KR101996871B1 - Novel 3-substituted-2-oxoindoline-based hydroxamic acids compound - Google Patents
Novel 3-substituted-2-oxoindoline-based hydroxamic acids compound Download PDFInfo
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- KR101996871B1 KR101996871B1 KR1020170075124A KR20170075124A KR101996871B1 KR 101996871 B1 KR101996871 B1 KR 101996871B1 KR 1020170075124 A KR1020170075124 A KR 1020170075124A KR 20170075124 A KR20170075124 A KR 20170075124A KR 101996871 B1 KR101996871 B1 KR 101996871B1
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- South Korea
- Prior art keywords
- methyl
- doublet
- oxoindolin
- compound
- dmso
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
본 발명은 히스톤 탈아세틸화 효소 억제 활성을 갖는 신규 3-치환된-2-옥소인돌린 기반 히드록삼산 화합물에 관한 것으로서, 히드록삼산(hydroxamic acid); 인돌린(indoline) 유도체; 및 상기 히드록삼산 및 상기 인돌린 유도체를 연결하는 트리아졸(triazole) 단량체를 포함한다.
상기와 같은 본 발명에 따르면, 신규한 히드록삼산 화합물을 제공함으로써, 강력한 히스톤 탈아세틸화 효소(histone deacetylase, HDAC)의 억제 활성을 가지며, 다양한 암세포에 대해 증식억제 효과가 있다.The present invention relates to a novel 3-substituted-2-oxoindolin-based hydroxamic acid compound having a histone deacetylase inhibitory activity, comprising: hydroxamic acid; Indoline derivatives; And a triazole monomer connecting the hydroxamic acid and the indolin derivative.
According to the present invention as described above, by providing a novel hydroxamic acid compound, it has an inhibitory activity of a powerful histone deacetylase (HDAC), and has a proliferation inhibitory effect on various cancer cells.
Description
본 발명은 히스톤 탈아세틸화 효소 억제 활성을 갖는 신규 3-치환된-2-옥소인돌린 기반 히드록삼산 화합물에 관한 것으로서, 더욱 상세하게는 강력한 히스톤 탈아세틸화 효소(histone deacetylase, HDAC)의 억제 활성을 가지며, 다양한 암세포에 대해 증식억제 활성을 가지는 신규한 화합물에 관한 것이다.The present invention relates to a novel 3-substituted-2-oxoindolin-based hydroxamic acid compound having histone deacetylase inhibitory activity, and more particularly to the inhibition of potent histone deacetylase (HDAC). It relates to a novel compound having activity and proliferation inhibitory activity against various cancer cells.
과거 항암제의 개발에서 높은 독성을 가지며, 비특이적이고, 암세포에 대하여 내성을 보이는 경향이 있는 항암제에 대한 결과가 있었다. 최근, 암 분자 병리학의 이점을 가지면서, 많은 문자 타겟이 항암제 개발을 위하여 이용되어 왔다. 이 중, 단백질 키나아제(protein kinases)는 요즘 가장 큰 표적 약물군 중 하나이다. 또한, 텔로머레이스(telomerase), 파르네실전달효소(farnesyltransferase) 및 히스톤 탈아세틸화 효소(histone deacetylase)는 항암제 개발에 있어서 관심도가 증가하는 표적이다.In the past, the development of anticancer agents has resulted in anticancer agents that are highly toxic, nonspecific and tend to be resistant to cancer cells. Recently, with the benefit of cancer molecular pathology, many letter targets have been used for anticancer drug development. Of these, protein kinases are one of the largest target drug groups these days. In addition, telomerase, farnesyltransferase and histone deacetylase are targets of increasing interest in anticancer drug development.
히스톤 탈아세틸화 효소(histone deacetylase, HDAC)은 히스톤 단백질들의 꼬리 부위에 있는 라이진 잔기로부터의 아세틸기를 제거하는 효소 그룹(group)이다. 따라서 HDACs는 라이신 탈아세틸화 효소라고도 불린다. 진핵생물에서는 18개의 HDAC 동형 단백질이 확인되었다. 이들의 효모 기원 효소와 도메인 구조에 대한 서열 상동성(homology)에 기초하여 4개의 클래스(class)로 분류된다. 클래스 Ⅰ의 HDACs는 HDAC 1, 2, 3 및 8의 4개의 구성원을 포함하고, 클래스 Ⅱa와 클래스 Ⅱb의 HDACs는 현재까지 HDAC 4, 5, 6, 7, 9 및 10의 6개의 구성원을 가지고 있다. HDAC 1, 2, 3 및 8은 능동적으로 세포 증식을 촉진하고 세포자멸을 차단하는 것으로 논의되어 왔다. 다른 한편으로, HDAC 3, 4, 5 및 8는 세포 분화를 차단한다. HDAC 4, 6, 7 및 10과 같은 HDAC의 다른 동형단백질은 암세포 전이에 중요한 두 과정인, 세포이동 및 신생혈관생성을 촉진하는 것을 알려져있다. 이러한 HDAC 동형단백질들의 저해는 암 세포 아포토시스(apoptosis), 분화 등과 관련된 수많은 상황들의 감소를 유도한다는 것을 동물모델과 임상적으로 확인되었다. 이는 다양한 암세포 형태로의 세포 주기를 차단한다. 따라서, 최근에HDACs는 항암제 설계 및 개발에 있어서의 분자 타겟으로 관심이 커지고 있다. 수반은 연구그룹에서 해당 분야에 대한 연구가 활발히 진행되고 있으며, 그 결과, 단쇄지방산(short-chain fatty acids)(e.g. phenylbutyric acid, Valproic acid), 히드록삼산(hydroxamic acids)(e.g. SAHA or suberoylanilide hydroxamic acid), 환형 펩타이드(cyclic peptide)(e.g. desipeptiede) 및 벤즈아마이드(benzeamides) 등을 포함하는 구조적으로 다양한 HDAC 저해제가 보고되었다.Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from lysine residues at the tail of histone proteins. HDACs are therefore also called lysine deacetylase. In eukaryotes, 18 HDAC isoforms have been identified. They are classified into four classes based on sequence homology to their yeast origin enzymes and domain structure. Class I HDACs include four members of HDACs 1, 2, 3 and 8, and class IIa and class IIb HDACs to date have six members of HDAC 4, 5, 6, 7, 9 and 10. . HDACs 1, 2, 3 and 8 have been discussed to actively promote cell proliferation and block apoptosis. On the other hand, HDACs 3, 4, 5 and 8 block cell differentiation. Other isoproteins of HDAC such as HDAC 4, 6, 7, and 10 are known to promote cell migration and angiogenesis, two processes important for cancer cell metastasis. Inhibition of these HDAC isoproteins has been clinically confirmed in animal models and induces a reduction in numerous conditions associated with cancer cell apoptosis, differentiation and the like. It blocks the cell cycle into various cancer cell types. Therefore, in recent years, HDACs have been of increasing interest as molecular targets in anticancer drug design and development. Accompanied by research groups in the field, active research is being conducted on short-chain fatty acids (eg phenylbutyric acid, Valproic acid), hydroxamic acids (eg SAHA or suberoylanilide hydroxamic). Structurally diverse HDAC inhibitors have been reported, including acid), cyclic peptides (eg desipeptiede) and benzamides.
최근에, 4가지의 HDAC 저해제가 몇몇의 암에 대하여 치료제로의 사용을 승인받았다. SAHA로 널리 알려진 suberoylanilide hydroxamic acid(상표명 Zolinza??)는 2066년 10월 미국 FDA로부터 피부 T세포 림프종(cutaneous t-cell lymphoma, CTCL)를 치료하는 첫 HDAC 저해제로서 승인을 받았다. Romidepsin(상표명 Istodax??) 또한, 같은 암질환에 대하여 2009년 미국 FDA로부터 승인을 받았다. 2014년 7월에는, belinostat(PXD101)이 미국으로부터 말초 T-세포 림프종(peripheral T-cell lymphoma)에 대한 저해제로서 승인을 받았다. 2015년 2월에는 panobinostat(LBH-589, 상표명 Farydak??)이 미국 FDA로부터 다발성 골수증(multiple myeloma)을 치료하는 임상 승인을 받았다. 2015년 초, 중국 FDA 또한 chidamide(상표명 Epidaza??)가 재발성 또는 난치성 말초 T-세포 림프종(peripheral T-cell lymphoma)에 대한 임상 승인을 하였다. entinostat(MS-27-527), mocetinostat(MGCD0103) 및 givinostat(ITF2357) 등과 같은 많은 HDAC 저해제들이 여러 형태의 암을 치료하기 위하여 다양한 섹션으로 현재 연구 중에 있다. Recently, four HDAC inhibitors have been approved for use as therapeutics for some cancers. Suberoylanilide hydroxamic acid, known as SAHA (trade name Zolinza ?? ), was approved by the US FDA in October 2066 as the first HDAC inhibitor to treat cutaneous t-cell lymphoma (CTCL). Romidepsin (trade name Istodax ?? ) also received approval from the US FDA in 2009 for the same cancer disease. In July 2014, belinostat (PXD101) was approved by the United States as an inhibitor of peripheral T-cell lymphoma. In February 2015, panobinostat (LBH-589, trade name Farydak ?? ) received clinical approval from the US FDA for the treatment of multiple myeloma. At the beginning of 2015, the Chinese FDA also approved a chidamide (Petradaza ?? ) for recurrent or refractory peripheral T-cell lymphoma. Many HDAC inhibitors, such as entinostat (MS-27-527), mocetinostat (MGCD0103) and givinostat (ITF2357), are currently being studied in various sections to treat various forms of cancer.
본 발명의 목적은, 강력한 히스톤 탈아세틸화 효소(histone deacetylase, HDAC)의 억제 활성을 가지며, 다양한 암세포에 대해 증식억제 활성을 가지는 신규한 히드록삼산 화합물을 제공함에 있다.An object of the present invention is to provide a novel hydroxamic acid compound having an inhibitory activity of a powerful histone deacetylase (HDAC) and having a proliferation inhibitory activity against various cancer cells.
상기 목적을 달성하기 위하여, 본 발명은 히드록삼산(hydroxamic acid); 인돌린(indoline) 유도체; 및 상기 히드록삼산 및 상기 인돌린 유도체를 연결하는 트리아졸(triazole) 단량체를 포함하는 신규한 화합물을 제공하는 것을 본 발명의 일 측면으로 한다.In order to achieve the above object, the present invention is hydroxamic acid; Indoline derivatives; And it is an aspect of the present invention to provide a novel compound comprising a triazole monomer that connects the hydroxamic acid and the indolin derivatives.
상기 인돌린 유도체는 3-치환된-인돌린-2-온(3-substituted-2-one)일 수 있으며, 상기 3-치환된-인돌린-2-온은 3-(히드록시이미노)인돌린-2온(3-(hydroxyimino)indolin-2-one) 또는 3-(메톡시이미노)인돌린-2온(3-(methoxyimino)indolin-2-one)일 수 있다.The indolin derivative may be 3-substituted-2-one, and the 3-substituted-indolin-2-one is 3- (hydroxyimino) indole 3- (hydroxyimino) indolin-2-one or 3- (methoxyimino) indolin-2-one.
상기 트리아졸 단량체는 1H-1,2,3-트리아졸(1H-1,2,3-triazole)일 수 있다.The triazole monomer may be 1H-1,2,3-triazole.
상기 화합물은 하기 화학식 1로 표시될 수 있으며,The compound may be represented by the following Formula 1,
[화학식 1][Formula 1]
(상기 R1은 수소, F, Cl, Br, 메틸, 메톡시로 이루어진 군에서 선택되는 것이며, 상기 R2는 수소 또는 메틸이며, 상기 A는 프로판, 부탄 또는 스티렌이다.)(The R 1 is selected from the group consisting of hydrogen, F, Cl, Br, methyl, methoxy, R 2 is hydrogen or methyl, and A is propane, butane or styrene.)
상기 화합물은 하기 화학식 2 또는 화학식 3으로 표시될 수 있다.The compound may be represented by the following formula (2) or (3).
[화학식 2][Formula 2]
[화학식 3][Formula 3]
(상기 R1은 수소, F, Cl, Br, 메틸, 메톡시로 이루어진 군에서 선택되는 것이며, 상기 n은 3 또는 4이며, 상기 X는 -OH 또는 -OCH3이다.)(The R1 is selected from the group consisting of hydrogen, F, Cl, Br, methyl, methoxy, the n is 3 or 4, the X is -OH or -OCH 3 ).
상기 화합물은 히스톤 탈아세틸화효소(histone deacetylase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는 것일 수 있다.The compound may have an activity of promoting acetylation of histones through inhibition of histone deacetylases.
상기와 같은 본 발명에 따르면, 신규한 히드록삼산 화합물을 제공함으로써, 강력한 히스톤 탈아세틸화 효소(histone deacetylase, HDAC)의 억제 활성을 가지며, 다양한 암세포에 대해 증식억제 효과가 있다.According to the present invention as described above, by providing a novel hydroxamic acid compound, it has an inhibitory activity of a powerful histone deacetylase (HDAC), and has a proliferation inhibitory effect on various cancer cells.
또한, 본 발명의 신규한 화합물은 강력한 항암제의 활성성분으로 제공될 수 있는 효과가 있다.In addition, the novel compounds of the present invention have the effect that can be provided as an active ingredient of a powerful anticancer agent.
도 1은 본 발명의 일 실시예에 따른 화합물 5a의 시뮬레이션된 도킹 포즈(docking pose)의 입체적 구조를 도시한 것이다.
도 2는 본 발명의 일 실시예에 따른 화합물 5b의 시뮬레이션된 도킹 포즈(docking pose)의 입체적 구조를 도시한 것이다.
도 3은 본 발명의 일 실시예에 따른 화합물 7a의 시뮬레이션된 도킹 포즈(docking pose)의 입체적 구조를 도시한 것이다.
도 4는 본 발명의 일 실시예에 따른 화합물 7b의 시뮬레이션된 도킹 포즈(docking pose)의 입체적 구조를 도시한 것이다.1 illustrates a three-dimensional structure of a simulated docking pose of
2 illustrates a three-dimensional structure of a simulated docking pose of
3 illustrates a three-dimensional structure of a simulated docking pose of
4 illustrates a three-dimensional structure of a simulated docking pose of compound 7b according to one embodiment of the present invention.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.
실험재료 및 방법.Experimental Materials and Methods.
합성화학 Synthetic chemistry
모든 생성물들은 균일하게 얻었으며, 이들은 Whatman 250μm Silica Gel GF Uniplates 상에서 박막 크로마토그래피(thin-layer chromatography, TLC)를 행하고 254 nm 및 365 nm 에서의 UV광에서 시각화하여 확인하였다. 모든 생성물들은 97% 또는 그 이상의 순도를 가지며, HPLC에 의하여 결정되였다. 끓는점은 Gallenkamp Melting Point Apparatus(LabMerchant, London, United Kingdom)를 사용하여 측정하였고, 보정되지 않았다. 생성물의 정제는 결정화 방법 및/또는 고정상으로서 Merck silica gel 60(240 - 400 mesh)를 사용하여 오픈 실리카젤 컬럼 플래쉬 크로마토그래피를 통해 행하였다. 핵자기공명스펙트럼(1H NMR)은 다르게 지정하지 않으면 테트라메틸실란을 내부표준물질로 사용하고 디메틸설폭사이드-d6(DMSO-d6)를 용매로 사용하여 Bruker 500 MHz 분광기상에서 측정하였다. 화학적 이동(chemical shift)은 내부표준물질인 테트라메틸실란으로 부터의 다운필드로 ppm(parts per million)으로 기록하였다. 질량분석은 전자이온화(electron ionization, EI), 전기분무이온화(electrospray ionization, ESI)를 포함한 상이한 이온화 모드에서, PE Biosystems API 200 (Perkin Elmer, Palo Alto, CA, USA) 및 Mariner®(Azco Biotech, Inc. Oceanside, CA, USA) 질량 분광기를 사용하여 각각 측정하였다. 시약 및 용매는 다르게 지정하지 않는 한 Aldrich 또는 Fluka Chemical Corp. (Milwaukee, WI,USA) 또는 머크(Merck)사로부터 구입하여 사용하였다.All products were obtained uniformly, which were confirmed by thin-layer chromatography (TLC) on Whatman 250 μm Silica Gel GF Uniplates and visualized in UV light at 254 nm and 365 nm. All products had a purity of 97% or higher and were determined by HPLC. Boiling point was measured using Gallenkamp Melting Point Apparatus (LabMerchant, London, United Kingdom) and was not calibrated. Purification of the product was done via open silica gel column flash chromatography using Merck silica gel 60 (240-400 mesh) as crystallization method and / or stationary phase. Nuclear magnetic resonance spectra ( 1 H NMR) were measured on a Bruker 500 MHz spectrometer using tetramethylsilane as internal standard and dimethylsulfoxide-d6 (DMSO-d6) as solvent unless otherwise specified. Chemical shifts were reported in parts per million (ppm) downfield from tetramethylsilane, an internal standard. Mass spectrometry was performed on PE Biosystems API 200 (Perkin Elmer, Palo Alto, Calif., USA) and Mariner ® (Azco Biotech, Inc.) in different ionization modes including electron ionization (EI), electrospray ionization (ESI). Inc. Oceanside, Calif., USA) respectively. Reagents and solvents are designated Aldrich or Fluka Chemical Corp. unless otherwise specified. (Milwaukee, WI, USA) or Merck was used.
