KR19990012061A - HYDENTOIN DERIVATIVES USEFUL AS PANESSyltransferase inhibitor - Google Patents
HYDENTOIN DERIVATIVES USEFUL AS PANESSyltransferase inhibitor Download PDFInfo
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- KR19990012061A KR19990012061A KR1019970035333A KR19970035333A KR19990012061A KR 19990012061 A KR19990012061 A KR 19990012061A KR 1019970035333 A KR1019970035333 A KR 1019970035333A KR 19970035333 A KR19970035333 A KR 19970035333A KR 19990012061 A KR19990012061 A KR 19990012061A
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Abstract
본 발명은 파네실 전이효소 억제활성을 갖는 하기 화학식 1로 표시되는 하이덴토인(hydantoin; 이미다졸리딘-2,4-디온) 유도체, 그의 이성질체 및 약제학적으로 허용 가능한 염, 수화물 또는 용매화물, 그의 제조 방법 및 그를 포함하는 약학적 조성물에 관한 것이다.The present invention relates to a hydantoin derivative (imidazolin-2,4-dione) derivative represented by the following general formula (1) having a phenesyltransferase inhibitory activity, an isomer thereof and a pharmaceutically acceptable salt, hydrate or solvate thereof, To a process for its preparation and to a pharmaceutical composition comprising the same.
(상기 화학식 1에서 R1, R2, R3및 R4는 명세서에 정의한 바와 같다.)Wherein R 1 , R 2 , R 3 and R 4 are as defined in the specification.
본 발명의 하이덴토인 유도체 및 그의 약제학적으로 허용되는 염은 파네실 전이 효소의 활성을 억제하는 작용을 하므로 항암제로 유용하게 사용될 수 있다.The hydantoin derivatives of the present invention and pharmaceutically acceptable salts thereof may be useful as anticancer drugs because they inhibit the activity of the panesyl transferase.
Description
본 발명은 화학식 1로 표시되는 하이덴토인 유도체, 그의 이성질체 및 약제학적으로 허용가능한 염, 수화물 또는 용매화물, 그의 제조 방법 및 그를 유효성분으로 함유하는 파네실 전이효소 저해제용 약학적 조성물에 관한 것이다.The present invention relates to a hydantoin derivative represented by the general formula (1), an isomer thereof and a pharmaceutically acceptable salt, hydrate or solvate thereof, a process for producing the same, and a pharmaceutical composition for a panesyltransferase inhibitor containing the same as an active ingredient.
Ras 단백질은 세포의 성장과 분화에 중요한 역활을 하는 21 kDa 크기의 단백질로서 구아닌 뉴클레오타이드와 결합하며, 구아노신 트리포스페이트(GTP)를 구아노신 다이 포스페이트(GDP)로 가수분해하거나 GDP를 GTP로 인산화하는 작용을 하는 GTPase 회로에 참여하여 세포 신호전달 경로에 관련되어 있다고 알려져 있으며, 세포성장과 분화에 관련되어 있고, 포유동물 세포에서 3가지ras유전자로부터 생성되며 188개의 아미노산 잔기로 이루어진 K-Ras4B 단백질 또는 아미노산 189개로 이루어진 H-Ras, K-Ras4A, N-Ras 단백질의 4가지 종류가 있다효소로서 세포내에서 특이적인 를 조절하는 분자 스위치로 작용하는 것으로 알려져있다 (Bourne, H. R.; Sanders, D. A.; McCormick, F., Nature, 1991 , 349, 117).Ras protein is a 21 kDa protein that plays an important role in the growth and differentiation of cells. It binds to the guanine nucleotide and hydrolyzes guanosine triphosphate (GTP) to guanosine diphosphate (GDP) or phosphorylates GDP to GTP Ras4B protein, which is involved in cell growth and differentiation and is produced from three ras genes in mammalian cells and is composed of 188 amino acid residues, H-Ras, K-Ras4A, and N-Ras proteins, which are composed of 189 amino acids, are known to function as molecular switches that specifically control intracellular enzymes (Sanders, DA, McCormick , F. , Nature, 1991 , 349 , 117).
Ras 단백질의 12, 13, 61번 위치에 있는 아미노산들은 GTP의 인산기 가까이 위치하고 있어서, 이 아미노산의 잔기들은 GTP의 가수분해에 관여하는 물분자의 공간적 위치에 큰 영향을 미친다. 인체에서 발생하는 암의 경우, 이 위치의 아미노산들의 돌연변이가 일어나면서 암을 유발하는 형태(발암성 Ras)가 되는 것이 그 원인인데, 이러한 돌연변이 Ras 단백질은 고유의 GTPase 활성을 잃어 GTP가 결합되어 활성화된 상태로 계속 존재하게 된다. 따라서, 이러한 돌연변이 Ras 단백질은 계속적으로 세포 신호를 전달하게 되어 발암성이 유발되는 것으로 보고되었으며, 실제로 췌장암, 폐암 및 피부암 등이ras유전자와 밀접하게 관련이 있는 것으로 알려져 있다(Bos, J. L.Cancer Res.,1989,49, 4682).The amino acids at positions 12, 13 and 61 of the Ras protein are located near the phosphate group of GTP, and the residues of these amino acids have a great influence on the spatial position of the water molecule involved in the hydrolysis of GTP. In the case of cancers occurring in the human body, the mutation of the amino acids at this position causes the cancer-causing form (carcinogenic Ras). This mutant Ras protein has lost its intrinsic GTPase activity, As shown in FIG. Therefore, it has been reported that such mutant Ras proteins continuously transmit cellular signals, resulting in carcinogenesis. In fact, pancreatic cancer, lung cancer and skin cancer are known to be closely related to the ras gene (Bos, JL Cancer Res. , ≪ / RTI > 1989 , 49 , 4682).
Ras 단백질이 생물학적으로 활성화 상태에 있기 위해서는 세포막에 부착되어야 하며, Ras 단백질이 세포막에 부착되기 위해서는 우선 세포막 내의 지질층과 용이하게 결합할 수 있어야 한다. Ras 단백질은 파네실기가 결합하여 소수화되는데, 이러한 과정을 구체적으로 언급하자면 파네실화에 관여하는 Ras 파네실 전이효소(Farnecyltransferase)에 의한 과정, Ras 단백질 카복시 말단에 존재하는 3개 아미노산으로 구성된 AAX 펩티드 절단 효소에 의한 과정, 메틸 전이효소 및 팔미토일 전이효소 등에 의한 과정 등이 있으며, 이러한 과정들에 의하여 Ras 단백질의 카복시 말단이 변형된다. 이 단계들 중 첫번째인 파네실화는 파네실 전이효소(FTase)라는 효소에 의하여 진행되는데 Ras 단백질의 탄소 말단에 있는 CA1A2X라는 네 개의 아미노산으로 구성된 펩티드가 기질로서 이용된다. 여기서 A1, A2는 전기적 부하를 띄지않는 지방족의 아미노산이고 X는 메티오닌, 알라닌, 세린 등이다. 이 파네실화는 C(시스테인)부위에 일어나 황에테르 결합을 형성하는데, 특히 H-Ras와 N-Ras 단백질의 경우는 그의 카복시 말단 근처에 존재하는 또 다른 시스테인에 팔미토일화가 일어난다. 이러한 파네실화의 결과로 Ras 단백질은 소수성(Hydrophobicity)이 증가하게 되어 파네실화된 Ras 단백질은 세포막에 용이하게 부착될 수 있게 된다. 파네실화된 Ras 단백질은 다시 그의 카복시 말단의 3개의 아미노산이 AAX 펩티드 절단효소에 의해 떨어져 나가서 메틸화되어 파네실기가 세포막 내의 지질 이중층(lipid bilayer) 또는 다른 수용체와 용이하게 결합할 수 있다. 이렇게 생성된 Ras 단백질은 메틸 전이효소에 의하여 메틸에스테르화되는데, 그 결과 Ras 단백질의 전기적 부하상태나 공간적인 구조의 변화가 일어날 것으로 예상되며, 소수성도 증가하게 되므로 Ras 단백질이 세포막에 더욱 용이하게 부착될 수 있다.In order for the Ras protein to be biologically active, it must be attached to the cell membrane. In order for the Ras protein to attach to the cell membrane, it must first be able to readily bind to the lipid layer in the cell membrane. The Ras protein is conjugated to the phannaceous group to become hydrophobic. Specifically, the process involves a process by Ras panesyltransferase involved in pannisylation, an AAX peptide cleavage consisting of three amino acids at the Ras protein carboxy terminus Enzymatic processes, methyltransferases and palmitoyltransferases, and the like. These processes modify the carboxy terminus of the Ras protein. The first of these steps, panesylation, is carried out by an enzyme called panesyltransferase (FTase), in which a peptide consisting of four amino acids CA 1 A 2 X at the carbon end of the Ras protein is used as a substrate. Where A 1 and A 2 are aliphatic amino acids with no electrical load and X is methionine, alanine, serine, and the like. This panesylation takes place at the C (cysteine) site and forms a sulfur ether bond, especially in the case of H-Ras and N-Ras proteins, palmitoylation to another cysteine present near its carboxy terminus. As a result of this panesylation, the hydrophobicity of Ras protein is increased, so that the pannicylated Ras protein can be easily attached to the cell membrane. The panesylated Ras protein is again methylated by the AAX peptide cleavage enzyme by its 3 amino acids at its carboxy terminus, so that the panesyl group can easily bind to the lipid bilayer or other receptor in the cell membrane. The resulting Ras protein is methylated by the methyltransferase. As a result, the electrical load and spatial structure of the Ras protein are expected to change, and the hydrophobicity is also increased. Therefore, the Ras protein is more easily attached to the cell membrane .
한편, K-Ras4B 의 경우는 H-Ras, N-Ras 와는 달리 팔미토일화에 필요한 시스테인 대신 폴리베이직 도메인 (Poly basic domain)이라 불리는 여러개의 라이신 염기가 배열된 부위를 가지고 있으며, 이 부위가 세포막내의 음이온성 지질과의 결합을 더욱 용이하게 해주는 것으로 알려져 있다.On the other hand, in contrast to H-Ras and N-Ras, K-Ras4B has a region in which a plurality of lysine bases called poly basic domains are arranged instead of cysteine necessary for palmitoylation, Lt; RTI ID = 0.0 > anionic < / RTI >
Ras 단백질이 세포막에 최적의 조건으로 부착되기 위해서는 상기의 모든 변형단계가 필요하지만, Ras 단백질이 생물학적 활성을 나타내는데는 파네실화 자체만으로도 충분하다. 따라서, 상기 세 단계중 첫번째 단계인 파네실화 과정을 저해하면 돌연변이 Ras 단백질이 세포막에 부착되는 것을 막을 수 있어 돌연변이 Ras 단백질이 세포신호를 계속 전달하여 세포를 분열 및 증식시키는 것을 막을 수 있게 된다. 따라서 파네실화를 저해하는 물질을 개발하는 것이 곧 항암제를 개발하는 것이라고 인식되어 최근에 여러 기관에서 이에 대한 많은 연구가 활발히 진행되고 있다(J. E. Busset al.,Chemistry Biology,1995,2, 787).In order for Ras protein to adhere to cell membranes at optimal conditions, all of the above-mentioned modification steps are required. However, paneisylation alone is sufficient for Ras protein to exhibit biological activity. Therefore, inhibition of the first step of the above three steps, pannicillation, can prevent the mutant Ras protein from attaching to the cell membrane, thereby preventing the mutant Ras protein from continuing to transmit the cell signal to divide and multiply the cell. Therefore, the development of a substance that inhibits pannicillation has been recognized as the development of an anticancer drug, and many studies have recently been actively conducted by various organizations (JE Buss et al. , Chemistry Biology , 1995 , 2 , 787).
