KR102498789B1 - Hepsin inhibitors and pharmaceutical composition for prevention and treatment of the metastasis of prostate cancer - Google Patents
Hepsin inhibitors and pharmaceutical composition for prevention and treatment of the metastasis of prostate cancer Download PDFInfo
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Abstract
본 발명은 전이성 전립선암에서 과발현되는 헵신의 기능을 제어하는 화합물 유도체 및 이를 포함하는 전이성 전립선암의 예방 및 치료용 약학 조성물에 관한 것으로서, 더욱 구체적으로는, 하기 화학식 1로 표시되는 화합물 유도체 및 이를 포함하는 전립선암 전이 예방 및 치료용 약학 조성물에 관한 것이다:
<화학식 1>
상기 식에서 R1은 수소원자, CO-R', 및 COOR'로 이루어진 군으로부터 선택된 하나의 기이고, R2는 C1 내지 C18의 알킬기, 알킬렌기 또는 알키닐기, 및 치환된 벤질, 페닐 또는 피리디닐 (여기서 치환체는 수소, 할로, C1-6 알콕시, C1-6 알킬티오, CN, 하이드록시기임), R3는 일치환, 이치환 또는 삼치환된 페닐, 티아졸, 벤조티아졸, 이미다졸, 피라졸, 티오펜, 피롤 또는 피리디닐 (여기서, 치환체는 (a) 수소, (b) 할로겐, (c) C1-6 알콕시, (d) C1-6 알킬티오, (e) CN, (f) C1-6 알킬, (g) C1-6 플루오로알킬, (h) N3, (i) -CO2R, (j) 하이드록시 그룹 중에서 선택된다.
본 발명에 따르면, 전립선암 전이가 진행되는 경우 과발현되는 헵신의 활성을 효과적으로 억제할 수 있는 화합물 및 이를 포함하는 약학 조성물을 제공하며, 이를 이용해서 전이성 전립선암을 조기에 진단하거나 치료할 수 있다.The present invention relates to a compound derivative controlling the function of hepsin overexpressed in metastatic prostate cancer and a pharmaceutical composition for preventing and treating metastatic prostate cancer comprising the same, and more specifically, to a compound derivative represented by the following formula (1) and the same It relates to a pharmaceutical composition for preventing and treating prostate cancer metastasis comprising:
<Formula 1>
In the above formula, R 1 is a hydrogen atom, a group selected from the group consisting of CO-R' and COOR', and R 2 is a C1 to C18 alkyl group, an alkylene group or an alkynyl group, and a substituted benzyl, phenyl or pyridinyl group. (wherein the substituent is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkylthio, CN, or hydroxy group), R 3 is mono-, di-, or tri-substituted phenyl, thiazole, benzothiazole, or dazole, pyrazole, thiophene, pyrrole or pyridinyl, wherein the substituents are (a) hydrogen, (b) halogen, (c) C 1-6 alkoxy, (d) C 1-6 alkylthio, (e) CN , (f) C 1-6 alkyl, (g) C 1-6 fluoroalkyl, (h) N 3 , (i) -CO 2 R, and (j) hydroxy groups.
According to the present invention, a compound capable of effectively inhibiting the activity of hepsin, which is overexpressed when metastasis of prostate cancer progresses, and a pharmaceutical composition containing the same are provided, and metastatic prostate cancer can be diagnosed or treated early using the same.
Description
본 발명은 전이성 전립선암에 과발현되는 헵신 단백질을 저해하는 신규 화합물 및 이를 유효성분으로 함유하는 약학 조성물에 관한 것이다.The present invention relates to a novel compound that inhibits hepsin protein overexpressed in metastatic prostate cancer and a pharmaceutical composition containing the same as an active ingredient.
전립선암은 미국 남성에서 가장 빈번하게 발생되고, 종양과 관련된 남성 사망 원인의 두 번째에 해당되는 암이다. 최근에 우리나라에서도 식생활의 서구화 및 고령화에 따라 성인 남성의 전립선암의 발생빈도가 증가하는 추세이다. 초기에 전립선암이 전립선 내에만 국한되어 발견되는 경우에는 근치적 전립선 적출술, 방사선 치료, 호르몬 요법을 통하여 효과적으로 암을 제어하여 환자의 생존율은 매우 높다. 하지만 전립선암이 뼈, 림프절 등 신체의 다른 장기로 전이되는 경우에는 진단과 치료가 용이하지 않아 사망률이 급격하게 증가한다. 임상적으로 혈청 전립성 특이항원 (PSA) 측정이 전립선암의 조기 진단에 사용되고 있지만, PSA는 전립선암의 전이나 재발에 있어서 전이 부위나 치료 효과를 모니터링하는 데에는 효율성이 매우 낮은 상황이다. 치료적인 측면에서는 전이성 전립선암에서 과발현되는 단백질을 타겟으로 한 승인을 받은 약물은 없는 상황이다. Prostate cancer is the most frequent cancer in men in the United States and the second leading cause of tumor-related death in men. Recently, in Korea, the incidence of prostate cancer in adult men is increasing due to the westernization of diet and aging. In the early stage, when prostate cancer is found confined to the prostate, radical prostatectomy, radiation therapy, and hormone therapy can effectively control the cancer, resulting in a very high survival rate. However, when prostate cancer metastasizes to other organs in the body, such as bones and lymph nodes, diagnosis and treatment are not easy, leading to a rapid increase in mortality. Clinically, serum prostate specific antigen (PSA) measurement is used for early diagnosis of prostate cancer, but PSA is very inefficient in monitoring the metastasis site or treatment effect in metastasis or recurrence of prostate cancer. In terms of treatment, there are no approved drugs targeting proteins overexpressed in metastatic prostate cancer.
