KR20210018666A - Composition for inhibiting angiogenesis and uses thereof - Google Patents
Composition for inhibiting angiogenesis and uses thereof Download PDFInfo
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- KR20210018666A KR20210018666A KR1020190096603A KR20190096603A KR20210018666A KR 20210018666 A KR20210018666 A KR 20210018666A KR 1020190096603 A KR1020190096603 A KR 1020190096603A KR 20190096603 A KR20190096603 A KR 20190096603A KR 20210018666 A KR20210018666 A KR 20210018666A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Abstract
Description
혈관신생을 억제하는 데 사용하기 위한 조성물 및 그 용도에 관한 것이다.It relates to a composition for use in inhibiting angiogenesis and its use.
우리 몸의 모든 세포는 혈관에서 산소와 영양분을 공급받고 노폐물을 제거한다. 체내에서는 모세혈관이 그물망처럼 퍼져서 이와 같은 기능을 한다. 혈관은 어릴 때부터 빠르게 만들어지는데, 기존의 혈관에서 새로운 혈관을 형성하는 다단계의 과정을 혈관신생이라 일컫는다. 혈관신생은 태아기에 비해 성인이 되면서 크게 줄어든다. 그러나 성인에서도 혈관 신생이 많이 일어나는 경우가 있는데, 이는 질환과 연관된 경우가 많다. 예를 들어, 암이나 당뇨성 망막증의 경우에는 혈관 생성 증가가 일어난다. 반대로 심근경색이나 뇌경색의 경우에는 혈관 생성 억제가 일어난다. 혈관 생성은 여러 인자들이 서로 밀접하게 연관되어 혈관내피세포의 증식을 촉진하거나 억제하면서 일어난다. 이렇듯 성인에서의 혈관 신생은 많은 질환에서 병의 진행이나 치료에 중요한 역할을 한다.All cells in our body receive oxygen and nutrients from blood vessels and remove waste products. In the body, capillaries are spread like a net and function like this. Blood vessels are made rapidly from childhood, and the multi-step process of forming new blood vessels from existing blood vessels is called angiogenesis. Angiogenesis significantly decreases with adulthood compared to the prenatal period. However, there are many cases of angiogenesis in adults, which are often associated with diseases. For example, in the case of cancer or diabetic retinopathy, increased angiogenesis occurs. Conversely, in the case of myocardial infarction or cerebral infarction, angiogenesis inhibition occurs. Angiogenesis occurs when several factors are closely related to each other to promote or inhibit proliferation of vascular endothelial cells. As such, angiogenesis in adults plays an important role in disease progression or treatment in many diseases.
암세포는 무한히 증식하는 세포로 스스로의 성장을 위해 많은 영양분과 산소가 필요하다. 암세포는 이를 공급받기 위해 새로운 혈관이 필요하기 때문에, 스스로 새로운 혈관의 성장을 자극한다는 사실이 알려져 있다. 따라서, 혈관신생을 억제하는 것은 암세포의 성장을 억제하는 중요한 요소가 된다. 현재 혈관신생을 억제하는 약물은 여러 가지가 연구되어 있으나(한국 공개 특허 10-1997-0000227), 관련 질환을 정복하는데 대안적인 화합물이 여전히 요구되고 있다.Cancer cells are cells that proliferate infinitely and require a lot of nutrients and oxygen for their own growth. Because cancer cells need new blood vessels to receive them, it is known that they stimulate the growth of new blood vessels by themselves. Therefore, inhibiting angiogenesis becomes an important factor in inhibiting the growth of cancer cells. Currently, various drugs for inhibiting angiogenesis have been studied (Korean Patent Laid-Open Patent 10-1997-0000227), but alternative compounds are still required to overcome related diseases.
일 양상은 하기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 혈관신생을 억제하는데 사용하기 위한 약학적 조성물을 제공하는 것이다:One aspect is a pharmaceutical composition for use in inhibiting angiogenesis, comprising any one or more compounds selected from compounds represented by the following formulas (I) to (IV), or a pharmaceutically acceptable salt thereof, as an active ingredient Is to provide:
[화학식(Ⅰ)][Chemical Formula (Ⅰ)]
, ,
[화학식(Ⅱ)][Chemical Formula (Ⅱ)]
, ,
[화학식(Ⅲ)] [Chemical Formula (III)]
, ,
[화학식(Ⅳ)][Chemical Formula (IV)]
. .
화학식(Ⅳ)다른 양상은 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 혈관신생을 억제하는데 사용하기 위한 건강기능식품 조성물을 제공하는 것이다.Formula (IV) Another aspect is used to inhibit angiogenesis, including any one or more compounds selected from compounds represented by Formulas (I) to (IV), or a pharmaceutically acceptable salt thereof as an active ingredient. It is to provide a health functional food composition for.
또 다른 양상은 하기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 개체에게 투여하는 단계를 포함하는, 개체에서 혈관신생을 억제하는 방법을 제공하는 것이다.Another aspect is to inhibit angiogenesis in an individual comprising administering to the individual any one or more compounds selected from compounds represented by the following formulas (I) to (IV), or a pharmaceutically acceptable salt thereof. To provide a way.
본 명세서에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 명세서의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법과 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다.All technical terms used in the present specification, unless otherwise defined, are used in the same sense as those of ordinary skill in the art generally understand in the related field of the present specification. In addition, although preferred methods and samples are described herein, those similar or equivalent are included in the scope of the present invention.
일 양상은 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 혈관신생을 억제하는데 사용하기 위한 약학적 조성물을 제공한다.One aspect is a pharmaceutical composition for use in inhibiting angiogenesis, comprising as an active ingredient any one or more compounds selected from compounds represented by Formulas (I) to (IV), or a pharmaceutically acceptable salt thereof Provides.
상기 화합물 (Ⅰ)은 스코울레린(scoulerine)이라고도 하며, IUPAC명은 (13aS)-3,10-디메톡시-5,8,13,13a-테트라히드로-6H-이소퀴노[3,2-a]이소퀴놀린-2.9-디올이다.The compound (I) is also referred to as scoulerine, and the IUPAC name is (13aS)-3,10-dimethoxy-5,8,13,13a-tetrahydro-6H-isoquino[3,2-a] Isoquinoline-2.9-diol.
상기 화합물 (Ⅱ)는 PF-477736라고도 하며, IUPAC명은 (2R)-2-아미노-2-시클로헥실-N-[2-(1-메틸-1H-피라졸-4-일)-6-옥소-5,6-디히드로-1H-[1,2]디아제피노[4,5,6-cd]인돌-8-일]-아세트아미드이다. The compound (II) is also referred to as PF-477736, and the IUPAC name is (2R)-2-amino-2-cyclohexyl-N-[2-(1-methyl-1H-pyrazol-4-yl)-6-oxo -5,6-dihydro-1H-[1,2]diazepino[4,5,6-cd]indol-8-yl]-acetamide.
상기 화합물 (Ⅲ)은 VU-0365114라고도 하며, IUPAC명은 1-[(1,1'-비페닐)-4-일메틸]-5-(트리플루오로메톡시)-1H-인돌-2,3-디온이다.The compound (III) is also referred to as VU-0365114, and the IUPAC name is 1-[(1,1'-biphenyl)-4-ylmethyl]-5-(trifluoromethoxy)-1H-indole-2,3- It's Dion.
