KR100565008B1 - 4-Hydrazino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof - Google Patents
4-Hydrazino-3-cyclobutene-1,2-dione derivatives and processes for the preparation thereof Download PDFInfo
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Abstract
본 발명은 시스테인 프로티아제 (Cysteine proteases), 특히 파파인 (Papain) 계열의 카뎁신(Cathepsins)에 우수한 억제 활성을 갖는 신규의 4-하이드라지노-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 4-hydrazino-3-cyclobutene-1,2-dione derivatives having excellent inhibitory activity against Cysteine proteases, especially Papain family of Catepsins. Or a non-toxic salt thereof, a preparation method thereof, and a composition comprising the same as an active ingredient.
4-하이드라지노-3-사이클로부텐-1,2-다이온 유도체, 시스테인 프로티아제4-hydrazino-3-cyclobutene-1,2-dione derivatives, cysteine proteases
Description
본 발명은 시스테인 프로티아제 (Cysteine proteases), 특히 파파인 (Papain) 계열의 카뎁신(Cathepsins)에 우수한 억제 활성을 갖는 신규의 4-하이드라지노-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 4-hydrazino-3-cyclobutene-1,2-dione derivatives having excellent inhibitory activity against Cysteine proteases, especially Papain family of Catepsins. Or a non-toxic salt thereof, a preparation method thereof, and a composition comprising the same 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)], 리노바이러스 3C (Rhinovirus 3C) 프로티아제는 감기 질환에 관여하는 것으로 보고되고 있다 [Q. M. Wang, Exp. Opin. Ther. Patents, 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)], Catepsin B, are 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)], rhinovirus 3C proteases have been reported to be involved in cold disease [Q. M. Wang, Exp. Opin. Ther. Patents, 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 시스테인 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); W. W. Smith, et. al., Exp. Opin. Ther. Patents, 9 (6), 683 (1999)]
이에 본 발명자들은 새로운 기본구조를 갖는 시스테인 프로티아제 저해제를 개발하고자 연구를 거듭한 결과, 4-하이드라지노-3-사이클로부텐-1,2-다이온 유도체가 카뎁신 K를 포함한 시스테인 프로티아제를 효과적으로 억제한다는 것을 발견하여 본 발명을 완성하게 되었다.Accordingly, the present inventors have conducted research to develop a cysteine protease inhibitor having a new basic structure, and as a result, the 4-hydrazino-3-cyclobutene-1,2-dione derivative is a cysteine protea containing kaepsin K. The present invention has been completed by discovering that it effectively inhibits agents.
따라서, 본 발명은 시스테인 프로티아제에 우수한 억제 활성을 갖는 4-하이드라지노-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 4-hydrazino-3-cyclobutene-1,2-dione derivative or non-toxic 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 4-하이드라지노-3-사이클로부텐-1,2-다이온 유도체 또는 그의 무독성 염이 제공된다.According to the present invention, a 4-hydrazino-3-cyclobutene-1,2-dione derivative represented by the following general formula (1) having an excellent inhibitory activity on cysteine proteases, in particular, papain-based capidine, or a non-toxic salt thereof This is provided.
상기 식에서, R1은 벤질옥시카보닐아미노기로 치환된 직쇄상 또는 분지상 C3-C8 알킬 또는 알케닐; 또는 (AA)-NH-이다. 여기서 (AA)는 N-말단 아미노기가 벤질옥시카보닐기로 치환된 아미노산 잔기이다.Wherein R 1 is a straight or branched C 3 -C 8 alkyl or alkenyl substituted with a benzyloxycarbonylamino group; Or (AA) -NH-. Wherein (AA) is an amino acid residue in which the N-terminal amino group is substituted with a benzyloxycarbonyl group.
R2는 수소; 또는 직쇄상 또는 분지상 C1-C7 알킬을 나타내고,R 2 is hydrogen; Or straight or branched C 1 -C 7 alkyl,
R3 및 R4는 서로 독립적으로 수소; 직쇄상 또는 분지상 C1-C 7 알킬; 벤질카복실; 피리딜; 4-트리플루오로메틸피리딜; 이미다졸린일; 토실; 또는 치환 또는 비치 환된 페닐, 벤질, 또는 벤조일을 나타내거나; R3 및 R4는 이들이 결합되어 있는 질소원자와 함께 벤조페논아민기를 형성하거나, 서로 고리를 이루어 몰포린, 피페리딘, 2-메톡시메틸피롤리딘, 4-메틸피페라진, 5-치환-하이단토인, 또는 프탈이미드를 나타낸다.R 3 and R 4 is independently of each other hydrogen; Straight or branched C 1 -C 7 alkyl; Benzyl carboxyl; Pyridyl; 4-trifluoromethylpyridyl; Imidazolinyl; Chubby; Or substituted or unsubstituted phenyl, benzyl, or benzoyl; R 3 and R 4 together with the nitrogen atom to which they are attached form a benzophenoneamine group or ring together to form a morpholine, piperidine, 2-methoxymethylpyrrolidine, 4-methylpiperazine, 5-substituted-hydan Toyne or phthalimide.
R1의 정의중, 아미노산 잔기(AA)는 천연 또는 합성 아미노산 잔기를 포함하며, 이러한 아미노산으로는 글라이신, 살코신, 알라닌, 베타-알라닌, 발린, 노르발린(norvaline), 루신, 아이소루신, 노르루신(norleucine), 세린, 트레오닌, 시스테인, 메치오닌, 페닐알라닌, 페닐글라이신, 트립토판, 타이로신, 프롤린, 히드록시프롤린, 글루탐산, 아스파탐산(aspartic acid), 글루타민, 아스파라긴, 라이신, 아르기닌, 히스티딘, 또는 오르니틴 등이 포함되며, 이 중에서 글라이신, 루신, 프롤린 또는 오르니틴이 바람직하다.In the definition of R 1 , amino acid residues (AA) include natural or synthetic amino acid residues, which include glycine, salcosine, alanine, beta-alanine, valine, norvaline, leucine, isoleucine, nor Leucine, serine, threonine, cysteine, methionine, phenylalanine, phenylglycine, tryptophan, tyrosine, proline, hydroxyproline, glutamic acid, aspartamic acid, glutamine, asparagine, lysine, arginine, histidine, or ornithine And the like, of which glycine, leucine, proline or ornithine are preferred.
본 발명의 화합물중, R1의 바람직한 예는 다음과 같다.Among the compounds of the present invention, preferred examples of R 1 are as follows.
본 발명의 화합물중, R3의 바람직한 예는 다음과 같다.Among the compounds of the present invention, preferred examples of R 3 are as follows.
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, 파모산, 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, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid Salts prepared from salicylic acid, 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 화 합물로부터 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 the 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 화학식 2의 화합물과 R2NH-NR3R4를 반응시키는 것을 포함하는 화학식 1의 화합물 또는 그의 무독성 염의 제조방법을 포함한다.The present invention also includes a method for preparing a compound of Formula 1 or a non-toxic salt thereof comprising reacting a compound of Formula 2 with R 2 NH-NR 3 R 4 .
이를 반응식으로 나타내면 다음과 같다.This is represented by the following scheme.
상기 반응식에서 R5는 직쇄상 또는 분지상 C1∼C4알킬이며, R1, R2 ,R3, 및 R4 는 상기에서 정의한 것과 동일하다.In the above scheme, R 5 is linear or branched C 1 -C 4 alkyl, and R 1 , R 2 , R 3 , and R 4 are the same as defined above.
상기 제조방법은 염기 존재하에서 바람직하게 수행될 수 있으며, 사용가능한 염기로는 트라이에틸아민, 다이아이소프로필에틸아민, N-메틸몰포린 등을 포함한다.The preparation method may be preferably carried out in the presence of a base, and available bases include triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
또한, 바람직한 반응용매로는 다이클로로메탄, 테트라하이드로퓨란, 메탄올, 에탄올, 다이메틸포름아마이드 등의 극성 유기용매가 포함되며, 반응온도는 통상적으로 -20 ∼ 80 ℃, 더욱 바람직하게는 상온이 바람직하다.In addition, preferred reaction solvents include polar organic solvents such as dichloromethane, tetrahydrofuran, methanol, ethanol and dimethylformamide, and the reaction temperature is usually -20 to 80 ° C, more preferably room temperature. Do.
