KR20100023681A - Use in anti-cancer agent of 2,3-dihydro-5-methoxy-2-phenyl-4h-1-benzopyran-4-on - Google Patents

Use in anti-cancer agent of 2,3-dihydro-5-methoxy-2-phenyl-4h-1-benzopyran-4-on Download PDF

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KR20100023681A
KR20100023681A KR1020080082566A KR20080082566A KR20100023681A KR 20100023681 A KR20100023681 A KR 20100023681A KR 1020080082566 A KR1020080082566 A KR 1020080082566A KR 20080082566 A KR20080082566 A KR 20080082566A KR 20100023681 A KR20100023681 A KR 20100023681A
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cancer
benzopyran
dihydro
methoxy
phenyl
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이영한
임융호
용연중
신순영
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건국대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 

Abstract

PURPOSE: A 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one(5-methoxyflavanone) compound is provided to activate p53 expression, induce apoptosis, and to prevent and treat cancer. CONSTITUTION: A pharmaceutical composition for preventing and treating cancer contains 0.01-50 weight% of 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one(5-methoxyflavanone) of chemical formula 1 or its pharmaceutically acceptable salt The cancer is a cancer caused by p53 such as colon cancer, liver cancer, lung cancer, cervical cancer, bladder cancer, breast cancer, prostate cancer, and stomach cancer.

Description

2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온의 항암제로서의 용도 {Use in anti-cancer agent of 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on}Use of anti-cancer agent of 2,3-dihydro-5-methoxy-2 as anticancer agent of 2,3-dihydro-5-methoxy-2-phenyl-4eth-1-benzopyran-4-one -phenyl-4H-1-benzopyran-4-on}

본 발명은 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)] 화합물의 항암제로서의 용도에 관한 것으로, 더욱 상세하게는 p53의 발현을 활성화시키는 하기 화학식 1의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물과 상기 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물에 관한 것이다. The present invention provides 2,3-dihydro-5-methoxy-2-phenyl-4H--1-benzopyran-4-one (2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran -4-on) [aka, 5-methoxyflavanone] compound for use as an anticancer agent, and more specifically, 2,3-dihydro- of formula 1 to activate the expression of p53 Preventing and treating cancer diseases, including 5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound and the compound or a pharmaceutically acceptable salt thereof It relates to a pharmaceutical composition for.

[화학식 1][Formula 1]

Figure 112008060069979-PAT00002
Figure 112008060069979-PAT00002

세포는 성장(Growth)과 분화(Differentiation)를 통해서 내적/외적 자극에 대응하여 지속적으로 성장하기도 하고 스스로 사멸하기도 한다. 또한, 세포의 성장과 분화를 진행하기 위한 세포주기(Cell cycle) 과정은 세포의 성장/분화를 위한 준비단계와 DNA의 합성과 세포 분화 단계로 구성되며, G1, S, G2/M 단계로 순환적으로 진행된다.Through growth and differentiation, cells continue to grow and die on their own in response to internal and external stimuli. In addition, the cell cycle process for the growth and differentiation of cells consists of the preparation stage for cell growth / differentiation, the synthesis of DNA and the stage of cell differentiation, circulating in the G1, S, G2 / M stages. Proceeds to the enemy.

MDM2(Murine double mutation 2)와 결합된 p53 단백질은 불활성의 상태로 세포에 존재하지만 세포주기의 과정에서 이상 세포가 발생하면 MDM2가 분리되어 활성화된 형태로 된다. 활성화된 p53의 주요 기능은 불완전한 세포의 분화를 정지시키기 위하여 세포주기 단계 중 G2/M 단계의 진행을 정지시키고 p21 단백질의 발현을 유도하여 G1 단계에서 세포주기를 억제(Cell cycle arrest)하고, 이상 세포의 세포자기사멸을 유도하는 기능을 한다. 즉, p53에 의해서 발현되는 p21은 사이클린 D(Cyclin D)와 CDK2(Cyclin dependent kinase 2)의 복합체에 결합하여 세포주기 과정을 억제한다(Cancer Res; 68:(5), March 1, 2008).The p53 protein combined with MDM2 (Murine double mutation 2) is present in the cells in an inactive state, but when abnormal cells occur during the cell cycle, MDM2 is separated and activated. The main function of the activated p53 is to stop the progression of the G2 / M phase of the cell cycle phase and to induce the expression of p21 protein in order to stop the differentiation of incomplete cells and to inhibit the cell cycle at the G1 phase (Cell cycle arrest), Induces apoptosis of cells. That is, p21 expressed by p53 binds to a complex of Cyclin D and Cyclin dependent kinase 2 (CDK2) to inhibit cell cycle processes (Cancer Res; 68: (5), March 1, 2008).

