KR101119793B1 - Composition comprising piperidine compounds as an active ingredient showing inhibitory activity of peroxiredoxin - Google Patents

Composition comprising piperidine compounds as an active ingredient showing inhibitory activity of peroxiredoxin Download PDF

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KR101119793B1
KR101119793B1 KR1020090001185A KR20090001185A KR101119793B1 KR 101119793 B1 KR101119793 B1 KR 101119793B1 KR 1020090001185 A KR1020090001185 A KR 1020090001185A KR 20090001185 A KR20090001185 A KR 20090001185A KR 101119793 B1 KR101119793 B1 KR 101119793B1
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cancer
piperidine
biphenyl
carboxamide
cgx
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KR20100081784A (en
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창동신
이서구
최용석
양연주
백진영
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이화여자대학교 산학협력단
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

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Abstract

본 발명은 퍼옥시레독신의 활성 저해제로서 사용되는 피페리딘계 화합물을 유효성분으로 포함하는 암 질환의 치료 및 예방을 위한 약학조성물을 제공한다. 구체적으로, 본 발명의 피페리딘계 유도체들은 암세포에서 퍼옥시레독신의 활성을 저해함으로써, 암 질환의 치료 및 예방을 위한 약학조성물로 이용가능하다.The present invention provides a pharmaceutical composition for the treatment and prevention of cancer diseases comprising a piperidine-based compound used as an active inhibitor of peroxyredoxin as an active ingredient. Specifically, the piperidine derivatives of the present invention can be used as a pharmaceutical composition for the treatment and prevention of cancer diseases by inhibiting the activity of peroxyredoxin in cancer cells.

퍼옥시레독신, 암질환, 피페리딘 Peroxyredoxin, cancer disease, piperidine

Description

퍼옥시레독신의 활성저해작용을 갖는 피페리딘계 화합물을 유효성분으로 포함하는 조성물 {Composition comprising piperidine compounds as an active ingredient showing inhibitory activity of peroxiredoxin}Composition comprising piperidine compounds as an active ingredient showing inhibitory activity of peroxiredoxin}

본 발명은 퍼옥시레독신의 활성 저해제로서 사용되는 피페리딘계 유도체 화합물들을 유효성분으로 포함하는 암 질환의 치료 및 예방을 위한 약학조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for the treatment and prevention of cancer diseases comprising piperidine derivative compounds used as inhibitors of peroxyredoxin as an active ingredient.

[문헌 1] Schumacker PT, Cancer Cell 10(3): pp175-6, 2006Schumacker PT, Cancer Cell 10 (3) : pp 175-6, 2006

[문헌 2] Cabello CM, Bair WB, 3rd and Wondrak GT, Curr. Opin. Investig. Drugs 8(12): pp1022-37, 2007[2] Cabello CM, Bair WB, 3rd and Wondrak GT, Curr. Opin. Investig. Drugs 8 (12) : pp1022-37, 2007

[문헌 3] Wu XJ and Hua X, Cancer Biol. Ther. 6(5): pp646-7, 2007Document 3 Wu XJ and Hua X, Cancer Biol. Ther. 6 (5) : pp646-7, 2007

[문헌 4] Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP and Schweigerer L, Nature 368(6468): pp237-9, 1994[4] Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP and Schweigerer L, Nature 368 (6468) : pp237-9, 1994

[문헌 5] Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W, Nature 407(6802): pp390-5, 2000[Reference 5] Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W, Nature 407 (6802) : pp390-5, 2000

[문헌 6] Zhou Y, Hileman EO, Plunkett W, Keating MJ and Huang P, Blood 101(10): pp4098-104, 2003Zhou Y, Hileman EO, Plunkett W, Keating MJ and Huang P, Blood 101 (10) : pp4098-104, 2003

[문헌 7] Cicek M, Iwaniec UT, Goblirsch MJ, Vrabel A, Ruan M, Clohisy DR, Turner RR and Oursler MJ, Cancer Res. 67(21): pp10106-11, 20077 Cicek M, Iwaniec UT, Goblirsch MJ, Vrabel A, Ruan M, Clohisy DR, Turner RR and Oursler MJ, Cancer Res. 67 (21) : pp 10106-11, 2007

[문헌 8] Casarez EV, Dunlap-Brown ME, Conaway MR and Amorino GP, Cancer Res. 67(17): pp8316-24, 2007Document 8 Casarez EV, Dunlap-Brown ME, Conaway MR and Amorino GP, Cancer Res. 67 (17) : pp8316-24, 2007

[문헌 9] Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS and Woo HA, Curr. Opin. Cell Biol. 17(2): pp183-9, 2005Document 9 Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS and Woo HA, Curr. Opin. Cell Biol. 17 (2) : pp183-9, 2005

[문헌 10] Noh DY, Ahn SJ, Lee RA, Kim SW, Park IA and Chae HZ, Anticancer Res. 21(3B): pp2085-90, 2001Document 10 Noh DY, Ahn SJ, Lee RA, Kim SW, Park IA and Chae HZ, Anticancer Res. 21 (3B) : pp2085-90, 2001

[문헌 11] Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H and Yoshida H, Cancer Lett. 145(1-2): pp127-32, 1999[11] Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H and Yoshida H, Cancer Lett. 145 (1-2) : pp 127-32, 1999

[문헌 12] Yanagawa T, Iwasa S, Ishii T, Tabuchi K, Yusa H, Onizawa K, Omura K, Harada H, Suzuki H and Yoshida H, Cancer Lett. 156(1): pp27-35,200012. Yanagawa T, Iwasa S, Ishii T, Tabuchi K, Yusa H, Onizawa K, Omura K, Harada H, Suzuki H and Yoshida H, Cancer Lett. 156 (1) : pp27-35,2000

[문헌 13] Park SY, Yu X, Ip C, Mohler JL, Bogner PN and Park YM, Cancer Res. 67(19): pp9294-303, 2007Document 13 Park SY, Yu X, Ip C, Mohler JL, Bogner PN and Park YM, Cancer Res. 67 (19) : pp9294-303, 2007

[문헌 14] Chang JW, Jeon HB, Lee JH, Yoo JS, Chun JS, Kim JH and Yoo YJ, Biochem. Biophys. Res. Commun. 289(2): pp507-12, 2001Document 14 Chang JW, Jeon HB, Lee JH, Yoo JS, Chun JS, Kim JH and Yoo YJ, Biochem. Biophys. Res. Commun. 289 (2) : pp507-12, 2001

[문헌 15] Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and Van Etten RA, Nature 424(6948): pp561-5, 2003[15] Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and Van Etten RA, Nature 424 (6948) : pp561-5, 2003

[문헌 16] Neumann CA and Fang Q, Current Opinion in Pharmacology 7(4): pp375-380, 2007[16] Neumann CA and Fang Q, Current Opinion in Pharmacology 7 (4) : pp375-380, 2007

[문헌 17] Zhang B, Wang Y, Liu K, Yang X, Song M and Bai Y, Biochem. Pharmacol. 75(3): pp660-7, 2008Reference 17 Zhang B, Wang Y, Liu K, Yang X, Song M and Bai Y, Biochem. Pharmacol. 75 (3) : pp660-7, 2008

[문헌 18] Chen MF, Keng PC, Shau H, Wu CT, Hu YC, Liao SK and Chen WC, Int. J. Radiat. Oncol. Biol. Phys. 64(2): pp581-91, 2006[Reference 18] Chen MF, Keng PC, Shau H, Wu CT, Hu YC, Liao SK and Chen WC, Int. J. Radiat. Oncol. Biol. Phys. 64 (2) : pp581-91, 2006

[문헌 19] Wang T, Tamae D, LeBon T, Shively JE, Yen Y and Li JJ, Cancer Res. 65(22): pp10338-46,2005[19] Wang T, Tamae D, LeBon T, Shively JE, Yen Y and Li JJ, Cancer Res. 65 (22) : pp10338-46,2005

[문헌 20] Gay CA and Gebicki JM, Analytical Biochemistry 304(1): pp42-46, 200220. Gay CA and Gebicki JM, Analytical Biochemistry 304 (1) : pp42-46, 2002

[문헌 21] Chang TS, Cho CS, Park S, Yu S, Kang SW and Rhee SG, J. Biol. Chem. 279(40): pp41975-84, 2004Reference 21 Chang TS, Cho CS, Park S, Yu S, Kang SW and Rhee SG, J. Biol. Chem. 279 (40) : pp 41975-84, 2004

[문헌 22] van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP. Cytometry. 31(1): pp 1-9, 199822. van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP. Cytometry . 31 (1) : pp 1-9, 1998

암은 인류가 해결해야 할 난치병 중의 하나로, 전 세계적으로 이를 치유하기 위한 개발에 막대한 자본이 투자되고 있는 실정이며, 우리나라의 경우, 1983년 이후로 한국인의 사망원인 중 제 1위의 질병으로서 연간 약 10만명 이상이 진단되고, 약 6만명 이상이 사망하고 있다. 이러한 암의 유발 인자인 발암물질로는 흡연, 자외선, 화학물질, 음식물 및 기타 환경인자들이 있으나, 그 유발 원인이 다양하여 치료제의 개발이 어려울뿐만 아니라 발생하는 부위에 따라 치료제의 효과 또한 각기 다르다. Cancer is one of the incurable diseases that humanity has to solve, and huge capital has been invested in the development to cure it all over the world.In Korea, it is the number one disease cause of death among Koreans since 1983. More than 100,000 people are diagnosed, and about 60,000 or more are dead. Carcinogens, which cause the cancer, include smoking, ultraviolet rays, chemicals, food, and other environmental factors. However, various causes of the cancer are difficult to develop a therapeutic agent, and the effects of the therapeutic agent also vary depending on the site of occurrence.