상기 화합물 (Ⅳ)는 JNJ-10191584라고도 하며, IUPAC명은 (6-클로로-1H-벤즈이미다졸-2-일)-(4-메틸피페라진-1-일)메탄온이다.The compound (IV) is also referred to as JNJ-10191584, and the IUPAC name is (6-chloro-1H-benzimidazol-2-yl)-(4-methylpiperazin-1-yl)methanone.
상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물은 이와 동일한 활성을 나타내는 유도체를 포함할 수 있다. 또한, 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물은 그의 이성질체를 포함한다.The compounds represented by the formulas (I) to (IV) may include derivatives exhibiting the same activity. In addition, the compounds represented by the formulas (I) to (IV) include isomers thereof.
본 명세서에서, “억제”란 상기 조성물의 투여에 의해 혈관신생이 감소되는 모든 행위를 의미하며, 치료를 위해 사용하는 행위를 포함한다.In the present specification, “inhibition” refers to all actions in which angiogenesis is reduced by administration of the composition, and includes actions used for treatment.
본 명세서에서 용어, “치료(treatment)”란 질병을 앓거나 또는 질병이 발병할 위험이 있는 개체에게, 상기 개체의 상태의 개선, 질병 진행의 지연, 증상 발생의 지연 또는 증상 진행의 둔화 등을 포함한 효과를 제공하는 임의의 형태의 치료 또는 예방(prevention)을 의미한다. 따라서, 용어 “치료”는 증상의 발생을 예방하는, 개체의 예방적 치료를 포함한다. 또한, 상기 “치료” 및 “예방”은 증상의 치유 또는 완전한 제거를 의미하도록 의도되지 않는다.In the present specification, the term "treatment" refers to improvement of the condition of the individual, delaying the progression of the disease, delaying the occurrence of symptoms, or slowing the progression of symptoms, etc. to an individual suffering from or at risk of developing a disease. It means any form of treatment or prevention that provides an inclusive effect. Thus, the term “treatment” includes prophylactic treatment of an individual, preventing the occurrence of symptoms. Further, the "treatment" and "prevention" are not intended to mean cure or complete elimination of symptoms.
본 명세서에서, “혈관신생(angiogenesis)”은 기존의 혈관에서 새로운 혈관을 형성하는 다단계의 과정을 뜻한다. 일 구체예에 따르면, 혈관신생이 과다하게 발생하는 것과 관련된 질환은 암, 당뇨병성 망막질환, 미숙아 망막증, 신생혈관 녹내장, 증식성 망막증, 혈관유착, 모세관 확장증, 화농성 육아종, 지루성 피부염, 동맥경화증, 자궁내막증, 비만, 류마티스 관절염, 크론병, 건선, 전립선 비대증, 또는 신사구체질환일 수 있다.In the present specification, "angiogenesis" refers to a multi-step process of forming new blood vessels from existing blood vessels. According to one embodiment, diseases related to excessive angiogenesis are cancer, diabetic retinal disease, retinopathy of prematurity, neovascular glaucoma, proliferative retinopathy, vascular adhesion, telangiectasia, purulent granulomas, seborrheic dermatitis, arteriosclerosis, Endometriosis, obesity, rheumatoid arthritis, Crohn's disease, psoriasis, enlarged prostate, or glomerular disease.
일 구체예에 따르면, 상기 “암”은 조직 내에서 무제한의 증식을 하는, 미분화된 세포로 구성된 종괴(腫塊) 또는 종양을 말한다. 상기 약학적 조성물은 어떠한 암에도 사용될 수 있으며, 췌장암, 폐암, 유방암, 위암, 간암, 대장암, 피부암, 두부 또는 경부암, 자궁암, 난소암, 뇌암, 후두암, 전립선암, 방광암, 식도암, 갑상선암, 방광암, 신장암, 또는 직장암일 수 있다.According to one embodiment, the "cancer" refers to a mass or tumor composed of undifferentiated cells that proliferates unlimitedly in a tissue. The pharmaceutical composition can be used for any cancer, and pancreatic cancer, lung cancer, breast cancer, stomach cancer, liver cancer, colon cancer, skin cancer, head or neck cancer, uterine cancer, ovarian cancer, brain cancer, laryngeal cancer, prostate cancer, bladder cancer, esophageal cancer, thyroid cancer, bladder cancer , Kidney cancer, or rectal cancer.
상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물은 유리 형태로 또는 약학적으로 허용 가능한 염의 형태일 수 있다. 상기 용어, “약학적으로 허용 가능한”은 대상체, 예컨대 인간 대상체에 투여될 때 생리학적으로 용인 가능하고, 전형적으로 알레르기 반응 또는 유사한 부작용을 생산하지 않는 조성물을 말한다. 예를 들어, 인간에서의 사용에 대하여 주 정부 또는 연방 정부의 규제 기관에 의해 승인되었거나, 대한민국 약전(Korean Pharmacopoeia), 미국 약전 또는 다른 일반적으로 인정되는 약전에 나열되었음을 의미할 수 있다.The compounds represented by Formulas (I) to (IV) may be in free form or in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable” refers to a composition that is physiologically acceptable when administered to a subject, such as a human subject, and typically does not produce an allergic reaction or similar side effects. For example, it may mean that it has been approved by a state or federal regulatory agency for use in humans, or listed in the Korean Pharmacopoeia, the US Pharmacopoeia, or other generally accepted pharmacopoeia.
본 명세서에서 용어, “염”은 상술한 화합물에서 발견된 치환기에 따라, 비교적 무독성인 산 또는 염기로 제조된 화합물의 염일 수 있다. 일 구체예의 화합물이 비교적 산성인 기능성을 함유할 때, 염기 부가 염은 이러한 중성 형태의 화합물을, 순수한(pure) 또는 적합한 불활성 용매 중에서, 충분한 양의 원하는 염기와 접촉시킴으로써 얻어질 수 있다. 약학적으로 허용 가능한 염기 부가 염의 예는 나트륨, 칼륨, 칼슘, 암모늄, 유기 아미노산, 또는 마그네슘 염, 또는 유사한 염일 수 있으나, 이에 한정되지는 않는다.In the present specification, the term “salt” may be a salt of a compound prepared with a relatively non-toxic acid or base, depending on the substituent found in the above-described compound. When the compounds of one embodiment contain relatively acidic functionality, base addition salts can be obtained by contacting the compound in its neutral form with a sufficient amount of the desired base, either in pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts may be sodium, potassium, calcium, ammonium, organic amino acids, or magnesium salts, or similar salts, but are not limited thereto.
일 구체예의 화합물이 비교적 염기성인 기능성을 함유할 때, 산 부가 염은 이러한 중성 형태의 화합물을, 순수한 또는 적합한 불활성 용매 중에서, 충분한 양의 원하는 산과 접촉시킴으로써 얻어질 수 있다. 약학적으로 허용 가능한 산 부가 염의 예는 염산, 브롬화수소산, 질산, 탄산, 일수소탄산, 인산, 일수소인산, 이수소인산, 황산, 일수소황산, 요오드화수소산, 또는 아인산 등과 같은 무기산으로부터 유래된 것들뿐만 아니라, 아세트산, 프로피온산, 아이소부티르산, 말레산, 말론산, 벤조산, 숙신산, 수베르산, 푸마르산, 만델산, 프탈산, 벤젠설폰산, p-톨릴설폰산, 시트르산, 타르타르산, 메탄설폰산 등과 같은 비교적 무독성인 유기산으로부터 유래된 염을 포함하나, 이에 한정하는 것은 아니다. 또한 아르기네이트 등과 같은 아미노산의 염, 및 글루쿠론산 또는 갈락투론산 등과 같은 유기산의 염을 포함할 수 있다.When the compounds of one embodiment contain relatively basic functionality, acid addition salts can be obtained by contacting the compound in this neutral form with a sufficient amount of the desired acid, either in pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts are derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbon acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid, or phosphorous acid. In addition to those, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Salts derived from such relatively non-toxic organic acids are included, but are not limited thereto. It may also include salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid.
