicals or free radicals) (Fridorich L., Science, 201, pp175-180, 1978). Free radicals, strong oxidants, are unpaired electrons. Free radicals are produced by the redox reaction of various organisms and can cause oxidative damage to the degradation of edible fats or to various biomaterials (lipids, proteins, nucleic acids, carbohydrates), which can result in mutations (Yen GC et al., J. Agric. Food Chem., 43, pp27-32, 1995). Unsaturated fatty acids in the phospholipids constituting the biomembrane are initiated by the free radicals such as active oxygen species and proceed in a cascade. Therefore, the peroxidation reaction by free radical not only enhances the permeability of the cell membrane, but also induces overall cytotoxicity, thereby leading to aging phenomenon and various disease pathologies, thereby also involved in the carcinogenesis process. The radical action has a great influence on the progression of various chronic diseases such as atopic diseases, cancer, hypertension, myocardial infarction, arteriosclerosis, rheumatism, cataract and Parkinson's disease, which are related to oxidative stress (DeSouza LC et al., Bioorg (Pike J et al., Int. J. Vitam., Nutr. Res., 65, pp117-786, 2004) 120, 1995).

따라서 산화적 손상으로부터 예방하기 위한 대체 물질의 항산화적인 평가는 매우 활발하게 연구되고 있다. 항산화제는 산소를 제거하거나 흡수하는 것이 아니라 자유라디칼과 반응함으로써 특정 비타민류와 필수 아미노산등의 손실을 최소화 하거나, 유지 제품의 산패를 지연 또는 방지하는 목적으로 사용된다. 식품 또는 의약품 등에 많이 사용되는 합성 항산화제로는 부틸화 하이드록시아니솔 (BHA, Butylated hydroxyanisole), 부틸화 하이드록시톨루엔 (BHT, Butylated hydroxytoluene), 프로필 갈레이트 (PG, Propyl galate), 터셔리부틸 하이드로퀴논 (TBHQ, Tertiary butyl hydroquinone) 등이 있으나, 이들을 실험동물에 고농도로 투여할 경우에는 간 비대증이 유발되거나 발암성을 나타내는 것으로 알려져 있다. 특히 부틸화 하이드록시톨루엔은 여러 연구 결과를 통하여 실험동물의 간에서 마이크로솜 효소 활성 (microsomal enzyme activity)을 증가시킨다는 것이 알려지면서, 이들 페놀계 합성 항산화제의 안전성에 대하여 논란이 제기되어 현재에는 그 사용량이 법적으로 규제되어 있다(Brannen AL, J. Amer. Oil Chem. Soc., 52, pp59-63, 1975 ; Ito N et al., J. Natl. Cancer Inst., 70, p343, 1983 ; Chan KM et al., J. Food. Sci., 58, pp1-4, 1993). 이에 따라 항산화 효과가 높으면서 안전하고 경제적인 식물기원의 천연 항산화제를 개발하고자 하는 많은 연구가 기대 속에 이루어지고 있다(Larson RA, Phytochemistry, 27, pp969-978, 1988). 최근 천연물을 대상으로 한 연구가 활발히 수행되면서 천연물에 함유되어 있는 2차 대사산물이 생리활성물질로서 주요 관심사가 되고 있으며 특히, 항산화성 물질에 대한 연구가 활발히 진행되고 있는데, 현재까지 알려진 천연 항산화 물질로는 토코페롤 (tocopherol)류, 플라보노이드 (flavonoid)류, 고시폴(gossypol), 세사몰 (sesamol), 오리자놀 (oryzanol) 및 비타민 C 등을 들 수 있다(Huson B et al., Food Chem., 19, pp537-541, 1987 ; Frankel, E.N. Food Chem., 57, p51, 1996 ; Giese J, Food Technol., 5, pp73-81, 1996 ; Pszcczola DE, Food Tech., 55, pp51-59, 2001). 이 중 토코페롤 (tocopherol)과 L-아스코르브산 (L-ascorbic acid)이 천연 항산화제로 선호되고 있는데, 그중 토코페롤은 안전성이 높으나 단독으로는 산화반응 저지 능력이 낮으며(Halliwell B et al., FASEB J., 2, pp2867-2870, 1988) 가격이 비싸다는 단점이 있다.Therefore, antioxidative evaluation of alternative substances to prevent oxidative damage has been actively studied. Antioxidants are used not to remove or absorb oxygen, but to react with free radicals to minimize the loss of certain vitamins and essential amino acids, or to retard or prevent rancidity of preserved products. Synthetic antioxidants commonly used in foods or pharmaceuticals include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), tertiary butyl hydro- Quinone (TBHQ, Tertiary butyl hydroquinone). However, when they are administered to experimental animals at a high concentration, it is known that hepatic hypertrophy is induced or carcinogenic. In particular, butylated hydroxytoluene has been known to increase microsomal enzyme activity in the liver of experimental animals through various studies, and the safety of these phenolic synthetic antioxidants has been controversial. It is well known that the use is legally regulated (Brannen AL, J. Amer. Oil Chem. Soc., 52, pp 59-63, 1975; Ito N et al., J. Natl. Cancer Inst., 70, p343, 1983; KM et al., J. Food. Sci., 58, pp. 1-4, 1993). Therefore, many studies have been made in anticipation of developing a safe and economical natural antioxidant with high antioxidant effect (Larson RA, Phytochemistry, 27, pp969-978, 1988). Recently, studies on natural products have been actively carried out, and secondary metabolites contained in natural products have become a major concern as physiologically active substances. Particularly, studies on antioxidative substances have been actively carried out. Examples thereof include tocopherols, flavonoids, gossypol, sesamol, oryzanol, and vitamin C (Huson B et al., Food Chem., 19 , Pszcczola DE, Food Tech., 55, pp 51-59, 2001), pp. 537-541, 1987; Frankel, EN Food Chem., 57, p 51, 1996; Giese J, Food Technol., 5, pp 73-81, . Among them, tocopherol and L-ascorbic acid are preferred as natural antioxidants. Among them, tocopherol has high safety but low oxidation inhibition ability alone (Halliwell B et al., FASEB J ., 2, pp2867-2870, 1988).

한편, 퍼옥시좀(Peroxisome)은 이러한 대사기능 이상의 원인이 되는 세포 내 소기관 중 하나로서, 산소, 포도당, 지질 및 호르몬의 대사에 있어 중요한 역할을 하며, 세포 증식 및 분화의 조절, 염증 매개체들의 조절에도 폭 넓게 영향을 미친다. 또한 퍼옥시좀은 지질대사와 포도당대사를 통하여 인슐린 감수성뿐만 아니라 세포막과 비만세포의 형성에 영향을 주고, 산화적 스트레스에 영향을 주어 노화 및 종양 발생(tumorigenesis)에 있어서 중요한 역할을 한다. 퍼옥시좀 증식체 활성화 수용체(peroxisome proliferator-activated receptor : PPAR)는 리간드(ligand) 결합에 의해 유전자 발현을 조절하는 핵 수용체(nuclear receptors) 중 하나로서, 여러 가지 지방산이 내인성 리간드(endogenous ligand)로 작용한다. 현재 밝혀진 PPAR은 퍼옥시좀 증식체 활성화 수용체 알파(PPARα), 퍼옥시좀 증식체 활성화 수용체 베타(PPARβ/δ) 및 퍼옥시좀 증식체 활성화 수용체 감마(PPARγ)의 세 가지이다.On the other hand, peroxisome is one of the intracellular organelles responsible for the metabolic dysfunction. It plays an important role in metabolism of oxygen, glucose, lipid and hormone, and regulates cell proliferation and differentiation, regulation of inflammation mediators It also has a wide influence. In addition, peroxisome affects not only insulin sensitivity but also cell membrane and mast cell formation through lipid metabolism and glucose metabolism, and plays an important role in aging and tumorigenesis by affecting oxidative stress. The peroxisome proliferator-activated receptor (PPAR) is one of the nuclear receptors that regulate gene expression by ligand binding, and various fatty acids are endogenous ligands. . The PPARs currently identified are the peroxisome proliferator activated receptor alpha (PPARα), peroxisome proliferator activated receptor beta (PPARβ / δ), and peroxisome proliferator activated receptor gamma (PPARγ).

PPARα는 주로 혈관벽, 간, 심장, 근육, 신장 및 갈색 지방조직 등에서 발견되며, 작용제(agonist)인 피브레이트(fibrate)류와 함께 동맥경화증을 예방하거나 발병을 지연시키고 지방 산화 촉진을 통한 항비만 작용을 한다. PPARβ 또는 PPARδ는 피부, 뇌 또는 지방 조직에서 많이 발견되며, 콜레스테롤 역수송, 유수화(myelination) 및 상처 회복에 관여하고, 지방산 대사와 에너지 생체항상성(homeostasis)에 중요한 조절자로서 작용한다. PPARγ는 지방 조직에서 가장 많이 발견되고, 그 밖에 혈관 내피, 대식세포, 췌장의 β세포에서 발견되며, 지방세포의 분화를 조절하고 전신 지질 항상성에 결정적인 역할을 한다. PPARγ의 전체적 또는 부분적 활성화 화합물은 지방 세포의 분화를 억제하여 비만을 효과적으로 치료할 수 있으며, 부분적 활성화 화합물은 비만 치료뿐 아니라 고혈당증의 치료에 효과적이다. 이와 같이 PPAR의 작용에 의해 조절되는 각종 질환들의 예방 및 치료를 위해 PPAR의 활성을 보다 효과적으로 조절할 수 있는 새로운 화합물에 대한 필요성이 제기되고 있다.PPARα is found mainly in the blood vessel wall, liver, heart, muscle, kidney and brown adipose tissue. It acts as an agonist for the prevention of atherosclerosis or delaying onset of the disease, . PPARβ or PPARδ is found in many skin, brain or adipose tissues and is involved in cholesterol reverse transport, myelination and wound repair, and acts as an important regulator of fatty acid metabolism and energy homeostasis. PPARγ is found most commonly in adipose tissue, and is found in other endothelial, macrophage, and β-cells of the pancreas, and regulates adipocyte differentiation and plays a crucial role in systemic lipid homeostasis. The total or partial activation compound of PPARy can effectively treat obesity by inhibiting differentiation of adipocytes, and the partial activation compound is effective for the treatment of hyperglycemia as well as obesity treatment. Thus, there is a need for a novel compound capable of more effectively controlling the activity of PPAR for the prevention and treatment of various diseases controlled by the action of PPAR.

본 발명의 목적은 피부미백 활성을 갖는 신규 화합물을 제공하는 데에 있다.It is an object of the present invention to provide novel compounds having skin whitening activity.

또한, 본 발명의 다른 목적은 항산화 활성을 갖는 신규 화합물을 제공하는 데에 있다.Another object of the present invention is to provide a novel compound having an antioxidative activity.

또한, 본 발명의 또다른 목적은 PPAR 활성을 갖는 신규 화합물을 제공하는 데에 있다.Still another object of the present invention is to provide a novel compound having PPAR activity.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 이성질체를 제공한다:In order to achieve the above object, the present invention provides a compound represented by the formula (1) or an isomer thereof:

[화학식 1][Formula 1]

상기 식에서, R¹ 내지 R⁴는 각각 같거나 다를 수 있으며, H, OH, C1 내지 C4의 알콕시, 아세톡시 또는 할로겐 중 어느 하나이고, X는 N 또는 C-COOH 중 어느 하나이며, Y는 NH₂, C1 내지 C4의 알킬 또는 페닐 중 어느 하나일 수 있다.Wherein R ¹ to R ⁴ may be the same or different, respectively, H, OH, C 1 to C 4 alkoxy, acetoxy or halogen, X is N or C-COOH, and Y is NH ₂ , C1 to C4 alkyl or phenyl.

본 발명에 따른 화합물은 하기 화학식 2로 표시되는 화합물 또는 이의 이성질체일 수 있다:The compound according to the present invention may be a compound represented by Formula 2 or an isomer thereof:

[화학식 2](2)

상기 식에서, R¹ 내지 R⁴는 각각 같거나 다를 수 있으며, H, OH 또는 C1 내지 C4의 알콕시 중 어느 하나일 수 있다.In the above formula, R ¹ to R ⁴ may be the same or different, and may be any of H, OH, or C1 to C4 alkoxy.

보다 상세하게는, 상기 화합물은 (E)-2-(4-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxybenzylidene)hydrazinecarboxamide] (화합물 1); (E)-2-(3,4-디하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4-Dihydroxybenzylidene)hydrazinecarboxamide] (화합물 2); (E)-2-(2,4-디하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2,4-Dihydroxybenzylidene)hydrazinecarboxamide] (화합물 3); (E)-2-(4-하이드록시-3-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxy-3-methoxybenzylidene)hydrazinecarboxamide] (화합물 4); (E)-2-(3-에톡시-4-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3-Ethoxy-4-hydroxybenzylidene)hydrazinecarboxamide] (화합물 5); (E)-2-(3-하이드록시-4-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3-Hydroxy-4-methoxybenzylidene)hydrazinecarboxamide] (화합물 6); (E)-2-(4-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Methoxybenzylidene)hydrazinecarboxamide] (화합물 7); (E)-2-(3,4-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4-Dimethoxybenzylidene)hydrazinecarboxamide] (화합물 8); (E)-2-(2,4-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2,4-Dimethoxybenzylidene)hydrazinecarboxamide] (화합물 9); (E)-2-(2-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2-Hydroxybenzylidene)hydrazinecarboxamide] (화합물 10); (E)-2-(3,4,5-트리메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4,5-Trimethoxybenzylidene)hydrazinecarboxamide] (화합물 11); 및 (E)-2-(4-하이드록시-3,5-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxy-3,5-dimethoxybenzylidene)hydrazinecarboxamide] (화합물 12)로 이루어진 군에서 선택된 어느 하나일 수 있다.More specifically, the compound may be selected from ( E ) -2- (4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 1); ( E ) -2- (3,4-dihydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4-Dihydroxybenzylidene) hydrazinecarboxamide] (Compound 2); ( E ) -2- (2,4-dihydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (2,4-Dihydroxybenzylidene) hydrazinecarboxamide] (Compound 3); ( E ) -2- (4-hydroxy-3-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxy-3-methoxybenzylidene) hydrazinecarboxamide] (Compound 4); ( E ) -2- (3-ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (3-Ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide] (Compound 5); ( E ) -2- (3-hydroxy-4-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3-Hydroxy-4-methoxybenzylidene) hydrazinecarboxamide] (Compound 6); ( E ) -2- (4-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Methoxybenzylidene) hydrazinecarboxamide] (Compound 7); ( E ) -2- (3,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 8); ( E ) -2- (2,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (2,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 9); ( E ) -2- (2-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (2-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 10); ( E ) -2- (3,4,5-trimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4,5-Trimethoxybenzylidene) hydrazinecarboxamide] (Compound 11); And ( E ) -2- (4-hydroxy-3,5-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxy-3,5-dimethoxybenzylidene) hydrazinecarboxamide] (Compound 12) It may be any one selected from the group consisting of.