그간의 연구 결과, 파네실 전이효소를 저해했을 때 Ras 단백질로 형질전환된 세포성장이 저해될 뿐만 아니라 Ras 단백질에 의해 변형된 세포 형질이 개선되는 것이 관찰되었으며, 실제로 파네실 전이효소의 몇몇 저해제들은 발암성 Ras 단백질의 세포내 프레닐기에 의한 반응을 선택적으로 저해하는 것으로 밝혀졌다 [Kokl, N. E.et al.,Proc. Natl. Acad. Sci. USA,1994,91, 9141; Kokl, N. E.et al.,Nature Medicine,1995,1, 792].As a result of these studies, it has been observed that inhibition of Panesyltransferase inhibits Ras protein-transformed cell growth as well as improvement of cell traits modified by Ras protein. In fact, several inhibitors of panesyltransferase It has been shown to selectively inhibit the response of the carcinogenic Ras protein to intracellular prenyl groups [Kokl, NE et al. , Proc. Natl. Acad. Sci. USA , 1994 , 91 , 9141; Kokl, NE et al. , Nature Medicine , 1995 , 1 , 792].
두 개의 기질인 파네실기와 Ras 단백질을 결합하여 반응물을 생성하는 파네실 전이효소의 저해제는 크게 세가지로 나눌 수 있다. 먼저 파네실기 (FPP)를 경쟁적으로 저해할 수 있는 화합물, 둘째로는 Ras 단백질의 C-말단의 작용을 저해하는 화합물, 그리고 파네실 전이효소가 두 기질을 사용하는 촉매반응의 활성화 단계를 모사하는 안정한 화합물을 저해제로 응용하는 것이다.The inhibitor of the panesyltransferase, which combines two substrates, the pansysyl group and the Ras protein, to form a reactant, can be roughly divided into three types. First, a compound capable of competitively inhibiting fenesylate (FPP), a compound that inhibits the action of the C-terminus of the Ras protein, and a phenesyl transferase that mimics the activation step of a catalytic reaction using two substrates Stable compounds as inhibitors.
지금까지 연구된 대부분의 저해제는 Ras 단백질의 C-말단에 있는 프레닐기의 도입반응을 매개하는 CAAX 모티브에 연관된 것들로서, 파네실 전이효소의 Ras 단백질 기질에 대한 경쟁적 저해기전을 응용한 것이다. 예로서 콜 (Kohl, N. E.) 등은 CAAX를 모사한 시스테인 티올 (thiol)기를 함유한 펩타이드 변형체 및 이를 개선한 저해제를 연구하였으며 [미국 특허 5,141,851; Kohl, N. E.et al.,Science, 1993,260, 1934; PCT/US95/12224, Grahamet al.], 셉티 (Sebti S. M.) 등은 펩타이드의 골격구조를 페닐기로 변형한 파네실 전이효소 저해제를 연구하였다 [Sebti, S. M.et al.,J. Biol. Chem.,1995,270, 26802]. 또한 향정신성 의약품 골격구조 중 벤조다이아제핀을 펩타이드의 턴 (turn) 모사구조로 활용한 변형체가 보고된 바 있으며 [James, G. L.et al.,Science,1993,260, 1937], 펩타이드 구조에서 벗어난 트리사이클릭 유기화합물을 골격으로 한 저해제가 연구되었다 [Bishop, W. R.et al.,J. Biol. Chem.,1995,270, 30611].Most of the inhibitors studied so far are related to the CAAX motif that mediates the introduction of the phenyl group at the C-terminus of the Ras protein, applying a competitive inhibition mechanism to the Ras protein substrate of the panesyltransferase. For example, Kohl, N. E. et al. Have investigated peptide modifications containing cysteine thiol groups mimicking CAAX and inhibitors that improve them [US Pat. No. 5,141,851; Kohl, N. E.et al.,Science, 1993,260, 1934; PCT / US95 / 12224, Grahamet al.And Sebti S. M. et al. Have studied a panesyltransferase inhibitor that has been modified to the phenyl group of the skeletal structure of the peptide [Sebti, S. M.et al.,J. Biol. Chem.,1995,270, 26802]. There have also been reported modifications using benzodiazepine as a turn mimicking structure of the peptide in psychotropic drug skeletal structures [James, G. L. et al.et al.,Science,1993,260, ≪ / RTI > 1937], inhibitors with a skeleton of a tricyclic organic compound deviating from the peptide structure have been studied [Bishop, W. R.et al.,J. Biol. Chem.,1995,270, 30611].
한편 파네실 전이효소의 촉매반응 단계를 모사하는 저해제의 연구는 풀터 (Poulter, C. D.) 등이 파네실 전이효소가 프레닐기를 전이하는 작용기전이 전자 친화적 치환반응 (Electriphilic Displacement)임을 제시한 후 [Poulter, C. D.et al.,Poc. Natl. Acad. Sci. USA], 반응이 전이 상태 (transition state)에서 양성 부하를 요구하는 것에 착안하여 프레닐기에 전이 상태의 양성 부하를 연결시킨 새로운 형태의 저해제를 연구하였다 [Poulter, C. D.et al.,J. Am. Chem. Soc.,1996,118, 8761].On the other hand, studies of inhibitors that simulate the catalytic reaction steps of the panesyltransferase have suggested that the action mechanism of the panesyltransferase, such as Poulter (CD), is an electronophilic substitution reaction (Electrophilic Displacement) Poulter, CD et al. , Poc. Natl. Acad. Sci. USA ], a novel form of inhibitor that links the transfected positive load to the phenyl group has been studied, focusing on the fact that the reaction requires a positive load in the transition state (Poulter, CD et al. , J. Am. Chem. Soc. , 1996 , 118 , 8761].
그러나 최근 인체 암에서 많은 경우 K-Ras 활성화가 주요 원인이며, 상기한 대부분의 프레닐 전이효소 제해제들의 경우 H-Ras 또는 N-Ras 에 의해 형질전환된 세포의 성장을 저해하는 효력보다는 K-Ras 활성화에 의해 형질전환된 세포의 성장을 저해하는 효력이 떨어진다는 것이 규명되어 K-Ras 활성을 효과적으로 저해할 수 있는 새로운 저해제의 연구가 주목받고 있다.However, K-Ras activation is a major cause in many human cancers in recent years. In most of the above-mentioned prenyltransferase cleavage, K-Ras activation is more effective than inhibition of H-Ras or N-Ras- Ras activation has been found to be ineffective in inhibiting the growth of transformed cells, and thus a new inhibitor capable of effectively inhibiting K-Ras activity has been attracting attention.
이에 본 발명자들은 파네실 전이효소의 촉매반응의 전이상태를 모사할 수 있는 구조특성을 갖는 화합물을 개발하고자 연구를 계속하여 오던 중, 파네실 전이효소의 촉매반응의 전이상태를 모사함으로써 파네실 전이효소의 작용을 저해할 수 있는 하이덴토인 유도체를 합성하여 본 발명을 완성하였다.Therefore, the inventors of the present invention have been studying to develop a compound having a structural characteristic capable of simulating the transition state of a catalytic reaction of a panesyltransferase, The present inventors have completed the present invention by synthesizing a hydantoin derivative capable of inhibiting the action of an enzyme.
본 발명의 목적은 파네실 전이 효소의 활성을 저해하는 작용을 하는 화학식 1의 하이덴토인 유도체, 그의 제조 방법 및 그를 유효성분으로 함유하는 항암제용 악학적 조성물을 제공하는 것이다.It is an object of the present invention to provide a hydantoin derivative of the formula (1), which acts to inhibit the activity of the panesyl transferase, a process for its preparation, and a malignant composition for an anticancer agent containing the same as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명에서는 파네실 전이 효소의 활성을 억제함으로써 항암효과를 갖는 하기 화학식 1의 하이덴토인 유도체, 그의 이성질체 및 약제학적으로 허용 가능한 염, 수화물 또는 용매화물, 그의 제조 방법 및 그를 유효성분으로 함유하는 항암제용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a hydantoin derivative represented by the following formula (1), an isomer thereof and a pharmaceutically acceptable salt, hydrate or solvate thereof having an anticancer effect by inhibiting the activity of a panesyltransferase, The present invention provides a pharmaceutical composition for an anticancer agent containing the same as an active ingredient.
화학식 1Formula 1
상기 화학식 1에서,In Formula 1,
1 R1은 저급알킬; 방향족; 저급알킬이 치환된 방향족; 할로겐이 치환된 방향족; 바이싸이클릭 방향족; 질소 및 황 원자가 포함된 방향족 중에서 선택되고,1 R 1 is lower alkyl; Aromatic; Lower alkyl substituted aromatic; Halogen-substituted aromatic; Bicyclic aromatic; Nitrogen and sulfur atoms,
2 R2는 저급알킬; 방향족; 저급알킬이 치환된 방향족; 할로겐이 치환된 방향족; 질소 및 황 원자가 포함된 방향족; 바이싸이클릭 방향족 중에서 선택되고,2 R 2 is lower alkyl; Aromatic; Lower alkyl substituted aromatic; Halogen-substituted aromatic; Aromatic containing nitrogen and sulfur atoms; And a bicyclic aromatic,
3 R3는 아미노산기 또는 하기 화학식 2로 표시될 수 있다.3 R 3 may be an amino acid group or represented by the following formula (2).
상기 화학식 2에서,In Formula 2,
A 는 1) 수소, 2) 저급 알킬, 3) 할로겐, 시아노(CN), 니트로(NO2), 카복시(COOH), 아미드, 티오아미드, SR 및 저급 알킬이 치환된 방향족, 4) 할로겐, 시아노, 니트로, 카복실레이트(COOR), 아미드, 티오아미드, SR 또는 저급 알킬이 치환되고 질소 또는 황 원자가 포함된 방향족 또는 5) 상기 4)의 방향족이 치환된 저급알킬 중에서 선택이 되며(SR 및 COOR 에서 R 은 수소 또는 저급 알킬을 의미한다),A is selected from the group consisting of 1) hydrogen, 2) lower alkyl, 3) halogen, cyano (CN), nitro (NO 2 ), carboxy (COOH), amido, thioamide, SR and lower alkyl substituted aromatic, (5) a lower alkyl substituted with an aromatic group of the above 4), wherein SR and / or NR < 5 > are each independently selected from the group consisting of hydrogen, cyano, nitro, carboxylate (COOR), amide, thioamide, SR or lower alkyl substituted with nitrogen or sulfur atom In COOR, R is hydrogen or lower alkyl),
B 및 C 는 각각 독립적으로 수소, 할로겐 또는 저급 알킬 중에서 선택이 되며,B and C are each independently selected from hydrogen, halogen or lower alkyl,
n 은 0 내지 4 중에서 선택이 된다.and n is selected from 0 to 4.