외부의 자극이나 내부 신호 전달과정에서 생성되는 이상 세포의 성장과 분화를 억제하기 위한 과정이 세포의 사멸이다. 세포의 사멸은 네크로시스(Necrosis)와 세포자기사멸(Apoptosis)로 이루어지는데, 네크로시스는 물리적인 자극으로 인한 세포의 사멸을 의미하며 주변 세포에 염증(Inflammation)을 유발하는 것이 특징이고, 세포자기사멸은 세포의 정상적인 성장과 분화를 위해 세포의 정상 유무를 점검하고 세포의 분화에 적당하지 않은 세포는 스스로 사멸 과정으로 진행시켜 정상세 포의 항상성을 유지하는 과정이다. 또한, 세포자기사멸은 세포의 내적/외적 불완전한 요소를 제어하기 위한 과정으로 세포의 기능과 양적 균형을 이루기 위해서 스스로 조절하는 반응이다.Cell death is a process for suppressing the growth and differentiation of abnormal cells generated by external stimuli or internal signal transduction. Cell death is composed of necrosis and apoptosis. Necrosis means apoptosis due to physical stimulation and is characterized by inflammation of surrounding cells. Apoptosis is a process of maintaining normal cell homeostasis by checking whether cells are normal for normal growth and differentiation, and proceeding to self-killing of cells that are not suitable for cell differentiation. In addition, apoptosis is a process for controlling the internal and external incomplete elements of the cell is a self-regulating reaction to achieve a quantitative balance with the function of the cell.

세포의 자기사멸 과정은 세포의 응축(Condensation), 염색실(Chromatin)의 응축과 DNA의 단편을 동반하는 작은 수포(Apoptotic body)들로 분리되며, 주변 세포에 의해서 제거된다. 이러한 과정에서 정상적인 DNA보다 길이가 짧은 DNA나 일정한 크기의 DNA 조각이 제거되는 단편(DNA ladder) 현상이 나타난다(Experimental Cell Research 256, 12-18, 2000). The cell self-apoptosis process is separated into small apoptotic bodies accompanied by condensation of cells, condensation of chromatin and fragments of DNA, and removed by surrounding cells. In this process, DNA ladders, which are shorter than normal DNA or fragments of a certain size, are removed (Experimental Cell Research 256, 12-18, 2000).

또한, 이중 나선 DNA 가운데 한 가닥의 DNA에 손상이 발생하면 이를 수정 보완하기 위해서 염기제거수리(BER, Base Excision Repair) 작용이 진행된다. BER 작용의 주요 단백질인 PARP(Poly ADP-Ribose Polymerase)는 DNA의 손상된 부위(Nick)에 결합하여 손상된 DNA가 복구될 수 있도록 여러 가지 단백질이 복합체를 구성하는데 중심 역할을 하지만, 세포가 자기사멸과정으로 진행하게 되면 PARP는 단편 조각(PARP cleavage)을 생성하기 때문에 PARP의 조각 단편의 생성을 통해서 세포가 자기사멸과정 중임을 알 수 있다(Oncogene 27, 3710-3720, 2008). 따라서, PARP 조각의 생성유무와 세포주기의 억제는 암세포의 지속적인 성장을 제어하는 주요 점검 과정이다.In addition, when damage occurs in one strand of DNA of double-stranded DNA, Base Excision Repair (BER) is performed to compensate for this. PARP (Poly ADP-Ribose Polymerase), a major protein of BER action, plays a central role in complexing various proteins so that the damaged DNA can be repaired by binding to the damaged site of DNA. As PARP generates fragment fragments (PARP cleavage), it can be seen that cells are in the process of self-killing through the generation of fragment fragments of PARP (Oncogene 27, 3710-3720, 2008). Therefore, the generation of PARP fragments and the inhibition of the cell cycle are the main screening processes to control the continuous growth of cancer cells.