본 발명에 따른 화합물은 하기 화학식 3으로 표시되는 화합물 또는 이의 이성질체일 수 있다:The compound according to the present invention may be a compound represented by Formula 3 or an isomer thereof:

[화학식 3](3)

상기 식에서, R¹ 내지 R⁴는 각각 같거나 다를 수 있으며, H, OH, C1 내지 C4의 알콕시, 아세톡시 또는 할로겐 중 어느 하나일 수 있다.Wherein R ¹ to R ⁴ may be the same or different, and each may be any one of H, OH, C1 to C4 alkoxy, acetoxy or halogen.

보다 상세하게는, 상기 화합물은 (Z)-2-아세트아미도-3-(4-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxyphenyl)acrylic acid] (화합물 13); (Z)-2-아세트아미도-3-(3,4-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4-dihydroxyphenyl)acrylic acid] (화합물 14); (Z)-2-아세트아미도-3-(2,4-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(2,4-dihydroxyphenyl)acrylic acid] (화합물 15); (Z)-2-아세트아미도-3-(4-하이드록시-3-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxy-3-methoxyphenyl)acrylic acid] (화합물 16); (Z)-2-아세트아미도-3-(3-에톡시-4-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3-ethoxy-4-hydroxyphenyl)acrylic acid] (화합물 17); (Z)-2-아세트아미도-3-(3-하이드록시-4-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3-hydroxy-4-methoxyphenyl)acrylic acid] (화합물 18); (Z)-2-아세트아미도-3-(4-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-methoxyphenyl)acrylic acid] (화합물 19); (Z)-2-아세트아미도-3-(3,4-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4-dimethoxyphenyl)acrylic acid] (화합물 20); (Z)-2-아세트아미도-3-(3,5-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,5-dihydroxyphenyl)acrylic acid] (화합물 21); (Z)-2-아세트아미도-3-(2,4-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(2,4-dimethoxyphenyl)acrylic acid] (화합물 22); (Z)-2-아세트아미도-3-(2-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(2-hydroxyphenyl)acrylic acid] (화합물 23); (Z)-2-아세트아미도-3-(3,4,5-트리메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4,5-trimethoxyphenyl)acrylic acid] (화합물 24); (Z)-2-아세트아미도-3-(4-하이드록시-3,5-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid] (화합물 25); (E)-2-아세트아미도-3-(4-아세톡시-3-브로모페닐)아크릴산 [(E)-2-Acetamido-3-(4-acetoxy-3-bromophenyl)acrylic acid] (화합물 26); 및 (Z)-2-아세트아미도-3-(4-아세톡시-3-브로모페닐)아크릴산 [(Z)-2-Acetamido-3-(4-acetoxy-3-bromophenyl)acrylic acid] (화합물 27)으로 이루어진 군에서 선택된 어느 하나일 수 있다.More specifically, the compound is ( Z ) -2-acetamido-3- (4-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxyphenyl) acrylic acid] (Compound 13 ); ( Z ) -2-acetamido-3- (3,4-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4-dihydroxyphenyl) acrylic acid] (Compound 14); ( Z ) -2-acetamido-3- (2,4-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2,4-dihydroxyphenyl) acrylic acid] (Compound 15); ( Z ) -2-acetamido-3- (4-hydroxy-3-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxy-3-methoxyphenyl) acrylic acid] (compound 16); ( Z ) -2-acetamido-3- (3-ethoxy-4-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3-ethoxy-4-hydroxyphenyl) acrylic acid] (compound 17); ( Z ) -2-acetamido-3- (3-hydroxy-4-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3-hydroxy-4-methoxyphenyl) acrylic acid] (compound 18); ( Z ) -2-acetamido-3- (4-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-methoxyphenyl) acrylic acid] (Compound 19); ( Z ) -2-acetamido-3- (3,4-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4-dimethoxyphenyl) acrylic acid] (Compound 20); ( Z ) -2-acetamido-3- (3,5-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,5-dihydroxyphenyl) acrylic acid] (Compound 21); ( Z ) -2-acetamido-3- (2,4-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2,4-dimethoxyphenyl) acrylic acid] (Compound 22); ( Z ) -2-acetamido-3- (2-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2-hydroxyphenyl) acrylic acid] (Compound 23); ( Z ) -2-acetamido-3- (3,4,5-trimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4,5-trimethoxyphenyl) acrylic acid] (compound 24); ( Z ) -2-acetamido-3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid] (compound 25); ( E ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( E ) -2-Acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid] (Compound 26); And ( Z ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid] ( Compound 27) may be any one selected from the group consisting of.

본 발명에 따른 화합물은 하기 화학식 4로 표시되는 화합물 또는 이의 이성질체일 수 있다:The compound according to the present invention may be a compound represented by Formula 4 or an isomer thereof:

[화학식 4][Chemical Formula 4]

상기 식에서, R은 OH 또는 C1 내지 C4의 알콕시 중 어느 하나일 수 있다.Wherein R may be either OH or alkoxy of C1 to C4.

보다 상세하게는, 상기 화합물은 (Z)-2-벤즈아미도-3-(4-하이드록시페닐)아크릴산 [(Z)-2-Benzamido-3-(4-hydroxyphenyl)acrylic acid]; 또는 (Z)-2-벤즈아미도-3-(4-메톡시페닐)아크릴산 [(Z)-2-Benzamido-3-(4-methoxyphenyl)acrylic acid]에서 선택된 어느 하나일 수 있다.More specifically, the compound may be selected from ( Z ) -2-benzamido-3- (4-hydroxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-hydroxyphenyl) acrylic acid]; Or ( Z ) -2-benzamido-3- (4-methoxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-methoxyphenyl) acrylic acid].

본 발명에 있어서, 상기 이성질체는 모든 입체이성질체, 예를 들어 다양한 R 및 Z 치환기 상의 비대칭 탄소로 인해 존재할 수 있는 것(거울상 이성질체(이는 비대칭 탄소가 존재하지 않는 경우에도 존재할 수 있음) 및 부분입체이성질체를 포함)이 본 발명의 범위 내에서 고려된다. 본 발명의 화합물의 각각의 입체이성질체는 예를 들어, 실질적으로 다른 이성질체가 없거나, 또는 예를 들어 라세미체로 또는 모든 입체이성질체 또는 선택된 입체이성질체와 혼합될 수 있다. In the present invention, the isomers can exist due to asymmetric carbons on all stereoisomers, for example, various R and Z substituents (enantiomers (which may be present even when no asymmetric carbons are present) and diastereomers). Are considered within the scope of the present invention. Each stereoisomer of a compound of the invention can be, for example, substantially free of other isomers, or mixed, for example, with racemates or with all stereoisomers or selected stereoisomers.

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 약학조성물 또는 화장료조성물일 수 있다.The present invention also provides a skin whitening composition comprising the above-mentioned compound as an active ingredient. The composition may be a pharmaceutical composition or a cosmetic composition.

또한, 본 발명은 상기 화합물을 유효성분으로 함유하는 산화 관련 질환의 예방 또는 치료용 항산화용 조성물을 제공한다. 상기 조성물은 약학조성물 또는 건강식품일 수 있다.The present invention also provides a composition for antioxidation for the prevention or treatment of an oxidation-related disease containing the above-mentioned compound as an active ingredient. The composition may be a pharmaceutical composition or a health food.

상기 산화 관련 질환은 피부노화, 피부색소침착증, 주름, 건선 또 습진 중에서 선택된 어느 하나일 수 있다. The oxidation-related disease may be any one selected from skin aging, skin pigmentation, wrinkles, psoriasis, and eczema.

또한, 본 발명은 상기 화합물을 유효성분으로 함유하며, 퍼옥시좀 증식체 활성화 수용체(Peroxisome Proliferator-activated Receptor: PPAR)의 작용에 의해 조절되는 질환의 예방 또는 치료용 조성물을 제공한다. 상기 조성물은 약학조성물 또는 건강식품일 수 있다. In addition, the present invention provides a composition for preventing or treating diseases, which contains the compound as an active ingredient and is regulated by the action of a peroxisome proliferator-activated receptor (PPAR). The composition may be a pharmaceutical composition or a health food.

상기 PPAR은 퍼옥시좀 증식체 활성화 수용체 알파(PPARα) 또는 퍼옥시좀 증식체 활성화 수용체 감마(PPARγ)일 수 있으며, 상기 질환은 비만, 대사성 질환 또는 심혈관계 질환 중에서 선택된 어느 하나일 수 있다.The PPAR may be peroxisome proliferator activated receptor alpha (PPARa) or peroxisome proliferator activated receptor gamma (PPAR gamma), and the disease may be selected from obesity, metabolic disease or cardiovascular disease.

상기 대사성 질환은 고지질혈증, 당뇨병증, 고인슐린혈증, 고요산혈증, 고콜레스테롤혈증, 고중성지방혈증, 대사증후군(Syndrome X) 및 내피기능장애 중에서 선택된 어느 하나일 수 있으며, 상기 심혈관계 질환은 고혈압, 응집전 상태(Precoagulant state), 이상 지질혈증 및 아테롬성 경화증성 질환 중에서 선택된 어느 하나일 수 있다.The metabolic diseases may be any one selected from hyperlipidemia, diabetes mellitus, hyperinsulinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Syndrome X and endothelial dysfunction, Hypertension, precoagulant state, dyslipidemia, and atherosclerotic disease.

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 100mg/kg으로, 바람직하게는 0.01 내지 10mg/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 it is 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / Lt; / RTI >

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 is a 50% lethal amount (LC ₅₀ ) is 2 g / kg or more as the stability is secured, it 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 건강식품은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강식품은 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 예를들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다. The health food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food may be used together with food or food additives other than the compound according to the present invention as an active ingredient, And the like. 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 건강식품에 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 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 the purpose of health control, Since the active ingredient has no problem in terms of safety, it can be used in an amount exceeding the above range.

상기 건강식품의 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 type of the health food, and examples thereof include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, Drinks, alcoholic beverages and vitamin complexes.

본 발명에 따른 화합물들은 티로시나아제를 억제하는 피부미백 활성을 지니므로 피부미백용 약학조성물 또는 화장품에 유용하게 사용될 수 있고, 항산화 활성을 지니므로 피부노화 등의 예방 또는 치료에 유용하게 사용될 수 있으며, 또한 PPAR 활성 특히, PPARα 및 PPARγ 활성을 지니므로 비만, 대사성 질환 또는 심혈관계 질환을 예방하고 치료하는 데에 유용한 약학조성물 또는 건강식품으로 사용될 수 있다.Since the compounds according to the present invention have a skin whitening activity inhibiting tyrosinase, they can be usefully used in pharmaceutical compositions or cosmetics for skin whitening, and have antioxidative activity, so they can be effectively used for preventing or treating skin aging and the like , And PPAR < / RTI > activity, in particular PPARa and PPARgamma, and thus can be used as a pharmaceutical composition or health food useful in the prevention and treatment of obesity, metabolic diseases or cardiovascular diseases.

도 1은 본 발명에 따른 화합물의 항산화 활성을 나타낸 것이고,
도 2는 본 발명에 따른 화합물의 티로시네이즈 억제 활성을 나타낸 것이고,
도 3은 본 발명에 따른 화합물의 PPARα 증진 활성을 나타낸 것이고,
도 4는 본 발명에 따른 화합물의 PPARγ 증진 활성을 나타낸 것이다.Figure 1 shows the antioxidant activity of the compounds according to the invention,
Figure 2 shows the tyrosinase inhibitory activity of the compounds according to the invention,
Figure 3 shows the PPAR [alpha] promoting activity of the compounds according to the invention,
Figure 4 shows the PPARgamma enhancing activity of the compounds according to the invention.

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.

<< 실시예Example 1> 화합물 1 내지 12 합성 1> Compound 1 to 12 Synthesis

하기 표 1은 (E)-2-(치환된 벤질리덴)하이드라진 카르복사마이드 유도체 [(E)-2-(substituted benzylidene)hydrazinecarboxamide analog] 화합물 1 - 12의 치환 패턴을 설명하기 위한 것이다.Table 1 below illustrates the substitution patterns of (E) -2- (substituted benzylidene) hydrazine carboxamide derivatives [(E) -2- (substituted benzylidene) hydrazinecarboxamide analog] compounds 1-12.

화합물compound R¹ R ¹ R² R ² R³ R ³ R⁴ R ⁴ 1One HH HH OHOH HH 22 HH OHOH OHOH HH 33 OHOH HH OHOH HH 44 HH OMeOMe OHOH HH 55 HH OEtOEt OHOH HH 66 HH OHOH OMeOMe HH 77 HH HH OMeOMe HH 88 HH OMeOMe OMeOMe HH 99 OMeOMe HH OMeOMe HH 1010 OHOH HH HH HH 1111 HH OMeOMe OMeOMe OMeOMe 1212 HH OMeOMe OHOH OMeOMe

OMe는 메톡시기, OEt는 에톡시기를 나타냄.OMe stands for methoxy group and OEt stands for ethoxy group.

(E)-2-(치환된 벤질리덴)하이드라진 카르복사마이드 유도체 [(E)-2-(substituted benzylidene)hydrazinecarboxamide analog] 화합물 1 - 12는 다음과 같이 합성하였다. 즉, 물(1 mL)에 용해된 세미카르바자이드 염산염(semicarbazide hydrochloride; 202 - 301 mg, 1.1 eq.)의 교반 용액에 중탄산나트륨 수용액을 첨가하여 pH를 3 내지 4로 조절하였다. 에탄올(2 mL)에 용해된 치환된 벤즈알데히드 (300 mg, 1.53 - 2.46 mmol, 1.0 eq.) 용액을 몇방울 첨가한 후, 반응 혼합물을 상온에서 1시간 동안 교반하고 1시간 동안 환류시켰다. 이렇게 생성된 침전물을 여과하고 물 및 에틸 아세테이트 또는 메틸렌 클로라이드로 세척하여 화합물 1 내지 12를 얻었다 (36.0 - 94.8% 수율).( E ) -2- (substituted benzylidene) hydrazine carboxamide derivative [(E) -2- (substituted benzylidene) hydrazinecarboxamide analog] Compounds 1-12 were synthesized as follows. That is, the pH was adjusted to 3 to 4 by adding an aqueous sodium bicarbonate solution to a stirred solution of semicarbazide hydrochloride (202-301 mg, 1.1 eq.) Dissolved in water (1 mL). After several drops of a substituted benzaldehyde (300 mg, 1.53-2.46 mmol, 1.0 eq.) Solution dissolved in ethanol (2 mL), the reaction mixture was stirred at room temperature for 1 hour and refluxed for 1 hour. The precipitate thus produced was filtered and washed with water and ethyl acetate or methylene chloride to give compounds 1 to 12 (36.0-94.8% yield).