헵신(hepsin)은 90%이상의 전립선암 조직에서 발현되고 전이성 전립선암에서의 mRNA수치가 정상 전립선 또는 전립성 비대증에 비하여 10배 이상 높은 것으로 보고되어 있다. 헵신은 제 2형 트립신 유사 세린 프로테아제 (type II trypsin-line serine protease, TTSP)로 413개의 아미노산으로 구성된 단백질로 활성 부위가 세포외부에 위치하고 있다. 헵신은 전립선암에 초기 단계에서 과발현되어 전립선암의 진행과 전이가 되는 동안 발현이 높은 상태를 유지하고 있다. 헵신 발현은 기저세포막 (basement membrane)의 파괴 정도와 상관관계가 매우 높은 것을 고려하면 헵신의 활성이 기저세포막 파괴에 영향을 미치는 것으로 보고되고 있다. 동물 실험에서 전립선에서의 헵신 발현이 높은 경우에는 전립선암이 뼈, 간, 폐로 전이가 되는 것이 보고되었다. 혭신은 pro-HGF를 절단하여 HGF-MET 신호전달체계를 활성화 시키는 것으로 알려져 있다.It has been reported that hepsin is expressed in more than 90% of prostate cancer tissues and its mRNA level in metastatic prostate cancer is more than 10 times higher than that in normal prostate or prostatic hyperplasia. Hepsin is a type II trypsin-line serine protease (TTSP), a protein composed of 413 amino acids, and the active site is located outside the cell. Hepsin is overexpressed in prostate cancer at an early stage and remains highly expressed during progression and metastasis of prostate cancer. Considering that the expression of hepsin has a very high correlation with the degree of destruction of the basement membrane, it has been reported that the activity of hepsin affects the destruction of the basement membrane. In animal experiments, it has been reported that prostate cancer metastasizes to the bone, liver, and lung when hepsin expression is high in the prostate. It is known that hyosin activates the HGF-MET signaling system by cleaving pro-HGF.
따라서, 헵신의 활성 부위에 결합하여 저해활성을 갖는 소정의 화합물 및 그 약학적으로 허용 가능한 염을 유효성분으로 함유하는 전립선암 전이 저해 약학 조성물을 제시하고자 한다.Accordingly, it is intended to propose a pharmaceutical composition for inhibiting prostate cancer metastasis containing a compound having inhibitory activity by binding to the active site of hepsin and a pharmaceutically acceptable salt thereof as an active ingredient.
이에, 본 발명에서는 헵신에 의한 HGF-MET 신호전달체계를 제어하여 전립선암의 전이를 억제하는 효과를 발휘함으로써, 전이성 전립선암 예방 및 치료에 탁월한 효능을 나타내는 화합물 및 이를 포함하는 약학 조성물을 제공하고자 한다.Therefore, in the present invention, to provide a compound exhibiting excellent efficacy in preventing and treating metastatic prostate cancer by controlling the HGF-MET signaling system by hepsin to inhibit metastasis of prostate cancer, and a pharmaceutical composition containing the same do.
본 발명은 상기 과제를 해결하기 위해서, 하기 화학식 1로 표시되는 화합물을 제공한다:In order to solve the above problems, the present invention provides a compound represented by Formula 1 below:
상기 식에서 R1은 수소원자, CO-R', 및 COOR'로 이루어진 군으로부터 선택된 하나의 기이고, R2는 C1 내지 C18의 알킬기, 알킬렌기 또는 알키닐기, 및 치환된 벤질, 페닐 또는 피리디닐 (여기서 치환체는 수소, 할로, C1-6 알콕시, C1-6 알킬티오, CN, 하이드록시기임), R3는 일치환, 이치환 또는 삼치환된 페닐, 티아졸, 벤조티아졸, 이미다졸, 피라졸, 티오펜, 피롤 또는 피리디닐 (여기서, 치환체는 (a) 수소, (b) 할로겐, (c) C1-6 알콕시, (d) C1-6 알킬티오, (e) CN, (f) C1-6 알킬, (g) C1-6 플루오로알킬, (h) N3, (i) -CO2R, (j) 하이드록시 그룹 중에서 선택된다.In the above formula, R 1 is a hydrogen atom, a group selected from the group consisting of CO-R' and COOR', and R 2 is a C1 to C18 alkyl group, an alkylene group or an alkynyl group, and a substituted benzyl, phenyl or pyridinyl group. (wherein the substituent is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkylthio, CN, or hydroxy group), R 3 is mono-, di-, or tri-substituted phenyl, thiazole, benzothiazole, or dazole, pyrazole, thiophene, pyrrole or pyridinyl, wherein the substituents are (a) hydrogen, (b) halogen, (c) C 1-6 alkoxy, (d) C 1-6 alkylthio, (e) CN , (f) C 1-6 alkyl, (g) C 1-6 fluoroalkyl, (h) N 3 , (i) -CO 2 R, and (j) hydroxy groups.
본 발명에 따르면, 상기 화학식 1의 화합물은 하기 화학식 1a 내지 1h로 이루어진 군으로부터 선택된 어느 하나의 화합물일 수 있다:According to the present invention, the compound of Formula 1 may be any one compound selected from the group consisting of the following
<화학식 1a><
<화학식 1b><
<화학식 1c><
<화학식 1d><
<화학식 1e><
<화학식 1f><
<화학식 1g><
<화학식 1h><
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 그 염을 유효성분으로 함유하는 전립선암 전이 예방, 진단 및 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing, diagnosing and treating metastasis of prostate cancer containing the compound represented by Formula 1 or a salt thereof as an active ingredient.