이에 본 발명자들은 항암 억제 단백질인 p53의 발현을 증가시켜 암세포의 세포 자기사멸 유도 및 세포주기를 억제할 수 있는 효과를 가진 화합물을 찾고자 예의 노력한 결과, 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)]이 p53 발현을 활성화시키는 것을 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have made efforts to find a compound having an effect of inhibiting the cell cycle and inducing apoptosis of cancer cells by increasing the expression of p53, an anticancer inhibitory protein, and thus, 2,3-dihydro-5-methoxy- 2-phenyl-4H-1-benzopyran-4-one (2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on) [aka, 5-methoxyflavanone ( 5-methoxyflavanone)] completed the present invention by confirming that activating p53 expression.

결국, 본 발명은 p53에 대해 발현을 증가시키는 활성을 갖는 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물 및 상기 화합물의 항암제로서의 용도를 제공하는데 그 주된 목적이 있다. Eventually, the present invention provides 2,3-dihydro-5-methoxy-2-phenyl-4ech-1-benzopyran-4-one (5-methoxyflavanone) with activity to increase expression for p53. Its main purpose is to provide a compound and its use as an anticancer agent.

상기 목적을 달성하기 위하여, 본 발명은 p53 발현을 활성화시킴으로써 세포자기사멸을 유도하고, 세포주기를 억제하는 하기 화학식 1의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)] 화합물을 제공한다.In order to achieve the above object, the present invention induces apoptosis by activating p53 expression, and inhibits the cell cycle 2,3-dihydro-5-methoxy-2-phenyl-4 H- 1-benzopyran-4-one (2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on) [aka, 5-methoxyflavanone] compound to provide.

[화학식 1][Formula 1]

Figure 112008060069979-PAT00003
Figure 112008060069979-PAT00003

또한, 본 발명은 상기의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물의 항암제로서의 용도를 제공한다.The present invention also provides the use of the above-mentioned 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound as an anticancer agent. .

구체적으로, 본 발명은 상기 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물을 제공한다. Specifically, the present invention is the 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound or a pharmaceutically acceptable thereof It provides a pharmaceutical composition for the prevention and treatment of cancer diseases, including salt.

상기 암 질환은 일반적인 암 질환을 포함하되, 특히 p53의 이상으로 야기되는 일반적인 암 질환을 포함하며, 바람직하게는 대장암, 위암, 전립선암, 유방암, 신장암, 간암, 뇌종양, 폐암, 자궁암, 결장암, 방광암, 췌장암, 혈액암 등의 예방 또는 치료에 사용될 수 있으나 이들로 한정되는 것은 아니다. The cancer disease includes general cancer diseases, in particular general cancer diseases caused by abnormalities of p53, preferably colon cancer, stomach cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, brain tumor, lung cancer, uterine cancer, colon cancer It may be used for the prevention or treatment of bladder cancer, pancreatic cancer, hematological cancer and the like, but is not limited thereto.

본 발명의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)]은 암세포에서 p53을 발현시켜 세포사멸을 유도하고 G2/M 단계의 세포주기를 억제하는 효과를 갖고 있으므로 암 예방 및 치료를 위한 약학조성물 로 유용하게 이용될 수 있다.2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one of the present invention (2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran -4-on) (also known as 5-methoxyflavanone) expresses p53 in cancer cells, induces apoptosis and inhibits the G2 / M phase cell cycle. Since it has an effect, it can be usefully used as a pharmaceutical composition for cancer prevention and treatment.

이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

본 발명은 p53 발현을 활성화시킴으로써 세포자기사멸을 유도하고, 세포주기를 억제하는 하기 화학식 1의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)] 화합물을 제공한다.The present invention induces apoptosis by activating p53 expression, and inhibits the cell cycle 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4- Provided is a (2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on) (aka 5-methoxyflavanone) compound.

[화학식 1][Formula 1]

Figure 112008060069979-PAT00004
Figure 112008060069979-PAT00004

본 발명에 있어서, 상기 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물은 식물로부터 추출, 분리하거나 당 업계에 잘 알려진 합성방법에 의해 제조가 가능하다.In the present invention, the 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound may be extracted from plants or separated from sugar It can be produced by synthetic methods well known in the art.

