KR101506792B1 - New phenoxytriazine compound or pharmaceutically acceptable salt thereof having inhibitory activity on Hsp90 and medical use thereof - Google Patents
New phenoxytriazine compound or pharmaceutically acceptable salt thereof having inhibitory activity on Hsp90 and medical use thereof Download PDFInfo
- Publication number
- KR101506792B1 KR101506792B1 KR1020130077187A KR20130077187A KR101506792B1 KR 101506792 B1 KR101506792 B1 KR 101506792B1 KR 1020130077187 A KR1020130077187 A KR 1020130077187A KR 20130077187 A KR20130077187 A KR 20130077187A KR 101506792 B1 KR101506792 B1 KR 101506792B1
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- South Korea
- Prior art keywords
- hsp90
- pharmaceutically acceptable
- acceptable salt
- compound
- phenoxytriazine
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Abstract
본 발명은 Hsp90 억제 활성을 갖는 신규 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염 및 이의 의학적 용도에 관한 것으로, 상기 페녹시트리아진계 화합물은 Hsp90의 억제 효과가 우수하여, Hsp90의 억제를 통한 암질환 또는 퇴행성 신경질환을 일으키는 Hsp90 클라이언트 단백질의 분해를 유도하여 암질환 또는 퇴행성 신경질환과 같은 Hsp90 매개 질환의 치료 또는 예방용 의약품 또는 건강식품으로 유용하게 사용될 수 있다. The present invention relates to a novel phenoxytriazine compound having Hsp90 inhibitory activity, or a pharmaceutically acceptable salt thereof and a medicinal use thereof, wherein the phenoxy triazine compound is excellent in inhibiting effect of Hsp90, Cancer diseases or degenerative neurological diseases, thereby being useful as medicines or health foods for the treatment or prevention of Hsp90 mediated diseases such as cancer diseases or neurodegenerative diseases.
Description
본 발명은 Hsp90 억제 활성을 갖는 신규 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염 및 이의 의학적 용도에 관한 것이다. The present invention relates to a novel phenoxytriazine-based compound having Hsp90 inhibitory activity, or a pharmaceutically acceptable salt thereof and a medicinal use thereof.
Hsp90 단백질은 진핵세포 내부에 가장 많이 존재하는 샤페론 중 하나로서, 세포성장 분화, 생존에 관련된 다양한 단백질들의 안정화 및 활성 조절을 담당한다. 클라이언트 단백질로 불리는 Hsp90의 기질 단백질에는 50여 가지의 암을 유발하는 단백질들이 포함되어 있는데, Hsp90 활성이 억제될 경우 Hsp90 클라이언트 단백질들은 프로테아좀에 의해 분해된다.The Hsp90 protein is one of the most abundant chaperones within eukaryotic cells, and is responsible for the stabilization and regulation of various proteins involved in cell growth differentiation, survival. The substrate protein of Hsp90, called the client protein, contains over 50 cancer-causing proteins. When Hsp90 activity is inhibited, the Hsp90 client proteins are degraded by the proteasome.
따라서, Hsp90 활성 억제제는 다양한 암유발 단백질을 동시에 감소시키는 효과를 나타낼 수 있으므로 폭넓은 종류의 암에 적용될 수 있는 항암제로 크게 주목받고 있다. 특히, Hsp90은 다양한 암유발 단백질을 동시에 감소시키므로, 저항성을 가지는 암 치료에 효과를 나타내는 것으로 보고되어 있다. Therefore, Hsp90 activity inhibitor can attenuate various cancer-inducing proteins at the same time, and thus has attracted much attention as an anticancer agent that can be applied to a wide variety of cancers. In particular, Hsp90 has been shown to be effective in the treatment of cancer with resistance, since it simultaneously reduces various cancer-inducing proteins.
또한, Hsp90 클라이언트 단백질 중에는 퇴행성 신경질환을 일으키는 단백질도 존재하여 Hsp90 억제제가 퇴행성 신경질환 치료제로서도 활용될 수 있음이 보고되어 있다.In addition, it has been reported that Hsp90 inhibitor may be used as a therapeutic agent for degenerative neurological diseases, because proteins that cause degenerative neuropathy are also present in the Hsp90 client proteins.
한편, 한국공개특허 제2007-0038565호에서는 Hsp90 억제제로서 1H-인다졸-6-올 화합물 및 그의 염을 개시하고 있다.Korean Patent Publication No. 2007-0038565 discloses 1H-indazol-6-ol compounds and salts thereof as Hsp90 inhibitors.
본 발명에서는 새로운 구조의 Hsp90 억제제를 개발하여, 이를 비소세포성 폐암을 포함한 암질환 치료제 또는 알츠하이머병을 포함한 퇴행성 신경질환 치료제로서 사용하는 의학적 용도를 제공하고자 한다. In the present invention, a new structure of Hsp90 inhibitor is developed, and it is intended to provide a medical use for treating a cancer disease including non-small cell lung cancer or a therapeutic agent for a neurodegenerative disease including Alzheimer's disease.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 제공한다:In order to accomplish the above object, the present invention provides a phenoxytriazine compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
R1, R2 또는 R3는 각각 동일하거나 다를 수 있으며, 수소, 하이드록시, C1 내지 C4의 알킬 및 C1 내지 C4의 알콕시로 이루어진 군에서 선택된 어느 하나이며,R 1 , R 2 or R 3 may be the same or different and is any one selected from the group consisting of hydrogen, hydroxy, C 1 to C 4 alkyl and C 1 to C 4 alkoxy,
X는 염소, 브롬, 요오드 또는 불소에서 선택된 할로겐 원소일 수 있다.X may be a halogen element selected from chlorine, bromine, iodine or fluorine.