일 구체예의 어떤 특정 화합물은 화합물을 염기 또는 산 부가 염으로 전환시키는 염기성 및 산성 기능성 둘 다를 함유할 수도 있다.Certain specific compounds of one embodiment may contain both basic and acidic functionality that converts the compound into a base or acid addition salt.
중성 형태의 화합물은 염을 염기 또는 산과 접촉시키고 통상적인 방식으로 모체 화합물을 단리시킴으로써 재생될 수도 있다. 화합물의 모체 형태는 다양한 염 형태와는 특정 물리적 성질, 예컨대 극성 용매에서의 용해도가 상이하지만, 그렇지 않으면 염은 구체예의 목적을 위해 화합물의 모체 형태와 동등할 수 있다.The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salt may be equivalent to the parent form of the compound for the purposes of embodiments.
상기 조성물의 활성 성분은, 일반적으로 비독성인 제약상 허용되는 담체와 함께 혼합될 수 있다. 사용 가능한 담체에는 고체상, 반고체상 또는 액체상의 포도당, 유당, 아라비아 고무, 젤라틴, 만니톨, 전분 페이스트, 삼규산 마그네슘염, 활석, 옥수수 전분, 각질, 코로이드성 실리카, 감자 전분, 우레아, 쇄 길이가 중간 정도인 트리글리세리드, 덱스트란 및 제제의 제조에 사용하기에 적합한 기타 담체를 포함할 수 있다.The active ingredients of the composition may be mixed with a pharmaceutically acceptable carrier, which is generally non-toxic. Available carriers include solid, semi-solid or liquid glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, and chain length. Medium triglycerides, dextran and other carriers suitable for use in the preparation of the formulation may be included.
활성 성분을 포함하는 약학적 조성물은 경구용으로 사용하기에 적합한 제형, 예를 들면 다층정, 유핵정, 속방정, 당의정, 필름코팅정, 장용코팅정, 젤라틴 코팅정, 저작정, 속붕해정(orally disintegrating tablet), 서방정, 구강정(박칼정), 설하정, 구중정(트로키제), 내복용 산제, 외복용 산제, 과립제, 경질 및 연질캡슐제, 환제, 마이크로캡슐, 시럽제, 엘릭서제, 주정제, 방향수제, 레모네이드제 또는 콜로디온제일 수 있다. 경구용으로 사용되는 조성물은 제약 조성물의 제조를 위해 당 업계에 공지된 임의의 방법에 따라 제조될 수 있고, 이들 조성물은 약제학적으로 우수하고 입에 맞는 제제를 제공하기 위해 결합제, 붕해제, 활택제, 감미제, 착색제 등과 같은 첨가제들을 포함할 수 있다.Pharmaceutical compositions containing the active ingredient are formulated for oral use, such as multi-layered tablets, nucleated tablets, immediate-release tablets, dragees, film-coated tablets, enteric-coated tablets, gelatin-coated tablets, chewable tablets, fast disintegrating tablets ( orally disintegrating tablet), sustained-release tablet, oral tablet (bakkal tablet), sublingual tablet, gujung tablet (troche), powder for internal use, powder for external use, granules, hard and soft capsules, pills, microcapsules, syrup, elixir, It may be a spirit tablet, a fragrance, a lemonade, or a collodion. Compositions used for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and these compositions are excellent in pharmaceutically and in order to provide a formulation suitable for the mouth, a binder, a disintegrant, a lubricant Additives such as agents, sweeteners, colorants, and the like may be included.
상기 결합제는 의약품의 분말 입자 간의 부착력을 증가시키고 결합력을 주어 성형을 용이하게 하고, 정제의 물리적인 형태를 유지시키는 역할을 하는 것으로, 백당, 포도당, 전분, 젤라틴, 포비돈, 셀룰로오스 유도체, 분무건조유당, 무수유당, 미결정셀룰로오스, 메틸 셀룰로오스, 및 인산일수소칼슘에서 선택되는 어느 하나 이상일 수 있다.The binder increases the adhesion between the powder particles of a pharmaceutical product and provides bonding force to facilitate molding and maintains the physical shape of the tablet.Sucrose, glucose, starch, gelatin, povidone, cellulose derivatives, spray-dried lactose , Anhydrous lactose, microcrystalline cellulose, methyl cellulose, and may be any one or more selected from calcium monohydrogen phosphate.
상기 붕해제는 고형제가 흡수되기 전에 소화관에서 분해되어지기 위해 확장하는 데 필요한 것으로, 전분, 전호화전분, 카르복시메틸셀룰로오스, 알긴산, 메틸셀룰로오스, 전분글리콜산나트륨, 크로스포비돈 또는 크로스카멜로오스일 수 있으나, 이에 한정되는 것은 아니다.The disintegrant is required to expand to be decomposed in the digestive tract before the solid agent is absorbed, and may be starch, pregelatinized starch, carboxymethylcellulose, alginic acid, methylcellulose, sodium starch glycolate, crospovidone or croscarmellose. , But is not limited thereto.
상기 활택제는 의약품의 제조 시 미끄러움을 제공하여 마찰을 감소시키기 위해 사용하는 물질로, 탈크, 옥수수전분, 연무질이산화규소, 라우릴황산나트륨, 폴리에틸렌 글리콜, 스테아린산마그네슘, 스테아린산칼슘, 왁스, 및 이의 임의의 조합일 수 있다.The lubricant is a substance used to reduce friction by providing slipperiness in the manufacture of pharmaceuticals.Talc, corn starch, aerosol silicon dioxide, sodium lauryl sulfate, polyethylene glycol, magnesium stearate, calcium stearate, wax, and any thereof It may be a combination of.
상기 감미제는 식품 또는 의약 조성물에 감미를 부여함으로써 복약 순응도를 향상시킬 목적으로 부가하는 첨가제를 의미한다. 상기 감미제는 약제학적으로 허용되는 임의의 감미제일 수 있으며, 예를 들어 설탕, 수크랄로스, 프락토올리고당, 자일리톨, 말토덱스트린, 스테비아 추출물(stevioside), 아스파탐, 올리고당, 소르비톨, 과당, 꿀, 엿기름, 물엿, 요리당, L-글루타민산, L-글루타민산나트륨, 사카린, 사카린나트륨, 구연산, 주석산, 주석산나트륨, 젖산 아디핀산, 푸마르산, 푸마르산나트륨, 감자 추출물(피로즐친), 감초 추출물(glycyrrhetenic acid), 타강카 추출물(monellin), 타우마틴, 아세설팜, 둘신, 시클라민산나트륨(cyclamate sodium), 및 이들의 임의의 조합에서 선택될 수 있으나, 이에 한정된 것은 아니다.The sweetening agent refers to an additive added for the purpose of improving medication compliance by imparting sweetness to a food or pharmaceutical composition. The sweetener may be any sweetener that is pharmaceutically acceptable, for example sugar, sucralose, fructooligosaccharide, xylitol, maltodextrin, stevioside, aspartame, oligosaccharide, sorbitol, fructose, honey, malt, starch syrup , Cooking sugar, L-glutamic acid, L-glutamic acid sodium, saccharin, saccharin sodium, citric acid, tartaric acid, sodium tartrate, lactic acid adipic acid, fumaric acid, sodium fumarate, potato extract (pyrozelzine), licorice extract (glycyrrhetenic acid), taganca extract (monellin), taumatin, acesulfame, dulcin, sodium cyclamate, and any combination thereof, but are not limited thereto.
