KR20190114299A - RHOA inhibitor and use thereof - Google Patents
RHOA inhibitor and use thereof Download PDFInfo
- Publication number
- KR20190114299A KR20190114299A KR1020180036793A KR20180036793A KR20190114299A KR 20190114299 A KR20190114299 A KR 20190114299A KR 1020180036793 A KR1020180036793 A KR 1020180036793A KR 20180036793 A KR20180036793 A KR 20180036793A KR 20190114299 A KR20190114299 A KR 20190114299A
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- KR
- South Korea
- Prior art keywords
- rhoa
- group
- pharmaceutically acceptable
- inhibitor
- acceptable salt
- Prior art date
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Abstract
Description
본 발명은 RhoA 억제제 및 이의 용도에 관한 것으로, 보다 상세하게는 하기화학식 1의 구조를 갖는 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염, 이를 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 치료용 약학적 조성물, 및 이를 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 개선용 건강기능식품에 관한 것이다.The present invention relates to a RhoA inhibitor and its use, and more particularly, to a RhoA inhibitor having a structure of Formula 1 or a pharmaceutically acceptable salt thereof, and a disease caused by an increase in RhoA expression or activity comprising the same as an active ingredient. The present invention relates to a preventive or therapeutic pharmaceutical composition, and a nutraceutical for preventing or improving a disease caused by an increase in RhoA expression or activity including the same as an active ingredient.
[화학식 1][Formula 1]
RhoA(Ras homolog gene family member A)는 Rho 패밀리의 작은 GTPase 단백질이다. RhoA 활성의 영향은 모두 잘 알려져 있지는 않지만, 주로 세포 골격 조절, 주로 액틴 스트레스 섬유 형성 및 액토미오신 수축과 연관된다. 인간에서는 RhoA 유전자에 의해 암호화된다. RhoA는 여러 작동인자(effectors)에 따라 작용한다. 그 중에서도, ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) 및DIAPH1 (Diaphanous Homologue 1)이 가장 잘 설명된다. RhoA는 특히 세포 골격 역학, 전사, 세포 주기 진행 및 세포 변형과 같은 다른 기능에서 중요한 조절 인자로 간주된다.Ras homolog gene family member A (RhoA) is a small GTPase protein of the Rho family. The effects of RhoA activity are not all well known, but are mainly associated with cytoskeletal regulation, mainly actin stress fiber formation and actomyosin contraction. In humans, it is encoded by the RhoA gene. RhoA acts on several effectors. Among them, ROCK1 (Rho-associated, coiled-coil containing protein kinase 1) and DIAPH1 (Diaphanous Homologue 1) are best described. RhoA is considered an important regulatory factor, particularly in other functions such as cytoskeletal dynamics, transcription, cell cycle progression and cell transformation.
RhoA는 다양한 질환과 관련되어 있는데, 악성 전립선암, 위암, 고환암 등에서 상승된 RhoA의 발현이 확인된바 있다 (Schmidt, Lucy J. (2012). Molecular Endocrinology. 26 (5): 716-735; Zhang S et al. Molecular Cancer Research. 7 (4): 570-580)).RhoA is associated with various diseases, and elevated expression of RhoA has been identified in malignant prostate cancer, gastric cancer and testicular cancer (Schmidt, Lucy J. (2012). Molecular Endocrinology. 26 (5): 716-735; Zhang S et al. Molecular Cancer Research. 7 (4): 570-580).
또한, 본 발명자들은 선행 연구를 통해(Hae Ryung Chang et al., Gut., 0:1, 2014), 초기 위암에서 RhoA 단백질이 과발현되는 것을 확인하였으며, siRNA를 이용하여 RhoA 유전자의 발현을 억제하거나, RhoA 억제제를 처리하면, 종양형성을 억제할 수 있는 것을 확인하였다.In addition, the present inventors confirmed that the RhoA protein is overexpressed in early gastric cancer (Hae Ryung Chang et al., Gut., 0: 1, 2014), and by using siRNA to suppress the expression of the RhoA gene or , RhoA inhibitors, it was confirmed that the tumor formation can be suppressed.
RhoA는 또한 만성 골수성 백혈병(CML)과도 관련이 있다. 골수세포가 제대로 기능하지 못하게 하는 줄기세포 질환인 CML은 액틴 중합과 연관되며, RhoA와 같은 신호 단백질은 액틴의 중합을 조절한다. 정상과 영향을 받은 호중구 사이에 나타나는 단백질의 차이로 인해, RhoA는 핵심 요소가 되었고, 추가의 실험은 또한 RhoA-억제 경로가 CML 세포의 전반적인 성장을 방지한다는 것을 입증하였다. 결과적으로, RhoA는 CML 치료에 대한 유전자 치료 기술의 치료학적 타겟으로 중요한 잠재력을 갖는다.RhoA is also associated with chronic myeloid leukemia (CML). CML, a stem cell disease that causes bone marrow cells to function poorly, is associated with actin polymerization, and signal proteins such as RhoA regulate the polymerization of actin. Due to the difference in protein between normal and affected neutrophils, RhoA has become a key factor and further experiments have also demonstrated that the RhoA-inhibiting pathway prevents the overall growth of CML cells. As a result, RhoA has important potential as a therapeutic target for gene therapy techniques for CML therapy.
RhoA 억제제로 알려진 '로신(Rhosin)'은 2012년 6월 신시내티 어린이 병원의 연구원으로부터 합성되었다. 로신은 암의 증식을 억제하고 신경 세포 재생을 촉진하는 기능을 가지며, 특히 암 관련 세포의 성장을 방지하기 위해 Rho GTPases를 특이적으로 타겟팅한다. 유방암 세포에서 로신은 투여량 의존적으로 암세포의 성장을 억제하였으며, 천식과 당뇨병에도 효과가 있음이 입증되었다.Known as a RhoA inhibitor, 'Rhosin' was synthesized in June 2012 from a researcher at Cincinnati Children's Hospital. Rosine has the function of inhibiting cancer proliferation and promoting neuronal regeneration, and specifically targets Rho GTPases to prevent the growth of cancer-related cells. Rosine inhibited the growth of cancer cells in a dose-dependent manner and has been shown to be effective in asthma and diabetes.
이와 같은 배경 하에, 본 발명자들은 RhoA를 타겟으로 하여, 로신보다 더욱 효과적인 신규한 RhoA 억제제를 고안하고 이의 RhoA 억제 활성을 확인함으로써 본 발명을 완성하였다.Against this background, the inventors have completed the present invention by designing a novel RhoA inhibitor that is more effective than Rosine by targeting RhoA and confirming its RhoA inhibitory activity.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로, 본 발명의 목적은 로신 보다 효과적으로 RhoA를 억제하는 신규한 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.The present invention has been made to solve the above problems, and an object of the present invention is to provide a novel RhoA inhibitor or a pharmaceutically acceptable salt thereof that inhibits RhoA more effectively than rosine.
본 발명의 다른 목적은, 상기 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease caused by RhoA expression or increased activity, including the RhoA inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또 다른 목적은, 상기 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Still another object of the present invention is to provide a dietary supplement for preventing or ameliorating diseases caused by an increase in RhoA expression or activity including the RhoA inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
상술한 본 발명의 과제를 해결하기 위해 본 발명은, 하기 화학식 1의 구조를 갖는 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 제공한다:In order to solve the above problems of the present invention, the present invention provides a RhoA inhibitor or a pharmaceutically acceptable salt thereof having the structure of Formula 1 below:
[화학식 1] [Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
R은 -S(=O)2R1, -C(=O)R2 또는 -C(=O)R3R2일 수 있고,R may be -S (= 0) 2 R 1 , -C (= 0) R 2 or -C (= 0) R 3 R 2 ,
R1은 비치환되거나 또는 C1- 4알킬로 치환된 페닐일 수 있으며,R 1 may be a phenyl substituted with unsubstituted or C 1- 4 alkyl Beach,
R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; S, N 및 O로 이루어진 군에서 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 헤테로사이클릭 고리가 융합된 페닐; 비페닐; 벤질; S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 모노사이클릭 헤테로아릴; 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 9- 또는 10-원 바이사이클릭 헤테로아릴일 수 있고,R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, halo (halo), or a nitro-substituted phenyl; Phenyl fused to a 5- or 6-membered heterocyclic ring comprising one or two heteroatoms selected from the group consisting of S, N and O; Biphenyl; benzyl; 5- or 6-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of S, N and O; Or 9- or 10-membered bicyclic heteroaryl including 1 to 4 heteroatoms selected from the group consisting of S, N and O,
R3은 C1- 4알킬; C1- 4알콕시; C1- 4알킬티오; 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 헤테로사이클릭기일 수 있다.R 3 is C 1- 4 alkyl; C 1- 4 alkoxy; C 1- 4 alkylthio; Or a 5- or 6-membered heterocyclic group comprising one or two heteroatoms selected from the group consisting of S, N and O.