제조예.Preparation example.
1-((1H-1,2,3,-트리아졸-4-일)메틸)-3-(히드록시이미노)인돌린-2-논(1-((1H-1,2,3-Triazol-4-yl)methyl)-3-substituted-indolin-2-ones) 구조를 포함하는 N-히드록시알케인아마이드(N-hydroxyalkanamides) 또는 N-히드록시프로펜아마이드(N-hdroxypropenamides)(화합물 4, 5, 7, 11)은 본원 명세서 반응식 1 내지 3에서와 같이 합성된다. 1-(( 1H- 1,2,3, -triazol-4-yl) methyl) -3- (hydroxyimino) indolin-2-non (1-(( 1H- 1,2,3 N-hydroxyalkanamides or N-hdroxypropenamides (Triazol-4-yl) methyl) -3-substituted-indolin-2-ones) Compounds 4, 5, 7, 11) are synthesized as in Schemes 1 to 3 herein.
제조예 1. N-히드록시 헥세인아마이드(화합물 4a-4g 및 5a-5g)의 합성Preparation Example 1 Synthesis of N-hydroxy hexaneamide (Compounds 4a-4g and 5a-5g)
하기 반응식 1을 참조하며, DMF(dimethylformamide) (3 mL)내의 이사틴(isatin)(1)(1 mmoL)이 용해된 각각 용액에 K2CO3(165.5 mg, 1.2 mmoL)을 첨가하였다. 혼합물을 80 ℃에서 1 시간 동안 교반한 후, KI(8.3 mg, 0.05 mmol)을 첨가하였다. 이후, 15 분 동안 교반한 후, 브롬화 프로파르길(propargyl bromide) 80% 용해된 톨투엔 0.15 mL를 혼합물에 천천히 떨어뜨린다. 혼합물을 60 ℃에서 3 시간 동안 교반 시킨다. 교반이 완료된 후, 혼합물을 냉각시키고, 얼음물이 투입하여 pH ~4로 산성화 시킨다. 오렌지 색의 고체가 형성되고, 고체를 거른 후, 건조하여 추가적인 정제없이 이사틴 프로파르길(propargyl isatin, 2)을 제조한다.Referring to Scheme 1 below, K2CO3 (165.5 mg, 1.2 mmoL) was added to each solution in which isatin (1) (1 mmoL) in DMF (dimethylformamide) (3 mL) was dissolved. The mixture was stirred at 80 ° C. for 1 h and then KI (8.3 mg, 0.05 mmol) was added. Thereafter, after stirring for 15 minutes, 0.15 mL of propargyl bromide dissolved toluene 80% is slowly dropped into the mixture. The mixture is stirred at 60 ° C. for 3 hours. After stirring is complete, the mixture is cooled, and iced water is added to acidify to pH ˜4. An orange solid is formed, the solid is filtered off and dried to prepare isargin propargyl (2) without further purification.
제조된 이사틴 프로파르길 화합물 용액 각각을 methyl azidoesters(1 mmol) in acetonitrile(2 mL)를 혼합한 후, 상온에서 10 분 동안 교반시킨다. 이후, CuI(19.1 mg, 0.1 mmol)을 첨가한다. 혼합물을 50 ℃에서 반응이 완료될 때(12 내지 24 시간)까지 교반시킨다. 이후 각각의 혼합물을 감압 하에서 증발시켜 잔류물을 생성하고, 이를 50 ml의 DCM에 재용해시킨다. 혼합물을 여과하고 DCM 막을 감압 하에서 증발시켜 중간체 에스터(3)를 수득한다. 중간체 에스터를 메탄올과 테트라하이드로퓨란(tetrahydrofuran)(2/1, 5ml)의 혼합물에 용해시킨다. 이후, hydroxylamine-HCl(685 mg, 10 mmol)을 첨가한 후, NaOH 용액(400 mg in 1 mL of water)를 한방울씩 떨어뜨리면서 첨가한다. 혼합물을 상온에서 반응이 종결될 때까지 교반시킨다. 반응이 종결된 혼합물을 얼음물이 투입하고, pH ~7까지 중화시킨고, 5 % HCl 용액을 한 방울씩 떨어뜨려 산성화시켜 침전시킨다. 침전물을 여과하고, 건조한 후 메탄올에서 재결정화하여 화합물 4,5를 수득한다. 화합물 4 및 5의 각 위치에 대한 번호를 하기 표시예 1에 도시하였다.Each of the prepared isatin propargyl compound solutions was mixed with methyl azidoesters (1 mmol) in acetonitrile (2 mL), and then stirred at room temperature for 10 minutes. Then CuI (19.1 mg, 0.1 mmol) is added. The mixture is stirred at 50 ° C. until the reaction is complete (12 to 24 hours). Each mixture is then evaporated under reduced pressure to yield a residue, which is redissolved in 50 ml of DCM. The mixture is filtered and the DCM membrane is evaporated under reduced pressure to give intermediate ester (3). Intermediate ester is dissolved in a mixture of methanol and tetrahydrofuran (2/1, 5 ml). Then, hydroxylamine-HCl (685 mg, 10 mmol) is added, and then NaOH solution (400 mg in 1 mL of water) is added drop by drop. The mixture is stirred at room temperature until the reaction is complete. The reaction mixture was terminated with ice water, neutralized to pH ˜7, and acidified by dropping 5% HCl solution dropwise. The precipitate is filtered off, dried and recrystallized in methanol to give compound 4,5. The numbers for each position of compounds 4 and 5 are shown in Display Example 1 below.
[반응식 1]Scheme 1
[표시예 1][Display Example 1]
(1) N-히드록시-6-(4-((3-(히드록시아미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헥산아마이드(N-Hydroxy-6-(4-((3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)hexanamide)(4a)(1) N-hydroxy-6- (4-((3- (hydroxyamino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl Hexaneamide (N-Hydroxy-6- (4-((3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) hexanamide) ( 4a )
황색 고체; 수율: 67%. mp: 181 - 182oC. R f = 0.41 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3456 (NH); 3180 (OH); 3031 (CH, aren); 2886 (CH, CH2);1719(C=O);1609,1544(C=C). 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.47 (1H, s, NOH); 10.31 (1H, s, NH); 8.65 (1H, s, OH); 8.08 (1H, s, H-8); 7.99 (1H, d, J = 7.5 Hz, H-4'); 7.40 (1H, t, J = 7.75 Hz, H-6'); 7.10 (1H, d, J = 8 Hz, H-7'); 7.07 (1H, t, 7.75 Hz, H-5'); 4.97 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,90 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.51 - 1.45 (2H, m, H-3a, H-3b); 1.20 - 1.15 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.92; 162.75; 143.44; 142.60; 141.79; 131.93; 126.84; 123.19; 122.72; 115.29; 109.64; 49.24; 34.67; 31.99; 29.31; 25.39; 24.63. HR-MS (ESI) m/z calculated for C17H20N6O4Na [M+Na]- 395.1444.Found,395.1474 [M + Na]+.Yellow solid; Yield 67%. mp: 181-182 o C. R f = 0.41 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3456 (NH); 3180 (OH); 3031 (CH, aren); 2886 (CH, CH 2 ); 1917 (C = O); 1609,1544 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.47 (1H, s, NOH); 10.31 (1H, s, NH); 8.65 (1 H, s, OH); 8.08 (1 H, s, H-8); 7.99 (1H, doublet, J = 7.5 Hz, H-4 '); 7.40 (1H, t, J = 7.75 Hz, H-6 '); 7.10 (1H, doublet, J = 8 Hz, H-7 '); 7.07 (1H, t, 7.75 Hz, H-5 '); 4.97 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,90 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.51-1.45 (2H, m, H-3a, H-3b); 1.20-1.15 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.92; 162.75; 143.44; 142.60; 141.79; 131.93; 126.84; 123.19; 122.72; 115.29; 109.64; 49.24; 34.67; 31.99; 29.31; 25.39; 24.63. HR-MS (ESI) m / z calculated for C 17 H 20 N 6 O 4 Na [M + Na] - 395.1444.Found, 395.1474 [M + Na] +.
(2) 6-(4-((5-플루오로-3-(히드록시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헥산아마이드(6-(4-((5-Fluoro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyhexanamide)(4b)(2) 6- (4-((5-fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyhexaneamide (6- (4-((5-Fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyhexanamide) (4b)
황색 고체; 수율: 65%. mp: 179 - 180oC. R f = 0.43 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3425 (NH); 3199 (OH); 3007 (C-H, aren); 2942, 2860 (CH, CH2);1711,1654(C=O). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 13.75(1H,s,NOH);10.30(1H,s,NH);8.64(1H,s,OH);8.09(1H,s,H-8);7.75(1H,dd,J = 8.0 Hz, J' = 2.5 Hz, H-4'); 7.29 (1H, td, J = 9.25 Hz, J' = 2.5 Hz, H-6'); 7.12 (1H, dd, J = 8.5 Hz, J' = 4.0 Hz, H-7'); 4.98 (2H, s, H-9a, H-9b); 4.28 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.49 - 1.46 (2H, m, H-3a, H-3b); 1.20 - 1.15 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.86; 162.57;157.95; 143.12; 141.62; 138.91; 123.18; 118.12; 115.76; 113.81; 110.70; 49.22; 34.79; 31.97; 29.28; 25.36; 24.40. Anal. Calcd. For C17H19FN6O4(390.37):C, 52.30; H, 4.91; N, 21.53. Found: C, 52.33; H, 4.94; N, 21.50. Yellow solid; Yield 65%. mp: 179-180 o C. R f = 0.43 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3425 (NH); 3199 (OH); 3007 (CH, aren); 2942, 2860 (CH, CH 2 ); 1711, 1654 (C = O). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.75 (1H, s, NOH); 10.30 (1H, s, NH); 8.64 (1H, s, OH); 8.09 (1H, s, H-8); 7.75 (1H, doublet of doublets, J = 8.0 Hz, J ' = 2.5 Hz, H-4'); 7.29 (1H, t d, J = 9.25 Hz, J ' = 2.5 Hz, H-6'); 7.12 (1H, doublet of doublets, J = 8.5 Hz, J ′ = 4.0 Hz, H-7 ′); 4.98 (2H, s, H-9a, H-9b); 4.28 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.49-1.46 (2H, m, H-3a, H-3b); 1.20-1.15 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.86; 162.57; 157.95; 143.12; 141.62; 138.91; 123.18; 118.12; 115.76; 113.81; 110.70; 49.22; 34.79; 31.97; 29.28; 25.36; 24.40. Anal. Calcd. For C 17 H 19 FN 6 O 4 (390.37): C, 52.30; H, 4.91; N, 21.53. Found: C, 52.33; H, 4.94; N, 21.50.
(3) 6-(4-((5-클로로-3-(히드록시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헥산아마이드(6-(4-((5-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyhexanamide)(4c)(3) 6- (4-((5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyhexaneamide (6- (4-((5-Chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyhexanamide) ( 4c )
황색 고체; 수율: 64%. mp: 183-184oC. R f = 0.44 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3281 (NH); 3200 (OH); 3023 (C-H, aren); 2941, 2858 (C-H, CH2);1712,1654(C=O);1610(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 10.32 (1H, s, NH); 8.66 (1H, s, OH); 8.09 (1H, s, H-8); 7.96 (1H, d, J = 1.5 Hz, H-4'); 7.48 (1H, dd, J = 8.5 Hz, J' = 1.5 Hz, H-6'); 7.14 (1H, d, J = 8.5 Hz, H-7'); 4.98 (2H, s, H-9a, H-9b); 4.28 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.50 - 1.45 (2H, m, H-3a, H-3b); 1.22 -1.17 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.90; 162.40; 142.68; 141.54; 141.33; 131.35; 126.54; 126.08; 123.19; 116.42; 111.24; 49.24; 34.82; 31.98; 29.29; 25.37; 24.42. Anal. Calcd. For C17H19ClN6O4(406.82):C, 50.19; H, 4.71; N, 20.66. Found: C, 50.22; H, 4.74; N, 20.62. Yellow solid; Yield 64%. mp: 183-184 o C. R f = 0.44 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3281 (NH); 3200 (OH); 3023 (CH, aren); 2941, 2858 (CH, CH 2 ); 1712, 1654 (C = O); 1610 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 10.32 (1H, s, NH); 8.66 (1 H, s, OH); 8.09 (1 H, s, H-8); 7.96 (1H, doublet, J = 1.5 Hz, H-4 ′); 7.48 (1H, doublet of doublets, J = 8.5 Hz, J ′ = 1.5 Hz, H-6 ′); 7.14 (1H, doublet, J = 8.5 Hz, H-7 '); 4.98 (2H, s, H-9a, H-9b); 4.28 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.50-1.45 (2H, m, H-3a, H-3b); 1.22 -1.17 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.90; 162.40; 142.68; 141.54; 141.33; 131.35; 126.54; 126.08; 123.19; 116.42; 111.24; 49.24; 34.82; 31.98; 29.29; 25.37; 24.42. Anal. Calcd. For C 17 H 19 ClN 6 O 4 (406.82): C, 50.19; H, 4.71; N, 20.66. Found: C, 50.22; H, 4. 74; N, 20.62.
(4) 6-(4-((5-브로모-3-(히드록시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헥산아마이드(6-(4-((5-Bromo-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyhexanamide)(4d)(4) 6- (4-((5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyhexaneamide (6- (4-((5-Bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyhexanamide) ( 4d )
황색 고체; 수율: 62%. mp: 186-188oC. R f = 0.46 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3490 (NH); 3199 (OH); 3028 (C-H, aren); 2940, 2858 (CH, CH2);1710,1654(C=O);1606(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 13.82 (1H, s, NOH); 10.31 (1H, s, NH); 8.65 (1H, s, OH); 8.08 (2H, s, H-8, H-4'); 7.61 (1H, d, J = 7.5 Hz, H-6'); 7.09 (1H, d, J = 7.5 Hz, H-7'); 4.98 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 6.75 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.0 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.49 - 1.47 (2H, m, H-3a, H-3b); 1.22 - 1.17 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.88; 162.28; 142.56; 141.72; 141.52; 134.18; 128.78; 123.17; 116.85; 114.19; 111.75; 49.24; 34.80; 31.98; 29.29; 25.37; 24.42. Anal. Calcd. For C17H19BrN6O4(451.28):C, 45.25; H, 4.24; N, 18.62. Found: C, 45.28; H, 4.26; N, 18.60. Yellow solid; Yield 62%. mp: 186-188 o C. R f = 0.46 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3490 (NH); 3199 (OH); 3028 (CH, aren); 2940, 2858 (CH, CH 2 ); 1710, 1654 (C = O); 1606 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.82 (1H, s, NOH); 10.31 (1H, s, NH); 8.65 (1 H, s, OH); 8.08 (2H, s, H-8, H-4 '); 7.61 (1H, doublet, J = 7.5 Hz, H-6 '); 7.09 (1H, doublet, J = 7.5 Hz, H-7 '); 4.98 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 6.75 Hz, H-6a, H-6b); 1,91 (2H, t, J = 7.0 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.49-1.47 (2H, m, H-3a, H-3b); 1.22-1.17 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.88; 162.28; 142.56; 141.72; 141.52; 134.18; 128.78; 123.17; 116.85; 114.19; 111.75; 49.24; 34.80; 31.98; 29.29; 25.37; 24.42. Anal. Calcd. For C 17 H 19 BrN 6 O 4 (451.28): C, 45.25; H, 4. 24; N, 18.62. Found: C, 45.28; H, 4. 26; N, 18.60.
