KR100710991B1 - 3-Cyclobutene-1,2-dione derivatives and processes for the preparation thereof - Google Patents

3-Cyclobutene-1,2-dione derivatives and processes for the preparation thereof Download PDF

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KR100710991B1
KR100710991B1 KR1020010045319A KR20010045319A KR100710991B1 KR 100710991 B1 KR100710991 B1 KR 100710991B1 KR 1020010045319 A KR1020010045319 A KR 1020010045319A KR 20010045319 A KR20010045319 A KR 20010045319A KR 100710991 B1 KR100710991 B1 KR 100710991B1
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cyclobutene
dione
amino
benzyloxycarbonyl
lucyl
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KR20030010397A (en
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이종욱
이봉용
이춘호
황현준
김남철
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주식회사유한양행
동아제약주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms

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Abstract

본 발명은 시스테인 프로티아제 (Cysteine proteases), 특히 파파인 (Papain) 계열의 카뎁신 (Cathepsins)에 우수한 억제 활성을 갖는 신규의 3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염, 이들의 제조방법, 및 이들을 유효성분으로 포함하는 조성물에 관한 것이다.
The present invention relates to novel 3-cyclobutene-1,2-dione derivatives or non-toxic salts thereof having excellent inhibitory activity against Cysteine proteases, especially Papain family of Cadepsins. It relates to a method for producing and a composition comprising these as an active ingredient.

3-사이클로부텐-1,2-다이온, 시스테인 프로티아제, 카뎁신3-cyclobutene-1,2-dione, cysteine protease, capidine

Description

3-사이클로부텐-1,2-다이온 유도체 및 그의 제조방법 {3-Cyclobutene-1,2-dione derivatives and processes for the preparation thereof}3-cyclobutene-1,2-dione derivatives and method for preparing the same {3-Cyclobutene-1,2-dione derivatives and processes for the preparation etc}

본 발명은 시스테인 프로티아제 (Cysteine proteases), 특히 파파인 (Papain) 계열의 카뎁신 (Cathepsins)에 우수한 억제 활성을 갖는 신규의 3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염, 이들의 제조방법, 및 이들을 유효성분으로 포함하는 조성물에 관한 것이다.The present invention relates to novel 3-cyclobutene-1,2-dione derivatives or non-toxic salts thereof having excellent inhibitory activity against Cysteine proteases, especially Papain family of Cadepsins. It relates to a method for producing and a composition comprising these as an active ingredient.

시스테인 프로티아제, 특히 파파인 (Papain) 계열의 카뎁신 (Cathepsins)은 인간을 포함한 동물에서 생리학적 단백질 분해과정, 예를들어 결체조직(connective tissue)의 분해과정에 관여한다. 그러나, 생체내에서 이들 효소가 증가할 경우 다양한 질병을 유발할 수 있다. 예를들어, 칼페인 (Calpain) 프로티아제는 뇌졸증(Stroke)이나 기타의 알쯔하이머 질병과 같은 신경퇴행성 질환 (Neurogdegenerative disease)에 관여하는 것으로 보고되고 있고 [G. J. Wells, et. al., Exp. Opin. Ther. Patents, 8(12), 1707(1998)], 카뎁신 B (Cathepsin B)는 암의 전이 (Metastasis)에 관여하는 것으로 보고되고 있으며 [S. Michaud, et.al., Exp. Opin. Ther. Patents, 8(6), 645(1998)], 카뎁신 L (Cathepsin L)은 만성 류마티스 관절염 (Chronic rheumatoid arthritis) 및 골관절염 (Osteoarthritis)에 관여하는 것으로 보고되고 있으며 [H-H Otto & T. Schirmeister, Chem. Rev., 97, 133(1997)], 카뎁신 S (Cathepsin S)는 만성기도폐색증상 (Chronic Obstructive Pulomonary Disease, COPD)에 관여하는 것으로 보고되고 있다 [WO0049007, WO0049008, WO0048992]. 이밖에도 파파인 (Papain) 계열 이외에서, 케스페이스 (Caspase) 프로티아제들은 골관절염 (Osteoarthritis)을 비롯한 여러 염증 질환에 연관되고 있는 것으로 보고되고 있으며, 여러 종류의 메탈로프로티아제 (Metaloprotease)들은 고혈압 (hypertension), 종양 (Tumor) 및 관절염 (Arthritis)을 포함하는 염증 질환과 연계되어 있는 것으로 보고되고 있으며 [D. D. Fairlie et. al. J. Med. Chem., 43(3), 305(2001)], 리노바이러스 3C (Rhinovirus 3C) 프로티아제는 감기 질환에 관여하는 것으로 보고되고 있다 [Q. M. Wang, Exp. Opin. Ther. Patent, 8(9), 1151(1998)].Cysteine proteases, in particular Papain family of Catepsins, are involved in physiological proteolytic processes in animals, including humans, for example, the degradation of connective tissue. However, increasing these enzymes in vivo can cause a variety of diseases. For example, Calpain proteases have been reported to be involved in neurodegenerative diseases such as stroke or other Alzheimer's disease [G. J. Wells, et. al., Exp. Opin. Ther. Patents, 8 (12), 1707 (1998)], and Catepsin B, have been reported to be involved in metastasis of cancer, and [S. Michaud, et.al., Exp. Opin. Ther. Patents, 8 (6), 645 (1998)], and Cadepsin L, are reported to be involved in chronic rheumatoid arthritis and Osteoarthritis, [HH Otto & T. Schirmeister, Chem . Rev., 97, 133 (1997)], Cadepsin S has been reported to be involved in Chronic Obstructive Pulomonary Disease (COPD) [WO0049007, WO0049008, WO0048992]. In addition to the Papain family, caspase proteases have been reported to be associated with a variety of inflammatory diseases including osteoarthritis, and various types of metalloproteases have been described as hypertension ( hypertension, tumor, and arthritis, which have been reported to be associated with inflammatory diseases [D. D. Fairlie et. al. J. Med. Chem., 43 (3), 305 (2001)], rhinovirus 3C proteases have been reported to be involved in cold disease [Q. M. Wang, Exp. Opin. Ther. Patent, 8 (9), 1151 (1998).

특히 이중에서도, 카뎁신 K (Cathepsin K)는 뼈의 재형성 (remodeling) 과정에 있어서 뼈의 흡수에 관여하는 파골세포(osteoclasts)에 선택적이면서도 다량으로 분포하면서 뼈의 유기질 분해과정에서 중추적인 역할을 담당한다는 사실이 규명되면서부터, 이 프로티아제 저해기전을 표적으로 하는 새로운 골다공증 치료제를 개발하려는 많은 시도가 있다. [W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9(6), 683 (1999)]Especially among them, catepsin K plays a pivotal role in the bone's organic breakdown, with selective and large distribution of osteoclasts involved in bone resorption in bone remodeling. Since it has been identified, many attempts have been made to develop new therapeutic agents for osteoporosis that target this protease inhibitory mechanism. [W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9 (6), 683 (1999)]

예를 들어, 비닐술폰기를 갖는 유사펩타이드가 카뎁신 K를 포함하는 시스테 인 프로티아제에 대하여 비가역적 저해작용을 갖는다는 것이 개시된 바 있다. [J. T. Palmer, et. al., J. Med. Chem., 38, 3139 (1995); W. W. Roush, et. al., J. Am. Chem. Soc., 120, 10994 (1998)]For example, it has been disclosed that analogous peptides with vinylsulfone groups have an irreversible inhibitory effect on cysteine proteases, including kadepsin K. [J. T. Palmer, et. al., J. Med. Chem., 38, 3139 (1995); W. W. Roush, et. al., J. Am. Chem. Soc., 120, 10994 (1998)]

또한, 1,3-다이아미노-프로판-2-온을 기본구조로 하여 다수의 펩타이드성 및 유사펩타이드 유도체들이 카뎁신 K를 포함하는 시스테인 프로티아제에 대하여 가역적 저해작용을 갖는다는 것이 개시된 바 있다. [D. S. Yamashita, et. al., J. Am. Chem. Soc., 119, 11351 (1997); S. K. Thompson, et. al., Proc. Nacl. Acad. Sci., 94, 14249 (1997); WO9808802; WO9848799; WO9849152, WO9850342; WO9850534; WO9911637] It has also been disclosed that, based on 1,3-diamino-propan-2-one, a number of peptidic and similar peptide derivatives have a reversible inhibitory action on cysteine proteases, including kadepsin K. . [D. S. Yamashita, et. al., J. Am. Chem. Soc., 119, 11351 (1997); S. K. Thompson, et. al., Proc. Nacl. Acad. Sci., 94, 14249 (1997); WO9808802; WO9848799; WO9849152, WO9850342; WO9850534; WO9911637]

이밖에도, 펩타이드성 알데히드(JP8092193; JP8151394; JP10147564; WO9825899) 및 펩타이드성 에폭시숙신아마이드(WO9847887)가 시스테인 프로티아제에 대한 비가역 저해제로서 개시된 바 있으며, 펩타이드성 3-케토-헤테로고리 유도체(WO9850533)가 카뎁신 K 저해제로서 개시된 바 있다.In addition, peptidic aldehydes (JP8092193; JP8151394; JP10147564; WO9825899) and peptidic epoxy succinamides (WO9847887) have been disclosed as irreversible inhibitors for cysteine proteases, and peptidic 3-keto-heterocyclic derivatives (WO9850533) It has been disclosed as a kadipsin K inhibitor.

그러나, 상기 선행기술에서 개시된 화합물은 대부분 펩타이드성 고분자 화합물이기 때문에, 생체내 가수분해 효소 등에 불안정한 경향을 갖고 있어서 실제로 골다공증 치료제를 포함한 각종 질환의 치료제로 개발하기에는 어려움이 많은 것으로 보고되고 있다. [M. Sato, et. al., J. Med. Chem., 42, 3 (1999); W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9(6), 683 (1999)]
However, since the compounds disclosed in the prior art are mostly peptidic polymer compounds, they have a tendency to be unstable in vivo hydrolase and the like, and it is reported that there are many difficulties in developing them in the treatment of various diseases including osteoporosis therapeutics. [M. Sato, et. al., J. Med. Chem., 42, 3 (1999); WW Smith, et. al., Exp. Opin. Ther. Patents, 9 (6), 683 (1999)]

이에 본 발명자들은 새로운 기본구조를 갖는 시스테인 프로티아제 저해제를 개발하고자 연구를 거듭한 결과, 3-사이클로부텐-1,2-다이온 유도체가 카뎁신 K를 포함한 시스테인 프로티아제를 효과적으로 억제한다는 것을 발견하여 본 발명을 완성하게 되었다. Therefore, the present inventors have conducted research to develop a cysteine protease inhibitor having a new basic structure, and as a result, the 3-cyclobutene-1,2-dione derivative effectively inhibits cysteine protease including kadipsin K. Discovered to complete the present invention.

따라서, 본 발명은 시스테인 프로티아제에 우수한 억제 활성을 갖는 3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염을 제공하는 것을 목적으로 한다.Accordingly, an object of the present invention is to provide a 3-cyclobutene-1,2-dione derivative or a nontoxic salt thereof having excellent inhibitory activity on cysteine proteases.

또한, 본 발명의 목적은 이들의 제조방법을 제공하는 것을 포함한다.It is also an object of the present invention to provide methods for their preparation.

또한, 본 발명의 목적은 이들을 유효성분으로 포함하는 시스테인 프로티아제 억제 조성물을 제공하는 것을 포함한다.
It is also an object of the present invention to provide a cysteine protease inhibitor composition comprising these as an active ingredient.

본 발명에 따라, 시스테인 프로티아제 특히, 파파인 계열의 카뎁신에 우수한 억제 활성을 갖는 하기 화학식 1로 표시되는 3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염이 제공된다.According to the present invention, there is provided a 3-cyclobutene-1,2-dione derivative represented by the following general formula (1) having a superior inhibitory activity on cysteine proteases, in particular, papain-based capidine, or a non-toxic salt thereof.

Figure 112001018636964-pat00013
Figure 112001018636964-pat00013

상기 식에서, R1은 (N-벤질옥시카보닐-루실)아미노이다. Wherein R 1 is (N-benzyloxycarbonyl-lusyl) amino.

R2 는 메톡시; 하이드록시; 페녹시벤질옥시; 피리딜프로폭시; 직쇄상 또는 분지상 C2-C7 알킨일; 페닐아세틸렌-1-일; 나프틸; 티오펜일; 퓨릴; 아지도; 시아노; 2,3-다이옥소인돌일; 메톡시벤질설파닐; 피리딜; 또는 페녹시, 사이클로펜틸옥시, 또는 2,2,3,3-테트라플루오로프로필옥시로 치환된 피리딜이거나,R 2 is methoxy; Hydroxy; Phenoxybenzyloxy; Pyridylpropoxy; Straight or branched C 2 -C 7 alkynyl; Phenylacetylen-1-yl; Naphthyl; Thiophenyl; Furyl; Azido; Cyano; 2,3-dioxoindoleyl; Methoxybenzylsulfanyl; Pyridyl; Or pyridyl substituted with phenoxy, cyclopentyloxy, or 2,2,3,3-tetrafluoropropyloxy, or

화학식 2, 3, 또는 4의 기를 나타낸다.Group represented by the formula (2), (3) or (4).