현재 사용되는 항암제로는 효소제제 또는 백신 등의 생물학적 제제, 순수합성 의약품 및 천연물 유래의 의약품 등이 있으며, 이 중 유전자, 효소, 백신 등을 이용한 항암제는 실용단계에 있는 상태가 아니며 화학요법에 의해 개발된 항암제는 상당한 독성을 지니고 있고, 암 세포만을 선택적으로 제거하지 못해 암 세포뿐만 아니라 정상세포도 파괴시키는 부작용이 있으며, 최근에는 이에 대한 암 세포의 내성이 발생되어 암 치료에 효과적이지 못한 상태이다. 따라서 암의 발생 후 이의 치료뿐 아니라, 암의 발생을 예방하기 위한 독성이 적고, 암 세포의 내성을 유발시키지 않는 효과적인 항암제의 개발이 절실히 필요하다.Currently used anticancer agents include biological preparations such as enzyme preparations or vaccines, pure synthetic medicines, and medicines derived from natural products. Among them, anticancer drugs using genes, enzymes, vaccines, etc. are not in a practical stage and are used by chemotherapy. The developed anticancer drugs have considerable toxicity and have side effects of destroying not only cancer cells but also normal cells because they cannot selectively remove only cancer cells, and recently, cancer cells have become resistant to this and are ineffective for treating cancer. . Therefore, there is an urgent need to develop an effective anticancer agent that is less toxic for preventing cancer and develops cancer cells.

임상에서 항암요법이 실패하는 이유들 중의 하나는 항암제와 방사선에 대한 암세포의 저항성 획득이다. 항암제 투여 또는 방사선 조사에 의해 암세포의 사멸이 일어날 때에 생성이 증가되는 활성산소종(ROS, reactive oxygen species)이 암세포 의 사멸을 증가시키는 기전을 매개하고 있다(Schumacker PT, Cancer Cell 10(3): pp175-6, 2006; Cabello CM, Bair WB, 3rd and Wondrak GT, Curr. Opin. Investig. Drugs 8(12): pp1022-37, 2007). ROS를 소멸시키는 작용을 하는 항산화 효소들의 발현증가는 암세포가 사멸작용에 대한 저항성을 획득하게 되는 주요 원인들 중의 하나로 인식되고 있다. 암세포는 악성 표현형(malignant phenotype)을 유지하기 위해서 많은 에너지를 필요로 하기 때문에 정상세포에 비해 매우 증가된 대사율(metabolic rate)를 유지하며, 이 때 대사 부산물로 다량의 ROS가 발생하는데, 산화적 스트레스(oxidative stress)에 노출된 환경을 견디기 위해 항산화 단백질 (antioxidant protein)의 발현을 증가시켜 의존하고 있는 상태를 유지하고 있다. 따라서, 항산화 시스템(antioxidant system)을 저해시켜 ROS량을 급증시키게 되면, 정상세포는 새로이 항산화 단백질(antioxidant protein)의 발현을 증가시켜 방어 작용을 할 수 있으나, 암세포의 경우에는 형질전환(transformation) 과정에서 이미 상당히 발현이 증가되어 있어서 발현을 증가시켜 방어하는 기전이 원활히 작동할 수 없어 정상세포에 비해 훨씬 더 많은 산화적 손상(oxidative damage)을 받아 세포사멸(cell death)이 유발된다. 이런 점을 이용해 암세포에 항산화 단백질 (antioxidant protein)의 기능 저해작용이 있는 물질들을 처리하면 세포로부터 ROS 생성이 증가되고, 증가된 ROS에 의해 암세포의 사멸이 유도되는 과정을 응용하는 다양한 항암제로 개발하기 위한 연구가 수행되고 있다(Wu XJ and Hua X, Cancer Biol. Ther. 6(5): pp646-7, 2007; Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP and Schweigerer L, Nature 368(6468): pp237-9, 1994). One of the reasons that chemotherapy fails in the clinic is the acquisition of cancer cell resistance to anticancer drugs and radiation. Reactive oxygen species (ROS), whose production is increased when cancer cells are killed by chemotherapy or radiation, mediate the mechanism by which cancer cells are killed (Schumacker PT, Cancer Cell 10 (3) : ... pp175-6, 2006; Cabello CM, Bair WB, 3rd and Wondrak GT, Curr Opin Investig Drugs 8 (12): pp1022-37, 2007). Increasing the expression of antioxidant enzymes that act to kill ROS is recognized as one of the major causes of cancer cells acquire resistance to killing action. Because cancer cells require a lot of energy to maintain a malignant phenotype, they maintain a significantly increased metabolic rate compared to normal cells, resulting in a large amount of ROS as a metabolite byproduct, oxidative stress. In order to withstand the environment exposed to oxidative stress, the expression of antioxidant proteins is increased to maintain a state of dependence. Therefore, when the ROS amount is increased by inhibiting the antioxidant system, the normal cells may newly act to increase the expression of antioxidant proteins, but in the case of cancer cells, the transformation process There is already a significant increase in expression of the cells, and the mechanism of increasing expression to defend against them is not able to operate smoothly, resulting in much more oxidative damage than normal cells, leading to cell death. Taking advantage of this, the treatment of substances that inhibit the function of antioxidant proteins in cancer cells increases the ROS production from the cells, and the development of various anticancer agents that apply the process of inducing the death of cancer cells by the increased ROS Studies have been carried out (Wu XJ and Hua X, Cancer Biol. Ther. 6 (5) : pp646-7, 2007; Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP and Schweigerer L, Nature 368 (6468) : pp237-9, 1994).

예를 들어, 2-메톡시에스트라디올(2-methoxyestradiol, 2-ME)는 다양한 암환자에 대하여 임상 1상 또는 2상 시험들이 진행 중이고, β-페닐에틸 이소티오시아네이트(β-phenylethyl isothiocyanate)는 폐암환자에 대한 임상 1상이 진행 중이며, 알세틱 트리옥시드(Arsenic trioxide, As2O3)의 경우에는 미국 FDA 승인을 받아 세파론사(Cephalon)가 트리세녹스(Trisenox)라는 상품명으로 백혈병 환자에 이미 처방되고 있는 상황이며, 2-ME는 수퍼옥사이드 디스무테이스(Superoxide dismutase)를 억제하여 수퍼옥사이드 라디칼(superoxide anion)을 포함한 ROS 증가를 통해 백혈구 세포(leukemia cells)의 세포괴사(apoptosis)를 유도해 암세포를 선별적으로 사멸시킬 수 있다(Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W, Nature 407(6802): pp390-5, 2000). 또한 만성 림프구성 백혈구 세포 (chronic lymphocytic leukemia cell)(Zhou Y, Hileman EO, Plunkett W, Keating MJ and Huang P, Blood 101(10): pp4098-104, 2003), 유방암(breast cancer) 세포의 세포 사멸을 일으키며(Cicek M, Iwaniec UT, Goblirsch MJ, Vrabel A, Ruan M, Clohisy DR, Turner RR and Oursler MJ, Cancer Res. 67(21): pp10106-11, 2007) 전립선암(prostate cancer)에서 방사선 민감성(radiosensitivity)을 증가시킨다고 보고되고 있다(Casarez EV, Dunlap-Brown ME, Conaway MR and Amorino GP, Cancer Res. 67(17): pp8316-24, 2007).For example, 2-methoxyestradiol (2-ME) is undergoing phase 1 or phase 2 trials in various cancer patients, and β-phenylethyl isothiocyanate. Is undergoing a phase 1 clinical trial for lung cancer patients, and cephalon is already prescribed for leukemia patients under the trademark Trisenox under the US FDA approval for Arsenic trioxide (As2O3). 2-ME inhibits superoxide dismutase and induces cell death by inducing apoptosis of leukemia cells through an increase in ROS including superoxide anion. Selective killing (Huang P, Feng L, Oldham EA, Keating MJ and Plunkett W, Nature 407 (6802) : pp390-5, 2000). In addition, chronic lymphocytic leukemia cells (Zhou Y, Hileman EO, Plunkett W, Keating MJ and Huang P, Blood 101 (10) : pp4098-104, 2003), apoptosis of breast cancer cells (Cicek M, Iwaniec UT, Goblirsch MJ, Vrabel A, Ruan M, Clohisy DR, Turner RR and Oursler MJ, Cancer Res. 67 (21) : pp10106-11, 2007) Radiation Sensitivity in Prostate Cancer has been reported to increase radiosensitivity (Casarez EV, Dunlap-Brown ME, Conaway MR and Amorino GP, Cancer Res. 67 (17) : pp8316-24, 2007).

사람의 항산화 효소들 중에서 퍼옥시레독신(peroxiredoxin, Prx)은 ROS의 일종인 H2O2를 제거하는 작용을 하는 퍼옥시데이즈(peroxidase)로서, 6종류의 이형 (isoform)이 존재하며 이들은 세포내 거의 모든 부분(세포질, 미토콘드리아, 핵, 퍼옥시즘(peroxisome), 소포체(endoplasmic reticulum))에 존재한다(Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS and Woo HA, Curr. Opin. Cell Biol. 17(2): pp183-9, 2005).Among the human antioxidant enzymes, peroxiredoxin (Prx) is a peroxidase that functions to remove H 2 O 2 , a type of ROS, and there are six types of isoforms. In almost every part of the body (cytoplasm, mitochondria, nucleus, peroxisome, endoplasmic reticulum) (Rhee SG, Kang SW, Jeong W, Chang TS, Yang KS and Woo HA, Curr. Opin. Cell Biol. 17 (2) : pp183-9, 2005).

실제로 다양한 종류의 암 조직이나 세포에서 여러 Prx 이형(isoform)들의 발현량이 증가됨이 국내연구진들을 포함한 많은 연구그룹들에 의해 보고되었다. 즉, Prx I의 발현이 유방암(Noh DY, Ahn SJ, Lee RA, Kim SW, Park IA and Chae HZ, Anticancer Res. 21(3B): pp2085-90, 2001), 구강/갑상선암(oral/thyroid cancer) (Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H and Yoshida H, Cancer Lett. 145(1-2): pp127-32, 1999; Yanagawa T, Iwasa S, Ishii T, Tabuchi K, Yusa H, Onizawa K, Omura K, Harada H, Suzuki H and Yoshida H, Cancer Lett. 156(1): pp27-35, 2000), 전립선암(Park SY, Yu X, Ip C, Mohler JL, Bogner PN and Park YM, Cancer Res. 67(19): pp9294-303, 2007), 폐암(Chang JW, Jeon HB, Lee JH, Yoo JS, Chun JS, Kim JH and Yoo YJ, Biochem. Biophys. Res. Commun. 289(2): pp507-12, 2001)에서 증가된다.Indeed, increased expression levels of various Prx isoforms in various cancer tissues and cells have been reported by many research groups including domestic researchers. In other words, the expression of Prx I may be related to breast cancer (Noh DY, Ahn SJ, Lee RA, Kim SW, Park IA and Chae HZ, Anticancer Res. 21 (3B) : pp2085-90, 2001), oral / thyroid cancer (Yanagawa T, Ishikawa T, Ishii T, Tabuchi K, Iwasa S, Bannai S, Omura K, Suzuki H and Yoshida H, Cancer Lett. 145 (1-2) : pp127-32, 1999; Yanagawa T, Iwasa S , Ishii T, Tabuchi K, Yusa H, Onizawa K, Omura K, Harada H, Suzuki H and Yoshida H, Cancer Lett. 156 (1) : pp27-35, 2000), Prostate cancer (Park SY, Yu X, Ip C, Mohler JL, Bogner PN and Park YM, Cancer Res. 67 (19) : pp9294-303, 2007), lung cancer (Chang JW, Jeon HB, Lee JH, Yoo JS, Chun JS, Kim JH and Yoo YJ, Biochem Biophys.Res.Commun . 289 (2) : pp507-12, 2001).