(5) N-히드록시-6-(4-((3-(히드록시아미노)-5-메틸-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헥산아마이드(N-Hydroxy-6-(4-((3-(hydroxyimino)-5-methyl-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)hexanamide)(4e)(5) N-hydroxy-6- (4-((3- (hydroxyamino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazole -1-yl) hexaneamide (N-Hydroxy-6- (4-((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol- 1-yl) hexanamide) ( 4e )
황색 고체; 수율: 67%. mp: 176-177oC. R f = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3433 (NH); 3278 (OH); 3044 (C-H, aren); 2926, 2867 (C-H, CH2);1719(C=O);1628,1466(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 10.31 (1H, s, NH); 8.65 (1H, s, OH); 8.06 (1H, s, H-8); 7.83 (1H, s , H-4'); 7.20 (1H, d, J = 7.5 Hz, H-6'); 6.98 (1H, d, J = 7.5 Hz, H-7'); 4.94 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 6.5 Hz, H-6a H-6b); 2.27 (3H, s, CH3);1,90(2H,t,J = 6.75 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.49 - 1.46 (2H, m, H-3a, H-3b); 1.18 - 1.16 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.89; 162.75; 143.56; 141.84; 140.34; 132.08; 131.73; 127.34; 123.13; 115.34; 109.39; 49.22; 34.67; 31.99; 29.32; 25.38; 24.43; 20.49. Anal. Calcd. For C18H22N6O4(386.41):C, 55.95; H, 5.74; N, 21.75. Found: C, 55.98; H, 5.71; N, 21.77. Yellow solid; Yield 67%. mp: 176-177 o C. R f = 0.49 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3433 (NH); 3278 (OH); 3044 (CH, aren); 2926, 2867 (CH, CH 2 ); 1917 (C = O); 1628,1466 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 10.31 (1H, s, NH); 8.65 (1 H, s, OH); 8.06 (1 H, s, H-8); 7.83 (1 H, s, H-4 '); 7.20 (1H, doublet, J = 7.5 Hz, H-6 '); 6.98 (1H, doublet, J = 7.5 Hz, H-7 '); 4.94 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 6.5 Hz, H-6a H-6b); 2.27 (3H, s, CH 3 ); 1,90 (2H, t, J = 6.75 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.49-1.46 (2H, m, H-3a, H-3b); 1.18-1.16 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.89; 162.75; 143.56; 141.84; 140.34; 132.08; 131.73; 127.34; 123.13; 115.34; 109.39; 49.22; 34.67; 31.99; 29.32; 25.38; 24.43; 20.49. Anal. Calcd. For C 18 H 22 N 6 O 4 (386.41): C, 55.95; H, 5. 74; N, 21.75. Found: C, 55.98; H, 5.71; N, 21.77.
(6) N-히드록시-6-(4-((3-(히드록시아미노)-5-메톡시-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헥산아마이드(N-Hydroxy-6-(4-((3-(hydroxyimino)-5-methoxy-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)hexanamide)(4f)(6) N-hydroxy-6- (4-((3- (hydroxyamino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H-1,2,3-tria Zol-1-yl) hexaneamide (N-Hydroxy-6- (4-((3- (hydroxyimino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol -1-yl) hexanamide) ( 4f )
황색 고체; 수율: 57%. mp: 171-173oC. R f = 0.52 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3395 (NH); 3269, 3199 (OH); 3020 (C-H, aren); 2943, 2856 (C-H, CH2);1704,1652(C=O);1599(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.52 (1H, s, NOH); 10.31 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1H, s, H-8); 7.58 (1H, d, J = 2.0 Hz, H-4'); 7.03 - 6.98 (2H, m, H-6', H-7'); 4.94 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a H-6b); 3.73 (3H, s, OCH3),1.91(2H,t,J = 7.25 Hz, H-2a, H-2b); 1.77 - 1.74 (2H, m, H-5a, H-5b); 1.50 - 1.47 (2H, m, H-3a, H-3b); 1.20 - 1.16 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.86; 162.58; 155.19; 143.64; 141.81; 136.21; 123.11; 116.83; 115.82; 113.09; 110.22; 55.63; 49.19; 34.69; 31.96; 29.27; 25.35; 24.39. Anal. Calcd. For C18H22N6O5(402.41):C, 53.73; H, 5.51; N, 20.88. Found: C, 53.76; H, 5.54; N, 20.85. Yellow solid; Yield 57%. mp: 171-173 o C. R f = 0.52 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3395 (NH); 3269, 3199 (OH); 3020 (CH, aren); 2943, 2856 (CH, CH 2 ); 1704,1652 (C = O); 1599 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.52 (1H, s, NOH); 10.31 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1 H, s, H-8); 7.58 (1H, doublet, J = 2.0 Hz, H-4 '); 7.03-6.98 (2H, m, H-6 ', H-7'); 4.94 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a H-6b); 3.73 (3H, s, OCH 3 ), 1.91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.74 (2H, m, H-5a, H-5b); 1.50-1.47 (2H, m, H-3a, H-3b); 1.20-1.16 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.86; 162.58; 155.19; 143.64; 141.81; 136.21; 123.11; 116.83; 115.82; 113.09; 110.22; 55.63; 49.19; 34.69; 31.96; 29.27; 25.35; 24.39. Anal. Calcd. For C 18 H 22 N 6 O 5 (402.41): C, 53.73; H, 5.51; N, 20.88. Found: C, 53.76; H, 5.54; N, 20.85.
(7) 6-(4-((7-클로로-3-(히드록시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헥산아마이드(6-(4-((7-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyhexanamide)(4g)(7) 6- (4-((7-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyhexaneamide (6- (4-((7-Chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyhexanamide) ( 4g )
황색 고체; 수율: 64%. mp: 185-186oC. R f = 0.45 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3440 (NH); 2928, 2860 (CH, aren); 1720, 1637 (C=O); 1603, 1535 (C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 13.85 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.07 (1H, d, J = 7.0 Hz, H-4'); 8.03 (1H, s, H-8); 7.40 (1H, d, J = 8.0 Hz, H-6'); 7.11 (1H, t, J = 7.5 Hz, H-5'); 5.31 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,90 (2H, m, H-2a, H-2b); 1.75 (2H, m, H-5a, H-5b); 1.48 (2H, m, H-3a, H-3b); 1.19 - 1.16 (2H, m, H-4a, H-4b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.85; 163.64; 143.25; 142.21; 138.45; 133.76; 125.83; 124.22; 122.43; 118.30; 114.81; 49.19; 37.07; 31.97; 29.33; 25.33; 24.41. Anal. Calcd. For C17H19ClN6O4(406.82):C, 50.19; H, 4.71; N, 20.66. Found: C, 50.23; H, 4.69; N, 20.61. Yellow solid; Yield 64%. mp: 185-186 o C. R f = 0.45 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3440 (NH); 2928, 2860 (CH, aren); 1720, 1637 (C = O); 1603, 1535 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.85 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.07 (1H, doublet, J = 7.0 Hz, H-4 '); 8.03 (1 H, s, H-8); 7.40 (1H, doublet, J = 8.0 Hz, H-6 '); 7.11 (1H, t, J = 7.5 Hz, H-5 '); 5.31 (2H, s, H-9a, H-9b); 4.27 (2H, t, J = 7.0 Hz, H-6a, H-6b); 1,90 (2H, m, H-2a, H-2b); 1.75 (2H, m, H-5a, H-5b); 1.48 (2H, m, H-3a, H-3b); 1.19-1.16 (2H, m, H-4a, H-4b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.85; 163.64; 143.25; 142.21; 138.45; 133.76; 125.83; 124.22; 122.43; 118.30; 114.81; 49.19; 37.07; 31.97; 29.33; 25.33; 24.41. Anal. Calcd. For C 17 H 19 ClN 6 O 4 (406.82): C, 50.19; H, 4.71; N, 20.66. Found: C, 50.23; H, 4.69; N, 20.61.
(8) N-히드록시-7-(4-((3-(히드록시아미노)-5-메틸-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헵타아마이드(N-Hydroxy-7-(4-((3-(hydroxyimino)-5-methyl-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)heptanamide)(5a)(8) N-hydroxy-7- (4-((3- (hydroxyamino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazole -1-yl) heptaamide (N-Hydroxy-7- (4-((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol- 1-yl) heptanamide) ( 5a )
황색 고체; 수율: 69%. mp: 185 - 186oC. R f = 0.51 (DCM : MeOH : AcOH = 90 : 5 : 1). IR ( KBr , cm -1 ): 3201, 3129 (OH); 3036 (C-H, aren); 2935, 2861 (C-H, CH2);1713,1641(C=O);1608(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.47 (1H, s, NOH); 10.31 (1H, s, NH); 8.64 (1H, s, OH); 8.09 (1H, s, H-9); 7.99 (1H, d, J = 7.5 Hz, H-4'); 7.39 (1H, t, J = 7.75 Hz, H-6'); 7.10 (1H, d, J = 8.0 Hz, H-7');7.07(1H,t,J = 7.5 Hz, H-5'); 4.97 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.75 Hz, H-7a, H-7b); 1,90 (2H, t, J = 7.0 Hz, H-2a, H-2b); 1.76 - 1.73 (2H, m, H-6a, H-6b); 1.44 - 1.42 (2H, m, H-3a, H-3b); 1.22 - 1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 169.04; 162.73; 143.44; 142.59; 141.79; 131.90; 126.83; 123.20; 122.71; 115.29; 109.62; 49.29; 34.67; 32.12; 29.45; 27.87; 25.48; 24.88. Anal. Calcd. For C18H22N6O4(386.41):C, 55.95; H, 5.74; N, 21.75. Found: C, 55.92; H, 5.77; N, 21.73. Yellow solid; Yield 69%. mp: 185-186 o C. R f = 0.51 (DCM: MeOH: AcOH = 90: 5: 1). IR ( KBr , cm- 1 ): 3201, 3129 (OH); 3036 (CH, aren); 2935, 2861 (CH, CH 2 ); 1713,1641 (C = O); 1608 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.47 (1H, s, NOH); 10.31 (1H, s, NH); 8.64 (1 H, s, OH); 8.09 (1 H, s, H-9); 7.99 (1H, doublet, J = 7.5 Hz, H-4 '); 7.39 (1H, t, J = 7.75 Hz, H-6 '); 7.10 (1H, d, J = 8.0 Hz, H-7 '); 7.07 (1H, t, J = 7.5 Hz, H-5'); 4.97 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.75 Hz, H-7a, H-7b); 1,90 (2H, t, J = 7.0 Hz, H-2a, H-2b); 1.76-1.73 (2H, m, H-6a, H-6b); 1.44-1.42 (2H, m, H-3a, H-3b); 1.22-1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 169.04; 162.73; 143.44; 142.59; 141.79; 131.90; 126.83; 123.20; 122.71; 115.29; 109.62; 49.29; 34.67; 32.12; 29.45; 27.87; 25.48; 24.88. Anal. Calcd. For C 18 H 22 N 6 O 4 (386.41): C, 55.95; H, 5. 74; N, 21.75. Found: C, 55.92; H, 5.77; N, 21.73.
(9) 7-(4-((5-플루오로-3-(히드록시아미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헵타아마이드(7-(4-((5-Fluoro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide)(5b)(9) 7- (4-((5-fluoro-3- (hydroxyamino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyheptaamide (7- (4-((5-Fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyheptanamide) ( 5b )
황색 고체; 수율: 72%. mp: 187 - 188oC. R f = 0.50 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3424 (NH); 3247, 3143 (OH); 2937, 2861 (C-H, CH2);1720,1647(C=O);1477(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.76 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.08 (1H, s, H-9); 7.75 (1H, dd, J = 8.0 Hz, J' = 2.0 Hz, H4'); 7.28 (1H, td, J = 9.0 Hz, J' = 2.5 Hz, H-6');7.12(1H,dd,J = 8.5 Hz, J' = 3.5 Hz, H-7'); 4.97 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 1,96 (2H, t, J = 6.5 Hz, H-2a, H-2b); 1.76 - 1.73 (2H, m, H-6a, H-6b); 1.45 - 1.42 (2H, m, H-3a, H-3b); 1.22 - 1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 169.09; 162.63; 158.02, 143.18; 141.68; 138.95; 123.24; 118.14; 115.81; 113.85; 110.72; 49.33; 34.82; 32.11; 29.45; 27.86; 25.50; 24.88. Anal. Calcd. For C18H21FN6O4(404.40):C, 53.46; H, 5.23; N, 20.78. Found: C, 53.46; H, 5.23; N, 20.78. Yellow solid; Yield 72%. mp: 187-188 o C. R f = 0.50 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3424 (NH); 3247, 3143 (OH); 2937, 2861 (CH, CH 2 ); 1720, 1647 (C = O); 1477 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.76 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.08 (1 H, s, H-9); 7.75 (1H, doublet of doublets, J = 8.0 Hz, J ' = 2.0 Hz, H4'); 7.28 (1H, t d, J = 9.0 Hz, J ' = 2.5 Hz, H-6'); 7.72 (1H, dd, J = 8.5 Hz, J ' = 3.5 Hz, H-7'); 4.97 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 1,96 (2H, t, J = 6.5 Hz, H-2a, H-2b); 1.76-1.73 (2H, m, H-6a, H-6b); 1.45-1.42 (2H, m, H-3a, H-3b); 1.22-1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 169.09; 162.63; 158.02, 143.18; 141.68; 138.95; 123.24; 118.14; 115.81; 113.85; 110.72; 49.33; 34.82; 32.11; 29.45; 27.86; 25.50; 24.88. Anal. Calcd. For C 18 H 21 FN 6 O 4 (404.40): C, 53.46; H, 5. 23; N, 20.78. Found: C, 53.46; H, 5. 23; N, 20.78.
(10) 7-(4-((5-클로로-3-(히드록시아미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헵타아마이드(7-(4-((5-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide)(5c)(10) 7- (4-((5-chloro-3- (hydroxyamino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyheptaamide (7- (4-((5-Chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyheptanamide) ( 5c )
황색 고체; 수율: 75%. mp: 185 - 186oC. R f = 0.52 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3433 (NH); 3213 (OH); 3042 (C-H, aren); 2930, 2861 (C-H, CH2);1725,1638(C=O);1610(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.82 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.09 (1H, s, H-9); 7.96 (1H, s, H-4'); 7.48 (1H, d, J = 7.75 Hz, H-6'); 7.14 (1H, d, J = 7.75 Hz, H-7'); 4.98 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.25 Hz, H-7a, H-7b); 1,90 (2H, m, H-2a, H-2b); 1.75 (2H, m, H-6a, H-6b); 1.43 (2H, m, H-3a, H-3b); 1.23 - 1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 169.01; 162.38; 142.72; 141.59; 141.36; 131,36; 126.54; 126.09; 123.21; 116.41; 111.26; 49.30; 34.82; 32.09; 29.43; 27.84; 25.48; 24.86. Anal. Calcd. For C18H21ClN6O4(420.85):C, 51.37; H, 5.03; N, 19.97. Found: C, 51.34; H, 5.07; N, 20.01. Yellow solid; Yield 75%. mp: 185-186 o C. R f = 0.52 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3433 (NH); 3213 (OH); 3042 (CH, aren); 2930, 2861 (CH, CH 2 ); 1725, 1638 (C = O); 1610 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.82 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.09 (1 H, s, H-9); 7.96 (1H, s, H-4 '); 7.48 (1H, doublet, J = 7.75 Hz, H-6 '); 7.14 (1H, doublet, J = 7.75 Hz, H-7 '); 4.98 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.25 Hz, H-7a, H-7b); 1,90 (2H, m, H-2a, H-2b); 1.75 (2H, m, H-6a, H-6b); 1.43 (2H, m, H-3a, H-3b); 1.23-1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 169.01; 162.38; 142.72; 141.59; 141.36; 131,36; 126.54; 126.09; 123.21; 116.41; 111.26; 49.30; 34.82; 32.09; 29.43; 27.84; 25.48; 24.86. Anal. Calcd. For C 18 H 21 ClN 6 O 4 (420.85): C, 51.37; H, 5.03; N, 19.97. Found: C, 51.34; H, 5.07; N, 20.01.