또한, 본 발명은 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 Hsp90(Heat Shock Protein 90: 열충격단백질 90) 매개 질환 치료 또는 예방용 약학조성물을 제공한다.The present invention also provides a pharmaceutical composition for treating or preventing Hsp90 (Heat Shock Protein 90: heat shock protein 90) -mediated disease comprising the phenoxytriazine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient do.
또한, 본 발명은 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 Hsp90(Heat Shock Protein 90: 열충격단백질 90) 매개 질환 예방 또는 개선용 건강식품을 제공한다.The present invention also provides a health food for preventing or ameliorating Hsp90 (Heat Shock Protein 90: Heat shock protein 90) mediated diseases comprising the phenoxytriazine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient do.
본 발명에 따른 페녹시트리아진계 화합물은 Hsp90의 억제 효과가 우수하여, Hsp90의 억제를 통한 암질환 또는 퇴행성 신경질환을 일으키는 Hsp90 클라이언트 단백질의 분해를 유도하여 암질환 또는 퇴행성 신경질환과 같은 Hsp90 매개 질환의 치료 또는 예방용 의약품 또는 건강식품으로 유용하게 사용될 수 있다. The phenoxytriazine compound according to the present invention is excellent in the inhibitory effect of Hsp90 and induces the degradation of Hsp90 client protein causing cancer or degenerative neurological disease through inhibition of Hsp90 and thereby inhibits Hsp90 mediated diseases such as cancer diseases or degenerative neurological diseases Or as a medicament or a health food for the treatment or prevention of < / RTI >
도 1은 본 발명에 따른 페녹시트리아진계 화합물의 H1975 세포 증식 억제 효과를 나타낸 것이고,
도 2는 본 발명에 따른 페녹시트리아진계 화합물의 Hsp90 연관 단백질 저해 효과를 보여주는 웨스턴 블랏 결과이고,
도 3 및 도 4는 본 발명에 따른 페녹시트리아진계 화합물 3a 및 3b의 농도별 Hsp90 연관 단백질 저해 효과를 보여주는 웨스턴 블랏 결과이고,
도 5는 본 발명에 따른 페녹시트리아진계 화합물 3b의 Hsp90 결합부위를 보여주는 사진이다. 1 shows the effect of inhibiting H1975 cell proliferation of the phenoxytriazine compound according to the present invention,
2 is a Western blotting result showing the Hsp90-related protein inhibitory effect of the phenoxytriazine compound according to the present invention,
FIGS. 3 and 4 are Western blotting results showing Hsp90-related protein inhibitory effects according to the concentrations of the
5 is a photograph showing the Hsp90 binding site of the
본 발명은 하기 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 제공한다:The present invention provides a phenoxytriazine-based compound represented by the following general formula (I): or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
R1, R2 또는 R3는 각각 동일하거나 다를 수 있으며, 수소, 하이드록시, C1 내지 C4의 알킬 및 C1 내지 C4의 알콕시로 이루어진 군에서 선택된 어느 하나이며,R 1 , R 2 or R 3 may be the same or different and is any one selected from the group consisting of hydrogen, hydroxy, C 1 to C 4 alkyl and C 1 to C 4 alkoxy,
X는 염소, 브롬, 요오드 또는 불소에서 선택된 할로겐 원소일 수 있다.X may be a halogen element selected from chlorine, bromine, iodine or fluorine.
바람직하게는, 상기 페녹시트리아진계 화합물은 상기 화학식 1에서 R1, R2 또는 R3는 각각 동일하거나 다를 수 있으며, 수소, C1 내지 C2의 알킬 및 C1 내지 C2의 알콕시로 이루어진 군에서 선택된 어느 하나이며, X는 염소 또는 브롬에서 선택된 할로겐 원소일 수 있다.Preferably, the phenoxytriazine compound is represented by the general formula (1) wherein R 1 , R 2 or R 3 may be the same or different and is selected from the group consisting of hydrogen, C 1 to C 2 alkyl and C 1 to C 2 alkoxy And X may be a halogen element selected from chlorine or bromine.
상기 페녹시트리아진계 화합물은 다음 반응식 1과 같은 방법을 통해 합성할 수 있다:The phenoxytriazine compound can be synthesized by the following reaction scheme 1:
[반응식 1][Reaction Scheme 1]
즉, 본 발명의 페녹시트리아진계 화합물은 시아누르산 염화물(4)과 페놀(9a-b)을 2,6-루티딘 존재 하에서 반응시켜 2,4-다이클로로-6-치환-1,3,5-트리아진(10a-b)을 얻는 단계; 및 상기 2,4-다이클로로-6-치환-1,3,5-트리아진(10a-b)을 아세톤 용매 하에서 수산화암모늄을 처리하여 2-아미노-4-클로로-6-치환-1,3,5-트리아진(3a-b)을 얻는 단계를 거쳐 합성될 수 있다.That is, the phenoxytriazine compound of the present invention is obtained by reacting cyanuric chloride (4) and phenol (9a-b) in the presence of 2,6-lutidine to obtain 2,4-dichloro- , 5-triazine (10a-b); And 2,4-dichloro-6-substituted-1,3,5-triazine (10a-b) were treated with ammonium hydroxide in an acetone solvent to give 2-amino- , And 5-triazine (3a-b).