<실시예 1-1> (E)-2-(4-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxybenzylidene)hydrazinecarboxamide] (화합물 1) 합성Example 1-1 Synthesis of ( E ) -2- (4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 1)

흰색 고체; 반응 시간, 2 h; 수율, 92.6%; ¹H NMR (500 MHz, DMSO-d₆) δ 10.01 (s, 1 H), 9.72 (s, 1 H), 7.72 (s, 1 H), 7.51 (d, 2 H, J = 8.5 Hz), 6.75 (d, 2 H, J = 8.5 Hz), 6.36 (br s, 2 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 159.1, 157.6, 140.3, 128.8, 126.5, 116.1;White solid; Reaction time, 2 h; Yield, 92.6%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.01 (s, 1 H), 9.72 (s, 1 H), 7.72 (s, 1 H), 7.51 (d, 2 H, J = 8.5 Hz), 6.75 (d, 2H, J = 8.5 Hz), 6.36 (br s, 2H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 159.1, 157.6, 140.3, 128.8, 126.5, 116.1;

<실시예 1-2> (E)-2-(3,4-디하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4-Dihydroxybenzylidene)hydrazinecarboxamide] (화합물 2) 합성<Example 1-2> (E) -2- (3,4- dihydroxy-benzylidene) hydrazine carboxamide [(E) -2- (3,4- Dihydroxybenzylidene) hydrazinecarboxamide] ( Compound 2) Synthesis

흰색 고체; 반응 시간, 2 h; 수율, 89.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1 H), 9.26 (s, 1 H), 8.92 (s, 1 H), 7.62 (s, 1 H), 7.05 (d, 1 H, J = 1.6 Hz), 6.88 (dd, 1 H, J = 2.0, 8.0 Hz), 6.68 (d, 1 H, J = 8.0 Hz), 6.26 (s, 2 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.5, 147.6, 146.1, 140.8, 126.9, 119.7, 116.1, 113.8;White solid; Reaction time, 2 h; Yield, 89.9%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1 H), 9.26 (s, 1 H), 8.92 (s, 1 H), 7.62 (s, 1 H), 7.05 (d, 1 H, J = 1.6 Hz), 6.88 (dd, 1 H, J = 2.0, 8.0 Hz), 6.68 (d, 1 H, J = 8.0 Hz), 6.26 (s, 2 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.5, 147.6, 146.1, 140.8, 126.9, 119.7, 116.1, 113.8;

<실시예 1-3> (E)-2-(2,4-디하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2,4-Dihydroxybenzylidene)hydrazinecarboxamide] (화합물 3) 합성<Example 1-3> (E) -2- (2,4- dihydroxy-benzylidene) hydrazine carboxamide [(E) -2- (2,4- Dihydroxybenzylidene) hydrazinecarboxamide] ( Compound 3) Synthesis

흰색 고체; 반응 시간, 2 h; 수율, 91.2%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 2 H), 9.60 (s, 1 H), 7.97 (s, 1 H), 7.45 (d, 1 H, J = 8.4 Hz), 6.24 - 6.20 (m, 4 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 160.3, 158.0, 157.3, 139.4, 128.9, 112.8, 108.1, 103.0;White solid; Reaction time, 2 h; Yield, 91.2%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.91 (s, 2 H), 9.60 (s, 1 H), 7.97 (s, 1 H), 7.45 (d, 1 H, J = 8.4 Hz), 6.24-6.20 (m, 4H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 160.3, 158.0, 157.3, 139.4, 128.9, 112.8, 108.1, 103.0;

<실시예 1-4> (E)-2-(4-하이드록시-3-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxy-3-methoxybenzylidene)hydrazinecarboxamide] (화합물 4) 합성<Example 1-4> (E) -2- (4- hydroxy-3-methoxy-benzylidene) hydrazine carboxamide [(E) -2- (4- Hydroxy-3-methoxybenzylidene) hydrazinecarboxamide] ( compound 4) synthetic

흰색 고체; 반응 시간, 2 h; 수율, 93%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1 H), 9.26 (s, 1 H), 7.67 (s, 1 H), 7.33 (s, 1 H), 6.93 (d, 1 H, J = 8.0 Hz), 6.71 (d, 1 H, J = 8.0 Hz), 6.41 (br s, 2 H), 3.77 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.6, 148.6, 148.6, 140.4, 127.0, 121.7, 115.8, 109.6, 56.3;White solid; Reaction time, 2 h; Yield, 93%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.99 (s, 1 H), 9.26 (s, 1 H), 7.67 (s, 1 H), 7.33 (s, 1 H), 6.93 (d, 1 H, J = 8.0 Hz), 6.71 (d, 1 H, J = 8.0 Hz), 6.41 (br s, 2 H), 3.77 (s, 3 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.6, 148.6, 148.6, 140.4, 127.0, 121.7, 115.8, 109.6, 56.3;

<실시예 1-5> (E)-2-(3-에톡시-4-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3-Ethoxy-4-hydroxybenzylidene)hydrazinecarboxamide] (화합물 5) 합성Example 1-5 ( E ) -2- (3-ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (3-Ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide] (Compound 5) synthetic

흰색 고체; 반응 시간, 2 h; 수율, 82.7%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1 H), 9.17 (s, 1 H), 7.66 (s, 1 H), 7.31 (d, 1 H, J = 2.0 Hz), 6.92 (dd, 1 H, J = 2.0, 8.0 Hz), 6.72 (d, 1 H, J = 8.0 Hz), 6.40 (br s, 2 H), 4.03 (q, 2 H, J = 6.8 Hz), 1.29 (t, 3 H, J = 6.8 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.6, 148.9, 147.8, 140.5, 127.0, 121.7, 115.9, 110.9, 64.5, 15.4;White solid; Reaction time, 2 h; Yield, 82.7%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1 H), 9.17 (s, 1 H), 7.66 (s, 1 H), 7.31 (d, 1 H, J = 2.0 Hz), 6.92 (dd, 1 H, J = 2.0, 8.0 Hz), 6.72 (d, 1 H, J = 8.0 Hz), 6.40 (br s, 2 H), 4.03 (q, 2 H, J = 6.8 Hz), 1.29 (t, 3H, J = 6.8 Hz); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.6, 148.9, 147.8, 140.5, 127.0, 121.7, 115.9, 110.9, 64.5, 15.4;

<실시예 1-6> (E)-2-(3-하이드록시-4-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3-Hydroxy-4-methoxybenzylidene)hydrazinecarboxamide] (화합물 6) 합성<Example 1-6> (E) -2- (3- hydroxy-4-methoxy-benzylidene) hydrazine carboxamide [(E) -2- (3- Hydroxy-4-methoxybenzylidene) hydrazinecarboxamide] ( compound 6) synthetic

흰색 고체; 반응 시간, 2 h; 수율, 87.1%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1 H), 8.98 (s, 1 H), 7.66 (s, 1 H), 7.13 (s, 1 H), 6.98 (d, 1 H, J = 8.4 Hz), 6.87 (d, 1 H, J = 8.4 Hz), 6.31 (s, 2 H), 3.75 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.4, 149.5, 147.3, 140.4, 128.4, 119.7, 113.3, 112.4, 56.3;White solid; Reaction time, 2 h; Yield, 87.1%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1 H), 8.98 (s, 1 H), 7.66 (s, 1 H), 7.13 (s, 1 H), 6.98 (d, 1 H, J = 8.4 Hz), 6.87 (d, 1 H, J = 8.4 Hz), 6.31 (s, 2H), 3.75 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.4, 149.5, 147.3, 140.4, 128.4, 119.7, 113.3, 112.4, 56.3;

<실시예 1-7> (E)-2-(4-메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Methoxybenzylidene)hydrazinecarboxamide] (화합물 7) 합성Example 1-7 Synthesis of ( E ) -2- (4-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Methoxybenzylidene) hydrazinecarboxamide] (Compound 7)

흰색 고체; 반응 시간, 2 h; 수율, 87.3%; ¹H NMR (500 MHz, DMSO-d₆) δ 10.09 (s, 1 H), 7.77 (s, 1 H), 7.63 (d, 2 H, J = 8.5 Hz), 6.92 (d, 2 H, J = 8.5 Hz), 6.41 (br s , 2 H), 3.76 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 160.7, 157.5, 139.8, 128.7, 128.1, 114.7, 55.9;White solid; Reaction time, 2 h; Yield, 87.3%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.09 (s, 1 H), 7.77 (s, 1 H), 7.63 (d, 2 H, J = 8.5 Hz), 6.92 (d, 2 H, J = 8.5 Hz), 6.41 (br s, 2H), 3.76 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 160.7, 157.5, 139.8, 128.7, 128.1, 114.7, 55.9;

<실시예 1-8> (E)-2-(3,4-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4-Dimethoxybenzylidene)hydrazinecarboxamide] (화합물 8) 합성Example 1-8 Synthesis of ( E ) -2- (3,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 8)

흰색 고체; 반응 시간, 2 h; 수율, 69.8%; ¹H NMR (500 MHz, DMSO-d₆) δ 10.09 (s, 1 H), 7.75 (s, 1 H), 7.42 (d, 1 H, J = 1.5 Hz), 7.07 (dd, 1 H, J = 1.5, 8.0 Hz), 6.93 (d, 1 H, J = 8.0 Hz), 6.49 (br s, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.5, 150.5, 149.7, 140.1, 128.3, 121.5, 111.9, 108.9, 56.2, 56.1;White solid; Reaction time, 2 h; Yield 69.8%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.09 (s, 1 H), 7.75 (s, 1 H), 7.42 (d, 1 H, J = 1.5 Hz), 7.07 (dd, 1 H, J = 1.5, 8.0 Hz), 6.93 (d, 1H, J = 8.0 Hz), 6.49 (br s, 2H), 3.80 (s, 3H), 3.77 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.5, 150.5, 149.7, 140.1, 128.3, 121.5, 111.9, 108.9, 56.2, 56.1;

<실시예 1-9> (E)-2-(2,4-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2,4-Dimethoxybenzylidene)hydrazinecarboxamide] (화합물 9) 합성Example 1-9 Synthesis of ( E ) -2- (2,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (2,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 9)

흰색 고체; 반응 시간, 2 h; 수율, 84.3%; ¹H NMR (500 MHz, DMSO-d₆) δ 10.05 (s, 1 H), 8.08 (s, 1 H), 7.89 (d, 1 H, J = 8.5 Hz), 6.58 (s, 1 H), 6.54 (d, 1 H, J = 8.5 Hz), 6.35 (br s, 2 H), 3.81 (s, 3 H), 3.80 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 162.2, 159.0, 157.5, 135.6, 127.3, 116.3, 106.8, 98.7, 56.3, 56.0;White solid; Reaction time, 2 h; Yield, 84.3%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.05 (s, 1 H), 8.08 (s, 1 H), 7.89 (d, 1 H, J = 8.5 Hz), 6.58 (s, 1 H), 6.54 (d, 1H, J = 8.5 Hz), 6.35 (br s, 2H), 3.81 (s, 3H), 3.80 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 162.2, 159.0, 157.5, 135.6, 127.3, 116.3, 106.8, 98.7, 56.3, 56.0;

<실시예 1-10> (E)-2-(2-하이드록시벤질리덴)하이드라진카르복사마이드 [(E)-2-(2-Hydroxybenzylidene)hydrazinecarboxamide] (화합물 10) 합성Example 1-10 Synthesis of ( E ) -2- (2-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (2-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 10)

흰색 고체; 반응 시간, 2 h; 수율, 94.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1 H), 9.92 (s, 1 H), 8.09 (s, 1 H), 7.71 (dd, 1 H, J = 1.6, 7.6 Hz), 7.12 (td, 1 H, J = 1.6, 8.0 Hz), 6.81 (d, 1 H, J = 8.0 Hz), 6.77 (t, 1 H, J = 7.6 Hz), 6.36 (br s, 2 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.2, 156.5, 138.0, 130.8, 127.3, 121.3, 119.9, 116.6;White solid; Reaction time, 2 h; Yield, 94.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1 H), 9.92 (s, 1 H), 8.09 (s, 1 H), 7.71 (dd, 1 H, J = 1.6, 7.6 Hz ), 7.12 (td, 1 H, J = 1.6, 8.0 Hz), 6.81 (d, 1 H, J = 8.0 Hz), 6.77 (t, 1 H, J = 7.6 Hz), 6.36 (br s, 2 H ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.2, 156.5, 138.0, 130.8, 127.3, 121.3, 119.9, 116.6;

<실시예 1-11> (E)-2-(3,4,5-트리메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(3,4,5-Trimethoxybenzylidene)hydrazinecarboxamide] (화합물 11) 합성Example 1-11 ( E ) -2- (3,4,5-trimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4,5-Trimethoxybenzylidene) hydrazinecarboxamide] (Compound 11) synthetic

흰색 고체; 반응 시간, 2 h; 수율, 74.2%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1 H), 7.70 (s, 1 H), 6.97 (s, 2 H), 6.53 (s, 2 H), 3.77 (s, 6 H), 3.63 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.5, 153.8, 139.8, 138.9, 131.0, 104.5, 60.7, 56.6;White solid; Reaction time, 2 h; Yield 74.2%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.21 (s, 1 H), 7.70 (s, 1 H), 6.97 (s, 2 H), 6.53 (s, 2 H), 3.77 (s, 6 H), 3.63 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.5, 153.8, 139.8, 138.9, 131.0, 104.5, 60.7, 56.6;

<실시예 1-12> (E)-2-(4-하이드록시-3,5-디메톡시벤질리덴)하이드라진카르복사마이드 [(E)-2-(4-Hydroxy-3,5-dimethoxybenzylidene)hydrazinecarboxamide] (화합물 12) 합성<Example 1-12> (E) -2- (4- hydroxy-3,5-dimethoxy-benzylidene) hydrazine carboxamide [(E) -2- (4- Hydroxy-3,5-dimethoxybenzylidene) hydrazinecarboxamide] (Compound 12) Synthesis

흰색 고체; 반응 시간, 2 h; 수율, 36%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1 H), 8.62 (s, 1 H), 7.66 (s, 1 H), 6.93 (s, 2 H), 6.45 (br s, 2 H), 3.75 (s, 6 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 157.6, 148.7, 140.5, 137.5, 125.8, 104.8, 56.7.White solid; Reaction time, 2 h; Yield, 36%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1 H), 8.62 (s, 1 H), 7.66 (s, 1 H), 6.93 (s, 2 H), 6.45 (br s, 2 H), 3.75 (s, 6 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 157.6, 148.7, 140.5, 137.5, 125.8, 104.8, 56.7.

<실시예 2> 화합물 13a 내지 26a 합성Example 2 Synthesis of Compounds 13a to 26a

하기 표 2는 (Z)-4-(치환된 벤질리덴)-2-메틸옥사졸-5(4H)-온 유사체[(Z)-4-(substituted benzylidene)-2-methyloxazol-5(4H)-one analog] 화합물 13a - 26a의 치환 패턴을 설명하기 위한 것이다.Table 2 below shows (Z) -4- (substituted benzylidene) -2-methyloxazol-5 (4H) -one analog [(Z) -4- (substituted benzylidene) -2-methyloxazol-5 (4H) -one analog] To explain the substitution pattern of the compounds 13a to 26a.