본 발명의 바람직한 일실시예에 따르면, 상기 R1은 비치환된 페닐일 수 있고, R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; 헤테로원자 O를 2개 포함하는 5-원 헤테로사이클릭 고리가 융합된 페닐; 비페닐; 벤질; 헤테로원자 O 또는 N을 1개 포함하는 5-원 또는 6-원 모노사이클릭 헤테로아릴; 헤테로원자 N을 1개 포함하는 9-원 바이사이클릭 헤테로아릴일 수 있으며, R3은 C1- 4알킬, C1- 4알콕시, C1- 4알킬티오 또는 헤테로원자 N을 1개 포함하는 5- 원 헤테로사이클릭기일 수 있다.According to one preferred embodiment of the invention, the R 1 can be an unsubstituted phenyl, R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, halo (halo), or a nitro-substituted phenyl; Phenyl fused to a 5-membered heterocyclic ring containing two heteroatoms O; Biphenyl; benzyl; 5- or 6-membered monocyclic heteroaryl containing one heteroatom O or N; Cyclic 9-membered bicyclic containing one heteroatom N and may be heteroaryl, R 3 is a C 1- 4 alkyl, C 1- 4 alkoxy, C 1- 4 containing one alkyl thio or a hetero atom N 5-membered heterocyclic group.
본 발명의 다른 바람직한 일실시예에 따르면, 상기 화학식 1의 R은 다음으로 이루어진 군에서 선택된 어느 하나일 수 있다:According to another preferred embodiment of the present invention, R in Formula 1 may be any one selected from the group consisting of:
, , , , , , , , , , , , 및. , , , , , , , , , , , , And .
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 RhoA 억제제는 RhoA 단백질의 바인딩 도메인에 특이적으로 결합하여 RhoA 단백질의 활성을 억제할 수 있다.According to another preferred embodiment of the present invention, the RhoA inhibitor may specifically bind to the binding domain of the RhoA protein to inhibit the activity of the RhoA protein.
본 발명은 또한, 전술한 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating a disease caused by an increase in RhoA expression or activity comprising the above-described RhoA inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 전술한 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a dietary supplement for preventing or ameliorating a disease caused by an increase in RhoA expression or activity comprising the above-described RhoA inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 바람직한 일실시예에 따르면, 상기 RhoA 발현 또는 활성 증가로 야기되는 질환은 암, 만성 골수성 백혈병, 당뇨병 및 천식으로 이루어진 군에서 선택되는 1종 이상일 수 있다.According to a preferred embodiment of the present invention, the disease caused by the increase in RhoA expression or activity may be one or more selected from the group consisting of cancer, chronic myeloid leukemia, diabetes mellitus and asthma.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 암은 위암, 유방암, 전립선암 및 고환암으로 이루어진 군에서 선택되는 1종 이상일 수 있다.According to another preferred embodiment of the present invention, the cancer may be one or more selected from the group consisting of gastric cancer, breast cancer, prostate cancer and testicular cancer.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염은 0.5 내지 2.5 μM의 농도로 투여될 수 있다.According to another preferred embodiment of the present invention, the RhoA inhibitor or a pharmaceutically acceptable salt thereof may be administered at a concentration of 0.5 to 2.5 μM.
본 발명은 신규한 RhoA 억제제 및 이를 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방, 개선 또는 치료용 조성물을 제공한다. 본 발명의 RhoA 억제제는 기존의 RhoA 억제제인 로신보다 RhoA 발현 또는 활성을 억제하는 효과가 뛰어나므로, RhoA 발현 또는 활성 증가로 야기되는 질환, 특히 위암을 예방, 개선 또는 치료하는데 현저한 효과를 나타낸다. 또한, 상대적으로 낮은 농도에서도 위암세포의 생존율을 억제하는 효과가 뛰어나기 때문에 적은 양으로도 위암을 효율적으로 예방, 개선 또는 치료할 수 있다.The present invention provides a novel RhoA inhibitor and a composition for preventing, ameliorating or treating a disease caused by an increase in RhoA expression or activity comprising the same as an active ingredient. Since the RhoA inhibitor of the present invention is more effective in inhibiting RhoA expression or activity than Rosine, which is a conventional RhoA inhibitor, it exhibits a remarkable effect in preventing, ameliorating or treating diseases caused by RhoA expression or increased activity, particularly gastric cancer. In addition, since the effect of inhibiting the survival rate of gastric cancer cells is excellent even at a relatively low concentration, even a small amount can effectively prevent, improve or treat gastric cancer.
도 1은 JK-201 내지 JK-207 화합물의 농도에 따른 위암 세포주 AGS, SNU668 및 MKN1의 세포 생존율을 그래프로 나타낸 것이다.
도 2는 JK-201 내지 JK-207 화합물의 농도에 따른 위암 세포주 SNU216, SNU620 및 SNU601의 세포 생존율을 그래프로 나타낸 것이다.
도 3은 JK-208 내지 JK-214 화합물의 농도에 따른 위암 세포주 AGS, SNU668 및 MKN1의 세포 생존율을 그래프로 나타낸 것이다.
도 4는 JK-208 내지 JK-214 화합물의 농도에 따른 위암 세포주 SNU216, SNU620 및 SNU601의 세포 생존율을 그래프로 나타낸 것이다.
도 5는 위암 세포주 AGS, MKN1 및 SNU601에서 JK-201 내지 JK-206 화합물의 RhoA 억제 활성을 그래프로 나타낸 것이다.
도 6은 위암 세포주 SNU620, SNU668 및 SNU216에서 JK-201 내지 JK-206 화합물의 RhoA 억제 활성을 그래프로 나타낸 것이다.
도 7은 위암 세포주 AGS, MKN1 및 SNU601에서 JK-207 내지 JK-214 화합물의 RhoA 억제 활성을 그래프로 나타낸 것이다.
도 8은 위암 세포주 SNU620, SNU668 및 SNU216에서 JK-207 내지 JK-214 화합물의 RhoA 억제 활성을 그래프로 나타낸 것이다.
도 9는 위암 세포주 AGS, SNU668, MKN1, SNU216 및 SNU601에서 JK-206 화합물의 세포 이동 억제 활성을 그래프로 나타낸 것이다.Figure 1 graphically shows the cell viability of gastric cancer cell lines AGS, SNU668 and MKN1 according to the concentration of the JK-201 to JK-207 compound.
Figure 2 graphically shows the cell viability of gastric cancer cell lines SNU216, SNU620 and SNU601 according to the concentration of the JK-201 to JK-207 compound.
Figure 3 graphically shows the cell viability of gastric cancer cell lines AGS, SNU668 and MKN1 according to the concentration of the JK-208 to JK-214 compound.
Figure 4 graphically shows the cell viability of gastric cancer cell lines SNU216, SNU620 and SNU601 according to the concentration of the JK-208 to JK-214 compound.
FIG. 5 graphically shows the RhoA inhibitory activity of JK-201 to JK-206 compounds in gastric cancer cell lines AGS, MKN1 and SNU601.
Figure 6 graphically shows the RhoA inhibitory activity of JK-201 to JK-206 compounds in gastric cancer cell lines SNU620, SNU668 and SNU216.
Figure 7 graphically shows the RhoA inhibitory activity of JK-207 to JK-214 compounds in gastric cancer cell lines AGS, MKN1 and SNU601.
FIG. 8 graphically shows the RhoA inhibitory activity of JK-207 to JK-214 compounds in gastric cancer cell lines SNU620, SNU668 and SNU216.
9 graphically shows the cell migration inhibitory activity of JK-206 compounds in gastric cancer cell lines AGS, SNU668, MKN1, SNU216 and SNU601.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
상술한 바와 같이, 본 발명자들은 RhoA 억제제로 알려진 로신보다 RhoA 억제 활성이 뛰어난 신규 RhoA 억제제를 고안하고, 이의 효과를 위암 세포주에 대해 확인함으로써 본 발명을 완성하였다.As described above, the present inventors have completed the present invention by designing a novel RhoA inhibitor having superior RhoA inhibitory activity to rosin known as a RhoA inhibitor, and confirming its effect against gastric cancer cell lines.
본 발명은 신규한 RhoA 억제제 및 이를 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방, 개선 또는 치료용 조성물을 제공한다. 본 발명의 RhoA 억제제는 기존의 RhoA 억제제인 로신보다 RhoA 발현 또는 활성을 억제하는 효과가 뛰어나므로, RhoA 발현 또는 활성 증가로 야기되는 질환, 특히 위암을 예방, 개선 또는 치료하는데 현저한 효과를 나타낸다. 또한, 상대적으로 낮은 농도에서도 위암세포의 생존율을 억제하는 효과가 뛰어나기 때문에 적은 양으로도 위암을 효율적으로 예방, 개선 또는 치료할 수 있다.The present invention provides a novel RhoA inhibitor and a composition for preventing, ameliorating or treating a disease caused by an increase in RhoA expression or activity comprising the same as an active ingredient. Since the RhoA inhibitor of the present invention is more effective in inhibiting RhoA expression or activity than Rosine, which is a conventional RhoA inhibitor, it exhibits a remarkable effect in preventing, ameliorating or treating diseases caused by RhoA expression or increased activity, particularly gastric cancer. In addition, since the effect of inhibiting the survival rate of gastric cancer cells is excellent even at a relatively low concentration, even a small amount can effectively prevent, improve or treat gastric cancer.