상기 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염은 Hsp90(Heat Shock Protein 90: 열충격단백질 90)에 결합하여 이를 억제할 수 있다.The phenoxytriazine compound or a pharmaceutically acceptable salt thereof may bind to and inhibit Hsp90 (Heat Shock Protein 90: Thermal Shock Protein 90).
상기 약제학적으로 허용가능한 염으로는 약제학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 유리산으로는 무기산과 유기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 아황산, 인산 등을 사용할 수 있고, 유기산으로는 구연산, 초산, 말레산, 퓨마르산, 글루코산, 메탄설폰산, 아세트산, 글리콘산, 석신산, 타타르산, 4-톨루엔설폰산, 갈락투론산, 엠본산, 글루탐산, 시트르산, 아스파르탄산 등을 사용할 수 있다. Such pharmaceutically acceptable salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid.
또한, 본 발명의 페녹시트리아진계 화합물은 약제학적으로 허용가능한 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, the phenoxytriazine-based compound of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 화합물을 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.
본 발명에 따른 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염은 Hsp90 활성을 억제하며, Her2, Met, Akt 등의 암유발 단백질을 감소시키고, Hsp70을 증가시키고, 더불어, 분자 모델링을 통해 이러한 화합물들이 Hsp90 단백질의 N-말단 ATP 포켓에 결합함을 확인하였다.The phenoxytriazine compound according to the present invention or a pharmaceutically acceptable salt thereof inhibits Hsp90 activity, reduces cancer-causing proteins such as Her2, Met and Akt, increases Hsp70 and, in addition, Confirming that the compounds bind to the N-terminal ATP pocket of the Hsp90 protein.
본 발명은 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 Hsp90(Heat Shock Protein 90: 열충격단백질 90) 매개 질환 치료 또는 예방용 약학조성물을 제공한다.The present invention provides a pharmaceutical composition for the treatment or prevention of Hsp90 (Heat Shock Protein 90: heat shock protein 90) -mediated disease comprising the phenoxytriazine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 Hsp90 매개 질환은 암질환, 퇴행성 신경질환 및 바이러스 감염증으로 이루어진 군에서 선택된 질환일 수 있다.The Hsp90 mediated disease may be a disease selected from the group consisting of cancer diseases, degenerative neurological diseases and viral infections.
상기 암질환은 비소세포성 폐암, 유방암, 자궁암 및 췌장암으로 이루어진 군에서 선택된 질환일 수 있으며, 상기 퇴행성 신경질환으로는 뇌졸중, 중풍, 기억력 상실, 기억력 손상, 치매, 건망증, 파킨슨병, 알츠하이머병, 피크(Pick)병, 크로이츠펠트-야콥(Creutzfeld-Kacob)병, 헌팅턴병 및 루게릭병으로 이루어진 군에서 선택되는 질환일 수 있다.The cancer diseases may be selected from the group consisting of non-small cell lung cancer, breast cancer, uterine cancer and pancreatic cancer. Examples of the degenerative neurological diseases include stroke, paralysis, memory loss, memory loss, dementia, forgetfulness, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease and Lou Gehrig's disease.
본 발명의 한 구체예에서, 상기 약학조성물은 약학조성물의 제조에 통상적으로 사용하는 사용하는 적절한 담체, 부형제, 붕해제, 감미제, 피복제, 팽창제, 윤활제, 활택제, 향미제, 항산화제, 완충액, 정균제, 희석제, 분산제, 계면활성제, 결합제 및 윤활제로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다.In one embodiment of the present invention, the pharmaceutical composition may be formulated with suitable carriers, excipients, disintegrants, sweeteners, coatings, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers , At least one additive selected from the group consisting of a bacteriostatic agent, a diluent, a dispersant, a surfactant, a binder and a lubricant.
구체적으로 담체, 부형제 및 희석제는 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 및 광물유를 사용할 수 있으며, 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제할 수 있다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용할 수 있다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 있으며 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기재로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. 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. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
본 발명의 다른 구체예에서, 상기 약학조성물은 통상적인 방법에 따라 과립제, 산제, 피복정, 정제, 환제, 캡슐제, 좌제, 겔, 시럽, 즙, 현탁제, 유제, 점적제 또는 액제로 제형화하여 사용할 수 있다.In another embodiment of the present invention, the pharmaceutical composition may be formulated into granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, Can be used.
본 발명의 일실시예에 따르면, 상기 약학조성물은 정맥내, 동맥내, 복강내, 근육내, 동맥내, 복강내, 흉골내, 경피, 비측내, 흡입, 국소, 직장, 경구, 안구내 또는 피내 경로를 통해 통상적인 방식으로 대상체로 투여할 수 있다.According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, Can be administered to the subject in a conventional manner via the intradermal route.
상기 페녹시트리아진계 화합물의 바람직한 투여량은 대상체의 상태 및 체중, 질환의 종류 및 정도, 약물 형태, 투여경로 및 기간에 따라 달라질 수 있으며 당업자에 의해 적절하게 선택될 수 있다. 본 발명의 일실시예에 따르면 이에 제한되는 것은 아니지만 1일 투여량이 0.01 내지 200 mg/kg, 구체적으로는 0.1 내지 200 mg/kg, 보다 구체적으로는 0.1 내지 100 mg/kg 일 수 있다. 투여는 하루에 한 번 투여할 수도 있고 수회로 나누어 투여할 수도 있으며, 이에 의해 본 발명의 범위가 제한되는 것은 아니다.The preferred dosage of the phenoxytriazine compound may be varied depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
본 발명에 있어서, 상기 '대상체'는 인간을 포함하는 포유동물일 수 있으나, 이들 예에 한정되는 것은 아니다.In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
또한 본 발명은 화학식 1로 표시되는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 Hsp90(Heat Shock Protein 90: 열충격단백질 90) 매개 질환 예방 또는 개선용 건강식품을 제공한다.The present invention also provides a health food for preventing or improving Hsp90 (Heat Shock Protein 90: Heat shock protein 90) -mediated disease comprising the phenoxytriazine compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient .
본 발명의 한 구체예에서, 상기 건강식품은, 전체 건강식품 100 중량부에 대하여 페녹시트리아진계 화합물을 0.01 내지 90 중량부, 0.1 내지 90 중량부, 1 내지 90 중량부, 또는 10 내지 90 중량부로 포함할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, the health food comprises 0.01 to 90 parts by weight, 0.1 to 90 parts by weight, 1 to 90 parts by weight, or 10 to 90 parts by weight of the phenoxytriazine compound, But are not limited thereto.
본 발명의 다른 구체예에서, 상기 건강식품은 유기산, 인산염, 항산화제, 유당 카제인, 덱스트린, 포도당, 설탕 및 솔비톨로 이루어진 군에서 선택되는 하나 이상의 첨가제를 추가로 포함할 수 있다. 유기산은 이에 제한되는 것은 아니지만 구연산, 후말산, 아디픽산, 젖산 또는 사과산일 수 있으며, 인산염은 이에 제한되는 것은 아니지만 인산나트륨, 인산칼륨, 산성피로인산염 또는 폴리인산염(중합인산염)일 수 있으며, 항산화제는 이에 제한되는 것은 아니지만 폴리페놀, 카테킨, 알파-토코페롤, 로즈마리 추출물, 감초 추출물, 키토산, 탄닌산 또는 피틴산 등의 천연 항산화제일 수 있다.In another embodiment of the present invention, the health food may further comprise at least one additive selected from the group consisting of organic acids, phosphates, antioxidants, lactose casein, dextrin, glucose, sugar and sorbitol. The organic acid can be, but is not limited to, citric acid, fumaric acid, adipic acid, lactic acid or malic acid, and the phosphate can be sodium phosphate, potassium phosphate, acid pyrophosphate or polyphosphate (polymeric phosphate) But are not limited to, natural antioxidants such as polyphenols, catechins, alpha-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid or phytic acid.
본 발명의 또 다른 구체예에서, 상기 건강식품은 상기 유효성분 이외에도 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 또한 본 발명의 일실시예에 따른 식품 조성물은 천연 과일 주스, 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In another embodiment of the present invention, the health food may contain flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and aging agents (cheese, chocolate, etc.) Organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the food composition according to one embodiment of the present invention may contain flesh for the production of natural fruit juice, fruit juice drink and vegetable drink.
본 발명의 일실시예에 따르면, 건강식품의 제형은 이에 제한되는 것은 아니지만 고형, 분말, 과립, 정제, 캡슐, 액상 또는 음료 형태일 수 있다. According to one embodiment of the invention, the formulation of a health food may be in the form of solid, powder, granule, tablet, capsule, liquid or drink, although not limited thereto.
또한 상기 건강식품은 이에 제한되는 것은 아니지만 과자류, 당류, 아이스크림 제품류, 유가공품, 식육제품, 어육제품, 두부류 또는 묵류, 식용유지류, 면류, 다류, 음료류, 특수영양식품, 건강보조식품, 조미식품, 얼음, 인삼제품류, 김치절임식품, 건포류, 과일, 야채, 과일 또는 야채의 건조제품, 절단제품, 과일쥬스, 야채쥬스, 이들의 혼합쥬스, 칩류, 면류, 축산가공식품, 수산가공식품, 유가공식품, 발효유식품, 두류식품, 곡류식품, 미생물발효식품, 제과제빵, 양념류, 육가공류, 산성음료수, 감초류, 허브류 등의 식품의 제조에 사용될 수 있다.
In addition, the health food includes but is not limited to confectionery, saccharides, ice cream products, dairy products, meat products, fish meat products, tofu or glue, edible oils, noodles, Dried products of ginseng products, kimchi pickles, dried fruits, fruits, vegetables, fruits or vegetables, cutting products, fruit juices, vegetable juices, mixed juice thereof, nuts, noodles, processed livestock products, processed marine products, , Fermented milk food, bean curd food, cereal food, fermented microorganism food, confectionery bakery, condiments, meat processing, acidic beverage, licorice, herb.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
<실시예 1> 화합물 3a 내지 3b 합성Example 1 Synthesis of
시아누르산 염화물(4)과 페놀(9a-b)을 2,6-루티딘 존재 하에서 실온에서 18시간 동안 반응시켜 2,4-다이클로로-6-치환-1,3,5-트리아진(10a-b)을 얻었고, 상기 2,4-다이클로로-6-치환-1,3,5-트리아진(10a-b)을 아세톤 용매 하에서 수산화암모늄을 실온에서 24시간 동안 처리하여 2-아미노-4-클로로-6-치환-1,3,5-트리아진(3a-b)을 합성하였다.Cyanuric acid chloride (4) and phenol (9a-b) were reacted at room temperature for 18 hours in the presence of 2,6-lutidine to obtain 2,4-dichloro-6-substituted-1,3,5-triazine 10a-b), and the 2,4-dichloro-6-substituted-1,3,5-triazine (10a-b) was treated with ammonium hydroxide in acetone solvent at room temperature for 24 hours to give 2-amino- 4-chloro-6-substituted-1,3,5-triazine (3a-b) was synthesized.
