WO2003082838A1 - Nouvel inhibiteur de la methionine aminopeptidase - Google Patents

Nouvel inhibiteur de la methionine aminopeptidase Download PDF

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WO2003082838A1
WO2003082838A1 PCT/CN2003/000213 CN0300213W WO03082838A1 WO 2003082838 A1 WO2003082838 A1 WO 2003082838A1 CN 0300213 W CN0300213 W CN 0300213W WO 03082838 A1 WO03082838 A1 WO 03082838A1
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substituted
group
aryl
fluorenyl
inhibitor according
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PCT/CN2003/000213
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Fajun Nan
Qizhuang Ye
Jingya Li
Zhiying Liu
Qunli Luo
Yongmei Cui
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Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
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Priority to EP03711802A priority Critical patent/EP1500655A4/en
Priority to AU2003221230A priority patent/AU2003221230A1/en
Priority to US10/509,823 priority patent/US20050113420A1/en
Publication of WO2003082838A1 publication Critical patent/WO2003082838A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a class of small molecule organic compounds showing high inhibitory activity against methionyl aminopeptidases (MetAPs) and showing certain selectivity to different MetAPs subtypes, so it can be used as a new type of antitumor And lead compounds for antibacterial research.
  • MetAPs methionyl aminopeptidases
  • the translation of all proteins in the cytoplasm of prokaryotic cells begins at the N-terminus of methionine, whereas in eukaryotic cells, mitochondria and chloroplasts the translation of proteins begins at N-formylated methionine and formylated
  • the group is generally removed by a deformylase in the process that accompanies translation.
  • methionyl aminopeptidases selectively remove the N-terminal methionine of nascent proteins or polypeptide chains. Removal of the methionine at the N-terminus of the nascent protein or polypeptide chain plays a key role in the post-translational modification of the protein and the accurate localization and function of the cell.
  • Escherichia coli methionyl aminopeptidase was the first member of methionyl aminopeptidase to be discovered. Later, enzymes with similar structure and function were also found in yeast and mammals, respectively. From the comparison of the sequences, the C-terminus of this type of methionyl aminopeptidase has high homology, but the N-terminus extends a sequence similar to the zinc finger structure. This sequence structure was later confirmed by experiments. Sequences that bind to ribosomes have no effect on protease activity (J. Biol. Chem. 1990; 265: 19892-19897). This type of enzyme and E.
  • coli methionyl peptidase were classified as type I enzymes; later people purified and cloned from pig liver and cloned into another type of methionyl peptidase (J, Biol. Chem. 1992; 267: 20667-20673), the sequence comparison of the C-terminus with E.
  • coli methionyl aminopeptidase is less than the type I enzyme (a sequence of about 60 amino acids is inserted at the C-terminus), in which The N-terminus is replaced by some poly-neutral and acidic amino acid residues in the zinc finger structure sequence (this part of the structure has been confirmed to be an inhibitor of phosphorylation of protein translation initiation factors in eukaryotic cells and does not affect the activity of proteases).
  • type II enzymes such as yeast, Drosophila, mouse, and human type II methionyl aminopeptidase.
  • Methionyl aminopeptidase is widely present in the cells of various organisms in the biological world and has a certain selectivity for substrates. Experiments with both endogenous proteins or recombinantly expressed proteins or polypeptides as substrates have shown (Biochemistry. 1987; 26: 8242-8246) that only when the protein or peptide substrate is N-terminal methionine
  • the second amino acid (P, ') belongs to a non-polar chain less than 3.68 ⁇ in order to be digested by methionyl aminopeptidase.
  • the amino acid at the Pi' position is any of the following seven amino acids and can be converted Thiaminyl peptidases: Gly, Ala, Ser, Thr, Pro, Val, and Cys (J. Bacteriol. 1987; 169: 751-757; Biochemistry. 1999; 38: 14810-14819).
  • the basic function of methionyl aminopeptidase in the cell is to remove the N-terminal methionine of the newly synthesized protein in the cell, laying the foundation for the subsequent function of the protein. for post-translational modification of proteins, cells in the accurate positioning, direct degradation of protein (J. Biol Ch em 1982; 257 :.. 3532-3536) and normal play function plays a key role.
  • the current inhibitors of methionyl aminopeptidase can be divided into covalent binding inhibitors and non-covalent binding inhibitors.
  • Another class of inhibitors are transition state analogs and reaction products, which also have a similar inhibition mechanism as Bestatin analogs (Biochemistry. 1999: 38: 14810-14819).
  • Non-covalent inhibitors are targeted to the substrate properties of MetAPs, and a substrate analogue inhibitor engineered with Bestatin, an effective inhibitor of leucine aminopeptidase.
  • Bestatin an effective inhibitor of leucine aminopeptidase.
  • Tumors can obtain nutrients and oxygen from the host through tumor blood vessels, and can also pass tumors. Blood vessels continuously deliver metastatic cells to the host, and continue to grow and induce angiogenesis in other parts of the body, leading to tumor metastasis. Inhibiting tumor angiogenesis by inhibiting tumor angiogenesis is one of the most active areas of antitumor drug research today. The anti-tumor effect of fumagillin and its analogs is achieved by acting on the vascular system of tumors, and by specifically inhibiting the growth of vascular endothelial cells and thus tumor growth.