상기 착색제는 제조 과정에서의 변색을 보충하고, 식욕을 돋우기 위해서 식품에 첨가하는 색소를 말하는 것으로, 캐러멜, 카로틴, 수용성 안나토, 황산구리, 산화제이철, 구리, 철 클로로필린나트륨, 산화티타늄 및 이들의 임의의 조합에서 선택될 수 있다.The colorant refers to a colorant added to food to supplement discoloration in the manufacturing process and to increase appetite.Caramel, carotene, water-soluble annato, copper sulfate, ferric oxide, copper, sodium iron chlorophyllin, titanium oxide, and their It can be selected from any combination.
또한, 비독성의 약학적으로 허용되는 부형제와 함께 활성 성분을 포함하는 정제는 공지의 방법에 의해 제조될 수 있다. 사용되는 부형제는, 예를 들면 옥수수전분, 미결정셀룰로오스, 감자전분, 덱스트린, 밀전분, 알긴산나트륨, 유당, 메틸셀룰로오스, 백당, 카르복시메틸셀룰로오스나트륨, 포도당, 카올린, 과당, 요소, 만니톨, 콜로이드성실리카겔, 침강탄산칼슘, 히드록시프로필스타치, 합성규산알루미늄, 히드록시프로필메칠셀룰로오스, 인산일수소칼슘, 황산칼슘, 프로필렌글리콜, 염화나트륨, 카제인, 탄산수소나트륨, 젖산칼슘, 정제 라놀린, 프리모젤일 수 있다.In addition, tablets containing the active ingredient together with non-toxic pharmaceutically acceptable excipients can be prepared by known methods. Excipients used are, for example, corn starch, microcrystalline cellulose, potato starch, dextrin, wheat starch, sodium alginate, lactose, methylcellulose, sucrose, sodium carboxymethylcellulose, glucose, kaolin, fructose, urea, mannitol, colloidal silica gel. , Precipitated calcium carbonate, hydroxypropyl starch, synthetic aluminum silicate, hydroxypropyl methylcellulose, calcium monohydrogen phosphate, calcium sulfate, propylene glycol, sodium chloride, casein, sodium hydrogen carbonate, calcium lactate, purified lanolin, primogelyl water have.
정제는 피복되지 않거나 또는 위장관에서의 분해 및 흡수를 지연시키기 위해 공지의 방법으로 피복되어 보다 긴 기간 동안 작용이 유지될 수 있다. 예를 들면, 글리세릴 모노스테아레이트 또는 글리세릴 디스테아레이트와 같은 시간 지연 물질을 사용할 수 있다. 이들은 또한 피복되어 방출을 제어하기 위한 삼투성 치료 정제를 형성할 수 있다.The tablets may be uncoated or coated in a known manner to delay decomposition and absorption in the gastrointestinal tract so that the action can be maintained for a longer period of time. For example, it is possible to use a time delay material such as glyceryl monostearate or glyceryl distearate. They can also be coated to form osmotic therapeutic tablets to control release.
일부의 경우에서, 경구용 제제는 활성 성분이 비활성 고체상 희석제, 예를 들면 탄산 칼슘, 인산 칼슘 또는 카올린과 혼합되는 경질 젤라틴 캡슐의 형태로 사용될 수 있다. 또한, 이들은 활성 성분이 물 또는 유상 매질, 예를 들면 땅콩유, 액상 파라핀 또는 올리브유와 혼합되는 연성 젤라틴 캡슐의 형태일 수 있다.In some cases, oral preparations can be used in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid-phase diluent, such as calcium carbonate, calcium phosphate or kaolin. In addition, they may be in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.
상기 약학적 조성물은 무균의 주사 가능 현탁액 형태일 수 있다. 이와 같은 현탁액은 적합한 분산제 또는 습윤제 및 현탁제를 사용하여 공지의 방법에 따라 제제될 수 있다. 또한, 무균 주사 가능 제제는 비독성의 비경구적으로 허용되는 희석제 또는 용액제 중의 무균 주사 가능 용액제 또는 현탁제, 예를 들면 1,3-부탄디올 중의 용액제일 수 있다. 무균 고정유는 통상적으로 용매 또는 현탁 매질로 사용된다. 이와 같은 목적을 위하여, 합성 모노- 또는 디글리세리드, 지방산, 참기름과 같은 천연 식물성유, 코코넛유, 땅콩유, 목화씨유 등 또는 에틸 올레에이트 등과 같은 합성 지방 운반제를 포함하는 임의의 무자극성 고정유가 사용될 수 있다. 필요에 따라 완충제, 보존제 등이 혼입될 수 있다.The pharmaceutical composition may be in the form of a sterile injectable suspension. Such suspensions can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. Further, the sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solution, for example a solution in 1,3-butanediol. Sterile fixed oils are usually used as a solvent or suspension medium. For this purpose, any non-irritating fixed oil including synthetic mono- or diglycerides, fatty acids, natural vegetable oils such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or synthetic fat carriers such as ethyl oleate, etc. Can be used. If necessary, a buffering agent, a preservative, and the like may be incorporated.
상기 분산제는 카올린, 산화알루미늄, 산화티탄, 소르비탄세스퀴올, 실리콘수지, 아라비아고무, 에틸셀룰로오스, 탄산칼슘, 벤토나이트, 카보머 및 이들의 임의의 조합으로 이루어진 군으로부터 선택될 수 있으며, 상기 희석제는 유당, 미세결정셀룰로오스, 만니톨, 수크로스, 락토스, 소르비톨, 자일리톨, 글루코스 및 이들의 임의의 조합으로 이루어진 군에서 선택되는 것일 수 있으나, 이에 한정되는 것은 아니다.The dispersant may be selected from the group consisting of kaolin, aluminum oxide, titanium oxide, sorbitan sesquiol, silicone resin, arabic rubber, ethyl cellulose, calcium carbonate, bentonite, carbomer, and any combination thereof, and the diluent It may be selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and any combination thereof, but is not limited thereto.
상기 완충제는 약제학적으로 허용되는 임의의 pH 완충제일 수 있으며, 알칼리금속 인산염 또는 알칼리금속 붕산염의 완충제가 있고, 더 구체적으로는 나트륨 또는 칼륨의 인산염 또는 붕산염 완충제가 있다.The buffering agent may be any pharmaceutically acceptable pH buffering agent, an alkali metal phosphate or alkali metal borate buffering agent, and more specifically, a sodium or potassium phosphate or borate buffering agent.