본 발명의 일 구현예에 따르면, 상기 약학 조성물은 전이성 자궁암을 포함하는 헵신이 과발현되는 암종의 예방, 진단 및 치료에 사용될 수 있다.According to one embodiment of the present invention, the pharmaceutical composition can be used for the prevention, diagnosis, and treatment of carcinomas in which hepsin is overexpressed, including metastatic uterine cancer.
본 발명의 다른 구현 예에 따르면, 상기 약학 조성물은 담체, 희석제, 보조제 및 안정화제로 이루어진 군으로부터 선택된 하나 이상의 성분을 더 포함할 수 있다.According to another embodiment of the present invention, the pharmaceutical composition may further include one or more components selected from the group consisting of carriers, diluents, adjuvants, and stabilizers.
본 발명의 또 다른 구현 예에 따르면, 상기 안정화제는 단백질, 당질, 완충제 및 그 혼합물로 이루어진 군으로부터 선택될 수 있다.According to another embodiment of the present invention, the stabilizer may be selected from the group consisting of proteins, carbohydrates, buffers, and mixtures thereof.
본 발명에 따르면, 전립선암 전이가 진행되는 경우 과발현되는 헵신의 활성을 효과적으로 억제할 수 있는 화합물 및 이를 포함하는 약학 조성물을 제공하며, 이를 이용해서 전이성 전립선암을 조기에 진단하거나 치료할 수 있다.According to the present invention, a compound capable of effectively inhibiting the activity of hepsin, which is overexpressed when metastasis of prostate cancer progresses, and a pharmaceutical composition containing the same are provided, and metastatic prostate cancer can be diagnosed or treated early using the same.
도 1a 및 1b는 본 발명에 따른 헵신 저해 화합물 유도체의 합성 과정을 개략적으로 도시한 흐름도이다.1a and 1b are flow charts schematically illustrating a synthesis process of a hepsin-inhibiting compound derivative according to the present invention.
이하, 본 발명을 더욱 상세하게 설명하기로 한다.Hereinafter, the present invention will be described in more detail.
본 발명자들은 하기 화학식 1의 일반식을 갖는 화합물들은 전이성 전립선암에서 과발현되는 핵심적인 단백질 중의 하나인 헵신과 결합하여 헵신의 기능을 효과적으로 저해함을 확인하였으며, 이를 기반으로 본 발명을 완성하게 되었다:The present inventors confirmed that the compounds having the general formula of Formula 1 bind to hepsin, one of the key proteins overexpressed in metastatic prostate cancer, and effectively inhibit the function of hepsin, and based on this, the present invention was completed:
<화학식 1><
상기 식에서 R1은 수소원자, CO-R', 및 COOR'로 이루어진 군으로부터 선택된 하나의 기이고, R2는 C1 내지 C18의 알킬기, 알킬렌기 또는 알키닐기, 및 치환된 벤질, 페닐 또는 피리디닐 (여기서 치환체는 수소, 할로, C1-6 알콕시, C1-6 알킬티오, CN, 하이드록시기임), R3는 일치환, 이치환 또는 삼치환된 페닐, 티아졸, 벤조티아졸, 이미다졸, 피라졸, 티오펜, 피롤 또는 피리디닐 (여기서, 치환체는 (a) 수소, (b) 할로겐, (c) C1-6 알콕시, (d) C1-6 알킬티오, (e) CN, (f) C1-6 알킬, (g) C1-6 플루오로알킬, (h) N3, (i) -CO2R, (j) 하이드록시 그룹 중에서 선택된다.In the above formula, R 1 is a hydrogen atom, a group selected from the group consisting of CO-R' and COOR', and R 2 is a C1 to C18 alkyl group, an alkylene group or an alkynyl group, and a substituted benzyl, phenyl or pyridinyl group. (wherein the substituent is hydrogen, halo, C 1-6 alkoxy, C 1-6 alkylthio, CN, or hydroxy group), R 3 is mono-, di-, or tri-substituted phenyl, thiazole, benzothiazole, or dazole, pyrazole, thiophene, pyrrole or pyridinyl, wherein the substituents are (a) hydrogen, (b) halogen, (c) C 1-6 alkoxy, (d) C 1-6 alkylthio, (e) CN , (f) C 1-6 alkyl, (g) C 1-6 fluoroalkyl, (h) N 3 , (i) -CO 2 R, and (j) hydroxy groups.
상기 화학식 1로 표시되는 헵신 저해 유도체는 공통적으로 아르기닌 (arginine)의 아미노산 서열을 포함하며, 필요에 따라서 상기 아미노산 서열의 N-말단에 R1에 다른 아미노산을 결합시키거나, R2 위치에 천연 아미노산 또는 인공 아미노산 잔기를 부가할 수 있거나, R3 위치에 다양한 치환된 페닐기나 헤테로 방향족기를 도입할 수 있다.The hepsin-inhibiting derivative represented by Formula 1 commonly includes an amino acid sequence of arginine, and if necessary, another amino acid is bound to R 1 at the N-terminus of the amino acid sequence, or a natural amino acid at the R 2 position. Alternatively, artificial amino acid residues may be added, or various substituted phenyl groups or heteroaromatic groups may be introduced at the R 3 position.