화합물compound R¹ R ¹ R² R ² R³ R ³ R⁴ R ⁴ 13a13a HH HH OAcOac HH 14a14a HH OAcOac OAcOac HH 15a15a OHOH HH OAcOac HH 16a16a HH OMeOMe OAcOac HH 17a17a HH OEtOEt OAcOac HH 18a18a HH OAcOac OMeOMe HH 19a19a HH HH OMeOMe HH 20a20a HH OMeOMe OMeOMe HH 21a21a HH OAcOac HH OAcOac 22a22a OMeOMe HH OMeOMe HH 23a23a OHOH HH HH HH 24a24a HH OMeOMe OMeOMe OMeOMe 25a25a HH OMeOMe OAcOac OMeOMe 26a26a HH BrBr OAcOac HH

OMe는 메톡시기, OEt는 에톡시기, OAc는 아세톡시기를 나타냄.OMe represents a methoxy group, OEt represents an ethoxy group, and OAc represents an acetoxy group.

(Z)-4-(치환된 벤질리덴)-2-메틸옥사졸-5(4H)-온 유사체[(Z)-4-(substituted benzylidene)-2-methyloxazol-5(4H)-one analog] 화합물 13a - 26a는 다음과 같이 합성하였다. 즉, 아세트산 무수물(1.5 eq. + 추가적 1.0 eq. × 페놀성 하이드록시기의 개수)에 용해된 벤즈알데히드(300 mg), N-아세틸글리신(1.1 eq.) 및 아세트산 나트륨(0.5 eq. + 추가적 0.5 eq. × 페놀성 하이드록시기의 개수)의 혼합물을 1 내지 7 시간 동안 환류시켰다. 냉각 후, 플라스크를 0℃로 유지하고 소량의 메틸 알콜과 물 또는 메틸 알콜 없이 물을 첨가하였다. 반응 혼합물을 0℃로 유지하고 생성된 침전물을 여과하며, 물로 세척하여 고상 생성물을 얻었다. (Z) -4- (substituted benzylidene) -2-methyloxazol-5 (4H) -one analog [(Z) -4- (substituted benzylidene) -2-methyloxazol-5 (4H) -one analog] Compounds 13a-26a were synthesized as follows. That is, benzaldehyde (300 mg), N-acetylglycine (1.1 eq.) And sodium acetate (0.5 eq. + Additional 0.5) dissolved in acetic anhydride (1.5 eq. + Additional 1.0 eq. X number of phenolic hydroxy groups). eq. x number of phenolic hydroxy groups) was refluxed for 1-7 h. After cooling, the flask was kept at 0 ° C. and water was added without a small amount of methyl alcohol and water or methyl alcohol. The reaction mixture was kept at 0 ° C. and the resulting precipitate was filtered and washed with water to give a solid product.

14a, 17a, 22a 및 25a의 화합물의 경우에는 반응 혼합물을 0℃로 유지시켜도 침전물이 생성되지 않았다. 에틸 아세테이트 또는 메틸렌 클로라이드와 물 간의 분배, 얻어진 유기층의 건조 및 증발 후, 14a의 경우 헥산과 에틸 아세테이트 (2:1)를, 17a 및 25a의 경우 메틸렌 클로라이드, 22a의 경우 헥산과 메틸렌 클로라이드 (1:4)를 이용하여 실리카겔 컬럼 크로마토그래피를 통해 정제하여 고상의 화합물 14a, 17a, 22a 및 25a를 얻었다.For the compounds of 14a, 17a, 22a and 25a, no precipitate was formed even when the reaction mixture was kept at 0 ° C. After partitioning between ethyl acetate or methylene chloride and water, drying and evaporation of the resulting organic layer, hexane and ethyl acetate (2: 1) for 14a, methylene chloride for 17a and 25a, hexane and methylene chloride for 22a (1: Purification via silica gel column chromatography using 4) afforded solid compounds 14a, 17a, 22a and 25a.

<실시예 2-1> (Z)-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-4-((2-Methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 13a) 합성Example 2-1 ( Z ) -4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -4-((2-Methyl- 5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 13a) Synthesis

반응 시간, 1 h; 수율, 43%; ¹H NMR (400 MHz, CD₃OD) δ 8.15 (d, 2 H, J = 8.8 Hz), 7.17 (d, 2 H, J = 9.2 Hz), 7.10 (s, 1 H), 2.36 (s, 3 H), 2.27 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 169.6, 167.8, 167.2, 152.9, 133.3, 131.2, 130.9, 129.3, 122.0, 19.7, 14.2;Reaction time, 1 h; Yield, 43%; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.15 (d, 2 H, J = 8.8 Hz), 7.17 (d, 2 H, J = 9.2 Hz), 7.10 (s, 1 H), 2.36 (s, 3 H), 2.27 (s, 3H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 169.6, 167.8, 167.2, 152.9, 133.3, 131.2, 130.9, 129.3, 122.0, 19.7, 14.2;

<실시예 2-2> (Z)-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)-1,2-페닐렌 디아세테이트 [(Z)-4-((2-Methyl-5-oxooxazol-4(5H)-ylidene)methyl)-1,2-phenylene diacetate] (화합물 14a) 합성Example 2-2 ( Z ) -4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) -1,2-phenylene diacetate [( Z ) -4 Synthesis of-((2-Methyl-5-oxooxazol-4 (5H) -ylidene) methyl) -1,2-phenylene diacetate] (Compound 14a)

반응 시간, 3 h; 수율, 49.7%; ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, 1 H, J = 2.0 Hz), 7.77 (dd, 1 H, J = 2.0, 8.4 Hz), 7.18 (d, 1 H, J = 8.8 Hz), 6.95 (s, 1 H), 2.29 (s, 3 H), 2.24 (s, 3 H), 2.22 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.2, 168.0, 167.6, 167.0, 144.4, 142.5, 133.4, 132.0, 130.9, 129.2, 126.8, 124.0, 20.8, 20.7, 15.8;Reaction time, 3 h; Yield, 49.7%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, 1 H, J = 2.0 Hz), 7.77 (dd, 1 H, J = 2.0, 8.4 Hz), 7.18 (d, 1 H, J = 8.8 Hz ), 6.95 (s, 1H), 2.29 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.2, 168.0, 167.6, 167.0, 144.4, 142.5, 133.4, 132.0, 130.9, 129.2, 126.8, 124.0, 20.8, 20.7, 15.8;

<실시예 2-3> (Z)-3-하이드록시-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-3-Hydroxy-4-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 15a) 합성Example 2-3 ( Z ) -3-hydroxy-4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -3-Hydroxy Synthesis of 4-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 15a)

반응 시간, 3 h; 수율, 33.9%; ¹H NMR (500 MHz, DMSO-d₆) δ 9.74 (s, 1 H), 8.60 (s, 1 H), 7.30 (d, 1 H, J = 8.5 Hz), 7.25 (d, 1 H, J = 2.0 Hz), 7.12 (dd, 1 H, J = 2.0, 8.5 Hz), 2.29 (s, 3 H), 2.15 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.9, 169.6, 158.0, 151.6, 150.6, 129.2, 124.8, 123.8, 119.7, 118.1, 110.4, 24.6, 21.5;Reaction time, 3 h; Yield, 33.9%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.74 (s, 1 H), 8.60 (s, 1 H), 7.30 (d, 1 H, J = 8.5 Hz), 7.25 (d, 1 H, J = 2.0 Hz), 7.12 (dd, 1H, J = 2.0, 8.5 Hz), 2.29 (s, 3H), 2.15 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 170.9, 169.6, 158.0, 151.6, 150.6, 129.2, 124.8, 123.8, 119.7, 118.1, 110.4, 24.6, 21.5;

<실시예 2-4> (Z)-2-메톡시-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-2-Methoxy-4-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 16a) 합성Example 2-4 ( Z ) -2-methoxy-4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -2-Methoxy Synthesis of 4-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 16a)

반응 시간, 3 h; 수율, 48.9%; ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, 1 H, J = 1.6 Hz), 7.52 (dd, 1 H, J = 1.6, 8.0 Hz), 7.07 (d, 1 H, J = 8.0 Hz), 7.06 (s, 1 H), 3.87 (s, 3 H), 2.37 (s, 3 H), 2.30 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.9, 167.2, 166.4, 151.5, 142.3, 132.7, 132.2, 130.8, 126.0, 123.3, 115.5, 56.2, 20.9, 15.9;Reaction time, 3 h; Yield, 48.9%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, 1 H, J = 1.6 Hz), 7.52 (dd, 1 H, J = 1.6, 8.0 Hz), 7.07 (d, 1 H, J = 8.0 Hz ), 7.06 (s, 1H), 3.87 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 167.2, 166.4, 151.5, 142.3, 132.7, 132.2, 130.8, 126.0, 123.3, 115.5, 56.2, 20.9, 15.9;

<실시예 2-5> (Z)-2-에톡시-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-2-Ethoxy-4-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 17a) 합성Example 2-5 ( Z ) -2-ethoxy-4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -2-Ethoxy Synthesis of -4-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 17a)

반응 시간, 3 h; 수율, 28%; ¹H NMR (500 MHz, CDCl₃) δ 7.90 (d, 1 H, J = 1.5 Hz), 7.55 (dd, 1 H, J = 1.5, 8.5 Hz), 7.09 (d, 1 H, J = 8.5 Hz), 7.08 (s, 1 H), 4.13 (q, 2 H, J = 7.0 Hz), 2.40 (s, 3 H), 2.33 (s, 3 H), 1.43 (t, 3 H, J = 7.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 168.8, 168.0, 166.3, 150.9, 142.7, 132.6, 132.1, 130.9, 125.9, 123.3, 116.5, 64.7, 20.8, 15.9, 14.8;Reaction time, 3 h; Yield, 28%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90 (d, 1 H, J = 1.5 Hz), 7.55 (dd, 1 H, J = 1.5, 8.5 Hz), 7.09 (d, 1 H, J = 8.5 Hz ), 7.08 (s, 1 H), 4.13 (q, 2 H, J = 7.0 Hz), 2.40 (s, 3 H), 2.33 (s, 3 H), 1.43 (t, 3 H, J = 7.0 Hz ); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 168.0, 166.3, 150.9, 142.7, 132.6, 132.1, 130.9, 125.9, 123.3, 116.5, 64.7, 20.8, 15.9, 14.8;

<실시예 2-6> (Z)-2-메톡시-5-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-2-Methoxy-5-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 18a) 합성Example 2-6 ( Z ) -2-methoxy-5-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -2-Methoxy -5-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 18a) Synthesis

반응 시간, 3 h; 수율, 32.7%; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, 1 H, J = 2.0 Hz), 7.76 (dd, 1 H, J = 2.0, 8.8 Hz), 7.00 (s, 1 H), 6.95 (d, 1 H, J = 8.4 Hz), 3.84 (s, 3 H), 2.34 (s, 3 H), 2.30 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 169.0, 168.1, 165.6, 153.9, 140.1, 132.4, 131.4, 130.5, 126.6, 126.3, 112.3, 56.2, 20.8, 15.8;Reaction time, 3 h; Yield, 32.7%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (d, 1 H, J = 2.0 Hz), 7.76 (dd, 1 H, J = 2.0, 8.8 Hz), 7.00 (s, 1 H), 6.95 (d , 1 H, J = 8.4 Hz), 3.84 (s, 3 H), 2.34 (s, 3 H), 2.30 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 168.1, 165.6, 153.9, 140.1, 132.4, 131.4, 130.5, 126.6, 126.3, 112.3, 56.2, 20.8, 15.8;

<실시예 2-7> (Z)-4-(4-메톡시벤질리덴)-2-메틸옥사졸-5(4H)-온 [(Z)-4-(4-Methoxybenzylidene)-2-methyloxazol-5(4H)-one] (화합물 19a) 합성Example 2-7 ( Z ) -4- (4-methoxybenzylidene) -2-methyloxazol-5 (4H) -one [( Z ) -4- (4-Methoxybenzylidene) -2-methyloxazol -5 (4H) -one] (Compound 19a) Synthesis

반응 시간, 3 h; 수율, 22.2%; ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, 2 H, J = 8.8 Hz), 7.08 (s, 1 H), 6.93 (d, 2 H, J = 8.8 Hz), 3.84 (s, 3 H), 2.36 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 165.1, 162.3, 134.5, 131.7, 130.6, 126.4, 114.7, 55.6, 15.8;Reaction time, 3 h; Yield, 22.2%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, 2 H, J = 8.8 Hz), 7.08 (s, 1 H), 6.93 (d, 2 H, J = 8.8 Hz), 3.84 (s, 3 H), 2.36 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.4, 165.1, 162.3, 134.5, 131.7, 130.6, 126.4, 114.7, 55.6, 15.8;

<실시예 2-8> (Z)-4-(3,4-디메톡시벤질리덴)-2-메틸옥사졸-5(4H)-온 [(Z)-4-(3,4-Dimethoxybenzylidene)-2-methyloxazol-5(4H)-one] (화합물 20a) 합성Example 2-8 ( Z ) -4- (3,4-dimethoxybenzylidene) -2-methyloxazol-5 (4H) -one [( Z ) -4- (3,4-Dimethoxybenzylidene) -2-methyloxazol-5 (4H) -one] (Compound 20a)

반응 시간, 3 h; 수율, 21.8%; ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, 1 H, J = 2.0 Hz), 7.46 (dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (s, 1 H), 6.86 (d, 1 H, J = 8.4 Hz), 3.91 (s, 3 H), 3.90 (s, 3 H), 2.35 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.3, 165.1, 152.1, 149.3, 131.8, 130.7, 127.5, 126.6, 114.1, 111.1, 56.2, 56.1, 15.9;Reaction time, 3 h; Yield, 21.8%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (d, 1 H, J = 2.0 Hz), 7.46 (dd, 1 H, J = 2.0, 8.4 Hz), 7.03 (s, 1 H), 6.86 (d , 1 H, J = 8.4 Hz), 3.91 (s, 3 H), 3.90 (s, 3 H), 2.35 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.3, 165.1, 152.1, 149.3, 131.8, 130.7, 127.5, 126.6, 114.1, 111.1, 56.2, 56.1, 15.9;

<실시예 2-9> (Z)-5-(2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)-1,3-페닐렌 디아세테이트 [(Z)-5-((2-Methyl-5-oxooxazol-4(5H)-ylidene)methyl)-1,3-phenylene diacetate] (화합물 21a) 합성Example 2-9 ( Z ) -5- (2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) -1,3-phenylene diacetate [( Z ) -5- ((2-Methyl-5-oxooxazol-4 (5H) -ylidene) methyl) -1,3-phenylene diacetate] (Compound 21a)