Figure 112001018636964-pat00018
Figure 112001018636964-pat00018

Figure 112001018636964-pat00003
Figure 112001018636964-pat00003

Figure 112001018636964-pat00004
Figure 112001018636964-pat00004

R3 는 직쇄상 또는 분지상 C1-C4 알킬; 페닐; 직쇄상 또는 분지상 C1 -C4 알킬, 모노- 또는 디- 할로겐, 시아노, 다이메톡시, 또는 트라이플루오로메톡시로 치환된 페닐; 벤질옥시; 티오펜; 또는 퀴놀린을 나타낸다.R 3 is straight or branched C 1 -C 4 alkyl; Phenyl; Phenyl substituted with straight or branched C 1 -C 4 alkyl, mono- or di-halogen, cyano, dimethoxy, or trifluoromethoxy; Benzyloxy; Thiophene; Or quinoline.

R4 는 수소; C1-C3 알킬; C3-C7 환상 알킬; 페닐; 페녹시페닐; 나프틸; 벤질;
R 4 is hydrogen; C 1 -C 3 alkyl; C 3 -C 7 cyclic alkyl; Phenyl; Phenoxyphenyl; Naphthyl; benzyl;

모노- 또는 디- 할로게노페닐; 벤질옥시페닐; 또는 바이페닐을 나타낸다.Mono- or di-halogenophenyl; Benzyloxyphenyl; Or biphenyl.

R5 는 수소; 아이소부티릴; t-부톡시카보닐; C3-C7 환상알킬카보닐; 퓨로일; 몰포린카보닐; 나프토일; 벤조일; 클로로벤조일; 벤젠설포닐; 다이클로로벤젠설포닐; 톨릴카바모일; 또는 벤질티오카바모일을 나타낸다,R 5 is hydrogen; Isobutyryl; t-butoxycarbonyl; C 3 -C 7 cyclicalkylcarbonyl; Furoyl; Morpholinecarbonyl; Naphthoyl; Benzoyl; Chlorobenzoyl; Benzenesulfonyl; Dichlorobenzenesulfonyl; Tolyl carbamoyl; Or benzylthiocarbamoyl,

본 발명에 따른 화합물은 무독성 염의 형태일 수 있으며, 그 염으로는 프로티아제 저해제 분야에서 통상적으로 사용가능한 무독성염, 예를 들면, 비독성 무기산 또는 유기산으로부터 생성된 염의 형태일 수 있다. 이러한 통상적인 비독성 염에는 염산, 브롬화수소산, 황산, 설팜산, 인산, 질산, 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 말레산, 하이드록시말레산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 설파닐산, 2-아세톡시-벤조산, 푸마르산, 톨루엔술폰산, 메탄다이술폰산, 에탄다이술폰산, 옥살산, 또는 트리플루오로아세트산으로부터 제조된 염을 포함한다.The compounds according to the invention may be in the form of non-toxic salts, which may be in the form of non-toxic salts commonly used in the field of protease inhibitors, for example salts produced from non-toxic inorganic or organic acids. Such conventional non-toxic salts include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, Salts prepared from sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanedisulfonic acid, ethanedisulfonic acid, oxalic acid, or trifluoroacetic acid.

본 발명에 따른 화합물의 무독성 염은 염기성 잔기를 함유하는 본 발명의 화합물로부터 통상적인 방법으로 제조할 수 있다. 일반적으로, 염은 유기 염기를 화학량론적 양 또는 과량의 목적하는 염-형성 무기산 또는 유기산과 적합한 용매 또는 용매들의 다양한 배합물 중에서 반응시켜 제조할 수 있다.Non-toxic salts of the compounds according to the invention can be prepared by conventional methods from compounds of the invention containing basic moieties. In general, salts can be prepared by reacting an organic base in a stoichiometric amount or in excess of the desired salt-forming inorganic or organic acid with a suitable solvent or various combinations of solvents.

또한, 본 발명은 화학식5의 화합물에 R2-Li 또는 R2-MgBr을 반응시켜 화학식6의 화합물을 제조한 후, 본 발명자들의 선행출원 제2000-4835호 및 제2000-4836호 에서 개시한 제조방법에 따라 화학식6의 화합물로 부터 화학식1의 화합물 또는 그의 무독성 염을 제조하는 제조방법을 포함한다.In addition, the present invention after producing the compound of formula (VI) by reacting the Li or R 2- R 2 -MgBr to a compound of formula (5) disclosed in the prior application by the present inventors 2000-4835) and (2000-4836 No. It includes a method for producing a compound of Formula 1 or a non-toxic salt thereof from the compound of Formula 6 according to the preparation method.

또한, 화학식5의 화합물에, 공지의 방법 [L, S. Liebeskind, et. al., J. Org. Chem., 58, 3543 (1980)]에 따라, (트라이-n-부틸스텐닐)트라이메틸실란을 반응시켜 화학식7a의 화합물을 제조한 후, 화학식7a의 화합물에 R1-할라이드를 반응시켜 화학식7b의 화합물을 제조할수 있다. In addition, to the compound of formula (5), known methods [L, S. Liebeskind, et. al., J. Org. Chem., 58, 3543 (1980)] to prepare a compound of formula 7a by reacting (tri-n-butylstenyl) trimethylsilane, and then reacting the compound of formula 7a with R 1 -halide The compound of 7b can be prepared.

또한, 화학식7b의 화합물에 R2-할라이드를 반응시켜 화학식1의 화합물을 제조할 수 있으며, 이 단계는 팔라듐, 또는 벤질클로로비스(트라이페닐포스핀)팔라듐 및/또는 염화구리 등의 촉매존재하에서 반응시키는것이 바람직하다. In addition, the compound of Formula 1 may be prepared by reacting a compound of Formula 7b with R 2 -halide, and this step may be performed in the presence of a catalyst such as palladium or benzylchlorobis (triphenylphosphine) palladium and / or copper chloride. It is preferable to react.

이를 반응식으로 나타내면 다음과 같다.This is represented by the following scheme.

Figure 112001018636964-pat00019
Figure 112001018636964-pat00019

상기 반응식에서 SnBu3는 트라이-n-부틸스텐닐을 나타내고, R6는 직쇄상 또는 분지상 C1-C4 알킬이며, R1 및 R2는 상기에서 정의한 바와 동일하다. In the above scheme, SnBu 3 represents tri-n-butylstenyl, R 6 is linear or branched C 1 -C 4 alkyl, and R 1 and R 2 are the same as defined above.

상기 제조방법에서 바람직한 반응용매로는 테트라하이드로퓨란, 다이메틸포 름아마이드, 에틸에테르 등의 극성 유기용매가 포함되며, 반응온도는 통상적으로 -50 ∼ 80 ℃, 더욱 바람직하게는 상온이 바람직하다.Preferred reaction solvents in the preparation method include polar organic solvents such as tetrahydrofuran, dimethylformamide and ethyl ether, and the reaction temperature is usually -50 to 80 ° C, more preferably room temperature.

본 발명은 화학식 1의 화합물 또는 그의 무독성 염을 유효성분으로 함유하고 약제학적으로 허용 가능한 담체를 함유하는 시스테인 프로티아제 억제 조성물을 포함한다. The present invention includes a cysteine protease inhibitory composition containing a compound of formula (1) or a nontoxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

본 발명에 따른 조성물은 락토즈, 옥수수전분 등의 부형제, 마그네슘 스테아레이트 등의 윤활제, 공지되어 사용가능한 유화제, 현탁제, 완충제, 등장화제 등을 포함할 수 있으며, 경우에 따라 감미제 및/또는 향미제를 포함할 수 있다.The composition according to the invention may comprise excipients such as lactose, corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, isotonic agents and the like which are well known and can be used, and in some cases sweetening and / or flavoring It may include the agent.

본 발명에 따른 조성물은 경구투여하거나, 정맥내, 복강내, 피하, 직장 및 국소 투여를 포함한 비경구 투여를 실시할 수 있다. 즉, 본 발명에 따른 조성물은 정제 또는 캡슐제 형태로, 또는 수성용제 또는 현탁제로서 투여할 수 있다. 경구용 정제의 경우 통상 사용되는 담체에는 락토즈 및 옥수수 전분이 포함되고, 마그네슘 스테아레이트와 같은 윤활제를 통상 가할 수 있다. 캡슐제 형태의 경우 유용한 희석제로서 락토즈 및 건조 옥수수 분말을 포함할 수 있다. 경구용으로 수성 현탁제가 필요할 경우 유화제 및 현탁제를 포함할 수 있다. 경우에 따라 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 통상 활성 성분의 멸균 용액을 제조하고, 용액의 pH를 적합하게 조절할 수 있는 완충제를 포함할 수 있으며, 정맥내 투여의 경우 등장화제를 포함할 수 있다. 또한, 본 발명에 따른 조성물은 pH가 7.4인 염수와 같은 약제학적으로 허용되는 담체를 포함하는 수용액제의 형태가 될 수 있으며, 용액제의 형태로 국소적으로 환자의 근육내 혈류에 도입할 수 있다.The composition according to the invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, rectal and topical administration. That is, the composition according to the present invention may be administered in the form of a tablet or capsule, or as an aqueous solvent or suspension. In the case of oral tablets, carriers commonly used include lactose and corn starch, and lubricants such as magnesium stearate can usually be added. Useful diluents for capsule form may include lactose and dry corn powder. If an aqueous suspension is required for oral use, it may include emulsifiers and suspensions. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, a sterile solution of the active ingredient is usually prepared, and may include a buffer that can suitably adjust the pH of the solution, and for intravenous administration will include isotonic agents. Can be. In addition, the composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4, and may be locally introduced into the patient's intramuscular blood flow in the form of a solution. have.

본 발명에 따른 화합물은 인간을 포함한 포유동물의 치료를 위하여 시스테인 계열의 프로티아제 활성을 효과적으로 억제함으로써 골다공증 (Osteoporosis), 골관절염 (Osteoarthritis), 고칼슘 (Hypercalcemia) 질환, 파제트 (Pagets) 질환, 류마티스 관절염 (Rheumatoid Arthritis), 또는 기타 골질환 (Bone disease) 환자에게 투여될 수 있다. 또한, 뇌졸증 (Stroke), 알쯔하이머 질환 (Alzheimers disease), 감기 질환, 또는 암의 전이 (Cancer Metastasis)에 해당하는 암환자에도 투여될 수 있으며, 투여용량은 통상 0.1㎍ ∼ 1,000mg 범위로 경구, 정맥내, 근육내 등으로 투여될 수 있으나, 각 환자의 연령, 체중, 또는 환자의 증상에 따라 투여용량을 변화시켜 투여될 수 있다.The compound according to the present invention effectively inhibits cysteine-based proteases activity for the treatment of mammals including humans, thereby causing osteoporosis, osteoarthritis, hypercalcemia disease, Pagets disease, rheumatoid It may be administered to patients with Rheumatoid Arthritis, or other Bone disease. It can also be administered to cancer patients with stroke, Alzheimer's disease, cold disease, or cancer metastasis, and the dosage is usually in the range of 0.1 μg to 1,000 mg. It may be administered intramuscularly, intramuscularly, etc., but may be administered by varying the dosage depending on the age, weight, or symptoms of each patient.

이하, 본 발명 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다.
Hereinafter, the present invention will be described in more detail. However, this does not limit the scope of the invention.

실시예 1. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온의 제조Example 1. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione

3-아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (1.0 g, 15.7 mmol)을 다이클로로메탄/다이메틸포름아마이드 (40 ml/30 ml) 용액에 녹인 후에 N-벤질옥시카보닐-L-루실 (4.17 g, 15.7 mmol), 1-하이드록시벤조트리아졸 (HOBt; 2.34 g, 17.3 mmol), 트라이에틸아민 (3.3 ml, 21.3 mmol), 1-에틸-3-(3-다이메틸 아미노프로필)카보다이아미드 염산염 (EDC; 3.32 g, 17.3 mmol)을 가하고 실온에서 24시간 교반하였다. 반응용액을 다이클로로메탄으로 희석한 후에 유기층을 중조 포화 용액으로 세척하고 건조 및 농축한다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (1.4 g)을 수득하였다.3-amino-4-methoxy-3-cyclobutene-1,2-dione (1.0 g, 15.7 mmol) was dissolved in dichloromethane / dimethylformamide (40 ml / 30 ml) solution and then N-benzyl Oxycarbonyl-L-Lucyl (4.17 g, 15.7 mmol), 1-hydroxybenzotriazole (HOBt; 2.34 g, 17.3 mmol), triethylamine (3.3 ml, 21.3 mmol), 1-ethyl-3- ( 3-dimethyl aminopropyl) carbodiamide hydrochloride (EDC; 3.32 g, 17.3 mmol) was added and stirred at room temperature for 24 hours. After diluting the reaction solution with dichloromethane, the organic layer is washed with a saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.4 g).