  • methionyl aminopeptidase especially hMetAPII
  • hMetAPII can be used as a target for a new type of anti-angiogenesis drug, and its effective and specific inhibitor can be used as a new type of anti-tumor drug.
  • the present invention designs and synthesizes novel small molecule organic compounds as MetAPs inhibitors, and conducts in-depth research on the relationship between its structure and activity. While elucidating the mechanism of action of MetAPs under pathological conditions, it also finds anticancer and antiinfective drugs Lead compounds.
  • Another object of the present invention is to provide a method for synthesizing such compounds.
  • the class of methionyl aminopeptidase inhibitors of the present invention has the following structure:
  • ⁇ ⁇ of the embankment group a substituted alkyl with, C 3 -C 6 cycloalkyl group embankment, embankment substituted cycloalkyl group, an aryl group, pyridyl group; a C r C 4 alkyl with a nitro group, a carboxyl group, an aldehyde group, Substituted aryl, amine, amido, mercapto, substituted aryl, substituted pyridyl, and heterocyclic ring or substituted heterocyclic ring R 5 , fluorenyl group 11, dC 4 , substituted fluorenyl group, C 3 -C 6 cycloalkyl group, substituted cyclofluorenyl group, aryl group, pyridyl group, nitro group, carboxyl group, aldehyde group, alkoxy group, amine group, amine Aryl, amido, mercapto substituted aryl
  • X is 0, S, N, and heteroatoms.
  • the invention is implemented by the following steps:
  • Compound I and II are condensed to form compound III, where Y is 0H, C1 or other reactive groups.
  • Compound I and II undergo a condensation reaction in the following solvents: CH2Cl2, DMF, CH2CICH2CK toluene, benzene, water, dioxane or at If necessary, use a mixed solvent, such as: CH2CI2 / DMF (1: 1 V / V).
  • the condensing agent used can be DCC, ECD, DIC, HBTU, etc. according to the nature of the compound, and a small amount of activator such as HOBT is added according to the needs of the reaction. , Pentafluorophenol, molecular sieves, etc.
  • the reaction requires the addition of a base as a catalyst, such as triethylamine, diethylpropylethylamine, pyridine, DMAP, usually the reaction temperature is from -20 ° C to room temperature, but in some cases In general, it requires heating, generally from 50 ° -130 ° C.
  • the reaction time also depends on the reactive group of the reactant. For example, when Y is C1, the reaction can be completed within minutes. Some reactions require longer time, usually TLC is used to determine the reaction completion degree. After the reaction is completed, it is generally extracted with solvents such as ethyl acetate, dichloromethane, chloroform, etc., and then washed with 5% HC1, water, and saturated brine, and dried. The solvent was removed under reduced pressure and low temperature, concentrate was purified by column chromatography to give the final product III, the yield depending on the nature of the reactants I and II varies from 20% --95% of the product obtained by NMR spectroscopic analysis to prove
  • Compound II can be synthesized according to the method of J. Org. Chem. 63, 196-200 (1998).
  • the EMetAP protein was cloned and expressed in large quantities in E. coli system. After saturated (NH4) 2S04 precipitation and Q-Sepharose column chromatography purification, apo-eMetAP was obtained, and finally incubated with an appropriate concentration of divalent cobalt ion Then, a highly active enzyme can be obtained for screening of the enzyme inhibitor.
  • eMetAP can hydrolyze the thioester bond of the synthetic substrate Met-S-C-Phe.
  • the product Met-SH reacts quickly with an excess of DTNB.
  • the present invention shows that the synthesized series of compounds are a new class of methionyl phthalamide enzyme inhibitors. Compared with inhibitors of such enzymes known now, the structure is relatively simple and easy to prepare. And some of them have the best inhibitory activity on methionyl phthalase eMetAP. detailed description
  • ⁇ -NMR was measured with a Varian Mercury AMX300 instrument; MS was measured with a VG ZAB-HS or VG-7070 instrument, all are EI sources (70ev) unless specified; all solvents have been re-distilled before use. Water solvents are obtained by drying in accordance with standard methods; all reactions are performed under the protection of Ar gas and TLC is used unless otherwise stated. Tracking, and were washed with saturated brine and dried over anhydrous MgS0 4 post-processing procedure; purified addition products are stated using silica gel (200-300 Mesh) column chromatography; silica gel used, and comprising 200-300 mesh GF 254 is produced by Qingdao Ocean Chemical Plant or Yantai Yuanbo Silicone Company.