반응 시간, 7 h; 수율, 31.4%; ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, 2 H, J = 2.0 Hz), 7.01 (s, 1 H), 6.99 (t, 1 H, J = 2.0 Hz), 2.39 (s, 3 H), 2.29 (s, 6 H); ¹³C NMR (100 MHz, CDCl₃) δ 169.0, 167.5, 167.3, 151.3, 135.1, 134.2, 129.1, 122.5, 118.3, 21.3, 15.9;Reaction time, 7 h; Yield, 31.4%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (d, 2 H, J = 2.0 Hz), 7.01 (s, 1 H), 6.99 (t, 1 H, J = 2.0 Hz), 2.39 (s, 3 H), 2.29 (s, 6H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 167.5, 167.3, 151.3, 135.1, 134.2, 129.1, 122.5, 118.3, 21.3, 15.9;

<실시예 2-10> (Z)-4-(2,4-디메톡시벤질리덴)-2-메틸옥사졸-5(4H)-온 [(Z)-4-(2,4-Dimethoxybenzylidene)-2-methyloxazol-5(4H)-one] (화합물 22a) 합성Example 2-10 ( Z ) -4- (2,4-dimethoxybenzylidene) -2-methyloxazol-5 (4H) -one [( Z ) -4- (2,4-Dimethoxybenzylidene) -2-methyloxazol-5 (4H) -one] (Compound 22a)

반응 시간, 3 h; 수율, 25.2%; ¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, 1 H, J = 8.5 Hz), 7.68 (s, 1 H), 6.59 (dd, 1 H, J = 2.0, 9.0 Hz), 6.43 (d, 1 H, J = 2.5 Hz), 3.88 (s, 3 H), 3.87 (s, 3 H), 2.37 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 164.4, 164.1, 161.1, 134.4, 129.7, 126.0, 115.9, 106.3, 97.9, 55.9, 55.7, 15.8;Reaction time, 3 h; Yield, 25.2%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.66 (d, 1 H, J = 8.5 Hz), 7.68 (s, 1 H), 6.59 (dd, 1 H, J = 2.0, 9.0 Hz), 6.43 (d , 1 H, J = 2.5 Hz), 3.88 (s, 3 H), 3.87 (s, 3 H), 2.37 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.6, 164.4, 164.1, 161.1, 134.4, 129.7, 126.0, 115.9, 106.3, 97.9, 55.9, 55.7, 15.8;

<실시예 2-11> (Z)-4-(2-하이드록시벤질리덴)-2-메틸옥사졸-5(4H)-온 [(Z)-4-(2-Hydroxybenzylidene)-2-methyloxazol-5(4H)-one] (화합물 23a) 합성Example 2-11 ( Z ) -4- (2-hydroxybenzylidene) -2-methyloxazol-5 (4H) -one [( Z ) -4- (2-Hydroxybenzylidene) -2-methyloxazol -5 (4H) -one] (Compound 23a) Synthesis

반응 시간, 3 h; 수율, 36.3%; ¹H NMR (500 MHz, CDCl₃) δ 8.67 (s, 1 H), 8.12 (s, 1 H), 7.50 (d, 1 H, J = 7.5 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 7.31 (d, 1 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 8.0 Hz), 2.25 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 169.7, 159.0, 150.1, 129.8, 128.0, 125.4, 124.2, 123.5, 120.0, 116.5, 24.9;Reaction time, 3 h; Yield, 36.3%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.67 (s, 1 H), 8.12 (s, 1 H), 7.50 (d, 1 H, J = 7.5 Hz), 7.43 (t, 1 H, J = 8.0 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.28 (t, 1H, J = 8.0 Hz), 2.25 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.7, 159.0, 150.1, 129.8, 128.0, 125.4, 124.2, 123.5, 120.0, 116.5, 24.9;

<실시예 2-12> (Z)-2-메틸-4-(3,4,5-트리메톡시벤질리덴)옥사졸-5(4H)-온 [(Z)-2-Methyl-4-(3,4,5-trimethoxybenzylidene)oxazol-5(4H)-one] (화합물 24a) 합성Example 2-12 ( Z ) -2-methyl-4- (3,4,5-trimethoxybenzylidene) oxazol-5 (4H) -one [( Z ) -2-Methyl-4- (3,4,5-trimethoxybenzylidene) oxazol-5 (4H) -one] (Compound 24a) Synthesis

반응 시간, 3 h; 수율, 63.8%; ¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 2 H), 7.04 (s, 1 H), 3.92 (s, 9 H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.1, 165.9, 153.4, 142.0 (C4′), 131.9, 131.6, 128.7, 109.8, 61.2, 56.4, 16.0;Reaction time, 3 h; Yield, 63.8%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (s, 2 H), 7.04 (s, 1 H), 3.92 (s, 9 H), 2.40 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.1, 165.9, 153.4, 142.0 (C4 ′), 131.9, 131.6, 128.7, 109.8, 61.2, 56.4, 16.0;

<실시예 2-13> (Z)-2,6-디메톡시-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-2,6-Dimethoxy-4-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 25a) 합성Example 2-13 ( Z ) -2,6-dimethoxy-4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -2 , 6-Dimethoxy-4-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 25a)

반응 시간, 4 h; 수율, 44.4%; ¹H NMR (400 MHz, CDCl₃) δ 7.38 (s, 2 H), 6.99 (s, 1 H), 3.84 (s, 6 H), 2.36 (s, 3 H), 2.32 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.5, 167.9, 166.4, 152.5, 134.5, 132.8, 131.5, 131.1, 109.2, 56.4, 20.6, 15.9;Reaction time, 4 h; Yield, 44.4%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (s, 2 H), 6.99 (s, 1 H), 3.84 (s, 6 H), 2.36 (s, 3 H), 2.32 (s, 3 H) ; ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.5, 167.9, 166.4, 152.5, 134.5, 132.8, 131.5, 131.1, 109.2, 56.4, 20.6, 15.9;

<실시예 2-14> (Z)-2-브로모-4-((2-메틸-5-옥소옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-2-Bromo-4-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 26a) 합성Example 2-14 ( Z ) -2-bromo-4-((2-methyl-5-oxooxazole-4 (5H) -ylidene) methyl) phenyl acetate [( Z ) -2-Bromo Synthesis of 4-((2-methyl-5-oxooxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 26a)

반응 시간, 4 h; 수율, 66.6%; ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, 1 H, J = 1.6 Hz), 7.96 (dd, 1 H, J = 1.6, 8.4 Hz), 7.17 (d, 1 H, J = 8.8 Hz), 6.99 (s, 1 H), 2.39 (s, 3 H), 2.35 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.4, 167.5, 167.3, 150.1, 136.7, 133.7, 132.8, 132.5, 128.5, 124.3, 117.1, 21.0, 16.0;Reaction time, 4 h; Yield, 66.6%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (d, 1 H, J = 1.6 Hz), 7.96 (dd, 1 H, J = 1.6, 8.4 Hz), 7.17 (d, 1 H, J = 8.8 Hz ), 6.99 (s, 1 H), 2.39 (s, 3 H), 2.35 (s, 3 H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.4, 167.5, 167.3, 150.1, 136.7, 133.7, 132.8, 132.5, 128.5, 124.3, 117.1, 21.0, 16.0;

<실시예 3> 화합물 13 내지 27 합성Example 3 Synthesis of Compounds 13-27

하기 표 3은 (Z)-2-아세트아미도-3-(치환된 페닐)아크릴산 유도체 [(Z)-2-acetamido-3-(substituted phenyl)acrylic acid derivative] 화합물 13 - 27의 치환 패턴을 설명하기 위한 것이다.Table 3 (Z) -2- acetamido-3- (substituted phenyl) acrylic acid derivative [(Z) -2-acetamido- 3- (substituted phenyl) acrylic acid derivative] Compound 13 - 27 substitution pattern of To illustrate.

또는

or

화합물compound R¹ R ¹ R² R ² R³ R ³ R⁴ R ⁴ 1313 HH HH OHOH HH 1414 HH OHOH OHOH HH 1515 OHOH HH OHOH HH 1616 HH OMeOMe OHOH HH 1717 HH OEtOEt OHOH HH 1818 HH OHOH OMeOMe HH 1919 HH HH OMeOMe HH 2020 HH OMeOMe OMeOMe HH 2121 HH OHOH HH OHOH 2222 OMeOMe HH OMeOMe HH 2323 OHOH HH HH HH 2424 HH OMeOMe OMeOMe OMeOMe 2525 HH OMeOMe OHOH OMeOMe 2727 HH BrBr OAcOac HH

(Z)-2-아세트아미도-3-(치환된 페닐)아크릴산 유도체 [(Z)-2-acetamido-3-(substituted phenyl)acrylic acid derivative] 화합물 13 - 27은 다음과 같이 합성하였다. 즉, 아세톤 (2 mL)과 물 (2 mL)에 용해된 (Z)-4-(치환된 벤질리덴)-2-메틸옥사졸-5(4H)-온 유사체 13a - 26a (79 - 245 mg)와 탄산나트륨 (3.0 eq. + 3.0 eq × 출발물질의 아세틸기의 갯수) 용액을, 화합물 19a, 20a, 22a, 23a 및 24a의 경우에는 상온에서 또는 화합물 13a - 18a, 21a, 25a 및 26a의 경우에는 60℃에서 가열하여 교반하였다. 아세톤이 제거된 후, 반응 혼합물은 6 N HCl을 이용하여 pH 2로 산성화 시켰다. 화합물 13a, 15a, 18a - 20a, 22a - 24a 및 26a의 경우 생성된 침전물을 여과하고 물로 세척하여 고상의 화합물 13, 15, 18 - 20, 22 - 24 및 26 - 27을 얻었다. 이때, 화합물 26a의 경우에는 (E) 및 (Z) 이성질체(isomers)로 각각 두 개의 산물 (화합물 26과 화합물 27)이 얻어졌다. 또한, 화합물 14a, 16a, 17a, 21a 및 25a의 경우, 메틸렌 클로라이드와 메탄올(5:1)을 용출액(eluent)으로 이용하여 실리카 겔 칼럼 크로마토그래피를 수행하여, 고상의 화합물 14, 16, 17, 21 및 25를 얻었다.( Z ) -2-acetamido-3- (substituted phenyl) acrylic acid derivative [( Z ) -2-acetamido-3- (substituted phenyl) acrylic acid derivative] Compounds 13 to 27 were synthesized as follows. That is, ( Z ) -4- (substituted benzylidene) -2-methyloxazol-5 (4H) -one analog 13a-26a (79-245 mg) dissolved in acetone (2 mL) and water (2 mL) ) And a solution of sodium carbonate (3.0 eq. + 3.0 eq x number of acetyl groups in the starting material) at room temperature for compounds 19a, 20a, 22a, 23a and 24a or for compounds 13a-18a, 21a, 25a and 26a The mixture was heated and stirred at 60 ° C. After acetone was removed, the reaction mixture was acidified to pH 2 with 6 N HCl. For compounds 13a, 15a, 18a-20a, 22a-24a and 26a, the resulting precipitate was filtered and washed with water to give solid compounds 13, 15, 18-20, 22-24 and 26-27. In this case, in the case of compound 26a, two products (compound 26 and compound 27) were obtained as ( E ) and ( Z ) isomers, respectively. In addition, in the case of compounds 14a, 16a, 17a, 21a, and 25a, silica gel column chromatography was performed using methylene chloride and methanol (5: 1) as eluents to obtain solid compounds 14, 16, 17, 21 and 25 were obtained.

<실시예 3-1> (Z)-2-아세트아미도-3-(4-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxyphenyl)acrylic acid] (화합물 13) 합성<Example 3-1> (Z) -2- acetamido-3- (4-hydroxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (4-hydroxyphenyl) acrylic acid] ( compound 13) synthesis

반응 시간, 7 h; 수율, 32.9%; ¹H NMR (500 MHz, CD₃OD) δ 7.48 (d, 2 H, J = 8.5 Hz), 7.47 (s, 1 H), 6.81 (d, 2 H, J = 9.0 Hz), 2.12 (s, 3 H); ¹³C NMR (100 MHz, CD₃OD) δ 172.3, 167.6, 159.3, 135.7, 132.0, 125.0, 122.4, 115.5, 21.5;Reaction time, 7 h; Yield, 32.9%; ¹ H NMR (500 MHz, CD ₃ OD) δ 7.48 (d, 2 H, J = 8.5 Hz), 7.47 (s, 1 H), 6.81 (d, 2 H, J = 9.0 Hz), 2.12 (s, 3 H); ¹³ C NMR (100 MHz, CD ₃ OD) δ 172.3, 167.6, 159.3, 135.7, 132.0, 125.0, 122.4, 115.5, 21.5;

<실시예 3-2> (Z)-2-아세트아미도-3-(3,4-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4-dihydroxyphenyl)acrylic acid] (화합물 14) 합성<Example 3-2> (Z) -2- acetamido-3- (3,4-hydroxyphenyl) acrylate [(Z) -2-Acetamido- 3- (3,4-dihydroxyphenyl) acrylic acid (Compound 14) Synthesis

반응 시간, 8 h; 수율, 84.5%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1 H), 7.10 (s, 1 H), 7.05 (s, 1 H), 6.86 (d, 1 H, J = 7.2 Hz), 6.70 (d, 1 H, J = 7.2 Hz), 1.94 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.9, 167.4, 147.9, 145.7, 133.6, 125.6, 124.4, 123.8, 117.4, 116.2, 23.3;Reaction time, 8 h; Yield, 84.5%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (s, 1 H), 7.10 (s, 1 H), 7.05 (s, 1 H), 6.86 (d, 1 H, J = 7.2 Hz), 6.70 (d, 1H, J = 7.2 Hz), 1.94 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.9, 167.4, 147.9, 145.7, 133.6, 125.6, 124.4, 123.8, 117.4, 116.2, 23.3;

<실시예 3-3> (Z)-2-아세트아미도-3-(2,4-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(2,4-dihydroxyphenyl)acrylic acid] (화합물 15) 합성<Example 3-3> (Z) -2- acetamido-3- (2,4-di-hydroxyphenyl) acrylate [(Z) -2-Acetamido- 3- (2,4-dihydroxyphenyl) acrylic acid (Compound 15) Synthesis

반응 시간, 6 h; 수율, 13.9%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1 H), 9.52 (s, 1 H), 8.45 (s, 1 H), 7.46 (d, 1 H, J = 8.0 Hz), 6.74 (d, 1 H, J = 8.4 Hz), 6.69 (s, 1 H), 2.08 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.4, 160.1, 158.5, 152.1, 129.6, 126.4, 121.7, 114.2, 112.1, 102.6, 24.5;Reaction time, 6 h; Yield, 13.9%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1 H), 9.52 (s, 1 H), 8.45 (s, 1 H), 7.46 (d, 1 H, J = 8.0 Hz), 6.74 (d, 1H, J = 8.4 Hz), 6.69 (s, 1H), 2.08 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 170.4, 160.1, 158.5, 152.1, 129.6, 126.4, 121.7, 114.2, 112.1, 102.6, 24.5;

<실시예 3-4> (Z)-2-아세트아미도-3-(4-하이드록시-3-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxy-3-methoxyphenyl)acrylic acid] (화합물 16) 합성<Example 3-4> (Z) -2- acetamido-3- (4-hydroxy-3-methoxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (4-hydroxy-3- methoxyphenyl) acrylic acid] (Compound 16) Synthesis