본 발명은 하기 화학식 1의 구조를 갖는 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 제공한다:The present invention provides a RhoA inhibitor or a pharmaceutically acceptable salt thereof having the structure of Formula 1:
[화학식 1] [Formula 1]
상기 화학식 1에서,In Chemical Formula 1,
R은 -S(=O)2R1, -C(=O)R2 또는 -C(=O)R3R2이고,R is -S (= 0) 2 R 1 , -C (= 0) R 2 or -C (= 0) R 3 R 2 ,
R1은 비치환되거나 또는 C1- 4알킬로 치환된 페닐이며,R 1 is phenyl substituted by unsubstituted or C 1- 4 alkyl Beach,
R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; S, N 및 O로 이루어진 군에서 선택된 1 또는 2개의 헤테로원자를 포함하는 비치환된 5- 또는 6-원 헤테로사이클릭 고리가 융합된 비치환된 페닐; 비페닐; 벤질; S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 비치환된 5- 또는 6-원 모노사이클릭 헤테로아릴; 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 비치환된 9- 또는 10-원 바이사이클릭 헤테로아릴이고,R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, halo (halo), or a nitro-substituted phenyl; Unsubstituted phenyl fused to an unsubstituted 5- or 6-membered heterocyclic ring comprising one or two heteroatoms selected from the group consisting of S, N and O; Biphenyl; benzyl; Unsubstituted 5- or 6-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of S, N and O; Or an unsubstituted 9- or 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of S, N and O,
R3은 C1- 4알킬, C1- 4알콕시, C1- 4알킬티오 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 헤테로사이클릭기일 수 있다.R 3 is C 1- 4 alkyl, C 1- 4 alkoxy, C 1- 4 alkylthio or S, N, and 5-or 6 membered heterocyclic containing one or two heteroatoms selected from the group consisting of O It may be a flag.
달리 명시되지 않는 한, 본원에 사용된 용어 "알킬"은 직쇄형, 분지형 또는 사이클릭 모이어티를 갖는 포화된 1가 탄화수소 라디칼을 포함한다. 예를 들어, 알킬 라디칼은 메틸, 에틸, 프로필, 이소프로필, 사이클로프로필, n-부틸, 이소부틸, sec-부틸, t-부틸, 사이클로부틸, n-펜틸, 3-(2-메틸)부틸, 2-펜틸, 2-메틸부틸, 네오펜틸, 사이클로펜틸, n-헥실, 2-헥실, 2-메틸펜틸 및 사이클로헥실을 포함한다. 유사하게, C1- 4알킬은 1, 2, 3 또는 4개의 탄소 원자를 가진 직쇄형 또는 분지형 알킬을 의미하며, 바람직하게는 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸 및 t-부틸로 이루어진 군에서 선택된 1종일 수 있다.Unless otherwise specified, the term "alkyl" as used herein includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals are methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C 1- 4 alkyl is 1, 2, 3 or 4 means a straight-chain or branched alkyl having carbon atoms and preferably methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, sec-butyl and t-butyl may be selected from the group consisting of.
본원에 사용된 용어 "할로겐"은, 달리 명시되지 않는 한, 플루오로, 클로로, 브로모 또는 아이오도(iodo)를 의미한다. 바람직한 할로겐기는 F, Cl 및 Br을 포함한다.As used herein, the term "halogen" means fluoro, chloro, bromo or iodo, unless otherwise specified. Preferred halogen groups include F, Cl and Br.
본원에 사용된 용어 "아릴"은, 달리 명시되지 않는 한, 탄소 고리(ring) 원자를 함유하는 비치환되거나 치환된 모노- 또는 폴리사이클릭 고리(ring) 시스템을 나타내며, 나프틸, 바이페닐 등의 탄소수 6 내지 12의 탄화수소환을 포함한다.As used herein, the term "aryl" refers to an unsubstituted or substituted mono- or polycyclic ring system containing carbon ring atoms, unless otherwise specified, naphthyl, biphenyl, and the like. And a hydrocarbon ring having 6 to 12 carbon atoms.
또한, 용어 "헤테로아릴"은 S, N 및 O로 이루어진 군에서 선택되는 1 내지 4개의 헤테로 원자를 포함하는 5 내지 12-원의 방향족 라디칼을 의미하며, 5 내지 6원의 모노사이클릭 헤테로아릴 라디칼 및 벤젠 고리 또는 피리딘 고리와 융합되어 형성된 바이사이클릭 헤테로아릴 라디칼을 포함한다. 예를 들면 모노사이클릭 헤테로아릴은 싸이아졸, 피라졸, 옥사졸, 이미다졸, 피롤, 퓨란, 싸이오펜, 아이소싸이아졸, 아이소옥사졸, 트라이아졸, 싸이아다이아졸, 테트라졸, 옥사다이아졸, 트리아진, 피리딘, 피리다진, 피리미딘, 피라진 등을 포함한다. 또한, 바이사이클릭 헤테로아릴은 벤조싸이아졸, 벤조옥사졸, 벤즈이미다졸, 벤조퓨란, 벤조싸이오펜, 벤즈아이속사졸, 인돌, 인돌린, 퀴놀린, 아이소퀴놀린, 퀴나졸린, 이미다조피리딘, 옥사졸로피리딘 등을 포함한다.The term "heteroaryl" also means a 5-12 membered aromatic radical comprising 1-4 heteroatoms selected from the group consisting of S, N and O, and a 5-6 membered monocyclic heteroaryl Radicals and bicyclic heteroaryl radicals formed by fusion with a benzene ring or a pyridine ring. For example, monocyclic heteroaryl is thiazole, pyrazole, oxazole, imidazole, pyrrole, furan, thiophene, isothiazole, isoxazole, triazole, thiadiazole, tetrazole, oxadiazole , Triazine, pyridine, pyridazine, pyrimidine, pyrazine and the like. In addition, bicyclic heteroaryl is benzothiazole, benzoxazole, benzimidazole, benzofuran, benzothiophene, benzisoxazole, indole, indolin, quinoline, isoquinoline, quinazoline, imidazopyridine, oxa Zolopyridine and the like.
용어 "헤테로사이클"이란 헤테로원자 S, N 및 O로 이루어진 군에서 선택되는 1개 이상, 바람직하게는 동일하거나 상이한 헤테로원자를 1 내지 4개 포함하는 3 내지 12원의 모노- 또는 폴리-사이클릭 고리를 의미하며, 방향족 고리는 포함하지 않는다. 예를 들어, 피롤리딘, 이미다졸린, 이미다졸리딘, 피라졸린, 피라졸리딘, 피페리딘, 모폴린, 피페라진, 테트라하이드로퓨란, 테트라하이드로피리미딘-2(1H)-온, 이미다졸리딘-2-온 등을 포함한다. 바람직하게는, 상기 헤테로사이클은 5 내지 6원의 모노-사이클릭 고리일 수 있으며, 예를 들어, 피롤리딘, 모폴린, 피페라진, 테트라하이드로퓨란, 피페리딘, 또는 다이옥솔레인(dioxolane) 등일 수 있다.The term "heterocycle" means a 3 to 12 membered mono- or poly-cyclic containing at least one, preferably 1 to 4, identical or different heteroatoms selected from the group consisting of heteroatoms S, N and O Ring, and does not include aromatic ring. For example, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, morpholine, piperazine, tetrahydrofuran, tetrahydropyrimidin-2 (1H) -one, Imidazolidin-2-ones and the like. Preferably, the heterocycle may be a 5-6 membered mono-cyclic ring, for example pyrrolidine, morpholine, piperazine, tetrahydrofuran, piperidine, or dioxolane ) And the like.
본원에 사용된 용어 "알콕시"는 별도의 기재가 없는 한 O-알킬기를 포함한다. 여기서 알킬은 탄소수 1 내지 4개의 C1-4 알킬일 수 있다.As used herein, the term "alkoxy" includes O-alkyl groups unless otherwise noted. Wherein alkyl may be C 1-4 alkyl having 1 to 4 carbon atoms.
본원에 사용된 용어 "알킬티오"는 별도의 기재가 없는 한 S- 알킬기를 포함한다. 여기서 알킬은 탄소수 1 내지 4개의 C1-4 알킬일 수 있다.As used herein, the term "alkylthio" includes S-alkyl groups unless otherwise noted. Wherein alkyl may be C 1-4 alkyl having 1 to 4 carbon atoms.
본 발명의 RhoA 억제제에 있어서, 바람직하게는, 상기 R1은 비치환된 페닐일 수 있고, 상기 R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; 헤테로원자 O를 2개 포함하는 5-원 헤테로사이클릭 고리가 융합된 페닐; 비페닐; 벤질; 헤테로원자 O 또는 N을 1개 포함하는 5-원 또는 6-원 모노사이클릭 헤테로아릴; 헤테로원자 N을 1개 포함하는 9-원 바이사이클릭 헤테로아릴일 수 있으며; R3은 C1- 4알킬, C1- 4알콕시, C1- 4알킬티오 또는 헤테로원자 N을 1개 포함하는 5- 원 헤테로사이클릭기일 수 있다.In the RhoA inhibitory agent of the present invention, preferably, wherein R 1 is unsubstituted phenyl, and may be, the R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, substituted by halo (halo), or nitro ring Phenyl; Phenyl fused to a 5-membered heterocyclic ring containing two heteroatoms O; Biphenyl; benzyl; 5- or 6-membered monocyclic heteroaryl containing one heteroatom O or N; 9-membered bicyclic heteroaryl containing one heteroatom N; R 3 may be an cyclic C 1- 4 alkyl, C 1- 4 alkoxy, C 1- 4 5- membered heteroaryl containing one to alkylthio, or N heteroatoms.