뉴만 등(Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and Van Etten RA, Nature 424(6948): pp561-5, 2003)은 Prx I 유전자를 노크아웃(knockout) 시킨 마우스의 배아 섬유아세포 (embryonic fibroblast)가 정상인 것에 비하여 증식속도가 저하된 결과를 보고, 처음에는 Prx I이 종양 억제제(tumor suppressor)일 것이라고 생각하였으나, 뉴만 등 의 리뷰(Neumann CA and Fang Q, Current Opinion in Pharmacology 7(4): pp375-380, 2007)를 통하여, 대표적인 종양 억제제인 p53은 암세포에 발현을 증가시키면 세포사멸을 유도하지만 Prx I의 발현을 증가시키면 세포사멸을 일으키기는커녕 오히려 사멸을 억제시키는 결과가 나타나는 것으로 보아 Prx I은 암세포의 사멸을 증강시키는 H2O2를 제거시키는 기능을 통해 종양 억제제(tumor preventor)로 작용한다고 해석하였고, 아울러 Prx I의 활성저해는 항암제 개발을 위한 신규 목적물 (novel target)임을 제시하고 있다.Neumann et al. (Neumann CA, Krause DS, Carman CV, Das S, Dubey DP, Abraham JL, Bronson RT, Fujiwara Y, Orkin SH and Van Etten RA, Nature 424 (6948) : pp561-5, 2003) When the embryonic fibroblasts of mice knocked out were found to have a lowered proliferation rate compared to normal embryonic fibroblasts, they initially thought that Prx I was a tumor suppressor. Through Neumann CA and Fang Q, Current Opinion in Pharmacology 7 (4) : pp375-380, 2007), p53, a representative tumor suppressor, induces apoptosis by increasing expression in cancer cells, but apoptosis by increasing expression of Prx I. the cause, let alone rather seen as a result of suppressed apoptosis appears Prx I was interpreted to act through the ability to remove the H 2 O 2 to enhance the killing of tumor cells by tumor suppressor (tumor preventor), as well as the bow of Prx I Inhibition has been suggested that a new target product (novel target) for cancer drug development.

실제로 암세포에서 Prx I의 발현을 억제시키면 결장암(intestinal cancer)(Zhang B, Wang Y, Liu K, Yang X, Song M and Bai Y, Biochem. Pharmacol. 75(3): pp660-7, 2008), 폐암(Chen MF, Keng PC, Shau H, Wu CT, Hu YC, Liao SK and Chen WC, Int. J. Radiat. Oncol. Biol. Phys. 64(2): pp581-91, 2006)에서 세포의 증식속도가 느려지고 방사선에 대한 민감도가 증가함. Prx I과 비슷한 세포질에 존재하는 Prx인 Prx II의 발현이 증가되면 방사선의 자극에 대한 세포사멸이 억제된다(Wang T, Tamae D, LeBon T, Shively JE, Yen Y and Li JJ, Cancer Res. 65(22): pp10338-46, 2005).Indeed, suppressing the expression of Prx I in cancer cells results in colon cancer (Zhang B, Wang Y, Liu K, Yang X, Song M and Bai Y, Biochem. Pharmacol. 75 (3) : pp660-7, 2008), Proliferation of cells in lung cancer (Chen MF, Keng PC, Shau H, Wu CT, Hu YC, Liao SK and Chen WC, Int. J. Radiat. Oncol. Biol. Phys. 64 (2) : pp581-91, 2006) Slow down and increase sensitivity to radiation. Increased expression of Prx II, a Prx present in the cytoplasm similar to Prx I, inhibits apoptosis due to radiation stimulation (Wang T, Tamae D, LeBon T, Shively JE, Yen Y and Li JJ, Cancer Res. 65 (22) : pp 10338-46, 2005).

본 발명자들은 종양 억제제(tumor preventor)로 작용하고 있는 Prx I의 활성 저해제를 발굴하고, 이를 항암제 또는 방사선 요법시 보조제로 개발하는 연구를 진행하여, 본 발명을 완성하게 되었다.The present inventors have completed the present invention by finding an inhibitor of Prx I activity that acts as a tumor preventor and developing it as an anticancer agent or an adjuvant for radiation therapy.

상기 목적을 달성하기 위하여, 본 발명은 Prx I 활성에 대한 강력한 억제 활성을 나타내는, 하기 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물, 그 이성체 및 이의 약리학적으로 허용가능한 염을 유효성분으로 함유하는 암질환의 치료 및 예방을 위한 약학 조성물을 제공한다:In order to achieve the above object, the present invention provides a piperidine-based compound having a structure of the general formula (I), an isomer thereof, and a pharmacologically acceptable salt thereof, which exhibits a potent inhibitory activity against Prx I activity, as an active ingredient. Provided are pharmaceutical compositions for the treatment and prevention of cancer diseases containing:

Figure 112009000868353-pat00001
Figure 112009000868353-pat00001

상기 식에서,Where

P는 페닐기 또는 질소함유 5원 내지 6원환이며;P is a phenyl group or a nitrogen-containing 5- to 6-membered ring;

X는 케톤기(C=O) 또는 설포닐기(SO2)이며;X is a ketone group (C═O) or a sulfonyl group (SO 2 );

Q는 수소원자, 히드록시기, 할로겐 원자, 니트로기, C1 내지 C3 저급알킬기, C1 내지 C3 저급 알콕시기, C1 내지 C3 저급 알킬 케토기 및 C1 내지 C3 저급알킬에스테르기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환된 페닐기, 페닐아민기 또는 스티렌기(styrene)이다. Q is substituted with at least one substituent selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen atom, a nitro group, a C1 to C3 lower alkyl group, a C1 to C3 lower alkoxy group, a C1 to C3 lower alkyl keto group and a C1 to C3 lower alkyl ester group Phenyl group, phenylamine group or styrene.

상기 일반식 (Ⅰ)에 속하는 화합물군 중에 바람직하기로는 P는 페닐기 또는 피롤기인 화합물 군; X는 케톤기(C=O) 또는 설포닐기(SO2)인 화합물군; Q는 수소원자, 할로겐 원자, 메톡시기, 에톡시기, 및 메틸게톤기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환된 페닐기, 페닐아민기 또는 스티렌기인 화합물군이다.In the compound group which belongs to the said general formula (I), Preferably, P is a compound group which is a phenyl group or a pyrrole group; X is a compound group which is a ketone group (C═O) or a sulfonyl group (SO 2 ); Q is a compound group that is a phenyl group, phenylamine group or styrene group substituted with one or more substituents selected from the group consisting of a hydrogen atom, a halogen atom, a methoxy group, an ethoxy group and a methylgetone group.

상기 일반식 (Ⅰ)에 속하는 화합물군 중에 가장 바람직한 화합물로는 하기와 같은 화합물들,As the most preferable compound among the compound group belonging to the general formula (I), the following compounds,

(1) (E)-1-(4-(비페닐-4-일메틸)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온{(E)-1-(4-(biphenyl-4-ylmethyl)piperidin-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C52; Catalog No. CGX-10716804), (1) (E) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2-en-1-one {(E ) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C52 ; Catalog No. CGX-10716804),

(2) [4-([1,1'-비페닐]-4-일메틸)-1-피페리딘일](3,5-디클로로페닐)-메타논{4-([1,1'-biphenyl]-4-yl methyl)-1-piperidinyl](3,5-dichlorophenyl)-methanone; C53; Catalog No.CGX-10716746), (2) [4-([1,1'-biphenyl] -4-ylmethyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone {4-([1,1'- biphenyl] -4-yl methyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone; C53 ; Catalog No.CGX-10716746),

(3) [4-(비페닐]-4-일메틸)-1-(2-클로로페닐설포닐)-피페리딘{4-(biphenyl]-4-yl methyl)-1-(2-chlorophenylsulfonyl)-piperidine; C54; Catalog No.CGX-10716998),(3) [4- (biphenyl] -4-ylmethyl) -1- (2-chlorophenylsulfonyl) -piperidine {4- (biphenyl] -4-yl methyl) -1- (2-chlorophenylsulfonyl ) -piperidine; C54 ; Catalog No.CGX-10716998),

(4) N-(3-아세틸페닐)-4-(비페닐-4-일메틸)피페리딘-1-카르복사미드{N-(3-acetyl)-4-(biphenyl-4-yl methyl)piperidine-1-carboxamide; C55; Catalog No.CGX-10717147),(4) N- (3-acetylphenyl) -4- (biphenyl-4-ylmethyl) piperidine-1-carboxamide {N- (3-acetyl) -4- (biphenyl-4-yl methyl ) piperidine-1-carboxamide; C55 ; Catalog No.CGX-10717147),

(5) 4-(비페닐-4-일메틸)-N-(4-메톡시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide; C56; Catalog No.CGX-10717144),(5) 4- (biphenyl-4-ylmethyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (4- methoxyphenyl) piperidine-1-carboxamide; C56 ; Catalog No.CGX-10717144),

(6) 4-(비페닐-4-일메틸)-N-(3-메톡시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide; C57; Catalog No.CGX-10717141), (6) 4- (biphenyl-4-ylmethyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (3- methoxyphenyl) piperidine-1-carboxamide; C57 ; Catalog No.CGX-10717141),

(7) 4-(1H-피롤-1-일)벤질)-N-(4-에톡시페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(4-ethoxyphenyl)piperidine-1-carboxamide; C58; Catalog No.CGX-10717125), (7) 4- (1H-pyrrol-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide {(4- (1H-pyrrol-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide; C58 ; Catalog No.CGX-10717125),

(8) 4-(1H-피롤-1-일)벤질)-N-(3-아세틸페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(3-acetylphenyl)piperidine-1-carboxamide; C59; Catalog No.CGX-10717124) 및 (8) 4- (1H-pyrrol-1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide {(4- (1H-pyrrol-1-yl) benzyl)- N- (3-acetylphenyl) piperidine-1-carboxamide; C59 ; Catalog No.CGX-10717124) and

(9) (E)-1-(4-1H-피롤-1-일)벤질)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온(E)-1-(4-1H-pyrrol-1-yl)benzyl)piperidinle-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C80; Catalog No.CGX-10716786)을 들 수 있다.(9) (E) -1- (4-1H-pyrrole-1-yl) benzyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2-en-1-one (E ) -1- (4-1H-pyrrol-1-yl) benzyl) piperidinle-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C80 ; Catalog No. CGX-10716786).