1H NMR (CDCl3) δ 9.94 (s, 1H), 7.20-7.40 (s, 5H), 5.33 (d, 1H), 5.17 (s, 2H), 4.56 (s, 3H), 1.60-1.80 (m, 3H), 0.90-1.00 (m, 6H)
 1 H NMR (CDCl 3 ) δ 9.94 (s, 1H), 7.20-7.40 (s, 5H), 5.33 (d, 1H), 5.17 (s, 2H), 4.56 (s, 3H), 1.60-1.80 (m , 3H), 0.90-1.00 (m, 6H)

실시예 2. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(3-페녹시벤질옥시)-3-사이클로부텐-1,2-다이온의 제조Example 2. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenoxybenzyloxy) -3-cyclobutene-1,2-dione

실시예 1의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (100 mg, 0.27 ml)과 3-페녹시벤질알콜 (56 ml)을 톨루엔 (2 ml)에 녹인 후에 120oC에서 4시간동안 교반한다. 용매를 제거한 후에 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (16 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione (100 mg, 0.27 ml) and 3-phenoxy of Example 1 Benzyl alcohol (56 ml) is dissolved in toluene (2 ml) and then stirred at 120 ° C. for 4 hours. After removing the solvent the residue was purified by silica gel chromatography to give the title compound (16 mg).

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.8(m, 3H), 4.43(brs, 1H), 5.12(s, 2H), 5.42(d, 1H), 5.80(s, 2H), 7.0-7.4(m, 14H), 10.00(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.8 (m, 3H), 4.43 (brs, 1H), 5.12 (s, 2H), 5.42 (d, 1H), 5.80 (s , 2H), 7.0-7.4 (m, 14H), 10.00 (s, 1H)

실시예 3. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[3-(4-피리딜)프로필옥시]-3-사이클로부텐-1,2-다이온의 제조Example 3. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [3- (4-pyridyl) propyloxy] -3-cyclobutene-1,2-dione

실시예 2의 3-페녹시벤질알콜 대신에 3-(4-피리딜)프로판올을 사용하는 것을 제외하고는, 실시예 2과 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method as Example 2 except for using 3- (4-pyridyl) propanol instead of 3-phenoxybenzyl alcohol of Example 2.

1H NMR (CDCl3) δ 0.9-1.1(m, 6H), 1.6-1.8(m, 3H), 2.04(m, 2H), 2.74(t, 2H), 4.20(t, 2H), 4.42(m, 1H), 5.18(s, 2H), 7.15(d, 2H), 7.4(s, 5H), 8.57(d, 2H)
 1 H NMR (CDCl 3 ) δ 0.9-1.1 (m, 6H), 1.6-1.8 (m, 3H), 2.04 (m, 2H), 2.74 (t, 2H), 4.20 (t, 2H), 4.42 (m , 1H), 5.18 (s, 2H), 7.15 (d, 2H), 7.4 (s, 5H), 8.57 (d, 2H)

실시예 4. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-하이드록시-3-사이클로부텐-1,2-다이온의 제조Example 4. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-hydroxy-3-cyclobutene-1,2-dione

실시예 1의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (100 mg, 0.27 ml)과 염산 1N 수용액 (2 ml) 혼합물을 50oC에서 4시간동안 교반한 후, 용매를 제거시키고 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (10 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione (100 mg, 0.27 ml) of Example 1 and aqueous 1N hydrochloric acid solution ( 2 ml) The mixture was stirred at 50 ° C. for 4 hours, then the solvent was removed and purified via silica gel chromatography to give the title compound (10 mg).

1H NMR (DMSO-d6 + TFA) δ 7.20-7.60 (m, 5H), 5.00-5.20 (s, 2H), 4.40 (m, 1H), 1.35-1.90 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (DMSO-d6 + TFA) δ 7.20-7.60 (m, 5H), 5.00-5.20 (s, 2H), 4.40 (m, 1H), 1.35-1.90 (m, 3H), 0.80-1.20 (m , 6H)

실시예 5. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-비닐-3-사이클로부텐-1,2-다이온의 제조Example 5. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-vinyl-3-cyclobutene-1,2-dione

단계 1. 3-에톡시-4-메틸-3-사이클로부텐-1,2-다이온의 제조 Step 1. Preparation of 3-ethoxy-4-methyl-3-cyclobutene-1,2-dione                     

다이에틸스쿠아레이트 (1.5 g, 8.82 mmol)과 무수 테트라하이드로퓨란 (45 ml) 혼합용액에 1.0 M 비닐리튬 (8.82 ml, 8.82 mmol)을 -78oC에서 첨가한 후 혼합물을 10분간 교반하였다. 무수 트라이플루오로아세트산 (1.49 ml, 10.6 mmol)과 10% 염화암모늄 수용액 (7.5 ml)을 -78oC에서 첨가한 후 상온까지 교반하였다. 혼합물을 에테르와 5% 중조로 층분리 후 유기층을 건조 및 정제하여 표제화합물 (700 mg)을 수득하였다.1.0 M vinyllithium (8.82 ml, 8.82 mmol) was added to a mixed solution of diethylsquarate (1.5 g, 8.82 mmol) and anhydrous tetrahydrofuran (45 ml) at -78 ° C, and the mixture was stirred for 10 minutes. . Trifluoroacetic anhydride (1.49 ml, 10.6 mmol) and 10% aqueous ammonium chloride solution (7.5 ml) were added at -78 ° C. and then stirred to room temperature. The mixture was layered with ether and 5% sodium bicarbonate, and the organic layer was dried and purified to give the title compound (700 mg).

1H NMR (CDCl3) δ 4.78 (q, 2H), 2.20 (s, 3H), 1.49 (t, 3H) 1 H NMR (CDCl 3 ) δ 4.78 (q, 2H), 2.20 (s, 3H), 1.49 (t, 3H)

단계 2. 3-아미노-4-메틸-3-사이클로부텐-1,2-다이온의 제조Step 2. Preparation of 3-amino-4-methyl-3-cyclobutene-1,2-dione

상기 단계 1의 3-에톡시-4-메틸-3-사이클로부텐-1,2-다이온 (140 mg, 1.0 mmol)을 에탄올 (2 ml)에 녹인 후 포화된 에타노익암모니아 용액 (2 ml)를 첨가하여 상온에서 5시간동안 교반한다. 용매 제거 후, 혼합물을 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (80 mg)을 수득하였다.
The 3-ethoxy-4-methyl-3-cyclobutene-1,2-dione (140 mg, 1.0 mmol) of step 1 was dissolved in ethanol (2 ml) and then saturated ethanoammonium solution (2 ml) It is added and stirred for 5 hours at room temperature. After removal of the solvent, the mixture was purified via silica gel chromatography to give the title compound (80 mg).

단계 3. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메틸-3-사이클로부텐-1,2-다이온의 제조Step 3. Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methyl-3-cyclobutene-1,2-dione

N-(벤질옥시카보닐)-L-루신 (334 mg, 1.30 mmol), N-하이드록시벤조트리아졸 (HOBt; 213 mg, 1.45 mmol), 트라이에틸아민 (220 ml, 1.57mmol) 과 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염 (EDCI; 278 ml, 1.57 mmol)혼합용액 에 상기 단계 2의 3-아미노-4-메틸-3-사이클로부텐-1,2-다이온 (70 mg, 0.63 mmol)을 다이클로로메탄/다이메틸포름아마이드 (10 ml/10 ml)용액을 적가한 후, 상온에서 24시간동안 교반한다. 반응용액을 다이클로로메탄으로 희석한 후 포화된 중조용액으로 세척하여 무수 소듐설페이트로 탈수 및 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (120 mg)을 수득하였다. N- (benzyloxycarbonyl) -L-leucine (334 mg, 1.30 mmol), N-hydroxybenzotriazole (HOBt; 213 mg, 1.45 mmol), triethylamine (220 ml, 1.57 mmol) and 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 278 ml, 1.57 mmol) in the mixture solution of 3-amino-4-methyl-3-cyclobutene-1,2- Ionic (70 mg, 0.63 mmol) was added dropwise to a dichloromethane / dimethylformamide (10 ml / 10 ml) solution, followed by stirring at room temperature for 24 hours. The reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dehydrated and concentrated with anhydrous sodium sulfate. The residue was purified by silica gel chromatography to give the title compound (120 mg).

1H NMR (CDCl3) δ 10.50 (brs, 1H), 7.20-8.20 (m, 10H), 5.75 (d, 1H), 5.00-5.40 (m, 2H), 4.40-4.70 (m, 1H), 1.50-2.00 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 10.50 (brs, 1H), 7.20-8.20 (m, 10H), 5.75 (d, 1H), 5.00-5.40 (m, 2H), 4.40-4.70 (m, 1H), 1.50 -2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 6. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(3,3-다이메틸부틴-1-일) -3-사이클로부텐-1,2-다이온의 제조Example 6 of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (3,3-dimethylbutyn-1-yl) -3-cyclobutene-1,2-dione Produce

3-에톡시-4-(3,3-다이메틸부틴-1-일) -3-사이클로부텐-1,2-다이온 (100 mg)을 에탄올 (10 ml)에서 수소촉매화 반응을 수행하여 3-에톡시-4-(3,3-다이메틸부틸) -3-사이클로부텐-1,2-다이온 (88 mg)을 수득하였다. 상기 실시예 5의 단계 2에서의 3-에톡시-4-메틸-3-사이클로부텐-1,2-다이온 대신에 3-에톡시-4-(3,3-다이메틸부틸) -3-사이클로부텐-1,2-다이온을 사용하는 것을 제외하고는 실시예 5의 단계1과 동일한 방법을 사용하여 표제화합물 (77 mg)을 수득하였다.Hydroxylation of 3-ethoxy-4- (3,3-dimethylbutyn-1-yl) -3-cyclobutene-1,2-dione (100 mg) in ethanol (10 ml) was carried out 3-Ethoxy-4- (3,3-dimethylbutyl) -3-cyclobutene-1,2-dione (88 mg) was obtained. 3-ethoxy-4- (3,3-dimethylbutyl) -3-in place of 3-ethoxy-4-methyl-3-cyclobutene-1,2-dione in step 2 of Example 5 above The title compound (77 mg) was obtained using the same method as the step 1 of Example 5 except for using cyclobutene-1,2-dione.

1H NMR (CDCl3) δ 8.10-8.40 (m, 2H), 7.20-7.80 (m, 8H), 5.85 (m, 1H), 5.60 (m, 1H), 5.00-5.40 (m, 2H), 1.60-2.00 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 8.10-8.40 (m, 2H), 7.20-7.80 (m, 8H), 5.85 (m, 1H), 5.60 (m, 1H), 5.00-5.40 (m, 2H), 1.60 -2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 7. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(페닐아세틸렌) -3-사이클로부텐-1,2-다이온의 제조Example 7. Preparation of 3-[(N-benzyloxycarbonyl) -L-rusil] amino-4- (phenylacetylene) -3-cyclobutene-1,2-dione

상기 실시예 5의 단계1에서의 메틸리튬 대신에 페닐아세틸렌리튬을 사용하는것을 제외하고는 동일한 방법을 사용하여 표제화합물 (66 mg)을 수득하였다.The title compound (66 mg) was obtained using the same method except that phenylacetylene lithium was used instead of methyl lithium in Step 1 of Example 5.

1H NMR (CDCl3) δ 8.10-8.40(m, 2 H), 7.20-7.80(m, 8H), 5.85(m, 1H), 5.60(m, 1H), 5.00-5.40(m, 2H), 1.60-2.00(m, 3H), 0.80-1.20(m, 6H)
 1 H NMR (CDCl 3 ) δ 8.10-8.40 (m, 2H), 7.20-7.80 (m, 8H), 5.85 (m, 1H), 5.60 (m, 1H), 5.00-5.40 (m, 2H), 1.60-2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 8. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(2-페닐에테닐)-3-사이클로부텐-1,2-다이온의 제조Example 8. Preparation of 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (2-phenylethenyl) -3-cyclobutene-1,2-dione

단계 1. 4-(1-메틸에톡시)-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제조Step 1. Preparation of 4- (1-methylethoxy) -3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

다이아이소프로필 스쿠아레이트와 (트라이-n-부틸스테닐)트라이메틸실란을 테트라하이드로퓨란 (50 ml)에 녹인 후 -23 oC에서 교반하였다. n-테트라부틸암모니움시아나이드를 테트라하이드로퓨란에 녹인 용액을 적가하여 반응 용액의 색깔 변화가 노란색을 나타내었다. 반응 혼합물을 농축하여 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.9 g)을 수득하였다.
Diisopropyl squarate and (tri-n-butylstenyl) trimethylsilane were dissolved in tetrahydrofuran (50 ml) and stirred at -23 ° C. A solution of n-tetrabutylammonium cyanide dissolved in tetrahydrofuran was added dropwise to give a yellow color change in the reaction solution. The reaction mixture was concentrated and purified via column chromatography to give the title compound (0.9 g).

단계 2. 4-아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제 조Step 2. Preparation of 4-amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

상기 단계 1의 4-(1-메틸에톡시)-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (2.96 g, 6.90 mmol)을 0 oC 에서 다이클로로메탄 (50 ml)에 녹인 후 암모니아 가스을 통과시키며 교반하였다. 반응 혼합물을 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.9 g)을 수득하였다.
4- (1-methylethoxy) -3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (2.96 g, 6.90 mmol) of step 1 was added at 0 ° C. It was dissolved in chloromethane (50 ml) and stirred through ammonia gas. The reaction mixture was purified via column chromatography to give the title compound (0.9 g).