(11) 7-(4-((5-브로모-3-(히드록시아미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헵타아마이드(7-(4-((5-Bromo-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide)(5d)(11) 7- (4-((5-bromo-3- (hydroxyamino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyheptaamide (7- (4-((5-Bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl ) -N-hydroxyheptanamide) ( 5d )
황색 고체; 수율: 77%. mp: 190 - 191oC. R f = 0.55 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3430 (NH); 3218 (OH); 3043 (C-H, aren); 2858 (C-H, CH2);1721,1640(C=O);1606(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.81 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.09 (2H, s, H-9, H-4'); 7.60 (1H, dd, J = 8.5 Hz, J' = 2,0 Hz, H-6'); 7.09 (1H, d, J = 8.5 Hz, H-7'); 4.98 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77 - 1.73 (2H, m, H-6a, H-6b); 1.46 - 1.41 (2H, m, H-3a, H-3b); 1.22 - 1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 169.01; 162.26; 142.56; 141.74; 141.51; 134.18; 128.80; 123.18; 116.85; 114.18; 111.74; 49.30; 34.80; 32.10; 29.44; 27.86; 25.48; 24.86. Anal. Calcd. For C18H21BrN6O4(465.30):C, 46.46; H, 4.55; N, 18.06. Found: C, 46.49; H, 4.58; N, 18.03. Yellow solid; Yield 77%. mp: 190-191 o C. R f = 0.55 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3430 (NH); 3218 (OH); 3043 (CH, aren); 2858 (CH, CH 2 ); 1721, 1640 (C = O); 1606 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.81 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.09 (2H, s, H-9, H-4 '); 7.60 (1H, doublet of doublets, J = 8.5 Hz, J ′ = 2,0 Hz, H-6 ′); 7.09 (1H, doublet, J = 8.5 Hz, H-7 '); 4.98 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 1,91 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.77-1.73 (2H, m, H-6a, H-6b); 1.46-1.41 (2H, m, H-3a, H-3b); 1.22-1.17 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 169.01; 162.26; 142.56; 141.74; 141.51; 134.18; 128.80; 123.18; 116.85; 114.18; 111.74; 49.30; 34.80; 32.10; 29.44; 27.86; 25.48; 24.86. Anal. Calcd. For C 18 H 21 BrN 6 O 4 (465.30): C, 46.46; H, 4.55; N, 18.06. Found: C, 46.49; H, 4.58; N, 18.03.
(12) N-히드록시-7-(4-((3-(히드록시아미노)-5-메틸-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헵타아마이드(N-Hydroxy-7-(4-((3-(hydroxyimino)-5-methyl-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)heptanamide)(5e)(12) N-hydroxy-7- (4-((3- (hydroxyamino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazole -1-yl) heptaamide (N-Hydroxy-7- (4-((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol- 1-yl) heptanamide) ( 5e )
황색 고체; 수율: 68%. mp: 182 - 183oC. R f = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3431 (NH); 3253 (OH); 3057 (C-H, aren); 2926, 2858 (CH, CH2);1719,1640(C=O);1466(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 13.42 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1H, s, H-9); 7.83 (1H, s, H-4'); 7.20 (1H, t, J = 8.0 Hz, H-6'); 6.98 (1H, d, J = 8.0 Hz, H-7'); 4.95 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 2.27 (3H, s, CH3);1,90(2H,t,J = 7.25 Hz, H-2a, H-2b); 1.76 -1.73 (2H, m, H-6a, H-6b); 1.44 - 1.42 (2H, m, H-3a, H-3b); 1.22 - 1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.99; 162.72; 143.56; 141.81; 140.34; 132.06; 131.71; 127.34; 123.13; 115.32; 109.37; 49.26; 34.66; 32.10; 29.44; 27.86; 25.47; 24.86; 20.46. Anal. Calcd. For C19H24N6O4(400.43):C, 56.99; H, 6.04; N, 20.99. Found: C, 57.02; H, 6.07; N, 21.01. Yellow solid; Yield 68%. mp: 182-183 o C. R f = 0.49 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3431 (NH); 3253 (OH); 3057 (CH, aren); 2926, 2858 (CH, CH 2 ); 1917, 1640 (C = O); 1466 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.42 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1 H, s, H-9); 7.83 (1 H, s, H-4 '); 7.20 (1H, t, J = 8.0 Hz, H-6 '); 6.98 (1H, doublet, J = 8.0 Hz, H-7 ′); 4.95 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a, H-7b); 2.27 (3H, s, CH 3 ); 1,90 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.76 -1.73 (2H, m, H-6a, H-6b); 1.44-1.42 (2H, m, H-3a, H-3b); 1.22-1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.99; 162.72; 143.56; 141.81; 140.34; 132.06; 131.71; 127.34; 123.13; 115.32; 109.37; 49.26; 34.66; 32.10; 29.44; 27.86; 25.47; 24.86; 20.46. Anal. Calcd. For C 19 H 24 N 6 O 4 (400.43): C, 56.99; H, 6.04; N, 20.99. Found: C, 57.02; H, 6.07; N, 21.01.
(13) N-히드록시-7-(4-((3-(히드록시아미노)-5-메톡시-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)헵타아마이드(N-Hydroxy-7-(4-((3-(hydroxyimino)-5-methoxy-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)heptanamide)(5f)(13) N-hydroxy-7- (4-((3- (hydroxyamino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H-1,2,3-tria Zol-1-yl) heptaamide (N-Hydroxy-7- (4-((3- (hydroxyimino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol -1-yl) heptanamide) ( 5f )
황색 고체; 수율: 64%. mp: 184 - 186oC. R f = 0.51 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3423 (NH); 3230 (OH); 3032 (C-H, aren); 2933, 2859 (C-H, CH2);1704,1642(C=O);1598,1554(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 10.31 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1H, s, H-9); 7.58 (1H, d, J = 2.5 Hz, H-4'); 7.03 - 6.98 (2H, m, H-6', H-7'); 4.94 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a H-7b); 3.73 (3H, s, OCH3);1.90(2H,t,J = 7.25 Hz, H-2a, H-2b); 1.76 - 1.73 (2H, m, H-6a, H-6b); 1.45 - 1.40 (2H, m, H-3a, H-3b); 1.23 - 1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 168.99; 162.61; 155.21; 143,69; 141.83; 136.21; 123.13; 116.81; 115.85; 113.10; 110.22; 55.65; 49.27; 34.70; 32.08; 29.44; 27.85; 25.47; 24.86. Anal. Calcd. For C19H24N6O5(416.43):C, 54.80; H, 5.81; N, 20.18. Found: C, 54.84; H, 5.85; N, 20.14. Yellow solid; Yield 64%. mp: 184-186 o C. R f = 0.51 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3423 (NH); 3230 (OH); 3032 (CH, aren); 2933, 2859 (CH, CH 2 ); 1704,1642 (C = O); 1598,1554 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 10.31 (1H, s, NH); 8.63 (1H, s, OH); 8.06 (1 H, s, H-9); 7.58 (1H, doublet, J = 2.5 Hz, H-4 '); 7.03-6.98 (2H, m, H-6 ', H-7'); 4.94 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 7.0 Hz, H-7a H-7b); 3.73 (3H, s, OCH 3 ); 1.90 (2H, t, J = 7.25 Hz, H-2a, H-2b); 1.76-1.73 (2H, m, H-6a, H-6b); 1.45-1.40 (2H, m, H-3a, H-3b); 1.23-1.16 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 168.99; 162.61; 155.21; 143,69; 141.83; 136.21; 123.13; 116.81; 115.85; 113.10; 110.22; 55.65; 49.27; 34.70; 32.08; 29.44; 27.85; 25.47; 24.86. Anal. Calcd. For C 19 H 24 N 6 O 5 (416.43): C, 54.80; H, 5.81; N, 20.18. Found: C, 54.84; H, 5.85; N, 20.14.
(14) 7-(4-((7-클로로-3-(히드록시아미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)-N-히드록시헵타아마이드 (7-(4-((7-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-N-hydroxyheptanamide)(5g)(14) 7- (4-((7-chloro-3- (hydroxyamino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyheptaamide (7- (4-((7-Chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) -N-hydroxyheptanamide) ( 5g )
황색 고체; 수율: 76%. mp: 185 - 186oC. R f = 0.52 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3425 (NH); 2924, 2855 (C-H, CH2);1716(C=O);1638(C=C). ESI-MS (m/z): 339 [M+2H]-. 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 13.84 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.07 (1H, d, J = 7.5 Hz, H-4'); 8.03 (1H, s, H-9); 7.40 (1H, d, J = 8 Hz, H-6'); 7.11 (1H, t, J = 7.75 Hz, H-5'); 5.31 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.5 Hz, H-7a H-7b); 1,90 (2H, t, J = 6.75 Hz, H-2a, H-2b); 1.75 - 1.73 (2H, m, H-6a, H-6b); 1.44 - 1.41 (2H, m, H-3a, H-3b); 1.23 - 1.15 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 169.03; 163.64; 143.28; 142.22; 138.46; 133.76; 125.84; 124.23; 122.39; 118.32; 114.80; 49.25; 37.08; 32.13; 29.48; 27.88; 25.44; 24.91. Anal. Calcd. For C18H21ClN6O4(420.85):C, 51.37; H, 5.03; N, 19.97. Found: C, 51.39; H, 5.00; N, 19.95.Yellow solid; Yield 76%. mp: 185-186 o C. R f = 0.52 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3425 (NH); 2924, 2855 (CH, CH 2 ); 1716 (C = O); 1638 (C = C). ESI-MS ( m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 13.84 (1H, s, NOH); 10.30 (1H, s, NH); 8.63 (1H, s, OH); 8.07 (1H, doublet, J = 7.5 Hz, H-4 '); 8.03 (1H, s, H-9); 7.40 (1H, doublet, J = 8 Hz, H-6 '); 7.11 (1H, t, J = 7.75 Hz, H-5 '); 5.31 (2H, s, H-10a, H-10b); 4.27 (2H, t, J = 6.5 Hz, H-7a H-7b); 1,90 (2H, t, J = 6.75 Hz, H-2a, H-2b); 1.75-1.73 (2H, m, H-6a, H-6b); 1.44-1.41 (2H, m, H-3a, H-3b); 1.23-1.15 (4H, m, H-4a, H-4b, H-5a, H-5b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 169.03; 163.64; 143.28; 142.22; 138.46; 133.76; 125.84; 124.23; 122.39; 118.32; 114.80; 49.25; 37.08; 32.13; 29.48; 27.88; 25.44; 24.91. Anal. Calcd. For C 18 H 21 ClN 6 O 4 (420.85): C, 51.37; H, 5.03; N, 19.97. Found: C, 51.39; H, 5.00; N, 19.95.
제조예 2. N-히드록시 아크릴아마이드(화합물 7a-7g)의 합성Preparation Example 2 Synthesis of N-hydroxy Acrylamide (
화합물 7a-7g는 하기 반응식 2에 도시된 바와 같이, 세단계의 과정을 통하여 합성된다. 합성과정은 상기 제조예 1과 동일하게 실시하되, methyl azidoesters 대신에 4-azidomethylcinnamate를 이용한다. 화합물 7의 각 위치에 대한 번호를 하기 표시예 2에 도시하였다.
[반응식 2]Scheme 2
[표시예 2][Display Example 2]
(1) (E)-N-히드록시-3-(4-((4-((3-(히드록시이미노)-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(7a)(1) (E) -N-hydroxy-3- (4-((4-((3- (hydroxyimino) -2-oxoindolin-1-yl) -1H-1,2,3- Triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (hydroxyimino) -2-oxoindolin-1-yl) methyl)- 1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (7a)
황색 고체; 수율: 50%. mp: 179 - 180oC. R f = 0.43 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3414 (NH), 3241 (OH), 2918, 2849 (CH, CH2),1717,1661(C=O),1609,1464(C=C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 8.17 (1H, s, H-12); 7.99 (1H, d, J = 7.0 Hz, H-4'); 7.53 (2H, d, J = 7.5 Hz, H-5, H-9); 7.42 (1H, d, J = 15.5 Hz, H-3); 7.39 (1H, t, J = 7.5 Hz, H-6'); 7.28 (2H, d, J = 7.5 Hz , H-6, H-8); 7.11 - 7.06 (2H, m, H-5', H-7'); 6.45 (1H, d, J = 15.5 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 163.83, 162.56, 143.43, 142.54, 142.29, 137.62, 137.05, 134.71, 131.86, 127.82, 126.82, 123.64, 122.75, 122.44, 119.57, 115.35, 109.61, 52.49, 34.66. HR-MS (ESI) m/z calculated for C21H17N6O4[M-H]- 417.1311.Found,417.1306 [M-H]-.Yellow solid; Yield 50%. mp: 179-180 o C. R f = 0.43 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3414 (NH), 3241 (OH), 2918, 2849 (CH, CH 2 ), 1717,1661 (C = O), 1609,1464 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.17 (1H, s, H-12); 7.99 (1H, doublet, J = 7.0 Hz, H-4 '); 7.53 (2H, doublet, J = 7.5 Hz, H-5, H-9); 7.42 (1H, doublet, J = 15.5 Hz, H-3); 7.39 (1H, t, J = 7.5 Hz, H-6 '); 7.28 (2H, doublet, J = 7.5 Hz, H-6, H-8); 7.11-7.06 (2H, m, H-5 ', H-7'); 6.45 (1H, doublet, J = 15.5 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 163.83, 162.56, 143.43, 142.54, 142.29, 137.62, 137.05, 134.71, 131.86, 127.82, 126.82, 123.64, 122.75, 122.44, 119.57, 115.35, 109.61 34.66. HR-MS (ESI) m / z calculated for C 21 H 17 N 6 O 4 [M − H] − 417.1311. Found, 417.1306 [MH] − .
(2) (E)-3-(4-((4-((5-플루오로-3-(히드록시이미노)-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((5-Fluoro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(7b)(2) (E) -3- (4-((4-((5-fluoro-3- (hydroxyimino) -2-oxoindolin-1-yl) -1H-1,2,3- Triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((5-Fluoro-3- (hydroxyimino) -2-oxoindolin-1- yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (7b)
황색 고체; 수율: 54%. mp: 203 - 204oC. R f = 0.45 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): ): 3421 (NH), 3213 (OH), 3047 (CH, aren), 2917, 2852 (CH, CH2),1709,1664(C=O),1619,1476(C=C). 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 10.76 (1H, s, NH); 9.04 (1H, s, OH); 8.17 (1H, s, H-12); 7.75 (1H, dd, J = 8.25 Hz, J' = 2.75 Hz,H-4');7.53(2H,d,J = 8.0 Hz, H-5, H-9); 7.42 (1H, d, J = 15.75 Hz, H-3); 7.30 - 7.26 (3H, m, H-6', H-6, H-8); 7.13 (1H, dd, J = 8.75 Hz, J' = 4.25 Hz, H-7'); 6.44 (1H, d, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 162.64, 158.00, 143.12, 142.11, 138.87, 137.62, 137.01, 134.69, 128.43, 127.80, 123.63, 119.55, 118.08, 115.80, 113.80, 110.67, 52.47, 34.77. HR-MS (ESI) m/z calculated for C21H16FN6O4[M-H]- 435.1217.Found,435.1215 [M-H]- . Yellow solid; Yield 54%. mp: 203-204 o C. R f = 0.45 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ):) : 3421 (NH), 3213 (OH), 3047 (CH, aren), 2917, 2852 (CH, CH 2 ), 1709,1664 (C = O), 1619,1476 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 10.76 (1H, s, NH); 9.04 (1H, s, OH); 8.17 (1 H, s, H-12); 7.75 (1H, doublet of doublets, J = 8.25 Hz, J ' = 2.75 Hz, H-4'); 7.53 (2H, d, J = 8.0 Hz, H-5, H-9); 7.42 (1H, doublet, J = 15.75 Hz, H-3); 7.30-7.26 (3H, m, H-6 ', H-6, H-8); 7.13 (1H, doublet of doublets, J = 8.75 Hz, J ' = 4.25 Hz, H-7'); 6.44 (1H, doublet, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 162.64, 158.00, 143.12, 142.11, 138.87, 137.62, 137.01, 134.69, 128.43, 127.80, 123.63, 119.55, 118.08, 115.80, 113.80, 110.67, 34.47, 34.47, 34.47 HR-MS (ESI) m / z calculated for C 21 H 16 FN 6 O 4 [M − H] − 435.1217.Found, 435.1215 [MH] − .