반응 시간, 4 h; 수율, 72.9%; ¹H NMR (500 MHz, DMSO-d₆) δ 9.36 (s, 1 H), 7.27 (s, 1 H), 7.18 (s, 1 H), 7.05 (d, 1 H, J = 6.5 Hz), 6.79 (d, 1 H, J = 6.5 Hz), 3.75 (s, 3 H), 1.97 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.3, 148.8, 147.9, 133.4, 125.6, 124.9, 124.7, 116.1, 114.1, 56.1, 23.2;Reaction time, 4 h; Yield, 72.9%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.36 (s, 1 H), 7.27 (s, 1 H), 7.18 (s, 1 H), 7.05 (d, 1 H, J = 6.5 Hz), 6.79 (d, 1H, J = 6.5 Hz), 3.75 (s, 3H), 1.97 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.8, 167.3, 148.8, 147.9, 133.4, 125.6, 124.9, 124.7, 116.1, 114.1, 56.1, 23.2;

<실시예 3-5> (Z)-2-아세트아미도-3-(3-에톡시-4-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3-ethoxy-4-hydroxyphenyl)acrylic acid] (화합물 17) 합성<Example 3-5> (Z) -2- acetamido-3- (3-ethoxy-4-hydroxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (3-ethoxy-4- hydroxyphenyl) acrylic acid] (compound 17) synthesis

반응 시간, 8 h; 수율, 100%; ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 1 H), 7.25 (s, 1 H), 7.17 (s, 1 H), 7.04 (d, 1 H, J = 8.0 Hz), 6.81 (d, 1 H, J = 8.0 Hz), 4.00 (q, 2 H, J = 6.5 Hz), 1.96 (s, 3 H), 1.31 (t, 3 H, J = 6.5 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.7, 167.3, 149.2, 147.0, 133.5, 125.5, 124.9, 124.6, 116.2, 115.3, 64.3, 23.2, 15.4;Reaction time, 8 h; Yield, 100%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.35 (s, 1 H), 7.25 (s, 1 H), 7.17 (s, 1 H), 7.04 (d, 1 H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 4.00 (q, 2H, J = 6.5 Hz), 1.96 (s, 3H), 1.31 (t, 3H, J = 6.5 Hz); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.7, 167.3, 149.2, 147.0, 133.5, 125.5, 124.9, 124.6, 116.2, 115.3, 64.3, 23.2, 15.4;

<실시예 3-6> (Z)-2-아세트아미도-3-(3-하이드록시-4-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3-hydroxy-4-methoxyphenyl)acrylic acid] (화합물 18) 합성<Example 3-6> (Z) -2- acetamido-3- (3-hydroxy-4-methoxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (3-hydroxy-4- methoxyphenyl) acrylic acid] (Compound 18) Synthesis

반응 시간, 4 h; 수율, 18.2%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1 H), 9.27 (s, 1 H), 9.15 (s, 1 H), 7.14-6.91 (m, 4 H), 3.76 (s, 3 H), 1.97 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.3, 149.6, 146.9, 132.9, 127.1, 125.4, 123.4, 116.9, 112.4, 56.2, 23.3;Reaction time, 4 h; Yield, 18.2%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.49 (s, 1 H), 9.27 (s, 1 H), 9.15 (s, 1 H), 7.14-6.91 (m, 4 H), 3.76 (s , 3H), 1.97 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.8, 167.3, 149.6, 146.9, 132.9, 127.1, 125.4, 123.4, 116.9, 112.4, 56.2, 23.3;

<실시예 3-7> (Z)-2-아세트아미도-3-(4-메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-methoxyphenyl)acrylic acid] (화합물 19) 합성<Example 3-7> (Z) -2- acetamido-3- (4-methoxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (4-methoxyphenyl) acrylic acid] ( compound 19) synthesis

반응 시간, 3 h; 수율, 42.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.49 (br s, 1 H), 9.31 (s, 1 H), 7.55 (d, 2 H, J = 8.4 Hz), 7.19 (s, 1 H), 6.93 (d, 2 H, J = 8.8 Hz), 3.74 (s, 3 H), 1.94 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.3, 160.7, 132.4, 132.3, 126.9, 125.6, 114.7, 55.9, 23.2;Reaction time, 3 h; Yield, 42.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.49 (br s, 1 H), 9.31 (s, 1 H), 7.55 (d, 2 H, J = 8.4 Hz), 7.19 (s, 1 H) , 6.93 (d, 2H, J = 8.8 Hz), 3.74 (s, 3H), 1.94 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.8, 167.3, 160.7, 132.4, 132.3, 126.9, 125.6, 114.7, 55.9, 23.2;

<실시예 3-8> (Z)-2-아세트아미도-3-(3,4-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4-dimethoxyphenyl)acrylic acid] (화합물 20) 합성<Example 3-8> (Z) -2- acetamido-3- (3,4-dimethoxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (3,4-dimethoxyphenyl) acrylic acid] (Compound 20) Synthesis

반응 시간, 3 h; 수율, 61.3%; ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1 H), 9.39 (s, 1 H), 7.29 (d, 1 H, J = 2.0 Hz), 7.21 (s, 1 H), 7.19 (dd, 1 H, J = 1.5, 8.5 Hz), 6.98 (d, 1 H, J = 8.5 Hz), 3.77 (s, 3 H), 3.75 (s, 3 H), 1.98 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.7, 167.2, 150.5, 149.0, 132.7, 126.9, 125.7, 124.5, 113.3, 112.1, 56.2, 56.0, 23.2;Reaction time, 3 h; Yield, 61.3%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.49 (s, 1 H), 9.39 (s, 1 H), 7.29 (d, 1 H, J = 2.0 Hz), 7.21 (s, 1 H), 7.19 (dd, 1 H, J = 1.5, 8.5 Hz), 6.98 (d, 1 H, J = 8.5 Hz), 3.77 (s, 3 H), 3.75 (s, 3 H), 1.98 (s, 3 H ); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.7, 167.2, 150.5, 149.0, 132.7, 126.9, 125.7, 124.5, 113.3, 112.1, 56.2, 56.0, 23.2;

<실시예 3-9> (Z)-2-아세트아미도-3-(3,5-디하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,5-dihydroxyphenyl)acrylic acid] (화합물 21) 합성<Example 3-9> (Z) -2- acetamido-3- (3,5-di-hydroxyphenyl) acrylate [(Z) -2-Acetamido- 3- (3,5-dihydroxyphenyl) acrylic acid (Compound 21) Synthesis

반응 시간, 8 h; 수율, 94.4%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.48 (s, 1 H), 9.37 (s, 1 H,), 9.35 (s, 1 H,), 6.92 (s, 1 H,), 6.45 (s, 2 H,), 6.20 (s, 1 H), 1.94 (s, 3 H,); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.8, 167.1, 158.9, 135.7, 132.2, 127.7, 108.6, 104.4, 23.2;Reaction time, 8 h; Yield, 94.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1 H), 9.37 (s, 1 H,), 9.35 (s, 1 H,), 6.92 (s, 1 H,), 6.45 ( s, 2H,), 6.20 (s, 1H), 1.94 (s, 3H,); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.8, 167.1, 158.9, 135.7, 132.2, 127.7, 108.6, 104.4, 23.2;

<실시예 3-10> (Z)-2-아세트아미도-3-(2,4-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(2,4-dimethoxyphenyl)acrylic acid] (화합물 22) 합성<Example 3-10> (Z) -2- acetamido-3- (2,4-dimethoxyphenyl) acrylic acid [(Z) -2-Acetamido- 3- (2,4-dimethoxyphenyl) acrylic acid] (Compound 22) Synthesis

반응 시간, 4 h; 수율, 38.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (s, 1 H), 9.22 (s, 1 H), 7.58 (d, 1 H, J = 8.4 Hz), 7.43 (s, 1 H), 6.56 (s, 1 H), 6.54 (d, 1 H, J = 8.4 Hz), 3.79 (s, 3 H), 3.76 (s, 3 H), 1.90 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.7, 167.3, 162.3, 159.5, 130.7, 126.6, 125.4, 115.5, 106.2, 98.7, 56.4, 56.1, 23.2;Reaction time, 4 h; Yield 38.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.39 (s, 1 H), 9.22 (s, 1 H), 7.58 (d, 1 H, J = 8.4 Hz), 7.43 (s, 1 H), 6.56 (s, 1H), 6.54 (d, 1H, J = 8.4 Hz), 3.79 (s, 3H), 3.76 (s, 3H), 1.90 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.7, 167.3, 162.3, 159.5, 130.7, 126.6, 125.4, 115.5, 106.2, 98.7, 56.4, 56.1, 23.2;

<실시예 3-11> (Z)-2-아세트아미도-3-(2-하이드록시페닐)아크릴산 [(Z)-2-Acetamido-3-(2-hydroxyphenyl)acrylic acid] (화합물 23) 합성<Example 3-11> (Z) -2- acetamido-3- (2-hydroxyphenyl) acrylate [(Z) -2-Acetamido- 3- (2-hydroxyphenyl) acrylic acid] ( compound 23) synthesis

반응 시간, 7 h; 수율, 74.8%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1 H), 8.56 (s, 1 H), 7.65 (d, 1 H, J = 7.6 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.33 (d, 1 H, J = 8.0 Hz), 7.28 (t, 1 H, J = 7.6 Hz), 2.12 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 170.9, 158.1, 150.3, 130.2, 128.5, 125.6, 125.2, 124.2, 120.2, 116.5, 24.6;Reaction time, 7 h; Yield, 74.8%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.71 (s, 1 H), 8.56 (s, 1 H), 7.65 (d, 1 H, J = 7.6 Hz), 7.45 (t, 1 H, J = 7.6 Hz), 7.33 (d, 1H, J = 8.0 Hz), 7.28 (t, 1H, J = 7.6 Hz), 2.12 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 170.9, 158.1, 150.3, 130.2, 128.5, 125.6, 125.2, 124.2, 120.2, 116.5, 24.6;

<실시예 3-12> (Z)-2-아세트아미도-3-(3,4,5-트리메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(3,4,5-trimethoxyphenyl)acrylic acid] (화합물 24) 합성Example 3-12 ( Z ) -2-acetamido-3- (3,4,5-trimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4,5- trimethoxyphenyl) acrylic acid] (Compound 24) Synthesis

반응 시간, 5 h; 수율, 67.3%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.62 (br s, 1 H), 9.46 (s, 1 H), 7.16 (s, 1 H), 6.96 (s, 2 H), 3.74 (s, 6 H), 3.65 (s, 3 H), 1.96 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.7, 167.1, 153.3, 139.0, 132.1, 129.7, 127.2, 108.0, 60.7, 56.5, 23.1;Reaction time, 5 h; Yield, 67.3%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.62 (br s, 1 H), 9.46 (s, 1 H), 7.16 (s, 1 H), 6.96 (s, 2 H), 3.74 (s, 6 H), 3.65 (s, 3H), 1.96 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.7, 167.1, 153.3, 139.0, 132.1, 129.7, 127.2, 108.0, 60.7, 56.5, 23.1;

<실시예 3-13> (Z)-2-아세트아미도-3-(4-하이드록시-3,5-디메톡시페닐)아크릴산 [(Z)-2-Acetamido-3-(4-hydroxy-3,5-dimethoxyphenyl)acrylic acid] (화합물 25) 합성Example 3-13 ( Z ) -2-acetamido-3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxy- 3,5-dimethoxyphenyl) acrylic acid] (Compound 25) Synthesis

반응 시간, 8 h; 수율, 100%; ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1 H), 7.17 (s, 1 H), 6.95 (s, 2 H), 3.72 (s, 6 H), 1.95 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.7, 167.2, 148.2, 137.9, 133.5, 125.1, 124.4, 108.5, 56.5, 23.1;Reaction time, 8 h; Yield, 100%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1 H), 7.17 (s, 1 H), 6.95 (s, 2 H), 3.72 (s, 6 H), 1.95 (s, 3 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.7, 167.2, 148.2, 137.9, 133.5, 125.1, 124.4, 108.5, 56.5, 23.1;

<실시예 3-14> (E)-2-아세트아미도-3-(4-아세톡시-3-브로모페닐)아크릴산 [(E)-2-Acetamido-3-(4-acetoxy-3-bromophenyl)acrylic acid] (화합물 26) 합성Example 3-14 ( E ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( E ) -2-Acetamido-3- (4-acetoxy-3- bromophenyl) acrylic acid] (Compound 26)

반응 시간, 4 h; 수율, 70.7%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1 H), 7.43 (s, 1 H), 7.11 (d, 1 H, J = 6.8 Hz), 6.92 (s, 1 H), 6.87 (d, 1 H, J = 6.8 Hz), 1.91 (s, 3 H), 1.77 (s, 3 H);Reaction time, 4 h; Yield, 70.7%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.87 (s, 1 H), 7.43 (s, 1 H), 7.11 (d, 1 H, J = 6.8 Hz), 6.92 (s, 1 H), 6.87 (d, 1H, J = 6.8 Hz), 1.91 (s, 3H), 1.77 (s, 3H);

<실시예 3-15> (Z)-2-아세트아미도-3-(4-아세톡시-3-브로모페닐)아크릴산 [(Z)-2-Acetamido-3-(4-acetoxy-3-bromophenyl)acrylic acid] (화합물 27) 합성Example 3-15 ( Z ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-acetoxy-3- bromophenyl) acrylic acid] (Compound 27) Synthesis

반응 시간, 4 h; 수율, 23.4%; ¹H NMR (400 MHz, DMSO-d₆) δ 12.68 (s, 1 H), 9.54 (s, 1 H), 7.90 (d, 1 H, J = 2.0 Hz), 7.62 (dd, 1 H, J = 2.0, 8.4 Hz), 7.28 (d, 1 H, J = 8.4 Hz), 7.15 (s, 1 H), 2.30 (s, 3 H), 1.95 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 169.9, 168.9, 166.8, 148.6, 134.4, 134.2, 130.8, 129.1, 128.9, 124.9, 116.4, 23.2, 21.2.Reaction time, 4 h; Yield 23.4%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1 H), 9.54 (s, 1 H), 7.90 (d, 1 H, J = 2.0 Hz), 7.62 (dd, 1 H, J = 2.0, 8.4 Hz), 7.28 (d, 1H, J = 8.4 Hz), 7.15 (s, 1H), 2.30 (s, 3H), 1.95 (s, 3H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 169.9, 168.9, 166.8, 148.6, 134.4, 134.2, 130.8, 129.1, 128.9, 124.9, 116.4, 23.2, 21.2.

<< 실시예Example 4> 화합물 28a 및 28b 합성 4> Synthesis of Compounds 28a and 28b

하기 (Z)-4-(치환된 벤질리덴)-2-페닐옥사졸-5(4H)-온 유도체 [(Z)-4-(substituted benzylidene)-2-phenyloxazol-5(4H)-one analog] 화합물 28a 및 28b는 다음과 같이 합성하였다.(Z) -4- (substituted benzylidene) -2-phenyloxazol-5 (4H) -one derivative [(Z) -4- (substituted benzylidene) -2-phenyloxazol-5 (4H) -one analog Compounds 28a and 28b were synthesized as follows.