단계 3. 3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제조Step 3. Preparation of 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

상기 단계 2의 4-아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (0.9 g, 2.33 mmol)을 다이클로로메탄/다이메틸포름아마이드 (40 ml/ 30 ml)에 녹인 후 N-(벤질옥시카보닐)-루신 (1.24 g, 4.66 mmol), N-하이드록시벤조트리아졸 (HOBt; 0.69 g, 5.13 mmol), 트라이에틸아민 (0.98 g, 6.99 mmol)과 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염(EDCI; 0.98 g, 5.13 mmol)에 첨가하여 상온에서 24시간 동안 교반하였다. 다이클로로메탄으로 희석한 후 포화된 중조용액으로 세척하였다. 유기층을 소듐설페이트로 건조한 후 농축시켜 얻은 잔사를 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.79 g)을 수득하였다.4-Amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (0.9 g, 2.33 mmol) of step 2 was diluted with dichloromethane / dimethylformamide (40 ml / 30 ml) and then N- (benzyloxycarbonyl) -leucine (1.24 g, 4.66 mmol), N-hydroxybenzotriazole (HOBt; 0.69 g, 5.13 mmol), triethylamine (0.98 g, 6.99 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 0.98 g, 5.13 mmol) and stirred at room temperature for 24 hours. Diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the title compound (0.79 g).

1H NMR (CDCl3) δ 0.8-1.8 (m, 36H), 4.46(brs, 1H), 5.0-5.2(m, 3H), 7.2-7.4(s, 5H), 10.02(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.8 (m, 36H), 4.46 (brs, 1H), 5.0-5.2 (m, 3H), 7.2-7.4 (s, 5H), 10.02 (s, 1H)

단계 4. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(2-페닐에테닐)-3-사이클로부텐-1,2-다이온Step 4. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (2-phenylethenyl) -3-cyclobutene-1,2-dione

상기 단계 3의 3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (30 mg)과 베타-아이오도스타이렌 (20 ml)를 다이메틸포름아마이드 (1.0 ml)에 녹여 촉매량의 벤질클로로비스(트라이페닐포스핀)팔라듐과 요오드화구리를 첨가하여 상온에서 교반하였다. 반응 혼합물을 에틸아세테이트 (10 ml)로 희석하고 염화암모늄 수용액 (10 ml)로 1회 세척하였다. 유기층을 에틸아세테이트로 이산화규소 플러그를 통과하여 얻은 잔사를 컬럼크로마토그래피를 통하여 정제하여 (6.4 mg)의 표제화합물을 수득하였다. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (30 mg) of step 3 above; Beta-iodostyrene (20 ml) was dissolved in dimethylformamide (1.0 ml), and a catalytic amount of benzylchlorobis (triphenylphosphine) palladium and copper iodide were added and stirred at room temperature. The reaction mixture was diluted with ethyl acetate (10 ml) and washed once with aqueous ammonium chloride solution (10 ml). The organic layer was purified by column chromatography using ethyl acetate through a plug of silicon dioxide, to obtain (6.4 mg) of the title compound.

1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.5-1.9(m, 3H), 4.56(brs, 1H), 5.18(s, 2H), 5.35(d, 1H), 7.2-7.4(m, 8H), 7.6-7.7(m, 2H), 7.8-8.3(q, 2H), 10.18(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 4.56 (brs, 1H), 5.18 (s, 2H), 5.35 (d, 1H), 7.2-7.4 (m, 8H), 7.6-7.7 (m, 2H), 7.8-8.3 (q, 2H), 10.18 (s, 1H)

실시예 9. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(4-페녹시페닐)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 9. 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (4-phenoxyphenyl) ethenyl] -3-cyclobutene-1,2-da Preparation of ions

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 베타-아이오도-(4-페녹시)스타이렌을 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (9 mg)을 수득하였다. The title compound (9 mg) was obtained by the same method except for using beta-iodo- (4-phenoxy) styrene instead of beta-iodostyrene in Step 4 of Example 8. It was.                     

1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.5-1.9(m, 3H), 4.53(brs, 1H), 5.18(s, 2H), 5.28(d, 1H), 6.98-7.42(m, 12H), 7.6-7.7(d, 2H), 7.7-8.3(q, 2H), 10.08(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 4.53 (brs, 1H), 5.18 (s, 2H), 5.28 (d, 1H), 6.98-7.42 (m, 12H), 7.6-7.7 (d, 2H), 7.7-8.3 (q, 2H), 10.08 (s, 1H)

실시예 10. 3-[N-(4-벤질옥시카보닐)-L-루실] 아미노 -4-[2-(나프-2-일)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 10. 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (naph-2-yl) ethenyl] -3-cyclobutene-1,2-da Preparation of ions

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-아이오도에티닐나프탈렌을 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained using the same method except that 2-iodoethynylnaphthalene was used instead of beta-iodostyrene in step 4 of Example 8.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.9(m, 3H), 4.56(brs, 1H), 5.20(m, 3H), 7.2-7.4(m, 5H), 7.4-7.5(m, 2H), 7.8-8.0(m, 3H), 8.0-8.4(q, 2H), 9.94(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 4.56 (brs, 1H), 5.20 (m, 3H), 7.2-7.4 (m, 5H), 7.4 -7.5 (m, 2H), 7.8-8.0 (m, 3H), 8.0-8.4 (q, 2H), 9.94 (s, 1H)

실시예 11. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3-페닐프로펜-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 11 of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenylpropen-1-yl) -3-cyclobutene-1,2-dione Produce

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 3-페닐-1-프로페닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (7 mg)을 수득하였다.The title compound (7 mg) was obtained using the same method except that 3-phenyl-1-propenyl iodo was used instead of beta-iodostyrene in step 4 of Example 8.

1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.5-1.9(m, 3H), 3.62(d, 2H), 4.48(brs, 1H), 5.17(s, 2H), 5.25(d, 1H), 7.2-7.7(m, 12H), 10.06(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 3.62 (d, 2H), 4.48 (brs, 1H), 5.17 (s, 2H), 5.25 (d , 1H), 7.2-7.7 (m, 12H), 10.06 (s, 1H)

실시예 12. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-사이클로헥실에테닐)-3-사이클로부텐-1,2-다이온의 제조Example 12 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-cyclohexylethenyl) -3-cyclobutene-1,2-dione

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-(사이클로헥실)에테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (5 mg)을 수득하였다.The title compound (5 mg) was obtained using the same method except that 2- (cyclohexyl) ethenyl iodo was used instead of beta-iodostyrene in step 4 of Example 8.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.1-2.4(m, 14H), 4.56(brs, 1H), 5.16(s, 2H), 5.35(brs, 1H), 7.0-7.5(m, 7H), 10.08(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.1-2.4 (m, 14H), 4.56 (brs, 1H), 5.16 (s, 2H), 5.35 (brs, 1H), 7.0-7.5 (m, 7H), 10.08 (s, 1H)

실시예 13. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(3-벤질옥시페닐)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 13. 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (3-benzyloxyphenyl) ethenyl] -3-cyclobutene-1,2-da Preparation of ions

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-(3-벤질옥시페닐)에테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (7 mg)을 수득하였다.The title compound (7 mg) was obtained by the same method except that 2- (3-benzyloxyphenyl) ethenyl iodo was used instead of beta-iodostyrene in step 4 of Example 8. It was.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-2.0(m, 3H), 4.53(brs, 1H), 5.0-5.4(m, 5H), 7.0-7.6(m, 14H), 7.77-8.23(q, 2H), 10.13(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-2.0 (m, 3H), 4.53 (brs, 1H), 5.0-5.4 (m, 5H), 7.0-7.6 (m, 14H) , 7.77-8.23 (q, 2H), 10.13 (s, 1H)

실시예14. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(3-클로로페닐)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 14. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (3-chlorophenyl) ethenyl] -3-cyclobutene-1,2-dione

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-(3-클로로페닐)에테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (7 mg)을 수득하였다.The title compound (7 mg) was obtained by the same method except that 2- (3-chlorophenyl) ethenyl iodo was used instead of beta-iodostyrene in step 4 of Example 8 above. .

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.9(m, 3H), 4.48(brs, 1H), 5.0-5.4(m, 3H), 7.1-7.8(m, 9H), 7.8-8.2(q, 2H), 10.15(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 4.48 (brs, 1H), 5.0-5.4 (m, 3H), 7.1-7.8 (m, 9H) , 7.8-8.2 (q, 2H), 10.15 (s, 1H)

실시예 15 . 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(4-바이페닐)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 15. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (4-biphenyl) ethenyl] -3-cyclobutene-1,2-dione

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-(4-바이페닐)에테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method except using 2- (4-biphenyl) ethenyl iodo instead of beta-iodostyrene in step 4 of Example 8 above. .

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.9(m, 3H), 4.53(brs, 1H), 5.0-5.3(m, 3H), 7.2-7.8(m, 14H), 7.8-8.2(q, 2H), 10.08(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.9 (m, 3H), 4.53 (brs, 1H), 5.0-5.3 (m, 3H), 7.2-7.8 (m, 14H) , 7.8-8.2 (q, 2H), 10.08 (s, 1H)

실시예 16. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(부텐-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 16 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (buten-1-yl) -3-cyclobutene-1,2-dione

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 1-부테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method except that 1-butenyl iodo was used instead of beta-iodostyrene in step 4 of Example 8.

1H NMR (CDCl3) δ 0.8-1.0(m, 9H), 1.5-2.0(m, 5H), 4.45(brs, 1H), 5.0-5.2(m, 3H), 7.2-7.4(m, 7H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 9H), 1.5-2.0 (m, 5H), 4.45 (brs, 1H), 5.0-5.2 (m, 3H), 7.2-7.4 (m, 7H)

실시예 17. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(2,3-다이클로로페닐)에테닐]-3-사이클로부텐-1,2-다이온의 제조Example 17. 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (2,3-dichlorophenyl) ethenyl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 8의 단계 4에서의 베타-아이오도스타이렌 대신에 2-(2,3-다이클로로페닐)에테닐 아이오도를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (9 mg)을 수득하였다.The title compound (9 mg) was obtained in the same manner as in Example 4, except that 2- (2,3-dichlorophenyl) ethenyl iodo was used instead of beta-iodostyrene in Step 4 Obtained.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-2.0(m, 3H), 4.50(brs, 1H), 5.0-5.3(m, 3H), 7.2-7.8(m, 8H), 7.8-8.6(q, 2H), 10.12(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-2.0 (m, 3H), 4.50 (brs, 1H), 5.0-5.3 (m, 3H), 7.2-7.8 (m, 8H) , 7.8-8.6 (q, 2H), 10.12 (s, 1H)

실시예 18. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-피리딜)-3-사이클로부텐-1,2-다이온의 제조Example 18 Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-pyridyl) -3-cyclobutene-1,2-dione

3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (30 mg)과 2-아이오도피리딘 (20 ml)를 다이메틸포름아마이드 (1.0 ml)에 녹여 촉매량의 벤질클로로비스(트라이페닐포스핀)팔라듐과 요오드화구리를 첨가하여 상온에서 교반하였다. 반응 혼합물을 에틸아세테이트 (10 ml)로 희석하고 염화암모늄 수용액 (10 ml)로 1회 세척하였다. 유기층을 에틸아세테이트로 이산화규소 플러그를 통과하여 얻은 잔사를 컬럼크로마토그래피를 통하여 정제하여 (6.4 mg)의 표제화합물을 수득하였다. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (30 mg) with 2-iodo Pyridine (20 ml) was dissolved in dimethylformamide (1.0 ml), and a catalytic amount of benzylchlorobis (triphenylphosphine) palladium and copper iodide were added and stirred at room temperature. The reaction mixture was diluted with ethyl acetate (10 ml) and washed once with aqueous ammonium chloride solution (10 ml). The organic layer was purified by column chromatography using ethyl acetate through a plug of silicon dioxide, to obtain (6.4 mg) of the title compound.

1H NMR (CDCl3) δ 7.2-7.6(m, 9H), 5.0-5.4(m, 3H), 4.4(m, 1H), 1.5-1.9(m, 3H), 0.8-1.0(m, 6H)
 1 H NMR (CDCl 3 ) δ 7.2-7.6 (m, 9H), 5.0-5.4 (m, 3H), 4.4 (m, 1H), 1.5-1.9 (m, 3H), 0.8-1.0 (m, 6H)

실시예 19. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-타이에닐)-3-사이클로부텐-1,2-다이온의 제조Example 19 Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-taienyl) -3-cyclobutene-1,2-dione

실시예 1의 메틸리튬 대신에 2-타이에닐리튬을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (60 mg)을 수득하였다.The title compound (60 mg) was obtained using the same method as Example 1 except for using 2-thienyllithium instead of the methyllithium of Example 1.

1H NMR (CDCl3) δ 10.25 (brs, 1H), 8.05 (m, 1H), 7.90 (m, 1H), 7.10-7.50 (m, 6H), 5.60 (m, 1H), 5.10-5.40 (s, 2H), 4.60 (m, 1H), 1.55-2.00 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 10.25 (brs, 1H), 8.05 (m, 1H), 7.90 (m, 1H), 7.10-7.50 (m, 6H), 5.60 (m, 1H), 5.10-5.40 (s , 2H), 4.60 (m, 1H), 1.55-2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 20. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-퓨릴)-3-사이클로부텐-1,2-다이온의 제조Example 20 Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-furyl) -3-cyclobutene-1,2-dione

실시예 1의 메틸리튬 대신에 2-퓨릴리튬을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (75 mg)을 수득하였다.The title compound (75 mg) was obtained using the same method as Example 1 except for using 2-furyllithium instead of the methyllithium of Example 1.