상기 보존제는 상기 약학적 조성물의 성상, 향, 맛, 함량, 미생물 번식의 변화를 억제하기 위한 첨가제를 의미한다. 상기 보존제는 약제학적으로 허용되는 임의의 보존제일 수 있으며, 예를 들어 벤잘코늄염화물, 벤질알코올 또는 이들의 임의의 조합일 수 있다. 상기 보존제의 함량은 약학적 조성물의 성상, 향, 맛, 함량, 미생물 번식의 변화를 억제하기 위해 필요한 양일 수 있으며, 구체적인 종류에 따라 달라질 수 있다.The preservative refers to an additive for suppressing changes in the properties, flavor, taste, content, and reproduction of microorganisms of the pharmaceutical composition. The preservative may be any pharmaceutically acceptable preservative, for example, benzalkonium chloride, benzyl alcohol, or any combination thereof. The content of the preservative may be an amount necessary to suppress changes in the properties, aroma, taste, content, and reproduction of microorganisms of the pharmaceutical composition, and may vary according to specific types.
또한 상기 약학적 조성물은 좌제로 투여될 수도 있다. 보통 온도에서는 고체상이지만 직장 강에서 액체화 또는 용해되어 약제를 방출하는 위텝솔, 마크로골, 트윈 61, 카카오지, 라우린지, 및 글리세로제라틴으로부터 선택된 하나 이상의 성분을 혼합하여 제조할 수 있다.In addition, the pharmaceutical composition may be administered as a suppository. It is solid at normal temperature, but can be prepared by mixing one or more components selected from Withepsol, Macrogol, Tween 61, cacao butter, laurinji, and glycerogeratin, which are liquidized or dissolved in the rectal cavity to release the drug.
상기 약학적 조성물은 질병의 진행 시에 또는 질병 상태에 바람직한 효과를 미치기에 약학적으로 유효한 양으로 투여한다. 상기 “약학적으로 유효한 양”은 의학적 치료에 적용 가능한 합리적인 이익/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성률 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1 kg 당 0.01 내지 100 mg 또는 치료학적으로 유효한 양을 매일 또는 격일 투여하거나, 1일 1 내지 5회로 나누어 투여할 수 있다. 그러나 유효량은 투여 경로, 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 양이 어떠한 방법으로도 범위를 한정하는 것은 아니다.The pharmaceutical composition is administered in a pharmaceutically effective amount because it exerts a desirable effect on the progression of the disease or on the disease state. The “pharmaceutically effective amount” means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the age, sex, condition, weight, and body weight of the patient. It may vary depending on the degree of absorption, inertness and excretion rate, the type of disease, and the drug used in combination, and generally 0.01 to 100 mg per 1 kg of body weight or a therapeutically effective amount is administered daily or every other day, or 1 to 5 per day. It can be administered in divided doses. However, since the effective amount may increase or decrease according to the route of administration, severity, sex, weight, age, etc., the amount is not limited in any way.
일 구체예에 따르면, 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택된 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 조성물에, 다른 항암제를 더 포함하는 조성물을 제공한다.According to an embodiment, a composition further comprising another anticancer agent in a composition comprising any one or more compounds selected from compounds represented by Formulas (I) to (IV), or a pharmaceutically acceptable salt thereof as an active ingredient Provides.
상기 항암제는 암의 치료와 예방에 사용될 수 있는 모든 물질을 의미한다. 상기 항암제는 젬시타빈, 시스플라틴, 옥살리플라틴, 5-플루오로우라실, 카페시타빈, 이리노테칸, 파클리탁셀, 베바시주맙, 세툭시맙, 에를로티닙, 테가푸르, 지메라실, 또는 오테라실일 수 있으나, 이에 한정되는 것은 아니다. 상기 약학적 조성물과 항암제의 병용 투여는 항암제 치료 전/후 또는 동시에 투여되는 것을 포함할 수 있다.The anticancer agent refers to any substance that can be used for the treatment and prevention of cancer. The anticancer agent may be gemcitabine, cisplatin, oxaliplatin, 5-fluorouracil, capecitabine, irinotecan, paclitaxel, bevacizumab, cetuximab, erlotinib, tegapur, jimeracil, or oteracil. , But is not limited thereto. The combined administration of the pharmaceutical composition and the anticancer agent may include administration before/after or simultaneously with the anticancer agent treatment.
상기 약학적 조성물은 개별 치료제로 투여하거나, 항암제 외에 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition may be administered as an individual therapeutic agent, or may be administered in combination with other therapeutic agents other than an anticancer agent, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.
다른 양상은 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 혈관신생을 억제하는데 사용하기 위한 건강기능식품 조성물을 제공한다.Another aspect is a health functional food for use in inhibiting angiogenesis, comprising any one or more compounds selected from the compounds represented by Formulas (I) to (IV), or a pharmaceutically acceptable salt thereof as an active ingredient The composition is provided.
상기 약학적 조성물에 대한 설명에서 언급된 용어 또는 요소 중 이미 언급된 것과 동일한 것은 상술한 바와 같다.Among the terms or elements mentioned in the description of the pharmaceutical composition, the same as those already mentioned are as described above.
본 명세서에서, “건강기능식품”이란, 건강보조의 목적으로 특정성분을 원료로 하거나 식품 원료에 들어있는 특정성분을 추출, 농축, 정제, 혼합 등의 방법으로 제조, 가공한 식품을 말하며, 상기 성분에 의해 생체방어, 생체리듬의 조절, 질병의 방지와 회복 등 생체조절기능을 생체에 대하여 충분히 발휘할 수 있도록 설계되고 가공된 식품을 말하는 것이다.In this specification, the term "health functional food" refers to a food manufactured and processed by extracting, concentrating, refining, mixing, or extracting, concentrating, refining, or mixing a specific ingredient contained in a food ingredient as a raw material for the purpose of health supplementation. It refers to foods designed and processed to sufficiently exert biological control functions such as biological defense, biological rhythm control, disease prevention and recovery, etc. by ingredients.
상기 건강기능식품에 포함될 수 있는 성분으로, 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물, 또는 이의 약제학적으로 허용 가능한 염을 포함하는 성분 외에, 다른 성분에는 특별한 제한이 없으며 통상의 식품과 같이 여러 가지 생약추출물, 식품 보조 첨가제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 또한, 식품 보조첨가제를 추가로 첨가할 수도 있는바, 식품보조첨가제는 당업계에 통상적인 식품보조첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함한다.As a component that can be included in the health functional food, there is no particular limitation on other components other than the component including the compound represented by Formulas (I) to (IV) or a pharmaceutically acceptable salt thereof, and Likewise, various herbal extracts, food supplements, or natural carbohydrates may be included as additional ingredients. In addition, food supplementary additives may be additionally added, and food supplementary additives include food supplementary additives common in the art, such as flavoring agents, flavoring agents, coloring agents, fillers, and stabilizers.
상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등)) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.Examples of the natural carbohydrate include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have.
상기 식품의 종류에 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 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 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함할 수 있다.There is no particular limitation on the type of food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, drinks, There are alcoholic beverages and vitamin complexes, and may include all health foods in the usual sense.
또 다른 양상은 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물로부터 선택되는 어느 하나 이상의 화합물, 또는 이의 약학적으로 허용 가능한 염을 개체에게 투여하는 단계를 포함하는, 개체에서 혈관신생을 억제하는 방법을 제공한다.Another aspect is the step of administering to the individual any one or more compounds selected from the compounds represented by Formulas (I) to (IV), or a pharmaceutically acceptable salt thereof, to inhibit angiogenesis in an individual. Provides a way.
상기 설명에서 언급된 용어 또는 요소 중 이미 언급된 것과 동일한 것은 상술한 바와 같다.Among the terms or elements mentioned in the above description, the same as those already mentioned are as described above.