(3) (E)-3-(4-((4-((5-클로로-3-(히드록시이미노)-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((5-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide((7c)(3) (E) -3- (4-((4-((5-chloro-3- (hydroxyimino) -2-oxoindolin-1-yl) -1H-1,2,3-tria Zol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((5-Chloro-3- (hydroxyimino) -2-oxoindolin-1-yl ) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((7c)
황색 고체; 수율: 51%. mp: 237 - 239oC. R f = 0.38 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3386 (NH), 3141 (OH), 3031 (C-H, aren), 2852 (CH, CH2),1714,1652(C=O),1608,1463(C=C). 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 8.17 (1H, s, H-12); 7.96 (1H, s, H-4'); 7.54 (2H, d, J = 7.5 Hz, H-5, H-9); 7.48 (1H, d, J = 8.25 Hz, H-6'); 7.43 (1H, d, J = 15.75 Hz, H-3); 7.30 (2H, d, J = 7.5 Hz, H-6, H-8); 7.15 (1H, d, J = 8.25 Hz, H-7'); 6.45 (1H, d, J = 15.75 Hz, H-2); 5.57 (2H, s, H-10a, H-10b), 4.99 (2H, s, H-13a, H-13b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 166.56. 162.45, 143.80, 142.68, 142.02, 141.31, 137.62, 136.99, 134.71, 131.32, 128.44, 127.81, 126.09, 123.63, 119.56, 116.45, 111.24, 52.50, 34.81. HR-MS (ESI) m/z calculated for C21H16ClN6O4[M-H]- 451.0922.Found,451.0939 [M-H]- . Yellow solid; Yield 51%. mp: 237-239 o C. R f = 0.38 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3386 (NH), 3141 (OH), 3031 (CH, aren), 2852 (CH, CH 2 ), 1714,1652 (C = O), 1608,1463 (C = C ). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.17 (1H, s, H-12); 7.96 (1H, s, H-4 '); 7.54 (2H, doublet, J = 7.5 Hz, H-5, H-9); 7.48 (1H, doublet, J = 8.25 Hz, H-6 '); 7.43 (1H, doublet, J = 15.75 Hz, H-3); 7.30 (2H, doublet, J = 7.5 Hz, H-6, H-8); 7.15 (1H, doublet, J = 8.25 Hz, H-7 '); 6.45 (1H, doublet, J = 15.75 Hz, H-2); 5.57 (2H, s, H-10a, H-10b), 4.99 (2H, s, H-13a, H-13b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 166.56. 162.45, 143.80, 142.68, 142.02, 141.31, 137.62, 136.99, 134.71, 131.32, 128.44, 127.81, 126.09, 123.63, 119.56, 116.45, 111.24, 52.50, 34.81. HR-MS (ESI) m / z calculated for C 21 H 16 ClN 6 O 4 [MH] - 451.0922.Found, 451.0939 [MH] -.
(4) (E)-3-(4-((4-((5-브로모-3-(히드록시이미노)-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((5-Bromo-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(7d)(4) (E) -3- (4-((4-((5-bromo-3- (hydroxyimino) -2-oxoindolin-1-yl) -1H-1,2,3- Triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((5-Bromo-3- (hydroxyimino) -2-oxoindolin-1- yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (7d)
황색 고체; 수율: 55%. mp: 215 - 216oC. R f = 0.47 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3423 (NH), 3190 (OH), 3042 (C-H, aren), 1717, 1657 (C=O), 1606, 1463 (C=C). 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 8.17 (1H, s, H-12); 8.09 (1H, s, H-4'); 7.60 (1H, d, J = 8.5 Hz, H-6'); 7.54 (2H, d, J = 8.0 Hz, H-5, H-9); 7.42 (1H, d, J = 15.75 Hz, H-3); 7.29 (2H, d, J = 8.5 Hz, H-6, H-8); 7.10 (1H, d, J = 8.5 Hz, H-7'); 6.45 (1H, d, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 C NMR (125 MHz, DMSO-d 6 , ppm): δ 162.35, 142.56, 142.02, 141.65, 137.60, 137.00, 134.69, 134.10, 128.74, 128.44, 127.81, 123.62, 120.66, 119.56, 116.90, 114.21, 111.71, 52.49, 34.79. HR-MS (ESI) m/z calculated for C21H18BrN6O[M-H]- 495.0416[79Br],497.0396[81Br].Found,497.1259 [M-H]- . Yellow solid; Yield 55%. mp: 215-216 o C. R f = 0.47 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3423 (NH), 3190 (OH), 3042 (CH, aren), 1717, 1657 (C═O), 1606, 1463 (C═C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.17 (1H, s, H-12); 8.09 (1 H, s, H-4 '); 7.60 (1H, doublet, J = 8.5 Hz, H-6 '); 7.54 (2H, doublet, J = 8.0 Hz, H-5, H-9); 7.42 (1H, doublet, J = 15.75 Hz, H-3); 7.29 (2H, doublet, J = 8.5 Hz, H-6, H-8); 7.10 (1H, doublet, J = 8.5 Hz, H-7 '); 6.45 (1H, doublet, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.98 (2H, s, H-13a, H-13b). 13 C NMR (125 MHz, DMSO-d 6 , ppm) : δ 162.35, 142.56, 142.02, 141.65, 137.60, 137.00, 134.69, 134.10, 128.74, 128.44, 127.81, 123.62, 120.66, 119.56, 116.90, 114.21, 111.21, 111.111 52.49, 34.79. HR-MS (ESI) m / z calculated for C 21 H 18 BrN 6 O [M−H] − 495.0416 [ 79 Br], 497.0396 [ 81 Br]. Found, 497.1259 [MH] − .
(5) (E)-N-히드록시-3-(4-((4-((3-(히드록시이미노)-5-메틸-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(hydroxyimino)-5-methyl-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(7e)(5) (E) -N-hydroxy-3- (4-((4-((3- (hydroxyimino) -5-methyl-2-oxoindolin-1-yl) -1H-1, 2,3-triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (hydroxyimino) -5-methyl-2-oxoindolin -1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (7e)
황색 고체; 수율: 52%. mp: 218 - 220oC. R f = 0.32 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3193 (OH), 3038 (C-H, aren), 2872 (CH, CH2),1703,1658(C=O),1615,1480(C=C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 8.15 (1H, s, H-12); 7.83 (1H, s, H-4'); 7.53 (2H, d, J = 7.75 Hz, H-5, H-9); 7.42 (1H, d, J = 16.0 Hz, H-3); 7.29 (2H, d, J = 7.75 Hz, H-6, H-8); 7.19 (1H, d, J = 8.0 Hz, H-6'); 6.98 (1H, d, J = 8.0 Hz, H-7'); 6.45 (1H, d, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.95 (2H, s, H-13a, H-13b), 2.27 (3H, s, CH3). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 162.78, 143.55, 142.31, 140.33, 137.63, 137.04, 134.68, 132.08, 131.76, 128.68, 128.43, 127.80, 127.38, 123.56, 119.54, 115.35, 109.36, 52.45, 34.66, 20.50. HR-MS (ESI) m/z calculated for C22H19N6O4[M-H]- 431.1468.Found,431.1468 [M-H]- . Yellow solid; Yield 52%. mp: 218-220 o C. R f = 0.32 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3193 (OH), 3038 (CH, aren), 2872 (CH, CH 2 ), 1703,1658 (C═O), 1615,1480 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.15 (1H, s, H-12); 7.83 (1 H, s, H-4 '); 7.53 (2H, doublet, J = 7.75 Hz, H-5, H-9); 7.42 (1H, doublet, J = 16.0 Hz, H-3); 7.29 (2H, doublet, J = 7.75 Hz, H-6, H-8); 7.19 (1H, doublet, J = 8.0 Hz, H-6 ′); 6.98 (1H, doublet, J = 8.0 Hz, H-7 ′); 6.45 (1H, doublet, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.95 (2H, s, H-13a, H-13b), 2.27 (3H, s, CH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 162.78, 143.55, 142.31, 140.33, 137.63, 137.04, 134.68, 132.08, 131.76, 128.68, 128.43, 127.80, 127.38, 123.56, 119.54, 115.35, 109.36. 34.66, 20.50. HR-MS (ESI) m / z calculated for C 22 H 19 N 6 O 4 [M − H] − 431.1468.Found, 431.1468 [MH] − .
(6) (E)-N-히드록시-3-(4-((4-((3-(히드록시이미노)-5-메톡시-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(hydroxyimino)-5-methoxy-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(7f)(6) (E) -N-hydroxy-3- (4-((4-((3- (hydroxyimino) -5-methoxy-2-oxoindolin-1-yl) -1H-1 , 2,3-triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (hydroxyimino) -5-methoxy-2- oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (7f)
황색 고체; 수율: 53%. mp: 211 - 212oC. R f = 0.24 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3193 (OH), 3031 (C-H, aren), 2834 (CH, CH2),1714,1659(C=O),1626,1481(C=C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 8.15 (1H, s, H-12); 7.58 (1H, d, J = 2.0 Hz, H-4'); 7.53 (2H, d, J = 7.75 Hz, H-5, H-9); 7.42 (1H, d, J = 15.75 Hz, H-3); 7.29 (2H, d, J = 7.75 Hz, H-6, H-8); 7.03 - 6.97 (2H, m, H-6', H-7'); 6.44 (1H, d, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.95 (2H, s, H-13a, H-13b), 3.72 (3H, s, OCH3). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 162.67, 155.24, 143.69, 142.35, 137.64, 137.06, 136.20, 134.70, 128.49, 127.83, 123.59, 119.55, 116.85, 115.88, 113.11, 110.24, 55.67, 52.48, 34.71. Anal. Calcd. For C22H20N6O5(448.15):C, 58.92; H, 4.50; N, 18.74. Found: C, 58.95; H, 4.53; N, 18.71. HR-MS (ESI) m/z calculated for C22H19N6O5[M-H]- 447.1417.Found,447.1510 [M-H]- . Yellow solid; Yield 53%. mp: 211-212 o C. R f = 0.24 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3193 (OH), 3031 (CH, aren), 2834 (CH, CH 2 ), 1714,1659 (C = O), 1626,1481 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.15 (1H, s, H-12); 7.58 (1H, doublet, J = 2.0 Hz, H-4 '); 7.53 (2H, doublet, J = 7.75 Hz, H-5, H-9); 7.42 (1H, doublet, J = 15.75 Hz, H-3); 7.29 (2H, doublet, J = 7.75 Hz, H-6, H-8); 7.03-6.97 (2H, m, H-6 ', H-7'); 6.44 (1H, doublet, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 4.95 (2H, s, H-13a, H-13b), 3.72 (3H, s, OCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 162.67, 155.24, 143.69, 142.35, 137.64, 137.06, 136.20, 134.70, 128.49, 127.83, 123.59, 119.55, 116.85, 115.88, 113.11, 110.24, 55.67, 55.67. 34.71. Anal. Calcd. For C 22 H 20 N 6 O 5 (448.15): C, 58.92; H, 4.50; N, 18.74. Found: C, 58.95; H, 4.53; N, 18.71. HR-MS (ESI) m / z calculated for C 22 H 19 N 6 O 5 [M − H] − 447.1417. Found, 447.1510 [MH] − .
(7) (E)-3-(4-((4-((7-클로로-(히드록시이미노)-5-메톡시-2-옥소인돌린-1-일)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((7-Chloro-3-(hydroxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(7g)(7) (E) -3- (4-((4-((7-chloro- (hydroxyimino) -5-methoxy-2-oxoindolin-1-yl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((7-Chloro-3- (hydroxyimino) -2-oxoindolin- 1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (7g)
황색 고체; 수율: 52%. mp: 227 - 228oC. R f = 0.36 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm -1 ): 3381 (NH), 3181 (OH), 3016 (C-H, aren), 2920, 2878 (CH, CH2),1727,1651(C=O),1604,1467(C=C). 1 H-NMR(500MHz,DMSO-d 6 , ppm): δ 8.11 (1H, s, H-12); 8.09 (1H, dd, J = 8.0 Hz, J = 1.0 Hz, H-4'); 7.53 (2H, d, J = 8.0 Hz, H-5, H-9); 7.41 (1H, d, J = 16.0 Hz, H-3); 7.36 (1H, d, J = 8.0 Hz, H-6'); 7.25 (2H, d, J = 8.0 Hz, H-6, H-8); 7.09 (1H, t, J = 8.0 Hz, H-5'); 6.45 (1H, d, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 5.32 (2H, s, H-13a, H-13b). 13 CNMR(125MHz,DMSO-d 6 , ppm): δ 163.89, 162.54, 143.89, 142.21, 138.03, 137.59, 137.20, 134.64, 133.28, 128.27, 127.79, 125.38, 124.17, 122.89, 119.56, 118.46, 114.65, 52.43, 37.02. HR-MS (ESI) m/z calculated for C21H16ClN6O4[M-H]- 451.0922.Found,451.0939 [M-H]- . Yellow solid; Yield 52%. mp: 227-228 o C. R f = 0.36 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3381 (NH), 3181 (OH), 3016 (CH, aren), 2920, 2878 (CH, CH 2 ), 1727,1651 (C = O), 1604,1467 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm) : δ 8.11 (1H, s, H-12); 8.09 (1H, doublet of doublets, J = 8.0 Hz, J = 1.0 Hz, H-4 ′); 7.53 (2H, doublet, J = 8.0 Hz, H-5, H-9); 7.41 (1H, doublet, J = 16.0 Hz, H-3); 7.36 (1H, doublet, J = 8.0 Hz, H-6 '); 7.25 (2H, doublet, J = 8.0 Hz, H-6, H-8); 7.09 (1H, t, J = 8.0 Hz, H-5 '); 6.45 (1H, doublet, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b), 5.32 (2H, s, H-13a, H-13b). 13 CNMR (125 MHz, DMSO-d 6 , ppm) : δ 163.89, 162.54, 143.89, 142.21, 138.03, 137.59, 137.20, 134.64, 133.28, 128.27, 127.79, 125.38, 124.17, 122.89, 119.56, 118.46, 114.65, 114.65 37.02. HR-MS (ESI) m / z calculated for C 21 H 16 ClN 6 O 4 [MH] - 451.0922.Found, 451.0939 [MH] -.
제조예 3. N-히드록시 아크릴아마이드(화합물 11a-11g)의 합성Preparation Example 3 Synthesis of N-hydroxy Acrylamide (Compound 11a-11g)
화합물 11a-11g는 하기 반응식 3에 도시된 바와 같이, 화합물 8을 출발물질로 하여 세단계의 과정을 통하여 합성된다. 합성과정은 상기 제조예 2와 동일하게 실시하되, 출발물질로써 화합물 8을 이용한다. 화합물 11의 각 위치에 대한 번호는 표시예 2에 도시한 것과 동일하다.Compounds 11a-11g are synthesized through a three step process using Compound 8 as a starting material, as shown in Scheme 3 below. Synthesis was carried out in the same manner as in Preparation Example 2, using compound 8 as a starting material. The number for each position of compound 11 is the same as that shown in Display Example 2.