상기 제조방법에서 출발물질로 사용되는 화학식 2의 화합물은 하기 반응식2 에 따라 제조할 수 있다.Compound of Formula 2 used as a starting material in the preparation method may be prepared according to the following Scheme 2.
상기 반응식에서 R1'은 (AA)-NH-이며, (AA)는 상기에서 정의한 바와 같다. R1''는 벤질옥시카보닐아미노기로 치환된 직쇄상 또는 분지상 C3-C8 알킬 또는 알케닐이다.R 1 ′ in the scheme is (AA) —NH—, and (AA) is as defined above. R 1 '' is straight or branched C 3 -C 8 alkyl or alkenyl substituted with a benzyloxycarbonylamino group.
즉, 화학식3의 화합물에, 공지의 방법[A. H. Schmidt, Synthesis, 961 (1980)]에 따라, 암모니아를 반응시켜 화학식 4의 화합물을 제조한 후, 화학식 4의 화합물에 천연 또는 합성 아미노산을 염기 및/또는 융합제 존재하에서 반응시켜 화학식 2a의 화합물을 제조할 수 있다. 사용가능한 염기로는 트리에틸아민, 피리딘 등의 통상의 유기염기나 중수소나트륨, 탄산칼륨 등의 통상의 무기 염기를 포함하며, 융합제로는 1-하이드록시벤조트리아졸 및 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염과 같은 적절한 활성 에스테르화제를 사용할 수 있다. 사용가능한 반응용매로는 벤젠, 다이메틸포름아미드, 아세토나이트릴 또는 다이클로로메탄 등의 극성, 비극성 유기 용매, 또는 이들의 혼합용매를 포함한다.In other words, known compounds [A. H. Schmidt, Synthesis, 961 (1980)] to prepare a compound of formula 4 by reacting ammonia and then reacting the compound of formula 4 with a natural or synthetic amino acid in the presence of a base and / or a fusion agent to Compounds can be prepared. Usable bases include conventional organic bases such as triethylamine and pyridine, and common inorganic bases such as sodium deuterium, potassium carbonate, etc., and fusion agents include 1-hydroxybenzotriazole and 1-ethyl-3- ( Suitable active esterifying agents can be used, such as 3-dimethylaminopropyl) carbodiimide hydrochloride. Reaction solvents that can be used include polar, nonpolar organic solvents such as benzene, dimethylformamide, acetonitrile or dichloromethane, or mixed solvents thereof.
또한, 화학식3의 화합물에, 공지의 방법 [L. S. Liebeskind, et. al., J. Org. Chem., 58, 3543 (1980)]에 따라, (트라이-n-부틸스텐닐)트라이메틸실란을 반응시켜 화학식5의 화합물을 제조한 후, 화학식5의 화합물에 R1''-할라이드를 반응시켜 화학식 2b의 화합물을 제조할 수 있다. 화학식5의 화합물에 R1''-할라이드를 반응시키는 단계는 팔라듐, 또는 벤질클로로비스(트라이페닐포스핀)팔라듐 및/또는 염화구리 등의 촉매존재하에서 반응시키는 것이 바람직하다.In addition, to the compound of the formula (3), a known method [LS Liebeskind, et. al., J. Org. Chem., 58, 3543 (1980)] to prepare a compound of formula 5 by reacting (tri-n-butylstenyl) trimethylsilane, and then reacting the compound of formula 5 with R 1 '' -halide. To prepare a compound of formula 2b. The step of reacting the R 1 '' -halide with the compound of Formula 5 is preferably carried out in the presence of a catalyst such as palladium or benzylchlorobis (triphenylphosphine) palladium and / or copper chloride.
본 발명은 화학식1로 표시되는 4-하이드라지노-3-사이클로부텐-1,2-다이온 유도체를 유효성분으로 함유하고 약제학적으로 허용 가능한 담체를 함유하는 시스테인 프로티아제 억제 조성물을 포함한다. The present invention includes a cysteine protease inhibitory composition containing a 4-hydrazino-3-cyclobutene-1,2-dione derivative represented by Formula 1 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 활성성분을 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 완충제로 포함할 수 있으며, 정맥내 투여의 경우 용질의 총 농도는 제제에 등장성이 부여되도록 조절할 수 있는 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, the active ingredient 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 be included as a buffer to suitably adjust the pH of the solution. For intravenous administration, the total concentration of the solute is It may include isotonic agents that can be adjusted to impart isotonicity to the formulation. 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 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 이것이 본 발명의 범위를 제한하는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples. However, this does not limit the scope of the invention.
실시예 1. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(몰포린-4-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 1. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (morpholin-4-yl) amino-3-cyclobutene-1,2-dione
단계 1. 3-아미노-4-에톡시-3-사이클로부텐-1,2-다이온의 제조Step 1. Preparation of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione
3,4-다이에톡시-3-사이클로부텐-1,2-다이온 (7.37 g, 43.3 mmol)의 무수 에틸에테르 (450 ml) 용액에 녹인 후에 0 ℃로 냉각하였다. 이 용액에 암모니아를 1시간동안 통과 시킨 후, 15분간 환류시켜 과량의 암모니아를 제거한 다음, 농축하여 노란색의 표제화합물 (6 g, 98 %)을 수득하였다. 이 화합물은 더 이상의 정제 없이 다음 공정에 사용하였다. It was dissolved in anhydrous ethyl ether (450 ml) solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (7.37 g, 43.3 mmol) and then cooled to 0 ° C. After passing ammonia through the solution for 1 hour, the mixture was refluxed for 15 minutes to remove excess ammonia, and then concentrated to give the title compound (6 g, 98%) as yellow. This compound was used in the next process without further purification.
단계 2. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-에톡시-3-사이클로부텐-1,2-다이온의 제조Step 2. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4-ethoxy-3-cyclobutene-1,2-dione
상기 단계 1의 3-아미노-4-메틸-3-사이클로부텐-1,2-다이온 (1 g, 7.09 mmol)을 다이클로로메탄/다이메틸포름아마이드 (40 ml/30 ml) 용액에 녹인 후에 N-벤질옥시카보닐-L-루신 (3.76 g, 14.18 mmol), 1-하이드록시벤조트리아졸 (HOBt; 2.39 g, 17.7 mmol), 트라이에틸아민 (2.96 ml, 21.3 mmol), 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염 (EDC; 2.99 g, 15.6 mmol)을 가하고 실온에서 18 시간 동안 교반하였다. 반응용액을 다이클로로메탄으로 희석한 후에 유기층을 5% 중조 (NaHCO3) 수용액으로 세척하고 건조 및 농축한다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (2.2 g, 80 %)을 수득하였다.3-amino-4-methyl-3-cyclobutene-1,2-dione (1 g, 7.09 mmol) of step 1 was dissolved in dichloromethane / dimethylformamide (40 ml / 30 ml) solution. N-benzyloxycarbonyl-L-leucine (3.76 g, 14.18 mmol), 1-hydroxybenzotriazole (HOBt; 2.39 g, 17.7 mmol), triethylamine (2.96 ml, 21.3 mmol), 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC; 2.99 g, 15.6 mmol) was added and stirred at rt for 18 h. After diluting the reaction solution with dichloromethane, the organic layer is washed with 5% sodium bicarbonate (NaHCO 3), dried and concentrated. The residue was purified by silica gel chromatography to give the title compound (2.2 g, 80%).
1H NMR (CDCl3) δ 9.98 (s, 1H), 7.20-7.60 (m, 5H), 5.41 (d, 1H), 5.12 (s, 2H), 4.87 (q, 2H), 4.53 (m, 1H), 1.60-1.90 (m, 3H), 1.50 (t, 3H), 0.80-1.20 (m, 6H) 1 H NMR (CDCl 3 ) δ 9.98 (s, 1H), 7.20-7.60 (m, 5H), 5.41 (d, 1H), 5.12 (s, 2H), 4.87 (q, 2H), 4.53 (m, 1H ), 1.60-1.90 (m, 3H), 1.50 (t, 3H), 0.80-1.20 (m, 6H)
단계 3. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(몰포린-4-일)아미노-3-사이클로부텐-1,2-다이온의 제조Step 3. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (morpholin-4-yl) amino-3-cyclobutene-1,2-dione
상기 단계 2의 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-에톡시-3-사이클로부텐-1,2-다이온 (40 mg, 0.113 mmol)을 에탄올 (3 ml)에 녹인후에 4-아미노몰포린 (11 mg, 0.136 mmol)과 트라이에틸아민 (0.042 ml, 0.3 mmol)을 가하고 상온에서 약 1시간 동안 교반하였다. 반응혼합물을 농축한 후에 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (27 mg, 55%)을 수득하였다. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4-ethoxy-3-cyclobutene-1,2-dione (40 mg, 0.113 mmol) of step 2 was added to ethanol (3 After dissolving in ml), 4-aminomorpholine (11 mg, 0.136 mmol) and triethylamine (0.042 ml, 0.3 mmol) were added and stirred at room temperature for about 1 hour. After the reaction mixture was concentrated, the residue was purified by silica gel chromatography to obtain the title compound (27 mg, 55%).