[반응식 2][Reaction Scheme 2]
합성된 화합물 분석을 위한 분석 방법은 다음과 같다. Merck 실리카겔 60 F254 플레이트를 이용하여 박막크로마토그래피(TLC)를 수행하였다. TLC 플레이트는 UV, p-아니스알데히드, 세륨 몰리브덴 암모늄, 닌하이드린 및 과망간산칼륨 염색의 조합을 이용하여 시각화 하였다. 플래쉬 크로마토그래피는 Merck 실리카겔 60(0.040-0.063 mm, 230-400 mesh)을 이용하여 알려진 방법(J Org Chem 43:29232925, 1978)에 따라 수행하였다. NMR 분석은 Bruker 400 (400 MHz for 1H; 100 MHz for 13C) 분광분석기를 이용하여 수행하였다. The analytical methods for analyzing the synthesized compounds are as follows. Thin film chromatography (TLC) was performed using a Merck silica gel 60 F 254 plate. TLC plates were visualized using a combination of UV, p -anisaldehyde, cerium molybdenum ammonium, ninhydrin and potassium permanganate staining. Flash chromatography was performed according to a known method ( J Org Chem 43: 29232925, 1978) using Merck silica gel 60 (0.040-0.063 mm, 230-400 mesh). NMR analysis was performed using a Bruker 400 (400 MHz for 1 H; 100 MHz for 13 C) spectrometer.
1) 화합물 3b 합성1) Synthesis of
시아누르산 염화물(0.5 g, 4.1 mmol), 2,6-자일레놀(0.75 g, 4.1 mmol) 및 2,6-루티딘(0.53 g, 4.9 mol) 혼합물을 아세톤에 첨가하여 실온에서 12시간 동안 반응시켰다. 용매인 아세톤을 감압 하에서 제거하고, 남아있는 잔사를 에틸아세테이트에 용해시켰다. 상기 유기층을 물로 세정하고 Na2SO4로 건조하며 감압 하에서 농축하여 화합물 10b를 얻었다. 상기 화합물 10b를 다음과 같이 정제하였다. 즉, 화합물 10b(0.4 g, 1.5 mmol) 및 수산화암모늄(0.68 g, 11.2 mmol)을 아세톤에 용해시켜 실온에서 12시간 동안 교반시켰다. 아세톤을 감압 하에서 제거하고, 용출액으로 헥산-에틸아세테이트(4:1) 용액을 사용하여 남아있는 잔사를 실리카겔 컬럼 크로마토그래피에 의해 정제하여 화합물 3b(수율: 89%)를 얻었다.A mixture of cyanuric chloride (0.5 g, 4.1 mmol), 2,6-xylenol (0.75 g, 4.1 mmol) and 2,6-lutidine (0.53 g, 4.9 mol) Lt; / RTI > The solvent acetone was removed under reduced pressure and the remaining residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over Na 2 SO 4 , and concentrated under reduced pressure to obtain compound 10b. The compound 10b was purified as follows. Compound 10b (0.4 g, 1.5 mmol) and ammonium hydroxide (0.68 g, 11.2 mmol) were dissolved in acetone and stirred at room temperature for 12 hours. The acetone was removed under reduced pressure, and the remaining residue was purified by silica gel column chromatography using a hexane-ethyl acetate (4: 1) solution as an eluent to obtain
Rf = 0.15 (1:4 ethyl acetate: hexane). Rf = 0.15 (1: 4 ethyl acetate: hexane).
1H NMR (400 MHz, DMSO-d6) (ppm) 2.07 (s, 6H), 7.07-7.15 (m, 3H), 8.10 (br s, 1H), 8.13 (br s, 1H); 1 H NMR (400 MHz, DMSO- d6) (ppm) 2.07 (s, 6H), 7.07-7.15 (m, 3H), 8.10 (br s, 1H), 8.13 (br s, 1H);
13C NMR (100 MHz, DMSO-d6) (ppm) 16.43, 126.30, 129.17, 130.26, 149.14, 168.74, 170.10, 170.83; ESI MS (m/e) = 251 [M+1] 13 C NMR (100 MHz, DMSO- d6 ) (ppm) 16.43, 126.30, 129.17, 130.26, 149.14, 168.74, 170.10, 170.83; ESI MS ( m / e ) = 251 [M + 1] <
2) 화합물 3a 합성2) Synthesis of
화합물 3a(수율: 69%)도 앞선 화합물 3b와 동일한 방법으로 합성하였다.
Rf = 0.11 (1:4 ethyl acetate: hexane). Rf = 0.11 (1: 4 ethyl acetate: hexane).
1H NMR (400 MHz, MeOH-d4/DMSO-d6) (ppm) 3.25 (s, 3H), 6.41 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H); ESI MS (m/e) = 253 [M+1]
1 H NMR (400 MHz, MeOH- d4 / DMSO- d6) (ppm) 3.25 (s, 3H), 6.41 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H); ESI MS ( m / e ) = 253 [M + 1] <
<실시예 2> 화합물 1a 내지 1c 합성≪ Example 2 > Synthesis of
실시예 1과 동일한 방법으로 화합물 1a 내지 1c를 합성하였다. 즉, 시아누르산 염화물(4)과 벤질알코올(5a-c)을 2,6-루티딘 존재 하에서 실온에서 18시간 동안 반응시켜 2,4-다이클로로-6-치환-1,3,5-트리아진(6a-c)을 얻었고, 상기 2,4-다이클로로-6-치환-1,3,5-트리아진(6a-c)을 아세톤 용매 하에서 수산화암모늄을 실온에서 24시간 동안 처리하여 2-아미노-4-클로로-6-치환-1,3,5-트리아진(1a-c)을 합성하였다.