[반응식 3]Scheme 3
(1) (E)-N-히드록시-3-(4-((4-((3-(메톡시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(methoxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(11a)(1) (E) -N-hydroxy-3- (4-((4-((3- (methoxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (methoxyimino) -2-oxoindolin-1-yl) methyl ) -1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (11a)
황색 고체; 수율: 64%. mp: 217 - 218oC. Rf = 0.55 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3424 (NH); 3265 (OH); 3130 (CH, aren); 2939 (CH, CH2);1719(C=O);1632,1596(C=C).1H-NMR(500MHz,DMSO-d6, ppm): δ 10.77 (1H, s, NH); 9.05 (1H, s, OH); 8.18(1H,s,H-12);7.89(1H,d,J = 7.5 Hz, H-4'); 7.54 (2H, d, J = 8.0 Hz, H-5, H-9); 7.44 (1H, t, J = 7.5 Hz, H-6'); 7.42 (1H, d, J = 15.5 Hz, H-3); 7.29 (2H, d, J = 8.0 Hz, H-6, H-8); 7.13 (1H, d, J = 8.0 Hz, H-7'); 7.09 (1H, t, J = 8.0 Hz, H-5'); 6.45 (1H, d, J = 15.5 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.22 (3H, s, NOCH3). 13CNMR(125MHz,DMSO-d6, ppm): δ 162.00; 143.22; 142.10; 137.63; 137.03; 134.71; 132.86; 128.45; 127.82; 127.76; 127.33; 123.66; 122.92; 119.57; 115.00; 109.92; 64.54; 52.50; 34.78. HR-MS (ESI) m/z calculated for C22H19N6O4[M-H]- 431.1468.Found,431.1458 [M-H]-.Yellow solid; Yield 64%. mp: 217-218 o C. R f = 0.55 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3424 (NH); 3265 (OH); 3130 (CH, aren); 2939 (CH, CH 2 ); 1917 (C = O); 1632,1596 (C = C). 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 10.77 (1H, s, NH); 9.05 (1H, s, OH); 8.18 (1H, s, H-12); 7.89 (1H, d, J = 7.5 Hz, H-4 '); 7.54 (2H, doublet, J = 8.0 Hz, H-5, H-9); 7.44 (1H, t, J = 7.5 Hz, H-6 '); 7.42 (1H, doublet, J = 15.5 Hz, H-3); 7.29 (2H, doublet, J = 8.0 Hz, H-6, H-8); 7.13 (1H, doublet, J = 8.0 Hz, H-7 '); 7.09 (1H, t, J = 8.0 Hz, H-5 '); 6.45 (1H, doublet, J = 15.5 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.22 (3H, s, NOCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 162.00; 143.22; 142.10; 137.63; 137.03; 134.71; 132.86; 128.45; 127.82; 127.76; 127.33; 123.66; 122.92; 119.57; 115.00; 109.92; 64.54; 52.50; 34.78. HR-MS (ESI) m / z calculated for C 22 H 19 N 6 O 4 [M − H] − 431.1468.Found, 431.1458 [MH] − .
(2) (E)-3-(4-((4-((5-플루오로-3-(메톡시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((5-Fluoro-3-(methoxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(11b)(2) (E) -3- (4-((4-((5-fluoro-3- (methoxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2, 3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((5-Fluoro-3- (methoxyimino) -2-oxoindolin- 1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (11b)
황색 고체; 수율: 62%. mp: 209-211oC. Rf = 0.53 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3445 (NH); 3243 (OH); 3136 (CH, aren); 2940 (CH, CH2);1719(C=O);1608,1514(C=C).ESI-MS (m/z): 449.0 [M-H]-.1H-NMR(500MHz,DMSO-d6, ppm): δ 8.18 (1H, s, H-12); 7.68 (1H, dd, J = 8.0 Hz, J' = 2.5 Hz, H-4'); 7.53 (2H, d, J = 8.0 Hz, H-5, H-9); 7.42 (1H, d, J = 15.75 Hz, H-3); 7.32 (1H, td, J = 9.0 Hz, J' = 2.5 Hz, H-6'); 7.29 (2H, d, J = 8.0 Hz, H-6, H-8); 7.14 (1H, dd, J = 8.5 Hz, J' = 4.0 Hz, H-7'); 6.44 (1H, d, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.23 (3H, s, NOCH3). 13CNMR(125MHz,DMSO-d6, ppm): δ 161.57; 157.77; 142.67; 141.62; 139.39; 139.37; 136.57; 134.62; 128.10; 127.46; 123.28; 118.67; 115.32; 114.01; 110.65; 64.43; 52.32; 34.74. Anal. Calcd. For C22H19FN6O4(450.15):C, 58.66; H, 4.25; N, 18.66. Found: C, 58.69; H, 4.23; N, 18.65.Yellow solid; Yield 62%. mp: 209-211 o C. R f = 0.53 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3445 (NH); 3243 (OH); 3136 (CH, aren); 2940 (CH, CH 2 ); 1917 (C = O); 1608,1514 (C = C). ESI-MS (m / z): 449.0 [M − H] − . 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 8.18 (1H, s, H-12); 7.68 (1H, doublet of doublets, J = 8.0 Hz, J ′ = 2.5 Hz, H-4 ′); 7.53 (2H, doublet, J = 8.0 Hz, H-5, H-9); 7.42 (1H, doublet, J = 15.75 Hz, H-3); 7.32 (1H, t d, J = 9.0 Hz, J '= 2.5 Hz, H-6'); 7.29 (2H, doublet, J = 8.0 Hz, H-6, H-8); 7.14 (1H, doublet of doublets, J = 8.5 Hz, J ′ = 4.0 Hz, H-7 ′); 6.44 (1H, doublet, J = 15.75 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.23 (3H, s, NOCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 161.57; 157.77; 142.67; 141.62; 139.39; 139.37; 136.57; 134.62; 128.10; 127.46; 123.28; 118.67; 115.32; 114.01; 110.65; 64.43; 52.32; 34.74. Anal. Calcd. For C 22 H 19 FN 6 O 4 (450.15): C, 58.66; H, 4. 25; N, 18.66. Found: C, 58.69; H, 4. 23; N, 18.65.
(3) (E)-3-(4-((4-((5-클로로-3-(메톡시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((5-Chloro-3-(methoxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(11c)(3) (E) -3- (4-((4-((5-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3 -Triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((5-Chloro-3- (methoxyimino) -2-oxoindolin-1 -yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (11c)
황색 고체; 수율: 60%. mp: 219-220oC. Rf = 0.50 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3445 (NH); 3243 (OH); 3137 (CH, aren); 2940 (CH, CH2);1719(C=O);1608,1514(C=C). ESI-MS (m/z): 465.0 [M-H]-.1H-NMR(500MHz,DMSO-d6, ppm): δ 10.77(1H,s,NH);9.04(1H,s,OH);8.18 (1H, s, H-12); 7.85 (1H, s, H-4'); 7.65 (1H, d, J = 7.75 Hz, H-6'); 7.52 (2H, d, J = 7.5 Hz, H-5, H-9); 7.42 (1H, d, J = 16.0 Hz, H-3); 7.28 (2H, d, J = 7.5 Hz, H-6, H-8); 7.15 (1H, d, J = 7.75 Hz, H-7'); 6.51 (1H, d, J = 16.0 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.24 (3H, s, NOCH3). 13CNMR(125MHz,DMSO-d6, ppm): δ 161.62; 143.15; 142.41; 141.97; 141.84; 137.76; 134.70; 134.09; 132.24; 128.50; 127.80; 126.54; 123.69; 119.70; 116.13; 111.48; 64.83; 52.49; 34.91. Anal. Calcd. For C22H19ClN6O4(466.12):C, 56.60; H, 4.10; N, 18.00. Found: C, 56.63; H, 4.12; N, 17.97.Yellow solid; Yield 60%. mp: 219-220 o C. R f = 0.50 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3445 (NH); 3243 (OH); 3137 (CH, aren); 2940 (CH, CH 2 ); 1917 (C = O); 1608,1514 (C = C). ESI-MS (m / z): 465.0 [M − H] − . 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 10.77 (1H, s, NH); 9.04 (1H, s, OH); 8.18 (1H, s, H-12); 7.85 (1 H, s, H-4 '); 7.65 (1H, doublet, J = 7.75 Hz, H-6 '); 7.52 (2H, doublet, J = 7.5 Hz, H-5, H-9); 7.42 (1H, doublet, J = 16.0 Hz, H-3); 7.28 (2H, doublet, J = 7.5 Hz, H-6, H-8); 7.15 (1H, doublet, J = 7.75 Hz, H-7 '); 6.51 (1H, doublet, J = 16.0 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.98 (2H, s, H-13a, H-13b); 4.24 (3H, s, NOCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 161.62; 143.15; 142.41; 141.97; 141.84; 137.76; 134.70; 134.09; 132.24; 128.50; 127.80; 126.54; 123.69; 119.70; 116.13; 111.48; 64.83; 52.49; 34.91. Anal. Calcd. For C 22 H 19 ClN 6 O 4 (466.12): C, 56.60; H, 4.10; N, 18.00. Found: C, 56.63; H, 4. 12; N, 17.97.
(4) (E)-N-히드록시-3-(4-((4-((3-(메톡시이미노)--5-메틸-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(methoxyimino)-5-methyl-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(11e)(4) (E) -N-hydroxy-3- (4-((4-((3- (methoxyimino)-5-methyl-2-oxoindolin-1-yl) methyl) -1H -1,2,3-triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (methoxyimino) -5-methyl- 2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (11e)
황색 고체; 수율: 62%. mp: 203 - 204oC. Rf = 0.49 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3434 (NH); 3137 (CH, aren); 2922, 2852 (CH, CH2);1719(C=O);1617(C=C). ESI-MS (m/z): 339 [M+2H]-.1H-NMR (500 MHz, DMSO-d6, ppm): δ 8.16 (1H, s, H-12); 7.72 (1H, s, H-4'); 7.65 (2H, d, J = 7.5 Hz, H-5, H-9); 7.55 (1H, d, J = 16.0 Hz, H-3); 7.28 (2H, d, J = 7.5 Hz, H-6, H-8);7.23(1H,d,J = 7.5 Hz, H-6'); 7.00 (1H, d, J = 7.5 Hz, H-7'); 6.52 (1H, d, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 4.95 (2H, s, H-13a, H-13b); 4.20 (3H, s, NOCH3);2.26(3H,s,CH3).13CNMR(125MHz,DMSO-d6, ppm): δ 161.96; 143.31; 143.11; 142.13; 140.97; 137.79; 134.08; 133.02; 131.97; 128.49; 128.33; 127.74; 123.61; 119.76; 115.02; 109.65; 64.45; 52.43; 34.75; 20.41. Anal. Calcd. For C23H22N6O4(446.17):C, 61.87; H, 4.97; N, 18.82. Found: C, 61.85; H, 5.00; N, 18.86.Yellow solid; Yield 62%. mp: 203-204 o C. R f = 0.49 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3434 (NH); 3137 (CH, aren); 2922, 2852 (CH, CH 2 ); 1917 (C = O); 1615 (C = C). ESI-MS (m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 8.16 (1H, s, H-12); 7.72 (1H, s, H-4 '); 7.65 (2H, doublet, J = 7.5 Hz, H-5, H-9); 7.55 (1H, doublet, J = 16.0 Hz, H-3); 7.28 (2H, doublet, J = 7.5 Hz, H-6, H-8); 7.33 (1H, d, J = 7.5 Hz, H-6 '); 7.00 (1H, doublet, J = 7.5 Hz, H-7 '); 6.52 (1H, doublet, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 4.95 (2H, s, H-13a, H-13b); 4.20 (3H, s, NOCH 3 ); 2.26 (3H, s, CH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 161.96; 143.31; 143.11; 142.13; 140.97; 137.79; 134.08; 133.02; 131.97; 128.49; 128.33; 127.74; 123.61; 119.76; 115.02; 109.65; 64.45; 52.43; 34.75; 20.41. Anal. Calcd. For C 23 H 22 N 6 O 4 (446.17): C, 61.87; H, 4.97; N, 18.82. Found: C, 61.85; H, 5.00; N, 18.86.
(5) (E)-N-히드록시-3-(4-((4-((3-(메톡시이미노)-5-메톡시-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)아크릴아마이드((E)-N-Hydroxy-3-(4-((4-((3-(methoxyimino)-5-methoxy-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)acrylamide)(11f)(5) (E) -N-hydroxy-3- (4-((4-((3- (methoxyimino) -5-methoxy-2-oxoindolin-1-yl) methyl) -1H -1,2,3-triazol-1-yl) methyl) phenyl) acrylamide ((E) -N-Hydroxy-3- (4-((4-((3- (methoxyimino) -5-methoxy- 2-oxoindolin-1-yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) acrylamide) (11f)
황색 고체; 수율: 58%. mp: 207 - 208oC. Rf = 0.53 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3432 (NH); 3139 (OH); 2939 (CH, CH2);1719(C=O);1632,1595(C=C). ESI-MS (m/z): 339 [M+2H]-.1H-NMR (500 MHz, DMSO-d6, ppm): δ 10.76 (1H, s, NH); 9.03 (1H, s, OH); 8.16 (1H, s, H-12); 7.66 (1H, d, J = 8.0 Hz, H-7'); 7.54 (2H, d, J = 7.5 Hz, H-5, H-9); 7.47 (1H, s, H-4'); 7.42 (1H, d, J = 16.0 Hz, H-3); 7.28 (2H, d, J = 7.5 Hz, H-6, H-8); 7.03 (1H, d, J = 8.0 Hz, H-6'); 6.51 (1H, d, J = 16.0 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.95 (2H, s, H-13a, H-13b); 4.21 (3H, s, NOCH3);3.73(3H,s,OCH3). 13CNMR(125MHz,DMSO-d6, ppm): δ 167.51; 161.88; 155.33, 143.47; 143.34; 137.71; 136.84; 134.06; 128.88; 128.53; 127.84; 123.62; 119.59; 117.69; 115.57; 113.73; 110.55; 64.62; 55.78; 53.22; 34.82. Anal. Calcd. For C23H22N6O5(462.17):C, 59.73; H, 4.79; N, 18.17. Found: C, 59.75; H, 4.77; N, 18.20.Yellow solid; Yield 58%. mp: 207-208 o C. R f = 0.53 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3432 (NH); 3139 (OH); 2939 (CH, CH 2 ); 1917 (C = O); 1632,1595 (C = C). ESI-MS (m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 10.76 (1H, s, NH); 9.03 (1H, s, OH); 8.16 (1 H, s, H-12); 7.66 (1H, doublet, J = 8.0 Hz, H-7 ′); 7.54 (2H, doublet, J = 7.5 Hz, H-5, H-9); 7.47 (1H, s, H-4 '); 7.42 (1H, doublet, J = 16.0 Hz, H-3); 7.28 (2H, doublet, J = 7.5 Hz, H-6, H-8); 7.03 (1H, doublet, J = 8.0 Hz, H-6 '); 6.51 (1H, doublet, J = 16.0 Hz, H-2); 5.57 (2H, s, H-10a, H-10b); 4.95 (2H, s, H-13a, H-13b); 4.21 (3H, s, NOCH 3 ); 3.73 (3H, s, OCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 167.51; 161.88; 155.33, 143.47; 143.34; 137.71; 136.84; 134.06; 128.88; 128.53; 127.84; 123.62; 119.59; 117.69; 115.57; 113.73; 110.55; 64.62; 55.78; 53.22; 34.82. Anal. Calcd. For C 23 H 22 N 6 O 5 (462.17): C, 59.73; H, 4.79; N, 18.17. Found: C, 59.75; H, 4.77; N, 18.20.