가장 바람직하게는, R1은 페닐일 수 있고, 상기 R2는 하이드록시, 메톡시, 플루오로 또는 니트로로 치환된 페닐; 다이옥솔레인이 융합된 페닐; 비페닐; 벤질; 퓨릴(furyl); 피리딜(pyridyl); 벤즈이미다졸일(benzimidazolyl)일 수 있으며, R3은 메틸, 메톡시, 메틸티오 또는 피롤리딘일(pyrrolidinyl)일 수 있다.Most preferably, R 1 may be phenyl, wherein R 2 is phenyl substituted with hydroxy, methoxy, fluoro or nitro; Phenyl fused to dioxolane; Biphenyl; benzyl; Furyl; Pyridyl; May be benzimidazolyl, and R 3 may be methyl, methoxy, methylthio or pyrrolidinyl.
본 발명의 바람직한 일실시예에 따르면, 상기 화학식 1의 R은 다음으로 이루어진 군에서 선택된 어느 하나일 수 있다:According to a preferred embodiment of the present invention, R in Formula 1 may be any one selected from the group consisting of:
, , , , , , , , , , , , 및. , , , , , , , , , , , , And .
본 발명의 바람직한 다른 일실시예에 따르면, 상기 RhoA 억제제는 RhoA 단백질의 바인딩 도메인에 특이적으로 결합하여 RhoA 단백질의 활성을 억제할 수 있다.According to another preferred embodiment of the present invention, the RhoA inhibitor may specifically bind to the binding domain of the RhoA protein to inhibit the activity of the RhoA protein.
본 발명에서 RhoA란 Ras homolog geen family, member A의 줄임말로, 스트레스 섬유의 형성에서 액틴 세포 골격을 조절하는 것으로 알려져 있는 작은 GTPase 단백질이다. In the present invention, RhoA is an abbreviation of Ras homolog geen family, member A, a small GTPase protein known to regulate actin cytoskeleton in the formation of stress fibers.
RhoA 는 LIM 키나아제를 자극하는 ROCK (RhoA kinase)를 활성화시키며, 그 후 코필린(cofilin)을 자극, 세포의 액틴 세포 골격을 효과적으로 재구성한다. 신경 세포의 경우, RhoA 경로의 활성화는 성장 원뿔 (growth cone) 붕괴를 초래하여 신경 경로와 축삭의 성장 및 복구를 억제한다. 다양한 요소에 의한 RhoA 경로의 억제는 몇몇 개선된 수준의 신경 섬유 수초의 재형성을 야기한다. RhoA activates ROCK (RhoA kinase), which stimulates LIM kinase, then stimulates cofilin, effectively reconstituting the actin cytoskeleton of cells. In the case of neurons, activation of the RhoA pathway leads to growth cone collapse, which inhibits the growth and repair of nerve pathways and axons. Inhibition of the RhoA pathway by various factors causes some improved levels of nerve fiber myelin remodeling.
공지된 RhoA 억제제로는 로신(Rhosin)이 있으며, 하기 화학식 2로 표시된다.Known RhoA inhibitors include Rhosin, which is represented by the following formula (2).
[화학식 2][Formula 2]
본 발명자들은 상기 로신으로부터 하기 화학식 1로 표시되는 신규한 RhoA 억제제를 제조하였다.The present inventors have prepared a novel RhoA inhibitor represented by the following formula (1) from the rosin.
[화학식 1][Formula 1]
본 발명자들은 이전 연구를 통해, 신규 RhoA 억제제로서 하기 화학식 3의 화합물을 개발하였고, 이를 JK-122로 명명한바 있다.The inventors of the previous study, as a novel RhoA inhibitor, developed the compound of formula 3, which was named JK-122.
[화학식 3][Formula 3]
본 발명에서는 RhoA를 타겟으로 하는 활성 및 선택성의 개발을 위해, 백본으로서 JK-122와 로신의 구조적 특성을 결합한 하이드라지드 모이어티(hydrazide moiety)를 이용하여 신규 RhoA 억제제를 설계하였고, 하기 화학식 4의 구조를 갖는 히트 화합물(hit compound)을 도출하였다.In the present invention, for the development of activity and selectivity targeting RhoA, a novel RhoA inhibitor was designed using a hydrazide moiety that combines the structural properties of JK-122 and rosin as a backbone. A hit compound having a structure of was obtained.
[화학식 4][Formula 4]
타겟 하이드라지드의 합성을 위해, 시판되는 벤즈하이드라지드가 사용되었고, 실온에서 (또는 가열) 메탄올 또는 에탄올에서 적절한 알데하이드와 반응시켜 상응하는 최종 생성물을 수득하였다. 이에 대한 반응식은 하기 반응식 1로 나타내었다.For the synthesis of the target hydrazide, commercial benzhydrazide was used and reacted with the appropriate aldehyde in methanol or ethanol at room temperature (or heated) to give the corresponding final product. The reaction scheme is shown in Scheme 1 below.
[반응식 1]Scheme 1
*시약 및 반응 조건: 메탄올 또는 에탄올, 환류, 0.5-6시간Reagents and reaction conditions: methanol or ethanol, reflux, 0.5-6 hours
반응식 1을 통해 상기 화학식 4에서 Ar이 인 화학식 5의 화합물을 합성하였고, 하기 화학식 5의 화합물을 기반으로 하여 최종적으로 화학식 1의 구조를 갖는 히트 화합물을 도출하였다.Ar in Chemical Formula 4 through Scheme 1 The compound of Formula 5 was synthesized, and a heat compound having a structure of Formula 1 was finally derived based on the compound of Formula 5.
[화학식 5][Formula 5]
본 발명의 신규한 RhoA 억제제는 대표적으로 하기 기재된 일반적인 방법으로 제조될 수 있으나, 이에 한정되지 않으며, 하기 제조방법 외에도 당분야에서 통상적으로 사용되고 있는 제조방법에 의해 제조될 수 있다.The novel RhoA inhibitor of the present invention may be prepared by the general method described below, but is not limited thereto, and may be prepared by a manufacturing method commonly used in the art, in addition to the following manufacturing method.
화학식 1의 화합물의 일반적인 합성 방법General Synthetic Methods of Compounds of Formula 1
메탄올 또는 에탄올에 용해된 4- 페녹시벤즈알데하이드 (1 mmol) 및 적절한 하이드라지드 화합물 (1 mmol)의 혼합물을 환류 하에 실온에서 또는 가열하여 0.5 내지 4 시간 동안 교반하였다. 반응 과정은 TLC로 모니터링 하였다. 반응 완료 후, 내용물을 실온으로 냉각시키고 교반하면서 차가운 얼음물(5 mL)에 부었다. 고체를 여과 및 건조하고 메탄올 또는 에탄올을 사용하여 재결정화에 의해 정제하여 하이드라지드 산물인 JK-201 내지 JK-214를 수득하였다.A mixture of 4-phenoxybenzaldehyde (1 mmol) and the appropriate hydrazide compound (1 mmol) dissolved in methanol or ethanol was stirred at reflux at room temperature or by heating for 0.5-4 hours. The reaction process was monitored by TLC. After completion of the reaction, the contents were cooled to room temperature and poured into cold ice water (5 mL) with stirring. The solid was filtered and dried and purified by recrystallization with methanol or ethanol to give the hydrazide products JK-201 to JK-214.
수득된 JK-201 내지 JK-214의 14 종의 화합물은 상기 화학식 1에서 R이 순서대로 하기에 기재된 치환기로 치환된 것이다: (JK-201), (JK-202), (JK-203), (JK-204), (JK-205), (JK-206), (JK-207), (JK-208), (JK-209), (JK-210), (JK-211), (JK-212), (JK-213) 및(JK-214).The 14 compounds of JK-201 to JK-214 obtained are those in which R in Formula 1 is substituted with the substituents described below in order: (JK-201), (JK-202), (JK-203), (JK-204), (JK-205), (JK-206), (JK-207), (JK-208), (JK-209), (JK-210), (JK-211), (JK-212), (JK-213) and (JK-214).
본 발명에서 제공하는 상기 14 종의 화합물은 로신과 마찬가지로 RhoA의 바인딩 도메인에 특이적으로 결합할 수 있는 것을 확인하였으며, 로신보다 높은 결합능을 보인다는 것을 확인하였다.It was confirmed that the 14 compounds provided in the present invention can specifically bind to the binding domain of RhoA as in Rosine, and showed higher binding capacity than Rosine.
본 발명에 따른 화학식 1의 화합물은 약학적으로 허용 가능한 염의 형태로 사용할 수 있다. 상기 염으로는 약학적으로 또는 생리학적으로 허용되는 다양한 유기산 또는 무기산에 의해 형성된 산부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요오드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 다이카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피온산, 옥살산, 말론산, 숙신산, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디온산, 벤조산, 클로로벤조산, 메틸벤조산, 디니트로 벤조산, 하이드록시 벤조에이트, 메톡시벤조산, 프탈산, 테레프탈레이트, 벤젠설폰산, 톨루엔설폰산, 클로로벤젠설폰산, 크실렌설폰산, 페닐아세트산, 페닐프로피온산, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트, 트라이플루오로아세트산 등을 사용하여 제조할 수 있다.The compound of formula 1 according to the present invention can be used in the form of a pharmaceutically acceptable salt. As the salts, acid addition salts formed by various organic or inorganic acids that are pharmaceutically or physiologically acceptable are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanediodes. Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propionic acid, oxalic acid, malonic acid, succinic acid, suverate, sebacate, Fumarate, maleate, butyne-1,4-dioate, hexane-1,6-diionic acid, benzoic acid, chlorobenzoic acid, methylbenzoic acid, dinitro benzoic acid, hydroxy benzoate, methoxybenzoic acid, phthalic acid, terephthalate, Benzenesulfonic acid, toluenesulfonic acid, chlorobenzenesulfonic acid, xylenesulfonic acid, phenylacetic acid, phenylpropionic acid, phenyl Thirate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, tri It can be prepared using fluoroacetic acid or the like.