4 R4는 수소 또는 화학식 3으로 표시될 수 있다.4 R 4 may be hydrogen or represented by the formula (3).
상기 화학식 3에서,In Formula 3,
R5는 1) 아미노산기, 2) N-메틸 아미노산기, 3) 아미노산의 잔기가 산화된 아미노산기 중에서 선택이 되며,R 5 is selected from the group consisting of 1) an amino acid group, 2) an N-methylamino group, and 3) an amino acid group in which a residue of an amino acid is oxidized,
R6은 1) 수소, 2) 저급알킬, 3) 할로겐, 시아노, 카복실레이트(COOR), 아미드, 티오아미드, SR 또는 SO2R 이 치환된 저급 알킬, 4) 질소 또는 황 원자가 포함된 방향족, 5) 할로겐, 시아노, 카복실레이트, 아미드, 티오아미드, SR, SO2R 또는 저급 알킬 등이 치환된 방향족으로 치환된 저급 알킬, 6) 할로겐, 시아노, 카복실레이트, 아미드, 티오아미드, SR, SO2R 또는 저급 알킬이 치환되고 질소 또는 황 원자가 포함된 사이클릭알칸(cyclic alkanes) 혹은 방향족 중에서 선택이 되며(COOR, SR 및 SO2R 에서 R은 저급 알킬을 의미한다),R 6 is selected from the group consisting of 1) hydrogen, 2) lower alkyl, 3) halogen, cyano, carboxylate (COOR), amide, thioamide, lower alkyl substituted with SR or SO 2 R 4) , 5) halogen, cyano, carboxylate, amide, thioamide, SR, SO 2 R, or a lower alkyl or the like is substituted with substituted aromatic lower alkyl, 6) halogen, cyano, carboxylate, amide, thioamide, SR, SO 2 R or cyclic alkanes substituted with lower alkyl and containing a nitrogen or sulfur atom, or aromatic (R in COOR, SR and SO 2 R means lower alkyl),
R7및 R8은 각각 독립적으로 수소, 할로겐, 시아노, 카복실레이트, 아미드, 티오아미드, SR, SO2R, 알콕시 중에서 선택이 되며(여기서 R은 저급 알킬을 의미한다),R 7 and R 8 are each independently selected from hydrogen, halogen, cyano, carboxylate, amide, thioamide, SR, SO 2 R, alkoxy wherein R is lower alkyl,
R9는 저급 알킬 또는 방향족이 치환된 저급 알킬 중에서 선택이 되며,R 9 is selected from lower alkyl or aromatic substituted lower alkyl,
X 는 CH2, CO, S 또는 SO2중에서 선택이 되며,X is selected from CH 2 , CO, S or SO 2 ,
n 은 0 내지 2 중에서 선택된다.and n is selected from 0 to 2.
본 명세서에서 사용되는 용어 저급 알킬은 메틸, 에틸, 이소프로필, 이소부틸, t-부틸을 포함하는 탄소 수 1 내지 4의 직쇄 또는 측쇄알킬을 의미하고,As used herein, the term lower alkyl means straight or branched chain alkyl having 1 to 4 carbon atoms including methyl, ethyl, isopropyl, isobutyl, t-butyl,
본 명세서에서 사용되는 용어 질소 및 황 원자가 포함된 방향족은 모노 또는 바이싸이클릭 방향족(bicyclic aromatics)으로 한 개 내지 두 개의 질소 또는 황 원자가 방향족환 내에 포함되어 있는 것을 의미한다.As used herein, the term aromatic containing nitrogen and sulfur atoms means mono- or bicyclic aromatics in which one or two nitrogen or sulfur atoms are contained within the aromatic ring.
본 명세서에서 사용된 아미노산에 관한 약어들은 아미노산 및 펩타이드에 대한 생화학적 명명법에 관한 IUPAC-IUB 합동 회의에 따른 것이다[Eur. J. Biochem.,1984,158, 9-31].The amino acid abbreviations used herein are in accordance with the IUPAC-IUB Joint Meeting on Biochemical Nomenclature for Amino Acids and Peptides [ Eur. J. Biochem. , 1984, 158, 9-31].
본 발명의 화합물들은 비대칭 탄소 중심을 가지고 있으며, 라세미체, 라세미화합물 및 각각의 부분 입체이성체로서 존재할 수 있으며, 모든 이성체는 본 발명에 포함된다.The compounds of the present invention have asymmetric carbon centers and can exist as racemates, racemates and individual diastereomers, and all isomers are included in the present invention.
또한, 본 발명은 약제학적으로 허용가능한 염, 수화물 또는 용매화물 형태의 화합물을 포함할 수 있다.In addition, the present invention may include compounds in the form of pharmaceutically acceptable salts, hydrates or solvates.
본 발명에 따르는 화학식 1의 화합물 중 대표적인 화합물에는 다음과 같은 물질이 있다.Representative compounds of the compounds of formula (I) according to the present invention include the following substances.
1) 2-(2-{3-[3-(1H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산 메틸 에스테르.1) 2- (2- {3- [3- (1H-Imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidine -1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester.
2) 2-(2-{3-[3-(1H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산.2) Synthesis of 2- (2- {3- [3- (1H-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidine -L-yl} -acetylamino) -4-methylsulfanyl-butyric acid.
3) 2-(2-{3-[2-(1H-이미다졸-4-일)-에틸]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산 메틸 에스테르.3) Synthesis of 2- (2- {3- [2- (1H-imidazol-4-yl) -ethyl] -5- methyl-5-naphthalen- -1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester.
4) 2-(2-{3-[2-(1H-이미다졸-4-일)-에틸]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산.4) 2- (2- {3- [2- (lH-imidazol-4-yl) -ethyl] -5- methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidine -L-yl} -acetylamino) -4-methylsulfanyl-butyric acid.
5) 2-{2-[3-(3H-이미다졸-4-일-메틸)-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산 메틸 에스테르.5) Preparation of 2- {2- [3- (3H-imidazol-4-yl-methyl) -5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidazolidin- ] -Acetylamino} -4-methylsulfanyl-butyric acid methyl ester.
6) 2-{2-[3-(3H-이미다졸-4-일-메틸)-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산.6) Preparation of 2- {2- [3- (3H-imidazol-4-yl-methyl) -5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidazolidin- ] -Acetylamino} -4-methylsulfanyl-butyric acid.
7) 2-(2-{3-[3-(4-시아노-벤질)-이미다졸-4-일-메틸]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산 메틸 에스테르.7) 2- (2- {3- [3- (4-Cyano-benzyl) -imidazol-4-yl- methyl] -5- methyl-5-naphthalen- -Imidazolidin-1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester.
8) 2-(2-{3-[3-(4-시아노-벤질)-이미다졸-4-일-메틸]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산.8) 2- (2- {3- [3- (4-Cyano-benzyl) -imidazol-4-yl- methyl] -5- methyl-5-naphthalen- -Imidazolidin-1-yl} -acetylamino) -4-methylsulfanyl-butyric acid.
9) 2-(2-{3-[3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세트아미노)-3-티오펜-2-일-프로피온산.9) 2- (2- {3- [3- (3H-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- 1 -yl-2,4- dioxo-imidazolidine Yl} -acetylamino) -3-thiophen-2-yl-propionic acid.
10) 3-{3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-1-(2-옥소-2-타이아졸리딘-3-일-에틸)-이미다졸리딘-2,4-디온.10) 3- {3- (3H-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- -Ethyl) -imidazolidin-2,4-dione.
11) 1-[2-(1,1-디옥소-타이아졸리딘-3-일)-3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-이미다졸리딘-2,4-디온.11) 1- [2- (1,1-Dioxo-thiazolidin-3-yl) -3- (3H- imidazol-4-yl) -propyl] -5- -Yl-imidazolidin-2, < / RTI > 4-dione.
12) 3-{3-(3H-이미다졸-4-일)-프로필]-5-메틸-1-{2-[2-(2-메틸설파닐-에틸)-타이아졸리딘-3-일]-2-옥소-에틸}-5-나프탈렌-1-일-이미다졸리딘-2,4-디온.12) 3- {3- (3H-imidazol-4-yl) -propyl] -5-methyl-1- {2- [2- Yl] -2-oxo-ethyl} -5-naphthalen-1-yl-imidazolidin-2,4-dione.
13) 2-(2-{3-[3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설포닐-부티릭산13) Synthesis of 2- (2- {3- [3- (3H-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- 1 -yl-2,4-dioxo-imidazolidine -L-yl} -acetylamino) -4-methylsulfonyl-butyric acid
14) 2-{2-[3-(3-이미다졸-1-일-프로필]-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산14) 2- {2- [3- (3-Imidazol-1-yl-propyl] -5-methyl-5-naphthalen- ] -Acetylamino} -4-methylsulfanyl-butyric acid
15) 2-{2-[3-(2-이미다졸-1-일-에틸)-5-메틸-5-나프탈렌-1-일-2,4-다이옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산15) 2- {2- [3- (2-Imidazol-1-yl-ethyl) -5-methyl-5-naphthalen- ] -Acetylamino} -4-methylsulfanyl-butyric acid
또한, 본 발명에서는 하이덴토인 유도체의 제조 방법이 제공되는데, 본 발명의 화합물의 제조 방법은 다음과 같은 단계로 요약될 수 있다.Also, the present invention provides a method for preparing a hydantoin derivative. The method for preparing the compound of the present invention can be summarized as follows.
1) 반응식 1의 구조식 (Ⅰ)로 표시되는 케톤 화합물로부터 구조식(Ⅱ)의 하이덴토인을 합성하는 단계(1 단계),1) a step (step 1) of synthesizing a hydride of the formula (II) from the ketone compound represented by the formula (I) in the reaction scheme 1,
2) 상기 1 단계에서 얻은 하이덴토인(Ⅱ)과 알콜 유도체를 미쯔노부(Mitsunobu) 반응을 시켜 3-N 위치를 알킬화시켜 구조식(Ⅲ)의 화합물을 얻는 단계(2 단계) 및2) a step (step 2) of alkylating the 3-N position by a Mitsunobu reaction between the hydantoin (II) obtained in the above step 1 and an alcohol derivative to obtain a compound of the formula (III)
3) 상기 2 단계에서 얻은 화합물을 알킬화하여 1-N 위치에 원하는 치환기를 도입시켜 화학식 1의 화합물을 얻는 단계(3 단계).3) alkylating the compound obtained in the above step 2 to introduce the desired substituent at the 1-N position to obtain the compound of formula 1 (step 3).