1H NMR (CDCl3) δ 10.10 (brs, 1H), 7.78 (m, 1H), 7.20-7.50 (m, 6H), 6.65 (m, 1H), 5.55 (d, 1H), 5.00-5.30 (m, 2H), 4.45-4.65 (m, 1H), 1.60-2.00 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 10.10 (brs, 1H), 7.78 (m, 1H), 7.20-7.50 (m, 6H), 6.65 (m, 1H), 5.55 (d, 1H), 5.00-5.30 (m , 2H), 4.45-4.65 (m, 1H), 1.60-2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 21. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(3-페녹시-피리딘-4-일)-3-사이클로부텐-1,2-다이온의 제조Example 21. Preparation of 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenoxy-pyridin-4-yl) -3-cyclobutene-1,2-dione

실시예 8의 베타-아이오도스타이렌 대신에 3-페녹시-4-아이오도벤젠을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법을 사용하여 표제화합물 (4 mg)을 수득하였다.The title compound (4 mg) was obtained in the same manner as in Example 8 except for using 3-phenoxy-4-iodobenzene instead of beta-iodostyrene in Example 8.

1H NMR (CDCl3) δ 7.70-7.30 (m,13H), 5.10 (s,2H), 4.30-4.10 (m,1H),1.80 (m,2H), 1.45 (m,1H), 0.95 (s,6H)
 1 H NMR (CDCl 3 ) δ 7.70-7.30 (m, 13H), 5.10 (s, 2H), 4.30-4.10 (m, 1H), 1.80 (m, 2H), 1.45 (m, 1H), 0.95 (s , 6H)

실시예 22. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(3-사이클로펜틸옥시-피리딘-4-일)-3-사이클로부텐-1,2-다이온의 제조Example 22. of 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (3-cyclopentyloxy-pyridin-4-yl) -3-cyclobutene-1,2-dione Produce

실시예 8의 베타-아이오도스타이렌 대신에 3-사이클로펜틸옥시-4-아이오도벤젠을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법을 사용하여 표제화합물 (4 mg)을 수득하였다.The title compound (4 mg) was obtained in the same manner as in Example 8 except for using 3-cyclopentyloxy-4-iodobenzene in place of the beta-iodostyrene of Example 8.

1H NMR (CDCl3) δ 7.70-7.20 (m,8H), 5.20 (m,1H), 5.10 (s,2H), 4.30-4.10 (m,1H),2.00-1.40 (m,11H), 0.95 (s,6H)
 1 H NMR (CDCl 3 ) δ 7.70-7.20 (m, 8H), 5.20 (m, 1H), 5.10 (s, 2H), 4.30-4.10 (m, 1H), 2.00-1.40 (m, 11H), 0.95 (s, 6H)

실시예 23. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-[3-(2,2,3,3-테트라플루오로-프로폭시)피리딘-4-일)]-3-사이클로부텐-1,2-다이온의 제조Example 23. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- [3- (2,2,3,3-tetrafluoro-propoxy) pyridin-4-yl)] Preparation of 3-cyclobutene-1,2-dione

실시예 8의 베타-아이오도스타이렌 대신에 4-아이오도-3-(2,2,3,3-테트라플루오로-프로폭시)피리딘을 사용하는 것을 제외하고는, 실시예 8과 동일한 방법을 사용하여 표제화합물 (5 mg)을 수득하였다.Same method as in Example 8, except using 4-iodo-3- (2,2,3,3-tetrafluoro-propoxy) pyridine in place of the beta-iodostyrene of Example 8. Was used to give the title compound (5 mg).

1H NMR (CDCl3) δ 7.80-7.20 (m,8H), 6.10 (m,1H), 5.45 (m,1H), 5.20 (m,1H), 5.10 (s,2H), 4.70 (m,1H), 4.30-4.10 (m,1H), 2.00-1.40 (m,11H), 0.95 (s,6H)
 1 H NMR (CDCl 3 ) δ 7.80-7.20 (m, 8H), 6.10 (m, 1H), 5.45 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 4.70 (m, 1H ), 4.30-4.10 (m, 1H), 2.00-1.40 (m, 11H), 0.95 (s, 6H)

실시예 24. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(t-부톡시카보닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 24. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (t-butoxycarbonyl) pyrrolidin-2-yl] -3-cyclobutene-1 Of 2-, dione

상기 실시예 1의 단계 1에서의 메틸리튬 대신에 N-(t-부톡시카보닐)피롤리딘-2-일리튬을 사용하는 것을 제외하고는 실시예 1의 단계 1과 동일한 방법을 사용하여 표제화합물 (95 mg)을 수득하였다.Using the same method as Step 1 of Example 1, except that N- (t-butoxycarbonyl) pyrrolidine-2-ylithium was used instead of methyllithium in Step 1 of Example 1 The title compound (95 mg) was obtained.

1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 5.00-5.60 (m, 4H), 4.45 (m, 1H), 3.35- 3.70 (m, 2H), 1.90-2.40 (m, 4H), 1.20-1.90 (m, 12H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 5.00-5.60 (m, 4H), 4.45 (m, 1H), 3.35- 3.70 (m, 2H), 1.90-2.40 (m, 4H) , 1.20-1.90 (m, 12H), 0.80-1.20 (m, 6H)

실시예 25. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(피롤리딘-2-일)-3-사이클로부텐-1,2-다이온 염산염의 제조Example 25 Preparation of 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (pyrrolidin-2-yl) -3-cyclobutene-1,2-dione hydrochloride

상기 실시예 24의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(t-부톡시카보닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온 (100 mg)을 에틸아세테이트 (2 ml) 에 녹인 용액에 3N-염산/에틸아세테이트 (2 ml)를 첨가하여 실온에서 2시간 동안 교반하였다. 여과하여 백색의 고체를 아이소프로필에테르로 세척한 후 표제화합물 (65 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (t-butoxycarbonyl) pyrrolidin-2-yl] -3-cyclobutene- of Example 24, supra To a solution of 1,2-dione (100 mg) in ethyl acetate (2 ml) was added 3N-hydrochloric acid / ethyl acetate (2 ml) and stirred at room temperature for 2 hours. Filtration washed the white solid with isopropyl ether to give the title compound (65 mg).

1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 6.40 (m, 1H), 4.95-5.40 (m, 2H), 4.60 (brs, 1H), 3.40-3.75 (brs, 2H), 1.90-2.70 (m, 4H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 6.40 (m, 1H), 4.95-5.40 (m, 2H), 4.60 (brs, 1H), 3.40-3.75 (brs, 2H), 1.90 -2.70 (m, 4H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)

실시예 26. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(사이클로헥산카보닐(피롤리딘-2-일)]-3-사이클로부텐-1,2-다이온의 제조Example 26. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (cyclohexanecarbonyl (pyrrolidin-2-yl)]-3-cyclobutene-1, Preparation of 2-dione

상기 실시예 25의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(피롤리딘-2-일)-3-사이클로부텐-1,2-다이온 염산염 (10 mg)을 다이클로로메탄 (1 ml)에 녹인 용액에 사이클로헥산카보닐 클로라이드(10 mg)과 트라이에틸아민 (0.05 ml)를 상온에서 적가하여 5시간 교반하였다. 반응 혼합물을 크로마토그래피를 통하여 정제하여 표 제화합물 (7 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (pyrrolidin-2-yl) -3-cyclobutene-1,2-dione hydrochloride of Example 25 above (10 mg) ) Was dissolved in dichloromethane (1 ml) and cyclohexanecarbonyl chloride (10 mg) and triethylamine (0.05 ml) were added dropwise at room temperature, followed by stirring for 5 hours. The reaction mixture was purified via chromatography to give the title compound (7 mg).

1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 5.00-5.75 (m, 4H), 4.50 (m, 1H), 3.50-3.90 (m, 2H), 1.20-2.60 (m, 18H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 5.00-5.75 (m, 4H), 4.50 (m, 1H), 3.50-3.90 (m, 2H), 1.20-2.60 (m, 18H) , 0.80-1.20 (m, 6H)

실시예27. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2-퓨로일) 피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 27. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2-furoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione Produce

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 2-퓨로일을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (9 mg)을 수득하였다.The title compound (9 mg) was obtained using the same method as Example 26 except for using 2-furoyl instead of the cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.10-7.65 (m, 7H), 6.50 (m, 1H), 5.00-5.70 (m, 4H), 4.55 (m, 1H), 3.90-4.20 (m, 2H), 2.00-2.60 (m, 4H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.10-7.65 (m, 7H), 6.50 (m, 1H), 5.00-5.70 (m, 4H), 4.55 (m, 1H), 3.90-4.20 (m, 2H), 2.00 -2.60 (m, 4H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)

실시예 28. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(아이소부티릴)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 28. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (isobutyryl) pyrrolidin-2-yl] -3-cyclobutene-1,2- Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 아이소부티릴 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (6 mg)을 수득하였다. The title compound (6 mg) was obtained in the same manner as Example 26 except for using isobutyryl chloride instead of cyclohexanecarbonyl chloride of Example 26.                     

1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 4.90-5.80 (m, 4H), 4.45 (m, 1H), 3.40-3.90 (m, 2H), 2.80 (m, 1H), 0.80-2.40 (m, 19H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 4.90-5.80 (m, 4H), 4.45 (m, 1H), 3.40-3.90 (m, 2H), 2.80 (m, 1H), 0.80 -2.40 (m, 19H)

실시예 29. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(몰포린카보닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 29. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (morpholin carbonyl) pyrrolidin-2-yl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 4-몰포린카보닐 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (6 mg)을 수득하였다.The title compound (6 mg) was obtained using the same method as Example 26 except for using 4-morpholinecarbonyl chloride instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 5.00-5.80 (m, 4H), 4.45 (m, 1H), 3.20-4.00 (m, 10H), 1.50-2.40 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 5.00-5.80 (m, 4H), 4.45 (m, 1H), 3.20-4.00 (m, 10H), 1.50-2.40 (m, 7H) , 0.80-1.20 (m, 6H)

실시예 30. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(1-나프토일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 30. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (1-naphthoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 1-나프토일 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (9 mg)을 수득하였다.The title compound (9 mg) was obtained using the same method as Example 26 except for using 1-naphthoyl chloride instead of the cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.20-8.20 (m, 12H), 5.60-6.00 (m, 2H), 4.95-5.30 (m, 2H), 4.50 (m, 1H), 3.20-3.60 (m, 2H), 1.50-2.50 (m, 7H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.20-8.20 (m, 12H), 5.60-6.00 (m, 2H), 4.95-5.30 (m, 2H), 4.50 (m, 1H), 3.20-3.60 (m, 2H) , 1.50-2.50 (m, 7H), 0.80-1.20 (m, 6H)

실시예 31. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤조일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 31. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione Manufacture

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 벤조일 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (8 mg)을 수득하였다.The title compound (8 mg) was obtained using the same method as Example 26 except for using benzoyl chloride instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.25-7.70 (m, 10H), 5.55-5.80 (m, 2H), 5.15 (m, 2H), 4.50 (m, 1H), 3.50-3.90 (m, 2H), 1.50-2.50 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.25-7.70 (m, 10H), 5.55-5.80 (m, 2H), 5.15 (m, 2H), 4.50 (m, 1H), 3.50-3.90 (m, 2H), 1.50 -2.50 (m, 7H), 0.80-1.20 (m, 6H)

실시예 32. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2-클로로벤조일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 32. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2-chlorobenzoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 2-클로로벤조일 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained by the same method as Example 26 except for using 2-chlorobenzoyl chloride instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.30-7.60 (m, 9H), 5.50-5.80 (m, 2H), 5.00-5.30 (m, 2H), 4.50 (m, 1H), 3.30-3.60 (m, 2H), 1.50-2.50 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.30-7.60 (m, 9H), 5.50-5.80 (m, 2H), 5.00-5.30 (m, 2H), 4.50 (m, 1H), 3.30-3.60 (m, 2H) , 1.50-2.50 (m, 7H), 0.80-1.20 (m, 6H)

실시예 33. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤젠설포닐)피롤리딘-2- 일]-3-사이클로부텐-1,2-다이온의 제조Example 33. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzenesulfonyl) pyrrolidin-2-yl] -3-cyclobutene-1,2- Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 2-벤젠설포닐 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (12 mg)을 수득하였다.The title compound (12 mg) was obtained using the same method as Example 26 except for using 2-benzenesulfonyl chloride instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.30-8.20 (m, 9H), 5.10-5.80 (m, 4H), 4.50 (m, 1H), 3.20-3.90 (m, 2H), 1.50-2.40 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.30-8.20 (m, 9H), 5.10-5.80 (m, 4H), 4.50 (m, 1H), 3.20-3.90 (m, 2H), 1.50-2.40 (m, 7H) , 0.80-1.20 (m, 6H)

실시예 34. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2,5-다이클로로벤젠설포닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 34. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2,5-dichlorobenzenesulfonyl) pyrrolidin-2-yl] -3-cyclo Preparation of Butene-1,2-dione

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 2,5-다이클로로벤젠설포닐 클로라이드을 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method as Example 26 except for using 2,5-dichlorobenzenesulfonyl chloride instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.20-8.10 (m, 8H), 5.10-5.80 (m, 4H), 4.50 (m, 1H), 3.60-3.90 (m, 2H), 1.50-2.40 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-8.10 (m, 8H), 5.10-5.80 (m, 4H), 4.50 (m, 1H), 3.60-3.90 (m, 2H), 1.50-2.40 (m, 7H) , 0.80-1.20 (m, 6H)

실시예 35. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(3-톨루오일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 35. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (3-toluoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 3-톨릴아이소시아 네이트를 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained by the same method as Example 26 except for using 3-tolylisocyanate instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 6.60-7.60 (m, 9H), 5.00-5.50 (m, 4H), 4.55 (m, 1H), 3.40-4.00 (m, 2H), 1.40-2.50 (m, 10H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 6.60-7.60 (m, 9H), 5.00-5.50 (m, 4H), 4.55 (m, 1H), 3.40-4.00 (m, 2H), 1.40-2.50 (m, 10H) , 0.80-1.20 (m, 6H)

실시예 36. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤질티오카바모일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온의 제조Example 36. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzylthiocarbamoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2 Preparation of Dion

상기 실시예 26의 사이클로헥산카보닐 클로라이드 대신에 벤질아이소티오시아네이트를 사용하는 것을 제외하고는 실시예 26과 동일한 방법을 사용하여 표제화합물 (13 mg)을 수득하였다.The title compound (13 mg) was obtained in the same manner as Example 26 except for using benzylisothiocyanate instead of cyclohexanecarbonyl chloride of Example 26.