상기 구조식 (Ⅰ)로 표시되는 본 발명의 화합물들은 당해 기술분야에서 통상적인 방법에 따라 약학적으로 허용가능한 염 및 용매화물로 제조될 수 있다.      The compounds of the present invention represented by the above formula (I) may be prepared with pharmaceutically acceptable salts and solvates according to methods conventional in the art.

염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 산 부가염은 통상의 방법, 예를 들면 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올(예, 글리콜 모노메틸에테르)을 가열하고 이어서 상기 혼합물을 증발시켜서 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.      Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethyl ether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered.

이 때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 질산, 주석산 등을 사용할 수 있고 유기산으로는 메탄술폰산, p-톨루엔술폰산, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산 (lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 히드로 아이오딕산(hydro iodic acid) 등을 사용할 수 있다.In this case, organic acids and inorganic acids may be used as the free acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. may be used as the inorganic acid, and methanesulfonic acid, p -toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydro iodic acid, etc. have.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리토 금속염은, 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리토금속 수산화물 용액 중에 용해하고, 비용해 화합물염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이 때, 금속염으로서는 특히 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하며, 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리토 금속염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. An alkali metal or alkaline earth metal salt is obtained by, for example, dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

상기의 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물에 존재할 수 있는 산성 또는 염기성기의 염을 포함한다. 예를 들면, 약학적으로 허용가능한 염으로는 히드록시기의 나트륨, 칼슘 및 칼륨 염이 포함되며, 아미노기의 기타 약학적으로 허용가능한 염으로는 히드로브로마이드, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메탄설포네이트(메실레이트) 및 p-톨루엔설포네이트(토실레이트) 염이 있으며, 당업계에서 알려진 염의 제조방법이나 제조과정을 통하여 제조될 수 있다.Pharmaceutically acceptable salts of the piperidine-based compound having the structure of formula (I) are acidic or basic which may be present in the piperidine-based compound having the structure of formula (I), unless otherwise indicated. Salts of groups. For example, pharmaceutically acceptable salts include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, hydrogen phosphate, dihydrogen Phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, and methods or processes for preparing salts known in the art It can be prepared through.

또한, 상기의 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물은 비대칭 중심을 가지므로 상이한 거울상 이성질체 형태로 존재할 수 있으며, 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물의 모든 광학 이성질체 및 R 또는 S형 입체 이성질체 및 이들의 혼합물도 본 발명의 범주 내에 포함되는 것으로 한다. 본 발명은 라세미체, 하나 이상의 거울상 이성질체 형태, 하나 이상의 부분 입체 이성질체 형태 또는 이들의 혼합물의 용도를 포함하며, 당업계에서 알려진 이성질체의 분리 방법이나 제조과정을 포함한다.In addition, the piperidine-based compound having the structure of the general formula (I) may have asymmetric centers and thus exist in different enantiomeric forms, and all optical isomers of the piperidine-based compound having the structure of the general formula (I) and R or S type stereoisomers and mixtures thereof are also included within the scope of the present invention. The present invention encompasses the use of racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof, and includes methods or processes for the separation of isomers known in the art.

따라서, 본 발명은 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물을 유효성분으로 포함하는 Prx I 활성에 대한 저해제를 제공한다.Accordingly, the present invention provides an inhibitor for Prx I activity comprising a piperidine-based compound having the structure of Formula (I) as an active ingredient.

본 발명은 Prx I 활성에 대한 강력한 억제 활성을 나타내는, 상기 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물, 그 이성체 및 이의 약리학적으로 허용가능한 염을 유효성분으로 함유하는 항암 보조제를 제공한다.      The present invention provides an anticancer adjuvant containing a piperidine-based compound having the structure of Formula (I), an isomer thereof and a pharmacologically acceptable salt thereof as an active ingredient, which exhibits potent inhibitory activity against Prx I activity. .

본 발명자는 상기 피페리딘계 화합물들이 퍼옥시레독신(peroxiredoxin, Prx) 활성을 강력하게 억제함을 Prx I 활성 측정법을 수행하는 HTS 시험법, H2O2 정량 통한 Prx I 활성 측정법(FOX assay), 세포의 생존 능력(cell viability) 측정시험법, 세포내 ROS 측정시험법, 세포사멸(Cell apoptosis)의 측정법 등을 통하여 본 발명의 피페리딘계 화합물이 상기 Prx I의 활성뿐만 아니라 암세포의 증식도 강력하게 억제함을 확인하였다.The present inventors found that the piperidine-based compounds strongly inhibited peroxiredoxin (Prx) activity, HTS assay for performing Prx I activity assay, Prx I activity assay (FOX assay) by H 2 O 2 quantification (FOX assay) Through the cell viability assay, cell ROS assay, cell apoptosis, piperidine-based compounds of the present invention not only the activity of Prx I but also the proliferation of cancer cells Strong inhibition was confirmed.

또 다른 양태로서, 본 발명은 피페리딘계 화합물을 포함하는, 퍼옥시레독신 활성 증가로 기인한 암질환을 예방, 치료하기 위한 약제학적 조성물과 피페리딘계 화합물을 사용하여 상기 질병을 치료하는 방법에 관한 것이다. In another aspect, the present invention is a method for treating the disease using a piperidine-based compound and a pharmaceutical composition for preventing and treating cancer diseases caused by increased peroxyredoxin activity, including piperidine-based compound It is about.

본 발명에서 용어 "예방"이란 피페리딘계 화합물을 포함하는 조성물의 투여로 퍼옥시레독신 활성 증가로 기인한 암질환을 억제시키거나 발병을 지연하는 모든 행위를 말하며, "치료"란 상기 약제학적 조성물의 투여로 퍼옥시레독신 활성 증가로 기인한 암질환을 호전시키거나 이롭게 변경하는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action of inhibiting or delaying the onset of cancer diseases caused by an increase in peroxyredoxin activity by administration of a composition containing a piperidine-based compound. By the administration of the composition is meant any action that improves or beneficially alters cancer disease due to increased peroxyredoxin activity.

본 발명에서 퍼옥시레독신(peroxiredoxin, Prx) 활성 증가로 기인한 암질환의 예로는, 유방암, 구강/갑상선암(oral/thyroid cancer), 전립선암, 결장암, 폐암, 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 자궁암, 유방암, 폐암, 임파선암, 갑상선암, 전립선암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암, 담낭암 등을 포함하고, 바람직하게는, 유방암, 구강/갑상선암(oral/thyroid cancer), 전립선암 , 결장암, 폐암, 보다 바람직하게는, 전립선 암, 결장암, 또는 폐암을 들 수 있으나, 이에 제한되지는 않는다. Examples of cancer diseases caused by increased peroxiredoxin (Prx) activity in the present invention, breast cancer, oral / thyroid cancer, prostate cancer, colon cancer, lung cancer, colon cancer, small intestine cancer, rectal cancer, Anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer, gallbladder cancer and the like, preferably, breast cancer Oral / thyroid cancer, oral / thyroid cancer, prostate cancer, colon cancer, lung cancer, more preferably prostate cancer, colon cancer, or lung cancer.

본 발명의 화합물을 포함하는 조성물은 통상의 방법에 따른 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다. Compositions comprising a compound of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.

본 발명의 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.       Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

본 발명의 화합물을 포함하는 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. The compositions comprising the compounds of the present invention are each formulated in the form of oral dosage forms, external preparations, suppositories, or sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., in accordance with conventional methods. Can be used.

상세하게는, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액 제, 유제, 시럽제 등이 해당되는 데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 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, 글리세로젤라틴 등이 사용될 수 있다.      More specifically, when formulating the composition, it can be prepared using a diluent or an excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, and the like. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may contain at least one excipient such as starch, calcium carbonate, sucrose, or the like. ), Lactose, gelatin and the like can be mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, solution solutions, emulsions, and syrups.In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc. May be included. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

본 발명의 화합물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나, 바람직한 효과를 위해서, 본 발명의 화합물은 0.0001~100 mg/kg으로, 바람직하게는 0.001~100 mg/kg의 양을 일일 1회 내지 수회로 나누어 투여할 수 있다. 조성물에서 본 발명의 화합물은 전체 조성물 총 중량에 대하여 0.0001~10 중량%, 바람직하게는 0.001~1 중량%의 양으로 존재하여야 한다. Preferred dosages of the compounds of the present invention depend on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, but may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention may be administered in an amount of 0.0001 to 100 mg / kg, preferably in an amount of 0.001 to 100 mg / kg once to several times a day. The compound of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.

또한, 본 발명의 화합물의 약학적 투여 형태는 이들의 약학적 허용가능한 염의 형태로도 사용될 수 있고, 또한 단독으로 또는 타 약학적 활성 화합물과 결합뿐만 아니라 적당한 집합으로 사용될 수 있다. In addition, the pharmaceutical dosage forms of the compounds of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable collection.