상기 반응식 1은 구조식 (I)로 표시되는 케톤 화합물이 축합반응을 거쳐 구조식 (Ⅱ)의 하이덴토인 화합물이 되고, 이 하이덴토인 화합물과 이미다졸 유도체를 미쯔노부 반응을 시켜 구조식 (Ⅲ)의 화합물을 얻는다. 구조식 (Ⅲ)의 화합물은 치환반응 및 아미드커플링 등의 반응을 거쳐서 화학식 1의 화합물인 구조식 (Ⅳ)의 화합물을 얻는다.In the above Reaction Scheme 1, the ketone compound represented by the structural formula (I) undergoes a condensation reaction to give a hydantoin compound of the structural formula (II), and the hydantoin compound and the imidazole derivative are subjected to a Mitsunobu reaction to obtain a compound of the structural formula . The compound of the formula (III) is subjected to a reaction such as a substitution reaction and an amide coupling to obtain a compound of the formula (IV), which is a compound of the formula (1).
상기 반응식 1의 반응을 보다 구체적으로 설명하기 위하여 하기 반응식 2에R1이 나프탈렌-1-일기이고, R2가 메틸기이고, R3가 3H-이미다졸-4-일-프로필기이며, R4가 2-아세틸아미노-4-메틸설파닐-부티릭산기인 화학식 1의 하이덴토인 화합물을 제조하는 경우를 나타내었다.This in order to explain the reaction of Scheme 1 and more particularly R 1 in scheme 2 and naphthalene-1-yl group, and R 2 is a methyl group, R 3 is 3H- imidazol-4-yl-is propyl, R 4 Is a 2-acetylamino-4-methylsulfanyl-butyric acid group.
즉, 하기 반응식 2의 구조식 (I)로 표시되는 1-아세토나프톤이 축합반응을 거쳐 구조식 (Ⅱ)의 하이덴토인 화합물이 되고, 이 하이덴토인 화합물과 이미다졸 유도체를 미쯔노부 반응을 시켜 구조식 (Ⅲ)의 화합물을 얻는다. 구조식 (Ⅲ)의 화합물은 치환반응 및 아미드커플링 등의 반응을 거쳐서 화학식 1의 화합물인 구조식 (Ⅳ)의 화합물을 얻는다.That is, 1-acetonaphthone represented by the structural formula (I) of the following reaction formula 2 is subjected to a condensation reaction to give a hydridoin compound of the formula (II), and the hydantoin compound and the imidazole derivative are subjected to a Mitsunobu reaction, III < / RTI > The compound of the formula (III) is subjected to a reaction such as a substitution reaction and an amide coupling to obtain a compound of the formula (IV), which is a compound of the formula (1).
한편, 하기 반응식 3은 상기 반응식 1의 미쯔노부 반응에 사용되는 이미다졸 유도체를 합성하는 방법을 도시한 것이다.Meanwhile, the following Reaction Scheme 3 shows a method for synthesizing an imidazole derivative used in the Mitsunobu reaction of the above Reaction Scheme 1.
상기 반응식 3은 이미다졸로부터 3-이미다졸-1-일-프로판올 및 2-이미다졸-1-일-에탄올을 제조하는 경우에 대한 것으로, 상기 반응식 3을 통하여 제조된 3-이미다졸-1-일-프로판올 및 2-이미다졸-1-일-에탄올은 이미다졸로부터 첨가반응 및 환원반응(a) 또는 치환반응 및 환원반응(b) 등을 통하여 제조될 수 있다. 상기 반응식 3에 대해서는 후술하는 제조예 1 및 제조예 2에 의하여 상세히 설명하기로 한다.Scheme 3 illustrates the preparation of 3-imidazol-1-yl-propanol and 2-imidazol-1-yl-ethanol from imidazole. One-propanol and 2-imidazol-1-yl-ethanol can be prepared from imidazole by an addition reaction and a reduction reaction (a) or a substitution reaction and a reduction reaction (b). Scheme 3 will be described in detail in Production Examples 1 and 2 described below.
이하 실시예에 의하여 본 발명의 하이덴토인 화합물의 제조 방법을 상세히 설명하기로 한다. 단 하기 실시예는 본 발명을 예시하는 것일 뿐 본 발명이 실시예에 의하여 한정되는 것은 아니다. 실시예에 앞서 본 발명의 화합물을 제조하는데 사용되는 물질의 제조방법을 제조예에 의하여 설명한다.Hereinafter, a method for preparing the inventive hardenin compound will be described in detail with reference to Examples. The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Prior to Examples, the preparation methods of the materials used to prepare the compounds of the present invention will be described by way of Preparation Examples.
제조예 1 3-이미다졸-1-일-프로판올의 제조Preparation 1 Preparation of 3-imidazol-1-yl-propanol
(단계 1) 3-이미다졸-1-일-프로피오네이트의 제조(Step 1) Preparation of 3-imidazol-1-yl-propionate
이미다졸 5.0 g(73.4 mmol)과 메틸 아크릴레이트 12.6 g(148.6 mmol)을 아세토니트릴에 녹인 후 8시간 동안 끓였다. 감압증류하여 아세토니트릴과 과량의 메틸 아크릴레이트를 제거한 다음, 에틸 아세테이트를 가하고 염화나트륨 포화용액으로 씻어 주었다. 다음 유기용매를 감압증류하여 제거시켜 표제화합물(11.1 g, 수율: 90%)을 얻었다.5.0 g (73.4 mmol) of imidazole and 12.6 g (148.6 mmol) of methyl acrylate were dissolved in acetonitrile and boiled for 8 hours. The acetonitrile and excess methyl acrylate were removed by distillation under reduced pressure, and then ethyl acetate was added and washed with a saturated sodium chloride solution. The organic solvent was distilled off under reduced pressure to obtain the title compound (11.1 g, yield: 90%).
1H NMR (CDCl3) δ(ppm) 2.75 (2H, t), 3.46 (3H, s), 4.24 (2H, t), 6.89 (1H, s), 7.00 (1H, s), 7.46 (1H, s). 1 H NMR (CDCl 3) δ (ppm) 2.75 (2H, t), 3.46 (3H, s), 4.24 (2H, t), 6.89 (1H, s), 7.00 (1H, s), 7.46 (1H, s).
FAB Mass (M+H): 169FAB Mass (M + H): 169
(단계 2) 3-이미다졸-1-일-프로판올의 제조(Step 2) Preparation of 3-imidazol-1-yl-propanol
상기 (단계 1)에서 제조한 화합물 1.1 g (6.6 mmol)을 테트라하이드로퓨란 50 ml에 녹인 후 리튬알루미늄하이드라이드[LiAlH, 0.26 g (6.6 mmol)]를 가하고 1시간 동안 끓였다. 다음 1N 농도의 수산화나트륨용액을 가하고 에틸 아세테이트로 추출하였다. 감압 증류로 유기용매를 제거하여 표제화합물(0.77 g, 수율: 93%)을 얻었다.1.1 g (6.6 mmol) of the compound prepared in (step 1) was dissolved in 50 ml of tetrahydrofuran, lithium aluminum hydride [LiAlH, 0.26 g (6.6 mmol)] was added, and the mixture was boiled for 1 hour. Next, 1N sodium hydroxide solution was added and extracted with ethyl acetate. The organic solvent was removed by distillation under reduced pressure to obtain the title compound (0.77 g, yield: 93%).
1H NMR (CDCl3) d(ppm) 1.67 (2H, m), 3.26 (2H,t), 3.78 (2H, t), 6.60 (1H, s), 6.75 (1H, s), 7.14 (1H, s). 1 H NMR (CDCl 3) d (ppm) 1.67 (2H, m), 3.26 (2H, t), 3.78 (2H, t), 6.60 (1H, s), 6.75 (1H, s), 7.14 (1H, s).
FAB Mass (M+H): 127FAB Mass (M + H): 127
제조예 2 2-이미다졸-1-일-에탄올의 제조Preparation 2 Preparation of 2-imidazol-1-yl-ethanol
(단계 1) 2-이미다졸-1-일-에틸 아세테이트의 제조(Step 1) Preparation of 2-imidazol-1-yl-ethyl acetate
이미다졸 5.0 g(73.4 mmol)과 에틸 브로모아세테이트 3.36 ml(29.4 mmol)를 디메틸포름아마이드 50 ml에 녹인 후, 4시간 동안 교반시켰다. 다음 감압증류로 디메틸포름아마이드를 제거한 뒤 에틸 아세테이트를 가하고 염화나트륨 포화용액으로 씻어 주었다. 유기용매를 감압증류하여 제거시켜 표제화합물 (0.77 g, 수율: 17%)을 얻었다.5.0 g (73.4 mmol) of imidazole and 3.36 ml (29.4 mmol) of ethyl bromoacetate were dissolved in 50 ml of dimethylformamide, followed by stirring for 4 hours. The dimethylformamide was then removed by distillation under reduced pressure, ethyl acetate was added, and the residue was washed with a saturated solution of sodium chloride. The organic solvent was distilled off under reduced pressure to obtain the title compound (0.77 g, yield: 17%).
1H NMR (CDCl3) d(ppm) 1.29 (3H,t), 4.25 (2H,q), 4.70 (2H, s), 6.95 (1H, s), 7.10 (1H, s), 7.49 (1H, s). 1 H NMR (CDCl 3) d (ppm) 1.29 (3H, t), 4.25 (2H, q), 4.70 (2H, s), 6.95 (1H, s), 7.10 (1H, s), 7.49 (1H, s).
FAB Mass (M+H): 155FAB Mass (M + H): 155
(단계 2) 2-이미다졸-1-일-에탄올의 제조(Step 2) Preparation of 2-imidazol-1-yl-ethanol
상기 (단계 1)에서 제조한 화합물 0.77 g(5.0 mmol)을 테트라하이드로퓨란 20 ml에 녹인 후, 반응 혼합물에 리튬알루미늄하이드라이드 0.2 g(5.0 mmol)를 가하고 1시간 동안 끓였다. 다음 1N 농도의 수산화나트륨용액을 가하고 에틸 아세테이트로 추출하였다. 유기용매를 감압증류로 제거한 다음 메탄올-메틸렌클로라이드 혼합용매로 크로마토그래피를 실시하여 표제화합물(0.51 g, 수율: 91%)을 얻었다.0.77 g (5.0 mmol) of the compound prepared in (step 1) was dissolved in 20 ml of tetrahydrofuran, 0.2 g (5.0 mmol) of lithium aluminum hydride was added to the reaction mixture, and the mixture was boiled for 1 hour. Next, 1N sodium hydroxide solution was added and extracted with ethyl acetate. The organic solvent was removed by distillation under reduced pressure, and then the residue was subjected to chromatography using a methanol-methylene chloride mixed solvent to obtain the title compound (0.51 g, yield: 91%).