[반응식 3][Reaction Scheme 3]
1) 화합물 1a 합성1)
Yield: 79%. Rf = 0.38 (2:3 ethyl acetate: hexane). Yield: 79%. Rf = 0.38 (2: 3 ethyl acetate: hexane).
1H NMR (400 MHz, CDCl3) (ppm) 3.82 (s, 3H), 4.47 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H); ESI MS (m/e) = 267 [M+1] 1 H NMR (400 MHz, CDCl 3) (ppm) 3.82 (s, 3H), 4.47 (s, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H) ; ESI MS ( m / e ) = 267 [M + 1] <
2) 화합물 1b 합성2) Synthesis of
Yield: 88%. Rf = 0.31 (2:3 ethyl acetate: hexane). Yield: 88%. Rf = 0.31 (2: 3 ethyl acetate: hexane).
1H NMR (400 MHz, MeOH-d4/DMSO-d6) (ppm) 5.35 (s, 2H), 6.06 (s, 2H), 6.92 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 7.6, 1.6 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H); ESI MS (m/e) = 281 [M+1] 1 H NMR (400 MHz, MeOH- d4 / DMSO- d6) (ppm) 5.35 (s, 2H), 6.06 (s, 2H), 6.92 (d, J = 7.6 Hz, 1H), 7.02 (dd, J = 7.6, 1.6 Hz, 1 H), 7.06 (d, J = 1.6 Hz, 1 H); ESI MS ( m / e ) = 281 [M + 1] <
3) 화합물 1c 합성3) Synthesis of
Yield: 82%. Rf = 0.23 (2:3 ethyl acetate: hexane). Yield: 82%. Rf = 0.23 (2: 3 ethyl acetate: hexane).
1H NMR (400 MHz, CDCl3) (ppm) 3.83 (s, 3H), 3.86 (s, 6H), 5.32 (s, 2H), 6.66 (s, 2H); ESI MS (m/e) = 327 [M+1]
1 H NMR (400 MHz, CDCl 3) (ppm) 3.83 (s, 3H), 3.86 (s, 6H), 5.32 (s, 2H), 6.66 (s, 2H); ESI MS ( m / e ) = 327 [M + 1] <
<실시예 3> 화합물 2a 내지 2c 합성Example 3 Synthesis of
실시예 1과 동일한 방법으로 화합물 2a 내지 2c를 합성하였다. 즉, 시아누르산 염화물(4)과 아닐린(5a-c)을 2,6-루티딘 존재 하에서 실온에서 18시간 동안 반응시켜 2,4-다이클로로-6-치환-1,3,5-트리아진(8a-c)을 얻었고, 상기 2,4-다이클로로-6-치환-1,3,5-트리아진(8a-c)을 아세톤 용매 하에서 수산화암모늄을 실온에서 24시간 동안 처리하여 2-아미노-4-클로로-6-치환-1,3,5-트리아진(2a-c)을 합성하였다.
[반응식 4][Reaction Scheme 4]
1) 화합물 2a 합성1)
Yield: 61%. Rf = 0.48 (2:3 ethyl acetate: hexane). Yield: 61%. Rf = 0.48 (2: 3 ethyl acetate: hexane).
1H NMR (400 MHz, MeOH-d4/DMSO-d6) (ppm) 7.03 (t, J = 7.6 Hz, 1H) 7.30 (t, J = 7.6 Hz, 2H), 7.71 (bs, 2H); ESI MS (m/e) = 222 [M+1]≪ 1 > H NMR (400 MHz, MeOH- d4 / DMSO- d6 ) (ppm) 7.03 (t, J = 7.6 Hz, 1H) 7.30 (t, J = 7.6 Hz, 2H), 7.71 (bs, 2H); ESI MS ( m / e ) = 222 [M + 1] <
2) 화합물 2b 합성2) Synthesis of
Yield: 63%. Rf = 0.12 (2:3 ethyl acetate: hexane). Yield: 63%. Rf = 0.12 (2: 3 ethyl acetate: hexane).
1H NMR (400 MHz, acetone-d6) (ppm) 6.80 (d, J = 8.8 Hz, 2H), 7.54 (bs, 2H), 8.22 (s, 1H), 8.59 (s, 1H); ESI MS (m/e) = 238 [M+1] 1 H NMR (400 MHz, acetone- d6 ) (ppm) 6.80 (d, J = 8.8 Hz, 2H), 7.54 (bs, 2H), 8.22 (s, 1H), 8.59 (s, 1H); ESI MS ( m / e ) = 238 [M + 1] <
3) 화합물 2c 합성3) Synthesis of
Yield: 77%. Rf = 0.12 (1:4 ethyl acetate: hexane). Yield: 77%. Rf = 0.12 (1: 4 ethyl acetate: hexane).