1H NMR (CDCl3) δ 7.30-7.60 (m, 5H), 5.45 (m, 1H), 5.00-5.30 (m, 2H), 3.60-4.00 (m, 5H), 2.60-3.60 (m, 4H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.30-7.60 (m, 5H), 5.45 (m, 1H), 5.00-5.30 (m, 2H), 3.60-4.00 (m, 5H), 2.60-3.60 (m, 4H) , 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 2. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(피페리딘-1-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 2. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (piperidin-1-yl) amino-3-cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 1-아미노피페리딘을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다. The title compound (15 mg) was obtained in the same manner as in Example 1, except that 1-aminopiperidine was used instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 10.50 (brs, 1H), 8.50 (s, 1H), 7.20-7.60 (m, 5H), 5.60 (d, 1H), 5.00-5.30 (s, 2H), 4.50 (m, 1H), 2.80-3.00 (m, 4H), 1.20-2.00 (m, 9H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 10.50 (brs, 1H), 8.50 (s, 1H), 7.20-7.60 (m, 5H), 5.60 (d, 1H), 5.00-5.30 (s, 2H), 4.50 (m , 1H), 2.80-3.00 (m, 4H), 1.20-2.00 (m, 9H), 0.80-1.20 (m, 6H)
실시예 3. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(4-메틸피페라진-1-일)아미노 -3-사이클로부텐-1,2-다이온의 제조Example 3. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (4-methylpiperazin-1-yl) amino-3-cyclobutene-1,2-dione Produce
실시 예 1의 단계 3에서의 4-아미노몰포린 대신에 1-아미노-4-메틸피페라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (25 mg)을 수득하였다. The title compound (25 mg) was obtained in the same manner as in Example 1, except that 1-amino-4-methylpiperazine was used instead of 4-aminomorpholine in Step 3 of Example 1 .
1H NMR (CDCl3) δ 8.45 (s, 1H), 7.20-7.60 (m, 5H), 5.55 (d, 1H), 5.10-5.30 (m, 2H), 4.45 (m, 1H), 2.50-3.20 (m, 8H), 2.38 (s, 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 8.45 (s, 1H), 7.20-7.60 (m, 5H), 5.55 (d, 1H), 5.10-5.30 (m, 2H), 4.45 (m, 1H), 2.50-3.20 (m, 8H), 2.38 (s, 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 4. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(벤조페논하이드라존-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 4. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (benzophenonehydrazone-1-yl) -3-cyclobutene-1,2-dione
실시 예 1의 단계 3에서의 4-아미노몰포린 대신에 벤조페논하이드라존을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (12 mg)을 수득하였다. The title compound (12 mg) was obtained in the same manner as in Example 1, except that benzophenonehydrazone was used instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 10.60 (m, 2H), 7.20-8.00 (m, 15H), 5.70 (m, 1H), 5.00-5.40 (m, 2H), 4.45 (m, 1H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 10.60 (m, 2H), 7.20-8.00 (m, 15H), 5.70 (m, 1H), 5.00-5.40 (m, 2H), 4.45 (m, 1H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예5. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-[2-(2-클로로페닐)하이드라진-1-일]-3-사이클로부텐-1,2-다이온의 제조Example 5. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- [2- (2-chlorophenyl) hydrazin-1-yl] -3-cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-클로로페닐하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다. The title compound (15 mg) was obtained using the same method as Example 1 except for using 2-chlorophenylhydrazine in place of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 7.00-7.80 (m, 9H), 5.00-5.50 (m, 3H), 4.20-4.60 (m, 1H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.00-7.80 (m, 9H), 5.00-5.50 (m, 3H), 4.20-4.60 (m, 1H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 6. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-2-[(4-트라이플루오로메틸)피리미딘-2-일]하이드라진-1-일-3-사이클로부텐-1,2-다이온의 제조Example 6. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4-2-[(4-trifluoromethyl) pyrimidin-2-yl] hydrazin-1-yl-3 Preparation of Cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-하이드라지노-4-(트라이플루오로메틸)피리미딘을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (24 mg)을 수득하였다. The title compound was prepared in the same manner as in Example 1, except that 2-hydrazino-4- (trifluoromethyl) pyrimidine was used instead of 4-aminomorpholine in Step 3 of Example 1 (24 mg) was obtained.
1H NMR (CDCl3) δ 10.70 (brs, 1H), 8.65 (m, 1H), 6.90-7.60 (m, 6H), 5.75 (d, 1H), 5.00-5.30 (m, 2H), 4.40-4.70 (m, 1H), 1.45-1.90 (m, 3H), 0.80-1.20 (m, 6H) 1 H NMR (CDCl 3 ) δ 10.70 (brs, 1H), 8.65 (m, 1H), 6.90-7.60 (m, 6H), 5.75 (d, 1H), 5.00-5.30 (m, 2H), 4.40-4.70 (m, 1H), 1.45-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 7. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-[2-(2-피리딜)하이드라진-1-일]-3-사이클로부텐-1,2-다이온의 제조Example 7. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- [2- (2-pyridyl) hydrazin-1-yl] -3-cyclobutene-1,2- Preparation of Dion
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-하이드라지노피리딘을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다. The title compound (20 mg) was obtained using the same method as Example 1 except for using 2-hydrazinopyridine instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 8.05-8.30 (m, 1H), 6.60-7.70 (m, 9H), 5.80 (m, 1H), 5.00-5.30 (m, 2H), 4.30-4.70 (m, 1H), 1.40-1.80 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 8.05-8.30 (m, 1H), 6.60-7.70 (m, 9H), 5.80 (m, 1H), 5.00-5.30 (m, 2H), 4.30-4.70 (m, 1H) , 1.40-1.80 (m, 3H), 0.80-1.20 (m, 6H)
실시예 8. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(1-메틸하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 8. Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (1-methylhydrazin-1-yl) -3-cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 메틸하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다. The title compound (10 mg) was obtained in the same manner as in Example 1, except that methylhydrazine was used instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 5.00-5.40 (m, 2H), 4.00-4.60 (m, 2H), 2.50-3.60 (m, 3H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 5.00-5.40 (m, 2H), 4.00-4.60 (m, 2H), 2.50-3.60 (m, 3H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 9. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(2-페닐아세틸하이드라진-1- 일)-3-사이클로부텐-1,2-다이온의 제조Example 9 Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (2-phenylacetylhydrazin-1-yl) -3-cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 페닐아세틸하이드라자이드을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다. The title compound (15 mg) was obtained in the same manner as in Example 1 except for using phenylacetylhydrazide instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 10.80 (brs, 1H), 8.50 (m, 1H), 7.00-7.70 (m, 10H), 5.70 (m, 1H), 5.00-5.40 (m, 2H), 4.45 (m, 1H), 3.45-3.80 (m, 2H), 1.40-1.80 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 10.80 (brs, 1H), 8.50 (m, 1H), 7.00-7.70 (m, 10H), 5.70 (m, 1H), 5.00-5.40 (m, 2H), 4.45 (m , 1H), 3.45-3.80 (m, 2H), 1.40-1.80 (m, 3H), 0.80-1.20 (m, 6H)
실시예 10. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(2-메틸페닐하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 10 Preparation of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (2-methylphenylhydrazin-1-yl) -3-cyclobutene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-메틸페닐하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (25 mg)을 수득하였다. The title compound (25 mg) was obtained in the same manner as in Example 1 except that 2-methylphenylhydrazine was used instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 7.00-7.60 (m, 9H), 5.60-6.25 (m, 1H), 5.00-5.60 (m, 2H), 4.10-4.60 (m, 1H), 2.00-2.50 (m, 3H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.00-7.60 (m, 9H), 5.60-6.25 (m, 1H), 5.00-5.60 (m, 2H), 4.10-4.60 (m, 1H), 2.00-2.50 (m, 3H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 11. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-[2-(2-이미다졸린일)하이드라진-1-일]-3-사이클로부텐-1,2-다이온의 제조Example 11. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- [2- (2-imidazolinyl) hydrazin-1-yl] -3-cyclobutene-1, Preparation of 2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-하이드라지노-2-이미다졸린을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (12 mg)을 수득하였다. The title compound (12 mg) was prepared in the same manner as in Example 1, except that 2-hydrazino-2-imidazoline was used instead of 4-aminomorpholine in Step 3 of Example 1 Obtained.