(6) (E)-3-(4-((4-((7-클로로-3-(메톡시이미노)-2-옥소인돌린-1-일)메틸)-1H-1,2,3-트리아졸-1-일)메틸)페닐)-N-히드록시아크릴아마이드((E)-3-(4-((4-((7-Chloro-3-(methoxyimino)-2-oxoindolin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)phenyl)-N-hydroxyacrylamide)(11g)(6) (E) -3- (4-((4-((7-chloro-3- (methoxyimino) -2-oxoindolin-1-yl) methyl) -1H-1,2,3 -Triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide ((E) -3- (4-((4-((7-Chloro-3- (methoxyimino) -2-oxoindolin-1 -yl) methyl) -1H-1,2,3-triazol-1-yl) methyl) phenyl) -N-hydroxyacrylamide) (11g)
황색 고체; 수율: 66%. mp: 219-221oC. Rf = 0.50 (DCM : MeOH : AcOH = 90 : 5 : 1). IR (KBr, cm-1): 3424 (NH); 3265 (OH); 3130 (CH, aren); 2939 (CH, CH2);1719(C=O);1633,1596(C=C). ESI-MS (m/z): 339 [M+2H]-.1H-NMR (500 MHz, DMSO-d6, ppm): δ 10.76 (1H, s, NH); 9.04 (1H, s, OH); 8.14 (1H, s, H-12); 7.94 (1H, d, J = 7.0 Hz, H-4'); 7.56 - 7.53 (2H, m, H-3, H-6'); 7.43 (2H, d, J = 8.0 Hz, H-5, H-9); 7.26 (2H, d, J = 8.0 Hz, H-6, H-8); 7.10 (1H, t, J = 7.5 Hz, H-5'); 6.51 (1H, d, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 5.31 (2H, s, H-13a, H-13b); 4.25 (3H, s, NOCH3). 13CNMR(125MHz,DMSO-d6, ppm): δ 167.44; 162.85; 143.57; 143.17; 141.95; 139.03; 137.66; 134.64; 128.49; 127.78; 126.34; 124.35; 122.91; 117.99; 114.99; 64.91; 52.45; 37.02. Anal. Calcd. For C22H19ClN6O4(466.12):C, 56.60; H, 4.10; N, 18.00. Found: C, 56.61; H, 4.15; N, 18.02.Yellow solid; Yield 66%. mp: 219-221 o C. R f = 0.50 (DCM: MeOH: AcOH = 90: 5: 1). IR (KBr, cm −1 ): 3424 (NH); 3265 (OH); 3130 (CH, aren); 2939 (CH, CH 2 ); 1917 (C = O); 1633,1596 (C = C). ESI-MS (m / z): 339 [M + 2H] - . 1 H-NMR (500 MHz, DMSO-d 6 , ppm): δ 10.76 (1H, s, NH); 9.04 (1H, s, OH); 8.14 (1 H, s, H-12); 7.94 (1H, doublet, J = 7.0 Hz, H-4 ′); 7.56-7.53 (2H, m, H-3, H-6 '); 7.43 (2H, doublet, J = 8.0 Hz, H-5, H-9); 7.26 (2H, doublet, J = 8.0 Hz, H-6, H-8); 7.10 (1H, t, J = 7.5 Hz, H-5 '); 6.51 (1H, doublet, J = 16.0 Hz, H-2); 5.56 (2H, s, H-10a, H-10b); 5.31 (2H, s, H-13a, H-13b); 4.25 (3H, s, NOCH 3 ). 13 CNMR (125 MHz, DMSO-d 6 , ppm): δ 167.44; 162.85; 143.57; 143.17; 141.95; 139.03; 137.66; 134.64; 128.49; 127.78; 126.34; 124.35; 122.91; 117.99; 114.99; 64.91; 52.45; 37.02. Anal. Calcd. For C 22 H 19 ClN 6 O 4 (466.12): C, 56.60; H, 4.10; N, 18.00. Found: C, 56.61; H, 4. 15; N, 18.02.
실험예 1. 항암활성 평가를 위한 암세포주에 대한 세포독성 분석Experimental Example 1. Cytotoxicity Analysis of Cancer Cell Lines for Anticancer Activity Evaluation
SW620 (대장암세포), PC3 (전립선암세포), 및 AsPC-1(췌장암세포) 세포주의 인간 암세포주는 한국생명공학연구소(Korea Research Institute of Bioscience and Biotechnology, KRIBB)에 있는 암세포 은행으로부터 구입하였으며, 이를 이용하여 상기 제조예 1 내지 3에서 합성된 화합물의 암세포주에 대한 세포독성을 분석하였다. 세포독성 분석에서 세포 배양을 위한배지, 혈청 및 다른 시약들은 GIBCO Co. Ltd.(Grand Island, New York, USA)로부터 구입하였다. 세포들은 DMEM(Dulbecco's Modified Eagle Medium)에서 밀집(confluence)까지 배양된다. 세포들은 트립신으로 처리되고, 세포 배양 배지에 3 × 104 cells/mL의 농도로 부유된다. 첫날, 96 웰 플레이트의 각각의 웰에 180 μL의 세포현탁액으로 분주한다. 플레이트는 37 ℃에서 24 시간 동안 5 % CO2 인규베이터에서 배양된다. 화합물을 초기에 디메틸설폭사이드(DMSO)에 용해시키고, 배양배지에 의하여 적정 농도로 희석하였다. 이후, 상기의 각각 화합물 샘플 20 μL를, 다양한 농도로 세로 현탁액으로 분주하고 24 시간동안 배양된 96 웰 플레이트의 각각의 웰에 첨가하였다. 각 플레이트를 48 시간 동안 추가적으로 배양하였다. 각각의 화합물들의 세포독성은 다소 변형된 비색법(colorimetric method, Skehan, P.; Storeng, R.; Scudiero, D.; Monk, A.; MacMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd. M.R. New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.)에 의하여 측정하였다. IC50 값은 Probit 방법으로 계산되었으며, 각 화합물에 대해 측정한 값은 3회의 독립적 측정결과(SD≤10%)의 평균 값으로 나타내었다.Human cancer cell lines of SW620 (colon cancer cells), PC3 (prostate cancer cells), and AsPC-1 (pancreatic cancer cells) cell lines were purchased from the cancer cell bank at the Korea Research Institute of Bioscience and Biotechnology (KRIBB). The cytotoxicity to the cancer cell lines of the compounds synthesized in Preparation Examples 1 to 3 were analyzed. Media, serum and other reagents for cell culture in cytotoxicity assays were determined by GIBCO Co. Ltd. (Grand Island, New York, USA). Cells are cultured from Dulbecco's Modified Eagle Medium (DMEM) to confluence. Cells are treated with trypsin and suspended in cell culture medium at a concentration of 3 × 10 4 cells / mL. On the first day, each well of a 96 well plate is dispensed with 180 μL of cell suspension. Plates are incubated in a 5% CO 2 incubator for 24 hours at 37 ° C. The compound was initially dissolved in dimethylsulfoxide (DMSO) and diluted to the appropriate concentration by the culture medium. 20 μL of each of the above compound samples were then added to each well of a 96 well plate, which was dispensed in a longitudinal suspension at various concentrations and incubated for 24 hours. Each plate was further incubated for 48 hours. Cytotoxicity of the individual compounds was somewhat modified by the colorimetric method, Skehan, P .; Storeng, R .; Scudiero, D .; Monk, A .; MacMahon, J .; Vistica, D .; Warren, JT; Bokesch , H .; Kenney, S .; Boyd.MR New colorimetric cytotoxicity assay for anticancer drug screening. J. Natl. Cancer Inst. , 1990, 82, 1107-1112. IC 50 values were calculated using the Probit method, and the measured values for each compound were expressed as the average of three independent measurements (SD≤10%).
실험예 2. HDAC2 효소 분석Experimental Example 2 HDAC2 Enzyme Assay
HDAC2 효소는 BPS Bioscience (San Diego, CA, USA)로부터 구입하고, HDAC 효소 활성 분석은 제조사 지시서에 따라 형광 HDAC 분석 키트 (BPS Bioscience)를 사용하여 행하였다. 간략히 설명하면, HDAC2 효소들을 HDAC 형광 기질의 존재하에서 37 ℃에서 30 분간 비히클(vehicle) 또는 다양한 농도의 분석 시료 또는 SAHA와 함께 배양하였다. 반응 혼합물에서 형광단을 생성하는 HDAC 분석 현상액을 첨가하고, VICTOR3 (PerkinElmer, Waltham, MA, USA)을 사용하여 여기 파장 360 nm 및 방출 파장 460 nm으로 형광을 측정하였다. 측정된 활성에서 비히클-처리된 대조군 효소 활성을 차감하고, IC50 값은 GraphPad Prism (GraphPad Software, San Diego, CA, USA)을 사용하여 측정하였다.HDAC2 enzyme was purchased from BPS Bioscience (San Diego, Calif., USA) and HDAC enzyme activity assay was performed using a fluorescent HDAC assay kit (BPS Bioscience) according to manufacturer's instructions. Briefly, HDAC2 enzymes were incubated with vehicle or various concentrations of analytical samples or SAHA for 30 minutes at 37 ° C. in the presence of an HDAC fluorescent substrate. HDAC assay developer generating fluorophores in the reaction mixture was added and fluorescence was measured at excitation wavelength 360 nm and emission wavelength 460 nm using VICTOR3 (PerkinElmer, Waltham, MA, USA). Subtracted vehicle-treated control enzyme activity from measured activity and IC50 values were determined using GraphPad Prism (GraphPad Software, San Diego, Calif., USA).
실험예 3. 도킹 연구Experimental Example 3. Docking Study
AutoDock Vina program(The Scripps Research Institute, CA, USA)를 사용하여 도킹 연구(dockingstudy)를 수행하였다. SAHA와의 복합체를 형성하는 HDAC2의 구조들은 Protein Data Bank (PDB)(PDB ID: 4LXZ)으로부터 얻었다. 화합물들에 대한 좌표들은 GlycoBioChem PRODRG2 Server(http://davapc1.bioch.dundee.ac.uk/prodrg/)를 사용하여 생성하였다. 도킹 연구에 대한 그리드 맵(grid map)은 SAHA 결합자리상의 중앙에 위치하게 하였고, 복합체 구조로부터 SAHA를 제거한 후에 1.0 의 간격으로 26 x 26 x 22 포인트를 포함하도록 하였다. AutoDock Vina program을 eight-way multithreading으로 수행시키고, 다른 파라미터들은 AutoDock Vina program에서 디폴트 세팅으로 하였다.Docking studies were performed using the AutoDock Vina program (The Scripps Research Institute, CA, USA). The structures of HDAC2, which form a complex with SAHA, were obtained from Protein Data Bank (PDB) (PDB ID: 4LXZ). Coordinates for the compounds were generated using the GlycoBioChem PRODRG2 Server (http://davapc1.bioch.dundee.ac.uk/prodrg/). The grid map for the docking study was centered on the SAHA binding site and included 26 x 26 x 22 points at intervals of 1.0 after removal of the SAHA from the complex structure. The AutoDock Vina program was run in eight-way multithreading and the other parameters were set to the default settings in the AutoDock Vina program.
실험결과 및 고찰Experimental Results and Discussion
1. 화합물의 합성1. Synthesis of Compound
히드록삼산(hydroxamic acid) 4 내지 5는 반응식 1에 도시된 바와 같이, 3 단계의 과정을 통하여 합성되었다. 최초단계는, 디메틸폼아마이드(DMF) 존재 하에 염기조건(K2CO3)에서 및 프로파르길이사틴(2)을 제공하기 위한 촉매량의 KI의 조건에서의 이사틴(1)과 브롬화프로파르길의 친핵성 치환반응이다. 두 번째 단계는, 에스터 중간체(3)을 제공하기 위한 프로파르길 화합물(2)와 각각의 메틸 아지도알카노에이트(methyl azidoalkanoates)(including methyl 6-azidohexanoate, and methyl 7-azidohexanoate)와의 클릭 반응(Click reaction)이다. 이 반응은 천천히 반응이 진행되며, 용매로서 아세토나이트릴(acetonitrile)과 촉매로서 요오드화 구리(CuI, cupric iodide)를 이용하였다. 전체 과정에서, 에스터 중간체는 반응 잔여물의 적정에 의하여 침전되며, 찬물에서 아세토나이트릴의 증발에 의하여 얻어진다. 최종단계는 히드록실아민 히드록클로라이드(hydroxylamine hydrochloride)와 에스터(3)의 친핵성 아실 치환 반응을 포함한다. 이 반응은 0 내지 5 ℃에서 테트라히드로퓨란과 메탄올을 포함하는 용매 혼합물과 알칼리 조건하에 발생된다. 화합물 4, 5의 전체 수율은 적정수준이다.Hydroxamic acid 4 to 5 was synthesized through a three step process, as shown in Scheme 1. The first step is isatin (1) and propargyl bromide under basic conditions (K 2 CO 3 ) in the presence of dimethylformamide (DMF) and under conditions of catalytic amount of KI to provide propargylsatin (2). Is a nucleophilic substitution reaction. The second step is a click reaction of propargyl compound (2) with respective methyl azidoalkanoates (including methyl 6-azidohexanoate, and methyl 7-azidohexanoate) to provide an ester intermediate (3). (Click reaction). The reaction proceeded slowly, using acetonitrile as a solvent and copper iodide (CuI, cupric iodide) as a catalyst. In the whole process, the ester intermediate is precipitated by titration of the reaction residue and is obtained by evaporation of acetonitrile in cold water. The final step involves the nucleophilic acyl substitution reaction of hydroxylamine hydrochloride with ester (3). This reaction takes place under alkaline conditions with a solvent mixture comprising tetrahydrofuran and methanol at 0-5 ° C. Overall yields of compounds 4 and 5 are at appropriate levels.
화합물 7a 내지 7g는 반응식 2에 도시된 바와 같이, 3 단계의 과정을 통하여 합성되었다. 반응과정은 화합물 4 내지 5의 과정과 유사하나, methyl azidoesters 대신에 4-azidomethylcinnamate를 이용하였다. 화합물 11a 내지 11g는 반응식 3에 도시된 바와 같이 3 단계의 과정을 통하여 화합물 8로부터 합성되었다. 반응과정은 화합물 7a 내지 7g의 과정과 유사하며, 출발물질인 화합물 8은 인용문헌(Nam, N.H.; Huong, T.L.; Dung, D.T.M.; Oanh, D.T.K.; Dung, P.T.P.; Quyen, D.; Kim, K.R.; Han, B.W.; Kim, Y.S.; Hong, J.T.; Han, S.B. Novel isatin-based hydroxamic acids as histone deacetylase inhibitors and antitumor agents. Eur. J. Med. Chem., 2013, 70, 477-486)에 의하여 얻을 수 있다.
합성된 화학물의 구조는 IR, MS, 1H 및 1C NMR을 포함하는 스페특럼 데이터의 분석에 기반하여 결정된다. 히드록실아민과 인돌린 고리 3번 위치의 옥소 그룹과의 동시 축합반응은 상기 조건하에 발생되었다. The structure of the synthesized chemical is determined based on analysis of speculum data including IR, MS, 1 H and 1 C NMR. Co-condensation of hydroxylamine with an oxo group at position 3 of the indolin ring occurred under these conditions.
2. 생물학적 활성2. Biological Activity
합성한 히드록삼산(화합물 4a 내지 4g, 5a 내지 5g, 7a 내지 7g, 11a 내지 11g)는 잠재적으로 HDAC 저해제로서 활동하는 세포독성제로서 설계되었으므로, 우선적으로 SW620 (대장암세포), PC3 (전립선암세포), AsPC-1(췌장암세포) 및 NCI-H23(폐암세포)의 4개의 인간 암세포주에 대한 각 화합물들의 세포독성을 다소 변형된 SRB(sulforhodmine B) 세포 증식 분석을 이용하여 스크리닝하였다. IC50 값(μM)은 Probit 방법으로 계산되었으며, 각 화합물에 대해 측정한 값은 3회의 독립적 측정결과의 평균 값으로 나타내었다. 이 결과를 하기 표 1에 정리하였으며, SAHA를 양성조절제로 이용하였으며 SAHA의 IC50 값(μM) 또한, 표 1에 정리하였다.Synthetic hydroxamic acid (compounds 4a to 4g, 5a to 5g, 7a to 7g, 11a to 11g) was designed as a cytotoxic agent that potentially acts as an HDAC inhibitor, and therefore, preferentially SW620 (colon cancer cells), PC3 (prostate cancer cells) ), AsPC-1 (pancreatic cancer cells) and NCI-H23 (lung cancer cells) cytotoxicity of each compound against four human cancer cell lines were screened using a slightly modified sulforhodmine B cell proliferation assay. IC 50 values (μM) were calculated by the Probit method, and the measured values for each compound were expressed as the average of three independent measurements. The results are summarized in Table 1 below, SAHA was used as a positive regulator and IC 50 values (μM) of SAHA were also summarized in Table 1.
compound
R
MW
LogP 1
Cytotoxicity (IC 50 , 2 mM) / Cell lines 3
Inhibition
(IC50, 2 mM)
HDAC2
Inhibition
(IC 50 , 2 mM)
(1Calculated by ChemDraw 9.0 software; 2The concentration (mM) of compounds that produces a 50% reduction in enzyme activity or cell growth, the numbers represent the averaged results from triplicate experiments with deviation of less than 10%.; 3Celllines:SW620,colon cancer; PC3, prostate cancer; AsPC-1, pancreatic cancer; NCI-H23, lung cancer; 4SAHA,suberoylanilideacid,apositivecontrol.)( 1 Calculated by ChemDraw 9.0 software; 2 The concentration (mM) of compounds that produces a 50% reduction in enzyme activity or cell growth, the numbers represent the averaged results from triplicate experiments with deviation of less than 10% .; 3 Celllines: SW620, colon cancer; PC3, prostate cancer; AsPC-1, pancreatic cancer; NCI-H23, lung cancer; 4 SAHA, suberoylanilideacid, apositivecontrol.)