또한, 본 발명은 상기의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물을 제공한다. In addition, the present invention is the above 2,3-dihydro-5-methoxy-2-phenyl-4 H--1-benzopyran-4-one (5-methoxyflavanone) compound or a pharmaceutically acceptable thereof It provides a pharmaceutical composition for the prevention and treatment of cancer diseases, including salt.

본 발명에 있어서, 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4- 온(5-메톡시플라바논) 화합물은 p53 발현을 활성화시켜 세포주기 억제(Cell cycle arrest)와 세포자기사멸(Apoptosis)을 유도함으로써 암세포의 증식을 제어하는 것을 특징으로 한다.In the present invention, 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound activates p53 expression to inhibit cell cycle It is characterized by controlling the proliferation of cancer cells by inducing (Cell cycle arrest) and apoptosis.

또한, 본 발명의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물은 통상의 치환기들의 합성 및 분획 방법을 통하여도 합성할 수 있다.(Herbert O. House, Modern Synthetic Reactions, 2nd Ed., The Benjamin/Cummings Publishing Co., 1972).In addition, the 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound of the present invention is a method for synthesizing and fractionating conventional substituents. (Herbert O. House, Modern Synthetic Reactions, 2nd Ed., The Benjamin / Cummings Publishing Co., 1972).

또한, 본 발명의 조성물에 포함되는 화학식 1의 화합물은 또한 이의 염의 형태로도 사용될 수 있으며, 이러한 염은 약제학적으로나 생리학적으로 허용되는 다양한 유기산 또는 무기산과의 산 부가 염을 포함한다. In addition, the compounds of formula 1 included in the compositions of the present invention may also be used in the form of their salts, which salts include acid addition salts with various organic or inorganic acids that are pharmaceutically or physiologically acceptable.

이때, 무기산으로는 염산, 황산 등의 할로겐산 또는 인산 등을 사용할 수 있고, 유기산으로는 카르복실산, 포스폰산, 술폰산, 아세트산, 프로피온산, 옥탄산, 데칸산, 글리콜산, 락트산, 푸마르산, 숙신산, 아디프산, 말산, 타르타르산, 시트르산, 글루탐산, 아스파르트산, 말레산, 벤조산, 살리실산, 프탈산, 페닐아세트산, 벤젠술폰산, 2-나프탈렌술폰산, 메틸황산, 에틸황산, 도데실황산 등을 사용할 수 있다.At this time, a halogen acid or phosphoric acid such as hydrochloric acid and sulfuric acid may be used as the inorganic acid, and as the organic acid, carboxylic acid, phosphonic acid, sulfonic acid, acetic acid, propionic acid, octanoic acid, decanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid , Adipic acid, malic acid, tartaric acid, citric acid, glutamic acid, aspartic acid, maleic acid, benzoic acid, salicylic acid, phthalic acid, phenylacetic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, methyl sulfuric acid, ethyl sulfuric acid, dodecyl sulfate, etc. may be used. .

또한, 본 발명의 암 질환의 예방 및 치료용 약학조성물은 조성물 총 중량에 대하여 상기 화합물을 0.01 내지 50중량%로 포함한다. In addition, the pharmaceutical composition for the prevention and treatment of cancer diseases of the present invention comprises 0.01 to 50% by weight of the compound relative to the total weight of the composition.

또한, 본 발명의 조성물은 상기한 화학식 1의 화합물, 또는 이들의 화합물 이외에 약리학적으로나 생리학적으로 허용되는 담체, 부형제, 희석제를 추가로 포 함할 수 있다.In addition, the composition of the present invention may further comprise a pharmacologically or physiologically acceptable carrier, excipient, diluent in addition to the compound of formula (1), or a compound thereof.

또한, 본 발명의 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 형태 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구투여하거나 정맥내, 복강내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다. 이러한 조성물에 포함될 수 있는 적합한 담체, 부형제 및 희석제의 예로는 락토오스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 비정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수있다. 상기 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 포함할 수 있다.In addition, the composition of the present invention is formulated in various forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, oral formulations, such as aerosols, sterile injectable solutions, etc. It can be used orally and can be administered through various routes including oral administration, intravenous, intraperitoneal, subcutaneous, rectal, topical administration and the like. Examples of suitable carriers, excipients and diluents that may be included in such compositions include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, amorphous cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like. The composition may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives and the like.