이때, 본 발명에 따른 상기 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 화합물을 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 또한 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시키거나, 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.At this time, the acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound of formula 1 in an excess of aqueous acid solution, and the salt is mixed with a water miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. It may also be prepared by evaporating the solvent or excess acid from the mixture followed by drying, or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 리튬, 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예를 들면, 질산은)과 반응시켜 얻는다.Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is pharmaceutically suitable to prepare lithium, sodium, potassium or calcium salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).
나아가, 아미노산을 사용하여 약학적으로 허용 가능한 염을 만들 수 있다. 아미노산염으로는 예를 들면, 글라이신, 알라닌, 페닐알라닌, 발린, 라이신, 글루타믹산 등의 천연 아미노산을 제조하는 것이 제약상 적합하다.Furthermore, amino acids can be used to make pharmaceutically acceptable salts. As an amino acid salt, it is pharmaceutically suitable to manufacture natural amino acids, such as glycine, alanine, phenylalanine, valine, lysine, glutamic acid, for example.
본 발명의 화학식 1의 구조를 갖는 화합물은 라세미체, 광학이성질체, 부분입체이성질체, 광학이성질체의 혼합물 또는 부분입체이성질체의 혼합물 형태일 수 있다.Compounds having the structure of Formula 1 of the present invention may be in the form of racemates, optical isomers, diastereomers, mixtures of optical isomers or mixtures of diastereomers.
본원에 사용된 용어 "광학이성질체"는, 하나 이상의 카이랄 탄소의 존재로 인하여 서로 겹쳐지지 않는 거울상인 입체이성질체 2개 중 하나를 의미한다.As used herein, the term "optical isomer" refers to one of two stereoisomers that are mirror images that do not overlap with each other due to the presence of one or more chiral carbons.
용어 "부분입체이성질체"는, 광학이성질체가 아닌 입체이성질체를 의미하고, 화합물의 2개 이상의 입체이성질체가 등가의 카이랄 중심 중 하나 이상 (전부는 아님)에서 다른 구조를 갖는 경우에 발생하므로 서로 거울상이 아니다.The term "diastereomer" refers to a stereoisomer that is not an optical isomer, and occurs when two or more stereoisomers of the compound have different structures at one or more (but not all) of the equivalent chiral centers, and thus are mirror images of each other. This is not it.
본 명세서에서 사용된 용어 "라세미체"는, 다른 입체-구조인 2개의 광학이성질체가 등량이고, 광학활성이 결여된 것을 의미한다.The term "racemate" as used herein means that two stereoisomers, which are different stereo-structures, are equivalent and lack optical activity.
본 발명은 또한, 전술한 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating a disease caused by an increase in RhoA expression or activity comprising the above-described RhoA inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 약학적 조성물은 RhoA 발현 또는 활성 증가로 야기되는 질환, 즉, RhoA 억제가 필요한 질환의 예방 또는 치료용으로 사용되며, 예를 들어, 암, 만성 골수성 백혈병, 당뇨병 및 천식으로 이루어진 군에서 선택되는 1종 이상일 수 있으나, 이로 한정되는 것은 아니다.The pharmaceutical composition of the present invention is used for the prevention or treatment of diseases caused by increased RhoA expression or activity, i.e., a disease requiring RhoA inhibition, for example, in a group consisting of cancer, chronic myeloid leukemia, diabetes mellitus and asthma. It may be one or more selected, but is not limited thereto.
이때, 본 발명의 약학적 조성물은 RhoA의 과발현 또는 과도한 활성 증가로 야기되는 모든 암의 예방 또는 치료에 제한 없이 사용될 수 있고, 예를 들어 위암, 유방암, 전립선암 및 고환암으로 이루어진 군에서 선택되는 1종 이상의 암의 예방 또는 치료에 사용될 수 있다.At this time, the pharmaceutical composition of the present invention can be used without limitation in the prevention or treatment of all cancers caused by overexpression or excessive activity increase of RhoA, for example, selected from the group consisting of gastric cancer, breast cancer, prostate cancer and testicular cancer. It can be used for the prevention or treatment of more than one type of cancer.
본 발명의 약학적 조성물이 투여되는 투여 경로 및 투여 방식은 특별히 제한되지 않으며, 목적하는 해당 부위에 상기 조성물을 포함하는 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. 구체적으로, 상기 조성물은 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 그 투여 경로의 비제한적인 예로는, 구강, 직장, 국소, 정맥내, 복강내, 근육내, 동맥내, 경피, 비측내 또는 흡입 등을 통하여 투여되는 것을 들 수 있다.The route of administration and mode of administration to which the pharmaceutical composition of the present invention is administered is not particularly limited and may be in accordance with any route of administration and mode of administration as long as the composition comprising the composition can reach the desired site of interest. Specifically, the composition may be administered through various routes, oral or parenteral, and non-limiting examples of the route of administration include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, nasal What is administered through intralateral or inhalation etc. are mentioned.
본 발명의 약학적 조성물은 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있으며, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조된다. The pharmaceutical composition of the present invention may be administered in various oral and parenteral dosage forms for clinical administration, and when formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc., which are commonly used, may be used. Are prepared using.
경구투여를 위한 고형 제제에는 정제, 환자, 산제, 과립제, 캡슐제, 트로키제 등이 포함되며, 이러한 고형 제제는 하나 이상의 본 발명의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로스(sucrose) 또는 락토오스(lactose) 또는 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구 투여를 위한 액상 제제로는 현탁제, 내용 액제, 유제 또는 시럽제 등이 해당 되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, which form at least one excipient such as starch, calcium carbonate, water, or the like. It is prepared by mixing cross, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions or syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Can be.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제, 좌제 등이 포함된다. 비수성용제, 현탁 용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
또한, 본 발명에 따른 화학식 1로 표시되는 화합물의 인체에 대한 효과적인 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 일반적으로 약 0.001-100 mg/kg/일이며, 바람직하게는 0.01-35 mg/kg/일이다. 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.07-7000 mg/일이며, 바람직하게는 0.7-2500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the effective dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally about 0.001-100 mg / kg / day, preferably 0.01-35 mg / kg / day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg / day, preferably 0.7-2500 mg / day, once a day at regular intervals according to the judgment of the doctor or pharmacist. Multiple doses may be administered.
본 발명은 또한, 전술한 RhoA 억제제 또는 이의 식품학적으로 허용 가능한 염을 유효성분으로 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 예방 또는 개선용 건강기능식품을 제공한다.The present invention also provides a dietary supplement for preventing or ameliorating a disease caused by an increase in RhoA expression or activity comprising the above-mentioned RhoA inhibitor or a food acceptable salt thereof as an active ingredient.
본 발명의 건강기능식품에 유효성분으로 포함되는 상기 RhoA 억제제 및 이의 RhoA 억제 효과는 앞서 설명한 바와 동일하므로, 그 기재를 생략한다.Since the RhoA inhibitor and its RhoA inhibitory effect, which are included as an active ingredient in the health functional food of the present invention, are the same as described above, the description thereof is omitted.
본 발명에 따른 건강기능식품은 RhoA 발현 또는 활성 증가로 야기되는 질환, 즉, RhoA 억제가 필요한 질환의 예방 또는 개선을 목적으로 식품, 음료 등의 건강기능식품에 첨가할 수 있다.The health functional food according to the present invention can be added to health functional foods such as foods and beverages for the purpose of preventing or improving diseases caused by RhoA expression or increased activity, that is, diseases requiring RhoA inhibition.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the kind of food. Examples of foods to which the substance may be added include dairy products, various soups, drinks, meat, sausages, breads, biscuits, rice cakes, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products and dairy products, and the like includes all the health functional foods in the conventional sense.
본 발명에 따른 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강기능식품 중의 상기 조성물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The dietary supplement composition containing the compound of formula 1 according to the present invention or a food acceptable salt thereof as an active ingredient may be added to a food as it is or used with other foods or food ingredients, and may be appropriately used according to a conventional method. Can be used. The mixing amount of the active ingredient can be suitably determined according to the purpose of use (prevention or improvement). In general, the amount of the composition in the dietary supplement may be added at 0.1 to 90 parts by weight of the total food weight. However, in the case of long-term intake for health and hygiene or health control purposes, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety.
본 발명의 건강기능식품 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 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, 에리트라이톨 등의 당알코올이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강기능성 식품 조성물 100 당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The nutraceutical composition of the present invention is not particularly limited to other ingredients except for containing the compound as essential ingredients in the indicated ratios, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 dietary food compositions of the present invention.