본 발명에 따른 유도체는 도면 1a와 1b에서 서술된 방법으로 제조할 수 있는 바, 예를 들어 C-말단의 케톤 (ketone)을 합성하기 위해서, 기능기를 보호한 아르기닌의 Weinreb 아미드인 전구 물질과 페닐 혹은 헤테로방향족의 리튬염과 반응시켜 다양한 형태의 유도체를 제조할 수 있다.The derivative according to the present invention can be prepared by the method described in Figures 1a and 1b, for example, in order to synthesize a C-terminal ketone, a precursor, which is a Weinreb amide of arginine with a functional group protected, and phenyl Alternatively, various types of derivatives may be prepared by reacting with heteroaromatic lithium salts.
또한, 본 발명에서는 상기 화학식 1로 표시되는 화합물 유도체 또는 그 염을 유효성분으로 함유하는 전립선암 전이의 예방 및 치료용 약학 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing and treating metastasis of prostate cancer, containing the compound derivative represented by Formula 1 or a salt thereof as an active ingredient.
본 발명에서, "유효 성분으로 포함"이라는 용어는, 원하는 생물학적 효과를 실현하는데 필요하거나 또는 충분한 양으로 해당 성분이 포함되는 것을 의미한다. 실제 적용에 있어서 유효 성분으로 포함되는 양의 결정은 대상 질병을 치료하기 위한 양으로서, 다른 독성을 야기하지 않는 사항을 고려해서 결정될 수 있으며, 예를 들어 치료되는 질병 또는 병태, 투여되는 조성물의 형태, 피험체의 크기, 또는 질병 또는 병태의 심각도 등과 같은 다양한 인자에 따라서 변화될 수 있다. 본 발명이 속하는 분야에서 통상의 기술을 지닌 기술자라면 과도한 실험을 동반하지 않고 개별적 조성물의 유효량을 경험적으로 결정할 수 있다.In the present invention, the term "included as an active ingredient" means that the component is included in an amount necessary or sufficient to realize a desired biological effect. In actual application, the amount to be included as an active ingredient is an amount to treat a target disease, and may be determined in consideration of matters that do not cause other toxicity, for example, the disease or condition to be treated, the type of composition to be administered, It can vary according to various factors such as the size of the subject, or the severity of the disease or condition. Effective amounts of individual compositions can be determined empirically without undue experimentation by those skilled in the art to which this invention pertains.
본 발명에 따른 약학 조성물은 전립선암의 전이의 예방 및 치료에 사용가능한 바, 이에 제한되는 것은 아니지만, 헵신이 과발현되는 자궁암 등 다양한 고형암일 수 있다.The pharmaceutical composition according to the present invention can be used for the prevention and treatment of metastasis of prostate cancer, but is not limited thereto, and may be used for various solid cancers such as cervical cancer in which hepsin is overexpressed.
또한, 본 발명에 따른 약학 조성물은 전이성 전립선암의 예방 및 치료용 약물과 함께 복합 제제의 형태로 투여되거나, 또는 담체, 희석제, 보조제 및 안정화제 등과 같은 기타 성분을 포함할 수도 있다.In addition, the pharmaceutical composition according to the present invention may be administered in the form of a combined preparation together with a drug for preventing and treating metastatic prostate cancer, or may contain other components such as carriers, diluents, adjuvants, and stabilizers.
예를 들어, 본 발명에 따른 조성물의 형태는 투여하고자 하는 모드에 따라서 다양하게 선택될 수 있으며, 이에 제한되는 것은 아니지만, 예를 들어 정제, 환약, 분말, 캡슐, 겔, 연고, 유체 또는 현탁액 등의 고상, 반고상 또는 액상의 투약 형태일 수 있고, 정확한 투약량의 단독 투여에 적절한 단위 투약 형태로 투여될 수 있다. 또한, 상기 조성물은 인간 투여를 위한 약학 조성물을 제형화하는데 일반적으로 사용되는 수성-기제 운반제로 정의되는 약학적으로 허용 가능한 담체, 희석제, 보조제, 안정화제를 원하는 제형에 의존하여 포함할 수 있다. 예를 들어, 희석제로는 증류수, 생리 식염수, 링거액, 포도당 용액, 및 행크스(Hank's) 용액 등을 고려해 볼 수 있다. 본 발명에 따른 약학적 조성물은 또한 다른 고형암의 전이 예방 및 치료용 약물 제제 또는 약학 제제 등과 함께 복합 제제의 형태로 투여될 수도 있고, 통상의 기술자라면 다양한 종류의 알러지 및 천식 질환 예방 및 치료용 약물을 고려해 볼 수 있다. 이러한 담체, 희석제, 보조제 및 안정화제 등과 같은 기타 성분의 유효량은 성분의 용해성, 생물학적 활성 등으로 환산하여 약학적으로 허용 가능한 제형을 획득하는데 유효한 양이다.For example, the form of the composition according to the present invention may be variously selected depending on the mode to be administered, but is not limited thereto, for example, tablets, pills, powders, capsules, gels, ointments, fluids or suspensions, etc. It can be a solid, semi-solid or liquid dosage form, and can be administered in unit dosage form suitable for single administration of a precise dosage. In addition, the composition may include pharmaceutically acceptable carriers, diluents, adjuvants, and stabilizers, which are defined as aqueous-based vehicles generally used in formulating pharmaceutical compositions for human administration, depending on the desired formulation. For example, distilled water, physiological saline, Ringer's solution, glucose solution, and Hank's solution may be considered as the diluent. The pharmaceutical composition according to the present invention may also be administered in the form of a combined preparation together with drug preparations or pharmaceutical preparations for the prevention and treatment of metastasis of other solid cancers, and for those skilled in the art, various types of allergy and asthmatic disease prevention and treatment drugs can be considered. An effective amount of other components such as carriers, diluents, adjuvants, and stabilizers is an amount effective to obtain a pharmaceutically acceptable formulation in terms of solubility, biological activity, and the like of the components.