1H NMR (CDCl3) δ 7.20-7.60 (m, 10H), 5.00-5.80 (m, 4H), 3.25-4.30 (m, 5H), 1.50-2.40 (m, 7H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 10H), 5.00-5.80 (m, 4H), 3.25-4.30 (m, 5H), 1.50-2.40 (m, 7H), 0.80-1.20 (m, 6H)

실시예 37. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-아지도-3-사이클로부텐-1,2-다이온의 제조Example 37 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-azido-3-cyclobutene-1,2-dione

실시예 1의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (100 mg, 0.27 mmol)과 소듐아자이드 (0.56 mmol)을 다이메틸포름아마이드 (2 ml)에 녹인 후에 60oC에서 4시간동안 교반한다. 용매를 제거한 후에 잔사 를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (12 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione (100 mg, 0.27 mmol) and sodium azide ( 0.56 mmol) is dissolved in dimethylformamide (2 ml) and then stirred at 60 ° C. for 4 hours. After removing the solvent, the residue was purified by silica gel chromatography to give the title compound (12 mg).

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.6-1.8(m, 3H), 4.43(br, 1H), 5.1-5.4(m, 3H), 6.18(s, 1H), 7.2-7.4(m, 5H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.6-1.8 (m, 3H), 4.43 (br, 1H), 5.1-5.4 (m, 3H), 6.18 (s, 1H), 7.2 -7.4 (m, 5H)

실시예 38. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-시아노-3-사이클로부텐-1,2-다이온의 제조Example 38 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-cyano-3-cyclobutene-1,2-dione

실시예 1의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (100 mg, 0.27 mmol)과 소듐시안 (0.56 mmol)을 다이메틸포름아마이드 (2 ml)에 녹인 후에 60oC에서 4시간동안 교반한다. 용매를 제거한 후에 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (15 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione (100 mg, 0.27 mmol) and sodium cyan (0.56) in Example 1 mmol) is dissolved in dimethylformamide (2 ml) and stirred at 60 ° C. for 4 hours. After removing the solvent the residue was purified by silica gel chromatography to give the title compound (15 mg).

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.8(m, 3H), 4.43(brs, 1H), 5.1-5.4(m, 3H), 6.18(s, 1H), 7.2-7.4(m, 5H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.8 (m, 3H), 4.43 (brs, 1H), 5.1-5.4 (m, 3H), 6.18 (s, 1H), 7.2 -7.4 (m, 5H)

실시예 39. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-메톡시벤질설파닐)-3-사이클로부텐-1,2-다이온의 제조Example 39 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-methoxybenzylsulfanyl) -3-cyclobutene-1,2-dione

실시예 1의 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온 (100 mg, 0.27 mmol)과 4-메톡시벤질티올 (0.56 mmol)을 다이클로로메탄 (2 ml)에 녹인 후에 상온에서 18시간동안 교반한다. 용매를 제거한 후에 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (15 mg)을 수득하였다.3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-methoxy-3-cyclobutene-1,2-dione (100 mg, 0.27 mmol) and 4-methoxy of Example 1 Benzylthiol (0.56 mmol) is dissolved in dichloromethane (2 ml) and stirred at room temperature for 18 hours. After removing the solvent the residue was purified by silica gel chromatography to give the title compound (15 mg).

1H NMR (CDCl3) δ 7.20-7.60 (m, 7H), 6.80-7.00 (d, 2H), 5.65 (d, 1H), 5.10-5.40 (m, 2H), 4.50-4.95 (m, 3H), 3.82 (s, 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 7H), 6.80-7.00 (d, 2H), 5.65 (d, 1H), 5.10-5.40 (m, 2H), 4.50-4.95 (m, 3H) , 3.82 (s, 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)

실시예 40. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-메톡시벤질설파닐)-3-사이클로부텐-1,2-다이온의 제조Example 40 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-methoxybenzylsulfanyl) -3-cyclobutene-1,2-dione

실시예 4의 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-메톡시벤질설파닐)-사이클로부텐-1,2-다이온 (50 mg)을 다이클로로메탄 (2 ml)에 녹인 후에 MCPBA (20 mg)을 가하고 상온에서 4시간동안 교반한다. 용매를 제거한 후에 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (15 mg)을 수득하였다.3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-methoxybenzylsulfanyl) -cyclobutene-1,2-dione (50 mg) of Example 4 was prepared. After dissolving in dichloromethane (2 ml), MCPBA (20 mg) is added and stirred at room temperature for 4 hours. After removing the solvent the residue was purified by silica gel chromatography to give the title compound (15 mg).

1H NMR (CDCl3) δ 7.30-7.60 (m, 7H), 6.90-7.00 (m, 2H), 5.40 (m, 1H), 5.15-5.30 (s, 2H), 4.65 (s, 2H), 4.50 (m, 1H), 3.85 (s, 3H), 1.50-2.00 (m, 3H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.30-7.60 (m, 7H), 6.90-7.00 (m, 2H), 5.40 (m, 1H), 5.15-5.30 (s, 2H), 4.65 (s, 2H), 4.50 (m, 1H), 3.85 (s, 3H), 1.50-2.00 (m, 3H), 0.80-1.20 (m, 6H)

실시예 41. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(1H-2,3-다이옥소인돌-5-일)-3-사이클로부텐-1,2-다이온의 제조Example 41. 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (1H-2,3-dioxoindol-5-yl) -3-cyclobutene-1,2 Preparation of Dion

단계 1. 4-(1-메틸에톡시)-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제조Step 1. Preparation of 4- (1-methylethoxy) -3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

다이아이소프로필 스쿠아레이트와 (트라이-n-부틸스테닐)트라이메틸실란을 테트라하이드로퓨란 (50 ml)에 녹인 후 -23 oC에서 교반하였다. n-테트라부틸암모니움시아나이드를 테트라하이드로퓨란에 녹인 용액을 적가하여 반응 용액의 색깔 변화가 노란색을 나타내었다. 반응 혼합물을 농축하여 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.9 g)을 수득하였다.
Diisopropyl squarate and (tri-n-butylstenyl) trimethylsilane were dissolved in tetrahydrofuran (50 ml) and stirred at -23 ° C. A solution of n-tetrabutylammonium cyanide dissolved in tetrahydrofuran was added dropwise to give a yellow color change in the reaction solution. The reaction mixture was concentrated and purified via column chromatography to give the title compound (0.9 g).

단계 2. 4-아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제조Step 2. Preparation of 4-amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

상기 단계 1의 4-(1-메틸에톡시)-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (2.96 g, 6.90 mmol)을 0 oC 에서 다이클로로메탄 (50 ml)에 녹인 후 암모니아 가스을 통과시키며 교반하였다. 반응 혼합물을 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.9 g)을 수득하였다.
4- (1-methylethoxy) -3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (2.96 g, 6.90 mmol) of step 1 was added at 0 ° C. It was dissolved in chloromethane (50 ml) and stirred through ammonia gas. The reaction mixture was purified via column chromatography to give the title compound (0.9 g).

단계 3. 3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온의 제조Step 3. Preparation of 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione

상기 단계 2의 4-아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (0.9 g, 2.33 mmol)을 다이클로로메탄/다이메틸포름아마이드 (40 ml/ 30 ml)에 녹인 후 N-(벤질옥시카보닐)-루신 (1.24 g, 4.66 mmol), N-하이드록시벤조트리아졸 (HOBt; 0.69 g, 5.13 mmol), 트라이에틸아민 (0.98 g, 6.99 mmol)과 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염(EDCI; 0.98 g, 5.13 mmol)에 첨가하여 상온에서 24시간 동안 교반하였다. 다이클로로메탄으로 희석한 후 포화된 중조용액으로 세척하였다. 유기층을 소듐설페이트로 건조한 후 농축시켜 얻은 잔사를 컬럼크로마토그래피를 통하여 정제하여 표제화합물 (0.79 g)을 수득하였다.4-Amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (0.9 g, 2.33 mmol) of step 2 was diluted with dichloromethane / dimethylformamide (40 ml / 30 ml) and then N- (benzyloxycarbonyl) -leucine (1.24 g, 4.66 mmol), N-hydroxybenzotriazole (HOBt; 0.69 g, 5.13 mmol), triethylamine (0.98 g, 6.99 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 0.98 g, 5.13 mmol) and stirred at room temperature for 24 hours. Diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography to give the title compound (0.79 g).

1H NMR (CDCl3) δ 0.8-1.8 (m, 36H), 4.46(brs, 1H), 5.0-5.2(m, 3H), 7.2-7.4(s, 5H), 10.02(s, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.8 (m, 36H), 4.46 (brs, 1H), 5.0-5.2 (m, 3H), 7.2-7.4 (s, 5H), 10.02 (s, 1H)

단계 4. 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(2-페닐에테닐)-3-사이클로부텐-1,2-다이온Step 4. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (2-phenylethenyl) -3-cyclobutene-1,2-dione

상기 단계 3의 3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스테닐)-3-사이클로부텐-1,2-다이온 (30 mg)과 5-아이오도이사틴 (20 ml)를 다이메틸포름아마이드 (1.0 ml)에 녹여 촉매량의 벤질클로로비스(트라이페닐포스핀)팔라듐과 요오드화구리를 첨가하여 상온에서 교반하였다. 반응 혼합물을 에틸아세테이트 (10 ml)로 희석하고 염화암모늄 수용액 (10 ml)로 1회 세척하였다. 유기층을 에틸아세테이트로 이산화규소 플러그를 통과하여 얻은 잔사를 컬럼크로마토그래피를 통하여 정제하여 (5 mg)의 표제화합물을 수득하였다. 3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstenyl) -3-cyclobutene-1,2-dione (30 mg) of step 3 above; 5-iodoisatin (20 ml) was dissolved in dimethylformamide (1.0 ml), and a catalytic amount of benzylchlorobis (triphenylphosphine) palladium and copper iodide were added and stirred at room temperature. The reaction mixture was diluted with ethyl acetate (10 ml) and washed once with aqueous ammonium chloride solution (10 ml). The residue obtained by passing the silicon dioxide plug through ethyl acetate with ethyl acetate was purified by column chromatography to obtain (5 mg) of the title compound.                     

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-2.0(m, 3H), 4.42(m, 1H), 5.24(m, 3H), 7.02(d, 1H), 7.2-7.4(m, 5H), 7.88(s, 1H), 8.24(m, 1H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-2.0 (m, 3H), 4.42 (m, 1H), 5.24 (m, 3H), 7.02 (d, 1H), 7.2-7.4 (m, 5H), 7.88 (s, 1H), 8.24 (m, 1H)

실시예 42. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-메틸-N-(t-부톡시카보닐)아미노메틸]-3-사이클로부텐-1,2-다이온의 제조Example 42. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N-methyl-N- (t-butoxycarbonyl) aminomethyl] -3-cyclobutene-1, Preparation of 2-dione

단계 1. 3-에톡시-4-메틸-3-사이클로부텐-1,2-다이온의 제조Step 1. Preparation of 3-ethoxy-4-methyl-3-cyclobutene-1,2-dione

다이에틸스쿠아레이트 (1.5 g, 8.82 mmol)과 무수 테트라하이드로퓨란 (45 ml) 혼합용액에 1.0 M N-메틸-N-(t-부톡시카보닐)아미노메틸리튬 (8.82 ml, 8.82 mmol)을 -78oC에서 첨가한 후 혼합물을 10분간 교반하였다. 무수 트라이플루오로아세트산 (1.49 ml, 10.6 mmol)과 10% 염화암모늄 수용액 (7.5 ml)을 -78oC에서 첨가한 후 상온까지 교반하였다. 혼합물을 에테르와 5% 중조로 층분리 후 유기층을 건조 및 정제하여 표제화합물 (700 mg)을 수득하였다.1.0 M N-methyl-N- (t-butoxycarbonyl) aminomethyllithium (8.82 ml, 8.82 mmol) in a mixed solution of diethylsquarate (1.5 g, 8.82 mmol) and anhydrous tetrahydrofuran (45 ml) Was added at -78 o C and then the mixture was stirred for 10 min. Trifluoroacetic anhydride (1.49 ml, 10.6 mmol) and 10% aqueous ammonium chloride solution (7.5 ml) were added at -78 ° C. and then stirred to room temperature. The mixture was layered with ether and 5% sodium bicarbonate, and the organic layer was dried and purified to give the title compound (700 mg).