상기 표 1을 참조하면, N-히드록시알칸아마이드 타입의 히드록삼산의 경우(화합물 4a 내지 4g, 5a 내지 5g), 히드록삼산 부분과 1-((1H-1,2,3-트리아졸-4-일)메틸)-3-치환된-인돌린-2-온 사이의 6C 사슬을 가지는 화합물(5a 내지 5g)가 5C 사슬을 가지는 화합물(4a 내지 4g)과 비교하여 상당히 높은 세포독성을 보였다. Referring to Table 1, in the case of the N-hydroxyalkanamide type of hydroxamic acid (Compounds 4a to 4g, 5a to 5g), the hydroxamic acid portion and 1-((1H-1,2,3-triazole Compounds with 6C chains between -4-yl) methyl) -3-substituted-indolin-2-ones (5a to 5g) have significantly higher cytotoxicity compared to compounds with 5C chains (4a to 4g) Seemed.
전자 흡인기(electron withdrawing groups)과 전자 방출기(electron releasing group)에 따른 영향은 명확히 구별되지 않았다(화합물 5b, 5d vs. 화합물 5e, 5f; 화합물 4b, 4d vs. 화합물 4e, 4f). 치환기의 위치에 따른 영향과 관련하여, 5번 위치에서 치환기가 7번 위치에서의 치환기보다 유리한 것으로 확인되었다. 보다 구체적으로, 화합물 5c(IC50 값, 3.25 내지 5.06 μM)은 화합물 5g(IC50 값, 5.54 내지 9.15 μM)보다 상당히 높은 세포독성을 가진다. 특히, 화합물 4(IC50 값, 3.74 내지 12.49 μM)의 세포독성은 화합물 4g(IC50 값, 15.68 내지 43.31 μM)의 세포독성 보다 상당히 강하였다. 그러나, 일반적으로 이러한 화합물은 세포독성과 관련하여 강한 것이 아니다. 화합물 4a 내지 4g와 화합물 5a 내지 5g의 14 종의 화합물 중에서, 3 종의 화합물(화합물 5c, 5d 및 5 e)만이 낮은 마이크로함량의 범위에서 4개 인간 암세포주 실험 시, 상대적으로 우수한 IC50 값에 따른 세포독성 프로파일을 보여주었으며, 상기의 세 개의 화합물의 IC50 값만이 SAHA의 IC50 값과 유사하였다.The effects of electron withdrawing groups and electron releasing groups were not clearly distinguished (
본 발명의 히드록삼산이 HDAC 저해제로서 거동하는 확인하기 위하여, HDAC2를 이용하여 HDAC 억제 활성에 대하여 화합물을 스크리닝하였다. 다수의 히스톤 단백질을 탈아세틸화하므로, HDAC2를 초기 스크리닝 대상으로 하였다. HDAC2는 암세포 증식과 관련된 여러 분야에서 많은 중요한 역할을 수행하는 것을 입증되었으며, 세포자멸(apoptosis)의 억제를 야기하는 중요 단백질 중 하나이다. 화합물 4a 내지 4g, 화합물 5a 내지 5g의 HDAC2 억제 활성은 표 1에 정리하였으며, 표 1을 참조하면, 화합물 4a, 4b, 4f, 4g를 제외한 상기 화합물들의 HADC2 억제 능력은 SAHA의 수준에 이른다. HDAC2 억제와 관련하여, 3 종의 화합물(화합물 4d, 5a, 5e)는 SAHA 보다 다소 높은 활성을 보였다. 그러나, 강한 HDAC2 저해능이 항상 우수한 세포독성과 관련되는 것은 아니다. 구체적으로, 화합물 4d는 HDAC2 저해와 관련하여 0.93 μM의 IC50 값을 가지나, SRB 분석에서 IC50 값은 10.50 내지 19.74 μM으로 상대적으로 높은 값을 가진다. 그럼에도, 화합물 4a 내지 4g, 화합물 5a 내지 5g는 HDAC2 저해와 세포독성 사이의 높은 관련성을 보인다. 구체적으로, 화합물 5e는 우수한 HDAC2 저해 활성(IC50, 0.75 μM)과 우수한 세포독성 프로파일(IC50, 1.95 내지 3.15 μM)을 가지며, 화합물 4g는 가장낮은 HDAC2 저해 활성(IC50, 6.15 μM)과 4개의 인간 암세포주에 대하여 가장 낮은 세포독성 프로파일(IC50, 15.68 내지 43.31 μM)을 가진다.In order to confirm that the hydroxamic acid of the present invention behaves as an HDAC inhibitor, the compounds were screened for HDAC inhibitory activity using HDAC2. Since many histone proteins are deacetylated, HDAC2 was targeted for initial screening. HDAC2 has been shown to play many important roles in several fields related to cancer cell proliferation and is one of the important proteins that causes the inhibition of apoptosis. The HDAC2 inhibitory activity of Compounds 4a to 4g and Compounds 5a to 5g are summarized in Table 1, and referring to Table 1, the HADC2 inhibitory ability of the compounds except for Compounds 4a, 4b, 4f, and 4g reaches the level of SAHA. With respect to HDAC2 inhibition, three compounds (
전체적으로, N-하이드록시프로펜아마이드(화학물 7a 내지 7g)는 화합물 5a 내지 5g와 비교하여 다소 향상된 세포독성을 보인다. 전자 흡인 또는 전자 방출과는 무관한, 5번 또는 7번 위치에서의 치환은 다소 또는 상당히 세포 독성을 강화하였다(화합물 7b 내지 7g vs. 화합물 7a). 4종의 화합물(화합물 7c 내지 7f)는 세폭독성 분석에서 SAHA와 유사하였다. 7번 위치에서 치환은 5번 위치에 치환보다 세포독성에 보다 적합하였다(화합물 7g vs. 화합물 7c). 4개의 인간 암세포주에 대한 분석에서, 화합물 7g는 가장 강력한 세포독성 효과를 보였으며, 대략 SAHA보다 5 내지 6 배 높은 세포독성을 보였다(화합물 7g IC50, 0.62 sowl 0.83 μM vs. SAHA IC50, 3.18 내지 3.75 μM)Overall, N-hydroxypropeneamide (
화합물 11a 내지 11g에서, 화합물 11c 및 화합물 11g는 각각 5번과 7번 위치에서 염소(chlorine)을 포함하며, 화합물 7g 수준의 세포독성 효능을 보인다. 특히, 화합물 11c는 SAHA 보다 10배 정도 세포독성이 향상되었으며, 이는 본 발명의 화합물 중에서 가장 높은 세포독성 효력에 해당한다. 한편, 화합물 11e와 11f는 전자 방출기(electron releasing groups)이 세포독성을 다소 약화시킨 것으로 보인다. 화합물 11e와 11f는 화합물 11a 내지 11g 사이에서, 가장 낮은 세포독성을 보인다. 또한, 화합물 11e와 11f는 HDAC2 저해 활성이 가장 낮다. 따라서, 화합물들의 세포독성과 HDAC2 저해 능력과의 관련성을 상세히 기술하지 않았으나, 본 발명의 결과로부터 어느 정도의 관련성이 관찰된다.In compounds 11a to 11g, compound 11c and compound 11g contain chlorine at positions 5 and 7, respectively, and exhibit cytotoxic efficacy of 7 g of compound. In particular, compound 11c has a 10-fold improvement in cytotoxicity than SAHA, which corresponds to the highest cytotoxic effect among the compounds of the present invention. Compounds 11e and 11f, on the other hand, appear to have somewhat weakened cytotoxicity by electron releasing groups. Compounds 11e and 11f show the lowest cytotoxicity between compounds 11a-11g. In addition, compounds 11e and 11f have the lowest HDAC2 inhibitory activity. Thus, although the relationship between the cytotoxicity of the compounds and the ability to inhibit HDAC2 has not been described in detail, some relevance is observed from the results of the present invention.
3. 도킹 연구3. Docking Research
히스톤-H3 및 히스톤-H4 탈아세틸화는 주로 HDAC2와 HDAC3에 의하여 조절된다. SAHA(PDB ID: 4LXZ)와의 복합체 내 HDAC2의 결정구조는 Lauffer 및 공동 연구자들에 의하여 보고되었다.(Wu, L.; Smythe, A.M.; Stinson, S.F.; Mullendore, L.A.; Monks, A.; Scudiero, D.A.; Paull, K.D.; Koutsoukos, A.D.; Rubinstein, L.V.; Boyd, M.R.; Shoemaker, R.H. Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res., 1992, 52, 3029-3034.) 따라서, 히드록삼산과 HDAC와의 상호관련성을 분석하기 위하여 도킹 실험을 위한 도킹 템플레이트로서 SAHA와의 복합체 내 HDAC2의 결정구조를 선정하였다. 복합체 구조로부터 SAHA를 제거한 후에 AutoDock Vina program을 이용하여 HDAC2 결정구조에 대해 SAHA와 함께 대조군 도킹실험을 수행하였다. 실험결과를 하기 표 2에 정리하였다.Histone-H3 and histone-H4 deacetylation are mainly regulated by HDAC2 and HDAC3. The crystal structure of HDAC2 in complex with SAHA (PDB ID: 4LXZ) has been reported by Lauffer and co-workers (Wu, L .; Smythe, AM; Stinson, SF; Mullendore, LA; Monks, A .; Scudiero, DA; Paull, KD; Koutsoukos, AD; Rubinstein, LV; Boyd, MR; Shoemaker, RH Multidrug-resistant phenotype of disease-oriented panels of human tumor cell lines used for anticancer drug screening. Cancer Res ., 1992 , 52 , 3029 Therefore, the crystal structure of HDAC2 in the complex with SAHA was selected as a docking template for the docking experiment to analyze the correlation between hydrosamic acid and HDAC. After removing the SAHA from the complex structure, a control docking experiment with SAHA was performed on the HDAC2 crystal structure using the AutoDock Vina program. The experimental results are summarized in Table 2 below.
본 도킹 실험에서, 본 발명에서 합성된 히드록삼산은 SAHA 보다 높은 결합 친화성(Binding Afficity)를 가지면서 효소의 활성부위에 위치하였다. 이들 화합물의 안정화 에너지는 -7.0 내지 ??9.8 kcal/mol로서 SAHA와 비교하여 유사하거나 매우 낮은 값을 가진다. 구체적으로, HDAC2에 대한 예상되는 결합 모드의 안정화 에너지는 화합물 7a 및 7c에 대하여 각각 ??9.7 및 ??9.8 kcal/mol이 될 것으로 계산되었는데, 반면 SAHA에 대한 안정화 에너지 값은 ??7.4 kcal/mol이었다(결정구조에서 원래 SAHA로부터의 r.m.s.d 거리는 0.609/2.056 Å이다). 도킹 실험결과, 아연이온(회색 구)은 HDAC2의 3개 잔기인 Asp181, His183 및 Asp269에 의해 배위결합 되었다. 본 발명에서 합성된 화합물들 모두는 SAHA의 방식과 유사한 방식으로 아연이온과 결합하였다. 모든 화합물에서, 인돌린과 히드록삼산 부위를 연결하는 1-alkyl-4-methyl-1H-1,2,3-triazole이 Phe155 및 Phe210 사이에 단단히 끼워져 들어가는 것이 확인되었으며(도 1 내지 도 4 참조), 이러한 끼워져 들어가는 구조에 의한 상호작용이 화합물들과 HDAC2와의 높은 결합 친화도에 기여할 것이다. In this docking experiment, the hydroxamic acid synthesized in the present invention was located at the active site of the enzyme with a higher binding affinity than SAHA. Stabilization energies of these compounds range from -7.0 to ?? 9.8 kcal / mol and have similar or very low values compared to SAHA. Specifically, the expected stabilization energy of binding mode for HDAC2 was calculated to be ?? 9.7 and ?? 9.8 kcal / mol for
결론conclusion
본 발명에서 강한 HDAC2 저해 활성 및 4개의 인간 암세포주(SW620(대장암세포), PC3(전립선암세포), AsPC-1(췌장암세포) 및 NCI-H23(폐암세포))에 대하여 강한 세포독성을 가지는 4-methyl-1H-1,2,3-triazole 링커를 포함하는 3-hydroxyimino-2-ocoindoline 기반 히드록삼산의 4개의 시리즈 화합물을 합성하였다. 본 결과로부터 3-hydroxyimino-2-oxoindolines는 히드록삼산 HDAC 저해제로서의 보호기를 제공함을 알 수 있다. 또한, 3-hydroxyimino-2-oxoindoline 부위의 벤젠 고리에서의 상이한 치환은 상당부분 화합물의 HDAC 저해와 세포독성 특성에 영향을 미친다. 특히, 1-alkyl-4-methyl-1H-1,2,3-triazole 링커는 HDAC 저해 활성에 영향이 있다.In the present invention, 4 having strong HDAC2 inhibitory activity and strong cytotoxicity against four human cancer cell lines (SW620 (colon cancer cells), PC3 (prostate cancer cells), AsPC-1 (pancreatic cancer cells) and NCI-H23 (lung cancer cells)) Four series compounds of 3-hydroxyimino-2-ocoindoline-based hydroxamic acid containing -methyl-1H-1,2,3-triazole linker were synthesized. From the results, it can be seen that 3-hydroxyimino-2-oxoindolines provide a protecting group as a hydroxamic acid HDAC inhibitor. In addition, different substitutions in the benzene ring at the 3-hydroxyimino-2-oxoindoline site significantly affect HDAC inhibition and cytotoxic properties of the compounds. In particular, 1-alkyl-4-methyl-1H-1,2,3-triazole linker has an effect on HDAC inhibitory activity.
이상, 본 발명내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적인 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의해 정의된다고 할 것이다. As mentioned above, specific portions of the present disclosure have been described in detail, and it is apparent to those skilled in the art that such specific techniques are merely preferred embodiments, and thus the scope of the present disclosure is not limited thereto. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (7)
상기 화합물은 하기 화학식 1 또는 3으로 표시되는 것을 특징으로 하는 신규한 화합물:
[화학식 1]
[화학식 3]
상기 식에서 R1은 수소, F, Cl, Br, 메틸 및 메톡시로 이루어진 군에서 선택되는 것이며, 상기 R2는 메틸이고, 상기 A는 프로필렌, 부틸렌 또는
Hydroxamic acid; Indoline derivatives; And a triazole monomer connecting the hydroxamic acid and the indolin derivative,
The compound is a novel compound, characterized in that represented by the following formula (1) or (3):
[Formula 1]
[Formula 3]
Wherein R 1 is selected from the group consisting of hydrogen, F, Cl, Br, methyl and methoxy, R 2 is methyl, and A is propylene, butylene or
상기 화합물은 히스톤 탈아세틸화효소(histone deacetylase)의 억제를 통해 히스톤의 아세틸화를 촉진하는 활성을 갖는 것을 특징으로 신규한 화합물.The method of claim 1,
The compound is a novel compound, characterized in that it has the activity of promoting the acetylation of histones through the inhibition of histone deacetylase.
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