또한, 상기 안정화제는 단백질, 당질, 완충제 및 그 혼합물로 이루어진 군으로부터 선택될 수 있다.In addition, the stabilizer may be selected from the group consisting of proteins, carbohydrates, buffers, and mixtures thereof.
이하, 실시예를 통해서 본 발명을 더욱 구체적으로 설명하기로 하되, 하기 실시예는 본 발명의 이해를 돕기 위한 것일 뿐, 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples, but the following examples are only for helping understanding of the present invention, and do not limit the scope of the present invention.
실시예 1. 본 발명에 따른 화합물 유도체의 합성Example 1. Synthesis of compound derivatives according to the present invention
화합물 유도체는 도 1a 또는 1b에 도시한 합성 방법에 따라서 제조하였으며, 하기 화학식 1a 내지 1h에 구체적인 화합물들을 표시하였다.Compound derivatives were prepared according to the synthesis method shown in FIG. 1a or 1b, and specific compounds are shown in
<화학식 1a><
<화학식 1b><
<화학식 1c><
<화학식 1d><
<화학식 1e><
<화학식 1f><
<화학식 1g><
<화학식 1h><
구체적으로, Leu-2-Chlorotrityl Resin을 출발물질로 사용하였으며, Fmoc-아미노산의 커플링 (coupling)에 의한 펩타이드 사슬의 연장은 N-히드록시벤조-트리아졸 (HOBt)과 O-(벤조트리아졸-1-일)-N,N,N,N-테트라메틸우로늄 헥사플루오로포스페이트 (HBTU)법을 사용하여 진행하였다. 각 펩타이드의 아미노 말단의 Fmoc-아미노산을 커플링시킨 후, 20% 피페리딘/N-메틸피롤리돈 (NMP) 용액으로 Fmoc기를 제거하고 NMP 및 디클로로메탄 (DCM)으로 수차례 세척한 다음 질소 가스로 건조시켰다. 여기에 TFA (트리플루오로아세트산)-티오아니솔-물 (95 : 2.5 : 2.5 vol./vol.) 용액을 가하고, 보호기의 제거 및 레진으로부터 펩타이드를 분리시킨 다음, 디에틸에테르로 펩타이드를 침전시켰다. 이렇게 하여 얻은 조 화합물은 0.1% TFA가 포함된 아세토니트릴과 0.1% TFA가 포함된 물을 전개 용매로 사용하여 아세토니트릴 농도 구배법 (acetonitrile gradient method)에 의한 정제형 역상-HPLC 컬럼을 이용하여 정제하였다.Specifically, Leu-2-Chlorotrityl Resin was used as a starting material, and extension of the peptide chain by Fmoc-amino acid coupling resulted in N-hydroxybenzo-triazole (HOBt) and O-(benzotriazole). -1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate (HBTU) method was used. After coupling the Fmoc-amino acid at the amino terminal of each peptide, the Fmoc group was removed with a 20% piperidine/N-methylpyrrolidone (NMP) solution, washed several times with NMP and dichloromethane (DCM), and then nitrogen dried with gas. A solution of TFA (trifluoroacetic acid)-thioanisole-water (95:2.5:2.5 vol./vol.) was added thereto, the protecting group was removed and the peptide was separated from the resin, and then the peptide was precipitated with diethyl ether. made it The crude compound obtained in this way was purified using a purified reverse-phase-HPLC column by the acetonitrile gradient method using acetonitrile containing 0.1% TFA and water containing 0.1% TFA as developing solvents. did
하기에는 제조된 화학식 1a 내지 1h의 화합물들 각각에 대한 NMR과 MS 데이터를 나타내었다.NMR and MS data for each of the prepared compounds represented by
화합물 1a:
(S)-2-acetamido-N-((S)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)-4-methylpentanamide(S)-2-acetamido-N-((S)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 8.03 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.37 (dd, J = 4.3 Hz and J = 9.8 Hz, 1H), 4.21 (dd, J = 6.1 Hz and J = 9.1 Hz, 1H), 3.213.09 (m, 2H), 2.211.85 (m, 2H), 1.91 (s, 3H), 1.801.71 (m, 2H), 1.691.56 (m, 1H), 1.541.35 (m, 2H), 0.81 (d, J = 6.4 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H); 13C NMR (75MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 20.9. ESI LRMS (m/z) calcd for C17H28N6O3S:396.2, found:397.1 [M+H]+.1H NMR (600 MHz, D2O)δ ppm 8.03 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.37 (dd, J = 4.3 Hz and J = 9.8 Hz, 1H) , 4.21 (dd, J = 6.1 Hz and J = 9.1 Hz, 1H), 3.213.09 (m, 2H), 2.211.85 (m, 2H), 1.91 (s, 3H), 1.801.71 (m, 2H) ), 1.691.56 (m, 1H), 1.541.35 (m, 2H), 0.81 (d, J = 6.4 Hz, 3H), 0.81 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.5, 20.9, 21.9 ESI LRMS (m/z) calcd for C17H28N6O3S:396.2, found:397.1 [M+H] + .
