tert-butyl (2S)-N-benzenesulfonyl-2,3-diaminopropionate | 156185-89-6

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: tert-butyl (2S)-N-benzenesulfonyl-2,3-diaminopropionate
• 英文别名: tert-butyl 3-amino-2(S)-phenylsulfonylaminopropionate；(S)-t-butyl 3-amino-2-phenylsulfonylaminopropionate；(S)-2-benzenesulfonylamino-3-amino-propionic acid tert-butyl ester；t-butyl 3-amino-(2S)-benzenesulfonylamino-propionate；Tert-butyl (2S)-3-amino-2-benzenesulfonamidopropanoate；tert-butyl (2S)-3-amino-2-(benzenesulfonamido)propanoate
• CAS: 156185-89-6
• 化学式: C₁₃H₂₀N₂O₄S
• 分子量: 300.379
• InChiKey: FWNGNBTXQHWMHJ-NSHDSACASA-N

物化性质

• 沸点：
  446.6±55.0 °C(Predicted)
• 密度：
  1.217±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  20
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  107
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl (2S)-N-benzenesulfonyl-2,3-diaminopropionate 在 palladium on activated charcoal 氨 、 氢气 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 (S)-2-Benzenesulfonylamino-3-(3,4-diamino-benzoylamino)-propionic acid tert-butyl ester
  参考文献：
  名称：

  Design, synthesis and biological evaluation of nonpeptide integrin antagonists

  摘要：

  Recent studies demonstrated that peptide and antibody antagonists of integrin alpha(v)beta(3) block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck's arylether/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (alpha(v)beta(3), alpha(IIb)beta(3), and alpha(v)beta(5)) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of alpha(IIb)beta(3) (IC50 = 14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 mu g/embryo). (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00090-x
• 作为产物：
  描述：

  N-phenylsulfonyl-L-asparagine 在 sodium hydroxide 、 硫酸 、 溴 作用下， 以 乙二醇二甲醚 、 水 为溶剂， 生成 tert-butyl (2S)-N-benzenesulfonyl-2,3-diaminopropionate
  参考文献：
  名称：

  Design, synthesis and biological evaluation of nonpeptide integrin antagonists

  摘要：

  Recent studies demonstrated that peptide and antibody antagonists of integrin alpha(v)beta(3) block angiogenesis and tumor growth. In this article, the design, synthesis and biological evaluation of a series of nitroaryl ether-based, nonpeptide mimetics are described. The design of these compounds was based on Merck's arylether/alpha-aminoacid/guanidine framework and incorporates a novel nitroaryl system. The synthesized mimetics were tested against a variety of integrins (alpha(v)beta(3), alpha(IIb)beta(3), and alpha(v)beta(5)) in order to determine their binding selectivity and ability to inhibit cell adhesion. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. From the generated compound library, compounds 16 and 19 proved to be potent and selective inhibitors of alpha(IIb)beta(3) (IC50 = 14 nM) whereas compound 11 showed excellent in vivo inhibition of angiogenesis (at 30 mu g/embryo). (C) 1998 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00090-x

文献信息

• Quinolizinones as integrin inhibitors
  申请人：Biochem Pharma, Inc.

  公开号：US06630488B1

  公开（公告）日：2003-10-07

  The present invention is directed towards novel compounds that are effective inhibitors of integrins, particularly &agr;IIb&bgr;3 or &agr;v integrins such as &agr;v&bgr;3 and &agr;v&bgr;5. One embodiment of the present invention comprises a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt, solvate, or metabolic precursor thereof. R1, R2, R3, and R4 are defined herein.

  本发明涉及一种新型化合物，它们是有效的整合素抑制剂，特别是αIIbβ3或αv整合素，如αvβ3和αvβ5。本发明的一个实施例包括式(I)或式(II)的化合物，或其药学上可接受的盐、溶剂或代谢前体。R1、R2、R3和R4在此处被定义。
• Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part 2: Synthesis of potent αvβ3/αIIbβ3 dual antagonists
  作者：Minoru Ishikawa、Dai Kubota、Mikio Yamamoto、Chizuko Kuroda、Maki Iguchi、Akihiro Koyanagi、Shoichi Murakami、Keiichi Ajito