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Description

一类甲硫氨酰氨肽酶抑制剂 技术领域
本发明涉及一类小分子有机化合物对甲硫氨酰氨肽酶 （MetAPs ) 显示了高的抑制活 性， 并对不同的 MetAPs亚型表现出一定的选择性， 因而可作为一类新的抗肿瘤和抗菌药 物研究的先导化合物。 背景技术
在原核细胞的细胞质内所有蛋白质的翻译都起始于 N端的甲硫氨酸， 然而在真核细 胞、 线粒体和叶绿体中蛋白质的翻译起始于 N—甲酰化甲硫氨酸， 甲酰化基团一般是在伴 随翻译的过程中被去甲酰化酶作用后除去。 不论在真核细胞还是在原核细胞中， 甲硫氨酰 氨肽酶（MetAPs )有选择性的切除新生蛋白或多肽链的 N端甲硫氨酸。 新生蛋白或多肽链 N端甲硫氨酸的切除对于蛋白的翻译后修饰以及在细胞的准确定位和功能的正常发挥起着 关键的作用。
大肠杆菌甲硫氨酰氨肽酶是最先发现的甲硫氨酰氨肽酶成员， 随后人们分别在酵母 和哺乳动物中也发现了结构和功能类似的酶。从序列的比较来看， 这类甲硫氨酰氨肽酶的 C端有着很高的同源性， 但是 N端却延伸了一段类似锌指结构的序列， 这段序列结构后来 被实验证实是与核糖体结合序列， 对蛋白酶活性没有影响（J. Biol. Chem. 1990 ; 265 : 19892-19897)。 该类酶与大肠杆菌甲硫氨酰氨肽酶被划分为 I型酶； 后来人们从猪肝中分 离纯化并克隆到另一类甲硫氨酰氨肽酶 (J, Biol. Chem. 1992 ; 267 : 20667-20673) ,序列比较 其 C端与大肠杆菌甲硫氨酰氨肽酶的同源性要比 I型酶低一些 （C未端插入了一段约 60 个氨基酸的序列）， 在其 N端是由一些多聚中性和酸性氨基酸残基取代锌指结构序列 （这 部分结构被证实是真核细胞内蛋白翻译起始因子磷酸化的抑制子， 并不影响蛋白酶的活 性）， 为了与 I型区分， 人们将该类酶分为 II型酶， 如陆续发现的酵母、 果蝇、 小鼠和人 的 II型甲硫氨酰氨肽酶。
甲硫氨酰氨肽酶广泛存在于生物界各种生物的细胞中， 对底物具有一定的选择性。 不论是内源性的蛋白还是体外重组表达的蛋白或是多肽作为底物的实验都表明 (Biochemistry. 1987 ; 26 : 8242-8246) ,只有当蛋白或多肽底物 N端甲硫氨酸后的第二个氨 基酸（Ρ,' )属于非极性链小于 3. 68λ，才能被甲硫氨酰氨肽酶酶解.目前认为 Pi'位置的氨 基酸是以下七种氨基酸中任一便能被甲硫氨酰氨肽酶作用： Gly、 Ala, Ser、 Thr、 Pro, Val和 Cys (J. Bacteriol. 1987； 169： 751-757； Biochemistry. 1999 ; 38 : 14810-14819) . 甲硫氨酰氨肽酶在细胞内的基本功能是切除细胞内新合成蛋白的 N端甲硫氨酸，为蛋 白质的后续功能奠定基础.新生蛋白或多肽链 N端甲硫氨酸的切除， 对于蛋白的翻译后修 饰、 在细胞的准确定位、 蛋白的直接降解（J. Biol. Chem. 1982 ; 257 : 3532-3536)和功能的正 常发挥起着关键的作用。
目前甲硫氨酰氨肽酶的抑制剂根据作用方式， 我们可将它们分为共价结合抑制剂和 非共价结合抑制剂。另外还有一类抑制剂是过度态类似物和反应产物， 它们也具有相似于 Bestatin类似物的抑制机理（Biochemistry. 1999 : 38 : 14810-14819)。
通过共价结合方式抑制甲硫氨酰氨肽酶的化合物是一类能够特异抑制血管内皮细胞 生长的药物， 烟曲霉素（fumagill in)和它的衍生物 TNP- 470 ( IC50为纳摩尔级）。 研究表 明， 人源的 hMetAP II是细胞内 fumagillin和 TNP-470的作用靶点， 该类化合通过共价 修饰 hMetAP II 催化区保守氨基酸残基 His , 从而达到抑制该蛋白酶的活性 (Proc. Natl. Acad. Sci. USA. 1998； 95： 15183-15188)。
非共价抑制剂是针对于 MetAPs的底物特性，以亮氨酰氨肽酶的有效抑制剂 Bestatin 为模板改造的底物类似物抑制剂。 将 Bestatin的 Ρ^Π Ρ, '位置替之以异亮氨酸和丙氨酸， 结果是一个不能被水解的底物类似物， 它的抑制活性 IC50为 5μΜ， 是目前报道的 eMetAP 最好的抑制剂。
Figure imgf000004_0001
Pi Pi'