1H NMR (CDCl3) δ(ppm) 3.78 (2H, t), 3.98 (2H, t), 6.85 (1H, s), 6.94 (1H, s), 7.36 (1H, s). 1 H NMR (CDCl 3) δ (ppm) 3.78 (2H, t), 3.98 (2H, t), 6.85 (1H, s), 6.94 (1H, s), 7.36 (1H, s).
FAB Mass (M+H): 113FAB Mass (M + H): 113
〈실시예 1 2-(2-{3-[3-(1H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부 티릭산 메틸 에스테르의 제조Example 1 Synthesis of 2- (2- {3- [3- (1H-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- 1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester
(단계 1) 5-메틸-5-나프탈렌-1-일-이미다졸리딘-2,4-디온의 제조(Step 1) Preparation of 5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione
1-아세토나프톤 30 g(0.18 mol)과 시아노칼륨[KCN, 23g(0.35 mol)]을 메탄올 900 ml에 녹인 후, 암모늄카보네이트[(NH4)2CO3, 169g(1.8 mol)]과 증류수 900 ml를 넣고 70℃에서 12시간 동안 교반하였다. 메탄올을 감압 증류하여 제거한 후 4회 동안 에틸 아세테이트를 각각 500 ml씩 사용하여 추출하였다. 다음 에틸 아세테이트를 감압 증류하여 제거시켜 표제화합물(38.2 g, 수율: 90%)을 얻었다.After dissolving 30 g (0.18 mol) of 1-acetonaphthone and 23 g (0.35 mol) of potassium cyanide [KCN] in 900 ml of methanol, ammonium carbonate [(NH 4 ) 2 CO 3 , 169 g 900 ml of distilled water was added, and the mixture was stirred at 70 ° C for 12 hours. Methanol was removed by distillation under reduced pressure and extracted with 500 ml of ethyl acetate each time for 4 times. Then, ethyl acetate was distilled off under reduced pressure to obtain the title compound (38.2 g, yield: 90%).
1H NMR (CDCl3) δ(ppm) 2.15 (3H, s), 6.35 (1H, s), 7.44 (1H, t), 7.53 (2H, m), 7.70 (1H, d), 7.89 (1H, d) 7.93 (1H, d), 7.99 (1H, d), 8.52 (1H, br). 1 H NMR (CDCl 3) δ (ppm) 2.15 (3H, s), 6.35 (1H, s), 7.44 (1H, t), 7.53 (2H, m), 7.70 (1H, d), 7.89 (1H, d) 7.93 (1H, d), 7.99 (1H, d), 8.52 (1H, br).
FAB Mass (M+H): 241FAB Mass (M + H): 241
(단계 2) 3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1- 일-이미다졸리딘-2,4-디온의 제조(Step 2) To a solution of 3- [3- (3-triphenylmethyl-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- 1 -yl-imidazolidin- Produce
상기 (단계 1)에서 얻은 5-메틸-5-나프탈렌-1-일-이미다졸리딘-2,4-디온 0.60 g(2.51 mmol), 3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 1.02g(2.76 mmol) 및 트리페닐포스핀(Ph3P, 0.87g(3.3 mmol)을 테트라하이드로퓨란 50ml에 녹인 후, 다이에틸 아조다이카르복실레이트[DEAD, 0.52ml(3.3 mmol)]를 가하고 24 시간 동안 교반시켰다. 테트라하이드로퓨란을 감압증류로 제거한 후, 에틸 아세테이트로 크로마토그래피를 실시하여 표제 화합물(1.17 g, 수율: 80%)을 얻었다.0.60 g (2.51 mmol) of 5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione obtained in the above (step 1) and 3- (3-triphenylmethyl- (1.03 g, 2.76 mmol) and triphenylphosphine (Ph 3 P, 0.87 g, 3.3 mmol) were dissolved in 50 ml of tetrahydrofuran, and then diethyl azodicarboxylate [DEAD, 0.52 ml ) Was added and stirred for 24 hours. The tetrahydrofuran was removed by distillation under reduced pressure, and then the residue was subjected to chromatography using ethyl acetate to give the title compound (1.17 g, yield: 80%).
1H NMR (CDCl3) d(ppm) 2.04 (5H, m),2.60 (2H, t), 3.67 (2H, t), 6.59 (1H, s), 7.05 (1H, s),7.15 (6H, m), 7.32 (9H, m), 7.37 (1H, t), 7.44 (2H, d), 7.63 (1H, d), 7.79 (1H, d), 7.86 (1H, d), 7.91 (1H, d). 1 H NMR (CDCl 3) d (ppm) 2.04 (5H, m), 2.60 (2H, t), 3.67 (2H, t), 6.59 (1H, s), 7.05 (1H, s), 7.15 (6H, m), 7.32 (9H, m), 7.37 (IH, t), 7.44 (IH, d), 7.63 ).
FAB Mass (M+H): 591FAB Mass (M + H): 591
(단계 3) 2-{3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌 -1-일-2,4-디옥소-이미다졸리딘-1-일}-에틸 아세테이트의 제조(Step 3) 2- {3- [3- (3-Triphenylmethyl-imidazol-4-yl) -propyl] -5-methyl- Lt; / RTI > aziridin-1-yl} -ethyl acetate
상기 (단계 2)에서 얻은 3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-이미다졸리딘-2,4-디온(0.082 g, 0.14 mmol)과 에틸 브로모아세테이트(0.023 ml, 0.21 mmol)를 디메틸포름아마이드 5 ml에 녹인 후, 소디움하이드라이드[NaH, 0.017g(0.21 mmol)]를 가하고 1시간 동안 교반시켰다. 디메틸포름아마이드를 감압 증류로 제거하여 얻은 화합물을 에틸 아세테이트에 녹인 후, 10% 시트릭 산(citric acid)으로 씻어 주었다. 에틸 아세테이트를 감압증류하여 표제화합물(0.092g, 수율 99%)을 얻었다.3- (3-Triphenylmethyl-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- 1 -yl-imidazolidin- (0.082 g, 0.14 mmol) and ethyl bromoacetate (0.023 ml, 0.21 mmol) were dissolved in 5 ml of dimethylformamide, sodium hydride (NaH, 0.017 g, 0.21 mmol) . Dimethylformamide was removed by distillation under reduced pressure, and the obtained compound was dissolved in ethyl acetate and washed with 10% citric acid. Ethyl acetate was distilled under reduced pressure to obtain the title compound (0.092 g, yield 99%).
1H NMR (CDCl3) d(ppm) 1.10 (3H, t), 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.80 (2H, t), 4.02 (2H, m), 4.10 (2H, q), 6.60 (1H, s), 7.13 (6H, m), 7.33 (11H, m), 7.46 (3H, m), 7.69 (1H, d), 7.89 (2H, m). 1 H NMR (CDCl 3) d (ppm) 1.10 (3H, t), 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.80 (2H, t), 4.02 (2H, (1H, m), 7.10 (2H, q), 6.60 (1H, s), 7.13 (6H, m), 7.33 ).
FAB Mass (M+H): 677FAB Mass (M + H): 677
(단계 4) 2-(2-{3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프 탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설 파닐-부티릭산 메틸 에스테르의 제조(Step 4) 2- (2- {3- [3- (3-Triphenylmethyl-imidazol-4-yl) -propyl] -5- Dioxo-imidazolidin-1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester
상기 (단계 3)에서 얻은 2-{3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세트 산 에틸에스테르 0.092g (0.14 mmol)를 테트라하이드로퓨란-증류수(3:1) 혼합용매에 녹인 후, 리튬하이드록사이드[LiOH, 0.0058g(0.14mmol)]을 가하고 1 시간 동안 교반하였다. 감압 증류와 진공하에서 완전히 건조시킨 화합물을 디메틸포름아마이드 5 ml에 녹였다. 이 용액에 메티오닌 메틸 에스테르 0.041g (0.21 mmol), N-하이드록시벤조트리아졸 0.037g (0.28 mmol) 및 3-에틸-(디메틸아미노)-프로필 카보디이미드 0.04g (0.28 mmol)을 가하고 상온에서 12 시간 동안 교반시켰다. 디메틸포름아마이드를 감압증류로 제거한 뒤 30 ml의 에틸 아세테이트를 가하고 이것을 10% 시트릭산 용액 10 ml로 2회 세척하였고, 탄산칼륨 포화용액 10 ml로 2회 세척하였으며, 염화나트륨 포화용액으로 세척하였다. 다음 에틸 아세테이트-헥산 혼합용매로 크로마토그래피를 실시하여 표제화합물[0.11 g(0.13 mmol), 수율: 95%]을 얻었다.2- {3- [3- (3-Triphenylmethyl-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- 1-yl} -acetic acid ethyl ester (0.092 g, 0.14 mmol) was dissolved in a mixed solvent of tetrahydrofuran and distilled water (3: 1), and then lithium hydroxide [LiOH, 0.0058 g mmol) was added thereto, and the mixture was stirred for 1 hour. The compound, which was completely dried under vacuum distillation and vacuum, was dissolved in 5 ml of dimethylformamide. 0.041 g (0.21 mmol) of methionine methyl ester, 0.037 g (0.28 mmol) of N-hydroxybenzotriazole and 0.04 g (0.28 mmol) of 3-ethyl- (dimethylamino) -propyl carbodiimide were added to this solution, Stir for 12 hours. The dimethylformamide was removed by distillation under reduced pressure, 30 ml of ethyl acetate was added, and the mixture was washed twice with 10 ml of a 10% citric acid solution, twice with 10 ml of a saturated solution of potassium carbonate and washed with a saturated sodium chloride solution. The residue was subjected to chromatography using an ethyl acetate-hexane mixed solvent to obtain the title compound [0.11 g (0.13 mmol), yield: 95%].
1H NMR (CDCl3) δ(ppm) 1.84 (2H, m), 1.98 (6H, m), 2.14 (2H, m), 2.40 (2H, t), 2.71 (2H, t), 3.38 (1H, dd), 3.62 (3H, s), 3.80 (2H, m), 4.46 (1H, m), 6.64 (1H, d), 6.75 (1H, dd), 7.14 (6H, m), 7.24-7.53 (13H, m), 7.72 (1H, d), 7.89 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.84 (2H, m), 1.98 (6H, m), 2.14 (2H, m), 2.40 (2H, t), 2.71 (2H, t), 3.38 (1H, dd), 3.62 (3H, s), 3.80 (2H, m), 4.46 (1H, m), 6.64 , < / RTI > m), 7.72 (1H, d), 7.89 (2H, m).