본 발명의 약학 조성물은 쥐, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

상기에 언급한 바와 같이, 본 발명은 퍼옥시레독신(peroxiredoxin, Prx) 활성 억제제인 피페리딘계 화합물을 제공하고자 하는 것으로 본 발명의 피페리딘계 화합물을 유효성분으로 하는 약학 조성물은 퍼옥시레독신 활성 증가로 기인한 암질환의 치료 및 예방을 위한 약제로 이용가능하다.As mentioned above, the present invention is to provide a piperidine-based compound which is a peroxiredoxin (Prx) activity inhibitor, the pharmaceutical composition comprising the piperidine-based compound of the present invention as an active ingredient is peroxyredoxin It can be used as a medicament for the treatment and prevention of cancer diseases caused by increased activity.

이하, 본 발명을 하기에 의거하여 좀더 상세하게 설명하고자 한다. 단, 하기 참고예, 실시예 및 실험예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following. However, the following Reference Examples, Examples and Experimental Examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

참고예 1. 시약 및 기기Reference Example 1. Reagents and Instruments

황산 헥사하이드레이트 암모늄 철(Ammonium iron(ll) sulfate hexahydrate), 퍼클로릭산(perchloric acid), 자이레놀 오렌지(xylenol orange) 등은 시그마-알드리치사(Sigma-Aldrich, Brooklyn, NY, USA)로부터 구입하였다. 사람의 폐암상피세포인 A549 세포는 아메리칸 타입 컬쳐 콜렉션(American Type Culture Collection, Manassas, VA, USA)으로부터 구입하였다. 5-(및 6-)크로로메틸-2‘,7’-디클로디하이드로플루레신 디아세테이트(5-(and 6-)chloromethyl-2′,7′- dichlorodihydrofluorescein diacetate, CM-H2DCFDA), 프로피디움아오디드 (propidiumiodide, PI), 트립신/EDTA (trypsin/EDTA) 혼합용액 등은 인비트로젠사 (Invitrogen, Carlsbad, CA, USA)으로부터 구입하였다. 아넥신-V-플루오스 염색키트(Annexin-V-Fluos staining kit, Cat. No. 11-988-549-001)는 로쉬 어플라이드 사이언스사(Roche Applied Science, Penzberg, Germany)로부터 구입하였다. Ammonium iron (ll) sulfate hexahydrate, perchloric acid, xylenol orange, etc. were purchased from Sigma-Aldrich, Brooklyn, NY, USA. . Human lung cancer epithelial cells A549 cells were purchased from the American Type Culture Collection (Manassas, VA, USA). 5- (and 6-) chloromethyl-2 ', 7'-dichlorodihydrofluresin diacetate (5- (and 6-) chloromethyl-2', 7'-dichlorodihydrofluorescein diacetate, CM-H 2 DCFDA), Propidiumiodide (PI), trypsin / EDTA mixed solution, and the like were purchased from Invitrogen (Invitrogen, Carlsbad, Calif., USA). Annexin-V-Fluos staining kit (Cat. No. 11-988-549-001) was purchased from Roche Applied Science, Penzberg, Germany.

실시예 1. 시료화합물Example 1 Sample Compound

본 실험에 사용한 화합물들 즉, (1) (E)-1-(4-(비페닐-4-일메틸)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온{(E)-1-(4-(biphenyl-4-ylmethyl)piperidin-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C52; Catalog No.CGX-10716804), (2) [4-([1,1'-비페닐]-4-일메틸)-1-피페리딘일](3,5-디클로로페닐)-메타논{4-([1,1'-biphenyl]-4-yl methyl)-1-piperidinyl](3,5-dichlorophenyl)-methanone; C53; Catalog No.CGX-10716746), (3) [4-(비페닐]-4-일메틸)-1-(2-클로로페닐설포닐)-피페리딘{4-(biphenyl]-4-yl methyl)-1-(2-chlorophenylsulfonyl)-piperidine; C54; Catalog No.CGX-10716998),(4) N-(3-아세틸페닐)-4-(비페닐-4-일메틸)피페리딘-1-카르복사미드{N-(3-acetyl)-4-(biphenyl-4-yl methyl)piperidine-1-carboxamide; C55; Catalog No.CGX-10717147),(5) 4-(비페닐-4-일메틸)-N-(4-메톡시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide; C56; Catalog No.CGX-10717144),(6) 4-(비페닐-4-일메틸)-N-(3-메톡 시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide; C57; Catalog No.CGX-10717141), (7) 4-(1H-피롤-1-일)벤질)-N-(4-에톡시페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(4-ethoxyphenyl)piperidine-1-carboxamide; C58; Catalog No.CGX-10717125), (8) 4-(1H-피롤-1-일)벤질)-N-(3-아세틸페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(3-acetylphenyl)piperidine-1-carboxamide; C59; Catalog No.CGX-10717124) 및 (9) (E)-1-(4-1H-피롤-1-일)벤질)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온(E)-1-(4-1H-pyrrol-1-yl)benzyl)piperidinle-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C80; Catalog No.CGX-10716786)은 AMRI Direct 사 (Albany, NY, USA)로부터 구입한 25,000여 개의 화합물로 이루어진 라이브래리로부터 선택하여 하기 실험예의 시료로 사용하기 위하여 1 mg/ml 농도 또는 다량으로 재구입한 4-(1H-피롤-1-일)벤질)-N-(3-아세틸페닐)피페리딘-1-카르복사미드 (4-(1H-pyrrol-1-yl)benzyl)-N-(3-acetylphenyl)piperidine-1-carboxamide)을 10 mM 농도로 각각 디메틸설폭사이드 (dimethylsulfoxide; DMSO)에 녹인 스톡(stock) 용액으로 96-웰 플레이트에 -80℃의 온도를 유지하며 보관하였다.Compounds used in this experiment, namely (1) (E) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2- En-1-one {(E) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C52 ; Catalog No.CGX-10716804), (2) [4-([1,1'-biphenyl] -4-ylmethyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone {4 -([1,1'-biphenyl] -4-yl methyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone; C53 ; Catalog No.CGX-10716746), (3) [4- (biphenyl] -4-ylmethyl) -1- (2-chlorophenylsulfonyl) -piperidine {4- (biphenyl] -4-yl methyl ) -1- (2-chlorophenylsulfonyl) -piperidine; C54 ; Catalog No.CGX-10716998), (4) N- (3-acetylphenyl) -4- (biphenyl-4-ylmethyl) piperidine-1-carboxamide {N- (3-acetyl) -4 -(biphenyl-4-yl methyl) piperidine-1-carboxamide; C55 ; Catalog No.CGX-10717147), (5) 4- (biphenyl-4-ylmethyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide; C56 ; Catalog No.CGX-10717144), (6) 4- (biphenyl-4-ylmethyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide; C57 ; Catalog No.CGX-10717141), (7) 4- (1H-pyrrole-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide {(4- (1H- pyrrol-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide; C58 ; Catalog No.CGX-10717125), (8) 4- (1H-pyrrole-1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide {(4- (1H-pyrrol -1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide; C59 ; Catalog No.CGX-10717124) and (9) (E) -1- (4-1H-pyrrole-1-yl) benzyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2 -En-1-one (E) -1- (4-1H-pyrrol-1-yl) benzyl) piperidinle-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C80 ; Catalog No.CGX-10716786) was selected from Live Larry consisting of more than 25,000 compounds purchased from AMRI Direct (Albany, NY, USA) and repurchased at a concentration of 1 mg / ml or in large quantities for use as a sample of the following experimental example. One 4- (1H-pyrrol-1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide (4- (1H-pyrrol-1-yl) benzyl) -N- ( 3-acetylphenyl) piperidine-1-carboxamide) was a stock solution dissolved in dimethylsulfoxide (DMSO) at a concentration of 10 mM, and stored at -80 ° C in a 96-well plate.

실험예 1. 고처리능력비검색법(High through-put screening (HTS))Experimental Example 1. High Through-put Screening (HTS)

액체 핸들링 워크스테이션(Liquid handling workstation, Beckmann Coulter Co.)을 이용하여 AMRI 다이렉스사로부터 구입한 25,000개의 화합물로 이루어진 라 이브레리에 대하여 시험관 내 실험(in vitro)에서 Prx I의 활성을 직접 억제하는 물질을 발굴하기 위한 Prx I 활성 측정법을 수행하는 HTS을 실시하였다. Directly inhibits the activity of Prx I in vitro for a library of 25,000 compounds purchased from AMRI Dyrex using the Liquid handling workstation (Beckmann Coulter Co.). HTS was performed to perform Prx I activity assay to find material.

HTS를 위한 Prx I의 활성 측정은 니코틴아미드 아데닌 디뉴클레오티드 포스페이트(nicotineamide adenine dinucleotide phosphate, NADPH)에서 유래하는 환원력이 티오레독신(thioredoxin, Trx)과 티오레독신 환원효소(thioredoxin reductase, TrxR)에 의해 산화된 Prx에 연속적으로 전달되는 원리를 이용하여 김 등의 방법(Kim JA, Park S, Kim K, Rhee SG and Kang SW, Anal. Biochem. 338(2): pp216-23, 2005)을 이용하여 확립하였다. Determination of Prx I activity for HTS is based on the fact that the reducing power derived from nicotineamide adenine dinucleotide phosphate (NADPH) is reduced by thioredoxin (Trx) and thioredoxin reductase (TrxR). Using the method of Kim, et al. (Kim JA, Park S, Kim K, Rhee SG and Kang SW, Anal. Biochem. 338 (2) : pp216-23, 2005) Established.

이전의 분석방법에서 이용되는 포유류의 TrxR은 활성부위에 셀레노시스테인(selenocysteine)을 함유하고 있는 단백질이어서 복잡한 정제과정을 거쳐 랫트의 간이나 사람의 태반으로부터 얻어야만 했기 때문에 HTS에 대한 시간적경제적인 장애 요인으로 작용하는 단점을 지니고 있다. 반면에 효모(yeast)의 TrxR은 활성부위에 셀레노시스테인이 아닌 시스테인(cysteine)을 지니고 있는데 그 활성은 유지되고 있기 때문에, 이를 대장균에 대량으로 발현시켜 단시간에 얻을 수 있는 장점이 있다. 따라서, 포유류의 Trx와 TrxR 대신 효모의 Trx(yTrx)와 TrxR(yTrxR)을 이용한 방법을 응용하여 HTS 시스템에 적합한 Prx I의 활성 측정방법을 확립하였다. Prx I, yTrx, yTrxR 등의 단백질을 김 등의 방법에 준하여 발현시키고 정제한 것을 사용하였다. TrxR in mammals used in previous assays is a protein that contains selenocysteine in its active site and has to be obtained from rat liver or human placenta through a complex purification process. It has the disadvantage of acting as a factor. On the other hand, yeast TrxR has a cysteine rather than selenocysteine in the active site, and because its activity is maintained, it can be obtained in a short time by expressing it in large amounts in E. coli. Therefore, the method of measuring the activity of Prx I suitable for the HTS system was established by applying the method using the yeast Trx (yTrx) and TrxR (yTrxR) instead of mammalian Trx and TrxR. Proteins such as Prx I, yTrx, and yTrxR were expressed and purified according to the method of laver and the like.