상기 외에 본 발명의 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용 되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강기능식품 조성물은 천연 과일쥬스 및 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition to the above, the health functional food composition containing the compound of formula 1 of the present invention or a food acceptable salt thereof as an active ingredient is a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors. , Colorants and neutralizers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, etc. It may contain. In addition, the health functional food composition of the present invention may contain a flesh for preparing natural fruit juice and fruit juice beverage and vegetable beverage.
이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 화학식 1의 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 함유하는 건강기능식품 조성물 100 중량부 당 0.1 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.These components can be used independently or in combination. The ratio of such additives is not so important, but it is generally selected from the range of 0.1 to about 20 parts by weight per 100 parts by weight of the nutraceutical composition containing the compound of formula 1 of the present invention or a food acceptable salt thereof as an active ingredient. to be.
추가로, 본 발명은 화학식 1의 구조를 갖는 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염의 약학적으로 유효한 양을 이를 필요로 하는 개체에게 투여하는 것을 포함하는 RhoA 발현 또는 활성 증가로 야기되는 질환의 치료 방법을 제공한다.In addition, the present invention provides a method for treating a disease caused by increased RhoA expression or activity comprising administering to a subject in need thereof a pharmaceutically effective amount of a RhoA inhibitor having a structure of Formula 1 or a pharmaceutically acceptable salt thereof. Provide a method.
본원에서 사용된 용어 "약학적으로 유효한 양"은, RhoA 발현 또는 활성 증가로 야기되는 질환을 예방, 완화 또는 치료하기 위한 효능 및 작용을 나타내고 달성하기에 충분한 양을 의미한다.As used herein, the term “pharmaceutically effective amount” means an amount sufficient to exhibit and achieve efficacy and action for preventing, alleviating or treating a disease caused by increased RhoA expression or activity.
본 발명의 치료 방법에 있어서, RhoA 억제제 또는 이의 약학적으로 허용 가능한 염의 투여량, 투여 경로 및 투여 형태 등은 앞서 전술한 바와 같다.In the method of treatment of the present invention, the dosage, route of administration and dosage form of the RhoA inhibitor or a pharmaceutically acceptable salt thereof is as described above.
본원에서 사용된 용어 "개체"란, RhoA 발현 또는 활성 증가로 야기되는 질환이 발병하였거나 발병할 수 있는 인간을 포함한 쥐, 생쥐, 가축 등의 모든 동물을 의미한다. 구체적으로 인간을 포함한 포유동물일 수 있으나, 이에 제한되지 않는다.As used herein, the term "individual" means all animals, including rats, mice, livestock, etc., including humans, who may or may have a disease caused by increased RhoA expression or activity. Specifically, it may be a mammal including a human, but is not limited thereto.
용어 "투여"란 적절한 방법으로 개체에게 소정의 물질을 도입하는 것을 의미한다. 구체적으로, 본 발명의 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염은 개체에게 단독으로 투여되거나, 다른 치료제와 동시, 순차적, 또는 역순으로 병용 투여될 수 있다.The term "administration" refers to the introduction of a substance to an individual in a suitable manner. In particular, the RhoA inhibitor of the present invention or a pharmaceutically acceptable salt thereof may be administered to an individual alone, or may be administered concurrently, sequentially, or in reverse order with other therapeutic agents.
본 발명의 RhoA 발현 또는 활성 증가로 야기되는 질환의 치료 방법은 수술, 방사선 치료, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용될 수 있다.The method of treating a disease caused by the increase in RhoA expression or activity of the present invention may be combined with methods using surgery, radiation therapy, hormone therapy, chemotherapy and biological response modifiers.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 RhoA 억제제, 이의 약학적으로 허용 가능한 염 또는 이의 식품학적으로 허용 가능한 염은 0.5 내지 2.5 μM의 농도로 투여될 수 있다.According to another preferred embodiment of the present invention, the RhoA inhibitor, its pharmaceutically acceptable salt or its food acceptable salt may be administered at a concentration of 0.5 to 2.5 μM.
이하 본 발명을 바람직한 실시예를 참고로 하여 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있도록 상세히 설명한다. 그러나 본 발명은 여러 가지 상이한 형태로 구현될 수 있으며 여기에서 설명하는 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to a preferred embodiment so that those skilled in the art can easily practice the present invention. As those skilled in the art would realize, the described embodiments may be modified in various different ways, all without departing from the spirit or scope of the present invention.
본 발명의 화학식 1의 구조를 갖는 화합물의 합성Synthesis of Compound Having Structure of Formula 1 of the Present Invention
메탄올 또는 에탄올에 용해된 4- 페녹시벤즈알데하이드 (1 mmol) 및 적절한 하이드라지드 화합물 (1 mmol)의 혼합물을 환류 하에 실온에서 또는 가열하여 0.5 내지 4 시간 동안 교반하였다. 반응 과정은 TLC로 모니터링 하였다. 반응 완료 후, 내용물을 실온으로 냉각시키고 교반하면서 차가운 얼음물(5 mL)에 부었다. 고체를 여과 및 건조하고 메탄올 또는 에탄올을 사용하여 재결정화에 의해 정제하여 하이 드라자이드 산물인 JK-201 내지 JK-214를 수득하였다.A mixture of 4-phenoxybenzaldehyde (1 mmol) and the appropriate hydrazide compound (1 mmol) dissolved in methanol or ethanol was stirred at reflux at room temperature or by heating for 0.5-4 hours. The reaction process was monitored by TLC. After completion of the reaction, the contents were cooled to room temperature and poured into cold ice water (5 mL) with stirring. The solid was filtered and dried and purified by recrystallization with methanol or ethanol to give the hydrazide products JK-201 to JK-214.
수득된 JK-201 내지 JK-214의 14 종의 화합물은 상기 화학식 1에서 R이 순서대로 하기에 기재된 치환기로 치환된 것이다: (JK-201), (JK-202), (JK-203), (JK-204), (JK-205), (JK-206), (JK-207), (JK-208), (JK-209), (JK-210), (JK-211), (JK-212), (JK-213) 및(JK-214).The 14 compounds of JK-201 to JK-214 obtained are those in which R in Formula 1 is substituted with the substituents described below in order: (JK-201), (JK-202), (JK-203), (JK-204), (JK-205), (JK-206), (JK-207), (JK-208), (JK-209), (JK-210), (JK-211), (JK-212), (JK-213) and (JK-214).
공기 또는 수분에 민감한 모든 반응은 질소 대기 하에서 수행하였다. 시약은 Aldrich 및 TCI에서 구입하였다. 달리 명시되지 않는 한, 모든 무수 용매는 반응 전에 CaH2, P2O5, 또는 Na/벤조페논 상에서 증류시켰다. 분석 박층 크로마토그래피(TLC)는 머크(Merk)로부터 구입한 시판되는 예비 코팅된 TLC 플레이트 (실리카겔 60, F-254)을 사용하여 수행하였다. 스팟은 자외선 (254 nm의 램프) 하에 관찰되거나, 또는 임의의 다음의 용액에 담근 후 탄화로 착색하여 검출하였다: 에탄올 또는 과망간산 칼륨 수용액에 용해된 포스포몰리브덴산(PMA). 플래쉬 컬럼 크로마토그래피를 실리카겔 60(0.040~0.063 mm, 230-400 mesh, 머크) 상에서 수행하였다. 적외선 스펙트럼은 Agilent Cary670 기기에 기록되었다. 1H NMR 스펙트럼 (CDCl3, CD3OD, D2O 또는 DMSO-d 6)은 Agilent 400-MR (400 MHz) 상에 기록되었다. 화학적 이동은 용매 피크에 대해 ppm(δ)으로 보고되었다. 1H NMR 데이터는 피크 다중도로 보고 되었다: 단일선(singlet)은 s; 이중선(doublet)은 d; 이중선들의 이중선은 dd; 이중선들의 이중선의 이중선은 ddd; 삼중선(triplet)은 t; 모의 삼중선(pseudo triplet)은 pseudo t; 넓은 단일선은 brs; 및 다중선은 m. 커플링 상수는 헤르츠(Hertz)로 보고 되었다. 13C NMR 스펙트라(CDCl3, CD3OD, D2O 또는 DMSO-d 6)는 Agilent 400-MR (100 MHz) 상에 기록되었다. 화학적 이동은 용매 피크에 대해 ppm(δ)으로 보고되었다. 질량 스펙트럼은 메틸렌 클로라이드 또는 메탄올의 ESI+ 소스 상에 기록되었다.All reactions sensitive to air or moisture were carried out under a nitrogen atmosphere. Reagents were purchased from Aldrich and TCI. Unless otherwise specified, all anhydrous solvents were distilled on CaH 2 , P 2 O 5 , or Na / benzophenone before the reaction. Analytical thin layer chromatography (TLC) was performed using commercially precoated TLC plates (Silica gel 60, F-254) purchased from Merck. Spots were detected under ultraviolet light (lamp at 254 nm) or by soaking in any of the following solutions and staining with carbonization: phosphomolybdic acid (PMA) dissolved in ethanol or potassium permanganate aqueous solution. Flash column chromatography was performed on silica gel 60 (0.040-0.063 mm, 230-400 mesh, Merck). Infrared spectra were recorded on an Agilent Cary670 instrument. 1 H NMR spectra (CDCl 3 , CD 3 OD, D 2 O or DMSO- d 6 ) were recorded on Agilent 400-MR (400 MHz). Chemical shifts are reported in ppm (δ) for solvent peaks. 1 H NMR data was reported as peak multiplicity: singlet was s; Doublet is d; The doublet of doublets is dd; The doublet of doublets of doublets is ddd; The triplet is t; Pseudo triplets are pseudo t; Broad singlet brs; And the polyline is m. Coupling constants were reported in Hertz. 13 C NMR spectra (CDCl 3 , CD 3 OD, D 2 O or DMSO- d 6 ) were recorded on Agilent 400-MR (100 MHz). Chemical shifts are reported in ppm (δ) for solvent peaks. Mass spectra were recorded on an ESI + source of methylene chloride or methanol.