eMetAP的非共价抑制剂 近几年来， 肿瘤化疗取得了相当的进步， 肿瘤患者生存时间明显延长， 特别是对白 血病、 恶性淋巴瘤等的治疗有了突破， 但对危害人类生命健康最严重的、 占恶性肿瘤 90% 以上的实体瘤的治疗未能达到满意的效果。 药学家和肿瘤 学家越来越深刻地认识到： 睪 提高肿瘤治疗的疗效， 必须从肿瘤发生发展的机制着手， 才能取得新的突破性进展。 抗肿 瘤药物正从传统的细胞毒性药物， 向针对机制的多环节作用的新型抗肿瘤药物发展。肿瘤 的血管系统是一个崭新的、 有希望的抗肿瘤治疗靶点， 因为肿瘤的生长和转移依赖于新生 血管生成 （angiogenesis ) ，肿瘤既可通过肿瘤血管从宿主获取营养和氧气， 又可通过肿 瘤血管源源不断地向宿主输送转移细胞， 并在机体的其它部位继续生长和诱导血管生成， 导致肿瘤转移。通过抑制肿瘤血管生成来抑制肿瘤血管生成是当今抗肿瘤药物研究最活跃 的领域之一。烟曲霉素及其类似物所具有的抗肿瘤作用， 正是通过作用于肿瘤的血管系统 而实现， 通过特异性的抑制血管内皮细胞生长进而抑制肿瘤生长。 这说明， 甲硫氨酰氨肽 酶特别是 hMetAPII 可作为一种新型的抗新生血管生成药物的作用靶点， 对它有效而特异 性的抑制剂可作为新型的抗肿瘤药物。
在原核生物中仅有 MetAP MetAPs基因的敲除实验表明，大肠杆菌、伤寒沙门氏菌以 及酵母都不能再继续生长， 这说明 MetAP,在原核生物的生长过程中非常重要的作用， 因而 能选择性抑制 MetAP,的化合物有可能作为一类新型的抗细菌感染药物。 发明内容
发明目的： 本发明设计与合成新型的小分子有机化合物作为 MetAPs抑制剂， 并对其 结构与活性关系进行深入的研究， 在阐明 MetAPs在病理条件下的作用机制的同时找到抗 癌、 抗感染药物的先导化合物。
本发明的另一个目的是提供该类化合物的合成方法。
本发明所述一类甲硫氨酰氨肽酶抑制剂具有如下结构：
Figure imgf000005_0001
其中！^为^^ 的垸基、 取代垸基、 C3-C6的环垸基、 取代环垸基、 芳基、 吡啶基； 由 CrC4的垸基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰 氨基、 巯基的取代芳基、 取代 吡啶基和具有如下结构的杂环或取代杂环
Figure imgf000005_0002
R5、 为 11、 d-C4的垸基、 取代垸基、 C3-C6的环烷基、 取代环垸基、 芳基、 吡 啶基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰氨基、 巯基的取代芳基、 取代吡啶基； 为11、 d-C4垸基、 取代垸基、 芳基、 由^^ 的垸基、 硝基、 羧基、 酸基、 烷氧 基、 胺基、 酰 氨基、 巯基的取代芳基；
为11、 c,-c4垸基、 取代 垸基、 卤素； 芳基、 取代芳基；
为11、 d-Ct垸基、 取代烷基、 取代芳基；
X为 0、 S、 N、 杂原子。
本发明通过下列步骤实施：
根据化学反应式
Figure imgf000006_0001
化合物 I与 II缩合得化合物 III， 其中 Y为 0H、 C1或其它活性基团， 化合物 I与 II 在如下溶剂中进行缩合反应， CH2Cl2、 DMF、 CH2CICH2CK 甲苯、 苯、 水、 二氧六环或 在需要时使用混合溶剂， 例如： CH2CI2/DMF ( 1 : 1 V/V)， 所使用的缩合剂根据化合物性 质可为 DCC、 ECD、 DIC、 HBTU等， 根据反应需要时加入少量活化剂， 例如 HOBT、 五 氟苯酚、 分子筛等， 有时反应还需加入碱作催化剂， 如三乙胺、 二乙丙基乙基胺、 吡啶、 DMAP、 通常反应温度从 -20°C—室温， 但在某些情况下， 则需加热， 一般从 50°-130°C， 反应时间同样视反应物的活化基团而定， 例如 Y为 C1时可在几分钟内完成反应， 一些反 应则需时间长一些， 通常用 TLC来测定反应完成程度， 反应完毕后一般用醋酸乙酯或二 氯甲垸、 氯仿等溶剂提取， 依次用 5%HC1、 水、 饱和食盐水洗， 经干燥后， 低温减压除 去溶剂， 浓缩物经柱层析得最终产物 III， 产率视反应物 I和 II的性质而变化， 从 20%— 95%, 得到的产物用 NMR等方法来证明
化合物 II可根据 J.Org.Chem. 63,196-200(1998)的方法合成。
Figure imgf000007_0001
9
Figure imgf000008_0001
ClZOO/CON3/X3d 8£8丽 £0 OAV
Figure imgf000009_0001
生物活性测试
用大肠杆菌系统克隆并大量表达 eMetAP蛋白，经饱和（NH4) 2S04沉淀及 Q- Sepharose 柱层析纯化后， 得到脱辅基酶 (apo-eMetAP)， 最后经与适当浓度的两价钴离子孵育后， 得 到高活性的酶可以进行该酶抑制剂的筛选。
药物筛选模型的测试原理
eMetAP可以水解合成底物 Met- S- C- Phe 的硫酯键， 产物 Met-SH迅速与过量的 DTNB 反应， 产生的 3-羧基 -4-硝基硫代苯酚盐在 412 nm处有吸收（ ε 412= 13600 Μ- 1. cm- 1)。 通过 SpectraMAX 340检测 412 nm处的的光吸收变化来确定酶活性。
操作步骤：
采用常规筛选方法 （Anal Biochem. 2000, 280: 159-65 )