1H NMR (CDCl3) δ4.78 (q, 2H), 2.20 (s, 3H), 1.49 (t, 3H) 1 H NMR (CDCl 3 ) δ 4.78 (q, 2H), 2.20 (s, 3H), 1.49 (t, 3H)

단계 2. 3-아미노-4-메틸-3-사이클로부텐-1,2-다이온의 제조Step 2. Preparation of 3-amino-4-methyl-3-cyclobutene-1,2-dione

상기 단계 1의 3-에톡시-4-메틸-3-사이클로부텐-1,2-다이온 (140 mg, 1.0 mmol)을 에탄올 (2 ml)에 녹인 후 포화된 암모니아-에탄올 용액 (2 ml)를 첨가하여 상온에서 5시간동안 교반한다. 용매 제거 후, 혼합물을 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (80 mg)을 수득하였다.
The 3-ethoxy-4-methyl-3-cyclobutene-1,2-dione (140 mg, 1.0 mmol) of step 1 was dissolved in ethanol (2 ml) and then saturated ammonia-ethanol solution (2 ml) It is added and stirred for 5 hours at room temperature. After removal of the solvent, the mixture was purified via silica gel chromatography to give the title compound (80 mg).

단계 3. 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-메틸-N-(t-부톡시카보닐)아미노메틸]-3-사이클로부텐-1,2-다이온의 제조Step 3. 3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N-methyl-N- (t-butoxycarbonyl) aminomethyl] -3-cyclobutene-1,2 Preparation of Dion

N-(벤질옥시카보닐)-L-루신 (334 mg, 1.30 mmol), N-하이드록시벤조트리아졸 (HOBt; 213 mg, 1.45 mmol), 트라이에틸아민 (0.22 ml, 1.57 mmol) 과 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염 (EDCI; 278 mg, 1.57 mmol)/다이클로로메탄/다이메틸포름아마이드 (10 ml/10 ml)용액혼합용액에 상기 단계 2의 3-아미노-4-메틸-3-사이클로부텐-1,2-다이온 (70 mg, 0.63 mmol)을 적가한 후, 상온에서 24시간동안 교반한다. 반응용액을 다이클로로메탄으로 희석한 후 포화된 중조용액으로 세척하고, 유기층을 무수 소듐설페이트로 탈수 및 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (110 mg)을 수득하였다. N- (benzyloxycarbonyl) -L-leucine (334 mg, 1.30 mmol), N-hydroxybenzotriazole (HOBt; 213 mg, 1.45 mmol), triethylamine (0.22 ml, 1.57 mmol) and 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI; 278 mg, 1.57 mmol) / dichloromethane / dimethylformamide (10 ml / 10 ml) -Amino-4-methyl-3-cyclobutene-1,2-dione (70 mg, 0.63 mmol) is added dropwise and then stirred at room temperature for 24 hours. The reaction solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, and the organic layer was dehydrated and concentrated with anhydrous sodium sulfate. The residue was purified by silica gel chromatography to give the title compound (110 mg).

1H NMR (CDCl3) δ 7.40 (s, 5H), 5.45 (d, 1H), 5.20 (s, 2H), 4.40-4.80 (m, 3H), 3.00 (s, 3H), 1.40-2.00 (m, 12H), 0.80-1.20 (m, 6H)
 1 H NMR (CDCl 3 ) δ 7.40 (s, 5H), 5.45 (d, 1H), 5.20 (s, 2H), 4.40-4.80 (m, 3H), 3.00 (s, 3H), 1.40-2.00 (m , 12H), 0.80-1.20 (m, 6H)

실시예 43. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-프로파노일-3-사이클로부텐-1,2-다이온의 제조Example 43 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-propanoyl-3-cyclobutene-1,2-dione

3-[N-(벤질옥시카보닐)-L-루실]아미노-3-(트라이-n-부틸스타닐)-3-사이클로부텐-1,2-다이온 (86.4 mg)과 프로파노일 클로라이드 (6.2 mg)을 무수 테트라하이 드로퓨란 (1.5 ml)에 녹이고, 촉매량의 벤질클로로비스(트라이페닐포스핀)팔라듐과 요오드화 구리를 첨가한 후 출발물질이 사라질때 까지 50 oC에서 교반하였다. 에틸아세테이트로 희석한 후 포화된 염화암모늄 용액(10 ml)으로 1회 세척한 후 유기층을 에틸아세테이트/이산화규소를 통해 여과한다. 용매를 농축시키고 크로마토그래피를 통하여 정제하여 표제화합물 (22 mg)을 수득하였다.3- [N- (benzyloxycarbonyl) -L-lucyl] amino-3- (tri-n-butylstannyl) -3-cyclobutene-1,2-dione (86.4 mg) with propanoyl chloride (6.2 mg) was dissolved in anhydrous tetrahydrofuran (1.5 ml), and a catalytic amount of benzylchlorobis (triphenylphosphine) palladium and copper iodide were added and stirred at 50 ° C. until the starting material disappeared. After diluting with ethyl acetate and washing once with saturated ammonium chloride solution (10 ml), the organic layer was filtered through ethyl acetate / silicon dioxide. The solvent was concentrated and purified via chromatography to give the title compound (22 mg).

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.2-2.0(m, 8H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 5H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-2.0 (m, 8H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 5H)

실시예 44. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(아이소부티릴)-3-사이클로부텐-1,2-다이온의 제조Example 44 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (isobutyryl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 아이소부티릴 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method except that isobutyryl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.2-1.8(m, 10H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 5H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-1.8 (m, 10H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 5H)

실시예 45. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-발레릴-3-사이클로부텐-1,2-다이온의 제조Example 45. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-valeryl-3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 발레릴 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained using the same method except that valeryl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 9H), 1.2-1.8(m, 9H), 4.42(m, 1H), 5.0-5.2(m, 3H), 7.0-7.4(m, 5H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 9H), 1.2-1.8 (m, 9H), 4.42 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.4 (m, 5H)

실시예 46. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-벤조일-3-사이클로부텐-1,2-다이온의 제조Example 46 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-benzoyl-3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 발레릴 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained using the same method except that valeryl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.5-1.8(m, 3H), 4.56(brs, 1H), 5.14(d, 2H), 5.44(m, 1H), 7.2-8.3(m, 11H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.5-1.8 (m, 3H), 4.56 (brs, 1H), 5.14 (d, 2H), 5.44 (m, 1H), 7.2-8.3 (m, 11 H)

실시예 47. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(시아노벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 47 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (cyanobenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-시아노벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (22 mg)을 수득하였다.The title compound (22 mg) was obtained using the same method except that 4-cyanobenzoyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 9H)

실시예 48. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-t-부틸벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 48 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-t-butylbenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-t-부톡시벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method except that 4-t-butoxybenzoyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.2-1.4(s, 9H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.2-8.0(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-1.4 (s, 9H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H) , 7.2-8.0 (m, 9H)

실시예 49. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2,4-다이클로로벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 49. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2,4-dichlorobenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 2,4-다이클로로벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (13 mg)을 수득하였다.The title compound (13 mg) was obtained using the same method except using 2,4-dichlorobenzoyl chloride instead of the propanoyl chloride of Example 43, above.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.2-7.6(m, 8H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.2-7.6 (m, 8H)

실시예 50. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-톨루일)-3-사이클로부텐-1,2-다이온의 제조Example 50. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-toluyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-톨루일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (13 mg)을 수득하였다.The title compound (13 mg) was obtained using the same method except that 4-toluyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 2.40(s, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 2.40 (s, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0 -7.8 (m, 9H)

실시예 51. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-에틸벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 51. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-ethylbenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-에틸벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (9 mg)을 수득하였다.The title compound (9 mg) was obtained using the same method except that 4-ethylbenzoyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.32(t, 3H), 1.6-2.0(m, 3H), 2.83(q, 2H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-8.1(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.32 (t, 3H), 1.6-2.0 (m, 3H), 2.83 (q, 2H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-8.1 (m, 9H)

실시예 52. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3,4-다이메톡시벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 52 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3,4-dimethoxybenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 3,4-다이메틸벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (11 mg)을 수득하였다.The title compound (11 mg) was obtained using the same method except using 3,4-dimethylbenzoyl chloride instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 3.95(s, 6H), 4.37(m, 1H), 5.0-5.2(m, 3H), 6.86(d, 1H), 7.2-7.8(m, 7H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 3.95 (s, 6H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 6.86 (d, 1H), 7.2-7.8 (m, 7H)

실시예 53. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-플루오르벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 53 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-fluorobenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-플루오르벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (12 mg)을 수득하였다.The title compound (12 mg) was obtained using the same method except that 4-fluorobenzoyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 9H)

실시예 54. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3,4-다이플루오르벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 54. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3,4-difluorobenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 3,4-다이플루오르벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (12 mg) 을 수득하였다.The title compound (12 mg) was obtained using the same method except using 3,4-difluorobenzoyl chloride in place of the propanoyl chloride of Example 43, above.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 8H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 8H)

실시예 55. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-트라이플루오르메톡시벤조일)-3-사이클로부텐-1,2-다이온의 제조Example 55 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-trifluoromethoxybenzoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 4-트라이플루오르메톡시벤조일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다.The title compound (10 mg) was obtained using the same method except that 4-trifluoromethoxybenzoyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.8(m, 9H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.8 (m, 9H)

실시예 56. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-벤질옥시아세틸-3-사이클로부텐-1,2-다이온의 제조Example 56 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-benzyloxyacetyl-3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 벤질옥시아세틸 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (27 mg)을 수득하였다.The title compound (27 mg) was obtained using the same method except that benzyloxyacetyl chloride was used instead of the propanoyl chloride of Example 43.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.0-4.6(m, 3H), 5.0-5.2(m, 5H), 7.2-7.5(m, 10H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.0-4.6 (m, 3H), 5.0-5.2 (m, 5H), 7.2-7.5 (m, 10H)

실시예 57. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-타이에닐)-3-사이클로부텐-1,2-다이온의 제조Example 57 Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-taienyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 티오펜-2-카보닐 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다.The title compound (20 mg) was obtained using the same method except using thiophene-2-carbonyl chloride in place of the propanoyl chloride of Example 43, above.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.0-7.6(m, 8H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.0-7.6 (m, 8H)

실시예 58. 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-퀴녹사노일)-3-사이클로부텐-1,2-다이온의 제조Example 58. Preparation of 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-quinoxanoyl) -3-cyclobutene-1,2-dione

상기 실시예 43의 프로파노일 클로라이드 대신에 2-퀴녹사노일 클로라이드를 사용하는 것을 제외하고는 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다.The title compound (15 mg) was obtained using the same method except that 2-quinoxanoyl chloride was used instead of the propanoyl chloride of Example 43, above.

1H NMR (CDCl3) δ 0.8-1.0(m, 6H), 1.4-1.8(m, 3H), 4.37(m, 1H), 5.0-5.2(m, 3H), 7.2-7.8(m, 10H)
 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.4-1.8 (m, 3H), 4.37 (m, 1H), 5.0-5.2 (m, 3H), 7.2-7.8 (m, 10H)

시험예 1. 카뎁신 K 억제 시험Test Example 1. Kadipsin K Inhibition Test

인체 재조합 카뎁신 K를 공지의 방법[Biol, Pharm. Bull, 19(8), 1026-1031(1996), J. Biol. Chem. 271, 2126-2132(1996)]에 따라 제조하였다. Human recombinant Kadipsin K is known in the art [Biol, Pharm. Bull, 19 (8), 1026-1031 (1996), J. Biol. Chem. 271, 2126-2132 (1996).

상기 카뎁신 K를 효소원으로 하여, 공지의 방법[J. Bone. Mineral Res. 12, 1396(1997)]으로 본 발명의 화합물의 카뎁신 K 억제 시험을 수행하였다. A well-known method [J. Bone. Mineral Res. 12, 1396 (1997)] was conducted on the kadepsin K inhibition test of the compounds of the present invention.

즉, 20 mM 시스테인과 5 mM의 EDTA를 포함한 완충용액(NaOAc, pH5.5) 100 mM 에 25 μM의 농도가 되도록 기질 (Cbz-Phe-Arg-AMC, Bachem사)을 첨가한 후, 본 발명의 화합물을 디메틸술폭사이드에 녹여 가하고 (이때 반응용액내의 디메틸술폭사이드의 최종 농도가 2%가 되도록 하였다.), 37℃에서 1 시간동안 반응시킨 후, 여기(excitation) 파장 360 nm, 방출(emission) 파장 460 nm의 조건으로 형광측정기(fluorometer)를 사용하여 형광도를 측정하였다. That is, after adding a substrate (Cbz-Phe-Arg-AMC, Bachem) to a concentration of 25 μM to 100 mM buffer (NaOAc, pH5.5) containing 20 mM cysteine and 5 mM EDTA, the present invention Was dissolved in dimethyl sulfoxide (the final concentration of dimethyl sulfoxide in the reaction solution was 2%), the reaction was carried out at 37 ° C for 1 hour, and then the excitation wavelength 360 nm, emission ) Fluorescence was measured using a fluorometer under a wavelength of 460 nm.