1H NMR (400 MHz, MeOH-d4/DMSO-d6) (ppm) 6.63 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 6.77(dt, J = 7.6 Hz, 1.6 Hz, 1H), 6.91 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.30 (d, J = 8 Hz, 1H); ESI MS (m/e) = 256 [M+1]
1 H NMR (400 MHz, MeOH- d4 / DMSO- d6) (ppm) 6.63 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 6.77 (dt, J = 7.6 Hz, 1.6 Hz, 1H), 6.91 ( dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.30 (d, J = 8 Hz, 1H); ESI MS ( m / e ) = 256 [M + 1]
<실험예 1> 세포 증식에 미치는 페녹시트리아진계 화합물의 효과 검토 <Experimental Example 1> Examination of effect of phenoxytriazine compound on cell proliferation
게피티닙 저항성 비소세포성 폐암 세포주인 H1975 세포를 L-글루타민, 스트렙토마이신(500 mg/ml), 페니실린(100 units/ml) 및 10% 우태혈청(FBS)을 포함하는 RPMI1640 배지에서 배양하였다. 세포는 37℃, 5% CO2 조건으로 배양되었고, 웰당 3000 개의 세포가 96-웰-플레이트에 분주되어 배지 부피를 100㎕로 하여 하룻밤 동안 배양되었다. Gemetitinib-resistant non-small cell lung cancer cell line H1975 cells were cultured in RPMI 1640 medium containing L-glutamine, streptomycin (500 mg / ml), penicillin (100 units / ml) and 10% fetal calf serum (FBS). Cells were cultured at 37 ° C under 5% CO 2 , and 3000 cells per well were dispensed into 96-well-plates and cultured overnight to a volume of 100 μl.
다음날, 1% DMSO를 대조군으로 하여, 다양한 농도(0, 10, 50, 70, 100 및 150 μM)의 페녹시트리아진계 화합물을 각 웰에 첨가하였다. 세포는 37℃ 에서 72시간 동안 배양되었고, 세포 생존률이 Promega Cell Titer 96 Aqueous One Solution Cell Proliferation Assay 를 사용하여 측정되었다. 첨가된 각 페녹시트리아진계 화합물 및 대조군과 배양 후, 20 μM 의 분석 기질 용액이 각 웰에 추가되었고, 플레이트는 37℃ 에서 추가로 1시간 동안 배양되었다. 490 nm의 흡광도에서 Tecan infinite F200 Pro 플레이트 리더를 사용하여 결과를 측정하였고, 측정값은 DMSO만이 처리된 대조군의 흡광도 대비 퍼센트로 표현되었다. The following day, phenothiotriazine compounds of varying concentrations (0, 10, 50, 70, 100 and 150 μM) were added to each well with 1% DMSO as a control. The cells were incubated at 37 ° C for 72 hours and cell viability was measured using the Promega Cell Titer 96 Aqueous One Solution Cell Proliferation Assay. After incubation with each added phenoxytriazine compound and the control, 20 [mu] M assay substrate solution was added to each well and the plate was incubated at 37 [deg.] C for an additional 1 hour. The results were measured using a Tecan infinite F200 Pro plate reader at 490 nm absorbance and the readings were expressed as a percentage of the absorbance of the treated group with DMSO only.
그 결과, 도 1과 같이 화합물 1b를 제외한 모든 화합물들에서 농도의존적으로 세포 증식을 억제하였다.
As a result, as shown in Fig. 1, all of the compounds except
<실험예 2> 페녹시트리아진계 화합물의 Hsp 90 연관 단백질 저해 효과 검토<Experimental Example 2> Hsp 90-related protein inhibitory effect of phenoxytriazine-based compounds
H1975 세포를 L-글루타민, 스트렙토마이신(500 mg/ml), 페니실린(100 units/ml) 및 10% 우태혈청(FBS)을 포함하는 RPMI1640 배지에서 배양하였다. 세포는 37℃, 5% CO2 조건으로 배양되었고, 60 mm 배양 디쉬 (5 Ⅹ 105/디쉬)에 분주되어 하룻밤 동안 배양되었다. H1975 cells were cultured in RPMI 1640 medium containing L-glutamine, streptomycin (500 mg / ml), penicillin (100 units / ml) and 10% fetal calf serum (FBS). Cells were cultured at 37 ° C, 5% CO 2, and cultured overnight in a 60 mm culture dish (5 × 10 5 / dish).
다음날, 1% DMSO를 음성 대조군, 겔다나마이신(GA, 1μM)을 양성 대조군으로 사용하였고, 40 μM의 농도로 각 페녹시트리아진계 화합물을 첨가하고 추가로 24시간 동안 배양하였다. 세포는 Hsp90 클라이언트 단백질(Her2, Met, Akt) 및 Hsp70, Hsp90의 발현 수준을 분석하기 위해 수득되었고, 각 지표 단백질을 웨스턴 블롯팅 하였으며, 액틴을 로딩 대조군으로 사용하였다. The following day, 1% DMSO was used as a negative control, geldanamycin (GA, 1 μM) as a positive control, each phenoxytriazine compound was added at a concentration of 40 μM and incubated for an additional 24 hours. Cells were obtained to analyze the expression levels of Hsp90 client proteins (Her2, Met, Akt) and Hsp70, Hsp90, Western blotting each indicator protein, and using actin as a loading control.
그 결과, 도 2와 같이 화합물 3a 및 3b에서 효과적으로 Hsp90 클라이언트 단백질(Her2, Met, Akt)의 발현이 감소되고, Hsp70의 발현은 증가함을 확인할 수 있었다. 한편, 화합물 1a에서는 Hsp90 클라이언트 단백질(Her2, Met)의 발현 감소가 유도되지 않았으며, Hsp70의 발현도 증가되지 않아서 화합물 1a의 세포 증식 억제효과는 Hsp90 억제와는 무관한 것으로 확인되었다.