85 uL의 반응액(50 mM HepesNaOH buffer(pH 7.0), 1 mM EDTA, 0.9 μM Prx I, 1.5 μM yTrx, 0.8 μM yTrxR 이 85 μl에 포함됨)을 96-웰 플레이트의 각 웰에 미리 넣어두고, 여기에 5 uL의 화합물(최종농도 50 ug/ml) 또는 대조군으로 용매인 DMSO와 5 uL의 NADPH(최종농도 0.2 mM)를 가하고 2분동안 상온에서 반응시켰다. 여기에 H2O2 제거반응을 유발하기 위하여 5 uL의 H2O2(최종농도 0.1 mM)를 가하고, 340 nm에서의 NADPH의 흡광도 감소를 15분동안 모니터링 하였다. Prx I의 퍼옥시데이즈(peroxidase) 활성은 DMSO를 가한 대조군에서 반응 시작 후 3분동안 나타나는 NADPH 흡광도의 변화 정도를 100% 활성도로 기준 삼고, 각각의 화합물을 가한 경우에 나타나는 활성도의 변화를 비교하였다. 데이터는 2개의 실험치를 평균값± 평균의 표준오차로 표시하였다(표 1 참조).85 uL of reaction solution (50 mM HepesNaOH buffer (pH 7.0), 1 mM EDTA, 0.9 μM Prx I, 1.5 μM yTrx, 0.8 μM yTrxR contained in 85 μl) was previously placed in each well of a 96-well plate, To this was added 5 uL of compound (final concentration 50 ug / ml) or 5 μL of NADPH (final concentration 0.2 mM) as a solvent and DMSO as a control and reacted at room temperature for 2 minutes. To induce H 2 O 2 elimination reaction, 5 uL of H 2 O 2 (final concentration 0.1 mM) was added, and a decrease in absorbance of NADPH at 340 nm was monitored for 15 minutes. Peroxidase activity of Prx I was compared based on the degree of change of NADPH absorbance at 100% activity for 3 minutes after the start of the reaction in the control group in which DMSO was added, and the change in activity when each compound was added was compared. . The data are presented as two standard values of mean ± standard error of the mean (see Table 1).

물질명Material name Prx Ⅰ 활성 (%)Prx I activity (%) 대조군Control group 100.00±1.89100.00 ± 1.89 C52C52 8.02±1.408.02 ± 1.40 C53C53 8.08±1.578.08 ± 1.57 C54C54 9.99±1.469.99 ± 1.46 C55C55 9.03±2.089.03 ± 2.08 C56C56 11.56±2.5811.56 ± 2.58 C57C57 10.61±2.5310.61 ± 2.53 C58C58 12.07±0.8412.07 ± 0.84 C59C59 10.04±2.3010.04 ± 2.30 C80C80 9.42±1.079.42 ± 1.07

실험결과, 상기 표 1에 나타난 바와 같이, 화합물들에 대하여 Prx I 활성 어세이법을 수행한 결과, 9개의 화합물들이 Prx I의 활성을 약 80% 이상 저해시키는 효과가 있음을 확인할 수 있었으며, 이들 화합물들의 구조를 분석한 결과, 공통적인 화학구조를 지니고 있음을 확인할 수 있었다. As a result, as shown in Table 1, as a result of performing the Prx I activity assay for the compounds, it was confirmed that nine compounds have an effect of inhibiting the activity of Prx I by more than about 80%, these As a result of analyzing the structure of the compounds, it was confirmed that they have a common chemical structure.

실험예 2. H2O2 정량 통한 Prx I 활성 측정Experimental Example 2 Determination of Prx I Activity by H 2 O 2 Quantitation

반응액 중 H2O2량을 직접 정량하는 방법은 Gay 등(Gay CA and Gebicki JM, Analytical Biochemistry 304(1): pp42-46, 2002)의 실레놀 오렌지 내의 철 산화 어세이법(ferrous oxidation in xylenol orange(FOX) assay)을 이용하였다. The method of directly quantifying the amount of H 2 O 2 in the reaction solution is carried out by ferrous oxidation in silenol orange of Gay et al. (Gay CA and Gebicki JM, Analytical Biochemistry 304 (1) : pp42-46, 2002). xylenol orange (FOX) assay was used.

다양한 농도의 화합물들를 가한 것 이외에는 상기의 HTS에서 언급한 방법과 동일한 조건에서 30분동안 반응시킨 100 uL의 반응액에 100 ul의 FOX 시약(22 mM 과염소산 (perchloric acid), 50 uM 실레놀 오렌지(xylenol orange), 50 uM 황산 제1철 암모늄 용액(ferreous ammonium sulfate)을 섞고, 상온에서 1시간 반응시킨 뒤 560 nm에서 흡광도를 측정하였다. Except for the addition of various concentrations of compounds, 100 ul of FOX reagent (22 mM perchloric acid, 50 uM silenol orange) xylenol orange), 50 uM ferrous ammonium sulfate solution (ferreous ammonium sulfate) was mixed, and reacted at room temperature for 1 hour, and the absorbance was measured at 560 nm.

Prx I의 퍼옥시데이즈 활성은 DMSO를 가한 대조군에서 반응 후 나타나는 H2O2농도의 변화를 100% 활성도로 기준 삼고, 각각의 화합물들을 다양한 농도로 가한 경우에 나타나는 활성변화를 비교하였다. 시그마플롯 소프트웨어(SigmaPlot software)를 이용하여 각각의 화합물들에 대하여 다양한 로그(log) 스케일 농도에 대한 퍼옥시다아제 활성 곡선을 작성하고, 활성을 50% 억제하는 농도(IC50)를 구하였다(표 2 참조).Peroxidase activity of Prx I was based on the change of H 2 O 2 concentration after the reaction in the control group added DMSO as a 100% activity, and compared to the change in activity when each compound was added at various concentrations. SigmaPlot software was used to generate peroxidase activity curves for various log scale concentrations for each compound and to obtain a concentration (IC 50 ) that inhibits the activity by 50% (Table 2). Reference).

물질명Material name IC50 (μM)IC 50 ([mu] M) C52C52 20.70±3.3020.70 ± 3.30 C53C53 19.40±1.4019.40 ± 1.40 C54C54 9.99±11.109.99 ± 11.10 C55C55 13.40±4.1013.40 ± 4.10 C56C56 10.80±5.6010.80 ± 5.60 C57C57 16.20±6.0016.20 ± 6.00 C58C58 14.80±6.0014.80 ± 6.00 C59C59 11.30±2.4011.30 ± 2.40 C80C80 13.70±3.0013.70 ± 3.00

또한 9개의 물질들의 Prx I 활성에 대한 IC50(half-inhibitory concentration) 값을 구하기 위하여 NADPH, yTrx, yTrxR로 이루어진 환원 시스템을 이용하고, 반응액 중에 남아 있는 H2O2 농도를 540 nm에서 측정하는 FOX 어세이법을 이용하였다.In addition, using a reduction system consisting of NADPH, yTrx, yTrxR to determine the IC 50 (half-inhibitory concentration) value for the Prx I activity of the nine substances, the concentration of H 2 O 2 remaining in the reaction solution at 540 nm FOX assay was used.

실험결과, 상기 표 2에 나타난 바와 같이, 화합물 C52, C53, C54의 IC50값은 약 20 uM 정도, 그 이외의 것은 10~15 uM 정도로 측정됨을 확인할 수 있었다.As a result, as shown in Table 2, the IC 50 value of compounds C52, C53, C54 was about 20 uM, it could be confirmed that the other than 10 ~ 15 uM measured.

실험예 3. 세포의 생존 능력 (cell viability) 측정Experimental Example 3. Measurement of Cell Viability

10% 우태혈청(fetal bovine serum; HyClone, Catalog No. SH30397.03)과 1% 페니실린-스트렙토마이신(penicillin-streptomycin; Hycolne, Catalog No. SV30010)를 포함한 F-12 Nutrient Mixture Ham 액상배지(JBI, Catalog No. LM010-03)를 이용하여 96-웰 플레이트에서 배양한 A549 세포에 화합물 10 uM을 가한 후 48시간 동안 배양했다. 배양한 후, 각 100 uL의 배지를 포함한 각 웰에 10 ul의 세포분열용액(cell proliferation reagent) WST-1(Roche Co., Catalog No. 11-644-807-001)를 첨가한 후 37℃, 5% CO2조건의 배양기에서 4시간 동안 반응시켰다. 650 nm에서 흡광도를 측정하고 대조군(background control)에 대한 흡광도는 450 nm에서 측정하여 두 값의 차이를 구하였다. DMSO를 가한 대조군에서 나타나는 흡광도를 100% 생존도로 기준 삼고, 각각의 화합물들을 가한 경우에 생존도의 변화를 비교하였다. 데이터는 3개의 실험치를 평균값±평균의 표준오차로 표시하였다(표 3 참조).F-12 Nutrient Mixture Ham liquid medium (JBI, including 10% fetal bovine serum (HyClone, Catalog No. SH30397.03) and 1% penicillin-streptomycin (Hycolne, Catalog No. SV30010) Catalog No. LM010-03) was used to add 10 uM of the compound to A549 cells cultured in 96-well plates, followed by incubation for 48 hours. After incubation, 10 ul of cell proliferation reagent WST-1 (Roche Co., Catalog No. 11-644-807-001) was added to each well containing 100 uL of medium, followed by 37 ° C. , 4 hours in a 5% CO 2 incubator. The absorbance was measured at 650 nm and the absorbance for the background control was measured at 450 nm to determine the difference between the two values. Based on the absorbance of the control group added DMSO to 100% viability, the change in viability was compared with each compound added. The data were expressed as three experimental values as the standard error of the mean ± mean (see Table 3).