1H NMR (CDCl3) δ 7.20-7.60 (m, 5H), 5.00-5.40 (m, 3H), 4.40-4.80 (m, 1H), 3.40-4.00 (m, 4H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 5H), 5.00-5.40 (m, 3H), 4.40-4.80 (m, 1H), 3.40-4.00 (m, 4H), 1.40-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 12. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-[2-(2-나이트로벤조일)하이드라진-1-일]-3-사이클로부텐-1,2-다이온의 제조Example 12. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- [2- (2-nitrobenzoyl) hydrazin-1-yl] -3-cyclobutene-1,2 Preparation of Dion
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 2-나이트로벤조일하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다. The title compound (15 mg) was obtained using the same method as Example 1 except for using 2-nitrobenzoylhydrazine in place of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 10.80 (brs, 1H), 7.00-8.25 (m, 9H), 5.60-6.00 (m, 1H), 5.00-5.40 (m, 2H), 4.20-4.70 (m, 1H), 1.40-1.90 (m, 3H), 0.60-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 10.80 (brs, 1H), 7.00-8.25 (m, 9H), 5.60-6.00 (m, 1H), 5.00-5.40 (m, 2H), 4.20-4.70 (m, 1H) , 1.40-1.90 (m, 3H), 0.60-1.20 (m, 6H)
실시예 13. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(5-벤질옥시벤질히단토인-3-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 13. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (5-benzyloxybenzylhydantoin-3-yl) amino-3-cyclobutene-1,2-da Preparation of ions
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 3-아미노-5-벤질옥시벤질히단토인을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합 물 (15 mg)을 수득하였다. Title compound (15 mg) using the same method as Example 1 except for using 3-amino-5-benzyloxybenzylhydantoin in place of 4-aminomorpholine in Step 3 of Example 1 Obtained.
1H NMR (CDCl3) δ 6.80-7.60 (m, 14H), 5.55 (m, 1H), 5.00-5.30 (m, 4H), 4.00-4.70 (m, 2H), 2.80-3.40 (m, 2H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 6.80-7.60 (m, 14H), 5.55 (m, 1H), 5.00-5.30 (m, 4H), 4.00-4.70 (m, 2H), 2.80-3.40 (m, 2H) , 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 14. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(5-벤질히단토인-3-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 14 of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (5-benzylhydantoin-3-yl) amino-3-cyclobutene-1,2-dione Produce
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 3-아미노-5-벤질히단토인을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다.The title compound (20 mg) was obtained in the same manner as in Example 1, except that 3-amino-5-benzylhydantoin was used instead of 4-aminomorpholine in Step 3 of Example 1 .
1H NMR (CDCl3) δ 7.20-7.60 (m, 10H), 5.60 (m, 1H), 5.05-5.40 (m, 2H), 4.00-4.70 (m, 2H), 2.80-3.45 (m, 2H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.20-7.60 (m, 10H), 5.60 (m, 1H), 5.05-5.40 (m, 2H), 4.00-4.70 (m, 2H), 2.80-3.45 (m, 2H) , 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 15. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(2-벤질-2-페닐하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 15. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (2-benzyl-2-phenylhydrazin-1-yl) -3-cyclobutene-1,2-da Preparation of ions
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 1-벤질-1-페닐하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다. The title compound (20 mg) was obtained using the same method as Example 1 except for using 1-benzyl-1-phenylhydrazine in place of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 6.80-7.60 (m, 15H), 5.60 (d, 1H), 5.00-5.25 (s, 2H), 4.60 (s, 2H), 4.45 (m, 1H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 6.80-7.60 (m, 15H), 5.60 (d, 1H), 5.00-5.25 (s, 2H), 4.60 (s, 2H), 4.45 (m, 1H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 16. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(2-메틸-2-페닐하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 16. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (2-methyl-2-phenylhydrazin-1-yl) -3-cyclobutene-1,2-da Preparation of ions
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 1-메틸-1-페닐하이드라진을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다. The title compound (20 mg) was obtained in the same manner as in Example 1, except that 1-methyl-1-phenylhydrazine was used instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 9.05 (s, 1H), 6.80-7.60 (m, 10H), 5.70 (d, 1H), 5.00-5.30 (m, 2H), 4.50 (m, 1H), 3.28 (s, 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 9.05 (s, 1H), 6.80-7.60 (m, 10H), 5.70 (d, 1H), 5.00-5.30 (m, 2H), 4.50 (m, 1H), 3.28 (s , 3H), 1.50-1.90 (m, 3H), 0.80-1.20 (m, 6H)
실시예 17. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-[(S)-2-(메톡시메틸)피롤리딘-1-일]아미노-3-사이클로부텐-1,2-다이온의 제조Example 17. 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4-[(S) -2- (methoxymethyl) pyrrolidin-1-yl] amino-3-cyclo Preparation of Butene-1,2-dione
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 (S)-1-아미노-2-(메톡시메틸)피롤리딘을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (20 mg)을 수득하였다. Using the same method as in Example 1, except for using (S) -1-amino-2- (methoxymethyl) pyrrolidine instead of 4-aminomorpholine in Step 3 of Example 1 The title compound (20 mg) was obtained.
1H NMR (CDCl3) δ 8.45 (brs, 1H), 7.20-7.50 (m, 5H), 5.80 (d, 1H), 5.00-5.30 (s, 2H), 4.48 (m, 1H), 2.70-3.60 (m, 8H), 1.50-2.20 (m, 7H), 0.80-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 8.45 (brs, 1H), 7.20-7.50 (m, 5H), 5.80 (d, 1H), 5.00-5.30 (s, 2H), 4.48 (m, 1H), 2.70-3.60 (m, 8H), 1.50-2.20 (m, 7H), 0.80-1.20 (m, 6H)
실시예 18. 3-[(N-벤질옥시카보닐)-L-루신일]아미노-4-(2-토릴술포닐하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 18. of 3-[(N-benzyloxycarbonyl) -L-leucineyl] amino-4- (2-tolylsulfonylhydrazin-1-yl) -3-cyclobutene-1,2-dione Produce
실시예 1의 단계 3에서의 4-아미노몰포린 대신에 토릴술포닐하이드라자이드를 사용하는 것을 제외하고는, 실시예 1과 동일한 방법을 사용하여 표제화합물 (13 mg)을 수득하였다. The title compound (13 mg) was obtained in the same manner as Example 1 except for using tolylsulfonylhydrazide instead of 4-aminomorpholine in Step 3 of Example 1.
1H NMR (CDCl3) δ 10.80 (brs, 1H), 7.00-8.25 (m, 9H), 5.60-6.00 (m, 1H), 5.00-5.40 (m, 2H), 4.20-4.70 (m, 1H), 2,2 (s, 3H), 1.40-1.90 (m, 3H), 0.60-1.20 (m, 6H)
1 H NMR (CDCl 3 ) δ 10.80 (brs, 1H), 7.00-8.25 (m, 9H), 5.60-6.00 (m, 1H), 5.00-5.40 (m, 2H), 4.20-4.70 (m, 1H) , 2,2 (s, 3H), 1.40-1.90 (m, 3H), 0.60-1.20 (m, 6H)
실시예 19. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-2-[(4-트리플루오로메틸)피리미딘-2-일]하이드라진-1-일-3-사이클로부텐-1,2-다이온의 제조Example 19. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-2-[(4-trifluoromethyl) pyrimidine- Preparation of 2-yl] hydrazin-1-yl-3-cyclobutene-1,2-dione
단계 1. N-벤질옥시카보닐-L-루신-N-메틸-N-메톡시아마이드의 제조 Step 1.Preparation of N-benzyloxycarbonyl-L-leucine-N-methyl-N-methoxyamide
N,O-다이메틸하이드록실아민 (4.4 g, 44.2 mmol), N-벤질옥시카보닐-L-루신 (10.0 g, 37.7 mmol), 1-하이드록시벤조트리아졸 (HOBt; 7.6 g, 56.6 mmol), 트라이에틸아민 (15.7 ml, 113.0 mmol), 1-에틸-3-(3-다이메틸아미노프로필)카보다이이미드 염산염 (EDC; 10.8 g, 56.5 mmol)을 다이메틸포름아마이드 (100 ml)에 녹인 후에 실온에서 18 시간 동안 교반하였다. 반응용액을 에틸아세테이트 (200 ml)로 희석한 후에, 유기층을 5% 중조 (NaHCO3) 수용액으로 세척하고 소듐술페이트로 탈수 및 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (11.6 g, 100%)을 수득하였다.N, O-dimethylhydroxylamine (4.4 g, 44.2 mmol), N-benzyloxycarbonyl-L-leucine (10.0 g, 37.7 mmol), 1-hydroxybenzotriazole (HOBt; 7.6 g, 56.6 mmol ), Triethylamine (15.7 ml, 113.0 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC; 10.8 g, 56.5 mmol) in dimethylformamide (100 ml) After thawing, the mixture was stirred at room temperature for 18 hours. After diluting the reaction solution with ethyl acetate (200 ml), the organic layer was washed with 5% sodium bicarbonate (NaHCO 3 ), dehydrated and concentrated with sodium sulfate. The residue was purified by silica gel chromatography to give the title compound (11.6 g, 100%).