(E)-N'-(4- 페녹시벤질리덴 ) 벤젠설포노하이드라지드 ( JK -201): 1H NMR (400 MHz, DMSO-d 6 ) δ 11.46 (s, 1H), 7.89 (m, 3H), 7.61 (m, 5H), 7.41 (t, J = 8.0 ㎐, 2H), 7.18 (t, J = 8.0 ㎐, 1H), 7.04 (d, J = 8.0 ㎐, 2H), 6.98 (d, J = 8.0 ㎐, 2H). (E) -N '-(4- phenoxybenzylidene ) benzenesulfonohydrazide ( JK- 201) : 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.46 (s, 1H), 7.89 (m , 3H), 7.61 (m, 5H), 7.41 (t, J = 8.0 μs, 2H), 7.18 (t, J = 8.0 μs, 1H), 7.04 (d, J = 8.0 μs, 2H), 6.98 (d , J = 8.0 μs, 2H).
(E)-4- 하이드록시 -N'-(4- 페녹시벤질리덴 ) 벤조하이드라지드 ( JK -202): 1H NMR (400 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 10.12 (s, 1H), 8.42 (s, 1H), 7.81 (d, J = 8.0 ㎐, 2H), 7.72 (d, J = 8.0 ㎐, 2H), 7.43 (t, J = 8.0 ㎐, 2H), 7.20 (t, J = 8.0 ㎐, 1H), 7.09 (d, J = 8.0 ㎐, 2H), 7.05 (d, J = 8.0 ㎐, 2H) , 6.86 (d, J = 8.0 ㎐, 2H). (E) -4- hydroxy -N '- (4- phenoxy-benzylidene) benzoyl hydrazide (JK -202): 1 H NMR (400 MHz, DMSO- d 6) δ 11.60 (s, 1H), 10.12 (s, 1H), 8.42 (s, 1H), 7.81 (d, J = 8.0 μs, 2H), 7.72 (d, J = 8.0 μs, 2H), 7.43 (t, J = 8.0 μs, 2H), 7.20 (t, J = 8.0 kPa, 1H), 7.09 (d, J = 8.0 kPa, 2H), 7.05 (d, J = 8.0 kPa, 2H), 6.86 (d, J = 8.0 kPa, 2H).
(E)-4- 메톡시 -N'-(4- 페녹시벤질리덴 ) 벤조하이드라지드 ( JK -203): 1H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 8.43 (s, 1H), 7.91 (d, J = 8.0 ㎐, 2H), 7.73 (d, J = 8.0 ㎐, 2H), 7.43 (t, J = 8.0㎐, 2H), 7.20 (t, J = 8.0㎐, 1H), 7.07(m, 6H), 3.83 (s, 3H). (E) -4- methoxy -N '- (4- phenoxy-benzylidene) benzoyl hydrazide (JK -203): 1 H NMR (400 MHz, DMSO- d 6) δ 11.69 (s, 1H), 8.43 (s, 1H), 7.91 (d, J = 8.0 ㎐, 2H), 7.73 (d, J = 8.0 ㎐, 2H), 7.43 (t, J = 8.0㎐, 2H), 7.20 (t, J = 8.0 I, 1H), 7.07 (m, 6H), 3.83 (s, 3H).
(E)-4- 플루오로 -N'-(4- 페녹시벤질리덴 ) 벤조하이드라지드 ( JK -204): 1H NMR (400 MHz, DMSO-d 6 ) δ 11.83 (s, 1H), 8.43 (s, 1H), 7.99 (m, 2H), 7.75 (d, J = 8.0㎐, 2H), 7.44 (t, J = 8.0 ㎐, 2H), 7.37 (t, J = 8.0㎐, 2H), 7.20 (t, J = 8.0 ㎐, 1H), 7.09 (d, J = 8.0㎐, 2H), 7.06 (d, J = 8.0 ㎐, 2H). (E) -4- fluoro--N '- (4- phenoxy-benzylidene) benzoyl hydrazide (JK -204): 1 H NMR (400 MHz, DMSO- d 6) δ 11.83 (s, 1H), 8.43 (s, 1H), 7.99 (m, 2H), 7.75 (d, J = 8.0 μs, 2H), 7.44 (t, J = 8.0 μs, 2H), 7.37 (t, J = 8.0 μs, 2H), 7.20 (t, J = 8.0 μs, 1H), 7.09 (d, J = 8.0 μs, 2H), 7.06 (d, J = 8.0 μs, 2H).
(E)-3-니트로-N'-(4- 페녹시벤질리덴 ) 벤조하이드라지드 ( JK -205): 1H NMR (400 MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 8.44 (d, J = 8.0㎐, 1H), 8.37 (d, J = 8.0㎐, 1H), 7.84 (t, J = 8.0 ㎐, 1H), 7.77 (d, J = 8.0, 2H), 7.44 (t, J = 8.0 ㎐, 2H), 7.21 (t, J = 8.0 ㎐, 1H), 7.10 (d, J = 8.0 ㎐, 2H), 7.07 (d, J = 8.0 ㎐, 2H). (E) -3- nitro -N '- (4- phenoxy-benzylidene) benzoyl hydrazide (JK -205): 1 H NMR (400 MHz, DMSO- d 6) δ 12.12 (s, 1H), 8.76 (s, 1H), 8.47 (s, 1H), 8.44 (d, J = 8.0 μs, 1H), 8.37 (d, J = 8.0 μs, 1H), 7.84 (t, J = 8.0 μs, 1H), 7.77 (d, J = 8.0, 2H), 7.44 (t, J = 8.0 ㎐, 2H), 7.21 (t, J = 8.0 ㎐, 1H), 7.10 (d, J = 8.0 ㎐, 2H), 7.07 (d, J = 8.0 μs, 2H).
(E)-N'- (4-페녹시벤질리덴)벤조[d][1,3]디옥솔 -5- 카보하이드라지드 ( JK -206): 1H NMR (400 MHz, DMSO-d 6 ) δ 11.66 (s, 1H), 8.42 (s, 1H), 7.73 (d, J = 8.0㎐, 2H), 7.53 (d, J = 8.0 ㎐, 1H), 7.44 (m, 3H), 7.20 (t, J = 8.0 ㎐, 1H), 7.07 (m, 5H), 6.13 (s, 2H). (E) -N'- (4- phenoxy-benzylidene) benzo [d] [1,3] dioxol-5-carbonyl hydrazide (JK -206): 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.66 (s, 1H), 8.42 (s, 1H), 7.73 (d, J = 8.0 μs, 2H), 7.53 (d, J = 8.0 μs, 1H), 7.44 (m, 3H), 7.20 (t , J = 8.0 μs, 1H), 7.07 (m, 5H), 6.13 (s, 2H).
위암 세포 생존 Gastric Cancer Cell Survival 어세이Assay
2-1. 세포 배양2-1. Cell culture
본 발명에서 사용된 인간 위 종양 세포주는 수득 후, 6개월 안에 사용되었다. 세포주는 5%의 CO2, 37℃ 환경에서 보관되었다. 구체적으로 인간 위 종양 세포주는 AGS (ATCC, USA), MKN1 (RIKEN), SNU-668 (KCLB), SNU-620(KCLB), SNU-601(KCLB) 및 SNU-216 (KCLB)가 사용되었으며, RPMI-1640 (Invitrogen, USA)와 10% 소태아혈청(Hyclone)의 조건에서 배양되었다.Human gastric tumor cell lines used in the present invention were used within 6 months after harvesting. Cell lines were stored in a 5% CO 2 , 37 ° C environment. Specifically, human gastric tumor cell lines were AGS (ATCC, USA), MKN1 (RIKEN), SNU-668 (KCLB), SNU-620 (KCLB), SNU-601 (KCLB), and SNU-216 (KCLB). Incubated in RPMI-1640 (Invitrogen, USA) and 10% fetal bovine serum (Hyclone).
2-2. MTS 2-2. MTS 어세이Assay
상기 실시예 2-1의 6종의 위암 세포를 각각 96웰 플레이트에 3 × 103/웰로 접종하고, 72시간 동안 다양한 농도의 JK-201 내지 JK-214의 화합물에 노출시켰다. 14종의 화합물의 세포 생존 효과는 3-4,5-디메틸티아졸-2-일)-5-(3-카르복시메톡시페닐)-2-(4-설포페닐)-2H-테트라졸리움(MTS; Promega, USA) 어세이로 평가되었다. IC50 값은 DMSO로 처리된 대조군과 비교하여 50% 세포 성장 억제로 정의된다. 값은 각 약물 농도에 대한 3회의 독립적인 실험으로부터 3중 웰 (triplicate wells)의 평균을 나타낸다.The six gastric cancer cells of Example 2-1 were each seeded at 3 × 10 3 / well in 96 well plates and exposed to various concentrations of JK-201 to JK-214 compounds for 72 hours. The cell survival effects of 14 compounds were 3-4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS ; Promega, USA) assay. IC 50 values are defined as 50% cell growth inhibition compared to the control treated with DMSO. Values represent the average of triplicate wells from three independent experiments for each drug concentration.