본 명세서에서, “개체”란 질병의 치료를 필요로 하는 모든 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말, 및 소 등의 포유류일 수 있다.In the present specification, the term “individual” means all subjects in need of treatment of a disease, and more specifically, mammals such as human or non-human primates, mice, dogs, cats, horses, and cattle Can be
본 명세서에서, "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학적 조성물을 도입하는 것을 의미하며, 투여 경로는 목적 조직에 도달할 수 있는 한 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있다.In the present specification, "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the route of administration may be administered through various routes, either oral or parenteral, as long as it can reach the target tissue. .
일 양상에 따르면, 상기 화학식 (Ⅰ) 내지 (Ⅳ)로 표시되는 화합물에 대하여 시험관(in vitro) 및 생체 내(in vivo)에서 실험한 결과, 세포 독성에 대한 부작용은 적으면서도 대조군에 비하여 혈관신생을 현저하게 억제하는 효과가 나타남을 확인하였다. 따라서, 혈관신생을 억제함으로써 혈관신생과 관련된 질환인 암, 망막질환, 혈관질환, 건선과 같은 피부질환 등을 치료하는 데 사용할 수 있다. 특히, 암은 그 종류가 다양하므로, 여러 가지 암에 적용할 수 있으며, 다른 항암제와 병용함으로써 시너지효과를 가져올 수도 있다.According to one aspect, as a result of in vitro and in vivo experiments on the compounds represented by Formulas (I) to (IV), angiogenesis was less than that of the control group while having fewer side effects on cytotoxicity. It was confirmed that the effect of remarkably suppressing appears. Therefore, it can be used to treat angiogenesis-related diseases such as cancer, retinal diseases, vascular diseases, skin diseases such as psoriasis, by suppressing angiogenesis. In particular, since cancer has a variety of types, it can be applied to various cancers, and synergistic effects may be brought about by being used in combination with other anticancer agents.
도 1a는 일 구체예에 따라, 대조군(Con)과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 각각 1 nM, 10 nM, 100 nM의 농도로 인간탯줄정맥내피세포인 HUVEC과 접촉시키고 24시간이 지난 후 결과를 나타낸 사진이다.
도 1b는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 인간탯줄정맥내피세포인 HUVEC과 접촉시키고 24시간이 지난 후 살아있는 세포의 수를 상대적으로 정량화한 그래프이다.
도 2a는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 인간탯줄정맥내피세포인 HUVEC과 접촉시키고 6시간이 지난 후 튜브 형성의 결과를 나타낸 사진이다.
도 2b는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 인간탯줄정맥내피세포인 HUVEC과 접촉시키고 6시간이 지난 후 튜브의 길이를 상대적으로 정량화한 그래프이다.
도 2c는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 인간탯줄정맥내피세포인 HUVEC과 접촉시키고 6시간이 지난 후 Calcein-PI 염색을 한 결과를 나타낸 사진이다.
도 3a는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 췌장암 세포주인 PANC-1과 접촉시키고 24시간이 지난 후 결과를 나타낸 사진이다.
도 3b는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 췌장암 세포주인 PANC-1과 접촉시키고 24시간이 지난 후 결과를 상대적으로 정량화한 그래프이다.
도 3c는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지( Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 췌장암 세포주인 MIA-PaCa-2와 접촉시키고 24시간이 지난 후 결과를 나타낸 사진이다.
도 3d는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 100 nM의 농도로 췌장암 세포주인 MIA-PaCa-2와 접촉시키고 24시간이 지난 후 결과를 상대적으로 정량화한 그래프이다.
도 4a는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)의 농도를 동일하게 동물피하에 주입된 마트리겔에 접촉시킨 결과를 나타낸 사진이다.
도 4b는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)의 농도를 동일하게 동물피하에 주입된 마트리겔에 접촉시킨 결과를 상대적으로 정량한 그래프이다.
도 4c는 일 구체예에 따라, 대조군과 함께 화합물 (Ⅰ) 내지 (Ⅳ)의 농도를 동일하게 동물피하에 주입된 마트리겔에 접촉시킨 결과를 나타낸 표이다.1A shows, according to an embodiment, a control group (Con) and compounds (I) to (IV) at a concentration of 1 nM, 10 nM, and 100 nM, respectively, contacting human umbilical vein endothelial cells, HUVEC, and 24 hours elapsed. This is a picture showing the results after.
FIG. 1B shows, according to an embodiment, of a living cell after 24 hours of contacting compounds (I) to (IV) with human umbilical vein endothelial cells at concentrations of 1 nM, 10 nM, and 100 nM and 24 hours. It is a graph that is a relatively quantified number.
2A is a diagram illustrating a tube formation after 6 hours of contacting compounds (I) to (IV) with human umbilical vein endothelial cells at concentrations of 1 nM, 10 nM, and 100 nM, according to an embodiment, and 6 hours. This is a picture showing the results.
Figure 2b is the length of the tube after 6 hours after contacting with human umbilical vein endothelial cells HUVEC at concentrations of 1 nM, 10 nM, and 100 nM of compounds (I) to (IV) together with a control according to an embodiment. Is a relatively quantified graph.
Figure 2c is a control according to one embodiment, the compound (I) to (IV) with a concentration of 1 nM, 10 nM, 100 nM in contact with human umbilical vein endothelial cells HUVEC and after 6 hours Calcein-PI This is a picture showing the result of dyeing.
3A is a photograph showing the results after 24 hours after contacting the compounds (I) to (IV) with the pancreatic cancer cell line PANC-1 at a concentration of 1 nM, 10 nM, and 100 nM according to an embodiment, to be.
FIG. 3B is a diagram showing the results after 24 hours after contacting the compounds (I) to (IV) with the pancreatic cancer cell line PANC-1 at concentrations of 1 nM, 10 nM, and 100 nM, according to an embodiment. This is a quantified graph.
Figure 3c shows the results after 24 hours of contacting the compounds (I) to (IV) with the control group with the pancreatic cancer cell line MIA-PaCa-2 at a concentration of 1 nM, 10 nM, and 100 nM, according to an embodiment. This is the picture shown.
FIG. 3D shows the results after 24 hours of contacting compounds (I) to (IV) with a control group with a pancreatic cancer cell line MIA-PaCa-2 at a concentration of 1 nM, 10 nM, and 100 nM, according to an embodiment. This is a relatively quantified graph.
4A is a photograph showing a result of contacting Matrigel injected under the skin of an animal at the same concentration of compounds (I) to (IV) together with a control, according to an embodiment.
FIG. 4B is a graph for relatively quantifying the result of contacting Matrigel injected under the skin of an animal with the same concentration of compounds (I) to (IV) together with a control group according to one embodiment.
4C is a table showing the results of contacting Matrigel injected under the skin of an animal at the same concentration of compounds (I) to (IV) together with a control group according to one embodiment.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.
실시예 1. 실험 재료 및 실험 준비Example 1. Experimental materials and experimental preparation
1-1. 세포의 배양1-1. Cell culture
ATCC(American Type Culture Collection, ATCC, VA, USA)에서 HUVEC을 구입하였다. HUVEC은 HUVEC 배지(LONZA)에서 배양되었으며, 37 ℃를 유지하면서 인큐베이터에서 5% CO2 및 95% 공기 중으로 배양되었다.HUVEC was purchased from ATCC (American Type Culture Collection, ATCC, VA, USA). HUVECs were cultured in HUVEC medium (LONZA), and cultured in 5% CO 2 and 95% air in an incubator at 37°C.