FAB Mass (M+H): 794FAB Mass (M + H): 794
(단계 5) 2-(2-{3-[3-(1H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부 티릭산 메틸 에스테르의 제조(Step 5) 2- (2- {3- [3- (1H-Imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- 1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester
상기 (단계 4)에서 얻은 2-(2-{3-[3-(3-트리페닐메틸-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산 메틸 에스테르 0.11 g (0.13 mmol)과 트리이소프로필실란 0.053 ml(0.26 mmol) 을 메틸렌클로라이드 5 ml에 녹인 후 트리플로로아세트산 5 ml을 가하고 상온에서 1 시간 동안 교반하였다. 유기 용매를 감압 증류하여 제거하고, 탄산칼륨(K2CO3) 포화용액으로 pH를 10으로 조절한 후 1N 농도의 10 ml의 에틸 아세테이트로 추출하였다. 유기 용매를 감압 증류하여 제거하고 메탄올-메틸렌클로라이드 혼합용매로 크로마토그래피를 실시하여 표제화합물(0.068 g, 수율: 95%)을 얻었다.(2- {3- [3- (3-Triphenylmethyl-imidazol-4-yl) -propyl] -5- (0.13 mmol) of methyl ester and 0.053 ml (0.26 mmol) of triisopropylsilane in 5 ml of methylene chloride was added to a solution of methyl 5-chloro-5-methoxybenzenesulfonate ml, then 5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The organic solvent was removed by distillation under reduced pressure, the pH was adjusted to 10 with a saturated solution of potassium carbonate (K 2 CO 3 ), and the mixture was extracted with 10 ml of 1 N ethyl acetate. The organic solvent was distilled off under reduced pressure, and the residue was subjected to chromatography using a methanol / methylene chloride mixed solvent to obtain the title compound (0.068 g, yield: 95%).
1H NMR (CDCl3) δ(ppm) 1.88 (2H, m), 2.00 (3H, s), 2.06 (3H, s), 2.14 (2H, m), 2.45 (2H, t), 2.76 (2H, m), 3.38 (1H, dd), 3.69 (3H, d), 3.82 (2H, m), 4.54 (1H, m), 6.87 (1H, d), 7.60-7.40 (5H, m), 7.72 (1H, d), 7.91 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.88 (2H, m), 2.00 (3H, s), 2.06 (3H, s), 2.14 (2H, m), 2.45 (2H, t), 2.76 (2H, m), 3.38 (1H, dd), 3.69 (3H, d), 3.82 (2H, m), 4.54 (1H, m), 6.87 (1H, d), 7.60-7.40 , < / RTI > d), 7.91 (2H, m).
FAB Mass (M+H): 552FAB Mass (M + H): 552
실시예 2 2-(2-{3-[3-(1H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부 티릭산 리튬염의 제조Example 2 Synthesis of 2- (2- {3- [3- (1H-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- Di-l-yl} -acetylamino) -4-methylsulfanyl-butyric acid lithium salt
상기 실시예 1에서 얻은 2-(2-{3-[3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐-부티릭산 메틸 에스테르 0.068 g(0.12 mmol)을 테트라하이드로퓨란-증류수(3:1) 혼합용매에 녹인 후, 리튬하이드록사이드 0.005 g(0.12mmol)을 가하고 1시간 동안 교반하였다. 반응혼합물을 감압증류와 진공하에서 완전히 건조시켜 표제화합물을 얻었다.(2- {3- [3- (3H-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- (0.028 g, 0.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran and distilled water (3: 1), and then lithium hydroxide 0.005 g (0.12 mmol) of sodium chloride was added and stirred for 1 hour. The reaction mixture was completely dried under reduced pressure and in vacuo to give the title compound.
ESI Mass (M + Li+): 538ESI Mass (M + Li < + & gt ; ): 538
실시예 3 2-(2-{3-[2-(1H-이미다졸-4-일)-에틸]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐- 부티릭산 메틸 에스테르의 제조.Example 3 Synthesis of 2- (2- {3- [2- (1H-imidazol-4-yl) -ethyl] -5- methyl-5-naphthalen- Di-l-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 2-(3-트리페닐메틸-이미다졸-4-일)-에탄올을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 32 mg을 얻었다.Prepared by the same method as in Example 1 using 2- (3-triphenylmethyl-imidazol-4-yl) -ethanol instead of 3- (3-triphenylmethyl-imidazol- 32 mg of the title compound was obtained.
1H NMR (CDCl3) δ(ppm) 1.88 (2H, m), 2.01 (3H, s), 2.08 (3H, s), 2.20 (1H, t), 2.45 (1H, t), 3.20 (2H, m), 3.37 (1H, dd), 3.70 (3H, d), 4.05 (2H, m), 4.54 (1H, m), 6.97 (1H, s), 7.71-7.30 (6H, m), 7.90 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.88 (2H, m), 2.01 (3H, s), 2.08 (3H, s), 2.20 (1H, t), 2.45 (1H, t), 3.20 (2H, m), 3.37 (1H, dd), 3.70 (3H, d), 4.05 (2H, m), 4.54 (1H, m), 6.97 (1H, s), 7.71-7.30 , m).
FAB Mass (M+H): 538FAB Mass (M + H): 538
실시예 4 2-(2-{3-[2-(1H-이미다졸-4-일)-에틸]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설파닐- 부티릭산 리튬염의 제조.Example 4 Synthesis of 2- (2- {3- [2- (1H-imidazol-4-yl) -ethyl] -5- methyl-5-naphthalen- Di-l-yl} -acetylamino) -4-methylsulfanyl-butyric acid lithium salt.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 2-(3-트리페닐메틸-이미다졸-4-일)-에탄올을 이용하여 상기 실시예 2와 같은 방법으로 제조하여 표제화합물 20 mg을 얻었다.Was prepared in the same manner as in Example 2 using 2- (3-triphenylmethyl-imidazol-4-yl) -ethanol instead of 3- (3-triphenylmethyl-imidazol- 20 mg of the title compound was obtained.
ESI Mass (M-Li++2H): 524ESI Mass (M-Li < + & gt ; + 2H): 524
실시예 5 2-{2-[3-(3H-이미다졸-4-일-메틸)-5-메틸-5-나프탈렌-1-일-2,4-디 옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산 메 틸 에스테르의 제조.Example 5 Synthesis of 2- {2- [3- (3H-imidazol-4-yl-methyl) -5-methyl-5-naphthalen- Yl] -acetylamino} -4-methylsulfanyl-butyric acid methyl ester.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 2-(3-트리페닐메틸-이미다졸-4-일)-메탄올을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 25 mg을 얻었다.Was prepared in the same manner as in Example 1 using 2- (3-triphenylmethyl-imidazol-4-yl) -methanol instead of 3- (3-triphenylmethyl-imidazol- 25 mg of the title compound was obtained.
1H NMR (CDCl3) δ(ppm) 1.80 (2H, m), 1.98 (3H, s), 2.00 (3H, s), 2.08 (1H, t), 2.38 (1H, t), 3.38 (1H, dd), 3.67 (3H, d), 4.45 (1H, m), 4.88 (2H, d), 6.80 (1H, m), 7.08 (3H, m), 7.34 (1H, m), 7.45 (1H, m), 7.68 (1H, d), 7.82 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.80 (2H, m), 1.98 (3H, s), 2.00 (3H, s), 2.08 (1H, t), 2.38 (1H, t), 3.38 (1H, m), 7.35 (1H, m), 7.45 (1H, m), 7.40 (1H, dd) ), 7.68 (1 H, d), 7.82 (2 H, m).
FAB Mass (M+1): 524FAB Mass (M + 1): 524
실시예 6 2-{2-[3-(3H-이미다졸-4-일-메틸)-5-메틸-5-나프탈렌-1-일-2,4-디 옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산 리 튬염의 제조.Example 6 Preparation of 2- {2- [3- (3H-imidazol-4-yl-methyl) -5-methyl-5-naphthalen- Yl] -acetylamino} -4-methylsulfanyl-butyric acid lithium salt.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 2-(3-트리페닐메틸-이미다졸-4-일)-메탄올을 이용하여 상기 실시예 2와 같은 방법으로 제조하여 표제화합물 15 mg을 얻었다.Was prepared in the same manner as in Example 2 using 2- (3-triphenylmethyl-imidazol-4-yl) -methanol instead of 3- (3-triphenylmethyl-imidazol- 15 mg of the title compound was obtained.
ESI Mass (M-Li++2H): 510ESI Mass (M-Li < + & gt ; + 2H): 510
실시예 7 2-(2-{3-[3-(4-시아노-벤질)-이미다졸-4-일-메틸]-5-메틸-5-나프 탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸 설파닐-부티릭산 메틸 에스테르의 제조.Example 7 2- (2- {3- [3- (4-Cyano-benzyl) -imidazol-4-yl- methyl] -5- methyl-5-naphthalen- Dioxo-imidazolidin-1-yl} -acetylamino) -4-methylsulfanyl-butyric acid methyl ester.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 1-(4-시아노벤질)-5-히드록시메틸 이미다졸을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 40 mg을 얻었다.(4-cyanobenzyl) -5-hydroxymethylimidazole in place of 3- (3-triphenylmethyl-imidazol-4-yl) 40 mg of a compound was obtained.
1H NMR (CDCl3) δ(ppm) 1.85 (2H, m), 2.00 (3H, s), 2.06 (4H, m), 2.45 (1H, t), 3.36 (1H, dd), 3.71 (3H, d), 4.50 (1H, m), 4.71 (2H, m), 5.48 (2H, dd), 6.90 (1H, m), 7.08 (1H, m), 7.14 (2H, m), 7.39-7.75 (7H, m), 7.91 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.85 (2H, m), 2.00 (3H, s), 2.06 (4H, m), 2.45 (1H, t), 3.36 (1H, dd), 3.71 (3H, m), 7.14 (2H, m), 7.39-7.75 (7H, m), 4.50 (1H, , < / RTI > m), 7.91 (2H, m).
FAB Mass (M+H): 639FAB Mass (M + H): 639
실시예 8 2-(2-{3-[3-(4-시아노-벤질)-이미다졸-4-일-메틸]-5-메틸-5-나프 탈렌-1-일-2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸 설파닐-부티릭산 리튬염의 제조.Example 8 2- (2- {3- [3- (4-Cyano-benzyl) -imidazol-4-yl- methyl] -5- methyl-5-naphthalen- Dioxo-imidazolidin-1-yl} -acetylamino) -4-methylsulfanyl-butyric acid lithium salt.
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 1-(4-시아노벤질)-5-히드록시메틸 이미다졸을 이용하여 상기 실시예 2와 같은 방법으로 제조하여 표제화합물 8 mg을 얻었다.Was prepared in the same manner as in Example 2 using 1- (4-cyanobenzyl) -5-hydroxymethylimidazole in place of 3- (3-triphenylmethyl-imidazol- 8 mg of a compound was obtained.
FAB Mass (M + H): 631FAB Mass (M + H): 631
실시예 9 2-(2-{3-[3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세트아미노)-3-티오펜-2-일 -프로피온산 리튬염의제조.Example 9 Synthesis of 2- (2- {3- [3- (3H-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- Di-l-yl} -acetamino) -3-thiophen-2-yl-propionic acid lithium salt.
메티오닌 메틸 에스테르 대신 3-티오펜-2-일-프로피온산 메틸 에스테르를 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 25 mg을 얻었다.Prepared by the same method as in Example 1 using 3-thiophen-2-yl-propionic acid methyl ester instead of methionine methyl ester to obtain the title compound (25 mg).