1H NMR (CDCl3) δ 7.2-7.4(s, 5H), 5.23(d, 1H), 5.10(s, 2H), 4.43(m, 1H), 3.70(s, 3H), 3.20(s, 3H), 1.6-1.8(m, 3H), 0.8-1.0(m, 6H) 1 H NMR (CDCl 3 ) δ 7.2-7.4 (s, 5H), 5.23 (d, 1H), 5.10 (s, 2H), 4.43 (m, 1H), 3.70 (s, 3H), 3.20 (s, 3H ), 1.6-1.8 (m, 3H), 0.8-1.0 (m, 6H)
단계 2. N-벤질옥시카보닐-L-루신알의 제조Step 2. Preparation of N-benzyloxycarbonyl-L-leucine
상기 단계 1의 N-벤질옥시카보닐-L-루신-N-메틸-N-메톡시아마이드 (11.6 g, 37.7 mmol)을 무수 테트라하이드로퓨란 (100 ml)에 녹인 후에, 리튬알루미늄하이드라이드 (1.65 g, 43.3 mmol)을 -45 ℃에서 가한 다음에 반응 온도를 5 ℃로 천천히 상승시켰다. 반응혼합물을 다시 -35 ℃로 냉각한 후에 1N-염산수용액 (60 ml)를 천천히 적가하고 생성된 고체를 여과 제거하였다. 여과용액을 에틸아세테이트로 희석한 후에 유기층을 물로 세척하고 탈수 및 농축하여 표제화합물 (7.14 g, 76%)을 수득하였다.N-benzyloxycarbonyl-L-leucine-N-methyl-N-methoxyamide (11.6 g, 37.7 mmol) of step 1 was dissolved in anhydrous tetrahydrofuran (100 ml), followed by lithium aluminum hydride (1.65 g, 43.3 mmol) was added at -45 ° C, and the reaction temperature was then slowly raised to 5 ° C. After cooling the reaction mixture to -35 ° C, 1N aqueous hydrochloric acid solution (60 ml) was slowly added dropwise, and the resulting solid was filtered off. The filtrate was diluted with ethyl acetate, and then the organic layer was washed with water, dehydrated and concentrated to give the title compound (7.14 g, 76%).
1H NMR (CDCl3) δ 9.85(s, 1H), 7.2-7.4(s, 5H), 5.20(d, 1H), 5.11(s, 2H), 4.43(m, 1H), 1.6-1.8(m, 3H), 0.8-1.0(m, 6H) 1 H NMR (CDCl 3 ) δ 9.85 (s, 1H), 7.2-7.4 (s, 5H), 5.20 (d, 1H), 5.11 (s, 2H), 4.43 (m, 1H), 1.6-1.8 (m , 3H), 0.8-1.0 (m, 6H)
단계 3. 3(S)-(N-벤질옥시카보닐)아미노-1-아이오도-5-메틸-트랜스-1-헥센의 제조 Step 3. Preparation of 3 (S)-(N-benzyloxycarbonyl) amino-1-iodo-5-methyl-trans-1-hexene
상기 단계 2의 N-벤질옥시카보닐-L-루신알 (3.0 g, 12.1 mmol)과 아이오도포름 (9.4 g, 24.0 mmol)을 무수 테트라하이드로퓨란 (50 ml)에 녹인후에 염화크롬 (8.85 g, 72.0 mmol) 테트라하이드로퓨란 (50 ml) 현탁액을 0 ℃에서 가한 다음에 3시간동안 교반을 계속하였다. 반응혼합물을 여과한 후에 테트라부틸암모늄플로라이드 테트라하이드로퓨란용액 (1 M, 40 ml)를 적가하여 과량의 아이도포름을 제거하고 농축한다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (2.13 g, 47%)을 수득하였다.N-benzyloxycarbonyl-L-leucineal (3.0 g, 12.1 mmol) and iodoform (9.4 g, 24.0 mmol) in step 2 were dissolved in anhydrous tetrahydrofuran (50 ml), followed by chromium chloride (8.85 g). , 72.0 mmol) tetrahydrofuran (50 ml) suspension was added at 0 ° C. and stirring continued for 3 hours. After filtering the reaction mixture, tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 40 ml) was added dropwise to remove excess iodoform and concentrated. The residue was purified by silica gel chromatography to give the title compound (2.13 g, 47%).
1H NMR (CDCl3) δ 7.3-7.5(s, 5H), 6.2-6.6(m, 2H), 5.0-5.2(s, 2H), 4.62(m, 1H), 4.23(m, 1H), 1.6-1.8(m, 3H), 0.8-1.0(m, 6H) 1 H NMR (CDCl 3 ) δ 7.3-7.5 (s, 5H), 6.2-6.6 (m, 2H), 5.0-5.2 (s, 2H), 4.62 (m, 1H), 4.23 (m, 1H), 1.6 -1.8 (m, 3H), 0.8-1.0 (m, 6H)
단계 4. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온의 제조Step 4. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-isopropoxy-3-cyclobutene-1,2-dione Manufacture
상기 단계 3의 3(S)-(N-벤질옥시카보닐)아미노-1-아이오도-5-메틸-트랜스-1-헥센 (1.5 g, 4.0 mmol)과 4-아이소프로폭시-3-트라이부틸스텐일-3-사이클로부텐-1,2-다이온 (1.6 g, 3.6 mmol)을 무수 다이메틸포름아마이드 (10 ml)에 녹인후에 촉매량의 벤질클로로비스(트라이페닐포스핀)팔라듐 (166 mg, 6 mmol %)와 염화구리 (63 mg, 9 mmol)을 상온에서 가한 다음에 3시간동안 교반을 계속하였다. 반응혼합물을 에틸아세테이트로 희석한 후에 유기층을 포화 암모늄클로라이드 수용애 및 10%-불소화나트륨 수용액으로 세척하고 탈수 및 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (1.0 g, 65%)을 수득하였다. 3 (S)-(N-benzyloxycarbonyl) amino-1-iodo-5-methyl-trans-1-hexene (1.5 g, 4.0 mmol) and 4-isopropoxy-3-tri in step 3 above. Butylstenyl-3-cyclobutene-1,2-dione (1.6 g, 3.6 mmol) was dissolved in anhydrous dimethylformamide (10 ml) and then catalytic amount of benzylchlorobis (triphenylphosphine) palladium (166 mg , 6 mmol%) and copper chloride (63 mg, 9 mmol) were added at room temperature, followed by stirring for 3 hours. After diluting the reaction mixture with ethyl acetate, the organic layer was washed with saturated ammonium chloride solution and 10% aqueous sodium fluoride solution, dehydrated and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.0 g, 65%).