1-2. 동물모델1-2. Animal model
이 연구는 기관 동물 관리 및 사용위원회의 규정 및 지침에 따라 승인되고 실시되었다. 동물의 고통을 최소화하고, 실험하는 동물의 수를 줄이기 위해 많은 노력을 기울였다. 오리엔트바이오(성남, 한국)에서 수컷 Balb/c 마우스를 얻었고, 상기 마우스를 동물시설에서 12 시간의 명암 사이클을 유지하면서 자유롭게 먹을 수 있는 식량과 물을 섭취하게 하였다.This study was approved and conducted in accordance with the regulations and guidelines of the Institutional Animal Care and Use Committee. A lot of effort has been made to minimize the pain of animals and to reduce the number of animals tested. Male Balb/c mice were obtained from Orient Bio (Seongnam, Korea), and the mice were allowed to consume freely edible food and water while maintaining a 12-hour light and dark cycle in an animal facility.
실시예 2. 세포 생존률 억제 효과 확인Example 2. Confirmation of the effect of inhibiting cell viability
화합물 (Ⅰ) 내지 (Ⅳ)가 세포의 생존률에 영향을 미치는지 여부를 확인하기 위하여, Cell Viability Assay를 수행하였다.In order to confirm whether compounds (I) to (IV) affect the viability of cells, a Cell Viability Assay was performed.
HUVEC 생존력에 대한 화합물 (Ⅰ) 내지 (Ⅳ)의 영향을 CCK-8 분석으로 조사하였다. 세포를 96-웰 플레이트에 시딩(seeding)을 한 후, 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 및 100 nM의 농도로 첨가하였다. 화합물이 처리되지 않은 군은 대조군으로 사용하였다. 24시간 후, CCK-8 용액(2 mg / ml) 10 μl를 각 웰에 첨가하고, 37℃에서 2시간 후, 생존 가능한 세포에 의해 형성된 CCK-8 용액의 결정물을 확인하였다. 흡광도를 측정하는 엘리자리더기(BioRad)를 사용하여 450 nm에서 OD 흡광도를 검출하고 기록하였다.The influence of compounds (I) to (IV) on HUVEC viability was investigated by CCK-8 assay. After the cells were seeded in a 96-well plate, compounds (I) to (IV) were added at concentrations of 1 nM, 10 nM, and 100 nM. The group not treated with the compound was used as a control. After 24 hours, 10 μl of a CCK-8 solution (2 mg/ml) was added to each well, and after 2 hours at 37°C, crystals of the CCK-8 solution formed by viable cells were confirmed. OD absorbance was detected and recorded at 450 nm using a biorad that measures absorbance.
그 결과, 하기 표 1, 도 1a, 및 도 1b에서 나타낸 바와 같이, 대조군(Con)과 함께 상기 화합물을 1 nM, 10 nM, 100 nM의 농도로 HUVEC에 접촉시키고 24시간이 지난 후, HUVEC의 생존이 약간 감소했으나 통계적으로 유의하지 않음을 관찰하였다. 이와 같은 결과는 화합물 (Ⅰ) 내지 (Ⅳ)의 혈관신생 억제 활성이 세포에 대한 직접적인 독성에 의한 것이 아니라 또 다른 억제 기전이 있음을 암시하며, 화합물 (Ⅰ) 내지 (Ⅳ)의 부작용이 크지 않을 것임을 예상할 수 있다.As a result, as shown in Table 1, FIG. 1A, and FIG. 1B, the compound was brought into contact with HUVEC at a concentration of 1 nM, 10 nM, and 100 nM together with a control (Con), and after 24 hours, HUVEC It was observed that survival was slightly decreased, but not statistically significant. These results suggest that the angiogenesis inhibitory activity of compounds (I) to (IV) is not due to direct toxicity to cells, but to another inhibitory mechanism, and the side effects of compounds (I) to (IV) may not be significant. Can be expected.
실시예 3. 튜브 형성 억제 효과 확인Example 3. Confirmation of the effect of inhibiting tube formation
화합물 (Ⅰ) 내지 (Ⅳ)가 튜브 형성 억제 효과를 보이는지 확인하기 위해, 관형성 어세이(tube formation assay)를 수행하였고, 생존력을 확인하기 위해, Calcein-PI(propidium iodide) 염색을 수행하였다.In order to confirm whether compounds (I) to (IV) exhibit an inhibitory effect on tube formation, a tube formation assay was performed, and in order to confirm viability, Calcein-PI (propidium iodide) staining was performed.
내피 세포의 형태 형성에 대한 화합물 (Ⅰ) 내지 (Ⅳ)의 영향을 마트리겔(BD Biosciences)에서의 모세관 형성 분석을 사용하여 실험하였다. 간략하게, 1.5×105 세포/웰의 세포 밀도로 마트리겔을 예비 코팅된 96-웰 플레이트 상에 시딩하고, 화합물을 처리하지 않은 대조군과 함께, 1, 10 및 100 nM의 농도로 상기 화합물 (Ⅰ) 내지 (Ⅳ)을 처리하여, 그 결과를 나타내었다. 6 시간 후, 배지를 제거하고 세포를 고정시키고 투과성으로 만든 후, 세포 액틴 및 핵에 대해 Calcein(Thermo Fisher Scientific, MA, USA) 및 Propidium Iodide(PI; 시그마 알드리치, St. LM, USA)를 사용하여 염색하였다. 화합물을 처리한 시료 간의 튜브 형성 차이를 확인하기 위하여, 이미지 J(NIH, ML, USA) 소프트웨어를 통해 튜브의 길이 및 폭을 통계적으로 분석하였다.The effect of compounds (I) to (IV) on the morphogenesis of endothelial cells was tested using a capillary tube formation assay in Matrigel (BD Biosciences). Briefly, Matrigel was seeded on a pre-coated 96-well plate at a cell density of 1.5×10 5 cells/well, and the compound (I) at concentrations of 1, 10 and 100 nM, along with a control group not treated with the compound, ) To (IV) were processed, and the results were shown. After 6 hours, the medium was removed, the cells were fixed and made permeable, and then Calcein (Thermo Fisher Scientific, MA, USA) and Propidium Iodide (PI; Sigma Aldrich, St. LM, USA) were used for cell actin and nuclei. And dyed. In order to confirm the difference in tube formation between the samples treated with the compound, the length and width of the tube were statistically analyzed through Image J (NIH, ML, USA) software.
그 결과, 하기 표 2, 도 2a, 및 2b에 나타낸 바와 같이, HUVEC 세포의 튜브형성이 화합물 (Ⅰ) 내지 (Ⅳ)에 의해 통계적으로 유의하게 억제됨을 관찰할 수 있었다. 또한, 2c에서 HUVEC 세포의 생존이 화합물 (Ⅰ) 내지 (Ⅳ)에 의해 큰 변화가 없음을 관찰할 수 있었다. 따라서, 화합물 (Ⅰ) 내지 (Ⅳ)는 정상세포에 대한 부작용은 적으면서도 세포의 이동(migration)을 억제시켜서 우수한 혈관신생 억제 활성을 나타냄을 확인할 수 있었다.As a result, it was observed that the tube formation of HUVEC cells was statistically significantly inhibited by compounds (I) to (IV), as shown in Table 2 below, FIGS. 2A and 2B. In addition, it was observed that the survival of HUVEC cells in 2c was not significantly changed by compounds (I) to (IV). Therefore, it was confirmed that compounds (I) to (IV) exhibited excellent angiogenesis inhibitory activity by inhibiting migration of cells while having few side effects to normal cells.