물질명Material name 생존 세포수(대조군에 대한 %)Viable cell count (% of control) 대조군Control group 100.00±4.66100.00 ± 4.66 C52C52 100.67±8.33100.67 ± 8.33 C53C53 110.93±7.49110.93 ± 7.49 C54C54 112.45±3.30112.45 ± 3.30 C55C55 71.54±8.53a 71.54 ± 8.53 a C56C56 65.01±0.55a 65.01 ± 0.55 a C57C57 78.77±0.37a 78.77 ± 0.37 a C58C58 62.00±1.15a 62.00 ± 1.15 a C59C59 39.73±3.19a 39.73 ± 3.19 a C80C80 81.46±3.3281.46 ± 3.32 ap<0.05로 대조군에 비하여 통계적으로 유의적인 차이가 있음을 표시함
(통계처리는 student t-test를 적용하였음) a p <0.05 indicating a statistically significant difference from the control
(Statistics applied student t -test)

처리process 경과시간(시)Elapsed time (hours) 상대적인 생존 세포수
(흡광도450 nm-흡광도650 nm)Relative viable cell number
(Absorbance 450 nm -absorbance 650 nm ) 대조군
Control
00 0.51±0.040.51 ± 0.04 2424 0.83±0.020.83 ± 0.02 4848 1.51±0.041.51 ± 0.04 7272 2.56±0.032.56 ± 0.03 C59(10μM)
C59 (10 μM)
00 0.52±0.060.52 ± 0.06 2424 0.64±0.080.64 ± 0.08 4848 0.78±0.02a 0.78 ± 0.02 a 7272 1.24±0.13a 1.24 ± 0.13 a ap<0.05로 대조군에 비하여 통계적으로 유의적인 차이가 있음을 표시함
(통계처리는 student t-test를 적용하였음) a p <0.05 indicating a statistically significant difference from the control
(Statistics applied student t -test)

실험결과, 상기 표 3에 나타난 바와 같이, 정상세포에 비하여 Prx I의 발현이 많이 증가되어 있는 것으로 보고된 인간 폐의 선암(human lung adenocarcinoma)인 A549 세포의 증식에 대한 9개 물질의 영향을 확인하였다. 각각의 물질을 10 uM 농도로 처리한 후, 48 시간이 경과한 후 WST-1 어세이법(Roche Co.)로 세포의 생존능력을 측정하였다. 5개 물질(C55-C59)을 처리하면 세포의 증식이 유의적으로 억제되는 효과가 있고, C59에 의한 성장억제가 가장 효과임을 확인 할 수 있었다.Experimental results, as shown in Table 3, confirmed the effect of nine substances on the proliferation of A549 cells, a human lung adenocarcinoma (human lung adenocarcinoma) reported to increase the expression of Prx I much compared to normal cells It was. Each material was treated at a concentration of 10 uM, and after 48 hours, the viability of the cells was measured by the WST-1 assay (Roche Co.). Treatment of five substances (C55-C59) has the effect of significantly inhibiting the proliferation of cells, it was confirmed that the growth inhibition by C59 is the most effective.

또한, 상기 표 4에 나타난 바와 같이, 세포 성장 저해가 가장 탁월한 C59 (10 uM 농도)를 처리한 후 시간이 경과함에 따라 나타나는 A549 세포의 성장저해효과를 살펴보았다. 24시간 경과 시에는 유의적인 효과가 나타나지 않았지만, 48시간 이후에는 성장이 억제되는 효과가 시간이 경과됨에 따라 유의적으로 증가됨을 확인할 수 있었다. In addition, as shown in Table 4, the growth inhibition effect of A549 cells appeared over time after treatment with C59 (10 uM concentration), the most excellent cell growth inhibition. There was no significant effect after 24 hours, but after 48 hours, the effect of inhibiting growth was found to increase significantly with time.

이러한 결과는 C59가 Prx I의 활성을 억제시킴으로써 암세포 내에서 생성되는 H2O2를 제거할 수 있는 능력이 점점 저하되어, 시간이 경과됨에 따라 세포 내 H2O2 축적량이 점점 증가되어 세포의 생존능력을 억제시키기 때문이라고 사료되었다. These results indicate that C59 inhibits the activity of Prx I, and thus the ability to remove H 2 O 2 produced in cancer cells is gradually decreased, and as time passes, H 2 O 2 accumulation is increased in cells. It is thought to be because it inhibits viability.

실험예 4. 세포내 ROS 측정Experimental Example 4. Intracellular ROS Measurement

상기 화합물들의 세포내 ROS 함량을 측정하기 위하여 문헌의 실험방법을 통해 CM-H2DCFDA 염료와 유세포분류기(flow cytometry)를 이용하여 실험을 수행하였다 (Chang TS, Cho CS, Park S, Yu S, Kang SW and Rhee SG, J. Biol. Chem. 279(40): pp41975-84,2004). In order to determine the intracellular ROS content of the compounds were carried out using a CM-H 2 DCFDA dye and flow cytometry through the experimental method of the literature (Chang TS, Cho CS, Park S, Yu S, Kang SW and Rhee SG, J. Biol. Chem. 279 (40) : pp 41975-84, 2004).

세포를 트립신/EDTA(trypsin 0.25%/EDTA 1 mM)를 사용해 배양접시에서 떼어낸 뒤 인산완충용액(phosphate buffered saline, PBS)로 현탁시킨후 270xg에서 3분 동안 원심분리하였다. 세포를 다시 1% FBS 포함하나, 페놀레드는 포함하지 않는 Dulbecco's minimal essential 배양배지(JBI, Catalog No.LM001-10)에 현탁시킨 후, 270xg으로 3분동안 원심분리했다가 현탁과정을 반복했다. 세포 현탁액에 5 uM의 CM-H2DCFDA 염료(Invitrogen, Catalog No.C6827)를 가하고 차광하여, 37℃, 5% CO2조건의 배양기에서 30분 동안 반응시켰다. 염색반응을 정지하기 위하여 30분 이후로는 4℃에 보관하였다. 발생되는 형광을 유세포 분석기(Becton Dickinson, Catalog No.BDB013396-2)의 FL-1 채널을 통해 측정하였다. 25,000 개의 세포 내에서 ROS에 의해 산화된 CM-DCF가 나타내는 형광도의 평균값(MFI, mean fluorescence intensity)을 WinMDI 소프트웨어를 이용하여 구하고 비교하였다. 데이터는 3개의 실험치를 평균값±평균의 표준오차로 표시하였다(표 5 참조).Cells were removed from the culture dish using trypsin / EDTA (trypsin 0.25% / EDTA 1 mM), suspended in phosphate buffered saline (PBS), and centrifuged at 270xg for 3 minutes. The cells were again suspended in Dulbecco's minimal essential culture medium (JBI, Catalog No. LM001-10) containing 1% FBS but not phenol red, followed by centrifugation at 270xg for 3 minutes and the suspension was repeated. 5 uM of CM-H 2 DCFDA dye (Invitrogen, Catalog No. C6827) was added to the cell suspension and shaded, and reacted for 30 minutes in an incubator at 37 ° C and 5% CO 2 . In order to stop the dyeing reaction was stored at 4 ℃ after 30 minutes. The generated fluorescence was measured through the FL-1 channel of a flow cytometer (Becton Dickinson, Catalog No. BDB013396-2). The mean fluorescence intensity (MFI) of CM-DCF oxidized by ROS in 25,000 cells was calculated using WinMDI software and compared. The data was expressed as three experimental values as the standard error of the mean value ± mean (see Table 5).

처리process 경과시간(시)Elapsed time (hours) 세포 내 ROS의 수준
(CM-DCF의 평균 형광도)Level of intracellular ROS
(Mean Fluorescence of CM-DCF) DMSODMSO 00 9.77±0.319.77 ± 0.31 4848 8.64±0.308.64 ± 0.30 7272 14.69±1.3014.69 ± 1.30 C59 (10μM)C59 (10 μM) 00 9.74±0.069.74 ± 0.06 4848 30.90±3.29a 30.90 ± 3.29 a 7272 124.61±21.75a 124.61 ± 21.75 a ap<0.05로 대조군에 비하여 통계적으로 유의적인 차이가 있음을 표시함
(통계처리는 student t-test를 적용하였음) a p <0.05 indicating a statistically significant difference from the control
(Statistics applied student t -test)

실험결과, 상기 표 5에 나타난 바와 같이, C59에 의한 세포의 생존능력 저하가 Prx I 저해에 따른 세포내 ROS 의 증가에 기인하는 것인지 확인한 결과, C59 10 uM를 처리하고 48, 72 시간이 경과되었을 때 세포내 ROS 양이 현저히 증가됨을 확인할 수 있었다.As a result of the experiment, as shown in Table 5, it was confirmed that the decrease in viability of the cells by C59 is due to the increase of intracellular ROS following Prx I inhibition. When the intracellular ROS amount was confirmed to be significantly increased.

실험예 5. 세포사멸의 측정Experimental Example 5. Measurement of Apoptosis

Roche사에서 구입한 Annexin-V-Fluos kit(Roche co., 11 988 549 001)내에 있는 방법에 준하여 세포를 PI 염료와 동시에 염색하여 유세포 분석기를 이용하여 세포사멸을 분석하였다(van Engeland M, Nieland LJ, Ramaekers FC, Schutte B, Reutelingsperger CP. Cytometry. 31(1): pp 1-9, 1998).Cells were stained at the same time as the PI dye using the Annexin-V-Fluos kit purchased from Roche (Roche co., 11 988 549 001) and analyzed for cell death using a flow cytometer (van Engeland M, Nieland). .. LJ, Ramaekers FC, Schutte B, Reutelingsperger CP Cytometry 31 (1): pp 1-9, 1998).