경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 탄산칼슘, 수크로스, 락토오스, 젤라틴 등을 섞어 제형화한다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크와 같은 윤활제들도 사용된다.Solid preparations 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, lactose, gelatin, and the like. Mix and formulate. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

경구용 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 액체 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to commonly used simple diluents such as water and liquid paraffin.

비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동 결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 주사제의 기제로는 용해제, 등장화제, 현탁화제, 유화제, 안정화제 및 방부제와 같은 종래의 첨가제를 포함할 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. Bases for injectables may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.

본 발명에 있어서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.By "administration" in the present invention is meant to provide the patient with the desired material in any suitable way, the route of administration of the composition of the present invention being oral or parenteral via all common routes as long as the target tissue can be reached. May be administered. In addition, the composition can be administered by any device in which the active agent can migrate to the target cell.

본 발명에서 "환자"는 본 발명의 조성물을 투여하여 증상이 호전될 수 있는 질환을 가진 인간과 원숭이, 개, 염소, 돼지, 또는 쥐 등의 동물을 의미한다. 본 발명에 따른 조성물은 인간(치료, 억제 또는 예방)용일 뿐만 아니라 상업적으로 유용한 다른 동물들에게도 적용될 수 있다.In the present invention, "patient" means a human and an animal such as a monkey, dog, goat, pig, or rat having a disease that can improve symptoms by administering the composition of the present invention. The composition according to the invention can be applied not only for humans (treatment, inhibition or prevention) but also to other commercially useful animals.

다른 양태로서, 본 발명은 상기 화학식 1의 화합물 또는 약제학적으로 허용 가능한 이들의 염을 포함하는 조성물을 환자에게 투여함으로써 암과 암 전이를 억제하고, 예방 및 치료하는 방법을 제공한다. 본 발명의 조성물은 종래의 상기 질환 치료제와 병행하여 투여할 수 있다.In another aspect, the present invention provides a method for inhibiting, preventing and treating cancer and cancer metastasis by administering to a patient a composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof. The composition of the present invention can be administered in parallel with the conventional disease treatment.

본 발명의 조성물은 약제학적으로 유효한 양으로 투여한다.The composition of the present invention is administered in a pharmaceutically effective amount.

본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type, severity, and activity of the patient's disease. , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent drug use, and other factors well known in the medical arts. The compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.

구체적으로, 본 발명에 따른 화합물의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏당 1 내지 50 ㎎, 바람직하게는 1 내지 10 ㎎을 매일 또는 격일로 투여하거나 1일 1 내지 3 회로 나누어 투여할 수 있다.Specifically, the effective amount of the compound according to the present invention may vary depending on the age, sex and weight of the patient, and generally 1 to 50 mg, preferably 1 to 10 mg per kg body weight is administered daily or every other day. It may be administered in 1 to 3 times a day.

그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.However, the dosage may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.

이하, 실시예에 의하여 본 발명을 더욱 상세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail with reference to Examples.

단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시 예에 한정되는 것은 아니다. However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

실시예 1. 세포자기사멸 유도 효과 확인 ⅠExample 1. Confirmation of apoptosis induction effect Ⅰ

본 발명에서는 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)의 세포자기사멸 유도 효과를 확인하기 위하여, HeLa 세포(인간 자궁 암세포)를 ATCC(American Type Culture Collection, 미국)에서 분양받아 INDOFINE社(Hillsborough, NJ, 미국)에서 구입한 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)으로 처리한 후 0, 12, 24시간 경과 후 p53의 발현 증가와 PARP의 조각단편을 조사하기 위하여 웨스턴 블롯 분석을 하였다. In the present invention, in order to confirm the effect of induction of apoptosis of 2,3-dihydro-5-methoxy-2-phenyl-4h-1-benzopyran-4-one (5-methoxyflavanone), HeLa 2,3-dihydro-5-methoxy-2-phenyl-4H- purchased from INDOFINE (Hillsborough, NJ, USA) obtained from ATCC (American Type Culture Collection, USA) After treatment with 1-benzopyran-4-one (5-methoxyflavanone), Western blot analysis was performed to investigate the increased expression of p53 and fragments of PARP after 0, 12 and 24 hours.