筛选选取 2 μg/ml, 20 μ§ ΐ和 100 μ§ ΐ三个化合物浓度进行初步筛选， 当抑制 活性高于 50%时， 取 8个浓度测定该活性化合物 IC5。。
本发明的优点：
本发明说明合成的一系列化合物为一类全新结构的甲硫氨酰氨酞酶抑制剂， 与现在 已知的这类酶的抑制剂相比， 结构相对简单， 易于制备。 而且其中的某些化合物对甲硫氨 酰氨酞酶 eMetAP的抑制活性为当前最好的。 具体实施方式
下面结合具体实施例对本发明作进一步阐述， 但不限制本发明。
Ή-NMR用 Varian MercuryAMX300型仪测定； MS用 VG ZAB-HS或 VG-7070型仪 测定， 除注明外均为 EI源 （70ev) ；所有溶剂在使用前均经过重新蒸馏， 所使用的无水溶 剂均是按标准方法干燥处理获得； 除说明外， 所有反应均是在 Ar气保护下进行并用 TLC 跟踪， 后处理时均经饱和食盐水洗和无水 MgS04干燥过程； 产品的纯化除说明外均使用 硅胶 (200-300 mesh)的柱色谱法； 所使用的硅胶， 包括 200-300目和 GF254为青岛海洋化工 厂或烟台缘博硅胶公司生产。
1 . 化合物 6的制备
Figure imgf000010_0001
将邻硝基苯甲酰氯（5mmol)溶于二氯甲烷（ 15ml )，加入 2-氨基噻唑 (500mg,5mmol), 三乙胺 （ 0.75ml，5mmol)， 室温下反应 8h,加入二氯甲垸稀释淬灭。 将所有反应物转移至 分液漏斗中， 用 5 %盐酸洗涤。 在分液漏斗上层 （水层） 接近于二氯甲垸层分界处有固体 漂浮。将固体用二氯甲烷洗 , 经柱色谱纯化 (石油醚 ： 乙酸乙酯 =3 : 1， V V)得到白色固体 产物 6 503mg， 产率 40.4%。
Ή NMR (DMSO,300MHz):
δ (ppm) 8.18(d, J =8.1 Hz ,1H), 7.91—7.86 (m, 1H), 7.82-7.77(m, 2H), 7.55 (d, J = 3.6Hz ,1H), 7.34 (d, J= 3.6 Hz, 1H)
2. 化合物 18的制法
Figure imgf000010_0002
将 15 ( 195mg,1.26mmol) ,2—羧基吡啶（ 156mg,1.26mmol) ,DCC (270mg,1.30mmol)、 DMAP ( l lmg,cat) 的混合物中加入二氯甲垸 （5ml) ，氩气保护， 室温下搅拌 8小时。 用 乙酸乙酯稀释,过滤，滤液蒸除溶剂,残留物经柱色谱纯化 (石油醚 ： 乙酸乙酯 =4： 1, V/V)得 到 247mg白色固体产物 18， 产率 75.7%。
Ή NMR (CDCl3,300MHz):
δ (ppm)11.08(s.,lH), 8.62 (d, J = 5.2Hz, 1H), 8.27 (d, J = 7.8Hz, 1H), 7.92(dt, J= 7.8,7.8,1.5 Hz, 1H), 7.51 (dd, J= 7.8,5.2 Hz, 1H), 2.72 (d, J= 13.5 Hz, 4H), 1.88(s,4H);
l3C NMR (CDC13, 300MHz): δ (ppm)
161.76(1C),154.61(1C),148.76(1CH),148.18(1C),145.17(1C),137.90(1CH),127.33(1CH), 123.59(1C), 122.91(1CH), 26.65(1 CH2), 23.56(1CH2),23.23(2CH2);
3. 化合物 19的制法：
Figure imgf000011_0001
将 19a (28mg,0.197mmol ) ,2—羧基吡啶（25mg,0.197mmol )，DCC (43mg,0.20mmol)、 DMAP (cat) 的混合物中加入二氯甲垸 （1ml ) ，氩气保护， 室温下搅拌 8小时。 用乙酸乙 酯稀释,过滤，滤液蒸除溶剂,残留物经柱色谱纯化 (石油醚 ： 乙酸乙酯 =5 ： 1 , V/V), 得到 14mg白色固体产物 19。 产率 75.7%。
Ή NMR (CDCl3,300MHz):
δ (ppm)11.02(s.,lH), 8.61 (dd, J = 4.8,1.5Hz, IH), 8.27 (d, J = 7.5Hz, IH), 7.91(dt, J= 7.5,7.5,1.5 Hz, IH), 7.50 (ddd, J= 7.5,4.8,1.5 Hz, IH), 2.62 (q, J= 7.5,7.5,7.5 Hz, 2H), 2.34(s,3H), 1.22 (t, J= 7.5,7.5 Hz, 3H),;
4. 化合物 22的制备：
、COOH
Figure imgf000011_0002
22a 22
将 22a ( 23mg,0.131mmol ) ,2—羧基吡啶 （ 17mg,0.131mmol,leq ) ,DCC