화합물 1b:
(S)-2-acetamido-N-((R)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)-4-methylpentanamide (S)-2-acetamido-N-((R)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 8.03 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.34 (dd, J = 4.3 Hz and J = 9.9 Hz, 1H), 4.23 (dd, J = 5.7 Hz and J = 9.4 Hz, 1H), 3.14 (t, J = 7.4 Hz, 2H), 2.081.87 (m, 2H), 1.92 (s, 3H), 1.791.71 (m, 2H), 1.691.55 (m, 1H), 1.551.40 (m, 2H), 0.83 (d, J = 6.3 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H); 13C NMR (75MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.2, 52.7, 40.4, 39.9, 27.5, 24.5, 24.3, 21.9, 21.6, 21.9. ESI LRMS (m/z) calcd for C17H28N6O3S:396.2, found:397.1 [M+H]+.1H NMR (600 MHz, D2O)δ ppm 8.03 (d, J = 3.1 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.34 (dd, J = 4.3 Hz and J = 9.9 Hz, 1H) , 4.23 (dd, J = 5.7 Hz and J = 9.4 Hz, 1H), 3.14 (t, J = 7.4 Hz, 2H), 2.081.87 (m, 2H), 1.92 (s, 3H), 1.791.71 ( m, 2H), 1.691.55 (m, 1H), 1.551.40 (m, 2H), 0.83 (d, J = 6.3 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.2, 52.7, 40.4, 39.9, 27.5, 24.5, 24.6, 21.9, 21.9 ESI LRMS (m/z) calcd for C17H28N6O3S:396.2, found:397.1 [M+H] + .
화합물 1c:
(S)-2-acetamido-N-((S)-1-(benzo[d]thiazol-2-yl)-5-guanidino-1-oxopentan-2-yl)-4-methylpentanamide(S)-2-acetamido-N-((S)-1-(benzo[d]thiazol-2-yl)-5-guanidino-1-oxopentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 8.11 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.5, 1H), 7.617.50 (m, 2H), 5.41 (dd, J = 4.4 Hz and J = 9.8 Hz, 1H), 4.19 (dd, J = 6.1 Hz and J = 7.6 Hz, 1H), 3.203.15 (m, 2H), 2.142.03 (m, 1H), 2.04 (s, 3H), 1.901.76 (m, 1H), 1.741.65 (m, 2H), 1.451.33 (m, 3H), 0.73 (d, J = 6.2 Hz, 3H), 0.67 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C21H30N6O3S: 446.2, found: 447.6 [M+H]+.1H NMR (600 MHz, D2O)δ ppm 8.11 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.5, 1H), 7.617.50 (m, 2H), 5.41 (dd, J = 4.4 Hz) and J = 9.8 Hz, 1H), 4.19 (dd, J = 6.1 Hz and J = 7.6 Hz, 1H), 3.203.15 (m, 2H), 2.142.03 (m, 1H), 2.04 (s, 3H) , 1.901.76 (m, 1H), 1.741.65 (m, 2H), 1.451.33 (m, 3H), 0.73 (d, J = 6.2 Hz, 3H), 0.67 (d, J = 6.2 Hz, 3H) ); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C21H30N6O3S: 446.2, found: 447.6 [M+H] + .
화합물 1d:
(S)-2-acetamido-N-((R)-1-(benzo[d]thiazol-2-yl)-5-guanidino-1-oxopentan-2-yl)-4-methylpentanamide(S)-2-acetamido-N-((R)-1-(benzo[d]thiazol-2-yl)-5-guanidino-1-oxopentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 8.08 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4, 1H), 7.657.53 (m, 2H), 5.34 (dd, J = 4.3 Hz and J = 9.8 Hz, 1H), 4.274.19 (m, 1H), 3.223.12 (m, 2H), 2.152.00 (m, 1H), 1.88 (s, 3H), 1.841.75 (m, 1H), 1.701.60 (m, 2H), 1.471.34 (m, 3H), 0.77 (d, J = 6.1 Hz, 3H), 0.71 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C21H30N6O3S:446.2, found:447.5 [M+H]+.1H NMR (600 MHz, DO)δ ppm 8.08 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4, 1H), 7.657.53 (m, 2H), 5.34 (dd, J = 4.3 Hz) and J = 9.8 Hz, 1H), 4.274.19 (m, 1H), 3.223.12 (m, 2H), 2.152.00 (m, 1H), 1.88 (s, 3H), 1.841.75 (m, 1H) ), 1.701.60 (m, 2H), 1.471.34 (m, 3H), 0.77 (d, J = 6.1 Hz, 3H), 0.71 (d, J = 6.1 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C21H30N6O3S:446.2, found:447.5 [M+H] + .
화합물 1e:
(S)-2-acetamido-N-((S)-5-guanidino-1-oxo-1-phenylpentan-2-yl)-4-methylpentanamide(S)-2-acetamido-N-((S)-5-guanidino-1-oxo-1-phenylpentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 7.80 (d, J = 8.1 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 5.24 (dd, J = 4.4 Hz and J = 9.6 Hz, 1H), 4.13 (dd, J = 6.2 Hz and J = 9.1 Hz, 1H), 3.173.07 (m, 2H), 1.951.85 (m, 1H), 1.89 (s, 3H), 1.711.63 (m, 1H), 1.601.53 (m, 2H), 1.401.31 (m, 2H), 1.301.25 (m, 1H), 0.75 (d, J = 6.4 Hz, 3H), 0.71 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C20H31N5O3:389.2, found:390.6 [M+H]+.1H NMR (600 MHz, D2O)δ ppm 7.80 (d, J = 8.1 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 5.24 (dd, J = 4.4 Hz and J = 9.6 Hz, 1H), 4.13 (dd, J = 6.2 Hz and J = 9.1 Hz, 1H), 3.173.07 (m, 2H), 1.951.85 (m, 1H), 1.89 ( s, 3H), 1.711.63 (m, 1H), 1.601.53 (m, 2H), 1.401.31 (m, 2H), 1.301.25 (m, 1H), 0.75 (d, J = 6.4 Hz, 3H), 0.71 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C20H31N5O3:389.2, found:390.6 [M+H] + .