  DOI：10.1016/j.bmc.2005.10.061

  日期：2006.4

  indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity

  我们合成了我们的原型整联蛋白α（v）beta3拮抗剂1的4-氨基哌啶衍生物，以试图增加活性和水溶性。在C-末端为1的中央芳香环和/或苯环中引入一个或两个亲水部分，可增加水溶性并增强对细胞粘附的抑制作用。结构-活性关系（SAR）研究的结果表明，中央芳香环和哌啶环之间的扭转角以及磺酰胺部分的酸度可能对α（v）beta3受体结合活性很重要。这些化合物中的一些是新颖和有效的alpha（v）beta3 / alpha（IIb）beta3双拮抗剂，具有可接受的水溶性和令人满意的早期吸收，分布，代谢，排泄和毒性（ADMET）分布。
• Tricyclic pharmacophore-based molecules as novel integrin αvβ3 antagonists. Part IV: Preliminary control of αvβ3 selectivity by meta-oriented substitution
  作者：Dai Kubota、Minoru Ishikawa、Midori Ishikawa、Naokazu Yahata、Shoichi Murakami、Kazuyuki Fujishima、Masafumi Kitakaze、Keiichi Ajito

  DOI：10.1016/j.bmc.2006.01.062

  日期：2006.6

  antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore

  为了建立具有三环药效基团的αvbeta3/ alphaIIbbeta3双重拮抗剂的体内功效，需要相应的αvbeta3选择性拮抗剂作为对照。我们最初采用两种合成方法，基于RGD识别模式或中心苯环与相邻杂环之间的二面角的修饰来获得αvbeta3选择性拮抗剂，但事实均未成功。然而，在具有三环药效基团的化合物家族中，首次合成了具有中心苯环的间位取代作用的新型拮抗剂，其对αvbeta3的选择性较对alphaIIbbeta3的选择性弱。对元导向拮抗剂的优化提供了不仅在受体结合试验中表现出抑制活性的alphavbeta3选择性拮抗剂，
• A Scalable Synthesis of MN-447, an Antagonist for Integrins α_vβ₃ and α_IIbβ₃
  作者：Minoru Ishikawa、Masaki Tsushima、Dai Kubota、Yumiko Yanagisawa、Yukiko Hiraiwa、Yasuo Kojima、Keiichi Ajito、Naomichi Anzai

  DOI：10.1021/op800073z

  日期：2008.7.1

  (2S)-Benzenesulfonylamino-3-[3-methoxy-4-4-(1,4,5,6-tetrahydro-pyrimidin-2-ylamino)piperidin-1-yl}benzoylamino]propionic acid, MN-447, is a potent antagonist of the integrins alpha(v)beta(3) and alpha(IIb)beta(3)-Herein, we report a novel synthetic protocol that produces MN-447 in an overall yield of 45%. This protocol, when compared with the original synthetic route for MN-447, is more cost-effective, requires fewer steps, does not require chromatographic purification of intermediates and MN-447, and increases the overall yield by 35%. This report focuses on the synthetic strategies that were developed for this protocol. Now, the large quantities of MN-447 that are needed for preclinical and toxicological studies can be readily obtained.

  (2S)-对甲苯磺酰氨基-3-[3-甲氧基-4-4-(四氢嘧啶-2-基氨基)哌啶-1-基}苯甲酰氨基]丙二酸，即MN-447，是一种有效的整合素αvβ3和αIIbβ3拮抗剂。本文中，我们报告了一种新型的合成方案，该方案使MN-447的总体产率达到45%。与MN-447原有的合成路线相比，新方案更具成本效益，步骤更少，不需要对中间体和MN-447进行色谱纯化，并将总体产率提高了35%。本报告重点介绍了为该方案开发的合成策略。如今，大量用于临床前和毒理学研究所需的MN-447可以轻松获得。
• Design and Synthesis of a New Class of Selective Integrin α5β1 Antagonists
  作者：Roland Stragies、Frank Osterkamp、Gunther Zischinsky、Doerte Vossmeyer、Holger Kalkhof、Ulf Reimer、Grit Zahn

  DOI：10.1021/jm070002v

  日期：2007.8.1

  ligands, we derived a new class of integrin alpha5beta1 antagonists (1). Several synthesis strategies were applied to evaluate the chemical space around the essential pharmacophore groups R1 to R3 to obtain highly active and selective pyrrolidine derivatives as integrin alpha5beta1 antagonists. Integrin selectivity was controlled by switching from a sulfonamide moiety to a mesitylene amide moiety for R3

  从具有肽配体的复合体中整合素αvbeta3的结构加上非肽配体的SAR数据出发，我们得出了一类新的整合素α5β1拮抗剂（1）。应用了几种合成策略来评估基本药效基团R1至R3周围的化学空间，以获得作为整联蛋白α5β1拮抗剂的高活性和选择性吡咯烷衍生物。整联蛋白的选择性是通过从R 3的磺酰胺部分转换为均三甲苯酰胺部分来控制的。该发现代表用于调节对其他相关整联蛋白受体的选择性的一般特征。基于各种体外研究的令人鼓舞的结果，选择了活性最高的化合物用于动物模型和临床前开发的进一步体内研究。