1H NMR (CDCl3) δ 7.38(s, 5H), 6.98(dd, 1H), 6.47(d, 1H), 5.45(m, 1H), 5.14(s, 2H), 4.74(d, 1H), 4.43(m ,1H), 1.4-1.8(m, 9H), 0.8-1.0 (m, 6H) 1 H NMR (CDCl 3 ) δ 7.38 (s, 5H), 6.98 (dd, 1H), 6.47 (d, 1H), 5.45 (m, 1H), 5.14 (s, 2H), 4.74 (d, 1H), 4.43 (m, 1H), 1.4-1.8 (m, 9H), 0.8-1.0 (m, 6H)
단계 5. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-2-[(4-트리플루오로메틸)피리미딘-2-일]하이드라진-1-일-3-사이클로부텐-1,2-다이온의 제조Step 5. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-2-[(4-trifluoromethyl) pyrimidine-2 Preparation of -yl] hydrazin-1-yl-3-cyclobutene-1,2-dione
상기 단계 4의 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온 (17.5 mg, 3.6 mmol)을 에탄올 (1 ml)에 녹인 후에 2-하이드라지노-4-(트라이플루오로메틸)피리미딘 (15 mg)을 상온에서 가한 다음에 2시간동안 교반을 계속하였다. 반응혼합물을 농축하고 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (9.5 mg)을 수득하였다.3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-isopropoxy-3-cyclobutene-1,2- in step 4 above After dissolving ions (17.5 mg, 3.6 mmol) in ethanol (1 ml), 2-hydrazino-4- (trifluoromethyl) pyrimidine (15 mg) was added at room temperature followed by stirring for 2 hours. . The reaction mixture was concentrated and the residue was purified by silica gel chromatography to give the title compound (9.5 mg).
1H NMR (CDCl3) δ 8.63 (d, 1H), 7.2-7.4 (m, 7H), 6.8-7.2 (m, 4H), 6.40 (d, 1H), 4.9-5.2 (m, 2H), 4.23 (brs, 1H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
1 H NMR (CDCl 3 ) δ 8.63 (d, 1H), 7.2-7.4 (m, 7H), 6.8-7.2 (m, 4H), 6.40 (d, 1H), 4.9-5.2 (m, 2H), 4.23 (brs, 1H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
실시예 20. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-(프탈이미도-1-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 20. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4- (phthalimido-1-yl) amino-3-cyclo Preparation of Butene-1,2-dione
실시예 19의 단계 5에서의 2-하이드라지노-4-(트리플루오로메틸)피리미딘 대신에 N-아미노프탈이미드를 사용하는 것을 제외하고는, 실시예 19와 동일한 방법을 사용하여 표제화합물 (10 mg)을 수득하였다. Using the same method as Example 19, except for using N-aminophthalimide instead of 2-hydrazino-4- (trifluoromethyl) pyrimidine in Step 5 of Example 19 The title compound (10 mg) was obtained.
1H NMR (CDCl3) δ 7.7-8.0 (m, 4H), 7.2-7.4 (m, 7H), 4.9-5.2 (m, 2H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.7-8.0 (m, 4H), 7.2-7.4 (m, 7H), 4.9-5.2 (m, 2H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
실시예 21. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-(몰포린 -4-일)아미노-3-사이클로부텐-1,2-다이온의 제조Example 21. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4- (morpholin-4-yl) amino-3-cyclobutene Preparation of -1,2-dione
실시예 19의 단계 5에서의 2-하이드라지노-4-(트리플루오로메틸)피리미딘 대신에 4-아미노몰포린을 사용하는 것을 제외하고는, 실시예 19와 동일한 방법을 사용하여 표제화합물 (13 mg)을 수득하였다. The title compound was prepared in the same manner as in Example 19, except that 4-aminomorpholine was used instead of 2-hydrazino-4- (trifluoromethyl) pyrimidine in Step 5 of Example 19 (13 mg) was obtained.
1H NMR (CDCl3) δ 7.2-7.4 (m, 7H), 5.0-5.2 (m, 2H), 3.5-3.9 (m, 4H), 2.4-3.0 (m, 4H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
1 H NMR (CDCl 3 ) δ 7.2-7.4 (m, 7H), 5.0-5.2 (m, 2H), 3.5-3.9 (m, 4H), 2.4-3.0 (m, 4H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H)
실시예 22. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-(2-벤질 -2-페닐하이드라진-1-일)-3-사이클로부텐-1,2-다이온의 제조Example 22. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4- (2-benzyl-2-phenylhydrazin-1-yl) Preparation of 3-cyclobutene-1,2-dione
실시예 19의 단계 5에서의 2-하이드라지노-4-(트리플루오로메틸)피리미딘 대신에 1-벤질-1-페닐하이드라진을 사용하는 것을 제외하고는, 실시예 19와 동일한 방법을 사용하여 표제화합물 (15 mg)을 수득하였다. The same method as in Example 19 was used except that 1-benzyl-1-phenylhydrazine was used instead of 2-hydrazino-4- (trifluoromethyl) pyrimidine in Step 5 of Example 19 To give the title compound (15 mg).
1H NMR (CDCl3) δ 7.65 (s, 1H), 6.8-7.4 (m, 17H), 6.45 (d, 1H), 5.0-5.2 (s, 2H), 4.2-4.8 (m, 3H), 1.2-1.8 (m, 3H), 0.8-1.0 (m, 6H) 1 H NMR (CDCl 3 ) δ 7.65 (s, 1H), 6.8-7.4 (m, 17H), 6.45 (d, 1H), 5.0-5.2 (s, 2H), 4.2-4.8 (m, 3H), 1.2 -1.8 (m, 3H), 0.8-1.0 (m, 6H)
실시예 23. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-(몰포린-4-일)아미노 -3-사이클로부텐-1,2-다이온의 제조Example 23. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4- (morpholin-4-yl) amino-3-cyclobutene-1,2-da Preparation of ions
단계 1. 3(S)-(N-t-부톡시카보닐)아미노-1-아이오도-5-메틸-트랜스-1-헥센의 제조Step 1. Preparation of 3 (S)-(N-t-butoxycarbonyl) amino-1-iodo-5-methyl-trans-1-hexene
N-t-부톡시카보닐-L-루신알 (3.0 g, 13.9 mmol)과 아이오도포름 (10.9 g, 27.8 mmol)을 무수 테트라하이드로퓨란 (70 ml)에 녹인후에 염화크롬 (10.3 g, 83.6 mmol) 테트라하이드로퓨란 (50 ml) 현탁액을 0 ℃에서 가한 다음에 3시간동안 교반을 계속하였다. 반응혼합물을 여과한 후에 테트라부틸암모늄플로라이드 테트라하이드로퓨란용액 (1 M, 40 ml)를 적가하여 과량의 아이오도포름을 제거하고 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (1.75 g, 37%)을 수득하였다.Chromium chloride (10.3 g, 83.6 mmol) after dissolving Nt-butoxycarbonyl-L-leucine (3.0 g, 13.9 mmol) and iodoform (10.9 g, 27.8 mmol) in anhydrous tetrahydrofuran (70 ml) Tetrahydrofuran (50 ml) suspension was added at 0 ° C. and stirring continued for 3 hours. After filtering the reaction mixture, tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 40 ml) was added dropwise to remove excess iodoform and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.75 g, 37%).
1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.3-1.8 (m, 12H), 4.15 (brs, 1H), 4.40 (brs, 1H), 6.2-6.5 (m, 2H) 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.3-1.8 (m, 12H), 4.15 (brs, 1H), 4.40 (brs, 1H), 6.2-6.5 (m, 2H)
단계 2. 3-[3(S)-(N-t-부톡시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온의 제조Step 2. 3- [3 (S)-(Nt-butoxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-isopropoxy-3-cyclobutene-1,2-dione Manufacture
상기 단계 1의 3(S)-(N-t-부톡시카보닐)아미노-1-아이오도-5-메틸-트랜스-1-헥센 (1.75 g, 5.16 mmol)과 4-아이소프로폭시-3-트라이부틸스텐일-3-사이클로부텐-1,2-다이온 (2.01 g, 4.69 mmol)을 무수 다이메틸포름아마이드 (10 ml)에 녹인후에 촉매량의 벤질클로로비스(트리페닐포스핀)팔라듐 (236 mg, 6 mmol %)와 염화구리 (63 mg, 9 mmol)을 상온에서 가한 다음에 3시간동안 교반을 계속하였다. 반응혼합물을 에틸아세테이트로 희석한 후에 유기층을 포화 암모늄클로라이드 수용액 및 10%-불소화나트륨 수용액으로 세척하고 탈수 및 농축하였다. 잔사를 실리카겔 크로마토그래피를 통하여 정제하여 표제화합물 (1.0 g, 61%)을 수득하였다.3 (S)-(Nt-butoxycarbonyl) amino-1-iodo-5-methyl-trans-1-hexene (1.75 g, 5.16 mmol) and 4-isopropoxy-3-tri in step 1 Butylstenyl-3-cyclobutene-1,2-dione (2.01 g, 4.69 mmol) was dissolved in anhydrous dimethylformamide (10 ml), followed by catalytic amount of benzylchlorobis (triphenylphosphine) palladium (236 mg , 6 mmol%) and copper chloride (63 mg, 9 mmol) were added at room temperature, followed by stirring for 3 hours. After diluting the reaction mixture with ethyl acetate, the organic layer was washed with saturated aqueous ammonium chloride solution and 10% sodium fluoride solution, dehydrated and concentrated. The residue was purified by silica gel chromatography to give the title compound (1.0 g, 61%).