또는

or

즉, 아세트산 무수물 (1.5 eq. + 추가적 1.0 eq. × 벤즈알데히드의 하이드록시기 갯수)에 용해된 치환된 벤즈알데히드 (1.0 eq.), 히푸르산 (1.1 eq.) 및 NaOAc (1.0 eq.)의 용액을 60℃에서 가열하였다. 냉각 후, 메탄올과 물을 첨가하였다. 얻어진 침전물을 여과하고 물과 메탄올로 세척하여 화합물 28a 및 28b을 얻었다.That is, a solution of substituted benzaldehyde (1.0 eq.), Hypofuric acid (1.1 eq.) And NaOAc (1.0 eq.) Dissolved in acetic anhydride (1.5 eq. + Additional 1.0 eq. X number of hydroxy groups of benzaldehyde). Heated at 60 ° C. After cooling, methanol and water were added. The obtained precipitate was filtered and washed with water and methanol to give compounds 28a and 28b.

<실시예 4-1> (Z)-4-((5-옥소-2-페닐옥사졸-4(5H)-일리덴)메틸)페닐 아세테이트 [(Z)-4-((5-Oxo-2-phenyloxazol-4(5H)-ylidene)methyl)phenyl acetate] (화합물 28a) 합성Example 4-1 (Z) -4-((5-oxo-2-phenyloxazole-4 (5H) -ylidene) methyl) phenyl acetate [(Z) -4-((5-Oxo- 2-phenyloxazol-4 (5H) -ylidene) methyl) phenyl acetate] (Compound 28a) Synthesis

반응 시간, 10 min; 수율, 63.9%; ¹H NMR (500 MHz, CDCl₃) δ 8.24 (d, 2 H, J = 8.5 Hz), 8.18 (d, 2 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 7.5 Hz), 7.54 (t, 2 H, J = 7.5 Hz), 7.23 (d, 2 H, J = 8.0 Hz), 7.22 (s, 1 H), 2.34 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 169.2, 167.8, 163.9, 152.9, 134.0, 133.7, 133.4, 131.4, 130.7, 129.2, 128.6, 125.7, 122.4, 21.5;Reaction time, 10 min; Yield, 63.9%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.24 (d, 2 H, J = 8.5 Hz), 8.18 (d, 2 H, J = 8.0 Hz), 7.63 (t, 1 H, J = 7.5 Hz), 7.54 (t, 2H, J = 7.5 Hz), 7.23 (d, 2H, J = 8.0 Hz), 7.22 (s, 1H), 2.34 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.2, 167.8, 163.9, 152.9, 134.0, 133.7, 133.4, 131.4, 130.7, 129.2, 128.6, 125.7, 122.4, 21.5;

<실시예 4-2> (Z)-4-(4-메톡시벤질리덴)-2-페닐옥사졸-5(4H)-온 [(Z)-4-(4-Methoxybenzylidene)-2-phenyloxazol-5(4H)-one] (화합물 28b) 합성Example 4-2 (Z) -4- (4-methoxybenzylidene) -2-phenyloxazol-5 (4H) -one [(Z) -4- (4-Methoxybenzylidene) -2-phenyloxazol -5 (4H) -one] (compound 28b) synthesis

반응 시간, 10 min; 수율, 27.7%; ¹H NMR (500 MHz, CDCl₃) δ 8.19 (d, 2 H, J = 8.5 Hz), 8.17 (d, 2 H, J = 8.5 Hz), 7.60 (t, 1 H, J = 7.5 Hz), 7.52 (t, 2 H, J = 7.5 Hz), 7.22 (s, 1 H), 7.00 (d, 2 H, J = 8.0 Hz), 3.89 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃) δ 168.2, 162.7, 162.4, 134.8, 133.2, 132.1, 131.3, 129.1, 128.4, 126.8, 126.0, 114.7, 55.7.Reaction time, 10 min; Yield, 27.7%; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.19 (d, 2 H, J = 8.5 Hz), 8.17 (d, 2 H, J = 8.5 Hz), 7.60 (t, 1 H, J = 7.5 Hz), 7.52 (t, 2H, J = 7.5 Hz), 7.22 (s, 1H), 7.00 (d, 2H, J = 8.0 Hz), 3.89 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.2, 162.7, 162.4, 134.8, 133.2, 132.1, 131.3, 129.1, 128.4, 126.8, 126.0, 114.7, 55.7.

<실시예 5> 화합물 28 및 29 합성Example 5 Synthesis of Compounds 28 and 29

하기 (Z)-2-벤즈아미도-3-(치환된 페닐)아크릴산 유도체 [(Z)-2-Benzamido-3-(4-hydroxyphenyl)acrylic acid analogue] 화합물 28 및 29는 다음과 같이 합성하였다.(Z) -2-benzamido-3- (substituted phenyl) acrylic acid derivatives [(Z) -2-Benzamido-3- (4-hydroxyphenyl) acrylic acid analogue] Compounds 28 and 29 were synthesized as follows. .

또는

or

즉, 아세톤과 물 (1:1)에 용해된 화합물 28a (1.0 eq.) 또는 화합물 28b (1.0 eq.) 및 Na₂CO₃ (2.0 eq. + 2.0 eq. × 아세틸기의 개수) 용액을 환류시켰다. 아세톤을 증발시킨 후, 6N HCl을 이용하여 반응 혼합물의 pH 2로 산성화 시켰다. 물을 1/2 부피까지 증발시킨 후, 얻어진 침전물을 여과하고 물로 세척하였다.That is, refluxing a solution of Compound 28a (1.0 eq.) Or Compound 28b (1.0 eq.) And Na ₂ CO ₃ (2.0 eq. + 2.0 eq. × acetyl group) dissolved in acetone and water (1: 1) I was. After evaporation of acetone, the reaction mixture was acidified to pH 2 with 6N HCl. After evaporating the water to 1/2 volume, the precipitate obtained was filtered off and washed with water.

<실시예 5-1> (Z)-2-벤즈아미도-3-(4-하이드록시페닐)아크릴산 [(Z)-2-Benzamido-3-(4-hydroxyphenyl)acrylic acid] (화합물 28) 합성Example 5-1 ( Z ) -2-benzamido-3- (4-hydroxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-hydroxyphenyl) acrylic acid] (Compound 28) synthesis

반응 시간, 6 h; 수율, 84.9%; ¹H NMR (500 MHz, DMSO-d₆) δ 12.49 (s, 1 H), 9.91 (s, 1 H), 9.78 (s, 1 H), 7.98 (d, 2 H, J = 7.5 Hz), 7.58 (t, 1 H, J = 7.5 Hz), 7.53-7.50 (m, 4 H), 7.39 (s, 1 H), 6.76 (d, 2 H, J = 8.0 Hz); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.3, 166.6, 159.5, 134.6, 134.4, 132.6, 132.4, 129.1, 128.3, 125.3, 124.7, 116.2;Reaction time, 6 h; Yield, 84.9%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.49 (s, 1 H), 9.91 (s, 1 H), 9.78 (s, 1 H), 7.98 (d, 2 H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.53-7.50 (m, 4H), 7.39 (s, 1H), 6.76 (d, 2H, J = 8.0 Hz); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 167.3, 166.6, 159.5, 134.6, 134.4, 132.6, 132.4, 129.1, 128.3, 125.3, 124.7, 116.2;

<실시예 5-2> (Z)-2-벤즈아미도-3-(4-메톡시페닐)아크릴산 [(Z)-2-Benzamido-3-(4-methoxyphenyl)acrylic acid] (화합물 29) 합성Example 5-2 ( Z ) -2-benzamido-3- (4-methoxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-methoxyphenyl) acrylic acid] (Compound 29) synthesis

반응 시간, 8 h; 수율, 55.1%; ¹H NMR (500 MHz, DMSO-d₆) δ 12.57 (s, 1 H), 9.83 (s, 1 H), 7.98 (d, 2 H, J =7.0 Hz), 7.63 (d, 2 H, J = 9.0 Hz), 7.58 (m, 1 H), 7.52 (t, 2 H, J = 7.5 Hz), 7.44 (s, 1 H), 6.95 (d, 2 H, J = 9.0 Hz), 3.75 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ 167.2, 166.6, 160.8, 134.3, 134.1, 132.4, 132.3, 129.1, 128.3, 126.8, 125.6, 114.8, 55.9.Reaction time, 8 h; Yield, 55.1%; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.57 (s, 1 H), 9.83 (s, 1 H), 7.98 (d, 2 H, J = 7.0 Hz), 7.63 (d, 2 H, J = 9.0 Hz), 7.58 (m, 1H), 7.52 (t, 2H, J = 7.5 Hz), 7.44 (s, 1H), 6.95 (d, 2H, J = 9.0 Hz), 3.75 (s , 3 H); ¹³ C NMR (100 MHz, DMSO-d ₆ ) δ 167.2, 166.6, 160.8, 134.3, 134.1, 132.4, 132.3, 129.1, 128.3, 126.8, 125.6, 114.8, 55.9.

<실험예 1> <Experimental Example 1> In vitroIn vitro ROS 소거활성 분석 ROS scavenging activity analysis

1. 혈관내피세포(YPEN-1) 준비1. Preparation of vascular endothelial cells (YPEN-1)

YPEN-1 세포(rat prostatic endothelial cell line)는 ATCC(American Type Culture Collection, Manassas, VA, USA)로부터 받았고, 상기 세포는 2mM L-글루타민, 100mg/ml 스트렙토마이신, 2.5mg/L 암포테리신B, 그리고 5% 불활성화된 태아소혈청(FBS)이 함유된 DMEM(Dulbecco's Modified Eagle Medium, Nissui, Tokyo, Japan)을 이용하여 배양하였다. 또한 세포는 5% CO₂와 95% 공기가 함유된 습한 대기와 같은 조건에서 37℃를 유지하였다. 그리고 5% FBS를 첨가하지 않은 것을 무혈청 배지(SFM, serum-free medium)로 사용하였다. 100mm 플라스틱플라스크(Corning Co., New York, USA)에 2일에 한번씩 서브배양하여 세포주를 유지하였다.YPEN-1 cells (rat prostatic endothelial cell line) were obtained from ATCC (American Type Culture Collection, Manassas, Va., USA) and the cells were treated with 2 mM L-glutamine, 100 mg / ml streptomycin, 2.5 mg / L amphotericin B , And DMEM (Dulbecco's Modified Eagle Medium, Nissui, Tokyo, Japan) containing 5% inactivated fetal bovine serum (FBS). Cells were also maintained at 37 ° C in conditions such as humid atmospheres containing 5% CO ₂ and 95% air. And 5% FBS was used as serum-free medium (SFM). The cells were sub-cultured in a 100 mm plastic flask (Corning Co., New York, USA) once every two days to maintain the cell line.

2. ROS 측정2. ROS measurement

종래 알려진 방법(Chem Res Toxicol. 5: 227-231, 1992)에 따른 DCFDA(2',7'-dichlorodihydrofluorescein diacetate) 분석법으로 측정하였다. 즉, 99.9%의 에탄올에 용해한 12.5mM DCFDA와 3차 증류수에 용해한 600U/ml 에스테라아제를 -20℃에 스탁용액으로 저장하였으며, 실험 시 10mM DCFDA와 6U/ml 에스테라아제를 혼합하여 조제된 DCFH(2',7'-dichlorodihydrofluorescein) 용액을 22℃에서 20분간 배양한 후 사용 전까지 암소에서 냉동 보관하였다. 지용성의 DCFDA가 에스테라아제 또는 산화적 가수 분해를 받아 비형광성인 DCFH로 탈아세틸화되며, DCFH는 활성산소에 의해 산화되어 강한 형광을 나타내는 DCF(2',7'-dichlorofluorescein)가 되므로, excitation 파장 485nm 및 emission 파장 530nm에서 형광광도계(GENios, TECAN)로 측정하였다. 활성산소 생성원으로는 SIN-1(3-morpholinosydnonimine hydrochloride) 50μM을 혈관내피세포에 1시간 동안 전처리 하여 사용하였다.Was measured by the DCFDA (2 ', 7'-dichlorodihydrofluorescein diacetate) assay according to a known method (Chem Res Toxicol. 5: 227-231, 1992). That is, 12.5 mM DCFDA dissolved in 99.9% ethanol and 600 U / ml esterase dissolved in tertiary distilled water were stored at -20 ° C. in a stock solution, and DCFH (2 ') prepared by mixing 10 mM DCFDA and 6 U / , 7'-dichlorodihydrofluorescein) solution was incubated at 22 ° C for 20 minutes and stored frozen in a cow until use. Since the fat-soluble DCFDA is deacetylated with non-fluorescent DCFH by esterase or oxidative hydrolysis and DCFH is oxidized by active oxygen to become DCF (2 ', 7'-dichlorofluorescein) exhibiting strong fluorescence, the excitation wavelength is 485 nm And a fluorescence photometer (GENios, TECAN) at an emission wavelength of 530 nm. SIN-1 (3-morpholinosydnonimine hydrochloride) 50 μM was used as a source of active oxygen for 1 hour.

그 결과, 도 1과 같이 혈관내피세포에서 발생한 ROS를 양성대조군인 트롤록스(Trolox)만큼 소거하는 효과가 큰 화합물로서 화합물 2, 14, 16, 17, 25를 선별할 수 있었다.As a result, as shown in FIG. 1, compounds 2, 14, 16, 17, and 25 were selected as compounds having a greater effect of erasing ROS generated from vascular endothelial cells as much as trolox, a positive control group.

<실험예 2> 티로시나아제 억제 효과 검토&Lt; Experimental Example 2 > Study on 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. Tyrosinase activity was assayed according to a known method ( Life Sci. , 1999, 65, 241-246) via slight modifications. 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).

그 결과, 도 2와 같이 화합물 1이 양성대조군인 코지산(Kojic Acid)과 유사한 티로시네이즈 억제 활성을 나타내는 것을 확인할 수 있었다.As a result, as shown in FIG. 2, it was confirmed that Compound 1 exhibited tyrosinase inhibitory activity similar to that of kojic acid, which is a positive control group.