( 29mg,0.14mmol)、 DMAP ( cat) 的混合物中加入二氯甲垸 （2ml) ，氩气保护， 室温下搅 拌 8小时。 用乙酸乙酯稀释,过滤,滤液蒸除溶剂,残留物经柱色谱纯化 (石油醚 ： 乙酸乙酯 =5: 1 , V/V)得到 21 mg青色固体产物 22。
Ή NMR (CDCl3,300MHz):
δ (ppm)11.25(s.,lH), 8.66 (d, J= 4.5Hz, IH), 8.30 (d, J= 7.8Hz, IH), 7.92(dd, J- 7.8,7.8 Hz, IH), 7.89 (d, J= 7.8 Hz, 2H), 7.53 (dd, J= 7.8,4.5 Hz, I H), 7.43 (t, J= 7.8,7.8 Hz, 2H), 7.33 (t, J= 7.8,7.8 Hz, 1H),7.22 (s,lH);
13C NMR (CDC13, 300MHz): δ (ppm)
162.34(1C),157.45(1C),150.73(1C),148.86(1CH),147.98(1C),138.02(1CH),
134.63(1C),128.98(2CH),128.27(1 CH),127.59(1CH),126.34(2CH),
123.08(1CH),108.21(1CH);
5. 化合物 36的制备
Figure imgf000011_0003
36
将 33(20mg,0.09mmol)溶于二氯甲垸 ( 4ml )， 加入三乙胺 ( 0.1ml ) , -78°C下注入 苯甲酰氯（0.13mmol， 1.5eq) , 保持同温下反映 3h,自然升至室温,再反应 2h,得到淡黄色溶 液。抽干， 溶于二氯甲焼 /甲苯 ， 经柱色谱纯化 (石油醚 ： 乙酸乙酯 =3： 1, V/V)得到化合物 36。
Ή NMR (CDCl3,300MHz):
δ (ppm) 11.33(br.,lH), 8.60(d, J =4.5Hz ,1H), 8.29 (d, J = 7.5Hz, 2H), 7.75-7.63(m,3H), 7.56 (t, J= 4.5,4.5Hz ,2H), 7.50(d, J= 3.0Hz, 1H)， 7.05 (d, J=3.0Hz,lH).
13C NMR (CDC13, 300MHz): δ (ppm)
165.13(1C), 160.29(1C), 157.82(1C), 148.59(1C), 146.03(1 CH), 139.88(1C),
137.87(1CH), 134.12(1CH), 133.90(1CH), 130.85(2CH), 129.13(1C), 128.88(2CH), 128.74(1CH), 113.83(1CH);
EIMS (m/z): 325(M+, 7%) , 226(8), 197(6), 127 (16), 105(69)
97 (53) , 91 (69)， 85 (63) , 71 (100) , 69(88);
7. 化合物 44的合成
Figure imgf000012_0001
将 33 ( 98mg,0.45mmol )中加入二氯甲垸（ 8ml：),再加入三乙胺 (0.1 ml,68mg,0.67mmol)， 然后将溶于二氯甲垸的酰氯在一 78Γ下加入。 同温下反应 lh,然后自然升至室温， 继续反 应过夜。 反应液淡黄色混浊。 抽干， 溶于二氯甲烷 /甲苯， 经柱色谱纯化 (石油醚 ： 乙酸 乙酯 =3 : 1 , V V)得到 48mg白色固体产物， 为化合物 44:
Ή NMR (CDCl3,300MHz):
δ (ppm) 8.55(dd, J=4.2,1.5Hz ,ΙΗ), 8.25 (d, J= 16Hz, 1H), 7.69-7.59(m, 3H), 7.51 (d, J = 3.6Hz ,1H)， 7.40(dt, J= 8,0,1.5 Hz, 1H), 7.03-6.94 (q, J =8.0,18Hz, 2H),6.99 (d, J= 3.6 Hz, 1H) , 6.89 (d, J= 3.6 Hz, 1H);
13C NMR (CDC13, 300MHz): δ (ppm)
165.67(1C), 160.45(1 C), 158.89(1C), 157.80(1C), 148.49(1C), 145.75(1CH),
143.47(1CH), 139.98(1C), 138.09(1CH), 133.86(1CH), 132.35(1 CH), 129.76(1CH),
128.62(1CH), 123.16(1 C), 120.91(1CH), 116.93(1CH), 113.75(1CH), 111.38(1CH),
55.67(1CH3);
EIMS (m/z): 381(M+, 7%) , 353 (8), 324(16), 225 (52), 221(26)
161 (90) , 127 (28) , 123 (47) , 95 (49), 71 (60), 69 (100).