1H NMR (CD3OD) δ(ppm) 1.95 (3H, d), 2.10 (2H, m), 2.74 (2H, m), 3.20 (2H, m), 3.78 (2H, t), 4.00 (1H, dd), 4.71 (1H, m), 6.68-6.90 (3H, m), 7.12 (1H, m), 7.34-7.54 (5H, m), 7.59 (1H, t), 7.99 (2H, q). 1 H NMR (CD 3 OD) δ (ppm) 1.95 (3H, d), 2.10 (2H, m), 2.74 (2H, m), 3.20 (2H, m), 3.78 (2H, t), 4.00 (1H (d, 1H, dd), 4.71 (1H, m), 6.68-6.90 (3H, m), 7.12 (1H, m), 7.34-7.54 (5H, m), 7.59
ESI Mass (M-Li++2H): 560ESI Mass (M-Li < + & gt ; + 2H): 560
실시예 10 3-{3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일-1-(2- 옥소-2-티아졸리딘-3-일-에틸)-이미다졸리딘-2,4-디온의제조.Example 10 3- {3- (3H-imidazol-4-yl) -propyl] -5-methyl-5-naphthalen- -Ethyl) -imidazolidin-2,4-dione.
메티오닌 메틸 에스테르 대신 티아졸리딘을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 60 mg을 얻었다.Prepared by the same method as in Example 1 above using thiazolidine instead of methionine methyl ester to give the title compound (60 mg).
1H NMR (CDCl3) δ(ppm) 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.00 (2H, br), 3.75 (2H, t), 3.80 (2H, t), 4.02 (2H, m), 4.50 (2H, t), 6.60 (1H, s), 7.13 (6H, m), 7.33 (11H, m), 7.46 (3H, m), 7.69 (1H, d), 7.89 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.00 (2H, br), 3.75 (2H, t), 3.80 (2H, m), 7.46 (3H, m), 7.69 (1H, d), 4.02 (2H, ), 7.89 (2 H, m).
FAB Mass (M+H): 478FAB Mass (M + H): 478
실시예 11 1-[2-(1,1-디옥소-티아졸리딘-3-일)-3-(3H-이미다졸-4-일)-프로 필]-5-메틸-5-나프탈렌-1-일-이미다졸리딘-2,4-디온의 제조Example 11 1- [2- (1,1-Dioxo-thiazolidin-3-yl) -3- (3H-imidazol- Preparation of 1-yl-imidazolidin-2,4-dione
메티오닌 메틸 에스테르 대신 1,1-디옥소-티아졸리딘을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 15 mg을 얻었다.Prepared by the same method as in Example 1 above using 1,1-dioxo-thiazolidine instead of methionine methyl ester, and 15 mg of the title compound was obtained.
1H NMR (CDCl3) δ(ppm) 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.24 (2H,t), 3.80 (2H, t), 4.02 (4H, m), 4.40 (2H, br), 6.60 (1H, s), 7.13 (6H, m), 7.33 (11H, m), 7.46 (3H, m), 7.69 (1H, d), 7.89 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 2.02 (3H, s), 2.15 (2H, m), 2.70 (2H, t), 3.24 (2H, t), 3.80 (2H, t), 4.02 (4H, m), 4.40 (2H, br), 6.60 (1H, s), 7.13 (6H, m), 7.33 (11H, m), 7.46 ).
FAB Mass (M+H): 510FAB Mass (M + H): 510
실시예 12Example 12 3-{3-(3H-이미다졸-4-일)-프로필]-5-메틸-1-{2-[2-(2-메틸설파닐 -에틸)-티아졸리딘-3-일]-2-옥소-에틸}-5-나프탈렌-1-일-이미다 졸리딘-2,4-디온의 제조3- {3- (3H-imidazol-4-yl) -propyl] -5-methyl-1- {2- [2- Oxo-ethyl} -5-naphthalen-1-yl-imidazolidin-2,4-dione
메티오닌 메틸 에스테르 대신 2-메틸설파닐-에틸-티아졸리딘을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 25 mg을 얻었다.Ethyl-thiazolidine instead of methionine methyl ester to give the title compound (25 mg).
1H NMR (CDCl3) δ(ppm) 1.90 (1H, m)2.05 (4H, m), 2.15 (2H, m), 2.57 (2H, m), 2.70 (2H, t), 2.85 (2H, m), 2.96(1H, m), 3.32 (1H, m), 3.80 (2H, t), 4.02 (2H, m), 4.52 (1H, t), 6.60 (1H, s), 7.13 (6H, m), 7.33 (11H, m), 7.46 (3H, m), 7.69 (1H, d), 7.89 (2H, m). 1 H NMR (CDCl 3) δ (ppm) 1.90 (1H, m) 2.05 (4H, m), 2.15 (2H, m), 2.57 (2H, m), 2.70 (2H, t), 2.85 (2H, m ), 2.96 (1H, m), 3.32 (1H, m), 3.80 (2H, t), 4.02 , 7.33 (11H, m), 7.46 (3H, m), 7.69 (1H, d), 7.89 (2H, m).
FAB Mass (M+H): 552FAB Mass (M + H): 552
실시예 13Example 13 2-(2-{3-[3-(3H-이미다졸-4-일)-프로필]-5-메틸-5-나프탈렌-1-일 -2,4-디옥소-이미다졸리딘-1-일}-아세틸아미노)-4-메틸설포닐- 부티릭산 리튬 염의 제조2- (2- {3- [3- (3H-imidazol-4-yl) -propyl] -5- methyl-5-naphthalen- 1-yl- 2,4-dioxo-imidazolidin- - yl} -acetylamino) -4-methylsulfonyl-butyric acid lithium salt
메티오닌 메틸 에스테르 대신 4-메틸설포닐-부티릭산 메틸 에스테르를 이용하여 상기 실시예 1과 같은 방법으로 제조하여표제화합물 24 mg을 얻었다.Methylsulfonyl-butyric acid methyl ester instead of methionine methyl ester in Example 1 to obtain 24 mg of the title compound.
FAB Mass (M+H): 576FAB Mass (M + H): 576
실시예 14Example 14 2-{2-[3-(3-이미다졸-1-일-프로필]-5-메틸-5-나프탈렌-1-일-2,4- 디옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭 산 리튬염의 제조2- {2- [3- (3-Imidazol-l-yl-propyl] -5-methyl-5-naphthalen- 1-yl-2,4-dioxo-imidazolidin- Acetylamino} -4-methylsulfanyl-butyric acid lithium salt
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 3-이미다졸-1-일-프로판올을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 24 mg을 얻었다.Prepared by the same method as in Example 1 using 3-imidazol-1-yl-propanol instead of 3- (3-triphenylmethyl-imidazol-4-yl) -propanol to yield 24 mg of the title compound.
ESI Mass (M-Li++2H): 552ESI Mass (M-Li < + & gt ; + 2H): 552
실시예 15Example 15 2-{2-[3-(2-이미다졸-1-일-에틸)-5-메틸-5-나프탈렌-1-일-2,4-다 이옥소-이미다졸리딘-1-일]-아세틸아미노}-4-메틸설파닐-부티릭산 리튬염의 제조Methyl-5-naphthalen-1-yl-2,4-dioxo-imidazolidin-1 -yl] -Acetylamino} -4-methylsulfanyl-butyric acid lithium salt
3-(3-트리페닐메틸-이미다졸-4-일)-프로판올 대신 2-이미다졸-1-일-에탄올을 이용하여 상기 실시예 1과 같은 방법으로 제조하여 표제화합물 27 mg을 얻었다.Prepared by the same method as in Example 1 using 2-imidazol-1-yl-ethanol instead of 3- (3-triphenylmethyl-imidazol-4-yl) -propanol to give the title compound 27 mg.
ESI Mass (M-Li++2H): 538ESI Mass (M-Li < + & gt ; + 2H): 538
본 발명의 화합물의 파네실 전이효소 억제능을 확인하기 위하여 하기와 같이 실험을 실시하였다.In order to confirm the inhibitory effect of the compounds of the present invention on the phenesyl transferase, experiments were carried out as follows.
〈실험예 1〉Ras 파네실 전이 효소 억제능 분석<Experimental Example 1> Ras panesyl transferase inhibition assay
본 실험에서는 폼프리아노(Pomplianoet al.; Biochemistry, 1992 , 31, 3800) 등의 방법을 개선하여 유전자 재조합 기술에 의해 제조된 Ras 파네실 전이효소를 사용하였으며, Ras 기질(Ras-CVLS) 단백질은 이미 보고된(Chunget al., Bichimica et Biophysica Act, 1992 , 278,1129) 방법에 의하여 정제 사용하였다.In this experiment, Ras panesyltransferase produced by recombinant DNA technology was used to improve Ras-CVLS protein (Ras-CVLS) protein by improving methods such as Pompliano et al .; Biochemistry, 1992 , Was purified by the method previously reported (Chung et al., Bichimica et Biophysica Act, 1992 , 278, 1129).
효소 반응은 25 mmol의 포타슘 클로라이드, 25 mmol의 마그네슘 클로라이드, 10 mmol DTT 및 50 μmol의 징크 클로라이드를 함유한 50 μl의 50 mM 소디움 히피스 완충용액에서 수행하였으며, 1.5 μmol의 Ras 기질 단백질, 0.15 μmol의 트리튬-파네실 피로 포스테이트와 4.5 nmol의 파네실 전이효소가 사용되었다.The enzyme reaction was carried out in 50 μl of 50 mM sodium hippite buffer containing 25 mmol of potassium chloride, 25 mmol of magnesium chloride, 10 mmol of DTT and 50 μmol of zinc chloride, and 1.5 μmol of Ras substrate protein, 0.15 μmol Of tris (4-hydroxyphenyl) pyransphosphate and 4.5 nmol of the phoenesis transferase were used.