1H NMR (CDCl3) δ 0.8-1.0 (m, 12H), 1.2-1.8 (m, 12H), 4.37 (m, 1H), 4.46 (m, 1H), 5.44 (m, 1H), 6.45 (d, 1H), 6.97 (dd, 1H) 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 12H), 1.2-1.8 (m, 12H), 4.37 (m, 1H), 4.46 (m, 1H), 5.44 (m, 1H), 6.45 (d , 1H), 6.97 (dd, 1H)
단계 3. 3-[3(S)-(N-t-부톡시카보닐)아미노-5-메틸헥실]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온의 제조Step 3. Preparation of 3- [3 (S)-(N-t-butoxycarbonyl) amino-5-methylhexyl] -4-isopropoxy-3-cyclobutene-1,2-dione
상기 단계 2의 3-[3(S)-(N-t-부톡시카보닐)아미노-5-메틸-트랜스-1-헥센일]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온 (1.0 g, 2.85 mmol)을 에틸아세테이트 (50 ml)에 녹인 후에 팔라듐/카본 (0.2 g, 10%) 촉매하에서 수소 기압 (50 psi)하에서 3시간 동안 진탕시켰다. 반응혼합물을 여과 후 농축하여 표제화합물 (0.93 g, 92%)을 수득하였다.3- [3 (S)-(Nt-butoxycarbonyl) amino-5-methyl-trans-1-hexenyl] -4-isopropoxy-3-cyclobutene-1,2- in step 2 above Ions (1.0 g, 2.85 mmol) were dissolved in ethyl acetate (50 ml) and then shaken for 3 hours under hydrogen pressure (50 psi) under a palladium / carbon (0.2 g, 10%) catalyst. The reaction mixture was filtered and concentrated to give the title compound (0.93 g, 92%).
1H NMR (CDCl3) δ0.8-1.0 (m, 12H), 1.2-1.8 (m, 12H), 4.27 (m, 1H), 5.41 (m, 1H) 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 12H), 1.2-1.8 (m, 12H), 4.27 (m, 1H), 5.41 (m, 1H)
단계 4. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-하이드록시-3-사 이클로부텐-1,2-다이온의 제조Step 4. Preparation of 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4-hydroxy-3-cyclobutene-1,2-dione
상기 단계 3의 3-[3(S)-(N-t-부톡시카보닐)아미노-5-메틸헥실]-4-아이소프로폭시-3-사이클로부텐-1,2-다이온 (0.93 g, 2.63 mmol)을 테트라하이드로퓨란 (50 ml)과 12N-염산 (5 ml)에 녹인 후에 상온에서 2일 동안 교반을 계속하였다. 반응혼합물을 농축하여 3-[3(S)-아미노-5-메틸헥실]-4-하이드록시-3-사이클로부텐-1,2-다이온-염산염 (1.02 g)을 수득하여 더 이상의 정제 없이 다음반응을 진행하였다. 이 잔사를 1N-수산화나트륨 수용액 (4 ml)에 녹이 벤질옥시클로로포메이트 (2 mmol)을 가하고 상온에서 2시간 동안 교반을 계속하였다. 반응 혼합물을 에틸에테르로 추출하고 농축하여 표제화합물 (380 mg, 63%)을 수득하였다.3- [3 (S)-(Nt-butoxycarbonyl) amino-5-methylhexyl] -4-isopropoxy-3-cyclobutene-1,2-dione of step 3 (0.93 g, 2.63 mmol) was dissolved in tetrahydrofuran (50 ml) and 12N hydrochloric acid (5 ml), and stirring was continued at room temperature for 2 days. The reaction mixture was concentrated to give 3- [3 (S) -amino-5-methylhexyl] -4-hydroxy-3-cyclobutene-1,2-dione-hydrochloride (1.02 g) without further purification. The next reaction was carried out. This residue was dissolved in 1N aqueous sodium hydroxide solution (4 ml) and benzyloxychloroformate (2 mmol) was added thereto, and stirring was continued at room temperature for 2 hours. The reaction mixture was extracted with ethyl ether and concentrated to give the title compound (380 mg, 63%).
1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.2-1.8 (m, 5H), 2.4-2.8 (m, 2H), 3.54 (m, 1H), 5.0-5.2 (m, 3H), 7.2-7.4 (s, 5H) 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-1.8 (m, 5H), 2.4-2.8 (m, 2H), 3.54 (m, 1H), 5.0-5.2 (m, 3H) , 7.2-7.4 (s, 5H)
단계 5. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-에톡시-3-사이클로부텐-1,2-다이온의 제조Step 5. Preparation of 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4-ethoxy-3-cyclobutene-1,2-dione
상기 단계 4의 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-하이드록시-3-사이클로부텐-1,2-다이온 (0.37 g, 1.07 mmol)을 벤젠 (50 ml)과 에탄올 (50 ml)에서 6시간 동안 환류시켰다. 반응혼합물을 농축하고 크로마토그래피로 분리하여 표제화합물 (100 mg, 26%)을 수득하였다. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4-hydroxy-3-cyclobutene-1,2-dione of step 4 (0.37 g, 1.07 mmol) ) Was refluxed for 6 hours in benzene (50 ml) and ethanol (50 ml). The reaction mixture was concentrated and separated by chromatography to give the title compound (100 mg, 26%).
1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.2-2.0(m, 8H), 2.64 (t, 2H), 3.76(m, 1H), 4.58 (d, 1H), 4.76 (q, 2H), 5.0-5.2 (s, 2H), 7.2-7.4 (s, 5H) 1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-2.0 (m, 8H), 2.64 (t, 2H), 3.76 (m, 1H), 4.58 (d, 1H), 4.76 (q , 2H), 5.0-5.2 (s, 2H), 7.2-7.4 (s, 5H)
단계 6. 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-(몰포린-4-일)아미노-3-사이클로부텐-1,2-다이온의 제조Step 6. 3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4- (morpholin-4-yl) amino-3-cyclobutene-1,2-dione Manufacture
상기 단계 5의 3-[3(S)-(N-벤질옥시카보닐)아미노-5-메틸헥실]-4-에톡시-3-사이클로부텐-1,2-다이온 (17 mg), 4-아미노몰포린 (15 mg)과 트라이에틸아민 (0.1 ml)를 에탄올 (1 ml)에서 6시간 동안 상온에서 교반시켰다. 반응혼합물을 농축하고 크로마토그래피로 분리하여 표제화합물 (6.0 mg)을 수득하였다.3- [3 (S)-(N-benzyloxycarbonyl) amino-5-methylhexyl] -4-ethoxy-3-cyclobutene-1,2-dione (17 mg), 4 of step 5 above; Aminomorpholine (15 mg) and triethylamine (0.1 ml) were stirred in ethanol (1 ml) for 6 hours at room temperature. The reaction mixture was concentrated and separated by chromatography to give the title compound (6.0 mg).
1H NMR (CDCl3) δ 0.8-1.0 (m, 6H), 1.2-2.0 (m, 5H), 2.4-3.0 (m, 4H), 3.4-3.8 (m, 1H), 4.24 (m, 1H), 4.4-5.4 (m, 5H), 7.2-7.4 (s, 5H)
1 H NMR (CDCl 3 ) δ 0.8-1.0 (m, 6H), 1.2-2.0 (m, 5H), 2.4-3.0 (m, 4H), 3.4-3.8 (m, 1H), 4.24 (m, 1H) , 4.4-5.4 (m, 5H), 7.2-7.4 (s, 5H)
시험예 1. 카뎁신 K 억제 시험
Test Example 1. Kadipsin K Inhibition Test
인체 유방암 세포인 MCF-7 세포(ATCC HTB-22)로부터 공지의 방법[A. L. Littlewood-Evans, et. al., Cancer Res., 57, 5386 (1997)]에 따라 카뎁신 K를 제조하였다. Known methods from MCF-7 cells (ATCC HTB-22), which are human breast cancer cells [A. L. Littlewood-Evans, et. al., Cancer Res., 57, 5386 (1997).