세포의 배양은 1.5 X 106개의 HeLa 세포를 24시간 배양하여 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)을 40 ㎍/㎖ 농도로 처리하고, 정상적인 세포(대조군)와 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)이 처리된 세포(처리군)에서 배양된 세포들을 0, 12, 24시간 경과하면 라이시스 버퍼(lysis buffer)로 용해한 후, 고속원심분리기를 이용하여 상등액과 용해된 세포 조각들을 분리시킨 다음 동량의 단백질 시료로 균질화 시킨 표준 시료를 에스디에스-폴리아크릴아마이드 겔(SDS-polyacrylamide gel) 전기영동으로 세포에 존재하는 단백질들을 분리하였다. Cell culture was performed by incubating 1.5 X 10 6 HeLa cells for 24 hours to obtain 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone). ) Was treated at a concentration of 40 μg / ml, and normal cells (control) and 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxypla After 0, 12 and 24 hours, cells cultured in Banon-treated cells (treatment group) were lysed with lysis buffer, and the supernatant and lysed cell fragments were separated using a high-speed centrifuge. Proteins homogenized with the same amount of protein samples were separated from the cells present in the cells by SDS-polyacrylamide gel electrophoresis.

전기영동으로 분리된 겔에서 셀룰로스 멤브레인에 옮겨진 블롯들은 일차항체(Primary antibody)에 반응과 세척 및 이차항체(Secondary antibody)를 반응시킨 후 향상된 화학발광(enhanced chemiluminescence) 감지 시스템(Amersham Pharmacia Biotech, Piscataway, NJ)으로 단백질의 발현 변화량을 측정하였다. The blots transferred to the cellulose membrane from the electrophoresis separated gels were subjected to an enhanced chemiluminescence detection system (Amersham Pharmacia Biotech, Piscataway, Co., Ltd.) after reacting the primary antibody, washing and reacting the secondary antibody. NJ) was measured for the amount of change in the expression of the protein.

도 1에서 나타난 바와 같이, 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)의 처리에 의하여 p53의 발현이 증가하였으며, 세포사멸의 주요 현상인 PARP의 조각단편이 시간 의존적으로 유발되었음이 확인되었다. As shown in FIG. 1, the expression of p53 was reduced by treatment of 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone). It was confirmed that fragmentation of PARP, a major phenomenon of cell death, was induced in a time dependent manner.

실시예 2. 세포자기사멸 유도 효과 확인 Ⅱ Example 2. Confirmation of apoptosis induction effect II

본 발명에서는 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)의 세포자기사멸 유도 및 세포주기 억제 효과를 확인하기 위해, 유세포분리측정기(Fluorescent Activating Cell Sorting; FACS, BD Science, 미국)를 이용하여 DNA가 응축되어 염색시약인 PI(Propidium Iodine)가 DNA에 끼어들어가지 못하여 발생하는 sub-G1의 영역 증가, 자기사멸에 의한 세포 조각(Apoptotic body)의 생성으로 유발되는 sub-G1 영역 증가와 p53의 발현 증가로 인한 G2/M 단계의 억제를 측정하였다.In the present invention, the effect of induction of apoptosis and cell cycle inhibition of 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) was confirmed. In order to increase the area of sub-G1 caused by DNA condensation using the Fluorescent Activating Cell Sorting (FACS, BD Science, USA), the staining reagent PI (Propidium Iodine) could not enter the DNA. Inhibition of the G2 / M phase due to increased sub-G1 region and increased expression of p53 induced by the production of apoptotic bodies by apoptosis was measured.

이때, 세포배양은 상기 실시예 1에서와 동일하게 수행하였으며, 처리 후 0, 12, 24시간이 경과하면 트립신-EDTA(1%)을 가해 세포를 떼어낸 다음 고속원심분리하여 세포를 수확하고, 70% 에탄올로 세포를 고정시켜 PI(Propidium Iodine)로 염색한 후 상기 유세포측정기로 세포주기 진행에 따른 DNA 양의 변화에 따른 세포 주기의 진행 상태를 확인하였다. At this time, the cell culture was carried out in the same manner as in Example 1, 0, 12, 24 hours after treatment, trypsin-EDTA (1%) was added to remove the cells, and then centrifuged to harvest the cells, After fixing the cells with 70% ethanol and staining with PI (Propidium Iodine), the flow cytometer was used to confirm the progress of the cell cycle according to the change in the amount of DNA according to the cell cycle progression.