As a result, it was confirmed that the expression of Hsp90 client protein (Her2, Met, Akt) was decreased and the expression of Hsp70 was effectively increased in the
<실험예 3> 화합물 3a 및 3b의 농도별 Hsp 90 연관 단백질 저해 효과 검토<Experimental Example 3> Inhibitory effect of Hsp 90-associated protein on the concentrations of the
실험예 1과 동일한 방법으로, 가장 효율적으로 Hsp90을 억제하는 것으로 확인된 화합물 3a 및 3b의 다양한 농도에서 Hsp90 클라이언트 단백질(Her2, Met, Akt), Hsp90 및 Hsp70의 발현 수준을 검토한 결과, 도 3 및 도 4와 같이 농도의존적으로 Hsp90 클라이언트 단백질(Her2, Met, Akt)의 발현이 감소되고, Hsp70의 발현은 증가함을 확인할 수 있었다.
As a result of examining the expression levels of Hsp90 client proteins (Her2, Met, Akt), Hsp90 and Hsp70 at various concentrations of the
<실험예 4> 화합물 3b의 Hsp 90 결합부위 확인Experimental Example 4 Confirmation of Hsp 90 Binding Site of
Molecular Graphics Laboratory of the Scripps Research Institue로부터 제공받은 Autodock 4.2 모델링을 이용하여 화합물 3b의 결합부위를 확인하였다. 100_100_100배율로 확대된 Hsp90의 N-말단 도메인의 중심 사각부위 및 0.375 Å 간격이 리간드 도킹 실험을 위해 선택되었다. The binding site of
그 결과, 도 5와 같이 상호작용하며 화합물 3b가 Hsp90 단백질의 N-말단 ATP 포켓에 결합함을 확인할 수 있었다.
As a result, it was confirmed that
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
Claims (8)
[화학식 1]
상기 화학식 1에서,
R1 및 R3가 각각 수소, R2가 C1 내지 C2의 알콕시; 또는 R1 및 R3가 각각 C1 내지 C2의 알킬, R2가 수소에서 선택된 어느 하나이며,
X는 염소임.1. A phenoxytriazine compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]
In Formula 1,
R 1 and R 3 are each hydrogen and R 2 is C 1 to C 2 alkoxy; Or an R 1 and R 3 are each a C1 to C2 alkyl, R 2 is any one selected from hydrogen,
X is chlorine.
상기 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염은 Hsp90(Heat Shock Protein 90: 열충격단백질 90)에 결합하여 이를 억제하는 것을 특징으로 하는 페녹시트리아진계 화합물 또는 이의 약제학적으로 허용가능한 염.The method according to claim 1,
Wherein the phenoxytriazine compound or a pharmaceutically acceptable salt thereof binds to and inhibits Hsp90 (Heat Shock Protein 90: Thermal Shock Protein 90), or a pharmaceutically acceptable salt thereof.
[화학식 1]
상기 화학식 1에서,
R1, R2 또는 R3는 각각 동일하거나 다를 수 있으며, 수소, 하이드록시, C1 내지 C4의 알킬 및 C1 내지 C4의 알콕시로 이루어진 군에서 선택된 어느 하나이며,
X는 염소, 브롬, 요오드 또는 불소에서 선택된 할로겐 원소임.A pharmaceutical composition for treating or preventing a cancerous disease, comprising a phenoxytriazine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[Chemical Formula 1]
In Formula 1,
R 1 , R 2 or R 3 may be the same or different and is any one selected from the group consisting of hydrogen, hydroxy, C 1 to C 4 alkyl and C 1 to C 4 alkoxy,
X is a halogen atom selected from chlorine, bromine, iodine or fluorine.
상기 암질환은 비소세포성 폐암, 유방암, 자궁암 및 췌장암으로 이루어진 군에서 선택된 질환인 것을 특징으로 하는 약학조성물.5. The method of claim 4,
Wherein said cancer is a disease selected from the group consisting of non-small cell lung cancer, breast cancer, uterine cancer and pancreatic cancer.
[화학식 1]
상기 화학식 1에서,
R1, R2 또는 R3는 각각 동일하거나 다를 수 있으며, 수소, 하이드록시, C1 내지 C4의 알킬 및 C1 내지 C4의 알콕시로 이루어진 군에서 선택된 어느 하나이며,
X는 염소, 브롬, 요오드 또는 불소에서 선택된 할로겐 원소임.1. A health food for preventing or ameliorating cancer diseases comprising an effective ingredient of a phenoxytriazine compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
In Formula 1,
R 1 , R 2 or R 3 may be the same or different and is any one selected from the group consisting of hydrogen, hydroxy, C 1 to C 4 alkyl and C 1 to C 4 alkoxy,
X is a halogen atom selected from chlorine, bromine, iodine or fluorine.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1575516A (en) * | 1977-05-09 | 1980-09-24 | Ici Ltd | Chloro-s-triazine/hexamethylenetetramine reaction products and their use in bonding rubber to copper or polyester |
| US5100459A (en) * | 1988-12-15 | 1992-03-31 | Basf Aktiengesellschaft | Substituted sulfonylureas |
| US20020040026A1 (en) * | 1996-03-27 | 2002-04-04 | Chorvat Robert John | Aryloxy-and arylthiosubstituted pyrimidines and triazines and derivatives thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1575516A (en) * | 1977-05-09 | 1980-09-24 | Ici Ltd | Chloro-s-triazine/hexamethylenetetramine reaction products and their use in bonding rubber to copper or polyester |
| US5100459A (en) * | 1988-12-15 | 1992-03-31 | Basf Aktiengesellschaft | Substituted sulfonylureas |
| US20020040026A1 (en) * | 1996-03-27 | 2002-04-04 | Chorvat Robert John | Aryloxy-and arylthiosubstituted pyrimidines and triazines and derivatives thereof |
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