실시예 4. 췌장암 세포주 독성 확인Example 4. Pancreatic cancer cell line toxicity confirmation
각 화합물이 실제 췌장암 세포주에 억제 효과를 나타내는지 여부를 확인하기 위하여, 췌장암세포주 및 MTT를 이용한 실험을 수행하였다.In order to confirm whether each compound actually exhibits an inhibitory effect on a pancreatic cancer cell line, an experiment was performed using a pancreatic cancer cell line and MTT.
인체 췌장암 세포주 2주 (MIA PaCa-2, PANC-1)는 모두 ATCC (american type culture collection; Manassas, VA)로부터 구입하였으며, ATCC에 의해 제시된 프로토콜에 의해 세포주들을 성장 배지에서 배양하였다. 즉, PANC-1 및 MIA PaCa-2 세포는 10% 우태아혈청(FBS; Hyclone, Logan, UT)과 1% Antimycotic antibiotics(Caisson Laboratories, Rockland)가 첨가된 DMEM(Invitrogen Gibco, Grand Island, NY)에서 배양하였다. 배양한 세포를 96-웰 플레이트(Corning Inc., Corning NY)에 부착시킨 뒤, 24시간 이후 상기 화합물 (Ⅰ) 내지 (Ⅳ)를 1 nM, 10 nM, 및 100 nM의 농도로 처리하였다. 다시 24시간 이후 CCK-8를 적용하여 사진을 촬영하였다. 같은 배양액으로 96-웰 플레이트에 부착시켜 배양한 세포를 대조군으로 하였다.Two human pancreatic cancer cell lines (MIA PaCa-2, PANC-1) were all purchased from ATCC (american type culture collection; Manassas, VA), and cell lines were cultured in a growth medium according to the protocol suggested by ATCC. That is, PANC-1 and MIA PaCa-2 cells are DMEM (Invitrogen Gibco, Grand Island, NY) with 10% fetal bovine serum (FBS; Hyclone, Logan, UT) and 1% Antimycotic antibiotics (Caisson Laboratories, Rockland) added. Cultured in. After attaching the cultured cells to a 96-well plate (Corning Inc., Corning NY), the compounds (I) to (IV) were treated at concentrations of 1 nM, 10 nM, and 100 nM after 24 hours. After 24 hours, a photo was taken by applying CCK-8. Cells cultured by attaching to a 96-well plate with the same culture medium were used as a control.
그 결과, 하기 표 3 내지 4 및 도 3a 내지 3d에 나타낸 바와 같이, 췌장암 세포주에서 MTT로 약물 후보군의 세포 생존력을 측정함으로써 각 화합물의 췌장암 세포주에 대한 독성 효과 및 형태학적 변화를 관찰할 수 있었다. 췌장암 세포주에 통계적으로 유의하게 독성을 나타내므로 췌장암에 대한 치료 효과가 있다고 판단할 수 있었다.As a result, as shown in Tables 3 to 4 and FIGS. 3A to 3D, by measuring the cell viability of the drug candidate group with MTT in the pancreatic cancer cell line, toxic effects and morphological changes of each compound to the pancreatic cancer cell line could be observed. Since it was statistically significant toxic to pancreatic cancer cell lines, it could be judged that there was a therapeutic effect on pancreatic cancer.
실시예 5. 동물모델에서 혈관신생 억제 효과 확인Example 5. Confirmation of angiogenesis inhibitory effect in an animal model
각 화합물이 실제 생체 내에서 혈관신생을 억제하는지 확인하기 위해, 마트리겔 플러그 분석을 통하여 동물모델에서 혈관신생 억제 효과를 확인하는 실험을 수행하였다.In order to confirm whether each compound actually inhibits angiogenesis in vivo, an experiment was performed to confirm the angiogenesis inhibitory effect in an animal model through Matrigel plug analysis.
구체적으로, BALB/c 마우스에서의 마트리겔 플러그로 분석을 수행하였다. 수컷 BALB/c 마우스(5-6 주령)를 4개의 다른 치료군으로 무작위로 나누어 병원균이 없는 상태로 유지했다. 마우스를 각각 헤파린 (64U) 및 VEGF (150 ng / ㎖)로 처리하고, 동시에 화합물 (Ⅰ) 내지 (Ⅳ)를 5 μM의 농도로 처리한 마트리겔(BD Biosciences) 500 ㎕를 주사하였다. 마트리겔에 VEGF 및 헤파린만을 처리한 동물은 대조군으로 포함되었다. 마우스를 7일 후에 희생시키고 마트리겔 플러그를 제거하고 사진을 찍었다. 기능성 혈관 형성을 정량하기 위해 Drabkin 헤모글로빈 분석을 사용하여 헤모글로빈(Hb)의 양을 측정하였다.Specifically, analysis was performed with a Matrigel plug in BALB/c mice. Male BALB/c mice (5-6 weeks old) were randomly divided into 4 different treatment groups and kept free of pathogens. Mice were treated with heparin (64U) and VEGF (150 ng/ml), respectively, and at the same time, 500 μl of Matrigel (BD Biosciences) treated with compounds (I) to (IV) at a concentration of 5 μM was injected. Animals treated with only VEGF and heparin on Matrigel were included as controls. Mice were sacrificed after 7 days, and the Matrigel plug was removed and a picture was taken. To quantify functional blood vessel formation, the amount of hemoglobin (Hb) was measured using a Drabkin hemoglobin assay.
그 결과, 도 4에 나타낸 바와 같이, 화합물 (Ⅰ) 내지 (Ⅳ)는 마트리겔 플러그에서 혈관 신생 억제 효과를 통계적으로 유의하게 나타냄을 관찰할 수 있었다. 따라서, 상기 화합물 (Ⅰ) 내지 (Ⅳ)의 혈관 신생 억제 효과는 동물모델에서도 적용됨을 확인할 수 있었다.As a result, as shown in Fig. 4, it was observed that the compounds (I) to (IV) showed statistically significant angiogenesis inhibitory effect in the Matrigel plug. Therefore, it was confirmed that the angiogenesis inhibitory effect of the compounds (I) to (IV) was also applied to an animal model.
Claims (9)
[화학식(Ⅰ)]
,
[화학식(Ⅱ)]
,
[화학식(Ⅲ)]
,
[화학식(Ⅳ)]
. A pharmaceutical composition for use in inhibiting angiogenesis, comprising as an active ingredient any one or more compounds selected from compounds represented by the following formulas (I) to (IV), or a pharmaceutically acceptable salt thereof:
[Chemical Formula (Ⅰ)]
,
[Chemical Formula (Ⅱ)]
,
[Chemical Formula (III)]
,
[Chemical Formula (IV)]
.
[화학식(Ⅰ)]
,
[화학식(Ⅱ)]
,
[화학식(Ⅲ)]
,
[화학식(Ⅳ)]
. A method for inhibiting angiogenesis in an individual, comprising administering to the individual any one or more compounds selected from compounds represented by the following formulas (I) to (IV), or a pharmaceutically acceptable salt thereof:
[Chemical Formula (Ⅰ)]
,
[Chemical Formula (Ⅱ)]
,
[Chemical Formula (III)]
,
[Chemical Formula (IV)]
.
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KR20120004523A (en) * | 2009-04-11 | 2012-01-12 | 어레이 바이오파마 인크. | Checkpoint kinase 1 inhibitors for potentiating dna damaging agents |
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