<실험예 3> PPAR 분석<Experimental Example 3> PPAR analysis

20㎕ 시료, 10㎕ 4X Fluormone Pan-PPAR Green을 384 well plate에 분주하였으며 10㎕ 4X PPARα-LBD/Tb-anti-GST 또는 10㎕ 4X PPARγ-LBD/Tb-anti-GST 항체를 각각 PPARα와 PPARγ 분석에 사용하였다. 이때, 시료 화합물을 DMSO에 용해시켜 최종 시료 농도를 100μM로 사용하였으며, DMSO 최종 농도를 1% 이내로 유지하였다. 상기 반응혼합물을 2 내지 6 시간 동안 실온에서 방치한 후, 마이크로플레이트리더 (Hewlett Packard)를 이용하여 exitation : 340nm, emmition : 485 nm 및 exitation : 340nm, emmition : 520 nm에서 각각 흡광도를 측정하여 520 nm / 485 nm 값을 계산하였다. 이때, 음성대조군이 100이라고 가정하였을 때 100에서 음성대조군에 대한 각각 시료들의 값을 뺀 수치를 경쟁활성율(competitive activation rate)이라고 정의 하였습니다. 즉, 경쟁활성율은 음성대조군에 대한 각각 시료들의 결합 비율을 의미한다.20 μL sample, 10 μL 4X Fluormone Pan-PPAR Green was dispensed into 384 well plate and 10 μL 4X PPARα-LBD / Tb-anti-GST or 10 μL 4X PPARγ-LBD / Tb-anti-GST antibody was used for PPARα and PPARγ, respectively. Used for analysis. At this time, the sample compound was dissolved in DMSO to use a final sample concentration of 100 μM, and the final concentration of DMSO was maintained within 1%. The reaction mixture was allowed to stand at room temperature for 2 to 6 hours and then the absorbance was measured at exitation 340 nm, emittion 485 nm and exitation 340 nm and emissive 520 nm using a microplate reader (Hewlett Packard) / 485 nm was calculated. At this time, when the negative control group is assumed to be 100, a value obtained by subtracting the values of the respective samples for the negative control group from 100 is defined as the competitive activation rate. That is, the competitive activity rate means the binding ratio of each sample to the negative control group.

1. PPARα1. PPARα

PPARα 활성은 양성대조군인 페노피브레이트(fenofibrate)의 결합활성이 높지 않아 3단계로 나누었다. 즉, 양성대조군과 비슷한 값(3~10)은 '≒ feno', 양성대조군보다는 활성이 조금 강한 값(10~25)은 '> feno', 활성이 매우 강한 값(25~)은 '>> feno' 로 나타내었으며, 측정시 음성대조군보다 높은 값이 나온 물질을 'ND' 라고 정의하였다. ND가 나오는 이유는 시료 화합물 자체에서 형광을 띄기 때문이라 사료된다. PPARα activity was divided into three steps because the binding activity of the positive control fenofibrate was not high. In other words, 'feno' is similar to positive control (3 ~ 10), '> feno' is more active than positive control (10 ~ 25) feno ', and a substance having a higher value than the negative control in the measurement was defined as' ND'. The reason for the occurrence of ND is that the sample compound itself fluoresces.

도 3에 도시된 바와 같이, 화합물 10, 15 및 23이 양성대조군인 페노피브레이트보다 매우 뛰어난 PPARα 활성화제인 것으로 확인되었다.As shown in FIG. 3, compounds 10, 15 and 23 were found to be PPARα activators much better than fenofibrate, a positive control.

2. PPARγ2. PPARγ

PPARγ 활성은 양성대조군인 로지글리타존(Rosiglitazone)과 비슷한 정도의 활성을 나타내는 물질을 '≒ Rosi', 로지글리타존보다 뛰어난 활성을 나타내는 물질을 '> Rosi' 로 나타내었으며, PPARα와 마찬가지로 측정시 음성대조군보다 높은 값이 나온 물질을 'ND' 라고 정의하였다. The PPARγ activity was expressed as' ≒ Rosi 'as a positive control substance and as> Rosi' as a positive control substance. Similar to that of rosiglitazone, the activity of PPARγ was higher than that of negative control This substance was defined as 'ND'.

도 4에 도시된 바와 같이, 화합물 15 및 23이 양성대조군인 로지글리타존보다 뛰어난 PPARγ 활성화제인 것으로 확인되었다.As shown in FIG. 4, compounds 15 and 23 were found to be PPARγ activators superior to the positive control rosiglitazone.

특히, PPARα 및 PPARγ를 동시에 활성화할 수 있는 활성화제로는 화합물 15 및 23을 들 수 있다.In particular, activators capable of simultaneously activating PPARα and PPARγ include compounds 15 and 23.

<실험예 4> 독성실험<Experimental Example 4> Toxicity test

웅성 Balb/c 마우스에 화합물 2, 화합물 15, 화합물 23을 0.5% 메틸셀룰로즈 용액에 각각 현탁하여 0.5g/kg, 1g/kg 및 2g/kg의 용량으로 1회 단회 경구투여하고 7일간 마우스의 생존율 및 체중을 조사하였다.In male Balb / c mice, Compound 2, Compound 15, and Compound 23 were suspended in 0.5% methylcellulose solution, respectively, and administered once orally at a dose of 0.5 g / kg, 1 g / kg, and 2 g / kg, and the survival rate of the mouse for 7 days. And body weight.

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 oral LD 50 was found to be a safe substance of 2 g / kg or more.

하기에 본 발명에 따른 화합물 23을 포함하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, the preparation examples of the composition comprising the compound 23 according to the present invention will be described, but the present invention is not intended to be limited thereto but merely to explain in detail.

<처방예 1> 약학조성물의 처방예&Lt; Prescription Example 1 > Prescription Example of Pharmaceutical Composition

<처방예 1-1> 산제의 제조&Lt; Prescription Example 1-1 > Preparation of powder

화합물 23 20 mg, 유당 100 mg 및 탈크 10 mg을 혼합하고 기밀포에 충진하여 산제를 제조하였다.A powder was prepared by mixing 20 mg of compound 23, 100 mg of lactose and 10 mg of talc and filling into an airtight bag.

<처방예 1-2> 정제의 제조&Lt; Prescription Example 1-2 > Preparation of tablets

화합물 23 20 mg, 옥수수전분 100 mg, 유당 100 mg 및 스테아린산 마그네슘 2 mg을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.A tablet was prepared by mixing 20 mg of Compound 23, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, followed by compression according to a conventional method for preparing a tablet.

<처방예 1-3> 캅셀제의 제조&Lt; Prescription Example 1-3 > Preparation of capsules

화합물 23 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 compound 23, 100 mg of corn starch, 100 mg of lactose and 2 mg of magnesium stearate were mixed, and the above ingredients were mixed and filled into gelatin capsules according to a conventional capsule preparation method to prepare a capsule.

<처방예 1-4> 주사제의 제조&Lt; Prescription Example 1-4 > Preparation of injection

화합물 23 10 mg, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조하였다.10 mg of compound 23, an appropriate amount of sterile distilled water for injection, and an appropriate amount of pH adjusting agent were mixed, and then prepared in the above-described content of ingredients per ampoule (2 ml) according to a conventional method for preparing an injection.

<처방예 1-5> 연고제의 제조&Lt; Prescription Example 1-5 > Preparation of ointment preparation

화합물 23 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.Compound 23 10 mg, PEG-4000 250 mg, PEG-400 650 mg, white petrolatum 10 mg, paraoxybenzoic acid methyl 1.44 mg, 0.18 mg of paraoxybenzoic acid propyl and the remaining amount of purified water were prepared according to the conventional method for preparing an ointment. It was.

<처방예 2> 화장료 조성물의 처방예&Lt; Prescription Example 2 > Prescription Example of Cosmetic Composition

<처방예 2-1> 영양 로션의 제조&Lt; 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 23을 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 parts 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 emulsification, the mixture was thermally cooled to 50 ° C. while stirring using a stirrer, and then a small amount of perfume was added thereto. .

<처방예 2-2> 영양 크림의 제조&Lt; 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 23을 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 emulsification, the mixture was cooled to 35 ° C. while stirring using a stirrer, and then compound 23 was added, cooled to 25 ° C., and aged.

<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 23과 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 stirring, a part of purified water was added and mixed for 30 minutes, and then a part of purified water was slowly added, stirred for 30 minutes, cooled to 35 ° C, compound 23 and flavor was added, cooled to 25 ° C, and aged I was.

<처방예 3> 건강보조식품&Lt; Prescription Example 3 >

<처방예 3-1> 건강식품의 제조&Lt; Prescription Example 3-1 > Preparation of health food

화합물 23 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 건강식품을 제조하였다.1 mg of compound 23, vitamin mixture (70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B, 0.15 mg of vitamin B 2, 0.5 mg of vitamin B 6, 0.2 μg of vitamin B 12, vitamin C 10 mg, biotin 10 μg, nicotinic acid amide 1.7 mg, folic acid 50 μg, pantothenate 0.5 mg) and mineral mixture (1.75 mg ferrous sulfate, 0.82 mg zinc oxide, 25.3 mg magnesium carbonate, 15 mg potassium monophosphate, calcium diphosphate dibasic) 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg) were mixed, granules were prepared, and health food was prepared according to a conventional method.

<처방예 3-2> 건강음료의 제조&Lt; Prescription Example 3-2 > Preparation of health drink

화합물 23 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.
1 mg of compound 23, 1000 mg of citric acid, 100 g of oligosaccharide, 2 g of plum concentrate, 1 g of taurine, and purified water were added to make the total 900 ml. After stirring and heating at 85 ° C. for an hour, the resulting solution was collected by filtration into a sterilized 2 L container, sealed sterilized and then refrigerated.

Claims

A cosmetic composition for skin whitening containing a compound represented by the following Formula 1 or an isomer thereof as an active ingredient:
[Chemical Formula 1]

Wherein R ¹ to R ⁴ may be the same or different, respectively, H, OH, C 1 to C 4 alkoxy, acetoxy or halogen, X is N or C-COOH, and Y is NH ₂ , C1 to C4 alkyl or phenyl.

The cosmetic composition for skin whitening according to claim 1, wherein the compound is a compound represented by the following Chemical Formula 2:
(2)

Wherein each of R ¹ to R ⁴ may be the same or different and is any one of H, OH, and C1 to C4 alkoxy.

The compound of claim 2, wherein the compound is selected from ( E ) -2- (4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 1); ( E ) -2- (3,4-dihydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4-Dihydroxybenzylidene) hydrazinecarboxamide] (Compound 2); ( E ) -2- (2,4-dihydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (2,4-Dihydroxybenzylidene) hydrazinecarboxamide] (Compound 3); ( E ) -2- (4-hydroxy-3-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxy-3-methoxybenzylidene) hydrazinecarboxamide] (Compound 4); ( E ) -2- (3-ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (3-Ethoxy-4-hydroxybenzylidene) hydrazinecarboxamide] (Compound 5); ( E ) -2- (3-hydroxy-4-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3-Hydroxy-4-methoxybenzylidene) hydrazinecarboxamide] (Compound 6); ( E ) -2- (4-methoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Methoxybenzylidene) hydrazinecarboxamide] (Compound 7); ( E ) -2- (3,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 8); ( E ) -2- (2,4-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (2,4-Dimethoxybenzylidene) hydrazinecarboxamide] (Compound 9); ( E ) -2- (2-hydroxybenzylidene) hydrazinecarboxamide [( E ) -2- (2-Hydroxybenzylidene) hydrazinecarboxamide] (Compound 10); ( E ) -2- (3,4,5-trimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (3,4,5-Trimethoxybenzylidene) hydrazinecarboxamide] (Compound 11); And ( E ) -2- (4-hydroxy-3,5-dimethoxybenzylidene) hydrazinecarboxamide [( E ) -2- (4-Hydroxy-3,5-dimethoxybenzylidene) hydrazinecarboxamide] (Compound 12) Cosmetic composition for skin whitening, characterized in that any one selected from the group consisting of.

The cosmetic composition for skin whitening according to claim 1, wherein the compound is a compound represented by the following Chemical Formula 3:
(3)

Wherein R ¹ to R ⁴ may each be the same or different and are any of H, OH, C 1 to C 4 alkoxy, acetoxy or halogen.

The compound according to claim 4, wherein the compound is ( Z ) -2-acetamido-3- (4-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxyphenyl) acrylic acid] (Compound 13 ); ( Z ) -2-acetamido-3- (3,4-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4-dihydroxyphenyl) acrylic acid] (Compound 14); ( Z ) -2-acetamido-3- (2,4-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2,4-dihydroxyphenyl) acrylic acid] (Compound 15); ( Z ) -2-acetamido-3- (4-hydroxy-3-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxy-3-methoxyphenyl) acrylic acid] (compound 16); ( Z ) -2-acetamido-3- (3-ethoxy-4-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3-ethoxy-4-hydroxyphenyl) acrylic acid] (compound 17); ( Z ) -2-acetamido-3- (3-hydroxy-4-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3-hydroxy-4-methoxyphenyl) acrylic acid] (compound 18); ( Z ) -2-acetamido-3- (4-methoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-methoxyphenyl) acrylic acid] (Compound 19); ( Z ) -2-acetamido-3- (3,4-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4-dimethoxyphenyl) acrylic acid] (Compound 20); ( Z ) -2-acetamido-3- (3,5-dihydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,5-dihydroxyphenyl) acrylic acid] (Compound 21); ( Z ) -2-acetamido-3- (2,4-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2,4-dimethoxyphenyl) acrylic acid] (Compound 22); ( Z ) -2-acetamido-3- (2-hydroxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (2-hydroxyphenyl) acrylic acid] (Compound 23); ( Z ) -2-acetamido-3- (3,4,5-trimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (3,4,5-trimethoxyphenyl) acrylic acid] (compound 24); ( Z ) -2-acetamido-3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-hydroxy-3,5-dimethoxyphenyl) acrylic acid] (compound 25); ( E ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( E ) -2-Acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid] (Compound 26); And ( Z ) -2-acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid [( Z ) -2-Acetamido-3- (4-acetoxy-3-bromophenyl) acrylic acid] ( Compound 27) a cosmetic composition for skin whitening, characterized in that any one selected from the group consisting of.

The cosmetic composition for skin whitening according to claim 1, wherein the compound is a compound represented by Formula 4 below:
[Chemical Formula 4]

Wherein R is either OH or alkoxy of C1 to C4.

The compound of claim 6, wherein the compound is selected from ( Z ) -2-benzamido-3- (4-hydroxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-hydroxyphenyl) acrylic acid]; Or ( Z ) -2-benzamido-3- (4-methoxyphenyl) acrylic acid [( Z ) -2-Benzamido-3- (4-methoxyphenyl) acrylic acid] Whitening cosmetic composition.

delete

A pharmaceutical composition containing the compound represented by the following formula (1) or an isomer thereof as an active ingredient and selected from skin aging, skin pigmentation, wrinkles, psoriasis and eczema:
[Chemical Formula 1]

delete

It contains a compound represented by the formula (1) or an isomer thereof as an active ingredient, by the action of any one of the peroxysome proliferator-activated receptor (PPAR) selected from obesity, metabolic disease or cardiovascular disease Pharmaceutical compositions for the prevention or treatment of controlled diseases:
[Chemical Formula 1]

delete

The method according to claim 11, wherein the metabolic disease is characterized in that any one selected from hyperlipidemia, diabetes, hyperinsulinemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X) and endothelial dysfunction Pharmaceutical composition.

The pharmaceutical composition of claim 11, wherein the cardiovascular disease is any one selected from hypertension, precoagulant state, dyslipidemia, and atherosclerosis disease.