상기 카뎁신 K를 효소원으로 하여, 공지의 방법[J. Bone. Mineral Res. 12, 1396 (1997)]으로 본 발명의 화합물의 카뎁신 K 억제시험을 수행하였다. A well-known method [J. Bone. Mineral Res. 12, 1396 (1997)] was carried out a Kadipsin K inhibition test of the compound of the present invention.
즉, 완충용액(NaOAc, pH5.5) 270㎕ 에 25 μM의 농도가 되도록 기질 (Z-Phe-Arg-AMC, Bachem사)을 가한 후, 본 발명의 화합물을 디메틸술폭사이드에 녹여 가한 다음, 카뎁신 K 5㎕를 가하였다. 37℃에서 1 시간동안 반응시킨 후, 반응정지 용액 (stop solution; 클로로아세테이트 완충용액, pH4.0) 0.8ml를 가하여 반응을 종결시켰다. 샘플 1 ml을 취하여 여기(excitation) 파장 360 nm, 방출(emission) 파장 460 nm의 조건으로 형광측정기(fluorometer)를 사용하여 형광도를 측정하였다. 여기서 기준값(Blank)으로는 반응 완충용액 290㎕l에 기질만 첨가된 용액을 사용하였다.That is, after adding a substrate (Z-Phe-Arg-AMC, Bachem) to 270 μl of buffer solution (NaOAc, pH5.5) to a concentration of 25 μM, the compound of the present invention was dissolved in dimethyl sulfoxide, and then added. 5 [mu] l of kadipsin K was added. After reacting at 37 ° C. for 1 hour, 0.8 ml of a stop solution (chloroacetate buffer solution, pH4.0) was added to terminate the reaction. 1 ml of the sample was taken and fluorescence was measured using a fluorometer under conditions of an excitation wavelength of 360 nm and an emission wavelength of 460 nm. As a reference value (Blank), a solution in which only a substrate was added to 290 μl of reaction buffer was used.
500 nM의 본 발명의 화합물이 카뎁신 K 활성을 억제하는 억제율 및 카뎁신 K 활성을 50% 억제하는 농도(IC50)는 다음 표1 및 표2와 같다.Inhibition rate of the compound of the present invention of 500 nM inhibits the kadepsin K activity and the concentration (IC 50 ) that inhibits the kadepsin K activity 50% are shown in Table 1 and Table 2.
상기 표1 및 표2의 결과로부터 확인할 수 있는 바와 같이, 본 발명에 따른 화합물은 매우 우수한 카뎁신 K 활성 억제 효과를 갖고 있음을 알 수 있다.
As can be seen from the results of Table 1 and Table 2, it can be seen that the compound according to the present invention has a very good inhibitory effect of kadepsin K activity.
시험예 2. 카뎁신 B 및 L 억제 시험
Test Example 2 Kadepsin B and L Inhibition Test
본 발명에 따른 화합물의 카뎁신 B 및 L 에 대한 억제시험을 다음과 같이 수행하였다.Inhibition tests on kadipsin B and L of the compounds according to the invention were carried out as follows.
(1) 카뎁신 B 억제시험(1) kadipsin B inhibition test
완충용액(NaH2PO4, pH6.0)에 녹인 카뎁신 B (Cathepsin B; bovine spleen, Sigma사)에 본 발명의 화합물을 디메틸술폭사이드에 녹여 가하고 25℃에서 10분간 전배양 (preincubation)한 후 기질로서 Z-Arg-Arg-pNA (Bachem사)를 가하여 96-웰-플레이트 (96-well plate)에서 반응을 개시하였다. 25℃에서 1시간동안 서서히 진탕하면서 배양한 후 405nm에서 반응액 중에 유리된 p-나이트로아닐린 (p-nitroaniline)의 흡광도를 측정하여 카뎁신 B 활성 억제율(%)을 구하였다.The compound of the present invention was dissolved in dimethyl sulfoxide in Kadepsin B (Cathepsin B; bovine spleen, Sigma) dissolved in buffer solution (NaH 2 PO 4 , pH6.0) and preincubated at 25 ° C. for 10 minutes. Then Z-Arg-Arg-pNA (Bachem) was added as a substrate to initiate the reaction in a 96-well plate. After culturing with shaking at 25 ° C. for 1 hour, the absorbance of p-nitroaniline liberated in the reaction solution at 405 nm was measured to determine the rate of inhibition of Kadipsin B activity (%).
(2) 카뎁신 L 억제시험(2) Kadipsin L inhibition test
완충용액(NaOAc, pH5.5)에 녹인 카뎁신 L (Cathepsin L; human liver, Calbiochem사)에 본 발명의 화합물을 디메틸술폭사이드에 녹여 가하고 25℃에서 5분간 전배양한 후 기질로서 Z-Phe-Arg-AMC(Bachem사)를 가하여 반응을 개시하였다. 25℃에서 1시간동안 서서히 진탕하면서 배양하였다. 반응액 1 ml을 형광측정기를 사용하여 여기파장 360 nm, 방출파장 460 nm에서 반응액 중에 유리된 AMC의 형광도를 측정하여 카뎁신 L 활성 억제율(%)을 구하였다. The compound of the present invention was added to dimethylsulfoxide by dissolving the compound of the present invention in cadepsin L (human liver, Calbiochem) dissolved in a buffer solution (NaOAc, pH5.5) and pre-cultured at 25 ° C. for 5 minutes, and then Z-Phe as a substrate. Arg-AMC (Bachem) was added to initiate the reaction. Incubation was performed slowly at 25 ° C. for 1 hour. 1 ml of the reaction solution was measured using a fluorometer to measure the fluorescence of AMC liberated in the reaction solution at an excitation wavelength of 360 nm and an emission wavelength of 460 nm, thereby determining the inhibition rate of Kadipsin L activity (%).
상기와 같이 측정하여 얻어진 카뎁신 B 및 L 에 대한 억제율(%)는 다음 표3과 같다.Inhibition rate (%) for the Kadipsin B and L obtained by measuring as described above is shown in Table 3.
상기 표3의 결과로부터 확인할 수 있는 바와 같이, 본 발명에 따른 화합물은 여러 시스테인 프로티아제들에 대하여도 우수한 억제 효과를 갖고 있음을 확인할 수 있다.As can be seen from the results of Table 3, it can be seen that the compound according to the present invention has an excellent inhibitory effect against various cysteine proteases.
Claims (4)
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| CZ2014321A3 (en) * | 2014-05-09 | 2016-01-13 | Vysoká škola chemicko- technologická v Praze | Dioxocyclobutenyl hydrazones and their anti-cancer activities |
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| KR880000968A (en) * | 1986-06-19 | 1988-03-30 | 야마모도 다꾸마 | Semiconductor memory |
| US5763474A (en) * | 1996-07-17 | 1998-06-09 | American Home Products Corporation | Substituted N-arylmethylamino derivatives of cyclobutene-3,4-diones |
| KR100206055B1 (en) * | 1991-01-22 | 1999-07-01 | 이곤 이. 버그 | (((2-amino-3,4-dioxo-1-cyclo-buten-1-yl)amino)alkyl)-acid derivatives |
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| KR880000968A (en) * | 1986-06-19 | 1988-03-30 | 야마모도 다꾸마 | Semiconductor memory |
| KR100206055B1 (en) * | 1991-01-22 | 1999-07-01 | 이곤 이. 버그 | (((2-amino-3,4-dioxo-1-cyclo-buten-1-yl)amino)alkyl)-acid derivatives |
| US5763474A (en) * | 1996-07-17 | 1998-06-09 | American Home Products Corporation | Substituted N-arylmethylamino derivatives of cyclobutene-3,4-diones |
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| CN106811492A (en) * | 2017-01-18 | 2017-06-09 | 长兴制药股份有限公司 | A kind of preparation method of scheme for lacosamide |
| CN106811492B (en) * | 2017-01-18 | 2019-11-01 | 长兴制药股份有限公司 | A kind of preparation method of scheme for lacosamide |
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