본 발명의 화합물의 카뎁신 K 활성 억제율 (%) 및 카뎁신 K 활성을 50% 억제하는 농도(IC50)는 다음 표1과 같다.Table 1 shows the inhibition rate (%) and the depth (IC 50 ) of inhibiting the Kadepsin K activity of the compound of the present invention 50%.

화합물compound % (1 μM)% (1 μM) % (0.5 μM)% (0.5 μM) IC50 (nM)IC 50 (nM) 실시예 1Example 1 57.757.7 실시예 2Example 2 86.186.1 실시예 5Example 5 84.284.2 38.638.6 실시예 12Example 12 65.465.4 실시예 14Example 14 61.961.9 실시예 17Example 17 57.957.9 실시예 25Example 25 78.578.5 실시예 32Example 32 59.859.8

상기 시험예 1의 결과로 부터 본 발명에 따른 화학식 1의 화합물은 매우 우수한 카뎁신 (Cathepsin) 활성 억제 효과를 갖고 있음을 확인할 수 있다.It can be seen from the results of Test Example 1 that the compound of Formula 1 according to the present invention has a very good effect of inhibiting Catepsin activity.

Claims (4)

하기 화학식 1로 표시되는 3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염.3-cyclobutene-1,2-dione derivative represented by the following formula (1) or a non-toxic salt thereof.
Figure 112001018636964-pat00014
Figure 112001018636964-pat00014
 상기 식에서, R1은 (N-벤질옥시카보닐-루실)아미노이다. Wherein R 1 is (N-benzyloxycarbonyl-lusyl) amino. R2 는 메톡시; 하이드록시; 페녹시벤질옥시; 피리딜프로폭시; 직쇄상 또는 분지상 C2-C7 알킨일; 페닐아세틸렌-1-일; 나프틸; 티오펜일; 퓨릴; 아지도; 시아노; 2,3-다이옥소인돌일; 메톡시벤질설파닐; 피리딜; 또는 페녹시, 사이클로펜틸옥시, 또는 2,2,3,3-테트라플루오로프로필옥시로 치환된 피리딜이거나,R 2 is methoxy; Hydroxy; Phenoxybenzyloxy; Pyridylpropoxy; Straight or branched C 2 -C 7 alkynyl; Phenylacetylen-1-yl; Naphthyl; Thiophenyl; Furyl; Azido; Cyano; 2,3-dioxoindoleyl; Methoxybenzylsulfanyl; Pyridyl; Or pyridyl substituted with phenoxy, cyclopentyloxy, or 2,2,3,3-tetrafluoropropyloxy, or 화학식 2, 3, 또는 4를 나타낸다. Formula 2, 3, or 4 is shown.
Figure 112001018636964-pat00020
Figure 112001018636964-pat00020
Figure 112001018636964-pat00008
Figure 112001018636964-pat00008
Figure 112001018636964-pat00009
Figure 112001018636964-pat00009
 R3 는 직쇄상 또는 분지상 C1-C4 알킬; 페닐; 직쇄상 또는 분지상 C1 -C4 알킬, 모노- 또는 디- 할로겐, 시아노, 다이메톡시, 또는 트라이플루오로메톡시로 치환된 페닐; 벤질옥시; 티오펜; 또는 퀴놀린을 나타낸다.R 3 is straight or branched C 1 -C 4 alkyl; Phenyl; Phenyl substituted with straight or branched C 1 -C 4 alkyl, mono- or di-halogen, cyano, dimethoxy, or trifluoromethoxy; Benzyloxy; Thiophene; Or quinoline. R4 는 수소; C1-C3 알킬; C3-C7 환상 알킬; 페닐; 페녹시페닐; 나프틸; 벤질;R 4 is hydrogen; C 1 -C 3 alkyl; C 3 -C 7 cyclic alkyl; Phenyl; Phenoxyphenyl; Naphthyl; benzyl; 모노- 또는 디- 할로게노페닐; 벤질옥시페닐; 또는 바이페닐을 나타낸다.Mono- or di-halogenophenyl; Benzyloxyphenyl; Or biphenyl. R5 는 수소; 아이소부티릴; t-부톡시카보닐; C3-C7 환상알킬카보닐; 퓨로일; 몰포린카보닐; 나프토일; 벤조일; 클로로벤조일; 벤젠설포닐; 다이클로로벤젠설포닐; 톨릴카바모일; 또는 벤질티오카바모일을 나타낸다,R 5 is hydrogen; Isobutyryl; t-butoxycarbonyl; C 3 -C 7 cyclicalkylcarbonyl; Furoyl; Morpholinecarbonyl; Naphthoyl; Benzoyl; Chlorobenzoyl; Benzenesulfonyl; Dichlorobenzenesulfonyl; Tolyl carbamoyl; Or benzylthiocarbamoyl, 제1항에 있어서, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-메톡시-3-사이클로부텐-1,2-다이온,The compound of claim 1, wherein 3-[(N-benzyloxycarbonyl) -L-rusil] amino-4-methoxy-3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(3-페녹시벤질옥시)-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenoxybenzyloxy) -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[3-(4-피리딜)프로필옥시]-3-사이클로부텐 -1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [3- (4-pyridyl) propyloxy] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-하이드록시-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-hydroxy-3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-비닐-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4-vinyl-3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(3,3-다이메틸부틴-1-일)-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (3,3-dimethylbutyn-1-yl) -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(페닐아세틸렌) -3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (phenylacetylene) -3-cyclobutene-1,2-dione, 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(2-페닐에테닐)-3-사이클로부텐-1,2-다이온,3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (2-phenylethenyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(4-페녹시페닐)에테닐]-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (4-phenoxyphenyl) ethenyl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실] 아미노 -4-[2-(나프-2-일)에테닐]-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (naph-2-yl) ethenyl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3-페닐프로펜-1-일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenylpropen-1-yl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-사이클로헥실에테닐)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-cyclohexylethenyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(3-벤질옥시페닐)에테닐]-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (3-benzyloxyphenyl) ethenyl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(3-클로로페닐)에테닐]-3-사이클로부 텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (3-chlorophenyl) ethenyl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(4-바이페닐)에테닐]-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (4-biphenyl) ethenyl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(부텐-1-일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (buten-1-yl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-[2-(2,3-다이클로로페닐)에테닐]-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- [2- (2,3-dichlorophenyl) ethenyl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-피리딜)-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-pyridyl) -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-타이에닐)-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-taienyl) -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(2-퓨릴)-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (2-furyl) -3-cyclobutene-1,2-dione, 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(3-페녹시-피리딘-4-일)-3-사이클로부텐-1,2-다이온,3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (3-phenoxy-pyridin-4-yl) -3-cyclobutene-1,2-dione, 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-(3-사이클로펜틸옥시-피리딘-4-일)-3-사이클로부텐-1,2-다이온,3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- (3-cyclopentyloxy-pyridin-4-yl) -3-cyclobutene-1,2-dione, 3-[N-(벤질옥시카보닐)-L-루실]아미노-4-[3-(2,2,3,3-테트라플루오로-프로폭시)피리딘-4-일)]-3-사이클로부텐-1,2-다이온,3- [N- (benzyloxycarbonyl) -L-lucyl] amino-4- [3- (2,2,3,3-tetrafluoro-propoxy) pyridin-4-yl)]-3-cyclo Butene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(t-부톡시카보닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (t-butoxycarbonyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-da ion, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-(피롤리딘-2-일)-3-사이클로부텐-1,2-다이온 염산염,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- (pyrrolidin-2-yl) -3-cyclobutene-1,2-dione hydrochloride, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(사이클로헥산카보닐(피롤리딘-2-일)]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (cyclohexanecarbonyl (pyrrolidin-2-yl)]-3-cyclobutene-1,2-dione , 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2-퓨로일) 피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2-furoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(아이소부티릴)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-rusil] amino-4- [N- (isobutyryl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(몰포린카보닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (morpholin carbonyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(1-나프토일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (1-naphthoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤조일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2-클로로벤조일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2-chlorobenzoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤젠설포닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzenesulfonyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(2,5-다이클로로벤젠설포닐)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (2,5-dichlorobenzenesulfonyl) pyrrolidin-2-yl] -3-cyclobutene-1, 2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(3-톨루오일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (3-toluoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-(벤질티오카바모일)피롤리딘-2-일]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N- (benzylthiocarbamoyl) pyrrolidin-2-yl] -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-아지도-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-azido-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-시아노-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-cyano-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-메톡시벤질설파닐)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-methoxybenzylsulfanyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-메톡시벤질설파닐)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-methoxybenzylsulfanyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(1H-2,3-다이옥소인돌-5-일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (1H-2,3-dioxoindol-5-yl) -3-cyclobutene-1,2-dione, 3-[(N-벤질옥시카보닐)-L-루실]아미노-4-[N-메틸-N-(t-부톡시카보닐)아미노메틸]-3-사이클로부텐-1,2-다이온,3-[(N-benzyloxycarbonyl) -L-lucyl] amino-4- [N-methyl-N- (t-butoxycarbonyl) aminomethyl] -3-cyclobutene-1,2-dione , 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-프로파노일-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-propanoyl-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(아이소부티릴)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (isobutyryl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-발레릴-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-valeryl-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-벤조일-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-benzoyl-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(시아노벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (cyanobenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-t-부틸벤조일)-3-사이클로부텐-1,2- 다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-t-butylbenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2,4-다이클로로벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2,4-dichlorobenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-톨루일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-toluyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-에틸벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-ethylbenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3,4-다이메톡시벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3,4-dimethoxybenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-플루오르벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-fluorobenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(3,4-다이플루오르벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (3,4-difluorobenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(4-트라이플루오르메톡시벤조일)-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (4-trifluoromethoxybenzoyl) -3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-벤질옥시아세틸-3-사이클로부텐-1,2-다이온,3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4-benzyloxyacetyl-3-cyclobutene-1,2-dione, 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-타이에닐)-3-사이클로부텐-1,2-다이온, 및 3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-taienyl) -3-cyclobutene-1,2-dione, and 3-[N-(4-벤질옥시카보닐)-L-루실]아미노-4-(2-퀴녹사노일)-3-사이클로부텐-1,2-다이온으로 구성된 군으로부터 선택된 것을 특징으로 하는 3-사이클로부텐-1,2-다이 온 유도체 또는 그의 무독성 염.3- [N- (4-benzyloxycarbonyl) -L-lucyl] amino-4- (2-quinoxanoyl) -3-cyclobutene-1,2-dione 3-cyclobutene-1,2-dione derivatives or non-toxic salts thereof. 화학식7b의 화합물에 R2-할라이드를 반응시키는 것을 포함하는 화학식 1의 화합물 또는 그의 무독성 염의 제조방법.A process for preparing a compound of Formula 1 or a non-toxic salt thereof, comprising reacting a R 2 -halide with a compound of Formula 7b.
Figure 112001018636964-pat00015
Figure 112001018636964-pat00015
Figure 112001018636964-pat00016
Figure 112001018636964-pat00016
 상기 식에서, SnBu3는 트라이-n-부틸스텐닐을 나타내고, R1 및 R2는 제1항에서 정의한 바와 같다.Wherein SnBu 3 represents tri-n-butylstenyl and R 1 and R 2 are as defined in claim 1. 화학식 1의 화합물 또는 그의 무독성 염과 약제학적으로 허용가능한 담체를 포함하는 골다공증(Osteoporosis), 골관절염(Osteoarthritis), 고칼슘(Hypercalcemia) 질환, 파제트(Pagets) 질환 또는 류마티스 관절염(Rheumatoid Arthritis)의 예방 또는 치료용 조성물.Prevention of Osteoporosis, Osteoarthritis, Hypercalcemia Disease, Pagets Disease or Rheumatoid Arthritis Therapeutic composition.
Figure 112007006303407-pat00017
Figure 112007006303407-pat00017
 상기 식에서 R1 및 R2는 제1항에서의 정의한 바와 같다.Wherein R 1 and R 2 are as defined in claim 1.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03206068A (en) * 1990-01-06 1991-09-09 Ikeda Mohandou:Kk Cyclobutene-1,2-dione derivative
WO1994029277A1 (en) * 1993-06-14 1994-12-22 Smithkline Beecham Plc AMILINO- OR PYRIDYLAMINO- CYCLOBUTENE- 1,2-DIONE DERIVATIVES AS cGMP PHOSPHODIESTERASE INHIBITORS
KR20010077202A (en) * 2000-02-01 2001-08-17 김선진 4-Hydrazino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof
KR100565007B1 (en) * 2000-02-01 2006-03-30 주식회사유한양행 4-Hydroxylamino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03206068A (en) * 1990-01-06 1991-09-09 Ikeda Mohandou:Kk Cyclobutene-1,2-dione derivative
WO1994029277A1 (en) * 1993-06-14 1994-12-22 Smithkline Beecham Plc AMILINO- OR PYRIDYLAMINO- CYCLOBUTENE- 1,2-DIONE DERIVATIVES AS cGMP PHOSPHODIESTERASE INHIBITORS
KR20010077202A (en) * 2000-02-01 2001-08-17 김선진 4-Hydrazino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof
KR100565007B1 (en) * 2000-02-01 2006-03-30 주식회사유한양행 4-Hydroxylamino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof

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