화합물 1f:
(S)-2-acetamido-N-((R)-5-guanidino-1-oxo-1-phenylpentan-2-yl)-4-methylpentanamide(S)-2-acetamido-N-((R)-5-guanidino-1-oxo-1-phenylpentan-2-yl)-4-methylpentanamide
1H NMR (600 MHz, D2O)δ ppm 7.81 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 5.21 (dd, J = 4.4 Hz and J = 9.5 Hz, 1H), 4.16 (dd, J = 5.9 Hz and J = 9.3 Hz, 1H), 3.163.07 (m, 2H), 1.921.87 (m, 1H), 1.89 (s, 3H), 1.721.65 (m, 1H), 1.581.53 (m, 2H), 1.411.65 (m, 2H), 1.351.29 (m, 1H), 0.78 (d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C20H31N5O3:389.2, found:390.4 [M+H]+.1H NMR (600 MHz, D2O)δ ppm 7.81 (d, J = 8.5 Hz, 2H), 7.60 (t, J = 7.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 2H), 5.21 (dd, J = 4.4 Hz and J = 9.5 Hz, 1H), 4.16 (dd, J = 5.9 Hz and J = 9.3 Hz, 1H), 3.163.07 (m, 2H), 1.921.87 (m, 1H), 1.89 ( s, 3H), 1.721.65 (m, 1H), 1.581.53 (m, 2H), 1.411.65 (m, 2H), 1.351.29 (m, 1H), 0.78 (d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C20H31N5O3:389.2, found:390.4 [M+H] + .
화합물 1g:1 g of compound:
(S)-2-acetamido-N1-((S)-1-(((S)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)pentanediamide(S)-2-acetamido-N1-((S)-1-(((S)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)amino)-4 -methyl-1-oxopentan-2-yl)pentanediamide
1H NMR (300 MHz, D2O)δ ppm 8.03 (d, J = 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.35 (dd, J = 3.8 and 9.0 Hz, 1H), 4.404.00 (m, 2H), 3.193.10 (m, 2H), 2.482.19 (m, 4H), 2.101.80 (m, 4H), 1.94 (s, 3H), 1.741.42 (m, 3H), 0.87 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 5.7 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C22H36N8O5S:524.3, found:525.6 [M+H]+.1H NMR (300 MHz, D2O) δ ppm 8.03 (d, J = 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.35 (dd, J = 3.8 and 9.0 Hz, 1H), 4.404. 00 (m, 2H), 3.193.10 (m, 2H), 2.482.19 (m, 4H), 2.101.80 (m, 4H), 1.94 (s, 3H), 1.741.42 (m, 3H), 0.87 (d, J = 6.3 Hz, 3H), 0.83 (d, J = 5.7 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C22H36N8O5S:524.3, found:525.6 [M+H] + .
화합물 1h:
(S)-2-acetamido-N1-((S)-1-(((R)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)pentanediamide(S)-2-acetamido-N1-((S)-1-(((R)-5-guanidino-1-oxo-1-(thiazol-2-yl)pentan-2-yl)amino)-4 -methyl-1-oxopentan-2-yl)pentanediamide
1H NMR (300 MHz, D2O)δ ppm 8.03 (d, J = 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.38 (dd, J = 4.2 and 9.0 Hz, 1H), 4.384.12 (m, 2H), 3.223.08 (m, 2H), 2.442.18 (m, 4H), 2.101.79 (m, 4H), 1.94 (s, 3H), 1.711.42 (m, 3H), 0.83 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, D2O)δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 24.2, 21.9, 21.5, 21.0. ESI LRMS (m/z) calcd for C22H36N8O5S:524.3, found:525.6 [M+H]+.1H NMR (300 MHz, D2O) δ ppm 8.03 (d, J = 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 5.38 (dd, J = 4.2 and 9.0 Hz, 1H), 4.384. 12 (m, 2H), 3.223.08 (m, 2H), 2.442.18 (m, 4H), 2.101.79 (m, 4H), 1.94 (s, 3H), 1.711.42 (m, 3H), 0.83 (d, J = 6.3 Hz, 3H), 0.81 (d, J = 6.2 Hz, 3H); 13C NMR (75 MHz, D2O) δ ppm 191.9, 175.0, 174.1, 163.9, 163.1, 162.7, 156.7, 145.1, 128.7, 55.1, 52.6, 40.4, 39.8, 27.7, 24.4, 21.0,2, 21.0,2, 21.0. ESI LRMS (m/z) calcd for C22H36N8O5S:524.3, found:525.6 [M+H] + .