도 2에서 같이, 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)의 처리 후 24시간 이후 세포사멸을 의미하는 G0 영역이 약 8.8% 정도 증가하였으며, 12시간 후 약 21%의 G2/M 단계의 세포주기 억제가 확인되 어, 본 발명에 따른 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)은 암세포의 자기사멸 유도와 G2/M 단계의 세포주기억제 기작을 통해 암 예방 및 치료가 가능함을 알 수 있었다.As shown in Figure 2, means apoptosis 24 hours after the treatment of 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) The G0 region was increased by about 8.8%, and after 12 hours, the cell cycle inhibition of the G2 / M stage was confirmed by about 21%. Thus, 2,3-dihydro-5-methoxy-2-phenyl according to the present invention was confirmed. -4H-1-benzopyran-4-one (5-methoxyflavanone) was able to prevent and treat cancer through the induction of self-killing of cancer cells and cell cycle inhibition mechanism of G2 / M stage.

도 1은 본 발명의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)에 의한 p53의 발현 증가와 PARP 단편 조각 유발 효과를 확인한 웨스턴 블롯 결과이다. 1 shows increased expression of p53 and PARP fragments by 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) of the present invention. Western blot results confirm the effect of fragmentation.

도 2는 본 발명의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논)에 의한 세포자기사멸 유도와 G2/M 단계의 세포주기 억제 효과를 확인한 유세포분리측정분석 결과이다.Figure 2 shows the induction of apoptosis and G2 / by 2,3-dihydro-5-methoxy-2-phenyl-4 H--1-benzopyran-4-one (5-methoxyflavanone) of the present invention Flow cytometry analysis results confirming the cell cycle inhibitory effect of M phase.

Claims (5)

p53 발현을 활성화시킴으로써 세포사멸을 유도하고, 세포주기를 억제하는 하기 화학식 1의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on)[일명, 5-메톡시플라바논(5-methoxyflavanone)].2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one of formula (1), which induces apoptosis by activating p53 expression and inhibits the cell cycle (2, 3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-on) (aka 5-methoxyflavanone). [화학식 1][Formula 1]
Figure 112008060069979-PAT00005
Figure 112008060069979-PAT00005
 상기 제 1항의 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플라바논) 화합물 또는 이의 약학적으로 허용되는 염을 포함하는 암 질환의 예방 및 치료를 위한 약학조성물. 2,3-dihydro-5-methoxy-2-phenyl-4H--1-benzopyran-4-one (5-methoxyflavanone) compound of claim 1 or a pharmaceutically acceptable salt thereof Pharmaceutical composition for the prevention and treatment of cancer diseases. 제 2항에 있어서, 3. The method of claim 2, 상기 2,3-디하이드로-5-메톡시-2-페닐-4에이치-1-벤조피란-4-온(5-메톡시플 라바논) 화합물은 p53 발현을 활성화시켜 세포주기 억제(Cell cycle arrest)와 세포자기사멸(Apoptosis)을 유도함으로써 암세포의 증식을 제어하는 것을 특징으로 하는 약학조성물.The 2,3-dihydro-5-methoxy-2-phenyl-4H-1-benzopyran-4-one (5-methoxyflavanone) compound inhibits cell cycle by activating p53 expression. A pharmaceutical composition, characterized by controlling cancer cell proliferation by inducing arrest) and apoptosis. 제 2항에 있어서,3. The method of claim 2, 상기 암 질환은 p53 유전자의 이상으로 야기되는 암인 것을 특징으로 하는 약학조성물. The cancer disease is a pharmaceutical composition, characterized in that the cancer caused by abnormalities of the p53 gene. 제 2항 또는 제 4항에 있어서,The method according to claim 2 or 4, 상기 암 질환은 대장암, 위암, 전립선암, 유방암, 신장암, 간암, 뇌종양, 폐암, 자궁암, 결장암, 방광암, 췌장암, 혈액암을 포함하는 것을 특징으로 하는 약학조성물.The cancer disease, colon cancer, stomach cancer, prostate cancer, breast cancer, kidney cancer, liver cancer, brain tumors, lung cancer, uterine cancer, colon cancer, bladder cancer, pancreatic cancer, hematological composition, characterized in that it comprises blood cancer.
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