8. 化合物 47的制备 ■0、
N COCI
Figure imgf000013_0001
47
室温下在酰氯中加入二氯甲垸（2ml ) ,再加入 2-氨基噻唑（11. 4mg, 0. 114睡 ol) ,氩气 保护， 加入三乙胺（19ul γ, 0. 114匪 ol)， 反应过夜。 抽干， 加入二氯甲垸 （10ml ) ，用水洗
( 3 X 3ml ) ，饱和食盐水洗（3ml) .千燥 （无水 MgS04)。 过滤， 滤液浓缩， 溶于二氯甲垸， 经柱色谱纯化 (石油醚 ： 乙酸乙酯 =1 ： 1, V/V)得到 6mg红色固体产物， 为化合物 47:
Ή NMR (CDCl3,300MHz):
δ (ppm)8.25 (dd, J= 2.7， 2.7 Hz, 1H), 7.52—7.50 (m, 3H), 7.42-7.32(m, 5H), 7.02(d, J= 3.6 Hz, 1H);
13C NMR (CDC13, 300MHz): δ (ppm)
161.30(1C), 158.38(1C), 156.33(1C), 140.73(1CH), 137.80(1CH), 136.47(1C), 135.85(1C), 129.06(2CH), 128.54(1CH), 128.42(1CH), 127.12(1CH), 127.06(1 CH), 123.50(1CH), 113.64(1CH), 71.14( 1 CH2 );
EIMS (m/z): 311(M+, 6%) , 220 (7), 197(8), 189 (43), 123 (19) , 111 (29) , 97 (44) , 91(100). 85 (55), 71(83), 69 (78).
9. 化合物 51的制备
H2N- Nj)
Figure imgf000013_0002
51a 51
将 51a ( 40mg, 0. 165mmol ) 中 加 入 DCC ( 41mg, 0. 198隱 ol ) DMAP ( 10mg, 0. 083睡 ol, 0. 5eq)、活化的 4A分子筛 ( lOOmg) ,氩气保护下，注入重蒸甲苯（ lml ) , 室温搅拌 20min,加入 2氨基噻唑（17mg， 0. 165誦 ol ), 于 70°C下搅拌 1. 5小时。 过滤， 滤 液直接上柱， 经柱色谱纯化 (石油醚 ： 乙酸乙酯 =3 : 1, V/V)得到白色固体产物 4mg。
Ή NMR (CDC13, 300MHz):
δ (ppm) 9.40 (dd, J = 8.4,1.5Hz,lH), 8.36(dd, J = 4.5 Hz, 1H), 8.12-8.09 (m, 2H), 7.62-7.55 (m, 5H), 7.09 (d, J= 3.6 Hz, 1H);
EIMS (m/z): 324 (M+, 7), 239(6), 225 (19), 197 (11), 125 (25), 121 (11) 111(39), 97 (60)， 85 (65), 71 (100), 69 (96). 10. 化合物 53的制备
Figure imgf000014_0001
53a 53
将 53a ( 75mg,0.288mmol ) 中力 tl入 DCC ( 77mg,0.375mmol,1.3eq )、 DMAP
( 18mg,0.144mmol,0.5eq )、活化的 4A分子筛（ 1 OOmg ) , 氩气保护下，注入重蒸甲苯（ 1ml ) , 室温搅拌 20min,加入 2-氨基噻唑 （29mg，0.288mmol)， 70°C下搅拌 3小时。 过滤， 滤液直 接上柱，经柱色谱纯化 (石油醚 ： 乙酸乙酯 =1 : 1, V V)得到 13mg白色固体产物,化合物 53。
Ή NMR (CDCl3,300MHz):
δ (ppm) 12.49 (s, 1H), 11.38(br.,lH), 9.36 (dd，J= 8.4,0.9Hz, 1H), 8.36(dd, J= 4.5,0.9 Hz, 1H), 8.14-8.10 (m, 2H), 7.61-7.57 (m, 2H), 7.28-7.22 (m, 2H),7.10 (d, J= 3.6 Hz, 1H);
Ή, Ή -COSY NMR(CDC13,300MHz):
相关峰： CH-CH-CH , CH(2H)-CH(2H) , CH-CH;
13C NMR (CDC13, 300MHz): δ (ppm)
167.27(1 C), 165.53(1C), 165.12(1C), 163.91(1C), 157.06(1 C), 142.79(1CH),
139.47(1C), 138.62(1CH), 131.52(1C), 130.33(1CH), 130.21(1CH),129.17(1CH), 129.04(1CH), 116.45(1CH), 116.16(1CH),114.46(1CH);
11、 化合物 55-59的制备 化合物 55-59的制备按下列通式进行:
Figure imgf000014_0002
将 I ( lmmol ), 2-氨基噻唑（ 120mg, 1.2mmol) , HOBT ( 162mg, 1.2mmol) ,EDC(230mg, 1.2mmol), 少量 4人分子筛的混合物中注入 lOmL重蒸 DMF, rt搅拌反应过夜。用乙酸乙 酯稀释,过滤,水洗三次除去 DMF， 饱和食盐水洗， 有机相无水 MgS04干燥。 旋转蒸除溶 剂，残留物经柱色谱纯化。
Figure imgf000014_0003
55
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Claims

权 利 要 求 书
1 . 一类结构式如下的甲硫氨酰氨肽酶抑制剂
Figure imgf000016_0001
其中 1^为 4的烷基、 取代垸基、 c3-c6的环垸基、 取代环垸基、 芳基、 吡啶基； 由 d-C4的垸基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰 氨基、 巯基的取代芳基、 取代 吡啶基和具有如下结构的杂环或取代杂环
Figure imgf000016_0002
R5、 R6为 H、 -C4的烷基、 取代垸基、 C3-C6的环垸基、 取代环烷基、 芳基、 吡啶 基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰氨基、 巯基的取代芳基、 取代吡啶基；