그 결과, 도 1 내지 4에 나타난 바와 같이 JK-201 내지 JK-214의 화합물 모두 6 종의 위암 세포에 대해 농도 의존적으로 로신보다 우수한 위암 세포 억제 활성을 나타냄을 확인하였다.As a result, as shown in FIGS. 1 to 4, all of the compounds of JK-201 to JK-214 showed gastric cancer cell inhibitory activity superior to rosine in a concentration-dependent manner for 6 gastric cancer cells.
RhoARhoA 활성 측정 Active measurement
활성 및 GTP 결합 RhoA는 제조사의 지침에 따라 Cytoskeleton Inc. (USA)로부터 구입한 RhoA G-LISA 활성 분석 키트를 사용하여 측정하였다. 구체적으로, JK-201 내지 JK-214를 실시예 2-1의 6종의 위암 세포에 48 시간 동안 처리 하였다. 이후의 분석을 위해 단백질 용해물을 수집하였다. 그 다음, 제조사의 지시에 따라 포획된 활성 RhoA의 검출을 위해 RhoA 특이적 항체를 사용하여 G-LISA 플레이트상에서 단백질 용해물을 테스트하였다. 모든 경우에, G-LISA 키트에 제공된 구성적으로 활성인 RhoA 단백질을 어세이의 정확성을 확인하기 위한 양성 대조군으로 사용하였다. 마이크로 플레이트 판독기를 사용하여 490 nm에서 흡광도를 측정하여 신호를 판독하였다.Active and GTP-binding RhoA was prepared according to the manufacturer's instructions. Measurements were made using the RhoA G-LISA Activity Assay Kit purchased from (USA). Specifically, JK-201 to JK-214 were treated with the six gastric cancer cells of Example 2-1 for 48 hours. Protein lysates were collected for later analysis. Protein lysates were then tested on G-LISA plates using RhoA specific antibodies for detection of active RhoA captured according to the manufacturer's instructions. In all cases, the constitutively active RhoA protein provided in the G-LISA kit was used as a positive control to confirm the accuracy of the assay. The signal was read by measuring the absorbance at 490 nm using a micro plate reader.
그 결과, 도 5 내지 8에 나타난 바와 같이 위암 세포주의 종류에 따라 다르지만 14종의 화합물은 전반적으로 RhoA 활성을 억제함을 확인하였다.As a result, as shown in Figs. 5 to 8, it was confirmed that the compounds of the 14 kinds of compounds, depending on the type of gastric cancer cell line, generally suppress RhoA activity.
세포 이동 Cell migration 어세이Assay
상기 실시예 2 및 3의 결과를 바탕으로, 활성이 가장 우수한 JK-206 화합물을 이용하여 세포 이동 어세이를 수행하였다. 구체적으로, 실시예 2-1에서 5종의 위암 세포, 즉 AGS, SNU668, MKN1, SNU216 및 SNU601 위암 세포(2×105)를 각각 보이덴 챔버 (0.8μm 공극 크기, Corning, Corning, NY, USA)에 파종하였다. FBS를 함유하는 배지를 사용하여 바닥 챔버를 채웠다. 이동된 세포를 Diff-Quick kit (Thermo Fisher, Waltham, MA, USA)로 염색하고 역상 현미경으로 촬영하였다. 각 웰로부터 3 현미경 필드(microscopic field)에서 세포 수를 세고, 이동된 세포의 비율을 대조군 세포와 비교하여 측정하였다.Based on the results of Examples 2 and 3, a cell migration assay was performed using the JK-206 compound having the highest activity. Specifically, in Example 2-1, five gastric cancer cells, that is, AGS, SNU668, MKN1, SNU216, and SNU601 gastric cancer cells (2 × 10 5 ), respectively, were prepared in a Boeden chamber (0.8 μm pore size, Corning, Corning, NY, USA). The bottom chamber was filled using medium containing FBS. The migrated cells were stained with a Diff-Quick kit (Thermo Fisher, Waltham, Mass., USA) and photographed with a reversed phase microscope. From each well the cells were counted in 3 microscopic fields and the percentage of migrated cells was measured by comparison with control cells.
그 결과, 도 9에 나타난 바와 같이 JK-206 화합물 처리에 의한 6 종의 위암 세포의 이동 억제 효과가 로신보다 현저하게 우수함을 확인하였다.As a result, as shown in FIG. 9, it was confirmed that the migration inhibitory effect of six kinds of gastric cancer cells by JK-206 compound treatment was significantly superior to that of Rosine.
Claims (12)
[화학식 1]
상기 화학식 1에서,
R은 -S(=O)2R1, -C(=O)R2 또는 -C(=O)R3R2이고,
R1은 비치환되거나 또는 C1-4알킬로 치환된 페닐이며,
R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; S, N 및 O로 이루어진 군에서 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 헤테로사이클릭 고리가 융합된 페닐; 비페닐; 벤질; S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 모노사이클릭 헤테로아릴; 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 내지 4개의 헤테로원자를 포함하는 9- 또는 10-원 바이사이클릭 헤테로아릴이고,
R3은 C1- 4알킬; C1- 4알콕시; C1- 4알킬티오; 또는 S, N 및 O로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로원자를 포함하는 5- 또는 6-원 헤테로사이클릭기이다.A RhoA inhibitor having a structure of Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Chemical Formula 1,
R is -S (= 0) 2 R 1 , -C (= 0) R 2 or -C (= 0) R 3 R 2 ,
R 1 is phenyl unsubstituted or substituted with C 1-4 alkyl,
R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, halo (halo), or a nitro-substituted phenyl; Phenyl fused with a 5- or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of S, N and O; Biphenyl; benzyl; 5- or 6-membered monocyclic heteroaryl comprising one or two heteroatoms selected from the group consisting of S, N and O; Or 9- or 10-membered bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from the group consisting of S, N and O,
R 3 is C 1- 4 alkyl; C 1- 4 alkoxy; C 1- 4 alkylthio; Or a 5- or 6-membered heterocyclic group comprising one or two heteroatoms selected from the group consisting of S, N and O.
R1은 비치환된 페닐이고,
R2는 비치환되거나 또는 하이드록시, C1- 4알콕시, 할로(halo) 또는 니트로로 치환된 페닐; 헤테로원자 O를 2개 포함하는 5-원 헤테로사이클릭 고리가 융합된 페닐; 비페닐; 벤질; 헤테로원자 O 또는 N을 1개 포함하는 5-원 또는 6-원 모노사이클릭 헤테로아릴; 헤테로원자 N을 1개 포함하는 9-원 바이사이클릭 헤테로아릴이며,
R3은 C1- 4알킬, C1- 4알콕시, C1- 4알킬티오 또는 헤테로원자 N을 1개 포함하는 5- 원 헤테로사이클릭기인 것을 특징으로 하는 RhoA 억제제 또는 이의 약학적으로 허용 가능한 염.The method of claim 1,
R 1 is unsubstituted phenyl,
R 2 is unsubstituted or substituted by hydroxy, C 1- 4 alkoxy, halo (halo), or a nitro-substituted phenyl; Phenyl fused to a 5-membered heterocyclic ring containing two heteroatoms O; Biphenyl; benzyl; 5- or 6-membered monocyclic heteroaryl containing one heteroatom O or N; 9-membered bicyclic heteroaryl containing one heteroatom N,
R 3 is C 1- 4 alkyl, C 1- 4 alkoxy, C 1- 4 alkylthio or N heteroatom one five-membered heterocyclic group that features RhoA inhibitor or a pharmaceutically acceptable thereof, which comprises one possible salt.
, , , , , , , , , , , , 및.The RhoA inhibitor or a pharmaceutically acceptable salt thereof according to claim 1, wherein R in Formula 1 is any one selected from the group consisting of:
, , , , , , , , , , , , And .
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KR102224059B1 (en) * | 2020-11-13 | 2021-03-08 | 한림대학교 산학협력단 | Anticancer drug containing RhoA peptide inhibitor as an active ingredient |
WO2022071777A1 (en) * | 2020-09-29 | 2022-04-07 | 연세대학교 산학협력단 | Composition and method for prevention or treatment of respiratory disease |
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WO2022071777A1 (en) * | 2020-09-29 | 2022-04-07 | 연세대학교 산학협력단 | Composition and method for prevention or treatment of respiratory disease |
KR102224059B1 (en) * | 2020-11-13 | 2021-03-08 | 한림대학교 산학협력단 | Anticancer drug containing RhoA peptide inhibitor as an active ingredient |
WO2022102867A1 (en) * | 2020-11-13 | 2022-05-19 | 이엘메드 주식회사 | Anti-cancer drug containing rhoa peptide inhibitor as an active ingredient |
CN114929257A (en) * | 2020-11-13 | 2022-08-19 | Elmed株式会社 | Anticancer agent comprising RHOA peptide inhibitor as active ingredient |
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