세포를 트립신 0.25%/EDTA 1 mM를 사용해 배양접시에서 떼어내어 PBS에 현탁시키고, 27xg에서 3분동안 원심분리했다. 106개의 세포를 100 uL의 반응완충용액 (10 mM HEPES-NaOH, pH 7.4, 140 mM NaCl, 5 mM CaCl2를 포함)에 현탁시키고, 여기에 1 ug/ml 아넥신-V-플루오스(Annexin-V-Fluos; Roche co., 11 988 549 001)와 1 ug/ml PI 염료(Roche co., 11 988 549 001)를 넣고 차광하여 상온에서 15분동안 반응시켰다. 추가적인 염색을 막기 위해서 15분 이후로는 4℃에 보관하였다. 아넥신-V-플루오스와 PI에 의해 발생되는 형광을 유세포 분석기의 FL-1과 FL-3 채널을 통해 측정한 후 4사분면 분석법을 이용하여 세포사멸의 정도를 측정하고 비교하였다. 즉, 세포 표면에 포스파티딜 세린(phosphatidyl serine)의 노출이 증가되어 여기에 아넥신 V의 결합이 현저히 증가되거나, 세포막의 손상으로 인하여 세포내로 PI가 유입된 세포들은 사멸이 일어난 것으로 분석하였다. 데이터는 3개의 실험치를 평균값±평균의 표준오차로 표시하였다(표 6 참조).Cells were removed from the culture dish using trypsin 0.25% / EDTA 1 mM and suspended in PBS and centrifuged at 27 × g for 3 minutes. 10 6 cells are suspended in 100 uL of reaction buffer solution (containing 10 mM HEPES-NaOH, pH 7.4, 140 mM NaCl, 5 mM CaCl 2 ), where 1 ug / ml Annexin-V-Fluoride ( Annexin-V-Fluos; Roche co., 11 988 549 001) and 1 ug / ml PI dye (Roche co., 11 988 549 001) were added and shielded for 15 minutes at room temperature. After 15 minutes was stored at 4 ℃ to prevent further staining. Fluorescence generated by Annexin-V-Fluorescence and PI was measured through the FL-1 and FL-3 channels of the flow cytometer, and then the degree of cell death was measured and compared using a quadrant analysis. In other words, the exposure of phosphatidyl serine to the cell surface was increased, which significantly increased the binding of Annexin V to it, or the cells infiltrated with PI due to damage to the cell membrane were analyzed to be killed. The data were expressed as three experimental values as the standard error of the mean ± mean (see Table 6).

처리process 경과시간(시)Elapsed time (hours) 세포 사멸(%)Cell death (%) DMSODMSO 00 3.86±0.123.86 ± 0.12 4848 3.99±0.313.99 ± 0.31 7272 3.58±0.033.58 ± 0.03 C59 (10μM)C59 (10 μM) 00 3.10±0.313.10 ± 0.31 4848 15.30±1.01a 15.30 ± 1.01 a 7272 21.62±1.39a 21.62 ± 1.39 a ap<0.05로 대조군에 비하여 통계적으로 유의적인 차이가 있음을 표시함
(통계처리는 student t-test를 적용하였음) a p <0.05 indicating a statistically significant difference from the control
(Statistics applied student t -test)

실험결과, 상기 표 6에 나타난 바와 같이, C59에 의한 세포의 생존능력 저하가 세포사멸에 의한 결과인지를 확인하기 위하여 세포를 PI와 아넥신-V-플루오스로 표지하여 유세포 분석기로 분석한 결과, C59 10 uM를 처리하고 48, 72 시간이 경과되었을 때 세포사멸이 현저히 증가됨을 확인할 수 있었다.As a result of the experiment, as shown in Table 6 above, the cells were labeled with PI and Annexin-V-Fluoride and analyzed by flow cytometry to confirm whether the cell viability was lowered by C59. After 48 and 72 hours after treatment with C59 10 uM, apoptosis was remarkably increased.

Claims (9)

Prx I 활성에 대한 강력한 억제 활성을 나타내는, 하기 일반식 (Ⅰ)의 구조를 갖는 피페리딘계 화합물 또는 이의 약리학적으로 허용가능한 염을 유효성분으로 함유하는 암질환의 치료 및 예방을 위한 약학 조성물:A pharmaceutical composition for the treatment and prevention of cancer diseases containing a piperidine-based compound having a structure of the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, which exhibits potent inhibitory activity against Prx I activity:
Figure 112010083241126-pat00002
Figure 112010083241126-pat00002
 상기 식에서, P는 페닐기 또는 피롤기이며,Wherein P is a phenyl group or a pyrrole group, X는 케톤기(C=O) 또는 설포닐기(SO2)이며, Q는 할로겐 원자, 메톡시 및 아세틸기로 구성된 군으로부터 선택된 하나 이상의 치환기로 치환된 페닐기, 페닐아민기 또는 스티렌기(styrene)이다.X is a ketone group (C═O) or a sulfonyl group (SO 2 ), and Q is a phenyl group, phenylamine group or styrene substituted with one or more substituents selected from the group consisting of halogen atoms, methoxy and acetyl groups . 삭제delete 삭제delete 삭제delete 제 1항에 있어서, 상기 일반식 (Ⅰ) 화합물은 (1) (E)-1-(4-(비페닐-4-일메틸)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온{(E)-1-(4-(biphenyl-4-ylmethyl)piperidin-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C52; CGX-10716804), (2) [4-([1,1'-비페닐]-4-일메틸)-1-피페리딘일](3,5-디클로로페닐)-메타논{4-([1,1'-biphenyl]-4-yl methyl)-1-piperidinyl](3,5-dichlorophenyl)-methanone; C53;Catalog No.CGX-10716746 ), (3) [4-(비페닐]-4-일메틸)-1-(2-클로로페닐설포닐)-피페리딘{4-(biphenyl]-4-yl methyl)-1-(2-chlorophenylsulfonyl)- piperidine; C54; Catalog No.CGX-10716998), (4) N-(3-아세틸페닐)-4-(비페닐-4-일메틸)피페리딘-1-카르복사미드{N-(3-acetyl)-4-(biphenyl-4-yl methyl)piperidine-1-carboxamide; C55; Catalog No.CGX-10717147), (5) 4-(비페닐-4-일메틸)-N-(4-메톡시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(4-methoxyphenyl)piperidine-1-carboxamide; C56; Catalog No.CGX-10717144 ), (6) 4-(비페닐-4-일메틸)-N-(3-메톡시페닐)피페리딘-1-카르복사미드{4-(biphenyl-4-yl methyl)-N-(3-methoxyphenyl)piperidine-1-carboxamide; C57; Catalog No.CGX-10717141), (7) 4-(1H-피롤-1-일)벤질)-N-(4-에톡시페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(4-ethoxyphenyl)piperidine-1-carboxamide; C58; Catalog No.CGX-10717125), (8) 4-(1H-피롤-1-일)벤질)-N-(3-아세틸페닐)피페리딘-1-카르복사미드{(4-(1H-pyrrol-1-yl)benzyl)-N-(3-acetylphenyl)piperidine-1-carboxamide; C59; Catalog No.CGX-10717124) 및 (9) (E)-1-(4-1H-피롤-1-일)벤질)피페리딘-1일)-3-(2-클로로페닐)프로프-2-엔-1-온(E)-1-(4-1H-pyrrol-1-yl)benzyl)piperidinle-1yl)-3-(2-chlorophenyl)prop-2-en-1-one; C80; Catalog No.CGX-10716786) 로부터 선택된 화합물인 조성물.A compound according to claim 1, wherein the compound of general formula (I) comprises (1) (E) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl ) Prop-2-en-1-one {(E) -1- (4- (biphenyl-4-ylmethyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C52 ; CGX-10716804), (2) [4-([1,1'-biphenyl] -4-ylmethyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone {4-([ 1,1'-biphenyl] -4-yl methyl) -1-piperidinyl] (3,5-dichlorophenyl) -methanone; C53 ; Catalog No.CGX-10716746), (3) [4- (biphenyl] -4-ylmethyl) -1- (2-chlorophenylsulfonyl) -piperidine {4- (biphenyl] -4- yl methyl) -1- (2-chlorophenylsulfonyl)-piperidine; C54 ; Catalog No.CGX-10716998), (4) N- (3-acetylphenyl) -4- (biphenyl-4-ylmethyl) piperidine-1-carboxamide {N- (3-acetyl) -4 -(biphenyl-4-yl methyl) piperidine-1-carboxamide; C55 ; Catalog No.CGX-10717147), (5) 4- (biphenyl-4-ylmethyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (4-methoxyphenyl) piperidine-1-carboxamide; C56 ; Catalog No.CGX-10717144), (6) 4- (biphenyl-4-ylmethyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide {4- (biphenyl-4-yl methyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide; C57 ; Catalog No.CGX-10717141), (7) 4- (1H-pyrrole-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide {(4- (1H- pyrrol-1-yl) benzyl) -N- (4-ethoxyphenyl) piperidine-1-carboxamide; C58 ; Catalog No.CGX-10717125), (8) 4- (1H-pyrrole-1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide {(4- (1H-pyrrol -1-yl) benzyl) -N- (3-acetylphenyl) piperidine-1-carboxamide; C59 ; Catalog No.CGX-10717124) and (9) (E) -1- (4-1H-pyrrole-1-yl) benzyl) piperidin-1yl) -3- (2-chlorophenyl) prop-2 -En-1-one (E) -1- (4-1H-pyrrol-1-yl) benzyl) piperidinle-1yl) -3- (2-chlorophenyl) prop-2-en-1-one; C80 ; Catalog No. CGX-10716786). 제 1항에 있어서, 상기 암질환은 유방암, 전립선암, 결장암, 폐암, 대장암, 소장암, 직장암, 항문암, 식도암, 췌장암, 위암, 신장암, 자궁암, 유방암, 폐암, 임파선암, 갑상선암, 전립선암, 백혈병, 피부암, 결장암, 뇌종양, 방광암, 난소암 또는 담낭암인 조성물.According to claim 1, wherein the cancer disease is breast cancer, prostate cancer, colon cancer, lung cancer, colon cancer, small intestine cancer, rectal cancer, anal cancer, esophageal cancer, pancreatic cancer, stomach cancer, kidney cancer, uterine cancer, breast cancer, lung cancer, lymph gland cancer, thyroid cancer, A composition that is prostate cancer, leukemia, skin cancer, colon cancer, brain tumor, bladder cancer, ovarian cancer or gallbladder cancer. 제 6항에 있어서, 상기 암질환은 유방암, 전립선암 , 결장암 또는 폐암인 조성물.The composition of claim 6, wherein the cancer disease is breast cancer, prostate cancer, colon cancer, or lung cancer. 삭제delete 삭제delete
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