상세히 기술하면 파네실 전이효소를 첨가한 후 37℃ 에서 30분간 반응을 지속시킨후 1 M의 염산을 함유한 에탄올 용액 1 ml 를 첨가하여 반응을 정지시키고, 생성된 침전물을 필터바인딩을 위한 호퍼 하베스터 (호퍼 #FH 225V)를 사용하여 GF/B 필터에 흡착시킨후, 에탄올을 사용하여 세척하고, 건조시킨 필터를 LKB 베타 카운터를 사용, 방사능을 측정하였다. 효소 역가검정은 Ras 기질 단백질과 파네실 효소의 농도가 정량적 역가를 나타내는 기질 불포화 상태에서 측정되었으며, 합성된 화합물은 디메틸설폭사이드(DMSO) 용매에 용해하여 전체 반응액의 5% 이내에서 첨가하여 효소 저해능을 평가하였다. 효소 저해능은 시료가 없는 상태에서 Ras 기질 단백질에 도입된 파네실에 대해 시료 존재하에서 측정된 파네실 도입량을 백분율로 표시하였으며, 50% 효소 활성을 저해하는 농도를 각 시료의 IC50으로 결정하였다. 시료의 선택적 저해능을 평가하기 위한 제라닐제라닐 전이효소는 샤버등 (Schaberet al.,J.Biol. Chem. 1990, 265, 14701)의 방법을 변형하여 소뇌로부터 정제하여 사용하였으며, 파네실 전이효소 반응과 유사 조건에서 제라닐제라닐 전이효소의 특이 기질인 제라닐제라닐 피로 포스페이트와 Ras-CVIL 기질 단백질을 사용하여 파네실 전이효소에 대한 실험방법과 동일하게 수행하였다.In detail, the reaction was continued for 30 minutes at 37 ° C. after the addition of the panesyl transferase enzyme. The reaction was terminated by adding 1 ml of 1 M hydrochloric acid-containing ethanol solution, and the resulting precipitate was transferred to hopper harvester (Hopper #FH 225V), washed with ethanol, dried, and the radioactivity was measured using a LKB beta counter. The enzyme activity test was carried out in the presence of Ras substrate protein and panesyl enzyme in the substrate unsaturated state, and the compound was dissolved in dimethylsulfoxide (DMSO) solvent and added within 5% of the total reaction solution. The performance was evaluated. The enzyme inhibitory activity was determined by the percentage of the panesyl introduced in the presence of the sample for the panesyl introduced into the Ras substrate protein in the absence of the sample, and the IC 50 of each sample was determined to inhibit the 50% enzyme activity. The geranyl geranyl transferase for the evaluation of the selective inhibitory activity of the sample was modified from the cerebellum by modification of the method of Schaber et al. (J. Biol. Chem. 1990, 265 , 14701) The enzymatic reaction was carried out in the same manner as in the experimental procedure for the Panesyl transferase using geranyl geranyl pyrophosphate and Ras-CVIL substrate protein, which are specific substrates of the geranyl geranyl transferase under similar conditions.
〈실험예 2〉세포내 Ras 파네실 전이효소의 억제효능 분석<Experimental Example 2> Inhibitory effect of intracellular Ras panesyltransferase
본 실험에서는 돌연 변이에 의해 형질 전환 활성을 갖는 C-Harvey-Ras 단백질을 발현하는 Rat2 세포주와 K-Ras의 카복시 말단의 다염기성 라이신 도메인으로 치환한 H-Ras와 결합 단백질로 형질전환된 Rat2 세포주(특허출원 제97-14409호)를 사용하였으며, 실험 방법은 드크루 등 (Declue. J. E.et al.,Cancer Research,1991,51, 712)에 의해 보고된 방법을 변형하여 수행하였다. 하기에 실험을 상세히 기술하기로 한다.In this experiment, Rat2 cell line expressing C-Harvey-Ras protein having transformation activity by mutation, H-Ras substituted with polybasic lysine domain of carboxy terminal of K-Ras, and Rat2 cell line transformed with binding protein (Patent Application No. 97-14409) was used, and the experimental method was carried out by modifying the method reported by Decque et al. (Dec. JE et al. , Cancer Research , 1991 , 51 , 712). Hereinafter, the experiment will be described in detail.
형질 전환된 Rat2 피브로 블라스트 세포주를 60mm 세포 배양 디쉬에 3×105세포를 분주하여 37℃ 세포 배양기에서 48 시간 동안 배양하여 50% 이상 밀도로 자란후 시료를 처리한다. 이때 시료용매는 디메틸설폭사이드(DMSO)를 사용하였으며, 대조군 및 시험군 모두 1% 디메틸설폭사이드 농도를 사용하렸다. 시료를 처리한 뒤 4시간 후에 배지 1 ㎖ 당 150 μCi의 방사성 동위원소(35S)로 표지된 메티오닌을 첨가하고 20시간 배양한 후 생리 식염수로 세포를 세척하였다. 세포 용해를 위해 1 ㎖의 차가운 세포 용해 완충 용액 (5 mmol의 마그네슘 클로라이드, 1 mmol의 DTT, 1% NP 40, 1 mmol의 EDTA, 1 mmol의 PMSF, 2 μmol의 루펩틴, 2 μmol의 펩스타틴 A 및 2 μmol의 안티페인을 포함하는 50 mM의 소디움 히피스 완충용액)을 사용하여, 세포가 용해된 상등액을 고속원심분리(12,000 g×5분)하여 얻었다. 상등액의 방사성 동이원소 표지량을 측정하여 면역 침전 반응시 정량적 결과를 얻을수 있도록 표준화한 후 Ras 단백질에 특이적 결합을 하는 단일클론 항체인 Y13-259 (Furth, M. E.et al.,J. Virol,1982,43, 294]를 넣어 4℃ 에서 15 시간 반응시켰다. 이 용액에 다시 고트에서 유래된 쥐의 면역글로블린에 대한 항체가 결합된 프로테인 A(Protein A)-아가로즈 현탁액을 넣어 1시간 동안 4℃에서 반응시킨 후 면역 반응 침전물을 비특이적 결합물을 제거하기 위해 완충용액(50 mmol의 소디움 클로라이드, 0.5% 소디움디옥시콜레이트, 0.5% NP 40 및 0.1% SDS를 포함하는 50 mM 트리스 클로라이드 완충욕액)으로 세척한다. 침전물의 분석을 위해 전기영동 방법을 사용하며, 침전물을 전기영동 시료 완충액에 끓인 후 13.5퍼센트의 SDS 폴리아크릴아마이드젤을 사용하여 전기영동을 수행하였다. 전기영동 후 젤을 고정하고 건조시킨 다음 X-ray 필름에 감광시킨 후 현상 인화하였다. 실험결과로부터 세포내 Ras 파네실 전이효소의 억제 효능은 Ras 단백질의 파네실이 결합된 밴드와 결합되지 않은 밴드의 강도를 측정하여 50%의 파네실 결합이 저해된 시료농도를 CIC50로 결정하였다.The transformed Rat2 fibroblast cell line is divided into 3 × 10 5 cells in a 60 mm cell culture dish, cultured in a 37 ° C. cell incubator for 48 hours, grown to a density of 50% or more, and treated. At this time, dimethyl sulfoxide (DMSO) was used as a sample solvent, and 1% dimethyl sulfoxide concentration was used in both the control and test groups. Methionine labeled with 150 μCi of radioisotope ( 35 S) per ml of medium was added for 4 hours after the sample was treated, and the cells were washed with physiological saline after culturing for 20 hours. For cell lysis, 1 ml of cold cell lysis buffer (5 mmol of magnesium chloride, 1 mmol of DTT, 1% NP 40, 1 mmol of EDTA, 1 mmol of PMSF, 2 μmol of rupeptin, 2 μmol of pepstatin A and 50 mM sodium hypophosphate buffer containing 2 μmol of antipain) was obtained by high-speed centrifugation (12,000 g × 5 min) of the supernatant in which the cells were dissolved. The radioactive iodine labeling of the supernatant was standardized to obtain quantitative results in the immunoprecipitation reaction, and then the monoclonal antibody Y13-259 (Furth, ME et al. , J. Virol , 1982 , 43 , 294], and reacted for 15 hours at 4 ° C. To this solution, protein A-agarose suspension to which the antibody against the immunoglobulin of the rat derived from the gut was added, (50 mM Tris-HCl buffer buffer containing 50 mmol of sodium chloride, 0.5% sodium deoxycholate, 0.5% NP40 and 0.1% SDS) to remove nonspecific binding. The electrophoresis was carried out using 13.5% SDS polyacrylamide gel after boiling the precipitate in electrophoresis sample buffer. . After the electrophoresis, the gel was fixed, dried, sensitized to X-ray film, and then developed for development. From the experimental results, the inhibitory effect of intracellular Ras kinetic transferase was not associated with the band of Panesyl- The intensity of the band was measured to determine the sample concentration at which 50% panesyl bonding was inhibited as CIC 50 .
본 발명에서 얻어진 화합물들에 대하여 상기와 같은 실험을 수행한 결과 IC50은 50 μM 이하에서, CIC50은 100 μM 이하에서 파네실 전이효소의 작용을 억제하는 것으로 나타났다.As a result of the above experiments, the compounds obtained in the present invention were found to inhibit the action of the panesyl transferase at an IC 50 of 50 μM or less and a CIC 50 of 100 μM or less.
이상에서 살펴본 바와 같이, 본 발명의 화합물은 Ras 단백질의 파네실기를 전이하는 효소인 파네실 전이효소의 작용을 억제함으로써 Ras 단백질의 작용을 억제하는 신규한 하이덴토인 유도체 화합물이다.As described above, the compound of the present invention is a novel herbicide derivative compound that inhibits the action of the Ras protein by inhibiting the action of the panesyltransferase, an enzyme that transfers the panesyl group of the Ras protein.
본 발명의 화합물은, Ras 파네실 전이효소 억제효능 분석실험 결과에서도 알 수 있듯이(IC50≤ 50 μM, CIC50≤ 100 μM) 우수한 파네실 전이효소 억제능을 가짐으로써 항암제로 유용하게 이용될 수 있다.The compound of the present invention can be effectively used as an anticancer agent by having an excellent inhibitory effect on panesyltransferase (IC 50 ≤ 50 μM, CIC 50 ≤ 100 μM) as shown in the results of the Ras panesyltransferase inhibitory activity assay .
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| KR1019970035333A KR19990012061A (en) | 1997-07-26 | 1997-07-26 | HYDENTOIN DERIVATIVES USEFUL AS PANESSyltransferase inhibitor |
| KR1019980029459A KR100384116B1 (en) | 1997-07-26 | 1998-07-22 | Hydantoin derivative having farnesyl transferase inhibiting activity |
| US09/463,551 US6384061B1 (en) | 1997-07-26 | 1998-07-24 | Hydantoin compounds and methods related thereto |
| AU84647/98A AU729341B2 (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitory activity for farnesyl transferase |
| JP2000504116A JP2001510829A (en) | 1997-07-26 | 1998-07-24 | Hydantoin Derivatives with Funesyltransferase Inhibitory Activity |
| ZA986623A ZA986623B (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitor activity for farnesyl transferase |
| PCT/KR1998/000225 WO1999005117A1 (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitory activity for farnesyl transferase |
| EP98935376A EP1000036A1 (en) | 1997-07-26 | 1998-07-24 | Hydantoin derivatives having an inhibitory activity for farnesyl transferase |
| ARP980103683A AR015412A1 (en) | 1997-07-26 | 1998-07-27 | HYDANTOIN DERIVATIVES THAT SHOW AN INHIBITING ACTIVITY AGAINST FARNESIL TRANSFERASA, PROCEDURE FOR THE PREPARATION AND COMPOSITION OF ANTI-CANCERQUE UNDERSTANDS THESE DERIVATIVES |
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| WO2003018135A1 (en) * | 2001-08-24 | 2003-03-06 | Wyeth Holdings Corporation | Method of using 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones for inhibition of farnesyl-protein transferase |
| WO2003018554A1 (en) | 2001-08-24 | 2003-03-06 | Wyeth Holdings Corporation | 3-substituted-3-(substitutedsulfonyl or sulfanyl)pyrrolidine-2,5-diones useful for inhibition of farnesyl-protein transferase |
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