실시예 2. 형광법을 이용한 헵신 저해 효능 평가Example 2. Evaluation of hepsin inhibition efficacy using fluorescence method
헵신과 마트립타제 (matriptase)는 세린프로타제 (serine protease)의 일종으로 Boc-Gln-Ala-Arg-AMC기질과 반응하여 AMC는 7-아미도-4-메틸쿠마린 (7-amino-4-methylcoumarin)으로 최대 여기 380 nm와 최대 방출 460 nm 형광분광광도계를 이용하여 헵신과 마트립타제의 기질 분해능력을 측정할 수 있다. 따라서, 본 발명에 따른 화합물들이 헵신과 마트립타제의 기능을 효과적으로 저해하는지를 확인하기 위해서는, Boc-Gln-Ala-Arg-AMC 기질의 분해에서 생기는 7-아미도-4-메틸쿠마린의 양을 측정하여 얻을 수 있다.Hepsin and matriptase are serine proteases that react with Boc-Gln-Ala-Arg-AMC substrate to form AMC into 7-amido-4-methylcoumarin (7-amino-4-methylcoumarin). methylcoumarin), the substrate degrading ability of hepsin and matriptase can be measured using a fluorescence spectrophotometer with a maximum excitation of 380 nm and a maximum emission of 460 nm. Therefore, in order to confirm whether the compounds according to the present invention effectively inhibit the functions of hepsin and matriptase, the amount of 7-amido-4-methylcoumarin generated from the degradation of the Boc-Gln-Ala-Arg-AMC substrate was measured can be obtained by
이러한 사실을 확인하기 위해서, 본 실시예에서는 하기와 같은 실험을 수행하였다: 화합물을 DMSO에 녹여 0.1 nM에서 100 μM 용액을 만들었다. 최종 처리 농도는 DMSO가 2%로 이하로 유지하였다. 헵신과 마트립타제를 TNC 완충액 (25 mM Tris, 150 mM NaCl, 5 mM CaCl2, 0.01% Triton X-100, pH 8)에 녹여 96-웰 플레이트에 가해주었다. 각 웰당 헵신과 마트립타제의 농도는 0.3 nM로 맞추었다. 화합물과 헵신 또는 마트립타제를 TNC 완충액을 넣어 각 웰당 100 μL를 유지하였다. 30분간 인큐베이션 (incubation) 한 후에, 반응액에 헵신과 마트립타제의 기질인 Boc-Gln-Ala-Arg-AMC (150 μM)을 넣어준 후 상온에서 30 분, 60분, 120분에 최대 여기 380 nm와 최대 방출 460 nm 형광분광광도계를 이용하여 7-아미도-4-메틸쿠마린을 농도를 측정하였다. 상등액을 제거하고 TSLP (100 ng/mL)와 적정 농도 (0.3, 3, 30 μM)의 펩타이드를 혼합하여 세포 위에 30분 동안 처리한 다음, 세포를 싸이토픽스 (cytofix)로 고정하였다. 하기 표 1에는 화합물 2 내지 9의 농도-의존 그래프 계산식을 통하여 얻어진 50%저해 농도를 나타내었다.In order to confirm this fact, in this example, the following experiment was performed: The compound was dissolved in DMSO to make a 0.1 nM to 100 μM solution. The final treatment concentration was kept below 2% DMSO. Hepsin and matriptase were dissolved in TNC buffer (25 mM Tris, 150 mM NaCl, 5 mM CaCl2, 0.01% Triton X-100, pH 8) and added to a 96-well plate. The concentrations of hepsin and matriptase per well were adjusted to 0.3 nM. The compound and hepsin or matriptase were added in TNC buffer to maintain 100 μL per well. After incubation for 30 minutes, Boc-Gln-Ala-Arg-AMC (150 μM), a substrate for hepsin and matriptase, was added to the reaction solution, and maximum excitation was performed at room temperature for 30 minutes, 60 minutes, and 120 minutes. The concentration of 7-amido-4-methylcoumarin was measured using a 380 nm and 460 nm maximum emission spectrophotometer. The supernatant was removed, and TSLP (100 ng/mL) and appropriate concentrations (0.3, 3, 30 μM) of peptide were mixed and treated on the cells for 30 minutes, and then the cells were fixed with Cytofix. Table 1 below shows the 50% inhibitory concentration obtained through the concentration-dependence graph calculation formula of
종합하면, 본 발명에 따른 화합물들은 전이성 전립선암에서 과발현되어 기저세포막 파괴에 관여하는 헵신의 결합부위에 강력하게 결합하여 활성을 효과적으로 억제함으로써 전이성 전립선암의 예방 및 치료가 가능해진다.In summary, the compounds according to the present invention strongly bind to the binding site of hepsin, which is overexpressed in metastatic prostate cancer and is involved in basal cell membrane destruction, and effectively inhibits its activity, thereby enabling prevention and treatment of metastatic prostate cancer.
Claims (7)
<화학식 1a>
<화학식 1b>
<화학식 1c>
<화학식 1d>
<화학식 1e>
<화학식 1f>
<화학식 1g>
<화학식 1h>
<Formula 1a>
<Formula 1b>
<Formula 1c>
<Formula 1d>
<Formula 1e>
<Formula 1f>
<Formula 1g>
<Formula 1h>
상기 약학 조성물은 전이성 자궁암을 포함하는 헵신이 과발현되는 암종의 예방, 진단 및 치료에 사용되는 것을 특징으로 하는 전립선암 전이 예방 및 치료용 약학 조성물.According to claim 4,
The pharmaceutical composition is a pharmaceutical composition for the prevention and treatment of prostate cancer metastasis, characterized in that it is used for the prevention, diagnosis and treatment of carcinomas in which hepsin is overexpressed, including metastatic uterine cancer.
상기 약학 조성물은 담체, 희석제, 보조제 및 안정화제로 이루어진 군으로부터 선택된 하나 이상의 성분을 더 포함하는 것을 특징으로 하는 전립선암 전이 예방 및 치료용 약학 조성물.According to claim 4,
The pharmaceutical composition is a pharmaceutical composition for preventing and treating prostate cancer metastasis, characterized in that it further comprises one or more components selected from the group consisting of carriers, diluents, adjuvants and stabilizers.
상기 안정화제는 단백질, 당질, 완충제 및 그 혼합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 전립선암 전이 예방 및 치료용 약학 조성물.According to claim 6,
The stabilizer is a pharmaceutical composition for preventing and treating prostate cancer metastasis, characterized in that selected from the group consisting of proteins, carbohydrates, buffers and mixtures thereof.
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