为11、 -C4烷基、 取代垸基、 芳基、 C 的垸基硝基、 羧基、 醛基、 烷氧基、 胺基、 酰氨基、 巯基的取代芳基；
为^1、 CrG烷基、 取代 -( 4烷基、 卤素； 芳基、 取代芳基；
R4为H、 d-C4烷基、 取代垸基、 取代芳基；
X为 0、 S、 N、 杂原子。
2. 根据权利要求 1所述的甲硫氨酰氨肽酶抑制剂， 其特征在于：
当 为吡啶、 取代吡啶包括卤素、 酰胺、 垸氧基、 羟基、 羧基、 酯基、 醚时， R2为 H;
为 Br 、 垸基；
R4为H、 垸基、 取代芳基。
3. 根椐权利要求 1所述的甲硫氨酰氨肽酶抑制剂， 其特征在于：
当 ^为芳基、 取代芳基包括硝基、 胺基、 - 的烷氧基、 羟基、 羧基、 苄基时 R2为 H;
! 3为 卤素、 d-C4烷基；
为 -C4垸基、 取代芳基。
4. 根椐权利要求 1所述的甲硫氨酰氨肽酶抑制剂， 其特征在于： 当 R,为杂环或取代杂环时
R2为 H
R3为 H
R4为 H
R5、 为1^、 d-C4的垸基、 取代垸基、 C3-C6的环垸基、 取代环垸基、 芳基、 吡 啶基、 硝基、 羧基、 醛基、 垸氧基、 胺基、 酰 氨基、 巯基的取代芳基、 取代吡啶基；
5.如权利要求 1所述的甲硫氨酰氨肽酶抑制剂的制备方法，其特征在于由 Y为羟基、 卤素或其他活性基团的 R1COY与
Figure imgf000017_0001
6. 根椐权利要求 4 所述的甲硫氨酰氨肽酶抑制剂的制备方法其特征在于缩合剂为 DCC、 EDC、 DIC、 HBTU。
7. 根椐权利要求 4所述的甲硫氨酰氨肽酶抑制剂的制备方法其特征在于缩合反应溶 剂为二氯甲垸、 二甲基呋喃、 二氯乙垸、 甲苯、苯、水、 二氧六环或上述溶剂的混合溶剂。
8. 根椐权利要求 4所述的甲硫氨酰氨肽酶抑制剂的制备方法其特征在于反应温度为 -20°C至室温或加热温度从 50°C至 130°C。
9. 根椐权利要求 4所述的甲硫氨酰氨肽酶抑制剂的制备方法其特征在于缩合反应时 加入活化剂 HOBT、 五氟苯酚或分子筛。
10.根椐权利要求 4所述的甲硫氨酰氨肽酶抑制剂的制备方法其特征在于缩合反应时 用三乙胺、 二乙丙基乙基胺、 吡啶、 DMAP碱作催化剂。
11. 如权利要求 1所述甲硫氨酰氨肽酶抑制剂作为抗肿瘤或抗感染药物先导化合物。
PCT/CN2003/000213 2002-04-02 2003-03-25 Nouvel inhibiteur de la methionine aminopeptidase WO2003082838A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP03711802A EP1500655A4 (en) 2002-04-02 2003-03-25 NEW INHIBITOR OF METHIONINE AMINOPEPTIDASE
AU2003221230A AU2003221230A1 (en) 2002-04-02 2003-03-25 New methionine aminopeptidase inhibitor
US10/509,823 US20050113420A1 (en) 2002-04-02 2003-03-25 Methionine aminopeptidase inhibitor

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CNB021112304A CN100357283C (zh) 2002-04-02 2002-04-02 一类甲硫氨酰氨肽酶抑制剂
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US7390908B2 (en) 2001-08-17 2008-06-24 Astrazeneca Ab Compounds effecting glucokinase
US7408069B2 (en) 2005-08-05 2008-08-05 Bristol-Myers Squibb Company Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives
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US7199140B2 (en) 2001-06-26 2007-04-03 Astrazeneca Ab Vinyl phenyl derivatives as GLK activators
US7390908B2 (en) 2001-08-17 2008-06-24 Astrazeneca Ab Compounds effecting glucokinase
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US7230108B2 (en) 2002-11-19 2007-06-12 Astrazeneca Ab Quinoline derivatives as glucokinase ligands
US7408069B2 (en) 2005-08-05 2008-08-05 Bristol-Myers Squibb Company Preparation of 2-amino-thiazole-5-carboxylic-acid derivatives
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WO2008120754A1 (ja) * 2007-03-30 2008-10-09 Taisho Pharmaceutical Co., Ltd. ピコリン酸アミド化合物

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CN1448392A (zh) 2003-10-15
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AU2003221230A1 (en) 2003-10-13
EP1500655A1 (en) 2005-01-26
EP1500655A4 (en) 2006-03-29

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